OA21139A

OA21139A - Inhibiting human integrin ALPHA4BETA7.

Info

Publication number: OA21139A
Application number: OA1202200154
Authority: OA
Inventors: Bruce N. Rogers; Matthew G. Bursavich; Dan CUI; James E. Dowling; Kristopher N. Hahn; Bryce A. Harrison; Fu-Yang Lin; Blaise S. LIPPA; Dawn M. Troast; Cheng Zhong; KyleD. KONZE; Aleksey I. Gerasyuto; Byungchan Kim; Salma RAFI; Tyler DAY; Eugene Hickey; Evelyne HOUANG; Robert Zahler
Original assignee: Morphic Therapeutic, Inc.
Priority date: 2019-10-16
Filing date: 2020-10-16
Publication date: 2024-02-02

Abstract

Disclosed are small molecule antagonists of human α4β7 integrin, and methods of using them to treat a number of diseases and conditions. <img file="OA21139A_A0001.tif"/>

Description

TECHNICAL FIELD

Disclosed are novel compounds and related methods useful for the inhibition of the αφ₇integrin. The compounds and methods disclosed herein are applicable to the development of médicaments for the treatment of αφ₇ integrin-mediated conditions, such as inflammatory bowel disease (IBD), ulcerative colitis (UC), and Crohn’s disease (CD).

BACKGROUND

Integrins are noncovalently associated α/β heterodimeric cell surface receptors involved in numerous cellular processes. Differential expression of integrins can regulate a cell's adhesive properties, allowing different leukocyte populations to be recruited to spécifie organs in response to different inflammatory signais. The eu integrins, including αφ₇, play a rôle in lymphocyte migration throughout the gastrointestinal tract. They are expressed on most leukocytes, including B and T lymphocytes, where they médiate cell adhesion via sélective binding to its primary ligand, mucosal addressin cell adhesion molécule (MAdCAM). Memory T lymphocytes expressing the αφ₇ integrin preferentially migrate into the gastrointestinal tract via firm adhesion to mucosal vascular addressin cell adhesion molécule 1 (MAdCAM-1).

Inhibitors of spécifie integrin-ligand interactions hâve been used for the treatment of varions diseases. For example, monoclonal antibodies displaying high binding afïinity for αφ? hâve displayed therapeutic benefits for gastrointestinal auto-inflammatory/autoimmune diseases, such as Crohn's disease, and ulcerative colitis. However, these thérapies also hâve certain undesirable properties for the patient. A monoclonal antibody αφ? integrin inhibitor is administered by parentéral administration, has a long half-life with inability to rapidly modify exposures, and a reduced activity due to anti-drug antibody formation. Monoclonal antibody thérapies can be challenging to manufacture in comparison to small molécule, thérapies. In addition, some thérapies that inhibit αφ₇ hâve also interfered with αφι integrin-ligand interactions, thereby resulting in dangerous side effects to the patient. Activity at oupi integrin is implicated in emergence of progressive multifocal leukoencephalopathy (PML), a life-threatening and progressive brain infection, in immunosuppressed patients.

There remains a medical need for an effective and safe oral αφγ integrin inhibitor as an important addition to the therapeutic armamentarium for cupîintegrin-mediated conditions, such as inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn’s disease (CD).

SUMMARY

In certain embodiments, the invention relates to compounds of Formula (I):

(I) wherein

Ra, Rb, and Rc are independently selected from the group consisting of H, Me, halide, CF3, C(H)F2, C(F)H2, -CN, - OCF3, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (Ci-Cs)-alkoxy, -ClHkCFs.and substituted or unsubstituted -(Ci-Csjalkylene-N(Rx)(R_y); provided that at least one of Ra, Rb, and Rc is -(Ci-C5)alkylene-N-(Rx)(R_y);

Rx and R_y are independently selected from the group consisting of H and substituted or unsubstituted (Ci-Cô)-alkyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered ring;

Ri is substituted or unsubstituted (Ci-C6)-alkyl, substituted or unsubstituted (C1-C4)alkylene-(C3-C6)-cycloalkyl, or substituted or unsubstituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy;

^R5a

R2 is ^R5d

Rj_a and Rjb are independently selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, -OH, -CN, halide, CF3, C(H)F2, C(F)H2.-(Ci-C4)alkoxy, -OCF₃, and substituted or unsubstituted (Ci-C4)-alkylene-(Ci-C₄)-alkoxy; provided that R3a and R3b are not both H;

R3c is selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, halide, CF3, C(H)F2, C(F)H2, -(Ci-C4)-alkoxy, -OCF3 -CN, and substituted or unsubstituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy;

R_3d is selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, hydroxyl, halide, and -(Ci-C4)-alkoxy;

R4 is H, or substituted or unsubstituted (Ci-Ci)-alkyl;

R$a, and Rs_e are independently selected from the group consisting of H, CN, halide, CF₃, C(H)F2, C(F)H2, -CH2CF3, substituted or unsubstituted (C3-Cô)-cycloalkyI, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl hydroxyl, and (Ci-C4)-alkoxy; and

Rsb, Rsc, and R_5dare independently selected from the group consisting of H, CN, halide, CF3, C(H)F₂, C(F)H₂, -CH2CF3, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C3-C₆)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (Ci-C4)-alkoxy;

or a pharmaceutically acceptable sait thereof.

In some aspects of the invention, a compound of Formula (I) can be a compound wherein one and only one of Ra, Rb, and Rc is substituted or unsubstituted -(Ci-C5)alkylene-N-(Rx)(R_y); Ri is (Ci-Cô) alkyl (e.g, isobutyl); R3a and Rab are independently selected from the group consisting of H, (Ci-C₄)-alkyl (e.g., methyl), halide (e.g, F or Cl), CF3, C(H)F₂, and C(F)H₂, provided that R3a and R3b are not both H; and R4 is H.

In some examples, a compound of Formula (I) can be a compound wherein one and only one of R_a, Rb, and Rc is substituted or unsubstituted -(Ci-Cs)alkylene-N-(Rx)(R_y); Rx and R_y are each independently unsubstituted (Ci-C₆)-alkyl (e.g., methyl) or R_x and R_y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered heterocyclyl ring; Ri is unsubstituted (Ci-Cô) alkyl (e.g., isobutyl); R_3a and R₃b are independently selected from the group consisting of H, unsubstituted (Ci-C4)-alkyl (e.g., methyl, ethyl, etc.), halide (e.g., F or Cl), CFj, C(H)F2, and C(F)H2, provided that R_3a and R₃b are not both H; R_3c is selected from the group consisting of: H, F, Cl, hydroxyl, substituted or unsubstituted (Ci-C₄)-alkyl (e.g., methyl), substituted or unsubstituted (C₃-Cô)-cycIoalkyl (e.g., cyclopropyl), (Ci-C4)-alkoxy (e.g., methoxy); R_3d is selected from the group consisting of H, halide (e.g., F, or Cl), substituted or unsubstituted (Ci-C4)-alkyl (e.g., methyl), and hydroxyl; and R4 is H. In some examples, a compound of Formula (I), Formula (la) and/or Formula (Ib) can be a compound wherein one and only one of Ra, Rb, and Rc is substituted or unsubstituted -(Ci-Cs)alkylene-N-(Rx)(R_y); Rx and R_yeach independently unsubstituted methyl or R_x and R_y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered heterocyclyl ring; Ri is isobutyl; R_3aand R_3b are independently selected from the group consisting of unsubstituted (Ci-C4)-alkyl (e.g., methyl), halide (e.g., F or Cl), CF₃, C(H)F₂, and C(F)H₂, R₃c and R_3d are both H; and R₄ is H. For instance, a compound of Formula (I), Formula (la) and/or Formula (Ib) can be a compound wherein Ri is isobutyl; R_3a and R₃b are independently selected from the group consisting of unsubstituted (Ci-C4)-alkyl (e.g., methyl), halide (e.g., F or Cl), CF₃, C(H)F2, and C(F)H2, R_3c and R₃d are both H; R4 is H; and Rs_a, and Rs_e are each substituted or unsubstituted (Ci-Ci)-alkyl (e.g., methyl). A compound of Formula (I) can be a compound wherein one and only one of R;,, Rb, and Rc is substituted or unsubstituted -(Ci-Cs)alkylene-N-(Rx)(R_y); Rx and R_y each independently unsubstituted methyl or R_x and R_y taken together with the N to which they are attached form a 46 membered heterocyclyl ring optionally substituted with halide (e.g., F); Ri is isobutyl; R_3a and R_3b are independently selected from the group consisting of unsubstituted (Ci-C4)-alkyI (e.g., methyl), halide (e.g., F or Cl), CF₃, C(H)F₂, and C(F)H₂, Rîc and R_3d are both H; R₄ is H; R_5a, and R_5e are each substituted or unsubstituted (Ci-C4)-alkyl (e.g., methyl), and Rsb, Rsc, and Rsa are each independently selected from the group consisting of H, CN, halide (e.g., F, CI), CF₃, C(H)F2, C(F)H2, (Ci-Cs)-alkyl, hydroxyl, and (Ci-C4)-alkoxy. In certain embodiments, the invention relates to a méthod of treating auto-inflammatory/autoimmune diseases, such as Crohn’s disease, and ulcerative colitis; comprising the step of: administering to a subject in need thereof a therapeutically effective amount of any one of the compounds described herein.

In some embodiments, a compound of Formula (I) can be a compound of Formula (la):

O ^R5a (la) or a pharmaceutically acceptable sait thereof, wherein Ra, Rb, Rc, Ri, Rja, Rîb, Rîc, Rjd, Rsa, Rsb, R_5c, Rsd, Rse, and R» in Formula (la) are each independently defmed as above with respect to Formula (I).

(Ib) or a pharmaceutically acceptable sait thereof, wherein Ra, Rb, Rc, Ri, Rîa, Rîb, Rîc, Rjd, Rsa, Rsb, R_5c, Rsd, Rse, and R4 in Formula (la) are each independently defmed as above with respect to Formula (I).

Methods of preparing and isolating the compounds of Formula (I), Formula (la) and/or 15 Formula (Ib) are also provided herein.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 is a table (Table 1) summarizing in vitro inhibition of Ο4β? integrin by exemplary compounds (i.e., data obtained from the fluorescence polarization assay of Example 5, and the ligand binding assay of Example 6).

Figure 2 is a table (Table 2) providing additional exemplary compounds.

Figure 3 is a table (Table 5) summarizing in vitro inhibition of αφ? integrin by exemplary compounds (i.e., data obtained from the fluorescence polarization assay of Example 5, and the ligand binding assay of Example 6).

Figure 4 is a table (Table 6) summarizing in vitro inhibition of αφ? integrin by exemplary compounds (i.e., data obtained from the fluorescence polarization assay of Example 5, and the ligand binding assay of Example 6).

DETAILED DESCRIPTION

In certain embodiments, the invention relates to compounds that antagonize αφ? integrin. The compounds will be useful for the treatment of diseases that are treatable by the inhibition of αφί integrin (e.g., Crohn's disease (CD), and ulcerative colitis (UC)).

DEFINITIONS

For convenience, before further description of the présent invention, certain terms employed in the spécification, examples and appended daims are collected here. These définitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, ail technical and scientific terms used herein hâve the same meaning as commonly understood by a person of ordinary skill in the art.

In order for the présent invention to be more readily understood, certain terms and phrases are defined below and throughout the spécification.

The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) ofthe grammatical object ofthe article. By way of example, “an element means one element or more than one element.

The phrase “and/or,” as used herein in the spécification and in the daims, should be understood to mean “either or both” of the éléments so conjoined, i.e., éléments that are conjunctively présent in some cases and disjunctively présent in other cases. Multiple éléments listed with “and/or” should be construed in the sanie fashion, i.e., “one or more” of the éléments so conjoined. Other éléments may optionally be présent other than the éléments specifically identified by the “and/or” clause, whether related or unrelated to those éléments specifically identified. Thus, as a non-limiting example, a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including éléments other than B); in another embodiment, to B only (optionally including éléments other than A); in yet another embodiment, to both A and B (optionally including other éléments); etc.

As used herein in the spécification and in the daims, “or” should be undcrstood to hâve the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of éléments, and, optionally, additional unlisted items. Only ternis clearly indicated to the contrary, such as “only one of ’ or “exactly one of,” or, when used in the daims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of éléments. In general, the terni “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by ternis of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the daims, shall hâve its ordinary meaning as used in the field of patent law.

As used herein in the spécification and in the daims, the phrase “at least one, in reference to a list of one or more éléments, should be understood to mean at least one element selected from any one or more of the éléments in the list of éléments, but not necessarily including at least one of each and every element specifically listed within the list of éléments and not excluding any combinations of éléments in the list of éléments. This définition also allows that éléments may optionally be présent other than the éléments specifically identified within the list of éléments to which the phrase “at least one” refers, whether related or unrelated to those déments specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, at least one of A or B,” or, equivalently “at least one of A and/or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B présent (and optionally including éléments other than B); in another embodiment, to at least one, optionally including more than one, B, with no A présent (and optionally including éléments other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other éléments); etc.

It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

In the daims, as well as in the spécification above, ail transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

Certain compounds contained in compositions of the présent invention may exist in particular géométrie or stereoisomeric forms. In addition, polymers of the présent invention may also be optically active. The présent invention contemplâtes ail such compounds, including cisand trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be présent in a substituent such as an alkyl group. Ail such isomers, as well as mixtures thereof, are intended to be included in this invention.

If, for instance, a particular enantiomer of compound of the présent invention is desired, it may be prepared by asymmetric synthesis, or by dérivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Altematively, where the molécule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographie means well known in the art, and subséquent recovery of the pure enantiomers.

Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a ^,3C- or ^,4C-enriched carbon are within the scope of this invention.

The terms “α4β7”, “a4B7”, “a4b7”, “alpha-4 beta-7” and “alpha 4 beta 7” and the like as used herein ail refer to αφ?.

The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in canying or transporting the subject Chemical from one organ or portion of the body, to anothcr organ or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingrédients of the formulation, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its dérivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter; (9) oils, such as peanut oil, cottonsced oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnésium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonie saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions of the présent invention are non-pyrogenic, i.e., do not induce signifïcant température élévations when administered to a patient.

The term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the sait thus formed. Représentative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stéarate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19.)

In other cases, the compounds useful in the methods of the présent invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The tcrm “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable métal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Représentative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnésium, and aluminum salts, and the like. Représentative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).

A “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment, refers to an amount of the compound in a préparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, améliorâtes a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit/risk ratio applicable to any medical treatment.

The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted State of the host animal) then the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

The term “patient” refers to a mammal in need of a particular treatment. In certain embodiments, a patient is a primate, canine, feline, or equine. In certain embodiments, a patient is a human.

An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. A straight aliphatic chain is limited to unbranched carbon chain moieties. As used herein, the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group.

“Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or 1 up to 30 carbon atoms if no spécification is made. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. In certain embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer. Alkyl goups may be substituted or unsubstituted. As used herein, “Me” and -CH3 both refer to methyl.

As used herein, the term “alkylene” refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene -(CH₂)-, ethylene -(CH2CH2)-, n-propylene -(CH2CH2CH2)-, isopropylene (CH2CH(CH3))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.

Cycloalkyl means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Likewise, preferred cycloalkyls hâve from 3-10 carbon atoms in their ring structure, and more preferably hâve 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted.

Unless the number of carbons is otherwise specified, “lower alkyl,” as used herein, means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Likewise, “lower alkenyl” and “lower alkynyl” hâve similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl.

The term “aryl” as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl groups include 5- to

12-membered rings, more preferably 6- to 10-membered rings The term “aryl” also includes polycyclic ring Systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phénol, aniline, and the like. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.

The term “halo”, “halide”, or “halogen” as used herein means halogen and includes, for example, and without being limited thercto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo.

The terms “heterocyclyl” or “heterocyclic group” refer to 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldéhyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, and the like.

The term “carbonyl” is art-recognized and includes such moieties as can be represented by the formula:

O o ^A_x.-Ri5 or A_xA_Ri6 wherein X’ is a bond or represents an oxygen or a sulfur, and R15 represents a hydrogen, an alkyl, an alkenyl, -(CH2)_m-Rio or a pharmaceutically acceptable sait, Riô represents a hydrogen, an alkyl, an alkenyl or -(CH2)_m-Rio, where m and Rio are as defined above. Where X’ is an oxygen and R15 or Riô is not hydrogen, the formula represents an “ester.” Where X’ is an oxygen, and R15 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when Ris is a hydrogen, the formula represents a “carboxylic acid”. Where X’ is an oxygen, and Riô is a hydrogen, the formula represents a “formate.” On the other hand, where X’ is a bond, and Ris is not hydrogen, the above formula represents a “ketone” group. Where X’ is a bond, and Ris is a hydrogen, the above formula represents an “aldéhyde” group.

As used herein, the term “substituted” is contemplated to include ail permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above, and for example substituted with one or more substituents selected from alkyl, cycloalkyl, heterocyclylakyl, halogen, OH, OMe, C(H)F2, C(F)H2, CF3, C(H)2CF3, SF5, CHFCH2amine, Clhamine, and CN. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may hâve hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, élimination, etc.

As used herein, the term “nitro” means -NO2; the term “halogen” désignâtes -F, -Cl, -Br, or -I; the term “hydroxyl” means -OH; and the term “cyano” means -CN;.

As used herein, the définition of each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its définition elsewhere in the same structure.

The term “prodrug” as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molécule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal.

For purposes of this invention, the Chemical éléments are identified in accordance with the Periodic Table of the Eléments, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

EXEMPLARY COMPOUNDS

In some embodiments, the invention relates to a compound of Formula (I), Formula (la), or Formula (Ib):

or a pharmaceutically acceptable sait thereof;

wherein

Ra, Rb, and Rc are independently selected from the group consisting of H, Me, halide, CF3, C(H)F₂, C(F)H₂, -CN, - OCF₃, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (Ci-Cs)-alkoxy, -CH₂CF3,and substituted or unsubstituted -(Ci-Cs)alkylene-N(Rx)(R_y); provided that at least one of Ra, Rb, and Rc is -(C|.C5)alkylene-N-(Rx)(R_y);

R_x and R_y are independently selected from the group consisting of H and substituted or unsubstituted (Ci-Cô)-alkyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered ring;

Ri is substituted or unsubstituted (Ci-Cô)-alkyl, substituted or unsubstituted (C1-C4)alkylene-(C3-C6)-cycloalkyl, or substituted or unsubstituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy;

R3a and R.3b are independently selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C3-Cô)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, -OH, -CN, halide, CF3, C(H)F₂, C(F)H₂,-(Ci-C4) alkoxy, -OCF3, and substituted or unsubstituted (Ci-C4)-aIkylene-(Ci-C4)-alkoxy; provided that Rja and Rjb are not both H;

R_3c is selected from the group consisting of H, substituted or unsubstituted (Ci-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, halide, CF3, C(H)F2, C(F)H2, -(Ci-C4)-alkoxy, -OCF3 -CN, and substituted or unsubstituted (Ci-C4)-alkyIene-(Ci-C4)-alkoxy;

R4 is H, or substituted or unsubstituted (Ci-C4)-alkyl;

R_5a, and Rs_e are independently selected from the group consisting of H, CN, halide, CF3, C(H)F₂, C(F)H2, -CH2CF3. substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl hydroxyl, and (Ci-C4)-alkoxy; and

Rsb, Rsc, andRsaare independently selected from the group consisting of H, CN, halide, CF3, C(H)F₂, C(F)H2, -CH2CF3, substituted or unsubstituted (Ct-Cs)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (Ci-C4)-alkoxy.

In some embodiments, a compound of Formula (la) can be a compound wherein: Ra is Me; Rb, is substituted or unsubstituted -(Ci-C5)alkylene-N-(Rx)(Ry); Rx and R_y are independently selected from the group consisting of H and substituted or unsubstituted (Ci-C₆)-alkyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered ring; Rc is H; Ri is (Ci-C₆)-alkyl; R_3a is halide; R_3b is (Ci-Cs)-alkyl; R₃c is H; R_3d is H; R₄ is H; Rsa, and R₅e are (CiCs)-alkyl; and Rsb, Rsc, andR_5dare independently selected from the group consisting of H, CN, halide, CF3, C(H)F₂, C(F)H₂, -CH2CF3, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C3-C₆)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (Ci-C4)-alkoxy, or a pharmaceutically acceptable sait thereof.

In some embodiments, a compound of Formula (la) can be a compound wherein: Ra is Me; Rb, is substituted or unsubstituted 4Ci.C₅)alkylene-N-(R_x)(R_y); R_x and R_y are independently selected from the group consisting of H and substituted or unsubstituted (Ci-Cô)-alkyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered ring; Rc is H; Ri is (Ci-Cô)-alkyl; R_3a is halide; R_3b is halide; R_3c is H; R_3d is H; R4 is H; R_Sa, and R_Se are (C1-C5)alkyl; and R_5b, Rse, and R₅d are independently selected from the group consisting of H, CN, halide, CF₃, C(H)F2, C(F)H2, -CH₂CF₃,substituted or unsubstituted (Ci-C5)-alkyl, substituted or unsubstituted (C₃-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (Ci-C4)-alkoxy, or a pharmaceutically acceptable sait thereof.

In some embodiments, a compound of Formula (la) can be a compound wherein: Ra is H; Rb, is substituted or unsubstituted -(C|.C5)alkylene-N-(R_x)(R_y); R_x and R_y are independently selected from the group consisting of H and substituted or unsubstituted (Ci-C6)-alkyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered ring; Rc is CH(F)2î Ri is (Ci-Cô)-alkyl; R_3a is halide; R_3b is (Ci-Cs)-alkyl; R_3c is H; R₃a is H; R4 is H; R_5a, and Rs_e are (Ci-Cs)-alkyl; and Rsb, Rse, and Rsa are independently selected from the group consisting of H, CN, halide, CF₃, C(H)F2, C(F)H2, -CHzCFü, substituted or unsubstituted (Ci-C5)-alkyl, substituted or unsubstituted (C₃-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (Ci-C4)-alkoxy, or a pharmaceutically acceptable sait thereof.

In some embodiments, a compound of Formula (la) can be a compound wherein: Ri is H; Rb, is substituted or unsubstituted -(C|.Cs)alkylene-N-(R_x)(Ry); R_x and R_y are independently selected from the group consisting of H and substituted or unsubstituted (Ci-C6)-alkyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered ring; Rc is halide; Ri is (Ci-C₆)-alkyl; R_3a is halide; R_3b is (Ci-Cs)-alkyl; R_3c is H; R₃d is H; R₄ is H; Rsa, and Rse are (Ci-Cs)-alkyl; and R_5b, Rse, and Rsa are independently selected from the group consisting of H, CN, halide, CF₃, C(H)F₂, C(F)H₂, -CH₂CF₃, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C₃-C6)-cycloalkyI, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (Ci-C₄)-alkoxy, or a pharmaceutically acceptable sait thereof.

In some embodiments, a compound of Formula (la) can be a compound wherein: Ra is CF₃; R_b, is substituted or unsubstituted -(Ci-C5)alkylene-N-(R_x)(R_y); R_x and R_y are independently selected from the group consisting of H and substituted or unsubstituted (Ci-Cô)alkyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered ring; Rc is H; Ri is (Ci-Cô)-alkyl; Rj_a is halide; Rjb is (Ci-Cs)-alkyl; Rj_c is H; Rjd is H; R4 is H; R_5a, and R_5e are (Ci-Cs)-alkyl; and Rsb, Rsc, and Rsd are independently selected from the group consisting of H, CN, halide, CF3, C(H)Fz, C(F)Hz, -CH2CF3, substituted or unsubstituted (C1-C5)alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered hcterocycloalkyl, hydroxyl, and (Ci-C₄)-alkoxy, or a pharmaceutically acceptable sait thereof.

In some embodiments, a compound of Formula (la) can be a compound wherein: R3 is CF3; Rb, is substituted or unsubstituted -(Ci.C5)alkylene-N-(Rx)(R_y); Rx and R_y are independently selected from the group consisting of H and substituted or unsubstituted (Ci-Ce)alkyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered ring; Rc is H; Ri is (Ci-Cô)-alkyl; Rs_a is halide; R3b is CF3; Rsc is H; R3d is H; R4 is H; Rsa, and R_5e are (Ci-C₅)-alkyl; and R₅b, Rsc, andRsdare independently selected from the group consisting of H, CN, halide, CF3, C(H)F2, C(F)H2, -CH2CF3, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (Ci-C₄)-alkoxy, or a pharmaceutically acceptable sait thereof.

In some embodiments, a compound of Formula (la) can be a compound wherein: Ra is CF3; Rb, is substituted or unsubstituted -(Ci-C5)alkylene-N-(Rx)(R_y); Rx and R_y are independently selected from the group consisting of H and substituted or unsubstituted (Ci-Cô)alkyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered ring; Rc is H; Ri is (Ci-C₆)-alkyl; R_3a is halide; R3b is halide; R_3c is H; R3d is H; R₄ is H; R_5a, and R_5e are (Ci-Cs)-alkyl; and R₅b, Rsc, andRsdare independently selected from the group consisting of H, CN, halide, CF3, C(H)F2, C(F)H2, -CH2CF3. substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (Ci-C₄)-alkoxy, or a pharmaceutically acceptable sait thereof.

In some embodiments, a compound of Formula (la) can be a compound wherein: Ra is CF3; Rb is substituted or unsubstituted -(Ci-Cs)alkylene-N-(Rx)(R_y); Rx and R_y are independently selected from the group consisting of H and substituted or unsubstituted (Ci-Cô)-alkyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered ring; Rc is H; Ri is (Ci-C6)-alkyl; Rj_a is halide; Rîb is (C3-C6)-cycloalkyl; R3c is H; Rîd is halide; R4 is H; Rsa, and Rse are (Ci-Cs)-alkyl; and Rsb, Rse, andRsdare independently selected from the group consisting of H, CN, halide, CFj, C(H)F₂, C(F)H₂, -CH₂CF₃. substituted or unsubstituted (Ci-C₅)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (Ci-C4)-alkoxy, or a pharmaceutically acceptable sait thereof.

In some embodiments, a compound of Formula (la) can be a compound wherein: R_a is CF3; Rb is substituted or unsubstituted -(Ci-C5)alkylene-N-(R_x)(R_y); Rx and R_y are independently selected from the group consisting of H and substituted or unsubstituted (Ci-C6)-alkyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered ring; Rc is H; Ri is (Ci-Cô)-alkyl; Rs_a is halide; R3b is CF3; Rsc is H; R3d is halide; R4 is H; Rsa, and Rse are (C1-C5)alkyl; and Rsb, Rse, andRsdare independently selected from the group consisting of H, CN, halide, CF3, C(H)F₂, C(F)H₂, -CH₂CF₃, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (Ci-C-0-alkoxy, or a pharmaceutically acceptable sait thereof.

In some embodiments, a compound of Formula (la) can be a compound wherein: Ra is CF3; Rb is substituted or unsubstituted -(Ci.Cs)alkylene-N-(R_x)(R_y); R_x and R_y are independently selected from the group consisting of H and substituted or unsubstituted (Ci-Cô)-alkyl; or R_x and Ry taken together with the N to which they are attached form a 4-6 membered ring; Rc is H; Ri is (Ci-Cô)-alkyl; R3a is halide; R3b is (Ci-Cs)-alkyl; R3c is H; Rsa is halide; R4 is H; Rsa, and Rse are (Ci-Cs)-alkyl; and Rsb, Rse, andRsdare independently selected from the group consisting of H, CN, halide, CF3, C(H)F₂, C(F)H₂, -CH₂CF3, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (Ci-CO-alkoxy, or a pharmaceutically acceptable sait thereof.

In some embodiments, a compound of Formula (la) can be a compound wherein Rs_a, is halide or (Ci-Cs)-alkyl; Rsb is H, halide or substituted or unsubstituted (Ci-Cs)-alky; Rs_c is H, halide, substituted or unsubstituted (Ci-Cs)-alkyl, or substituted or unsubstituted (C3-C6)cycloalkyl; and Rsais selected from the group consisting of H, halide, CF3, C(H)F₂, C(F)H₂, CH₂CF3, substituted or unsubstituted (Ci-C5)-alkyl, substituted or unsubstituted (Cî-Cô) cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (C1-C4)alkoxy; and R5e is halide or or (Ci-Cs)-alkyl.

In some embodiments, a compound of Formula (I) can be a compound of Formula (la), Formula (Ib), Formula (le) and/or Formula (Id):

wherein Ra, Rb, Rc, Ri, R?a, Rjb, Rîc, R3d, Rsa, Rsb, Rse, Rsd, Rse, and R4 in Formula (la),

Formula (Ib), Formula (le) and Formula (Id) are each independently defmed as above with respect to Formula (I).

In some embodiments, a compound of Formula (I) can be a compound of Formula (II), including compounds of Formula (Ha), Formula (Ilb) or Formula (Ile):

Ra ,N_X

R_x Ry (II)

(Ha)

(Ilb)

wherein Ra, Rc, Rîa, Rjb, Rîc, Rsa, Rsa, Rsb, Rsc, Rsd, and Rse, are as described in Formula (I); p is 1, 2, or 3; q is 0, 1,2 or 3; r is an 0, 1, 2, 3 or 4; s is 0, 1, 2, 3, 4 or 5; and each Rd is independently selected from the group consisting of halide, (Ci-Cs)-alkyl, (Ci-C4)-alkoxy, -CF3, C(H)F₂, -OCF3, and -CN. In some embodiments, at least one instance of Rd is F or Cl. In some embodiments, at least one instance of Rd is methyl. In some embodiments, at least one instance of Rd is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds of Formula (Ha), wherein q is 1. In certain embodiments, the invention relates to any one of the aforementioned compounds of Formula (Ilb), wherein r is 1. In certain embodiments, the invention relates to any one of the aforementioned compounds of Formula (Ile), wherein s is

1.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ri is unsubstituted (Ci-Cô)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ri is substituted (Ci-Cô)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ri is substituted or unsubstituted (Ci-CO-alkyl. In certain embodiments, Ri is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, sec-butyl, or t-butyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ri is selected from the group consisting of

embodiments, the invention relates to any one of the aforementioned compounds, wherein Ri is substituted (Ci-C4)-alkylene-(C₃-C6)-cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ri is unsubstituted (Ci-C4)-alkylene-(C₃-C6)cycloalkyl. In certain embodiments, Ri is In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ri is substituted (Ci-C4)-alkylene- (C1-C4)alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ri is unsubstituted (Ci-C4)-alkylene- (Ci-C4)-alkoxy. In certain embodiments, Ri is Χ~^0Μ®. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ri is . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ri is .

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_3a is H; provided that R_3a and R₃b are not both H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_3a is unsubstituted (Ci-C4)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_3a is substituted (Ci-C4)-alkyl. In certain embodiments, the substituted (Ci-Cs)-alkyl, is substituted with a halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, R_3a is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_3a is substituted (C₃-C₆)-cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R₃a is substituted or unsubstituted (C₃-Cô)cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_3a is cyclopropyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_3a is halide. In some embodiments, the halide is Cl or F. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_3a is CF₃. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_3a is C(H)F2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_3a is C(F)H2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_3a is substituted -(Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_3a is unsubstituted -(Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_3a is -OCF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_3a is substituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_3a is unsubstituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy. In certain embodiments, (Ci-C4)-alkylene-(Ci-C4)-alkoxy isCHzOMe. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_3a is F.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R₃b is H; provided that R_3a and R₃b are not both H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R₃b is unsubstituted (Ci-CO-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R₃b is substituted (Ci-C4)-alkyl. In certain embodiments, the substituted (Ci-Cs)-alkyl, is substituted with a halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, R₃b is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R₃b is substituted (C₃-C6)-cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R₃b is substituted or unsubstituted (C₃-Cô)cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R₃b is cyclopropyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R₃b is halide. In some embodiments, the halide is Cl or F. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R₃b is CF₃. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R₃b is C(H)F2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R₃b is C(F)Hz. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R₃b is substituted -(Ci-CO-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R₃b is unsubstituted -(Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R₃b is -OCF₃. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R₃b is substituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rjb is unsubstituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy. In certain embodiments, (Ci-C4)-alkylene-(Ci-C4)-alkoxy is CH₂OMe. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rîb is selected from the group consisting of (Ci-C4)-alkylene optionally substituted with one or more halide and (C3-C6)-cycloaIkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is selected from the group consisting of methyl, cyclopropyl and CF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3b is methyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3b is selected from the group consisting of halide, (Ci-C4)-alkylene optionally substituted with one or more halide and (C3-C6)-cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3b is selected from the group consisting of F, Cl, methyl, and CF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3b is methyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3b is F. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3b is Cl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3b is CF3.

In certain embodiments, R_2a and R3b are independently selected from the group consisting of H, (Ci-Cs)-alkyl, halide, CF3, C(H)F₂, and C(F)H₂; provided that R_2a and Rjb are not both H. For example, R_2a and Rjb can be independently selected from the group consisting of H, methyl, Cl, F, CF3, C(H)F₂, and C(F)H₂; provided that R_3a and R₃b are not both H. In certain embodiments, R_3a is halide and R₃b is selected from the group consisting of (Ct-CO-alkylene optionally substituted with one or more halide and (C3-C6)-cycloalkyl. In certain embodiments, R_3a is F and Rab is selected from the group consisting of (Ci-Cû-alkylene optionally substituted with one or more halide and (C3-Cô)-cycloalkyl. In certain embodiments, R3_a is F and R3b is selected from the group consisting of methyl, cyclopropyl and CF3. In certain embodiments, R3a is F and R3b is selected from the group consisting of F, Cl, methyl, and CF3. In certain embodiments, R_3a is F and R3b is selected from the group consisting of F, Cl, methyl, cyclopropyl and CF3.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rîc is selected from the group consisting of: H, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted cyclopropyl, hydroxyl, methoxy, halide, CFj, C(H)F2, C(F)H2, and -CN. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rîc is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rjc is unsubstituted (Ci-C4)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rac is substituted (Ci-C4)-alkyl. In certain embodiments, the substituted (Ci-Cs)-alkyl, is substituted with a halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, Rj_c is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3c is substituted (C3C6)-cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3_C is substituted or unsubstituted (C3-C6)-cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsc is cyclopropyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3_C is halide. In some embodiments, the halide is Cl or F. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3c is CF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3_C is C(H)F2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3c is C(F)H2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3c is substituted -(Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3_C is unsubstituted -(Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3c is -OCF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3c is substituted (CiC4)-alkylene-(Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3_C is unsubstituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy. In certain embodiments, (Ci-C4)-alkylene-(Ci-C4)-alkoxy is -CfhOMe.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3c is H; R3a is halide; and R3b is selected from the group consisting of (CiC4)-alkylene optionally substituted with one or more halide and (C3-C6)-cycloaIkyl. In certain embodiments, Rs_c is H; Rsa is F; and Rsb is selected from the group consisting of (C1-C4)alkylene optionally substituted with one or more halide and (C3-Cô)-cycloalkyl. In certain embodiments, R3c is H; R3a is F; and R3b is selected from the group consisting of methyl, cyclopropyl and CF3. In certain embodiments, R3c is H; Rsa is F; R3b is selected from the group consisting of F, Cl, methyl, and CF3· In certain embodiments, R3c is H; R3a is F; Rsb is selected from the group consisting of F, Cl, methyl, cyclopropyl and CF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3d is selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, hydroxyl, halide, methoxy, halide, CF3, C(H)F2, and C(F)H2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3d is unsubstituted (Ci-C4)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is substituted (Ci-C4)-alkyl. In certain embodiments, the substituted (Ci-C5)-alkyl, is substituted with a halogen. In certain embodiments, the halogen is F. In certain embodiments, R3a is methyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is substituted (C3-C6)-cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rse is substituted or unsubstituted (Cs-Cô)cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is cyclopropyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is halide. In some embodiments, the halide is CI or F In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is CF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is C(H)F2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is C(F)H2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is substituted -(Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is unsubstituted -(Ci-C4)-alkoxy. In certain embodiments, -(Ci-C4)-alkoxy is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is -OCF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is substituted (CiC4)-alkylene-(Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rjd is unsubstituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy. In certain embodiments, (Ci-C4)-alkylene-(Ci-C4)-alkoxy is—CFbOMe.

In some embodiments, Rj_c and Rîd are the same. In some embodiments, Rjc and Rsa are both H. In some embodiments, Rjc and Rjd are different. In some embodiments, Rj_c is H and Rsd is H or halide. In some embodiments, Rj_c is H and Rsa is F.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rj_c and R3d are both H; Rî_a is halide; and R3b is selccted from the group consisting of (Ci-C4)-alkylene optionally substituted with one or more halide and (C3-C6)cycloalkyl. In certain embodiments, R3c and R3d are both H; R3a is F; and Rîb is selected from the group consisting of (Ci-C4)-alkylenc optionally substituted with one or more halide and (C3C6)-cycloalkyl. In certain embodiments, R3c and R3d are both H; Rja is F; and Rsb is selected from the group consisting of methyl, cyclopropyl and CF3. In certain embodiments, R3c and R3d are both H; R3a is F; R3b is selected from the group consisting of F, Cl, methyl, and CF3. In certain embodiments, R3_C and R3d are both H; R3a is F; R3b is selected from the group consisting of F, Cl, methyl, cyclopropyl and CF3.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3c is H; R3d is F; R3a is halide; and Rsb is selected from the group consisting of (Ci-C4)-alkylene optionally substituted with one or more halide and (C3-C6)cycloalkyl. In certain embodiments, R3C is H; R3d is F; Rsa is F; and R3b is selected from the group consisting of (Ci-C4)-alkylene optionally substituted with one or more halide and (C3-C6)cycloalkyl. In certain embodiments, R3c is H; Rsa is F; R3a is F; and R3b is selected from the group consisting of methyl, cyclopropyl and CF3. In certain embodiments, Rjc is H; Rjd is F; R_3a is F; R_3b is selected from the group consisting of F, CI, methyl, and CF3. In certain embodiments, R_3c is H; R₃d is F; R_3a is F; Rsb is selected from the group consisting of F, Cl, methyl, cyclopropyl and CF3.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R» is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R4 is substituted (Ci-CO-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R4 is unsubstituted (Ci-C4)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R4 is methyl, ethyl, n-propyl, or i-propyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R4 is methyl or ethyl.

In certain embodiments, Rs_a is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is substituted or unsubstituted (Ci-C4)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rs_a is unsubstituted (Ci-C4)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is substituted (Ci-C4)-alkyl. In certain embodiments, the substituted (Ci-Cs)-alkyl, is substituted with one or more halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, Rsa is methyl, ethyl, isopropyl, npropyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, R$_a is methyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is halide. In some embodiments, the halide is Cl or F. In certain embodiments, Rsa is substituted (Cî-C6)-cycloalkyl. In certain embodiments, Rsa is unsubstituted (C3-C6)-cycloalkyl. In some embodiments, (C3-Cô)-cycloalkyl is cyclopropyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is CF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is C(H)F2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is C(F)H2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rs_a is (Ci-C4)-alkoxy. In some embodiments, (Ci-C4)-alkoxy is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R$_a is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is hydroxyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is -OCF3. In certain embodiments, Rs_a is CN. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is substituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_5a is unsubstituted (Ci-C4)-alkylene-(Ct-C₄)-alkoxy. In certain embodiments, (C1-C4)alkylene-(Ci-C4)-alkoxy is -CHzOMe. In certain embodiments, Rsa is CH2OH.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is CN. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is unsubstituted (Ci-C4)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is substituted (Ci-C4)-alkyl. In certain embodiments, the substituted (Ci-Cs)-alkyl, is substituted with a halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, Rsb is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, Rsa is methyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is halide. In some embodiments, the halide is Cl or F. In certain embodiments, Rsb is substituted (C3-C6)-cycloalkyl. In certain embodiments, Rsb is unsubstituted (C3-C6)-cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is CF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is C(H)F2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is C(F)H2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is (Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is hydroxyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is -OCF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is substituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is unsubstituted (Ci-C4)-alkylene-(Ci-C4)alkoxy. In certain embodiments, (Ci-C4)-alkyIene-(Ci-C4)-alkoxy is -CIbOMe. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is hydrogen.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rs_c is CN. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rj_c is unsubstituted (Ci-C4)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsc is substituted (Ci-C4)-alkyl. In certain embodiments, the substituted (Ci-C₅)-alkyl, is substituted with a halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, Rsc is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, Rsc is methyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R$_c is halide. In some embodiments, the halide is Cl or F. In certain embodiments, Rsc is substituted (C3-C6)-cycloalkyl. In certain embodiments, Rsc is cyclopropyl. In certain embodiments, Rsc is unsubstituted (C3-C6)-cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsc is CF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsc is C(H)F2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R$_c is C(F)H2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsc is (Ci-Ci)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rs_c is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rs_c is hydroxyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsc is —OCF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsc is substituted (Ci-C4)-alkylene-(CiC4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsc is unsubstituted (Ci-C4)-alkylene-(Ci-C4)-aIkoxy. In certain embodiments, (Ci-C₄)-alkylene-(Ci-C4)-alkoxy is -CH₂OMe. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsc is hydrogen.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is CN. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is unsubstituted (Ci-C4)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is substituted (Ci-C4)-alkyl. In certain embodiments, the substituted (Ci-Cs)-alkyl, is substituted with a halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, Rsa is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, Rsa is methyl In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is halide. In some embodiments, the halide is Cl or F. In certain embodiments, Rsa is substituted (C3-C6)-cycloalkyl. In certain embodiments, Rsa is unsubstituted (C3-C6)-cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is CF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is C(H)F2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is C(F)H2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is (Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is hydroxyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is -OCF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is substituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is unsubstituted (Ci-C4)-alkylene-(Ci-C4)alkoxy. In certain embodiments, (Ci-C4)-alkyIene-(Ci-C4)-alkoxy is -CFbOMe. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is hydrogen.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rs_e is CN. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rse is unsubstituted (Ci-C4)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rse is substituted (Ci-C4)-alkyl. In certain embodiments, the substituted (Ci-Cs)-alkyl, is substituted with a halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, Rse is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, Rse is methyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rs_e is halide. In some embodiments, the halide is Cl or F. In certain embodiments, Rse is substituted (C3-C6)-cycloalkyl. In certain embodiments, Rse is unsubstituted (C3-C6)-cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rs_e is CF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rse is C(H)F2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rs_e is C(F)H2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rse is (Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_5e is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rse is hydroxyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rse is -OCF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rse is substituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rs_e is unsubstituted (Ci-C4)-alkylene-(Ci-C4)alkoxy. In certain embodiments, (Ci-C4)-alkylene-(Ci-C4)-alkoxy is -CHzOMe. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rse is hydrogen.

In certain embodiments, Rsb is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is isubstituted or unsubstituted (Ci-C4)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is unsubstituted (Ci-C4)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is substituted (Ci-C4)-alkyl. In certain embodiments, the substituted (Ci-Cs)-alkyl, is substituted with one or more halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, Rsb is methyl, ethyl, isopropyl, npropyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is halide. In some embodiments, the halide is Cl or F. In certain embodiments, R_5b is substituted (C3-C₆)-cycIoalkyl. In certain embodiments, Rsb is unsubstituted (C3-C6)-cycloalkyl. In some embodiments, (C3-C6)-cycloalkyl is cyclopropyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is CF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is C(H)F2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is C(F)H2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is (Ci-CO-alkoxy. In some embodiments, (Ci-C4)-alkoxy is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is hydroxyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R₅b is -OCF3. In certain embodiments, Rsb is CN. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_5b is substituted (Ci-C₄)-alkylene-(Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsb is unsubstituted (Ci33

C4)-aIkylene-(Ci-C4)-alkoxy. In certain embodiments, (Ci-C4)-alkylene-(Ci-C4)-alkoxy isCHaOMe. In certain embodiments, Rsb is CH2OH.

In certain embodiments, Rs_c is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsc is isubstituted or unsubstituted (Ci-C4)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rs_a is unsubstituted (Ci-C4)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsc is substituted (Ci-C4)-alkyl. In certain embodiments, the substituted (Ci-Cs)-alkyl, is substituted with one or more halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, Rsc is methyl, ethyl, isopropyl, npropyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rs_c is halide. In some embodiments, the halide is Cl or F. In certain embodiments, Rsc is substituted (C₃-C₆)-cycloalkyl. In certain embodiments, R_5c is unsubstituted (C₃-C6)-cycloalkyl. In some embodiments, (C₃-C₆)-cycloalkyl is cyclopropyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsc is CF₃. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsc is C(H)F2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsc is C(F)H2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsc is (Ci-C4)-alkoxy. In some embodiments, (Ci-Cû-alkoxy is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsc is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_5c is hydroxyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsc is —OCF₃. In certain embodiments, Rsc is CN. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_5a is substituted (Ci-C4)-alkylene-(Ci-C₄)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsc is unsubstituted (CiC4)-alkylene-(Ci-C4)-alkoxy. In certain embodiments, (Ci-C4)-alkylene-(Ci-C4)-alkoxy is CFbOMe. In certain embodiments, Rs_c is CH2OH.

In certain embodiments, Rsd is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is substituted or unsubstituted (Ci-C₄)-alkyl.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is unsubstituted (Ci-C4)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is substituted (CrCO-alkyl. In certain embodiments, the substituted (Ci-Cs)-alkyl, is substituted with one or more halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, Rsa is methyl, ethyl, isopropyl, npropyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is halide. In some embodiments, the halide is Cl or F. In certain embodiments, Rsa is substituted (C3-C6)-cycloalkyl. In certain embodiments, Rsa is unsubstituted (C3-C6)-cycloalkyl. In some embodiments, (C3-C6)-cycloalkyl is cyclopropyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is CF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is C(H)F2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is C(F)H2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is (Ci-C4)-alkoxy. In some embodiments, (Ci-C4)-alkoxy is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is hydroxyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is -OCF3. In certain embodiments, Rsa is CN. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is substituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rsa is unsubstituted (CiC4)-alkylene-(Ci-C4)-alkoxy. In certain embodiments, (Ci-C4)-alkylene-(Ci-C4)-alkoxy is CH2ÛMe. In certain embodiments, Rsa is CH2OH.

In certain embodiments, Rs_e is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rs_e is substituted or unsubstituted (Ci-C4)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R$_e is unsubstituted (Ci-C4)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rs_e is substituted (Ci-C4)-alkyl. In certain embodiments, the substituted (Ci-Cs)-alkyl, is substituted with one or more halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, Rj_e is methyl, ethyl, isopropyl, n propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rse is halide. In some embodiments, the halide is Cl or F. In certain embodiments, Rse is substituted (C3-C6)-cycloalkyl. In certain embodiments, Rse is unsubstituted (C3-C6)-cycIoalkyl. In some embodiments, (C3-C6)-cycloalkyl is cyclopropyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rs_c is CF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rse is C(H)F2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rse is C(F)H2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rse is (Ci-CO-alkoxy. In some embodiments, (Ci-C4)-alkoxy is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rse is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rs_c is hydroxyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rse is -OCF3. In certain embodiments, Rse is CN. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rs_e is substituted (Ci-C₄)-alkylene-(Ci-C₄)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rse is unsubstituted (CiC4)-alkylene-(Ci-C4)-alkoxy. In certain embodiments, (Ci-C4)-alkylene-(Ci-C4)-aIkoxy is — CH2ÛMe. In certain embodiments, Rse is CH2OH.

In some embodiments, Rs_a and R$_e are identical. For example, Rsa and Rs_e can both be substituted or unsubstituted (Ci-CO-alkyl. In some examples, Rsa and Rs_e are both unsubstituted (Ci-C4)-alkyl (e.g., methyl). In some examples, R$_a and Rs_eare both unsubstituted methyl.

In some embodiments, Rsb and Rsa are identical. For example, Rs_a and Rsecan both be hydrogen.

In some embodiments, Rsa and Rse are both substituted, and Rsb and Rsa are both hydrogen. For example, Rs_a and Rs_ecan both be (the same or different) substituted or unsubstituted (Ci-C4)-alkyl. In some examples, Rsa and Rsecan both be unsubstituted (C1-C4)alkyl (e.g., methyl) and Rsb and Rsa are both hydrogen. In some examples, Rs_a and R$_eare both unsubstituted methyl and Rsb and Rsa are both hydrogen. In some embodiments, Rs_a, and Rse are independently selected from the group consisting of H, CN, halide, CFj, C(H)F2, C(F)H2, (CiCs)-alkyl, hydroxyl, and (Ci-C4)-alkoxy.

In some embodiments, Rs_c is hydrogen, halide (e.g., F), substituted or unsubstituted (CiC4)-aIkoxy (e.g., methoxy), or substituted or unsubstituted (Ci-C4)-alkyl (e.g., methyl).

In some embodiments, Rsa and Rie are both substituted or unsubstituted (Ci-Cs)-alkyl, both Rsb and Rsd are hydrogen and Rsc is hydrogen, halide (e.g., F), substituted or unsubstituted (Ci-C₄)-alkoxy (e.g., methoxy), or substituted or unsubstituted (Ci-CO-alkyl (e.g, methyl). For example, Rsa and Rs_ecan both be methyl; Rsb and Rsd are both hydrogen; and Rsc is selected from the group consisting of hydrogen, halide (e.g., F), substituted or unsubstituted (C1-C4)alkoxy (e.g., methoxy), and substituted or unsubstituted (Ci-C4)-aIkyl (e.g, methyl). In some examples, Rs_a and R^can both be methyl; Rsb and Rsa are both hydrogen; and Rsc is selected from the group consisting of hydrogen, F, Cl, methoxy, and methyl. In some examples, Rsa, Rsc and Rs_eare each methyl; and Rsb and Rsd are both hydrogen. In some embodiments, Rsb, Rsc, and R_5d are independently selected from the group consisting of H, CN, halide, CF3, C(H)F2, C(F)H2, (Ci-C5)-alkyl, hydroxyl, and (Ci-C4)-alkoxy.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_a, Rb and Rc comprise a chargcd amine. At least one of R_a, Rb and Rc can be a substituted or unsubstituted -(Ci-C5)alkylene-N-(Rx)(Ry); wherein R_x and R_y are independently selected from the group consisting of H, substituted or unsubstituted (Ci-Cô)alkyl, or substituted or unsubstituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy; or R_x and R_y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered heterocyclyl ring.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein only one of Ra, Rb and Rc is a substituted or unsubstituted —(C iCs)alkylene-N-(Rx)(R_y); wherein R_x and R_y are independently selected from the group consisting of H, substituted or unsubstituted (Ci-C6)-alkyl, or substituted or unsubstituted (Ci-C4)-alkylene(Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein only one of Ra, Rb and Rc is a substituted or unsubstituted -(CiC₅)alkylene-N-(R_x)(Ry); wherein R_x and R_y are independently selected from the group consisting of substituted or unsubstituted (Ci-Cô)-alkyl, or substituted or unsubstituted (C i-C-O-alkylene(Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein only one of Ra, Rb and Rc is a substituted or unsubstituted —(CiC₅)alkylene-N-(R_x)(Ry); wherein R_x and R_y are independently selected from the group consisting S of substituted or unsubstituted (Ci-C6)-alkyl.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein only one of Ra, Rb and Rc is a substituted or unsubstituted -(CiC₅)alkylene-N-(Rx)(R_y); wherein Rx and R_y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered heterocyclyl ring. In certain embodiments, the 10 invention relates to any one of the aforementioned compounds, wherein only one of Ra, Rb and R_c is a substituted or unsubstituted -(Ci-Cs)alkylene-N-(Rx)(Ry); wherein R_x and R_y taken together with the N to which they are attached form a 4-6 membered heterocyclyl ring optionally substituted with one or more halide (e.g., F, Cl).

In some embodiments, Ra, Rb, and Rc are independently selected from the group 15 consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, halide, CF3, C(H)F₂, C(F)H₂, substituted or unsubstituted (Ci-C4)-alkoxy, -OCF3, and at least one of Ra, Rb, and Rc is —(CiC3)alkylene-N-(Rx)(R_y) wherein R_x and R_y are independently selected from the group consisting of H and (Ci-C6)-alkyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered heterocyclyl ring optionally substituted with one or more halide (e.g., F, or Cl).

In some embodiments, Ra, Rb, and Rc are independently selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, halide, CF3, C(H)F₂, C(F)H₂, substituted or unsubstituted (Ci-C4)-aIkoxy, -OCF3, and at least one of Ra, Rb, and R_c is (CiC₃)alkylene-N-(Rx)(R_y) wherein R_x and R_y are independently selected from the group consisting of (Ci-Cô)-alkyl (e.g., methyl); or R_x and R_y taken together with the N to which they are attached 25 form a 4-6 membered heterocyclyl ring optionally substituted with one or more halide (e.g., F, or

Cl).

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein only one of Ra, Rb and Rc is selected from the group consisting of

certain embodiments, the invention relates to any one of the aforementioned compounds,

wherein only one of Ra, Rb and Rc is selected from the group consisting of:

. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein only one of Ra, Rb and Rc is

selected from the group consisting of:

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ra is selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, halide, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (Ci-C4)-alkoxy, and OCF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ra is selected from the group consisting of H, substituted or unsubstituted (Ci-C₅)-alkyl, halide, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (Ci-C4)-alkoxy, and OCF3; and one of Rb and Rc is a substituted or unsubstituted -(Ci-C5)alkylene-N-(R_x)(R_y); wherein R_x and R_y are independently selected from the group consisting of H, substituted or unsubstituted (Ci-Cô)-alkyl, or substituted or unsubstituted (Ci-C4)-alkyIene-(Ci-C4)-alkoxy; or

R_x and R_y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered heterocyclyl ring.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ra is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ra is Me. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ra is halide. In some embodiments, halide is Cl or F. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ra is CF₃. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ra is C(H)Fz. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ra is C(F)H2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ra is substituted (Ci-Ci)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ra is unsubstituted (Ci-CO-alkoxy. In some embodiments, (Ci-CO-alkoxy is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ra is OCF₃. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ra is substituted -(Ci-C5)alkylene-N-(R_x)(R_y). In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ra is unsubstituted -(CiCs)alkylene-N-(R_x)(R_y). In some embodiments, -(Ci-C5)alkylene of-(Ci-C5)alkylene-N-(R_x)(R_y) is substituted with one or more halide or -(Ci-C4)alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein —(Ci-Cs)alkylene-N-(R_x)(R_y) is -<Ci-C4)alkylene-N-(R_x)(R_y).

In some embodiments, Ra is substituted (Ci-Cs)-alkyl, substituted (Ci-CO-alkoxy, or substituted -(Ci-C5)alkylene-N-(R_x)(R_y), wherein substituted means substituted with halide or (Ci-C4)-alkoxy. In some embodiments, Ra is substituted (Ci-C5)-alkyl, substituted (Ci-C4)-alkoxy, or substituted -(Ci-C5)alkylene-N-(R_x)(R_y), wherein substituted means substituted with F or methoxy. In some embodiments, Ra is selected from the group consisting of F ,

, and MeO . In some embodiments,

Ra I , and I . In some embodiments, R_a is I , or I .In some embodiments, Ra is CF3.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ra is selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, halide, CF3, C(H)F₂, C(F)H₂, substituted or unsubstituted (Ci-C₄)-alkoxy, and -OCF_;and R_b is a substituted or unsubstituted -(Ci-Cs)alkylene-N-(R_x)(R_y); wherein R_x and R_y are independently selected from the group consisting of H, substituted or unsubstituted (Ci-C6)-aikyl, or substituted or unsubstituted (Ci-C₄)-alkylene-(Ci-C4)-alkoxy; or R_x and R_y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered heterocyclyl ring.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rb is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rb is Me. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_b is halide. In some embodiments, halide is Cl or F. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rb is CF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_b is C(H)F₂. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rb is C(F)H₂. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rb is substituted (Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rb is unsubstituted (Ci-CO-alkoxy. In some embodiments, (Ci-C4)-alkoxy is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rb is OCF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rb is substituted -(Ci-C5)alkylene-N-(R_x)(R_y). In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rb is unsubstituted —(CiC5)alkylene-N-(R_x)(R_y). In some embodiments, -(Ci-C5)alkylene of-(Ci-Cs)alkylene-N-(R_x)(R_y) is substituted with one or more halide or -(Ct-COalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein —(Ci-Cs)alkylene-N-(R_x)(R_y) is -<Ci-C4)alkylene-N-(R_x)(R_y).

In some embodiments, Rb is substituted (Ci-C5)-alkyl, substituted (Ci-C4)-alkoxy, or substituted -(Ci-C5)alkylene-N-(R_x)(R_y), wherein substituted means substituted with halide or (Ci-C4)-alkoxy. In some embodiments, Rb is substituted (Ci-Cs)-alkyl, substituted (Ci-C4)-alkoxy, or substituted -(Ci-Cs)alkylene-N-(R_x)(R_y), wherein substituted means substituted with F or methoxy. In some embodiments, Rb is-(Ci-C5)alkylene-N-(R_x)(R_y) wherein R_x and R_y are each methyl, or wherein R_x and R_y taken together with the N to which they are attached form a 4-6 membered heterocyclyl ring optionally substituted with one or more halide (e.g., F, or Cl). In some embodiments, Rb is-(C2-C3)alkylene-N-(R_x)(R_y) wherein R_x and Ry are each methyl, or wherein R_x and R_y taken together with the N to which they are attached form a 4-6 membered heterocyclyl ring optionally substituted with one or more halide (e.g., F, or Cl). In some embodiments, Rb is-(C2-C3)alkyIene-N-(R_x)(Ry) wherein R_x and Ry are each methyl, or wherein R_x and R_y taken together with the N to which they are attached form a 4-membered heterocyclyl ring optionally substituted with one or more halide (e.g., F, or Cl). In some embodiments, Rb is(C₂-C3)alkylene-N-(R_x)(R_y) wherein R_x and R_y are each methyl, or wherein R_x and R_y taken together with the N to which they are attached form a 4-6 membered heterocyclyl ring optionally substituted with one or more halide (e.g., F, or Cl). In some embodiments, Rb is-(C2-C3)alkyleneN-(R_x)(R_y) wherein R_x and R_y are each methyl, or wherein R_x and R_y taken together with the N to which they are attached form a 4-membered heterocyclyl ring optionally substituted with one or more halide (e.g., F, or Cl).

In certain embodiments, the invention relates to any one of the aforementioned compounds, ^Re'sC/^N^^X

R_b is Rô , wherein x is 1 or 2; Rô is H and Rô' is (Ct-C4)alkyl optionally substituted with one or more halide (e.g., CF3), or Rô and Rô' together form a substituted or unsubstituted 3-6 member cycloalkyl or heterocycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, Rb is » wherein x is 1 or 2; Rô is H and Rô is (Ci-C4)alkyl optionally substituted with one or more halide (e.g., CF3), or Rô and Rô' together form a 3-6 member cycloalkyl or heterocycloalkyl optionally substituted with halide (e.g., F), (CiC₄)alkyl (e.g., methyl), (Ci-C4)alkoxy (e.g., methoxy), (C3-Cô)cycloalkyl (e.g., spirocyclopropyl) or (C3-C₆)heterocycloalkyl (e.g., azaspiro[3.3]heptyl). In some embodiments, R_b is selected from the group consisting of F

MeO . In some embodiments, Rb । , and I . In certain embodiments, the invention relates to any one of the aforementioned compounds, Rb is selected from the group consisting of: F

and MeO . In some embodiments, Rb is । , or । .In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rb is

selected from the group consisting of:

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rc is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rc is Me. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rc is halide. In some embodiments, halide is Cl or F. In 15 certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rc is CF₃. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rc is C(H)F₂. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rc is C(F)H₂. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rc is substituted (Ci-C4)-alkoxy. In some embodiments, (Ci-C4)-alkoxy is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rc is unsubstituted (Ci-C4)-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rc is OCF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rc is substituted -(Ci-C5)alkylene-N-(R_x)(R_y). In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Rc is unsubstituted -(^c«Cs)alkylene-N-(Rx)(R_y). In some embodiments, -(Ci-Csjalkylene of-(Ci-C5)alkylene-N-(R_x)(R_y) is substituted with one or more halide or -(Ci-C4)alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein —(Ci-Cs)alkylene-N-(R_x)(R_y) is -(Ci-C4)alkylene-N-(R_x)(R_y).

In some embodiments, Rc is substituted (Ci-Cs)-alkyl, substituted (Ci-C4)-alkoxy, or substituted -(Ci-Cs)alkylene-N-(R_x)(R_y), wherein substituted means substituted with halide or (Ci-C4)-alkoxy. In some embodiments, Rc is substituted (Ci-Cs)-alkyl, substituted (Ci-C4)-alkoxy, or substituted -(Ci-C₅)alkylene-N-(R_x)(R_y), wherein substituted means substituted with F or methoxy.

In some embodiments, Rc is selected from the group consisting of F ,

F—JZj

L I \_J V—^J and MeO . In some embodiments,

Rc I , and । .

In some embodiments, at least one of Ra, Rb, and Rc is H.

In some embodiments, at least one of Ra, Rb, and Rc is a charged amine; and at least one of Ra, Rb, and Rc is H.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_x is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_x is substituted (Ci-C6)-alkyI. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_x is unsubstituted (Ci-C6)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_x is substituted (Ci-C4)-alkyl. In some embodiments (Ci-Ce)-alkyl is substituted with OMe, CN, or halide. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_x is unsubstituted (Ci-C4)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_x is (Ci-C4)-alkylene-(Ci-C4)-alkoxy. In some embodiments, (Ci-C4)-alkylene-(Ci-C4)-alkoxy is -(CH₂)2OMe. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_x is Me.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_y is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_y is substituted (Ci-Ce)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_y is unsubstituted (Ci-Cô)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_y is substituted (Ci-C4)-alkyl. In some embodiments, (Ci-C₆)-alkyl is substituted with OMe, CN, or halide. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_y is unsubstituted (Ci-C4)-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_y is (Ci-C4)-alkylene-(Ci-C4)-alkoxy. In some embodiments, (Ci-C4)-alkylene-(Ci-C₄)-alkoxy is -fCH₂)2OMe. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_y is Me.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_x is Me; and R_y is Me.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R_x and R_y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered ring. In some embodiments, the 4-6 membered ring is a substituted or unsubstituted heterocycloalkyl. In some embodiments, the substituted 4-6 membered heterocyclalkyl is substituted with halide of (Ci-Cé)alkyl. In some embodiments, the 4-6 membered ring is a substituted or unsubstituted heteroaryl. In some embodiments, the substituted 4-6 membered heteroaryl is substituted with halide of (Ci-Cô)alkyl. In some ô embodiments, the 4-6 membered ring is selected from O ,

F, OMe, and F .

In some embodiments, Rx and R_y taken together with the N to which they are attached form ' . In some embodiments, R_x and R_y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered ring of the formula ^y, wherein y is 0, 1 or 2, and R? is H, halide, alkoxy, spirocyclic 3-5 member cycloalkyl, and spirocyclic 3-5 member heterocycloalkyl.

In some embodiments, Ra is (Ci-Cs)-alkyl optionally substituted with halide; Rb is —(CiCs)alkylene-N-(Rx)(R_y) wherein R_x and R_y are each methyl, or wherein R_x and R_y taken together with the N to which they are attached form a 4-5 membered heterocyclyl ring optionally substituted with one or more halide or alkoxy (e.g., methoxy); and Rc is hydrogen, halide or (Ci-Cs)-alkyl optionally substituted with halide. In some embodiments, Ra is methyl optionally substituted with halide; Rb is -(C₂-C₃)alkylene-N-(Rx)(R_y) wherein R_x and R_y are each methyl, or wherein Rx and R_y taken together with the N to which they are attached form a 4-5 membered heterocyclyl ring optionally substituted with one or more halide (e.g., F); and Rc is hydrogen, halide or methyl optionally substituted with halide. In some embodiments, Ra is methyl or CF₃; Rb is -(C2C₃)alkylene-N-(R_x)(R_y) wherein R_x and R_y are each methyl, or wherein R_x and R_y taken together with the N to which they are attached form a 4-5 membered heterocyclyl ring optionally substituted with one or more F or methoxy, and Rc is hydrogen, F, CH2F, CHF2, CF₃.

In certain embodiments, the invention relates to a compound of Formula (la) or (Ib):

(Ib) wherein

Ri, R3c, Rîd, Rsa, Rsb, Rsc, Rsd, Rse, Ra, Rb, and Rc are as defined above with respect to Formula (I);

R4 is H; and at least one of Ra, Rb, and Rc is -(Ci-C₃)alkylene-N(Rx)(Ry);

Rx and R_y are independently selected from the group consisting of H and methyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered ring; and

R_3a, and R_3b are each independently selected from the group consisting of methyl and F.

In certain embodiments, the invention relates to any one of the compounds depicted in Figure 1. In certain embodiments, the invention relates to any one of the compounds depicted in Figure 2. In certain embodiments, the invention relates to any one of the compounds depicted in Figure 3. In certain embodiments, the invention relates to any one of the compounds depicted in Figure 4.

In certain embodiments, a compound is a compound of Formula (I) that is not a compound depicted in Figure 1. In certain embodiments, a compound is a compound of Formula (I) that is not a compound depicted in Figure 2. In certain embodiments, a compound is a compound of Formula (I) that is not a compound depicted in Figure 3. In certain embodiments, a compound is a compound of Formula (I) that is not a compound depicted in Figure 4. In certain embodiments, a compound is a compound of Formula (I) that is not a compound depicted in Figure 2, Figure 3 or Figure 4.

In certain embodiments, the invention relates to a compound of Formula (Ilia):

wherein Ri, Ra, R_x, R_y, Rsb, Rsb, Rse, Rsa, are as defined above with respect to Formula (I).

In certain embodiments, the invention relates to a compound of Formula (IVa):

(IVa), wherein Ri, Ra, R_x, R_y, Rîb, Rsb, Rse, Rsa, are as defined above with respect to Formula (I).

In certain embodiments, the invention relates to a compound selected from the group consisting of:

(3S)-3-(4,5-difluoro-2',6'-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-lyl)ethyl)-4-methyl-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid;

(3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-415 methylpentanamido)-3-(4-fluoro-2',6^,-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid;

(3S)-3-(2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yI)-4methylpentanamido)-3-(3',4-difluoro-2’,5,6'-trimethyl-[ 1,1 ’-biphenyl]-3-yl)propanoic acid;

(3S)-3-(2-(5-(2-(azetidin- l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(4-fluoro-3^,-methoxy-2^,,5,6’-trimethyl-[ 1,1 '-biphenyl]-3-yl)propanoic acid;

(3S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoicacid;

(3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(5-(2-(3methoxyazetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)propanoicacid;

(3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoic acid;

(3S)-3-(4,4’-difluoro-2’₎5,6’-trimethyl-[l,r-biphenyl]-3-yl)-3-(2-(3-(difluoromethyl)-5-(2(dimethylamino)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid;

(3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-5methylhexanamido)-3-(4-fluoro-2',5,6^,-trimethylbiphenyl-3-yl)propanoic acid;

(3S)-3-(4-fluoro-2',5,6^,-trimethyl-[l,r-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3fluoroazetidin-1 -yl)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methyIpentanamido)propanoic acid; and (3S)-3-(4-fluoro-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((R)-3fluoropyrrolidin-1 -yl)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid.

or a pharmaceutically acceptable sait thereof.

pharmaceutically acceptable sait thereof.

(S)-3-(4,5-difluoro-2',6’-dimethyl-[ 1,1 ’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin5 1 -yl)ethyl)-4-methyl-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid;

(S)-3-((S)-2-(5-(2-(azetidin- l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[ 1,1 '-biphenyl]-3yl)propanoic acid;

(S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-410 methylpentanamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[ 1,1 ’-biphenyl]-3-yl)propanoic acid;

(S)-3-((S)-2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoic acid;

(S)-3-(4,4'-difluoro-2',5,6^,-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid;

(S)-3-(5-chloro-4-fluoro-2',6’-dimethyl-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3methoxyazetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)propanoic acid;

(S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)-4methylpentanamido)-3-(4-fluoro-2',4',5,6^,-tetramethyl-[ 1,1 '-biphenyl]-3-yl)propanoic acid;

(S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(3-(difluoromethyl)-5(2-(dimethylamino)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid;

(S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-5methylhexanamido)-3-(4-fluoro-2',5,6'-trimethyl-[ 1,1 -biphenyl]-3-yl)propanoic acid;

(S)-3-(4-fluoro-2',5,6’-trimethyl-[l,r-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3fluoroazetidin-1 -yl)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid; and (S)-3-(4-fluoro-2',5,6’-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-((R)-3fluoropyrrolidin-1 -yl)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid;

or a pharmaceutically acceptable sait thereof.

(S>>M4S«l>nunf»r6<di«KtbvHI _φ

(t4^krtw«<>Z$6'*<naM<h>Hl.r-bY>iKMi|->An(«rif*KBC acU.

(S>..V(Sh2-($-(2’(*Aa»Jia-t-}lk-Un1>-2-ov>-mnni*<o<»rth'i)rndui-ll2ll>->lk->-e^h'tpi»rt»anudo)·'(4-nuK9>.r>ew<hox-x*r.S 6-4nneU\l-(l.l-biphemlHAlTropenoK kU.

<K<>4-(tfUkuKM^«lipnJ»l(2n^lM-«M<Vtre«««mm«k*lp««(WkM« *-«J ($>.Η4.ί^Μικ»^Γ4,6·-ίηβ»Λ^ΗΙ.ΙΜ>φΙίαηΐρ·Ο)·Μ(5).2·<5Χ2ΧΛ»«ΜΛ\Ι»»ι«»Κ·ι^Ι>2-ον>4{fnnunnMMihUipwAa- l(2t l>^l)U-^<rtv»i*-r4oMrekk>)pnpQ«>^ k»L

(^rtM^l-.-rJAMcttamcAU-ll rJwpJKwvth^lifK^wHw *.»J

(Sb304'-ddluoa>-r.56Mnmcili\Hl |'-biphcnxl|-3->l>-3-«S)-2-(H<i'nüoro«Kth}l>M2· (dtmcthtlaminoteihjIhï-dxopxndm-UIH^IH-mcthUpcntaearnKioîpropaftOiC >ad. J

(S> >HOk24M244m>fl»r» b· ^»Μ*4^·«ίιχΜ-·χ«ψ'ηώ·-1ΐ2ΗΜΐ>·5-·«Α'β*«**··ΛΨ>0·Λ·>·ο· Τ3 6-.«μμΙ»ΗΙ «oi

(5>.Μ4·ίΙ««···Γ56··<ηακϋινΗΙ.|··»Ηρ»*βνΙ|·'->Ι>·Μ<5»·2·<'·Λ»Μ<»$-<2·<'·η*«<Λ<Μ»»Λ-Ι*’»βΛνΙ>·2· . <AiT»idiM(2ll>*1M-«»rttftlpcn(aum»A>çt»T«niwc *c*» and

(8).ΪΗ4·ί^^3Λ^,·»ηιηβΛ)ΗΙ3·4ΐ(*ΛηΙΗ·>Ι>·ΐ·((3).2^ϊ4ΐΐΜ«»>$-(2<(Κ>3·Πυιΐ«ψ*τι«Μιη·Ι· >)Knh'l^2K>vo|^nJmJ(2n>}IM-nwth\lpcnujiem>Ji>»ptnpanaic κκΙ , or a pharmaceutically acceptable sait thereof.

In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein the compound is in the form of a pharmaceutically acceptable sait.

Structure	Name
	(S)-3-((S)-2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-
	(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(5-cyclopropyl-2,4difluoro-2*,4^,,6'-trimethyl-[ 1,1 ’-biphenyl]-3-
F^^F F	yl)propanoic acid;
' i XX^ ^F 0 = oX-	(3S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(5-cyclopropyl-2,3',4trifluoro-2',6'-dimethyl-[l, 1 *-biphenyl]-3·
F	yl)propanoic acid

Structure

Name

(S)-3-((S)-2-(5-(3-(dimethylamino)propyl)-2-oxo-4(trifluoromethyl)pyridin· 1 (2H)-yl)-4methylpentanamido)-3-(2,4,4'-trifluoro-2’,6'dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoic acid (3S)-3-((S)-2-(5-(3-(dimethylamino)propyl)-2-oxo4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,3^,,4-trifluoro-2',4',5,6'tetramethyl-[l ,r-biphenyl]-3-yl)propanoic acid (3S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4,4'-trifluoro-2',3',6'trimethyl-5-(trifluoromethyl)-[ 1,1 '-biphenyl]-3yl)propanoic acid

Structure

Name

(S)-3-(2,4-difluoro-2',4',6-trimethyl-5(trifluoromethyl)-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(5(2-(dimethylamino)ethyl)-2-oxo-4(tri fluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)propanoic acid (S)-3-((S)-2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(2,4-difluoro-2',4^,,6'trimethyl-5-(trifluoromethyl)-[ 1,1 -biphenyl]-3yl)propanoic acid (S)-3-((S)-2-(5-(3-(azetidin-l-yl)propyl)-2-oxo-4(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(2,4-difluoro-2’,4',6'trimethyl-5-(trifluoromethyl)-[ 1,1 '-biphenyl]-3yl)propanoic acid

Name

Structure

(S)-3-(2,4-difluoro-2',4',6^,-trimethyl-5(trifluoromethyl)-[l,r-biphenyl]-3-yl)-3-((S)-2-(5(3-(dimethylamino)propyl)-2-oxo-4(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)propanoic acid (S)-3-(4'-cyclopropyl-2,4-difluoro-2',6'-dimethyl-5(trifluoromethyl)-[l,l*-biphenyl]-3-yl)-3-((S)-2-(5(3-(dimethylamino)propyl)-2-oxo-4(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)propanoic acid (3S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4( tri fluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(2,3',4-trifluoro-2',4',6'trimethyl-5-(trifluoromethyl)-[ 1,1 ’-biphenyl]-3yl)propanoic acid

EXEMPLARY PHARMACEUTICAL COMPOSITIONS

Compounds of Formula (I) can be formulated in varions pharmaceutical compositions. A compound of Formula (I) (including compounds of Formula (la) and Formula (Ib) as provided herein), as well as pharmaceutically acceptable salts thereof, may be the active pharmaceutical ingrédient (API) combined with one or more other ingrédients to form a drug substance pharmaceutical composition. The drug substance (DS) pharmaceutical composition can comprise the API (i.e., a compound of Formula (I) or pharmaceutically acceptable sait thereof) and one or more pharmaceutically acceptable carriers, diluents, and/or excipients. The carrier(s), diluent(s) or excipient(s) can be selected to be compatible with the other ingrédients of the formulation and appropriately safe and effective for an intended therapy. A desired weight concentration of the compound of Formula (I) as the active pharmaceutical ingrédient (API) can be combined with the other inactive ingrédients to form a drug substance (DS) in a formulation batch. Pharmaceutically acceptable compositions can be formulated for administration by an appropriate route, for example by the oral delivery (including as a capsule or tablet) in unit dosage forms. Such compositions may be prepared by bringing into association the active pharmaceutical ingrédient (API) comprising a compound of Formula (I) with the carrier(s) or excipient(s).

In certain embodiments, the invention provides a pharmaceutical composition formulated for oral delivery of an ο^βγ integrin integrin inhibitor, the composition comprising the cuP? integrin inhibitor compound of formula (I) as an API and a pharmaceutically acceptable carrier formulated for oral therapeutic administration of the αφγ integrin inhibitor compound.

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound of Formula (la), or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound of Formula (Ib), or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (3S)-3-(4,5-difluoro-2',6'-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-lyl)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (3S)-3-(2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)4-methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (3S)-3-(2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)4-methyIpentanamido)-3-(3^,,4-difluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)4-methylpentanamido)-3-(4-fluoro-3'-methoxy-2',5,6^,-trimethyl-[l,l’-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (3S)-3-(4,4'-difluoro-2’,5,6'-trimethyl-[l,l'-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (3S)-3-(5-chloro-4-fluoro-2',6’-dimethyl-[l,r-biphenyl]-3-yl)-3-(2-(5-(2-(3methoxyazetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6^,-tetramethylbiphenyl-3-yl)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(3(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-l(2H)-yl)-4methylpentanamido)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l (2H)-yl)-5methylhexanamido)-3-(4-fluoro-2^,,5,6'-trimethylbiphenyl-3-yl)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (3S)’3-(4-fluoro-2^,,5,6'-trimethyl-[l,l'-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (3S)-3-(4-fluoro-2’,5,6'-trimethyl-[ 1,1 ’-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((R)-3fluoropyrrolidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)-4-methyIpentanamido)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (S)-3-(4,5-difluoro-2',6'-dimethyl-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3fluoroazetidin-1 -yl)ethyl)-4-methyl-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)-4-methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[ 1,1 ’-biphenyl]-362 yl)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l (2H)yl)-4-methylpentanamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[ l, 1 ’-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (S)-3-((S)-2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-1 (2H)yl)-4-methylpentanamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3yl)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (S)-3-(4,4’-difluoro-2',5,6^,-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6’-tetramethyl-[ 1,1 ’-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (S)-3-(4,4'-difluoro-2',5,6’-trimethyl-[l,r-biphenyl]-3-yl)-3-((S)-2-(3(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-l(2H)-yl)-4methylpentanamido)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1 (2H)-yl)-5methylhexanamido)-3-(4-fluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (S)-3-(4-fluoro-2',5,6'-trimethyl-[ l, l '-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention provides a pharmaceutical composition comprising the compound (S)-3-(4-fluoro-2',5,6'-trimethyl-[l, 1 ’-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2((R)-3-fluoropyrrolidin-1 -yl)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient (API).

In certain embodiments, the invention relates to a pharmaceutical composition comprising 10 a compound selected from the group consisting of:

τιζΧ 1 ($)-)44 M>nwwn-*6*-dne<ta4-|t |'-b^h«iiyt|-)-)O-)-«S)-24$42-<>-O«>f<*Mn4»t-yD«iiyn-4.meihy)-3ot<5>ynd»)(2Hlyl)4«Kilk)4penUMmdn)prop«nnK and F IA UL i 7^ il r O \ CM (T44>|1unn>2* S ô'-tnexlhxl·)) acid ’ OH i Λ ΎΎ' ΎΤτχΥτ ¹ (S>-t44.4^--diniM»t>T.5.6Mnin«^ü|tJ^>»pfce»d|-VAl>-M(S>2-($<14<l»me<hvUnui»k<hU>2<>v>--l-

ÇÇ-Jk' |P ^*1 ^°n F (S>H(S>2-<M2-(Me<>di*-l-*1)cik*O2^rvn-*-(inftuuninicHix<)(KnJ*>t(2l(>yf>4-«twAx4pc«tMMnHk>)·)· F ^^*χ^_χζ*χ_χ^χ' OH (441w<>-V-«wthoxy2\5.6Mn^nh\Hl.lM*plwll«'-y|)fwrç»eftOK Mtd. * OOy y/_s-X Il *** |M>vUM| UI>14(S>24M24J^lkm««Mia-tA4>cthd>-2' oxo-Hmnuiwuaiciiixiipndw-KZKyUl-i-flKthxIpcMaMMMjxIrnifMmMC aud. *

(44lunrrb2’4'$6**Mr»m«h\Hl.r4>ip>*fml|-Mtywnrtnmc ack!

(5)-3-(4 r-diHuoro-rj 6Mnm«MI-|l |·-^ρΛαηΙ|·3^ΙΗΗ(5>·2-(3-«1ιΠ«>ΜΗη«Ιη1>·$·<2· (difnctlnbmino)clhxl)-2-o\opindift-l(2H)-)l>-4-tncilnlpcM«uinMio)pfopaHMC aod

(5).Η4-ηυ>νι>-3'Λ6Μηι<κ<Ι«}ΗΙ.Ι^,4>φΐΜη!|·)·)Ι>-3Λ<^)-2-(3-η*νο>Μ2·((Κ»->α>*>ηγ>τη>!ιαυ)·Ι- . . «« . t i

3Πα )l)e^\l>-2-av>p\T>hn-l(211>-U>-4-«wth\lpcn<*ium»JolpnTp«x*c * ΟΓ 3 ρΠ3ΓΙΪ130€11ΐ1031Ι^ 3CCCpt301C S31T thereof.

In certain embodiments, the invention relates to a pharmaceutical composition comprising a compound selected from the group consisting of, or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrediend (API):

Structure

Name

(S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(5-cyclopropyl-2,4difluoro-2',4',6’-trimethyI-[ 1,1 ’-biphenyl]-3yl)propanoic acid;

(3S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-1 (2H)-y1)-4methylpentanamido)-3-(5-cyclopropyl-2,3',4trifluoro-2',6'-dimethyl-[ 1,1 '-biphenyl]-3yl)propanoic acid (S)-3-((S)-2-(5-(3-(dimethylamino)propyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4,4'-trifluoro-2',6’dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoic acid

Name

Structure

(3S)-3-((S)-2-(5-(3-(dimethylamino)propyl)-2-oxo4-(tri fluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(2,3^,,4-trifluoro-2',4^,,5,6'tetramethyl-[ 1,1 -biphenyl]-3-yl)propanoic acid (3S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4,4^,-trifluoro-2',3',6'trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoic acid (S)-3-(2,4-difluoro-2',4',6'-trimethyl-5(trifluoromethyl)-[l,l'-biphenyl]-3-yl)-3-((S)-2-(5(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid

Structure

Name

(S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4-difluoro-2',4',6’trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoic acid (S)-3-((S)-2-(5-(3-(azetidin-l-yl)propyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4-difluoro-2^,,4',6'trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoic acid (S)-3-(2,4-difluoro-2',4',6^,-trimethyl-5(trifluoromethyl)-[ 1, r-biphenyl]-3-yl)-3-((S)-2-(5(3-(dimethylamino)propyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid

Structure

Name

(S)-3-(4'-cyclopropyl-2,4-difluoro-2',6'-dimethyl-5(trifluoromethyl)-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(5(3-(dimethylamino)propyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid (3S)-3-((S)-2-(5-(2-(azetidin-I-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(2,3',4-trifluoro-2',4^,,6'trimethyl-5-(trifluoromethyl)-[l,l'-biphenyl]-3yl)propanoic acid.

Pharmaceutically acceptable compositions comprising the compound of Formula (I) can be prepared by various procedures. For example, the compounds of Formula (I) can be formulated with suitable excipients, diluents, or carriers, and formed into tablets, or capsules, and other suitable dosage forms.

Pharmaceutical compositions can be provided in unit dose forms containing a predetermined amount of API comprising a compound of Formula (I) per unit dose. Such a unit may contain, a desired amount of a compound of the Formula (I) or pharmaceutically acceptable sait thereof, depending on the condition being treated, the route of administration and the âge, weight and condition of the patient. Such unit doses may therefore be administered at a desired dose interval. The concentration of active compound in the drug composition will dépend on varions applicable parameters and considérations such as the absorption, inactivation and excrétion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, spécifie dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingrédient can be administered at once, or can be divided into a number of smaller doses to be administered at varying intervals of time.

In certain embodiments, the mode of administration of the active compound is oral. Oral compositions will generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. Pharmaceutical compositions comprising a compound of Formula (I) formulated for oral delivery can be prepared in a unit dosage form, such as a capsule at a desired dosage strength of the compound of Formula (I). For oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as éthanol, glycerol, water and the like. For oral administration in the form of a tablet or capsule, the compound of Formula (I) can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier. Other examples of excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, and sugars; and binding agents such as cellulose dérivatives. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, naturel sugars, naturel and synthetic gums, and the like. Lubricants and/or glidants can be used in these dosage forms.

The tablets, pills, capsules, troches and the like can contain any of the following ingrédients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or com starch; a lubricant such as magnésium stéarate or Sterotes; a glidant such as colloïdal Silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, unit dosage forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, or other enteric agents.

The compound can be administered as a component of an élixir, suspension, syrup, wafer, or the like. A syrup can contain, in addition to the active compound(s), sucrose or sweetener as a sweetening agent and certain preservatives, dyes and colorings and flavors.

The compounds can be formulated as solutions appropriate for parentéral administration, for example, by intramuscular, subcutaneous or intravenous routes. For example, a compound of Formula (I) can be dissolved in a suitable bufifer. A pharmaceutical composition comprising a desired concentration of a compound of Formula (I) can be formulated as an injectable drug solution in (useful, e.g., in preclinical animal studies).

EXEMPLARY METHODS

Compounds inhibiting αφ? are useful for development of médicaments to treat ulcerative colitis and Crohn’s disease patients. Ulcerative colitis (UC) and Crohn’s disease (CD) patients sufifer from autoimmune inflammation in the digestive tract and for many of these patients, the CD4⁺ memory T cells drive the progression and flare ups of the disease via their ability to secrete pro-inflammatory, effector cytokines within the gut, impacting the surrounding immune cells and tissue. The progression and flare ups of these disease conditions are believed to include extravasation of T cells leaving the blood to enter tissue in the gut leading to inflammatory conditions found in UC and CD via integrin related mechanisms. The inhibition of αφγ can disrupt this mechanism, thereby preventing the localization of T cells to the tissue and effectively treating and preventing disease such as UC and CD. T cell homing to the gut requires surface expression of integrin ct4p7 and chemokine receptor CCR9. While CCR9 is utilized by the cell to migrate against the gradient of CCL25 expressed in the small intestine, αφγ is a tethering molécule which binds the ligand, mucosal addressin cell adhesion molécule 1 (MAdCAM-1). Integrin αφγ binds MAdCAM-1 with high affinity facilitating rolling and firm adhesion of cells followed by extravasation into tissue.

Pharmaceutical compositions can comprise compounds that inhibit the αφγ integrin on inflammatory cells that énables adhesion of these cells to mucosal addressin cell adhesion molécule-1 (MAdCAM-1), and inhibiting or preventing these cells from entering the gut lamina propria and gut associated lymphoid tissue.

Compounds of Formula (I) were evaluated using a fluorescent polarization (FP) assay, as described in Example 5. FP assays are used to evaluate potency of compounds on purified protein. The FP assays consists of measuring purified integrin αβ heterodimer ecto domains or headpiece binding to surrogate or truncated ligands. Results of the FP assay for exemplary compounds of Formula (I) are provided herein.

Compounds of Formula (I) were further evaluated using a Ligand binding assay (LBA) as described in Example 6 to examine compound potency of free ligand binding to receptors expressed on cells. The MAdCAM ligand binding assay uses flow cytometry to measure the binding of fluorescently-labeled MAdCAM-l-Fc to RPMI 8866 cells in the presence of Mn++. This assay assesses the binding of compounds to native full-length receptors on the cell surface. One advantage of the MAdCAM ligand binding assay is its ability to quantify and discriminate the activity of potent compounds that exceed the FP assay’s functional sensitivity limit [~10nM in Mn]. Ligand binding assays (LBA) are used to examine compound potency and selectivity offree ligand binding to receptors expressed on cells.

In some embodiments, compounds of the invention can be selected from one or more of the following numbered embodiments:

1. A compound of Formula (I):

wherein

Ra, Rb, and Rc are independently selected from the group consisting of H, Me, halide, CF₃, C(H)F₂, C(F)H₂, and -(Ci-C₅)alkylene-N-(Rx)(R_y); provided that at least one of Ra, R_b, and Rc is -(Ci-C5)alkylene-N-(R_x)(R_y);

Ri is substituted or unsubstituted (Ci-Cô)-alkyl, substituted or unsubstituted (C1-C4)alkylene-(C3-Cô)-cycloalkyl, or substituted or unsubstituted (Ci-C4)-alkylene- (Ci-C4)-alkoxy;

R3a and R3b are independently selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, -OH, -CN, halide, CF3, C(H)F₂, C(F)H₂,-(Ci-C4)alkoxy, -OCF3, and substituted or unsubstituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy; provided that R3a and R3b are not both H;

R3c, and R_3d are H;

R4 is H, or substituted or unsubstituted (Ci-CO-alkyl;

Rsa, and Rse are independently selected from the group consisting of H, CN, halide, CF3, C(H)F₂, C(F)H₂, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted (Ci-C5)-alkyl, hydroxyl, and (Ci-C4)-alkoxy; and

R_5b, Rse, and Rsa are independently selected from the group consisting of H, CN, halide, CF3, C(H)F₂, C(F)H₂, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C3Cô)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (CiC4)-alkoxy;

or a pharmaceutically acceptable sait thereof.

2. The compound of embodiment l, wherein Ri is methyl, cthyl, n-propyl, iso-propyl, nbutyl, iso-butyl, sec-butyl, or t-butyl.

3. The compound of embodiment 2, wherein Ri is iso-butyl.

4. The compound of embodiment 1, wherein Ri is ^v .

5. The compound of embodiment 1, wherein Ri is .

6. The compound of any one of embodiments 1-5, wherein R_3a and R₃b are independently selected from the group consisting of halide, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C₃-C6)-cycloalkyl, substituted or unsubstituted (Ci-C4)-alkoxy, CF₃, C(H)F2, and C(F)H2.

7. The compound of embodiment 6, wherein R_3a and R₃b are independently selected from the group consisting of halide and (Ci-C4)-alkyl.

8. The compound of embodiment 7, wherein halide is Cl or F.

9. The compound of embodiment 7 or 8, wherein (Ci-CO-alkyl is methyl.

10. The compound of any one of embodiments 1-7, wherein R_3a is methyl; and R₃b is F.

11. The compound of any one of embodiments 1-7, wherein R_3a is F; and R₃b is methyl.

12. The compound of any one of embodiments 1-11, wherein R4 is H.

13. The compound of any one of embodiments 1-11, wherein R4 is methyl, ethyl, npropyl, iso-propyl.

14. The compound of any one of embodiments 1-13, wherein Rs_a and Rse are independently selected from the group consisting of halide, CF₃, C(H)F2, C(F)H2, and substituted or unsubstituted (Ci-C4)-alkyl.

15. The compound of any one of embodiments 1-14, wherein Rsa is halide.

16. The compound of embodiment 15, wherein Rsa is F or Cl.

17. The compound of any one of embodiments 1-14, wherein Rsa is CF₃.

18. The compound of any one of embodiments 1-14, wherein Rsa is C(H)Fi.

19. The compound of any one of embodiments 1-14, wherein Rsa is C(F)H2.

20. The compound of any one of embodiments 1-14, wherein Rs_a is unsubstituted (CiC4)-alkyl.

21. The compound of embodiment 20, wherein Rs_a is methyl.

22. The compound of any one of embodiments 1-14, wherein Rsa is substituted (C1-C5)alkyl, substituted with at least one halide.

23. The compound of any one of embodiments 1-14, wherein Rsa is unsubstituted (CiCO-alkoxy.

24. The compound of embodiment 23, wherein Rsa is OMe.

25. The compound of any one of embodiments 1-24, wherein Rs_e is halide.

26. The compound of embodiment 25, wherein Rse is F or Cl.

27. The compound of any one of embodiments 1-24, wherein Rse is CF₃.

28. The compound of any one of embodiments 1-24, wherein Rse is C(H)F2.

29. The compound of any one of embodiments 1-24, wherein Rse is C(F)H2.

30. The compound of any one of embodiments 1-24, wherein Rs_e is unsubstituted (CiC4)-alkyl.

31. The compound of embodiment 30, wherein Rse is methyl.

32. The compound of any one of embodiments 1-24, wherein Rse is substituted (C1-C5)alkyl, substituted with at least one halide.

33. The compound of any one of embodiments 1-24, wherein Rs_e is unsubstituted (CiC4)-alkoxy.

34. The compound of embodiment 33, wherein Rse is OMe.

35. The compound of any one of embodiments 1-34, wherein Rsb, Rse, andRsd are independently selected from the group consisting of H, halide, CF3, C(H)Fî, C(F)H2, substituted or unsubstituted (Ci-Cs)-alkyl, and substituted or unsubstituted (C1-C4)alkoxy.

36. The compound of any one of embodiments 1-35, wherein Rsb is H.

37. The compound of any one of embodiments 1-35, wherein Rsb is halide.

38. The compound of embodiment 37, wherein Rsb is Cl or F.

39. The compound of any one of embodiments 1-35, wherein Rsb is CF3.

40. The compound of any one of embodiments 1-35, wherein Rsb is C(H)F2.

41. The compound of any one of embodiments 1-35, wherein Rsb is C(F)H2.

42. The compound of any one of embodiments 1-35, wherein Rsb is unsubstituted (CiC₄)-alkyl.

43. The compound of embodiment 37, wherein Rsb is methyl.

44. The compound of any one of embodiments 1-35, wherein Rsb is unsubstituted (CiC4)-alkoxy.

45. The compound of embodiment 44, wherein Rsb is OMe.

46. The compound of any one of embodiments 1-35, wherein Rsb is unsubstituted (C3C6)-cycloalkyl.

47. The compound of embodiment 46, wherein Rsb is cyclopropyl.

48. The compound of any one of embodiments 1-47, wherein Rsc is H.

49. The compound of any one of embodiments 1-47, wherein Rsc is halide.

50. The compound of embodiment 49, wherein Rsc is Cl or F.

51. The compound of any one of embodiments 1-47, wherein Rsc is CF3.

52. The compound of any one of embodiments 1-47, wherein Rsc is C(H)F2.

53. The compound of any one of embodiments 1-47, wherein Rsc is C(F)H2.

54. The compound of any one of embodiments 1-47, wherein Rsc is unsubstituted (CiCO-alkyl.

55. The compound of embodiment 54, wherein Rsc is methyl.

56. The compound of any one of embodiments 1-47, wherein Rsc is unsubstituted (CiC4)-alkoxy.

57. The compound of embodiment 56, wherein Rsc is OMe.

58. The compound of any one of embodiments 1 -47, wherein Rsc is unsubstituted (C3Côj-cycloalkyl.

59. The compound of embodiment 58, wherein Rsb is cyclopropyl.

60. The compound of any one of embodiments 1-59, wherein Rsd is H.

61. The compound of any one of embodiments 1-59, wherein Rsd is halide.

62. The compound of embodiment 61, wherein Rsd is Cl or F.

63. The compound of any one of embodiments 1-59, wherein Rsd is CF3.

64. The compound of any one of embodiments 1-59; wherein R$d is C(H)F2.

65. The compound of any one of embodiments 1-59, wherein Rsa is C(F)H2.

66. The compound of any one of embodiments 1-59, wherein Rsa is unsubstituted (CiC4)-alkyl.

67. The compound of embodiment 66, wherein Rsa is methyl.

68. The compound of any one of embodiments 1-67, wherein Rsa is unsubstituted (CiC4)-alkoxy.

69. The compound of embodiment 68, wherein Rsa is OMe.

70. The compound of any one of embodiments 1-67, wherein Rsa is unsubstituted (C3C6)-cycloalkyl.

71. The compound of embodiment 70, wherein Rsa is cyclopropyl.

72. The compound of any one of embodiments 1-35, wherein Rsb, and Rsa are each H.

73. The compound of any one of embodiments 1-72, wherein Ra is H.

74. The compound of any one of embodiments 1-72, wherein Ra is Me.

75. The compound of any one of embodiments 1-72, wherein R_a is halide.

76. The compound of embodiment 75, wherein Ra is Cl or F.

77. The compound of any one of embodiments 1-72, wherein Ra is CF3.

78. The compound of any one of embodiments 1-72, wherein Ra is C(H)F2.

79. The compound of any one of embodiments 1-72, wherein Ra is C(F)H2.

80. The compound of any one of embodiments 1-72, wherein Ra is unsubstituted -(CiC3)alkylene-N-(R_x)(Ry).

81. The compound of any one of embodiments 1-72, wherein Ra is substituted —(C1C3)alkylene-N-(R_x)(Ry), substituted with F or OMe.

82. The compound of any one of embodiments 1-81, wherein Rb is H.

83. The compound of any one of embodiments 1-81, wherein Rb is Me.

84. The compound of any one of embodiments 1-81, wherein Rb is halide.

85. The compound of embodiment 84, wherein R_b is Cl or F.

86. The compound of any one of embodiments 1-81, wherein Rb is CF₃.

87. The compound of any one of embodiments 1-81, wherein R_b is C(H)F2.

88. The compound of any one of embodiments 1-81, wherein R_b is C(F)H2.

89. The compound of any one of embodiments 1-81, wherein Rb is unsubstituted -(CiC₃)alkylene-N-(Rx)(R_y).

90. The compound of any one of embodiments 1-81, wherein Rb is substituted -(CiC₃)alkylene-N-(R_x)(Ry), substituted with F or OMe.

91. The compound of any one of embodiments 1-90, wherein Rc is H.

92. The compound of any one of embodiments 1-90, wherein Rc is Me.

93. The compound of any one of embodiments 1-90, wherein Rc is halide.

94. The compound of embodiment 93, wherein Rc is Cl or F.

95. The compound of any one of embodiments 1-90, wherein Rc is CF₃.

96. The compound of any one of embodiments 1-90, wherein Rc is C(H)F2.

97. The compound of any one of embodiments 1-90, wherein Rc is C(F)H2.

98. The compound of any one of embodiments 1-90, wherein Rc is unsubstituted —(CiC₃)alkylene-N-(Rx)(Ry).

99. The compound of any one of embodiments 1-90, wherein Rc is substituted -(CiC3)alkylene-N-(Rx)(R_y), substituted with F or OMe.

100. The compound of any one of embodiments 1-99, wherein R_x is H.

101. The compound of any one of embodiments 1-99, wherein R_x is unsubstituted (CiC₆)-alkyl.

102. The compound of any one of embodiments 1-100, wherein R_y is H.

103. The compound of any one of embodiments 1-100, wherein R_y is unsubstituted (Ci-C₆)-alkyl.

104. The compound of any one of embodiments 1 -72, 80-81,89-90, and 98-99, wherein R_x and R_y taken together with the N to which they are attached form a unsubstituted 4-6 membered ring.

105. The compound of any one of embodiments 1 -72, 80-81, 89-90, and 98-99, wherein R_x and R_y taken together with the N to which they are attached form a substituted 4-6 membered ring, substituted with at least one halide, substituted or unsubstituted (C1-C4) alkyl, or OMe.

106. The compound of embodiment 104 or 105, wherein the 4-6 membered ring is a 36 membered heterocycloalkyl.

107. The compound of embodiment 104 or 105, wherein the 4-6 membered ring is a 45 membered heterocycloalkyl.

108. The compound of embodiment 1, wherein the compound is a compound of Formula (la):

wherein at least one of Ra, Rb, and Rc is -(Ci-C3)alkylene-N(R_x)(R_y);

R_x and R_y are independently selected from the group consisting of H and methyl; or

R_x and R_y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered ring ; and

R3a, and R3b are each independently selected from the group consisting of methyl and F.

109. The compound of embodiment 108, wherein Rs_a, and Rse are independently unsubstituted (C1-C4) alkyl.

110. The compound of embodiment 108 or 109, wherein Rb is unsubstituted -(CiC3)alkylene-N(R_x)(R_y).

111. The compound of embodiment 1 or 108, wherein Ra is selected from the group consisting of H, C(H)F₂, CF3, and Me.

112. The compound of embodiment 1 or 108, wherein Rb is selected from the group

113. The compound of embodiment 1 or 108, wherein Rb is selected from the group consisting of I , and I

114. The compound of embodiment 1 or 108, wherein Rc is H or F.

115. The compound of any one of embodiments 1 and 108-114, wherein Ri is selected

116. The compound of any one of embodiments 108-115, wherein Rsa is CF3.

117. The compound of any one of embodiments 108-115, wherein Rs_a is C(H)F2.

118. The compound of any one of embodiments 108-115, wherein Rs_a is C(F)H2.

119. The compound of any one of embodiments 108-115, wherein Rs_a is methyl.

120. The compound of any one of embodiments 108-115, wherein Rsa is OMe.

121. The compound of any one of embodiments 108-115, wherein Rs_a is F or Cl.

122. The compound of any one of embodiments 108-121, wherein Rsb is H.

123. The compound of any one of embodiments 108-121, wherein Rsb is CF3.

124. The compound of any one of embodiments 108-121, wherein Rsb is C(H)F2.

125. The compound of any one of embodiments 108-121, wherein Rsb is C(F)H2.

126. The compound of any one of embodiments 108-121, wherein Rsb is methyl.

127. The compound of any one of embodiments 108-121, wherein Rsb is OMe.

128. The compound of any one of embodiments 108-121, wherein Rsb is F or Cl.

129. The compound of any one of embodiments 108-128, wherein Rse is H.

130. The compound of any one of embodiments 108-128, wherein Rsc is CF3.

131. The compound of any one of embodiments 108-128, wherein Rs_c is C(H)F2.

132. The compound of any one of embodiments 108-128, wherein Rsc is C(F)H2.

133. The compound of any one of embodiments 108-128, wherein Rsc is methyl.

134. The compound of any one of embodiments 108-128, wherein Rsc is OMe.

135. The compound of any one of embodiments 108-128, wherein Rsc is F or Cl.

136. The compound of any one of embodiments 108-135, wherein Rsa is H.

137. The compound of any one of embodiments 108-135, wherein Rsa is CF3.

138. The compound of any one of embodiments 108-135, wherein Rsa is C(H)F2.

139. The compound of any one of embodiments 108-135, wherein Rsa is C(F)H2.

140. The compound of any one of embodiments 108-135, wherein Rsa is methyl.

141. The compound of any one of embodiments 108-135, wherein Rsa is OMe.

142. The compound of any one of embodiments 108-135, wherein Rsa is F or Cl.

143. The compound of any one of embodiments 108-142, wherein R$e is CF3.

144. The compound of any one of embodiments 108-142, wherein Rse is C(H)F2.

145. The compound of any one of embodiments 108-142, wherein Rse is C(F)H2.

146. The compound of any one of embodiments 108-142, wherein Rs_e is methyl.

147. The compound of any one of embodiments 108-142, wherein Rs_e is OMe.

148. The compound of any one of embodiments 108-142, wherein Rse is F or Cl.

149. The compound of any one of embodiments 1, and 108-121, wherein at least one of Rsb, Rse, andRsd is H.

150. The compound of any one of embodiments 1, and 108-121, wherein at least two of R₅b, Rse, and Rsa is H.

151. The compound of any one of embodiments 1, and 108-121, wherein Rsb, Rse, and R_5d are H.

152. The compound of any one of embodiments 1, and 108-151, wherein Rj_a is H.

153. The compound of any one of embodiments 1, and 108-151, wherein Rj_a is methyl.

154. The compound of any one of embodiments 1, and 108-151, wherein Rs_a is halide.

155. The compound of any one of embodiments l,and 108-151, wherein Rj_a is CFj.

156. The compound of any one of embodiments 1, and 108-151, wherein Rj_a is

C(H)F₂.

157. The compound of any one of embodiments 1, and 108-151, wherein Rj_a is C(F)H₂.

158. The compound of any one of embodiments 1, and 108-151, wherein Rs_a is OMe.

159. The compound of any one of embodiments 1, and 108-158, wherein Rîb is H.

160. The compound of any one of embodiments 1, and 108-158, wherein Rjb is methyl.

161. The compound of any one of embodiments 1, and 108-158, wherein Rjb is halide.

162. The compound of any one of embodiments 1, and 108-158, wherein Rîb is CF3.

163. The compound of any one of embodiments 1, and 108-158, wherein Rjb is C(H)F₂.

164. The compound of any one of embodiments 1, and 108-158, wherein R₃b is

C(F)H₂.

165. The compound of any one of embodiments 1, and 108-158, wherein R₃b is OMe.

166. The compound of any one of embodiments 1, and 108-158, wherein R₃b is OCF₃.

167. The compound of any one of embodiments 1, and 108-158, wherein R₃b is cyclopropyl.

168. The compound of any one of embodiments 108-151, wherein R_3a is methyl and R₃b is F.

169. The compound of any one of embodiments 108-151, wherein R_3a is F and R₃b is methyl.

170. The compound of embodiment 1, wherein the compound is selected from any one of the compounds of Figure 1, or an enantiomer thereof.

171. The compound of embodiment 1, wherein the compound is a compound of Formula (le) (le) or a pharmaceutically acceptable sait thereof, wherein

Ra, Rb, and Rc are independently selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, halide, CF₃, C(H)F₂, C(F)H₂, substituted or unsubstituted (C1-C4) alkoxy, -OCF3, and substituted or unsubstituted -(Ci-Cs)alkylene-N-(R_x)(R_y); provided that one of Ra, Rb, and Rc is -(Ci-C5)alkylene-N-(R_x)(R_y);

R_x and R_y are independently selected from the group consisting of H, substituted or unsubstituted (Ci-Cô)-alkyl, or substituted or unsubstituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy; or R_x and R_y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered heterocyclyl ring;

R3a and R3b are independently selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, -OH, -CN, halide, CF3, C(H)F₂, C(F)H₂,-(Ci-C4)alkoxy, -OCF3, and substituted or unsubstituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy, provided that R3a and R_3b are not both H;

R3c is selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, halide, CF3, C(H)F₂, C(F)H₂, -(Ci-C4)-alkoxy, -OCF3 -CN, and substituted or unsubstituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy;

R₃d is selected from the group consisting of H, substituted or unsubstituted (Ci-C5)-alkyl, hydroxyl, halide, and -(Ci-C4)-alkoxy;

Rsa, and Rs_e are independently selected from the group consisting of H, CN, halide, CF3, C(H)F₂, C(F)H₂, substituted or unsubstituted (Ci-Cs)-alkyl, hydroxyl, and (Ci-CO-alkoxy; and

R_5b, Rse, and Rsd are independently selected from the group consisting of H, CN, halide, CF3, C(H)F₂, C(F)H₂, substituted or unsubstituted (Ci-Cs)-alkyl, hydroxyl, and (Ci-C4)-alkoxy;

or a pharmaceutically acceptable sait thereof.

172. A compound selected from the group consisting of:

(3S)-3-(2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid;

(3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(3’,4-difluoro-2',5,6'-trimethyl-[ 1,1 ’-biphenyl]-3-yl)propanoic acid;

(3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-3’-methoxy-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)propanoic acid;

(3S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4mcthylpentanamido)propanoic acid;

(3S)-3-(5-chloro-4-fluoro-2',6*-dimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(5-(2-(3methoxyazetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)propanoic acid;

(3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethy)biphenyl-3-yl)propanoic acid;

(3S)-3-(4,4’-difluoro-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(3-(difluoromethyl)-5-(2(dimethylamino)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid;

(3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-5methylhexanamido)-3-(4-fluoro-2',5,6'-trimethyIbiphenyl-3-yl)propanoic acid;

(3S)-3-(4-fluoro-2^,,5,6'-trimethyl-[ 1,1 ’-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)-4-methyIpentanamido)propanoic acid;

(3S)-3-(4-fluoro-2',5,6’-trimethyl-[ 1,1 ’-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((R)-3fluoropyrrolidin-1 -yl)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid; and (3S)-3-(5-chloro-4-fluoro-2’,6'-dimethyl-[ 1,1 ’-biphenyl]-3-yl)-3-(2-(5-(2-(3methoxyazetidin-1 -yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

173. The compound of embodiment 1, wherein the compound is the compound:

or a pharmaceutically acceptable sait thereof.

174. The compound of embodiment 1, wherein the compound is the compound:

or a pharmaceutically acceptable sait thereof.

175. The compound of embodiment 1, wherein the compound is the compound:

or a pharmaceutically acceptable sait thereof.

176. The compound of embodiment 1, wherein the compound is the compound:

or a pharmaceutically acceptable sait thereof.

177. The compound of embodiment 1, wherein the compound is the compound:

or a pharmaceutically acceptable sait thereof.

178. The compound of embodiment 1, wherein the compound is the compound:

or a pharmaceutically acceptable sait thereof.

179. The compound of embodiment 1, wherein the compound is the compound:

or a pharmaceutically acceptable sait thereof.

180. The compound of embodiment 1, wherein the compound is the compound:

CH

or a pharmaceutically acceptable sait thereof.

181. The compound of embodiment 1, wherein the compound is the compound:

or a pharmaceutically acceptable sait thereof.

182. The compound of embodiment 1, wherein the compound is the compound:

or a pharmaceutically acceptable sait thereof.

183. The compound of embodiment 1, wherein the compound is the compound:

or a pharmaceutically acceptable sait thereof.

184. The compound of embodiment 1, wherein the compound is the compound:

or a pharmaceutically acceptable sait thereof.

185. The compound of embodiment 1, wherein the compound is (3S)-3-(4,5-difluoro2^,,6'-dimethylbiphcnyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-l-yl)ethyl)-4-methyl-2oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

186. The compound of embodiment 1, wherein the compound is (3S)-3-(2-(5-(2(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

187. The compound of embodiment 1, wherein the compound is (3S)-3-(2-(5-(2- (azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(3',4-difluoro-2’,5,6’-trimethyl-[ 1,1 '-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

188. The compound of embodiment 1, wherein the compound is (3S)-3-(2-(5-(2- (azetidin-1 -yl)ethyl)-2-oxo-4-(tri fluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[l,r-biphenyl]-3yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

189. The compound of embodiment 1, wherein the compound is (3S)-3-(4,4’-difluoro2',5,6'-trimethyl-[ 1,1 ’-biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

190. The compound of embodiment 1, wherein the compound is (3S)-3-(5-chloro-4fluoro-2’,6'-dimethyl-[l,r-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-l-yl)ethyl)2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

191. The compound of embodiment 1, wherein the compound is (3S)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(4-fluoro-2',4',5,6^,-tetramethylbiphenyl-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

192. The compound of embodiment 1, wherein the compound is (3S)-3-(4,4'-difluoro2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yI)-3-(2-(3-(difluoromethyl)-5-(2(dimethylamino)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

193. The compound of embodiment 1, wherein the compound is (3S)-3-(2-(5-(2(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-5-methylhexanamido)-3-(4fluoro-2^,,5,6'-trimethylbiphenyl-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

194. The compound of embodiment 1, wherein the compound is (3S)-3-(4-fluoro-2',5,6'- trimethyl-[l,r-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

195. The compound of embodiment 1, wherein the compound is (3S)-3-(4-fluoro-2',5,6- trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1 yl)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

196. The compound of embodiment 1, wherein the compound is (3S)-3-(5-chloro-4fluoro-2',6'-dimethyl-[ 1,1 -biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1 -yl)ethyl)2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

197. The compound of embodiment 1, wherein the compound is (S)-3-(4,5-difluoro2',6'-dimethyl-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1 -yl)ethyl)-4methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

198. The compound of embodiment 1, wherein the compound is (S)-3-((S)-2-(5-(2(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[ 1,1 ’-biphenyl]-3yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

199. The compound of embodiment 1, wherein the compound is (S)-3-((S)-2-(5-(2(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yI)-4methylpentanamido)-3-(3',4-difluoro-2’,5,6'-trimethyl-[ 1,1 ’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

200. The compound of embodiment 1, wherein the compound is (S)-3-((S)-2-(5-(2(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

201. The compound of embodiment 1, wherein the compound is (S)-3-(4,4'-difluoro2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

202. The compound of embodiment 1, wherein the compound is (S)-3-(5-chloro-4fluoro-2',6'-dimethyl-[ 1,1 ’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-l yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

203. The compound of embodiment 1, wherein the compound is (S)-3-((S)-2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l, 1 '-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

204. The compound of embodiment 1, wherein the compound is (S)-3-(4,4'-difluoro2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(3-(difluoromcthyl)-5-(2(dimethylamino)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

205. The compound of embodiment 1, wherein the compound is (S)-3-((S)-2-(5-(2(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-5-methylhexanamido)-3-(4fluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

206. The compound of embodiment 1, wherein the compound is (S)-3-(4-fluoro-2',5,6trimethyl-[l,r-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

207. The compound of embodiment 1, wherein the compound is (S)-3-(4-fluoro-2',5,6'trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1 yl)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

208. The compound of embodiment 1, wherein the compound is (S)-3-(5-chloro-4fluoro-2',6'-dimethyl-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1 yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

209. A pharmaceutical composition, comprising a compound of any one of embodiments 1-208; and a pharmaceutically acceptable excipient.

210. A method of inhibiting αφ? integrin in a cell, comprising contacting the cell with a compound of any one of embodiments 1-208 under conditions effective to reduce the adhesion of the cell to MAdCAM-1.

211. A method of reducing the adhesion of a cell comprising an O4p7 integrin to MAdCAM-1, the method comprising contacting the cell with a compound of any one of embodiments 1-208 under conditions effective to reduce the adhesion of the cell to MAdCAM-1.

212. A method of treating inflammatory bowel disease, ulcerative colitis, or Crohn’s disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-208

In some embodiments, compounds of the invention can be a compound of Formula (I):

(I) wherein

R_a, Rb, and Rc are independently selected from the group consisting of H, Me, halide, CF3, C(H)F2, C(F)H2, and -(Ci-C5)aIkylene-N-(R_x)(R_y); provided that at least one of Ra, Rb, and Rc is -(Ci.Cs)alkylene-N-(Rx)(R_y);

Rx and R_y are independently selected from the group consisting of H and substituted or unsubstituted (Ci-Cô)-alkyl; or Rx and R_y taken together with the N to which they are attached form a 4-6 membered ring;

Ri is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl;

Rîa and R₃b are independently selected from the group consisting of halide, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C₃-C6)-cycloalkyl, substituted or unsubstituted (Ci-C4)-alkoxy, CF₃, C(H)F₂, and C(F)H₂;

R_3c, and R₃d are H;

R» is H;

Rsa is methyl;

Rsb is selected from the group consisting of H, CN, halide, CF₃, C(H)F₂, C(F)H₂, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C₃-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (Ci-C4)-alkoxy;

Rsc is methyl;

R_5d is H;

Rse is selected from the group consisting of H, CN, halide, CF₃, C(H)F₂, C(F)H₂, substituted or unsubstituted (C₃-C6)-cycloalkyl, substituted or unsubstituted (Ci-Cs)-alkyl, hydroxyl, and (Ci-CO-alkoxy;

or a pharmaceutically acceptable sait thereof.

In some embodiments, compounds of the invention can be a compound of Formula (la):

wherein

Ra, Rb, and Rc are independently selected from the group consisting of H, Me, halide, CF₃, C(H)F₂, C(F)H₂, and -(Ci-C₅)alkylene-N-(Rx)(Ry); provided that at least one of Ra, Rb, and Rc is -(Ci-Cs)alkylene-N-(R_x)(R_y);

at least one of Ra, Rb, and Rc is -(Ci-C₃)alkylene-N(R_x)(R_y);

R_x and R_y are independently selected from the group consisting of H and methyl; or R_xand R_y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered ring ;

Ri is substituted or unsubstituted (Ci-Cô)-alkyl, substituted or unsubstituted (C1-C4)alkylene-(C₃-C6)-cycloalkyl, or substituted or unsubstituted (Ci-C4)-alkylene- (Ci-C4)-alkoxy;

R_3a, and R₃b are each independently selected from the group consisting of methyl and F, and R_3a is halide;

R_3c, and R₃d are H;

R4 is H, or substituted or unsubstituted (Ci-C4)-alkyl;

Rsa is selected from the group consisting of H, CN, halide, CF₃, C(H)F₂, C(F)H₂, substituted or unsubstituted (C₃-C6)-cycloalkyl, substituted or unsubstituted (Ci-Cs)-alkyl, hydroxyl, and (Ci-C4)-alkoxy; and

Rsb, and Rs_c are independently selected from the group consisting of H, CN, halide, CF₃, C(H)F₂, C(F)H₂, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C₃-C6)cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (C1-C4)alkoxy; and

Rsd is H;

Rje ïs methyl;

or a pharmaceutically acceptable sait thereof.

In some embodiments, compounds of the invention can be a compound of Formula (le)

wherein

Ra, Rb, and Rc arc independently selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, halide, CF₃, C(H)F2, C(F)H₂, substituted or unsubstituted (C1-C4)alkoxy, -OCF3, and substituted or unsubstituted-(Ci-Cs)alkylene-N-(Rx)(R_y); provided that one of Ra, Rb, and Rc is -(Ct-Cs)alkylene-N-(Rx)(R_y);

Rx and R_y are independently selected from the group consisting of H, substituted or unsubstituted (Ci-Cô)-alkyl, or substituted or unsubstituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy; or Rx and R_y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered heterocyclyl ring;

R_3a is halide and R3b is selected from the group consisting of H, substituted or unsubstituted (Ci-CsJ-alkyl, substituted or unsubstituted (C3-Cô)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, -OH, -CN, halide, CF3, C(H)F2, C(F)H2,-(Ci-C4)· alkoxy, -OCF3, and substituted or unsubstituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy;

R_3c is H, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C3-C6)cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, halide, CF3,

C(H)F2, C(F)H₂, -(Ci-C₄)-alkoxy, -OCF3 -CN, and substituted or unsubstituted (Ci-C₄)-aIkylene(Ci-C₄)-alkoxy;

R.3d is selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, hydroxyl, halide, and -(Ci-C₄)-alkoxy;

Rsa, and Rs_c are independently selected from the group consisting of H, CN, halide, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (Ci-Cs)-alkyl, hydroxyl, and (Ci-C₄)-alkoxy; and

Rsb, Rsc, and Rsa are independently selected from the group consisting of H, CN, halide, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (Ci-Cs)-alkyl, hydroxyl, and (Ci-C₄)-alkoxy;

or a pharmaceutically acceptable sait thereof.

In some embodiments, compounds of the invention can be a compound (3S)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(2fluoro-3-methyl-5-((S)-2-methylpiperidin-1 -yl)phenyl)propanoic acid

pharmaceutically acceptable sait thereof.

In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the subject is a mammal. In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the subject is human.

EXAMPLES

The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of

100 certain aspects and embodiments of the présent invention, and are not intended to limit the invention.

Examples 1-4 describe the synthesis of certain compounds presented in Figure 1, including compounds of Formula (la) and Formula (Ib). Compounds in Figure 1 can be prepared as a mixture of diastereomeric compounds (e.g., as disclosed in Examples 1-4) having a (35) configuration (i.e., at the stereocenter beta to the carboxylic acid moiety), and a mixture of diastereomers at the chiral center covalently bound to the pyridone ring nitrogen atom of Formula (I) (e.g., as shown in Formula (Ib)).

In Figure 1, compounds having greater activity in the fluorescence polarization (FP) assay of Example 5 are shown with the stereochemistry of Formula (la). Example 5 describes a fluorescence polarization (FP) assay. Example 6 describes a ligand binding (LB) assay. Example 7 describes a cell adhesion (CA) assay.

Additional Embodiments

In some embodiments, a compound can be selected from one or more of the enumerated embodiments provided below:

1. A compound of Formula (I):

(I) wherein

Ra, Rb, and Rc are independently selected from the group consisting of H, Me, halide, CF₃, C(H)F₂, C(F)H₂, and-(Ci-C5)alkylene-N-(R_x)(R_y); provided that at least one of Ra, Rb, and Rc is -(Ci.Cs)alkylene-N-(Rx)(R_y);

101

Ri is substituted or unsubstituted (Ci-C6)-alkyl, substituted or unsubstituted (C1-C4)alkylene-(C3-C6)-cycloalkyl, or substituted or unsubstituted (Ci-C4)-alkylene- (Ci-C4)-alkoxy;

R_2a and R3b are independently selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, -OH, -CN, halide, CF3, C(H)F₂, C(F)H₂,-(Ci-C4)alkoxy, -OCF3, and substituted or unsubstituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy; provided that R3a and R₃b are not both H;

R3c, and R₃d are H;

R4 is H, or substituted or unsubstituted (Ci-C4)-alkyI;

Rsa, and Rs_c are independently selected from the group consisting of H, CN, halide, CF3, C(H)F₂, C(F)H₂, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted (Ci-C5)-alkyl, hydroxyl, and (Ci-C»)-alkoxy; and

Rsb, Rsc, and Rsd are independently selected from the group consisting of H, CN, halide, CF₃, C(H)F₂, C(F)H₂, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C3C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (CiC4)-alkoxy;

or a pharmaceutically acceptable sait thereof.

2. The compound of embodiment l, wherein Ri is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl.

102

3. The compound of embodiment 2, wherein Ri is iso-butyl.

4. The compound of embodiment 1, wherein Ri is ^v .

5. The compound of embodiment 1, wherein Ri is ^0Me.

6. The compound of any one of embodiments 1-5, wherein R_3a and R₃b are independently selected from the group consisting of halide, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C₃-C6)-cycloalkyl, substituted or unsubstituted (C1-C4)-alkoxy, CF₃, C(H)F₂, and C(F)H₂.

8. The compound of embodiment 7, wherein halide is Cl or F.

9. The compound of embodiment 7 or 8, wherein (Ci-C4)-alkyl is methyl.

12. The compound of any one of embodiments 1-11, wherein R4 is H.

13. The compound of any one of embodiments 1-11, wherein R4 is methyl, ethyl, n-propyl, isopropyl.

14. The compound of any one of embodiments 1-13, wherein Rs_a and Rs_e are independently selected from the group consisting of halide, CF₃, C(H)F₂, C(F)H₂, and substituted or unsubstituted (Ci-C4)-alkyl.

15. The compound of any one of embodiments 1-14, wherein Rsa is halide.

16. The compound of embodiment 15, wherein Rs_a is F or Cl.

17. The compound of any one of embodiments 1-14, wherein Rsa is CF₃.

103

18. The compound of any one of embodiments 1-14, wherein Rsa is C(H)F2.

19. The compound of any one of embodiments 1-14, wherein Rsa is C(F)H2.

20. The compound of any one of embodiments 1-14, wherein Rsa is unsubstituted (Ci-C4)-alkyl.

21. The compound of embodiment 20, wherein Rsa is methyl.

22. The compound of any one of embodiments 1-14, wherein Rsa is substituted (Ci-C5)-alkyl, substituted with at least one halide.

23. The compound of any one of embodiments 1-14, wherein Rs_a is unsubstituted (C1-C4)alkoxy.

24. The compound of embodiment 23, wherein Rsa is OMe.

25. The compound of any one of embodiments 1-24, wherein Rse is halide.

26. The compound of embodiment 25, wherein Rs_e is F or Cl.

27. The compound of any one of embodiments 1-24, wherein Rse is CF3.

28. The compound of any one of embodiments 1-24, wherein Rse is C(H)F2.

29. The compound of any one of embodiments 1-24, wherein Rse is C(F)H2.

30. The compound of any one of embodiments 1-24, wherein Rse is unsubstituted (Ci-CO-alkyl.

31. The compound of embodiment 30, wherein Rse is methyl.

32. The compound of any one of embodiments 1-24, wherein Rse is substituted (Ci-C5)-alkyl, substituted with at least one halide.

33. The compound of any one of embodiments 1-24, wherein Rs_e is unsubstituted (C1-C4)alkoxy.

34. The compound of embodiment 33, wherein Rse is OMe.

104

35. The compound of any one of embodiments 1-34, wherein Rsb, Rse, and Rsa are independently selected from the group consisting of H, halide, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (Ci-Cs)-alkyl, and substituted or unsubstituted (Ci-C4)-alkoxy.

36. The compound of any one of embodiments 1-35, wherein Rsb is H.

37. The compound of any one of embodiments 1-35, wherein Rsb is halide.

38. The compound of embodiment 37, wherein Rsb is Cl or F.

39. The compound of any one of embodiments 1-35, wherein Rsb is CF3.

40. The compound of any one of embodiments 1-35, wherein Rsb is C(H)F2.

41. The compound of any one of embodiments 1-35, wherein Rsb is C(F)H2.

42. The compound of any one of embodiments 1-35, wherein Rsb is unsubstituted (Ci-C4)-alkyl.

43. The compound of embodiment 37, wherein Rsb is methyl.

44. The compound of any one of embodiments 1-35, wherein Rsb is unsubstituted (C1-C4)alkoxy.

45. The compound of embodiment 44, wherein Rsb is OMe.

46. The compound of any one of embodiments 1-35, wherein Rsb is unsubstituted (C3-C6)cycloalkyl.

47. The compound of embodiment 46, wherein Rsb is cyclopropyl.

48. The compound of any one of embodiments 1-47, wherein Rse is H.

49. The compound of any one of embodiments 1-47, wherein Rse is halide.

50. The compound of embodiment 49, wherein Rse is Cl or F.

51. The compound of any one of embodiments 1-47, wherein Rse is CF3.

105

52. The compound of any one of embodiments 1-47, wherein R$c is C(H)F2.

53. The compound of any one of embodiments 1-47, wherein Rsc is C(F)H2.

54. The compound of any one of embodiments 1-47, wherein Rsc is unsubstituted (Ci-C4)-alkyl.

55. The compound of embodiment 54, wherein Rsc is methyl.

56. The compound of any one of embodiments 1-47, wherein Rsc is unsubstituted (C1-C4)alkoxy.

57. The compound of embodiment 56, wherein Rsc is OMe.

58. The compound of any one of embodiments 1-47, wherein Rs_c is unsubstituted (Cî-Cô)cycloalkyl.

59. The compound of embodiment 58, wherein Rsb is cyclopropyl.

60. The compound of any one of embodiments 1-59, wherein Rsa is H.

61. The compound of any one of embodiments 1-59, wherein Rsa is halide.

62. The compound of embodiment 61, wherein Rsa is Cl or F.

63. The compound of any one of embodiments 1-59, wherein Rsa is CF3.

64. The compound of any one of embodiments 1-59, wherein Rsa is C(H)F2.

65. The compound of any one of embodiments 1-59, wherein Rsa is C(F)H2.

66. The compound of any one of embodiments 1-59, wherein Rsa is unsubstituted (Ci-C4)-alkyl.

67. The compound of embodiment 66, wherein Rsa is methyl.

68. The compound of any one of embodiments 1-67, wherein Rsa is unsubstituted (C1-C4)alkoxy.

69. The compound of embodiment 68, wherein Rsa is OMe;

106

70. The compound of any one of embodiments 1-67, wherein Rsa is unsubstituted (C3-C6)cycloalkyl.

71. The compound of embodiment 70, wherein Rsa is cyclopropyl.

73. The compound of any one of embodiments 1-72, wherein Ra is H.

74. The compound of any one of embodiments 1-72, wherein R_a is Me.

75. The compound of any one of embodiments 1-72, wherein Ra is halide.

76. The compound of embodiment 75, wherein Ra is Cl or F.

77. The compound of any one of embodiments 1-72, wherein Ra is CF3.

78. The compound of any one of embodiments 1-72, wherein Ra is C(H)F₂.

79. The compound of any one of embodiments 1-72, wherein Ra is C(F)H₂.

81. The compound of any one of embodiments 1-72, wherein Ra is substituted -(Ci-C3)alkyleneN-(R_x)(Ry), substituted with F or OMe.

82. The compound of any one of embodiments 1-81, wherein Rb is H.

83. The compound of any one of embodiments 1-81, wherein R_b is Me.

84. The compound of any one of embodiments 1-81, wherein Rb is halide.

85. The compound of embodiment 84, wherein Rb is Cl or F.

86. The compound of any one of embodiments 1-81, wherein Rb is CF3.

87. The compound of any one of embodiments 1-81, wherein Rb is C(H)F₂.

107

88. The compound of any one of embodiments 1-81, wherein Rb is C(F)H₂.

90. The compound of any one of embodiments 1-81, wherein Rb is substituted -(Ci-C₃)alkyleneN-(R_x)(Ry), substituted with F or OMe.

91. The compound of any one of embodiments 1-90, wherein Rc is H.

92. The compound of any one of embodiments 1-90, wherein R_c is Me.

93. The compound of any one of embodiments 1-90, wherein Rc is halide.

94. The compound of embodiment 93, wherein Rc is Cl or F.

95. The compound of any one of embodiments 1-90, wherein Rcis CF₃.

96. The compound of any one of embodiments 1-90, wherein Rc is C(H)F₂.

97. The compound of any one of embodiments 1-90, wherein Rc is C(F)H₂.

98. The compound of any one of embodiments 1-90, wherein Rc is unsubstituted -(CiC₃)alkylene-N-(R_x)(Ry).

99. The compound of any one of embodiments 1-90, wherein Rc is substituted -(Ci-C₃)alkyleneN-(Rx)(R_y), substituted with F or OMe.

100. The compound of any one of embodiments 1 -99, wherein R_x is H.

101. The compound of any one of embodiments 1-99, wherein R_x is unsubstituted (Ci-Cô)alkyl.

102. The compound of any one of embodiments 1-100, wherein R_y is H.

103. The compound of any one of embodiments 1-100, wherein R_y is unsubstituted (Ci-Cô)- alkyl.

108

104. The compound of any one of embodiments 1-72, 80-81,89-90, and 98-99, wherein Rx and R_y taken together with the N to which they are attached form a unsubstituted 4-6 membered ring.

105. The compound of any one of embodiments 1-72, 80-81,89-90, and 98-99, wherein Rx and R_y taken together with the N to which they are attached form a substituted 4-6 membered ring, substituted with at least one halide, substituted or unsubstituted (C1-C4) alkyl, or OMe.

106. The compound of embodiment 104 or 105, wherein the 4-6 membered ring is a 3-6 membered heterocycloalkyl.

107. The compound of embodiment 104 or 105, wherein the 4-6 membered ring is a 4-5 membered heterocycloalkyl.

(la) wherein at least one of Ra, Rb, and Rc is -(Ci-C₃)alkylene-N(R_x)(Ry);

R_x and R_y are independently selected from the group consisting of H and methyl; or Rx and R_y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered ring ; and

R_3a, and R₃b are each independently selected from the group consisting of methyl and

F.

109

109. The compound of embodiment 108, wherein Rsa, and Rse are independently unsubstituted (C1-C4) alkyl.

110. The compound of embodiment 108 or 109, wherein Rb is unsubstituted -(Ci-C3)alkyleneN(Rx)(Ry).

112. The compound of embodiment 1 or 108, wherein Rb is selected from the group consisting of F ,and MeO

113. The compound of embodiment 1 or 108, wherein Rb is selected from the group consisting

Ν·ν of । , and ।

114. The compound of embodiment 1 or 108, wherein Rc is H or F.

115. The compound of any one of embodiments 1 and 108-114, wherein Ri is selected from the group consisting of

116. The compound of any one of embodiments 108-115, wherein Rsa is CF3.

117. The compound of any one of embodiments 108-115, wherein Rsa is C(H)F₂.

118. The compound of any one of embodiments 108-115, wherein Rsa is C(F)H₂.

119. The compound of any one of embodiments 108-115, wherein Rsa is methyl.

120. The compound of any one of embodiments 108-115, wherein Rsa is OMe.

121. The compound of any one of embodiments 108-115, wherein R$a is F or Cl.

110

122. The compound of any one of embodiments 108-121, wherein Rsb is H.

123. The compound of any one of embodiments 108-121, wherein Rsb is CF₃.

124. The compound of any one of embodiments 108-121, wherein Rsb is C(H)F₂.

125. The compound of any one of embodiments 108-121, wherein Rsb is C(F)H₂.

126. The compound of any one of embodiments 108-121, wherein Rsb is methyl.

127. The compound of any one of embodiments 108-121, wherein Rsb is OMe.

128. The compound of any one of embodiments 108-121, wherein Rsb is F or Cl.

129. The compound of any one of embodiments 108-128, wherein Rs_c is H.

130. The compound of any one of embodiments 108-128, wherein Rsc is CF₃.

131. The compound of any one of embodiments 108-128, wherein Rsc is C(H)F₂.

132. The compound of any one of embodiments 108-128, wherein Rsc is C(F)H₂.

133. The compound of any one of embodiments 108-128, wherein Rs_c is methyl.

134. The compound of any one of embodiments 108-128, wherein Rsc is OMe.

135. The compound of any one of embodiments 108-128, wherein Rsc is F or Cl.

136. The compound of any one of embodiments 108-135, wherein Rsa is H.

137. The compound of any one of embodiments 108-135, wherein Rsa is CF₃.

138. The compound of any one of embodiments 108-135, wherein Rsa is C(H)F₂.

139. The compound of any one of embodiments 108-135, wherein Rsa is C(F)H₂.

140. The compound of any one of embodiments 108-135, wherein Rsa is methyl.

141. The compound of any one of embodiments 108-135, wherein Rsa is OMe.

111

142. The compound of any one of embodiments 108-135, wherein Rsa is F or Cl.

143. The compound of any one of embodiments 108-142, wherein Rs_e is CF3.

144. The compound of any one of embodiments 108-142, wherein Rse is C(H)F2.

145. The compound of any one of embodiments 108-142, wherein Rse is C(F)H2.

146. The compound of any one of embodiments 108-142, wherein Rs_e is methyl.

147. The compound of any one of embodiments 108-142, wherein Rs_e is OMe.

148. The compound of any one of embodiments 108-142, wherein Rsc is F or Cl.

149. The compound of any one of embodiments 1, and 108-121, wherein at least one of Rsb, Rsc, and Rsa is H.

150. The compound of any one of embodiments 1, and 108-121, wherein at least two of Rsb, Rsc, and Rsa is H.

151. The compound of any one of embodiments 1, and 108-121, wherein Rsb, Rsc, and Rsa are H.

152. The compound of any one of embodiments 1, and 108-151, wherein R_3a is H.

153. The compound of any one of embodiments 1, and 108-151, wherein R_3a is methyl.

154. The compound of any one of embodiments 1, and 108-151, wherein R_3a is halide.

155. The compound of any one of embodiments 1, and 108-151, wherein R_3a is CF3.

156. The compound of any one of embodiments 1, and 108-151, wherein R_3a is C(H)F2.

157. The compound of any one of embodiments 1, and 108-151, wherein R_3a is C(F)H2.

158. The compound of any one of embodiments 1, and 108-151, wherein R_3a is OMe.

159. The compound of any one of embodiments 1, and 108-158, wherein Rjb is H.

112

160. The compound of any one of embodiments 1, and 108-158, wherein R₃b is methyl.

161. The compound of any one of embodiments l,and 108-158, wherein R₃bis halide.

162. The compound of any one of embodiments 1, and 108-158, wherein R₃b is CF₃.

163. The compound of any one of embodiments 1, and 108-158, wherein R₃b is C(H)F2.

164. The compound of any one of embodiments 1, and 108-158, wherein R₃b is C(F)H2.

171. The compound of embodiment 1, wherein the compound is a compound of Formula (le)

or a pharmaceutically acceptable sait thereof, wherein

Ra, Rb, and Rc are independently selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, halide, CF₃, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C4)

113 alkoxy, -OCF3, and substituted or unsubstituted -(Ci-C5)alkylene-N-(R_x)(R_y); provided that one of Ra, Rb, and Rc is -(Ci-C5)alkylene-N-(R_x)(R_y);

R_x and R_y are independentiy selected from the group consisting of H, substituted or unsubstituted (Ci-C6)-alkyl, or substituted or unsubstituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy; or R_x and R_y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered heterocyclyl ring;

R_3a and Rab are independentiy selected from the group consisting of H, substituted or unsubstituted (Ci-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, -OH, -CN, halide, CF3, C(H)F2, C(F)H2,-(Ci-C4)alkoxy, -OCF3, and substituted or unsubstituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy; provided that R3a and R3b are not both H;

R3c is selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, halide, CF3, C(H)F2, C(F)H2, -(Ci-C4)-alkoxy, -OCF3 -CN, and substituted or unsubstituted (Ci-C4)-aIkylene-(Ci-C4)-alkoxy;

R₃d is selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, hydroxyl, halide, and -(Ci-C4)-alkoxy;

R_5a, and Rie are independentiy selected from the group consisting of H, CN, halide, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (Ci-Cs)-alkyl, hydroxyl, and (C1-C4)-alkoxy; and

Rsb, Rse, and Rsd are independentiy selected from the group consisting of H, CN, halide, CF₃, C(H)F₂, C(F)H₂, substituted or unsubstituted (Ci-Cs)-alkyl, hydroxyl, and (Ci-C₄)-alkoxy;

or a pharmaceutically acceptable sait thereof.

172. A compound selected from the group consisting of:

(3S)-3-(4,5-difluoro-2’,6'-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-lyl)ethyl)-4-methyl-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid;

114 (3S)-3-(2-(5-(2-(azetidin- l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(4-fluoro-2’,6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid;

(3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(3',4-difluoro-2’,5,6'-trimethyl-[ 1,1 ’-biphenyl]-3-yl)propanoic acid;

(3S)-3-(2-(5-(2-(azetidin- l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(4-fluoro-3'-methoxy-2’,5,6’-trimethyl-[ 1,1 '-biphenyl]-3-yI)propanoic acid;

(3S)-3-(4,4^,-difluoro-2',5,6’-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid ;

(3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[l,r-biphenyl]-3-yl)-3-(2-(5-(2-(3methoxyazetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)propanoic acid;

(3S)-3-(4,4’-difluoro-2^,,5,6^,-trimethyl-[l,l'-biphenyl]-3-yl)-3-(2-(3-(difluoromethyl)-5-(2(dimethylamino)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid;

(3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-5methylhexanamido)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propanoic acid;

(3S)-3-(4-fluoro-2’,5,6'-trimethyl-[l,r-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3fluoroazetidin-1 -yl)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid;

(3S)-3-(4-fluoro-2',5,6’-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((R)-3fluoropyrrolidin-1 -yl)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid; and (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[l,r-biphenyl]-3-yl)-3-(2-(5-(2-(3methoxyazetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l (2H)-yl)-4methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

115

173. The compound of embodiment 1, wherein the compound is the compound:

or a pharmaceutically acceptable sait thereof.

174. The compound of embodiment 1, wherein the compound is the compound:

or a pharmaceutically acceptable sait thereof.

175. The compound of embodiment 1, wherein the compound is the compound:

or a pharmaceutically acceptable sait thereof.

116

176. The compound of embodiment 1, wherein the compound is the compound:

or a pharmaceutically acceptable sait thereof.

177. The compound of embodiment 1, wherein the compound is the compound:

or a pharmaceutically acceptable sait thereof.

178. The compound of embodiment 1, wherein the compound is the compound:

117

or a pharmaceutically acceptable sait thereof.

179. The compound of embodiment 1, wherein the compound is the compound:

or a pharmaceutically acceptable sait thereof.

180. The compound of embodiment 1, wherein the compound is the compound:

CM

or a pharmaceutically acceptable sait thereof.

118

181. The compound of embodiment 1, wherein the compound is the compound:

or a pharmaceutically acceptable sait thereof.

182. The compound of embodiment 1, wherein the compound is the compound:

or a pharmaceutically acceptable sait thereof.

183. The compound of embodiment 1, wherein the compound is the compound:

119 or a pharmaceutically acceptable sait thereof.

184. The compound of embodiment 1, wherein the compound is the compound:

or a pharmaceutically acceptable sait thereof.

185. The compound of embodiment 1, wherein the compound is (3S)-3-(4,5-difluoro-2',6*dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-l-yl)ethyl)-4-methyl-2-oxopyridinl(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

186. The compound of embodiment 1, wherein the compound is (3S)-3-(2-(5-(2-(azetidin-lyl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

187. The compound of embodiment 1, wherein the compound is (3S)-3-(2-(5-(2-(azetidin-lyl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(3^,,4-difiuoro2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

188. The compound of embodiment 1, wherein the compound is (3S)-3-(2-(5-(2-(azetidin-lyl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-3'methoxy-2',5,6’-trimethyl-[l,l'-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

120

189. The compound of embodiment 1, wherein the compound is (3S)-3-(4,4’-difluoro-2’,5,6’trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

190. The compound of embodiment 1, wherein the compound is (3S)-3-(5-chloro-4-fluoro-2',6dimethyl-[ 1,1 ’-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1 -yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

191. The compound of embodiment 1, wherein the compound is (3S)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

192. The compound of embodiment 1, wherein the compound is (3S)-3-(4,4’-difluoro-2’,5,6'trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

193. The compound of embodiment 1, wherein the compound is (3S)-3-(2-(5-(2- (dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-5-methylhexanamido)-3-(4-fluoro2^,,5,6'-trimethylbiphenyl-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

194. The compound of embodiment 1, wherein the compound is (3S)-3-(4-fluoro-2',5,6'trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3-fiuoroazetidin-1 -yl)ethyl)-2oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

195. The compound of embodiment 1, wherein the compound is (3S)-3-(4-fluoro-2',5,6trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-l -yl)ethyl)-2oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

196. The compound of embodiment 1, wherein the compound is (3S)-3-(5-chloro-4-fluoro-2',6'- dimethyl-[ 1,1 ’-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1 -yl)ethyl)-2-oxo-4121 (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

197. The compound of embodiment 1, wherein the compound is (S)-3-(4,5-difluoro-2',6'dimethyl-[l,l’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-l-yl)ethyl)-4-methyl-2oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

198. The compound of embodiment 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azetidin-lyl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro2',6’-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

199. The compound of embodiment 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azetidin-lyl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(3',4-difluoro2',5,6'-trimethyl-[l,T-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

200. The compound of embodiment 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azetidin-lyl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-3'methoxy-2',5,6'-trimethyl-[l,T-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

201. The compound of embodiment 1, wherein the compound is (S)-3-(4,4'-difluoro-2',5,6'trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

202. The compound of embodiment 1, wherein the compound is (S)-3-(5-chloro-4-fluoro-2',6dimethyl-[ 1,1 ’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1 -yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

203. The compound of embodiment 1, wherein the compound is (S)-3-((S)-2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3

122 (4-fluoro-2',4',5,6’-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

204. The compound of embodiment 1, wherein the compound is (S)-3-(4,4'-difluoro-2',5,6'trimethyl-[ 1,1 ’-biphenyl]-3-yl)-3-((S)-2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

205. The compound of embodiment 1, wherein the compound is (S)-3-((S)-2-(5-(2(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-5-methylhexanamido)-3-(4-fluoro2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

206. The compound of embodiment 1, wherein the compound is (S)-3-(4-fluoro-2',5,6'trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3-fluoroazetidin-1 -yl)ethyl)-2oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

207. The compound of embodiment 1, wherein the compound is (S)-3-(4-fluoro-2',5,6'trimethyl-[l,r-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-2oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

208. The compound of embodiment 1, wherein the compound is (S)-3-(5-chloro-4-fluoro-2’,6'- dimethyl-[l,r-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

209. A pharmaceutical composition, comprising a compound of any one of embodiments 1-

208; and a pharmaceutically acceptable excipient.

210. A method of inhibiting αφγ integrin in a cell, comprising contacting the cell with a compound of any one of embodiments 1-208 under conditions effective to reduce the adhesion of the cell to MAdCAM-1.

123

211. A method of reducing the adhesion of a cell comprising an cuP? integrin to MAdCAM-1, the method comprising contacting the cell with a compound of any one of embodiments 1 208 under conditions effective to reduce the adhesion of the cell to MAdCAM-1.

212. A method of treating inflammatory bowel disease, ulcerative colitis, or Crohn’s disease, 5 comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-208

In some embodiments, the following compound of Formula (I):

wherein

Ra, Rb, and Rc are independently selected from the group consisting of H, Me, halide, CFj, C(H)F₂, C(F)H₂, and -(Ci.C5)alkylene-N-(Rx)(Ry); provided that at least one of Ra, Rb, and Rc is -(Ci-Cs)alkylene-N-(Rx)(Ry);

Rx and R_y are independently selected from the group consisting of H and substituted or 15 unsubstituted (Ci-C₆)-alkyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered ring;

124

Rja and Rjb are independently selected from the group consisting of H, (Ci-Cs)-alkyl, (C₃-Cô)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, -OH, -CN, halide, CF₃, C(H)F₂, C(F)H₂.-(Ci-C4)-alkoxy, -OCF₃, and substituted or unsubstituted (C1-C4)alkylene-(Ci-C4)-alkoxy; provided that R_3a and R₃b are not both H;

R_3c, and R₃₍j are H;

Rds H;

Rs_a, and R$e are independently methyl;

Rsb, and Rse are independently selected from the group consisting of H, CN, halide, CF₃, C(H)F₂, C(F)H₂, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C₃-Cô)cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (C1-C4)alkoxy;

Rsd is H; and wherein the compound of Formula (I) is selected from the group consisting of:

a. (S)-3-(4,5-difluoro-2',6'-dimethyl-[l,l'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-lyl)ethyl)-4-methyl-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid;

b. (S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-2^,,6'-dimethyl-5-(trifluoromethyl)-[ 1,1 '-biphenyl]-3yl)propanoic acid;

c. (S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(3',4-difluoro-2',5,6’-trimethyl-[ 1,1 ’-biphenyl]-3-yl)propanoic acid;

d. (S)-3-((S)-2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)propanoic acid;

e. (S)-3-(4,4^,-difluoro-2',5,6^,-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid;

125

f. (S)-3-(5-chloro-4-fluoro-2',6’-dimethyl-[ 1,1 ’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3methoxyazetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)propanoic acid;

g. (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-2^,,4',5,6'-tetramethyl-[ 1,1 '-biphenyl]-3-yl)propanoic acid;

h. (S)-3-(4,4^,-difluoro-2’,5,6’-trimethyl-[ 1,1 *-biphenyl]-3-yi)-3-((S)-2-(3-(difluoromethyl)-5-(2(dimethylamino)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid;

i. (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1 (2H)-yl)-5methylhexanamido)-3-(4-fluoro-2’,5,6’-trimethyl-[ 1,1 ’-biphenyl]-3-yl)propanoic acid;

j. (S)-3-(4-fluoro-2',5,6’-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3fluoroazetidin-1 -yl)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid; and

k. (S)-3-(4-fluoro-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-((R)-3fluoropyrrolidin-1 -yl)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid;

or a pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is (S)-3-(4,5-difluoro-2',6'-dimethyl-[l,rbiphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is (S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',6’-dimethyl-5(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is (S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(3’,4-difluoro-2',5,6*trimethyl-[l,l’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is (S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2oxO'4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-3'-methoxy-2',5,6'trimethyl-[l,l’-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

126

In some embodiments, wherein the compound is (S)-3-(4,4’-difluoro-2',5,6^,-trimethyI-[l,rbiphenyl]-3-yl)-3 -((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is (S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[l,rbiphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)-4-methylpentanamido)-3-(4-fluoro-2^,,4',5,6'tetramethyl-[I,r-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is (S)-3-(4,4'-difluoro-2',5,6’-trimethyl-[l,l’biphenyl]-3-yl)-3-((S)-2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-l(2H)yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4methyl-2-oxopyridin-1 (2H)-yl)-5-methyIhexanamido)-3-(4-fluoro-2^,,5,6^,-trimethyl-[ 1,1'biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is (S)-3-(4-fluoro-2',5,6'-trimethyl-[l,rbiphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3-fluoroazetidin-1 -yl)ethyl)-2-oxopyridin-1 (2H)-yl)-4methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is (S)-3-(4-fluoro-2',5,6'-trimethyl-[l,rbiphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxopyridin-l(2H)yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) as the active pharmaceutical ingrédient:

127 (I) wherein

Ra, Rb, and Rc are independently selected from the group consisting of H, Me, halide, CF₃, C(H)F2, C(F)H2, and -(Ci.C5)alkylene-N-(R_x)(R_y); provided that at least one of Ra, Rb, and Rc is -(Ci.C5)alkylene-N-(R_x)(R_y);

R_x and R_y are independently selected from the group consisting of H and substituted or unsubstituted (Ci-Cô)-alkyl; or Rx and R_y taken together with the N to which they are attached form a 4-6 membered ring;

R₂ is ^R5d ;

R_3a and R₃b are independently selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C₃-C₆)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, -OH, -CN, halide, CF₃, C(H)F2, C(F)H2.-(Ci-C₄)alkoxy, -OCF₃, and substituted or unsubstituted (Ci-C₄)-alkylene-(Ci-C₄)-alkoxy; provided that R_3a and R₃b are not both H;

R_3c, and R₃d are H;

R« is H;

Rsa, and Rs_e are independently methyl;

R_5b, and R_5c are independently selected from the group consisting of H, CN, halide, CF₃, C(H)F2, C(F)H2, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C₃-Cô)cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (Ci-C₄)alkoxy;

128

Rsa is H; and wherein the compound of Formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is

129

, or a pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is

, or a pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is

, or a pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is

pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is

130

, or a pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is

pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is

pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is

sait thereof.

In some embodiments, wherein the compound is

131

or a pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is

pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is

pharmaceutically acceptable sait thereof.

In some embodiments, a compound of Formula (la):

132 wherein:

Ra, isCF₃;

Rb is substituted or unsubstituted -(Ci-Cs)alkylene-N-(Rx)(Ry);

R_x and Ry are independently substituted or unsubstituted (Ci-Cô)-alkyl; or R_x and Ry taken together with the N to which they are attached form a 4-6 membered ring;

Rcis H;

Ri is substituted or unsubstituted (Ci-Cô)-alkyl;

R_3a and R₃b are independently selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C₃-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, -OH, -CN, halide, CF₃, C(H)F2, C(F)H2,-(Ci-C4)-alkoxy, -OCF₃, and substituted or unsubstituted (C1-C4)alkylene-(Ci-C4)-alkoxy; provided that R_3a and R₃b are not both H;

R_3c is H;

R₃a is halide;

R4 is H;

Rs_a, and R$_e are each independently selected from (Ci-Cs)-alkyl; and

R_5b, Rsc, and Rsa are independently selected from the group consisting of H, CN, halide, CF₃, C(H)F2, C(F)H2, -CH2CF₃. substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C₃-Cô)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (Ci-C4)-alkoxy;

wherein the compound of Formula (I) is selected from the group consisting of:

133

134

135

136

In some embodiments, wherein the compound is

137

, or a pharmaceutically acceptable sait thereof.

In some embodiments,, wherein the compound is

, or a pharmaceutically acceptable sait thereof.

In some embodiments,, wherein the compound is

138

, or a pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is

139

thereof.

In some embodiments, wherein the compound is

140

The compound of claim 25, wherein the compound is

pharmaceutically acceptable sait thereof.

The compound of claim 25, wherein the compound is

141

, or a pharmaceutically acceptable sait thereof.

In some embodiments, wherein the compound is

142

F

F , or a pharmaceutically acceptable sait thereof.

In some embodiments, a pharmaceutical composition comprising a compound of the présent application or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient. In some embodiments, the the invention relates to a compound of Formula (I), Formula 5 (la), or Formula (Ib):

143

(Ib) or a pharmaceutically acceptable sait thereof;

wherein

Ra, Rb, and Rc are independently selected from the group consisting of H, Me, halide, CF₃, C(H)F₂, C(F)H₂, -CN, - OCF3, substituted or unsubstituted (Ci-C₅)-alkyl, (Ci-C₅)-alkoxy, CH₂CF3,and substituted or unsubstituted -(Ci-C₅)alkylene-N-(R_x)(R_y); provided that at least one of Ra, Rb, and Rc is -(Ci-C5)alkylene-N-(R_x)(R_y), wherein the substituted (Ci-Cs)-alkyl is substituted with halide, amino, or (CiC4)-alkylamino; and the substituted -(Ci-C₅)alkylene-N-(R_x)(R_y) is substituted with halide or (Ci-Ci)-alkoxy;

R_x and R_y are independently selected from the group consisting of H and (Ci-Cô)-alkyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered ring;

Ri is (Ci-Cô)-alkyl, (Ci-C4)-alkylene-(C3-C6)-cycloalkyl, or (Ci-C4)-alkylene-(Ci-C4)alkoxy;

144

Rj_a and Rjb are independently selected from the group consisting of H, (Ci-Cs^alkyl, (Cj-C6)-cycloalkyl, 3-6 membered heterocycloalkyl, -OH, -CN, halide, CF3, C(H)F₂, C(F)H₂,(Ci-C4)-alkoxy, -OCF3, and (Ci-C4)-alkylene-(Ci-C4)-alkoxy; provided that Rsa and Rjb are not both H;

R_3c is selected from the group consisting of H, (Ci-Cs)-alkyl, (C3-C6)-cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyl, halide, CF3, C(H)F₂, C(F)H₂, -(Ci-C4)-alkoxy, -OCF3 CN, and (Ci-C4)-alkylene-(Ci-C4)-alkoxy;

R₃d is selected from the group consisting of H, (Ci-Cs)-alkyl, hydroxyl, halide, and -(CiCi)-alkoxy;

R4 is H, or (Ci-C4)-alkyl;

Rsa, and Rse are independently selected from the group consisting of H, CN, halide, CF3, C(H)F₂, C(F)H₂, -CH₂CF3.(C3-C₆)-cycloalkyl, (Ci-Cs)-alkyl, 3-6 membered heterocycloalkyl hydroxyl, and (Ci-Ci)-alkoxy; and

Rsb, Rse and Rsdare independently selected from the group consisting of H, CN, halide, CF₃, C(H)F₂, C(F)H₂, -CH₂CF₃.(Ci-C5)-alkyl, (C3-C₆)-cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyl, and (Ci-CO-alkoxy.

In one embodiment of the above Formula (Ib), the compound is not a compound recited in Figure 1.

In one embodiment of the above Formula (Ib), the compound is a compound recited in Figure 2 and/or 3.

In some embodiments, the the invention relates to a compound of Formula (I), Formula (la), or Formula (Ib):

145

(I)

(Ib) or a pharmaceutically acceptable sait thereof;

wherein

146

Ra, Rb, and Rc are independently selected from the group consisting of H, Me, halide, CF₃, C(H)F₂, C(F)H₂, -CN, - OCF₃, substituted or unsubstituted (Ci-Cs)-alkyl, (Ci-Cs)-alkoxy, CH₂CF₃,and substituted or unsubstituted -(Ci-C5)alkylene-N-(R_x)(R_y); provided that at least one of Ra, Rb, and Rc is -(Ci-C5)alkylene-N-(Rx)(R_y), wherein the substituted (Ci-Cs)-alkyl is substituted with halide, amino, or (CiC4)-alkylamino; and the substituted -(Ci-C5)alkylene-N-(R_x)(R_y) is substituted with halide, (Ci-Cs)-alkyl, (Ci-C₅)-alkyl-OCH₃, (Ci-C4)-haloalkyl, (C₃-C₆)-cycloalkyl,(CiC4)-alkoxy, or heterocyclyl;

Rx and R_y are independently selected from the group consisting of H and (Ci-C6)-alkyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered ring;

Ri is substituted or unsubstituted (Ci-Cô)-alkyl, (Ci-C4)-alkylene-(C₃-C6)-cycloalkyl, or (C i -CO-alkylene-(C i -C4)-alkoxy, wherein the substituted (Ci-C6)-alkyl is substituted with halide or (C₃-C6)-cycloalkyl;

R_3a and R₃b are independently selected from the group consisting (Ci-Cs)-alkyl, (C₃-C6)cycloalkyl, 3-6 membered heterocycloalkyl, -OH, -CN, halide, CF₃, C(H)F₂, C(F)H₂,-(Ci-C4)alkoxy, -OCF₃, and (Ci-C4)-alkylene-(Ci-C4)-alkoxy; provided that R_3a and R₃b are not both H;

R_3c is selected from the group consisting of H, (Ci-Cs)-alkyl, (C₃-C6)-cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyl, halide, CF₃, C(H)F₂, C(F)H₂, -(Ci-Ci)-alkoxy, -OCF₃ CN, and substituted or unsubstituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy;

R₃d is selected from the group consisting of H, (Ci-Cs)-alkyl, hydroxyl, halide, and -(CiC4)-alkoxy;

R4 is H, or (Ci-CO-alkyl;

147

R_5a, and Rs_e are independently selected from the group consisting of H, CN, halide, CF₃, C(H)Fi, C(F)H₂, -CH2CF₃.(C₃-C6)-cycloalkyl (Ci-Cs)-alkyl, 3-6 membered heterocycloalkyl hydroxyl, and (Ci-CO-alkoxy; and

R_5b) Rsc, andRsaare independently selected from the group consisting of H, CN, halide, CF₃, C(H)F₂, C(F)H₂, -CH2CF₃.(Ci-C₅)-alkyl, (C₃-C₆)-cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyl, and (Ci-C4)-alkoxy.

In one embodiment of the above Formula (Ib), the compound is not a compound recited in Figure l.

In some embodiments, a compound of Formula (I) can be a compound of Formula (Ib), (Ib), wherein

Ra is selected from the group consisting of hydrogen, and (Ci-Cs)-alkyl optionally substituted with halide;

Rb is-(Ci.C5)alkylene-N-(Rx)(Ry);

Rx and R_y are independently selected from the group consisting of (Ci-Cô)-alkyl; or R_xand R_y taken together with the N to which they are attached form a 4-6 membered ring optionally substituted with halide or (Ci-C4)-alkoxy;

Rc are is selected from the group consisting of hydrogen and (Ci-Cs)-alkyl optionally substituted with halide;

Ri is (Ci-Cô)-alkyl;

148

R_3a is halide;

Rîb is selected from the group consisting of (Ci-Cs)-alkyl optionally substituted with halide, and (C₃-C6)-cycIoalkyl;

R_3c is hydrogen;

R₃d is selected from the group consisting of H and halide;

R4 is hydrogen;

Rsa, and Rse are each (Ci-Cs)-alkyl; and

Rsb, Rsc, and Rsa are independently selected from the group consisting of H, CN, halide, (Ci-Csj-alkyl optionally substituted with halide (e.g., CF₃, C(H)F2, C(F)H2, -CH2CF₃), (C₃-C6)cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyl, and (Ci-C4)-alkoxy.

In some embodiments, a compound of Formula (I) can be a compound of Formula (la),

wherein

Ra is selected from the group consisting of hydrogen, and methyl optionally substituted with halide;

Rb is -(Ci-C5)alkyIene-N-(R_x)(Ry);

Rx and R_y are independently selected from the group consisting of methyl and ethyl; or R_x and R_y taken together with the N to which they are attached form a 4-5 membered ring optionally substituted with F or methoxy;

Rc are is selected from the group consisting of hydrogen and methyl optionally substituted with halide;

149

Ri is selected from the group consisting of isobutyl and isopentyl;

Rîa is F;

Rîb is selected from the group consisting of (Ci-Cs)-alkyl optionally substituted with F, and (C₃-C6)-cycloalkyl;

R_3c is hydrogen;

R₃d is selected from the group consisting of H and F;

R4 is hydrogen;

Rsa, and Rs_e are each methyl;

Rsb and Rsd are independently selected from the group consisting of H, F, methyl and methoxy; and

Rsc is selected from the group consisting of F, methyl and cyclopropyl.

(la) wherein

Rb is -(C|.C5)alkylene-N-(R_x)(Ry);

R_x and R_y are methyl; or R_x and R_y taken together with the N to which they are attached form a 4-5 membered ring optionally substituted with F or methoxy;

150

Ri is selected from the group consisting of isobutyl and isopentyl;

Rîa is F;

R₃b is selected from the group consisting of (Ci-Cs)-alkyl optionally substituted with F, and (C3-C6)-cycloalkyl;

R3_C is hydrogen;

R3d is F;

Ri is hydrogen;

Rsa, and Rs_e are each methyl;

R_Sb and Rsd are independently selected from the group consisting of H, F, methyl and methoxy; and

Rsc is selected from the group consisting of F, methyl and cyclopropyl.

(la) or a pharmaceutically acceptable sait thereof, wherein Ra, Rb, Rc, Ri, R3a, R₃b, R3c, Rîd, Rsa, Rsb, R_5c, Rsd, Rse, and R» in Formula (la) are each independently defined as above with respect to Formula (I), and provided that the compound of Formula (la) is not a compound selected from the group consisting of:

151

152

In some embodiments, a compound of Formula (I) can be a compound of Formula (Ib):

153 (Π>) or a pharmaceutically acceptable sait thereof, wherein Ra, Rb, Rc, Ri, R3a, Rsb, Rîc, R3d, Rsa, Rsb, R_5c, Rsd, Rse, and R4 in Formula (la) are each independentiy defined as above with respect to Formula (I), and provided that the compound of Formula (la) is not a compound selected from the group consisting of:

154

In some embodiments, a compound can be a compound of Formula (I)

(I) wherein

155

Ra, Rb, and Rc are independently selected from the group consisting of H, Me, halide, CF₃, C(H)F2, C(F)H2, and -(Ci-C5)alkylene-N-(Rx)(R_y); provided that at least one of Ra, Rb, and Rc is -(Ci.Cs)alkylene-N-(Rx)(R_y);

Rx and R_y are independently selected from the group consisting of H and substituted or unsubstituted (Ci-C6)-alkyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered ring;

r₂ is Rsd ;

R_3a and R₃b are independently selected from the group consisting of H, (Ci-Cs)-alkyl, (C₃-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, -OH, -CN, halide, CF₃, C(H)F2, C(F)H₂.-(C|-C4)-alkoxy, -OCF₃, and substituted or unsubstituted (Ci-C₄)alkylene-(Ci-C4)-alkoxy; provided that R_3a and R₃b are not both H;

R_3c, and R₃d are H;

R4 is H;

Rsa, and Rs_e are independently methyl;

Rsb, and Rsc are independently selected from the group consisting of H, CN, halide, CF₃, C(H)F2, C(F)H2, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C₃-Cô)cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (C1-C4)alkoxy,

Rsd is H; and provided the compound of Formula (I) is not a compound selected from the group consisting of:

156

a. (S)-3-(4,5-difluoro-2',6'-dimethyl-[ 1,1 ’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1yl)ethyl)-4-methyl-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid;

b. (S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-2’,6'-dimethyl-5-(trifluoromethyl)-[ 1,1 ’-biphenyl]-3yl)propanoic acid;

c. (S)-3-((S)-2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[ 1,1 ’-biphenyl]-3-yl)propanoic acid;

d. (S)-3-((S)-2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(4-fluoro-3'-methoxy-2',5,6’-trimethyl-[ 1,1 '-biphenyl]-3-yl)propanoic acid;

e. (S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid;

f. (S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[ 1,1 ’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3methoxyazetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)propanoic acid;

g. (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-2’,4',5,6'-tetramethyl-[ 1,1 '-biphenyl]-3-yl)propanoic acid;

h. (S)-3-(4,4'-difluoro-2’,5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(3-(difluoromethyl)-5-(2(dimethylamino)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid;

i. (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1 (2H)-yl)-5methylhexanamido)-3-(4-fluoro-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)propanoic acid;

j. (S)-3-(4-fluoro-2',5,6'-trimethyl-[l, 1 '-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3fluoroazetidin-1 -yl)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid; and

k. (S)-3-(4-fluoro-2',5,6’-trimethyl-[l,r-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-((R)-3fluoropyrrolidin- l-yl)ethyl)-2-oxopyridin-l (2H)-yl)-4-methylpentanamido)propanoic acid;

or a pharmaceutically acceptable sait thereof.

In some embodiments, a compound can be a compound of Formula (la)

157 (la), wherein:

Ra, is CF₃;

Rb is substituted or unsubstituted -(Ci-C5)alkylene-N-(R_x)(R_y);

R_x and R_y are independently substituted or unsubstituted (Ci-Cô)-alkyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered ring;

Rc is H;

Ri is substituted or unsubstituted (Ci-C6)-alkyl;

R_3a and R₃b are independently selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C₃-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, -OH, -CN, halide, CF₃, C(H)F2, C(F)H2.-(Ci-C4)-alkoxy, -OCF₃, and substituted or unsubstituted (C1-C4)alkylene-(Ci-C₄)-alkoxy; provided that R_3a and R₃b are not both H;

R_3c is H;

R₃d is halide;

R4 is H;

Rsa, and Rs_e are each independently selected from (Ci-Cs)-alkyl; and

Rsb, Rsc, and Rsd are independently selected from the group consisting of H, CN, halide, CF₃, C(H)F2, C(F)H2, -CH2CF₃, substituted or unsubstituted (Ci-Cs)-alkyl,

158 substituted or unsubstituted (C₃-C₆)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (Ci-C4)-alkoxy;

or a pharmaceutically acceptable sait thereof;

provided the compound of Formula (la) is not selected from the group consisting of:

159

In some embodiments, a compound can be a compound of Formula (Ib)

wherein:

Ra, isCFj;

Rb is substituted or unsubstituted -(Ci-C5)alkylene-N-(Rx)(R_y);

Rx and R_y are independently substituted or unsubstituted (Ci-Cô)-alkyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered ring;

RcisH;

Ri is substituted or unsubstituted (Ci-Cô)-alkyl;

Rja and R₃b are independently selected from the group consisting of H, substituted or unsubstituted (Ci-C5)-alkyl, substituted or unsubstituted (C₃-Cô)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, -OH, -CN, halide, CF3, C(H)F2, C(F)H2.-(Ci-C4)-alkoxy, -OCF3, and substituted or unsubstituted (C1-C4)15 alkylene-(Ci-C4)-alkoxy; provided that R3a and R3b are not both H;

R3c is H;

R3d is halide;

R4 is H;

R_5a, and Rs_e are each independently selected from (Ci-Cs)-alkyl; and

160

R_5b, Rse, and Rsd are independentiy selected from the group consisting of H, CN, halide, CF₃, C(H)F₂, C(F)H₂, -CH₂CF₃, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C₃-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (Ci-C4)-alkoxy;

or a pharmaceutically acceptable sait thereof;

provided the compound of Formula (Ib) is not selected from the group consisting of:

161

Example 1. General Schemes for the synthesis of α4β7 inhibitors β-amino acid synthesis

The synthesis of β-amino acids can be achieved using well known procedures described in the literature, such as but not limited to “Enantioselective Synthesis of β-Amino Acids,” Second Edition, Editors: Eusebio Juaristi, Vadim A. Soloshonok, First published:27 January 2005, John Wiley & Sons, Inc.; Ellman et. Al Acc. Chem. Res.2002.35,984-995; Franklin A.

Davis and Bang-Chi Chen Chem. Soc. Rev., 1998,27,13-18; Jacobsen, M. F.; Skrydstrup, T. J. Org. Chem. 2003, 68, 7122; Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819 ;and Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999,64,12.

Rcductive Aminations ? j? NaBH(OAc)₃

R'^N'H H^R HOAcin R H

DCM or DCE

Procedure A: A mixture of amine (1 equiv.), aldéhyde (1.2 equiv.) in DCM (1-2 mL/mmol amine) was stirred at room température for 30 min. Then NaBH(OAc)j (1.5 equiv.) was added portion-wise and stirred at room température ovemight. The solvent was concentrated in vacuo and the residue was purified by silica gel chromatography to provide the desired amine.

Procedure B: A mixture of aldéhyde (1 equiv.), amine (1.05-2 equiv.) in DCE (3-4 mL/mmol of aldéhyde) was stirred at room température for 10-30 mins. Then NaBH(OAc)₃ (3-4 equiv.) was added portion-wise and stirred at room température 1-16 until complété by LC/MS. The solvent was concentrated in vacuo and the residue was purified by silica gel chromatography to provide the desired amine.

Procedure C: A mixture of aldéhyde (1 equiv.), AcOH (1.2 equiv), amine (1.05-2 equiv.) in DCM (2-3 mL/mmol aldéhyde) and MeOH (0.5 mL/mmol aldéhyde) was stirred at room température for 15-30 mins Then NaBH(OAc)₃ (2 equiv.) was added portion-wise and stirred at

162 room température 1-16 until complété by LC/MS. The solvent was concentrated in vacuo and the residue was purified by silica gel chromatography to provide the desired amine.

Alkylations

R r'ⁿ'h

K₂CO₃

Procedure A: To a solution of amine (1 equiv.) in MeCN (3-4 mL/mmol amine) was added mesylate (1.5 equiv.) and K2CO3 (3 equiv.). The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC to give the alkylated product.

R R'^N'H

K₂CO₃

R

Procedure B: To a solution of amine (1 equiv.) in MeCN (3-4 mL/mmol amine) was added alkylbromide (2 equiv.) and K2CO3 (2 equiv.). The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC to give the alkylated product.

Phénol Deprotections

HBr/AcOH

A mixture of methoxypyridine (1 equiv.) in 44% HBr/AcOH (10 mL/mmol of substrate) was heated at 55-75°C for 5-16 hours until complété by LCMS. The reaction was concentrated in vacuo and the residue purified by reverse phase HPLC to give the phénol product.

163

Wittig Reactions

CTR + KOtBu

PhaP O dioxane

Cl

Procedure A: A mixture of (methoxymethyl)triphenylphosphonium chloride (1.5 equiv.), tBuOK (2.5 equiv.) in dioxane (2 mL/mmol phosphonium sait) was stirred at room température for 15 minutes. Then aldéhyde (1 equiv.) in THF (1 mL/mmol aldéhyde) was added. The mixture was stirred for 2-16 h at room température. The reaction mixture was worked up (diluted with water and extracted with EtOAc; combined extacts dried overNazSO-j, filtered and concentrated) and purified by silica gel chromatography to give the enol ether product.

Procedure B: A mixture of (methoxymethyl)triphenylphosphonium chloride (1.1 equiv.), tBuOK (2.5 equiv.) in THF (4 mL/mmol phosphonium sait) was stirred at 0°C for 1 h. Then aldéhyde (1 equiv.) in THF (2 mL/mmol aldéhyde) was added. The mixture was stirred for 16 h at room température. The reaction mixture was worked up (diluted with water and extracted with EtOAc; combined extacts dried over Na2SÛ4, filtered, and concentrated) and purified by silica gel chromatography to give the enol ether product.

Enol Ether to Aldéhyde

TFAorHCO₂H DCM

Procedure A: Enol ether (1 equiv.) was treated with TFA (2 mL/mmol) at room température for 4 hours. The solvent was removed in vacuo to provide the desired aldéhyde.

Procedure B: Enol ether (1 equiv.) was treated with HCOOH (2 mL/mmol) at 70°C for 2 hours. The solvent was removed in vacuo to provide the desired aldéhyde.

Procedure C: To a solution of enol ether (1 equiv.) in DCM (15 mL/mmol enol ether) was added TFA (2 mL/mmol) and water (0.25 mL/ mmol enol ether). The reaction was stirred at 45°C for 18 h. The reaction was worked up (quenched with NaHCCh, extracted with DCM;

164 combined extracts dried over NazSQ*, filtered, and concentrated) to provide the desired aldéhyde.

Stille Reaction

Pd(PPh₃)₄DMF

To a solution of arylbromide (1 equiv.) and allylstannane (1.2 equiv.) under N2 in DMF (3 mL/mmol arylbromide) was added Pd(PPh₃)₄ (0.1 equiv.). The reaction was stirred at 100°C for 16 hours. The reaction was concentration in vacno then diluted with EtOAc, poured into 20% aq. KF and stirred for 1 h and extracted. The combined organic layers were dried over Na₂SO4, filtered and concentrated, and purified by silica gel chromatography to provide the desired product.

Alkcne to Aldéhyde

K₂OsO₄, NalO₄

THF/H₂O

To a solution of alkene (1 equiv.) in THF/H2O (1:1) (10 mL/mmol of alkene) at 0°C was added K2OSO4-2H2O (0.01 equiv.). The mixture was stirred at 0°C for 5 min then NaIO₄ (3 equiv.) in H₂O (1 mL/mmol alkene) was added dropwise and stirred at 0°C for 1 h then warmed to room température and stirred until complété by LCMS. The reaction was worked up (dilute with water and extract with EtOAc; combined organic layers were dried over Na2SO₄, filtered, and concentrated) to give the desired aldéhyde.

Ester to Acid

165

LiOH-H₂O MeOH

The ester (1 equiv.) was treated with L1OH-H2O (3-5 equiv.) in MeOH (1-3 mL/mmol ester) and water (1-3 mL/mmol ester) at room température for 1-5 h. The reaction was acidified with IN HCl to pH=3 and concentrated. The residue was purified by prep HPLC to give the desired carboxylic acid product.

Amine protection

A mixture of amine (1 equiv.), DIE A (3 equiv.), and BOC2O (2 equiv.) was stirred in DCM (5 10 mL/mmole amine) at room température for 16 h until complété by LCMS. The reaction was worked up (wash with 0.5 N HCl, sat. NaHCOa, brine, extract with DCM; combined organic layers were dried over Na2SÛ4, filtered, and concentrated) and purified by silica gel chromatography.

Préparation of arylborane

A mixture of arylbromide (1 equiv.), Β2ΡΠ12 (1.2 equiv.), Pd(dppf)Ch (0.05 equiv.), and KOAc (3 equiv.) in dioxane (10 mL/mmol arylbromide) was stirred at 110 °C for 2-5 h under N2 until

166 complété by LCMS. The reaction was filtered, concentrated in vacuo, and purified by silica gel chromotagraphy to provide the desired arylborane.

Suzuki Coupling

Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds” N. Miyaura; A.

Suzuki Chem. Rev. 1995, 957,2457-2483.

Pd(dppf)CI₂, K₂CO₃dioxane, H₂O

Procedure A: To a solution of arylborane (1 equiv.) in dioxane (10 mL/mmol arylborane) was added arylbromide (1.2 equiv.), Pd(dppf)C12 (0.1 equiv.), K2CO3 (2 equiv.), and water (2 mL/mmol). The réaction was stirred at 110 °C for 3 h under N2. The réaction was worked up (washed with brine and extracted with EtOAc; combined extracts dried over Na2SÛ4, filtered, and concentrated) and purified by silica gel chromatography to provide the desired biaryl product.

Procedure B: To a solution of arylbromide (1 equiv.) and arylborane (1.1 equiv.) in dioxane (10 mL/mmol arylbromide) was added K2CO3 (2 equiv.) in water (2 mL/mmol) and Pd(dppf)Ch (0.1 equiv.). The reaction was stirred at 110 °C for 2 h under N2. The reaction was worked up (washed with brine and extracted with EtOAc; combined extracts dried over Na2SO4, filtered, and

167 concentrated) and purified by silica gel chromatography to provide the desired biaryl product.

Procedure C: A mixture of arylbromide (1 equiv.), arylborane (2.0 equiv), K2CO3 (3 equiv.), and Pd(dppf)C12 (0.05 equiv.) in dioxane (10 mL/mmol arylbromide) and water (1 mL/mmol) was stirred at 110°C for 2 h under N2 until complété by LCMS. The reaction was worked up (washed with brine and extracted with EtOAc; combined extracts dried over Na2SO4, filtered, and concentrated) and purified by silica gel chromatography to provide the desired biaryl product.

Boc dcprotection

BocHNz,.

HCl/ dioxane

Boc-protected amine (1 equiv.) in DCM (4 mL/mmol amine) was added 4M HCl-dioxane (12 equiv.). The reaction was stirred for 1-2 h until complété by LCMS. The reaction was concentrated in vacuo to give the desired amine.

t-butylsulfinyl deprotection

HCl-dioxane

O^<S'NH O

NH₂ O

DCM

OEt

To a solution of t-butylsulfinylamine (1 equiv.) in DCM (0.5 mL/mmol amine) was added 4M HCl-dioxane (1.7 equiv.). The reaction was stirred for 0.5-1 h until complété by LCMS. The reaction was concentrated and purified by prep HPLC to give the desired amine.

168

Amide Bond Formation “Peptide Coupling Reagents, More than a Letter Soup” A. El-Faham, F. Albericio Chem. Rev. 2011,111, 11,6557-6602; “Amide bond formation and peptide coupling” C. A. G. N. Montalbetti; V. Falque Tetrahedron 2005, 61,10827-10852.

h₂n_vr TCFH, NMI

L^OEt CH₃CN O

A mixture of amine (1 equiv.), carboxylic acid (1 equiv.), TCFH (2 equiv.), and NMI (4 equiv.) in CH3CN (10 mL/mmol amine) was stirred at room température for 1-2 h until complété by LCMS. The reaction was conccntrated in vacuo and purified by silica gel chromatography to give the desired amide product.

Ester Hydrolysis

o

LiOH-H₂O

The ester (1 equiv.) was treated with LiOH-HiO (3-5 equiv.) in MeOH (1-3 mL/mmol ester) and water (1-3 mL/mmol ester) at room température for 1-5 h. The reaction was acidified with IN HCl to pH=4-5 and concentrated. The residue was purified by prep HPLC to give the desired carboxylic acid product.

Analytical Mcthods LCMS Analytical Methods

Final compounds were analyzed using LC/MS conditions, with UV detector monitoring at 214 nm and 254 nm, and mass spectrometry scanning 110-800 amu in ESI+ ionization mode.

LC/MS A: column: XBridge Cl8, 4.6 X 50 mm, 3.5 pm; mobile phase: A water (10 mM ammonium hydrogen carbonate), B CH₃CN; gradient: 5%-95% B in 1.4 min, then 1.6 min hold;

169 flow rate: 1.8 mL/min; oven température 50 °C.

LC/MS B: column: SunFire C18,4.6 X 50 mm, 3.5 pm; mobile phase: A water (0.01% TFA), B CH3CN; gradient: 5%-95% B in 1.5 min, then 1.5 min hold; flow rate: 2.0 mL/min; oven température 50 °C.

LC/MS C: column: XBridge Cl8,4.6 X 50 mm, 3.5 pm; mobile phase: A water (10 mM ammonium hydrogen carbonate), B CH3CN; gradient: 5%-95%B in 1.5min, then 1.5 min hold; flow rate: 1.8 mL/min; oven température 50 °C.

LC/MS D: column: Poroshell 120 EC-C138,4.6 X 30 mm, 2.7 pm; mobile phase: A water (0.01% TFA), B CH3CN (0.01% TFA); gradient: 5%-95% B in 1.2 min, then 1.8 min hold; flow rate: 2.2 mL/min; oven température 50 °C.

Example 2 A. Préparation of Intermediates

Préparation of ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-((^rrbutoxycarbonyl)amino)propanoate

Step 1: 5-bromo-2-fluoro-3-methylbenzaldehyde

To a mixture of 4-bromo-l-fluoro-2-methylbenzene (10.0 g, 52.9 mmol, 1.0 eq) in anhydrous THF (100.0 mL) under nitrogen atmosphère at -78 °C was added Lithium diisopropylamide (2.0 M, 39.7 mL, 79.4 mmol, 1.5 eq) dropwise over the period of 10 mins and stirred at -78°C for 1 hour. DMF (15.0 mL) was added dropwise and the mixture was stirred at -78°C for 2 hours. LCMS showed that the reaction was completed. The reaction mixture was quenched with a saturated NH4CI solution (aq) (100 mL) at 0 °C, extracted with EtOAc (100 mL x 2). The organic layer was washed with brine (100 mL), dried over anhydrous Na₂SO4, filtered and

170 concentrated in vacuo. The residue obtained was purified by silica gel column (pet ether: EtOAc 9:1) to provide 5-bromo-2-fluoro-3-methylbenzaldehyde as a white solid (8.0 g). Yield 70% (ESI 218.9 [M+H]⁺).

Step 2: (Æ, £)-Y-(5-bromo-2-fluoro-3-methylbenzylidene)-2-methylpropane-2-suIfinamide

To a mixture of 5-bromo-2-fluoro-3-methylbenza!dehyde (8.0 g, 36.9 mmol, 1.00 eq) and (Æ)-2methylpropane-2-sulfinamide (5.4 g, 44.3 mmol, 1.2 eq) in anhydrous THF (80 mL) under nitrogen atmosphère was added Ti(OEt)4 (12.6 g, 55.4 mmol, 1.50 eq) dropwise at room température with the température maintained below 30 °C. The reaction mixture was warmed to 40 °C and stirred for 1 hour. LCMS showed that the reaction was completed. Water (80 mL) and EtOAc (80 mL) was added into the mixture and stirred at room température for 5 mins. The mixture was filtered and washed with EtOAc (50 mL). The fîltrate was separated. The organic layer was washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude product (R, £)-7V-(5-bromo-2-fluoro-3methylbenzylidene)-2-methylpropane-2-sulfinamide as a yellow solid (12.0 g, crude) which was used in the next step without further purification. Yield 100% (ESI 320.0 [M+H] ⁺).

Step 3: ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((jR)-terrbutylsulfinyl)amino)propanoate

To a mixture of Zn (12.2 g, 187.5 mmol, 5.0 eq) in anhydrous THF (200 mL) under nitrogen atmosphère was added chlorotrimethylsilane (0.8 g, 7.5 mmol, 0.2 eq) dropwise at room température. The mixture was stirred at 60 °C for 1 hour under nitrogen atmosphère and cooled

171 to 20-30°C. Ethyl 2-bromoacetate (1.57 g, 9.4 mmol, 0.25 eq) was added dropwise at 20-30 °C. When the reaction mixture started to be exothermic, the rest of ethyl 2-bromoacetate (14.4 g, 86.3 mmol, 2.3 eq) was added dropwise during which time the reaction mixture was kept at 5060 °C. After the completion of the addition, the reaction mixture was stirred at 60°C for 1 hour under nitrogen atmosphère. The reaction mixture was cooled to 0 °C, {R, £)-N-(5-bromo-2fluoro-3-methylbenzylidene)-2-methylpropane-2-sulfinamide (12.0 g, 37.5 mmol) in anhydrous THF (30 mL) was added dropwise and stirred at 25 °C for 1 hour. LCMS showed that the reaction was completed. MTBE (150 mL) and a solution of citric acid (3 g) in water (100 mL) were added into the mixture. The mixture was separated. The aqueous layer was extracted with MTBE (150 mL x 2). The combined organic phase was washed with brine (200 mL), dried over anhydrous NaiSCh, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 3:1) to provide ethyl (5)-3-(5-bromo-2-fluoro-3-methylphenyl)-3(((jR)-/er/-butylsulfinyl)amino)propanoate (9.0 g). Yield 59% (ESI 408.0 [M+H]⁺).

Step 4: ethyl (5)-3-amino-3-(5-bromo-2-fluoro-3-methylphcnyI)propanoate

HCI/1,4-dioxane

To a solution of ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((7?)-/er/butylsulfinyl)amino)propanoate (8.0 g, 19.6 mmol, 1.00 eq) in DCM (20 mL) was added HC1dioxane (4 M, 20 mL, 80.0 mmol, 4.08 eq) and stirred at room température for 4 hours. LCMS showed that the reaction was completed. The mixture was filtered and concentrated in vacuo to give crude product ethyl (S)-3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propanoate as a yellow oil (8.0 g) used in the next step without further purification. Yield 100% (ESI 304.2 [M+H] ⁺).

Step 5: ethyl (5)-cthyl 3-(5-bromo-2-fluoro-3-methyiphenyI)-3-(teributoxycarbonylamino)propanoate

172

Boc₂O. DIEA, DCM

To a solution of ethyl (S)-3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propanoate (8.0 g, 19.6 mmol, 1.00 eq) in DCM (100 mL) was added DIEA (7.6 g, 59.0 mmol, 3.00 eq) and BociO (8.6 g, 39.2 mmol, 2.00 eq). The reaction mixture was stirred at room température for 16 hours. LCMS showed that the reaction was completed. The reaction mixture was diluted with DCM (200 mL) and washed with 0.5 N HCl (50 mL x 3), saturated NaHCCh (50 mL) and brine (50 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 3:1) to provide ethyl (5)-3-(5-bromo-2fluoro-3-methylphenyl)-3-((fôr/-butoxycarbonyl)amino)propanoate as a brown oil (6.0 g). Yield 75% (ESI 404.1 (M+H)⁺).

Préparation of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5 tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate

A mixture of ethyl (5)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-((/<?r/butoxycarbonyl)amino)propanoate (1.0 g, 2.48 mmol, 1.0 eq), bis(pinacolato)diboron (756.28 mg, 2.98 mmol, 1.2 eq), Pd(dppf)C12 (90.65 mg, 0.13 mmol, 0.05 eq) and KOAc (729.12 mg, 7.44 mmol, 3.0 eq) in 1,4-dioxane (20 mL) was stirred at 110 °C for 3 hours under nitrogen atmosphère. The reaction mixture was cooled to room température, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 2:1) to give (5)

173 ethyl 3-(/eri-butoxycarbonylamino)-3-(2-fluoro-3-methyI-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)propanoate as a colorless oil (1.0 g). Yield 89% (ESI 452.2 (M+H)⁺).

Préparation of ethyl (S)-3-amino-3-(2’,4-difluoro-5,6’-dimethyI-(l,l’-biphenyl]-35 yl)propanoate

Step 1: ethyl (S')-3-((tert^,-butoxycarbonyl)amino)-3-(2’,4-difluoro-5,6’-dimethyI-[l,rbiphenyl]-3-yl)propanoate

To a solution of ethyl (5)-3-((ter/-butoxycarbonyl)amino)-3-(2-fIuoro-3-methyl-5-(4,4,5,510 tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (300 mg, 0.66 mmol, 1.0 eq) in dioxane (5 mL) was added 2-bromo-l-fluoro-3-methylbenzene (150 mg, 0.79 mmol, 1.2 eq), Pd(dppf)C12 (48 mg, 0.066 mmol, 0.1 eq), K2CO3 (182 mg, 1.32 mmol, 2.0 eq) and water (1 mL). The reaction mixture was stirred at 110 °C for 3 hours under nitrogen atmosphère. Water (10 mL) was added and the solution was extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine ( 100 mL), dried over anhydrous Na2SO4. filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 8:1) to provide ethyl (5)-3-((/ert-butoxycarbonyl)amino)-3-(2^,,4-difluoro-5,6'-dimethyl-[l,l'biphenyl]-3-yl)propanoate as a colorless oil (210 mg). Yield 73% (ESI 334.1 [M+H-100]⁺).

Step 2: ethyl (5)-3-amino-3-(2’,4-difluoro-5,6’-dimethyl-(l,l’-biphenyl]-3-yl)propanoate

174

To a stirred solution of ethyl (S)-3-((/cvr-butoxycarbonyl)amino)-3-(2',4-difluoro-5,6'-dimethyl[l,l'-biphenyl]-3-yl)propanoate (210 mg, 0.48 mmol, 1.0 eq) in DCM (2 mL) was added HC1dioxane (4 M, 3.0 mL, 6.0 mmol, 12.5 eq). The mixture was stirred at room température for 2 hours. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo to provide ethyl (S)-3-amino-3-(2',4-difluoro-5,6'-dimethyl-[l,r-biphenyl]-3-yl)propanoate as a colorless oil (160 mg). Yield 99% (ESI 334.1 (M+H]⁺).

Préparation of ethyl (S)-3-amino-3-(2'-cyano-4-fluoro-5,6'-dimethyl-[l,l’-biphenyl]-310 yl)propanoate hydrochloride

Step 1: ethyl (5)-3-((tert-butoxycarbonyl)amino)-3-(2’-cyano-4-fluoro-5,6’-dimethyl-|l,l’ biphenylJ-3-yl)propanoate

To a solution of ethyl (5)-3-((reri-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,515 tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (350 mg, 0.77 mmol, 1.0 eq) in dioxane (10 mL) was added 2-bromo-3-methylbenzonitrile (226 mg, 1.16 mmol, 1.5 eq), Pd(dppf)Ch (56 mg, 0.077 mmol), K2CO3 (193 mg, 1.4 mmol, 1.8 eq) and water (2 mL). The reaction mixture was stirred at 110 °C for 3 hours under nitrogen atmosphère. Water (20 mL) was added and the

175 solution was extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous NazSCh, filtered and concentrated in vactio. The residue was purified by silica gel column (petroleum ether: EtOAc 4:1) to provide ethyl butoxycarbonyl)amino)-3-(2'-cyano-4-fluoro-5,6’-dimethyl-[ 1,1 ’-biphenyl]-3-yl)propanoate as a colorless oil (260 mg). Yield 76% (ESI 341.1 [M+H-100]⁺).

Step 2: ethyl (S)-3-amino-3-(2’-cyano-4-fluoro-5,6’-dimethyl-[l,l’-biphenyl]-3yl)propanoate hydrochloridc

To a stirred solution of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2’-cyano-4-fluoro-5,6’dimethyl-[l,r-biphenyl]-3-yl)propanoate (230 mg, 0.52 mmol, 1.0 eq) in DCM (2 mL) was added HCl-dioxane (4 M, 2.0 mL, 4.0 mmol, 7.7 eq). The mixture was stirred at room température for 1 hour. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo to provide ethyl (S)-3-amino-3-(2'-cyano-4-fluoro-5,6'-dimethyI-[l,rbiphenyl]-3-yl)propanoate hydrochloride as a yellow oil (180 mg). Yield 91% (ESI 341.1 [M+H]⁺).

Préparation of ethyl (5)-3-amino-3-(2’-chIoro-4-fluoro-5,6*-dimethyI-(l,l’-biphenylJ-3yl)propanoate

Step 1: ethyl (5)-3-((re’r^,r-butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro-5,6*-dimethyl-[l,l'biphenyl]-3-yI)propanoate

176

A mixture of ethyl (S)-3-((ter/-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (1.0 g, 2.22 mmol, 1.00 eq), 2-bromo-lchloro-3-methylbenzene (543 mg, 2.66 mmol, 1.20 eq), K2CO3 (613 mg, 4.44 mmol, 2.0 eq) and Pd(dppf)C12 (81 mg, 0.11 mmol, 0.05 eq) in dioxane ( 10 mL) and H2O (2 mL) was stirred at 110 °C for 2 hours under nitrogen atmosphère. Water (30 mL) was added and the solution was extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 2:1) to provide ethyl (5)-3-((^/7butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[ 1,1 '-biphenyl]-3-yl)propanoate as a colorless oil (800 mg). Yield 80% (ESI 450.18 [M+H]⁺).

Step 2: ethyl (S)-3-amino-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[l,l'-biphenyl]-3yl)propanoate

To a mixture of ethyl (5)-3-((ier/-butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro-5,6'-dimethyl[l,l'-biphenyl]-3-yl)propanoate (300 mg, 0.67 mmol, 1.00 eq) in DCM (9 mL) was added HC1dioxane (4 M, 9.0 mL, 36.0 mmol, 53.73 eq) and stirred at room température for 1 hour. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo to provide ethyl (S)-3-amino-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[l,r-biphenyl]-3-yl)propanoate as a white solid (200 mg) used directly in the next reaction without further purification. Yield 86% (ESI 350.1[M+H]⁺).

177

Préparation of ethyl (5)-3-amino-3-(2’-cycIopropyI-4-fluoro-5,6’-dimethyI-[l,l’-biphenyI]3-yl)propanoate

Step 1: ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2’-cycIopropyl-4-fluoro-5,6’-dimethyI[1,1 ’-biphenyl]-3-yi)propanoate

A mixture of ethyl (S)-3-((/er/-butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[l,rbiphenyl]-3-yl)propanoate (500 mg, 1.12 mmol, 1.00 eq), cyclopropylboronic acid (116 mg, 1.35 mmol, 1.20 eq), K3PO4 (475 mg, 2.24 mmol, 2.00 eq), PCy₃ (31 mg, 0.11 mmol, 0.10 eq) and Pd(OAc)2 (11 mg, 0.11 mmol, 0.10 eq) in dioxane (10 mL) and H₂O (2 mL) was stirred at 110 °C for 36 hours under nitrogen atmosphère. Water (30 mL) was added and the solution was extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 2:1) to provide ethyl (S)-3-((tertbutoxycarbonyl)amino)-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[ 1,1 ’-biphenyl]-3-yl)propanoate as a colorless oil (400 mg). Yield 79% (ESI 456.2 (M+H]⁺).

Step 2: ethyl (S)-3-amino-3-(2’-cycIopropyI-4-fluoro-5,6*-dimethyI-[l,l’-biphenyI[-3yi)propanoate

To a mixture of ethyl (S)-3-((ter/-butoxycarbonyl)amino)-3-(2'-cyclopropyl-4-fluoro-5,6'dimethyl-[l,l'-biphenyl]-3-yl)propanoate (400 mg, 0.88 mmol, 1.0 eq) in DCM (9 mL) was

178 added HCl-dioxane (4 M, 9.0 mL, 36.0 mmol, 40.9 eq) and stirred at room température for 1 hour. LCMS showed that the réaction was completed. The mixture was concentrated in vacuo to provide ethyl (<S)-3-amino-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[ 1,1 ’-biphenyl]-3yl)propanoate as a white solid (300 mg) used directly in the next reaction without further purification. Yield 96% (ESI 356.2 [M+H]⁺).

Préparation of ethyl (5)-3-amino-3-(4-fluoro-4’-methoxy-2’,5,6’-trimethyl-|l,l’-biphenyIj-3yl)propanoate hydrochloride

Step 1: ethyl (S)-3-amino-3-(2’-ethyI-4-fluoro-5,6'-dimethyl-[l,l’-biphenyl]-3-yI)propanoate hydrochloride

To a solution of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (350 mg, 0.77 mmol, 1.0 eq) in dioxane (10 mL) was added 1-ethyl-2-iodo-3-methylbenzene (286 mg, 1.16 mmol, 1.5 eq), Pd(dppf)Ch (56 mg, 0.077 mmol, 0.1 eq), K2CO3 (193 mg, 1.4 mmol, 1.8 eq) and water (2 mL). The reaction mixture was stirred at 110 °C for 3 hours under nitrogen atmosphère. Water (10 mL) was added and the solution was extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 4:1) to provide ethyl (S)3-((/erZ-butoxycarbonyl)amino)-3-(2'-ethyl-4-fluoro-5,6'-dimethyl-[ 1,1 ’-biphenyl]-3yl)propanoate as a colorless oil (240 mg). Yield 70% (ESI 344.2 [M+H-100]⁺).

Step 2: ethyl (5)-3-amino-3-(2’-ethyl-4-fluoro-5,6'-dimethyI-|l,l'-biphenyI]-3-yl)propanoate hydrochloride

179

To a stirred solution of ethyl (5)-3-((/eri-butoxycarbonyl)amino)-3-(2'-ethyl-4-fluoro-5,6'dimethyl-[l,r-biphenyl]-3-yl)propanoate (210 mg, 0.47 mmol, l.O eq) in DCM (2 mL) was added HCl-dioxane (4 M, 3.0 mL, 6.0 mmol, 12.8 eq). The mixture was stirred at room température for 1 hour. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo to provide ethyl (S)-3-amino-3-(2'-ethyl-4-fluoro-5,6'-dimethyl-[l,rbiphenyl]-3-yl)propanoate hydrochloride as a colorless oil (170 mg). Yield 94% (ESI 344.1 [M+H]⁺).

Préparation of (S)-ethyl 3-amino-3-(4-fluoro-2’-methoxy-5,6’-dimcthylbiphenyl-3yl)propanoate

Step 1: ethyl (5)-3-(((7?)-rerr-butylsuIfinyl)amino)-3-(4-fluoro-2’,4’,5,6'-tetramethyl-[l,rbiphenyI|-3-yl)propanoate

A mixture of (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(2-fluoro-3-methyl-5-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (1 g, 2.22 mmol, 1.0 eq), 2-bromo-lmethoxy-3-methylbenzene (666 mg, 3.33 mmol, 1.5 eq), K2CO3 (919 mg, 6.66 mmol, 3.0 eq) and Pd(dppf)C12(162 mg, 0.222 mmol, 0.1 eq) in dioxane (15 mL) and H2O (1.5 mL) was stirred at 100°C under nitrogen atmosphère for 3 hours. LCMS showed the reaction was completed. The

180 reaction mixture was cooled to room température. Water (50 mL) was added and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na₂SÛ4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 2:1) to provide (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(4fluoro-2'-methoxy-5,6'-dimethylbiphenyl-3-yl)propanoate as a yellow oil (0.96 g). Yield 97% (ESI 346.1 [M+H]⁺).

Step 2: (S)-ethyl 3-amino-3-(4-fluoro-2’-methoxy-5,6’-dimethylbiphenyl-3-yl)propanoate

To a stirred solution of (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(4-fluoro-2'-methoxy-5,6'dimethylbiphenyl-3-yl)propanoate (0.96 g, 2.15 mmol, 1.0 eq) in DCM (7 mL) was added HC1dioxane (4 M, 2.15 mL, 4 eq) and stirred at 25 °C for 2 hours. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8/40 g column (A: water 10 mM NfhHCOj.B: MeOH, 0-100%) to provide (S)-ethyl 3-amino-3-(4-fluoro-2'-methoxy-5,6'-dimethylbiphenyl-3-yl)propanoate as a yellow oil (0.6 g). Yield 81% (ESI 346.1 [M+H]⁺).

Préparation of (S)-ethyl 3-amino-3-(4-fluoro-2'-methoxy-5-methyl-6'(trifluoromethyl)bîphenyl-3-yl)propanoate

Step 1: l-methoxy-2-nitro-3-(trifluoromethyl)benzene

F₃C

181

To a mixture of 2-nitro-3-(trifluoromethyl)phenol (1.5 g, 7.25 mmol, 1.0 eq) in acetone (20 mL) was added K2CO3 (3 g, 21.75 mmol, 3 eq} and CH3I (5.15 g, 36.25 mmol, 5 eq) and stirred at room température for 16 hours. LCMS showed that the reaction was completed. The reaction mixture was filtered, washed with EtOAc (20 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 2:1) to provide l-methoxy-2nitro-3-(trifluoromethyl)benzene as a white solid (1.3 g). Yield 81% .

Step 2:2-methoxy-6-(trifluoromethyl)aniline

10%Pd/C ------------>.

EtOH, H₂

To a mixture of l-methoxy-2-nitro-3-(trifluoromethyl)benzene (1.3 g, 5.88 mmol, 1.0 eq) in EtOH (20 mL) was added 10%Pd/C (700 mg) and stirred at room température for 16 hours under H2 atmosphere(2L, 1 atm). LCMS showed that the reaction was completed. The reaction mixture was filtered and the filtrated concentrated in vacuo to provide 2-methoxy-6(trifluoromethyl)aniline as a white solid (0.75 g). Yield 67% (ESI 192.1 [M+H]⁺).

Step 3:2-bromo-l-methoxy-3-(trifluoromethyl)benzene

t-BuONO, CuBr p₃c

Br

To a mixture of 2-methoxy-6-(trifluoromethyl)aniline (700 mg, 3.66 mmol, 1.0 eq) in MeCN (15 mL) was added t-BuONO (565 mg, 5.49 mmol, 1.5 eq) and CuBr (628 mg, 4.39 mmol, 1.2 eq).

The mixture was stirred at 60°C for 2 hours. LCMS showed that the reaction was completed. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 10:1) to provide 2-bromo-l-methoxy-3-(trifluoromethyl)benzene as a colorless oil (400 mg). Yield 43%.

Step 4: (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(4-fluoro-2’-methoxy-5-methyl-6’(trifluoromethyl)biphenyI-3-yI)propanoate

182

A mixture of 2-bromo-l-methoxy-3-(trifluoromethyl)benzene (400 mg, 1.57 mmol, 1.00 eq), (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)propanoate (708 mg, 1.57 mmol, 1.0 eq), K₂CÛ3(650 mg, 4.71 mmol, 5 3.0 eq) and Pd(dppf)Cl₂ (115 mg, 0.157 mmol, 0.1 eq) in dioxane (8 mL) and H₂O (0.8 mL) was stirred at 110°C for 4 hours under nitrogen atmosphère. LCMS showed that the reaction was completed. The mixture was cooled to room température. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic phases was washed with brine (30 mL), dried over anhydrous Na₂SC>4, filtered and concentrated in vacuo. The residue was 10 purified by silica gel column (pet ether: EtOAc 10:1) to provide (S)-ethyl 3-(tertbutoxycarbonylamino)-3-(4-fluoro-2'-methoxy-5-methyl-6’-(trifluoromethyl)biphenyl-3yl)propanoate (400 mg) as a colorless oil. Yield 51% (ESI 400.1 [M-Boc]⁺).

Step 5: (S)-ethyl 3-amino-3-(4-fluoro-2’-methoxy-5-methyl-6’-(trifluoromethyl)bîphenyl-3yl)propanoate

To a stirred solution of (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(4-fluoro-2'-methoxy-5mcthyl-6'-(trifluoromethyl)biphenyl-3-yl)propanoate (400 mg, 0.8 mmol, 1.00 eq) in DCM (6 mL) was added HCl-dioxane (4 M, 0.8 mL, 3.2 mmol, 4 eq) and stirred at room température for 2 hours. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo

183 and the residue was purified by reverse phase HPLC on a Cl8/120g column (A: water 10 mM ΝΗ₄ΗΟΟ₃,Β: MeOH, 0-100%) to provide (S)-ethyl 3-amino-3-(4-fluoro-2’-methoxy-5-methyI6'-(trifluoromethyl)biphenyl-3-yl)propanoate (280 mg) as a colorless oil. Yield 87% (ESI 400.1 [M+H]⁺).

Préparation of (S)-ethyl 3-amino-3-(2’,6’-dÎchloro-4-fluoro-5-methylbiphenyl-3yl)propanoate

Step 1: (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(2’,6*-dichloro-4-fluoro-5methyIbiphenyl-3-yI)propanoate

To a mixture of methyl (S)-ethyl 3-(5-bromo-2-fluoro-3-methylphenyl)-3-(tertbutoxycarbonylamino)propanoate (0.5 g, 1.29 mmol, 1 eq) and 2,6-dichIorophenyIboronic acid (0.26 g, 1.36 mmol, 1.1 eq) in dioxane (10 mL) was added a solution of K₃CO₃ (0.34 g, 2.48 mmol, 2 eq) in HiO (2 mL) and Pd(dppf)C12 (90 mg, 0.124 mmol, 0.1 eq). The mixture was heated to 110 °C for 2 hours under nitrogen atmosphère. The mixture was cooled to room température. Water (20 mL) was added and the solution was extracted with EtOAc (20 mL x 3). The combined organic phases were concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 1:1) to provide (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(2’,6'dichloro-4-fluoro-5-methylbiphenyl-3-yl)propanoate a colorless oil (0.550 g). Yield 94% (ESI 470.4 [M+H]⁺).

Step 2: (S)-methyl 3-amino-3-(2’,6'-dichloro-4-fluoro-5-methyIbiphenyI-3-yi)propanoate

184

To a mixture of methyl (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(2',6'-dichloro-4-fluoro-5methylbiphenyl-3-yl)propanoate (0.55 g, l.2l mmol, 1 eq) in DCM (6 mL) was added HC1dioxane (4 M, 3 mL, 12 mmol, 10 eq). The mixture was stirred at room température for 1 hour. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo to give crude product (S)-ethyl 3-amino-3-(2^,,6'-dichloro-4-fluoro-5-methylbiphenyl-3-yl)propanoate as a white solid (0.42 g) used directly in the next reaction without further purification. Yield 98% (ESI 370.3[M+H]⁺).

Préparation of ethyl (5)-3-amino-3-(2’,4-difluoro-4’,5,6’-trimethyl-[l,l’-biphenylj-3yl)propanoate

Step 1:2-fluoro-4,6-dimethylaniIine

I k₂co₃

Pd(dppf)CI₂I I ___________________________________________________ ^x O ^x dioxane/H₂O

A mixture of 2,4-dibromo-6-fluoroaniline (5.0 g, 18.59 mmol, 1.0 eq), 2,4,6-trimethyl1,3,5,2,4,6-trioxatriborinane (3.5 M in THF, 21.2 mL, 74.36 mmol, 4.0 eq), Pd(dppf)C12 (680 mg, 0.93 mmol, 0.05 eq) and K2CO3 (7.71 g, 55.78 mmol, 3.0 eq) in dioxane (60 mL) and H2O (8 mL) was stirred at 110 °C for 12 hours under nitrogen atmosphère. The mixture was cooled to room température. Water (30 mL) was added and the solution was extracted with EtOAc (35 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column

185 (Petroleum ether: EtOAc 20:1) to provide 2-fluoro-4,6-dimethylaniline as a yellow oil (2.16 g).

Yield 83.5% (ESI 140.2 [M+H]⁺).

Step 2:2-bromo-l-fluoro-3,5-dimethylbenzene

nh₂t-BuONO

CuBr₂,MeCN

To a stirred solution of 2-fluoro-4,6-dimethylaniline (1.0 g, 7.2 mmol, 1.0 eq) and CuBr₂(4.8 g, 21.6 mmol, 3.0 eq) in MeCN (7 mL) was added tert-Butyl nitrite (1.68 g, 14.4 mmol, 2.0 eq) and stirred at 60 °C for 1 hour under nitrogen atmosphère. LCMS showed that the reaction was completed. The mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether) to provide 2-bromo-l-fluoro-3,5-dimethylbenzene as a yellow oil (560 mg). Yield 38%.

Step 3: ethyl (5)-3-((tert-butoxycarbonyl)amino)-3-(2’,4-difluoro-4’,5,6’-trimethyI-[l,l*biphenyll-3-yl)propanoate

A mixture of ethyl (S)-3-((terZ-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (556 mg, 1.23 mmol, 1.0 eq), 2-bromol-fluoro-3,5-dimethylbenzene (250 mg, 1.23 mmol, 1.0 eq), Pd(dppf)Cl₂ (45 mg, 0.062 mmol, 0.05 eq) and K2CO3 (510 mg, 3.69 mmol, 3.0 eq) in dioxane (6 mL) and water (2 mL) was stirred at 110 °C for 2 hours under nitrogen atmosphère. Water (35 mL) was added and the solution was extracted with EtOAc (25 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na₂SO4. filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 7:1) to provide ethyl (S)-3-((fôri186 butoxycarbonyl)amino)-3-(2',4-difluoro-4',5,6'-trimethyl-[ 1,l'-biphenyl]-3-yI)propanoate as a yellow oil (365 mg). Yield 66% (ESI 348.1 [M+H-100]⁺).

Step 4: ethyl (S)-3-amino-3-(2’,4-difluoro-4’,5,6’-triinethyI-[l,r-biphenyl]-3-yl)propanoate

To a stirred solution of ethyl (S)-3-((/eri-butoxycarbonyl)amino)-3-(2',4-difluoro-4',5,6'trimethyl-[l,r-biphenyl]-3-yl)propanoate (720 mg, 1.29 mmol, 1.0 eq) in DCM (2 mL) was added HCI-dioxane (4 M, 2.0 mL, 4.0 mmol, 3.1 eq) and stirred at room température for 1 hour. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo to provide ethyl (5)-3-amino-3-(2',4-difluoro-4',5,6^,-trimethyl-[l,r-biphenyl]-3-yl)propanoate as a yellow oil (450 mg). Yield 93% (ESI 348.1 [M+H]⁺).

Préparation of (S)-ethyl 3-amino-3-(2’,6’-dichloro-4-fluoro-4’,5-dimethylbiphenyl-3yl)propanoate

Step 1: l,3-dichloro-2-iodo-5-methylbenzene

To a mixture of 2,6-dichloro-4-methylaniline (2.5 g, 14.3 mmol, 1.0 eq) in acetonitrile (10 mL) and water (1 mL) was added 4-methylbenzenesulfonic acid (9.8 g, 57.1 mmol, 4 eq) and stirred at 0 °C for 10 mins. A solution of NaNCh (2.0 g, 28.6 mmol, 2 eq) in H2O (2 mL) was added dropwise and the mixture was stirred at 0 °C for 30 mins. Then a solution of potassium iodide (3.0 g, 17.9 mmol, 1.5 eq) in H₂O (2 mL) was added and heated to 50 °C for 2 hours under

187 nitrogen atmosphère. Water (20 mL) was added and the solution was extracted with EtOAc (20 mL x 3). The combined organic phases were concentrated in vacito and the residue was purified by silica gel column (pet ether: EtOAc 1:1) to give l,3-dichloro-2-iodo-5-methylbenzene as a colorless oil (1.8 g). Yield 44.2% (ESI 286.9[M+H]+).

Step 2: (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(2’,6*-dichloro-4-fluoro-4’,5 dimethyIbiphenyl-3-yI)propanoate

To a mixture of methyl (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(2-fluoro-3-methyl-5-(4,4,5,5tetramethyl-I,3,2-dioxaborolan-2-yl)phenyl)propanoate(1.5 g, 3.43 mmol, 1 eq} and 1,310 dichloro-2-iodo-5-methylbenzene (2.0 g, 6.86 mmol, 2 eq} in dioxane (10 mL) was added a solution of K2CO3 (1.9 g, 13.72 mmol, 4 eq} in H₂O (2 mL) and Pd(dppf)Cl₂ (250 mg, 0.343 mmol, 0.1 eq}. The mixture was heated to 110 °C for 2 hours under nitrogen atmosphère. Water (20 mL) was added and the solution was extracted with EtOAc (20 mL x 3). The combined organic phases were concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 1:1) to give methyl (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(2',6^,-dichloro-4fluoro-4',5-dimethylbiphenyl-3-yl)propanoate as a colorless oil (1.3 g). Yield 78.3% (ESI 484.4 [M+H]⁺).

Step 3: (S)-ethyl 3-amino-3-(2',6’-dichloro-4-fluoro-4’,5-dimethylbiphenyl-3-yl)propanoate

188

To a mixture of methyl (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(2’,6'-dichloro-4-fluoro-4',5dimethylbiphenyl-3-yl)propanoate (1.3 g, 2.76 mmol, 4 eq) in DCM (6 mL) was added HC1dioxane (4 M, 3 mL, 12 mmol, 4.3 eq). The mixture was stirred at room température for 1 hour.

LCMS showed that the reaction was completed. The mixture was concentrated in vacuo to give crude (S)-ethyl 3-amino-3-(2',6'-dichloro-4-fluoro-4',5-dimethylbiphenyl-3-yl)propanoate as a white solid (1.0 g) used directly in the next reaction without further purification. Yield 91% (ESI 384.3 [M+H]⁺).

Préparation of ethyl (S)-3-amino-3-(4-fluoro-2',5,6’-trimethyl-il,l’-biphenyl|-3yl)propanoate

Step 1: ethyl (S)-3-(((/î)-/ert-butylsuIfÎnyI)amino)-3-(4-fluoro-2’,5,6’-trimethyl-(l,l’ biphenyl]-3-yl)propanoate

b<oh)₂

Pd(dppf)CI₂ K₂C0₃dioxane/H₂0110°C

A mixture of ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((Æ)-/eributylsulfmyl)amino)propanoate (4.0 g, 9.8 mmol, 1.00 eq), (2,6-dimethylphenyl)boronic acid (2.9 g, 19.6 mmol, 2.00 eq), K₂CO₃ (4.1 g, 29.4 mmol, 3.0 eq), Pd(dppf)Cl₂ (717 mg, 0.98 mmol, 0.05 eq) in dioxane (24 mL) and H₂O (9 mL) was stirred at 110°C for 2 hours under nitrogen atmosphère. LCMS showed that the reaction was completed. The mixture was cooled to room

189 température. Water (30 mL) was added and the solution was extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na^SCL, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 1:1) to provide ethyl (S)-3-(((7?)-/er/-butylsulfinyl)amino)-3-(4-fiuoro-2^,,5,6'-trimethyl5 [l,l'-biphenyl]-3-yl)propanoate (4.0 g) as a yellow oil. Yield 94% (ESI 434.1 [M+H]⁺).

Step 2: ethyl (S)-3-amino-3-(4-fluoro-2',5,6'-trimethyl-[l,l'-biphenyl]-3-yI)propanoate

HCI-dioxane

DCM

To a stirred solution of ethyl (5)-3-(((Â)-rerr-butylsulfinyl)amino)-3-(4-fluoro-2',5,6'-trimethyl[l,l'-biphenyl]-3-yl)propanoate (4.0 g, 9.2 mmol, 1.00 eq) in DCM (6 mL) was added HC110 dioxane (4 M, 4 mL, 16.0 mmol, 1.7 eq). The mixture was stirred at room température for 30 mins. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8/120g column (A: water 10 mM NH4HCO3.B: MeOH, 0-100%) toprovide ethyl (S)-3-amino-3-(4-fiuoro-2',5,6'-trimethyl-[l,rbiphenyl]-3-yl)propanoate (2.0 g) as a colorless oil. Yield 61% (ESI 330.1 [M+H]⁺).

Préparation of ethyl (S)-3-amino-3-(4,4'-difluoro-2\5,6’-triniethyHl,r-biphenylJ-3yl)propanoate

Step 1: ethyl ($)-3-(((Æ)-tert-butyIsulfinyi)amino)-3-(4,4’-difluoro-2’,5,6’-trimethyl-[l,l’biphenyl|-3-yl)propanoate

190

A mixture of ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((Â)-/er/butylsulfmyl)amino)propanoate (6.0 g, 14.7 mmol, 1.00 eq), (4-fluoro-2,6dimethylphenyl)boronic acid (3.7g, 22.1 mmol, 1.5 eq), KiCO3(6.1 g, 44.1 mmol, 3.0 eq) and Pd(dppf)Ch(l.l g, 1.47 mmol, 0.01 eq) in dioxane (50 mL) and H2O (5 mL) was stirred at 110°C under nitrogen atmosphère for 1 hour. LCMS showed that the reaction was completed. The mixture was cooled to room température. Water (50 mL) was added and the solution was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 1:1) to provide ethyl (S)-3-(((R)-tertbutylsulfinyl)amino)-3-(4,4’-difluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate as a yellow oil (5.5 g). Yield 83% (ESI 452.0 (M+H)⁺)

Stcp 2: ethyl (S)-3-amino-3-(4,4MifIuoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate

To the solution of ethyl (S)-3-(((/0-tert-butylsulfmyl)amino)-3-(4,4’-difluoro-2^,,5,6’-trimethyl[l,r-biphenyl]-3-yl)propanoate (5.5 g, 12.2 mmol, 1.00 eq) in DCM (6 mL) was added HCldioxane (4M, 6 mL, 24.0 mmol, 1.97 eq) and stirred at room température for 1 hour. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18 / 120 g column (A: water/0.01%TFA,B: MeOH, 0-100%) to provide ethyl (S)-3-amino-3-(4,4'-difluoro2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate as a yellow solid (4.0 g). Yield 95% (ESI 348.1 (M+H)⁺).

Préparation of ethyl (S)-3-amino-3-(4’-chIoro-4-fluoro-2’,5,6’-triniethyl-[l,l’-biphcnyll-3' yl)propanoate Step 1:2-(4-chloro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane

191

To a solution of 2-bromo-5-chloro-l,3-dimethylbenzene (4.0 g, 18.2 mmol, 1.0 eq) in anhydrous THF (40 mL) under nitrogcn atmosphère was added n-BuLi (2 N, 11.0 mL, 22.0 mmol, 1.2 eq) at -78 °C. The reaction mixture was stirred at -78 °C for 40 mins and 2-isopropoxy-4,4,5,5tetramethyl-l,3,2-dioxaborolane (5.1 g, 27.5 mmol, 1.5 eq) in anhydrous THF (40 mL) was added and stirred at -78 °C for 3 hours. After completion, a saturated NH4CI solution (aq) (100 mL) was added. The mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaiSCh, filtered and concentrated in vacuo. The residue obtained was purified by silica gel (petroleum ether: EtOAc 2:1) to give the desired 2-(4-chloro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane as a white solid (4.4 g). Yield 90%.

Step 2: ethyl (S)-3-amino-3-(4’-chloro-4-fluoro-2’,5,6’-trimethyl-[l,r-biphenyl]-3yl)propanoate

A mixture of ethyl (5)-3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propanoate (500 mg, 1.7 mmol, 1.0 eq), 2-(4-chloro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (544 mg, 2.04 mmol, 1.2 eq), Pd(dppf)Ch (62 mg, 0.085 mmol, 0.05 eq) and K2CO3 (704 mg, 5.1 mmol, 3.0 eq) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 110 °C for 2 hours under nitrogen atmosphère. Water (20 mL) was added and the solution was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column

192 (petroleum ether: EtOAc 1:2) to provide ethyl (S)-3-amino-3-(4'-chloro-4-fluoro-2',5,6'trimethyl-[l,l'-biphenyl]-3-yl)propanoate as a colorless oil (250 mg). Yield 41% (ESI 364.2 (M+H]⁺).

Préparation of ethyl (S)-3-amino-3-(4-fluoro-2’,4',5,6'-tetramethyl-[l,l'-biphenyl]-3yl)propanoate

Step 1: ethyl (5)-3-(((jR’)-i'err-butylsulfinyl)amino)-3-(4-fluoro-2’,4’,5,6'-tetramethyl-[l,rbiphenyl]-3-yl)propanoate

A mixture of ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((/?)-/erZbutylsulfmyl)amino)propanoate (3.8 g, 9.3 mmol, 1.0 eq), mesitylboronic acid (3.05 g, 18.6 mmol, 2.0 eq), K₂CO₃(3.85 g, 27.9 mmol, 3.0 eq) and Pd(dppf)Cl₂ (340 mg, 0.465 mmol, 0.05 eq) in Dioxane (30 mL) and H₂O (5 mL) was stirred at 110°C under nitrogen atmosphère for 2 hours. LCMS showed the reaction was complété. The reaction mixture was cooled to room température. Water (80 mL) was added and the mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (150 mL), dried over Na₂SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 1:1) to provide ethyl (5)-3-(((R)-Zert-butylsulfinyl)amino)-3-(4-fluoro-2’,4’,5,6'-tetramethyl-[l,Γbiphenyl]-3-yl)propanoate as a yellow oil (3.1 g). Yield 75% (ESI 448.2 [M+H]⁺).

Stop 2: ethyl (S)-3-amino-3-(4-fluoro-2’,4’,5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoate

193

To a stirred solution of ethyl (S)-3-(((/î)-ter/-butylsulfinyl)amino)-3-(4-fluoro-2’,4',5,6'tetramethyl-[l,l'-biphenyl]-3-yl)propanoate (3.1 g, 6.94 mmol, 1.0 eq) in DCM (7 mL) was added HCl-dioxane (4 M, 6.8 mL, 3.9 eq) and stirred at 25 °C for 2 hours. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8/40 g column (A: water 10 mM NHiHCOj.B: MeOH, 0-100%) to provide (S)-ethyl 3-amino-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoate as a yellow oil (1.6 g). Yield 67% (ESI 344.2 [M+H]⁺).

Example: Préparation of ethyl (5)-3-amino-3-(4-fluoro-2’,5,6’-trimethyl-4’(trifluoromethyI)-|l,l'-biphenyll-3-yI)propanoatehydrochIoride

Step 1: 2,6-dimethyl-4-(trifluoromethyl)aniline

Br

K₂CO₃Pd(dppf)CI₂ dioxane/H₂O

A mixture of 2,6-dibromo-4-(trifluoromethyl)aniline (638 mg, 2.00 mmol, 1.0 eq), 2,4,6trimethyl-l,3,5,2,4,6-trioxatriborinane (3.5 M in THF, 3.43 mL, 12.00 mmol, 6.0 eq), K2CO3 (1.10 g, 7.96 mmol, 3.98 eq) and Pd(dppf)Cl₂ (245 mg, 0.30 mmol, 0.15 eq) in dioxane (6 mL) and water (1 mL) was stirred at 90 °C for 8 hours under nitrogen atmosphère. The mixture was filtered through a pad of Celite, washed with ethyl acetate (100 mL) and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 20:1) to provide 2,6-dimethyl-4-(trifluoromethyl)aniline as a colorless oil (1.63 g). Yield 48% (ESI 190.1 (M+H)⁺).

194

Step 2: 2-bromo-l,3-dimethyl-5-(trifluoromethyl)benzene

A mixture of 2,6-dimethyl-4-(trifluoromethyl)aniline (793 mg, 4.19 mmol, 1.0 eq), tert-butyl nitrite (0.94 mL, 7.84 mmol, 1.9 eq) and copper(I) bromide (794 mg, 5.53 mmol, 1.3 eq) in anhydrous acetonitrile (16 mL) was stirred at 60 °C for 2 hours under nitrogen atmosphère. LCMS showed that the reaction was completed. The mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (Petroleum ether: EtOAc 6:1) to provide 2-bromo-l,3-dimethyl-5-(trifluoromethyl)benzene as a colorless oil (975 mg). Yield 46%. Ή NMR (400 MHz, DMSO-d₆) δ: 7.55 (s, 2H), 2.42 (s, 6H).

Step 3: ethyl (S)-3-((fôrt-butoxycarbonyl)amino)-3-(4-fluoro-2’,5,6’-trimethyl-4’· (trifluoromethyl)-[l,l’-biphenyl]-3-yl)propanoate

PdCI₂(dppf) / K₂CO₃

1,4-dioxane / H₂O

To a solution of ethyl (S)-3-((ierZ-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (519 mg, 1.15 mmol, 1.0 eq) in dioxane (36 mL) was added 2-bromo-l,3-dimethyl-5-(trifluoromethyl)benzene (306 mg, 1.21 mmol, 1.1 eq), Pd(dppf)Ch (188 mg, 0.23 mmol, 0.2 eq), K2CO3 (477 mg, 3.45 mmol, 3.0 eq) and water (3.6 mL). The reaction mixture was stirred at 110 °C for 18 hours under nitrogen atmosphère. The mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 6:1) to provide ethyl (5)-3-((ieri-butoxycarbonyl)amino)-3-(4fluoro^'^ô’-trimethyM'-itrifluoromethylHLr-biphenylJ-S-yDpropanoate as a light brown oil (308 mg). Yield 54%. (ESI 398.1 [M+H-100]⁺).

195

Step 5: ethyl (S)-3-amino-3-(4-fluoro-2’,5,6’-trimethyI-4’-(trifluoromethyI)-[l,l’-biphenyIl3-yl)propanoate hydrochloride

To a stirred solution of ethyl (5)-3-((Zeri-butoxycarbonyl)amino)-3-(4-fluoro-2',5,6'-trimethyl-4'· (trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (308 mg, 0.62 mmol, 1.0 eq) in DCM (4 mL) was added HCl-dioxane (4 M, 4.0 mL, 16.0 mmol, 25.8 eq). The mixture was stirred at room température for 2 hours. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo to provide ethyl (S)-3-amino-3-(4-fluoro-2’,5,6'-trimethyl-4'(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate hydrochloride as a yellow oil (260 mg). Yield 97% (ESI 398.1 [M+H]⁺).

Préparation of ethyl (5)-3-amino-3-(4’-cyclopropyl-4-fluoro-2’,5,6’-trimethyl-[l,l*biphenylJ-3-yl)propanoate

Step 1:4-cyclopropyI-2,6-dimethylaniline

To a mixture of4-bromo-2,6-dimethylaniline (2.0 g, 10.0 mmol, 1.0 eq), cyclopropylboronic acid (1.03 g, 12.0 mmol, 1.2 eq) in toluene (15 mL) under nitrogen atmosphère was added a solution of K3PO4 (4.2 g, 20.0 mmol, 2.0 eq) in H₂O (3 mL), PCy₃ (280.0 mg, 1.0 mmol, 0.1 eq) and Pd(OAc)2 (224.0 mg, 1.0 mmol, 0.1 eq). The mixture was stirred at 100 °C for 4 hours under nitrogen atmosphère. Water (30 mL) was added and the solution was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SÛ4, fdtered and concentrated in vacuo. The residue was purified by silica gel column

196 (petroleum ether: EtOAc 2:1) to provide 4-cyclopropyl-2,6-dimethylaniline (0.8 g) used in the next step without further purification. Yield 93% (ESI 162.2 [M+H]⁺).

Step 2:2-bromo-5-cyclopropyl-l,3-dimethyIbenzene

p-TsOH,CuBr ----------------*NaNO₂/H₂O, CH₃CN

To a mixture of4-cyclopropyl-2,6-dimethyIaniline (800.0 mg, 4.9 mmol, 1.0 eq) in ACN (10 mL) and H2O (1 mL) was added p-toluenesulphonic acid (3.4 g, 19.8 mmo, 4.0 eq). The mixture was stirred at 0 °C for 10 mins under under nitrogen atmosphère. A solution of NabKh (685.0 mg, 9.93 mmol, 2.0 eq) in H2O (2 mL) was added dropwise and the mixture was stirred 0 °C for 30 mins. CuBr (4.4 g, 19.8 mmol, 4.0 eq) was added to the reaction mixture and stirred at room température for 4 hours. Water (50 mL) was added and the solution was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 19:1) to provide 2-bromo-5-cyclopropyl-l,3-dimethylbenzene as a yellow oil (800.0 mg) used in the next step without further purification. Yield 49% (ESI 225.1 (Μ+ΗΓ, 227.1 (M+H)⁺).

Step 3: ethyl (5)-3-((fert-butoxycarbonyl)amino)-3-(4'-cyclopropyl-4-fluoro-2',5,6'trimethyI-[l,l’-biphenyl]-3-yl)propanoate

To a mixture of 2-bromo-5-cyclopropyl-l,3-dimethylbenzene (800 mg, 3.6 mmol, 1.0 eq) and ethyl (S)-3-((iert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2

197 dioxaborolan-2-yl)phenyl)propanoate (1.6 g, 3.6 mmol, 1.0 eq) in 1,4-dioxane (10 mL) under nitrogen atmosphère was added a solution of K2CO3 (1.0 g, 7.2 mmol, 2.0 eq) in H2O (1 mL) and Pd(dppf)Cl₂ (260 mg, 0.36 mmol, 0.1 eq). The mixture was stirred at 110 °C for 2 hours under nitrogen atmosphère. Water (30 mL) was added and the solution was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na₂SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (Petroleum ether: EtOAc 19:1) to provide ethyl (5)-3-((ier/-butoxycarbonyl)amino)-3-(4'cyclopropyl-4-fluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoateas a brown oil (500 mg). Yield 30% (ESI 370.1 [M-100+H]⁺).

Step 4: ethyl (S)-3-amino-3-(4^cyclopropyl-4-fluoro-2’,5,6’-triniethyl-[l,r-biphenyll-3yl)propanoate hydrochloride

To a stirred solution of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-cyclopropyl-4-fluoro2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate (900 mg, 1.91 mmol, 1.0 eq) in DCM (5 mL) was added HCI-dioxane (4 M, 5.0 mL, 20.0 mmol, 10.47 eq) and stirred at room température for 1 hour. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo to provide ethyl (S)-3-amino-3-(4'-cyclopropyl-4-fluoro-2',5,6^,-trimethyl-[l,r-biphenyl]3-yl)propanoate hydrochloride as a green-yellow foam (710 mg). Yield 91% (ESI 370.2 (M+H]⁺).

Préparation of ethyl (5)-3-amino-3-(4-fluoro-4’-methoxy-2’,5,6’-trimethyI-ll,l’-biphenyl]-3yl)propanoate hydrochloride

198

Step 1: ethyl (5)-3-((fert-butoxycarbonyI)amîno)-3-(4-fluoro-4’-methoxy-2’,5,6’-trimethyl· [l,l’-biphenyl]-3-yl)propanoate

To a solution of ethyl (S)-3-((7erZ-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,55 tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (350 mg, 0.77 mmol, 1.0 eq) in dioxane (10 mL) was added 2-bromo-5-methoxy-l,3-dimethylbenzenc (166 mg, 0.77 mmol, 1.0 eq), Pd(dppf)Cl₂ (56 mg, 0.077 mmol, 0.1 eq), K2CO3 (213 mg, 1.54 mmol, 2.0 eq) and water (2 mL). The reaction mixture was stirred at 110 °C for 3 hours under nitrogen atmosphère. Water (10 mL) was added and the solution was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4. filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 7:1) to provide ethyl (S)-3-((ter/-butoxycarbonyl)amino)-3-(4-fluoro-4'-methoxy-2',5,6'trimethyl-[l,l'-biphenyl]-3-yl)propanoate as a colorless oil (230 mg). Yield 65% (ESI 360.2 [M+H-100]⁺).

Step 2: ethyl (S)-3-amino-3-(4-fluoro-4’-methoxy-2’,5,6’-trimethyl-[l,l’-biphenyl]-3 yl)propanoate hydrochloride

199

To a stirred solution of ethyl (S)-3-((/er/-butoxycarbonyl)amino)-3-(4-fluoro-4'-methoxy-2',5,6'trimethyl-[l,r-biphenyl]-3-yl)propanoate (200 mg, 0.43 mmol, 1.0 eq) in DCM (7 mL) was added HCl-dioxane (4 M, 2.0 mL, 4.0 mmol, 9.3 eq). The mixture was stirred at room température for 1 hour. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo to provide ethyl (5)-3-amino-3-(4-fluoro-4'-methoxy-2',5,6'-trimethyl[l,r-biphenyl]-3-yl)propanoate hydrochloride as a yellow oil (160 mg). Yield 93% (ESI 360.2 [M+H]⁺).

Préparation of ethyl (S)-3-amino-3-(4’-cyano-4-fluoro-2’,5,6’-trimethyI-(l,r-biphenyl]-3yl)propanoate

Step 1: ethyl (S)-3-((r<?ri-butoxycarbonyl)amino)-3-(4'-cyano-4-fluoro-2',5,6'-trimethyl[l,l’-biphenyI]-3-yl)propanoate

A mixture of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5· tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate(450 mg, 1 mmol, 1.0 eq), 4-bromo-3,5dimethylbenzonitrile (316 mg, 1.5 mmol, 1.5 eq), Pd(dppf)CI₂ (37 mg, 0.05 mmol, 0.05 eq) and K2CO3 (414 mg, 3 mmol, 3.0 eq) in 1,4-dioxane (8 mL) and water (2 mL) was stirred at 110 °C for 2 hours under nitrogen atmosphère. Water (10 mL) was added and the solution was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 1:1) to provide ethyl (S)-3-((tert-butoxycarbonyl)amino)-3(4’-cyano-4-fluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate as a colorless oil (320 mg). Yield 70% (ESI 455.2 (M+H]⁺).

200

Step 2: ethyl (S>3-amino-3-(4*-cyano-4-fIuoro-2’,5,6’-trimethyl-[l,l’-biphenyll-3yl)propanoate

To a stirred solution of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-cyano-4-fluoro-2^,,5,6’5 trimethyl-[ 1,1 '-biphenyl]-3-yl)propanoate (320 mg, 0.7 mmol, 1.0 eq) in DCM (2 mL) was added

HCl-dioxane (4 M, 2.0 mL, 4.0 mmol, 5.7 eq). The mixture was stirred at room température for 2 hours. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo to provide ethyl (S)-3-amino-3-(4'-cyano-4-fluoro-2^,,5,6^,-trimethyl-[ 1,1 ’-biphenyl]-3-yl)propanoate as a colorless oil (250 mg). Yield 100% (ESI 355.1 [M+H]⁺).

Préparation of ethyl (S)-3-amino-3-(4’-((dimethyIamino)methyl)-4-fluoro-2’,5,6’-trimethyl[1,1 ’-biphenyI[-3-yI)propanoate

Step 1: ethyl (5)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-4’-forniyl-2*,5,6’-triniethyl[ l,r-biphenyl[-3-yl)propanoate

201

A mixture of ethyl (S)-3-((terZ-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (465 mg, 1.03 mmol, 1.1 eq), 4-bromo3,5-dimethylbenzaldehyde (200 mg, 0.93 mmol, 1.0 eq), K2CO3 (259 mg, 1.87 mmol, 2.0 eq) and l,r-Bis(diphenylphosphino) ferrocene-palladium(II)dichloride dichloromethane complex (68 mg, 0.09 mmol, 0.1 eq) in dioxane (10 mL) and H2O (1 mL) was stirred at 80 °C for 3 hours under nitrogen atmosphère. LCMS showed that the reaction was completed. The mixture was cooled to room température. Water (50 mL) was added and the solution was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SÛ4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 1:3) to provide ethyl (5)-3-((/erZ-butoxycarbonyl)amino)-3-(4-fluoro4'-formyl-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate as a yellow oil (300 mg). Yield 64% (ESI 358.1 [M+H-100D

Step 2: ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4’-((dimethylamino)methyI)-4-fluoro2*,5,6’-trimethyl-[l,l’-biphenyl]-3-yI)propanoate

A mixture of ethyl (S)-3-((te/7-butoxycarbonyl)amino)-3-(4-fluoro-4'-formyl-2',5,6'-trimethyl[l,l'-biphenyl]-3-yl)propanoate (1.3 g, 2.8 mmol, 1.0 eq) and dimethylamine hydrochloride (233 mg, 2.9 mmol, 1.05 eq) in DCE (10 mL) was stirred at room température for 30 mins. Sodium triacetoxyborohydride (1.2 g, 5.6 mmol, 2.0 eq) was added and stirred at room température for 16 hours. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH 9:1) to provide ethyl (S)-3-((ieri-butoxycarbonyl)amino)-3-(4'((dimethylamino)methyl)-4-fluoro-2^,,5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate as a yellow oil (800 mg). Yield 58.7% (ESI 487.2 (M+H)⁺).

202

Step 3: ethyl (S)-3-amino-3-(4’-((dimethylamino)methyl)-4-fluoro-2’,5,6^,-trimethyl-(l,l’ biphenylJ-3-yl)propanoate

To a stirred solution of ethyl (S)-3-((ic77-butoxycarbonyl)amino)-3-(4'-((dimethylamino)methyl)5 4-fluoro-2',5,6’-trimethyl-[l, 1 ’-biphenyl]-3-yl)propanoate (800 mg, 1.64 mmol, 1.0 eq) in DCM (10 mL) was added HCl-dioxane (4 M, 3mL, 12.0 mmol) and stirred at room température for 1 hour. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo and the residue was purified by reverse phase on a C18 / 40 g column (A: water 10 mM NH4HCO3.B: MeOH, 0-100%) to provideethyl (S)-3-amino-3-(4’-((dimethylamino)methyl)-410 fluoro-2’,5,6'-trimethyl-[ 1,1 ’-biphenyl]-3-yl)propanoate as a white solid (600 mg). Yield 94% (ESI 387.2 (M+H)⁺).

Préparation of ethyl (S)-3-amino-3-(4-fluoro-4’-((3-fluoroazetidin-l-yl)methyl)-2’,5,6’trimethyl-[l,l’-biphenyl]-3-yl)propanoate

Step 1: ethyl (S)-3-((tert-butoxycarbonyI)amino)-3-(4-fluoro-4'-((3-fluoroazetidin-lyl)methyl)-2',5,6’-trimethyl-[l,r-biphenylJ-3-yI)propanoate

203

A mixture of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-4’-formyl-2’,5,6'-trimethyl[l,r-biphenyl]-3-yl)propanoate (1.3 g, 2.8 mmol, 1.0 eq) and 3-fluoroazetidine hydrochloride (233 mg, 2.9 mmol, 1.05 eq) in DCM (10 mL) was stirred at room température for 30 mins.

Sodium triacetoxyborohydride (1.2 g, 5.6 mmol, 2.0 eq) was added and stirred at room température for 16 hours. The solvent was removed in vacuo and the residue was purifîed by silica gel column (DCM: MeOH 9:1) to provide ethyl (5)-3-(((R)-terr-butylsulfmyl)amino)-3-(4fluoro-4'-((3-fluorocyclobutyl)methyl)-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)propanoate as yellow oil (800 mg). Yield 54.7% (ESI 517.2 [M+H]⁺).

Step 2: ethyl (S)-3-amino-3-(4-fluoro-4’-((3-fluoroazetidin-l-yl)methyl)-2’,5,6Mrimethyl[l,l’-biphenyl)-3-yl)propanoate

To a solution of ethyl (S)-3-((rert-butoxycarbonyl)amino)-3-(4-fluoro-4'-((3-fluoroazetidin-l yl)methyl)-2',5,6’-trimethyl-[l,r-biphenyl]-3-yl)propanoate (800 mg, 1.5 mmol, 1.0 eq) in DCM

204 (10 mL) was added HCl-dioxane (4M, 10.0 mL, 40.0 mmol, 26.7 eq) and stirred at room température for 1 hour. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC onaC18 /120 g column (A: water/0.01%TFA,B: MeOH, 0-100%) to provide ethyl (5)-3-amino-3-(4-fluoro-4'-((3-fluoroazetidin-l-yl)methyl)-2’,5,6'-trimethyl-[ 1,1biphenyl]-3-yl)propanoate as a white solid (500 mg). Yield 78% (ESI 417.1 [M+H]⁺).

Préparation of ethyl (Y)-3-amino-3-(2'-cyclopropyl-4-fluoro-4',5,6'-trimethyl-[l,l'biphenyl]-3-yl)propanoate

Step 1: 2-bromo-l-chloro-3,5-dimethylbenzene

t-BuONO _rCuBrj, ACN, 60°C, 2h

To a mixture of 2-chloro-4,6-dimethyIaniline (3.0 g, 19.3 mmol, 1.00 eq) and CuBr₂ (21.5 g, 96.5 mmol, 5.00 eq) in ACN (50 mL) was added t-BuONO (5.96 g, 58.9 mmol, 3.00 eq) and stirred at 60 °C for 2 hours under nitrogen atmosphère. The mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (pet ether 100%) to give compound 2-bromo-l-chloro-3,5-dimethylbenzene as colorless oil (2.8 g). Yield: 67% (ESI 220 [M+H]+).

Step 2: ethyl (5)-3-((fer/-butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro-4',5,6'-trimethyl|l,l’-biphenyl]-3-yl)propanoate

To a mixture of 2-bromo-l-chloro-3,5-dimethylbenzene (483 mg, 2.2 mmol, 1.10 eq), ethyl (S)3-((fért-butoxycarbonyl)amino)-3-(2-fluoro-3-methyI-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan

205

2-yl)phenyl)propanoate (902 mg, 2.0 mmol, 1.00 eq) in dioxane (10 mL) under nitrogen atmosphère was added a solution of K2CO3 (552 mg, 4.0 mmol, 2.00 eq) in H₂O (5 mL) and Pd(dppf)C12 (146 mg, 0.2 mmol, 0.10 eq). The mixture was stirred at 100 °C for 2 hours under nitrogen atmosphère. Water (30 mL) was added and the solution was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (70 mL), dried over anhydrous Na2SO4. filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10:1) to provide ethyl (S)-3-((ieri-butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro4’,5,6’-trimethyl-[l,r-biphenyl]-3-yl)propanoate as colorless oil (880 mg). Yield 95% (ESI 364 [M-100+H]*).

Step 3: ethyl (5>3-((te/7-butoxycarbonyl)amino)-3-(2'-cydopropyl-4-fluoro-4',5,6'trimethyl-[l,l’-biphenyl]-3-yI)propanoate

To a solution of ethyl (₁S)-3-((ter/-butoxycarbonyl)amino)-3-(2'-chIoro-4-fluoro-4',5,6'-trimethyl[l,l'-biphenyl]-3-yl)propanoate (880 mg, 1.9 mmol, 1.00 eq), cyclopropylboronic acid (327 mg, 3.8 mmol, 2.00 eq) in toluene (10 mL) under nitrogen atmosphère was added a solution of K3PO4 (807 mg, 3.8 mmol, 2.00 eq) in H2O (2 mL), Pd(OAc)2 (43 mg, 0.19 mmol, 0.10 eq) and PCy3 (107 mg, 0.38 mmol, 0.20 eq). The mixture was stirred at 110 °C for 36 hours under nitrogen atmosphère. Water (30 mL) was added and the solution was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (70 mL), dried over anhydrous Na2SO4. filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether EtOAc 2:1) to provide ethyl (S)-3-((/erZ-butoxycarbonyl)amino)-3-(2'-cyclopropyl-4-fluoro4',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate as a gray solid (625 mg). Yield 70% (ESI 370 [M-100+H]⁺).

Step 4: ethyl (S)-3-amino-3-(2’-cyclopropyI-4-fluoro-4’,5,6'-trimethyl-ll,r-biphenyl]-3yl)propanoate hydrochloride

206

To a solution of ethyl (₁S)-3-((/err-butoxycarbonyl)amino)-3-(2'-cyclopropyl-4-fluoro-4',5,6’trimethyl-[l,r-biphenyl]-3-yl)propanoate (250 mg, 0.53 mmol, 1.00 eq) in 1,4-dioxane (6 mL) was added HCl-dioxane (4M4.0 mL, 16.0 mmol, 30.2 eq). The mixture was stirred at room température for 1 hour. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo to provide ethyl (S)-3-amino-3-(2'-cyclopropyl-4-fluoro-4',5,6'-trimethyl[l,l'-biphenyl]-3-yl)propanoate hydrochloride as a white solid (215 mg), used directly in the next reaction without further purification. Yield 100% (ESI 370 [M+H]⁺).

Préparation of ethyl (S)-3-amino-3-(3',4-difluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3 yl)propanoate

Step 1:2-bromo-6-fluoro-3-methylbenzaldehyde

Br

DMF, LPA

THF, -78°C, 3h

Br

To a mixture of 2-bromo-4-fluoro-l-methylbenzene (5.0 g, 26.5 mmol, 1.00 eq) in anhydrous THF (50 mL) under nitrogen atmosphère was added lithium diisopropylamide (2.0 M, 14.6 mL, 29.2 mmol, 1.10 eq¹) at -78°C and stirred at -78°C for 1 hour. DMF (3.87 g, 53 mmol, 2.00 eq) was added to the reaction mixture at -78°C and stirred at -78°C for 0.5 hour, then slowly warmed to room température and stirred for 2 hours. The reaction was quenched with water (20 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous NaiSO·!, filtered and concentrated in vacuo to give the crude product 2-bromo-6-fluoro-3-methylbenzaldehyde as a brown liquid (4.2 g). Yield 73%. Ή NMR (400 MHz, MeOD) δ 10.02 (s, 1H), 7.45-7.17 (m, 1H), 7.05-7.00 (m, 1H), 2.26 (s, 3H).

207

Step 2: (2-bromo-6-fluoro-3-methylphenyl)methanol

To a mixture of 2-bromo-6-fluoro-3-methylbenzaldehyde (3.0 g, 13.8 mmol, 1.00 eq) in MeOH (30 mL) under nitrogen atmosphère was added NaBFL (1.5 g, 41.4 mmol, 3.00 eq) at 0°C and stirred at room température for 2 hours. The mixture was quenched with water (50 mL), extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (80 mL), dried over anhydrous NaiSO.», filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10:1) to provide (2-bromo-6-fluoro-3methylphenyl)methanol as a white solid (2.7 g). Yield 90%

Step 3: (2-bromo-3-(bromomethyl)-4-fluoro-l-methylbenzene

To a mixture of (2-bromo-6-fluoro-3-methylphenyl)methanol (3.2 g, 14.6 mmol, 1.00 eq) in THF (50 mL) under nitrogen atmosphère was added PBn (3 mL, 29.2 mmol, 2.00 eq) at room température and stirred for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 99:1) to provide 2-bromo-3(bromomethyl)-4-fluoro-l-methylbenzene as a white solid (3.58 g). Yield 90% Ή NMR (400 MHz, MeOD) δ 7.33-7.30 (m, 1H), 7.09-7.04 (m, 1H), 4.72 (d, J=2.0 Hz, 2H), 2.40 (s, 3H).

Step 4:2-bromo-4-fluoro-l,3-dimethyibenzene

NaBHL, AaNO^

DMF, 25°C, 0.5h

Br

To a mixture of 2-bromo-3-(bromomethyl)-4-fluoro-l-methylbenzene (2.0 g, 7.09 mmol, 1.00 eq) in DMF (20 mL) was added NaBH4 (0.536 g, 14.18 mmol, 2.00 eq) and AgNOj (2.4 g, 14.18

208 mmol, 2.00 eq) at room température. The reaction was stirred at room température for 0.5 hour. The mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na^SO.}, filtered and concentrated in vacuo. The residue was purified by silica gel column (DCM 100%) to provide 2-bromo-4-fluoro-l,3-dimethylbenzene as colorless oil (1.00 g). Yield 69% Ή NMR (400 MHz, CDCh) δ 7.09 - 7.01 (m, 1H), 6.90 (t, J= 8.7 Hz, 1H), 2.37 (s, 3H), 2.34 (d, J= 2.4 Hz, 3H).

Step 5: ethyl (5)-3-((tert-butoxycarbonyl)amino)-3-(3’,4-difluoro-2’,5,6’-trimethyl-[l,l’biphenyl]-3-yl)propanoate

To a mixture of 2-bromo-4-fluoro-l,3-dimethylbenzene (800 mg, 3.93 mmol, 1.00 eq), ethyl (5)3-((ie/7-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan2-yl)phenyl)propanoate (1.77 g, 3.93 mmol, 1.00 eq) in dioxane (12 mL) under nitrogen atmosphère was added a solution of K2CO3 (1.08 g, 7.86 mmol, 2.00 eq) in H2O (2 mL) and Pd(dppf)Ch (658 mg, 0.39 mmol, 0.10 eq). The mixture was stirred at 100 °C for 2 hours under nitrogen atmosphère. Water (30 mL) was added and the solution was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (70 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC on a C18/40 g column (A: water 10 mM NfLHCOj.B: MeOH, 0~100%) to provide ethyl (5)-3((ter/-butoxycarbonyl)amino)-3-(3’,4-difluoro-2',5,6'-trimethyl-[l,l'-biphenyl]-3-yl)propanoate as colorless oil (1.2 g). Yield 68% (ESI 348.1 [M-100+H]⁺).

Step 6: ethyl (5)-3-amino-3-(3',4-difluoro-2’,5,6’-trimethyl-ll,l’-biphenyIl-3-yl)propanoate hydrochloride

209

To a mixture of product ethyl (S)-3-((re/7-butoxycarbonyl)amino)-3-(3',4-difluoro-2',5,6'trimcthyl-[l,r-biphenyl]-3-yl)propanoate (1.2 g, 2.68 mmol, 1.00 eq) in 1,4-dioxane (6 mL) was added HCl-dioxane (4M 4.0 mL, 16.0 mmol, 5.97 eq). The mixture was stirred at room température for 1 hour. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo to provide ethyl (5)-3-amino-3-(3',4-difluoro-2',5,6'-trimethyl-[l,rbiphenyl]-3-yl)propanoate hydrochloride (1.0 g crude) used directly in the next reaction without further purification. (ESI 348.2 [M+H]⁺).

Préparation of (S)-ethyl 3-amino-3-(4-fluoro-3’-methoxy-2’,5,6’-trimethylbiphenyl-3yl)propanoate

Step 1: l-bromo-2,4-dimethyl-3-nitrobenzene

To a mixture of l,3-dimethyl-2-nitrobenzene (10 g, 66 mmol, 1.0 eq) in DCM (100 mL) was added FeBr₃ (390 mg, 211.32 mmol, 0.02 eq) and Fe ( 1.12 g, 20 mmol, 0.3 eq). Br₂ ( 11.6 g, 72.6 mmol, 1.1 eq) was added dropwise and stirred at 60°C for 16 hours. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column (pet ether) to provide 1bromo-2,4-dimethyl-3-nitrobenzene as a white solid (10 g). Yield 66%.

Step 2: l-methoxy-2,4-dimethyl-3-nitrobenzene

210

NaOCH₃, CuBr

MeOH, DMF

To a mixture of l-bromo-2,4-dimethyl-3-nitrobenzene (8 g, 35 mmol, 1.0 eq) in MeOH (80 mL) and DMF (80 mL) was added NaOCHj (5.67 g, 105 mmol, 3 eq) and CuBr (1 g, 7 mmol, 0.2 eq) at room température. The mixture was stirred at 110°C for 16 hours. The réaction mixture was filtered. The filtrate was diluted with water (100 mL), extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NajSO-i, filtered and concentrated in vacuo. The residue was purified by silica gel column (100% pet ether) to provide l-methoxy-2,4-dimethyl-3-nitrobenzene as a colorless oil (5.8 g). Yield 91% (ESI 182.2 [M+H]*).

Step 3: 3-methoxy-2,6-dimethylaniline

NH₄CI, Zn

MeOH. H₂O

To a mixture of l-methoxy-2,4-dimethyl-3-nitrobenzene (5.8 g, 32 mmol, 1.0 eq) in MeOH (60 mL) and H₂O (6 mL) at 0°C was added NH4CI (5.18 g, 96 mmol, 3.0 eq) and Zn (20.8 g, 320 mmol, 10 eq). The mixture was stirred at room température for 4 hours. LCMS showed that the reaction was completed. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 1:1) to provide 3-methoxy-2,6dimethylaniline as yellow oil (2.8 g). Yield 58% (ESI 152.2[M+H]⁺).

Step 4: 2-bromo-4-methoxy-l,3-dimethylbenzene

211

To a mixture of 3-methoxy-2,6-dimethylaniline (2 g, 13.24 mmol, 1.0 eq) in MeCN (30 mL) was added t-BuONO (2.06 g, 20 mmol, 1.5 eq) at 0°C, then CuBr(2.27 g, 15.89 mmol, 1.2 eq) was added. The mixture was stirred at 60°C for 2 hours. LCMS showed that the reaction was completed. The reaction mixture was concentrated in vacuo and purified by silica gel column (pet ether) to provide 2-bromo-4-methoxy-l,3-dimethylbenzene as a colorless oil (800 mg). Yield 28%.

Step 5: (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(4-fluoro-3’-methoxy-2’,5,6’trimethylbiphenyl-3-yl)propanoate

A mixture of 2-bromo-4-methoxy-l,3-dimethylbenzene (700 mg, 3.27 mmol, 1.00 eq), (S)-ethyl 3-(tert-butoxycarbonyIamino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenyl)propanoate (1.47 g, 3.27 mmol, 1.0 eq), K.2CO3(L35 g, 9.81 mmol, 3 eq) and Pd(dppf)Cl₂ (239 mg, 0.327 mmol, 0.1 eq) in dioxane (10 mL) and H₂O (1 mL) was stirred at 110°C for 4 hours under nitrogen atmosphère. LCMS showed that the reaction was completed. The mixture was coolcd to room température. Water (30 mL) was added and the solution was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SÛ4. filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 5:1) to provide (S)-ethyl 3-(tert-butoxycarbonylamino)-3(4-fluoro-3'-methoxy-2',5,6'-trimethylbiphenyl-3-yl)propanoate (1 g) as a colorless oil. Yield 67% (ESI 360.1 [M-Boc+1]⁺).

Step 6: (S)-ethyl 3-amino-3-(4-fluoro-3’-methoxy-2',5,6’-trimethylbiphenyI-3-yl)propanoate

212

To a stirred solution of (S)-ethyl 3-(tert-butoxycarbonyIamino)-3-(4-fluoro-3^,-methoxy-2',5,6’trimethylbiphenyi-3-yl)propanoate (1 g, 2.18 mmol, 1.00 eq) in DCM (8 mL) was added HC1dioxane (4 M, 2.18 mL, 8.72 mmol, 4 eq). The mixture was stirred at room température for 2 hours. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo and the residue was purifïed by reverse phase HPLC on a C18/80g column (A: water 10 mM NILHCOj.B: MeOH, 0-100%) to provide (S)-ethyl 3-amino-3-(4-fluoro-3'-methoxy-2^,,5,6'trimethylbiphenyl-3-yl)propanoate (600 mg) as a colorless oil. Yield 77% (ESI 360.1 (M+H]⁺).

Préparation of ethyl (S')-3-amino-3-(6'-cyano-4-fluoro-2',3',5-trimethyI-[l,r-biphenyl]-310 yl)propanoate

Step 1: ethyl (S)-3-(((Æ)-tert-butylsulfînyl)amino)-3-(6’-cyano-4-fluoro-2*,3’,5-trimethyl | l,l’-biphenyl]-3-yI)propanoate

K3PO4, X-phosPdG2 dioxane,H₂O, 80°C

A mixture of ethyl (5)-3-(((7?)-i<?r/-butylsulfinyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,515 tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate ( 1.7 g, 3.6 mmol,, 2.0 eq), 2-chioro-3,4dimethylbenzonitrile (300 mg, 1.8 mmol, 1.0 eq), K3PO4 (1.2 g, 5.4 mmol, 3.0 eq) and XPhosPdG2 (140 mg, 0.18 mmol, 0.1 eq) in dioxane (30 mL) and H2O (3 mL) was stirred at 80 °C for 2 hours under nitrogen atmosphère. LCMS showed that the reaction was completed. The

213 mixture was cooled to room température. Water (20 mL) was added and the solution was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SÛ4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 1:1) to provide ethyl (S)-3-(((Æ)-terrbutylsulfinyl)amino)-3-(6’-cyano-4-fluoro-2',3^,,5-trimethyl-[ 1,1 ’-biphenyl]-3-yl)propanoate (500 mg) as a yellow oil. Yield 60% (ESI 459.3 [M+H]⁺).

Step 2: ethyl (S)-3-amino-3-(6'-cyano-4-fIuoro-2',3',5-trimethyl-ll,r-biphenyl]-3yl)propanoate

To a stirred solution of ethyl (5)-3-(((/?)-/ert-butylsulfinyl)amino)-3-(6^,-cyano-4-fluoro-2^,,3',5trimethyl-[l,r-biphenyl]-3-yl)propanoate (500 mg, 1.1 mmol, 1.0 eq) in DCM (10 mL) was added HCl-dioxane (4 M, 10 mL, 40.0 mmol, 36.4 eq). The mixture was stirred at room température for 1 hour. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl 8/40 g column (A: water 10 mM NH₄HCO3,B: MeOH, 0-100%) to provide ethyl (<S)-3-amino-3-(6'cyano-4-fluoro-2',3',5-trimethyl-[l,r-biphenyl]-3-yl)propanoate (200 mg) as a colorless oil. Yield 51.8% (ESI 355.2 [M+H]⁺).

Préparation of (S)-ethyl 3-amino-3-(3',4-difluoro-2',4’,5,6'-tetramethylbiphenyI-3yl)propanoate

Step 1: (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(3’,4-difluoro-2’,4’,5,6’tetramethyIbiphenyl-3-yI)propanoate

214

Ο

Το a mixture of (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(2-fluoro-3-methyl-5-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (500 mg, 1.14 mmol, 1 eq) and 2-bromo4-fluoro-l,3,5-trimethylbenzene (309 mg, 1.43 mmol, 1.2 eq) in dioxane (10 mL) was added a solution of KiCOj (314.6 mg, 2.28 mmol, 2 eq) in H₂O (2 mL) and Pd(dppf)Cl₂ (80 mg, 0.11 mmol, 0.1 eq). The mixture was heated to 110 °C for 2 hours under nitrogen atmosphère. Water (20 mL) was added and the solution was extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 1:1) to give methyl (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(3',4-difluoro10 2^,,4',5,6'-tetramethylbiphenyl-3-yl)propanoate as a colorless oil (500 mg). Yield 97.8% (ESI 461.5 [M+H]⁺).

Step 2: (S)-ethyl 3-amino-3-(3’,4-difluoro-2',4’,5,6'-tetramethyIbiphenyl-3-yl)propanoate

To a mixture of methyl (S)-methyl 3-(tert-butoxycarbonylamino)-3-(3^,,4-difluoro-2',4',5,6’15 tetramethylbiphenyl-3-yl)propanoate (500 mg, 1.12 mmol, 1 eq) in DCM (6 mL) was added HCl-dioxane (4 M, 3 mL, 12 mmol, 10 eq). The mixture was stirred at room température

215 for 1 hour. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo to give crude product (S)-ethyl 3-amino-3-(3',4-difluoro-2',4',5,6'-tetramethylbiphenyl-3yl)propanoate as a white solid (300 mg) used directly in the next reaction without further purification. Yield 77% (ESI 361.4s (M+H]⁺).

Préparation of ethyl (S)-3-(5-bromo-3-chIoro-2-fluorophenyl)-3-(((7î)-fértbutylsulfïnyl)amino)propanoate

Step 1: (Æ, E)-7V-(5-bromo-3-chIoro-2-fluorobenzylidene)-2-methylpropane-2-sulfïnamide

Ti(OEt)_4l THF

To a mixture of 5-bromo-3-chloro-2-fluorobenzaldehyde (10.0 g, 42.2 mmol, 1.00 eq) and (R)-2methylpropane-2-sulfinamide (5.6 g, 46.4 mmol, 1.1 eq) in anhydrous THF (100 mL) under nitrogen atmosphère was added Ti(OEt)4 (14.4 g, 63.3 mmol, 1.50 eq) dropwise at room température and the température maintained below 30 °C. The reaction mixture was warmed to 35 °C and stirred for 1 hour. LCMS showed that the reaction was completed. Water (100 mL) and EtOAc (100 mL) were added into the mixture and stirred at room température for 5 mins. The mixture was filtered and washed with EtOAc (50 mL). The filtrate was separated. The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4. filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 4:1) to provide (R, £)-N-(5-bromo-3-chloro-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide as a yellow oil (14.0 g). Yield 98% (ESI 341.9 (M+H)⁺).

Step 2: ethyl (S)-3-(5-bromo-3-chloro-2-fluorophenyI)-3-(((Æ)-terrbutylsu!finyl)amino)propanoate

216

To a mixture of Zn (13.0 g, 205.5 mmol, 5.00 eq) in anhydrous THF (200 mL) under nitrogen atmosphère was added chlorotrimethylsilane (888 mg, 8.22 mmol, 0.2 eq) dropwise at room température and stirred at 50 °C under nitrogen atmosphère for 1 hour. The mixture was cooled to 20-30°C. Ethyl 2-bromoacetate (17.1 g, 102.7 mmol, 2.50 eq) was added dropwise at room température under nitrogen atmosphère and stirred at 60 °C under for 1 hour. The reaction mixture was cooled to room température. A solution of (R, E)-#-(5-bromo-3-chloro-2fluorobenzylidene)-2-methylpropane-2-sulfinamide (14.0 g, 41.1 mmol, 1.00 eq) in anhydrous THF (20 mL) was added dropwise into the mixture at room température under nitrogen atmosphère and stirred at room température for 1 hour. LCMS showed that the reaction was completed. Water (100 mL) and EtOAc (100 mL) was added into the mixture and stirred at room température for 5 mins. The mixture was filtered. The filtrate was extracted with EtOAc (100 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 4:1) to provide ethyl (S)-3-(5-bromo-3-chloro-2-fluorophenyl)-3(((7?)-ii^>r/-butyIsulfinyl)amino)propanoate as a yellow oil (12.0 g). Yield 73% (ESI 429.9 (M+H)⁺).

Préparation of ethyl (S)-3-amino-3-(5-chloro-4-fluoro-2',6’-diniethyl-[l,l’-biphenyI]-3yl)propanoate

Step 1: ethyl (5)-3-(((Æ)-tert-butyIsulfinyI)amino)-3-(5-chloro-4-fluoro-2’,6’-dimethyI-|l,l’ biphenyl]-3-yl)propanoate

217

B'^0H

OH Pd(dppf)CI₂. K₂CO₃---------------------------* dioxane/H₂0,110°C

A mixture of ethyl (S)-3-(5-bromo-3-chloro-2-fluorophenyl)-3-(((/?)-ier/butylsulfinyl)amino)propanoate (4.0 g, 9.6 mmol, 1.00 eq), K2CO3 (8.0 g, 57.6 mmol, 2.0 eq) Pd(dppf)Ch(1.4 g, 1.9 mmol, 0.1 eq) and (2,6-dimethylphenyl)boronic acid (2.8 g, 19.2 mmol, 2.00 eq) in dioxane (40 mL) and H₂O (4 mL) was stirred at 80 °C for 16 hours under nitrogen atmosphère. The reaction mixture was cooled to room température and poured into 50 mL of water and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SÛ4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10:1) to provide ethyl (S)-3-(((R)-tertbutylsulfmyl)amino)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[l,l’-biphenyl]-3-yl)propanoate as a yellow oil (3.0 g). Yield 71% (ESI 454.1 (M+H)⁺)

Step 2: ethyl (S)-3-amino-3-(5-chIoro-4-fluoro-2',6’-dimethyl-[l,r-biphenyl]-3yl)propanoate

To a mixture of ethyl (5)-3-(((/?)-ZerZ-butylsulfinyl)amino)-3-(5-chloro-4-fluoro-2',6'-dimethyl[l,r-biphenyl]-3-yl)propanoate (3.0 g, 43.66 mmol, 1.0 eq) in DCM (20 mL) was added HC1dioxane (4 M, 20 mL, 80 mmol, 1.8 eq). The mixture was stirred at room température for 1 hour. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8/120g column (A: water 10 mM NILHCOj.B: MeOH, 0-100%) to provide ethyl (S)-3-amino-3-(5-chloro-4-fluoro-2',6'218 dimethyl-[l,l’-biphenyl]-3-yl)propanoate as a white solid (1.8 g). Yield 78% (ESI 350.0 [M+H]⁺).

Préparation of ethyl (S)-3-amino-3-(5-chIoro-4,4'-difluoro-2’,6’-dimethyl-[l,r-biphenyI]-3 yl)propanoate

Step 1: ethyl (5)-3-(((/?)-rert-butylsulfinyl)amino)-3-(5-chloro-4,4'-difluoro-2’,6’-dimethyl[l,l’-biphenyl]-3-yl)propanoate

To a mixture of ethyl (5)-3-(5-bromo-3-chloro-2-fluorophenyl)-3-(((7?)-Zer/butylsulfinyl)amino)propanoate (2.0 g, 4.66 mmol, 1.0 eq) and (4-fluoro-2,6dimethylphenyl)boronic acid (940 mg, 5.59 mmol, 1.2 eq) in dioxane (20 mL) was added a solution of K2CO3 (1.3 g, 9.32 mmol, 2.0 eq) in H2O (2 mL) and Pd(dppf)Cl₂ (341 mg, 0.47 mmol, 0.1 eq). The mixture was heated to 110 °C for 2 hours under nitrogen atmosphère. The reaction mixture was cooled to room température and poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SÛ4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 1:1) to provide ethyl (>S)-3-(((/?)-ZerZ-butylsulfinyl)amino)-3(5-chloro-4,4'-difluoro-2’,6'-dimethyl-[l,r-biphenyl]-3-yl)propanoate as a colorless oil (1.2 g). Yield 54% (ESI 472.1 [M+H]⁺).

Step 2: ethyl (S)-3-amino-3-(5-chloro-4,4’-difluoro-2’,6’-dimethyl-[l,r-biphenyl]-3yl)propanoate

219

To a mixture of ethyl (S)-3-(((Æ)-Zeri-butylsuIfinyl)amino)-3-(5-chloro-4,4'-difluoro-2',6'dimethyl-[l,r-biphenyl]-3-yl)propanoate (1.2 g, 2.54 mmol, 1.0 eq) in DCM (6 mL) was added HCl-dioxane (4 M, 3 mL, 12 mmol, 4.7 eq). The mixture was stirred at room température for 1 hour. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/80g column (A: water 0.01% TFA, B: MeOH, 0-100%) to provide ethyl (S)-3-amino-3-(5-chloro-4,4'-difluoro-2',6’dimethyl-[l,r-biphenyl]-3-yl)propanoate as a white solid (900 mg). Yield 96% (ESI 368.1 [M+H]⁺).

Préparation of ethyl (S)-3-amino-3-(5-chloro-4-fluoro-2’,4’,6’-trimethyI-[l,l*-biphenyIJ-3yl)propanoatc

Step 1: ethyl (S)-3-(((Æ)-tert-butyIsuIfinyl)amino)-3-(5-chloro-4-fluoro-2’,4',6^,-trimethyl [l,l’-biphenylJ-3-yI)propanoate

A mixture of ethyl (5)-3-(5-bromo-3-chloro-2-fluorophenyl)-3-(((7?)-ZerZbutylsulfinyl)amino)propanoate (2.0 g, 4.66 mmol, 1.0 eq), mesitylboronic acid (1.5 g, 9.33 mmol, 2.0 eq), K2CO3 (1.29 g, 9.32 mmol, 2.0 eq) and Pd(dppf)C12 (341 mg, 0.466 mmol, 0.1 eq) in dioxane (20 mL) and H2O (2 mL) was stirred at 110 °C under nitrogen atmosphère ovemight. After completion and cooling to room température, the reaction mixture was poured

220 into water (50 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL) and dried over anhydrous NaiSCb, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 1:1) to provide ethyl (S)3-(((7?)-Zer/-butylsulfinyl)amino)-3-(5-chloro-4-fiuoro-2',4^,,6'-trimethyl-[ 1,1 ’-biphenyl]-3yl)propanoate as a yellow oil (1.9 g). Yield 87% (ESI 468 (M+H)⁺).

Step 2: ethyl (5)-3-amino-3-(5-chloro-4-fluoro-2’,4’,6'-trimethyl-[l,l’-biphenyI]-3yl)propanoate

To a mixture of ethyl (S)-3-(((7?)-/er/-butylsulfinyl)amino)-3-(5-chloro-4-fluoro-2',4',6'trimethyl-[l,l'-biphenyl]-3-yl)propanoate (1.9 g, 4.06 mmol, 1.0 eq) in DCM (20 mL) was added HCl-dioxane (4 M, 3 mL, 12 mmol, 3.0 eq). The mixture was stirred at room température for 1 hour. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8/120g column (A: water 10 mM NH₄HCO3,B: MeOH, 0-100%) to provide ethyl (Y)-3-amino-3-(5-ch!oro-4-fiuoro-2',4',6'trimethyl-[l,l'-biphenyl]-3-yl)propanoate as a white solid (1.3 g). Yield 88% (ESI 364.1 (M+H)⁺).

Préparation of ethyl (S)-3-(5-bromo-2,3-difluorophenyl)-3-(((jR)-terrbutylsulfinyl)amino)propanoate

Step 1: (Æ, E)-A-(5-bromo-2,3-difluorobenzylidene)-2-methylpropane-2-sulfinamide

Br

Ti(OEt)₄, THF

221

To a mixture of 5-bromo-2,3-difluorobenzaldehyde (4.5 g, 20.36 mmol, 1.0 eq) and (R)-2methylpropane-2-sulfinamide (2.7 g, 22.40 mmol, 1.1 eq) in anhydrous THF (50 mL) under nitrogen atmosphère was added Ti(OEt)4 (9.3 g, 40.72 mmol, 2.0 eq) dropwise at room température while maintaining the température below 30 °C. The reaction mixture was warmed to 35 °C and stirred for 1 hour. LCMS showed that the reaction was completed. Water (50 mL) and EtOAc (50 mL) was added into the mixture and stirred at room température for 10 mins. The mixture was filtered and washed with EtOAc (50 mL). The filtrate was separated. The organic layer was washed with water (70 mL) and brine (70 mL), dried over anhydrous Na2SO₄. filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 4:1) to provide (R, £)-N-(5-bromo-2,3-difluorobenzylidene)-2-methyIpropane-2-sulfinamide as a yellow oil (6.0 g). Yield 91% (ESI 325.9 (M+H)⁺).

Step 2: ethyl (5)-3-(5-bromo-2,3-difluorophenyl)-3-(((Æ)-tertbutylsulfinyl)amino)propanoate

To a mixture of Zn (3.2 g, 49.2 mmol, 4.00 eq) in anhydrous THF (20 mL) under nitrogen atmosphère was added chlorotrimethylsilane (267 mg, 2.46 mmol, 0.2 eq) dropwise at room température. The mixture was stirred at 50 °C for 1 hour under nitrogen atmosphère and cooled to 20-30°C. Ethyl 2-bromoacetate (5.1 g, 30.75 mmol, 2.50 eq) was added dropwise at room température under nitrogen atmosphère and then stirred at 60 °C for 1 hour under nitrogen atmosphère. The reaction mixture was cooled to room température. A solution of (R,E)-N-(5bromo-2,3-difluorobenzylidene)-2-methylpropane-2-sulfinamide(4.0 g, 12.3 mmol, 1.00 eq) in anhydrous THF (5 mL) was added dropwise into the mixture at room température under nitrogen atmosphère and stirred at room température for 1 hour. LCMS showed that the reaction was completed. Water (150 mL) and EtOAc (150 mL) were added into the mixture and stirred at room température for 10 mins. The mixture was filtered and washed with EtOAc (50 mL). The filtrate was separated. The organic layer was washed with water (100 mL) and brine (100 mL),

222 dried over anhydrous Na₂SÛ4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 3:1) to provide ethyl (5)-3-(5-bromo-2,3-difluorophenyl)-3(((7?)-/eri-butylsulfinyl)amino)propanoate as a colorless oil (2.7 g). Yield 53% (ESI 412.0 (M+H)⁺).

Préparation of ethyl (S)-3-amino-3-(4,5-difluoro-2’,6’-dimethyl-[l,l’-biphenyl]-3yl)propanoate

Step 1: ethyl (S)-3-(((7?)-ter/-butylsulfinyl)amino)-3-(4,5-difluoro-2',6'-dimethyl-[l,r biphenylJ-3-yI)propanoate

b'^oh

OH Pd(dppf)CI₂, K₂CO₃---------------------------» dioxane/H₂0,110°C

A mixture of ethyl (S)-3-(5-bromo-2,3-difluorophenyl)-3-(((7?)-/er/butylsulfinyl)amino)propanoate (1.0 g, 2.4 mmol, 1.00 eq), K₂COj (664 mg, 4.8 mmol, 2.0 eq) Pd(dppf)Cl₂(175 mg, 0.24 mmol, 0.1 eq) and (2,6-dimethylphenyl)boronic acid (720 mg, 4.8 mmol, 2.00 eq) in dioxane (12 mL) and H₂O (1.2 mL) was stirred at 110 °C under nitrogen atmosphère for 2 hours. LCMS showed that the reaction was completed. The reaction mixture was poured into 50 mL of water and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether. EtOAc 2.1) to give desired product ethyl (S)-3-(((/?)-te/ï-butylsulfinyl)amino)-3-(4,5-difluoro-2',6'-dimethyl[l,r-biphenyI]-3-yl)propanoateas a yellow oil (900 mg). Yield 85% (ESI 438.1 (M+H)⁺).

Step 2: ethyl (5>3-amino-3-(4,5-difluoro-2’,6’-dimethyl-[l,l’-bîphenyII-3-yI)propanoate

223

To a mixture of ethyl (S)-3-(((A)-fc'r/-butylsulfinyl)amino)-3-(4,5-difluoro-2',6'-dimethyl-[l,l'biphenyl]-3-yl)propanoate (900 mg, 2.06 mmol, 1.0 eq) in DCM (4 mL) was added HCl-dioxane (4 M, 2 mL, 8.0 mmol, 3.88 eq). The mixture was stirred at room température for 1 hour. LCMS 5 showed that the reaction was completed. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8/40 g column (A: water/0.01%TFA,B: MeOH, 0-100%) to provide ethyl (S)-3-amino-3-(4,5-difluoro-2',6’-dimethyl-[l,r-biphenyl]-3yl)propanoate as a light yellow solid (800 mg). Yield 90% (ESI 334.1 [M+H]⁺).

Préparation of ethyl (5)-3-amino-3-(4,4',5-trifluoro-2’,6’-dimethyI-ll,r-bîphenyl]-3yl)propanoatc

Step 1: ethyl (S)-3-(((Æ)-tert-butylsulfinyl)amino)-3-(4,4’,5-trifluoro-2’,6’-dimethyl-[l,l’biphenyI]-3-yI)propanoate

A mixture of ethyl (ô)-3-(5-bromo-2,3-difluorophenyl)-3-(((7?)-/errbutylsulfinyl)amino)propanoate (1.1 g, 2.68 mmol, 1.00 eq), K₃PO4(1.7 g, 8.04 mmol, 3.00 eq), X-Phos Pd G2 (212 mg, 0.27 mmol, 0.10 eq) and (4-fluoro-2,6-dimethylphenyl)boronic acid (900 mg, 5.36 mmol, 2.00 eq) in THF (10 mL) and H₂O (2 mL) was stirred at 50 °C under nitrogen atmosphère for 2 hours. LCMS showed that the reaction was completed. The reaction mixture was poured into 50 mL of water and extracted with EtOAc (50 mL x 3). The combined

224 organic layers were washed with brine (100 mL), dried over anhydrous Na₂SÛ4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 1:1) to provide ethyl (S)-3-(((7?)-ieri-butylsulfinyl)amino)-3-(4,4',5-trifluoro-2^,,6’-dimethyl-[l,rbiphenyl]-3-yl)propanoate as a brown oil (1 g). Yield 82% (ESI 456.1 (M+H)⁺)

Step 2: ethyl ($)-3-amino-3-(4,4',5-trifluoro-2’,6'-dimethyl-[l,r-biphenyl]-3-yl)propanoate

To a mixture of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4,4',5-trifluoro-2',6’-dimethyl[l,l’-biphenyl]-3-yl)propanoate (1.0 g, 2.2 mmol, 1.0 eq) in DCM (4 mL) was added HC1dioxane (4 M, 2 mL, 4.0 mmol, 1.8 eq). The mixture was stirred at room température for 1 hour. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/80g column (A: water 10 mM NH4HCO3, B: MeOH, 0-100%) to provide ethyl (ô)-3-amino-3-(4,4',5-trifluoro-2',6'-dimethyl-[l,rbiphenyl]-3-yl)propanoate as a white solid (750 mg). Yield 97% (ESI 352.1 [M+H]⁺).

Préparation of ethyl (S)-3-amino-3-(4,5-difluoro-2’,4’,6’-trimethyI-[l,r-biphenyl|-3 yl)propanoate

Scheme:

Step 1: ethyl (S)-3-(((70-teri-butylsulfinyl)amino)-3-(4,5-difluoro-2’,4',6'-trimethyl-[l,rbiphenyI]-3-yl)propanoate

225

A mixture of ethyl (S)-3-(5-bromo-2,3-difluorophenyl)-3-(((A)-/er/butylsulfinyl)amino)propanoate (1.5 g, 3.65 mmol, 1.0 eq), mesitylboronic acid(1.2 g, 7.30 mmol, 2.0 eq), K2CO3 (1.5 g, 10.95 mmol, 3.0 eq) and Pd(dppf)Cl₂ (267 mg, 0.365 mmol, 0.1 eq) in dioxane (10 mL) and H₂O (1 mL) was stirred at 110 °C under nitrogen atmosphère for 1 hour. LCMS showed that the reaction was completed. The mixture was cooled to room température, poured into water (30 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SÛ4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 2:1) to provide ethyl (S)-3-(((7?)-ierZ-butylsulfinyl)amino)-3-(4,5-difluoro-2',4',6'-trimethyl-[ 1, Γbiphenyl]-3-yl)propanoate as a yellow oil (1.4 g). Yield 85% (ESI 452.2 (M+H)⁺).

Step 2: ethyl (5)-3-amino-3-(4,5-difluoro-2',4’,6'-trimethyI-il,r-biphenyl]-3-yl)propanoate

To a mixture of ethyl (S)-3-(((/?)-/er/-butylsulfinyl)amino)-3-(4,5-difluoro-2',4',6'-trimethyl-[l,rbiphenyl]-3-yl)propanoate (1.4 g, 3.1 mmol, 1.0 eq) in DCM (20 mL) was added HCl-dioxane (4 M, 2 mL, 8.0 mmol, 2.58 eq). The mixture was stirred at room température for 1 hour. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8/120g column (A: water/0.01%TFA,B: MeOH, 0-100%) to provide ethyl (S)-3-amino-3-(4,5-difluoro-2',4',6'-trimethyl-[l,r-biphenyl]-3yl)propanoate as a light yellow solid (1.0 g). Yield 93% (ESI 348.1 (M+H)⁺).

226

Préparation of ethyl (S)-3-(5-bromo-2-fluoro-3-(trifluoromethyl)phenyl)-3-(((/?)-fôrtbutylsulfinyl)amino)propanoate

Step 1: 5-bromo-2-fluoro-3-(trifluoromethyl)benzaIdehyde

To a solution of 4-bromo-l-fluoro-2-(trifluoromethyl)benzene (10.0 g, 41.15 mmol, 1.00 eq) in anhydrous THF (50 mL) under nitrogen atmosphère at -78 °C was added Lithium diisopropylamide (2.0 M, 30.9 mL, 61.73 mmol, 1.50 eq) dropwise and stirred at -78 °C for 1 hour under nitrogen atmosphère. DMF ( 15 mL) was added dropwise and the mixture was stirred at -78 °C for 1 hour. The mixture was quenched with IM HCl aqueous solution (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NazSO.», fdtered and concentrated in vacuo. The residue obtained was purified by silica gel column (pet ether: EtOAc 20:1) to provide 5-bromo-2-fluoro-3(trifluoromethyl)benzaldehyde as a white solid (8.0 g). Yield 72%.'H NMR (400 MHz, CDCh) δ 10.34 (s, 1H), 8.19 (dd, J= 5.4,2.4 Hz, 1H), 7.98 (dd, J= 6.1,2.5 Hz, 1H).

Step 2: (Λ, E)-/V-(5-bromo-2-fluoro-3-(triiluoromethyI)benzylidene)-2-niethyIpropane-2sulflnamide

To a mixture of 5-bromo-2-fluoro-3-(trifluoromethyl)benzaldehyde (8.0 g, 29.50 mmol, 1.00 eq) and (jR)-2-methylpropane-2-sulfinamide (3.9 g, 32.45 mmol, 1.1 eq) in anhydrous THF (100 mL) under nitrogen atmosphère was added Ti(OEt)4 (13.0 g, 59.00 mmol, 2.00 eq) dropwise at room température and maintained the température below 30 °C. The reaction mixture was stirred at room température for 1 hour under nitrogen atmosphère. LCMS showed that the reaction was completed. Water (100 mL) and EtOAc (100 mL) was added into the mixture and stirred at room température for 5 mins. The mixture was filtered and washed with EtOAc (50 mL). The filtrate

227 was separated. The organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous NaaSQi, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 5:1) to provide (R, jE)-A-(5-bromo-2-fIuoro-3(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide as a yellow oil (8.0 g). Yield 72% (ESI 373.9 (M+H)⁺).

Step 3: ethyl (S)-3-(5-bromo-2-fluoro-3-(trifluoromethyl)phenyl)-3-(((lî)-ferrbutylsulfinyl)amino)propanoate

To a mixture of Zn (5.6 g, 85.6 mmol, 4.00 eq) in anhydrous THF (100 mL) under nitrogen atmosphère was added chlorotrimethylsilane (465 mg, 4.28 mmol, 0.2 eq) dropwise at room température. The mixture was stirred at 45 °C for 1 hour under nitrogen atmosphère and cooled to 20-30°C. Ethyl 2-bromoacetate (8.9 g, 53.5 mmol, 2.50 eq) was added dropwise at room température. The reaction mixture was stirred at 50 °C for 1 hour under nitrogen atmosphère and then cooled to room température. A solution of (J?,£)W-(5-bromo-2-fluoro-3(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide (8.0 g, 21.4 mmol, 1.00 eq) in anhydrous THF (10 mL) was added dropwise into the mixture at room température under nitrogen atmosphère. The mixture was stirred at room température for 1 hour. LCMS showed that the réaction was completed. Water (100 mL) and EtOAc (100 mL) was added into the mixture and stirred at room température for 5 mins. The mixture was filtered and washed with EtOAc (100 mL). The filtrate was separated. The organic layer was washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 4:1) to provide ethyl (S)-3-(5-bromo2-fluoro-3-(trifluoromethyl)phenyl)-3-(((/?)-^rZ-butylsulfimyl)amino)propanoate as a colorless oil (6.3 g). Yield 64% (ESI 462.0 (M+H)⁺).

228

Préparation of ethyl (S)-ethyl 3-amino-3-(4-fluoro-2’,6’-dimethyI-5(trifluoromethyl)biphenyI-3-yl)propanoate

Step 1: ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2’,6’-dimethyl-5(trifluoromethyl)-[l,l’-biphenyl)-3-yl)propanoate

Pd(dppf)CI₂. Cs₂CO₃

Dioxane

To a solution of ethyl (S)-3-(5-bromo-2-fluoro-3-(trifluoromethyl)phenyl)-3-(((R)-tertbutylsulfinyl)amino)propanoate (3 g, 6.49 mmol) and (2,6-dimethylphenyl)boronic acid (1.46 g, 9.73 mmol) in Dioxane (24 mL) was added a solution of Cs2CO3 (4.23 g, 12.98 mmol) in Water (8 mL). The reaction was purged with N2 for 5 min, followed by addition of PdC12(dppf) (0.712 10 g, 0.973 mmol) and another N2 purge for 1 min. The reaction was stirred at 70C for 4 hours. The reaction mixture was diluted into 250 mL EtOAc, then washed with IN HCl (250 mL), Sat. NaHCO3 (205 mL) and Brine (250 mL). The residue was concentrated and purified by silica gel chromatography to provide ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2^,,6’-dimethyl5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (2.71 g). Yield 86% (ESI 488 (M+H)+).

Step 2: (S)-ethyl 3-amino-3-(4-fluoro-2’,6’-dimethyI-5-(trifluoromethyI)biphenyl-3yl)propanoate

229

To a solution of (S)-ethyl 3-((R)-l,l-dimethylethylsulfinamido)-3-(4-fluoro-2',6^,-dimethyl-5(trifluoromethyl)biphenyl-3-yl)propanoate (0.93 g, 1.9 mmol, 1.00 eq) in DCM (8 mL) was added HCl-dioxane (4M, 1.9 mL, 7.6 mmol, 4 eq) and stirred at room température for 2 hours. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18 / 120 g column (A: water/0.01%TFA,B: MeOH, 0-100%) to provide (R)-ethyl 3-amino-3(4-fluoro-2^,,6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate as a yellow solid (0.6 g). Yield 82% (ESI 384.1 (M+H)⁺).

Préparation of ethyl (S)-3-amino-3-(4,4'-difluoro-2’,6’-dimethyl-5-(trifluoromethyl)-ll,rbiphenyl]-3-yl)propanoate

Step 1: ethyl (S)-3-(((Æ)-ferf-butylsulfinyI)amino)-3-(4,4'-difluoro-2',6'-dimethyl-5(trifluoromethyl)-[l,r-biphenylj-3-yI)propanoate

A mixture of ethyl (S)-3-(5-bromo-2-fluoro-3-(trifluoromethyl)phenyl)-3-(((7?)-/cr/butylsulfinyl)amino)propanoate (2.0 g, 4.3 mmol, 1.00 eq), K2CO3 (1.8 g, 12.9 mmol, 3.00 eq), Pd(dppf)C12(315 mg, 0.43 mmol, 0.10 eq) and (4-fluoro-2,6-dimethylphenyl)boronic acid (1.1g, 6.45 mmol, 1.50 eq) in dioxane (50 mL) and H₂O (5 mL) was stirred at 110 °C for 2 hours under nitrogen atmosphère. LCMS showed that the reaction was completed. The reaction mixture was poured into 50 mL of water, extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SÛ4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 3:1) to provideethyl (5)3-(((7?)-icTZ-butylsulfinyl)amino)-3-(4,4'-difluoro-2',6'-dimethyl-5-(trifluoromethyl)-[ 1,1'biphenyl]-3-yl)propanoate as a colorless oil (1.4 g). Yield 64% (ESI 506.0 (M+H)⁺)

230

Step 2: ethyl (5)-3-amino-3-(4,4'-difIuoro-2',6'-dimcthyl-5-(trifluoromethyl)-[l,l'biphenyl]-3-yI)propanoate

To a mixture of ethyl (S)-3-(((7?)-ter/-butylsulfmyl)amino)-3-(4,4^,-difluoro-2^,,6'-dimethyl-5(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (1.4 g, 2.77 mmol, 1.0 eq) in DCM (10 mL) was added HCl-dioxane (4 M, 6 mL, 24.0 mmol, 8.66 eq). The mixture was stirred at room température for 1 hour. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8/120g column (A: water/0.01%TFA,B: MeOH, 0-100%) to provide ethyl (S)-3-amino-3-(4,4'-difluoro2^,,6^,-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate as a colorless oil (880 mg). Yield 79% (ESI 402.1 [M+H]⁺).

Préparation of (S)-ethyl 3-amino-3-(4-fluoro-2',3',5,6'-tetramethylbiphenyl-3-yl)propanoate

Step 1: (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(4-fluoro-2’,3’,5,6’-tetramethylbiphenyl-3yl)propanoate

To a mixture of (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)propanoate (3.0 g, 6.7 mmol), 2,3,6-trimethylphenyl trifluoromethanesulfonate (2.2 g, 8.0 mmol) and KjPO4(4.3 g, 20.1 mmol) in dioxane (30 mL) and H₂O (3 mL) was added X-Phos Pd G2 (550 mg, 0.7 mmol). The mixture was heated to 110°C for 1 hr under nitrogen atmosphère. Water (50 mL) was added and the solution was extracted with EtOAc (60 mL x 3). The combined organic phases were concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 2:1) to

231 provide (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(4-fluoro-2',3',5,6'-tetramethylbiphenyl-3-yl)propanoate as a dark solid (1.7 g). Yield 57 % (ESI 344.1 [M+H-100]⁺).

Step 2: (S)-ethyI 3-amino-3-(4-fluoro-2',3’,5,6’-tetramethyIbiphenyl-3-yl)propanoate

To a mixture of (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(4-fluoro-2',3',5,6'-tetramethylbiphenyl-3yl)propanoate (1.7 g, 3.8 mmol) in DCM (2 mL) was added HCl-dioxane (4M, 5 mL, 20.0 mmol) and the mixture was stirred at rt for 30 minutes. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/120g column (A: water lOmM NH4HCO3. B: CH3CN, 0-100%) to provide (S)-ethyl 3-amino-3-(4-fluoro-2',3',5,6'-tetramethylbiphenyl-3-yl)propanoate as a colorless oil (1.0 g). Yield 76 % (ESI 344.1 [M+H]⁺).

Préparation of ethyl (S)-3-amino-3-(4-fluoro-2',4',6’-trimethyl-5-(trinuoromethyl)-[l,r-biphenyl]-3yl)propanoate

Step 1: ethyl (S)-3-(((R)-tert-butylsuIfinyl)amino)-3-(2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2 dioxaborolan-2-yl)-3-(trinuoromethyl)phenyl)propanoate

butylsulfinyl)amino)propanoate (2.8 g, 6.1 mmol), KOAc (1.8 g, 18.3mmol), Pd(dppf)Ch (446 mg, 0.61 mmol) and (4,4,4',4',5,5,5',5^,-octamethyl-2,2^,-bi(l,3,2-dioxaborolane) (2.3 g, 9.15 mmol) in dioxane (30 mL) was stirred at 100 °C for 2 hours under nitrogen. The reaction mixture was poured into 50 mL of water and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous NazSO₄, filtered and the fîltrate concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 3:1) to provideethyl (S)-3-(((/?)-tert-butylsulfinyl)amino)-3-(2-fluoro5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl)propanoate as a colorless oil (2.6 g). Yield 84 % (ESI 510.1 (M+H)⁺)

232

Step 2: ethyl (S)-3-(((Æ)-tert-butylsuirinyl)amino)-3-(3',4-difluoro-2',6'-dimethyl-5 (trifluoromethyl)-[l,l’-biphenyl]-3-yl)propanoate

A mixture of ethyl (S)-3-(((A)-tert-butylsuIfinyl)amino)-3-(2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl)propanoate (600 mg, 1.2 mmol), K2CO₃(497mg, 3.6 mmol), Pd(dppf)Cb (88 mg, 0.12 mmol) and 2-bromo-4-fluoro-l,3-dimethylbenzene (363.6 mg, 1.8 mmol) in dioxane (6 mL) and H2O (0.6 mL) was stirred at 110 °C under nitrogen for 2 hours. The reaction mixture was poured into 20 mL of water and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO₄, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 3:1) to provideethyl (5)-3-(((Æ)-tertbutylsulfinyl)amino)-3-(3',4-difluoro-2^,,6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoateas a colorless oil (460 mg). Yield 77 % (ESI 506.1 (M+H)⁺)

Step 3: ethyl (S)-3-amino-3-(3',4-dinuoro-2’,6’-dimethyl-5-(trifluoromethyl)-[l,l’-biphenylJ-3yl)propanoate

To a mixture of ethyl (5)-3-(((Æ)-tert-butylsulfinyl)amino)-3-(3',4-difluoro-2',6'-dimethyl-5(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (460 mg, 0.91 mmol) in EtOH (5 mL) was added HC1dioxane (4 M, 2 mL, 8.0 mmol). The mixture was stirred at room température for 1 hour. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/40g column (A: water/0.05%TFA, B: MeOH, 0-100%) to provideethyl (5)-3-amino-3-(3',4-difluoro-2',6'-dimethyl-5(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate as a colorless oil (230 mg). Yield 63% (ESI 402.1 [M+H]⁺).

Préparation of ethyl (Sl-S-amino-S-ld-fluoro-r^ô’-trimethyl-S-itrifluoromethyl)-! 1,1 ’-biphenyl]-3 yl)propanoate

233

Step 1: ((S)-ethyl 3-((R)-l,l-dimethylethyIsuIfinamido)-3-(4-fluoro-3’-methoxy-2’,6’-dimethyI-5(trifluoromethyl)biphenyl-3-yl)propanoate

A mixture of (S)-ethyl 3-((R)-l,l-dimethylethylsulfinamido)-3-(2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl)propanoate (600 mg, 1.18 mmol), K^COj (488 mg, 3.54 mmol), Pd(dppf)Ch (43 mg, 0.06 mmol) and 2-bromo-4-methoxy-l,3-dimethylbenzene (300 mg, 1.42 mmol) in dioxane (10 mL) and H₂O (1 mL) was stirred at 110 °C under nitrogen atmosphère for 1 hour. The reaction mixture was poured into 50 mL of water and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SC>4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 3:2) to provide (S)ethyl 3-((R)-l,l-dimethylethylsulfinamido)-3-(4-fluoro-3'-methoxy-2',6^,-dimethyl-5(trifluoromethyl)biphenyl-3-yl)propanoate as a colorless oil (400 mg). Yield 65 % (ESI 518.3 (M+H)⁺)

Step 2: (S)-ethyl 3-amino-3-(4-fluoro-3’-methoxy-2’,6’-dimethyl-5-(trifluoromethyI)biphenyl-3yl)propanoate

To a mixture of (S)-ethyl 3-((R)-l,l-dimethylethylsulfinamido)-3-(4-fluoro-3'-methoxy-2',6’-dimethyl-5(trifluoromethyl)biphenyi-3-yl)propanoate (400 mg, 0.77 mmol) in DCM (2 mL) was added HCl-dioxane (4 Μ, 1 mL, 4.0 mmol). The mixture was stirred at room température for 1 hour. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: CH3CN, 0-100%) to provide (S)-ethyl 3-amino-3-(4-fluoro-3^,-methoxy-2',6'dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate (200 mg). Yield 63% (ESI 414.1 [M+H]*).

Préparation of ethyl (S)-3-amino-3-(4-fluoro-2’,4',6’-trimethyl-5-(trifluoromethyI)-[l,l ’-biphenyl]-3yl)propanoate

Step 1: 23,6-trimethylphenyI trifluoromethanesulfonate

234

OH

Tf₂O, NEtj

DCM. 0°C

OTf

To a mixture of 2,3,6-trimethylphenol (5 g, 36.8 mmol), NEtj (9.3 g, 92.0 mmol) in DCM (100 mL) was added Tf₂O ( 15.6 g, 55.2 mmol) at 0 °C dropwise and stirred at room température for 3 hours. The reaction mixture was poured into 100 mL of water and extracted with DCM (100 x 3mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO₄, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (pet ether) to provide 2,3,6trimethylphenyl trifluoromethanesulfonate as a colorless oil (8 g). Yield 80 % (ESI 269.3 (M+H)⁺).

Step 2: (S)-ethyl 3-((R)-l,l-dimethylethylsuirinamido)-3-(4-fluoro-2’,3^,,6’-trimethyl-5 (trifluoromethyl)biphenyl-3-yl)propanoate

Xphos Pd G2. K3PO4 dioxane/HjO. 110°C,1hr

To a mixture of (S)-ethyl 3-((R)-l,l-dimethylethylsulfinamido)-3-(2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl)propanoate (400 mg, 0.79 mmol), 2,3,6-trimethylphenyl trifluoromethanesulfonate (253 mg, 0.94 mmol) and K₃PO₄(502 mg, 2.37 mmol) in dioxane (10 mL) and H2O (1 mL) was added Xphos Pd G2 (63 mg, 0.08 mmol). The mixture was heated to 110°C for 30 mins under nitrogen atmosphère. Water (20 mL) was added and the solution was extracted with EtOAc (20 mL x 3). The combined organic phases were concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 2:1) to provide (S)-ethyl 3-((R)-l,l-dimethylethylsulfinamido)-3-(4-fluoro2',3^,,6'-trimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate as a dark solid (300 mg). Yield 76 % (ESI 502.1 [M-100+H]*).

Step 3: (S)-ethyl3-amino-3-(4-fluoro-2’,3’,6’-trimethyl-5-(trifiuoromethyl)biphenyI-3-yl)propanoate

HCI/dioxane, rt, 30 mins

235

To a mixture of (S)-ethyl 3-((R)-l,l-dimethylethylsulfinamido)-3-(4-fluoro-2',3',6'-trimethyl-5(trifluoromethyl)biphenyl-3-yl)propanoate (300 mg, 0.6 mmol) in DCM (ImL) was added HCl-dioxane (4N, 1 mL, 2.5 mmol) and the mixture was stirred at room température for 0.5 hr. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: CH3CN, 0-100%) to provide (S)-ethyl 3-amino-3-(4-fluoro-2',3',6'-trimethyl-5(trifluoromethyl)biphenyl-3-yl)propanoate as a colorless oil (170 mg). Yield 71% (ESI 398.1(M+H)⁺).

Préparation of ethyl (S)-3-amino-3-(4-fluoro-2',4',6’-trimethyI-5-(trifluoromethyl)-[ l,l’-biphenyl]-3yl)propanoate

Step 1: (S)-ethyl 3-((R)-l,l-dimethylethylsuIfinamido)-3-(4-fluoro-2’,4',6’-trimethyl-5 (trifluoromethyl)biphenyl-3-yl)propanoate

PdCI₂.dppf, K₂C0₃dioxane/HjO, 11O°C.1hr

To a mixture of (S)-ethyl 3-(5-bromo-2-fluoro-3-(trifluoromethyl)phenyl)-3-((R)-l,ldimethylethylsulfinamido)propanoate (461 mg, 1.0 mmol), mesitylboronic acid (197 mg, 1.2 mmol) and K2COj(414 mg, 3.0 mmol) in dioxane (10 mL) and H2O (1 mL) was added Pd(dppf)Cl2 (73 mg, 0.1 mmol). The mixture was heated to 110°C for 2 hrs under nitrogen atmosphère. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The combined organic phases were concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 2:1) to provide (S)-ethyl 3-((R)-l,ldimethylethylsulfinamido)-3-(4-fluoro-2',4^,,6'-trimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate as a dark solid (400 mg). Yield 80 % (ESI 502.1 [M-100+H]').

Step 2: (S)-ethyl3-amino-3-(4-fluoro-2’,4’,6’-trimethyl-5-(trifluoromethyl)biphenyI-3-yl)propanoate

HCI/dioxane.

rt, 30 mins

To a mixture of (S)-ethyl 3-((R)-l,l-dimethylethylsulfmamido)-3-(4-fluoro-2',4’,6'-trimethyl-5 (trifluoromethyl)biphenyl-3-yl)propanoate (400 mg, 0.8 mmol) in DCM (ImL) and EtOH (2mL) was

236 added HCl-dioxane (4M, 2 mL, 8 mmol) and stirred at rt for 0.5 hr. The mixture was concentrated in vacuo to provide theproduct as a yellow oil (350 mg, crude).(ESI 398.1[M+H]⁺).

Préparation of ethyl (3S)-3-amino-3-(2,4,4’-trifluoro-2’,3’,6’-trimethyI-5-(trinuoromethyl)-[l,l’ biphenyl]-3-yl)propanoate

Step 1; 2,6-dibromo-4-fluoro-3-methylaniline

To a mixture of 4-fluoro-3-methylaniline (50.0 g, 400 mmol,) in MeOH (120 mL) and DCM (120 mL) was added bromine (52 mL, 1.0 mol) dropwise at room température over 1.5 hour and stirred at room température for 4 hours. IN Na^S^Oj aqueous solution (300 mL) and ethyl acetate (500 mL) was added and stirred for 10 mins, then carefully basified with IN Na₂COj aqueous solution (300 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 * 100 mL). The combined organic layers were washed with IN NajSiOj aqueous solution (300 mL) and brine (200 mL) dried over Na2SOj, filtered and concentrated in vacuo to provide 2,6-dibromo-4-fluoro-3- methylaniline as a white solid (80 g). Yield 70.7 % (ESI 284.0[M+H]⁺).

Step 2: 4-fluoro-2,3,6-trimethylaniline

methylboronic acid

Pd(dppf)CI₂

F

NH2

To a solution of ethyl 2,6-dibromo-4-fluoro-3-methylaniline (50.0 g, 273 mmol) in dioxane (500.0 mL) and water (50 mL) was added methylboronic acid (49.0 g, 819 mmol), K.2CO3 (111.0 g, 819 mmol) and 1,1Bis(diphenylphosphino) ferrocene-palladium(II)dichloride dichloromethane complex (10.0 g, 13.65 mmol).The mixture was stirred at 110 °C ovemight. The reaction was poured into water (500 mL) and extracted with Ethyl Acetate (500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 1:5) to provide 4-fluoro-2,3,6-trimethylaniline as a colorless oil (20.0 g). Yield 47.6 % (ESI 154.3 (M+H)⁺)

Step 3: 2-bromo-5-fluoro-l,3,4-trimethylbenzene

237

tBuONO

CuBr

F

Br

To a mixture of 4-fluoro-2,3,6-trimethylaniline (3.8 g, 24.8 mmol) in MeCN (30 mL) was added t-BuONO (3.8 g, 37.2 mmol) at 0°C, then CuBr(4.3 g, 29.7 mmol) was added. The mixture was stirred at 60°C for 2 hours. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column (pet ether) to provide 2-bromo-5-fluoro-1,3,4-trimethylbenzene as acolorless oil (1.3 g). Yield 33.9 % .

Step 4: ethyl (3S)-3-(((R)-tert-butyIsuirinyl)amino)-3-(2,4,4’-trinuoro-2',3’,6’-trimethyl-5(trifluoromethyl)-[l,l ’-biphenyl]-3-yl)propanoate

A mixture of (3-((S)-l-(((R)-tert-butylsulfinyl)amino)-3-ethoxy-3-oxopropyl)-2,4-difluoro-5(trifluoromethyl)phenyl)boronic acid (1.5 g, 3.3 mmol), 2-bromo-5-fluoro-l,3,4-trimethylbenzene (950 mg, 4.3 mmol), K3PO4 (2.1 g, 9.9 mmol), X-Phos Pd G2 (285 mg, 0.33 mmol) in dioxane (10 mL) and H₂O (2 mL) was stirred at 110°C for 2h under N2 atmosphère. The mixture was poured into water (100 mL) and extracted with EtOAc (100 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 1:1) to provide ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,4,4^,-trifluoro-2',3',6’-trimethyl-5(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (380 mg) as a yellow oil. Yield 21.3% ( ESI 538.0(M+H)⁺).

Step 5: ethyl (3S)-3-amino-3-(2,4,4’-trinuoro-2'3’,6’-trimethyl-5-(trifluoromethyI)-(l,r-biphenyl)-3yl)propanoate

238

To a solution of ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,4,4'-trifluoro-2',3',6'-trimethyl-5(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (380 mg, 0.70 mmol) in DCM (5 mL) was added HCldioxane (4 M, 5 mL) and stirred at at room température for 1 hour. The mixture was concentrated in vacuo to provide ethyl (3S)-3-amino-3-(2,4,4'-trifluoro-2^,,3',6'-trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoateas a yellow oil (340 mg) used directly in the next step without further purification. Yield 100% (ESI 434.2 [M+H]⁺).

Préparation of ethyl (3S)-3-amino-3-(3’-cycIopropyI-2,4-dinuoro-2’,6'-dimethyl-5-(trifluoromethyl)[l,l’-biphenyI]-3-yI)propanoate

Step 1: 3-bromo-2,6-dimethylaniline ,X^^Br ^^Br

Zn. NH₄CI

NO₂ MeOH/H₂O nh₂

To a mixture of l-bromo-2,4-dimethyl-3-nitrobenzene (3.0 g, 13.0 mmol) in MeOH (30 mL) and H₂O (3 mL) at 0°C was added NH4CI (2.1 g, 39.0 mmol) and Zn (8.5 g, 130.0 mmol). The mixture was stirred at room température for 20 hours. The reaction mixture was filtercd and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 3:2) to provide 3-bromo-2,6dimethylaniline as a brown solid (2.0 g). Yield 77 % (ESI 200.1 [M+H]*).

Step 2: 3-cyclopropyl-2,6-dimethylaniline

OH λ

Br Γ>—B

OH K₃PO^ jfY

X-Phos.Pd₂(dba)₃

NH₂ toluene/H₂0,110°C NH₂

A mixture of 3-bromo-2,6-dimethylaniline (1.5 g, 7.5 mmol), cyclopropylboronic acid (3.2 g, 37.5 mmol), X-Phos (357.5 mg, 0.75 mmol), Pd₂(dba)₃ (343.4 mg, 0.38 mmol) and K3PO4 (4.8 g, 22.5 mmol) in 1,4dioxane (10 mL) and water (1 mL) was stirred at 110 °C for ovemight under nitrogen atmosphère. The reaction mixture was cooled to room température, filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 5:1) to provide 3-cyclopropyl-2,6-dimethylaniline as a colorless oil (1.1 g). Yield 91 % (ESI 162.2 [M+H] ).

Step 3: l-cyclopropyI-3-iodo-2,4-dimethylbenzene

239

To a mixture of 3-cyclopropyl-2,6-dimethyIaniline (1.1 g, 6.8 mmol) in CHjCN (10 mL) and H₂O (1 mL) was added p-toluenesulphonic acid (5.9 g, 34.0 mmo). The mixture was stirred at 0 °C for 10 mins under under nitrogen atmosphère. A solution of NaNCh (703.8 mg, 10.2 mmol) in H2O (2 mL) was added dropwise and the mixture was stirred 0 °C for 1 hour. Then Kl (3.4 g, 20.4 mmol) was added to the reaction mixture and stirred at 0 °C for 2 hours. After completion, water (20 mL) was added and the solution was extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4. filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether) to provide l-cyclopropyl-3-iodo-2,4-dimethylbenzene as a colorless oil (240 mg) used without further purification. Yield 13%. 'H NMR (400 MHz, CDCh) δ 6.98 (d, J- 7.8 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 2.63 (s, 3H), 2.44 (s, 3H), 1.94 - 1.85 (m, 1H), 0.95 - 0.86 (m, 2H), 0.62 - 0.55 (m, 2H).

Step 4: ethyl (35)-3-(((Æ)-tert-butylsuirinyl)amino)-3-(3’-cycIopropyI-2,4-difluoro-2’,6’-dimethyl-5(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate

A mixture of (3-((5)-l-(((Æ)-tert-butylsulfinyl)amino)-3-ethoxy-3-oxopropyl)-2,4-difluoro-5(trifluoromethyl)phenyl)boronic acid (350 mg, 0.79 mmol), l-cyclopropyl-3-iodo-2,4-dimethyibenzene (240 mg, 0.88 mmol), X-Phos Pd G2 (62.1 mg, 0.08 mmol) and K3PO4 (503.1 mg, 2.37 mmol) in 1,4dioxane (10 mL) and water (1 mL) was stirred at 105 °C for 1 hour under nitrogen atmosphère. TheThe reaction mixture was cooled to room température, filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 3:2) to provide ethyl (3S)-3-(((R)-/er/-butylsulfinyl)amino)-3-(3^,-cyclopropyl-2,4-difluoro-2',6'-dimethyl-5(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate as a brown oil (270 mg). Yield 63% (ESI 546.2 (M+H]⁺).

Step 5: ethyl (3S)-3-amino-3-(3’-cycIopropyl-2,4-difluoro-2’,6’-dimethyl-5-(trinuoromethyl)-[l,rbîphenyI]-3-yl)propanoate

240

To a mixture of ethyl (3S)-3-(((/?)-/erZ-butylsulfinyl)amino)-3-(3'-cyclopropyl-2,4-difluoro-2',6'-dimethyI5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (270.0 mg, 049 mmol) in EtOH (2 mL) was added HCldioxane (4 M, 2 mL, 8.0 mmol). The mixture was stirred at room température for 1 hour. The mixture was concentrated in vacuo to provide ethyl (3S)-3-amino-3-(3'-cyclopropyl-2,4-difluoro-2',6'-dimethyl-5(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate as a colorless oil (210.0 mg), used without further purification. Yield 96% (ESI 442.2 [M+H]⁺).

Préparation of (3S)-ethyI 3-amino-3-(3'-cyclopropoxy-2,4-difluoro-2’,6’-dimethyl-5(trîfluoromethyl)biphenyl-3-yl)propanoate

Step 1: 2-bromo-4-cycIopropoxy-l,3-dimethylbeiizene

A mixture of 3-bromo-2,4-dimethylphenol (1.0 g, 4.98 mmol), bromocyclopropane (3.0 g, 24.8 mmol) and Cs2COj(4.9 g, 14.9 mmol) in NMP (20 mL) was stirred at 140 °C for 20 hours. The mixture was cooled to room température and poured into NH4CI (aq.) (20 mL). The solution was extracted with EtOAc (200 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous NaiSOj, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether) to provide 2-bromo-4cyclopropoxy-l,3-dimethylbenzene as a colorless oil (1.0 g). Yield 83 % . *H NMR (400 MHz, CDClj) δ 7.07 (d, J= 8.4 Hz, 1H), 7.04 (d, J= 8.6 Hz, 1H), 3.75 - 3.65 (m, 1H), 2.35 (s, 3H), 2.27 (s, 3H), 0.79 0.73 (m, 4H).

Step 2: (3S)-ethyl 3-(3'-cyclopropoxy-2,4-dinuoro-2',6'-dimethyI-5-(trifluoromethyl)biphenyI-3-yI)3-((Æ)-l,l-dimethylethylsuIfinamido)propanoate

241

To a mixture of 3-((S)-l-((R)-l,l-dimethylethyIsulfinamido)-3-ethoxy-3-oxopropyl)-2,4-difluoro-5(trifluoromethyl)phenylboronic acid (400 mg, 0.9 mmol), 2-bromo-4-cyclopropoxy-l,3-dimethylbenzene (260 mg, 1.1 mmol) and KjPO4(636 mg, 3.0 mmol) in dioxane (5 mL) and Η₂Ο (0.5 mL) was added XPhos Pd G2 (79 mg, 0.1 mmol). The mixture was heated to 110°C for 1 hr under nitrogen atmosphère. Water (10 mL) was added and the solution was extracted with EtOAc (20 mL x 3). The combined organic phases were concentrated in vacuo and the residue was purified by silica gel column (pet ether EtOAc 2:1) to provide (35)-ethyl 3-(3'-cyclopropoxy-2,4-diiluoro-2',6’-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)-3((R)-l,l-dimethylethylsulfinamido)propanoate as a dark solid (300 mg). Yield 59 % (ESI 562.1 [M+H]⁺).

Step 3: (3S)-ethyl 3-amino-3-(3’-cyclopropoxy-2,4-difluoro-2’,6’-dimethyl-5(trifluoromethyl)biphenyl-3-yI)propanoate

To a mixture of (3S)-ethyl 3-(3'-cyclopropoxy-2,4-difluoro-2’,6'-dimethyl-5-(trifluoromethyl)biphenyl-3yl)-3-((Æ)-l,l-dimethylethylsulfinamido)propanoate (300 mg, 0.53 mmol) in DCM (1 mL) was added 4M HCl-dioxane (0.5 mL, 2.0 mmol). The mixture was stirred at rt for 0.5 hr. The mixture was concentrated in vacuo and the residue was purified by reverse phase on a C18/120g column (A: water lOmMNILHCOj.B: CHjCN, 0-100%) to provide (3S)-ethyl 3-amino-3-(3'-cyclopropoxy-2,4-difluoro-2’,6’-dimethyl-5(trifluoromethyl)biphenyl-3-yl)propanoate as a colorless oil (150 mg). Yield 62 % (ESI 458.1 [M+H]⁺).

Préparation of ethyl (S)-3-amino-3-(2,4-difluoro-2’,6’-dimethyl-4',5-bis(trifluoromethyl)-[l,rbiphenyl]-3-yl)propanoate

Step 1: ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,4-difluoro-2’,6’-dimethyI-4’,5bis(trifluoromethyl)-[l,l’-biphenyl]-3-yl)propanoate

242

A mixture of (3-((S)-l-(((R)-tert-butylsulfinyl)amino)-3-ethoxy-3-oxopropyl)-2,4-difluoro-5(trifluoromethyl)phenyl)boronic acid (900 mg, 2.0 mmol), K₃PO4(1.06 g, 5.0 mmol), X-Phos Pd G2 (157 mg, 0.2 mmol) and 2-bromo-l,3-dimethyl-5-(trifluoromethyl)benzene (607 mg, 2.4 mmol) in dioxane (20 mL) and H₂O (2 mL) was stirred at 100 °C under nitrogen atmosphère for 2 hours. The reaction mixture was poured into 50 mL of water and extracted with EtOAc (50 x 3mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NazSO^, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 3:2) to provide ethyl (S)-3-(((R)tert-butylsulfinyl)amino)-3-(2,4-difluoro-2^,,6-dimethyl-4',5-bis(trifluoromethyl)-[l,l'-biphenyl]-3yl)propanoate as a yellow solid (730 mg). Yield 63.6% (ESI 574.2 (M+H)⁺)

Step 2: ethyl (S)-3-amino-3-(2,4-dinuoro-2’,6’-dimethyl-4’,5-bis(trinuoromethyI)-[l,l’-biphenylJ-3yl)propanoate

To a mixture of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,4-difluoro-2',6'-dimethyl-4’,5bis(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (730 mg, 1.27 mmol) in DCM (4 mL) was added HC1dioxane (4 Μ, 1 mL, 4.0 mmol). The mixture was stirred at room température for 1 hour. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/40g column (A: water 10 mM NH4HCO3, B: CH3CN, 0-100%) to provide ethyl (S)-3-amino-3-(2,4-difluoro-2',6^,-dimethyl4',5-bis(trifluoromethyl)-[l,l'-biphenyl]-3-yl)propanoate (280 mg). Yield47% (ESI 470.0 [M+H] ).

Préparation of ethyl (S)-3-(3-bromo-5-cyclopropyl-2,6-difluorophenyl)-3-(((R)-tertbutylsulfinyl)amino)propanoate

243

Step 1: 5-cyclopropyl-2,4-difluoroaniline

To a solution of 5-bromo-2,4-difluoroaniline (15.0 g, 72.1 mmol) in Toluene (50 mL) and H₂O (55 mL) under nitrogen atmosphère at room température was added X-phos (1.7 g, 3.6 mmol), Pd₂dbaj (3.3 g, 3.6 mmol), cyclopropylboronic acid (12.4 g, 144.2 mmol) and KjPO4(30.9 g, 144.2 mmol) and stirred at 100 °C for 16 hours under nitrogen atmosphère. The reaction was filtered and washed with EtOAc (50 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 10:1) to provide 5-cyclopropyl-2,4-difluoroaniline as white solids (12.0 g). Yield 92 % (ESI 170.2 (M+H)⁺).

Step 2: l-bromo-5-cyclopropyl-2,4-difluorobenzene

Br

To a mixture of 5-cyclopropyl-2,4-difluoroaniline (12.0 g, 71.0 mmol) and CuBr (25.5 g, 177.5 mmol) in ACN (200 mL) and H₂O (40 mL) at 0 °C was added p-Toluenesulfonic acid (54.0 g, 284.0 mmol) and then stirred for 1 hour. To the mixture was added a solution of NaNO₂(7.3 g, 106.5 mmol) in H₂O (20 mL) dropwise. The mixture was extracted with EtOAc (80 mL x 3). The organic layer was washed with brine, dried over Na₂SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether) to provide l-bromo-5-cyclopropyl-2,4-difluorobenzene (7.0 g, yield: 42%) as a colorless oil .

Step 3: 3-bromo-5-cyclopropyl-2,6-difluorobenzaldehyde

Br Br

To a solution of l-bromo-5-cyclopropyl-2,4-difluorobenzene(7.0 g, 30.0 mmol) in THF (50 mL) at -78 °C was added LDA(22.6 mL, 45.2 mmol) dropwise and stirred at -78 °C for Ih. Then DMF(5 mL) was added dropwise and stirred at -78 °C for another Ih. The reaction mixture was warmed to r.t. and quenched with saturated NH4CI (20 mL) aquous solution and stirred at room teperature for 30 mins. The the mixture was

244 extracted with EtQAc(100 mL x 3). The organic layer was washed with brine, dried overNaaSCh, filtered and concentrated in vacuo to provide 3-bromo-5-cyclopropyl-2,6-difluorobenzaldehyde as a yellow oil without further purification (6.5 g, yield:88%).

Step 4: (R,E)-N-(3-bromo-5-cyclopropyl-2,6-difluorobenzylidene)-2-methyIpropane-2-suIfinamide

To a mixture of 3-bromo-5-cyclopropyl-2,6-difluorobenzaldehyde (7.3 g, 29.4 mmol) and (R)-2methylpropane-2-sulfmamide (4.3 g, 35.3 mmol) in anhydrous THF (50 mL) under nitrogen atmosphère was added Ti(OEt)₄ ( 10.0 g, 44.1 mmol) dropwise at room température. During which the température was maintained below 30 °C. The reaction mixture was stirred at room température for 1 hour under nitrogen atmosphère. Water (100 mL) and EtOAc (100 mL) was added into the mixture and stirred at room température for 5 mins. The mixture was filtered and washed with EtOAc (50 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 5:1) to provide (R,E)-N-(3-bromo5-cyclopropyl-2,6-difluorobenzylidene)-2-methylpropane-2-sulfinamide as a yellow oil (6.3 g). Yield 61% (ESI 364.0 (M+H)⁺, 366.0 (M+2+H)*).

Step 5: ethyl (S)-3-(3-bromo-5-cyclopropyl-2,6-difluorophenyl)-3-(((R)-tertbutylsulfinyl)amino)propanoate

To a mixture of Zn (10.0 g, 149.3 mmol) in anhydrous THF (100 mL) under nitrogen atmosphère was added chlorotrimethylsilane (1.0 g, 9.8 mmol) dropwise at room température. The mixture was stirred at 50 °C for 1 hour under nitrogen atmosphère. This mixture was then cooled to 20-30°C. Ethyl 2-bromoacetate (12.4 g, 74.3 mmol) was added dropwise at room température and the mixture was stirred at 50 °C for 1 hour under nitrogen atmosphère. The reaction mixture was cooled to room température. A solution of (R,E)N-(3-bromo-5-cyclopropyl-2,6-difluorobenzylidene)-2-methylpropane-2-sulfinamide (9.0 g, 24.7 mmol) in anhydrous THF (10 mL) was added dropwise into the mixture at room température and the mixture was stirred at room température for 1 hour. Water (100 mL) and EtOAc (100 mL) was added into the mixture

245 and stirred at room température for 5 mins. The mixture was filtered and washed with EtOAc (100 mL x 2). The organic layer was washed with water (100 mL) and brine (100 mL), dried over anhydrous NaiSOj, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 2:1) to provide ethyl (S)-3-(3-bromo-5-cyclopropyl-2,6-difluorophenyl)-3-(((R)-tertbutylsulfinyl)amino)propanoate as a colorless oil (7.1 g). Yield 78 % (ESI 452.0 (M+H)⁺,454.0(M+2+H)⁺).

Préparation of ethyl (S)-3-amino-3-(5-cycIopropyl-2,4-difluoro-2',6'-dimethyI-[l,r-biphenyi]-3yl)propanoate

Step 1: ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-cyclopropyl-2,4-dinuoro-2’,6’-dimethyI-[l,l’biphenyl|-3-yl)propanoate

K3PO4

A mixture of ethyl (S)-3-(3-bromo-5-cyclopropyl-2,6-difluorophenyl)-3-(((R)-tertbutylsulfinyl)amino)propanoate (800.0 mg, 1.77 mmol), (2,6-dimethylphenyl)boronic acid (380.0 mg, 2.3 mmol), X-Phos Pd G2 (133.0 mg, 0.17 mmol) and KjPO^l.l g, 5.31 mmol) in Toluene (7 mL) and H₂O (0.7 mL) was stirred at 100 °C for 4 hours under a nitrogen atmosphère. The reaction was concentrated in vacuo and the residue purified by silica gel column (pet ether:EtOAc = 3:1) to provide ethyl (S)-3-(((R)tert-butylsulfinyl)amino)-3-(5-cyclopropyl-2,4-difluoro-2',6'-dimethyl-[ 1,1 '-biphenyl]-3-yl)propanoate (700.0 mg, Yield 83%) as a light yellow foam (ESI 478.2 [M+H]*).

Step 2: ethyl (S)-3-amino-3-(5-cycIopropyI-2,4-difluoro-2',6'-dimethyl-[l,r-biphenyl]-3yl)propanoate

To the solution of ethyl (S)-3-(((R)-tert-butylsulfînyl)amino)-3-(5-cyclopropyl-2,4-difluoro-2’,6'-dimethyI[l,l'-biphenyl]-3-yl)propanoate (700.0 mg, 1.47 mmol) in DCM (8 mL) was added HCl-dioxane (4M, 1.9

246 mL, 7.6 mmol) and stirred at room température for 1 hour. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18 / 120 g column (A: water/0.01%TFA.B: MeOH, 0-100%) to provide ethyl (S)-3-amino-3-(5-cyclopropyl-2,4-difluoro-2',6'-dimethyl-[l,r-biphenyl]-3yl)propanoate hydrochloride as a yellow solid (500 mg). Yield 91% ( ESI 374.2 (M+H)⁺).

Préparation of ethyl (S)-3-amino-3-(5-cyclopropyl-2,4-difluoro-2’,4’,6’-trimethyl-Il,r-biphenyl]-3yl)propanoate

Step 1: (S)-ethyI 3-(5-cyclopropyl-2,4-difluoro-2',4',6'-trimethylbiphenyl-3-yl)-3-((Æ)-l,l dimethylethylsulfinamido)propanoate

To a mixture of (S)-ethyl 3-(3-bromo-5-cyclopropyl-2,6-difluorophenyl)-3-((Â)-l,ldimethylethylsulfinamido)propanoate (600 mg, 1.3 mmol), mesitylboronic acid (246 mg, 1.5 mmol) and K₃PO4(848 mg, 43.0 mmol) in dioxane (10 mL) and H₂O (1 mL) was added X-Phos Pd G2 (79 mg, 0.1 mmol). The mixture was heated to 110°C for 2 hrs under a nitrogen atmosphère. Water (20 mL) was added and the solution was extracted with EtOAc (20 mL x 3). The combined organic phases were concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 2:1) to provide (S)-ethyI 3(5-cyclopropyl-2,4-difluoro-2',4',6'-trimethylbiphenyl-3-yl)-3-((Æ)-l,ldimethylethylsulfinamido)propanoate as a dark solid (400 mg). Yield 80 % (ESI 492.1 [M-100+H] ).

Step 2: ethyl (S)-3-amino-3-(5-cyclopropyl-2,4-dinuoro-2’,4’,6’-trimethyl-il,l'-bîphenyIl-3 yl)propanoate

247

To a mixture of (S)-ethyl 3-(5-cyclopropyl-2,4-difluoro-2',4',6'-trimethylbiphenyl-3-yl)-3-((R)-l,ldimethylethylsulfmamido)propanoate (550 mg, 1.12 mmol) in DCM (ImL) and EtOH (2mL) was added 4M HCl-dioxane (2 mL, 5.0 mmol) and the mixture was stirred at rt for 0.5 hr. Then the mixture was concentrated in vacuo to provide ethyl (S)-3-amino-3-(5-cyclopropyl-2,4-difluoro-2’,4',6’-trimethyl-[l,rbiphenyl]-3-yl)propanoate as a yellow oil (360 mg, crude) used directly in the next reaction. (ESI 388.1(M+H)⁺).

Préparation of ethyl (S)-3-amino-3-(5-cycIopropyl-2,4,4’-trinuoro-2’,6’-dimethyl-[l,r-biphenyl]-3yl)propanoate

Step 1 : ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-cyclopropyI-2,4,4’-trinuoro-2’,6’-dimethyI[l,l’-biphenyI]-3-yl)propanoate

To a mixture of ethyl (S)-3-(3-bromo-5-cyclopropyl-2,6-difluorophenyl)-3-(((R)-tertbutylsulfinyl)amino)propanoate (700 mg, 1.55 mmol), 4-fluoro-2,6-dimethylphenylboronic acid (260 mg, 1.55 mmol), and K3PO4 (657 mg, 3.1 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added X-Phos Pd G2 (117 mg, 0.16 mmol). The mixture was stirred at 90°C for 1 hour. The solvent was concentrated in vacuo and the residue was purified by silica gel column (petroleum ether: EtOAc 5:1) to provide ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-cyclopropyl-2,4,4'-trifluoro-2',6’-dimethyl-[l,r-biphenyl]-3yl)propanoate as a pale yellow oil (420.0 mg). Yield 54.6% (ESI 496.2 (M+H)⁺).

Step 2: ethyl (S)-3-amino-3-(5-cyclopropyl-2,4,4'-trifluoro-2',6'-dimethyl-[l,r-biphenyl]-3yl)propanoate

248

A mixture of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-cyclopropyl-2,4,4'-trifluoro-2',6'-dimethyl[l,l'-biphenyl]-3-yl)propanoate (420 mg, 0.85 mmol) in HCl-dioxane (4 M, 3 mL, 12 mmol) was stirred at room température for 1 hour. The mixture was concentrated in vacuo to provide ethyl (S)-ethyl 3amino-S-ÎS-cyclopropyl-Z^^’-trifluoro-Z'jô'-dimethylbiphenyl-S-yOpropanoate as a colorless oil (290 mg) used without further purification. Yield 87.4% (ESI 392.1 [M+H]⁺).

Préparation of ethyl (3S)-3-amino-3-(5-cyclopropyl-2,3’,4-trifluoro-2’,6’-dimethyI-{l,l’-biphenyI)-3yl)propanoate

Step 1: ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(3-cyclopropyl-2,6-difluoro-5-(4,4,5,5 tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate

X-phosPdG2 KOAc dioxane

A mixture of ethyl . (S)-3-(3-bromo-5-cyclopropyl-2,6-difluorophenyl)-3-(((R)-tertbutylsulfinyl)amino)propanoate (800 mg, 1.8 mmol), KOAc (529 mg, 5.4 mmol), Xphos-PdGz (142 mg, 0.18 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (686 mg, 2.7 mmol) in dioxane (10 mL) was stirred at 110 °C for 2 hours under a nitrogen atmosphère. The reaction mixture was poured into 15 mL of water and extracted with EtOAc (15 x 3mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na^SO-i, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 3:1) to provide ethyl (S)-3-(((R)-tertbutylsulfinyl)amino)-3-(3-cyclopropyl-2,6-difluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenyl)propanoate as a colorless oil (500 mg). Yield 56 % (ESI 500.2 (M+H)⁺)

Step 2: ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-cyclopropyl-2,3’,4-trifluoro-2^,,6’-dimethyl|l,l’-biphenyl]-3-yl)propanoate

X-phosPdG2 O

K3PO4 dioxane/HjO

A mixture of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(3-cyclopropyl-2,6-difluoro-5-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (500 mg, 1.0 mmol), K₃PO4(636 mg, 3.0 mmol),

249

Xphos-PdGî (78.7 mg, 0.1 mmol) and 2-bromo-4-fluoro-l,3-dimethylbenzene (263 mg, 1.3 mmol) in dioxane (10 mL) and H2O (1 mL) was stirred at 110 °C for 2 hours under a nitrogen atmosphère. The reaction mixture was poured into 15 mL of water and extracted with EtOAc (15 x 3mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaiSCh, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 3:1) to provide ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-cyclopropyl-2,3',4-trifluoro-2’,6'-dimethyl-[l,r-biphenyl]-3yl)propanoate as a colorless oil (200 mg). Yield 40 % (ESI 496.2 (M+H)⁺)

Step 3: ethyl (35)-3-amino-3-(5-cyclopropyl-23’,4-trinuoro-2’,6’-dimethyI-[l,l’-biphenyI]-3yl)propanoate

To a mixture of ethyl (3S)-3-(((R)-tert-butylsiilfinyl)amino)-3-(5-cyclopropyl-2,3',4-trifluoro-2',6'dimethyl-[l,l'-biphenyl]-3-yl)propanoate (200 mg, 0.4 mmol) in EtOH (2 mL) was added HCl-dioxane (4 M, 2 mL, 8.0 mmol). The mixture was stirred at room température for 1 hour. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/40g column (A: water/0.01%TFA. B: MeOH, 0-100%) to provide ethyl (35)-3-amino-3-(5-cyclopropyl-2,3',4-trifluoro2',6'-dimethyl-[l,r-biphenyl]-3-yl)propanoate oil (120 mg). Yield 76% (ESI 392.2 [M+H]*).

Example 2B. Préparation of Intermediates

Préparation of 2-(5-((dimethylamino)methyl)-2-oxopyridin-l(2H)-yl)-4-methyIpentanoic acid

Step 1:5-((dimethylamino)methyl)pyridin-2(lH)-one

H (2M in THF)

NaBH(OAc)₃

A mixture of 6-oxo-l,6-dihydropyridine-3-carbaldehyde (2 g, 16.2 mmol), dimethylamine (2M in THF, 4 mL) in DCM (10 mL) was stirred at room température for 30 mins. Then

250

NaBH(OAc)î (5.2 g, 24.39 mmol) was added portion-wise and stirred at room température ovemight. The solvent was concentrated in vacuo and the residue purified by reverse phase HPLC (Eluent A: water 10 mM NEUHCCh.Eluent B: MeOH, gradient A->B 0-100%) to provide 5-((dimethylamino)methyl)pyridin-2(lH)-one as a yellow oil (1 g). Yield 41% (ESI 153 (M+H)⁺).

Step 2: ethyl 2-(5-((dimethylamino)methyI)-2-oxopyridin-l(2H)-yl)-4-methyIpentanoate

A mixture of 5-((dimethylamino)methyl)pyridin-2(lH)-one (500 mg, 3.28 mmol), K2CO3 (1.36 g, 9.86 mmol) and ethyl 4-methyl-2-(methylsulfonyloxy)pentanoate (1.17g, 4.93 mmol) in CHjCN (20 mL) was stirred at 70 °C ovemight. The solvent was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 1:2) to provide ethyl 2-(5((dimethylamino)methyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoate as a yellow oil (300 mg). Yield 31% (ESI 295(M+H)⁺).

Step 3:2-(5-((dimethylamino)methyl)-2-oxopyridin-l(2H)-yI)-4-methylpentanoic acid

Ethyl 2-(5-((dimethylamino)methyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoate (300 mg, 1.02 mmol) was treated with LiOH-H₂O (120 mg, 3.02 mmol) in methanol (2 mL) and water (1 mL) at room température for 2 hours. The reaction was acidified with IN HCl to pH = 3. The solvent was removed in vacuo and the residue was purified by preparatory-HPLC A conditions (30-80% MeCN) to provide 2-(5-((dimethylamino)methyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoic acid as a white solid (100 mg). Yield 37% (ESI 267(M+H)⁺).

251

Préparation of 2-(4-((dimethyIamino)methyl)-2-oxopyridin-l(2H)-yI)-4-methylpentanoic acid

Step 1:2-oxo-2,3-dihydropyridine-4-carbaIdehyde

CK ^Se°2 ^ΙΨΌΗ Ή Ό

A mixture of 4-methylpyridin-2-ol (3 g, 27.5 mmol) and SeOi (4 g, 35.8 mmol) in dioxane (40 mL) was refluxed under N₂ atmosphère ovemight and filtered. The filtrate was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH = 1: 10) to provide 2-oxo-2,3dihydropyridine-4-carbaldehyde as a yellow oil (300 mg). Yield 9% (ESI 124 (M+H)⁺)

Step 2:4-((dîmethyIamino)methyl)pyridin-2(lH)-one

A mixture of 2-oxo-2,3-dihydropyridine-4-carbaldehyde (300 mg, 2.4 mmol), dimethylamine (2M in THF, 6 mL) in DCM (5 mL) was stirred at room température for 30 minutes.

NaBH(OAc)î (775.6 mg, 3.65 mmol) was added portion-wise and stirred at room température ovemight. The solvent was concentrated in vacuo and the residue was purified by reverse phase HPLC (Eluent A: water 10 mM NH4HCO3,Eluent B: MeOH, gradient A->B 0-100%) to provide 4-((dimethylamino)methyl)pyridin-2(lH)-one as a yellow oil (150 mg). Yield 41% (ESI 153 (M+H)⁺).

Step 3: ethyl 2-(4-((dimethylamino)methyl)-2-oxopyridin-l(2H)-yl)-4-methyIpentanoate

252

A mixture of4-((dimethylamino)methyl)pyridin-2(lH)-one (150 mg, 0.98 mmol), K₂CO₃(409 mg, 2.96 mmol) and ethyl 4-methyl-2-(methylsulfonyloxy)pentanoate (350 mg, 1.47 mmol) in CH₃CN (5 mL) was stirred at 70 °C ovemight. The solvent was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 1:2) to provide ethyl 2-(4((dimethylamino)methyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoate as a yellow oil (100 mg). Yield 35% (ESI 295(M+H)⁺).

Step 4:2-(4-((dimethy)amino)methyl)-2-oxopyridin-l(2H)-yI)-4-methylpentanoic acid

Ethyl 2-(4-((dimethylamino)methyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanoate ( 100 mg, 0.33 mmol) was treated with LiOH-H₂O (40 mg, 1.01 mmol) in methanol (2 mL) and water (1 mL) at room température for 2 hours. The solvent was removed in vacuo and the residue was purified by preparatory-HPLC A (30-80% MeCN) to provide 2-(4-((dimethylamino)methyl)-2-oxopyridinl(2H)-yl)-4-methylpentanoic acid as a white solid (80 mg). Yield 90% (ESI 267(M+H)⁺).

Préparation of Acid 3: 2-(5-((3,3-difluoroazetidin-l-yl)methyl)-2-oxopyridin-l(2/0-yl)-4mcthylpentanoic acid

Step 1:5-((3,3-difluoroazetidin-l-yl)methyl)pyridin-2(ljFf)-one

253

Ο

A mixture of6-oxo-l,6-dihydropyridine-3-carbaldehyde (153 mg, 1.24 mmol) and 3,3difluoroazetidine hydrochloride (193 mg, 1.49 mmol) in MeOH (3 mL) was stirred at room température for 30 mins. NaBHjCN (231 mg, 3.73 mmol) was added and stirred at room température for 1 hour. The solvent was removed in vacuo to provide the crude 5-((3, 3difluoroazetidin-l-yl)methyl)pyridin-2(lH)-one as white solid (248 mg) used without further purification. (ESI 201.1 (M+H)⁺).

Step 2: ethyl 2-(5-((3,3-difIuoroazetidin-l-yl)methyl)-2-oxopyridin-l(2//)-yl)-4methylpentanoate

A mixture of 5-((3,3-difluoroazetidin-l-yl)methyl)pyridin-2(lH)-one (248 mg, 1.24 mmol), ethyl 4-methyI-2-(methylsulfonyloxy)pentanoate (443 mg, 1.86 mmol) and K2CO₃(514 mg, 3.72 mmol) in MeCN (5 mL) was stirred at 80 °C ovemight. The mixture was filtered and washed with MeCN (5 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel column (petroleum ether: EtOAc 2:1) to provide ethyl 2-(5-((3,3-difluoroazetidin-lyl)methyI)-2-oxopyridin-l(2//)-yl)-4-methylpentanoate as a colorless oil (150 mg). Yield 36% (ESI 343.1 (M+H)⁺).

Step 3: 2-(5-((3,3-difluoroazetidin-l-yl)methyl)-2-oxopyridin-l(2/7)-yl)-4-methyIpentanoic acid

254

Ethyl 2-(5-((3,3-difluoroazetidin-1 -yl)methyl)-2-oxopyridin-1 (2/7)-yl)-4-methylpentanoate (151 mg, 0.44 mmol) was treated with LiOH-FbO (28 mg, 0.66 mmol) in THF (3 mL) and H2O (0.5 mL) at room température for 30 mins. The mixture was acidified to pH 4~5 with IN HCl. The 5 mixture was concentrated in vacuo to provide 2-(5-((3,3-difluoroazetidin-l-yl)methyl)-2oxopyridin-l(2/y)-yl)-4-methylpentanoic acid as white solid (138 mg) used without further purification. Yield 100% (ESI 315.1 (M+H)⁺).

Préparation of 4-methyI-2-(5-(morpholinomethyl)-2-oxopyridin-l(2H)-yl)pentanoic acid Step 1: ethyl 2-(5-formyI-2-oxopyrîdin-l(2H)-yI)-4-methylpentanoate

A mixture of 6-oxo-l,6-dihydropyridine-3-carba!dehyde (400 mg, 3.2 mmol), ethyl 4-methyl-2(methylsulfonyloxy)pentanoate (1 g, 4.2 mmol) and K2CO3 (1.1 g, 8 mmol) in MeCN (10 mL) was stirred at 80°C ovemight. The mixture was filtered and washed with MeCN (5 mL). The filtrate was concentrated in vacuo and purified by silica gel column (pet ether: EtOAc 4:1) to provide ethyl 2-(5-formyl-2-oxopyridin-l(2H)-yl)-4-methylpentanoate as a colorless oil (650 mg). Yield 70% (ESI 266.3 (M+H)⁺).

Step 2: ethyl 2-(5-((3-fluoroazetidin-l-yI)methyI)-2-oxopyridin-l(2//)-yl)-4methylpentanoate

255

NHHCI

NaBH(OAc)₃, DCE. a.t., 16 h

A mixture of ethyl 2-(5-formyl-2-oxopyridin-l(2H)-yI)-4-methylpentanoate (300 mg, 1.13 mmol) and 3-fluoroazetidine hydrochloride (251 mg, 2.26 mmol) in DCE (4 mL) was stirred at room température for 30 mins. Sodium triacetoxyborohydride (959 mg, 4.52 mmol) was added and stirred at room température ovemight. The mixture was concentrated in vacuo and purified by silica gel column (DCM: MeOH 10:1) to provide ethyl 2-(5-((3-fluoroazetidin-l-yl)methyl)2-oxopyridin-l(2H)-yl)-4-methylpentanoate as a colorless oil (264 mg). Yield 72% (ESI 325.2 (M+H)⁺).

Step 3: 2-(5-((3-fluoroazctidin-l-yl)methyl)-2-oxopyridin-l(2Z/)-yl)-4-methylpentanoic acid

Ethyl 2-(5-((3-fluoroazetidin-l-yl)methyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoate (264 mg, 0.81 mmol) was treated with LiOH-H₂O (171 mg, 4 mmol) in EtOH (4 mL) and H₂O (1 mL) at room température for 2 hours. The mixture was acidified to pH 4~5 with IN HCl. The mixture was concentrated in vacuo and purified by silica gel column (DCM: MeOH 10:1) to provide 215 (5-((3-fluoroazetidin-1 -yl)methyl)-2-oxopyridin-1 (2//)-yl)-4-methylpentanoic acid as a white solid (217 mg). Yield 90% (ESI 297.1 (M+H)⁺).

Préparation of 4-methyl-2-(5-(morpholinomethyi)-2-oxopyridin-l(2H)-yl)pentanoic acid

Step 1: ethyl 4-methyl-2-(5-(morpholinomethyl)-2-oxopyridin-l(2H)-yl)pentanoate

256

NaBH(OAc)₃

MeOH, rt, 1h

A mixture of ethyl 2-(5-formyl-2-oxopyridin-l(2H)-yl)-4-methylpentanoate (300 mg, 1.13 mmol) and morpholine (147 mg, 1.70 mmol) in DCE (5 mL) was stirred at room température for 30 mins. NaBH(OAc)j (715 mg, 3.39 mmol) was added and stirred at room température for 1 hour. The solvent was removed in vacuo and the residue purified by silica gel column (DCM: MeOH 2:1) to provide ethyl 4-methyl-2-(5-(morpholinomethyl)-2-oxopyridin-l(2H)yl)pentanoate as yellow oil (150 mg). Yield 39% (ESI 337.2 (M+H)⁺).

Step 2:4-methyI-2-(5-(morpholinomethyl)-2-oxopyridin-l(2H)-yl)pentanoic acid

Ethyl 4-methyl-2-(5-(morpholinomethyl)-2-oxopyridin-l(2H)-yl)pentanoate (150 mg, 0.45 mmol) was treated with LiOH-HiO (56 mg, 1.34 mmol) in THF (3 mL) and HjO (0.5 mL) at room température for 2 hours. The mixture was acidifîed to pH 4~5 with IN HCl. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8/40 g column (A: water 10 mM NH4HCOj,B: MeOH, 0~100%) to provide 4-methyl-2-(5(morpholinomethyl)-2-oxopyridin-l(2H)-yl)pentanoic acid as white solid (110 mg). Yield 80% (ESI 309.3 (M+H)⁺).

Préparation of 2-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-l(2H)-yI)-4-methylpentanoic acid

Step 1: ethyl 2-(5-(((R)-3-fluoropyrrolidin-l-yl)methyl)-2-oxopyridin-l(2H)-yI)-4methylpentanoate

257

F-’'

A mixture of ethyl 2-(5-formyl-2-oxopyridin-l(2H)-yI)-4-methylpentanoate (300 mg, 1.13 mmol), (R)-3-fluoropyrrolidine hydrochioride (284 mg, 2.26 mmol) and triethylamine (0.31 mL, 2.26 mmol) in DCE (10 mL) was stirred at room température for 30 mins. Sodium triacetoxyborohydride (959 mg, 4.52 mmol) was added and stirred at room température ovemight. The mixture was concentrated in vacuo and purified by silica gel column (DCM: McOH 10:1) to provide ethyl 2-(5-(((R)-3-fhioropyrrolidin-l-yl)methyl)-2-oxopyridin-l(2H)yl)-4-methylpentanoate as a colorless oil (237 mg). Yield 62% (ESI 339.2 (M+H)⁺).

Step 2:2-(5-(((R)-3-fluoropyrrolidin-l-yI)methyl)-2-oxopyridin-l(2H)-yl)-4methylpentanoic acid

Ethyl 2-(5-(((R)-3-fluoropyrrolidin-1 -yl)methyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanoate (426 mg, 1.13 mmol) was treated with LÎOH-H2O (237 mg, 5.65 mmol) in EtOH (6 mL) and H2O (0.6 mL) at room température for 2 hours. The mixture was acidified to pH 4~5 with IN HCl. The mixture was concentrated in vacuo and the residue purified by silica gel column (DCM: MeOH 10:1) to provide 2-(5-(((R)-3-fluoropyrrolidin-l-yl)methyl)-2-oxopyridin-l(2H)yl)-4-methylpentanoic acid as a white solid (348 mg). Yield 99% (ESI 311.1 (M+H)⁺).

Préparation of 2-(5-(3-(dimethylamino)azetidin-l-yl)-4-methyI-2-oxopyridin-l(2H)-yl)-4methylpentanoic acid

Step 1: ethyl 2-(5-bromo-4-methyl-2-oxopyridin-l(2H)-yI)-4-methylpentanoate

258

A mixture of 5-bromo-4-methylpyridin-2(IH)-one (3.0 g, 16 mmol, 1.0 eq), K2CO3 (4.4 g, 32 mmol, 2.0 eq) and ethyl 4-methyl-2-((methyIsulfonyl)oxy)pentanoate (5.7 g, 24 mmol, 1.5 eq) in CH3CN (50 mL) was stirred at 80°C for 16 h. LCMS showed the reaction was completed. The mixture was filtered and washed with CH3CN (20 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 3:1) to provide ethyl 2-(5bromo-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanoate as a yellow oil (4.5 g). Yield 85% (ESI 330 (M+H)⁺). Ή NMR (500 MHz, CDCI3) δ 7.46 (s, 1H), 6.49 (d, J= 0.6 Hz, 1H), 5.67 (dd, J= 10.6, 5.3 Hz, 1H), 4.20 (qd, J= ΊΛ, 0.8 Hz, 2H), 2.24 (d, J= 0.8 Hz, 3H), 1.97 -1.93 (m, 1H), 1.87- 1.80 (m, 1H), 1.51-1.43 (m, 1H), 1.27 (t, J= 7.1 Hz, 3H), 0.95 (t,J= 6.3 Hz,

6H).

Step 2: ethyl 2-(5-(3-(dimethylamino)azetidin-l-yI)-4-methyl-2-oxopyridin-l(2H)-yl)-4methylpentanoate

To a solution of ethyl 2-(5-bromo-4-methyl-2-oxopyridin-l(2H)-yl)-4-methyIpentanoate (2.0 g,

6.06 mmol, 1.0 eq), N,N-dimethylazetidin-3-amine dihydrochloride (1.57 g, 9.07 mmol, 1.5 eq), and CSCO3 (8.0 g, 24.5 mmol, 4.0 eq) in toluene (50 mL) was added BINAP (376 mg, 0.606 mmol, 0.1 eq) and Pd2dba3 (250 mg, 0.27 mmol, 0.05 eq) under N2 and then heated to 120 °C for 3h. LCMS showed the reaction was completed. The mixture was filtered and washed with both EtOAc (20 mL) and EtOH (20 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 1:1) to provide ethyl 2-(5-(3(dimethylamino)azetidin-1 -yl)-4-methyl-2-oxopyridin-1 (2H)-yl)-4-methylpentanoate (1.4 g).

Yield 66% (ESI 350 (M+H)⁺).

Step 3:2-(5-(3-(dimethylamino)azetidin-l-yi)-4-methyl-2-oxopyridin-l(2H)-yl)-4methylpentanoic acid

259

Ethyl 2-(5-(3-(dimethylamino)azetidin-1 -yl)-4-methyl-2-oxopyridin-1 (2H)-yl)-4methylpentanoate(1.4 g, 4.0 mmol, 1.0 eq) was treated with LiOH-HzO (840 mg, 20.0 mmol, 5.0 eq) in THF (20 mL) and water (6 mL) at room température for 2 hours. The MeOH was removed and the aqueous material acidified with IN HCl to pH 4. The mixture was purified by reverse phase HPLC in neutral condition (A: water. B: MeOH, 60%B) to provide 2-(5-(3(dimethylamino)azetidin-l-yl)-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanoic acid as a white solid (800 mg). Yield 62% (ESI 322 (M+H)⁺). 1H- NMR (400 MHz, MeOD) δ 6.75 (s,

1H), 6.31 (s, 1H), 5.45-5.38(m, 1H), 3.87-3.28(m, 2H), 3.24(s, 3H), 3.17-2.42(m, 6H), 2.19

2.06(m, 3H), 1.24-1.19(m, 1H), 0.85-0.74(m, 6H).

Préparation of 2-(5-((dimethyIamino)methyI)-2-oxo-4-(trifluoromethyI)pyridin-l(2^)-yl)-4methylpentanoic acid Step 1 : l-(6-methoxy-4-(trifluoromethyl)pyridin-3-yI)-7V,A-dimethylmethanamine ^F3^C\zî\/^O\ ΝΗ^

Y ï ___ù__I \ T

NaBH(OAc)3 '

A mixture of 6-methoxy-4-(trifluoromethyl)nicotinaldehyde (0.5 g, 2.44 mmol), dimethylamine (2.0 M in THF, 1.5 mL, 2.92 mmol) in DCE (10 mL) was stirred at room température for 15 mins. NaBH(OAc)₃ (1.03 g, 4.88 mmol) was added and stirred at room température for 3 hours. The solvent was removed in vacuo and the residue purified by silica gel column (DCM: MeOH 10:1) to provide l-(6-methoxy-4-(trifluoromethyl)pyridin-3-yl)-N,N-dimethylmethanamine as yellow oil (220 mg). Yield 38% (ESI 235.1(M+H)⁺).

Step 2:5-((dimethylamino)methyl)-4-(trifluoromethyI)pyridin-2-oI

I I Π ^44% HBr/AcOH |

A mixture of l-(6-methoxy-4-(trifluoromethyl)pyridin-3-yl)-N,N-dimethylmethanamine (220 mg, 0.94 mmol) in 33% HBr/AcOH (10 mL) was heated at 75°C for 16 hours. The solvent was

260 removed in vacuo and the residue was purified by reverse phase HPLC on a Cl 8/40 g column (A: water 10 mM NIMICCh.B: MeOH, 0-100%) to provide 5-((dimethylamino)methyl)-4(trifluoromethyl)pyridin-2-ol as a red solid (180 mg). Yield 87% (ESI 221.1 (M+H)⁺).

Step 3: ethyl 2-(5-((dimethylamino)methyI)-2-oxo-4-(trifluoromethyI)pyridin-l(2Â0-yI)-4-

A mixture of 5-((dimethylamino)methyl)-4-(trifluoromethyl)pyridin-2-ol (150 mg, 0.68 mmol), ethyl 4-methyl-2-(methylsulfonyloxy)pentanoate (194 mg, 0.816 mmol) and K2CO3 (281.5 mg, 2.04 mmol) in MeCN (10 mL) was stirred at 80°C ovemight. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC on a Cl 8/40 g column (A: water 10 mM NH4HCO3.B: MeOH, 0~100%) to provide ethyl 2-(5-((dimethylamino)methyl)-2-oxo-4(trifluoromethyl)pyridin-l(2//)-yI)-4-methylpentanoate (170 mg). Yield 68% (ESI 363.1 (M+H)⁺).

Step 4: 2-(5-((dimethyIamino)methyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2jF7)-yI)-4methylpentanoic acid

Ethyl 2-(5-((dimethylamino)methyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanoate (170 mg, 0.47 mmol) was treated with LÎOH-H2O (98.7 mg, 2.35 mmol) in MeOH (10 mL) and H2O (2 mL) at room température for 2 hours. The mixture was acidified to pH 4~5 with IN HCl and purified by reverse phase HPLC on a Cl8/40 g column (A: water 10 mM NH4HCO3.B: MeOH, 0~100%) to provide 2-(5-((dimethylamino)methyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoic acid as white solid (120 mg). Yield 76% (ESI 335.2 (M+H)⁺).

261

Préparation of 2-(5-(2-(dimethyIamino)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoic acid

Step 1:5-(2-methoxyvinyl)pyridin-2(lH)-one t-BuOK, THF

A mixture of (methoxymethyl)triphenylphosphonium chloride (12.5 g, 36.6 mmol), t-BuOK (6.83 g, 61 mmol) in dioxane (60 mL) was stirred at room température for 15 minutes. Then 6oxo-l,6-dihydropyridine-3-carbaldehyde (3 g, 24.4 mmol) in 20 mLTHF was added. The mixture was stirred for 16 h at room température. To the reaction mixture was added 80 mL water. The mixture was extracted with EtOAc (80 mL x 2) and the aqueous phase concentrated in vacuo. The residue was purified by reverse phase HPLC (Eluent A: water 10 mM NH4HCO3, Eluent B: MeOH, gradient A->B 0~100%) to provide 5-(2-methoxyvinyl)pyridin-2(lH)-one as a red oil (1.3 g). Yield 35% (ESI 152.2 (M+H)⁺).

Step 2:2-(6-oxo-l,6-dihydropyridin-3-yl)acetaIdehyde

HCOOH, 70°C CK

5-(2-methoxyvinyl)pyridin-2(lH)-one (1.2 g, 7.95 mmol) was treated with HCOOH (20 mL) at 70°C for 2 hours. The solvent was removed in vacuo to provide the crude product 2-(6-oxo-l,6dihydropyridin-3-yl)acetaldehyde as a red oil (0.8 g, crude). (ESI 138.3 (M+H)⁺).

Step 3:5-(2-(dimethylamino)ethyl)pyridin-2(lH)-one

CK

O DCM/MeOH(4/1), AcOH NaBH(OAc)₃

A mixture of methyl 2-(6-oxo-l,6-dihydropyridin-3-yl)acetaldehyde (750 mg, 5.47 mmol), AcOH (394 mg, 6.56 mmol) and dimethylamine (40% in water) (1.23 g, 10.94 mmol) in DCM (10 mL) and MeOH (2.5 mL) was stirred at room température for 30 minutes then NaBH(OAc)₃(2.32 g, 10.94 mmol) was added. The mixture was stirred at room température ovemight. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH

262

2:1) to provide 5-(2-(dimethylamino)ethyl)pyridin-2(lH)-one as yellow oil (500 mg). Yield 55% (ESI 167.2 (M+H)⁺).

Step 4: ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-l(2H)-yI)-4-methylpentanoate

A mixture of methyl 5-(2-(dimethylamino)ethyl)pyridin-2(lH)-one (500 mg, 3 mmol), ethyl 4methyl-2-(methy!sulfonyloxy)pentanoate (1.07 g, 4.5 mmol) and K2CO3 (828 mg, 6 mmol) in MeCN (15 mL) was stirred at 70°C ovemight. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH 1:2) to provide methyl ethyl 2-(5-(2(dimethylamino)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoate as a white solid (100 mg). Yield 11% (ESI 309.2(M+H)⁺).

Step 5: 2-(5-(2-(dimethyIamino)ethyl)-2-oxopyridin-l(2H)-yI)-4-methylpentanoic acid

Ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoate (100 mg, 0.32 mmol) was treated with L1OH-H2O (54 mg, 1.28 mmol) in EtOH (3 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with 1 N HCl. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC (Eluent A: water 10 mM NH4HCO3. Eluent B: MeOH, gradient A->B 0-100%) to provide 2-(5-(2(dimethylamino)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoic acid as white solids (70 mg). Yield 78% (ESI 281.2(M+H)⁺).

Préparation of 2-(4-(2-(dimethylamino)ethyI)-2-oxopyridin-l(2H)-yl)-4-methylpentanoic acid

Step 1: ethyl 2-(4-bromo-2-oxopyridin-l(2H)-yl)-4-methylpentanoate

263

A mixture of4-bromopyridin-2(lH)-one (1.2 g, 6.94 mmol), K2CO₃(l.92 g, 13.88 mmol) and ethyl 4-methyl-2-(methylsulfonyloxy)pentanoate (1.98 g, 8.33 mmol) in CH₃CN (20 mL) was stirred at 80°C ovemight. The solvent was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 1:1) to give ethyl 2-(4-bromo-2-oxopyridin-l(2H)-yl)-4methylpentanoate as a yellow oil (1.6 g). Yield 73% (ESI 316.1(M+H)⁺).

Step 2: ethyl 2-(4-(2-(benzyIoxycarbonyIamino)ethyI)-2-oxopyridin-l(2H)-yl)-4mcthylpentanoate

A mixture of ethyl 2-(4-bromo-2-oxopyridin-l(2H)-yl)-4-methylpentanoate (1.6 g, 5.0 mmol), potassium benzyl N-[2-(trifluoroboraly)ethyl]carbamate (1.71 g, 6 mmol), Pd(dppf)C12 (366 mg, 0.5 mmol) and Na₂CO₃ (1.06 g, 10 mmol) in 1,4-dioxane (20 mL) and H₂O (10 mL) was stirred at 90°C under N2 atmosphère for 4 hours. The reaction was concentrated and purified by reverse phase HPLC on a C18/40 g column (A: water/0.01%TFA,B: MeOH, 0~100%) to provide ethyl 2-(4-(2-(benzyloxycarbonylamino)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanoate as a yellow oil (700 mg). Yield 35% (ESI 415.1 (M+H)⁺).

Step 3: ethyl 2-(4-(2-aminoethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoate

Ethyl 2-(4-(2-(benzyloxycarbonylamino)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanoate (0.7 g, 1.7 mmol) was treated with TFA (10 mL) at 50°C for 4 hours. The solvent was removed in

264 vacuo and the residue was purified by reverse phase HPLC on a Cl8/40 g column (A: water 10 mMNFLHCCh, B: MeOH, 0-100%) to provide ethyl 2-(4-(2-aminoethyl)-2-oxopyridin-l(2H)yl)-4-methylpentanoate as a red oil (0.4 g). Yield 84%. (ESI 281.2 (M+H)⁺).

Step 4: ethyl 2-(4-(2-(dimethylamino)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoate

H₂N

HCHO

NaBH(OAc)3

To a mixture of ethyl 2-(4-(2-aminoethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoate (400 mg, 1.43 mmol) in MeOH (10 mL) was added HCHO (37% in H₂O, 1 mL) and stirred at room température for 5 mins. NaBH(OAc)₃ (1.21 g, 5.72 mmol) was added and stirred at room température for 1 hour. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC on a C18/40 g column (A: water 10 mM NH4HCO₃, B: MeOH, 0-100%) to provide ethyl 2-(4-(2-(dimethylamino)ethyl)-2-oxopyridin-l(2H)-yI)-4-methylpentanoate as yellow oil (400 mg). Yield 91% (ESI 309.2(M+H)⁺).

Step 5: 2-(4-(2-(dimethylamino)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoic acid

LiOH

Ethyl 2-(4-(2-(dimethylamino)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoate (400 mg, 1.3 mmol) was treated with LiOH-HjO (218 mg, 5.2 mmol) in MeOH (4 mL) and H₂O (1 mL) at room température for 1 hour. The mixture was acidified to pH 4-5 with IN HCl. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8/40 g column (A: water/0.01%TFA,B: MeOH, 0-100%) to give 2-(4-(2-(dimethylamino)ethyl)-2oxopyridin-l(2H)-yl)-4-methylpentanoic acid as white solid (310 mg). Yield 85% (ESI 281.2(M+H)⁺).

265

Préparation of 2-(3-(2-(dimethy!amino)ethyI)-2-oxopyridin-l(2/7)-yl)-4-methylpentanoic acid

Step 1: ethyl 2-(3-bromo-2-oxopyridin-l(2JT)-yI)-4-methylpentanoate

A mixture of3-bromopyridin-2(lZ/)-one (1 g, 5.78 mmol), K2CCh(1.6 g, 11.56 mmol) and ethyl 4-methyl-2-(methylsulfonyloxy)pentanoate (1.65 g, 6.94 mmol) in CH3CN (20 mL) was stirred at 80°C ovemight. The solvent was concentrated in vacuo and purified by silica gel column (petroleum ether: EtOAc 1:1) to provide ethyl 2-(3-bromo-2-oxopyridin-l(2/7)-yl)-4methylpentanoate as a white solid (1.6 g). Yield 88% (ESI 316.1(M+H)⁺).

Step 2: ethyl 2-(3-(2-(benzyloxycarbonyIamino)ethyl)-2-oxopyridin-l(2Z/)-yl)-4methylpentanoate

A mixture of ethyl 2-(3-bromo-2-oxopyridin-l(2H)-yl)-4-methylpentanoate (1 g, 3.17 mmol), potassium benzyl yV-[2-(trifluoroboryl)ethyl]carbamate (1.08 g, 3.8 mmol), Pd(dppf)Cb (36 mg, 0.16 mmol), CS2CO3 (2 g, 6.34 mmol) and RuPhos (144 mg, 0.32 mmol) in 1,4-dioxane (20 mL) and H2O (10 mL) was stirred at 110 °C for 2 hours. The reaction was concentrated and purified by reverse phase HPLC on a C18/40 g column (A: water/0.01%TFA,B: MeOH, 0—100%) to give ethyl 2-(3-(2-(benzyloxycarbonylamino)ethyl)-2-oxopyridin-l(2fl)-yl)-4-methylpentanoate as a yellow oil (1.1 g). Yield 84% (ESI 415.2 (M+H)⁺).

Step 3: ethyl 2-(3-(2-aminoethyl)-2-oxopyridin-l(2Z7)-yl)-4-methylpentanoatc

266

Ethyl 2-(3-(2-(benzyloxycarbonylamino)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanoate (1.07 g, 2.58 mmol) was treated with TFA (20 mL) at 50 °C for 4 hours. The solvent was removed in vacuo and the residue purified by reverse phase HPLC on a Cl 8/40 g column (A:

water 10 mM NH4HCO₃, B: MeOH, 0-100%) to provide ethyl 2-(3-(2-aminoethyl)-2oxopyridin-l(277)-yl)-4-methylpentanoate as a yellow oil (0.6 g). Yield 83%. (ESI 281.2 (M+H)⁺).

Step 4: ethyl 2-(3-(2-(dimethylamino)ethyl)-2-oxopyridin-l(2/Z)-yl)-4-methylpentanoate

To a mixture of ethyl 2-(3-(2-aminoethyl)-2-oxopyridin-l(2i/)-yl)-4-methylpentanoate (600 mg, 2.14 mmol) in MeOH (10 mL) was added HCHO (37% in H₂O,1 mL). The mixture was stirred at room température for 5 mins. NaBH(OAc)₃ (1.81 g, 8.56 mmol) was added and stirred at room température for 1 hour. The solvent was removed in vacuo and the residue purified by reverse phase HPLC on a Cl8/40 g column (A: water 10 mM NH4HCO₃, B: MeOH, 0-100%) to provide ethyl 2-(3-(2-(dimethylamino)ethyl)-2-oxopyridin-1 (2?/)-yl)-4-methylpentanoate as yellow oil (600 mg). Yield 91% (ESI 309.2(M+H)⁺).

Step 5: 2-(3-(2-(dimethylamino)ethyl)-2-oxopyridin-l(2Z/)-yl)-4-methylpentanoic acid

267

Ethyl 2-(3-(2-(dimethylamino)ethyl)-2-oxopyridin-l(2//)-yl)-4-methylpentanoate (600 mg, 1.95 mmol) was treated with LiOH monohydrate (328 mg, 7.8 mmol) in EtOH (4 mL) and H₂O (1 mL) at room température for 1 hour. The mixture was acidified to pH 4~5 with IN HCl aqueous solution. The mixture was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40 g column (A: water/0.01%TFA,B: MeOH, 0~100%) to give 2-(3-(2(dimethylamino)ethyl)-2-oxopyridin-l(2Z/)-yl)-4-methylpentanoic acid as white solid (500 mg). Yield 92% (ESI 281.2(M+H)⁺).

Préparation of Acid 9: 2-(5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)-4methylpentanoic acid Step 1: 5-(2-(azetidin-l-yl)ethyl)pyridin-2(lH)-one

Amixture ofmethyl 2-(6-oxo-l,6-dihydropyridin-3-yl)acetaldehyde (1.0 g, 7.29 mmol) and azetidine (416 mg, 7.30 mmol) in MeOH (10 mL) was stirred at room température for 30 mins. NaBH(OAc)i (4.6 g, 21.9 mmol) was added and stirred at room température for 1 hour. The solvent was removed in vacuo and the residue purified by silica gel column (DCM: MeOH 2:1) to provide 5-(2-(azetidin-l-yl)ethyl)pyridin-2(lH)-one as yellow oil (800 mg). Yield 62% (ESI 179.1 (M+H)⁺).

Step 2: ethyl 2-(5-(2-(azetidin-l-yl)ethyI)-2-oxopyridin-l(2H)-yl)-4-methyIpentanoate

268

A mixture of 5-(2-(azetidin-l-yl)ethyl)pyridin-2(lH)-one (800 mg, 4.49 mmol), ethyl 4-methyl2-(methylsuIfonyloxy)pentanoate (2.2 g, 6.74 mmol) and K2CO3 (1.8 g, 13.47 mmol) in MeCN (40 mL) was stirred at 80°C ovemight. The mixture was filtered and washed with MeCN (5 mL). The filtrate was concentrated in vacuo and the residue purified by reverse phase HPLC on a Cl8/80 g column (A: water/0.01%TFA,B: MeOH, 0-100%) toprovide ethyl 2-(5-(2-(azetidin-lyl)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoate as a colorless oil (600 mg). Yield 42% (ESI 321.2 (M+H)⁺).

Step 3: 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoic acid

Ethyl 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoate (600 mg, 1.88 mmol) was treated with LÎOH-H2O (394 mg, 9.40 mmol) in THF (10 mL) and H2O (2 mL) at room température for 1 hour. The mixture was acidifîed to pH 4~5 with IN HCl. The mixture was concentrated in vacuo and the residue purified by reverse phase HPLC on a Cl8/40 g column (A: water 10 mM NHiHCCh.B: MeOH, 0-100%) to provide 2-(5-(2-(azetidin-lyl)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoic acid as red solid (150 mg). Yield 27% (ESI 293.2 (M+H)⁺).

Préparation of 2-(5-(2-(3-fluoroazetidin-l-yI)ethyl)-2-oxopyridin-l(2H)-yl)-4methylpentanoic acid Step 1:5-(2-(3-fluoroazetidin-l-yl)ethyl)pyridin-2(lH)-one

269

A mixture of2-(6-oxo-l,6-dihydropyridin-3-yl)aceta!dehyde (1.5 g, 11 mmol), AcOH (0.8 g, 13.2 mmol) and 3-fluoroazetidine hydrochloride (1.47 g, 13.2 mmol) in MeOH (30 mL) was stirred at room température for 30 mins. NaBH(OAc)₃ (4.66 g, 22 mmol) was added and stirred at room température for 3 hours. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC on a Cl8/120 g column (A: water 10 mM NH4HCOj,B: MeOH, 0-100%) to provide 5-(2-(3-fluoroazetidin-l-yl)ethyl)pyridin-2(lH)-one asa yellow oil (2 g, crude). (ESI 197.2 (M+H)⁺).

Step 2: ethyl 2-(5-(2-(3-fluoroazetidin-l-yl)ethyI)-2-oxopyridin-l(2H)-yl)-4methylpentanoate

Amixture of 5-(2-(3-fluoroazetidin-l-yl)ethyl)pyridin-2(lH)-one (1.9 g, 9.7 mmol), ethyl 4methyl-2-(methylsulfony!oxy)pentanoate (3.45 g, 14.5 mmol) and Cs2CO3(9.5 g, 29.1 mmol) in toluene (40 mL) was stirred 110°C ovemight. The solvent was removed in vacuo and the residue purified by reverse phase HPLC on a Cl8/120 g column (A: water 10 mM NH4HCO3.B: MeOH, 0-100%) to provide ethyl 2-(5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)-4methylpentanoate as a yellow oil (650 mg). Yield 20% (ESI 339.1(M+H)⁺).

Step 3:2-(5-(2-(3-fluoroazetidin-l-yi)ethyI)-2-oxopyridin-l(2H)-yl)-4-methylpentanoic acid

Ethyl 2-(5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoate (650 mg,

270

1.92 mmol) was treated with LiOH-HzO (322 mg, 7.68 mmol) in MeOH (10 mL) and H₂O (2.5 mL) at room température for 2 hours. The mixture was acidifîed to pH 4~5 with IN HCl, purified by reverse phase HPLC on a C18/40 g column (A: water 10 mM NH4HCO3. B: MeOH, 0-100%) to provide 2-(5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)-4methylpentanoic acid as a white solid (350 mg). Yield 59% (ESI 311.2(M+H)⁺).

Préparation of 3-cyclopropyI-2-(5-(2-(3-fluoroazetidin-l-yl)ethyI)-2-oxopyridin-l(2H)yl)propanoic acid

Step 1: (S)-2-bromo-3-cyclopropylpropanoic acid

NaNO₂/HBr,H₂O

OH 0°C-rt.16h

To a solution of (S)-2-amino-3-cyclopropylpropanoic acid (5.0 g, 38.7 mmol) in H₂O (50 mL) was added 40% HBr (60 mL). The reaction mixture was stirred at 0 °C for 10 min. A solution of sodium nitrite (4.5 g, 24 mmol) in H2O (10 mL) was added. The reaction mixture was stirred at 0 °C for 30 min and warmed to room température ovemight. The reaction mixture was extracted with EtOAc (100 mL X 3). The organic layer was washed with brine (100 mL) and dried over Na₂SO4, filtered and concentrated in vacuo to provide (S)-2-bromo-3-cyclopropylpropanoic acid as a colorless oil used directly in the next reaction without further purification (5.0 g). Yield 74% (ESI 194 (M+H)⁺).

Step 2: ethyl (S)-2-bromo-3-cyclopropylpropanoate

To a solution of (S)-2-bromo-3-cyclopropylpropanoic acid (1 g, 5.2 mmol) in EtOH (20 mL) was added SOCI2 (1.8 g, 15.6 mmol) and stirred at ambient température for 2 hours. The solvent was removed in vacuo to provide ethyl 2-bromo-3-cyclopropylpropanoate as a white solid (1.2 g, crude) used directly in the next réaction. (ESI 221.0 (M+H)⁺).

Step 3: ethyl 3-cyclopropyl-2-(5-(2-(3-fluoroazetidin-l-yI)ethyI)-2-oxopyridin-l(2H)yl)propanoate

271 .

A mixture of ethyl 2-bromo-3-cyclopropylpropanoate (800 mg, 3.64 mmol), 5-(2-(3fluoroazetidin-l-yl)ethyl)pyridin-2(lH)-one (1.07 g, 5.46 mmol) and K2CO3 (1.5 g, 10.92 mmol) in MeCN (10 mL) was stirred at 80 °C ovemight. The mixture was filtered and washed with MeCN (10 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel column (pctroleum ether; EtOAc 2:1) to provide ethyl 3-cyclopropyl-2-(5-(2-(3-fluoroazetidin-lyl)ethyl)-2-oxopyridin-l(2H)-yl)propanoate as a colorless oil (400 mg). Yield 32% (ESI 337.2 (M+H)⁺).

Step 4:3-cycIopropyI-2-(5-(2-(3-fluoroazetidin-l-yI)ethyl)-2-oxopyridin-l(2H)-yI)propanoic

Ethyl 3-cyclopropyl-2-(5-(2-(3-fluoroazctidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)propanoate (400 mg, 1.20 mmol) was treated with LiOH-ILO (201 mg, 4.80 mmol) in EtOH (4 mL) and H2O (1 mL) at room température for 2 hours. The mixture was acidified to pH 4-5 with IN HCl. The mixture was concentrated in vacuo and the residue was purified by silica gel column (DCM: MeOH 10:1) to provide 3-cyclopropyl-2-(5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H)yl)propanoic acid as a white solid (310 mg). Yield 85% (ESI 309.15 (M+H)⁺).

Préparation of 2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyI)-2-oxopyridin-l(2H)-yl)-4methylpentanoic acid Step 1: ethyl 2-(5-bromo-2-oxopyridin-l(2£0-yl)-4-methylpentanoate

272

A mixture of 5-bromopyridin-2-o! (12.0 g, 69.0 mmol), K2CO3 (19.1 g, 138.0 mmol) and ethyl 4methyl-2-(methylsulfonyloxy)pentanoate (18.5 g,77.7 mmol) in CH3CN (230 mL) was stirred at 80°C ovemight. The solvent was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 1:2) to provide ethyl 2-(5-bromo-2-oxopyridin-l(2//)-yl)-4methylpentanoate as a yellow oil (13.0 g). Yield 60% (ESI 316.0(M+H)⁺).

Step 2: ethyl 2-(5-aIlyl-2-oxopyridin-l(2//)-yl)-4-methyIpentanoate

A mixture of ethyl 2-(5-bromo-2-oxopyridin-l(27/)-yl)-4-methylpentanoate (13.0 g, 41.1 mmol), allyltributylstannane (14.9 g, 45.1 mmol), Pd2dba3(1.8 g, 2.06 mmol), PCyj (1.1 g, 4.11 mmol) and CsF (12.5 g, 82.2 mmol) in anhydrous dioxane (50 mL) was stirred under N₂at 100°C for 16 h. The mixture was cooled to room température and quenched with saturated NH4CI solution (100 mL) and extracted with EtOAc (100 mL). The aqueous layer was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 19:1) to provide ethyl 2-(5-allyI-2-oxopyridin-l(2//)-yl)-4methylpentanoate as a yellow solid (7.1 g). Yield 62% (ESI 278.1 (M+H)⁺).

Step 3: ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)pyridin-l(2JÏ)-yl)pentanoate

To a solution of ethyl 2-(5-allyl-2-oxopyridin-l(2/7)-yl)-4-methylpentanoate (7.1 g, 25.6 mmol) in THF/H2O (80 mL/30 mL) was added a solution of K2OSO4-2H2O (94.0 mg, 0.26 mmol) in

H₂O (4 mL) and stirred at room température for 1 h. A solution of NaIO₄ (10.8 g, 51.2 mmol) in

273

Η?Ο (20 mL) was added and stirred at room température for 2 h. LCMS showed the reaction was completed. The reaction mixture was diluted with 100 mL of water and extracted with EtOAc (120 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)pyridin1 (2//)-yl)pentanoate as a yellow oil (7.0 g, crude) used directly in the next reaction without further purification. (ESI 280.3 (M+H)⁺).

Step 4: ethyl 2-(5-(2-((Æ)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxopyridin-l(2Z/)-yI)-4methylpentanoate

To a mixture of ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)pyridin-l(2/7)-yl)pentanoate (7.0 g, 25.0 mmol) in DCE (70 mL) at 25 °C was added (7?)-3-fluoropyrrolidine hydrochloride (2.7 g, 25.0 mmol) and stirred at 25 °C for 30 mins. Then NaBH(OAc)î (10.6 g, 50.0 mmol) was added at 5 °C and stirred at 25 °C for 16 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel column (DCM: MeOH 19:1) to give compound ethyl 2-(5-(2-((Æ)-3fluoropyrrolidin-l-yl)ethyl)-2-oxopyridin-l(2fl)-yl)-4-methylpentanoate (1.3 g) as a yellow oil.

Yield: 15% (ESI 353.2 (M+H)⁺).

Step 5:2-(5-(2-((R)-3-fluoropyrroIidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)-4methylpentanoic acid

Ethyl 2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoate (1.3 g, 3.69 mmol) was treated with LÎOH-H2O (775.0 mg, 18.4 mmol) in MeOH (12 mL) and water (5 mL) at room température for 2 hours. The MeOH was removed in vacuo, acidified with IN HCl to pH = 5. The residue was purified by reverse phase HPLC on a Cl 8/120 g column (A: water. B: MeOH, 0-100%) to provide 2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxopyridinl(2H)-yl)-4-methylpentanoic acid as a white solid (1.03 g). Yield 86% (ESI 325.1 (M+H)⁺).

274

Préparation of 2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4methylpentanoic acid

Step 1: (E)-2-methoxy-5-(2-methoxyvinyl)-4-inethylpyridine

A mixture of (methoxymethyl)triphenyl phosphonium chloride (8.5 g, 24.8 mmol) and t-BuOK (4.6 g, 41.3 mmol) in THF (40 mL) was stirred at room température for 20 mins. 6-methoxy-4methylnicotinaldehyde (2.5 g, 16.5 mmol) in 10 mLof THF was added and the mixture stirred at room température for 2 hours. The reaction mixture was poured into 40 mL of water and extracted with EtOAc (50 mL x 2). The organic phase was concentrated in vacuo and the residue purified by reverse phase HPLC on a Cl 8/40 g column (A: water 10 mM NH4HCO3.B: MeOH, 0-100%) to provide (E)-2-methoxy-5-(2-methoxyvinyl)-4-methylpyridine as a colorless oil (1.8 g). Yield 61% (ESI 180.1(M+H)⁺).

Step 2:2-(6-methoxy-4-methylpyridin-3-yl)acetaldehyde

ο.

(E)-2-methoxy-5-(2-methoxyvinyl)-4-methylpyridine (1.8 g, 10 mmol) was treated with TFA (20 mL) at room température for 4 hours. The solvent was removed in vacuo to provide 2-(6methoxy-4-methylpyridin-3-yl)acetaldehyde as a red oil (1.5 g, crude) used without further purification. (ESI 166.1 (M+H)⁺).

Step 3:2-(6-methoxy-4-methylpyridin-3-yi)-N,N-dimethylethanamine

HN

NaBH(OAc)₃

A mixture of2-(6-methoxy-4-methylpyridin-3-yl)acetaldehyde (1.45 g, 8.78 mmol), dimethylamine (2M in THF, 17.5 mL, 35.72 mmol) and AcOH (0.8 g, 13.2 mmol) in DCE (30 mL) was stirred at room température for 15 mins. NaBH(OAc)j (3.71 g, 17.5 mmol) was added and stirred at room température for 3 hours. The solvent was removed in vacuo and the residue purified by silica gel column (DCM: MeOH 10:1) to provide 2-(6-methoxy-4-methylpyridin-3

275 yl)-N,N-dimethylethanamine as a yellow oil (850 mg). Yield 50% (ESI 195.1(M+H)⁺).

Step 4:5-(2-(dimethylamino)ethyI)-4-methylpyridin-2-ol

A mixture of 2-(6-methoxy-4-methylpyridin-3-yl)-N,N-dimethylethylamine (850 mg, 4.38 mmol) in HBr/AcOH (20 mL) was heated at 75°C for 16 h. The solvent was removed in vacuo and the residue purified by reverse phase HPLC on a Cl8/40 g column (A: water 10 mM NHîHCOî.B: MeOH, 0-100%) to provide 5-(2-(dimethylamino)ethyl)-4-methylpyridin-2-ol as a red solid (650 mg). Yield 82% (ESI 181.1 (M+H)⁺).

Step 5: ethyl 2-(5-(2-(dimethylamino)ethyI)-4-methyl-2-oxopyridin-l(2H)-yl)-4methylpentanoate

A mixture of 5-(2-(dimethylamino)ethyl)-4-methylpyridin-2-ol (650 g, 3.6 mmol), ethyl 4methyl-2-(methylsulfonyloxy)pentanoate (1.71 g, 7.2 mmol) and K2CO3 (1.49 g, 10.8 mmol) in MeCN (20 mL) was stirred at 80°C ovemight. The solvent was removed in vacuo and the residue purified by reverse phase HPLC on a Cl8/40 g column (A: water 10 mM NH4HCO3.B: MeOH, 0-100%) to provide ethyl 2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4methylpentanoate (500 mg). Yield 43% (ESI 323.2(M+H)⁺).

Step 6:2-(5-(2-(dimethyIamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanoic

LiOH

Ethyl 2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l (2H)-yl)-4-methylpentanoate (500

276 mg, 1.55 mmol) was treated with LiOH-HzO (260 mg, 6.2 mmol) in MeOH (10 mL) and H2O (2 mL) at room température for 2 hours. The mixture was acidified to pH 4-5 with IN HCl and purified by reverse phase HPLC on a Cl8/40 g column (A: water 10 mM NH4HCO3.B: MeOH, 0-100%) to provide 2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4methylpentanoic acid as a white solid (420 mg). Yield 92% (ESI 295.2(M+H)⁺).

Préparation of 2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l (2H)-yl)-5methylhexanoic acid

Step 1: (R)-2-bromo-5-methyIhexanoic acid

To a mixture of (R)-2-amino-5-methylhexanoic acid (30 g, 207 mmol) in 40% HBr (200 mL) and H₂O (200 mL) at 0°C was added a solution of NaNO2 (17 g, 248 mmol) in H2Û(15 mL) dropwise. The mixture was stirred at room température ovemight. The mixture was extracted with DCM (200 mL). The organic phase was washed with brine (200 mL), dried over Na₂SO4, concentrated in vacuo to provide (R)-2-bromo-5-methylhexanoic acid as a yellow oil (30 g). Yield 70% (ESI 21L1(M+H)⁺).

Step 2: ethyl 2-bromo-5-methylhexanoate

To a mixture of (R)-2-bromo-5-methylhexanoic acid (30 g, 144 mmol) in EtOH (200 mL) at 0°C was added SOCh (86 g, 720 mmol). The mixture was stirred for 4 h at room température. The solvent was removed in vacuo to provide ethyl 2-bromo-5-methylhexanoate as a colorless oil (35 g, crude). (ESI 239.1 (M+H)⁺).

Step 3: ethyl 2-(5-bromo-4-methyl-2-oxopyridin-l(2H)-yl)-5-methyIhexanoate

277

A mixture of 5-bromo-4-methylpyridin-2(lH)-one (8 g, 42.78 mmol), Cs2COj(27.9 g, 85.56 mmol) and ethyl 2-bromo-5-methylhexanoate (15 g, 64.17 mmol) in toluene (160 mL) was stirred at 110 °C for 4hours. The solvent was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 4:1 ) to provide ethyl 2-(5-bromo-4-methyl-2-oxopyridinl(2H)-yl)-5-methy!hexanoateas a colorless oil (6.5 g). Yield 44% (ESI 346.1(M+H)⁺).

Step 4: (E)-ethyl 2-(5-(2-ethoxyvinyl)-4-methyl-2-oxopyridin-l(2H)-yl)-5-methylhexanoate

A mixture of ethyl 2-(5-bromo-4-methyl-2-oxopyridin-l(2H)-yl)-5-methylhexanoate (5.4 g, 15.7 10 mmol), (E)-2-(2-ethoxyvinyI)-4,4,5,5-tetramethyI-1,3,2-dioxaborolane (6.22 g, 31.4 mmol),

Pd(PPhj)4 (912 mg, 0.79 mmol) and K2CO3 (4.33 g, 31.4 mmol) in 1,4-dioxane (70 mL) and water (7 mL) was stirred at 70°C under N2 for 20 h. The reaction mixture was diluted with 100 mL of water, extracted with EtOAc (100 mL x 2). The combined oiganic phase was washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 1:1) to provide (E)-ethyl 2-(5-(2ethoxyvinyl)-4-methyl-2-oxopyridin-l(2H)-yl)-5-methylhexanoate (3.8 g) as a yellow oil. Yield 72% (ESI 336.2 (M+H)⁺).

Step 5: ethyl 5-methyl-2-(4-methyl-2-oxo-5-(2-oxoethyl)pyridin-l(2H)-yl)hexanoate

278

(E)-ethyl 2-(5-(2-ethoxyvinyl)-4-methyl-2-oxopyridin-l(2H)-yl)-5-methylhexanoate (3.8 g,

11.34 mmol) was treated with TFA (40 mL) at room température for 1 hour. The solvent was removed in vacuo and the residue was purified by silica gel column (EtOAc) to provide ethyl 5methyl-2-(4-methyl-2-oxo-5-(2-oxoethyl)pyridin-l(2H)-yl)hexanoate as a colorless oil (2 g). Yield 57% (ESI 308.2 (M+H)⁺).

Step 6: ethyl 2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-5methylhexanoate

To a mixture of ethyl 5-methyl-2-(4-methyl-2-oxo-5-(2-oxoethyl)pyridin-l(2H)-yl)hexanoate (2 g, 6.51 mmol) in DCM (30 mL) was added dimethylamine (2 M) (6.5 mL, 13.02 mmol) and stirred at room température for 20 minutes. Then NaBH(OAc)₃ (2.76 g, 13.02 mmol) was added and stirred at room température for 4 h. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH 10:1) to provide ethyl 2-(5-(2(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-5-methylhexanoate as a colorless oil (1.4 g). Yield 64% (ESI 337.3 (M+H)⁺).

Step 7: 2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-5-methyIhexanoic acid

279

Ethyl 2 - (5- (2- (dimethylamino)ethyl) - 4-methyl - 2 - oxopyridin - 1(2H) - yl) - 5 methylhexanoate (1.4 g, 4.17 mmol) was treated with LiOH-HzO (700 mg, 16.68 mmol) in MeOH (20 mL) and H₂O (4 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with 1 N HCl. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC on a C18/40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0~100%) to provide 2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-5methylhexanoic acid (900 mg) as a white solid. Yield 70% (ESI 309.2(M+H)⁺).

Préparation of 2-(5-(2-(3-fluoroazetidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2H)-yI)-4methylpentanoic acid

Step 1: 5-(2-(3-fluoroazetidin-l-yI)ethyI)-4-methylpyridin-2-ol

A mixture of 2-(6-hydroxy-4-methylpyridin-3-yl)acetaldehyde (2 g, 13.2 mmol), 3fluoroazetidine hydrochloride (2.2 g, 19.8 mmol) in MeOH (20 mL) was stirred at room température for 30 mins. NaBH(OAc)₃ (5.6 g, 26.4 mmol) was added and stirred at room température for 2 hours. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH 2:1) to provide 5-(2-(3-fluoroazetidin-l-yl)ethyl)-4-methylpyridin-2ol as a yellow oil (1 g). Yield 36% (ESI 211.1(M+H)⁺).

Step 2: ethyl 2-(5-(2-(3-fluoroazetidin-l-yl)ethyI)-4-methyl-2-oxopyridin-l(2H)-yl)-4methylpentanoate

O

A mixture of methyl 5-(2-(dimethylamino)ethyl)pyridin-2(lH)-one (1 g, 4.76 mmol), ethyl 4methyl-2-(methylsulfony!oxy)pentanoate (1.36 g, 5.71 mmol) and K₂CO₃(1.97 g, 14.28 mmol) in MeCN (20 mL) was stirred at 85°C ovemight. The solvent was removed in vacuo and the

280 residue purified by silica gel column (DCM: MeOH 1:2) to provide ethyl 2-(5-(2-(3fluoroazetidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanoate as a white solid (500 mg). Yield 30% (ESI 353.2(M+H)⁺).

Step 3:2-(5-(2-(3-fluoroazetidin-l-yl)ethy))-4-methyl-2-oxopyridin-l(2H)-yl)-4methylpentanoic acid

LiOH H₂O

-----►

MeOH, H₂O

Ethyl 2-(5-(2-(3-fluoroazetidin- l-yl)ethyl)-4-methyl-2-oxopyridin-1 (2H)-yl)-4-methylpentanoate (500 mg, 1.42 mmol) was treated with L1OH-H2O (298 mg, 7.1 mmol) in MeOH (10 mL) and H2O (2.5 mL) at room température for 2 hours. The mixture was acidified to pH 4-5 with IN HCl, purified by reverse phase HPLC on a C18/40 g column (A: water 10 mM NHîHCOî.B: MeOH, 0-100%) to give 2-(5-(2-(3-fluoroazetidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)4-methylpentanoic acid as a white solid (360 mg). Yield 78% (ESI 325.1(M+H)⁺).

Préparation of 2-(5-(2-((R)-3-fluoropyrroIidin-l-yl)ethyl)-4-methyI-2-oxopyridin-l(2H)-yl)

4-methylpentanoic acid

Step 1: ethyl 2-(5-allyl-4-methyI-2-oxopyridin-l(2H)-yl)-4-methyIpentanoate

CsF, Pd₂dba₃,PCy₃dioxane, 100°C, 16h

A mixture of ethyl 2-(5-bromo-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanoate (2.9 g, 8.78 mmol), allyltributylstannane (3.5 g, 10.54 mmol), Pd₃dba₃ (402 mg, 0.44 mmol), PCy₃ (247 mg, 0.88 mmol) and CsF (2.7 g, 17.56 mmol) in anhydrous dioxane (100 mL) was stirred at 100°C for 16 h. The mixture was cooled to room température. The mixture was filtered and washed with dioxane (20 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 3:1) to provide ethyl 2-(5-allyl-4-methyl-2-oxopyridinl(2H)-yl)-4-methylpentanoate as a yellow oil (1.6 g). Yield 60% (ESI 292 (M+H)⁺).

Step 2: ethyl 4-methyI-2-(4-methyI-2-oxo-5-(2-oxoethyl)pyridin-l(2H)-yI)pentanoate

281

To a solution of ethyl 2-(5-allyl-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanoate (1.6 g, 5.49 mmol) in THF/FhO (20 mL/10 mL) was added a solution of K2OSO4-2H2O (20 mg, 0.055 mmol) in H2O (1 mL) dropwise and stirred at room température for 1 h. A solution of NaIO₄ (2.3 g, 10.98 mmol) in H2O (5 mL) was added dropwise and stirred at room température for 3 h.

LCMS showed the reaction was completed. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (50 mLx 3). The combined organic phase was dried over anhydrous Na2SO₄, filtered and concentrated in vacuo to provide ethyl 4-methyl-2-(4-methyl-2-oxo-5-(2oxoethyl)pyridin-l(2H)-yl)pentanoate as a brown oil which was used in next step without further purification. (ESI 294 (M+H)⁺).

Step 3: ethyl 2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4-

A mixture of ethyl 4-methyl-2-(4-methyl-2-oxo-5-(2-oxoethyl)pyridin-l(2H)-yl)pentanoate (950 mg, 3.24 mmol) and (R)-3-fluoropyrrolidine hydrochloride (814 mg, 6.48 mmol) in DCE (20 mL) was stirred at room température for 1 h. Then NaBH(OAc)₃ (2.1 g, 9.72 mmol) was added and stirred at room température for 2 h. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/40 g column (A: water/10 mM NH4HCO₃,B: MeOH, 0-100%) to provide ethyl 2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-4-methyl-2oxopyridin-l(2H)-yl)-4-methylpentanoate as a yellow oil (550 mg). Yield 46% (ESI 367 (M+H)⁺).

Step 4:2-(5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4methylpentanoic acid

282

Ethyl 2-(5-(2-((R)-3-fluoropyrrolidin-1 -yl)ethyl)-4-methyl-2-oxopyridin-1 (2H)-yl)-4methylpentanoate (550 mg, 1.50 mmol) was treated with LiOH-HzO (120 mg, 4.50 mmol) in THF (6 mL) and water (2 mL) at room température for 2 hours. The reaction was acidified with

IN HCl to pH = 8. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC on a Cl8/40 g column (A: water/10 mM NHîHCOj.B: MeOH, 0~100%) to provide 2-(5-(2-((R)-3-fluoropyrrolidin-1 -yl)ethyl)-4-methyl-2-oxopyridin-1 (2H)-yl)-4-methylpentanoic acid as a white solid (270 mg). Yield 53% (ESI 339 (M+H)⁺).

Préparation of 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4mcthylpentanoic acid Step 1 : (E)-2-methoxy-5-(2-methoxyvinyl)-4-(trifluoromethyI)pyridine

To a solution of (methoxymethyl)triphenylphosphonium chloride (1.0 g, 2.95 mmol) in THF (13.406 mL) at 0°C was added potassium tert-butoxide (376 mg, 3.35 mmol). After stirring for 1 hour at 0°C, a solution of 6-methoxy-4-(trifluoromethyl)nicotinaldehyde (550 mg, 2.68 mmol) in THF (6.5 mL) was added. The reaction was allowed to stir ovemight at room température and quenched with a NH4CI solution. The mixture was extracted (EtOAc x 3), concentrated and purified by silica gel chromatography (0-100 Ethyl acetate: Hexanes) to provide (E)-2-methoxy5-(2-methoxyvinyl)-4-(trifluoromethyl)pyridine (450 mgs). Yield 72% (ESI 234.2 (M+H)⁺).

Step 2:2-(6-methoxy-4-(trifluoromethyl)pyridin-3-yl)acetaIdehyde

283

To a solution of (E)-2-methoxy-5-(2-methoxyvinyl)-4-(trifluoromethyl)pyridine (450 mg, 1.930 mmol) in DCM (29.689 mL) was added TFA (0.595 mL, 7.72 mmol) and water (0.591 mL, 32.8 mmol). The reaction was stirred for 18 hrs at 45 °C. The reaction was diluted with DCM and quenched with NaHCOj. The mixture was washed with water, dried with NaaSCh, filtered and concentrated to provide 2-(6-methoxy-4-(trifluoromethyl)pyridin-3-yl)acetaldehyde (343 mgs) used without further purification. Yield 81% (ESI 220.18 (M+H)⁺).

Step 3:5-(2-(azetidin-l-yl)ethyI)-2-methoxy-4-(trifluoromethyl)pyridine

To a solution of 2-(6-methoxy-4-(trifluoromethyl)pyridin-3-yl)acetaldehyde (4 g, 18.1 mmol) in DCE (50 mL) was added azetidine hydrochloride (3.4 g, 36.2 mmol). The reaction mixture was stirred at room température for 20 mins. NaBH(OAc)î (7.7 g, 36.2 mmol) was added and stirred at room température for 16 hours. The reaction mixture was quenched by addition of MeOH (20 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8/80 g column (A: water 10 mM NH4HCO3, B: MeOH, 0-100%) to provide 5-(2-(azetidin-l-yl)ethyl)-2-methoxy-4-(trifluoromethyl)pyridine as a yellow oil (3 g). Yield 63% (ESI 261.2(M+H)⁺).

Step 4:5-(2-(azetidin-l-yI)ethyl)-4-(trifIuoromethyl)pyridin-2(lH)-one

A mixture of 5-(2-(azetidin-l-yl)ethyl)-2-methoxy-4-(trifluoromethyl)pyridine (2.95 g, 11.3 mmol) in HBr/AcOH (20 mL) was stirred at 50°C for 5 h. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8/80 g column (A: water 10 mM NH4HCO3, B: MeOH, 0-100%) to provide 5-(2-(azetidin-l-yl)ethyl)-4(trifluoromethyl)pyridin-2(lH)-one as a yellow oil (710 mg). Yield 25% (ESI 247.1(M+H)⁺).

Step 5: ethyl 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoate

284

To a solution of 5-(2-(azetidin-l-yl)ethyl)-4-(trifluoromethyl)pyridin-2(lH)-one (710 mg, 2.9 mmol) in MeCN (10 mL) was added ethyl 4-methyl-2-(methylsulfonyloxy)pentanoate (1.1 g, 4.4 mmol) and K2CO3 (1.2 g, 8.7 mmol). The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8/40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0~100%) to provide ethyl 2-(5(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(tri fluoromethyl)pyridin-1 (2H)-yl)-4-methylpentanoate as a yellow oil (500 mg). Yield 44% (ESI 389.2(M+H)⁺).

Step 6: 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)-yl)-4methyipentanoic acid

Ethyl 2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoate (500 mg, 1.3 mmol) was treated with L1OH-H2O (270 mg, 6.5 mmol) in EtOH (5 mL) and water (1 mL) at room température for 2 hours. The reaction mixture was neutralized with 2 N HCl and concentrated in vacuo. The residue was purified by reverse phase HPLC on a C18/40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0~100%) to provide 2-(5-(2-(azetidinl-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methyIpentanoic acid as a yellow oil (410 mg). Yield 88% (ESI 361.2(M+H)⁺).

Préparation of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyi)pyridin-l(2H)-yl)-4methylpentanoic acid

Step 1:2-(6-methoxy-4-(trifluoromethyI)pyridin-3-yl)-N,N-dimethylethan-l-amine

285

Ο

Το a solution of 2-(6-methoxy-4-(trifluoromethyl)pyridin-3-yl)acetaldehyde (0.34 g, 1.6 mmol) in DCE (7.8 mL) was added dimethylamine (3.9 mL, 7.8 mmol) and acetic acid (0.05 mL, 0.78 mmol) and stirred for 1 hour. To the solution was added sodium triacetoxyborohydride (0.6 g, 3.1 5 mmol). The reaction was allowed to stir for 12 hours then concentrated and purified by silica gel chromatography (0-35% DCM (1% TEA):MeOH 0-30%) to provide 2-(6-methoxy-4(trifluoromethyl)pyridin-3-yl)-N,N-dimethyIethan-l-amine (305 mg). Yield 79% (ESI 249.27 (M+H)⁺).

Step 2:5-(2-(dimethylamino)ethyl)-4-(trifIuoromethyl)pyridin-2(lH)-one

HBr (33% in Acetic Acid) (4.04 mL, 24.57 mmol) was added to 2-(6-methoxy-4(trifluoromethyl)pyridin-3-yl)-N,N-dimethylethan-l-amine (0.305 g, 1.229 mmol) and heated to 75 °C in a pressure vessel. After 4 hours, the solvent was removed and the residue purify by silica gel chromatography (0-25% DCM:MeOH with 1% TEA as a modifier) to provide 5-(215 (dimethylamino)ethyl)-4-(trifluoromethyl)pyridin-2(lH)-one (219 mg). Yield 76% (ESI 235.15 (M+H)⁺). ‘H NMR (400 MHz, MeOD) δ 7.56 (s, 1H), 6.85 (s, 1H), 2.76 (m, 2H), 2.61 (m, 1H), 2.37 (m, 6H)

Step 3: ethyl 2-(5-(2-(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)-4methylpentanoate

286

A mixture of5-(2-(dimethylamino)ethyl)-4-(trifluoromethyl)pyridin-2(lH)-one (685 mg, 2.92 mmol), K2CO₃(1.60 g, 11.55 mmol) and ethyl 4-methyl-2-(methylsulfonyloxy)pentanoate (1.60 g, 6.70 mmol) in CH3CN (60 mL) was stirred at 85°C ovemight. The solvent was concentrated in vacuo and the residue was purified by silica gel column (DCM: MeOH 2:1) to give ethyl 2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4-methylpentanoate as brown oil (390 mg). Yield 35% (ESI 377.2 (M+H)⁺). Ή NMR (500 MHz, MeOD) δ 7.84 (s, 1H), 6.68 (s, 1H), 5.51 (dd, J= 11.0, 5.0 Hz, 1H), 4.23 (q, J= 7.0 Hz, 2H), 2.77 (t, J= 8.0 Hz, 2H), 2.53 (t, J =8.0 Hz, 2H), 2.33 (s, 6H), 2.18-2.12 (m, 1 H), 2.08-2.02 (m, 1H), 1.46-1.38 (m, 1H),

1.27 (t, J= 7.0 Hz, 3H), 0.97 (t, J= 7.0 Hz, 6H).

Step 4:2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)-yl)-4methylpentanoic acid

Ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanoate (390 mg, 1.0 mmol) was treated with LiOH monohydrate (435 mg, 10.36 mmol) in EtOH (10 mL) and H2O (1 mL) at room température for 1 hour. The mixture was acidified to pH 4~5 with IN HCl aqueous solution. The mixture was concentrated in vacuo and purified by silica gel column (MeOH: EtOAc 1:2) to give 2-(5-(2-(dimethylamino)ethyl)-2-oxo4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methyIpentanôic acid as an oil (358 mg). Yield 99% (ESI 349.1 (M+H)⁺).

Préparation of 2-(5-(2-(dimethylamino)ethyI)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)-yl)-3methylbutanoic acid

Step 1: ethyl 2-(5-(2-(dimethylamino)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-3methylbutanoate

287

To a solution of 5-(2-(dimethylamino)ethyl)-4-(trifluoromethyl)pyridin-2(lH)-one (2.4 g, 10.2 mmol) in MeCN (40 mL) was added ethyl 2-bromo-3-methylbutanoate (4.3 g, 20.4 mmol) and K2CO3 (2.8 g, 20.4 mmol). The reaction mixture was stirred at 80°C for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8/40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0-100%) to provide ethyl 2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-3-methylbutanoate as a yellow oil (2.6 g). Yield 69% (ESI 363.2(M+H)⁺).

Step 2:2-(5-(2-(dimethyIamino)ethy))-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-3methylbutanoic acid

LiOH

Ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-3methylbutanoate (2.6 g, 7.1 mmol) was treated with L1OH-H2O (1.47 g, 35 mmol) in EtOH (15 mL) and water (3 mL) at room température for 2 h. The reaction mixture was neutralized with 2 N HCl, concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8/40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0-100%) to provide 2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-3-methylbutanoic acid as a yellow oil (1.8 g). Yield 75% (ESI 335.2(M+H)⁺).

Préparation of3-cydopropyl-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l (2/7)-yl)propanoic acid

Step 1: ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)-3cyclopropylpropanoate

288

A mixture of 5-bromo-4-(trifluoromethyl)pyridin-2-ol (2.5 g, 10.33 mmol), CszCOj (6.7 g, 20.66 mmol) and ethyl 2-bromo-3-cyclopropylpropanoate (3.4 g, 15.50 mmol) in toluene (100 mL) was stirred at 110 °C for 16 h. LCMS showed the reaction was completed. The mixture was filtered and washed with EtOAc (20 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 10:1) to provide ethyl 2-(5-bromo-2-oxo-4(trifluoromethyl)pyridin-l(27/)-yl)-3-cyclopropylpropanoate as a colorless oil (1.5 g). Yield 38% (ESI 384.0 (M+H)⁺).

Step 2: ethyl 2-(5-allyl-2-oxo-4-(trifluoromcthyl)pyridin-l(2H)-yl)-3-cyclopropyIpropanoate

^x^-SnBua

Pd₂(dba)₃. PCy₃CsF, dioxane, 100°C

To a solution of ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-l(27/)-yl)-3cyclopropylpropanoate (2.3 g, 6.02 mmol) and allyltributylstannane (2.4 g, 7.22 mmol) under nitrogen atmosphère in dioxane (50 mL) was added Pd?dbaj (348 mg, 0.30 mmol), PCyj (168 mg, 0.60 mmol), CsF (1.8 g, 12.04 mmol) and stirred at 100°C for 16 h. The mixture was cooled to room température. A saturation NH4CI solution (100 mL) and EtOAc (100 mL) was added to the mixture and the the aqueous layer was extracted with EtOAc (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10:1) to provide ethyl 2-(5-allyl-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-3-cyclopropylpropanoate as a colorless oil (1.5 g). Yield 72% (ESI 344.0 (M+H)⁺)·

Step 3: ethyl 3-cyclopropyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(27f)yl)propanoate

289

K₂OsO₄ h₂o

NalO₄, THF/H₂O

To a solution of ethyl 2-(5-a!lyl-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-3cyclopropylpropanoate (1.5 g, 4.37 mmol) in THF/H2O (20 mL/20 mL) was added a solution of K20s04-2H20(16.0 mg, 0.0437 mmol) in H2O (3 mL) and stirred at room température for 1 hour. A solution ofNaIÛ4(1.8 g, 8.74 mmol) in H₂O (10 mL) was added dropwise and the mixture was stirred at room température for another hour. LCMS showed the reaction was completed. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was dried over anhydrous Na₂SO4, filtered and concentrated in vacuo to provide ethyl 3-cyclopropyl-2-(2-oxo-5-(2-oxoethyl)-4(trifluoromethyl)pyridin-l(2/7)-yl)propanoate as a brown oil used directly in the next reaction without fiirther purification (1.5 g, crude). (ESI 346.1 (M+H)⁺).

Step 4: ethyl 3-cyclopropyl-2-(5-(2-(dimethyIamino)ethyI)-2-oxo-4(trifluoromethyI)pyridin-l(2fi^,)-yl)P^roP^anoate

To a mixture of ethyl 3-cyclopropyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2/7)yl)propanoate (1.5 g, 4.34 mmol) in DCE (20 mL) at 25 °C was added dimethylamine hydrochloride (708 mg, 8.68 mmol) and stirred for 1 hour. NaBH(OAc)s (2.8 g, 13.02 mmol) was added at 5 °C and stirred at 25 °C for 16 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel column (DCM: MeOH 10:1) to provideethyl 3-cyclopropyl2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l (2Z7)-yl)propanoate as a colorless oil (400 mg) Yield 25% (ESI 375.1 [M+H]⁺).

Step 5:3-cyclopropyl-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridml(2/7)-yl)propanoic acid

290

Ethyl 3-cyclopropyl-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (277)yl)propanoate (400 mg, 1.07 mmol) was treated with LiOH-H₂O (224 mg, 5.35 mmol) in EtOH (5 mL) and water (2 mL) and the mixture was stirred at room température for 30 minutes. The mixture was acidified with IN HCl to pH 5-6 and purified by reverse phase HPLC on a Cl8/120 g column (A: water/10 mM NILHCCh.B: MeOH, 0-100%) to provide 3-cyclopropyl-2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yl)propanoic acid as a white solid (150 mg). Yield 41% (ESI 347.0 (M+H)⁺).

Préparation of2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-5methylhexanoic acid

Step 1: ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-5-methylhexanoate

A mixture of 5-bromo-2-hydroxy-4-(trifluoromethyl)pyridine (6.00 g, 24.79 mmol), ethyl 2bromo-5-methylhexanoate (8.82 g, 37.19 mmol) and Cs₂CCh (24.24 g, 74.38 mmol) in anhydrous toluene (120 mL) was heated at 110 °C under nitrogen atmosphère for 3 h. The solvent was removed in vacuo and the residue was purified by silica gel column (petroleum ether: EtOAc 23:1) to provide ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-5methylhexanoate as brown oil (5.9 g). Yield 59%. (ESI 400.0 (M+H)⁺, ESI 422.0 (M+Na)⁺). Step 2: (E)-ethyl 2-(5-(2-ethoxyvinyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-5methylhexanoate

291

A mixture of ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-5-methylhexanoate (5.56 g, 13.97 mmol), (E)-l-ethoxyethene-2-boronic acid pinacol ester (4.15 g, 20.95 mmol), tetrakis(triphenylphosphine)palladium(0) (2.42 g, 2.10 mmol) and K2CO3 (5.79 g, 41.91 mmol) in co-solvent of anhydrous 1,4-dioxane (140 mL) and water (14 mL) was heated at 70 °C under nitrogen atmosphère for 20 h. The solvent was removed in vacuo and the residue was purified by silica gel column (petroleum ether: EtOAc 10:1) to provide (E)-ethyl 2-(5-(2-ethoxyvinyl)-2oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-5-methylhexanoatc as brown oil (3.4 g). Yield 63%. (ESI 390.1 (M+H)⁺).

Step 3: ethyl 5-methyI-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyI)pyridin-l(2H)-

TFA

DCM, a.t, 1 h

Trifluoroacetic acid (32 mL, 430.80 mmol) was added to a stirring solution of (E)-ethyl 2-(5-(2ethoxyvinyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-5-methylhexanoate (5.2 g, 13.35 mmol) in DCM (64 mL) and the reaction mixture was stirred at room température for 1 h. The solvent was removed in vacuo to provide ethyl 5-methyI-2-(2-oxo-5-(2-oxoethyl)-4(trifluoromethyl)pyridin-l(2H)-yl)hexanoate as brown oil (5.2 g, crude). (ESI 362.1 (M+H)⁺). Step 4: ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)-yl)-5methylhcxanoate

NaBH(OAc)₃Z DIEA DCE, a.t., 18 h

The mixture of ethyl 5-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2H)292 yl)hexanoate (1.6 g, 4.45 mmol) and dimethylamine (60 mL, 2M in THF, 120 mmol) in 1,2dichloroethane (43 mL) was stirred at ambient température for 1 h. Sodium triacetoxyborohydride (14.91 g, 70.34 mmol) was added in one portion and stirred at ambient température for 18 h. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH 3:1) to provide ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-5-methylhexanoate as brown oil (1.2 g). Yield 72%. (ESI 391.1 (M+H)⁺).

Step 5: 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-5-

Ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yI)-5methylhexanoate (925 mg, 2.37 mmol) was treated with LiOH monohydrate (298 mg, 7.11 mmol) in EtOH (10 mL) and H2O (0.7 mL) at room température for 3 h. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NH-jHŒh.B: MeOH, 0-80%) to provide 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-5methylhexanoic acid as a yellow solid (617 mg). Yield 72% (ESI 363.1 (M+H)⁺).

Préparation of (3R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)yl)-3-methylpentanoic acid Step 1: ethyl (3R)-2-bromo-3-methylpentanoate

O O

To a mixture of (2R,3R)-2-bromo-3-methylpentanoic acid (5 g, 25.6 mmol) in EtOH (50 mL) at 0°C was added SOCh (6.1 g, 51.2 mmol). The mixture was stirred for 4 h at room température.

The solvent was removed in vacuo to provide ethyl (3R)-2-bromo-3-methylpentanoate as a yellow oil (5.3, crude). (ESI 223 (M+H)⁺).

293

Step 2: ethyl (3R)-2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridîn-l(2H)-yI)-3methylpentanoate

O

To a stirred solution of 5-bromo-4-(trifluoromethyl)pyridin-2(lH)-one (3.50 g, 14.52 mmol) and ethyl (3R)-2-bromo-3-methylpentanoate (3.54 g, 15.97 mmol) in toluene (50 mL) was added CS2CO3 (5.38 g, 16.58 mmol) and stirred at 110°C for 2 hours. The reaction was cooled to room température, filtered and washed with 20 mL of EtOAc. The filtrate was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 20:1) to provide ethyl (3R)2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-3-methylpentanoate as a white solid (2.2 g). Yield 40% (ESI 384.0(M+H)⁺).

Step 3: ethyl (3R)-2-(5-alIyl-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-3-methy)pentanoate

To a solution of ethyl (3R)-2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-3methylpentanoate (2.2 g, 5.74 mmol) and allyltributylstannane (2.28 g, 6.89 mmol) underN2 atmosphère in DMF (15 mL) was added Pd(PPh₃)4 (0.67 g, 0.58 mmol) and stirred at 100°C for 16 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with 50 mL of EtOAc, poured into 20% aq. KF (100 mL), stirred at 20°C for 1 hour and then filtered and washed with 100 mL of EtOAc. The filtrate was extracted with EA (100 mL x 3). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 20:1) to provide ethyl (3R)-2-(5-allyl-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-3-methylpentanoate as a colorless oil (1.51 g). Yield 76% (ESI 346(M+H)⁺).

Step 4: ethyl (3R)-3-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyI)pyridin-l(2H)y))pentanoate

294

To a mixture of ethyl (3R)-2-(5-allyl-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-3methylpentanoate (1.51 g, 4.36 mmol) in THF (15 mL) and H₂O (10 mL) at 0 °C was added K₂OsÛ4-2H₂O (130 mg, 0.345 mmol) and stirred at 0 °C for 5 mins. Then a solution of NaIÛ4 (2.80 g, 13.08 mmol) in H₂O (5 mL) was added dropwise and stirred at 0 °C for 2 hours and then at 25 °C for 2 hours. The mixture was quenched with a saturated Na₂S₂O3 solution (50 mL) and the mixture was extracted with EA (60 mL x 3). The combined organics were washed with brine (30 mL x 3), dried over anhydrous Na₂SÛ4. filtered and concentrated in vacuo to providecrude product ethyl (3R)-3-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridinl(2H)-yl)pentanoate (1.5 g, crude) as yellow oil. (ESI 348(M+H)⁺).

Step 5: ethyl (3R)-2-(5-(2-(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)yI)-3-methy!pentanoate

To a mixture of ethyl (3R)-3-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2H)yl)pentanoate ( 1 g, 2.87 mmol) in DCE (10 mL) at 25 °C was added dimethylamine hydrochloride (700 mg, 8.62 mmol) and stirred at 25 °C for 10 min. Then NaBH(OAc)3 (1.22 g, 5.74 mmol) was added and stirred at 25 °C for 2 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel column (DCM: MeOH 10:1) to provide ethyl (3R)-2(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-3-methylpentanoate as a yellow oil (550 mg). Yield 51% (ESI 377 (M+H)⁺).

Step 6: (3R)-2-(5-(2-(dimethyIamino)ethyI)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)-yl)-3methylpentanoic acid

295

Ethyl (3R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-3methylpentanoate (550 mg, 1.46 mmol) was treated with LiOH-HzO (240 mg, 5.84 mmol) in MeOH (5 mL) and water (l mL) at room température for 1 hour. The MeOH was removed and the aqueous material acidified with IN HCl to pH 4. The mixture was purified by reverse phase HPLC on a Cl8/40 g column (A: water 10 mM NH₄HCO₃,B: MeOH, 0-100%) to provide (3R)2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-3-methylpentanoic acid as a yellow oil (400 mg). Yield 78.5% (ESI 349 (M+H)⁺).

Préparation of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l (27/)yl)pentanoic acid Step 1: ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)pentanoate

To a stirred solution of 5-bromo-4-(trifluoromethyl)pyridin-2(l//)-one (2 g, 8.29 mmol) and methyl 2-bromo-4-methylpentanoate (2.24 g, 10.78 mmol) in toluene (40 mL) was added Cs2CO₃ (5.38 g, 16.58 mmol) portionwise and stirred at 110°C for 2 hours. The reaction mixture was diluted with 50 mLof EtOAc, filtered and washed with 20 mLof EtOAc. The filtrate was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 20:1) to provide ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)pentanoate as a white solid (2.3 g). Yield 65% (ESI 372.0(M+H)⁺).

Step 2: ethyl (E)-2-(5-(2-cthoxyvinyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yl)pentanoate

296

A mixture of ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)pentanoate (2.2 g, 5.96 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.35 g, 6.85 mmol), Pd(PPhj)4 (206 mg, 0.17 mmol) and K2CO3 (1.64 g, 11.92 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was stirred at 70°C under N2 for 20 h. The reaction mixture was poured into 100 mL of water, extracted with EA (50 mL x 3). The combined organic phase was washed with brine (150 mL), dried over anhydrous Na₂SÛ4, filtered and concentrated in vacuo, purified by silica gel column (pet ether EtOAc 10:1) to provide ethyl (£)-2-(5-(2-ethoxyvinyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)pentanoate as a white solid (1 g). Yield 46% (ESI 362.1 (M+H)⁺).

Step 3: ethyl 2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2jF7)-yl)pentanoate

To a mixture of (E)-2-(5-(2-ethoxyvinyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yl)pentanoate (920 mg, 2.55 mmol) in DCM (20 mL) was added TFA (10 mL). The mixture was stirred at room température for 4 hours. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo to give crude product ethyl 2-(2-oxo-5-(2-oxoethyl)-4 (trifluoromethyl)pyridin-l(2/y)-yl)pentanoate as a yellow oil (800 mg) used directly in the next reaction without further purification. Yield 94% (ESI 334.1 [M+H]⁺).

Step 4: ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(27/)yl)pentanoate

To a mixture of ethyl 2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2/7)-yl)pentanoate (750 mg, 2.25 mmol) in DCE (10 mL) at 25 °C was added dimethylamine (2M in THF, 1.7 mL,

297

3.4 mmol) and stirred at 25 °C for 10 min. NaBH(OAc)j (950 mg, 4.5 mmol) was added and stirred at 25 °C for 2 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel column (DCM: MeOH 10:1) to provide ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo4-(trifluoromethyl)pyridin-l(2H)-yl)pentanoate as a yellow oil (630 mg). Yield 77% (ESI 363.1 (M+H)⁺).

Step 5:2-(5-(2-(dimethyIamino)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2fi^r)-yl)pentanoic acid

Ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)pentanoate (630 g, 1.74 mmol) was treated with L1OH-H2O (142 mg, 3.48 mmol) in MeOH (6 mL) and water (3 mL) at 20 °C for 1 hour. The MeOH was removed and the remaining aqueous acidified with IN HCl to pH = 4. The mixture was purified by reverse phase HPLC on a Cl 8/40 g column (A: water 10 mM NH4HCO₃,B: MeOH, 0-100%) to provide 2-(5-(2-(dimethylamino)ethyl)-2-oxo4-(trifluoromethyl)pyridin-l(2fi)-yl)pcntanoic acid as a yellow oil (430 mg). Yield 73% (ESI 335.1 (M+H)⁺).

Préparation of 2-(5-(2-(3-methoxyazetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyI)pyridinl(2H)-yl)-4-methylpentanoic acid

Step 1:2 (E)-ethyi 2-(5-(2-ethoxyvinyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoate

Pd(PPh₃)_4> K₂CO₃,1,4-dioxane, water, 70°C,20h

To a solution of ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoate (12 g, 31 mmol) in 1,4-dioxane (150 mL) and water (15 mL) was added (E)-2(2-ethoxyvinyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (9.3 g, 45.5 mmol), K?CO₃ (12.8 g, 93 mmol) and Pd(PPh₃)4 (1.8 g, 1.55 mmol). The reaction mixture was stirred at 70°C for 20 h. The

298 reaction mixture was cooled to room température, diluted with EtOAc (300 mL) and washed with brine, dried over Na₂SO4, concentrated in vacuo. The residue was purified by silica gel column (pet. Ether: EtOAc 1:2) to provide (E)-ethyl 2-(5-(2-ethoxyvinyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoate as a yellow oil (9 g). Yield 76% (ESI 376.1(M+H)⁺).

Step 2: ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2H)yl)pentanoate

A mixture of (E)-ethyl 2-(5-(2-ethoxyvinyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoate (9 g, 24 mmol) in TFA (25 mL) and DCM (25 mL) was stirred at room température for 16 h. The reaction mixture was concentrated in vacuo to give crude ethyl 4methyL2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2H)-yl)pentanoate as a yellow oil (9 g). Yield 100% (crude) (ESI 348.1(M+H)⁺).

Step 3: ethyl 2-(5-(2-(3-methoxyazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanoate

To a solution of ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2H)yl)pentanoate (10 g crude, 24 mmol) in DCE (100 mL) was added 3-methoxyazetidine hydrochloride (5.9 g, 48 mmol) and stirred at room température for 20 min. NaBH(OAc)₃ (10.1 g, 48 mmol) was added and stirred at room température for 1 h. The reaction was quenched with MeOH (30 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8/120 g column (A: water 10 mM NH4HCO₃, B: MeOH, 0-100%) to provide ethyl 2-(5-(2-(3-methoxyazetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoate as a yellow oil (8 g). Yield 79% (ESI 419.2(M+H)⁺).

299

Step 4:2-(5-(2-(3-methoxyazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid

Ethyl 2-(5-(2-(3-methoxyazetidin-l-yI)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoate (8 g, 19 mmol) was treated with L1OH-H2O (2.4 g, 57 mmol) in EtOH (60 mL) and water (12 mL) at room température for 2 h. The reaction mixture was neutralized by 2 N HCl and concentrated in vacuo. The residue was purified by reverse phase HPLC on a C18/120 g column (A: water 10 mM NH4HCO3, B: MeOH, 0-100%) to provide 2-(5-(2-(3methoxyazetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4-methylpentanoic acid as a yellow solid (6 g). Yield 80% (ESI 391.1(M+H)⁺).

Préparation of 2-(5-(2-(dimethyIamino)ethyl)-3-methyI-2-oxopyridin-l(2H)-yï)-4methylpentanoic acid Step 1: ethyl 2-(5-bromo-3-methyl-2-oxopyridin-l(2Z7)-yI)-4-methylpentanoate

Me

A mixture of 5-((dimethylamino)methyl)pyridin-2(lH)-one (500 mg, 3.28 mmol), K2CO3 (1.36 g, 9.86 mmol) and ethyl 4-methyI-2-(methylsulfonyloxy)pentanoate (1.17g, 4.93 mmol) in CH3CN (20 mL) was stirred at 80 °C ovemight. The solvent was removed in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 1:2) to provide ethyl 2-(5((dimethylamino)methyl)-2-oxopyridin-l(2/7)-yl)-4-methylpentanoate as a yellow oil (300 mg). Yield 31% (ESI 330 (M+H)⁺).

Step 2: ethyl 2-(5-aIlyl-3-methyl-2-oxopyridin-l(227)-yl)-4-methylpentanoate

300

Me

CsF,PCy3,Pd₂dba3 100 °C,5h

Me

To a solution of ethyl 2-(5-bromo-3-methyl-2-oxopyridin-l(2/7)-yl)-4-methylpentanoate (2.5 g,

7.57 mmol) and allyltributylstannane (2.5 g, 7.57 mmol) under N₂ atmosphère in dioxane (25 mL) was added Pd₂(dba)₃ (0.3 g, 0.38 mmol) and CsF (2.3 g,15.1 mmol) and PCy₃ (212.0 mg, 0.76 mmol) and stirred at 100 °C for 5 hours. The mixture was cooled to room température, filtered and washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 20:1) to provide ethyl 2-(5-allyl-3-methyl-2oxopyridin-l(2H)-yl)-4-methylpentanoate as a colorless oil (1.61 g). Yield 73% (ESI 292 (M+H)⁺).

Step 3: ethyl 4-methyI-2-(3-niethyI-2-oxo-5-(2-oxoethyl)pyridin-l(2H)-yi)pentanoate

To a solution of ethyl 2-(5-allyl-3-methyl-2-oxopyridin-l(2/7)-yI)-4-methylpentanoate (1.61 g, 5.53 mmol) in THF/H₂O (24 mL/12 mL) was added a solution of K₂OsO4-2H₂O(21 mg, 0.058 mmol) in H₂O (4 mL) and stirred at room température for 1 h. A solution of NaIO4 (2.37 g, 11.1 mmol) in H₂O (20 mL) was added and stirred at room température for 2 h. LCMS showed the reaction was completed. The reaction mixture was diluted with 100 mL of water and extracted with EtOAc (100 mL x 3). The combined organic phase was dried over anhydrous Na₂SO4, filtered and concentrated in vacuo to give the crude product ethyl 4-methyl-2-(3-methyl-2-oxo-5(2-oxoethyl)pyridin-l(2//)-yl)pentanoate as a yellow oil (1.6 g, crude) used directly in the next reaction. (ESI 294.1 (M+H)⁺)·

Step 4: ethyl 2-(5-(2-(dimethylamino)ethyl)-3-methyl-2-oxopyridin-l(2Z/)-yl)-4methylpentanoate

301

A mixture of ethyl 4-methyl-2-(3-methyl-2-oxo-5-(2-oxoethyl)pyridin-l(27/)-yl)pentanoate (2 g, 16.2 mmol), dimethylamine (2M in THF) (41 mL) in DCE (10 mL) was stirred at room température for 30 mins. Then NaBH(OAc)₃ (5.2 g, 24.39 mmol) was added and stirred at room température ovemight. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/40 g column (A: water 10 mM NH4HCO₃,B: MeOH, 0-100%) to provide ethyl 2-(5-(2-(dimethylamino)ethyl)-3-methyl-2-oxopyridin-l(2/7)-yl)-4methylpentanoate as a yellow oil (1 g). Yield 46% (ESI 323.2 (M+H)⁺).

Step 5: 2-(5-(2-(dimethyIamino)ethyl)-3-methyI-2-oxopyridin-l(2£0-yl)-4-methylpentanoic acid

Ethyl 2-(5-((dimethylamino)methyl)-2-oxopyridin-l(2Â/)-yl)-4-methylpentanoate (606 mg, 1.88 mmol) was treated with LiOH-HzO (395 mg, 9.4 mmol) in THF (8 mL) and water (3 mL) at room température for 2 hours. The reaction was acidified with IN HCl to pH = 3-4. The solvent was removed in vacuo and the residue was purified by preparatory-HPLC A (30-80% MeCN) to provide 2-(5-(2-(dimethylamino)ethyl)-3-methyl-2-oxopyridin-1 (2i/)-yl)-4-methylpentanoic acid as a white solid (480 mg). Yield 87% (ESI 295(M+H)⁺).

Préparation of 2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-l(2H)-yl)-4methylpentanoic acid

Step 1:5-bromo-3-(difluoromethyl)-2-methoxypyridine

To a mixture of 5-bromo-2-methoxynicotinaldehyde (10.0 g, 46.3 mmol) in diy DCM (100 mL)

302 under Nî at 0°C was added DAST (29.8 g, 185.2 mmol) and stirred at 0°C for 2 days. The reaction was quenched with 100 mL of a saturated NaHCO3 solution. The aqueous layer was extracted with DCM (100 mL x 3). The combined organic layers were washed with NaHCCh (sat, 100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 5-bromo-3-(difluoromethyl)-2-methoxypyridine as a yellow oil (11.0 g). Yield 100% (ESI 238.1 (M+H)⁺).

Step 2:5-bromo-3-(difluoromethyI)pyridin-2-ol

A mixture of 5-bromo-3-(difluoromethyl)-2-methoxypyridine (11.0 g, 46.2 mmol) in HBr (33% in acetic acid, 100 mL) was stirred at room température for 5 hours and then at 40°C for 75 mins.

The mixture was concentrated and poured into 100 mL of saturated NaHCCh solution and extracted with DCM. The combined oiganic layers dried over Na2SÜ4 and concentrated in vacuo to give 5-bromo-3-(difluoromethyl)pyridin-2-ol as a white solid (8.5 g) used without further purification. Yield 73.2% (ESI 226.0(M+H)⁺).

Step 3: ethyl 2-(5-bromo-3-(difluoromethyl)-2-oxopyridin-l(2H)-yl)-4

A mixture of 5-bromo-3-(difluoromethyl)pyridin-2-ol (7.0 g, 31.2 mmol), ethyl 4-methyl-2((methylsulfonyl)oxy)pentanoate (14.0 g, 37.4 mmol) and K2CO3 (14.0 g, 62.5 mmol) in ACN (100 mL) was stirred at 80°C ovemight. The mixture was filtered and washed with ACN (20 mL). The filtrate was concentrated in vacuo and the residue purified by silica gel column (pet ether: EtOAc 4:1) to provide ethyl 2-(5-bromo-3-(difluoromethyl)-2-oxopyridin-l(2H)-yl)-4 as a white solid (10.0 g). Yield 80.3% (ESI 366.0(M+H)⁺).

Step 4: ethyl 2-(5-allyl-3-(difluoromethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoate

303

A mixture of ethyl 2-(5-bromo-3-(difluoromethyI)-2-oxopyridin-l(2H)-yl)-4 (6.0 g, 16.2 mmol), allyltributylstannane (7.0 g, 19.2 mmol), CsF (5.0 g, 32.4 mmol), Pd(dba)j (720 mg, 1.62 mmol) and PCyj (450 mg, 0.135 mmol) in dioxane (100 mL) was stirred at 100°C ovemight. The mixture was poured into water (200 mL), extracted with EtOAc (100 mLx 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 4:1) to give ethyl 2-(5allyl-3-(difluoromethyl)-2-oxopyridin-l(2H)-yl)-4 as a white solid (3.0 g). Yield 71.6% (ESI 328.1(M+H)+).

Step 5: ethyl 2-(3-(difluoromethyl)-2-oxo-5-(2-oxoethyI)pyridin-l(2H)-yl)-4-

To a mixture of ethyl 2-(5-allyl-3-(difluoromethyl)-2-oxopyridin-l(2H)-yl)-4 (3.0 g, 9.1 mmol) in THF/H2O (2/1,100 mL) was added K2OSO4 (33.7 mg, 0.09 mmol) and stirred at room température for 1 hour. NaIÛ4 (3.9, 18.3 mmol) was added and the mixture was stirred for 2 hours. The mixture was poured into water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed brine (200 mL) and dried over Na2SO4, filtered and concentrated in vacuo to give ethyl 2-(3-(difluoromethyI)-2-oxo-5-(2-oxoethyl)pyridin-l(2H)yl)-4-methylpentanoate as a yellow oil (3.0 g, crude) used without further purification. (ESI 330.1 (M+H)+).

Step 6: ethyl 2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-l(2H)-yl)-4methylpentanoate

304

A mixture of ethyl 2-(3-(difluoromethyl)-2-oxo-5-(2-oxoethyl)pyridin-l(2H)-yl)-4methylpentanoate (3.0 g, 9.1 mmol), dimethylamine (2M in THF, 14 mL, 28 mmol) in DCE (50 mL) was stirred at room température for 30 mins. NaBH(OAc)j (3.8 g, 18.2 mmol) was added portion-wise and the reaction was stirred at room température ovemight. The solvent was concentrated in vacuo and the residue purified by reverse phase HPLC on a Cl8/120 g column (A: water 10 mM NH₄HCO₃,B: MeOH, 0-100%) to give ethyl 2-(3-(difluoromethyl)-5-(2(dimethylamino)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoate as a yellow oil (2.0 g). Yield 33.6% (ESI 359.2 (M+H)⁺).

Step 7:2-(3-(difluoromethyI)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-l(2H)-yl)-4methylpentanoic acid

A mixture of ethyl 2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-l(2H)-yl)-4methylpentanoate (2.0 g, 5.5 mmol) was treated with LiOH-HzO (40 mg, 1.01 mmol) in THF (20 mL) and water (10 mL) at room température for 2 hours. The solvent was removed in vacuo and the residue purified by reverse phase HPLC on a Cl8/120 g column (A: water 10 mM NH₄HCO₃, B: MeOH, 0-100%) to give 2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridinl(2H)-yl)-4-methylpentanoic acid as a white solid (1.2 g). Yield 85.6% (ESI 331.1(M+H)⁺).

Préparation of 2-(5-(2-(dimethylamino)ethyi)-3-fluoro-2-oxopyridin-l (2ZZ)-yI)-4methylpentanoic acid

Step 1: ethyl 2-(5-bromo-3-fluoro-2-oxopyridin-l(2/7)-yl)-4-methyIpentanoate

305

A mixture of 5-bromo-3-fluoropyridin-2-ol (5.0 g, 15.6 mmol), K2CO3 (7.36 g, 53.3 mmol) and ethyl 4-methyl-2-(methyIsulfonyloxy)pentanoate (9.9 g, 23.4 mmol) in CH3CN (180 mL) was stirred at 80°C ovemight. The solvent was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 1:2) to give ethyl 2-(5-bromo-3-fluoro-2-oxopyridin-1(277)yl)-4-methylpentanoate as a yellow oil (6.5 g). Yield 81% (ESI 334.0(M+H)⁺).

Step 2: ethyl 2-(5-aIlyl-3-fluoro-2-oxopyridin-l(2H)-yl)-4-methyIpentanoate

A mixture of ethyl 2-(5-bromo-3-fluoro-2-oxopyridin-l(2/7)-yl)-4-methylpentanoate (5.0 g, 7.6 mmol), allyltributylstannane (6.0 g, 9.1 mmol), Pdzdbas (240.0 mg, 0.76 mmol), PCy3 (450 mg, 0.76 mmo), CsF (4.6 g, 15.1 mmol) in anhydrous dioxane (100 mL) was stirred underNiat 100°C for 16 h. The mixture was cooled to room température and diluted with a saturated NH4CI solution (100 mL) and EtOAc (100 mL). Separated the mixture and the aqueous layer was extracted with EtOAc (100 mLx 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 4:1) to provide ethyl 2-(5-allyl-3-fluoro-4-methyl-2oxopyridin-l(2/7)-yl)-4-methylpentanoate as a yellow solid (3.0 g). Yield 69% (ESI 296.2 (M+H)⁺).

Step 3: ethyl 2-(3-fluoro-2-oxo-5-(2-oxoethyI)pyridin-l(2H)-yl)-4-methylpentanoatc

To a solution of ethyl 2-(5-allyl-3-fluoro-4-methyl-2-oxopyridin-l(2Z7)-yl)-4-methylpentanoate

306 (5.5 g, 18.6 mmol) in THF/H2O (60 mL/20 mL) was added a solution of K2OSO4-2H2O (60.0 mg, 0.16 mmol) in H2O (4 mL) and stirred at room température for 1 h. A solution of NaICh (7.8 g, 37.2 mmol) in H2O (20 mL) was added and stirred at room température for 2 h. LCMS showed the reaction was completed. The reaction mixture was diluted with 100 mL of water and extracted with EtOAc (120 mL x 3). The combined organic phase was dried over anhydrous Na2SÛ4, filtered and concentrated in vacuo to give the crude product ethyl 2-(3-fluoro-2-oxo-5(2-oxoethyl)pyridin-l(277)-yl)-4-methylpentanoate as a yellow oil (5.0 g, crude) used directly in the next reaction without further purification. (ESI 298.1 (M+H)⁺).

Step 4: ethyl 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-l(2H)-yl)-4methylpentanoate

To a mixture of ethyl 2-(3-fluoro-2-oxo-5-(2-oxoethyl)pyridin-l(2H)-yl)-4-methylpentanoate (1.2 g, 4.0 mmol) in DCE (50 mL) at 25 °C was added dimethylamine (2.0 M in THF, 8.0 mL, 16.0 mmol) and stirred at 25 °C for 30 mins. NaBH(OAc)₃ (1.7 g, 8.0 mmol) was added at 5 °C and stirred at 25 °C for 16 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel column (DCM: MeOH 10:1) to provide ethyl 2-(5-(2(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-l(2Z7)-yl)-4-methylpentanoate (800 mg) as a colorless oil. Yield 60% (ESI 327.1 (M+H)⁺).

Step 5:2-(5-(2-(dimethyIamino)ethyl)-3-fluoro-2-oxopyridin-l (2H)-yl)-4-methylpentanoic acid

Ethyl 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-l (2H)-yl)-4-methylpentanoate (800 mg, 2.45 mmol) was treated with LiOH-H2Û (310.0 mg, 7.35 mmol) in THF (4 mL) and water ( 1 mL) at room température for 2 hours. The THF was removed and the aqueous acidified with IN HCl to pH 5~6. The residue was purified by reverse phase HPLC on a Cl8/120 g column (A: water 10 mM NH4HCO₃,B: MeOH, 0100%) to provide 2-(5-(2-(dimethylamino)ethyl)-3

307 fluoro-2-oxopyridin-l(2/7)-yl)-4-methylpentanoic acid as a white solid (700 mg). Yield 88% (ESI 299.2 (M+H)⁺).

Préparation of 2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-y))-4 methylpentanoic acid

Step 1: ethyl 2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)-4methylpentanoate

F

To a mixture of ethyl 2-(3-fluoro-2-oxo-5-(2-oxoethyl)pyridin-l(2H)-yl)-4-methylpentanoate (5 g, 15 mmol) in DCE (70 mL) at 25 °C was added 3-fluoroazetidine hydrochloride (1.8 g, 22.5 mmol) and stirred at 25 °C for 10 min. NaBH(OAc)j (6.4 g, 30 mmol) was added at 5 °C and stirred at 25 °C for 2 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel column (DCM: MeOH 10:1) to provide ethyl 2-(3-fluoro-5-(2-(3-fluoroazetidin-lyI)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoate (3.8 g) as yellow oil. Yield: 63% (ESI 357.2 (M+H)⁺).

Step 2:2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yI)ethyI)-2-oxopyridin-l(2H)-yl)-4methylpentanoic acid

Methyl ethyl 2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)-4methylpentanoate (86 mg, 0.24 mmol) was treated with LiOH monohydrate (50 mg, 1.2 mmol) in THF (3 mL) and H2O (0.5 mL) at room température for 1 hour. The reaction mixture was acidified to pH 4~5 with IN HCl. The residue was purified by reverse phase HPLC on a Cl8/120 g column (A: water 10 mM NH4HCO3. B: MeOH, 0-100%) to provide 2-(3-fluoro-5-(2-(3-, fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanoic acid as a white solid (55

308 mg). Yield 70% (ESI 329.1 (M+H)⁺).

Préparation of 2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H) yl)pentanoic acid

Step 1: ethyl 2-(5-bromo-3-fluoro-2-oxopyridin-l(2H)-yI)pentanoate

A mixture of 5-bromo-3-fluoropyridin-2(lH)-one (2.1 g, 11.0 mmol), ethyl 2-bromopentanoate (3.43 g, 16.5 mmol) and CS2CO3 (7.17 g, 22.0 mmol) in Toluene (50 mL) was stirred at 110°C ovemight. The reaction mixture was filtered, washed with EtOAc, concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 2:1) to provide ethyl 2-(5-bromo-3fluoro-2-oxopyridin-l(2H)-yl)pentanoate as a white oil (2.9 g). Yield 82% (ESI 320.02(M+H)⁺).

Step 2: ethyl 2-(5-allyl-3-fluoro-2-oxopyridin-l(2H)-yl)pentanoate

A mixture of ethyl 2-(5-bromo-3-fluoro-2-oxopyridin-l(2H)-yl)pentanoate (2.9 g, 13.2 mmol), 2allyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2.66 g, 15.8 mmol), Pd(dppf)C12 (482.5 mg, 0.66 mmol), and K3PO4 (5.60 g, 26.4 mmol) in 1,4-dioxane (30 mL) and H₂O (5 mL) was stirred at 80°C for 2 hours. The reaction mixture was diluted with 50 mL of water, extracted with EA (60 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue purified by silica gel column (pet ether: EtOAc 1:2) to provide ethyl 2-(5-allyl-3-fluoro-2-oxopyridin-l(2H)-yl)pentanoate as a white oil (1.9 g). Yield 75% (ESI 282.24(M+H)⁺).

Step 3: ethyl 2-(3-fluoro-2-oxo-5-(2-oxoethyl)pyridin-l(2H)-yl)pentanoate

309

To a mixture of ethyl ethyl 2-(5-allyl-3-fluoro-2-oxopyridin-l(2H)-yl)pentanoate (1.9 g, 6.7 mmol) in THF (20 mL) and H₂O (30 mL) was added K₂OsO4 (25.8 mg, 0.07 mmol) and stirred at room température for 1 hour. NaICh (3.9,13.4 mmol) was added and the mixture was stirred at room température for 2 hours. The mixture was poured into water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed brine (100 mL), dried over Na₂SO4, filtered and concentrated in vacuo to provide ethyl 2-(3-fluoro-2-oxo-5-(2oxoethyl)pyridin-l(2H)-yl)pentanoate as a yellow oil (1.7 g, crude) used directly in the next reaction. (ESI 284.12(M+H)+).

Step 4: ethyl 2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyI)-2-oxopyridin-l(2H)-

Vnh

NaBH(OAc)₃

Amixture of ethyl 2-(3-fluoro-2-oxo-5-(2-oxoethyl)pyridin-l(2H)-yl)pentanoate (1.7 g, 6 mmol), AcOH (0.44 g, 7.2 mmol) and 3-fluoroazetidine hydrochloride (1.0 g, 9.0 mmol) in MeOH (30 mL) was stirred at room température for 30 mins. NaBH(OAc)₃ (2.54 g, 12 mmol) was added and stirred at room température for 2 hours. The solvent was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 4:1) to provide ethyl 2-(3fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)pentanoate as a yellow oil (700 mg). Yield 40% (ESI 343.18(M+H)⁺).

Step 5:2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyI)-2-oxopyridin-l(2H)-yI)pentanoic acid

310

LiOH

Ethyl 2-(3-fiuoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)pentanoate (700 mg, 2.05 mmol) was treated with LiOH-HzO (344 mg, 8.2 mmol) in EtOH (4 mL) and H2O (1 mL) at room température for 2 hours. The mixture was acidified to pH 4~5 with IN HCl. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8/40 g column (A: water 10 mM NILHCOj.B: MeOH, 20%) to provide 2-(3-fluoro-5-(2-(3fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)pentanoic acid as a yellow solid (500 mg). Yield 78% (ESI 315.14 (M+H)⁺).

Préparation of (3Æ)-2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2Z/)-yl)-3methylpentanoic acid Step 1: (2Æ, 3Æ)-2-bromo-3-methylpcntanoic acid î 9 NaNO₂/HBr,H₂O ! 9

ÜH₂ ër

To a solution of D-isoleucine (10.0 g, 76.23 mmol) in H2O (50 mL) was added 40% HBr in water (100 mL). The reaction mixture was cooled to 0 °C. A solution of sodium nitrite (7.9 g, 114.35 mmol) in H2O (10 mL) was added dropwise. Then the reaction mixture was stirred at room température for 3 hours. The reaction mixture was extracted with EtOAc (100 mL X 3). The organic layer was washed with brine (50 mL) and dried over anhydrous Na2SÛ4, filtered and concentrated in vacuo to provide (2Æ, 37?)-2-bromo-3-methylpentanoic acid as a brown oil used directly in the next reaction without further purification (14.0 g). Yield 95% (ESI 195.1 (M+H)⁺).

Step 2: methyl (37?)-2-bromo-3-methylpentanoate

I ⁰ I o . JLrA ™s^n₂ I ji OH --------► ër MeOH/CHCI₃, rt, X

311

A mixture of (21?, 37?)-2-bromo-3-methylpentanoic acid (12.6 g, 64.60 mmol) in MeOH/CHCh (30 mL/90 mL) was cooled to 0°C. (Diazomethyl)trimethylsilane (2.0 M in hexane; 64.6 m L, 129.20 mmol) was added dropwise. The mixture was stirred at room température for 1 hour.

LCMS showed that the reaction was completed. The mixture was concentrated in vacuo to provide methyl (37?)-2-bromo-3-methylpentanoate as a yellow oil used directly in the next reaction without further purification (12.0 g). Yield 89% (ESI 209.1 (M+H)⁺).

Step 3: methyl (3/?)-2-(5-bromo-3-fluoro-2-oxopyridin-l(2jF/)-yl)-3-methylpentanoate

Br

A mixture of 5-bromo-3-fluoropyridin-2(li/)-one (3.1 g, 16.15 mmol), Cs2COj(10.5 g, 32.3 mmol) and methyl (31?)-2-bromo-3-methylpentanoate (5.06 g, 24.23 mmol) in dioxane (100 mL) was stirred at 110°C for 16 h. LCMS showed the reaction was completed. The mixture was filtered and washed with EtOAc (20 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 10:1) to provide methyl (3R)-2-(5-bromo-3fluoro-2-oxopyridin-l(2H)-yl)-3-methylpentanoate as a colorless oil (2.2 g). Yield 43% (ESI 322.0 (M+H)⁺).

Step 4: methyl (37?)-2-(5-allyl-3-fluoro-2-oxopyridin-l(2H)-yI)-3-methylpentanoate

A mixture of methyl (37?)-2-(5-bromo-3-fluoro-2-oxopyridin-I(277)-yl)-3-methylpentanoate (2.2 g, 6.87 mmol), 2-allyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (3.5 g, 20.61 mmol), Pd(dppf)Ch (251 mg, 0.34 mmol) and K3PO4 (2.9 g, 13.74 mmol, 2.0 eq) in dioxane (100 mL) and H2O(10 mL) was stirred under nitrogen atmosphère at 80°C for 16 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 10:1) to provide methyl (3À)-2-(5-allyl-3-fluoro-2-oxopyridin-l(2/y)-yl)-3-methylpentanoate as a yellow oil (1.2 g). Yield 55% (ESI 282.1 (M+H)⁺).

Step 5: methyl (37?)-2-(3-fluoro-2-oxo-5-(2-oxoethyl)pyridin-l(277)-yl)-3-methylpentanoate

312

To a solution of methyl (37?)-2-(5-allyl-3-fluoro-2-oxopyridin-l(2//)-yl)-3-niethylpentanoate (1.2 g, 4.27 mmol) in THF/H₂O (20 mL/20 mL) was added a solution of K2OsO4-2H₂O(15.7 mg, 0.043 mmol) in H2O (3 mL) and stirred at room température for 1 hour. Then a solution of NaICh (1.8 g, 8.54 mmol) in H2O (10 mL) was added dropwise and the mixture was stirred at room température for 2 hours. LCMS showed the reaction was completed. The reaction mixture was diluted with H2O (50 mL), extracted with EtOAc (50 mL x 3). The combined organic phase was dried over anhydrous Na2SÛ4, filtered and concentrated in vacuo to provide methyl (37?)-2-(3fluoro-2-oxo-5-(2-oxoethyl)pyridin-l(2//)-yl)-3-methylpentanoate as a colorless oil used directly in the next reaction without further purification (1.3 g, crude). (ESI 284.1 (M+H)⁺).

Step 6: methyl (3/?)-2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2//)-yl)-3methylpentanoate

To a mixture of methyl (3jR)-2-(3-fluoro-2-oxo-5-(2-oxoethyl)pyridin-l(2/7)-yl)-3methylpentanoate (1.3 g, 4.59 mmol) in DCE (20 mL) at 25 °C was added 3-fluoroazetidine hydrochloride (768 mg, 6.89 mmol) and stirred at 25 °C for 1 hour. NaBH(OAc)₃ (2.9 g, 13.77 mmol) was added at 5 °C and stirred at 25 °C for 16 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel column (DCM: MeOH 20:1) to provide methyl (37?)-2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2jW)-yl)-3-methylpentanoate as a brown oil (800 mg). Yield 51% (ESI 343.1 [M+H]⁺).

Step 7: (3Æ)-2-(3-fluoro-5-(2-(3-fIuoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2ZZ)-yl)-3methylpentanoic acid

313

Methyl (3/î)-2-(3-fluoro-5-(2-(3-fluoroazetidin-1 -yI)ethyl)-2-oxopyridin-l (2/7)-y 1)-3methylpentanoate (800 mg, 2.34 mmol) was treated with LiOH-HzO (491 mg, 11.7 mmol) in EtOH (5 mL) and water (2 mL) and the mixture was stirred at room température for 30 minutes. The mixture was acidified with IN HCl to pH 5-6, concentrated and purified by reverse phase HPLC on a C18/40 g column (A: water/0.01%TFA,B: MeOH, 0-100%) to provide (3/?)-2-(3fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2//)-yl)-3-methylpentanoic acid as a white solid (600 mg). Yield 78% (ESI 329.2 (M+H)⁺).

Préparation of 3-cyclopropyl-2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridinl(2H)-yI)propanoic acid Step 1: ethyl 2-(5-bromo-3-fluoro-2-oxopyridin-l(2/7)-yl)-3-cyclopropylpropanoate

Br

A mixture of 5-bromo-3-fluoropyridin-2(l//)-one (2.0 g, 10.4 mmol), CS2CO3 (6.5 g, 20.8 mmol) and ethyl 2-bromo-3-cyclopropylpropanoate (2.7 g, 12.4 mmol) in toluene (50 mL) was stirred at 110 °C for 16 hours. LCMS showed the reaction was completed. The mixture was filtered and washed with EtOAc (20 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 4:1) to provide ethyl 2-(5-bromo-3-fluoro-2-oxopyridinl(27/)-yl)-3-cyclopropylpropanoate as a yellow oil (2.0 g). Yield 58% (ESI 333 (M+H)⁺).

Step 2: ethyl 2-(5-allyI-3-fluoro-2-oxopyridin-l(2Z/)-yl)-3-cyclopropylpropanoate

314

A mixture of ethyl 2-(5-bromo-3-fluoro-2-oxopyridin-l(2/7)-yl)-3-cyclopropylpropanoate (1.5 g, 4.5 mmol), allyltributylstannane (1.5 g, 5.4 mmol), CsF (1.4 g, 9 mmol), Pd(dba)j (126 mg, 0.45 mmol) and PCyj (206 mg, 0.225 mmol) in dioxane (100 mL) was stirred at 100 °C ovemight. The mixture was poured into water (200 mL) and extracted with EtOAc'(100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na^SO-i, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 4:1) to provide ethyl 2-(5-allyl-3-fluoro-2-oxopyridin-l(2//)-yl)-3-cyclopropylpropanoate as a yellow oil (1.0 g). Yield 83% (ESI 294(M+H)+)·

Step 3: ethyl 3-cycIopropyl-2-(3-fluoro-2-oxo-5-(2-oxoethyl)pyridin-l(2H)-yl)propanoate

To a solution of ethyl 2-(5-allyl-3-fluoro-2-oxopyridin-l(2/7)-yl)-3-cyclopropylpropanoate (800 mg, 2.7 mmol) in THF/H2O (60 mL/20 mL) was added a solution of K2OSO4-2H2O (10 mg, 0.027 mmol) in H2O (4 mL) and stirred at room température for 1 h. Then a solution of NaIO4 (1.1 g, 5.4 mmol) in H2O (20 mL) was added and stirred at room température for 2 h. LCMS showed the reaction was completed. The reaction mixture was diluted with 100 mL of water and extracted with EtOAc (100 mLx 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide ethyl 3-cyclopropyl-2-(3-fluoro-2-oxo-5(2-oxoethyl)pyridin-l(2/f)-yl)propanoate as a yellow oil used directly in the next reaction without further purification (820 mg, crude). (ESI 296 (M+H)⁺).

Step 4: ethyl 3-cyclopropyl-2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin315 l(27/)-yl)propanoatc

A mixture of ethyl 3-cyclopropyl-2-(3-fluoro-2-oxo-5-(2-oxoethyl)pyridin-l(27/)-yl)propanoate (500 mg, 1.7 mmol) and 3-fluoroazetidine hydrochloride (188 mg, 1.7 mmol) in DCE (20 mL) was stirred at room température for 10 minutes. NaBH(OAc)₃ (530 g, 1.5 mmol) was added and stirred at room température for 2 h. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic phase was dried over anhydrous Na^SO-i, filtered and concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl 8/40 g column (A: water 10 mM NHkHCCh.B: MeOH, 0-100%) to provide ethyl 3-cyclopropyl-2-(3fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(27V)-yl)propanoate as a yellow oil (300 mg). Yield 31% (ESI 355 (M+H)⁺).

Step 5:3-cycIopropyl-2-(3-fluoro-5-(2-(3-fluoroazctidin-l-yl)ethyI)-2-oxopyridin-l(277)yl)propanoic acid

Ethyl 3-cycIopropyl-2-(3-fluoro-5-(2-(3-fluoroazetidin-1 -yl)ethyl)-2-oxopyridin-1 (2H)yl)propanoate (300 mg, 0.84 mmol) was treated with LiOH-HzO (178 mg, 4.20 mmol) in THF (10 mL) and water (5 mL) at room température for 2 hours. The reaction mixture was acidified to pH 5 with IN HCl and concentrated. The mixture was purified by reverse phase HPLC on a Cl8 / 40 g column (A: water,B: MeOH, 0-100%) to provide 2-(3-fluoro-5-(2-(3-fluoroazetidin-lyl)ethyl)-4-methyl-2-oxopyridin-l(2//)-yl)-4-methylpentanoic acid as a white solid (200 mg). Yield 86% (ESI 327 (M+H)⁺).

316

Préparation of 2-(3-fIuoro-5-(2-(3-fIuoroazetidin-l-yI)ethyI)-2-oxopyridin-l(2Z7)-yl)-3methylbutanoic acid

Step 1: ethyl 2-(5-bromo-3-fluoro-2-oxopyridin-l(2Z7)-yl)-3-methyIbutanoate

N'X) ACN, 80°C

H

A mixture of 5-bromo-3-fluoropyridin-2(l£/)‘^one (5.0 g, 26.2 mmol, 1.0 eq), K2CO3 (7.2 g, 52.4 mmol, 2.0 eq) and ethyl 2-bromo-3-methylbutanoate (6.5 g, 31.4 mmol, 1.2 eq) in ACN (100 mL) was stirred at 80 °C for 16 hours. LCMS showed the reaction was completed. The mixture was filtered and washed with EtOAc (20 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 4:1) to provide ethyl 2-(5-bromo-3fluoro-2-oxopyridin-l(27/)-yl)-3-methylbutanoate as a yellow oil (3.0 g). Yield 36% (ESI 320.1 (M+H)⁺).

Step 2: ethyl 2-(5-allyl-3-fluoro-2-oxopyridin-l(2Z7)-yl)-3-methylbutanoate

Pd(dppf)CI₂, K3PO4

A mixture of ethyl 2-(5-bromo-3-fluoro-2-oxopyridin-l(2Z7)-yl)-3-methylbutanoate (3.0 g, 9.4 mmol, 1 eq), 2-allyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.9 g, 11.3 mmol, 1.2e<?), Pd(dppf)Ch (343.6 mg, 0.47 mmol, 0.05 eq) and K3PO4 (4.0 g, 18.8 mmol, 2.0 eq) in dioxane (100 mL) and H2O (10 mL) was stirred at 100 °C ovemight. Water (200 mL) was added and the solution was extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 4:1) to provide ethyl 2-(5-allyl-3fluoro-2-oxopyridin-l(2i/)-yl)-3-methylbutanoate as a yellow oil (2.4 g). Yield 92% (ESI 282.0 (M+H)+).

Step 3: ethyl 2-(3-fluoro-2-oxo-5-(2-oxoethyl)pyridin-l(2/i0-yl)-3-methylbutanoate

317

To a solution of ethyl 2-(5-allyl-3-fluoro-2-oxopyridin-l(2//)-yl)-3-methylbutanoate (2.4 g, 8.6 mmol, 1.0 eq) in THF (100 mL) and H₂O (30 mL) was added a solution of K₂OsO4-2H₂O (32 mg, 0.086 mmol, 0.01 eq) in H₂O (4 mL). The mixture was stirred at room température for 1 hour. Then a solution of NalOj (3.7 g, 17.2 mmol, 2.0 eq) in H₂O (20 mL) was added and stirred at room température for 2 hours. LCMS showed the reaction was completed. Water (100 mL) was added and the solution was extracted with EtOAc (100 mLx 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na₂SO4, filtered and concentrated in vacuo to provide ethyl 2-(3-fluoro-2-oxo-5-(2-oxoethyl)pyridin-l(2//)-yl)-3-methylbutanoate as a yellow oil used directly in the next reaction without further purification (1.6 g, crude). (ESI 284.1 (M+H)⁺).

Step 4: ethyl 2-(3-fhioro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2jFZ)-yl)-3methylbutanoate

A mixture of ethyl 2-(3-fluoro-2-oxo-5-(2-oxoethyI)pyridin-l(2/7)-yl)-3-methylbutanoate (1.6 g, 5.7 mmol, 1.0 eq) and 3-fluoroazetidine hydrochloride (427.5 mg, 5.7 mmol, 1.0 eq) in MeOH (20 mL) was stirred at room température for 10 minutes. NaBH(OAc)₃ (1.8 g, 8.6 mmoL 1.5 eq) was added and stirred at room température for 2 hours. LCMS showed the reaction was completed. The solvent was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 1:1) to provide ethyl 2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2oxopyridin-l(2/7)-yl)-3-methylbutanoate as a yellow oil (700 mg).Yield 24% for two steps (ESI 343.1 (M+H)⁺).

Step 5:2-(3-fIuoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)-3318 methylbutanoic acid

Ethyl 2-(3-fluoro-5-(2-(3-fluoroazetidin-l -yl)ethyl)-2-oxopyridin-l (2//)-yl)-3-methylbutanoate (700 mg, 2.0 mmol, 1.0 eq) was treated with LiOH-HzO (336 mg, 8.0 mmol, 4.0 eq) in MeOH (10 mL) and water (5 mL) at room température for 2 hours. The reaction mixture was acidifled to pH 5 with IN HCl and concentrated. The mixture was purified by reverse phase HPLC on a Cl8 / 40 g column (A: water 10 mM NH₄HCO3,B: MeOH, 0-100%) to provide 2-(3-fluoro-5-(2-(3fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2/^:/)-yl)-3-methylbutanoic acid as a white solid (500 mg). Yield 78% (ESI 315.1 (M+H)⁺).

Préparation of 2-(3-fluoro-5-(2-((7?)-3-fluoropyrroIidin-l-yl)ethyl)-2-oxopyridin-l(2/Z)-yl)4-methyIpentanoic acid

Step 1: ethyl 2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxopyridin-l(2//)-yl)-4methylpentanoate

To a mixture of ethyl 2-(3-fluoro-2-oxo-5-(2-oxoethyl)pyridin-l(2J7)-yl)-4-methylpentanoate (3.3 g, 11.2 mmol) in DCE (70 mL) at 25 °C was added (R)-3-fluoropyrrolidine hydrochloride (1.4 g, 11.2 mmol) and stirred at 25 °C for 30 mins. NaBH(OAc)j (4.6 g, 22.4 mmol) was added at 5 °C and stirred at 25 °C for 16 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel column (DCM: MeOH 10:1) to give compound ethyl 2-(3-fluoro-5-(2((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxopyridin-l(2j7)-yl)-4-methylpentanoate (1.7 g) as a yellow oil. Yield 41% (ESI 371.2 (M+H)⁺).

Step 2:2-(3-fluoro-5-(2-((Æ)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxopyridin-l(2£f)-yl)-4methylpentanoic acid

319

Ethyl 2-(3-fluoro-5-(2-((J?)-3-fluoropyrrolidin-1 -yl)ethyl)-2-oxopyridin-1 (2/7)-yl)-4methylpentanoate (1.7 g, 4.59 mmol) was treated with L1OH-H2O (960.0 mg, 23.0 mmol, 5.0 eq) in MeOH (12 mL) and water (5 mL) at room température for 2 hours. The MeOH was removed and the aqueous acidified with IN HCl to pH = 5. The residue was purified by reverse phase

HPLC on a Cl 8/40 g column (A: water 10 mMNH4HCO₃,B: MeOH, 0~100%) to provide 2-(3 fluoro-5-(2-((_JR)-3-fluoropyrrolidin-1 -yl)ethyl)-2-oxopyridin-1 (2Z/)-yl)-4-methylpentanoic acid as a white solid (1.1g). Yield 70% (ESI 343.1 (M+H)⁺).

Préparation of 2-(5-(2-(dimethylamino)ethyl)-3-fIuoro-4-methyl-2-oxopyridin-l(2H)-yl)-4methylpentanoic acid Step 1:3-fluoro-4-methylpyridin-2(lH)-one

F

A mixture of 4-methylpyridin-2(lH)-one (10 g, 92 mmol, 1.0 eq) and selectfluor (16 g, 46 mmol, 0.5 eq) in CHCl₃ (100 mL) and water (100 mL) was stirred at 35°C for 16 h. The reaction mixture was diluted with a saturated NaCl solution (100 mL) and extracted with DCM (100 mL x 3). The combined organic phase was dried over anhydrous NaiSCh, filtered and concentrated in vacuo. The residue was purified by silica gel column (EtOAc: DCM: MeOH 100: 10:6) to provide 3-fluoro-4-methylpyridin-2(lH)-one as a whitle solid (2.4 g). Yield 21% (ESI 128 (M+H)⁺). 'HNMR (400 MHz, CDC13) δ 13.53 (s, 1H), 7.20 (dd, J= 6.6,0.6 Hz, 1H), 6.14 (t, J= 6.1 Hz, 1H), 2.24 (d, J= 2.5 Hz, 3H). ¹⁹F NMR (376 MHz, CDC13) δ -140.20.

Step 2:5-bromo-3-fluoro-4-methylpyridin-2(lH)-one

To a solution of 3-fluoro-4-methylpyridin-2(lH)-one (2.4 g, 18.9 mmol, 1.0 eq) in DMF (20 mL) was added NBS (3.7 g, 20.8 mmol, 1.1 eq) and stirred at 30°C for 1 h. The reaction mixture was

320 purified by reverse phase HPLC (A: water(0.01%TFA); B ACN, 45% of B) to provide 5-bromo3-fluoro-4-methylpyridin-2(lH)-one as a whitle solid (3 g). Yield 77% (ESI 206 (M+H)⁺). ^lH NMR (500 MHz, CDCI3) δ 7.42 (d, J= 1.3 Hz, 1H), 2.31 (d, J= 3.0 Hz, 3H).

Step 3: ethyl 2-(5-bromo-3-fluoro-4-methyl-2-oxopyridin-l(2H)-yi)-4-methyIpentanoate

A mixture of 5-bromo-3-fluoro-4-methylpyridin-2(lH)-one (3.0 g, 14.6 mmol, 1.0 eq), K2CO3 (4 g, 29.3 mmol, 2.0 eq) and ethyl 4-methyl-2-((methylsulfonyl)oxy)pentanoate (7 g, 29.3 mmol, 2 eq) in CH3CN (50 mL) was stirred at 80°C for 16 h. LCMS showed the reaction was completed. The mixture was filtered and washed with CH3CN (20 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 4:1) to provide ethyl 2-(5-bromo-3-fluoro-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanoate as a yellow oil (4.5 g). Yield 89% (ESI 348 (M+H)⁺).

Step 4: ethyl 2-(5-allyl-3-fluoro-4-methyl-2-oxopyridin-l(2H)-yl)-4-methyIpentanoate

A mixture of ethyl 2-(5-bromo-3-fluoro-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanoate (4.5 g, 13 mmol, 1.0 eq), allyltributylstannane (35.6 g, 16.9 mmol, 1.3 eq), Pdzdba3(595 mg, 0.65 mmol, 0.05 eq), PCy3 (364 mg, 1.3 mmol, 0.1 eq) and CsF (4 g, 26 mmol, 2.0 eq) in anhydrous dioxane (100 mL) was stirred under N2 at 100°C for 16 hours. The mixture was cooled to room température. A saturated NH4C1 solution (100 mL) was added and the solution was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 4:1) to provide ethyl 2-(5-allyl-3-fluoro-4methyl-2-oxopyridin-l(2H)-yl)-4-methy!pentanoate as a yellow solid (2 g). Yield 50% (ESI 310

321 (Μ+Η)⁺). Ή NMR (400 MHz, CDCh) Ô 6.86 (s, 1H), 5.93 - 5.84 (m, IH), 5.77 - 5.73 (m, 1H), 5.18 - 5.03 (m, 2H), 4.20 (q, J= 8 Hz, 2H), 3.18 - 3.14 (m, 2H), 2.13 (d, J= 2.8 Hz, 3H), 2.01 1.94 (m, 1H), 1.90- 1.84 (m, 1H), 1.45-1.37 (m, 1H), 1.26 (t, J = 8 Hz, 2H), 0.98-0.91 (m, 6H).

Step 5: ethyl 2-(3-fluoro-4-methyl-2-oxo-5-(2-oxoethyl)pyridin-l(2H)-yl)-4methylpentanoate

To a solution of ethyl 2-(5-allyl-3-fluoro-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanoate (1.8 g, 5.8 mmol, 1.0 eq) in THF/H2O (60 mL/20 mL) was added a solution of K₂OsO4-2H2O(21 mg, 0.058 mmol, 0.01 eq) in H₂O (4 mL) and stirred at room température for 1 h. Then a solution of NaIO₄ (1.25 g, 11.7 mmol, 2.0 eq) in H2O (20 mL) was added and stirred at room température for 2 h. LCMS showed the reaction was completed. The reaction mixture was diluted with 100 mL of water and extracted with EtOAc (100 mL x 3). The combined organic phase was dried over anhydrous Na₂SÛ4, filtered and concentrated in vacuo to provide ethyl 2-(3-fluoro-4methyl-2-oxo-5-(2-oxoethyl)pyridin-l(2H)-yl)-4-methylpentanoate as a yellow oil used directly in the next reaction without further purification (2 g, crude). (ESI 312 (M+H)⁺).

Step 6: ethyl 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-4-methyl-2-oxopyridîn-l(2H)-yl)-4methylpentanoate

A mixture of ethyl 2-(3-fluoro-4-methyl-2-oxo-5-(2-oxoethyl)pyridin-l(2H)-yl)-4methylpentanoate (2.0 g, 6.42 mmol) and dimethylamine (9.64 mL, 19.27 mmol) (2.0 M) in THF was added in DCE (32.1 mL) and stirred at room température for 10 mins. NaBH(OAc)j (4.08 g, 19.3 mmol, 3.0 eq) was added to the reaction mixture and stirred at room température for 2 h..

322

The mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic phase was dried over anhydrous Na₂SÛ4. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC in NH4HCO3 condition (A: water 10 mM NH4HCÛ3,B: MeOH, 0-100%) to provide ethyl 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-4methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanoate (1.41g, 4.14 mmol, 64.5% yield) as yellow oil. (ESI 341 (M+H)⁺).

Step 7: 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-4-methyl-2-oxopyridin-l(2H)-yl)-4methylpentanoic acid

LiOH

Ethyl 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-4-methyl-2-oxopyridin-1 (2H)-yl)-4methylpentanoate (1.41 g, 4.14 mmol) was treated with lithium hydroxide (0.496 g, 20.71 mmol) in MeOH (10 mL) and water (5 mL) at room température for 2 hours. The MeOH was removed and the aqueous acidified with IN HCl to pH = 5. The residue was purified by reverse phase HPLC in neutral condition (A: water. B: MeOH, 0-100%) to provide 2-(5-(2(dimethylamino)ethyl)-3-fluoro-4-methyI-2-oxopyridin-l(2H)-yl)-4-methyIpentanoic acid (1.21 g, 3.87 mmol, 94% yield) (ESI 313 (M+H)⁺).

Préparation of 2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2H)yl)-4-methylpentanoic acid Step 1: ethyl 2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-4methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanoate

A mixture of ethyl 2-(3-fluoro-4-methyl-2-oxo-5-(2-oxoethyl)pyridin-l(2H)-yl)-4323 methylpentanoate (2 g, 6.4 mmol) and 3-fluoroazetidine hydrochloride (2.1 g, 19.3 mmol, 3.0 eq) in DCE (20 mL) was stirred at room température for 10 minutes. NaBH(OAc)j (4.2 g, 19.3 mmol, 3.0 eq) was added to the reaction mixture and stirred at room température for 2 h. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic phase was dried over anhydrous Na₂SO4, filtered and concentrated in vacuo and the residue was purified by reverse phase HPLC (A: water 10 mM NH4HCO3, B: MeOH, 70%B) to provide ethyl 2-(3-fluoro-5-(2-(3-fluoroazetidin-l -yl)ethyl)-4-methyl-2-oxopyridin-l (2H)-yl)-4methylpentanoate as a yellow oil (1 g). Yield 42% (ESI 371 (M+H)⁺).

Step 2:2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2H)-yI)-4methylpentanoic acid

Ethyl 2-(3-fluoro-5-(2-(3-fluoroazetidin-1 -yl)ethyl)-4-methyl-2-oxopyridin-1 (2H)-yl)-4 methylpentanoate (1 g, 2.7 mmol, 1.0 eq) was treated with L1OH-H2O (567 mg, 13.5 mmol, 5.0 eq) in MeOH (10 mL) and water (5 mL) at room température for 2 hours. The reaction mixture was acidified to pH 5 with IN HCI and concentrated. The mixture was purified by reverse phase

HPLC in neutral condition (A: water. B: MeOH, 60%B) to provide 2-(3-fluoro-5-(2-(3fIuoroazetidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanoic acid as a white solid (800 mg). Yield 86% (ESI 343 (M+H)⁺).

Préparation of2-(3-fluoro-5-(2-(3-methoxyazetidin-l-yl)ethyl)-4-methyl-2-oxopyridin l(2Z7)-yl)-4-methylpentanoic acid

Step 1: ethyl 2-(3-fIuoro-5-(2-(3-methoxyazetidin-l-yl)ethyl)-4-niethyl-2-oxopyridin-l(2//)-

A mixture of ethyl 2-(3-fiuoro-4-methyl-2-oxo-5-(2-oxoethyl)pyridin-l(2Z/)-yl)-4324 methylpentanoate (4.5 g, 14.4 mmol) and 3-methoxyazetidine hydrochloride (2.7 g, 21.7 mmol) in DCE (20 mL) was stirred at room température for Ih. NaBH(OAc)j (6.2 g, 29.2 mmol) was added and stirred at room température for 2 h. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic phase was dried over anhydrous Na^SO-j, filtered and concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8/120 g column (A: water 10 mM NILHCCh.B: MeOH, 0-100%) to provide ethyl 2-(3fluoro-5-(2-(3-methoxyazetidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2//)-yl)-4methylpentanoate as a yellow oil (2.7 g). Yield 49% (ESI 383.1 (M+H)⁺).

Step 2:2-(3-fluoro-5-(2-(3-methoxyazetidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4methylpentanoic acid

Ethyl 2-(3-fluoro-5-(2-(3-methoxyazetidin-1 -yl)ethyl)-4-methyI-2-oxopyridin-1 (2H)-yl)-4methylpentanoate (3.0 g, 7.9 mmol) was treated with LiOH-FhO (1.6 g, 39.3 mmol) in EtOH (20 mL) and water (5 mL) at room température for 2 hours. The EtOH was removed and the aqueouse acidified with IN HCl to pH 5 and concentrated. The mixture was purified by reverse phase HPLC on a Cl8/120 g column (A: water.B: MeOH, 0-100%) to provide 2-(3-fluoro-5-(2 (3-fluoroazetidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanoic acid as a white solid (2.4 g). Yield 86% (ESI 355.3 (M+H)⁺).

Préparation of2-(5-(2-(dimethylamino)ethyI)-3-fluoro-2-oxo-4-(trifluoromethyl)pyridinl(27f)-yl)-4-methylpentanoic acid

Step 1:5-bromo-3-fluoro-4-(trifluoromethyl)pyridin-2-oI bKzx, ίι N Ii N ? NBS, TFA, _r II ï

F₃(jY'OH aCN, 80°C FsuV^OH

A mixture of 3-fluoro-4-(trifluoromethyl)pyridin-2-ol (16.0 g, 88.35 mmol) and NBS (23.5 g, 132.53 mmol) in TFA (32 mL) and MeCN (320 mL) was stirred at 80°C for 24 hours. LCMS showed the reaction was completed. The reaction was concentrated in vacuo and the residue was

325 purified by silica gel column (petroleum ether: EtOAc l: l) to provide 5-bromo-3-fluoro-4(trifluoromethyl)pyridin-2-ol as a white solid (19.7 g). Yield 86% (ESI 259.9 (M+H)⁺).

Step 2: ethyl 2-(5-bromo-3-fluoro-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanoate

A mixture of 5-bromo-3-fluoro-4-(trifluoromethyl)pyridin-2-ol (19.7 g, 75.77 mmol), CS2CO3 (49.3 g, 151.54 mmol) and ethyl 4-methyl-2-((methylsulfonyl)oxy)pentanoate (23.5 g, 98.5 mmol) in toluene (100 mL) was stirred at 110°C for 2 h. LCMS showed the reaction was completed. The mixture was filtered and washed with EtOAc (20 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 10:1) to provide ethyl 2-(5-bromo-3-fluoro-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanoate as a white solid (12.4 g). Yield 41% (ESI 402.0 (M+H)⁺).

Step 3: ethyl (£)-2-(5-(2-ethoxyvinyl)-3-fluoro-2-oxo-4-(trifIuoromethyl)pyridin-l(2ZZ)-yl)-

A mixture of ethyl 2-(5-bromo-3-fluoro-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methylpentanoate (9.7 g, 24.12 mmol), (£)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane (5.7 g, 28.94 mmol), Pd(PPh₃)4 (832 mg, 0.72 mmol,) and K2CO3 (6.7 g, 48.24 mmol) in 1,4-dioxane (100 mL) and water (10 mL) was stirred at 70°C underN2 for 20 h. The reaction mixture was poured into 100 mL of water and extracted with EtOAc (100 mL x 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether. EtOAc 10:1) to provide ethyl (E)-2-(5-(2-ethoxyvinyl)-3-fluoro-2-oxo-4-(trifluoromethyl)pyridin-l(22/)-yl)-4methylpentanoate (6.0 g). Yield 63% (ESI 394.1 (M+H)⁺).

326

Step 4: ethyl 2-(3-fhioro-2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2Z/)-yI)-4-

To a mixture of ethyl (E)-2-(5-(2-ethoxyvinyI)-3-fluoro-2-oxo-4-(trifluoromethyl)pyridin-1(2/7)yl)-4-methylpentanoate (6.0 g, 15.25 mmol) in DCM (50 mL) was added TFA (5 mL). The mixture was stirred at room température for 3 hours. LCMS showed that the reaction was completed. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with saturated NaHCOj (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude product ethyl 2-(3-fluoro-2-oxo-5-(2-oxoethyl)4-(trifluoromethyl)pyridin-l(277)-yl)-4-methylpentanoate as a colorless oil (5.5 g) used directly in the next reaction without further purification. Yield 99% (ESI 366.1 [M+H]⁺).

Step 5: ethyl 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxo-4-(trifluoromethyl)pyridin1 (2/7)-yI)-4-methylp en tanoate

To a mixture of ethyl 2-(3-fluoro-2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanoate (5.5 g, 15.06 mmol) in DCE (100 mL) at 25 °C was added dimethylamine hydrochloride (2.5 g, 30.12 mmol) and stirred for 1 hour. NaBH(OAc)j (6.4 g, 30.12 mmol) was added at 5 °C and stirred at 25 °C for 16 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel column (DCM: MeOH 10:1) to provide ethyl 2-(5-(2(dimethylamino)ethyI)-3-fluoro-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanoate as a brown oil (4.5 g) Yield 76% (ESI 395.1 [M+H]⁺).

Step 6: 2-(5-(2-(dimethyIamino)ethyl)-3-fluoro-2-oxo-4-(trifluoromethyI)pyridin-l(2Z0-y04-mcthylpentanoic acid

327

Ethyl 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methylpentanoate (4.5 g, 11.41 mmol) was treated with LiOH-HzO (2.4 g, 57.05 mmol) in EtOH (10 mL) and water (2 mL) and the mixture was stirred at room température for 1 hour. The mixture was acidified with IN HCl to pH = 5~6, concentrated and purified by reverse phase HPLC on a Cl8/40 g column (A: water 10 mM NH4HCO3.B: MeOH, 0-100%) to provide 2-(5(2-(dimethylamino)ethyl)-3-fluoro-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanoic acid as a white solid (3.7 g). Yield 89% (ESI 367.1 (M+H)⁺).

Préparation of 4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)pentanoic acid

Step 1: ethyl 4-methyl-2-(5-(2-(3-methylazetidin-l-yl)cthyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)pentanoate

’NHHCI ⁷ (10eq)

NaBH(OAc)₃ (2.0 eq), DCE (15 V) 25 °C, 12 hrs

To a mixture of ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2H)-yl)pentanoate (16.0 g, 36.8 mmol, 1.00 eq) in DCE (100 mL) at 25 °C was added 3-methylazetidine (2.62 g, 36.8 mmol, 1.00 eq, HCl) and sodium triacetoxyborohydride (15.6 g, 73.7 mmol, 2.00 eq). The mixture was stirred at 0 °C for 10 mins, then 25 °C for 12 hrs. The mixture was diluted with Η₂Ο (100 mL) and extracted with DCM (50.0 mL x 2). The combined organic phase was washed with brine (100 mL), dried over NaaSOi, filtered and concentrated under reduced pressure. Purification by column chromatography (S1O2, Petroleum ether: Ethyl acetate = 100: 1 to 0: 1) provided ethyl 4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)pentanoate (9.00 g, 22.3 mmol, 61% yield) as a yellow oil. 1H NMR: (400 MHz, MeOD) δ 7.86 (s, 1H), 6.90 (s, 1H), 5.52-5.56 (m, 1H), 4.08-4.12 (m, 2H), 3.73-3.74 (m, 4H), 3.59-3.61 (m, 2H), 3.81-3.20 (m, 2H), 2.79-2.81 (m, 3H), 2.05-2.09 (m, 2H), 1.86-1.89 (m, 4H), 1.30-1.50 (m, 7H), 1.25-1.29 (m, 6H), 0.95-0.98 (m, 6H).

328

Step 2: 4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)pentanoic acid

LiOH (3 0 eq)

THF (11 V), H₂O(3V) 0 ’C. 12 tirs

To a solution of ethyl 4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)pentanoate (9.00 g, 19.0 mmol, 1.00 eq) in THF (80.0 mL) and H₂O (8.00 mL) was added LiOH.H₂O (2.39 g, 57.0 mmol, 3.00 eq) at 0 °C. The mixture was stirred at 20 °C for 12 hrs. The reaction mixture was adjusted to pH = 7 with aq.lM HCl and concentrated under reduced pressure. The resulting residue was purified byprep-HPLC (column: Phenomenex luna cl8 250mm* 100mm*lOum; mobile phase: [water (0.05%HCl)-ACN]; B%: 9%-39%, 20min), concentrated under reduced pressure, then lyophilized to provide 4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)pentanoic acid (4.70 g, 12.0 mmol, 64% yield) as a white solid. 1H NMR: (400 MHz, MeOD) δ 7.79 (s, 1H), 6.87 (s, 1H), 5.60-5.64 (m, 1H), 4.20-4.30 (m, 2H), 3.75-3.85 (m, 2H), 3.35-3.40 (m, 2H), 2.85-2.89 (m, 3H), 2.02-2.09 (m, 2H), 1.26-1.35 (m, 4H), 0.92-0.96 (m, 6H).

Préparation of 2-(5-(2-(3-(fluoromethyl)azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)-4-methylpentanoic acid

Step 1: ethyl 2-(5-(2-(3-(fluoromethyl)azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)yl)-4-methylpentanoate

NaBH(OAc)₃ (2.0 eq). DCE (15 V) 25 ’C. 12 hrs

(10 eq)

To a mixture of ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2H)-yl)pentanoate (12.0 g, 24.1 mmol, 1.00 eq) in DCE (100 mL) at 25 °C was added 3-(fluoromethyl)azetidine (3.04 g, 24.1 mmol, 1.00 eq, HCl) and DIPEA (6.25 g, 48.3 mmol, 8.42 mL, 2.00 eq) stirred at 0 °C for 10 mins. Sodium triacetoxyborohydride (10.2 g, 48.3 mmol, 2.00 eq) was added at 5 °C and then stirred at 25 °C for 12 hrs. The mixture was diluted with H2O (100 mL) and extracted with DCM (50.0 mL x 2). The combined organic phase was washed with brine (100 mL), dried over Na₂SÛ4, filtered and concentrated under reduced pressure to provide ethyl 2-(5-(2-(3-(fluoromethyl)azetidin-l-yI)ethyl)-2-oxo-4-(trifluoromethyl)pyridin

329 l(2H)-yl)-4-methylpentanoate (10.1 g, 24.0 mmol, 99.3% yield) as a yellow oil used without fiirther purification.

Step 2: 2-(5-(2-(3-(fluoromethyl)azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpcntanoic acid

LiOH (3 eq)

THF (11 V), H₂O(3V) 0°C. 12 hrs

To a solution of ethyl 2-(5-(2-(3-(fluoromethyl)azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanoate (10.1 g, 24.0 mmol, 1.00 eq) in THF (80.0 mL) and H₂O (10.0 mL) was added LiOH.H₂O (3.02 g, 72.0 mmol, 3.00 eq) at 0 °C. The mixture was stirred at 20 °C for 12 hrs. The reaction mixture was adjusted to (pH = 7) with aq.lM HCl and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna cl8 250mm* 100mm* 10um;mobile phase: [water(0.05%HCl)-ACN];B%: 6%-36%,20min) and concentrated under reduced pressure, then lyophilized to give 2-(5-(2-(3-(fluoromethyl)azetidin-l -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)yI)-4-methylpentanoic acid (4.50 g, 11.4 mmol, 47.7% yield) as a white solid. 1H NMR: (400 MHz, MeOD) Ô 7.82 (s, 1H), 6.89 (s, 1H), 5.59-5.63 (m, 1H), 4.50-4.62 (m, 2H), 4.3-4.32 (m, 2H), 4.11-4.14 (m, 2H), 3.37-3.41 (m, 6H), 2.86-2.90 (m, 2H), 2.06-2.10 (m, 2H), 1.53-1.55 (m, 1H), 0.93-0.97 (m, 6H).

Préparation of 2-(5-(2-(3-(methoxymethy!)azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanoic acid

Step 1: ethyl 2-(5-(2-(3-(methoxymethyl)azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanoate

Na8H(OAc)₃ (2.0 eq). DCE (15 V) °C. 12 hrs

(1.0 eq)

To a mixture of ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2H)-yl)pentanoate (11.0 g, 22.1 mmol, 1.00 eq) in DCE (100 mL) at 25 °C was added 3-(methoxymethyl)azetidine hydrochloride (3.05 g, 22.1 mmol, 1.00 eq) and DIPEA (5.73 g, 44.3 mmol, 7.72 mL, 2.00 eq) stirred at 0 °C for 10 mins. Sodium triacetoxyborohydride (9.40 g, 44.3 mmol, 2.00 eq) was added at 5 °C and stirred

330 at 25 °C for 12 hrs. The mixture was diluted with H>0 (100 mL) and extracted with DCM (50.0 mL x 2). The combined organic phase was washed with brine (100 mL), dried overNa^SCh, filtered and concentrated under reduced pressure to provide ethyl 2-(5-(2-(3-(methoxymethyl)azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoate (9.50 g, 21.9 mmol, 99.0% yield) as a yellow oil used without further purification.

Step 2: 2-(5-(2-(3-(methoxymethyI)azetidin-l-yl)ethyI)-2-oxo-4-(triiluoromethyl)pyridin-l(2H)-yl)4-methylpcntanoic acid

To a solution of ethyl 2-(5-(2-(3-(methoxymethyl)azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanoate (9.50 g, 21.9 mmol, 1.00 eq) in THF (80.0 mL) and H₂O (10.0 mL) was added L1OH.H2O (1.84 g, 43.9 mmol, 2.00 eq) at 0 °C. The mixture was stirred at 20 °C for 12 hrs. The reaction mixture was adjusted to (pH = 7) with aq.lM HCl and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna cl8 250mm* 100mm* 10um;mobile phase: [water(0.05%HCl)-ACN];B%: 6%-36%,20min) and concentrated under reduced pressure, then lyophilized to give 2-(5-(2-(3-(methoxymethyl)azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanoic acid (5.10 g, 12.6 mmol, 57.4% yield) as a yellow solid. 1H NMR: (400 MHz, MeOD) δ 7.86 (s, 1H), 6.89 (s, 1H), 5.58-5.62 (m, 1H), 4.07-4.26 (m, 4H), 3.36-3.49 (m, 7H), 3.07 (s, 1H), 2.84-2.88 (m, 2H), 2.07-2.11 (m, 2H), 1.37-1.41 (m, 1H), 0.94-0.97 (m, 6H).

Préparation of 2-(5-(2-(33-dimcthylazetidin-l-yI)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)4-methylpentanoic acid

Step 1: ethyl 2-(5-(2-(3,3-dimethylazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoate

(1.1 eq)

NaBH(OAch (2.0 eq), DCE (6 V) 25’C, 12 hrs

To a mixture of ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2H)-yi)pentanoate (20 g, 46.1 mmol) in DCE (140 mL) at 25 °C was added 3,3-dimethylazetidine hydrochloride (6.16 g, 50.7

331 mmol, HCl) and DIPEA (11.9 g, 92.1 mmol, 16.1 mL). After stirring at 10 °C for 10 mins, NaBH(OAc)₃(19.5 g, 92.1 mmol) was added at 5 °C and stirred at 25 °C for 12 hrs. The mixture was diiuted with H2O (200 mL) and the mixture was extracted with DCM (200 mL x 2). The combined organic phase was washed with brine (200 mL), dried over NazSOi, filtered and concentrated under reduced pressure provide ethyl 2(5-(2-(3,3-dimethylazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoate (20 g) as a yellow oil used without further purification.

Step 2: 2-(5-(2-(3,3-dimethyIazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid

LiOH (2 eq)

THF (5 V), H₂O (1 V) 0°C. 12 hrs

To a mixture of ethyl 2-(5-(2-(3,3-dimethylazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)-4-methylpentanoate (20 g, 48.0 mmol) in THF (100 mL) and H2O (20 mL) was added LiOH.HjO (4.03 g, 96.0 mmol) in one portion at 15 °C under N2. The mixture was stirred at 15 °C for 2 hrs. The reaction mixture was adjusted to (pH = 6) with IM HCl and then concentrated under reduced pressure. The residue was purified by prep-HPLC (HCl condition), concentrated under reduced pressure, then lyophilizcd to give 2-(5-(2-(3,3-dimethylazetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l (2H)-yl)4-methylpentanoic acid (6.55 g, 16.7 mmol, 28% yield) as pink solid. 1H NMR: (400 MHz, MeOD) δ 7.94 (s, 1H), 6.91 (s, 1H), 5.59-5.63 (dd, 7=4.0 Hz, 12 Hz, 1H), 4.02-4.04 (m, 2H), 3.85-3.92 (m, 2H), 3.34-3.49 (m, 2H), 2.83-2.96 (m, 2H), 2.04-2.20 (m, 2H), 1.39-1.48 (m, 4H), 1.32 (s, 3H), 0.95-0.97 (d, J = 8.0 Hz, 6H )

Préparation of 2-(5-(2-(2-azaspiro[3.3]heptan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)-4-methylpentanoic acid

Step 1: ethyl 2-(5-(2-(3-(methoxymethyl)azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin1 (2H)-yl)-4-methylpentanoate

NaBH(OAc), (2.0 eq). DCE (15 V) °C, 12 hrs

332

To a mixture of ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2H)-yl)pentanoate (11.0 g, 22.1 mmol, 70.0% purity, 1.00 eq) in DCE (100 mL) at 25 °C was added 2-azaspiro[3.3]heptane (2.96 g, 22.1 mmol, 1.00 eq, HCl) and DIPEA (5.73 g, 44.3 mmol, 7.72 mL, 2.00 eq). Aller stirring at 0 °C for 10 mins, sodium triacetoxyborohydride (9.40 g, 44.3 mmol, 2.00 eq) was added at 5 °C and stirred at 25 °C for 12 hrs. The mixture was diluted with H₂O (100 mL) and extracted with DCM (50.0 mL x 2). The combined organic phase was washed with brine (100 mL), dried overNajSO-t, filtered and concentrated under reduced pressure to provide ethyl 2-(5-(2-(2-azaspiro[3.3]heptan-2-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoate (9.49 g, 22.1 mmol, 99.9% yield) as a yellow oil used without further purification.

Step 2: 2-(5-(2-(2-azaspiro(3.3Jheptan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid

UOH 2 eq)

THF (11 V).H₂O(3V)

O’C. 12 hrs

To a solution of ethyl 2-(5-(2-(2-azaspiro[3.3]heptan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)-4-methylpentanoate (9.50 g, 22.1 mmol, 1.00 eq) in THF (80.0 mL) and H2O (10.0 mL) was added LÎOH.H2O (1.86 g, 44.3 mmol, 2.00 eq) at 0 °C. The mixture was stirred at 20 °C for 12 hrs. The reaction mixture was adjusted to (pH = 7) with aq.lM HCl and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna cl8 250mm* 100mm* 10um;mobile phase: [water(0.05%HCl)-ACN];B%: 6%-36%,20min) and concentrated under reduced pressure, then lyophilized to give 2-(5-(2-(2-azaspiro[3.3]heptan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)-4-methylpentanoic acid (5.50 g, 13.3 mmol, 60.0% yield) as a white solid. 1H NMR: (400 MHz, MeOD) δ 7.86 (s, 1H), 6.90 (s, 1H), 5.60-5.64 (m, 1H), 4.11-4.25 (m, 4H), 3.32-3.36 (m, 2H), 2.83-2.87 (m, 2H), 2.07-2.11 (m, 6H),1.86-1.90 (m, 1H), 1.37-1.39 (m, 1H), 0.94-0.97 (m, 6H).

Préparation of 2-(5-(2-(5-azaspiro[2.3]hexan-5-yl)ethyl)-2-oxo-4-(trifluoroinethyl)pyridin-l(2H)-yl)4-methylpentanoic acid

Step 1: ethyl 2-(5-(2-(5-azaspiro[2.3]hexan-5-yl)ethyl)-2-oxo-4-(trînuoromethyI)pyridin-l(2H)-yl)-4methylpentanoate

333

V⁷'⁷ (10 eq)

NaBH(OAc)₃ (2.0 eq), DCE (10 V) 25 °C. 12 hrs

To a mixture of ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyI)pyridin-l(2H)-yl)pentanoate (10.0 g, 20.1 mmol, 70.0% purity, 1.00 eq) in DCE (100 mL) at 25 °C was added 5-azaspiro[2.3]hexane (2.05 g, 17.1 mmol, 0.85 eq, HCl). After stirring at 0 °C for 10 mins, sodium triacetoxyborohydride (8.54 g, 40.3 mmol, 2.00 eq) was added, the mixture was stirred at 25 °C for 12 hrs. The mixture was diluted with Η₂Ο (100 mL) and extracted with DCM (50.0 mL x 2). The combined organic phase was washed with brine (100 mL), dried over NaiSOq, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, Petroleum ether: Ethyl acetate = 100: 1 to 0: 1) to provideethyl 2-(5-(2-(5-azaspiro[2.3]hexan-5-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanoate (5.10 g, 12.3 mmol, 61.0% yield) as a yellow oil.

Step 2: 2-(5-(2-(5-azaspiro[2.3]hexan-5-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid

LiOH (3.0 eq)

THF (5 V), HjO (1 V) 20 °C. 12 hrs

To a solution of ethyl 2-(5-(2-(5-azaspiro[2.3]hexan-5-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)-4-methylpentanoate (5.10 g, 12.3 mmol, 1.00 eq) in THF (30.0 mL) and H2O (3.00 mL) was added LiOH.H₂O (1.55 g, 36.9 mmol, 3.00 eq) at 0 °C. The mixture was stirred at 20 °C for 12 hrs. The reaction mixture was adjusted to (pH = 7) with aq.lM HCl and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna cl8 250mm* 100mm* 10um;mobile phase: [water(0.05%HCl)-ACN];B%: 10%-40%,25min) and concentrated under reduced pressure, then lyophilized to give 2-(5-(2-(5-azaspiro[2.3]hexan-5-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l (2H)-yl)4-methylpentanoic acid (2.40 g, 5.53 mmol, 44.9% yield) as a white solid. 1H NMR: (400 MHz, MeOD) δ 7.86 (s, 1H), 6.89 (s, 1H), 5.62 (t, J= 7.2Hz, 1H), 4.27 (s, 4H), 3.47-3.55 (m, 2H), 2.90-2.94 (m, 2H), 2.06-2.12 (m, 2H), 1.34-1.39 (m, 1H), 0.94-0.97 (m, 6H), 0.81 (s, 4H).

Préparation of 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)-yl)-4methylpentanoic acid

334

Step 1: ethyl 2-(5-(3-(dimethyIamino)prop-l-yn-l-yl)-2-oxo-4-(trifIuoromethyl)pyridin-l(2H)-yl)-4methylpentanoate

(1,2 eq)

Cul (0.1 eq). DMF(6V) PdlPPhjtjCIj (0.05 eq) TEA (20 eq). 1 hr 110’C

To a solution of ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoate (68.0 g, 177 mmol, 1.00 eq) in THF (408 mL) was added N,N-dimethylprop-2-yn-l-amine (19.1 g, 230 mmol, 24.4 mL, 1.3 eq), Cul (3.37 g, 17.7 mmol, 0.10 eq), Pd(PPh₃)₂C12 (6.21 g, 8.85 mmol, 0.05 eq) and TEA (358 g, 3.54 mol, 493 mL, 20 eq). The reation mixture was stirred at 25 °C for 12 hrs. The reaction was diluted with ethyl acetate, washed twice with saturated ammonium chloride solution and once with brine. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by silica gel chromatography (Petroleum ether: Ethyl acetate=3 : I) to give ethyl 2-(5-(3-(dimethylamino)prop-1 -yn-1 -yl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanoate (20.0 g, 51.8 mmol, 29.2% yield) as a yellow oil.

Step 2: ethyl 2-(5-(3-(dimethyIamino)propyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoate

H₂.Pd/C

EIOH. 50 psi 25’C. 12 hr

To a solution of ethyl 2-(5-(3-(dimethylamino)prop-l-yn-l-yl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)-4-methylpentanoate (20.0 g, 51.8 mmol, 1 eq) in EtOH (200 mL) was added Pd/C (6.00 g, 2.59 mmol, 5% purity, 0.05 <?<?). The mixture was stirred under H2 (50 psi) at 15 C for 24 hr. The reaction mixture was filtered and the filtrate concentrated to give ethyl 2-(5-(3-(dimethylamino)propyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoate (19.7 g, 44.4 mmol, 85.7% yield) as a yellow oil.

Step 3: 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid

LiOH.HjO (2 eq)

THF/HjO (5 VI1V) 20’C, 12 hrs

335

To a solution of ethyl 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoate (19.7 g, 50.4 mmol, 1 eq) in THF (98.0 mL) and H₂O (20.0 mL) was added LiOH.HjO (4.23 g, 101 mmol, 2.00 eq) at 0 °C. The reaction mixture was warmed to 20 °C and stirred at 20 °C for 12 hrs. The reaction mixture was adjusted to pH = 7 with IN aqueous HCl and concentrated under vacuum to give the crude product. The crude product was purified by prep-HPLC (column: Phenomenex luna Cl8 (250*70mm, 10 um); mobile phase: [water (0.05% HC1)-ACN]; B%: 15%-45%, 20 min)to provide 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4-methylpentanoic acid (5.40 g, 13.5 mmol, 26.8% yield, HCl) as a white solid. Ή NMR: 400 MHz D₂O δ: 7.71 (s, 1H), 7.00 (s,lH), 5.40-5.45 (d, J= 20 Hz, 1H), 3.13-3.17 (m, 2H), 2.84 (s, 6H), 2.65-2.67 (m, 2H), 1.95-1.99 (m, 4H), 1.25-1.30 (m, 1H), 0.86 (s, 9H)

Préparation of 2-(5-(2-(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-fluoro4-methyIpentanoic acid

Step 1: 2-fluoro-2-methylpropyl trifluoromethanesulfonate

Tf₂0(1.3eq) 2.6-Lutidine (1.3 eq)

OCM (12 V) 0 °c.1 hr

To a solution of alcohol (100 g, 1.09 mol, 1.00 eq) and 2,6-LUTIDINE (151 g, 1.41 mol, 164 mL, 1.30 eq) in DCM (1.20 L) was added Tf₂O (398 g, 1.41 mol, 233 mL, 1.30 eq) dropwise at 0 °C. The solution was stirred at 0 °C for 1 hr. The reaction mixture was washed with 1 N HCl (2 x 1.00 L) and sat.NaHCOj (2 x 1.00 L). The combined organic layer was dried over Na₂SO4, filtered and concentrated under vacuum (150 mbar, 25 °C) to give 2-fluoro-2-methylpropyl trifluoromethanesulfonate (214 g) as a light yellow oil used without further purification.

Step 2: ethyl 2-((diphenylmethyIene)amino)-4-fIuoro-4-methylpentanoate

(1.16 eq) KOtBu (1.05 eq)

DMF (5 V) 0~25’C. 12.5 hrs

To a solution of KOtBu (97.0 g, 864 mmol, 1.05 eq) in DMF (1.10L) was added ethyl 2((diphenylmethylene)amino)acetate (220 g, 823 mmol, 1.00 eq) at 0 °C. After stirring for 0.5 hr, 2-fluoro2-methylpropyl trifluoromethanesulfonate (214 g, 955 mmol, 1.16 eq) was added. The reaction solution

336 was warmed to 25 °C and stirred for 12 hrs. The reaction was poured into 5% aqueous NH4CI (0.80 L) and extracted with EtOAc (2.00 L and 1.00 L). The combined organic layers were washed with brine, dried over Na^SO-j and concentrated under vacuum to give the crude product. The crude product was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 100:1 - 0:1) to provide ethyl 2-((diphenylmethylene)amino)-4-fluoro-4-methylpentanoate (220 g) as a light yellow oil.

Step 3: 2-amino-4-fluoro-4-methylpentanoic acid

KOH (2.0 eq)

H20(3V) EtOH (6V)

To a solution of ethyl 2-((diphenylmethylene)amino)-4-fluoro-4-methylpentanoate (220 g, 644 mmol, 1.00 eq) in EtOH (1.32 L) was added KOH (72.3 g, 1.29 mol, 2.00 eq) in H₂O (660 mL) at 25 °C. The reaction solution was stirred for 1 hr at 25 °C. The reaction was adjusted to pH=7 with HCl (1 M). The reaction solution was extracted with EtOAc (0.80 L x 2), the combined aqueous phase was concentrated under reduced pressure to give 2-amino-4-fluoro-4-methylpentanoic acid (203 g, 48% purity, HCl) as a white solid used without further purification. 1H NMR 400 MHz CDCh δ: 4.00-4.03 (m, 1H), 2.19-2.23 (m, 2H), 1.43-1.50 (m, 6H).

Step 4: 2-bromo-4-fluoro-4-methylpentanoic acid

NaNO₂(2.0eq) HBf(4.72eq)

HjO (2 V) 0-15’C, 13 hrs

To a solution of 2-amino-4-fluoro-4-methylpentanoic acid (203 g, 1.09 mol, 1.00 eq, HCl) in HBr (4 M, 1.29 L, 40% purity, 4.72 eq) was added dropwise a solution of NaNO₂ (151 g, 2.19 mol, 2.00 eq) in H₂O (608 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hr, warmed to 15 °C and stirred at 15 °C for 12 hrs. The reaction mixture was extracted with MTBE (1.00 L and 500 mL). The organic layers were combined, washed with brine, dried over anhydrous Na₂SO4, filtered and concentrated under vacuum. The residue was dissolved in MTBE (50.0 mL) and concentrated under vacuum to give 2-brotno-4-fluoro-4methylpentanoic acid (127 g) as a yellow oil used without further purification. 1H NMR: 400 MHz CDCh δ: 4.61-4.65 (m, 1H), 4.41-4.44 (m, 1H), 2.70-2.76 (m, 2H), 2.44-2.48 (m, 2H), 1.21-1.48 (m, 6H).

Step 5: ethyl 2-bromo-4-fluoro-4-methylpentanoate

337 ο

VS» SQCI;(1.0eq)

EtOH(5V)

To a solution of 2-bromo-4-fluoro-4-methylpentanoic acid (127 g, 596 mmol, 1.00 eq) in EtOH (520 mL) was added SOC1₂ (70.9 g, 596 mmol, 43.2 mL, 1.00 eq) at 0 °C. The reaction solution was stirred for 2 hrs at 60 °C. The solution was poured into H₂O (400 mL) and extracted with MTBE (500 mL x 2). The combined organic was washed with brine (500 mL), dried over anhydrous Na₂SO4, filtered and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography (SiO₂, petroleum etherzethyl acetate= 100:1 to 10:1) to provide ethyl 2-bromo-4-fluoro4-methylpentanoate (90.0 g) as a yellow oil. 'H NMR: 400 MHz CDCh δ: 4.38-4.42 (m, 1H), 4.21-4.26 (m, 2H), 2.69-2.76 (m, 1H), 2.25-2.26 (m, 1H), 0.85-1.39 (m, 9H).

Step 6: ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-fluoro-4-methylpentanoate

o

(0.6 eq)

K₂COj (2.0 eq) THF (15 V) 25 - 80’C, 12 hrs

To a solution of 5-bromo-4-(trifluoromethyl)pyridin-2-ol (60.0 g, 249 mmol, 1.00 eq) and K₂COj (103 g, 747 mmol, 2.00 eq) in THF (900 mL) was added ethyl 2-bromo-4-fluoro-4-methylpentanoate (151 g, 622 mmol, 2.50 eq) at 0 °C. The mixture was heated to 70 °C and stirred at 70 °C for 12 hrs. The reaction was poured into aqueous NH4CI (1.00 L) at 0 °C and extracted with MBTE (1.00 L and 500 mL). The combined organic layer was washed with brine, dried over Na₂SÛ4 and concentrated under vacuum to give the crude product. The crude product was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 100 : 1 ~ 0 : 1) to give ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)-4-fluoro-4-methylpentanoate (40.0 g, 99.5 mmol) as a white solid. 'H NMR: 400 MHz CDCh δ: 7.66 (s, 1H), 6.94 (s, 1H), 5.48-5.51 (m, 1H), 4.22-4.27 (m, 2H), 2.56-2.65 (m, 1H), 2.30-2.32 (m, 1H), 1.261.59 (m,9H).

Step 6: ethyl 2-(5-allyl-2-oxo-4-(trinuoromethyl)pyridin-l(2H)-yl)-4-fluoro-4-methylpentanoate

j _eq)

Pd(PPh₃)₄ (0.1 eq). DMF (6 V) 25-100°C, 16 hrs

338

To a solution of ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-fluoro-4methylpentanoate (25.0 g, 62.2 mmol, 1.00 eq) and allyltributylstannane (24.5 g, 74.0 mmol, 22.7 mL, 1.10 eq) in DMF (150 mL) was added Pd(PPh₃)₄ (7.18 g, 6.22 mmol, 0.10 eq) in one portion at 25 °C under N2. The mixture was heated to 100 °C and stirred at 100 °C for 12 hrs. The reaction mixture was poured into a solution of KF (10.0 eq) in H2O (200 mL) and ethyl acetate (200 mL). The resulting suspension was stirred at 15 °C for 0.5 hr, filtered and the filtrate was extracted with ethyl acetate (300 mL and 200 mL). The combined organic layer was washed with brine, dried over anhydrous Na₂SO4, filtered and concentrated under vacuum to give the crude product. The crude product was purified by column chromatography (S1O2, petroleum ether: ethyl acetate = 100 : 1 ~ 0 : 1) to afford ethyl 2-(5-allyl2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-fluoro-4-methylpentanoate (19.8 g, 54.5 mmol, 87.7 % yield) as a light yellow oil. Ή NMR: 400 MHz CDCb δ: 7.23 (s, 1H), 6.89 (s, 1H), 5.88-5.93 (m, 1H), 5.45-5.47 (m, 1H), 5.10-5.21 (m, 2H), 4.19-4.26 (m, 2H), 3.29-3.30 (m, 2H), 2.57-2.68 (m, 1H), 2.302.37 (m, 1H), 0.93-1.40 (m, 9H).

Step 7: ethyl 2-(5-(2,3-dihydroxypropyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)-yl)-4-fluoro-4methylpentanoate o OsO₄/H₂O (0 03 eq) O

NalO₄(1.1eq)

L. THF (10 V). Η₂Ο(6 V)

0-25°C, 12hre p_F

To a solution of ethyl 2-(5-allyl-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-fluoro-4-methylpentanoate (19.8 g, 54.5 mmol, 1.00 eq) in THF (198 mL) and H2O (20.0 mL) was added K2OSO4/2H2O (602 mg, 1.64 mmol, 0.03 eq) at 0 °C. Then a solution ofNalCL (11.7 g, 54.5 mmol, 3.02 mL, 1.00 eq) in H2O (100 mL) was added dropwise at 0 °C and the solution stirred at 0 °C for 2 hrs. The solution was warmed to 25 °C and was stirred at 25 °C for 1 hr. The mixture was quenched with a sat.Na₂S2O₃ solution (200 mL) and filtered. The filtrate was extracted with ethyl acetate (500 mL x 2), dried over anhydrous Na₂SC>4, filtered and concentrated under vacuum to give ethyl 2-(5-(2,3-dihydroxypropyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-fluoro-4-methylpentanoate (21.0 g, crude) as a brown oil used without further purification.

Step 8: ethyl 4-fluoro-4-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trinuoromethyl)pyridin-l(2H)yl)pentanoate

NalQ, (1.6 eq)

THF (12 V). H₂0(6V) 0-15’C.4hre

339

To a solution of ethyl 2-(5-(2,3-dihydroxypropyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-fluoro-4methylpentanoate (21.0 g, 52.9 mmol, 1.00 eq) in THF (252 mL) was added a solution of NalO» (17.0 g, 79.3 mmol, 4.39 mL, 1.50 eq) in H2O (100 mL) at 0 °C. The solution was stirred at 0 °C for 2 hrs, warmed to 25 °C and stirred at 25 °C for 2 hrs. The mixture was quenched with a sat. NazSîOj solution (150 mL) and filtered. The filtrate was extracted with ethyl acetate (250 mL x 2) and the combined organic layer washed with 1 N HCl (100 mL) and brine (100 mL), dried over anhydrous Na^SOi and filtered. AcOH (21.0 mL) was added to the filtrate and the solution concentrated under vacuum to give ethyl 4-fluoro-4-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-1 (2H)-yl)pentanoate (21.0 g) as a brown oil used without further purification.

Step 9: ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-fluoro-4methylpentanoate

Me₂NH/HCI(1.5 eq) NaBH(OAc)₃ (2,0 eq)

DCE (32 V) 5-25°C. 12.3 hrs

To a solution of ethyl 4-fluoro-4-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2H)yl)pentanoate (13.3 g, 36.4 mmol, 1.00 eq) in DCE (80.0 mL) was added NaBH(OAc)j (15.4 g, 72.8 mmol, 2.00 eq) and DIEA (9.41 g, 72.8 mmol, 12.7 mL, 2.00 eq) at 25 °C. The solution was stirred at 25 °C for 20 mins, cooled to 5 °C and MezNH/HCl (4.45 g, 54.6 mmol, 1.50 eq) was added.. The reaction solution was warmed to 25 °C and stirred for 12 hrs. The reaction mixture was diluted with H2O (50.0 mL) and was extracted with DCM (100 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuumto give 6-6 (14.9 g, crude) as a brown oil. Compound ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l (2H)-yl)-4-fluoro-4methylpentanoate was used without further purification.

Step 10: 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-fluoro-4methylpentanoic acid

UOH.H3O (3.0 eq) _

THF (5 V). H₂O (1 V) 0-20’C. 12 hrs

To a solution of ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4fluoro-4-methylpentanoate (14.9 g, 37.8 mmol, 1.00 eq) in THF (75.0 mL) and H2O (15.0 mL) was added LiOH.HiO (4.76 g, 113 mmol, 3.00 eq) at 0 °C. The reaction solution was warmed to 20 °C and stirred

340 for 12 hrs. The reaction mixture was adjusted to pH = 7 with 1 N HCl (50.0 mL) and concentrated under vacuum to give the crude product. The crude product was purified by pre-HPLC (column: Agela DuraShell C18 250 * 80 mm * 10 um; mobile phase: [water (10 mM NH₄HCO₃) - ACN]; B%: 5% - 30%, 20min). Then the solution was concentrated under vacuum to give 2-(5-(2-(dimethylamino)ethyl)-2-oxo4-(trifluoromethyl)pyridin-l(2H)-yl)-4-fluoro-4-methylpentanoic acid (2.00 g, 5.35 mmol, 14.2% yield, 98% purity) as a white solid. Ή NMR: 400 MHz D₂O δ: 7.79 (s, 1H), 6.97 (s, 1H), 5.51-5.53 (m, 1H), 3.27-3.31 (m, 2H), 3.00-3.04 (m, 2H), 2.91 (s, 6H), 249-2.58 (m, 2H), 1.34 (t, J= 24.4 Hz, 6H).

methylpentanoate

Préparation of 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trinuoromethyl)pyridin-l(2II)-yl)-4-fluoro-4methylpentanoic acid

Step 1: ethyl 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-fluoro-4ClHHCl 0 -^5e<l> NaBH(0Ac)3 (2.0 eq) DCE (32 V) 25 °C, 12.5 hrs

To a solution of ethyl 4-fluoro-4-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2H)yl)pentanoate (21.0 g, 57.5 mmol, 1.00 eq) in DCE (126 mL) was added NaBH(OAc)₃ (24.4 g, 115 mmol, 2.00 eq) at 25 °C. The solution was stirred at 25 °C for 20 mins, cooled to 5 °C and azetidine-HCl (5.38 g, 57.5 mmol, 1.00 eq) was added. The reaction solution was warmed to 25 °C and stirred for 12 hrs. The reaction mixture was diluted with H₂O (50.0 mL) and was extracted with DCM (100 mL). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to give ethyl 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-fluoro-4methylpentanoate (11.5 g, 25.2 mmol, 43.8% yield) as a brown oil. HNMR: 400 MHz CDC1₃ δ: 7.51 (s, 1H), 6.86 (s, 1H), 5.47-5.50 (m, 1H), 4.14-4.25 (m, 1H), 3.40-3.43 (m, 3H), 2.17-2.76 (m, 6H), 1.25-1.47 (m, 9H).

Step 2: 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-fluoro-4methylpentanoic acid

UOH H;O (3.0 eq)

THF (5 V). HjO (1 V) 0-20°C. 12 hrs

341

To a solution of ethyl 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-fluoro4-methylpentanoate (11.5 g, 28.30 mmol, 1.00 eq) in THF (69.0 mL) and HjO (36.0 mL) was added LÎOH.H2O (4.75 g, 113.19 mmol, 3.00 eq) at 0 °C. The reaction solution was warmed to 20 °C and stirred for 12 hrs. The reaction mixture was adjusted to pH = 7 with 1 N HCl (50.0 mL) and concentrated under vacuum to give the crude product. The crude product was purified by reversed-phase HPLC (0.10 % ΝΗ3Ή2Ο) to give 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-fluoro-4methylpentanoic acid (5.00 g, 12.8 mmol, 45.1% yield) as an off-white solid. 'H NMR: 400 MHz D₃O δ: 7.70 (s, 1H), 6.95 (s, 1H), 5.52 (s, 1H), 3.49-3.53 (m, 4H), 2.83-2.87 (m, 2H), 2.52-2.68 (m, 4H), 2.152.18 (m, 2H), 1.29-1.42 (m, 6H).

Préparation of ethyl 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4fluoro-4-methylpentanoate

Step 1: 2-bromo-4,4-dimethylpentanoic acid

NaNOjfZOeq) HBf(4.72eq)

HjO(2V) 0-1S°C. 13 hrs

A solution of 2-amino-4,4-dimethylpentanoic acid (35.0 g, 241 mmol, 1.00 eq) in HBr (4 M, 284 mL, 40% purity, 4.72 eq) was added dropwise over NaNCh (16.6 g, 241 mmol, 1.00 eq) in H2O (70.0 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hr, warmed to 15 °C and stirred at 15 °C for 12 hrs. The reaction mixture was extracted with MTBE (20.0 mL). The organic layer was washed with brine (20.0 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in MTBE (20.0 mL) and concentrated under reduced pressure to give to give 2-bromo-4,4-dimethylpentanoic acid (31.0 g) as a yellow oil used without further purification. 1H NMR: 400 MHz CDCb δ: 4.28-4.32 (m, 1H), 2.32-2.38 (m, 1H), 1.92-1.97 (m, 1H), 0.95 (s, 9 H).

Step 2: ethyl 2-bromo-4,4-dimethylpentanoate

SOCIj(1.6eq)

EtOH(2V) 0-80 °C, 12 hrs

To a solution of 2-bromo-4,4-dimethylpentanoic acid (31.0 g, 148 mmol, 1.00 eq) in EtOH (62 mL) was added SOCh (28.2 g, 237 mmol, 17.2 mL, 1.60 eq) at 0 °C. The solution was warmed to 80 °C and stirred for 12 hrs. The mixture was concentrated under reduced pressure and the residue was dissolve in MTBE

342 (60 mL) and washed with aqueous NaHCCh (60 mL). The organic layer was washed with brine (100 mL), dried over NaiSCL and concentrated under vacuum to give ethyl 2-bromo-4,4-dimethylpentanoate (29.0 g, crude) as a yellow oil. IH NMR: 400 MHz CDCh δ: 4.20-4.30 (m, 3H), 2.33-2.40 (m, IH), 1.89-1.94 (m, IH), 1.29-1.32(m, 3H), 0.93 (s, 9H).

Step 3: ethyl 2-(5-bromo-2-oxo-4-(trinuoromethyl)pyridin-l(2H)-yl)-4,4-dimethylpentanoate

K₂CO₃ (3.0 eq). THF (15 V) 0-70'C. 36 hrs

To a solution of 5-bromo-4-(trifluoromethyl)pyridin-2-ol (22.0 g, 90.9 mmol, 1.00 eq) and K₂CO₃ (37.7 g, 273mmol, 3.00 eq) in THF (330 mL) was added ethyl 2-bromo-4,4-dimethylpentanoate (28.0 g, 118 mmol, 1.30 eq) at 0 °C. The mixture was heated to 70 °C and stirred for 14 hrs. The reaction was poured into water (400 mL) and extracted with MTBE (400 mL x 2). The combined organic phase was washed with brine (200 mL x 2), dried with anhydrous Na₂SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 3 :1) to give ethyl 2(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4,4-dimethylpentanoate (23.0 g, 57.8 mmol, 63.5% yield) as a yellow oil.

Step 4: ethyl 2-(5-allyl-2-oxo-4-(trinuoromethyl)pyridin-l(2H)-yl)-4,4-dimethylpentanoate

allyllributylstamane ^^SnBu, 8B(1.1eq)

Pd(PPh₃)₄ (0 1 eq). DMF (6 V) 25 -100’C. 16 hrs

To a mixture of ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4,4-dimethylpentanoate (23.0 g, 57.8 mmol, 1.00 eq) and allyltributylstannane (21.0 g, 63.5 mmol, 19.5 mL, 1.10 eq) in DMF (132 mL) was added Pd(PPhj)4 (3.34 g, 2.89 mmol, 0.05 eq) in one portion at 20 °C. The reaction was purged with N₂ (3x) and stirred at 100 °C for 4 hrs under N₂. The reaction was dissolved in water (100 mL) and KF (23.0 g), extracted with MTBE (100 mL),dried with anhydrous Na₂SÛ4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Petroleum ether; Ethyl acetate=3 :1) to give ethyl 2-(5-allyl-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4,4dimethylpentanoate (15.0 g, 41.74 mmol, 72.3% yield) as a yellow oil.

343

Step 5: ethyl 2-(5-(23-dihydroxypropyl)-2-oxo-4-(triiluoromethyl)pyridin-l(2H)-yl)-4,4dimethylpentanoate

K₂OsO₄/H₂O (0.02 eq)

NalO₄(1.1 eq)

THF (10V), H₂0 (6 V) 0-25°C,3hra

To a solution of ethyl 2-(5-allyl-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4,4-dimethylpentanoate (15.0 g, 49.1 mmol, 1.00 eq) in H₂O (15.0 mL) and THF (150 mL) was added K2OSO4.2H2O (362 mg, 982. umol, 0.02 eq) at 0 °C. The solution was stirred at 0 °C for 15 mins. Then a solution of NalCL (11.6 g, 54.0 mmol, 2.99 mL, 1.10 eq) in H2O (15.0 mL) was added dropwise at 0 °C and was stirred for 2 hrs at 0 °C. The reaction was warmed to 25 °C and stirred for 12 hrs. The mixture was quenched with a saturated Na₂SO₃ solution, extracted with EtOAc (200 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to give ethyl 2-(5-(2,3-dihydroxypropyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4,4-dimethylpentanoate (16.9 g, crude) as a yellow oil used without further purification.

Step 6: ethyl 4,4-dimethyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoroniethyl)pyridin-l(2H)-yl)pentanoate

To a solution of ethyl 2-(5-(2,3-dihydroxypropyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4,4dimethylpentanoate (16.9 g, 43.0 mmol, 1.00 eq) in THF (200 mL) was added a solution of NaIO₄ (14.7 g, 68.7 mmol, 3.81 mL, 1.60 eq) in H2O (100 mL) at 0 °C. The solution was stirred at 0 °C for 2 hrs, then warmed to 25 °C and stirred for 2 hrs. The mixture was quenched with a saturated Na₂SO₃solution and extracted with EtOAc (300 mL). The organic layer was washed with 1 N HCl solution and brine, then dried over anhydrous Na₂SO₄, filtered. AcOH was added to the filtrate and concentration under reduced pressure provided ethyl 4,4-dimethyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2H)yl)pentanoate (16.8 g, crude) as a yellow oil used without further purification.

Step 7: ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)-yI)-4,4dimethylpentanoate

MejNH (1.5 eq) NaBH(OAch (2.0 eq)

DCE (32 V) 5-25 “C. 12 hrs

344

To a solution of ethyl 4,4-dimethyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2H)yl)pentanoate (8.40 g, 23.3 mmol, 1.00 eq) in DCE (268 mL) was added Me?NH (2.84 g, 34.9 mmol, 1.50 eq) at 25 °C. The solution was stirred at 25 °C for 15 mins, then NaBH(OAc)j (9.85 g, 46.5 mmol, 2.00 eq) was added portion-wise at 5 °C, and the solution stirred at 25 °C for 12 hrs. The reaction mixture was diluted with H₂O (200 mL) and extracted with DCM (100 mL). The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to give ethyl 2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4,4-dimethylpentanoate (7.30 g, crude) as a brown oil used without further purification.

Step 8: 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)-4,4dimethylpentanoic acid

LiOH.HzO (3 0 eq)

THF (5 V), H₂O (1 V) 0-20 °C. 12 hrs

To a solution of ethyl 2-(5-(2-(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4,4dimethylpentanoate (7.30 g, 18.7 mmol, 1.00 eq) in THF (36.5 mL) and Η₂Ο (7.30 mL) was added L1OH.H2O (1.57 g, 37.4 mmol, 2.00 eq) at 0 °C. The reaction mixture was warmed to 20 °C and stirred for 12 hrs. The reaction mixture was adjusted to pH = 7 with IN aqueous HCl and concentrated under vacuum to give the crude product. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*15um; mobile phase: [water (0.1%TFA)-ACN]; B%: 10%-35%, 20 min). Lyophilization give 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4,4dimethylpentanoic acid (0.51 g, 511 umol, 2.74% yield, HCl) as a yellow solid. 'H NMR: 400 MHz D2O δ: 7.89 (s, 1H), 6.99 (s, 1H), 5.45-5.47 (d, J= 12.0 Hz, 1H), 3.25-3.29 (m, 2H), 2.98-3.03 (m, 1H), 2.92 (s, 6H), 2.18-2.22 (m, 1H), 1.98-2.04 (m, 2H), 0.78 (s, 9H)

Step 1: ethyl 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifiuoromethyl)pyridin-l(2H)-yl)-4,4dimethylpentanoate

l-NHHCI (1.5 eq)

NaBH(OAc)₃ (2.0 eq) DIPEA (2.0 eqJ.OCE (6 V) 5-25’C, 12 hrs

345

To a solution of ethyl 4,4-dimethyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-l(2H)yl)pentanoate (8.40 g, 23.3 mmol, 1.00 eq) in DCE (268 mL) was added azetidine hydrochloride (3.26 g, 34.9 mmol, 1.50 eq) and DIPEA (6.01 g, 46.5 mmol, 8.10 mL, 2.00 eq) at 25 °C. The solution was stirred for 15 mins, then NaBH(OAc)₃ (9.85 g, 46.5 mmol, 2.00 eq) was added portion-wise at 5 °C, and the solution was stirred at 25 °C for 12 hrs. The reaction mixture was diluted with H₂O (200 mL) and extracted with DCM (100 mL). The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to give ethyl 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4,4-dimethylpentanoate (10.9 g, crude) as a yellow oil used without further purification.

Step 2: 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4,4dimethylpentanoic acid

LiOH.H;O (2.0 eq)

THF (5V),H₂O(1 V) 0-20’C, 12 hrs

To a solution of ethyl 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4,4dimethylpentanoate (10.9 g, 27.0 mmol, 1.00 eq) in THF (54.5 mL) and H₂O (10.9 mL) was added LiOH.H₂O (2.27 g, 54.2 mmol, 2.00 eq) at 0 °C. The reaction mixture was warmed to 20 °C and stirred for 12 hrs. The reaction mixture was adjusted to pH = 7 with IN aqueous HCl and concentrated under vacuum to give the crude product. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*15um; mobile phase: [water (0.1%TFA)-ACN]; B%: 10%-35%, 23 min). Lyophilization provided 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4,4dimethylpentanoic acid (0.32 g, 857 umol, 3.16% yield) as a white solid *H NMR: 400 MHz D₂O δ: 7.85 (s, 1H), 6.98 (s, 1H), 5.45 (s, 1H), 4.22 (m, 2H), 4.01-4.05 (m, 2H), 3.34-3.35 (m, 2H), 2.83 (m, 2H), 1.97-2.54 (m, 4H), 0.77 (s, 9H).

Préparation of 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4,4dimethylpcntanoic acid

Step 1: ethyl 2-(5-(3-(dimethylamino)prop-l-yn-l-yl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)4,4-dimethylpentanoate

346

(1.2 eq)

Cul (0.1 eq). DMF (6 V) Pd(PPhjhCI₂ (0.05 eq)

TEA (20 eq), 1 hr 110 °C

Ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4,4-dimethylpentanoate (1.00 g, 2.51 mmol, 1.00 eq), N,N-dimethylprop-2-yn-l-amine (251 mg, 3.01 mmol, 320 uL, 1.20 eq), TEA (5.08 g, 50.2 mmol, 6.99 mL, 20.0 eq), Pd(PPh))₂Cl₂ (88.1 mg, 126 umol, 0.05 eq) and Cul (47.8 mg, 251 umol, 0.10 eq) were added to a micro wave tube in DMF (6 mL). The sealed tube was heated under microwave conditions at 110 °C for 1 hr. The reaction was poured into water and extracted with MTBE (100 mL x 2). The combined organic phase was washed with brine (50 mL x 2), dried with anhydrous Na₂SÛ4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Petroleum cther: Ethyl acetate= 5 :1) to give ethyl 2-(5-(3-(dimethylamino)prop-l-yn-l-yl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4,4-dimethylpentanoate (0.52 g, 1.3 mmol, 52.5% yield) as a yellow oil.

Step 2: ethyl 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)-yl)-4,4dimethylpentanoate

Hj. Pd/C Pd(OH)j

EtOH. 15 psi 80 °C. 0.5 hr

To a solution of ethyl 2-(5-(3-(dimethylamino)prop-l-yn-l-yl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)-4,4-dimethylpentanoate (3.70 g, 9.24 mmol, 1.00 eq) in EtOH (170 mL) was added Pd/C (1.10 g) and Pd(OH)₂ (1.10 g). The mixture was stirred under H₂ (50 psi) at 80 °C for 0.5 hr. The reaction mixture was filtered and concentrated to give ethyl 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4,4-dimethylpentanoate used without further purification.

Step 3: 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4,4dimethylpentanoic acid

LiOH.H₂O (2 eq)

THF/HjO (5 V/ IV) 20 °C. 12hra

To a solution of ethyl 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4,4dimethylpentanoate (3.70 g, 9.15 mmol, 1.00 eq) in THF (18.5 mL) and H₂O (3.70 mL) was added

347

LiOH.FhO (768 mg, 18.3 mmol, 2.00 eq) at 0 °C. The reaction mixture was warmed to 20 °C and stirred for 12 hrs. The reaction mixture was adjusted to pH = 7 with IN aqueous HCl and concentrated under vacuum to give the crude product. The crude product was purified by prep-HPLC (column: Phenomenex luna Cl8 (250*70mm, 15 um); mobile phase: [water(0.05%HCl)-ACN]; B%: 5%-35%, 20 min) to give 2(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4,4-dimethylpentanoic acid (2.2 g, 5.33 mmol, 58.25% yield) as a white solid. 'H NMR: 400 MHz D?O5: 7.83 (s, 1H), 7.00 (s,lH), 5.50-5.52 (m, 1H), 3.15-3.19 (m, 2H), 2.85 (s, 6H), 2.67-2.70 (m, 2H), 2.22-2.26 (m, 1H), 1.98-2.09 (m, 3H), 0.82 (s, 9H).

Example 3: Synthesis of examplary compounds of the invention Prep-HPLC Methods

Crude samples were dissolved in MeOH and purified by prep HPLC using a Gilson 215 instrument, détection wavelength 214 nm:

Prep HPLC A: column: Xtimate Cl8,21.2 * 250 mm, 10 pm; mobile phase: A water (10 mM ammonium hydrogen carbonate), B CH3CN; gradient elution as in text; flow rate: 30 mL/min.

Prep HPLC B: column: Xtimate C18,21.2 * 250 mm, 10 pm; mobile phase: A water (0.1% formic acid), B CH3CN; gradient elution as in text; flow rate: 30 mL/min.

3-1. Préparation of (35)-3-(4,5-difluoro-2’,6’-dimethylbiphenyI-3-yl)-3-(2-(5-(2-(3fluoroazetidin-l-yI)ethyI)-4-methyI-2-oxopyridin-l(2Z/)-yl)-4methylpentanamido)propanoic acid (compounds D-Pl and D-P2)

Step 1: (35)-ethyI 3-(4,5-difluoro-2’,6’-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidinl-yl)ethyl)-4-methyI-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoate

348

A mixture of 2-(5-(2-(3-fluoroazetidin-1 -yl)ethyl)-4-methyl-2-oxopyridin-1 (277)-yl)-4methylpentanoic acid (84 mg, 0.26 mmol), (5)-ethyl 3-amino-3-(4,5-difluoro-2',6'dimethylbiphenyl-3-yl)propanoate (173 mg, 0.52 mmol), TCFH (94 mg, 0.34 mmol), and NMI 5 (0.30 mL, 3.76 mmol) in acetonitrile (5 mL) was stirred at room température for 2 hours. The reaction mixture was poured into 100 mL of EtOAc, washed with water (30 mL), brine (30 mL), dried over NazSOi, filtered and concentrated in vacuo. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18/40 g column (A: water/0.01%TFA, B: MeOH, 0-64%) to provide (35)-ethyl 3-(4,5-difluoro-2^,,6'-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(310 fluoroazetidin-1 -yl)ethyl)-4-methyl-2-oxopyridin-1 (27/)-yl)-4-methylpentanamido)propanoate as a white solid (131 mg). Yield 79% (ESI 640.2 (M+H)⁺).

Step 2: (35)-3-(4,5-dinuoro-2’,6’-dimethyIbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-lyl)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid

(35)-ethyl 3-(4,5-difluoro-2',6'-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-l-yl)ethyl)4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoate (131 mg, 0.20 mmol) was treated with LiOH monohydrate (72 mg, 1.71 mmol) in EtOH (12.5 mL) and H₂O (0.25 mL) at room température for 16 hours. The reaction mixture was acidifîed to pH 4-5 with concentrated

349

HCI. The reaction mixture was concentrated in vacuo and purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products D-Pl (23 mg) and D-P2 (23 mg) as white solids.

D-Pl ESI 612.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.46 (s, 1H), 7.14 (t, J= 8.0 Hz, 1H), 7.07 (t, J= 6.0 Hz, 2H), 6.93 - 6.89 (m, 1H), 6.81 (d, J= 5.5 Hz, 1H), 6.27 (s, 1H), 5.59 - 5.54 (m, 2H), 5.28 - 5.12 (m, 1H), 4.07 - 3.94 (m, 2H), 3.74 - 3.60 (m, 2H), 3.05 - 2.99 (m, 2H), 2.79 - 2.69 (m,2H), 2.65-2.59 (m, 2H), 2.20 (s, 3H), 1.99 (s, 3H), 1.92 (t, J= 7.0 Hz, 2H), 1.85 (s, 3H), 1.44 - 1.36 (m, IH), 0.93 (d, J= 6.5 Hz, 3H), 0.90 (d, J= 6.5 Hz, 3H).

D-P2 ESI 612.2 (M+H)⁺.*H NMR (500 MHz, MeOD) δ 7.46 (s, 1H), 7.14 (t, J= 8.0 Hz, 1H), 7.07 (t, J= 6.0 Hz, 2H), 6.93 - 6.89 (m, 1H), 6.81 (d, J= 5.5 Hz, 1H), 6.27 (s, 1H), 5.59 - 5.54 (m, 2H), 5.28 - 5.12 (m, 1H), 4.07 - 3.94 (m, 2H), 3.75 - 3.60 (m, 2H), 3.06 - 2.98 (m, 2H), 2.79 - 2.69 (m, 2H), 2.65 - 2.59 (m, 2H), 2.20 (s, 3H), 1.99 (s, 3H), 1.92 (t, J= 7.0 Hz, 2H), 1.85 (s, 3H), 1.44 - 1.36 (m, 1H), 0.93 (d, J= 6.5 Hz, 3H), 0.90 (d, J= 6.5 Hz, 3H).

3-2. Préparation of (3S)-3-(3-cyclopropyl-2-(5-(2-(3-fluoroazetidin-l-y))ethyl)-2oxopyridin-l(2jF7)-yl)propanamido)-3-(4,5-difluoro-2',6’-dimethyl-|l,r-biphenyl]-3yl)propanoic acid (compounds E-Pl and E-P2)

Step 1: ethyl (3S)-3-(3-cyclopropyl-2-(5-(2-(3-fluoroazetidin-l-yI)ethyI)-2-oxopyridin-l(2fl) yl)propanamido)-3-(4,5-difluoro-2’,6’-dimethyl-[l,l'-biphenyI]-3-yl)propanoate

A mixture of ethyl (S>3-amino-3-(4,5-difluoro-2',6'-dimethyl-[l,r-biphenyl]-3-yl)propanoatc (90 mg, 0.27 mmol), 3-cyclopropyl-2-(5-(2-(3-fiuoroazetidin-l-yI)ethyl)-2-oxopyridin-l(2//)yl)propanoic acid (125 mg, 0.40 mmol), HOBT (73 mg, 0.54 mmol), EDCI (104 mg, 0.54 mmol) and TEA (120 mg, 0.81 mmol) in DMF (2 mL) was stirred at 50 °C for 4 hours. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a Cl8 / 40 g column

350 (A: water 10 mM NHîHCOj.B: MeOH, 0-100%) to provide ethyl (3S)-3-(3-cyclopropyl-2-(5(2-(3-fluoroazetidin-1 -yl)ethyl)-2-oxopyridin-1 (2//)-yl)propanamido)-3-(4,5-difluoro-2',6’dimethyl-[l,r-biphenyl]-3-yl)propanoate as a yellow oil (60 mg). Yield 35% (ESI 624.2 (M+H)⁺).

Step 2: (3S)-3-(3-cycIopropyl-2-(5-(2-(3-fluoroazetidin-l-yI)ethyl)-2-oxopyridin-l(2//)yl)propanamido)-3-(4,5-difIuoro-2’,6'-dimethyI-[l,l^,-biphenyl]-3-yl)propanoic acid

Ethyl (3S)-3-(3-cyclopropyl-2-(5-(2-(3-fluoroazetidin-1 -yl)ethyl)-2-oxopyridin-1 (2//)yl)propanamido)-3-(4,5-difluoro-2',6'-dimethyl-[l,r-biphenyl]-3-yl)propanoate (50 mg, 0.08 mmol) was treated with LiOH-HîO (13 mg, 0.32 mmol) in MeOH (2 mL) and H₂O (0.5 mL) at room température for 1 hour. The reaction mixture was acidified to pH 4-5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products E-Pl (1 mg) and E-P2 (1 mg) as white solids.

E-Pl ESI 596.2(M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.47 (s, IH), 7.33 (d, J= Ί2 Hz, 1H), 7.07 - 6.99 (m, 3H), 6.88 - 6.80 (m, 1H), 6.71 -6.70 (m, 1H), 6.34 (d, 9.2 Hz, 1H), 5.45 (s,

2H), 5.19 - 5.03 (m, 1H), 3.96 - 3.84 (m, 2H), 3.57 (s, 2H), 2.97 - 2.96 (m, 2H), 2.67 (s, 2H), 2.50 (s, 2H), 1.91 (s, 5H), 1.79 (s, 3H), 0.55 (s, 1H), 0.35 - 0.34 (m, 2H), 0.07 - 0.00 (m, 2H).

E-P2 ESI 596.2(M+H)⁺. ‘H NMR (500 MHz, MeOD) δ 7.49 (s, 1H), 7.41 (d, J= 9.0 Hz, 1H), 7.15 - 6.84 (m, 5H), 6.50 (d, J= 9.3 Hz, 1H), 5.57- 5.44 (m, 2H), 5.19- 5.07 (m, 1H), 3.95 3.59 (m, 3H), 2.99 (s, 2H), 2.59 - 2.54 (m, 4H), 2.15 - 2.12 (m, 1H), 1.99 - 1.95 (m, 8H), 0.52 0.47 (m, 1H), 0.25 - 0.23 (m, 2H), 0.01 - 0.05 (m, 2H).

3-3. Préparation of (35)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2Z0-yl)-3-methylbutanamido)-3-(4-fluoro-2’,4’,5,6’tetramethylbiphenyl-3-yl)propanoic acid (compounds F-Pl and F-P2)

351

Step 1: (35)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(227)yI)-3-methylbutanamido)-3-(4-fluoro-2',4’,5,6’-tetramethylbiphenyl-3-yl)propanoate

A mixture of 2-(5 -(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (277)-yl)-3methylbutanoic acid (150 mg, 0.45 mmol), (5)-ethyl 3-amino-3-(4-fluoro-2',4^,,5,6'tetramethylbiphenyl-3-yl)propanoate (154 mg, 0.45 mmol), HATU (205 mg, 0.54 mmol) and DIEA (175 mg, 1.35 mmol) in DCM (5 mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH 4: 1) to provide (3S)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2/f)-yl)-3-mcthylbutanamido)-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoate as a brown oil (100 mg). Yield 33% (ESI 660.3 (M+H)⁺).

Step 2: (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(27/)-yI)-3methylbutanamido)-3-(4-fluoro-2’,4’,5,6’-tetramethylbiphcnyl-3-yl)propanoic acid

(3S)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (277)-y l)-3 methylbutanamido)-3-(4-fluoro-2',4',5,6’-tetramethylbiphenyl-3-yl)propanoate (100 mg, 0.15 mmol) was treated with L1OH-H2O (32 mg, 0.75 mmol) in MeOH (3 mL) and H2O (1 mL) at room température for 3 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products F-Pl (30.0 mg) and F-P2 (32.0 mg) as white solids.

F-Pl ESI 632.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.95 (s, 1H), 6.89 (s, 1H), 6.84 - 6.76 (m, 3H), 6.67 (s, 1H), 5.65 - 5.54 (m, 1H), 5.26 (d, J= 11.3 Hz, IH), 3.06- 2.85 (m, 4H), 2.80

352

2.63 (m, 8H), 2.53 - 2.38 (m, 1H), 2.34 - 2.23 (m, 6H), 1.95 (s, 3H), 1.63 (s, 3H), 1.17 (d, J= 6.5 Hz, 3H), 0.80 (d, J= 6.5 Hz, 3H).

F-P2 ESI 632.2 (M+H)⁺. >H NMR (400 MHz, MeOD) δ 8.11 - 7.95 (m, 1H), 7.02 - 6.83 (m, 5H), 5.76 (s, 1H), 5.24 (d, J= 10.9 Hz, 1H), 3.27 - 2.90 (m, 4H), 2.81 (d, J= 3.7 Hz, 6H), 2.66 2.36 (m, 3H), 2.31 (d, J= 5.7 Hz, 6H), 1.95 (t, J= 5.8 Hz, 6H), 0.95 (s, 3H), 0.82 - 0.66 (m, 3H).

3-4. Préparation of (3S)-3-(2-(5-(2-(azetidin-l-yI)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2Z/)-yl)-4-methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3yi)propanoic acid (compounds G-Pl and G-P2)

Step 1: (3S)-ethyI 3-(2-(5-(2-(azetidin-l-yl)cthyl)-2-oxo-4-(trifluoronicthyl)pyridin-l(2//)yl)-4-methylpentanamido)-3-(4-fluoro-2’,6’-dimethyl-5-(trifluoromethyl)biphenyl-3yl)propanoate

A mixture of 2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (27/)-yl)-4 methylpentanoic acid (150 mg, 0.42 mmol), (S)-ethyl 3-amino-3-(4-fluoro-2',6’-dimethyl-5(trifluoromethyl)biphenyl-3-yl)propanoate (161 mg, 0.42 mmol), TCFH (235 mg, 0.84 mmol), and NMI (138 mg, 1.68 mmol) in acetonitrile (4 mL) was stirred at room température for 2 hours. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NH-iHCOj.B: MeOH, 0-100%) toprovide (3S)-ethyl 3-(2(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4-methylpentanamido)-3(4-fluoro-2^,,6'-dimethyl-5-(trifIuoromethyl)biphenyl-3-yl)propanoate as colorless oil (155 mg). Yield 51% (ESI 726.1 (M+H)⁺).

353

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyi)pyridin-l(2Z0-yl)-4 mcthyIpentanamido)-3-(4-fluoro-2',6^,-dimethyI-5-(trifluoromethyl)biphenyI-3-yl)propanoic

(3S)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methyIpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate (155 mg, 0.21 mmol) was treated with LiOH monohydrate (35 mg, 0.84 mmol) in MeOH (4 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The mixture was concentrated in vacuo and the residue was purified by prepHPLC A (30-65% MeCN) to give the diastereomeric products G-Pl (37.8 mg) and G-P2 (49.6 mg) as white solids.

G-Pl ESI 698.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.85 (s, 1H), 7.41 (d, J= 5.0 Hz, 1H), 7.36-7.27 (m, 1H), 7.21 - 7.09 (m, 3H), 6.74 (s, 1H), 5.71 - 5.54 (m, 2H), 4.04 (t, J= 8.1 Hz, 4H), 3.29 (t, J= 6.7 Hz, 2H), 2.86-2.82 (m, 2H), 2.78 -2.68 (m, 2H), 2.50 - 2.36 (m, 2H), 2.08 1.93 (m, 5H), 1.86 (s, 3H), 1.44 - 1.41 (m, 1H), 1.13 - 0.79 (m, 6H).

G-P2 ESI 698.2 (M+H)+. Ή NMR (400 MHz, MeOD) δ 7.76 (s, 1H), 7.50 - 7.44 (m, 1H), 7.41 -7.33 (m, 1H), 7.22-7.18 (m, 1H), 7.14 (d, J = 7.4 Hz, 2H), 6.90 (s, 1H), 5.813-5.80 (m, 1H), 5.64 (t, J= Ί.Ί Hz, 1H), 4.13 (t, J= 8.0 Hz, 4H), 3.55 - 3.34 (m, 2H), 2.99-2.88 (m, 1H), 2.85 -2.81 (m, 1H), 2.71-2.66 (m, 1H), 2.60-2.54 (m, 1H), 2.53-2.43 (m, 2H), 2.07-1.93 (m, 7H), 1.76 - 1.61 (m, 1H), 1.42 - 1.37 (m, 1H), 0.95 - 0.83 (m, 6H).

3-5. Préparation of ((3S)-3-(2-(3-(difluoromethyl)-5-(2-(dimethyIammo)ethyI)-2oxopyridin-l(2//)-yl)-4-methyIpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r biphenyll-3-yl)propanoic acid (compounds H-Pl and H-P2)

354

Step 1: ethyl (3S)-3-(2-(3-(difluoromethyI)-5-(2-(dimethylaniino)ethyl)-2-oxopyridin-l(2//)yl)-4-methyIpentanamido)-3-(4-fluoro-2’,4’,5,6*-tetramethyl-[l,l’-biphenyl]-3yl)propanoate

A mixture of ethyl (S)-3-amino-3-(4-fluoro-2',4’,5,6’-tetramethyl-[ 1,1 '-biphenyl]-3-yl)propanoate hydrochloride (120 mg, 0.35 mmol), 2-(3-(difluoromethyI)-5-(2-(dimethylamino)ethyl)-2oxopyridin-l(2//)-yl)-4-methylpentanoic acid (138 mg, 0.42 mmol), TCFH (147 mg, 0.52 mmol) and NMI (86 mg, 1.05 mmol) in acetonitrile (5 mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM:MeOH 4:1) to provide ethyl (3S)-3-(2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2oxopyridin-1 (2//)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4’,5,6'-tetramethyl-[ 1,1 '-biphenyl]-3yl)propanoate as a brown solid (150 mg). Yield 65.2% (ESI 656.2 (M+H)⁺).

Step 2: (3S)-3-(2-(3-(difluoromethyl)-5-(2-(dimethyIainino)ethyl)-2-oxopyridin-l(2ZZ)-yl)-4methylpentanamido)-3-(4-fluoro-2’,4’,5,6’-tetramethyl-[l,l’-bipheny)]-3-yI)propanoic acid

Ethyl (35)-3-(2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1 (277)-yl)-4methylpentanamido)-3-(4-fluoro-2',4’,5,6’-tetramethyl-[ 1,1 '-biphenyl]-3-yl)propanoate ( 150 mg, 0.23 mmol) was treated with LiOH-H₂O (95.5mg, 2.3 mmol) in THF (3 mL) and H₂O (1 mL) at room température for 3 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The

355 solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-70% MeCN) to give the diastereomeric products H-Pl (24.0 mg) and H-P2 (33.0 mg) as white solids.

H-Pl ESI 628.3 (M+H)⁺. ’H NMR (400 MHz, MeOD) δ 7.71 (s, 2H), 6.78 (s, 2H), 6.76 - 6.62 (m, 2H), 6.42 (t, 7= 55.1 Hz, 1H), 5.49 - 5.45 (m, 1H), 5.30 (t, J= 5.7 Hz, 1H), 3.20 - 3.10 (m, 1H), 3.09 - 3.02 (m, 1H), 2.83 - 2.70 (m, 2H), 2.61 (s, 6H), 2.58 - 2.50 (m, 1H), 2.48 - 2.39 (m, IH), 2.22-2.10 (m, 6H), 1.94- 1.84 (m, 2H), 1.83 (s, 3H), 1.73 (s, 3H), 1.36- 1.29 (m, 1H), 0.89-0.78 (m, 6H).

H-P2 ESI 628.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.70 (s, 2H), 6.79 - 6.71 (m, 4H), 6.49 (t, 7=55.1 Hz, 1H), 5.50-5.45 (m, 2H), 3.30-3.23 (m, 1H), 3.18-3.13 (m, 1H), 2.85-2.74 (m, 2H), 2.70 (s, 6H), 2.54 - 2.43 (m, 1H), 2.39 - 2.29 (m, 1H), 2.18 (s, 6H), 1.93 - 1.85 (m, 1 H), 1.83 (d, J =5.9 Hz, 6H), 1.76 - 1.62 (m, 1 H), 1.33 - 1.30 (m, 1 H), 0.80 - 0.77 (m, 6H).

3-6. Préparation of (33)-3-(4,4’-difluoro-2’,5,6’-trimethyI-Il,r-biphenyI]-3-yI)-3-(2-(3(difluoromethyl)-5-(2-(dimethyIamino)ethy))-2-oxopyridin-l(2Z0-yl)-4methylpentanamido)propanoic acid (compounds I-Pl and I-P2)

Step 1: ethyl (33)-3-(4,4’-difluoro-2·,5,6'-trimethyI-|l,r-biphenyl|-3-yI)-3-(2-(3(difluoromethyl)-5-(2-(dimethylaniino)ethyl)-2-oxopyridin-l(2Z7)-yl)-4methylpentanamido)propanoate

A mixture of 2-(3-(difluoromethyI)-5-(2-(dimethylamino)ethyI)-2-oxopyridin-1 (2H)-yl)-4methylpentanoic acid (120 mg, 0.39 mmol), ethyl (5)-3-amino-3-(4,4'-difiuoro-2^,,5,6'-trimethyl[l,l'-biphenyl]-3-yl)propanoate hydrochloride (120 mg, 0.36 mmol), TCFH (120 mg, 0.54 mmol), and NMI (75 mg, 1.08 mmol) in acetonitrile (5 mL) was stirred at room température for 20 hours. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC

356 on a C18 / 40 g column (A: water 10 mM NHiHCOj.B: MeOH, 0~100%) to provide ethyl (35)3-(4,4'-difluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)-3-(2-(3-(difluoromethyl)-5-(2(dimethylamino)ethyl)-2-oxopyridin-l(2//)-yI)-4-methylpentanamido)propanoate as brown solid (150 mg). Yield 63.2% (ESI 660.3 (M+H)⁺).

Step 2: (35)-3-(4,4'-difluoro-2',5,6'-trimcthyl-[l,l'-biphenyl]-3-yl)-3-(2-(3-(difluoromethyl)5-(2-(dimethylamino)ethyl)-2-oxopyridin-l(2Z0-yl)-4-methy)pentanamido)propanoic acid

Ethyl (35)-3-(4,4’-difluoro-2',5,6'-trimethyI-[l, r-biphenyl]-3-yl)-3-(2-(3-(difluoromethyl)-5-(2(dimethyIamino)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoate (150 mg, 0.23 mmol) was treated with LiOH monohydrate (100 mg, 2.3 mmol) in EtOH (6 mL) and H₂O (0.8 mL) at 36°C for 1 hour. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to provide the diastereomeric products I-Pl (20 mg) and I-P2 (22 mg) as white solids.

I-Pl ESI 632.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.72 (s, 2H), 6.74 - 6.67 (m, 4H), 6.46 (t, J= 55.2 Hz, 1H), 5.48-5.44 (m, 1H), 5.33-5.30 (m, 1H), 3.20-3.16 (m, 1H), 3.12-3.04 (m, 1H), 2.84 - 2.73 (m, 2H), 2.65 (s, 6H), 2.59 - 2.42 (m, 2H), 2.17 (s, 3H), 1.95 - 1.83 (m, 5H), 1.78 (s, 3H), 1.39 - 1.29 (m, 1H), 0.85 - 0.75 (m, 6H).

I-P2 ESI 632.2 (M+H)⁺. ’H NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 7.81 (s, IH), 6.90 - 6.78 (m, 4H), 6.65 (t, J= 55.2 Hz, 1H), 5.63 - 5.57 (m, 2H), 3.48 - 3.38 (m, 1H), 3.32 - 3.23 (m, 1H), 3.02 - 2.87 (m, 2H), 2.83 (s, 6H), 2.67 - 2.54 (m, 1H), 2.50 - 2.41 (m, 1H), 2.32 (d, J= 1.6 Hz, 3H), 2.07-2.01 (m, 1H), 2.00 (d, J= 6.2 Hz, 6H), 1.88 - 1.76 (m, 1H), 1.50- 1.39 (m, 1H), 0.96-0.86 (m, 6H).

3-7. Préparation of (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2H)yI)-5-methylhexanamido)-3-(4-fluoro-2',5,6’-trimethylbiphenyI-3-yl)propanoic acid (compounds J-Pl and J-P2)

357

Step 1: (3S)-ethyl 3-(2-(5-(2-(dimethyIamino)ethyl)-4-methyI-2-oxopyridin-l(2//)-yl)-5methylhexanamido)-3-(4-fluoro-2’,5,6’-trimethylbiphenyl-3-yI)propanoate

O

A mixture of 2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1 (2//)-yl)-5-methylhexanoic 5 acid (150 mg, 0.49 mmol), (S)-ethyl 3-amino-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3yl)propanoate (161 mg, 0.49 mmol), TCFH (274 mg, 0.98 mmol), and NMI (201 mg, 2.45 mmol) in acetonitrile (5 mL) was stirred at room température for 2 hours. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NfLHCCh.B: MeOH, 0-100%) to provide (3S)-cthyl 3-(2-(5-(210 (dimethylamino)ethyl)-4-methyl-2-oxopyridin-1 (27/)-yl)-5-methylhexanamido)-3-(4-fluoro2',5,6’-trimethylbiphenyl-3-yl)propanoate as colorless oil (170 mg). Yield 56% (ESI 620.2 (M+H)⁺).

Step 2: (3S)-3-(2-(5-(2-(dimethyIamino)ethyI)-4-methyI-2-oxopyridin-l(2Z/)-y0-515 methylhexanamido)-3-(4-fluoro-2’,5,6’-trimethyIbiphenyl-3-yI)propanoic acid

(3S)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(27/)-yl)-5methylhexanamido)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propanoate (170 mg, 0.27 mmol)

358 was treated with LiOH monohydrate (57 mg, 1.35 mmol) in MeOH (4 mL) and H2O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The reaction mixture was concentrated in vacuo and purified by prep-HPLC A (30-60% MeCN) to provide the diastereomeric products J-Pl (50 mg) and J-P2 (60.4 mg) as white solids.

J-Pl ESI 592.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.57 (s, 1 H), 7.17 -7.10 (m, 1H), 7.07 (d,J=8.1 Hz, 2H), 6.87-6.82 (m,2H), 6.33 (s, 1H), 5.49 (t,J=5.7Hz, 1H), 5.39 (s, 1H),3.26 - 3.05 (m, 2H), 2.88 (d, J= 7.9 Hz, 2H), 2.82 - 2.69 (m, 6H), 2.69 - 2.58 (m, 2H), 2.26 (t, J= 15.5 Hz, 6H), 2.22-2.10 (m, 1H), 1.97 (d,J= 16.6 Hz,4H), 1.91 (s,3H), 1.60- 1.53 (m, 1H), 1.29-1.14 (m, 1H), 1.09- 1.04 (m, 1H), 0.89-0.87 (m, 6H).

J-P2 ESI 592.3 (M+H)+. Ή NMR (400 MHz, MeOD) δ 7.55 (s, 1H), 7.15-7.07 (m, 3H), 6.91 (d,J=6.9 Hz, 2H), 6.43 (s, 1H), 5.67-5.64 (m, 1H), 5.42 (t,J= 7.7 Hz, 1H), 3.31-3.25 (m, 1H), 3.25-3.14 (m, 1H), 2.99-2.88 (m,2H), 2.86 (d,J= 17.8 Hz, 6H), 2.65-2.60 (m, 1H), 2.51-2.45 (m, 1H), 2.38-2.19 (m, 6H), 2.19-2.06 (m, lH),2.00(s, 6H), 1.86- 1.77 (m, 1H), 1.57-1.50 (m, 1H), 1.17-1.09 (m, 1H), 1.07-1.01 (m, 1H), 0.84 (t, J = 6.4Hz, 6H).

3-8. Préparation of (3S)-3-(2-(5-(2-(dimcthylamino)ethyl)-3-fluoro-2-oxopyridin-l(277)yI)-4-methylpentanamido)-3-(4-fluoro-2’,6’-dimethyl-5-(trifluoromethyI)biphenyl-3yl)propanoic acid (compounds K-Pl and K-P2)

Step 1: (3S)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-l(2.H)-yl)-4methylpentanamido)-3-(4-fluoro-2’,6’-dimethyl-5-(trifluoromethyl)biphenyl-3yl)propanoate

359

A mixture of 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1 (2//)-yl)-4-methylpentanoic acid (130 mg, 0.44 mmol), (5)-ethyl 3-amino-3-(4-fluoro-2’,6'-dimethyl-5(trifluoromethyl)biphenyl-3-yl)propanoate (169 mg, 0.44 mmol), TCFH (246 mg, 0.88 mmol), and NMI (144 mg, 1.76 mmol) in acetonitrile (4 mL) was stirred at room température for 2 hours. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NHîHCOj.B: MeOH, 0-100%) to provide (3S)-ethyl 3-(2(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-l(2//)-yl)-4-methylpentanamido)-3-(4fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate as yellow oil (150 mg). Yield 51% (ESI 664.2 (M+H)⁺).

Step 2: (35)-3-(2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-l(277)-yl)-4methylpentanamido)-3-(4-fluoro-2’,6’-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid

(3S)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-l(277)-yl)-4methylpentanamido)-3-(4-fluoro-2’,6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate (150 mg, 0.23 mmol) was treated with LiOH monohydrate (39 mg, 0.92 mmol) in MeOH (4 mL) and H₂O (1 mL) at 36°C for 2 hours. The reaction mixture was acidified to pH 4-5 with IN HCl. The reaction mixture was concentrated in vacuo and purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products K-Pl (41 mg) and K-P2 (46.8 mg) as white solids.

K-Pl ESI 636.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.53 (s, IH), 7.47 - 7.44 (m, IH), 7.33 - 7.28 (m, 2H), 7.23 - 7.17 (m, IH), 7.16 - 7.08 (m, 2H), 5.65 - 5.61 (m, IH), 5.46 (t, J= 5.7 Hz, IH), 3.38 (d, 7.8 Hz, IH), 3.24 - 3.17 (m, IH), 2.95 - 2.84 (m, 2H), 2.82 - 2.64 (m, 7H),

2.60-2.54 (m, IH), 2.08 - 1.97 (m, 5H), 1.94 (s, 3H), 1.43 (s, IH), 0.96 - 0.9l(m, 6H).

K-P2 ESI 636.2 (M+H)+. Ή NMR (400 MHz, MeOD) δ 7.38 (s, IH), 7.33 - 7.28 (m, 2H), 7.24 (d, J= 6.3 Hz, IH), 7.12 - 6.99 (m, 3H), 5.55 - 5.49 (m, 2H), 3.36 - 3.25 (m, IH), 3.18 - 3.12

360 (m, 1H), 2.91-2.79 (m, 1H), 2.73 (d, J= 11.7 Hz, 7H), 2.52 - 2.48 (m, 1 H), 2.39-2.32 (m, 1 H), 2.00-1.79 (m, 7H), 1.75 - 1.68 (m, 1 H), 1.29 - 1.24 (m, 1 H), 0.81 - 0.78 (m, 6H).

3-9. Préparation of (35)-3-(4,5-difluoro-2’,6’-dimethyl-(l,l’-biphenylj-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yl)-4methylpentanamido)propanoic acid (compounds L-Pl and L-P2)

Step 1: ethyl (35)-3-(4,5-difluoro-2^,,6’-dimethyl-[l,l’-biphenylj-3-y))-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2Z/)-yl)-4methylpentanamido)propanoate

A mixture of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanoic acid (100 mg, 0.29 mmol), ethyl (5)-3-amino-3-(4,5-difluoro-2',6'-dimethyl[l,l'-biphenyl]-3-yl)propanoate (96 mg, 0.29 mmol), TCFH (100 mg, 0.34 mmol) and NMI (96.0 mg, 1.14 mmol) in CH₃CN (3 mL) was stirred at room température for 1.5 hours. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a Cl8 / 40 g column (A: water 10 mMNH₄HCO₃.B: MeOH, 0-100%) to provide ethyl (35)-3-(4,5-difluoro-2’,6’dimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanamido)propanoate as a yellow solid (131 mg). Yield 68.1% (ESI 664.2 [M+H]⁺).

Step 2: (35)-3-(4,5-difluoro-2’,6’-dimethyl-[l,l’-biphenyll-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Æ)-yl)-4methylpentanamido)propanoic acid

361

Ethyl (35)-3-(4,5-difluoro-2',6'-dimethyl-[ 1,1 -biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanamido)propanoate (131.0 mg, 0.19 mmol) was treated with LiOH-IhO (100.0 mg, 2.38 mmol) in THF (2 mL) and water (0.5 mL) at 30°C for 1 hour. The reaction mixture was acidifîed to pH 4~5 with 2N HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric product L-Pl (11.1 mg) and L-P2 (19.0 mg) as white solids.

L-Pl ESI 636.1 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.77 (s, 1H), 7.05 - 6.92 (m, 3H), 6.83 6.76 (m, 2H), 6.63 (s, 1H), 5.58 - 5.45 (m, 2H), 3.03 - 2.96 (m, 2H), 2.84- 2.81 (m, 2H), 2.65 (s, 6H), 2.62 - 2.60 (m, 2H), 1.92 - 1.79 (m, 5H), 1.72 (s, 3H), 1.33 - 1.30 (m, 1 H), 0.86 - 0.81 (m, 6H).

L-P2 ESI 636.1 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.72 (s, 1H), 7.07 - 6.97 (m, 3H), 6.90 - 6.80 (m, 3H), 6.77 (s, 1H), 5.63 - 5.59 (m, 1H), 5.49 (t, J= 7.6 Hz, 1H), 3.22 - 3.08(m, 2H), 2.88 (t, J = 6.9 Hz, 2H), 2.72 (s, 6H), 2.58-2.38 (m, 2H), 1.92 - 1.83 (m, 7H), 1.64 - 1.56 (m, 1H), 1.33 - 1.24 (m, 1H), 0.77 (d, J= 6.5 Hz, 6H).

3-10. Préparation of (3S)-3-(4,4’-difluoro-2’,6’-dimethyl-5-(trifluoromethyl)-Jl,rbiphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-3-methyl-2-oxopyridin-l(2H)-yl)-4methylpentanamido)propanoic acid (compounds M-Pl and M-P2)

Step 1: ethyl (35)-3-(4,4'-difluoro-2',6'-dimcthyI-5-(trifluoromethyl)-[l,r-biphcnyl]-3-yl)-3(2-(5-(2-(dimethyIamino)ethyl)-3-methyl-2-oxopyridin-l(2ZZ)-yl)-4methylpentanamido)propanoate

362

A mixture of 2-(5-(2-(dimethylamino)ethyl)-3-methyl-2-oxopyridin-1 (2Z7)-yl)-4methylpentanoic acid (160 mg, 0.54 mmol), ethyl (S)-3-amino-3-(4,4'-difluoro-2',6'-dimethyl-5(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (260 mg, 0.64 mmol), TCFH (226 mg, 0.81 mmol), NMI (221.4 mg, 2.7 mmol) and CHîCN (5 mL) was stirred at room température for 1 hour. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NHiHCCh.B: MeOH, 0~100%) to provide ethyl (35)-3(4,4'-difluoro-2',6'-dimethyl-5-(trifluoroinethyl)-[ 1,1 '-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-3-methyl-2-oxopyridin-1 (277)-yl)-4-methylpentanamido)propanoate as a colorless oil (180 mg). Yield 50% (ESI 678.3 (M+H)⁺).

Step 2: (35)-3-(4,4'-difluoro-2’,6’-dimethyI-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)-3-(2-(5(2-(dinietliylamino)ethyl)-3-methyl-2-oxopyridin-l(2//)-yl)-4methylpentanamido)propanoic acid

Ethyl (35)-3-(4,4’-difluoro-2',6’-dimethyl-5-(trifluoromethyl)-[ 1,1 ’-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-3-methyl-2-oxopyridin- l(2//)-yl)-4-methylpentanamido)propanoate ( 180 mg, 0.26 mmol) was treated with L1OH-H2O (39 mg, 0.92 mmol) in EtOH (3 mL) and H₂O (1 mL) at room température for 1 hour. The reaction mixture was acidified to pH 4~5 with IN HCl.

353

The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products M-Pl (50 mg) and M-P2 (53.0 mg) as white solids.

M-Pl ESI 650.3 (M+H)⁺. «H NMR (400 MHz, MeOD) δ 7.52 (s, 1H), 7.39 (s, 1H), 7.33 - 7.18 (m, 2H), 6.88 (d, J= 9.6 Hz, 2H), 5.56 - 5.47 (m, 2H), 3.28 - 3.17 (m, 2H), 2.84 - 2.69 (m, 9H), 2.63-2.57(m, 1 H),2.06- 1.92(m, 8H), 1.86(s, 3H), 1.48- 1.38 (m, IH), 0.95-0.90(m, 6H).

M-P2 ESI 650.3 (M+H)⁺. ‘H NMR (400 MHz, MeOD) δ 7.56 (s, 1H), 7.43 (s, 1H), 7.38 - 7.22 (m, 2H), 6.92 - 6.87 (m, 2H), 5.65 - 5.54 (m, 2H), 3.46 - 3.39 (m, 1H), 3.29 - 3.24 (m, 1H), 2.97 - 2.75 (m, 8H), 2.67 - 2.61 (m, 1 H), 2.51 - 2.45 (m, 1 H), 2.05 - 1.90 (m, 11 H), 1.45 - 1.38 (m, 1H), 0.94-0.88 (m, 6H).

3-11. Préparation of (35)-3-(2-(5-(2-(dimethyIamino)ethyl)-3-fIuoro-2-oxo-4(trifluoromethyI)pyridin-l(2Z0-yI)-4-methyIpentanamido)-3-(4-fIuoro-4’-methoxy-2’,5,6’trimcthyi-(l,l’-biphenylJ-3-yI)propanoic acid (compounds P-Pl and P-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxo-4(trifluoromethyI)pyridin-l(2£0-yl)-4-niethyIpentanamido)-3-(4-fluoro-4’-methoxy-2^,,5,6’trimethyl-[l,r-biphenyI]-3-yI)propanoate

A mixture of ethyl (S)-3-amino-3-(4-fluoro-4'-methoxy-2',5,6'-trimethyl-[l,r-biphenyl]-3yl)propanoate (220 mg, 0.60 mmol), 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxo-4(trifluoromethyl)pyridin-l(2/7)-yl)-4-methylpentanoic acid (100 mg, 0.55 mmol), TCFH (230 mg, 0.82 mmol), and NMI (177 mg, 2.18 mmol) in acetonitrile (10 mL) was stirred at room température for 20 hours. The reaction mixture was concentrated in vacuo and purified by

364 reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NHiHCCh.B: MeOH, 0~100%) to provide ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxo-4(trifluoromethyl)pyridin-l(2ί0-yl)-4-methylpentanamido)-3-(4-fluoro-4'-methoxy-2',5,6^,trimethyl-[l,r-biphenyl]-3-yl)propanoate (214 mg) as a white solid. Yield 56% (ESI 708.3 (M+H)⁺).

Step 2: (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxo-4-(trifluoromethyl)pyridinl(2^0-yl)-4-methyIpentanamido)-3-(4-fluoro-4’-methoxy-2’,5,6^,-trimethyI-[l,l’-biphenyi]-3yl)propanoic acid

Ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)yl)-4-methylpentanamido)-3-(4-fluoro-4^,-methoxy-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3yl)propanoate (214 mg, 0.30 mmol) was treated with LiOH-HiO (52 mg, 1.24 mmol) in MeOH (3 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prepHPLC A (30-60% CH3CN) to give the diastereomeric products P-Pl (39.8 mg) and P-P2 (48.6 mg) as white solids.

P-Pl ESI 680.4(M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.69 (s, 1H), 6.88 - 6.85(m, 2H), 6.64 (d, J= 10.6 Hz, 2H), 5.73 - 5.65 (m, 1H), 5.55 (t, J= 6.8 Hz, 1H), 4.92 (s, 3H), 3.79 (s, 3H), 3.17-2.92 (m, 4H), 2.82-2.69 (m, 7H), 2.29 (s, 3H), 2.10- 1.94 (m, 5H), 1.83 (s, 1H), 1.51 1.41(m, 1H), 0.97 - 0.93 (m, 6H).

P-P2 ESI 680.3 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.60 (s, 1H), 6.91 (t, J= 7.1 Hz, 2H), 6.67 (s, 2H), 5.73 - 5.70 (m, 1H), 5.61 (t, J= 7.5 Hz, 1H), 3.80 (s, 3H), 3.23 - 3.18 (m, 2H), 3.18 - 2.95 (m, 2H), 2.83 (s, 6H), 2.65 - 2.61 (m, 1H), 2.52 - 2.47 (m, 1H), 2.32 (s, 3H), 2.11 - 1.95 (m, 7H), 1.72 - 1.66 (m, 1H), 1.45-1.41 (m, 1H), 0.94-0.85 (m, 6H).

365

3-12. Préparation of (3S)-3-(2-(5-(2-(azctidin-l-yl)ethyi)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpcntananiido)-3-(4,4'-difluoro-2’,6'-diniethyl-5-(trifluoromethyl)-[l,rbiphenyl]-3-yl)propanoic acid (compounds R-Pl and R-P2)

Step 1: ethyl (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(27/)yl)-4-methylpentanamido)-3-(4,4’-difluoro-2’,6’-dimethyl-5-(trifIuoromethyI)-[l,rbiphenyl|-3-yl)propanoate

A mixture of 2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2/7)-yl)-4methylpentanoic acid (100 mg, 0.28 mmol), ethyl (S)-3-amino-3-(4,4'-difluoro-2',6'-dimethyl-5(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (112 mg, 0.28 mmol), NMI (69 mg, 0.84 mmol) and TCFH (95 mg, 0.34 mmol) in CH₃CN (5 mL) was stirred at room température for 2 hours. The solvent was removed in vacuo and the residue was purified by silica gel column (MeOH/DCM 7%) to provide ethyl (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2jfir)-yl)-4-methylpentanamido)-3-(4,4’-difluoro-2’,6^,-dimethyl-5(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate as a yellow oil (180 mg). Yield 87% (ESI 744.1 [M+H]⁺).

Step 2: (35)-3-(2-(5-(2-(azetidin-l-yl)ethyi)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4,4'-difluoro-2’,6’-dimethyl-5-(trifluoromethyl)-[l,l*-biphenyl]-3yl)propanoic acid

366

Ethyl (3S)-3-(2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2//)-yl)-4methylpentanamido)-3-(4,4'-difluoro-2',6'-dÎmethyl-5-(trifluoromethyl)-[ 1,1 '-biphenyl]-3yl)propanoate (180 mg, 0.24 mmol) was treated with LiOH-H₂O (50 mg, 1.20 mmol) in THF (3 mL), MeOH (2 mL) and H₂O (1 mL) at room température for 16 hours. The reaction mixture was acidified to pH 4-5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products R-Pl (65.0 mg) and R-P2 (35.0 mg) as white solids.

R-Pl ESI 716.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.85 (s, 1H), 7.40 - 7.32 (m, 2H), 6.90 6.86 (m, 2H), 6.75 (s, 1H), 5.64-5.60 (m,2H), 4.07 (t,J= 8.1 Hz, 4H), 3.36-3.33 (m, 1H), 3.31 - 3.27 (m, 1H), 2.91 - 2.69 (m, 4H), 2.49 - 2.44 (m, 2H), 2.06 - 1.97 (m, 5H), 1.89 (s, 3H), 1.48-1.36 (m, 1H), 0.99-0.91 (m, 6H).

R-P2 ESI 716.2 (M+H)⁺ ‘H NMR (400 MHz, MeOD) δ 7.75 (s, 1H), 7.45 - 7.38 (m, 2H), 6.92 (s, 1H), 6.90 (s, 2H), 5.82 - 5.78 (m, 1H), 5.63 (t, J= 7.7 Hz, 1H), 4.15 (t, J= 7.9 Hz, 4H), 3.45 - 3.35 (m, 2H), 2.99 - 2.80 (m, 2H), 2.69 - 2.42 (m, 4H), 2.03 - 1.92 (m, 7H), 1.76 - 1.63 (m, 1H), 1.44 - 1.37 (m, 1H), 0.92 - 0.89 (m, 6H).

3-13. Préparation of (S)-3-(4,5-difluoro-2*,6’-dimethyl-[l,l’-biphenyIJ-3-yl)-3-((S)-2-(5-(2(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (compounds S-Pl and S-P2)

367

Step 1: ethyl (S)-3-(4,5-difluoro-2’,6’-dimethyI-[l,r-biphenyl]-3-yI)-3-((S)-2-(5-(2 (dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanamîdo)propanoate

A mixture of 2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1 (2H)-yI)-4methylpentanoic acid (80 mg, 0.27 mmol), ethyl (S)-3-amino-3-(4,5-difluoro-2',6'-dimethyl[l,l’-biphenyl]-3-yl)propanoate (100 mg, 0.30 mmol), EDCI (77 mg, 0.41 mmol), TEA (0.2 mL) and HOBt (36mg, 0.27 mmol) in acetonitrile (10 mL) was stirred at room température for 20 hours. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a Cl8 / 40 g column (A: water 10 mM NH4HCCh,B: MeOH, 0~100%) to provide ethyl (S)-3-(4,5difluoro-2',6'-dimethyl-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoate as yellow oil (75 mg). Yield 45% (ESI 610.3 (M+H)⁺).

Step 2: (S)-3-(4,5-difluoro-2’,6’-dimethyI-[l,r-biphenyI)-3-yI)-3-((S)-2-(5-(2 (dimethyIamino)ethyI)-4-methyI-2-oxopyridin-l(2H)-yI)-4-methylpentanamido)propanoic acid

Ethyl (S)-3-(4,5-difluoro-2’,6'-dimethyl-[ 1,1 '-biphenyl]-3-yl)-3-((S)-2-(5-(2(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoate (75 mg, 0.12 mmol) was treated with LiOH monohydrate (26 mg, 0.62 mmol) in MeOH (2 mL) and H₂O (1 mL) at room température for 2 h. The reaction mixture was acidified to pH 4~5 with IN

368

HCl. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC A (3060% MeCN) to give the diastereomeric products S-Pl (28 mg) and S-P2 (38 mg) as white solids.

S-Pl ESI 582.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.58 (s, 1H), 7.19 - 7.14 (m, 1H), 7.10 (d, J= 8.6 Hz, 2H), 6.96 - 6.90 (m, 1H), 6.83 (d, J= 5.8 Hz, 1H), 6.33 (s, 1H), 5.57 (s, 1H), 5.52 - 5.47 (m, 1H), 3.33 - 3.13 (m, 2H), 2.88 (t, J= Ί3 Hz, 2H), 2.79 (s, 6H), 2.72 - 2.60 (m, 2H), 2.26 (s, 3H), 2.03 - 1.90 (m, 8H), 1.40 (d, J= 7.3 Hz, 1H), 0.95 - 0.91 (m, 6H).

S-P2 ESI 582.2 (M+H)⁺.’H NMR (500 MHz, MeOD) δ 7.54 (s, 1H), 7.19 - 7.15 (m, 1H), 7.11 (d, J= 7.8 Hz, 2H), 7.01 - 6.95 (m, 1H), 6.90 (d, J= 5.9 Hz, 1H), 6.42 (s, 1H), 5.67 - 5.64 (m, 1H), 5.61 - 5.55 (m, 1H), 3.24 - 3.18 (m, 1H), 2.97 - 2.84 (m, 8H), 2.63 (dd, J= 15.2,4.2 Hz, 1H), 2.49 (dd, J= 15.2, 9.9 Hz, 1H), 2.27 (s, 3H), 2.02 (s, 6H), 1.99 - 1.93 (m, 1 H), 1.81 - 1.73 (m, 1H), 1.41- 1.37 (m, 1H), 0.90-0.88 (m, 6H).

3-14. Préparation of (3S)-3-(2-(5-(2-(dimethyIamino)ethyI)-4-methyl-2-oxopyridin-l(2A0yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyi]-3-yI)propanoic acid (compounds T-Pl and T-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(dimethyIamino)ethyl)-4-methyI-2-oxopyridin-l(217)-yl)-4methylpentanamido)-3-(4-fluoro-2’,4’,5,6’-tetramethy!-[l,l’-biphenyl]-3-yl)propanoate

A mixture of 2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1 (2/7)-yl)-4methylpentanoic acid (100.0 mg, 0.34 mmol), ethyl (iS)-3-amino-3-(4-fluoro-2’,4’,5,6'tetramethyl-[l,l'-biphenyl]-3-yl)propanoate (117.0 mg, 0.34 mmol), TCFH (190.4 mg, 0.68 mmol), NMI (115.5 mg, 1.36 mmol) in CH3CN (5 mL) was stirred at room température for 2 hours. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a

369

C18 / 40 g column (A: water 10 mM NH4HCO3.B: MeOH, 0-100%) to provide ethyl (35)-3-(2(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)-3-(4fluoro-2',4',5,6’-tetramethyl-[l,r-biphenyl]-3-yl)propanoate as a white oil (95.0 mg). Yield 45% (ESI 620.3 (M+H)⁺).

Step 2 : (35)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyI-2-oxopyridin-l (2Z7)-yI)-4methylpentanamido)-3-(4-fluoro-2*,4’,5,6’-tetramethyl-[l,r-biphenylj-3-yi)propanoic acid

Ethyl (35)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1 (2Z/)-yl)-4methylpentanamido)-3-(4-fluoro-2’,4',5,6'-tetramethyl-[ 1,1 ’-biphenyl]-3-yl)propanoate (95.0 mg, 0.15 mmol) was treated with L1OH-H2O (25.2 mg, 0.60 mmol) in MeOH (4 mL) and H2O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4—5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products T-Pl (26.2 mg) and T-P2 (58.3 mg) as white solids.

T-Pl ESI 592.3(M+H)⁺. ’H NMR (400 MHz, MeOD) δ 7.54 (s, 1H), 6.89 (d, J= 3.6 Hz, 2H), 6.85 - 6.72 (m, 2H), 6.32 (s, 1H), 5.69 - 5.56 (m, 1H), 5.53 - 5.41 (m, 1H), 3.04 - 2.84 (m, 2H), 2.79 (t, J = 7.3 Hz, 2H), 2.71-2.51 (m, 8H), 2.36 - 2.17 (m, 9H), 2.06 - 1.88 (m, 5H), 1.83 (s, 3H), 1.51 - 1.30 (m, 1H), 1.02-0.82 (m, 6H).

T-P2 ESI 592.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.56 (s, 1H), 6.98 - 6.82 (m, 4H), 6.44 (s, 1H), 5.69 - 5.50 (m, 2H), 3.20 (d, J= 38.2 Hz, 2H), 2.85 (d, J= 33.5 Hz, 8H), 2.70 - 2.40 (m, 2H), 2.38 - 2.19 (m, 9H), 2.04 - 1.87 (m, 7H), 1.85 - 1.70 (m, 1 H), 1.47 - 1.26 (m, 1 H), 0.99 0.78 (m, 6H).

370

3-15. Préparation of(33)-3-(4-fluoro-3*-methoxy-2’,5,6'-trimethyl-[l,l’-biphenylJ-3-yl)-3(2-(5-(2-(3-methoxyazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyi)pyridin-l(2//)-yl)-4methylpentanamido)propanoic acid (compounds N-Pl and N-P2)

Step 1: ethyl (3S)-3-(4-fluoro-3’-methoxy-2’,5,6’-trimethyl-[l,l’-biphenyll-3-yl)-3-(2-(5-(2(3-methoxyazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yl)-4methylpentanamido)propanoate

A mixture of 2-(5-(2-(3-methoxyazetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2/Y)yl)-4-methylpentanoic acid (272 mg, 0.70 mmol, 1.25 eq), ethyl (S)-3-amino-3-(4-fluoro-3'methoxy-2*,5,6’-trimethyl-[l,r-biphenyl]-3-yl)propanoate (200 mg, 0.56 mmol, 1.00 eq), NMI (0.5 mL) and TCFH (232 mg, 0.83 mmol, 1.50 eq) in CH3CN (5 mL) was stirred at room température for 1 hour. The solvent was concentrated in vacuo and the residue was purified by prep-HPLC A (30-60% CILCN) to provide ethyl (3S)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl[1,1 '-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1 -yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanamido)propanoate (201 mg). Yield 49% (ESI 732.2 [M+H]*).

Step 2: (3S)-3-(4-fluoro-3'-methoxy-2’,5,6'-trimethyl-[l,r-biphenylJ-3-yl)-3-(2-(5-(2-(3methoxyazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2£0-yl)-4methylpentanamido)propanoic acid

371

Ethyl (35)-3-(4-fluoro-3'-methoxy-2',5,6^,-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(5-(2-(3methoxyazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/f)-yl)-4methylpentanamido)propanoate (201 mg, 0.27 mmol, 1.00 eq) was treated with L1OH-H2O (44 mg, 1.08 mmol, 4.00 eq) in MeOH (10 mL) and H₂O (5 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% CH3CN) to give the diastereomeric products N-Pl (31 mg) and N-P2 (41 mg) as white solids.

N-Pl ESI 704.4(M+H)⁺. ’H NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 7.03 - 6.79 (m, 5H), 5.69 5.58 (m, 2H), 4.21 -4.18 (m, 3H), 3.83 (s, 3H), 3.76 - 3.70 (m, 2H), 3.31 (s, 3H), 3.24 - 3.20 (m, 2H), 2.84 - 2.72 (m, 4H), 2.29(s, 3H), 1.98 (t, J= 7.6 Hz, 2H), 1.92 - 1.68 (m, 6H), 1.48 1.41 (m, 1H), 0.98 - 0.93 (m, 6H).

N-P2 ESI 704.4 (M+H)+. Ή NMR (400 MHz, MeOD) δ 7.76 (s, 1H), 7.05 (d, J= 8.4 Hz, 1H), 7.01 - 6.80 (m, 4H), 5.74 - 5.62 (m, 2H), 4.24 (s, 3H), 3.84 (s, 3H), 3.75 - 3.66 (m, 2H), 3.31 (s, · 3H), 3.30 - 3.15 (m, 2H), 2.85 - 2.63 (m, 4H), 2.33 (s, 3H), 2.09 - 1.89 (m, 4H), 1.86 (d, J= 3.1 Hz, 3H), 1.74-1.67 (m, 1H), 1.42- 1.39 (m, 1H), 0.90 (d, J= 6.3 Hz, 6H).

3-16. Préparation of (3S)-3-(2-(5-(2-(dimethyIamino)ethyl)-2-oxo-4(trifluoromethyI)pyridin-l(2fl^r)-yl)-4-methylpentanamido)-3-(4-fluoro-3'-methoxy-2’,5,6’trimethyI-[l,r-biphenyIj-3-yI)propanoic acid (compounds U-Pl and U-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)yl)-4-methylpentanamido)-3-(4-fluoro-3’-methoxy-2’,5,6’-trimethyl-[l,r-biphenyl]-3yl)propanoate

A mixture of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2//)-yl)-4methylpentanoic acid (232 mg, 0.67 mmol, 1.20 eq), ethyl (S)-3-amino-3-(4-fluoro-3’-methoxy

372

2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate (200 mg, 0.56 mmol, 1.00 eq), NMI (0.5 mL) and TCFH (233 mg, 0.83 mmol, 1.50 eq) in CHsCN (5 mL) was stirred at room température for 1 hour. The solvent was concentrated in vacuo and the residue was purified by prep-HPLC A (30-60% CH3CN) to provide ethyl (35)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(27y)-yl)-4-methylpentanamido)-3-(4-fluoro-3’-methoxy-2’,5,6'trimethyl-[l,l'-biphenyl]-3-yl)propanoate as a white solid (250 mg). Yield 65% (ESI 690.2 [M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanamidoVS-id-fluoro-S’-methoxy-l^Sjô’-trimethyl-llJ’-biphenyll-Syl)propanoic acid

Ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2A/)-yl)-4methylpentanamido)-3-(4-fluoro-3'-methoxy-2’,5,6'-trimethyl-[ 1,1 ’-biphenyl]-3-yl)propanoate (250 mg, 0.32mmol, 1.00 eq) was treated with L1OH-H2O (19 mg, 0.81 mmol, 2.50 eq) in MeOH (5 mL) and H2O (0.5 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prepHPLC A (30-60% CH3CN) to give the diastereomeric products U-Pl (40.0 mg) and U-P2 (55.0 mg) as white solids.

U-Pl ESI 662.3(M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.90(s, 1H), 7.04 - 6.99 (m, 1H), 6.86 6.76 (m, 4H), 5.70-5.66 (m, 1H), 5.58-5.55 (m, 1H), 3.83 (s, 3H), 3.15-3.03 (m, 2H), 2.972.93 (m, 2H), 2.74- 2.69 (m, 8H), 2.29 (s, 3H), 2.00 - 1.96 (m, 2H), 1.92 - 1.67 (m, 6H), 1.48 1.41 (m, 1H), 0.97 - 0.93 (m, 6H).

U-P2 ESI 662.3 (M+H)⁺. *H NMR (400 MHz, MeOD) δ 7.84(s, 1H), 7.05 (d, J= 8.5 Hz, 1H), 7.03 - 6.79 (m, 4H), 5.73 - 5.69 (m, 1H), 5.61 (t, J= 7.7 Hz, 1H), 3.84 (s, 3H), 3.33 - 3.22 (m, 2H), 3.01- 2.98 (m, 2H), 2.82 (s, 6H), 2.67- 2.62 (m, 1H), 2.55- 2.49 (m, 1H), 2.32 (s, 3H), 2.24

373

- 1.88 (m, 4H), 1.86 (d, J= 3.1 Hz, 3H), 1.81 - 1.60 (m, 1H), 1.45-1.37 (m, 1H), 0.90-0.88 (m, 6H).

3-17. Préparation of (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2£0-yl)-4-methylpentanamido)-3-(4-fluoro-4’-methoxy-2’,5,6’trimethyI-[l,l'-biphenyl]-3-yl)propanoic acid (compounds V-Pl and V-P2)

Step 1: ethyl (35)-3-(2-(5-(2-(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(217)yI)-4-methylpentanamido)-3-(4-fluoro-4’-methoxy-2’,5,6’-trimethyI-[l,l’-biphenyl]-3y))propanoate

NMI, TCFH CH₃CN, 1.5 h

A mixture of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yl)-4methylpentanoic acidd (170 mg, 0.49 mmol), ethyl (5)-3-amino-3-(4-fluoro-4^,-methoxy-2',5,6'trimethyl-[l,r-biphenyl]-3-yl)propanoate (176 mg, 0.49 mmol), NMI (160 mg, 1.96 mmol) and TCFH (205.8 mg, 0.74 mmol) in CHjCN (10 mL) was stirred at room température for 1.5 hours. The solvent was concentrated in vacuo and the residue was purified by silica gel column (DCM: MeOH 9:1) to provide ethyl (35)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2//)-yl)-4-methyIpentanamido)-3-(4-fiuoro-4'-methoxy-2',5,6'trimethyl-[l,r-biphenyl]-3-yl)propanoate as a yellow solid (131 mg). Yield 39% (ESI 690.3 [M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methy!pentanamido)-3-(4-fluoro-4’-methoxy-2’,5,6’-trimethyI-[l,l’-biphenyl]-3yl)propanoic acid

374

Ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2//)-yl)-4methylpentanamido)-3-(4-fluoro-4'-methoxy-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate (131 mg, 0.19 mmol) was treated with LiOH-H₂O (32 mg, 0.76 mmol) in MeOH (10 mL) and H₂O (5 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (3060% CH3CN) to give the diastereomeric products V-Pl (24 mg) and V-P2 (15 mg) as white solids.

V-Pl ESI 662.3 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.90 (s, 1H), 6.85 (t, J= 7.6 Hz, 2H), 6.76 (s, 1H), 6.63 (d, J= 18.7 Hz, 2H), 5.68 (t, J= 7.9 Hz, 1H), 5.57 - 5.54 (m, IH), 3.80 (s, 3H), 3.12 - 3.02 (m, 2H), 2.98 - 2.90 (m, 2H), 2.90 - 2.46 (m, 8H), 2.28 (s, 3H), 2.06 - 1.94 (m, 5H), 1.80 (s, 3H), 1.48 - 1.41 (m, 1H), 0.97 - 0.93 (m, 6H).

V-P2 ESI 662.3 (M+H)⁺. ‘H NMR (500 MHz, MeOD) δ 7.87 (s, 1H), 6.92 - 6.90 (m, 3H), 6.67 (s, 2H), 5.73-5.70 (m, 1H), 5.62 (t, J= 7.6 Hz, 1H), 3.80 (s, 3H), 3.30 - 3.20 (m, 2H), 3.01 2.97 (m, 2H), 2.83 (s, 6H), 2.70 - 2.59 (m, 1H), 2.55 - 2.50 (m,lH), 2.32 (s, 3H), 1.98 (d, J= 4.0 Hz, 7H), 1.73 - 1.68 (m, 1 H), 1.43 - 1.36 (m, 1 H), 0.90 - 0.88 (m, 6H).

3-18. Préparation of (3S)-3-(5-chIoro-4-fluoro-2’,6’-dimethyI-[l,l’-biphenyl]-3-yI)-3-(2-(5(2-(3-methoxyazetidin-l-yI)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2fl)-yl)-4methylpentanamido)propanoic acid (compounds W-Pl and W-P2)

Step 1: ethyl (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-|l,r-biphenylj-3-yl)-3-(2-(5-(2-(3methoxyazctidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)-yl)-4methylpentanamido)propanoate

375

A mixture of2-(5-(2-(3-methoxyazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2//)yl)-4-methylpentanoic acid (167 mg, 0.43 mmol), ethyl (S)-3-amino-3-(5-chloro-4-fluoro-2',6'dimethyl-[l,r-biphenyl]-3-yl)propanoate (150 mg, 0.43 mmol), TCFH (182 mg, 0.65 mmol) and NMI (176 mg, 2.15 mmol) in CHjCN (4 mL) was stirred at 40°C for 2 hours. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a Cl8 / 40 g column (A: water 10 mM NHiHCCh.B: MeOH, 0~100%) to provide ethyl (35)-3-(5-chloro-4-fluoro2',6’-dimethyl-[l,r-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2//)-yI)-4-methylpentanamido)propanoate as a yellow oil (150 mg). Yield 48% (ESI 722.2 (M+H)⁺).

Step 2: (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyI-|l,r-biphenyl]-3-yI)-3-(2-(5-(2-(3methoxyazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromcthyl)pyridin-l(2//)-yl)-4methylpentanamido)propanoic acid

Ethyl (3S)-3-(5-chloro-4-fluoro-2’,6'-dimethyl-[l,r-biphenyl]-3-yl)-3-(2-(5-(2-(3methoxyazetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)propanoate (150 mg, 0.21 mmol) was treated with L1OH-H2O (42 mg, 1 mmol) in MeOH (3 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% CH3CN) to give the diastereomeric products W-Pl (46 mg) and W-P2 (57 mg) as white solids.

376

W-Pl ESI 694.2 (M+H)⁺. *H NMR (400 MHz, MeOD) δ 7.85 (s, 1H), 7.21 - 7.00 (m, 5H), 6.74 (s, 1H), 5.72-5.50 (m,2H),4.27-4.08 (m,3H), 3.80-3.61 (m, 2H), 3.31 (s, 3H), 3.26-3.09 (m, 2H), 2.86 - 2.70 (m, 4H), 2.09 - 1.93 (m, 5H), 1.84 (s, 3H), 1.50 - 1.37 (m, 1 H), 1.04 - 0.83 (m, 6H).

W-P2 ESI 694.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.75 (s, 1H), 7.26 - 7.06 (m, 5H), 6.90 (s, 1H), 5.79 - 5.70 (m, 1H), 5.63 (t, J= 7.7 Hz, 1H), 4.44 - 4.22 (m, 3H), 3.98 - 3.76 (m, 2H), 3.41 - 3.34 (m, 5H), 2.99 - 2.74 (m, 2H), 2.70 - 2.49 (m, 2H), 2.08 - 1.89 (m, 7H), 1.77 - 1.62 (m, 1H), 1.48 - 1.32 (m, 1H), 0.90 (d, J= 6.4 Hz, 6H).

3-19. Préparation of (35)-3-(5-chIoro-4,4'-difluoro-2',6’-dimethyl-[l,r-biphenylj-3-yl)-3(2-(5-(2-(3-methoxyazetidin-l-yI)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z0-yi)-4methylpentanamido)propanoic acid (compounds X-Pl and X-P2)

Step 1: (35)-3-(5-chloro-4,4’-difluoro-2’,6’-dimethyI-[l,l’-biphenyI]-3-yI)-3-(2-(5-(2-(3methoxyazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z7)-yl)-4methylpentanamido)propanoate ethyl

A mixture of 2-(5-(2-(3-methoxyazetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2/7)yl)-4-methylpentanoic acid (160 mg, 0.41 mmol), ethyl (S)-3-amino-3-(5-chloro-4,4'-difluoro2',6'-dimethyl-[l,r-biphenyl]-3-yl)propanoate (150 mg, 0.41 mmol), TCFH (174 mg, 0.62 mmol) and NMI (168 mg, 2.05 mmol) in CHjCN (4 mL) was stirred at 40 °C for 2 hours. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NH4HCO3.B: MeOH, 0-100%) to provide ethyl (3S)-3-(5-chloro-4,4difluoro-2',6'-dimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1 -yl)ethyl)-2-oxo-4

377 (trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanamido)propanoateas a yellow oil (150 mg).

Yield 49% (ESI 740.2 (M+H)⁺).

Step 2: (35)-3-(5-chloro-4,4'-difluoro-2',6'-dimethyl-[l,r-biphenyl]-3-yl)-3-(2-(5-(2-(3methoxyazetidin-l-yl)ethyl)-2-oxo-4-(tiïfluoromethyl)pyridin-l(2Z7)-yl)-4methylpentanamido)propanoic acid

Ethyl (3S)-3-(5-chloro-4,4'-difluoro-2',6^,-dimethyl-[ 1,1 *-biphenyl]-3-yl)-3-(2-(5-(2-(3methoxyazetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2/7)-yl)-4methylpentanamido)propanoate (150 mg, 0.20 mmol) was treated with LiOH-HzO (42 mg, 1 mmol) in MeOH (3 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% CH3CN) to give the diastereomeric products X-Pl (35 mg) and X-P2 (49 mg) as white solids.

X-Pl ESI 712.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.85 (s, 1H), 7.13 (d, J= 6.6 Hz, 1H), 7.07 - 7.00 (m, 1H), 6.90 - 6.79 (m, 2H), 6.74 (s, 1H), 5.72 - 5.48 (m, 2H), 4.26 - 4.07 (m, 3H), 3.80 - 3.64 (m, 2H), 3.32 (s, 3H), 3.19 (t, J= 6.2 Hz, 2H), 2.86 - 2.71 (m, 4H), 2.08 - 1.95 (m, 5H), 1.86 (d, J =4.4 Hz, 3H), 1.51-1.36 (m, 1H), 1.01-0.88 (m, 6H).

X-P2 ESI 712.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.74 (s, IH), 7.25 - 7.16 (m, 1H), 7.15 - 7.05 (m, 1H), 6.93 - 6.83 (m, 3H), 5.81 - 5.68 (m, 1H), 5.63 (t, J= 7.7 Hz, 1H), 4.44 - 4.23 (m, 3H), 3.95 - 3.78 (m, 2H), 3.40 - 3.34 (m, 5H), 3.00 - 2.75 (m, 2H), 2.70 - 2.47 (m, 2H), 2.08 - 1.93 (m, 7H), 1.76 - 1.64 (m, 1 H), 1.47 - 1.33 (m, 1 H), 0.96 - 0.84 (m, 6H).

378

3-20. Préparation of (3S)-3-(4,4’-difluoro-2’,5,6’-trimethylbiphenyl-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-5methylhexanamido)propanoic acid (compounds Y-Pl and Y-P2)

Step 1: (35)-ethyI 3-(4,4’-difluoro-2',5,6’-trimethylbiphenyl-3-yl)-3-(2-(5-(25 (dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(27/)-yl)-5methylhexanamido)propanoate

F

O

A mixture of2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-5methylhexanoic acid (273 mg, 0.75 mmol), (<S)-ethyl 3-amino-3-(4,4'-difluoro-2',5,6'10 trimethylbiphenyl-3-yl)propanoate hydrochloride (164 mg, 0.39 mmol), TCFH (211 mg, 0.75 mmol), and NMI (0.45 mL, 5.70 mmol) in acetonitrile (9 mL) was stirred at room température for 16 hours. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a Cl8 /40 g column (A: water 10 mM NHiHCOj.B: MeOH, 0-80%) to provide (35)ethyl 3-(4,4’-difluoro-2',5,6'-trimethylbiphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-415 (trifluoromethyl)pyridin-1 (2//)-yl)-5-methylhexanamido)propanoate as a brown solid (262 mg). Yield 97% (ESI 692.3 (M+H)⁺).

Step 2: (35)-3-(4,4'-difluoro-2’,5,6’-trimethylbiphenyl-3-yI)-3-(2-(5-(2 (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yI)-5methylhexanamido)propanoic acid

379

(3S)-ethyl 3-(4,4'-difluoro-2',5,6'-trimethylbiphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2oxo-4-(trifluoiOmethyl)pyridin-l(277)-yI)-5-methylhexanamido)propanoate (262 mg, 0.38 mmol) was treated with LiOH monohydrate (80 mg, 1.90 mmol) in EtOH (6 mL) and H2O (0.10 mL) at 36°C for 1 hour. The reaction mixture was acidified to pH 4~5 with IN HCl. The reaction mixture was concentrated in vacuo and purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products Y-Pl (68 mg) and Y-P2 (66 mg) as white solids.

Y-Pl ESI 664.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.89 (s, 1H), 6.87 - 6.85 (m, 1H), 6.83 - 6.78 (m, 2H), 6.76 - 6.73 (m, 1H), 6.70 (s, 1H), 5.56 - 5.52 (m, 1H), 5.50 - 5.46 (m, 1H), 3.10 - 3.03 (m, 2H), 2.95 - 2.91 (m, 2H), 2.75 - 2.66 (m, 8H), 2.26 (d, J= 1.2 Hz, 3H), 2.22 - 2.14 (m, 1 H), 2.00- 1.92 (m, 4H), 1.78 (s, 3H), 1.60 - 1.53 (m, 1 H), 1.29 - 1.18 (m, 1 H), 1.13 - 1.04 (m, 1H), 0.88 (d, J= 2.8 Hz, 3H), 0.86 (d, J= 2.8 Hz, 3H).

Y-P2 ESI 664.2 (M+H)+. Ή NMR (400 MHz, MeOD) δ 7.92 (s, 1H), 6.95 - 6.93 (m, 1H), 6.91 - 6.88 (m, 1H), 6.87 (s, 1H), 6.82 (s, 1H), 6.80 (s, 1H), 5.72 - 5.68 (m, 1H), 5.47 (t, J= Ί.6 Hz, 1H), 3.24 - 3.12 (m, 2H), 3.02 - 2.93 (m, 2H), 2.78 (t, J= 5.8 Hz, 6H), 2.67 - 2.62 (m, 1H), 2.58 - 2.52 (m, 1 H), 2.30 (d, J = 1.6 Hz, 3H), 2.13 - 2.04 (m, 1 H), 2.00 (s, 3H), 1.99 (s, 3H), 1.84 1.75 (m, 1H), 1.52 - 1.44 (m, 1H), 1.15 - 0.99 (m, 2H), 0.80 (d, J= 4.0 Hz, 3H), 0.77 (d, J= 4.5 Hz, 3H).

3-21. Préparation of (3S)-3-(2-(5-(2-(dimethy!amino)ethyl)-2-oxo-4(trifluoromethyI)pyridin-l(2£0-yl)-5-methylhexanamido)-3-(4-fluoro-2’,5,6’-trimethyl[l,l’-biphenyl]-3-yl)propanoic acid (compounds Z-Pl and Z-P2)

380

Step 1: (35)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2jF7) yl)-5-methylhexanamido)-3-(4-fïuoro-2’,5,6’-trimethylbiphenyl-3-yl)propanoate

A mixture of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-55 methylhexanoic acid (283 mg, 0.78 mmol), (5)-ethyl 3-amino-3-(4-fluoro-2',5,6’trimethylbiphenyl-3-yl)propanoate hydrochloride (170 mg, 0.46 mmol), TCFH (248 mg, 0.88 mmol), and NMI (0.21 mL, 2.63 mmol) in acetonitrile (10 mL) was stirred at room température for 20 hours. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a Cl8 / 40 g column (A: water 10 mM NHiHCCh.B: MeOH, 0~100%) to provide (35)10 ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (277)-yl)-5methylhexanamido)-3-(4-fluoro-2’,5,6'-trimethylbiphenyl-3-yl)propanoate as a brown solid (223 mg). Yield 71% (ESI 674.3 (M+H)⁺).

Step 2: (35)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-5 methylhexanamido)-3-(4-fluoro-2’,5,6’-trimethyl-[l,l’-biphenyl]-3-yl)propanoic acid

(3S)-ethyl3-(2-(5-(2-(dimethylamino)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-5methylhexanamido)-3-(4-fluoro-2’,5,6'-trimethylbiphenyl-3-yI)propanoate (223 mg, 0.33 mmol) was treated with LiOH monohydrate (35 mg, 0.82 mmol) in EtOH (6 mL) and H₂O (0.08 mL) at

381 °C for 1 h. The reaction mixture was acidified to pH 4~5 with IN HCl. The reaction mixture was concentrated in vacuo and purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products Z-Pl (60 mg) and Z-P2 (59 mg) as white solids.

Z-Pl ESI 646.3 (M+H)⁺.'H NMR (400 MHz, MeOD) δ 7.89 (s, 1H), 7.09 (t, J= 7.4 Hz, 1H), 7.04 (d, J= 6.8 Hz, 1H), 7.00 (d, J= 7.2 Hz, 1H), 6.89 - 6.87 (m, 1H), 6.84 (d, J= 7.0 Hz, 1H), 6.71 (s, 1H), 5.57 - 5.54 (m, 1H), 5.51 - 5.47 (m, 1H), 3.12 - 3.02 (m, 2H), 2.93 (t, J= 7.9 Hz, 2H), 2.74 (s, 6H), 2.73 - 2.69 (m, 2H), 2.27 (d, J= 1.4 Hz, 3H), 2.24 - 2.14 (m, 1H), 2.02 - 1.90 (m,4H), 1.79(s,3H), 1.61-1.51 (m, 1H), 1.27- 1.18(m, 1H), 1.13- 1.03 (m, 1H), 0.88(d,J= 2.4 Hz, 3H), 0.86 (d, J= 2.4 Hz, 3H).

Z-P2 ESI 646.3 (M+H)+. Ή NMR (400 MHz, MeOD) δ 7.87 (s, 1 H), 7.13 - 7.05 (m, 3H), 6.94 - 6.88 (m, 3H), 5.73 - 5.69 (m, 1H), 5.45 (t, J= 7.6 Hz, 1H), 3.27 - 3.15 (m, 2H), 2.98 (t, J= 6.8 Hz, 2H), 2.80 (s, 6H), 2.66 - 2.61 (m, 1H), 2.55 - 2.49 (m, 1H), 2.31 (d, J= 1.2 Hz, 3H), 2.14 2.05 (m, 1H), 1.99 (d, J= 2.6 Hz, 6H), 1.82- 1.73 (m, 1H), 1.56-1.46 (m, 1H), 1.16-0.99 (m, 2H), 0.81 (t,J=6.5 Hz, 6H).

3-22. Préparation of (3S)-3-(4-fluoro-2',4’,5,6’-tetramethyI-|l,l’-biphenyI]-3-yl)-3-(2-(5-(2(3-mcthoxyazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromcthyl)pyridin-l(2/7)-yl)-4methylpentanamido)propanoic acid (compounds AA-P1 and AA-P2)

Step 1: ethyl (3S)-3-(4-fluoro-2',4',5,6'-tetramethyl-ll,l'-biphenyl]-3-yl)-3-(2-(5-(2-(3mcthoxyazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoate

A mixture of 2-(5-(2-(3-methoxyazetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)yl)-4-methylpentanoic acid (168 mg, 0.43 mmol), ethyl (iS)-3-amino-3-(4-fluoro-2',4',5,6'

382 tetramethyl-[l,r-biphenyl]-3-yl)propanoate (150 mg, 0.43 mmol), TCFH (182 mg, 0.65 mmol) and NMI (177 mg, 2.2 mmol) in CH3CN (4 mL) was stirred at 40 °C for 2 hours. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a Cl8 / 40 g column (A: water 10 mM NH4HCO3.B: MeOH, 0-100%) to provide ethyl (3S)-3-(4-fluoro-2’,4’,5,6'tetramethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1 -yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2f/)-yl)-4-methylpentanamido)propanoate as a yellow oil (160 mg). Yield 51% (ESI 716.2 (M+H)⁺).

Step 2: (3S)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l’-biphenylj-3-yI)-3-(2-(5-(2-(3methoxyazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)-yl)-4methylpentanamido)propanoic acid

Ethyl (35)-3-(4-fluoro-2',4',5,6'-tetramethyl-[ 1,1 ’-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2//)-yl)-4-methylpentanamido)propanoate ( 160 mg, 0.22 mmol) was treated with L1OH-H2O (42 mg, 1 mmol) in MeOH (3 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4-5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% CH3CN) to give the diastereomeric products AA-P1 (46 mg) and AA-P2 (61 mg) as white solids.

AA-P1 ESI 688.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 6.97 - 6.81 (m, 4H), 6.75 (s, 1H), 5.75 - 5.52 (m, 2H), 4.20 - 4.00 (m, 3H), 3.61 (d, J= 11.2 Hz, 2H), 3.30 (s, 3H), 3.14 (t, J= 6.9 Hz, 2H), 2.87 - 2.66 (m, 4H), 2.29 (s, 6H), 2.04 - 1.90 (m, 5H), 1.80 (s, 3H), 1.50 - 1.38 (m, 1H), 1.05 - 0.88 (m, 6H).

AA-P2 ESI 688.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.74 (s, 1H), 6.97 - 6.84 (m, 5H), 5.80 - 5.69 (m, 1H), 5.62 (t, J= 7.7 Hz, 1H), 4.46 - 4.21 (m, 3H), 3.93 - 3.76 (m, 2H), 3.40 3.34 (m, 5H), 3.04 - 2.76 (m, 2H), 2.70 - 2.45 (m, 2H), 2.38 - 2.21 (m, 6H), 2.07 - 1.88 (m, 7H), 1.75 - 1.61 (m, 1 H), 1.49 - 1.33 (m, 1 H), 1.03 - 0.83 (m, 6H).

383

3-23. Préparation of (3S)-3-(4-fluoro-2',5,6’-trimethyl-[l,l^,-biphenyI]-3-yl)-3-(2-(5-(2-(3methoxyazetidin-l-yl)ethyl)-2-oxo-4-(trifliioromethyl)pyridin-l(2/7)-yl)-4methylpentanamido)propanoic acid (compounds AB-P1 and AB-P2)

Step 1: ethyl (3S>3-(4-fluoro-2’,5,6'-trimethyI-(l,r-biphenyI]-3-yI)-3-(2-(5-(2-(3methoxyazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2jF7)-yI)-4methylpentanamido)propanoate

A mixture of 2-(5-(2-(3-methoxyazetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (27/)yl)-4-methylpentanoic acid (180 mg, 0.46 mmol), ethyl (5)-3-amino-3-(4-fluoro-2',5,6'trimethyl-[l,l’-biphenyl]-3-yl)propanoate (150 mg, 0.46 mmol), TCFH (193 mg, 0.69 mmol) and NMI (188 mg, 2.3 mmol) in CH3CN (4 mL) was stirred at 40 °C for 2 hours. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a Cl8 / 40 g column (A: water 10 mM NH4HCO3.B: MeOH, 0-100%) to provide ethyl (3S)-3-(4-fluoro-2’,5,6'trimethyl-[ 1,1 ’-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1 -yl)ethyl)-2-oxo-4(triiluoromethyl)pyridin-l(277)-yl)-4-methylpentanamido)propanoate as a yellow oil (140 mg). Yield 43% (ESI 702.1 (M+H)⁺).

Step 2: (3S)-3-(4-fluoro-2’,5,6’-trimethyl-il,l’-biphenyi]-3-yl)-3-(2-(5-(2-(3methoxyazetidin-l-yI)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z7)-yl)-4methylpentanamido)propanoic acid

384

Ethyl (3S)-3-(4-fluoro-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1 yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (27'7)-yl)-4-methylpentanamido)propanoate ( 140 mg, 0.20 mmol) was treated with LiOH-H₂O (42 mg, 1 mmol) in MeOH (3 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4-5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% CH₃CN) to give the diastereomeric products AB-P1 (34 mg) and AB-P2 (46 mg) as white solids.

AB-P1 ESI 674.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 7.16 - 6.98 (m, 3H), 6.88 (t, J= 7.5 Hz, 2H), 6.76 (s, 1H), 5.74 - 5.53 (m, 2H), 4.24 - 4.04 (m, 3H), 3.70 - 3.53 (m, 2H), 3.30 (s, 3H), 3.14 (t, J= 7.1 Hz, 2H), 2.84 - 2.66 (m, 4H), 2.30 (s, 3H), 2.03 - 1.91 (m, 5H), 1.84 (s, 3H), 1.52- 1.34 (m, 1H), 1.14-0.86 (m, 6H).

AB-P2 ESI 674.3 (M+H)⁺. ‘H NMR (400 MHz, MeOD) δ 7.75 (s, 1H), 7.20-7.06 (m, 3H), 7.00-6.86 (m, 3H), 5.84-5.71 (m, 1H), 5.62 (t,J=7.7 Hz, 1H), 4.46 - 4.22 (m, 3H), 3.97 3.75 (m, 2H), 3.42 - 3.34 (m, 5H), 3.00 - 2.76 (m, 2H), 2.69 - 2.45 (m, 2H), 2.34 (d, J= 1.7 Hz, 3H), 2.09- 1.92 (m, 7H), 1.71-1.59 (m, 1H), 1.49- 1.35 (m, 1H), 1.04-0.83 (m, 6H).

3-24. Préparation of (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2ΛF)-yl)-4-methylpentanamido)-3-(4-fIuoro-2’,4',5,6^, tetramethylbiphenyl-3-yI)propanoic acid (compounds AC-P1 and AC-P2)

Step 1: (3S)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(227)yl)-4-methylpentanamido)-3-(4-fluoro-2’,4*,5,6’-tetramethylbiphenyI-3-yl)propanoate

385

A mixture of 2-(5-(2-(dimethylamino)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-1 (2J7)-yl)-4methylpentanoic acid (150 mg, 0.43 mmol, 1.0 eq), (S)-ethyl 3-amino-3-(4-fluoro-2',4’,5,6’tetramethylbiphenyl-3-yl)propanoate (148 mg, 0.361 mg, 1.29 mmol, 3 eq), TCHF (361 mg, 1.29 mmol, 3 eq) and NMI (176 mg, 2.15 mmol, 5.0 eq) in CH3CN (5 mL) was stirred at room température for 16 hours. LCMS showed that the reaction was completed. The solvent was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8 / 40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0-100%) to provide (3S)-ethyl 3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4-methylpentanamido)-3-(4fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoate as a yellow solid (130 mg). Yield 45% (ESI 674.2 (M+H]⁺).

Step 2: (35)-3-(2-(5-(2-(dimethyIamino)cthyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yl)-4methylpentanamido)-3-(4-fluoro-2’,4’,5,6’-tetramethylbiphenyl-3-yl)propanoic acid

(3S)-ethyl 3-(2-(5-(2-(dimethyiamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2/7)-yl)-4methylpentanamido)-3-(4-fluoro-2',4^,,5,6'-tetramethylbiphenyl-3-yl)propanoate (130 mg, 0.19 mmol, 1.0 eq) was treated with LiOH-HaO (40 mg, 0.95 mmol, 5.0 eq) in MeOH (4 mL) and water (1 mL) at 28 °C for 1 hour. LCMS showed that the reaction was completed. The reaction mixture was acidified to pH 5-6 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products ACPI (42 mg) and AC-P2 (34 mg) as white solids.

AC-P1 ESI 646.3 (M+H)+. Ή NMR (400 MHz, MeOD) δ 7.90 (s, 1H), 6.89 (s, 1H), 6.84 (d, J= 8.0 Hz, 3H), 6.74 (s, 1H), 5.68 (t, J= 8.0 Hz, 1H), 5.57-5.54 (m, 1H), 3.12-3.06 (m, 2H), 2.95 (d, J= 7.4 Hz, 2H), 2.78 - 2.67 (m, 8H), 2.29 (d, J= 4.2 Hz, 6H), 2.02 - 1.93 (m, 5H), 1.77 (s, 3H), 1.47-1.41 (m, 1H), 0.97-0.93 (m, 6H).

386

AC-P2 ESI 646.3 (M+H)+. Ή NMR (400 MHz, MeOD) δ 7.87 (s, 1H), 6.90 (d, J= 5.8 Hz, 5H), 5.73-5.70 (m, 1H), 5.62 (t, 7.6 Hz, 1H), 3.30 - 3.17 (m, 2H), 3.00 (t, J= 6.5 Hz, 2H), 2.82 (s,

6H), 2.66-2.60 (m, 1H), 2.55-2.49 (m, 1H), 2.31 (d, J= 7.7 Hz, 6H), 2.01-1.96 (m, 7H), 1.76 1.66 (m, 1H), 1.43-1.36 (m, 1H), 0.93 - 0.84 (m, 6H).

3-25. Préparation of (35)-3-(4,4’-difluoro-2’,5,6’-trimethyl-[l,l’-biphenyl]-3-yl)-3-(2-(5-(2(dimethyIamino)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(21T)-yl)pentanamido)propanoic acid (compounds AD-P1 and AD-P2)

Step 1: ethyl (35)-3-(4,4’-difluoro-2’,5,6’-trimethyl-|l,r-biphenyl]-3-yI)-3-(2-(5-(2(dimethyIamino)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2fi^r)-yl)pentanamido)propanoate

A mixture of ethyl (5)-3-amino-3-(4,4'-difluoro-2^,,5,6'-trimethyI-[l,r-biphenyl]-3-yl)propanoate (150 mg, 0.43 mmol), 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)yl)-4-methylpentanoic acid (174 mg, 0.52 mmol), TCFH (180 mg, 0.64 mmol) and NMI (70 mg, 0.86 mmol) in CH3CN (5 mL) was stirred at 20 °C for 2 hours. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a Cl8 / 40 g column (A: water 10 mM NH4HCO3.B: MeOH, 0-100%) to provide ethyl (35)-3-(4,4'-difluoro-2',5,6’-trimethyl-[l,l’biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z7)yl)pentanamido)propanoate as a yellow oil (200 mg). Yield 70% (ESI 664.3 (M+H)⁺).

Step 2: (35)-3-(4,4’-difluoro-2’,5,6’-trimethyl-[l,l’-biphenyl]-3-yI)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)pentanamido)propanoic acid

387

Ethyl (35)-3-(4,4'-difluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2//)-yl)pentanamido)propanoate (200 mg, 0.3 mmol) was treated with L1OH-H2O (37 mg, 0.9 mmol) in MeOH (2 mL) and H2O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCI. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products AD-P1 (57 mg) and AD-P2 (51 mg) as white solids.

AD-P1 ESI 636.2(M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.90 (s, 1H), 6.89 - 6.77 (m, 4H), 6.74 (s, 1H), 5.58 - 5.55 (m, 2H), 3.16- 3.13 (m, 2H), 2.98 - 2.95 (m, 2H), 2.81 (s, 6H), 2.75-2.72 (m, 2H), 2.29 (s, 3H), 2.18 -2.12 (m, 1H), 2.01 -2.00 (m, 4H), 1.82 (m, 3H), 1.36-1.31 (m, 2H), 0.97 (t,J=7.4 Hz, 3H).

AD-P2 ESI 636.2(M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.84 (s, 1H), 6.93 - 6.89 (m, 3H), 6.84 (d, J= 9.6 Hz, 2H), 5.72 - 5.69 (m, 1H), 5.52 (t, J= 7.6 Hz, 1H), 3.28 - 3.22 (m, 2H), 3.02 2.99 (m, 2H), 2.83 (s, 6H), 2.65 - 2.61 (m, 1H), 2.55 - 2.50 (m, 1H), 2.32 (t, J= 6.4 Hz, 3H), 2.10-2.05 (m, 1H),2.O1 (s, 6H), 1.84- 1.79 (m, 1H), 1.25- 1.23 (m, 2H), 0.90 (t, J =7.4 Hz, 3H).

3-26. Préparation of (35)-3-(2*,6’-dichloro-4,4’-difluoro-5-methyI-[l,l’-biphenyl]-3-yl)-3(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z7)-yl)-4methylpentanamido)propanoic acid (compounds AE-P1 and AE-P2)

Step 1: ethyl (35)-3-(2’,6’-dichloro-4,4*-difluoro-5-methyHl,l^,-biphenyI]-3-yl)-3-(2-(5-(2(dimethyIamino)ethyI)-2-oxo-4-(trifluoromethyI)pyridin-l(2fl)-yl)-4methylpentanamido)propanoate

388

A mixture of ethyl (S)-3-amino-3-(2',6^,-dichloro-4,4’-difluoro-5-methyl-[l,r-biphenyI]-3yl)propanoate hydrochloride (450 mg, 1.06 mmol), 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanoic acid (370 mg, 1.06 mmol), TCFH (356 mg, 1.27 mmol) and NMI (261 mg, 3.18 mmol) in CH₃CN (10 mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM:MeOH 4:1) to provide ethyl (35)-3-(2',6^,-dichloro-4,4'-difluoro-5-methyl[1,1 ^,-biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2/7)yl)-4-methylpentanamido)propanoate as a brown solid (610 mg). Yield 80% (ESI 718.0 (M+H)⁺).

Step 2: (3$)-3-(2’,6’-dichIoro-4,4’-difluoro-5-methyl-[l,r-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methylpcntanamido)propanoic acid

Ethyl (3S)-3-(2’,6'-dichloro-4,4'-difluoro-5-methyl-[l,r-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methylpentanamido)propanoate (110 mg, 0.15 mmol) was treated with LiOH-H₂O (32 mg, 0.75 mmol) in THF (3 mL) and HzO (1 mL) at room température for 3 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was

389 purified by prep-HPLC A (30-60% MeCN) to provide the diastereomeric products AE-P1 (29.0 mg) and AE-P2 (31.0 mg) as white solids.

AE-P1 ESI 690.0 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.89 (s, 1H), 7.38 - 7.5 (m, 1H), 7.29 -7.25 (m, 1H), 6.99 (t, J= 7.5 Hz, 2H), 6.77 (s, 1H), 5.71 (t, J= 8.0 Hz, 1H), 5.60 - 5.56 (m, 1H), 3.05-2.91 (m, 4H), 2.80-2.60 (m, 8H), 2.29 (t, J= 0.8 Hz, 3H), 1.99 (t, J= 7.5 Hz, 2H), 1.49 - 1.42 (m, 1H), 0.98 - 0.93 (m, 6H).

AE-P2 ESI 690.0 (M+H)⁺. ’H NMR (400 MHz, MeOD) δ 7.88 (s, 1H), 7.37 (t, J= 9.0 Hz, 2H), 7.09 - 7.03 (m, 2H), 6.92 (s, 1H), 5.76 - 5.72 (m, 1H), 5.65 (t, J= 7.7 Hz, 1H), 3.29 - 3.10 (m, 2H), 3.00 (t, J= 6.6 Hz, 2H), 2.80 (s, 6H), 2.66 - 2.61 (m, 1H), 2.56 - 2.50 (m, 1H), 2.34 (d, J= 1.4 Hz, 3H), 2.01 - 1.94 (m, 1H), 1.77 - 1.61 (m, 1H), 1.43 - 1.37 (m, 1H), 0.90 - 0.87 (m, 6H).

3-27. Préparation of (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2£0-yI)-4-methylpentanamido)-3-(3’,4-difluoro-2’,5,6*-trimethyl-(l,l’-biphenyl]-3yl)propanoic acid (compounds AF-P1 and AF-P2)

Step 1: ethyl (35)-3-(2-(5-(2-(azetidin-l-yI)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2ZZ)yl)-4-methylpentanamido)-3-(3*,4-difluoro-2’,5,6’-trimethyI-[l,l’-biphenyl]-3-yl)propanoate

TCFH.NMl.CH3CN.rt

A mixture of ethyl (5)-3-amino-3-(3',4-difluoro-2’,5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate (120.0 mg, 0.34 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)yl)-4-methylpentanoic acid (122.4 mg, 0.34 mmol), TCFH (190.4 mg, 0.68 mmol), NMI (115.5 mg, 1.36 mmol) in CH3CN (5 mL) was stirred at room température for 2 hours. The solvent was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8 / 40 g column (A: water 10 mM NHqHCCh.B: MeOH, 0-100%) to provide ethyl (35)-3-(2-(5-(2390 (azetîdin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2/7)-yl)-4-methylpentanamido)-3-(3',4difluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate as a white oil (90.0 mg). Yield 38% (ESI 690.3 (M+H)⁺).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yi)ethyi)-2-oxo-4-(trifluoromethyI)pyridin-l(2jF/)-yI)-4methylpentanamido)-3-(3’,4-difluoro-2’,5,6’-trimethy!-[l,l*-biphenylJ-3-yl)propanoic acid

Ethyl (3S)-3-(2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methyIpentanamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)propanoate (90 mg, 0.13 mmol) was treated with LiOH-H₂O (22 mg, 0.52 mmol) in MeOH (4 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was rcmoved in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to provide the diastereomeric products AF-P1 (15 mg) and AF-P2 (15 mg) as white solids.

AF-P1 ESI 662.2(M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 7.14 - 7.01 (m, 1H), 7.00 - 6.84 (m, 3H), 6.79 (d, J = 7.3 Hz, 1H), 5.70 - 5.51 (m, 2H), 4.13 - 3.94 (m, 4H), 3.28 - 3.18 (m, 2H), 2.86 (t, J = 6.9 Hz, 2H), 2.72 (d, J = 6.5 Hz, 2H), 2.54 - 2.37 (m, 2H), 2.31 (s, 3H), 2.06 - 1.95 (m, 3H), 1.96 - 1.70 (m, 5H), 1.50 - 1.32 (m, 1 H), 1.01 - 0.83 (m, 6H).

AF-P2 ESI 662.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.74 (s, 1 H), 7.19 - 7.04 (m, 1H), 7.03 - 6.82 (m, 4H), 5.85 - 5.70 (m, 1H), 5.61 (t, J= 7.6 Hz, 1H), 4.13 (t, J= 7.5 Hz, 4H), 3.41 (s, 2H), 2.94 (d, J= 15.8 Hz, 1H), 2.87 - 2.73 (m, 1H), 2.70 - 2.58 (m, 1H), 2.56 - 2.40 (m, 3H), 2.35 (d, J = 1.5 Hz, 3H), 2.00 (t, J = 7.6 Hz, 4H), 1.94 - 1.85 (m, 3H), 1.73 - 1.57 (m, 1 H), 1.48 - 1.36 (m, 1H), 0.91 (d, J= 6.6 Hz, 6H).

391

3-28. Préparation of (35>3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2jF7)-yl)-4-methylpentanamido)-3-(4-fluoro-3'-methoxy-2',5,6’-trimethyl-[l,r-biphenyl]-3yl)propanoic acid (compounds AG-P1 and AG-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(27/)yl)-4-methylpentanamido)-3-(4-fluoro-3’-methoxy-2*,5,6*-trimethyl-[l,l’-biphenyl]-3yl)propanoate

A mixture of 2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yi)-4methylpentanoic acid (160 mg, 0.44 mmol, 1.0 eq), ethyl (S)-3-amino-3-(4-fluoro-3'-methoxy2',5,6’-trimethyl-[l,r-biphenyl]-3-yl)propanoate (158 mg, 0.44 mmol, 1.0 eq), Ν,Ν,Ν,ΝTetramethylchloroformamidinium hexafluorophosphate (246 mg, 0.88 mmol, 2 eq) and NMI (144 mg, 1.76 mmol, 4.0 eq) in CHjCN (5 mL) was stirred at room température for 2 hours. LCMS showed that the reaction was completed. The solvent was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0-100%) to provide ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2//)-yl)-4-mcthylpentanamido)-3-(4-fluoro-3'-methoxy-2',5,6'trimethyl-[l,r-biphenyl]-3-yl)propanoate as a yellow solid (170 mg). Yield 55% (ESI 702.1 [M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trinuoromcthyl)pyridin-l(277)-yl)-4methyIpentanamido)-3-(4-fluoro-3’-methoxy-2’,5,6’-trimethyl-[l,l’-biphenyI]-3yl)propanoic acid

392

Ethyl (35)-3-(2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2/7)-yl)-4methylpentanamido)-3-(4-fluoro-3'-methoxy-2’,5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)propanoate (170 mg, 0.24 mmol, 1.0 eq) was treated with LiOH-IbO (40 mg, 0.96 mmol, 4.0 eq) in MeOH (4 mL) and water (1 mL) at 30°C for 1 hour. LCMS showed that the reaction was completed. The reaction mixture was acidifïed to pH 5~6 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to provide the diastereomeric Products AG-P1 (50.8 mg) and AG-P2 (60 mg) as white solids.

AG-P1 ESI 674.3 (M+H)+. Ή NMR (500 MHz, MeOD) δ 7.83 (s, 1H), 7.03 (t, J= 7.8 Hz, 1H), 6.92 - 6.76 (m, 4H), 5.63-5.59 (m, 2H), 4.03 - 3.97 (m, 4H), 3.83 (s, 3H), 3.32 - 3.24 (m, 2H), 2.86 (t, J= 6.7 Hz, 2H), 2.72 - 2.70 (m, 2H), 2.49 - 2.37 (m, 2H), 2.30 (s, 3H), 1.99 (t, J= 7.6 Hz, 2H), 1.89 (d, J= 37.2 Hz, 3H), 1.78 (d, J = 34.9 Hz, 3H), 1.49 - 1.34 (m, 1H), 0.96 - 0.92 (m, 6H).

AG-P2 ESI 674.2 (M+H)+. Ή NMR (500 MHz, MeOD) δ 7.74 (s, 1H), 7.06 (d, J= 8.3 Hz, 1H), 6.94-6.89 (m, 3H), 6.84 (d, J= 8.4 Hz, 1H), 5.79-5.76 (m, 1H), 5.60 (t, J= 7.6 Hz, 1H), 4.14 (t, J = 8.0 Hz, 4H), 3.84 (d, J= 1.1 Hz, 3H), 3.50- 3.40 (m, 1H), 3.36 (d, J= 9.5 Hz, 1H), 2.94 (d, J = 16.2 Hz, 1H), 2.86- 2.76 (m, 1H), 2.69 - 2.61 (m, 1H), 2.57 - 2.44 (m, 3H), 2.34 (d, J= 1.3 Hz, 3H), 2.05 - 1.96 (m, 1H), 1.93 (d, J= 6.2 Hz, 3H), 1.86 (d, J= 4.9 Hz, 3H), 1.68-1.63 (m, 1H), 1.45-1.40 (m, 1H), 0.90 (d, J= 6.3 Hz, 6H).

3-29. Préparation of (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyI)pyridin-l(27/)-yl)-4-methylpentanamido)-3-(2'-ethyl-4-fluoro-5,6'dimethyl-[l,l’-biphenyl]-3-yl)propanoic acid (compounds AH-P1 and AH-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)-4-methylpentanamido)-3-(2’-ethyl-4-fluoro-5,6’-diniethyl-[l,l’-biphenyi]-3393 yl)propanoate

A mixture of ethyl (S)-3-amino-3-(2'-ethyl-4-fluoro-5,6'-dimethyl-[l,r-biphenyl]-3yl)propanoate (150 mg, 0.43 mmol), 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2/y)-yl)-4-methylpentanoic acid (101 mg, 0.52 mmol), TCFH (180 mg, 0.64 mmol) and NMI (70 mg, 0.86 mmol) in CH3CN (5 mL) was stirred at 20 °C for 2 hours. The solvent was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8 Z 40 g column (A: water 10 mM NHiHCCh.B: MeOH, 0-100%) to provide ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yl)-4methylpentanamido)-3-(2’-ethyl-4-fluoro-5,6'-dimethyl-[ 1,1 '-biphenyl]-3-yl)propanoate as a yellow oil (180 mg). Yield 62% (ESI 674.2 (M+H)⁺).

Step 2: (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2f0-yl)-4methyIpentanamido)-3-(2’-ethyI-4-fluoro-5,6’-dimethyI-[l,r-biphenylJ-3-yI)propanoic acid

Ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2//)-yl)-4methylpentanamido)-3-(2'-ethyl-4-fluoro-5,6'-dimethyl-[ 1,1 '-biphenyl]-3-yl)propanoate ( 150 mg, 0.22 mmol) was treated with L1OH-H2O (28 mg, 0.66 mmol) in MeOH (2 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4-5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products AH-P1 (66 mg) and AH-P2 (46 mg) as white solids.

394

AH-P1 ESI 646.3(M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.90 (s, 1H), 7.16 - 7.05 (m, 3H), 6.90 - 6.86 (m, 2H), 6.76 (d, J= 7.9 Hz, 1H), 5.70 - 5.57 (m, 2H), 3.09 (d, J= 7.1 Hz, 2H), 2.95 (d, J = 7.2 Hz, 2H), 2.75 - 2.70 (m, 8H), 2.34 - 2.29 (m, 4H), 2.20 - 2.18 (m, 1H), 2.00 - 1.96 (m, 3H), 1.79 (s, 1H), 1.47 - 1.39 (m, 1H), 1.02 - 0.92 (m, 8H), 0.83 (t, J= 7.5 Hz, 2H).

AH-P2 ESI 646.3(M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.84 (d, J= 6.6 Hz, 1H), 7.18 (t, J= 7.5 Hz, 1H), 7.12 - 7.07 (m, 2H), 6.96 - 6.89 (m, 3H), 5.74 - 5.70 (m, 1H), 5.61 (t, J= 7.6 Hz, 1H), 3.31-3.14 (m, 2H), 3.00 (t, J= 6.7 Hz, 2H), 2.81 (d, J= 1.2 Hz, 6H), 2.62-2.61 (m, 1H), 2.57-2.44(m, 1H), 2.36-2.31 (m, 5H), 2.00- 1.97 (m, 4H), 1.71-1.65 (m, 1H), 1.42-1.37 (m, 1 H), 1.02 - 0.98 (m, 3H), 0.88 (d, J = 6.5 Hz, 6H).

3-30. Préparation of (3$)-3-(5-chloro-4-fluoro-2’,4’»6’-trîmethyl-[l,l’-biphenyl]-3-yl)-3-(2(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2fl)-yl)-4methylpentanamido)propanoic acid (compounds AI-P1 and AI-P2)

Step 1: ethyl (35)-3-(5-chloro-4-fluoro-2’,4’,6’-trîmethyl-[l,r-biphenylJ-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanamido)propanoate

A mixture of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanoic acid (120 mg, 0.34 mmol), ethyl (S)-3-amino-3-(5-chloro-4-fluoro-2’,4^,,6'trimethyl-[l,r-biphenyl]-3-yl)propanoate (145 mg, 0.40 mmol), TCFH (142 mg, 0.51 mmol), NMI (139.4 mg, 1.7 mmol) in CH3CN (4 mL) was stirred at room température for 1 hour. The solvent was concentrated in vacuo and the residue was by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NHqHCOa.B: MeOH, 0—100%) to provide ethyl (3S)-3-(5-chloro-4fluoro-2',4',6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4395 (trifluoromethyl)pyridin-l(2/7)-yl)-4-methylpentanamido)propanoate as a red oil (175 mg). Yield 74% (ESI 694.2 (M+H)⁺).

Step 2: (3S)-3-(5-chIoro-4-fluoro-2’,4’,6’-trimethyl-il,l’-biphenyl]-3-yI)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2ff)-yl)-4methylpentanamido)propanoic acid

Ethyl (3S)-3-(5-chloro-4-fluoro-2',4',6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2//)-yl)-4methylpentanamido)propanoate (175 mg, 0.25 mmol) was treated with L1OH-H2O (52.5 mg, 1.25 mmol) in EtOH (3 mL) and H2O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products AIP1 (29 mg) and AI-P2 (23 mg) as white solids.

AI-P1 ESI 666.2 (M+H)⁺. ’H NMR (400 MHz, MeOD) δ 7.90 (s, 1H), 7.08 - 7.06 (m, 1H), 7.01 -6.98 (m, 1H), 6.92 (s, lH),6.87(s, 1H),6.71 (s, 1H), 5.70-5.65 (m, 1H), 5.56-5.62 (m, 1H), 3.17-2.89 (m, 4H), 2.82-2.63 (m, 8H), 2.30 (s, 3H), 2.08 - 1.91 (m, 5H), 1.76 (s, 3H), 1.52 1.38 (m, 1H), 1.03 - 0.83 (m, 6H).

AI-P2 ESI 666.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.89 (s, 1H), 7.16 - 7.13 (m, 1H), 7.08 - 67.05 (m, 1H), 6.93 (s, 2H), 6.89 (s, 1H), 5.77 - 5.54 (m, 2H), 3.28 - 3.17 (m, 2H), 3.02 - 2.98 (m, 2H), 2.83 (s, 6H), 2.71 - 2.47 (m, 2H), 2.31 (s, 3H), 2.11 - 1.87 (m, 7H), 1.83 - 1.64 (m, 1H), 1.46-1.23 (m, 1H), 1.06-0.62 (m, 6H).

3-31. Préparation of (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2//)-yl)-4-methylpentanamido)-3-(2',4-difluoro-4',5,6'-trimethylbiphenyl-3-yl)propanoic acid (compounds AJ-P1 and AJ-P2)

396

Step 1: ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(tiïfluoromethyl)pyridin-l(2jE/)yI)-4-methylpentanamido)-3-(2’,4-difluoro-4’,5,6’-trimethyl-[l,r-biphenyIJ-3-yl)propanoate

A mixture of 2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 methylpentanoic acid (150 mg, 0.42 mmol), ethyl (S)-3-amino-3-(2^,,4-difluoro-4’,5,6’-trimethyl[l,l’-biphenyl]-3-yl)propanoate (145 mg, 0.42 mmol), TCFH (141 mg, 0.50 mmol) and NMI (104 mg, 1.26 mmol) in CH3CN (5 mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM:MeOH 4:1) to provide ethyl (3S)-3-(2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2//)-yl)-4methylpentanamido)-3-(2',4-difluoro-4’,5,6’-trimethyl-[ 1,1 '-biphenyl]-3-yl)propanoateas a white solid (130 mg). Yield 45% (ESI 690.3 (M+H)⁺).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethy))pyridin-l(2F0-yl)-4methylpentanamido)-3-(2’,4-difluoro-4’,5,6’-trimethylbiphenyl-3-yl)propanoic acid

Ethyl (35)-3-(2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (27¥)-yl)-4methylpentanamido)-3-(2',4-difluoro-4',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate (130 mg, 0.19 mmol) was treated with LiOH-HiO (40 mg, 0.95 mmol) in THF (3 mL) and H2O (1 mL) at room température for 3 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products AJ-P1 (30.0 mg) and AJ-P2 (29.7 mg) as white solids.

397

AJ-P1 ESI 662.2 (M+H)+. Ή NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 6.99 (t, J= 6.3 Hz, 2H), 6.92 (s, 1H), 6.79 (t, J= 4.9 Hz, 2H), 5.68 (t, J= 8.0 Hz, 1H), 5.59 (t, J= 6.6 Hz, 1H), 4.00 3.96 (m, 4H), 3.30 - 3.25 (m, 2H), 2.85 (t, J= 6.9 Hz, 2H), 2.72 - 2.70 (m, 2H), 2.44 - 2.37 (m, 2H), 2.35 (s, 3H), 2.29 (d, J= 1.2 Hz, 3H), 2.05 (s, 3H), 2.00 (t, J= 7.6 Hz, 2H), 1.45 - 1.40 (m, 1H), 0.95 (t, J = 7.1 Hz, 6H).

AJ-P2 ESI 662.2 (M+H)⁺. ^lH NMR (400 MHz, MeOD) δ 7.76 (s, 1H), 7.08 (d, J= 6.5 Hz, 1H), 7.04 (d, J= 6.9 Hz, 1H), 6.93 (d, J= 8.1 Hz, 2H), 6.82 (d, J= 10.4 Hz, 1H), 5.78 - 5.74 (m, 1H), 5.64 (t, J= Ί.Ί Hz, 1H), 4.11 (t, J= 8.0 Hz, 4H), 3.44 - 3.38 (m, 1H), 2.96 - 2.89 (m, 1H), 2.84 2.76 (m, 1H), 2.67 - 2.62 (m, 1H), 2.57 - 2.43 (m, 3H), 2.35 - 2.33 (m, 6H), 2.11 (s, 3H), 2.02 1.94 (m, 1 H), 1.71 - 1.64 (m, 1 H), 1.44 - 1.30 (m, 2H), 0.91 - 0.88 (m, 6H).

3-32. Préparation of (35)-3-(4,4’-difluoro-2*,5,6’-trimethyl-[l,l’-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyi)-2-oxo-4-(trifluoromethyl)pyridin-l(2j60-yl)-4methylpcntanamido)propanoic acid (compounds AK-P1 and AK-P2)

Step 1: ethyl (35)-3-(4,4’-difluoro-2’,5,6^,-trimethyl-|l,l’-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trÎfluoromethyl)pyridin-l(2ZZ)-yl)-4methylpentanamido)propanoate

A mixture of ethyl (S)-3-amino-3-(4,4'-difluoro-2’,5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate (150 mg, 0.43 mmol), 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2/7)yl)-4-methylpentanoic acid (180 mg, 0.51 mmol), TCFH (240 mg, 0.86 mmol) and NMI (106 mg, 1.29 mmol) in CHjCN (5 mL) was stirred at 20 °C for 2 hours. The solvent was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl 8 /40 g column (A: water

398 mM NH4HCO3.B: MeOH, 0-100%) to provide ethyl (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl[1,1 '-biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l (2H)yl)-4-methylpentanamido)propanoate as a yellow oil (120 mg). Yield 41% (ESI 678.1 (M+H)⁺).

Step 2: (35)-3-(4,4’-difluoro-2’,5,6*-trimethyI-[l,l’-biphenyl]-3-yl)-3-(2-(5-(2(dimetliylamino)ethyl)-2-oxo-4-(trifluoroniethyl)pyridin-l(2Z/)-yl)-4methylpentanamido)propanoic acid

Ethyl (33)-3-(4,4'-difluoro-2',5,6’-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (217)-yl)-4methylpentanamido)propanoate (100 mg, 0.14 mmol) was treated with L1OH-H2O (18 mg, 0.44 mmol) in MeOH (2 mL) and H2O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4-5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to provide the diastereomeric products AK-P1 (36 mg) and AK-P2 (32 mg) as white solids.

AK-P1 ESI 650.3(M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.91 (s, 1H), 6.88 - 6.74 (m, 5H), 5.69 (t, J= 8.1 Hz, 1H), 5.58 - 5.54 (m, 1H), 3.19 - 3.07 (m, 2H), 3.02 - 2.95 (m, 2H), 2.84 - 2.67 (m, 8H), 2.30 (t, J= 8.2 Hz, 3H), 2.03 - 1.94 (m, 5H), 1.80 (d, J= 9.4 Hz, 3H), 1.48 - 1.39 (m, 1H), 0.97-0.88 (m, 6H).

AK-P2 ESI 650.2(M+H)⁺. ’H NMR (400 MHz, MeOD) δ 7.88 (s, 1H), 6.93 - 6.83 (m, 5H), 5.71 - 5.62 (m, 2H), 3.19 (s, 2H), 3.00 - 2.97 (m, 2H), 2.80 (s, 6H), 2.67 - 2.57 (m, 2H), 2.32 (d, J= 1.5 Hz, 3H), 2.01 - 1.93 (m, 7H), 1.79 - 1.74 (m, 1 H), 1.42 - 1.35 (m, 1 H), 0.90 - 0.87 (m, 6H).

399

3-33. Préparation of (35)-3-(4,4'-difluoro-2’,5,6’-trimethyl-[l,r-biphenyl|-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-3-fluoro-4-methyl-2-oxopyridin-l(2Z0-yl)-4methylpentanamido)propanoic acid (compounds AL-P1 and AL-P2)

Step 1: ethyl (S)-3-(4,4’-difluoro-2’,5,6’-trimethyI-[l,l’-biphenyl]-3-yI)-3-((S)-2-(5-(2 (dimethylamino)ethyl)-3-fluoro-4-methyl-2-oxopyridin-l(2H)-yl)-4methylpentanamido)propanoate

To a solution of 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-4-methyl-2-oxopyridin-l(2H)-yl)-4methylpentanoic acid (1g, 3.20 mmol) and HATU (2.434 g, 6.40 mmol) in DMF (16.01 mL) was added TEA (0.892 mL, 6.40 mmol) at room température. After stirring for 5 minutes, ethyl (S)3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate (1.668 g, 4.80 mmol) in 5.0 mL DMF was added to the solution. The reaction mixture was dilluted with 200 mL of water and 10 mL of brine. The mixture was washed (EtOAc; 200 mL X 3). The combined organic phase was dried over Na₂SO4, conentrated and purified by silica gel column (DCM: MeOH 10: 1) to provide ethyl (S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)-3-((S)2-(5-(2-(dimethylamino)ethyl)-3-fiuoro-4-methyl-2-oxopyridin-l(2H)-yl)-4methylpentanamido)propanoate (1.76 g, 86% yield) as pinkish oil. (ESI 642 (M+H)⁺)

Step 2: (35)-3-(4,4’-difluoro-2’,5,6’-trimethyl-[l,l’-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-3-fluoro-4-methyl-2-oxopyridin-l(2Z/)-yl)-4methylpentanamido)propanoic acid

400

Ethyl (3S)-3-(4,4^,-difluoro-2’,5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-3-fluoro-4-methyl-2-oxopyridin-1 (2//)-yl)-4methylpentanamido)propanoate (1.65 g, 2.6 mmol, 1.0 eq) was treated with LiOH monohydrate (391 mg, 9.3 mmol, 4.0 eq) in methanol (5 mL), THF (5 mL) and H₂O (5 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl aqueous solution, concentrated in vacuo and the residue was purified by prep HPLC A to provide the diastereomeric products AL-P1 (383 mg) and AL-P2 (239 mg) as white solids.

AL-P1 ESI 614.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.48 (s, IH), 6.86 - 6.81 (m, 4H), 5.66- 5.60 (m, IH), 5.50 - 5.47 (m, IH), 3.22 -3.12 (m, 2H), 2.93 -2.89 (m, 2H), 2.77 (s, 6H), 2.72 - 2.61 (m, 2H), 2.29 (d, 1.6 Hz, 3H), 2.25 (d, J = 2.8 Hz, 3H), 2.00 - 1.93 (m, 5H), 1.88 (s, 3H), 1.46 - 1.36 (m, IH), 0.95 -0.90 (m, 6H).

AL-P2 ESI 614.2 (M+H)⁺. *H NMR (400 MHz, MeOD) δ 7.43 (s, IH), 6.88 (dd, J= 24.6,8.2 Hz, 4H), 5.66 - 5.57 (m, 2H), 3.27 - 3.13 (m, 2H), 2.97 - 2.93 (m, 2H), 2.86 (s, 6H), 2.62 - 2.57 (m, IH), 2.51 - 2.39 (m, IH), 2.33 (d, J= 1.7 Hz, 3H), 2.25 (d, J= 2.7 Hz, 3H), 2.05 - 1.93 (m, 7H), 1.80-1.73 (m, IH), 1.41 - 1.34 (m, IH), 0.91-0.89 (m, 6H).

3-34. Préparation of (35)-3-(2-(5-(2-(dimethyIamino)ethyl)-3-fluoro-4-methyl-2oxopyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2’,5,6'-trimethyl-[l,r-biphenylj-3yl)propanoic acid (compounds AM-P1 and AM-P2)

401

To a solution of 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-4-methyl-2-oxopyridin-l(2H)-yl)-4methylpentanoic acid (1g, 3.20 mmol) and HATU (2.434 g, 6.40 mmol) in DMF ( 16.01 mL) was added TEA (0.892 mL, 6.40 mmol) at room température. After stirring for 5 minutes, ethyl (S)3-amino-3-(4,4^,-difluoro-2',5,6’-trimethyl-[l,r-biphenyl]-3-yl)propanoate (1.668 g, 4.80 mmol) in 5.0 mL DMF was added to the solution. The reaction mixture was dilluted with 200 mL of water and 10 mL of brine. The mixture was washed (EtOAc; 200 mL X 3). The combined organic phase was dried over Na₂SO4, conentrated and purified by silica gel column (DCM: MeOH 10: 1) to provide ethyl (S)-3-(4,4'-difluoro-2',5,6^,-trimethyl-[l,r-biphenyl]-3-yl)-3-((S)2-(5-(2-(dimethylamino)ethyl)-3-fluoro-4-methyl-2-oxopyridin-l(2H)-yl)-4methylpentanamido)propanoate (1.76 g, 86% yield) as pinkish oil. (ESI 642 (M+H)⁺)

Step 2: (35)-3-(4,4’-difluoro-2',5,6'-trimethyl-[l,l*-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-3-fIuoro-4-methyl-2-oxopyridin-l(2Z7)-yl)-4methylpentanamido)propanoic acid

Ethyl (35)-3-(2-(5-(2-(dimethylamino)ethyl)-3-fluoro-4-methyl-2-oxopyridin-1 (2/7)-yl)-4methylpentanamido)-3-(4-fluoro-2^,,5,6'-trimethyl-[l,l’-biphenyl]-3-yl)propanoate (1.2 g, 1.93 mmol) was treated with LiOH-H₂O (162 mg, 3.85 mmol) in THF (12 mL) and H₂O (2 mL) at room température for 30 mins. The reaction mixture was acidified to pH 4~5 with 2N HCl. The solvent was removed in vacuo and the residue was purified by purified by prep-HPLC A (3060% MeCN) to give the diastereomeric products AM-P1 (482 mg) and AM-P2 (237mg) as white solids.

AM-P1 ESI 596.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.47 (s, 1H), 7.16 - 7.01 (m, 3H), 6.90 - 6.79 (m, 2H), 5.68 - 5.64 (m, 1H), 5.51 -5.48 (m, 1H), 3.17 - 3.08 (m, 2H), 2.92 - 2.88

402 (m, 2H), 2.76 (s, 6H), 2.72 - 2.44 (m, 2H), 2.29 (s, 3H), 2.23 (d, J= 2.6 Hz, 3H), 1.99 - 1.94 (m, 5H), 1.87 (s, 3H), 1.42 - 1.38 (m, 1H), 0.94 - 0.90 (m, 6H).

AM-P2 ESI 596.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.39 (s, 1H), 7.15 - 7.08 (m, 3H), 6.93 - 6.90 (m, 2H), 5.67 - 5.60 (m, 2H), 3.32 - 3.28 (m, 1H), 3.22 - 3.16 (m, 1H), 2.96 - 2.92 (m, 2H), 2.84 (s, 6H), 2.63 - 2.58 (m, 1H), 2.50 - 2.43 (m, 1H), 2.32 (d, J= 1.6 Hz, 3H), 2.24 (d, 7=2.8 Hz, 3H), 2.01-1.93 (m, 7H), 1.78-1.71 (m, 1H), 1.41-1.34 (m, 1H), 0.90(d,7= 6.8 Hz, 6H).

3-35. Préparation of (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2Z7)-yl)-4-methylpentanamido)-3-(4-fluoro-2’,4',5,6’-tetrainethyl-[l,r-biphenyl]-3yl)propanoic acid (compounds AN-PI and AN-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)yl)-4-methylpentanamido)-3-(4-fluoro-2’,4’,5,6’-tetramethyl-[l,l’-biphenylj-3yl)propanoate

A mixture of2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methylpentanoic acid (150 mg, 0.41 mmol), ethyl (S)-3-amino-3-(4-fluoro-2',4',5,6'-tetramethyl[l,l’-biphenyl]-3-yl)propanoate (141 mg, 0.41 mmol), TCFH (230 mg, 0.82 mmol),NMI (135 mg, 1.64 mmol) in CH₃CN (5 mL) was stirred at room température for 2 hours. The solvent was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8 / 40 g column (A: water 10 mM NH4HCO₃,B: MeOH, 0-100%) to provide ethyl (35)-3-(2-(5-(2(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (277)-yl)-4-methylpentanamido)-3-(4fluoro-2',4’,5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoate as a white oil (90 mg). Yield 32% (ESI 686.3 (M+H)⁺).

403

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2jF/)-yl)-4methylpentanamido)-3-(4-fluoro-2’,4*,5,6’-tetramethyI-[l,l’-biphenyl]-3-yl)propanoic acid

Ethyl (35)-3-(2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2/¥)-yl)-4methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[ 1,1 '-biphenyl]-3-yl)propanoate (90 mg, 0.14 mmol) was treated with LiOH-H₂O (24 mg, 0.56 mmol) in MeOH (4 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products AN-P1 (22 mg) and AN-P2 (22 mg) as white solids.

AN-PI ESI 658.3(M+H)⁺. ’H NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 6.96 - 6.83 (m, 4H), 6.80 (s, 1H), 5.73 - 5.50 (m, 2H), 4.03 (s, 4H), 3.15 (s, 2H), 2.86 (t, J= 6.7 Hz, 2H), 2.77 - 2.62 (m, 2H), 2.51 -2.38 (m, 2H), 2.30 (s, 6H), 2.09- 1.91 (m, 5H), 1.85 (s, 3H), 1.49-1.30 (m, 1H), 1.04-0.83 (m, 6H).

AN-P2 ESI 658.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.75 (s, 1H), 6.92 (t, J= 7.5 Hz, 5H), 5.84 - 5.72 (m, 1H), 5.61 (t, J= 7.6 Hz, 1H), 4.14 (s, 4H), 3.42 (s, 2H), 2.94 (d, J= 16.0 Hz, 2H), 2.87 - 2.59 (m, 2H), 2.56 - 2.41 (m, 2H), 2.37 - 2.25 (m, 6H), 2.05 - 1.88 (m, 7H), 1.72 1.59 (m, 1H), 1.47 - 1.34 (m, 1H), 0.96 - 0.82 (m, 6H).

3-36. Préparation of (35)-3-(2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridinl(2£/)-yl)-4-methylpentanamido)-3-(5-chloro-4-fluoro-2’,6’-dimethyl-[l,r-biphenyl]-3yl)propanoic acid (compounds AO-PI and AO-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)yI)-4-methylpentanamido)-3-(5-chloro-4-fluoro-2’,6’-dimethyl-[l,r-biphenyl]-3yl)propanoate

404

A mixture of 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methylpentanoic acid (150 mg, 0.42 mmol), ethyl (5)-3-amino-3-(5-chloro-4-fluoro-2',6’dimethyl-[l,r-biphenyl]-3-yl)propanoate (154 mg, 0.42 mmol), TCFH (180 mg, 0.63 mmol) and

NMI (100 mg, 1.26 mmol) in CH3CN (5 mL) was stirred at 40°C for 2 hours. The solvent was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl 8 / 40 g column (A: water 10 mM NH4HCO3.B: MeOH, 0-100%) to provide ethyl (35)-3-(2-(5-(2(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanamido)-3-(5chloro-4-fluoro-2’,6'-dimethyl-[l,r-biphenyl]-3-yl)propanoate as a yellow oil (150 mg). Yield

52.8% (ESI 692.0 (M+H)⁺).

Step 2: ethyl (35)-3-(2-(5-(2-(azetidin-l-yl)cthyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)yI)-4-methylpentanamido)-3-(5-chloro-4-fluoro-2',6’-dimethyI-[l,l^,-biphenyll-3yl)propanoate

Ethyl (35)-3-(2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2/7)-yl)-4methylpentanamido)-3-(5-chloro-4-fluoro-2^,,6^,-dimethyl-[l,r-biphenyl]-3-yl)propanoate (150 mg, 0.22 mmol) was treated with LiOH-HzO (95.5 mg, 2.3 mmol) in MeOH (4 mL) and H2O (4 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4-5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60%

405

CH3CN) to give the diastereomeric products AO-PI (29 mg) and AO-P2 (34 mg) as white solids.

AO-PI ESI 664.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.72 (s, IH), 7.11 - 6.90 (m, 5H), 6.65 (s, IH), 5.60 - 5.40 (m, 2H), 3.91 (t, J= 8.2 Hz, 4H), 3.21 - 3.11 (m, 2H), 2.73 (t, J= 7.0 Hz, 2H), 2.67 - 2.55 (m, 2H), 2.41 - 2.25 (m, 2H), 1.96 - 1.83 (m, 5H), 1.77 (s, 3H), 1.36 - 1.24 (m, IH), 0.88-0.77 (m, 6H).

AO-P2 ESI 664.2 (M+H)⁺. ‘H NMR (400 MHz, MeOD) δ 7.75 (s, IH), 7.26 - 7.07 (m, 5H), 6.90 (s, IH), 5.86 - 5.74 (m, IH), 5.62 (t, J= Ί.6 Hz, IH), 4.14 (t, J= 7.9 Hz, 4H), 3.49 - 3.36 (m, 2H), 3.01 - 2.74 (m, 2H), 2.71 - 2.62 (m, IH), 2.59 - 2.43 (m, 3H), 2.12 - 1.91 (m, 7H), 1.77 - 1.58 (m, IH), 1.49 - 1.32 (m, IH), 0.90 (d, J = 6.6 Hz, 6H).

3-37. Préparation of (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2f7)-yl)-4-methylpentanamido)-3-(4-fluoro-2’,5,6’-trimethyl-[l,r-biphenyI]-3yl)propanoic acid (compounds AP-P1 and AP-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)yl)-4-methylpentanamido)-3-(4-fluoro-2’,5,6’-trimethyl-[l,l’-biphenyI]-3-yl)propanoate

A mixture of 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanoic acid (262 mg, 0.73 mmol, 1.20 eq), ethyl (<S)-3-amino-3-(4-fluoro-2',5,6’trimethyl-[l,l’-biphenyl]-3-yl)propanoate (200 mg, 0.61 mmol, 1.00 eq), NMI (0.5 mL) and TCFH (255mg, 0.91 mmol, 1.50 eq) in CHjCN (5 mL) was stirred at room température for 1 hour. The solvent was concentrated in vacuo and the residue was purified reverse phase HPLC on a C18/40 g column (A: water 10 mM NH4HCO3.B: MeOH, 0-100%) to provide ethyl (35)-3406 (2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2//)-yl)-4methylpentanamido)-3-(4-fluoro-2',5,6^,-trimethyl-[I,r-biphenyl]-3-yl)propanoate as a white solid (300 mg). Yield 73.5% (ESI 672.3 [M+H]⁺).

Step 2: (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(27Z)-yl)-4methylpentanamido)-3-(4-fluoro-2’,5,6’-trimethyI-[l,l’-bîphenyI]-3-yl)propanoîc acid

Ethyl (3S)-3-(2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2/7)-yl)-4methylpentanamido)-3-(4-fluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate (300 mg, 0.45 mmol, 1.00 eq) was treated with L1OH-H2O (100 mg, 2.38 mmol, 5.00 eq) in MeOH (5 mL) and HzO (1 mL) at room température for 1 hour. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (3060% MeCN) to give AP-P1 (30 mg) and AP-P2 (50 mg) as white solids.

AP-P1 ESI 644.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 7.17 - 7.02 (m, 3H), 6.96 - 6.85 (m, 2H), 6.80 (s, 1H), 5.71- 5.56 (m, 2H), 4.13 - 3.94 (m, 4H), 3.33 - 3.29 (m, 2H), 2.86 (t, J= 6.7 Hz, 2H), 2.71 (d, J= 6.1 Hz, 2H), 2.48 - 2.40 (m, 2H), 2.31 (d, J= 1.7 Hz, 3H), 2.07 1.92 (m, 5H), 1.89 (s, 3H), 1.45 - 1.39 (m, 1H), 0.99 - 0.84 (m, 6H).

AP-P2 ESI 644.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.75 (s, 1H), 7.12 - 7.08 (m, 3H), 6.97 - 6.9I(m, 3H), 5.79 - 5.76 (m, 1H), 5.61 (t, J= 7.6 Hz, 1H), 4.14 (t, J= 7.5 Hz, 4H), 3.53 - 3.34 (m, 2H), 2.94 (d, J= 15.6 Hz, 1H), 2.88 - 2.71 (m, 1H), 2.68 - 2.63 (m, 1H), 2.54 - 2.44 (m, 3H), 2.34 (s, 3H), 2.02 - 1.96 (m, 7H), 1.75 - 1.54 (m, 1H), 1.45 - 1.39 (m, 1H), 0.90 (d, J= 6.4 Hz, 6H).

3-38. Préparation of (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridinl(2Z0-yl)-4-^metbylp^entanam>d°)^_3-(4,4’-difluoro-2’,5,6’-trimethyl-[l,l’-biphenyIJ-3yl)propanoic acid (compounds AQ-P1 and AQ-P2)

407

Step 1: ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z0yI)-4-methyIpentanamido)-3-(4,4’-difluoro-2’,5,6’-trimethyl-[l,l’-biphenyl]-3-yl)propanoate

A mixture of 2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2/7)-yl)-45 methylpentanoic acid (165 mg, 0.46 mmol), ethyl (S)-3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl[l,l'-biphenyl]-3-yl)propanoate (160 mg, 0.46 mmol), TCFH (193 mg, 0.69 mmol) and NMI (188 mg, 2.3 mmol) in CH3CN (4 mL) was stirred at 40 °C for 2 hours. The solvent was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl8 /40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0-100%) to provide ethyl (35)-3-(2-(5-(210 (azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2Z7)-yl)-4-methylpentanamido)-3-(4,4’difluoro-2’,5,6’-trimethyl-[l,r-biphenyl]-3-yl)propanoate as a yellow oil (200 mg). Yield 62% (ESI 690.2 (M+H)⁺).

Step 2: (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifhioromethyl)pyridin-l(2/7)-yl)-4methy)pentanamido)-3-(4,4'-difIuoro-2',5,6'-trimethyl-[l,l'-biphenyI]-3-yl)propanoic acid

Ethyl (35)-3-(2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (217)-yl)-4methylpentanamido)-3-(4,4^,-difluoro-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)propanoate (200 mg, 0.29 mmol) was treated with LÎOH-H2O (42 mg, 1 mmol) in MeOH (3 mL) and H2O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4-5 with IN HCl. The

408 solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% CHjCN) to give the diastereomeric products AQ-P1 (54 mg) and AQ-1-P2 (53 mg) as white solids.

AQ-P1 ESI 662.2 (M+H)⁺. ‘H NMR (400 MHz, MeOD) δ 7.86 (s, 1H), 6.94 - 6.74 (m, 5H), 5.72 - 5.55 (m, 2H), 4.05 (t, J= 8.0 Hz, 4H), 3.33 - 3.25 (m, 2H), 2.86 (t, J= 7.1 Hz, 2H), 2.77 - 2.64 (m, 2H), 2.55 - 2.38 (m, 2H), 2.30 (s, 3H), 2.06 - 1.94 (m, 5H), 1.87 (s, 3H), 1.53 - 1.34 (m, 1H), 1.01-0.86 (m, 6H).

AQ-P2 ESI 662.2 (M+H)⁺. ’H NMR (400 MHz, MeOD) δ 7.78 (s, 1H), 6.98 - 6.89 (m, 3H), 6.85 (d, J= 9.6 Hz, 2H), 5.80 - 5.70 (m, 1H), 5.63 (t, J= 7.6 Hz, 1H), 4.14 (s, 4H), 3.52 - 3.36 (m, 2H), 2.97-2.43 (m, 6H), 2.33 (s, 3H), 2.06-1.93 (m, 7H), 1.77- 1.63 (m, 1H), 1.49- 1.29 (m, 1H), 0.96-0.84 (m, 6H).

3-39. Préparation of (35)-3-(4,4'-difluoro-2’,5,6'-trimcthyl-[l,r-biphenyl]-3-yl)-3-(2-(5-(2(3-fluoroazetidin-l-yl)ethyl)-4-methyI-2-oxopyridin-l(2/7)-yl)-4methylpentanamido)propanoic acid (compounds AR-P1 and AR-P2)

Step 1: ethyl (35)-3-(4,4’-difluoro-2’,5,6’-trimethyl-[l,r-biphenyl]-3-yl)-3-(2-(5-(2-(3fluoroazetidin-l-yI)ethyl)-4-methyI-2-oxopyridin-l(2H)-yl)-4methylpentanamido)propanoate

A mixture of 2-(5-(2-(3-fluoroazetidin-1 -yl)ethyl)-4-methyl-2-oxopyridin-1 (2/7)-yl)-4methylpentanoic acid (112 mg, 0.34 mmol), ethyl (S)-3-amino-3-(4,4'-difiuoro-2’,5,6'-trimethyl[l,l'-biphenyl]-3-yI)propanoate (100 mg, 0.29 mmol), TCFH (120 mg, 0.43 mmol) and NMI (71 mg, 0.87 mmol) in CH3CN (5 mL) was stirred at room température for 2 hours. The solvent was concentrated in vacuo and the residue was purified by reverse phase HPLC on a CI8 Z 40 g

409 column (A: water 10 mM NHqHCOj.B: MeOH, 0~100%) to provîde ethyl (35)-3-(4,4'-difluoro2',5,6'-trimethyl-[ l, 1 *-biphenyl]-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-l-yl)ethyl)-4-methyl-2oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoate as a yellow oil (150 mg). Yield 79.7% (ESI 654.3 (M+H)⁺).

Step 2: (35)-3-(4,4’-difluoro-2’,5,6’-trimethyI-[l,l’-biphenyI]-3-yl)-3-(2-(5-(2-(3fluoroazetidin-l-yI)ethyI)-4-methyi-2-oxopyridin-l(2/7)-yl)-4methylpentanamido)propanoic acid

Ethyl ethyl (35)-3-(4,4'-difluoro-2', 5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(5-(2-(3fluoroazetidin-1 -yl)ethyl)-4-methyl-2-oxopyridin-1 (2/7)-yl)-4-methyIpentanamido)propanoate (150 mg, 0.23 mmol) was treated with LiOH-H₂O (100 mg, 2.3 mmol) in THF (3 mL) and H₂O (3 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% CH3CN) to give the diastereomeric products AR-P1 (43 mg) and AR-P2 (36 mg) as white solids.

AR-P1 ESI 626.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.49 (s, 1H), 6.92 - 6.68 (m, 4H), 6.30 (s, 1H), 5.74 - 5.52 (m, 2H), 5.30 - 5.12 (m, 1H), 4.15 - 3.90 (m, 2H), 3.75 - 3.57 (m, 2H), 3.05 - 3.00 (m, 2H), 2.85 - 2.62 (m, 3H), 2.32 - 2.27 (m, 4H), 2.22 (d, J= 1.2 Hz, 3H), 1.99 (s, 3H), 1.96 - 1.92 (m, 2H), 1.85 (s, 3H), 1.45 - 1.35 (m, 1H), 0.96 - 0.91 (m, 6H).

AR-P2 ESI 626.2 (M+H)⁺. ‘H NMR (400 MHz, MeOD) δ 7.33 (s, 1H), 6.87 - 6.81 (m, 4H), 6.30 (s, 1H), 5.62 - 5.43 (m, 2H), 5.34 - 5.08 (m, 1H), 4.37 - 4.12 (m, 2H), 4.00 - 3.76 (m, 2H), 3.19 - 3.11 (m, 2H), 2.79 - 2.67 (m, 1H), 2.62 - 2.36 (m, 3H), 2.20 (d, J= 1.6 Hz, 3H), 2.12 (s, 3H), 1.89 (s, 6H), 1.85 - 1.75 (m, 1H), 1.69 - 1.58 (m, 1H), 1.32-1.21 (m, 1H), 0.82 - 0.72 (m, 6H).

410

3-40. Préparation of (35)-3-(4,4'-difIuoro-2',5,6'-trimethylbiphenyl-3-yl)-3-(2-(5-(2-((7?)-3fluoropyrrolidin-l-yl)ethyl)-4-methyi-2-oxopyridin-l(2jE7)-yi)-4methylpentanamido)propanoic acid (compounds AS-PI and AS-P2)

Step 1: (35)-ethyl 3-(4,4’-difluoro-2',5,6'-trimethylbiphenyl-3-yl)-3-(2-(5-(2-((/?)-35 fluoropyrrolidin-l-yl)ethyi)-4-methyl-2-oxopyridin-l methylpentanamido)propanoate

A mixture of 2-(5-(2-((Æ)-3-fluoropyrrolidin-l-yl)ethyI)-4-methyl-2-oxopyridin-l(2/7)-yl)-4methylpentanoic acid (120 mg, 0.36 mmol), (5)-ethyl 3-amîno-3-(4,4'-difluoro-2',5,6'10 trimethylbiphenyl-3-yl)propanoate (123 mg, 0.36 mmol),TCFH (114 mg, 0.41 mmol) and NMI (84 mg, 1.02 mmol) in CH3CN (5 mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM:MeOH 4:1) to provide (3S)-ethyl 3-(4,4'-difluoro-2’,5,6'-trimethylbiphenyl-3-yl)-3-(2-(5-(2-((7?)-3fluoropyrrolidin-1 -yl)ethyl)-4-methyl-2-oxopyridin-1 (2//)-yl)-4-methylpentanamido)propanoate as a white solid (120 mg). Yield 51% (ESI 668.2 (M+H)⁺).

Step 2: (35)-3-(4,4'-difluoro-2',5,6'-trimethylbiphcnyl-3-yl)-3-(2-(5-(2-((7?)-3fluoropyrrolidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2Z/)-yl)-4methy]pentanamido)propanoic acid

411 (3S)-ethyl 3-(4,4'-difluoro-2',5,6'-trimethylbiphenyl-3-yl)-3-(2-(5-(2-((/?)-3-fluoropyrrolidin-1 yl)ethyl)-4-methyl-2-oxopyridin-l(2/7)-yl)-4-methylpentanamido)propanoate (120 mg, 0.18 mmol)) was treated with LiOH-H₂O (32 mg, 0.75 mmol) in THF (3 mL) and H₂O (1 mL) at room température for 3 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% CHjCN) to give the diastereomeric products AS-P1 (28.0 mg) and AS-P2 (43.0 mg) as white solids.

AS-PI ESI 640.3 (M+H)⁺. ’H NMR (400 MHz, MeOD) δ 7.56 (s, IH), 6.84-6.79 (m, 4H), 6.26 (s, IH), 5.65 - 5.60 (m, IH), 5.55 - 5.50 (m, IH), 5.35 - 5.52 (m, IH), 3.38 - 3.33 (m, IH), 3.32 -2.66 (m, 9H), 2.39-2.11 (m, 8H), 1.98- 1.92 (m, 5H), 1.81 (s, 3H), 1.46-1.39 (m, IH), 0.960.91 (m, 6H).

AS-P2 ESI 640.3 (M+H)+. Ή NMR (400 MHz, MeOD) δ 7.57 (s, IH), 6.90- 6.82 (m, 4H), 6.42 (s, IH), 5.64 -5.58 (m, 2H), 5.40- 5.24 (m, IH), 3.51 - 3.37 (m, 3H), 3.32- 3.10 (m, 3H), 2.92 - 2.76 (m, 2H), 2.68 - 2.55 (m, 2H), 2.40 - 2.21 (m, 8H), 2.05 - 1.88 (m, 7H), 1.80 - 1.73 (m, 1 H), 1.41 - 1.34 (m, I H), 0.96 - 0.87 (m, 6H).

3-41. Préparation of (33)-3-(4,4’-difluoro-2’,5,6’-trimethyI-ll,l*-biphenyl]-3-yI)-3-(2-(3fluoro-5-(2-((jR)-3-fluoropyrroIidin-l-yl)ethyl)-2-oxopyridin-l(2Z0^_yl)^_4· methylpentanamido)propanoic acid (compounds AT-P1 and AT-P2)

Step 1: ethyl (33)-3-(4,4’-difluoro-2’,5,6’-trimethyl-[l,l’-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxopyridin-l(2Z7)-yl)-4methylpentanamido)propanoate

F

A mixture of 2-(3-fluoro-5-(2-((Æ)-3-fluoropyrrolidin-1 -yl)ethyl)-2-oxopyridin-1 (2//)-yl)-4methylpentanoic acid (120 mg, 0.35 mmol), ethyl (5)-3-amino-3-(4,4'-difIuoro-2’,5,6’-trimethyl

412

[l,l’-biphenyI]-3-yl)propanoate (140 mg, 0.42 mmol), TCFH (117 mg, 0.42 mmol) and ΝΜΊ (86 mg, 1.05 mmol) in CH3CN (5 mL) was stirred at 40 °C for 2 hours. The solvent was concentrated in vacuo and the residue was purified by reverse phase HPLC on a Cl 8 / 40 g column (A: water 10 mMNHqHCOj.B: MeOH, 0-100%) to provide ethyl (35)-3-(4,4'-difluoro-2',5,6'-trimethyl[ 1, r-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((Æ)-3-fluoropyrrolidin-1 -yl)ethyl)-2-oxopyridin-1 (2//)yl)-4-methylpentanamido)propanoate as a yellow oil (150 mg). Yield 63.8% (ESI 672.3 (M+H)⁺).

Step 2: ethyl (35)-3-(4,4’-difluoro-2’,5,6’-trimethyI-[l,l’-biphenyIl-3-yl)-3-(2-(3-fluoro-5-(2((7?)-3-f!uoropyrroIidin-l-yI)ethyl)-2-oxopyridin-l(2//)-yI)-4methylpentanamido)propanoate

Ethyl (35)-3-(4,4'-difluoro-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((7?)-3fluoropyrrolidin-1 -yl)ethyl)-2-oxopyridin-1 (2//)-yl)-4-methylpentanamido)propanoate (150 mg, 0.22 mmol) was treated with LiOH-HjO (94 mg, 2.2 mmol) in MeOH (5 mL) and H₂O (5 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4-5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% CHjCN) to give the diastereomeric products AT-P1 (28 mg) and AT-P2 (37 mg) as white solids.

AT-P1 ESI 644.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.50 (s, 1H), 7.37 (d, J = 10.1 Hz, 1H), 6.92 - 6.77 (m, 4H), 5.74 - 5.62 (m, 1H), 5.57 - 5.46 (m, 1H), 5.27 (d, J= 53.4 Hz, 1H), 3.29 - 2.96 (m, 6H), 2.84 - 2.56 (m, 4H), 2.40 - 2.10 (m, 5H), 2.07 - 1.90 (m, 5H), 1.87 (s, 3H), 1.49 - 1.38 (m, 1H), 1.03 - 0.89 (m, 6H).

AT-P2 ESI 644.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.49 (s, 1H), 7.41 (d, J = 10.3 Hz, 1H), 6.97 - 6.76 (m, 4H), 5.67 (t, J= 7.7 Hz, 1H), 5.62 - 5.52 (m, 1H), 5.33 (d, J= 55.0 Hz,

413

1H), 3.69 - 3.34 (m, 6H), 2.92 - 2.77 (m, 2H), 2.65 - 2.43 (m, 2H), 2.30 (d, J= 17.3 Hz, 5H), 2.10-1.89 (m, 7H), 1.86 - 1.74 (m, 1H), 1.48 -1.34 (m, 1H), 0.95-0.86 (m, 6H).

3-42. Préparation of (3S)-3-(4-fluoro-2’,5,6’-trimethyl-[l,l’-biphenyl]-3-yl)-3-(2-(3-fluoro5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yI)-4methylpentanamido)propanoic acid (compounds AU-P1 and AU-P2)

Step 1: ethyl (35)-3-(4-fluoro-2’,5,6’-trimethyl·[l,l’-bipheny)]-3-yI)-3-(2-(3-fluoro-5-(2-((J^)3-fluoropyrrolidin-l-yl)ethyl)-2-oxopyridin-l(2Z/)-yl)-4-methylpentananiido)propanoate

A mixture of 2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1 -yl)ethyl)-2-oxopyridin-1 (2H)-yl)-4methylpentanoic acid (150 mg, 0.44 mmol), ethyl (S)-3-amino-3-(4-fluoro-2',5,6^,-trimethyl-[l,rbiphenyl]-3-yl)propanoate (144 mg, 0.44 mmol), TCFH (148 mg, 0.53 mmol), NMI (108 mg, 1.32 mmol) in CH3CN (4 mL) was stirred at room température for 1 hour. LCMS showed that the reaction was completed. The solvent was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/120g column (A: water 10 mM NHîHCOj.B: CH3CN, 0-100%) to provide ethyl (35)-3-(4-fluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)-3-(2-(3-fluoro5-(2-((7?)-3-fluoropyrrolidin-1 -yl)ethyl)-2-oxopyridin-1 (277)-yl)-4methylpentanamido)propanoate as a colorless oil (130 mg). Yield 45% (ESI 654.2 (M+H)⁺). Step 2; (35)-3-(4-fluoro-2',5,6'-trimethyl-[ 1,1 '-biphenyI]-3-yl)-3-(2-(3-fluoro-5-(2-((Æ)-3fluoropyrro!idin-l-yl)ethyl)-2-oxopyridin-l(2/7)-yl)-4-methylpentanamido)propanoic acid

414

Ethyl (35)-3-(4-fluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((/?)-3fluoropyrrolidin-1 -yl)ethyl)-2-oxopyridin-1 (2/7)-yl)-4-methylpentanamido)propanoate (130 mg, 0.20 mmol) was treated with L1OH-H2O (83 mg, 2.0 mmol) in THF (2 mL) and H2O (1 mL) at 35 °C for 1 hour. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products AU-P1 (33 mg) and AU-P2 (53 mg) as white solids.

AU-P1 ESI 626.2 (M+H)+. Ή NMR (400 MHz, MeOD) δ 7.51 (s, 1H), 7.38 - 7.35 (m, 1H), 7.15 - 7.06 (m, 3H), 6.88 - 6.81 (m, 2H), 5.73 - 5.68 (m, 1 H), 5.53 - 5.50 (m, 1 H), 5.35 -5.19 (m, 1H), 3.44 - 3.35 (m, 1H), 3.30 - 3.08 (m, 5H), 2.80 - 2.65 (m, 4H), 2.37 - 2.18 (m, 5H), 1.98-1.95 (m, 5H), 1.88 (s, 3H), 1.47-1.40 (m, 1H), 097-0.93 (m, 6H).

AU-P2 ESI 626.2 (M+H)+. Ή NMR (400 MHz, MeOD) δ 7.50 (s, 1H), 7.41 - 7.38 (m, 1H), 7.14 - 7.07 (m, 3H), 6.93 - 6.90 (m, 2H), 5.70 - 5.66 (m, 1H), 5.61 - 5.58 (m, 1H), 5.40 - 5.25 (m, 1H), 3.65 - 3.37 (m, 5H), 3.30 - 3.25 (m, 1H), 2.91 - 2.79 (m, 2H), 2.64 - 2.48 (m, 2H), 2.39 - 2.25 (m, 5H), 2.00 - 1.94 (m, 7H), 1.84 - 1.75 (m, 1H), 1.43 - 1.35 (m, 1H), 0.92 - 0.89 (m, 6H).

3-43. Préparation of (35)-3-(4-fluoro-2^,,5,6’-trimethyl-[l,l’-biphenylJ-3-yl)-3-(2-(3-fluoro5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(27/)-yl)-4-methylpentanamido)propanoic acid (compounds AV-P1 and AV-P2)

Step 1: ethyl (35)-3-(4-fluoro-2*,5,6’-trimethyl-[l,l’-biphenylJ-3-yl)-3-(2-(3-fluoro-5-(2-(3fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2//)-yl)-4-methyIpentanamido)propanoate

F

415

A mixture of ethyl (S)-3-amino-3-(4-fiuoro-2',5,6'-trimethyl-[l,l'-biphenyl]-3-yl)propanoate (142 mg, 0.43 mmol), 2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2Æ)-yl)-4methylpentanoic acid (120 mg, 0.36 mmol), TCHF (151 mg, 0.54 mmol) and NMI (147.6 mg, 1.8 mmol) in CH3CN (4 mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC on a Cl 8 / 40 g column (A: water 10 mM NH4HCOj,B: MeOH, 0-100%) to provide ethyl (3S)-3-(4-fluoro-2',5,6’-trimethyl-[l,rbiphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3-fluoroazeiidin-l-yl)ethyl)-2-oxopyridin-l(2/7)-yl)-4methylpentanamido)propanoate as a yellow solid(l 10 mg). Yield 48% (ESI 640.2 [M+H]⁺).

Step 2: (3S)-3-(4-fluoro-2’,5,6’-trimethyl-[l,r-biphenyl]-3-yI)-3-(2-(3-fluoro-5-(2-(3fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2/7)-yl)-4-mcthylpentanamido)propanoic acid

Ethyl (3S)-3-(4-fluoro-2',5,6'-trimethyl-[ 1,1 ’-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2//)-yl)-4-methylpentanamido)propanoate (110 mg, 0.17 mmol) was treated with LiOH-HzO (36 mg, 0.86 mmol) in THF (20 mL) and water (8 mL) at 30 °C for 1 hour. The reaction mixture was acidified to pH 4-5 with 2N HCl. The solvent was removed in vacuo and the residue was purified by preparotary HPLC B to give the diastereomeric product AV-P1 (40 mg) and AV-P2 (39 mg) as white solids.

AV-P1 ESI 612.3 (M+H)⁺.'H NMR (400 MHz, MeOD) δ 7.76 (s, 0.18H, FA), 7.50 - 7.27 (m, 2H), 7.23 - 7.02 (m, 3H), 6.96 - 6.75 (m, 2H), 5.69 (t, J= 8.0 Hz, 1H), 5.50 (t, J= 6.1 Hz, 1H), 5.20 (d, J= 57.4 Hz, 1H), 4.11 (s, 1H), 3.95 (s, 1H), 3.75 - 3.53 (m, 2H), 3.21 - 3.05 (m, 2H), 2.85 - 2.52 (m, 4H), 2.30 (s, 3H), 2.05 - 1.82 (m, 8H), 1.56 - 1.32 (m, 1H), 1.06 - 0.83 (m, 6H).

416

AV-P2 ESI 612.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 8.36 (s, 0.27H, FA), 7.51 - 7.29 (m, 2H), 7.09 (t, J= 7.6 Hz, 3H), 6.94 (t, J= 7.0 Hz, 2H), 5.80 - 5.58 (m, 2H), 5.57 - 5.18 (m, 1H), 4.54-4.21 (m, 2H), 4.16 - 3.93 (m, 2H), 3.39 (d, J= 5.5 Hz, 2H), 2.83 - 2.48 (m, 4H), 2.33 (d, J= 1.6 Hz, 3H), 2.00 (s, 7H), 1.88 - 1.66 (m, 1H), 1.54 - 1.26 (m, 1H), 1.23 - 0.69 (m, 6H).

3-44. Préparation of (35)-3-(2-(5-(2-(dimethylamino)ethyl)-3-methyl-2-oxopyridin-l(2i/)yI)-4-methylpentanamido)-3-(4-fluoro-2*,5,6^,-trimethyl-[l,l’-biphenylj-3-yI)propanoic acid (compounds AW-P1 and AW-P2)

Step 1: ethyl (35)-3-(2-(5-(2-(dimethyIamino)ethyI)-3-methyl-2-oxopyridin-l(277)-yl)-4methylpentanamido)-3-(4-fluoro-2’,5,6^,-trimethyl-[l,l’-biphenyl)-3-yl)propanoate

A mixture of ethyl (5)-3-amino-3-(4-fluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate (130.0 mg, 0.44 mmol), 2-(5-(2-(dimethylamino)ethyl)-3-methyl-2-oxopyridin-l(2/7)-yl)-4methylpentanoic acid (145.0 mg, 0.44 mmol), TCHF (131 mg, 0.47 mmol) and NMI (96.0 mg, 1.17 mmol) in CHjCN (4 mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC on a Cl8/40 g column (A: water 10 mM NH4HCO3.B: MeOH, 0-100%) to provide ethyl (35)-3-(2-(5-(2(dimethylamino)ethyl)-3-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate as a yellow solid (130 mg). Yield 48.6% (ESI 606.2 (M+H]⁺).

Step 2: (35)-3-(2-(5-(2-(dimethylamino)ethyl)-3-methyl-2-oxopyridin-l(2//)-yl)-4methylpentanamido)-3-(4-fluoro-2’,5,6’-trimethyl-[l,l’-biphenylJ-3-yI)propanoic acid

417

Ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-3-methyl-2-oxopyridin-1 (2H)-yl)-4methylpentanamido)-3-(4-fluoro-2',5,6'-trimethyl-[ 1,1 ’-biphenyl]-3-yl)propanoate ( 130.0 mg, 0.21 mmol) was treated with LiOH-I hO (46.0 mg, 1.0 mmol) in THF (6 mL) and water (3 mL) at 30 °C for 1 hour. The reaction mixture was acidified to pH 4-5 with 1 N HCl. The solvent was removed in vacuo and the residue was purified by Prep HPLC A (30-60% MeCN) to give the diastereomeric products AW-P1 (30.3 mg) and AW-P2 (46.0 mg) as white solids.

AW-P1 ESI 578.3 (Μ+Η)⁺.Ή NMR (400 MHz, MeOD) δ 7.46 (s, 1H), 7.43 (s, 1H),7.I7 - 7.07 (m, 3H), 6.88-6.86 (m, 1H), 6.74-6.71 (m, 1H), 5.57-5.54 (m, 1H), 5.36 (t, J = 5.0 Hz, 1H), 3.38-3.5 (m, 1H), 3.19-3.06 (m, 1 H), 2.83-2.77 (m, 2H), 2.67 (s, 6H), 2.64-2.59 (m, 1H), 2.53 - 2.47 (m, 1H), 2.30 (d, J= 1.7 Hz, 3H), 2.05 (s, 3H), 1.98 - 1.93 (m, 8H), 1.48 - 1.39 (m, 1H), 0.95-0.89 (m, 6H).

AW-P2 ESI 578.3 (M+H)⁺.’H NMR (400 MHz, MeOD) δ 7.51 (s, 1H), 7.41 (s, 1H), 7.17 - 7.02 (m, 3H), 6.89 - 6.87 (m, 1 H), 6.81 - 6.79 (m, 1 H), 5.64 - 5.60 (m, 1 H), 5.55 - 5.51 (m, 1 H), 3.45 - 3.38 (m, 1H), 3.30 - 3.23 (m, 1H), 2.97 - 2.72 (m, 8H), 2.61 - 2.56 (m, 1H), 2.45 - 2.39 (m, 1H), 2.31 (d, J= 1.8 Hz, 3H), 2.06- 1.80 (m, 11H), 1.46-1.39 (m, 1H), 0.94-0.88 (m, 6H).

3-45. Préparation of (35)-3-(2-(5-(2-(dimethyIamino)ethyl)-3-fluoro-2-oxopyridin-l(2fif)yl)-4-methyIpentanamido)-3-(4-fluoro-2’,5,6’-trimethyIbiphenyl-3-yl)propanoic acid (compounds AX-P1 and AX-P2)

Step 1: (35)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-l(2/7)-yl)-4methylpentanamido)-3-(4-fluoro-2’,5,6’-trimethylbiphenyI-3-yl)propanoate

418

A mixture of 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1 (27/)-yl)-4-methylpentanoic acid (109 mg, 0.36 mmol), (5)-ethyl 3-amino-3-(4-fluoro-2’,5,6'-trimethylbiphenyl-3yl)propanoate (120 mg, 0.36 mmol), TCFH (114 mg, 0.41 mmol) and NMI (84 mg, 1.02 mmol) in CH3CN (5 mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM:MeOH 4:1) to provide (35)-ethyl 3-(2(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)-3-(4fluoro-2',5,6'-trimethylbiphenyl-3-yl)propanoate as a white solid (130 mg). Yield 59% (ESI 610.2 (M+H)⁺).

Step 2: (3S)-3-(2-(5-(2-(dimethyIamino)ethyl)-3-fluoro-2-oxopyridin-l(277)-yl)-4methylpentanamido)-3-(4-fluoro-2’,5,6’-trimethylbiphenyl-3-yI)propanoic acid

(35)-ethyI 3-(2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1 (2/7)-yl)-4methylpentanamido)-3-(4-fluoro-2’,5,6'-trimethylbiphenyl-3-yl)propanoate (130 mg, 0.21 mmol)) was treated with LiOH-HzO (32 mg, 0.75 mmol) in THF (3 mL) and H₂O (1 mL) at room température for 3 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was purified by pre-HPLC A (30-60% MeCN) to give the diastereomeric products AX-P1 (32.0 mg) and AX-P2 (35.0 mg) as white solids.

AX-P1 ESI 582.1 (M+H)⁺.'H NMR (400 MHz, MeOD) δ 7.48 (s, 1H), 7.40 (d, J= 10.2 Hz, 1H), 7.15-7.08 (m, 3H), 6.86 (d,J= 6.8 Hz, 1H), 6.78 (d, J=6.4 Hz, 1H), 5.67 (t,J= 8.1 Hz, 1H), 5.43 (t, J= 5.5 Hz, 1H), 3.18-3.13 (m, 1H), 3.03 - 2.99 (m, 1H), 2.81 -2.77 (m, 2H), 2.68

419

2.53 (m, 8H), 2.29 (s, 3H), 2.00 - 1.94 (m, 5H), 1.92 (s, 3H), 1.45 - 1.39 (m, 1H), 0.96 - 0.90 (m, 6H).

AX-P2 ESI 582.1 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.50 (s, 1H), 7.43 - 7.40 (m, 1H), 7.15 - 7.07 (m, 3H), 6.91 (d, J= 6.9 Hz, 2H), 5.66 - 5.58 (m, 2H), 3.41 - 3.34 (m, 1H), 3.28 3.22 (m, 1H), 2.99 - 2.91 (m, 1H), 2.85 - 2.81 (m, 7H), 2.61 - 2.55 (m, 1H), 2.47-2.41 (m, 1H), 2.32 (d, J= 1.8 Hz, 3H), 2.04-1.97 (m, 7H), 1.85- 1.77 (m, 1H), 1.44-1.36 (m, 1H), 0.920.89 (m, 6H).

3-46. Préparation of (35)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2//)yl)-4-methylpentanamido)-3-(4-fluoro-2’,5,6’-trimethyIbiphenyI-3-yI)propanoic acid (compounds AZ-P1 and AZ-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(dimethyIamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4methyIpentanamido)-3-(4-fluoro-2’,5,6’-trimethyl-Il,l’-biphenyIj-3-yl)propanoate

A mixture of 2-(5-(2-(dimethylamino)ethyl)-4-methyI-2-oxopyridin-1 (2J/)-yl)-4methylpentanoic acid (100 mg, 0.34 mmol), ethyl (5)-3-amino-3-(4-fluoro-2',5,6'-trimethyl-[l,rbiphenyl]-3-yl)propanoate (112 mg, 0.34 mmol), TCFH (115 mg, 0.41 mmol), NMI (84 mg, 1.02 mmol) in CH3CN (5 mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM:MeOH 4:1) to provide ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2//)-yl)-4-methylpentanamido)3-(4-fluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate as a white solid (90 mg). Yield 44% (ESI 606.2 (M+H)⁺).

Step 2: (35)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(277)-yl)-4methylpentanamido)-3-(4-fluoro-2’,5,6’-trimethyIbiphenyl-3-yl)propanoic acid

420

Ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1 (27¥)-yl)-4methylpentanamido)-3-(4-fluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate (90 mg, 0.15 mmol)) was treated with LiOH-H₂O (32 mg, 0.75 mmol) in THF (3 mL) and H₂O (1 mL) at room température for 3 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products AZ-P1 (30.0 mg) and AZ-P2 (26.0 mg) as white solids.

AZ-P1 ESI 578.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.57 (s, 1H), 7.18 - 7.03 (m, 3H), 6.86-6.81 (m,2H), 6.35 (s, 1H), 5.59-5.55 (m, 1H), 5.49-5.46 (m, 1H), 3.25-3.16(m, 1H), 3.13 - 3.108 (m, 1H), 2.87 (t, J= 7.2 Hz, 2H), 2.75 (s, 6H), 2.70-2.59 (m, 2H), 2.29 (d, J= 1.5 Hz, 3H), 2.26 (s, 3H), 1.99 - 1.94 (m, 5H), 1.90 (s, 3H), 1.46 - 1.37 (m, 1 H), 0.94 - 0.89 (m, 6H).

AZ-P2 ESI 578.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.55 (s, 1H), 7.15 - 7.07 (m, 3H), 6.90 (d, J= 6.9 Hz, 2H), 6.43 (s, 1H), 5.65 - 5.56 (m, 2H), 3.31 - 3.28 (m, 1H), 3.22 - 3.15 (m, 1H), 2.98 - 2.88 (m, 2H), 2.84 (s, 6H), 2.63 - 2.59 (m, 1H), 2.50 - 2.44 (m, 1H), 2.32 (d, J= 1.5 Hz, 3H), 2.26 (s, 3H), 2.03 - 1.91 (m, 7H), 1.80 - 1.72 (m, 1H), 1.42 - 1.32 (m, 1H), 0.90 - 0.88 (m, 6H).

3-47. Préparation of (35)-3-(2-(5-(2-(dimethyIamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2/7)-yl)-4-methylpentanamido)-3-(4-fluoro-2',5,6'-trimethyl[l,l’-biphenyI]-3-yl)propanoic acid (compounds BA-P1 and BA-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/Z)yl)-4-methyIpentanamido)-3-(4-fluoro-2’,5,6’-trimethyl-[l,l’-biphenylJ-3-yI)propanoate

421

A mixture of ethyl (S)-3-amino-3-(4-fluoro-2',5,6’-trimethyl-[l,r-biphenyl]-3-yl)propanoate (95.0 mg, 0.29 mmol), 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)yl)-4-methylpentanoic acid (100.0 mg, 0.29 mmol), TCHF (97.0 mg, 0.35 mmol) and NMI (71.0 5 mg, 0.87 mmol) in CHjCN (4 mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC on a Cl8/40 g column (A: water 10 mM NH4HCO3.B: MeOH, 0-100%) to provide ethyl (35)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4-methylpentanamido)-3-(4fluoro-2',5,6’-trimethyl-[l,r-biphenyl]-3-yl)propanoate as a yellow solid (100.0 mg). Yield

52.3% (ESI 660.2 [M+H]⁺).

Step 2: (35)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methy)pentanamido)-3-(4-fluoro-2*,5,6’-trimethyl-[l,l’-biphenyl]-3-yl)propanoic acid

Ethyl (35)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (217)-y 1 )-415 methylpentanamido)-3-(4-fluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate (100.0 mg, 0.15 mmol) was treated with LiOH-H₂O (32.0 mg, 0.75 mmol) in THF (3 mL) and water (1 mL) at 30 °C for 1 hour. The reaction mixture was acidified to pH 4-5 with 2N HCl. The solvent was

422 removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products BA-P1 (16.4 mg) and BA-P2 (12.5 mg) as white solids.

BA-P1 ESI 632.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.77 (s, IH), 7.03 - 6.86 (m, 3H), 6.79 - 6.70 (m, 2H), 6.64 (s, IH), 5.56 (t, J= 8.0 Hz, IH), 5.48 - 5.38 (m, IH), 2.98 - 2.92 (m, 2H), 2.83 - 2.78 (m, 2H), 2.62-2.59 (m, 8H), 2.17 (s, 3H), 1.87 (d, J= 11.3 Hz, 5H), 1.71 (s, 3H), 1.34 - 1.30 (m, 1 H), 0.85 - 0.81 (m, 6H).

BA-P2 ESI 632.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.71 (s, IH), 7.03 - 6.95 (m, 3H), 6.82 - 6.77 (m, 3H), 5.60- 5.57 (m, IH), 5.49 (t, 7= 7.7 Hz, IH), 3.15 - 3.06 (m, 2H), 2.88 (t, J= 6.6 Hz, 2H), 2.70 (s, 6H), 2.54 - 2.50 (m, 1 H), 2.42 - 2.37 (m, 1 H), 2.21 (s, 3H), 1.90 - 1.85 (m, 7H), 1.62- 1.52 (m, IH), 1.33 - 1.22 (m, IH), 0.79-0.77 (m, 6H).

3-48. Préparation of (3S)-3-(2-(5-(3-(azetidin-l-yI)propyl)-2-oxo-4-(trifluoromethyI)pyridinl(2Zf)-yl)-4-methylpentananudo)-3-(2,2',4-trinuoro-4',6'-diinethyI-5-(triiluoromethyl)biphenyl-3yl)propanoic acid (compounds IID-P1 and HD-P2 )

Step 1: (3S)-ethyl 3-(2-(5-(3-(azetidin-l-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4 methylpentanamido)-3-(2,2’,4-trifluoro-4’,6’-dimethyl-5-(trinuoromethyl)biphenyl-3-yl)propanoate

A mixture of 2-(5-(3-(azetidin-1 -yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (277)-y 1)-4methylpentanoic acid (100 mg, 0.28 mmol), (3S)-ethyl 3-amino-3-(2,2',4-trifluoro-4',6'-dimethyl-5(trifluoromethyl)biphenyl-3-yl)propanoate (120 mg, 0.29 mmol), NMI (71 mg, 0.87 mmol) and TCFH (98 mg, 0.35 mmol) in CHjCN (4 mL) was stirred at room température for 2 hours. The solvent was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: CH3CN, 0-100%) to provide (3S)-ethyl 3-(2-(5-(3-(azetidin-l-yl)propyl)-2oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4-methylpentanamido)-3-(2,2',4-trifluoro-4',6'-dimethyl-5(trifluoromethyl)biphenyl-3-yl)propanoate as a yellow oil (110 mg). Yield 52 % (ESI 776.3 [M+H]*).

423

Step 2: (3S)-3-(2-(5-(3-(azetÎdin-l-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)-4methylpentanamido)-3-(2,2’,4-trifluoro-4*,6’-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid

(3S)-ethyl 3-(2-(5-(3-(azetidin-l-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yI)-4methylpentanamido)-3-(2,2',4-trifluoro-4',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate (110 mg, 0.14 mmol) was treated with LiOH-H₂O (24 mg, 0.56 mmol) in EtOH (3mL) and H₂O (1 mL) at room température for 1 hour. The reaction mixture was acidified to pH 5~6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% CHjCN) to give the diastereomeric products HD-P1 (27 mg) and HD-P2 (28 mg) as white solids.

HD-P1 ESI 748.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.77 (s, 1H), 7.53 - 7.43 (m, 1H), 6.98 (s, 1H), 6.90 - 6.73 (m, 2H), 5.81 - 5.71 (m, 2H), 4.05 (t, J= 8.1 Hz, 4H), 3.14 (t, J= Ί.Ί Hz, 2H), 3.01 - 2.89 (m, 1H), 2.84 - 2.53 (m, 3H), 2.51 - 2.30 (m, 5H), 2.18 - 1.90 (m, 5H), 1.90 - 1.66 (m, 2H), 1.46 - 1.23 (m, 1H), 1.06-0.86 (m, 6H).

HD-P2 ESI 748.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 7.52 (t, J= ΊΑ Hz, 1H), 7.00 (s, 1H), 6.93 - 6.75 (m, 2H), 5.89 - 5.73 (m, 1H), 5.69-5.62 (m, 1H), 4.17 - 3.93 (m, 4H), 3.21 - 3.00 (m, 2H), 2.94-2.84 (m, 1H), 2.75-2.56 (m, 3H), 2.51 -2.30(m, 5H), 2.10 (d, J= 11.8 Hz, 3H), 1.98-1.55 (m, 4H), 1.42 - 1.22 (m, 1H), 0.92 - 0.80 (m, 6H).

3-49. Préparation of (3$)-3-(2-(5-(3-(azetidin-l-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanamido)-3-(2,4-difluoro-2’,6’-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]3-yl)propanoic acid (compounds HE-P1 and HE-P2)

Step 1: ethyl (3S)-3-(2-(5-(3-(azetidin-l-yl)propyl)-2-oxo-4-(trinuoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4-difluoro-2’,6’-dimethyl-5-(trinuoromethyl)-[l,r-biphenyl]-3yl)propanoate

424

A mixture of ethyl (S)-3-amino-3-(2,4-difluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoate (116 mg, 0.29 mmol), 2-(5-(3-(azetidin-l-yl)propyl)-2-oxo-4-(trifIuoromethyl)pyridinl(2H)-yl)-4-methylpentanoic acid (100 mg, 0.27 mmol), TCFH (151 mg, 0.54 mmol) and NMI (110 mg, 1.35 mmol) in CHjCN (2 mL) was stirred at 25 °C for 2 hr. The solvent was concentrated in vacuo and the residue was purified The reaction was concentrated and purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: MeOH, 0~90%) to provide ethyl (3S)-3-(2-(5-(3-(azetidin-lyl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(2,4-difIuoro-2',6'dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yI)propanoate as a yellow solid (120 mg). Yield 58.6 % (ESI 758.3 [M+H]*).

Step 2: (3S)-3-(2-(5-(3-(azetidin-l-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4-difluoro-2’,6’-dimethyl-5-(trinuoromethyI)-[l,l’-biphenyl]-3yl)propanoic acid

Ethyl (3S)-3-(2-(5-(3-(azetidin-l-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4-difluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (120 mg, 0.16 mmol) was treated with LiOH-H2O (13 mg, 0.32 mmol) in EtOH (2 mL) and H2O (0.5 mL) at room température for 30 mins. The reaction mixture was acidified to pH 5~6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (40-65% CH3CN) to give the diastereomeric products HE-P1 (40 mg) and HE-P2 (42 mg) as yellow solids.

HE-P1 ESI 730.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) 8 7.75 (s, 1H), 7.37 (t, J= 7.6 Hz, 1H), 7.23 7.16 (m, 1H), 7.14 - 7.08 (m, 2H), 6.78 (s, 1H), 5.78 - 5.70 (m, 2H), 3.88 (s, 4H), 3.05 - 2.91 (m, 3H),

425

2.76 - 2.70 (m, 1H), 2.66 - 2.57 (m, 2H), 2.41 - 2.32 (m, 2H), 2.09 - 1.91 (m, 6H), 1.90 (s, 3H), 1.77 1.69 (m, 1H), 1.36 - 1.30 (m, 1H), 0.99 - 0.85 (m, 6H).

HE-P2 ESI 730.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 7.44 (t, J= 7.5 Hz, 1H), 7.25 7.19 (m, 1H), 7.15 (d, J= 7.4 Hz, 2H), 6.84 (s, 1H), 5.85 - 5.79 (m, 1H), 5.63 (t, J= 7.6 Hz, 1H), 4.08 (s, 4H), 3.18 - 3.05 (m, 2H), 2.95 - 2.87 (m, 1H), 2.71 - 2.59 (m, 3H), 2.48 - 2.39 (m, 2H), 2.02 (d, J = 5.7 Hz, 6H), 1.95 - 1.78 (m, 3H), 1.70 - 1.60 (m, 1H), 1.34 - 1.27 (m, 1H), 0.90 - 0.82 (m, 6H).

3-50. Préparation of(3S)-3-(2-(5-(2-(diethylamino)ethyl)-2-oxo-4-(triiluoromethyl)pyridin-l(2H)yl)-4-methyIpentanamido)-3-(2,4-dinuoro-2’,4’,6’-trimethyl-5-(trifluoromethyl)-Il,l’-biphenyll-3yl)propanoic acid (compounds HF-P1 and HF-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(diethylamino)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)-4methyIpentanamido)-3-(2,4-difIuoro-2’,4*,6’-trimethyI-5-(trinuoromethyl)-[l,r-biphenylJ-3yl)propanoate

A mixture of ethyl (S)-3-amino-3-(2,4-difluoro-2',4’,6^,-trimethyl-5-(trifluoromethyl)-[l,l'-biphenyl]-3yl)propanoate (125 mg, 0.3 mmol), 2-(5-(2-(diethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)-4-methylpentanoic acid (120 mg, 0.32 mmol), TCFH (150 mg, 0.54 mmol) and NMI (110 mg, 1.35 mmol) in CHjCN (2.5 mL) was stirred at 50 °C for 30 mins. The reaction was concentrated in vacuo and the residue purifïedThe reaction was concentrated and purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: MeOH, 0~90%) to provide ethyl (3S)-3-(2-(5-(2(diethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methyIpentanamido)-3-(2,4-difluoro2',4',6^,-trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate as a yellow solid (140 mg). Yield 60.3% (ESI 774.3 [M+H]⁺).

Step 2: (35)-3-(2-(5-(2-(diethyIamino)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4-difIuoro-2’,4',6'-trimethyl-5-(trinuoromethyI)-[l,r-biphenyI]-3yl)propanoic acid

426

Ethyl (3S)-3-(2-(5-(2-(diethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4-difluoro-2',4',6'-trimethyl-5-(trifluorornethyl)-[ 1,1 -biphenyl]-3-yl)propanoate (140 mg, 0.18 mmol) was treated with LiOH-H₂O (23 mg, 0.54 mmol) in EtOH (3 mL) and H₂O (1 mL) at room température for 30 mins. The reaction mixture was acidified to pH 5~6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (35-60% CH3CN) to give the diastereomeric products HF-P1 (46 mg) and HF-P2 (50 mg) as white solids.

HF-P1 ESI 746.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.89 (s, 1H), 7.33 (t, J= 7.6 Hz, 1H), 6.94 (d, J = 4.0 Hz, 2H), 6.82 (s, 1H), 5.79 - 5.67 (m, 2H), 3.25 - 3.11 (m, 6H), 3.04 - 2.88 (m, 3H), 2.78 - 2.69 (m, 1H), 2.29 (s, 3H), 2.06 - 1.91 (m, 5H), 1.86 (s, 3H), 1.42 - 1.35 (m, 1H), 1.28 (t, J= 7.3 Hz, 6H), 0.94 (t, J =6.5 Hz, 6H).

HF-P2 ESI 746.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.88 (s, 1H), 7.39 (t, J= 7.6 Hz, 1H), 6.96 (s, 2H), 6.88 (s, 1H), 5.82 - 5.64 (m, 2H), 3.29 - 3.15 (m, 6H), 2.96 (t, J= 7.7 Hz, 2H), 2.91 - 2.82 (m, 1H), 2.70 (d,J= 15.0 Hz, 1H),2.31 (s, 3H), 1.98 (d, J= 4.2 Hz, 6H), 1.92-1.79 (m, 1H), 1.77-1.67 (m, 1H), 1.36 - 1.23 (m, 7H), 0.93 - 0.82 (m, 6H).

3-51. Préparation of (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyi)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)yI)-4-methylpentanamido)-3-(3’-cyclopropoxy-2,4-dinuoro-2’,6’-dimethyI-5(trifluoromethyl)biphenyl-3-yI)propanoic acid (compounds HG-P1 and HG-P2)

Step 1: (3S)-ethyI 3-(2-(5-(2-(azetidin-l-yI)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamîdo)-3-(3’-cyclopropoxy-2,4-difluoro-2’,6’-dimethyI-5-(trifluoromethyl)biphenyl-3yl)propanoate

427

A mixture of (35)-ethyl 3-amino-3-(3'-cyclopropoxy-2,4-difluoro-2',6'-dimethyl-5(trifluoromethyl)biphenyl-3-yl)propanoate (150 mg, 0.33 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoic acid (119 mg, 0.33 mmol), TCFH (174 mg, 0.62 mmol) and NMI (82 mg, 1.0 mmol) in MeCN (5mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH 97: 3) to provide (35)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(3'-cyclopropoxy-2,4-difluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3yl)propanoate as a colorless oil (130 mg). Yield 53% (ESI 800.3 (M+H)⁺).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trîfluoromethyl)pyridin-l(2H)-yl)-4methyIpentanamido)-3-(3’-cycIopropoxy-2,4-difluoro-2’,6’-dimethyI-5-(trifIuoromethyl)biphenyl-3yl)propanoic acid

(3S)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(tnfluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(3'-cyclopropoxy-2,4-difluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3yl)propanoate (120 mg, 0.16 mmol) was treated with LiOH-HiO (35 mg, 0.9 mmol) in EtOH (3 mL) and HiO (1 mL) at room température for 2 hours. The reaction mixture was acidifîed to pH 4-5 with IN HCl. The reaction was concentrated in vacuo and the residue purifiedThe reaction was concentrated in vacuo and the residue purifiedby prep-HPLC A (30-60% CH3CN) to give the diastereomeric products HG-P1 (30.1 mg) and HG-P2 (42.0 mg) as white solids.

HG-P1 ESI 772.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 7.35 (t, J= 7.5 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.09 (d,J=8.0 Hz, 1H), 6.85 (s, 1H), 5.71-5.68 (m, 2H),4.04 (t, J= 8.0 Hz,4H), 3.823.73 (m, 1H), 3.29 - 3.18 (m, 2H), 2.92 (dd, J= 15.0,8.7 Hz, 1H), 2.84 (t, 6.8 Hz, 2H), 2.77- 2.69

428 (m, 1H), 2.48 - 2.37 (m, 2H), 2.04 - 1.85 (m, 5H), 1.81 - 1.69 (m, 3H), 1.38 (dd, 7= 13.7,7.2 Hz, 1H), 0.93 (t, J= 6.2 Hz, 6H), 0.78 (dd, 7= 11.2,5.2 Hz, 2H), 0.70 (t, J= 6.8 Hz, 2H).

HG-P2 ESI 772.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.41 (t, 7= 7.6 Hz, 1H), 7.25 (d, 7= 8.4 Hz, 1H), 7.12 (d,7= 8.4 Hz, 1H), 6.90 (d,7= 13.3 Hz, 1H), 5.90 (dd,7= 10.8,4.2 Hz, 1H), 5.63 (t,7=7.7Hz, 1H),4.12 (t,7= 8.0Hz,4H),3.79-3.75 (m, 1H),3.48-3.33 (m,2H), 3.01 -2.76(m, 3H), 2.60 (dd, J = 15.5,4.1 Hz, 1H), 2.53 - 2.35 (m, 2H), 2.02- 1.85 (m, 4H), 1.81 (d, 7= 3.2 Hz, 3H), 1.76 1.67 (m, 1H), 1.34-1.30 (m, 1H), 1.02-0.81 (m, 6H), 0.81-0.75 (m, 2H),0.70(d,7=3.1 Hz,2H).

3-52. Préparation of (3S)-3-(2-(5-(2-(azctidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z7)yl)-4-niethyIpentanamido)-3-(5-cyclopropyI-2,3',4-trifluoro-2',6'-dimethyl-[l,r-biphenyl]-3yl)propanoic acid (compounds HH-P1 and HH-P2)

Step 1 : ethyl (35)-3-(2-(5-(2-(azetidin-l-yI)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z7)-yl)-4methylpentanamido)-3-(5-cyclopropyI-23’,4-trifluoro-2’,6’-dimethyl-Il,l’-biphenyl]-3yl)propanoate

A mixture of ethyl (35)-3-amino-3-(5-cyclopropyl-2,3',4-trifluoro-2',6^,-dimethyl-[l,r-biphenyl]-3yl)propanoate (120 mg, 0.3 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)yl)-4-methylpentanoic acid (108 mg, 0.3 mmol), TCFH (\26 mg, 0.45 mmol) and NMI (123 mg, 1.5 mmol) in CHjCN (3 mL) was stirred at room température ovemight. The reaction was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: MeOH, 20-95%) to provide ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(5-cyclopropyl-2,3',4-trifluoro-2',6'dimethyl-[l,r-biphenyl]-3-yl)propanoate as a light yellow solid (140 mg). Yield 62% (ESI 734.2 [Μ+ΗΓ).

429

Step 2: (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2ZZ)-yl)-4methylpentanamido)-3-(5-cycIopropyl-23’,4-trinuoro-2’,6’-dimethyl-[l,l’-biphenyI]-3-yl)propanoic

Ethyl (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifiuoromcthyl)pyridin-l(277)-yl)-4methylpentanamido)-3-(5-cyclopropyl-2,3',4-trifluoro-2’,6'-dimethyl-[l,r-biphenyl]-3-yl)propanoate(140 mg, 0.19 mmol) was treated with LiOH-H₂O (24 mg, 0.57 mmol) in EtOH (2 mL) and water (0.5 mL) at room température for 1 hour. The reaction mixture was acidified to pH 4~5 with 2N HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (20-85% MeCN) to give the diastereomeric products HH-P1 (35 mg) and HH-P2 (58 mg) as white solids.

HH-P1 ESI 706.2 (M+H)⁺ 'H NMR (400 MHz, MeOD) δ 7.80 (s, IH), 7.12 - 7.03 (m, IH), 7.00 - 6.91 (m, IH), 6.87 (s, IH), 6.62 (t, J = 8.0 Hz, IH), 5.80 - 5.58 (m, 2H), 4.00 (t, J= 7.7 Hz, 4H), 3.30 - 3.19 (m, 2H), 2.97 - 2.78 (m, 3H), 2.71 - 2.62 (m, IH), 2.49 - 2.34 (m, 2H), 2.13 - 1.76 (m, 9H), 1.46 - 1.33 (m, IH), 1.00 - 0.86 (m, 8H), 0.66 (d, J= 4.8 Hz, 2H).

HH-P2 ESI 706.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.70 (s, IH), 7.14 -7.04 (m, IH), 7.02 - 6.87 (m, 2H), 6.67 (t, J= 8.1 Hz, IH), 5.98 - 5.86 (m, IH), 5.62 (t, J= 7.7 Hz, IH), 4.11 (t, J= 8.1 Hz, 4H), 3.45 -3.33 (m, 2H), 2.99- 2.71 (m, 3H), 2.60 - 2.36 (m, 3H), 2.17 -2.03 (m, IH), 2.00 - 1.86 (m, 7H), 1.80 - 1.67 (m, IH), 1.41 - 1.29 (m, IH), 1.06 - 0.94 (m, 2H), 0.93 - 0.82 (m, 6H), 0.72 - 0.62 (m, 2H).

3-53. Préparation of(3S)-3-(2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yll^-methylpentanamîdol-S-lS-cycIopropyl^d^’-trinuoro-l’jô’-dimethyHLl’-biphenylJ-Syl)propanoic acid (compounds HI-P1 and HI-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(5-cyclopropyl-2,4,4’-trinuoro-2’,6’-dimethyl-[l,l’-biphenyl]-3yl)propanoate

430

A mixture of 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoic acid (150 mg, 0.42 mmol), ethyl (S)-3-amino-3-(5-cyclopropyl-2,4,4'-trifluoro-2',6'-dimethyl-[l,l'biphenyl]-3-yl)propanoate (162 mg, 0.42 mmol), NMI (0.14mL) and TCFH (141 mg, 0.504 mmol) in CHjCN (5 mL) was stirred at room température for 1 hour. The solvent was concentrated in vacuo and the residue was purified by prep-HPLC A (30-90% CHjCN) to provide ethyl (3S)-3-(2-(5-(2-(azetidin-lyl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(5-cyclopropyl-2,4,4’trifluoro-2’,6'-dimethyl-[l,l'-biphenyl]-3-yl)propanoate as a white solid (160 mg). Yield 52% (ESI 734.3 (M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4 methylpentanamido)-3-(5-cyclopropyl-2,4,4’-trifluoro-2’,6*-dimethyI-[l,l’-biphenyl]-3-yl)propanoic

Ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(5-cyclopropyI-2,4,4'-trifluoro-2',6'-dimethyl-[l,l'-biphenyl]-3-yl)propanoate (160 mg, 0.22 mmol) was treated with LiOH-HiO (46 mg, 1.1 mmol) in MeOH (4 mL) and HiO (0.4 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-70% CHjCN) to give the diastereomeric products HI-P1 (44.0 mg) and HI-P2 (36.0 mg) as white solids.

HI-P1 ESI 706.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 6.91 - 6.79 (m, 3H), 6.61 (t, J= 8.2Hz, 1H), 5.82-5.71 (m, 1H), 5.67(t,J=8.1 Hz, 1H),4.O1 (t, J=8.1 Hz,4H), 3.28-3.22 (m, 2H),

431

2.94 - 2.79 (m, 3H), 2.72 - 2.60 (m, 1H), 2.49 - 2.34 (m, 2H), 2.11 - 1.87 (m, 9H), 1.45 - 1.33 (m, 1H), 1.04 - 0.85 (m, 8H), 0.70 - 0.60 (m, 2H).

HI-P2 ESI 706.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.69 (s, 1H), 6.93 (s, 1H), 6.86 (d, 9.6 Hz,

2H), 6.66 (t,J= 8.1 Hz, 1H), 5.98-5.85(m, 1H), 5.62 (t,.7=7.7 Hz, 1H), 4.12 (t,J= 8.1 Hz,4H), 3.443.34 (m, 2H), 2.97 - 2.72 (m, 3H), 2.58 - 2.36 (m, 3H), 2.14 - 2.04 (m, 1H), 2.02 - 1.88 (m, 7H), 1.80 1.66 (m, 1H), 1.46 - 1.26 (m, 1H), 1.07 - 0.96 (m, 2H), 0.94 - 0.81 (m, 6H), 0.72 - 0.63 (m, 2H).

3-54. Préparation of (3S)-3-(2,4-difluoro-3^,-methoxy-2’,6’-dimethyl-5-(trinuoromethyl)-Il,l’biphenyl]-3-yl)-3-(2-(5-(3-(dimethyIamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)-4methylpentanamido)propanoic acid (compounds HJ-P1 and HJ-P2)

Step 1: ethyl (3S)-3-(2,4-difluoro-3’-methoxy-2’,6’-dimethyl-5-(trifluoromethyI)-[l,r-biphenyll-3yl)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoate

A mixture of 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid (150 mg, 0.41 mmol), ethyl (3S)-3-amino-3-(2,4-difluoro-3'-methoxy-2',6'dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (176 mg, 0.41 mmol), NMI (0.15mL) and TCFH (141 mg, 0.507 mmol) in CH3CN (5 mL) was stirred at room température for 1 hour. The solvent was concentrated in vacuo and the residue was purified by prep-HPLC A (30-90% CH3CN) to provide ethyl (3S)-3-(2,4-difluoro-3'-methoxy-2',6^,-dimethyl-5-(trifluoromethyl)-[l, 1 '-biphenyl]-3-yl)-3-(2-(5-(3(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (160 mg). Yield 52% (ESI 776.3 [M+H]⁺).

Step 2: (3S)-3-(2,4-dinuoro-3’-methoxy-2',6'-dimethyl-5-(trinuoromethyl)-[l,l’-biphenylJ-3-yl)-3-(2 (5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4432 methylpentanamido)propanoic acid

Ethyl (3S)-3-(2,4-difluoro-3'-methoxy-2',6^,-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)-3-(2-(5-(3(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (160 mg, 0.21 mmol) was treated with LiOH-fLO (46 mg, 1.1 mmol) in MeOH (4 mL) and H₂O (0.4 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-70% CHjCN) to give the diastereomeric products HJ-P1 (36.0 mg) and IIJ-P2 (41.0 mg) as white solids.

HJ-P1 ESI 748.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.76 (s, 1H), 7.34 (t, J= 7.5 Hz, 1H), 7.127.03 (m, 1H), 6.89 (d, J= 8.3 Hz, 1H), 6.80 (s, 1H), 5.82 - 5.67 (m, 2H), 3.82 (s, 3H), 3.08 (t, J= 8.1 Hz, 2H), 2.98 - 2.91 (m, 1H), 2.80 (s, 6H), 2.75 - 2.58 (m, 3H), 2.10 - 1.69 (m, 10H), 1.35 (s, 1H), 0.93 (d, J = 6.6 Hz, 6H).

HJ-P2 ESI 748.3 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 7.39 (t, J= 7.6 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 6.91 (d, J= 8.4 Hz, 1H), 6.85 (s, 1H), 5.88 - 5.77 (m, 1H), 5.62 (t, J= 7.6 Hz, 1H), 3.84 (s, 3H), 3.15 - 2.95 (m, 2H), 2.96-2.84 (m, 1H), 2.79 (s, 6H), 2.70 - 2.58 (m, 3H), 2.11 - 1.83 (m, 9H), 1.72 - 1.57 (m, 1 H), 1.42 - 1.17 (m, 1 H), 0.97 - 0.70 (m, 6H).

3-55. Préparation of (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2f0yI)-4-methylpentanamido)-3-(3’-cyclopropyl-2,4-dîfluoro-2’,6’-dimethyl-5-(trifluoromethyl)-[l,l’biphenylj-3-yl)propanoic acid (compounds HK-P1 and HK-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(azetidin-l-yI)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yl)-4mcthyIpentanamido)-3-(3^,-cyclopropyI-2,4-diiluoro-2’,6’-dimethyI-5-(trinuoromethyI)-[l,l’biphenyI]-3-yI)propanoate

433

A mixture of ethyl (35)-3-amino-3-(3'-cyclopropyl-2,4-difluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,rbiphenyl]-3-yl)propanoate (210.0 mg, 0.48 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoic acid (136.9 mg, 0.38 mmol), TCFH (134.7 mg, 0.48 mmol) and NMI (118.2 mg, 1.44 mmol) in CH3CN (5 mL) was stirred at room température for 16 hours. The reaction was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: MeOH, 0~100%) to provide ethyl (35)-3-(2-(5-(2(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanamido)-3-(3'cyclopropyl-lA-difluoro^'.ô'-dimethyl-S-OrifluoromethyO-l 1,1 ’-biphenyl]-3-yl)propanoate as a light yellow solid (100.0 mg). Yield 34% (ESI 784.3 [M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z7)-yl)-4methylpentanamido)-3-(3’-cyclopropyl-2,4-diiluoro-2’,6’-dimethyl-5-(trinuoromethyl)-[l,l’biphenyl]-3-yl)propanoic acid

Ethyl (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(270-yl)-4methylpentanamido)-3-(3'-cyclopropyl-2,4-difluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,l -biphenyl]-3yl)propanoate (100.0 mg, 0.13 mmol) was treated with L1OH-H2O (16.4 mg, 0.39 mmol) in EtOH (2 mL) and water (0.5 mL) at room température for 1 hour. The reaction mixture was acidified to pH 4~5 with 2N HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-80% MeCN) to give the diastereomeric products HK-P1 (5.6 mg) and HK-P2 (48.8 mg) as white solids.

HK-P1 ESI 756.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.79 (d, J= 3.7 Hz, 1H), 7.36 (t, J= 7.6 Hz, 1H), 7.07-6.97 (m, 2H), 6.86 (d, J= 3.2 Hz, 1H), 5.78-5.65 (m,2H),4.04 (t,J= 8.1 Hz,4H), 3.29-3.21 (m,

434

2H), 2.96 - 2.88 (m, 1H), 2.84 (t, J= 6.8 Hz, 2H), 2.77 - 2.70 (m, 1H), 2.51 - 2.35 (m, 2H), 2.11 - 1.96 (m, 4H), 1.97 - 1.82 (m, 5H), 1.44 - 1.31 (m, 1H), 0.96 - 0.89 (m, 8H), 0.65 - 0.54 (m, 2H).

HK-P2 ESI 756.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.43 (t, J= 7.6 Hz, 1H), 7.08 7.00 (m, 2H), 6.91 (s, 1H), 5.91 (d, J= 8.6 Hz, 1H), 5.67 - 5.61 (m, 1H), 4.12 (t, J= 8.1 Hz, 4H), 3.344 3.32 (m, 2H), 2.97 - 2.74 (m, 3H), 2.64 - 2.57 (m, 1H), 2.51 - 2.39 (m, 2H), 2.10 (d, J= 2.5 Hz, 3H), 1.99 - 1.86 (m, 5H), 1.76 - 1.67 (m, 1H), 1.40 - 1.28 (m, 1H), 0.96 - 0.83 (m, 8H), 0.65 - 0.57 (m, 2H).

3-56. Préparation of (3S)-3-(5-cyclopropyl-2,4-difluoro-2’,4',6'-trimethylbiphenyI-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methyIpentanamido)propanoic acid (compounds HL-P1 and HL-P2)

Step 1: (3S)-ethyI 3-(5-cyclopropyl-2,4-difluoro-2’,4’,6’-trimethyIbiphenyl-3-yl)-3-(2-(5-(2(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoate

A mixture of (S)-ethyl 3-amino-3-(5-cyclopropyl-2,4-difluoro-2',4',6'-trimethylbiphenyl-3-yl)propanoate (120 mg, 0.31 mmol), 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid (108 mg, 0.31 mmol), TCFH (174 mg, 0.62 mmol) and NMI (82 mg, 1.0 mmol) in MeCN (5mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH 97: 3) to provide (35)-ethyl 3-(5-cyclopropyl2,4-difluoro-2',4',6'-trimethylbiphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate as a colorless oil (130 mg). Yield 59% (ESI 718.3 (M+H)⁺).

Step 2: (3S)-3-(5-cyclopropyl-2,4-dinuoro-2*,4’,6^,-trimethyIbiphenyl-3-yI)-3-(2-(5-(2(dimethylamino)ethyI)-2-oxo-4-(trinuoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid

435

(35)-ethyl 3-(5-cyclopropyl-2,4-difluoro-2^,,4',6'-trimethylbiphenyl-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (130 mg, 0.18 mmol) was treated with L1OH-H2O (38 mg, 0.9 mmol) in EtOH (3 mL) and H2O (1 mL) at room température for 2 hours. The reaction mixture was acidîfied to pH 4~5 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% CH3CN) to give the diastereomeric products HL-P1 (50.2 mg) and HL-P2 (41.8 mg) as white solids.

HL-P1 ESI 690.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.87 (s, 1H), 6.88 (t, J= 18.3 Hz, 3H), 6.56 (t, J= Ί& Hz, 1H), 5.71 (dd, J= 15.9, 7.0 Hz, 2H), 3.08 (d, J= 7.9 Hz, 2H), 3.00 - 2.81 (m, 3H), 2.84 2.55-2.50 (m, 7H), 2.27 (s, 3H), 2.09 - 2.00 (m, 1H), 1.96 (dd, J = 14.8,7.0 Hz, 2H), 1.92 (s, 3H), 1.84 (s, 3H), 1.40-1.38 (m, 1H), 0.93 (t, J= 6.5 Hz, 8H), 0.63 (d, J= 5.1 Hz, 2H).

HL-P2 ESI 690.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.87 (s, 1H), 6.88 (t, J= 18.3 Hz, 3H), 6.56 (t, J= 7.8 Hz, 1H), 5.71 (dd, J= 15.9,7.0 Hz, 2H), 3.08 (d, J= 7.9 Hz, 2H), 3.00 - 2.81 (m, 3H), 2.84 2.55-2.50 (m, 7H), 2.27 (s, 3H), 2.09 - 2.00 (m, 1H), 1.96 (dd, J= 14.8,7.0 Hz, 2H), 1.92 (s, 3H), 1.84 (s, 3H), 1.40-1.37 (m, 1H), 0.93 (t, J= 6.5 Hz, 8H), 0.63 (d, J= 5.1 Hz, 2H).

3-57. Préparation of (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2II)yI)-4-methyIpentanamido)-3-(5-cyclopropyl-2,4-difiuoro-2’,4’,6’-trimethylbiphenyl-3-yl)propanoic acid (compounds HM-P1 and HM-P2)

Step 1: (35)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamÎdo)-3-(5-cyclopropyl-2,4-difluoro-2’,4',6*-trimethylbiphenyl-3-yI)propanoate

436

A mixture of (S)-ethyl 3-amino-3-(5-cycIopropyl-2,4-difluoro-2',4',6'-trimethylbiphenyl-3-yl)propanoate (120 mg, 0.31 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid (112 mg, 0.31 mmol), TCFH (174 mg, 0.62 mmol) and NMI (82 mg, 1.0 mmol) in MeCN (5mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH 97: 3) to provide (35)-ethyl 3-(2-(5-(2-(azetidinl-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(5-cyclopropyl-2,4difluoro-2',4',6'-trimethylbiphenyl-3-yl)propanoate as a colorless oil (120 mg). Yield 53% (ESI 730.3 (M+H)*).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yI)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)-4methyIpentanamido)-3-(5-cycIopropyI-2,4-difluoro-2’,4’,6’-trimethyIbiphenyI-3-yl)propanoic acid

(3S)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(5-cyclopropyl-2,4-difluoro-2',4',6'-trimethylbiphenyl-3-yl)propanoate (120 mg, 0.16 mmol) was treated with LiOH-H₂O (35 mg, 0.9 mmol) in EtOH (3 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4-5 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% CHjCN) to give the diastereomeric products IIM-P1 (30.2 mg) and HM-P2 (31.8 mg) as white solids.

HM-P1 ESI 702.3 (M+H)*. 1H NMR (400 MHz, MeOD) δ 7.80 (s, 1H), 6.97 - 6.79 (m, 3H), 6.58 (t, J= 8.1 Hz, 1H), 5.84-5.61 (m,2H),4.00(t,J= 8.1 Hz,4H), 3.30-3.21 (m, 2H), 2.88-2.85 (m, 3H),2.67

437 (dd, J= 14.8,4.8 Hz, 1H), 2.48-2.37 (m, 2H), 2.28 (d, J= 6.4 Hz, 3H), 2.13 - 1.96 (m, 3H), 1.90 (d, J= 21.3 Hz, 6H), 1.46 - 1.31 (m, 1H), 0.94 -0.90(m, 8H), 0.64-0.62 (m, 2H).

IIM-P2 ESI 702.3 (M+H)*. 1H NMR (400 MHz, MeOD) δ 7.70 (s, 1H), 7.00 - 6.86 (m, 3H), 6.63 (t, J = 8.2 Hz, 1H), 5.93 (dd, J= 11.4,3.5 Hz, 1H), 5.62 (t, J= 7.7 Hz, 1H), 4.11 (t, J= 8.0 Hz, 4H), 3.50 - 3.33 -3.3O(m, 2H), 2.97 - 2.76 (m, 3H), 2.47-2.45 (m, 3H), 2.29 (s, 3H), 2.08-2.05 (m, 1H), 2.00 - 1.89 (m, 7H), 1.74-1.70 (m, 1H), 1.37 -1.35(m, 1H), 1.04 - 0.95 (m, 2H), 0.88 (dd, J= 11.4, 6.6 Hz, 6H), 0.670.65 (m, 2H).

3-58. Préparation of (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)yl)-4-methylpentanamido)-3-(2,4-diiluoro-2’3’,6’-trimethyl-5-(trifluoromethyl)-Il,l*-biphenyl)-3yl)propanoic acid (compounds HN-P1 and HN-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanamido)-3-(2,4-difluoro-2^,,3’,6’-trimcthyl-5-(trifluoromethyl)-l 1,1 ’-biphenyl]-3yl)propanoate

A mixture of2-(5-(2-(azetidin-l-yl)ethyi)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)-yl)-4-methylpentanoic acid (120.0 mg, 0.33 mmol), ethyl (3S)-3-amino-3-(2,4-difluoro-2^,,3',6'-trimethyl-5-(trifluoromethyl)[l,l'-biphenyl]-3-yl)propanoate (138.3 mg, 0.33 mmol), TCFH (184.8 mg, 0.66 mmol) and NMI (108.2 mg, 1.32 mmol) in CHjCN (10 mL) was stirred at room température for 1 hour. The reaction was concentrated in vacuo and the residue purified by silica gel column (DCM: MeOH 4: 1) to provide ethyl (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2fi)-yl)-4-methylpentanamido)3-(2,4-difluoro-2',3',6^,-trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate as a brown solid (125.0 mg). Yield 50% (ESI 758.7 (M+H)⁺).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Zf)-yl)-4methylpentanamido)-3-(2,4-difluoro-2’,3’,6’-trimethyl-5-(trifluoromethyl)-[l,l’-biphenyll-3yl)propanoic acid

438

Ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methylpentanamido)-3-(2,4-difluoro-2',3',6^,-trimethyl-5-(trifluoromethyl)-[ 1,1 '-biphenyl]-3-yl)propanoate (122 mg, 0.16 mmol) ) was treated with LiOH-lLO (26.9 mg, 0.64 mmol) in MeOH (4 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products HN-P1 (36.1 mg) and HN-P2 (37.6 mg) as white solids.

HN-P1 ESI 730.7(M+H)⁺. 1H NMR (400 MHz, DMSO) δ 9.29 (d, J= 6.4 Hz, 1H), 7.72 (s, 1H), 7.50 (t, J= 7.3 Hz, 1H), 7.14 (d, J= 7.8 Hz, 1H), 7.04 (t, J= Ί.6 Hz, 1H), 6.71 (d, J = 5.1 Hz, 1H), 5.58 - 5.50 (m, 1H), 5.44 (s, 1H), 3.18 - 3.03 (m, 5H), 2.98 - 2.79 (m, 3H), 2.39 - 2.30 (m, 2H), 2.23 (d, J= 6.6 Hz, 3H), 1.99 - 1.63 (m, 10H), 1.28 (d, J= 35.1 Hz, 1H), 0.90-0.70 (m, 6H).

HN-P2 ESI 730.7 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.42 (t, J= 7.6 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1 H), 7.04 (d, J = 7.7 Hz, 1 H), 6.91 (s, 1 H), 5.98 - 5.84 (m, 1 H), 5.63 (d, J = 7.7 Hz, 1 H), 4.12 (t, J= 8.1 Hz, 4H), 3.43 - 3.34 (m, 2H), 2.92 - 2.77 (m, 3H), 2.63 - 2.53 (m, 1H), 2.53 - 2.42 (m, 2H), 2.29 (s, 3H), 1.98 - 1.85 (m, 7H), 1.77- 1.66 (m, 1H), 1.39- 1.27 (m, 1H), 0.92-0.76 (m, 6H).

3-59. Préparation of(3S)-3-(2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2II)yl)-4-methylpentanamido)-3-(2,3’,4-trifluoro-2’,6’-dimethyl-5-(trifluoromethyl)biphenyI-3yl)propanoic acid (compounds HO-P1 and IIO-P2 )

Step 1: (3S)-ethyI 3-(2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trinuoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(23\4-trinuoro-2’,6’-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate

439

A mixture of (3S)-ethyl 3-amino-3-(2,3^,,4-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3yl)propanoate (100 mg, 0.24 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanoic acid (86 mg, 0.24 mmol), NMI (59 mg, 0.72 mmol) and TCFH (101 mg, 0.36 mmol) in CH₃CN (5 mL) was stirred at 50°C for 1 hour. The solvent was concentrated in vacuo and the residue was purified by silica gel column (DCM: MeOH 12:1) to provide (3S)-ethyl 3-(2-(5-(2(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(2,3’,4trifluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate as a yellow oil (116 mg). Yield 63.8 % (ESI 762.3 [M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yI)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methyIpentanamido)-3-(2,3',4-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid

(3S)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,3’,4-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate (116 mg, 0.15 mmol) was treated with L1OH-H2O (18.9 mg, 0.45 mmol) in EtOH (2 mL) and water (0.5 mL) at room température for 1 hour. The reaction mixture was acidified to pH 4~5 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-80% MeCN) to give the diastereomeric products HO-P1 (34 mg) and HO-P2 (26 mg) as white solids.

HO-P1 ESI 734.1 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.80 (s, 1H), 7.43 (t, J= 7.5 Hz, 1H), 7.13 (d, J= 6.3 Hz, 1H), 7.02 (t, J= 8.9 Hz, 1H), 6.84 (s, 1H), 5.76 - 5.65 (m, 2H), 4.05 (t, 8.1 Hz, 4H), 3.29

440

-3.18 (m, 2H), 2.96 - 2.87 (m, 1H), 2.84 (t, J= 6.9 Hz, 2H), 2.79- 2.72 (m, 1H), 2.49- 2.41 (m, 2H), 1.99- 1.89 (m, 8H), 1.39- 1.33 (m, 1H), 0.96 - 0.91 (m, 6H).

HO-P2 ESI 734.1 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.74 (s, 1H), 7.49 (t, J= Ί.6 Hz, 1H), 7.21 7.12 (m, 1 H), 7.05 (t, J = 9.0 Hz, 1H), 6.91 (s, 1H), 5.92 -5.86(m, 1 H), 5.64 (t, J = 7.7 Hz, 1H), 4.11 (t, J= 8.1 Hz, 4H), 3.39 - 3.31 (m, 2H), 2.93 - 2.75 (m, 3H), 2.66 - 2.59 (m, 1H), 2.49 - 2.41 (m, 2H), 2.00 (s, 3H), 1.96-1.86(m,4H), 1.76- 1.71 (m, 1H), 1.36- 1.29(m, 1 H), 0.91 -0.86(m,6H).

3-60. Préparation of (3S)-3-(2-(5-(2-(azetidin-l-yI)ethyl)-2-oxo-4-(trinuoromethyl)pyridin-l(2fiF)yl)-4-methylpentanamido)-3-(4’-chIoro-2,4-difluoro-2’,6^,-dimethyI-5-(trifluoromethyl)-[l,l’biphenyl]-3-yI)propanoic acid (compounds HP-PI and IIP-P2)

Step 1: ethyl (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-I(277)-yl)-4methylpentanamido)-3-(4’-chloro-2,4-difluoro-2*,6’-dimethyl-5-(trifluoromethyl)-[l,l’-biphenyl]-3yl)propanoate

A mixture of ethyl (S)-3-amino-3-(4'-chloro-2,4-difluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,l'biphenyl]-3-yl)propanoate (120.0 mg, 0.28 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanoic acid (100.9 mg, 0.28 mmol), TCFH (95.4 mg, 0.34 mmol) and NMI (115.0 mg, 1.40 mmol) in CH3CN (5 mL) was stirred at room température ovemight. The reaction was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3. B: MeOH, 0—100%) to provide ethyl (35)-3-(2-(5-(2-(azetidin-lyl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4'-chloro-2,4-difluoro2',6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate as a light yellow solid (80.0 mg). Yield 37% (ESI 778.2 (M+H]^f).

Step 2: (3S)-3-(2-(5-(2-(azctidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)-yI)-4methylpentanamido)-3-(4’-chloro-2,4-difluoro-2’,6’-dimethyl-5-(trifluoromethyl)-[l,l’-biphenyl]-3y!)propanoic acid

441

Ethyl (3S)-3-(2-(5-(2-(azetidin-l -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2//)-yl)-4methylpentanamido)-3-(4'-chloro-2,4-difluoro-2',6'-dimethyl-5-(trifluoromethyl)-[ 1,1 -biphenyl]-3yl)propanoate (80.0 mg, 0.10 mmol) was treated with LiOH-HiO (12.6 mg, 0.30 mmol) in EtOH (2 mL) and water (0.5 mL) at room température for 30 mins. The reaction mixture was acidified to pH 4~5 with 2N HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-80% MeCN) to give the diastereomeric products HP-PI (12.5 mg) and HP-P2 (24.5 mg) as white solids.

HP-PI ESI 750.2 (M+H)⁺ 'H NMR (400 MHz, MeOD) δ 7.79 (s, IH), 7.43 (t, J= 7.5 Hz, IH), 7.17 (s, 2H), 6.85 (s, IH), 5.80 - 5.62 (m, 2H), 4.06 (t, J= 8.1 Hz, 4H), 3.39 - 3.32 (m, IH), 3.28 - 3.21 (m, IH), 2.98 - 2.65 (m, 4H), 2.55 - 2.36 (m, 2H), 2.07 - 1.95 (m, 5H), 1.93 (s, 3H), 1.48 - 1.30 (m, 1 H), 0.93 (t, J = 6.5 Hz, 6H).

HP-P2 ESI 750.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.72 (s, IH), 7.49 (t, J= 7.6 Hz, IH), 7.20 (s, 2H), 6.92 (s, IH), 5.92-5.86 (m, IH), 5.63 (t, J = 7.7 Hz, IH), 4.12 (t, 7= 8.1 Hz,4H), 3.47-3.32(m, 2H), 2.99 - 2.72 (m, 3H), 2.64 - 2.57 (m, IH), 2.50 - 2.40 (m, 2H), 2.02 (d, 7= 1.8 Hz, 6H), 1.97 - 1.85 (m, IH), 1.79- 1.65 (m, IH), 1.40-1.28 (m, IH), 0.91 - 0.85 (m, 6H).

3-61. Préparation of(3S)-3-(2,4-difluoro-2’,6’-dimethyl-5-(trifluoromethyI)-[l,l’-biphenyl]-3-yl)3-(2-(5-(2-(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyI)pyr -idin-l(2H)-yl)-4methylpentanamido)propanoic acid (compounds HQ-P1 and HQ-P2)

Step 1: ethyl (3S)-3-(2,4-difluoro-2’,6’-dimethyI-5-(trifluoromethyl)-[l,l^,-biphenyI]-3-yl)-3-(2-(5-(2(dimethyIamino)ethyI)-2-oxo-4-(trinuoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoate

442

A mixture of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid (86 mg, 0.23 mmol), ethyl (S)-3-amino-3-(2,4-difluoro-2',6’-dimethyl-5(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate hydrochloride (92.0 mg, 0.23 mmol), TCFH (78.0 mg, 0.28 mmol) and NMI (38.0 mg, 0.46 mmol) in CHjCN (4 mL) was stirred at room température for 2 hrs. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/40g column (A: water lOmM NHiHCOj.B: MeOH, 0~100%) to provide ethyl (3S)-3-(2,4-difluoro2',6*-dimethyl-5-(trifluoromethyl)-[l,l'-biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl) -2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate as a yellow solid (90.0 mg). Yield 53.4% (ESI 732.2 [M+H]⁺).

Step 2: (3S)-3-(2,4-difluoro-2’,6’-dimethyl-5-(trifluoromethyl)-[l,l’-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)-yI)-4-methylpentanamido)propanoic acid

Ethyl (3S)-3-(2,4-difluoro-2^,,6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (90.0 mg, 0.12 mmol) was treated with L1OH-H2O (29.0 mg, 0.68 mmol) in EtOH (3 mL) and water (1 mL) at 30 °C for 1 hour. The reaction mixture was acidified to pH 4-5 with 2N HCl. The reaction was concentrated in vacuo and the residue purified by Prep HPLC A (30-80% MeCN) to give the diastereomeric products HQ-P1 (15.1 mg) and HQ-P2 (35.4 mg) as white solids.

443

HQ-P1 ESI 704.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.86 (s, 1H), 7.37 (t, J= 7.5 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.15 - 7.03 (m, 2H), 6.82 (s, 1H), 5.76 - 5.60 (m, 2H), 3.12-3.09 (m, 2H), 2.98-2.92 (m, 3H), 2.78-2.72 (m, 7H), 2.09 - 1.92 (m, 5H), 1.90 (s, 3H), 1.49-1.31 (m, 1H), 0.99 - 0.89 (m, 6H).

HQ-P2 ESI 704.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.44 (t, J= 7.7 Hz, 1H), 7.26 7.17 (t, J= 16.0 Hz, 1H), 7.14 (d, J= 7.6 Hz, 2H), 6.90 (s, 1H), 5.84-5.80 (m, 1H), 5.66 (t, 7.6 Hz,

1H), 3.26-3.18 (m, 2H), 2.97 (t, J= 7.3 Hz, 2H), 2.90-2.75 (τη, 7H), 2.68-2.65 (m, 1H), 2.02 (d, J= 3.1 Hz, 6H), 1.96- 1.82 (m, 1H), 1.77-1.72 (m, 1H), 1.34-1.29 (m, 1H), 0.90-0.85 (m, 6H).

3-62. Préparation of (3S)-3-(2-(5-(2-(azetidin-l-yI)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)yl)-4-methyIpentanamîdo)-3-(2,3^,,4-trifluoro-2’,4’,6’-trimethyI-5-(trinuoromethyl)-[l,l’-biphenyI]3-yl)propanoic acid (compounds HR-P1 and HR-P2)

Step 1: ethyl (3S')-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluorometliyl)pyridin-l(217)-yl)-4methylpentanamido)-3-(2,3*»4-trifluoro-2’,4’,6’-trimethyl-5-(trinuoromethyI)-[l,l’-biphenyl]-3yl)propanoate

NMI.TCFH

A mixture of ethyl (3S)-3-amino-3-(2,3',4-trifluoro-2',4',6'-trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]3-yl)propanoate (90 mg, 0.21 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanoic acid (81 mg, 0.21mmol), NMI (0.2 mL) and TCFH (88 mg, 0.32 mmol) in CH3CN (3 mL) was stirred at room température for 2 hours. The solvent was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: CH3CN, 0-100%) to provideethyl (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(27/)-yl)-4-methylpentanainido)-3-(2,3',4-trifluoro-2^,,4',6'-trimethyl-5(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate as a white solid (80 mg). Yield 50% (ESI 776.2 [Μ+ΗΓ).

444

Step 2: (35)-3-(2-(5-(2-(azetidin-l-yI)ethyl)-2-oxo-4-(trinuoromethyl)pyridin-l(2Z7)-yl)-4methylpentanamido)-3-(23’,4-triiluoro-2’,4’,6’-trimethyl-5-(trifluoromethyl)-[l,l’-biphenylj-3yl)propanoic acid

Ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yl)-4methylpentanamido)-3-(2,3^,,4-trifluoro-2',4',6'-trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoate (80 mg, 0.1 mmol) was treated with LiOH-H₂O (13 mg, 0.3 mmol) in MeOH (2.0 mL) and H₂O (0.5 mL) at room température for 2 hours. The reaction mixture was acidified to pH 5~6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (50-80% CHjCN) to give the diastereomeric products HR-P1 (22.0 mg) and HR-P2 (25.0 mg) as white solids.

HR-P1 ESI 748.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 7.40 (t, J= 7.5 Hz, 1H), 6.99 (d, J= 7.9 Hz, 1H), 6.85 (d, J= 3.0 Hz, 1H), 5.78 - 5.60 (m, 2H), 4.04 (t, J= 8.0 Hz, 4H), 3.29 - 3.20 (m, 2H), 2.95 - 2.80 (m, 3H), 2.77 - 2.68 (m, 1H), 2.51 - 2.37 (m, 2H), 2.25 (d, J= 1.6 Hz, 3H), 2.09 - 1.75 (m, 8H), 1.37 (s, 1H), 0.93 (t, J= 6.4 Hz, 6H).

HR-P2 ESI 748.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.72 (s, 1H), 7.46 (t, J= 7.5 Hz, 1H), 7.03 (d, J= 7.6 Hz, 1H), 6.91 (s, 1H), 5.87 - 5.82 (m, 1H), 5.63 (t, J= 7.7 Hz, 1H), 4.12 (t, J= 7.8 Hz, 4H), 3.45 - 3.34 (m, 2H), 2.95 - 2.74 (m, 3H), ), 2.64 - 2.56 (m, 1H), 2.50 - 2.36 (m, 2H), 2.27 (d, J= 1.5 Hz, 3H), 2.02 - 1.83 (m, 7H), ), 1.78 - 1.65 (m, 1H), ), 1.40 -1.26 (m, 1H), ), 0.93 - 0.84 (m, 6H).

3-63. Préparation of (3S)-3-(2-(5-(3-(dimethyIamino)propyI)-2-oxo-4-(trîfluoromethyl)pyridinl(2H)-yl)-4-methylpentanamido)-3-(2,3*,4-triiluoro-2’,6’-dimethyl-5-(trifluoromethyl)biphenyl-3yl)propanoic acid (compounds HS-P1 and IIS-P2 )

Step 1: (3S)-ethyl3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifIuoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,3',4-triiluoro-2',6'-dimethyl-5-(trinuoromethyl)biphenyl-3-yl)propanoate

445

A mixture of (3S)-ethyl 3-amino-3-(2,3’,4-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3yl)propanoate (100 mg, 0.24 mmol), 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanoic acid (86 mg, 0.24 mmol), NMI (59 mg, 0.72 mmol) and TCFH (101 mg, 0.36 mmol) in CHjCN (5 mL) was stirred at 50°C for 1 hour. The solvent was concentrated in vacuo and the residue was purified by silica gel column (DCM: MeOH 15:1) to provide (3S)-ethyl 3-(2-(5-(3(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(2,3',4trifluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate as a yellow oil (110 mg). Yield 60.4 % (ESI 764.3 (M+Hf).

Step 2: (3S)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)-yl)-4mcthyIpentanamido)-3-(2,3’,4-tnfluoro-2’,6'-dimethyl-5-(trinuoromethyl)biphenyl-3-yl)propanoic acid

(3S)-ethyl 3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,3’,4-trifluoro-2’,6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate(110 mg, 0.14 mmol) was treated with LiOH-HjO (18.1mg, 0.43 mmol) in EtOH (2 mL) and water (0.5 mL) at room température for 1 hour. The reaction mixture was acidified to pH 4~5 with IN HCI. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-80% MeCN) to give the diastereomeric products HS-P1 (29 mg) and HS-P2 (30 mg) as white solids.

HS-P1 ESI 736.2 (M+H)⁺. *H NMR (400 MHz, DMSO) δ 9.23 (d, J= 6.5 Hz, 1H), 7.73 (s, 1H), 7.61 (t, J = 6.9 Hz, 1H), 7.21 - 7.11 (m, 2H), 6.71 (s, 1H), 5.64 - 5.53 (m, 1H), 5.45 - 5.41 (m, 1H), 2.98 - 2.81 (m, 3H), 2.47 - 2.35 (m, 2H), 2.31-2.26 (m, 2H), 2.16 (s, 6H), 1.93 - 1.73 (m, 8H), 1.61-1.55 (m, 2H), 1.32 - 1.29 (m, 1H), 0.92 - 0.83 (m, 6H).

446

HS-P2 ESI 736.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.80 (s, IH), 7.46 (t, J= 7.5 Hz, IH), 7.20 7.12 (m, IH), 7.04 (t, J= 9.0 Hz, IH), 6.85 (s, IH), 5.85 - 5.69 (m, IH), 5.64 (t, J= 7.7 Hz, IH), 3.11 2.96 (m, 2H), 2.96 - 2.89 (m, IH), 2.79 (s, 6H), 2.70 - 2.60 (m, 3H), 2.05 - 1.84 (m, 9H), 1.70 - 1.60 (m, IH), 1.36 - 1.26 (m, IH), 0.89 - 0.82 (m, 6H).

3-64. Préparation of (3S)-3-(2,4-dinuoro-2’3\6’-trimethyl-5-(trifluoromethyl)-il,l’-biphenyI]-3yl)-3-(2-(5-(3-(dimethyIamino)propyl)-2-oxo-4-(trinuoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid (HT-P1 and IIT-P2)

Step 1: ethyl (3S)-3-(2,4-difluoro-2',3',6'-trimethyl-5-(triiluoromethyl)-[l,r-biphenyl]-3-yl)-3-(2-(5(3-(dimethylamino)propyI)-2-oxo-4-(trinuoromethyI)pyridin-l(2H)-yl)-4methylpentanamido)propanoate

A mixture of ethyl (3S)-3-amino-3-(2,4-difluoro-2',3^,,6'-trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoate (160 mg, 0.39 mmol), 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanoic acid (153 mg, 0.42 mmol), TCFH (218 mg, 0.78 mmol) and NMI (160 mg, 1.95 mmol) in CH3CN (5 mL) was stirred at room température for 2 hours. The reaction was concentrated and purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: CH3OH, 0-85%) to provide ethyl (3S)-3-(2,4-difluoro-2’,3^,,6'-trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoate as a yellow solid (120 mg). Yield 43.9 % (ESI 760.3 [M+H]⁺).

Step 2: (3S)-3-(2,4-difluoro-2'3\6'-trimethyI-5-(trifluoromethyl)-[l,l’-biphenyl]-3-yl)-3-(2-(5-(3(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)-4methylpentanamido)propanoic acid

447

(3S)-3-(2,4-diiluoro-2',3^,,6^,-trimethyl-5-(trifluoromethyl)-[l, 1 '-biphenyl]-3-yl)-3-(2-(5-(3(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (120 mg, 0.17 mmol) was treated with LiOH-H₂O (22 mg, 0.52 mmol) in EtOH (4 mL) and H2O (1 mL) at room température for 2 hr. The reaction mixture was acidified to pH 5~6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-65% CH3CN) to give the diastereomeric products HT-P1 (20 mg) and HT-P2 (23 mg) as white solids.

HT-P1 ESI 732.2 (M+H)⁺. Ή NMR (400 MHz, DMSO) δ 9.22 (d, J= 6.3 Hz, 1H), 7.73 (s, 1H), 7.49 (t, J= 7.4 Hz, 1H), 7.14 (m, J= 7.7 Hz, 1H), 7.04 (t, J= 8.0 Hz, 1H), 6.72 (d, J= 5.5 Hz, 1H), 5.68 - 5.54 (m, 1H), 5.46 (d,J= 6.1 Hz, 1H), 3.44 (m, 1H), 2.97 (m,J= 16.3,8.5 Hz, 1H), 2.90-2.75 (m, 1H), 2.46 -2.34 (m, 2H), 2.31-2.22 (m, 5H), 2.16 (s, 6H), 1.84 (m, J= 18.7,9.9 Hz, 5H), 1.73 (d, J= 29.3 Hz, 3H), 1.63 - 1.49 (m, 2H), 1.27 (m, J= 13.6, 6.8 Hz, 1H), 0.85 (m, J= 10.1, 6.6 Hz, 6H).

HT-P2 ESI 732.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.81 (s, 1H), 7.40 (t, J= 7.6 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.05 (d, J= 7.7 Hz, 1H), 6.87 (s, 1H), 5.84 (m, J= 9.8,4.5 Hz, IH), 5.64 (t, J= 7.6 Hz, 1H), 3.15 - 2.97 (m, 2H), 2.94 - 2.83 (m, 1H), 2.80 (s, 6H), 2.72 - 2.57 (m, 3H), 2.30 (d, J= 2.3 Hz, 3H), 2.09 - 1.85 (m, 9H), 1.66 (m, J= 14.1, 7.2 Hz, 1H), 1.33 (m, J= 13.1,6.6 Hz, 1H), 0.95 - 0.71 (m, 6H).

3-65. Préparation of (3S)-3-(4^,-cyclopropyl-2,4-difluoro-2’,6’-dimethyl-5-(trifluoromethyI)-[l,l’biphenyl]-3-yl)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid (compounds HU-P1 and HU-P2)

Step 1: ethyl (35)-3-(4’-cyclopropyl-2,4-difluoro-2’,6’-dimethyl-5-(triiIuoromethyl)-[l,r-biphenyl]3-yl)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trinuoromethyl)pyridin-l(277)-yl)-4methylpentanamido)propanoate

448

A mixture of ethyl (S)-3-amino-3-(4'-cyclopropyl-2,4-4111000)-2^6-4101611^1-5-(1011000)01611^1)-(1,1biphenyl]-3-yl)propanoate (140.0 mg, 0.32 mmol), 2-(5-(3-(dimethylamino)propyl)-2-oxo-4(trifluoromethyl)pyridin-l(2/?)-yl)-4-methylpentanoic aeid (116.0 mg, 0.32 mmol), TCFH (106.6 mg, 0.38 mmol) and NMI (131.4 mg, 1.60 mmol) in CHjCN (5 mL) was stirred at room température ovemight. The reaotion was ooncentrated in vaeuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH₄HCOj. B: MeOH, 0-100%) to provide ethyl (35)-3-(4'cyclopropyl-2,4-difluoro-2',6^,-dimethyl-5-(trifluoromethyl)-[l,l’-biphenyl]-3-yl)-3-(2-(5-(3(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate as a light yellow solid (150.0 mg). Yield 60% (ESI 786.3 [M+H]⁺).

Step 2: (3S)-3-(4’-cycIopropyl-2,4-difluoro-2’,6’-dimethyl-5-(trifluoromethyl)-(l,l’-biphenyIl-3-yl)3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpcntanamido)propanoic acid

Ethyl (35)-3-(4'-cyclopropyl-2,4-difluoro-2',6'-dimethyl-5-(triiluoromethyl)-[l,l'-biphenyl]-3-yl)-3-(2-(5(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-I(2//)-yl)-4-methylpentanamido)propanoate (150.0 mg, 0.19 mmol) was treated with LiOH-ILO (23.9 mg, 0.57 mmol) in EtOH (2 mL) and water (0.5 mL) at room température for 1 hour. The reaction mixture was acidified to pH 4-5 with 2N HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-80% MeCN) to give the diastereomeric products HU-P1 (54.5 mg) and HU-P2 (50.5 mg) as white solids.

HU-P1 ESI 758.3 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.76 (s, 1H), 7.34 (t, J= 7.6 Hz, 1H), 6.87 6.76 (m, 3H), 5.81 - 5.67 (m, 2H), 3.12 - 3.04 (m, 2H), 2.98 - 2.90 (m, 1H), 2.79 (s, 6H), 2.76 - 2.57 (m, 3H), 2.11 - 1.79 (m, 11H), 1.41 - 1.27 (m, 1H), 0.99-0.89 (m, 8H), 0.71 -0.65 (m, 2H).

449

HU-P2 ESI 758.3 (M+H)⁺ *H NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 7.39 (t, J= Ί6 Hz, 1H), 6.85 (s, 3H), 5.85 - 5.79 (m, 1H), 5.62 (t, J= 7.6 Hz, 1H), 3.13 - 2.94 (m, 2H), 2.93 - 2.84 (m, 1H), 2.79 (s, 6H), 2.70 - 2.57 (m, 3H), 2.09 - 1.81 (m, 10H), 1.70 - 1.58 (m, 1H), 1.36 - 1.26 (m, 1H), 0.99 - 0.92 (m, 2H), 0.89 - 0.83 (m, 6H), 0.72 - 0.65 (m, 2H).

3-66. Préparation of (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanamido)-3-(2,2’,4-trifluoro-4’,5,6’-trîmethyl-(l,l^,-biphenyIj-3-yl)propanoic acid (compounds HV-P1 and HV-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,2',4-trifluoro-4',5,6'-trimethyl-[l,l'-biphenyl]-3-yI)propanoate

A mixture of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanoicacid(142mg, 0.41 mmol),ethyl (3S)-3-amino-3-(2,2',4-trifluoro-4',5,6’-trimethyl-[l,lbiphenyl]-3-yl)propanoate hydrochloride (150.0 mg, 0.41 mmol), TCFH (137.0 mg, 0.48 mmol) and NMI (67.0 mg, 0.81 mmol) in CHjCN (4 mL) was stirred at room température for 2 hrs. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3.B: MeOH, 0—100%) to provide ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido) -3-(2,2',4-trifluoro-4',5,6'-trimethyl[l,l'-biphenyl]-3-yl)propanoate as a yellow solid (160.0 mg). Yield 56.1% (ESI 696.2 [M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(dimethyIamino)ethyI)-2-oxo-4-(trifluoromethyl)pyridîn-l(2H)-yl)-4methylpentanamido)-3-(2,2’,4-trifluoro-4^,,5,6’-trimethyl-[l,l’-biphenyl]-3-yl)propanoic acid

450

Ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo~4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,2',4-trifluoro-4',5,6'-trimethyl-[l, 1 '-biphenyl]-3-yl)propanoate ( 160.0 mg, 0.23 mmol) was treated with LiOH-HjO (50.0 mg, 1.15 mmol) in EtOH (3 mL) and water (1 mL) at 30 °C for 1 hour. The reaction mixture was acidified to pH 4~5 with 2N HCl. The reaction was concentrated in vacuo and the residue purified by Prep HPLC A (30-80% MeCN) to give the diastereomeric products HV-P1 (41.3 mg) and HV-P2 (45.5 mg) as white solids.

HV-P1 ESI 668.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.86 (s, 1H), 7.02 - 6.89 (m, 2H), 6.83-6.77 (m, 2H), 5.77 - 5.64 (m, 2H), 3.11-3.07 (m, 2H), 2.97-2.91 (m, 3H), 2.74-2.66 (m, 7H), 2.33 (s, 3H), 2.23 (s, 3H), 2.06-1.96 (m, 5H), 1.42-1.39 (m, 1H), 0.95-0.92 (m, 6H).

IIV-P2 ESI 668.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.82 (s, 1H), 7.03 (t, J= 8.2 Hz, 1H), 6.93 (d, J = 16.0 Hz, 2H), 6.82 (d, J= 10.3 Hz, 1H), 5.87-5.82(m, 1H), 5.67-5.63 (m, 1H), 3.23-3.13 (m, 2H), 2.982.95 (m, 2H), 2.82-2.79 (m, 7H), 2.57 - 2.51 (m, 1H), 2.34 (s, 3H), 2.27 (s, 3H), 2.08 (d, J= 6.1 Hz, 3H), 1.95-1.88 (m, 1H), 1.79-1.70 (m, 1H), 1.40 - 1.25 (m, 1H), 0.93 - 0.80 (m, 6H).

3-67. Préparation of (3S)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridinl(2Z0-yl)-4-methyIpentanamido)-3-(2,4,4*-trinuoro-2’,6’-dimethyl-5-(trinuoromethyl)-[l,rbiphenyl]-3-yl)propanoic acid (compounds HW-P1 and HW-P2)

Step 1: ethyl (3S)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifhioromethyI)pyridin-l(2E0-yl)-4methylpentanamido)-3-(2,4,4*-trifluoro-2’,6’-dimethyl-5-(trifluoromethyI)-[l,l’-biphenyIj-3yl)propanoate

451

A mixture of 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanoic acid (100.0 mg, 0.28 mmol), ethyl (S)-3-amino-3-(2,4,4'-trifluoro-2’,6'-dimethyl-5(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (117.3 mg, 0.28 mmol), TCFH (156.8 mg, 0.56 mmol) 5 andNMI (91.8 mg, 1.12 mmol) in CH3CN (10 mL) was stirred at room température for 1 hour. The reaction was concentrated in vacuo and the residue purified by silica gel column (DCM: MeOH 4: 1) to provide ethyl (3S)-3-(2-(5-(3-(dimethyIamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(27f)-yl)-4methylpentanamido)-3-(2,4,4^,-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate as a brown solid (150.0 mg). Yield 71% (ESI 764.7 (M+H)⁺).

Step 2: (3S)-3-(2-(5-(3-(dimethylaniino)propyl)-2-oxo-4-(trifluoromethyI)pyridin-l(277)-yl)-4methyIpentanamido)-3-(2,4,4’-trinuoro-2^,,6’-dimethyI-5-(trifluoromethyI)-[l,r-biphenyl]-3yl)propanoic acid

Ethyl (3S)-3-(2-(5-(3-(dimethyIamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(227)-yl)-415 methylpentanamido)-3-(2,4,4'-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l, 1 '-biphenyl]-3-yl)propanoate (150 mg, 0.20 mmol) ) was treated with LiOH-H₂O (33.6 mg, 0.80 mmol) in MeOH (4 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products HW-P1 (60.1 mg) and IIW-P2 (50.0 mg) as white solids.

HW-P1 ESI 736.6 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.76 (s, 1H), 7.39 (t, 7= 7.5 Hz, 1H), 6.88 (d, 7= 9.3 Hz, 2H), 6.80 (s, 1H), 5.78 - 5.67 (m, 2H), 3.14 - 3.02 (m, 2H), 3.01 - 2.88 (m, 1H), 2.80 (s, 6H), 2.75 - 2.55 (m, 3H), 2.12-1.84 (m, 10H), 1.34 (s, 1H), 0.94 (d, 7= 6.6 Hz, 6H).

452

HW-P2 ESI 736.6 (M+H)\ 1H NMR (400 MHz, MeOD) δ 7.79 (s, IH), 7.45 (t, J= 7.6 Hz, 1H), 6.96 6.80 (m, 3H), 5.86 - 5.75 (m, 1H), 5.62 (t, J= 7.6 Hz, 1H), 3.14 - 2.97 (m, 2H), 2.97 - 2.85 (m, 1H), 2.79 (s, 6H), 2.71 - 2.50 (m, 3H), 2.07 - 1.87 (m, 8H), 1.67 - 1.52 (m, 1H), 1.35 - 1.25 (m, 1H), 0.93 - 0.77 (m, 6H).

3-68. Préparation of (35)-3-(2-(5-(3-(azetidin-l-yl)propyI)-2-oxo-4-(trifluoromethyl)pyridinl(2/7)-yl)-4-methylpentanamido)-3-(2,4-diiluoro-2',4',5,6'-tetramethylbiphenyI-3-yI)propanoic acid (compounds HX-P1 and HX-P2)

Step 1: (3S)-ethyl 3-(2-(5-(3-(azetidin-l-yl)propyl)-2-oxo-4-(trifIuoromethyl)pyridin-l(2Z7)-yI)-4methylpentanamido)-3-(2,4-dinuoro-2’,4’,5,6’-tetramethylbiphenyl-3-yl)propanoate

A mixture of 2-(5-(3-(azetidin-l-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yI)-4methylpentanoic acid (100 mg, 0.27 mmol), (S)-ethyl 3-amino-3-(2,4-difluoro-2',4',5,6tetramethylbiphenyl-3-yl)propanoate (97 mg, 0.27 mmol), NMI (0.5 mL) and TCFH (378 mg, 1.35 mmol) in CHjCN (5 mL) was stirred at room température for 1 hour. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-90% CHjCN) to provide (35)-ethyl 3-(2-(5-(3(azetidin-l-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanamido)-3-(2,4-difluoro2',4’,5,6'-tetramethylbiphenyl-3-yl)propanoate as a white solid (140 mg). Yield 73% (ESI 718.3 [M+H]⁺).

Step 2: (35)-3-(2-(5-(3-(azetidin-l-yl)propyl)-2-oxo-4-(trinuoromethyl)pyridin-l(2/7)-yl)-4methyIpentanamido)-3-(2,4-difluoro-2’,4’,5,6'-tetramethyIbiphenyi-3-yl)propanoic acid

453

(35)-ethyl 3-(2-(5-(3-(azetidin-l-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(27/)-yI)-4methylpentanamido)-3-(2,4-difluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoate (140 mg, 0.20 mmol) was treated with LiOH-HiO (76 mg, 1.80 mmol) in MeOH (5 mL) and H2O (0.5 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-70% CH3CN) to give the diastereomeric products HX-P1 (41.0 mg) and HX-P2 (40.0 mg) as white solids.

HX-P1 ESI 690.3(M+H)\ Ή NMR (400 MHz, MeOD) δ 7.77 (s, 1H), 6.91 - 6.83 (m, 3H), 6.79 (s, 1H), 5.84 - 5.66 (m, 2H), 4.05 (t, 8.2 Hz, 4H), 3.14 (t, J= 7.5 Hz, 2H), 3.04 - 2.89 (m, 1H), 2.73 - 2.56 (m, 3H), 2.49 - 2.35 (m, 2H), 2.28 (s, 3H), 2.23 (s, 3H), 2.00 (t, J= 7.6 Hz, 2H), 1.91 (d, J= 21.2 Hz, 6H), 1.86 - 1.69 (m, 2H), 1.40 - 1.27 (m, 1H), 0.98 - 0.87 (m, 6H).

HX-P2 ESI 690.3 (M+H)⁺. ‘H NMR (400 MHz, MeOD) δ 7.78 (s, 1H), 6.97 - 6.79 (m, 4H), 5.91 - 5.81 (m, 1H), 5.56 (t, J= 7.5 Hz, 1H), 4.16 - 3.95 (m, 4H), 3.17 - 2.97 (m, 2H), 2.93 - 2.81 (m, 1H), 2.70 2.51 (m, 3H), 2.48 - 2.37 (m, 2H), 2.29 (s, 3H), 2.27 (s, 3H), 2.04 - 1.69 (m, 9H), 1.65 - 1.52 (m, 1H), 1.41-1.22 (m, 1H), 0.94 - 0.78 (m, 6H).

3-69. Préparation of(35)-3-(4’-cyclopropyI-2,4-difluoro-2’,6*-dimethyI-5-(trifluoromethyl)-[l,rbiphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(27/)-yl)-4methylpentanamido)propanoic acid (compounds HY-P1 and HY-P2)

Step 1: ethyl (3S)-3-(4’-cyclopropyl-2,4-difIuoro-2’,6’-dimethyl-5-(trifluoromethyl)-[l,r-biphenyI]3-yI)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trinuoromethyl)pyridin-l(2/7)-yI)-4mcthylpentanamido)propanoate

454

A mixture of ethyl (S)-3-amino-3-(4'-cyclopropyl-2,4-difiuoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,rbiphenyl]-3-yl)propanoate (140.0 mg, 0.29 mmol), 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2£/)-yl)-4-methylpentanoic acid (101.0 mg, 0.29 mmol), TCFH (97.6 mg, 0.35 mmol) and NMI (71.4 mg, 0.87 mmol) in CHjCN (5 mL) was stirred at room température ovemight. The reaction was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3. B: MeOH, 0~100%) to provide ethyl (3S)-3-(4'-cyclopropyl-2,4-difluoro2',6’-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)-3-(2-(5-(2’(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanamido)propanoate as a light yellow solid (130.0 mg). Yield 57% (ESI 772.3 [M+H]*).

Step 2: (3S)-3-(4'-cycIopropyl-2,4-diiluoro-2',6'-dimethyl-5-(trifluoromethyI)-[l,r-biphenyI]-3-yl)3-(2-(5-(2-(diniethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methylpentanamido)propanoic acid

Ethyl (3S)-3-(4'-cyclopropyl-2,4-difluoro-2’,6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)-3-(2-(5(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2W)-yl)-4-methylpentanamido)propanoate (130.0 mg, 0.17 mmol) was treated with LiOH-H₂O (21.4 mg, 0.51 mmol) in EtOH (2 mL) and water (0.5 mL) at room température for 30 mins. The reaction mixture was acidified to pH 5~6 with 2N HCl.

The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-80% MeCN) to give the diastereomeric products HY-P1 (40 mg) and HY-P2 (50.3 mg) as white solids.

455

HY-P1 ESI 744.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.85 (s, 1H), 7.34 (t, J= Ί.(> Hz, 1H), 6.82 (d, J = 4.5 Hz, 3H), 5.73 - 5.67 (m, 2H), 3.17 - 3.01 (m, 2H), 2.99 - 2.89 (m, 3H), 2.79 - 2.68 (m, 7H), 2.05 1.91 (m, 5H), 1.91 - 1.79 (m, 4H), 1.44 - 1.33 (m, 1H), 0.98 - 0.91 (m, 8H), 0.72 - 0.64 (m, 2H).

HY-P2 ESI 744.3 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.41 (t, J= 7.6 Hz, 1H), 6.90 (s, 1H), 6.85 (s, 2H), 5.85 - 5.78 (m, 1H), 5.65 (t, J= 7.8 Hz, 1H), 3.27 - 3.12 (m, 2H), 2.96 (t, J= 7.1 Hz, 2H), 2.89 - 2.75 (m, 7H), 2.70 - 2.62 (m, 1H), 1.97 (d, J= 3.3 Hz, 6H), 1.94 - 1.83 (m, 2H), 1.79 - 1.65 (m, 1H), 1.38 - 1.24 (m, 1H), 1.01 - 0.92 (m, 2H), 0.91 - 0.84 (m, 6H), 0.75 - 0.63 (m, 2H).

3-70. Préparation of (35)-3-(2,4-difluoro-2', 4’, 6'-trimethyl-5-(trifluoromethyl)biphenyl-3-yI)-3-(2(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid (compounds 1IZ-P1 and HZ-P2)

Step 1: (35)-ethyI 3-(2,4-difluoro-2',4’,6^,-trimethyl-5-(trinuoromethyl)biphenyI-3-yl)-3-(2-(5-(3(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)-4methylpentanamido)propanoate

A mixture of (5)-ethyl 3-amino-3-(2,4-difluoro-2',4',6'-trimethyl-5-(trifluoromethyl)biphenyl-3yl)propanoate (208 mg, 0.50 mmol), 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methy1pentanoic acid (180 mg, 0.50 mmol), TCFH (280 mg, 1.0 mmol) and NMI (123 mg, 1.5 mmol) in MeCN (5 mL) was stirred at room température for 3 hrs. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH 97: 3) to provide (35)-ethyl 3-(2,4difluoro-2',4',6'-trimethyl-5-(trifluoromethyl)biphenyl-3-yl)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate as a colorless oil (200 mg). Yield 53% (ESI 760.3 (M+H)⁺).

Step 2: (35)-3-(2,4-difiuoro-2',4',6'-trimethyl-5-(trifIuoromethyl)biphenyI-3-yl)-3-(2-(5-(3(dimethyIamino)propyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)-4456 methylpentanamido)propanoic acid

(3S)-ethyl 3-(2,4-difluoro-2^,,4',6'-trimethyl-5-(trifluoromethyl)biphenyl-3-yl)-3-(2-(5-(3(dimethylamino)propyl)-2-oxo-4-(tri fluoromethyl)pyridin-1 (2H)-yl)-4-methylpentanamido)propanoate (200 mg, 0.26 mmol) was treated with LiOH-HaO (55 mg, 1.3 mmol) in EtOH (3 mL) and H2O (1 mL) at room température for 2 hours. The reaction mixture was acidifîed to pH 4~5 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% CHjCN) to give the diastereomeric products HZ-P1 (7.0 mg) and HZ-P2 (62.0 mg) as white solids.

HZ-P1 ESI 732.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.76 (s, 1H), 7.35 (t, J= 7.6 Hz, 1H), 6.94 (s, 2H), 6.80 (s, 1H), 5.79 - 5.70 (m, 2H), 3.14 - 3.07 (m, 2H), 2.95-2.90 (m, 1H), 2.81 (s, 6H), 2.72 - 2.58 (m, 3H), 2.30 (s, 3H), 2.11-1.92 (m, 7H), 1.87 (s, 3H), 1.34 (s, 1H), 0.94 (d, J= 6.5 Hz, 6H).

HZ-P2 ESI 732.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 7.40 (t, J= 7.6 Hz, 1H), 6.97 (s, 2H), 6.85 (s, 1H), 5.82-5.80 (m, 1H), 5.62 (t, J= 7.6 Hz, 1H), 3.15-2.95 (m, 2H), 2.89-2.85 (m, 1H), 2.79 (s, 6H), 2.63 -2.60(m, 3H), 2.31 (s, 3H), 2.08 - 1.83 (m, 9H), 1.72 - 1.58 (m, IH), 1.31-1.25 (m, 1H), 0.86-0.82 (m, 6H).

3-71. Préparation of (3S)-3-(4'-cyclopropyl-2,4-difluoro-2',5,6'-trimethylbiphenyl-3-yl)-3-(2-(5-(3(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid (compounds IA-P1 and IA-P2)

Step 1: (35)-ethyl 3-(4’-cycIopropyl-2,4-difluoro-2’,5,6’-trimethylbiphenyl-3-yl)-3-(2-(5-(3(dimethylamino)propyI)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)-yI)-4methylpentanamido)propanoate

457

A mixture of (S)-ethyl 3-amino-3-(4'-cycIopropyl-2,4-difluoro-2',5,6-trimethylbiphenyl-3-yl)propanoate (107 mg, 0.28 mmol), 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid (100 mg, 0.28 mmol), TCFH (157 mg, 0.56 mmol) and NMI (69 mg, 0.84 mmol) in MeCN (5 mL) was stirred at room température for 3 hrs. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM:MeOH 97: 3) to provide (3S)-ethyl 3-(4'-cycIopropyl2,4-difluoro-2’,5,6'-trimethylbiphenyl-3-yl)-3-(2-(5-(3-(dimethyiamino)propyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate as a colorless oil (100 mg). Yield 49% (ESI 732.3 (M+H)⁺).

Step 2: (3S)-3-(4'-cyclopropyl-2,4-diiluoro-2',5,6’-trimethylbiphenyl-3-yl)-3-(2-(5-(3(dimethylamino)propyl)-2-oxo-4-(trifluoromethy])pyridin-l(2II)-yl)-4methylpentanamido)propanoic acid

(3S)-ethyl 3-(4'-cyclopropyl-2,4-difluoro-2^,,5,6'-trimethylbiphenyl-3-yl)-3-(2-(5-(3(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (100 mg, 0.14 mmol) was treated with L1OH-H2O (27 mg, 0.65 mmol) in EtOH (3 mL) and H2O (1 mL) at room température for 2 hours. The reaction mixture was acidifîed to pH 4~5 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% CH3CN) to give the diastereomeric products IA-P1 (37.3 mg) and IA-P2 (38.5 mg) as white solids.

IA-P1 ESI 704.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.78 (d, J= 13.1 Hz, 1H), 6.84 (t, J= 8.0 Hz, 1H), 6.79-6.75 (m, 3H), 5.78 - 5.67 (m, 2H), 3.10 - 3.00 (m, 2H), 2.93 -2.90(m, 1H), 2.77 (s, 6H), 2.69

458

2.59 (m, 3H), 2.24 (d, J= 18.1 Hz, 3H), 2.08 - 1.97 (m, 3H), 1.97 - 1.74 (m, 8H), 1.34-1.30 (m, 1H), 1.02 - 0.82 (m, 8H), 0.72 - 0.56 (m, 2H).

IA-P2 ESI 704.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 6.89 (t, J= 8.2 Hz, 1H), 6.82 (d, J = 16.3 Hz, 3H), 5.84-5.80 (m, 1H), 5.57 (t, J= 7.5 Hz, 1H), 3.01-3.00 (m, 2H), 2.85 -2.83(m, 1H), 2.77 (s, 6H), 2.68-2.59 (m, 2H), 2.53-2.51 (m, 1H), 2.26 (s, 3H), 2.05 - 1.83 (m, 10H), 1.62-1.60 (m, 1H), 1.34-1.30 (m, 1H), 1.03 - 0.91 (m, 2H), 0.86-0.83 (m, 6H), 0.71 - 0.64 (m, 2H).

3-72. Préparation of (3S)-3-(2-(5-(2-(2-azaspiro[3.4]octan-2-yl)ethyl)-2-oxo-4(trinuoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(2,4-difluoro-2’,5,6’-trimethyl-[l,l*biphenylJ-3-yl)propanoic acid (IB-P1 and IB-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(2-azaspiro[3.4]octan-2-yI)ethyl)-2-oxo-4-(trifluoromethyI)pyridinl(2H)-yl)-4-methyIpentanamido)-3-(2,4-diiluoro-2’,5,6’-trimethyl-[l,l’-biphenyl]-3-yl)propanoate

A mixture of ethyl (S)-3-amino-3-(2,4-difluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate (140 mg, 0.40 mmol), 2-(5-(2-(2-azaspiro[3.4]octan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid (182 mg, 0.54 mmol), TCFH (224 mg, 0.80 mmol) and NMI (164 mg, 2.0 mmol) in CHjCN (5 mL) was stirred at room température for 2 hours. The reaction was concentrated and purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: CH3OH, 0~85%) to provide ethyl (3S)-3-(2-(5-(2-(2-azaspiro[3.4]octan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)-4-methylpentanamido)-3-(2,4-difluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate as a yellow solid (130 mg). Yield 43.3 % (ESI 744.3 [M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(2-azaspiro[3.4]octan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)4-methylpentanamido)-3-(2,4-difluoro-2’,5,6’-trimethyl-[ 1,1 *-biphenyl]-3- yl)propanoic acid

459

Ethyl (3S)-3-(2-(5-(2-(2-azaspiro[3.4]octan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4-difluoro-2',5,6’-trimethyl-[ 1,1 '-biphenyl]-3-yl)propanoate (130 mg, 0.17 mmol) was treated with LiOH-HzO (22 mg, 0.52 mmol) in EtOH (4 mL) and H₂O (1 mL) at room température for 2 hr. The reaction mixture was acidified to pH 5~6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-65% CHjCN) to give the diastereomeric products IB-P1 (48 mg) and IB-P2 (65 mg) as white solids.

IB-P1 ESI 716.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.90 (s, 1 H), 7.18 (m, 7= 24.2, 7.1 Hz, 3H), 6.94 (m, 7= 14.9,6.5 Hz, 2H), 5.87 (m, 7= 9.8,4.8 Hz, IH), 5.75 (m, 7= 9.4,6.8 Hz, IH), 3.95 (d, 7= 9.1 Hz, 4H), 3.38 (m, 1 H), 3.32 (m, 7= 7.3 Hz, 1 H), 3.03 (m, 7= 15.2, 9.9 Hz, 1 H), 2.93 (t, 7 = 6.7 Hz, 2H), 2.70 (m, 7= 15.3,4.9 Hz, IH), 2.31 (s, 3H), 2.11 - 1.98 (m, 8H), 1.92 (d, 7= 6.3 Hz, 4H), 1.75 1.56 (m, 4H), 1.51 - 1.38 (m, IH), 0.99 (m,7= 6.6,1.2 Hz, 6H).

IB-P2 ESI 716.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.71 (s, IH), 7.22-7.05 (m, 3H), 6.99- 6.73 (m, 2H), 5.92 (m,7= 11.5,3.4 Hz, IH), 5.62 (t,7= 7.7 Hz, IH), 3.99 (s, 4H), 3.43-3.31 (m, 2H), 2.95-2.75 (m, 3H), 2.47 (m, 7= 16.1, 3.6 Hz, IH), 2.28 (s, 3H), 2.01 (d, 7= 5.5 Hz, 6H), 1.91 (m, 7= 26.9,12.0, 7.3 Hz, 5H), 1.74 - 1.56 (m, 5H), 1.44 - 1.26 (m, IH), 0.89 (m, 7= 9.1,6.6 Hz, 6H).

3-73. Préparation of (35)-3-(2,4-difluoro-2’,5,6’-trimethyI-3’-(trinuoromethyl)-[l,r-biphenyl]-3yl)-3-(2-(5-(2-(dimethylamino)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2/f)-yI)-4methylpentanamido)propanoic acid (compounds IC-P1 and IC-P2)

Step 1: ethyl (35)-3-(2,4-difluoro-2’,5,6’-trimethyl-3’-(trinuoromethyl)-[l,l’-biphenyIJ-3-yl)-3-(2-(5(2-(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methylpentanamido)propanoate

460

A mixture of ethyl (35)-3-amino-3-(2,4-difluoro-2',5,6^,-trimethyl-3^,-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoate (170.0 mg, 0.41 mmol), 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin1 (2/7)-yl)-4-methyl pentanoic acid (142.8 mg, 0.49 mmol), TCFH (137.5 mg, 0.76 mmol) and NMI (68.8 mg, 1.64 mmol) in CHjCN (5 mL) was stirred at room température ovemight. The reaction was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3. B: MeOH, 0-100%) to provide ethyl (35)-3-(2,4-difluoro-2',5,6'-trimethyl-3 (trifluoromethyl)-[ 1,1 ’-biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanamido)propanoate as a light yellow solid (210.0 mg). Yield 69% (ESI 746.3 [M+H]⁺).

Step 2: (35)-3-(2,4-difluoro-2’,5,6’-trimethyl-3’-(trifluoromethyl)-[l,V-biphenyIJ-3-yI)-3-(2-(5-(2(dimethyIamino)ethyl)-2-oxo-4-(trinuoromethyl)pyridin-l(277)-yl)-4-methyIpentanamido)propanoic acid

Ethyl (35)-3-(2,4-difluoro-2', 5,6'-trimethyl-3-(trifluoromethyl)-[l,r-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanamido)propanoate (210.0 mg, 0.28 mmol) was treated with L1OH-H2O (35.2 mg, 0.84 mmol) in EtOH (2 mL) and water (0.5 mL) at room température for 1 hour. The reaction mixture was acidified to pH 4-5 with 2N HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-80% MeCN) to give the diastereomeric products IC-P1 (53.3 mg) and IC-P2 (78.3 mg) as white solids.

IC-P1 ESI 718.3 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.87 (d, J= 3.6 Hz, 1H), 7.56 (d, J= 8.1 Hz, 1H), 7.26 (d, J= 8.2 Hz, 1H), 6.90 (t, J= 8.1 Hz, 1H), 6.83 (s, 1H), 5.75 - 5.64 (m, 2H), 3.18 - 3.01 (m, 2H), 3.00 - 2.85 (m, 3H), 2.79 - 2.64 (m, 7H), 2.25 (s, 3H), 2.10 - 1.94 (m, 8H), 1.46 - 1.33 (m, 1H), 0.96 0.90 (m, 6H).

461

IC-P2 ESI 718.3 (M+H)⁺ 'H NMR (400 MHz, MeOD) δ 7.81 (s, IH), 7.58 (d, J= 8.1 Hz, IH), 7.29 (d, J = 8.1 Hz, IH), 6.96 (t, J = 8.2 Hz, IH), 6.90 (s, IH), 5.86-5.80 (m, 1 H), 5.66-5.60 (m, IH), 3.28-3.10 (m, 2H), 3.01 - 2.94 (m, 2H), 2.86 - 2.74 (m, 7H), 2.62 - 2.55 (m, IH), 2.29 (s, 3H), 2.12 (s, 3H), 2.07 (d, J=3.9Hz,3H), 1.97-1.82(m, IH), 1.80-1.66(m, IH), 1.39-1.28 (m, IH),0.90-0.82(m,6H).

3-74. Préparation of (3S)-3-(2-(5-(2-(2-azaspiro[3.3]heptan-2-yl)ethyl)-2-oxo-4(trifluoromethyI)pyridin-l(2H)-yl)-4-methyIpentanamido)-3-(2,4-difluoro-2’,5,6’-trimethyl-[l,rbiphenylJ-3-yl)propanoic acid (compounds ID-P1 and ID-P2)

Step 1: ethyl (35)-3-(2-(5-(2-(2-azaspiro(3.3]heptan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin l(2H)-yl)-4-methylpentanamido)-3-(2,4-difIuoro-2’,5,6’-trimethyl-[l,r-biphenyl]-3-yl)propanoate

A mixture of ethyl (S)-3-amino-3-(2,4-difluoro-2',5,6^,-trimethyl-[l,l'-biphenyl]-3-yl)propanoate (220 mg, 0.63 mmol), 2-(5-(2-(2-azaspiro[3.3]heptan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid (240 mg, 0.6 mmol), TCFH (336 mg, 1.2 mmol) and NMI (246 mg, 3.0 mmol) in CHjCN (4 mL) was stirred at 25 °C for 16 hr. The reaction was concentrated and purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: MeOH, 0~90%) to provide ethyl (3S)-3-(2-(5-(2-(2-azaspiro[3.3]heptan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4-difluoro-2',5,6’-trimethyl-[l,r-biphenyl]-3-yl)propanoate as a yellow solid (310 mg). Yield 70.8 % (ESI 730.4 [M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(2-azaspiro[3.3]heptan-2-yl)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)yl)-4-methyIpentanamido)-3-(2,4-difluoro-2’,5,6’-trimethyI-[l,r-biphenyIJ-3-yl)propanoic acid

462

Ethyl (35)-3-(2-(5-(2-(2-azaspiro[3.3]heptan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpcntanamido)-3-(2,4-difluoro-2^,,5,6 -trimethyl-[ 1,1 '-biphenyl]-3-yl)propanoate (310 mg, 0.42 mmol) was treated with LiOH-HaO (54 mg, 1.28 mmol) in EtOH (4 mL) and HjO (1 mL) at room température for 30 min. The reaction mixture was acidifïed to pH 5~6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (40-60% CHjCN) to give the diastereomeric products ID-P1 (72 mg) and ID-P2 (96 mg) as white solids.

ID-P1 ESI 702.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.81 (s, 1 H), 7.18 - 7.03 (m, 3H), 6.94 - 6.83 (m, 2H), 5.83-5.75(m, 1H), 5.69 (t, J = 7.9 Hz, 1H), 3.96 (s,4H), 3.28-3.13(m, 2H), 3.02-2.91 (m, 1H), 2.85 (s, 2H), 2.64 (d, J= 15.1 Hz, 1H), 2.24 (t, J= 7.4 Hz, 7H), 2.04 - 1.89 (m, 8H), 1.88 - 1.76 (m, 2H), 1.43 - 1.33 (m, 1H), 0.98 - 0.88 (m, 6H).

ID-P2 ESI 702.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.71 (s, 1H), 7.19 - 7.07 (m, 3H), 6.97 - 6.88 (m, 2H), 5.95 - 5.86 (m, 1H), 5.61 (t, J= 7.7 Hz, 1H), 4.10 (s, 4H), 3.41 - 3.31 (m, 2H), 2.95 - 2.74 (m, 3H), 2.52 - 2.39 (m, 1H), 2.36 - 2.17 (m, 7H), 2.01 (d, J= 6.7 Hz, 6H), 1.98 - 1.89 (m, 1H), 1.90 - 1.79 (m, 2H), 1.75 - 1.64 (m, 1 H), 1.42 - 1.33 (m, 1 H), 0.93 - 0.83 (m, 6H).

3-75. Préparation of (3S)-3-(2-(5-(2-(azetidin-l-yI)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)-4-methyipentanamido)-3-(2,4-difluoro-3^,-methoxy-2*,6’-dimethyI-5-(trifluoromethyi)-[l,rbiphenyl]-3-yl)propanoic acid (compounds IE-P1 and IE-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4-dinuoro-3’-methoxy-2’,6’-dimethyl-5-(trifluoromethyl)-[l,l’-biphenyl]3-yl)propanoate

TCFH NMI

A mixture of ethyl (3S)-3-amino-3-(2,4-difluoro-3'-methoxy-2',6^,-dimethyl-5-(trifluoromethyl)-[l,l'biphenyl]-3-yl)propanoate (150 mg, 0.35 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoic acid (150 mg, 0.41 mmol), TCFH (213 mg, 0.76 mmol) and NMI (156 mg, 1.9 mmol) in CHjCN (3 mL) was stirred at 50 °C for 30 min. The reaction was concentrated and purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO5, B:

463

MeOH, 0-90%) to provide ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin1 (2H)-yl)-4-methylpentanamido)-3-(2,4-difluoro-3'-methoxy-2',6'-dimethyl-5-(trifluoromethyl)-[ 1,1*biphenyl]-3-yl)propanoateas a yellow solid (180 mg). Yield 66.4 % (ESI 774.3 [M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l (2H)-yI)-4methylpentanamido)-3-(2,4-difluoro-3^,-methoxy-2’,6’-dimethyI-5-(trifluoromethyI)-[l,r-biphenyI]3-yl)propanoic acid

Ethyl (3S)-3-(2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(2,4-difluoro-3'-methoxy-2^,,6’-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoate (180 mg, 0.23 mmol) was treated with LiOH-H₂O (30 mg, 0.7 mmol) in EtOH (2 mL) and H₂O (0.5 mL) at room température for 30 min. The reaction mixture was acidified to pH 5-6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (35-60% CH3CN) to give the diastereomeric products IE-P1 (46 mg) and IE-P2 (53 mg) as white solids.

IE-P1 ESI 746.3 (M+H)\ Ή NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 7.36 (t, J= 7.3 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.93 - 6.83 (m, 2H), 5.76 - 5.65 (m, 2H), 4.04 (t, 7.9 Hz, 4H), 3.83 (s, 3H), 3.29 - 3.19 (m, 2H), 2.95 - 2.88 (m, 1 H), 2.84 (t, J= 6.7 Hz, 2H), 2.76 - 2.69 (m, 1H), 2.48 - 2.39 (m, 2H), 2.04 1.95 (m, 2H), 1.85 (t, J= 30.1 Hz, 6H), 1.41 - 1.32 (m, 1H), 0.93 (t, J= 6.5 Hz, 6H).

IE-P2 ESI 746.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.74 (s, 1H), 7.42 (t, J= 7.6 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.92 (d, J= 6.3 Hz, 2H), 5.96 - 5.84 (m, 1H), 5.64 (t, J= 7.7 Hz, 1H), 4.12 (t, J= 8.1 Hz, 4H), 3.84 (s, 3H), 3.43 - 3.31 (m, 2H), 2.96 - 2.74 (m, 3H), 2.69 - 2.57 (m, 1H), 2.53 - 2.39 (m, 2H), 1.98 - 1.82 (m, 7H), 1.76 - 1.65 (m, 1H), 1.39 - 1.27 (m, 1H), 0.92 - 0.83 (m, 6H).

3-76. Préparation of(3S)-3-(2,4-difluoro-2’,4’,6*-trimethyl-5-(trifluoromethyl)-[l,r-biphenylJ-3yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid (compounds IF-PI and IF-P2)

464

Step 1: ethyl (3S)-3-(2,4-difluoro-2',4',6'-trimethyl-5-(trifiuoromethyl)-[l,r-biphenyl]-3-yl)-3-(2-(5(2-(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2II)-yl)-4methylpentanamido)propanoate

A mixture of ethyl (5)-3-amino-3-(2,4-difluoro-2',4^,,6'-trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoate (210 mg, 0.5 mmol), 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanoic acid (200 mg, 0.57 mmol), TCFH (364 mg, 1.3 mmol) and NMI (246 mg, 3.0 mmol) in CH3CN (4 mL) was stirred at 50 °C for 1 hr. The reaction was concentrated and purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: MeOH, 0-90%) to provide ethyl (35)-3-(2,4-difluoro-2’,4’,6'-trimethyl-5-(trifluoromcthyl)-[ 1,1 '-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoateas a yellow solid (330 mg). Yield 88.5 % (ESI 746.3 [M+H]⁺).

Step 2: (3S)-3-(2,4-difIuoro-2’,4’,5,6’-tetramethyI-[l,l*-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-niethyIpentanamido)propanoic acid

Ethyl (3S)-3-(2,4-difluoro-2',4^,,6’-trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (330 mg, 0.44 mmol) was treated with LiOH-H?O (56 mg, 1.34 mmol) in MeOH (4 mL) and H₂O (1 mL) at room température for 30 min. The reaction mixture was acidified to pH 5-6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-58% CHjCN) to give the diastereomeric products IF-PI (96 mg) and IF-P2 (94 mg) as white solids.

465

IF-PI ESI 718.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.86 (s, 1H), 7.34 (t, 7.6 Hz, 1H), 6.94 (d, J = 3.7 Hz, 2H), 6.82 (s, 1H), 5.76 - 5.65 (m, 2H), 3.12 - 3.04 (m, 2H), 2.99 - 2.88 (m, 3H), 2.80-2.70 (m,7H), 2.29 (s, 3H), 2.06-1.92 (m, 5H), 1.86 (s, 3H), 1.44-1.33 (m, 1H), 0.93 (t,J=7.0 Hz, 6H).

IF-P2 ESI 718.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.84 (s, IH), 7.41 (t, J= 7.6 Hz, 1H), 6.97 (s, 2H), 6.89 (s, 1H), 5.85 - 5.76 (m, 1H), 5.66 (t, J= 7.8 Hz, 1H), 3.25 - 3.09 (m, 2H), 2.96 (t, J= 7.2 Hz, 2H), 2.90-2.81 (m, 1H), 2.79 (s, 6H), 2.71 - 2.62 (m, 1H), 2.31 (s, 3H), 1.98 (d, J= 3.1 Hz, 6H), 1.93 1.81 (m, 1H), 1.76-1.67 (m, 1H), 1.36-1.27 (m, 1H), 0.92-0.82 (m, 6H).

3-77. Préparation of (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyI)pyridin-l(2fl)yll-^-methylpentanamidol-S-iljd-difluoro^’/l’^’-trimethyl-S-itrifluoroinethyObiphenyl-Syl)propanoic acid (compounds IG-P1 and IG-P2)

Step 1: (3S)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifIuoromethyl)pyridin-l(2/7)-yl)-4methy!pentanamido)-3-(2,4-difluoro-2’,4’,6’-trimethyI-5-(trifluoromethyI)biphenyl-3-yI)propanoate

A mixture of 2-(5-(2-(azetidin-l -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4-methylpentanoic acid (150 mg, 0.41 mmol), (S)-ethyl 3-amino-3-(2,4-difluoro-2',4^,,6'-trimethyl-5(trifluoromethyl)biphenyl-3-yl)propanoate (173 mg, 0.41 mmol), NMI (0.5 mL) and TCFH (364 mg, 1.30 mmol) in CH3CN (5 mL) was stirred at room température for 1 hour. The solvent was concentrated in vacuo and the residue was purified by prep-HPLC A (30-90% CH3CN) to provide (3S)-ethyl 3-(2-(5-(2(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2W)-yl)-4-methylpentanamido)-3-(2,4-difluoro2',4',6'-trimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate as a white solid (150 mg). Yield 54% (ESI 758.2 [M+H]⁺).

Step 2: (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4-dinuoro-2’,4’,6’-trimethyI-5-(triiluoromethyl)biphenyl-3-yI)propanoic acid

466

(35)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanamido)-3-(2,4-difluoro-2',4^,,6'-trimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate (150 mg, 0.19 mmol) was treated with L1OH-H2O (42 mg, 1.00 mmol) in MeOH (4 mL) and H2O (0.4 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-70% CH3CN) to give the diastereomeric products IG-P1 (33.0 mg) and IG-P2 (51.0 mg) as white solids.

IG-P1 ESI 730.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 7.37 (t, J= 7.5 Hz, 1H), 6.95 (s, 2H), 6.85 (s, 1H), 5.79 - 5.65 (m, 2H), 4.03 (t, J= 8.1 Hz, 4H), 3.27 - 3.20 (m, 2H), 3.00 - 2.69 (m, 4H), 2.50 - 2.38 (m, 2H), 2.30 (s, 3H), 2.05 - 1.83 (m, 8H), 1.52 - 1.28 (m, 1H), 0.93 (t, J= 6.4 Hz, 6H).

IG-P2 ESI 730.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.43 (t, J= 7.6 Hz, 1H), 6.97 (s, 2H), 6.91 (s, 1H), 6.00-5.83 (m, 1 H), 5.63 (t, J = 7.7 Hz, 1H),4.11 (t,J=8.0 Hz, 4H), 3.50 - 3.33 (m, 2H), 2.99 - 2.75 (m, 3H), 2.69 - 2.57 (m, 1H), 2.49 - 2.37 (m, 2H), 2.31 (s, 3H), 2.02 - 1.84 (m, 7H), 1.77 - 1.64 (m, 1 H), 1.46 - 1.19 (m, 1 H), 1.03 - 0.80 (m, 6H).

3-78. Préparation of (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2jW)yl)-4-methylpentanamido)-3-(4^,-cyclopropyI-2,3’,4-trinuoro-2’,6’-dimethyl-5-(trifluoromethyl)(l,l’-biphenyl]-3-yl)propanoic acid (compounds IH-P1 and IH-P2)

Step 1: ethyl (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2jF/)-yl)-4methylpentanamido)-3-(4^,-cyclopropyI-2,3*,4-trifluoro-2’,6’-dimethyl-5-(trifluoromethyl)-[l,rbiphenylJ-3-yl)propanoate

467

A mixture of ethyl (3S)-3-amino-3-(4'-cyclopropyl-2,3',4-trifluoro-2',6^,-dimethyl-5-(trifluoromethyl)[l,l'-biphenyl]-3-yI)propanoate (80 mg, 0.17 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(277)-yl)-4-methylpentanoic acid (120 mg, 0.33 mmol), TCFH(74 mg, 0.26 mmol), and 1-methylimidazole (57 mg, 0.70 mmol) in acetonitrile (5 mL) was stirred at room température for 2 hours. The mixture was purified by reverse phase HPLC on a C18 / 40g column (A: water 10 mM NH4HCO3, B: MeOH, 0-100%) to provide ethyl (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(277)-yl)-4-methylpentanamido)-3-(4'-cyclopropyl-2,3',4-trifluoro-2',6'dimethyl-5-(trifluoromethyl)-[l,l'-biphenyl]-3-yl)propanoate (100 mg) as a brown solid. Yield 71.4 % (ESI 802.3 (M+H)⁺).

Step 2: (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/f)-yl)-4methylpentanamido)-3-(4’-cycIopropyl-2,3',4-trinuoro-2’,6’-dimethyl-5-(trifluoromethy!)-[l,l’biphenyl]-3-yl)propanoic acid

Ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2_JF/)-yl)-4methylpentanamido)-3-(4^,-cyclopropyl-2,3',4-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]3-yl)propanoate (100 mg, 0.13 mmol) was treated with L1OH-H2O (27 mg, 0.65 mmol) in MeOH (5 mL) and H2O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 6-7 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% CH3CN) to give the diastereomeric products IH-P1 (13.8 mg) and IH-P2 (16.7 mg) as white solids.

468

IH-P1 ESI 774.2 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 7.39 (t, J= 7.5 Hz, 1H), 6.85 (d, J = 4.6 Hz, 1H), 6.71 - 6.68 (m, 1H), 5.74 - 5.67 (m, 2H), 4.02 (t, J= 7.8 Hz, 4H), 3.30 - 3.26 (m, 2H), 2.93 - 2.70 (m, 4H), 2.48 - 2.38 (m, 2H), 2.12 - 1.96 (m, 3H), 1.93 - 1.91 (m, 3H), 1.86 - 1.82 (m, 3H), 1.41 -1.36 (m, 1H), 1.01- 0.92 (m, 8H), 0.75 - 0.69 (m, 2H).

IH-P2 ESI 774.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.72 (s, 1H), 7.46 (t, J= 7.6 Hz, 1H), 6.92 (s, 1H), 6.72 (d, 7= 7.2 Hz, 1 H), 5.87-5.91 (m, 1H),5.63 (t,7=7.6Hz, 1H), 4.12 (t,7= 8.0 Hz,4H), 3.443.33 (m, 2H), 2.93 - 2.77 (m, 3H), 2.63- 2.58 (m, 1H), 2.49 - 2.41 (m, 2H), 2.13- 2.06 (m, 1H), 1.95 1.88 (m, 7H), 1.75 - 1.68 (m, 1H), 1.37 - 1.29 (m, 1H), 1.02 - 0.97 (m, 2H), 0.91 - 0.86(m, 6H), 0.77 0.74 (m, 2H).

3-79. Préparation of (35)-3-(2,4-difluoro-2’,4’,6’-trimethyl-5-(trifluoroinethyI)-[l,r-biphenyI]-3yl)-3-(4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyi)-2-oxo-4-(trifluoromethyl)pyridin-l(2J/)yl)pentanamido)propanoic acid (compounds II-P1 and II-P2)

Step 1: ethyl (35)-3-(2,4-diiluoro-2’,4’,6’-trimethyI-5-(trifluoromethyl)-[l,l’-biphenyl]-3-yl)-3-(4methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyI)pyridin-l(2//)yl)pentanamido)propanoate

A mixture of ethyl (5)-3-amino-3-(2,4-difluoro-2',4^,,6'-trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoate (120 mg, 0.29 mmol), 4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)pentanoic acid (108 mg, 0.29 mmol), TCFH (120 mg, 0.43 mmol) and NMI (119 mg, 1.45 mmol) in CHjCN (3 mL) was stirred at room température ovemight. The reaction was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3. B: MeOH, 20-95%) to provide ethyl (35)-3-(2,4-difluoro-2',4',6'-trimethyl-5(trifluoromethyl)-[l,l'-biphenyl]-3-yl)-3-(4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2Z7)-yl)pentanamido)propanoate as a light yellow solid (150 mg). Yield 67% (ESI 772.2 [M+Hf ).

469

Step 2: (35)-3-(2,4-difluoro-2',4',6'-trimethyl-5-(trifluoromethyI)-[l,r-biphcnyl]-3-yl)-3-(4-methyl2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2H^r)yl)pentanamido)propanoic acid

Ethyl (35)-3-(2,4-difluoro-2',4’,6’-trimethyl-5-(trifluoromethyl)-[ 1,1 '-biphenyl]-3-yl)-3-(4-methyl-2-(5-(2(3-methylazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)pentanamido)propanoate (150 mg, 0.19 mmol) was treated with LiOH-HjO (24 mg, 0.57 mmol) in EtOH (2 mL) and water (0.5 mL) at room température for 1 hour. The reaction mixture was acidified to pH 4~5 with 2N HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (20-85% MeCN) to give the diastereomeric products Π-Ρ1 (33 mg) and II-P2 (49 mg) as white solids.

Π-Ρ1 ESI 744.3 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 7.37 (t, J= 7.5 Hz, 1H), 6.95 (s, 2H), 6.84 (s, 1H), 5.77 - 5.61 (m, 2H), 4.12 (t, J= 9.2 Hz, 2H), 3.67 (t, J= 8.8 Hz, 2H), 3.28 - 3.20 (m, 2H), 3.00 - 2.78 (m, 4H), 2.76 - 2.67 (m, 1H), 2.30 (s, 3H), 2.05 - 1.95 (m, 5H), 1.89 (s, 3H), 1.45 - 1.30 (m, 1H), 1.24 (d, J= 6.9 Hz, 3H), 0.96 - 0.84 (m, 6H).

II-P2 ESI 744.3 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.42 (t, J= 7.6 Hz, 1H), 6.98 (s, 2H), 6.91 (s, 1H), 5.89 - 5.82 (m, 1H), 5.63 (t, J= 7.7 Hz, 1H), 4.20 (d, J= 9.9 Hz, 2H), 3.75 (s, 2H), 3.45 - 3.34 (m, 2H), 3.02 - 2.85 (m, 4H), 2.65 - 2.53 (m, 1H), 2.31 (s, 3H), 2.03 - 1.84 (m, 7H), 1.75 1.65 (m, 1H), 1.42-1.18 (m, 4H), 0.95-0.85 (m, 6H).

3-80. Préparation of (35)-3-(2,4-diiluoro-2’, 4’, 5,6'-tetramethyl-[l,l'-biphenyl]-3-yI)-3-(2-(5-(3(dimethyIamino)propyl)-2-oxo-4-(trinuoromethyI)pyridin-l(2fi)-yI)-4methylpentanamido)propanoic acid (compounds IJ-P1 and IJ-P2)

Step 1: ethyl (35)-3-(2,4-difluoro-2’,4’,5,6’-tetramethyl-(l,l’-bipheny!j-3-yl)-3-(2-(5-(3(dimethy!amino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yI)-4methylpentanamido)propanoate

470

A mixture of ethyl (5)-3-amino-3-(2,4-difluoro-2',4’,5,6^,-tetramethyl-[l,l'-biphenyl]-3-yl)propanoate (120.0 mg, 0.33 mmol), 2-(5-(3-(dimethyIamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanoic acid (119.6 mg, 0.33 mmol), TCEW(138.9 mg, 0.50 mmol) and NMI (81.3 mg, 0.99 mmol) in CHjCN (3 mL) was stirred at 50°C for 0.5hour. The reaction was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH₄HCOj. B: MeOH, 0—100%) to provide ethyl (35)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[ 1,l'-biphenyl]-3-yl)-3-(2-(5-(3(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)*yl)‘4^methylpentanamido)propanoateas a light yellow solid (160.0 mg). Yield 68% (ESI 706.2 [M+H]⁺).

Step 2: (35)-3-(2,4-difluoro-2’,4’,5,6’-tetramethyl-[l,l’-biphenyl]-3-yl)-3-(2-(5-(3(dimethylamino)propyl)-2-oxo-4-(trinuoromethyl)pyridin-l(2J/)-yI)-4methylpentanamido)propanoic acid

Ethyl (35)-3-(2,4-difluoro-2',4’,5,6-tetramethyl-[l,r-biphenyl]-3-yl)-3-(2-(5-(3-(dimethylamino)propyl)2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (160.0 mg, 0.23 mmol) was treated with LiOH-HjO (29.0 mg, 0.69 mmol) in EtOH (2 mL) and water (0.5 mL) at room température for 30 mins. The reaction mixture was acidified to pH 4~5 with 2N HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-80% MeCN) to give the diastereomeric products IJP1 (52.0 mg) and IJ-P2 (44.0 mg) as white solids.

IJ-P1 ESI 678.3 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.77 (s, 1H), 6.94 - 6.75 (m, 4H), 5.78 - 5.72 (m, 2H), 3.09 - 3.02 (m, 2H), 2.98 - 2.90 (m, 1H), 2.78 (s, 6H), 2.73 - 2.59 (m, 3H), 2.28 (s, 3H), 2.23 (s, 3H), 2.11 - 1.96 (m, 3H), 1.97 - 1.81 (m, 7H), 1.41 - 1.26 (m, IH), 0.95-0.91 (m, 6H).

471

IJ-P2 ESI 678.3 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.79 (s, IH), 6.98 - 6.80 (m, 4H), 5.88 - 5.82 (m, 1H), 5.57 (t, J= 7.5 Hz, 1H), 3.08 - 2.92 (m, 2H), 2.91 - 2.73 (m, 7H), 2.72 - 2.45 (m, 3H), 2.28 (d, J= 10.7 Hz, 6H), 2.03 - 1.88 (m, 9H), 1.66 - 1.58 (m, 1H), 1.39 - 1.27 (m, 1H), 0.90 - 0.83 (m, 6H).

3-81. Préparation of (35)-3-(2,4-difluoro-2’,3’,6’-trimethyl-5-(trifluoromethyI)-[l,r-biphenyl|-3yI)-3-(2-(5-(2-(ethyl(methyl)amino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2jEZ)-yl)-4methylpentanamido)propanoic acid (compounds IK-P1 and IK-P2)

Step 1: ethyl (35)-3-(2,4-difluoro-2',3',6'-trimethyl-5-(trifIuoromethyl)-[l,r-biphenyl|-3-yl)-3-(2-(5(2-(ethyl(methyl)amino)ethyI)-2-oxo-4-(trifiuoromethyl)pyridin-l(2Z/)-yl)-4methylpentanamido)propanoate tcfh,nmi,ch₃cn

A mixture of 2-(5-(2-(ethyl(inethyl)amino)ethyl)-2-oxo-4-(trifiuoromethyl)pyridin-l (2H)-yl)-4methylpentanoic acid (100.0 mg, 0.28 mmol), ethyl (3S)-3-amino-3-(2,4-difluoro-2',3',6'-trimethyl-5(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (116.2 mg, 0.28 mmol), TCFH (156.8 mg, 0.56 mmol) and NMI (91.8 mg, 1.12 mmol) in CILCN (10 mL) was stirred at room température for 1 hour. The reaction was concentrated in vacuo and the residue purified by silica gel column (DCM:MeOH 4:1) to provide ethyl (35)-3-(2,4-difluoro-2’, 3', 6'-trimethyl-5-(trifluoromethyl)-[l, l'-biphenyl]-3-yl)-3-(2-(5-(2(ethyl(methyl)amino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4-methylpentanamido)propanoate as a brown solid (110.0 mg). Yield 52% (ESI 760.7 (M+H)⁺).

Step 2: (35)-3-(2,4-difluoro-2’,3’,6’-trimethyl-5-(trifluoroinethyl)-[l,r-biphenyl]-3-yl)-3-(2-(5-(2(ethyl(methyI)amino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z7)-yI)-4methylpentanamido)propanoic acid

472

Ethyl (35)-3-(2,4-difluoro-2',3',6'-trimethyl-5-(trifluoromethyl)-[l,l’-biphenyl]-3-yl)-3-(2-(5-(2(ethyI(methyl)amino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanamido)propanoate (l 10 mg, 0.14 mmol) was treated with LiOH-H₂O (23.5 mg, 0.56 mmol) in MeOH (4 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4-5 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products IK-P1 (34.1 mg) and IK-P2 (29.4 mg) as white solids.

IK-P1 ESI 732.7(M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.88 (s, 1H), 7.32 (t, J= 7.6 Hz, 1H), 7.10 (d, J = Ί.Ί Hz, 1H), 7.04 - 6.96 (m, 1H), 6.82 (d, J= 4.5 Hz, 1H), 5.78 - 5.66 (m, 2H), 3.19 - 3.05 (m, 4H), 3.00 - 2.85 (m, 3H), 2.80 - 2.70 (m, 4H), 2.26 (d, J= 2.0 Hz, 3H), 2.03 - 1.87 (m, 5H), 1.81 (d, J = 15.0 Hz, 3H), 1.43 - 1.32 (m, 1H), 1.26 (d, J= 7.3 Hz, 3H), 0.93 (d, J= 6.9 Hz, 6H).

IK-P2 ESI 732.7 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.87 (s, 1H), 7.39 (t, J= 7.6 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 7.03 (d, J= 7.9 Hz, 1H), 6.88 (s, 1H), 5.85 - 5.75 (m, 1H), 5.71 - 5.61 (m, 1H), 3.27 3.09 (m, 4H), 3.00 - 2.84 (m, 3H), 2.79 (s, 3H), 2.72 - 2.62 (m, 1H), 2.28 (d, J= 2.1 Hz, 3H), 1.98 - 1.79 (m, 7H), 1.82- 1.68 (m, 1 H), 1.41 - 1.22 (m, 4H), 0.92-0.78 (m, 6H).

3-82. Préparation of (35)-3-(2,4-difluoro-3'-methoxy-2',6'-dimethyl-5-(trifluoromethyl)biphenyl3-yI)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trinuoromethyl)pyridin-l(277)-yl)-4methylpentanamido)propanoic acid (compounds IL-P1 and IL-P2 )

Step 1: (3S)-ethyl 3-(2,4-difluoro-3*-methoxy-2’,6’-dimethyI-5-(trifluoromethyl)biphenyl-3-yI)-3-(2(5-(2-(dimethyIamino)ethyI)-2-oxo-4-(triiluoromethyl)pyridin-l(2£0-yI)-4methylpentanamido)propanoate

473

A mixture of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanoic acid (122 mg, 0.35 mmol), (35)-ethyl 3-amino-3-(2,4-difluoro-3'-methoxy-2',6dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate (150 mg, 0.35 mmol), NMI (86 mg, 1.05 mmol) and TCFH (147 mg, 0.53 mmol) in CHjCN (4 mL) was stirred at room température for 2 hours. The solvent was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCOJ, B: CHjCN, 0-100%) to provide (35)-ethyl 3-(2,4-difluoro-3methoxy-2^,,6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2/7)-yl)-4-methylpentanamido)propanoate as a yellow oil (180 mg). Yield 68 % (ESI 762.3 (M+H]⁺).

Step 2: (35)-3-(2,4-dif1uoro-3^,-methoxy-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/f)-yl)-4-methyIpentanamido)propanoic acid

(35)-ethyl 3-(2,4-difluoro-3^,-methoxy-2^,,6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z7)-yl)-4-methylpentanamido)propanoate (180 mg, 0.24 mmol) was treated with LiOH-HjO (40 mg, 0.96 mmol) in EtOH (3mL) and H₂O (1 mL) at room température for 1 hour. The reaction mixture was acidified to pH 5-6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% CHjCN) to give the diastereomeric products IL-P1 (47 mg) and IL-P2 (57 mg) as white solids.

IL-P1 ESI 734.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.86 (s, 1H), 7.34 (t, J= 7.6 Hz, 1H), 7.12 7.05 (m, 1H), 6.92 - 6.81 (m, 2H), 5.78 - 5.63 (m, 2H), 3.82 (s, 3H), 3.19 - 3.04 (m, 2H), 3.02 - 2.87 (m, 3H), 2.83 - 2.69 (m, 7H), 2.09 - 1.93 (m, 2H), 1.93 - 1.73 (m, 6H), 1.45 - 1.33 (m.lH), 0.93 (t, J= 7.1 Hz, 6H).

IL-P2 ESI 734.2 (M+H)\ Ή NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.40 (t, J= 1.1 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 7.00 - 6.84 (m, 2H), 5.86 - 5.77 (m, 1H), 5.66 (t, J= 7.7 Hz, 1H), 3.84 (s, 3H), 3.26 - 3.06 (m, 2H), 3.01 - 2.71 (m, 9H), 2.78 - 2.50 (m, 1H), 2.02 - 1.80 (m, 7H), 1.80 - 1.55 (m, 1H), 1.53 - 1.22 (m, 1H), 0.97-0.77 (m,6H).

474

3-83. Préparation of (35)-3-(2,4-dinuoro-2',3',6'-trimethyl-5-(trifluoromethyl)biphenyI-3-yl)-3-(2(5-(2-(diniethylamino)ethyl)-2-oxo-4-(trifIiioromethyl)pyridin-l(2Z7)-yl)-4methylpentanamido)propanoic acid (compounds IM-P1 and IM-P2)

Step 1: (35)-ethyl 3-(2,4-difluoro-2',3',6'-trimethyl-5-(trifluoromethyl)biphenyl-3-yl)-3-(2-(5-(2(dimethylamino)ethyi)-2-oxo-4-(trinuoromethyl)pyridin-l(2//)-yI)-4methylpentanamido)propanoate

A mixture of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid (100 mg, 0.29 mmol), (35)-ethyl 3-amino-3-(2,4-difluoro-2',3',6'-trimethyl-5(trifluoromethyl)biphenyl-3-yl)propanoate (120 mg, 0.29 mmol), NMI (0.5 mL) and TCFH (378 mg, 1.35 mmol) in CHjCN (5 mL) was stirred at room température for 1 hour. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-90% CH3CN) to provide (35)-ethyl 3-(2,4-difluoro2',3',6’-trimethyl-5-(trifluoromethyl)biphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(27ï)-yl)-4-methylpentanamido)propanoate as a white solid (130 mg). Yield 60% (ESI 746.3 [M+H]*).

Step 2: (35)-3-(2,4-diiluoro-2'3',6'-trimethyl-5-(trifluoromethyl)biphenyl-3-yI)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromcthyl)pyridin-l(2W)yl)*4-mcthylpentanamido)propanoic acid

475 (3S)-ethyl 3-(2,4-difluoro-2',3',6'-trimethyl-5-(trifluoromethyl)biphenyl-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanamido)propanoate (130 mg, 0.17 mmol) was treated with LiOH-HjO (42 mg, 1.00 mmol) in MeOH (4 mL) and H₂O (0.5 mL) at room température for 2 hours. The reaction mixture was acidifted to pH 4-5 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-70% CH3CN) to give the diastereomeric products IM-P1 (35.0 mg) and IM-P2 (30.0 mg) as white solids.

IM-P1 ESI 718.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.86 (s, 1H), 7.33 (s, 1H), 7.10 (d, J= Ί6 Hz, 1H), 7.05 - 6.95 (m, 1H), 6.83 (d, J= 4.1 Hz, 1H), 5.76 - 5.62 (m, 2H), 3.17 - 3.02 (m, 2H), 2.98 - 2.86 (m, 3H), 2.75 (d, J= 14.0 Hz, 7H), 2.27 (d, 2.8 Hz, 3H), 2.04 - 1.88 (m, 5H), 1.82 (d, J= 15.0 Hz,

3H), 1.43 - 1.23 (m, 1H), 1.00-0.86 (m, 6H).

IM-P2 ESI 718.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.40 (t, J= 7.7 Hz, 1H), 7.12 (d, J= 7.8 Hz, 1H), 7.04 (d, J= 7.8 Hz, 1H), 6.90 (s, 1H), 5.89 - 5.76 (m, 1H), 5.65 (t, J= 7.8 Hz, 1H), 3.26 - 3.11 (m, 2H), 2.97 (t, J = 7.0 Hz, 2H), 2.90 - 2.75 (m, 7H), 2.73 - 2.60 (m, 1 H), 2.29 (s, 3H), 2.00 1.84 (m, 7H), 1.80-1.66 (m, 1 H), 1.39-1.23 (m, 1 H), 0.95 - 0.82 (m, 6H).

3-84. Préparation of (3S)-3-(2,4-difluoro-2’,6’-dimethyl-5-(trifluoromethyI)-Il,r-biphenyl]-3-yl)3-(2-(5-(3-(dimcthylamino)propyl)-2-oxo-4-(triiluoromethyl)pyridin-l(2H)-yI)-4methylpentanamido)propanoic acid (IN-P1 and IN-P2)

Step 1: ethyl (3S)-3-(2,4-difluoro-2’,6’-dimethyl-5-(triiluoromethyI)-|l,l*-biphenyI]-3-yl)-3-(2-(5-(3(dimethyIamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)-4methylpentanamido)propanoate ’f'CFj tcfh. nmi. ch₃cn N rt. 2 hr ¹

A mixture of ethyl (S)-3-amino-3-(2,4-difluoro-2^,,6'-dimethyI-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoate (136 mg, 0.34 mmol), 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyi)pyridinl(2H)-yl)-4-methylpentanoic acid (120 mg, 0.30 mmol), TCFH (168 mg, 0.60 mmol) and NMI (123 mg, 1.5 mmol) in CH3CN (2 mL) was stirred at room température for 2 hours. The reaction was concentrated and purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: CH3OH,

476

0-85%) to provide ethyl (3S)-3-(2,4-difluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)-3(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoate as a yellow oil (120 mg). Yield 43.3 % (ESI 746.3 [M+H]*).

Step 2: (3S)-3-(2,4-difluoro-2’,6’-dimethyl-5-(trinuoromethyI)-[l,l’-biphenyll-3-yl)-3-(2-(5-(3(dimethylamino)propyI)-2-oxo-4-(trinuoromethyI)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid

Ethyl (3S)-3-(2,4-difluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)-3-(2-(5-(3(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (120 mg, 0.16 mmol) was treated with LiOH-PhO (17 mg, 0.40 mmol) in EtOH (4 mL) and H₂O (1 mL) at room température for 2 hrs. The reaction mixture was acidified to pH 5~6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-65% CHjCN) to give the diastereomeric products IN-P1 (33 mg) and IN-P2 (36 mg) as white solids.

IN-P1 ESI 718.2 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.77 (s, 1H), 7.38 (m,J= 7.6 Hz, 1H), 7.16(m, J= 7.7, 6.3 Hz, 3H), 6.80 (s, 1H), 5.75 (m, J= 16.2, 8.0 Hz, 2H), 3.10 (s, 2H), 2.95 (m, J= 15.7, 9.3 Hz, 1H), 2.81 (s, 6H), 2.77 - 2.59 (m, 3H), 2.08 - 1.89 (m, 10H), 1.34 (s, 1H), 0.94 (d, J= 6.6 Hz, 6H).

IN-P2 ESI 718.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 7.43 (m, J= 7.6 Hz, 1H), 7.27 7.09 (m, 3H), 6.85 (s, 1H), 5.82 (m, J= 10.0,4.8 Hz, 1H), 5.62 (m, J= 7.6 Hz, 1H), 3.17 - 2.97 (m, 2H), 2.91 - 2.80 (m, 3H), 2.80 (s, 4H), 2.69 - 2.54 (m, 3H), 2.20 - 1.81 (m, 9H), 1.73 - 1.53 (m, 1H), 1.31 (m, J= 13.3,6.6 Hz, 1H), 0.86 (m, J= 9.8, 6.7 Hz, 6H).

3-85. Préparation of (3S)-3-(4’-cyclopropyI-23’,4-trifluoro-2’,5,6’-trimethyI-[l,l’-biphenyI]-3-yI)3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)-yl)-4methylpentanamido)propanoic acid

Step 1: ethyl (3S)-3-(4’-cycIopropyl-2,3’,4-trifluoro-2’,5,6’-trimethyl-[l,l*-biphenyl]-3-yl)-3-(2-(5-(3(diniethylamino)propyl)-2-oxo-4-(trifiuoromethyl)pyridin-l(2H)-yl)-4477 methylpentanamido)propanoate

A mixture of ethyl (3S)-3-amino-3-(4-cyclopropyl-2,3',4-trifluoro-2',5,6’-trimethyl-[l,r-biphenyl]-3yl)propanoate(197 mg, 0.48 mmol), 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridinl(2//)-yl)-4-methylpentanoic acid (160 mg, 0.44 mmol), TCFH(185 mg, 0.66 mmol), and 1methylimidazole (144 mg, 1.76 mmol) in acetonitrile (8 mL) was stirred at room température for 2 hours. The mixture was purified by reverse phase HPLC on a C18 / 40g column (A: water 10 mM NH4HCO3. B: MeOH, 0-100%) to provide ethyl (3S)-3-(4'-cyclopropyl-2,3^,,4-trifluoro-2',5,6'-trimethyl-[l,r-biphenyl]3-yl)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/f)-yl)-4methylpentanamido)propanoate (230 mg) as a yellow solid. Yield 70.0% (ESI 750.3 (M+H)⁺).

Step 2: (35)-3-(4'-cyclopropyI-2,3',4-trifluoro-2',5,6'-trimethyl-[l,r-biphenyl|-3-yl)-3-(2-(5-(3(dimethyIamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yl)-4methylpentanamido)propanoic acid

Ethyl (3S)-3-(4'-cyclopropyl-2,3',4-trifluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)-3-(2-(5-(3(dimethylamino)propyl)-2-oxo-4-(trifluoromcthyl)pyridin-l(2//)-yl)-4-methylpentanamido)propanoate (230 mg, 0.31 mmol) was treated with L1OH-H2O (51.6 mg, 1.23 mmol) in MeOH (5 mL) and H2O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 6-7 with 2N HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% CH3CN) to give the diastereomeric products IO-P1 (79.7 mg) and IO-P2 (60.6 mg) as white solids.

478

IO-P1 ESI 722.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ Ί.ΊΊ (s, IH), 6.86 (t, J= 8.2 Hz, IH), 6.80 (d, J = 3.5 Hz, IH), 6.65 - 6.63 (m, IH), 5.77 - 5.7I(m, 2H), 3.07 (t, J= 7.8 Hz, 2H), 2.96 - 2.90 (m, IH), 2.79 (s, 6H), 2.73 - 2.59 (m, 3H), 2.23 (s, 3H), 2.12-1.82 (m, 1 IH), 1.38 - 1.32 (m, 1 H), 1.01 - 0.92 (m, 8H), 0.77 - 0.70(m, 2H).

IO-P2 ESI 722.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.79 (s, IH), 6.90 (t, J = 8.2 Hz, IH), 6.85 (s, IH), 6.67 (d, J= 7.3 Hz, IH), 5.85 - 5.85 (m, IH), 5.57 (t, J= 6.9 Hz, IH), 3.14 - 3.11 (m, 2H), 2.89 2.78 (m, 7H), 2.68 - 2.52 (m, 3H), 2.27 (s, 3H), 2.14 - 1.89 (m, 1 OH), 1.66 - 1.57 (m, 1 H), 1.36-1.29 (m, IH), 1.03 - 0.92 (m, 2H), 0.86 (t, J= 7.8 Hz, 6H), 0.76 - 0.70 (m, 2H),.

3-86. Préparation of (3S)-3-(2-(5-(3-(azetidin-l-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridinl(2Æ)-yl)-4-methyIpentanamido)-3-(2,4-difluoro-2’,4',6’-trimethyl-5-(trinuoromethyl)-[l,rbiphenyl]-3-yl)propanoic acid (compounds IP-PI and IP-P2)

Step 1: ethyl (35)-3-(2-(5-(3-(azetidin-l-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)-4methylpentanamido)-3-(2,4-difluoro-2',4',6'-trimethyI-5-(trifluoromethyl)-[I,r-biphenyl]-3yl)propanoate

A mixture of ethyl (5)-3-amino-3-(2,4-difluoro-2',4',6'-trimethyl-5-(trifluoromethyl)-[ 1,1 -biphenyl]-3yl)propanoate (112.0 mg, 0.27 mmol), 2-(5-(3-(azetidin-l-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridinl(2/7)-yl)-4-methylpentanoic acid (100.0 mg, 0.27 mmol), TCFH (151.2 mg, 0.54 mmol) and NMI (88.6 mg, 1.08 mmol) in CH₃CN (8 mL) was stirred at room température for 1 hour. The reaction was concentrated in vacuo and the residue purified by silica gel column (DCM: MeOH 4: 1) to provide ethyl (3S)-3-(2-(5-(3-(azetidin-1 -yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2/7)-yl)-4-methylpentanamido)3-(2,4-difluoro-2',4',6'-trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate as a brown solid (130.0 mg). Yield 63% (ESI 772.6 (M+H)⁺).

Step 2: (3S)-3-(2-(5-(3-(azetidin-l-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(27Z)-yl)-4methyIpentanamido)-3-(2,4-difluoro-2’,4’,6’-trimethyI-5-(trifluoromethyl)-[l,l^,-biphenyl)-3yl)propanoic acid

479

Ethyl (35)-3-(2-(5-(3-(azetidin-l-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(27ï)-yl)-4methylpentanamido)-3-(2,4-difluoro-2',4',6'-trimethyl-5-(trifluoromethyl)-[ 1,1 ’-biphenyl]-3-yl)propanoate (130 mg, 0.17 mmol) ) was treated with LiOH-FhO (28.6 mg, 0.68 mmol) in MeOH (4 mL) and H2O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products IP-PI (38.0 mg) and IP-P2 (42.0 mg) as white solids.

IP-PI ESI 744.7 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.76 (s, 1H), 7.34 (d, J= ΊΑ Hz, 1H), 6.94 (s, 1H), 6.79 (s, 2H), 5.74 (d, J=4.1 Hz, 2H), 4.08 (t, J= 7.7 Hz, 4H), 3.21 - 3.11 (m, 2H), 2.97 - 2.89 (m, 1H), 2.71 - 2.58 (m, 3H), 2.45 (s, 2H), 2.30 (s, 3H), 2.06 - 1.91 (m, 5H), 1.83 (d, J= 43.4 Hz, 5H), 1.34 (s, 1H), 0.93 (d,J=6.5 Hz, 6H).

IP-P2 ESI 744.7 (M+H)\ 1H NMR (400 MHz, MeOD) δ 7.78 (s, 1H), 7.40 (t, J= 7.7 Hz, 1H), 6.90 (d, J = 55.2 Hz, 3H), 5.87- 5.78 (m, 1H), 5.61 (t, J= 7.6 Hz, 1H), 4.15 -3.99 (m, 4H), 3.19-2.97 (m, 2H), 2.94 - 2.82 (m, 1H), 2.69 - 2.54 (m, 3H), 2.50 - 2.37 (m, 2H), 2.31 (s, 3H), 2.03 - 1.71 (m, 9H), 1.73 1.53 (m, 1H), 1.39 - 1.20 (m, 1H), 0.89 - 0.72 (m, 6H).

3-87. Préparation of (35)-3-(2-(5-(2-(ethyl(methyl)amino)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanamido)-3-(23\4-trifluoro-2’,6’-dimethyl-5-(trifluoromethyl)biphenyI-3yl)propanoic acid (compounds IQ-P1 and IQ-P2)

Step 1: (3S)-ethyl3-(2-(5-(2-(ethyl(methyl)amino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)4-methylpentanamido)-3-(23’,4-trifluoro-2’,6’-dimethyI-5-(trinuoromethyI)biphenyI-3yl)propanoate

480

A mixture of (3S)-ethyl 3-amino-3-(2,3',4-trifluoro-2’,6'-dimethyl-5-(trifluoromethyl)biphenyl-3yl)propanoate (118 mg, 0.28 mmol), 2-(5-(2-(ethyl(methyl)amino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoic acid (100 mg, 0.28 mmol), TCFH (157 mg, 0.56 mmol) and NMI (69 mg, 0.84 mmol) in MeCN (5 mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH 97: 3) to provide (3S)-ethyl 3-(2-(5-(2-(ethyl(methyl)amino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,3',4-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoateasa colorless oil (120 mg). Yield 55% (ESI 764.3 (M+H)⁺).

Step 2: (35)-3-(2-(5-(2-(ethyl(methyl)amino)ethyl)-2-oxo-4-(triiluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(23’,4-trifluoro-2*,6'-dimethyl-5-(trifIuoromethyI)biphenyl-3-yI)propanoic acid

(3S)-ethyl 3-(2-(5-(2-(ethyl(methyl)amino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,3^,,4-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate (100 mg, 0.13 mmol) was treated with LiOH-HjO (27 mg, 0.65 mmol) in EtOH (3 mL) and H2O (1 mL) at room température for 3 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% CH3CN) to give the diastereomeric products IQ-P1 (30.3 mg) and IQ-P2 (23.1 mg) as white solids.

IQ-P1 ESI 736.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.88 (s, 1H), 7.39 (t, J= 7.2 Hz 1H), 7.13-7.10 (m, 1H), 7.01 (t, J= 8.8 Hz 1H), 6.81 (d, J= 2.0 Hz, 1H), 5.72-5.68 (m, 2H), 3.15-3.08 (m, 4H), 2.97481

2.92 (m, 3H), 2.79-2.74 (m, 4H), 2.02-1.87 (m, 8H), 1.38-1.35 (m, IH), 1.28 (t, J= 7.2 Hz, 3H), 0.930.90 (m, 6H).

IQ-P2 ESI 736.3 (M+H)\ IH NMR (400 MHz, MeOD) δ 7.87 (s, IH), 7.46 (t, J= 7.5 Hz, IH), 7.23 7.11 (m, IH), 7.04 (t, 7=8.9 Hz, IH), 6.88 (s, IH), 5.78-5.75 (m, IH), 5.68 (t, J =7.8 Hz, IH), 3.283.08 (m, 4H), 2.97 (t, J= 7.5 Hz, 2H), 2.90 -2.84 (m, IH), 2.80 (s, 3H), 2.72-2.70 (m, IH), 2.00 (d, J= 3.2 Hz, 3H), 1.93-1.90 (m, 3H), 1.86-1.83 (m, IH), 1.80 - 1.68 (m, IH), 1.37 - 1.22 (m, 4H), 0.87 0.85(m, 6H).

3-88. Préparation of (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trinuoromethyl)pyridin1 (2H)-yl)-4-methyIpentanamido)-3-(2,4,4’-trifluoro-2’,6’-dimethyl-5-(trifluoromethyl)-[ 1,1’biphenyl]-3-yl)propanoic acid (compounds IR-P1 and IR-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(dimethyiamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4,4’-triiluoro-2’,6’-dimethyl-5-(trifluoromethyl)-[l,l’-biphenyl|-3yl)propanoate

H₂N^

A mixture of ethyl (S)-3-amino-3-(2,4,4’-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoate (100 mg, 0.24 mmol), 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanoic acid (100 mg, 0.29 mmol), TCFH (150 mg, 0.52 mmol) and NMI (106 mg, 1.3 mmol) in CHjCN (3 mL) was stirred at 50 °C for 1 hr. The reaction was concentrated and purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: MeOH, 0~90%) to provide ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4,4'-trifluoro-2^,,6'-dimethyl-5-(trifluoromethyl)-[ 1,1 -biphenyl]-3-yl)propanoate as a yellow solid (110 mg). Yield 61.1 % (ESI 750.3 (M+Hf).

Step 2: (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trinuoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4,4’-triiluoro-2^,,6’-dimethyl-5-(trifIuoromethyl)-[l,r-biphenyl]-3yl)propanoic acid

482

Ethyl (3S)-3-(2,4-difluoro-2^,,4',6'-trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (110 mg, 0.15 mmol) was treated with LiOH-H₂O (13 mg, 0.3 mmol) in EtOH (2 mL) and H₂O (0.5 mL) at room température for 30 mins. The reaction mixture was acidified to pH 5~6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (35-60% CHjCN) to give the diastereomeric products IR-P1 (32 mg) and IR-P2 (39 mg) as white solids.

IR-P1 ESI 722.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.87 (s, 1H), 7.41 (t, J= 7.5 Hz, 1H), 6.95 6.86 (m, 2H), 6.84 (s, 1H), 5.79 - 5.62 (m, 2H), 3.12 (s, 2H), 3.02 - 2.88 (m, 3H), 2.85 - 2.68 (m, 7H), 2.11 - 1.84 (m, 8H), 1.45 - 1.36 (m, 1H), 1.02 - 0.88 (m, 6H).

IR-P2 ESI 722.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.46 (t, J= 7.6 Hz, 1H), 6.92 (d, J = 9.9 Hz, 3H), 5.80 (dd, J= 9.9,5.6 Hz, 1H), 5.65 (t, J= 7.7 Hz, 1H), 3.25 - 3.14 (m, 2H), 2.96 (t, J= 7.0 Hz, 2H), 2.91 - 2.73 (m, 7H), 2.67 (d, J= 13.7 Hz, 1H), 2.03 (d, 2.6 Hz, 6H), 1.93 - 1.84 (m, 1H), 1.78

- 1.69 (m, 1H), 1.36 - 1.27 (m, 1H), 0.95 - 0.79 (m, 6H).

3-89. Préparation of (35)-3-(2-(5-(2-(azetidin-l-yI)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2ZZ)yI)-4-methylpentanamido)-3-(2,4-dinuoro-2’,4’,5,6'-tetramethylbiphenyl-3-yl)propanoic acid (compounds IS-P1 and IS-P2)

Step 1: (3S)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methylpentanamido)-3-(2,4-difluoro-2^,,4',5,6’-tetramethylbiphenyl-3-yl)propanoate

483

A mixture of 2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2Z/)-yl)-4-methylpentanoic acid (240 mg, 0.66 mmol), (S)-ethyl 3-amino-3-(2,4-difluoro-2',4',5,6 -tetramethylbiphenyl-3yl)propanoate (240 mg, 0.66 mmol), NMI (0.5 mL) and TCFH (378 mg, 1.35 mmol) in CHjCN (5 mL) was stirred at room température for 1 hour. The solvent was concentrated in vacuo and the residue was purified byprep-HPLC A (30-90% CHsCN) to provide (3S)-ethyi 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo4-(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanamido)-3-(2,4-difiuoro-2',4',5,6'tetramethylbiphenyl-3-yl)propanoate as a white solid (290 mg). Yield 62% (ESI 704.3 [M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyI)pyridin-l(2/jO-yl)-4methy!pentanamido)-3-(2,4-difluoro-2’,4^,,5,6’-tetramethyIbiphenyI-3-yI)propanoic acid

(3S)-ethyl 3-(2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2/7)-yl)-4methylpentanamido)-3-(2,4-difluoro-2',4',5,6’-tetramethylbiphenyl-3-yl)propanoate (290 mg, 0.41 mmol) was treated with LiOH-lLO (86 mg, 2.05 mmol) in MeOH (5 mL) and H₂O (0.5 mL) at room température for 2 hours. The reaction mixture was acidîfted to pH 4~5 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-70% CH3CN) to give the diastereomeric products ISP1 (66.0 mg) and IS-P2 (93.0 mg) as white solids.

IS-P1 ESI 675.9(M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 6.90 (s, 2H), 6.86 (s, 2H), 5.83 5.71 (m, 1H), 5.67 (t,J=6.1 Hz, 1H), 3.99 (t,J= 8.1 Hz,4H), 3.27-3.18 (m,2H), 2.94-2.78 (m,3H), 2.72 - 2.60 (m, 1H), 2.47 - 2.34 (m, 2H), 2.26 (d, J= 15.9 Hz, 6H), 2.06 - 1.93 (m, 5H), 1.90 (s, 3H), 1.50 - 1.29 (m, 1H), 0.92 (t, J= 6.1 Hz, 6H).

IS-P2 ESI 676.0 (M+H)⁺. *H NMR (400 MHz, MeOD) δ 7.68 (s, 1H), 7.02 - 6.85 (m, 4H), 5.97 - 5.87 (m, 1 H), 5.61 (t, J= 7.7 Hz, 1 H), 4.11 (t, J= 8.1 Hz, 4H), 3.47 - 3.32 (m, 2H), 2.97 - 2.72 (m, 3H), 2.54 - 2.39 (m, 3H), 2.28 (d, J= 6.5 Hz, 6H), 2.00 - 1.87 (m, 7H), 1.79 - 1.66 (m, 1H), 1.46 - 1.26 (m, 1H), 0.94 0.80 (m, 6H).

484

3-90. Préparation of Préparation of (35)-3-(2-(5-(3-(dimethyIamino)propyI)-2-oxo-4(trifluoromethyOpyridin-HZZO-yO^-methylpentanamidol-S-iZjZ’^-trifluoro^’jô’-dimethyl-S(trifluoromethyl)-[l,l’-biphenyI]-3-yI)propanoic acid (compounds IT-P1 and IT-P2)

Step 1: ethyl ethyl (35)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)yl)-4-methyIpentanamido)-3-(2,2’,4-trifluoro-4’,6’-dimethyI-5-(trifluoromethyl)-[l,l’-biphenyi]-3yl)propanoate

A mixture of ethyl (3S)-3-amino-3-(2,2',4-trifluoro-4^,,6^,-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoate (120.0 mg, 0.29 mmol), 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridinl(2/7)-yl)-4-methylpentanoic acid (105.0 mg, 0.29 mmol), TCFH (123.2 mg, 0.44 mmol) and NMI (118.9 mg, 1.45 mmol) in CH3CN (3 mL) was stirred at room température ovemight. The reaction was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3. B: MeOH, 0-100%) to provide ethyl (3S)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo4-(trifluoromethyl)pyridin-l(2/7)-yl)-4-methylpentanamido)-3-(2,2',4-trifluoro-4',6'-dimethyl-5(trifluoromethyl)-[l,l'-biphenyl]-3-yl)propanoate as a light yellow solid (160.0 mg). Yield 73% (ESI 764.3 [Μ+ΗΠ.

Step 2: (3S)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z7)-yI)-4methyIpentanamido)-3-(2,2’,4-trifluoro-4’,6’-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoic acid

Ethyl (3S)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2/7)-yl)-4methylpentanamido)-3-(2,2',4-trifluoro-4^,,6^,-dimethyl-5-(trifluoromethyl)-[ 1,1 '-biphenyl]-3-yl)propanoate

485 (160.0 mg, 0.21 mmol) was treated with LiOH-HjO (26.5 mg, 0.63 mmol) in EtOH (2 mL) and water (0.5 mL) at room température for 1 hour. The reaction mixture was acidified to pH 4~5 with 2N HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-80% MeCN) to give the diastereomeric products IT-P1 (30.0 mg) and IT-P2 (49.0 mg) as white solids.

IT-P1 ESI 736.2 (M+H)⁺ 'H NMR (400 MHz, MeOD) δ 7.77 (s, 1H), 7.52 - 7.43 (m, 1H), 6.98 (s, 1H), 6.90 - 6.75 (m, 2H), 5.84 - 5.67 (m, 2H), 3.08 (t, J= 8.1 Hz, 2H), 2.97 - 2.87 (m, 1H), 2.83 - 2.55 (m, 9H), 2.35 (s, 3H), 2.13-1.82 (m, 7H), 1.40 - 1.27 (m, 1H), 0.97-0.90 (m, 6H).

IT-P2 ESI 736.2 (M+H)⁺ *H NMR (400 MHz, MeOD) δ 7.80 (s, 1H), 7.52 (t, J= 7.5 Hz, 1H), 7.00 (s, 1H), 6.93 - 6.80 (m, 2H), 5.84 - 5.75 (m, 1H), 5.70 - 5.60 (m, 1H), 3.15 - 2.96 (m, 2H), 2.93 - 2.72 (m, 7H), 2.70-2.59 (m, 3H), 2.37 (s, 3H), 2.15 - 1.84 (m, 6H), 1.75-1.55 (m, 1H), 1.37-1.15 (m, 1H), 0.92 -0.80 (m, 6H).

3-91. Préparation of Préparation of (3S)-3-(2-(5-(2-(ethyI(methyl)amino)ethyl)-2-oxo-4(trinuoromethyl)pyridin-l(2ZZ)-yl)-4-methylpentanamido)-3-(2,4,4’-trifluoro-2’,6’-dimethyl-5(trifluoromethyl)-[l,l'-biphenyl]-3-yl)propanoic acid (compounds IU-P1 and IU-P2)

Step 1 : ethyl (35)-3-(2-(5-(2-(ethyI(methyl)amino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2ZZ)-yl)4-methylpentanamido)-3-(2,4,4^,-trifluoro-2’,6’-dimethyl-5-(triiluoromethyl)-[l,l’-biphenyIj-3yl)propanoate

A mixture of ethyl (S)-3-amino-3-(2,4,4^,-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,l'-biphenyl]-3yl)propanoate ( 120mg, 0.29 mmol),2-(5-(2-(ethyl(methyl)amino)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2Z/)-yl)-4-methylpentanoic acid (100 mg, 0.29 mmol), TCFH (162.4 mg, 0.58 mmol) and NMI (119.0 mg, 1.45 mmol) in CHjCN (3 mL) was stirred at room température ovemight. The reaction was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NHîHCOj. B: MeOH, 20~90%) to provide ethyl (35)-3-(2-(5-(2-(ethyl(methyl)amino)ethyl)-2oxo-4-(trifluoromethyl)pyridin-l(2Z7)'yl)4*methylpentanamido)-3-(2,4,4-trifluoro-2',6'-dimethyl-5486 (trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate as a light yellow solid (160.0 mg). Yield 73% (ESI

764.3 [M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(ethyl(methyl)amino)ethyI)-2-oxo-4-(trifluoromethyI)pyridin-l(2//)-yl)-4methyIpentanamido)-3-(2,4,4’-triiluoro-2’,6’-dimethyl-5-(trifluoromethyl)-[l,l’-biphenyl]-3yl)propanoic acid

Ethyl (3S)-3-(2-(5-(2-(ethyl(methyl)amino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yl)-4methylpentanamido)-3-(2,4,4’-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (160.0 mg, 0.21 mmol) was treated with LiOH-HjO (26.5 mg, 0.63 mmol) in EtOH (3 mL) and water (1 mL) at room température for 1 hour. The reaction mixture was acidified to pH 4~5 with 2N HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-90% MeCN) to give the diastereomeric products IU-P1 (34.0 mg) and IU-P2 (32.0 mg) as white solids.

IU-P1 ESI 736.2 (M+H)^+IH NMR (400 MHz, MeOD) δ 7.87 (s, 1H), 7.39 (t, J= 7.5 Hz, 1H), 6.93 - 6.75 (m, 3H), 5.78 - 5.65 (m, 2H), 3.22 - 3.04 (m, 4H), 3.02 - 2.88 (m, 3H), 2.83 - 2.70 (m, 4H), 2.07 - 1.86 (m, 8H), 1.43 - 1.23 (m, 4H), 0.94 (t, J= 6.8 Hz, 6H).

IU-P2 ESI 736.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.85 (s, 1H), 7.45 (t, J= 7.5 Hz, 1H), 6.96 6.81 (m, 3H), 5.83 - 5.74 (m, 1H), 5.66 (t, J= 7.8 Hz, 1H), 3.27 - 3.09 (m, 4H), 2.97 (t, J= ΊΑ Hz, 2H), 2.92 - 2.63 (m, 5H), 2.03 (d, J= 3.5 Hz, 6H), 1.92 -1.82 (m, 1H), 1.79 - 1.65 (m, 1H), 1.37 - 1.25 (m, 4H), 0.94-0.81 (m, 6H)

3-92. Préparation of Préparation of (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyI)pyridin-l(2Z0-yI)-4-methylpentanamido)-3-(2,4,4^,-trifluoro-2’,6’-dimethyI-5(trifluoromethyl)-[l,l’-biphenyl]-3-yl)propanoic acid (compounds IV-P1 and IV-P2)

487

Step 1: ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2ÂiF)-yl)'4methylpentanamido)-3-(2,4,4’-trinuoro-2’,6’-dimethyI-5-(trifluoromethyI)-[l,l’-biphenyI]-3yl)propanoate

NMI TCFH

A mixture of ethyl (S)-3-amino-3-(2,4,4'-trifluoro-2',6'-dimethyl-5-(trifiuoromethyl)-[l,r-biphenyl]-3yl)propanoate (120.0 mg, 0.29 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin1 (277)-yl)-4-methyl pentanoic acid (103.0 mg, 0.29 mmol), TCFH (162.4 mg, 0.58 mmol) and NMI (118.9 mg, 1.45 mmol) in CH3CN (3 mL) was stirred at room température ovemight. The reaction was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmMNH4HCO3, B: MeOH, 20~80%) to provide ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2Z/)-yl)-4-niethylpentanamido)-3-(2,4,4'-trifluoro-2^,,6^,-dimethyl-5(trifiuoromethyl)-[l,l'-biphenyl]-3-yl)propanoate as a light yellow solid (180.0 mg). Yield 82.6% (ESI 762.3 [M+H]⁺).

Step 2: (35)-3-(2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(triiluoromethyI)pyridin-l (2H)-yl)-4methyIpentanamido)-3-(2,4,4’-trifluoro-2’,6’-dimethyl-5-(trifIuoromethyI)-[l,r-biphenyI]-3yl)propanoic acid

Ethyl (3S)-3-(2-(5-(2-(azetidin-l-yi)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2£0-yl)-4methyIpentanamido)-3-(2,4,4^,-trifluoro-2^,,6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (180.0 mg, 0.24 mmol) was treated with LiOH-H₂O (30.2 mg, 0.72 mmol) in EtOH (3 mL) and water (1 mL) at room température for 1 hour. The reaction mixture was acidified to pH 4~5 with 2N HCI. The

488 reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-90% MeCN) to give the diastereomeric products IV-P1 (34.0 mg) and IV-P2 (27.0 mg) as white solids.

IV-P1 ESI 734.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 7.41 (t, J= 7.5 Hz, 1H), 6.97 - 6.78 (m, 3H), 5.78 - 5.60 (m, 2H), 4.05 (t, J= 7.8 Hz, 4H), 3.29 - 3.20 (m, 2H), 2.97 - 2.80 (m, 3H), 2.78 2.69 (m, 1H), 2.53-2.38 (m, 2H), 2.08 - 1.90 (m, 8H), 1.45 - 1.31 (m, 1H), 0.93 (t, J= 6.4 Hz, 6H).

IV-P2 ESI 734.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.48 (t, J= 7.6 Hz, 1H), 7.00 6.86 (m, 3H), 5.95 - 5.85 (m, 1H), 5.63 (t, J= 7.7 Hz, 1H), 4.12 (t, J= 7.9 Hz, 4H), 3.50 - 3.34 (m, 2H), 2.96 - 2.73 (m, 3H), 2.65 - 2.55 (m, 1H), 2.52 - 2.40 (m, 2H), 2.03 (d, J= 1.7 Hz, 6H), 1.96 - 1.85 (m, 1H), 1.78 - 1.65 (m, 1H), 1.40 - 1.25 (m, 1H), 0.95 - 0.82 (m, 6H).

3-93. Préparation of Préparation of (3S)-3-(2-(5-(3-(dimethyIamino)propyl)-2-oxo-4(trifiuoromethyl)pyridin-l(2Z7)-yl)-4-methyIpentanamido)-3-(2,3',4-trifluoro-2’,4',5,6'-tetramethyl[l,l’-biphenyl]-3-yI)propanoic acid (compounds IW-P1 and IW-P2)

Step 1: ethyl (3S)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yl)-4 methylpentanamido)-3-(2,3’,4-trinuoro-2’,4’,5,6*-tetramethyl-[l,l’-biphenyl]-3-yl)propanoate

A mixture of ethyl (3S)-3-amino-3-(2,3’,4-trifluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoate (170 mg, 0.45 mmol), 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methylpentanoic acid (151 mg, 0.54 mmol), TCFH (213.2 mg, 0.76 mmol) and NMI (177 mg, 2.16 mmol) in CH3CN (3 mL) was stirred at room température ovemight. The reaction was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3. B: MeOH, 20-95%) to provide ethyl (3S)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4(trifluoromethyl)pyridin-l(2f/)-yl)-4-methylpentanamido)-3-(2,3^,,4-trifluoro-2',4',5,6'-tetramethyl-[l,rbiphenyl]-3-yl)propanoate as a light yellow solid (210.0 mg). Yield 65% (ESI 724.2 [M+H]*).

Step 2: (3S)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trinuoromethyl)pyridin-l(2jE/)-yl)-4methylpentanamido^S-iZXd-trinuoro-Z'^’Aô’-tetramethyl-11,1 ’-biphenyI]-3-yl)propanoic acid

489

Ethyl (35)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanamido)-3-(2,3',4-trifluoro-2',4^,,5,6'-tetramethyl-[ 1,1 -biphenyl]-3-yl)propanoate (210.0 mg, 0.29 mmol) was treated with LiOH-H->O (36.5 mg, 0.87 mmol) in EtOH (2 mL) and water (0.5 mL) at room température for 1 hour. The reaction mixture was acidified to pH 4~5 with 2N HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (20-85% MeCN) to give the diastereomeric products IW-P1 (68 mg) and IW-P2 (52 mg) as white solids.

IW-P1 ESI 696.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 6.98 - 6.80 (m, 3H), 5.83 - 5.69 (m, 2H), 3.09 (t, J= 7.9 Hz, 2H), 3.00 - 2.90 (m, 1 H), 2.81 (d, J= 0.8 Hz, 6H), 2.73 - 2.58 (m, 3H), 2.26 (d, J = 1.3 Hz, 6H), 2.15 - 1.78 (m, 10H), 1.43 -1.30 (m, 1H), 1.00 - 0.90 (m, 6H).

IW-P2 ESI 696.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 7.02 - 6.79 (m, 3H), 5.89 - 5.79 (m, 1H), 5.57 (t, J= 7.6 Hz, 1H), 3.09 - 2.95 (m, 2H), 2.91 - 2.71 (m, 7H), 2.70 - 2.47 (m, 3H), 2.32 2.19 (m, 6H), 2.07 - 1.83 (m, 9H), 1.67 - 1.55 (m, 1H), 1.37-1.27 (m, 1H), 0.90-0.80 (m, 6H).

3-94. Préparation of Préparation of (3S)-3-(2-(5-(2-(azetidin-l-yI)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2/7)-yl)-4-methylpentanamido)-3-(2,3’,4-trifluoro-2’,4’,5,6^,-tetramethyI[l,l’-biphenyI]-3-yl)propanoic acid (compounds IX-P1 and IX-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyI)pyridin-l(2fi')-y^I)-4methyIpentanamido)-3-(23',4-triiluoro-2’,4’,5,6’-tetramethyl-[l,l'-biphenyl]-3-yI)propanoate

490

A mixture of ethyl (3S)-3-amino-3-(2,3',4-trifluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoate (170 mg, 0.45 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanoic acid (162 mg, 0.45mmol), NMI (0.5 mL) and TCFH (241 mg, 0.86 mmol) in CH3CN (3 mL) was stirred at room température for 2 hours. The solvent was concentrated in vacuo and the residue was purified by prep-HPLC A (50-80% CH3CN) to provideethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4-methylpentanamido)-3-(2,3^,,4-trifluoro-2',4',5,6'-tetramethyl[l,l-biphenyl]-3-yl)propanoate as a white solid (200 mg). Yield 62% (ESI 722.1 (M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifIuoromethyl)pyridin-l(2jF/)-yl)-4methylpentanamido)-3-(2,3',4-trifluoro-2',4',5,6’-tetramethyl-|l,r-biphenyl]-3-yl)propanoic acid

Ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methylpentanamido)-3-(2,3^,,4-trifluoro-2',4',5,6'-tetramethyI-[ 1,1 '-biphenyl]-3-yl)propanoate (200 mg, 0.28 mmol) was treated with L1OH-H2O (35 mg, 0.84mmol) in MeOH (3.0 mL) and H2O (1.0 mL) at room température for 2 hours. The reaction mixture was acidifted to pH 5~6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (50-80% CH3CN) to give the diastereomeric products IX-P1 (42.0 mg) and IX-P2 (53.0 mg) as white solids.

IX-P1 ESI 694.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 7.01 - 6.77 (m, 3H), 5.84 - 5.58 (m, 2H), 4.00 (t, J= 8.0 Hz, 4H), 3.29 - 3.20 (m, 2H), 2.95 - 2.80 (m, 3H), 2.70 - 2.60 (m, 1H), 2.50 2.35 (m, 2H), 2.24 (d, J= 3.4 Hz, 6H), 2.04 - 1.80 (m, 8H), 1.45 - 1.33 (m, 1H), 0.93 (t, J= 6.1 Hz, 6H).

IX-P2 ESI 694.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.69 (s, IH), 7.00 - 6.90 (m, 3H), 5.97 - 5.85 (m,lH), 5.61 (t, J= 7.7 Hz, 1H), 4.10 (t, J= 8.0 Hz, 4H), 3.47 - 3.34 (m, 2H), 2.96 - 2.73 (m, 3H), 2.57 2.37 (m, 3H), 2.31 - 2.17 (m, 6H), 1.99 - 1.84 (m, 7H), 1.78 - 1.65 (m, 1H), 1.42 - 1.30 (m, 1H), 0.93 0.82 (m, 6H).

491

3-95. Préparation of ((3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifIuoromethyl)pyridin-l(2//)yl)-4-methylpentanamido)-3-(2,2’,4-trifluoro-4’,6’-dimethyI-5-(trinuoromethyl)biphenyI-3yl)propanoic acid (compounds IY-P1 and IY-P2 )

Step 1: (35)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanamido)-3-(2,2',4-trifluoro-4',6'-dimethyI-5-(trifluoromethyl)biphenyl-3-yl)propanoate

A mixture of2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoic acid (115 mg, 0.32 mmol), (35)-ethyl 3-amino-3-(2,2^,,4-trifluoro-4’,6'-dimethyl-5(trifluoromethyl)biphenyl-3-yl)propanoate (120 mg, 0.29 mmol), NMI (71 mg, 0.87 mmol) and TCFH (98 mg, 0.35 mmol) in CHjCN (4 mL) was stirred at room température for 2 hours. The solvent was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmMNHiHCOj, B: CH₃CN, 0-100%) to provide (3S)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanamido)-3-(2,2',4-trifluoro-4',6'-dimethyl-5(trifluoromethyl)biphenyl-3-yl)propanoate as a yellow oil (140 mg). Yield 64 % (ESI 762.3 [M+H]⁺).

Step 2: ((35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2jfiF)-yl)-4methyIpentanamido)-3-(2,2',4-trifluoro-4’,6’-dimethyI-5-(trinuoromethyl)biphenyl-3-yl)propanoic acid

(35)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yl)-4methylpentanamido)-3-(2,2',4-trifluoro-4',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate(140 mg, 0.19 mmol) was treated with LiOH-HjO (32 mg, 0.76 mmol) in EtOH (3mL) and H₂O (1 mL) at room température for 1 hour. The reaction mixture was acidified to pH 5-6 with IN HCl. The reaction

492 was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% CHjCN) to give the diastereomeric products IY-P1 (36 mg) and IY-P2 (51 mg) as white solids.

IY-P1 ESI 734.2 (M+H)⁺. 'HNMR (400 MHz, MeOD) δ 7.81 (s, IH), 7.55 - 7.45 (m, 1H), 6.98 (s, 1H), 6.89 - 6.80 (m, 2H), 5.79 - 5.67 (m, 2H),4.12 - 3.97 (m, 4H), 3.35-3.12 (m, 2H), 3.00 - 2.66 (m, 4H), 2.52 - 2.27 (m, 5H), 2.16 - 1.88 (m, 5H), 1.44 - 1.30 (m, 1H), 0.98 - 0.90 (m, 6H).

IY-P2 ESI 734.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.01 (s,

1H), 6.99 - 6.85 (m, 2H), 5.97 - 5.82 (m, 1H), 5.66 (t, J= 7.7 Hz, 1H), 4.12 (t, J= 8.0 Hz, 4H), 3.45 - 3.31 (m, 2H), 2.97 - 2.76 (m, 3H), 2.66 - 2.57 (m, 1H), 2.53 - 2.39 (m, 2H), 2.37 (s, 3H), 2.11 (d, 5.0 Hz,

3H), 1.97 - 1.86 (m, 1H), 1.78 - 1.67 (m, 1H), 1.40 - 1.27 (m, 1H), 0.95 - 0.81 (m, 6H).

3-96. Préparation of (3S)-3-(2-(5-(2-(dimethylamino)ethyI)-2-oxo-4-(trifluoromethyl)pyridinl(2Z/)-yl)-4-methyIpentanamido)-3-(2,2',4-trifIuoro-4',6'-dimethyl-5-(trifluoromethyI)biphenyl-3yl)propanoic acid (compounds IZ-P1 and IZ-P2 )

Step 1: (35)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanamido)-3-(2,2’,4-trifluoro-4^,,6’-dimethyl-5-(trifluoromethyl)biphenyI-3-yI)propanoate

TCFH.NMI.MeCN

A mixture of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid (110 mg, 0.32 mmol), (3S)-ethyl 3-amino-3-(2,2',4-trifluoro-4',6'-dimethyl-5(trifluoromethyl)biphenyl-3-yl)propanoate (120 mg, 0.29 mmol), NMI (71 mg, 0.87 mmol) and TCFH (98 mg, 0.35 mmol) in CHjCN (4 mL) was stirred at room température for 2 hours. The solvent was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: CH3CN, 0-100%) to provide (35)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo4-(trifluoromethyl)pyridin-l(2jF7)-yl)-4-methylpentanamido)-3-(2,2',4-trifluoro-4',6^,-dimethyI-5(trifluoromethyl)biphenyl-3-yl)propanoate as a yellow oil (140 mg). Yield 65 % (ESI 750.3 [M+H]⁺).

493

Step 2: (35)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanamido)-3-(2,2’,4-trifluoro-4',6’-dimethyl-5-(trifluoromethyl)biphenyl-3-yI)propanoic acid

(3S)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methylpentanamido)-3-(2,2^,,4-trifluoro-4',6^,-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate(140 mg, 0.19 mmol) was treated with LiOH-HjO (32 mg, 0.76 mmol) in EtOH (3mL) and H?O (1 mL) at room température for 1 hour. The reaction mixture was acidified to pH 5-6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% CH3CN) to give the diastereomeric products IZ-P1 (38 mg) and IZ-P2 (52 mg) as white solids.

1Z-P1 ESI 722.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.86 (s, 1H), 7.56 - 7.36 (m, 1H), 6.97 (s, 1H), 6.89 - 6.80 (m, 2H), 5.79 - 5.64 (m, 2H), 3.18 - 3.03 (m, 2H), 3.02 - 2.87 (m, 3H), 2.81 - 2.69 (m, 7H), 2.35 (s, 3H), 2.12-1.90 (m, 5H), 1.48 - 1.31 (m, 1H), 0.99-0.87 (m, 6H).

IZ-P2 ESI 722.2 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 7.53 (t, J= 7.5 Hz, 1H), 7.00 (s, 1H), 6.94 - 6.83 (m, 2H), 5.87 - 5.77 (m, 1H), 5.73 - 5.63 (m, 1H), 3.27 - 3.06 (m, 2H), 3.01 - 2.92 (m, 2H), 2.91 - 2.73 (m, 7H), 2.73 - 2.60 (m, 1H), 2.36 (s, 3H), 2.11 (d, J= 6.6 Hz, 3H), 1.97 - 1.63 (m, 2H), 1.43 - 1.20 (m, 1H), 0.98 - 0.82 (m, 6H).

3-97. Préparation of (35)-3-(2,4-difluoro-2’,5,6’-trimethyl-4’-(triiluoromethyl)biphenyl-3-yl)-3-(2(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4-methylpentanamido) propanoic acid (compounds JA-P1 and JA-P2 )

Step 1: (35)-ethyï 3-(2,4-difluoro-2’,5,6’-trimethyI-4’-(trifluoromethyl)biphenyI-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(triiluoromethyI)pyridin-l(2jF/)-yI)-4methylpentanamido)propanoate

494

A mixture of (5)-ethyl 3-amino-3-(2,4-difluoro-2',5,6'-trimethyl-4'-(trifluoromethyl)biphenyl-3yl)propanoate (170 mg, 0.41 mmol), 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(277)-yl)-4-methylpentanoic acid (140 mg, 0.41 mmol), NMI (100 mg, 1.23 mmol) and TCFH (140 mg, 0.49 mmol) in CHjCN (6 mL) was stirred at room température for 2 hours. The solvent was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: CH3CN, 0-100%) to provide (35)-ethyl 3-(2,4-difluoro-2',5,6’-trimethyl-4'(trifluoromethyl)biphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2Z/)-yl)-4-methylpentanamido)propanoate as a yellow oil (200 mg). Yield 66 % (ESI 746.1 [M+H]⁺).

Step 2: (35)-3-(2,4-difIuoro-2',5,6'-trimethyl-4'-(trifluoromethyl)biphcnyl-3-yI)-3-(2-(5-(2(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4-methylpentanamido)propanoic acid

LiOH-H₂O EtOH/HjO

(35)-ethyl 3-(2,4-difluoro-2',5,6'-trimethyl-4'-(trifluoromethyl)biphenyl-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanamido)propanoate (200 mg, 0.27 mmol) was treated with L1OH-H2O (45 mg, 1.08 mmol) in EtOH (3mL) and H2O (1 mL) at room température for 1 hour. The reaction mixture was acidified to pH 5-6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% CH3CN) to give the diastereomeric products JA-P1 (56 mg) and JA-P2 (65 mg) as white solids.

JA-P1 ESI 718.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.87 (s, 1H), 7.39 (d, J= 2.4 Hz, 2H), 6.92 (t, J = 8.1 Hz, 1H), 6.82 (s, 1H), 5.75 - 5.65 (m, 2H), 3.17 - 2.83 (m, 5H), 2.82 - 2.65 (m, 7H), 2.25 (s, 3H), 2.07 (s, 3H), 2.02 - 1.91 (m, 5H), 1.54 - 1.27 (m, 1H), 0.93 (t, J = 6.8 Hz, 6H).

495

JA-P2 ESI 718.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.42 (s, 2H), 6.98 (t, 8.1 Hz,

1H), 6.90 (s, 1H), 5.88 - 5.84 (m, 1H), 5.63 (t, 7.7 Hz, 1H), 3.29 - 3.09 (m, 2H), 3.04 - 2.92 (m, 2H),

2.88-2.76 (m, 7H), 2.62 - 2.52 (m, 1H), 2.29 (s, 3H), 2.09 (d, J= 3.4 Hz, 6H), 1.95 - 1.68 (m, 2H), 1.40 - 1.25 (m, 1H), 0.92 - 0.82 (m, 6H).

3-98. Préparation of (3S)-3-(2-(5-(2-(5-azaspiroI2.3]hexan-5-yl)ethyi)-2-oxo-4(trifluoromethyl)pyridin-l(2ZZ)-yl)-4-methylpentanamido)-3-(2,4-difluoro-2',4',5,6'tetramethylbiphenyl-3-yl)propanoic acid (compounds JB-P1 and JB-P2 )

Step 1: (3S)-ethyl 3-(2-(5-(2-(5-azaspiro[2.3]hexan-5-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2/7)-yl)-4-methylpentanamido)-3-(2,4-difluoro-2’,4’,5,6’-tetramethylbiphenyI-3-yl)propanoate

A mixture of (S)-ethyl 3-amino-3-(2,4-difluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoate (160 mg, 0.43 mmol), 2-(5-(2-(5-azaspiro[2.3]hexan-5-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2/7)-yl)-4methylpentanoic acid (150 mg, 0.39 mmol), NMI (100 mg, 1.17 mmol) and TCFH (130 mg, 0.47 mmol) in CHjCN (6 mL) was stirred at room température for 2 hours. The solvent was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: CH3CN, 0-100%) to provide (3S)-ethyl 3-(2-(5-(2-(5-azaspiro[2.3]hcxan-5-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2/7)-yl)-4-methylpentanamido)-3-(2,4-difluoro-2',4',5,6'-tetramethylbiphenyI3-yI)propanoate as a yellow oil (210 mg). Yield 75 % (ESI 730.3 [M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(5-azaspiro[2.3]hexan-5-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z7)-yl)4-methylpentanamido)-3-(2,4-dinuoro-2^,,4’,5,6’-tetramethylbiphenyI-3-yl)propanoic acid

496 (3S)-ethyl 3-(2-(5-(2-(5-azaspiro[2.3]hexan-5-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methylpentanamido)-3-(2,4-difluoro-2^,,4',5,6'-tetramethylbiphenyl-3-yl)propanoate (210 mg, 0.29 mmol) was treated with LiOH-H₂O (37 mg, 0.87 mmol) in EtOH (3mL) and H₂O (1 mL) at room température for 1 hour. The reaction mixture was acidifïed to pH 5~6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% CHjCN) to give the diastereomeric products JB-P1 (50 mg) and JB-P2 (55 mg) as white solids.

JB-P1 ESI 702.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.83 (s, IH), 6.97 - 6.76 (m, 4H), 5.80 - 5.61 (m, 2H), 4.04 (s, 4H), 3.45 - 3.32 (m, 2H), 3.12 - 2.81 (m, 3H), 2.70 - 2.61 (m, 1H), 2.28 (s, 3H), 2.24 (s, 3H), 2.01 - 1.93 (m, 5H), 1.89 (s, 3H), 1.58 - 1.26 (m, 1H), 0.98 - 0.89 (m, 6H), 0.72 (s, 4H).

JB-P2 ESI 702.3 (M+H)⁺. *H NMR (400 MHz, MeOD) δ 7.75 (s, 1H), 7.07 - 6.86 (m, 4H), 5.96 - 5.89(m, 1H), 5.64 (t, J= 7.7 Hz, 1H), 4.34 - 4.02 (m, 4H), 3.66 - 3.37 (m, 2H), 3.11 - 2.71 (m, 3H), 2.56 - 2.48 (m, 1H), 2.37-2.19 (m, 6H), 2.10-1.87 (m, 7H), 1.77-1.60 (m, 1H), 1.46 - 1.30 (m, 1H), 1.00-0.64 (m, 10H).

3-99. Préparation of (35)-3-(2,4-difluoro-2',3',5,5',6'-pentamethylbiphenyl-3-yl)-3-(2-(5-(2(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4-methylpentanamido)propanoic acid (compounds JC-P1 and JC-P2 )

Step 1: (35)-ethyI 3-(2,4-difluoro-2',3',5,5',6'-pentamethylbiphenyl-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoate

A mixture of (5)-ethyl 3-amino-3-(2,4-difluoro-2',3',5,5',6'-pentamethylbiphenyl-3-yl)propanoate (160 mg, 0.43 mmol), 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yl)-4methylpentanoic acid (150 mg, 0.43 mmol), NMI (110 mg, 1.29 mmol) and TCFH (150 mg, 0.52 mmol) in CHjCN (6 mL) was stirred at room température for 2 hours. The solvent was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: CH3CN, 0-100%) to provide (35)-ethyl 3-(2,4-difluoro-2',3',5,5',6'-pentamethylbiphenyl-3-yl)-3-(2-(5

497 (2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanamido)propanoate as a yellow oil (200 mg). Yield 69 % (ESI 706.2 [M+H]’).

Step 2: (35)-3-(2,4-difluoro-2',3',5,5’,6'-pentamethylbiphenyl-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yl)-4-methyIpentanamido)propanoic acid

LiOH-HjO

EtOH/H₂O

(35)-ethyl 3-(2,4-difluoro-2',3',5,5',6^,-pentamethylbiphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo4-(trifluoromethyl)pyridin-l(27/)-yl)-4-methylpentanamido)propanoate (200 mg, 0.28 mmol) was treated with LiOH-H₂O (47 mg, 1.12 mmol) in EtOH (3mL) and H₂O (1 mL) at room température for 1 hour.

The reaction mixture was acidified to pH 5~6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% CHjCN) to give the diastereomeric products JC-P1 (56 mg) and JC-P2 (64 mg) as white solids.

JC-P1 ESI 678.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.89 (s, 1H), 6.97 (s, 1H), 6.88 - 6.79 (m, 2H), 5.84 - 5.63 (m, 2H), 3.18 - 2.89 (m, 5H), 2.79 - 2.65 (m, 7H), 2.32 - 2.17 (m, 9H), 1.98 (t, J= 7.6 Hz, 2H), 1.86 (s, 3H), 1.76 (s, 3H), 1.47 - 1.34 (m, 1 H), 0.95 (t, J = 6.9 Hz, 6H).

JC-P2 ESI 678.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.86 (s, 1H), 6.99 (s, 1H), 6.94 - 6.84 (m, 2H), 5.91 - 5.84 (m, 1H), 5.66 (t, J= 7.7 Hz, 1H), 3.28 - 3.10 (m, 2H), 3.09 - 2.92 (m, 2H), 2.89 - 2.73 (m, 7H), 2.70 - 2.52 (m, 1H), 2.28 (s, 3H), 2.25 (s, 6H), 1.99 - 1.82 (m, 7H), 1.83 - 1.61 (m, 1H), 1.49 - 1.25 (m, 1H), 0.94-0.84 (m, 6H).

3-100. Préparation of (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(triiluoromethyl)pyridin-l(27/)yl)-4-fluoro-4-methylpentanamido)-3-(2,4-difluoro-2’,5,6’-trimethyI-4’-(trifluoromethyl)biphenyl-3yl)propanoic acid (compounds JD-P1 and JD-P2 )

Step 1: (35)-ethyI 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)-yl)-4fluoro-4-methylpentanamido)-3-(2,4-difIuoro-2’,5,6’-trimethyl-4’-(trifluoromethyl)biphenyl-3yl)propanoate

498

A mixture of 2-(5-(2-(azetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4-fluoro-4methylpentanoic acid (100mg, 0.26 mmol), (S)-ethyl 3-amino-3-(2,4-difluoro-2',5,6'-trimethyl-4(trifluoromethyl)biphenyl-3-yl)propanoate (120 mg, 0.29 mmol), NMI (64 mg, 0.78 mmol) and TCFH (90 mg, 0.32 mmol) in CHjCN (4 mL) was stirred at room température for 2 hours. The solvent was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: CH3CN, 0-100%) to provide (3S)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2£0-yl)-4-fluoro-4-methylpentanamido)-3-(2,4-difluoro-2',5,6^,-trimethyl-4'(trifluoromethyl)biphenyl-3-yl)propanoate as a yellow oil (80 mg). Yield 39 % (ESI 776.1 (M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2/7)-yl)-4-fluoro-4methylpentanamido)-3-(2,4-difluoro-2’,5,6'-trimethyI-4’-(trinuoromethyl)biphenyl-3-yI)propanoic acid

LiOH-H;O

EtOH/H₂O

(35)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-fluoro-4methylpentanamido)-3-(2,4-difluoro-2',5,6^,-trimethyl-4^,-(trifluoromethyl)biphenyl-3-yl)propanoate (80 mg, 0.10 mmol) was treated with L1OH-H2O (17 mg, 0.40 mmol) in EtOH (3mL) and H2O (1 mL) at room température for 1 hour. The reaction mixture was acidified to pH 5-6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% CH3CN) to give the diastereomeric products JD-P1 (17 mg) and JD-P2 (15 mg) as white solids.

JD-P1 ESI 748.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.86 (s, 1H), 7.39 (s, 2H), 6.93 (t, J= 8.1 Hz, 1H), 6.81 (s, 1H), 6.08 - 5.62 (m, 2H), 4.03 (t, J= 8.0 Hz, 4H), 3.30 - 3.18 (m, 3H), 2.98 - 2.75 (m, 3H), 2.72 - 2.62 (m, 1H), 2.58 - 2.36 (m, 4H), 2.25 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H), 1.45 - 1.28 (m, 6H).

499

JD-P2 ESI 748.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.69 (s, 1H), 7.42 (s, 2H), 6.99 (t, J= 8.2 Hz, 1H), 6.92 (s, 1H), 5.95 - 5.88 (m, 1H), 5.78 (t, J = 6.7 Hz, 1H), 4.11 (t, J= 7.9 Hz, 4H), 3.46 - 3.31 (m, 2H), 3.00 - 2.69 (m, 3H), 2.64 - 2.38 (m, 4H), 2.30 (s, 3H), 2.26 - 2.15 (m, 1H), 2.09 (s, 6H), 1.36 - 1.24 (m, 6H).

3-101. Préparation of (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(27/)yl)-4-methylpentanamido)-3-(2,4-difluoro-2’,5,6’-trimethyl-4'-(trifluoromethyl)biphenyI-3yl)propanoic acid (compounds JE-PI and JE-P2 )

Step 1: (35)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2f/)-yl)-4methylpentanamido)-3-(2,4-difluoro-2’,5,6’-trimethyI-4’-(trifluoromethyI)biphenyI-3-yl)propanoate

A mixture of2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methyipentanoic acid (160 mg, 0.44 mmol), (5)-ethyl 3-amino-3-(2,4-difluoro-2',5,6'-trimethyl-4(trifluoromethyl)biphenyl-3-yl)propanoate (180 mg, 0.44 mmol), NMI (110 mg, 1.32 mmol) and TCFH (150 mg, 0.53 mmol) in CH3CN (6 mL) was stirred at room température for 2 hours. The solvent was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water 10mMNH4HCO3, B: CH3CN, 0-100%) to provide (3S)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanamido)-3-(2,4-difluoro-2',5,6'-trimethyl-4'(trifluoromethyl)biphenyl-3-yl)propanoate as a yellow oil (180 mg). Yield 54 % (ESI758.2 [M+H]⁺).

Step 2: of (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(27/)-yl)-4methyIpentanamido)-3-(2,4-difluoro-2’,5,6’-trimethyI-4’-(trifluoromethyI)biphenyI-3-yI)propanoic acid

500

(3S)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanamido)-3-(2,4-difluoro-2',5,6'-trimethyl-4'-(trifluoromethyl)biphenyl-3-yl)propanoate(180 mg, 0.24 mmol) was treated with LiOH-H₂O (30 mg, 0.72 mmol) in EtOH (3mL) and H₂O (1 mL) at room température for 1 hour. The reaction mixture was acidified to pH 5~6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% CH3CN) to give the diastereomeric products JE-P1 (48 mg) and JE-P2 (55 mg) as white solids.

JE-PI ESI 730.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.80 (s, IH), 7.39 (s, 2H), 6.94 (t, 7= 8.1 Hz, IH), 6.86 (s, IH), 5.79 - 5.63 (m, 2H), 4.02 (t, 7= 8.1 Hz, 4H), 3.35 - 3.20 (m, 2H), 2.98 - 2.80 (m, 3H), 2.72 - 2.63 (m, IH), 2.49 - 2.37 (m, 2H), 2.26 (s, 3H), 2.08 (s, 3H), 2.05 - 1.93 (m, 5H), 1.50 - 1.28 (m, IH), 0.93 (t, 7=6.1 Hz, 6H).

JE-P2 ESI 730.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.69 (s, IH), 7.42 (s, 2H), 6.99 (t, 7= 8.2 Hz, IH), 6.92 (s, IH), 5.96 - 5.88 (m, IH), 5.61 (t, 7= 7.7 Hz, IH), 4.11 (t, 7= 8.1 Hz, 4H), 3.46 - 3.31 (m, 2H), 2.97 - 2.73 (m, 3H), 2.60 - 2.38 (m, 3H), 2.30 (s, 3H), 2.10 (d, 7= 2.6 Hz, 6H), 1.99 - 1.89 (m, IH), 1.80-1.66 (m, IH), 1.51-1.22 (m, IH), 0.92-0.83 (m, 6H).

3-102. Préparation of (35)-3-(2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)-4-methylpentanamido)-3-(2,4-difluoro-2’,5,6’-trimethyl-[l,l’-biphenyl]-3-yl)propanoic acid (compounds JF-P1 and JF-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4-difluoro-2’,5,6^,-trimethyl-[l,l’-biphenylJ-3-yl)propanoate

501

A mixture of ethyl (S)-3-amino-3-(2,4-difluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate (240 mg, 0.6 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid (253 mg, 0.66 mmol), TCFH (336 mg, 1.2 mmol) and NMI (246 mg, 3.0 mmol) in CHjCN (4 mL) was stirred at 60 °C for 30 min. The reaction was concentrated and purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: MeOH, 0-90%) to provide ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)3-(2,4-difluoro-2^,,5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate as a yellow solid (280 mg). Yield 67.7 % (ESI 690.3 [M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4-difluoro-2’,5,6’-trimethyl-[l,l’-biphenyI]-3-yI)propanoic acid

Ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4-difluoro-2',5,6-trimethyl-[l, 1 '-biphenyl]-3-yl)propanoate (280 mg, 0.41 mmol) was treated with LiOH-ILO (50 mg, 1.2 mmol) in MeOH (4 mL) and H₂O (1 mL) at room température for 30 min. The reaction mixture was acidifted to pH 5-6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (35-58% CH3CN) to give the diastereomeric products JF-P1 (74 mg) and JF-P2 (81 mg) as white solids.

JF-P1 ESI 662.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 7.17 - 7.03 (m, 3H), 6.94 - 6.85 (m,2H), 5.78-5.71 (m, 1H),5.67(t,J= 8.1 Hz, 1H),4.O1 (t,J= 8.1 Hz,4H),2.94-2.79(m,3H),2.71 - 2.59 (m, 1H), 2.48 - 2.36 (m, 2H), 2.25 (s, 3H), 2.06 - 1.88 (m, 8H), 1.42- 1.33 (m, 1H), 0.93 (t, J= 6.5 Hz, 6H).

502

JF-P2 ESI 662.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.69 (s, 1H), 7.20 - 7.04 (m, 3H), 6.98 - 6.90 (m, 2H), 5.97 - 5.88 (m, 1H), 5.61 (t, J= 7.7 Hz, 1H), 4.12 (s, 4H), 3.47 - 3.33 (m, 2H), 2.93 - 2.74 (m, 3H), 2.59-2.40 (m, 3H), 2.29 (s, 3H), 2.01 (d, J= 2.4 Hz, 6H), 1.96- 1.87 (m, 1H), 1.80-1.68 (m, 1H), 1.42 - 1.30 (m, 1H), 0.92 - 0.83 (m, 6H).

3-103. Préparation of (3S)-3-(2-(5-(2-(azetidin-l-yI)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yI)-4-methylpentanamido)-3-(2,4-difluoro-2’,6’-dimethyl-5-(trifluoromethyI)-[l,l’-biphenyI]-3yl)propanoic acid (compounds JG-P1 and JG-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(azetidin-l-yI)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2II)-yl)-4methylpentanamido)-3-(2,4-difluoro-2^,,6’-dimethyl-5-(trifluoromethyl)-[l,l’-biphenyI]-3yl)propanoate

A mixture of ethyl (S)-3-amino-3-(2,4-difluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoate (240 mg, 0.6 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)-4-methylpentanoic acid (230 mg, 0.58 mmol), TCFH (325 mg, 1.16 mmol) and NMI (238 mg, 2.9 mmol) in CH₃CN (4 mL) was stirred at 50°C for 30 mins. The reaction was purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: MeOH, 0~90%) to provide ethyl (3S)-3-(2(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(2,4difluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate as a yellow solid (250 mg). Yield 58.0 % (ESI 744.3 [M+H]*).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yI)ethyl)-2-oxo-4-(trinuoromethyl)pyridin-l(2H)-yI)-4methylpentanamido)-3-(2,4-dinuoro-2',6’-dimethyl-5-(trifluoromethyl)-[l,l’-biphenyl]-3yl)propanoic acid

503

Ethyl (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4-difluoro-2',6'-dimethyl-5-(trifluoromethyl)-[ 1,1 '-biphenyl]-3-yl)propanoate (250 mg, 0.34 mmol) was treated with LiOH-HjO (58 mg, 1.37 mmol) in MeOH (4 mL) and ILO (1 mL) at room température for 30 mins. The reaction mixture was acidified to pH 5~6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (40-61% CHjCN) to give the diastereomeric products JG-P1 (72 mg) and JG-P2 (78 mg) as white solids.

JG-P1 ESI 716.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.80 (s, 1H), 7.40 (t, J= 7.5 Hz, 1H), 7.25 7.15 (m, 1H), 7.12 (d, J= 7.7 Hz, 2H), 6.85 (s, 1H), 5.77 - 5.66 (m, 2H), 4.04 (t, J= 8.0 Hz, 4H), 3.28 (s, 2H), 2.92 (Μ, 1H), 2.84 (t, J= 6.8 Hz, 2H), 2.76 (s, 1H), 2.46 - 2.38 (m, 2H), 2.05 - 1.95 (m, 5H), 1.95 (d, J= 13.7 Hz, 3H), 1.38 (s, 1H), 0.93 (t, J= 6.4 Hz, 6H).

JG-P2 ESI 716.3 (M+H)\ Ή NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.46 (t, J= 7.7 Hz, 1H), 7.25 - 7.19 (m, 1H), 7.15 (d,7= 7.6 Hz, 2H), 6.91 (s, 1H), 5.91 (Μ, 1H), 5.64 (t, 7= 7.6 Hz, 1H), 4.12 (t,7= 7.8 Hz, 4H), 3.47 - 3.32 (m, 2H), 2.95 - 2.77 (m, 3H), 2.65 - 2.55 (m, 1H), 2.50 - 2.40 (m, 2H), 2.02 (d, 7= 2.2 Hz, 6H), 1.96 - 1.88 (m, 1H), 1.75 - 1.67 (m, 1H), 1.39 - 1.28 (m, 1H), 0.92 - 0.84 (m, 6H).

3-104. Préparation of (35)-3-(2,4-difluoro-2',4’,5,6*-tetramethyl-[ 1,1 '-biphenyl]-3-yI)-3-(2-(5-(2(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (compounds JH-P1 and JH-P2)

Step 1: ethyl (35)-3-(2,4-difluoro-2’,4’,5,6’-tetramethyl-Il,r-biphenyIJ-3-yI)-3-(2-(5-(2(dimethyIamino)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoate

504

A mixture of ethyl (5)-3-amino-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoate (220 mg, 0.61 mmol), 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid (250 mg, 0.65 mmol), TCFH (364 mg, 1.3 mmol) and NMI (266 mg, 3.25 mmol) in CH3CN (4.5 mL) was stirred at 60°C for 30 mins. The reaction was concentrated and purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: MeOH, 0~80%) to provide ethyl (35)-3-(2,4-difluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yI)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo4-(trifluoromethyl)pyridin-I(2H)-yl)-4-methylpentanamido)propanoate as a yellow solid (300 mg). Yield 71.1 % (ESI 692.3 [M+H]⁺).

Step 2: (35)-3-(2,4-difluoro-2’,4’,5,6’-tetramethyl-[l,l’-biphenyl]-3-yI)-3-(2-(5-(2(dimethylamino)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid

Ethyl (35)-3-(2,4-difluoro-2',4',5,6’-tetramethyl-[ 1,1 -biphenyl]-3-yI)-3-(2-(5-(2-(dimethylamino)ethyl)-2oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (300 mg, 0.43 mmol) was treated with LiOH-H₂O (56 mg, 1.34 mmol) in MeOH (4 mL) and H₂O (1 mL) at room température for 1 hr. The reaction mixture was acidified to pH 5~6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (35-62% CH3CN) to give the diastereomeric products JH-P1 (113 mg) and JH-P2 (87 mg) as white solids.

JH-P1 ESI 664.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.86 (s, IH), 6.96 - 6.77 (m, 4H), 5.81 - 5.63 (m, 2H), 3.10 (d, J= 21.9 Hz, 2H), 2.98 - 2.86 (m, 3H), 2.76 - 2.63 (m, 7H), 2.25 (d, J= 19.9 Hz, 6H), 2.01 - 1.92 (m, 5H), 1.87 (s, 3H), 1.44 - 1.35 (m, IH), 0.93 (t, J= 6.8 Hz, 6H).

505

JH-P2 ESI 664.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.83 (d, J= 11.6 Hz, 1H), 7.01 - 6.84 (m, 4H), 5.85 (d, J= 8.7 Hz, 1H), 5.63 (s, 1H), 3.25 - 3.09 (m, 2H), 3.05 - 2.91 (m, 2H), 2.77 (s, 7H), 2.55 (d, J= 14.8 Hz, 1H), 2.28 (d, J= 10.3 Hz, 6H), 1.96 (d, J= 3.6 Hz, 6H), 1.93 - 1.85 (m, 1H), 1.80- 1.67 (m, 1H), 1.39-1.27 (m, 1H), 0.93 - 0.81 (m, 6H).

3-105. Préparation of (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2ZZ)yI)-4-mcthylpentanamido)-3-(2,4-difluoro-2^,,5,6’-trimethyl-3’-(triiluoromethyl)-[l,l’-biphenyI]-3yl)propanoic acid (compounds JI-P1 and JI-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2fl)-yl)-4methyIpentanamido)-3-(2,4-difluoro-2’,5,6’-trimethyl-3’-(trifluoromethyI)-Il,r-biphenyI]-3yl)propanoate

A mixture of ethyl (3S)-3-amino-3-(2,4-difluoro-2',5,6'-trimethyl-3'-(trifluoromethyl)-[ 1,1 '-biphenyl]-3yl)propanoate (174.5 mg, 0.42 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2Z/)-yl)-4-methylpentanoic acid (150.0 mg, 0.42 mmol), TCFH (140.3 mg, 0.50 mmol) and NMI (137.9 mg, 1.68 mmol) in CHjCN (5 mL) was stirred at room température ovemight. The reaction was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: MeOH, 0-100%) to provide ethyl (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2/f)-yl)-4-methylpentanamido)-3-(2,4-difluoro-2',5,6'-trimethyl-3'(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate as a light yellow solid (160.0 mg). Yield 51% (ESI 758.3 [M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanamido)-3-(2,4-dinuoro-2’,5,6’-trimethyl-3'-(trifluoromethyl)-[l,l’-biphenyl]-3yl)propanoic acid

506

Ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanamido)-3-(2,4-difluoro-2',5,6^,-trimethyl-3'-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (160.0 mg, 0.21 mmol) was treated with LiOH-HjO (26.4 mg, 0.63 mmol) in EtOH (2 mL) and water (0.5 mL) at room température for 1 hour. The reaction mixture was acidified to PH 4~5 with 2N HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-80% MeCN) to give the diastereomeric products JI-P1 (39.5 mg) and JI-P2 (53.3 mg) as white solids.

JI-P1 ESI 730.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.80 (d, J= 4.4 Hz, 1 H), 7.57 (d, J = 8.1 Hz, 1 H), 7.27(d,J=8.0Hz, lH),6.92(t, J=8.2Hz, 1H), 6.86(s, 1H), 5.79-5.61 (m,2H),4.01 (t,J=8.I Hz,4H), 3.37 - 3.31 (m, 1H), 3.29 - 3.20 (m, 1H), 2.95 - 2.80 (m, 3H), 2.71 - 2.64 (m, 1H), 2.49 - 2.35 (m, 2H), 2.26 (s, 3H), 2.14 - 1.92 (m, 8H), 1.46 - 1.30 (m, 1H), 0.93 (t, J= 6.7 Hz, 6H).

JI-P2 ESI 730.1 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.70 (s, 1H), 7.59 (d, J= 8.1 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 6.98 (t,J=8.2Hz, 1H), 6.92(s, 1H),5.94-5.88(m, 1H),5.64-5.58 (m, 1H),4.10(t, J= 8.0 Hz, 4H), 3.44 - 3.32 (m, 2H), 2.96 - 2.74 (m, 3H), 2.58 - 2.37 (m, 3H), 2.30 (s, 3H), 2.12 (s, 3H), 2.07 (d, J= 2.6 Hz, 3H), 2.00 - 1.86 (m, 1H), 1.80 -1.66 (m, 1 H), 1.41 - 1.31 (m, 1H), 0.92 - 0.85 (m, 6H).

3-106. Préparation of (35)-3-(2,4-difluoro-2’,5,6’-trimethyl-3’-(trifluoromethyl)-[l,l’-biphenylJ-3yl)-3-(2-(5-(3-(dimethylamino)propyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid (compounds JJ-P1 and JJ-P2)

Step 1: ethyl (35)-3-(2,4-difluoro-2’,5,6’-trimethyl-3’-(trifluoromethyl)-[l,r-biphenyl]-3-yl)-3-(2-(5(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoate

507

A mixture of ethyl (35)-3-amino-3-(2,4-difluoro-2^,,5,6^,-trimethyl-3'-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoate (114.6 mg, 0.28 mmol), 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridinl(2Z/)-yl)-4-methylpentanoic acid (100.0 mg, 0.28 mmol), TCFH (95.4 mg, 0.34 mmol) and NMI (92.0 mg, 1.12 mmol) in CHjCN (5 mL) was stirred at room température ovemight. The reaction was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: MeOH, 0-100%) to provide ethyl (35)-3-(2,4-difluoro-2’,5,6'-trimethyl-3'(trifluoromethyl)-[l,l'-biphenyl]-3-yl)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4(trifluoromethyl)pyridin-l(2/7)-yl)-4-methylpentanamido)propanoate as a light yellow solid (100.0 mg). Yield 48% (ESI 760.3 [M+H]⁺).

Step 2: (35)-3-(2,4-difluoro-2',5,6'-trimethyl-3'-(trifluoromethyl)-[l,r-biphenyI]-3-yl)-3-(2-(5-(3(dimethylamino)propyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2/7)-yl)-4methylpentanamido)propanoic acid

Ethyl (35)-3-(2,4-difluoro-2’,5,6^,-trimethyl-3'-(trifluoromethyl)-[l,r-biphenyl]-3-yl)-3-(2-(5-(3(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2W)-yl)-4-methylpentanamido)propanoate (100.0 mg, 0.13 mmol) was treated with LiOH-H₂O (16.4 mg, 0.39 mmol) in EtOH (2 mL) and water (0.5 mL) at room température for 1 hour. The reaction mixture was acidified to pH 4-5 with 2N HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-80% MeCN) to give the diastereomeric products JJ-P1 (6.0 mg) and JJ-P2 (36.5 mg) as white solids.

JJ-P1 ESI 732.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.77 (d, J= 3.4 Hz, 1H), 7.56 (d, J= 8.1 Hz, 1H), 7.26 (d, J= 8.0 Hz, 1H), 6.90 (t, J= 8.1 Hz, 1H), 6.79 (s, 1H), 5.81 - 5.67 (m, 2H), 3.14 - 3.00 (m, 2H),

508

2.97 - 2.89 (m, 1H), 2.78 (s, 6H), 2.72 - 2.58 (m, 3H), 2.25 (s, 3H), 2.11 - 1.81 (m, 10H), 1.41 - 1.29 (m, 1H), 0.93 (d, J =6.6 Hz,6H).

JJ-P2 ESI 732.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 7.58 (d, J= 8.1 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.95 (t, J= 8.1 Hz, 1H), 6.84 (s, 1H), 5.86 - 5.80 (m, 1H), 5.61 - 5.55 (m, 1H), 3.11 -2.91 (m, 2H), 2.91 - 2.82 (m, 1H), 2.77 (s, 6H), 2.70 - 2.51 (m, 3H), 2.29 (s, 3H), 2.14 - 2.04 (m, 6H), 2.03 1.88 (m, 3H), 1.67 - 1.58 (m, 1H), 1.38 - 1.28 (m, 1H), 0.92 - 0.81 (m, 6H).

3-107. Préparation of (3<S)-3-(2-(5-(2-(dimethylamino)ethyI)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanamido)-3-(23’,4-trifluoro-2’,6’-dimethyI-5-(trifluoromethyl)biphenyl-3yl)propanoic acid (compounds JK-P1 and JK-P2)

Step 1: (3S)-ethyI 3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifiuoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,3’,4-trinuoro-2',6’-dimethyl-5-(trifluoromethyl)biphenyI-3-yl)propanoate

A mixture of (3S)-ethyl 3-amino-3-(2,3',4-trifluoro-2’,6'-dimethyl-5-(trifluoromethyl)biphenyl-3yl)propanoate (120 mg, 0.29 mmol), 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yI)-4-methylpentanoic acid (100 mg, 0.29 mmol), TCFH (157 mg, 0.56 mmol) and NMI (69 mg, 0.84 mmol) in MeCN (5 mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH 97: 3) to provide (3S)-ethyl 3-(2(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(2,3^,,4trifluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate as a colorless oil (120 mg). Yield 55% (ESI 750.3 (M+H)⁺).

Step 2: (35)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2II)-yl)-4methyIpentanamido)-3-(23^,,4-trifiuoro-2’,6’-dimethyI-5-(trinuoromethyl)biphenyl-3-yI)propanoic acid

509

(3S)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,3',4-tri fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate (100 mg, 0.13 mmol) was treated with L1OH-H2O (27 mg, 0.65 mmol) in EtOH (3 mL) and H2O (1 mL) at room température for 3 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (30-60% CH3CN) to give the diastereomeric products JK-P1 (30.3 mg) and JK-P2 (23.1 mg) as white solids.

JK-P1 ESI 722.3 (M+Hf. 1H NMR (400 MHz, DMSO) δ 9.26 (d, J= 6.4 Hz, 1H), 7.78 (s, 1H), 7.62 (t, J= 7.5 Hz, 1H), 7.25 - 7.12 (m, 2H), 6.70 (s, 1H), 5.58-5.55 (m, 1H), 5.46 (d, J = 6.2 Hz, 1H), 3.04 2.87 (m, 2H), 2.67 - 2.52 (m, 2H), 2.36 (t, J= 7.3 Hz, 2H), 2.18 (s, 6H), 1.96 - 1.73 (m, 8H), 1.35 - 1.27 (m, 1H), 0.85-0.83 (m, 6H).

JK-P2 ESI 722.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 7.48 (t, J= 7.6 Hz, 1H), 7.24 7.10 (m, 1H), 7.04 (t, J= 9.0 Hz, 1H), 6.90 (s, 1H), 5.80-5.78 (m, 1H), 5.66 (t, J= 7.8 Hz, 1H), 3.19-3.15 (m, 2H), 2.96 (t, J= 7.2 Hz, 2H), 2.92 - 2.76 (m, 7H), 2.69-2.66 (m, 1H), 2.00 (d, J= 2.4 Hz, 3H), 1.97 1.92 (m, 3H), 1.93 - 1.86 (m, 1H), 1.79 - 1.70 (m, 1H), 1.33-1.30 (m, 1H), 0.88 -0.85(m, 6H).

3-108. Préparation of (3S)-3-(4-methyl-2-(5-(2-(3-methyIazetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyI)pyridin-l(2H)-yl)pentanamido)-3-(2,3’,4-trifluoro-2*,6^,-dimethyI-5(trifluoromethyl)biphenyl-3-yI)propanoic acid (compounds JL-P1 and JL-P2 )

Step 1: (3S)-ethyl 3-(4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyI)pyridin-l(2H)-yI)pentanamido)-3-(2,3’,4-trifluoro-2’,6’-dimethyI-5(trifluoromethyI)biphenyI-3-yl)propanoate

510

A mixture of (3S)-ethyl S-amino-S-^S’^-trifluoro^'jô'-dimethyl-S-itrifluoromethyObiphenyl-Syl)propanoate (120 mg, 0.28 mmol), 4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)pentanoic acid (105 mg, 0.28 mmol), NMI (69 mg, 0.84 mmol) and TCFH (117 mg, 0.42 mmol) in CH3CN (10 mL) was stirred at 50°C for 1 hour. The solvent was concentrated in vacuo and the residue was purified by silica gel column (DCM: MeOH 10:1) to provide (3S)-ethyl 3-(4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)pentanamido)-3-(2,3',4-trifluoro-2^,,6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoateasa yellow oil (151 mg). Yield 68.0 % (ESI 776.3 [M+H]’).

Step 2: (3S)-3-(4-methyI-2-(5-(2-(3-methyIazetidin-l-yI)ethyl)-2-oxo-4-(trinuoromethyl)pyridinl(2II)-yI)pentanamido)-3-(2,3’,4-trinuoro-2*,6*-dimethyl-5-(trifluoromethyI)biphenyl-3yl)propanoic acid

LiOH

(3S)-ethyl 3-(4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)pentanamido)-3-(2,3',4-trifluoro-2',6^,-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate(151 mg, 0.19 mmol) was treated with LiOH-H₂O (24.5 mg, 0.58 mmol) in EtOH (3 mL) and water (1 mL) at room température for 1 hour. The reaction mixture was acidified to pH 4~5 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (20-70% MeCN) to give the diastereomeric products JL-P1 (49 mg) and JL-P2 (51 mg) as white solids.

JL-P1 ESI 748.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.81 (s, 1H), 7.42 (t, J= 7.5 Hz, 1H), 7.13 (t, J = 5.9 Hz, 1H), 7.02 (t, J= 8.9 Hz, 1H), 6.84 (s, 1H), 5.77 - 5.65 (m, 2H), 4.13 (t, J= 9.2 Hz, 2H), 3.67 (t, J= 8.8 Hz, 2H), 3.30-3.20 (m, 2H), 2.89 -2.81 (m, 5H), 2.04 - 1.83 (m, 8H), 1.41 - 1.35 (m, 1H), 1.24 (d, J= 6.9 Hz, 3H), 0.93 (t, J= 6.0 Hz, 6H).

511

JL-P2 ESI 748.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.77 (s, 1H), 7.49 (t, J= 7.5 Hz, 1H), 7.20 7.13 (m, 1 H), 7.04 (t, J = 8.9 Hz, lH),6.90(s, 1H), 5.89 -5.81 (m, 1H), 5.66 (t, J= 7.8 Hz, 1H), 4.13 (t, J= 9.2 Hz, 2H), 3.66 (s, 2H), 3.30 (s, 2H), 2.96 - 2.74 (m, 4H), 2.68 - 2.62 (m, 1H), 2.00 (d, J= 2.2 Hz, 3H), 1.97-1.83 (m,4H), 1.77-1.71 (m, 1H), 1.36-1.29 (m, 1H), 1.25 (d, J =6.9 Hz, 3H), 0.90-0.85 (m, 6H).

3-109. Préparation of(3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(triiluoromethyl)pyridin-l(2H)yl)-4-methyIpentanamido)-3-(2,4-dinuoro-3’-methoxy-2’,5,6’-trimethyI-[l,l’-biphenylJ-3yl)propanoic acid (compounds JM-P1 and JM-P2)

Step 1: ethyl (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)-4methylpentanamido)-3-(2,4-difIuoro-3'-methoxy-2’,5,6’-trimethyl-[l,l^,-biphenyll-3-yl)propanoate

TCFH NMI

A mixture of ethyl (3S)-3-amino-3-(2,4-difluoro-3'-methoxy-2',5,6'-trimethyl-[l,r-biphenyl]-3yl)propanoate (190 mg, 0.5 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)-4-methylpentanoic acid (198 mg, 0.55 mmol), TCFH (302 mg, 1.08 mmol) and NMI (220 mg, 2.7 mmol) in CHjCN (4 mL) was stirred at 25 °C for 1 hr. The reaction was concentrated and purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: MeOH, 0~90%) to provide ethyl (3S)-3-(2-(5-(2-(azetidÎn-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4-difluoro-3'-methoxy-2^,,5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate as a yellow solid (250 mg). Yield 69.4 % (ESI 720.3 [M+H]⁺).

Step 2: (35)-3-(2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)-yl)-4methyIpentanamido)-3-(2,4-dinuoro-3*-methoxy-2',5,6'-trimethyl-(l,l’-biphenyl]-3-yI)propanoic acid

512

Ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4-difluoro-3'-methoxy-2',5,6^,-trimethyl-[l,r-biphenyl]-3-yl)propanoate (250 mg, 0.35 mmol) was treated with LiOH-HzO (42 mg, 1 mmol) in EtOH (4 mL) and H2O (1 mL) at room température for 30 min. The reaction mixture was acidifîed to pH 5-6 with IN HCl. The reaction was concentrated in vacuo and the residue purified by prep-HPLC A (35-65% CH3CN) to give the diastereomeric products JM-P1 (68 mg) and JM-P2 (86 mg) as white solids.

JM-P1 ESI 692.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.79 (s, 1H), 7.04 (d, J= 8.4 Hz, 1H), 6.90 6.79 (m, 3H), 5.77 - 5.63 (m, 2H), 3.99 (t, J= 8.0 Hz, 4H), 3.81 (s, 3H), 3.30 - 3.23 (m, 2H), 2.94 - 2.81 (m, 3H), 2.70 - 2.61 (m, 1H), 2.46 - 2.35 (m, 2H), 2.24 (s, 3H), 1.97 (t, J= 7.6 Hz, 2H), 1.93 - 1.77 (m, 6H), 1.44 - 1.34 (m, 1H), 0.92 (t, J= 6.2 Hz, 6H).

JM-P2 ESI 692.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.69 (s, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.96 6.82 (m, 3H), 5.95 - 5.87 (m, 1H), 5.61 (t, J= 7.7 Hz, 1H), 4.12 (t, J= 8.1 Hz, 4H), 3.82 (s, 3H), 3.47 3.33 (m, 2H), 2.98 - 2.73 (m, 3H), 2.56 - 2.40 (m, 3H), 2.28 (s, 3H), 1.97 - 1.88 (m, 4H), 1.86 (d, J= 3.0 Hz, 3H), 1.78 - 1.68 (m, 1H), 1.41 - 1.30 (m, 1H), 0.88 (dd, J= 10.5, 6.6 Hz, 6H).

3-110. Préparation of (35)-3-(4,4'-difluoro-2',5,6'-trimethyl-[l,l'-biphenyl]-3-yl)-3-(2-(3-fluoro-5(2-(3-fluoroazetidin-l-yI)ethyl)-2-oxopyridin-l(2//)-yl)-4-methylpentanamido)propanoic acid(JNP1 and JN-P2)

Step 1: ethyl (35)-3-(4,4'-difluoro-2',5,6’-trimethyl-[l,l'-biphenyl]-3-yI)-3-(2-(3-fluoro-5-(2-(3fluoroazetidin-l-yl)ethyI)-2-oxopyridin-l(2Z0-yl)-4-methylpentanamido)propanoate

513

A mixture of 2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2//)-yl)-4-methylpentanoic acid (200.0 mg, 0.61 mmol), ethyl (5)-3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3yl)propanoate (260.0 mg, 0.61 mmol), TCHF (205.0 mg, 0.73 mmol) and NMI (150.0 mg, 1.83 mmol) in CHjCN (4 mL) was stirred at room température for 1.5 hours. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC on a C18 / 40g column (A: water lOmM NH4HCO3, B: MeOH, 0-100%) to provide ethyl (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)-3-(2-(3fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2Z7)-yl)-4-methylpentanamido)propanoate as a yellow solid (210.0 mg). Yield 52.5% (ESI 658.3 [M+H]⁺).

Step 2: (35)-3-(4,4’-difluoro-2’,5,6’-trimethyl-(l,r-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2J7)-yl)-4-methylpentanamido)propanoic acid

Ethyl (35)-3-(4,4'-difluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3-fluoroazetidin-lyl)ethyl)-2-oxopyridin-l(2/7)-yI)-4-methylpentanamido)propanoate (210.0 mg, 0.32 mmol) was treated with LiOH-HîO (150.0 mg, 3.2 mmol) in THF (4 mL) and water (2 mL) at 30 °C for 1 hour. The reaction mixture was acidified to pH 4-5 with 2N HCl. The solvent was removed in vacuo and the residue purified by prep-HPLC A (30-60% MeCN) to provide the diastereomeric products JN-P1 (81 mg) and JN-P2 (83 mg) as white solids.

JN-P1 ESI 630.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.30 (s, 1H), 7.25 - 7.22 (m, 1H), 6.77 - 6.75 (m, 1H), 6.72 - 6.69 (m, 3H), 5.55 (t, J= 8.0 Hz, 1H), 5.40 - 5.37 (m, 1H), 5.18 - 5.01 (m, 1H), 3.99 3.82 (m, 2H), 3.66 - 3.48 (m, 2H), 3.06 - 2.99 (m, 2H), 2.66 - 2.50 (m, 4H), 2.18 (d, J= 1.5 Hz, 3H), 1.89 - 1.81 (m, 5H), 1.78 (s, 3H), 1.34 - 1.27 (m, 1 H), 0.85 - 0.78 (m, 6H).

514

JN-P2 ESI 630.2 (M+H)\ 'H NMR (400 MHz, MeOD) δ 7.27 - 7.23 (m, 2H), 6.80 (d, J= 6.9 Hz, 2H), 6.73 (d, J = 9.6 Hz, 2H), 5.56-5.49 (m, 2H), 5.28 - 5.11 (m, 1 H), 4.33 - 4.18 (m, 2H), 3.97 - 3.83 (m, 2H), 3.27 - 3.22 (m, 2H), 2.64 - 2.35 (m, 4H), 2.21 (d, J= 1.9 Hz, 3H), 1.89 - 1.82 (m, 7H), 1.69 - 1.62 (m, 1H), 1.31 - 1.21 (m, 1H), 0.83-0.78 (m, 6H).

3-111. Préparation of (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2ZZ)yI)-4-methyIpentanamido)-3-(3’,4-difluoro-2’,6’-dimethyI-5-(trifluoromethyl)-[l,l’-biphenyll-3yl)propanoic acid

Step 1: ethyl (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)-yl)-4methyIpentanamido)-3-(3’,4-dinuoro-2’,6’-dimethyl-5-(triiluoroniethyl)-[l,r-biphenyl]-3yl)propanoate

A mixture of ethyl (5)-3-amino-3-(3',4-difluoro-2',6'-dimethyl-5-(trifluoromcthyl)-[l,r-biphenyl]-3yl)propanoate (230mg, 0.57 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)yl)-4-methylpentanoic acid (205 mg, 0.57 mmol), NMI (0.6 mL) and TCFH (241 mg, 0.86 mmol) in CHjCN (3 mL) was stirred at room température for 2.0 hour. The solvent was concentrated in vacuo and the residue was purified by prep-HPLC A (50-80% CH3CN) to provideethyl (3S)-3-(2-(5-(2-(azetidin-lyl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanamido)-3-(3^,,4-difluoro-2’,6’dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate as a white solid (320 mg). Yield 76% (ESI 744.2 [Μ+ΗΓ).

Step 2 : (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l (2ZZ)-yI)-4methylpentanamido)-3-(3’,4-difluoro-2’,6’-dimethyI-5-(trifluoromethyI)-[l,l’-biphenyI)-3yl)propanoic acid

515

Ethyl (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromcthyl)pyridin-l(2//)-yl)-4methylpentanamido)-3-(3',4-difluoro-2',6'-dimethyl-5-(trifIuoromethyl)-[l,r-biphenyl]-3-yl)propanoate (320 mg, 0.43 mmol) was treated with LiOH-H₂O (35 mg, 0.84mmol) in MeOH (3.0 mL) and H₂O (1.0 mL) at room température for 2 hours. The reaction mixture was acidifïed to pH 5~6 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (50-80% CHjCN) to provide the diastereomeric products JO - PI (100 mg) and JO - P2 (102 mg) as white solids.

JO-PI ESI 716.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 7.42 - 7.29 (m, 2H), 7.18 - 7.03 (m, 1H), 6.98 (t,J = 9.0 Hz, 1H), 6.71 (d,J= 10.0 Hz, 1H), 5.70-5.50 (m,2H),4.05 (t, J =8.1 Hz,4H), 3.30 - 3.25 (m, 1H), 2.87 - 2.65 (m, 4H), 2.50 - 2.38 (m, 2H), 2.08 - 1.86 (m, 5H), 1.83 - 1.68 (m, 3H), 1.47 - 1.33 (m, 1H), 0.93 - 0.85 (m, 6H).

JO-P2 ESI 716.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.48 - 7.38 (m, 2H), 7.19 - 7.09 (m, 1H), 7.00 (t, J= 9.0 Hz, 1H), 6.88 (s, 1H), 5.88 - 5.78 (m, 1H), 5.61 (t, J= 7.5 Hz, 1H), 4.13 (t, J= 8.1 Hz, 4H), 3.49 - 3.32 (m, 2H), 2.97 - 2.73 (m, 2H), 2.70 - 2.40 (m, 4H), 2.05 - 1.85 (m, 7H), 1.73 - 1.60 (m, 1H), 1.44 - 1.26 (m, 1H), 0.87 (d, J= 6.6 Hz, 6H).

3-112. Préparation of (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yI)-4-methyIpentanamido)-3-(4-fluoro-3^,-methoxy-2’,6’-dimethyl-5-(trifluoromethyl)biphenyl-3yl)propanoic acid (compounds JP-P1 and JP-P2 )

Step 1: (3S)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trinuoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-3’-methoxy-2^,,6’-dimethyl-5-(trinuoromethyl)biphenyI-3yl)propanoate

516

A mixture of (S)-ethyl 3-amino-3-(4-fluoro-3'-methoxy-2',6^,-dimethyl-5-(trifluoromethyl)biphenyl-3yl)propanoate (200 mg, 0.48 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanoic acid (173 mg, 0.48 mmol), NM1 (120 mg, 1.44 mmol) and TCFH (160 mg, 0.58 mmol) in CHjCN (8 mL) was stirred at room température for 2 hours. The solvent was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: CH3CN, 0-100%) to provide (3S)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyi)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-3^,-methoxy-2^,,6'-dimethyl-5(trifluoromethyl)biphenyl-3-yl)propanoate as a yellow oil (270 mg). Yield 72 % (ESI 756.2 [M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(triiluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-nuoro-3'-methoxy-2',6*-dimethyl-5-(trinuoromethy!)biphenyI-3yl)propanoic acid

LiOH-HjO

EtOH/HjO

(3S)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-3'-methoxy-2',6^,-dimethyl-5-(trifluoromethyI)biphenyl-3-yl)propanoate (270 mg, 0.36 mmol) was treated with LiOH-H₂O (60 mg, 1.44mmol) in EtOH (3mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 5-6 with IN HCl. The solvent was removed in vacuo and the residue purified by prep-HPLC A (30-60% CHjCN) to give the diastereomeric products JP-P1 (75 mg) and JP-P2 (85 mg) as white solids.

JP-P1 ESI 727.8 (M+H)⁺. 1H NMR (400 MHz, MeOD) 8 7.83 (s, 1H), 7.36 - 7.25 (m, 2H), 7.05 (t, J= 8.7 Hz, 1H), 6.87 - 6.73 (m, 2H), 5.64 - 5.59 (m, 2H), 4.04 (t, J= 8.1 Hz, 4H), 3.82 (s, 3H), 3.29 - 3.25

517 (m, 2H), 2.85 - 2.69 (m, 4H), 2.47 - 2.39 (m, 2H), 2.05 - 1.94 (m, 2H), 1.91 - 1.68 (m, 6H), 1.43 - 1.37 (m, IH), 0.94-0.90 (m, 6H).

JP-P2 ESI 727.8 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.73 (s, IH), 7.42 - 7.31 (m, 2H), 7.09 (d, J= 8.3 Hz, IH), 6.89 - 6.87 (m, 2H), 5.81 - 5.78 (m, IH), 5.61 (t, J= 7.6 Hz, IH), 4.13 (t, J= 8.0 Hz, 4H), 3.83 (s, 3H), 3.44 - 3.32 (m, 2H), 2.94 - 2.42 (m, 6H), 2.00 - 1.84 (m, 7H), 1.68 - 1.61 (m, IH), 1.41 1.34 (m, IH), 0.87 - 0.85 (m, 6H).

3-113. Préparation of (S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyI)pyridinl(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2’,3’,6’-trimethyI-5-(triiluoromethyl)biphenyl-3yl)propanoic acid (compounds JQ-P1 and JQ-P2)

Step 1 : (S)-ethyl 3-((S)-2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-2'3',6’-trimethyI-5-(trifluoromethyl)biphenyl-3-yl)propanoate

A mixture of (S)-ethyl 3-amino-3-(4-fluoro-2',3',6'-trimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate (170 mg, 0.43 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid (155 mg, 0.43 mmol), TCFH (241 mg, 0.86 mmol) and NMI (106 mg, 1.3 mmol) in MeCN (5mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM : MeOH 10:1) to provide (S)-ethyl 3-((S)-2-(5-(2(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridm-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro2^,,3',6'-trimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate as a colorless oil (200 mg). Yield 63% (ESI 740.3 (M+H)⁺).

Step 2: (S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l (2H)-yl)-4methylpentanamido)-3-(4-fluoro-2'3',6'-trimethyl-5-(trifluoromethyI)biphenyl-3-yl)propanoic acid

518

(S)-ethyl 3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-2’,3^,,6^,-trimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate (200 mg, 0.27 mmol) was treated with LiOH-HaO (53 mg, 1.27 mmol) in EtOH (3 mL) and H2O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was rcmoved in vacuo and the residue purified by prep-HPLC A (30-60% CHjCN) to give the diastereomeric products JQ-P1 (62 mg) and JQ-P2 (87 mg) as white solids.

JQ-P1 ESI 712.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.82 (d, J = 5.2 Hz, 1H), 7.36 (s, 1H), 7.29 7.22 (m, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.03 - 6.92 (m, 1H), 6.75 (d, J = 16.4 Hz, 1H), 5.62-5.60 (m, 2H), 4.05 (t, J = 7.9 Hz, 4H), 3.30 (s, 2H), 2.83 (d, J = 3.3 Hz, 2H), 2.76 - 2.64 (m, 2H), 2.54 - 2.37 (m, 2H), 2.26 (s, 3H), 2.06 - 1.95 (m, 2H), 1.99-1.92 (m, 3H), 1.78 (s, 3H), 1.39 (d, J = 6.4 Hz, 1H), 0.94-0.90 (m, 6H).

JQ-P2 ESI 712.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.41 (d, J = 6.4 Hz, 1H), 7.32 (d, J = 6.3 Hz, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.88 (s, 1H), 5.80 (d, J - 10.3 Hz, 1H), 5.61 (t, J = 7.7 Hz, 1H), 4.13 (t, J = 7.9 Hz, 4H), 3.34-3.29 (m, 2H), 2.91 (d, J = 16.4 Hz, 1H), 2.85 - 2.74 (m, 1H), 2.68-2.64 (m, 1H), 2.58-2.38 (m, 3H), 2.28 (s, 3H), 1.98-1.93 (m, 7H), 1.67-1.64 (m, 1H), 1.39-1.37 (m, lH),0.87 (s, 6H).

3-114. Préparation of (3S)-3-(2-(5-(2-(azetîdin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yI)-4-fluoro-4-methylpentanamido)-3-(4-fIuoro-2’,4*,6’-trimethyl-5-(trifluoromethyl)biphenyl-3yl)propanoic acid (compounds JR-P1 and JR-P2)

Step 1: (3S)-ethyI 3-(2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4fluoro-4-methylpentanamido)-3-(4-fluoro-2’,4*,6*-trimethyl-5-(trifluoromethyl)biphenyI-3yl)propanoate

519

A mixture of (S)-ethyl 3-amino-3-(4-fluoro-2',4',6'-trimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate (170 mg, 0.43 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-fluoro4-methylpentanoic acid (163 mg, 0.43 mmol), TCFH (241 mg, 0.86 mmol) and NMI (106 mg, 1.3 mmol) in MeCN (5mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue purified by silica gel column (DCM:MeOH 97: 3) to provide (3S)-ethyI 3-(2-(5-(2-(azetidin-lyl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-fluoro-4-methylpentanamido)-3-(4-fluoro-2',4',6'trimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate as a colorless oil (100 mg). Yield 31% (ESI 758.3 (M+H)⁺).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)-yl)-4-fluoro-4methylpentanamido)-3-(4-fluoro-2’,4’,6'-trimethyl-5-(trinuoromethyl)biphenyl-3-yl)propanoîc acid

(3S)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-fluoro-4methylpentanamido)-3-(4-fluoro-2',4',6'-trimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate (100 mg, 0.13 mmol) was treated with LiOH-H₂O (27 mg, 0.65 mmol) in EtOH (3 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% CHjCN) to give the diastereomeric products JR-P1 (36 mg) and JR-P2 (22 mg) as white solids.

JR-P1 ESI 730.3 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.90 (s, IH), 7.26 (d, J « 6.4 Hz, 2H), 6.92 (s, 2H), 6.58 (s, IH), 5.65 (s, IH), 5.59 - 5.50 (m, IH), 4.09 (t, J = 8.1 Hz, 4H), 3.33 (d, J = 11.0 Hz, 2H), 2.90 - 2.40 (m, 8H), 2.30 (s, 3H), 1.99 - 1.90 (m, 3H), 1.84 (d, J = 15.3 Hz, 3H), 1.46 - 1.25 (m, 6H).

JR-P2 ESI 730.3 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.73 (s, IH), 7.43 (d, J = 4.9 Hz, IH), 7.32 (d, J = 6.5 Hz, IH), 6.94 (s, 2H), 6.88 (s, IH), 5.78 (t, J = 6.6 Hz, 2H), 4.14 (s, 4H), 3.51 - 3.36 (m, 2H), 2.92

520 (d, J = 15.8 Hz, 1H), 2.82-2.79 (m, 1H), 2.68 - 2.42 (m, 5H), 2.30 (s, 3H),2.16- 2.13 (m, 1H), 1.95 (d, J =

3.6 Hz, 6H), 1.34-1.31 (m, 6H).

3-115. Préparation of (3S)-3-(2-(5-(3-(dimethylamino)propyI)-2-oxo-4-(trifluoromethyl)pyridinl(2£0-yI)-4-methylpentanamîdo)-3-(4-fluoro-2*,4',6’-trimethyl-5-(trifluoromethyl)-[l,l’-biphenyI]3-yl)propanoic acid (compounds JS-P1 and JS-P2)

Step 1: ethyl (3S)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methylpentanamido)-3-(4-fluoro-2’,4’,6’-trimethyl-5-(trifluoromethyl)-[l,l’-biphenyl]-3yl)propanoate

A mixture of ethyl (S)-3-amino-3-(4-fluoro-2',4',6'-trimethyl-5-(trifluoromethyl)-[l,l^,-biphenyl]-3yl)propanoate (290 mg, 0.73 mmol), 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridinl(2//)-yl)-4-methylpentanoic acid (240 mg, 0.662 mmol), ΧΛζΜΝ-tetramethylchloroformamidinium hexafluorophosphate (278 mg, 0.993 mmol) and l-methylimidazole (217 mg, 2.65 mmol) in acetonitrile (10 mL) was stirred at room température for 2 hours. The mixture was purified by reverse phase HPLC on a C18 / 40g column (A: water 10 mM NHjHCOj.B: MeOH, 0-100%) to provide ethyl (35)-3-(2-(5-(3(dimethylamino)propyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanamido)-3-(4-fluoro2',4',6’-trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (370 mg) as a white solid. Yield 75% (ESI 742.2 (M+H)⁺).

Step 2: (35)-3-(2-(5-(3-(dimethyIamino)propyI)-2-oxo-4-(trifiuoromethyI)pyridin-l(2//)-yl)-4methylpentanamido)-3-(4-fluoro-2’,4’,6’-trimethyl-5-(trifluoromethyI)-[l,l’-biphenyl]-3yl)propanoic acid

LiOH

521

Ethyl (35)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)-yl)-4methylpentanamido)-3-(4-fluoro-2',4',6'-trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (370 mg, 0.50 mmol) was treated with LiOH-H₂O (84 mg, 2.0 mmol) in MeOH (5 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidifïed to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% CHaCN) to give the diastereomeric products JS-P1 (123 mg) and JS-P2 (91 mg) as white solids.

JS-P1 ESI 713.9 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.78 (s, 1H), 7.35 (d, J= 5.0 Hz, 1H), 7.30 7.21 (m, 1H), 6.91 (d, J= 13.8 Hz, 2H), 6.68 (s, 1H), 5.70-5.66 (m, 1H), 5.59 (t, J= 6.8 Hz, 1H), 3.09 3.04 (m, 2H), 2.79 (s, 6H), 2.74-2.63(m, 4H), 2.29 (s, 3H), 2.03 - 1.95 (m, 7H), 1.78 (s, 3H), 1.42 - 1.33 (m, 1H), 0.94-0.9 l(m,6H).

JS-P2 ESI 713.9 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.80 (s, 1H), 7.37 - 7.30(m, 2H), 6.94 (s, 2H), 6.83 (s, 1H), 5.76 - 5.72 (m, 1H), 5.58 (t, J= 7.6 Hz, 1H), 3.05 - 3.00 (m, 2H), 2.79 (s, 6H), 2.74 - 2.49 (m, 4H), 2.30 (s, 3H), 2.03 - 1.91 (m, 9H), 1.67 - 1.60(m, 1H), 1.37 - 1.29 (m, 1H), 0.86 - 0.83 (m, 6H).

3-116. Préparation of (3S)-3-(2-(5-(2-(5-azaspiro[2.3]hexan-5-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2Z7)-yl)-4-methylpentanamido)-3-(4-fluoro-2’,6’-dimethyl-5(trifluoromethyl)-[l,l’-biphenyIJ-3-yl)propanoic acid (compounds JT-P1 and JT-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(5-azaspiro[23]hexan-5-yl)ethyl)-2-oxo-4-(trinuoromethyI)pyridinl(2/7)-yI)-4-methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoate

A mixture of ethyl (S)-3-amino-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoate hydrochloride (150 mg, 0.36 mmol), 2-(5-(2-(5-azaspiro[2.3]hexan-5-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanoic acid (139.0 mg, 0.36 mmol), TCHF (120.6 mg, 0.43 mmol) and NMI (88.7 mg, 1.08 mmol) in CHjCN (5 mL) was stirred at room température ovemight. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC on a C18/40g

522 column (A: water lOmM NH4HCO3.B: MeOH, 0-100%) to provide ethyl (35)-3-(2-(5-(2-(5azaspiro[2.3]hexan-5-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)-yl)-4-methylpentanamido)-3-(4fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate as a light yellow solid (100 mg).

Yield 37% (ESI 752.3 [M+H]⁺).

Step 2: (35)-3-(2-(5-(2-(5-azaspiro[2.3] hexan-5-yl)ethyl)-2-oxo-4-(triiluoromethyl)pyridin-l(2Z7)-yl)4-methylpentanamido)-3-(4-nuoro-2’,6’-dimethyI-5-(trifluoromethyl)-[l,l’-biphenyI]-3yl)propanoic acid

Ethyl (35)-3-(2-(5-(2-(5-azaspiro[2.3]hexan-5-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (100.0 mg, 0.13 mmol) was treated with LiOH-ILO (16.4 mg, 0.39 mmol) in EtOH (2 mL) and water (0.5 mL) at room température for 1 hour. The reaction mixture was acidified to pH 5~6 with 2N HCl. The solvent was removed in vacuo and the residue purified by prep-HPLC A (30-80% MeCN) to give the diastereomeric products JT-P1 (29 mg) and JT-P2 (38 mg) as white solids.

JT-P1 ESI 724.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 7.40 (d, J= 5.2 Hz, 1H), 7.29 (d, J = 6.3 Hz, 1H), 7.19 - 7.06 (m, 3H), 6.73 (s, 1H), 5.67 - 5.60 (m, 2H), 4.10 (s, 4H), 3.42 - 3.33 (m, 2H), 2.87 (t, J= 7.1 Hz, 2H), 2.72 (d, J= 6.9 Hz, 2H), 2.07- 1.90 (m, 5H), 1.84 (s, 3H), 1.46-1.34 (m, 1H), 1.00 -0.88(m, 6H), 0.75 (s, 4H).

JT-P2 ESI 724.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.75 (s, 1H), 7.46 - 7.43 (m, 1H), 7.37 - 7.34 (m, 1H), 7.21 - 7.10 (m, 3H), 6.88 (s, 1H), 5.81 - 5.76 (m, 1H), 5.63 (t, J= 7.7 Hz, 1H), 4.26 - 4.09 (m, 4H), 3.53 - 3.39 (m, 2H), 3.03 - 2.75 (m, 2H), 2.70 - 2.50 (m, 2H), 2.04 - 1.91 (m, 7H), 1.69 - 1.60 (m, 1H), 1.45 - 1.35 (m, 1H), 0.90 - 0.86 (m, 6H), 0.83 - 0.72 (m, 4H).

3-117. Préparation of (3S)-3-(2-(5-(2-(5-azaspiro[2.3]hexan-5-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2’,4’,5,6’tetramethylbiphenyI-3-yl)propanoic acid (compounds JU-P1 and JU-P2 )

523

Step 1: (3S)-ethyI 3-(2-(5-(2-(5-azaspirol23]hexan-5-yI)ethyl)-2-oxo-4-(trifluoromethy!)pyridin l(2II)-yl)-4-methylpentanamido)-3-(4-fluoro-2’,4’,5,6^,-tetramethylbiphenyI-3-yl)propanoate

A mixture of 2-(5-(2-(5-azaspiro[2.3]hexan-5-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid (150 mg, 0.39 mmol), (S)-ethyl 3-amino-3-(4-fluoro-2',4’,5,6'-tetramethylbiphenyl3-yl)propanoate (133 mg, 0.39 mmol), NMI (160 mg, 1.96 mmol) and TCHF (218 mg, 0.78 mmol) in CH3CN (5 mL) was stirred at room température for 1.5 hours. The solvent was concentrated in vacuo and the residue purified by silica gel column (DCM: MeOH 9:1) to provide (3S)-ethyl 3-(2-(5-(2-(5azaspiro[2.3]hexan-5-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4fluoro-2^,,4',5,6'-tetramethylbiphenyl-3-yl)propanoateas a colorless oil (180 mg). Yield 65 % (ESI 712.3 [M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(5-azaspiro[2.3]hexan-5-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoic acid

(3S)-ethyl 3-(2-(5-(2-(5-azaspiro[2.3]hexan-5-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-2^,,4',5,6'-tetramethylbiphenyl-3-yl)propanoate (180 mg, 0.25 mmol) was treated with L1OH-H2O (53 mg, 1.27 mmol) in EtOH (3 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue purified by prep-HPLC A (30-60% CH3CN) to give the diastereomeric products JU-P1 (51 mg) and JU-P2 (60 mg) as white solids.

524

JU-P1 ESI 684.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.75 (s, 1H), 6.92 - 6.89 (m, 5H), 5.60 (t, J = 7.2 Hz, 1H), 5.75-5.72 (m, 1H), 4.27 (d, J = 8.1 Hz, 4H), 3.55 - 3.40 (m, 2H), 2.98 - 2.53 (m, 4H), 2.28 (s, 3H), 2.30 (s, 3H), 2.08- 1.93 (m, 7H), 1.99-1.95 (m, 1H), 1.42-1.40 (m, 1H), 1.09-0.69 (m, 10H).

JU-P2 ESI 684.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.75 (s, 1H), 7.00 - 6.80 (m, 5H), 5.74-5.70 (m, 1H), 5.60 (t, J = 7.6 Hz, 1H), 4.18 (s, 4H), 3.58 - 3.42 (m, 2H), 2.97 (d, J = 16.0 Hz, 1H), 2.89 - 2.74 (m, 1H), 2.67-2.63 (m, 1H), 2.53-2.50 (m, 1H), 2.29 (d, J = 11.2 Hz, 6H), 2.03-1.97 (m, 7H), 1.65-1.61 (m, 1H), 1.43-1.41 (m, 1H), 0.88 (d, J = 5.6 Hz, 6H), 0.77 (t, J = 10.3 Hz, 4H).

3-118. Préparation of (3S)-3-(4-fluoro-2’,3’,6’-trimethyl-5-(trifluoromethyI)biphenyl-3-yI)-3-(2-(5(2-(3-(methoxymethyI)azetidin-l-yI)ethyI)-2-oxo-4-(trifIuoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid (compounds JV-P1 and JV-P2 )

Step 1: (3S)-ethyl 3-(4-fluoro-2',3',6'-trimethyl-5-(trifluoromethyl)biphenyl-3-yl)-3-(2-(5-(2-(3(methoxymethyl)azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoate

A mixture of (S)-ethyl 3-amino-3-(4-fluoro-2^,,3',6'-trimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate (240 mg, 0.60 mmol), 2-(5-(2-(3-(methoxymethyl)azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanoic acid (242 mg, 0.60 mmol), NMI (197 mg, 1.8 mmol) and TCFH (252 mg, 0.9 mmol) in CHjCN (8 mL) was stirred at room température for 2 hours. The solvent was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/40g column (A: water lOmM NILHCOj, B: CHjCN, 0-100%) to provide (3S)-ethyl 3-(4-fluoro-2',3',6'-trimethyl-5(trifluoromethyl)biphenyl-3-yl)-3-(2-(5-(2-(3-(methoxymethyl)azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate as a yellow oil (270 mg). Yield 57 % (ESI 784.0 [M+H]⁺).

Step 2: (3S)-3-(4-fluoro-2’,3’,6’-trimethyI-5-(trifluoromethyl)biphenyl-3-yl)-3-(2-(5-(2-(3(methoxymethyl)azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)-yI)-4methylpentanamido)propanoic

525

(3S)-ethyl 3-(4-fluoro-2',3',6'-trimethyI-5-(trifluoromethyl)biphenyl-3-yl)-3-(2-(5-(2-(3(methoxymethyl)azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoate (270 mg, 0.34 mmol) was treated with LiOH-H₂O (57 mg, 1.36 mmol) in EtOH (3mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidifîed to pH 5~6 with IN HCl. The solvent was removed in vacuo and the residue was purified by prep-HPLC A (3060% CHjCN) to give the diastereomeric products JV-P1 (67 mg) and JV-P2 (90 mg) as white solids.

JV-P1 ESI 755.9 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.83 (d, J= 5.9 Hz, 1H), 7.38 - 7.24 (m, 2H), 7.08 - 6.95 (m, 2H), 6.74 (d, J= 19.4 Hz, 1H), 5.64-5.60 (m, 2H), 4.13-4.09 (m, 2H), 3.89 - 3.81 (m, 2H), 3.47 - 3.38 (m, 5H), 3.28 - 3.24 (m, 2H), 3.05 - 2.95 (s, 1H), 2.89 - 2.66 (m, 4H), 2.26 (d, J= 2.9 Hz, 3H), 2.06 - 1.89 (m, 5H), 1.76 - 1.75 (m, 3H), 1.44 - 1.36 (m, IH), 0.94 - 0.91 (m, 6H).

JV-P2 ESI 755.9 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.42 - 7.31 (m, 2H), 7.09 - 7.00 (m, 2H), 6.88 (s, 1H), 5.81 - 5.78 (m, 1H), 5.61 (t, J= 7.6 Hz, 1H), 4.25 - 4.17 (m, 2H), 3.98 - 3.88 (m, 2H), 3.50 (d, J= 4.4 Hz, 2H), 3.45 - 3.32 (m, 5H), 3.11 - 3.02 (m,lH), 2.94 - 2.74 (m, 2H), 2.68 - 2.51 (m, 2H), 2.28 (s, 3H), 2.00 - 1.89 (m, 7H), 1.69 - 1.61 (m, 1H), 1.42 - 1.33 (m, 1H), 0.88 - 0.86 (m, 6H).

3-119. Préparation of (S)-3-((R)-2-(5-(2-(2-azaspiro[3.3]heptan-2-yl)ethyI)-2-oxo-4(trinuoromethyI)pyridin-l(2H)-yl)-4-methyIpentanamido)-3-(3’,4-dinuoro-2’,5,6’-trimethyl-[l,rbiphenyl]-3-yl)propanoic acid (compounds JW-P1 and JW-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(2-azaspiro|3.3]heptan-2-yI)ethyI)-2-oxo-4-(trifIuoromethyl)pyridinl(2H)-yl)-4-methylpentanamido)-3-(3’,4-difluoro-2’,5,6’-trimethyI-[l,l’-biphenyl]-3-yI)propanoate

526

A mixture of2-(5-(2-(2-azaspiro[3.3]heptan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid (250.0 mg, 0.63 mmol), ethyl (S)-3-amino-3-(3',4-difluoro-2',5,6-trimethyl-[l,rbiphenyI]-3-yI)propanoate hydrochloride (218.0 mg, 0.63 mmol), TCHF (210.0 mg, 0.75 mmol) and NMI (155.0 mg, 1.89 mmol) in CH3CN (5 mL) was stirred at room température for 2 hrs. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3.B: CH3CN, 0-100%) to provide ethyl (3S)-3-(2-(5-(2-(2-azaspiro[3.3]heptan-2yl)ethyl)-2-oxo-4-(trifluoromethyl)pyri -din-l(2H)-yl)-4-methylpentanamido)-3-(3',4-difluoro-2',5,6’trimethyl-[l,r-biphenyl]-3-yl)propanoate as a yellow solid (300.0 mg). Yield 66.1% (ESI 730.0 [M+H]*).

Step 2: (S)-3-((R)-2-(5-(2-(2-azaspiro[3.3]heptan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl) pyridinl(2H)-yl)-4-methylpentanamido)-3-(3’,4-difluoro-2’,5,6’-trimethyl-[l,r-biphenyl]-3-yl)propanoic acid

Ethyl (3S)-3-(2-(5-(2-(2-azaspiro[3.3]heptan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl) pyridine-l(2H)-yl)-4methylpentanamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[l,r-biphen yl]-3-yl)propanoate (300.0 mg, 0.41 mmol) was treated with LiOH-HjO (86.0 mg, 2.05 mmol) in EtOH (4 mL) and water (2 mL) at 30 °C for 1 hour. The reaction mixture was acidified to pH 4-5 with 2N HCl. The solvent was removed in vacuo and the residue was purified by Prep HPLC A (30-60% MeCN) to give the diastereomeric products JWP1 (64 mg) and JW-P2 (85 mg) as white solids.

JW-P1 ESI 702.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.82 (s, 1H), 7.10 - 6.99 (m, 1H), 6.96 - 6.81 (m, 3H), 6.76 (d, J= 6.0 Hz, 1H), 5.65-5.59 (m, 2H), 4.05 - 3.88 (m, 4H), 3.26 - 3.12 (m, 2H), 2.83 (t, J= 7.0 Hz, 2H), 2.68 (d, J= 6.6 Hz, 2H), 2.33 - 2.15 (m, 7H), 2.00 - 1.73 (m, 10H), 1.46 - 1.32 (m, 1H), 0.940.91 (m, 6H).

JW-P2 ESI 702.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.72 (s, 1 H), 7.11 - 7.02 (m, 1H), 6.98 - 6.81 (m, 4H), 5.73 (dd, J= 11.0, 3.4 Hz, 1H), 5.60 (t, J= 7.2 Hz, 1H), 4.12-4.09 (m, 4H), 3.32-3.3 (m, 2H), 2.88-2.85 (m, 2H), 2.60-2.45 (m, 2H), 2.39 - 2.19 (m, 7H), 2.03 - 1.78 (m, 9H), 1.66 - 1.54 (m, 1H), 1.43-1.38 (m, 1H), 0.90-0.88 (m, 6H).

527

3-120. Préparation of (3S)-3-(2-(5-(2-(2-azaspiro[3.3jheptan-2-yI)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(27/)-yl)-4-niethyIpentanamido)-3-(4-fIuoro-2',4',5,6'-tetraniethyl-[l,rbiphenylJ-3-yl)propanoic acid (compounds JX-P1 and JX-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(2-azaspiro[3.3]heptan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(217)-yl)-4-methyIpentanamido)-3-(4-fluoro-2^,,4’,5,6’-tetramethyl-[l,l’-biphenylj-3-yl)propanoate

A mixture of 2-(5-(2-(2-azaspiro[3.3]heptan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2J7)-yl)-4methylpentanoic acid (250mg, 0.63 mmol), ethyl (5)-3-amino-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'biphenyl]-3-yl)propanoate (216 mg, 0.63 mmol), NMI (0.6 mL) and TCFH (213 mg, 0.76 mmol) in CHjCN (3 mL) was stirred at room température for 2 hours. The solvent was concentrated in vacuo and the residue was purified by prep-HPLC A (50-70% CH3CN) to provide ethyl (35)-3-(2-(5-(2-(2azaspiro[3.3]heptan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4fluoro-2',4’,5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoateas a white solid (280 mg). Yield 62% (ESI 726.2 (M+H]⁺).

Step 2: (35)-3-(2-(5-(2-(2-azaspiro[3.3]heptan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(217)y|)-4-methylpentanamido)-3-(4-fluoro-2’,4’,5,6’-tetramethyl-[l,l’-biphenyl]-3-yl)propanoic acid

Ethyl (35)-3-(2-(5-(2-(2-azaspiro[3.3]heptan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[ 1,1 ’-biphenyl]-3-yl)propanoate (280 mg, 0.39mmol) was treated with L1OH-H2O (33 mg, 0.78 mmol) in MeOH (3.0 mL) and H2O (1.0 mL) at room température for 2 hours. The reaction mixture was acidified to pH 5~6 with IN HCl. The solvent

528 was removed in vacuo and the residue was purified by prep-HPLC A (50-80% CHjCN) to give the diastereomeric products JX-P1 (57 mg) and JX-P2 (127 mg) as white solids.

JX-P1 ESI 698.3(M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 6.92 - 6.78 (m, 4H), 6.74 (s, 1H), 5.67 (t, J= 8.0 Hz, 1H), 5.59 (t, 7= 6.8 Hz, 1H), 4.02 - 3.87 (m, 4H), 3.27- 3.15 (m, 2H), 2.82 (t,7= 7.0 Hz, 2H), 2.68 (d,7= 6.8 Hz, 2H), 2.33 - 2.15 (m, 10H), 2.03 - 1.90 (m, 5H), 1.87 - 1.73 (m, 5H), 1.45 1.34 (m, 1H), 0.92 (t, 7= 6.2 Hz, 6H).

JX-P2 ESI 698.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.72 (s, 1H), 6.93 - 6.85 (m, 5H), 5.75 - 5.70 (m, 1H), 5.62 - 5.58 (m, 1H), 4.11 (s, 4H), 3.40 - 3.32 (m, 2H), 2.91 (d, 7= 16.0 Hz, 1H), 2.83 - 2.75 (m, 1H), 2.62 - 2.53 (m, 1H), 2.51 - 2.43 (m, 1H), 2.38 - 2.20 (m, 10H), 2.03 - 1.79 (m, 9H), 1.63 - 1.57 (m, 1H), 1.45 - 1.38 (m, 1H), 0.88 (d,7= 6.6 Hz, 6H).

3-121. Préparation of (3S)-3-(2-(5-(2-(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyI)pyridinl(2Z/)-yl)-4-fluo^ro-4-methyIpentanamido)-3-(4-fluoro-2',4',6’-trimethyl-5-(trifluoromethyl)-[l,l'biphenyl]-3-yl)propanoic acid (compounds JY-P1 and JY-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4fluoro-4-methylpentanamido)-3-(4-fluoro-2’,4’,6*-trimethyI-5-(trifluoromethyI)-il,l’-biphenyl]-3yl)propanoate

NMI .TCFH

A mixture of2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-fluoro-4methylpentanoic acid (270 mg, 0.74 mmol), ethyl (.S)-3-amino-3-(4-fluoro-2',4',6'-trimethyl-5(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (200 mg, 0.74 mmol), NMI (0.5 mL) and TCFH (294 mg, 1.11 mmol) in CHjCN (3 mL) was stirred at room température for 2 hours. The solvent was concentrated in vacuo and the residue purified by prep-HPLC A (50-80% CHjCN) to provide ethyl (3S)3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4-fluoro-4methylpentanamido)-3-(4-fluoro-2^,,4',6^,-trimethyl-5-(trifluoromethyl)-[ 1,1 ’-biphenyl]-3-yl)propanoate as a white solid (300 mg). Yield 55% (ESI 746.2 [M+H]⁺).

529

Step 2: (35)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2jfir)-yl)-4-iluoro4-methylpentanamido)-3-(4-fluoro-2’,4',6’-trimethyl-5-(trifluoromethyl)-[l,r-biphenyll-3yl)propanoic acid

Ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifIuoromethyl)pyridin-l(2H)-yl)-4-fluoro-4methylpentanamido)-3-(4-fluoro-2',4',6'-trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (300 mg, 0.40mmol) was treated with LiOH-H?O (34 mg, 0.80 mmol) in MeOH (3 mL) and H₂O (1.0 mL) at room température for 2 hours. The reaction mixture was acidifïed to pH 4-5 with IN HCl. The solvent was removed in vacuo and the residue purified by prep-HPLC A (50-80% CH3CN) to give the diastereomeric products JY-P1 (111 mg) and JY-P2 (102 mg) as white solids.

JY-P1 ESI 717.9(M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.95 (s, 1H), 7.35 - 7.20 (m, 2H), 6.90 (d, J= 13.6 Hz, 2H), 6.59 (s, 1H), 5.79 (s, 1H), 5.59 - 5.50 (m, 1H), 3.19 - 3.06 (m, 2H), 3.00 - 2.88 (m, 2H), 2.82 - 2.57 (m, 8H), 2.55 - 2.42 (m, 2H), 2.29 (s, 3H), 1.93 (s, 3H), 1.75 (s, 3H), 1.43 - 1.25 (m, 6H).

JY-P2 ESI 717.9 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.40 (d, J= 6.3 Hz, 1H), 7.31 (d, J = 6.4 Hz, 1H), 6.94 (s, 2H), 6.87 (s, 1H), 5.80 - 5.68 (m, 2H), 3.27 - 3.14 (m, 2H), 2.98 (t, J= 6.4 Hz, 2H), 2.84 (s, 6H), 2.65 - 2.48 (m, 3H), 2.30 (s, 3H), 2.25 - 2.12 (m, 1H), 1.95 (s, 6H), 1.37 -1.25 (m, 6H).

3-122. Préparation of (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trinuoromethyl)pyridinl(2/Z)-yl)-4-methylpentanamido)-3-(4-fluoro-2’,4’,6’-trimethyl-5-(trifluoromethyI)-[l,r-biphenylJ3-yl)propanoic acid (compounds JZ-P1 and JZ-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(triiluoromethyl)pyridin-l(2/7)-yl)-4methylpentanamido)-3-(4-fluoro-2’,4’,6’-trimethyl-5-(trifluoromethyl)-[l,l’-biphenyl]-3yl)propanoate

530

A mixture of ethyl (S)-3-amino-3-(4-fluoro-2',4’,6'-trimethyl-5-(triiluoromethyl)-[l,r-biphenyl]-3yl)propanoate (301 mg, 0.76 mmol), 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2/7)-yl)-4-methylpentanoic acid (240 mg, 0.69 mmol), TCHF (290 mg, 1.04 mmol) and NMI (226 mg, 2.76 mmol) in acetonitrile (10 mL) was stirred at room température for 2 hours. The mixture was purified by reverse phase HPLC on a C18 / 40g column (A: water 10 mM NH4HCO3, B: MeOH, 0~100%) to provide ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2A0-yl)-4methylpentanamido)-3-(4-fluoro-2',4',6’-trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (380 mg) as a white solid. Yield 75.6 % (ESI 728.1 (M+H)⁺).

Step 2: (35)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifIuoromethyl)pyridin-l(2Z7)-yI)-4methyIpentanamido)-3-(4-fluoro-2',4’,6'-trimethyl-5-(trifluoromethyI)-Il,l’-biphenyl]-3yl)propanoic acid

LiOH

Ethyl (3S)-3-(2-(5-(2-(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2fl)-yl)-4methylpentanamido)-3-(4-iluoro-2',4^,,6'-trimethyl-5-(trifluoromethyl)-[ 1,1 ’-biphenyl]-3-yl)propanoate (380 mg, 0.52 mmol) was treated with L1OH-H2O (88 mg, 2.1 mmol) in MeOH (5 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue purified by prep-HPLC A (30-60% CH3CN) to provide the diastereomeric products JZ-P1 (116 mg) and JZ-P2 (88 mg) as white solids.

JZ-P1 ESI 699.9 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.87 (s, 1H), 7.33 (d, J= 5.0 Hz, 1H), 7.25 (d, J= 8.0 Hz, 1H), 6.92 (s, 1H), 6.88 (s, 1H), 6.68 (s, 1H), 5.66 - 5.54 (m, 2H), 3.13 - 3.05 (m, 2H), 2.95

531

2.91 (m, 2H), 2.77 (s, 6H), 2.73 - 2.70 (m, 2H), 2.29 (s, 3H), 1.99 - 1.94 (m, 5H), 1.74 (s, 3H), 1.46 1.38 (m, 1H), 0.95 - 0.91 (m, 6H).

JZ-P2 ESI 699.9 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.38 (d, J = 4.9 Hz, 1H), 7.32 (d, J = 6.4 Hz, 1H), 6.94 (s, 2H), 6.87 (s, 1H), 5.73 - 5.69 (m, 1H), 5.60 (t, 7.7 Hz, 1H), 3.18 - 3.28 (m, 2H),

2.98 (t, J= 7.0 Hz, 2H), 2.83 (s, 6H), 2.68 - 2.52 (m, 2H), 2.30 (s, 3H), 2.00 - 1.93 (m, 7H), 1.74 - 1.67 (m, 1H), 1.40 - 1.33 (m, 1H), 0.88 - 0.86 (m, 6H).

3-123. Préparation of(35)-3-(4-fluoro-2’,4’,6’-trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)-3(4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4-(trinuoromethyl)pyridin-l(27/)yl)pentanamido)propanoic acid (compounds KA-P1 and KA-P2)

Step 1: ethyl (3S)-3-(4-fluoro-2’,4’,6’-trimethyI-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)-3-(4methyl-2-(5-(2-(3-methylazetidin-l-yI)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)yl)pentanamido)propanoate

TCFH.NMACN

A mixture of ethyl ethyl 4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2//)-yl)pentanoic acid (190.7 mg, 0.51 mmol), ethyl (S)-3-amino-3-(4-fluoro2',4’,6'-trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (202.5 mg, 0.51 mmol), TCFH (285.6 mg, 1.02 mmol) and NMI (167.3 mg, 2.04 mmol) in CH₃CN (10 mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue purified by silica gel column (DCM: MeOH 4:1) to provide ethyl (35)-3-(4-fluoro-2’,4',6'-trimethyl-5-(trifluoromethyl)-[l,rbiphenyl]-3-yl)-3-(4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(227)-yl)pentanamido)propanoate as a brown solid (250 mg). Yield 65% (ESI 754.3 (M+H)⁺).

Step 2:(3S)-3-(4-fluoro-2^,,4^,,6’-trimethyl-5-(triiluoromethyl)-[l,r-biphenyl]-3-yl)-3-(4-methyl-2-(5(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z7)-yl)pentanamido)propanoic acid

532

UOH-HjO

Ethyl (35)-3-(4-fluoro-2',4',6^,-trimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)-3-(4-methyl-2-(5-(2-(3methylazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)pentanamido)propanoate (250.0 mg, 0.33 mmol) ) was treated with LiOH-H₂O (54.6 mg, 1.3 mmol) in MeOH (4 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products KA-P1 (96 mg) and KA-P2 (87 mg) as white solids.

KA-P1 ESI 726.3(M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.41 - 7.31 (m, 1H), 7.32 - 7.17 (m, 1H), 6.91 (d, J= 11.7 Hz, 2H), 6.70 (s, 1H), 5.69 - 5.53 (m, 2H), 4.21 - 4.04 (m, 2H), 3.66 (t, J= 8.7 Hz, 2H), 2.98 - 2.79 (m, 3H), 2.77 - 2.63 (m, 2H), 2.29 (s, 3H), 2.06 - 1.89 (m, 5H), 1.78 (d, J= 11.5 Hz, 3H), 1.49-1.31 (m, 1H), 1.23 (d, J= 6.9 Hz, 3H), 0.98 - 0.81 (m, 6H).

KA-P2 ESI 726.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.46 - 7.36 (m, 1H), 7.36 - 7.23 (m, 1 H), 6.91 (d,7=27.6 Hz,3H), 5.83-5.73 (m, 1H), 5.61 (t,7=7.6 Hz, 1H),4.28-4.10 (m, 2H), 3.83 - 3.64 (m, 2H), 3.45 - 3.33 (m, 2H), 3.02 - 2.86 (m, 2H), 2.86 - 2.73 (m, 1H), 2.69 - 2.45 (m, 2H), 2.30 (s, 3H), 2.04 - 1.87 (m, 7H), 1.68 - 1.56 (m, 1H), 1.44 - 1.19 (m, 4H), 0.86 (d, J= 6.6 Hz, 6H).

3-124. Préparation of (S)-3-(4-fluoro-2’,5,6MrimethylbiphenyI-3-yI)-3-((S)-2-(5-(2-(3(fluoromethyl)azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid (compounds KB-P1 and KB-P2 )

Step 1 : (3S)-ethyI 3-(4-fluoro-2’,5,6’-trimethyIbiphenyI-3-yl)-3-(2-(5-(2-(3-(fluoromethyl)azetidin-l y|)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)-4-methylpentanamido)propanoate

533

A mixture of 2-(5-(2-(3-(fluoromethyl)azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid (180 mg, 0.46 mmol), (S)-ethyl 3-amino-3-(4-fluoro-2',5,6’-trimethylbiphenyl-3yl)propanoate (151 mg, 0.46 mmol), NMI (160 mg, 1.96 mmol) and TCFH (252 mg, 0.9 mmol) in CH3CN (5 mL) was stirred at room température for 1.5 hours. The solvent was removed in vacuo and the residue purified by silica gel column (DCM: MeOH 9:1) to provide (3S)-ethyl 3-(4-fluoro-2’,5,6*trimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-(fluoromethyl)azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate as a colorless oil (230 mg). Yield 71 % (ESI 704.3 [M+H]⁺).

Step 2:3-(4-fluoro-2’,5,6’-trimethyibiphenyI-3-yl)-3-((S)-2-(5-(2-(3-(nuoromethyl)azetidin-lyl)ethyI)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid

Ethyl 3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-(fluoromethyl)azetidin-l-yl)ethyl)-2-oxo4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (230 mg, 0.33 mmol) was treated with LiOH-H₂O (69 mg, 1.64 mmol) in EtOH (3 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue purified by prep-HPLC A (30-60% CHjCN) to provide diastereomeric products KB-P1 (50 mg) and KB-P2 (101 mg) as white solids.

KB-P1 ESI 676.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.82 (s, 1H), 7.07 -7.03 (m, 3H), 6.93 - 6.82 (m, 2H), 6.75 (s, 1H), 5.70 - 5.55 (m, 2H), 4.57 (d, J = 4.4 Hz, 1H), 4.45 (d, J = 4.1 Hz, 1H), 4.03 (t, J = 9.4 Hz, 2H), 3.82 - 3.67 (m, 2H), 3.13-3.10 (m, 3H), 2.80 (t, J = 7.0 Hz, 2H), 2.71 (d, J = 6.3 Hz, 2H), 2.28 (d, J = 1.6 Hz, 3H), 2.02-1.90 (m, 5H), 1.84 (s, 3H), 1.41-1.39 (m, 1H), 0.93-0.90 (m, 6H).

KB-P2 ESI 676.3 (M+H)T 1H NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.15 - 7.00 (m, 3H), 7.00 - 6.82 (m, 3H), 5.75 (m, 1H), 5.60 (t, J = 7.6 Hz, 1H), 4.60 (t, J = 7.3 Hz, 1H), 4.49 (t, J = 7.5 Hz, 1H), 4.25-4.22 (m,2H), 4.04-3.84 (m, 2H), 3.45 - 3.32 (m, 2H), 3.25-3.11 (m, 1 H), 2.92-2.90 (m, 1H), 2.84-2.74 (m, 1H), 2.63-2.60 (m, 1H), 2.50 -2.48 (m, 1H), 2.31 (d, J = 1.8 Hz, 3H), 2.04 - 1.84 (m, 7H), 1.64 -1.60 (m, 1H), 1.41-1.39 (m, 1H), 0.87 (d, J = 6.6 Hz, 6H).

534

3-125. Préparation of (3S)-3-(4’-cyclopropyI-4-fluoro-2^,,5,6’-trimethylbiphenyl-3-yI)-3-(2-(5-(2(diniethylamino)ethyl)-2-oxo-4-(trinuoromethyl)pyridin-l(2H)-yl)-4-methyIpentanamido)propanoic acid (compounds KC-P1 and KC-P2)

Step 1: (S)-ethyl 3-(5-bromo-2-fluoro-3-methyIphenyI)-3-((S)-2-(5-(2-(dimethylamino)ethyI)-2-oxo4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methyIpentanamido)propanoate

F TCFH. NMI. ACN

RT. 3hrs

A mixture of (S)-ethyl 3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propanoate (8.6 g, 28.0 mmol), 2(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoic acid (9.8 g, 28.0 mmol), TCFH (9.4 g, 34.0mmol) and NMI (6.9 g, 84.0 mmol) in MeCN (5mL) was stirred at room température for 3 hrs. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM:MeOH 97: 3) to provide (S)-ethyl 3-(5-bromo-2-fluoro-3-methylphenyl)-3-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoateasa white solid (12.2 g). Yield 68% (ESI 634.3 (M+H)⁺).

Step 2: (S)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)-4methyIpentanamido)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaboroIan-2yl)phenyl)propanoate

BjPiOj. Pd(dppf)CI₂. KOAc dioxane, 110 C, 2 tas

A mixture of (S)-ethyl 3-(5-bromo-2-fluoro-3-methylphenyI)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methyIpentanamido)propanoate (633 mg, 1.0 mmol) in dioxane (5 mL) was added B₂Pin₂(508 mg, 2.0 mmol), Pd(dppf)Cl₂ (73 mg, 0.1 mmol) and KOAc (294 mg, 3.0 mmol). The mixture was heated to 110°C for 2 hrs under nitrogen atmosphère. Water (20 mL) was added and the solution was extracted with EtOAc (20 mL«3). The combined organic phases were concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 2:1) to provide (S)-ethyl 3-(2(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(2

535 fluoro-3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (600 mg) as a dark solid. Yield 88 % (ESI 682.1 [M+H]+).

Step 3: (3S)-ethyl 3-(4'-cyclopropyl-4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)-3-(2-(5-(2(dimethylamino)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2II)-yl)-4methylpentanamido)propanoate

To a mixture of 2-bromo-5-cyclopropyl-l,3-dimethylbenzene (100 mg, 0.45 mmol), (3S)-ethyl 3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(2-fluoro-3methyI-5-(4,4,5,5-tetramethyl-l,3,2-dioxaboroIan-2-yl)phenyl)propanoate (300 mg, 0.45 mmol) in dioxane (10 mL) and H₂O (1 mL)was added Pd(dpp0Cl₂(37 mg, 0.05 mmol) and K₂COj (207 mg, 1.5 mmol). The mixture was heated to 110°C for 2 hrs under nitrogen atmosphère. Water (20 mL) was added and the solution was extracted with EtOAc (20 mL χ·3). The combined organic phases were concentrated in vacuo and the residue purified by silica gel column (pet ether: EtOAc 2:1) to provide (3S)-ethyl 3-(4’cyclopropyl-4-fluoro-2',5,6'-trimethyIbiphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (150 mg). Yield 48 % (ESI 700.1 (M+H]+).

Step 4: (3S)-3-(4'-cycIopropyl-4-fluoro-2',5,6’-trimethylbiphenyl-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)-yI)-4-methylpentanamido)propanoic

A mixture of (3S)-ethyl 3-(4'-cyclopropyl-4-fIuoro-2',5,6'-trimethylbiphenyl-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate in EtOH (3 mL) and H₂O (1 mL) was treated with LiOH-H₂O (42 mg, 1.0 mmol ) at room température for 30 mins. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products KC-P1 (39 mg) and KC-P2 (35 mg) as white solids.

536

KC-P1 ESI 672.1 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.90 (s, 1H), 6.84 (t, J = 5.9 Hz, 2H), 6.78 (s, 1H), 6.74 (d, J = 4.4 Hz, 2H), 5.68 (t, J = 8.1 Hz, 1H), 5.61 - 5.48 (m, 1H), 3.07 (d, J = 7.3 Hz, 2H), 2.94 (d, J = 7.0 Hz, 2H), 2.72 (d, J = 9.8 Hz, 8H), 2.27 (d, J = 1.3 Hz, 3H), 2.02 - 1.92 (m, 5H), 1.85-1.83 (m, 1H), 1.76 (s, 3H), 1.43-1.40 (m, 1H), 1.00 - 0.87 (m, 8H), 0.70 - 0.63 (m, 2H).

KC-P2 ESI 672.1 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.75 (d, J = 12.3 Hz, 1H), 6.79 (t, J = 6.1 Hz, 3H), 6.69 (s, 2H), 5.60 (d, J = 6.9 Hz, 1H), 5.51 (t, J = 7.6 Hz, 1H), 3.18 - 3.04 (m, 2H), 2.89 (t, J = 6.6 Hz, 2H), 2.71 (s, 6H), 2.48-2.45 (m, 2H), 2.21 (s, 3H), 1.87-1.85 (m, 7H), 1.76-1.73 (m, 1H), 1.58 - 1.55 (m, 1H), 1.32- 1.25 (m, 1H), 0.88-0.81 (m,2H), 0.81 -0.69 (m, 6H), 0.63-0.52(m,2H).

3-126. Préparation of (3S)-3-(2-(5-(2-(2-azaspiro[3.3jheptan-2-yl)ethyl)-2-oxo-4(trifluoromethyI)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fIuoro-2^,,6’-dimethyI-5(trifluoromethyl)-[l,r-biphenylj-3-yl)propanoic acid (KD-P1 and KD-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(2-azaspiro[3.3]heptan-2-yl)ethyl)-2-oxo-4-(trifIuoromethyl)pyridinl(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2’,6’-dimethyl-5-(trifluoromethyl)-[l,l’-biphenyl]-3yl)propanoate

TCFH. NMI. CH₃CN rt.2hr

A mixture of ethyl (S)-3-amino-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoate (220 mg, 0.57 mmol), 2-(5-(2-(2-azaspiro[3.3]heptan-2-yI)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoic acid (228 mg, 0.57 mmol), TCFH (319 mg, 1.14 mmol) and NMI (234 mg, 2.85 mmol) in CH₃CN (5 mL) was stirred at room température for 2 hours. The reaction was concentrated and purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: CH3OH, 0-80%) to provide ethyl (3S)-3-(2-(5-(2-(2-azaspiro[3.3]heptan-2-yl)ethyl)-2oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',6^,-dimethyl-5(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoate (290 mg). Yield 66.4 % (ESI 766.3 [M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(2-azaspiro[3.3] heptan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl) pyridin-l(2H)yl)-4-methylpentanamido)-3-(4-fluoro-2’,6’-dimethyl-5-(trinuoromethyl)-[l,r-biphenyl]-3yl)propanoic acid

537

Ethyl (3S)-3-(2-(5-(2-(2-azaspiro[3.3]heptan-2-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[ 1,1 '-biphenyl]-3-yl)propanoate (290 mg, 0.38 mmol) was treated with LiOH-H2O(48 mg, 1.14 mmol) in EtOH (4 mL) and H2O (1 mL) at room température for 30 min. LCMS showed that the reaction was completed. The reaction mixture was acidified to pH 5~6 with IN HCl. The solvent was removed in vacuo and the residue purified by prepHPLC A (35-63% CH3CN) to give the diastereomeric products KD-P1 (97 mg) and KD-P2 (114 mg) as white solids.

KD-P1 ESI 738.3 (M+H)⁺. *H NMR (400 MHz, MeOD) δ 7.82 (s, 1H), 7.39 (d, J= 5.1 Hz, 1H), 7.29 (d, J= 4.8 Hz, 1H), 7.20 - 7.04 (m, 3H), 6.73 (s, 1H), 5.68 - 5.59 (m, 2H), 4.01 (s, 4H), 3.29 - 3.16 (m, 2H), 2.83 (t, J= 7.0 Hz, 2H), 2.71 (d, J= 6.9 Hz, 2H), 2.25 (t, J= 7.7 Hz, 4H), 2.03 - 1.93 (m, 5H), 1.88 1.78 (m, 5H), 1.43-1.34 (m, 1H),O.93 (t,J=6.4 Hz, 6H).

KD-P2 ESI 738.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.44 (d, J= 5.5 Hz, 1H), 7.35 (d, J= 6.2 Hz, 1H), 7.23 - 7.08 (m, 3H), 6.87 (s, 1H), 5.82 - 5.73 (m, 1H), 5.62 (t, J= 7.6 Hz, 1H), 4.11 (s, 4H), 3.41 -3.315 (m, 2H), 2.90 (à,J= 16.4 Hz, 1H), 2.84-2.72 (m, 1H), 2.66-2.48 (m, 2H), 2.38-2.23 (m, 4H), 2.06 - 1.92 (m, 7H), 1.92-1.81 (m, 2H), 1.68 - 1.57 (m, 1H), 1.46 - 1.34(m, 1H), 0.93 - 0.84 (m, 6H)

3-127. Préparation of(3S)-3-(4-fluoro-2',6’-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)-3-(2 (5-(2-(3-(methoxymethyl)azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid (KE-P1 and KE-P2)

Step 1: ethyl (3S)-3-(4-iluoro-2’,6’-dimethyl-5-(trinuoromethyl)-[l,r-biphenyl]-3-yl)-3-(2-(5-(2-(3(methoxymethyl)azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoate

538

A mixture of ethyl (S)-3-amino-3-(4-fluoro-2',6^,-dimethyl-5-(trifluoromethyl)-[l,l'-biphenyl]-3yl)propanoate (200 mg, 0.52 mmol), 2-(5-(2-(3-(methoxymethyl)azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoic acid (210 mg, 0.52 mmol), TCFH (291 mg, 1.04 mmol) and NMI (213 mg, 2.6 mmol) in CHjCN (5 mL) was stirred at room température for 2 hours. The reaction was concentrated and purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: CH3OH, 0-85%) to provide ethyl (3S)-3-(4-iluoro-2’,6'-dimethyl-5-(trifluoromethyl)-[l,rbiphenyl]-3-yl)-3-(2-(5-(2-(3-(methoxymethyl)azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanamido)propanoate as a yellow solid (250 mg). Yield 62.4 % (ESI 770.3 [M+H]*).

Step 2: (3S)-3-(4-iluoro-2’,6’-dimethyI-5-(trifluoromethyl)-fl,l’-biphenyIJ-3-yI)-3-(2-(5-(2-(3 (methoxymethyl)azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid

Ethyl (3S)-3-(4-fluoro-2',6^,-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)-3-(2-(5-(2-(3(methoxymethyl)azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoate (250 mg, 0.32 mmol) was treated with L1OH-H2O (40 mg, 0.96 mmol) in EtOH (4 mL) and H₂O (1 mL) at room température for 2 hr. The reaction mixture was acidified to pH 5~6 with IN HCl. The solvent was removed in vacuo and the residue purified by prep-HPLC A (30-65% CH3CN) to give the diastereomeric products KE-P1 (91 mg) and KE-P2 (104 mg) as white solids.

KE-P1 ESI 742.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.82 (s, 1H), 7.39 (d, J= 5.0 Hz, 1H), 7.33 7.26 (m, 1H), 7.17 (t, J=7.5 Hz, 1H), 7.14-7.05 (m, 2H), 6.73 (s, 1H), 5.62 (t, J= 6.8 Hz, 2H), 4.194.04 (m, 2H), 3.95 - 3.81 (m, 2H), 3.46 (d, J= 4.1 Hz, 2H), 3.41 (s, 3H), 3.29 - 3.24 (m, 2H), 3.01 (s,

539

1H), 2.83 (t, J= 7.0 Hz, 2H), 2.75 - 2.66 (m, 2H), 2.03 - 1.94 (m, 5H), 1.84 (s, 3H), 1.43 - 1.35 (m, 1H), 0.98-0.85 (m, 6H).

KE-P2 ESI 742.3 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.51 - 7.28 (m, 2H), 7.3 - 7.01 (m, 3H), 6.88 (s, 1H), 5.90 - 5.71 (m, 1H), 5.61 (t, J= 7.6 Hz, 1H), 4.31 - 4.11 (m, 2H), 4.07 - 3.80 (m, 2H), 3.53 - 3.47 (m, 2H), 3.43 (s, 3H), 3.40 - 3.31 (m, 2H), 3.12 - 3.00 (m, 1H), 2.96 - 2.86 (m, 1H), 2.84 2.73 (m, 1H), 2.70 - 2.61 (m, 1H), 2.59 - 2.48 (m, 1H), 2.04 - 1.91 (m, 7H), 1.71 - 1.60 (m, 1H), 1.43 1.32 (m, 1H), 0.87 (d, J= 6.5 Hz, 6H).

3-128. Préparation of (3S)-3-(4-fluoro-2',5,6'-trimethyl-[l,l’-biphenyl]-3-yI)-3-(2-(5-(2-(3(methoxymethyl)azetidin-l-yI)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)-4methylpentanamido)propanoic acid (compounds KF-P1 and KF-P2)

Step 1: ethyl (S)-3-(4-fluoro-2^,,5,6’-trimethyl-[l,l’-biphenyI]-3-yI)-3-((S)-2-(5-(2-(3(methoxymethyI)azetidin-l-yl)ethyI)-2-oxo-4-(trifIuoromethyI)pyridin-l(2H)-yl)-4methylpentanamido)propanoate

A mixture of (S)-2-(5-(2-(3-(methoxymethyl)azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanoic acid (277.0 mg, 0.68 mmol), ethyl (S)-3-amino-3-(4-fluoro-2',5,6-trimethyl[l,l'-biphenyl]-3-yl)propanoate (230.0 mg, 0.70 mmol), TCHF (211.0 mg, 0.84 mmol) and NMI (115.0 mg, 1.4 mmol) in CHjCN (5 mL) was stirred at room température for 1.5 h. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH₄HCOj,B: MeOH, 0-100%) to provide ethyl (S)-3-(4-fluoro-2',5,6^,-trimethyl-[l,rbiphenyl]-3-yl)-3-((S)-2-(5-(2-(3-(methoxymethyl)azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanamido)propanoate (300 mg). Yield 61.2% (ESI 715.9 [M+H]*).

Step 2: (3S)-3-(4-fluoro-2^,,5,6’-trimethyI-ll,l’-biphenyI]-3-yI)-3-(2-(5-(2-(3(methoxymethyl)azetidin-l-yl)ethyl)-2-oxo-4-(trifiuoromethyl)pyridin-l(2H)-yl)-4540 methylpentanamido)propanoicacid

Ethyl (S)-3-(4-fluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-(methoxymethyl)azetidin-lyl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoate (300.0 mg, 0.42 mmol) was treated with LiOH-H₂O (88.0 mg, 2.1 mmol) in EtOH (4 mL) and water (2 mL) at 30 °C for 1 hour. The reaction mixture was acidified to pH 4-5 with 2N HCl. The solvent was removed in vacuo and the residue purified by purified by Prep HPLC A (30-80% MeCN) to give the diastereomeric product KF-P1 (66 mg) and KF-P2 (113 mg) as white solids.

KF-P1 ESI 688.3 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.81 (s, 1H), 7.13 - 6.98 (m, 3H), 6.87 (dd, J= 13.1, 6.8 Hz, 2H), 6.77 (s, 1H), 5.68 - 5.52 (m, 2H), 4.08 (t, J= 9.6 Hz, 2H), 3.84-3.77 (m, 2H), 3.49 3.37 (m, 5H), 3.26 (t, J = 7.2 Hz, 2H), 2.98 (m, 1 H), 2.83 (t, J = 6.8 Hz, 2H), 2.69 (d, J = 6.8 Hz, 2H), 2.28 (s, 3H), 2.03 - 1.90 (m, 5H), 1.85 (s, 3H), 1.45 - 1.33 (m, 1H), 0.94-0.89 (m, 6H).

KF-P2 ESI 688.3 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.72 (s, 1H), 7.13-7.05 (m, 3H), 6.98 - 6.83 (m, 3H), 5.75 (dd, J= 10.9,3.4 Hz, 1H), 5.59 (t, J= 7.6 Hz, 1H), 4.21 (dd, J= 17.0,7.5 Hz, 2H), 3.94 (dd, J = 23.0, 13.3 Hz, 2H), 3.50 (d, J=4.7 Hz, 2H), 3.47-3.35 (m, 5H), 3.07-3.05 (m, 1H), 2.91-2.89 (m, 1H), 2.82-2.80 (m, 1H),2.65-2.60(dd, J= 15.5,3.5Hz, 1H),2.49(dd,J= 15.5,11.0Hz, 1H),2.31 (s,3H), 2.00-1.93 (m, 7H), 1.67-1.60 (m, 1H), 1.43 - 1.33 (m, 1H), 0.88-0.86 (m, 6H).

3-129. Préparation of(3S)-3-(4-fluoro-2’,6’-dimethyI-5-(trifluoromethyI)-[l,r-biphenyl]-3-yl)-3-(4methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)pentanamido)propanoic acid (compounds KG-P1 and KG-P2)

Step 1: ethyl (3S)-3-(4-fluoro-2’,6’-dimethyl-5-(trinuoromethyl)-[l,r-biphenyI]-3-yl)-3-(4-methyl-2(5-(2-(3-methylazetidin-l-yl)ethyi)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)pentanamido)propanoate

541

A mixture of ethyl (S)-3-amino-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3yl)propanoate (250 mg, 0.65 mmol), 4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)pentanoic acid (243 mg, 0.65 mmol), TCFH (364 mg, 1.3 mmol) and

NMI (267 mg, 3.25 mmol) in CH3CN (5 mL) was stirred at 60 °C for 1.5 hours. The reaction mixture was purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: CH3CN, 0-100%) to provide ethyl (3S)-3-(4-fluoro-2',6-dimethyl-5-(trifluoromethyl)-[l,l'-biphenyl]-3-yl)-3-(4methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)pentanamido)propanoate as a yellow solid (300 mg). Yield 62.4 % (ESI 739.3 [M+H]⁺).

Step 2 : (3S)-3-(4-fluoro-2’,6'-dimethyl-5-(trifluoromethyl)-[l, 1 ’-biphenyl)-3-yl)-3-(4-methyl-2-(5-(2(3-methylazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)pentanamido)propanoic acid

Ethyl (3S)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)-3-(4-methyl-2-(5-(2-(315 methylazetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l (2H)-yl)pentanamido)propanoate(300 mg, 0.41 mmol) was treated with LiOH-HjO (52 mg, 1.23 mmol) in EtOH (4 mL) and H₂O (1 mL) at room température for 30 min. LCMS showed that the reaction was completed. The reaction mixture was acidified to pH 5-6 with IN HCl. The solvent was removed in vacuo and the residue purified by prepHPLC A (30-60% CHjCN) to give the diastereomeric products KG-P1 (88 mg) and KG-P2 (106 mg) as 20 white solids.

KG-P1 ESI 711.3 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.82 (s, 1H), 7.39 (d, J= 4.8 Hz, 1H), 7.29 (d, J= 4.9 Hz, 1H), 7.20 - 7.04 (m, 3H), 6.73 (s, 1H), 5.62 (t, J= 6.7 Hz, 2H), 4.14 (t, J= 9.1 Hz, 2H), 3.68

542 (t, J= 8.4 Hz, 2H), 3.295 - 3.25 (m, 2H), 2.96 - 2.87 (m, 1 H), 2.83 (t, J= 6.9 Hz, 2H), 2.75 - 2.66 (m, 2H), 2.03 - 1.92 (m, 5H), 1.85(s, 3H), 1.43 - 1.35 (m, 1H), 1.24 (d, J= 6.8 Hz, 3H), 0.9 - 0.88 (m, 6H).

KG-P2 ESI 711.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.44 (d, J= 6.4 Hz, 1H), 7.38 7.33 (m, 1H), 7.33-7.21 (m, 3H), 6.88 (s, 1H), 5.82-5.76 (m, 1H), 5.61 (t, J= 7.6 Hz, 1H), 4.21 (t, J= 9.4 Hz, 2H), 3.76 (t, J= 8.5 Hz, 2H), 3.45 - 3.33 (m, 2H), 3.00 - 2.86 (m, 2H), 2.83 - 2.74 (m, 1H), 2.69-2.47 (m, 2H), 2.04 - 1.90 (m, 7H), 1.69-1.59 (m, 1H), 1.43-1.33 (m, 1H), 1.28 (d, J= 6.9 Hz, 3H), 0.87 (d, J= 6.6 Hz, 6H).

3-130. Préparation of (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)yl)-4,4-dimethyIpentanamido)-3-(4-fluoro-2',5,6’-trimethyIbiphenyI-3-yl)propanoic acid (compounds KII-P1 and KH-P2)

Step 1 : (3S)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4,4dimethyIpentanamido)-3-(4-fluoro-2’,5,6’-trimethylbiphenyl-3-yI)propanoate

A mixture of 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(27/)-yl)-4,4dimethylpentanoic acid (300 mg, 0.80 mmol), (S)-ethyl 3-amino-3-(4-fluoro-2',5,6’-trimethylbiphenyl-3yl)propanoate (264 mg, 0.80 mmol), NMI (0.5 mL) and TCFH (336 mg, 1.20 mmol) in CHjCN (5 mL) was stirred at room température for 1 hour. The solvent was concentrated in vacuo and the residue purified by prep-HPLC A (30-90% CHjCN) to provide (3S)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo4-(trifluoromethyl)pyridin-l(2//)-yl)-4,4-dimethylpentanamido)-3-(4-fluoro-2',5,6^,-trimethylbiphenyl-3yl)propanoate as a white solid (250 mg). Yield 45% (ESI 686.3 [M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4,4dimethylpentanamido)-3-(4-fluoro-2’,5,6'-trimethylbiphenyl-3-yl)propanoic acid

543

(3S)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trinuoromethyl)pyridin-l(27f)-yl)-4,4dimethylpentanamido)-3-(4-fluoro-2’,5,6'-trimethylbiphenyl-3-yl)propanoate (250 mg, 0.36 mmol) was treated with LiOH-H₂O (76 mg, 1.80 mmol) in MeOH (5 mL) and H₂O (0.5 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue purified by prep-HPLC A (30-60% CH3CN) to give the diastereomeric products KH-P1 (72 mg) and KH-P2 (75 mg) as white solids.

KII-P1 ESI 658.3(M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.92 (s, 1 H), 7.17 - 7.00 (m, 3H), 6.86 (d, J= 6.9 Hz, 2H), 6.73 (s, 1H), 5.68 (s, 1H), 5.54 (t, J= 6.5 Hz, 1H), 4.02 (t, J= 8.1 Hz, 4H), 3.27 (t, J=7A Hz, 2H), 2.83 (t, J= 7.0 Hz, 2H), 2.70 (d, J= 6.5 Hz, 2H), 2.49 - 2.36 (m, 2H), 2.29 (d, J= 1.7 Hz, 3H), 2.23 - 2.10 (m, 1H), 2.03 - 1.95 (m, 4H), 1.86 (s, 3H), 0.90 (s, 9H).

KH-P2 ESI 658.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.75 (s, 1 H), 7.19 - 7.07 (m, 3H), 7.02 - 6.85 (m, 3H), 5.87 - 5.72 (m, 1H), 5.69 - 5.55 (m, 1H), 4.15 (s, 4H), 3.47 - 3.35 (m, 2H), 3.01 - 2.75 (m, 2H), 2.71 - 2.41 (m, 4H), 2.41 - 2.27 (m, 4H), 2.00 (d, J= 6.9 Hz, 6H), 1.49 (d, J= 13.2 Hz, 1H), 0.88 (s, 9H).

3-131. Préparation of (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifIuoromethyI)pyridinl(2//)-yl)-4,4-dimethyIpentanamido)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propanoic acid (compounds KI-P1 and KI-P2)

Step 1 : (3S)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(27/)-yl)-4,4dimethylpentanamido)-3-(4-fluoro-2^,,5,6’-trimethylbiphenyl-3-yl)propanoate

544

A mixture of 2-(5-(2-(dimethylamino)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4,4dimethylpentanoic acid (250 mg, 0.69 mmol), (S)-ethyl 3-amino-3-(4-fluoro-2’,5,6'-trimethylbiphenyl-3yl)propanoate (227 mg, 0.69 mmol), NMI (0.5 mL) and TCFH (291 mg, 1.04 mmol) in CHjCN (5 mL) was stirred at room température for 1 hour. The solvent was concentrated in vacuo and the residue purified by prep-HPLC A (30-90% CHjCN) to provide (3S)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-2oxo-4-(triiluoromethyl)pyridin-l(2H)-yl)-4,4-dimethylpentanamido)-3-(4-fluoro-2',5,6'trimethylbiphenyl-3-yl)propanoate as a white solid (200 mg). Yield 43% (ESI 674.2 [M+H]*).

Step 2: (3S)-3-(2-(5-(2-(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(27/)-yl)-4,4dimethylpentanamido)-3-(4-fluoro-2’,5,6’-trimethylbiphenyl-3-yl)propanoic acid

(3S)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4,4dimethylpentanamido)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propanoate (200 mg, 0.30 mmol) was treated with LiOH-H₂O (63 mg, 1.50 mmol) in MeOH (5 mL) and H₂O (0.5 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4-5 with IN HCl. The solvent was removed in vacuo and the residue purified by prep-HPLC A (30-60% CHjCN) to give the diastereomeric products KI-P1 (67 mg) and KI-P2 (62 mg) as white solids.

KI-P1 ESI 646.3(M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.97 (s, 1H), 7.15 - 6.98 (m, 3H), 6.84 (d, J= 7.1 Hz, 2H), 6.70 (s, 1H), 5.74 (s, 1H), 5.58 - 5.44 (m, 1H), 3.12 - 2.84 (m, 4H), 2.77 - 2.64 (m, 8H), 2.28 (d, J = 1.6 Hz, 3H), 2.20 - 2.11 (m, 1 H), 2.02 -1.90 (m, 4H), 1.79 (s, 3H), 0.91 (s, 9H).

KI-P2 ESI 646.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.87 (s, 1H), 7.19 - 7.04 (m, 3H), 7.00 - 6.85 (m, 3H), 5.73 (d, J= 10.3 Hz, 1H), 5.66 - 5.56 (m, 1H), 3.32 - 3.15 (m, 2H), 3.07 - 2.95 (m, 2H), 2.83 (s, 6H), 2.66 - 2.44 (m, 2H), 2.32 (d, J= 1.6 Hz, 3H), 2.30 - 2.23 (m, 1H), 1.99 (d, 7= 4.0 Hz, 6H), 1.65 1.51 (m, 1H), 0.86 (d, 7= 1.7 Hz, 9H).

545

3-132. Préparation of (3S)-3-(2-(5-(3-(dimethylainino)propyl)-2-oxo-4-(trinuoromethyl)pyridinl(2Æ)-yl)-4-methylpentanamido)-3-(4-fluoro-2’,4’,5,6'-tetramethyl-{l,l’-biphenyl|-3-yl)propanoic acid (compounds KJ-P1 and KJ-P2)

Step 1: ethyl (35)-3-(2-(5-(3-(dimethylamino)propyi)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methyIpentanamido)-3-(4-fluoro-2^,,4’,5,6’-tetramethyl-[l,l’-biphenylJ-3-yl)propanoate

O CIHHjN'

TCFH. NMI, CHjCN

A mixture of ethyl (S)-3-amino-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoate hydrochloride (239.3 mg, 0.63 mmol), 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridinl(2//)-yl)-4-methylpentanoic acid (230.0 mg, 0.63 mmol), TCHF (213.2 mg, 0.76 mmol) and NMI (206.9 mg, 2.52 mmol) in CHjCN (5 mL) was stirred at room température ovemight. The solvent was removed in vacuo and the residue purified by reverse phase HPLC on a C 18/40g column (A: water lOmM NH₄HCOj,B: MeOH, 0-100%) to provide ethyl (35)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4(trifluoromethyl)pyridÎn-l(2//)-yl)-4-methylpentanamido)-3-(4-fluoro-2*,4*,5,6'-tetramethyl-[l,l’biphenyl]-3-yl)propanoate as a light yellow solid (270.0 mg). Yield 62% (ESI 688.3 (M+H]⁺).

Step 2: (3S)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyI)pyridin-l(217)-yl)-4methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyI-[l,r-biphenyl]-3-yl)propanoic acid

LiOH-HjO.

EtOH/HjO

Ethyl (3S)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentanamido)-3-(4-fluoro-2',4',5,6^,-tetramethyl-[l,r-biphenyl]-3-yl)propanoate(270.0 mg, 0.39 mmol) was treated with L1OH-H2O (49.1 mg, 1.17 mmol) in EtOH (2 mL) and water (0.5 mL) at room température for 1 hour. The reaction mixture was acidified to PH 4-5 with 2N HCl. The solvent was

546 removed in vacuo and the residue purified by prep-HPLC A (30-80% MeCN) to give the diastereomeric products KJ-P1 (84 mg) and KJ-P2 (74 mg) as white solids.

KJ-P1 ESI 660.0 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.80 (s, 1H), 6.95 - 6.78 (m, 4H), 6.72 (s, IH), 5.75 - 5.69 (m, 1H), 5.58 (t, J= 6.8 Hz, 1H), 3.12 - 2.97 (m, 2H), 2.78 (s, 6H), 2.72 - 2.62 (m, 4H), 2.33 - 2.23 (m, 6H), 2.05 - 1.88 (m, 7H), 1.80 (s, 3H), 1.43 - 1.34 (m, 1H), 0.96 - 0.92 (m, 6H).

KJ-P2 ESI 660.0 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 6.93 - 6.86 (m, 4H), 6.84 (s, 1H), 5.77 - 5.72 (m, 1 H), 5.60 - 5.53 (m, 1H), 3.09 - 2.94 (m, 2H), 2.79 (s, 6H), 2.73 - 2.45 (m, 4H), 2.36 2.26 (m, 6H), 2.10-1.85 (m, 9H), 1.65-1.54 (m, 1H), 1.42-1.30 (m, 1H), 0.87-0.81 (m, 6H).

3-133. Préparation of (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)yl)-4-methylpentanamido)-3-(3',4-difluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid (compounds KK-P1 and KK-P2)

Step 1: ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methyIpentanamido)-3-(3’,4-difluoro-2’,4’,5,6’-tetramethyl-[l,r-biphenyI]-3-yl)propanoate

A mixture of2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifiuoromethyl)pyridin-l(2H)-yl)-4-methylpentanoic acid (230.0 mg, 0.64 mmol), ethyl (S)-3-amino-3-(3',4-difluoro-2’,4',5,6'-tetramethyl-[l,r-biphenyl]-3yl)propanoate hydrochloride (230.0 mg, 0.64 mmol), TCHF (214.0 mg, 0.76 mmol) and NMI (105.0 mg, 1.28 mmol) in CHjCN (5 mL) was stirred at room température for 2 hours. The solvent was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3.B: MeOH, 0-100%) to provideethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-1 (2H)-yl)-4-methylpentanamido)-3-(3^,,4-difluoro-2',4',5,6'-tetramethyl-[ 1,1'biphenyl]-3-yl)propanoate as a yellow solid (220 mg). Yield 50.1% (ESI 704.3 [M+H]⁺).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l (2H)-yl)-4methylpentanamido)-3-(3’,4-dinuoro-2',4',5,6^,-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid

547

Ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(3',4-difluoro-2',4',5,6'-tetramethyl-[l, 1 '-biphenyl]-3-yl)propanoate (220.0 mg, 0.31 mmol) was treated with LiOH-HjO (66.0 mg, 1.55 mmol) in EtOH (4 mL) and water (2 mL) at 30 °C for 1 hour. The reaction mixture was acidified to pH 4~5 with 2N HCl. The solvent was removed in vacuo and the residue purified by Prep HPLC A (30-80% MeCN) to give the diastereomeric products KK-P1 (85 mg) and KK-P2 (84 mg) as white solids.

KK-P1 ESI 676.1 (M+H)⁺ 'H NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 6.94-6.76 (m, 3H), 6.77 (d, J= 9.2 Hz, 1H), 5.68 - 5.54 (m, 2H), 4.07-4.02 (s, 4H), 3.28 (d, J = 6.7 Hz, 2H), 2.85 (t, J= 6.9 Hz, 2H), 2.712.68 (m„ 2H), 2.43 (m, 2H), 2.30 (s, 3H), 2.25 (s, 3H), 2.00 (t, J= 7.5 Hz, 2H), 1.95 - 1.88 (m, 3H), 1.80 (d, J= 16.8 Hz, 3H), 1.42-4.41 (m, 1H), 0.96-0.92 (m, 6H).

KK-P2 ESI 676.1 (M+H)⁺ 'H NMR (400 MHz, MeOD) δ 7.62 (s, 1H), 6.84-6.78 (m, 4H), 5.64 (dd, J= 10.8,3.3 Hz, 1H), 5.49 (t, J= 7.6 Hz, 1H), 4.04-3.99 (m, 4H), 3.31-3.21 (m, 2H), 2.84-2.69 (m, 2H), 2.55-2.50 (m, 1H), 2.44 - 2.29 (m, 3H), 2.22 (d, J= 1.7 Hz, 3H), 2.14 (d, J= 1.6 Hz, 3H), 1.91-1.78 (m, 7H), 1.60 - 1.49 (m, 1H), 1.37 - 1.22 (m, 1H), 0.80 - 0.73 (m, 6H).

3-134. Préparation of(3S)-3-(4-fluoro-3’-methoxy-2’,5,6’-trimethylbiphenyI-3-yl)-3-(4-methyl-2-(5(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4-(trinuoromethyl)pyridin-l(2H)-yl)pentanamido)propanoic acid (compounds KL-P1 and KL-P2 )

Step 1 : (3S)-ethyl 3-(4-fluoro-3’-methoxy-2’,5,6’-trimethylbiphenyI-3-yl)-3-(4-methyl-2-(5-(2-(3mcthylazetidin-l-yI)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)pentanamido)propanoate

548

A mixture of4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)pentanoic acid (170 mg, 0.45 mmol), (S)-ethyl 3-amino-3-(4-fluoro-3-methoxy-2',5,6trimethylbiphenyl-3-yl)propanoate (163 mg, 0.45 mmol), NMI (160 mg, 1.96 mmol) and TCFH (252 mg, 0.9 mmol) in CHjCN (5 mL) was stirred at room température for 1.5 hours. The solvent was concentrated in vacuo and the residue purified by silica gel column (DCM: MeOH 9:1) to provide (3S)-ethyl 3-(4fluoro-3-methoxy-2',5,6'-trimethylbiphenyl-3-yl)-3-(4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)pentanamido)propanoate as a yellow solid (220 mg). Yield 68 % (ESI 716.3 (M+H]⁺).

Step 2: (3S)-3-(4-fluoro-3’-methoxy-2’,5,6’-trimethyIbiphenyI-3-yI)-3-(4-methyl-2-(5-(2-(3methyIazetidin-l-yl)ethyI)-2-oxo-4-(trinuoromethyl)pyridin-l(2H)-yl)pentanamido)propanoic acid

O (3S)-ethyl 3-(4-fluoro-3'-methoxy-2',5,6^,-trimethylbiphenyl-3-yl)-3-(4-methyl-2-(5-(2-(3-methylazetidinl-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)pentanamido)propanoate (220 mg, 0.31 mmol) was treated with LiOH-HiO (64 mg, 1.53 mmol) in EtOH (3 mL) and HjO (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4-5 with IN HCl. The solvent was removed in vacuo and the residue purified by prep-HPLC A (30-80% CH₃CN) to give the diastereomeric products KL-P1 (73 mg) and KL-P2 (100 mg) as white solids.

KL-P1 ESI 688.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.84 (s, IH), 7.02 (t, J = 7.7 Hz, 1H), 6.92 6.67 (m, 4H), 5.73 - 5.51 (m, 2H), 4.18- 4.00 (m, 2H), 3.82 (s, 3H), 3.70 - 3.55 (m, 2H), 3.31 - 3.22 (m, 2H), 3.01 - 2.79 (m, 3H), 2.70 (d, J = 6.0 Hz, 2H), 2.32 (d, J = 25.7 Hz, 3H), 1.98 (t, J = 7.5 Hz, 2H), 1.82-1.80 (m, 6H), 1.49 - 1.37 (m, 1H), 1.24 (d, J = 6.9 Hz, 3H), 0.94-0.90 (m, 6H).

KL-P2 ESI 688.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.74 (s, 1H), 7.05 (d, J = 8.3 Hz, 1H), 7.00 6.84 (m, 3H), 6.83 (d, J = 8.4 Hz, 1H), 5.76-5.75 (m, 1H), 5.60 (t, J = 7.5 Hz, 1H), 4.21 (t, J = 9.3 Hz, 2H), 3.83 (d, J = 1.0 Hz, 3H), 3.80 - 3.67 (m, 2H), 3.46 - 3.35 (m, 2H), 3.04 - 2.86 (m, 2H), 2.85 - 2.74 (m, 1H), 2.71 - 2.59 (m, 1H), 2.50-2.48 (m, 1H), 2.33 (d, J = 1.7 Hz, 3H), 2.06 - 1.95 (m, 1H), 1.93 (d, J = 6.5 Hz, 3H), 1.85 (d, J = 5.3 Hz, 3H), 1.68 - 1.56 (m, 1H), 1.42-1.40 (m, 1H), 1.29 (d, J = 6.9 Hz, 3H), 0.89 (d, J = 6.6 Hz, 6H).

549

3-135. Préparation of (35)-3-(2-(5-(2-(33-dimethylazetidin-l-yI)ethyI)-2-oxo-4(trifluoromethyl)pyridin-l (27/)-yl)-4-met hylpentanamido)-3-(4-fluoro-2',5,6'-tri methyl-[ 1,1 ’biphenyl]-3-yl)propanoic acid (compounds KM-P1 and KM-P2)

Step 1: ethyl (35)-3-(2-(5-(2-(3,3-dimethylazetidin-l-y))ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2/7)-yl)-4-methylpentanamido)-3-(4-fluoro-2’,5,6’-trimethyI-[l,r-biphenylj-3-yl)propanoate

A mixture of ethyl (5)-3-amÎno-3-(4-fluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate (216.6 mg, 0.59 mmol), 2-(5-(2-(3,3-dimethylazetidin-1 -yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (27¥)-yl)-4methylpentanoic acid (230.0 mg, 0.59 mmol), TCHF (199.2 mg, 0.71 mmol) and NMI (145.3 mg, 1.77 mmol) in CHjCN (5 mL) was stirred at 40 °C for 1 hour. The solvent was removed in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3,B: MeOH, 0-100%) to provide ethyl (35)-3-(2-(5-(2-(3,3-dimethylazetidin-l-yl)ethyl)-2-oxo-4(tri fluoromethyl)pyridin-1 (2/7)-yD'4'^methylpentanamido)-3 -(4-fluoro-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3yl)propanoate as a light yellow solid (270.0 mg). Yield 65% (ESI 700.3 [M+H] ).

Step 2: (35)-3-(2-(5-(2-(33-dimethyIazetidin-l-yl)cthyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)-yl) 4-methylpentanamido)-3-(4-fluoro-2’,5,6’-trimethyl-[l,r-biphenyl]-3-yl)propanoic acid

LjQH-HgO^ EtOH-HjO

Ethyl (35)-3-(2-(5-(2-(3,3-dimethylazetidin-l-yl)ethyl)-2-oxo-4-(trifIuoromethyl)pyridin-l(2f/)-yl)-4methylpentanamido)-3-(4-fluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoate (270.0 mg, 0.39 mmol) was treated with L1OH-H2O (49.1 mg, 1.17 mmol) in EtOH (2 mL) and H₂O (0.5 mL) at room température for 1 hour. The reaction mixture was acidified to pH 4~5 with 2N HCl. The solvent was

550 removed in vacuo and the residue purified by prep-HPLC A (30-80% MeCN) to give the diastereomeric products KM-P1 (83 mg) and KM-P2 (96 mg) as white solids.

KM-P1 ESI 672.3 (M+H)⁺ 'H NMR (400 MHz, MeOD) δ 7.87 (s, 1H), 7.15 - 7.02 (m, 3H), 6.94 - 6.84 (m, 2H), 6.78 (s, 1H), 5.72 - 5.61 (m, 2H), 3.84 - 3.71 (m, 4H), 3.32 - 3.20 (m, 2H), 2.85 (t, J= 7.1 Hz, 2H), 2.78 - 2.66 (m, 2H), 2.29 (d, 7= 1.4 Hz, 3H), 2.04 - 1.94 (m, 5H), 1.85 (s, 3H), 1.45 - 1.38 (m, 1H), 1.34 (s, 6H), 0.94 (t, J= 6.6 Hz, 6H).

KM-P2 ESI 672.3 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.17 - 7.05 (m, 3H), 6.98 - 6.87 (m, 3H), 5.80 - 5.75 (m, 1H), 5.62 (t, J= Ί.6 Hz, 1H), 3.91 (s, 4H), 3.42 (t, J= 5.9 Hz, 2H), 3.00 - 2.74 (m, 2H), 2.66 - 2.46 (m, 2H), 2.33 (d, J= 1.7 Hz, 3H), 2.05 - 1.94 (m, 7H), 1.66 - 1.58 (m, 1H), 1.47 1.35 (m, 7H), 0.89 (d, J= 6.6 Hz, 6H).

3-136. Préparation of (3S)-3-(2-(5-(2-(dimethyIamino)ethyI)-2-oxo-4-(trinuoromethyl)pyridinl(2ZZ)-yl)-4-methyIpentanamido)-3-(4-nuoro-2'3’,5,6’-tetramethyI-[l,r-biphenyll-3-yl)propanoic acid (compounds KN-P1 and KN-P2)

Step 1: 2,3,6-trimethyIphenyl trifluoromethanesulfonate

Tf₂O, NEt_âDCM

OTf

A mixture of 2,3,6-trimethylphenol (5.0 g, 36.7 mmol) and triethylamine (11.1 g, 110.1 mmol) in DCM (100 mL) was cooled at 0 °C. Trifluoromethanesulfonic anhydride (15.5 g, 55.1 mmol) was added dropwise to the reaction mixture and the mixture was stirred at 0 °C for 3 hours. The mixture was quenched with a NH4CI aqueous solution (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous NajSCL. filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (pet ether) to provide 2,3,6-trimethylphenyl trifluoromethanesulfonate as a colourless oil (8.0 g). Yield 81 % (no Mass) Ή NMR (400 MHz, CDCb) δ 7.03 (dd, J= 19.3, 7.8 Hz, 2H), 2.35 (s, 3H), 2.27 (d, 7= 5.2 Hz, 6H).

Step 2: ethyl (35)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methyIpentanamido)-3-(4-nuoro-2’3',5,6’-tetramethyl-[l,r-biphenyIl-3-yl)propanoate

551

A mixture of ethyl (35)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methylpentanamido)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenyl)propanoate (250.0 mg, 0.37 mmol), 2,3,6-trimethylphenyl trifluoromethanesulfonate (119.1 mg, 0.44 mmol), CS2CO3 (361.6 mg, 1.11 mmol) and Pd(PPhj)₄ (42.7 mg, 0.037 mmol) in toluene (6 mL) and H2O (0.6 mL) was stirred at 110 °C under a nitrogen atmosphère for 20 hours. LCMS showed that the reaction was completed. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (EtOAc) to provide ethyl (35)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(27/)-yl)-4-methylpentanamido)-3-(4-fluoro2',3’,5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoate a light yellow oil (110 mg). Yield 45 % (ESI 674.3 (M+H)⁺)

Step 3: (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifiuoromethyl)pyridin-l(2//)-yl)-4methylpentanamido)-3-(4-fluoro-2'3’,5,6’-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid

Ethyl (35)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2A/)-yl)-4methylpentanamido)-3-(4-fluoro-2',3',5,6'-tetramethyl-[l,r-biphenyl]-3-yI)propanoate (110.0 mg, 0.16 mmol) was treated with LiOH-H₂O (35.6 mg, 0.80 mmol) in EtOH (2 mL) and water (0.5 mL) at room température for 1 hour. The reaction mixture was acidified to pH 4~5 with 2N HCl. The solvent was removed in vacuo and the residue purified by prep-HPLC A (30-80% MeCN) to provide the diastereomeric products KN-P1 (47 mg) and KN-P2 (39 mg) as white solids.

KN-P1 ESI 646.3 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.91 (d, J= 8.6 Hz, 1H), 7.02 (d, J= Ί.Ί Hz, 1H), 6.97 - 6.72 (m, 4H), 5.71 - 5.66 (m, 1H), 5.58 - 5.54 (m, 1H), 3.16 - 3.00 (m, 2H), 2.96 - 2.91 (m, 2H), 2.79-2.64 (m, 8H), 2.32-2.21 (m, 6H), 1.99-1.88 (m, 2H), 1.92 (d,J= 12.7 Hz, 3H), 1.74 (d, J= 9.6 Hz, 3H), 1.47 - 1.39 (m, 1H), 0.96 - 0.9 l(m, 6H).

552

KN-P2 ESI 646.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.88 (s, IH), 7.03 (d, J= 7.7 Hz, IH), 6.97 (d, J = 7.7 Hz, IH), 6.94 - 6.85 (m, 3H), 5.74 - 5.70 (m, IH), 5.62 (t, J= 7.7 Hz, IH), 3.28 - 3.16 (m, 2H), 3.03 - 2.95 (m, 2H), 2.82 (d, J= 4.2 Hz, 6H), 2.67 - 2.61 (m, IH), 2.56 - 2.49 (m, 1 H), 2.32 (d, J= 1.5 Hz, 3H), 2.27 (s, 3H), 2.03 - 1.84 (m, 7H), 1.74- 1.65 (m IH), 1.42- 1.35 (m, IH), 0.92- 0.82 (m, 6H).

3-137. Préparation of (35)-3-(4,4’-dinuoro-2’,5,6’-trimethylbiphenyl-3-yl)-3-(2-(5-(2(dimethyIamino)ethyl)-3-iluoro-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yI)-4methylpentanamido)propanoic acid (compounds KO-P1 and KO-P2)

Step 1 : (35)-ethyl 3-(4,4’-difluoro-2’,5,6'-trimethylbiphenyl-3-yl)-3-(2-(5-(2-(dimethyIamino)ethyl) 3-fluoro-2-oxo-4-(trifluoromethyl)pyridin-l(27/)-yl)-4-methylpentanamido)propanoate

A mixture of 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methylpentanoic acid (150 mg, 0.41 mmol), (5)-ethyl 3-amino-3-(4,4'-difluoro-2^,,5,6'-trimethylbiphenyl3-yl)propanoate (142 mg, 0.41 mmol), TCFH (230 mg, 0.82 mmol) and NMI (67 mg, 0.82 mmol) in CHjCN (6 mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue purified by silica gel column (DCM: MeOH 10:1) to provide (35)-ethyl 3-(4,4’-difluoro-2',5,6'trimethylbiphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxo-4-(trifluoromethyl)pyridinl(2/7)-yl)-4-methylpentanamido)propanoate as a yellow oil (120 mg). Yield 42% (ESI 696.1 (M+H)⁺).

Step 2: (35)-3-(4,4'-difluoro-2*,5,6’-trimethylbiphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-3fluoro-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4-methylpentanamido)propanoic acid

553 (3S)-ethyl 3-(4,4'-difluoro-2',5,6'-trimethylbiphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2oxo-4-(trifluoromethyl)pyridin-l(2fi)-yl)-4-methylpentanamido)propanoate (120 mg, 0.17 mmol) ) was treated with L1OH-H2O (36 mg, 0.85 mmol) in MeOH (4 mL) and H₂O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue purified by prep-HPLC A (30-60% MeCN) to provide the diastereomeric products KO-P1 (42 mg) and KO-P2 (47 mg) as white solids.

KO-P1 ESI 668.2(M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.71 (s, IH), 6.88 - 6.79 (m, 4H), 5.68 (t, J= 8.0 Hz, IH), 5.55 (t,7=6.8 Hz, IH), 3.09 (d,7= 7.2 Hz, 2H), 3.00 (d,7= 7.9 Hz, 2H), 2.81 -2.68(m, 8H), 2.29 (s, 3H), 1.98 (d, 7 = 10.1 Hz, 5H), 1.83 (s, 3H), 1.48 -1.41 (m, 1 H), 0.96 - 0.92 (m,, 6H).

KO-P2 ESI 668.2 (M+H)⁺ 'H NMR (400 MHz, MeOD) δ 7.66 (s, IH), 6.93 (t, 7= 7.5 Hz, 2H), 6.84 (d, 7 = 9.6 Hz, 2H), 5.74 - 5.70 (m, IH), 5.63 (t,7= 7.6 Hz, IH), 3.29 - 3.15 (m, 2H), 3.06 - 3.00 (m, 2H), 2.83 (d,7= 7.9 Hz, 6H), 2.67 - 2.59 (m, IH), 2.55 - 2.49 (m, IH), 2.32 (d, 7= 1.2 Hz, 3H), 2.08 - 1.96 (m, 7H), 1.76 - 1.66 (m, IH), 1.42 - 1.37 (m, IH), 0.90 - 0.85 (m, 6H).

3-138. Préparation of (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2A0 yl)-4-methy!pentanamido)-3-(4-nuoro-4’-methoxy-2’,5,6’-trimethylbiphenyl-3-yl)propanoic acid (compounds KP-P1 and KP-P2)

Step 1: (3S)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-4’-methoxy-2’,5,6’-trimethyIbiphenyI-3-yl)propanoate

A mixture of (S)-ethyl 3-amino-3-(4-fluoro-4'-methoxy-2',5,6'-trimethylbiphenyl-3-yl)propanoate (170 mg, 0.47 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanoic acid (169 mg, 0.47 mmol), TCFH (263 mg, 0.94 mmol) and NMI (241 mg, 2.94 mmol) in CH3CN (6 mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue purified by silica gel column (DCM: MeOH 10: 1) to provide (35)-ethyl 3-(2-(5-(2-(azetidin-lyl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2fl)-yI)-4-methylpentanamido)-3-(4-fluoro-4'-methoxy2',5,6^,-trimethylbiphenyl-3-yl)propanoate as a yellow oil (140 mg). Yield 42% (ESI 702.2 (M+H)⁺).

554

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2ÆF)-yl)-4methylpentanamido)-3-(4-nuoro-4’-methoxy-2’,5,6’-trimethylbiphenyl-3-yI)propanoic acid

(3S)-ethyl 3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-4'-methoxy-2',5,6'-trimethylbiphenyl-3-yl)propanoate (140 mg, 0.2 mmol) ) was treated with L1OH-H2O (42 mg, 1 mmol) in MeOH (4 mL) and H2O (1 mL) at room température for 2 hours. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue purified by prep-HPLC A (30-60% MeCN) to provide the diastereomeric products KP-P1 (48 mg) and KP-P2 (47 mg) as white solids.

KP-P1 ESI 674.2(M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.85 (s, 1H), 6.89 - 6.85 (m, 2H), 6.80 (s, 1H), 6.64 (d, J= 6.8 Hz, 2H), 5.67 - 5.57 (m, 2H), 4.05 - 4.00 (m, 4H), 3.79 (s, 3H), 3.29 (d, J= 6.6 Hz, 2H), 2.86 (t, J= 6.9 Hz, 2H), 2.77 - 2.65 (m, 2H), 2.53 - 2.38 (m, 2H), 2.29 (d, J= 1.3 Hz, 3H), 2.06 - 1.92 (m, 5H), 1.86 (s, 3H), 1.51 - 1.29 (m, 1H), 0.96 - 0.92 (m, 6H).

KP-P2 ESI 674.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.75 (s, 1H), 6.95 - 6.90 (m, 3H), 6.67 (s, 2H), 5.79 - 5.75 (m, 1H), 5.61 (t, J= 7.6 Hz, 1H), 4.14 (t, J= 8.0 Hz, 4H), 3.80 (s, 3H), 3.46 - 3.41(m, 1H), 3.39-3.34(m, 1H), 2.96-2.92(m, 1H), 2.84-2.81 (m, 1H), 2.67-2.63(m, 1H), 2.55-2.44 (m,3H), 2.32 (d, J= 1.4 Hz, 3H), 2.05 - 1.93 (m, 7H), 1.71 - 1.61 (m, 1H), 1.45 - 1.38 (m, 1H), 0.90-0.88 (m, 6H).

3-139. Préparation of (3S)-3-(3-cyclopropyl-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyI)pyridin-l(2£0-yl)propanamido)-3-(4-iluoro-2’,4’,5,6’-tetramethyl-[l,l’-biphenyl|3-yl)propanoic acid (compounds KQ-P1 and KQ-P2)

Step 1: ethyl (3S)-3-(3-cyclopropyl-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyI)pyridinl(2//)-yl)propanamido)-3-(4-fluoro-2',4’,5,6'-tetramethyl-(l,l'-biphenyl]-3-yl)propanoate

555

A mixture of ethyl (S)-3-amino-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoate (162.4 mg, 0.47 mmol), 3-cyclopropyl-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2jH)yl)propanoic acid (150.0 mg, 0.43 mmol), TCHF (144.8 mg, 0.52 mmol) and NMI (105.9 mg, 1.29 mmol) in CHjCN (5 mL) was stirred at room température for 1 hour. The solvent was removed in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NFLHCOj.B: MeOH, 0-100%) to provide ethyl (3S)-3-(3-cyclopropyI-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(217)-yl)propanamido)-3-(4-fluoro-2^l,4',5,6'-tetramethyl-[l,r-biphenyl]-3yl)propanoate as a yellow solid (120.0 mg). Yield 41.2% (ESI 672.3 [M+H]⁺).

Step 2: (3S)-3-(3-cyclopropyl-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trinuoromethyl)pyridinl(2Z7)-yl)propanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid

Ethyl (3S)-3-(3-cyclopropyl-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)yl)propanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoate (100.0 mg, 0.15 mmol) was treated with LiOH-HiO (18.9 mg, 0.45 mmol) in EtOH (2 mL) and water (0.5 mL) at room température for 0.5 hour. The reaction mixture was acidified to pH 6-7 with 2N HCl. The solvent was removed in vacuo and the residue purified by prep-HPLC A (30-80% MeCN) to provide the diastereomeric products KQ-P1 (22 mg) and KQ-P2 (20 mg) as white solids.

KQ-P1 ESI 644.2 (Μ+Η)⁺ Ή NMR (400 MHz, MeOD) δ 7.74 (s, 1H), 6.78 - 6.61 (m, 4H), 6.55 (s, 1H), 5.49 - 5.37 (m, 2H), 2.94 - 2.88 (m, 2H), 2.82 - 2.69 (m, 2H), 2.66 - 2.44 (m, 8H), 2.19 - 2.03 (m, 6H), 1.92 - 1.85 (m, 1H), 1.82 - 1.71 (m, 4H), 1.60 (s, 3H), 0.56 - 0.38 (m, 1H), 0.34 - 0.19 (m, 2H), 0.07 - 0.17 (m,2H).

KQ-P2 ESI 644.2 (M+H)⁺ Ή NMR (400 MHz, MeOD) δ 7.82 (s, 1H), 6.98 - 6.79 (m, 5H), 5.70 (dd, J= 10.3,4.1 Hz, 1H), 5.57 (t, J= 7.4 Hz, 1H), 3.27 - 3.15 (m, 2H), 2.96 (t, J= 6.9 Hz, 2H), 2.79 (s, 6H), 2.69 - 2.42 (m, 2H), 2.34 - 2.20 (m, 6H), 2.14 - 1.99 (m, 1H), 1.92 (d, J= 10.7 Hz, 6H), 1.67 - 1.49 (m, 1H), 0.55 (dd, J= 13.0,6.4 Hz, 1H), 0.57 - 0.53 (m, 2H), 0.08 - -0.16 (m, 2H).

556

3-140. Préparation of (3S)-3-(4-fluoro-2',4’,5,6’-tetramethylbiphenyl-3-yl)-3-(4-methyI-2-(5-(2-(3methylazetidin-l-yl)ethyl)-2-oxo-4-(trinuoromethyl)pyridin-l(2H)-yl)pentanamido)propanoic acid (compounds KR-P1 and KR-P2 )

Step 1: (3S)-ethyl 3-(4-fluoro-2’,4^,,5,6’-tetramethylbiphenyI-3-yl)-3-(4-methyI-2-(5-(2-(3methylazetidin-l-yl)ethyl)-2-oxo-4-(trinuoromethyI)pyridin-l(2H)-yl) pentanamido)propanoate

A mixture of 4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)pentanoic acid (240 mg, 0.58 mmol), (S)-ethyl 3-amino-3-(4-fluoro-2',4’,5,6’-tetramethylbiphenyl-3yl)propanoate (200 mg, 0.58 mmol), NMI (142 mg, 1.74 mmol) and TCFH (243 mg, 0.87 mmol) in CH3CN (10 mL) was stirred at 50°C for 1 hour. The solvent was concentrated in vacuo and the residue purified by silica gel column (DCM: MeOH 15:1) to provide (3S)-ethyl 3-(4-ί1υοΓθ-2',4^,,5,6'tetramethylbiphenyl-3-yl)-3-(4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)pentanamido)propanoate as a yellow oil (310 mg). Yield 75.7 % (ESI 700.3 [M+Hf).

Step 2: (3S)-3-(4-fluoro-2’,4',5,6^,-tetramethylbiphenyI-3-yl)-3-(4-methyl-2-(5-(2-(3-methylazetidin l-yl)ethyl)-2-oxo-4-(trifIuoromethyl)pyridin-l(2II)-yI) pentanamido) propanoic acid

(3S)-ethyl 3-(4-fluoro-2’,4',5,6^,-tetramethylbiphenyl-3-yI)-3-(4-methyl-2-(5-(2-(3-methyIazetidin-lyl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl) pentanamido)propanoate (310 mg, 0.44 mmol) was treated with LiOH-H₂O (56 mg, 1.33 mmol) in EtOH (2 mL) and H₂O (1 mL) at room température for 30

557 mins. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue purified by prep-HPLC A (30-70% CHjCN) to provide the diastereomeric products KR-P1 (60 mg) and KR-P2 (118 mg) as white solids.

KR-P1 ESI 672.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.85 (s, 1H), 6.86 - 6.82 (m, 4H), 6.75 (s, 1H), 5.66 - 5.64 (m, 1H), 5.61 - 5.53 (m, 1H), 4.14-4.01 (m, 2H), 3.63 - 3.59 (m, 2H), 3.30 - 3.20 (m, 2H), 2.89-2.82 (m, 3H), 2.73 - 2.64 (m, 2H), 2.29 (s, 6H), 2.01 - 1.90 (m, 5H), 1.81 (s, 3H), 1.49- 1.36 (m, 1H), 1.24 (d, J= 6.9 Hz, 3H), 0.94 (t, J= 7.2 Hz, 6H).

KR-P2 ESI 672.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.76 (s, 1H), 6.98 - 6.83 (m, 5H), 5.78 - 5.76 (m, 1H), 5.61 - 5.59 (m, 1H), 4.24 - 4.21 (m, 2H), 3.75 - 3.70 (m, 2H), 3.47 - 3.33 (m, 2H), 3.01 - 2.85 (m, 2H), 2.88 - 2.73 (m, 1H), 2.65 - 2.61 (m, 1H), 2.58 - 2.44 (m, 1H), 2.33 - 2.22 (m, 6H), 2.01 - 1.86 (m, 7H), 1.60- 1.55 (m, 1H), 1.45 - 1.34 (m, 1H), 1.29 (d, J= 6.9 Hz, 3H), 0.85-0.80 (m, 6H).

3-141. Préparation of (3S)-3-(4-fluoro-2’,5,6’-trimethylbiphenyI-3-yl)-3-(4-methyI-2-(5-(2-(3methylazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)-yl)pentanamido)propanoic acid (compounds KS-P1 and KS-P2 )

Step 1 : (3S)-ethyl 3-(4-fluoro-2^,,5,6’-trimethylbiphenyl-3-yI)-3-(4-methyl-2-(5-(2-(3-methyIazetidinl-yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)pentanamido)propanoate

A mixture of4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)pentanoic acid (250 mg, 0.61 mmol), ethyl (S)-3-amino-3-(4-fluoro-4’-methoxy-2',5,6'-trimethyl-[l,l'biphenyl]-3-yl)propanoate (201 mg, 0.61 mmol), NMI (150 mg, 1.83 mmol) and TCFH (256 mg, 0.91 mmol) in CHjCN (10 mL) was stirred at 50°C for 1 hour. The solvent was concentrated in vacuo and the residue purified by silica gel column (DCM: MeOH 10:1) to providet (3S)-ethyl 3-(4-fluoro-2',5,6trimethylbiphenyl-3-yl)-3-(4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)-2-oxo-4558 (trifluoromethyl)pyridin-l(2H)-yl)pentanamido)propanoate as a yellow oil (320 mg). Yield 76.6 % (ESI 686.2 [M+H]⁺).

Step 2: (3S)-3-(4-fluoro-2’,5,6’-trimethylbiphenyl-3-yl)-3-(4-methyI-2-(5-(2-(3-methylazetidin-lyI)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)pentanamido)propanoicacid

(3S)-ethyl 3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)-3-(4-methyl-2-(5-(2-(3-methylazetidin-l-yl)ethyl)2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)pentanamido)propanoate (320 mg, 0.47 mmol) was treated with LiOH-H₂O (59 mg, 1.41 mmol) in EtOH (2 mL) and H₂O (1 mL) at room température for 30 mins. The reaction mixture was acidified to pH 4~5 with IN HCl. The solvent was removed in vacuo and the residue purified by prep-HPLC A (30-60% CH3CN) to provide the diastereomeric products KS-P1 (75 mg) and KS-P2 (132 mg) as white solids.

KS-P1 ESI 658.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.86 (s, 1H), 7.15 - 6.99 (m, 3H), 6.94 - 6.81 (m, 3H), 6.76 (s, 1H), 5.61 - 5.63 (m, 2H), 4.07 -4.09 (m, 2H), 3.60 - 3.62 (m, 2H), 3.22 - 3.24 (m, 2H), 2.94 - 2.76 (m, 3H), 2.72 - 2.62 (m, 2H), 2.28 - 2.29 (m, 2H ), 2.03 - 1.93 (m, 5H), 1.85 (s, 3H), 1.41 1.42 ( m, 1H), 1.24 (d, J= 6.9 Hz, 3H), 0.97 - 0.88 (m, 6H).

KS-P2 ESI 658.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.76 (s, 1H), 7.11 - 7.09 (m, 3H), 6.98 - 6.81 (m, 3H),5.77-5.75 (m, 1H), 5.61 (t,7=7.6 Hz, 1H),4.21-4.18 (m,2H),3.75-3.72(m,2H),3.443.34 (m, 2H), 3.05 - 2.85 (m, 2H), 2.85-2.71 (m, 1H), 2.65-2.63 (m, 1H), 2.52-2.50 (m, 1H), 2.33 (d, 7= 1.4 Hz, 3H), 2.03 - 1.90 (m, 7H), 1.65 - 1.59 (m, 1H), 1.43 - 1.38 (m, 1H), 1.29 (d,7= 6.9 Hz, 3H), 0.89-0.82 (m,6H).

3-142. Préparation of (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridinl(2H)-yl)-4-methylpentanamido)-3-(2,4,4’-trifluoro-2’,3’,6’-triniethyl-5-(trifluoromethyl)[l,l’-biphenyl]-3-yl)propanoic acid (compounds KT-P1 and KT-P2)

559

Step 1: ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yl)-4-methylpentanamido)-3-(2,4,4’-trifluoro-2’,3*,6’-trimethyl-5-(trifluoromethyl)-[l,l’biphenyl]-3-yl)propanoate

A mixture of ethyl (3S)-3-amino-3-(2,4,4'-trifluoro-2',3',6^,-trimethyl-5-(trifluoromethyl)-[l,rbiphenyl]-3-yl)propanoate (140 mg, 0.32 mmol), 2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanoic acid (116 mg, 0.32 mmol), TCFH (179 mg, 0.64 mmol) and NMI (131 mg, 1.6 mmol) in CHjCN (5 mL) was stirred at room température for 2 hours. The solvent was removed in vacuo and the residue purified by reverse phase HPLC on a C18/40g column (A: water lOmM NH4HCO3, B: CH3OH, 0-85%) to provide ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4,4^,-trifluoro-2',3',6’-trimethyl-5-(trifluoromethyl)-[ 1,1 -biphenyl]-3yl)propanoate as a yellow solid (140 mg). Yield 56.4 % (ESI 776.3 [M+H]*).

Step 2: (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifIuoromethyl)pyridin-l(2H)-yl)-4methylpentanamidoI-S-iZ^d’-trifluoro^’^’^’-trlmethyl-S-Grifluoromethyl)-!!,!’biphenyl]-3-yl)propanoic acid

Ethyl (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(2,4,4'-trifluoro-2',3',6'-trimethyl-5-(trifluoromethyl)-[ 1,1 ’-biphenyl]-3

560 yl)propanoate (140 mg, 0.18 mmol) was treated with L1OH-H2O (22 mg, 0.54 mmol) in EtOH (4 mL) and H2O (1 mL) at room température for 2 hrs. The reaction mixture was acidified to pH 5-6 with IN HCl. The solvent was removed in vacuo and the residue purified by prep-HPLC A (30-65% CH3CN) to provide the diastereomeric products KT-P1 (24 mg) and KT-P2 (30 mg) as white solids.

KT-P1 ESI 748.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.81 (s, 1H), 7.39 (m, 7= 7.5 Hz, 1H), 6.99- 6.80 (m, 2H), 5.71 (m, J= 9.2,5.9 Hz, 2H), 4.12 (m, J= 8.1 Hz,4H), 3.42-3.30 (m, 2H), 2.99 - 2.71 (m, 4H), 2.52 - 2.35 (m, 2H), 2.18 (s, 3H), 2.09 - 1.93 (m, 5H), 1.86 (s, 3H), 1.45 - 1.32 (m, 1H), 0.94 (m, J= 6.9 Hz, 6H).

KT-P2 ESI 748.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.72 (s, 1H), 7.44 (m, J= 7.6 Hz, 1H), 7.00 - 6.77 (m, 2H), 5.90 (d, J= 8.1 Hz, 1H), 5.63 (m, J= 7.7 Hz, 1H), 4.12 (m, J = 8.1 Hz, 4H), 3.39 (m, J= 19.1,13.7 Hz, 2H), 2.86 (m, 7= 14.4, 13.3 Hz, 3H), 2.60 (m, 7= 15.6,4.2 Hz, 1H), 2.45 (m,7=8.1 Hz, 2H), 2.20 (s, 3H), 1.94 (m, 7= 21.4,9.3,4.8 Hz,7H), 1.72 (m,J= 14.4, 7.3 Hz, 1H), 1.33 (m, 7= 13.4, 6.7 Hz, 1H), 0.88 (m, 7= 10.6,6.6 Hz, 6H).

Example 4: Characterization of examplary compounds of the invention

The following compounds were synthesized using procedures similar to the ones used in example 3.

4-1. (35)-3-(4,5-difluoro-2',6'-dimethylbiphenyI-3-yl)-3-(2-(5-(((Æ)-3-fluoropyrrolidin-lyl)methyl)-2-oxopyridin-l (2/7)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds BB-P1 and BB-P2)

BB-P1 ESI 598.2 (M+H)⁺. ‘H NMR (500 MHz, MeOD) δ 7.74 (d, 7= 2.1 Hz, 1H), 7.53 - 7.42 (m, 1H), 7.16 - 7.00 (m, 3H), 6.93 - 6.80 (m, 2H), 6.42 (d, 7= 9.3 Hz, 1H), 5.71 (t, 7= 8.1 Hz, 1H), 5.55 (t,7=7.1 Hz, 1H), 5.34-5.13 (m, 1H), 3.80-3.61 (m, 2H), 3.17-2.93 (m, 3H), 2.83

561

-2.63 (m, 3H), 2.33-2.16 (m, 1H), 2.16-2.02 (m, 1H), 1.98 (s, 3H), 1.92 (t,J= 7.6 Hz, 2H), 1.83 (s, 3H), 1.47-1.33 (m, 1H), 0.99-0.87 (m, 6H).

BB-P2 ESI 598.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.69 (d, J= 2.2 Hz, 1H), 7.62 - 7.51 (m, 1 H), 7.16 - 7.01 (m, 3H), 6.99 - 6.84 (m, 2H), 6.54 (d, J = 9.3 Hz, 1 H), 5.80 - 5.69 (m, 1 H), 5.51-5.45 (m, 1H), 5.33 (d, J= 54.4 Hz, 1H), 4.18 (d, J= 13.2 Hz, 1H), 3.83 (d, J= 13.2 Hz, 1H), 3.55 - 3.31 (m, 4H), 2.73 - 2.64 (m, 1H), 2.58 - 2.46 (m, 1H), 2.42 - 2.18 (m, 2H), 2.03 1.86 (m, 7H), 1.58 - 1.36 (m, 2H), 0.84 (s, 6H).

4-2. (35)-3-(4,5-difluoro-2',6'-dÎniethylbiphenyl-3-yl)-3-(2-(5-(2-((Æ)-3-fluoropyrrolidinl-yl)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds BC-P1 and BC-P2)

OH

BC-P1 ESI 612.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.63 (s, 1H), 7.45 (d, J= 9.3 Hz, 1H), 7.22 - 7.04 (m, 3H), 6.98 - 6.87 (m, 1H), 6.80 (d, J= 5.1 Hz, 1H), 6.43 (d, J= 9.3 Hz, 1H), 5.68 - 5.57 (m, 1H), 5.50 (d, J= 5.7 Hz, 1H), 5.29 (d, J= 53.5 Hz, 1H), 3.48 - 3.33 (m, 1H), 3.31 3.02 (m, 5H), 2.83 - 2.57 (m, 4H), 2.42 - 2.10 (m, 2H), 2.05 - 1.81 (m, 8H), 1.51-1.35 (m, 1H), 0.98-0.79 (m, 6H).

BC-P2 ESI 612.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.61 (s, 1H), 7.47 (d, J= 9.3 Hz, 1H), 7.19 - 7.00 (m, 3H), 6.97 - 6.90 (m, 1H), 6.86 (d, J= 4.7 Hz, 1H), 6.51 (d, J= 9.2 Hz, 1H), 5.66 - 5.52 (m, 2H), 5.36 (s, 1H), 3.66-3.32 (m, 5H), 3.16 (s, 1H), 2.83 (s, 2H), 2.63 — 2.42 (m, 2H), 2.30 (d, 29.3 Hz, 2H), 2.05 - 1.85 (m, 8H), 1.45 - 1.30 (m, 1H), 0.88 (t, J= 6.1 Hz,

6H).

4-3. (35)-3-(4,5-difluoro-2*-methyI-6’-(trifluoromethyI)-[l,l’-biphenyl]-3-yl)-3-(2-(5-(2(dimcthylamino)ethyl)-4-methyl-2-oxopyridin-l(27/)-yl)-4-methyIpentanamido)propanoic acid (diastereomeric compounds BD-P1 and BD-P2)

562

BD-P1 ESI 636.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.65 - 7.46 (m, 4H), 7.03 - 6.87 (m, 2H), 6.30 (d, J= 21.6 Hz, 1H), 5.55-5.52 (m, 2H), 3.18 - 3.02 (m, 2H), 2.88-2.84 (m, 2H), 2.78 (s, 3H)), 2.75(S,3H), 2.67-2.64 (m, 2H), 2.25 (s, 3H), 2.06 (s, 2H), 1.97 - 1.85 (m, 3H), 1.45 5 1.35 (m, 1H), 0.94-0.90 (m, 6H).

BD-P2 ESI 636.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.67 - 7.44 (m, 4H), 7.08 - 6.91 (m, 2H), 6.42 (d, J= 20.9 Hz, 1H), 5.70 - 5.51 (m, 2H), 3.32 - 3.23 (m, 1H), 3.20-3.18 (m, 1H), 2.99 - 2.74 (m, 8H), 2.64-2.59 (m, 1H), 2.52-2.47 (m, 1H), 2.28-2.26 (d, J = 10.0 Hz, 3H), 2.07-2.06 (d, J= 6.6 Hz, 3H), 2.00 - 1.88 (m, 1 H), 1.81 - 1.65 (m, 1H), 1.43 - 1.32 (m, 1H), 0.90-0.87 (m,

6H).

4-4. (35)-3-(4-fluoro-2’,5,6’-trimethyIbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-lyl)ethyI)-2-oxopyridin-l (2Z7)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds BE-P1 and BE-P2)

BE-P1 ESI 594.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.52 (d, J= 2.1 Hz, 1H), 7.47 - 7.39 (m, 1H), 7.19 - 7.02 (m, 3H), 6.89 (d, J= 5.6 Hz, 1H), 6.83 - 6.73 (m, 1H), 6.48 (d, J= 9.3 Hz, 1H), 5.69 - 5.57 (m, 1H), 5.54 - 5.43 (m, 1H), 5.33 - 5.09 (m, 1H), 4.20 - 4.06 (m, IH), 4.03

563

3.87 (m, IH), 3.78 - 3.63 (m, 2H), 3.27 - 3.06 (m, 2H), 2.77 - 2.53 (m, 4H), 2.31 (d, J= 1.3 Hz, 3H), 2.03 - 1.85 (m, 8H), 1.58 - 1.34 (m, 1H), 1.03-0.84 (m, 6H).

BE-P2 ESI 594.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.57 - 7.41 (m, 2H), 7.23 - 7.05 (m, 3H), 6.92 (d, J= 6.9 Hz, 2H), 6.56 (d, J= 9.3 Hz, 1H), 5.67 - 5.57 (m, 2H), 5.46 - 5.17 (m, 1H), 4.50 - 4.24 (m, 2H), 4.08 - 3.89 (m, 2H), 3.42 - 3.35 (m, 2H), 2.86 - 2.60 (m, 3H), 2.57 - 2.45 (m, 1H), 2.33 (s, 3H), 2.05 - 1.91 (m, 7H), 1.86 - 1.71 (m, 1H), 1.48 - 1.32 (m, 1H), 0.91 (t, J= 6.3 Hz, 6H).

4-5. (35)-3-(5-chloro-4-fluoro-2*,6’-dimethyl-[l,r-biphenylJ-3-yl)-3-(2-(3-fluoro-5-(2-(3fluoroazetidin-l-yl)ethyI)-2-oxopyridin-l(2jH)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds BD2-P1 and BD2-P2)

BD2-P1 ESI 632.1 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.69 - 7.28 (m, 2H), 7.23 - 7.05 (m, 4H), 6.97 (dd, J= 6.3,1.9 Hz, 1H), 5.69 (dd, J= 9.4,6.8 Hz, 1H), 5.52 (t, J= 6.4 Hz, 1H), 5.25 (dt, J= 57.2,4.2 Hz, 1H), 4.15 (dt, J= 44.5,9.1 Hz, 2H), 3.96 - 3.70 (m, 2H), 3.23 (dt, J= 11.3, 5.6 Hz, 2H), 2.94 - 2.45 (m, 4H), 2.13 - 1.80 (m, 8H), 1.59 - 1.25 (m, 1H), 1.15 - 0.78 (m, 6H).

BD2-P2 ESI 632.1 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.54 - 7.27 (m, 2H), 7.14 (dt, J= 12.8, 6.1 Hz, 5H), 5.87 - 5.52 (m, 2H), 5.30 (dt, J= 57.3,4.4 Hz, 1H), 4.43 - 4.14 (m, 2H), 4.06 - 3.75 (m, 2H), 3.33 - 3.25 (m, 2H), 2.87 - 2.40 (m, 4H), 2.17-1.85 (m, 7H), 1.88 - 1.67 (m, 1H), 1.50- 1.22 (m, 1H), 0.91 (d, J= 6.6 Hz, 6H).

4-6. (3S)-3-(5-chIoro-4-fluoro-2’,6’-dimethyl-[l,r-biphenyI]-3-yl)-3-(2-(3-fluoro-5-(2((7?)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxopyridin-l(2//)-yl)-4-mcthylpentanamido)propanoic acid (diastereomeric compounds BE2-P1 and BE2-P2)

564

BE2-P1 ESI 646.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.51 (s, 1H), 7.37 (d, J= 10.2 Hz, 1H), 7.16 - 7.08 (m, 4H), 6.98 - 6.97 (m, 1H), 5.71 - 5.67 (m, 1H), 5.52 - 5.49 (m, 1H), 5.35 5.21 (m, 1H), 3.41 - 3.12 (m, 6H), 2.81 - 2.69 (m, 4H), 2.37 - 2.20 (m, 2H), 2.05 - 1.88 (m, 8H), 1.44 - 1.40 (m, 1H), 0.96 - 0.92 (m, 6H).

BE2-P2 ESI 646.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.51 (s, 1H), 7.40 (d, J= 10.2 Hz, 1 H), 7.18 - 7.06 (m, 5H), 5.70 - 5.58 (m, 2H), 5.41 - 5.27 (m, 1H), 3.67 - 3.21 (m, 6H), 2.88 2.83 (m, 2H), 2.60 - 2.53 (m, 2H), 2.39 - 2.27 (m, 2H), 1.97 - 1.83 (m, 7H), 1.83 - 1.76 (m, 1H), 1.40 - 1.35 (m, 1H), 0.91 - 0.89 (m, 6H).

4-7. (35)-3-(5-chloro-4-fluoro-2',6’-diinethyl-|l,l'-biphenyI]-3-yl)-3-(2-(5-(2(diinethylaniino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(21¥)-yl)-4methylpentanamido)propanoic acid (diastereomeric compounds BF-P1 and BF-P2)

BF-P1 ESI 652.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.91 (s, 1H), 7.11- 7.03 (m, 5H), 6.75 (s, 1H), 5.82 - 5.62 (m, 1H), 5.62 - 5.46 (m, 1H), 3.21 - 2.89 (m, 4H), 2.83 (s, 6H), 2.77 - 2.72 (m, 2H), 2.05 - 1.89 (m, 5H), 1.83 (s, 3H), 1.46 - 1.40 (m, 1H), 0.98 - 0.93 (m, 6H).

BF-P2 ESI 652.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.91 (s, 1H), 7.24 - 7.04 (m, 5H), 6.89 (s, 1H), 5.75 - 5.70 (m, 1H), 5.66 - 5.62 (m, 1H), 3.29 - 3.21 (m, 2H), 3.09 - 2.98(m, 2H), 2.84 (d, J =5.9 Hz, 6H), 2.68-2.53 (m,2H), 2.03-1.86 (m, 7H), 1.76-1.69 (m, 1H), 1.42-1.33 (m, 1 H), 0.88 - 0.86 (m, 6H).

565

4-8. (35)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(27f)-yI)-4niethylpentananiido)-3-(4-fhioro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid (diastereomeric compounds BG-P1 and BG-P2)

BG-P1 ESI 686.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.90 (s, IH), 7.39 (d, J= 4.8 Hz, 1H), 7.31 (d,.7=6.3 Hz, 1H), 7.19 (t,J= 7.5 Hz, 1H), 7.13 (d,J= 7.1 Hz, 1H), 7.09 (d, J = 7.4 Hz, 1H), 6.73 (s, 1H), 5.73 - 5.64 (m, 1H), 5.62 - 5.59 (m, 1H), 3.17-3.12 (m, 2H), 2.97 (d, J= 8.4 Hz, 2H), 2.80 (d, J= 11.1 Hz, 6H), 2.76 - 2.73 (m, 2H), 2.11 - 1.89 (m, 5H), 1.82 (s, 3H), 1.47 1.41 (m, 1H), 0.98 - 0.93 (m, 6H).

BG-P2 ESI 686.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.85 (s, IH), 7.44 (d, J= 5.4 Hz, 1H), 7.38 (d, J= 6.6 Hz, IH), 7.22-7.18 (m, IH), 7.14 (d, J= 73 Hz, 2H), 6.90 (s, IH), 5.765.72(m, IH), 5.64 (t, J= 7.7 Hz, IH), 3.25 (d, J= 8.1 Hz, 2H), 3.00 (t, J= 7.0 Hz, 2H), 2.85 (s, 6H), 2.71 - 2.66 (m, 1 H), 2.61 - 2.54 (m, I H), 2.02 (d, J = 2.4 Hz, 6H), 1.99 - 1.94 (m, 1 H), 1.78 - 1.68 (m, IH), 1.46 - 1.30 (m, IH), 0.91 - 0.89 (m, 6H).

4-9. (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-3-methyl-2-oxopyridin-l(2Z0-yl)-4methylpentanamido)-3-(4-fluoro-2^,,6*-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid (diastereomeric compounds BH-P1 and BH-P2)

566

BH-P1 ESI 632.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.52 (s, 1H), 7.42 (s, 1H), 7.32 (d, J= 4.9 Hz, 1H), 7.24-7.18 (m, 2H), 7.17 - 7.10 (m, 2H), 5.52 (s, 1H), 5.45 (t, J= 5.3 Hz, 1H), 3.37 (d, J= 7.6 Hz, 1H), 3.32 - 3.29 (m, 1H), 3.27 - 3.17 (m, 1H), 2.82 (t, J= 6.5 Hz, 2H), 2.74 (s, 6H), 2.71 - 2.66 (m, 1H), 2.56 - 2.51 (m, 1H), 2.03 (d, J= 14.9 Hz, 1H), 1.97 (d, J= 7.2 Hz, 6H), 1.94 (s, 3H), 1.44 - 1.39 (m, 1H), 0.95 - 0.90 (m, 6H).

BH-P2 ESI 632.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.86 (s, 1H), 7.44 (d, J= 4.8 Hz, 1H), 7.38 (d, J= 6.5 Hz, 1H), 7.22-7.18 (m, 1H), 7.14 (d, J= 7.2 Hz, 2H), 6.90 (s, 1H), 5.76-5.72 (m, 1H), 5.64 (t, J= 7.6 Hz, 1H), 3.35 (s, 3H), 3.25 (s, 2H), 3.00 (t, J= 7.1 Hz, 2H), 2.86 (s, 6H), 2.70 - 2.54 (m, 2H), 2.02 (d, J = 2.4 Hz, 6H), 1.99 - 1.92 (m, 1 H), 1.77 - 1.72 (m, 1 H), 1.46 1.30 (m, 1H), 0.91 - 0.89 (m, 6H).

4-10. (3S)-3-(2',6'-dichloro-4,4'-difluoro-5-methylbiphenyI-3-yl)-3-(2-(3-fluoro-5-(2-(3fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2Z/)-yl)-4-methylpentanamido)propanoic acid (diastereomcric compounds BI-P1 and BI-P2)

GI-P1 ESI 670.1 (M+H)⁺. ‘H NMR (400 MHz, MeOD) δ 7.42 (s, 1H), 7.40 - 7.32 (m, 3H), 7.01 (d, J= 6.7 Hz, 1H), 6.96 (d, J= 6.6 Hz, 1H), 5.70 (t, J= 8.1 Hz, 1H), 5.59 - 5.46 (m, 1H), 5.32 5.08 (m, 1H), 4.18 - 3.92 (m, 2H), 3.82 - 3.57 (m, 2H), 3.22 - 3.03 (m, 2H), 2.79 - 2.53 (m, 4H), 2.31 (d, J= 1.3 Hz, 3H), 1.97 (t, J= 7.6 Hz, 2H), 1.51 - 1.33 (m, 1H), 1.01-0.86 (m, 6H). GI-P2 ESI 670.1 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.45 - 7.31 (m, 4H), 7.14 - 6.99 (m, 2H), 5.75 - 5.61 (m, 2H), 5.42 - 5.18 (m, 1H), 4.44 - 4.21 (m, 2H), 4.11 - 3.85 (m, 2H), 3.36 3.34 (m, 2H), 2.80-2.44 (m, 4H), 2.34 (d, J= 1.3 Hz, 3H), 2.03 - 1.90 (m, 1H), 1.83 - 1.70 (m, 1H), 1.47 - 1.30 (m, 1H), 0.99 - 0.86 (m, 6H).

4-11. (3S)-3-(3-cyclopropyl-2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yI)ethyl)-2-oxopyridinl(2H)-yl)propanamido)-3-(4,4'-difluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoic acid (diastereomcric compounds BJ-P1 and BJ-P2)

567

BJ-P1 ESI 628.2 (M+H)⁺. ’H NMR (400 MHz, MeOD) δ 7.37 (s, 1H), 7.26 (d, J= 10.2 Hz, 1H), 6.91 - 6.64 (m, 4H), 5.55 (t, J= 7.6 Hz, 1H), 5.48 - 5.40 (m, 1H), 5.13 (d, J= 57.3 Hz, 1H), 3.98 (d, J= 16.3 Hz, 2H), 3.63 (s, 2H), 3.03 (d, J= 6.5 Hz, 2H), 2.74 - 2.59 (m, 2H), 2.59 - 2.50 (m, 3H), 1.99 - 1.85 (m, 5H), 1.81 (d, J = 9.0 Hz, 3H), 0.56 (d, J= 7.3 Hz, 1H), 0.36 (d, J= 8.0 Hz, 2H), 0.13--0.07 (m, 2H).

BJ-P2 ESI 628.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.50 - 7.28 (m, 2H), 7.03 - 6.71 (m, 4H), 5.75 - 5.55 (m, 2H), 5.30 (d, J= 57.3 Hz, 1H), 4.47 - 4.17 (m, 2H), 4.12 - 3.75 (m, 2H), 3.44 - 3.32 (m, 2H), 2.82 - 2.46 (m, 4H), 2.32 (s, 3H), 2.18 - 1.91 (m, 7H), 1.77 - 1.60 (m, 1H), 0.58 (s, 1H), 0.42 - 0.23 (m, 2H), 0.15 - -0.07 (m, 2H).

4-12. (35)-3-(4,4’-difluoro-2’,5,6’-trimethyl-[l,l’-biphenyl]-3-yl)-3-((3Æ)-2-(3-fluoro-5-(2(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(217)-yl)-3-methyIpentanamido)propanoic acid (diastcreomeric compounds BK-P1 and BK-P2)

BK-P1 ESI 630.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.52 (s, 1H), 7.31-7.28 (m, 1H), 6.866.76 (m, 4H), 5.66 - 5.55 (m, 1H), 5.35-5.33 (d, J= 11.2 Hz, 1H), 5.23.5.09 (m, 1H), 3.85-3.80 (m, 2H), 3.52-3.49 (m, 2H), 2.91-2.88 (t, J= 6.7 Hz, 2H), 2.80 - 2.78 (m, 2H), 2.55-2.52 (t, J= 7.1 Hz, 2H), 2.28 (d, J = 1.5 Hz, 4H), 1.98 (s, 3H), 1.75 (s, 3H), 1.69-1.68 (m, 1H), 1.30-1.26 (m, 1H), 1.03-0.99 (t, J= ΊΑ Hz, 3H), 0.75-0.74 (d, J= 6.6 Hz, 3H).

BK-P2 ESI 630.2 (M+H)⁺. ‘H NMR (400 MHz, MeOD) δ 7.46 (s, 1H), 7.36-7.34 (d, J= 10.3 Hz, 1H), 7.00-6.93 (dd, J= 20.7,6.6 Hz, 2H), 6.86-6.84 (d, J= 9.6 Hz, 2H), 5.75-5.72 (dd, J=

568

10.3,4.1 Hz, 1H), 5.39 - 5.23 (m, 2H), 4.47 - 4.22 (m, 2H), 4.09 - 3.85 (m, 2H), 3.30-3.28 (m, 2H), 2.75-2.72 (m, 2H), 2.67 - 2.47 (m, 2H), 2.41 - 2.20 (m, 4H), 2.02 (s, 6H), 1.17-1.10 (m, 1H), 1.08 - 0.88 (m, 4H), 0.85-0.81 (t, J= 7.2 Hz, 3H).

4-13. (35)-3-(4,4’-difluoro-2’,5,6’-trimethyl-[l,l’-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)-3-mcthyIbutanamido)propanoic acid (diastereomeric compounds BL-P1 and BL-P2)

BL-P1 ESI 616.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.52 (s, 1H), 7.29 (d, J= 10.9 Hz, 1H), 6.94 - 6.65 (m, 4H), 5.62 (s, 1H), 5.26 (d, J= 11.1 Hz, 1H), 5.07 (s, 1H), 3.75 (s, 2H), 3.15 (s, IH), 2.78 (s, 5H), 2.48 (d,J=31.1 Hz, 3H), 2.28 (s, 3H), 1.98 (s,3H), 1.74 (s, 3H), 1.14 (d, J = 6.4 Hz, 3H), 0.78 (d, J= 6.6 Hz, 3H).

BL-P2 ESI 616.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.44 (s, 1H), 7.40-7.28 (m, 1H), 7.02 - 6.72 (m, 4H), 5.88 - 5.62 (m, 1H), 5.38 (s, 2H), 5.24 (d, J= 11.0 Hz, 2H), 4.32 (s, 2H), 3.97 (s, 2H), 2.74 (d, J= 5.1 Hz, 2H), 2.66 - 2.39 (m, 3H), 2.33 (d, J =1.6 Hz, 3H), 2.01 (d, J= 3.3 Hz, 6H), 1.00 (d, J= 6.4 Hz, 3H), 0.75 (d, J= 6.7 Hz, 3H).

4-14. (3S)-3-(2'-cycIopropyl-4-fluoro-5,6'-dimethyI-(l,r-biphenyl]-3-yl)-3-(2-(5-(2(dimcthylamino)ethyl)-2-oxo-4-(trifluoromcthyl)pyridin-l(2H)-yl)-4methylpentanamido)propanoic acid (diastereomeric compounds BM-P1 and BM-P2)

569

BM-P1 ESI 658.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.91 (d, J= 5.9 Hz, 1H), 7.13 (t, J= 7.7 Hz, 1H), 7.07 - 6.87 (m, 3H), 6.76 (d, 7= 11.4 Hz, 2H), 5.83 - 5.64 (m, 1H), 5.57 (t, 7= 5.9 Hz, 1H), 3.18-2.98 (m, 2H), 2.94 (d,7= 7.1 Hz, 2H), 2.82 (d,7= 4.7 Hz, 1H), 2.80-2.48 (m, 8H), 2.32 (d, 7 = 17.2 Hz, 3H), 2.12 - 1.89 (m, 3H), 1.81 (s, 1 H), 1.57-1.26 (m, 2H), 1.02 0.83 (m, 6H), 0.75 - 0.61 (m, IH), 0.60 - 0.22 (m, 3H).

BM-P2 ESI 658.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.83 (d, 7= 11.7 Hz, 1H), 7.28 - 6.65 (m, 6H), 5.82 - 5.43 (m, 2H), 3.30 - 3.09 (m, 2H), 2.99 (t, 7= 6.9 Hz, 2H), 2.80 (d, 7= 2.6 Hz, 6H), 2.70-2.42 (m, 2H), 2.33 (d,7= 1.6 Hz, 3H), 2.10- 1.90(m,4H), 1.80- 1.60(m, 1H), 1.55 - 1.28 (m, 2H), 1.00 - 0.80 (m, 6H), 0.79-0.45 (m, 4H).

4-15. (35)-3-(5-chloro-4,4*-difluoro-2’,6’-dimethyI-[l,l’-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2/7)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds BN-P1 and BN-P2)

BN-P1 ESI 650.2 (M+H)⁺. ‘H NMR (400 MHz, MeOD) δ 7.38 (s, 1H), 7.34 - 7.27 (m, 1H), 7.12 - 7.06 (m, 1H), 6.96 - 6.88 (m, 1H), 6.81 (d, 7= 9.6 Hz, 2H), 5.65 - 5.52 (m, 1H), 5.45 (t, 7 = 6.3 Hz, 1H), 5.18 (d, 7= 57.7 Hz, 1H), 4.14 - 3.88 (m, 2H), 3.72 (s, 2H), 3.10 (s, 2H), 2.78 2.52 (m, 4H), 2.02 - 1.75 (m, 8H), 1.46 - 1.28 (m, IH), 0.98 - 0.76 (m, 6H).

BN-P2 ESI 650.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.33 (d, 7= 8.4 Hz, 2H), 7.19 - 7.09 (m, IH), 7.06 - 6.94 (m, IH), 6.83 (d, 7= 9.6 Hz, 2H), 5.70 - 5.51 (m, 2H), 5.27 (d,7= 57.4 Hz, IH), 4.32 (s, 2H), 4.00 (s, 2H), 2.76 - 2.35 (m, 4H), 1.96 (d, 7= 13.7 Hz, 6H), 1.94 - 1.85 (m, IH), 1.80- 1.67 (m, IH), 1.39- 1.24 (m, 1 H), 0.96-0.63 (m,6H).

4-16. (3S)-3-(2-(5-(2-(azetidin-l-yI)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z7)-yl)-4methyIpentanamido)-3-(4-fluoro-2’-methoxy-5-methyI-6’-(trifluoromethyl)biphenyl-3yl)propanoic acid (diastereomeric compounds BO-P1 and BO-P2)

570

Ο

ΒΟ-Ρ1 ESI 714.2 (M+H)⁺. 1H NMR (500 MHz, MeOD) δ 7.83 (d, J= 6.8 Hz, 1H), 7.57 - 7.48 (m, 1H), 7.41 - 7.25 (m, 2H), 7.04 - 6.96 (m, 1H), 6.93 (t, J= 7.0 Hz, 1H), 6.82 (d, J= 10.1 Hz, 1H), 5.74 - 5.60 (m, 2H), 4.09 - 3.89 (m, 4H), 3.72 (d, J= 21.5 Hz, 3H), 3.32 -3.19 (m, 2H), 5 2.94 - 2.81 (m, 2H), 2.77 - 2.62 (m, 2H), 2.50 - 2.34 (m, 2H), 2.29 (s, 3H), 2.06 - 1.89 (m, 2H),

1.53 - 1.32 (m, 1H), 0.96-0.92 (m, 6H).

BO-P2 ESI 714.1 (M+H)⁺. *H NMR (500 MHz, MeOD) δ 7.71 (d, J= 4.3 Hz, 1H), 7.54 (t, J= 8.2 Hz, 1H), 7.37 (d, J= 8.0 Hz, 1H), 7.33 (d, 8.3 Hz, 1H), 7.07 - 7.00 (m, 1H), 6.97 (d, J=

6.6 Hz, 1H), 6.91 (d, J= 4.9 Hz, 1H), 5.85 - 5.72 (m, 1H), 5.63 - 5.59 (m, 1H), 4.14 (s, 4H), 10 3.75 (d, J= 2.7 Hz, 3H), 3.40 (d, J= 25.2 Hz, 2H), 2.94 (d, J= 16.0 Hz, 1H), 2.82 (d, J= 9.4 Hz,

H), 2.70-2.57 (m, 1H), 2.54-2.42 (m, 3H),2.32 (s, 3H), 2.08 - 1.91 (m, 1H), 1.70-1.57 (m, 1H), 1.46- 1.41 (m, 1H), 0.91 (t, J =4.9 Hz, 6H).

4-17. (3S)-3-(3',4-difluoro-2',5,6'-trimethyl-|l,l’-biphenyI]-3-yI)-3-(2-(3-fluoro-5-(2-(315 fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds BP-PI and BP-P2)

BP-PI ESI 630.3 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.42 (s, 1H), 7.34 (d, J= 10.6 Hz, 1H), 7.15 - 7.02 (m, 1H), 7.01 - 6.76 (m, 3H), 5.67 (t, J= 7.6 Hz, 1H), 5.51 (s, 1H), 5.20 (d, J=

571

57.8 Hz, 1H), 4.00 (d, J= 43.3 Hz, 2H), 3.76 - 3.45 (m, 2H), 3.09 (d, J= 5.7 Hz, 2H), 2.842.50 (m, 4H), 2.31 (s, 3H), 2.02 - 1.64 (m, 8H), 1.48 - 1.18 (m, 1H), 1.06 - 0.77 (m, 6H). BP-P2 ESI 630.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.37 (d, J= 10.7 Hz, 2H), 7.16 - 7.03 (m, 1H), 6.95 (t, J= 8.9 Hz, 3H), 5.75 - 5.52 (m, 2H), 5.30 (d, J= 57.4 Hz, 1H), 4.30 (d, J= 18.4 Hz, 2H), 3.97 (s, 2H), 3.31 - 3.14 (m, 2H), 2.84 - 2.42 (m, 4H), 2.34 (d, J= 1.3 Hz, 3H), 2.03 - 1.84 (m, 7H), 1.83- 1.66 (m, 1 H), 1.50 - 1.21 (m, 1H), 0.99 - 0.75 (m, 6H).

4-18. (3S)-3-(4-fluoro-2',5,6'-trimethyI-[l,r-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3methoxyazctidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2jF/)-yl)-4methylpentanamido)propanoic acid (compounds BQ-P1 and BQ-P2)

BQ-P1 ESI 638.3 (M+H)⁺. ’H NMR (400 MHz, MeOD) δ 7.39 (s, 1H), 7.16 - 7.04 (m, 3H), 6.88 (t, J= 7.3 Hz, 2H), 5.64-5.53 (m, 2H), 4.24-4.08 (m, 3H), 3.73-3.61 (m, 2H), 3.30-3.26 (m, 5H), 2.83-2.67 (m, 4H), 2.31 (s, 3H), 2.24 (t, J= 6.7 Hz, 3H), 2.02-1.92 (m, 8H), 1.40-1.35 (m, 1H), 0.96-0.90 (m, 6H).

BQ-P2 ESI 638.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.20 (s, 1H), 7.04-6.94 (m, 3H), 6.846.80 (t, J= 7.6 Hz, 2H), 5.61 - 5.42 (m, 2H), 4.37 - 4.09 (m, 3H), 3.83-3.70 (m, 2H), 3.383.22(m,5H), 2.83-2.32(m,4H), 2.22 (d, J= 1.6 Hz, 3H), 2.10 (d, J= 2.8 Hz, 3H), 1.96-1.80 (m, 7H), 1.63 - 1.52 (m, 1 H), 1.32- 1.19 (m, 1H), 0.79-0.78 (m, 6H).

4-19. (35)-3-(4-fluoro-2',5,6'-trimcthyl-[l,r-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3fluoroazetidin-l-yi)ethyl)-2-oxopyridin-l(2Z/)-yl)pentanamido)propanoic acid (diastereomeric compounds BR-P1 and BR-P2)

572

BR-P1 ESI 598.3 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.49 - 7.23 (m, 2H), 7.19 - 7.00 (m, 3H), 6.96 - 6.66 (m, 2H), 5.74 - 5.44 (m, 2H), 5.19 (d, 7= 57.3 Hz, IH), 3.94 (s, 2H), 3.77 3.41 (m, 2H), 3.18 - 3.00 (m, 2H), 2.87 - 2.47 (m, 4H), 2.38 - 2.22 (m, 3H), 2.22 - 2.06 (m, 5 1 H), 2.06 - 1.73 (m7H), 1.44 - 1.20 (m, 2H), 1.06 - 0.78 (m, 3H).

BR-P2 ESI 598.3 (M+H)⁺. ’H NMR (400 MHz, MeOD) δ 7.44 - 7.29 (m, 2H), 7.18 - 7.01 (m, 3H), 6.99 - 6.79 (m, 2H), 5.73 - 5.49 (m, 2H), 5.24 (d, 7= 57.6 Hz, IH), 4.11 (s, 2H), 3.73 (d, 7 = 9.2 Hz, 2H), 3.14 (d,7= 6.1 Hz, 2H), 2.75-2.48 (m, 4H), 2.33 (d,7= 1.7 Hz, 3H), 2.162.04 (m, IH), 2.02 (t, 7= 8.9 Hz, 6H), 1.91 - 1.76 (m, IH), 1.35 - 1.12 (m, 2H), 0.91 (t, 7= 7.4 10 Hz, 3H).

4-20. (35)-3-(2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyI)pyridin-l(2fl)-yl)-4methylpentanamido)-3-(5'-cyano-4-fluoro-2’,5-dimethyl-[l,r-biphenyl]-3-yl)propanoic acid (diastereomeric compounds BS-P1 and BS-P2)

BS-P1 ESI 655.3 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.84 (s, IH), 7.69 - 7.57 (m, IH), 7.54 (s, IH), 7.47 (d, 7= 8.0 Hz, IH), 7.17 - 7.01 (m, 2H), 6.82 (s, IH), 5.75 - 5.43 (m, 2H), 4.04 (t, 7= 8.1 Hz, 4H), 3.15 (s, 2H), 2.85 (t, 7= 6.9 Hz, 2H), 2.78 - 2.61 (m, 2H), 2.52 - 2.37

573 (m, 2H), 2.31 (d, J= 7.7 Hz, 6H), 2.11 - 1.90 (m, 2H), 1.42 (d, J= 7.2 Hz, 1H), 0.96 (t, J= 6.4 Hz, 6H).

BS-P2 ESI 655.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.74 (s, 1H), 7.68 - 7.60 (m, 1H), 7.56 (d,J= 1.6Hz, 1H), 7.49 (d,J= 7.9 Hz, 1H), 7.16(d,J=6.7Hz,2H), 6.93 (s, 1H), 5.83-5.71 (m, 1H), 5.64 (t, J= 7.7 Hz, 1H), 4.15 (t, J= 8.0 Hz, 4H), 3.42 (d, J= 15.1 Hz, 2H), 3.01 - 2.75 (m, 2H), 2.70 - 2.42 (m, 4H), 2.41 - 2.26 (m, 6H), 2.10 - 1.93 (m, 1H), 1.79-1.63 (m, 1H), 1.55 - 1.29 (m, 1H), 0.93 (t, J= 6.4 Hz, 6H).

4-21. (3S)-3-(2-(5-(2-(azetÎdin-l-y])ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(27/)-yl)-4methylpentananiido)-3-(2'-cyano-4-fluoro-4',5-dimethyI-[l,l'-biphenyl]-3-yl)propanoic acid (diastereomeric compounds BT-P1 and BT-P2)

BT-P1 ESI 655.3 (M+H)⁺. ‘H NMR (400 MHz, MeOD) δ 7.85 (s, 1H), 7.60 (s, 1H), 7.47 (s, 1H), 7.36 - 7.30 (s, 3H), 6.74 (s, 1H), 5.78 - 5.59 (m, 2H), 3.84 - 3.80 (m, 4H), 3.15 - 3.10 (m, 2H), 2.75 - 2.72 (m, 4H), 2.43 (s, 3H), 2.34 - 2.30 (m, 5H), 2.06 - 2.01 (m, 2H), 1.40 - 1.37 (m, 1H), 0.99-0.96 (m, 6H).

BT-P2 ESI 655.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.72 (s, 1H), 7.66 (s, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.51 - 7.34 (m, 3H), 6.92 (s, 1H), 5.75 - 5.69 (m, 2H), 4.05 - 4.01 (m, 4H), 2.95 2.55 (m, 5H), 2.46 - 2.37 (m, 9H), 2.06 - 1.96 (m, 1H), 1.85 - 1.75 (m, 1H), 1.49 - 1.37 (m, 1H),), 0.94-0.92 (m, 6H).

4-22. (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2£0-yl)-4methylpentanamido)-3-(6’-cyano-3’,4-difluoro-2’,5-dimethyl-[l,l’-biphenyl]-3-yl)propanoic acid (diastereomeric compounds BU-P1 and BU-P2)

574

BU-P1 ESI 673.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.83 (s, IH), 7.71-7.62 (m, IH), 7.317.27 (t, J= 8.8 Hz, IH), 7.14-7.10(m,2H), 6.80-6.75 (d, J =22.1 Hz, IH), 5.76-5.62 (m, 2H), 4.02-3.97 (m, 4H), 3.32-3.15 (m, 2H), 2.95 - 2.60 (m, 4H), 2.51 - 2.25 (m, 5H), 2.11-1.93 (m, 5 5H), 1.45-1.44 (m, 1 H), 0.97-0.96 (m, 6H).

BU-P2 ESI 673.3 (M+H)⁺. ‘H NMR (400 MHz, MeOD) δ 7.81 - 7.66 (m, 2H), 7.37 - 7.08 (m, 3H), 6.92 (s, IH), 5.85 - 5.56 (m, 2H), 4.16-4.10 (m, 4H), 3.43-3.42 (m, 2H), 3.02 - 2.75 (m, 2H), 2.66(d,J= 12.1 Hz, 1 H), 2.62-2.30 (m, 6H), 2.18- 1.95 (m, 4H), 1.80- 1.64(m, IH), 1.45-1.38 (m, IH), 0.92-0.91 (m, 6H).

4-23. (35)-3-(2-(5-(2-(azetidin-l-yl)cthyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4methyIpentanamido)-3-(2^,-cyano-4,5’-difluoro-4’,5-dimethylbiphenyl-3-yI)propanoic acid (diastcrcomeric compounds BV-P1 and BV-P2)

575

BV-P1 ESI 673.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.96 (s, 1H), 7.73 - 7.46 (m, 2H), 7.31 (d,7=4.5 Hz, 1H), 7.07-6.69 (m, 1H), 5.75 (s, 1H), 5.62(t, 7=6.8 Hz, 1H), 3.96(s,4H), 3.27 - 3.11 (m, 2H), 2.92 - 2.58 (m, 4H), 2.45 - 2.21 (m, 8H), 2.12 - 1.91 (m, 2H), 1.41 (s, 1H), 1.04-0.88 (m, 6H).

BV-P2 ESI 673.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.78 (d, J= 7.6 Hz, 1H), 7.72 (s, 1H), 7.47-7.38 (m, 2H), 7.32 (d, J= 10.2 Hz, 1H), 6.93 (s, 1H), 5.78-5.65 (m, 2H), 4.13 (t, J= 8.0 Hz, 4H), 3.48-3.35 (m, 2H), 2.99 - 2.75 (m, 2H), 2.70 - 2.42 (m, 4H), 2.37 (s, 6H), 2.11 - 1.93 (m, 1H), 1.85-1.71 (m, 1H), 1.51-1.30 (m, 1H), 1.05-0.85 (m, 6H).

4-24. (3S)-3-(2-(5-(2-(azetidin-l-yI)ethy!)-2-oxo-4-(trifluoromethyl)pyridin-l(2i/)-yl)-4methyIpentanamido)-3-(2^,-cyano-4-fluoro-4’-methoxy-5-methyl-[l,l’-biphenyI]-3yl)propanoic acid (diastereomeric compounds BW-P1 and BW-P2)

BW-P1 ESI 671.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.93 (s, 1H), 7.44 (s, 1H), 7.26 (s, 2H), 7.15 (d, J= 52.3 Hz, 2H), 6.75 (s, 1H), 5.80 - 5.70 (m, IH), 5.68 - 5.60 (m, 1H), 3.95 (d, J = 7.9 Hz, 4H), 3.90 (d, J= 10.4 Hz, 3H), 3.24 (m, 2H), 2.81 (m, 1H), 2.75 (m, 3H), 2.46 - 2.35 (m, 2H), 2.31 (s, 3H), 2.04 (m, 2H), 1.48 -1.38 (m, 2H), 0.98 (m, 6H).

BW-P2 ESI 671.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.72 (s, 1H), 7.50 (d, 7= 8.7 Hz, 1H), 7.38 (ddm, 2H), 7.35 - 7.29 (m, 2H), 6.93 (s, 1H), 5.75 (m, 1H), 5.70 (t, 7= 7.7 Hz, 1H), 4.11 (m, 4H), 3.91 (s, 3H), 3.39 (m, 2H), 2.94 (d, 7= 16.7 Hz, 1H), 2.86 - 2.77 (m, 1H), 2.66 (m, 1H), 2.55 (m, 1H), 2.50 - 2.41 (m, 2H), 2.37 (s, 3H), 2.02 (m, 1H), 1.83 - 1.74 (m, 1H), 1.41 (m, 2H), 0.93 (m, 6H).

576

4-25. (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2£F)^_yl)4methylpentanamido)-3-(2’-cyano-5’-ethyI-4-fluoro-5-methyl-(l,l’-biphenyI]-3-yI)propanoic acid (diastereomeric compounds BX-P1 and BX-P2)

BX-P1 ESI 669.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.96 - 7.83 (m, 1H), 7.70 (d, J= 7.9 Hz, 1H), 7.46 - 7.16 (m, 4H), 6.76 (s, 1H), 5.82 - 5.48 (m, 2H), 4.07 - 3.90 (m, 4H), 3.31 - 3.14 (m, 2H), 2.88 - 2.66 (m, 6H), 2.49 - 2.30 (m, 5H), 2.13-1.99 (m, 2H), 1.52-1.21 (m, 4H), 0.97 (d, J =6.6 Hz, 6H).

BX-P2 ESI 669.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.84 - 7.66 (m, 2H), 7.47 - 7.28 (m, 10 4H), 6.93 (s, 1H), 5.73 (t, J= 7.7 Hz, 2H), 4.16 (t, J= 8.0 Hz, 4H), 3.53 - 3.34 (m, 2H), 3.04 2.30 (m, HH), 2.10-1.93 (m, 1H), 1.89-1.77(m, 1H), 1.46-1.23 (m,4H), 1.01-0.83 (m, 6H).

4-26. (35)-3-(4,4'-difluoro-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)-3-(2-(3-fliioro-5-(2-(3fluoroazetidin-l-yl)ethyI)-2-oxopyridin-l(2ÆF)-yi)pentanamido)propanoic acid (diastereomeric compounds BY-P1 and BY-P2) (S) F ^MeX)H

577

BY-P1 ESI 616.3 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.43 (s, IH), 7.38 - 7.27 (m, IH), 6.91 - 6.68 (m, 4H), 5.67 - 5.44 (m, 2H), 5.21 (d, J= 57.3 Hz, IH), 4.02 (d, J= 35.4 Hz, 2H), 3.83 - 3.54 (m, 2H), 3.20 - 2.99 (m, 2H), 2.82 - 2.53 (m, 4H), 2.29 (d, J= 1.6 Hz, 3H), 2.24 2.08 (m, IH), 2.05 - 1.92 (m, 4H), 1.88 (s, 3H), 1.42-1.21 (m, 2H), 0.96 (t, J= 7.4 Hz, 3H). BY-P2 ESI 616.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) 8 7.44 - 7.28 (m, 2H), 7.01 - 6.76 (m, 4H), 5.69 - 5.49 (m, 2H), 5.29 (d, 57.4 Hz, IH), 4.38 - 4.13 (m, 2H), 4.02 - 3.74 (m, 2H),

3.37 - 3.20 (m, 2H), 2.81 - 2.43 (m, 4H), 2.33 (d, J= 1.7 Hz, 3H), 2.16 - 2.04 (m, IH), 2.01 (s, 6H), 1.90 - 1.77 (m, IH), 1.35 - 1.09 (m, 2H), 0.92 (t, J= 7.4 Hz, 3H).

4-27. (35)-3-(2-(5-(2-(dimethy)amino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)yl)pentanamido)-3-(4-fluoro-2’,5,6’-trimethyl-[l,l’-biphenyl]-3-yl)propanoic acid (diastereomeric compounds BZ-P1 and BZ-P2)

BZ-P1 ESI 618.3 (M+H)⁺. >H NMR (500 MHz, MeOD) δ 7.90 (s, 1 H), 7.11 - 7.02 (m, 3H), 6.90 - 6.86 (m, 2H), 6.74 (s, IH), 5.59 - 5.56 (m, 2H), 3.18-3.14 (m, 2H), 2.99 (d, J= 22.6 Hz, 2H), 2.81 (s, 6H), 2.76-2.73 (m, 2H), 2.29 (s, 3H), 2.19-2.12 (m, IH), 2.02-1.95 (m, 4H), 1.80 (s, 3H), 1.37 - 1.30 (m, 2H), 0.96 (t, J= 7.3 Hz, 3H).

BZrP2 ESI 618.3 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.86 (s, IH), 7.14 - 7.65 (m, 3H), 6.95 - 6.89 (m, 3H), 5.73 (d, J= 13 Hz, IH), 5.53 (t, J= 7.6 Hz, IH), 3.33 - 3.20 (m, 2H), 3.01 (t, J = 6.8 Hz, 2H), 2.82 (s, 6H), 2.68 - 2.62 (m, IH), 2.56 - 2.51 (m, IH), 2.32 (s, 3H), 2.07 - 2.00 (m, 7H), 1.82- 1.72 (m, IH), 1.23 (s, 2H), 0.89 (d, J= 3.5 Hz, 3H).

578

4-28. (35)-3-(5-chloro-4-fluoro-2',6'-diniethyl-[l,l'-biphenyI]-3-yI)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)-yl)-5methylhexanamido)propanoic acid (diastereomeric compounds CA-P1 and CA-P2)

CA-P1 ESI 666.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.88 (s, IH), 7.13 (t, J = 7.6 Hz, 1H), 7.09 - 7.06 (m, 2H), 7.04 (s, 1H), 7.02 (s, 1H), 6.69 (s, 1H), 5.53 (t, J= 7.2 Hz, 1H), 5.49 - 5.45 (m, 1H), 3.16 - 3.04 (m, 2H), 2.94 (t, J= 8.0 Hz, 2H), 2.76 (s, 6H), 2.73 - 2.71 (m, 2H), 2.23 2.14 (m, 1H), 1.99 (s, 3H), 1.97-1.91 (m, 1H), 1.79 (s, 3H), 1.63-1.51 (m, 1 H), 1.27 - 1.18 (m, 1H), 1.13 - 1.04 (m, 1H), 0.88 (d, J= 3.2 Hz, 3H), 0.86 (d, J= 3.6 Hz, 3H).

CA-P2 ESI 666.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.86 (s, IH), 7.17 - 7.13 (m, 2H), 7.10-7.08(m, 3H), 6.88 (s, IH), 5.71-5.68 (m, IH), 5.46 (t, J = 7.4 Hz, IH), 3.28-3.15 (m, 2H), 2.98 (t, J= 7.0 Hz, 2H), 2.81 (s, 6H), 2.68 - 2.63 (m, IH), 2.58 - 2.52 (m, 1 H), 2.16 - 2.05 (m, 1 H), 2.01 (s, 3H), 2.00 (s, 3H), 1.83- 1.74 (m, IH), 1.56- 1.46 (m, IH), 1.16-0.99 (m, 2H), 0.82 (d, J= 5.2 Hz, 3H), 0.80 (d, J= 4.8 Hz, 3H).

4-29. (35)-3-(2-(5-(2-(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4methylpentananiido)-3-(2-fluoro-3-methyI-5-((5)-2-methylpiperidin-l-yl)phenyI)propanoic acid (diastereomeric compounds CB-P1 and CB-P2) (S) ^MeJDH (S) N

579

CB-P1 ESI 625.4 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.92 (s, 1H), 6.91 - 6.74 (m, 3H), 5.74 (t, J = 8.0 Hz, 1H), 5.49 (t, J =7.0 Hz, 1H), 3.49-3.38 (m, 1H), 3.13-2.82 (m, 6H), 2.77 - 2.62 (m, 8H), 2.21 (s, 3H), 2.01 (t, J= 7.6 Hz, 2H), 1.91 - 1.36 (m, 7H), 0.98 (d, J= 6.5 Hz, 6H), 0.79 (d, .7=6.4 Hz, 3H).

CB-P2 ESI 625.4 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.89 (s, 1H), 7.01 - 6.78 (m, 3H), 5.74 - 5.55 (m, 2H), 3.59 - 3.44 (m, 1H), 3.30 - 3.14 (m, 2H), 3.08 - 2.90 (m, 4H), 2.82 (s, 6H), 2.62 - 2.42 (m, 2H), 2.25 (d, J= 1.7 Hz, 3H), 2.04 - 1.35 (m, 9H), 0.99 - 0.86 (m, 9H).

4-30. (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyI)pyridin-l(2£0-yI)-4methyIpentanamido)-3-(2’-cyclopropyI-4,5’-difluoro-5-methyI-[l,l’-biphenyl]-3yl)propanoic acid (diastercomeric compounds CC-P1 and CC-P2)

CC-P1 ESI 674.4 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.87 (s, 1H), 7.23 - 7.17 (m, 2H), 7.03 - 6.98 (m, 2H), 6.89 - 6.82 (m, 2H), 5.73 - 5.56 (m, 2H), 4.09 (t, J= 8.1 Hz, 4H), 3.35 3.32 (m, 2H), 2.87 - 2.84 (m, 2H), 2.76 - 2.75 (m, 2H), 2.48 - 2.43 (m, 2H), 2.31 (d, J= 1.6 Hz, 3H), 2.05-1.97 (m, 2H), 1.81 - 1.74 (m, 1 H), 1.16 - 1.39 (m, 1 H), 0.97 - 0.91 (m, 6H), 0.79 0.74 (m, 2H), 0.57 - 0.53 (m, 2H).

CC-P2 ESI 674.3 (M+H)⁺. ‘H NMR (400 MHz, MeOD) δ 7.74 (s, 1H), 7.27 - 7.21 (m, 2H), 7.05 - 6.91 (m, 4H), 5.77 - 5.74 (m, 1H), 5.64 (t, J= 7.6 Hz, 1H), 4.14 (t, J= 8.1 Hz, 4H), 3.42 - 3.32 (m, 2H), 2.96 - 2.81 (m, 2H), 2.67 - 2.45 (m, 4H), 2.35 (t, J= 8.8 Hz, 3H), 2.03 - 1.96 (m, 1 H), 1.83 - 1.66 (m, 2H), 1.42 - 1.38 (m, 1 H), 0.92 - 0.89 (m, 6H), 0.84 - 0.79 (m, 2H), 0.63-0.59 (m, 2H).

580

4-31. (3S)-3-(2-(5-(2-(azctidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yl)-4methylpentanamido)-3-(6’-cyano-4-fluoro-2’,3’,5-trimethyl-[l,l’-biphenyI]-3-yI)propanoic acid (diastereomeric compounds CD-P1 and CD-P2)

CD-P1 ESI 669.4 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.85 (d, J= 8.9 Hz, IH), 7.61 - 7.27 (m, 2H), 7.16 - 6.95 (m, 2H), 6.77 (d, J= 35.8 Hz, 1H), 5.80 - 5.43 (m, 2H), 4.11 - 3.86 (m, 4H), 3.31-3.15 (m, 2H), 2.94 - 2.60 (m, 4H), 2.51 - 2.24 (m, 8H), 2.15-1.89 (m, 5H), 1.56 1.38 (m, IH), 1.09 - 0.83 (m, 6H).

CD-P2 ESI 669.4 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.72 (d, J= 6.8 Hz, IH), 7.54 (d, J= 10 7.9 Hz, IH), 7.36 (d, J= 7.9 Hz, IH), 7.22 - 7.05 (m, 2H), 6.91 (s, IH), 5.90-5.53 (m, 2H),

4.32 - 3.89 (m, 4H), 3.54 - 3.33 (m, 2H), 3.11 - 2.29 (m, 12H), 2.07 - 1.92 (m, 4H), 1.83 - 1.64 (m, IH), 1.52- 1.30 (m, IH), 0.97-0.81 (m, 6H).

4-32. (3$)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z0-yl)-415 methylpentanamido)-3-(5'-cyano-4-fluoro-2’,4’,5-trimethyl-(l,l*-biphenyI]-3-yI)propanoic acid (diastereomeric compounds CE-P1 and CE-P2)

581

CE-P1 ESI 669.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.74 (s, 1H), 7.26 (d, J = 40.1 Hz, 2H), 6.96 (t, J= 7.5 Hz, 2H), 6.65 (s, 1H), 5.74 - 5.22 (m, 2H), 3.92 (t, J= 8.1 Hz, 4H), 3.21 3.09 (m, 2H), 2.66 (dt, J= 11.9,7.1 Hz, 4H), 2.49 - 2.19 (m, 5H), 2.15 (d, J = 20.6 Hz, 6H), 1.90 5 (m, J= 13.4,6.1 Hz, 2H), 1.47- 1.10 (m, 1H), 0.83 (t, J= 6.2 Hz, 6H).

CE-P2 ESI 669.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.75 (s, 1H), 7.42 (d, J= 42.0 Hz, 2H), 7.13 (d, J = 6.4 Hz, 2H), 6.92 (s, IH), 5.92 - 5.45 (m, 2H), 4.14 (t, J= 8.0 Hz, 4H), 3.40 (d, J= 16.8 Hz, 2H), 2.92 (s, 2H), 2.75 - 2.55 (m, 1H), 2.52 - 2.41 (m, 6H), 2.40 - 2.18 (m, 6H), 2.12- 1.88 (m, 1H), 1.82- 1.53 (m, 1H), 1.53 -1.20 (m, 1H), 0.92 (t, J= 6.6 Hz, 6H).

4-33. (35)-3-(4,5-difluoro-2’,6’-dimethyl-I1,1 ’-biphenyl]-3-yI)-3-(2-(5-(2-(dimethylamino)ethyl)-2oxopyridin-l(2/7)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds CF-P1 and CF-P2)

CF-P1 ESI 568.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.64 (d, J= 2.0 Hz, 1H), 7.54 - 7.51 (m, 1H), 15 7.18 (t, J= 7.5 Hz, 1H), 7.11 (t, J= 6.8 Hz, 2H), 6.99 - 6.90 (m, 1H), 6.78 (d, J= 5.9 Hz, 1H), 6.52 (d, J = 9.3 Hz, 1H), 5.61-5.56 (m, 1H), 5.42 (t, J =5.6 Hz, 1H), 3.32-3.19 (s, 1H), 3.24-3.10 (m, 1H), 2.88 - 2.80 (m, 2H), 2.73 (s, 6H), 2.70 - 2.64 (m, 1H), 2.59 - 2.53 (m, 1H), 2.06 - 1.89 (m, 8H), 1.50 - 1.36 (m, 1H), 0.97-0.90 (m, 6H).

582

CF-P2 ESI 568.2 (M+H)⁺. 1H NMR (500 MHz, MeOD) δ Ή NMR (500 MHz, MeOD) δ 7.65 (d, J= 2.1 Hz, 1H), 7.54 - 7.50 (m, 1H), 7.22 - 7.13 (m, 1H), 7.14 - 7.07 (m, 2H), 7.01 - 6.90 (m, 1H), 6.88 (d, J= 5.8 Hz, 1H), 6.54 (d, J= 9.3 Hz, 1H), 5.66 - 5.52 (m, 2H), 3.38 - 3.34 (m, 1H), 3.28 - 3.21 (m, 1H), 2.98 - 2.86 (m, 1H), 2.86 - 2.73 (m, 7H), 2.64 - 2.59 (m, 1H), 2.51 - 2.44 (m, 1H), 2.08 - 1.91 (m, 7H), 1.92 -1.81 (m, 1H), 1.49 - 1.35 (m, 1H), 0.93 - 0.88 (m, 6H).

4-34. (35)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-l(2II)-yl)-4-methylpentanamido)-3(4,4’,5-trifluoro-2’,6’-dimethyl-[l,l’-biphenyI)-3-yI)propanoic acid (diastereomeric compounds CGP1 and CG-P2)

CG-P1 ESI 586.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.65 (s, 1H), 7.57 - 7.48 (m, 1H), 6.99 - 6.90 (m, 1H), 6.87 (d, J= 8.8 Hz, 2H), 6.79 (d, J= 5.8 Hz, 1H), 6.52 (d, J= 9.4 Hz, 1H), 5.56 (s, 1H), 5.42 (t, J= 5.6 Hz, 1H), 3.32 - 3.27 (m, 1H), 3.23 - 3.16 (m, 1H), 2.93 - 2.80 (m, 2H), 2.75 (s, 6H), 2.70 - 2.62 (m, 1H), 2.59 - 2.52 (m, 1H), 2.10 - 1.91 (m, 8H), 1.44 (s, 1H), 0.98 - 0.87 (m, 6H).

CG-P2 ESI 586.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.65 (d, J= 2.1 Hz, 1H), 7.56 - 7.50 (m, 1H), 7.01 - 6.94 (m, 1H), 6.90 - 6.81 (m, 3H), 6.55 (d, J= 9.3 Hz, 1H), 5.64 - 5.54 (m, 2H), 3.45 - 3.36 (m, 1H), 3.31 - 3.24 (m, 1H), 2.99 - 2.90 (m, 1H), 2.90 - 2.78 (m, 7H), 2.64 - 2.55 (m, 1H), 2.51 - 2.41 (m, 1H), 2.07-1.95 (m, 7H), 1.92-1.83 (m, 1H), 1.46-1.36 (m, 1H), 0.96-0.86 (m, 6H).

4-35. (35)-3-(4,5-dinuoro-2’,6’-dimethyl-[l,l*-biphenyl]-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-lyl)ethyl)-2-oxopyridin-l(2H)-yl)-4-methyIpentanamido)propanoic acid (diastereomeric compounds CH-P1 and CH-P2)

OH

583

CH-P1 ESI 598.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.54 (d, J= 1.9 Hz, 1H), 7.46 - 7.40 (m, 1H), 7.21 - 7.14 (m, 1H), 7.11 (d, J= 7.3 Hz, 2H), 6.99 - 6.90 (m, 1H), 6.81 (d, J= 5.9 Hz, 1H), 6.47 (d, J= 9.3 Hz, 1H), 5.62 (t, J= 8.1 Hz, 1H), 5.51 (t, J= 6.1 Hz, 1H), 5.31 - 5.14 (m, IH), 4.17 - 3.96 (m, 2H), 3.82 - 3.67 (m, 2H), 3.21 - 3.11 (m, 2H), 2.78 - 2.58 (m, 4H), 2.03 - 1.89 (m, 8H), 1.47 - 1.40 (m, 1H), 0.97-0.88 (m, 6H).

CII-P2 ESI 598.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.53 (d, J= 2.0 Hz, 1H), 7.49 - 7.42 (m, 1H), 7.16 (d, J= 7.4 Hz, 1H), 7.11 (d, J= Ί.Ί Hz, 2H), 7.03 - 6.94 (m, 1H), 6.92 (d, J= 5.9 Hz, 1H), 6.55 (d, J = 9.3 Hz, 1H), 5.68 - 5.60 (m, 2H), 5.41 - 5.22 (m, 1H), 4.47 - 4.27 (m, 2H), 4.09 - 3.94 (m, 2H), 3.37 (s, 2H),2.79-2.62 (m,3H), 2.60-2.50 (m, 1H), 2.03 (d, J= 2.2Hz, 6H), 1.98-1.91 (m, 1H), 1.841.76 (m, 1H), 1.47-1.37 (m, 1H), 0.91 (t, J= 6.1 Hz, 6H).

4-36. (35)-3-(4-fluoro-2’,5,6'-trimethyl-[l,r-biphenyl]-3-yl)-3-(2-(5-(2-(3-iluoroazetidin-lyl)ethyl)-4-methyl-2-oxopyridin-l(2//)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds CI-P1 and CI-P2)

CI-P1 ESI 608.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 8.45 (s, 0.47HCOOH), 7.54 (s, 1H), 7.15 7.05 (m, 3H), 6.89 - 6.81 (m, 2H), 6.30 (s, 1H), 5.68 - 5.48 (m, 2H), 5.40- 5.14 (m, 1H), 4.35-4.13 (m, 2H), 4.06 - 3.86 (m, 2H), 3.26 - 3.20 (m, 2H), 2.88 - 2.65 (m, 4H), 2.29 (s, 3H), 2.23 (s, 3H), 2.01 - 1.89 (m, 5H), 1.85 (s, 3H), 1.48 - 1.38 (m, 1H), 0.98 - 0.91 (m, 6H).

CI-P2 ESI 608.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 8.45 (s, 0.23HCOOH), 7.46 (s, 1H), 7.20 - 7.02 (m, 3H), 6.93 (d, J= 5.0 Hz, 2H), 6.44 (s, 1H), 5.75 - 5.54 (m, 2H), 5.34 (d, J= 57.3 Hz, 1H), 4.48-4.35 (m, 2H), 4.16 - 3.96 (m, 2H), 3.42 - 3.34 (m, 2H), 2.90 - 2.82 (m, 1H), 2.74 - 2.63(m, 2H), 2.60-2.52 (m, 1H), 2.33 (s, 3H), 2.25 (s, 3H), 2.07 - 1.85 (m, 7H), 1.82 - 1.70 (m, 1H), 1.44 - 1.34 (m, 1H), 0.91 0.87 (m, 6H).

584

4-37. (35)-3-(2-(5-((dimethylammo)methyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-2’,5,6'-trimethyl-[l,l'-biphenyl]-3-yl)propanoic acid (diastereomeric compounds CJ-P1 and CJ-P2)

CJ-P1 ESI 618.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 8.07 (s, 1H), 7.15 - 7.00 (m, 3H), 6.94 - 6.83 (m, 2H), 6.77 (s, 1H), 5.75 (t,J=8.1Hz, 1H), 5.63-5.52 (m, 1H), 3.83 - 3.59 (m,2H), 2.82-2.72 (m, 2H), 2.52 (s, 6H), 2.29 (d, J= 1.3 Hz, 3H), 2.05 - 1.95 (m, 5H), 1.80 (s, 3H), 1.49 - 1.37 (m, 1H), 1.01 0.91 (m, 6H).

CJ-P2 ESI 618.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 8.09 (s, 1H), 7.18 - 7.00 (m, 3H), 7.00 - 6.84 (m, 3H), 5.81 - 5.70 (m, 1H), 5.63 - 5.46 (m, 1H), 4.10 (d, J= 14.4 Hz, 1H), 3.87 (d, J= 14.4 Hz, 1H), 2.79-2.55 (m, 8H), 2.34 (d, J= 1.5 Hz, 3H), 2.05 -1.93 (m, 7H), 1.71 - 1.61 (m, 1H), 1.48-1.39 (m, 1H), 0.93-0.82 (m, 6H).

4-38. (35)-3-(4,4*-difluoro-2’, 5,6’-trimethyl-[l,l'-biphenyl]-3-yI)-3-(2-(5-((dimethyIamino)methyl)2-oxo-4-(trifluoromethyl)pyridin-l(2/7)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds CK-P1 and CK-P2)

CK-P1 ESI 636.1 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 8.06 (s, 1H), 6.95 - 6.72 (m, 5H), 5.75 (t, J= 8.1 Hz, 1H), 5.62 - 5.56 (m, 1H), 3.79 - 3.65 (m, 2H), 2.86 - 2.65 (m, 2H), 2.52 (s, 6H), 2.29 (s, 3H), 2.04 - 1.93 (m, 5H), 1.81 (s, 3H), 1.50 - 1.38 (m, 1H), 0.96 (t, J= 7.4 Hz, 6H).

585

CK-P2 ESI 636.1 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 8.08 (s, IH), 6.95 - 6.88 (m, 3H), 6.85 (d, J= 9.6 Hz, 2H), 5.76 - 5.70 (m, IH), 5.55 (t, 7= 7.5 Hz, IH), 4.08 (d, 7= 14.4 Hz, IH), 3.85 (d, 7= 14.4 Hz, IH), 2.79 - 2.52 (m, 8H), 2.34 (s, 3H), 2.03 - 1.93 (m, 7H), 1.70 - 1.61 (m, IH), 1.50 - 1.38 (m, IH), 0.95-0.80 (m, 6H).

4-39. (3S)-3-(2-(5-((dimethylamino)methyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)-yl)-4methylpentanamido)-3-(4-nuoro-2’,4’,5,6’-tetramethyI-[l,l’-biphenyl]-3-yl)propanoic acid (diastereomeric compounds CL-P1 and CL-P2)

CL-P1 ESI 632.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 8.05 (s, IH), 6.92 - 6.82 (m, 4H), 6.76 (s, IH), 5.75 (t, 7= 8.1 Hz, IH), 5.63 - 5.50 (m, IH), 3.78 - 3.62 (m, 2H), 2.88 - 2.65 (m, 2H), 2.50 (s, 6H), 2.29 (d, 7= 3.7 Hz, 6H), 2.03 - 1.89 (m, 5H), 1.76 (s, 3H), 1.52 - 1.36 (m, IH), 0.96 (t, 7= 7.2 Hz, 6H).

CL-P2 ESI 632.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 8.09 (s, IH), 6.95 - 6.83 (m, 5H), 5.81 - 5.68 (m, IH), 5.54 (t,7= 7.4 Hz, IH), 4.09 (d,7= 14.4 Hz, IH), 3.85 (d,7= 14.3 Hz, IH), 2.81-2.52 (m, 8H), 2.32 (d,7= 9.8 Hz, 6H), 1.97 (t, 7= 9.1 Hz, 7H), 1.71 - 1.58 (m, IH), 1.50- 1.34 (m, IH), 0.88 (d, 7=6.4 Hz, 6H).

4-40. (3S)-3-(4,5-difluoro-2’,4’,6’-trimcthyHl,l’-biphenyI]-3-yl)-3-(2-(5-((dimethyIamino)methyl)

2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds CM-P1 and CM-P2)

586

CM-P1 ESI 636.2 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.99 (s, 1H), 6.92 - 6.84 (m, 4H), 6.72 (s, 1H), 5.82 - 5.68 (m, 1H), 5.61 - 5.55 (m, 1H), 3.61 - 3.48 (m, 2H), 2.83 - 2.65 (m, 2H), 2.38 (s, 6H), 2.30 (s, 3H), 2.03 - 1.92 (m, 5H), 1.73 (s, 3H), 1.49 - 1.37 (m, 1H), 0.99 - 0.93 (m, 6H).

CM-P2 ESI 636.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 8.08 (s, 1H), 7.02 - 6.84 (m, 5H), 5.77 - 5.72 (m, 1H), 5.59 - 5.52 (m, 1H), 4.08 (d, J= 14.4 Hz, 1H), 3.85 (d, J= 14.4 Hz, 1H), 2.79 - 2.75 (m, 1H), 2.70-2.54 (m,7H), 2.31 (s, 3H), 2.02-1.87 (m, 7H), 1.74-1.57 (m, 1H), 1.49-1.37 (m, 1H),O.910.86 (m, 6H).

4-41. (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-l(2ZZ)-yl)-4methylpentanamido)-3-(4,4’,5-trinuoro-2',6’-dimethyl-[l,l’-biphenyl]-3-yl)propanoicacid (diastereomcric compounds CN-P1 and CN-P2)

CN-P1 ESI 604.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.44 (s, 1H), 7.34 - 7.30 (m, 1H), 6.96 - 6.75 (m, 4H), 5.76 - 5.71 (m, 1H), 5.60 - 5.48 (m, 1H), 2.76 - 2.55 (m, 6H), 2.39 (s, 6H), 2.07 - 1.90 (m, 5H), 1.84 (s, 3H), 1.49 - 1.33 (m, 1H), 0.98 - 0.92 (m, 6H).

CN-P2 ESI 604.2 (M+H)⁺. *H NMR (400 MHz, MeOD) δ 7.50 (s, 1H), 7.46 - 7.10 (m, 1H), 7.04 - 6.93 (m, 1H), 6.91 - 6.84 (m, 3H), 5.67 - 5.57 (m, 2H), 3.47 - 3.37 (m, 1H), 3.31 - 3.21 (m, 1H), 3.02 - 2.91 (m, 1H),2.90-2.79(m, 7H),2.64-2.57 (m, 1H),2.50-2.42(m, 1H),2.07- 1.92(m,7H), 1.90- 1.78 (m, 1H), 1.47- 1.31 (m, 1H), 0.94-0.89 (m, 6H).

4-42. (3S)-3-(4,5-difIuoro-2^,,4^,,6’-trimethyl-[l,l'-biphenyl]-3-yI)-3-(2-(5-(2-(dimethyIamino)ethyI)3-fluoro-2-oxopyridin-l(2H)-yl)-4-methyIpentanamido)propa -noie acid (diastereomcric compounds CO-PI and CO-P2)

587

CO-PI ESI 600.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.49-7.44 (m, 2H), 6.92 (t, J= 8.2 Hz, 3H), 6.76 (d, J= 6.0 Hz, 1H), 5.65-5.61 (m, 1H), 5.40 (t, J= 5.6 Hz, 1H), 3.19-3.15 (m, 2H), 2.90-2.84 (m, 3H), 2.75 - 2.63 (m, 7H), 2.57-2.52 (m, 1H), 2.31 (s, 3H), 2.03 - 1.87 (m, 9H), 1.46-1.40 (m, 1H), 0.985 0.91 (m, 6H).

CO-P2 ESI 600.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.37-7.29 (m, 2H), 6.87 - 6.71 (m, 4H), 5.57 5.42 (m, 2H), 3.34 - 3.24 (m, 1H), 3.18 - 3.07 (m, 1H), 2.87-2.81 (m, 1H), 2.73-2.70 (m, 7H), 2.50-2.45 (m, 1H), 2.36-2.30 (m, 1H), 2.19 (s, 3H), 1.96 - 1.80 (m, 7H), 1.74 - 1.63 (m, 1H), 1.30-1.25 (m, 1H), 0.81-0.79 (m, 6H).

4-43. (3S)-3-(2-(5-(2-(3-iluoroazetïdin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2Z/)-yl)-4methylpentanamido)-3-(4,4',5-trifluoro-2',6’-dimethylbiphenyl-3-yI)propanoic acid (diastereomeric compounds CP-P1 and CP-P2)

CP-P1 ESI 630.2 (M+H) ⁺. IH NMR (400 MHz, MeOD) δ 7.49 (s, 1H), 6.99 - 6.89 (m, 1H), 6.89 - 6.76 (m, 3H), 6.29 (s, 1H), 5.66 - 5.50 (m, 2H), 5.40 - 5.10 (m, 1H), 4.14 - 3.90 (m, 2H), 3.86 - 3.55 (m, 2H), 3.03 (s, 2H), 2.86 - 2.53 (m, 4H), 2.23 (s, 3H), 2.06 - 1.90 (m, 5H), 1.86 (s, 3H), 1.49 - 1.32 (m, 1H), 1.02-0.84 (m, 6H).

588

CP-P2 ESI 630.2 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.49 (s, IH), 7.09 - 6.86 (m, 4H), 6.44 (s, IH), 5.72 - 5.55 (m, 2H), 5.30 (d, J= 57.8 Hz, IH), 4.28 (s, 2H), 3.93 (s, 2H), 3.19 (s, 2H), 2.87 - 2.50 (m, 4H), 2.25 (s, 3H), 2.04 (s, 6H), 1.93 - 1.73 (m, 2H), 1.47 - 1.28 (m, IH), 0.91 - 0.85 (m, 6H).

4-44. (35)-3-(5-chloro-4,4*-difIuoro-2’,6’-dimethyIbiphenyl-3-yl)-3-(2-(5-(2-(dimethyIamino)ethyl)2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds CQ-P1 and CQ-P2) (S) ^Cl \ JDH

CQ-P1 ESI 670.2 (M+H)⁺. IHNMR(400MHz,MeOD) δ 7.90 (s, IH), 7.13-7.11 (m, IH), 7.04-7.02 (m, IH), 6.88-6.81 (m, 2H), 6.74 (s, IH), 5.69 - 5.65 (m, IH), 5.57-5.53 (m, IH), 3.16-3.10 (m, 2H), 2.97 - 2.94 (m, 2H), 2.80 (s, 6H), 2.74 - 2.71 (m, 2H), 2.02 - 1.98 (m, 5H), 1.84 (s, 3H), 1.47 - 1.40 (m, IH), 0.98-0.93 (m, 6H).

CQ-P2 ESI 670.2 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.86 (s, IH), 7.20 - 7.18 (m, IH), 7.07 (d, 7= 6.1 Hz, IH), 6.88 (d, J= 11.2 Hz, 3H), 5.73 - 5.67 (m, IH), 5.63 (t, J= 7.6 Hz, IH), 3.30 - 3.18 (m, 2H), 3.01 (t, J= 6.9 Hz, 2H), 2.85 (s, 6H), 2.69 - 2.60 (m, IH), 2.58 - 2.52 (m, IH), 2.03 - 1.95 (m, 7H), 1.77 - 1.70 (m, IH), 1.41 - 1.36 (m, IH), 0.91 - 0.89 (m, 6H).

4-45. (3S)-3-(5-chIoro-4,4’-difIuoro-2’,6’-dimethylbiphenyI-3-yI)-3-(2-(5-(2-(3-fluoroazetidin-lyl)ethyl)-4-methyl-2-oxopyridin-l(2/Z)-yl)-4-methy!pentanamido)propanoic acid (diastereomeric compounds CR-P1 and CR-P2)

589

CR-P1 ESI 646.2 (M+H)⁺. IHNMR(400MHz, MeOD) δ 7.50(s, 1H), 7.15-7.13 (m, 1H), 6.99-6.97 (m, 1H), 6.88-6.85 (m, 2H),6.29 (s, 1H), 5.64-5.49 (m, 2H), 5.32-5.18 (m, 1H), 4.11-4.07 (m,2H), 3.85-3.72 (m, 2H), 3.10 (t, J= 6.9 Hz, 2H), 2.82 - 2.62 (m, 4H), 2.24 (s, 3H), 2.09 - 1.90 (m, 5H), 1.89 5 (d, J = 8.2 Hz, 3H), 1.43 - 1.38 (m, 1 H), 0.96 - 0.92 (m, 6H).

CR-P2 ESI 646.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.45 (s, 1H), 7.21-7.18 (m, 1H), 7.08 - 7.06 (m, 1H), 6.89 (d, J= 9.6 Hz, 2H), 6.43 (s, 1H), 5.73 - 5.53 (m, 2H), 5.43 - 5.25 (m, 1H), 4.44 -4.41 (m, 2H), 4.16-4.01 (m, 2H), 3.39- 3.36 (m, 2H), 2.91 -2.87 (m, 1H), 2.73 - 2.62 (m, 2H), 2.52-2.49 (m, 1H), 2.25 (s, 3H), 2.03 (s, 6H), 1.98 - 1.88 (m, 1H), 1.81 - 1.72 (m, 1H), 1.44 - 1.33 (m, 1H), 0.91 - 0.89 10 (m, 6H).

4-46. (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)-yI)-4methylpentanamido)-3-(4,4',5-trifluoro-2',6'-dimethylbiphenyl-3-yl)propanoic acid (diastereomeric compounds CS-P1 and CS-P2)

CS-P1 ESI 654.2 (M+H) ⁺. 1H NMR (400 MHz, MeOD) δ 7.89 (s, 1H), 6.98 - 6.78 (m, 4H), 6.75 (s, 1H), 5.69 - 5.65 (m, 1H), 5.59 - 5.56 (m, 1H), 3.15- 3.06 (m, 2H), 2.95 (d, J= 6.2 Hz, 2H), 2.77 (s, 6H), 2.74 - 2.71 (m, 2H), 2.13 - 1.91 (m, 5H), 1.85 (s, 3H), 1.50 - 1.40 (m, 1H), 0.98 - 0.94 (m, 6H).

590

CS-P2 ESI 654.2 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.86 (s, IH), 7.05 - 6.96 (m, IH), 6.95 - 6.83 (m, 4H), 5.73 - 5.69 (m, IH), 5.63 (t, J= 7.7 Hz, IH), 3.28 - 3.14 (m, 2H), 2.99 (t, J= 7.0 Hz, 2H), 2.82 (s, 6H), 2.69 - 2.64 (m, 1 H), 2.62-2.52 (m, 1 H), 2.03 (d, J = 2.1 Hz, 6H), 1.99 - 1.94 (m, 1 H), 1.77 1.72 (m,, IH), 1.45 - 1.31 (m, IH), 0.91 - 0.89 (m, 6H).

4-47. (3S)-3-(5-chloro-4,4’-difluoro-2’,6’-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-lyl)ethyl)-2-oxopyridin-l(277)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds CT-P1 and CT-P2)

CT-P1 ESI 632.2 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.59 (s, IH), 7.46 - 7.43 (m, IH), 7.15 - 7.13 (m, IH), 7.00- 6.92 (m, IH), 6.87 (d, J= 9.6 Hz, 2H), 6.45 (d, J= 9.3 Hz, IH), 5.68 - 5.57 (m, IH), 5.51 (t, J= 6.2 Hz, IH), 5.38 - 5.16 (m, IH), 4.25 - 4.04 (m, 2H), 3.96 - 3.76 (m, 2H), 3.25 - 3.13 (m, 2H), 2.83 - 2.58 (m, 4H), 2.08 - 1.92 (m, 5H), 1.88 (s, 3H), 1.47 - 1.40 (m, IH), 0.97 - 0.92 (m, 6H).

CT-P2 ESI 632.2 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.54 (s, IH), 7.49 (d, J= 8.8 Hz, IH), 7.20 7.18 (m, IH), 7.04 (d, J= 4.5 Hz, IH), 6.88 (d, J= 9.6 Hz, 2H), 6.56 (d, J= 9.1 Hz, IH), 5.71 - 5.57 (m, 2H), 5.34 (d, J= 59.0 Hz, IH), 4.40 (s, 2H), 4.08 (s, 2H), 3.42 (s, IH), 2.70 (d, J= 52.7 Hz, 3H), 2.52 (s, IH), 2.03 (d, J= 3.5 Hz, 6H), 1.99 - 1.93 (m, 2H), 1.88 - 1.76 (m, IH), 1.49 - 1.31 (m, IH), 0.91 (t, J= 6.7 Hz, 6H).

4-48. (35)-3-(4,4'-difluoro-2',5,6'-trimethylbiphenyl-3-yl)-3-(2-(5-(2-(dimethyIamino)ethyl)-3fluoro-2-oxopyridin-l(2Z0-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds CU-P1 and CU-P2)

591

CU-P1 ESI 600.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.52 (s, 1H), 7.47-7.44 (m, 1H), 6.91 - 6.81 (m, 3H), 6.78 (d, J= 6.8 Hz, 1H), 5.64 - 5.60 (m, 1H), 5.40 (t, J= 5.6 Hz, 1H), 3.36 (d, J= 6.1 Hz, 1H), 3.24 - 3.12 (m, 1H), 2.97 - 2.77 (m, 2H), 2.73 (s, 6H), 2.70 - 2.61 (m, 1H), 2.57 - 2.52 (m, 1H), 2.30 (d, 5 J= 1.6 Hz, 3H), 2.12-1.96 (m,5H), 1.95 (s, 3H), 1.52-1.37 (m, 1H), 0.97-0.91 (m, 6H).

CU-P2 ESI 600.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.50 (s, 1H), 7.45 - 7.42 (m, 1H), 6.89 (t, J= 6.1 Hz, 2H), 6.84 (d, J = 9.6 Hz, 2H), 5.66 - 5.62 (m, 1 H), 5.59 - 5.56 (m, 1 H), 3.47 - 3.36 (m, 1H), 3.30 - 3.25 (m, 1H), 3.00 - 2.94 (m, 1H), 2.90 - 2.77 (m, 7H), 2.61 - 2.56 (m, 1H), 2.46 - 2.40 (m, 1H), 2.32 (d, J= 1.8 Hz, 3H), 2.09 - 1.94 (m, 7H), 1.87-1.79 (m, 1H), 1.48 - 1.37 (m, 1H), 0.93 - 0.90 (m, 6H).

4-49. (3S)-3-(5-chloro-4,4*-dinuoro-2’,6’-dimethylbiphenyI-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)3-fluoro-2-oxopyridin-l(2Z/)-yl)-4-methylpentananiido)propanoic acid (diastereomeric compounds CV-P1 and CV-P2)

CV-P1 ESI 620.2 (M+H)*. 1H NMR (400 MHz, MeOD) δ 7.53 (s, 1H), 7.46 - 7.43 (m, 1H), 7.15 - 7.12 (m, 1H), 6.95 - 6.93 (m, 1H), 6.87 (d, J= 9.6 Hz, 2H), 5.65 - 5.61 (m, 1H), 5.42 (t, J= 5.8 Hz, 1H), 3.31 - 3.26 (m, 1H), 3.20 - 3.15 (m, 1H), 2.96 - 2.81 (m, 2H), 2.75 (s, 6H), 2.70 - 2.65 (m, 1H), 2.59 - 2.54 (m, 1H), 2.19-1.78 (m, 8H), 1.46-1.40 (m, 1H), 0.97-0.91 (m, 6H).

592

CV-P2 ESI 620.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.50 (s, IH), 7.45 - 7.42 (m, 1H), 7.18 - 7.16 (m, 1H), 7.04- 7.02 (m, 1H), 6.88 (d, J= 9.6 Hz, 2H), 5.67 - 5.63 (m, 1H), 5.59 - 5.56 (m, 1H), 3.46 3.36 (m, 1H), 3.29 - 3.22 (m, 1H), 2.98 - 2.92 (m, 1H), 2.86 - 2.84 (m, 1H), 2.82 (s, 6H), 2.62 - 2.58 (m, 1H), 2.51-2.41 (m, 1H), 2.03 (d, J= 1.5 Hz, 6H), 1.97 (t, J= 7.1 Hz, 1H), 1.90-1.78 (m, 1H), 1.41 1.36 (m, 1H), 0.97 - 0.74 (m, 6H).

4-50. (35)-3-(4,4'-difluoro-2',5,6'-trimethylbiphenyl-3-yI)-3-(2-(5-(2-(dimethyIamino)ethyl)-4mcthyI-2-oxopyridin-l(2ZZ)-yl)-4-methylpentananiido)propanoic acid (diastereomeric compounds CW-P1 and CW-P2)

F

O

CW-P1 ESI 596.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.59 (s, 1H), 6.83 (t, J= 7.2 Hz, 4H), 6.32 (s, 1H), 5.70 -5.56 (m, 1H), 5.54-5.47 (m, 1H), 3.21 -3.06 (m, 2H), 2.95-2.83 (m, 2H), 2.79 (s, 6H), 2.73 - 2.55 (m, 2H), 2.35 - 2.20 (m, 6H), 2.07 - 1.91 (m, 5H), 1.85 (s, 3H), 1.50 - 1.29 (m, 1H), 1.02 0.83 (m, 6H).

CW-P2 ESI 596.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.57 (s, 1H), 6.99 - 6.78 (m, 4H), 6.43 (s, 1H), 5.71 - 5.53 (m, 2H), 3.28 - 3.06 (m, 2H), 2.97 - 2.85 (m, 2H), 2.81 (s, 6H), 2.66 - 2.56 (m, 1H), 2.56-2.40 (m, 1H), 2.36 - 2.24 (m, 6H), 2.05 - 1.89 (m, 7H), 1.86 - 1.72 (m, 1H), 1.43 - 1.28 (m, 1H), 0.89 (t,J= 5.2 Hz, 6H).

4-51. (3S)-3-(4*-chloro-4-fluoro-2^,,5,6*-trimethylbiphenyl-3-yl)-3-(2-(5-(2-(dimethyIamino)ethyl)4-methyl-2-oxopyridin-l(2/0*yl)*4*^mcthyIpentanamido)propanoic acid (diastereomeric compounds CX-P1 and CX-P2)

593 (S) ^Me \ ^OH

CX-P1 ESI 612.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.58 (s, 1H), 7.11 (d, J= 2.5 Hz, 2H), 6.92 6.76 (m, 2H), 6.32 (s, 1H), 5.61 - 5.41 (m, 2H), 3.25 - 3.05 (m, 2H), 2.88 (t, J= 7.3 Hz, 2H), 2.78 (s, 6H), 2.71 - 2.54 (m, 2H), 2.28 (d, J= 13.0 Hz, 6H), 2.05 - 1.92 (m, 5H), 1.88 (s, 3H), 1.48 - 1.32 (m, 5 1H), 1.04-0.85 (m, 6H).

CX-P2 ESI 612.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.55 (s, 1H), 7.13 (s, 2H), 6.93 - 6.84 (m, 2H), 6.42 (s, 1H), 5.70 - 5.54 (m, 2H), 3.24 - 3.11 (m, 2H), 2.99 - 2.76 (m, 8H), 2.64 - 2.42 (m, 2H), 2.36 2.20 (m, 6H), 2.03 - 1.90 (m, 7H), 1.83 - 1.72 (m, 1H), 1.47 - 1.28 (m, 1H), 0.90 (t, J= 6.2 Hz, 6H).

4-52. (3S)-3-(2-(5-(2-(dimethyIamino)ethyl)-3-fluoro-2-oxopyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyI-[l,r-biphenyl]-3-yl)propanoic acid (diastereomeric compounds CY-P1 and CY-P2) (S) F ^Me\ .OH

CY-P1 ESI 596.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.59 - 7.37 (m, 2H), 6.96 - 6.64 (m, 4H), 5.76 15 -5.58(m, 1 H), 5.39 (t, J = 5.5 Hz, 1H), 3.42 - 3.25 (m, 1 H), 3.23 - 3.06 (m, lH),2.96-2.76(m,2H),

2.73 - 2.46 (m, 8H), 2.41 - 2.22 (m, 6H), 2.05 - 1.88 (m, 8H), 1.44 (m, J= 13.7,6.7 Hz, 1H), 0.93 (m, J = 17.3, 6.6 Hz, 6H).

CY-P2 ESI 596.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.51 (s, 1H), 7.42 (m, J= 10.3,2.1 Hz, 1H), 6.89 (m, J= 7.0,4.6 Hz, 4H), 5.62 (m, J= 14.0,9.4,5.4 Hz, 2H), 3.43 - 3.30 (m, 1H), 3.23 (s, 1H), 2.93

594 (m, J= 9.6,4.9 Hz, IH), 2.87-2.75 (m, 7H), 2.59 (m, J= 14.9,4.0 Hz, IH), 2.44 (m, J= 14.8, 10.1 Hz, IH), 2.34 - 2.22 (m, 6H), 2.05 - 1.91 (m, 7H), 1.84 - 1.72 (m, IH), 1.46 - 1.22 (m, IH), 0.91 (m, J= 6.6, 3.1 Hz, 6H).

4-53. (3S)-3-(4-fluoro-2’,4’,5,6’-tetramethyl-[l,r-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((R)-3fluoropyrrolidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yI)-4-methylpentanamido)propanoic acid (diastereomeric compounds CZ-P1 and CZ-P2)

CZ-P1 ESI 640.2 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.50 (s, IH), 7.41 - 7.31 (m, IH), 6.91 (s, 2H), 6.85 (d, J= 7.0 Hz, IH), 6.79 (d, J= 6.7 Hz, IH), 5.70 (s, IH), 5.49 (s, IH), 5.24 (d, J= 53.7 Hz, IH), 3.26 - 3.00 (m, 5H), 2.88 - 2.56 (m, 4H), 2.41 - 2.13 (m, 9H), 2.07 - 1.90 (m, 5H), 1.85 (s, 3H), 1.53 - 1.26 (m, IH), 1.05 - 0.80 (m, 6H).

CZrP2 ESI 640.2 (M+H)⁺. IH NMR (500 MHz, MeOD) δ 7.49 (s, IH), 7.47 - 7.36 (m, IH), 6.90 (d, J = 8.8 Hz, 4H), 5.67 (t, J = 7.7 Hz, IH), 5.61 -5.52 (m, IH), 5.33 (d, J = 54.6 Hz, IH), 3.73 - 3.38 (m, 5H), 3.28 (s, IH), 2.97 - 2.76 (m, 2H), 2.65 - 2.43 (m, 2H), 2.41 - 2.19 (m, 6H), 2.07 - 1.88 (m, 7H), 1.84 1.73 (m, 1 H), 1.51 -1.20 (m, IH), 0.91 (d, J = 6.5 Hz, 6H).

4-54. (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-3-methyl-2-oxopyridin-l(2H)-yI)-4methylpentanamido)-3-(4-fluoro-2’,4’,5,6'-tetramethyl-[l,r-biphenylJ-3-yl)propanoic acid (diastereomeric compounds DA-P1 and DA-P2)

595

DA-P1 ESI 592.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.35(S, 1H), 7.32(S, 1H), 6.80 (d, J= 8.4 Hz, 2H), 6.73 (d, J= 5.5 Hz, 1H), 6.59 (d, J= 6.7 Hz, 1H), 5.48-5.46 (m, 1H), 5.23 (t, J= 5.1 Hz, 1H), 3.08 2.98 (m, 1H), 2.68-2.67 (m, 2H), 2.56 (s, 6H), 2.51-2.35 (m, 3H), 2.25 - 2.11 (m, 6H), 1.97 - 1.74 (m, 5 11 H), 1.36 - 1.24 (m, 1 H), 0.88 - 0.76 (m, 6H).

DA-P2 ESI 592.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.40 (s, 1H), 7.29 (s, 1H), 6.78-6.74 (m, 3H), 6.67 (d, J= 7.0 Hz, 1H), 5.52-5.48 (m, 1H), 5.42-5.39 (m, 1H), 3.33-3.27 (m, 1H), 3.20-3.14 (m, 1H), 2.85-2.61 (m, 8H), 2.49-2.44 (m, 1H), 2.33-2.27 (m, 1H), 2.18 (s, 6H), 1.97-1.67 (m, 11H), 1.38 1.24 (m, 1H), 0.82-0.77 (m, 6H).

4-55. (3S)-3-(4,4’-difluoro-2’,6’-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds DB-P1 and DB-P2)

DB-P1 ESI 654.3 (M+H)*. 1H NMR (400 MHz, MeOD) δ 7.55 (s, 1 H), 7.50 - 7.37 (m, 1 H), 7.40 - 7.25 (m, 2H), 6.89 (d, J = 9.6 Hz, 2H), 5.73 - 5.55 (m, 1H), 5.47 (t, J = 5.9 Hz, 1H), 3.27 - 3.13 (m, 1H), 2.98 - 2.82 (m, 3H), 2.78 (s, 6H), 2.73-2.64 (m, 1H), 2.63 - 2.50 (m, 1H), 2.13 - 1.97 (m, 5H), 1.93 (s, 3H), 1.42 (s, 1H), 1.11 - 0.79 (m, 6H).

596

DB-P2 ESI 654.3 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.51 (s, IH), 7.48 - 7.41 (m, IH), 7.38 (t, J = 6.0 Hz, 2H), 6.90 (d, J = 9.6 Hz, 2H), 5.76 - 5.43 (m, 2H), 3.42 (d, J = 10.1 Hz, IH), 3.28 (d, J = 12.8 Hz, IH), 2.96 (d, J = 9.5 Hz, IH), 2.85 (d, J = 7.2 Hz, 6H), 2.74 - 2.54 (m, IH), 2.55 - 2.34 (m, IH), 2.15 1.93 (m, 6H), 1.93 - 1.72 (m, IH), 1.52 - 1.27 (m, IH), 0.92 (t, J = 6.5 Hz, 6H).

4-56. (3S)-3-(4-fluoro-2’,4’,5,6’-tetramethyIbiplienyl-3-yl)-3-(2-(3-fIuoro-5-(2-(3-fluoroazetidin-lyI)ethyl)-2-oxopyridin-l(2H)-y!)-4-methylpentanamido)propanoic acid (diastereomeric compounds DC-P1 and DC-P2)

DC-P1 ESI 626.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.45 - 7.33 (m, 2H), 6.96 - 6.85 (m, 3H), 6.83-6.75 (m, IH), 5.69 (t,J= 8.1 Hz, IH), 5.52-5.45 (m, IH), 5.30-5.10 (m, IH), 4.23 - 4.09 (m, IH), 4.02 - 3.89 (m, IH), 3.78 - 3.62 (m, 2H), 3.26- 3.16 (m, 2H), 2.78 - 2.56 (m, 4H), 2.36 - 2.25 (m, 6H), 2.00 - 1.92 (m, 5H), 1.88 (s, 3H), 1.48 - 1.39 (m, IH), 0.98 - 0.86 (m, 6H).

DC-P2 ESI 626.3 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.45 - 7.35 (m, 2H), 6.97 - 6.86 (m, 4H), 5.76 - 5.62 (m, 2H), 5.42 - 5.20 (m, IH), 4.49 - 4.28 (m, 2H), 4.12-3.95 (m, 2H), 3.44 - 3.36 (m, 2H), 2.78 - 2.63 (m, 2H), 2.67 - 2.52 (m, IH), 2.61 - 2.52 (m, IH), 2.37 - 2.25 (m, 6H), 2.01 - 1.91 (m, 7H), 1.85 - 1.69 (m, IH), 1.43 -1.36(m, IH), 0.96 - 0.85 (m, 6H).

4-57. (35)-3-(2'-chloro-4,4’-difluoro-5,6’-dimethyI-[l,l’-biphenylJ-3-yI)-3-(2-(3-nuoro-5-(2-(3fluoroazetidin-l-yI)ethyl)-2-oxopyridin-l(2.H)-yI)-4-methylpentanamido)propanoic acid (diastereomeric compounds DD-P1 and DD-P2)

597

DD-P1 ESI 650.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) <5 7.43 - 7.34 (m, 2H), 7.17 - 7.13 (m, 1H), 7.06-7.01 (m, 1 H), 6.89-6.85 (m, 1 H), 5.72 - 5.67 (m, 1 H), 5.54-5.49 ( m, 1H), 5.32 - 5.09 (m, 1H), 4.15 - 3.65 (m, 4H), 3.19 - 3.10 (m, 2H), 2.78 - 2.60 (m, 4H), 2.31 (s, 3H), 2.08 - 1.92 (m, 5H), 1.49 1.39 (m, 1H), 0.97- 0.93 (m, 6H).

DD-P2 ESI 650.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.39 - 7.36 (m, 2H), 7.15 (d, J= 8.5 Hz, 1H), 7.08 - 6.96 (m, 3H), 5.73 - 5.61 (m, 2H), 5.41 - 5.22 (m, 1H), 4.48-4.28 (m, 2H), 4.11 - 3.94 (m, 2H), 3.42 - 3.33 (m, 2H), 2.80 - 2.47 (m, 4H), 2.34 (d, J= 1.8 Hz, 3H), 2.09 (d, J= 2.7 Hz, 3H), 2.03 - 1.90 (m, 1H), 1.83 - 1.72 (m, 1H), 1.44 - 1.30 (m, 1H), 0.94 - 0.89 (m, 6H).

4-58. (35)-3-(2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yI)ethyl)-2-oxopyridin-l(2i7)-yl)-4methylpentanamido)-3-(2',4,4'-trinuoro-5,6'-dimcthylbiphenyl-3-yl)propanoic acid (diastercomeric compounds DE-PI and DE-P2)

DE-PI ESI 634.2(M+H)⁺. lHNMR(400MHz, MeOD)87.43 (s, 1H),7.36(d, J= 10.3 Hz, 1H),7.O2 (d, J= 6.8 Hz, 1H), 6.98 - 6.89 (m, 2H), 6.85 (t, J= 9.2 Hz, 1H), 5.69 (t, J= 8.1 Hz, 1H), 5.53 - 5.50 (m, 1H), 5.30 - 5.08 (m, 1H), 4.09 - 3.99 (m, 2H), 3.77 - 3.63 (m, 2H), 3.15 - 3.12 (m, 2H), 2.79 - 2.69 (m, 2H),2.66-2.62(m,2H),2.31 (s, 3H),2.09(s,3H), 1.97(t,J= 7.6Hz,2H), 1.51 - 1.37(m, 1H),O.980.93 (m, 6H).

DE-P2 ESI 634.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.43 - 7.32 (m, 2H), 7.06 (d, J= 6.7 Hz, 2H), 6.93 (d, J= 9.3 Hz, 1H), 6.88 - 6.83 (m, 1H), 5.74 - 5.59 (m, 2H), 5.39 - 5.24 (m, 1H), 4.42 - 4.32 (m, 2H), 4.10 - 3.88 (m, 2H), 3.40 - 3.37 (m, 2H), 2.81 - 2.71 (m, 2H), 2.65 - 2.60 (m, 1H), 2.55 - 2.48 (m, 1H), 2.34 (d, J= 1.6 Hz, 3H), 2.16 (s, 3H), 2.03 - 1.93 (m, 1H), 1.86 - 1.75 (m, 1H), 1.45 - 1.33 (m, 1H), 0.93-0.91 (m, 6H).

598

4-59. (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(triiluoromethyl)pyridin-l(2H)-yI)-4methylpentanamido)-3-(2^,-cycIopropyI-4,4'-difluoro-5,6'-dimethyl-[l,l'-biphenyI]-3-yl)propanoîc acid (diastereomeric compounds DF-P1 and DF-P2)

DF-P1 ESI 688.2 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 6.95 (dd, J= 19.9,7.2 Hz, 2H), 6.86 - 6.64 (m, 2H), 6.55 - 6.23 (m, 1H), 5.75 - 5.49 (m, 2H), 3.85 (t, J= 7.7 Hz, 4H), 3.33 (m, J= 3.2, 1.6 Hz, 2H), 3.13 (m, J = 6.8 Hz, 2H), 2.90 - 2.58 (m, 2H), 2.51 - 2.21 (m, 5H), 2.01 (d, J= 5.3 Hz, 4H), 1.87 (s, 1H), 1.40 (s, 2H), 1.07 - 0.85 (m, 6H), 0.75 (m, J= 8.6,3.5 Hz, 1H), 0.66 - 0.43 (m, 3H).

DF-P2 ESI 688.2 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.74 (d, J= 11.5 Hz, 1H), 6.94 (m, J= 46.9, 28.6, 8.1 Hz, 4H), 6.50 (d, J = 10.4 Hz, 1H),5.78 (m,J=11.0,3.1Hz, 1H), 5.62 (m,J= 7.3 Hz, 1H), 4.13 (m, J= 8.0 Hz, 4H), 3.50 - 3.32 (m, 2H), 2.94 (d, J= 16.3 Hz, 1H), 2.81 (d, J= 7.7 Hz, 2H), 2.68 2.61 (m, 1H), 2.57 - 2.42 (m, 3H), 2.34 (d, J= 1.1 Hz, 3H), 2.05 - 1.79 (m, 4H), 1.65 (m, J= 13.9,7.1 Hz, 1H), 1.50 - 1.30 (m, 2H), 0.88 (d, J= 6.6 Hz, 6H), 0.74 (m, 14.0,7.3 Hz, 2H), 0.60 (m, J= 6.4,

5.0 Hz, 2H).

4-60. (3S)-3-((3R)-2-(5-(2-(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yl)-3methyIpentanamido)-3-(4-nuoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoic acid (diastereomeric compounds DG-P1 and DG-P2)

DG-P1 ESI 646.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.94 (s, IH), 6.89 (s, 1H), 6.82 - 6.75 (m, 3H), 6.66 (s, 1H), 5.65 - 5.53 (m, 1H), 5.33 (d, J= 11.3 Hz, IH), 3.05 - 2.83 (m, 5H), 2.82- 2.62 (m,

599

6H), 2.40 - 2.18 (m, 8H), 2.03 - 1.88 (m, 3H), 1.78 - 1.67 (m, 1H), 1.63 (s, 3H), 1.38 - 1.21 (m, 1H), 1.07 - 0.96 (m, 3H), 0.75 (d, J= 6.5 Hz, 3H).

DG-P2 ESI 646.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.92 (s, 1H), 6.91 - 6.72 (m, 5H), 5.69 - 5.52 (m, 1H), 5.21 (d, J= 10.9 Hz, 1H), 3.14 - 2.79 (m, 3H), 2.68 (s, 6H), 2.55 - 2.36 (m, 2H), 2.22 - 2.06 (m, H), 1.84 (d, 7= 3.6 Hz, 4H), 1.32 - 0.99 (m, 3H), 0.93 - 0.61 (m, 7H).

4-61. (3S)-3-(2’,6’-dichIoro-4-fluoro-4’,5-dimethyIbiphenyl-3-y!)-3-(2-(5-(2-(dimethylamino)ethyI)2-oxo-4-(trifluoromethyl)pyridin-l(27Z)-yl)-3-methylbutanamido)propanoic acid (diastereomeric compounds DH-P1 and DH-P2)

DH-P1 ESI 672.1 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ: 7.91 (s, 1H), Ί2Ί (d, J= 6.0 Hz, 1H), 7.14 (d, J =5.2 Hz, 1H), 6.90 (t, 7= 6.0 Hz, 2H), 6.67 (d, 7= 5.6 Hz, 1H), 5.64-5.60 (m, 1H), 5.29 (d, J= 11.2 Hz, 1H), 2.97 - 2.85 (m, 4H), 2.78 - 2.61 (m, 8H), 2.46 - 2.40 (m, 1H), 2.36 (s, 3H), 2.27 (s, 3H), 1.16 (d, J= 6.4 Hz, 3H), 0.78 (d, J= 6.4 Hz, 3H).

DH-P2 ESI 672.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ: 8.01 (s, 1H), 7.30 (s, 2H), 7.09 - 7.07 (m, 1H), 7.00 (d, 7=7.2 Hz, IH), 6.90 (s, 1H), 5.78-5.74 (m, 1H), 5.23 (d, 7= 11.2 Hz, 1H), 3.27-3.20 (m, 1H), 3.17 - 3.11 (m, 1H), 3.09 - 3.01 (m, 1H), 2.99 - 2.93 (m, 1H), 2.78 (s, 6H), 2.61 - 2.50 (m, 2H), 2.47-2.37 (m, 4H), 2.31 (d,7= 1.2 Hz, 3H), 0.94 (d,7= 6.4 Hz, 3H), 0.71 (d,7= 6.8 Hz, 3H).

4-62. (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trinuoromethyl)pyridin-l(2Z0-yl)-4methylpentanamidol-S-ÎZ’-cyclopropyl-d-fluoro-d'^ô’-trimethyl-ÎH’-biphenylJ-S-yOpropanoic acid (diastereomeric compounds DI-PI and DI-P2)

600

DI-PI ESI 684.3 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.84 (s, IH), 6.97 - 6.78 (m, 4H), 6.58 (s, 1H), 5.69 - 5.59 (m, 2H), 3.97 - 3.94 (m, 4H), 3.26 - 3.21 (m, 2H), 2.86 - 2.81 (m, 2H), 2.72 - 2.68 (m, 2H), 2.46 - 2.38 (m, 2H), 2.29 (d, J= 4.9 Hz, 6H), 2.03 - 1.97 (m, 3H), 1.85 (s, 2H), 1.48 - 1.31 (m, 2H), 0.98 - 0.91 (m, 6H), 0.67 (d, J= 8.4 Hz, 1H), 0.59 - 0.44 (m, 3H).

DI-P2 ESI 684.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.73 (d, J= 10.5 Hz, 1H), 7.02 - 6.96 (m, 2H), 6.91 (s, 1H), 6.90 (s, 1H), 6.59 (s, 1H), 5.78 - 5.75 (m, 1H), 5.64 - 5.59 (m, 1H), 4.14 - 4.10 (m, 4H), 3.47 - 3.38 (m, 2H), 2.97 - 2.92 (m, 1H), 2.85 - 2.75 (m, 1H), 2.69 - 2.60 (m, 1H), 2.55 - 2.45 (m, 3H), 2.34 (s, 3H), 2.29 (s, 3H), 2.05 - 1.96 (m, 4H), 1.71-1.61 (m, 1H), 1.49 - 1.39 (m, 2H), 0.90 (d, J= 6.6 Hz, 6H), 0.70 - 0.66 (m, 2H), 0.58 - 0.55 (m, 2H).

4-63. (3S)-3-(2’,6’-dichloro-4-fluoro-5-methylbiphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2· oxo-4-(trifluoromethyl)pyridin-l(2Z7)-yl)-4-methyIpentanamido)propanoic acid (diastereomeric compounds DJ-P1 and DJ-P2)

DJ-P1 ESI 672.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ: 7.89 (s, 1H), 7.46 (d, J= 8.0 Hz, 1H), 7.39 (d, J= 7.2 Hz, 1H), 7.32 (t, J= 8.0 Hz, 1H), 7.00 - 6.96 (m, 2H), 6.75 (s, 1H), 5.72 - 5.68 (m, 1H), 5.60 5.56 (m, 1H), 3.10 - 3.01 (m, 2H), 2.94 - 2.92 (m, 2H), 2.74 - 2.65 (m, 8H), 2.27 (d, J= 1.2 Hz, 3H), 2.01 - 1.93 (m, 2H), 1.47 - 1.41 (m, 1H), 0.95 (d, J= 6.4 Hz, 3H), 0.93 (d, J= 6.4 Hz, 3H).

DJ-P2 ESI 672.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ: 7.91 - 5.88 (m, 1H), 7.47 (d, J= 8.0 Hz, 2H), 7.35 - 7.31 (m, 1H), 7.08 - 7.02 (m, 2H), 6.89 (s, 1H), 5.78 - 5.74 (m, 1H), 5.64 (t, J= 7.6 Hz, 1H), 3.27 -3.15 (m, 2H), 3.06 - 2.95 (m, 2H), 2.80 (s, 6H), 2.65 - 2.60 (m, 1H), 2.55 - 2.49 (m, 1H), 2.32 (s, 3H), 1.99-1.92 (m, 1H), 1.71 - 1.64 (m, 1H), 1.41 -1.34 (m, 1H), 0.86-0.84 (m, 6H).

4-64. (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2//)-yI)-4methyIpentanamido)-3-(4-fluoro-2',5,6'-trimethyl-4'-(trifluoromethyl)biphenyI-3-yl)propanoic acid (diastereomeric compounds DK-P1 and DK-P2)

601

DK-P1 ESI 712.2 (M+H)⁺. IH NMR (400 MHz, MeOD) δ: 7.88 (s, IH), 7.39 (s, IH), 7.35 (s, IH), 6.91 (t, J= 6.2 Hz, 2H), 6.70 (s, IH), 5.66 - 5.57 (m, 2H), 4.04 (t, J= 8.2 Hz, 4H), 3.29 (t, 7= 7.4 Hz, 2H), 2.84 (t, 7= 7.2 Hz, 2H), 2.78 - 2.67 (m, 2H), 2.48 - 2.40 (m, 2H), 2.30 (d, 7= 1.2 Hz, 3H), 2.08 (s, 3H), 2.03 - 1.99 (m, 2H), 1.91 (s, 3H), 1.47 - 1.40 (m, IH), ), 0.95 (d, 7= 6.8 Hz, 3H), 0.93 (d, 7= 6.4 Hz, 3H).

DK-P2 ESI 712.2 (M+H)⁺. IH NMR (400 MHz, MeOD) δ: 7.74 (s, IH), 7.41 (s, 2H), 6.98 (s, IH), 6.96 (s, IH),6.90(s, IH),5.79-5.76(m, IH),5.60(t,7=8.0Hz, IH),4.15 (t,7= 8.0Hz,4H),3.48-3.42 (m, IH), 3.38 - 3.33 (m, IH), 2.98 - 2.91 (m, IH), 2.84 - 2.77 (m, IH), 2.69 - 2.64 (m, IH), 2.55 - 2.45 (m, 3H), 2.35 (d,7= 1.6 Hz, 3H), 2.09 (s, 3H), 2.08 (s, 3H), 2.03 - 1.96 (m, IH), 1.69 - 1.62 (m, IH), 1.46 - 1.36 (m, IH), 0.89 (d,7= 1.6 Hz, 3H), 0.87 (d,7= 2.0 Hz, 3H).

4-65. (3S)-3-(2’-chloro-4-fluoro-5,6’-dimethyl-[l,l’-biphenyl)-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methyIpentanamido)propanoic acid (diastereomeric compounds DL-P1 and DL-P2)

DL-P1 ESI 652.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.90 (d, 7= 4.5 Hz, IH), 7.37 - 7.09 (m, 3H), 6.93 (m, 7= 10.9,4.9 Hz, 2H), 6.75 (d, 7= 6.5 Hz, IH), 5.68 (m, 7= 30.2,23.4 Hz, 2H), 3.00 (d,7= 50.0 Hz, 4H), 2.73 (d,7= 14.3 Hz, 8H), 2.30 (s, 3H), 2.13-1.83 (m, 5H), 1.45 (d,7= 6.4 Hz, IH), 0.96 (m,7 = 12.9, 6.6,2.5 Hz, 6H).

602

DL-P2 ESI 652.2 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.88 (s, IH), 7.34 - 7.09 (m, 3H), 7.11 - 6.51 (m, 3H), 5.69 (m, J= 21.6, 10.6,4.3 Hz, 2H), 3.15 (s, 2H), 2.98 (s, 2H), 2.88 - 2.53 (m, 8H), 2.34 (s, 3H), 2.08 (d, J = 5.6 Hz, 3H), 1.98 - 1.81 (m, 1 H), 1.78 (s, 1 H), 1.40 (s, 1 H), 0.89 (m, J = 6.4,4.6 Hz, 6H).

4-66. (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trinuoromethyI)pyridin-l(2H)-yI)-4methylpentanamido)-3-(2',4-difluoro-5,6'-dimethylbiphenyl-3-yl)propanoic acid (diastereomeric compounds DM*P1 and DM-P2)

DM-P1 ESI 648.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.84 (s, IH), 7.30 - 7.23 (m, IH), 7.16 -7.09 (m, IH), 7.06 -6.92 (m, 3H), 6.81 (s, IH), 5.71 - 5.60 (m, 2H), 4.01 (t, J= 8.1 Hz, 4H), 3.29 (s, 2H), 2.86 (t, J= 6.8 Hz, 2H), 2.72 (d, J= 6.6 Hz, 2H), 2.46 - 2.36 (m, 2H), 2.36 - 2.31 (m, 3H), 2.10 (s, 3H), 2.00 (t, J= 7.6 Hz, 2H), 1.51-1.42 (m, IH), 0.98 - 0.93 (m, 6H).

DM-P2 ESI 648.2 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.75 (s, IH), 7.31 -7.19 (m, IH), 7.15 - 7.04 (m, 3H), 6.99 (t, J= 8.8 Hz, IH), 6.92 (s, IH), 5.81 -5.75 (m, IH), 5.64 (t, J= 7.6 Hz, IH), 4.14 (t, J= 8.0 Hz, 4H), 3.49-3.35 (m, 2H), 2.94 (d, J= 15.7 Hz, IH), 2.87-2.75 (m, IH), 2.69-2.56 (m, IH), 2.57 - 2.43 (m, 3H), 2.35 (d, J= 1.5 Hz, 3H), 2.17 (d, J= 8.1 Hz, 3H), 2.04 - 1.95 (m, IH), 1.72 - 1.62 (m, IH), 1.46 -1.32 (m, IH), 0.97 -0.91 (m, 6H).

4-67. (35)-3-(3’,4-difluoro-2’,4’,5,6’-tetramethyIbiphenyl-3-yI)-3-(2-(5-(2-(dimethyIamino)ethyI)-2oxo-4-(trifluoromethyI)pyridin-l(2/7)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds DN-P1 and DN-P2)

603

DN-P1 ESI 664.2 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.85 (s, 1H), 7.01 - 6.79 (m, 4H), 5.78 - 5.58 (m, 2H), 3.29 - 3.07 (m, 2H), 3.04 - 2.89 (m, 2H), 2.81 (s, 6H), 2.70 - 2.42 (m, 2H), 2.33 (s, 3H), 2.26 (s, 3H),2.13-1.83 (m,7H), 1.81-1.60(m, 1H), 1.52-1.30(m, 1H), 1.02-0.81 (m,6H).

DN-P2 ESI 664.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.91 (s, 1 H), 6.99-6.68 (m, 4H), 5.82-5.50 (m, 2H), 3.19 - 2.89 (m, 4H), 2.83 - 2.54 (m, 8H), 2.38 - 2.22 (m, 6H), 2.13-1.80 (m, 5H), 1.72 (d, J= 14.7 Hz, 3H), 1.51-1.36 (m, 1H), 1.06 - 0.84 (m, 6H).

4-68. (3S)-3-(2-(5-(2-(azctidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yl)-410 methylpentanamido)-3-(4’-cyano-4-nuoro-2’,5,6'-trimethylbiphenyl-3-yl)propanoic acid (diastereomeric compounds DO-PI and DO-P2) (S) F Me \ .OH

DO-PI ESI 669.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 7.47 (d, J= 10.3 Hz, 2H), 6.91 (d, J= 6.7 Hz, 2H), 6.75 (s, 1H), 5.59 (d, J= 7.7 Hz, 2H), 4.06 (t, J= 8.1 Hz, 4H), 3.31 - 3.27 (m, 2H), 15 2.98 - 2.85 (m, 2H), 2.79 - 2.64 (m, 2H), 2.58 - 2.39 (m, 2H), 2.31 (s, 3H), 2.14 - 1.88 (m, 8H), 1.54 1.27 (m, 1H), 1.10 - 0.80 (m, 6H).

DO-P2 ESI 669.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.74 (s, 1H), 7.50 (s, 2H), 7.06 - 6.84 (m, 3H), 5.90-5.71 (m, 1H), 5.61 (t,J=7.6 Hz, 1H), 4.10 (s, 4H), 3.36 (s, 2H), 3.09-2.74 (m, 2H), 2.74604

2.60 (m, 1H), 2.55-2.39 (m, 3H), 2.35 (s, 3H), 2.13- 1.89 (m, 7H), 1.75- 1.62 (m, 1H), 1.50- 1.35 (m, 1H), 0.98-0.81 (m, 6H).

4-69. (3S)-3-(2^,-cyano-4-fluoro-5,6’-dimethyIbiphenyl-3-yl)-3-(2-(5-(2-(dimethyIamino)ethyl)-2oxo-4-(trifluoromcthyl)pyridin-l (2H)-yl)-4-mcthylpcntanamido)propanoic acid (diastereomeric compounds DP-P1 and DP-P2) p Me

DP-P1 ESI 643.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.89 (s, 1H), 7.59 (s, 2H), 7.43 (t, J= 7.7 Hz, 1H), 7.06 (s, 2H), 6.71 (d, J= 26.7 Hz, 1H), 5.73 (s, 1H), 5.60 (d, J= 73 Hz, 1H), 3.10 (s, 2H), 2.93 (d, J = 8.3 Hz, 2H), 2.80 - 2.69 (m, 8H), 2.32 (s, 3H), 2.19 (s, 2H), 2.00 (s, 3H), 1.49 - 1.42 (m, 1H), 1.000.92 (m, 6H).

DP-P1 ESI 643.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.81 (s, 1H), 7.66 - 7.52 (m, 2H), 7.45 (t, J= 7.7 Hz, 1H), 7.13 (d, J= 6.4 Hz, 2H), 6.90 (s, 1H), 5.77 - 5.59 (m, 2H), 3.23 (s, 2H), 3.01 (s, 2H), 2.83 (s, 6H), 2.69 - 2.53 (m, 1H), 2.58 - 2.49 (m, 1H), 2.37 (d, J= 1.6 Hz, 3H), 2.19 (s, 3H), 2.05 - 1.96 (m, 1H), 1.81 (s, 1H), 1.42- 1.36 (m, 1H), 0.99-0.91 (m, 6H).

4-70. (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z7)-yl)-4methylpentanamido)-3-(4-fluoro-2’-methoxy-5,6*-dimethylbiphenyl-3-yl)propanoic acid (diastereomeric compounds DQ-P1 and DQ-P2) (S) ^Me \ /OH

605

DQ-P1 ESI 660.2 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.82 (s, 1H), 7.21 (t, J= 8.0 Hz, 1H), 6.99 6.82 (m, 5H), 5.70 - 5.62 (m, 2H), 4.01 - 3.96 (m, 4H), 3.66 (s, 3H), 3.30 - 3.27 (m, 2H), 2.88 - 2.85 (m, 2H), 2.71 (d, J= 7.4 Hz, 2H), 2.45 - 2.39 (m, 2H), 2.29 (s, 3H), 2.02 - 1.93 (m, 5H), 1.45 -1.38 (m, 1H), 0.97 - 0.93 (m, 6H).

DQ-P2 ESI 660.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.22 (t, J= 8.0 Hz, 1H), 7.00 6.87 (m, 5H), 5.79 - 5.75 (m, 1H), 5.62 (t, J= 7.6 Hz, 1H), 4.13 (t, J= 7.9 Hz, 4H), 3.68 (s, 3H), 3.49 3.35 (m, 2H), 2.97- 2.91 (d, 7= 16.1 Hz, 1H), 2.85 - 2.77 (m, 1H), 2.66 - 2.62(m, 1H), 2.56 - 2.42 (m, 3H), 2.32 (d, 7= 1.7 Hz, 3H), 2.04 (s, 3H), 2.02 - 1.97 (m, 1H), 1.72 - 1.60 (m, 1H), 1.49 - 1.36 (m, 1H), 0.91 (d,7=6.5 Hz, 6H).

4-71. (35)-3-(2’-cycIopropyl-4-nuoro-4’,5,6’-trîmethyI-[l,l’-biphenylJ-3-yI)-3-(2-(5-(2(dimethylamino)ethyl)-4-methyI-2-oxopyridin-l(277)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds DR-P1 and DR-P2)

DR-P1 ESI 618.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.57 (d, 7= 1.8 Hz,l), 6.91 - 6.84 (m, 3H), 6.57 (d,7= 11.0 Hz, 1H), 6.38 (d,7= 8.9 Hz, 1H), 5.59 (d,7= 5.8 Hz, 1H), 5.46 (t, 7= 5.9 Hz, 1H), 3.22 - 3.06 (m, 2H), 2.87 (t,7= 7.1 Hz, 2H), 2.74 (s, 6H), 2.71 - 2.56 (m, 2H), 2.27 (d, 7= 13.3 Hz, 9H), 2.04 - 1.87 (m, 5H), 1.48 - 1.38 (m, 2H), 0.95 - 0.89 (m, 6H), 0.72 - 0.67 (m, 1H), 0.63 - 0.55 (m, 1H), 0.53 -0.48(ra,2H).

DR-P2 ESI 618.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.54 (d, 7= 10.5 Hz, 1H), 6.98 - 6.89 (m, 2H), 6.89(s, IH), 6.59(s, 1H), 6.44(d,7=5.1 Hz, 1H),5.65-5.56(m,2H), 3.34-3.26(m,2H), 3.20-3.13 (m, 2H), 2.94 - 2.88 (m, 2H), 2.81 (d, 7= 2.0 Hz, 6H), 2.64 - 2.57 (m, IH), 2.48 - 2.41 (m, IH), 2.322.246 (m, 9H), 1.99 - 1.92 (m, 4H), 1.81-1.74 (m, IH), 1.49 - 1.33 (m, IH), 0.92 - 0.85 (m, 6H), 0.68 - 0.63 (m, 2H), 0.58 - 0.51 (m, 2H).

606

4-72. (3S)-3-(4’-cyclopropyl-4-fluoro-2’,5,6*-triniethyl-[l,l’-biphenyl]-3-yI)-3-(2-(5-(2(dimethylamino)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds DS-P1 and DS-P2)

DS-P1 ESI 618.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.46 (s, 1H), 6.84 - 6.65 (m, 3H), 6.45 (d, J= 11.2 Hz, 1H), 6.27 (d, J= 8.7 Hz, 1H), 5.48-5.46 (m, 1H), 5.33 (d, J= 5.6 Hz, 1H), 3.15-2.95 (m, 2H), 2.78-2.74 (m, 3H), 2.60 (d, J= 25.4 Hz, 6H), 2.58 - 2.40 (m, 2H), 2.17 (s, 6H), 2.13(s, 3H), 1.95 - 1.73 (m, 5H), 1.34-1.28 (m, 2H), 0.86 - 0.73 (m, 6H), 0.62 - 0.32 (m, 4H).

DS-P2 ESI 618.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.43(s, 1H), 7.40(s, 1H), 6.84 (t, 6.2 Hz,

2H), 6.77 (s, 1H), 6.47 (s, 1H), 6.32 (d, J= 5.5 Hz, 1H), 5.52-5.44 (m, 2H), 3.09-3.06 (m, 1H), 2.88 2.67 (m, 8H), 2.51-2.45 (m, 1H), 2.37-2.29 (m, 1H), 2.24 - 2.09 (m, 9H), 1.85-1.81 (m, 4H), 1.70 - 1.59 (m, 1H), 1.39 - 1.16 (m, 2H), 0.78-0.76 (m, 6H), 0.54 (t, J= 7.6 Hz, 2H), 0.45 (d, J= 4.5 Hz, 2H).

4-73. (3S)-3-(2’-chIoro-4,4^,-dinuoro-5,6’-dimethyI-[l,l’-biphenyI]-3-yl)-3-(2-(5-(215 (dimethylamino)ethyl)-2-oxo-4-(trifIuoromethyl)pyridin-l(2Z/)-yi)-4-methylpentanamido)propanoic acid (diastereomeric compounds DT-P1 and DT-P2)

607

DT-P1 ESI 670.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.90 (d, J= 3.1 Hz, 1H), 7.14 - 6.92 (m, 4H), 6.76 (d, J= 5.6 Hz, 1H), 5.72 - 5.65 (m, 1H), 5.60 - 5.56 (m, 1H), 3.10 - 2.87 (m, 4H), 2.76 - 2.66 (m, 8H), 2.30 (s, 3H), 2.09- 1.91 (m, 5H), 1.47-1.41 (m, 1H), 1.00-0.92 (m, 6H).

DT-P2 ESI 670.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 7.16 - 7.12 (m, 1H), 7.07 - 6.95 (m, 3H), 6.91 (d, J= 2.7 Hz, 1H), 5.74 - 5.59(m, 2H), 3.32 - 3.21 (m, 2H), 3.03 - 2.99 (m, 2H), 2.84 (d, J = 2.9 Hz, 6H), 2.67 - 2.49 (m, 2H), 2.34 (d, J= 1.6 Hz, 3H), 2.03 - 1.90 (m, 1H), 1.76 - 1.67 (m, 1H), 1.46 - 1.37 (m, 1H), 0.92 - 0.89 (m, 6H).

4-74. (3<S)-3-(2',6’-dichloro-4-fluoro-4’,5-dimethyl-[l,l*-biphenylJ-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-inethyIpentanamido)propanoic acid (diastereomeric compounds DU-PI and DU-P2)

DU-PI ESI 686.1 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.90 (s, 1H), 7.31 (s, 1H), 7.23 (s, 1H), 7.02 6.91 (m, 2H), 6.76 (s, IH), 5.76 - 5.66 (m, 1H), 5.63 - 5.53 (m, 1H), 3.15 - 3.04 (m, 2H), 2.94 (t, J= 11.0 Hz, 2H), 2.80 - 2.66 (m, 8H), 2.38 (s, 3H), 2.29 (d, J= 1.3 Hz, 3H), 2.04 - 1.92 (m, 2H), 1.51-1.42 (m, 1H), 1.01-0.90 (m, 6H).

DU-P2 ESI 686.1 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.88 (s, 1H), 7.32 (s, 2H), 7.09 - 6.99 (m, 2H), 6.91 (s, 1H), 5.79-5.71 (m, 1H), 5.65 (t, J= 7.7Hz, 1H), 3.30- 3.15 (m, 2H), 3.00 (t, J= 6.8 Hz,2H), 2.81 (s, 6H), 2.67 - 2.50 (m, 2H), 2.39 (s, 3H), 2.33 (d, J= 1.5 Hz, 3H), 2.02 - 1.92 (m, 1H), 1.73 - 1.65 (m, 1H), 1.44 - 1.36 (m, 1H), 0.91 - 0.85 (m, 6H).

4-75. (3S)-3-(2-(5-(2-(dimethyIamino)ethyl)-4-methyI-2-oxopyridin-l(2//)-yl)-4methyIpcntananiido)-3-(4-fluoro-2',5,6'-trimethyi-4'-(trifluoromethyl)biphenyl-3-yl)propanoic acid (diastereomeric compounds DV-P1 and DV-P2)

608

DV-P1 ESI 646.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ: 7.59 (s, 1H), 7.40 (s, 1H), 7.38 (s, 1H), 6.89 (d, J= 6.8 Hz, IH), 6.84 (d, J= 6.4 Hz, 1H), 6.28 (s, IH), 5.55 (t, J= 5.6 Hz, 1H), 5.49 (t, J= 6.0 Hz, 1H), 3.16 - 3.08 (m, 2H), 2.87 (t, J= 7.2 Hz, 2H), 2.78 (s, 6H), 2.73 - 2.68 (m, IH), 2.65 - 2.60 (m, IH), 2.31 (s, 3H), 2.25 (s, 3H), 2.08 (s, 3H), 2.01 - 1.90 (m, 5H), 1.45 - 1.38 (m, IH), 0.94 (d, J= 6.4 Hz, 3H), 0.91 (d,J=6.8 Hz, 3H).

DV-P2 ESI 646.3 (M+H)⁺. IH NMR (400 MHz, MeOD) δ: 7.55 (s, IH), 7.41 (s, 2H), 6.95 - 6.93 (m, IH), 6.90 (d, J= 6.4 Hz, IH), 6.41 (s, IH), 5.63 - 5.60 (m, IH), 5.58 - 5.56 (m, IH), 3.38 - 3.36 (m, IH), 3.25-3.19(m, IH), 2.95-2.90 (m, 2H), 2.85 (s, 6H), 2.64 - 2.59(m, IH), 2.50-2.44(m, IH), 2.34 (d, J= 1.6 Hz, 3H), 2.26 (s, 3H), 2.08 (s, 6H), 2.00 - 1.93 (m, IH), 1.83 - 1.76 (m, IH), 1.42 - 1.35 (m, IH), 0.89 (t, J= 6.4 Hz, 6H).

4.76. (3S)-3-(4’-cycIopropyl-4-fluoro-2’,5,6’-trimethyI-[l,l’-biphenyl]-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-3-fluoro-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds DW-P1 and DW-P2) (s; Me

DW-P1 ESI 636.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.47 (s, IH), 6.94 - 6.78 (m, 3H), 6.57 (d, J= 12.7 Hz, IH), 5.74-5.57 (m, IH), 5.46 (t,J=5.9 Hz, IH), 3.25-3.10(m, 2H), 2.92 (t, J = 6.9 Hz, 2H), 2.75 (s, 6H), 2.70 - 2.52 (m, 2H), 2.30-2.25 (m, 9H), 1.99-1.88 (m, 5H), 1.46-1.39 (m, 2H), 0.97 - 0.86 (m, 6H), 0.72-0.43 (m, 4H).

609

DW-P2 ESI 636.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.42 (d, J= 11.3 Hz, 1H), 6.97 (t, J= 8.2 Hz, 2H), 6.89 (s, 1H), 6.59 (s, 1H), 5.72 - 5.52 (m, 2H), 3.32-3.22 (m, 2H), 2.98-2.90 (m, 2H), 2.85 (s, 6H), 2.67 - 2.38 (m, 2H), 2.32-2.25 (m, 9H), 2.00-1.98 (m, 4H), 1.83 - 1.67 (m, 1H), 1.51 - 1.26 (m, 2H), 0.90 (d, J= 6.6 Hz, 6H), 0.70 - 0.48 (m, 4H).

4-77. (3S)-3-(4-nuoro-2’,4’,5,6’-tetramethyI-[l,l’-biphenyl]-3-yI)-3-(2-(3-fluoro-5-(2-(3methoxyazetidin-l-yl)ethyl)-4-methyI-2-oxopyridin-l(2H)-yI)-4-methyIpentanamido)propanoic acid (diastereomcric compounds DX-P1 and DX-P2)

DX-P1 ESI 652.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.26 (s, 1H), 6.84 - 6.68 (m, 4H), 5.54 - 5.45 (m, 1H), 5.41 (t, J= 6.3 Hz, 1H), 4.14-3.93 (m, 3H), 3.64 - 3.54 (m, 1H), 3.52-3.50 (m, 1H), 3.253.16(m, 5H), 2.74-2.55 (m, 4H), 2.18(s, 6H),2.12 (d, J= 4.0 Hz, 3H), 1.88 - 1.74 (m, 8H), 1.29-1.25 (m, 1H), 0.83-0.78 (m, 6H).

DX-P2 ESI 652.3 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.20 (s, 1H), 6.85 - 6.72 (m, 4H), 5.61 - 5.43 (m, 2H), 4.36 - 4.08 (m, 3H), 3.84 - 3.61 (m, 2H), 3.32-3.22(m, 5H), 2.82-2.78 (m, 1H), 2.64-2.56 (m, 1H), 2.51-2.47 (m, 1H), 2.39-2.32 (m, 1H), 2.23 - 2.13 (m, 6H), 2.10 (d, J= 2.7 Hz, 3H), 1.90 - 1.73 (m, 8H), 1.68 - 1.51 (m, 1H), 1.32- 1.20 (m, 1H), 0.79-0.74 (m, 6H).

4-78. (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)-4methyIpentanamido)-3-(4,4’-difluoro-2',5,5'-trimethylbiphenyI-3-yl)propanoic acid (diastereomcric compounds DY-P1 and DY-P2)

610

DY-P1 ESI 662.2 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.84 (s, IH), 7.03-7.00 (m, 3H), 6.93 (d, J= 10.6 Hz, IH), 6.81 (s, IH), 5.70 - 5.63 (m, IH), 5.59 (t, J= 6.Ί Hz, IH), 4.02 (t, J= 8.2 Hz, 4H), 3.30 (s, 2H), 2.86 (t, J= 6.9 Hz, 2H), 2.71 (d, J= 6.8 Hz, 2H), 2.42 -2.39( m, 2H), 2.30 (d, J= 1.4 Hz, 3H), 2.25 5 (s, 3H), 2.15 (s, 3H), 2.02 -2.19(m, 2H), 1.48-1.39 (m, IH), 0.96-0.90 (m, 6H).

DY-P2 ESI 662.2 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.73 (s, IH), 7.09-7.06 (m, 2H), 7.04 (d, J= 8.1 Hz, IH), 6.99 - 6.88 (m, 2H), 5.75-5.70 (m, IH), 5.64 (t, J= 7.7 Hz, IH), 4.15 (t, J= 8.0 Hz, 4H), 3.42-3.40 (m, 2H), 2.95 (d, J= 16.2 Hz, IH), 2.82 -2.80(m, IH), 2.64-2.60 (m, IH), 2.55 - 2.43 (m, 3H), 2.34 (s, 3H), 2.26 (s, 3H), 2.20 (s, 3H), 2.04 - 1.97 (m, IH), 1.71-1.68 (m, IH), 1.43-1.38 (m, IH), 0.92 10 (t, J= 6.3 Hz, 6H).

4-79. (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methyIpentanamido)-3-(4-nuoro-4’-metIioxy-2’,5^^,-trimethyI-il,l’-biphenyl]-3-yl)propanoic acid (diastereomeric compounds DZ-P1 and DZ-P2)

DZ-P1 ESI 674.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.83 (s, IH), 7.03 (t, J= 7.3 Hz, 2H), 6.90 (s, IH), 6.83 (s, IH), 6.78 (s, IH), 5.67 (t, J= 8.0 Hz, IH), 5.59 (t, J= 6.7 Hz, IH), 3.99 (t, J= 8.2 Hz, 4H), 3.86 (s, 3H), 3.29 (d, J= 3.5 Hz, 2H), 2.85 (t, J= 6.7 Hz, 2H), 2.71 (d, J= 6.7 Hz, 2H), 2.44 - 2.34 (m,

611

2H), 2.29 (d, J= 1.6 Hz, 3H), 2.18 (s, 6H), 2.02 (t, J= 7.5 Hz, 2H), 1.46 - 1.39 (m, IH), 0.96 (t, J= 6.2 Hz, 6H).

DZ-P2 ESI 674.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.74 (s, IH), 7.14 - 7.03 (m, 2H), 6.93 (s, 2H), 6.80 (s, IH), 5.80 - 5.71 (m, IH), 5.64 (t, J= 7.6 Hz, IH), 4.14 (t, J= 8.0 Hz, 4H), 3.86 (s, 3H), 3.50 3.36 (m, 2H), 2.95 (d, J= 15.7 Hz, IH), 2.87 - 2.78 (m, IH), 2.67 - 2.60 (m, IH), 2.57 - 2.42 (m, 3H), 2.33 (d, J= 1.6 Hz, 3H), 2.20 (d, J= 19.2 Hz, 6H), 2.05 - 1.96 (m, IH), 1.73 - 1.65 (m, IH), 1.47- 1.37 (m, IH), 0.92 (t, J= 6.7 Hz, 6H).

4-80. (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)-yl)-4methyIpentanamido)-3-(4'-cyano-4,5’-difluoro-2',5-dimethylbiphenyl-3-yl)propanoic acid (diastereomeric compounds EA-P1 and EA-P2)

EA-P1 ESI 673.3 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.86 (s, IH), 7.67 (d, J= 6.6 Hz, IH), 7.24 7.07 (m, 3H), 6.79 (d, J= ΊΑ Hz, IH), 5.78 - 5.50 (m, 2H), 4.10 (t, J= 8.1 Hz, 4H), 3.41 - 3.34 (m, 2H), 2.92 - 2.65 (m, 4H), 2.61 - 2.40 (m, 2H), 2.32 (s, 3H), 2.23 (s, 3H), 2.15 - 1.86 (m, 2H), 1.54 - 1.38 (m, IH), 0.97 (t, .7=6.6 Hz, 6H).

EA-P2 ESI 673.3 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.75 - 7.59 (m, 2H), 7.25 - 7.16 (m, 3H), 6.93 (s, IH), 5.80 - 5.55 (m, 2H), 4.16 (t, J= 7.9 Hz, 4H), 3.50 - 3.37 (m, 2H), 3.04 - 2.77 (m, 2H), 2.72 2.43 (m, 4H), 2.36 (s, 3H), 2.28 (s, 3H), 2.06 - 1.96 (m, IH), 1.83 - 1.64 (m, IH), 1.53 - 1.29 (m, IH), 0.97-0.89 (m, 6H).

4-81. (3.S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(27/)-yl)-4methylpentanamido)-3-(5'-cyano-4,4’-dinuoro-2',5-dimethyl-[l,l'-biphenyl]-3-yl)propanoic acid (diastereomeric compounds EB-P1 and EB-P2)

612

EB-P1 ESI 673.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.85 (s, IH), 7.55 (d, J= 6.7 Hz, IH), 7.32 (d, J= 10.3 Hz, IH), 7.10 (d, J= 6.4 Hz, 2H), 6.81 (s, IH), 5.65 - 5.55 (m, 2H), 4.03 (t, J= 8.0 Hz,4H), 3.32 - 3.26 (m, 2H), 2.84 (t, J= 7.0 Hz, 2H), 2.78 - 2.67 (m, 2H), 2.51 - 2.36 (m, 2H), 2.36 - 2.25 (m, 5 6H), 2.14 - 1.92 (m, 2H), 1.52-1.36 (m, IH), 0.97 (t, J= 6.1 Hz, 6H).

EB-P2 ESI 673.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.74 (s, IH), 7.57 (d, J= 6.7 Hz, IH), 7.34 (d, J= 10.2 Hz, IH), 7.14 (d, J= 6.7 Hz, 2H), 6.93 (s, IH), 5.76 - 5.71 (m, IH), 5.63 (t, J= 7.7 Hz, IH), 4.13 (t, J= 7.9 Hz, 4H), 3.49 - 3.35 (m, 2H), 3.00 - 2.87 (m, IH), 2.88 - 2.75 (m, IH), 2.68 - 2.60 (m, IH), 2.57 - 2.42 (m, 3H), 2.39-2.28 (m, 6H), 2.05 - 1.95 (m, IH), 1.79 - 1.63 (m, IH), 1.48 - 1.37 (m, 10 IH), 0.92 (t, J= 6.6 Hz, 6H).

4-82. (3S)-3-(2-(5-(2-(dimethylamino)ethyI)-3-fluoro-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)4-methylpentanamido)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propanoic acid (diastereomeric compounds EC-P1 and EC-P2)

EC-P1 ESI 650.2 (M+H)+. IH NMR (500 MHz, MeOD) δ 7.70 (s, IH), 7.12 (t, J= 7.5 Hz, IH), 7.08 7.02 (m, 2H), 6.89-6.85 (m, 2H), 5.69 (t, J= 8.0 Hz, IH), 5.61 - 5.54 (m, IH), 3.09-3.02 (m, 2H), 2.99 (d, J= 7.3 Hz, 2H), 2.74-2.70 (m, 8H), 2.30 (s, 3H), 2.05 - 1.94 (m, 5H), 1.86 (s, 3H), 1.44 (m, IH), 0.940.90 (m, 6H).

613

EC-P2 ESI 650.2 (M+H)+. IH NMR (500 MHz, MeOD) δ 7.62 (s, IH), 7.18 - 7.07 (m, 3H), 6.94 (t, J= 6.8 Hz, 2H), 5.73-5.70 (m, IH), 5.61 (t, J= 7.6 Hz, IH), 3.31 - 3.18 (m, 2H), 3.11 - 2.95 (m, 2H), 2.84 (s, 6H), 2.65-2.60 (m, IH), 2.52 -2.48(m, IH), 2.35-2.32 (m, 3H), 2.08 - 1.94 (m, 7H), 1.74 - 1.64 (m, IH), 1.42-1.39 (m, IH), 0.90 (d, J= 6.6 Hz, 6H).

4-83. (35)-3-(2-(5-(2-(dimethyIamino)ethyl)-3-iluoro-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyIbiphenyl-3-yI)propanoic acid (diastereomeric compounds ED-P1 and ED-P2)

ED-P1 ESI 664.2 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.69 (s, IH), 6.96 - 6.77 (m, 4H), 5.72 - 5.66 (m, IH), 5.56 (s, IH), 3.09- 2.90 (m, 4H), 2.71 (d, J= 4.8 Hz, 8H), 2.29 (s, 6H), 2.08 - 1.91 (m, 5H), 1.82 (s, 3H), 1.44 (s, IH), 0.95-0.90 (m, 6H).

ED-P2 ESI 664.2 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.62 (d, J= 12.1 Hz, IH), 6.97 - 6.85 (m, 4H), 5.72-5.69 (m, IH), 5.62 (t, J= 7.6 Hz, IH), 3.22 (qd, J = 13.0, 6.1 Hz, 2H), 3.13 - 2.89 (m, 2H), 2.82 (s, 6H), 2.64-2.60 (m, IH), 2.49-2.45(m, IH), 2.36 - 2.23 (m, 6H), 2.04 - 1.90 (m, 7H), 1.74 - 1.64 (m, IH), 1.41-1.38 (m, IH), 0.90-0.86 (m, 6H).

4-84. (35)-3-(4,4’-difluoro-2’,5,6’-trimethylbiphenyI-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-lyl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2ZZ)*yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds EE-P1 and EE-P2)

614

EE-P1 ESI 692.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.84 (s, IH), 6.96 - 6.68 (m, 5H), 5.75 - 5.48 (m, 2H), 4.26 - 4.01 (m, 3H), 3.74 - 3.52 (m, 2H), 3.31 (s, 3H), 3.14 (t, J= 6.8 Hz, 2H), 2.87 - 2.63 (m, 4H), 2.30 (s, 3H), 2.05 - 1.92 (m, 5H), 1.85 (s, 3H), 1.54 - 1.36 (m, 1H), 1.07 - 0.87 (m, 6H).

EE-P2 ESI 692.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.74 (s, IH), 7.04 - 6.78 (m, 5H), 5.80 - 5.70 (m, IH), 5.62 (t, J= 7.7 Hz, IH), 4.49 - 4.21 (m, 3H), 4.01 - 3.74 (m, 2H), 3.46 - 3.35 (m, 5H), 3.03 2.77 (m, 2H), 2.68 - 2.44 (m, 2H), 2.34 (d, J= 1.7 Hz, 3H), 2.12 - 1.90 (m, 7H), 1.74 - 1.57 (m, IH), 1.53 - 1.32 (m, IH), 0.99 - 0.83 (m, 6H).

4-85. (3S)-3-(2-(5-(2-(dimethyIamino)ethyI)-2-oxo-4-(trifIuoromethyl)pyridin-l(2II)yI)pentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyI-[l,l'-biphenyl]-3-yl)propanoic acid (diastereomeric compounds EF-P1 and EF-P2)

EF-P1 ESI 632.2(M+H)⁺. IH NMR (500 MHz, MeOD) δ 7.88 (s, IH), 6.92 - 6.79 (m, 4H), 6.74 (s, IH), 15 5.66 - 5.45 (m, 2H), 3.11 - 2.85 (m, 5H), 2.78 - 2.68 (m, 7H), 2.32 - 2.22 (m, 6H), 2.18-2.08 (m, IH),

2.06 - 1.92 (m, 4H), 1.78 (s, 3H), 1.41 - 1.24 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H).

EF-P2 ESI 632.2 (M+H)⁺. IH NMR (500 MHz, MeOD) δ 7.82 (s, IH), 6.90 (d, J = 7.1 Hz, 5H), 5.79 5.64 (m, IH), 5.52 (t, J = 7.6 Hz, IH), 3.30 - 3.15 (m, 2H), 3.00 (t, J = 6.6 Hz, 2H), 2.83 (s, 6H), 2.69 615

2.59 (m, 1H), 2.58 - 2.44 (m, 1H), 2.31 (d, J = 9.7 Hz, 6H), 2.13-2.01 (m, 1H), 1.97 (s, 6H), 1.91 - 1.73 (m, 1H), 1.39 - 1.02 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H).

4-86. (3S)-3-(2-(5-(2-(dimethylamino)ethyI)-4-methyl-2-oxopyridin-l(2Z0-yl)-SmethyIhexanamido)-3-(4-fluoro-2',4’,5,6’-tetramethylbiphenyl-3-yl)propanoic acid (diastereomeric compounds EF2-P1 and EF2-P2)

EF2-P1 ESI 606.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.57 (s, 1H), 6.90 (s, 2H), 6.85 - 6.80 (m, 2H), 6.34 (s, 1H), 5.48 (t, J= 6.0 Hz, 1H), 5.42 - 5.37 (s, 1H), 3.24 - 3.02 (m, 2H), 2.89 - 2.85 (m, 2H), 2.76 (s, 6H), 2.71 - 2.60 (m, 2H), 2.30 (d, J= 4.9 Hz, 6H), 2.25 (s, 3H), 2.22 - 2.14 (m, 1H), 1.95 (s, 4H), 1.87 (s, 3H), 1.60-1.53 (m, 1H), 1.25-1.14 (m, 1H), 1.12-1.00 (m, 1H), 0.89-0.87 (m, 6H).

EF2-P2 ESI 606.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.54 (s, 1H), 6.98 - 6.78 (m, 4H), 6.44 (s, 1H), 5.66 - 5.63 (m, 1H), 5.42 (t, J= 7.7 Hz, 1H), 3.31 - 3.28 (m, 1H), 3.26 - 3.14 (m, 1H), 2.99 - 2.88 (m, 2H), 2.84 (s, 6H), 2.64 - 2.59 (m, 1H), 2.50 - 2.43 (m, 1H), 2.39 - 2.28 (m, 6H), 2.27 (s, 3H), 2.16 2.07 (m, 1H), 1.96 (s, 6H), 1.89-1.74 (m, 1 H), 1.57- 1.50 (m, 1 H), 1.15 - 1.11 (m, 1H), 1.08-0.97 (m, 1H), 0.85 (t, 7=6.5 Hz, 6H).

4-87. (35)-3-(4,4'-difluoro-2',5,6'-trimethylbiphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-4methyl-2-oxopyridin-l(2/7)-yl)-5-methylhexanamido)propanoic acid (diastereomeric compounds EG-P1 and EG-P2)

616

EG-P1 ESI 610.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.58 (s, 1H), 6.84 (t, J= 9.1 Hz, 4H), 6.32 (s, 1H), 5.50 (t, J= 6.2 Hz, 1H), 5.44 - 5.33 (m, 1H), 3.24 - 3.06 (m, 2H), 2.90 - 2.84 (m, 2H), 2.78 (s, 6H), 2.73 - 2.62 (m, 2H), 2.28 (d, J = 14.1 Hz, 6H), 2.22 - 2.11 (m, 1 H), 2.00 - 1.96 (m, 4H), 1.89 (s, 3H), 5 1.60-1.54 (m, 1H), 1.29- 1.15 (m, 1H), 1.10-1.03 (m, 1H), 0.89-0.87 (m,6H).

EG-P2 ESI 610.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.54 (s, 1H), 6.90 (d, J= 6.9 Hz, 2H), 6.84 (d, J= 9.6 Hz, 2H), 6.44 (s, 1H), 5.66 - 5.62(m, 1H), 5.43 (t, J= 7.6 Hz, 1H), 3.38 - 3.35 (m, 1H), 3.24 3.20 (m, 1H), 3.00 - 2.89 (m, 2H), 2.85 (s, 6H), 2.64 - 2.59 (m, 1H), 2.50 - 2.44 (m, 1H), 2.33 (d, J= 4 Hz, 3H), 2.28 (s, 3H), 2.17-2.07 (m, 1H), 2.01 (s, 6H), 1.87-1.77 (m, 1H), 1.57-1.51 (m, 1H), 1.2010 1.09 (m, 1 H), 1.08 - 0.97 (m, 1 H), 0.85 (t, J= 6.4 Hz, 6H).

4-88. (35)-3-(4,4'-difIuoro-2',5,6'-triniethyl-[l,r-biplienyI]-3-yl)-3-(2-(3-fluoro-5-(2-(3methoxyazetidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2Z/)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds EH-P1 and EH-P2)

EH-P1 ESI 656.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.40 (s, 1H), 6.95 - 6.72 (m, 4H), 5.71 - 5.47 (m, 2H), 4.27 - 4.16 (m, 2H), 4.16 - 4.07 (m, 1 H), 3.81 - 3.69 (m, 1 H), 3.70 - 3.58 (m, 1 H), 3.30 (s, 3H), 3.25 (t, J= 6.8 Hz, 2H), 2.88 - 2.63 (m, 4H), 2.37 - 2.16 (m, 6H), 2.06 - 1.82 (m, 8H), 1.49 - 1.28 (m, 1H), 0.97-0.90 (m,6H).

617

EH-P2 ESI 656.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.33 (s, IH), 6.96 - 6.89 (m, 2H), 6.84 (d, J= 9.7 Hz, 2H), 5.72 - 5.58 (m, 2H), 4.39 - 4.14 (m, 3H), 3.85 - 3.65 (m, 2H), 3.31 - 3.20 (m, 5H), 2.93 2.78 (m, 1H), 2.77 - 2.55 (m, 2H), 2.54 - 2.45 (m, 1H), 2.33 (d, J= 1.7 Hz, 3H), 2.22 (d, J= 2.7 Hz, 3H), 2.06 - 1.86 (m, 7H), 1.81 - 1.66 (m, 1 H), 1.344 - 1.32 (m, 1 H), 0.90 (d, J = 6.6 Hz, 6H).

4-89. (3S)-3-(5-cliloro-4-fluoro-2’,4’,6*-trimethyIbiphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)etliyI)3-fluoro-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds EI-P1 and EI-P2)

EI-P1 ESI 684.2 (M+H)⁺. 1H NMR (500 MHz, MeOD) δ 7.65 (s, 1H), 7.13 (d, J= 6.3 Hz, 1H), 7.08 (d, J= 6.1 Hz, 1H), 6.93 (s, 2H), 5.66 (d, J= 5.4 Hz, 2H), 3.13-2.89 (m, 4H), 2.70 (s, 6H), 2.67 - 2.62 (m, 1 H), 2.62 - 2.53 (m, 1 H), 2.30 (s, 3H), 1.98 (d, J = 6.9 Hz, 7H), 1.74 -1.70(m, 1 H), 1.40 - 1.33 (m, 1 H), 0.89 (d, J =5.6 Hz, 6H).

EI-P2 ESI 684.2 (M+H)⁺.

1HNMR(5OO MHz, MeOD)δ 7.67 (s, 1H), 7.10 (d,J= 6.9 Hz, 1H), 7.02(d,J=6.1 Hz, 1H), 6.91 (d,J = 13.0 Hz, 2H), 5.68 (t, J= 8.1 Hz, 1H), 5.55 (t, J= 7.0 Hz, 1H), 3.08 (s, 2H), 2.98 (d, J= 7.7 Hz, 2H), 2.73 (d, J= 9.7 Hz, 8H), 2.30 (s, 3H), 2.04 - 1.93 (m, 5H), 1.83 (s, 3H), 1.44-1.40 (m, 1H), 0.96 -0.92(m, 6H).

4-90. (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(triiluoromethyI)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4'-cyano-4-fluoro-2^,,5,5'-trimethyl-[l,r-biphenyl]-3-yI)propanoic acid (diastereomeric compounds EJ-P1 and EJ-P2)

618

EJ-P1 ESI 669.3 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.72 (s, IH), 7.45 (s, IH), 7.10 (s, IH), 7.06 6.92 (m, 2H), 6.65 (s, IH), 5.57 - 5.40 (m, 2H), 3.92 (t, J= 8.1 Hz, 4H), 2.73-2.70 (m, 2H), 2.60 (d, J= 7.6 Hz, 2H), 2.40 (s, 3H), 23.0-2.33(m, 2H), 2.36-2.30 (m, 2H), 2.19 (s, 3H), 2.09 (s, 3H), 1.94-1.88 (m, 5 2H), 1.35 - 1.21 (m, IH), 0.86-0.83 (m, 6H).

EJ-P2 ESI 669.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.61 (s, IH), 7.47 (s, IH), 7.13 (s, IH), 7.10 6.98 (m, 2H), 6.80 (s, IH), 5.65-5.62 (m, IH), 5.52 (t, J= 7.7 Hz, IH), 4.04 (t, 7= 8.1 Hz, 4H), 3.40 3.25 (m, 2H), 2.86 - 2.64 (m, 2H), 2.54-2.49 (m, IH), 2.45 - 2.30 (m, 6H), 2.23 (d, J= 1.5 Hz, 3H), 2.14 (s, 3H), 1.95 - 1.81 (m, IH), 1.63 - 1.52 (m, IH), 1.31-1.26 (m, IH), 0.84-0.78 (m, 6H).

4-91. (3S)-3-(4-fluoro-4’-methoxy-2’,5,6*-trimethyl-(l,l’-biphenyl]-3-yl)-3-(2-(5-(2-(3methoxyazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2/7)-yl)-4methylpentanamido)propanoic acid (diastereomeric compounds EK-P1 and EK-P2)

EK-P1 ESI 704.4 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.85 (s, IH), 6.86 (t, J= 6.2 Hz, 2H), 6.77 (s, IH),6.65 (s, IH),6.62(s, IH), 5.67(t, J= 8.0Hz, IH),5.61 -5.56(m, IH),4.25-4.09 (m, 3H), 3.79(s, 3H), 3.71 - 3.61 (m, 2H), 3.31(s, 3H), 3.17 (t, 7= 6.8 Hz, 2H), 2.81 (t, 7= 6.9 Hz, 2H), 2.76 - 2.69 (m, 2H), 2.28 (s, 3H), 2.04 - 1.97 (m, 5H), 1.82 (s, 3H), 1.48 - 1.41 (m, IH), 0.98 - 0.93 (m, 6H).

619

EK-P2 ESI 704.4 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.75 (s, 1H), 6.96 - 6.90 (m, 3H), 6.67 (s, 2H), 5.76 - 5.72(m, IH), 5.63 (t, J= 7.7 Hz, IH), 4.44 -4.26 (m, 3H), 3.98 - 3.92 (m, 1H), 3.88 - 3.83 (m, 1H), 3.80 (s, 3H), 3.42 - 3.35 (m, 5H), 2.97 - 2.80 (m, 2H), 2.67 - 2.62 (m, IH), 2.56 - 2.50 (m, IH), 2.33 (d, J= 1.6 Hz, 3H), 2.04-1.94 (m, 7H), 1.73 - 1.64 (m, IH), 1.47-1.39 (m, IH), 0.92-0.89 (m, 6H).

4-92. (3S)-3-(4’-cyano-4-fluoro-2',5,6'-trimcthyl-Il,l'-biphenyl]-3-yl)-3-(2-(5-(2(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z7)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds EL-P1 and EL-P2)

EL-P1 ESI 657.4 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.88 (s, IH), 7.45 (d, J= 21.6 Hz, 2H), 6.88 (d, J= 5.6 Hz, 2H), 6.71 (s, IH), 5.72 - 5.47 (m, 2H), 3.08 - 2.85 (m, 4H), 2.79 - 2.57 (m, 8H), 2.30 (d, J= 1.4 Hz, 3H), 2.11 - 1.93 (m, 5H), 1.88 (s, 3H), 1.50 - 1.37 (m, IH), 1.06 - 0.86 (m, 6H).

EL-P2 ESI 657.4 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.84 (s, IH), 7.49 (s, 2H), 7.02 - 6.74 (m, 3H), 5.75 - 5.53 (m, 2H), 3.25 - 3.06 (m, 2H), 2.98 (t, J= 6.9 Hz, 2H), 2.78 (s, 6H), 2.70 - 2.48 (m, 2H), 2.34 (d, J= 1.4 Hz, 3H), 2.14-1.86 (m, 7H), 1.79- 1.62 (m, IH), 1.46-1.31 (m, IH), 0.95-0.82 (m, 6H).

4-93. (3S)-3-(4’-chloro-4-fluoro-2’,5,6’-trimethyIbiphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)2-oxo-4-(triiluoromethyl)pyridin-l(2ZZ)*yl)*4*methylpentanamido)propanoic acid (diastereomeric compounds EM-P1 and EM-P2) ° O <ΌΗ

EM-P1 ESI 666.3 (M+H)⁺. IH NMR (400 MHz, MeOD) δ 7.91 (s, IH), 7.08 (d, J= 24.1 Hz, 2H), 6.91 6.80 (m, 2H), 6.72 (s, IH), 5.68 (t, J= 8.0 Hz, IH), 5.59 - 5.48 (m, 1 H), 3.18 - 3.02 (m, 2H), 2.95 (t, J=

620

7.0 Hz, 2H), 2.82 - 2.63 (m, 8H), 2.29 (s, 3H), 2.04 - 1.91 (m, 5H), 1.79 (s, 3H), 1.58 - 1.30 (m, 1H), 1.04-0.86 (m, 6H).

EM-P2 ESI 666.3 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.88 (s, 1H), 7.13 (s, 2H), 6.94 - 6.83 (m, 3H), 5.81 - 5.68 (m, 1H), 5.62 (t, J= 7.7 Hz, 1H), 3.30 - 3.16 (m, 2H), 3.01 (t, J= 6.8 Hz, 2H), 2.83 (s, 6H), 2.72 - 2.45 (m, 2H), 2.33 (d, J= 1.1 Hz, 3H), 1.98 (d, 7H), 1.75-1.63 (m, 1H), 1.51 - 1.33 (m, IH), 0.87 (d, J =6.6 Hz, 6H).

4-94. ((35)-3-(4-fluoro-2’,5,6'-trimethylbiphenyl-3-yI)-3-(2-(5-(2-((7î)-3-fluoropyrrolidin-lyl)ethyl)-4-methyl-2-oxopyridin-l(2//)-yI)-4-methyIpentanainido)propanoic acid (diastereomeric compounds EN-P1 and EN-P2)

EN-PI ESI 622.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.54 (s, 1H), 7.16 - 7.02 (m, 3H), 6.87 - 6.78 (m, 2H), 6.27 (s, 1H), 5.73 - 5.50 (m, 2H), 5.34 - 5.15 (m, IH), 3.31 - 3.23 (m, 1H), 3.22 - 3.00 (m, 2H), 2.94 - 2.80 (m, 3H), 2.78 - 2.59 (m, 4H), 2.36 - 2.09 (m, 8H), 2.01-1.91 (m, 5H), 1.83 (s, 3H), 1.50 1.37 (m, IH), 0.97-0.89 (m, 6H).

EN-P2 ESI 622.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.56 (s, IH), 7.22 - 7.02 (m, 3H), 6.91 (d, J= 6.8 Hz, 2H), 6.42 (s, IH), 5.65 - 5.57 (m, 2H), 5.41 - 5.24 (m, IH), 3.62 - 3.35 (m, 3H), 3.31 - 3.09 (m, 3H), 2.94 - 2.74 (m, 2H), 2.68 - 2.49 (m, 2H), 2.39 - 2.22 (m, 8H), 2.10-1.89 (m, 7H), 1.82 - 1.70 (m, IH), 1.49-1.31 (m, IH), 0.95-0.85 (m, 6H).

4-95. (3S)-3-(4-fluoro-2’,4^,,5,6’-tetramethyl-Il,l’-biphenyl]-3-yl)-3-(2-(5-(2-(3-fIuoroazetidin-lyl)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds EO-P1 and EO-P2)

621

EO-P1 ESI 608.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.52 (s, IH), 7.39 (d, J= 9.0 Hz, IH), 6.96 6.79 (m, 3H), 6.73 (s, IH), 6.43 (d,J= 9.5 Hz, IH), 5.74-5.46 (m, 2H), 5.14 (d,J= 57.6 Hz, IH), 3.77 (s, 2H), 3.50 (s, 2H), 2.88 (s, 2H), 2.79 - 2.60 (m, 2H), 2.51 (s, 2H), 2.29 (d, J= 14.1 Hz, 6H), 1.96 (d, J = 12.7 Hz, 5H), 1.80 (s, 3H), 1.42 (s, IH), 1.03 - 0.79 (m, 6H).

EO-P2 ESI 608.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.60 - 7.40 (m, 2H), 6.90 (d, J= 7.8 Hz, 4H), 6.57 (d, J= 9.2 Hz, IH), 5.70 - 5.57 (m, 2H), 5.32 (d, 57.4 Hz, IH), 4.51 -4.26 (m, 2H), 4.14 - 3.87 (m, 2H), 3.39 (d, J= 5.3 Hz, 2H), 2.85 - 2.44 (m, 4H), 2.35 - 2.17 (m, 6H), 2.04 - 1.86 (m, 7H), 1.86 1.73 (m, IH), 1.48 - 1.33 (m, IH), 0.90 (t, J= 6.3 Hz, 6H).

4-96. (3S)-3-(4,4’-difluoro-2’,5,6’-trimethyHl,l’-biphenyl|-3-yI)-3-(2-(5-(2-(3-fluoroazetidin-lyI)ethyl)-2-oxopyridin-l(2H)-yI)-4-methyIpentanamido)propanoic acid (diastereomeric compounds EP-P1 and EP-P2)

EP-P1 ESI 612.2 (M+H)⁺. *H NMR (400 MHz, MeOD) δ 7.54 (s, IH), 7.43 (dd, J= 9.2, 2.3 Hz, IH), 6.87-6.82 (m, 3H), 6.76 (d, J= 6.7 Hz, IH), 6.46 (d, J= 9.3 Hz, IH), 5.63 (d, J= 7.9 Hz, IH), 5.54-5.43 (m, IH), 5.20 (d, J= 57.2 Hz, IH), 4.09-3.88 (m, 2H), 3.71-3.55 (m, 2H), 3.10-3.02 (m, 2H), 2.80 - 2.53 (m, 4H), 2.29 (s, 3H), 2.03 -1.92 (m, 5H), 1.87 (s, 3H), 1.50 - 1.36 (m, IH), 0.97-0.92 (m, 6H).

EP-P2 ESI 612.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.41 (s, IH), 7.38-7.35 (m, IH), 6.79 (t, J= 6.1 Hz, 2H), 6.73 (d, J= 9.7 Hz, 2H), 6.45 (d, J= 9.3 Hz, IH), 5.53-5.48 (m, 2H), 5.20 (d, 57.2 Hz, IH),

622

4.39 - 4.14 (m, 2H), 3.99-3.87 (m, 2H), 3.32 - 3.25 (m, 2H), 2.67 - 2.48 (m, 3H), 2.40-2.34 (m, 1H), 2.21 (d,J= 1.7Hz,3H), 1.90-1.81 (m,7H), 1.72-1.64 (m, 1H), 1.33-1.22 (m, 1H), 0.79 (t, J = 6.6 Hz, 6H).

4-97. (35)-3-(4,4’-difluoro-2’,5,6’-trimethyl-|l,l*-biphenyI]-3-yl)-3-(2-(3-fluoro-5-(2-(3fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(27/)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds EQ-P1 and EQ-P2)

EQ-P1 ESI 630.2 (M+H)⁺. ’H NMR (400 MHz, MeOD) δ 7.30 (s, 1H), 7.25 - 7.22 (m, 1H), 6.77 - 6.75 (m, 1H), 6.72 - 6.69 (m, 3H), 5.55 (t, J= 8.0 Hz, IH), 5.40 - 5.37 (m, 1H), 5.18 5.01 (m, 1H), 3.99 - 3.82 (m, 2H), 3.66 - 3.48 (m, 2H), 3.06 - 2.99 (m, 2H), 2.66 - 2.50 (m, 4H), 2.18 (d, J= 1.5 Hz, 3H), 1.89-1.81 (m, 5H), 1.78 (s, 3H), 1.34 - 1.27 (m, 1H), 0.85 - 0.78 (m, 6H).

EQ-P2 ESI 630.2 (M+H)⁺. *H NMR (400 MHz, MeOD) δ 7.27 - 7.23 (m, 2H), 6.80 (d, J = 6.9 Hz, 2H), 6.73 (d, J= 9.6 Hz, 2H), 5.56 - 5.49 (m, 2H), 5.28 - 5.11 (m, 1H), 4.33 - 4.18 (m, 2H), 3.97 - 3.83 (m, 2H), 3.27 - 3.22 (m, 2H), 2.64 - 2.35 (m, 4H), 2.21 (d, J= 1.9 Hz, 3H), 1.89 1.82 (m, 7H), 1.69-1.62 (m, 1 H), 1.31 - 1.21 (m, 1H), 0.83-0.78 (m, 6H).

4-98. (35)-3-(4,5-difluoro-2',6’-dimethyl-[l,l’-biphenylJ-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2oxopyridin-l(2JZ)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds ER-P1 and ER-P2)

623

ER-P1 ESI 568.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.64 (d, J= 2.0 Hz, IH), 7.54 - 7.51 (m, IH), 7.18 (t, J= 7.5 Hz, IH), 7.11 (t, J= 6.8 Hz, 2H), 6.99 - 6.90 (m, IH), 6.78 (d, J= 5.9 Hz, IH), 6.52 (d, J= 9.3 Hz, IH), 5.61 - 5.56 (m, IH), 5.42 (t, J= 5.6 Hz, IH), 3.32 -3.19 (s, IH), 3.24 - 3.10 (m, IH), 2.88 2.80 (m, 2H), 2.73 (s, 6H), 2.70 - 2.64 (m, IH), 2.59 - 2.53 (m, IH), 2.06 - 1.89 (m, 8H), 1.50 - 1.36 (m, IH), 0.97-0.90 (m, 6H).

ER-P2 ESI 568.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ Ή NMR (500 MHz, MeOD) δ 7.65 (d, J= 2.1 Hz, IH), 7.54 - 7.50 (m, IH), 7.22 - 7.13 (m, IH), 7.14 - 7.07 (m, 2H), 7.01 - 6.90 (m, IH), 6.88 (d, J= 5.8 Hz, IH), 6.54 (d, J= 9.3 Hz, IH), 5.66 - 5.52 (m, 2H), 3.38 - 3.34 (m, IH), 3.28 - 3.21 (m, IH), 2.98 - 2.86 (m, IH), 2.86-2.73 (m, 7H), 2.64 - 2.59 (m, IH), 2.51 - 2.44 (m, IH), 2.08 - 1.91 (m, 7H), 1.92 1.81 (m, IH), 1.49 - 1.35 (m, IH), 0.93 - 0.88 (m, 6H).

4-99. (35)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-l(2II)-yl)-4-methylpentanamido)-3(4,4’,5-trifluoro-2’,6’-dimethyl-[l,r-biphcnylJ-3-yl)propanoic acid (diastereomeric compounds ESP1 and ES-P2)

ES-P1 ESI 586.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.65 (s, IH), 7.57 - 7.48 (m, IH), 6.99 - 6.90 (m, IH), 6.87 (d, 7= 8.8 Hz, 2H), 6.79 (d, 7= 5.8 Hz, IH), 6.52 (d, 7= 9.4 Hz, IH), 5.56 (s, IH), 5.42 (t, 7 = 5.6 Hz, IH), 3.32-3.27 (m, IH), 3.23-3.16 (m, IH), 2.93 -2.80 (m, 2H), 2.75 (s, 6H), 2.70 - 2.62 (m, IH), 2.59-2.52 (m, IH), 2.10- 1.91 (m, 8H), 1.44 (s, IH), 0.98-0.87 (m, 6H).

ES-P2 ESI 586.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.65 (d, 7= 2.1 Hz, IH), 7.56 - 7.50 (m, IH), 7.01 - 6.94 (m, IH), 6.90 - 6.81 (m, 3H), 6.55 (d, 7= 9.3 Hz, IH), 5.64 - 5.54 (m, 2H), 3.45 - 3.36 (m,

624

IH), 3.31 - 3.24 (m, IH), 2.99 - 2.90 (m, IH), 2.90- 2.78 (m, 7H), 2.64 - 2.55 (m, IH), 2.51 -2.41 (m, IH), 2.07 - 1.95 (m, 7H), 1.92 - 1.83 (m, IH), 1.46 - 1.36 (m, IH), 0.96 - 0.86 (m, 6H).

4-100. (35)-3-(4,5-dinuoro-2',6’-dimethyl-[l,l’-biphenyl]-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-lyl)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds ET-P1 and ET-P2)

ET-P1 ESI 598.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.54 (d, J= 1.9 Hz, IH), 7.46 - 7.40 (m, IH), 7.21 - 7.14 (m, IH), 7.11 (d, J= 7.3 Hz, 2H), 6.99 - 6.90 (m, IH), 6.81 (d, J= 5.9 Hz, IH), 6.47 (d, J= 9.3 Hz, IH), 5.62 (t,J= 8.1 Hz, IH), 5.51 (t,J= 6.1 Hz, IH), 5.31-5.14 (m, IH), 4.17-3.96 (m,2H), 3.823.67 (m, 2H), 3.21 - 3.11 (m, 2H), 2.78 - 2.58 (m, 4H), 2.03 - 1.89 (m, 8H), 1.47 - 1.40 (m, IH), 0.97 0.88 (m, 6H).

ET-P2 ESI 598.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.53 (d, J= 2.0 Hz, IH), 7.49 - 7.42 (m, IH), 7.16 (d, J= 7.4 Hz, IH), 7.11 (d, J= 7.7 Hz, 2H), 7.03 - 6.94 (m, IH), 6.92 (d, J= 5.9 Hz, IH), 6.55 (d, J = 9.3 Hz, IH), 5.68 - 5.60 (m, 2H), 5.41 - 5.22 (m, IH), 4.47 -4.27 (m, 2H), 4.09 - 3.94 (m, 2H), 3.37 (s, 2H), 2.79 - 2.62 (m, 3H), 2.60 - 2.50 (m, IH), 2.03 (d, J= 2.2 Hz, 6H), 1.98 - 1.91 (m, IH), 1.84 - 1.76 (m, IH), 1.47- 1.37 (m, IH), 0.91 (t, J= 6.1 Hz, 6H).

4-101. (35)-3-(4-fluoro-2’,5,6’-trimethyl-[l,r-biphenyI]-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-lyl)ethyl)-4-methyl-2-oxopyridin-l(2£0-yl)-4-methyIpentanamido)propanoic acid (diastereomeric compounds EU-P1 and EU-P2)

F Me

625

EU-P1 ESI 608.2 (M+H)⁺- Ή NMR (500 MHz, MeOD) δ 8.45 (s, 0.47HCOOH), 7.54 (s, 1H), 7.15 - 7.05 (m, 3H), 6.89 - 6.81 (m, 2H), 6.30 (s, 1H), 5.68 - 5.48 (m, 2H), 5.40 - 5.14 (m, 1H), 4.35 - 4.13 (m, 2H), 4.06 - 3.86 (m, 2H), 3.26 - 3.20 (m, 2H), 2.88 - 2.65 (m, 4H), 2.29 (s, 3H), 2.23 (s, 3H), 2.01 - 1.89 (m, 5H), 1.85 (s, 3H), 1.48 - 1.38 (m, 1H), 0.98 - 0.91 (m, 6H).

EU-P2 ESI 608.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 8.45 (s, 0.23HCOOH), 7.46 (s, 1H), 7.20 - 7.02 (m, 3H), 6.93 (d, J= 5.0 Hz, 2H), 6.44 (s, 1H), 5.75 - 5.54 (m, 2H), 5.34 (d, J= 57.3 Hz, 1H), 4.48-4.35 (m, 2H), 4.16 - 3.96 (m, 2H), 3.42 - 3.34 (m, 2H), 2.90 - 2.82 (m, 1H), 2.74 - 2.63(m, 2H), 2.60 - 2.52 (m, 1H), 2.33 (s, 3H), 2.25 (s, 3H), 2.07 - 1.85 (m, 7H), 1.82 - 1.70 (m, 1H), 1.44 - 1.34 (m, 1H), 0.91 0.87 (m, 6H).

4-102. (3S)-3-(2-(5-((dimethyIamino)methyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-2^,,5,6’-trimethyl-[l,l’-biphenyI]-3-yl)propanoic acid (diastereomeric compounds EV-P1 and EV-P2)

EV-P1 ESI 618.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 8.07 (s, 1H), 7.15 - 7.00 (m, 3H), 6.94 - 6.83 (m, 2H), 6.77 (s, 1H), 5.75 (t, J= 8.1 Hz, 1H), 5.63 - 5.52 (m, 1H), 3.83 - 3.59 (m, 2H), 2.82 - 2.72 (m, 2H), 2.52 (s, 6H), 2.29 (d, J= 1.3 Hz, 3H), 2.05 - 1.95 (m, 5H), 1.80 (s, 3H), 1.49 - 1.37 (m, 1H), 1.01 0.91 (m, 6H).

EV-P2 ESI 618.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 8.09 (s, 1 H), 7.18 - 7.00 (m, 3H), 7.00 - 6.84 (m, 3H), 5.81 - 5.70 (m, 1H), 5.63 - 5.46 (m, 1H), 4.10 (d, J= 14.4 Hz, IH), 3.87 (d, J= 14.4 Hz, 1H), 2.79 - 2.55 (m, 8H), 2.34 (d, J= 1.5 Hz, 3H), 2.05 - 1.93 (m, 7H), 1.71 - 1.61 (m, 1H), 1.48 - 1.39 (m, 1H), 0.93-0.82 (m, 6H).

4-103. (35)-3-(4,4’-difluoro-2’,5,6'-trimethyl-[l,l’-biphenyl]-3-yl)-3-(2-(5-((dimethyIamino)methyl)2-oxo-4-(trifluoromethyl)pyridin-l(2Â7)-yl)*4-methylpentanamido)propanoic acid (diastereomeric compounds EW-P1 and EW-P2)

626

EW-P1 ESI 636.1 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 8.06 (s, 1H), 6.95 - 6.72 (m, 5H), 5.75 (t, J = 8.1 Hz, 1H), 5.62 - 5.56 (m, 1H), 3.79 - 3.65 (m, 2H), 2.86 - 2.65 (m, 2H), 2.52 (s, 6H), 2.29 (s, 3H), 2.04 - 1.93 (m, 5H), 1.81 (s, 3H), 1.50 - 1.38 (m, 1H), 0.96 (t, J= 7.4 Hz, 6H).

EW-P2 ESI 636.1 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 8.08 (s, 1H), 6.95 - 6.88 (m, 3H), 6.85 (d, J= 9.6 Hz, 2H), 5.76 - 5.70 (m, 1H), 5.55 (t, J= 7.5 Hz, 1H), 4.08 (d, J= 14.4 Hz, 1H), 3.85 (d, J= 14.4 Hz, 1H), 2.79 - 2.52 (m, 8H), 2.34 (s, 3H), 2.03 - 1.93 (m, 7H), 1.70 - 1.61 (m, 1H), 1.50 - 1.38 (m, 1H), 0.95 - 0.80 (m, 6H).

4-104. (3S)-3-(2-(5-((dimethyIamino)methyI)-2-oxo-4-(trifluoromethyl)pyridin-l(27/)-yI)-4methyIpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l’-biphenyl]-3-yl)propanoic acid (diastereomcric compounds EX-PI and EX-P2)

EX-PI ESI 632.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 8.05 (s, 1H), 6.92 - 6.82 (m, 4H), 6.76 (s, 1H), 5.75 (t, J= 8.1 Hz, 1H), 5.63 - 5.50 (m, 1H), 3.78 - 3.62 (m, 2H), 2.88 - 2.65 (m, 2H), 2.50 (s, 6H), 2.29 (d, J= 3.7 Hz, 6H), 2.03 - 1.89 (m, 5H), 1.76 (s, 3H), 1.52 - 1.36 (m, 1 H), 0.96 (t, J- 7.2 Hz, 6H).

EX-P2 ESI 632.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 8.09 (s, 1H), 6.95 - 6.83 (m, 5H), 5.81 - 5.68 (m, 1H), 5.54 (t, J= 7.4 Hz, 1H), 4.09 (d, J= 14.4 Hz, 1H), 3.85 (d, J= 14.3 Hz, 1H), 2.81 - 2.52 (m, 8H), 2.32(d,J=9.8 Hz,6H), 1.97 (t,J=9.1 Hz,7H), 1.71-1.58 (m, 1H), 1.50- 1.34(m, lH),0.88 (d,.7=6.4 Hz, 6H).

627

4-105. (3S)-3-(4,5-difluoro-2’,4’,6’-trimethyI-[l,l’-biphcnyIj-3-yl)-3-(2-(5-((dimethylamino)methyI)2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds EY-P1 and EY-P2)

EY-P1 ESI 636.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.99 (s, IH), 6.92 - 6.84 (m, 4H), 6.72 (s, IH), 5.82 - 5.68 (m, IH), 5.61 - 5.55 (m, IH), 3.61 - 3.48 (m, 2H), 2.83 - 2.65 (m, 2H), 2.38 (s, 6H), 2.30 (s, 3H), 2.03-1.92(m, 5H), 1.73 (s, 3H), 1.49-1.37 (m, IH), 0.99-0.93 (m, 6H).

EY-P2 ESI 636.2 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 8.08 (s, IH), 7.02 - 6.84 (m, 5H), 5.77 - 5.72 (m, IH), 5.59 - 5.52 (m, IH), 4.08 (d, J= 14.4 Hz, IH), 3.85 (d, J= 14.4 Hz, IH), 2.79 - 2.75 (m, IH), 2.70 - 2.54 (m, 7H), 2.31 (s, 3H), 2.02 - 1.87 (m, 7H), 1.74 - 1.57 (m, IH), 1.49 - 1.37 (m, IH), 0.91 0.86 (m, 6H).

4-106. (35)-3-(2-(5-(2-(dimethylamino)ethyI)-3-fluoro-2-oxopyridin-l(2ZZ)-yI)-4methyIpentanamido)-3-(4,4',5-trifluoro-2’,6'-dimethyI-[l,l'-biphenyI]-3-yl)propanoic acid (diastereomeric compounds EZ-P1 and EZ-P2)

EZ-P1 ESI 604.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.44 (s, IH), 7.34 - 7.30 (m, IH), 6.96 - 6.75 (m, 4H), 5.76 - 5.71 (m, IH), 5.60 - 5.48 (m, IH), 2.76 - 2.55 (m, 6H), 2.39 (s, 6H), 2.07 - 1.90 (m, 5H), 1.84 (s, 3H), 1.49 - 1.33 (m, IH), 0.98 - 0.92 (m, 6H).

EZ-P2 ESI 604.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.50 (s, IH), 7.46 - 7.10 (m, IH), 7.04 - 6.93 (m, IH), 6.91 - 6.84 (m, 3H), 5.67 - 5.57 (m, 2H), 3.47 - 3.37 (m, IH), 3.31 - 3.21 (m, IH), 3.02 - 2.91

628 (m, IH), 2.90 - 2.79 (m, 7H), 2.64 - 2.57 (m, IH), 2.50 - 2.42 (m, IH), 2.07 - 1.92 (m, 7H), 1.90 - 1.78 (m, IH), 1.47-1.31 (m, IH), 0.94 - 0.89 (m, 6H).

4-107. (3S)-3-(4,5-dinuoro-2’,4’,6’-trimethyl-[l,r-biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)5 3-fluoro-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propa -noie acid (diastereomeric compounds FA-PI and FA-P2)

FA-PI ESI 600.2 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.49-7.44 (m, 2H), 6.92 (t, J= 8.2 Hz, 3H), 6.76 (d, J= 6.0 Hz, IH), 5.65-5.61 (m, IH), 5.40 (t, J= 5.6 Hz, IH), 3.19-3.15 (m, 2H), 2.90-2.84 (m, 3H), 2.75 10 -2.63 (m, 7H), 2.57-2.52 (m, IH), 2.31 (s, 3H), 2.03-1.87 (m, 9H), 1.46-1.40 (m, IH), 0.98-0.91 (m, 6H).

FA-P2 ESI 600.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.37-7.29 (m, 2H), 6.87 - 6.71 (m, 4H), 5.57 5.42 (m, 2H), 3.34 - 3.24 (m, IH), 3.18 - 3.07 (m, IH), 2.87-2.81 (m, IH), 2.73-2.70 (m, 7H), 2.50-2.45 (m, IH), 2.36-2.30 (m, IH), 2.19 (s, 3H), 1.96 - 1.80 (m, 7H), 1.74 - 1.63 (m, IH), 1.30-1.25 (m, IH), 0.81-0.79 (m, 6H).

4-108. (3S)-3-(2-(5-(2-(3-fluoroazetidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2Z7)-yl)-4methylpentanamido)-3-(4,4',5-trifluoro-2',6'-dimethylbiphenyl-3-yl)propanoic acid (diastereomeric compounds FB-P1 and FB-P2)

629

FB-P1 ESI 630.2 (M+H)⁺. M NMR (400 MHz, MeOD) δ 7.49 (s, IH), 6.99 - 6.89 (m, 1H), 6.89 - 6.76 (m, 3H), 6.29 (s, 1H), 5.66 - 5.50 (m, 2H), 5.40 - 5.10 (m, 1H), 4.14 - 3.90 (m, 2H), 3.86 - 3.55 (m, 2H), 3.03 (s, 2H), 2.86 - 2.53 (m, 4H), 2.23 (s, 3H), 2.06 - 1.90 (m, 5H), 1.86 (s, 3H), 1.49 - 1.32 (m, 1H), 1.02 5 -0.84(m,6H).

FB-P2 ESI 630.2 (M+H)⁺. *H NMR (400 MHz, MeOD) δ 7.49 (s, 1H), 7.09 - 6.86 (m, 4H), 6.44 (s, 1H), 5.72 - 5.55 (m, 2H), 5.30 (d, J= 57.8 Hz, 1H), 4.28 (s, 2H), 3.93 (s, 2H), 3.19 (s, 2H), 2.87 - 2.50 (m, 4H), 2.25 (s, 3H), 2.04 (s, 6H), 1.93 - 1.73 (m, 2H), 1.47- 1.28 (m, 1H), 0.91 -0.85 (m, 6H).

4-109. (35)-3-(5-chloro-4,4’-difluoro-2’,6*-dimethyIbiphenyl-3-yI)-3-(2-(5-(2-(dimethyIamino)ethyl)2-oxo-4-(trifluoromethyl)pyridin-l(2Z7)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds FC-P1 and FC-P2) (S) ^F ^Cl \ X)H

FC-P1 ESI 670.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.90 (s, 1H), 7.13 - 7.11 (m, 1H), 7.04 - 7.02 15 (m, 1H), 6.88 - 6.81 (m, 2H), 6.74 (s, 1H), 5.69 - 5.65 (m, 1H), 5.57 - 5.53 (m, 1H), 3.16 - 3.10 (m, 2H),

2.97 - 2.94 (m, 2H), 2.80 (s, 6H), 2.74 - 2.71 (m, 2H), 2.02 - 1.98 (m, 5H), 1.84 (s, 3H), 1.47 - 1.40 (m, 1H), 0.98 - 0.93 (m, 6H).

630

FC-P2 ESI 670.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.86 (s, IH), 7.20 - 7.18 (m, IH), 7.07 (d, J = 6.1 Hz, IH), 6.88 (d, J= 11.2 Hz, 3H), 5.73 - 5.67 (m, IH), 5.63 (t, J= 7.6 Hz, IH), 3.30 - 3.18 (m, 2H), 3.01 (t, J= 6.9 Hz, 2H), 2.85 (s, 6H), 2.69 - 2.60 (m, IH), 2.58 - 2.52 (m, IH), 2.03 - 1.95 (m, 7H), 1.77 - 1.70 (m, IH), 1.41 - 1.36 (m, IH), 0.91 - 0.89 (m, 6H).

4-110. (3S)-3-(5-chIoro-4,4’-difIuoro-2’,6*-dimethyIbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-lyl)ethyl)-4-methyl-2-oxopyridin-l(2jH)-yl)-4-methyIpentanamido)propanoic acid (diastereomeric compounds FD-P1 and FD-P2)

FD-P1 ESI 646.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.50 (s, IH), 7.15 - 7.13 (m, IH), 6.99 - 6.97 (m, IH), 6.88 - 6.85 (m, 2H), 6.29 (s, IH), 5.64 - 5.49 (m, 2H), 5.32 - 5.18 (m, IH), 4.11 - 4.07 (m, 2H), 3.85 - 3.72 (m, 2H), 3.10 (t, J= 6.9 Hz, 2H), 2.82 - 2.62 (m, 4H), 2.24 (s, 3H), 2.09 - 1.90 (m, 5H), 1.89 (d, J= 8.2 Hz, 3H), 1.43 - 1.38 (m, IH), 0.96 - 0.92 (m, 6H).

FD-P2 ESI 646.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.45 (s, IH), 7.21 - 7.18 (m, IH), 7.08 - 7.06 (m, IH), 6.89 (d, J= 9.6 Hz, 2H), 6.43 (s, IH), 5.73 - 5.53 (m, 2H), 5.43 - 5.25 (m, IH), 4.44 - 4.41 (m, 2H), 4.16 - 4.01 (m, 2H), 3.39- 3.36 (m, 2H), 2.91 - 2.87 (m, IH), 2.73 - 2.62 (m, 2H), 2.52 - 2.49 (m, IH), 2.25 (s, 3H), 2.03 (s, 6H), 1.98 - 1.88 (m, IH), 1.81 - 1.72 (m, IH), 1.44-1.33 (m, IH), 0.91 -0.89 (m, 6H).

4-111. (35)-3-(2-(5-(2-(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2Z0-yl)-4methyIpentanamido)-3-(4,4',5-trifIuoro-2',6'-dimethylbiphenyl-3-yl)propanoic acid (diastereomeric compounds FE-P1 and FE-P2)

631

FE-P1 ESI 654.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.89 (s, IH), 6.98 - 6.78 (m, 4H), 6.75 (s, IH), 5.69 - 5.65 (m, IH), 5.59 - 5.56 (m, IH), 3.15- 3.06 (m, 2H), 2.95 (d, J= 6.2 Hz, 2H), 2.77 (s, 6H), 2.74 -2.71 (m, 2H), 2.13-1.91 (m, 5H), 1.85 (s, 3H), 1.50-1.40 (m, IH), 0.98-0.94 (m, 6H).

FE-P2 ESI 654.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.86 (s, IH), 7.05 - 6.96 (m, IH), 6.95 - 6.83 (m, 4H), 5.73 - 5.69 (m, IH), 5.63 (t, J= 7.7 Hz, IH), 3.28 - 3.14 (m, 2H), 2.99 (t, J= 7.0 Hz, 2H), 2.82 (s, 6H), 2.69-2.64 (m, IH), 2.62-2.52 (m, IH), 2.03 (d, J= 2.1 Hz, 6H), 1.99-1.94 (m, IH), 1.77- 1.72 (m,, IH), 1.45 - 1.31 (m, IH), 0.91 - 0.89 (m, 6H).

4-112. (3S)-3-(5-chloro-4,4’-difIuoro-2’,6’-dimethylbiphenyl-3-yI)-3-(2-(5-(2-(3-fIuoroazetidin-lyl)ethyl)-2-oxopyridin-l(27/)-yl)-4-methyIpentanamido)propanoic acid (diastereomeric compounds FF-P1 and FF-P2)

FF-P1 ESI 632.2 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.59 (s, IH), 7.46 - 7.43 (m, IH), 7.15 - 7.13 15 (m, IH), 7.00 - 6.92 (m, IH), 6.87 (d, J= 9.6 Hz, 2H), 6.45 (d, J= 9.3 Hz, IH), 5.68 - 5.57 (m, IH), 5.51 (t, J= 6.2 Hz, IH), 5.38 - 5.16 (m, IH), 4.25 - 4.04 (m, 2H), 3.96 - 3.76 (m, 2H), 3.25 - 3.13 (m, 2H), 2.83-2.58 (m, 4H), 2.08 - 1.92 (m, 5H), 1.88 (s, 3H), 1.47 - 1.40 (m, 1 H), 0.97 - 0.92 (m, 6H).

FF-P2 ESI 632.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.54 (s, IH), 7.49 (d, J = 8.8 Hz, IH), 7.20 7.18 (m, 1 H), 7.04 (d, J = 4.5 Hz, 1 H), 6.88 (d, J = 9.6 Hz, 2H), 6.56 (d, J = 9.1 Hz, 1 H), 5.71 - 5.57 (m,

632

2H), 5.34 (d, J = 59.0 Hz, IH), 4.40 (s, 2H), 4.08 (s, 2H), 3.42 (s, IH), 2.70 (d, J= 52.7 Hz, 3H), 2.52 (s, IH), 2.03 (d, J= 3.5 Hz, 6H), 1.99 - 1.93 (m, 2H), 1.88 - 1.76 (m, IH), 1.49 - 1.31 (m, IH), 0.91 (t, J= 6.7 Hz, 6H).

4-113. (35)-3-(4,4*-difluoro-2’,5,6*-trimethylbiphenyl-3-yI)-3-(2-(5-(2-(dimethylamino)ethyl)-3fluoro-2-oxopyridin-l(2/7)-yI)-4-methylpentanamido)propanoic acid (diastereomeric compounds FG-P1 and FG-P2)

FG-P1 ESI 600.3 (M+H)⁺. *H NMR (400 MHz, MeOD) δ 7.52 (s, IH), 7.47 - 7.44 (m, IH), 6.91 - 6.81 (m, 3H), 6.78 (d, J= 6.8 Hz, IH), 5.64 - 5.60 (m, IH), 5.40 (t, J= 5.6 Hz, IH), 3.36 (d, J= 6.1 Hz, IH), 3.24 - 3.12 (m, IH), 2.97 - 2.77 (m, 2H), 2.73 (s, 6H), 2.70 - 2.61 (m, IH), 2.57 - 2.52 (m, IH), 2.30 (d, J = 1.6 Hz, 3H), 2.12-1.96 (m, 5H), 1.95 (s, 3H), 1.52- 1.37 (m, IH), 0.97-0.91 (m, 6H).

FG-P2 ESI 600.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.50 (s, IH), 7.45 - 7.42 (m, IH), 6.89 (t, J= 6.1 Hz, 2H), 6.84 (d, J= 9.6 Hz, 2H), 5.66 - 5.62 (m, IH), 5.59 - 5.56 (m, IH), 3.47 - 3.36 (m, IH), 3.30 - 3.25 (m, IH), 3.00 - 2.94 (m, IH), 2.90 - 2.77 (m, 7H), 2.61 - 2.56 (m, IH), 2.46 - 2.40 (m, IH), 2.32 (d, J= 1.8 Hz, 3H), 2.09 - 1.94 (m, 7H), 1.87 - 1.79 (m, IH), 1.48 - 1.37 (m, IH), 0.93 - 0.90 (m, 6H).

4-114. (35)-3-(5-chloro-4,4'-difluoro-2',6'-dimethylbiphenyI-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)3-fluoro-2-oxopyridin-l(2Z/)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds FH-P1 and FH-P2)

633

FH-P1 ESI 620.2 (M+H)⁺. *H NMR (400 MHz, MeOD) δ 7.53 (s, IH), 7.46 - 7.43 (m , IH), 7.15 - 7.12 (m, IH), 6.95 - 6.93 (m, IH), 6.87 (d, J= 9.6 Hz, 2H), 5.65 - 5.61 (m, IH), 5.42 (t, 7 = 5.8 Hz, IH), 3.31 - 3.26 (m, IH), 3.20-3.15 (m, IH), 2.96-2.81 (m, 2H), 2.75 (s, 6H), 2.70-2.65 (m, IH), 2.59-2.54 (m, 5 IH), 2.19-1.78 (m, 8H), 1.46-1.40 (m, IH), 0.97-0.91 (m, 6H).

FH-P2 ESI 620.2 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.50 (s, IH), 7.45 - 7.42 (m, IH), 7.18 - 7.16 (m, IH), 7.04-7.02(m, IH), 6.88 (d,7= 9.6Hz, 2H), 5.67-5.63 (m, IH), 5.59-5.56 (m, IH), 3.46-3.36 (m, IH), 3.29 - 3.22 (m, IH), 2.98 - 2.92 (m, IH), 2.86 - 2.84 (m, IH), 2.82 (s, 6H), 2.62 - 2.58 (m, IH), 2.51 -2.41 (m, IH), 2.03 (d,7= 1.5 Hz, 6H), 1.97(t,7= 7.1 Hz, IH), 1.90- 1.78 (m, IH), 1.41 - 1.36 (m, 10 IH), 0.97 - 0.74 (m, 6H).

4-115. (35)-3-(4,4’-dinuoro-2’,5,6’-trimethylbiphenyI-3-yl)-3-(2-(5-(2-(dimethyIamino)ethyl)-4methyl-2-oxopyridin-l(2Z/)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds FI-P1 and FI-P2)

FI-P1 ESI 596.3 (M+H)⁺. *Η NMR (400 MHz, MeOD) δ 7.59 (s, IH), 6.83 (t, 7= 7.2 Hz, 4H), 6.32 (s, IH), 5.70 - 5.56 (m, IH), 5.54 - 5.47 (m, IH), 3.21 - 3.06 (m, 2H), 2.95 - 2.83 (m, 2H), 2.79 (s, 6H), 2.73 2.55 (m, 2H), 2.35 - 2.20 (m, 6H), 2.07 - 1.91 (m, 5H), 1.85 (s, 3H), 1.50 - 1.29 (m, IH), 1.02 - 0.83 (m, 6H).

634

FI-P2 ESI 596.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.57 (s, IH), 6.99 - 6.78 (m, 4H), 6.43 (s, 1H), 5.71 - 5.53 (m, 2H), 3.28 - 3.06 (m, 2H), 2.97 - 2.85 (m, 2H), 2.81 (s, 6H), 2.66 - 2.56 (m, 1H), 2.56 2.40 (m, 1H), 2.36 - 2.24 (m, 6H), 2.05 - 1.89 (m, 7H), 1.86 - 1.72 (m, 1H), 1.43 - 1.28 (m, 1H), 0.89 (t, J= 5.2 Hz, 6H).

4-116. (3S)-3-(4’-chloro-4-fluoro-2’,5,6^,-trimethylbiphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)ethyI)4-methyl-2-oxopyridin-l(2//)-yl)-4-methyipentanamido)propanoic acid (diastereomeric compounds FJ-P1 and FJ-P2)

FJ-P1 ESI 612.2 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.58 (s, 1H), 7.11 (d, J= 2.5 Hz, 2H), 6.92 - 6.76 (m, 2H), 6.32 (s, 1H), 5.61 - 5.41 (m, 2H), 3.25 - 3.05 (m, 2H), 2.88 (t, J= 7.3 Hz, 2H), 2.78 (s, 6H), 2.71 - 2.54 (m, 2H), 2.28 (d, J= 13.0 Hz, 6H), 2.05 - 1.92 (m, 5H), 1.88 (s, 3H), 1.48 - 1.32 (m, 1H), 1.04 0.85 (m, 6H).

FJ-P2 ESI 612.2 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.55 (s, 1H), 7.13 (s, 2H), 6.93 - 6.84 (m, 2H), 6.42 (s, 1H), 5.70 - 5.54 (m, 2H), 3.24 - 3.11 (m, 2H), 2.99 - 2.76 (m, 8H), 2.64 - 2.42 (m, 2H), 2.36 2.20 (m, 6H), 2.03 - 1.90 (m, 7H), 1.83 - 1.72 (m, 1H), 1.47 -1.28 (m, 1H), 0.90 (t, J= 6.2 Hz, 6H).

4-117, (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[l,l'-biphenyl]-3-yl)propanoic acid (diastereomeric compounds FK-PI and FK-P2)

635

FK-P1 ESI 596.3 (M+H)⁺. *H NMR (400 MHz, MeOD) δ 7.59 - 7.37 (m, 2H), 6.96 - 6.64 (m, 4H), 5.76 - 5.58 (m, 1H), 5.39 (t, J= 5.5 Hz, IH), 3.42 - 3.25 (m, 1H), 3.23 - 3.06 (m, 1H), 2.96 - 2.76 (m, 2H), 2.73-2.46 (m, 8H), 2.41-2.22 (m, 6H), 2.05 - 1.88 (m, 8H), 1.44 (m, J= 13.7,6.7 Hz, 1H), 0.93 (m, J= 5 17.3, 6.6 Hz, 6H).

FK-P2 ESI 596.3 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.51 (s, 1H), 7.42 (m, J= 10.3,2.1 Hz, 1H), 6.89 (m, J= 7.0,4.6 Hz, 4H), 5.62 (m, J= 14.0, 9.4, 5.4 Hz, 2H), 3.43 - 3.30 (m, 1H), 3.23 (s, 1H), 2.93 (m, J = 9.6,4.9 Hz, 1H), 2.87 - 2.75 (m, 7H), 2.59 (m, J= 14.9, 4.0 Hz, 1H), 2.44 (m, J= 14.8, 10.1 Hz, 1H), 2.34 - 2.22 (m, 6H), 2.05 - 1.91 (m, 7H), 1.84 - 1.72 (m, 1H), 1.46 - 1.22 (m, 1H), 0.91 (m, J= 6.6, 3.1 10 Hz, 6H).

4-118. (3S)-3-(4-fluoro-2^,,4’,5,6’-tetramethyI-[l,r-biphenyI]-3-yl)-3-(2-(3-fluoro-5-(2-((R)-3IluoropyrroIidin-l-yl)ethyl)-2-oxopyridin-l(2II)-yl)-4-methyIpentanamido)propanoic acid (diastereomeric compounds FL-P1 and FL-P2)

FL-P1 ESI 640.2 (M+H)⁺. 1H NMR (400 MHz, MeOD) δ 7.50 (s, 1H), 7.41 - 7.31 (m, 1H), 6.91 (s, 2H), 6.85 (d, J= 7.0 Hz, 1H), 6.79 (d, J= 6.7 Hz, 1H), 5.70 (s, 1H), 5.49 (s, 1H), 5.24 (d, J= 53.7 Hz, 1H), 3.26 - 3.00 (m, 5H), 2.88 - 2.56 (m, 4H), 2.41 - 2.13 (m, 9H), 2.07 - 1.90 (m, 5H), 1.85 (s, 3H), 1.53 -1.26 (m, 1H), 1.05-0.80 (m,6H).

636

FL-P2 ESI 640.2 (M+H)⁺. IH NMR (500 MHz, MeOD) δ 7.49 (s, IH), 7.47 - 7.36 (m, IH), 6.90 (d, J = 8.8 Hz, 4H), 5.67 (t, J = 7.7 Hz, IH), 5.61 - 5.52 (m, IH), 5.33 (d, J = 54.6 Hz, IH), 3.73 - 3.38 (m, 5H), 3.28 (s, IH), 2.97 - 2.76 (m, 2H), 2.65 - 2.43 (m, 2H), 2.41 - 2.19 (m, 6H), 2.07 - 1.88 (m, 7H), 1.84 1.73 (m, IH), 1.51 - 1.20 (m, IH), 0.91 (d, J = 6.5 Hz, 6H).

4-119. (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-3-methyl-2-oxopyridin-l(2H)-yl)-4methyIpentanamido)-3-(4-fluoro-2',4’,5,6'-tetramethyI-[l,l'-biphenyI]-3-yl)propanoic acid (diastereomeric compounds FM-P1 and FM-P2)

FM-P1 ESI 592.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.35(S, IH), 7.32(S, IH), 6.80 (d, J= 8.4 Hz, 2H), 6.73 (d, J= 5.5 Hz, IH), 6.59 (d, J= 6.7 Hz, IH), 5.48-5.46 (m, IH), 5.23 (t, J= 5.1 Hz, IH), 3.08 2.98 (m, IH), 2.68-2.67 (m, 2H), 2.56 (s, 6H), 2.51-2.35 (m, 3H), 2.25 - 2.11 (m, 6H), 1.97 - 1.74 (m, 1 IH), 1.36- 1.24 (m, IH), 0.88 - 0.76 (m, 6H).

FM-P2 ESI 592.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.40 (s, IH), 7.29 (s, IH), 6.78-6.74 (m, 3H), 6.67 (d, J= 7.0 Hz, IH), 5.52-5.48 (m, IH), 5.42-5.39 (m, IH), 3.33-3.27 (m, IH), 3.20-3.14 (m, IH), 2.85 - 2.61 (m, 8H), 2.49-2.44 (m, IH), 2.33-2.27 (m, IH), 2.18 (s, 6H), 1.97 - 1.67 (m, 1 IH), 1.38 - 1.24 (m, IH), 0.82-0.77 (m, 6H).

4-120. (3S)-3-(4,4^,-difluoro-2’,6’-dimethyl-5-(trifluoromethyl)-[l,r-biphenyl|-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds FN-P1 and FN-P2)

637

FN-P1 ESI 654.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.55 (s, 1H), 7.50 - 7.37 (m, 1H), 7.40 - 7.25 (m, 2H), 6.89 (d, J = 9.6 Hz, 2H), 5.73 - 5.55 (m, 1H), 5.47 (t, J = 5.9 Hz, 1H), 3.27 - 3.13 (m, 1H), 2.98 2.82 (m, 3H), 2.78 (s, 6H), 2.73-2.64 (m, 1H), 2.63-2.50 (m, 1H), 2.13 -1.97 (m, 5H), 1.93 (s, 3H), 1.42 5 (s, 1H), 1.11-0.79 (m,6H).

FN-P2 ESI 654.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.51 (s, 1H), 7.48 - 7.41 (m, 1H), 7.38 (t, J = 6.0 Hz, 2H), 6.90 (d, J = 9.6 Hz, 2H), 5.76 - 5.43 (m, 2H), 3.42 (d, J = 10.1 Hz, 1H), 3.28 (d, J = 12.8 Hz, 1H), 2.96 (d, J = 9.5 Hz, 1H), 2.85 (d, J = 7.2 Hz, 6H), 2.74 - 2.54 (m, 1H), 2.55 - 2.34 (m, IH), 2.15 - 1.93 (m, 6H), 1.93 - 1.72 (m, 1H), 1.52 - 1.27 (m, 1H), 0.92 (t, J = 6.5 Hz, 6H).

4-121. (3S)-3-(4-fluoro-2*,4^,,5,6’-tetramethylbiphenyI-3-yI)-3-(2-(3-nuoro-5-(2-(3-fluoroazetidin-lyl)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds FO-P1 and FO-P2)

FO-P1 ESI 626.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.45 - 7.33 (m, 2H), 6.96 - 6.85 (m, 3H), 6.83 - 6.75 (m, 1H), 5.69 (t, J= 8.1 Hz, 1H), 5.52 - 5.45 (m, 1H), 5.30 - 5.10 (m, 1H), 4.23 - 4.09 (m, 1H), 4.02 - 3.89 (m, 1H), 3.78 - 3.62 (m, 2H), 3.26 - 3.16 (m, 2H), 2.78 - 2.56 (m, 4H), 2.36 - 2.25 (m, 6H), 2.00 - 1.92 (m, 5H), 1.88 (s, 3H), 1.48 - 1.39 (m, 1H), 0.98 - 0.86 (m, 6H).

638

FO-P2 ESI 626.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.45 - 7.35 (m, 2H), 6.97 - 6.86 (m, 4H), 5.76 - 5.62 (m, 2H), 5.42 - 5.20 (m, IH), 4.49 - 4.28 (m, 2H), 4.12 - 3.95 (m, 2H), 3.44 - 3.36 (m, 2H), 2.78 2.63 (m, 2H), 2.67 - 2.52 (m, IH), 2.61 - 2.52 (m, IH), 2.37 - 2.25 (m, 6H), 2.01 - 1.91 (m, 7H), 1.85 1.69 (m, IH), 1.43 -1.36(m, IH), 0.96-0.85 (m, 6H).

4-122. (3S)-3-(2’-chIoro-4,4’-difluoro-5,6’-dimethyl-[l,l’-biphenyI]-3-yl)-3-(2-(3-fluoro-5-(2-(3fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2/7)-y])-4-methylpentanamido)propanoic acid (diastereomeric compounds FP-P1 and FP-P2)

FP-P1 ESI 650.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.43 - 7.34 (m, 2H), 7.17 - 7.13 (m, IH), 7.06 - 7.01 (m, 1 H), 6.89 - 6.85 (m, 1 H), 5.72 - 5.67 (m, 1 H), 5.54 - 5.49 ( m, 1 H), 5.32 - 5.09 (m, 1 H), 4.15 - 3.65 (m, 4H), 3.19 - 3.10 (m, 2H), 2.78 - 2.60 (m, 4H), 2.31 (s, 3H), 2.08 - 1.92 (m, 5H), 1.49 - 1.39 (m, IH), 0.97-0.93 (m,6H).

FP-P2 ESI 650.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.39 - 7.36 (m, 2H), 7.15 (d, J= 8.5 Hz, IH), 7.08 - 6.96 (m, 3H), 5.73 - 5.61 (m, 2H), 5.41 - 5.22 (m, IH), 4.48 - 4.28 (m, 2H), 4.11 - 3.94 (m, 2H), 3.42 - 3.33 (m, 2H), 2.80 - 2.47 (m, 4H), 2.34 (d, J= 1.8 Hz, 3H), 2.09 (d, J= 2.7 Hz, 3H), 2.03 - 1.90 (m, IH), 1.83 - 1.72 (m, IH), 1.44 - 1.30 (m, IH), 0.94 - 0.89 (m, 6H).

4-123. (35)-3-(2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yI)ethyl)-2-oxopyridîn-l(2i7)-yI)-4methyIpentanamido)-3-(2',4,4’-trifluoro-5,6'-dimethylbiphenyI-3-yl)propanoic acid (diastereomeric compounds FQ-P1 and FQ-P2)

639

FQ-P1 ESI 634.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.43 (s, IH), 7.36 (d, J= 10.3 Hz, IH), 7.02 (d, J=6.8 Hz, IH), 6.98-6.89(m, 2H), 6.85 (t,J=9.2Hz, IH), 5.69 (t,J= 8.1 Hz, IH), 5.53-5.50 (m, IH), 5.30 - 5.08 (m, IH), 4.09 - 3.99 (m, 2H), 3.77 - 3.63 (m, 2H), 3.15 - 3.12 (m, 2H), 2.79 - 2.69 (m, 2H), 2.66 - 2.62 (m, 2H), 2.31 (s, 3H), 2.09 (s, 3H), 1.97 (t, J= 7.6 Hz, 2H), 1.51 - 1.37 (m, IH), 0.98 - 0.93 (m, 6H).

FQ-P2 ESI 634.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.43 - 7.32 (m, 2H), 7.06 (d, J= 6.7 Hz, 2H), 6.93 (d, J= 9.3 Hz, IH), 6.88 - 6.83 (m, IH), 5.74 - 5.59 (m, 2H), 5.39 - 5.24 (m, IH), 4.42 - 4.32 (m, 2H), 4.10 - 3.88 (m, 2H), 3.40 - 3.37 (m, 2H), 2.81 - 2.71 (m, 2H), 2.65 - 2.60 (m, IH), 2.55 - 2.48 (m, IH), 2.34 (d, J= 1.6 Hz, 3H), 2.16 (s, 3H), 2.03 - 1.93 (m, IH), 1.86 - 1.75 (m, IH), 1.45 - 1.33 (m, IH), 0.93-0.9 l(m, 6H).

4-124. (3S)-3-(2-(5-(2-(azetidin-l-yI)ethyI)-2-oxo-4-(trifluoromethyI)pyridin-l(2H)-yI)-4niethylpentanamido)-3-(2'-cyclopropyl-4,4'-difluoro-5,6'-dimethyl-[l,l'-biphcnyl]-3-yl)propanoic acid (diastereomeric compounds FR-P1 and FR-P2)

FR-P1 ESI 688.2 (M+H)⁺. ’H NMR (400 MHz, MeOD) δ 7.84 (s, IH), 6.95 (dd, J= 19.9, 7.2 Hz, 2H), 6.86 - 6.64 (m, 2H), 6.55 - 6.23 (m, IH), 5.75 - 5.49 (m, 2H), 3.85 (t, J= 7.7 Hz, 4H), 3.33 (m, J= 3.2, 1.6 Hz, 2H), 3.13 (m, J= 6.8 Hz, 2H), 2.90 - 2.58 (m, 2H), 2.51 - 2.21 (m, 5H), 2.01 (d, J= 5.3 Hz, 4H), 1.87 (s, IH), 1.40 (s, 2H), 1.07-0.85 (m, 6H), 0.75 (m, J= 8.6,3.5 Hz, IH), 0.66-0.43 (m, 3H).

FR-P2 ESI 688.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.74 (d, J= 11.5 Hz, IH), 6.94 (m, J= 46.9, 28.6, 8.1 Hz, 4H), 6.50 (d, J= 10.4 Hz, IH), 5.78 (m, J= 11.0,3.1 Hz, IH), 5.62 (m, J= 7.3 Hz, 1H),4.13 (m, J= 8.0 Hz, 4H), 3.50 - 3.32 (m, 2H), 2.94 (d, J= 16.3 Hz, IH), 2.81 (d, J= 7.7 Hz, 2H), 2.68 - 2.61 (m, IH), 2.57-2.42 (m, 3H), 2.34 (d, J= 1.1 Hz, 3H), 2.05-1.79 (m, 4H), 1.65 (m, J= 13.9,7.1 Hz, IH), 1.50 -1.30 (m, 2H), 0.88 (d, J= 6.6 Hz, 6H), 0.74 (m, J= 14.0,7.3 Hz, 2H), 0.60 (m, J= 6.4,5.0 Hz, 2H).

4-125. (3S)-3-((3.R)-2-(5-(2-(dimethyIaïnino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z7)-yI)-3methylpentanamido)-3-(4-fluoro-2',4’,5,6’-tetramethylbiphenyl-3-yl)propanoic acid (diastereomeric compounds FS-PI and FS-P2)

640

FS-P1 ESI 646.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.94 (s, IH), 6.89 (s, IH), 6.82 - 6.75 (m, 3H), 6.66 (s, 1 H), 5.65 - 5.53 (m, 1 H), 5.33 (d, J= 11.3 Hz, IH), 3.05 - 2.83 (m, 5H), 2.82 - 2.62 (m, 6H), 2.40 -2.18 (m, 8H), 2.03- 1.88 (m, 3H), 1.78 - 1.67 (m, IH), 1.63 (s, 3H), 1.38- 1.21 (m, IH), 1.07-0.96(m, 3H), 0.75 (d,J=6.5 Hz, 3H).

FS-P2 ESI 646.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.92 (s, IH), 6.91 - 6.72 (m, 5H), 5.69 - 5.52 (m, IH), 5.21 (d, J= 10.9 Hz, IH), 3.14 - 2.79 (m, 3H), 2.68 (s, 6H), 2.55 - 2.36 (m, 2H), 2.22 - 2.06 (m, H), 1.84 (d, J= 3.6 Hz, 4H), 1.32 - 0.99 (m, 3H), 0.93 - 0.61 (m, 7H).

4-126. (3S)-3-(2',6'-dichloro-4-fluoro-4',5-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(dimethyIamino)ethyl)2-oxo-4-(trifluoromethyl)pyridin-l(27/)-y!)-3-methylbutanamido)propanoic acid (diastereomeric compounds FT-P1 and FT-P2)

FT-P1 ESI 672.1 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ: 7.91 (s, IH), 7.27 (d, J= 6.0 Hz, IH), 7.14 (d, J= 5.2 Hz, IH), 6.90 (t, J= 6.0 Hz, 2H), 6.67 (d, J= 5.6 Hz, IH), 5.64 - 5.60 (m, IH), 5.29 (d, J= 11.2 Hz, IH), 2.97 - 2.85 (m, 4H), 2.78 - 2.61 (m, 8H), 2.46 - 2.40 (m, IH), 2.36 (s, 3H), 2.27 (s, 3H), 1.16 (d, J= 6.4 Hz, 3H), 0.78 (d, J= 6.4 Hz, 3H).

FT-P2 ESI 672.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ: 8.01 (s, IH), 7.30 (s, 2H), 7.09 - 7.07 (m, IH), 7.00 (d, J= 7.2 Hz, IH), 6.90 (s, IH), 5.78 - 5.74 (m, IH), 5.23 (d, J= 11.2 Hz, IH), 3.27 - 3.20 (m, IH), 3.17 - 3.11 (m, IH), 3.09 - 3.01 (m, IH), 2.99 - 2.93 (m, IH), 2.78 (s, 6H), 2.61 - 2.50 (m, 2H), 2.47 2.37 (m, 4H), 2.31 (d, J= 1.2 Hz, 3H), 0.94 (d, J= 6.4 Hz, 3H), 0.71 (d, J= 6.8 Hz, 3H).

641

4-127. (3S)-3-(2-(5-(2-(azetidin-l-yI)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2//)-yl)-4methyIpentanamido)-3-(2’-cyclopropyl-4-nuoro-4’,5,6*-trÎmethyl-[l,l’-biphenyI]-3-yl)propanoic acid (diastereomeric compounds FU-P1 and FU-P2)

FU-P1 ESI 684.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.84 (s, IH), 6.97 - 6.78 (m, 4H), 6.58 (s, 1H), 5.69 - 5.59 (m, 2H), 3.97 - 3.94 (m, 4H), 3.26 - 3.21 (m, 2H), 2.86 - 2.81 (m, 2H), 2.72 - 2.68 (m, 2H), 2.46 - 2.38 (m, 2H), 2.29 (d, J= 4.9 Hz, 6H), 2.03 - 1.97 (m, 3H), 1.85 (s, 2H), 1.48-1.31 (m, 2H), 0.98 - 0.91 (m, 6H), 0.67 (d, J= 8.4 Hz, 1H), 0.59 - 0.44 (m, 3H).

FU-P2 ESI 684.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.73 (d, J= 10.5 Hz, 1H), 7.02 - 6.96 (m, 2H), 6.91 (s, 1H),6.90(s, 1H),6.59(s, 1H),5.78-5.75 (m, 1H),5.64-5.59(m, 1H),4.14-4.10(m,4H),3.47 - 3.38 (m, 2H), 2.97 - 2.92 (m, 1H), 2.85 - 2.75 (m, 1H), 2.69 - 2.60 (m, 1H), 2.55 - 2.45 (m, 3H), 2.34 (s, 3H), 2.29 (s, 3H), 2.05 - 1.96 (m, 4H), 1.71 - 1.61 (m, 1H), 1.49 - 1.39 (m, 2H), 0.90 (d, 6.6 Hz,

6H), 0.70 - 0.66 (m, 2H), 0.58 - 0.55 (m, 2H).

4-128. (3S)-3-(2’,6’-dichIoro-4-fluoro-5-methylbiphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2oxo-4-(trifluoromethyl)pyridin-l(2/Z)-yl)-4-methylpcntanamido)propanoic acid (diastereomeric compounds FV-P1 and FV-P2)

FV-P1 ESI 672.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ: 7.89 (s, 1H), 7.46 (d, J= 8.0 Hz, 1H), 7.39 (d, J= 7.2 Hz, 1H), 7.32 (t, J= 8.0 Hz, 1H), 7.00 - 6.96 (m, 2H), 6.75 (s, 1H), 5.72 - 5.68 (m, 1H), 5.60 - 5.56 (m, 1 H), 3.10 - 3.01 (m, 2H), 2.94 - 2.92 (m, 2H), 2.74 - 2.65 (m, 8H), 2.27 (d, J =1.2 Hz, 3H), 2.01 1.93 (m, 2H), 1.47 - 1.41 (m, 1H), 0.95 (d, J= 6.4 Hz, 3H), 0.93 (d, J= 6.4 Hz, 3H).

FV-P2 ESI 672.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ: 7.91 - 5.88 (m, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.35 - 7.31 (m, 1H), 7.08 - 7.02 (m, 2H), 6.89 (s, 1H), 5.78 - 5.74 (m, 1H), 5.64 (t, J= 7.6 Hz, 1H), 3.27

642

- 3.15 (m, 2H), 3.06 - 2.95 (m, 2H), 2.80 (s, 6H), 2.65 - 2.60 (m, IH), 2.55 - 2.49 (m, IH), 2.32 (s, 3H), 1.99-1.92 (m, IH), 1.71 - 1.64 (m, IH), 1.41 -1.34 (m, IH), 0.86-0.84 (m, 6H).

4-129. (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yI)-4methylpentanamido)-3-(4-fluoro-2',5,6'-trimethyl-4'-(trifluoromethyl)biphenyI-3-yl)propanoic acid (diastereomeric compounds FW-P1 and FVV-P2)

FW-P1 ESI 712.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ: 7.88 (s, IH), 7.39 (s, IH), 7.35 (s, IH), 6.91 (t, J= 6.2 Hz, 2H), 6.70 (s, IH), 5.66 - 5.57 (m, 2H), 4.04 (t, J= 8.2 Hz, 4H), 3.29 (t, J= 7.4 Hz, 2H), 2.84 (t, J= 7.2 Hz, 2H), 2.78 - 2.67 (m, 2H), 2.48 - 2.40 (m, 2H), 2.30 (d, J= 1.2 Hz, 3H), 2.08 (s, 3H), 2.03 1.99 (m, 2H), 1.91 (s, 3H), 1.47 - 1.40 (m, IH), ), 0.95 (d, J= 6.8 Hz, 3H), 0.93 (d, J= 6.4 Hz, 3H).

FW-P2 ESI 712.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ: 7.74 (s, IH), 7.41 (s, 2H), 6.98 (s, IH), 6.96 (s, IH), 6.90 (s, IH), 5.79 - 5.76 (m, IH), 5.60 (t, J= 8.0 Hz, IH), 4.15 (t, J= 8.0 Hz, 4H), 3.48 - 3.42 (m, IH), 3.38 - 3.33 (m, IH), 2.98 - 2.91 (m, IH), 2.84 - 2.77 (m, IH), 2.69 - 2.64 (m, IH), 2.55 - 2.45 (m, 3H), 2.35 (d, 1.6 Hz, 3H), 2.09 (s, 3H), 2.08 (s, 3H), 2.03 - 1.96 (m, IH), 1.69 - 1.62 (m, IH), 1.46 1.36 (m, IH), 0.89 (d, J= 1.6 Hz, 3H), 0.87 (d, J= 2.0 Hz, 3H).

4-130. (3S)-3-(2’-chloro-4-fluoro-5,6’-dimethyl-(l,l*-biphenyI]-3-yl)-3-(2-(5-(2(dimethyIamino)ethyI)-2-oxo-4-(trinuoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds FX-P1 and FX-P2) (S) F ^MeΛ3Η

643

FX-P1 ESI 652.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.90 (d, J = 4.5 Hz, IH), 7.37 - 7.09 (m, 3H), 6.93 (m, J= 10.9,4.9 Hz, 2H), 6.75 (d, J= 6.5 Hz, IH), 5.68 (m, J = 30.2, 23.4 Hz, 2H), 3.00 (d, J= 50.0 Hz, 4H), 2.73 (d, J = 14.3 Hz, 8H), 2.30 (s, 3H), 2.13 - 1.83 (m, 5H), 1.45 (d, J= 6.4 Hz, IH), 0.96 (m, J = 12.9, 6.6,2.5 Hz, 6H).

FX-P2 ESI 652.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.88 (s, IH), 7.34 - 7.09 (m, 3H), 7.11 - 6.51 (m, 3H), 5.69 (m, J= 21.6,10.6,4.3 Hz, 2H), 3.15 (s, 2H), 2.98 (s, 2H), 2.88 - 2.53 (m, 8H), 2.34 (s, 3H), 2.08 (d, J= 5.6 Hz, 3H), 1.98 - 1.81 (m, IH), 1.78 (s, IH), 1.40 (s, IH), 0.89 (m, J= 6.4,4.6 Hz, 6H).

4-131. (3S)-3-(2-(5-(2-(azetidin-l-yI)ethyl)-2-oxo-4-(triiluoromethyl)pyridin-l(2H)-yl)-4methyIpentanamido)-3-(2’,4-difluoro-5,6’-dimethyIbiphenyI-3-yI)propanoic acid (diastereomeric compounds FY-P1 and FY-P2)

FY-P1 ESI 648.2 (M+Hf. Ή NMR (400 MHz, MeOD) δ 7.84 (s, IH), 7.30 - 7.23 (m, IH), 7.16 -7.09 (m, IH), 7.06 -6.92 (m, 3H), 6.81 (s, IH), 5.71 - 5.60 (m, 2H), 4.01 (t, J= 8.1 Hz, 4H), 3.29 (s, 2H), 2.86 (t, J= 6.8 Hz, 2H), 2.72 (d, J= 6.6 Hz, 2H), 2.46 - 2.36 (m, 2H), 2.36 - 2.31 (m, 3H), 2.10 (s, 3H), 2.00 (t, J= 7.6 Hz, 2H), 1.51 - 1.42 (m, IH), 0.98 - 0.93 (m, 6H).

FY-P2 ESI 648.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.75 (s, IH), 7.31 -7.19 (m, IH), 7.15 - 7.04 (m, 3H), 6.99 (t, 8.8 Hz, IH), 6.92 (s, IH), 5.81 -5.75 (m, IH), 5.64 (t, J= 7.6 Hz, IH), 4.14 (t, J = 8.0

Hz, 4H), 3.49 - 3.35 (m, 2H), 2.94 (d, J= 15.7 Hz, IH), 2.87 - 2.75 (m, IH), 2.69 -2.56 (m, IH), 2.57 2.43 (m, 3H), 2.35 (d, J= 1.5 Hz, 3H), 2.17 (d, J= 8.1 Hz, 3H), 2.04 - 1.95 (m, IH), 1.72 - 1.62 (m, IH), 1.46 -1.32 (m, IH), 0.97 -0.91 (m, 6H).

4-132. (3S)-3-(3’,4-difluoro-2’,4’,5,6’-tetramethylbiphenyI-3-yI)-3-(2-(5-(2-(dimethylamino)ethyI)-2oxo-4-(trifluoromethyl)pyridin-l(2/Z)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds FZ-P1 and FZ-P2)

644

FZ-P1 ESI 664.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.85 (s, IH), 7.01 - 6.79 (m, 4H), 5.78 - 5.58 (m, 2H), 3.29 - 3.07 (m, 2H), 3.04 - 2.89 (m, 2H), 2.81 (s, 6H), 2.70 - 2.42 (m, 2H), 2.33 (s, 3H), 2.26 (s, 3H), 2.13-1.83 (m, 7H), 1.81-1.60 (m, 1H), 1.52-1.30 (m, 1H), 1.02-0.81 (m, 6H).

FZ-P2 ESI 664.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.91 (s, 1H), 6.99 - 6.68 (m, 4H), 5.82 - 5.50 (m, 2H), 3.19 - 2.89 (m, 4H), 2.83 - 2.54 (m, 8H), 2.38 - 2.22 (m, 6H), 2.13 - 1.80 (m, 5H), 1.72 (d, 7= 14.7 Hz, 3H), 1.51 - 1.36 (m, 1H), 1.06-0.84 (m, 6H).

4-133. (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyI)-2-oxo-4-(trifluoromethyl)pyridin-l(2//)-yi)-410 methylpentanamido)-3-(4'-cyano-4-fluoro-2’,5,6'-trimethylbiphenyl-3-yl)propanoic acid (diastereomeric compounds GA-P1 and GA-P2) (s; F ^Me

GA-P1 ESI 669.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.84 (s, IH), 7.47 (d, 7= 10.3 Hz, 2H), 6.91 (d, 7= 6.7 Hz, 2H), 6.75 (s, IH), 5.59 (d, 7= 7.7 Hz, 2H), 4.06 (t, 7= 8.1 Hz, 4H), 3.31 - 3.27 (m, 2H), 2.98 15 - 2.85 (m, 2H), 2.79 - 2.64 (m, 2H), 2.58 - 2.39 (m, 2H), 2.31 (s, 3H), 2.14 - 1.88 (m, 8H), 1.54 - 1.27 (m,

IH), 1.10-0.80 (m, 6H).

GA-P2 ESI 669.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.74 (s, IH), 7.50 (s, 2H), 7.06 - 6.84 (m, 3H), 5.90 - 5.71 (m, IH), 5.61 (t, 7 = 7.6 Hz, IH), 4.10 (s, 4H), 3.36 (s, 2H), 3.09 - 2.74 (m, 2H), 2.74 - 2.60

645 (m, 1H), 2.55 - 2.39 (m, 3H), 2.35 (s, 3H), 2.13 - 1.89 (m, 7H), 1.75 - 1.62 (m, 1H), 1.50 - 1.35 (m, 1H), 0.98-0.81 (m, 6H).

4-134. (3S)-3-(2'-cyano-4-nuoro-5,6'-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)ethyI)-2oxo-4-(trifIuoromethyI)pyridin-l(2II)-yl)-4-methylpentanamido)propanoic acid (diastereomcric compounds GB-P1 and GB-P2)

GB-P1 ESI 643.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.89 (s, 1H), 7.59 (s, 2H), 7.43 (t, J= 7.7 Hz, 1H), 7.06 (s, 2H), 6.71 (d, J= 26.7 Hz, 1H), 5.73 (s, 1H), 5.60 (d, J= 7.3 Hz, 1H), 3.10 (s, 2H), 2.93 (d, J = 8.3 Hz,2H),2.80-2.69(m, 8H),2.32(s,3H),2.19(s,2H),2.00 (s,3H), 1.49-1.42(m, 1H), 1.00-0.92 (m, 6H).

GB-P1 ESI 643.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.81 (s, 1H), 7.66 - 7.52 (m, 2H), 7.45 (t, J= 7.7 Hz, 1H), 7.13 (d, J= 6.4 Hz, 2H), 6.90 (s, 1H), 5.77 - 5.59 (m, 2H), 3.23 (s, 2H), 3.01 (s, 2H), 2.83 (s, 6H), 2.69 - 2.53 (m, 1H), 2.58 - 2.49 (m, 1H), 2.37 (d, J= 1.6 Hz, 3H), 2.19 (s, 3H), 2.05 - 1.96 (m, 1H), 1.81 (s, 1H), 1.42- 1.36 (m, 1H), 0.99-0.91 (m, 6H).

4-135. (35)-3-(2-(5-(2-(azetidin-l-yI)ethyI)-2-oxo-4-(trifluoromethyI)pyridin-l(2W)-yl)-4methylpentanamido)-3-(4-fluoro-2’-methoxy-5,6’-dimethylbiphenyI-3-yl)propanoîc acid (diastereomcric compounds GC-P1 and GC-P2)

646

GC-P1 ESI 660.2 (M+H)\ NMR (400 MHz, MeOD) δ 7.82 (s, IH), 7.21 (t, J= 8.0 Hz, IH), 6.99 - 6.82 (m, 5H), 5.70 - 5.62 (m, 2H), 4.01 - 3.96 (m, 4H), 3.66 (s, 3H), 3.30 - 3.27 (m, 2H), 2.88 - 2.85 (m, 2H), 2.71 (d, J= 7.4 Hz, 2H), 2.45-2.39 (m, 2H), 2.29 (s, 3H), 2.02 - 1.93 (m, 5H), 1.45 - 1.38 (m, IH), 0.97 - 0.93 (m, 6H).

GC-P2 ESI 660.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.73 (s, IH), 7.22 (t, J = 8.0 Hz, IH), 7.00 6.87 (m, 5H), 5.79 - 5.75 (m, IH), 5.62 (t, J= 7.6 Hz, IH), 4.13 (t, J= 7.9 Hz, 4H), 3.68 (s, 3H), 3.49 3.35 (m, 2H), 2.97- 2.91 (d, J = 16.1 Hz, IH), 2.85 - 2.77 (m, IH), 2.66 - 2.62(m, IH), 2.56 - 2.42 (m, 3H), 2.32 (d, J= 1.7 Hz, 3H), 2.04 (s, 3H), 2.02 - 1.97 (m, IH), 1.72 - 1.60 (m, IH), 1.49 - 1.36 (m, IH), 0.91 (d, 7=6.5 Hz, 6H).

4-136. (3S)-3-(2'-cyclopropyl-4-fluoro-4’,5,6’-trimethyI-[l,l’-biphenyl]-3-yl)-3-(2-(5-(2(dimethyIamino)ethyl)-4-methyl-2-oxopyridin-l(2ZiF)-yI)-4-methyIpentanamido)propanoic acid (diastereomeric compounds GD-P1 and GD-P2)

GD-P1 ESI 618.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.57 (d, J= 1.8 Hz,l), 6.91 - 6.84 (m, 3H), 6.57 (d, J= 11.0 Hz, IH), 6.38 (d, J= 8.9 Hz, IH), 5.59 (d, J= 5.8 Hz, IH), 5.46 (t, J= 5.9 Hz, IH), 3.22-3.06 (m, 2H), 2.87 (t, 7= 7.1 Hz, 2H), 2.74 (s, 6H), 2.71 - 2.56 (m, 2H), 2.27 (d, J= 13.3 Hz, 9H), 2.04 - 1.87 (m, 5H), 1.48 - 1.38 (m, 2H), 0.95 - 0.89 (m, 6H), 0.72 - 0.67 (m, IH), 0.63 - 0.55 (m, IH), 0.53 - 0.48 (m, 2H).

GD-P2 ESI 618.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.54 (d, J= 10.5 Hz, IH), 6.98 - 6.89 (m, 2H), 6.89 (s, IH), 6.59 (s, IH), 6.44 (d, 7= 5.1 Hz, IH), 5.65 -5.56 (m, 2H), 3.34 - 3.26 (m, 2H), 3.20 - 3.13 (m, 2H), 2.94 - 2.88 (m, 2H), 2.81 (d, J= 2.0 Hz, 6H), 2.64 - 2.57 (m, IH), 2.48 - 2.41 (m, IH), 2.32 2.246 (m, 9H), 1.99 - 1.92 (m, 4H), 1.81 - 1.74 (m, IH), 1.49 - 1.33 (m, IH), 0.92 - 0.85 (m, 6H), 0.68 - 0.63 (m, 2H), 0.58 - 0.51 (m, 2H).

647

4-137. (3S)-3-(4’-cyclopropyI-4-fluoro-2’,5,6’-trimethyl-[l,l’-biphenylJ-3-yl)-3-(2-(5-(2(dimethylamino)ethyl)-4-methyI-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds GE-P1 and GE-P2)

GE-P1 ESI 618.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.46 (s, IH), 6.84 - 6.65 (m, 3H), 6.45 (d, J= 11.2 Hz, IH), 6.27 (d, J= 8.7 Hz, IH), 5.48-5.46 (m, IH), 5.33 (d, J= 5.6 Hz, IH), 3.15-2.95 (m, 2H), 2.78-2.74 (m, 3H), 2.60 (d, J= 25.4 Hz, 6H), 2.58 - 2.40 (m, 2H), 2.17 (s, 6H), 2.13(s, 3H), 1.95 - 1.73 (m, 5H), 1.34-1.28 (m, 2H), 0.86 - 0.73 (m, 6H), 0.62 - 0.32 (m, 4H).

GE-P2 ESI 618.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.43(s, IH), 7.40(s, IH), 6.84 (t, J= 6.2 Hz, 10 2H), 6.77 (s, IH), 6.47 (s, IH), 6.32 (d, J= 5.5 Hz, IH), 5.52-5.44 (m, 2H), 3.09-3.06 (m, IH), 2.88 - 2.67 (m, 8H), 2.51-2.45 (m, IH), 2.37-2.29 (m, IH), 2.24 - 2.09 (m, 9H), 1.85-1.81 (m, 4H), 1.70 - 1.59 (m, IH), 1.39 - 1.16 (m, 2H), 0.78-0.76 (m, 6H), 0.54 (t, J= 7.6 Hz, 2H), 0.45 (d, J=4.5 Hz, 2H).

4-138. (3S)-3-(2'-chloro-4,4'-difluoro-5,6'-dimethyI-[l,l'-biphenyl]-3-yl)-3-(2-(5-(215 (dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)-yl)-4-methyIpentanamido)propanoic acid (diastereomeric compounds GF-P1 and GF-P2)

648

GF-P1 ESI 670.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.90 (d, J= 3.1 Hz, 1H), 7.14 - 6.92 (m, 4H), 6.76 (d, J = 5.6 Hz, 1H), 5.72 - 5.65 (m, 1H), 5.60 - 5.56 (m, 1H), 3.10 - 2.87 (m, 4H), 2.76 - 2.66 (m, 8H), 2.30 (s, 3H), 2.09 - 1.91 (m, 5H), 1.47-1.41 (m, 1H), 1.00 - 0.92 (m, 6H).

GF-P2 ESI 670.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 7.16 - 7.12 (m, 1H), 7.07 - 6.95 (m, 3H), 6.91 (d, J= 2.7 Hz, 1H), 5.74 - 5.59(m, 2H), 3.32 - 3.21 (m, 2H), 3.03 - 2.99 (m, 2H), 2.84 (d, J = 2.9 Hz, 6H), 2.67 - 2.49 (m, 2H), 2.34 (d, J= 1.6 Hz, 3H), 2.03 - 1.90 (m, 1H), 1.76 - 1.67 (m, 1H), 1.46 - 1.37 (m, 1H), 0.92 - 0.89 (m, 6H).

4-139. (3S)-3-(2’,6’-dichloro-4-nuoro-4’,5-dimethyl-(l,l’-biphenyl]-3-yI)-3-(2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-mcthyIpentanamido)propanoic acid (diastereomeric compounds GG-P1 and GG-P2)

GG-P1 ESI 686.1 (M+H)⁺. *H NMR (400 MHz, MeOD) δ 7.90 (s, 1H), 7.31 (s, 1H), 7.23 (s, IH), 7.02 6.91 (m, 2H), 6.76 (s, 1H), 5.76 - 5.66 (m, 1H), 5.63 - 5.53 (m, 1H), 3.15 - 3.04 (m, 2H), 2.94 (t, J= 11.0 Hz, 2H), 2.80 - 2.66 (m, 8H), 2.38 (s, 3H), 2.29 (d, J= 1.3 Hz, 3H), 2.04 - 1.92 (m, 2H), 1.51 - 1.42 (m, 1H), 1.01-0.90 (m, 6H).

GG-P2 ESI 686.1 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.88 (s, 1H), 7.32 (s, 2H), 7.09 - 6.99 (m, 2H), 6.91 (s, 1H), 5.79 - 5.71 (m, 1H), 5.65 (t, J= 7.7 Hz, 1H), 3.30 - 3.15 (m, 2H), 3.00 (t, J= 6.8 Hz, 2H), 2.81 (s, 6H), 2.67 - 2.50 (m, 2H), 2.39 (s, 3H), 2.33 (d, J= 1.5 Hz, 3H), 2.02 - 1.92 (m, 1H), 1.73 - 1.65 (m, 1H), 1.44 - 1.36 (m, 1H), 0.91 - 0.85 (m, 6H).

4-140. (3S)-3-(2-(5-(2-(dimethyIamino)ethyI)-4-methyl-2-oxopyridin-l(2Z7)-yl)-4methylpentanamido)-3-(4-fluoro-2’,5,6’-trimethyl-4’-(trinuoromethyl)biphenyl-3-yl)propanoic acid (diastereomeric compounds GH-P1 and GH-P2)

649

GH-P1 ESI 646.3 (M+H)⁺. ΉNMR (400 MHz, MeOD) δ: 7.59 (s, IH), 7.40 (s, IH), 7.38 (s, IH), 6.89 (d, J= 6.8 Hz, IH), 6.84 (d, J= 6.4 Hz, IH), 6.28 (s, IH), 5.55 (t, J= 5.6 Hz, IH), 5.49 (t, J= 6.0 Hz, IH), 3.16 - 3.08 (m, 2H), 2.87 (t, 7= 7.2 Hz, 2H), 2.78 (s, 6H), 2.73 - 2.68 (m, IH), 2.65 - 2.60 (m, IH), 2.31 (s, 3H), 2.25 (s, 3H), 2.08 (s, 3H), 2.01 - 1.90 (m, 5H), 1.45 - 1.38 (m, IH), 0.94 (d, J= 6.4 Hz, 3H), 0.91 (d, 7=6.8 Hz, 3H).

GH-P2 ESI 646.3 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ: 7.55 (s, IH), 7.41 (s, 2H), 6.95 - 6.93 (m, IH), 6.90 (d, J= 6.4 Hz, IH), 6.41 (s, IH), 5.63 - 5.60 (m, IH), 5.58 -5.56 (m, IH), 3.38 -3.36 (m, IH), 3.25 - 3.19 (m, IH), 2.95 - 2.90 (m, 2H), 2.85 (s, 6H), 2.64 - 2.59 (m, IH), 2.50 - 2.44 (m, IH), 2.34 (d, 7= 1.6 Hz, 3H), 2.26 (s, 3H), 2.08 (s, 6H), 2.00 - 1.93 (m, IH), 1.83 - 1.76 (m, IH), 1.42 - 1.35 (m, IH), 0.89 (t, 7= 6.4 Hz, 6H).

4-141. (3S)-3-(4'-cycIopropyI-4-fluoro-2^,,5,6’-trimethyI-[l,l’-biphenyi]-3-yl)-3-(2-(5-(2(dimethyIamino)ethyl)-3-fluoro-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds GI-P1 and GI-P2) (S) F ^Me \ /OH

GI-P1 ESI 636.3 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.47 (s, IH), 6.94 - 6.78 (m, 3H), 6.57 (d, 7 = 12.7Hz, IH),5.74-5.57(m, IH),5.46(t,7=5.9Hz, IH),3.25-3.10(m,2H),2.92(t,7= 6.9Hz,2H),2.75 (s, 6H), 2.70 - 2.52 (m, 2H), 2.30-2.25 (m, 9H), 1.99-1.88 (m, 5H), 1.46-1.39 (m, 2H), 0.97 - 0.86 (m, 6H), 0.72-0.43 (m, 4H).

650

GI-P2 ESI 636.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.42 (d, J= 11.3 Hz, IH), 6.97 (t, J= 8.2 Hz, 2H), 6.89 (s, IH), 6.59 (s, IH), 5.72 - 5.52 (m, 2H), 3.32-3.22 (m, 2H), 2.98-2.90 (m, 2H), 2.85 (s, 6H), 2.67 - 2.38 (m, 2H), 2.32-2.25 (m, 9H), 2.00-1.98 (m, 4H), 1.83 - 1.67 (m, IH), 1.51 - 1.26 (m, 2H), 0.90 (d, J= 6.6 Hz, 6H), 0.70 - 0.48 (m, 4H).

4-142. (3S)-3-(4-fluoro-2',4’,5,6'-tetramethyl-[l,l’-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3methoxyazetidin-l-yl)ethyI)-4-methyI-2-oxopyridin-l(2H)-yI)-4-methylpentanamido)propanoic acid (diastereomeric compounds GJ-P1 and GJ-P2)

GJ-P1 ESI 652.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.26 (s, IH), 6.84 - 6.68 (m, 4H), 5.54 - 5.45 (m, IH), 5.41 (t, J= 6.3 Hz, IH), 4.14-3.93 (m, 3H), 3.64 - 3.54 (m, IH), 3.52-3.50 (m, IH), 3.25-3.16(m, 5H),2.74-2.55 (m,4H),2.18(s,6H),2.12(d,J=4.0Hz,3H), 1.88-1.74 (m, 8H), 1.29-1.25 (m, IH),0.830.78 (m, 6H).

GJ-P2 ESI 652.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.20 (s, IH), 6.85 - 6.72 (m, 4H), 5.61 - 5.43 (m, 2H), 4.36-4.08 (m, 3H), 3.84-3.61 (m,2H), 3.32-3.22(m, 5H), 2.82-2.78 (m, IH), 2.64-2.56 (m, IH), 2.51-2.47 (m, IH), 2.39-2.32 (m, IH), 2.23 - 2.13 (m, 6H), 2.10 (d, J = 2.7 Hz, 3H), 1.90 - 1.73 (m, 8H), 1.68-1.51 (m, IH), 1.32 - 1.20 (m, IH), 0.79-0.74 (m, 6H).

4-143. (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methyIpentanamido)-3-(4,4’-dinuoro-2',5,5'-trimethyIbiphenyl-3-yl)propanoic acid (diastereomeric compounds GK-P1 and GK-P2)

651

GK-P1 ESI 662.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 7.03-7.00 (m, 3H), 6.93 (d, J = 10.6 Hz, 1H), 6.81 (s, 1H), 5.70 - 5.63 (m, 1H), 5.59 (t, J= 6.7 Hz, 1H), 4.02 (t, J= 8.2 Hz, 4H), 3.30 (s, 2H), 2.86 (t, J= 6.9 Hz, 2H), 2.71 (d, J= 6.8 Hz, 2H), 2.42 -2.39( m, 2H), 2.30 (d, J= 1.4 Hz, 3H), 2.25 5 (s, 3H), 2.15 (s, 3H), 2.02 -2.19(m, 2H), 1.48 - 1.39 (m, 1H), 0.96-0.90 (m, 6H).

GK-P2 ESI 662.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.09-7.06 (m, 2H), 7.04 (d, J= 8.1 Hz, 1H), 6.99 - 6.88 (m, 2H), 5.75-5.70 (m, 1H), 5.64 (t, J= 7.7 Hz, 1H), 4.15 (t, J= 8.0 Hz, 4H), 3.423.40 (m, 2H), 2.95 (d, J= 16.2 Hz, 1H), 2.82 -2.80(m, 1H), 2.64-2.60 (m, 1H), 2.55 - 2.43 (m, 3H), 2.34 (s, 3H), 2.26 (s, 3H), 2.20 (s, 3H), 2.04 - 1.97 (m, 1H), 1.71-1.68 (m, 1H), 1.43-1.38 (m, 1H), 0.92 (t, J=

6.3 Hz, 6H).

4-144. (3S)-3-(2-(5-(2-(azetidin-l-yI)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yI)-4methyIpentanamido)-3-(4-nuoro-4’-methoxy-2',5,5’-trimethyl-[l,r-biphenyI]-3-yl)propanoic acid (diastereomeric compounds GL-P1 and GL-P2)

GL-P1 ESI 674.3 (M+H)⁺. *H NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.03 (t, J= 13 Hz, 2H), 6.90 (s, 1H), 6.83 (s, 1H), 6.78 (s, 1H), 5.67 (t, J= 8.0 Hz, 1H), 5.59 (t, J= 6.7 Hz, 1H), 3.99 (t, J= 8.2 Hz, 4H), 3.86 (s, 3H), 3.29 (d, J= 3.5 Hz, 2H), 2.85 (t, J = 6.7 Hz, 2H), 2.71 (d, J= 6.7 Hz, 2H), 2.44 - 2.34 (m,

652

2H), 2.29 (d, J= 1.6 Hz, 3H), 2.18 (s, 6H), 2.02 (t, 7= 7.5 Hz, 2H), 1.46 - 1.39 (m, IH), 0.96 (t, 7= 6.2 Hz, 6H).

GL-P2 ESI 674.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.74 (s, IH), 7.14 - 7.03 (m, 2H), 6.93 (s, 2H), 6.80 (s, IH), 5.80-5.71 (m, IH), 5.64 (t,7= 7.6 Hz, IH), 4.14 (t,7= 8.0 Hz, 4H), 3.86 (s, 3H), 3.50-3.36 (m, 2H), 2.95 (d,7= 15.7 Hz, IH), 2.87 - 2.78 (m, IH), 2.67 - 2.60 (m, IH), 2.57 - 2.42 (m, 3H), 2.33 (d, 7= 1.6 Hz, 3H), 2.20 (d, 7= 19.2 Hz, 6H), 2.05 - 1.96 (m, IH), 1.73 - 1.65 (m, IH), 1.47 - 1.37 (m, IH), 0.92 (t, 7= 6.7 Hz, 6H).

4-145. (35)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(27Z)-yl)-4methylpentanamido)-3-(4'-cyano-4,5'-difluoro-2',5-dimethylbiphenyl-3-yl)propanoic acid (diastereomeric compounds GM-P1 and GM-P2)

GM-P1 ESI 673.3 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.86 (s, IH), 7.67 (d, 7= 6.6 Hz, IH), 7.24 7.07 (m, 3H), 6.79 (d, 7= 7.4 Hz, IH), 5.78 - 5.50 (m, 2H), 4.10 (t, 7= 8.1 Hz, 4H), 3.41 - 3.34 (m, 2H), 2.92 - 2.65 (m, 4H), 2.61 - 2.40 (m, 2H), 2.32 (s, 3H), 2.23 (s, 3H), 2.15 - 1.86 (m, 2H), 1.54 - 1.38 (m, IH), 0.97 (t, 7= 6.6 Hz,6H).

GM-P2 ESI 673.3 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.75 - 7.59 (m, 2H), 7.25 - 7.16 (m, 3H), 6.93 (s, IH), 5.80 - 5.55 (m, 2H), 4.16 (t, 7= 7.9 Hz, 4H), 3.50 - 3.37 (m, 2H), 3.04 - 2.77 (m, 2H), 2.72 - 2.43 (m, 4H), 2.36 (s, 3H), 2.28 (s, 3H), 2.06 - 1.96 (m, IH), 1.83 - 1.64 (m, IH), 1.53 - 1.29 (m, IH), 0.97 0.89 (m, 6H).

4-146. (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(277)-yl)-4methylpentanamido)-3-(5'-cyano-4,4’-difluoro-2’,5-dimethyl-[l,l'-biphenyll-3-yl)propanoic acid (diastereomeric compounds GN-P1 and GN-P2)

653

GN-P1 ESI 673.3 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.85 (s, 1H), 7.55 (d, J= 6.7 Hz, 1H), 7.32 (d, J= 10.3 Hz, 1H), 7.10 (d, J= 6.4 Hz, 2H), 6.81 (s, 1H), 5.65-5.55 (m, 2H), 4.03 (t, J= 8.0 Hz, 4H), 3.32 - 3.26 (m, 2H), 2.84 (t, J= 7.0 Hz, 2H), 2.78 - 2.67 (m, 2H), 2.51 - 2.36 (m, 2H), 2.36 - 2.25 (m, 6H), 5 2.14 - 1.92 (m, 2H), 1.52 - 1.36 (m, 1H), 0.97 (t, J= 6.1 Hz, 6H).

GN-P2 ESI 673.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.74 (s, 1H), 7.57 (d, J= 6.7 Hz, 1H), 7.34 (d, J= 10.2 Hz, 1H), 7.14 (d, J= 6.7 Hz, 2H), 6.93 (s, 1H), 5.76-5.71 (m, 1H), 5.63 (t,J=7.7 Hz, 1H), 4.13 (t, J= 7.9 Hz, 4H), 3.49 - 3.35 (m, 2H), 3.00 - 2.87 (m, 1H), 2.88 - 2.75 (m, 1H), 2.68 - 2.60 (m, 1H), 2.57 - 2.42 (m, 3H), 2.39 - 2.28 (m, 6H), 2.05 - 1.95 (m, 1H), 1.79 - 1.63 (m, 1H), 1.48 - 1.37 (m, 1H), 10 0.92 (t, J= 6.6 Hz, 6H).

4-147. (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)4-methyIpentanamido)-3-(4-fluoro-2’,5,6’-trimethylbiphenyl-3-yl)propanoic acid (diastereomeric compounds GO-PI and GO-P2) (S) ^Me \ X)H

GO-PI ESI 650.2 (M+H)+. Ή NMR (500 MHz, MeOD) δ 7.70 (s, 1H), 7.12 (t, J= 7.5 Hz, 1H), 7.08 7.02 (m, 2H), 6.89-6.85 (m, 2H), 5.69 (t, J= 8.0 Hz, 1H), 5.61 - 5.54 (m, 1H), 3.09-3.02 (m, 2H), 2.99 (d, J= Ί3 Hz, 2H), 2.74-2.70 (m, 8H), 2.30 (s, 3H), 2.05 -1.94 (m, 5H), 1.86 (s, 3H), 1.44 (m, 1H), 0.94-0.90 (m, 6H).

654

GO-P2 ESI 650.2 (M+H)+. Ή NMR (500 MHz, MeOD) δ 7.62 (s, IH), 7.18 - 7.07 (m, 3H), 6.94 (t, J= 6.8 Hz, 2H), 5.73-5.70 (m, IH), 5.61 (t, J= 7.6 Hz, IH), 3.31 - 3.18 (m, 2H), 3.11 - 2.95 (m, 2H), 2.84 (s, 6H), 2.65-2.60 (m, IH), 2.52 -2.48(m, IH), 2.35-2.32 (m, 3H), 2.08 - 1.94 (m, 7H), 1.74 - 1.64 (m, IH), 1.42-1.39 (m, IH), 0.90 (d, J= 6.6 Hz, 6H).

4-148. (35)-3-(2-(5-(2-(dimcthyIamino)ethyl)-3-fluoro-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)4-methyIpentanamido)-3-(4-fluoro-2',4’,5,6'-tetramethyIbiphenyl-3-yI)propanoic acid (diastereomeric compounds GP-P1 and GP-P2)

GP-P1 ESI 664.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.69 (s, IH), 6.96 - 6.77 (m, 4H), 5.72 - 5.66 (m, IH), 5.56 (s, IH), 3.09-2.90 (m,4H), 2.71 (d,J=4.8Hz, 8H), 2.29 (s, 6H), 2.08-1.91 (m, 5H), 1.82 (s, 3H), 1.44 (s, IH), 0.95-0.90 (m, 6H).

GP-P2 ESI 664.2 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.62 (d, J= 12.1 Hz, IH), 6.97 - 6.85 (m, 4H), 5.72-5.69 (m, IH), 5.62 (t, J= 7.6 Hz, IH), 3.22 (qd, J = 13.0, 6.1 Hz, 2H), 3.13 - 2.89 (m, 2H), 2.82 (s, 6H), 2.64-2.60 (m, IH), 2.49-2.45(m, IH), 2.36 - 2.23 (m, 6H), 2.04 - 1.90 (m, 7H), 1.74 - 1.64 (m, IH), 1.41-1.38 (m, IH), 0.90-0.86 (m, 6H).

4-149. (35)-3-(4,4’-difluoro-2’,5,6*-trimethylbiphenyI-3-yi)-3-(2-(5-(2-(3-methoxyazetidin-lyl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2ZO-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds GQ-P1 and GQ-P2)

655

GQ-P1 ESI 692.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 6.96 - 6.68 (m, 5H), 5.75 - 5.48 (m, 2H), 4.26 - 4.01 (m, 3H), 3.74 - 3.52 (m, 2H), 3.31 (s, 3H), 3.14 (t, J= 6.8 Hz, 2H), 2.87 - 2.63 (m, 4H), 2.30 (s, 3H), 2.05-1.92 (m, 5H), 1.85 (s, 3H), 1.54-1.36 (m, 1H), 1.07-0.87 (m, 6H).

GQ-P2 ESI 692.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.74 (s, 1H), 7.04 - 6.78 (m, 5H), 5.80 - 5.70 (m, 1H), 5.62 (t, J = 7.7 Hz, 1H), 4.49 - 4.21 (m, 3H), 4.01 - 3.74 (m, 2H), 3.46 - 3.35 (m, 5H), 3.03 2.77 (m, 2H), 2.68-2.44 (m, 2H), 2.34 (d, J= 1.7 Hz, 3H), 2.12 - 1.90 (m, 7H), 1.74 - 1.57 (m, 1H), 1.53 - 1.32 (m, 1H), 0.99 - 0.83 (m, 6H).

4-150. (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)yI)pentanamido)-3-(4-fluoro-2’,4’,5,6’-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid (diastereomeric compounds GR-P1 and GR-P2)

O

GR-P1 ESI 632.2(M+H)\ Ή NMR (500 MHz, MeOD) δ 7.88 (s, 1H), 6.92 - 6.79 (m, 4H), 6.74 (s, 1H), 15 5.66 - 5.45 (m, 2H), 3.11 - 2.85 (m, 5H), 2.78 - 2.68 (m, 7H), 2.32 - 2.22 (m, 6H), 2.18 - 2.08 (m, 1H),

2.06 - 1.92 (m, 4H), 1.78 (s, 3H), 1.41-1.24 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H).

GR-P2 ESI 632.2 (M+H)\ Ή NMR (500 MHz, MeOD) δ 7.82 (s, 1H), 6.90 (d, J = 7.1 Hz, 5H), 5.79 5.64 (m, 1H), 5.52 (t, J = 7.6 Hz, 1H), 3.30 - 3.15 (m, 2H), 3.00 (t, J = 6.6 Hz, 2H), 2.83 (s, 6H), 2.69 656

2.59 (m, IH), 2.58 - 2.44 (m, IH), 2.31 (d, J = 9.7 Hz, 6H), 2.13 - 2.01 (m, IH), 1.97 (s, 6H), 1.91-1.73 (m, IH), 1.39 - 1.02 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H).

4-151. (35)-3-(2-(5-(2-(dimethy!amino)ethyl)-4-methyI-2-oxopyridin-l(2Z0-yI)-5methylhexanamido)-3-(4-nuoro-2',4',5,6’-tetramethylbiphenyI-3-yI)propanoic acid (diastereomeric compounds GS-P1 and GS-P2)

GS-P1 ESI 606.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.57 (s, IH), 6.90 (s, 2H), 6.85 - 6.80 (m, 2H), 6.34 (s, IH), 5.48 (t, J= 6.0 Hz, IH), 5.42 - 5.37 (s, IH), 3.24 - 3.02 (m, 2H), 2.89-2.85 (m, 2H), 2.76 (s, 6H), 2.71 - 2.60 (m, 2H), 2.30 (d, J= 4.9 Hz, 6H), 2.25 (s, 3H), 2.22 - 2.14 (m, IH), 1.95 (s, 4H), 1.87 (s, 3H), 1.60 - 1.53 (m, IH), 1.25 - 1.14 (m, IH), 1.12 - 1.00 (m, IH), 0.89 - 0.87 (m, 6H).

GS-P2 ESI 606.3 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.54 (s, IH), 6.98 - 6.78 (m, 4H), 6.44 (s, IH), 5.66 - 5.63 (m, IH), 5.42 (t, J= 7.7 Hz, IH), 3.31 - 3.28 (m, IH), 3.26 - 3.14 (m, IH), 2.99 - 2.88 (m, 2H), 2.84 (s, 6H), 2.64-2.59 (m, IH), 2.50-2.43 (m, IH), 2.39 - 2.28 (m, 6H), 2.27 (s, 3H), 2.16 - 2.07 (m, IH), 1.96 (s, 6H), 1.89-1.74 (m, IH), 1.57- 1.50 (m, IH), 1.15-1.11 (m, IH), 1.08-0.97 (m, IH), 0.85 (t, J = 6.5 Hz, 6H).

4-152. (35)-3-(4,4’-difluoro-2’,5,6’-trimethylbiphenyl-3-yl)-3-(2-(5-(2-(dimethyIamino)ethyl)-4methyl-2-oxopyridin-l(2jH)-yl)*5-methylhexanamido)propanoic acid (diastereomeric compounds GT-P1 and GT-P2)

657

GT-P1 ESI 610.3 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.58 (s, IH), 6.84 (t, J= 9.1 Hz, 4H), 6.32 (s, IH), 5.50 (t, J= 6.2 Hz, IH), 5.44 - 5.33 (m, IH), 3.24 - 3.06 (m, 2H), 2.90 - 2.84 (m, 2H), 2.78 (s, 6H), 2.73 - 2.62 (m, 2H), 2.28 (d, 14.1 Hz, 6H), 2.22-2.11 (m, IH), 2.00- 1.96 (m, 4H), 1.89 (s, 3H), 1.60

- 1.54 (m, IH), 1.29-1.15 (m, IH), 1.10-1.03 (m, IH), 0.89-0.87 (m, 6H).

GT-P2 ESI 610.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.54 (s, IH), 6.90 (d, J= 6.9 Hz, 2H), 6.84 (d, J = 9.6 Hz, 2H), 6.44 (s, IH), 5.66 - 5.62(m, IH), 5.43 (t, J= Ί.6 Hz, IH), 3.38 - 3.35 (m, IH), 3.24 - 3.20 (m, IH), 3.00 - 2.89 (m, 2H), 2.85 (s, 6H), 2.64 - 2.59 (m, IH), 2.50 - 2.44 (m, IH), 2.33 (d, J= 4 Hz, 3H), 2.28 (s, 3H), 2.17-2.07 (m, IH), 2.01 (s, 6H), 1.87 - 1.77 (m, IH), 1.57- 1.51 (m, IH), 1.20- 1.09 10 (m, IH), 1.08 - 0.97 (m, IH), 0.85 (t, J= 6.4 Hz, 6H).

4-153. (35)-3-(4,4’-difluoro-2’,5,6’-trimethyI-[l,r-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3methoxyazetidin-l-yI)ethyl)-4-methyl-2-oxopyridin-l(277)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds GU-PI and GU-P2)

GU-PI ESI 656.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.40 (s, IH), 6.95 - 6.72 (m, 4H), 5.71 - 5.47 (m, 2H), 4.27 - 4.16 (m, 2H), 4.16 - 4.07 (m, IH), 3.81 - 3.69 (m, IH), 3.70 - 3.58 (m, IH), 3.30 (s, 3H), 3.25 (t, J= 6.8 Hz, 2H), 2.88 - 2.63 (m, 4H), 2.37 - 2.16 (m, 6H), 2.06 - 1.82 (m, 8H), 1.49 - 1.28 (m, IH), 0.97-0.90 (m,6H).

658

GU-P2 ESI 656.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.33 (s, IH), 6.96 - 6.89 (m, 2H), 6.84 (d, 7= 9.7 Hz, 2H), 5.72 - 5.58 (m, 2H), 4.39 - 4.14 (m, 3H), 3.85 - 3.65 (m, 2H), 3.31 - 3.20 (m, 5H), 2.93 2.78 (m, IH), 2.77-2.55 (m, 2H), 2.54-2.45 (m, IH), 2.33 (d, J= 1.7 Hz, 3H), 2.22 (d,7=2.7 Hz, 3H), 2.06 - 1.86 (m, 7H), 1.81 - 1.66 (m, IH), 1.344 - 1.32 (m, 1 H), 0.90 (d, J = 6.6 Hz, 6H).

4-154. (35)-3-(5-chIoro-4-fluoro-2’,4*,6’-trimethyIbiphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)3-fluoro-2-oxo-4-(triniioromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds GV-P1 and GV-P2)

GV-P1 ESI 684.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.65 (s, IH), 7.13 (d,7= 6.3 Hz, IH), 7.08 (d, 7= 6.1 Hz, IH), 6.93 (s, 2H), 5.66 (d, J= 5.4 Hz, 2H), 3.13 - 2.89 (m, 4H), 2.70 (s, 6H), 2.67 - 2.62 (m, IH), 2.62 - 2.53 (m, IH), 2.30 (s, 3H), 1.98 (d, J= 6.9 Hz, 7H), 1.74 -1.70(m, IH), 1.40 - 1.33 (m, IH), 0.89 (d, 7= 5.6 Hz, 6H).

GV-P2 ESI 684.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.67 (s, IH), 7.10 (d, 7= 6.9 Hz, IH), 7.02 (d, 7= 6.1 Hz, IH), 6.91 (d,7= 13.0 Hz, 2H), 5.68 (t, J = 8.1 Hz, IH), 5.55 (t, 7= 7.0 Hz, IH), 3.08 (s, 2H), 2.98 (d,7= 7.7 Hz, 2H), 2.73 (d,7= 9.7 Hz, 8H), 2.30 (s, 3H), 2.04-1.93 (m, 5H), 1.83 (s, 3H), 1.44-1.40 (m, IH), 0.96 -0.92(m, 6H).

4-155. (3S)-3-(2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4*-cyano-4-fluoro-2’,5,5’-trimethyl-[l,l’-biphenyI]-3-yI)propanoic acid (diastereomeric compounds GW-P1 and GW-P2)

659

GW-P1 ESI 669.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.72 (s, 1H), 7.45 (s, 1H), 7.10 (s, 1H), 7.06 6.92 (m, 2H), 6.65 (s, 1H), 5.57 - 5.40 (m, 2H), 3.92 (t, J= 8.1 Hz, 4H), 2.73-2.70 (m, 2H), 2.60 (d, J= 7.6 Hz, 2H), 2.40 (s, 3H), 23.0-2.33(m, 2H), 2.36-2.30 (m, 2H), 2.19 (s, 3H), 2.09 (s, 3H), 1.94-1.88 (m, 2H), 5 1.35 - 1.21 (m, 1H), 0.86-0.83 (m, 6H).

GW-P2 ESI 669.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.61 (s, 1H), 7.47 (s, 1H), 7.13 (s, 1H), 7.10 6.98 (m, 2H), 6.80 (s, 1H), 5.65-5.62 (m, 1H), 5.52 (t, J= 7.7 Hz, 1H), 4.04 (t, J= 8.1 Hz, 4H), 3.40 - 3.25 (m, 2H), 2.86 - 2.64 (m, 2H), 2.54-2.49 (m, 1H), 2.45 - 2.30 (m, 6H), 2.23 (d, J = 1.5 Hz, 3H), 2.14 (s, 3H), 1.95 - 1.81 (m, 1H), 1.63 - 1.52 (m, 1H), 1.31-1.26 (m, 1H), 0.84-0.78 (m, 6H).

4-156. (35)-3-(4-nuoro-4’-methoxy-2’,5,6’-trimethyl-[l,l*-biphenyl]-3-yl)-3-(2-(5-(2-(3methoxyazetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2Z/)-yi)-4methylpentanamido)propanoic acid (diastereomeric compounds GX-P1 and GX-P2)

GX-P1 ESI 704.4 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.85 (s, 1H), 6.86 (t, J= 6.2 Hz, 2H), 6.77 (s, 1H), 6.65 (s, 1H), 6.62 (s, 1H), 5.67 (t, J= 8.0 Hz, 1H), 5.61 - 5.56 (m, 1H), 4.25-4.09 (m, 3H), 3.79 (s, 3H), 3.71 - 3.61 (m, 2H), 3.31 (s, 3H), 3.17 (t, J= 6.8 Hz, 2H), 2.81 (t, J= 6.9 Hz, 2H), 2.76 - 2.69 (m, 2H), 2.28 (s, 3H), 2.04 - 1.97 (m, 5H), 1.82 (s, 3H), 1.48-1.41 (m, 1H), 0.98 - 0.93 (m, 6H).

660

GX-P2 ESI 704.4 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.75 (s, 1H), 6.96 - 6.90 (m, 3H), 6.67 (s, 2H), 5.76 - 5.72(m, 1H), 5.63 (t, J= 7.7 Hz, 1H), 4.44 - 4.26 (m, 3H), 3.98 - 3.92 (m, 1H), 3.88 - 3.83 (m, 1H), 3.80 (s, 3H), 3.42 - 3.35 (m, 5H), 2.97 - 2.80 (m, 2H), 2.67 - 2.62 (m, 1H), 2.56 - 2.50 (m, 1H), 2.33 (d, J = 1.6 Hz, 3H), 2.04 - 1.94 (m, 7H), 1.73 - 1.64 (m, 1 H), 1.47 - 1.39 (m, 1 H), 0.92 - 0.89 (m, 6H).

4.157. (3S)-3-(4’-cyano-4-fluoro-2’,5,6’-trimethyI-[l,l’-biphenyI]-3-yl)-3-(2-(5-(2(dimethyIamino)ethyl)-2-oxo-4-(trifluoromethyI)pyridin-l(2//)-yl)-4-methylpentanamido)propanoÎc acid (diastereomeric compounds GY-P1 and GY-P2)

NJS)

GY-P1 ESI 657.4 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.88 (s, 1H), 7.45 (d, J= 21.6 Hz, 2H), 6.88 (d, J= 5.6 Hz, 2H), 6.71 (s, 1H), 5.72 - 5.47 (m, 2H), 3.08 - 2.85 (m, 4H), 2.79 - 2.57 (m, 8H), 2.30 (d, J= 1.4 Hz, 3H), 2.11 - 1.93 (m, 5H), 1.88 (s, 3H), 1.50 - 1.37 (m, 1H), 1.06 - 0.86 (m, 6H).

GY-P2 ESI 657.4 (M+H)*. Ή NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 7.49 (s, 2H), 7.02 - 6.74 (m, 3H), 5.75 - 5.53 (m, 2H), 3.25 - 3.06 (m, 2H), 2.98 (t, J= 6.9 Hz, 2H), 2.78 (s, 6H), 2.70 - 2.48 (m, 2H), 2.34 (d,J=1.4 Hz, 3H), 2.14-1.86 (m, 7H), 1.79-1.62 (m, 1H), 1.46-1.31 (m, 1H), 0.95-0.82 (m, 6H).

4-158. (3S)-3-(4^,-chloro-4-fIuoro-2',5,6’-trimethyIbiphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)ethyI)2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds GZ-P1 and GZ-P2) ⁰ ο r oh

GZ-Pl ESI 666.3 (M+H)\ 'H NMR (400 MHz, MeOD) δ 7.91 (s, IH), 7.08 (d, J = 24.1 Hz, 2H), 6.91 6.80 (m, 2H), 6.72 (s, 1H), 5.68 (t, J= 8.0 Hz, 1H), 5.59 - 5.48 (m, 1H), 3.18 - 3.02 (m, 2H), 2.95 (t, J=

661

7.0 Hz, 2H), 2.82 - 2.63 (m, 8H), 2.29 (s, 3H), 2.04 - 1.91 (m, 5H), 1.79 (s, 3H), 1.58 - 1.30 (m, IH), 1.04 - 0.86 (m, 6H).

GZ-P2 ESI 666.3 (M+H)⁺. 'H NMR (400 MHz, MeOD) δ 7.88 (s, IH), 7.13 (s, 2H), 6.94 - 6.83 (m, 3H), 5.81 - 5.68 (m, IH), 5.62 (t, 7= 7.7 Hz, IH), 3.30 - 3.16 (m, 2H), 3.01 (t, 7= 6.8 Hz, 2H), 2.83 (s, 6H), 2.72 - 2.45 (m, 2H), 2.33 (d, 7= 1.1 Hz, 3H), 1.98 (d, 7H), 1.75 - 1.63 (m, IH), 1.51 - 1.33 (m, IH), 0.87 (d,7=6.6 Hz, 6H).

4-159. ((3S)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)-3-(2-(5-(2-((Æ)-3-fluoropyrrolidin-lyl)ethyl)-4-methyl-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds HA-P1 and HA-P2)

HA-P1 ESI 622.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.54 (s, IH), 7.16 - 7.02 (m, 3H), 6.87 - 6.78 (m, 2H), 6.27 (s, IH), 5.73 - 5.50 (m, 2H), 5.34 - 5.15 (m, IH), 3.31 - 3.23 (m, IH), 3.22 - 3.00 (m, 2H), 2.94 - 2.80 (m, 3H), 2.78 - 2.59 (m, 4H), 2.36 - 2.09 (m, 8H), 2.01-1.91 (m, 5H), 1.83 (s, 3H), 1.50 1.37 (m, IH), 0.97 -0.89 (m, 6H).

HA-P2 ESI 622.2 (M+H)⁺. Ή NMR (500 MHz, MeOD) δ 7.56 (s, IH), 7.22 - 7.02 (m, 3H), 6.91 (d, 7= 6.8 Hz, 2H), 6.42 (s, IH), 5.65 - 5.57 (m, 2H), 5.41 - 5.24 (m, IH), 3.62 - 3.35 (m, 3H), 3.31 - 3.09 (m, 3H), 2.94 - 2.74 (m, 2H), 2.68 - 2.49 (m, 2H), 2.39 - 2.22 (m, 8H), 2.10-1.89 (m, 7H), 1.82 - 1.70 (m, IH), 1.49 - 1.31 (m, IH), 0.95 - 0.85 (m, 6H).

4-160. (3S)-3-(4-fluoro-2',4',5,6’-tetramethyl-[l,r-biphenyl]-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-lyl)ethyl)-2-oxopyridin-l(2//)-yl)-4-methyIpentanamido)propanoic acid (diastereomeric compounds HB-P1 and HB-P2)

662

Ο

ΙΙΒ-Ρ1 ESI 608.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.52 (s, IH), 7.39 (d, J= 9.0 Hz, IH), 6.96 6.79 (m, 3H), 6.73 (s, IH), 6.43 (d, J= 9.5 Hz, IH), 5.74 -5.46 (m, 2H), 5.14 (d, J= 57.6 Hz, IH), 3.77 (s, 2H), 3.50 (s, 2H), 2.88 (s, 2H), 2.79 - 2.60 (m, 2H), 2.51 (s, 2H), 2.29 (d, J= 14.1 Hz, 6H), 1.96 (d, J = 12.7 Hz, 5H), 1.80 (s, 3H), 1.42 (s, IH), 1.03 - 0.79 (m, 6H).

HB-P2 ESI 608.3 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.60 - 7.40 (m, 2H), 6.90 (d, J= 7.8 Hz, 4H), 6.57 (d, J= 9.2 Hz, IH), 5.70 - 5.57 (m, 2H), 5.32 (d, J= 57.4 Hz, IH), 4.51 - 4.26 (m, 2H), 4.14 - 3.87 (m, 2H), 3.39 (d, J= 5.3 Hz, 2H), 2.85 - 2.44 (m, 4H), 2.35 - 2.17 (m, 6H), 2.04 - 1.86 (m, 7H), 1.86 1.73 (m, IH), 1.48 -1.33 (m, IH), 0.90 (t, J= 6.3 Hz, 6H).

4-161. (3S)-3-(4,4’-difluoro-2*,5,6*-trimethyl-[l,l’-biphenyl]-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-lyl)ethyI)-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid (diastereomeric compounds HC-P1 and HC-P2)

HC-P1 ESI 612.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.54 (s, IH), 7.43 (dd, J = 9.2, 2.3 Hz, IH), 6.87-6.82 (m, 3H), 6.76 (d, J= 6.7 Hz, IH), 6.46 (d, J= 9.3 Hz, IH), 5.63 (d, J= 7.9 Hz, IH), 5.54 - 5.43 (m, IH), 5.20 (d, J= 57.2 Hz, IH), 4.09-3.88 (m, 2H), 3.71-3.55 (m, 2H), 3.10-3.02 (m, 2H), 2.80 - 2.53 (m, 4H), 2.29 (s, 3H), 2.03 - 1.92 (m, 5H), 1.87 (s, 3H), 1.50 - 1.36 (m, IH), 0.97-0.92 (m, 6H).

HC-P2 ESI 612.2 (M+H)⁺. Ή NMR (400 MHz, MeOD) δ 7.41 (s, IH), 7.38-7.35 (m, IH), 6.79 (t, J= 6.1 Hz, 2H), 6.73 (d, J= 9.7 Hz, 2H), 6.45 (d, J= 9.3 Hz, IH), 5.53-5.48 (m, 2H), 5.20 (d, J= 57.2 Hz, IH),

663

4.39 - 4.14 (m, 2H), 3.99-3.87 (m, 2H), 3.32 - 3.25 (m, 2H), 2.67 - 2.48 (m, 3H), 2.40-2.34 (m, IH), 2.21 (d,7= 1.7 Hz, 3H), 1.90-1.81 (m,7H), 1.72-1.64(m, IH), 1.33-1.22(m, IH),0.79(t,7=6.6Hz,6H).

Introduction to the In Vitro Assays Described in Examples 5-7

Three in vitro assays were used to examine the cup? mechanistic process used by cells: 1) ligand:receptor affinity, 2) the avidity of those interactions on a cell’s surface, and 3) how those interactions fare under an imposing force. In Example 5, a Fluorescence Polarization (FP) assay is used to measure compound activity through binding compétition with the fluorescein-labeled peptide. In Example 6, the potency of compounds against cuP? is measured in the cell-based ligand binding assay (LBA), using RPMI8866 cells incubated with the compound samples in compétition with soluble MAdCAM-1 ligand. In Example 7, activity of compounds is evaluated in a cell adhesion assay that mechanistically tests what occurs in vivo when traflîcking cells utilize ouP? to adhéré to MAdCAM-1 expressing HEVs of the gut during the extravasation process. In the cell adhesion assay of Example 7, a MAdCAMl-(Fc) is coated on plastic, and a4p7 expressing cells (RPMI-8866) are allowed to adhéré to the coated surface in the presence of the test compounds. Next, the force of washing with buffer is applied to cells thereby testing the strength of that adhesion. Unattached cells are removed and the remaining adhèrent cells are quantified.

Example 5: Fluorescence polarization assays of compounds for oup? binding

Fluorescence Polarization (FP) assays were used to measure compound activity through binding compétition with the fluorescein-labeled peptide CRSDTLCGE{Lys(FITC)}. In the assay, 6.5 nM of integrin cuP? was incubated with the test compound in 2 mM manganèse chloride, 0.1 mM calcium chloride, 20 mM HEPES buffer at pH 7.3,150 mM sodium chloride, 0.01% Triton X-100, 2% DMSO, and 3 nM of the fluorescein-labeled peptide. Running the assays in 384-well plates, the integrin protein was pre-incubated with the test compounds for 15 minutes at 22°C before the fluorescein-labeled peptide was added. After the fluorescein-labeled peptide was added, the assay was incubated at 22°C for 1 hour and fluorescence polarization was measured. IC50 values were determined by non-linear régression, four-parameter curve fitting.

An ouP? inhibition potency measurement for compounds including certain compounds in Figure 1, Figure 3 and Figure 4 was made using the FP assay of Example 5. In Figure 1, the IC50 value obtained using the FP assay of Example 5 is provided as a numerical range (A: <5.55 nM;

664

B: 5.55-500 nM; C: >500 nM in Figure 1). In Figure 3 and Figure 4, the ICso value obtained using the FP assay of Example 5 is provided as a numerical range (A: <5 nM; B: 5-500 nM; C: >500 nM in Figure 3 and Figure 4).

An cuP? inhibition potency measurement was also performed using the FP assay of Example 5 for compounds in Table 3A, Table 3B and (comparative) Table 4 below, with results provided as a numerical range of the resulting ICso value (A: <10 nM; B: >10-500 nM; C: >500 nM in Table 3A, Table 3B and Table 4).

Examplc 6: Ligand binding assays

To measure the potency of compounds against αφγ in the cell-based ligand binding assay (LBA), RPMI 8866 cells were incubated with the compound samples in a volume of 10 pl at room température for 15 minutes in buffer containing 50 mM HEPES pH 7.3, 150 mM sodium chloride, 1% bovine sérum albumin, 3 mM manganèse chloride, 0.15 mM calcium chloride, 15 mM glucose, 1.5% dimethyl sulfoxide, and 0.025% e780 fixable viability dye. 5 ul of 33 nM MAdCAM-l-Fc fluorescently labeled with Dylight 650 in 50 mM HEPES pH 7.3, 150 mM sodium chloride, and 1% bovine sérum albumin was added to the cells. The samples were incubated for 45 minutes at room température, fixed with 0.8% formaldéhyde for 30 minutes at room température, and washed with 50 mM Tris pH 7.5, 150 mM NaCl, 1 mM EDTA, and 1% bovine sérum albumin. Fluorescence intensity for each cell was measured via flow cytometry. Dead cells were excluded from further analysis based on staining with the 780 fixable viability dye. Médian fluorescence intensity for Dylight 650 was determined for each sample and concentration-response curves were analyzed for IC50 values using 4-parameter non-linear régression analysis.

An Ο4β? ligand binding assay measurement was performed with the ligand binding assay of Example 6 for compounds listed in Figure 1, Figure 3 and Figure 4. In Figure 1, Figure 3 and Figure 4, the ICso value obtained using the LB assay of Example 6 is provided by numerical range (A: <5 nM; B: 5-500 nM; C: >500 nM in Figure 1, Figure 3 and Figure 4).

An O4p7 ligand binding assay measurement was also performed using the ligand binding assay of Example 6 for compounds in Table 3 A, Table 3B and (comparative) Table 4 below, with the resulting IC50 value provided as a numerical range (A: < ΙΟηΜ; B: >10-500 nM; C: >500 nM in Table 3A, Table 3B and Table 4).

665

Example 7: Ccll Adhesion Assay

Example 7 describes a cell adhesion assay. The cuP? cell adhesion measurement from the assay of Example 7 was obtained from compounds in the Table 3A and Table 3B below, as well as for the comparative compounds in Table 4, with results presented as a numerical range of the resulting ICso value (A: < 5 nM; B: 5 to <10 nM; C10-50 nM; D: >50 nM; E:>100nM and F>500nM for Table 3A, Table 3Β and Table 4).

To each well of a 96 well plate, 100 ug of recombinant human MAdCAM in lOOul PBS is added and incubated ovemight at 4°C. After incubation MAdCAM is removed by aspiration and 200 ul of PBS+ 1%BSA is added to block the plate for 2 hours at 37°C and 5% CO2. During this incubation dilution curves of compound are made in 100% DMSO in 96 well V bottom plates. 1.75ul of diluted compounds are then transferred to a new 96 well U bottom plate containing 20 ul of assay media (phosphate free DMEM + 25 mM HEPES + 1%BSA). To this an additional 155 ul of assay media is added with mixing by pipetting up and down. This mixture is allowed to incubate for 15 minutes at 37°C and 5% CO2. After incubation 175ul of assay media containing 2e6/mL RPMI8866 cells is added to compound containing wells without mixing and plate is allowed to incubate for another 15 minutes at 37°C and 5% CO2. During this incubation MAdCAM coated plates are removed from incubator and washed twice with 200 ul PBS+0.1%BSA. After cells hâve incubated with compound for 15 minutes they are mixed by pipetting up and down and 100 ul of mixture is transferred to the washed MAdCAM coated plates in triplicate. This plate is then incubated at 37°C and 5% CO2 for 1 hour. After incubation plates are washed twice with 200 ul and once with 50 ul of phénol free RPMI + 1%BSA. A final 50ul of phénol free RPMI +1%BSA is added to wells after last wash. Next 50 ul of Promega cell titer glow is added to the wells. Plate is incubated on shaker for 2 minutes at 200 RPM followed by another 8 minutes off shaker before having the luminescence read on a Biotek Citation 5 plate reader. Raw data is converted to % inhibition compared to bottom of curve and analyzed using a 4-parameter non linear curve in Prism to détermine ICso and IC90.

666

Table 3A. Selected Exemplary Compounds.

Compound	Example	FP Assay (Example 5)	LB Assay (Example 6)	CA Assay (Example 7)
	ÇXç^, ____ ji T	3-1 (D-P2)	A	A	A
ιΎΊΓ	3-4 (G-P2)	A	A	A
jCjC 'iXX ΓΥ ^>·*^^^^^	3-27 (AF-P2)	A	A	A
tV~J X-		3-28 (AG-P2)	A	A	A
'^^M'*^******^ I	ΎC~jC ^o ^>4--°	3-32 (AK-P2)	A	A	A
iOC^^ llfT Ύ)Ϊ \λ	3-18 (W-P2)	A	A	A

667

Compound	Example	FP Assay (Example 5)	LB Assay (Example 6)	CA Assay (Example 7)
Γ^Χΐ/ '	3-24 (AC-P2)	A	A	A
CM	3-6 (I-P2)	A	A	A
F νΑ·γ5ό	3-7 (J-P2)	A	A	A
**oc jj ^{1 r} ^XX	3-43 (AV-P2)	A	A	A
2ÿv^	3-42 (AU-P2)	A	A	A

668

669

670

Compound	Example	FP Assay (Example 5)	LB Assay (Example 6)	CA Assay (Example 7)
nX f	3-65 (HU-P2)	A	B	B
'^xC' ^f F	3-64 (HT-P2)	A	B	A

Table 4. Comparative Compounds

No.	Comparator Compound	FP Assay (Example 5)	LB Assay (Example 6)	CA Assay (Example 7)
C-l	y^A_tÂA„ /X	A	A	D

671

No.	Comparator Compound	FP Assay (Example 5)	LB Assay (Example 6)	CA Assay (Example 7)
C-2	rr lY) o o f T '^/ZXZ I	A	A	B
C-3	HO y-O j A~Y°Aj ^N·^-* ’^^X. /	A	A	C
C-4	w _o f T ---''H'^' I	A	B	E
C-5	Yo T ï ;	A	A	C
C-6	0 o F	A	A	C

672

No.	Comparator Compound	FP Assay (Example 5)	LB Assay (Example 6)	CA Assay (Example 7)
C-7	Λ S O	A	A	C
C-8	γγΜ-Α. JJ F	A		D
C-9	^^Γ^^Ϊ^^ΧΤ^?:ί?^^Χ'\|^Ν O O F	A	B	D
C-10	O o YY\AAk_w /^N\ c* F		B	E

673

No.	Comparator Compound	FP Assay (Example 5)	LB Assay (Example 6)	CA Assay (Example 7)
C-ll		' H >° ”ν.θ_Ηθ_Ι ?	A	B	F
C-12	f'T	A	B	F
C-13	Π /=\ /—-Π -CR^-q /=o O X	A	B	F
C-14	.jÇl c ⁰ k	X o °=/	A	B	F

674

No.	Comparator Compound	FP Assay (Example 5)	LB Assay (Example 6)	CA Assay (Example 7)
C-15	τι τι V-τι °=CK_ ^ZZ—^J '—Z ___/ \ —\ ^xzz 2=0 O z	B	B	F
C-16	Rn —ç 2=o X=< ^xiz 2=o o z	B		F
C-17	/'·< O e y —Ç 2=0 /⁼\ ^zz ' 2=o o Z	B		F
C-18	°=\ /^zZ—^J r—i, /·''( m—ç y —/ 2=o 2=( \zz —/ /O 2=° o Z	B		F
C-19	° \ # Z—J /T~\ —1 2=o \=/ ^IZ ' 2=° o Z	B		F

675

No.	Comparator Compound	FP Assay (Example 5)	LB Assay (Example 6)	CA Assay (Example 7)
C-20	x O o=Z z /)— \ ZXk 2=Z o=7 2— \ )=°	B		F
C-21	X O ^O=K ^O—' ZXv /=< o=Ç 2— \ /^°	B		F
C-22	X O o=/ z=\ 2 \ / ^2X 2=( O=«f Z=\ \\ // / \\ Λ \—fj \1—fj —\ 7^e0	A	B	F
C-23	çife„ ο	B		F
C-24	° x /7 z—J β— —1 2=0 2=/ 'IZ r—/ /--\ Z--^ΞΖ 2=0 o X	A		F

676

No.	Comparator Compound	FP Assay (Example 5)	LB Assay (Example 6)	CA Assay (Example 7)
C-25	x O o=^ \ /—²¹>=< O=( O— Çj~ >·' '—^J fi² \ /^°	B	B	F
C-26	ο	B
C-27	° \ # Z— Z—Λ / \ \ / -/ 2=0 \=Z \ ^²/=o O x	C
C-28	° \ /7 Z— f=\ /¹ ‘ \ \\ /) —Ç )e=O \ >° O x	B	B
C-29	° \ # Z— /=\ /!'··( ---K Λ —1 \=o /“^\ \χζ ' \ )=° O x	A		E

677

No.	Comparator Compound	FP Assay (Example 5)	LB Assay (Example 6)	CA Assay (Example 7)
C-30	θ	C

INCORPORATION BY REFERENCE

Ail of the U.S. patents and U.S. and PCT patent application publications cited herein are hereby incorporated by reference.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain using no more than routine expérimentation, many équivalents to the spécifie embodiments of the invention described herein. Such équivalents are intended to be encompassed by the following daims.

Claims

l. A compound of Formula (I):

5 wherein

Ra, Rb, and Rc are independentiy selected from the group consisting of H, Me, halide, CF₃, C(H)F₂, C(F)H₂, and -(C|.C5)alkylene-N-(R_x)(R_y); provided that at least one of Ra, R_b, and Rc is -(Ci.C5)aIkylene-N-(R_x)(R_y);

R_x and R_y are independentiy selected from the group consisting of H and substituted or 10 unsubstituted (Ci-Cô)-alkyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered ring;

Ri is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl;

R₃a and R₃b are independentiy selected from the group consisting of H, (Ci-C5)-alkyl, 15 (C₃-Cô)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, -OH, -CN, halide, CF₃, C(H)F₂, C(F)H₂.-(Ci-C0-alkoxy, -OCF₃, and substituted or unsubstituted (C1-C4)alkylene-(Ci-C4)-aîkoxy; provided that R_3a and R_3b are not both H;

R_3c, and R₃d are H;

679

R4 is H;

Rsa, and Rs_e are independently methyl;

Rsb, and R$_c are independently selected from the group consisting of H, CN, halide, CF3, C(H)F₂, C(F)H₂, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (Cî-Cô)5 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (C1-C4)alkoxy;

Rsa is H; and wherein the compound of Formula (I) is selected from the group consisting of:

a. (S)-3-(4,5-difluoro-2',6'-dimethyl-[ 1 ,r-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1 10 yl)ethyl)-4-methyl-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid;

b. (S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[ 1,1 ’-biphenyl]-3yl)propanoic acid;

c. (S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-415 methylpentanamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoic acid;

d. (S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-3'-methoxy-2',5,6’-trimethyl-[ 1,1 ’-biphenyl]-3-yl)propanoic acid;

e. (S)-3-(4,4’-difluoro-2’,5,6'-trimethyl-[l,r-biphenyl]-3-yl)-3-((S)-2-(5-(2-

20 (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)propanoic acid;

f. (S)-3-(5-chloro-4-fluoro-2’,6'-dimethyl-[ 1,1 ’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3methoxyazetidin-1 -yl)ethyl)-2-oxo-4-(tri fluoromethyl)pyridin-1 (2H)-yl)-4methylpentanamido)propanoic acid;

25 g. (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[ 1,1 '-biphenyl]-3-yl)propanoic acid;

680

h. (S)-3-(4,4'-difluoro-2’,5,6'-trimethyl-[ 1,1 ’-biphenyl]-3-yl)-3-((S)-2-(3-(difluoromethyl)-5-(2(dimethylamino)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid;

i. (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1 (2H)-yl)-5methylhexanamido)-3-(4-fluoro-2',5,6'-trimethyl-[ 1,1 '-biphenyl]-3-yl)propanoic acid;

j. (S)-3-(4-fluoro-2',5,6'-trimethyl-[ 1,1 ’-biphenyI]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid; and

k. (S)-3-(4-fluoro-2',5,6'-trimethyl-[ 1,1 ’-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-((R)-3fluoropyrrolidin-1 -yl)ethyl)-2-oxopyridin-1 (2H)-yl)-4-methylpentanamido)propanoic acid;

or a pharmaceutically acceptable sait thereof.
2. The compound of claim 1, wherein the compound is (S)-3-(4,5-difluoro-2',6'-dimethyl-[l,rbiphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-l-yl)ethyl)-4-methyl-2-oxopyridin-l(2H)yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.
3. The compound ofclaim 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azetidin-1 -yl)ethyl)2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',6’dimethyl-5-(trifluoromethyl)-[l,r-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.
4. The compound of claim 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)~4-methylpentanamido)-3-(3',4-difIuoro-2',5,6'trimethyl-[l,r-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.
5. The compound of claim 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azetidin-l-yl)ethyl)2-oxo-4-(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-3’-methoxy2',5,6'-trimethyl-[l,r-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.
6. The compound of claim 1, wherein the compound is (S)-3-(4,4’-difluoro-2',5,6'-trimethyl[1,1 ’-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifIuoromethyl)pyridinl(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.

681
7. The compound of claim 1, wherein the compound is (S)-3-(5-chloro-4-fluoro-2',6'-dimethyl[1,1 '-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1 -yl)ethyl)-2-oxo-4(trifluoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.
8. The compound ofclaim 1, wherein the compound is (S)-3-((S)-2-(5-(2(dimethylamino)ethyl)-2-oxo-4-(trifIuoromethyl)pyridin-l(2H)-yl)-4-methylpentanamido)-3(4-fluoro-2',4',5,6'-tetramethyl-[l,r-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.
9. The compound ofclaim 1, wherein the compound is (S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[ 1,1'biphenyl]-3-yl)-3-((S)-2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-

1 (2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.
10. The compound of claim 1, wherein the compound is (S)-3-((S)-2-(5-(2(dimethylamino)ethyl)-4-methyI-2-oxopyridin-l(2H)-yl)-5-methylhexanamido)-3-(4-fluoro2',5,6'-trimethyl-[l,l'-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable sait thereof.
11. The compound of claim 1, wherein the compound is (S)-3-(4-fluoro-2',5,6'-trimethyl-[l,rbiphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3-fluoroazetidin-l-yl)ethyl)-2-oxopyridin-l(2H)-yl)4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.
12. The compound of claim 1, wherein the compound is (S)-3-(4-fluoro-2',5,6'-trimethyl-[l,l'bÎphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-l-yl)ethyl)-2-oxopyridinl(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable sait thereof.
13. A pharmaceutical composition comprising a compound of Formula (I) as the active pharmaceutical ingrédient:

682

(D wherein

Ra, Rb, and Rc are independently selected from the group consisting of H, Me, halide, 5 CF3, C(H)F₂, C(F)H₂, and -(C].Cs)alkylene-N-(R_x)(Ry); provided that at least one of Ra, Rb, and Rc is -(Ci-C5)alkylene-N-(R_x)(Ry);

R_x and R_y are independently selected from the group consisting of H and substituted or unsubstituted (Ci-Cô)-alkyl; or R_x and R_y taken together with the N to which they are attached form a 4-6 membered ring;

10 Ri is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl;

Rîa and Rjb are independently selected from the group consisting of H, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C3-Cô)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, -OH, -CN, halide, CF3, C(H)F₂, C(F)H₂,-(Ci-C4)15 alkoxy, -OCF3, and substituted or unsubstituted (Ci-C4)-alkylene-(Ci-C4)-alkoxy; provided that R3a and R3b are not both H;

R₃c, and R3d are H;

R4 is H;

683

Rsa, and Rs_e are independently methyl;

Rsb, and Rs_c are independently selected from the group consisting of H, CN, halide, CFj, C(H)F₂, C(F)H₂, substituted or unsubstituted (Ci-Ci)-alkyl, substituted or unsubstituted (Cî-Cô)cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl, and (C1-C4)5 alkoxy;

Rsd is H; and wherein the compound of Formula (I) is selected from the group consisting of:

684

or a pharmaceutically acceptable sait thereof.
14. The composition of claim 13, wherein the compound is

or a pharmaceutically acceptable sait thereof.

5
15. The composition of claim 13, wherein the compound is

or a pharmaceutically acceptable sait thereof.
16. The composition of claim 13, wherein the compound is

, or a pharmaceutically acceptable sait thereof.
17. The composition of claim 13, wherein the compound is

685

OH , or a pharmaceutically acceptable sait thereof.
18. The composition of claim 13, wherein the compound is

or a pharmaceutically acceptable sait thereof.
19. The composition of claim 13, wherein the compound is

, or a pharmaceutically acceptable sait thereof.
20. The composition of claim 13, wherein the compound is
21. The composition of claim 13, wherein the compound is

686

, or a pharmaceutically acceptable sait thereof.
22. The composition of claim 13, wherein the compound is

or a pharmaceutically acceptable sait thereof.
23. The composition of claim 13, wherein the compound is

or a pharmaceutically acceptable sait thereof.
24. The composition of claim 13, wherein the compound is

, or a pharmaceutically acceptable sait thereof.
25. A compound of Formula (la):

687

wherein:

Ra, is CF₃;

5 Rb is substituted or unsubstituted -(Ci.C5)alkylene-N-(Rx)(Ry);

R_x and R_y are independently substituted or unsubstituted (Ci-C6)-alkyl; or R_x and Ry taken together with the N to which they are attached form a 4-6 membered ring;

Rc is H;

Ri is substituted or unsubstituted (Ci-Cô)-alkyl;

R_3a and R₃b are independently selected from the group consisting of H, substituted or unsubstituted (Ci-C5)-alkyl, substituted or unsubstituted (C₃-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, -OH, -CN, halide, CF₃, C(H)F₂, C(F)H₂.-(Ci-C4)-alkoxy, -OCF₃, and substituted or unsubstituted (C1-C4)15 alkylene-(Ci-C4)-aIkoxy; provided that R_3a and R₃b are not both H;

R_3c is H;

R₃d is halide;

R»is H;

688

Rsa, and Rse are each independently selected from (Ci-CsJ-alkyl; and

Rsb, Rsc, and Rsd are independently selected from the group consisting of H, CN, halide, CF3, C(H)F₂, C(F)H₂, -CH₂CF3, substituted or unsubstituted (Ci-Cs)-alkyl, substituted or unsubstituted (C3-Cô)-cycloalkyl, substituted or unsubstituted 3-6

5 membered heterocycloalkyl, hydroxyl, and (Ci-C-O-alkoxy;

wherein the compound of Formula (I) is selected from the group consisting of:

689

690

691

692
26. The compound of claim 25, wherein the compound is

, or a pharmaceutically acceptable sait thereof.
27. The compound of claim 25, wherein the compound is

, or a pharmaceutically acceptable sait thereof.

5
28. The compound of claim 25, wherein the compound is

693

, or a pharmaceutically acceptable sait thereof.
29. The compound of claim 25, wherein the compound is
30. The compound of claim 25, wherein the compound is

694

or a pharmaceutically acceptable sait thereof.
31. The compound of claim 25, wherein the compound is

, or a pharmaceutically acceptable sait thereof.
32. The compound of claim 25, wherein the compound is

695
33. The compound of claim 25, wherein the compound is

or a pharmaceutically acceptable sait thereof.
34. The compound of claim 25, wherein the compound is

696
35. The compound of claim 25, wherein the compound is
36. The compound of claim 25, wherein the compound is

697
37. A pharmaceutical composition comprising a compound of any one of daims 25-36 or a pharmaceutically acceptable sait thereof as the active pharmaceutical ingrédient.