OA19643A

OA19643A - Hepatitis B core protein modulators.

Info

Publication number: OA19643A
Application number: OA1201800102
Authority: OA
Inventors: Hans Maag; William Turner; Lee Daniel Arnold; Leping Li; Mark Bures; Simon Haydar; Samson FRANCIS
Original assignee: Assembly Biosciences, Inc.; Indiana University Research And Technology Corporation
Priority date: 2015-09-15
Filing date: 2016-09-15
Publication date: 2020-12-31

Abstract

The present disclosure provides, in part, compounds having allosteric effector properties against hepatitis B virus Cp. Also provided herein are methods of treating viral infections, such as hepatitis B, comprising administering to a patient in need thereof a disclosed compound.

Description

HEPATITIS B CORE PROTEIN MODULATORS

CROSS REFERENCE TO RELATED APPLICATIONS

This application daims priority to U.S. Provisional Application Number 62/218,815, filed September 15, 2015; hereby incorporated by reference in its entirety.

BACKGROUND

Hepatitis B (HBV) causes viral Hepatitis that can further lead to chronic liver disease and increase the risk of liver cirrhosis and liver cancer (hepatocellular carcinoma). Worldwide, about 2 billion people hâve been infected with HBV, around 360 million people are chronically infected, and every year HBV infection causes more than one half million deaths (2009; WHO, 2009). HBV can be spread by body fluids: from mother to child, by sex, and via blood products. Children bom to HBV -positive mothers may also be infected, unless vaccinated at birth.

The virus particle is composed of a lipid enveloped studded with surface protein (HBsAg) that surrounds the viral core. The core is composed of a protein shell, or capsid, built of 120 core protein (Cp) dimers, which in tum contains the relaxed circular DNA (rcDNA) viral genome as well as viral and host proteins. In an infected cell, the genome is found as a covalently closed circular DNA (cccDNA) in the host cell nucléus. The cccDNA is the template for viral RNAs and thus viral proteins. In the cytoplasm, Cp assembles around a complex of full-length viral RNA (the so-called pregenomic RNA or pgRNA and viral polymerase (P). After assembly, P reverse transcribes the pgRNA to rcDNA within the confines of the capsid to generate the DNA-fdled viral core. For convenience, we divide the assembly process at the point of capsid assembly and pgRNA-packaging. Steps preceding this event are “upstream”; steps following RNA-packaging are “downstream”.

At présent, chronic HBV is primarily treated with nucleos(t)ide analogs (e.g. entecavir) that suppress the virus while the patient remains on treatment but do not eliminate the infection, even after many years of treatment. Once a patient starts taking nucléotide analogs most must continue taking them or risk the possibility of a life threatening immune response to viral rebound. Further, nucleos(t)ide therapy may lead to the emergence of antiviral drug résistance (Deres and Rubsamen-Waigmann, 1999; Tennant et al., 1998; Zhang et al., 2003) and - in rare patients- adverse events hâve been reported (Ayoub and Keeffe ,2011).

The only FDA approved alternative to nucleos(t)ide analogs is treatment with interferon a or pegylated interferon a. Unfortunately, the adverse event incidence and profile of interferon ci can resuit in poor tolerability, and many patients are unable to complété therapy. Moreover, only a small percentage of patients are considered appropriate for interferon therapy, as only a small subset of patients are likely to hâve a sustained clinical response to a course of interferon therapy. As a resuit, interferon based thérapies are used in only a small percentage of ail diagnosed patients who elect for treatment.

Thus, current HBV treatments can range from palliative to watchful waiting. Nucleos(t)ide analogs suppress virus production, treating the symptom, but leave the infection intact. Interferon a has severe side effects and less tolerability among patients and is successful as a finite treatment strategy in only a small minority of patients. There is a clear on-going need for more effective treatments for HBV infections.

SUMMARY

Provided herein are compounds that can hâve properties such as those described below, where the compounds in some embodiments may be represented by:

wherein

R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^c, R^m, R^m’, R⁷⁷,R⁷⁸, R^Z and Y are defined herein. Also provided herein are methods of treating viral infections, such as hepatitis B, comprising administering to patient a disclosed compound.

For example, the présent disclosure is directed in part to compounds having allosteric effector properties against Hepatitis B virus Cp, a protein found as a dimer, a multimer, and as the protein shell of the HBV core. Without being bound by theory, disclosed compounds may ultimately target multimerization of viral core proteins, which is central to HBV infection, where the core protein multimerizes into shell, or capsid, and/or disclosed compounds may for example, ultimately target interaction of viral core proteins with other macromolecules, such as host or viral nucleic acid, host proteins, or other viral proteins. For example, disclosed compounds may be considered in some embodiments CpAM — core protein allosteric modifiers. CpAM interaction with core protein can allosterically favor an assembly-active form of Cp dimer and lead to viral capsid assembly at an inappropriate time or place or lead to non-standard intersubunit interactions, ail resulting in defective capsids. CpAMs may additionally or altematively affect steps of “upstream” of capsid assembly by altering the concentrations or nature of Cp available as dimer as compared to capsid or other multimeric forms. Disclosed compounds or CpAMs may, in some embodiments, noticeably affect functions upstream of viral assembly such as modulation of cccDNA transcription, RNA stability and/or protein-protein interactions.

Detailed Description

The features and other details of the disclosure will now be more particularly described. Before further description of the présent invention, certain ternis employed in the spécification, examples and appended claims are collected here. These définitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, ail technical and scientific ternis used herein hâve the same meaning as commonly understood by a person of ordinary skill in the art.

Définitions

As intended herein, the ternis a and an include singular as well as plural référencés unless the context clearly dictâtes otherwise. For example, the term an assembly effector can include one or more such effectors.

The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as Ci^alkyl, C|_4alkyl, and Ci^alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l-butyl, 3-methyl-2-butyl, 2-methyl-l-pentyl, 3-methyl-1-pentyl, 4methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-lbutyl, 3,3-dimethyl-l-butyl, 2-ethyl-l-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as C2-6alkenyl, and C^alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as Ci-ealkoxy, and C2-6alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.

The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, or 3-6 carbon atoms, referred to herein as C2-6alkynyl, and C3.6alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.

The terms “cycloalkyl” or a “carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as Cj.

₆cycloalkyl or C^cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl.

The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

The terms “heteroaryl” or “heteroaromatic group” as used herein refers to a monocyclic aromatic 5-6 membered ring System containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine or pyrimidine etc.

The terms “heterocyclyl” or “heterocyclic group” are art-recognized and refer to saturated or partially unsaturated 4-7 membered ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran etc

The terms “hydroxy” and “hydroxyl” as used herein refers to the radical -OH.

Treatment as used herein includes the alleviation, prévention, reversai, amelioration or control of a pathology, disease, disorder, process, condition or event, including viral infection. In this context, the terni treatment is further to be understood as embracing the use of a drug to inhibit, block, reverse, restrict or control progression of viral infection.

As used herein, the term “pharmaceutical composition” refers to compositions of matter comprising at least one pharmaceutical compound and optionally a pharmaceutically acceptable carrier.

As used herein, the term “pharmaceutical compound” or “drug” refers to a free compound, its therapeutically suitable salts, solvatés such as hydrates, spécifie crystal forms of the compound or its salts, or therapeutically suitable prodrugs of the compound.

Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergie or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, préparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.

The tenu “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and ail solvents, dispersion media, coatings, isotonie and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplémentai, additional, or enhanced therapeutic functions.

The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of ail enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may dénoté a chiral center implicitly. The présent invention encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may dénoté a chiral center implicitly.

The compounds of the disclosure may contain one or more double bonds and, therefore, exist as géométrie isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol dénotés a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or configuration wherein the ternis “Z” and “Æ” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond altematively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.

Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as géométrie isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic rings may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.”

Individual enantiomers and diastereomers of compounds of the présent invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by préparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, séparation of the resulting mixture of diastereomers by recrystallization or chromatography and libération of the optically pure product from the auxiliary, (2) sait formation employing an optically active resolving agent, (3) direct séparation of the mixture of optical enantiomers on chiral liquid chromatographie columns or (4) kinetic resolution using stereoselective Chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by wellknown methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective synthèses, a Chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the création of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective synthèses encompass both enantio- and diastereoselective transformations, and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaemo, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, éthanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

The invention also embraces isotopically labeled compounds of the invention which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ²H, ³H, ^l3C, ^l4C, ^l5N, ^l8O, ^l70,³¹P, ³²P, ³⁵S, ^l8F, and ³⁶Cl, respectively. For example, a compound of the invention may hâve one or more H atom replaced with deuterium. Certain isotopically-labeled disclosed compounds (e.g., those labeled with ³H and ^l4C) are usefùl in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon14 (i.e., ^l4C) isotopes are particularly preferred for their ease of préparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo halflife or reduced dosage requirements) and hence may be preferred in some circumstances.

Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

The term therapeutically suitable sait, refers to salts or zwitterions of pharmaceutical compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders and effective for their intended use. The salts may be prepared, for instance, during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water, and treated with at least one équivalent of an acid, for instance hydrochloric acid. The resulting sait may precipitate out and be isolated by filtration and dried under reduced pressure. Altematively, the solvent and excess acid may be removed under reduced pressure to provide the sait. Représentative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycérophosphate, hemisulfate, heptanoate, hexanoate, form ate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, paratoluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfùric, phosphoric, and the like. The amino groups of a compound may also be quatemized with alkyl chlorides, bromides, and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like.

Basic addition salts may be prepared, for instance, during the final isolation and purification of pharmaceutical compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a métal cation such as lithium, sodium, potassium, calcium, magnésium, or aluminum, or an organic primary, secondary, or tertiary amine. Quatemary amine salts may be derived, for example, from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,Ndimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, Ν,Ν-dibenzylphenethylamine, 1-ephenamine, and N,N'dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

The term “therapeutically suitable prodrug,” refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of subjects and are effective for their intended use. The term “prodrug” refers to compounds that are transformed in vivo to a pharmaceutical compound, for example, by hydrolysis in blood. The term “prodrug,” refers to compounds that contain, but are not limited to, substituents known as “therapeutically suitable esters.” The term “therapeutically suitable ester,” refers to alkoxycarbonyl groups appended to the parent molécule on an available carbon atom. More specifically, a “therapeutically suitable ester,” refers to alkoxycarbonyl groups appended to the parent molécule on one or more available aryl, cycloalkyl and/or heterocycle groups. Compounds containing therapeutically suitable esters are an example, but are not intended to limit the scope of compounds considered to be prodrugs. Examples of prodrug ester groups include pivaloyloxymethyl, acetoxymethyl,

- 10 phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art. Other examples of prodrug ester groups are found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Sériés, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

The terms pharmaceutically effective amount and “effective amount”, as used herein, refer to an amount of a pharmaceutical formulation that will elicit the desired therapeutic effect or response when administered in accordance with the desired treatment regimen.

US2011/0144086 describes the use of some diabenzothiazepine molécules (DBTs) as antimalarial “inhibitors of the plasmodial surface anion channel.” However, no study of DBT molécules as anti-virals has yet been reported.

In an embodiment, provided herein are compounds represented by:

NR^C R¹⁰ wherein

Y is selected from the group consisting of S(O)_y, C=O, C(Rⁿ)2, NRy and O wherein y is 0, 1, or 2;

R¹¹, for each occurrence, is selected from the group consisting of H, halogen, and Ci^alkyl (optionally substituted with one, two, or three halogens);

R y is selected from the group consisting of H, methyl, ethyl, propyl, propenyl, butyl, phenyl and benzyl, wherein Ry when not H may be optionally substituted by hydroxyl;

R^z is selected from the group consisting of H, methyl, ethyl, propyl, phenyl and benzyl;

R^ra and R^In are each independently selected from the group consisting of H, Ci^alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), and C2-6alkenyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl);

R^c is selected from the group consisting of H, Ci^alkyl and C2-6alkenyl;

R⁷⁷ is selected from the group consisting of H, halogen, cyano, and Ci_6alkyl;

R⁷⁸ is selected from the group consisting of H, halogen, cyano, Ci-ealkyl, carboxy, -C(O)-OC].₆alkyl; C₃.6cycloalkyl, -NR’R”; phenyl (optionally substituted with one, two, three or four substituents each independently selected from the group consisting of R⁷³); benzyl (optionally substituted with one or more substituents each independently selected from the group consisting of R⁷³), 4-7 membered heterocycle (optionally substituted with one or more substituents each independently selected from the group consisting of R⁷³); 4-6 membered monocyclic heteroaryl (optionally substituted with one or more substituents each independently selected from the group consisting of R⁷³); 9-10 membered bicyclic heteroaryl (optionally substituted with one or more substituents each independently selected from the group consisting of R⁷³), X²-R⁷⁹, and X²-Ci.6alkylene-R⁷⁹;

X² is selected from the group consisting of S(O)_W (wherein w is 0,1, or 2), O, -C(O)- and NR’;

R⁷⁹ is selected from the group consisting of H, hydroxyl, halogen, Ci^alkyl, -C(O)-O-Ci-6alkyl, heterocycle (optionally substituted by one or more substituents selected from the group consisting of halogen, NR’R’, -C(O)-O-Ci-6alkyl, carboxy and Ci^alkyl), -C(O)-NR’R”, -C (=NH)-NR’R”, heteroaryl, phenyl (optionally substituted by one or more substituents selected from the group consisting of halogen, NR’R’, -C(O)-O-Ci.6alkyl, carboxy, Ci-ealkoxy, and Ci. ealkyl), C₂-6alkenyl, C2-6alkynyl, Ci.₆alkoxy, carboxy, NR’R”, -C(O)-Ci-6alkyl, C₃.ecycloalkyl, -NR’-C(O)- Ci^alkyl, NR’-C(O)- O-Ci.6alkyl, -S(O)_w-Ci.ealkyl (where w is 0, 1 or 2), -S(O)_WNR’R” (where w is 0, 1 or 2), and -NR’-S(O)_W- Ci-ealkyl (where w is 0, 1 or 2));

R⁷³ is selected from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, oxo, Ci.ealkyl, -C(O)-O-Ci-6alkyl, heterocycle (optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, NR’R’, -C(O)-O-C]_6alkyl, carboxy and Ci-ealkyl), -C(O)-NR’-Ci-6alkyl, -C (=NH)-NR’R”, heteroaryl, phenyl, C2ôalkenyl, C2-6alkynyl, Ci.6alkoxy, carboxy, oxo, NR’R”, -C(O)-Ci.ealkyl, - C₃.ecycloalkyl,

NR’-C(O)- Ci-ealkyl, NR’-C(O)- O-Ci.6alkyl, -S(O)_w-Ci_6alkyl (where w is 0, 1 or 2), -S(O)_WNR’R” (where w is 1, 2 or 3), -NR’-S(O)_W- Ci.₆alkyl (where w is 0, 1 or 2), C(O)-NR’- Ci. ₆alkyl, C(O)-Ci.₃alkylene-NR’- C(O)-O- Ci.₆alkyl, X²- R⁷⁹; and X²-Ci.₆alkylene-R⁷⁹;

R’ is selected, independently for each occurrence, from H, methyl, ethyl, cyclopropyl, cyclobutyl, and propyl;

R” is selected, independently for each occurrence, from H, methyl, ethyl, propyl, (optionally substituted by hydroxyl), butyl (optionally substituted by hydroxyl), -C(O)-methyl and -C(O)ethyl, or R’ and R” taken together with the nitrogen to which they are attached may form a 4-7 membered heterocycle optionally substituted by one, two or more substituents selected from the group consisting of halogen, hydroxyl, NH2, -C(O)-O-Ci-3alkyl, -C(O)-Ci-3alkyl, carboxy, oxo, and Ci.₃alkyl;

each of moieties R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected for each occurrence from the group consisting of hydrogen, Ci^alkyl, Ci-ealkoxy, C2-6alkynyl, C2-6alkenyl, halogen, hydroxyl, nitro, cyano, and NR’R”;

wherein for each occurrence, Ci-ealkyl, C2-6alkenyl or C2-6alkynyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Cs-ecycloalkyl, C2-4alkenyl, C2-4alkynyl, Ci^alkoxy, NR’R”, NR’-S(O)_W- Ci.₂alkyl (where w is 0, 1 or 2), NR’-C(O)-Ci.₃alkyl, NR’-C(O)- O-C^alkyl, and S(O)_w-NR’R”(where w is 0, 1 or 2); Ci-galkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci^alkyl, NR’R”, -NR’-S(O)_W- C^alkyl (where w is 0, 1 or 2), and S(O)_WNR’R” (where w is 0, 1 or 2); Ci.6alkylene may be optionally substituted by a substituent selected from the group consisting of C3-6cycloalkyl, hydroxyl, cyano, and halogen;

and pharmaceutically acceptable salts and N-oxides thereof.

In some embodiments, Y may be selected from the group consisting of S(O)_y, C=O, C(Rⁿ)2, and O For example, Y may be S(O)_y

In an embodiment, y may be 1 or 2. In another embodiment, y may be 0. In a further embodiment, y may be 1. In another other embodiment, y may be 2.

For example, in some embodiments Y may be C=O. In some embodiments, Y may be NH.

For example, in some embodiments R⁷⁸ may be selected from the group consisting of C]_6 alkyl substituted with one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, and cyano; phenyl substituted with one, two, three or four substituents each independently selected from the group consisting of R⁷³; and X²-Ci-6alkyleneR⁷⁹.

For example, in some embodiments R78 may be selected from the group consisting of CF3, cyano, and phenyl substituted with one, two, three or four substituents each independently selected from the group consisting of R73.

For example, in some embodiments R78 may be selected from the group consisting of phenyl substituted with one, two, three or four substituents each independently selected from the group consisting of R73; benzyl (optionally substituted with one or more substituents each independently selected from the group consisting of R73), pyridinyl (optionally substituted with one or more substituents each independently selected from the group consisting of R73), pyrimidinyl (optionally substituted with one or more substituents each independently selected from the group consisting of R73), benzoimidazole (optionally substituted with one or more substituents each independently selected from the group consisting of R73), quinolinyl (optionally substituted with one or more substituents each independently selected from the group consisting of R73, thiazolyl, and pyrazolyl (optionally substituted with one or more substituents each independently selected from the group consisting of R73).

For example, in some embodiments R may be -NR’R”, wherein R’ and R” taken together with the nitrogen to which they are attached may form a 4-7 membered heterocycle optionally substituted by one, two or more substituents selected from the group consisting of halogen, hydroxyl, NH2, -C(O)-O-Ci-3alkyl, -C(O)-Ci-3alkyl, carboxy, oxo, and Ci^alkyl.

In one embodiment, R⁷⁷ may be H. In some embodiments, R⁷ may be H or halogen. In another embodiment, R¹⁰ may be H, halogen or methyl.

In certain embodiments, R^m and Rⁱⁿ may be each H. In other embodiments, R^z may be H. For example, in some embodiments each of R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ may be H.

- 14Also provided herein are compounds represented by:

NR⁰ R¹⁰ wherein

R⁷³ is selected from the group consisting of heterocycle (optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, NR’R’, -C(O)-O-Ci. ealkyl, carboxy and Ci-ealkyl), -C(O)-NR’-Ci.6alkyl, -C (=NH)-NR’R”, heteroaryl (optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, NR’R’, -C(O)-O-Ci-6alkyl, carboxy and Ci-ôalkyl), phenyl (optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, NR’R’, -C(O)-O-Ci.6alkyl, carboxy and Ci^alkyl), C2-6alkenyl, C2-6alkynyl, Ci-ealkoxy, carboxy, C(O)-Ci.₆alkyl, - C₃.₆cycloalkyl, NR’-C(O)- Ci.₆alkyl, NR’-C(O)- O-Ci_₆alkyl, -S(O)_w-Ci. ealkyl (where w is 0, 1 or 2), -S(O)_W-NR’R” (where w is 0, 1 or 2), -NR’-S(O)_W- Ci^alkyl (where w is 0, 1 or 2), C(O)-NR’- Ci-éalkyl, C(O)-Ci-3alkylene-NR’- C(O)-O- Cj^alkyl, X²R⁷⁹; and X²-Ci-6alkylene-R⁷⁹;

R⁶⁸ is independently selected for each occurrence from the group consisting of H, halogen, hydroxyl, Ci^alkyl and Ci.ôaikoxy;

R is selected from the group consisting of H, hydroxyl, halogen, Cuealkyl, -C(O)-O-Ci.6alkyl, heterocycle (optionally substituted by one or more substituents selected from the group consisting of halogen, NR’R’, -C(O)-O-Ci-6alkyl, carboxy and Ci-ealkyl), -C(O)-NR’R”, -C (=NH)-NR’R”, heteroaryl, phenyl (optionally substituted by one or more substituents selected from the group consisting of halogen, NR’R’, -C(O)-O-Ci-6alkyl, carboxy, Ci-ealkoxy , and Ci.

₆alkyl), C2-6alkenyl, C2-6alkynyl, Ci-6alkoxy, carboxy, NR’R”, -C(O)-C|.6alkyl, C3.6cycloalkyl, -NR’-C(O)- Ci-ealkyl, NR’-C(O)- O-Ci-6alkyl, -S(O)_w-Ci-6alkyl (where w is 0, 1 or 2), -S(O)_WNR’R” (where w is 0, 1 or 2), and -NR’-S(O)_W- Ci^alkyl (where w is 0, 1 or 2));

R” is selected, independently for each occurrence, from H, methyl, ethyl, propyl, (optionally substituted by hydroxyl), butyl (optionally substituted by hydroxyl), -C(O)-methyl and -C(O)ethyl, or R’ and R” taken together with the nitrogen to which they are attached may form a 4-7 membered heterocycle optionally substituted by one, two or more substituents selected from the group consisting of halogen, hydroxyl, NH2, -C(O)-O-Ci-jalkyl, -C(O)-Ci-3alkyl, carboxy, oxo, and Ci-3alkyl;

each of moieties R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected for each occurrence from the group consisting of hydrogen, Ci^alkyl, Ci_6alkoxy, C2-6alkynyl, C2-6alkenyl, halogen, hydroxyl, nitro, cyano, and NR’R”;

wherein for each occurrence, Ci_6alkyl, C2-6alkenyl or C2-6alkynyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C3-6cycloalkyl, C2-4alkenyl, C2-4alkynyl, Ci-aalkoxy, NR’R”, NR’-S(O)_W- Ci^alkyl (where w is 0, 1 or 2), NR’-C(O)-Ci-3alkyl, NR’-C(O)- O-Ci.3alkyl, and S(O)_W-NR’R”(where w is 0, 1 or 2); Ci-ôalkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci.₃alkyl, NR’R”, -NR’-S(O)_W- Ci^alkyl (where w is 0, 1 or 2), and S(O)_WNR’R” (where w is 0, 1 or 2); Ci.galkylene may be optionally substituted by a substituent selected from the group consisting of C₃.6cycloalkyl, hydroxyl, cyano, and halogen;

and pharmaceutically acceptable salts and N-oxides thereof.

Also provided herein are compounds represented by:

- 16 NR^C R¹⁰ wherein

Y is selected from the group consisting of S(O)_y> C=O, C(R'')2, NR_y and O wherein y is 0, 1, or 2;

R_Y is selected from the group consisting of H, methyl, ethyl, propyl, propenyl, butyl, phenyl and benzyl;

R^c is selected from the group consisting of H, Ci-ealkyl and C2-6alkenyl;

R⁵⁸ and R⁵⁹ are each independently selected from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, Cuealkyl, C₂-6alkenyl, C₂-6alkynyl, Ci_6alkoxy, NR’R”, -C(O)Ci-6alkyl, -C(O)-Ci-6alkoxy, phenyl, heteroaryl, Cs-gcycloalkyl, -S(O)_w-Ci.₆alkyl (where w is 0, 1 or 2), -S(O)_W-NR’R” (where w is 0, 1 or 2), and -NR’-S(O)_W- Ci^alkyl (where w is 0, 1 or 2); or form a phenyl, heterocyclic or heteroaryl ring (optionally substituted by one, two, or three substituents selected from the group consisting of hydrogen, Ci-ealkyl, C2-6alkynyl, C2₆alkenyl, halogen, hydroxyl, nitro, cyano, and NR’R”) and fused to the ring to which they are attached;

R” is selected, independently for each occurrence, from H, methyl, ethyl, propyl (optionally substituted by hydroxyl), butyl (optionally substituted by hydroxyl), -C(O)-methyl and -C(O)ethyl, or R’ and R” taken together with the nitrogen to which they are attached may form a 4-6 membered heterocycle optionally substituted by one or more substituents selected from the group consisting of halogen, NH2, -C(O)-O-Ci-6alkyl, -C(O)-Ci-6alkyl, carboxy and Ci^alkyl;

each of moieties R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected for each occurrence from the group consisting of hydrogen, Ci-galkyl, C₂-6alkynyl, C₂-6alkenyl, halogen, hydroxyl, nitro, cyano, and NR’R”;

wherein for each occurrence, Ci_6alkyl, C2-6alkenyl or C2-6alkynyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Cs-ecycloalkyl, C2-4alkenyl, C2-4alkynyl, Ci.aalkoxy, NR’R”, NR’-S(O)_W- Ci^alkyl (where w is 0, 1 or 2), NR’-C(O)- Ci^alkyl, NR’-C(O)- O-Ci.3alkyl, NR’-S(O)_W; and S(O)_W-NR’R”; C^ealkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci^alkyl, NR’R”, -NR’-S(O)_W- C|.2alkyl (where w is 0, 1 or 2), and S(O)_WNR’R”(where w is 0, 1 or 2); Ci-ealkylene may be optionally substituted by a substituent selected from the group consisting of Cs-ecycloalkyl, hydroxyl, cyano, and halogen;

and pharmaceutically acceptable salts and N-oxides thereof.

For example, in some embodiments, Y may be selected from the group consisting of S(O)_yjC=O, C(R’ *)₂, NR_Y and O wherein y is 0, 1, or 2.

For example, the présent disclosure also provides, in part, a compound selected from the group consisting a compound described in the Examples below and pharmaceutically acceptable salts thereof. In an embodiment, the présent disclosure provides a pharmaceutically acceptable composition comprising a disclosed compound, and a pharmaceutically acceptable excipient.

For example, the présent disclosure also provides, in part, a compound selected from the group consisting of (S)-ll-oxo-N-((2-(4-(2-(pynOlidin-2-yl)ethoxy)phenyl)thiazol-5-yl)methyl)10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; (S)-N-((2-(4-(2-(lmethylpyrrolidin-2-yl)ethoxy)phenyl)thiazol-5-yl)methyl)-l 1 -oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; (R)-N-((2-(4-((lmethylpyrrolidin-3-yl)methoxy)phenyl)thiazol-5-yl)methyl)-11 -oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4-(2-hydroxypropan-219643 yl)-1 H-pyrazol-1 -yl)thiazol-5-yl)methyl)-11 -oxo-10,11 -dihydrodibenzo[b,f] [ 1,4]thiazepine-8carboxamide 5, 5-dioxide; (E)-N-((2-(4-(3-hydroxyprop-1 -en-1 -yl)-1 H-pyrazol-1 -yl)thiazol-5yl)methyl)-l 1-oxo-10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; N((2-(4-(3 -(dimethylamino)propyl)-1 H-pyrazol-1 -yl)thiazol-5-yl)methyl)-11 -oxo-10,11 dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4-(3-hydroxypropyl)1 H-pyrazol-1 -yl)thiazol-5-yl)methyl)-11 -oxo-10,11 -dihydrodibenzo[b,f] [ 1,4] thiazepine-8carboxamide 5,5-dioxide; 1 l-oxo-N-((2-(4-(4-(piperidin-l-yl)but-l-yn-l-yl)phenyl)thiazol-5yl)methyl)-10,l l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4-(4(diethylamino)but-l -yn-1 -yl)phenyl)thiazol-5-yl)methyl)-11 -oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; 1 l-oxo-N-((2-(5-(3-(piperidin1 -yl)propoxy)pyridin-2-yl)thiazol-5-yl)methyl)-10,11 -dihydrodibenzo[b,f] [ 1,4] thiazepine-8carboxamide 5,5-dioxide; N-((2-(5-(3-morpholinopropoxy)pyridin-2-yl)thiazol-5-yl)methyl)1 l-oxo-10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(5-(3(diethylamino)propoxy)pyridin-2-yl)thiazol-5-yl)methyl)-11 -oxo-10,11dihydrodibenzo[b,f|[l,4]thiazepine-8-carboxamide 5,5-dioxide; 1 l-oxo-N-((2-(5-(4-(piperidin1 -yl)butyl)pyridin-2-yl)thiazol-5-yl)methyl)-10,11 -dihydrodibenzo [b,f] [ 1,4] thiazepine-8carboxamide 5,5-dioxide; N-((2-(5-(4-morpholinobutyl)pyridin-2-yl)thiazol-5-yl)methyl)-l 1oxo-10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(5-(4(diethylamino)butyl)pyridin-2-yl)thiazol-5-yl)methyl)-11 -oxo-10,11dihydrodibenzo[b,f| [ 1,4]thiazepine-8-carboxamide 5,5-dioxide; (R)-4-(3-(4-(5-((5,5-dioxido11 -oxo-10,11 -dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamido)methyl)thiazol-2yl)phenoxy)propyl)morpholine-3-carboxylic acid; (S)-4-(3-(4-(5-((5,5-dioxido-ll-oxo-10,lldihydrodibenzo[b,f][l,4]thiazepine-8-carboxamido)methyl)thiazol-2yl)phenoxy)propyl)morpholine-3-carboxylic acid; (S)-N-((2-(4-(3-(3methylmorpholino)propoxy)phenyl)thiazol-5-yl)methyl)-11 -oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; (R)-N-((2-(4-(3-(3methylmorpholino)propoxy)phenyl)thiazol-5-yl)methyl)-11 -oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; (R)-N-((2-(4-(3-(2methylmorpholino)propoxy)phenyl)thiazol-5-yl)methyl)-11 -oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; (S)-N-((2-(4-(3-(219643 methylmorpholino)propoxy)phenyl)thiazol-5-yl)methyl)-11 -oxo-10,11dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4-(3(dimethylamino)propoxy)cyclohexyl)thiazol-5-yl)methyl)-11 -oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4-(3-((2R,6R)-2,6dimethylmorpholino)propoxy)phenyl)thiazol-5-yl)methyl)-11 -oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4-(3-((2S,6S)-2,6dimethylmorpholino)propoxy)phenyl)thiazol-5-yl)methyl)-l 1 -oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4-(3-((2R,6S)-2,6dimethylmorpholino)propoxy)phenyl)thiazol-5-yl)methyl)-11 -oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(5-(3hydroxypropoxy)pyridin-2-yl)thiazol-5-yl)methyl)-11 -oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4-(3(cyclobutyl(methyl)amino)propoxy)phenyl)thiazol-5-yl)methyl)-11 -oxo-10,11dihydrodibenzo[b,f|[l,4]thiazepine-8-carboxamide 5,5-dioxide; 1 l-oxo-N-((2-(4-(3(pyrrolidin-1 -yl)propoxy)phenyl)thiazol-5-yl)methyl)-10,11dihydrodibenzo[b,f|[l,4]thiazepine-8-carboxamide 5,5-dioxide; methyl (3-(4-(5-((5,5-dioxido11 -oxo-10,11 -dihydrodibenzo [b ,f] [ 1,4]thiazepine-8-carboxamido)methyl)thiazol-2yl)phenoxy)propyl)-D-prolinate; (3-(4-(5-((5,5-dioxido-l l-oxo-10,11dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)piOpyl)-Dproline; ethyl (3-(4-(5-((5,5-dioxido-l l-oxo-10,1 l-dihydrodibenzo[b,f|[l,4]thiazepine-8carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)-L-prolinate; isopropyl (3-(4-(5-((5,5dioxido-11 -oxo-10,11 -dihydrodibenzo [b,f] [ 1,4]thiazepine-8-carboxamido)methyl)thiazol-2yl)phenoxy)propyl)-L-prolinate; methyl (S)-4-(3-(4-(5-((5,5-dioxido-l l-oxo-10,11dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamido)methyl)thiazol-2yl)phenoxy)propyl)morpholine-3-carboxylate; methyl (3-(4-(5-((5,5-dioxido-l l-oxo-10,11dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)-Lalaninate; (3-(4-(5-((5,5-dioxido-ll-oxo-10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)-L-alanine; methyl N-(3-(4-(5-((5,5-dioxido11 -oxo-10,11 -dihydrodibenzo [b,f] [ 1,4] thiazepine-8-carboxamido)methyl)thiazol-2yl)phenoxy)propyl)-N-methyl-L-alaninate; N-(3-(4-(5-((5,5-dioxido-l l-oxo-10,1119643 dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)-Nmethyl-L-alanine; methyl (3-(4-(5-((5,5-dioxido-l l-oxo-10,11dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)-Lvalinate; (3-(4-(5-((5,5-dioxido-l l-oxo-10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)-L-valine; methyl (2-(4-(5-((5,5-dioxido-l 1oxo-10,11 -dihydrodibenzo [b,f] [ 1,4]thiazepine-8-carboxamido)methyl)thiazol-2yl)phenoxy)ethyl)-L-prolinate; (2-(4-(5-((5,5-dioxido-l l-oxo-10,11dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)ethyl)-Lproline; methyl (4-(4-(5-((5,5-dioxido-l l-oxo-10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8carboxamido)methyl)thiazol-2-yl)phenyl)but-3-yn-l-yl)-L-prolinate; (4-(4-(5-((5,5-dioxido-l 1oxo-10,11 -dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenyl)but3-yn-l-yl)-L-proline; N-((2-(4-cyano-lH-pyrazol-l-yl)thiazol-5-yl)methyl)-ll-oxo-10,lldihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4-((l-ethylpiperidin-4yl)oxy)phenyl)thiazol-5-yl)methyl)-11 -oxo-10,11 -dihydrodibenzo[b,f] [ 1,4]thiazepine-8carboxamide 5,5-dioxide; N-((2-(4-(3-morpholinopropyl)phenyl)thiazol-5-yl)methyl)-l l-oxo10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; methyl (3-(4-(5-((9methyl-5,5-dioxido-l l-oxo-10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)-L-prolinate; (3-(4-(5-((9-methyl-5,5dioxido-11 -oxo-10,11 -dihydrodibenzo [b,f] [ 1,4]thiazepine-8-carboxamido)methyl)thiazol-2yl)phenoxy)propyl)-L-proline; N-((2-(4-cyano-1 H-pyrazol-1 -yl)thiazol-5-yl)methyl)-9-methyl1 l-oxo-10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; 9-methyl-N-((2(4-(2-morpholinoethoxy)phenyl)thiazol-5-yl)methyl)-11 -oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; 9-methyl-l l-oxo-N-((2-(4(piperidin-4-yloxy)phenyl)thiazol-5-yl)methyl)-10,11 -dihydrodibenzo[b,f] [ 1,4] thiazepine-8carboxamide 5,5-dioxide; N-((2-(4-((l-ethyIpiperidin-4-yl)oxy)phenyl)thiazol-5-yl)methyl)-9methyl-1 l-oxo-10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; (S)-N((2-(4-(3-(2-(hydroxymethyl)pynOlidin-l-yl)propoxy)phenyl)thiazol-5-yl)methyl)-9-methyl1 l-oxo-10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; (S)-N-((2-(4-(3(2-(methoxymethyl)pyrrolidin-1 -yl)propoxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11 -oxo10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; (S)-N-((2-(4-(3-(219643 cyanopyrrolidin-1 -yl)propoxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11 -oxo-10,11dihydrodibenzo[b,f|[l,4]thiazepine-8-carboxamide 5,5-dioxide; (S)-N-((2-(4-(3-(2-(lHtetrazol-5-yl)pyrrolidin-1 -yl)propoxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11 -oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; 9-methyl-N-((2-(4-(4morpholinobut-1 -yn-1 -yl)phenyl)thiazol-5-yl)methyl)-11 -oxo-10,11dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamide 5,5-dioxide; 9-methyl-N-((2-(4-(4morpholinobutyl)phenyl)thiazol-5-yl)methyl)-ll-oxo-10,lldihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4,4-difluoropiperidin-lyl)thiazol-5-yl)methyl)-9-methyl-l 1-oxo-10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8carboxamide 5,5-dioxide; N-((2-(4-methoxypiperidin-l-yl)thiazol-5-yl)methyl)-9-methyl-l 1oxo-10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; 9-methyl-N-((2-(4(3-morpholinopropyl)phenyl)thiazol-5-yl)methyl)-l l-oxo-10,11dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4-(( 1 isopropylpiperidin-4-yl)oxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11 -oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4-((l-(2-hydroxy-2methylpropyl)piperidin-4-yl)oxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11 -oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4-((l-ethylazetidin-3yl)oxy)phenyl)thiazol-5-yl)methyl)-9-methyl-l l-oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4-((l-isopropylazetidin3-yl)oxy)phenyl)thiazol-5-yl)methyl)-9-methyl-l l-oxo-10,11dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4-((3(dimethylamino)azetidin-1 -yl)methyl)phenyl)thiazol-5-yl)methyl)-9-methyl-11 -oxo-10,11dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4-((3(diethylamino)azetidin-1 -yl)methyl)phenyl)thiazol-5-yl)methyl)-9-methyl-11 -oxo-10,11dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4-([ 1,3'-biazetidin]-1 'ylmethyl)phenyl)thiazol-5-yl)methyl)-9-methyl-l l-oxo-10,11dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4-(azetidin-l ylmethyl)phenyl)thiazol-5-yl)methyl)-9-methyl-l l-oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; methyl (4-(5-((9-methyl-5,5dioxido-11 -oxo-10,11 -dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamido)methyl)thiazol-219643 yl)benzyl)-L-prolinate; (4-(5-((9-methyl-5,5-dioxido-l 1-oxo-10,11dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)benzyl)-L-proline; methyl (S)-4,4-difluoro-l-(4-(5-((9-methyl-5,5-dioxido-l l-oxo-10,11dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)benzyl)pyrrolidine-2carboxylate; (S)-4,4-difluoro-l-(4-(5-((9-methyl-5,5-dioxido-l l-oxo-10,11dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)benzyl)pynOlidine-2carboxylic acid; methyl (S)-4-(4-(5-((9-methyl-5,5-dioxido-l l-oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)benzyl)morpholine-3carboxylate; (S)-4-(4-(5-((9-methyl-5,5-dioxido-l l-oxo-10,11dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)benzyl)morpholine-3carboxylic acid; N-([2,2'-bithiazol]-5-ylmethyl)-9-methyl-l l-oxo-10,11dihydrodibenzo[b,f|[l,4]thiazepine-8-carboxamide 5,5-dioxide; N-([2,4'-bithiazol]-5ylmethyl)-9-methyl-1 l-oxo-10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5dioxide; N-((2-(4-(3-morpholinopropyl)phenyl)thiazol-5-yl)methyl)-l l-oxo-10,11dihydrodibenzo[b,f][l,4]oxazepine-8-carboxamide; 9-methyl-l l-oxo-N-((2-(4-(3-(piperidin-lyl)propoxy)phenyl)thiazol-5-yl)methyl)-10,l l-dihydrodibenzo[b,f][l,4]oxazepine-8carboxamide; 9-methyl-N-((2-(4-(3-morpholinopropoxy)phenyl)thiazol-5-yl)methyl)-l 1 -oxo10,11 -dihydrodibenzo[b,f] [ 1,4]oxazepine-8-carboxamide; N-((2-(4-(3(diethylamino)propoxy)phenyl)thiazol-5-yl)methyl)-9-methyl-l 1 -oxo-10,11dihydrodibenzo[b,f] [ 1,4]oxazepine-8-carboxamide; 9-methyl-N-((2-(4-(3morpholinopropyl)phenyl)thiazol-5-yl)methyl)-11 -oxo-10,11dihydrodibenzo[b,f][l,4]oxazepine-8-carboxamide; 9-methyl-N-((2-(4-(2morpholinoethoxy)phenyl)thiazol-5-yl)methyl)-l l-oxo-10,11dihydrodibenzo[b,f][l,4]oxazepine-8-carboxamide; N-((2-(4-((l-ethylpiperidin-4yl)oxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11 -oxo-10,11dihydrodibenzo[b,f][l,4]oxazepine-8-carboxamide; N-((2-(4-((l-isopropylpiperidin-4yl)oxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11 -oxo-10,11dihydrodibenzo[b,f][l,4]oxazepine-8-carboxamide; N-((2-(4-((l-(2-hydroxy-2methylpropyl)piperidin-4-yl)oxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11 -oxo-10,11dihydrodibenzo[b,f][l,4]oxazepine-8-carboxamide; N-((2-(4-((l-ethylazetidin-319643 yl)oxy)phenyl)thiazol-5-yl)methyl)-9-methyl-ll-oxo-10,lldihydrodibenzo[b,f][l,4]oxazepine-8-carboxamide; N-((2-(4-((l-isopropylazetidin-3yl)oxy)phenyl)thiazol-5-yl)methyl)-9-methyl-l l-oxo-10,11dihydrodibenzo[b,f][l,4]oxazepine-8-carboxamide; N-((2-(4-((3-(dimethylamino)azetidin-lyl)methyl)phenyl)thiazol-5-yl)methyl)-9-methyl-11 -oxo-10,11dihydrodibenzo[b,f|[l,4]oxazepine-8-carboxamide; methyl (4-(5-((9-methyl-l l-oxo-10,11dihydrodibenzo[b,f][l,4]oxazepine-8-carboxamido)methyl)thiazol-2-yl)benzyl)-L-prolinate; (4(5-((9-methyl-11 -oxo-10,11 -dihydrodibenzo[b,f] [ 1,4]oxazepine-8carboxamido)methyl)thiazol-2-yl)benzyl)-L-proline; methyl (S)-4,4-difluoro-1 -(4-(5-((9methyl-11 -oxo-10,11 -dihydrodibenzo[b,f] [ 1,4] oxazepine-8-carboxamido)methyl)thiazol-2yl)benzyl)pyrrolidine-2-carboxylate; (S)-4,4-difluoro-l-(4-(5-((9-methyl-l l-oxo-10,11dihydrodibenzo[b,f][l,4]oxazepine-8-carboxamido)methyl)thiazol-2-yl)benzyl)pyrrolidine-2carboxylic acid; N-([2,2'-bithiazol]-5-ylmethyl)-9-methyl-l l-oxo-10,11dihydrodibenzo[b,f][l,4]oxazepine-8-carboxamide; N-((2-(5-fluoropyridin-2-yl)thiazol-5yl)methyl)-9-methyl-1 l-oxo-10,1 l-dihydrodibenzo[b,f][l,4]oxazepine-8-carboxamide; N-((2(5-cyanopyridin-2-yl)thiazol-5-yl)methyl)-9-m ethyl-11 -oxo-10,11dihydrodibenzo[b,f] [ 1,4]oxazepine-8-carboxamide; 11 -oxo-N-((2-(4-(3-(piperidin-1 yl)propyl)-1 H-pyrazol-1 -yl)thiazol-5-yl)methyl)-10,11 -dihydrodibenzo[b,f] [ 1,4]thiazepine-8carboxamide 5,5-dioxide; 9-methyl-ll-oxo-N-((2-(4-(3-(piperidin-l-yl)propyl)-lH-pyrazol-lyl)thiazol-5-yl)methyl)-10,l l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide;

N-((2-(4-(3-(azetidin-1 -yl)propyl)-1 H-pyrazol-1 -yl)thiazol-5-yl)methyl)-9-methyl-11 -oxo10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4-(4-(azetidin-lyl)but-1 -yn-1 -yl)phenyl)thiazol-5-yl)methyl)-9-methyl-11 -oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4-(4-(azetidin-lyl)butyl)phenyl)thiazol-5-yl)methyl)-9-methyl-l l-oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; 9-methyl-N-((2-(4-(3morpholinopropyl)phenyl)thiazol-5-yl)methyl)-l l-oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; (S)-N-((2-(4-(3-(2cyanopyrrolidin-l -yl)propyl)phenyl)thiazol-5-yl)methyl)-9-methyl-11 -oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide; N-((2-(4-(3-(azetidin-l19643

-24yl)propyl)phenyl)thiazol-5-yl)methyl)-9-methyl-11 -oxo-10,11dihydrodibenzo[b,f|[l,4]thiazepine-8-carboxamide 5,5-dioxide; 9-methyl-l l-oxo-N-((2-(4-(3(piperidin-1 -yl)propyl)phenyl)thiazol-5-yl)methyl)-10,11 -dihydrodibenzo[b,f] [ 1,4]thiazepine8-carboxamide 5,5-dioxide; 2-(5-((9-methyl-5,5-dioxido-l 1-oxo-10,11dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)pyridine 1 -oxide; 9chloro-N-((2-(5-cyanopyridin-2-yl)thiazol-5-yl)methyl)-11 -oxo-10,11dihydrodibenzo[b,f][l,4]oxazepine-8-carboxamide; 6-(5-((9-methyl-5,5-dioxido-l 1-oxo-10,11dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)picolinic acid; methyl (S)-4,4-difluoro-l-(4-(5-((9-methyl-5,5-dioxido-l 1-oxo-10,11dihydrodibenzo[b,f] [ 1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)benzyl)pynOlidine-2carboxylate; 2-methyl-2-(5-((9-methyl-5,5-dioxido-l 1-oxo-10,11dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)propanoic acid; (S)4,4-difluoro-1 -(4-(5-((9-methyl-5,5-dioxido-11 -oxo-10,11 -dihydrodibenzo[b,f] [ 1,4]thiazepine8-carboxamido)methyl)thiazol-2-yl)benzyl)pyrrolidine-2-carboxylic acid; and pharmaceutically acceptable salts thereof. In an embodiment, the présent disclosure provides a pharmaceutically acceptable composition comprising a disclosed compound, and a pharmaceutically acceptable excipient.

In a further aspect, a method for treating a hepatitis B infection in a patient in need thereof is provided, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, and additional, different disclosed compound(s). In another embodiment, a method for treating a hepatitis B infection in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds.

For use in accordance with this aspect, the appropriate dosage is expected to vary depending on, for example, the particular compound employed, the mode of administration, and the nature and severity of the infection to be treated as well as the spécifie infection to be treated and is within the purview of the treating physician. Usually, an indicated administration dose may be in the range between about 0.1 to about 1000 pg/kg body weight. In some cases, the administration dose of the compound may be less than 400 pg/kg body weight. In other cases, the administration dose may be less than 200 pg/kg body weight. In yet other cases, the administration dose may be in the range between about 0.1 to about 100 pg/kg body weight. The dose may be conveniently administered once daily, or in divided doses up to, for example, four times a day or in sustained release form.

A compound may be administered by any conventional route, in particular: enterally, topically, orally, nasally, e.g. in the form of tablets or capsules, via suppositories, or parenterally, e.g. in the form of injectable solutions or suspensions, for intravenous, intra-muscular, sub-cutaneous, or intra-peritoneal injection. Suitable formulations and pharmaceutical compositions will include those formulated in a conventional manner using one or more physiologically acceptable carriers or excipients, and any of those known and commercially available and currently employed in the clinical setting. Thus, the compounds may be formulated for oral, buccal, topical, parentéral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (either orally or nasally).

For oral administration, pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnésium stéarate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). Tablets may be coated by methods well known in the art. Liquid préparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid préparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose dérivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid). Préparations may also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.

-26 Préparations for oral administration may also be suitably formulated to give controlled-release or sustained release of the active compound(s) over an extended period. For buccal administration the compositions may take the form of tablets or lozenges formulated in a conventional manner known to the skilled artisan.

A disclosed compound may also be formulated for parentéral administration by injection e.g. by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or émulsions in oily or aqueous vehicles, and may contain additives such as suspending, stabilizing and/or dispersing agents. Altematively, the compound may be in powder form for constitution with a suitable vehicle, e.g. stérile pyrogen-free water, before use. Compounds may also be formulated for rectal administration as suppositories or rétention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

In some cases, a disclosed compound may be administered as part of a combination therapy in conjunction with one or more antivirals. Example antivirals include nucleoside analogs, interferon a, and other assembly effectors, for instance heteroaryldihydropyrimidines (HAPs) such as methyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridin-2-yl)-l,4-dihydropyrimidine5-carboxylate (HAP-1). For example, provided herein is a method of treating patient suffering from hepatitis B comprising administering to a subject a first amount of a disclosed compound and a second amount of an antiviral, or other anti HBV agent, for example a second amount of a second compound selected from the group consisting of: another HBV caspid assembly promoter (such as certain compounds disclosed herein or for example, GLS4, BAY 41-4109, AT-130, DVR-23 (e.g., as depicted below),

DVR-23

NVR 3-778, NVR1221 (by code); and N890 (as depicted below):

other CpAMs such as those disclosed in the following patent applications hereby incorporated by reference: WO2014037480, WO2014184328, WO2013006394, WO2014089296, WO2014106019, WO2013102655, WO2014184350, WO2014184365, WO2014161888,

WO2014131847, WO2014033176, WO2014033167, and WO2014033170; Nucleoside analogs interfering with viral polymerase, such as entecavir (Baraclude), Lamivudine, (EpivirHBV), Telbivudine (Tyzeka, Sebivo), Adefovir dipivoxil (Hepsera), Tenofovir (Viread), Tenofovir alafenamide fumarate (TAF), prodrugs of tenofavir (e.g. AGX-1009), L-FMAU (Clevudine), LB80380 (Besifovir) and:

viral entry inhibitors such as Myrcludex B and related lipopeptide dérivatives; HBsAg sécrétion inhibitors such as REP 9AC’ and related nucleic acid-based amphipathic polymers, HBF-0529 (PBHBV-001), PBHBV-2-15 as depicted below: :

and BM601 as depicted below:

disruptors of nucleocapsid formation or integrity such as NZ-4/W28F:

HBc directed transbodies such as those described in Wang Y, et al, Transbody against hepatitis

B virus core protein inhibits hepatitis B virus réplication in vitro, Int. Immunopharmacol (2014), located at//dx.doi.org/10.1016/j.intimp.2015.01.028; antiviral core protein mutant (such as Cpl83-V124W and related mutations as described in WO/2013/010069, WO2014/074906 each incorporated by reference ); inhibitors of HBx-interactions such as RNAi, antisense and nucleic acid based polymers targeting HBV RNA;, e.g., RNAi (for example ALN-HBV, ARC-520, TKM-HBV, ddRNAi), antisense (ISIS-HBV), or nucleic acid based polymer: (REP 2139-Ca); immunostimulants such as Interferon alpha 2a (Roferon), Intron A (interferon alpha 2b), Pegasys (peginterferon alpha 2a), Pegylated IFN 2b, IFN lambda la and PEG IFN lambda la, Wellferon, Roferon, Infergen, lymphotoxin beta agonists such as CBE11 and BS1); Non-Interferon Immune enhancers such as Thymosin alpha-1 (Zadaxin) and Interleukin-7 (CYT107); TLR-7/9 agonists such as GS-9620, CYT003, Resiquimod; Cyclophilin Inhibitors such as NVP018; OCB-030; SCY-635; Alisporivir;

NIM811 and related cyclosporine analogs; vaccines such as GS-4774, TGI050, Core antigen vaccine; SMAC mimetics such as birinapant and other ΙΑΡ-antagonists; Epigenetic modulators such as KMT inhibitors (EZH1/2, G9a, SETD7, Suv39 inhibitors), PRMT inhibitors, HD AC inhibitors, SIRT agonists, HAT inhibitors, WD antagonists (e.g. OICR-9429), PARP inhibitors, APE inhibitors, DNMT inhibitors, LSD1 inhibitors, JMJD HDM inhibitors, and Bromodomain antagonists; kinase inhibitors such as TKB1 antagonists, PLK1 inhibitors, SRPK inhibitors, CDK2 inhibitors, ATM & ATR kinase inhibitors; STING Agonists; Ribavirin; N-acetyl cysteine ; NOV-205 (BAM205); Nitazoxanide (Alinia), Tizoxanide; SB 9200 Small Molécule Nucleic Acid Hybrid (SMNH); DV-601; Arbidol; FXR agonists (such as GW 4064 and Fexaramin); antibodies, therapeutic proteins, gene therapy, and biologics directed against viral components or interacting host proteins.

In some embodiments, the disclosure provides a method of treating a hepatitis B infection in a patient in need thereof, comprising administering a first compound selected from any one of the disclosed compounds, and one or more other HBV agents each selected from the group consisting of HBV capsid assembly promoters, HBF viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg sécrétion inhibitors, disruptors of nucleocapsid formation, cccDNA formation inhibitors, antiviral core protein mutant, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-7/9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinase inhibitors, and STING agonists. In some embodiments, the disclosure provides a method of treating a hepatitis B infection in a patient in need thereof, comprising administering an amount of a disclosed compound, and administering another HBV capsid assembly promoter.

In some embodiments, the first and second amounts together comprise a pharmaceutically effective amount. The first amount, the second amount, or both may be the same, more, or less than effective amounts of each compound administered as monotherapies. Therapeutically effective amounts of a disclosed compound and antiviral may be co-administered to the subject, i.e., administered to the subject simultaneously or separately, in any given order and by the same or different routes of administration. In some instances, it may be advantageous to initiate administration of a disclosed compound first, for example one or more days or weeks prior to initiation of administration of the antiviral. Moreover, additional drugs may be given in conjunction with the above combination therapy.

In another embodiment, a disclosed compound may be conjugated (e.g., covalently bound directly or through molecular linker to a free carbon, nitrogen (e.g. an amino group), or oxygen (e.g. an active ester) of a disclosed compound), with a détection moiety, e.g. a fluorophore moiety (such a moiety may for example re-emit a certain light frequency upon binding to a virus and/or upon photon excitation. Contemplated fluorophores include Alcxafluor® 488 (Invitrogen) and BODIPY FL (Invitrogen), as well as fluorescein, rhodamine, cyanine, indocarbocyanine, anthraquinones, fluorescent proteins, aminocoumarin, methoxycoumarin, hydroxycoumarin, Cy2, Cy3, and the like. Such disclosed compounds conjugated to a détection moiety may be used in e.g. a method for detecting HBV or biological pathways of HBV infection, e.g., in vitro or in vivo; and/or methods of assessing new compounds for biological activity.

EXAMPLES

The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that ail proposed reaction conditions, including choice of solvent, reaction atmosphère, reaction température, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality présent on various portions of the molécule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and altemate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials. At least some of the compounds identified as “intermediates” herein are contemplated as compounds of the invention.

Example 1 : Synthesis of Compounds

Synthesis of 11-oxo-10, 11-dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxylic acid (6): A common intermediate

Synthesis of methyl 4-((2-(methoxycarbonyI) phenyl) thio)-3-nitrobenzoate (3):

no₂

To a stimng solution of methyl 4-fluoro-3-nitrobenzoate 2 (30 g, 150.67 mmol) in DMF (300 mL) under inert atmosphère were added césium carbonate (58.76 g, 180.8 mmol) and methyl 2mercaptobenzoate 1 (22.6 mL, 165.47 mmol) at RT; heated to 55-60 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (1500 mL) and the precipitated solid was filtered to obtain the crude. The crude was washed with water (500 mL), hexane (200 mL) and dried in vacuo to afford compound 3 (48.8 g, 93%) as yellow solid. TLC: 20% EtOAc/ hexanes (R/. 0.4); 'H NMR (CDC1₃, 400 MHz): δ 8.85 (s, 1H), 7.99-7.92 (m, 2H), 7.66-7.56 (m, 3H), 6.93 (d, J= 8.6 Hz, 1H), 3.94 (s, 3H), 3.79 (s, 3H).

Synthesis of methyl 3-amino-4-((2-(methoxycarbonyl) phenyl) thio) benzoate (4):

-32To a stirring solution of compound 3 (48 g, 138.32 mmol) in MeOH (1000 mL) under inert atmosphère was added 10% Pd/C (20 g, wet) at RT under hydrogen atmosphère in an autoclave (100 psi pressure) and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with 50% MeOH/ CH2CI2 (500 mL). The filtrate was removed in vacuo to obtain the crude which as triturated with diethyl ether (200 mL), washed with hexane (200 mL) and dried in vacuo to afford compound 4 (40 g, 91%) as yellow solid. TLC: 10% EtOAc/ hexanes (R/. 0.3); *H NMR (DMSO-4 400 MHz): δ 7.95 (dd, 7=7.8, 1.4 Hz, 1H), 7.48-7.35 (m, 3H), 7.23 (td,7=7.5, 1.1 Hz, 1H), 7.15 (dd, J= 8.0, 1.8 Hz, 1H), 6.66 (dd, J= 8.2, 0.8 Hz, 1H), 5.67 (br s, 2H), 3.88 (s, 3H), 3.84 (s, 3H).

Synthesis of 3-amino-4-((2-carboxyphenyl) thio) benzoic acid (5):

To a stirring solution of compound 4 (40 g, 126.18 mmol) in THF: H2O (5:1, 400 mL) was added lithium hydroxide monohydrate (26 g, 619.0 mmol) at 0 °C; warmed to RT and stirred for 48 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 2 N HCl to ~2. The precipitated solid was filtered and dried in vacuo to afford compound 5 (34.6 g, 95%) as an offwhite solid. TLC: 30% EtOAc/ hexanes (R/. 0.1); ‘H NMR (DMSO-4 500 MHz): δ 13.00 (brs, 2H), 7.93 (dd,7=7.7, 1.0 Hz, 1 H), 7.42 (s, 1 H), 7.40-7.31 (m, 2H), 7.18 (t, J = 7.4 Hz, 1H), 7.13 (dd, 7=8.0, 1.6 Hz, 1H), 6.61 (d, 7=7.8 Hz, 1H), 5.55 (br s, 2H).

Synthesis of ll-oxo-10,11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxylic acid (6):

To a stirring solution of compound 5 (31 g, 107.26 mmol) in THF (600 mL) under inert atmosphère was added CDI (86.88 g, 536.29 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was 5 acidified with 2 N HCl to pH~4. The obtained solid was filtered and further dried by using toluene (2 x 200 mL) to afford compound 6 (26 g, 90%) as white solid. TLC: 10% MeOH/ CH₂C1₂ {Rf. 0.3); ’H NMR (DMSO-î/₆, 400 MHz): δ 13.22 (br s, 1H), 10.81 (s, 1H), 7.78 (s, 1H), 7.72-7.64 (m, 3H), 7.57-7.44 (m, 3H).

Synthesis of 7-methyl-ll-oxo-10, 11-dihydrodibenzo [ά,/] [1, 4] thiazepine-8-carboxylic

co₂h

CO₂Me NO₂

To a stimng solution of methyl 2-mercaptobenzoate 1 (514 mg, 3.08 mmol) in DMF (10 mL) under inert atmosphère were added césium carbonate (1.81 g, 5.57 mmol), compound 8 (560 mg, 2.78 mmol) at RT; heated to 60 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water (20 mL) and pH was adjusted to ~2 with 1 N HCl, filtered the precipitated solid and dried in vacuo to afford compound 10 (500 mg, 52%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.4); ‘H-NMR (DMSO-î/₆, 400 MHz): δ 13.47 (br s, 1H), 8.59 (s, 1H), 7.94 (d, J= 7.2 Hz, 1H), 7.68-7.60 (m, 3H), 6.83 (s, 1H), 3.72 (s, 3H), 2.40 (s, 3H).

Synthesis of methyl 3-amino-4-((2-(methoxycarbonyl) phenyl) thio)-5-methylbenzoate (H):

To a stirring solution of compound 10 (500 mg, 1.45 mmol) in THF: H₂O (2:1, 15 mL) was added lithium hydroxide monohydrate (300 mg, 7.31 mmol) at RT and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (15 mL), and pH was adjusted to ~2 with 1 N HCl, filtered the precipitated solid and dried in vacuo to afford crude compound 11 (500 mg) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ {Rf 0.1); *H-NMR (DMSO-4 400 MHz): δ 13.51 (br s, 2H), 8.57 (s, 1H), 7.92 (d, J= 7.2 Hz, 1H), 7.64-7.58 (m, 2H), 7.53 (t, J= 8.0 Hz, 1H), 6.89 (s, 1H), 2.41 (s, 3H).

Synthesis of 5-amino-4-((2-carboxyphenyl) thio)-2-methylbenzoic acid (12):

To a stirring solution of compound 11 (500 mg) in MeOH (15 mL) under inert atmosphère was added Pd/ C (250 mg) at RT and stirred under hydrogen atmosphère for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford crude compound 12 (430 mg) as an off-white solid. TLC: MeOH/ CH2CI2 (7?/ 0.1); LCMS: 84.24%; 304.5 (M⁺+l); (column; X-Select CSH C-18, (50 x 3.0 mm, 3.5 pm); RT 3.75 min. 0.05% TFA (Aq): ACN; 0.8 mL/min).

Synthesis of 7-methyl-ll-oxo-10, 11-dihydrodibenzo [6, /] [1, 4] thiazepine-8-carboxylic acid (13):

To a stirring solution of compound 12 (430 mg) in THF (20 mL) under inert atmosphère was added CDI (1.15 g, 7.09 mmol) at RT and stirred for 18 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo and neutralized with 1 N HCl, filtered the precipitated solid and dried in vacuo to afford the crude compound 13 (290 mg) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf. 0.5); 'H-NMR (DMSO-4 500 MHz): δ 13.15 (br s, 1H), 10.68 (s, 1H), 7.69-7.68 (m, 2H), 7.67-7.44 (m, 4H), 2.44 (s, 3H).

9-methyl-ll-oxo-10, 11-dihydrodibenzo {b, j\ [1, 4] thiazepine-8-carboxylic acid (20): A common intermediate

Synthesis of mixture of 4-fluoro-2-methyl-3-nitrobenzoic acid (8) and 4-fluoro-2-methyl-55 nitrobenzoic acid (9):

(minor)

To a stirring solution of 4-fluoro-2-methylbenzoic acid 7 (10 g, 64.51 mmol) in acetic acid (50 mL) under inert atmosphère was added fuming nitric acid (50 mL) at RT and heated to 80 °C for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL). The precipitate was filtered and dried in vacuo to afford mixture of compounds 8 and 9 (5.3 g, 40%) as white solid. TLC: 70% EtOAc/ hexanes(R/ 0.4); ‘H NMR (DMSO-rf₆,400 MHz): δ 13.30 (br s, 2H), 8.52 (d, J= 8.0 Hz, 2H), 8.10 (dd, J= 8.9 5.9, Hz, 1H), 7.60 (d, J = 12.5 Hz, 2H), 7.56 (t, J= 9.3 Hz, 1H), 2.63 (s, 6H), 2.48 (s, 3H); (^rH NMR showed mixture of compounds 8 & 9 in the ratio of 2: 1).

Synthesis of methyl 4-fluoro-2-methyl-3-nitrobenzoate (14) and methyl 4-fluoro-2-methyl5-nitrobenzoate (15):

15

To a stirring solution of compound 8 & 9 (10 g) in MeOH (100 mL) under argon atmosphère was conc. sulfuric acid (20 mL) at 0 °C and heated to reflux for 48 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford mixture of compounds 14 & 15 (6 g) as colorless thick syrup. TLC: 30% EtOAc/ hexane (R/. 0.5); ’H NMR (DMSOî/₆,500 MHz): δ 8.51 (d, J =7.8 Hz, 1H), 8.09 (dd, J = 8.8, 5.6 Hz, 0.5H), 7.63 (d, J= 12.4 Hz, 1H), 7.58 (t, J= 9.1 Hz, 0.5H), 3.87 (s, 4.5H), 2.62 (s, 3H), 2.45 (s, 1.5H); (Ή NMR showed mixture of compounds 14: 15 in the ratio of 2: 1).

Synthesis of methyl 4-((2-(methoxycarbonyl) phenyl) thio)-2-methyl-3-nitrobenzoate (16)

-38 and methyl 4-((2-(methoxycarbonyl) phenyl) thio)-2-methyl-5-nitrobenzoate (17):

no₂ no₂

17

To a stirring solution of compounds 14 & 15 (11 g) in DMF (100 mL) under inert atmosphère were added methyl 2-mercaptobenzoate 1 (10.4 g, 61.97 mmol), césium carbonate (18.5 g, 56.81 mmol) at 0 °C; heated to 80 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (200 mL), brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford mixture of compounds 16&17(12g)as yellow solid. TLC: 20% EtOAc/ hexanes (Rf. 0.2); LC-MS: 12.57% + 81.14%; 370.8 (M⁺+l); (column; X-Select CSH C18, (50 x 3.0 mm, 3.5 pm); RT 2.77 min. 0.05% Aq. TFA: ACN; 0.8 mL/min); RT 4.05, 4.14 min.

Synthesis of methyl 5-amino-4-((2-(methoxycarbonyl) phenyl) thio)-2-methylbenzoate (18) and Synthesis of methyl 3-amino-4-((2-(methoxycarbonyl) phenyl) thio)-2-methylbenzoate (18A):

18A

To a stirring solution of compound 16&17(14g, crude) in MeOH (500 mL) under inert atmosphère was added Pd/C (1.4 g, 50% wet) at RT and stirred under hydrogen atmosphère in an autoclave (6 kg/ cm² pressure) for 18 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with MeOH (100 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was recrystallized with EtOH (20 mL) and further purified through silica gel column chromatography column chromatography using 10% EtOAc/ hexanes to afford compound 18 (8 g, 63%%) and 18A (3 g, 30) as sticky off-white solids. TLC: 30% EtOAc/ hexanes (Rf 0.4);

'il NMR (DMSO-î/₆,400 MHz) (18): δ 7.94 (d, J = 7.1 Hz, 1H), 7.40 (t, J= 7.3 Hz, 1H), 7.337.26 (m, 2H), 7.22 (dt, J= 7.6, 1.1 Hz, 1H), 6.67 (dd, J= 8.2, 0.8 Hz, 1H), 5.41 (s, 2H), 3.89 (s, 3H), 3.83 (s, 3H), 2.33 (s, 3H).

*H NMR (DMSO-J₆, 400 MHz) (18A): δ 7.94 (dd, J = 7.8, 1.4 Hz, 1H), 7.42-7.38 (m, 1H), 7.32 (s, 1H), 7.26 (s, 1H), 7.22 (td, J=1.5, 1.0 Hz, 1H), 6.67 (dd, J= 8.1, 0.8 Hz, 1H), 5.41 (s, 2H), 3.88 (s, 2H), 3.82 (s, 3H), 2.33 (s, 3H).

Synthesis of 3-amino-4-((2-carboxyphenyI) thio)-2-methylbenzoic acid (19):

nh₂

To a stirring solution of compound 18A (2 g, 6.04 mmol) in THF: H₂O (4: 1, 50 mL) was added lithium hydroxide monohydrate (2.5 g, 10.0 mmol) at 0 °C; warmed to RT and stirred for 48 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (10 mL) and washed with diethyl ether (2 x 50 mL). The pH of the aqueous layer was acidified with 4 N HCl to ~1. The precipitated solid was filtered and dried in vacuo to afford compound 19 (1.2 g, 66%) as white solid. TLC: 2v60% MeOH/ CH₂C1₂ (Rf 0.2); 'H NMR (DMSO-rf₆,400 MHz): δ 13.01 (br s, 2H), 7.94 (d, J = 7.4 Hz, 1H), 7.36 (t, J= 7.8 Hz, 1H), 7.28 (d, J= 8.0 Hz, 1H), 7.20 (dt, J = 7.4, 6.3 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 7.4 Hz, 1H), 5.25 (br s, 2H), 2.27 (s, 3H).

Synthesis of 9-methyl-ll-oxo-10, 11-dihydrodibenzo [b, /] [1, 4] thiazepine-8-carboxylic acid (20):

To a stirring solution of compound 19 (2.6 g, 4.30 mmol) in THF (30 mL) under argon atmosphère was added CDI (3.5 g, 21.50 mmol) at RT; heated to 80 °C and stirred for 16 h.

The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (20 mL) and pH was adjusted with 4 N

HCl to ~2. The obtained solid was filtered, washed with diethyl ether and dried in vacuo to obtain compound 20(1.6 g, 67%) as an off white solid. TLC: 15% MeOH/ CH2CI2 (Rf. 0.2); *H NMR (DMSO-rf₆,400 MHz): δ 13.20 (br s, 1H), 10.23 (s, 1H), 7.74-7.60 (m, 1H), 7.56-7.51 (m, 2H), 7.50-7.42 (m, 3H), 2.47 (s, 3H).

Synthesis of 6-bromo-9-methyl-ll-oxo-10, 11-dihydrodibenzo [b, /] [1, 4] thiazepine-8carboxylic acid (32): A common intermediate

Synthesis of 5-bromo-4-fluoro-2-methylbenzoic acid (22) & 3-bromo-4-fluoro-215 methylbenzoic acid (23):

To a stirring solution of 4-fluoro-2-methylbenzoic acid 7 (10 g, 64.93 mmol) in H2SO4 (200 mL) at 0 °C under argon atmosphère was added A-bromosuccinimide (10.40 g, 58.44 mmol) portion wise for 15 min warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water, the precipitated solid was filtered and dried in vacuo to to afford mixture of compound 22 and 23 in the ratio of 2.5: 1 (14 g) as an off-white solid. TLC: 30% EtOAc/ hexanes (Λ/ 0.3); ¹HNMR (DMSO-4 400 MHz): δ 8.06 (d, J= 7.4 Hz, 1H), 7.82 (dd, J= 8.7, 5.9 Hz, 0.4 H), 7.37 (d, J = 9.9 Hz, 1H), 7.30 (t, J= 8.4 Hz, 0.4H), 2.62 (s, 1.2H), 2.50 (s, 3H);

Synthesis of 5-bromo-4-fluoro-2-methyl-3-nitrobenzoic acid & 3-bromo-4-fluoro-2methyl-5-nitrobenzoic acid (24&25):

25

To a stirring solution of compound 22 & 23 (14 g, 60.34 mmol) in sulphuric acid (70 mL) under inert atmosphère at 0 °C was added fuming nitric acid (70 mL) dropwise for 30 min at 0 °C warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (100 mL). The precipitated solid was fdtered, washed with water (100 mL) and dried in vacuo to afford mixture of compound 24 & 25 in the ratio of 2: 1 (10 g) as pale yellow solid. TLC: 30% EtOAc/ hexanes (R/. 0.2). *H NMR (DMSO-4 400 MHz): δ 13.86 (br s, 3H), 8.47 (d, J= 7.8 Hz, 1H), 8.30 (d, J= 6.9 Hz, 2H), 2.72 (s, 3H), 2.44 (s, 8H);

Synthesis of methyl 5-bromo-4-fluoro-2-methyl-3-nitrobenzoate (26) & methyl 3-bromo4-fluoro-2-methyl-5-nitrobenzoate (26&27):

To a stirring solution of compound 24 & 25 (10 g, 35.9 mmol) in MeOH (200 mL) under inert atmosphère was added concentrated sulfuric acid (10 mL) dropwise for 15 min at 0 °C; heated to reflux and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with ice-cold water (100 mL) and extracted with EtOAc (2 x 150 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford mixture of compound 26 & 27 in 2: 1 ratio (8 g) as an off-white solid. TLC: 10% EtOAc/ hexanes (R/. 0.5); ’H-NMR (DMSO-îZ₆, 400 MHz): δ 8.48 (d, J= 7.7 Hz, 0.4H), 8.33 (d, J= 7.0 Hz, 1H), 3.90 (s, 1.2H), 3.88 (s, 3H), 2.69 (s, 1.2H), 2.42 (s, 3H);

Synthesis of methyl 5-bromo-4-((2-(methoxycarbonyl) phenyl) thio)-2-methyl-3nitrobenzoate (28) & methyl 3-bromo-4-((2-(methoxycarbonyl) phenyl) thio)-2-methyl-5nitrobenzoate (29):

CO₂Me Br CO₂Me NO₂

29

To a stirring solution of compound 26 & 27 (8 g, 27.49 mmol) in DMF (50 mL) under argon atmosphère were added methyl 2-mercaptobenzoatel (5.5 g, 32.98 mmol), césium carbonate (9.8 g, 30.24 mmol) at RT; heated to 80 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (150 mL). The precipitated solid was filtered, washed with water (100 mL) and dried in vacuo to obtain the crude which was triturated with EtOH (10 mL) & diethylether (25 mL) filtered and dried in vacuo to afford mixture of compound 28 and 29 (6 g) as pale yellow solid. TLC: 20% EtOAc/ hexanes (Rf. 0.3); *H NMR (DMSO4, 400 MHz): δ 8.37 (s, 1H), 8.02 (dd, J= 7.8, 1.4 Hz, 1H), 7.54-7.45 (m, 1H), 7.38-7.32 (m, 1H), 6.62 (d, 7= 7.8 Hz, 1H), 3.91 (d,7 = 2.8 Hz, 6H), 2.38 (s, 3H); LC-MS no ionization.

-43 Synthesis of methyl 3-amino-5-bromo-4-((2-(methoxycarbonyl)phenyI)thio)-2methylbenzoate (30):

CO₂Me

ΟΟ₂Μβ Br

To a stirring solution of compound 28 & 29 (5 g, 11.39 mmol) in acetic acid (100 mL) was added iron powder (6.37 g, 113.89 mmol) at RT; heated to reflux and stirred for 16 h. The reaction was monitored by TLC; after completion, the reaction mixture was diluted with EtOAc (200 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was triturated with EtOH (25 mL) and dried in vacuo to afford compound 30 (2.6 g, 55%) as pale yellow solid. TLC: 20% EtOAc/ hexanes (R/. 0.4); 'η-NMR (DMSO-4 400 MHz): δ 7.99 (dd, J= 7.8, 1.4 Hz, 1H), 7.45-7.40 (m, 1H), 7.287.23 (m, 2H), 6.56 (dd, J= 8.2, 0.8 Hz, 1H), 5.77 (s, 2H), 3.91 (s, 3H), 3.84 (s, 3H), 2.20 (s, 3H); LC-MS: 97.59%; 412.1 (M + 2)⁺; (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.84 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 3-amino-5-bromo-4-((2-carboxyphenyl) thio)-2-methylbenzoic acid (31):

CO₂H Br

To a stirring solution of compound 30 (2 g, 4.89 mmol) in THF: H2O (4: 1, 25 mL) was added lithium hydroxide monohydrate (2.1 g, 50.00 mmol) portion wise for 10 min at 0 °C; warmed to RT and stirred for 48 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo and the aqueous layer was washed with diethylether (2x5 mL) The pH of the aqueous layer was acidified with 2 N HCl to ~1. The precipitated solid was filtered and further dried by zoetrope using toluene (10 mL) to afford compound 31 (1.6 g 86%) as an off-white solid. TLC: 20% EtOAc/ hexane (Rf. 0.2); *H-NMR (DMSO-4 500 MHz): δ 13.25 (br s, 2H), 7.98 (d, J= 7.5 Hz, 1H), 7.38 (t, J= 7.4 Hz, 1H),

7.27 -7.19 (m, 2H), 6.54 (d, J= 8.1 Hz, 1H), 5.67 (br s, 2H), 2.23 (s, 3H); LC-MS: 98.30%;

383.9 (M + 2)⁺; (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.08 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 6-bromo-9-methyl-ll-oxo-10, 11-dihydrodibenzo [b, /] [1, 4] thiazepine-8carboxylic acid (32):

To a stirring solution of compound 31 (2 g, 5.25 mmol) in THF (100 mL) under inert atmosphère was added CDI (4.4 g, 26.25 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold-water (50 mL) and washed with EtOAc (2 x 75 mL). The pH of the residue was adjusted to -2 using 1 N HCl. The precipitated solid was filtered, washed with water (50 mL) and further dried by azeotropic distillation using toluene to afford compound 32 (1.2 g, 63%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (R/. 0.4); 'H NMR (DMSO-d₆,400 MHz): δ 13.44 (br s, 1H), 10.36 (s, 1H), 7.78 (s, 1H), 7.70-7.64 (m, 1H), 7.56-7.51 (m, 1H), 7.51-7.44 (m, 2H), 2.40 (s, 3H); LC-MS: 97.42%; 363.9 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.23 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 9-methyl-ll-oxo-10, 11-dihydrodibenzo [b, f\ [1, 4] thiazepine-8-carboxylic acid (20): (Alternate Approach)

To a stirring solution of 6-bromo-9-methyl-l 1-oxo-10,11-dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxylic acid 32 (1 g, 2.75 mmol) in MeOH (20 mL) under inert atmosphère was added 10% Pd/ C (1 g, 50% wet) at RT and stirred under hydrogen atmosphère at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and eluted with 50%MeOH/ CH2CI2 (2 x 50 mL). The fdtrate was concentrated in vacuo to obtain the crude. The crude was diluted with water (20 mL) and the obtained solid was filtered dried in vacuo to afford compound 20 (300 mg, 38%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (À/ 0.4); *H NMR (DMSO-4 400 MHz): δ 13.15 (br s, 1H), 10.23 (s, 1H), 7.69-7.65 (m, 1H), 7.55-7.51 (m, 2H), 7.50-7.42 (m,

3H), 3.31 (s, 3H); LC-MS: 90.04%; 285.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.01 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 2-chIoro-ll-oxo-10, 11-dihydrodibenzo {b, /] [1, 4] thiazepine-8-carboxylic acid (40): A common intermediate

Synthesis of 5-chloro-2-((4-methoxybenzyl) thio) benzonitrile (35):

To a stirring solution of 5-chloro-2-fluorobenzonitrile 33 6.41 mmol) in DMF (10 mL) under inert atmosphère was added césium carbonate (2.30 g, 7.05 mmol) at RT; heated to 40 °C and to this was added (4-methoxyphenyl) methanethiol 34 (1.08 g, 7.05 mmol); heated to 60 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3-5% EtOAc/ hexanes to afford compound 35 (1 g, 54%) as white solid. TLC: 10% EtOAc/ hexanes (Rf 0.6); ‘H-NMR (CDC1₃, 500 MHz): δ 7.57 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.28-7.27 (m, 1H), 7.20 (d, J= 9.0 Hz, 2H), 6.81 (d, J= 9.0 Hz, 2H), 4.15 (s, 2H), 3.78 (s, 3H).

Synthesis of 5-chloro-2-mercaptobenzonitrile (36):

1x

A stirred solution of compound 35 (1 g, 3.47 mmol) in trifluoro acetic acid (10 mL) under inert atmosphère was stirred at 70 °C for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude compound 36 (590 mg) which was carried to the next step without further purification. TLC: 30% EtOAc/ hexanes (Rf. 0.2); ’H-NMR (CDC1₃, 500 MHz): δ 7.57 (s, 1H), 7.41 (d, J = 9.0 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 4.08 (s, 1H).

Synthesis of methyl 4-((4-chloro-2-cyanophenyl) thio)-3-nitrobenzoate (37):

To a stirring solution of compound 36 (620 mg, 3.11 mmol) in DMF (10 mL) under inert atmosphère was added césium carbonate (1.1 g, 3.42 mmol) at RT; heated to 40 °C and stirred for 10 min. To this was added methyl 4-fluoro-3-nitrobenzoate 2 (582 mg, 3.42 mmol) at 60 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 25% EtOAc/ hexanes to afford compound 37 (600 mg, 55%) as pale yellow solid. TLC: 30% EtOAc/hexanes (Rf. 0.4); ‘H-NMR (DMSO-</₆, 400 MHz): δ 8.66 (s, 1H), 8.33 (s, 1H), 8.058.03 (m, 1H), 7.98-7.92 (m, 2H), 7.02 (d, J= 8.4 Hz, 1H), 3.86 (s, 3H).

Synthesis of methyl 3-amino-4-((4-chloro-2-cyanophenyl) thio) benzoate (38):

To a stirring solution of compound 37 (450 mg, 1.29 mmol) in acetic acid (15 mL) under inert atmosphère was added iron powder (724 mg, 12.9 mmol) at RT; heated to 90 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was basified with saturated NaHCCb solution (15 mL) and extracted with CH2CI2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was triturated with 3% EtOAc/ hexanes (2x5 mL) to afford compound 38 (290 mg, 70%) as pale yellow solid. TLC: 20% MeOH/ CH2CI2 (Rf. 0.7); 'H-NMR (DMSO-rf₆, 400 MHz): δ 8.05 (s, 1H), 7.63-7.60 (m, 1H), 7.48 (s, 1H), 7.43 (d, J= 8.0 Hz, 1H), 7.14 (d, J= 8.8 Hz, 1H), 6.75 (d, J= 8.8 Hz, 1H), 5.88 (s, 2H), 3.84 (s, 3H).

Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-5-chlorobenzoic acid (39):

-48 ci

CO₂H

S co₂h 39

To a stirring solution of compound 38 (450 mg, 1.41 mmol) in MeOH (10 mL) was added potassium hydroxide (792 mg, 14.1 mmol) in water (3 mL) at 0 °C; heated to 90 °C and stirred for 9 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was acidified with 1 N HCl to pH~4.0. The obtained solid was filtered, washed with ether (2x5 mL) and dried in vacuo to afford compound 39 (350 mg, 76%) as an off-white solid. TLC: 20% MeOH/ CH₂C1₂ (Rf. 0.3); ’H-NMR (DMSO-î/₆, 400 MHz): δ 12.92 (br s, 2H), 7.89 (s, 1H), 7.44-7.38 (m, 3H), 7.14 (d, J= 8.8 Hz, 1H), 6.60 (d, J= 8.8 Hz, 1H), 5.64 (br s, 2H).

Synthesis of 2-chIoro-ll-oxo-10, 11-dihydrodibenzo [b, f\ [1, 4] thiazepine-8-carboxylic acid (40):

To a stirring solution of compound 39 (30 mg, 0.09 mmol) in THF (2 mL) under inert atmosphère was added CDI (45 mg, 0.27 mmol) at RT and stirred for 7 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was acidified with 2 N HCl to pH~4.0. The obtained solid was filtered, washed with ether (2x3 mL) and dried in vacuo to afford compound 40 (15 mg, 53%) as an off-white solid. TLC: 15% MeOH/ CH₂C1₂ (Rf. 0.5); 'H-NMR (DMSO-4 400 MHz): δ 13.05 (br s, 1H), 10.98 (s, 1H), 7.80 (s, 1H), 7.72-7.70 (m, 3H), 7.64 (s, 2H).

Synthesis of 3-chloro-ll-oxo-10, 11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxylic acid (47): A common intermediate

PA513177/OA/5598087.1

Synthesis of 4-chloro-2-((4-methoxybenzyl) thio) benzonitrile (42):

^^cn cr s

To a stirring solution of 4-chloro-2-fluorobenzonitrile 41 (1 g, 6.41 mmol) in DMF (25 mL) under inert atmosphère was added césium carbonate (2.30 g, 7.05 mmol) at RT; heated to 40 °C and to this was added (4-methoxyphenyl) methanethiol 34 (1.08 g, 7.05 mmol); heated to 60 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 4% EtOAc/ hexanes to afford compound 42 (900 mg, 48%) as white solid. TLC: 10% EtOAc/ hexanes (R/. 0.6); 'ïï-NMR (CDCI₃, 400 MHz): δ 7.51 (d, J = 8.4 Hz, 1H), 7.33 (s, 1H), 7.237.20 (m, 3H), 6.84 (d, J= 8.4 Hz, 2H), 4.19 (s, 2H), 3.79 (s, 3H).

Synthesis of 4-chloro-2-mercaptobenzonitrile (43):

-50A stirred solution of compound 42 (900 mg, 3.11 mmol) in trifluoro acetic acid (10 mL) under inert atmosphère at RT was heated to 70 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude compound 43 (527 mg) as brown solid. The crude was carried to the next step without further purification. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.1); ’H-NMR (CDC1₃, 400 MHz): δ 7.52 (d, J = 8.4 Hz, 1H), 7.41 (s, 1H), 7.22-7.19 (m, 1H), 4.13 (s, 1H).

Synthesis of methyl 4-((5-chloro-2-cyanophenyI) thio)-3-nitrobenzoate (44):

no₂

To a stimng solution of compound 43 (550 mg, 2.76 mmol) in DMF (15 mL) under inert atmosphère was added césium carbonate (988 mg, 3.04 mmol) at RT; heated to 40 °C and stirred for 10 min. To this was added methyl 4-fluoro-3-nitrobenzoate 2 (515 mg, 3.04 mmol) at 60 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL). The obtained solid was filtered, washed with 15% EtOAc/ hexanes (2x5 mL) and dried in vacuo to afford compound 44 (700 mg, 73%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf 0.3); ‘H-NMR (DMSO-4 500 MHz): δ 8.69 (s, 1H), 8.18-8.15 (m, 2H), 8.10 (d, J= 8.5 Hz, 1H), 7.92 (d, J= 8.5 Hz, 1H), 7.10 (d,J= 9.0 Hz, 1H), 3.90 (s, 3H).

Synthesis of methyl 3-amino-4-((5-chloro-2-cyanophenyl) thio) benzoate (45):

i T i Y

NH₂

To a stirring solution of compound 44 (700 mg, 2.01 mmol) in acetic acid (15 mL) under inert atmosphère was added iron powder (1.12g, 20.11 mmol) at RT; heated to 90 °C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was basified with 10% NaHCCh solution (20 mL) and extracted with CH2CI2 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 45 (500 mg, 78%) as yellow solid. TLC: 30% EtOAc/ hexanes (Rf. 0.8); ’fl-NMR (DMSO-4 500 MHz): δ 7.92 (d, J= 7.5 Hz, 1H), 7.51-7.43 (m, 3H), 7.17 (d, J= 8.0 Hz, 1H), 6.66 (s, 1H), 5.96 (s, 2H), 3.86 (s, 3H).

Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-4-chlorobenzoic acid (46):

nh₂

To a stirring solution of compound 45 (500 mg, 1.57 mmol) in MeOH (6 mL) was added potassium hydroxide (1.32 mg, 23.5 mmol) in water (6 mL) at 0 °C; heated to 90 °C and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The aqueous layer was acidified with 1 N HCl to pH~6.0. The obtained solid was filtered, washed with ether (2x7 mL) and dried in vacuo to afford compound 46 (375 mg, 74%) as an off-white solid. TLC: 20% MeOH/ CH₂C1₂ (Rf. 0.2); *H-NMR (CDCI3, 400 MHz): δ 8.05 (d, J= 8.4 Hz, 1H), 7.55-7.47 (m, 3H), 7.17-7.14 (m, 1H), 6.67 (s, 1H).

Synthesis of 3-chloro-ll-oxo-10, 11-dihydrodibenzo {b, /] [1, 4] thiazepine-8-carboxylic acid (47):

-52To a stirring solution of compound 46 (375 mg, 1.16 mmol) in THF (10 mL) under inert atmosphère was added CDI (564 mg, 3.48 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (15 mL) and acidified with 6 N HCl to pH~l .0. The obtained solid was filtered, washed with ether (2x5 mL) and dried in vacuo to afford compound 47 (285 mg, 81%) as an off-white solid. TLC: 20% MeOH/ CH₂C1₂ (Rf. 0.4); ’H-NMR (DMSOd₆, 400 MHz): δ 14.56 (br s, 2H), 10.90 (s, 1H), 9.11 (s, 1H), 7.71-7.65 (m, 4H).

Synthesis of l-fluoro-ll-oxo-10, 11-dihydrodibenzo [b, f\ [1, 4] thiazepine-8-carboxylic

Synthesis of methyl 2-fluoro-6-((4-methoxybenzyl) thio) benzoate (49):

F

CO₂Me

SPMB

-53To a stirring solution of methyl 2, 6-difluorobenzoate 48 (10 g, 58.13 mmol) in DMF (100 mL) under inert atmosphère were added (4-methoxyphenyl) methanethiol 34 (8.96 g, 58.13 mmol), césium carbonate (20.8 g, 63.95 mmol) at 0 °C; warmed to 10 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2 x 800 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10-15% EtOAc/ hexanes to afford compound 49 (7.5 g, 42%) as white solid. TLC: 10% EtOAc/ hexanes/: 0.3); ^XH NMR (DMSO-4 400 MHz) δ 7.53-7.44 (m, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.6 Hz, 2H), 7.15 (t, J= 9.0 Hz, 1H), 6.86 (d, J= 8.7 Hz, 2H), 4.22 (s, 2H), 3.72 (s, 3H), 3.33 (s, 3H).

Synthesis of methyl 2-fluoro-6-mercaptobenzoate (50):

A stirred solution of compound 49 (7.5 g, 24.5 mmol) in trifluoro acetic acid (100 mL) at RT under inert atmosphère was heated to 60-65 °C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed and dried in vacuo to obtain compound 50 (4.6 g) as brown syrup. The crude was carried forward for next step without further purification. TLC: 10% EtOAc/ hexanes (R/. 0.7).

Synthesis of methyl 2-fluoro-6-((4-(methoxycarbonyl)-2-nitrophenyl) thio) benzoate (51):

no₂51

To a stirring solution of methyl 4-fluoro-3-nitrobenzoate 2 (4.5 g, 22.61 mmol) in DMF (100 mL) under inert atmosphère were added compound 50 (4.6 g, crude), césium carbonate (11g,

-5433.91 mmol) at RT; heated to 60-65 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (600 mL) and stirred for 1 h. The precipitated solid was filtered, titurated with 10%EtOAc/ hexanes(2 x 20 mL) and dried in vacuo to afford compound 51 (7 g, 85%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf. 0.3); *H NMR (DMSO-7₆, 400 MHz): δ 8.65 (s, 1H), 8.08 (dd, J= 8.6, 1.9 Hz, 1H), 7.79-7.72 (m, 1H), 7.67-7.61 (m, 2H), 7.01 (d, J= 8.6 Hz, 1H), 3.88 (s, 3H), 3.72 (s, 3H).

Synthesis of methyl 2-((2-amino-4-(methoxycarbonyl) phenyl) thio)-6-fluorobenzoate (52): F nh₂52

To a stirring solution of compound 51 (7.09 g, 19.17 mmol) in MeOH (200 mL) under inert atmosphère was added 10% Pd/ C (3.5 g) at RT and stirred under hydrogen at 80 psi for 16 h in an autoclave. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and washed with 40% MeOH/ CH2CI2 (3 x 500 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude compound was triturated with 20% EtOAc/ hexanes (200 mL) and dried in vacuo to afford compound 52 (5 g, 78%) as an off-white solid. TLC: 20% EtOAc/ hexanes (Rf. 0.4); 'H NMR (DMSO-î/₆, 400 MHz): δ 7.45-7.36 (m, 3H), 7.197.11 (m, 2H), 6.68 (d, J = 7.7 Hz, 1H), 5.71 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H).

Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-6-fluorobenzoic acid (53):

ôc V°^2H nh₂

To a stirring solution of compound 52 (5 g, 14.92 mmol) in THF: H2O (5: 1, 90 mL) was added lithium hydroxide monohydrate (3.13 g, 74.62 mmol) at RT and stirred for 16 h and heated to °C for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (200 mL) and acidified with 2 N HCl to pH~4. The precipitated solid was filtered and dried in vacuo to afford compound 53 (4 g, 87%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.1); ^XH NMR (DMSO-4 400 MHz): δ 12.89 (br s, 1H), 7.42-7.36 (m, 2H), 7.35-7.31 (m, 1H), 7.14 -7.08 (m, 2H), 6.63 (d, J= 8.0 Hz, 1H), 5.75 (br s, 2H).

Synthesis of l-fluoro-ll-oxo-10, 11-dihydrodibenzo [b, /] [1, 4] thiazepine-8-carboxylic acid (54):

To a stirring solution of compound 53 (4 g, 13.02 mmol) in THF (100 mL) under inert atmosphère was added CDI (10.56 g, 65.1 mmol) at RT and stirred for 26 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with ice cold water (80 mL) and acidified with 2 N HCl to pH~4. The precipitated solid was filtered and dried in vacuo to afford compound 54 (3.3 g, 88%) as an offwhite solid. TLC: 15% MeOH/ CH₂C1₂ (R/. 0.2); ^XH NMR (DMSO-J₆, 400 MHz): δ 13.33 (br s, 2H), 11.00 (s, 1H), 7.77 (s, 1H), 7.69-7.67 (m, 2H), 7.53-7.47 (m, 1H), 7.42-7.39 (m, 1H), 7.35-7.29 (m, 1H).

Synthesis of 2-fluoro-ll-oxo-10, 11-dihydrodibenzo [b, /] [1, 4] thiazepine-8-carboxylic acid (61): A common intermediate

Synthesis of methyl-5-fluoro-2-((4-methoxybenzyl) thio) benzoate (56):

FC02Me

S'

To a stirring solution of methyl 2, 5-difluorobenzoate 55 (1 g, 5.80 mmol) in DMF (20 mL) under argon atmosphère were added (4-methoxyphenyl) methanethiol 34 (985 mg, 6.39 mmol), césium carbonate (2.07 g, 6.39 mmol) at RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with CH2CI2 (2x30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-7% EtOAc/ hexanes to afford compound 56 (700 mg, 40%) as white solid. TLC: 10% EtOAc/ hexanes (Rf. 0.3); ‘H-NMR (CDC1₃, 400 MHz): δ 7.64-7.61 (m, 1H), 7.32-7.29 (m, 3H), 7.17-7.09 (m, 1H), 6.86-6.82 (m, 2H), 4.09 (s, 2H), 3.90 (s, 3H), 3.79 (s, 3H).

Synthesis of methyl 5-fhioro-2-mercaptobenzoate (57):

A stirred solution of compound 56 (700 mg, 2.28 mmol) in trifluoro acetic acid (7 mL) at RT under argon atmosphère was heated to 60-65 °C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed and dried in vacuo to obtain compound 57 (380 mg, 89%) as brown syrup. TLC: 10% EtOAc/ hexanes (Rf. 0.7); *HNMR (DMSO-4 400 MHz): δ 7.70-7.58 (m, 2H), 7.42-7.35 (m, 1H), 5.42 (s, 1H), 3.86 (s, 3H).

Synthesis of methyl 5-fluoro-2-((4-(methoxycarbonyl)-2-nitrophenyl) thio) benzoate (58):

To a stirring solution of methyl 4-fluoro-3-nitrobenzoate 2 (350 mg, 1.75 mmol) in DMF (10 mL) under argon atmosphère were added compound 57 (360 mg, 1.93 mmol), césium carbonate (1.14 g, 3.51 mmol) at RT; heated to 60-65 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with CH2CI2 (2 x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 7-10% EtOAc/ hexanes to afford compound 58 (500 mg, 78%) as yellow solid. TLC: 10% EtOAc/ hexanes (Rf 0.3); ’H-NMR (DMSO-îZ₆, 400 MHz): δ 8.64 (s, 1H), 8.04-8.02 (m, 1H), 7.83-7.79 (m, 2H), 7.64-7.59 (m, 1H), 7.01 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.71 (s, 3H).

Synthesis of methyl 2-((2-amino-4-(methoxycarbonyl) phenyl) thio)-5-fluorobenzoate (59):

To a stirring solution of compound 58 (500 mg, 1.36 mmol) in MeOH (10 mL) under argon atmosphère was added 10% Pd/ C (300 mg) at RT and stirred under hydrogen atmosphère (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and washed with 20% MeOH/ CH2CI2 (2x30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 8-10% EtOAc/ hexanes to afford compound 59 (300 mg, 66%) as pale yellow solid. TLC: 30% EtOAc/ hexanes (Rf. 0.5); *H-NMR (DMSO-î/₆, 400 MHz): δ 7.78 (d, J= 9.6 Hz, 1H), 7.45-7.41 (m, 2H), 7.35-7.30 (m, 1H), 7.14 (d, J= 9.6 Hz, 1H), 6.68-6.65 (m, 1H), 5.70 (s, 2H), 3.89 (s, 3H), 3.83 (s, 3H).

Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-5-fluorobenzoic acid (60):

To a stirring solution of compound 59 (300 mg, 0.89 mmol) in THF: H2O (5: 1,6 mL) under argon atmosphère was added lithium hydroxide monohydrate (188 mg, 4.47 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (15 mL) and acidified with 6 N HCl to pH~4. The precipitated solid was filtered and dried in vacuo to afford compound 60 (180 mg, 66%) as white solid. TLC: 50% EtOAc/ hexanes (R/. 0.2); ’H-NMR (DMSO-4 400 MHz): δ 12.99-12.96 (m, 2H), 7.69 (d, J= 6.8 Hz, 1H), 7.40 (t, J= 7.2 Hz, 2H), 7.29 (t, J= 7.2 Hz, 1H), 7.13 (d, J= 7.2 Hz, 1H), 6.64-6.61 (m, 1H), 5.64-5.61 (m, 2H).

-59Synthesis of 2-fluoro-ll-oxo-10, 11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxylic acid (61): A common intermediate

To a stirring solution of compound 60 (180 mg, 0.58 mmol) in THF (10 mL) under argon atmosphère was added CDI (284 mg, 1.75 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with ice cold water (10 mL) and acidified with 6 N HCl to pH~4. The precipitated solid was filtered and dried in vacuo to afford compound 61 (80 mg, 47%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.2); 'll-NMR (DMSO-4 400 MHz): δ 13.30 (br s, 1H), 10.93 (s, 1H), 7.70 (s, 1H), 7.67 (d, J= 7.6 Hz, 2H), 7.59 (t, J= 7.6 Hz, 1H), 7.48 (t, J= 7.6 Hz, 1H), 7.40-7.35 (m, 1H).

Synthesis of 3-fluoro-ll-oxo-10, 11-dihydrodibenzo [b, /] [1, 4] thiazepine-8-carboxylic acid (68): A common intermediate

Synthesis of methyl 4-fluoro-2-((4-methoxybenzyl) thio) benzoate (63):

SPMB

CO₂Me

To a stirring solution of methyl 2-bromo-4-fluorobenzoate 62 (2 g, 8.58 mmol) in 1,4-dioxane (50 mL) under inert atmosphère were added (4-methoxyphenyl) methanethiol 34 (1.58 g, 10.25 mmol), césium carbonate (4.18 g, 12.80 mmol) at RT and purged under argon atmosphère for 30 min. To this was added Pd(dppf)2C12 (306 mg, 0.42 mmol); heated to 120 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 250 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 7% EtOAc/ hexanes to afford compound 63 (1.6 g, 61%) as an off-white solid. TLC: 10% EtOAc/ hexanes (Rf. 0.4); ’H NMR (CDC1₃, 400 MHz): δ 8.01 (dd, J= 8.7, 6.2 Hz, 1H), 7.34 (d, J = 7.9 Hz, 2H), 7.04 (dd, J= 10.3, 2.4 Hz, 1H), 6.88-6.80 (m, 3H), 4.09 (s, 2H), 3.88 (s, 3H), 3.80 (s, 3H).

Synthesis of methyl 4-fluoro-2-mercaptobenzoate (64):

G O 2 Μ Θ F'^^SH

A stirred solution of compound 63 (2.2 g, 7.18 mmol) in trifluoro acetic acid (30 mL) at RT under inert atmosphère was heated to 90 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain compound 64 (1.33 g, crude) as brown syrup. The crude was carried forward for next step without further purification. TLC: 10% EtOAc/hexanes (Rf. 0.8).

Synthesis of methyl 4-fluoro-2-((4-(methoxycarbonyl)-2-nitrophenyl) thio) benzoate (65):

To a stirring solution of methyl 4-fluoro-3-nitrobenzoate 2 (1.29 g, 6.93 mmol) in DMF (50 mL) under inert atmosphère were added césium carbonate (2.93 g, 9.01 mmol) and compound 64 (1.2 g, 6.03 mmol) at RT; heated to 55-60 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL), the precipitated solid was filtered to obtain the crude. The crude was washed with pentane (2 x 20 mL) and dried in vacuo to afford compound 65 (1.5 g, 68%) as yellow solid. TLC: 10% EtOAc/ hexanes (Rf. 0.3); ‘H-NMR (DMSO-rf₆, 400 MHz): δ 8.63 (s, 1H), 8.13-8.04 (m, 2H), 7.53-7.46 (m, 2H), 7.24 (d, J= 8.4 Hz, 1H), 3.89 (s, 3H), 3.72 (s, 3H).

Synthesis of 2-((4-carboxy-2-nitrophenyl) thio)-4-fluorobenzoic acid (66): ^ÿ^^C°^2H/^/CO₂H χχ XJ no₂

To a stirring solution of compound 65 (1.5 g, 4.10 mmol) in THF: H₂O (4: 1, 20 mL) was added lithium hydroxide monohydrate (690 mg, 16.4 mmol) at RT, heated to 80 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 2 N HCl to ~6. The precipitated solid was filtered and dried in vacuo to afford compound 66 (1.2 g, 86%) as an offwhite solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.2); ’H-NMR (DMSO-rf₆, 400 MHz): δ 13.46 (br s, 2H), 8.58 (s, 1H), 8.08-8.01 (m, 2H), 7.45-7.40 (m, 1H), 7.38-7.35 (m, 1H), 7.29 (d, J = 8.4 Hz, 1H).

Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-4-fluorobenzoic acid (67):

-62ΛΖ νη₂67

Το a stirring solution of compound 66 (1.2 g, 3.56 mmol) in MeOH (50 mL) under inert atmosphère was added 10% Pd/ C (300 mg) at RT and stirred under hydrogen atmosphère (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with MeOH (20 mL). The filtrate was removed in vacuo to obtain the crude which as triturated with 10% EtOAc/ npentane (50 mL) to afford compound 67 (1 g, 91%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.3); ^XH-NMR (DMSO-4 400 MHz): δ 12.96 (br s, 2H), 8.06-8.02 (m, 1H), 7.46 (s, 1H), 7.40 (d, J= 8.0 Hz, 1H), 7.16 (d, J= 8.0 Hz, 1H), 7.07-7.02 (m, 1H), 6.24 (d, J= 8.0 Hz, 1H), 5.67 (brs, 2H).

Synthesis of 3-fluoro-ll-oxo-10, 11-dihydrodibenzo [b, /] [1, 4] thiazepine-8-carboxylic acid (68):

F

To a stirring solution of compound 67 (1 g, 3.25 mmol) in THF (30 mL) under inert atmosphère was added CDI (1.61 g, 9.77 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was acidified with 2 N HCl to pH~4. The obtained solid was filtered, washed with water (20 mL), ether (2x5 mL) and dried in vacuo to afford compound 68 (760 mg, 80%) as white solid. TLC: 10% MeOH/ CH2CI2 (Rf. 0.3); *H-NMR (DMSO-4 400 MHz): δ 13.24 (br s, 1H), 10.83 (s, 1H), 7.78-7.74 (m, 2H), 7.69-7.66 (m, 2H), 7.47-7.44 (m, 1H), 7.35-7.30 (m, 1H).

Synthesis of 4-fluoro-ll-oxo-10, 11-dihydrodibenzo [b, f\ [1, 4] thiazepine-8-carboxylic acid (76): A common intermediate

To a stimng solution of 2, 3-difluorobenzoic acid 69 (1 g, 6.28 mmol) in MeOH (10 mL) under inert atmosphère was added Conc. H2SO4 (5 mL) at 0 °C and heated to reflux for 36 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (25 mL) and pH adjusted to ~8 with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 70 (800 mg, 74%) as an off-white solid. TLC: 40% EtOAc/ hexanes (Rf 0.8); ’h NMR (DMSO-4 500 MHz) δ 7.80 - 7.65 (m, 2H), 7.41-7.23 (m, 1H), 3.88 (s, 3H).

Synthesis of methyl 3-fluoro-2-((4-methoxybenzyl) thio) benzoate (71):

- 64 •CO₂Me ’SPMB

To a stirring solution of compound 70 (800 mg, 4.65 mmol) in DMF (10 mL) under inert atmosphère were added (4-methoxyphenyl) methanethiol 34 (282 mg, 5.11 mmol), césium carbonate (1.66 g, 5.11 mmol) at RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted water (25 mL) and extracted with ether (2 x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 71 (750 mg, 53%) as an off white solid. TLC: 20% EtOAc/ hexanes (Rf 0.4); 'H NMR (DMSO-4 500 MHz): δ 7.497.36 (m, 3H), 7.10 (d, J= 8.9 Hz, 2H), 6.79 (d, J= 8.9 Hz, 2H), 4.06 (s, 2H), 3.81 (s, 3H), 3.70 (s, 3H);

Synthesis of methyl 3-fluoro-2-mercaptobenzoate (72):

•CO₂Me

A stirred solution of compound 71 (750 mg, 2.45 mmol) in trifluoro acetic acid (7 mL) at RT under inert atmosphère was heated to 70 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain compound 72 (1.1 g, crude) as colorless liquid. The crude was carried forward for next step. TLC: 30% EtOAc/ hexanes (Rf. 0.8).

Synthesis of methyl 3-fluoro-2-((4-(methoxycarbonyl)-2-nitrophenyl) thio) benzoate (73):

To a stirring solution of compound 72 (5.96 g, 3.20 mmol) in DMF (100 mL) under inert atmosphère were added methyl 4-fluoro-3-nitrobenzoate 2 (5.8 g, 2.91 mmol), césium carbonate (10.41 g, 3.20 mmol) at RT; heated to 80 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (25 mL). The obtained solid was filtered, washed with hexane (2x10 mL) and dried in vacuo to afford compound 73 (7.8 g, 73%) as an pale yellow solid. TLC: 30% EtOAc/ hexanes (Rf. 0.5); ^XH NMR (DMSO-4 500 MHz): δ 8.67 (s, 1H), 8.05 (dd, J= 8.7, 1.7 Hz, 1H), 7.94-7.75 (m, 2H), 7.73-7.67 (m, 1H), 7.00 (d, J= 8.4 Hz, 1H), 3.88 (s, 3H), 3.77-3.64 (m, 3H).

Synthesis of methyl 2-((2-amino-4-(methoxycarbonyl) phenyl) thio)-3-fluorobenzoate (74):

To a stirring solution of compound 73 (670 mg, 1.83 mmol) in MeOH (10 mL) under inert atmosphère was added 10% Pd/C (150 mg) at RT and stirred under hydrogen atmosphère (balloon pressure) for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford compound 74 (500 mg, 81%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf 0.4); *H NMR (DMSO-î/₆, 400 MHz): δ 7.58-7.50 (m, 2H), 7.48-7.41 (m, 1H), 7.33 (s, 1H), 7.04 (s, 2H), 5.59 (br s, 2H), 3.82 (s, 3H), 3.79 (s, 3H).

Synthesis of 2-((2-amino-4-carboxyphenyI) thio)-3-fluorobenzoic acid (75):

To a stirring solution of compound 74 (500 mg, 1.49 mmol) in THF: H₂O (4: 1, 20 mL) was added lithium hydroxide monohydrate (376 mg, 8.95 mmol) at RT; heated to 80 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (25 mL) and washed with diethyl ether (2 x 25 mL). The aqueous layer was acidified with 2 N HCl to pH~4 and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude which was washed with diethyl ether (2x5 mL) and dried in vacuo to afford compound 75 (300 mg, 65%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (R/. 0.2); ^XH NMR (DMSO-4 500 MHz): δ 12.68 (br s, 2H), 7.54-7.45 (m, 2H), 7.39-7.32 (m, 1H), 7.28 (s, 1H), 7.09-7.06 (m, 1H), 7.02-6.96 (m, 1H), 5.56 (br s, 2H);

Synthesis of 4-fluoro-ll-oxo-10, 11-dihydrodibenzo [b, /] [1, 4] thiazepine-8-carboxylic acid (76):

o

F

To a stirring solution of compound 75 (300 mg, 0.97 mmol) in THF (15 mL) under inert atmosphère was added CDI (474 mg, 2.92 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 4 N HCl to ~2. The obtained solid was filtered, washed with diethyl ether (2x5 mL) and dried in vacuo to afford compound 76 (150 mg, 53%) as an off-white solid. TLC: 15% MeOH/ CH₂C1₂ (Rf. 0.5); ^XH NMR (DMSO-rf₆,400 MHz): δ 13.38 (br s, 1H), 10.92 (s, 1H), 7.79 (s, 1H), 7.75-7.66 (m, 2H), 7.55-7.46 (m, 3H).

Synthesis of 7-fluoro-ll-oxo-10, 11-dihydrodibenzo [b, /] [1, 4] thiazepine-8-carboxylic

Synthesis of methyl 2-fIuoro-4-((2-(methoxycarbonyl) phenyl) thio)-5-nitrobenzoate (78):

o

COOMe

To a stirring solution of methyl 2, 4-difluoro-5-nitrobenzoate 77 (9.0 g, 41.45 mmol) in DMF (100 mL) under inert atmosphère were added methyl 2-mercaptobenzoate 1 (6.97 g, 41.45 mmol), césium carbonate (14.82 g, 45.60 mmol) at 0 °C; warmed to 10 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (800 mL) and extracted with EtOAc (2 x 500 mL). The combined organic extracts were dried under sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 78 (11 g, 73%) as an off-white solid. TLC: 10% EtOAc/ hexanes (Rf 0.4); ‘H NMR (DMSO-rf₆,400 MHz): δ 8.69 (d, J= 6.8 Hz, 1H), 8.04-7.92 (m, 1H), 7.81-7.69 (m, 3H), 6.60 (d, J= 11.5 Hz, 1H), 3.88 (s, 3H), 3.73 (s, 3H).

Synthesis of methyl 5-amino-2-fluoro-4-((2-(methoxycarbonyl) phenyl) thio) benzoate (79):

PA513177/OA/5598087.1

To a stirring solution of compound 78 (11 g, 30.13 mmol) in MeOH (400 mL) under inert atmosphère was added 10% Pd/ C (5 g) at RT and stirred under hydrogen atmosphère (balloon pressure) for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with 30% MeOH/ CH2CI2 (3 x 60 mL). The filtrate was removed in vacuo to afford compound 79 (6.5 g, 64%) as an off-white solid. TLC: 20% EtOAc/ hexanes (A/ 0.4); *H NMR (DMSO-J₆,400 MHz): δ 8.01-7.88 (m, 1H), 7.45-7.40 (m, 1H), 7.34-7.24 (m, 3H), 6.72 (dd, J= 8.2, 0.8 Hz, 1H), 5.51 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H).

Synthesis of 5-amino-4-((2-carboxyphenyl) thio)-2-fluorobenzoic acid (80): 0

ÇXC COOH 80

To a stirring solution of compound 79 (6.5 g, 19.4 mmol) in THF: H2O (4: 1, 90 mL) was added lithium hydroxide monohydrate (4 g, 97.01 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 2 N HCl to ~4. The precipitated solid was filtered and dried in vacuo to afford compound 80 (4.5 g, 75.6%) as an off-white solid. TLC: 30% EtOAc/ hexane (Rf. 0.2); *H NMR (DMSO-î/₆,400 MHz): δ 13.19 (br s, 2H), 7.96 (dd, J = Ί.Ί, 1.5 Hz, 1H), 7.39 (t, J= 7.3 Hz, 1H), 7.30 (d, J= 6.6 Hz, 1H), 7.27-7.20 (m, 2H), 6.68 (dd, J= 8.2, 0.7 Hz, 1H), 5.42 (br s, 2H).

Synthesis of 7-fluoro-ll-oxo-10, 11-dihydrodibenzo [b, f\ [1, 4] thiazepine-8-carboxylic acid (81):

To a stimng solution of compound 80 (4.5 g, 14.65 mmol) in THF (100 mL) under inert atmosphère was added CDI (11.88 g, 73.28 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with 2 N HCl to pH~4; the precipitated solid was filtered, dried in vacuo to afford compound 81 (3.5 g, 83%) as an off-white solid. TLC: 15% MeOH/ CH₂C1₂ (Rf 0.2); *H NMR (DMSO-^,400 MHz): δ 13.61 (br s, 1H), 10.75 (s, 1H), 7.74-7.65 (m, 2H), 7.59-7.45 (m, 4H).

Synthesis of 7, 9-difhioro-ll-oxo-10, 11-dihydrodibenzo [b, f\ [1, 4] thiazepine-8-

Synthesis of 2, 4, 6-trifluoro-3-nitrobenzoic acid (83):

Το 2, 4, 6-trifluorobenzoic acid 82 (15 g, 85.22 mmol) at 0 °C, fiiming nitric acid (20 mL) was added dropwise for 10 min; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (500 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 83 (20 g) as pale yellow liquid. TLC: 5% MeOH/ CH₂C1₂+ 0.05 mL CH₃COOH (R/. 0.2); ’H NMR (DMSO-î/₆, 400 MHz): δ 14.12 (br s, 1H), 7.83 (td, J= 10.5, 2.1 Hz, 1H).

Synthesis of methyl 2, 4, 6-trifluoro-3-nitrobenzoate (84): F O

To a stirring solution of compound 83 (20 g) in MeOH (200 mL) under argon atmosphère was added concentrated sulfuric acid (20 mL) dropwise for 20 min at 0 °C and heated to reflux for 48 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (500 mL) and extracted with EtOAc (4 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-8% EtOAc/ hexanes to afford compound 84 (14 g, 70% for 2 steps) as pale yellow syrup. TLC: 20% EtOAc/ hexane (Rf. 0.8); 'H NMR (DMSO-</₆,400 MHz): δ 7.88 (td, J= 10.6, 2.2 Hz, 1H), 3.93 (s, 3H).

Synthesis of methyl 2, 6-difluoro-4-((2-(methoxycarbonyl) phenyl) thio)-3-nitrobenzoate (85):

-71 F O

OMe

COOMe

To a stirring solution of compounds 84 (14 g, 59.57 mmol) in DMF (300 mL) under inert atmosphère were added methyl 2-mercaptobenzoate 1 (11.1 g, 66.07 mmol), césium carbonate (38.77 g, 119.14 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (200 mL) and extracted with EtOAc (3 x 300 mL). The combined organic extracts were washed with water (200 mL), brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography to afford compound 85 (14.5 g, 64%) as yellow syrup. TLC: 10% EtOAc/ hexanes (Rf. 0.2); ^]H NMR (DMSO-î/₆, 500 MHz): δ 7.98 (dd, J= 7.7, 1.3 Hz, 1H), 7.66-7.61 (m, 1H), 7.59-7.55 (m, 1H), 7.46 (d,J=7.8Hz, 1 H), 7.19 (d, J = 9.3 Hz, 1 H), 3.93 (s, 3H), 3.81 (s, 3H).

Synthesis of methyl 3-amino-2, 6-difluoro-4-((2-(methoxycarbonyl) phenyl) thio) benzoate (86):

OMe

COOMe

To a stirring solution of compound 85 (18 g, 46.99) in MeOH (400 mL) under inert atmosphère was added Pd/C (9 g, 50% wet) at RT and stirred under hydrogen atmosphère in an autoclave (5 kg/cm² pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with MeOH (500 mL). The filtrate was concentrated in vacuo to afford compound 86 (15.1 g, 91%) as colorless semi solid. TLC: 20% EtOAc/ hexanes (Rf. 0.5); ’H NMR (DMSO-</₆,500 MHz): δ 8.00-7.93 (m, 1H), 7.48-7.42 (m, 1H), 7.31-7.21 (m, 2H), 6.76-6.64 (m, 1H), 5.54-5.47 (m, 2H), 3.91 (s, 3H), 3.89 (s, 3H).

-72 Synthesis of 3-amino-4-((2-carboxyphenyl) thio)-2, 6-difluorobenzoic acid (87):

F 0

COOH

To a stirring solution of compound 86 (15.1 g, 39.42 mmol) in THF: H2O (4: 1, 250 mL) was added lithium hydroxide monohydrate (8.3 g, 197.61 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, diluted with water (100 mL) and washed with EtOAc (2 x 100 mL). The pH of the aqueous layer was acidified with 4 N HCl to ~4. The precipitated solid was filtered, washed with water (100 mL), pentane (100 mL). The obtained solid was further dried using toluene (150 mL) to afford compound 87 (11 g, 79%) as an off-white solid. TLC: 20% EtOAc/ hexanes (Rf 0.2); ’H NMR (DMSO4,400 MHz): δ 13.24 (br s, 1H), 7.97 (dd, J = Ί.Ί, 1.4 Hz, 1H), 7.46-7.39 (m, 1H), 7.28-7.19 (m, 2H), 6.66 (d, J= 8.2 Hz, 1H), 5.39 (br s, 2H).

Synthesis of 7, 9-difluoro-ll-oxo-10, 11-dihydrodibenzo [b, /] [1, 4] thiazepine-8carboxylic acid (88):

F

To a stirring solution of compound 87 (10 g, 30.76 mmol) in THF (200 mL) under argon atmosphère was added CDI (14.9 g, 81.97 mmol) at RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (300 mL) and the pH was adjusted to ~3 with 2 N HCl. The obtained solid was filtered, washed with water (100 mL), pentane (50 mL) and diethyl ether (150 mL) and dried in vacuo to obtain compound 88 (2.83 g, 30%) as brick red solid. TLC: 15% MeOH/ CH2CI2 (Rf. 0.3); 'H NMR (DMSO-î/₆, 500 MHz): δ 14.19 (br s, 1H), 10.64 (s, 1H), 7.73-7.66 (m, 2H), 7.58- 7.48 (m, 3H).

Synthesis of ll-oxo-10,11-dihydrodibenzo {b,f\ [1, 4] thiazepine-8-carboxyIic acid 5-oxide

-73 (89): A common in ter médiate

To a stirring solution of 6 (2.5 g, 9.21 mmol) in CH2CI2 (50 mL) under inert atmosphère was added w-chloro perbenzoic acid (1.59 g, 9.21 mmol) at RT and stirred for 48 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was the volatiles were removed in vacuo to obtain the crude. The crude was triturated with 10% MeOH/ CH2CI2 (2x5 mL), isopropanol (10 mL) to afford compound 89 (2.3 g, 87%) as white solid. TLC: 10% MeOH/ CH2CI2 + 0.05 mL CH3COOH (Rf. 0.4); 'il NMR (DMSO-rf₆,500 MHz): δ 13.36 (br s, 1H), 11.08 (s, 1H), 7.96 (d, 7= 7.8 Hz, 1H), 7.92-7.87 (m, 1H), 7.85-7.66 (m, 3H), 7.63 (t, J= 7.8 Hz, 1H), 7.53 (t, J= 7.8 Hz, 1H);

Synthesis of ll-oxo-10, 11-dihydrodibenzo [6,/] [1, 4] thiazepine-8-carboxylic acid 5, 5-

(90):

To a stirring solution of 6 (500 mg, 1.84 mmol) in MeOH: CH2CI2 (1: 1, 20 mL) under argon atmosphère was added CH2N2 (insitu prepared using A-nitrosomethyl urea (0.95 g, 9.2 mmol) + KOH (0.51 g, 9.22 mmol) at 0 °C; warmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 90 (450 mg, 86%) as white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.5); ‘H-NMR (DMSO-î/₆, 500 MHz): δ 10.82 (s, 1H), 7.82 (s, 1H), 7.75-7.69 (m, 3H), 7.58-7.63 (m, 3H), 3.82 (s, 3H).

Synthesis of methyl ll-oxo-10, 11-dihydrodibenzo [b,/] [1, 4] thiazepine-8-carboxylate 5,

5-dioxide (91):

To a stirring solution of 90 (5 g, 17.54 mmol) in acetic acid (25 mL) was added 30% aqueous hydrogen peroxide (100 mL) at 0 °C; warmed to 50 °C and stirred for 72 h. The reaction was monitored by TLC; after completion of the reaction, the obtained solid was filtered, washed with water (100 mL), 10% EtOAc/ hexanes (100 mL) and dried in vacuo to afford compound 91 (3.5 g, 64%) as white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.3); *H NMR (DMSO-</₆, 500 MHz): δ 11.58 (s, 1H), 8.09 (d,J=8.4 Hz, 1H), 8.01-7.95 (m, 3H), 7.93-7.83 (m, 3H), 3.88 (s, 3 H);

Synthesis of ll-oxo-10, 11-dihydrodibenzo [b, /] [1, 4] thiazepine-8-carboxylic acid 5, 5dioxide (92):

-g-ouidazKiqj [t? ‘χ] [/ ‘7] ozuaqipojpÂqip-χχ ‘θχ-οχο-χχ-χΧρριιι-β |V|N^UI jo sisaqjuÂs si

anÂxoqjEDg-auidozBTqj |χ- ‘χ] [f ‘ç] ozuaqipojpÂqip-χχ ‘οχ-οχο-χχ-χΑχρπι-β jo sjsoqjuÂs •(H9 M 38'£-£0’8 ‘(HT ‘zH £’8 = C‘P) ΔΟ’8 ‘(Hl ^£s) gçqi ‘(m ‘s jq) 99ΎΙ g (^ZHIA[ 00^ ‘^-OSWa) HWN H( XlO :¼) ^rD^zH3 /H0⁹W %Ç =3Ί1 Ws sirm sr (%P8 8‘Z) Z6 punoduioo upqqo oj onov^ ui paup pire (qui çQ pqoop pidcudosi qpM paqsPM ‘poasqij snM pqos paureiqo aqi γ-Η^ °1 ÏDH KL ΐ P³UJPN^B P^UB Cl^m 0Z) qpM painpp sem snpissa oqq -οποόλ ui paAouioj sjsm sapjnpA sqj ‘υοτρυοι sqj jo uojpjduioo ς jayn ÎJH ^q ps-iopuom sbm ποτρυοι aqq 'q £ jqj paxips pire jqj 0} psuireM ίοθ o p intu oj joj asiM uopjod (fouiiu Ff££ ‘§ £’i) apipXqououi opixoïpAq uimqjq psppn sum (qui g 3 ‘j :3 :3) O^ZH ^:HO⁹W ^:dHLJ° S-irqxnu u ui (jouiui ^qq χ ‘§ çq) χβ punodiuoo jo uopnjos Sumps u oq

- 9L19643

-76To a stirring solution of 9-methyl-l l-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8carboxylic acid 20 (400 mg, 1.40 mmol) in MeOH (30 mL) under argon atmosphère was added CH₂N₂ [insitu prepared using A-nitrosomethyl urea (723 mg, 7.01 mmol) + 30% KOH solution (100 mL) in diethyl ether (200 mL)] at 0 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with diethyl ether (2 x 20 mL) and dried in vacuo to afford compound 93 (300 mg, 71%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.8); ‘H-NMR (DMSO-4 500 MHz): δ 10.40 (s, 1H), 7.83-7.79 (m, 1H), 7.72-7.65 (m, 2H), 7.64-7.56 (m, 3H), 3.95 (s, 3H), 2.58 (s, 3H); LC-MS: 95.08%; 299.8 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.38 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of methyl 9-methyl-l l-oxo-10, 11-dihydrodibenzo [b, f\ [1, 4] thiazepine-8carboxylate 5, 5-dioxide (94):

To a stirring solution of 93 (300 mg, 1.00 mmol) in acetic acid (4 mL) was added 30% hydrogen peroxide (8 mL) at 0 °C; warmed to 60 °C and stirred for 72 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with icecold water (50 mL), stirred for 15 min, the obtained solid was filtered, washed with water (100 mL) and dried in vacuo to afford compound 94 (210 mg, 63%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.3); ’h NMR (DMSO-î/₆, 500 MHz): δ 10.86 (s, 1H), 7.94-7.89 (m, 3H), 7.88-7.76 (m, 2H), 7.67 (d, J = 8.4 Hz, 1H), 3.83 (s, 3H), 2.43 (s, 3H). LC-MS: 94.24%; 331.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.22 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 9-methyl-l l-oxo-10, 11-dihydrodibenzo [b, /] [1, 4] thiazepine-8-carboxyIic acid 5, 5-dioxide (95):

To a stirring solution of compound 94 (230 mg, 0.69 mmol) in THF: MeOH: H₂O (2: 2: l, 20 mL) was added lithium hydroxide monohydrate (87 mg, 2.08 mmol) portion wise for 10 min at 0 °C; warmed to RT and stirred for 24 h. The reaction was monitored by TLC; after completion 5 of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (20 mL) and acidified with 3 N HCl to pH~3. The obtained solid was filtered, washed with water (20 mL) and dried in vacuo to obtain compound 95 (210 mg, 95%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.1); *H NMR (DMSO-4 400 MHz): δ 13.62 (br s, 1H), 10.85 (s, 1H), 7.97-7.84 (m, 4H), 7.82-7.79 (m, 1H), 7.65 (d, J= 8.4 Hz, 1H), 2.43 (s, 3H). LC-MS:

96.06%; 317.9 (M⁺+l); (column; X Select CSH C-18, (50 x 3.0 mm, 2.5 pm); RT 1.68 min. 2.5 mM Aq. NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH4OOCH, 0.8 mL/min).

Synthesis 9-methyl-ll-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxylic acid

5, 5-dioxide (104): A common intermediate

Synthesis of l-bromo-4-fluoro-2-methyl-3-nitrobenzene (97):

To l-fluoro-3-methyl-2-nitrobenzene 96 (5 g, 32.25 mmol) at 0 °C under argon atmosphère was added concentrated sulfuric acid: trifluoroacetic acid (1: 2, 45 mL). To this was added Nbromosuccinimide (8.61 g, 48.37 mmol) portion wise for 15 min; warmed to RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice-cold water (200 mL), the precipitated solid was filtered, washed with water (100 mL) and dried in vacuo to afford the crude. The crude was purified through silica gel flash column chromatography using 1-2% EtOAc/ hexanes to afford compound 97 (5.1 g, 68%). TLC: 5% EtOAc/ hexanes /: 0.8); TLC: 30% EtOAc/ hexanes (R/. 0.3). ¹H NMR (DMSOd₆,400 MHz): δ 7.96 (dd, J= 8.9, 5.2 Hz, 1H), 7.47 (t, J= 9.2 Hz, 1H), 22.35 (m, 3H);

- 79 Synthesis of methyl 2-((4-bromo-3-methyl-2-nitrophenyl) thio) benzoate (98):

0©2Μθ

To a stirring solution of compound 97 (5.1 g, 21.79 mmol) in DMF (80 mL) under argon atmosphère were added césium carbonate (10.62 g, 32.67 mmol), methyl 2-mercaptobenzoate 1 (4.03 g, 23.97 mmol) at RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (100 mL), the precipitated solid was filtered, washed with hexane (100 mL) and diethyl ether (100 mL) and dried in vacuo to afford compound 98 (7.0 g, 84%) as an off-white solid. TLC: 10% EtOAc/ hexanes (Rf 0.3); 'H NMR (DMSO-î/₆, 400 MHz): δ 8.09-7.85 (m, 2H), 7.55-7.46 (m, 2H), 7.34 (td, J= 7.6, 1.1 Hz, 1H), 6.81 (dd, J = 8.2, 0.8 Hz, 1H), 3.87 (s, 3H), 2.35 (s, 3H); LCMS: 98.98%; 383.2 (M+2)⁺; (Column; X-select CSH C-18 (50 x 3.0mm, 2.5 um); RT 4.99 min. 2.5 mM Aq. NH4OAC : ACN, 0.8 mL/min).

Synthesis of methyl 2-((2-amino-4-bromo-3-methylphenyl) thio) benzoate (99):

CO2M©

To a stirring solution of compound 98 (7 g, 18.32 mmol) in acetic acid (100 mL) was added iron powder (10.2 g, 182.7 mmol) at RT; heated to 80 °C and stirred for 16 h. The reaction was monitored by TLC and LC-MS; after completion of the reaction, the reaction mixture was filtered through celite, the filtrate was concentrated in vacuo. The residue was diluted with EtOAc (200 mL), washed with water (2 x 100 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to compound 99 (5.8 g, 90%) as an off-white solid. TLC: 10% EtOAc/hexanes {Rf 0.2); LC-MS: 98.31%; 353.9 (M⁺+2); (column; Ascentis

- 80 Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 3.06 min. 0.025% Aq. TFA + 5% ACN: ACN + 5%

0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 2-((2-amino-4-bromo-3-methylphenyl) thio) benzoic acid (100):

co₂h

100

To a stirring solution of compound 99 (4.8 g, 13.63 mmol) in THF: H₂O (3:1, 120 mL) was added lithium hydroxide monohydrate (1.72 g, 40.95 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (20 mL) and acidified with 2 N HCl to pH ~4-5. The obtained solid was filtered, washed with (50 mL) and dried in vacuo to obtain compound 100 (4 g, 87%) as an off-white solid. TLC: 20% EtOAc/ hexanes (Rf. 0.2); LC-MS: 98.82%; 339.9 (M⁺+2); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.67 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 8-bromo-9-methyldibenzo [b,f\ [1, 4] thiazepin-ll(101/)-one (101):

To a stirring solution of compound 100 (4.7 g, 13.90 mmol) in THF (100 mL) under inert atmosphère was added CDI (13.50 g, 83.32 mmol) at RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was adjusted to ~2 using 2 N HCl. The precipitated solid was filtered, washed with water (50 mL) and dried in vacuo to afford compound 101 (3 g, 68%) as white solid.

TLC: 30% EtOAc/ hexanes (Rf. 0.4) 'H NMR (DMSO-î/₆, 400 MHz): δ 10.36 (s, 1H), 7.687.63 (m, 1H), 7.54 - 7.49 (m, 1H), 7.49 - 7.36 (m, 4H), 2.41 (s, 3H);

- 81 Synthesis of methyl 9-methyl-ll-oxo-10, 11-dihydrodibenzo [b, f] [1, 4] thiazepine-8carboxylate (93):

To a stirring solution of compound 101 (1.5 g, 4.68 mmol) in MeOH (30 mL) in a Steel bomb under inert atmosphère were added dppf (259 mg, 0.46 mmol), sodium acetate (1.15 g, 14.02 mmol), Pd(OAc)₂ (105 mg, 0.46 mmol) at RT and heated to 100 °C under CO gas atmosphère (150 psi) and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column flash chromatography using 10-20% EtOAc/ hexanes to afford compound 93 (1.1 g, 79%). TLC: 20% EtOAc/ hexanes (Rf 0.2); LC-MS: 98.18%; 299.9 (M+l)⁺; (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.38 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of methyl 9-methyl-ll-oxo-10, 11-dihydrodibenzo [b, f\ [1, 4] thiazepine-8carboxylate 5, 5-dioxide (94):

To a compound 93 (1.1 g, 3.67 mmol) in 1, 2 dichloro ethane: CH3CN: H₂O (1: 1: 2, 40 mL) were added sodium metaperiodate (2.35 g, 11.03 mmol), ruthénium chloride (38 mg, 0.18 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion, the reaction mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (2 x 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 94 (1 g, 83%) as an white solid. TLC: 40% EtOAc/ hexanes (Rf

0.2); 'H NMR (DMSO-rf₆,400 MHz): δ 10.87 (s, 1H), 7.95-7.84 (m, 4H), 7.83 - 7.78 (m, 1H), 7.68 (d, J= 8.3 Hz, 1H), 3.85 (s, 3H), 2.45 (s, 3H); LC-MS: 98.10%; 332.0 (M+l)⁺; (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.16 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 9-methyl-ll-oxo-10, 11-dihydrodibenzo [b, /] [1, 4] thiazepine-8-carboxylic acid 5, 5-dioxide (95):

To a stirring solution of compound 94 (1.07 g, 3.23 mmol) in THF: H₂O (3: 1, 18 mL) was added lithium hydroxide monohydrate (407 mg, 9.69 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 2 N HCl to ~2. The precipitated solid was filtered, washed with water (50 mL), hexane (20 mL) and dried in vacuo to afford 95 (950 mg, 93%) as white solid. TLC: 5% MeOH/ CH₂C1₂ (Ry 0.1); 'H NMR (DMSO4,400 MHz): δ 3.63 (br s, 1H), 10.85 (s, 1H), 7.96-7.84 (m, 4H), 7.83 -7.78 (m, 1H), 7.67 (d, J= 8.1 Hz, 1H), 2.48 (s, 3H); LC-MS: 98.67%; 317.9 (M+l)⁺; (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.81 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 7-methyl-ll-oxo-10, 11-dihydrodibenzo {b, /] [1, 4] thiazepine-8-carboxylic acid 5, 5-dioxide (105): A common intermediate

Synthesis of methyl 4-((2-(methoxycarbonyl) phenyl) sulfonyl)-2-methyl-5-nitrobenzoate (102):

102

To a stirring solution of methyl 5-amino-4-((2-(methoxycarbonyl) phenyl) thio)-2methylbenzoate 16 & 17 (4 g, 12.08 mmol) in acetic acid (25 mL) was added 30% H2O2 (20 mL) at 0 °C; heated to 70 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and the pH was adjusted to ~7 using 10% Na2CO₃ solution (50 mL) and extracted with EtOAc (150 mL).

The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified by column chromatography using 30% EtOAc/ hexanes to afford compound 102 (1.2 g) as yellow syrup. TLC: 40% EtOAc/ hexanes {Rf 0.4); LC-MS: 34.05%; 392.1 (M-l)⁺; (column; X-select C18, (50 x 3.0 mm, 2.5 pm); RT 4.26 min. 2.5 mM Aq. NH4OAC: ACN: 0.8 mL/min).

Synthesis of methyl 5-amino-4-((2-(methoxycarbonyl) phenyl) sulfonyl)-2-methylbenzoate (103):

103

To a stimng solution of compound 102 (500 mg, 1.27 mmol) in MeOH (25 mL) under inert atmosphère was added 10% Pd/ C (200 mg, 50% wet) at RT under hydrogen atmosphère (balloon pressure) and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with MeOH (50 mL). The filtrate was removed in vacuo to obtain the crude compound 103 (300 mg, 60%, over 2 steps) as yellow syrup. TLC: 40% EtOAc/ hexanes (Rf 0.4); LC-MS: 98.20%; 364.1 (M⁺+l); (column; Ascentis Express Cl 8, (50 x 3.0 mm, 2.7 pm); RT 2.45 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). ’H NMR (DMSO-</₆,400 MHz): δ 8.11 (dd, J= 7.8,1.1 Hz, 1H), 7.84 - 7.70 (m, 2H), 7.65 (dd, J= 7.5, 1.3 Hz, 1H), 7.52 (s, 1H), 7.28 (s, 1H), 6.14 (s, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 2.35 (s, 3H);

Synthesis of 5-amino-4-((2-carboxyphenyl) sulfonyl)-2-methylbenzoic acid (104):

104

To a stimng solution of compound 103 (1.2 g, 3.26 mmol) in THF: H₂O (3: 1, 20 mL) was added lithium hydroxide monohydrate (692 mg, 16.48 mmol) at RT; heated to reflux and stirred for 32 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 2 N HCl to ~2. The precipitated solid was filtered and dried in vacuo to afford compound 104 (600 mg, 59%) as an off-white solid. The crude was carried for next step without further purification. TLC: 30% EtOAc/ hexanes (Rf 0.3); LC-MS: 81.82%; 335.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.78 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). ’H NMR (DMSO-î/₆, 400 MHz): δ 13.12 (br s, 1H), 8.05-7.97 (m, 1H),

- 85 7.74 (td, J = 7.5, 1.1 Hz, 1H), 7.66 (td,J=7.7, 1.4 Hz, 1H), 7.60 (dd, J =7.5, 1.1 Hz, 1H), 7.56 (s, 1H), 7.23 (s, 1H), 6.13 (br s, 2H), 2.33 (s, 3H);

Synthesis of 7-methyl-ll-oxo-10, 11-dihydrodibenzo [b, /] [1, 4] thiazepine-8-carboxylic 5 acid 5, 5-dioxide (105):

o o

105

To a stirring solution of compound 104 (650 mg, 1.94 mmol) in THF (15 mL) under inert atmosphère was added CDI (1.59 g, 9.70 mmol) at 0 °C; warmed to RT and stirred for 16 h.

The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was 10 acidified with 6 N HCl to pH ~2. The obtained solid was filtered and further dried and dried in vacuo to afford compound 105 (350 mg, 59%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf. 0.2); LC-MS: 71.53%; 317.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.45 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 7-ethyl-ll-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxylic acid 5, 5-dioxide (117): A common intermediate

C0₂Me

Br

To a stirring solution of 2-bromo-4-fluorobenzoic acid 106 (20 g, 91.32 mmol) in MeOH (200 5 mL) under inert atmosphère was added concentrated sulfuric acid (100 mL) dropwise for 20 min at 0 °C; heated to reflux and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with ice-cold water (100 mL) and extracted with EtOAc (300 mL). The organic extract was washed with saturated NaHCO3 solution (2 x 100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 62 (16.5 g, 78%) as pale yellow oil. TLC: 10% EtOAc/ hexanes (Rf. 0.8). 'H-NMR (DMSO-îZ₆, 500 MHz): δ 7.88 (dd, J= 8.8, 6.2 Hz, 1H), 7.75 (dd, J= 8.7, 2.6 Hz, 1H), 7.39 (td, J= 8.5, 2.6 Hz, 1H), 3.85 (s, 3H).

Synthesis of methyl 2-ethyl-4-fluorobenzoate (107): c 0 2 μ θ

107

To a stirring solution of zinc(II) bromide (19.3 g, 85.77 mmol) in THF (200 mL) under argon atmosphère was added ethyl magnésium bromide (28.6 mL, 85.83 mmol, 3 M solution in Et2O) dropwise for 10 min. The reaction mixture was cooled to -78 °C, added Pd(ddpf)C12 (3.13 g, 4.27 mmol) and compound 62 (10 g, 42.91 mmol), warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (2 x 150 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 2-4% EtOAc/ hexanes to afford compound 107 (6.5 g, 83%) as pale yellow liquid. TLC: 10% EtOAc/ hexanes (Rf 0.8). 'H-NMR (DMSO-î/î, 400 MHz): δ 7.86 (dd, J= 8.8, 6.1 Hz, 1H), 7.22 (dd, J= 10.2, 2.7 Hz, 1H), 7.14 (td, J= 8.5, 2.7 Hz, 1H), 3.82 (s, 3H), 2.92 (q, J= 7.4 Hz, 2H), 1.16 (t, J= 7.5 Hz, 3H).

Synthesis of methyl 2-ethyl-4-fluoro-5-nitrobenzoate (108):

108

To a stirring solution of compound 107 (6.5 g, 35.71 mmol) in concentrated sulphuric acid (100 mL) under inert atmosphère at 0 °C was added fuming nitric acid (1.5 mL, 35.70 mmol) dropwise for 5 min, warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (300 mL), extracted with EtOAc (2 x 200 mL), washed with saturated NaHCOs solution (2 x 50 mL) and brine (50 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified by combiflash chromatography using 5% EtOAc/ hexanes to afford compound 108 (1.8 g, 22%) as colorless liquid. TLC: 5% EtOAc/ hexanes (Rf 0.4). ^XH-NMR (DMSO-î/₆, 500 MHz): δ 8.52 (d, J= 8.1 Hz, 1H), 7.66 (d, J= 12.8 Hz, 1H), 3.89 (s, 3H), 3.01 (q, J= 7.5 Hz, 2H), 1.20 (t, J= 7.5 Hz, 3H).

Synthesis of methyl 2-ethyl-4-((2-(methoxycarbonyl) phenyl) thio)-5-nitrobenzoate (109):

CO₂Me

109

To a stirring solution of compound 108 (1.8 g, 7.92 mmol) in DMF (30 mL) under argon atmosphère were added methyl 2-hydroxybenzoate 1 (1.46 g, 8.72 mmol), césium carbonate (3.90 g, 11.90 mmol) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified by combiflash chromatography using 2-10% EtOAc/ hexanes to afford compound 109 (2.4 g, 81%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf 0.4). ‘H-NMR (DMSO-4 500 MHz): δ 8.59 (s, 1H), 7.97-7.92 (m, 1H), 7.75-7.65 (m, 3H), 6.84 (s, 1H), 3.87 (s, 3H), 3.70 (s, 3H), 2.79 (q, J= 7.5 Hz, 2H), 0.93 (t, J= 7.2 Hz, 3H).

Synthesis of methyl 5-amino-2-ethyl-4-((2-(methoxycarbonyl) phenyl) thio) benzoate (110):

CO₂Me

110

A stirring solution of compound 109 (2.4 g, 6.40 mmol) in MeOH (50 mL) was evacuated for 5 min and under inert atmosphère was added 10% Pd/C (1.2 g, 50% wet) at RT and stirred under hydrogen atmosphère (balloon pressure) at RT for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and washed with MeOH (100 mL). The crude was purified by combiflash chromatography using 5-20% EtOAc/ hexanes to afford compound 110 (1.4 g, 63%) as white solid. TLC: 10% EtOAc/ hexanes (Rf. 0.2); ’H NMR (DMSO-4 400 MHz): δ 7.95 (dd, J= 7.9, 1.4 Hz, 1H), 7.44-7.37 (m, 1H), 7.27-7.20 (m, 3H), 6.67 (dd, J = 8.2, 0.9 Hz, 1H), 5.42 (s, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 2.71 (q, J= 7.5 Hz, 2H), 1.08 (t, J= 7.4 Hz, 3H); LC-MS: 97.16%; 345.9 (M⁺+l);

(column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.88 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 5-amino-4-((2-carboxyphenyl) thio)-2-ethylbenzoic acid (111):

co₂h

111

To a stirring solution of compound 110 (1.4 g, 4.05 mmol) in THF: H₂O (3: 1, 40 mL) was added lithium hydroxide monohydrate (852 mg, 20.28 mmol) portion wise for 10 min at RT, heated to reflux and stirred for 24 h. The reaction was monitored by TLC and LC-MS; after completion of the reaction, the volatiles were removed in vacuo and the pH of the aqueous layer was acidified with 2 N HCl to ~3. The precipitated solid was filtered washed with water (50 mL), w-hexane (30 mL) dried in vacuo to afford compound 111 (1.0 g 78%) as an off-white solid. TLC: 20% EtOAc/ hexanes (Rf 0.1); ’H-NMR (DMSO-</₆, 400 MHz): δ 13.38-12.60 (m, 2H), 7.94 (dd,7=7.8, 1.4 Hz, 1H), 7.40-7.34 (m, 1H), 7.24 (d, 7= 11.2 Hz, 2H), 7.19 (td, 7 = 7.5, 1.1 Hz, 1H), 6.65 (dd, 7= 8.2, 0.8 Hz, 1H), 5.33 (br s, 2H), 2.74 (q, 7= 7.5 Hz, 2H), 1.09 (t, 7= 7.4 Hz, 3H); LC-MS: 99.36%; 317.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.09 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 7-ethyl-l l-oxo-10,11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxylic acid (112):

112

To a stirring solution of compound 111 (1 g, 3.15 mmol) in THF (20 mL) under inert atmosphère was added CDI (1.53 g, 9.46 mmol) at RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (50 mL), cooled to 0 °C and the pH was adjusted to ~2 using 2 N HCl. The precipitated solid was filtered, washed with water (50 mL), hexane (20 mL) and dried in vacuo to afford compound 112 (710 mg, 75%) as white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.3); ^XH NMR (DMSO4, 400 MHz): δ 13.12 (br s, 1H), 10.69 (s, 1H), 7.71-7.67 (m, 1H), 7.61 (s, 1H), 7.56-7.42 (m, 4H), 2.85 (q,7=7.4 Hz, 2H), 1.11 (t, 7= 7.5 Hz, 3H).

Synthesis of 7-ethyl-ll-oxo-10, 11-dihydrodibenzo {b,j\ [1, 4] thiazepine-8-carboxylic acid

5, 5-dioxide (113):

To a stirring solution of compound 112 (700 mg, 2.34 mmol) in 1, 2 dichloro ethane: CH3CN: H₂O (1: 1: 2, 40 mL) were added sodium metaperiodate (1.49 g, 6.99 mmol), ruthénium chloride (26.3 mg, 0.11 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC and LCMS; after completion the volatiles were removed in vacuo. The precipitated solid was filtered, washed with water (50 mL), hexane (20 mL) and diethylether (20 mL), dried in vacuo to afford compound 113 (650 mg, 84%) as pale brown solid. TLC: 10% MeOH/ CH2CI2 (Rf. 0.2); 'H-NMR (DMSO-4 400 MHz): δ 11.39 (s, 1H), 8.00-7.95 (m, 2H), 7.93-7.84 (m, 2H), 7.83 (s, 1H), 7.70 (s, 1H), 2.91 (q,7=7.4 Hz, 2H), 1.14 (t, 7= 7.5 Hz, 3H); LC-MS: 86.02%; 331.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.06 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 7-methoxy-ll-oxo-10, 11-dihydrodibenzo {b,f\ [1, 4] thiazepine-8-carboxylic acid 5, 5-dioxide (124): A common intermediate

PA'

Synthesis of methyl 4-fluoro-2-methoxy-5-nitrobenzoate (115):

O₂N^^^CO₂Me

115

To a stirring solution of methyl 4-fluoro-2-methoxybenzoate 114 (10 g, 27.17 mmol) in sulfùric 5 acid (14 mL) under inert atmosphère was added the mixture of nitric acid (0.90 mL, 21.73 mmol) and sulfuric acid (1 mL) at -5 °C and stirred for 5 min. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with CH2CI2 (2 x 30 mL). The combined quenched with ice-cold water (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with saturated NaHCO₃ solution (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 115 (5 g, 40%) as colorless syrup. TLC: 20% EtOAc/ hexanes (Rf 0.4); ‘H-NMR (CDC1₃, 400 MHz): δ 8.69 (d, J= 8.8 Hz, 1H), 6.83 (d, J = 12.8 Hz, 1H), 4.01 (s, 3H), 3.92 (s, 3H).

Synthesis of methyl 2-methoxy-4-((2-(methoxycarbonyl) phenyl) thio)-5-nitrobenzoate (116):

CO₂Me

116

CO₂Me

OMe

To a stirring solution of compound 115 (5 g, 21.8 mmol) in DMF (50 mL) under inert atmosphère were added methyl 2-mercaptobenzoate 1 (4 g, 24.01 mmol), césium carbonate (8.5 g, 26.16 mmol) at RT; heated to 80 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (250 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 25% EtOAc/ hexanes to afford compound 116 (6 g, 79%) as an off-white solid. TLC: 30% EtOAc/ hexanes (R/. 0.3); ’ll-NMR (CDC1₃, 400 MHz): δ 8.80 (s, 1H), 7.94-7.92 (m, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.61-7.59 (m, 2H), 6.30 (s, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.52 (s, 3H).

Synthesis of methyl 5-amino-2-methoxy-4-((2-(methoxycarbonyl) phenyl) thio) benzoate (117):

CO₂Me

117

To a stirring solution of compound 116 (6 g, 0.53 mmol) in MeOH (50 mL) under inert atmosphère was added 10% Pd/ C (600 mg) at RT and stirred under hydrogen atmosphère (balloon pressure) for 20 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 25% EtOAc/ hexanes to afford compound 117 (2 g, 36%) as sticky solid. TLC: 40% EtOAc/ hexanes (Rf. 0.5); *H NMR (CDCl₃,400 MHz): δ 8.04 (dd, J= 7.8, 1.4 Hz, 1H), 7.327.28 (m, 1H), 7.28-7.26 (m, 1H), 7.19-7.14 (m, 1H), 7.13 (s, 1H), 6.76 (dd, J= 8.2, 0.9 Hz, 1H), 4.06 (s, 2H), 3.97 (s, 3H), 3.91 (s, 3H), 3.81 (s, 3H); LC-MS: 95.75%; 347.9 (M⁺+l);

(column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.43 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 5-amino-4-((2-carboxyphenyl) thio)-2-methoxybenzoic acid (118): /ΤγΗ 2 N C O 2 H o xx

CO₂H

118

To a stirring solution of compound 117 (2 g, 5.76 mmol) in THF: H₂O (4: 1, 25 mL) was added lithium hydroxide monohydrate (1.69 g, 40.34 mmol) at RT; heated to 80 °C and stirred for 24 h. The reaction was monitored by TLC and LC-MS; after completion of the reaction, the volatiles were removed in vacuo. The pH of the aquesous layer was acidified with 2 N HCl to ~2. The precipitated solid was filtered, triturated with EtOAc (10 mL) and dried in vacuo to afford compound 118 (1.4 g 77%) as an off-white solid. TLC: 40% EtOAc/ hexanes (Rf 0.1); 'h NMR (DMSO-î/₆, 400 MHz): δ 13.19 (br s, 1H), 7.96 (dd,J=7.8, 1.5 Hz, 1H), 7.44-7.37 (m, 2H), 7.24 (td,J=7.5, 1.0 Hz, 1 H), 7.16 (s, 1H), 6.69 (dd, J= 0.8, 8.1 Hz, 1 H), 3.72 (s, 3H); LC-MS: 96.65%; 319.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.81 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 7-methoxy-ll-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxylic acid (119):

o

OMe

119

To a stirring solution of compound 118 (1.3 g, 4.07 mmol) in THF (25 mL) under inert atmosphère was added CDI (1.95 g, 12.22 mmol) at 0 °C; warmed to RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was adjusted to ~2 using 6 N HCl. The precipitated solid was filtered, washed with water (2 x 20 mL) dried in vacuo and triturated with 50%

-94EtOAc/ hexanes (5 mL) and dried in vacuo to afford compound 119 (1 g, 82%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Ry 0.4); ^XH NMR (DMSO-rf₆,500 MHz): δ 14.41 (br s, 1H), 10.55 (s, 1H), 7.71-7.67 (m, 1H), 7.56-7.44 (m, 4H), 7.28 (s, 1H), 3.81 (s, 3H);

Synthesis of 7-methoxy-ll-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxylic acid 5, 5-dioxide (120):

o

120

To a stirring solution of compound 119(1 g, 3.32 mmol) in 1, 2 dichloro ethane: CH3CN: H₂O (1: 1: 2, 40 mL) were added sodium metaperiodate (2.17 g, 9.96 mmol), ruthénium chloride (37.35 mg, 0.16 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion the volatiles were removed in vacuo to obtain the crude. The crude was triturated with EtOAc (10 mL) and dried in vacuo to afford compound 120 (700 mg, 64%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Ry 0.1); TLC eluted twice; H NMR (DMSO-ri₆, 500 MHz, DMSO-ri₆): δ 13.37 (br s, 1H), 11.25 (s, 1H), 8.01-7.95 (m, 2H), 7.90 (t, J= 7.5 Hz, 1H), 7.88-7.84 (m, 1H), 7.58 (s, 1H), 7.50 (s, 1H), 3.90 (s, 3H); LC-MS: 95.49%; 333.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.79 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 7-chloro-ll-oxo-10, 11-dihydrodibenzo [b, JJ [1, 4] thiazepine-8-carboxylic acid 5, 5-dioxide (130): A common intermediate

Synthesis of 2-chloro-4-((2-(methoxycarbonyl) phenyl) thio)-5-nitrobenzoic acid (122): ÇO₂N^^,CO₂H

002^6

122

To a stirring solution of 2-chloro-4-fluoro-5-nitrobenzoic acid 121 (5 g, 22.76 mmol) in DMF (100 mL) under inert atmosphère were added methyl 2-mercaptobenzoate 1 (4.2 g, 25.04 mmol), césium carbonate (3.1 g, 9.54 mmol) at RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with icecold water (100 mL) and washed with EtOAc (2 x 250 mL). The pH of the aqueous layer was adjusted to ~2 with 2 N HCl and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 1 -2 MeOH/ CH2CI2 to afford compound 122 (4 g, 48%) as yellow solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.5). *ΗNMR (DMSO/, 500 MHz): δ 13.97 (br s, 1H), 8.62 (s, 1H), 7.99-7.94 (m, 1H), 7.77-7.69 (m, 3H), 6.87 (s, 1H), 3.75 (s, 3H); LC-MS (Agilent lontrap): 77.39%; 366.1 (M-l)⁺; (column; X- select C-18 (50 x 3.0 mm, 2.5 um); RT 3.18 min. 2.5 mM Aq. NH4OAC: ACN; 0.8 mL/min).

PA513177/OA/5598087.1

- 96 Synthesis of 2-chloro-4-((2-(methoxycarbonyl) phenyl) sulfonyl)-5-nitrobenzoic acid (123):

ci

123

To a stirring solution of compound 122 (4 g, 10.89 mmol) in 1, 2 dichloro ethane: CH3CN: H₂O (1: 1: 2, 40 mL) were added sodium metaperiodate (7 g, 32.72 mmol), ruthénium chloride (10 mg, 0.048 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion the reaction mixture was diluted with water (100 mL) and washed with EtOAc (2 x 100 mL). The pH of the aqueous layer was adjusted to ~2 with 2 N HCl and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 123 (3.1 g, 72%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.1); *H-NMR (DMSO-d₆, 500 MHz): δ 14.53 (br s, 1H), 8.47 (s, 1H), 8.18-8.15 (m, 1H), 8.11 (s, 1H), 7.99-7.85 (m, 3H), 3.76 (s, 3H); LC-MS (Agilent Ion trap): 99.64%; 397.9 (M-l)⁺; (column; X-select C-18 (50 x 3.0 mm, 2.5 um); RT 2.97 min. 2.5 mM Aq. NH4OAC: ACN; 0.8 mL/min).

Synthesis of 5-amino-2-chloro-4-((2-(methoxycarbonyl) phenyl) sulfonyl) benzoic acid (124):

ci _^/°²ΥΥ/ΟΟ2η 0U7 ⁰ '0 NH2

124

To a stirring solution of compound 123 (2.9 g, 7.26 mmol) in MeOH (30 mL) was added stannous chloride (4.1 g, 21.80 mmol) at RT; heated to 60 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was added water (100 mL) and extracted with EtOAc (2 x 100 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 124 (1.2 g, 44%) as an off-white solid. TLC: 20% MeOH/ CH₂C1₂ (Rf. 0.3); ‘fl-NMR (DMSO-</₆, 400 MHz): δ 13.66 (br s, 1H), 8.26 (td,7=7.8, 1.1 Hz, 1H), 7.83 (td,7=7.4, 1.3 Hz, 1H), 7.77 (dd, 7=7.9, 1.9 Hz, 1H), 7.69 (dd,7=7.5, 1.3 Hz, 1H), 7.63 (s, 1H), 7.18 (s, 1H), 6.44 (s, 2H), 3.86 (s, 3H); LC-MS: 92.25%; 369.9 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.09 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 5-amino-4-((2-carboxyphenyl) sulfonyl)-2-chlorobenzoic acid (125):

ci

125

To a stirring solution of compound 124 (1 g, 2.71 mmol) in THF: H2O (3: 1, 20 mL) was added lithium hydroxide monohydrate (1.1 g, 27.10 mmol) portion wise at RT and stirred for 12 h. The reaction was monitored by TLC and LC-MS; after completion of the reaction, the volatiles were removed in vacuo. The pH of the aqueous layer was acidified with 2 N HCl to ~2. The precipitated solid was filtered and dried in vacuo to afford crude compound 125 (800 mg, 83%) as an off-white solid. TLC: 20% MeOH/ CH₂C1₂ (Rf 0.3).

Synthesis of 7-chloro-ll-oxo-10, 11-dihydrodibenzo [b, /] [1, 4] thiazepine-8-carboxylic acid 5, 5-dioxide (126):

To a stirring solution of compound 125 (800 mg, 2.25 mmol) in THF (20 mL) under inert atmosphère was added CDI (1.85 g, 11.26 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was adjusted to ~2 using 2 N HCl. The precipitated solid was filtered, washed with water (2 x 20 mL), hexanes (10 mL) and dried in vacuo to afford compound 126 (500 mg, 65%) as an off-white solid. TLC: 20% MeOH/ CH2CI2 (Rf

-98 0.4); 'H NMR (DMSO-4 400 MHz): δ 14.08 (br s, 1H), 11.56 (s, 1H), 8.01-7.96 (m, 3H), 7.96-7.85 (m, 2H), 7.74 (s, 1H); LC-MS (Agilent Ion trap): 86.33%; 336.0 (M-l)⁺; (column; X-select C-18 (50 x 3.0 mm, 2.5 um); RT 6.57 min. 2.5 mM Aq. NH4OAC: ACN; 1.0 mL/min).

Synthesis of 9-chloro-ll-oxo-10, 11-dihydrodibenzo (b, /] [1, 4] thiazepine-8-carboxylic

Synthesis of l-bromo-2, 4-dichloro-3-nitrobenzene (128):

ci

¹²⁸

To a stirring solution of l,3-dichloro-2-nitrobenzene 127 (5 g, 26.04 mmol) in concentrated sulfuric acid (150 mL) under inert atmosphère was added A-bromosuccinimide (4.6 g, 26.04 mmol) portion wise at RT and heated to 60 °C and stirred for 16 h. The reaction was poured into ice-cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic 15 extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude.

The crude was purified through silica gel column chromatography using 2% EtOAc/ hexanes to

- 99 afford compound 128 (4.9 g, 70%). TLC: 5% EtOAc/ hexanes (Rf 0.5); ^lH NMR (DMSO400 MHz): δ 8.11 (d, J= 8.8 Hz, 1H), 7.79 (d, J= 8.9 Hz, 1H).

Synthesis of methyl 3-amino-2, 4-dichlorobenzoate (129):

ci

129

To a stirring solution of compound 128 (7.5 g, 27.77 mmol) in MeOH: CH3CN (4: 1, 100 mL) under inert atmosphère in a Steel bomb were added triethylamine (12 mL, 83.33 mmol), dppf (1.53 g, 2.76 mmol), Pd(OAc)₂ (500 mg, 2.27 mmol) at RT; heated to 100 °C, under CO gas atmosphère (150 psi) and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column flash chromatography using 15% EtOAc/ hexanes to afford compound 129 (5 g, 82%). TLC: 30% EtOAc/ hexanes (Rf 0.5); 'il NMR (DMSO4,400 MHz): δ 7.34 (d, J= 8.1 Hz, 1H), 6.94 (d, J= 8.1 Hz, 1H), 5.79 (s, 2H), 3.83 (s, 3H);

Synthesis of methyl 2, 4-dichloro-3-nitrobenzoate (130): ci

O₂N

T

130

To a stirring solution of compound 129 (5 g, 22.72 mmol) in glacial acetic acid (25 mL) was added 30% H₂O₂ (25 mL) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and EtOAc (200 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 130 (4.1 g, 73%) as brown solid. TLC: 30% EtOAc/ hexanes (Rf 0.3); ^lH NMR (DMSO-7₆,400 MHz): δ 8.11 (d, J= 8.5 Hz, 1H), 7.96 (d, J = 8.7 Hz, 1H), 3.91 (s, 3H);

- 100 Synthesis of methyl 2-chloro-4-((2-(methoxycarbonyl) phenyl) thio)-3-nitrobenzoate (131):

ci

CO₂Me

131

To a stirring solution of compound 130 (4.1 g, 16.40 mmol) in DMF (100 mL) under argon atmosphère were added methyl 2-mercaptobenzoate 1 (2.75 g, 16.40 mmol), césium carbonate (16 g, 49.23 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (500 mL) and extracted with EtOAc (200 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to compound 131 (1 g, 16%) as white solid. TLC: 30% EtOAc/ hexanes (Rf 0.3). ‘H NMR (DMSO-r/₆.400 MHz): δ 8.08 (d, J = 8.3 Hz, 1H), 7.98 (dd, J= 7.8, 1.5 Hz, 1H), 7.73 (d, J= 8.3 Hz, 1H), 7.58-7.52 (m, 1H), 7.43 (td, J=7.6, 1.1 Hz, 1H), 7.02 (dd, J= 8.0, 0.6 Hz, 1H), 3.92 (s, 3H), 3.86 (s, 3H);

Synthesis of methyl 3-amino-2-chloro-4-((2-(methoxycarbonyl) phenyl) thio) benzoate (132):

CO₂Me

132 ci

CO₂Me

To a stirring solution of compound 131 (1 g, 2.62 mmol) in acetic acid (10 mL) was added iron powder (734 mg, 13.12 mmol) at RT; heated to 60 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo and the residue was diluted with EtOAc (200 mL). The organic layer was washed with saturated sodium bicarbonate solution (100 mL) and dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 132 (700 mg, 76%) as brown syrup. TLC: 40% EtOAc/ hexanes {Rf. 0.7). 'H NMR (DMSO-î/ô, 500 MHz): δ 7.97 (br d, J= 7.5 Hz, 1H), 7.47-7.42 (m, 2H), 7.26 (br t, J = 7.5 Hz, 1H), 6.97 (d,J=8.1 Hz, 1H), 6.65 (br d, J= 8.1 Hz, 1H), 5.76-5.73 (m, 2H), 3.89 (s, 3H), 3.87 (s, 3H); LC-MS: 90.61%; 351.8 (M⁺+l)_; (column; Ascentis Express

- 101 Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.82 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025%

Aq. TFA, 1.2 mL/min).

Synthesis of 3-amino-4-((2-carboxyphenyl) thio)-2-chlorobenzoic acid (133):

co₂h

133

To a stirring solution of compound 132 (700 mg, 1.99 mmol) in THF: H₂O (1: 1, 20 mL) was added lithium hydroxide monohydrate (837 mg, 19.94 mmol) portion wise for 10 min at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was adjusted to ~2 with 1 N HCl and extracted with EtOAc (2 x 50 mL) The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to compound 133 (500 mg, 78%) as a white solid. TLC: 40% EtOAc/ hexanes (Rf. 0.2).

'H NMR (DMSO-4 400 MHz): δ 13.29 (br s, 2H), 7.97 (dd, J = 7.8, 1.4 Hz, 1H), 7.44-7.38 (m, 2H), 7.26-7.21 (m, 1H), 6.95 (d, J = 7.9 Hz, 1H), 6.63 (d, J = Ί.6 Hz, 1H), 5.62 (br s, 2H); LC-MS: 94.65%; 323.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.98 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 9-chloro-ll-oxo-10, 11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxylic acid (134):

134

To a stirring solution of compound 133 (500 mg, 1.42 mmol) in THF (10 mL) under inert atmosphère was added CDI (2.30 g, 14.20 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was adjusted to ~2 using 1 N HCl. The precipitated solid was filtered, washed

- 102 - with hexane (20 mL) and dried in vacuo to afford compound 134 (300 mg, 69%) as an offwhite solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.4); ^XH NMR (DMSO-7₆,400 MHz): δ 13.62 ( br s, 1H), 10.41 (s, 1H), 7.72-7.63 (m, 2H), 7.58-7.54 (m, 1H), 7.53-7.46 (m, 3H); LC-MS: 93.51%; 305.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.02 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 9-chloro-ll-oxo-10, 11-dihydrodibenzo [b, f\ [1, 4] thiazepine-8-carboxylic acid 5, 5-dioxide (135):

135

To a stirring solution of compound 134 (290 mg, 0.95 mmol) in 1, 2 dichloro ethane: CH3CN: H₂O (1: 1: 2, 20 mL) were added sodium metaperiodate (622 mg, 2.85 mmol), ruthénium chloride (10.70 mg, 0.047 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion, the volatiles were removed in vacuo and the residue was extracted with EtOAc (2 x 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% MeOH/ CH₂C1₂ to afford compound 135 (230 mg, 72%) as brown solid. TLC: 40% MeOH/ CH₂C1₂ (Rf. 0.3); 'H NMR (DMSO4,400 MHz): δ 14.08 (br s, 1H), 11.13 (s, 1H), 8.01 (d, 7=8.2 Hz, 1H), 7.98-7.89 (m, 3H), 7.85 (dd,7=7.5, 1.4 Hz, 1H), 7.71 (d,7= 8.2 Hz, 1H); LC-MS: 99.61%; 335.9 (M-l)⁺; (column; Kinetex EVO C-18 (50 x 3.0 mm,2.6 um); RT 1.15 min. 2.5 mM Aq. NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of ll-oxo-7-(trifluoromethyl)-10, 11-dihydrodibenzo {b, /] [1, 4] thiazepine-8carboxylic acid 5, 5-dioxide (143): A common intermediate

- 103 -

Synthesis of methyl 4-fluoro-2-(trifluoromethyl) benzoate (137):

137

To a stirring solution of 4-fluoro-2-(trifluoromethyl) benzoic acid 136 (20 g, 96.10 mmol) in

MeOH (200 mL) under inert atmosphère was added concentrated sulfuric acid (18 .85 mL, 192.20 mmol) dropwise for 15 min at 0 °C; heated to reflux and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with ice-cold water (300 mL) and extracted with diethyl ether (2 x 300 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford mixture of compound 137 (10.8 g, 51%) as colorless syrup. TLC: 10% EtOAc/ hexanes (Ry 0.8). 'H NMR (400 MHz, DMSO-ri₆): δ 7.96 (dd, J= 8.7, 5.5 Hz, 1H), 7.81 (dd, J= 9.3, 2.6 Hz, 1H), 7.68 (td, J= 8.4, 2.5 Hz, 1H), 3.87 (s, 3H);

Synthesis of methyl 4-fluoro-5-nitro-2-(trifluoromethyI) benzoate (138):

- 104 -

no₂138

To a stirring solution of compound 137 (10.8 g, 48.64 mmol) in concentrated sulphuric acid (30 mL) under inert atmosphère at 0 °C was added fuming nitric acid (15 mL) dropwise for 30 min at 0 °C; heated to 65 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 °C and slowly quenched with ice-cold water (300 mL) and extracted with EtOAc (2 x 300 mL). The combined organic extracts were washed with saturated NaHCO3 solution (300 mL) and brine (300 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column flash chromatography using 5% EtOAc/ hexanes to afford compound 138 (3.5 g, 27%) as colorless syrup. TLC: 10% EtOAc/ hexanes (R/. 0.7). ^IH NMR (400 MHz, DMSO-rf₆): δ 8.63 (d, J= 7.3 Hz, 1H), 8.30 (d, J= 11.3 Hz, 1H), 3.92 (s, 3H);

Synthesis of methyl 4-((2-(methoxycarbonyl) phenyl) thio)-5-nitro-2-(trifluoromethyl) benzoate (139):

cf₃CO₂Mei _nr. .. oA no₂139

To a stirring solution of methyl 4-fluoro-5-nitro-2-(trifluoromethyl) benzoate 138 (4.00 g, 14.98 mmol) in DMF (80 mL) under inert atmosphère were added methyl 2-mercaptobenzoate 1 (2.52 g, 14.98 mmol) and césium carbonate (7.32 g, 22.47 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-7% EtOAc/ hexanes to afford compound 139 (5 g, 81%) as yellow syrup. TLC: 20% EtOAc/

- 105 - hexanes (Rf. 0.5); *H NMR (DMSO4,400 MHz): δ 8.68 (s, 1H), 8.03-7.96 (m, 1H), 7.777.70 (m, 3H), 7.25 (s, 1H), 3.90 (s, 3H), 3.74 (s, 3H);

Synthesis of methyl 5-amino-4-((2-(methoxycarbonyl) phenyl) thio)-2-(trifluoromethyl) benzoate (140):

çf₃^C°^2,%V,CO₂Me Γ X JT nh₂140

To a stirring solution of compound 139 (5 g, 12.04 mmol) in MeOH (100 mL) under inert atmosphère was added 10% Pd/C (2 g) at RT and stirred under hydrogen atmosphère (balloon pressure) at RT for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and eluted with 50% MeOH/ CH2CI2 (2 x 150 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20-25% EtOAc/ hexanes to afford compound 140 (3.5 g, 75%) as an off-white solid. TLC: 40% EtOAc/ hexanes (Rf 0.5); *H NMR (400 MHz, DMSO4): δ 7.96 (dd, J= 7.8, 1.4 Hz, 1H), 7.67 (s, 1H), 7.46-7.41 (m, 1H), 7.27-7.23 (m, 1H), 7.15 (s, 1H), 6.65 (dd, J= 8.1, 0.7 Hz, 1H), 6.40 (s, 2H), 3.88 (s, 3H), 3.84 (s, 3H);

Synthesis of 5-amino-4-((2-carboxyphenyl) thio)-2-(trifluoromethyl) benzoic acid (141): cf₃ ^V°₂H T αν nh₂141

To a stirring solution of compound 140 (3.5 g, 9.09 mmol) in THF: H2O (3: 1, 40 mL) was added lithium hydroxide monohydrate (1.90 g, 45.45 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (30 mL) and washed with diethylether (2 x 30 mL). The aqueous layer was acidified with 6 N HCl to pH ~4. The precipitated solid was filtered and dried in vacuo to afford compound 141 (2.8 g, 86%) as an

- 106 off-white solid. TLC: 40% EtOAc/ hexanes (Rf 0.2); ^!H NMR (400 MHz, DMSO-i/é): δ 13.32 (br s, 2H), 7.97 (dd, J= 7.8, 1.4 Hz, 1H), 7.64 (s, 1H), 7.45-7.38 (m, 1H), 7.27-7.20 (m, 1H), 7.15 (s, 1H), 6.63 (d, 7 = 8.0 Hz, 1H), 6.25 (br s, 2H);

Synthesis of ll-oxo-7-(trifhioromethyl)-10, 11-dihydrodibenzo [b, f] [1, 4] thiazepine-8carboxylic acid (142):

142

To a stirring solution of compound 141 (2.6 g, 7.28 mmol) in THF (50 mL) under inert atmosphère was added CDI (5.90 g, 36.41 mmol) at 0 °C; heated to 60 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was poured into ice-cold water (100 mL) and the pH was adjusted to ~2 using 6 N HCl. The precipitated solid was filtered and dried in vacuo to afford compound 142 (710 mg, 75%) as white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.3); ‘H NMR (400 MHz, DMSO4): δ 13.82 (br s, 1H), 11.04 (s, 1H), 7.96 (s, 1H), 7.75-7.69 (m, 1H), 7.647.45 (m, 4H);

Synthesis of ll-oxo-7-(trifluoromethyl)-10, 11-dihydrodibenzo {b, /] [1, 4] thiazepine-8carboxylic acid 5, 5-dioxide (143):

To a stirring solution of compound 142 (1.9 g, 5.60 mmol) in 1, 2 dichloro ethane: CH₃CN: H₂O (1: 1:2, 100 mL) were added sodium metaperiodate (3.6 g, 16.81 mmol), ruthénium chloride (58 mg, 0.28 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion, the volatiles were removed in vacuo. The solid obtained was filtered, washed with water (2 x 20 mL). The solid was dissolved in 20% MeOH/ CH₂C1₂(100 mL) and filtered through celite. The filtrate was concentrated in vacuo to obtain the crude,

- 107 - which was triturated with n-hexane (20 mL) and dried in vacuo to afford compound 143 (1.6 g, 77%) as an off-white solid. TLC: 15% MeOH/ CH2CI2 (Rf 0.2); *H NMR (400 MHz, DMSOd₆): δ 11.85 (s, 1H), 8.19 (s, 1H), 8.05-7.99 (m, 2H), 7.97-7.87 (m, 2H), 7.78 (s, 2H); LC-MS: 98.87%; 289.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.08 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-fluoro-ll-oxo-10, 11-dihydrodibenzo {b, /] [1, 4] thiazepine-8-carboxylic acid 5, 5-dioxide (144): A common intermediate

Synthesis of 4-fluoro-ll-oxo-10, 11-dihydrodibenzo [b,/] [1, 4] thiazepine-8-carboxylic acid 5, 5-dioxide (144):

To a stirring solution of 4-fluoro-l 1-oxo-10, 11-dihydrodibenzo \b,f [1,4] thiazepine-8carboxylic acid 76 (300 mg, 1.03 mmol) in 1, 2 dichloro ethane: CH₃CN: H2O (1: 1: 2, 12 mL) were added sodium metaperiodate (663 mg, 3.11 mmol), ruthénium chloride (10.7 mg, 0.05 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion the volatiles were removed in vacuo. The residue was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 144 (220 mg, 67%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.2); 'H-NMR (DMSO-î/₆, 400 MHz): δ 13.91-13.44

- 108 (m, 1H), 11.60 (s, 1H), 8.13 (d, J= 8.2 Hz, 1H), 7.94-7.84 (m, 3H), 7.77-7.64 (m, 2H); LCMS: 97.70%; 320.0 (M-l)⁺; (column; Kinetex EVO C-18 (50 x 3.0 mm,2.6 um); RT 1.27 min. 2.5 mM Aq. NH₄OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of ll-oxo-10, 11-dihydrodibenzo \b,j\ [1, 4] oxazepine-8-carboxylic acid (149):

Synthesis of methyl 4-(2-(methoxycarbonyI) phenoxy)-3-nitrobenzoate (146):

146

To a stirring solution of methyl 4-fluoro-3-nitrobenzoate 2 (5 g, 25.12 mmol) in DMF (75 mL) under argon atmosphère were added methyl 2-hydroxybenzoate 145 (4.2 g, 27.63 mmol), césium carbonate (8.98 g, 27.64 mmol), at RT; heated to 100 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (200 mL). The precipitated solid was filtered, washed with n- hexane (100 mL) and dried in vacuo to afford compound 146 (6.2 g, 75%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf 0.4); 'H NMR (DMSO-4 500 MHz): δ 8.54 (s, 1H),

- 109 -

8.11 (dd, 7= 8.8, 2.2 Hz, 1H), 8.02 (dd, 7=7.7, 1.6 Hz, 1H), 7.80 (td, 7= 7.8, 1.7 Hz, 1H), 7.52 (t, J= 7.4 Hz, 1H), 7.45 (d, 7= 7.8 Hz, 1H), 6.89 (d, 7= 8.7 Hz, 1H), 3.88 (s, 3H), 3.64 (s, 3 H).

Synthesis of methyl 3-amino-4-(2-(methoxycarbonyl) phenoxy) benzoate (147): o nh₂

To a stirring solution of compound 146 (2 g, 6.04 mmol) in MeOH (50 mL) was evacuated for 5 min and added 10% Pd/ C (1 g, 50% wet) under argon atmosphère at RT and stirred under hydrogen atmosphère (balloon pressure) at RT for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and washed with 20% MeOH/ CH2CI2 (200 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was purified by combiflash chromatography using 20% EtOAc/ hexanes to afford compound 147 (1.4 g, 77%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf 0.3); ’H NMR (DMSO-7₆, 400 MHz): δ 7.84 (dd, 7= 7.7, 1.6 Hz, 1H), 7.61-7.55 (m, 1H), 7.44 (s, 1H), 7.27 (t, 7= 7.2 Hz, 1H), 7.13 (dd, 7= 8.3, 2.0 Hz, 1H), 7.00 (d, 7= 8.0 Hz, 1H), 6.65 (d, 7= 8.3 Hz, 1H), 5.30 (br s, 2H), 3.80 (s, 3H), 3.74 (s, 3H).

Synthesis of 3-amino-4-(2-carboxyphenoxy) benzoic acid (148): o

To a stirring solution of compound 147 (1.4 g, 4.65 mmol) in THF: H2O (3: 1, 40 mL) was added lithium hydroxide monohydrate (976 mg, 23.23 mmol) at RT; heated to reflux and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the

- 110 volatiles were removed in vacuo. The pH of the residue was acidified to ~2 with 2 N HCl. The precipitated solid was filtered, washed with water (20 mL), «-pentane (20 mL) and dried in vacuo to afford compound 148 (700 mg, 56%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Ry 0.1); 'H NMR (DMSO-7₆, 400 MHz): δ 7.86 (dd, J= 7.7, 1.6 Hz, 1H), 7.63 (s, 1H), 7.62-7.57 (m, 1H), 7.37 (d, 7= 7.3 Hz, 1H), 7.31 (t,7=7.3 Hz, 1H), 7.06 (d, 7= 8.0 Hz, 1H), 6.69 (d, 7= 8.5 Hz, 1H).

Synthesis of ll-oxo-10, 11-dihydrodibenzo {b,f\ [1, 4] oxazepine-8-carboxylic acid (149): o.

149

To a stirring solution of compound 148 (700 mg, 2.56 mmol) in THF (20 mL) under argon atmosphère was added CDI (2.07 g, 12.77 mmol) at RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified to ~2 using 2 N HCl. The precipitated solid was filtered, washed with n-pentane (50 mL) and dried in vacuo to afford compound 149 (450 mg, 69%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Ry. 0.2); *H NMR (DMSO-7₆, 400 MHz): δ 13.03 (brs, 1H), 10.65 (s, 1H), 7.81-7.76 (m, 2H), 7.70 (dd, 7= 8.4, 2.2 Hz, 1H), 7.67-7.61 (m, 1H), 7.43 (d, 7= 8.4 Hz, 1H), 7.40-7.31 (m, 2H).

Synthesis of 9-methyl-ll-oxo-10, 11-dihydrodibenzo [6, /] [1, 4] oxazepine-8-carboxylic acid (153): A common intermediate

-111 -

Synthesis of methyl 2-(4-bromo-3-methyl-2-nitrophenoxy) benzoate (150)

CO₂Me

150

To a stirring solution of compound 97 (1.5 g, 6.41 mmol) in DMF (30 mL) under inert atmosphère were added césium carbonate (3.1 g, 9.54 mmol), methyl 2-hydroxybenzoate 145 (974 mg, 6.41 mmol) at RT; heated to 70 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (100 mL) and the precipitated solid was filtered, washed with water (20 mL), hexane (20 mL) and dried in vacuo to afford compound 150 (1.1 g, 48%) as apalebrown solid. TLC: 5%

EtOAc/hexanes (Rf. 0.3); ^rH NMR (DMSO-J6, 400 MHz): δ 7.94 (dd, J= 7.8, 1.8 Hz, 1H), 7.75-7.69 (m, 2H), 7.45 (td, 7= 7.6, 1.1 Hz, 1 H), 7.27 (dd, 7= 8.2, 0.9 Hz, 1 H), 6.65 (d, 7 = 9.0 Hz, 1H), 3.71 (s, 3H), 2.35 (s, 3H); LC-MS: 97.42%; 364.0 (M-l)⁺, 365.9 (M-2)⁺; (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 3.78 min. 2.5 mM Aq. NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of 8-bromo-9-methyldibenzo \b,j\ [1, 4] oxazepin-ll(1027)-one (151):

151

- 112 -

To a stirring solution of compound 150 (900 mg, 2.46 mmol) in acetic acid (30 mL) under inert atmosphère was added iron powder (676 mg, 12.29 mmol) at RT; heated to 90 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (60 mL) and extracted with EtOAc (2 x 75 mL). The combined organic extracts were washed with aqueous NaHCOs solution (2 x 50 mL) and brine (50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to compound 151 (750 mg, 91%) as pale brown solid. TLC: 10% EtOAc/ hexanes (Rf 0.2); *H-NMR (DMSO-J₆, 500 MHz): δ 10.17 (s, 1H), 7.72 (dd,7=7.7, 1.3 Hz, 1H), 7.637.57 (m, 1H), 7.43 (d,7=8.7 Hz, 1H), 7.38-7.30 (m, 2H), 7.20 (d,7=8.7 Hz, 1H), 2.39 (s, 3H); LC-MS: 92.00%; 305.9 (M⁺+2); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 3.10 min. 2.5 mM Aq. NH₄OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of methyl 9-methyl-ll-oxo-10, 11-dihydrodibenzo [b, /] [1, 4] oxazepine-8carboxylate (152):

152

To a stirring solution of compound 151 (800 mg, 2.63 mmol) in MeOH (80 mL) in a steel bomb were added dppf (145.7 mg, 0.26 mmol), sodium acetate (647 mg, 7.89 mmol), Pd(OAc)2 (59 mg, 0.26 mmol) at RT; heated to 120 °C under CO gas atmosphère (80 psi) and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column flash chromatography using 1020% EtOAc/ hexanes to afford compound 152 (500 mg, 68%). TLC: 20% EtOAc/ hexanes (Rf 0.2); 'HNMR(DMSO-7₆,400 MHz): δ 10.09 (s, 1 H), 7.73 (dd,7=7.8, 1.6 Hz, 1 H), 7.637.54 (m, 2H), 7.40-7.29 (m, 3H), 3.81 (s, 3H), 2.45 (s, 3H); LC-MS: 97.37%; 283.9 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 2.68 min. 2.5 mM Aq. NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

- 113 Synthesis of 9-methyl-ll-oxo-10, 11-dihydrodibenzo [b, f\ [1, 4] oxazepine-8-carboxylic acid (153):

153

To a stirring solution of compound 152 (550 mg, 1.94 mmol) in THF: H₂O (4: 1, 24 mL) was added lithium hydroxide monohydrate (245 mg, 5.83 mmol) RT and reflux for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (20 mL) and acidified with 2 N HCl to pH ~3-4. The obtained solid was filtered, washed with water (20 mL), n-hexane (20 mL), diethylether (20 mL) and dried in vacuo to obtain compound 153 (310 mg, 60%) as pale brown solid. TLC: 30% EtOAc/ hexanes (Rf. 0.1); ’H NMR (DMSO-4 400 MHz): δ 13.03 (br s, 1H), 10.05 (s, 1H), 7.73 (dd, J= 7.7, 1.7 Hz, 1H), 7.63-7.53 (m, 2H), 7.39-7.26 (m, 3H), 2.47 (s, 3H); LCMS: 99.95%; 269.9 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 1.17 min. 2.5 mM Aq. NH₄OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of 7-chloro-ll-oxo-10, 11-dihydrodibenzo {b, f\ [1, 4] oxazepine-8-carboxylic acid (155): A common intermediate

Synthesis of 2-chloro-4-(2-(methoxycarbonyl) phenoxy)-5-nitrobenzoic acid (154):

-114 -

CO₂Me

154

To a stirring solution of 2-chloro-4-fluoro-5-nitrobenzoic acid 121 (5 g, 22.76 mmol) in DMF (50 mL) under argon atmosphère were added methyl 2-hydroxybenzoate 145 (3.8 g, 25.04 mmol), césium carbonate (14.8 g, 45.53 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and washed with EtOAc (2 x 100 mL). The pH of the aqueous layer was acidifïed to ~2 with 2 N HCl and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, fdtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel chromatography using 2-10% MeOH/ CH2CI2 to afford compound 154 (6 g, 75%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.3). ’H-NMR (DMSO-4 400 MHz): δ 13.79 (br s, 1H), 8.55 (s, 1H), 8.02 (dd, J= 7.8, 1.8 Hz, 1H), 7.81-7.75 (m, 1H), 7.52 (td, J= 7.7, 1.1 Hz, 1H), 7.45 (dd, J = 8.2, 0.9 Hz, 1H), 6.85 (s, 1H), 3.69 (s, 3H); LC-MS (Agilent Ion trap): 94.80%; 352.7 (M⁺+l); (Column; X-select CSH C-18 (50 x 3 mm, 2.5 pm); RT 3.02 min. 2.5% Aq. NH₄OAc: ACN; 0.8 mL/min).

Synthesis of 7-chloro-ll-oxo-10, 11-dihydrodibenzo [b, /] [1, 4] oxazepine-8-carboxylic acid (155):

To a stirring solution of compound 154 (6 g, 17.09 mmol) in acetic acid (60 mL) was added iron powder (9.5 g, 170.94 mmol) at RT; heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (50 mL) and the pH was adjusted to ~2 with 6 N HCl. The precipitated solid was filtered and dried in vacuo afford compound 155 (4 g, 81 %) as an offwhite solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); *H-NMR (DMSO-4 400 MHz): δ 13.46 (br s, 1H), 10.68 (s, 1H), 7.78 (dd, J= 7.8, 1.6 Hz, 1H), 7.68-7.59 (m, 3H), 7.41-7.32 (m, 2H); LC19643

- 115 MS (Agilent Ion trap): 93.44%; 289.9 (M⁺+l); (Column; X-select CSH C-18 (50 x 3 mm, 2.5 pm); RT 2.58 min. 2.5% Aq. NH₄OAc: ACN; 0.8 mL/min).

Synthesis of ll-oxo-7-(trifhioromethyl)-10, 11-dihydrodibenzo [b, f] [1, 4] oxazepine-85 carboxylic acid (158): A common intermediate

Synthesis of methyl 4-(2-(methoxycarbonyI) phenoxy)-5-nitro-2-(trifluoromethyl) 10 benzoate (156):

156

To a stirring solution of compound 138 (3 g, 11.23 mmol) in DMF (50 mL) under argon atmosphère were added methyl 2-hydroxybenzoate 145 (1.7 g, 11.23 mmol), césium carbonate (5.49 g, 16.85 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by 15 TLC; after completion of the reaction, the reaction mixture was diluted with water (500 mL) and stirred for 1 h. The precipitated solid was filtered, washed with hexane (2x50 mL) and dried in vacuo to afford compound 156 (3.5 g, 78%) as pale yellow solid. TLC: 30% EtOAc/ hexanes (Rf 0.4); ‘H NMR (400 MHz, DMSO4): δ 8.63 (s, 1H), 8.02 (dd, J = 7.8, 1.8 Hz, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.58-7.48 (m, 2H), 7.10 (s, 1H), 3.90 (s, 3H), 3.68 (s, 3H);

- 116 LC-MS: 99.37%; 399.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.80 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of methyl ll-oxo-7-(trifluoromethyl)-10, 11-dihydrodibenzo [b, /] [1, 4] oxazepine-8-carboxylate (157):

o

157

To a stirring solution of compound 156 (3.3 g, 8.27 mmol) in acetic acid (50 mL) were added iron powder (4.6 g, 82.70 mmol) at RT; heated to 80 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo and the residue was diluted with EtOAc (200 mL) and filtered through celite. The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 30-35% EtOAc/ hexanes to afford compound 157 (1.9 g, 68%) as white solid. TLC: 40% EtOAc/ hexanes (Rf. 0.4). LC-MS: 98.04%; 338.2 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.55 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of ll-oxo-7-(trifluoromethyl)-10, 11-dihydrodibenzo [b, f\ [1, 4] oxazepine-8carboxylic acid (158):

158

To a stirring solution of compound 157 (2.2 g, 6.52 mmol) in THF: H2O (3: 1, 20 mL) was added lithium hydroxide monohydrate (1.37 g, 32.64 mmol) portion wise for 10 min at 0 °C; warmed to RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (20 mL) and acidified with 6 N HCl to pH ~4 and stirred for 2 h. The obtained solid was filtered, and

- 117 - dried in vacuo to obtain compound 158 (1.8 g, 86%) as white solid. TLC: 50% EtOAc/ hexanes (Rf 0.1); ^XH NMR (DMSO-</₆, 400 MHz): δ 13.70 (br s, 1H), 10.91 (s, 1H), 7.84 (s, 1H), 7.80 (dd, J= 7.8, 1.6 Hz, 1H), 7.70-7.62 (m, 2H), 7.47 (dd, 7= 8.1, 0.8 Hz, 1H), 7.37 (td, J= 7.6, 1.1 Hz, 1H); LC-MS: 99.92%; 321.9 (M-l)⁺; (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 0.94 min. 2.5 mM Aq. NH₄OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min);

Synthesis of ll-oxo-10, ll-dihydro-5H-dibenzo [b, e] [1, 4] diazepine-8-carboxylic acid (163): A common in ter médiate

Synthesis of methyl 4-((2-(methoxycarbonyI) phenyl) amino)-3-nitrobenzoate (160):

160

To a stirring solution of methyl 2-aminobenzoate 159 (5 g, 33.07 mmol) in A-Methyl-2pyrrolidone (13 'mL) under inert atmosphère were added diisopropylethylamine (18 mL, 103.46 mmol), methyl 4-fluoro-3-nitrobenzoate 2 (9.87 g, 49.21 mmol) at RT; heated to 120 °C in a sealed tube and stirred for 14 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with diethyl ether (100 mL) and stirred for 1 h.

- 118 -

The obtained solid was filtered, washed with EtOAc (100 mL) and dried in vacuo to afford compound 160 (2.9 g, 26%) as yellow solid. TLC: 30% EtOAc/ hexanes (Rf 0.4); *H NMR (DMSO4,400 MHz): δ 11.13 (s, 1 H), 8.67 (s, 1H), 8.11-7.94 (m, 2H), 7.70-7.62 (m, 2H), 7.58 (d, J= 9.0 Hz, 1H), 7.32-7.27 (m, 1H), 3.87 (s, 6H).

Synthesis of methyl 3-amino-4-((2-(methoxycarbonyl) phenyl) amino) benzoate (161):

161

To a stirring solution of compound 160 (5 g, 15.15 mmol) in MeOH (150 mL) under inert atmosphère was added 10% Pd/ C (2.5 g, 50% wet) at RT and stirred under hydrogen atmosphère (balloon pressure) at RT for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and washed with 20% MeOH/ CH2CI2 (600 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude washed with diethyl ether: «-pentane (1: 2, 30 mL) dried in vacuo to afford compound 161 (2.7 g, 60%) as yellow solid. TLC: 30% EtOAc/ hexanes (Rf. 0.3); 'H NMR (DMSO-î/₆, 400 MHz): δ 8.92 (s, 1H), 7.91 (dd, J = 8.0, 1.6 Hz, 1H), 7.46-7.45 (m, 1H), 7.43-7.36 (m, 1H), 7.21 (s, 2H), 6.95 (dd, J = 8.5, 0.6 Hz, 1H), 6.83-6.77 (m, 1H), 5.18 (s, 2H), 3.85 (s, 3H), 3.80 (s, 3H).

Synthesis of 3-amino-4-((2-carboxyphenyl) amino) benzoic acid (162):

162

To a stirring solution of compound 161 (2.7 g, 9.00 mmol) in THF: H2O (2.5: 1,210 mL) was added lithium hydroxide monohydrate (3.4 g, 81.00 mmol) at RT; heated to 65 °C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified to ~4 with 2 N HCl. The

- 119 - precipitated solid was filtered, washed with water (20 mL) and dried in vacuo to afford compound 162 (2.4 g, crude) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf 0.1); *H NMR (DMSO-r/₆ 400 MHz): δ 12.65 (br s, 2H), 9.20 (br s, 1H), 7.90 (dd, J= 8.0, 1.6 Hz, 1H), 7.44.7.42 (m, 1H), 7.39-7.35 (m, 1H), 7.20-7.18 (m, 2H), 6.92 (dd, J= 8.5, 0.7 Hz, 1H), 6.79 6.75 (m, 1H), 5.08 (br s, 2H).

Synthesis of ll-oxo-10, 1 l-dihydro-5Æ-dibenzo [b, e] [1, 4] diazepine-8-carboxylic acid (163):

163

To a stirring solution of compound 162 (2.4 g, 8.82 mmol) in THF (80 mL) under inert atmosphère was added CDI (5.8 g, 35.29 mmol) at RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was adjusted to ~2 using 2 N HCl. The precipitated solid was filtered, washed with n-pentane (50 mL) and dried in vacuo to afford compound 163 (1.9 g, 85%) as pale green solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); 'H NMR (DMSO-d₆,400 MHz): δ 12.66 (br s, 1H), 9.93 (s, 1H), 8.26 (s, 1H), 7.70 (d, J= 7.9 Hz, 1H), 7.58-7.50 (m, 2H), 7.36 (t, J= 7.0 Hz, 1H), 7.02 (dd, J= 17.4, 8.2 Hz, 2H), 6.91 (t, J= 7.4 Hz, 1H).

Synthesis of 5-methyl-ll-oxo-10, 1 l-dihydro-5Æ-dibenzo [b, e] [1, 4] diazepine-8carboxylic acid (177): A common intermediate

- 120 -

Synthesis of methyl 4-((2-(methoxycarbonyl) phenyl) (methyl) amino)-3-nitrobenzoate (164):

₅ 164

To a stirring solution of compound 160 (3 g, 9.09 mmol) in DMF (30 mL) under inert atmosphère were added césium carbonate (5.9 g, 18.15 mmol), methyl iodide (0.84 mL, 13.59 mmol) at RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (60 mL) and extracted with

EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 164 (2.73 g, 88%) as yellow solid. TLC: 30% EtOAc/ hexanes (Ry 0.4); 'H NMR (DMSO-7₆,400 MHz): δ 8.07 (s, 1H), 8.06 (d, 7= 7.8 Hz, 1H), 7.71 (dd,7=7.8, 1.5 Hz, 1H), 7.62 (t,7=7.3 Hz, 1H), 7.40-7.26 (m,

3H), 3.84 (s, 3H), 3.53 (s, 3H), 3.38 (s, 3H).

Synthesis of methyl 5-methyl-ll-oxo-10, ll-dihydro-5/7-dibenzo {b, e] [1, 4] diazepine-8carboxylate (165):

- 121 ο

165

Το a stirring solution of compound 164 (2.73 g, 7.93 mmol) in acetic acid (36 mL) under inert atmosphère was added iron powder (7 g, 127.2 mmol) at RT; heated to 80 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with CH2CI2 (50 mL), stirred for 2 h and filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was dissolved in CH2CI2 (200 mL), washed with saturated aqueous NaHCO₃ solution (100 mL), brine (100 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 165 (2 g, 91%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf 0.4); ^XH NMR (DMSOî/₆,500 MHz): δ 10.33 (s, 1H), 7.68 (dd, J=8.5, 1.9 Hz, 1H), 7.65-7.61 (m, 2H), 7.50 (t, J= 7.8 Hz, 1H), 7.28 (d, J= 8.4 Hz, 1H), 7.21 (d, J= 8.1 Hz, 1H), 7.10 (t, J= 7.4 Hz, 1H), 3.80 (s, 3H), 3.33 (s, 3H).

Synthesis of 5-methyl-ll-oxo-10, ll-dihydro-52f-dibenzo [b, e] [1, 4] diazepine-8carboxylic acid (166):

I

166

To a stirring solution of compound 165 (2 g, 7.09 mmol) in THF: H2O (1: 1, 80 mL) was added lithium hydroxide monohydrate (900 mg, 21.42 mmol) at RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was adjusted to ~2 with 2 N HCl. The precipitated solid was filtered and dried in vacuo to afford compound 166 (1.7 g, 89%) as an off-white solid. TLC: 40% EtOAc/ hexanes (Rf 0.2); ^XH NMR (DMSO-îZ₆, 400 MHz): δ 12.82 (br s, 1H), 10.33 (s, 1H), 7.70-7.60 (m, 3H), 7.51 (t, .7=7.8 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 7.21 (d, J=7.8Hz, 1H), 7.11 (t, 7.2 Hz, 1H), 3.32 (s, 3H).

- 122 Synthesis of 5-ethyl-l l-oxo-10, 1 l-dihydro-5//-dibenzo [b, e] [1, 4] diazepine-8-carboxylic acid (169): A common intermediate

Synthesis of methyl 4-(ethyl (2-(methoxycarbonyI) phenyl) amino)-3-nitrobenzoate (167):

To a stirring solution of compound 160 (2.9 g, 8.78 mmol) in DMF (40 mL) under inert atmosphère were added césium carbonate (6 g, 18.46 mmol), ethyl iodide (1.06 mL, 12.82 mmol) at RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (60 mL), extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude which was titurated with «-pentane (20 mL) to afford compound 167 (2.8 g, 89%) as pale yellow solid. TLC: 30% EtOAc/ hexanes (Rf. 0.5); ¹H NMR (DMSO-7₆, 500 MHz): δ 8.05 (dd, J= 9.0, 2.0 Hz, 1H), 8.02 (s, 1H), 7.62-7.57 (m, 2H), 7.45 (d, J= 9.0 Hz, 1H), 7.33 (d, J= 8.1 Hz, 1H), 7.28 (t, J= 7.5 Hz, 1H), 3.94 (q, J= 7.1 Hz, 2H), 3.82 (s, 3H), 3.44 (s, 3H), 1.20 (t,7=7.1 Hz, 3H).

Synthesis of methyl 5-ethyl-l l-oxo-10, ll-dihydro-5/7-dibenzo [b, e] [1, 4] diazepine-8carboxylate (168):

To a stirring solution of compound 167 (2.8 g, 7.82 mmol) in acetic acid (40 mL) under inert atmosphère was added iron powder (6.8 g, 125.1 mmol) at RT; heated to 80 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with CH2CI2 (50 mL), stirred for 2 h and filtered through celite. The filtrate was concentrated in vacuo to obtain the crude. The crude was diluted with CH₂C1₂ (200 mL), washed with saturated aqueous sodium bicarbonate solution (100 mL) and brine (100 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 168 (2.2 g, 96%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf 0.3); Ή NMR (DMSO-rf₆,500 MHz): δ 10.35 (br s, 1H), 7.70 (dd, J = 8.5, 1.9 Hz, 1H), 7.67 (s, 1H), 7.62 (d, J=7.5Hz, 1H), 7.51 (t,J=8.1 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.22 (d,J=8.1 Hz, 1H), 7.12 (t,J= 7.4 Hz, 1H), 3.31 (s, 5H), 1.11 (t, J= 6.9 Hz, 3H).

Synthesis of 5-ethyl-ll-oxo-10, ll-dihydro-5//-dibenzo {b, e] [1, 4] diazepine-8-carboxylic acid (169):

To a stirring solution of compound 168 (2.1 g, 7.09 mmol) in THF: H2O (1: 1, 60 mL) was added lithium hydroxide monohydrate (890 mg, 21.26 mmol) at RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified to ~2 with 2 N HCl. The precipitated solid was filtered, washed with water (50 mL) and dried in vacuo to afford compound 169 (1.6 g, 80%) as an off-white solid. TLC: 30% EtOAc/ hexanes {Rf 0.2); *H NMR (DMSO-rf₆,400 MHz): δ 12.82 (br s, 1H), 10.33 (s, 1H), 7.69-7.59 (m, 3H), 7.53-7.48 (m, 1H), 7.24 (dd, J= 19.7, 8.2 Hz, 2H), 7.12 (t, J= 7.5 Hz, 1H), 3.79 (br s, 2H), 1.12 (t, J= 7.0 Hz, 3H).

- 124 Synthesis of ll-oxo-5-propyl-10, ll-dihydro-5Æ-dibenzo [b, e] [1, 4] diazepine-8-

Synthesis of methyl3-amino-4-(2-(methoxycarbonyl) phenyl) (propyl) amino) benzoate (170):

170

To a stirring solution of methyl methyl 4-((2-(methoxycarbonyl) phenyl) amino)-310 nitrobenzoate 160 (2 g, 6.06 mmol) in DMF (50 mL) under argon atmosphère were added césium carbonate (5.9 g, 18.18 mmol), iodo propane (1.17 mL, 12.12 mmol) at RT; heated to 80 °C and stirred for 14 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (100 mL) and washed with water (75 mL), brine (75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-10% EtOAc/ hexanes to afford compound 170 (1.2 g, 53%) as yellow solid. TLC: 10% EtOAc/ hexanes (Rf. 0.4); ‘H NMR (DMSO-îZ₆, 400 MHz): δ 8.07 (dd, J = 8.9, 2.1 Hz, 1H), 8.01 (d, J= 2.1 Hz, 1H), 7.64-7.54 (m, 2H), 7.48 (d, J= 8.9 Hz, 1H), 7.36 (dd, J = 8.2, 0.8 Hz,

- 125 1H), 7.27 (td, J = 7.6, 1.1 Hz, 1H), 3.90-3.80 (m, 5H), 3.41 (s, 3H), 1.73-1.63 (m, 2H), 0.94 (t, J= 7.3 Hz, 3H).

Synthesis of methyl ll-oxo-5-propyl-10, ll-dihydro-5/7-dibenzo [b, e] [1,4] diazepine-8carboxylate (171):

To a stirring solution of compound 170 (1.2 g, 3.22 mmol) in AcOH (12 mL) under argon atmosphère was added Iron powder (2.8 g, 51.6 mmol) at RT and heated to 80 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with CH2CI2 filtered through celite and washed with CH₂C1₂ (100 mL). The filtrate was concentrated in vacuo. The residue was dissolved in CH2CI2 washed with saturated sodium bicarbonate solution (50 mL), brine solution (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was triturated with diethyl ether: pentane (1:1, 50 mL) filtered finally washed with pentane (30 mL) to afford compound 171 (700 mg, 70%) as off white solid. TLC: 20% EtOAc/ hexanes (Rf. 0.3); *H NMR (DMSO-7₆,400 MHz): δ 10.34 (s, 1H), 7.71-7.65 (m, 2H), 7.61 (dd,7=7.8, 1.6 Hz, 1H), 7.53-7.46 (m, 1H), 7.30 (d, 7= 8.4 Hz, 1H), 7.23 (d, 7= 8.0 Hz, 1H), 7.15-7.09 (m, 1H), 3.81 (s, 3H), 3.75-3.65 (br s, 2H), 1.54-1.55 (m, 2H), 0.87 (t, 7= 7.3 Hz, 3H); LC-MS: 93.58%; 310.9 (M⁺+l); (column; Ascentis Express C-18 (50 x 3.0 mm, 2.7 pm); RT 2.45 min. 0.025% Aq.TFA + 5% ACN: ACN + 5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of ll-oxo-5-propyl-10, ll-dihydro-5ZZ-dibenzo [b, e] [1, 4] diazepine-8carboxylic acid (172):

- 126 -

To a stimng solution of compound 171 (700 mg, 2.25 mmol) in THF: H2O (1: 1, 20 mL) was added lithium hydroxide monohydrate (284 mg, 6.76 mmol) at RT; and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in 5 vacuo. The pH of the residue was acidified to ~4 with 1 N HCl and stirred for 30 min. The precipitated solid was filtered, washed with water (30 mL) and dried in vacuo to afford compound 172 (550 mg, 82%) as an off-white solid. TLC: 20% EtOAc/ hexanes (Rf 0.1); 'H NMR (DMSO-rfé, 500 MHz): 12.81 (br s, 1H), 10.30 (s, 1H), 7.68-7.56 (m, 3H), 7.52-7.45 (m, 1H), 7.23 (dd, 7=9.0, 8.1 Hz, 2H), 7.09 (t,7=7.4 Hz, 1H), 3.71 (br d,7= 17.6 Hz, 2H), 1.5310 1.46 (m, 2H), 0.86 (t, 7= 7.4 Hz, 3H); LC-MS: 96.38%; 296.9 (M⁺+l); (column; Ascentis

Express C-18 (50 χ 3.0 mm, 2.7 pm); RT 2.14 min. 0.025% Aq.TFA + 5% ACN: ACN + 5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of 5-butyl-ll-oxo-10, ll-dihydro-5H-dibenzo [b, e] [1, 4] diazepine-8-carboxylic

Synthesis of methyl 5-butyl-10-(4-methoxybenzyl)-ll-oxo-10, 1 l-dihydro-5Æ-dibenzo {b, e] [1, 4] diazepine-8-carboxylate (174):

- 127 -

To a stirring solution of methyl 10-(4-methoxybenzyl)-l l-oxo-10,11-dihydro-5//-dibenzo [b, e] [1, 4] diazepine-8-carboxylate 173 (500 mg, 1.28 mmol) in DMF (10 mL) under argon atmosphère were added césium carbonate (1.25 g, 3.86 mmol), TBAI (cat 10 mg), bromo butane (1.4 mL, 12.8 mmol) in a sealed tube at RT; heated to 110 °C and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc (2x50 mL). The combined organic layer was washed with water and dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 1 % EtOAc/ CH₂C1₂ to afford compound 174 (300 mg, 28%) as an off white solid. TLC: 5% EtOAc/ CH₂C1₂ (Rf 0.6); *H NMR (400 MHz, DMSO-rf₆): δ 7.96 (d, J= 1.9 Hz, 1H), 7.69 (dd, J = 8.5, 1.9 Hz, 1H), 7.59 (dd,J=7.7, 1.6 Hz, 1H), 7.48-7.42 (m, 1H), 7.33 (d,J= 8.5 Hz, 1H), 7.21 (d, J= 8.0 Hz, 1H), 7.18-7.09 (m, 3H), 6.79 (d, J= 8.8 Hz, 2H), 5.60 (d, J= 15.6 Hz, 1H), 4.88 (d,J=15.6Hz, 1H), 3.80 (s, 3H), 3.71-3.70 (m, 1H), 3.68 (s, 3H), 3.66-3.60 (m, 1H), 1.561.49 (m, 1H), 1.41-1.23 (m, 3H), 0.82 (t, J= 7.3 Hz, 3H); LC-MS: 91.60%; 445.2 (M⁺+l); (column; Ascentis Express C-18 (50 x 3.0 mm, 2.7 pm); RT 3.04 min; 0.025% Aq.TFA + 5% ACN: ACN + 5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of methyl 5-butyl-ll-oxo-10, ll-dihydro-51/-dibenzo [b, e] [1, 4] diazepine-8carboxylate (175):

175

- 128 -

To a stirring solution of methyl 5-butyl-10-(4-methoxybenzyl)-l l-oxo-10, 11 -dihydro-5/7dibenzo [b, e] [1, 4] diazepine-8-carboxylate 174 (300 mg, 0.67 mmol) in trifluoroacetic acid (2 mL) at RT; heated to 60 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with saturated sodium bicarbonate solution (30 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layer was washed with water and dried over sodium sulfate, filtered and concentrated in vacuo to to afford compound 175 (200 mg crude) as an off white solid. TLC: 5% EtOAc/ CH₂C1₂ (Rf 0.2)^11 NMR (DMSO4,400 MHz): δ 10.32 (br s, 1H), 7.71-7.64 (m, 2H), 7.61 (dd, 7=7.7, 1.6 Hz, 1H), 7.53-7.45 (m, 1H), 7.31 (d, 7= 8.5 Hz, 1H), 7.24 (d,7=7.9 Hz, 1H), 7.15 - 7.09 (m, 1H), 3.81 (s, 3H), 3.77-3.58 (m, 2H), 1.58-1.44 (m, 2H), 1.39-1.29 (m, 2H), 0.82 (t, 7 = 7.3 Hz, 3H); LC-MS: 89.47%; 325.3 (M⁺+l); (column; X Select CSH C-18, (50 x 3.0 mm, 2.5 pm); RT 4.26 min; 2.5 mM Aq. NH4OOCH: ACN, 0.8 mL/min).

Synthesis of 5-butyl-l l-oxo-10, 1 l-dihydro-5H-dibenzo {b, e] [1, 4] diazepine-8-carboxylic acid (176):

To a stirring solution of compound 175 (200 mg, 0.61 mmol) in THF: H2O (1: 1, 10 mL) was added lithium hydroxide monohydrate (78 mg, 1.85 mmol) at RT; heated to 60 °C and stirred for 2.5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified to ~4 with 1 N HCl and stirred for 10 min. The precipitated solid was filtered, washed with water (30 mL), ether (20 mL) and pentane (20 mL) and dried in vacuo to afford compound 176 (110 mg, 58%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf 0.1); ^XH NMR (DMSO-î/₆, 400 MHz): δ 12.82 (br s, 1H), 10.30 (s, 1H), 7.69-7.61 (m, 3H), 7.54-7.46 (m, 1H), 7.29-7.23 (m, 2H), 7.11 (t,7 = 7.2 Hz, 1H), 3.86-3.64 (m, 2H), 1.55-1.43 (m, 2H), 1.40-1.29 (m, 2H), 0.82 (t,7= 7.3 Hz, 3H);

- 129 -

LC-MS: 99.00%; 311.0 (M⁺+l); (column; Ascentis Express C-18 (50 x 3.0 mm, 2.7 pm); RT

2.28 min. 0.025% Aq.TFA + 5% ACN: ACN + 5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of 5-isobutyl-ll-oxo-10, ll-dihydro-5Æ-dibenzo {b, e] [1, 4] diazepine-85

178

To a stirring solution of 2-nitrobenzoic acid 177 (20 g, 119.67 mmol) Lbutanol (540 mL) under argon atmosphère were added Boc-anhydride (78.35 g, 359.02 mmol), DMAP (2.90 g, 23.93 mmol) at 0 °C; warmed to RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with EtOAc (200 mL), washed with water (100 mL), brine (150 mL). The organic extract was dried

- 130 over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2-5% EtOAc/ hexanes to afford compound 178 (19 g, 71%) as colorless syrup. TLC: 10% EtOAc/ hexanes (Ry 0.6); *H-NMR (DMSO-Ts, 500 MHz): δ 8.01 (d, J= 7.8 Hz, 1H), 7.85-7.75 (m, 3H), 1.50 (s, 9H);

Synthesis of tert-butyl 2-aminobenzoate (179):

179

To a stirring solution of compound 178 (19 g, 85.11 mmol) in MeOH (200 mL) under inert atmosphère was added 10% Pd/C (10 g, 50% wet) at RT and stirred under hydrogen atmosphère (balloon pressure) at RT for 18 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and washed with MeOH (100 mL). The filtrate was concentrated in vacuo to afford compound 179 (17 g, crude) as colorless syrup. TLC: 10% EtOAc/ hexanes (Ry 0.8); ^XH NMR (400 MHz, DMSO-rfg): δ 7.64 (dd, 7=8.1, 1.6 Hz, 1H), 7.23-7.18 (m, 1H), 6.73 (dd,7=8.4, 0.9 Hz, 1H), 6.56 (br s, 2H), 6.51-6.47 (m, 1H), 1.53 (s, 9H);

Synthesis of m/7-butyl 4-fluoro-3-nitrobenzoate (181): 0₂N^^.C0₂ ^,Bu

U

181

To a stirring solution of 4-fluoro-3-nitrobenzoic acid 180 (10 g, 54.05 mmol) t-butanol (270 mL) under argon atmosphère were added Boc-anhydride (35 g, 162.16 mmol), DMAP (1.3 g, 10.81 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with EtOAc (150 mL), washed with water (75 mL), brine (100 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography (100-200 mesh) using 2-5% EtOAc/

- !

- 131 hexanes to afford compound 181 (14 g, crude) as colorless syrup. TLC: 10% EtOAc/ hexanes (R/ 0.8);

'H NMR (400 MHz, DMSO-î/₆): δ 8.52 (dd, J = Ί3, 2.3 Hz, 1H), 8.30-8.26 (m, 1H), 7.72 (dd, J= 11.0, 8.7 Hz, 1H), 1.47 (s, 9H);

Synthesis of tert-butyl 4-((2-(tert-butoxycarbonyl) phenyl) amino)-3-nitrobenzoate (182):

To a stirring solution of compound 181 (8 g, 42.42 mmol) in dry THF (150 mL) under argon atmosphère was added potassium tertbutoxide (82.9 mL, 82.90 mmol, 1.0 M sol. In THF) at 0 °C and stirred for 45 min; added compound 179 (15 g, 62.23 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL) and dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography (100-200 mesh) using 100% EtOAc to afford compound 182 (6 g 34%) as yellow liquid. TLC: 10% EtOAc/ hexanes (Rf 0.8); 'H NMR (500 MHz, DMSO-d₆): δ 10.94 (s, 1H), 8.60 (d, J= 2.0 Hz, 1H), 8.00-7.92 (m, 2H), 7.65-7.54 (m, 2H), 7.46 (d, J = 9.0 Hz, 1H), 7.30-7.25 (m, 1H), 1.56-1.49 (m, 18H);

Synthesis of tert-butyl 4-((2-(terZ-butoxycarbonyl) phenyl) (isobutyl)amino)-3nitrobenzoate (183):

To a stirring solution of compound 182 (4 g, 9.65 mmol) in DMF (100 mL) under argon atmosphère were added césium carbonate (6.28 g, 19.32 mmol), TBAI (713 mg, 1.93 mmol), 119643

- 132 bromo-2-methylpropane (8.4 mL, 48.66 mmol) in a sealed tube at RT; heated to 85 °C and stirred for 16 h. The reaction was monitored by TLC; after 16 h, the reaction mixture was diluted EtOAc (2 x 75 mL) and washed with water (150 mL), brine (100 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography (100-200 mesh) using 2-5% EtOAc/ hexanes to afford compound 183 (1 g, 22%) as colorless syrup. TLC: 10% EtOAc/ hexanes (Rf 0.5); ’H NMR (400 MHz, DMSO-d₆): δ 7.98 (dd, J = 8.9, 2.1 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.59-7.52 (m, 1H), 7.46 (d,J=8.9Hz, 1H), 7.40 (dd,J=7.8, 1.6 Hz, 1H), 7.33 (dd, J = 8.2, 0.8 Hz, 1H), 7.18 (td, J = 7.5, 1.0 Hz, 1H), 3.67 (d, J = 7.4 Hz, 2H), 2.13-2.05 (m, 1H), 1.49 (s, 9H), 1.14 (s, 9H), 0.98 (d, J= 6.7 Hz, 6H);

Synthesis of teri-butyl 3-amino-4-((2-(teri-butoxycarbonyl) phenyl) (isobutyl) amino) benzoate (184):

184

To a stirring solution of compound 183 (1.5 g, 3.19 mmol) in MeOH (100 mL) under inert atmosphère was added 10% Pd/C (1.5 g, 50% wet) at RT and stirred under hydrogen atmosphère (balloon pressure) at RT for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and washed with MeOH (100 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-10% EtOAc/ hexanes to afford compound 184 (1.4 g, quantitative) as colorless syrup. TLC: 10% EtOAc/ hexanes (Rf. 0.5); 'H NMR (500 MHz, DMSO-</₆): δ 7.42 (dd, J = 7.5, 1.2 Hz, 1H), 7.35-7.29 (m, 1H), 7.21 (d, J= 2.3 Hz, 1H), 7.10 (dd, J= 8.4, 2.0 Hz, 1H), 7.02 (t, J =1.2 Hz, 1H), 6.93 (dd, J = 11.6, 8.1 Hz, 2H), 5.13 (s, 2H), 3.17 (d, J =7.5 Hz, 2H), 1.86-1.8-0 (m, 1H), 1.49 (s, 9H), 1.42 (s, 9H), 0.83 (d, J =7.0 Hz, 6H);

- 133 Synthesis of 5-isobutyl-ll-oxo-10, ll-dihydro-5E/-dibenzo {b, e] [1, 4] diazepine-8carboxylic acid (185):

To a stirring solution of compound 184 (1 g, 2.27 mmol) in 1, 2-dichloroethane (25 mL) under inert atmosphère was added trifluoroacetic acid (3.5 mL, 45.55 mmol) at 0 °C; heated to 80 °C and stirred for 9 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was adjusted to ~8 using saturated sodium bicarbonate solution (10 mL), washed with EtOAc (2 x 75 mL). The pH of the aqueous layer was adjusted to ~1 with 1 N HCl and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 185 (500 mg, 60%) as brown solid. TLC: 30% EtOAc/ hexanes (Rf 0.2); 'H NMR (400 MHz, DMSO-t/é): δ 12.81 (br s, 1H), 10.31 (s, 1H), 7.69-7.59 (m, 3H), 7.52-7.45 (m, 1H), 7.28 (d, J= 8.4 Hz, 1H), 7.23 (d, J= 7.8 Hz, 1H), 7.14-7.07 (m, 1H), 3.63 - 3.46 (m, 2H), 1.83-1.70 (m, 1H), 0.89 (d, J= 6.5 Hz, 6H);

Synthesis of 5-allyl-ll-oxo-10, 1 l-dihydro-5Æ-dibenzo {b, e] [1, 4] diazepine-8-carboxylic acid (190): A common intermediate

- 134-

Synthesis of methyl ll-oxo-10, ll-dihydro-5//-dibenzo {b, ej [1, 4] diazepine-8carboxylate (186):

o

186

To a stirring solution of ll-oxo-10, 11-dihydro-5H-dibenzo [b, e] [1,4] diazepine-8-carboxylic acid 163 (4.5 g, 17.71 mmol) in 50% MeOH/ CH2CI2 under argon atmosphère was added diazomethane in diethyl ether (freshly prepared by addition of 7V-nitrosomethyl urea (9.1 g, 88.58 mmol) to mixture of 50% KOH solution (100 mL) and diethylether (200 mL) at 0°C) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2% MeOH/ CH2CI2 to afford compound 186 (3 g, 64%) as an off white solid. TLC: 5% MeOH / CH₂C1₂ (Rf. 0.6); ^XH NMR (400 MHz, DMSO-J₆): δ 9.94 (s, 1H), 8.32 (s, 1H), 7.71 (dd, J= 7.9, 1.6 Hz, 1H), 7.60-7.53 (m, 2H), 7.38-7.34 (m, 1H), 7.06 (d, J= 8.3 Hz, 1H), 7.02-6.98 (m, 1H), 6.95-6.89 (m, 1H), 3.79 (s, 3H);

- 135 LC-MS: 87.13%; 269.0 (M⁺+l); (column; Ascentis Express C-18 (50 x 3.0 mm, 2.7 pm); RT

2.05 min. 0.025% Aq.TFA + 5% ACN: ACN + 5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of methyl 10-(4-methoxybenzyl)-ll-oxo-10, ll-dihydro-5Æ-dibenzo [b, e] [1, 4] diazepine-8-carboxylate (173):

173

To a stirring solution of methyl 1 l-oxo-10, 11 -dihydro-5/7-dibenzo [b, e] [1,4] diazepine-8carboxylate 186 (3 g, 11.19 mmol) in DMF (30 mL) under inert atmosphère were added CS2CO3 (4.3 g, 13.43 mmol), PMBC1 (2.1 g, 13.43 mmol) at 0°C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water and extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with water (100 ml) and dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2% EtOAc/ CH₂C1₂ to afford compound 173 (1.7 g, 40%) as an off white solid. TLC: 5% EtOAc/ CH₂C1₂ (Rf. 0.6); 'H NMR (400 MHz, DMSO-rf₆): δ 8.32 (s, 1H), 7.85 (d, J= 1.8 Hz, 1H), 7.68 (dd,J=7.8, 1.4 Hz, 1H), 7.62 (dd, J= 8.3, 1.9 Hz, 1H), 7.41-7.35 (m, 1H), 7.20-7.18 (m, 3H), 7.09 (d, J = 7.5 Hz, 1H), 7.05-6.99 (m, 1H), 6.84 (d, J = 8.7 Hz, 2H), 5.16 (s, 2H), 3.77 (s, 3H), 3.70 (s, 3H); LC-MS: 94.69%; 389.1 (M⁺+l); (column; Ascentis Express C-18 (50 x 3.0 mm, 2.7 pm); RT 2.55 min. 0.025% Aq.TFA + 5% ACN: ACN + 5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of methyl 5-allyl-10-(4-methoxybenzyl)-ll-oxo-10, ll-dihydro-577-dibenzo (b, e] [1, 4] diazepine-8-carboxylate (188):

PA513177/OA/5598087.1

- 136 -

To a stirring solution of methyl 10-(4-methoxybenzyl)-l l-oxo-10, 1 l-dihydro-5/7-dibenzo [b, e] [1, 4] diazepine-8-carboxylate 173 (600 mg, 1.54 mmol) in DMF (10 mL) under argon atmosphère were added césium carbonate (1.5 g, 4.63 mmol), TBAI (0.057 mg, 0.15 mmol), 3bromoprop-l-ene (1.3 mL, 15.4 mmol) in a sealed tube at RT; heated to 120 °C and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (50 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with water (100 mL) and dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2% EtOAc/ hexanes to afford compound 188 (555 mg, 84%) as an off-white solid. TLC: 5% EtOAc/ hexanes (Rf. 0.6);^ NMR (DMSO-</₆,400 MHz): δ 7.95 (d, 7= 1.9 Hz, 1H), 7.67 (dd,7=8.5, 1.9 Hz, 1H), 7.61 (dd,7=7.7, 1.6 Hz, 1 H), 7.48-7.42 (m, 1H), 7.32 (d, 7= 8.7 Hz, 1H), 7.23-7.10 (m, 4H), 6.81 (d, 7= 8.7 Hz, 2H), 5.71-5.57 (m, 2H), 5.30 (dd, 7= 17.3, 1.5 Hz, 1H), 5.12 (dd, 7= 10.4, 1.4 Hz, 1H), 4.91 (d, 7= 15.6 Hz, 1H), 4.41 (t, 7= 5.7 Hz, 2H), 3.79 (s, 3H), 3.69 (s, 3H); LC-MS: 96.23%; 429.1 (M⁺+l); (column;

Ascentis Express C-18 (50 x 3.0 mm, 2.7 pm); RT 2.81 min; 0.025% Aq.TFA + 5% ACN: ACN + 5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of methyl 5-allyl-ll-oxo-10, ll-dihydro-51Z-dibenzo [b, e] [1, 4] diazepine-8carboxylate (189):

189

- 137 -

A mixture of methyl 5-allyl-10-(4-methoxybenzyl)-l l-oxo-10, 1 l-dihydro-577-dibenzo [b, e] [1,4] diazepine-8-carboxylate 188 (550 mg, 1.28 mmol) in trifluoroacetic acid (3 mL) at RT was heated to 60 °C and stirred for 1.5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with saturated sodium bicarbonate solution (30 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layer was washed with water and dried over sodium sulfate, filtered and concentrated in vacuo to to afford compound 189 (300 mg, 76%) as an off-white solid. TLC: 30% EtOAc/ CH₂C1₂ (Rf 0.3); *H NMR (500 MHz, DMSO-7₆): δ 10.38 (s, 1H), 7.70-7.66 (m, 2H), 7.62 (àà,J=in, 1.3 Hz, 1H), 7.51-7.46 (m, 1H), 7.29 (d, 7= 9.0 Hz, 1H), 7.22 (d,7=8.1 Hz, 1H), 7.12 (t, 7= 7.5 Hz, 1H), 5.79-5.65 (m, 1H), 5.33 (dd,7= 17.2, 1.0 Hz, 1H), 5.14 (d, 7= 9.5 Hz, 1H), 4.48-4.44 (m, 2H), 3.81 (s, 3H); LC-MS: 99.27%; 309.0 (M⁺+l); column; Ascentis Express C-18 (50 x 3.0 mm, 2.7 pm); RT 2.36 min; 0.025% Aq.TFA + 5% ACN: ACN + 5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of 5-allyl-l l-oxo-10, 1 l-dihydro-JÆ-dibenzo [b, e] [1,4] diazepine-8-carboxylic acid (190):

To a stirring solution of compound 189 (300 mg, 0.97 mmol) in THF: H₂O (1: 1, 15 mL) was added lithium hydroxide monohydrate (122 mg, 2.92 mmol) at RT; heated to 70 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified to ~4 with 1 N HCl and stirred for 15 min. The precipitated solid was filtered, washed with water (40 mL), diethylether (20 mL) and pentane (20 mL) and dried in vacuo to afford compound 190 (200 mg, 70%) as an offwhite solid. TLC: 50% EtOAc/ hexanes (Rf. 0.1); *H NMR (400 MHz, DMSO-7₀): δ 12.85 (br s, 1H), 10.35 (s, 1H), 7.67-7.59 (m, 3H), 7.52-7.44 (m, 1H), 7.26 (d, 7= 8.9 Hz, 1H), 7.21 (d, 7= 8.0 Hz, 1H), 7.11 (t,7=7.2 Hz, 1H), 5.80-5.66 (m, 1H), 5.33 (dd,7= 17.3, 1.6 Hz, 1H),

- 138 -

5.14 (dd, J= 10.4, 1.4 Hz, 1H), 4.45 (d, .7=2.4 Hz, 2H); LC-MS: 96.58%; 294.9 (M⁺+l);

(column; Ascentis Express C-18 (50 *3.0 mm, 2.7 pm); RT 2.06 min. 0.025% Aq.TFA + 5%

ACN: ACN + 5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of 5-(2-hydroxyethyl)-ll-oxo-10, ll-dihydro-52/-dibenzo [b, e] [1, 4] diazepine-

Synthesis of methyl 10-(4-methoxybenzyl)-ll-oxo-5-(2-oxoethyl)-10, 1 l-dihydro-5//dibenzo [b, e] [1, 4] diazepine-8-carboxylate (191):

¹⁹¹

To a stirring solution of methyl 5-allyl-10-(4-methoxybenzyl)-l l-oxo-10, 1 l-dihydro-5/7dibenzo [b, e] [1, 4] diazepine-8-carboxylate 188 (500 mg, 1.16 mmol) in 1, 4 dioxane: H2O (1: 1: 2, 40 mL) was added 2, 6-lutidine (0.27 mL, 2.30 mmol) at 25 °C followed by addition of osmium tetroxide (3.75 mL, 0.058 mmol, 0.4% solution in Mnitanol), sodium metaperiodate (1 g, 4.67 mmol) and stirred at RT for 16 h. The reaction was monitored by TLC; after completion the reaction mixture was quenched with ice-cold water (10 mL) and extracted with CH2CI2 (2 x 75 mL). The combined organic extracts were dried over sodium and concentrated in vacuo to

- 139 afford crude compound 191 (600 mg) as pale brown solid. TLC: 30% EtOAc/ hexanes (Rf 0.4); LC-MS: 40.34%; 431.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm);

RT 2.53 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of methyl 5-(2-hydroxyethyl)-10-(4-methoxybenzyl)-l l-oxo-10, 1 l-dihydio-5/7dibenzo [b, e] [1, 4] diazepine-8-carboxylate (192):

OH

192

To a stirring solution of methyl 10-(4-methoxybenzyl)-l l-oxo-5-(2-oxoethyl)-10, 11-dihydro5Æ-dibenzo \b, e] [1, 4] diazepine-8-carboxylate 191 (1.15 g, crude) in MeOH (30 mL) under argon atmosphère was added sodium borohydride (203 mg, 5.34 mmol) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH2CI2 (2 x 100 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to obtain the crude. The crude was purified through silicagel column chromatography (100-200 mesh) using 40-50% EtOAc/ hexanes to afford compound 192 (400 mg, 40%, over 2 steps) as an offwhite solid. TLC: 40% EtOAc/ hexanes (Rf 0.2); 'H NMR (400 MHz, DMSO-^): δ 7.92 (d, J = 1.8 Hz, 1H), 7.67 (dd,7=8.5, 1.9 Hz, 1H), 7.61 (dd,7=7.7, 1.6 Hz, 1H), 7.49-7.44 (m, 1H), 7.36 (d, J= 8.5 Hz, 1H), 7.27-7.21 (m, 3H), 7.16- 7.10 (m, 1H), 6.80 (d, J= 8.9 Hz, 2H), 5.64 (d, J = 15.7 Hz, 1H), 4.89 (d, 7= 15.9 Hz, 1H), 4.76 (t, J= 5.3 Hz, 1H), 3.91-3.80 (m, 2H), 3.78 (s, 3H), 3.68 (s, 3H), 3.56-3.48 (m, 2H); LC-MS: 94.51%; 432.1 (M⁺+l); (column;

Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 2.35 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of methyl ll-oxo-5-(2-(2, 2, 2-trifluoroacetoxy) ethyl)-10, ll-dihydro-517dibenzo {b, e] [1, 4] diazepine-8-carboxylate (193):

A mixture of methyl 5-(2-hydroxyethyl)-10-(4-methoxybenzyl)-l l-oxo-10, 1 l-dihydro-5Hdibenzo [b, e] [1,4] diazepine-8-carboxylate 192 (400 mg, 0.92 mmol) in trifluoroacetic acid (0.11 mL, 1.51 mmol) under inert atmosphère at RT was heated to 60 oC and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The residue was diluted with CH2CI2 (100 mL) and washed with saturated sodium bicarbonate solution (30 mL). The organic extracts were dried over sodium sulfate and concentrated in vacuo to afford 203 (450 mg, mixture of 193 (major) & 193A (minor)) as an off-white solid. TLC: 40% EtOAc/ hexanes (Rf 0.8); LC-MS: 80.01%; 409.0 (M⁺+l), 12.26%; 313.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.40 min, 1.91 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of 5-(2-hydroxyethyl)-l l-oxo-10, ll-dihydro-5Æ-dibenzo [b, e] [1, 4] diazepine8-carboxylic acid (194):

194

To a stirring solution of compound 193 & 193A (430 mg, mixture of compounds) in THF: H₂O (1: 1, 14 mL) was added lithium hydroxide monohydrate (221 mg, 5.26 mmol) portion wise for 10 min at RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 2 M HCl to ~1. The obtained solid was filtered and dried in vacuo to afford compound 194 (250 mg, 80%) as an off-white solid. TLC: 50% EtOAc/ hexanes (Rf 0.1); NMR (400 MHz,

- 141 -

DMSO-î/ô): δ 12.84 (br s, 1H), 10.30 (s, 1H), 7.68-7.59 (m, 3H), 7.54-7.47 (m, 1H), 7.29-7.23 (m, 2H), 7.14-7.08 (m, 1H), 4.66 (t, J= 4.6 Hz, 1H), 3.89-3.79 (m, 2H), 3.54-3.48 (m, 2H);

LC-MS: 92.62%; 298.9 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.66 min, 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of 6-oxo-6, ll-dihydro-5Æ-dibenzo [b, e] azepine-3-carboxylic acid (210): A common intermediate

o

CO₂Me NO₂ ¹⁹⁷

To a stirring solution of methyl 2-(bromomethyl) benzoate 195 (9 g, 39.30 mmol) in 1, 2 dimethoxy ethane (72 mL) was added Pd(PPh3)4 (1.81 g, 1.57 mmol) and purged under argon atmosphère for 10 min. To this were added (4-(ethoxycarbonyl)-2-nitrophenyl) boronic acid 196 (10.6 g, 44.41 mmol) dissolved in 1, 2 dimethoxy ethane: EtOH (2: 1, 108 mL) and 2 M 15 sodium carbonate solution (72 mL) and purged under argon atmosphère for 15 min at RT and stirred for 2 h. The reaction was monitored by TLC; after completion the reaction the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2-6% EtOAc/ hexanes to afford compound 197 (5.6 g, 41%) as an off19643

- 142 - white solid. TLC: 10% EtOAc/ hexanes (Rf. 0.3); 'h-NMR (DMSO-4 400 MHz): δ 8.45 (s, 1H), 8.11 (dd, J = 8.1, 1.8 Hz, 1H), 7.93 (dd,J=7.8, 1.4 Hz, 1H), 7.59 (td, J= 7.5, 1.5 Hz, 1H), 7.45 (td, J= 7.6, 1.1 Hz, 1H), 7.29 (d, J= 7.1 Hz, 1H), 7.21 (d, J= 8.2 Hz, 1H), 4.63 (s, 2H), 4.36 (q, J= 7.1 Hz, 2H), 3.70 (s, 3H), 1.33 (t, J=7.1 Hz, 3H).

Synthesis of 4-(2-carboxybenzyl)-3-nitrobenzoic acid (198):

198

To a stirring solution of compound 197 (5.6 g, 16.23 mmol) in THF: H2O (4: 1,615 mL) was added lithium hydroxide monohydrate (6.82 g, 162.31 mmol) portion wise for 10 min at RT heated to 60 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 2 N HCl to ~1. The obtained solid was filtered and dried in vacuo to obtain compound 198 (3.2 g, 66%) as yellow solid. TLC: 10% EtOAc/ hexanes (Rf. 0.1); *H-NMR (CD3OD-J4, 400 MHz): δ 8.34 (s, 1H), 8.00 (d, J= 8.0 Hz, 1H), 7.65-7.64 (m, 1H), 7.63 (t, J = 6.0 Hz, 1H), 7.53 (t, J= 6.0 Hz, 1H), 7.26 (d, J= 7.6 Hz, 1H), 7.13 (d, J= 8.0 Hz, 1H), 4.70 (s, 2H).

Synthesis of 3-amino-4-(2-carboxybenzyl) benzoic acid (199):

co₂h nh₂

199

To a stirring solution of compound 198 (1 g, 3.32 mmol) in MeOH (20 mL) under inert atmosphère was added 10% Pd/C (200 mg) at RT and stirred under hydrogen atmosphère (balloon pressure) at RT for 18 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and washed with MeOH (100 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude washed with diethyl ether

- 143 (30 mL) and dried in vacuo to afford compound 199 (830 mg, 92%) as pale brown solid. TLC: 10% MeOH/ CH₂C1₂ (Ry 0.2); ^XH NMR (DMSO-4 400 MHz): δ 12.48 ( br s, 1H), 7.81 (d, J = 7.4 Hz, 1H), 7.43 (t, J = 7.3 Ηζ,ΙΗ), 7.31 (t, J= 7.6 Ηζ,ΙΗ), 7.24 (s, 1H), 7.13 (d, J= 7.5 Hz, 1H), 7.02 (dd, J= 7.8, 1.4 Hz, 1H), 3.17 (s, 2H); LC-MS: 91.07%; 271.9 (M⁺+l); (column; X

Select CSH C-18, (50 x 3.0 mm, 3.5 pm); RT 2.51 min. 0.05% Aq.TFA: ACN, 0.8 mL/min).

Synthesis of 6-oxo-6, ll-dihydro-5/7-dibenzo {b, e] azepine-3-carboxylic acid (200):

200

To a stirring solution of compound 199 (830 mg, 3.06 mmol) in THF (20 mL) under inert atmosphère was added CDI (2.02 g, 12.25 mmol) at RT and stirred for 18 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was adjusted to ~2 using 4 N HCl. The precipitated solid was filtered, washed with and dried in vacuo to afford compound 200 (515 mg, 66%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Ry 0.3); ^XH NMR (DMSO-7₆, 400 MHz): δ 12.93 (br s, 1H), 10.57 (s, 1H), 7.74-7.67 (m, 2H), 7.64 (dd, J= 7.8, 1.7 Hz, 1H), 7.52-7.44 (m, 2H), 7.42-7.38 (m, 1H),

7.34 (td J= 7.5, 1.3 Hz, 1H), 3.98 (s, 2H); LC-MS: 99.31%; 253.9 (M⁺+l); (column; X Select

CSH C-18, (50 x 3.0 mm, 3.5 pm); RT 2.75 min. 0.05% Aq.TFA: ACN, 0.8 mL/min).

- 144Synthesis of ll-methyl-6-oxo-6, ll-dihydro-577-dibenzo [b, e] azepine-3-carboxylic acid

Synthesis of methyl 2-bromobenzoate (202):

202

- 145 -

To a stirring solution of 2-bromobenzoic acid 201 (15 g, 74.62 mmol) in MeOH (150 mL) under inert atmosphère was added concentrated sulfuric acid (4 mL, 75.04 mmol) dropwise for 5 min at 0 °C; heated to reflux and stirred for 18 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with ice-cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 202 (14 g, 93%) as colorless syrup. TLC: 10% EtOAc/ hexanes (Rf 0.5). ^rH NMR (CDC1₃, 400 MHz): δ 7.81-7.77 (m, 1H), 7.70-7.64 (m, 1H), 7.39-7.30 (m, 2H), 3.94 (s, 3H).

Synthesis of methyl 2-((trimethylsilyI) ethynyl) benzoate (203): o

203

To a stirring solution of methyl 2-bromobenzoate 202 (14 g, 65.11 mmol) in THF (150 mL) under inert atmosphère were added triphenylphosphine (426 mg, 1.62 mmol), Pd(PPh3)2C12 (4.57 g, 6.51 mmol), ethynyltrimethylsilane (18.4 mL, 130.23 mmol), triethyl amine (18.7 mL, 130.2 mmol) and purged under argon for 15 min. To this was added copper iodide (1.23 g, 6.51 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite washed with EtOAc (200 mL). The filtrate was washed with water (150 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2% EtOAc/ hexanes to afford compound 203 (11 g, 73%) a colorless syrup. TLC: 5% EtOAc/ hexanes (Rf 0.5); 'H NMR (CDCl₃,400 MHz) δ 7.92-7.88 (m, 1H), 7.60-7.55 (m, 1H), 7.44 (td, 7=7.6, 1.5 Hz, 1H), 7.36 (td, 7= 7.6, 1.3 Hz, 1H), 3.92 (s, 3H), 0.27 (s, 9H).

Synthesis of methyl 2-ethynylbenzoate (204):

- 146 ο

204

Το a stirring solution of compound 203 (45 g, 193.96 mmol) in MeOH (500 mL) under inert atmosphère was added potassium carbonate (40 g, 290.94 mmol) at RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite washed with CH2O2 (2 x 500 mL). The filtrate was removed in vacuo to obtain the crude. The crude was as purified through silica gel column chromatography using 2% EtOAc/ hexanes to afford compound 204 (31 g, 33%) as colorless syrup. TLC: 5% EtOAc/ hexanes (R/. 0.5); *H NMR (CDCl₃,400 MHz): δ 7.97-7.91 (m, 1H), 7.62 (dd, J = Ί.Ί, 1.1 Hz, 1H), 7.47 (td, J=7.6, 1.5 Hz, 1H), 7.40 (td, J=7.7, 1.4 Hz, 1H), 3.38 (s, 1H), 3.91 (s, 3H).

Synthesis of methyl 2-(l-(tributylstannyl) vinyl) benzoate (205): o ^Αγ3η(Βυ)₃

205

To a stirring solution of compound 204 (10 g, 62.5 mmol) and Pd(PPh₃)₂C12 (877 mg, 1.25 mmol) in THF (37 mL) under inert atmosphère was added tributyltin hydride (20.43 mL, 75 mmol) at RT and stirred for 2.5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2% EtOAc/ hexanes to afford compound 205 (28 g, 54%) as colorless syrup. TLC: 5% EtOAc/ hexanes (Rf. 0.8); 'H NMR (CDCl₃,400 MHz): δ 7.87 (dd, J = 7.8, 0.9 Hz, 1H), 7.41 (td,J=7.6, 1.4 Hz, 1H), 7.21 (td,J=7.6, 1.3 Hz, 1H), 7.01 (dd, J= Ί.Ί, 0.9 Hz, 1H), 5.67 (d, J= 2.8 Hz, 1H), 5.38 (d, J= 2.9 Hz, 1H), 3.82 (s, 3H), 1.49-1.39 (m, 6H), 1.30-1.20 (m, 6H), 0.90-0.83 (m, 15H).

Synthesis of methyl 4-iodo-3-nitrobenzoate (207):

- 147o

207

To a stirring solution of 4-iodo-3-nitrobenzoic acid 206 (15 g, 51.36 mmol) in MeOH (150 mL) under inert atmosphère was added concentrated sulphuric acid (15 mL) dropwise for 10 min at 0 °C; warmed to RT at stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with ice-cold water (500 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed saturated sodium bicarbonate solution (2 x 100 mL) dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 207 (13 g, 83%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf 0.8); 'H NMR (CDC1₃, 500 MHz) δ 8.45 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.88 (dd, J= 8.2, 1.9 Hz, 1H), 3.97 (s, 3H).

Synthesis of methyl 4-(l-(2-(methoxycarbonyl) phenyl) vinyl)-3-nitrobenzoate (208):

To a stirring solution of compound 205 (25 g, 5.52 mmol) in 1, 4-dioxane (40 mL) under inert atmosphère in a sealed tube were added methyl 4-iodo-3-nitrobenzoate 207 (1.86 g, 6.08 mmol), lithium chloride (813 mg, 19.35 mmol) and purged under argon for 20 min. To this was added Pd(dppf)C12 (2 g, 2.76 mmol) at RT; heated to 120 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite washed with EtOAc (2x50 mL). The filtrate was washed with water (2 x 50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 208 (1.3 g, 70%) colorless syrup. TLC: 20% EtOAc/ hexanes (Rf 0.4); 'H-NMR (CDCI3, 400 MHz): δ 8.30 (s, 1H), 8.17 (dd, J = 8.2, 1.8 Hz, 1H), 7.69-7.65 (m, 2H), 7.52-7.42 (m, 2H), 7.40-7.35 (m, 1H), 5.61 (s, 1H), 5.58 (s, 1H), 3.96 (s, 3H), 3.58 (s, 3H).

- 148 Synthesis of methyl 3-amino-4-(l-(2-(methoxycarbonyl) phenyl) ethyl) benzoate (209):

To a stirring solution of compound 208 (100 g, 0.29 mmol) in MeOH (10 mL) under inert atmosphère was added 10% Pd/ C (40 mg, dry) at RT and stirred under hydrogen atmosphère (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with CH2CI2 (2x50 mL). The filtrate was concentrated in vacuo to afford compound 209 (70 mg, 77%) as colorless syrup.

TLC: 20% EtOAc/ hexanes (Rf. 0.7); *H-NMR (DMSO-7₆, 500 MHz): δ 7.68 (dd, J= 7.8, 1.2 Hz, 1H), 7.46 (td, 7=7.6, 1.4 Hz, 1H), 7.32 (td, J= 7.5, 1.0 Hz, 1H), 7.24 (s, 1H), 7.21-7.15 (m, 2H), 7.14-7.10 (m, 1H), 5.09 (s, 2H), 4.85 (q, 7 = 6.9 Hz, 1H), 3.79 (s, 6H), 1.46 (d, 7= 7.0 Hz, 3H).

Synthesis of 3-amino-4-(l-(2-carboxyphenyl) ethyl) benzoic acid (210):

To a stirring solution of compound 209 (1.4 g, 4.47 mmol) in THF: H2O (4: 1, 20 mL) was added lithium hydroxide monohydrate (1.07 g, 22.3 mmol) at RT and heated to 70 °C and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 2 N HCl to ~4. The precipitated solid was filtered, washed with water (50 mL), «-pentane (30 mL) and dried in vacuo to afford compound 210 (900 mg, 71%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.2); *H-NMR (DMSO-4 500 MHz): δ 12.50 (br s, 1H), 7.70 (dd, 7= 7.8, 1.2 Hz, 1H), 7.40 (td, 7=7.6, 1.3 Hz, 1H), 7.28-7.23 (m, 2H), 7.19-7.17 (m, 2H), 7.09 (d,7=7.8 Hz, 1H), 4.98 (q, 7= 6.9 Hz, 1H), 1.44 (d, 7= 6.9 Hz, 3H).

- 149 Synthesis of ll-methyl-6-oxo-6, 1 l-dihydro-5Æ-dibenzo [6, e] azepine-3-carboxyIic acid (211):

211

To a stirring solution of compound 210 (900 mg, 3.15 mmol) in THF (20 mL) under inert atmosphère was added CDI (2.5 g, 15.7 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (15 mL) and pH was adjusted to ~4 with 2 N HCl. The obtained solid was filtered washed with water (30 mL), diethyl ether (20 mL) and dried in vacuo to afford compound 211 (750 mg, 89%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.3); LC-MS: 96.89%; 267.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.14 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 6, ll-dioxo-6, ll-dihydro-5Z7-dibenzo [b, e] azepine-3-carboxyIic acid (216):

Synthesis of methyl 4-(2-(methoxycarbonyl) benzoyl)-3-nitrobenzoate (213):

- 150 -

213

To a stirring solution of methyl 4-(l-(2-(methoxycarbonyl) phenyl) vinyl)-3-nitrobenzoate 212 (8 g, 23.46 mmol) in a mixture of CH2CI2: H2O (1:1, 500 mL) were added KMNO4 (37 g, 234.6 mmol), tetrabutylammonium hydrogensulfate (7.9 g, 23.46 mmol), sodium bicarbonate (9.8 g, 117.3 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with acetic acid (20 mL) and 10% sodium bisulfate solution (50 mL) and extracted with CH2CI2 (2 x 500 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified through silica gel column chromatography using 40% EtOAc/ hexanes to afford compound 213 (4 g, 50%) as colorless syrup. TLC: 30% EtOAc/ hexanes (Rf 0.5); ‘H-NMR (DMSO4, 500 MHz): δ 8.55 (s, 1H), 8.34 (dd, J= 18.0, 1.6 Hz, 1H), 7.82-7.65 (m, 4H), 7.56 (d, J = 7.5 Hz, 1H), 3.94 (s, 3H), 3.70 (s, 3H).

Synthesis of methyl 3-amino-4-(2-(methoxycarbonyl) benzoyl) benzoate (214): o ^OMe P °^Me °h₂n

214

To a stirring solution of compound 213 (4 g, 11.66 mmol) in a mixture of EtOH: H2O (1: 1, 60 mL) were added iron powder (6.5 g, 116.48 mmol) and ammonium chloride (6.1 g, 115.09 mmol) at RT; heated to 90 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with CH2Q2 (200 mL), filtered through celite, washed with 20% MeOH/ CH2CI2 (50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 1% MeOH/ CH2CI2 (50 mL) to afford compound 214 (2 g, 56%) as pale green solid. TLC: 20% MeOH/ CH2CI2 (Rf. 0.7); 'H-NMR

- 151 - (DMSO-rf₆, 500 MHz): δ 7.99 (d, J = 7.8 Hz, 1H), 7.75 (dd, J= 7.8, 1.2 Hz, 1H), 7.65 (td, J= 7.8, 1.2 Hz, 1H), 7.51 (s, 1H), 7.47-7.41 (m, 3H), 6.98 (d, J= 8.4 Hz, 1H), 6.90 (dd, J= 8.4,1.4 Hz, 1H), 3.62 (s, 3H), 3.31 (s, 3H).

Synthesis of 3-amino-4-(2-carboxybenzoyl) benzoic acid (215): (D

P ^oH₂N

215

To a stirring solution of compound 214 (2 g, 6.38 mmol) in THF: H₂O (4: 1, 30 mL) was added lithium hydroxide monohydrate (1.34 g, 31.94 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 2 N HCl to ~4. The precipitated solid was filtered washed with water (50 mL), triturated with diethyl ether (2 x 20 mL) and dried in vacuo to afford compound 215 (1.5 g 84%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Ry 0.2); ^XH-NMR (DMSO-J₆, 500 MHz): δ 13.04 (br s, 2H), 7.97 (d, J= 7.5 Hz, 1H), 7.72-7.67 (m, 1H), 7.63-7.59 (m, 1H), 7.45 (s, 1H), 7.41 (br s, 2H), 7.35 (d, J= 7.5 Hz, 1H), 6.97 (d, J= 8.4 Hz, 1H), 6.89 (dd, J= 8.4 ,1.4 Hz, 1H).

Synthesis of 6, ll-dioxo-6, ll-dihydro-5/Z-dibenzo [b, e] azepine-3-carboxylic acid (216):

216

To a stirring solution of compound 215 (750 mg, 2.63 mmol) in THF (20 mL) under inert atmosphère was added CDI (2.13 g, 13.15 mmol) 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with ice-cold water (15 mL) and the pH was adjusted to ~4 with 2 N HCl. The obtained solid was filtered washed with water (30 mL), diethylether (20 mL) and dried in vacuo to afford compound 216 (600 mg, 86%) as an off-white solid. TLC: 10%

- 152 MeOH/ CH₂C1₂ (Rf. 0.3); ^XH-NMR (DMSO-rf₆, 500 MHz): δ 13.30 (br s, 1H), 11.25 (s, 1H), 8.19 (d,J = 6.4 Hz, 1H), 7.96 (s, 1H), 7.89-7.79 (m, 4H), 7.72 (d, J=8.1 Hz, 1H).

Amines for compounds:

Commercial amines used in the préparation of compounds:

cihh₂n'Vt^S\ ^Η2Ν~Ό% /V nV h₂\'V_s^ h₂nV_sX_ci

217 218 219 220

Préparation of the amines:

Synthesis of 4-(5-(aminomethyl) thiazol-2-yl) benzonitrile hydrochloride (227):

Synthesis of 5-(azidomethyl)-2-chlorothiazole (222): To a stirring solution of 2-chloro-5(chloromethyl) thiazole 221 (10 g, 59.52 mmol) in EtOH (150 mL) under argon atmosphère was added sodium azide (5.8 g, 89.23 mmol) at RT and heated to reflux for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered, washed with EtOAc (100 mL) and the filtrate was concentrated in vacuo to obtain the crude.

The crude was purified through silica gel flash column chromatography using 5% EtOAc/ hexanes to afford compound 222 (10 g, 97%) as pale yellow oil. TLC: 10% EtOAc/ hexanes (Rf. 0.5); LC-MS: 99.33%; 174.7 (M⁺+l); (column; Ascentis Express Cl 8, (50 x 3.0 mm, 2.7 pm); RT 2.28 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

- 153 -

Synthesis of (2-chlorothiazol-5-yl) methanamine (223): To a stirring solution of compound 222 (10 g, 57.47 mmol) in THF: H2O (15: 1, 160 mL) was added triphenyl phosphine (15.05 g, 57.45 mmol) portion wise for 15 min at RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with EtOAc (3 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude compound 223 (10 g) as an offwhite solid; which was carried forward for next step without further purification. TLC: 10% EtOAc/ hexanes (Rf 0.2). LC-MS: 21.47% + 7.59%; 149.0 (M⁺+l); (column; X-select CSH ΟΙ 8 (50 x 3.0 mm, 2.5 pm); RT 0.73 min & 0.82 min. 2.5 mM NH4OOCH (Aq) + 5% ACN: ACN + 5% 2.5 mM NH4OOCH (Aq); 0.8 mL/min).

Synthesis of m/ t-buty! ((2-chlorothiazol-5-yl) methyl) carbamate (224): To a stirring solution of compound 223 (10 g, 67.56 mmol) in CH2Q2 (150 mL) under argon atmosphère were added triethylamine (19.48 mL, 135.05 mmol) at 0 °C and stirred for 10 min. To this was added Boc-anhydride (17.67 g, 81.05 mmol) at the same température; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (200 mL) and extracted with CH2CI2 (3 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 10-20% EtOAc/ hexanes to afford compound 224 (8 g, 56% over 2 steps) as pale yellow liquid. TLC: 20% EtOAc/ hexanes (Rf 0.8); ’ll-NMR (DMSO-dé, 400 MHz): δ 7.57 (d, J = 4.0 Hz, 1H), 7.49 (s, 1H), 4.24 (d, J= 6.1 Hz, 2H), 1.39 (s, 9H).

Synthesis of m/7-butyl ((2-(4-cyanophenyl) thiazol-5-yl) methyl) carbamate (226): To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl) carbamate 224 (1 g, 4.02 mmol) in 1, 2 dimethoxy ethane: H2O (4: 1, 30 mL) were added sodium carbonate (1.49 g, 14.08 mmol), (4-cyanophenyl) boronic acid 225 (710 mg, 4.82 mmol) and purged under argon atmosphère for 30 min. To this was added Pd(PPh3)4 (464 mg, 0.40 mmol) at RT; heated to 100 oC and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice-cold water (100 mL) and extracted with EtOAc (2 x 150

- 154- mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude purified through silicagel column chromatography using 30% EtOAc/ hexanes to afford compound 226 (550 mg, 43%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf: 0.3); 1H NMR (DMSO-d6, 500 MHz): δ 8.08 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.6 Hz, 2H), 7.81 (s, 1H), 7.61 (t, J = 5.9 Hz, 1H), 4.37 (d, J = 5.9 Hz, 2H), 1.40 (s, 9H); LC-MS: 97.93%; 315.9 (M++1); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.52 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-(5-(aminomethyl) thiazol-2-yl) benzonitrile hydrochloride (227): To a stirring solution of compound 226 (550 mg, 1.74 mmol) in CH2CI2 (10 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (5 mL) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with EtOAc (2x10 mL) and dried in vacuo to afford compound 227 (400 mg, 92%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf. 0.2); *H-NMR (DMSO-7_d, 500 MHz): δ 8.68 (br s, 3H), 8.12 (s, 1H), 8.10 (d, J= 4.3 Hz, 2H), 7.98 (d, J= 8.4 Hz, 2H), 4.38 (q, J= 5.4 Hz, 2H); LC-MS: 98.49%; 215.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.43 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 5-(aminomethyl) thiazol-2-amine dihydrochloride (230):

	(Boc)₂O	Jl )F-NHBoc	4 N HCl in 1,4-Dioxane	N Jl NH₂ HCl
NC^	< /·~νη₂		i~^s		I ^s
s	NICI₂,NaBH₄, MeOH	NHBoc	CH₂CI₂	NH₂. HCl
	228		229		230

Synthesis of tert-butyl ((2-((tert-butoxycarbonyl) amino) thiazol-5-yl) methyl) carbamate (229): To a stirring solution of 2-aminothiazole-5-carbonitrile 228 (300 mg, 2.40 mmol) in MeOH (50 mL) were added Boc-anhydride (1.5 mL, 7.20 mmol), nickel (II) chloride (571 mg, 2.40 mmol) at 0 °C. To this was added sodium borohydride (638 mg, 16.80 mmol) portion wise

- 155 for 10 min at 0 °C; warmed to RT and stirred for 18 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with EtOAc (100 mL) and water (75 mL), filtered through celite. The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to obtain compound 229 (300 mg) as colorless syrup. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.5); ^XH NMR (DMSO-î/₆, 500 MHz): δ 11.24 (br s, 1H), 7.38 (br s, 1H), 7.11 (s, 1H), 4.17 (d, J = 5.5 Hz, 2H), 1.39 (s, 9H), 1.37 (s, 9H).

Synthesis of 5-(aminomethyl) thiazol-2-amine dihydrochloride (230): To a stirring solution of compound 229 (300 mg) in CH2CI2 (10 mL) was added 4 N HCl in 1, 4-dioxane (5 mL) under argon atmosphère at 0-5 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed under reduced pressure. The obtained solid was washed with CH2CI2 (5 mL), EtOAc (5 mL) and dried in vacuo to afford compound 230 (120 mg, HCl sait) as yellow solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.2); ^XH NMR (DMSO-</₆,500 MHz): δ 9.31 (br s, 1H), 8.53 (br s, 2H), 8.14 (br s, 1H), 7.37 (br s, 1H), 7.27 (br s, 1H), 7.17 (br s, 1H), 4.07 (d, J= 5.5 Hz, 2H).

Synthesis of (2-ethylthiazol-5-yl) methanamine hydrochloride (239):

Synthesis of ethyl 2-chIoro-3-oxopropanoate (233): To a stirring solution of ethyl 2chloroacetate 231 (5 g, 40.98 mmol) and 232 (3.03 g, 40.98 mmol) in diisopropyl ether (100

- 156 - mL) under argon atmosphère was added potassium tert-butoxide (5.49 g, 45.08 mmol) portion wise for 10 min at 0 °C; warmed to RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the pH of the reaction mixture was adjusted to ~ 6 using 5 N HCl. The obtained solid was filtered, washed with diethyl ether (200 mL) and dried in vacuo to afford compound 233 (6 g) as pale brown syrup. TLC: 30% EtOAc/ hexanes (Rf. 0.2); LC-MS: 21.49% + 75.58%; 149.0 (M⁺-l); (column; X-Select C-18, (50 x 3.0 mm, 3.5 pm); RT 0.56 min, 0.77 min. 5 Mm Aq.NH4OAc: ACN 0.8 mL/min).

Synthesis of ethyl 2-ethyIthiazole-5-carboxylate (235): To a stirring solution of compound 233 (1g) in éthanol (25 mL) under argon atmosphère were added propanethioamide 234 (594 mg, 6.67 mmol), dry magnésium sulfate (4 g) at RT and heated to reflux for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, diluted with EtOAc (2 x 100 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution (2 x 100 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through flash column chromatography using 6% EtOAc/ hexanes to afford compound 235 (330 mg, 27%) as brown syrup. TLC: 10% EtOAc/ hexanes (Rf 0.4); 'ïï-NMR (DMSO-4 400 MHz): δ 8.29 (s, 1H), 4.30 (q,J= 7.1 Hz, 2H), 3.04 (q,J=7.5Hz, 2H), 1.31 (t,J=7.3 Hz, 3H), 1.29 (t,J=7.3 Hz, 3H).

Synthesis of (2-ethyIthiazol-5-yl) methanol (236): To a stirring suspension of lithium aluminium hydride (205 mg, 5.40 mmol) in dry THF (15 mL) under inert atmosphère was added compound 235 (500 mg, 2.70 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with 20% aqueous sodium hydroxide solution (3 mL), filtered through celite and washed with EtOAc (3 x 100 mL). The filtrate was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 236 (310 mg, 80%) as pale yellow solid. TLC: 50% EtOAc/ hexanes (Rf 0.4). 'H-NMR (CDC1₃, 400 MHz): δ 7.51 (s, 1H), 4.82 (s, 2H), 3.01 (q, J = 7.5 Hz, 2H), 1.38 (t, J= 7.6 Hz, 3H).

- 157 -

Synthesis of 5-(chloromethyl)-2-ethylthiazole (237): To a stirring solution of compound 236 (300 mg, 2.09 mmol) in CH2CI2 (15 mL) under inert atmosphère were added triethyl amine (0.6 mL, 4.20 mmol), DMAP (25.6 mg, 0.21 mmol) and methanesulfonyl chloride (0.19 mL, 2.51 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH2Q2 (3 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 237 (500 mg, crude) as pale yellow syrup. TLC: 30% EtOAc/ hexanes (Rf 0.8); LC-MS: 30.71%; 162.0 (M⁺+l); (column;

Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.14 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 5-(azidomethyl)-2-ethylthiazole (238): To a stirring solution of compound 237 (500 mg, 2.26 mmol) in DMF (20 mL) under inert atmosphère was added sodium azide (294 mg, 4.52 mmol) at RT and heated to 80 °C for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through flash column chromatography using 15% EtOAc/ hexanes to afford compound 238 (250 mg, 71%) as pale yellow syrup. TLC: 20% EtOAc/ hexanes (Rf 0.4); *H-NMR (CDCI3, 400 MHz): δ 7.56 (s, 1H), 4.49 (s, 2H), 3.03 (q, J= 7.6 Hz, 2H), 1.40 (t, J= 7.6 Hz, 3H);

Synthesis of (2-ethyIthiazol-5-yl) methanamine hydrochloride (239): To a stirring solution of compound 238 (250 mg, 1.48 mmol) in THF: H2O (5:1, 12 mL) was added triphenyl phosphine (780 mg, 2.97 mmol) at RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The obtained solid was fùrther dried using toluene (2x5 mL) to obtain the crude amine.

The above compound was dissolved in CH2CI2 (5 mL) added 4 N HCl in 1, 4-dioxane (4 mL) under inert atmosphère at 0 °C and stirred for 30 min. The volatiles were removed in vacuo to

- 158 - obtain the crude, which was triturated with EtOAc (2 mL), diethyl ether (2 mL) and pentane (5 mL) to afford compound 239 (180 mg, 68%) as an off-white solid. TLC: 5% MeOH/ CH2CI2 (Rf 0.2); 'fl NMR (DMSO-îZ₆, 500 MHz): δ 8.48 (br s, 3H), 7.74 (s, 1H), 4.25 (q, J= 5.5 Hz, 2H), 2.98 (q, J= 7.5 Hz, 2H), 1.28 (t, J= 7.5 Hz, 3H);

Synthesis of 4-(aminomethyI)-2V-methylthiazol-2-amine hydrochloride (242):

ÎlV CI^^S	mliR_nr MeNHo 240 ini-iüoc______________ N—N NHBoc 4 N HCI m 1,4-Dioxane Ν-'Ά NH₂ * \ >—s U /hci DIPEA CH Cl H CH₂UI₂ \|_\|
224	241 242

Synthesis of tert-butyl ((2-(methylamino) thiazol-4-yl) methyl) carbamate (241): A mixture of compound 224 (100 mg, 0.41 mmol) and methyl amine 240 (5 mL, 33% solution in EtOH) in a sealed tube under argon atmosphère was added diisopropyl ethylamine (0.2 mL, 1.21 mmol) under argon atmosphère at RT and heated to 120 °C for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was purified through silica gel column chromatography using 70% EtOAc/ hexanes to afford compound 241 (90 mg, 92%) as colorless sticky solid. TLC: 50% EtOAc/ hexanes (Rf 0.2); ‘H NMR (DMSO-rf_é,400 MHz): δ 7.26 (d, J= 5.6 Hz, 2H), 6.77 (s, 1H), 4.05 (d, J=5.7 Hz, 2H), 2.76 (d, J= 4.8 Hz, 3H), 1.38 (s, 9H).

Synthesis of 4-(aminomethyl)-A-methylthiazol-2-amine hydrochloride (242): To a stirring solution of compound 241 (90 mg, 0.37 mmol) in CH₂C12 (3 mL) under argon atmosphère was added 4 N HCl in 1, 4-dioxane (3 mL) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was titurated with diethyl ether (5 mL) and dried in vacuo to afford compound 242 (70 mg, HCl sait) as brown solid. TLC: 30% EtOAc/ hexanes (Rf 0.1); ^!H NMR (DMSO-î/^ 400 MHz): δ 9.73-9.27 (m, 1H), 8.39 (br s, 3H), 7.35 (s, 1H), 4.08 (q, J= 5.3 Hz, 2H), 2.95 (s, 3H).

Synthesis of 4-(aminomethyl)-.V, A-dimethylthiazol-2-amine hydrochloride (245):

- 159 -

Synthesis of tert-butyl ((2-(dimethylamino) thiazol-4-yl) methyl) carbamate (244): To a stirring solution of compound 224 (100 mg, 0.41 mmol) in CH₃CN (3 mL) under argon atmosphère were added dimethyl amine hydrochloride 243 (648 mg, 8.06 mmol) and diisopropyl ethylamine (0.2 mL, 1.21 mmol) in a sealed tube at RT and heated to 120 °C for 54 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (2 x 50 mL) washed with water (20 mL). The organic extract was dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 244 (80 mg, 77%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf 0.2); ’H NMR (DMSO-z/é, 400 MHz): δ 7.29 (t, J= 4.8 Hz, 1H), 6.89 (s, 1H), 4.08 (d, J= 5.9 Hz, 2H), 2.97 (s, 6H), 1.38 (s, 9H).

Synthesis of 4-(aminomethyl)-/V, A-dimethylthiazol-2-amine hydrochloride (245): To a stirring solution of compound 244 (100 mg, 0.38 mmol) in CH2CI2 (3 mL) under argon atmosphère was added 4 N HCl in 1, 4-dioxane (3 mL) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was titurated with diethyl ether (5 mL) and dried in vacuo to afford compound 245 (75 mg, HCl sait) as an off-white solid. TLC: 50% EtOAc/ hexanes (Rf 0.1); *H NMR (DMSO-îZ₆, 400 MHz): δ 8.44 (br s, 3H), 7.38 (s, 1H), 4.10 (q, J= 5.6 Hz, 2H), 3.14 (s, 6H).

- 160 Synthesis of (2-isopropylthiazol-5-yl) methanamine hydrochloride (251):

Synthesis of ethyl 2-isopropylthiazole-5-carboxylate (247): To a stirring solution of compound 233 (3.05 g) in éthanol (60 mL) under argon atmosphère were added 25 methylpropanethioamide 246 (1.5 g, 14.56 mmol), dry magnésium sulfate (5 g) at RT and heated to reflux for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with saturated sodium bicarbonate solution (100 mL), extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude.

The crude was purified through flash column chromatography using 2% EtOAc/ hexanes to afford compound 247 (550 mg, 17%) as brown syrup. TLC: 10% EtOAc/ hexanes (Rf 0.5); ^XH NMR (500 MHz, DMSO4) δ 8.31 (s, 1H), 4.30 (q, J = 7.0 Hz, 2H), 3.36-3.29 (m, 1H), 1.34 (d, 7= 6.9 Hz, 6H), 1.29 (t,7=7.1 Hz, 3H).

Synthesis of (2-isopropylthiazol-5-yl) methanol (248): To a stirring solution of compound 247 (550 mg, 2.76 mmol) in dry THF (10 mL) under inert atmosphère was added lithium aluminium hydride (210 mg, 5.52 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with 15% aqueous sodium hydroxide solution (3 mL), filtered

- 161 - through celite and washed with EtOAc (100 mL). The filtrate was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 248 (360 mg, 83%) as pale yellow syrup. TLC: 50% EtOAc/ hexanes (Rf. 0.3). 'H NMR (400MHz, DMSO-rf₆) δ 7.47 (s, 1H), 5.43 (t,J=5.7Hz, 1H), 4.61 (dd,J=5.6, 0.6 Hz, 2H), 3.26-3.19 (m, 1H), 1.30 (d, J = 6.9 Hz, 6H).

Synthesis of 5-(chloromethyl)-2-isopropyIthiazole (249): To a stirring solution of compound 248 (350 mg, 2.23 mmol) in CH2CI2 (20 mL) under inert atmosphère were added triethyl amine (0.64 mL, 4.45 mmol), DMAP (27.2 mg, 0.22 mmol) and methanesulfonyl chloride (0.2 mL, 2.67 mmol) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH2CI2 (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 249 (500 mg, crude) as pale yellow syrup. TLC: 40% EtOAc/hexanes (Rf 0.8); LC-MS: 70.54%; 175.8 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.34 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 5-(azidomethyl)-2-isopropylthiazole (250): To a stirring solution of compound 249 (500 mg, 2.26 mmol) in DMF (20 mL) under inert atmosphère was added sodium azide (445 mg, 6.85 mmol) at RT and heated to 80 °C for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 8% EtOAc/ hexanes to afford compound 250 (255 mg, 63%) as colorless liquid. TLC: 10% EtOAc/ hexanes (Rf. 0.4); ’H NMR (500 MHz, DMSOd₆\. δ = 7.67 (s, 1H), 4.69 (s, 2H), 3.29-3.24 (m, 1H), 1.32 (d, J = 6.9 Hz, 8H).

Synthesis of (2-isopropylthiazol-5-yl) methanamine hydrochloride (251): To a stirring solution of compound 250 (250 mg, 1.37 mmol) in THF: H₂O (5:1, 12 mL) was added triphenyl phosphine (720 mg, 2.74 mmol) at RT and stirred for 2 h. The reaction was monitored

- 162 - by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The obtained solid was further dried using toluene (2x5 mL) to obtain the crude amine.

The above crude compound was dissolved in CH2CI2 (5 mL) added 4 N HCl in 1, 4-dioxane (10 mL) under inert atmosphère at 0 °C and stirred for 30 min. The volatiles were removed in vacuo to obtain the crude, which was triturated with EtOAc (2 mL), diethyl ether (2 mL) and pentane (5 mL) to afford compound 251 (170 mg, 65%) as low melting hygroscopic solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.2); *H NMR (500 MHz, DMSO-^): δ 8.29 (br s, 2H), 7.72 (s, 1H), 4.25 (d, J= 5.8 Hz, 2H), 3.29-3.24 (m, 1H), 1.30 (d, J= 6.9 Hz, 6H)

Synthesis of (2-(trifluoromethyl) thiazol-5-yl) methanamine (255):

Synthesis of (2-(trifluoromethyl) thiazol-5-yl) methanol (253): To a stirring solution of ethyl 2-(trifluoromethyl) thiazole-5-carboxylate 252 (500 mg, 2.22 mmol) in THF (25 mL) under inert atmosphère was added lithium aluminium hydride (126 mg, 3.33 mmol) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with ice-cold water (5 mL), followed by 10% aqueous sodium hydroxide solution (3 mL), filtered through celite and washed with THF (10 mL). The filtrate was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 253 (300 mg, 73%) as pale yellow liquid. ^XH NMR (DMSO-î/₆, 400 MHz): δ 7.98 (s, 1H), 5.90 (t, J= 5.7 Hz, 2H), 4.79 (d, J= 5.6 Hz, 3H).

Synthesis of (2-(trifluoromethyl) thiazoi-5-yl) methyl methanesulfonate (254): To a stirring solution of compound 253 (200 mg, 1.09 mmol) in CH2CI2 (10 mL) under inert atmosphère

- 163 - were added triethyl amine (0.47 mL, 3.27 mmol), methanesulfonyl chloride (0.16 mL, 2.18 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with CH2CI2 (100 mL), washed with 10% NaHCOs solution (50 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 254 (200 mg) as yellow liquid. TLC: 40% EtOAc/hexanes (Rf 0.2); LC-MS: 24.48%; 261.8 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.29 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(trifluoromethyl) thiazol-5-yI) methanamine (255): To a stirring solution of compound 254 (200 mg, crude) in EtOH (10 mL) was added aqueous ammonia (10 mL) at 0 °C; heated to 100 °C and stirred for 16 h in a sealed tube. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% MeOH/ CH2CI2 to afford compound 255 (56 mg) as pale yellow sticky solid. 'H NMR (DMSO-î/_6;400 MHz): δ 7.92 (s, 1H), 6.80 (br s, 2H), 4.01 (s, 2H).

Synthesis of (4-(trifluoromethyl) thiazoI-5-yl) methanamine (263):

Synthesis of ethyl 2-chloro-4, 4, 4-trifluoro-3-oxobutanoate (257): To a stirring solution of ethyl 4, 4, 4-trifluoro-3-oxobutanoate 256 (10 g, 54.2 mmol) in CH2CI2 (25 mL) under inert

- 164- atmosphere was added sulfuryl chloride (5.2 mL, 65.0 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo at RT to afford compound 257 (5 g) as yellow liquid. TLC: 10% EtOAc/ hexanes (Rf 0.5). 'H NMR (CDCl₃,400 MHz): δ 5.62 (s, 1H), 4.29 (q, J= 7.2 Hz, 2H), 1.33 (t, J =7.2 Hz, 3H).

Synthesis of ethyl 2-amino-4-(trifluoromethyl) thiazole-5-carboxylate (259): To a stirring solution of compound 257 (5 g, crude) in éthanol (25 mL) under inert atmosphère was added thiourea 258 (3.3 g, 45.8 mmol) at RT and heated to reflux for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with diethyl ether (200 mL) and washed with water (100 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10-15% EtOAc/ hexanes to afford compound 259 (2.7 g, 49%) as pale yellow solid. TLC: 30% EtOAc/ hexanes (Rf. 0.5); 'H NMR (DMSO-î/₆, 400 MHz): δ 8.21 (s, 2H), 4.21 (q, J = 7.0 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H).

Synthesis of ethyl 4-(trifluoromethyl) thiazoIe-5-carboxylate (260): To a stirring solution of compound 259 (2.7 g, 11.25 mmol) in DMF (10 mL) under inert atmosphère was added tertbutyl nitrate (5.8 g, 56.25 mmol) at 0 °C; heated to 100 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with diethyl ether (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude. The crude was purified through silica gel column chromatography using 5-10% EtOAc/ hexanes to afford compound 260 (1.5 g, 60%) as pale yellow solid. TLC: 20% EtOAc/ hexanes (Rf 0.7); *H NMR (DMSO-^, 400 MHz): 9.41 (s, 1H), 4.35 (q, J= 7.0 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H).

Synthesis of (4-(trifluoromethyl) thiazol-5-yl) methanol (261): To a stirring solution of compound 260 (500 mg, 2.22 mmol) in THF (20 mL) under inert atmosphère was added

- 165 - lithium aluminium hydride (169 mg, 4.44 mmol) portion wise at 0 °C; warmed to RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with ice-cold water (1 mL), followed by 15% aqueous sodium hydroxide solution (1.5 mL), filtered through celite and washed with THF (10 mL). The filtrate was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 30% EtOAc/ hexanes to afford compound 261 (205 mg, 50%) as colorless liquid. ^XH NMR (DMSO-d^ 400 MHz): δ 9.12 (s, 1H), 6.15 (t, J= 5.6 Hz, 1H), 4.85-4.83 (m, 2H).

Synthesis of (4-(trifluoromethyl) thiazol-5-yl) methyl methanesulfonate (262): To a stirring solution of compound 261 (200 mg, 1.09 mmol) in CH2CI2 (10 mL) under inert atmosphère were added triethyl amine (0.47 mL, 3.27 mmol), methanesulfonyl chloride (0.23 mL, 2.73 mmol) at 0 °C; warmed to RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with CH₂C1₂ (2 x 50 mL), washed with water (100 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 262 (210 mg) as yellow liquid. TLC: 30% EtOAc/ hexanes (Rf 0.3); 'H NMR (DMSO-d₆,400 MHz): δ 9.29 (s, 1H), 5.64 (s, 2H), 3.34 (s, 3H).

Synthesis of (4-(trifluoromethyl) thiazol-5-yl) methanamine (263): To a stirring solution of compound 262 (200 mg, 0.76 mmol) in EtOH (10 mL) was added aqueous ammonia (10 mL) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% MeOH/ CH₂C1₂ to afford compound 263 (85 mg, 61%) as pale yellow sticky solid. ’h NMR (DMSO-d₆,400 MHz): 9.21 (s, 1H), 7.27 (br s, 2H), 4.32 (s, 2H).

Synthesis of 2-(thiazol-5-yl) propan-2-amine hydrochloride (270):

- 166 -

Synthesis of A-methoxy-A-methylthiazole-5-carboxamide (266): To a stirring solution of thiazole-5-carboxylic acid 264 (2 g, 15.44 mmol) in CH2CI2 (40 mL) under inert atmosphère were added EDCI.HC1 (3.26 g, 17.04 mmol), HOBt (1 g, 7.74 mmol), A,O-dimethyl hydroxylamine hydrochloride 265 (1.81 g, 18.59 mmol) and diisopropylethylamine (13.4 mL, 77.45 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (70 mL) and extracted with CH2CI2 (3 x 70 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 30-40% EtOAc/ hexanes to afford compound 266 (1.6 g, 60%) as white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.6); *H NMR (DMSO-7₆,400 MHz): 9.32 (s, 1H), 8.52 (s, 1H), 3.77 (s, 3H), 3.30 (s, 3H).

Synthesis of l-(thiazol-5-yl) ethan-l-one (267): To a stirring solution of compound 266 (1.6 g, 9.30 mmol) in dry THF (20 mL) under inert atmosphère was added methyl magnésium bromide (4.65 mL, 13.95 mmol, 3 M solution in Et2Û) dropwise for 10 min at -10 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride (30 mL) and extracted with EtOAc (2 x 60 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 25-30% EtOAc/ hexanes to afford compound 267 (1 g, 85%) as white solid. TLC: 50% EtOAc/ hexanes (Rf. 0.8); 'H NMR (DMSO-î/₆, 400 MHz): δ 9.40 (s, 1H), 8.71 (s, 1H), 2.60 (s, 3H).

- 167 Synthesis of 2-methyl-V-(l-(thiazol-5-yl) ethylidene) propane-2-sulfinamide (269): To a stirring solution of compound 267 (500 mg, 3.93 mmol) in THF (20 mL) under inert atmosphère was added 2-methylpropane-2-sulfinamide 268 (570 mg, 4.70 mmol) and titanium (IV) isopropoxide (2.23 g, 7.87 mmol) at RT and heated to reflux and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted diethyl ether (300 mL) and water (10 mL) and stirred for 10 min. The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 35-40% EtOAc/ hexanes to afford compound 269 (600 mg, 66%) as brown syrup. TLC: 40% EtOAc/ hexanes (Ry 0.3); 'il NMR (DMSO-rf₆,400 MHz): δ 9.29 (s, 1H), 8.58 (s, 1H), 2.75 (s, 3H), 1.15 (s, 9H).

Synthesis of 2-methyl-2V-(2-(thiazol-5-yl) propan-2-yl) propane-2-sulfinamide (270): To a stirring solution of compound 269 (300 mg, 1.30 mmol) in Toluene (10 mL) under inert atmosphère was added methyl magnésium bromide (2.6 mL,7.82 mmol, 3 M solution in Et₂O) dropwise for 10 min at -70 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride (30 mL) and extracted with EtOAc (2 x 60 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 60-70% EtOAc/ hexanes to afford compound 270 (140 mg, 44%) as yellow syrup. TLC: 5% MeOH/ CH₂C1₂(Ry 0.3); ^XH NMR (DMSO-</₆,400 MHz): δ 8.99 (s, 1H), 7.81 (s, 1H), 5.54 (s, 1H), 1.68 (s, 3H), 1.61 (s, 3H), 1.32 (s, 9H).

Synthesis of 2-(thiazoI-5-yl) propan-2-amine hydrochloride (271): To a stirring solution of compound 270 (100 mg, 0.40 mmol) in MeOH (4 mL) under inert atmosphère was added 2 M HCl in diethyl ether (4 mL) at 0 °C; warmed tb RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude which was washed with diethyl ether (2x10 mL) to afford compound 271 (65 mg, 90%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Ry 0.1); 'H NMR (DMSO-^ 400 MHz): δ 9.11 (s, 1H), 8.99 (br s, 3H), 8.04 (s, 1H), 1.78 (s, 6H).

- 168 Synthesis of (2-(teri-butyl) thiazol-5-yl) methanamine hydrochloride (277):

Synthesis of ethyl 2-(tert-butyl) thiazole-5-carboxylate (273): To a stirring solution of compound 233 (11.2 g, 74.66 mmol) in éthanol (100 mL) under argon atmosphère were added 2, 2-dimethylpropanethioamide 272 (8.73 g, 74.66 mmol) and dry magnésium sulfate (20 g) at RT and heated to reflux for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, diluted with water (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2-15% EtOAc/ hexanes to afford compound 273 (3.7 g, 23%) as pale yellow syrup. TLC: 20% EtOAc/ hexanes (Rf 0.6); 'ft-NMR (DMSO-7₆, 500 MHz): δ 8.29 (s, 1H), 4.28 (q, 7=7.2 Hz, 2H), 1.38 (s, 9H), 1.27 (t,7=7.1 Hz, 3H).

Synthesis of (2-(ter/-butyl) thiazol-5-yl) methanol (274): To a stirring solution of compound 273 (3.7 g, 20.10 mmol) in dry THF (50 mL) under inert atmosphère was added lithium aluminium hydride (1.5 g, 40.21 mmol) portion wise for 10 min at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with ice cold water (100 mL), filtered through

- 169 - celite and washed with EtOAc (2 x 100 mL). The filtrate was removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-20% EtOAc/ hexanes to afford compound 274 (1.7 g, 50%) as pale yellow thick syrup. TLC: 30% EtOAc/ hexanes (Rf 0.4). ’H-NMR (DMSO-4 500 MHz): δ 7.46 (s, 1H), 5.42 (t, J= 5.6 Hz, 1H), 4.60 (d, J = 5.5 Hz, 2H), 1.34 (s, 9H).

Synthesis of 2-(teri-butyl)-5-(chloromethyl) thiazole (275): To a stirring solution of compound 274 (1.7 g, 13.17 mmol) in CH2CI2 (50 mL) under inert atmosphère were added triethyl amine (2.3 mL, 19.76 mmol) and methanesulfonyl chloride (1.30 mL, 15.81 mmol) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated sodium carbonate (100 mL) and extracted with CH₂C12 (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 275 (2.5 g, crude) as colorless syrup. TLC: 30% EtOAc/hexanes (Rf 0.8); LC-MS: 61.93%; 190.2 (M⁺+l); (column; Xselect Cl8, (50 x 3.0 mm, 2.5 pm); RT 4.43 min. 2.5 mM Aq. NH4OAC: ACN: 0.8 mL/min).

Synthesis of 5-(azidomethyl)-2-(terZ-butyl) thiazole (276): To a stirring solution of compound 275 (2.5 g, crude) in DMF (25 mL) under inert atmosphère was added sodium azide (1.71 g, 26.45 mmol) at RT and heated to 80 °C for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-10% EtOAc/ hexanes to afford compound 276 (1 g, 38%) as colorless syrup. TLC: 20% EtOAc/ hexanes (Rf 0.5); *H-NMR (DMSO-4 500 MHz): 7.66 (s, 1H), 4.69 (s, 2H), 1.37 (s, 9H).

Synthesis of (2-(/c/7-butyl) thiazoI-5-yl) methanamine hydrochloride (277): To a stirring solution of compound 276 (1 g, 5.10 mmol) in THF: H₂O (4:1, 20 mL) was added triphenyl phosphine (2.67 g, 10.20 mmol) at 0 °C portion wise for 15 min; warmed to RT and stirred for

- 170 -

h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The obtained solid was further dried using toluene (2x5 mL) to obtain the crude amine.

The above compound (600 mg, crude) was dissolved in CH2CI2 (5 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (10 mL) at 0 °C; warmed to RT and stirred for 3 h. The volatiles were removed in vacuo to obtain the crude. The crude was washed with CH2CI2 (10 mL), diethyl ether (10 mL) and dried in vacuo to afford compound 277 (700 mg, 96%) as an off-white solid. TLC: 20% EtOAc/ hexanes (Rf. 0.2); 'H NMR (DMSO-îZ₆, 500 MHz): δ 8.49 (br s, 3H), 7.75 (s, 1H), 4.25 (q, J= 5.6 Hz, 2H), 1.37 (s, 9H).

Synthesis of 5-(aminomethyl) thiazole-2-carbonitrile (282):

Synthesis of 5-methyIthiazole-2-carbonitrile (279): To a stirring solution of 5-methylthiazol2-amine 278 (10 g, 87.71 mmol) in CH3CN (100 mL) under argon atmosphère were added tertbutyl nitrite (18 g, 17.54 mmol), copper (I) cyanide (23.6 g, 263.51 mmol) at RT; heated to reflux and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 279 (2 g, 20%) as white solid. TLC: 30% EtOAc/ hexanes (Rf 0.3); ’H-NMR (DMSO4, 400 MHz): δ 7.98 (s, 1H), 2.59 (s, 3H).

- 171 -

Synthesis of 5-(bromomethyl) thiazole-2-carbonitrile (280): To a stirring solution of compound 279 (2.4 g, 19.35 mmol) in CCI4 (50 mL) under argon atmosphère was added Nbromosuccinimide (3.4 g, 19.35 mmol), azobisisobutyronitrile (317 mg, 1.93 mmol) at RT; heated to reflux and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ hexanes to afford compound 280 (2 g, 51%) as yellow solid. TLC: 10% EtOAc/ hexanes (Rf 0.5); ’ft-NMR (DMSO-4 400 MHz): δ 8.26 (s, 1H), 5.14 (s, 2H).

Synthesis of 5-(azidomethyl) thiazole-2-carbonitrile (281): To a stirring solution of compound 280 (2 g, 9.85 mmol) in DMF (25 mL) under inert atmosphère was added sodium azide (1.9 g, 29.55 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 30% EtOAc/ hexanes to afford compound 281 (1 g, 62%) as yellow syrup. TLC: 30% EtOAc/ hexanes (Rf 0.4); ^!ΗNMR (DMSO-î/₆, 500 MHz): δ 7.95 (s, 1H), 4.95 (s, 2H).

Synthesis of 5-(aminomethyI) thiazole-2-carbonitrile (282): To a stirring solution of compound 281 (1 g, 6.06 mmol) in THF: H₂O (3: 1, 20 mL) was added triphenyl phosphine (3.1 g, 12.12 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, The crude was purified through silica gel column chromatography using 50% EtOAc/ hexanes to afford compound 282 (1 g, 62%) as yellow syrup. TLC: 80% EtOAc/ hexanes (Rf 0.4); ’HNMR (DMSO-4 400 MHz): δ 8.01 (s, 1H), 4.04 (s, 2H).

Synthesis of (2-(4-fluorophenyl) thiazol-5-yl) methanamine hydrochloride (285):

- 172 -

Synthesis of to/7-butyl ((2-(4-fluorophenyl) thiazol-5-yl) methyl) carbamate (284): To a stirring solution of compound 224 (500 mg, 2.01 mmol) in 2-methyltetrahydroftiran (50 mL) under argon atmosphère were added (4-fluorophenyl) boronic acid 283 (309 mg, 2.25 mmol), sodium carbonate (535 mg, 5.05 mmol) at RT and purged under argon atmosphère for 10 min. To this was added Pd(dppf)C12 (73.5 mg, 0.10 mmol); heated to 110 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 40% EtOAc/ hexanes to afford compound 284 (160 mg, 25%) as yellow solid. TLC: 40% EtOAc/ hexanes (Rf. 0.4); ’ft-NMR (DMSO4, 400 MHz): δ 7.94 (dd, J= 8.7, 5.5 Hz, 2H), 7.68 (s, 1H), 7.56 (t, J= 4.9 Hz, 1H), 7.32 (t, J= 8.7 Hz, 2H), 4.33 (d, J= 5.8 Hz, 2H), 1.40 (s, 9H).

Synthesis of (2-(4-fluorophenyl) thiazol-5-yl) methanamine hydrochloride (285): To a stirring solution of compound 284 (160 mg, 0.51 mmol) in CH2CI2 (5 mL) was added 4 N HCl in 1, 4-dioxane (2 mL) under argon atmosphère at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford compound 285 (100 mg, 94%) as pink solid. TLC: 40% EtOAc/ hexanes (Rf. 0.1); *H-NMR (DMSO-J₆, 400 MHz): δ 8.55 (br s, 3H), 8.01-7.96 (m, 3H), 7.36 (t, J= 8.8 Hz, 2H), 4.34 (q, 7= 5.7 Hz, 2H).

Synthesis of 2-((5-(aminomethyl) thiazol-2-yl) thio)-V, A-dimethylethan-l-amine hydrochloride (288):

- 173 -

Synthesis of tert-butyl ((2-((2-(dimethylamino) ethyl) thio) thiazol-5-yl) methyl) carbamate (287): To a stimng solution of tert-butyl ((2-chlorothiazol-5-yl) methyl) carbamate 224 (1 g, 4.03 mmol) in DMF (20 mL) under inert atmosphère was added 2-(dimethylamino) ethane-1thiol hydrochloride 286 (1.1 g, 8.06 mmol) and césium carbonate (4 g, 12.09 mmol) at RT in a sealed tube; heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice-cold water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 287 (1.1 g, 87%) as brown syrup. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.2); ‘H-NMR (DMSO-îZ₆, 500 MHz): δ 7.46 (s, 1H), 4.22 (d, J= 5.5 Hz, 2H), 3.28 (t, J= 7.1 Hz, 2H), 2.56 (t, J= 7.1 Hz, 2H), 2.16 (s, 6H), 1.38 (s, 9H).

Synthesis of 2-((5-(aminomethyl) thiazol-2-yl) thio)- V, W-dimethylethan- 1-amine hydrochloride (288): To a stirring solution of compound 287 (1.1 g, 3.47 mmol) in CH₂C1₂ (5 mL) was added 4 N HCl in 1, 4- dioxane (10 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was washed with diethyl ether (2x10 mL), npentane (2x10 mL) and dried in vacuo to afford compound 288 (700 mg, HCl sait) as an offwhite solid. TLC: 30% 10% MeOH/ CH₂C1₂ (Rf. 0.2); *H-NMR (DMSO-7₆, 500 MHz): δ

- 174-

8.67 (br s, 3H), 7.83 (s, 1H), 4.23 (q, J = 4.9 Hz, 2H), 3.63-3.57 (m, 2H), 3.41-3.34 (m, 2H),

2.77 (d, J= 4.6 Hz, 6H).

Synthesis of (2-phenylthiazol-5-yl) methanamine hydrochloride (291):

Synthesis of tert-butyl ((2-phenylthiazol-5-yl) methyl) carbamate (290): To a stirring solution of compound 224 (250 mg, 1.00 mmol) in 2-methyltetrahydrofuran (10 mL) under argon atmosphère were added phenylboronic acid 289 (136 mg, 1.10 mmol), sodium carbonate (265 mg, 2.50 mmol) at RT and purged under argon atmosphère for 20 min. To this was added Pd(dppf)C12 (36.5 mg, 0.05 mmol) at RT; heated to 110 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 290 (110 mg, 37%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.4); ’H-NMR (DMSO-4 500 MHz): δ 7.89 (d, 7= 6.4 Hz, 2H), 7.69 (s, 1H), 7.56 (t, 7= 6.4 Hz, 1H), 7.51-7.46 (m, 3H), 4.34 (d, J= 5.8 Hz, 2H), 1.40 (s, 9H).

Synthesis of (2-phenylthiazol-5-yl) methanamine hydrochloride (291): To a stirring solution of compound 290 (1.6 g, 5.51 mmol) in CH2CI2 (25 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (10 mL) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with diethyl ether (2x5 mL) and dried in vacuo to afford compound 291 (1 g, 83%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf 0.2); 'll-NMR (DMSO-J₆, 400 MHz): δ 8.25 (br s, 2H), 7.98 (s, 1H), 7.94-7.92 (m, 2H), 7.54-7.51 (m, 3H), 4.35 (q, 7= 6.0 Hz, 2H).

- 175 Synthesis of (2-methyIthiazol-5-yl) methanamine hydrochloride (297):

Synthesis of ethyl 2-methylthiazole-5-carboxylate (293): To a stirring solution of ethyl 2chloro-3-oxopropanoate 233 (26 g, 173.33 mmol) in éthanol (200 mL) under argon atmosphère were added ethanethioamide 292 (10 g, 133.33 mmol), dry magnésium sulfate (10 g) at RT and heated to reflux for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, diluted with EtOAc (500 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution (2 x 200 mL), brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through flash column chromatography using 6% EtOAc/ hexanes to afford compound 293 (8 g, 35%) as brown syrup. TLC: 25% EtOAc/ hexanes (Rf 0.7); 'ü-NMR (DMSO-4 500 MHz): δ 8.24 (s, 1H), 4.27 (q, J= 7.2 Hz, 2H), 2.70 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).

Synthesis of (2-methylthiazol-5-yl) methanol (294): To a stirring suspension of lithium aluminium hydride (3.1 g, 93.56 mmol) in dry THF (10 mL) under inert atmosphère was added compound 293 (8 g, 46.78 mmol) in dry THF (50 mL) dropwise for 15 min at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with 15% aqueous sodium hydroxide solution (10 mL), filtered through celite and washed with EtOAc (3 x 100 mL). The filtrate was

- 176 - dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 294 (5 g, 83%) as an off-white solid. TLC: 50% EtOAc/ hexanes (Rf 0.3). LC-MS: 97.32%; 130.22 (M⁺+l); (column; X-select CSH C18, (50 x 3.0 mm, 2.5 pm); RT 0.65 min. 2.5 mM Aq. NH₄OAc: ACN: 0.8 mL/min).

Synthesis of 5-(chloromethyl)-2-methylthiazole (295): To a stirring solution of compound 294 (5 g, 38.75 mmol) in CH2CI2 (150 mL) under inert atmosphère were added triethyl amine (8.3 mL, 58.13 mmol), methanesulfonyl chloride (4.6 mL, 46.51 mmol) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH₂C1₂ (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 295 (5 g, 87%) as pale yellow syrup. TLC: 30% EtOAc/ hexanes (Rf. 0.8); LC-MS: 77.92%; 147.7 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.71 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 5-(azidomethyl)-2-methylthiazole (296): To a stirring solution of compound 295 (5 g, 34.01 mmol) in DMF (100 mL) under inert atmosphère was added sodium azide (2.21 g, 34.01 mmol) at RT and heated to 80 °C for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 296 (2.3 g, 44%) as off-white thick syrup. TLC: 20% EtOAc/ hexanes (Rf 0.5); ’h-NMR (DMSO-rf₆, 500 MHz): δ 7.64 (s, 1H), 4.67 (s, 2H), 2.65 (s, 3H).

Synthesis of (2-methyIthiazol-5-yl) met h an amine hydrochloride (297): To a stirring solution of compound 296 (2.3 g, 14.93 mmol) in THF: H₂O (5: 1, 80 mL) was added triphenyl phosphine (7.8 g, 29.87 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to

- 177 - obtain the crude, which was triturated with diethyl ether (20 mL) to afford amine (900 mg, 47%) as colorless syrup. TLC: 10% MeOH/ CH2CI2 /: 0.2);

The above compound was dissolved in CH2CI2 (10 mL) added 4 N HCl in 1, 4-dioxane (5 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 3 h. The volatiles were removed in vacuo to obtain the crude, which was triturated with EtOAc (2 mL), diethyl ether (2 mL) to afford compound 297 (1.1 g, 95%) as an off-white solid. TLC: 10% MeOH/ CH2C1₂ /: 0.2); ‘fl NMR (DMSO-î/ô, 500 MHz): δ 8.59 (br. s, 3H), 7.74 (s, 1H), 4.23 (q, J= 5.6 Hz, 2H), 2.66 (s, 3H)

Synthesis of (4’-fhioro-[l, l'-biphenyl]-3-yl) methanamine hydrochloride (301):

Synthesis of tert-butyl (3-bromobenzyl) carbamate (299): To a stirring solution of (3bromophenyl) methanamine 298 (5 g, 26.88 mmol) in CH2CI2 (50 mL) under argon atmosphère were added triethylamine (1.16 mL, 80.59 mmol), Boc-anhydride (5.8 mL, 26.88 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with CH2CI2 (2 x 100 mL). The combined organic extracts were washed with water (25 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% EtOAc/ hexanes to afford compound 299 (5 g, 65%) as white solid. TLC: 10% EtOAc/ hexanes (Rf 0.6); *H-NMR (DMSO-4 400 MHz): δ 7.45-7.37 (m, 3H), 7.32-7.20 (m, 2H), 4.12 (d, J = 6.1 Hz, 2H), 1.39 (s, 9H).

- 178 Synthesis of teri-butyl ((4'-fluoro-[l, l'-biphenyl]-3-yl) methyl) carbamate (300): To a stirring solution of tert-butyl (3-bromobenzyl) carbamate 299 (100 mg, 0.34 mmol) in a mixture of toluene: EtOH (4: 1, 2.5 mL) under inert atmosphère were added 2 M aqueous sodium carbonate solution (0.5 mL) and (4-fluorophenyl) boronic acid 283 (58 mg, 0.41 mmol) and at RT and purged under argon atmosphère for 15 min. To this was added Pd(dppf)C12 (7.6 mg, 0.01 mmol) and heated to 80 °C for 6 h. The reaction was monitored by TLC; after completion of the reaction, the organic layer was separated dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2-8% EtOAc/ hexanes to afford compound 300 (100 mg, 95%) as an off-white solid. TLC: 10% EtOAc/ hexanes (Rf. 0.3); ^XH-NMR (DMSO-rfy 400 MHz): 7.67 (dd, J= 8.7, 5.4 Hz, 2H), 7.52-7.48 (m, 2H), 7.40 (t, J= 7.7 Hz, 2H), 7.29 (t, J= 8.8 Hz, 2H), 7.23 (d, J= 7.3 Hz, 1H), 4.19 (d, J= 6.0 Hz, 2H), 1.40 (s, 9H).

Synthesis of (4'-fluoro-[l, l'-biphenyl]-3-yl) methanamine hydrochloride (301): To a stirring solution of compound 300 (130 mg, 0.43 mmol) in CH2CI2 (2 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (2 mL) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford compound 301 (90 mg, 88%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.1); LC-MS: 98.27%; 201.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.76 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-morpholinothiazol-5-yl) methanamine hydrochloride (389):

- 179 Synthesis of tert-butyl ((2-morpholinothiazol-5-yl) methyl) carbamate (303): A stirred solution of compound 224 (300 mg, 1.21 mmol) in morpholine 302 (3 mL) under argon atmosphère was heated to 100 °C and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over sodium sulphate, filtered and concentrated in vacuo to afford compound 303 (250 mg, 69%) as a colorless semi solid. TLC: 30% EtOAc/hexanes (Rf. 0.3); ‘H-NMR (DMSO-4 400 MHz): 7.31 (t, J= 5.1 Hz, 1H), 6.94 (s, 1H), 4.09 (d, J= 5.8 Hz, 2H), 3.70-3.62 (m, 4H), 3.29-3.27 (m, 4H), 1.36 (s, 9H).

Synthesis of (2-morpholinothiazol-5-yl) methanamine hydrochloride (304): To a stirring solution of compound 303 (250 mg, 0.83 mmol) in CH2CI2 (20 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (10 mL) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with diethyl ether (2x5 mL) and dried in vacuo to afford compound 304 (200 mg, HCl sait) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.1); ’H-NMR (DMSO-4 500 MHz): δ 8.36 (br s, 3H), 7.31 (s, 1H), 4.11 (q,J = 5.4 Hz, 2H), 3.75-3.67 (m, 4H), 3.45-3.37 (m, 4H).

Synthesis of (2-(4-methylpiperazin-l-yl) thiazol-5-yl) methanamine hydrochloride (307):

Synthesis of tc/7-butyl ((2-(4-methylpiperazin-l-yl) thiazol-5-yl) methyl) carbamate (306):

A stirred solution of teri-butyl ((2-chlorothiazol-5-yl) methyl) carbamate 224 (200 mg, 0.80 mmol) in A-methyl-2-pyrrolidone (5 mL) was added 1-methylpiperazine 305 (5 mL) in a sealed tube under argon atmosphère was heated to 100 °C and stirred for 16 h. The reaction was

- 180 monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2Q2 to afford compound 306 (200 mg, 80%) as colorless syrup. TLC: 10% MeOH/ CH2CI2 (Rf 0.5); *H NMR (DMSO-7^ 500 MHz): 7.31 (t,7=6.1 Hz, 1H), 6.92 (s, 1H), 4.09 (d, 7= 5.5 Hz, 2H), 3.35-3.31 (m, 4H), 2.39 (t, 7= 4.8 Hz, 4H), 2.21 (s, 3H), 1.38 (s, 9H).

Synthesis of (2-(4-methylpiperazin-l-yl) thiazol-5-yl) methanamine hydrochloride (307): To a stirring solution of compound 306 (200 mg, 0.64 mmol) in CH2CI2 (5 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (5 mL) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with diethyl ether (2x5 mL) and dried in vacuo to afford compound 307 (240 mg, as HCl sait) as an off-white solid. TLC: 30% EtOAc/hexanes (Rf 0.1); *H-NMR (DMSO-7_é, 500 MHz): δ 11.37 (br s, 1H), 8.37 (br s, 3H), 7.29 (s, 1H), 4.12 (q,7 = 5.4 Hz, 2H), 4.00-3.98 (m, 2H), 3.50 - 3.41 (m, 4H), 3.23- 3.02 (m, 2H), 2.80 (s, 3H).

Synthesis of 4-(5-(aminomethyl) thiazol-2-yl)-N, V-dimethylaniline hydrochloride (312):

- 181 -

Synthesis of tert-butyl ((2-(4-nitrophenyl) thiazol-5-yl) methyl) carbamate (309): To a stirring solution of le/7-butyl ((2-chlorothiazol-5-yl) methyl) carbamate 224 (1 g, 4.02 mmol) in 5 1,2 dimethoxy ethane: H₂O (4: 1, 20 mL) was added sodium carbonate (1.5 g, 14.08 mmol) and purged under argon atmosphère for 30 min. To this was added Pd(PPh3)4 (464 mg, 0.40 mmol) and (4-nitrophenyl) boronic acid (308) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 30% EtOAc / hexanes to afford compound 309 (650 mg, 48%) as yellow solid. TLC: 30% EtOAc / hexanes (Ry 0.4); 'H NMR (DMSO-J₆,400 MHz): δ 8.32 (d, J= 9.0 Hz, 2H), 8.16 (d, J= 8.9 Hz, 2H), 7.84 (s, 1H), 7.63 (t, J= 5.7 Hz, 1H), 4.38 (d, J = 6.0 Hz, 2H), 1.40 (s, 9H); LC-MS: 92.61%; 335.9 (M⁺+l);

(column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.66 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

- 182 -

Synthesis of tert-butyl ((2-(4-aminophenyl) thiazol-5-yl) methyl) carbamate (310): To a stirring solution of compound 309 (500 mg, 1.49 mmol) in MeOH (20 mL) under inert atmosphère was added 10% Pd/C (150 mg) at RT and stirred under hydrogen atmosphère (balloon pressure) at RT for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and washed with MeOH (50 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude washed with 10% EtOAc / hexanes (20 mL) and dried in vacuo to afford compound 310 (350 mg, 77%) as an off-white solid. TLC: 30% EtOAc / hexanes (Rf 0.2); 'H NMR (DMSO-^, 400 MHz): δ 7.54 (d, J = 8.6 Hz, 2H), 7.48 (s, 2H), 6.59 (d, J = 8.6 Hz, 2H), 5.64 (br s, 2H), 4.26 (d, J= 5.9 Hz, 2H), 1.39 (s, 9H); LC-MS: 98.14%; 305.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.06 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of te/T-butyl ((2-(4-(dimethylamino) phenyl) thiazol-5-yl) methyl) carbamate (311): To a stirring solution of compound 310 (200 mg, 0.65 mmol) in MeOH (10 mL) under inert atmosphère were added paraformaldéhyde (98 mg, 3.27 mmol) and sodium cyanoborohydride (206 mg, 3.27 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with 10% MeOH/ CH2CI2 (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 311 (120 mg, 55%) as white solid. TLC: 30% EtOAc / hexanes (Rf 0.8); 'H NMR (DMSO4,500 MHz): δ 7.69 (d, J= 9.0 Hz, 2H), 7.52 (s, 1H), 7.49 (t, J= 5.5 Hz, 1H), 6.76 (d, J= 9.0 Hz, 2H), 4.28 (d, J= 5.8 Hz, 2H), 2.97 (s, 6H), 1.40 (s, 9H); LC-MS: 98.93%; 334.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.06 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-(5-(aminomethyl) thiazol-2-yl)-/V,/V-dimethylaniline hydrochloride (312): To a stirring solution of compound 311 (120 mg, 0.36 mmol) in CH2CI2 (5 mL) under inert

- 183 atmosphère was added 4 N HCl in 1, 4-dioxane (1 mL) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with diethylether (2x5 mL) and dried in vacuo to afford compound 312 (90 mg, 93%) as white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.2); ’H-NMR (DMSO-î/₆, 500 MHz): δ 8.53 (br s, 3H), 7.83 (s, 1H), 7.76 (d, J= 8.7 Hz, 2H), 6.86 (d, J= 7.2 Hz, 2H), 4.27 (q, J= 5.4 Hz, 2H), 2.99 (s, 6H); LC-MS: 98.98%; 233.8 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.51 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-(5-(aminomethyl) thiazol-2-yl)-3-fluorobenzonitrile hydrochloride (316):

Synthesis of 3-fluoro-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) benzonitrile (314): To a stirring solution of 4-bromo-3-fluorobenzonitrile 313 (15 g, 75.0 mmol) in 1,4-dioxane (200 mL) under inert atmosphère were added bis pinacolato diboron (28.56 g, 112.5 mmol), potassium acetate (25.76 g, 262.5 mmol) at RT and purged under argon atmosphère for 20 min; to this was added Pd(dppf)2C12 (5.5 g, 7.51 mmol) and purged under argon atmosphère for 20 min, heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with EtOAc (2 x 500 mL). The filtrate was concentrated in vacuo and the residue was diluted with H2O (500 mL) and extracted with EtOAc (2 x 700 mL). The combined organic extracts were dried over

- 184 - sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 15-20% EtOAc/ hexanes to afford compound 314 (10.2 g, 55%) as an off-white solid. TLC: 20% EtOAc/ hexanes (Rf 0.3); *ΗNMR (DMSO-4 400 MHz): δ 7.82-7.75 (m, 2H), 7.67 (dd, J= 7.7, 1.4 Hz, 1H), 1.30 (s, 12H).

Synthesis of tert-butyl ((2-(4-cyano-2-fluorophenyl) thiazol-5-yl) methyl) carbamate (315): To a stirring solution of compound 224 (8 g, 32.16 mmol) in 1, 2-dimethoxy ethane: H₂O (4: 1, 100 mL) under inert atmosphère were added compound 314 (10.4 g, 42.09 mmol), sodium carbonate (12 g, 113.20 mmol) in a sealed tube at RT and purged under argon atmosphère for 15 min, added Pd(dppf)Cl₂ (2.36 g, 3.22 mmol) and heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 800 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 25-30% EtOAc/ hexanes and triturated using 10% EtOAc/ hexanes to afford compound 315 (6.5 g, 61%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.3); *H-NMR (DMSO-rf₆, 400 MHz): δ 8.36 (t, J =1.9 Hz, 1H), 8.10 (dd, J= 11.3, 1.4 Hz, 1H), 7.91 (d, 7=2.4 Hz, 1H), 7.83 (dd, J= 8.2, 1.6 Hz, 1H), 7.62 (brt, J = 5.5 Hz, 1H), 4.40 (br d, J= 5.9 Hz, 2H), 1.40 (s, 9H); LC-MS: 94.47%; 333.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.61 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-(5-(aminomethyl) thiazol-2-yI)-3-fluorobenzonitrile hydrochloride (316): To a stirring solution of compound 315 (6.5 g, 19.51 mmol) in CH₂C1₂ (70 mL) was added 4 N HCl in 1, 4-dioxane (70 mL) under argon atmosphère at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with EtOAc (2 x 100 mL) and dried in vacuo to afford compound 316 (4.7 g; 89% as HCl sait) as white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.2); *H-NMR (DMSO-4 400 MHz): δ 8.60 (br s, 3H), 8.39 (t, J= 7.9 Hz, 1H), 8.23-8.08 (m, 2H),

- 185 -

7.87 (dd,7 = 8.2, 1.5 Hz, 1H), 4.42 (br s, 2H); LC-MS: 98.68%; 234.9 (M⁺+l); (column;

Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.40 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 5-(5-(aminomethyl) thiazol-2-yl) indolin-2-one hydrochloride (319):

Synthesis of m/Ÿ-butyl ((2-(2-oxoindoIin-5-yl) thiazol-5-yl) methyl) carbamate (318): To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl) carbamate 224 (1 g, 4.03 mmol) in 1, 4-dioxane: H₂O (4: 1, 30 mL) under inert atmosphère were added 5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) indolin-2-one 317 (1.3 g, 5.02 mmol) and potassium phosphate (2.60 g, 12.26 mmol) in sealed tube at RT and purged under inert atmosphère for 20 min. To this was added Pd(PPli3)4 (465 mg, 0.40 mmol) and heated to 110 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 2-4% MeOH/ CH₂C1₂ to afford compound 318 (600 mg, 43%) as pale yellow solid.

TLC: 5% MeOH/ CH₂C1₂ (Rf 0.2). ’fl-NMR (DMSO-7₆, 400 MHz): δ 10.58 (s, 1H), 7.71 (d, 7=5.1 Hz, 2H), 7.59 (s, 1H), 7.52 (t, 7= 5.8 Hz, 1H), 6.88 (d, 7= 8.5 Hz, 1H), 4.29 (d,7=5.8 Hz, 2H), 3.54 (s, 2H), 1.39 (s, 9H); LC-MS: 91.80%; 346.9 (M⁺+l); (column; Kinetex EVO ΟΙ 8 (50 X3.0mm,2.6um); RT 2.31 min. 2.5 mM Aq. NH₄OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of 5-(5-(aminomethyl) thiazol-2-yl) indolin-2-one hydrochloride (319): To a stirring solution of compound 318 (600 mg, 1.74 mmol) in CH₂C1₂ (10 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (10 mL) at 0 °C; warmed to RT and stirred for

- 186 -

h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude which was triturated with EtOAc (2x5 mL) and dried in vacuo to afford compound 319 (600 mg; crude) as yellow solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.1); *H-NMR (DMSO-4 400 MHz): δ 10.69 (s, 1H), 8.58 (br s, 3H), 7.90 (s, 1H), 7.80-

7.73 (m, 2H), 6.93 (d, J = 8.7 Hz, 1H), 4.31 (q, J= 5.5 Hz, 2H), 3.57 (s, 2H);

Synthesis of (2-(4-methoxybenzyl) thiazol-5-yl) methanamine hydrochloride (326):

Synthesis of (5-(((tert-butyldimethylsilyl) oxy) methyl) thiazol-2-yl) (4methoxyphenyl) methanol (322): To a stirring solution 5-(((teH-butyldimethylsilyl) oxy) methyl) thiazole 320 (6 g, 26.20 mmol) in dry THF (100 mL) under inert atmosphère was added w-butyl lithium (1.6 M solution in hexane, 24 mL, 39.30 mmol) dropwise for 10 min at -78 °C and stirred for 30 min. To this was added 4-methoxybenzaldehyde 321 (3.9 g, 28.80 mmol) at -78 °C and stirred at the same température for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (50

- 187- mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 322 (6 g, 63%) as colorless liquid. TLC: 20% EtOAc/ hexanes (Rf 0.2); 'il NMR (500 MHz, DMSO-4: δ 7.51 (s, 1H), 7.31 (d, J= 8.7 Hz, 2H), 6.89 (d, J= 8.4 Hz, 2H), 6.61 (d, J = 4.6 Hz, 1H), 5.81 (d, J= 4.3 Hz, 1H), 4.83 (s, 2H), 3.72 (s, 3H), 0.88 - 0.85 (m, 9H), 0.07 (s, 6H).

Synthesis of (2-(4-methoxybenzyl) thiazol-5-yl) methanol (323): To a stirring solution of compound 322 (6 g, 16.43 mmol) in 1, 2-dichloroethane (30 mL) under inert atmosphère were added trieythlsilane (2.65 mL, 82.19 mmol), trifluoroacetic acid (6.28 mL, 82.19 mmol) at 0 °C; heated to 60 °C and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 60% EtOAc/ hexanes to afford compound 323 (2.8 g, 73%) as sticky solid. TLC: 40% EtOAc/ hexanes (Rf 0.2); 'H NMR (500 MHz, DMSO-î/₆): δ 7.48 (s, 1H), 7.22 (d, J= 8.7 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 5.41 (br s, 1H), 4.57 (s, 2H), 4.18 (s, 2H), 3.72 (s, 3H); LC-MS: 90.27%; 235.9 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 2.03 min. 2.5 mM Aq. NH₄OOCH + 5% ACN: ACN + 5% 2. 5 mM Aq.NH₄OOCH; 0.8 mL/min).

Synthesis of 5-(chloromethyl)-2-(4-methoxybenzyl) thiazoie (324): To a stirring solution of compound 323 (2.8 g, 11.90 mmol) in CH2CI2 (30 mL) under inert atmosphère were added triethylamine (5.0 mL, 35.70 mmol), methanesulfonyl chloride (1.16 mL, 14.29 mmol) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with CH2CI2 (100 mL) and washed with water (75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 324 (2.1 g) as colorless liquid. TLC: 30% EtOAc/ hexanes (Rf 0.8); 'il NMR (500 MHz, DMSO-î/₆): δ 7.70 (s, 1H), 7.24 (d, J= 8.4 Hz, 2H), 6.89 (d, J= 8.4 Hz, 2H), 5.00 (s, 2H), 4.22 (s, 2H), 3.73 (s, 3H)

Synthesis of 5-(azidomethyl)-2-(4-methoxybenzyl) thiazoie (325): To a stirring solution of compound 324 (2.1 g, crude) in DMF (20 mL) under inert atmosphère was added sodium azide

- 188 - (1.61 g, 24.90 mmol) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to afford compound 325 (1.5 g) as colorless sticky solid. TLC: 20% EtOAc/ hexanes /: 0.4); 'H NMR (400 MHz, DMSO-d₆): δ 7.68 (s, 1H), 7.25 (d, J= 8.8 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 4.65 (s, 2H), 4.24 (s, 2H), 3.73 (s, 3H); LC-MS: 89.03%; 260.9 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 2.96 min. 2.5 mM Aq. NH₄OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH; 0.8 mL/min).

Synthesis of (2-(4-methoxybenzyl) thiazol-5-yl) methanamine hydrochloride (326): To a stirring solution of compound 325 (1.5 g, crude) in THF: H2O (10: 1, 22 mL) was added triphenyl phosphine (1.5 g, 5.76 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction; the volatiles were removed in vacuo to obtain the crude amine (1.3g crude).

To the above crude amine (1.3 g) in CH2CI2 (10 mL) was added 4 N HCl in 1, 4-dioxane (3 mL) under inert atmosphère at 0 °C and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with triturated with EtOAc (5 mL), CH2CI2 (5 mL) and dried in vacuo to afford compound 326 (830 mg, 53% HCl sait) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.1); *H NMR (400 MHz, DMSO-d₆): δ 8.33 (br s, 1H), 7.73 (s, 1H), 7.25 (d, J= 8.7 Hz, 2H), 6.91 (d, J= 8.8 Hz, 2H), 4.33-4.11 (m, 6H), 3.73 (s, 3H)

Synthesis of (5-(aminomethyl) thiazol-2-yl) (phenyl) methanone (332):

- 189 -

Synthesis of (5-(((tert-butyldimethylsilyl) oxy) methyl) thiazol-2-yl) (phenyl) methanone (328): To a stirring solution of 5-(((ZerLbutyldimethylsilyl) oxy) methyl) thiazole 320 (200 mg, 5 0.87 mmol) in dry THF (15 mL) under inert atmosphère was added «-butyl lithium (1.6 M solution in hexane, 0.82 mL, 1.30 mmol) dropwise for 5 min at -78 °C and stirred for 1 h. To this was added benzonitrile 327 (180 mg, 1.74 mmol) at -78 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with 1 N aqueous HCl (10 mL) at -78 °C and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 5-10% EtOAc/ hexanes to afford crude compound 328 (300 mg) as pale yellow liquid. TLC: 20% EtOAc/ hexanes (Rf 0.8); *H-NMR (DMSO-7₆, 500 MHz): δ 8.36 (d, J = 7.5 Hz, 2H), 8.08 (s, 1H), 7.86-7.82 (m, 2H), 7.76-7.69 (m, 1H), 5.04 (s, 2H), 0.91 (s, 9H), 0.12 (s, 6H);

Synthesis of (5-(hydroxymethyl) thiazol-2-yl) (phenyl) methanone (329): To a stirring solution of compound 328 (300 mg, 0.90 mmol) in THF (5 mL) under inert atmosphère was added tetrabutylammonium fluoride (1.0 M solution in THF, 1.35 mL, 1.35 mmol) at 0 °C and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the

- 190 - reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 10% EtOAc/ hexanes to afford crude compound 329 (100 mg, 52% over 2 steps) as pale yellow solid. TLC: 20% EtOAc/hexanes (Rf 0.1); LC-MS: 99.90%; 219.9 (M⁺+l); (column;

Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.02 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). *H-NMR (DMSO-4 400 MHz): δ 8.38-8.33 (m, 2H), 8.09-8.02 (m, 1H), 7.75-7.70 (m, 1H), 7.62-7.57 (m, 2H), 5.86 (t, J= 5.8 Hz, 1H), 4.81 (dd, J =5.1, 0.9 Hz, 2H).

Synthesis of (2-benzoylthiazol-5-yl) methyl methanesulfonate (330): To a stirring solution of compound 329 (100 mg, 0.45 mmol) in CH2CI2 (5 mL) under inert atmosphère were added triethyl amine (2.5 mL, 17.32 mmol) at 0 °C and stirred for 10 min. To this was added methanesulfonyl chloride (0.13 mL, 0.08 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL), extracted with CH2CI2 (2 x 50 mL), washed with saturated NaHCO₃ solution (30 mL) and brine (20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 330 (150 mg) as pale yellow liquid. TLC: 20% EtOAc/ hexanes (Rf 0.1); ’fl-NMR (DMSO-î/₆, 400 MHz): δ 8.38-8.33 (m, 2H), 8.25 (s, 1H), 7.76-7.71 (m, 1H), 7.64-7.56 (m, 2H), 5.22 (s, 2H), 2.42 (s, 3H).

Synthesis of (5-(azidomethyl) thiazol-2-yl) (phenyl) methanone (331): To a stirring solution of compound 330 (150 mg, 0.50 mmol) in DMF (150 mL) under inert atmosphère was added sodium azide (49 mg, 0.75 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC and LC-MS; after completion of the reaction, the reaction mixture was diluted with EtOAc (100 mL) and washed with ice-cold water (2 x 50 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 5-10% EtOAc/

- 191 hexanes to afford compound 331 (100 mg, 89%, over 2 steps) as pale yellow solid. TLC: 20% EtOAc/ hexanes (Ry 0.6); 'H-NMR (DMSO-4 400 MHz): δ 8.40-8.38 (m, 2H), 8.23 (s, 1H), 7.79-7.74 (m, 1H), 7.65-7.60 (m, 2H), 4.94 (s, 2H). LC-MS: 94.73%; 244.9 (M⁺+l); (column;

Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.65 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (5-(aminomethyl) thiazoI-2-yl) (phenyl) methanone (332): To a stirring solution of compound 331 (100 mg, 0.41 mmol) in THF: H₂O (5: 1, 12 mL) was added triphenyl phosphine (161 mg, 0.61 mmol) at 0 °C; warmed to RT and stirred for 20 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, further dried by azeotropic distillation using toluene (2x5 mL) to obtain the crude.

The above crude compound was diluted with CH₂C1₂ (1 mL) and under inert atmosphère was added 4 N HCl in 1, 4-dioxane (1 mL) at 0 °C, warmed to RT and stirred for 1 h. The volatiles were removed in vacuo and the crude was washed with diethyl ether (10 mL), hexane (10 mL) and triturated with CH₂C1₂: hexanes (4: 1,5 mL) to afford compound 332 (100 mg, 96%) as pale yellow solid. TLC: 5% MeOH/ CH₂C1₂ (Ry 0.2); LC-MS: 30.80%; 218.8 (M⁺+l)_; (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.51 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of l-(2-(5-(aminomethyl) thiazol-2-yl) phenyl)-2-methylpropan-2-ol hydrochloride (338):

- 192 -

Synthesis of methyl 2-(2-bromophenyl) acetate (334): To a stirring solution of 2-(2bromophenyl) acetic acid 333 (5 g, 23.25 mmol) in MeOH (100 mL) under inert atmosphère was added thionyl chloride (2.00 mL, 27.90 mmol) dropwise at 0 °C for 15 min; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with CH2CI2 (300 mL) and the pH was neutralized with saturated NaHCO3 solution (200 mL). The organic layer was separated dried over sodium sulphate, filtered and concentrated in vacuo to afford compound 334 (5 g, 94%) as colorless thick syrup. TLC: 20% EtOAc/ hexanes (Rf 0.8); *H-NMR (DMSO-î/ô, 400 MHz): δ 7.62 (dd,J=8.0, 1.1 Hz, 1H), 7.43-7.39 (m, 1H), 7.36 (td, J= 7.4, 1.1 Hz, 1H), 7.23 (td, J= Ί.6, 1.8 Hz, 1H), 3.83 (s, 2H), 3.63 (s, 3H);

Synthesis of methyl 2-(2-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) phenyl) acetate (335): To a stirring solution of compound 334 (4.5 g, 19.65 mmol) in 1, 4-dioxane (100 mL) under inert atmosphère were added bispinacolato diboron (5.98 g, 23.58 mmol), potassium acetate (8.30 g, 84.50 mmol) at RT and purged under argon atmosphère for 15 min; to this was added Pd(dppf)C12 (1.43 g, 1.96 mmol) and purged under argon atmosphère for 5 min, heated to 80 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with 50% MeOH/ CH2CI2 (2 x 80 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was purified

- 193 - through silica gel flash column chromatography using 10-12% EtOAc/ hexanes to afford compound 335 (3 g, 55%) as colorless syrup. TLC: 10% EtOAc/ hexanes (Rf. 0.4); ’H-NMR (CDC1₃, 400 MHz): δ 7.85 (br d, J= 7.2 Hz, 1H), 7.42-7.38 (m, 1H), 7.32-7.26 (m, 1H), 7.21 (br d, 7= 7.5 Hz, 1H), 4.00 (s, 2H), 3.68 (s, 3H), 1.34 (s, 12H);

Synthesis of methyl 2-(2-(5-(((tert-butoxycarbonyl) amino) methyl) thiazol-2-yl) phenyl) acetate (336): To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl) carbamate 224 (1 g, 4.02 mmol) in 1, 2-dimethoxy ethane: H2O (4: 1, 30 mL) under inert atmosphère were added compound 335 (1.33 g, 4.82 mmol) and potassium phosphate (2.55 g, 12.06 mmol) in sealed tube at RT and purged under argon atmosphère for 15 min. To this was added Pd(dppf)C12 (294 mg, 0.40 mmol) and heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 10-15% EtOAc/ hexanes to afford compound 336 (700 mg, 48%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf 0.4). ’H-NMR (DMSO-7₆, 400 MHz): δ 7.71-7.64 (m, 2H), 7.56 (t, 7= 5.6 Hz, 1H), 7.45-7.37 (m, 3H), 4.33 (d, J= 5.9 Hz, 2H), 4.06 (s, 2H), 3.52 (s, 3H), 1.40 (s, 9H);

Synthesis of Zc/Z-butyl ((2-(2-(2-hydroxy-2-methylpropyl) phenyl) thiazol-5-yl) methyl) carbamate (337): To a stirring solution of compound 336 (700 mg, 1.93 mmol) in anhydrous THF (20 mL) under inert atmosphère was added méthylmagnésium bromide (5.79 mL, 17.40 mmol, 3 M sol. In diethylether) at -10 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with aqueous saturated ammonium chloride solution (70 mL) and extracted with EtOAc (2 x 70 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel (100-200 mesh) column chromatography using 30-40% EtOAc/ hexanes to afford compound 337 (200 mg, 29%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.4); 'H-NMR (DMSO-4 400 MHz): δ 7.72 (s, 1H), 7.56 (t, 7= 5.6 Hz, 1H), 7.52 (dd,7=7.7, 1.1 Hz, 1H), 7.46-7.38 (m, 2H), 7.34 (dd, 7 = 7.5, 1.9 Hz, 1H), 4.99 (s, 1H), 4.35 (d, 7= 5.8 Hz, 2H), 3.07 (s, 2H), 1.40 (s, 9H), 1.00 (s, 6H);

- 194 Synthesis of l-(2-(5-(aminomethyl) thiazol-2-yl) phenyl)-2-methylpropan-2-oI hydrochloride (338): To a stirring solution of compound 337 (200 mg, 0.55 mmol) in CH₂C1₂(10 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (2 mL) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was triturated with diethyl ether (2x10 mL) and dried in vacuo to afford compound 338 (160 mg, HCl sait) as an off-white solid. TLC: 40% EtOAc/ hexanes (Rf. 0.1); *H-NMR (DMSO-4 400 MHz): δ 8.45 (br s, 3H), 8.00 (s, 1H), 7.53 (dd, J = 7.7, 1.1 Hz, 1H), 7.50-7.41 (m, 2H), 7.39-7.34 (m, 1H), 4.37 (q, J= 5.7 Hz, 2H), 3.11 (s, 2H), 0.99 (s, 6H);

Synthesis of [2, 2'-bithiazol]-5-ylmethanamine hydrochloride (345):

Synthesis of methyl [2, 2'-bithiazole]-5-carboxylate (341): To a stirring solution of methyl 2bromothiazole-5-carboxylate 339 (3 g, 13.51 mmol) in Toulene (50 mL) under inert atmosphère in a sealed tube were added 2-bromothiazole 340 (5.9 g, 40.41 mmol), diisopropylethylamine (1.7 mL, 13.50 mmol), tetrabutylammonium bromide (2.10 g, 6.52 mmol), Pd(OAc)₂ (150 mg, 0.66 mmol) at RT; heated to 100 °C and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column flash chromatography using 20% EtOAc/ hexanes to

- 195 - afford crude compound 341 (1.5 g, crude) which was carried to next step without further purification. TLC: 40% EtOAc/ hexanes (Rf 0.5);

Synthesis of [2, 2'-bithiazol]-5-ylmethanol (342): To a stirring solution of compound 341 (1.5 g, 6.63 mmol) in MeOH (10 mL) under inert atmosphère was added sodium borohydride (1.5 g, 39.82 mmol) portion wise for 15 min at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was diluted with EtOAc (100 mL) and washed with water (2 x 50 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column flash chromatography using 20% EtOAc/ hexanes to afford compound 342 (800 mg, 30%, over 2 steps) as colorless liquid. TLC: 40% EtOAc/ hexanes (Rf 0.4); ^XH-NMR (DMSO-î/₆, 400 MHz): δ 7.97 (d, J = 3.2 Hz, 1H), 7.90 (d, J= 3.05 Hz, 1H), 7.80 (s, 1H), 5.72 (t, J= 5.8 Hz, 1H), 4.73 (dd, J= 5.8, 0.9 Hz, 2H); LC-MS: 60.68%; 234.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.44 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of [2, 2'-bithiazol]-5-ylmethyI methanesulfonate (343): To a stirring solution of compound 342 (800 mg, 4.04 mmol) in CH2CI2 (10 mL) under inert atmosphère were added triethyl amine (1.73 mL, 12.12 mmol) and methanesulfonyl chloride (0.13 mL, 0.08 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL), extracted with EtOAc (2 x 50 mL) The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 343 (1.1 g, 99%) as brown liquid. TLC: 20% EtOAc/ hexanes (Rf. 0.1); ^XH-NMR (DMSO-76, 400 MHz): δ 8.02-7.99 (m, 2H), 7.96 (d, 7 = 3.2 Hz, 1H), 5.16 (s, 2H), 2.45 (s, 3H); LC-MS 88.94%; 278.9 (M⁺+l); (column; Ascentis Express Cl8, (50 χ 3.0 mm, 2.7 pm); RT 2.26 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 5-(azidomethyl)-2, 2'-bithiazoIe (344): To a stirring solution of compound 343 (1.1 g, 3.98 mmol) in DMF (10 mL) under inert atmosphère was added sodium azide (778 mg,

- 196 -

11.95 mmol) at RT; heated to 60 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL) The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to afford compound 344 (600 mg, 67%) as colorless liquid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.2); *H-NMR (DMSO-4 400 MHz): δ 8.00 (d, J= 3.2 Hz, 1H), 7.98 (s, 1H), 7.95 (d, 3.1 Hz, 1H), 4.82 (s, 2H); LC-MS: 88.41%; 223.8 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.20 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of [2, 2'-bithiazol]-5-ylmethanamine hydrochloride (345): To a stirring solution of compound 344 (600 mg, 2.69 mmol) in THF: H₂O (4: 1,5 mL) was added triphenyl phosphine (846 mg, 3.22 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was adjusted to ~2 with 1 N HCl. The aqueous layer was washed with EtOAc (2 x 25 mL). The aqueous layer was concentrated in vacuo and further dried by azeotropic distillation using toluene (10 mL) to afford compound 345 (600 mg, crude) as pale yellow solid. The crude was taken forwared for next step without fùrther purification. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.2).

Synthesis of (2-(pyridin-2-yl) thiazol-5-yl) methanamine hydrochloride (354):

- 197 -

Synthesis of picolinamide (347): To a stirring solution of picolinonitrile 346 (30 g, 296.91 mmol) in DMSO (300 mL) was added potassium carbonate (39.8 g, 288.35 mmmol) followed by slow addition of 30% H2O2 (300 mL, 10 vol) for 20 min at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (200 mL) and washed with water (2 x 100 mL). The aqueous layer was extracted with EtOAc (4 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 347 (45 g) as an off-white solid. TLC: 50% EtOAc/ hexanes (Rf 0.2).

Synthesis of pyridine-2-carbothioamide (348): To a stirring solution of compound 347 (45 g, 368.45 mmol) in THF (500 mL) under inert atmosphère was added P2S5 (81.97 g, 368.85 mmol) at 0 °C, RT; heated to reflux and stirred for 16 h. The reaction was monitored by TLC after 16 h, the reaction mixture was diluted with EtOAc (200 mL), washed with saturated

NaHCOs solution (2 x 80 mL). The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 348 (13 g, 26%) as pale yellow solid. TLC: 40% EtOAc/

- 198 - hexanes (Rf. 0.8). ‘H NMR (400 MHz, DMSO-7₆): δ 10.17 (br s, 1H), 9.91 (br s, 1H), 8.648.57 (m, 1H), 8.50 (td 7= 8.0, 1.0 Hz, 1H), 7.97 (td,7=7.8, 1.8 Hz, 1H), 7.61-7.57 (m, 1H).

Synthesis of 2-(pyridin-2-yI) thiazole-5-carbaldehyde (350): A mixture of compound 348 (6 g, 43.41 mmol) and pyridine (12 mL) in THF (120 mL) was heated to 50 °C for 15 min, added 2-bromomalonaldehyde 349 (9.2 g, 60.92 mmol), heated to reflux and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (100 mL) and washed with water (30 mL), brine (30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silicagel flash column chromatography using 5-20% EtOAc/ hexanes to afford compound 350 as brown solid. TLC: 20% EtOAc/ hexanes (Rf 0.3). 'HNMR (400 MHz, DMSO-dé): δ 10.11 (s, 1H), 8.82 (s, 1H), 8.73-8.70 (m, 1H), 8.24 (d,7 = 7.9 Hz, 1H), 8.07-8.03 (m, 1H), 7.63-7.60 (m, 1H); LC-MS: 94.69%; 190.8 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.93 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(pyridin-2-yl) thiazol-5-yl) methanol (351): To a stirring solution of compound 350 (1.5 g, 7.81 mmol) in MeOH (50 mL) under inert atmosphère was added sodium borohydride (600 mg, 15.78 mmol) portion wise for 15 min at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was diluted with EtOAc (100 mL) and washed with water (2 x 25 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 10-40% EtOAc/ hexanes to afford compound 351 (1 g, 30%, over 2 steps) as pale brown solid. TLC: 30% EtOAc/ hexanes (Rf 0.2); ’H NMR (400 MHz, DMSO-7₆): δ 8.65-8.58 (m, 1H), 8.10 (d, 7= 7.9 Hz, 1H), 7.97-7.92 (m, 1H), 7.80 (s, 1H), 7.49-7.45 (m, 1H), 5.63 (t, 7= 5.7 Hz, 1H), 4.72 (d, 7= 5.6 Hz, 2H); LC-MS: 99.64%; 192.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.47 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

- 199 Synthesis of 5-(chloromethyl)-2-(pyridin-2-yl) thiazole (352): To a stirring solution of compound 351 (1.0 g, 5.20 mmol) in CH2CI2 (20 mL) under inert atmosphère were added triethylamine (1.46 mL, 10.41 mmol), methanesulfonyl chloride (712 mg, 6.25 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with CH₂C1₂ (100 mL), washed with saturated NaHCO₃ solution (2 x 50 mL), brine (50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 352 (900 mg, 83%) as pale brown solid. TLC: 50% EtOAc/ hexanes (Rf 0.8); ^XH NMR (400 MHz, DMSOd₆): δ 8.70-8.60 (m, 1H), 8.13 (d, J= 7.9 Hz, 1H), 8.03 (s, 1H), 8.01-7.97 (m, 1H), 7.55-7.52 (m, 1H), 5.17 (d, J= 0.6 Hz, 2H); LC-MS: 97.86%; 210.9 (M⁺+l); (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 2.27 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 5-(azidomethyl)-2-(pyridin-2-yl) thiazole (353): To a stirring solution of compound 352 (900 mg, 4.28 mmol) in DMF (20 mL) under inert atmosphère was added sodium azide (557 mg, 8.56 mmol) at 0 °C; heated to 70 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (2 x 75 mL) washed with water (50 mL), brine (20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude compound 353 (850 mg, 91%) as pale brown solid. TLC: 20% EtOAc/ hexanes (Rf. 0.5); ^XH NMR (400 MHz, DMSO-d₆): δ 8.66-8.61 (m, 1H), 8.12 (d, J= 7.9 Hz, 1H), 8.00-7.95 (m, 2H), 7.53-7.51 (m, 1H), 4.80 (s, 2H); LC-MS: 96.94%; 217.8 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.21 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(pyridin-2-yl) thiazol-5-yl) methanamine hydrochloride (354): To a stirring solution of compound 353 (850 mg, 3.91 mmol) in THF: H₂O (15: 5, 25 mL) was added triphenyl phosphine (1.23 g, 4.69 mmol) at 0 °C; warmed to RT and stirred for 4 h. The

-200 - reaction was monitored by TLC; after completion of the reaction; the volatiles were removed in vacuo to obtain the crude amine (1.02 g crude). TLC: 20% EtOAc/ hexanes (Ry 0.1);

To the above crude amine (1.02 g) in CH₂C1₂ (50 mL) was added 4 N HCl in 1, 4-dioxane (5 mL) under inert atmosphère at 0 °C and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was triturated with diethyl ether (2 x 50 mL), CH2CI2 (2 x 60 mL), EtOAc (2 x 50 mL) and dried in vacuo to afford compound 354 (850 mg, 96%; HCl sait) as an hygroscopic offwhite solid. TLC: 5% MeOH/ CH₂C1₂ (Ry 0.2); 'H NMR (400 MHz, DMSO-</₆): δ 8.65 (br s, 3H), 8.12 (d, J= 7.0 Hz, 1H), 8.04 (s, 1H), 8.01-7.94 (m, 1H), 7.69-7.46 (m, 2H), 4.36-4.32 (m, 2H); LC-MS: 86.55%; 191.8 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 1.09 min. 2.5 mM Aq. NH4OOCH + 5% ACN: ACN: 5% 2.5 mM Aq. NH4OOCH; 0.8 mL/min).

Synthesis of 4-(5-(aminomethyl) thiazoI-2-yl) phénol hydrochloride (357):

Synthesis of m/Y-buty! ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl) carbamate (356): To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl) carbamate 224 (500 mg, 2.01 mmol) in 1, 2-dimethoxy ethane: H₂O (4: 1, 20 mL) were added sodium carbonate (640 mg, 6.03 mmol) and (4-hydroxyphenyl) boronic acid 355 (416 mg, 3.01 mmol) and purged under argon atmosphère for 30 min in a sealed tube. To this was added Pd(PPh₃)₄ (231 mg, 0.20 mmol) at RT; heated to 90 °C and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with EtOAc (200 mL), washed with water (100 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through

-201 - silica gel column chromatography using 40% EtOAc/ hexanes to afford compound 356 (250 mg, 41%) as an off-white solid. TLC: 50% EtOAc/ hexanes (Rf 0.5); *H-NMR (DMSO-i/é, 500 MHz): 9.92 (s, 1H), 7.69 (d, J= 8.4 Hz, 2H), 7.55 (s, 1H), 7.50 (t, J= 5.5 Hz, 1H), 6.83 (d, J= 8.7 Hz, 2H), 4.28 (d, J= 5.8 Hz, 2H), 1.38 (s, 9H).

Synthesis of 4-(5-(aminomethyl) thiazol-2-yl) phénol hydrochloride (357): To a stirring solution of compound 356 (150 mg, 0.49 mmol) in CH2CI2 (4 mL) was added 4 N HCl in 1, 4Dioxane (1.25 mL, 4.90 mmol) under inert atmosphère at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was washed with diethyl ether (2x10 mL) and dried in vacuo to afford compound 357 (110 mg, 93%; HCl sait) as white solid. TLC: 30% EtOAc/ hexanes (Rf 0.2); ‘H-NMR (DMSO-4 400 MHz): δ 10.07 (br s, 1H), 8.51 (br s, 3H), 7.84 (s, 1H), 7.74 (d, J = 8.4 Hz, 2H), 6.88 (d, J= 8.7 Hz, 2H), 4.28 (q, J= 5.4 Hz, 2H).

Synthesis of 2-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-V. A-dimethylethan-l-amine

Synthesis of tert-butyl ((2-(4-(2-(dimethylamino) ethoxy) phenyl) thiazol-5-yl) methyl) carbamate (359): To a mixture of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl) carbamate 356 (100 mg, 0.32 mmol) and 2-(dimethylamino) ethan-l-ol 358 (43 mg, 0.49 mmol) in THF (5 mL) under inert atmosphère were added diisopropyl azodicarboxylate (198 mg, 0.98 mmol) and triphenyl phosphine (256 mg, 0.98 mmol) at 0 °C; warmed to RT and

-202stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with CH2CI2 (100 mL) and washed with water (2x50 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3% MeOH/ CH₂C12 to afford compound 359 (60 mg, 49%) as white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.2); ¹ II NMR (DMSO-d₆,500 MHz): δ 7.83 (d, J = 8.7 Hz, 2H), 7.61 (s, 1 H), 7.53 (t, 7=5.2 Hz, 1H), 7.06 (d, 7= 9.0 Hz, 2H), 4.31 (d, 7=5.8 Hz, 2H), 4.19 (t, J= 5.4 Hz, 2H), 2.91 (br s, 2H), 2.42 (br s, 6H), 1.40 (s, 9H).

Synthesis of 2-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-/V, V-dimethylethan-1-amine hydrochloride (360): To a stirring solution of compound 359 (60 mg, 0.15 mmol) in CH2CI2 (3 mL) was added 4 N HCl in 1, 4- Dioxane (0.4 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was washed with diethyl ether (2x5 mL) and dried in vacuo to afford compound 360 (45 mg, 90%; HCl sait) as white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); LC-MS: 94.06%; 277.9 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 0.42 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(4-methoxyphenyl) thiazol-5-yl) methanamine hydrochloride (363):

-203 -

Synthesis of tert-butyl ((2-(4-methoxyphenyl) thiazoI-5-yl) methyl) carbamate (362a): To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl) carbamate 224 (1 g, 4.02 mmol) in DMF: H₂O (4: 1, 20 mL) were added sodium carbonate (464 mg, 0.40 mmol) and (4methoxyphenyl) boronic acid 361 (734 mg, 4.82 mmol) and purged under argon atmosphère for 20 min. To this was added Pd(PPh₃)4 (464 mg, 0.40 mmol) at RT; heated to 80 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with EtOAc (200 mL), washed with water (75 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 40% EtOAc/ hexanes to afford compound 362a (700 mg, 58%) as yellow solid. TLC: 30% EtOAc/ hexanes (Rf 0.2); ’ll-NMR (DMSO-î/₆, 500 MHz): δ 7.81 (d, J= 8.7 Hz, 2H), 7.59 (s, 1H), 7.51 (t, 7=6.1 Hz, 1H), 7.02 (d, 7= 8.7 Hz, 2H), 4.29 (d,7=5.5 Hz, 2H), 3.80 (s, 3H), 1.38 (s, 9H).

Synthesis of (2-(4-methoxyphenyl) thiazol-5-yl) methanamine hydrochloride (363): To a stirring solution of compound 362a (700 mg, 2.18 mmol) in CH₂C1₂ (20 mL) under argon atmosphère was added 4 N HCl in 1, 4-dioxane (2 mL) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford compound 363 (550 mg, 99%) as an off-white solid. TLC: 40% EtOAc/ hexanes (Rf. 0.1); 'H-NMR (DMSO-7₆, 500 MHz): δ 8.52 (br s, 3H), 7.90 (s, 1H), 7.87 (d, 7= 9.0 Hz, 2H), 7.07 (d, 7= 8.7 Hz, 2H), 4.32 (q, 7= 5.7 Hz, 2H), 3.83 (s, 3H).

-204Synthesis of teri-butyl ((2-(4-methoxyphenyl) thiazol-5-yl) methyl) carbamate (362b): To a stirring solution of teri-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl) carbamate 356 (150 mg, 0.49 mmol) in acetone (10 mL) under inert atmosphère were added potassium carbonate (203 mg, 1.47 mmol) and methyl iodide (0.09 mL, 1.47 mmol) at 0 °C; heated to 70 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (100 mL) and extracted with EtOAc (2x50 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 362b (105 mg, 67%) as white solid. TLC: 40% EtOAc/hexanes (Rf 0.8); ’h NMR (DMSO-î/₆, 400 MHz): δ 7.82 (d, J = 8.7 Hz, 2H), 7.61 (s, 1H), 7.53 (t,J=5.5Hz, 1H), 7.04 (d,J=8.7Hz, 2H), 4.31 (d, J= 5.8 Hz, 2H), 3.81 (s, 3H), 1.40 (s, 9H).

Synthesis of (2-(4-methoxyphenyl) thiazol-5-yl) methanamine hydrochloride (363): To a stirring solution of compound 362b (100 mg, 0.31 mmol) in CH2CI2 (5 mL) under inert atmosphère was added 4 N HCl in 1, 4- Dioxane (0.78 mL) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with diethyl ether (10 mL) and dried in vacuo to afford compound 363 (65 mg, 81%) as white solid. TLC: 5% MeOH/ CH2CI2 (Rf. 0.2); *H-NMR (DMSO-îZ₆, 500 MHz): δ 8.49 (br s, 3H), 7.90 (s, 1H), 7.87 (d, J= 8.7 Hz, 2H), 7.07 (d, J= 9.0 Hz, 2H), 4.32 (q, J= 5.4 Hz, 2H), 3.83 (s, 3H).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxyj-A, /V-dimethylpropan-l-amine hydrochloride (367):

-205 -

Synthesis of 3-chloro-Æ, A-dimethylpropan-1-amine (365): To a stirring solution of 3(dimethylamino) propan-l-ol 364 (2.0 g, 1.94 mmol) in CHCI3 (50 mL) under inert atmosphère was added thionyl chloride (4.22 mL, 58.23 mmol) at 0 °C; heated to 70 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with diethyl ether (2 x 30 mL) to afford compound 365 (2.5 g, 83%) as white solid. TLC: 5% MeOH/ CH2CI2 (Rf. 0.2); ’H-NMR (DMSO-4 500 MHz): δ 10.97 (br s, 1H), 3.74 (t, J = 6.4 Hz, 2H), 3.12 (t, J= 7.8 Hz, 2H), 2.72 (s, 6H), 2.20-2.12 (m, 2H).

Synthesis of tert-butyl ((2-(4-(3-(dimethylamino) propoxy) phenyl) thiazol-5-yI) methyl) carbamate (366): To a stirring solution of compound 356 (400 mg, 1.30 mmol) and compound 365 (411 mg, 2.61 mmol) in acetone (20 mL) under inert atmosphère was added potassium carbonate (541 mg, 3.91 mmol) at RT; heated to 80 °C and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2CI2 to afford compound 366 (350 mg, 68%) as off-white sticky solid. TLC: 5% MeOH/ CH2CI2 (Rf. 0.1); 'H NMR (DMSO-rf₆,400 MHz): δ 7.81 (d, J= 8.8 Hz, 2H), 7.60 (s,

-206 -

1H), 7.53 (t, J= 5.5 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 4.31 (d, J= 5.7 Hz, 2H), 4.06 (t, J= 6.3 Hz, 2H), 2.52-2.48 (m, 2H), 2.28 (s, 6H), 1.96-1.87 (m, 2H), 1.40 (s, 9H).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-A, A-dimethylpropan-l-amine hydrochloride (367): To a stirring solution of compound 366 (350 mg, 0.89 mmol) in CH2CI2 (5 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (2 mL) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with EtOAc (2 x 5 mL) and dried in vacuo to afford compound 367 (300 mg, 92%) as an off-white solid.

TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); ’H-NMR (DMSO-rf₆, 400 MHz): δ 10.86 (br s, 1H), 8.65 (br s, 3H), 7.91 (s, 1H), 7.87 (d, J= 8.9 Hz, 2H), 7.08 (d, J= 8.8 Hz, 2H), 4.31 (q, J = 5.6 Hz, 2H), 4.14 (t, J= 6.1 Hz, 2H), 3.28-3.15 (m, 2H), 2.76 (s, 3H), 2.77 (s, 3H), 2.23-2.14 (m, 2H).

Synthesis of 4-(5-((methylamino) methyl) thiazol-2-yl) phénol (369):

Synthesis of 1 -(2-chlorothiazol-5-yl)-A-methylmethanamine (368): To a stirring solution of 2-chloro-5-(chloromethyl) thiazole 221 (2 g, 11.90 mmol) in EtOH (15 mL) in a sealed tube under inert atmosphère were added methyl amine 240 (2 M in THF, 1.8 mL, 14.28 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (10 mL) extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2CI2 to afford compound 368 (600 mg, 31%) as colorless liquid. TLC: 30% EtOAc/ hexanes (Rf 0.7); *H NMR (DMSO-î/₆, 400 MHz): δ 7.57 (s, 1H), 4.08 (br s, 1H), 3.91 (s, 2H), 3.17 (s, 3H).

-207Synthesis of 4-(5-((methylamino) methyl) thiazol-2-yI) phénol (369): To a stirring solution of l-(2-chlorothiazol-5-yl)-A-methylmethanamine 368 (200 mg, 1.23 mmol) in 1, 2 dimethoxy ethane: H2O (4: 1, 15 mL) were added (4-hydroxyphenyl) boronic acid 355 (170 mg, 1.923 mmol), sodium carbonate (342 mg, 3.70 mmol) and purged under argon atmosphère for 30 min. To this was added Pd(PPh3)4 (142 mg, 0.12 mmol) at RT; heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2CI2 to afford compound 369 (70 mg, 25%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.3); 'HNMR (DMSO-J₆, 500 MHz): 9.96 (br s, 1H), 7.72 (d, J= 8.8 Hz, 2H), 7.63 (s, 1H), 6.85 (d, J = 8.8 Hz, 2H), 4.08 (br s, 1H), 3.91 (s, 2H), 3.17 (s, 3H).

Synthesis of (2-(4-(2-morpholinoethoxy) phenyl) thiazol-5-yl) methanamine hydrochloride

-208 -

Synthesis of tert-butyl ((2-(4-(2-morpholinoethoxy) phenyl) thiazol-5-yl) methyl) carbamate (371a): To a mixture of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl) carbamate 356 (250 mg, 0.81 mmol) in THF (5 mL) under inert atmosphère was added diisopropyl azodicarboxylate (495 mg, 2.45 mmol) and triphenyl phosphine (642 mg, 2.45 mmol) at 0 °C and stirred for 10 min. To this was added 2-morpholinoethan-l-ol 370 (128 mg, 0.98 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with CH2CI2 (100 mL) and washed with water (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3% MeOH/ CH2CI2 to afford compound 371a (170 mg, 50%) as white solid. TLC: 50% EtOAc/ hexanes (Rf 0.4); ^XH NMR (DMSO-î/₆, 400 MHz): δ 7.79 (d, J= 8.7 Hz, 2H), 7.59 (s, 1H), 7.51 (t, J= 5.5 Hz, 1H), 7.03 (d, J= 9.0 Hz, 2H), 5.74 (s, 1H), 4.29 (d, J= 6.1 Hz, 2H), 4.13 (t, J= 5.8 Hz, 2H), 3.593.54 (m, 4H), 2.69 (t, J= 5.8 Hz, 2H), 2.52-2.42 (m, 4H), 1.38 (s, 9H).

Synthesis of (2-(4-(2-morpholinoethoxy) phenyl) thiazol-5-yl) methanamine hydrochloride (372): To a stirring solution of compound 371a (170 mg, 0.40 mmol) in CH2CI2 (10 mL) was added 4 N HCl in 1, 4- Dioxane (1 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was washed with EtOAc (5 mL) and dried in vacuo

-209 to afford compound 372 (100 mg, 56%; HCl sait) as white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.2); ’H-NMR (DMSO-î/₆, 500 MHz): δ 8.56 (br s, 3H), 7.92 (s, 1H), 7.90 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 8.7 Hz, 2H), 4.52 (t, J = 4.8 Hz, 2H), 4.35-4.30 (m, 2H), 4.00- 3.94 (m, 2H), 3.85 (t, J= 11.3 Hz, 2H), 3.60-3.55 (m, 2H), 3.50 -3.47 (m, 2H), 3.25-3.15 (m, 2H).

Synthesis of (2-(4-(2-morpholinoethoxy) phenyl) thiazol-5-yl) methanamine hydrochloride (372): Approach-2

Synthesis of 4-(2-chloroethyl) morpholine hydrochloride (370a): To a stirring solution of 3(dimethylamino) propan-l-ol 370 (3.0 g, 23.07 mmol) in CHCI3 (50 mL) under inert atmosphère was added thionyl chloride (6.88 mL, 69.23 mmol) at 0 °C; heated to 70 °C and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with diethyl ether (2 x 30 mL) to afford compound 370a (3 g, 88%) as white solid. TLC: 5% MeOH/ CH2CI2 (Rf 0.2); 'H-NMR (DMSO-J₆, 500 MHz): 11.65(brs, 1H), 10.81 (br s, 1H), 4.06 (t, 7= 6.8 Hz, 1H), 3.98-3.90 (m, 2H), 3.86-3.77 (m, 2H), 3.54-3.36 (m, 3H), 3.22-3.03 (m, 2H).

Synthesis of nv7-butyl ((2-(4-(2-morpholinoethoxy) phenyl) thiazol-5-yl) methyl) carbamate (371b): To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl) carbamate 356 (150 mg, 0.49 mmol) and 4-(2-chloroethyl) morpholine hydrochloride 370a (145 mg, 0.98 mmol) in acetone (15 mL) under inert atmosphère was added potassium carbonate (203 mg, 2.45 mmol) at RT; heated to 70-80 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3% MeOH/ CH2CI2 to afford compound 371b (175 mg, 85%) as colorless thick syrup. TLC: 3% MeOH/ CH2CI2/: 0.5); 'H NMR (DMSO-d₆,400 MHz): δ 7.79 (d, J= 8.7 Hz, 2H), 7.59 (s, 1H), 7.51 (t, J= 5.5 Hz, 1H), 7.03 (d, J= 9.0 Hz, 2H), 5.74 (s, 1H), 4.29 (d, J= 6.1 Hz, 2H),

-210 -

4.13 (t, J= 5.8 Hz, 2H), 3.59-3.54 (m, 4H), 2.69 (t, J = 5.8 Hz, 2H), 2.52-2.42 (m, 4H), 1.38 (s, 9H).

Synthesis of (2-(4-(2-morpholinoethoxy) phenyl) thiazol-5-yl) methanamine hydrochloride (372): To a stirring solution of compound 371b (175 mg, 0.40 mmol) in CH2CI2 (5 mL) was added 4 N HCl in 1, 4- Dioxane (5 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was washed with diethyl ether (5 mL) and dried in vacuo to afford compound 372 (155 mg, 95%; HCl sait) as white solid. TLC: 10% MeOH/ CH2CI2 (Rf. 0.2); ‘H-NMR (DMSO-4 500 MHz): δ 8.56 (br s, 3H), 7.92 (s, 1H), 7.90 (d, J= 8.7 Hz, 2H), 7.14 (d, J= 8.7 Hz, 2H), 4.52 (t, J = 4.8 Hz, 2H), 4.35-4.30 (m, 2H), 4.00- 3.94 (m, 2H), 3.85 (t, 11.3 Hz, 2H), 3.60-3.55 (m, 2H), 3.50 -3.47 (m, 2H), 3.25-3.15 (m, 2H).

Synthesis of (2-(4-(3-(piperidin-l-yl) propoxy) phenyl) thiazol-5-yl) methanamine

Synthesis of tert-butyl ((2-(4-(3-(piperidin-l-yl) propoxy) phenyl) thiazol-5-yI) methyl) carbamate (374): To a stirring solution of ier/-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl) carbamate 356 (200 mg, 0.65 mmol) in diethyl ether (10 mL) under argon atmosphère were added triphenylphosphine (256 mg, 0.98 mmol), DIAD (198 mg, 0.98 mmol) and 3(piperidin-l-yl) propan-l-ol 373 (112 mg, 0.78 mmol) at 0 °C; warmed to RT and stirred for 6

-211 -

h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% MeOH/ CH2CI2+ 5 mL aqeous ammnia to afford compound 374 (280 mg, 80%) as an off white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); ‘H NMR (400 MHz, DMSO-î/₆):ô 7.81 (d, J= 8.8 Hz, 2H), 7.60 (s, 1H), 7.53 (t, J= 5.0 Hz, 1H), 7.02 (d, J= 8.8 Hz, 2H), 4.31 (d, J= 5.8 Hz, 2H), 4.06 (t, J= 6.3 Hz, 2H), 2.45-2.19 (m, 6H), 1.95-1.85 (m, 2H), 1.57-1.45 (m, 4H), 1.40 (s, 9H), 1.25-1.11 (m, 2H); LC-MS: 98.75%; 432.1 (M⁺+l); (column; Ascentis Express C-18 (50 x 3.0 mm, 2.7 pm); RT 1.94 min. 0.025% Aq.TFA + 5% ACN: ACN + 5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of (2-(4-(3-(piperidin-l-yl) propoxy) phenyl) thiazol-5-yl) methanamine hydrochloride (375): To a stirring solution of compound 374 (270 mg, 0.62 mmol) in CH2CI2 (5 mL) was added 4 N HCl in 1, 4-dioxane (5 mL) under argon atmosphère at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with diethyl ether (5 mL), pentane (5 mL) and dried in vacuo to afford compound 375 (190 mg; 83%) as an off white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.2); ’h NMR (400 MHz, DMSO-rf₆): δ 10.20 (br s, 1H), 8.48 (br s, 3H), 7.92-7.84 (m, 3H), 7.08 (d, J= 8.9 Hz, 2H), 4.32 (q, J = 5.5 Hz, 2H), 4.14 (t, J= 6.1 Hz, 2H), 3.48-3.43 (m, 2H), 3.22-3.13 (m, 2H), 2.94-2.81 (m, 2H), 2.26-2.16 (m, 2H), 1.85-1.67 (m, 6H); LC-MS: 99.67%; 332.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.05 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(4-(3-morpholinopropoxy) phenyl) thiazol-5-yl) methanamine hydrochloride (378):

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Synthesis of tert-butyl ((2-(4-(3-morpholinopropoxy)phenyl) thiazol-5-yl)methyl) carbamate (377): To a stirring solution tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl) carbamate 356 (200 mg, 0.65 mmol) in THF (10 mL) under argon atmosphère were added triphenyl phosphine (342 mg, 1.30 mmol), DIAD (258 mg, 1.30 mmol) and 3morpholinopropan-1 -ol 376 (0.13 mL, 0.98 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to obtain crude .The crude was purified through silica gel column chromatography using 100% EtOAc to afford compound 377 (250 mg crude) as an off-white solid. TLC: 100% EtOAc (Rf. 0.2). LC-MS: 66.02%; 434.1 (M⁺+l); (column; Ascentis Express C-18 (50 x 3.0 mm, 2.7 pm); RT 1.87 min. 0.025% Aq.TFA + 5% ACN: ACN + 5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of (2-(4-(3-morpholinopropoxy) phenyl) thiazol-5-yl) methanamine hydrochloride (378): To a stirring solution of compound 377 (250 mg, 0.57 mmol) in CH2CI2 (5 mL) under argon atmosphère was added 4 N HCl in 1, 4-dioxane (4 mL) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with diethyl ether (20 mL), EtOAc (10 mL) and dried in vacuo to afford compound 378 (125 mg; 83%) as an off white solid. TLC: 10% MeOH/ CH2CI2 (Rf. 0.2); 'H NMR (400 MHz, DMSO-î/₆): δ 9.29 (br s, 1H), 8.98-8.89

-213 (m, 2H), 7.81 (d, J = 8.8 Hz, 2H), 7.60 (s, 1H), 7.02 (d, J = 8.9 Hz, 2H), 4.34-4.30 (m, 2H), 4.11-3.99 (m, 4H), 3.60-3.53 (m, 8H), 1.94-1.86 (m, 2H); LC-MS: 96.49%; 334 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0mm, 2.6 um); RT 1.51 min. 2.5mM Aq.NH^OCH + 5% ACN: CAN + 5% 2.5mM Aq.NH₄OOCH; 1.2 mL/min).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-A-methyl-N-(2, 2, 2-

Synthesis of tert-butyl ((2-(4-(3-(methylamino) propoxy) phenyl) thiazol-5-yl) methyl) carbamate (380): To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl) carbamate 356 (1 g, 3.26 mmol) in dry diethyl ether (50 mL) under argon atmosphère were added triphenyl phosphine (2.56 g, 9.80 mmol), 3-(methylamino) propan-l-ol 379 (0.36 mL, 3.92 mmol) and diisopropyl azodicarboxylate (1.98 g, 9.80 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2x50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 15% MeOH/ CH2CI2 to afford compound 380 (600 mg, 49%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.2); LC-MS: 93.67%; 378.1 (M⁺+l); (column; Ascentis Express Cl 8, (50 x 3.0 mm, 2.7 pm); RT 1.84 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of terZ-butyl ((2-(4-(3-(methyl(2, 2, 2-trifluoroethyl) amino) propoxy) phenyl) thiazol-5-yl) methyl) carbamate (382): To a stirring solution of Ze/7-butyl ((2-(4-(319643

-214 (methylamino) propoxy) phenyl) thiazol-5-yl) methyl) carbamate 380 (400 mg, 1.06 mmol) in DMF (8 mL) under inert atmosphère were added triethylamine (0.44 mL, 3.18 mmol), 2, 2, 2trifluoroethyl trifluoromethanesulfonate 381 (0.22 mL, 1.59 mmol) at RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with with EtOAc (2 x 80 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 5-10% MeOH/ CH2CI2 to afford compound 382 (200 mg, 41%) as pale yellow liquid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.8). LC-MS: 88.52%; 181.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 0.37 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-A-methyl-N-(2, 2, 2-trifluoroethyl) propan-1-amine hydrochloride (383): To a stirring solution of compound 382 (100 mg, 0.21 mmol) in CH₂C1₂ (2 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (2 mL) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with diethyl ether (2x5 mL) and dried in vacuo to afford compound 383 (70 mg, HCl sait) as white solid. TLC: 30% EtOAc/ hexanes (Rf 0.2); LC-MS: 99.39%; 360.0 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.57 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-V, /V-diethylpropan-1- amine hydrochloride (389):

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Synthesis of tert-butyl ((2-(4-(3-hydroxypropoxy) phenyl) thiazol-5-yl) methyl) carbamate (385): To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl) carbamate 356 (500 mg, 1.63 mmol) in acetone (10 mL) under inert atmosphère were added potassium carbonate (676 mg, 4.90 mmol), 3-bromopropan-l-ol 384 (0.22 mL, 2.45 mmol) and at RT; heated to 60 °C and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc ( 2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 50% EtOAc/ hexanes to afford compound 385 (400 mg, 67%) as an off-white solid. TLC: 60% EtOAc/ hexanes (Rf 0.2). *H NMR (500 MHz, DMSOd₆y. δ 7.81 (d, J= 8.7 Hz, 2H), 7.60 (s, 1H), 7.52 ( t, J= 5.5 Hz, 1H), 7.03 (d, 7 = 9.3 Hz, 2H), 4.55 (t, 7= 5.2 Hz, 1H), 4.31 (d, 7= 5.8 Hz, 2H), 4.09 (t, J= 6.4 Hz, 2H), 3.61-3.52 (m, 2H),

1.90-1.85 (m, 2H), 1.40 (s, 9H); LC-MS: 95.79%; 365.0 (M⁺+l); (column; Ascentis Express

C18, (50 x 3.0 mm, 2.7 pm); RT 2.24 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

-216 Synthesis of 3-(4-(5-(((tert-butoxycarbonyl) amino) methyl) thiazol-2-yI) phenoxy) propyl methanesulfonate (386): To a stimng solution of compound 385 (300 mg, 0.82 mmol) in CH2CI2 (10 mL) under inert atmosphère were added triethylamine (0.23 mL, 1.64 mmol), methanesulfonyl chloride (0.07 mL, 0.98 mmol) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH2CI2 (2x50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 386 (350 mg, 96%) as pale yellow liquid. TLC: 60% EtOAc/ hexanes (Rf 0.6); 'H NMR (400 MHz, DMSO-7₆): δ 7.82 (d, J= 8.8 Hz, 2H), 7.61 (s, 1H), 7.55-7.46 (m, 1H), 7.06 (d, J= 8.9 Hz, 2H), 4.37 (t, J= 6.3 Hz, 2H), 4.31 (d, J= 6.0 Hz, 2H), 4.14 (t, 7= 6.2 Hz, 2H), 3.18 (s, 3H), 2.16 (t, J= 6.2 Hz, 2H), 1.40 (s, 9H); LC-MS: 97.12%; 443.0 (M⁺+l); (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 2.50 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of te/7-butyl ((2-(4-(3-(diethylamino) propoxy) phenyl) thiazol-5-yl) methyl) carbamate (388): To a stirring solution of compound 386 (350 mg, 0.79 mmol) in THF (5 mL) in a sealed tube under inert atmosphère was added diethylamine 387 (0.41 mL, 3.96 mmol) at RT; heated to 70 °C and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (50 mL) and extracted with EtOAc (2 x 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-10% MeOH/ CH2CI2 to afford compound 388 (220 mg, 66%) as pale yellow liquid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); ^XH NMR (400 MHz, CD3OD): δ 7.82 (d, 7= 8.9 Hz, 2H), 7.59 (s, 1H), 7.02 (d, 7= 8.9 Hz, 2H), 4.41 (s, 2H), 4.11 (t, 7= 6.0 Hz, 2H), 2.88-2.85 (m, 2H), 2.78 (q, 7= 7.3 Hz, 4H), 2.10-1.97 (m, 2H), 1.46 (s, 9H), 1.15 (t, 7= 7.2 Hz, 6H); LC-MS: 96.43%; 420.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.94 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

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Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-V. V-diethylpropan-1- amine dihydrochloride (389): To a stirring solution of compound 388 (300 mg, 0.71 mmol) in CH2CI2 (5 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (5 mL) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the 5 reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with diethyl ether (2 x 20 mL) and dried in vacuo to afford compound 389 (200 mg, 79%; HCl sait) as white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); *H NMR (400 MHz, DMSO-d₆) δ 10.53 (br s, 1H), 8.58 (br s, 3H), 7.91 (s, 1H), 7.87 (d, J= 8.9 Hz, 2H), 7.08 (d, J= 8.9 Hz, 2H), 4.32 (q, J= 5.5 Hz, 2H), 4.16 (t, J = 6.1 Hz, 2H), 3.22-3.04 (m, 6H), 2.20-2.10 (m, 2H), 1.24 (t, J= 10 7.2 Hz, 6H); LC-MS: 98.14%; 320.1 (M⁺+l); (column; Ascentis Express Cl 8, (50 x 3.0 mm,

2.7 pm); RT 1.03 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-(4-(5-(aminomethyl) thiazol-2-yI) phenoxy)-N, N-dimethylbutan-l-amine

-218 Synthesis of tert-butyl ((2-(4-(4-hydroxybutoxy) phenyl) thiazol-5-yl) methyl) carbamate (391): To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl) carbamate 356 (60 mg, 0.19 mmol) in acetone (5 mL) under inert atmosphère were added potassium carbonate (81 mg, 0.58 mmol), TBAI (7.2 mg, 0.019 mmol) and 4Chlorobutanol 390 (0.49 mL, 4.90 mmol) at RT; heated to reflux and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and washed with CH2CI2 (40 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silicagel flash column chromatography using 50% EtOAc/ hexanes; to afford compound 391 (40 mg, 54%) as brown syrup. TLC: 50% EtOAc/ hexanes (Rf 0.5); LC-MS: 99.31%; 379.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.29 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-(4-(5-(((tert-butoxycarbonyl) amino) methyl) thiazol-2-yl) phenoxy) butyl methanesulfonate (392): To a stirring solution of compound 391 (200 mg, 0.52 mmol) in CH2CI2 (5 mL) under inert atmosphère were added triethylamine (106 mg, 1.05 mmol), methanesulfonyl chloride (90 mg, 0.79 mmol) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with CH2CI2 (2 x 20 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution (30 mL) and water (30 mL); dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 392 (220 mg, 91%) as brown syrup. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.3); LC-MS: 97.66%; 457.1 (M⁺+l); (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 2.56 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of tert-butyl ((2-(4-(4-(dimethylamino) butoxy) phenyl) thiazol-5-yl) methyl) carbamate (393): To a stirring solution of compound 392 (220 mg, crude 0.48 mmol)) in THF (2 mL) in a sealed tube was added 2 M dimethylamine in THF (3 mL) at RT and heated to 60 °C for 6 h. The reaction was monitored by TLC; after completion the volatiles were removed in vacuo to obtain the crude. The crude was either purified through silica gel column

-219 chromatography using 5% MeOH/ CH2CI2 to afford 393 (180 mg, 84%) as brown syrup. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.3); ^]H NMR (400 MHz, DMSO4): δ 7.80 (d, J= 8.9 Hz, 2H), 7.60 (s, 1H), 7.52 (t, J= 5.2 Hz, 1H), 7.02 (d, J= 8.9 Hz, 2H), 4.31 (d, J= 5.8 Hz, 2H), 4.04 (t, J= 6.5 Hz, 2H), 2.24 (t, J= 7.2 Hz, 2H), 2.12 (s, 6H), 1.78-1.68 (m, 2H), 1.58-1.50 (m, 2H), 1.40 (s, 9H); LC-MS: 98.90%; 406.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.92 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-A. A-dimethylbutan-l-amine hydrochloride (394): To a stirring solution of compound 393 (230 mg, 0.56 mmol) in CH2CI2 (5 mL) was added 4 N HCl in 1, 4-dioxane (6 mL) under argon atmosphère at 0 °C; warmed to 10 RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with diethyl ether (5 mL) and dried in vacuo to afford 394 (135 mg; 70%) as an off white solid. TLC: 5% MeOH/ CH2CI2 (Rf. 0.1); 'H NMR (400 MHz, DMSO4): δ 10.41 (br s, 1H), 8.54 (br s, 3H), 7.95-7.84 (m, 3H), 7.117.05 (m, 2H), 4.32 (q, J = 5.5 Hz, 2H), 4.17-4.09 (m, 2H), 3.14-3.03 (m, 2H), 2.74 (s, 3H),

2.73 (s, 3H), 1.89-1.74 (m,4H);

-220 Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-W, W-dimethylbutan-l-amine

Synthesis of benzyl (3-oxobutyl) carbamate (397): To a stirring solution of 4-oxopentanoic acid 395 (3.5 g, 30.15 mmol) in benzene (50 mL) were added diphenyl phosphonic azide (8.30 g, 30.17 mmol) and triethylamine (4.4 mL, 30.17 mmol) at RT; heated to 50 °C for 30 min. To this was added benzyl alcohol 396 (4.8 g, 45.26 mmol) and heated to reflux and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The residue was diluted with EtOAc (100 mL), washed with 5% citric acid solution (50 mL) , saturated sodium bicarbonate solution (50 mL), water (50 mL), brine (100 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude. The crude was purified through silica gel column chromatography using 30% EtOAc/ hexanes to afford compound 397 (3 g, 45%) as pale yellow solid. TLC: 5% MeOH/ CH₂C1₂ (Ry 0.5); 'fi-NMR (DMSO-4 400 MHz): δ 7.40-7.27 (m,

5H), 7.20 (t, J= 5.3 Hz, 1H), 5.00 (s, 2H), 3.23-3.17 (m, 2H), 2.60 (t, J = 6.8 Hz, 2H), 2.08 (s,

3H); LC-MS: 80.94%; 222.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.98 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min);

-221 Synthesis of benzyl (3-hydroxybutyl) carbamate (398): To a stirring solution ofbenzyl (3oxobutyl) carbamate 397 (2 g, 9.05) in MeOH (50 mL) under argon atmosphère was added sodium borohydride (687 mg, 18.09 mmol) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH2CI2 (2 x 100 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to crude compound 398 (1.8 g, 90%) as colorless liquid. TLC: 30% EtOAc/ hexanes (Rf. 0.2); *H NMR (DMSO-r/^ 400 MHz): δ 7.41-7.27 (m, 5H), 7.15 (t, J= 4.9 Hz, 1H), 5.00 (s, 2H), 4.41 (d, J= 4.6 Hz, 1H), 3.66-3.56 (m, 1H), 3.11-3.00 (m, 2H), 1.49-1.42 (m, 2H), 1.04 (d, J= 5.8 Hz, 3H); LC-MS: 96.96%; 223.7 (M⁺+l); (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 1.99 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of ZerLbutyl ((2-(4-((4-(((benzyloxy) carbonyl) amino) butan-2-yl) oxy) phenyl) thiazol-5-yl) methyl) carbamate (399): To a stirring solution of terLbutyl ((2-(4hydroxyphenyl) thiazol-5-yl) methyl) carbamate 398 (2 g, 8.97 mmol) in diethyl ether (50 mL) under argon atmosphère were added triphenylphosphine (7.1 g, 26.91 mmol), DIAD (5.4 g, 26.91 mmol) and benzyl (3-hydroxybutyl) carbamate 356 (2.74 g, 8.97 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20-50% EtOAc/ hexanes to afford compound 399 (1.2 g, crude) as brown color sticky solid. TLC: 50% EtOAc/ hexanes (Rf. 0.4); LC-MS: 67.64%; 512.1 (M⁺+l); (column; Ascentis Express C-18 (50 x 3.0 mm, 2.7 pm); RT 2.87 min. 0.025% Aq.TFA + 5% ACN: ACN + 5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of m/7-butvl ((2-(4-((4-aminobutan-2-yl) oxy) phenyl) thiazol-5-yl) methyl) carbamate (400): To a stirring solution of terLbutyl ((2-(4-((4-(((benzyloxy) carbonyl) amino) butan-2-yl) oxy) phenyl) thiazol-5-yl) methyl) carbamate 399 (600 mg, 1.17 mmol) in MeOH (50 mL) under inert atmosphère was added 10% Pd/C (50% wet, 600 mg), ammonium formate (2.95 g, 46.96 mmol) at RT; heated to reflux and stirred for 24 h. The reaction was monitored

-222by TLC; after completion of the reaction, the reaction mixture was filtered through celite washed with 20% MeOH/ CH2CI2 (20 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was diluted with EtOAc (100 mL), washed with water (50 mL). The aqueous layer was extracted with EtOAc (2x50 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to obtain the crude. The crude was purified through silica gel (100-200 mesh) column chromatography using 10% MeOH/ CH2C1₂ to afford compound 400 (120 mg, 30%) as an colorless liquid. TLC: 15% MeOH/ CH2CI2 (Λ/ 0.2); Ή NMR (DMSO-i/i, 400 MHz): δ 7.79 (d, J= 8.9 Hz, 2H), 7.53 (t, J= 5.3 Hz, 1H), 7.02 (d, J= 8.9 Hz, 2H), 4.70-4.60 (m, 1H), 4.31 (d, J= 5.8 Hz, 2H), 2.76-2.64 (m, 2H), 1.87-1.75 (m, 1H), 1.72-1.61 (m, 1H), 1.40 (s, 9H), 1.26 (d, J= 6.1 Hz, 3H); LC-MS: 96.47%; 378.0 (M⁺+l)_;(column; Ascentis Express C-18 (50 x 3.0 mm, 2.7 pm); RT 1.90 min. 0.025% Aq.TFA + 5% ACN: ACN + 5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of nvr-butyl ((2-(4-((4-(dimethylamino) butan-2-yl) oxy) phenyl) thiazol-5-yl) methyl) carbamate (401): To a stirring solution of teri-butyl ((2-(4-((4-aminobutan-2-yl) oxy) phenyl) thiazol-5-yl) methyl) carbamate 400 (180 mg, 0.47 mmol) in MeOH (25 mL) under inert atmosphère were added paraformaldéhyde (143 mg, 4.77 mmol) and sodium cyanoborohydride (150 mg, 2.39 mmol) portion wise for 5 min at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL), washed with saturated sodium bicarbonate solution (50 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% MeOH/ CH₂C12 (5% aqueous ammonia) to afford compound 401 (90 mg, crude) as yellow solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.3); LC-MS: 54.78%; 406.1 (M⁺+l); (column; Ascentis Express C-18 (50 x 3.0 mm, 2.7 pm); RT 1.92 min. 0.025% Aq.TFA + 5% ACN: ACN + 5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-A, A-dimethylbutan-1-amine hydrochloride (402): To a stirring solution of ίβΠ-butyl ((2-(4-((4-(dimethylamino) butan-219643

-223 - yl) oxy) phenyl) thiazol-5-yl) methyl) carbamate 401 (90 mg, 0.22 mmol) in CH2CI2 (5 mL) was added 4 N HCl in 1, 4-dioxane (0.5 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford crude compound 402 (70 mg; HCl sait) as yellow sticky solid. TLC: 50% EtOAc/ hexanes (Rf 0.1); LC-MS: 79.21%; 306.0 (M⁺+l); (column; Ascentis Express Cl 8, (50 x 3.0 mm, 2.7 pm); RT 1.03 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-W-(2, 2, 2-trifluoroethyl)

Synthesis of tert-butyl ((2-(4-(3-azidopropoxy) phenyl) thiazol-5-yl) methyl) carbamate (403): To a stirring solution of 4 3-(4-(5-(((/erTbutoxycarbonyl) amino) methyl) thiazol-2-yl) phenoxy) propyl methanesulfonate 386 (1 g, 2.26 mmol) in DMF (10 mL) under inert atmosphère was added sodium azide (441 mg, 6.70 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted water (50 mL) and extracted with EtOAc (2 x 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the

-224crude which was triturated with diethylether (10 mL) and dried in vacuo to afford compound 403 (900 mg, 68%) as sticky solid. TLC: 3% MeOH/ CH₂C1₂ (Rf 0.8); 'H NMR (DMSO4, 500 MHz): δ 7.82 (d, J= 8.7 Hz, 2H), 7.61 (s, 1H), 7.53 (t, J= 5.5 Hz, 1H), 7.05 (d, J = 9.3 Hz, 2H), 4.31 (d, J= 5.8 Hz, 2H), 4.10 (t, J = 6.1 Hz, 2H), 3.52 (t, J= 6.7 Hz, 2H), 2.03-1.97 (m, 2H), 1.40 (s, 9H); LC-MS: 96.94%; 390.0 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.82 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of te/7-butyl ((2-(4-(3-aminopropoxy) phenyl) thiazol-5-yl) methyl) carbamate (404): To a stirring solution of compound 403 (900 mg, crude) in THF: H₂O (4: 1, 12.5 mL) was added triphenyl phosphine (606 mg, 2.31 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% MeOH/ CH₂C1₂ (10 mL aqueous ammonia) to afford compound 404 (530 mg, 63%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); *H-NMR (DMSO-rf₆, 500 MHz): δ 8.42 (s, 1H), 7.82 (d, J= 8.7 Hz, 2H), 7.61 (s, 1H), 7.54 (t, J= 5.5 Hz, 2H), 7.04 (d, J= 8.7 Hz, 2H), 4.31 (d, J = 5.8 Hz, 2H), 4.11 (t, J= 6.4 Hz, 2H), 2.88 (t, J= 7.2 Hz, 2H), 1.97 (p, J= 6.7 Hz, 2H), 1.40 (s, 9H); LC-MS: 99.67%; 364.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.84 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl ((2-(4-(3-((2, 2, 2-trifluoroethyl) amino) propoxy) phenyl) thiazol-5yl) methyl) carbamate (405): To a stirring solution of compound 404 (400 mg, 1.10 mmol) in DMF (5 mL) under inert atmosphère were added triethylamine (0.46 mL, 3.30 mmol), 2, 2, 2trifluoroethyl trifluoromethanesulfonate (0.47 mL, 3.30 mmol) at RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 80 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2% MeOH/ CH₂C1₂ to afford compound 405 (300 mg, 61%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf.

-225 -

0.7). LC-MS: 98.65%; 446.1 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.98 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-A-(2. 2, 2-trifluoroethyl) propan-l-amine hydrochloride (406): To a stirring solution of compound 405 (300 mg, 0.67 mmol) in CH2CI2 (5 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (3 mL) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with diethyl ether (2x10 mL) and dried in vacuo to afford compound 406 (230 mg, 89%; HCl sait) as brown solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); 'H NMR (400 MHz, DMSO-îZ₆): δ 10.15 (br, 2H), 8.56 (br s, 3H), 7.94-7.81 (m, 3H), 7.07 (d, J= 8.9 Hz, 2H), 4.92 (s, 2H), 4.32 (q, J= 5.4 Hz, 2H), 4.21-4.08 (m, 2H), 3.21 (t, J= 7.5 Hz, 2H), 2.27-2.18 (m, 2H); LC-MS: 98.51%; 346.0 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 1.97 min. 2.5 mM Aq. NH4OOCH: 5% ACN; 0.8 mL/min).

Synthesis of 7V-(3-(4-(5-(aminomethyl) thiazol-2-yI) phenoxy) propyl) acetamide

Synthesis of tert-butyl ((2-(4-(3-acetamidopropoxy) phenyl) thiazol-5-yl) methyl) carbamate (407): To a stirring solution of zu/7-butyl ((2-(4-(3-aminopropoxy) phenyl) thiazol5-yl) methyl) carbamate 404 (250 mg, 0.68 mmol) in CH2CI2 (20 mL) under inert atmosphère were added triethylamine (0.25 mL, 1.70 mmol), acetylchloride (0.053 mL, 0.75 mmol) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the

-226 - reaction, the reaction mixture was diluted with CH2CI2 (100 mL), washed with water (75 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford crude which was triturated with 10% EtOAc/ hexanes (10 mL), diethylether (5 mL) and dried in vacuo to afford compound 407 (220 mg, 79%) as colorless liquid. TLC: 10% MeOH/ CH2CI2 (Rf 0.6); ’H-NMR (DMSO-î/₆, 500 MHz): δ 8.11-8.02 (m, 0.6H), 7.90 (t, J= 4.6 Hz, 0.4H), 7.81 (d, J= 8.7 Hz, 2H), 7.61 (s, 1H), 7.53 (t, J= 5.5 Hz, 1H), 7.03 (dd, J= 9.0, 2.6 Hz, 2H), 4.31 (d, J= 5.8 Hz, 2H), 4.08-4.00 (m, 2H), 3.28-3.16 (m, 2H), 1.91-1.82 (m, 3.5H), 1.80 (s, 1.5H), 1.40 (s, 9H); LC-MS: 98.81%; 406.1 (M⁺+l); (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 2.18 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of 7V-(3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) propyl) acetamide hydrochloride (408): To a stirring solution of compound 407 (210 mg, 0.48 mmol) in CH2Q2 (5 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (3 mL) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with diethyl ether (2 x 50 mL), n-hexane (25 mL) and dried in vacuo to afford compound 408 (160 mg, 91%; HCl sait) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.2); *H-NMR (DMSO-4 500 MHz): δ 8.52 (br s, 3H), 7.90 (s, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.06 (dd, 7= 8.7, 2.9 Hz, 2H), 4.32 (q,7 = 5.8 Hz, 2H), 4.06 (q,7 = 5.8 Hz, 2H), 3.29-3.14 (m, 2H), 1.92-1.83 (m, 2H), 1.80 (s, 3H);

Synthesis of 2, 2'-((3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) propyl) azanediyl) bis (ethan-l-ol) hydrochloride (411):

-227 -

Synthesis of m/7-butvl ((2-(4-(3-(bis(2-hydroxyethyl) amino) propoxy) phenyl) thiazol-5-yl) methyl) carbamate (410): To a stirring solution of compound 386 (1.7 g, 3.84 mmol) in DMF (30 mL) under inert atmosphère were added 2,2'-azanediylbis(ethan-l-ol) 409 (807 mg, 7.69 mmol) and potassium carbonate (1.6 g, 11.52 mmol) at RT; heated to 100 °C and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with 10% MeOH/ CH2CI2 and washed with water. The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% MeOH/ CH2CI2 to afford compound 410 (400 mg, 23%) as sticky solid. TLC: MeOH/ CH₂C1₂ (Rf 0.3); 'H NMR (500 MHz, DMSO-î/ô): δ 7.80 (d, J= 8.7 Hz, 2H), 7.59 (s, 1H), 7.52 (br t, J= 5.5 Hz, 1H), 7.02 (d, J = 8.7 Hz, 2H), 4.54 (t, J= 4.9 Hz, 1H), 4.30 (d, J= 5.8 Hz, 2H), 4.08 (t, J= 6.4 Hz, 2H), 3.55 (q, J= 5.8 Hz, 2H), 1.89-1.84 (m, 2H), 1.39 (s, 9H); LC-MS: 89.41%; 452.1 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.80 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 2, 2’-((3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) propyl) azanediyl) bis (ethan-l-ol) hydrochloride (411): To a stirring solution of compound 410 (400 mg, 0.88 mmol) in CH₂C1₂ (10 mL) was added 4 N HCl in 1, 4-dioxane (2 mL) under argon atmosphère at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after

-228 completion of the reaction, the volatiles were removed in vacuo. The crude was triturated with isopropanol (3 mL), EtOAc (7 mL) and dried in vacuo to afford compound 411 (350 mg crude, HCl sait) as an off white solid. TLC: 10% MeOH/ CH₂C1₂ (Ry 0.1); ^JH NMR (400 MHz, DMSO-rfd: δ 11.53 (s, 1H), 9.49 (t, J= 5.7 Hz, 1H), 8.92-8.83 (m, 1H), 8.75-8.63 (m, 1H), 8.06 (d, J= 8.2 Hz, 1H), 8.01-7.96 (m, 2H), 7.92-7.80 (m, 6H), 7.73 (s, 1H), 7.03 (d, J= 8.9 Hz, 2H), 4.66 (d, J= 5.5 Hz, 2H), 4.04-3.89 (m, 2H), 3.38-3.32 (m, 1H), 3.28-3.20 (m, 1H), 2.85-2.71 (m, 2H), 2.28-2.18 (m, 1H), 1.89-1.79 (m, 2H), 1.73-1.63 (m, 1H), 1.41-1.28 (m, 1H);

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-A-isopropyl-/V-methylpropan-lamine hydrochloride (414):

Synthesis of tert-butyl ((2-(4-(3-(isopropyl (methyl) amino) propoxy) phenyl) thiazol-5-yl) methyl) carbamate (413): To a stirring solution of 3-(4-(5-(((/er/-butoxycarbonyl) amino) methyl) thiazol-2-yl) phenoxy) propyl methanesulfonate 356 (1.3 g, 2.94 mmol) in DMF (20 mL) under inert atmosphère were added potassium carbonate (1.22 g, 8.82 mmol), Nmethylpropan-2-amine 412 (430 mg, 5.89 mmol) at RT and stirred for 48 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (2 x 75 mL), washed with water (50 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 6% EtOAc/ hexanes to afford compound 413

-229 (300 mg, 32%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf 0.4). LC-MS: 96.38%;

420.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.92 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yI) phenoxy)-7V-isopropyl-A-methylpropan-lamine hydrochloride (414): To a stirring solution of compound 413 (300 mg, 0.71 mmol) in CH₂C1₂ (10 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (1 mL) at 0 °C;

warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with diethyl ether (2x10 mL) and dried in vacuo to afford compound 414 (260 mg, HCl sait) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.2); 'ft-NMR (DMSO-4 400 MHz): 10.41 (br s, 1H), 8.54 (br s, 3H), 7.92-7.85 (m, 3H), 7.08 (d, J= 8.7 Hz, 2H), 4.32 (q, J= 5.8 Hz, 2H), 4.15 (t, J= 6.1 Hz, 2H), 3.58-3.54 (m, 2H), 3.29-3.21 (m, 1H), 3.14-3.05 (m, 1H), 2.29-2.14 (m, 2H), 1.28 (d,7=7.0 Hz, 3H), 1.23 (d,7=6.4 Hz, 3H); Mass: 320.1 (M⁺+l);

Synthesis of /V-(3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) propyl)-Amethylcyclopropanamine hydrochloride (417):

Synthesis of tert-butyl ((2-(4-(3-(cyclopropyl (methyl) amino) propoxy) phenyl) thiazol-5yl) methyl) carbamate (416): To a stirring solution of 3-(4-(5-(((ter/-butoxycarbonyl) amino) methyl) thiazol-2-yl) phenoxy) propyl methanesulfonate 356 (1.0 g, 2.26 mmol) in DMF (10 mL) under inert atmosphère were added potassium carbonate (935 mg, 13.57 mmol), N

-230 methylcyclopropanamine 415 (963 mg, 13.57 mmol) at 0 °C; heated to 70 °C and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (2 x 75 mL), washed with water (50 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 5% MeOH/ CH2O2 to afford compound 416 (180 mg, 19%) as sticky solid. TLC: 5% MeOH/ CH2CI2 (Rf 0.4). LC-MS: 96.38%; 418.1 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.94 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). *H-NMR (DMSOd₆, 400 MHz): δ 7.80 ( d, J = 8.7 Hz, 2H), 7.60 (s, 1H), 7.53 (d, J= 5.8 Hz, 1H), 7.02 (d, J= 8.7 Hz, 2H), 4.31 (d, J= 5.8 Hz, 2H), 4.02 (t, J= 6.4 Hz, 2H), 2.62 (t, J= 7.0 Hz, 2H), 2.26 (s, 3H), 1.88 (p, 7 = 6.8 Hz, 2H), 1.65-1.60 (m, 1H), 1.40 (s, 9H), 0.45-0.38 (m, 2H), 0.29-0.24 (m, 2H);

Synthesis of A-(3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) propyl)-Amethylcyclopropanamine hydrochloride (417): To a stirring solution of compound 416 (180 mg, 0.43 mmol) in CH2CI2 (5 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (0.5 mL) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with diethyl ether (2x10 mL) and dried in vacuo to afford compound 417 (160 mg, HCl sait) as sticky solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.1); ‘H-NMR (DMSO-î/₆, 500 MHz): 11.00 (br s, 1H), 8.65 (br s, 3H), 7.91 (s, 1H), 7.87 (d, 7= 8.7 Hz, 2H), 7.08 (d, 7= 8.7 Hz, 2H), 4.31 (q,7= 5.8 Hz, 2H), 4.16 (t,7 = 6.1 Hz, 2H), 3.40-3.26 (m, 2H), 2.90-2.84 (m, 1H), 2.82 (d, 7= 4.6 Hz, 3H), 2.35-2.19 (m, 2H), 1.25-1.04 (m, 2H), 0.94-0.73 (m, 2H); LC-MS (Agilent Ion Trap): 90.32%; 318.3 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 2.72 min. 2.5 mM Aq. NH4OAC: ACN; 0.8 mL/min).

Synthesis of tert-butyl ((2-(4-((4-(diethylamino) butan-2-yl) oxy) phenyl) thiazol-5-yl) methyl) carbamate (419):

-231 -

Synthesis of m/7-butyl ((2-(4-((4-(diethylamino) butan-2-yI) oxy) phenyl) thiazol-5-yl) methyl) carbamate (418): To a stimng solution of tert-butyl ((2-(4-((4-aminobutan-2-yl) oxy) phenyl) thiazol-5-yl) methyl) carbamate 400 (200 mg, 0.53 mmol) in MeOH (20 mL) under inert atmosphère were added acetaldehyde (116 mg, 2.65 mmol), acetic acid (0.05 mL) and sodium cyanoborohydride (167 mg, 2.65 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 418 (200 mg, 87%) as colorless syrup. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.4); 'H NMR (DMSO-</₆, 400 MHz): δ 7.82 (d, J= 8.8 Hz, 2H), 7.61 (s, 1H), 7.53 (t, 7= 5.8 Hz, 1H), 7.04 (d, 7= 8.9 Hz, 2H), 4.74-4.50 (m, 1H), 4.31 (d, 7= 5.9 Hz, 2H), 3.14-2.93 (m, 6H), 1.41-1.38 (m, 11H), 1.30 (d, 7= 6.1 Hz, 3H), 1.17 (t, 7 = 7.1 Hz, 6H); LC-MS: 87.75%; 434.1 (M⁺+l); (column; Ascentis Express C-18 (50 x 3.0 mm, 2.7 pm); RT 2.03 min. 0.025% Aq.TFA + 5% ACN: ACN + 5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-A, A-diethylbutan-l-amine hydrochloride (419): To a stirring solution of ZeA-butyl ((2-(4-((4-(diethylamino) butan-2-yl) oxy) phenyl) thiazol-5-yl) methyl) carbamate 418 (200 mg, 0.46 mmol) in CH₂C1₂ (20 mL) was added 4 N HCl in 1, 4-dioxane (2 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford crude compound 419 (200 mg) as yellow sticky

-232 solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.1); LC-MS: 89.46%; 334.0 (M +l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.00 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of l-(((2-(4-(3-(azetidin-l-yl) propoxy) phenyl) thiazol-5-yl) methyl)-14-azanyl)-

Synthesis of tert-butyl ((2-(4-(3-(azetidin-l-yl) propoxy) phenyl) thiazol-5-yl) methyl) carbamate (421): To a stirring solution of compound 386 (1 g, 2.47 mmol) in DMF (30 mL) were added potassium carbonate (1.7 g, 12.37 mmol) and azetidine 420 (705 mg, 12.37 mmol) at RT under inert atmosphère. The reaction mixture was heated to 80 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2x30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% MeOH/CH₂C12 to afford crude compound 421 (130 mg) as yellow syrup. ¹H NMR (400 MHz, DMSO-^): δ 7.79 (d, J= 8.9 Hz, 2H), 7.59 (s, 1H), 7.54-7.48 (m, 1H), 7.00 (d, J = 8.8 Hz, 2H), 4.29 (d, J= 5.9 Hz, 2H), 4.04-3.97 (m, 2H), 3.08-3.05 (m, 4H), 2.47-2.42 (m, 2H), 1.96-1.90 (m, 2H), 1.691.67 (m, 2H), 1.38 (s, 9H); LC-MS: 70.31%; 404.1 (M⁺+l) (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 1.89 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

- 233 Synthesis of 1-(((2-(4-(3-(azetidin-l-yl) propoxy) phenyl) thiazol-5-yl) methyl)-14-azanyl)-2, 2, 2-trifluoroethan-l-one (422): To a stirring solution of compound 421 (130 mg, 0.29 mmol) in CH₂C1₂ (10 mL) was added trifluoroacetic acid (0.06 mL, 0.87 mmol) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford crude compound 422 (100 mg) as an off-white solid. This crude material was taken to next step without further purification. TLC: 70% EtOAc/ Hexane (Rf 0.1); LC-MS: 24.00%; 304.1 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 1.07 min. 2.5 mM NH4OOCH in water + 5% ACN: ACN + 5% 2.5 mM NH4OOCH in water, 0.8 mL/min).

Synthesis of l-(l-((4-(5-(aminomethyl) thiazol-2-yl) phenoxy) methyl) cyclopropyl)-A, N-

Synthesis of ethyl 1-cyanocyclopropane-l-carboxylate (425): To a stirring solution of ethyl 2-cyanoacetate 423 (5 g, 44.20 mmol) in acetone (100 mL) were added potassium carbonate (18.3 g, 132.60 mmol) and 1,2-dibromo ethane (8 mL, 88.4 mmol) 424 at RT under inert atmosphère. The reaction mixture was heated to 70 °C and stirred for 16 h. The reaction was

-234 monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and washed with acetone (200 mL). The filtrate was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the compound 425 (10 g, crude) as brown liquid. 'H NMR (400 MHz, CDC1₃): δ 4.27 (q, J= Ί 2 Hz, 2H), 1.68 (t, J= 3.5 Hz, 2H), 1.68 (t, 7= 3.5 Hz, 2H), 1.34 (t, 7=7.2 Hz, 3H)

Synthesis of l-(hydroxymethyl) cyclopropane-l-carbonitrile (426): To a stirring solution of compound 425 (4 g, 28.78 mmol) in 1, 2-dimethoxy ethane: MeOH (9: 1, 88 mL) was added sodium borohydride (8.7 g, 228.90 mmol) at RT under inert atmosphère. The reaction mixture was stirred at RT for 48 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with 10%MeOH/CH₂C12 (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 426 (1.4 g, 54%) as yellow color liquid. '14 NMR (400 MHz, CDC1₃): δ 4.25 (br s, 1H), 3.63 (s, 2H), 1.32-1.24 (m, 2H), 1.02-0.92 (m, 2H)

Synthesis of l-(hydroxymethyl) cyclopropane-l-carbonitrile (427): To a stirring solution of compound 426 (1 g, 10.31 mmol) in CH2CI2 (20 mL) under inert atmosphère were added triethyl amine (4.5 mL, 30.93 mmol), methane sulfonyl chloride (1.68 mL, 20.62 mmol) at 0 °C; stirred RT for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with water (20 mL) and extracted with CH2CI2 (2 x 20 mL). The combined organic extracts were washed with sodium bicarbonate solution (20 mL), brine (20 mL) dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude compound 427 (1.5 g) as brown liquid. TLC: 30% EtOAc/Hexane (Rf 0.5); ^XH NMR (400 MHz, CDC1₃): δ 4.19 (s, 2H), 3.15 (s, 3H), 1.49-1.44 (m, 2H), 1.21-1.16 (m, 2H)

Synthesis of nv7-butyl ((2-(4-((l-cyanocyclopropyl) methoxy) phenyl) thiazol-5-yl) methyl) carbamate (428): To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl) carbamate 356 (500 mg, 1.64 mmol) in DMF (10 mL) were added compound 427 (858 mg, 4.90 mmol) and potassium carbonate (1.13 g, 5.0 mmol) at RT under inert atmosphère. The

-235 reaction mixture was heated to 70 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was mixture was diluted with ice cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 2-5% MeOH/ CH2CI2 to afford compound 428 (500 mg, 79%) as colorless liquid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.6); ‘H NMR (500 MHz, DMSO-î/₆): δ 7.83 (d, J = 8.7 Hz, 2H), 7.62 (s, 1H), 7.54-7.52 (m, 1H), 7.06 (d, J= 8.7 Hz, 2H), 4.31 (d, J = 5.8 Hz, 2H), 4.10 (s, 2H), 1.40 (s, 9H), 1.21-1.12 (m, 4H); LC-MS: 85.37%; 386.1 (M⁺+l) (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 0.58 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of terZ-butyl ((2-(4-((l-(aminomethyl) cyclopropyl) methoxy) phenyl) thiazol-5yl) methyl) carbamate (429): To a stirring solution of compound 428 (400 mg, 1.04 mmol) in a mixture of methanol and ammonia (9:1, 50 mL) was added Raney Ni (100 mg) at RT under inert atmosphère. The reaction mixture was stirred under hydrogen atmosphère (balloon pressure) at RT for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through a pad of celite and the celite bed was washed with 10% MeOH/ CH₂C1₂ (50 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through neutral alumina column chromatography using 10% MeOH/ CH₂C1₂ to afford compound 429 (250 mg, 62%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); ‘H NMR (500 MHz, DMSO-d₆): δ 8.01-7.91 (m, 1H), 7.82 (d, J= 8.7 Hz, 2H), 7.60 (s, 1H), 7.57-7.55 (m, 1H), 7.03 (d, J = 8.7 Hz, 2H), 4.29 (d, J= 5.8 Hz, 2H), 4.11 4.03 (m, 1H), 3.97 (s, 2H), 2.91 (s, 2H), 1.38 (s, 9H), 0.79-0.72 (m, 2H), 0.70-0.64 (m, 2H); LC-MS: 89.88%; 390.1 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 2.33 min. 2.5 mM NH4OOCH in water + 5% ACN: ACN + 5% 2.5 mM NH4OOCH in water, 0.8 mL/min).

Synthesis of tert-butyl ((2-(4-((l-((dimethylamino) methyl) cyclopropyl) methoxy) phenyl) thiazol-5-yl) methyl) carbamate (430): To a stirring solution of compound 429 (250 mg, 0.64

-236 mmol) in methanol (25 mL) were added paraformaldéhyde (96 mg, 3.21 mmol) and sodium cyanoborohydride (202 mg, 3.21 mmol) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was dilute with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 2-5% MeOH/ CH2CI2 to afford compound 430 (160 mg, 59%) as an off white solid. TLC: 10% MeOH/ CH2CI2 (Rf. 0.5); LC-MS: 84.53%; 418.1 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 2.55 min. 2.5 mM NH4OOCH in water + 5% ACN: ACN + 5% 2.5 mM NH4OOCH in water, 0.8 mL/min).

l-(l-((4-(5-(aminomethyl) thiazol-2-yl) phenoxy) methyl) cyclopropyl)-7V, Ndimethylmethanamine hydrochloride (431): To a stirring solution of compound 430 (160 mg, 0.38 mmol) in CH2CI2 (20 mL) was added 4 N HCl in 1, 4-dioxane (2 mL) under argon atmosphère at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with ether (20 mL) to afford compound 431 (150 mg, HCl sait) as an off-white solid. TLC: 40% EtOAc/Hexane (Rf 0.1); 'H NMR (400 MHz, DMSO-d₆): δ), 8.60 (br s, 3H), 7.90 (s, 1H), 7.87 (d, J= 8.8 Hz, 2H), 7.06 (d, J= 8.9 Hz, 2H), 4.35-4.29 (m, 2H), 4.04 (s, 2H), 3.26-3.18 (m, 2H), 2.82 (d, J= 4.9 Hz, 6H), 0.82 (s, 4H); LC-MS: 94.00%; 318.3 (M⁺+l) (des-Boc); (column; Cortecs C18, (50 x 3.0 mm, 2.7 pm); RT 3.05 min. 2.5 mM Aq NH4HCO3: ACN, 0.8 mL/min);

Synthesis of l-(l-((4-(5-(aminomethyl) thiazol-2-yl) phenoxy) methyl) cyclobutyl)-A, Ndimethylmethanamine hydrochloride (439):

-237 -

Synthesis of ethyl 1-cyanocyclobutane-l-carboxylate (433): To a stirring solution of ethyl 2cyanoacetate 423 (7 g, 61.95 mmol) in acetone (300 mL) were added 1,3-dibromopropane 432 (9.47 mL, 92.92 mmol) and potassium carbonate (25.6 g, 185.84 mmol) at RT under inert atmosphère. The reaction mixture was heated to 70-80 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through a pad of celite and the celite bed was washed with EtOAc (100 mL). The filtrate was concentrated in vacuo to afford compound 433 (10 g) as pale yellow liquid. This crude material was taken to next step without further purification. TLC: 30% EtOAc/ hexanes (Rf 0.5).

Synthesis of l-(hydroxymethyl) cyclobutane-l-carbonitrile (434): To a stirring solution of compound 433 (5 g, crude) in a mixture of DME/MeOH (10:1, 110 mL) was added sodium borohydride (10 g, 261.44 mmol) portion wise at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 16 h. The reaction was monitored by

TLC; after completion of the reaction, the reaction mixture was quenched slowly with aqueous

-238 sodium bicarbonate solution (50 mL) and extracted with 10% MeOH/ CH₂C1₂ (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 434 (2 g) as pale yellow liquid. This crude material was taken to next step without further purification. TLC: 30% EtOAc/ hexanes (Rf 0.3).

Synthesis of (1-cyanocyclobutyl) methyl methanesulfonate (435): To a stirring solution of compound 434 (500 mg, crude) in CH₂C1₂ (10 mL) were added methanesulfonyl chloride (0.4 mL, 5.4 mmol) and triethylamine (0.94 mL, 6.75 mmol) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into aqueous sodium bicarbonate solution (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 435 (600 mg) as pale yellow liquid. This crude material was taken to next step without further purification. TLC: 30% EtOAc/ hexanes (Rf 0.4).

Synthesis of /m-butyl ((2-(4-((l-cyanocyclobutyl) methoxy) phenyl) thiazol-5-yl) methyl) carbamate (436): To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl) carbamate 356 (1.5 g, 4.9 mmol) in DMF (40 mL) were added compound 435 (3.24 g, 17.16 mmol) and potassium carbonate (2.03 g, 14.7 mmol) at RT under inert atmosphère. The reaction mixture was heated to 80 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was mixture was diluted with ice cold water (30 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 3% MeOH/ CH₂C1₂ to afford compound 436 (1.2 g, 61%) as an off white solid. TLC: 5% MeOH/ CH₂C1₂ (Rp 0.7); LC-MS: 87.97%; 400.1 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 3.38 min. 2.5 mM NH4OOCH in water + 5% ACN: ACN + 5% 2.5 mM NH4OOCH in water, 0.8 mL/min).

-239 Synthesis of tert-butyl ((2-(4-((l-(aminomethyl) cyclobutyl) methoxy) phenyl) thiazoI-5-yl) methyl) carbamate (437): To a stirring solution of compound 436 (900 mg, 2.25 mmol) in a mixture of methanol and ammonia (10:1, 66 mL) was added Raney Ni (200 mg) at RT under inert atmosphère. The reaction mixture was stirred under hydrogen atmosphère (balloon pressure) at RT for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through a pad of celite and the celite bed was washed with 10% MeOH/ CH2CI2 (50 mL). The filtrate was concentrated in vacuo to afford compound 437 (800 mg) as pale yellow sticky syrup. This crude material was taken to next step without further purification. TLC: 5% MeOH/ CH₂C1₂ (Ry 0.2); *H NMR (500MHz, DMSO-ri₆): δ 7.96 (s, 1H), 7.84-7.81 (m, 2H), 7.53 (br s, 1H), 7.10-7.06 (m, 2H), 4.30 (d, J= 4.6 Hz, 2H), 3.323.22 (m, 2H), 2.43-2.31 (m, 2H), 2.08-1.79 (m, 6H), 1.39 (s, 9H); LC-MS: 78.30%; 404.2 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.03 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl ((2-(4-((l-((dimethylamino) methyl) cyclobutyl) methoxy) phenyl) thiazol-5-yl) methyl) carbamate (438): To a stirring solution of compound 437 (800 mg, crude) in methanol (30 mL) were added paraformaldéhyde (297 mg, 9.92 mmol) and sodium cyanoborohydride (615 mg, 9.92 mmol) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was dilute with water (30 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 8% MeOH/ CH₂C1₂ to afford compound 438 (560 mg, 65%) as an off white solid. TLC: 5% MeOH/ CH₂C1₂ (Ry 0.5); *H NMR (500MHz, DMSO-ri₆): δ 7.83 (d, J= 8.7 Hz, 2H), 7.61 (s, 1H), 7.53 (t, J =52 Hz, 1H), 7.08 (d, J=8.1 Hz, 2H), 4.31 (d, J= 5.8 Hz, 2H), 4.16-4.05 (m, 2H), 3.17 (d, J = 5.2 Hz, 2H), 2.33-2.07 (m, 4H), 2.05-1.77 (m, 8H), 1.40 (s, 9H); LC-MS: 97.54%; 432.2 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.00 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

-240 Synthesis of l-(l-((4-(5-(aminomethyl) thiazol-2-yl) phenoxy) methyl) cyclobutyl)-Æ, Ndimethylmethanamine hydrochloride (439): To a stirring solution of compound 438 (560 mg, 1.3 mmol) in CH2CI2 (13 mL) was added 4 N HCl in 1, 4-dioxane (3 mL) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was triturated with EtOAc (20 mL), diethylether (20 mL) and dried in vacuo to afford compound 439 (450 mg, HCl sait) as an off white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.1); *H NMR (500MHz, DMSO-d₆): δ 8.65 (br s, 3H), 7.94-7.86 (m, 3H), 7.15 (d, J= 8.7 Hz, 2H), 4.31 (q, J= 5.2 Hz, 2H), 4.27 (s, 2H), 3.35 (d, J = 5.8 Hz, 2H), 2.78 (s, 3H), 2.77 (s, 3H), 2.14-1.88 (m, 6H); LC-MS: 98.70%; 332.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.39 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of l-((4-(5-(aminomethyl) thiazol-2-yl) phenoxy) methyl) cyclobutane-1carbonitrile hydrochloride (440):

Synthesis of l-((4-(5-(aminomethyl) thiazol-2-yl) phenoxy) methyl) cyclobutane-1carbonitrile hydrochloride (440): To a stirring solution of compound 436 (300 mg, 0.75 mmol) in CH2C12 (10 mL) was added 4 N HCl in 1, 4-dioxane (1 mL) under argon atmosphère at 0 oC; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with diethyl ether (10 mL), EtOAc (10 mL) and dried in vacuo to afford compound 440 (150 mg; HCl sait) as pale yellow solid. TLC: 5% MeOH/CH2C12 (Rf: 0.1); 1H NMR (400 MHz, DMSO-d6): δ 8.60 (br s, 3H), 7.92 (s, 1H), 7.89 (d, J = 8.9 Hz, 2H), 7.14 (d, J = 8.9 Hz, 2H), 4.34 (s, 2H), 4.32 (d, J = 5.6 Hz, 2H), 2.56-2.50 (m, 2H), 2.33-2.19 (m, 2H), 2.17- 2.07 (m, 2H); LC-MS:

-241 98.63%; 299.9 (M++1); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 2.05 min. 2.5 mM NH4OOCH in water + 5% ACN: ACN + 5% 2.5 mM NH4OOCH in water, 0.8 mL/min).

Synthesis of 4-(l-(5-(aminomethyl) thiazol-2-yI)-l//-pyrazol-4-yI)-A, A-dimethylbutan-15 amine hydrochloride (448) and 4-(l-(5-(aminomethyl)thiazol-2-yl)-lH-pyrazol-4-yI)-N,N-

Synthesis of terZ-butyl ((2-(4-bromo-lÆ-pyrazol-l-yl) thiazol-5-yl) methyl) carbamate (442): To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl) carbamate 224 (10 g, 10 40.32 mmol) in DMF (100 mL) under inert atmosphère were added 4-bromo-l/f-pyrazole 441 (5.92 g, 40.29 mmol), césium carbonate (39.4 g, 120.96 mmol) at RT; heated to 80 °C and

-242 stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (500 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 30% EtOAc/ hexanes to afford compound 442 (4.1 g, 29%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.3). *H-NMR (DMSO-î/₆, 500 MHz): δ 8.74 (s, 1H), 7.99 (s, 1H), 7.57 (t, J= 5.2 Hz, 1H), 7.46 (s, 1H), 4.27 (d,J=6.4 Hz, 2H), 1.40 (s, 9H); LC-MS: 83.58%; 359.0 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.69 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl ((2-(4-(4-hydroxybut-l-yn-l-yl)-l//-pyrazol-l-yl) thiazol-5-yl) methyl) carbamate (444): To a stirring solution of compound 442 (4.1 g, 11.45 mmol) in triethylamine (50 mL) were added but-3-yn-l-ol 443 (1.2 g, 17.18 mmol), Copper(I) iodide (22 mg, 0.11 mmol) and purged under argon atmosphère for 20 min. To this was added Pd(PPh3)₂Cl₂ (160 mg, 0.22 mmol) and purged under argon atmosphère for 10 min; heated to 80 °C and stirred for 2 h. The reaction was monitored by TLC; after completion the reaction mixture was diluted with water (75 mL) and extracted with EtOAC (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 40% EtOAc/ hexanes to afford compound 444 (2.7 g, crude) as an off-white solid. TLC: 50% EtOAc/hexanes (Rf 0.4); LC-MS: 62.79%; 349.0 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.25 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl ((2-(4-(4-hydroxybutyl)-l//-pyrazol-1-y 1) thiazol-5-yl) methyl) carbamate (445): To a stirring solution of compound 444 (2.7 g, 7.75 mmol) in MeOH (30 mL) under inert atmosphère was added 10% Pd/ C (800 mg, 50% w/w) at RT and stirred under hydrogen atmosphère (balloon pressure) at RT for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and eluted with

-243 10% MeOH/ CH2CI2 (100 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 50% EtOAc/ hexanes to afford compound 445 (1.8 g, 67%) as colorless thick syrup. TLC: 50% EtOAc/ hexanes (Rf 0.6); ‘H NMR (DMSO-î/₆, 500 MHz): δ 8.22 (s, 1H), 7.69 (s, 1H), 7.57-7.51 (m, 1H), 7.39 (s, 1H), 4.36 (t, J = 4.9 Hz, 1H), 4.25 (d, J = 5.8 Hz, 2H), 3.39-3.34 (m, 2H), 2.49-2.46 (m, 2H),1.63-1.54(m,2H), 1.49-1.43 (m, 2H), 1.40 (s, 9H); LC-MS: 99.7\5%; 353.1 (M⁺+l); (column; Ascentis Express C18, (50 ^x 3.0 mm, 2.7 pm); RT 2.19 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-(l-(5-(((terCbutoxycarbonyl) amino) methyl) thiazol-2-yl)-LH-pyrazol-4-yl) butyl methanesulfonate (446): To a stirring solution of compound 445 (1.8 g, 5.11 mmol) in CH₂C1₂ (20 mL) under inert atmosphère were added triethylamine (1.5 mL, 10.22 mmol), methanesulfonyl chloride (0.62 mL, 7.67 mmol) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (75 mL) extracted with CH2C12(2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude. The crude was purified through silica gel column chromatography using 50% EtOAc/ hexanes to afford crude compound 446 (2 g) as an off-white solid. TLC: 50% EtOAc/ hexanes (Rf 0.6); 'H NMR (DMSO-4 500 MHz): δ 8.27 (s, 1H), 7.71 (s, 1H), 7.58-7.51 (m, 1H), 7.39 (s, 1H), 4.27-4.20 (m, 4H), 3.15 (s, 3H), 2.56-2.51 (m, 2H), 1.73-1.61 (m, 4H), 1.40 (s, 9H); LC-MS: 95.12%; 431.1 (M⁺+l); (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 2.53 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of te/7-butvl ((2-(4-(4-(dimethylamino) butyl)-lH-pyrazol-l-yl) thiazol-5-yl) methyl) carbamate (447): To a stirring solution of compound 446 (1.4 g, 3.25 mmol) in THF (10 mL) in a sealed tube under inert atmosphère was added dimethylamine (5 mL) at RT; heated to 80 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2CI2 to afford compound 447 (220 mg, 69%) as brown syrup. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.2); ^XH NMR (DMSO-4 500 MHz): δ 8.23 (s,

-2441H), 7.69 (s, 1H), 7.58-7.52 (m, 1H), 7.39 (s, 1H), 4.25 (d, J= 5.8 Hz, 2H), 2.76-2.71 (m, 2H), 2.51-2.44 (m, 2H), 2.21 (t, J = 7.2 Hz, 2H), 2.10 (s, 6H), 1.56 (p, J = 7.5 Hz, 2H), 1.40 (s, 9H); LC-MS: 97.07%; 380.1 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.85 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-(l-(5-(aminomethyl) thiazol-2-yl)-lÆ-pyrazol-4-yl)-N, N-dimethylbutan-1amine hydrochloride (448): To a stirring solution of compound 447 (1 g, 2.63 mmol) in CH2CI2 (10 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (3 mL) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with diethyl ether (2x5 mL), hexane (5 mL) and dried in vacuo to afford crude compound 448 (750 mg, HCl sait) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.1); LC-MS: 57.57%; 315.1 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 0.31 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl ((2-(4-(4-(diethyIamino)butyl)-lH-pyrazol-l-yl)thiazol-5yl)methyl)carbamate (447A): To a stirring solution of compound 446 (2.0 g, 4.65 mmol) in THF (10 mL) in a sealed tube under inert atmosphère was added diethylamine (5 mL) at RT; heated to 80 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was purified through silica gel column chromatography using 6% MeOH/ CH2CI2 to afford compound 447A(1.6 g, 85%) as pale brown syrup. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); LC-MS: 99.53 %; 408.2 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.00 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-(l-(5-(aminomethyl)thiazol-2-yI)-lH-pyrazol-4-yl)-N,N-diethyl butan-1amine hydrochloride (448A): To a stirring solution of compound 447A (1.6 g, 3.93 mmol) in CH2CI2 (20 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (5 mL) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with diethyl ether (2x5 mL), hexane (5 mL) and dried in vacuo to afford crude compound 448A (750 mg, HCl sait) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.1); LC-MS:

-245 57.57%; 315.1 (M⁺+l); (column; Ascentis Express Cl 8, (50 x 3.0 mm, 2.7 pm); RT 0.31 min.

0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of ethyl (jE)-3-(l-(5-(aminomethyl) thiazol-2-yl)-lÆ-pyrazol-4-yl) acrylate hydrochloride (451):

Synthesis of ethyl (Æ)-3-(l-(5-(((teri-butoxycarbonyl) amino) methyl) thiazol-2-yl)-lHpyrazol-4-yl) acrylate (450): To a stirring solution of methyl tert-butyl ((2-(4-bromo-17Lpyrazol-1-yl) thiazol-5-yl) methyl) carbamate 442 (1.3 g, 3.61 mmol) in DMF (50 mL) under inert atmosphère in a sealed tube were added ethyl acrylate 449 (1.81 g, 18.10 mmol), diisopropylethylamine (2.0 mL, 10.86 mmol), purged under argon atmosphère for 30 min. To this were added P(o-tol)3 (330 mg, 1.08 mmol), Pd(OAc)2 (243 mg, 0.36 mmol) at RT; heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice-cold water (150 mL) and extracted with EtOAc (2 x 150 mL).The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude. The crude was purified through silica gel column chromatography using 30% EtOAc/ hexanes to afford compound 450 (550 mg, 40%) as an offwhite solid. TLC: 40% EtOAc/ hexanes (Rf 0.4); *H NMR (400 MHz, DMSO-7₆): δ 8.90 (s, 1H), 8.32 (s, 1H), 7.65-7.55 (m, 2H), 7.47 (s, 1H), 6.58 (d, J= 16.1 Hz, 1H), 4.27 (d, J= 5.9 Hz, 2H), 4.17 (q, 7 =7.1 Hz, 2H), 1.40 (s, 9H), 1.25 (t, 7= 7.2 Hz, 3H); LC-MS: 89.66%; 379.0 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 1.97 min. 2.5 mM Aq. NH4OOCH + 5% ACN: ACN : 5%2.5 mM Aq. NH4OOCH; 0.8 mL/min).

-246 Synthesis of ethyl (£)-3-(l-(5-(aminomethyl) thiazol-2-yl)-l/7-pyrazol-4-yl) acrylate hydrochloride (451): To a stirring solution of compound 450 (150 mg, 0.39 mmol) in CH2CI2 (5 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (1 mL) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with diethyl ether (2x5 mL), dried in vacuo to afford compound 451 (110 mg, 89%; HCl sait) as white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.1); 'H NMR (500 MHz, DMSO-î/₆): δ 8.93 (s, 1H), 8.45 (br s, 3H), 8.37 (s, 1H), 7.74 (s, 1H), 7.61 (d, J= 15.6 Hz, 1H), 6.59 (d, 7= 16.2 Hz, 1H),4.314.30 (m, 2H), 4.17 (q, 7= 7.0 Hz, 2H), 1.24 (t, 7= 7.0 Hz, 3H);

Synthesis of (2-(LH-pyrazol-l-yl) thiazol-5-yl) methanamine hydrochloride (455):

Synthesis of A-((2-chlorothiazol-5-yl) methyl)-l, 1,1-triphenylmethanamine (452): To a stirring solution of (2-chlorothiazol-5-yl) methanamine hydrochloride 223 (1.0 g, 5.43 mmol) in CH₂C1₂ (40 mL) under inert atmosphère were added triethyl amine (1.57 mL, 10.86 mmol), trityl chloride (1.57 mL, 6.46 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 452 (1.5 g, 71%) as white solid. TLC: 10% EtOAc/ (Rf. 0.8); *H-NMR (DMSO-7₆, 500 MHz): δ 7.46-7.40 (m, 5H), 7.36-7.27 (m, 5H), 7.26-7.17 (m, 5H), 3.97 (br t, 7= 8.4 Hz, 1H), 3.34-3.27 (m, 2H);

Synthesis of A-((2-(lH-pyrazol-l-yl) thiazoI-5-yl) methyl)-l, 1, 1-triphenylmethanamine (454): To a stirring solution of compound 452 (2 g, 0.51 mmol) in DMF (15 mL) under inert

-247 atmosphère were added 177-pyrazole 453 (70 mg, 1.02 mmol), césium carbonate (333 mg, 1.02 mmol) at RT; heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (3 0 mL) and extracted with EtOAc (2 x 60 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column flash chromatography using 5-7% EtOAc/ hexanes to afford compound 454 (110 mg, 51%) as an off-white solid. TLC: 15% EtOAc/ hexanes (Rf 0.4). ’H-NMR (DMSO-î/î, 400 MHz): δ 8.46 (d, J= 2.6, 0.6 Hz, 1H), 7.86 (d, J= 1.7 Hz, 1H), 7.48-7.44 (m, 6H), 7.38-7.30 (m, 7H), 7.24-7.19 (m, 3H), 6.62 (dd,7=2.5, 1.8 Hz, 1H), 3.87 (t, 7= 8.4 Hz, 1H), 3.31 (s, 2H); LC-MS (Agilent 6310 Ion trap): 99.52%; 423.2 (M+l)⁺; (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 5.33 min. 2.5 mM Aq. NH4OOCH: ACN; 0.8 mL/min).

Synthesis of (2-(lÆ-pyrazol-l-yl) thiazol-5-yl) methanamine hydrochloride (455): To a stirring solution of compound 454 (200 mg, 0.47 mmol) in CH2CI2 (5 mL) was added 4 N HCl in 1, 4-dioxane (1 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with diethyl ether (2x10 mL) and dried in vacuo to afford compound 455 (90 mg, 88%; HCl sait) as an off-white solid. TLC: 5% MeOH/ CH2CI2 (Rf 0.1); ’H-NMR (DMSO-î/ô, 400 MHz): δ 8.56 (br s, 2H), 8.50 (d, 7= 2.6 Hz, 1H), 7.88 (d,7= 1.5 Hz, 1H), 7.72 (s, 1H), 6.66-6.64 (m, 1H), 4.28 (br s, 2H); LC-MS: 95.50%; 181.9 (M+l)⁺; (column; Kinetex EVO C-18 (50 x 3.0 mm,2.6 um); RT 0.69 min. 2.5 mM Aq. NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of (2-(2H-l, 2, 3-triazoI-2-yl) thiazol-5-yl) methanamine hydrochloride (458A):

-248 -

Synthesis of7V-((2-(lH-l, 2, 3-triazol-l-yl) thiazol-5-yl)methyl)-l, 1, 1-triphenylmethanamine (457A) & V-((2-(2H-l, 2, 3-triazol-2-yl) thiazol-5-yl) methyl)-!, 1, 1-triphenylmethanamine (457B): To a stirring solution of A-((2-chlorothiazol-5-yl) methyl)-1, 1,1triphenylmethanamine 452 (1 g, 2.56 mmol) in DMF (15 mL) under inert atmosphère were added \H-\, 2, 3-triazole 456 (354 mg, 5.12 mmol), césium carbonate (2.5 g, 7.69 mmol) at RT; heated to 110 °C and stirred for 32 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 80 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through neutral alumina flash column chromatography using 5-10% EtOAc/ hexanes to afford compound 457A (250 mg) and 457B (230 mg) as white solids.

Analytical Data of 457A: TLC: 20% EtOAc/ hexanes (Rf 0.3). ‘H NMR (400 MHz, DMSOά₆γ δ 8.87 (d, J= 1.2 Hz, 1H), 8.05 (d, J= 1.2 Hz, 1H), 7.58 (s, 1H), 7.50-7.44 (m, 6H), 7.377.30 (m, 6H), 7.26-7.19 (m, 3H), 4.07 (t, J= 8.4 Hz, 1H), 3.40 (d, J= 8.4 Hz, 2H);

Analytical Data of 457B: TLC: 20% EtOAc/ hexanes (Rf. 0.3). 'H-NMR (DMSO-tfy 400 MHz): δ 8.25 (s, 2H), 7.50 (s, 1H), 7.48-7.44 (m, 6H), 7.34 (t, J= 7.7 Hz, 6H), 7.25-7.20 (m, 3H), 4.02 (t, J = 8.4 Hz, 1H), 3.38 (d, J= 8.2 Hz, 2H).

Synthesis of (2-(lH-l, 2, 3-triazol-l-yl) thiazol-5-yl) methanamine TFA sait (458A): To a stirring solution of compound 457A (200 mg, 0.47 mmol) in CH2CI2 (10 mL) under inert

-249 atmosphère were added trieythlsilane (0.15 mL, 0.94 mmol), trifluoroacetic acid (0.2 mL, 2.36 mmol) at 0 °C; warmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was washed with n-hexane to afford compound 458A (85 mg, 71) as white solid. TLC: 30% EtOAc/ hexanes (Rf 0.2); ‘H-NMR (DMSO-î/₆, 400 MHz): δ 8.92 (s, 1H), 8.46 (br s, 2H), 8.07 (s, 1H), 7.89 (s, 1H), 4.39 (br s, 2H); LC-MS: 88.52%; 181.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 0.37 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(2//-1, 2, 3-triazol-2-yl) thiazol-5-yl) methanamine hydrochloride (458B): To a stirring solution of A-((2-(2H-l, 2, 3-triazol-2-yl) thiazol-5-yl) methyl)-l, 1, 1triphenylmethanamine 457B (230 mg, 0.54 mmol) in CH2CI2 (5 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (3 mL) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with diethyl ether (2x10 mL) and dried in vacuo to afford compound 458B (90 mg, 76%; HCl sait) as white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.2); 'ïï-NMR (DMSO-4 400 MHz): δ 8.56 (br s, 3H), 8.28 (s, 2H), 7.83 (s, 1H), 4.34 (s, 2H); LC-MS (Agilent 6310 Ion trap): 95.92%; 182.1 (M⁺+l); (column; X-Select CSH C-18, (150 x 4.6 mm, 3.5 pm); RT 5.53 min. 2.5 mM Aq. NH₄OAc: ACN; 1.0 mL/min).

Synthesis of ethyl l-(5-(aminomethyl) thiazol-2-yl)-lH-pyrazole-4-carboxylate TFA sait (461):

4,

-250 -

Synthesis of ethyl l-(5-((tritylamino) methyl) thiazol-2-yl)-lÆ-pyrazole-4-carboxylate (460): To a stirring solution of A-((2-chlorothiazol-5-yl) methyl)-l, 1, 1-triphenylmethanamine 452 (500 mg, 1.28 mmol) in DMF (10 mL) under inert atmosphère were added ethyl 1Hpyrazole-4-carboxylate 459 (180 mg, 1.28 mmol), césium carbonate (833 mg, 2.56 mmol) at RT; heated to 90 °C and stirred for 10 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 60 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 20-25% EtOAc/ hexanes to afford compound 460 (200 mg, 32%) as white solid. TLC: 20% EtOAc/ hexanes (Rf 0.3). ^-NMR (DMSO-^, 400 MHz): δ 8.85 (s, 1H), 8.25 (s, 1H), 7.45 (br d, J= 7.4 Hz, 6H), 7.32 (t, J= 7.7 Hz, 6H), 7.21 (t, J= 7.3 Hz, 3H), 4.27 (q, J = 7.2 Hz, 2H), 3.96 (t, J= 8.4 Hz, 1H), 3.34 (d, J= 8.4 Hz, 3H), 1.30 (t, J= 7.1 Hz, 3H);

Synthesis of ethyl l-(5-(aminomethyl) thiazol-2-yl)-lÆ-pyrazole-4-carboxylate TFA sait (461): To a stirring solution of compound 460 (200 mg, 0.40 mmol) in CH2CI2 (20 mL) under inert atmosphère were added trieythlsilane (0.12 mL, 0.80 mmol), trifluoroacetic acid (0.16 mL, 2.02 mmol) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was washed diethylether (2x10 mL) and dried in vacuo to afford compound 461 (100

-251 mg, 71) as white solid. TLC: 30% EtOAc/ hexanes (Rf 0.2); ’H-NMR (DMSO-4 400 MHz): δ 8.91 (br s, 1H), 8.34 (br s, 2H), 8.28 (s, 1H), 7.78 (s, 1H), 4.34 (d, J= 4.0 Hz, 2H), 4.28 (q, J = 7.2 Hz, 2H), 1.30 (t, J= 7.1 Hz, 3H).

Synthesis of 2-(4-(4-morpholinobutyl) phenyl) thiazol-5-yl) methanamine hydrochloride

Synthesis of /crr butyl ((2-(4-bromophenyl) thiazol-5-yl) methyl) carbamate (463): To a stirring solution of teH-butyl ((2-chlorothiazol-5-yl) methyl) carbamate 224 (10 g, 40.29) in DME: H2O (4: 1, 100 mL) were added (4-bromophenyl) boronic acid 462 (6.43 g, 32.16 mmol) and sodium carbonate (14.91 g, 140.73 mmol) in a sealed tube at RT and purged under argon for 30 min. Then Pd(dppf)C12 (2.94 g, 4.02 mmol) was added at RT. The reaction mixture was heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (200 mL), and extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% EtOAc/Hexane to afford compound 463 (2.5 g, 17%) as white solid. TLC: 20% EtOAc/ hexanes (Rf 0.5). ¹II NMR (500 MHz, DMSO4): δ 7.84 (d, J= 8.1 Hz, 2H), 7.70 (d, J= 9.3 Hz, 2H), 7.67 (s, 1H), 7.57 (br s, 1H), 4.34 (brd, J= 5.8 Hz, 2H), 1.39 (s, 9H)

-252 Synthesis of tert-butyl ((2-(4-(4- hydroxybut-l-yn-l-yl) phenyl) thiazol-5-yl)methyl) carbamate (464): To a stirring solution of compound 463 (2.5 g, 3.79 mmol) in triethyl amine (30 mL) were added prop-2-yn-l-ol 443 (456 mg, 8.15 mmol), and copper iodide (12 mg, 0.06 mmol) at RT in a sealed tube and purged under argon atmosphère for 15 min. To this were added Pd(PPh3)₂Cl₂ (95 mg, 1.13 mmol) at RT; heated to 60 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles removed under reduced pressure. The residue was diluted with water (20 mL), and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, fdtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 40-50% EtOAc/Hexane to afford crude compound 464 (2.8 g, crude) as pale yellow solid. TLC: 50% EtOAc/ hexanes (Ry 0.3); LC-MS: 92.51%; 359.50 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.37 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl ((2-(4-(4-hydroxybutyl) phenyl) thiazol-5-yl) methyl) carbamate (465): To a stirring solution of tert-butyl ((2-(4-(4-hydroxybut-l-yn-l-yl) phenyl) thiazol-5-yl) methyl) carbamate 464 (1.3 g, 3.62 mmol) in MeOH (150 mL) under inert atmosphère was added 10% Pd/ C (700 mg, 50% w/w) at RT and stirred under hydrogen atmosphère (balloon pressure) at RT for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and eluted with 20% MeOH/ CH2CI2 (200 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was triturated with diethyl ether (15 mL) and dried in vacuo to afford compound 465 (800 mg, 61%) as colorless thick syrup. TLC: 5% MeOH/ CH₂C1₂ (Ry 0.4); 'H NMR (400 MHz, DMSO-</₆): δ 7.79 (d, J = 8.2 Hz, 2H), 7.65 (s, 1H), 7.59-7.52 (m, 1H), 7.30 (d, J= 8.2 Hz, 2H), 4.40-4.27 (m, 3H), 3.41 (t, J = 6.3 Hz, 2H), 2.62 (t, J=7.6Hz, 2H), 1.68-1.53 (m, 2H), 1.51-1.41 (m, 2H), 1.40 (s, 9H);

Synthesis of 4-(4-(5-(((tert-butoxycarbonyl) amino) methyl) thiazol-2-yl) phenyl) butyl methanesulfonate (466): To a stirring solution of compound 465 (250 mg, 0.69 mmol) in CH₂C1₂ (15 mL) under inert atmosphère were added triethyl amine (0.19 mL, 1.38 mmol) and

-253 methanesulfonyl chloride (94 mg, 0.82 mmol) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL), extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 466 (400 mg) as an off-white solid. TLC: 5% MeOH/ CH2CI2 (Rf 0.8); LC-MS: 93.89%; 441.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 μm); RT 2.63 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of «'/7-butyl ((2-(4-(4-morpholinobutyl) phenyl) thiazol-5-yl) methyl) carbamate (467): To a stirring solution of compound 466 (330 mg, crude) in THF (10 mL) in a sealed tube under inert atmosphère was added morpholine 302 (326 mg, 3.75 mmol) at RT; heated to 70 °C and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with EtOAc (50 mL), washed with water (50 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3% MeOH/ CH₂C1₂ to afford compound 467 (210 mg, 70%, over 2 steps) as colorless thick syrup. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.2); LC-MS: 97.07%; 432.1 (M⁺+l); (column;

Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.95 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(4-(4-morpholinobutyl) phenyl) thiazol-5-yl) methanamine hydrochloride (468): To a stirring solution of compound 467 (210 mg, 0.48 mmol) in CH2CI2 (10 mL) was added 4 N HCl in 1, 4-dioxane (2 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with EtOAc (2x5 mL), diethyl ether (5 mL) and dried in vacuo to afford compound 468 (160 mg, 90%; HCl sait) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.2); 'H NMR (400 MHz, DMSO-7₆): δ 11.06 (br s, 1H), 8.57 (br s, 3H), 7.95 (s, 1H), 7.85 (d, J= 8.2 Hz, 2H), 7.38 (d, J= 8.2 Hz, 2H),

-2544.33 (q, 7 = 5.4 Hz, 2H), 3.97-3.88 (m, 2H), 3.86-3.74 (m, 2H), 3.42-3.32 (m, 2H), 3.16-2.91 (m, 4H), 2.71-2.62 (m, 2H), 1.80-1.57 (m, 4H);

Synthesis of 4-(4-(5-(aminomethyl) thiazol-2-yl) phenyl)-JV-(tert-butyl) butan-l-amine hydrochloride (471):

Synthesis of tert-butyl ((2-(4-(4-(tert-butylamino) butyl) phenyl) thiazol-5-yl) methyl) carbamate (470): To a stirring solution of 4-(4-(5-(((ter/-butoxycarbonyl) amino) methyl) thiazol-2-yl) phenyl) butyl methanesulfonate 466 (400 mg, 0.90 mmol) in DMF (10 mL) under inert atmosphère were added 2-methylpropan-2-amine 469 (663 mg, 9.08 mmol) and potassium carbonate (250 mg, 1.81 mmol) in a sealed tube at RT; heated to70 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 8% MeOH/ CH2CI2 to afford crude compound 470 (260 mg) as colorless syrup. TLC: 10% MeOH/ CH2CI2 (Rf 0.3). 'H NMR (400 MHz, DMSO-7₆): δ 7.95 (s, 1H), 7.79 (d, 7= 8.2 Hz, 2H), 7.65 (s, 1H), 7.54 (t, J= 4.1 Hz, 1H), 7.31 (d, 7= 8.2 Hz, 2H), 4.32 (d, J= 5.8 Hz, 2H), 3.22-3.10 (m, 2H), 2.62 (t, J = 7.6 Hz, 2H), 1.67-1.59 (m, 2H), 1.40 (s, 9H), 1.34-1.24 (m, 2H), 1.01 (s, 9H); LC-MS: 98.88%; 191.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.04 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

-255 Synthesis of 4-(4-(5-(aminomethyl) thiazoI-2-yl) phenyl)-JV-(tert-butyl) butan-l-amine hydrochloride (471): To a stirring solution of compound 470 (260 mg, 0.62 mmol) in CH2CI2 (10 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (5 mL) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with diethyl ether (5 mL) and dried in vacuo to afford compound 471 (190 mg, 86%; HCl sait) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); 'il NMR (500 MHz, DMSO-7₆): δ 8.89-8.54 (m, 3H), 7.96 (s, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 4.64 (br s, 2H), 4.37-4.31 (m, 2H), 2.89-2.79 (m, 2H), 2.70-2.66 (m, 2H), 1.27 (s, 13H); LC-MS: 98.49%; 318.1 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.37 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(4-(4-(piperidin-l-yl) butyl) phenyl) thiazol-5-yl) methanamine hydrochloride (474):

Synthesis of tert-butyl ((2-(4-(4-(piperidin-l-yl) butyl) phenyl) thiazol-5-yl) methyl) carbamate (473): To a stirring solution of 4-(4-(5-(((teri-butoxycarbonyl) amino) methyl) thiazol-2-yl) phenyl) butyl methanesulfonate 466 (330 mg, 0.75 mmol) in THF (5 mL) in a sealed tube under inert atmosphère was added piperidine 472 (2 mL) at RT; heated to 90 °C and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was purified through silica gel column

-257 thiazol-2-yl) phenyl) butyl methanesulfonate 466 (340 mg, 0.77 mmol) in THF (10 mL) under inert atmosphère was added diethylamine 387 (3 mL) in a sealed tube at RT; heated to 90 °C and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2CI2 + aqueous ammonia (0.5 mL) to afford compound 475 (250 mg, 78%) as colorless syrup. TLC: 10% MeOH/ CH2CI2 (Rf 0.2). ^XHNMR (DMSO-4 400 MHz): δ 7.77 (d,7=8.1 Hz, 2H), 7.63 (s, 1H), 7.52 (t,7=5.5 Hz, 1H), 7.28 (d, 7= 8.1 Hz, 2H), 4.30 (d, J= 5.8 Hz, 2H), 2.60 (t, 7= 7.6 Hz, 2H), 2.42-2.26 (m, 8H), 1.56 (p, J= 7.5 Hz, 2H), 1.37 (s, 9H), 0.90 (t, J= 7.1 Hz, 6H); LC-MS: 99.61%; 418.2 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.04 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-(4-(5-(aminomethyl) thiazol-2-yl) phenyl)-A. V-diethylbutan- 1-amine hydrochloride (476): To a stirring solution of compound 475 (250 mg, 0.59 mmol) in CH2CI2 (5 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (2 mL) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with diethyl ether (5 mL), n-hexane (5 mL) and dried in vacuo to afford compound 476 (150 mg, 71%; HCl sait) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); ’H-NMR (DMSO-î/₆, 400 MHz): δ 10.51-10.23 (m, 1H), 8.63 (br s, 2H), 7.96 (s, 1H), 7.85 (d, 7= 8.2 Hz, 2H), 7.38 (d, 7= 8.2 Hz, 2H), 4.33 (q, 7= 5.5 Hz, 2H), 3.12-2.99 (m, 6H), 2.71-2.65 (m, 2H), 1.75-1.61 (m, 4H), 1.20 (t, 7= 7.2 Hz, 6H); LC-MS: 99.36%; 318.1 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.35 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 7V-(4-(4-(5-(aminomethyl) thiazol-2-yl) phenyl) butyl) acetamide hydrochloride (480):

-258 -

Synthesis of tert-butyl ((2-(4-(4-azidobutyl) phenyl) thiazol-5-yl) methyl) carbamate (477): To a stirring solution of 4-(4-(5-(((/ert-butoxycarbonyl) amino) methyl) thiazol-2-yl) phenyl) butyl methanesulfonate 466 (510 mg, 1.15 mmol) in DMF (10 mL) under inert atmosphère was added sodium azide (113 mg, 1.70 mmol) at RT and heated to 70 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted water (50 mL) and extracted with EtOAc (2 x 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain crude compound 477 (550 mg) as pale yellow oil. TLC: 5% MeOH/ CH2CI2 (Rf 0.8);

Synthesis of /u/7-butyl ((2-(4-(4-aminobutyl) phenyl) thiazol-5-yl) methyl) carbamate (478): To a stirring solution of compound 477 (550 mg, crude) in THF: H2O (4: 1, 30 mL) was added triphenyl phosphine (446 mg, 1.70 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted water (50 mL) and extracted with 10% MeOH/

CH2CI2 (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to obtain the crude. The crude was purified through silica gel column chromatography using 10% MeOH/ CH2CI2 to afford compound 478 (160 mg, 31%) as an offwhite solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.2); LC-MS: 97.99%; 362.1 (M⁺+l); (column;

PA513177/OA/5598087.1

- 259 -

Synthesis of tert-butyl ((2-(4-(4-acetamidobutyl) phenyl) thiazol-5-yl) methyl) carbamate (479): To a stirring solution of compound 478 (160 mg, 0.44 mmol) in CH2CI2 (10 mL) under inert atmosphère were added triethyl amine (0.12 mL, 0.88 mmol), acetyl chloride (52 mg, 0.66 mmol) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (50 mL) and extracted with EtOAc (2 x 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2CI2 to afford compound 479 (140 mg, 78%) as thick syrup. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.8); LC-MS: 98.01%; 404.1 (M⁺+l); (column; Ascentis Express C-18, (50 ^x 3.0 mm, 2.7 pm); RT 2.29 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of jV-(4-(4-(5-(aminomethyl) thiazol-2-yl) phenyl) butyl) acetamide hydrochloride (480): To a stirring solution of compound 479 (140 mg, 0.34 mmol) in CH₂C12 (10 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (3 mL) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with EtOAc (2 x 5 mL), diethyl ether (2x5 mL) and dried in vacuo to afford compound 480 (100 mg, 89%; HCl sait) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.2); 'H NMR (DMSO-î/₆, 400 MHz) δ = 8.64 (br s, 3H), 7.95 (s, 1H), 7.83 (d, J= 7.9 Hz, 2H), 7.34 (d, J= 8.0 Hz, 2H), 4.32 (q, J = 5.5 Hz, 2H), 3.09 - 3.00 (m, 2H), 2.63 (t, J= 7.6 Hz, 2H), 1.78 (s, 3H), 1.59 (p, J = 7.4 Hz, 2H), 1.41 (p, J= 7.2 Hz, 2H); LC-MS: 98.49%; 304.1 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.48 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-(4-(5-(aminomethyl) thiazol-2-yl) phenyl)- V-isopropyl- V-methyIbutan-lamine hydrochloride (482):

-260-

Synthesis of tert-butyl ((2-(4-(4-(isopropyl(methyl) amino) butyl) phenyl) thiazol-5-yl) methyl) carbamate (481): To a stirring solution of 4-(4-(5-(((ter/-butoxycarbonyl) amino) methyl) thiazol-2-yl) phenyl) butyl methanesulfonate 466 (100 mg, 0.22 mmol) in DMF (5 mL) under inert atmosphère were added A-methylpropan-2-amine 412 (50 mg, 0.68 mmol) and potassium carbonate (62 mg, 0.45 mmol) in a sealed tube at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2CI2 to afford compound 481 (80 mg) as colorless syrup. TLC: 5% MeOH/ CH2CI2 (Rf 0.2). LC-MS: 80.36%; 418.1 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.00 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-(4-(5-(aminomethyl) thiazol-2-yl) phenyl)-/V-isopropyl-7V-methylbutan-lamine hydrochloride (482): To a stirring solution of compound 481 (80 mg, 0.19 mmol) in CH2CI2 (5 mL) was added 4 N HCl in 1, 4-dioxane (1 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with EtOAc (2x4 mL), diethyl ether (2x4 mL) and dried in vacuo to afford compound 482 (60 mg, HCl sait) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); *H-NMR (DMSO-4 400 MHz): δ 10.02 (br s, 1H), 8.53 (br s, 3H), 7.95 (s, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.38 (d, J =

-261 -

8.7 Hz, 2H), 4.34 (q, J= 5.2 Hz, 2H), 3.53 - 3.45 (m, 2H), 3.13 - 3.03 (m, 1H), 2.99 - 2.88 (m, 1 H), 2.68 (br t, J= 7.5 Hz, 2H), 2.60 (d, J= 4.6 Hz, 3H), 1.79 - 1.54 (m, 4H), 1.31 - 1.17 (m, 6H); LC-MS: 83.54%; 318.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.33 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 2V-(4-(4-(5-(aminomethyl) thiazol-2-yl) phenyl) butyl)-.Vmethylcyclopropanamine hydrochloride (484):

Synthesis of tert-butyl ((2-(4-(4-(cyclopropyl (methyl) amino) butyl) phenyl) thiazol-5-yl) methyl) carbamate (483): To a stirring solution of 4-(4-(5-(((terLbutoxycarbonyl) amino) methyl) thiazol-2-yl) phenyl) butyl methanesulfonate 466 (200 mg, 0.45 mmol) in DMF (5 mL) under inert atmosphère were added 2V-methylcyclopropanamine hydrochloride 415 (98 mg, 0.90 mmol) and potassium carbonate (125 mg, 0.90 mmol) in a sealed tube at RT and stirred for 48 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2CI2 to afford compound 483 (80 mg, 43%) as colorless thick syrup. TLC: 10% MeOH/ CH2CI2 (Rf. 0.2). LC-MS: 99.65%; 416.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.02 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

-262Synthesis of 7V-(4-(4-(5-(aminomethyl) thiazol-2-yl) phenyl) butjl)-/Vmethylcyclopropanamine hydrochloride (484): To a stirring solution of compound 483 (220 mg, 0.53 mmol) in CH2CI2 (10 mL) was added 4 N HCl in 1, 4-dioxane (3 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with EtOAc (2x10 mL), diethyl ether (2x10 mL) and dried in vacuo to afford compound 484 (125 mg, 72%; HCl sait) as colorless thick syrup. TLC: 10% MeOH/ CH2CI2 (Rf 0.2); ^XH NMR (DMSO4,400 MHz): δ 10.14 (br s, 1H), 8.45 (br s, 3H), 7.94 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.38 (d, J= 8.3 Hz, 2H), 4.34 (q, J= 5.5 Hz, 2H), 3.24 - 3.14 (m, 2H), 2.78 (d, J=4.8Hz, 3H), 2.72 - 2.65 (m, 2H), 1.86 - 1.57 (m, 4H), 1.13-0.91 (m, 2H), 0.89 - 0.70 (m, 2H); LC-MS: 94.90%; 316.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.34 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of l-(5-(aminomethyI) thiazol-2-yl) piperidin-4-one hydrochloride (488):

Synthesis of tert-butyl ((2-(4-hydroxypiperidin-l-yl) thiazoi-5-yI) methyl) carbamate (486): To a stirring solution terLbutyl ((2-chlorothiazol-5-yl) methyl) carbamate 224 (500 mg, 2.01 mmol) in Λ-methyl pyrrolidinone (10 mL) under inert atmosphère were added piperidin-4ol 485 (408 mg, 4.03 mmol) and diisopropylethylamine (1.8 mL, 10.08 mmol) in a sealed tube and heated to 160 °C and stirred for 16 h. The reaction was monitored by TLC and LC-MS;

after completion the reaction mixture was diluted with water (50 mL) and extracted with

-263 EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 4% MeOH/ CH2CI2 to afford compound 486 (350 mg, 55%) as sticky solid. TLC: 5% MeOH/ CH₂Cl₂ (Rf 0.3); ’H-NMR (DMSO-4 500 MHz): δ 7.29 (t, J= 5.5 Hz, 1H), 6.88 (s, 1H), 4.74 (d, J= 4.0 Hz, 1H), 4.08 (d, J= 5.8 Hz, 2H), 4.05-4.01 (m, 1H), 3.72-3.60 (m, 3H), 3.15-3.07 (m, 2H), 1.85-1.71 (m, 2H), 1.45-1.40 (m, 2H), 1.38 (s, 9H); LCMS: 99.03%; 314.0 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.54 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of mn-butyl ((2-(4-oxopiperidin-l-yl) thiazol-5-yl) methyl) carbamate (487): To a stirring solution of compound 486 (1.7 g, 5.43 mmol) in EtOAc (40 mL) under inert atmosphère was added iodoxybenzoic acid (3.04 g, 10.86 mmol) at 0 °C; heated to 70 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite. The fitrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3% MeOH/ CH2CI2 to afford compound 487 (650 mg, crude) as colorless syrup. TLC: 5% MeOH/ CH2CI2 (Rf 0.6); LC-MS: 48.21%; 312.2 (M⁺+l); (Column; X-select CSH C-18 (50 x 3 mm, 2.5 pm); RT 3.37 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.0 mL/min).

Synthesis of l-(5-(aminomethyl) thiazol-2-yl) piperidin-4-one hydrochloride (488): To a stirring solution of compound 487 (750 mg, crude) in CH2CI2 (10 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (1 mL) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was washed with EtOAc (5 mL) and dried in vacuo to afford compound 488 (450 mg, 76%, HCl sait) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.1); *H-NMR (DMSO-J₆, 500 MHz): δ 8.36 (br s, 3H), 7.30 (s, 1H), 4.10 (q, J= 5.6 Hz, 2H), 3.83-3.78 (m, 4H), 2.52-2.49 (m, 4H);

Synthesis of l-(5-(aminomethyl) thiazol-2-yl)-l, 4-diazepan-5-one hydrochloride (492):

-264-

Synthesis of tert-butyl ((2-(4-(hydroxyimino) cyclohexyl) thiazol-5-yl) methyl) carbamate (488): To a stirring solution of compound 487 (900 mg, 2.89 mmol) in EtOH (25 mL) under argon atmosphère were added hydroxylamine hydrochloride (402 mg, 5.78 mmol) and sodium acetate (474 mg, 5.78 mmol) at RT; heated to reflux and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered washed with EtOAc and filtrate was concentrated in vacuo. The residue was diluted with water (20 mL) and extracted with EtOAc (2x20 mL). The combined organic extracts were washed with water and dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 488 (920 mg crude) as brown syrupy. TLC: 5% MeOH/ CH₂C1₂ (Ry 0.4); ‘H-NMR (DMSOd₆, 500 MHz): δ 13.15 (br s, 1H), 8.29 (br s, 3H), 8.14 (s, 1H), 8.05 (s, 1H), 7.76 (d, J= 8.1 Hz, 2H), 7.69 (dd, J= 8.4, 1.7 Hz, 1H), 7.65-7.62 (m, 1H), 7.56 (d, J= 8.4 Hz, 2H), 4.07 (q, J = 5.8 Hz, 2H); LC-MS: 65.42%; 327.0 (M⁺+2); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.63 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl ((2-(5-oxo-l, 4-diazepan-l-yl) thiazol-5-yl) methyl) carbamate (491): To a stirring solution of compound 488 (900 mg, 2.75 mmol) in acetone (5 mL) was added sodium carbonate (875 mg, 8.25 mmol in 15 mL water) in water (15 mL) and stirred for 5 min. To this was added p-toluene sulfonyl chloride 490 (786 mg, 4.12 mmol) at RT; and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (20 mL) and extracted

-265 with CH2CI2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 8% MeOH/ CH2CI2 to afford compound 491 (460 mg, 51%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.4); 'H-NMR (DMSO-î/₆, 500 MHz): δ 13.15 (br s, 1H), 8.29 (br s, 3H), 8.14 (s, 1H), 8.05 (s, 1H), 7.76 (d,7=8.1 Hz, 2H), 7.69 (dd, J = 8.4, 1.7 Hz, 1H), 7.65-7.62 (m, 1H), 7.56 (d, J= 8.4 Hz, 2H), 4.07 (q, J = 5.8 Hz, 2H); LCMS: 87.76%; 327.0 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.56 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of l-(5-(aminomethyl) thiazol-2-yl)-l, 4-diazepan-5-one hydrochloride (492): To a stirring solution of compound 491 (450 mg, 1.38 mmol) in CH2CI2 (10 mL) under argon atmosphère was added 4 N HCl in 1, 4-dioxane (15 mL) at 0 °C; warmed to RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with diethyl ether (40 mL), hexane (30 mL) and dried in vacuo to afford compound 492 (300 mg crude) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.4); 'H-NMR (DMSO-J₆, 500 MHz): δ 13.15 (br s, 1H), 8.29 (br s, 3H), 8.14 (s, 1H), 8.05 (s, 1H), 7.76 (d,7=8.1 Hz, 2H), 7.69 (dd,7=8.4, 1.7 Hz, 1H), 7.65-7.62 (m, 1H), 7.56 (d, 7= 8.4 Hz, 2H), 4.07 (q, 7= 5.8 Hz, 2H); LC-MS: 85.76%; 227 (M⁺+l); (column;

Kinetex EVO C-18, (50 x 3.0 mm, 2.6 pm); RT 0.36 min. 2.5 mM Aq. NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of (2-(morpholinomethyl) thiazol-5-yl) methanamine (500):

-266 -

Synthesis of 5-(((tert-butyldimethyisilyl) oxy) methyl) thiazole (494): To a stirring solution of thiazol-5-ylmethanol 493 (10 g, 86.95 mmol) in CH2CI2 (100 mL) under inert atmosphère were added imidazole (11.82 g, 173.9 mmol) and teA-Butyldimcthylsilyl chloride (15.72 g, 5 104.31 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC;

after completion of the reaction, the reaction mixture was diluted with water (200 mL) and extracted with CH₂C1₂ (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 494 (19 g, 95%) as pale yellow liquid. TLC: 20% EtOAc/ hexanes (Rf. 0.4); 'H-NMR (DMSO-î/₆, 400 MHz): δ 9.02 (s, 1H), 10 7.79 (s, 1H), 4.92 (s, 2H), 0.87 (s, 9H), 0.07 (s, 6H); LC-MS: 99.03%; 229.9 (M⁺+l); (column;

Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.91 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 5-(((tert-butyldimethylsilyI) oxy) methyl) thiazole-2-carbaldehyde (495): To a stirring solution of 5-(((terLbutyldimethylsilyl) oxy) methyl) thiazole compound 494 (2 g, 8.71 15 mmol) in dry THF (20 mL) under inert atmosphère was added n-butyl lithium (1.6 M solution in hexane, 8.16 mL, 13.07 mmol) dropwise for 10 min at -78 °C and stirred for 1 h. To this was added DMF (1.35 mL, 17.43 mmol) at -78 °C and stirred at the same température for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was

-267 quenched with saturated ammonium chloride solution (10 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 495 (2 g, 89%) as colorless liquid. TLC: 30% EtOAc/ hexanes (Rf. 0.4); *H-NMR (DMSO-4 400 MHz): δ 9.89 (s, 1H), 8.10 (s, 1H), 5.02 (s, 2H), 0.89 (s, 9H), 0.10 (s, 6H); LC-MS (Agilent 6310 Ion trap): 98.45%; 258.2 (M⁺+l); (column; X Select C-18(50x3.0 mm, 2.5 um); RT 5.02 min. 2.5 mM Aq. NH4OOCH: ACN, 0.8 mL/min).

Synthesis of 4-((5-(((iert-butyldimethylsilyl) oxy) methyl) thiazoi-2-yl) methyl) morpholine (496): To a stirring solution of compound 495 (2 g, 7.78 mmol) in 1, 2-dichloroethane (20 mL) under inert atmosphère were added morpholine (812 mg, 9.33 mmol) and sodium triacetoxyborohydride (3.3 g, 15.56 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (100 mL) and extracted with CH2CI2 (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 1050% EtOAc/ hexanes to afford compound 496 (1.3 g, 51%) as colorless thick syrup. TLC: 30% EtOAc / hexanes (Rf. 0.1); ^XH NMR (DMSO-</₆,500 MHz): δ 7.54 (s, 1H), 4.85 (s, 2H), 3.76 (s, 2H), 3.62-3.53 (m, 4H), 2.49-2.45 (m, 4H), 0.86 (s, 9H), 0.07 (s, 6H); LC-MS: 94.28%; 329.0 (M⁺+l); (column; Ascentis Express Cl 8, (50 x 3.0 mm, 2.7 pm); RT 2.06 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(morpholinomethyl) thiazol-5-yl) methanol (497): To a stirring solution of compound 496 (1.3 g, 3.96 mmol) in THF (30 mL) under inert atmosphère was added tetrabutylammonium fluoride (1.0 M solution in THF, 3.96 mL, 5.94 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 10-50% EtOAc/ hexanes to afford compound 497 (700 mg, 82%) as

-268 thick syrup. TLC: 50% EtOAc/ hexanes (Rf 0.1); *H-NMR (DMSO-/4, 400 MHz): δ 7.51 (s, 1H), 5.48 (t, J = 5.7 Hz, 1H), 4.63 (dd, J= 5.6, 0.8 Hz, 2H), 3.76 (s, 2H), 3.61-3.57 (m, 4H), 2.49-2.45 (m, 4H); LC-MS: 98.60%; 215.0 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 0.94 min. 2.5 mM Aq. NH₄OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min);

Synthesis of 4-((5-(chloromethyl) thiazol-2-yl) methyl) morpholine (498): To a stirring solution of compound 497 (700 mg, 3.25 mmol) in CH2CI2 (20 mL) under inert atmosphère were added triethyl amine (1.38 mL, 9.74 mmol) at 0 °C and stirred for 10 min. To this was added methanesulfonyl chloride (0.3 mL, 3.90 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated NaHCO₃ solution (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 498 (700 mg, 93%) as pale brown liquid. TLC: 30% EtOAc/hexanes (Rf 0.4); LC-MS: 89.79%; 232.9 (M⁺+l); (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 0.58 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-((5-(azidomethyl) thiazol-2-yl) methyl) morpholine (499): To a stirring solution of compound 498 (700 mg, 3.01 mmol) in DMF (20 mL) under inert atmosphère was added sodium azide (580 mg, 9.05 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC and LC-MS; after completion of the reaction, the reaction mixture was diluted with ice-cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 10-30% EtOAc/ hexanes to afford compound 499 (400 mg, 70%) as colorless thick syrup. TLC: 30% EtOAc/ hexanes (Rf 0.5); *H-NMR (DMSO-4 400 MHz): δ 7.70 (s, 1H), 4.70 (s, 2H), 3.80 (s, 2H), 3.62-3.58 (m, 4H), 2.51-2.49 (m, 4H);

-269 Synthesis of (2-(morpholinomethyl) thiazol-5-yl) methanamine (500): To a stirring solution of compound 499 (400 mg, 1.67 mmol) in THF: H₂O (4: 1, 10 mL) was added triphenyl phosphine (877 mg, 3.34 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC and LC-MS; after completion of the reaction, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 4-5% MeOH/ CH₂C1₂ to afford compound 500 (200 mg, 56%) as colorless thick syrup. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.2); ‘H-NMR (DMSO-îZ₆, 400 MHz): δ 7.48 (s, 1H), 3.90 (s, 2H), 3.74 (s, 2H), 3.63-3.56 (m, 4H), 2.97-2.72 (m, 2H), 2.48-2.45 (m, 4H); LC-MS: 99.68%; 213.9 (M⁺+l); (Column; Xselect CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 1.31 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.0 mL/min).

Synthesis of azepan-3-ol hydrochloride (503):

Synthesis of te/7-butyl 3-hydroxyazepane-l-carboxylate (502): To a stirring solution of tertbutyl 3-oxoazepane-l-carboxylate 501 (500 mg, 2.34 mmol) in MeOH (10 mL) under argon atmosphère was added sodium borohydride (134 mg, 3.52 mmol) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with CH₂C1₂ (2x50 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to afford compound 502 (450 mg, 89%) as colorless thick syrup. TLC: 30% EtOAc/ hexanes (Rf 0.4); *H-NMR (DMSO-c7₆, 400 MHz): δ 4.67 (t, J= 4.4 Hz, 1H), 3.81-3.43 (m, 3H), 3.082.88 (m, 1H), 2.80-2.65 (m, 1H), 1.72-1.58 (m, 4H), 1.56-1.33 (m, 9H), 1.30-1.17 (m, 1H).

-270 Synthesis of azepan-3-ol hydrochloride (503): To a stirring solution of compound 502 (450 mg, 2.09 mmol) in CH2CI2 (10 mL) was added 4 N HCl in 1, 4-dioxane (2 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was washed with CH2CI2 (5 mL), zz-pentane (10 mL) and dried in vacuo to afford compound 503 (200 mg, 63%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.1); 'H-NMR (DMSO-î/ô, 400 MHz): δ 9.27 (br s, 1H), 8.52 (br s, 1H), 5.35-5.25 (m, 1H), 4.03-3.96 (m, 1H), 3.15-2.94 (m, 4H), 1.85-1.44 (m, 6H).

Synthesis of (2-(oxazol-5-yl) thiazol-5-yl) methanamine (508):

Synthesis of (2-(oxazoI-5-yl)thiazoI-5-yI)methanol (505): To a stirring solution of 5-(((tertbutyldimethylsilyl) oxy) methyl) thiazole-2-carbaldehyde 495 (600 mg, 2.33 mmol) in dry

THF (20 mL) under inert atmosphère were added l-((isocyanomethyl) sulfonyl)-4methylbenzene 504 (455 mg, 2.33 mmol) and potassium carbonate (322 mg, 2.33 mmol) at RT; heated to 80 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture poured into ice-cold water (10 mL) and extracted with CH2CI2 (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered

-271 and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3% MeOH/ CH₂C12to afford compound 505 (200 mg, 53%) as white semi solid. TLC: 50% EtOAc/ hexanes (Rf. 0.4); 'Η-NMR (DMSO-4 400 MHz): δ 8.56 (s, 1H), 7.80-7.78 (m, 2H), 5.70 (t, J= 5.7 Hz, 1H), 4.73 (dd, J= 5.6, 0.9 Hz, 2H); LC-MS: 94.97%; 182.9 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm,2.6 um); RT 1.066 min. 2.5 mM Aq. NH₄OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of 5-(5-(chloromethyl) thiazoI-2-yI) oxazole (506): To a stirring solution of compound 505 (200 mg, 1.09 mmol) in CH₂C1₂ (5 mL) under inert atmosphère were added triethyl amine (0.317 mL, 2.19 mmol), methanesulfonyl chloride (0.168 mL, 2.19 mmol) at 0 °C; wasmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice-cold water (50 mL) and extracted with CH2CI2 (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 506 (200 mg) as colorless syrup. Which was taken forward for next step without further purification.TLC: 20% EtOAc/ hexanes (Rf 0.8);

Synthesis of 5-(5-(azidomethyl) thiazol-2-yl) oxazole (507): To a stirring solution of compound 506 (200 mg, crude) in DMF (5 mL) under inert atmosphère was added sodium azide (130 mg, 2.00 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into icecold water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 507 (100 mg, 48%) as thick brown syrup. TLC: 20% EtOAc/ hexanes (Rf. 0.6); ‘H-NMR (DMSO-îZ₆, 400 MHz): δ 8.60 (s, 1H), 7.98 (s, 1H), 7.86 (s, 1H), 4.83 (s, 2H); LC-MS: 95.22%; 207.9 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm,2.6 um); RT 2.00 min. 2.5 mM Aq. NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

-272 -

Synthesis of (2-(oxazol-5-yl) thiazol-5-yl) methanamine hydrochloride (508): To a stirring solution of compound 507 (100 mg, 0.48 mmol) in THF: H₂O (4: 1,5 mL) was added triphenyl phosphine (253 mg, 0.96 mmol) at RT and stirred for 6 h. The reaction was monitored by TLC and LC-MS; after completion of the reaction; the volatiles were removed in vacuo to obtain the crude amine (200 mg crude).

To the above crude amine (200 mg) in CH₂C1₂ (5 mL) was added 4 N HCl in 1, 4-dioxane (1 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with EtOAc (5 mL) and dried in vacuo to afford compound 508 (85 mg, HCl sait, crude) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Ry 0.1);

Synthesis of (2-(oxazol-2-yl) thiazoI-5-yl) methanamine hydrochloride (512):

Synthesis of 2-(tributylstannyl) oxazole (510): To a stirring solution of oxazole 509 (2 g, 28.98 mmol) in dry THF (50 mL) under inert atmosphère was added n-butyl lithium (19.9 mL, 31.88 mmol, 1.6 M solution in hexane) at -78 °C and stirred for 1 h. To this was added a tributyltin chloride (7.85 mL, 28.98 mmol) at -78 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with hexane (100 mL), the obtained solid was filtered through celite and the filtrate was concentrated in vacuo to afford crude compound 510 (8 g) as colorless liquid which was taken for next step without further purification. TLC: 10% EtOAc/ hexanes (Ry 0.8);

-273 Synthesis of te/7-butyl ((2-(oxazol-2-yl) thiazol-5-yl) methyl) carbamate (511): To a stirring solution of terZ-butyl ((2-chlorothiazol-5-yl) methyl) carbamate 224 (750 mg, 3.01 mmol) in 1, 4-dioxane (20 mL) was added 2-(tributylstannyl) oxazole 510 (4.32 g, 12.07 mmol) and purged under argon atmosphère for 30 min. To this was added Pd(PPh₃)4 (348 mg, 0.30 mmol) at RT; heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion the reaction the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 30% EtOAc/ hexanes and further purified by préparative HPLC purification to afford compound 511 (100 mg, 12%) as thick syrup. TLC: 30% EtOAc/ hexanes (Rf. 0.2); ‘H-NMR (DMSO-4 500 MHz): δ 8.32 (s, 1H), 7.83 (s, 1H), 7.63 (t, J= 6.1 Hz, 1H), 7.46 (s, 1H), 4.37 (br d, J= 5.8 Hz, 2H), 1.40 (s, 9H); LC-MS: 99.93%; 281.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.06 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(oxazoI-2-yl) thiazol-5-yl) methanamine hydrochloride (512): To a stirring solution of compound 511 (100 mg, 0.35 mmol) in CH2CI2 (5 mL) was added 4 N HCl in 1,4dioxane (0.5 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude which was washed with EtOAc (10 mL) and dried in vacuo to afford compound 512 (70 mg, 90%; HCl sait) as an off-white solid. TLC: 5% MeOH/ CH2CI2 (Rf. 0.1); 'H-NMR (DMSO-J₆, 400 MHz): δ 8.55 (br s, 3H), 8.37 (s, 1H), 8.10 (s, 1H), 7.51 (d, 1H), 4.40 (q, J= 5.6 Hz, 2H); LC-MS: 97.38%; 181.9 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 0.29 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

-274Synthesis of methyl (3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) propyl)-Z-prolinate hydrochloride (517):

Synthesis of methyl L-prolinate hydrochloride (515): To a stirring solution of L-proline 514 (5 g, 43.47 mmol) in MeOH (75 mL) under inert atmosphère was added thionyl chloride (3.15 mL, 65.21 mmol) drop wise at 0 °C for 15 min; and heated to reflux for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude compound 515 (6 g sait, quantitative) as colourless liquid. This material was taken to next step without further purification. TLC: 10% MeOH/ CH2CI2 (Rf 0.4); *H NMR (400 MHz, DMSO-î/₆): δ 10.85-10.21 (m, 1H), 9.33-8.59 (m, 1H), 4.40-4.18 (m, 1H), 4.053.82 (m, 1H), 3.75 (s, 3H), 3.29-3.16 (m, 2H), 2.32-2.18 (m, 1H), 2.06-1.82 (m, 2H);

Synthesis of 3-(4-(5-(((tert-butoxycarbonyl) amino) methyl) thiazol-2-yl) phenoxy) propyl trifluoromethanesulfonate (513): To a stirring solution of compound 385 (100 mg, 0.27 mmol) in CH2CI2 (10 mL) under argon atmosphère were added triethylamine (0.11 mL, 0.82 mmol) and triflic anhydride (0.1 mL, 0.54 mmol), at -40 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with

-275 water (20 mL) and extracted with CH2CI2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude compound 513 (120 mg) as viscous syrup. TLC: 5% MeOH/ CH2CI2 (Rf 0.6);

Synthesis of methyl (3-(4-(5-(((tert-butoxycarbonyl) amino) methyl) thiazol-2-yl) phenoxy) propyl)-£-prolinate (516): To a stirring solution of compound 513 (2.7 g, 5.44 mmol) in CH2CI2 (20 mL) under argon atmosphère were added triethylamine (1.5 mL, 10.88 mmol) and compound 515 (1.4 g, 10.88 mmol), at -40 °C and stirred for 5 min. warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH2Q2 (2 x 60 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 2% MeOH/ CH2CI2 to afford compound 516 (1.1 g, 42% for 2 steps) as viscous syrup. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.4); ^XH NMR (400 MHz, DMSO-</₆): δ 7.81 (d, J= 8.9 Hz, 2H), 7.60 (s, 1H), 7.52 (t, J= 5.6 Hz, 1H), 7.01 (d, J= 8.8 Hz, 2H), 4.30 ( d, J= 5.9 Hz, 2H), 4.06 (t, 7= 6.3 Hz, 2H), 3.56 (s, 3H), 3.23-3.14 (m, 1H), 3.03-3.00 (m, 1H), 2.82-2.73 (m, 1H), 2.56-2.53 (m, 1H), 2.40-2.33 (m, 1H), 2.07-1.89 (m, 1H), 1.90-1.73 (m, 5H), 1.40 (s, 9H); LC-MS: 96.16%; 476.2 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.97 min. 0.025% Aq. TFA + 5% ACN: ACN +; 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of methyl (3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) propyl)-£-prolinate hydrochloride (517): To a stirring solution of compound 516 (100 mg, 0.21 mmol) in CH2CI2 (5 mL) was added 4 N HCl in 1, 4-dioxane (1 mL) under argon atmosphère at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was triturated with diethyl ether (5 mL) and EtOAc (5 mL) and dried in vacuo to afford compound 517 (60 mg sait; 69%) as thick syrup. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.2); 'H NMR (500 MHz, DMSO-rf₆): δ 8.54 (br s, 3H), 7.927.85 (m, 3H), 7.08 (d, J= 8.7 Hz, 2H), 4.51 (q, 7= 7.9 Hz, 1H), 4.32 (q, 7= 5.2 Hz, 2H), 4.15 (t, 7= 5.8 Hz, 2H), 3.79 (s, 3H), 3.75-3.64 (m, 2H), 3.56-3.47 (m, 1H), 3.35-3.18 (m, 2H),

-276 -

2.47- 2.37 (m, 1H), 2.21-2.04 (m, 4H); LC-MS: 94.78%; 376.1 (M⁺+l)_; (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.23 min. 0.025% Aq. TFA + 5% ACN: ACN +; 5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of 2, 2, 2-trifluoro-l-(((2-(4-isopropyl-12Z-pyrazol-l-yl) thiazol-5-yl) methyl)-14azanyl) ethan-l-one (519):

Synthesis of 2-(l-(5-((tritylamino) methyl) thiazol-2-yl)-lÆ-pyrazol-4-yl) propan-2-ol (518): To a stirring solution of ethyl l-(5-((tritylamino) methyl) thiazol-2-yl)-177-pyrazole-4carboxylate 452 (2.5 g, 5.06 mmol) in anhydrous THF (20 mL) under inert atmosphère was added méthylmagnésium bromide (13 mL, 25.30 mmol, 2 M sol. In diethylether) at -10 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (60 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 20-25% EtOAc/ hexanes to afford compound 518 (1 g, 42%) as an off-white solid. TLC: 20% EtOAc/ hexanes (Rf 0.2); ^XH NMR (DMSO-d₆,400 MHz): δ 8.23 (s, 1H), 7.79 (s, 1H), 7.47-7.45 (m, 5H), 7.38-7.30 (m, 8H), 7.26-7.19 (m, 4H), 3.34-3.31 (m, 2H), 5.07 (s, 1H), 1.46 (s, 6H);

Synthesis of (2-(4-isopropyl-lÆ-pyrazol-l-yI) thiazoI-5-yl) methanamineTFA sait (519): To a stirring solution of compound 518 (300 mg, 0.62 mmol) in CH2CI2 (10 mL) under inert atmosphère were added trifluoroacetic acid (0.24 mL, 3.12 mmol), trieythlsilane (0.2 mL, 1.25 mmol) at 0 °C; warmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was washed diethylether (2x10 mL) and dried in vacuo to afford crude compound 519 (150 mg,

-277 68%) as white solid. TLC: 30% EtOAc/ hexanes (Rf 0.2); *H NMR (DMSO-7₆,400 MHz): δ 8.37 (br s, 3H), 8.26 (s, 1H), 7.80 (s, 1H), 7.66 (s, 1H), 4.30 (s, 2H), 2.91-2.84 (m, 1H), 1.22 (d, J= 6.9 Hz, 6H); LC-MS: 82.87%; 223.1 (M+l)⁺; (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 2.62 min. 2.5 mM Aq. NH₄OOCH: ACN; 0.8 mL/min).

Synthesis of Synthesis of l-(((2-(4-((3-(dimethylamino) azetidin-l-yl) methyl) phenyl) thiazol-5-yl) methyl)-14-azanyl)-2, 2, 2-trifluoroethan-l-one (524A):

Synthesis of fort-butyl ((2-(4-formylphenyl) thiazol-5-yl) methyl) carbamate (520): To a stirring solution of ZeW-butyl ((2-chlorothiazol-5-yl) methyl) carbamate 224 (1 g, 4.02 mmol) in

DME: H2O (4:1, 15 mL) were added (4-formylphenyl) boronic acid (905 mg, 6.03 mmol) and sodium carbonate (1.49 g, 14.08 mmol) in a sealed tube at RT and purged under argon for 30 min. Then Pd(dppf)C12 (294 mg, 0.40 mmol) was added at RT. The reaction mixture was heated to 90-95 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was dilured with water (30 mL), and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (30 mL), water (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/Hexane to afford compound 520 (600 mg, 47%) as pale yellow solid. TLC: 40% EtOAc/ hexanes (Rf 0.4). 'H NMR (500 MHz, DMSO-d₆): δ 10.05 (s, 1H), 8.12 (d, 7= 8.1 Hz, 2H), 8.01 (d,7=8.1 Hz,

-278 -

2H), 7.80 (s, 1H), 7.60 (br s, 1H), 4.37 (d, J = 5.8 Hz, 2H), 1.40 (s, 9H); LC-MS: 93.26%; 318.9 (M⁺+l) (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 2.91 min. 2.5 mM NH4OOCH in water + 5% ACN: ACN + 5% 2.5 mM NH4OOCH in water, 0.8 mL/min).

Synthesis of m/T-butyl 3-(dimethylamino) azetidine-l-carboxylate (522): To a stirring solution of compound 521 (2.5 g, 14.53 mmol) in 1, 2-dichloro ethane (25 mL) were added formaldéhyde solution (36% in H2O) (4.25 mL) and sodium triacetoxy borohydride (27.7 g, 13.08 mmol) at RT under inert atmosphère. The reaction mixture was stirred at RT for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was dilured with water (30 mL), basified with saturated sodium bicarbonate solution (20 mL) to pH~8 and extracted with EtOAc (2x30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude compound 522 (2.2 g, 75%) as pale yellow liquid. LC-MS: 88.00%; 101.3 (M⁺+l) (des-boc) (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 0.36 min. 5 mM Aq NH4OAC +ACN: 0.8 mL/min).

Synthesis of l-(3-(dimethylamino)-114-azetidin-l-yl)-2, 2, 2-trifluoroethan-l-one (523): To a stirring solution of compound 522 (2.2 g, 11 mmol) in CH2CI2 (20 mL) was added trifluoroacetic acid (6 mL) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with triturated with ether (20 mL) and dried in vacuo to obtain crude compound 523 (1.8 g, 76%) as white solid. TLC: 10% MeOH/CH₂Cl₂ (Rf 0.1); LC-MS: 80.67%; 101.3 (M⁺+l) (column; Atlantis T3, (150 x 4.6 mm, 3 pm); RT 2.41 min. 2.5mM Aq NH4OAC: ACN, 1.0 mL/min).

Synthesis of m/7-butyl ((2-(4-((3-(dimethylamino) azetidin-l-yl) methyl) phenyl) thiazol-5yl) methyl) carbamate (524): To a stirring solution of compound 520 (500 mg, 1.57 mmol) and compound 523 (235 mg, 2.35 mmol) in CH2CI2 (15 mL) were added potassium carbonate (260 mg, 1.88 mmol), sodium triacetoxy borohydride (666 mg, 3.14 mmol) and molecular sieves (500 mg) at RT under inert atmosphère. The reaction mixture was stirred at RT for 16 h.

-279 The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was dilured with water (15 mL), basified with saturated sodium bicarbonate solution (15 mL) to pH~8 and extracted with EtOAc (2x15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 6-10% MeOH/CH2C12 to afford compound 524 (400 mg, 63%) as pale yellow syrup. ^XH NMR (500 MHz, DMSO4): δ 7.83 (d, J = 7.5 Hz, 2H), 7.67 (s, 1H), 7.58-7.53 (m, 1H), 7.38 (d, J= 8.1 Hz, 2H), 4.33 (d, J= 5.2 Hz, 2H), 3.63 (s, 2H), 3.66-3.59 (m, 2H), 2.93-2.81 (m, 3H), 2.03 (s, 6H), 1.40 (s, 9H); LC-MS: 98.20%; 403.2 (M⁺+l) (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 1.69 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 1-(((2-(4-((3-(dimethylamino) azetidin-l-yl) methyl) phenyl) thiazol-5-yl) methyl)-14-azanyl)-2, 2, 2-trifluoroethan-l-one (524A): To a stirring solution of compound 524 (500 mg, 1.24 mmol) in CH2CI2 (5 mL) was added trifluoroacetic acid (2 mL) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with triturated with ether (10 mL) and dried in vacuo to obtain crude compound 524A (390 mg, 75%) as pale yellow solid. TLC: 10% MeOH/CH2C12 (Rf. 0.1); LCMS: 94.59%; 303.2 (M⁺+l); (column; Atlantis T3, (150 x 4.6 mm, 3 pm); RT 6.45 min.

2.5mM Aq NH₄OAc: ACN, 1.0 mL/min).

Synthesis of (2-(l-methyl-LH-pyrazol-3-yl) thiazol-5-yl) methanamine TFA sait (528):

-280 -

Synthesis of l-methyl-3-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lÆ-pyrazole (526): To a stirring solution of 3-bromo-l-methyl-IH-pyrazole 525 (1 g, 6.25 mmol) in 1, 4dioxane (60 mL) under inert atmosphère were added bispinacolato diboron (1.73 g, 6.83 mmol), potassium acetate (1.82 g, 18.63 mmol) at RT and purged under argon atmosphère for 20 min, added Pd(dppf)C12 (454 mg, 0.62 mmol) and heated to 120 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 526 (2.4 g, crude) as brown thick syrup. The crude was carried forward for next step without further purification. TLC: 50% EtOAc/ hexanes (Rf 0.3);

Synthesis of tert-butyl ((2-(l-methyl-LH-pyrazol-3-yl) thiazol-5-yl) methyl) carbamate (527): To a stirring solution of terZ-butyl ((2-chlorothiazol-5-yl) methyl) carbamate 224 (500 mg, 2.01 mmol) in 1, 2 dimethoxy ethane: H2O (4: 1, 75 mL) under inert atmosphère were added l-methyl-3-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyrazole 526 (3.9 g, crude), sodium carbonate (750 mg, 7.08 mmol) and purged under argon atmosphère for 20 min. To this was added Pd(PPh3)4 (270 mg, 0.23 mmol) at RT; heated to 110 °C and stirred for 16 h. The reaction was monitored by TLC; after completion the volatiles were removed in vacuo to obtain the crude. The residue was diluted with water (50 mL) and extracted with EtOAc (3 x 50

-281 - mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to obtain the crude. The crude was purified by préparative HPLC purification to afford compound 527 (160 mg, 27%) as an off-white solid. TLC: 70% EtOAc/ hexanes (Rf 0.4); *HNMR (DMSO-î7₆, 400 MHz): δ 7.80 (d, J= 2.3 Hz, 1H), 7.59 (s, 1H), 7.52 (br t, J= 5.3 Hz, 1H), 6.67 (d, J= 2.3 Hz, 1H), 4.30 (br d, J= 5.8 Hz, 2H), 3.31 (s, 3H), 1.40 (s, 9H); LC-MS: 96.60%; 294.9 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.04 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(l-methyl-l//-pyrazol-3-yl) thiazol-5-yl) methanamine TFA sait (528): To a stirring solution of ter 7b ut y 1 ((2-(l-methyl-lH-pyrazol-3-yl) thiazol-5-yl) methyl) carbamate 527 (50 mg, 0.17 mmol) in CH2CI2 (3 mL) under inert atmosphère was added trifluoroacetic acid (0.06 mL) at 0 °C; warmed to RT and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was titurated with diethylether (2x5 mL) and dried in vacuo to afford compound 528 (380 mg, 84%; HCl sait) as white solid. TLC: 40% EtOAc/ hexanes (Rf 0.1); ’ïï-NMR (DMSO-îZ₆, 400 MHz): δ 8.29 (br s, 3H), 7.84 (s, 1H), 7.82 (d, J = 2.1 Hz, 1H), 6.70 (d, J = 2.3 Hz, 1H), 4.31 (s, 2H), 3.89 (s, 3H); LC-MS (Agilent 6310 Ion Trap): 99.97%; 195.2 (M⁺+l); (column; X-Select HSS T3 (150 x 3 mm, 2.5 pm); RT 0.62 min. 2.5 mM Aq. NH4OAC: ACN; 0.6 mL/min).

Synthesis of tert-butyl (l-((5-(aminomethyl) thiazol-2-yl) methyl) piperidin-4-yl) carbamate (534):

-282 -

Synthesis of tert-butyl (l-((5-(((teH-butyldimethylsilyl) oxy) methyl) thiazol-2-yl) methyl) piperidin-4-yl) carbamate (530): To a stirring solution of 5-(((terCbutyldimethylsilyl) oxy) methyl) thiazole-2-carbaldehyde 495 (1.2 g, 4.66 mmol) in 1, 2-dichloroethane (50 mL) under 5 inert atmosphère were added ter/-butyl piperidin-4-ylcarbamate 529 (1.12 g, 5.60 mmol) and sodium triacetoxyborohydride (2.96 g, 14.00 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with CH2CI2 (200 mL), washed with water (100 mL) and brine (100 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude.

The crude was purified through silica gel column chromatography using 30% EtOAc/ hexanes to afford compound 530 (800 mg, 49%) as a pale yellow thick syrup. TLC: 20% EtOAc / hexanes (Ry 0.1); ’HNMR (DMSO-î/_6; 500 MHz): δ 7.52 (s, 1H), 6.76 (br d, J =1.2 Hz, 1H), 4.85 (s, 2H), 3.72 (s, 2H), 3.24-3.21 (m, 1H), 2.83- 2.79 (m, 2H), 2.14- 2.07 (m, 2H), 1.70-1.66 (m, 2H), 1.47-1.39 (m, 11H), 0.86 (s, 9H), 0.07 (s, 6H); LC-MS: 93.12%; 442.2 (M⁺+l)_; (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.18 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

-283 Synthesis of tert-butyl (l-((5-(hydroxymethyl) thiazol-2-yl) methyl) piperidin-4-yl) carbamate (531): To a stirring solution of compound 530 (800 mg, 1.81 mmol) in THF (15 mL) under inert atmosphère was added tetrabutylammonium fluoride (1.0 M solution in THF, 2.72 mL, 2.72 mmol) at 0 °C and stirred at the same température for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (100 mL) and extracted with EtOAc (2 x 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 4% MeOH/ CH2CI2 to afford compound 531 (650 mg, quantitative) as thick syrup. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.1); ‘H-NMR (DMSO4, 500 MHz): δ 7.48 (s, 1H), 6.77 (br d, J = 6.7 Hz, 1H), 5.46 (brt, J = 5.5 Hz, 1H), 4.62 (br d, J= 5.8 Hz, 2H), 3.71 (br s, 2H), 3.03-3.01 (m, 1H), 2.84-2.80 (m, 2H), 2.14-2.08 (m, 2H), 1.75-1.54 (m, 2H), 1.47-1.37 (m, HH); LC-MS: 94.85%; 328.0 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.40 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-((4-((tert-butoxycarbonyl) amino) piperidin-l-yl) methyl) thiazol-5-yl) methyl methanesulfonate (532): To a stirring solution of compound 531 (650 mg, 1.98 mmol) in CH2CI2 (30 mL) under inert atmosphère were added triethyl amine (1.43 mL, 9.93 mmol) at 0 °C and stirred for 10 min. To this was added methanesulfonyl chloride (453.2 mg, 3.97 mmol) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (2 x 50 mL) and extracted with CH2CI2 (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 532 (600 mg) as pale brown liquid. The crude taken forward for next step with out further purification. TLC: 10% MeOH/ CH2CI2 (Rf 0.4);

Synthesis of tert-butyl (l-((5-(azidomethyl) thiazol-2-yI) methyl) piperidin-4-yl) carbamate (533): To a stirring solution of compound 532 (600 mg, 1.48 mmol) in DMF (10 mL) under inert atmosphère was added sodium azide (284 mg, 4.44 mmol) at RT and stirred for 16 h. The

-284 reaction was monitored by TLC and LC-MS; after completion of the reaction, the reaction mixture was diluted with ice-cold water (100 mL) and extracted with EtOAc (2 x 75 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 70% EtOAc/ hexanes to afford compound 533 (400 mg, 76%) as thick syrup. TLC: 70% EtOAc/ hexanes (Rf 0.4); 'H-NMR (DMSO-4 500 MHz): δ 7.67 (s, 1H), 6.78 (br d, J = 7.5 Hz, 1H), 4.69 (s, 2H), 3.76 (s, 2H), 3.28-3.19 (m, 1H), 2.85-2.80 (m, 2H), 2.18-2.11 (m, 2H), 1.71-1.67 (m, 2H), 1.48-1.32 (m, 11H); LC-MS: 92.56%; 353.0 (M⁺+l); (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 1.80 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of tert-butyl (l-((5-(aminomethyl) thiazol-2-yl) methyl) piperidin-4-yl) carbamate (534): To a stirring solution of compound 533 (300 mg, 0.85 mmol) in THF: H2O (4: 1,5 mL) was added triphenyl phosphine (446 mg, 1.70 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC and LC-MS; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 4-5% MeOH/ CH2CI2 to afford compound 534 (250 mg, 91%) as semi solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.2); ’fl-NMR (DMSO-4 400 MHz): δ = 7.43 (s, 1H), 3.86 (s, 1H), 3.69 (s, 1H), 3.30 - 3.12 (m, 3H), 2.84-2.79 (m, 2H), 2.17 - 2.03 (m, 2H), 1.701.67 (m, 2H), 1.37 (s, 9H); LC-MS: 81.58%; 327.1 (M⁺+l); (column; Kinetex EVOC-18 (50 x 3.0 mm, 2.6 pm); RT 1.60 min. 2.5 mM Aq. NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH4OOCH, 0.8 mL/min).

Compound préparation

Acids similar to compound 6 (compounds 13, 20, 32, 40, 47, 54, 61, 68, 76, 81, 88, 149, 153, 155, 158, 200, 211, 216, 89, 92, 95, 105, 113, 120, 126, 135, 143, 144, 163, 169, 172, 176, 185, 190, 194) were synthesized as mentioned above and converted to final products either using commercially available amines or prepared amines employing typical procedures A and B, and the results are captured in the Table 1 :

-285 -

Typical procedure A:

To a stirring solution of compound 6 (100 mg, 0.36 mmol) in DMF (5 mL) under inert atmosphère were added EDCI.HC1 (105 mg, 0.55 mmol), HOBt (75 mg, 0.55 mmol), compound 255 (80 mg, 0.44 mmol) and diisopropylethylamine (0.19 mL, 1.10 mmol) at 0 °C warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was either directly dried in vacuo or triturated or purified through silica gel column chromatography to afford the desired compound.

Typical procedure B:

To a stirring solution of acid 105 (130 mg, 0.41 mmol) in DMF (6 mL) under inert atmosphère were added HATU (187 mg, 0.49 mmol) and stirred for 10 min. To this were added and compound 255 (83 mg, 0.49 mmol) and diisopropylethylamine (0.21 mL, 1.23 mmol) at 0 °C warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the diluted with water (10 mL) and extracted with 5% MeOH/ CH2CI2 (2x10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was either directly dried in vacuo or triturated or purified through silica gel column chromatography or préparative HP LC purification to afford the desired compound.

Table 1: Synthesis from compound 13, 20, 32, 40, 47, 54, 61, 68, 76, 81, 88, 149, 153, 155, 158, 200, 211, 216, 89, 92, 95, 105, 113, 120, 126, 135, 143, 144, 163, 169, 172, 176, 185,190, 194 and various commercial and synthesized amines.

Example	Structure	Proc	Rx.	Mass	Mass Spec.	^XH-NMR

-286 -

		edur e, Inte rme diat e, ami ne	Yiel d (%)	Spec. Found	Calculated
1421	0 . %NH P ⁿ'~'yYj H s J cf₃	A, 6, 255	21	435.9 (M⁺+l) 5	435.03 for C19H12F3N3 O₂S₂	1 H-NMR (DMSOd6, 400 MHz): δ 10.77 (s, 1H), 9.38 (t, J = 5.7 Hz, 1H), 8.05 (s, 1H), 7.727.66 (m, 3H), 7.60 (dd, J = 8.0, 1.8 Hz, 1H), 7.53 (td, J = 7.1, 1.6 Hz, 1H), 7.50-7.43 (m, 2H), 4.72 (d, J = 5.6 Hz, 2H);
1431	0 ÿ CF₃ H T^N	A, 6, 263	23	435.9 (M⁺+l)	435.03 for C₁₉H₁₂F₃N₃O₂S₂	1 H-NMR (DMSOd6, 400 MHz): δ 10.80 (s, 1H), 9.45 (t, J = 5.3 Hz, 1H), 9.09 (s, 1H), 7.70 (d, J = 8.0 Hz, 3H), 7.64-7.43 (m, 4H), 4.77 (d, J = 4.8 Hz, 2H);
1424	0 / ^NH /? fk Itn^ εγ _χΝΗ	A, 6, 242	53	396.9 (M⁺+l) 5	c₁₉h₁₆n₄o₂ S₂396.07	1H NMR (DMSOd6, 500 MHz): δ 10.77 (s, 1H), 9.03 (t, J = 5.6 Hz, 1H), 7.69-7.62 (m, 3H),

-287 -

						7.59-7.42 (m, 4H), 7.34-7.30 (m, 1H), 6.87 (s, 1H), 4.36 (d, J = 5.8 Hz, 2H), 2.72 (d, J = 4.9 Hz, 3H);
1425	0 V—NH 0 JCj'' ^νΛ^ν /XsX^ H N— /	A, 6, 245	61	411.0 (M⁺+l) 5	C20H18N4O2 s₂410.09	’H NMR (DMSO-/ 400 MHz): δ 10.75 (s, 1H), 9.05 (t, J = 5.7 Hz, 1H), 7.727.62 (m, 3H), 7.597.42 (m, 4H), 6.99 (s, 1H), 4.41 (d, J = 5.5 Hz, 2H), 2.95 (s, 6H);
1473	0 Xnh 0 _o /Cl Z xy/ // ^{b n}	A, 92, 220	18	419.8 (M⁺+l) 5	C₁₇Hi₀C1N₃O4S2 418.98	1H NMR (DMSOd6, 400 MHz): δ 13.19 (br s, 1H), 11.62 (s, 1H), 8.10 (d, J = 8.2 Hz, 1H), 8.07-7.97 (m, 4H), 7.95-7.85 (m, 2H), 7.63 (s, 1H);
1496	O vxo ω 1 X	A, 13, 217	34	381.9 (M⁺+l)	Ci₉H₁₅N₃O₂ S₂381.06	1H NMR (DMSOd6, 400 MHz): δ 10.63 (s, 1H), 9.008.95 (m, 2H), 7.79 (s, 1H), 7.66 (dd, J = 7.5, 1.5 Hz, 1H), 7.54-7.41 (m, 4H), 7.15 (s, 1H), 4.61 (d, J = 5.7 Hz, 2H), 2.23 (s, 3H);

- 288 -

1549	0 ^-NH 0 N	A, 6, 271	21	396.0 (M⁺+l)	395.08 for C20H17N3O2 s₂	'H NMR (DMSO-d^ 400 MHz): 10.72 (s, 1H), 8.87 (s, 1H), 8.62 (s, 1H), 7.727.60 (m, 4H), 7.587.42 (m, 4H), 1.74 (s, 6H);
1555	O o en i 7 IZ f	A, 6, 277	38	424.0 (M⁺+l) 9	423.11 for C22H21N3O2 s₂	'H-NMR (DMSO-d₆, 400 MHz): δ 10.78 (s, 1H), 9.19 (t, J = 5.6 Hz, 1H), 7.727.64 (m, 3H), 7.59 (dd, J= 8.2, 1.9 Hz, 1H), 7.56-7.51 (m, 2H), 7.50-7.43 (m, 2H), 4.57 (d, J = 5.6 Hz, 2H), 1.32 (s, 9H);
1556	o ^-NH 0 Ck -4 ^N'X-s f	A, 6, 285	38	461.9 (M⁺+l) 9	461.07 for c₂₄h₁₆fn₃o 2S2	‘H-NMR (DMSO-î4, 400 MHz): δ 10.78 (s, 1H), 9.28 (t, J = 5.3 Hz, 1H), 7.93 (dd, J= 8.9, 5.3 Hz, 2H), 7.78 (s, 1H), 7.73-7.65 (m, 3H), 7.60 (dd, J= 8.3, 1.8 Hz, 1H), 7.56-7.43 (m, 3H), 7.31 (t, J = 8.9 Hz, 2H), 4.65 (d, J=5.6Hz, 2H);
1598	O /Nti>^Oen 1 7 IZ Y 0	A, 6, 304	48	452.9 (M⁺+l) 9	452.10 for C22H2oN₄03 S₂	‘H-NMR (DMSO-d₆, 500 MHz): δ 10.76 (s, 1H), 9.08 (t, J = 5.5 Hz, 1H), 7.70-

-289 -

						7.63 (m, 3H), 7.607.42 (m, 4H), 7.05 (s, 1H), 4.42 (d, J = 5.5 Hz, 2H), 3.683.64 (m, 4H), 3.353.25 (m, 4H);
1604	Ο ΝΗ /? f X J N(CH₃)₂ Ν	Α, 6, 288	39	471.2 (Μ⁺+1) 5	470.09 for C22H22N4O2 S3	’H-NMR (DMSO-7₆, 500 MHz): δ 10.77 (s, 1H), 9.20 (t, J = 5.6 Hz, 1H), 7.727.64 (m, 3H), 7.597.43 (m, 5H), 4.54 (d, J = 5.5 Hz, 2H), 3.27 (t, J = 6.9 Hz, 2H), 2.56 (t, J = 6.8 Hz, 2H), 2.16 (s, 6H);
1605	G /Νί⁰ω 1 ζζ ο I	Α, 6, 357	38	459.9 (Μ⁺+1) 5	459.07 for C₂₄Hi₇N₃O₃s₂	‘H-NMR (DMSO-^, 500 MHz): δ 10.77 (s, 1H), 9.94 (s, 1H), 9.24 (t, J = 5.8 Hz, 1H), 7.72-7.65 (m, 5H), 7.62-7.43 (m, 5H), 6.83 (d, J = 8.7 Hz, 2H), 4.62 (d, J = 5.5 Hz, 2H);
1606	^χο ωΑ_ζ2 ι ω ° <5	Α, 6, 363	49	473.9 (Μ⁺+1) 5	473.09 for C₂₅Hi₉N₃O3 s₂	'H-NMR (DMSO-î/₆, 500 MHz): δ 10.78 (s, 1H), 9.25 (t, J = 5.6 Hz, 1H), 7.81 (d, J = 8.7 Hz, 2H), 7.73-7.65 (m, 4H), 7.63-7.43 (m, 4H), 7.02 (d, J = 8.7 Hz,

-290 -

						2H), 4.63 (d, J = 5.5 Hz, 2H), 3.80 (s, 3H);
1608	ο ^-ΝΗ Ο ___/*<^ch3>2 yr o'	A, 6, 360	23	531.0 (M⁺+l) 5	530.14 for C28H26N4O3 s₂	‘H NMR (DMSO-d_6;500 MHz): δ 10.77 (s, 1H), 9.28 (t, J = 5.1 Hz, 1H), 7.78 (d, J = 8.7 Hz, 2H), 7.72-7.59 (m, 5H), 7.55-7.41 (m, 3H), 7.01 (d, J = 8.7 Hz, 2H), 4.62 (d, J= 5.5 Hz, 2H), 4.10 (t, J = 5.6 Hz, 2H), 2.67 (t, J= 5.2 Hz, 2H), 2.24 (s, 6H);
1627	0 yNH P ï 'X N^__e H Y^_CN N	A, 6, 282	26	393.0 (M⁺+l) 5	392.04 for C₁₉H₁₂N4O2 S₂	’H-NMR (DMSO-d₆, 400 MHz): δ 10.77 (br s, 1H), 9.38 (t, J = 4.8 Hz, 1H), 8.12 (s, 1H), 7.72-7.65 (m, 3H), 7.63-7.42 (m, 4H), 4.72 (d, J = 5.4 Hz, 2H);
1758	O 'Y NH 0 oZxv yVoH	A, 13, 357	22	474.0 (M⁺+l) 5	473.09 for C25H19N3O3 s₂	‘H-NMR (DMSO-dg, 400 MHz): δ 10.63 (s, 1H), 9.97 (br s, 1H), 8.98 (t, J = 5.9 Hz, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.687.64 (m, 2H), 7.547.42 (m, 4H), 7.16 (s, 1H), 6.85 (d, J = 8.7 Hz, 2H), 4.58 (d,

-291 -

						J = 5.8 Hz, 2H), 2.25 (s, 3H);
1910	0 / ^NH /?	B°, 105, 255	10	482.1 (M+l)	481.04 for C20H14F3N3 o₄s₂	’H NMR (400 MHz, DMSO-î7₆): δ 11.35 (s, 1H), 9.28-9.26 (m, 1H), 8.06 (s, 1H), 7.99-7.94 (m, 2H), 7.91-7.81 (m, 3H), 7.32 (s, 1H), 4.73 (d, J = 4.0 Hz, 2H), 2.32 (s, 3H);
1911	0 Χ^ΝΗ 9 ^{0 0}	A, 105, 227	13	515.1 (M⁺+l)	514.08 for C26H18N4O4 s₂	*H NMR (400 MHz, DMSO-d₆): δ 11.35 (s, 1H), 9.21 (t, J = 5.9 Hz, 1H), 8.09 (d, J = 8.5 Hz, 2H), 7.99-7.93 (m, 4H), 7.92-7.81 (m, 4H), 7.32 (s, 1H), 4.69 (d, 7= 5.9 Hz, 2H), 2.34 (s, 3H);
1915	ο _οω 1 \ z œ Λ^ι wi O Z	A, 32, 227	52	561.0 (M⁺+l) 5	560.00 for C₂₆H₁₇BrN₄O₂S₂	1 H-NMR (DMSOd6, 400 MHz): δ 10.39 (s, 1H), 9.18 (t, J = 5.3 Hz, 1H), 8.09 (d, J = 8.0 Hz, 2H), 7.98-7.88 (m, 3H), 7.71-7.66 (m, 1H), 7.59-7.44 (m, 4H), 4.65 (d, J = 5.0 Hz, 2H), 2.25 (s, 3H);

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11106-A	^XP MeO₂C	A, 92, 517	40	661.1 (M⁺+l)	660.17 for C33H32N4O7 s₂	^XH NMR (500 MHz, DMSO-i/g): δ 11.51 (s, 1H), 9.44 (t, J = 5.8 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 8.01-7.96 (m, 2H), 7.93-7.77 (m, 6H), 7.72 (s, 1H), 7.00 (d, J = 8.7 Hz, 2H), 4.66 (d, J = 5.8 Hz, 2H), 4.05 (t, J = 6.1 Hz, 2H), 3.56 (s, 3H), 3.21-3.18 (m, 1H), 3.06-2.99 (m, 1H), 2.82-2.74 (m, 1H), 2.56-2.52 (m, 1H), 2.39-2.34 (m, 1H), 2.07-1.98 (m, 1H), 1.88-1.70 (m, 5H);
1914	0 /“^NH / p X ^H ΓζΥορ₃ Br N	A, 32, 255	94	528.3 (M⁺+l) 9	526.96 for C₂oHi3BrF3 N₃O₂S₂	'H-NMR (DMSO-îZ₆, 400 MHz): δ 10.39 (s, 1H), 9.24 (t, J = 5.6 Hz, 1H), 8.05 (s, 1H), 7.71-7.66 (m, 1H), 7.61-7.44 (m, 4H), 4.68 (d, J = 5.6 Hz, 2H), 2.23 (s, 3H);
1535	0 χ-ΝΠ / 0 CXX/ ηΎ⁵b Xs^ π // \ < ch₃N	A, 20, 297	69	395.8 (M⁺+l) 5	395.08 for C₂oHi₇N₃0₂S₂	‘H-NMR (DMSO-7₆, 400 MHz): δ 10.24 (s, 1H), 8.96 (t, J = 6.0 Hz, 1H), 7.677.63 (m, 1H), 7.557.40 (m, 5H), 7.05

-293 -

						(d, J = 7.8 Hz, 1H), 4.51 (d, J = 5.9 Hz, 2H), 2.59 (s, 3H), 2.27 (s, 3H);
1755	X ο s J ^{ω 0} θ	A, 20, 357	9	474.1 (M⁺+l) 9	473.09 for C₂₅Hi₉N₃O₃s₂	'H-NMR (DMSO-î/₆, 400 MHz): δ 10.24 (s, 1H), 9.96 (s, 1H), 9.01 (t, J = 5.8 Hz, 1H), 7.72 (d, J= 8.5 Hz, 2H), 7.67-7.62 (m, 2H), 7.54-7.40 (m, 4H), 7.08 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 4.58 (d, J = 5.6 Hz, 2H), 2.29 (s, 3H);
1766	0 γη ^Η f^CF₃ Ν	A, 20, 255	41	448.1 (M⁺-l);	449.05 for C₂oHi4F₃N₃ O₂s₂	‘H-NMR (DMSO-î7₆, 500 MHz): δ 10.24 (s, 1H), 9.15 (t, J = 5.8 Hz, 1H), 8.04 (s, 1H), 7.67-7.63 (m, 1H), 7.54-7.49 (m, 2H), 7.48-7.41 (m, 2H), 7.11 (d, J = 7.8 Hz, 1H), 4.69 (d, J = 5.8 Hz, 2H), 2.28 (s, 3H);
1767	0 /~^ΝΗ / ρ WLsfxx η y\ ο ο fyx	A, 95, 255	26	481.9 (M⁺+l) 9	481.04 for C₂oHi₄F₃N₃ O₄s₂	'H-NMR (DMS0-<4 400 MHz): δ 10.86 (br s, 1H), 9.30 (t, J = 5.8 Hz, 1H), 8.06 (s, 1H), 7.95-7.84 (m, 4H), 7.80 (td, J = 7.5, 1.4 Hz, 1H),

-294-

						7.38 (d, J = 8.2 Hz, 1H), 4.72 (d, J = 5.6 Hz, 2H), 2.31 (s, 3 H);
1752	T ο é ΣΙ I w ^ολ5	A, 54 357	7	477.9 (M⁺+l) 9	477.06 for C₂₄Hi₆FN₃O 3§₂	‘H-NMR (DMSO-ri₆, 400 MHz): δ 10.97 (br s, 1H), 9.95 (s, 1H), 9.27 (t, J = 5.5 Hz, 1H), 7.73-7.65 (m, 5H), 7.61 (dd, J = 8.3, 1.9 Hz, 1H), 7.52-7.46 (m, 1H), 7.40 (d, J = 7.4 Hz, 1H), 7.34-7.28 (m, 1H), 6.82 (d, J = 8.7 Hz, 2H), 4.62 (d, J = 5.5 Hz, 2H);
1746	ο n Vy~^oH	A, 61, 357	9	477.9 (M⁺+l) 5	477.06 for c₂₄h₁₆fn₃o 3§₂	'H-NMR (DMSO-4 400 MHz): δ 10.91 (s, 1H), 9.94 (s, 1H), 9.25 (br t, J = 5.6 Hz, 1H), 7.76-7.31 (m, 9H), 6.83 (d, J = 8.7 Hz, 2H), 4.62 (br d, J =5.6 Hz, 2H);
1747	duv^ N OH	A, 68 357	9	477.9 (M⁺+l) 5	477.06 for C₂₄Hi₆FN₃O 3S2	‘H-NMR (DMSO-îZ₆, 400 MHz): δ 10.80 (s, 1H), 9.92 (br s, 1H), 9.23 (t, J = 5.4 Hz, 1H), 7.76-7.57 (m, 7H), 7.43 (dd, J = 2.3, 8.4, 2.3 Hz, 1H), 7.30 (td, J = 8.5, 2.4 Hz, 1H),

-295 -

						6.80 (d, J = 8.5 Hz, 2H), 4.60 (d, J= 5.4 Hz, 2H);
1753	ω Γ 7 Ç ο τ	A, 76 357	12	477.9 (M⁺+l) 5	477.06 for C₂₄Hi₆FN₃O 3§₂	'H-NMR (DMSO-4 400 MHz): δ 10.90 (s, 1H), 9.95 (s, 1H), 9.26 (t, J = 5.5 Hz, 1H), 7.74-7.59 (m, 6H), 7.54-7.44 (m, 3H), 6.83 (d, J= 8.6 Hz, 2H), 4.62 (d, J = 5.5 Hz, 2H);
1904	0 V-ΝΗ ο Cx s ^η V ⁵\/=, F ^{0 0} (_y~CN	A^c, 144, 227	51	519.0 (M⁺+l) 5	518.05 for C₂₅H₁₅FN₄O ₄S₂	¹ H-NMR (DMSO-î7₆, 400 MHz): δ 1.58 (br s, 1H), 9.54 (t, J = 5.6 Hz, 1H), 8.13 (d, J= 8.7 Hz, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.93 (d, J = 8.8 Hz, 3H), 7.90-7.82 (m, 3H), 7.73 (d, J= 7.4 Hz, 1H), 7.70-7.64 (m, 1H), 4.72 (br à, J = 5.6 Hz, 2H);
1749	0 V- ΝΗ P θ/^_Ύ3	A, 81, 357	14	477.9 (M⁺+l) 5	477.06 for C₂₄Hi₆FN₃O 3§₂	‘H-NMR (DMSO-î/₆, 400 MHz): δ 10.72 (s, 1H), 9.96 (s, 1H), 9.04 (t, J = 5.3 Hz, 1H), 7.73-7.64 (m, 4H), 7.60-7.43 (m, 5H), 6.84 (d, J= 8.7 Hz, 2H), 4.61 (d, J = 5.8 Hz, 2H);

-296 -

1750	f y ®/ \ N	A, 88, 357	10	495.9 (M⁺+l) 5	495.05 for C₂₄Hi₅F₂N₃ O₃s₂	‘H-NMR (DMSO-4 400 MHz): δ 10.65 (br s, 1H), 9.96 (br s, 1H), 9.39 (t, J = 5.8 Hz, 1H), 7.74-7.64 (m, 4H), 7.58-7.46 (m, 4H), 6.85 (d, J = 8.7 Hz, 2H), 4.63 (d, J= 5.6 Hz, 2H);
1541	0 V-NH 0 ^CIV1. JV^_S N	A, 40, 297	59	415.9 (M⁺+l) ?	415.02 for Ci₉Hi₄C1N₃o₂s₂	’H NMR (DMSO-î/_6;400 MHz): δ 10.91 (s, 1H), 9.20 (t, J = 5.9 Hz, 1H), 7.717.64 (m, 3H), 7.627.55 (m, 3H), 7.49 (s, 1H), 4.55 (d, J = 5.7 Hz, 2H), 2.57 (s, 3H);
1760	0 %-NH p N X^A-OH	A^d, 40, 357	12	493.9 (M⁺+l) 5	493.03 for C₂₄Hi₆C1N₃o₃s₂	‘η-NMR (DMSO-î/₆, 400 MHz): δ 10.93 (br s, 1H), 9.95 (br s, 1H), 9.27 (t, J = 5.7 Hz, 1H), 7.74-7.60 (m, 7H), 7.57 (s, 2H), 6.83 (d, J = 8.7 Hz, 2H), 4.62 (d, J = 5.6 Hz, 2H);
1544	0 _ A™ P fi I; -^= Cl' ^H [F ÀcH, N	A, 47, 297	57	415.9 (M⁺+l) 5	415.02 for Ci₉Hi₄C1N₃ O₂s₂	‘H-NMR (DMSO-4 400 MHz): δ 10.86 (s, 1H), 9.20 (t, J = 5.7 Hz, 1H), 7.717.64 (m, 4H), 7.627.58 (m, 1H), 7.54 (dd, J = 8.4, 2.1 Hz,

-297-

						1H), 7.49 (s, 1H), 4.55 (d, J = 5.7 Hz, 2H), 2.57 (s, 3H);
1761	N ^/-OH	A, 47, 357	12	494.0 (M⁺+l)	493.03 for C₂₄Hi₆C1N₃ O₃s₂	*H-NMR (DMSO-rfe 400 MHz): δ 10.86 (s, 1H), 9.94 (s, IH), 9.25 (t, J = 5.9 Hz, IH), 7.71 (dd, J = 6.4, 1.8 Hz, 2H), 7.68 (s, 2H), 7.677.60 (m, 4H), 7.53 (dd, J = 8.3, 2.1 Hz, IH), 6.83 (d, J = 8.7 Hz, 2H), 4.62 (d, J = 5.6 Hz, 2H);
1772	cbk ¹¹ U />— rr 0 'N^³	A^a, 89, 255	54	451.9 (M⁺+l) 5	451.03 for Ci₉H₁₂F₃N₃ O₃S₂	'H-NMR (DMSO-J₆, 400 MHz): δ 11.06 (s, IH), 9.46 (t, J = 5.8 Hz, IH), 8.05 (s, IH), 7.88 (dd, J = 8.2, 1.5 Hz, IH), 7.84-7.77 (m, 2H), 7.76-7.68 (m, 3H), 7.63 (td, J = 7.5, 1.3 Hz, IH), 4.72 (d, J = 5.6 Hz, 2H);
1526	0 ¹¹ l x)—rw	A, 89, 297	21	397.9 (M⁺+l) 5	397.06 for Ci₉H₁₅N₃O₃s₂	‘H-NMR (DMSO-î7₆, 400 MHz): δ 11.05 (s, IH), 9.26 (t, J = 5.7 Hz, IH), 7.85 (dd, J = 8.3, 1.5 Hz, IH), 7.80 (dd, J = 7.6, 3.9 Hz, 2H), 7.76-7.67 (m, 3H),

- 298 -

						7.63 (td, J = 8.4, 1.1 Hz, 1H), 7.49 (s, 1H), 4.56 (d, J= 5.7 Hz, 2H), 2.56 (s, 3H);
1528	0 CW/, o'h	A, 92, 297	33	413.9 (M⁺+l) 7	413.05 for C₁₉H₁₅N₃O₄S₂	¹ H-NMR (DMSO-4 400 MHz): δ 11.50 (br s, 1H), 9.37 (t, J = 5.7 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.82 (m, 3H), 7.78 (dd, J= 8.3, 1.4 Hz, 1H), 7.50 (s, 1H), 4.58 (d, J = 5.6 Hz, 2H), 2.57 (s, 3H);
1529	0“θ ^ν^ΝΗ2	A, 92, 230	22	414.9 (M⁺+l) 7	414.05 for Ci₈Hi₄N₄O₄s₂	¹ H-NMR (DMSO-î/î, 400 MHz): 11.49 (br s, 1H), 9.18 (t, J = 5.4 Hz, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.98 (td, J = 7.3, 1.0 Hz, 2H), 7.93-7.81 (m, 3H), 7.77 (dd, J = 8.3,1.3 Hz, 1H), 6.80 (s, 1H), 6.79 ( br s, 2H), 4.38 (d, J= 5.5 Hz, 2H);
1525	0 oM. o'o S^^N O	A, 92, 291	32	475.9 (M⁺+l) 7	475.07 for C₂₄H₁₇N₃O₄s₂	¹ H-NMR QMSO-4 400 MHz): δ 11.52 (s, 1H), 9.47 (t, J = 5.7 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.98

-299 -

						(td, J = 7.6, 1.0 Hz, 2H), 7.93-7.79 (m, 7H), 7.54-7.39 (m, 3H), 4.69 (d, J = 5.6 Hz, 2H);
1550	0 Xnh P C// o”b //-	A, 92, 277	26	455.9 (M⁺+l)	455.10 for C22H21N3O4 s₂	’H-NMR (DMSO/, 500 MHz): δ 11.50 (s, 1H), 9.38 (t, J = 5.8 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 8.00-7.96 (m, 2H), 7.90 (td, J = 7 A, 1.3 Hz, 1H), 7.88-7.83 (m, 2H), 7.80 (dd, J = 8.2, 1.3 Hz, 1H), 7.54 (s, 1H), 4.60 (d, J = 5.8 Hz, 2H), 1.33 (s, 9H);
1551	0 dhk	A, 92, 239	42	427.9 (M⁺+l) 5	427.07 for C₂₀Hi₇N₃O4 s₂	‘H-NMR (DMSO-îZ₆, 500 MHz): δ 11.52 (s, 1H), 9.40 (t, J = 5.8 Hz, 1H), 8.04 (d, J= 8.4 Hz, 1H), 7.97 (t, J = 8.4 Hz, 2H), 7.90 (t, J = 7.1 Hz, 1H), 7.87-7.81 (m, 2H), 7.78 (d, J = 8.1 Hz, 1H), 7.53 (s, 1H), 4.58 (d, J= 5.8 Hz, 2H), 2.89 (q, J = 7.5 Hz, 2H), 1.23 (t, J=7.5Hz, 3H);

-300 -

1552	0 / ^NH i? V Λ ^NX-s H V^S\ /	A, 92, 251	34	441.9 (M⁺+l) 9	441.08 for C21H19N3O4 s₂	“H-NMR (DMSO-7₆, 400 MHz): δ 11.50 (s, 1H), 9.38 (t, J = 5.8 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.82 (m, 3H), 7.79 (dd, J = 8.3, 1.6 Hz, 1H), 7.54 (s, 1H), 4.60 (d, J = 5.7 Hz, 2H), 3.24-3.15 (m, 1H), 1.27 (d, J = 6.9 Hz, 6H);
1553	0 / ^NH /? ί x Jî n^x _s o'b îî_n^cf₃	A, 92, 255	16	468.3 (M⁺+l) 9	467.02 for C19H12F3N3 O4S2	‘H-NMR (DMSO-7₆, 400 MHz): δ 11.50 (s, 1H), 9.56 (t, J = 5.6 Hz, 1H), 8.088.04 (m, 2H), 7.98 (td, J = 7.7, 0.9 Hz, 2H), 7.94-7.83 (m, 3H), 7.81 (dd, J = 8.2, 1.4 Hz, 1H), 4.75 (d, J = 5.5 Hz, 2H);
1566	,fÇ O' \ Z zz i	A, 92, 285	34	486.9 (M⁺+l) 9	486.10 for C₂7Hi₉FN₂O ₄S	‘H-NMR (DMSO-7₆, 400 MHz): δ 11.52 (s, 1H), 9.31 (t, J = 5.7 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.82 (m, 4H), 7.66 (dd, 7 = 8.8, 5.5 Hz, 2H), 7.59-7.56 (m, 1H), 7.52 (d, 7 =

- 301 -

						7.8 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.32-7.25 (m, 3H), 4.54 (d, J = 5.9 Hz, 2H);
1584	Of-s-JjC' /=, N(CH_s)₂	A, 92, 360	47	563.0 (M+l) 5	562.13 for C28H26N4O5 s₂	’H NMR (DMSO-d_6;400 MHz): δ 11.52 (br s, 1H), 9.47 (t, J = 5.4 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.98 (td, J = 7.5, 1.0 Hz, 2H), 7.90 (td, J= ΊΑ, 1.3 Hz, 1H), 7.87-7.82 (m, 3H), 7.80 (d, J = 8.9 Hz, 2H), 7.72 (s, 1H), 7.02 (d, J = 8.8 Hz, 2H), 4.66 (d, J= 5.5 Hz, 2H), 4.09 (t, J = 5.8 Hz, 2H), 2.63 (t, J=5.8Hz, 2H), 2.21 (s, 6H);
1595	0 Ynh p ° ° °^H	A, 92, 357	50	492.0 (M⁺+l) 5	491.06 for C24H17N3O5 s₂	*H NMR (DMSO-d_dj500 MHz): δ 11.51 (s, 1H), 9.94 (s, 1H), 9.43 (t, J = 5.8 Hz, 1H), 8.05 (d, J= 8.4 Hz, 1H), 8.00-7.96 (m, 2H), 7.90 (td, J = 7.5, 1.2 Hz, 1H), 7.87-7.83 (m, 2H), 7.81 (dd, J = 8.2, 1.3 Hz, 1H), 7.71-7.67 (m, 3H), 6.83 (d, J =

- 302 -

						8.4 Hz, 2H), 4.65 (d, J=5.5Hz, 2H);
1596	ο _oο. / v 1 Ο \ ζ τζ s ο 1 1	A, 92, 363	60	506.0 (M⁺+l) 9	505.08 for C25H19N3O5 s₂	*H NMR (DMSO-ri_6;500 MHz): δ 11.51 (s, 1H), 9.45 (t, J = 5.6 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.98 (t, J = 8.5 Hz, 2H), 7.93-7.78 (m, 6H), 7.72 (s, 1H), 7.02 (d, J=9.0Hz, 2H), 4.66 (d, J = 5.5 Hz, 2H), 3.80 (s, 3H);
1587		A, 92, 372	58	605.0 (M⁺+l) 9	604.15 for C₃oH₂sN406 s₂	*H NMR (DMSO-î/₆, 400 MHz): δ 11.51 (s, 1H), 9.44 (t, J = 5.7 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.00-7.96 (m, 2H), 7.90 (td, J = 7.5, 1.5 Hz, 1H), 7.87-7.77 (m, 5H), 7.72 (s, 1H), 7.03 (d, J = 8.9 Hz, 2H), 4.66 (d, J = 5.6 Hz, 2H), 4.14 (t, J = 5.7 Hz, 2H), 3.59-3.55 (m, 4H), 2.70 (t, J = 5.7 Hz, 2H), 2.48-2.46 (m, 4H);
1590	0 V— ΝΗ ο C ίΛ-s /1°¾ °° Q-s	A, 92, 288	36	502.9 (M⁺+l) 9	502.08 for C22H22N4O4 S3	'H-NMR (DMSO-ri₆, 500 MHz): δ 11.50 (br s, 1H), 9.39 (t, J = 5.5 Hz, 1H), 8.04

-303 -

						(d, J = 8.4 Hz, 1H), 7.97 (t, J = 8.1 Hz, 2H), 7.93-7.75 (m, 4H), 7.57 (s, 1H), 4.57 (d, J = 5.8 Hz, 2H), 3.29-3.25 (m, 2H), 2.55 (t, J = 6.9 Hz, 2H), 2.15 (s, 6H);
1628	Ο Οχ / ν’ ίω 1 V ΙΖ Y ο ζ	A, 92, 282	20	424.9 (M⁺+l) 5	424.03 for C19H12N4O4 s₂	‘H-NMR (DMSO-d₆, 400 MHz): δ 11.53 (s, 1H), 9.59 (t, J = 5.4 Hz, 1H), 8.14 (s, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.98 (t, J = 7.3 Hz, 2H), 7.947.83 (m, 3H), 7.80 (d, J = 8.3 Hz, 1H), 7.82-7.78 (m, 1H), 4.76 (d, J = 5.5 Hz, 2H);
1645	^à'°	A, 92, 312	40	519.0 (M⁺+l) 5	518.11 for C₂₆H₂₂N₄O₄S₂	^XH-NMR (DMSO-ri₆, 400 MHz): δ 11.51 (s, 1H), 9.41 (t, J = 5.6 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.98 (t, J = 8.7 Hz, 2H), 7.90 (t, J = 7.1 Hz, 1H), 7.87-7.79 (m, 3H), 7.68 (d, J= 9.0 Hz, 2H), 7.63 (s, 1H), 6.74 (d, J = 9.0 Hz, 2H), 4.63 (d, J = 5.8 Hz, 2H), 2.96 (s,

- 304 -

						6H);
1648	Ο /—ΝΗ ρ cxxyWs Α ^Η II V ο ο %	Α, 92, 307	21	498.0 (Μ⁺+1) 9	497.12 for C23H23N5O4 s₂	¹ H-NMR (DMSO-îZ₆, 400 MHz): δ 11.50 (s, 1H), 9.27 (t, J = 5.7 Hz, 1H), 8.077.75 (m, 7H), 7.04 (s, 1H), 4.44 (d, J = 5.6 Hz, 2H), 3.333.31 (m, 4H), 2.402.34 (m, 4H), 2.19 (s, 3H);
1650	¹ Οχ Γ ν 1 Ρ ΙΖ p? χ^^ω	Α, 92, 218	35	399.9 (Μ⁺+1) 9	399.03 for Ci₈H₁₃N₃O₄s₂	*H-NMR (DMSO-4 400 MHz): δ 11.53 (br s, 1H), 9.66-9.58 (m, 1H), 8.08 (d, J = 8.2 Hz, 1H), 8.027.96 (m, 2H), 7.947.82 (m, 4H), 7.73 (d, J = 3.2 Hz, 1H), 7.63 (d, J = 3.3 Hz, 1H), 4.75 (d, J = 6.1 Hz, 2H);
1679	σ^οΛ-γ	Α, 92, 367	24	577.1 (Μ⁺+1) 9	576.15 for C₂9H₂₈N4O5 S₂	’H NMR (DMSO-(/₆, 400 MHz): δ 11.52 (br s, 1H), 9.44 (t, J = 5.7 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 8.00-7.95 (m, 2H), 7.93- 7.84 (m, 3H), 7.83-7.77 (m, 3H), 7.72 (s, 1H), 7.00 (d, J =8.9 Hz, 2H), 4.66 (d, J = 5.5 Hz, 2H), 4.04 (t, J = 6.4 Hz,

- 305 -

						2H), 2.34 (t, J = 7.1 Hz, 2H), 2.13 (s, 6H), 1.89-1.80 (m, 2H);
1763	Ο ex / ίω 1 X ΙΖ Κ	A, 92, 219	89	427.9 (M⁺+l) 5	427.07 for C20H17N3O4 s₂	1 H-NMR (DMSOd6, 400 MHz): δ 11.50 (br s, 1H), 9.29 (t, J = 5.6 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.98 (td, J = 7.5, 0.9 Hz, 2H), 7.93-7.75 (m, 4H), 4.49 (d, J = 5.6 Hz, 2H), 2.50 (s, 3H), 2.30 (s, 3H);
1814	^{0 0} SCI/-™	A^b’ 92, 316	88	519.1 (M⁺+l) ?	518.05 for C₂₅H₁₅FN₄O 4S2	'H-NMR (DMSO-î/₆, 400 MHz): δ 11.47 ( br s, 1H), 9.53 (t, J = 5.7 Hz, 1H), 8.35 (t, J = 7.9 Hz, 1H), 8.11- 7.95 (m, 5H), 7.93-7.79 (m, 5H), 4.75 (d, J = 5.6 Hz, 2H);
1661	ο _οο. / χ ;ω 1 S ? ο I	A, 92, 369	24	505.9 (M⁺+l) 5	505.08 for C₂₅H₁₉N₃O5 s₂	¹ H-NMR (DMSO-r/ή, 500 MHz) (rotamers): δ 11.44 (br s, 1H), 10.00 (br s, 1H), 8.04-7.96 (m, 3H), 7.94-7.82 (m, 2H), 7.81-7.71 (m, 3H), 7.49-7.38 (m, 2H), 6.86 (d, J= 8.4 Hz, 2H), 4.82, 4.59

- 306 -

						(s, 2H), 2.95, 2.76 (s, 3 H);
1821	°° C//	A^b, 92, 319	29	531.1 (M⁺+l) 5	530.07 for C₂₆Hi₈N₄O₅s₂	‘H-NMR (DMSO-î/ô, 500 MHz): δ 11.52 (s, 1H), 10.60 (s, 1H), 9.45 (t, J = 5.3 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.017.94 (m, 2H), 7.937.79 (m, 5H), 7.72 (d, J = 3.5 Hz, 3H), 6.88 (d, J = 8.3 Hz, 1H), 4.66 (d, J = 5.1 Hz, 2H), 3.54 (s, 2H);
1823-A	etc/, o 0 /	A^c, 92, 326	32	520.1 (M⁺+l) 5	519.09 for C₂₆H₂iN₃O₅s₂	'H NMR (DMSO-/ 500 MHz): δ 11.48 (br s, 1H), 9.35 (t, J = 5.5 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.97 (t, J = 8.1 Hz, 2H), 7.92- 7.80 (m, 3H), 7.76 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.21 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.56 (d, J = 5.8 Hz, 2H), 4.16 (s, 2H), 3.71 (s, 3H);
1840	etM-vZ	A, 92, 338	19	548.1 (M⁺+l) 5	547.12 for C₂₈H₂₅N₃O₅S₂	^XH NMR (400 MHz, DMSO-/ δ 11.52 (s, 1H), 9.49 (t, J = 5.8 Hz, 1H), 8.06 (d, J= 8.3 Hz, 1H), 7.98

-307 -

						(td, J = 7.8, 1.3 Hz, 2H), 7.93-7.79 (m, 5H), 7.50 (dd, J = 7.5, 0.9 Hz, 1H), 7.45-7.37 (m, 2H), 7.34-7.29 (m, 1H), 5.00 (s, 1H), 4.70 (d, J = 5.6 Hz, 2H), 3.07 (s, 2H), 0.99 (s, 6H);
1882	Ο,ο Οχ / V 'ω 1 Ο'\ ζ ΙΖ X	A^b, 92, 345	29	483.0 (M⁺+l) 7	482.02 for C₂₁Hi₄N₄O₄s₃	‘H NMR (DMSO-tfy 400 MHz): δ 11.51 (s, 1H), 9.50 (t, J = 5.6 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.01-7.94 (m, 3H), 7.93-7.78 (m, 6H), 4.70 (d, J = 5.6 Hz, 2H);
1906	0 y— ^νη ο	A^c, 92, 488	9	497.0 (M⁺+l) 7	496.09 for C₂₃H₂oN₄Os s₂	'H NMR (400 MHz, DMSOV): δ 11.51 (s, 1H), 9.33 (t, J = 5.8 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 8.00-7.96 (m, 2H), 7.93-7.83 (m, 3H), 7.79 (dd, J = 8.3, 1.6 Hz, 1H), 7.13 (s, 1H), 4.47 (d, J= 5.6 Hz, 2H), 3.74 (t, J = 6.2 Hz, 4H), 2.482.45 (m, 4H);
1973	Ο >-ΝΗ Ο ΟΟΥ-γν -ν. ^{00 ν}	A, 92, 492	48	512.1 (M⁺+l) 7	511.10 for C₂₃H₂₁N₅O₅	‘H NMR (400 MHz, DMSOV): δ 11.51 (s, 1H), 9.28 (t, J =

- 308 -

					S₂	5.8 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.94-7.83 (m, 3H), 7.79 (dd, J = 8.3, 1.5 Hz, 1H), 7.67 (t, J = 5.3 Hz, 1H), 7.03 (s, 1H), 4.45 (d, J = 5.5 Hz, 2H), 3.65-3.53 (m, 4H), 3.34-3.29 (m, 2H), 3.23-3.17 (m, 2H);
1927	àbX cTo	A, 92, 500	40	499.0 (M⁺+l) 9	498.10 for C₂₃H₂₂N₄O₅S2	‘H-NMR (DMSO-î/₆, 400 MHz): δ 11.51 (s, 1H), 9.39 (t, J = 5.6 Hz, 1H), 8.05 (br d, J = 8.2 Hz, 1H), 7.98 (t, J = 7.0 Hz, 2H), 7.93-7.77 (m, 4H), 7.57 (s, 1H), 4.61 (br d, J = 4.9 Hz, 2H), 3.73 (s, 2H), 3.59-3.54 (m, 4H), 2.47- 2.43 (m, 4H);
1885-A	O ^-NH 0 o'b s^^N ^/^NHBoc	A, 92, 534	25	612.1 (M⁺+l) 9	611.19 for C₂9H₃₃N5Oè s₂	1H NMR (DMSOd6, 400 MHz): δ 11.50 (s, 1H), 9.38 (t, J=5.7 Hz, 1H), 8.05 (d, J=8.3 Hz, 1H), 7.98 (dt, J = 7.5, 1.0 Hz, 2H), 7.94-7.82 (m, 3H), 7.79 (dd, J= 8.3, 1.5

-309 -

						Hz, IH), 7.55 (s, IH), 6.74 (d, J=7.5 Hz, IH), 4.60 (d, J=5.6 Hz, 2H), 3.69 (s, 2H), 3.26-3.08 (m, 2H), 2.84-2.75 (m, 2H), 2.15-2.04 (m, 2H), 1.74-1.60 (m, 2H), 1.43-1.33 (m, HH);
1929	cfe-K 0 0 S A'	A^c, 92, 332	19	503.7 (M⁺+l) 9	503.06 for C₂₅H₁₇N₃O5 S₂	¹ H-NMR (DMSO-î7₆, 400 MHz): δ 11.52 (s, IH), 9.57 (t, J = 5.8 Hz, IH), 8.368.30 (m, 2H), 8.12 (s, IH), 8.07 (d, J = 8.3 Hz, IH), 7.98 (td, J =7.5 , 1.1 Hz, 2H), 7.93-7.80 (m, 4H), 7.74-7.69 (m, IH), 7.61- 7.53 (m, 2H), 4.78 (d, J = 5.6 Hz, 2H);
1957	Ο /—ΝΗ ρ	A^c, 92, 508	26	467.0 (M⁺+l) 9	466.04 for C₂iH₁₄N₄O₅s₂	'H-NMR (DMSO-î/₆, 400 MHz): δ H.51 (s, IH), 9.51 (br t, J = 5.5 Hz, IH), 8.55 (s, IH), 8.06 (d, J = 8.3 Hz, IH), 8.017.95 (m, 2H), 7.937.77 (m, 6H), 4.70 (br d, J = 5.5 Hz, 2H);

- 310 -

1958	? zi À 1 ωί A / ^xo ° 07	A^c, 92, 512	48	466.9 (M⁺+l) 5	466.04 for C₂iH₁₄N₄O₅s₂	¹ h-nmr (dmso-4 400 MHz): δ 11.51 (s, 1H), 9.52 (t, J = 5.7 Hz, 1H), 8.31 (s, 1H), 8.06 (d, J= 8.3 Hz, 1H), 7.98 (td, J= 7.4, 1.0 Hz, 2H), 7.95-7.88 (m, 2H), 7.87-7.79 (m, 3H), 7.45 (s, 1H), 4.72 (d, J=5.6Hz, 2H);
1991	O / ^NH 1? ci _s MaA® ^H F^SV ®=Λ ^^-NHAc	A^c, 92, 408	44	591.4 (M⁺+l)	590.13 for c₂₉h₂₆n₄o₆S₂	‘H-NMR (DMSO-ô/₆, 400 MHz): δ 11.51 (s, 1H), 9.45 (t, J = 5.6 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.03-7.95 (m, 3H), 7.93-7.84 (m, 3H), 7.84-7.78 (m, 3H), 7.72 (s, 1H), 7.01 (dd, J = 8.9, 2.2 Hz, 2H), 4.66 (d, J = 5.5 Hz, 2H), 4.06-4.01 (m, 2H), 3.28-3.14 (m, 2H), 1.91-1.81 (m, 2H), 1.79 (s, 3H);
1992	° ° V_lZ °	A^c92, 375	45	617.1 (M⁺+l) 5	616.18 C₃₂H₃₂N₄O₅s₂	'H-NMR (DMSO-c/₆, 400 MHz): δ 11.52 (br s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.98 (td, J =7.5, 1.0 Hz, 2H), 7.93-7.79

-311 -

						(m, 6H), 7.72 (s, 1H), 7.02 (d, J = 8.9 Hz, 2H), 4.66 (d, J = 5.5 Hz, 2H), 4.08 ( t, J = 5.9 Hz, 2H), 3.04-2.70 (m, 4H), 2.30-2.14 (m, 2H), 2.12-1.93 (m, 2H), 1.75-1.18 (m, 6H);
1993	ο Υνη ,? fx xyA-x-s H Y-S. ^^NO°	A, 92, 378	35	619.3 (M⁺+l) 5	618.16 C31H30N4O6 s₂	*H-NMR (DMSO-X 400 MHz): δ 11.51 (s, 1H), 9.44 (t, J = 5.8 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.92-7.84 (m, 3H), 7.84-7.77 (m, 3H), 7.72 (s, 1H), 7.01 (d, J = 9.0 Hz, 2H), 4.66 (d, J = 5.6 Hz, 2H), 4.06 (t, J = 6.4 Hz, 2H), 3.59-3.53 (m, 4H), 2.41 (t, J = 7.2 Hz, 2H), 2.37-2.33 (m, 4H), 1.92-1.84 (m, 2H);
1994	O-O-o^'	A^c, 92, 383	38	645.0 (M⁺+l) 5	644.14 for C₃oH₂7F₃N4 o₅s₂	'H-NMR (DMSO-X 400 MHz): δ 11.51 (br s, 1H), 9.44 (t, J = 5.6 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.98 (td, J= 7.5, 0.8 Hz, 2H), 7.93-7.84 (m, 3H), 7.84-7.78

-312-

						(m, 3H), 7.72 (s, 1H), 7.00 (d, J= ΚΠ Hz, 2H), 4.66 (d, J = 5.5 Hz, 2H), 4.04 (t, J =6.2 Hz, 2H), 3.18 (q, J = 10.1 Hz, 2H), 2.67 (t, J = 7.0 Hz, 2H), 2.37 (s, 3H), 1.91-1.83 (m, 2H);
1998	ΟΗ	A^b, 92, 411	71	637.1 (M⁺+l) 9	636.17 for C31H32N4O7 s₂	'H-NMR (DMSO-î/₆, 400 MHz): δ 11.34 (br s, 1H), 9.45 (t, J = 5.8 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.98 (td, J = 7.4, 1.1 Hz, 2H), 7.93-7.84 (m, 3H), 7.84-7.77 (m, 3H), 7.72 (s, 1H), 7.01 (d, J = 8.9 Hz, 2H), 4.66 (d, J = 5.5 Hz, 2H), 4.424.25 (m, 2H), 4.06 (t, J = 6.4 Hz, 2H), 3.41 (t, J = 6.2 Hz, 4H), 2.61 (t, J = 6.8 Hz, 2H), 2.55-2.51 (m, 4H), 1.83 (p, J = 6.7 Hz, 2H);
11047	°'°	A^c, 92, 458 A	39	467.0 (M⁺+l) 9	466.05 for C20H14N6O4 s₂	'H-NMR (DMSO-ris, 400 MHz): δ 11.52 (s, 1H), 9.56 (t, J = 5.7 Hz, 1H), 8.85 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.03 (s,

-313 -

						1H), 7.98 (dd, J = 7.5, 1.2 Hz, 2H), 7.93-7.80 (m, 4H), 7.76 (s, 1H), 4.68 (d, J = 5.6 Hz, 2H);
11048	0 / ^NH /? o b kr ^N. /	A^c, 92, 458 B	23	467.0 (M⁺+l) ?	466.05 for C20H14N6O4 s₂	'H-NMR (DMSO-X 400 MHz): δ 11.51 (s, 1H), 9.52 (t, J = 5.6 Hz, 1H), 8.22 (s, 2H), 8.06 (d, J = 8.2 Hz, 1H), 7.98 (td, J= 7.6, 1.1 Hz, 2H), 7.93 -7.79 (m, 4H), 7.67 (s, 1H), 4.66 (d, 7= 5.6 Hz, 2H);
11053	°”° VaJh ^NEl;	A^c, 92, 476	41	603.20 (M⁺+l) 9	602.20 for C32H34N4O4 s₂	'H-NMR (DMSO-7₆, 400 MHz): δ 11.50 (br s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.06 (d, 7 = 8.1 Hz, 1H), 8.00-7.96 (m, 2H), 7.93-7.74 (m, 7H), 7.29 (d, 7 = 8.1 Hz, 2H), 4.68 (d, 7= 5.2 Hz, 2H), 2.62 (t, 7 = 7.5 Hz, 2H), 2.462.33 (m, 6H), 1.58 (p, J ⁼ 7.5 Hz, 2H), 1.44-1.36 (m, 2H), 0.92 (t, J = 7.0 Hz, 6H);
11054	Xk H	A^c, 92, 471	23	603.20 (M⁺+l) 9	602.20 for C32H34N4O4 s₂	‘H-NMR (DMSO-7₆, 400 MHz): δ 9.45 (t, 7= 5.6 Hz, 1H), 8.04

- 314 -

						(d, J = 8.3 Hz, 1H), 7.97 (td, J= 7.9, 1.3 Hz, 2H), 7.92-7.75 (m, 7H), 7.29 (d, J = 8.3 Hz, 2H), 4.67 (d, J= 5.5 Hz, 2H), 2.61 (t, J = 7.6 Hz, 2H), 2.54-2.44 (m, 3H), 1.62 (p, J = 7.7 Hz, 2H), 1.37 (td, J = 15.0, 7.3 Hz, 2H), 1.00 (s, 9H);
11055	°'^b	A^c, 92, 474	53	615.1 (M⁺+l) 5	614.20 for C33H34N4O4 s₂	^-NMR (DMSO-4 400 MHz): δ 11.50 (br s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.98 (td, J = 7.6, 1.1 Hz, 2H), 7.93-7.76 (m, 7H), 7.29 (d, J = 8.2 Hz, 2H), 4.68 (d, J = 5.6 Hz, 2H), 2.61 (t, J = 7.5 Hz, 2H), 2.30-2.19 (m, 6H), 1.57 (p, J = 7.5 Hz, 2H), 1.49-1.31 (m, 8H);
11056	ο %- ΝΗ Ο γχ η γ-s ^ο“° Ο	A, 92, 468	8	617.1 (Μ⁺+1) 5	616.18 for C3₂H3₂N4Os S₂	Ή NMR (400 MHz, DMSO-û^): δ 11.52 (s, 1H), 9.46 (t, J = 5.6 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.88 (m, 1H),

-315 -

						7.87-7.76 (m, 6H), 7.29 (d, J = 8.1 Hz, 2H), 4.68 (d, J= 5.5 Hz, 2H), 3.53 (t, J = 4.4 Hz, 4H), 2.62 (t, J = 7.5 Hz, 2H), 2.35-2.22 (m, 6H), 1.65-1.53 (m, 2H), 1.49-1.37 (m, 2H);
11057	ο ΝΗ ρ ci A-NHAc	A, 92, 480	26	589.1 (M⁺+l) 9	588.15 for C30H28N4O5 s₂	'H-NMR (DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.98 (td, J = 1.1, 7.5 Hz, 2H), 7.90 (td, J = 7.5, 1.4 Hz, 1H), 7.87-7.75 (m, 7H), 7.29 (d, J = 8.2 Hz, 2H), 4.68 (d, J = 5.5 Hz, 2H), 3.07- 3.00 (m, 2H), 2.61 (t, J = 7.6 Hz, 2H), 1.77 (s, 3H), 1.57 (td, J = 15.1, 7.6 Hz, 2H), 1.39 (p, J = 7.3 Hz, 2H);
11073	0 V ΝΗ ρ °'° χα/ο ^NEt₂	A^c, 92, 389	12	605.1 (M⁺+l) 9	604.18 for C31H₃2N₄O₅s₂	‘H NMR (400 MHz, Acetic acid): δ 8.16 (d, J = 8.7 Hz, 1H), 8.11-8.08 (m, 2H), 7.93-7.88 (m, 3H), 7.87-7.79 (m, 4H), 7.03 (d, J = 9.0 Hz,

- 316 -

						2H), 4.87 (s, 2H), 4.18 (t, J = 5.7 Hz, 2H), 3.46-3.22 (m, 6H), 2.34-2.23 (m, 2H), 1.35-1.28 (m, 6H);
11080	ο /—ΝΗ Ο ΟΟΟΛ-ν^	Α, 92, 402	18	591.1 (Μ⁺+1) 9	590.17 for C30H30N4O5 S₂	‘H-NMR (DMSO-î/₆, 400 MHz): δ 11.47 (m, 1H), 9.44 (t, J = 5.7 Hz, 1H), 8.17 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.98 (t, J = Ί.6 Hz, 2H), 7.937.76 (m, 6H), 7.72 (s, 1H), 7.00 (d, J = 8.7 Hz, 2H), 4.66 (d, J = 5.5 Hz, 2H), 4.57 (q, J = 5.5 Hz, 1H), 2.38 (t, J = 7.2 Hz, 2H), 2.17 (s, 6H), 1.87-1.66 (m, 2H), 1.26 (d, J = 6.0 Hz, 3H);
11091	ο /—ΝΗ P ° °	B^a, 92, 414	55	605.1 (Μ⁺+1) 9	604.18 for C₃1H₃₂N₄O₅s₂	*H NMR (400 MHz, DMSO-î/ô): δ 11.50 (br s, 1H), 9.44 (t, J = 5.8 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.98 (td, J = 7.5, 1.1 Hz, 2H), 7.92-7.84 (m, 3H), 7.83-7.76 (m, 3H), 7.72 (s, 1H), 7.00 (d, J = 8.8 Hz, 2H), 4.66 (d, J =

-317-

						5.5 Hz, 2Η), 4.04 (t, J = 6.3 Hz, 2H), 2.79-2.73 (m, 1H), 2.48-2.41 (m, 2H), 2.13 (s, 3H), 1.851.78 (m, 2H), 0.92 (d, J =6.5 Hz, 6H);
11092	ο Y- ΝΗ ο °“° νχ/ο \	Β\ 92, 417	37	603.2 (M⁺+l) 9	602.17 for C31H30N4O5 S₂	^!H NMR (400 MHz, CD3COOD): δ 8.14 (d, J = 8.5 Hz, 1H), 8.10-8.07 (m 2H), 7.93-7.86 (m, 3H), 7.86-7.78 (m, 4H), 7.02 (d, J = 8.8 Hz, 2H), 4.86 (s, 2H), 4.16 (t, J = 5.8 Hz, 2H), 3.57-3.48 (m, 2H), 3.03 (s, 3H), 2.81-2.76 (m, 1H), 2.43-2.32 (m, 2H), 1.33-1.22 (m, 2H), 0.94-0.92 (m, 2H);
11093	θ° \	A, 92, 482	13	603.1 (Μ⁺+1) 9	602.20 C32H34N4O4 s₂	Ή NMR (500 MHz, DMSO-ri_à): δ 11.50 (br s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.99-7.77 (m, 9H), 7.29 (d, J = 8.1 Hz, 2H), 4.68 (d, J = 5.8 Hz, 2H), 2.76-2.68 (m, 1H), 2.65-2.57 (m, 2H), 2.30 (t, J = 7.2 Hz, 2H), 2.05 (s,

-318 -

						3H), 1.61-1.54 (m, 2H), 1.41-1.36 (m, 2H), 0.90 (d, J= 7.0 Hz, 6H);
11099	o° N'' /	A^c, 92, 448	41	565.6 (M⁺+l)	564.16 for C27H28N6O4 s₂	^lH-NMR (DMSO/, 400 MHz): δ 11.48 (br s, 1H), 9.45 (t, J = 5.7 Hz, 1H), 8.22 (s, 1H), 8.05 (d, J = 8.3 Hz, 1H), 8.007.95 (m, 2H), 7.937.83 (m, 3H), 7.80 (dd, J = 8.3, 1.6 Hz, 1H), 7.68 (s, 1H), 7.50 (s, 1H), 4.59 (d, J = 5.6 Hz, 2H), 2.48-2.45 (m, 2H), 2.21 (t, J = 7.2 Hz, 2H), 2.10 (s, 6H), 1.55 (p, J = 7.5 Hz, 2H), 1.46-1.36 (m, 2H);
11100	dx/ NEt₂	A, 92, 448 A	38	593.1 (M⁺+l) 5	592.19 for C29H32N6O4 s₂	'H NMR (400 MHz, DMSO/): δ 11.56 (br s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.22 (s, 1H), 8.05 (d, J 8.2 Hz, 1H), 8.017.95 (m, 2H), 7.927.77 (m, 4H), 7.68 (s, 1H), 7.50 (s, 1H), 4.59 (d, J = 5.6 Hz, 2H), 3.30-3.14 (m, 8H), 1.58-1.51 (m,

-319 -

						2H), 1.45-1.36 (m, 2H), 0.93 (t, J = 7.0 Hz, 6H);
moi	àbm °°	A, 92, 419	32	619.1 (M⁺+l) 9	618.20 for C₃2H₃4N₄O₅S₂	*H NMR (400 MHz, CD₃COOD): δ 8.15 (d, J = 8.9 Hz, IH), 8.11-8.06 (m, 2H), 7.93-7.88 (m, 3H), 7.86-7.77 (m, 4H), 7.03 (d, J = 8.9 Hz, 2H), 4.87 (s, 2H), 4.73-4.63 (m, IH), 3.43-3.22 (m, 6H), 2.26-2.15 (m, 2H), 1.37 (d, J = 6.0 Hz, 3H), 1.35-1.30 (m, 6H);
H 102	O Vnh O .a-	A^c, 92, 406	14	631.1 (M⁺+l) 9	630.12 for C2₉H25F₃N₄O5S₂	'H NMR (400 MHz, DMSO-t4): δ 11.52 (s, IH), 9.45 (t, J = 5.8 Hz, IH), 8.06 (d, J = 8.4 Hz, IH), 8.00-7.98 (m, 2H), 7.92-7.79 (m, 6H), 7.72 (s, IH), 7.01 (d, J = 8.9 Hz, 2H), 4.66 (d, J = 5.5 Hz, 2H), 4.07 (t, J = 6.3 Hz, 2H), 3.27-3.17 (m, 2H), 2.76 (s, 2H), 1.90-1.83 (m, 2H);
11105	O / ^NH 9 ci ΛΑ-γ _sh v^s. o'o s. r—<\ \ N VjZ ° ^0	A, 92, 411	10	589.1 (M⁺+l)	588.15 for C₃qH28N₄O5 S₂	'H NMR (400 MHz, DMSO-c/₆): δ 11.52 (br s, IH), 9.46 (t, J

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						= 5.8 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.99-7.95 (m, 2H), 7.93-7.77 (m, 6H), 7.71 (s, 2H), 7.00 (d, J = 8.8 Hz, 2H), 4.65 (d, J = 5.5 Hz, 2H), 4.04-4.01 (m, 2H), 3.48-3.35 (m, 4H), 2.78-2.69 (m, 2H), 2.10-2.02 (m, 2H), 1.81-1.71 (m, 2H);
11116	να COOEt	A^c, 92, 461	45	538.0 (M⁺+l)	537.08 for C₂₄Hi₉N₅O₆s₂	¹ H-NMR (DMSO-J₆, 400 MHz): δ 11.47 (br s, 1H), 9.51 (t, J = 5.6 Hz, 1H), 8.84 (s, 1H), 8.21 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.00-7.95 (m, 2H), 7.93-7.77 (m, 4H), 7.63 (s, 1H), 4.64 (d, J = 5.5 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.0 Hz, 3H);
11112	0 / ^NH /9 (IXYn^ '—NMe₂	A^b, 92, 431	17	603.1 (M⁺+l)	602.17 for C₃iH₃₀N₄O₅S₂	’H NMR (400 MHz, DMSOV): δ 11.52 (s, 1H), 9.46 (t, J = 5.6 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.77 (m, 6H), 7.72 (s, 1H), 7.00 (d, J =8.9 Hz, 2H), 4.66

-321 -

						(d, J = 5.6 Hz, 2H), 3.90 (br s, 2H), 2.972.69 (m, 2H), 2.311.97 (m, 6H), 0.690.30 (m, 4H);
11113	ο / ^ΝΗ V cl χυα-^ _s ^Η /γ\ζ=\ ^Ο° NMe₂	A^b, 92, 439	61	617.1 (M⁺+l)	616.18 for C32H32N4O5 s₂	‘H NMR (400MHz, DMSO-riQ: δ 11.52 (br s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.99-7.94 (m, 2H), 7.92-7.83 (m, 3H), 7.83-7.78 (m, 3H), 7.71 (s, 1H), 7.04 (d, J = 8.8 Hz, 2H), 4.65 (d, J = 5.6 Hz, 2H), 4.07 (br s, 2H), 2.572.51 (m, 1H), 2.462.29 (m, 2H), 2.272.06 (m, 4H), 2.021.79 (m, 7H);
11118	0 /—ΝΗ Ο CO₂Et	A^c, 92, 451	27	564.1 (M⁺+l) 5	563.09 for C₂₆H2iN₅O₆s₂	’H NMR (400 MHz, DMSO-<): δ 11.51 (s, 1H), 9.48 (t, J = 5.7 Hz, 1H), 8.89 (s, 1H), 8.31 (s, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.00-7.79 (m, 6H), 7.62 (s, 1H), 7.59-7.57 (m, 1H), 6.56 (d, J = 16.1 Hz, 1H), 4.62 (d, J = 5.4 Hz, 2H), 4.19-4.14 (m, 2H), 1.24 (t, J =

-322 -

						7.1 Hz, 3H);
11142	° ° ΥΥο Yo	A^b, 92, 422	48	635.1 (M⁺+l)	588.15 for C30H28N4O5 s₂	*H NMR (400 MHz, DMSO-d₆): δ 11.52 (s, 1H), 9.45 (t, J = 5.8 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.00-7.96 (m, 2H), 7.92-7.77 (m, 6H), 7.72 (s, 1H), 7.00 (d, J = 8.9 Hz, 2H), 4.66 (d, J = 5.5 Hz, 2H), 4.04 (t, J = 6.3 Hz, 2H), 2.70-2.55 (m, 8H), 2.47-2.45 (m, 2H), 1.89-1.83 (m, 2H);
1901-A	0 / ^NH /9 ex ly^s H W Z=\ r/'o OMe t* -z~~v \ ^{U U CN}	A^c, 120, 227	57	531.1 (M⁺+l) 5	530.07 for C2₆Hi₈N₄O₅s₂	1H-NMR (DMSOd6, 400 MHz): δ 11.25 (br s, 1H), 9.07 (t, J = 6.0 Hz, 1H), 8.07 (d, J = 8.5 Hz, 2H), 8.01-7.82 (m, 7H), 7.66 (s, 1H), 7.51 (s, 1H), 4.70 (d, J = 5.6 Hz, 2H), 3.94 (s, 3H);
1768	çl° o, / v '(Λ 1 f O	A, 95 357	12	506.1 (M⁺+l) 9	505.08 for C2₅Hi₉N₃O₅s₂	’H-NMR (DMSO-X 400 MHz): δ 10.86 (br s, 1H), 10.00 (br s, 1H), 9.17 (br s, 1H), 7.98-7.77 (m, 5H), 7.75-7.65 (m, 3H), 7.35 (d, J = 7.2 Hz, 1H), 6.85 (d, J =

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						7.9 Hz, 2H), 4.60 (br s, 2H), 2.32 (br s, 3H);
1877	Ο /-νη / Ρ ϊ A N-X-S ^η 7%^ ° °	Α, 95, 227	68	515.1 (M⁺+l)	514.08 for C26H18N4O4 S₂	‘H-NMR (DMSO-4 500 MHz): δ 10.85 (s, 1H), 9.22 (t, J = 5.8 Hz, 1H), 8.08 (d, J = 8.1 Hz, 2H), 7.96-7.88 (m, 5H), 7.87-7.82 (m, 2H), 7.80-7.76 (m, 1H), 7.35 (d, J = 8.1 Hz, 1H), 4.67 (d, J= 5.8 Hz, 2H), 2.31 (s, 3H);
11046	ί Ϋ ^ζ S ζ \ „ο 1 «κ A / Ό ° <5	A^c, 92, 528	70	480.0 (M⁺+l) 5	479.07 for C22H₁₇N₅O₄S₂	1 H-NMR (DMSOd6, 400 MHz): δ 11.52 (br s, 1H), 9.43 (t, J = 5.7 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.97 (td, J = 8.4, 1.7 Hz, 2H), 7.92-7.81 (m, 3H), 7.81-7.77 (m, 2H), 7.70 (s, 1H), 6.66 (d, J = 2.3 Hz, 1H), 4.65 (d, J = 5.8 Hz, 2H), 3.87 (s, 3H);
11158	Ν— /	A^C, 92, 524 A	26	588.2 (Μ⁺+1) 9	587.17 for C₃qH29N5O₄s₂	'H NMR (400 MHz, DMSO< δ 11.52 (br s, 1H), 9.47 (t, J = 5.8 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H),

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						7.93 -7.77 (m, 7H), 7.36 (d, J = 8.2 Hz, 2H), 4.68 (d, J = 5.6 Hz, 2H), 3.62 (s, 2H), 3.39 (s, 2H), 2.87-2.85 (m, 3H), 2.03 (s, 6H);
11182	ΛνΧφ CN	A^C, 92, 440	37	585.1 (M⁺+l)	584.12 for C₃oH2₄N₄05 s₂	‘H NMR (400 MHz, DMSO-d₆): δ 11.52 (s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.00-7.96 (m, 2H), 7.93-7.78 (m, 6H), 7.74 (s, 1H), 7.09 (d, J = 8.9 Hz, 2H), 4.67 (d, J = 5.6 Hz, 2H), 4.32 (s, 2H), 2.432.40 (m, 2H), 2.312.21 (m, 2H), 2.172.01 (m, 2H);
11074	ώΧ, °“° ‘'N ^N\J	A^c, 95, 455	50	480.0 (M⁺+l) 3	479.07 for c₂₂h_I7n₅o₄s₂	'H-NMR (DMSO-X 400 MHz): δ 10.86 (s, 1H), 9.20 (t, J = 5.8 Hz, 1H), 8.47 (d, J = 2.3 Hz, 1H), 7.95-7.83 (m, 5H), 7.80 (td, J=, Ί.6, 1.5 Hz, 1H), 7.54 (s, 1H), 7.35 (d, J = 8.1 Hz, 1H), 6.62 (dd, J = 2.5, 1.8 Hz, 1H), 4.58 (d, J = 5.6 Hz, 2H), 2.32 (s, 3H);

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11077	0 Vnh / ο	A^c, 95, 354	57	491.08 (M⁺+l) 5	490.08 for C24H18N4O4 s₂	'H NMR (400 MHz, DMSO-d₆) δ 10.86 (br s, 1H), 9.21 (t, J = 5.3 Hz, 1H), 8.62 (d, J = 4.4 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.99-7.77 (m, 7H), 7.52-7.44 (m, 1H), 7.36 (d, J= 8.1 Hz, 1H), 4.67 (d, J = 5.6 Hz, 2H), 2.33 (s, 3H);
11041	0 V NH 0 à'b ^Et	A, 113, 255	37	496.0 (M⁺+l) 9	495.05 for C2iH₁₆F₃N₃O₄s₂	‘H NMR (DMSO-4 400 MHz): δ 11.37 (s, 1H), 9.31 (br t, J = 5.8 Hz, 1H), 8.06 (s, 1H), 8.00-7.94 (m, 2H), 7.92-7.81 (m, 3H), 7.30 (s, 1H), 4.73 (br d, J = 5.6 Hz, 2H), 2.752.63 (m, 2H), 1.07 (t, J=7.5Hz, 3H);
11042	O /—ΝΗ P ° ^{0 Et} ^N~V_jT--CN	A^c, 113 316	19	547.0 (M⁺+l) 9	546.08 for C₂7Hi₉FN₄O 4S2	‘H NMR (DMSO-d₆, 500 MHz): δ 11.15 (br s, 1H), 9.04 (br t, J=5.8 Hz, 1H), 8.15 (t, J = 8.1 Hz, 1H), 7.90 (br d, J = 11.0 Hz, 1H), 7.80-7.72 (m, 3H), 7.70-7.59 (m, 4H), 7.07 (s, 1H), 4.51 (br d, J = 5.8 Hz, 2H), 2.52-

-326 -

2.44 (m, 2H), 0.87 (t, J= 7.5 Hz, 3H);	'H NMR (400MHz, DMSO-î/₆): δ 11.18 (br s, 1H), 9.40 (t, J = 5.8 Hz, 1H), 8.06 (s, 1H), 8.02-7.93 (m, 3H), 7.90 (td, J = 7.5, 1.3 Hz, 1H), 7.84 (dd, J = 7.5, 1.7 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 4.75 (d, J=5.6Hz, 2H);	N 2 ¹¹ 22 22 N ΰ II 0 Ô N A CO „ ot <M II § '^ X X Y A S N g' ⁰⁰ , 2c A æ N FO O . i 0 ί r - Z t» 2 K - No ^,c m § » n ¹¹ B x < °° _ Q C'n 3- r~~ t- - I	‘H-NMR (DMSO-c?6, 400 MHz): δ 11.82 (br s, 1H), 9.47 (t, J = 5.5 Hz, 1H), 8.17 (s, 1H), 8.09-7.84 (m, 5H), 7.52 (s, 1H), 4.76 (br d, J = 5.3 Hz, 2H);
	500.98 for Ci₉HhC1F3 N3O4S2	552.01 for C25H14CIFN 4O4S2	535.01 for C2oHhF₆N₃ O₄s₂
	503.9 (M⁺+l) 9	553.0 (M⁺+l) 9	536.0 (M⁺+l) 9
	32	en	49
	- un uo < 2 P	- irl ·< CO — CO	A^a, 143, 255
	o'o %^cf₃	NO—— O 0	ob cf₃ <_n ^z?~^CF3
	11082	11083	1936

1558	1557	1734
ÇL_Oο' ι 7 ΙΖ	Çho O 1	HO-Z~\ N. ^h O O
Α, 149, 239	A, 149, 297	A, 200, 357 1
99	48	Œ
379.9 (Μ⁺+1) ?	1 365.8 (M⁺+l)	442.0 (M⁺+l) 5
379.10 for C20H17N3O3 S	I 365.08 for Ci₉Hi₅N₃O3 S	441.11 for C₂₅Hi₉N₃O3 S 1
'Η-NMR (DMSO/, 400 MHz): δ 10.62 (s, 1H), 9.12 (t, J = 5.6 Hz, 1H), 7.78 (dd, J = 7.5, 1.4 Hz, 1H), 7.69-7.58 (m, 3H), 7.52 (s, 1H),	‘H-NMR (DMSO-/ 400 MHz): δ 10.62 (s, 1H), 9.12 (t, J = 5.9 Hz, 1H), 7.78 (dd, J = 7.7, 1.7 Hz, 1H), 7.67 (s, 1H), 7.65-7.58 (m, 2H), 7.49 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.38-7.31 (m, 2H), 4.55 (d, J = 5.7 Hz, 2H), 2.57 (s, 3H);	^X 00 N )X UJ - Il m N K K O 01 χ xx 11 / ΙΛ CL II _ — T JL CL J> Il H- · · □ ω X J Ξ / 7, ç û-.· ? 4- ' ¹¹ to ¹¹ _o O 00 x; Lj 'J / Œ K A “ Il O N > -O / Il bo P N g /

-32719643

1561	1559
Œ Ο 1 ϊ ϊ Ή	ο 1 7 IZ
Α, 149, 285	A, 149, 251
00	h—‘
- ₊+ y μ- Ο X—✓	393.9 (M⁺+l) 9 i
445.09 for C₂₄Hi₆FN₃O ₃s	393.11 for C₂iHi9N₃O₃ S
‘η NMR (DMSO-ûQ 500 MHz): δ 10.64 (s, 1H), 9.22 (t, J = 4.8 Hz, 1H), 7.93 (dd, J = 8.0, 5.6 Hz, 2H), 7.78 (br s, 2H), 7.70 (s, 1H), 7.63 (d, J=3.5Hz, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.38-7.28 (m, 4H), 4.66 (d, J = 5.2 Hz, 2H);	I - ΰ F ^ς 7 > 7 F -F N K K Ui OJ Oi O> K ex θ' Çy y 00 II ω Çh ^Ό S y P* ù 9° “ 01 H II y § -JM, O 4^ >— <2 0 , _4^ 0C Z _z—_s p· A ¹¹ 7 M Q _ 7° £ m S y p. rf 7 o 3 2^ 5 ^{I J} ? 72 P N P >7 P- >7 N œ II S	7.41 (d, J = 8.3 Hz, 1H), 7.39-7.31 (m, 2H), 4.56 (d, J= 5.6 Hz, 2H), 2.90 (q, J = 7.5 Hz, 2H), 1.24 (t, J=7.5Hz, 3H);

- 328 19643

= £ ‘0 LZ£ ‘(HZ ‘ZH 8’9 = f ‘P) P9’P ‘(HZ ‘^) \£'L-6£'L ‘(Hl ‘ZH P’8 = f ‘P) ZVL ‘(HP ‘A* WL-QL'L ‘(Ht ‘ZH 6’9 = f ‘P) ZL'L ‘(Hl ‘ZH 9 5 = f ‘1) ΡΓ6 ‘(Hl ‘s) £9 01 2 :(zHA 009 VOSAd) ΉΑΝΉ]	% JOJ il-pgp	ζ (i+₊a) £'99P	PI	88Z ‘6PI ‘V	H 0 ²(^ero)n ^s f y Λ 0 HN— O	£191
•(HP M 8Z'£ -τε ε ‘(hp M £9'£ -89Ύ ‘(HZ ‘ZH Z’9 = Γ ‘P) £P‘P ‘(Hl ‘s) 90'Z ‘(HZ ‘m) WL -8£'L ‘(Ht ‘ZH p’8 = r‘p) OP® ‘(hz M IS'LS9’L ‘(Hl ‘s) 99'L ‘(Hl ‘ZH l'L=f ‘P) 8ZY ‘(Ht ‘ZH Z'9 = £ ‘1) Z0'6 ‘(Hl ‘s) Ζ9ΌΙ 2 :(ZHW 009 “VOS Ad) ΉΙΝΝ-Η,	S ^(ΑΝ°ΉΑ9 JQJ ΖΓ9ΕΡ	i (i+₊a) 6‘9£P	8P	P0£ ‘6PI ‘V	o^/ N. V Ί O O	1191
•(HZ ‘ZH 9’9 = Γ ‘P) P9’P ‘(HZ M 8Z'Z^_9£’Z ‘(HP M 8£Y-6PY ‘(HZ L9'L-£9'L ‘(Ht ‘s) 89'Z ‘(HZ M £L'L SEL ‘(HZ M P8’£ -88Y ‘(Hl ‘ZH Εξ = f ‘1) 81'6 ‘(Ht ‘s) 6901 2 :(zHA OOP WWd) ΗΑΝΉ,	S JOJOl’ZZP	ζ (l+₊A) £‘8ZP	9£	16Z ‘6PI ‘V	? JA ZI	Z991

- 6Z£19643

- 330 -

						6.9 Hz, 2H), 2.55 (t, J = 6.9 Hz, 2H), 2.15 (s, 6H);
1618	Ο Vnh P < -Z---(\ \_ N OH	A, 149, 357	34	444.0 (M⁺+l) 5	443.09 for C₂4H₁₇N₃O4 s	‘H-NMR (DMSO-V 500 MHz): δ 10.63 (s, 1H), 9.93 (s, 1H), 9.17 (t, J = 5.6 Hz, 1H), 7.78 (d, J= 6.7 Hz, 1H), 7.72-7.59 (m, 6H), 7.42 (d, J = 8.4 Hz, 1H), 7.387.31 (m, 2H), 6.83 (d, J = 8.7 Hz, 2H), 4.62 (d, J = 5.5 Hz, 2H);
1619		A, 149, 363	35	458.0 (M⁺+l) 5	457.11 for C₂₅H₁₉N₃O₄S	‘H-NMR (DMSO-V 500 MHz): δ 10.63 (s, 1H), 9.19 (t, J = 5.8 Hz, 1H), 7.82 (d, J = 8.7 Hz, 2H), 7.78 (dd, J = Ί.Ί, 1.6 Hz, 1H), 7.72-7.69 (m, 2H), 7.66-7.61 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.38-7.31 (m, 2H), 7.02 (d, J = 9.0 Hz, 2H), 4.64 (d, J=5.5Hz, 2H), 3.80 (s, 3H);
1621	O Vnh O	A, 149, 360	14	515.1 (M⁺+l) 5	514.17 for C₂₈H₂₆N₄O₄s	'H-NMR (DMSO-V 400 MHz): δ 10.61 (s, 1H), 9.17 (t, J = 5.3 Hz, 1H), 7.817.74 (m, 3H), 7.68

-331 -

						(d, J = 6.7 Hz, 2H), 7.61 (d, J = 7.5 Hz, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.36-7.29 (m, 2H), 7.01 (d, J = 8.4 Hz, 2H), 4.62 (d, J = 5.5 Hz, 2H), 4.11 (t, J = 5.5 Hz, 2H), 2.75-2.68 (m, 2H), 2.27 (br s, 6H);
1629	Ο ζτ Â 1 ο ο	Α, 149, 255	9	419.9 (Μ⁺+1) 5	419.06 for C19H12F3N3 O3S	'H-NMR (DMSO-X 400 MHz): δ 10.64 (s, 1H), 9.33 (t, J = 5.6 Hz, 1H), 8.05 (s, 1H), 7.78 (dd, J = 7.7, 1.6 Hz, 1H), 7.69 (s, 1H), 7.667.60 (m, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.39-7.31 (m, 2H), 4.72 (d, J = 5.6 Hz, 2H);
1698	0 Κνη ρ Χζ θ	Α, 149, 367	48	529.1 (Μ⁺+1) 3	528.18 for C₂₉H₂8N4O4 S	‘H NMR (DMSO-X 400 MHz): δ 10.63 (s, 1H), 9.19 (t, J = 5.8 Hz, 1H), 7.827.76 (m, 3H), 7.717.69 (m, 2H), 7.667.60 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.39-7.30 (m, 2H), 7.00 (d, J = 8.9 Hz, 2H), 4.63 (d, J= 5.7 Hz, 2H), 4.04 (t, J =

- 332 -

						6.5 Hz, 2H), 2.34 (t, J=7.1 Hz, 2H), 2.13 (s, 6H), 1.89-1.80 (m, 2H);
1769	0 / ^NH 9 CX ^N^s Αο'Ά h TA_	A^a, 149, 219	72	380.0 (M⁺+l) 9	379.10 for C20H17N3O3 S	'H-NMR (DMSO-4 500 MHz): δ 10.62 (s, IH), 9.04 (t, J = 5.6 Hz, IH), 7.78 (dd, J = Ί.Ί, 1.5 Hz, IH), 7.67-7.56 (m, 3H), 7.41 (d, J= 8.4 Hz, IH), 7.38-7.30 (m, 2H), 4.47 (d, J = 5.6 Hz, 2H), 2.542.50 (m, 3H), 2.30 (s, 3H);
1833	O />ÿ>^O O 1 zA° ό O	A^b, 149, 319	70	483.1 (M⁺+l) 9	482.51 for C₂₆Hi₈N₄O₄S	’H-NMR (DMSO-îZ₆, 500 MHz): δ 10.7410.46 (m, 2H), 9.20 (br s, IH), 7.82-7.58 (m, 6H), 7.47-7.29 (m, 4H), 6.88 (d, J = 7.2 Hz, IH), 4.64 (br s, 2H), 3.54 (br s, 2H);
1835-A	ctb^. IL J—x N \__ Cy 7°	A^C, 149, 326	32	472.1 (M⁺+l) 9	471.13 for C₂₆H₂₁N₃O₄s	'H NMR (500 MHz, DMSO-î/ô): δ 10.60 (s, IH), 9.09 (t, J = 5.5 Hz, IH), 7.797.76 (m, IH), 7.667.53 (m, 4H), 7.40 (d, J = 8.4 Hz, IH), 7.37-7.31 (m, 2H), 7.21 (d, J = 8.4 Hz,

- 333 -

						2H), 6.87 (d, J = 8.4 Hz, 2H), 4.53 (d, J = 5.5 Hz, 2H), 4.16 (s, 2H), 3.71 (s, 3H);
1941	0 /^^NH / p / d JC_s 7k,	A, 153, 255	55	434.0 (M⁺+l) 9	433.07 for C₂oH₁₄F3N3 O₃S	‘H NMR ((DMSOd₆, 400 MHz): δ 10.06 (s, 1H), 9.10 (t, J = 5.8 Hz, 1H), 8.04 (s, 1H), 7.72 (dd, J = 7.7, 1.7 Hz, 1H), 7.62-7.57 (m, 1H), 7.40-7.23 (m, 3H), 7.14 (d, J= 8.3 Hz, 1H), 4.69 (d, J = 5.8 Hz, 2H), 2.28 (s, 3H);
1913	0 J/—NH P ^N^S H V^s, /¾ ^cl k V N V/^CN	A, 155, 227	23	487.1 (M⁺+l) 9	486.06 for C₂₅H₁₅C1N₄O₃S	'H-NMR (DMSO-ri₆, 400 MHz): δ 10.64 (br s, 1H), 9.19 (br t, J = 5.4 Hz, 1H), 8.09 (br d, J = 8.0 Hz, 2H), 7.96 (br d, J = 8.2 Hz, 2H), 7.91 (s, 1H), 7.78 (br d, J = 7.3 Hz, 1H), 7.65 (br t, J = 7.3 Hz, 1H), 7.60 (s, 1H), 7.447.32 (m, 2H), 7.23 (s, 1H), 4.68 (br d, J = 5.4 Hz, 2H);
1732	O NH O H YA /¾. i < ·Λ-< v ^N V_jz ^OH	A, 166, 357	21	457.0 (M⁺+l) 9	456.13 for C₂5H₂oN₄0₃S	‘H-NMR (DMSO-riô, 400 MHz): δ 10.29 (s, 1H), 9.93 (s, 1H), 9.08 (t, J = 5.6 Hz,

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						1H), 7.72-7.54 (m, 6H), 7.53-7.47 (m, 1H), 7.25 (d, J= 8.7 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.10 (t, J=1A Hz, 1H), 6.82 (d, J = 8.7 Hz, 2H), 4.61 (d, J = 5.5 Hz, 2H);
1751	0 Υνη ο ' y J—< \ ^Et χΥ-ΟΗ	A, 169, 357	14	471.0 (M⁺+l) 5	470.14 for C26H22N4O3 S	'H-NMR (DMSO-X 400 MHz): δ 10.30 (s, 1H), 9.95 (br s, 1H), 9.07 (t, J = 5.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.65 (s, 1H), 7.63-7.57 (m, 3H), 7.52-7.46 (m, 1H), 7.24 (d, J= 8.4 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.13 7.08 (m, 1H), 6.82 (d, J = 8.8 Hz, 2H), 4.61 (d, J = 5.6 Hz, 2H), 3.78 (br d, J = 5.5 Hz, 2H), 1.12 (t, J =7.0 Hz, 3H);
11043	0 c&U y	A^c, 185 255	15	475.0 (M⁺+l) 9	474.13 for C23H21F3N4 O₂S	'H-NMR (DMSO-X 400 MHz): δ 10.29 (s, 1H), 9.22 (t, J = 5.6 Hz, 1H), 8.04 (s, 1H), 7.63-7.54 (m, 3H), 7.51-7.44 (m, 1H), 7.27 (d, J= 8.4 Hz, 1H), 7.21 (d, J =

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						8.1 Hz, 1H), 7.10 (t, J=7A Hz, 1H), 4.70 (d, J = 5.5 Hz, 2H), 3.54 ( d, J = 7.0 Hz, 2H), 1.81-1.69 (m, 1H), 0.89 ( dd, J = 5.3,4.1 Hz, 6H);
11044	Ο VnH Ο	Α^έ, 185, 316	15	526.1 (Μ⁺+1) 9	525.16 for C₂9H₂₄FN₅O ₂s	'H NMR (400 MHz, DMSO-d₆): δ 10.28 (s, 1H), 9.16 (t, J = 5.3 Hz, 1H), 8.35 (t, J=7.9Hz, 1H), 8.09 (d, J= 11.3 Hz, 1H), 7.99 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.71-7.70 (m, 1H), 7.64-7.51 (m, 3H), 7.47 (t, J = 7.0 Hz, 1H), 7.33-7.18 (m, 2H), 7.09 (t, J = 7.4 Hz, 1H), 4.70 (br d, J = 5.2 Hz, 2H), 3.54 (d, J = 5.5 Hz, 2H), 1.84-1.69 (m, 1H), 0.89 (s, 6H);
1920	0 Cnh 0	Α, 190, 255	47	459.1 (Μ⁺+1) 9	458.10 C₂₂H1₇F₃N₄ O₂S	*H NMR (400 MHz, DMSO-dô): δ 10.33 (s, 1H), 9.23 (br t, J = 5.6 Hz, 1H), 8.04 (s, 1H), 7.63-7.55 (m, 3H), 7.51-7.43 (m, 1H), 7.29-7.18 (m, 2H), 7.11 (t, J = Ί.6 Hz, 1H), 5.78-

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						5.66 (m, 1H), 5.33 (dd, J = 17.4, 1.2 Hz, 1H), 5.16-5.10 (m, 1H), 4.70 (d, J = 5.4 Hz, 2H), 4.45 (d, J = 5.3 Hz, 2H);
1546	0 / ^NH H hX^S t ^H {Tf ch₃	A, 211, 217	48%	364.0 (M⁺+l) 3	363.10 for C20H17N3O2 S	*H-NMR (DMSO-X 400 MHz): δ 10.6410.51 (m, 1H), 9.10 (t, J = 4.4 Hz, 1H), 8.95 (d, J = 2.Ί Hz, 1H), 7.82-7.75 (m, 1.5 H), 7.69-7.57 (m, 2H), 7.55-7.46 (m, 1.5 H), 7.43-7.29 (m, 3H), 4.64 (d, J = 2.8 Hz, 2H), 4.27-4.09 (m, 1H), 1.77, 1.44 (d, J=1A Hz, 3H);
1548	O ^-NH ο CH₃ ^CH3	A, 211 297	48%	377.9 (M⁺+l) 3	377.12 for C₂₁H₁₉N3O₂S	‘H-NMR (DMSOd₆, 400 MHz): δ 10.69- 10.44 (m, 1H), 9.05 (t, J = 4.5 Hz, 1H), 7.77 (d, J = 7.1 Hz, 0.5H), 7.65 (d, J=6.6Hz, 0.5H), 7.62-7.57 (m, 1.5 H), 7.54-7.46 (m, 2.5H), 7.43-7.29 (m, 3H), 4.58-4.49 (m, 2H), 4.28-4.07 (m, 1H), 2.56 (d, J = 2.6 Hz, 3H), 1.77, 1.43 (d, J = 7.3 Hz, 3H);

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1697	0 / ^NH p fT LAoAX h _z N	A, 149, 312	68	471.0 (M⁺+l) 9	470.14 for C26H22N4O3 S	1 H-NMR (DMSOd6, 400 MHz): δ 10.77 (s, 1H), 9.29 (t, J = 5.6 Hz, 1H), 7.95-7.90 (m, 1H), 7.85-7.74 (m, 6H), 7.56 (d, J = 8.4 Hz, 1H), 7.52-7.44 (m, 2H), 6.88 (d, J = 9.0 Hz, 2H), 4.74 (d, J = 5.8 Hz, 2H), 3.10 (s, 6H);
1754	O >-NH O ^H (p/x ^N VZ~^OH	A, 211, 357	37	456.0 (M⁺+l) 9	455.13 for C26H21N3O3 S	'H-NMR (DMSO-îZ₆, 400 MHz) (rotamers): δ 10.7410.45 (m, 1H), 9.93 (br s, 1H), 9.11 (t, J = 4.8 Hz, 1H), 7.807.46 (m, 7H), 7.437.28 (m, 3H), 6.83 (dd, J = 9.2, 2.5 Hz, 2H), 4.66-4.57 (m, 2H), 4.27-4.09 (m, 1H), 1.77 , 1.44 (d, J = 7.3 Hz, 3H);
1592	0 / ^NH /? sx-s CJ < Λόη₃ ⁰ N ³	A, 216, 297	42	377.8 (M⁺+l) 9	377.08 for C20H15N3O3 S	‘H-NMR (DMSO-î/₆, 500 MHz): 11.19 (s, 1H), 9.28 (t, J = 5.8 Hz, 1H), 8.20-8.14 (m, 1H), 7.87-7.76 (m, 5H), 7.60 (dd, J = 8.2, 1.3 Hz, 1H), 7.50 (s, 1H), 4.57 (d, J= 5.8 Hz, 2H), 2.57

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						(s, 3H);
1594	0 ΝΗ ρ ⁿ^\_s ⁰	A, 216, 291	30	440.5 (M⁺+l) 5	439.10 for C25H17N3O3 S	‘H NMR (400MHz, DMSO-d₆): δ 11.21 (br s, 1H), 9.40 (t, J = 5.6 Hz, 1H), 8.21 8.16 (m, 1H), 7.93 7.79 (m, 8H), 7.65 (dd, J = 8.3, 1.5 Hz, 1H), 7.52-7.44 (m, 3H), 4.70 (d, J = 5.5 Hz, 2H);
1916	0 V-NH 0	Ac, 172, 255	58	461.1 (M⁺+l) ?	460.12 C22H19F3N4 O₂S	1 H-NMR (DMSOd6, 400 MHz): δ 10.29 (s, 1H), 9.22 (t, J = 5.8 Hz, 1H), 8.04 (s, 1H), 7.627.56 (m, 3H), 7.517.45 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.13-7.08 (m, 1H), 4.70 (d, J = 5.5 Hz, 2H), 3.72 (t, J = 5.7 Hz, 2H), 1.571.44 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H);
1917	O V NH p OA n^x _s H Jy/^i ^l/Xj-GN	A^c, 172, 227	30	494.1 (M⁺+l) 5	493.16 C28H23N5O2 S	’H NMR (400 MHz, DMSOV): δ 10.29 (s, 1H), 9.15 (t, J = 5.7 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.96-7.88 (m, 3H), 7.64-7.56 (m, 3H), 7.51-7.44 (m, 1H),

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						7.29-7.18 (m, 2H), 7.10 (t, J = 7.4 Hz, 1H), 4.68 (d, J= 5.8 Hz, 2H), 3.77-3.69 (m, 2H), 1.55-1.47 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H);
1921	0 Vnh Ο cC-m-v,» ^n~Vz~^cn	A^c, 190, 227	46	492.1 (M⁺+l) 9	491.14 C28H21N5O2 S	‘H NMR (400 MHz, DMSO-d₆): δ 10.34 (s, 1H), 9.16 (t, J = 5.5 Hz, 1H), 8.06 (d, J = 8.3 Hz, 2H), 7.95-7.88 (m, 3H), 7.64-7.56 (m, 3H), 7.48 (t, J = 7.1 Hz, 1H), 7.29-7.17 (m, 2H), 7.10 (t, J = 7.5 Hz, 1H), 5.79-5.66 (m, 1H), 5.33 (d, J = 17.3 Hz, 1H), 5.13 (d, J= 10.2 Hz, 1H), 4.68 (d, J = 5.3 Hz, 2H), 4.44 (d, J = 4.9 Hz, 2H);
1922	0 y-NH o CCOA^ 9/~cf₃	A, 176, 255		475.1 (M⁺+l) 9	474.13 for C₂₃H₂₁F₃N4 O₂S	‘H NMR (400 MHz, DMSO-dô): δ 10.28 (s, 1H), 9.22 (t, J = 5.8 Hz, 1H), 8.04 (d, J = 0.9 Hz, 1H), 7.62-7.56 (m, 3H), 7.50-7.47 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.13-7.07

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						(m, 1H), 4.70 (d, J = 5.6 Hz, 2H), 3.793.72 (m, 2H), 1.531.43 (m, 2H), 1.381.28 (m, 2H), 0.82 (t, J =7.3 Hz, 3H);
1934	0 yNH p h V^s. θ“θ ^Cl CF₃	A, 126, 255	20	501.9 (M⁺+l) 9	500.98 for Ci₉HhC1F₃ n₃o₄s₂	1H-NMR (DMSOd6, 400 MHz): δ 11.50 (br s, 1H), 9.43 (t, J = 5.8 Hz, 1H), 8.06 (s, 1H), 8.02-7.96 (m, 3H), 7.95-7.85 (m, 2H), 7.43 (s, 1H), 4.76 (d, J = 5.8 Hz, 2H);
1935	Z O ZI X 1 wc oY° QJ	A, 126 227	35	535.1 (M⁺+l) 9	534.02 for C₂₅H₁₅C1N₄O₄s₂	1H NMR (400MHz, DMSO-d6): δ 11.52 (s, 1H), 9.36 (t, J = 5.8 Hz, 1H), 8.10 (d, J = 8.4 Hz, 2H), 8.02-7.94 (m, 5H), 7.93-7.85 (m, 3H), 7.43 (s, 1H), 4.72 (d, J = 5.8 Hz, 2H);
1942	O A^NH / p CYXp ^,/=, QjZ-CN	A^c, 153, 227	59	467.0 (M⁺+l) 9	466.11 for C₂₆H₁₈N₄O₃s	1H-NMR (DMSOd6, 400 MHz): δ 10.05 (s, 1H), 9.04 (t, J = 5.9 Hz, 1H), 8.09 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.5 Hz, 2H), 7.89 (s, 1H), 7.72 (dd, J = 7.7, 1.6 Hz, 1H), 7.64-7.55 (m, 1H),

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						7.38-7.29 (m, 2H), 7.26 (d, J = 8.3 Hz, IH), 7.13 (d, J = 8.3 Hz, IH), 4.65 (d, J = 5.8 Hz, 2H), 2.29 (s, 3H);
1971	Z 7 S. i ω; A / Ό ° O	A, 95, 316	64	533.0 (M⁺+l) 9	532 for C₂₆H₁₇FN₄O ₄S₂	*H NMR (400 MHz, DMSO4): δ 10.29 (s, IH), 9.15 (t, J = 5.7 Hz, IH), 8.06 (d, J = 8.4 Hz, 2H), 7.96-7.88 (m, 3H), 7.64-7.56 (m, 3H), 7.51-7.44 (m, IH), 7.29-7.18 (m, 2H), 7.10 (t, J = 7.4 Hz, IH), 4.68 (d, J = 5.8 Hz, 2H), 3.77-3.69 (m, 2H), 1.55-1.47 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H);
1974	! ^! Z O ÿ Az s	A, 166, 227	23	466.1 (M⁺+l) 9	465.13 for C₂₆H₁₉N₅O₂S	1 H-NMR (DMSOd6, 400 MHz): δ 10.30 (s, IH), 9.17 (t, J = 5.5 Hz, IH), 8.07 (d, J = 8.3 Hz, 2H), 7.92 (t, J = 8.5 Hz, 3H), 7.66-7.57 (m, 3H), 7.54- 7.47 (m, IH), 7.23 (t, J = 8.8 Hz, 2H), 7.10 (t, J = 7.4 Hz, IH), 4.68 (d, J = 5.6 Hz, 2H), 3.31 (s, 3H);

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1975	0 Jy—NH p (X χχ <^N '..s=-' H y ^S\/=\ C ^N~Vj/~^CN	A, 169 227	24	480.1 (M⁺+l) 5	479.14 for C27H21N5O2 S	1 H-NMR (DMSOd6, 400 MHz): δ 10.31 (s, 1H), 9.17 (t, J = 5.5 Hz, 1H), 8.06 (d, J = 8.3 Hz, 2H), 7.95- 7.87 (m, 3H), 7.66-7.56 (m, 3H), 7.49 (t, J = 7.0 Hz, 1H), 7.27-7.17 (m, 2H), 7.10 (t, J = 7.5 Hz, 1H), 4.68 (d, J = 5.4 Hz, 2H), 3.80-3.77 (m, 2H), 1.12 (t, J = 6.9 Hz, 3H);
11001	°'° ^Lrtz-o N(CH₃)_:	A, 92, 394	40	591.1 (M⁺+l) 3	590.17 for C30H30N4O5 s₂	‘H NMR (400 MHz, DMSOX): δ 11.47 (br s, 1H), 9.44 (t, J = 5.7 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.77 (m, 6H), 7.72 (s, 1H), 7.01 (d, J =8.9 Hz, 2H), 4.66 (d, J = 5.5 Hz, 2H), 4.03 (t, J = 6.5 Hz, 2H), 2.24 (t, J = 7.2 Hz, 2H), 2.12 (s, 6H), 1.77-1.68 (m, 2H), 1.58-1.49 (m, 2H);

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11117-A	Ο NH 0 Cl ,-ζ/' ^N^\-s H J-Λ ,N o'b <.Yn 1	A^c, 92, 519	26	508.0 (M⁺+l) 9	507.10 for C₂₄H₂₁N₅O₄s₂	*H NMR (400 MHz, DMSON₆): δ 11.52 (s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.21 (s, 1H), 8.06 (d, J= 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.78 (m, 4H), 7.73 (s, 1H), 7.50 (s, 1H), 4.60 (d, J = 5.5 Hz, 2H), 2.88-2.81 (m, 1H), 1.20 (d, J = 6.9 Hz, 6H);
11078	0 V-NH 0 ïNx ^N\_-s H N ³ OH	A^c, 194, 255	19	463.1 (M⁺+l) 9	462.10 for C₂iH₁₇F₃N₄ O₃S	‘H NMR (400 MHz, DMSO-Νί): δ 10.27 (s, 1H), 9.22 (t, J = 5.8 Hz, 1H), 8.04 (s, 1H), 7.63-7.56 (m, 3H), 7.52-7.46 (m, 1H), 7.31-7.21 (m, 2H), 7.11 (t, J = 7.5 Hz, 1H), 4.70 (d, J = 5.6 Hz, 2H), 4.66 (t, J = 5.4 Hz, 1H), 3.86-3.82 (m, 2H), 3.51 (q, J = 6.1 Hz, 2H);
11079	o—\ Γχ^° ï ÿ· O Z	A^c, 194, 316	26	514.1 (M⁺+l) 9	513.13 for C27H20FN5 03 S	‘H NMR (400 MHz, DMSO-î4): δ 10.27 (s, 1H), 9.17 (t, J = 5.9 Hz, 1H), 8.35 (t, J=1.9 Hz, 1H), 8.09 (dd, J= 11.1, 1.4 Hz, 1H), 7.99 (d, J = 2.3

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						Hz, 1H), 7.82 (dd, J = 8.2, 1.5 Hz, 1H), 7.62-7.56 (m, 3H), 7.52-7.46 (m, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H), 4.71 (d, J = 5.6 Hz, 2H), 4.66 (t, J = 5.4 Hz, 1H), 3.86-3.82 (m, 2H), 3.51 (q, J = 6.2 Hz, 2H);
11094	^Ν \	A, 92, 484	38	601.1 (M⁺+l) 9	600.19 for C32H32N4O4 s₂	'H NMR (400 MHz, DMSO-riQ: δ 11.51 (s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.98 (td, J = 7.4, 1.4 Hz, 2H), 7.90 (td, J = 1.5, 7.5 Hz, 1H), 7.87 - 7.75 (m, 6H), 7.28 (d, J = 8.3 Hz, 2H), 4.68 (d, J = 5.6 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H), 2,472.47 (m, 2H), 2.19 (br s, 3H), 1.55 (td, J = 7.3, 14.7 Hz, 3H), 1.48 - 1.39 (m, 2H), 0.38 (br d, J = 4.0 Hz, 2H), 0.24 (br s, 2H);

-345 -

C20-01	V y ΣΙ d 12 « 55	B, 20, 367	46	559.20 (M⁺ + 1)	558.18 for C30H30N4O3 s₂	‘h NMR (400 MHz, DMSO-d₆): δ 10.25 (s, 1H), 9.03 (t, J = 5.6 Hz, 1H), 7.81 (d, J = 8.8Hz, 2H), 7.68 - 7.64 (m, 2H), 7.53 - 7.43 (m, 4H), 7.10 - 7.01 (m, 3H), 4.59 (d, J = 5.6 Hz, 2H), 4.06 (t, J = 6.4 Hz, 2H), 2.45 (t, J = 6.4 Hz, 2H), 2.29 (s, 3H), 2.25 (s, 6H), 1.88 (t, J = 6.4 Hz, 2H)
C20-02	0 /// ^N\L·/ ⁰ ΰ/S M ^H fi >-N ri N	B, 20, 455	64	448.05 (M⁺+ 1)	447.08 for C₂₂H\|7N₅O2 s₂	’H NMR (400 MHz, DMSO-d,): δ 10.26 (s, 1H), 9.07 (t, J = 5.6 Hz, 1H), 8.47 (d, J = 1.6 Hz, 1H), 7.84 (s, 1H), 7.68 -7.64 (m, 1H), 7.52 - 7.43 (m, 5H), 7.08 (d, J = 8.4 Hz, 1H), 6.62 (s, 1H), 4.56 (d, J =5.6 Hz, 2H), 2.29 (s, 3H)
C38-01	ο. h ι 2 /Il o °	B, 95, 367	21	591.15 (M⁺ + 1)	590.17 for C₃₀H₃₀N₄O₅S₂	‘H NMR (400 MHz, DMSO-/: δ 10.87 (s, 1H), 9.18 (t, 1H), 7.94 - 7.77 (m, 7H), 7.71 (s, 1H), 7.35 (d, J = 8.0Hz, 1H), 7.03 (d, J = 8.0 Hz, 2H), 4.62 (d, J = 5.6 Hz,

-346 -

						2H), 4.08 (t, J = 6.0 Hz, 2H), 2.72 - 2.70 (m, 2H), 2.43 (s, 6H), 2.32 (s, 3H), 1.97- 1.94 (m, 2H)
C38-02	va® OSE Οχ _n-- 0 ⁰ N N	B, 95, 455	23	480.10 (M⁺ + 1)	479.07 for C22H17N5O4 s₂	‘H NMR (400 MHz, DMSO-<7₆): δ 10.87 (s, 1H), 9.21 (t, J= 5.6 Hz, 1H), 8.47 (s, 1H), 7.94 - 7.77 (m, 5H), 7.54 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.62 (s, 1H), 4.58 (d, J = 5.6 Hz, 2H), 2.32 (s, 3H)
C44-01	0 ^-ΝΗ / P h il //\_£ v_. / N \—N X	B, 153, 367	20	543 (M⁺ + 1)	542.20 for C30H30N4O4 S	‘H NMR (400 MHz, DMSO-ri₆): δ 10.05 (s, 1H), 8.97 (t, J = 5.9 Hz, 1H), 7.85 7.76 (m, 2H), 7.74 7.65 (m, 2H), 7.58 (td, J = Ί.Ί, 1.8 Hz, 1H), 7.37 - 7.21 (m, 3H), 7.10 (d, J = 8.3 Hz, 1H), 7.05 - 6.97 (m, 2H), 4.58 (d, J = 5.8 Hz, 2H), 4.04 (t, J= 6.4 Hz, 2H), 2.40 (t, J = 7.2 Hz, 2H), 2.27 (s, 3H), 2.18 (s, 6H), 1.86 (p, J = 6.6 Hz, 2H)

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C51-01	o' 0 ^N '—N	B, 135, 367	27	611 (M⁺ + 1)	610.11 for C29H27CIN4 O₅s₂	’H NMR (400 MHz, DMSO-d₆) δ 9.26 (t, J = 5.8 Hz, 1H), 8.00 - 7.76 (m, 7H), 7.71 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.06 6.98 (m, 2H), 4.64 (d, J = 5.6 Hz, 2H), 4.05 (t, J = 6.4 Hz, 2H), 2.37 (t, J = 6.8 Hz, 2H), 2.15 (s, 6H), 1.89 - 1.83 (m, 2H)
C51-02	ΥΥ^νηΡ P H IL /Λ d o ^N	B, 135, 455	20	500 (M⁺ + 1)	499.02 for C₂₁H₁₄C1N₅o₄s₂	’H NMR (400 MHz, DMSO-dô): δ 11.21 (s, 1H), 9.30 (t, J = 5.8 Hz, 1H), 8.47 (d, J=2.6 Hz, 1H), 8.03 - 7.79 (m, 6H), 7.57 - 7.45 (m, 2H), 6.62 (s, 1H), 4.60 (d, J = 5.8 Hz, 2H)

A^a: DIPEA (2 equiv); A^è: EDCI (2 equiv), HOBt (2 equiv), DIPEA (5 equiv); A^c: DIPEA (5 equiv); A^d: Column purification donc in neutral alumina (Eluent: 1: 1: 50, MeOH: NH₄OH: CH2CI2); B°: HATU (1.5 equiv), Amine (1.1 equiv), DIPEA (3 equiv)

Synthesis of A-((2-chlorothiazol-5-yl) methyl)-l l-oxo-10, 11-dihydrodibenzo {b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (535): A common intermediate

- 348 -

Synthesis of A-((2-chlorothiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (535): To a stirring solution of compound 92 (600 mg, 5 1.65 mmol) in DMF (15 mL) under inert atmosphère were added compound 223 (362 mg, 1.98 mmol), EDCI.HC1 (597 mg, 3.30 mmol), HOBt (445 mg, 3.30 mmol) and diisopropylethylamine (1.5 mL, 8.25 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic 10 ex tracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was triturated with EtOAc (10 mL), diethyl ether (10 mL), n-hexane (20 mL) and dried in vacuo to afford compound 535 (700 mg, 82%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.4); *H-NMR (DMSO-/4 400 MHz): δ 11.51 (br s, 1H), 9.48 (t, J= 5.5 Hz, 1H), 8.06 (d, J= 8.3 Hz, 1H), 7.98 (td, J=7A, 1.1 Hz, 2H), 7.93-7.83 (m, 3H), 7.79 (dd, J 15 =8.3, 1.5 Hz, 1H), 7.61 (s, 1H), 4.59 (d, J= 5.5 Hz, 2H).

Synthesis of A-fil-chlorothiazol-S-yl) methyl)-9-methyl-ll-oxo-10, 11-dihydrodibenzo {b.

/] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (536): A common intermediate

Synthesis of A-((2-chlorothiazol-5-yl) methyl)-9-methyl-l l-oxo-10, 11-dihydrodibenzo [b,f\

[1, 4] thiazepine-8-carboxamide 5, 5-dioxide (536): To a stirring solution of compound 95 (1.5 g, 4.73 mmol) in DMF (15 mL) under inert atmosphère were added EDCI.HC1 (1.36 g, 7.09

-349 mmol), HOBt (960 mg, 7.09 mmol), (2-chlorothiazol-5-yl) methanamine hydrochloride 223 (963 mg, 7.09 mmol) and diisopropylethylamine (4.1 mL, 23.65 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice-cold water (100 mL) and extracted with EtOAc (2 x 60 mL) and dried in vacuo to afford compound 536 (1.2 g, 57%) as white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.3); ’H NMR (DMSO-ri₆, 400 MHz): δ 10.86 (s, IH), 9.21 (t, J = 5.8 Hz, IH), 7.95-7.90 (m, 2H), 7.89-7.84 (m, 2H), 7.82-7.77 (m, IH), 7.60 (s, IH), 7.35 (d, J= 8.2 Hz, IH), 4.56 (d, J = 5.6 Hz, 2H), 2.31 (s, 3H); LC-MS: 99.42%; 448.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.08 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 7V-((2-(4-bromophenyl) thiazoI-5-yl) methyl)-!l-oxo-10, 11-dihydrodibenzo

[6,/J [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (538): A common intermediate

Synthesis of (2-(4-bromophenyl) thiazol-5-yl) methanamine hydrochloride (537): To a stirring solution of compound 463 (700 mg, 1.89 mmol) in CH₂C1₂ (4 mL) was added 4 N HCl in 1, 4- dioxane (3 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 3-4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was triturated with diethyl ether (2x5 mL) and dried in vacuo to afford compound 537 (680 mg, HCl sait) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.2); 'H NMR (DMSO-rf^ 400 MHz): δ 8.64 (br s, 3H), 8.00 (s, IH), 7.88 (d, J = 8.5 Hz, 2H), 7.72 (d, J= 8.7 Hz, 2H), 4.34 (q, J= 5.6 Hz, 2H);

- 350 -

Synthesis of A-((2-(4-bromophenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (538): To a stirring solution of 92 (400 mg, 1.32 mmol) in DMF (15 mL) under inert atmosphère were added HOBt (268 mg, 1.98 mmol), EDCI.HC1 (380 mg, 1.98 mmol), ((2-(4-bromophenyl) thiazol-5-yl) methanamine 537 (402 mg, 1.32 mmol) and diisopropylethylamine (1.2 mL, 6.60 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude, which was triturated with EtOAc (20 mL) and dried in vacuo to afford compound 538 (500 mg, 68%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.5); *H NMR (DMSO-î/₆, 400 MHz): δ 11.12 (br s, 1H), 9.48 (t,J=5.8Hz, 1H), 8.06 (d,J=8.2 Hz, 1H), 7.98 (td,J = 7.4, 1.1 Hz, 2H), 7.93-7.79 (m, 7H), 7.67 (d, J= 8.7 Hz, 2H), 4.69 (d, J= 5.6 Hz, 2H); LC-MS: 97.62%; 555.9 (M+2)⁺; (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.57 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of A-((2-chlorothiazol-5-yl) methyl)-! l-oxo-10, 11-dihydrodibenzo {b, /] [1, 4] oxazepine-8-carboxamide (539): A common intermediate

Synthesis of V-((2-chlorothiazol-5-vl) methyl)-! l-oxo-10,11-dihydrodibenzo \b,f\ [1, 4] oxazepine-8-carboxamide (539): To a stirring solution of compound 149 (500 mg, 1.96 mmol) in DMF (10 mL) under inert atmosphère were added compound 223 (398 mg, 2.15 mmol), EDCI.HC1 (561 mg, 2.94 mmol), HOBt (397 mg, 2.94 mmol) and diisopropylethylamine (1.75 mL, 9.80 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold-water (50 mL), extracted with EtOAc (2 x 100 mL). The combined

-351 - organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 8% MeOH/ CH2CI2 to afford compound 539 (390 mg, 52%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf. 0.4); 'H-NMR (DMSOV 500 MHz): δ 10.63 (s, 1H), 9.23 (t, J= 5.6 Hz, 1H),

7.78 (dd, J = Ί.Ί, 1.6 Hz, 1H), 7.68 (s, 1H), 7.65-7.58 (m, 3H), 7.43 (d, J = 8.4 Hz, 1H), 7.39-

7.31 (m, 2H), 4.56 (d, J=5.8 Hz, 2H).

The common intermediates 535, 536, 538 & 539 were converted to final products through the displacement reaction using amines or were coupled with either commercially available coupling reagents or prepared coupling reagents.

Commercially available amines for displacement reaction:

Préparation of amines for displacement reaction:

Synthesis of (3S, 6S)-azepane-3, 6-diol (550):

Synthesis of (3S, 6S)-l-benzylazepane-3, 6-diol (549): To a stirring solution of 1, 2-di(oxiran2-yl) ethane 547 (1.5 g, 13.14 mmol) in EtOH (40 mL) under argon atmosphère was added benzyl amine 548 (1.53 mL, 14.46 mmol) at RT and heated to reflux for 16 h. The reaction was

- 352 - monitored by TLC; after completion of the reaction, the volatiles were concentrated in vacuo to obtain the crude. The crude was purified préparative HPLC purification to afford compound 549 (600 mg, crude) as colorless liquid. TLC: 10% MeOH/ CH₂C1₂ (Ry 0.5); *H NMR (DMSO-</₆₎ 400 MHz): δ 7.36 - 7.28 (m, 4H), 7.26 - 7.19 (m, 1H), 4.38 (d, J = 4.8 Hz, 2H), 3.72 - 3.50 (m, 4H), 2.73-2.69 (m, 2H), 2.40- 2.37 (m, 2H), 1.88 - 1.67 (m, 2H), 1.48 -1.27 (m, 2H); LC-MS: 89.13%; 222.2 (M⁺ + l); (Column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 7.28 min. 2.5 mM (NH₄)₂CO₃: ACN, 1.0 mL/min).

Synthesis of (3S, 6S)-azepane-3,6-diol (550): To a stirring solution of compound 549 (500 mg, 0.22 mmol) in MeOH (25 mL) under inert atmosphère was added 10% Pd/C (50 mg, 50% wet) at RT and stirred under hydrogen atmosphère (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, and eluted with MeOH (10 mL). The filtrate was concentrated in vacuo to afford compound 550 (250 mg, 84%) as pale yellow solid. TLC: 10% MeOH/ CH₂C1₂ (Ry 0.1); 'HNMR (DMSO-î/₆, 400 MHz): δ 4.55-4.22 (m, 2H), 3.59-3.51 (m, 2H), 2.87-2.83 (m, 2H), 2.48-2.43 (m, 2H), 1.80-1.71 (m, 2H), 1.40-1.27 (m, 2H); Mass (Agitent 6310 Ion trap): 132.3 (M⁺+l);

Synthesis of l-benzyl-3, 3-dimethylpyrrolidine-2, 5-dione (552): To a stirring solution of 2, 2-dimethylsuccinic acid 551 (5 g, 34.21 mmol) in xylene (50 mL) under inert atmosphère was added benzyl amine 548 (4.03 g, 37.63 mmol) at RT; heated to 120 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with EtOAc (100 mL), washed with 5% sodium bicarbonate solution. The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo

- 353 - to obtain the crude. The crude compound was precipitated in isopropanol (100 mL) at -40 °C. The solvent was decanted and the obtained solid was and dried in vacuo to afford compound 552 (3 g, 40%) as white solid. TLC: 20% EtOAc/ hexanes (Rf 0.8); *H-NMR (DMSO-4 400 MHz): δ 7.35-7.20 (m, 5H), 4.55 (s, 2H), 2.65 (s, 2H), 1.22 (s, 6H); LC-MS: 99.27%; 217.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.27 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of l-benzyl-3, 3-dimethylpyrrolidine (553): To a stirring solution of compound 552 (3.0 g, 13.82 mmol) in THF (50 mL) under argon atmosphère was added lithium aluminium hydride (1.57 g, 41.47 mmol) portion wise for 10 min at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with saturated sodium sulfate and stirred for 20 min, filtered through celite. The celite pad was eluted with EtOAc (30 mL). The filtrate was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 553 (2.2 g, 85%) as colorless thick syrup. ^XH NMR (DMSO-X400 MHz): δ 7.32-7.27 (m, 4H), 7.25-7.19 (m, 1H), 3.52 (s, 2H), 2.56-2.47 (m, 2H), 2.21 (s, 2H), 1.51 (t, J= 7.1 Hz, 2H), 1.03 (s, 6H); LC-MS: 92.64%; 190.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.47 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 3, 3-dimethylpyrrolidine (554): To a stirring solution of compound 553 (1.5 g, 7.98 mmol) in MeOH (20 mL) under inert atmosphère was added 10% Pd/ C (500 mg) at RT and stirred under hydrogen atmosphère (70 psi) at RT; heated to 75 °C for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and eluted with 20%MeOH/ CH2CI2 (2 x 80 mL). The filtrate was concentrated in vacuo to afford compound 554 (500 mg, 64%) as colorless thick syrup. TLC: 5% MeOH/ CH2CI2 (Rf 0.2); ^XH NMR (DMSO-îZ₆, 400 MHz): δ 3.03 (t, J= 7.4 Hz, 2H), 2.65 (s, 2H), 1.55 (t, J= 7.3 Hz, 2H), 1.45-1.40 (m, 1H), 1.04 (s, 6H).

- 354 Commercially available cross coupling reagents used for preparing compounds:

OH

308

OH

555

556 557 225

OH

H

CH₃

558

559 560 561

562

OH

563

565 566 567

568

570 571 572

CN

- 355 Préparation of cross coupling reagents used in the préparation of compounds:

Synthesis of 2, 6-difluoro-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) phénol (586):

To a stirring solution of 4-bromo-2, 6-difluorophenol 585 (1 g, 4.80 mmol) in 1, 4-dioxane (25 mL) under inert atmosphère were added bis pinacolato diboron (1.83 g, 7.21 mmol), potassium carbonate (1.98 g, 14.40 mmol) and purged under argon atmosphère for 10 min. To this was added Pd(dppf)C12 (350 mg, 0.48 mmol) and the reaction mixture was heated to 100 °C for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, eluted with CH2CI2 (75 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2-5% EtOAc/ hexanes to compound 586 (620 mg, 50%) TLC: 10% EtOAc/ hexanes (Rf. 0.5).

Synthesis of (6-(dimethylamino) pyridin-3-yl) boronic acid hydrochloride (588):

Synthesis of (6-(dimethylamino) pyridin-3-yl) boronic acid hydrochloride (588): To a stirring solution of 5-bromo-.V, A-dimethylpyridin-2-amine 587 (250 mg, 1.24 mmol) in dry THF (10 mL) under inert atmosphère was added π-butyl lithium (1.6 M solution in hexane, 0.93 mL, 1.49 mmol) drop wise for 5 min at -78 °C and stirred for 30 min. To this was added

- 356 - triisopropyl borate (0.43 mL, 1.86 mmol) in dry THF (4 mL) at -78 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with 2 N aqueous HCl (10 mL). The volatiles were removed in vacuo to obtain the crude, which washed with diethylether (2x10 mL) to afford compound 588 (250 mg, crude) as an off-white thick syrup. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.1); LC-MS: 74.20%; 166.7 (M⁺+l); (column; Ascentis Express C18, (50 ^x 3.0 mm, 2.7 pm); RT 0.48 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (6-((tert-butoxycarbonyl) amino) pyridin-3-yl) boronic acid (591):

Synthesis of fôrt-butyl (5-bromopyridin-2-yl) carbamate (590): To a stirring solution of 5bromopyridin-2-amine 589 (1 g, 5.78 mmol) in THF (20 mL) under argon atmosphère were added triethyl amine (2.5 mL, 17.32 mmol), Boc-anhydride (1.51 g, 6.92 mmol) and DMAP (70 mg, 0.57 mmol) at 0 °C; heated to reflux and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 2-5% EtOAc/ hexanes to afford compound 590 (900 mg, 57%) as white solid. TLC: 5% EtOAc/ hexanes (Rf. 0.8); *H-NMR (CDC1₅, 400 MHz): δ 8.32 (d, J= 2.4 Hz, 1H), 8.02 (br s, 1H), 7.91 (d, J= 9.0 Hz, 1H), 7.75 (dd, J= 8.9, 2.4 Hz, 1H), 1.54 (s, 9H).

Synthesis of (6-((ter/-butoxycarbonyl) amino) pyridin-3-yl) boronic acid (591): To a stirring solution of compound 590 (250 mg, 0.91 mmol) and in dry THF (10 mL) under inert atmosphère was added n-butyl lithium (1.6 M solution in hexane, 1.72 mL, 2.74 mmol) drop wise for 10 min at -78 °C and stirred for 1 h . To this was added triisopropyl borate (0.31 mL, 1.37 mmol) at -78 °C and stirred for 1 h; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with

- 357 - water (5 mL) and the volatiles were removed in vacuo to obtain the crude. The pH of the crude was adjusted to ~5-6 with 1 N HCl. The volatiles were removed in vacuo to afford compound 591 (300 mg, crude) as white semi solid. TLC: 5% EtOAc/ hexanes (Rf. 0.1); LC-MS: 30.85%; 239.0 (M⁺+l); (column; X Select CSH C-18, (50 x 3.0 mm, 2.5 pm); RT 2.54 min. 2.5 mM Aq. NH₄OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of 2-methoxy-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yI) pyrimidine (594):

Synthesis of 5-bromo-2-methoxypyrimidine (593): Sodium métal (230 mg, 1.03 mmol) was dissolved in MeOH (25 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 1 h. To this was added 5-bromo-2-chloropyrimidine 592 (1 g, 0.51 mmol) at RT and stirred for 4 h. The reaction was monitored by TLC; after completion the volatiles were removed in vacuo to obtain the crude. The crude was diluted with ice-cold water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to afford compound 593 (900 mg, 92%). TLC: 10% EtOAc/ hexanes (Rf 0.3); ’H NMR (CDCl₃,500 MHz): δ 8.59 (s, 2H), 4.01 (s, 3H).

Synthesis of 2-methoxy-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) pyrimidine (594): To a stirring solution of 5-bromo-2-methoxypyrimidine 593 (500 mg, 2.65 mmol) in 1, 4-dioxane (25 mL) under inert atmosphère were added bis pinacolato diboron (1.34 g, 5.29 mmol), potassium acetate (779 mg, 7.95 mmol) at RT and stirred under argon atmosphère for 15 min. To this was added Pd(dppf)C12 (193 mg, 0.26 mmol) and heated to 90-100 °C and

-358 stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with EtOAc (2 x 75 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20-30% EtOAc/ hexanes to afford compound 594 (700 mg, crude).

TLC: 20% EtOAc/ hexanes (Rf 0.3); 'il NMR (CDCl₃,400 MHz): δ 8.81 (s, 2H), 4.03 (s, 3H), 1.21 (s, 12H).

Synthesis of N-(4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) phenyl)

Synthesis of /V-(4-bromophenyl) cyclopropanecarboxamide (597): To a stirring solution of 4-bromoaniline 595 (1 g, 5.81 mmol) in CH2CI2 (50 mL) under argon atmosphère were added diisopropylamine (2.1 mL, 11.62 mmol), cyclopropanecarbonyl chloride 596 (604 mg, 5.81 mmol) at 0 °C, warmed to RT and stirred for 2.5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with saturated sodium bicarbonate solution (30 mL) and extracted with CH2CI2 (25 mL). The organic layer was washed with water (30 mL) and dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 40% EtOAc/ hexanes to afford compound 597 (1.15 g, 83%) as an off-white solid. TLC: 40% EtOAc/ hexanes (Rf 0.3); ’H NMR (DMSO-îZ₆, 400 MHz): δ 10.29 (s, 1H), 7.58-7.54 (m, 2H), 7.48-7.44 (m, 2H), 1.79-1.72 (m, 1H), 0.82-0.78 (m, 4H); LC-MS: 99.73%; 239.7 (M⁺+l); (column; Kinetex EVO C-18, (50 x 3.0 mm, 2.6 pm); RT 2.71 min. 2.5 mM Aq. NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

- 359 Synthesis of 2V-(4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaboroIan-2-yI) phenyl) cyclopropanecarboxamide (598): To a stirring solution of/V-(4-bromophenyl) cyclopropanecarboxamide 597 (500 mg, 2.08 mmol) in 1, 4-dioxane (15 mL) under argon atmosphère were added bis pinacolato diboron (632 mg, 2.50 mmol), potassium acetate (510 mg, 5.20 mmol) at RT in a sealed tube and purged under argon atmosphère for 15 min. To this was added Pd(dppf)C12 (15 mg, 0.02 mmol) and purged under argon atmosphère for 10 min and heated to 110 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 40% EtOAc/ hexanes to afford compound 598 (520 mg, 87%) as an off-white solid. TLC: 40% EtOAc/ hexanes (Ry 0.3); '11 NMR (DMSO-î/₆, 400 MHz): δ 10.28 (s, 1H), 7.617.58 (m, 4H), 1.83-1.74 (m, 1H), 1.28 (s, 12H), 0.84-0.77 (m, 4H);

Synthesis of W-(4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) phenyl) acetamide (600):

Synthesis of Æ-(4-bromophenyl) acetamide (599): To a stirring solution of 4-bromoaniline 595 (1 g, 5.81 mmol) in CH2CI2 (50 mL) under argon atmosphère were added trifluoroacetic acid (1.6 mL, 11.62 mmol), acetic anhydride (0.6 mL, 5.81 mmol) at 0°C, warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH2CI2 (2 x 60 mL). The

-360 combined organic extracts were washed with saturated sodium bicarbonate (50 mL), brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 40% EtOAc/ hexanes to afford compound 599 (1.1 g, 92%) as an off white solid. TLC: 40% EtOAc/ hexanes (Rf. 0.3); ’H NMR (DMSO-<Z₆,400 MHz): δ 10.04 (br s, 1H), 7.57-7.53 (m, 2H), 7.48-7.44 (m, 2H), 2.04 (s, 3H); LC-MS: 99.65%; 211.9 (M-l)⁺; (column; Kinetex EVO C-18, (50 x 3.0 mm, 2.6 pm); RT 2.21 min. 2.5 mM Aq. NH₄OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of A-(4-(4, 4, 5, 5-tetramethyI-l, 3, 2-dioxaborolan-2-yl) phenyl) acetamide (600): To a stirring solution of A-(4-bromophenyl) acetamide 599 (500 mg, 2.33 mmol) in 1, 4dioxane (15 mL) under argon atmosphère were added bis pinacolato diboron (709 mg, 2.80 mmol), potassium acetate (572 mg, 5.84 mmol) at RT and purged under argon atmosphère for 15 min. To this was added Pd(dppf)Cl₂ (17 mg, 0.02 mmol) and purged under argon atmosphère for 20 min and heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 40% EtOAc/ hexanes to afford compound 600 (510 mg, 84%) as an off-white solid. TLC: 40% EtOAc/ hexanes (Rf 0.3); *H NMR (DMSO-î/₆, 500 MHz): δ 10.02 (s, 1H), 7.60-7.58 (m, 4H), 2.05 (s, 3H), 1.28 (s, 12H); LC-MS: 96.10%; 262 (M⁺+l); (column; Kinetex EVO C-18, (50 x 3.0 mm, 2.6 pm); RT 2.63 min. 2.5 mM Aq. NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of 1-(4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) phenyl) pyrrolidin-2-one (602):

Bis(pinacolato) diboron

CS2CO3, Pd(dppf)CI₂ CH₂CI₂1,4-dioxane: H₂0

602

-361 -

Synthesis of 1-(4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) phenyl) pyrrolidin-2-one (602): To a stirring solution of 1 -(4-bromophenyl) pyrrolidin-2-one 601 (1 g, 4.16 mmol) in 1, 4-dioxane: H2O (10: 1, 22 mL) in a sealed tube under inert atmosphère were added bis pinacolato diboron (1.27 g, 4.99 mmol), césium carbonate (1.62 g, 4.99 mmol) at RT and purged under argon atmosphère for 15 min. To this was added Pd(dppf)C12.CH2C12 (304 mg, 0.41 mmol) and purged under argon atmosphère for 30 min, heated to 100 °C and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 602 (800 mg,66%). TLC: 30% EtOAc/hexanes (Rf 0.3); LC-MS: 54.37%; 287.9 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.50 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of 6-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-3, 4-dihydroquinolin2(LH)-one (604):

Synthesis of 6-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-3, 4-dihydroquinolin2(l/f)-one (604): To a stirring solution of 6-bromo-3, 4-dihydroquinolin-2(177)-one 603 (500 mg, 2.21 mmol) in DMSO (25 mL) under inert atmosphère were added bis pinacolato diboron (671 mg, 2.65 mmol), potassium acetate (650 mg, 6.63 mmol) at RT and purged under argon atmosphère for 10 min. To this was added Pd(dppf)2C12 (161 mg, 0.22 mmol) and purged under argon atmosphère for 5 min; heated to 90 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (100 mL), washed ice-cold water (2 x 30 mL), brine (30 mL). The organic extract was dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 20-30% EtOAc/ hexanes to afford

-362 compound 604 (300 mg, crude) as semi-solid. TLC: 30% EtOAc/ hexanes (Rf. 0.3); *H NMR (DMS 0-6^,400 MHz): δ 10.21(s, ÎH), 7.50-7.39 (m, 2H), 6.83 (d, J= 7.8 Hz, 1H), 2.92-2.84 (m, 2H), 2.46-2.42 (m, 2H), 1.27 (s, 12H).

Synthesis of 5-fluoro-2-Iithium tri isopropyl borate sait (606):

Synthesis of 5-fluoro-2-lithium tri isopropyl borate sait (606): To a stirring solution of 2bromo-5-fluoropyridine 605 (500 mg, 2.84 mmol) and triisopropyl borate (0.8 mL, 3.4 mmol) in dry toluene (10 mL), dry THF (2 mL) under inert atmosphère was added /7-butyl lithium (2.5 M solution in hexane, 2.3 mL, 5.68 mmol) drop wise for 1.5 h at -78 °C and stirred for 30 min and warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which washed with hexane (2x10 mL) to afford compound 606 (800 mg sait, crude) as brown solid. This crude sait was taken up for the next reaction without purification. TLC: 10% EtOAc/ hexanes (Rf. 0.1);

Synthesis of 5-fluoro-2-lithium tri isopropyl borate sait (608):

Synthesis of 5-cyano-2-lithium triisopropyl borate sait (608): To a stirring solution of 2bromo-5-cyanopyridine 607 (1 g, 5.46 mmol) and triisopropyl borate (1.52 mL, 6.55 mmol) in dry toluene: dry THF (1:4; 25 mL) under inert atmosphère was added n-butyl lithium (2.5 M solution in hexane, 3.4 mL, 5.46 mmol) drop wise for 1.5 h at -78 °C and stirred for 30 min and warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which washed with

- 363 - hexane (2x10 mL) to afford compound 608 (1.6 g sait, crude) as yellow solid. The crude was taken forward next reaction without further purification. TLC: 10% MeOH/ CH2CI2 (Rf 0.2).

Synthesis of 2-(tributylstannyl) thiazole (610):

Synthesis of 2-(tributylstannyl) thiazole (610): To a stirring solution of 2-bromothiazole 609 (5 g, 30.48 mmol) in diethyl ether (50 mL) under inert atmosphère was added n-butyl lithium (12.2 mL, 33.53 mmol, 2.5 M solution in hexane) dropwise for 15 min at -70 °C and stirred for 30 min. To this a solution of tributyltin chloride (10 mL, 30.48 mmol) in diethyl ether (15 mL) was added dropwise for 10 min at -70 °C and stirred at the same température for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with diethylether (3x50 mL), washed with saturated potassium fluoride solution (50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 610 (11 g) as brown color syrup. The crude was carried forward for next step without further purification. TLC: 30% EtOAc/ hexanes (Rf 0.2); 'H NMR (CDCl₃,400 MHz): δ 8.17 (d, J= 3.0 Hz, IH), 7.54 (d, J= 3.0 Hz, IH), 1.58-1.50 (m, 6H), 1.34-1.27 (m, 6H), 1.16-1.10 (m, 6H), 0.89-0.83 (m, 9H) (NMR shows excess of tin reagent as impurity in the aliphatic région).

Synthesis of 5-(tributylstannyl) thiazole (611):

To a stirring solution of 2-bromothiazole 609 (5 g, 30.48 mmol) in diethyl ether (35 mL) under inert atmosphère was added π-butyl lithium (12.2 mL, 33.53 mmol, 2.5 M solution in hexane) at -70 °C and stirred for 30 min. To this was added a solution of tributyltin chloride (10 mL,

-364 30.48 mmol) in diethyl ether (15 mL) dropwise for 10 min at -70 °C and stirred at the same température for 4 h; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water ( 100 mL) and extracted with diethylether (3x50 mL) and washed with saturated potassium fluoride solution (50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 25-30% EtOAc/ hexanes to afford compound 611 (3.5 g, 31%) as white solid. TLC: 30% EtOAc/ hexanes (Rf 0.4); 'H NMR (DMSO-î/₆, 400 MHz): δ 9.35 (s, 1H), 7.89 (s, 1H), 1.58-1.47 (m, 6H), 1.34-1.24 (m, 6H), 1.13 (t, .7=8.0 Hz, 6H), 0.85 (t,J=7.3 Hz, 9H).

Synthesis of 5-methoxy-2-(tributylstannyl) pyridine (613):

Synthesis of 5-methoxy-2-(tributylstannyl) pyridine (613): To a stirring solution of 2bromo-5-methoxypyridine 612 (2 g, 10.64 mmol) in THF (25 mL) under inert atmosphère was added zi-butyl lithium (8.9 mL, 10.64 mmol, 1.6 M solution in hexane) at -78 °C and stirred for 30 min. To this was added tributyltin chloride (3.5 g, 10.64 mmol) drop wise for 10 min at -78 °C; warmed to RT and stirred for 2 h; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride (100 mL) and extracted with EtOAc (3 x 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through neutral alumina column chromatography using 10% EtOAc/ hexanes to afford compound 613 (3 g) as pale yellow liquid. TLC: 10% EtOAc/ hexanes (Rf 0.5); LC-MS: 75.23%; 400.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0

- 365 mm, 2.7 pm); RT 2.56 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-fluoro-2-(tributylstannyl) pyridine (615):

R	/χ, ^BrH	n-BuLi, CISnBu₃	F. H	^-/nBu₃
	II	Toluene
	614			615

Synthesis of 4-fluoro-2-(tributylstannyl) pyridine (615): To a stirring solution of 2-bromo-4fluoropyridine 614 (300 mg, 1.70 mmol) in toluene (10 mL) under inert atmosphère was added w-butyl lithium (1.2 mL, 2.04 mmol, 1.6 M solution in hexane) at -78 °C and stirred for 75 min. To this was added tributyltin chloride (0.55 mL, 2.04 mmol) drop wise for 10 min at -78 °C and stirred at the same température for 30 min; warmed to RT and stirred for 30 min. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (2x15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 615 (700 mg, crude) as colorless syrup. TLC: 10% EtOAc/ hexanes (Rf. 0.8); ^XH NMR (DMSO/400 MHz): δ 9.35 (s, 1H), 7.89 (s, 1H), 1.58-1.47 (m, 6H), 1.34-1.24 (m, 6H), 1.13 (t, 8.0 Hz, 6H), 0.85 (t, J= 7.3 Hz, 9H).

Synthesis of 2-(trimethylstannyl) isonicotinonitrile (617):

616

Pd(PPh₃)₄, Toluene hexamethyl ditin

Synthesis of 2-(trimethylstannyl) isonicotinonitrile (617): To a stirring solution of 2bromoisonicotinonitrile 616 (1.3 g, 7.10 mmol) in toluene (20 mL) under argon atmosphère was added hexamethyl ditin (1.7 mL, 8.52 mmol) at RT and purged under argon atmosphère for 20 min, added Pd(PPh₃)₄ (410 mg, 0.35 mmol) purged under argon atmosphère for 15 min; heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, eluted with EtOAc (50 mL). The

- 366 filtrate was concentrated in vacuo to afford crude compound 617 (2 g) as brown syrup which was carried forward for next step without further purification. TLC: 5% MeOH/ CH2CI2 (Rf 0.3).

Préparation

Compound 535, 536, 538 & 539 was synthesized as mentioned above and converted to final products throught displacement reaction or cross coupling reaction employing typical procedures D, E, F, G, H, I, J and K and the results are captured in the Table 2:

Typical Procedure D:

To a stirring solution of JV-((2-chlorothiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo [b, f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide 536 (150 mg, 0.34 mmol) in 1, 2 dimethoxy ethane: H2O (4: 1,8 mL) were added sodium carbonate (124 mg, 1.17 mmol), (3-chloro-4hydroxyphenyl) boronic acid 556 (80.4 mg, 0.46 mmol) and purged under argon atmosphère for 20 min. To this was added Pd(dppf)C12 (45 mg, 0.039 mmol) at RT; heated to 100-110 °C and stirred for 16 h. The reaction was monitored by TLC; after completion the volatiles were removed in vacuo to obtain the crude. The crude was either directly dried in vacuo or triturated or purified through silica gel column chromatography to afford the desired compound.

Typical Procedure E:

To a stirring solution of 7V-((2-chlorothiazol-5-yl) methyl)-l l-oxo-10, 11-dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide 536 (150 mg, 0.34 mmol) in 1, 4 dioxane: H2O (3: 1,10 mL) were added césium carbonate (341 mg, 1.04 mmol), (3-fluoro-4-hydroxyphenyl) boronic acid 555 (54 mg, 0.34 mmol) and purged under argon atmosphère for 15 min. To this

-367was added Pd(dppf)C12 (27 mg, 0.034 mmol) at RT; heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion the volatiles were removed in vacuo to obtain the crude. The crude was either directly dried in vacuo or triturated or purified through silica gel column chromatography to afford the desired compound.

Typical Procedure F:

A mixture of 7V-((2-chlorothiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide 536 (100 mg, 0.23 mmol) and piperidine 472 (2 mL) in a sealed tube was heated to 120 °C and stirred for 4 h. The reaction was monitored by TLC; after completion the volatiles were removed in vacuo to obtain the crude. The crude was either directly dried in vacuo or triturated or purified through silica gel column chromatography to afford the desired compound.

Typical Procedure G:

To a solution of mixture A-((2-chlorothiazol-5-yl) methyl)-! l-oxo-10, 11-dihydrodibenzo [b, f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide 536 (150 mg, 0.34 mmol) in A-methyl pyrrolidinone (5 mL) were added azepan-3-ol hydrochloride 503 (57.7 mg, 0.39 mmol) and diisopropylethylamine (0.23 mL, 1.73 mmol) in a sealed tube and heated to 160 °C and stirred for 24 h. The reaction was monitored by TLC and LC-MS; after completion the reaction mixture was diluted with water (50 mL) and extracted with 10% MeOH/ CH2CI2 (2 x 50 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was either directly dried in vacuo or triturated or purified through silica gel column chromatography to afford the desired compound.

Typical Procedure H:

To a stirring solution of A-((2-chlorothiazol-5-yl) methyl)-! l-oxo-10, 11-dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide 536 (250 mg, 0.57 mmol) in 1,4-dioxane (20 mL) under argon atmosphère in a sealed tube were added 5-(tributylstannyl) thiazoie 611 (324 mg, 0.86 mmol) at RT and purged under argon atmosphère for 15 min; to this was added Pd(dppf)C12 (42.2 mg, 0.057 mmol) at RT; heated to 110 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with 20% MeOH/ CH2CI2 (2x80 mL). The filtrate was concentrated in

-368 vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 10-12% EtOAc/ hexanes and further purified by préparative HPLC purification to afford the desired compound.

Typical Procedure I:

To a stirring solution of A-((2-chlorothiazol-5-yl) methyl)-! l-oxo-10, 11-dihydrodibenzo \b, f [1,4] thiazepine-8-carboxamide 5, 5-dioxide 536 (100 mg, 0.23 mmol) in DMF (10 mL) under argon atmosphère in a sealed tube were added 4-fluoro-l/f-pyrazole 541 (40 mg, 0.46 mmol), césium carbonate (150 mg, 0.46 mmol) at RT in a sealed tube and heated to 110 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, after completion the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was either directly dried in vacuo or triturated or purified through silica gel column chromatography/flash column chromatography to afford the desired compound.

Typical Procedure J:

To a stirring solution of 7V-((2-chlorothiazol-5-yl) methyl)-! l-oxo-10, 11-dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide 536 (200 mg, 0.36 mmol) in 1, 4-dioxane (20 mL) under argon atmosphère was added césium carbonate (450 mg, 1.38 mmol) in sealed tube at RT and purged under argon for 20 min. To this were added Pd₂(dba)3 (23 mg, 0.023 mmol), tBuXphos (14 mg, 0.032 mmol), 3,3-dimethylpyrrolidine 554 (137 mg, 1.38 mmol), at RT and purged under argon for 5 min; heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and eluted with EtOAc (2x30 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was either directly dried in vacuo or triturated or purified through silica gel column chromatography to afford the desired compound.

Typical Procedure K:

To a stirring solution 7V-((2-chlorothiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo [b, f] [1, 4] oxazepine-8-carboxamide 536 (150 mg, 0.38 mmol) in A-methyl-2-pyrrolidone (1 mL) under argon atmosphère was added N, TV-dimethylpiperidin-d-amine 544 (46 mg, 0.46 mmol) in

- 369 sealed tube at RT; heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC;

after completion of the reaction, the reaction mixture was diluted with water (25 mL), the precipitated solid was filtered, washed with CH3CN (5 mL), diethyl ether (10 mL) and dried in vacuo to afford to afford the desired compound.

-370 Table 2: Synthesis from compound 535, 536, 538, 539 common intermediates

Exampl e	Structure	Proc edur e, Inter medi ate, boro nie acid or boro nate ester s	Rx. Yiel d	Mass Spec. Found	Mass Spec. Calculai e d	‘h-nmr
1624	0 / ^NH /? v'x LC / n-\ _s h y^s _v /s_N ^{0 0}	535, 579	23	476.9 (M⁺+l );	476.06 for C₂₃H₁₆N₄O ₄s₂	'η-NMR (DMSO-riô, 400 MHz): δ 11.52 (s, 1H), 9.51 (t, J = 5.6 Hz, 1H), 9.08 (br s, 1H), 8.65 (d, J = 4.1 Hz, 1H), 8.24 (d, J = 7.9 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.98 (td, J = 7.5, 1.0 Hz, 2H), 7.93-7.79 (m, 5H), 7.51 (dd, J = 7.9, 4.8 Hz, 1H), 4.72 (d, J = 5.5 Hz, 2H);
1625	0 ^-NH 0 LL, ^ΝΆ-ε H Y^s _v /=,	535, 580	10	476.9 (M⁺+l );	476.06 for C₂₃H₁₆N₄O ₄S₂	’H-NMR (DMSO-ri₆, 400 MHz): δ 11.52 (s, 1H), 9.52 (t, J = 5.5 Hz, 1H), 8.68 (d,

-371 -

						J= 5.3 Hz, 2H), 8.06 (d, J = 8.2 Hz, 1H), 8.01-7.94 (m, 3H), 7.93-7.88 (m, 1H), 7.88-7.80 (m, 5H), 4.73 (d, J = 5.7 Hz, 2H);
1626	0 SrO	535, 581	27	477.9 (M⁺+l );	477.06 for C22H15N5O 4S2	¹ H-NMR (DMSO-ri₆, 400 MHz): δ 11.53 (s, 1H), 9.54 (t, J = 5.6 Hz, 1H), 9.26 (s, 2H), 9.25 (s, 1H), 8.07 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 3H), 7.90 (td, J = 7.5, 1.6 Hz, 1H), 7.87-7.80 (m, 3H), 4.74 (d, J = 5.6 Hz, 2H);
1636	O Vnh p	G^rf, 535, 544	63	526.0 (M⁺+l );	525.15 for C25H27N5O 4S2	'H-NMR (500 MHZ, DMSO-riQ: δ 11.49 (br s, 1H), 9.26 (t, J = 5.6 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 8.00-7.95 (m, 2H), 7.93-7.82 (m, 3H), 7.78 (dd, J = 8.4, 1.4 Hz, 1H), 7.02 (s, 1H), 4.44 (d, J= 5.5 Hz, 2H), 3.83-3.79 (m, 2H), 2.97-2.90 (m, 2H), 2.34-2.28 (m, 1H), 2.18 (br s, 6H), 1.81-1.77 (m,

-372 -

						2H), 1.45-1.32 (m, 2H);
1637	7k A-Xj ¹A 1 A / Ό	535, 573	15	516.0 (M⁺+l );	515.07 for C₂₅H_I7N₅O 4S₂	¹ H-NMR (DMSO-X 400 MHz): δ 12.62 (d, J = 11.5 Hz, 1H), 11.48 (br s, 1H), 9.46 (t, J = 5.1 Hz, 1H), 8.31 (br s, 1H), 8.12 (br s, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.017.95 (m, 2H), 7.937.80 (m, 4H), 7.807.54 (m, 3H), 4.69 (d,J=5.3 Hz, 2H);
1645-A	CA cl / v 'ω 1 'î ÿ Z O	D^a, 535, 308	19	521.0 (M⁺+l );	520.05 for C₂₄H₁₆N₄O ₆s₂	¹ H-NMR (DMSO-X 400 MHz): δ 11.51 (br s, 1H), 9.52 (t, J = 4.8 Hz, 1H), 8.31 (d, J = 8.8 Hz, 2H), 8.15 (d, J = 8.9 Hz, 2H), 8.06 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 3H), 7.93-7.80 (m, 4H), 4.73 (d, J = 5.5 Hz, 2H);
1654-A	ÇL° Ox / V ;ω 1 O' \ z ΙΣ ï O Z	D^a, 535, 225	40	501.0 (M⁺+l );	500.06 for C₂₅Hi₆N₄O ₄s₂	^lH-NMR (DMSO-X 400 MHz): δ 11.52 (s, 1H), 9.51 (t, J = 5.8 Hz, 1H), 8.098.04 (m, 3H), 8.017.79 (m, 9H), 4.72 (d, 7 =5.6 Hz, 2H);

- 373 -

1664	0 J?— NH 0 ° θ ^OH	E, 535, 555	14	509.9 (M⁺+l );	509.05 for C₂₄H₁₆FN₃O₅s₂	‘η-NMR (DMSO-î7₆, 400 MHz): δ 11.52 (br s, IH), 10.43 (br s, IH), 9.45 (t, J = 5.8 Hz, IH), 8.05 (d, J= 8.3 Hz, IH), 7.98 (td, J = 7.6. 0.8 Hz, 2H), 7.90 (td, J = 7.4, 1.2 Hz, IH), 7.87-7.78 (m, 3H), 7.72 (s, IH), 7.62 (dd, J = 12.1, 1.9 Hz, IH), 7.51 (dd, J = 8.7, 1.4 Hz, IH), 7.02 (t, J = 8.7 Hz, IH), 4.66 (d, J = 5.5 Hz, 2H);
1665	O ,O o, / ν' 1 Ο- \ z X IZ -7 O Z	E⁶, 535, 586	25	527.9 (M⁺+l );	527.04 for c₂₄h₁₅f₂n ₃O₃S₂	*H-NMR (DMSO-î/₆, 500 MHz): δ 11.52 (s, IH), 10.79 (br s, IH), 9.47 (t, J = 5.6 Hz, IH), 8.06 (d, J = 8.1 Hz, IH), 7.98 (t, J = 8.4 Hz, 2H), 7.93-7.79 (m, 4H), 7.76 (s, IH), 7.53 (d, J = 7.5 Hz, 2H), 4.67 (d, J =52 Hz, 2H);
1667	G .o / ν' ίω 1 O' \ z X s O Z	D⁶, 535, 556	10	525.9 (M⁺+l );	525.02 for C₂₄Hi₆C1N 3O₃S₂	‘H-NMR (DMSO-rZô, 400 MHz): δ 11.52 (br s, IH), 10.79 (br s, IH), 9.46 (t, J = 5.5 Hz, IH), 8.05 (d, J = 8.3 Hz, IH),

-374-

						8.01-7.95 (m, 2H), 7.93-7.78 (m, 5H), 7.72 (s, 1H), 7.65 (dd, J = 8.5, 2.1 Hz, 1H), 7.03 (d, J= 8.5 Hz, 1H), 4.66 (d, J = 5.4 Hz, 2H);
1668	r o y A I coi A. / Ό ° A7	D^d, 535, 574	44	525.9 (M⁺+l );	525.02 for C₂₄Hi₆C1N 30sS₂	'H-NMR (DMSO-dô, 400 MHz): δ 11.49 (s, 1H), 10.39 (s, 1H), 9.44 (t, J = 5.6 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.997.93 (m, 3H), 7.88 (t, J = 7.4 Hz, 1H), 7.85 -7.78 (m, 4H), 6.93 (d, J = 2.3 Hz, 1H), 6.85 (dd, J= 8.8, 2.2 Hz, 1H), 4.68 (d, J = 5.8 Hz, 2H);
1670	I o Y Λ Z \ ,o 1 coi A J o —K o	D^è, 535, 557	19	510.0 (M⁺+l );	509.05 for c₂₄h₁₆fn₃O₅s₂	¹ H-NMR (DMSO-d₆, 400 MHz): δ 11.51 (s, 1H), 10.46 (s, 1H), 9.44 (t, J = 5.8 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 8.017.95 (m, 3H), 7.937.77 (m, 5H), 6.776.67 (m, 2H), 4.68 (d, J =5.6 Hz, 2H);
1671-A	o NH P (C TY^N-Vs ^H F \/=N ^{0 0} V X~OCH₃ '—N	Ε^ύ, 535, 594	51	507.9 (M⁺+l );	507.07 for C₂₃Hi₇N₅O 5§₂	'H-NMR (DMSO-îZô, 400 MHz): δ 11.52 (s, 1H), 9.51 (t, J = 5.5 Hz, 1H), 9.06 (s,

- 375 -

						2H), 8.06 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.80 (m, 5H), 4.70 (d, J = 5.6 Hz, 2H), 3.98 (s, 3H);
1672	7 Z r?	D^c, 535, 591	53	491.9 (M⁺+l );	491.07 for C₂3Hi₇N₅O 4S₂	*H-NMR (DMSO-î/₆, 400 MHz): δ 11.52 (s, 1H), 9.43 (t, J = 5.8 Hz, 1H), 8.41 (d, J = 2.4 1H), 8.05 (d, J = 8.3 Hz, 1H), 8.00-7.95 (m, 2H), 7.93-7.78 (m, 5H), 7.66 (s, 1H), 6.516.44 (m, 3H), 4.64 (d, J=5.6 Hz, 2H);
1673	0 A- NH O i A N'X-S H y\ /=N ^{0 0} A-NH₂ N	D^e, 535, 558	47	493.0 (M⁺+l );	492.07 for c₂₂h₁₆n₆o 4§₂	¹ H-NMR (DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.68 (s, 2H), 8.05 (d, J = 8.3 Hz, 1H), 8.00-7.95 (m, 2H), 7.90 (td, J = 7.5, 1.5 Hz, 1H), 7.88-7.79 (m, 3H), 7.72 (s, 1H), 7.19 (s, 2H), 4.66 (d, J = 5.8 Hz, 2H);
1674	çc o, / χ1 o- \ z s	D^z, 535, 588	6	520.0 (M⁺+l );	519.10 for c₂₅h₂₁n₅o ₄s₂	‘H-NMR (DMSO-4 400 MHz):) δ 11.52 (s, 1H), 9.43 (br t, J = 5.6 Hz, 1H), 8.58 (d, J = 2.3 Hz, 1H),

-376 -

						8.05 (d, J = 8.2 Hz, 1H), 8.01-7.79 (m, 7H), 7.68 (s, 1H), 6.70 (d, J = 8.9 Hz, 1H), 4.65 (br d, J = 5.6 Hz, 2H), 3.08 (s, 6H);
1675	Ο yA-o ο. / ν -ω 1 Ο' \ ζ _Ι2 ^λο f ^,ζ ' X	D\ 535, 571	42	521.0 (M⁺+l );	520.10 for C₂₄H₂oN₆0 ₄S₂	'H-NMR (DMSO-V, 400 MHz): δ 11.52 (s, 1H), 9.45 (t, J = 5.8 Hz, 1H), 8.79 (s, 2H), 8.05 (d, J = 8.3 Hz, 1H), 7.98 (dd, J = 7.7, 1.1 Hz, 2H), 7.90 (td, J = 7.4, 1.4 Hz, 1H), 7.87-7.79 (m, 3H), 7.74 (s, 1H), 4.66 (d, J = 5.6 Hz, 2H), 3.18 (s, 6H);
1677-A	0 /—ΝΗ Ο cCm>s ,ν	535, 559	55	500.9 (Μ⁺+1 );	500.06 for C₂₅Hi₆N₄O ₄S₂	'H-NMR (DMS0-ri₆, 400 MHz): δ 11.52 (s, 1H), 9.51 (t, J = 5.8 Hz, 1H), 8.30 (s, 1H), 8.20 (dt, J = 8.3, 1.3 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.98 (dt, J = 7.5, 1.1 Hz, 2H), 7.94-7.79 (m, 6H), 7.69 (t, J = 7.8 Hz, 1H), 4.71 (d, J = 5.6 Hz, 2H);

-377 -

1972	0 z—NH 0 ou, y oo OH	F^û, 535, 550	53	529.1 (M⁺+l );	528.11 for C24H24N4O ₆s	'H NMR (400 MHz, DMSO-îZ₆): δ = 11.50 (s, 1H), 9.25 (t, J = 5.7 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.82 (m, 3H), 7.79 (dd, J = 8.3, 1.4 Hz, 1H), 6.95 (s, 1H), 4.87 (d, J = 4.6 Hz, 2H), 4.42 (d, J = 5.6 Hz, 2H), 3.74 (br s, 2H), 3.78-3.71 (m, 2H), 3.18-3.15 (m, 2H), 1.81 -1.79 (m, 2H), 1.40- 1.20 (m, 2H);
1804-A	0 J/—NH O su,-/· ° ° ^n^~~v^~och₃	D, 535, 560	37	520.0 (M⁺+l );	519.09 for C₂₆H2iN₃O 5S2	‘H-NMR (DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.45 (t, J = 5.6 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.97 (dd, J = 7.3, 1.1 Hz, 2H), 7.93-7.79 (m, 4H), 7.72-7.65 (m, 3H), 7.01 (d, J = 8.4 Hz, 1H), 4.66 (d, J = 5.6 Hz, 2H), 3.83 (s, 3H), 2.19 (s, 3H);
1805	° ° ^n\_/-^nh	D, 535, 561	38	516.0 (M⁺+l );	515.07 for C25H17N5O 4S2	‘H-NMR (DMSO-îZ₆, 400 MHz): δ 13.26 (s, 1H), 11.52 (s, 1H), 9.47 (t, J = 5.9 Hz, 1H), 8.31-8.28

-378 -

						(m, 1H), 8.16 (s, 1H), 8.06 (d, J= 8.3 Hz, 1H), 8.00-7.95 (m, 2H), 7.93-7.88 (m, 2H), 7.87 (s, 1H), 7.86-7.81 (m, 2H), 7.76 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 4.69 (d, 5.6 Hz, 2H);
1806-A	Ο / ^NH /? Ck-Os/./*’ ch₃	/, 535, 562	40	534.0 (M⁺+l );	533.11 for C27H23N3O 5S2	’H-NMR (DMSO-/ 400 MHz): δ 11.52 (s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.98 (td, J = 1.0, 7.3 Hz, 2H), 7.93-7.80 (m, 4H), 7.74 (s, 1H), 7.55 (s, 2H), 4.67 (d, J= 5.5 Hz, 2H), 3.68 (s, 3H), 2.26 (s, 6H);
1815	0 /NH O /Χ/Ν/ H lj\/=(	D, 535, 563	17	519.0 (M⁺+l );	518.05 for C₂₅Hi₅FN₄ O₄s₂	’H-NMR (DMSO-/ 400 MHz): δ 11.53 (s, 1H), 9.53 (t, J = 5.8 Hz, 1H), 8.087.94 (m, 6H), 7.937.80 (m, 5H), 4.73 (d, J =5.6 Hz, 2H);
1816	0 /NH /? QXYZ A ///// ^H //y// ° ° ^nY/cn	D^?, 535, 577	8	535.0 (M⁺+l );	534.02 for C₂₅Hi₅C1N ₄O₄S₂	'H NMR (DMSO/ 400 MHz): δ 11.51 (br s, 1H), 9.53 (t, J = 5.8 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.26 (d, J = 1.5 Hz,

-379 -

						1H), 8.06 (d, J = 8.3 Hz, 1H), 8.02 (s, 1H), 8.00-7.95 (m, 2H), 7.95-7.84 (m, 4H), 7.83-7.79 (m, 1H), 4.76 (d, J= 5.6 Hz, 2H);
1817	^{0 0} %X/-CN	IX 535, 570	16	535.0 (M⁺+l );	534.02 for C₂₅H₁₅C1N 4Û4§₂	‘H-NMR (DMSO-X 400 MHz): δ 11.52 (br s, 1H), 9.54 (t, J = 5.8 Hz, 1H), 8.19 (s, 1H), 8.08-8.05 (m, 2H), 8.03-7.95 (m, 4H), 7.93-7.78 (m, 4H), 4.73 (d, J = 5.6 Hz, 2H);
1819	ctbkvo ° ° hnJ-N⁷	iy, 535, 564	30	527.1 (M⁺+l );	526.08 for C₂₇Hi₈N₄O ₄S₂	¹ H-NMR (DMSO-X 400 MHz): δ 11.53 (s, 1H), 9.53 (t, J = 5.7 Hz, 1H), 8.93 (dd, J = 4.2, 1.7 Hz, 1H), 8.54 (s, 1H), 8.50 (dd, J= 8.5, 1.0 Hz, 1H), 8.28 (dd, J = 8.8, 2.1 Hz, 1H), 8.08 (t, J = 7.8 Hz, 2H), 7.98 (td, J = 7.8, 1.0 Hz, 2H), 7.94-7.81 (m, 5H), 7.59 (dd, J= 8.3, 4.2 Hz, 1H), 4.73 (d, J = 5.6 Hz, 2H);

- 380 -

1820	Ο o.Vv 1 Ο' \ ζ 1	D^, 535, 565	17	527.1 (M⁺+l );	526.08 for C₂₇H₁₈N₄O ₄S₂	‘H NMR (DMSO-^, 400 MHz): δ 11.53 (br s, 1H), 9.54 (t, J = 5.8 Hz, 1H), 9.34 (s, 1H), 8.56-8.50 (m, 2H), 8.23-8.18 (m, 2H), 8.07 (d, J = 8.3 Hz, 1H), 8.017.81 (m, 8H), 4.74 (d, J =5.6 Hz, 2H);
1826		D^r, 539, 575	16	471.6 (M⁺+l );	470.08 for c₂₅h₁₅fn₄O₃S	‘H NMR (DMSO-4 400 MHz): δ = 10.63 (s, 1H), 9.27 (t, J = 5.8 Hz, 1H), 8.35 (t, J = 7.9 Hz, 1H), 8.09 (dd, J= 11.3, 1.5 Hz, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.84-7.77 (m, 2H), 7.70 (d, J = 2.0 Hz, 1H), 7.677.60 (m, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.39-7.30 (m, 2H), 4.72 (d, J = 5.6 Hz, 2H);
1838	ο y—ΝΗ Ο ŒXyVvs OH	D°, 535, 566	61	506.0 (M⁺+l );	505.08 for C₂₅H₁₉N₃O 5S2	*H-NMR (DMSO-î/₆, 400 MHz): δ 11.52 (s, 1H), 9.49 (t, J = 5.7 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.94-7.80 (m, 5H), 7.69-7.63 (m, 2H),

-381 -

						7.47 (td J = 7.6, 1.1 Hz, 1H), 7.39-7.34 (m, 1H), 5.31 (t, J = 5.9 Hz, 1H), 4.794.66 (m, 4H);
1855	Ο Κνη ρ _ο 0	D⁰, 535, 567	40	554.0 (Μ⁺+1 );	553.04 for C₂₅H₁₉N₃O ₆s₃	‘H NMR (DMSO-V 500 MHz): δ 11.58 (br s, 1H), 9.52 (t, J = 5.8 Hz, 1H), 8.18 (d, J = 8.2 Hz, 2H), 8.10-8.04 (m, 1H), 8.01-7.94 (m, 4H), 7.92-7.82 (m, 5H), 4.72 (d, J = 5.5 Hz, 2H), 3.23 (s, 3H);
1856	ο Vnh ρ ο ° ° ^n'\l_/~s-_Nh₂ ο	D⁰, 535, 576	11	555.0 (Μ⁺+1 );	554.04 for C₂₄H₁₈N₄O ₆S₃	'H NMR (DMSO-V 400 MHz): δ 11.52 (br s, 1H), 9.52 (t, J = 5.8 Hz, 1H), 8.108.05 (m, 3H), 8.017.95 (m, 2H), 7.937.86 (m, 5H), 7.867.80 (m, 2H), 7.45 (s, 2H), 4.71 (d, J= 5.5 Hz, 2H);
1857	cJVv ° ° '^ο	D⁰, 535, 568	22	569.1 (Μ⁺+1 );	568.05 C₂₅H₂₀N₄O ₆s₃	'H NMR (DMSO-r/é, 400 MHz): δ 11.51 (br s, 1H), 10.08 (br s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.79 (m, 6H), 7.75 (s, 1H), 7.27 (d,

-382 -

						J = 8.7 Hz, 2H), 4.67 (d, J = 5.5 Hz, 2H), 3.05 (s, 3H);
1860	Ο 0 ^R '—/ '0	f 535, 545	14	533.0 (M⁺+l );	532.05 for c₂₂h₂₀n₄o 6§3	*H NMR (DMSO-4 400 MHz): δ 11.51 (s, 1H), 9.31 (t, J = 5.7 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.82 (m, 3H), 7.79 (d, J = 8.2 Hz, 1H), 7.09 (s, 1H), 4.46 (d, J = 5.6 Hz, 2H), 3.90-3.84 (m, 4H), 3.22-3.15 (m, 4H);
1879-A	ο ΝΗ ο V A. JT /”Ν'Χ.ο H )Γ \ N=. °°	H^c, 535, 613	26	507.0 (M⁺+l );	506.07 for C₂₄H₁₈N₄O sS₂	'H-NMR (DMSO-4 400 MHz): δ 11.51 (br s, 1H), 9.44 (t, J = 5.5 Hz, 1H), 8.30 (d, J = 2.6 Hz, 1H), 8.11-7.93 (m, 5H), 7.92-7.77 (m, 6H), 7.52 (dd, J = 8.7, 2.8 Hz, 1H), 4.67 (d, J = 5.4 Hz, 2H), 3.88 (s, 3H);
1881	O /—NH O ° ⁰ 7J~QQ~^CN	D, 535, 608	26	542 (M⁺+l );	501.06 for C₂₄Hi₅N₅O ₄S₂	’H NMR (DMSO-4 400 MHz): δ 11.51 (s, 1H), 9.52 (t, J = 5.7 Hz, 1H), 9.05 (d, J = 1.2 Hz, 1H), 8.42 (dd, J = 8.3, 2.1 Hz, 1H), 8.22 (d, J= 8.2

- 3S3 -

						Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.017.95 (m, 3H), 7.937.79 (m, 4H), 4.73 (d, J =5.6 Hz, 2H);
1905	0 / ^NH /? / ^N^s	F, 535, 472	68	483.1 (M⁺+l );	482.11 for C₂₃H₂₂N₄O ₄S₂	‘H-NMR (DMSO-Jd, 400 MHz): δ 11.50 (s, 1H), 9.25 (t, J = 5.2 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 8.00-7.95 (m, 2H), 7.93-7.81 (m, 3H), 7.78 (d, J = 8.4 Hz, 1H), 7.01 (s, 1H), 4.44 (d, J = 5.4 Hz, 2H), 3.35-3.30 (m, 4H), 1.56-1.52 (m, 6H);
1907	0 / ^NH 9 CJCPCj [τν o'o	G^b, 535, 540	26	497.1 (M⁺+l );	496.12 for c₂₄h₂₄n₄o 4§₂	‘H NMR (400 MHz, DMSO-î4): δ 11.50 (s, 1H), 9.23 (t, J = 5.6 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 8.00-7.95 (m, 2H), 7.92-7.81 (m, 3H), 7.79 (dd, J= 8.3, 1.4 Hz, 1H), 4.43 (d, J = 5.6 Hz, 2H), 3.483.43 (m, 4H), 1.741.66 (m, 4H), 1.521.43 (m, 4H);

‘0 SZ’6 KHI ‘s) OSTl 2 KzHW OOP ‘9P -OSWCI) ΉΜΝ HT	S^sqWh^d JOJ0r86P	( l-KW) l’66P	01	SSP ‘S£S ‘,0	^Η°Όχχ t y K U? O UN—Z O	6S81
Khz Μ εοτ -zvz KHZ M OS'Z -ZS'Z ‘(HZ ‘ZH VL = f ‘1) 98Ύ ‘(HZ ‘ZH 9'9 = f ‘P) 89Ψ ΚΗ6 M 5L'L-£6'L ‘(HZ M S6‘Z-IO’8 ‘(Hl ‘ZH Z‘8 = f ‘P) 90'8 ‘(Hl ‘ZH 8’2 = f ‘0 9P'6 ‘(Hl ‘s H) Zi/Il 2 KzHW OOP ‘9P -oswa) ΉΙΝΝ-ΗΙ	²S^sQ^N^H^D lOJOrSSS	( l+₊H) Γ6££	9Z	Z09 ‘S£S	Ç-XH-V AA O HN— O	8S81
Khi Μ δγι -6ΖΊ Khi M 9£’i -8ΡΊ ‘(HP hu) 9SI -Ç8 l ‘(Hl hu) 0l£ -0ΖΎ Khi M set -ορέ Khi M ερέ -zst Khz ‘^) 99Έ -18T Khz ‘zh s^-s = /‘p jq) ep’p Khi ‘zh ρ·ρ = / ‘p) £8’p Khi ‘s) 96’9 Khi ‘zh £1 ‘E’8 =r ‘PP) 6L'L KHE ‘^) Ζ8Έ-Ε6Έ Khz ‘^) s6’z-oo's Khi ‘zh et = r ‘p) po‘8 Khi ‘zh 9X = r h h) pz'6 Khi ‘s) os^-π 2 K^-oswa ‘ZHW OOP) H IN N H]	²S^sOW³H^kD JOJ ΖΓΖ19	K l+₊W) rzis	8Z	£0S ‘S£S ‘O	HO ô'û h 0 HN— O	8061

- pss19643

1930	1864
o-cQ H \ bT ? Pw? ^vcro O HN— O	O V-\^O O 1 K 0 Z c k°
D°, 535, 569	X, 539, 602
27	oo
531.0 (M⁺+l );	511.2 (M⁺+l ) i
530.07 for C₂₆Hi₈N₄O sS₂	510.14 for C₂₈H₂₂N₄O ₄s i i i
X NMR (DMSO-X 400 MHz): δ 11.52 (s, 1H), 9.98 (s, 1H), 9.50 (t, J = 5.8 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.80	IJ IJ IJ lu Ç ψ \|J - M Q. - E b LA OipNffiKbÔoio P E X -J tO II .. _k ~ A A O O O II tO W £ _ , _ A A Jx Z TJ JS E . . p . .J, /-S b >-> A LA A ' '—' æ 4^ A - A 00 Α œ 22 .O O to ^z LU Q\ , 4— CT 00 ~ ° S X ’ E Il ο E A P- À II ο ο E S 2 A P P _W L> <_ b to P P N Q k bo X P H ° b Ε£Ε^^ίο?°Χ£ΕΕΕ^ o N A A II O 4^ P N U	J = 5.6 Hz, 1H), 8.05-7.95 (m, 3H), 7.93-7.82 (m, 3H), 7.78 (d, J = 8.3 Hz, 1H), 7.01 (s, 1H), 4.74 (br s, 1H), 4.44 (d, J = 5.5 Hz, 2H), 3.72-3.58 (m, 3H), 3.15-3.06 (m, 2H), 1.79-1.74 (m, 2H), 1.44-1.34 (m, 2H);

- 385 19643

- 386 -

						(m, 5H), 7.57-7.54 (m, 1H), 7.31 (d, J = 7.3 Hz, 1H), 7.06 (t, J= 7.7 Hz, 1H), 4.71 (d, J = 5.5 Hz, 2H), 3.61 (s, 2H);
1931	o'o Q 1	D^p, 535, 598	16	559.1 (M⁺+l );	558.10 C₂₈H₂₂N₄O 5§₂	*H NMR (DMSO-î/₆, 400 MHz): δ 11.51 (br s, 1H), 10.40 (s, 1H), 9.45 (t, J = 5.8 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 8.007.95 (m, 2H), 7.927.78 (m, 6H), 7.74 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H), 4.67 (d, J = 5.6 Hz, 2H), 1.841.76 (m, 1H), 0.840.79 (m, 4H);
1932	0 V—NH 0 CCrCA-Vx cCo s^^N 9 HN^°	D^p, 535, 600	38	533.1 (M⁺+l );	532.09 C₂₆H₂₀N₄O 5§₂	‘H NMR (DMSO-î/₆, 400 MHz): δ 11.51 (s, 1H), 10.14 (s, 1H), 9.45 (t, J = 5.7 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.007.95 (m, 2H), 7.937.84 (m, 3H), 7.837.79 (m, 3H), 7.74 (s, 1H), 7.67 (d, J= 8.8 Hz, 2H), 4.67 (d, J = 5.5 Hz, 2H), 2.06 (s, 3H);

- 387 -

1951	ο / ^ΝΗ /? rx zyx^s ζ-λ ΜΥΑζ η ΥΛ /=Ζ Ά	D\ 535, 604	56	545.1 (M⁺+l );	544.09 for C₂₇H₂₀N₄O 5 $2	‘H NMR (DMSO-riô, 400 MHz): δ 11.52 (s, 1H), 10.29 (s, 1H), 9.46 (t, J = 5.7 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.007.95 (m, 2H), 7.937.80 (m, 4H), 7.737.64 (m, 3H), 6.91 (d, J = 8.3 Hz, 1H), 4.66 (d, J = 5.6 Hz, 2H), 2.94 (t, J = 7.5 Hz, 2H), 2.48-2.46 (m, 2H);
1953	°°	D, 538, 578	27	542.0 (M⁺+l )	541 for C₂₇H₁₉N₅O ₄S₂	'H NMR (DMSO-d₆, 400 MHz): δ 13.4512.95 (m, 1H), 11.52 (br s, 1H), 9.49 (t, J = 4.8 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.94-7.90 (m, 4H), 7.89-7.83 (m, 4H), 7.82-7.80 (m, 2H), 6.78 (s, 1H), 4.70 (d, J= 5.3 Hz, 2H);
1954	Ο ^-νη ρ ΓΧ °“° s—'	H^, 538, 610	20	559.0 (M⁺+l )	558 for C₂₇H_i8N₄O 4S3	1H NMR (DMSOd6, 400 MHz): δ 11.51 (br s, 1H), 9.50 (t, J = 5.7 Hz, 1H), 8.08-8.04 (m, 3H), 8.03-7.95 (m, 5H), 7.93-7.80 (m, 6H), 4.71 (d, J = 5.6 Hz,

- 388 -

						2H);
1959		D⁷, 535, 578	11	466.0 (M⁺+l )	465.06 C21H15N5O ₄S₂	1H NMR DMSO-d6, 400 MHz): δ 13.16 (br s, 1H), 11.51 (s, 1H), 9.43 (br t, J = 5.8 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.98 (td, J = 7.7, 1.1 Hz, 2H), 7.93-7.79 (m, 5H), 7.70 (s, 1H), 6.69 (t, J = 2.1 Hz, 1H), 4.65 (d, J = 5.8 Hz, 2H) ;
1956	oAW, θ”θ \ H N	H, 535, 611	6	483.0 (M⁺+l );	482.02 for C₂\|Hi₄N₄O 4S3	'H NMR (DMSO-X 400 MHz): δ 11.52 (br s, 1H), 9.50 (t, J = 5.8 Hz, 1H), 9.17 (s, 1H), 8.42 (s, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.01-7.96 (m, 2H), 7.90 (td, J = 7.5, 1.5 Hz, 1H), 7.87-7.80 (m, 3H), 7.78 (s, 1H), 4.68 (d, .7=5.6 Hz, 2H);
1960	0	K°, 535, 453	56	466.3 (M⁺+l );	465.06 for C₂iH₁₅N₅O 4S2	'H NMR (DMSO-X 500 MHz): δ 11.52 (s, 1H), 9.48 (t, J = 5.5 Hz, 1H), 8.46 (d, J = 2.9 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.99 (t, J = 8.7 Hz, 2H), 7.94-7.80 (m, 5H), 7.55 (s, 1H),

- 389 -

						6.61 (d, J = 1.7 Hz, 1H), 4.62 (d, J= 5.8 Hz, 2H);
1981	0 /—NH p o'b s^^N	J, 535, 554	35	497.0 (M⁺+l );	496.12 for C₂₄H₂₄N₄O ₄S₂	‘H NMR (DMSOO, 400 MHz): δ 11.50 (s, 1H), 9.24 (t, J = 5.7 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 8.00-7.95 (m, 2H), 7.92-7.82 (m, 3H), 7.78 (dd, J = 8.3, 1.4 Hz, 1H), 6.99 (s, 1H), 4.43 (d, J = 5.5 Hz, 2H), 3.38 (t, J = 6.9 Hz, 2H), 3.08 (s, 2H), 1.75 (t, J = 7.0 Hz, 2H), 1.06 (s, 6H);
11038	,_Ί F	I, 535, 541	48	483.9 (M⁺+l );	483.05 for C₂iH₁₄FN₅O₄S₂	‘H-NMR (DMSOO, 400 MHz): δ 11.51 (s, 1H), 9.48 (t, J = 5.6 Hz, 1H), 8.64 (d, J =4.1 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.01-7.95 (m, 3H), 7.93-7.78 (m, 4H), 7.55 (s, 1H), 4.61 (br d, J=5.6Hz, 2H);
11039	άΰό _%°° cf₃	i^a, 535, 542	46	534.0 (M⁺+l );	533.04 for c₂₂h₁₄f₃n ₅0₄s₂	'H-NMR (DMSOO, 400 MHz): δ 11.51 (s, 1H), 9.51 (t, J = 5.6 Hz, 1H), 9.16 (s, 1H), 8.32 (s, 1H), 8.06 (d, J = 8.2 Hz,

- 390 -

						1H), 7.98 (td, J = 7.5, 1.2 Hz, 2H), 7.93-7.84 (m, 3H), 7.81 (td, J= 4.9, 1.5 Hz, 1H), 7.65 (s, 1H), 4.64 (d, J= 5.5 Hz, 2H);
11040		D', 535, 606	9	495 (Μ⁺+1 );	494.05 for c₂₃h₁₅fn₄o₄s₂	'H NMR (DMSO-V 400 MHz): δ 11.49 (s, 1H), 9.45 (t, J = 5.9 Hz, 1H), 8.59 (d, J = 2.9 Hz, 1H), 8.12 (dd, J = 8.8, 4.6 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.98-7.93 (m, 2H), 7.90 - 7.76 (m, 6H), 4.66 (d, J = 5.6 Hz, 2H);
11045	Y V	I, 535, 543	18	483.9 (Μ⁺+1 );	483.05 for C₂iH₁₄FN₅ O₄s₂	*H-NMR (DMSO-V 400 MHz): δ 11.51 (s, 1H), 9.48 (t, J = 5.6 Hz, 1H), 8.44 (d, J =2.9 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.98 (t, J = 6.9 Hz, 2H), 7.94-7.77 (m, 4H), 7.54 (s, 1H), 6.46 (dd, J= 5.3, 2.7 Hz, 1H), 4.61 (d, J = 5.5 Hz, 2H);
11049	0 cCbA-v^ °'θ Ν^⁷	Η, 535, 584	19	483.1 (Μ⁺+1 );	482.02 for C₂iHi₄N₄O ₄S₃	¹ H-NMR (DMSO-V 400 MHz): δ 11.51 (s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 9.20 (d,

- 391 -

						J = 2.0 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.98 (td, J = 1.3, 8.3 Hz, 2H), 7.94-7.84 (m, 3H), 7.847.79 (m, 2H), 4.69 (d, J = 5.8 Hz, 2H);
11050	F	H^a, 535, 615	17	495.0 (M⁺+l );	494.05 for C23H15FN4 O4S2	’H-NMR (DMSO-c/₆, 400 MHz): δ 11.51 (s, 1H), 9.49 (t, J = 5.7 Hz, 1H), 8.64 (dd, J = 8.4, 5.6 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.78 (m, 6H), 7.45-7.39 (m, 1H), 4.71 (d, J = 5.8 Hz, 2H);
11051	°'° srW CN	H^b, 535, 617	18	502.0 (M⁺+l );	501.06 for C₂₄H₁₅N₅O 4S2	'H NMR (DMSO-4 400 MHz): δ 11.51 (s, 1H), 9.51 (t, J = 5.7 Hz, 1H), 8.84 (dd, J = 5.0, 0.8 Hz, 1H), 8.39 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.01-7.94 (m, 3H), 7.94-7.90 (m, 2H), 7.89-7.84 (m, 2H), 7.81 (dd, J = 8.2, 1.4 Hz, 1H), 4.72 (d, J = 5.6 Hz, 2H);

- 392 -

11150		D^;, 536, 606	20	509.1 (M⁺+l );	508.07 for C₂₄Hi₇FN₄O₄S₂	^XH NMR (DMSO/ 400 MHz): δ 10.85 (s, 1H), 9.21 (t, J = 5.8 Hz, 1H), 8.65 (d, J = 2.8 Hz, 1H), 8.16 (dd, J = 8.8, 4.6 Hz, 1H), 7.96-7.83 (m, 6H), 7.82-7.76 (m, 1H), 7.36 (d, J = 8.2 Hz, 1H), 4.66 (d, J = 6.0 Hz, 2H), 2.32 (s, 3H);
11152		D, 536, 578	34	480.1 (M⁺+l );	479.07 for C₂₂Hi₇N₅O ₄s₂	*H NMR (DMSO-/ 400 MHz): δ 10.85 (s, 1H), 9.16 (t, J = 5.8 Hz, 1H), 7.947.90 (m, 2H), 7.897.84 (m, 3H), 7.827.77 (m, 1H), 7.70 (s, 1H), 7.35 (d, J= 8.2 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 4.63 (d, J = 5.9 Hz, 2H), 2.32 (s, 3H);
11148	Yk -, F	i^b, 536, 541	23	498.0 (M⁺+l );	497.06 for c₂₂h₁₆fn₅O₄s₂	‘H-NMR (DMSO/, 400 MHz): δ 10.87 (s, 1H), 9.21 (t, J = 5.8 Hz, 1H), 8.67 (d, J =4.1 Hz, 1H), 8.00 (d, J = 4.0 Hz, 1H), 7.94-7.89 (m, 2H), 7.89 -7.84 (m, 2H), 7.79 (td, J = 7.8, 1.6 Hz, 1H), 7.55 (s,

- 393 -

						1H), 7.35 (d, J = 8.2 Hz, 1H), 4.58 (d, J = 5.8 Hz, 2H), 2.32 (s, 3H);
11149	0 /-NH / P ^H F c ⁰⁰ CF₃	I^b, 536, 542	19	548.1 (M⁺+l );	547.06 for C₂₃Hi₆F₃N ₅O₄S₂	‘H NMR (400 MHz, DMSO-îQ δ 10.87 (br s, 1H), 9.25 (t, J = 5.3 Hz, 1H), 9.18 (s, 1H), 8.34 (s, 1H), 8.00-7.75 (m, 5H), 7.64 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 4.61 (d, J = 5.3 Hz, 2H), 2.32 (s, 3H);
1694	^N \__,^N^	K, 539, 305	23	450.0 (M⁺+l )	934.28 for C₄₆H₄₇C1N ioOôS₂	‘H-NMR (DMSO-riô, 500 MHz): δ 10.62 (s, 1H), 9.01 (t, J = 5.8 Hz, 1H), 7.78 (dd, J = 7.8, 1.4 Hz, 1H), 7.68-7.58 (m, 3H), 7.41 (d, J= 8.4 Hz, 1H), 7.38-7.31 (m, 2H), 7.03 (s, 1H), 4.42 (d, J = 5.8 Hz, 2H), 3.34-3.29 (m, 4H), 2.44-2.37 (m, 4H), 2.22 (br s, 3H);
1695	0 / ^NH 9 L Y, JT /^· n'X-, S à HN-i	E, 539, 573	14	468.0 (M⁺+l );	467.11 for c₂₅h_I7n₅o ₃s	‘h-nmr (dmso-4 400 MHz): δ 10.64 (s, 1H), 9.23 (t, J = 5.3 Hz, 1H), 8.66 (br s, 1H), 8.14 (s, 1H), 7.84 (br d, J = 8.7

- 394 -

						Hz, 1H), 7.80-7.69 (m, 5H), 7.66-7.60 (m, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.397.31 (m, 2H), 4.67 (br d, J = 5.5 Hz, 2H);
1696	άϊΛ-., 4 yN 9 ΗΝ—	539, 572	41	467.0 (M⁺+l );	466.11 c₂₆h₁₈n₄o ₃S	'h-nmr (dmso-4 400 MHz): δ 11.31 (br s, 1H), 10.64 (s, 1H), 9.19 (t, J = 5.7 Hz, 1H), 8.08 (s, 1H), 7.78 (dd, J = Ί.Ί, 1.7 Hz, 1H), 7.71-7.69 (m, 2H), 7.66-7.61 (m, 3H), 7.46-7.40 (m, 3H), 7.38 -7.31 (m, 2H), 6.52 (t, J = 2.1 Hz, 1H), 4.64 (d, J = 5.6 Hz, 2H);
1700		E^c, 539, 555	8	461.9 (M⁺+l );	461.08 for c₂₄h₁₆fn₃O₄S	¹ H-NMR (DMSO-J₆, 400 MHz): δ 10.64 (s, 1H), 10.50 (br s, 1H), 9.19 (t, J = 5.8 Hz, 1H), 7.78 (dd, J = 7.7, 1.6 Hz, 1H), 7.71 - 7.69 (m, 2H), 7.66- 7.59 (m, 3H), 7.51 (dd, J = 8.4, 1.5 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.387.30 (m, 2H), 7.00 (t, J= 8.7 Hz, 1H), 4.63

- 395 -

						(br d, J = 5.6 Hz, 2H);
1701	Ο / ^ΝΗ η Λ X ϊ F Η N V//-OH F	E^b, 539, 586	30	479.9 (M⁺+l );	479.08 for C₂4H₁₅F₂N 3O4S	'H-NMR (DMSO-dé, 400 MHz): δ 10.65 (s, 1H), 9.21 (t, J = 5.6 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.40-7.31 (m, 4H), 7.70-7.60 (m, 5H), 4.67 (d, J = 5.2 Hz, 2H);
1702	Ο ^Υ~^ΝΗ ,9 ί X J Ν-Χ—ς CI ^{J Η}Τ.Χ»	D^b, 539, 556	64	477.9 (M⁺+l );	477.06 for C₂₄H₁₆C1N 3O4S	¹ H-NMR (DMSO-d₆, 500 MHz): δ 10.78 (br s, 1H), 10.64 (s, 1H), 9.21 (t, J = 5.5 Hz, 1H), 7.83-7.76 (m, 2H), 7.72-7.60 (m, 5H), 7.42 (d, J = 8.4 Hz, 1H), 7.387.31 (m, 2H), 7.05 (d, J = 8.4 Hz, 1H), 4.63 (d, J = 5.5 Hz, 2H);
1703	0 ,^ΝΗ ,9 Γχ ΧΥΥs ύ Η Υ⁵\Λ=Λ ^ν\_Α^0η	iy, 539, 574	62	477.9 (Μ⁺+1 );	477.06 for C₂₄H₁₆C1N 3O4S	*H-NMR (DMSO-dô, 400 MHz): δ 10.64 (s, 1H), 10.41 (s, 1H), 9.21 (t, J = 5.7 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.807.76 (m, 2H), 7.69 (s, 1H), 7.66-7.60 (m, 2H), 7.43 (d, J = 8.3 Hz, 1H), 7.38-7.31 (m, 2H), 6.94 (d, J =

-396 -

						2.5 Hz, 1H), 6.87 (dd, J = 8.8, 2.4 Hz, 1H), 4.67 (d, J = 5.6 Hz, 2H);
1704		D^b, 539, 557	13	461.9 (M⁺+l );	461.08 for c₂₄h₁₆fn₃O₄S	’H-NMR (DMSO-4 500 MHz): δ 10.62 (s, 1H), 10.45 (s, 1H), 9.19 (t, J = 5.8 Hz, 1H), 7.98 (t, J = 9.0 Hz, 1H), 7.807.74 (m, 2H), 7.69 (d, J = 2.0 Hz, 1H), 7.65-7.60 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.38-7.31 (m, 2H), 6.77-6.67 (m, 2H), 4.65 (d, J = 5.5 Hz, 2H);
1708	0 >- ΝΗ 0 CUCrW	D¹, 539, 588	25	472.0 (M⁺+l );	471.14 for C₂₅H₂iN₅O ₃S	'H NMR (DMSO-^, 500 MHz): δ 10.63 (s, 1H), 9.17 (t, J = 5.6 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 7.92 (dd, J = 9.0, 2.3 Hz, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.70-7.59 (m, 4H), 7.42 (d, J = 8.4 Hz, 1H), 7.397.31 (m, 2H), 6.70 (d, J = 9.0 Hz, 1H), 4.62 (br d, J = 5.5 Hz, 2H), 3.08 (s, 6H);

-397 -

1709-A	0 J-NH P Cx XW V-OV· H F V/^N //-och₃ '—N	d‘, 539, 594	27	460.0 (M⁺+l );	459.10 for C₂₃Hi₇N₅O ₄S	’h NMR (DMSO-V 400 MHz): δ 10.64 (s, 1H), 9.25 (t, J = 5.8 Hz, 1H), 9.06 (s, 2H), 7.85 (s, 1H), 7.78 (dd, J= 7.8, 1.6 Hz, 1H), 7.70 (d, J = 2.1 Hz, 1H), 7.667.60 (m, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.39-7.31 (m, 2H), 4.68 (d, J = 5.6 Hz, 2H), 3.98 (s, 3H);
1710	Y Y Z	E^a539, 558	6	445.0 (M⁺+l );	444.10 for c₂₂h₁₆n₆o ₃s	'H-NMR (DMSO-V 400 MHz): δ 10.63 (s, 1H), 9.20 (t, J = 5.8 Hz, 1H), 8.68 (s, 2H), 7.78 (dd, J = Ί.Ί, 1.6 Hz, 1H), 7.73-7.68 (m, 2H), 7.66-7.59 (m, 2H), 7.42 (d, J = 8.3 Hz, 1H), 7.39-7.31 (m, 2H), 7.17 (s, 2H), 4.63 (d, J = 5.6 Hz, 2H)
1711	0 / ^NH ? ci xyA^s v-ov' ^H f\v=n V Y'N⁷ N \	539, 571	14	473.0 (M⁺+l );	472.13 for C₂₄H₂₀N₆O ₃s	V-NMR (DMSO-<fy, 400 MHz): δ 10.63 (s, 1H), 9.20 (t, J = 5.7 Hz, 1H), 8.79 (s, 2H), 7.78 (dd, J = 7.8, 1.6 Hz, 1H), 7.73-7.68 (m, 2H), 7.66-7.60 (m, 2H),

- 398 -

						7.42 (d, J = 8.4 Hz, 1H), 7.38-7.31 (m, 2H), 4.64 (d, J = 5.5 Hz, 2H), 3.18 (s, 6H);
1714-A	O / ^NH P Uc-V iAs O	D^è, 539, 559	71	452.9 (M⁺+l );	452.09 for C₂₅Hi₆N₄O ₃S	‘H-NMR (DMSO-î/ô, 400 MHz): δ 10.64 (s, 1H), 9.26 (t, J = 5.6 Hz, 1H), 8.30 (s, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.87 (s, 1H), 7.78 (dd, J = Ί.Ί, 1.3 Hz, 1H), 7.71-7.61 (m, 4H), 7.43 (d, J = 8.4 Hz, 1H), 7.38-7.32 (m, 2H), 4.69 (d, J = 5.8 Hz, 2H);
1736-A	0 V NH 0 CMMo -	D, 539, 560	49	472.0 (M⁺+l );	471.13 C₂₆H₂iN₃O ₄S	‘H-NMR (DMSO-c/₆, 500 MHz): δ 10.64 (s, 1H), 9.19 (t, J = 5.3 Hz, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.73-7.60 (m, 6H), 7.42 (d, J = 8.1 Hz, 1H), 7.39 -7.31 (m, 2H), 7.01 (d, J = 8.4 Hz, 1H), 4.63 (d, J = 5.5 Hz, 2H), 3.83 (s, 3H), 2.19 (s, 3H);
1737	G _oο Γ B 9	E^rf, 539, 561	11	486.0 (M⁺+l );	467.11 for c₂₅h₁₇n₅o	‘H-NMR (DMSOO, 400 MHz): δ 13.26 (br s, 1H), 10.64 (br

-399 -

					₃S	s, 1H), 9.22 (t, J = 5.8 Hz, 1H), 8.30 (s, 1H), 8.16 (s, 1H), 7.90 (dd, J = 8.7, 1.4 Hz, 1H), 7.80-7.74 (m, 2H), 7.71 (s 1H), 7.67-7.58 (m, 3H), 7.43 (d, J = 8.4 Hz, 1H), 7.39-7.30 (m, 2H), 4.66 (d, J = 5.6 Hz, 2H);
1738-A	ο / ^NH H W X Jl N-X_e ,CH₃ H § ^/===( ch₃	D°, 539, 562	68	486.0 (M⁺+l );	485.14 for C₂₇H₂₃N₃O ₄s	*H-NMR (DMSO-dô, 500 MHz): δ 10.64 (s, 1H), 9.21 (t, J = 5.8 Hz, 1H), 7.78 (dd, J = 7.7, 1.6 Hz, 1H), 7.73-7.69 (m, 2H), 7.66-7.60 (m, 2H), 7.56 (s, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 4.64 (d, J = 5.8 Hz, 2H), 3.68 (s, 3H), 2.26 (s, 6H);
1831	o >-NH O cCm>v^ < -Z-/ V ^N V_y~-N	D°, 539, 564	16	479.1 (M⁺+l );	478.11 for C₂₇H₁₈N₄O ₃s	‘H NMR ((DMSOd₆, 400 MHz): δ 10.65 (s, 1H), 9.27 (t, J = 5.8 Hz, 1H), 8.93 (dd, J = 4.3, 1.8 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.50 (dd, J = 0.9, 8.6 Hz, 1H), 8.29 (dd, J = 8.8, 2.1

-400 -

						Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.88 (s, 1H), 7.79 (dd, J = 7.7, 1.7 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.68-7.56 (m, 3H), 7.44 (d, J = 8.4 Hz, 1H), 7.39-7.31 (m, 2H), 4.71 (d, J = 5.6 Hz, 2H)
1832	Ο Vnh P	D°, 539, 565	10	479.1 (M⁺+l );	478.11 for C₂₇H₁₈N₄O ₃s	*H NMR ((DMSOd₆, 400 MHz): δ 10.65 (s, 1H), 9.34 (s, 1H), 9.29 (br t, J = 5.7 Hz, 1H), 8.55 (d, J = 5.8 Hz, 1H), 8.51 (s, 1H), 8.21 (s, 2H), 7.95 (d, J = 5.6 Hz, 1H), 7.92 (s, 1H), 7.79 (dd, J = 7.7, 1.6 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.68-7.60 (m, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.40-7.29 (m, 2H), 4.72 (d, J = 5.5 Hz, 2H);
1861	O Vnh p _a 0	D^p, 539, 567	31	506.1 (M⁺+l );	505.08 for C₂₅Hi₉N₃O 5S2	'H NMR ((DMSOd₆, 400 MHz): δ 10.63 (s, 1H), 9.25 (t, J = 5.8 Hz, 1H), 8.13 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H), 7.89 (s, 1H),

-401 -

						7.77 (dd, J= 7.8, 1.4 Hz, 1H), 7.69 (d, J = 1.7 Hz, 1H), 7.61 (dd, J = 9.0, 2.0 Hz, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 4.68 (d, .7= 5.5 Hz, 2H);
1862	Ο ο 1 t $ °=ω=_Ο ζ I	D, 539, 576	15	507.1 (Μ⁺+1 );	506.07 for C₂₄Hi₈N₄O sS₂	*H NMR (DMSO-J₆, 400 MHz): δ 10.64 (s, 1H), 9.26 (t, J = 5.7 Hz, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.93-7.86 (m, 3H), 7.78 (dd, J= Ί.Ί, 1.4 Hz, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.677.59 (m, 2H), 7.497.40 (m, 3H), 7.397.30 (m, 2H), 4.69 (d, 5.6 Hz, 2H);
1863		D^p, 539, 568	25	521.0 (Μ⁺+1 );	520.09 for C₂₅H₂₀N₄O sS₂	*H NMR (400 MHz, DMSO-d₆) δ 10.63 (s, 1H), 10.05 (s, 1H), 9.20 (t, J = 5.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.77 (dd, J = 7.7, 1.7 Hz, 1H), 7.73 (s, 1H), 7.69 (d, J = 2.1 Hz, 1H), 7.65-7.60 (m Hz, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.37 -

-402 -

						7.30 (m, 2H), 7.26 (d, J = 8.8 Hz, 2H), 4.64 (d, J = 5.5 Hz, 2H), 3.04 (s, 3H);
1865	Ο ^^-νη ,9 Μ À, Jl 1 ΑΑοΑΑ η	G“’ 539, 485	34	451.1 (Μ⁺+1 );	450.14 for C₂₃H22N₄O ₄s	^lH NMR ((DMSOd₆, 400 MHz): δ 10.62 (s, 1H), 9.058.93 (m, 1H), 7.78 (dd, J = 7.7, 1.6 Hz, 1H), 7.71-7.55 (m, 3H), 7.44-7.28 (m, 3H), 6.99 (s, 1H), 4.73 (d, J = 4.1 Hz, 1H), 4.41 (d, J = 5.5 Hz, 2H), 3.76-3.52 (m, 3H), 3.14-3.05 (m, 2H), 1.82-1.70 (m, 2H), 1.46-1.33 (m, 2H);
1866	Ο ^-ΝΗ Ο fl ΧΥΛ-χ^ ^Ν <Α-Ο	Μ^α, 539, 545	14	485.1 (Μ⁺+1 );	484.09 C₂₂H₂oN₄0 5S2	‘H NMR (DMSO-t/ô, 400 MHz): δ 10.63 (s, 1H), 9.06 (t, J = 5.6 Hz, 1H), 7.78 (d, J = 6.7 Hz, 1H), 7.69-7.58 (m, 3H), 7.41 (d, J = 8.3 Hz, 1H), 7.38-7.30 (m, 2H), 7.07 (s, 1H), 4.44 (d, J = 5.5 Hz, 2H), 3.91-3.84 (m, 4H), 3.23-3.14 (m, 4H);

-403 -

		H,		435.0	434.05	*H NMR (DMSO/ 400 MHz): δ 10.63 (s, 1H), 9.25 (t, J = 5.5 Hz, 1H), 7.95 (d, J = 3.1 Hz, 1H), 7.90 (d, J = 3.1 Hz, 1H),
1893	Y^NH 9 H ΥΛ _zs X —Λ S N XJ	539, 610	9	(M⁺+l );	C₂iH_I4N₄O 3 $2	7.86 (s, 1H), 7.78 (dd, J = ΊΠ, 1.6 Hz, 1H), 7.69 (d, J= 2.0 Hz, 1H), 7.66-7.60 (m, 2H), 7.43 (d, J = 8.3 Hz, 1H), 7.397.31 (m, 2H), 4.67 (d, J=5.5Hz, 2H);

D^a: ΡάζΡΡΙ/ (0.1 equiv), reaction temp 90-100 °C; D^b: Pd(PPh3)4 (0.1 equiv), Na2CO2 (3.0 equiv); D^c: Pd(PPh3)₄ (0.1 equiv), boronic acid (2 equiv), Na₂CO₃ (5 equiv), reaction time 4 h; D^rf: Pd(PPh3)4 (0.1 equiv), reaction temp 110 °C; D^e: 1, 4-dioxane: H₂O (4: 1); D^f: Pd(PPh3)4 5 (0.1 equiv), reaction performed in a sealed tube; D^g: reaction performed at 80 °C; D¹: boronate ester (2 equiv); I>: Pd(PPh3)4 (0.1 equiv), boronic acid (2.5 equiv), Na₂CO₃ (5 equiv), 80-90 °C; D¹: Pd(PPh3)4 (0.1 equiv), boronic acid (2 equiv), Na2CO3 (5 equiv), reaction time 16 h; D°: Reaction performed in a sealed tube; D^p: DME: H2O (3: 1), Na₂CO₂ (3 equiv), boronic acid/Ester (1.2 equiv), reaction performed in sealed tube, reaction temp 120 °C, 16 h; D^q: 10 Reaction time 24 h; D^r: Cs2CO3 (3 equiv), reaction performed in sealed tube at 120 °C, reaction time 16 h; D^s: Na2CO₂ (3.5 equiv), boronic acid (3 equiv), Pd(dppf)Cl₂ (0.1 equiv), DME, sealed tube, 120 °C, 16 h; E^è: boronate ester (2.5 equiv), reaction time 16 h at 120 °C, sealed tube; E^c: Pd(PPh3)4 (0.1 equiv), 100 °C, reaction time 24 h; E^rf: Pd(PPh3)4 (0.1 equiv), 120 °C, reaction time 48 h; F°: Amine (3 equiv), 160 °C, 16 h;

G^a: Amine (3 equiv), DIPEA (3 equiv), 100 °C, 20 h; G^b: Amine (1.5 equiv), 110 °C, 16 h; G^c: Amine (2 equiv), 160 °C, 20 h; G^d Amine (2 equiv), DIPEA (3 equiv), 160 °C, 16 h; H^a: 700 mg of crude tin reagent was taken for the 200 mg batch; H^b: 2 g of crude tin reagent was taken

-404 for the 200 mg batch, Pd(dppf)Cl₂ (0.1 equiv), 100 °C, reaction time 16 h; H^d: tin reagent (1 equiv), Pd(dppf)Cl₂ (0.1 equiv), 1,4-dioxane, 110 °C, 16 h; H^d: tin reagent (5 equiv), 120 °C;

Γ: amine (1.2 equiv), Cs₂CO₃ (3 equiv); I^b: Cs₂CO₃ (2 equiv); Γ: amine (1.5 equiv), Xantphos (0.05 equiv), Pd₂(dba)₃ (0.025 equiv), Cs₂CO₃ (3.5 equiv) conventional heating, 100-110 °C;

h; J^b: Cs₂CO₃ (3 equiv), /-BuXphos (0.07 equiv), Pd₂(dba)₃ (0.05 equiv), 1,4-dioxane, sealed tube, 100 °C, 16 h ; K: amine (2 equiv), Cs₂CO₃ (5 equiv); NMP, sealed tube 120 °C, 16 h;

Synthesis of l-(thiazol-5-yl) ethan-l-one oxime (618): To a stirring solution of compound 267 (800 mg, 6.29 mmol) in MeOH (20 mL) under inert atmosphère was added hydroxyl amine hydrochloride (875 mg, 12.59 mmol) and pyridine (2 mL) dropwise for 5 min at 0 °C warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo diluted with water (50 mL) and stirred for 30 min. The precipitated solid was filtered dried in vacuo to afford compound 618 (800 mg, 90%) as white solid. TLC: 40% EtOAc/ hexanes (Ry 0.4, 0.6); 'H NMR (DMSO-Jé, 400 MHz) (Mixture of E/Z isomers): δ 11.86 (s, 1H), 11.41 (s, 0.6 H), 9.19 (s, 1H), 9.01 (s, 0.56 H), 8.35 (s, 1H), 8.15 (s, 0.65 H), 2.31 (s, 3H), 2.21 (s, 2H).

-405 Synthesis of l-(thiazol-5-yl) ethan-l-amine (619): To a stirring solution of compound 618 (800 mg, 5.63 mmol) in MeOH: acetic acid (1: 1, 20 mL) under inert atmosphère were zinc powder (2.2 g, 33.80 mmol) at RT; heated at 50 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite washed with MeOH (3x10 mL). The filtrate was removed in vacuo, the residue was diluted with water (20 mL), basified with aqueous ammonia (15 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude compound 619 (racemic) (700 mg, 92%) as brown syrup. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.4, 0.6); ’ll NMR (DMSO-î/₆, 400 MHz): δ 8.90 (s, IH), 7.71 (s, IH), 4.33-4.28 (m, IH), 3.38 (t, J = 6.4 Hz, IH), 1.87 (s, 3H).

Synthesis of 1 l-oxo-A-(l-(thiazol-5-yl) ethyl)-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8carboxamide (620 Racemic): Using typical procedure A the title compound was prepared with DBT-Acid (150 mg, 0.55 mmol) and compound 619 racemic (109 mg, 0.66) to afford compound 620 (Racemic) (100 mg, 48%); TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.5); 'H NMR (DMS 0-(¾ 400 MHz): δ 10.87 (br s, IH), 9.14 (d, J= 8.0 Hz, IH), 8.95 (s, IH), 7.79 (d, J= 3.6 Hz, 2H), 7.70-7.58 (m, 3H), 7.56-7.42 (m, 3H), 5.48-5.41 (m, IH), 1.60 (s, 3H); LC-MS: 98.31%; 381.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.03 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.68%; (column; Eclipse XDB C-18 (150 x 4.6 mm, 5.0 pm); RT 7.58 min. ACN : 0.05% TFA (Aq); 1.0 mL/min) (IP14012554); Chiral HPLC: 35.10%, R_t= 9.01 min (Chiralpak-IA, 250 x 4.6 mm, 5 pm); mobile phase (A) 0.1% DEA in rz-Hexane (B) CH₂C1₂: MeOH (50: 50) (A: B:: 63: 35); Flow Rate: 1.0 mL/min).

The racemic compound 620 (100 mg) was separated by préparative HPLC using a CHIRALPAK-IC column (250 x 20 mm x 5 pm) (10 mg loading; mobile phase (A) 0.1% DEA in w-Hexane (B) CH₂C1₂: MeOH: DMF (65: 35: 05) (A: B:: 75: 25) to afford 1432 (10 mg) and 1433 (15 mg) as an off-white solids.

Analytical Data of 1432:

-406 TLC: 5% MeOH/ CH₂C1₂ (Rf 0.5); *H NMR (DMSO-J₆,400 MHz): δ 10.75 (s, 1H), 9.02 (d, J= 7.8 Hz, 1H), 8.95 (s, 1H), 7.79 (s, 1H), 7.72-7.64 (m, 3H), 7.62-7.58 (m, 1H), 7.56-7.41 (m, 3H), 5.45 (t, J = 7.0 Hz, 1H), 1.57 (d, 7= 6.8 Hz, 3H); LC-MS: 96.06%; 381.8 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.03 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 95.02%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 pm); RT 7.79 min. ACN : 0.05% TFA (Aq); 1.0 mL/min) (IP15O1O53O); Chiral HPLC: 96.24%, R_t= 14.33 min (Chiralpak-IA, 250 x 4.6 mm, 5 pm); mobile phase (A) 0.1% DEA in n-Hexane (B) CH₂C1₂: MeOH:DMF (65: 35: 05) (A: B:: 75: 25); Flow Rate: 1.0 mL/min).

Analytical Data of 1433:

TLC: 5% MeOH/ CH₂C1₂ (Rf 0.5); ’fl NMR (DMSO-7₆,400 MHz): δ 10.75 (s, 1H), 9.03 (d, 7= 8.3 Hz, 1H), 8.95 (s, 1H), 7.79 (s, 1H), 7.71-7.63 (m, 3H), 7.62-7.58 (m, 1H), 7.56-7.42 (m, 3H), 5.48-5.47(m, 1H), 1.57 (d,7 = 6.9 Hz, 3H); LC-MS: 96.65%; 381.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.68 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 98.53%; (column; Zorbax SB ΟΙ 8 (150 x 4.6 mm, 3.5 pm); RT 7.76 min. ACN : 0.05% TFA (Aq); 1.0 mL/min) (IP 15010229). Chiral HPLC: 99.87%, R_t= 16.90 min (Chiralpak-IA, 250 x 4.6 mm, 5 pm); mobile phase (A) 0.1% DEA in n-Hexane (B) CH₂C1₂: MeOH: DMF (65: 35: 05) (A: B:: 75: 25); Flow Rate: 1.0 mL/min).

Synthesis of 1602:

-407 -

Synthesis of methyl (5-(((tert-butoxycarbonyl) amino) methyl) thiazol-2-yl) glycinate (622): To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl) carbamate 224 (500 mg, 2.01 mmol) in DMF (10 mL) were added methyl glycinate hydrochloride 621 (506 mg, 4.03 mmol), potassium iodide (334 mg, 2.01 mmol) and purged under argon atmosphère for 15 min in a sealed tube. To this were added and césium carbonate (1.97 g, 6.04 mmol) purged under argon atmosphère for 5 min; followed by addition of Pd₂(dba)₃ (92.3 mg, 0.10 mmol), ^zBu-Me4Xphos (96.9 mg, 0.20 mmol) at RT; heated to 100 °C and stirred for 18 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (100 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 40% EtOAc/ hexanes further purified by préparative HPLC purification to afford compound 622 (210 mg, 9%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf 0.5); 'H-NMR (DMSO-4 500 MHz): 7.81 (t, J = 5.2 Hz, 1H), 7.28 (t, J = 5.5 Hz, 1H), 6.75 (s, 1H), 4.04 (d, J = 5.5 Hz, 2H), 3.99 (d, J= 6.1 Hz, 2H), 3.62 (s, 3H), 1.38 (s, 9H).

-408 -

Synthesis of methyl (5-(aminomethyl) thiazoI-2-yl) glycinate hydrochloride (623): To a stirring solution of compound 622 (200 mg, 0.66 mmol) in CH2CI2 (5 mL) was added 4 N HCl in 1, 4- dioxane (5 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was triturated with diethyl ether (2x5 mL) and dried in vacuo to afford compound 623 (190 mg, HCl sait) as an off-white solid. TLC: 40% EtOAc/ hexanes (Rf 0.2); 'H-NMR (DMSO-î/₆, 400 MHz): δ 8.69 (br s, 1H), 8.23 (br s, 3H), 7.15 (s, 1H), 4.14-4.11 (m, 2H), 4.05 (q, J = 5.4 Hz, 2H), 3.64 (s, 3H).

Synthesis of methyl (5-((1 l-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) glycinate (624): To a stirring solution of compound 6 (100 mg, 0.49 mmol) in DMF (5 mL) under inert atmosphère were added compound 623 (90 mg, 0.37 mmol), EDCI.HC1 (137 mg, 0.75 mmol), HOBt (102 mg, 0.75 mmol) and diisopropylethylamine (0.35 mL, 1.89 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (50 mL). The obtained solid was filtered and dried in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 4-10% MeOH/ CH2CI2 to afford compound 624 (95 mg, 57%) as pale yellow solid. TLC: 10% MeOH/ CH2CI2 (Rf. 0.4); *HNMR (DMSOV 500 MHz): δ 10.75 (s, 1H), 9.03 (t, J= 6.1 Hz, 1H), 7.83 (t, J= 6.2 Hz, 1H), 7.72-7.63 (m, 3H), 7.59-7.42 (m, 4H), 6.86 (s, 1H), 4.37 (d, J = 5.8 Hz, 2H), 3.99 (d, J= 6.1 Hz, 2H), 3.61 (s, 3H).

Synthesis of (5-((1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) glycine (1 602): To a stirring solution of compound 624 (90 mg, 0.19 mmol) in THF: H2O (1: 1, 10 mL) was added lithium hydroxide monohydrate (46 mg, 0.99 mmol) at RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL), washed with EtOAc (2x10 mL). The pH of the aqueous layer was acidified with 4 N HCl to ~2. The precipitated solid was filtered,

-409 - washed with water (10 mL) and triturated with CH₃CN (5 mL) and dried in vacuo to afford 1602 (60 mg, 69%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf. 0.2); 'H-NMR (DMSO-î/ô, 500 MHz): δ 10.75 (s, 1H), 9.02 (t, J = 5.5 Hz, 1H), 7.71-7.62 (m, 3H), 7.60-7.43 (m, 5H), 6.85 (s, 1H), 4.37 (d, J= 5.5 Hz, 2H), 3.76 (d, 0 4.3 Hz, 2H); LC-MS: 93.40%;

440.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.77 min. 0.025%

Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 94.16%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 5.80 min. 0.05% TFA (Aq): ACN; 1.0 mL/min).

Synthesis of methyl 2-((5-(((terZ-butoxycarbonyl) amino) methyl) thiazol-2-yl) thio) acetate (626): To a stirring solution of terLbutyl ((2-chlorothiazol-5-yl) methyl) carbamate 224 (1 g,

4.03 mmol) in 1, 4-dioxane (10 mL) was added methyl thioglycolate 625 (1.3 mL, 12.09 mmol), potassium iodide (1.34 g, 8.06 mmol) and césium carbonate (2.62 g, 8.06 mmol) at RT in a sealed tube and purged under argon atmosphère for 15 min. To this were added Pd2(dba)₃(184 mg, 0.20 mmol), Xantphos (163 mg, 0.28 mmol) at RT; heated to 120 °C and stirred for

-410 -

h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with EtOAc (200 mL), washed with water (100 mL) and brine (50 mL). The organic extract was dried over sodium sulfate, fdtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20-30% EtOAc/ hexanes to afford compound 626 (620 mg, 48%) as pale yellow thick syrup. TLC: 30% EtOAc/ hexanes (Rf. 0.2); 'H-NMR (DMSO-î/₆, 500 MHz): δ 7.49 (t, J= 6.1 Hz, 1H), 7.47 (s, 1H),4.22 (d, J=5.8Hz, 2H),4.12(s, 2H), 3.65 (s, 3H), 1.38 (s, 9H).

Synthesis of methyl 2-((5-(aminomethyl) thiazol-2-yl) thio) acetate hydrochloride (627): To a stirring solution of compound 626 (500 mg, 1.57 mmol) in CH2CI2 (2 mL) was added 4 N HCl in 1, 4- dioxane (5 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was triturated with diethyl ether (2x5 mL) and dried in vacuo to afford compound 627 (400 mg, HCl sait) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf 0.2); ‘H-NMR (DMSO-d₆, 500 MHz): δ 8.47 (br s, 3H), 7.75 (s, 1H), 4.24 (q, J = 5.7 Hz, 2H), 4.18 (s, 2H), 3.66 (s, 3H).

Synthesis of methyl 2-((5-((1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8carboxamido) methyl) thiazol-2-yl) thio) acetate (628): To a stirring solution of compound 6 (150 mg, 0.58 mmol) in DMF (5 mL) under inert atmosphère were added compound 627 (139 mg, 0.64 mmol), EDCI.HC1 (224 mg, 1.17 mmol), HOBt (158 mg, 1.17 mmol) and diisopropylethylamine (0.30 mL, 1.76 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL), the precipitated solid was filtered and dried in vacuo to afford compound 628 (180 mg, 65%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.4); *HNMR (DMSO-dg 500 MHz): δ 10.75 (br s, 1H), 9.20 (t, J = 4.6 Hz, 1H), 7.71-7.62 (m, 3H), 7.59-7.40 (m, 5H), 4.53 (d, J = 52 Hz, 2H), 4.10 (s, 2H), 3.62 (s, 3H).

-411 Synthesis of 2-((5-((1 l-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) thio) acetic acid (1603): To a stirring solution of compound 628 (100 mg, 0.21 mmol) in THF: H₂O (5: 1,6 mL) was added lithium hydroxide monohydrate (15 mg, 0.31 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was volatiles were removed in vacuo. The crude was diluted with water (20 mL) and washed with EtOAc (2x10 mL). The pH of the aqueous layer was adjusted with 4 N HCl to ~2. The precipitated solid was filtered and dried in vacuo to afford 1603 (42 mg, 43%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); ‘H-NMR (DMSO-4 500 MHz): δ 10.76 (s, 1H), 9.21 (t, J= 5.8 Hz, 1H), 7.71-7.64 (m, 3H),

7.61-7.42 (m, 5H), 4.54 (d, J = 4.9 Hz, 2H), 3.99 (s, 2H); LC-MS: 95.88%; 457.9 (M⁺+l);

(column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.11 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 92.76%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 7.99 min. ACN + 0.5% TFA (Aq) + 0.5% TFA (Aq)+ 5% ACN; 1.0 mL/min).

Synthesis of di-tert-huixX ([2, 2’-bithiazole]-5, 5'-diylbis (methylene)) dicarbamate (631):

To a stirring solution of teH-butyl ((2-chlorothiazol-5-yl) methyl) carbamate 224 (2 g, 8.06

-412mmol) in Toluene: EtOH: H₂O (2: 2:1, 25 mL) under inert atmosphère was sodium carbonate (1.70 g, 16.12 mmol) at RT and purged under argon atmosphère for 30 min; added Pd(dppf)Cl₂(589 mg, 0.80 mmol) and heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 25% EtOAc/ hexanes to afford compound 631 (650 mg) as an off-white solid. TLC: 40% EtOAc/ hexanes (Ry 0.3); 'H-NMR (DMSO4, 500 MHz): δ 7.74 (s, 2H), 7.60 (br s, 2H), 4.34 (d, J= 6.1 Hz, 4H), 1.40 (s, 18H); LC-MS: 80.62%; 427.0 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.56 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of [2, 2'-bithiazole]-5, 5'-diyldimethanamine dihydrochloride (632): To a stirring solution of compound 631 (650 mg, 0.52 mmol) in CH₂C1₂ (15 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (1 mL) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was titurated with CH₂C1₂ (2x5 mL) and dried in vacuo to afford compound 632 (380 mg, 84%; HCl sait) as white solid. TLC: 40% EtOAc/ hexanes (Ry 0.1); LC-MS: 99.31%; 227.2 (M⁺+l); (column; Atlantis T3 (150 x 4.6 mm, 3 pm); RT 5.96 min. 2.5 mM Aq. NH₄OAc: ACN; 1.0 mL/min).

Synthesis of 2, 5-dioxopyrrolidin-l-yl ll-oxo-10,11-dihydrodibenzo [6,/] [1, 4] thiazepine-8-carboxylate (630): To a stirring solution of 6 (1 g, 3.69 mmol) in THF (20 mL) under inert atmosphère were added diisopropylethylamine (1.98 mL, 11.07 mmol), CDI (910 mg, 4.42 mmol) and M-hydroxysuccinirnide 629 (509 mg, 4.42 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite. The filtrate was diluted with EtOAc (2x50 mL) washed with water (50 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude, which was titurated with 10% diethylether/ pentane (10 mL) and dried in vacuo to afford compound 630 (1 g, 74%) as an white solid. TLC: 10%

-413 MeOH/ CH₂C1₂ (Rf. 0.8); 'il NMR (DMSO-îZ₆, 500 MHz): δ 10.89 (s, 1H), 7.91 (s, 1H), 7.857.80 (m, 2H), 7.71 (dd, J = 7.5, 1.2 Hz, 1H), 7.60-7.47 (m, 3H), 2.88 (s, 4H); LC-MS: 96.35%; 368.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.25 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis ofM((5'-(aminomethyl)-[2, 2'-bithiazol]-5-yl) methyl)-11-oxo-10, 11dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide (633): To a stirring solution of compound 630 (365 mg, 1.22 mmol) in DMF (15 mL) under inert atmosphère was added diisopropylethylamine (0.43 mL, 2.43 mmol) at 0 °C stirred for 10 min; added compound 632 (300 mg, 0.81 mmol), heated to 50 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (100 mL) and extracted with 10% MeOH/ CH₂C1₂ (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude with titurated with CH₂C1₂ (20 mL) and dried in vacuo to afford crude compound 633 (250 mg) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); LC-MS: 40.20%; 480.0 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.80 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of7V-((5'-(aminomethyl)-[2, 2'-bithiazol]-5-yl) methyl)-! 1-oxo-10, 11dihydrodibenzo \b,f\ [1,4] thiazepine-8-carboxamide hydrochloride (1735): To a stirring solution of compound 633 (250 mg, 0.52 mmol) in CH₂C1₂ (15 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (0.4 mL) at 0 °C; warmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was triturated with CH2O2 (10 mL), MeOH (5 mL) and further purified by préparative HPLC purification to afford 1735 (28 mg, 4%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (eluted 2 times) (Rf 0.1); X-NMR (DMSO-X 500 MHz): δ 10.79 (s, 1H), 9.33 (t, J= 5.8 Hz, 1H), 8.25 (br s, 3H), 7.97 (s, 1H), 7.88 (s, 1H), 7.72-7.67 (m, 3H), 7.60 (dd, J= 8.4, 2.0 Hz, 1H), 7.56-7.44 (m, 3H), 4.67 (d, J = 5.8 Hz, 2H), 4.37 (s, 2H); LC-MS: 99.23%; 480.0 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.77 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC

-414(purity): 96.62%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 5.52 min. ACN +

5% 0.05% TFA (Aq): 0.5% TFA (Aq) + 5% ACN; 1.0 mL/min, Diluent: DMSO: ACN: water).

-415 -

Synthesis of methyl 4-(5-(((tert-butoxycarbonyl) amino) methyl) thiazol-2-yl) benzoate (635): To a stimng solution of tert-butyl ((2-chlorothiazol-5-yl) methyl) carbamate 224 (500 mg, 2.01 mmol) in 2-methyltetrahydrofuran (10 mL) under argon atmosphère were added (4(methoxycarbonyl) phenyl) boronic acid 634 (435 mg, 2.41 mmol), sodium carbonate (427 mg, 4.02 mmol) at RT in a sealed tube and purged under argon atmosphère for 10 min. To this was added Pd(dppf)Cl₂ (73.7 mg, 0.10 mmol); heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with

EtOAc (100 mL), washed with water (50 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through mobile phase liquid chromatography using 10% EtOAc/ hexanes to afford compound 635 (280 mg, 40%) as pale yellow solid. TLC: 30% EtOAc/ hexanes (Rf 0.3); ¹ H-NMR (DMSO-î/ô, 500 MHz): δ 8.05-8.02 (m, 4H), 7.76 (s, 1H), 7.58 (t, J= 5.6 Hz, 1H), 4.35 (d, J = 6.1 Hz, 2H),

3.86 (s, 3H), 1.39 (s, 9H).

Synthesis of methyl 4-(5-(aminomethyl) thiazol-2-yl) benzoate hydrochloride (636): To a stirring solution of compound 635 (280 mg, 0.80 mmol) in CH₂C1₂ (10 mL) under inert

-416 atmosphère was added 4 N HCl in 1, 4-dioxane (10 mL) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with diethyl ether (2x30 mL) and dried in vacuo to afford compound 636 (200 mg, 88%) as pale brown solid. TLC: 30% EtOAc/ hexanes (Rf 0.2); 'H-NMR (DMSO-4 500 MHz): δ 8.57 (br s, 3H), 8.10-8.09 (m, 4H), 8.06 (s, 1H), 4.38 (d, J = 4.0 Hz, 2H), 3.89 (s, 3H).

Synthesis of methyl 4-(5-((1 l-oxo-10, 11-dihydrodibenzo \b,f\ [1,4] thiazepine-8carboxamido) methyl) thiazol-2-yl) benzoate (1599-A): To a stirring solution of compound 636 (200 mg, 0.74 mmol) in DMF (8 mL) under inert atmosphère were added EDCI.HC1 (211 mg, 1.10 mmol), HOBt (149 mg, 1.10 mmol), compound 248 (250 mg, 0.88 mmol) and diisopropylethylamine (0.70 mL, 3.69 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice-cold water (50 mL) and stirred for 10 min. The precipitated solid was filtered and dried in vacuo to obtain the crude. The crude was washed with diethyl ether (2x10 mL), n-pentane (2x10 mL) and dried in vacuo to afford compound 1599-A (140 mg, 38%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.5); 'H NMR (DMSO-ri_6j400 MHz): δ 10.78 (s, 1H), 9.31 (t, J = 5.5 Hz, 1H), 8.03 (s, 4H), 7.87 (s, 1H), 7.74-7.66 (m, 3H), 7.63-7.59 (m, 1H), 7.57-7.41 (m, 3H), 4.68 (d, J= 5.5 Hz, 2H), 3.87 (s, 3H); LC-MS: 94.78%; 502.3 (M⁺+l); (column; X-select CSH C-18 (50 x 3.0 mm, 2.5 pm); RT 3.95 min. 2.5 mM Aq NH₄OAc: ACN; 0.8 mL/min). HPLC (purity): 91.89%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 pm); RT 9.46 min. ACN: 0.05% TFA (Aq); 1.0 mL/min, Diluent: ACN: water).

Synthesis of 4-(5-((1 l-oxo-10, 11-dihydrodibenzo [b, f\ [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) benzoic acid (1599): To a stirring solution of 1 599-A (100 mg, 0.419 mmol) in THF: H₂O (4: 1,5 mL) was added lithium hydroxide monohydrate (21 mg, 0.49 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (10 mL) and the pH was adjusted to with 2 N HCl to ~4. The precipitated solid was filtered washed with water (50 mL) 20% EtOAc/ hexanes (5 mL), diethyl ether (5 mL), n-pentane (10 mL) and dried in vacuo to afford

-417 1599 (70 mg, 72%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf. 0.2); *H NMR (DMSO-ri_6j 400 MHz): δ 13.10 (br s, 1H), 10.79 (s, 1H), 9.31 (t,J=5.7Hz, 1H), 8.04-7.96 (m, 4H), 7.86 (s, 1H), 7.75-7.64 (m, 3H), 7.61 (dd, J=8.0, 1.7 Hz, 1H), 7.57-7.42 (m, 3H), 4.68 (d, J= 5.6 Hz, 2H). LC-MS: 92.86%; 488.3 (M⁺+l); (column; X-select CSH C-18 (50 x 3.0 mm,

2.5 pm); RT 2.93 min. 2.5 mM Aq NH₄OAc: ACN; 0.8 mL/min). HPLC (purity): 95.00%;

(column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 pm); RT 7.21 min. ACN + 5% 5 mM Aq NH₄OAc: 5 mM Aq NH₄OAc + 5% ACN; 0.8 mL/min), Diluent: ACN: water).

Synthesis of ethyl 2-(4-(5-(((tert-butoxycarbonyl) amino) methyl) thiazoI-2-yI) phenoxy) acetate (638): To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl) carbamate 356 (250 mg, 0.81 mmol) and ethyl 2-bromoacetate 637 (204 mg,1.22 mmol) in acetone (15 mL) under inert atmosphère was added potassium carbonate (338 mg, 2.45 mmol) 15 at RT; heated to 70 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (100 mL) and extracted with EtOAc (2 x 150 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford

-418 - compound 638 (250 mg, 78%) as an off-white solid. TLC: 20% EtOAc/ hexanes (Rf 0.5); ’ll NMR (DMSO-îZ₆, 500 MHz): δ 7.82 (d, J =8.7 Hz, 2H), 7.62 (s, 1H), 7.53 (t, J =5.5 Hz, 1H), 7.03 (d, J = 9.0 Hz, 2H), 4.85 (s, 2H), 4.31 (d, J = 5.8 Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 1.40 (s, 9H), 1.22 (t, J=1A Hz, 3H).

Synthesis of ethyl 2-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) acetate hydrochloride (639): To a stirring solution of compound 638 (250 mg, 0.63 mmol) in CH2CI2 (10 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (10 mL) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with diethyl ether (10 mL) and dried in vacuo to afford compound 639 (190 mg, 90%) as white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.2); ’H-NMR (DMSO-î/₆, 500 MHz): δ 8.55 (br s, 3H), 7.90 (s, 1H), 7.84 (d, J = 8.7 Hz, 2H), 7.04 (d, J= 8.7 Hz, 2H), 4.85 (s, 2H), 4.30 (q, J= 5.4 Hz, 2H), 4.16 (q, J= 7.2 Hz, 2H), 1.20 (t, J=1A Hz, 3H).

Synthesis of ethyl 2-(4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b, f [1,4] thiazepine8-carboxamido) methyl) thiazol-2-yl) phenoxy) acetate (640): To a stirring solution of compound 6 (75 mg, 0.27 mmol) in DMF (5 mL) under inert atmosphère were added compound 639 (100 mg, 0.30 mmol), EDCI.HC1 (80 mg, 0.41 mmol), HOBt (56 mg, 0.41 mmol), and diisopropylethylamine (0.27 mL, 1.47 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice-cold water (50 mL) and extracted with EtOAc (2 x 150 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3% MeOH/ CH2CI2 to afford compound 640 (80 mg, 53%) as white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.4); ‘H NMR (DMSO4,500 MHz): δ 10.77 (s, 1H), 9.25 (t, J= 4.9 Hz, 1H), 7.80 (d, J= 8.4 Hz, 2H), 7.74-7.65 (m, 4H), 7.60 (d, J= 7.8 Hz, 1H), 7.56-7.43 (m, 3H), 7.01 (d, J = 8.4 Hz, 2H), 4.84 (s, 2H), 4.64 (d, J= 5.2 Hz, 2H), 4.17 (q, J= 6.8 Hz, 2H), 1.21 (t, J = 6.9 Hz, 3H).

-419 Synthesis of 2-(4-(5-((1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) acetic acid (1607): To a stirring solution of compound 640 (80 mg, 0.15 mmol) in THF: H₂O (4: 1, 10 mL) was added lithium hydroxide monohydrate (32 mg, 0.77 mmol) at RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted water (50 mL) and the pH was acidified with 2 N HCl to ~6. The precipitated solid was filtered and dried in vacuo to afford 1607 (70 mg, 80%) as white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.2); 'H-NMR (DMSO-Jô, 500 MHz): δ 13.06 (br s, IH), 10.77 (s, IH), 9.25 (t, J=5.6Hz, IH), 7.80 (d,J = 9.0 Hz, 2H), 7.72-7.65 (m, 4H), 7.62-7.59 (m, IH), 7.55-7.43 (m, 3H), 6.99 (d, J = 9.0 Hz, 2H), 4.73 (s, 2H), 4.63 (d, J= 5.5 Hz, 2H); LC-MS: 96.16%; 517.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.17 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.19%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 pm); RT 7.98 min; 0.05% TFA (Aq) : 5% ACN; 1.0 mL/min, Diluent: ACN: water).

Synthesis of 1 l-oxo-A-((2-(3-oxoazepan-l-yl) thiazol-5-yl) methyl)-10, 11-dihydrodibenzo \b, f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide (1909): To a stirring solution of 1908 (100 mg, 0.19 mmol) in DMSO (10 mL) under inert atmosphère was added iodoxybenzoic acid (218 mg, 0.97 mmol) at RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (50 mL) and extracted with

-420 10% MeOH/ CH2Q2 (2 x 50 mL)., The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2CI2 to afford 1909 (60 mg, 60%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.5); *H-NMR (DMSO-/ 400 MHz): δ 11.50 (s, 1H), 9.29 (t, 5.7 Hz, 1H), 8.04 (d, J= 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.77 (m,

4H), 7.03 (s, 1H), 4.45 (d, J= 5.6 Hz, 2H), 4.15 (s, 2H), 3.66-3.59 (m, 2H), 2.28-2.23 (m, 2H), 1.86-1.64 (m, 4H); LC-MS: 91.22%; 511.1 (M⁺+l); (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 1.93 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 91.03%; (column; X-select CSH-C18 (150 x 4.6 mm, 3.5 pm); RT 9.10 min. 5 mM NH4OAC: ACN; 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of M-((2-(3-methoxybenzyl) thiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo [b, f [1,4] thiazepine-8-carboxamide 5, 5-dioxide (1822): To a stirring solution A-((2-(3methoxybenzyl) thiazol-5-yl) methyl)-! 1-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8carboxamide 5, 5-dioxide (1822-A) (150 mg, 0.28 mmol) in CH2CI2 (15 mL) under inert atmosphère was added BBrs (0.082 mL, 0.86 mmol) at 0 °C; warmed to RT and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with 10% MeOH/ CH2CI2 (50 mL). The precipitated solid was filtered, and washed with 10% NaHCOs solution (20 mL). The organic extract was dried over sodium sulfate and concentrated in vacuo to obtain the crude. The crude was purified through siicagel column chromatography using 4% MeOH/ CH2CI2, and further

-421 purified by second column chromatography using 8% isopropanol/ CH2CI2 to afford 1822 (50 mg, 34%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.4); 'H-NMR (DMSO-î/î, 500 MHz): δ 11.47 (s, 1H), 9.34 (t, J= 5.8 Hz, 1H), 8.03 (d, J= 8.1 Hz, 1H), 7.97 (br t, J=8.1 Hz, 2H), 7.92-7.82 (m, 2H), 7.81 (s, 1H), 7.76 (br d, J = 8.1 Hz, 1H), 7.55 (s, 1H), 7.08 (br d, J= 8.1 Hz, 2H), 6.69 (br d, J = 8.1 Hz, 2H), 4.55 (d, J= 5.2 Hz, 2H), 4.10 (s, 2H); LC-MS: 93.47%; 506.1 (M+l)⁺ column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.01 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 93.81%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 7.53 min. 0.05% TFA + 5% ACN : ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: DMSO: ACN : water).

Synthesis of A-((2-(4-hydroxybenzyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo \b, f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (1823): To a stirring solution of A-((2-(4methoxybenzyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1,4] thiazepine-8carboxamide 5, 5-dioxide (1823-A) (80 mg, 0.15 mmol) in CH₂C1₂ (6 mL) under inert atmosphère was added BBr₃ (0.029 mL, 0.30 mmol) at 0 °C; warmed to RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (10 mL) and the precipitated solid was filtered, and washed with 10% NaHCO₃ solution (20 mL). This was titurated with 30% isopropanol/ EtOAc (30 mL) to afford 1823 (68 mg, 87%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.4); ‘H-NMR (DMSO-î7₆, 500 MHz): δ 11.47 (s, 1H), 9.34 (fJ = 5.8 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.97

-422 (brt, /=8.1 Hz, 2H), 7.92-7.82 (m, 2H), 7.81 (s, 1H), 7.76 (br d, J= 8.1 Hz, 1H), 7.55 (s, 1H), 7.08 (br d, J= 8.1 Hz, 2H), 6.69 (br d, J= 8.1 Hz, 2H), 4.55 (d, J= 5.2 Hz, 2H), 4.10 (s, 2H); LC-MS: 93.47%; 506.1 (M+l)⁺ column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.01 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 93.81%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 7.53 min. 0.05% TFA + 5% ACN : ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: DMSO: ACN : water).

Synthesis of 1653

Synthesis of AA((2-(4-carbamimidoylphenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo \b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (1653): To a stirring solution of 7V-((2-(4-cyanophenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo [6,y] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide 1654-A (175 mg, 0.35 mmol) in dry THF (5 mL) under inert atmosphère was added LiHMDS (1 M solution in THF, 3.5 mL) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (10 mL), diluted with EtOAc (10 mL). The precipitated solid was filtered and dried in vacuo to obtain the crude. The crude was purified using préparative HPLC to afford 1653 (30 mg, 16%) as white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.4); ¹ H-NMR (DMSO-V 400 MHz): δ 11.54 (s, 1H), 9.54 (t, J= 5.7 Hz, 1H), 9.37 (s, 2H), 9.00 (br s, 2H), 8.12 (d, J = 8.5 Hz, 2H), 8.07 (d, J= 8.3 Hz, 1H), 8.01-7.96 (m, 2H), 7.93-7.86 (m, 5H), 7.84 (td, J= 7.9, 1.3 Hz, 2H), 4.72 (d, J= 5.6 Hz, 2H); LC-MS: 94.34%; 518.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.75 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC

-423 (purity): 90.29%; (column; Zorbax SB-C-18 (150 x 4.6 mm, 3.5 pm); RT 5.56 min. ACN + 5% 0.05% TFA (Aq): 0.05% TFA (Aq) + 5% ACN; 1.0 mL/min, Diluent: ACN: water).

Synthesis of 1677-B

Synthesis of A-((2-(3-carbamoylphenyl)thiazol-5-yl)methyl)-l l-oxo-10, 11-dihydrodibenzo [b, f[ [1,4] thiazepine-8-carboxamide 5, 5-dioxide (1677-B): To a stirring solution of V-((2-(3cyanophenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepine-8carboxamide 5, 5-dioxide 1677-A (226 mg, 0.45 mmol) in dry THF (8 mL) under inert atmosphère was added LiHMDS (1 M solution in THF, 4.5 mL) at 0 °C; warmed to RT and stirred for 18 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (10 mL) and stirred for 30 min. The precipitated solid was filtered, washed with water and dried in vacuo to afford 1677-B (30 mg, 13%) as an off-white solid. TLC: 10% MeOH/ CH2Q2 (Rf 0.2); *H-NMR (DMSO-dtf, 400 MHz): δ 11.40 (br s, 1H), 9.50 (br t, J= 4.8 Hz, lH),8.34(s, 1H), 8.16(br s, 1H), 8.04 (brt,J = 7.6 Hz, 2H), 8.00-7.78 (m, 8H), 7.56 (br t, J = 7.7 Hz, 1H), 7.47 (br s, 1H), 4.71 (br d, J = 5.3 Hz, 2H); LC-MS: 98.51%; 518.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.97 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.86%; (column; X-Select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 7.12 min. ACN + 5% 0.05% TFA (Aq): 0.05% TFA (Aq) + 5% ACN; 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of 1901-B

-424 -

Synthesis of A-((2-(4-cyanophenyl) thiazol-5-yl) methyl)-7-hydroxy-l l-oxo-10, 11dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (1901-B): To a stimng solution of A-((2-(4-cyanophenyl) thiazol-5-yl) methyl)-7-methoxy-l l-oxo-10, 11dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (1901-A) (150 mg, 0.28 mmol) in CH₂C1₂ (10 mL) under inert atmosphère was added BBr₃ (0.13 mL, 1.41 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with 10% MeOH/ CH₂C1₂ (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2% MeOH/ CH₂C1₂ and triturated EtOAc (5 mL), dried in vacuo to afford 1901-B (120 mg, 82%) as white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.5); ‘H-NMR (DMSO-d₆, 400 MHz): δ 11.82 (br s, 1H), 11.09 (s, 1H), 9.56 (br s, 1H), 8.06 (d, J = 8.3 Hz, 2H), 7.97-7.85 (m, 6H), 7.84-7.76 (m, 2H), 7.44 (s, 1H), 4.74 (d, J= 4.4 Hz, 2H); LCMS: 97.63%; 517.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.32 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.29%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 9.48 min. ACN + 5% 0.05% TFA 0.05% TFA + 5% ACN; 1.0 mL/min, Diluent: DMSO: ACN : water)

Synthesis of 1970

-425 Synthesis ofV-((2-(4-carbamoyl-2-fluorophenyl) thiazol-5-yl)methyl)-l 1-oxo-10, 11dihydrodibenzo [b,f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (1970): To a stirring solution of 1814 (100 mg, 0.19 mmol) in DMSO (5 mL) were added 30% H₂O₂ (2 mL, 20 vol) and potassium carbonate (267 mg, 1.93 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture diluted with water (30 mL) and stirred for 1 h. The precipitated solid was filtered, dried in vacuo to obtain the crude, which was triturated with EtOAc (2 x 20 mL) and dried in vacuo to afford 1970 (80 mg, 78%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Ry 0.4); 'H-NMR (DMSO-rié, 400 MHz): δ 11.50 (br s, 1H), 9.51 (brt, J=5.4 Hz, 1H), 8.25 (br t, J= 8.0 Hz, 1H), 8.13 (br s, 1H), 8.06 (br d, J= 8.3 Hz, 1H), 8.01-7.94 (m, 3H), 7.93-7.79 (m, 6H), 7.61 (br s, 1H), 4.74 (br d, J = 5.1 Hz, 2H); LC-MS: 98.08%; 537.1 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.98 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HP LC (purity): 96.22%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 7.37 min. 0.05% TFA + 5% ACN : ACN + 0.05% TFA + 5%; 1.0 mL/min; Diluent: DMSO: ACN: water).

Synthesis of 7/-((2-(4-( 177-pyrazol-l-yl) phenyl) thiazol-5-yl) methyl)-11-oxo-10, 11dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide (1952): To a stirring solution of A-((2-(4-bromophenyl) thiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide 538 (100 mg, 0.18 mmol) in A-methyl-2pyrrolidone (4 mL) under inert atmosphère were added IH-pyrazole 441 (24 mg, 0.35 mmol) and potassium phosphate tribasic (115 mg, 0.54 mmol), copper(I) iodide (17 mg, 0.09 mmol) in a sealed tube at RT and purged under argon atmosphère for 15 min; heated to 150 °C and

-426 stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3-5% MeOH/ CH2CI2 and triturated with diethylether (5 mL) to afford 1952 (30 mg, 31%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.5); *H-NMR (DMSO-J₆, 500 MHz): δ 11.52 (br s, 1H), 9.49 (t, J= 5.5 Hz, 1H), 8.58 (d, J= 2.3 Hz, 1H), 8.10-7.94 (m, 7H), 7.93-7.76 (m, 6H), 6.58 (s, 1H), 4.70 (d, J = 5.2 Hz, 2H); LC-MS: 95.99%; 542.0 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.31 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HP LC (purity): 92.85%; (Column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 10.00 min. 5 mM NH₄OAc: ACN; 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of 1806

Synthesis of A-((2-(4-hydroxy-3, 5-dimethylphenyl) thiazol-5-yl) methyl)-11-oxo-10, 11dihydrodibenzo [b,f [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (1806): To a stirring solution of A-((2-(4-methoxy-3, 5-dimethylphenyl) thiazol-5-yl) methyl)-! l-oxo-10, 11dihydrodibenzo [b,f] [1,4] thiazepine-8-carboxamide 5,5-dioxide (1806-A) (60 mg, 0.11 mmol) in CH2CI2 (10 mL) was added BBr₃ (0.03 mL, 0.33 mmol) at 0 °C; warmed to RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (10 mL) the precipitated solid was filtered and dried in vacuo to obtain the crude which was titurated with MeOH (2 mL) and dried in vacuo to afford 1806 (30 mg, 52%) as an off-white solid. TLC: 5% MeOH/ CH2CI2 (Rf 0.5); ^lH-NMR (DMSO-Jé, 400 MHz): δ 11.52 (s, 1H), 9.43 (t, J = 5.5 Hz, 1H), 8.75 (br s, 1H), 8.05 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.79 (m, 4H), 7.66 (s, 1H), 7.45 (s, 2H), 4.64 (d, J = 5.4 Hz, 2H), 2.19 (s, 6H); LC-MS: 97.68%; 520.0 (M⁺+l); (column; Ascentis Express C18,

-427 (50 x 3.0 mm, 2.7 pm); RT 2.24 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.67%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 8.43 min. 5% 0.05% TFA +5% ACN: ACN+5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: DMSO: ACN : water).

Synthesis of A-((2-(4-hydroxy-3-methylphenyl) thiazol-5-yl) methyl)-11-oxo-10, 11dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide (1804): To a stirring solution of A-((2-(4-methoxy-3-methylphenyl) thiazol-5-yl) methyl)-11-oxo-10, 11dihydrodibenzo [b,f] [1,4] thiazepine-8-carboxamide 5, 5-dioxide (1804-A) (80 mg, 0.15 mmol) in CH₂C1₂ (10 mL) was added BBr₃ (0.07 mL, 0.77 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (10 mL). The aqueous layer was basified with saturated sodium bicarbonate solution (10 mL) and the precipitated solid was filtered washed with diethyl ether (2x10 mL) and dried in vacuo to afford 1804 (40 mg, 52%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.3); ^[H NMR (DMSO-X 400 MHz): δ 11.51 (s, 1H), 9.85 (s, 1H), 9.43 (t, J= 5.7 Hz, 1H), 8.05 (d, J= 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.927.79 (m, 4H), 7.66 (s, 1H), 7.59 (s, 1H), 7.53 (dd, J= 8.3, 2.1 Hz, 1H), 6.83 (d, J= 8.4 Hz, 1H), 4.64 (d, J= 5.6 Hz, 2H), 2.15 (s, 3H); LC-MS: 99.14%; 506.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.15 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 99.24%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 8.13 min. 5% 0.05% TFA +5% ACN: ACN + 5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: DMSO: ACN: water).

-428 -

Synthesis of M((2-(5-hydroxypyridin-2-yl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (1879): To a stirring solution of 1879-A (50 mg, 0.098 mmol) in CH₂C1₂ (5 mL) was under inert atmosphère was added BBr₃ (1 mL) at 0 °C; warmed to RT and stirred for 120 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (10 mL). The volatiles were concentrated in vacuo. The pH of the residue was adjusted to ~7.0 with saturated NaHCO₃ solution (20 mL). The precipitated solid was filtered and dried in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 35% MeOH/ CH₂C1₂ to afford compound 1879 (20 mg, 42%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.4); ‘H-NMR (DMSO-î/₆, 500 MHz): δ 10.64 (s, IH), 9.84 (s, IH), 9.17 (t, J = 5.2 Hz, IH), 7.78 (d, J= 6.9 Hz, IH), 7.72-7.58 (m, 5H), 7.53 (d, J = 8.2 Hz, IH), 7.42 (d, J= 8.3 Hz, IH), 7.38-7.31 (m, 2H), 6.83 (d, J=8.3 Hz, IH), 4.62 (d, J=5.1 Hz, 2H), 2.15 (s, 3H); LC-MS: 95.08%; 457.9 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.19 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.99%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 pm); RT 7.56 min. ACN + 5% 0.05% TFA (Aq): 0.05% TFA (Aq) + 5% ACN; 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of 1671

-429 -

Synthesis ofA%(2-(2-hydroxypyrimidin-5-yl) thiazol-5-yl)methyl)-l l-oxo-10, 11dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (1671): To a stirring solution of 7V-((2-(2-methoxypyrimidin-5-yl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo [b,f] [1,4] thiazepine-8-carboxamide 5, 5-dioxide (1671-A) (80 mg, 0.15 mmol) in CH₂C1₂ (10 mL) was added BBr₃ (0.14 mL, 0.78 mmol) at 0 °C; warmed to RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (2 mL) and stirred for 10 min. The pH was adjusted to ~7 with saturated soadium bicarbonate solution. The precipitated solid was filtered, washed with water and dried in vacuo to afford 1671 (45 mg, 58%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.5); ‘H-NMR (DMSO-î/₆, 400 MHz): δ 12.43 (br s, 1H), 11.55 (br s, 1H), 9.48 (br s, 1H), 8.77-8.58 (m, 1H), 8.11-7.72 (m, 9H), 4.68-4.63 (m, 2H); LC-MS: 96.68%; 494.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.78 min.

0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity):

93.58%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 5.70 min. ACN + 5% 0.05% TFA : 0.05% TFA + 5% ACN; 1.0 mL/min, Diluent: DMSO: ACN : water).

-430 Synthesis of A-((2-(4-carbamoylphenyl) thiazol-5-yl) methyl)-9-methyl-l 1-oxo-10, 11dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (1878): To a stirring solution of 1877 (100 mg, 0.19 mmol) in DMSO (2 mL) were added potassium carbonate (134 mg, 0.97 mmol) and 30% H₂O₂ (0.22 mL, 1.95 mmol) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL), the precipitated solid was filtered and dried in vacuo to afford 1878 (75 mg, 73%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.3); *H-NMR (DMSO/ 400 MHz): δ 10.86 (br s, 1H), 9.20 (t, J = 5.6 Hz, 1H), 8.07 (br s, 1H), 7.98-7.87 (m, 4H), 7.94 - 7.75 (m, 6H), 7.46 (br s, 1H), 7.34 (d, J = 7.9 Hz, 1H), 4.67 (d, J= 5.6 Hz, 2H), 2.32 (s, 3H); LC-MS: 98.06%; 533.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.87 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.87%; (column; X select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 6.99 min. 0.05% TFA + 5% ACN : ACN + 5% 0.05% TFA ; 1.0 mL/min, Diluent: DMSO:ACN: water).

Synthesis of (3-(4-(5-((5,5-dioxido-l l-oxo-10, 11-dihydrodibenzo \b,f] /1, 4] thiazepine-8carboxamido) methyl) thiazol-2-yl) phenoxy)propyl)-L-proline (5) (11106): To a stirring solution of 11106-A (90 mg, 0.13 mmol) in THF: MeOH: H₂O (2:1:1, 8 mL) was added lithium hydroxide monohydrate (17 mg, 0.40 mmol) at 0 °C; warmed to RT, and stirred for 2 h. The

-431 - reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo and the pH of the residue was acidified with 2 N HCl to pH ~5-6. The obtained solid was filtered, washed with water (20 mL), diethyl ether (10 mL) and dried in vacuo to obtain 11106 (50 mg, 56%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.1); *H NMR (400 MHz, DMSOV): δ 11.52 (s, 1 H), 9.47 (t,/=5.7 Hz, 1H), 8.05 (d,/=8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.79 (m, 6H), 7.72 (s, 1H), 7.02 (d, /= 8.9 Hz, 2H), 4.66 (d, /= 5.5 Hz, 2H), 4.10 (t, J= 6.1 Hz, 2H), 3.52-3.46 (m, 2H), 3.18-3.12 (m, 1H), 3.04-2.98 (m, 1H), 2.85-2.78 (m, 1H), 2.20-2.10 (m, 1H), 2.06-2.00 (m, 2H), 1.97-1.83 (m, 2H), 1.75-1.65 (m, 1H); LC-MS: 95.82%; 647.1 (M+l)⁺; (column; Ascentis Express C-18 (50 x 3.0 mm, 2.7 pm); RT 1.84 min. 0.025% Aq.TFA + 5% ACN: ACN + 5% 0.025% Aq TFA, 1.2 mL/min); HPLC (purity): 95.18%;

(column; X-Select CSH-C-18 (150 x 4.6 mm, 3.5 pm); RT 6.28 min. 0.05% TFA + 5% ACN: ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: ACN : H₂O).

Synthesis of tert-butyl (3-((4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b, J] [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenyl) sulfonyl) propyl) carbamate (11032A): To a stirring solution of 11007-A (110 mg, 0.16 mmol) in 1, 2 dichloro ethane: CH3CN: H2O (1: 1: 2, 4 mL) were added sodium metaperiodate (106 mg, 0.49 mmol), ruthénium chloride (1.7 mg, 0.05 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion, the volatiles were removed in vacuo. The residue was diluted with water (50 mL) and extracted with CH2CI2 (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified

-432 - through silicagel column chromatography using 3% MeOH/ CH2CI2 to afford 11032-A (15 mg, 13%) as white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.4); ¹ H-NMR (DMSO-t/₆, 400 MHz):

11.52 (s, 1H), 9.52 (t, J= 5.8 Hz, 1H), 8.15 (d, J= 8.4 Hz, 2H), 8.01-7.94 (m, 4H), 7.93-7.81 (m, 5H), 7.65 (br s, 1H), 6.90-6.84 (m, 1H), 4.73 (d, J= 5.6 Hz, 2H), 3.37-3.30 (m, 2H), 2.96 (q, J = 5.6 Hz, 2H), 1.70-1.59 (m, 2H), 1.33 (s, 9H); LC-MS: 97.78%; 695.1 (M-l)⁺, (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 2.91 min. 2.5 mM Aq. NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min). HP LC (purity): 94.67%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 9.28 min. 0.05% TFA (Aq) + 5% ACN: ACN + 5% 0.5% TFA (Aq) ; 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of methyl (5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo (b,J} [1, 4] thiazepine-8carboxamido) methyl) thiazol-2-yl) glycinate (641): To a stirring solution of compound 623 (150 mg, 0.49 mmol) in DMF (10 mL) under inert atmosphère were added EDCI.HC1 (179 mg, 0.99 mmol), HOBt (133 mg, 0.99 mmol) and diisopropylethylamine (0.45 mL, 5.00 mmol) and methyl (5-(aminomethyl) thiazol-2-yl) glycinate hydrochloride 92 (109 mg, 0.55 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was

-433 triturated with diethyl ether: CH₃CN (4: 1, 10 mL) and the obtained solid was dried in vacuo to afford 641 (85 mg, 35%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.4); ‘H-NMR (DMSO4 400 MHz): δ 11.50 (s, 1H), 9.23 (t, J= 5.7 Hz, 1H), 8.03 (d, J= 8.3 Hz, 1H), 7.98 (dd, J=9.3, 1.8 Hz, 2H), 7.93-7.81 (m, 4H), 7.77 (dd, J= 8.3, 1.5 Hz, 1H), 6.88 (s, 1H), 4.40 (d, J = 5.6 Hz, 2H), 3.99 (d, J= 6.2 Hz, 2H), 3.61 (s, 3H).

Synthesis of (5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo (b,f\ [1, 4] thiazepine-8carboxamido) methyl) thiazol-2-yl) glycine (1583): To a stirring solution of compound 641 (70 mg, 0.14 mmol) in THF: H2O (3: 1,8 mL) was added lithium hydroxide monohydrate (13.8 mg, 0.28 mmol) at RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and washed with EtOAc (2 x 50 mL). The pH of the aqueous layer was acidified with 4 N HCl to ~2. The precipitated solid was filtered and dried in vacuo to afford 1583 (37 mg, 54%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); ‘H-NMR (DMSO-îZ₆, 500 MHz): δ 12.50 (br s, 1H), 11.49 (s, 1H), 9.23 (t, J=5.4 Hz, 1H), 8.03 (d, J= 8.3 Hz, 1H), 7.98 (td, J=1A, 0.9 Hz, 2H), 7.90 (td, J= 7.5, 1.3 Hz, 1H), 7.87-7.81 (m, 2H), 7.77 (dd, J= 8.2, 1.2 Hz, 1H), 7.73 (t, J = 5.7 Hz, 1H), 6.88 (s, 1H), 4.40 (d, J= 5.5 Hz, 2H), 3.88 (d, J= 6.0 Hz, 2H); LC-MS: 95.64%; 472.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.75 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.00%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 pm); RT 4.87 min. ACN + 5% 0.05% TFA (Aq) : 0.05% TFA (Aq) + 5% ACN; 1.0 mL/min).

Synthesis of 1580

-434Synthesis of 2-((5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8carboxamido) methyl) thiazol-2-yl) oxy) acetic acid (1580): To a stirring suspension of added sodium hydride (60%, 27.7 mg, 1.15 mmol) in THF (15 mL) under argon atmosphère was added ethyl 2-hydroxyacetate 642 (48 mg, 0.46 mmol) at 0 °C and stirred for 1 h. To this was added compound 535 (100 mg, 0.23 mmol) at 0 °C; heated to 60 °C and stirred for 16 h. The reaction was monitored by TLC and LC-MS; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and the extracted with EtOAc (2x10 mL). The pH of the aqueous layer was adjusted to ~4 using 2 N HCl and extracted with 5% MeOH/ CH2CI2 (3 x 50 mL). The combined organic extracts were dried over sodium sulfate, fdtered and concentrated in vacuo to obtain the crude. The crude compound was purified by préparative HPLC purification to afford 1580 (10 mg, 9%) as an off-white solid. TLC: 5% MeOH/ CH₂C12 + 0.1 mL CH3COOH (R_f: 0.2); 'H-NMR (DMSO-d₆, 400 MHz): δ 9.32 (br s, 1H), 8.03 (d, J= 8.3 Hz, 1H), 7.98 (td,J=7.4, 1.1 Hz, 2H), 7.93-7.82 (m, 4H), 7.78 (dd,J=8.3, 1.6 Hz, 1H), 7.00 (s, 1H), 4.49 (br s, 2H), 4.45 (d, J= 4.7 Hz, 2H); LC-MS: 95.67%; 473.8 (M⁺+l);

(column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.96 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 94.09%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 7.17 min. ACN: 0.05% TFA (Aq); 1.0 mL/min).

Synthesis of A-((2-(2-(dimethylamino) ethoxy) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (1586): To a stirring solution of 2-(dimethylamino) ethan-l-ol 643 (62 mg, 0.69 mmol) in dry THF (10 mL) was added sodium hydride (60%, 25 mg, 0.69 mmol) under argon atmosphère was added at 0 °C and stirred for 10 min. To this was added A-((2-chlorothiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo \b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide 535 (150 mg, 0.34 mmol) at

-435 0 °C; heated to 60 °C and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (20 mL) and the extracted with EtOAc (2x10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% MeOH/ CH₂C1₂ to afford compound to afford 1586 (40 mg, 24%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.4); ’H-NMR (DMSO-riô, 400 MHz): δ 11.51 (br s, 1H), 9.36 (t, J= 5.6 Hz, 1H), 8.05 (d,J=8.4 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.83 (m, 3H), 7.78 (dd, J= 8.2, 1.3 Hz, 1H), 7.08 (s, 1H), 4.47 (d, J= 5.8 Hz, 2H), 4.43 (t, J= 5.5 Hz, 2H), 2.81-2.73 (m, 2H), 2.28 (s, 6H); LC-MS: 95.67%; 487.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.58 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.75%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 pm); RT 5.23 min. ACN: 0.05% TFA (Aq); 1.0 mL/min).

Synthesis of 7V-((2-(3-(dimethylamino) propoxy) thiazol-5-yl) methyl)-! l-oxo-10, 11dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide (1680): To a stirring suspension of 3-(dimethylamino) propan-l-ol 644 (57 mg, 0.55 mmol) in THF (20 mL) under argon atmosphère was added sodium hydride (60%, 55 mg, 1.38 mmol) at 0 oC and stirred for 20 min. To this was added N-((2-chlorothiazol-5-yl) methyl)-! l-oxo-10, 11-dihydrodibenzo [b, f] [1,4] thiazepine-8-carboxamide 5, 5-dioxide 535 (200 mg, 0.46 mmol) at 0 oC; heated to 5060 oC and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated citric acid solution (10 mL) and extracted with 10% n-butanol/ EtOAc (2 x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through basic alumina flash column chromatography using 5% MeOH/ CH2C12,

-436 triturated with 20% CH2C12/ n-pentane (10 mL) and dried in vacuo to afford 1680 (80 mg, 35%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf: 0.2); 1 H-NMR (DMSO-d6, 400 MHz): δ 11.50 (br s, 1H), 9.33 (t, J = 5.7 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.90 (td, J = 7.5, 1.5 Hz, 1H), 7.86 (dd, J = 7.5, 1.6 Hz, 1H), 7.83 (s, 1H), 7.78 (dd, J = 8.3, 1.5 Hz, 1H), 7.07 (s, 1H), 4.46 (d, J = 5.5 Hz, 2H), 4.32 (t, J = 6.5 Hz, 2H), 2.28 (t, J = 7.0 Hz, 2H), 2.10 (s, 6H), 1.87-1.79 (m, 2H); LC-MS: 95.84%; 501.0 (M++1); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.70 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 94.58%; (column; Zorbax SBC C-18 (150 x 4.6 mm, 3.5 pm); RT 5.73 min. ACN: 0.05% TFA (Aq); 1.0 mL/min, Diluent: ACN: water).

Synthesis of/V-((2-chlorothiazol-5-yl) methyl)-7V-methyl-1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (645): To a stirring solution of 92 (200 mg, 0.66 mmol) in DMF (10 mL) under inert atmosphère were added EDCI.HC1 (190 mg, 0.99 mmol), HOBt (133 mg, 0.99 mmol), compound 368 (117 mg, 0.72 mmol) and diisopropylethylamine (0.36 mL, 1.98 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (70 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through

-437silicagel column chromatography using 5% MeOH/ CH₂Cl₂ to afford compound 645 (100 mg, 33%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.6); *H NMR (DMSO-^400 MHz): δ 11.44 (br s, IH), 8.03-7.96 (m, 3H), 7.93-7.83 (m, 2H), 7.72 (s, IH), 7.46-7.39 (m, 2H), 4.75 (s, 2H), 2.85 (s, 3H); LC-MS: 96.84%; 448.0 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.19 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of A-((2-(2-(dimethylamino) ethoxy) thiazol-5-yl) methyl)-N-methyl-l l-oxo-10, 11dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (1660): To a stirring solution of 2-(dimethylamino) ethan-l-ol 643 (176 mg, 0.98 mmol) in THF (20 mL) under argon atmosphère was added sodium hydride (60%, 47 mg, 1.98 mmol) at 0 °C and stirred for 20 min. To this was added compound 645 (300 mg, 0.99 mmol) at 0 °C; heated to 60 °C and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (1 mL). The volatiles were removed in vacuo to obtain the crude. The crude compound was purified through basis alumina column chromatography using 3% MeOH/ CH₂C1₂ to afford 1660 (20 mg, 4%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); 'H-NMR (DMSO-^, 500 MHz) (rotamers): δ 11.43 (br s, IH), 8.04-7.96 (m, 3H), 7.94-7.83 (m, 2H), 7.44-7.37 (m, 2H), 7.19, 7.01 (s, IH), 4.63 (s, 1.5 H), 4.41 (t, J = 5.4 Hz, 2.5 H), 2.91, 2.81 (s, 3H), 2.65-2.60 (m, 2H), 2.19 (s, 6H); LC-MS: 95.12%; 501.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.71 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.19%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 5.09 min. ACN + 5% 0.05% TFA (Aq): 0.05% TFA (Aq) + 5% ACN; 1.0 mL/min, Diluent: ACN; water).

Synthesis of 1589

- 438 -

Synthesis of methyl 2-((5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine8-carboxamido) methyl) thiazol-2-yl) thio) acetate (647): To a stirring solution of compound 92 (200 mg, 0.66 mmol) in DMF (5 mL) under inert atmosphère were added EDCI.HC1 (179 mg, 0.99 mmol), HOBt (133 mg, 0.99 mmol) and diisopropylethylamine (0.4 mL, 1.76 mmol) and methyl 2-((5-(aminomethyl) thiazol-2-yl) thio) acetate hydrochloride 646 (183 mg, 0.73 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL), the precipitated solid was filtered and dried in vacuo to afford compound 647 (160 mg, 48%) as pale brown solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.4); 'H-NMR (DMSO-^ 500 MHz): δ 11.50 (s, 1H), 9.41 (t, .7= 5.6 Hz, 1H), 8.05 (d,J=8.1 Hz, 1H), 7.98 (t,J= 8.4 Hz, 2H), 7.90 (t, J = 7.1 Hz, 1H), 7.88-7.82 (m, 2H), 7.78 (d,J=8.1 Hz, 1H), 7.59 (s, 1H), 4.57 (d, J= 5.5 Hz, 2H), 4.12 (s, 2H), 3.64 (s, 3H).

Synthesis of 2-((5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo (b,f\ [1, 4] thiazepine-8carboxamido) methyl) thiazol-2-yl) thio) acetic acid (1589): To a stirring solution of compound 647 (100 mg, 0.19 mmol) in THF: H₂O (1: 1, 10 mL) was added lithium hydroxide monohydrate (10 mg, 0.28 mmol) at RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 4 N HCl to ~4. The precipitated solid was filtered and dried in vacuo to afford 1589 (60 mg, 51%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); ’HNMR (DMSO-4 500 MHz): δ 12.89 (br s, 1H), 11.50 (s, 1H), 9.41 (t,J=5.4 Hz, 1H), 8.04 (d,

-439 J= 8.4 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.81 (m, 3H), 7.78 (d, J = 8.4 Hz, 1H), 7.58 (s, 1H), 4.57 (d, J= 5.5 Hz, 2H), 4.02 (s, 2H); LC-MS: 98.73%; 490.0 (M⁺+l); (column; X-select CSH Cl 8, (50 x 3.0 mm, 2.5 pm); RT 2.10 min. 2.5mM Aq.NH₄OOCH + 5% ACN + 5% 2.5 mM Aq.NH₄OOCH; .0.8 mL/min); HPLC (purity): 99.17%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 pm); RT 6.59 min. ACN + 5% 0.05% TFA (Aq) : 0.05% TFA (Aq) + 5% ACN; 1.0 mL/min).

Synthesis of methyl 4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine8-carboxamido) methyl) thiazol-2-yl) benzoate (648): To a stirring solution of compound 92 (200 mg, 0.66 mmol) in DMF (10 mL) under inert atmosphère were added EDCI.HC1 (189.1 mg, 0.99 mmol), HOBt (133.6 mg, 0.99 mmol) at RT and stirred for 5 min. To this was added methyl 4-(5-(aminomethyl) thiazol-2-yl) benzoate hydrochloride 636 (196.4 mg, 0.79 mmol) and diisopropylethylamine (0.59 mL, 3.29 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with icecold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 2% MeOH/ CH₂C1₂to afford compound 648 (130 mg, 37%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Ry

-440 -

0.3); 'H-NMR (DMSO-î/₆, 500 MHz): δ 11.52 (br s, 1H), 9.51 (t, J=5.6Hz, 1H), 8.08-8.01 (m, 5H), 7.98 (t, J = 8.5 Hz, 2H), 7.92-7.80 (m, 5H), 4.71 (d, J= 5.8 Hz, 2H), 3.87 (s, 3H).

Synthesis of 4-(5-((5, 5-dioxido-l 1-oxo-10, 11-dihydrodibenzo [b, f] [1, 4] thiazepine-85 carboxamido) methyl) thiazol-2-yl) benzoic acid (1585): To a stirring solution of compound 648 (80 mg, 0.15 mmol) in THF: H2O (5: 1,6 mL) was added lithium hydroxide monohydrate (19 mg, 0.45 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, volatiles were removed in vacuo. The crude was washed with EtOAc (2x10 mL). The obtained solid was dissolved in water (20 mL) and pH was adjusted to ~2 using 2 N HCl. The precipitated solid was filtered, washed with water (20 mL), «-pentane (50 mL) and dried in vacuo to afford 1585 (60 mg, 77%) as an off-white solid. TLC: 5% MeOH/ CH2CI2 (Rf. 0.2); *H-NMR (DMSO-ri_d, 500 MHz): δ 13.18 (br s, 1H), 11.52 (s, 1H), 9.51 (t, J = 5.6 Hz, 1H), 8.09-7.95 (m, 7H), 7.93-7.80 (m, 5H), 4.71 (d, J= 5.8 Hz, 2H); LC-MS: 92.54%; 519.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT

2.22 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 93.48%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 pm); RT 7.41 min. ACN + 5% 0.05% TFA (Aq) : 0.05% TFA (Aq) + 5% ACN; 1.0 mL/min).

Synthesis of 1645-B

-441 Synthesis of (2-(4-nitrophenyl) thiazol-5-yl) methanamine hydrochloride (649): To a stirring solution of teH-butyl ((2-(4-nitrophenyl) thiazol-5-yl) methyl) carbamate 309 (150 mg, 0.44 mmol) in CH2CI2 (5 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (1.5 mL) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with diethylether (2x5 mL) and dried in vacuo to afford compound 649 (110 mg, 91%) as yellow solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.2); ^-NMR (DMSO-(/₆, 500 MHz): δ 8.52 (br s, 3H), 8.36 (d, J = 9.0 Hz, 2H), 8.21 (d, J= 9.0 Hz, 2H), 8.12 (s, 1H), 4.41 (br s, 2H).

Synthesis of A-((2-(4-nitrophenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo [b, f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (650): To a stirring solution of 92 (100 mg, 0.33 mmol) in DMF (5 mL) under inert atmosphère were added EDCI.HC1 (95 mg, 0.49 mmol), HOBt (67 mg, 0.49 mmol), compound 649 (108 mg, 0.39 mmol) and diisopropylethylamine (0.18 mL, 0.99 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 3% MeOH/ CH2CI2 to afford compound 650 (80 mg, 47%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.5); *H NMR (DMSO-î/_6;

500 MHz): δ 11.52 (br s, 1H), 9.53 (t, J =5.5 Hz, 1H), 8.31 (d, J= 8.7 Hz, 2H), 8.15 (d, J = 8.7 Hz, 2H), 8.06 (d, J= 8.4 Hz, 1H), 8.01-7.95 (m, 3H), 7.92-7.79 (m, 4H), 4.73 (d, J= 5.5 Hz, 2H); LC-MS: 93.76%; 520.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.46 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of A-((2-(4-aminophenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide (1645-B): To a stirring solution of compound 650 (75 mg, 0.14 mmol) in MeOH (10 mL) under inert atmosphère was added 10% Pd/C (30 mg) at RT and stirred under hydrogen atmosphère (balloon pressure) at RT for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and washed with MeOH (100 mL). The filtrate was concentrated in vacuo to obtain the

-442 - crude, which was titurated with diethyl ether: «-pentane (1:1, 20 mL) and followed by silicagel column chromatography using 2-3% MeOH/ CH2CI2 to afford 1645-B (22 mg, 32%) as an offwhite solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); 'H NMR (DMSO/ 400 MHz): δ 11.48 (br s, 1H), 9.40 (t, J= 5.5 Hz, 1H), 8.05 (d, J= 8.3 Hz, 1H), 7.98 (td, J= 7.5, 0.9 Hz, 2H), 7.947.78 (m, 4H), 7.59 (s, 1H), 7.53 (d, J= 8.5 Hz, 2H), 6.57 (d, J= 8.6 Hz, 2H), 5.62 (s, 2H), 4.62 (d, J= 5.5 Hz, 2H); LC-MS: 97.21%; 491.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.97 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 96.45%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 9.06 min. ACN + 5 mM NH₄OAc: ACN; 1.0 mL/min, Diluent: ACN: water).

Synthesis of 1764

Synthesis of A-((2-(4-cyanophenyl) thiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (651): To a stirring solution of 92 (300 mg, 0.99 mmol) in DMF (15 mL) under inert atmosphère were added EDCI.HC1 (283 mg, 1.48 mmol), HOBt (200 mg, 1.48 mmol), compound 227 (274 mg, 1.08 mmol) and diisopropylethylamine (0.55 mL, 2.95 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (100 mL) and extracted with EtOAc (2 x 150 mL). The combined organic ex tracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 3% MeOH/ CH₂C1₂ to afford compound 651 (250 mg, 50%) as white solid. TLC: 5% MeOH/ CH2CI2 (Rf 0.6); *H NMR (DMSO/400 MHz): δ 11.52 (s, 1H), 9.52 (t, 5.7 Hz, 1H), 8.08-7.79 (m, 11H), 4.72 (à, J = 5.6 Hz, 2H); LC-MS: 99.46%; 501.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm,

-443 -

2.7 pm); RT 2.30 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 7V-((2-(4-carbamoylphenyl) thiazol-5-yl) methyl)-11-oxo-10, 11 dihydrodibenzo (b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (1764): To a stirring solution of compound

651 (100 mg, 0.20 mmol) in EtOH (5 mL) were added 30% H2O2 (5 mL) and 30% aqueous ammonia (5 mL) at 0 °C warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with CH2CI2 (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was washed with

EtOAc (2 x 10 mL) and dried in vacuo to afford 1764 (55 mg, 53%) as white solid. TLC: 7% MeOH/ CH2CI2 (Rf. 0.4); V-NMR (DMSO-V 400 MHz): δ 11.48 (br s, 1H), 9.50 (t, J= 5.8 Hz, 1H), 8.08-8.04 (m, 2H), 8.00-7.94 (m, 6H), 7.90 (td, J= 7.5, 1.4 Hz, 1H), 7.87-7.80 (m, 4H), 7.44 (br s, 1H), 4.71 (d, J = 5.6 Hz, 2H); LC-MS: 98.11%; 519.0 (M⁺+l); (column;

Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.98 min. 0.025% Aq. TFA + 5% ACN:

ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 98.61%; (column; X select CSH ΟΙ 8 (150 x 4.6 mm, 3.5 pm); RT 6.87 min. ACN + 5% 0.05% TFA (Aq): 0.05% TFA (Aq) + 5% ACN; 1.0 mL/min, Diluent: ACN: water).

-444Synthesis of W((2-(6-methoxypyridin-3-yl) thiazol-5-yl) methyl)-11-oxo-10, 11dihydrodibenzo [b,f] [1,4] thiazepine-8-carboxamide 5, 5-dioxide (1666): To a stirring solution of W((2-chlorothiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide 535 (300 mg, 0.69 mmol) in 1, 2 dimethoxy ethane: H₂O (4: 1, 10 mL) were added (6-methoxypyridin-3-yl) boronic acid 582 (127 mg, 0.84 mmol), sodium carbonate (220 mg, 2.07 mmol) in a sealed tube and purged under argon atmosphère for 15 min. To this was added Pd(PPh3)4 (80 mg, 0.069 mmol) at RT; heated to 110 °C and stirred for 16 h. The reaction was monitored by TLC; after completion the reaction mixture was diluted with water (50 mL) and extracted with 5% MeOH/ CH₂C1₂ (100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2-8% MeOH/ CH₂C1₂ to afford compound 1666 (140 mg, 27%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.4); *H-NMR (DMSO-ri₆, 500 MHz): δ 11.52 (s, 1H), 9.47 (t, J = 6.1 Hz, 1H), 8.68 (d, J =2.3 Hz, 1H), 8.16 (dd, J= 8.7,2.3 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.98 (t, J= 8.2 Hz, 2H), 7.93-7.78 (m, 5H), 6.92 (d, J = 8.7 Hz, 1H), 4.68 (d, J= 5.5 Hz, 2H), 3.90 (s, 3H); LC-MS: 96.23%; 507.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.23 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min) HPLC (purity): 94.46%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 8.40 min. ACN + 5% 0.5% TFA (Aq): 0.5% TFA (Aq) + 5% ACN; 1.0 mL/min, Diluent: ACN: water).

Synthesis of 7V-((2-(6-hydroxypyridin-3-yl) thiazol-5-yl) methyl)-! l-oxo-10, 11dihydrodibenzo [b,f [1,4] thiazepine-8-carboxamide 5, 5-dioxide (1669): To a stirring solution of 1666 (100 mg, 0.19 mmol) in DMF (5 mL) under inert atmosphère were added lithium chloride (43 mg, 0.99 mmol),//-toulene sulfonic acid (4 mg, 0.019 mmol) at RT in a sealed tube; heated to 110 °C and stirred for 16 h. The reaction was monitored by TLC and LCMS; after completion the reaction mixture was diluted with water (50 mL) and the precipitated was filtered, washed with CH₂C1₂ (5 mL) and dried in vacuo to afford 1669 (60 mg, 62%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.4); ^-NMR (DMSO-t/₆, 500 MHz): δ 11.96 (brs, 1H), 11.52 (br s, 1H), 9.45 (t,J=5.2 Hz, 1H), 8.05 (d,J=8.1 Hz, 1H), 7.98 (t, J= 8.1

-445 Hz, 2H), 7.94-7.83 (m, 5H), 7.80 (d, J= 8.1 Hz, 1H), 7.68 (s, 1H), 6.43 (d, J= 9.5 Hz, 1H), 4.64 (d, J = 5.5 Hz, 2H); LC-MS: 97.01%; 492.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.83 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 93.66%; (column; Zorbax SBC C-18 (150 x 4.6 mm, 3.5 pm); RT 5.81 min. ACN + 5% 0.05% TFA (Aq): 0.05% TFA (Aq) + 5% ACN; 1.0 mL/min, Diluent:DMSO: ACN: water).

Synthesis of 4-methoxy-2-(tributylstannyl) pyridine (653): To a stirring solution of 2bromo-4-methoxypyridine 652 (1 g, 5.39 mmol) in dry Toluene (40 mL) under inert atmosphère was added n-butyl lithium (3.98 mL, 6.38 mmol, 1.6 M solution in hexane) at -78 °C and stirred for 1 h. To this was added tributyltin chloride (7.85 mL, 28.98 mmol) at -78 °C; warmed to RT and stirred for 30 min. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 653 (1.5 g, 71%) as yellow liquid which was taken for next step without further purification. TLC: 20% EtOAc/ hexanes (Rf 0.8);

Synthesis of A-((2-(4-methoxypyridin-2-yl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo [b, f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (1880-A): To a stirring solution of A-((2-chlorothiazol-5-yl) methyl)-! l-oxo-10, 11-dihydrodibenzo \b,f [1, 4]

-446 thiazepine-8-carboxamide 5, 5-dioxide 535 (500 mg, 1.15 mmol) in 1, 4-dioxane (30 mL) under argon atmosphère were added compound 653 (1.37 g, 3.46 mmol) and purged under argon atmosphère for 30 min, added Pd(dppf)C12 (84 mg, 0.11 mmol) and heated to 110 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3% MeOH/ CH2CI2 to afford 1880-A (125 mg, 21%) as an offwhite solid. TLC: 5% MeOH/ CH₂C1₂ (Ry 0.5); ’H-NMR (DMSO-t^, 400 MHz): δ 11.51 (s, 1H), 9.47 (t, J= 5.8 Hz, 1H), 8.40 (d, J= 5.6 Hz, 1H), 8.06 (d, J= 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.90 (td, J =1.5, 1.4 Hz, 1H), 7.87-7.83 (m, 3H), 7.81 (dd, J= 8.3, 1.5 Hz, 1H), 7.58 (à, J = 2.4 Hz, 1H), 7.04 (dd, J= 5.7, 2.6 Hz, 1H), 4.69 (d, J= 5.6 Hz, 2H), 3.90 (s, 3H); LC-MS: 97.10%; 507.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.05 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 96.24%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 7.21 min. 0.05% TFA (Aq) + 5% ACN: ACN + 5% 0.05% ACN; 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis ofA-((2-(4-hydroxypyridin-2-yl) thiazol-5-yl) methyl)-11-oxo-10, 11dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (1880) : To a stirring solution of 1880-A (120 mg, 0.23 mmol) in DMF (10 mL) under inert atmosphère were added lithium chloride (206 mg, 4.74 mmol), p-toluenesulfonic acid (20 mg, 0.11 mmol) at RT; heated to 120-130 °C and stirred for 24 h. The reaction was monitored by TLC and LC-MS; after completion the reaction mixture was poured into ice-cold water (50 mL) and extracted with EtOAc (2 x 150 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography twice using 3% MeOH/ CH2CI2 to afford 1880 (15 mg, 13%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Ry 0.4); 'H-NMR (DMSO-ri₆, 400 MHz): δ 11.51 (br s, 1H), 10.96 (br s, 1H), 9.48-9.43 (m, 1H), 8.26 (br d, J = 3.5 Hz, 1H), 8.06 (br d, J = 8.2 Hz, 1H), 7.98 (br t, J= 7.3 Hz, 2H), 7.93-7.78 (m, 5H), 7.46 (br s, 1H), 6.81 (s, 1H), 4.68 (br d, J= 4.1 Hz, 2H); LC-MS: 99.60%; 492.9 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.76 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2

-447mL/min); ); HP LC (purity): 99.70%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 5.94 min. 0.05% TFA (Aq) + 5% ACN: ACN + 5% 0.05% ACN; 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of 2-(5-((5,5-dioxido-l l-oxo-10,11-dihydrodibenzo \b,j\ [1, 4] thiazepine-8carboxamido) methyl) thiazol-2-yl) pyridin-4-yl trifluoromethanesulfonate (654): To a stirring solution of 1880 (200 mg, 0.40 mmol) in CH2Q2 (10 mL) under inert atmosphère were added triethyl amine (1.67 mL, 1.21 mmol), triflic anhydride (0.1 mL, 0.60 mmol) at 0 °C; and stirred for 30 min. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (30 mL) and extracted with CH2CI2 (2x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 654 (210 mg crude) as an off white solid. The crude was taken forward next reaction without further purification. TLC: 5% MeOH/CH2C12 (Rf. 0.7); LC-MS: 41%; 624.9 (M⁺+l) ; (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 2.56 min, 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of A-((2-(4-(dimethylamino) pyridin-2-yl) thiazol-5-yl) methyl)-11-oxo-10,11dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxamide 5,5-dioxide (1889) : To a stirring

-448 solution of compound 654 (210 mg crude, 0.33 mmol) in THF (5 mL) in a sealed tube was added 2 M dimethylamine in THF (0.36 mL, 0.67 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3-4%

MeOH/ CH2CI2 and further purified by préparative HPLC purification to afford 1889 (10 mg, 6%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.4); *H-NMR (DMSO-d₆, 400 MHz): δ 11.54 (s, 1H), 9.56 (br s, 1H), 8.10 (dd, J= 16.7, 7.6 Hz, 2H), 7.98 (td, J=1A, 1.1 Hz, 3H), 7.93 -7.81 (m, 4H), 7.30 (d, J = 2.6 Hz, 1H), 6.88 (br s, 1H), 4.74 (br d, J= 5.5 Hz, 2H), 3.17 (br s, 6H); LC-MS: 95.94%; 520.0 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm,

2.6 um); RT 2.47 min. 2.5 mM Aq. NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.

NH4OOCH, 0.8 mL/min). HPLC (purity): 99.48%; (column; X select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 5.73 min. 0.05% TFA + 5% ACN: ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of tm-butvl (6-bromopyridin-3-yl) carbamate (656): To a stirring solution of 6bromopyridin-3-amine 655 (5 g, 28.90 mmol) in CH₂C1₂ (50 mL) under argon atmosphère were added Boc-anhydride (7.6 g, 34.86 mmol) and triethylamine (6.17 mL, 43.35 mmol) at 0 to 10

-449- °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL), filtered through celite and eluted with CH2CI2 (3 x 80 mL). The fitrate was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 5-7% EtOAc/ hexanes to afford compound 656 (5 g, 64%) as white solid. TLC: 20% EtOAc/ hexanes (Rf 0.8); *H-NMR (DMSO-/₆, 500 MHz): δ 9.72 (br s, 1H), 8.45 (s, 1H), 7.82 (dd, J= 8.4, 2.0 Hz, 1H), 7.53 (d, J= 8.7 Hz, 1H), 1.48 (s, 9H); LCMS: 91.60%; 272.9 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.48 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl (6-(tributylstannyl) pyridin-3-yl) carbamate (657): To a stirring solution of compound 656 (5 g, 18.31 mmol) in THF (50 mL) under argon atmosphère was added w-butyl lithium (23 mL, 36.63 mmol, 1.6 M solution in hexane) dropwise for 40 min at 78 °C and warmed to -10 °C and stirred for 40 min. To this was added tributylchlorostannane (8.92 g, 27.47 mmol) in THF (10 mL) at -78 °C and stirred for 1 h at the same température. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with saturated potassium fluoride solution (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silicagel flash column chromatography using 5-7% EtOAc/ hexanes to afford compound 657 (3 g, 34%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf 0.2); ^XH-NMR (DMSO-J₆, 400 MHz): δ 9.42 (s, 1H), 8.70 (s, 1H), 7.73 (dd, J = 8.0,2.3 Hz, 1H), 7.33 (d,/=8.2 Hz, 1H), 1.64-1.54 (m, 6H), 1.47 (s, 9H), 1.38-1.22 (m, 6H), 1.14-1.08 (m, 6H), 0.87 (t, /= 7.3 Hz, 9H); The aliphatic région shows tin reagent as impurity; LC-MS: 68.59%; 485.2 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.78 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl (6-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo \b,f [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) pyridin-3-yl) carbamate (658): To a stirring

-450solution of compound 535 (200 mg, 0.46 mmol) in 1, 4-dioxane (10 mL) under inert atmosphère were added compound 657 (670 mg, 1.38 mmol) and purged under argon atmosphère for 15 min, added Pd(dppf)C12 (34 mg, 0.046 mmol) and heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was fitered through celite washed with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 2-5% MeOH/ CH2CI2. The obtained compound was precipitated using 20% EtOAc/ hexanes to afford compound 658 (50 mg, 18%) as an off-white solid. TLC: 5% MeOH/ CH2Q2 (Rf 0.5); *HNMR (DMSO-dô, 400 MHz): δ 11.50 (s, 1H), 9.81 (s, 1H), 9.44 (t, J = 5.5 Hz, 1H), 8.59 (s, 1H), 8.07-7.76 (m, 10H), 4.66 (d, J= 5.3 Hz, 2H), 1.48 (s, 9H); LC-MS: 96.84%; 592.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.43 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of /V-((2-(5-aminopyndin-2-yl) thiazol-5-yl) methyl)-! 1-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (1886): To a stirring solution of compound 658 (50 mg, 0.08 mmol) in CH2CI2 (5 mL) was added 4 N HCl in 1, 4-dioxane (1 mL) under argon atmosphère at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The compound was dissolved in CH2CI2 (1 mL) and precipitated using n-hexane (10 mL) to afford 35 mg of semi-purified material. This was further purified by précipitation in Λ-m ethyl pyrrolidinone: H2O (1: 20, 21 mL) and stirred for 16 h. The solid obtained was filtered and dried in vacuo to afford 1886 (25 mg, 61%) as an off-white solid. TLC: 5% MeOH/ CH2CI2 (Rf. 0.3); ‘H-NMR (DMSO-rig, 400 MHz): δ 11.52 (s, 1H), 9.43 (t, J= 5.6 Hz, 1H), 8.05 (d, J= 8.3 Hz, 1H), 7.98 (td, J=7.6, 1.1 Hz, 2H), 7.93-7.79 (m, 5H), 7.77 (d, J= 8.5 Hz, 1H), 7.68 (s, 1H), 7.02 (dd, J= 8.5, 2.6 Hz, 1H), 4.63 (d, J= 5.6 Hz, 2H); LC-MS: 94.26%; 492.0 (M⁺+l)_;(column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.26 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity): 93.39%; (column; X-select

-451 CSH-C18 (150 x 4.6 mm, 3.5 pm); RT 8.69 min. 5mM NH4OAc: ACN; 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of terCbutyl (2-bromopyridin-4-yl) carbamate (660): To a stirring solution of 2bromopyridin-4-amine 659 (5 g, 28.90 mmol) in 1, 2-dichloro ethane (80 mL) under inert atmosphère were added triethylamine (9.53 mL, 86.70 mmol) Boc-anhydride (7.56 g, 34.67 mmol) at 0 °C; heated to 70 °C and stirred for 16 h. The reaction was monitored by TLC; after 10 completion of the reaction, the reaction the volatiles were concentrated in vacuo. The residue was diluted CH2CI2 (20 mL), washed with water (100 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 5-20% EtOAc/ hexanes to afford compound 660 (3.5 g, 44%) as an off white solid. TLC: 40% EtOAc/ hexanes (Rf 0.7); LC15 MS: 99.62%; 274.8 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.40 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

-452 Synthesis of terr-butyl (2-(triisopropoxy-14-boranyl) pyridin-4-yl) carbamate, lithium sait (661): To a stirring solution of tert-butyl (2-bromopyridin-4-yl) carbamate 660 (5 g, 18.31 mmol) and triisopropyl borate (1.52 mL, 6.55 mmol) in dry toluene: THF (4: 1; 100 mL) under inert atmosphère was added n-butyl lithium (2.5 M solution in hexane, 24.92 mL, 5.46 mmol) drop wise for 1.5 h at -78 °C and stirred for 30 min. To this was added triisopropyl borate (4.13 g, 21.97 mmol) and warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford compound 661 (7.2 g crude sait) as yellow solid. The crude was carried forward for next reaction without purification. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.1);

Synthesis of teri-butyl (2-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) pyridin-4-yl) carbamate (662): To a stirring solution of7V-((2-chlorothiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide 535 (2 g, 4.61 mmol) in 1, 2 dimethoxy ethane: H₂O (4: 1, 80 mL) were added sodium carbonate (1.46 g, 13.85 mmol), compound 661 (7.37 g crude) and purged under argon atmosphère for 20 min. To this was added Pd(dppf)Cl₂ (337 mg, 0.46 mmol) at RT; heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction; the reaction mixture was filtered through celite and washed with 10% MeOH/ CH₂C1₂ (2 x 100 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 3% MeOH/ CH₂C1₂ to afford compound 662 (380 mg) as brown solid. LC-MS: 67.12%; 542 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.20 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of A-((2-(4-aminopyridin-2-yl) thiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b.f [1,4] thiazepine-8-carboxamide 5,5-dioxide, TFA sait (1888): To a stirring solution of compound 662 (380 mg crude) in CH₂C1₂ (15 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (4 mL) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was triturated with diethyl ether (5 mL), n-pentane (10 mL) and further purified by préparative HPLC purification to afford 1888 (45 mg, 14%) as an off-white solid. . *H-NMR (DMSO-ri₆,

-453 400 MHz): δ 13.68 (br s, 1H), 11.55 (s, 1H), 9.65-9.56 (m, 1H), 8.10-8.02 (m, 3H), 7.98 (br t, J =7.3 Hz, 2H), 7.91 (td,J=7.0, 1.1 Hz, 1H), 7.88 - 7.80 (m, 3H), 7.29 (d,J=2.1 Hz, 1H), 6.78 (br d, J= 5.3 Hz, 1H), 4.75 (br d, J = 5.6 Hz, 2H); LC-MS: 99.93%; 492.0 (M⁺+l);

(column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.62 min. 0.025% Aq. TFA + 5%

ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 99.71%; (column; X select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 5.27 min. 0.05% TFA + 5% ACN : ACN + 5% 0.05% TFA ; 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of terZ-butyl 4-(5-bromopyridin-2-yl) piperazine-l-carboxylate (665): To a stirring solution 2, 5-dibromopyridine 663 (500 mg, 2.11 mmol) in 7V-methyl pyrrolidinone (2 mL) under inert atmosphère was added tert-butyl piperazine-l-carboxylate 664 (786 mg, 4.2 mmol) in a sealed tube and heated to 140 °C and stirred for 16 h. The reaction was monitored by TLC and LC-MS; after completion the reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL). The organic extract was dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 30% EtOAc/ hexanes to afford compound 665 (400 mg, 56%) as an off-

-454white solid. TLC: 30% EtOAc/ hexanes (Rf 0.2); ^XH-NMR (DMSO-4 400 MHz): δ 8.18 (d, J = 2.3 Hz, 1H), 7.70 (dd, J= 9.3, 2.6 Hz, 1H), 6.83 (d, J= 9.0 Hz, 1H), 3.49-3.44 (m, 4H), 3.42-3.37 (m, 4H), 1.42 (s, 9H); LC-MS: 99.81%; 341.9 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 3.62 min. 2.5 mM Aq. NH₄OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of terLbutyl 4-(5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) piperazine-l-carboxylate (666): To a stirring solution of compound 665 (400 mg, 1.16 mmol) in 1, 4-dioxane (25 mL) under inert atmosphère were added bispinacolato diboron (594 mg, 2.33 mmol), potassium acetate 343 mg, 3.50 mmol) at RT and purged under argon atmosphère for 15 min; to this was added Pd(dppf)Cl₂ (85 mg, 0.11 mmol) and purged under argon atmosphère for 5 min, heated to reflux and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10-50% EtOAc/ hexanes to afford compound 666 (420 mg, 43%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.4); LC-MS: 98.83%; 307.9 (M⁺+l) (Boronic acid); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.60 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of fert-butyl 4-(5-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo \b,f\ [1,4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) pyridin-2-yl) piperazine-l-carboxylate (11019-A): To a stirring solution of A-((2-chlorothiazol-5-yl) methyl)-! l-oxo-10, 11dihydrodibenzo \b,f [1,4] thiazepine-8-carboxamide 5, 5-dioxide 535 (300 mg, 0.73 mmol) in 1, 4-dioxane: H₂O (4: 1, 12 mL) under inert atmosphère were added compound 666 (410 mg, 1.46 mmol), césium carbonate (714 mg, 2.19 mmol) in a sealed tube at RT and purged under argon atmosphère for 15 min, added Pd(dppf)Cl₂ (54 mg, 0.073 mmol) and heated to 110 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction was monitored by TLC; after completion of the reaction, the volatiles were concentrated in vacuo to obtain the crude. The crude was purified through silica gel column

-455 chromatography using 10-50% EtOAc/ hexanes, triturated using CH₂C1₂: hexanes (10 mL) and dried in vacuo to afford 11019-A (150 mg, 33%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.4); 'H-NMR (DMSO-î7₆, 400 MHz): δ 11.52 (s, IH), 9.44 (t, J = 5.8 Hz, IH), 8.61 (d, J = 2.1 Hz, IH), 8.05 (d, J= 8.3 Hz, IH), 8.01-7.95 (m, 3H), 7.90 (td, J = 7.5, 1.4 Hz, IH), 7.87-7.83 (m, 2H), 7.81 (dd,J=8.3, 1.5 Hz, IH), 7.71 (s, IH), 6.90 (d,J=9.0Hz, IH), 4.66 (d, J= 5.5 Hz, 2H), 3.61-3.57 (m, 4H), 3.45-3.40 (m, 4H), 1.42 (s, 9H); LC-MS: 96.01%; 661.1 (M⁺+l) (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.34 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity): 95.67%; (column; X-select CSH-C18 (150 x 4.6 mm, 3.5 pm); RT 8.38 min. 0.05% TFA (Aq) + 5% ACN: ACN + 5% 0.05% TFA (Aq): 1.0 mL/min, Diluent: ACN: water).

Synthesis of 1 l-oxo-A-((2-(6-(piperazin-l-yl) pyridin-3-yl) thiazol-5-yl) methyl)-10, 11dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (11019): To a stirring solution of 11019-A (50 mg, 0.075 mmol) in CH₂C1₂ (5 mL) was added 4 N HCl in 1, 4-dioxane (5 mL) under argon atmosphère at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with CH₂C1₂: n-hexane (1: 1, 10 mL) and lypholized for 12 h to afford compound 11019 (40 mg; HCl sait) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.1); 'H-NMR (DMSO-d₆, 400 MHz): δ 11.53 (s, IH), 9.49 (t, J= 5.7 Hz, IH), 9.09 (br s, 2H), 8.64 (d, J =2.5 Hz, IH), 8.07-8.01 (m, 2H), 8.00-7.95 (m, 2H), 7.90 (td, J= 7.5, 1.5 Hz, IH), 7.88-7.83 (m, 3H), 7.73 (s, IH), 7.01 (d, J = 9.0 Hz, IH), 4.66 (d, J= 5.5 Hz, 2H), 3.86-3.80 (m, 4H), 3.21-3.14 (m, 4H); LC-MS: 95.23%; 561.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.74 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity): 96.14%; (column; X-select CSH-C18 (150 x 4.6 mm, 3.5 pm); RT 5.46 min. 0.05% TFA (Aq) + 5% ACN: ACN + 5% 0.05% TFA (Aq): 1.0 mL/min, Diluent: ACN: water).

Synthesis of 11016 & 11016-A

-456 -

Synthesis of teH-butyl 4-(4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) benzoyl) piperazine-l-carboxylate (11016-A): 5 To a stirring solution of 1585 (300 mg, 0.57 mmol) in DMF (10 mL) under inert atmosphère were added EDCI.HC1 (166 mg, 0.86 mmol), HOBt (117 mg, 0.86 mmol), tert-butyl piperazine-l-carboxylate 664 (119 mg, 0.63 mmol) and diisopropylethylamine (0.28 mL, 1.98 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted 10 with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 3-4% MeOH/ CH2CI2 to afford 11016-A (150 mg, 37%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.6); *H NMR (DMSO-cZ₆,400 ^MHz)^: δ 11.52 (br s, 1H), 9.49 (t, J= 5.8 Hz, 1H), 8.06 (d, J= 8.2 Hz, 1H), 8.02-7.92 (m, 4H), 7.91-7.80 (m, 15 5H), 7.51 (d, J= 8.4 Hz, 2H), 4.70 (br d, J = 5.6 Hz, 2H), 3.66-3.30 (m, 8H), 1.40 (s, 9H); LCMS: 97.25%; 686.1 (M-l)⁺; (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 2.88 min.

2. 5 mM Aq. NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min); HPLC (purity): 97.43%; (column; X-Select CSH-C-18 (150 x 4.6 mm, 3.5 pm); RT 10.12 min. 5 mM NH₄OAc: ACN; 1.0 mL/min, Diluent: DMSO: ACN: water).

-457 Synthesis of 1 l-oxo-7V-((2-(4-(piperazine-l-carbonyl) phenyl)thiazol-5-yl) methyl)-10, 11dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (11016): To a stirring solution of 11016-A (100 mg, 0.19 mmol) in CH2CI2 (10 mL) was added 4 N HCl in 1, 4-dioxane (0.5 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with diethyl ether (5 mL) and dried in vacuo to afford 11016 (80 mg; 66% HCl sait) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.1); 'H-NMR (DMSO-dô, 400 MHz): δ 11.50 (s, 1H), 9.49 (t, J= 5.8 Hz, 1H), 8.94 (br s, 2H), 8.04 (d, J= 8.3 Hz, 1H), 7.98-7.92 (m, 4H), 7.90-7.78 (m, 5H), 7.54 (d, J = 8.5 Hz, 2H), 4.68 (d, J= 5.6 Hz, 2H), 3.853.49 (m, 4H), 3.18-3.10 (m, 4H); LC-MS: 98.26%; 588.1 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.73 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 98.88%; (column; X-Select CSH-C-18 (150 x 4.6 mm, 3.5 pm); RT 5.61 min. ACN + 5% 0.05% TFA (Aq): 0.05% TFA (Aq) + 5% ACN; 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of 4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b, f] [1, 4] thiazepine-8carboxamido) methyl) thiazol-2-yl) benzoic acid (1585): To a stirring solution of compound 648 (80 mg, 0.15 mmol) in THF: H₂O (5: 1,6 mL) was added lithium hydroxide monohydrate (19 mg, 0.45 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, volatiles were removed in vacuo. The crude was washed with EtOAc (2x10 mL). The obtained solid was dissolved in water (20 mL) and pH was adjusted to ~2 using 2 N HCl. The precipitated solid was filtered, washed with water (20 mL), n-pentane (50 mL) and dried in vacuo to afford 1585 (60 mg, 77%) as an off-white solid. TLC:

-458 5% MeOH/ CH₂C1₂ (Rf. 0.2); 'H-NMR (DMSO-d₆, 500 MHz): δ 13.18 (br s, 1H), 11.52 (s, 1H), 9.51 (t, J= 5.6 Hz, 1H), 8.09-7.95 (m, 7H), 7.93-7.80 (m, 5H), 4.71 (d, J= 5.8 Hz, 2H); LC-MS: 92.54%; 519.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.22 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 93.48%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 pm); RT 7.41 min. ACN + 5% 0.05% TFA (Aq) : 0.05% TFA (Aq) + 5% ACN; 1.0 mL/min).

Préparation

1585 was synthesized as mentioned above and converted to final products as using commercially available amines employing typical procedure C and the results are captured in the Table 3:

To a stirring solution of 1585 (200 mg, 0.38 mmol) in DMF (5 mL) under inert atmosphère were added EDCI.HC1 (110 mg, 0.57 mmol), HOBt (77 mg, 0.57 mmol), and diisopropylethylamine (0.20 mL, 1.15 mmol) at 0 °C and stirred for 10 min; added compound 240 (2 M sol. in THF, 0.1 mL, 1.15 mmol) at the same température; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was either directly dried in vacuo or triturated or purified through silica gel column chromatography to afford the desired compound.

Commercial amines used in préparation:

-459 -

—nh₂	/NH	—nh₂	D^nh₂
240	243	469	667

Table 3: Synthesis from 1585 using varions amines

Example	Structure	Proced ure, Interm ediate, amine	Rx Yie Id (% )	Mass Spec. Found	Mass Spec. Calculated	’h-nmr
1943	O / ^NH H Ci ΧΎΧ^ε H o hn—	C, 1 585, 240	59	533.1 (M⁺+l) 9	532 for C₂₆H₂₀N₄O₅s₂	'h NMR (DMSOdf 400 MHz): δ 11.52 (br s, 1H), 9.50 (br t, J = 5.7 Hz, 1H), 8.52 (q, J = 4.2 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.02 - 7.94 (m, 4H), 7.93-7.89 (m, 3H), 7.89 - 7.81 (m, 4H), 4.71 (br d, J = 5.6 Hz, 2H), 2.79 (d,J = 4.5 Hz, 3H);
1944	Q il Z \ *O 1 wc A / Ό	C 1 585, 243	71	547.1 (M⁺+l) 9	546 for C₂₇H₂₂N₄O5 s₂	‘H NMR (DMSOd₆, 400 MHz): δ 11.52 (s, 1H), 9.49 (t, J = 5.7 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.95-7.80 (m, 7H), 7.49 (d, J = 8.2 Hz, 2H), 4.70 (d, J = 5.6 Hz, 2H), 3.04 -

-460 -

						2.82 (m, 6H);
1947	O /NH 0 ΥΥ/Ύ H //=, ₀ ^{0 0} Y A/ , HN—X	c^a 1 585, 469	41	575.1 (M⁺+l) 5	574 for C29H₂₆N₄O₅s₂	'H NMR (DMSOd₆, 500 MHz): δ 11.51 (br s, 1H), 9.48 (br t, J = 5.6 Hz, 1H), 8.05 (d, J= 8.1 Hz, 1H), 7.997.94 (m, 2H), 7.937.79 (m, 10H), 4.69 (br d, J = 5.8 Hz, 2H), 1.37 (s, 9H);
1949	HN—	c, 1 585, 667	67	559.1 (M⁺+l) 5	558 for C₂₈H₂₂N₄Os s₂	^lH NMR (DMSOd₆, 400 MHz): δ 11.52 (br s, 1H), 9.49 (br t, J = 5.4 Hz, 1H), 8.52 (br d, J = 3.5 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 8.02-7.76 (m, 11 H), 4.70 (br d, J = 5.5 Hz, 2H), 2.932.78 (m, 1H), 0.74 0.52 (m, 4H);

C^a: Reaction time 18 h

Synthesis of 11017 & 11017-A

-461 -

Synthesis of terLbutyl (2-(4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) benzamido) ethyl)carbamate (11017-A): To a stirring solution of 1585 (300 mg, 0.57 mmol) in DMF (10 mL) under inert atmosphère were added EDCI.HC1 (166 mg, 0.86 mmol), HOBt (117 mg, 0.86 mmol), ZerLbutyl (2-aminoethyl) carbamate 669 (102 mg, 0.63 mmol) and diisopropylethylamine (0.28 mL, 1.98 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 3-4% MeOH/ CH2CI2 and triturated with 5% MeOH/ CH2CI2 (2 mL) and zi-pentane (5 mL) and crystallized using A-methyl pyrrolidinone: H2O (10 mL) to afford 11017-A (150 mg, 39%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.6); ’H NMR (DMSO-V400 MHz): δ 11.52 (br s, 1H), 9.50 (br t, J= 5.8 Hz, 1H), 8.54 (br t, J = 4.9 Hz, 1H), 8.06 (d, J= 8.3 Hz, 1H), 8.02-7.80 (m, 11H), 6.90 (br t, J= 5.3 Hz, 1H), 4.71 (br d, J = 5.5 Hz, 2H), 3.31-3.27 (m, 2H), 3.15-3.05 (m, 2H), 1.37 (s, 9H); LC-MS: 99.83%; 660.1 (M1)⁺; (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 2.67 min. 2.5 mM Aq.

NH₄OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min); HPLC (purity): 99.17%; (column; X-Select CSH-C-18 (150 x 4.6 mm, 3.5 pm); RT 8.58 min. 0.05% TFA (Aq) + 5% ACN: ACN + 5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: DMSO: ACN).

-462 Synthesis of 7V-((2-(4-((2-aminoethyl) carbamoyl) phenyl) thiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (11017): To a stirring solution of 11017-A (100 mg, 0.15 mmol) in CH2CI2 (10 mL) was added 4 N HCl in 1, 4-dioxane (0.5 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with diethyl ether (5 mL) and dried in vacuo to afford 11017 (80 mg; 88% HCl sait) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Ry 0.1); 'H-NMR (DMSO-riô, 400 MHz): δ 11.53 (s, 1H), 9.53 (t, .7=5.8 Hz, 1H), 8.74 (t, J=5.5 Hz, 1H), 8.06 (d, J=8.2 Hz, 1H), 8.03-7.95 (m, 6H), 7.93-7.81 (m, 8H), 4.71 (br d, J= 5.6 Hz, 2H), 3.55-3.49 (m, 2H), 3.02-2.96 (m, 2H); LC-MS: 98.39%; 562.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.74 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 99.17%; (column; X-Select CSH-C-18 (150 x 4.6 mm, 3.5 pm); RT 8.58 min. 0.05% TFA (Aq) + 5% ACN: ACN + 5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: ACN: DMSO: MeOH).

Synthesis of 1 l-oxo-/V-((2-(4-(piperazin-l-yl) phenyl) thiazol-5-yl) methyl)-10, 11dihydrodibenzo [b,f] [1,4] thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (11018): To a stirring solution of 11018-A ( 100 mg, 0.15 mmol) in CH2CI2 (10 mL) was added 4 N HCl in 1, 4-dioxane (1 mL) under argon atmosphère at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with EtOAc (2x5 mL) and dried in vacuo to afford 1 1018 (75 mg, 88%; HCl sait) as yellow solid. TLC: 5% MeOH/ CH₂C1₂ (Ry 0.1); ‘H-NMR (DMSO-ri₆, 400 MHz): δ 11.53 (s, 1H), 9.49 (t, .7= 5.8 Hz, 1H), 9.18 (br s, 2H), 8.05 (d, J= 8.3 Hz, 1H), 7.98 (td, J= ΊΑ, 1.1 Hz, 2H), 7.93-7.81 (m, 4H), 7.76 (d, J = 8.9 Hz, 2H), 7.70 (s, 1H), 7.05 (d, J=

-463 -

8.9 Hz, 2H), 4.65 (br d, J= 5.6 Hz, 2H), 3.51-3.44 (m, 4H), 3.24-3.17 (m, 4H); LC-MS: 98.17%; 560.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.77 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity): 97.26%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 6.21 min. 0.05% TFA + 5% ACN : ACN + 0.05% TFA + 5%; 1.0 mL/min; Diluent: ACN: water).

Synthesis of ethyl 2-(4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepine8-carboxamido) methyl) thiazol-2-yl) phenoxy) acetate (670): To a stirring solution of compound 92 (150 mg, 0.49 mmol) in DMF (10 mL) under inert atmosphère were added EDCI.HC1 (142 mg, 0.29 mmol), HOBt (100 mg, 0.74 mmol), ethyl 2-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) acetate hydrochloride 639 (195 mg, 0.59 mmol) and diisopropylethylamine (0.45 mL, 2.47 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice-cold water (50 mL) and extracted with EtOAc (3 x 150 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3% MeOH/ CH2CI2 to afford compound 670 (110 mg, 39%) as white solid. TLC: 7% MeOH/ CH2CI2 (Rf 0.4); ‘H NMR (DMSO-7_à> 500 MHz): δ 11.51 (s, 1H), 9.45 (t, 7=5.8 Hz, 1H), 8.05 (d, J= 8.1 Hz, 1H), 8.00-7.95 (m, 2H), 7.90 (td, J= Ί.4, 1.3 Hz, 1H), 7.87-7.85 (m, 2H), 7.84-7.79 (m, 3H), 7.73 (s, 1H), 7.02 (d, J= 9.0 Hz, 2H), 4.85 (s, 2H), 4.67 (d, J= 5.8 Hz, 2H), 4.17 (q, J= 6.9 Hz, 2H), 1.21 (t, J= 7.1 Hz, 3H).

-464Synthesis of 2-(4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepine-8carboxamido) methyl) thiazol-2-yl) phenoxy) acetic acid (1581): To a stirring solution of compound 670 (80 mg, 0.13 mmol) in THF: H₂O (4: 1, 10 mL) was added lithium hydroxide monohydrate (18 mg, 0.42 mmol) at RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 2 N HCl to ~6. The precipitated solid was filtered triturated with 20% EtOAc/ hexanes (10 mL) and dried in vacuo to afford 1581 (60 mg, 79%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); ‘H-NMR (DMSO-ri₆, 500 MHz): δ 11.51 (s, 1H), 9.46 (t, J= 5.6 Hz, 1H), 8.04 (d, J= 8.4 Hz, 1H), 7.97 (t, J= 8.4 Hz, 2H), 7.89 (t, J= 7.1 Hz, 1H), 7.86-7.78 (m, 5H), 7.72 (s, 1H), 6.99 (d, J= 8.7 Hz, 2H), 4.73 (s, 2H), 4.65 (d, J= 5.5 Hz, 2H); LC-MS: 100%; 549.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.06 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 99.71%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 pm); RT 7.22 min. ACN : 0.05% TFA (Aq); 1.0 mL/min, Diluent: ACN: water).

Synthesis of tert-butyl 3-(((methylsulfonyl) oxy) methyl) azetidine-l-carboxylate (1595):

To a stirring solution of tert-butyl 3-(hydroxymethyl) azetidine-l-carboxylate 671 (500 mg, 2.67 mmol) in CH₂C1₂ (10 mL) under inert atmosphère were added triethylamine (0.77 mL, 5.34 mmol), methanesulfonyl chloride (0.24 mL, 2.94 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction

-465 mixture was diluted with CH2CI2 (75 mL), washed with water (2 x 50 mL) The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 672 (580 mg) as sticky solid. TLC: 60% EtOAc/ hexanes (Rf. 0.4); 'H NMR (DMSO-4 500 MHz): δ 4.34 (d, J= 6.4 Hz, 2H), 3.95-3.87 (m, 2H), 3.65-3.56 (m, 2H), 3.21 (s, 3H), 2.952.84 (m, 1H), 1.37 (s, 9H);

Synthesis of terLbutyl 3-((4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b,J} [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) methyl) azetidine-l-carboxylate (1995-A): To a stirring solution of V-((2-(4-hydroxyphenyl) thiazol-5-yl) methyl)-! l-oxo-10, 11-dihydrodibenzo [b, J\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide 1595 (600 mg, 1.22 mmol) in DMF (100 mL) under inert atmosphère were added 4-bromo-l//-pyrazole 672 (5.92 g, 40.29 mmol), césium carbonate (39.4 g, 120.96 mmol) at RT; heated to 80 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (500 mL) and extracted with with EtOAc (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 30% EtOAc/ hexanes to afford 1995-A (4.1 g, 29%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.3). ‘H-NMR (DMSO-î/₆, 400 MHz): δ 11.52 (s, 1H), 9.46 (t, J = 5.7 Hz, 1H), 8.59 (d, J = 5.5 Hz, 1H), 8.06 (d,J=8.1 Hz, 1H), 7.98 (t, J= 7.5 Hz, 1H), 7.93-7.79 (m, 5H), 7.73 (s, 1H), 7.07 (d, J= 8.7 Hz, 2H), 4.66 (d, J= 5.3 Hz, 2H), 4.18 (d, J= 5.3 Hz, 2H), 4.12-4.04 (m, 2H), 3.93-3.81 (m, 2H), 3.27-3.16 (m, 1H); LC-MS: 97.70%; 659.1 (M-l)⁺; (column; Kinetex EVO C-18 (50 x 3.0 mm,2.6 um); RT 1.27 min. 2.5 mM Aq. NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min); HPLC (purity): 99.67%; (column; X select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 10.33 min. 0.05% TFA + 5% ACN : ACN + 5% 0.05% TFA ; 1.0 mL/min, Diluent: ACN: water).

Synthesis of A-((2-(4-(azetidin-3-ylmethoxy) phenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide TFA sait (1995): To stirred solution of terLbutyl 3-((4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b,f[ [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) methyl) azetidine-l-carboxylate

-466 (1995-A) (200 mg, 0.30 mmol) in CH₂C1 under inert atmosphère was added trifluoroacetic acid (0.11 mL, 1.51 mmol) at 0 °C; wamred to RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with EtOAc (2x10 mL) and dried in vacuo to afford 1995 (90 mg, 5 43%, TFA sait) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.1); 'H-NMR (DMSOd₆, 400 MHz): δ 11.52 (s, 1H), 9.46 (t, J = 5.7 Hz, 1H), 8.60 (br s, 2H), 8.06 (d, .7=8.1 Hz, 1H), 7.98 (t, J = 7.5 Hz, 2H), 7.93-7.79 (m, 6H), 7.73 (s, 1H), 7.07 (d, J= 8.7 Hz, 2H), 4.66 (d, J = 5.3 Hz, 2H), 4.18 (d, J= 5.3 Hz, 2H), 4.12-4.04 (m, 2H), 3.93-3.81 (m, 2H), 3.27-3.16 (m, 1H); LC-MS: 96.93%; 491.0 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm);

RT 1.80 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 95.81%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 9.23 min. ACN + 5 mM NH₄OAc: ACN; 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of 1997

Synthesis of te/7-butyl 3-(hydroxymethyl) piperidine-l-carboxylate (674): To a stirring solution of piperidin-3-ylmethanol 673 (1 g, 8.69 mmol) in CH₂C1₂ (10 mL) under argon atmosphère were added triethylamine (3.66 mL, 26.08 mmol), Boc-anhydride (2.39 mL, 10.43

-467mmol) at 0 °C; warmed to RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with CH₂C1₂ (2x30 mL). The combined organic extracts were washed with water (40 mL) and brine (40 mL); dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 674 (1.6 g, 86%) as pale yellow liquid. TLC: 5% MeOH/ CH2Q2 (Rf 0.5); ‘HNMR (DMSO-4 400 MHz): δ 4.49 (t, J= 5.3 Hz, 1H), 4.04-3.87 (m, 1H), 3.81-3.76 (m, 1H), 3.30- 3.25 (m, 1H), 3.20-3.14 (m, 1H), 2.77-2.61 (m, 1H), 1.75-1.62 (m, 1H), 1.62-1.53 (m, 1H), 1.51-1.42 (m, 1H), 1.39 (s, 9H), 1.36-1.18 (m, 1H), 1.14-1.01 (m, 1H);

Synthesis of tert-butyl 3-(((methylsulfonyl) oxy) methyl) piperidine-l-carboxylate (675): To a stirring solution of compound 674 (500 mg, 2.487 mmol) in CH2CI2 (15 mL) under inert atmosphère were added triethylamine (1.04 mL, 7.46 mmol), methanesulfonyl chloride (0.24 mL, 3.73 mmol) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with CH₂C1₂ (2x30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL); dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 675 (600 mg crude) as pale yellow liquid. TLC: 30% EtOAc/ hexanes (Rf. 0.5); ‘H-NMR (DMSO-4 400 MHz): δ 4.13 - 4.02 (m, 2H), 3.73-3.69 (m, 1H), 3.17 (s, 3H), 2.92-2.78 (m, 2H), 1.85-1.67 (m, 3H), 1.65-1.55 (m, 1H), 1.39 (s, 9H), 1.36-1.12 (m, 2H);

Synthesis of tert-butyl 3-((4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b ,f] [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) methyl) piperidine-l-carboxylate (676): To a stirring solution of A-((2-(4-hydroxyphenyl) thiazol-5-yl) methyl)-l l-oxo-10, 11dihydrodibenzo [b,f [1,4] thiazepine-8-carboxamide 5, 5-dioxide 1 595 (400 mg, 0.81 mmol) in DMF (8 mL) were added césium carbonate (796 mg, 2.44 mmol), compound 675 (272 mg, 0.97 mmol) under argon atmosphère at RT; heated to 70 °C in a sealed tube and stirred for 16 h. The reaction was monitored by TLC; after completion, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2X 40 mL). The combined organic extracts were washed with water (40 mL) and brine (40 mL); dried over sodium sulfate, filtered and

-468 concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3% MeOH/ CH2CI2 to afford compound 676 (50 mg, 9%) as pale yellow solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.6); ^XH NMR (400 MHz, DMSO-d₆): δ 11.51 (s, 1H), 9.45 (t, J= 5.7 Hz, 1H), 8.05 (d, J= 8.3 Hz, 1H), 8.00-7.95 (m, 2H), 7.93-7.84 (m, 3H), 7.847.78 (m, 3H), 7.72 (s, 1H), 7.02 (d, J= 8.9 Hz, 2H), 4.66 (d, J= 5.6 Hz, 2H), 3.95-3.84 (m, 2H), 3.74-3.60 (m, 1H), 2.98-2.82 (m, 2H), 1.93-1.86 (m, 1H), 1.83-1.75 (m, 1H), 1.66-1.59 (m, 1H), 1.42-1.29 (m, 12H); LC-MS: 92.11%; 589.1 (M⁺+l) des BOC; (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 2.74 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of 1 l-oxo-A-((2-(4-(piperidin-3-ylmethoxy) phenyl) thiazol-5-yl) methyl)-10, 11dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (1997): To a stirring solution of compound 675 (38 mg, 0.055 mmol) in CH2CI2 (2 mL) was added 4 N HCl in 1, 4-dioxane (1 mL) under argon atmosphère at 0 °C; warmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with diethyl ether (5 mL) and dried in vacuo to afford 1997 (20 mg; 58%) as white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.1); ^XH NMR (400 MHz, DMSO-d₆): δ 11.53 (s, 1H), 9.49 (t, J = 5.7 Hz, 1H), 8.92-8.83 (m, 1H), 8.75-8.63 (m, 1H), 8.06 (d, J= 8.2 Hz, 1H), 8.01-7.96 (m, 2H), 7.92-7.80 (m, 6H), 7.73 (s, 1H), 7.03 (d, J= 8.9 Hz, 2H), 4.66 (d, J = 5.5 Hz, 2H), 4.04-3.89 (m, 2H), 3.38-3.32 (m, 1H), 3.28-3.20 (m, 1H), 2.85-2.71 (m, 2H), 2.28-2.18 (m, 1H), 1.89-1.79 (m, 2H), 1.73-1.63 (m, 1H), 1.41-1.28 (m, 1H); LC-MS: 99.93%; 589.1 (M⁺+l); (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 1.86 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.78%; (column; X select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 5.74 min. 0.05% TFA + 5% ACN: ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: ACN: water).

Synthesis of 11137 & 11138:

-469 10

Synthesis of benzyl 4-(hydroxymethyI) piperidine-l-carboxylate (678): To a stirring solution of piperidin-4-ylmethanol 677 (4 g, 34.72 mmol) in CH2CI2 (100 mL) were added triethylamine (15 mL, 104.17 mmol) followed by benzyl chloroformate (50% in toluene, 13 mL, 38.19 mmol) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with aqueous saturated sodium bicarbonate solution (40 mL) and extracted with EtOAC (2 x 40 mL). The combined organic extracts were washed dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 50% EtOAc/ hexanes to afford compound 678 (5 g, 58%) as Pale yellow liquid. TLC: 50% EtOAc/ hexanes (Rf 0.3); 'H NMR (500MHz, DMSO-t/ί): δ 7.44-7.27 (m, 5H), 5.06 (s, 2H), 4.46 (t, J = 5.2 Hz, IH), 4.03-3.98 (m, 2H), 3.24 (t, J=5.8Hz, 2H), 2.79-2.75 (m, 2H), 1.67-1.62 (m, 2H), 1.58-1.50 (m, IH), 1.050.96 (m, 2H); LC-MS: 89.34%; 250.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm,

-470 -

2. 7 pm); RT 2.06 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of benzyl 4-(((methylsulfonyl) oxy) methyl) piperidine-l-carboxylate (679): To a stirring solution of compound 678 (1.25 g, 5.02 mmol) in CH2CI2 (20 mL) were added methanesulfonyl chloride (0.5 mL, 6.02 mmol) and triethylamine (1.08 mL, 7.53 mmol) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured slowly into aqueous saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2x35 mL). The combined organic extracts were washed dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 679 (1.5 g) as pale yellow liquid. This crude material was taken to next step without further purification. TLC: 50% EtOAc/ hexanes (Rf 0.8); ‘H NMR (500MHz, DMSOV): δ 7.45-7.26 (m, 5H), 5.07 (s, 2H), 4.11-3.99 (m, 4H), 3.17 (s, 3H), 2.89-2.72 (m, 2H), 1.94-1.83 (m, 1H), 1.70-1.66 (m, 2H), 1.22-1.05 (m, 2H); LCMS: 91.59%; 328.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.37 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of benzyl 4-((4-(5-(((terributoxycarbonyl) amino) methyl) thiazol-2-yl) phenoxy) methyl) piperidine-l-carboxylate (680): To a stirring solution of terLbutyl ((2-(4hydroxyphenyl) thiazol-5-yl) methyl) carbamate 356 (1 g, 3.27 mmol) in DMF (15 mL) were added compound 679 (1.17 g, crude) and césium carbonate (2.66 g, 8.17 mmol) at RT under inert atmosphère. The reaction mixture was heated to 70 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 2% MeOH/ CH2CI2 to afford compound 680 (1.3 g, 74%) as an off white solid. TLC: 40% EtOAc/ hexanes (Rf 0.7); ^XH NMR (400MHz, DMSO-/₆): δ 7.80 (d, J= 8.8 Hz, 2H), 7.60 (s, 1H), 7.53 (t, J= 5.7 Hz, 1H), 7.40-7.29 (m, 5H), 7.02 (d, J = 8.9 Hz, 2H), 5.08 (s, 2H), 4.31 (d, J = 5.9 Hz, 2H), 4.09-4.03

-471 - (m, 2H), 3.90 (d, J= 6.4 Hz, 2H), 2.85-2.79 (m, 2H), 2.04-1.92 (m, 1H), 1.82-1.75 (m, 2H), 1.40 (s, 9H), 1.26-1.15 (m, 2H); LC-MS: 90.14%; 538.3 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 μm); RT 3.06 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of benzyl 4-((4-(5-(aminomethyl) thiazol-2-yl) phenoxy) methyl) piperidine-1carboxylate hydrochloride (681): To a stirring solution of compound 680 (1.3 g, 2.42 mmol) in CH₂C1₂ (15 mL) was added 4 N HCl in 1, 4-dioxane (4 mL) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was triturated with EtOAc (30 mL), diethylether (30 mL) and dried in vacuo to afford compound 681 (1.1 g, HCl sait) as an off white solid. TLC: 40% EtOAc/ hexanes (Rf. 0.1); *H NMR (500MHz, DMSO-r/₆): δ 8.64 (br s, 3H), 7.91 (s, 1H), 7.85 (d, J = 8.7 Hz, 2H), 7.41-7.29 (m, 5H), 7.06 (d, J= 8.7 Hz, 2H), 5.08 (s, 2H), 4.31 (q, J= 52 Hz, 2H), 4.08-4.03 (m, 2H), 3.91 (d, J= 6.4 Hz, 2H), 2.96-2.78 (m, 2H), 2.03-1.92 (m, 1H), 1.80-1.76 (m, 2H), 1.27-1.15 (m, 2H); LC-MS: 99.39%; 438.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.07 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of benzyl 4-((4-(5-((5, 5-dioxido-l 1-oxo-10, 11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) methyl) piperidine-l-carboxylate (682): To a stirring solution of 11-oxo-10, 11-dihydrodibenzo [b, f] [ 1, 4] thiazepine-8carboxylic acid 5, 5-dioxide 92 (200 mg, 0.66 mmol) in DMF (15 mL) were added compound 681 (312 mg, 0.66 mmol), EDCI.HC1 (189 mg, 0.99 mmol), HOBt (135 mg, 0.99 mmol) and diisopropylethylamine (0.6 mL, 0.33 mmol) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (20 mL) and extracted with EtOAc (2x30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through

-472 column chromatography using 4% MeOH/ CH2CI2 to afford compound 682 (310 mg, 65%) as an off white solid. TLC: 6% MeOH/ CH₂C1₂ (Rf 0.5); *H NMR (500MHz, DMSO/): δ 11.51 (s, 1H), 9.44 (t, J= 5.5 Hz, 1H), 8.06 (d, J= 8.1 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.83 (m, 3H), 7.83-7.77 (m, 3H), 7.72 (s, 1H), 7.40-7.30 (m, 5H), 7.01 (d, J= 9.3 Hz, 2H), 5.07 (s, 2H), 4.66 (d, J= 5.8 Hz, 2H), 4.07-4.03 (m, 2H), 3.89 (d, J= 6.4 Hz, 2H), 2.93-2.77 (m, 2H), 2.011.93 (m, 1H), 1.79-1.75 (m, 2H), 1.25-1.15 (m, 2H); LC-MS: 93.17%; 723.2 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.83 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 1 l-oxo-A-((2-(4-(piperidin-4-ylmethoxy) phenyl) thiazol-5-yl) methyl)-10, 11dihydrodibenzo [b, J} [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (11137): To a stirring solution of compound 682 (200 mg, 0.28 mmol) in CH₂C1₂ (5 mL) was added trimethylsilyl iodide (0.04 mL, 0.28 mmol) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 8% MeOH/ CH2CI2 to afford 11137 (83 mg, 50%) as an off white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.2); ’H NMR (400MHz, DMSO/:6 9.45 (t,J=5.6Hz, 1 H), 8.05 (d,J=8.3 Hz, 1H), 7.97 (td,J=7.6, 1.1 Hz, 2H), 7.93-7.77 (m, 6H), 7.72 (s, 1H), 7.01 (d, J= 8.8 Hz, 2H), 4.66 (d, J= 5.6 Hz, 2H), 3.85 (d, J= 6.3 Hz, 2H), 3.03-2.98 (m, 2H), 2.60-2.53 (m, 2H), 1.86-1.84 (m, 1H), 1.74-1.69 (m, 2H), 1.27-1.14 (m, 2H); LC-MS: 98.61%; 589.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.84 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of/V-((2-(4-((l-methylpiperidin-4-yl) methoxy) phenyl) thiazol-5-yl) methyl)-11oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (11138): To a stirring solution of 1 l-oxo-7V-((2-(4-(piperidin-4-ylmethoxy) phenyl) thiazol-5yl) methyl)-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide 11137

-473 (75 mg, 0.13 mmol) in methanol (5 mL) were added paraformaldéhyde (19 mg, 0.64 mmol) and sodium cyanoborohydride (39 mg, 0.64 mmol) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was dilute with ice cold water (20 mL) and extracted with 10% MeOH/ CH2CI2 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 8% MeOH/ CH₂C1₂ to afford A-methyl ated compound (50 mg) as an off white solid. TLC: 10% MeOH/ CH2CI2 (Rf. 0.7). This was taken forward for next step.

To a stirring solution of above 7V-methylated compound (50 mg) in CH2CI2 (2 mL) was added 4 N HCl in 1, 4-dioxane (0.5 mL) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was triturated with EtOAc (10 mL), diethylether (10 mL), followed by préparative HPLC purification to afford 11138 (38 mg, 46%, for two steps) as an off white solid. TLC: 10% MeOH/ CH2CI2 (Rf. 0.1); ^lH NMR (400MHz, DMSO-cZQ: δ 11.53 (s, 1H), 9.47 (t, J= 5.6 Hz, 1H), 9.29 (br s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.00-7.95 (m, 2H), 7.92-7.79 (m, 6H), 7.73 (s, 1H), 7.02 (d, J= 8.9 Hz, 2H), 4.66 (d, J=5.5 Hz, 2H), 3.92 (d, J = 5.6 Hz, 2H), 3.48-3.43 (m, 2H), 3.29-3.12 (m, 1H), 3.02-2.91 (m, 2H), 2.76 (d, J= 4.6 Hz, 3H), 2.02-1.94 (m, 2H), 1.561.43 (m, 2H); LC-MS: 99.63%; 603.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.85 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 99.37%; (column; X-Select CSH-C-18 (150 x 4.6 mm, 3.5 pm); RT 6.14 min. 0.05% TFA + 5% ACN : ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: ACN : H₂O).

Synthesis of 11104-A & 11104

-474-

Synthesis of tert-butyl (R)-2-(hydroxymethyl) pyrrolidine-l-carboxylate (684): To a stirring solution of (R)-pyrrolidin-2-ylmethanol 683 (1 g, 9.88 mmol) in CH₂C1₂ (20 mL) under inert atmosphère was added triethylamine (1.57 mL, 10.89 mmol) at 0 °C, followed by addition of

Boc-anhydride (2.5 mL, 10.89 mmol) at the same température; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL), diluted with 1 N HCl (10 mL). The aqueous layer was concentrated in vacuo to afford crude compound 684 (1.9 g) as colorless syrup which was carried forward for next step without further purification. TLC: 20% EtOAc/ hexanes (Rf 0.4);

^XH NMR (CDC1₃, 400 MHz): δ 4.74 (br d, J= 5.5 Hz, IH), 4.01-3.98 (m, IH), 3.73-3.56 (m, 2H), 3.54-3.44 (m, IH), 3.36-3.33 (m, IH), 2.09-1.97 (m, IH), 1.89-1.84 (m, 2H), 1.50 (s, 9H);

Synthesis of tert-butyl (R)-2-(((methylsulfonyl) oxy) methyl) pyrrolidine-l-carboxylate (685): To a stirring solution of compound 684 (1 g, crude) in CH₂C1₂ (20 mL) under inert atmosphère were added triethylamine (1.40 mL, 9.95 mmol), methanesulfonyl chloride (0.68 mL, 8.45 mmol) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL)

-475 and extracted with CH2CI2 (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 20% EtOAc/ hexanes to afford compound 685 (1.05 g, 38%, over 2 steps) as colorless liquid. TLC: 20% EtOAc/ hexanes (Rf 0.5); ^fH NMR (CDCI3, 400 MHz): δ 4.39-4.22 (m, 1.6H), 4.16-3.98 (m, 1.4H), 3.53-3.29 (m, 2H), 3.02 (s, 3H), 2.121.81 (m, 4H), 1.60 (s, 9H);

Synthesis of tert-butyl (R)-2-((4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo \b,f [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) methyl) pyrrolidine-l-carboxylate (11104-A): To a stirring solution of A-((2-(4-hydroxyphenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide 1595 (1 g, 2.03 mmol) in DMF (3 mL) under inert atmosphère were added terZ-butyl (A)-2-(((methylsulfonyl) oxy) methyl) pyrrolidine-l-carboxylate 685 (568 mg, 2.03 mmol), césium carbonate (1.99 g, 6.10 mmol) at RT; heated to 80 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 3% MeOH/ CH2CI2 to afford 11104-A (460 mg, 35%) as an offwhite solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.6); ^]H NMR (DMSO-î/₆, 400 MHz): δ 11.51 (s, 1H), 9.44 (t, J= 5.6 Hz, 1H), 8.05 (d, J= 8.2 Hz, 1H), 8.01-7.94 (m, 2H), 7.93-7.77 (m, 6H), 7.72 (s, 1H), 7.05 (d, J = 8.9 Hz, 2H), 4.66 (d, J= 5.6 Hz, 2H), 4.14-3.91 (m, 3H), 3.29-3.25 (m, 2H), 2.05-1.75 (m, 4H), 1.40 (s, 9H); LC-MS: 94.40%; 619.1 (M-^zBu)⁺ (Column; X-select CSH C-18 (150 x 3.0 mm, 2.7 pm); RT 2.70 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.0 mL/min); HPLC (purity): 96.20%; (column; X-Select CSH-C-18 (150 x 4.6 mm, 3.5 pm); RT 10.64 min. 0.05% TFA (Aq) + 5% ACN: ACN + 5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: ACN: H2O).

Synthesis of (7?)-l l-oxo-A-((2-(4-(pyrrolidin-2-ylmethoxy) phenyl) thiazol-5-yl) methyl)-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (11104):

-476 To a stirring solution of 11104-A (450 mg, 0.66 mmol) in CH2CI2 (10 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (4 mL) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with diethyl ether (5 mL), EtOAc (5 mL), w-pentane (5 mL) and dried in vacuo to afford 1 1104 (280 mg, 69%; HCl sait) as an off-white solid. TLC: 5% MeOH/ CH2CI2 (Rf 0.1); *H NMR (DMSO-d₆, 400 MHz): δ 11.53 (s, 1H), 9.48 (t, J= 5.8 Hz, 1H), 9.38 - 9.28 (m, 1H), 8.91 - 8.76 (m, 1H), 8.06 (d, J= 8.2 Hz, 1H), 8.01-7.96 (m, 2H), 7.93-7.80 (m, 6H), 7.74 (s, 1H), 7.08 (d, J= 8.9 Hz, 2H), 4.66 (d, J= 5.6 Hz, 2H), 4.32 (dd, J= 3.5, 10.7 Hz, 1H), 4.16 (dd, J = 8.5, 10.6 Hz, 1H), 3.99 - 3.87 (m, 1H), 3.27 - 3.16 (m, 2H), 2.18-2.09 (m, 1H), 2.04 - 1.86 (m, 2H), 1.79-1.70 (m, 1H); LC-MS: 94.56%; 575.1 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.82 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity): 95.85%; (column; X-Select CSH-C-18 (150 x 4.6 mm, 3.5 pm); RT 5.86 min. 0.05% TFA (Aq) + 5% ACN: ACN + 5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: ACN: H2O).

Synthesis of (A)-A-((2-(4-((l-methylpyrrolidin-2-yl) methoxy) phenyl) thiazol-5-yl)methyl)11-oxo-10,11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5,5-dioxide (11131): To a stirring solution of 11104 (120 mg, 0.19 mmol) in MeOH (10 mL) under inert atmosphère were added paraformaldéhyde (29 mg, 0.98 mmol) and sodium cyanoborohydride (62 mg, 0.98 mmol) at RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with CH₂C1₂ (3x15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column

-477 - chromatography using 4% MeOH/ CH2CI2 and 2 mL aqueous ammonia to obtain semi solid, which was washed further with diethyl ether and hexane and dried in vacuo to afford 11131 (100 mg, 63%) as an off whit solid. TLC: 10% MeOH/ CH2CI2 (Ry 0.6); 'H NMR (DMSO-0Y 400 MHz): δ 11.51 (br s, 1 H), 9.44 (t,J=5.7Hz, 1H), 8.05 (d,J=8.3 Hz, 1H), 7.98 (ddJ =

7.5, 1.0 Hz, 2H), 7.93-7.76 (m, 6H), 7.72 (m, 1H), 7.02 (d, J= 8.9 Hz, 1H), 4.66 (br d, J = 5.6

Hz, 2H), 4.01 (dd, J = 5.3, 9.6 Hz, 1H), 3.87 (dd, J= 6.0, 9.6 Hz, 1H), 2.99-2.92 (m, 1H), 2.70 - 2.65 (m, 1H), 2.62 - 2.54 (m, 1H), 2.25-2.14 (m, 1H), 2.02-1.90 (m, 1H), 1.73-1.64 (m, 2H), 1.63 - 1.53 (m, 1H); LC-MS: 97.99%; 589.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.67 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity): 98.46%; (column; X-Select CSH-C-18 (150 x 4.6 mm, 3.5 pm); RT 5.90 min. 0.05% TFA (Aq) + 5% ACN: ACN + 5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: ACN: H₂O).

-478 Synthesis of tert-butyl (5)-2-(hydroxymethyl) pyrrolidine-l-carboxylate (687): To a stirring solution of (5')-pyrrolidin-2-ylmethanol 686 (1 g, 9.88 mmol) in CH2CI2 (20 mL) under inert atmosphère was added triethylamine (1.57 mL, 10.89 mmol) at 0 °C, followed by addition of Boc-anhydride (2.5 mL, 10.89 mmol) at the same température; warmed to RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL), diluted with 1 N HCl (20 mL). The aqueous layer was concentrated in vacuo to afford crude compound 687 (1.9 g) as colorless syrup which was carried forward for next step without fùrther purification. TLC: 20% EtOAc/ hexanes (Rf 0.4); ‘H-NMR (CDC13, 500 MHz): δ 4.74-4.70 (m, 1H), 3.97 (d, J = 5.2 Hz, 1H), 3.68-3.54 (m, 2H), 3.49-3.42 (m, 1H), 3.36-3.28 (m, 1H), 2.07-1.94 (m, 1H), 1.90-1.74 (m, 2H), 1.47 (s, 9H);

Synthesis of terributyl (5)-2-(((methylsulfonyl) oxy) methyl) pyrrolidine-l-carboxylate (688): To a stirring solution of compound 687 (1 g, crude) in CH2Q2 (20 mL) under inert atmosphère were added triethylamine (1.40 mL, 9.95 mmol), methanesulfonyl chloride (0.68 mL, 8.45 mmol) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH2CI2 (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 688 (570 mg, crude) as colorless liquid. TLC: 20% EtOAc/ hexanes (Rf 0.5); The crude was carried forward for next step without further purification.

Synthesis of terLbutyl (5)-2-((4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) methyl) pyrrolidine-l-carboxylate (689): To a stirring solution of A-((2-(4-hydroxyphenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide 1 595 (1 g, 2.03 mmol) in DMF (20 mL) under inert atmosphère were added teri-butyl (5)-2-(((methylsulfonyl) oxy) methyl) pyrrolidine-l-carboxylate 688 (568 mg, crude), césium carbonate (1.99 g, 6.10 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x

-479 - mL). The combined organic extracts were dried over sodium sulfate, fdtered and concentrated in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 2% MeOH/CH₂Cl₂ to afford compound 689 (210 mg, 16%) as yellow solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.4); LC-MS: 94.40%; 619.1 (M⁺+l) (-^zBu) (Column; Xselect CSH C-18 (150 x 3.0 mm, 2.7 pm); RT 2.70 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.0 mL/min). *H-NMR (DMSO-d6, 400 MHz): δ 11.51 (s, 1H), 9.44 (t, J = 5.8 Hz, 1H), 8.05 (d, J= 8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.77 (m, 6H), 7.72 (s, 1H), 7.05 (d, J= 8.9 Hz, 2H), 4.66 (d, J= 5.6 Hz, 2H), 4.16-3.88 (m, 3H), 3.29-3.25 (m, 2H), 2.051.75 (m, 4H), 1.40 (s, 9H); LC-MS: 93.14%; 675.2 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 3.43 min. 2.5 mM Aq. NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH4OOCH, 0.8 mL/min).

Synthesis of (S)-l l-oxo-A-((2-(4-(pyrrolidin-2-ylmcthoxy) phenyl) thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b,f] [1,4] thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (11029): To a stirring solution of compound 689 (200 mg, 0.29 mmol) in CH₂C1₂ (10 mL) was added 4 N HCl in 1, 4- dioxane (10 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was washed with diethyl ether (5 mL), EtOAc (5 mL), hexane (5 mL) and dried in vacuo to afford 11029 (130 mg, HCl sait) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.1); *H NMR (DMSO-d₆, 400 MHz): δ 11.53 (s, 1H), 9.48 (t, J= 5.8 Hz, 1H), 9.42-9.28 (m, 1H), 8.94-8.73 (m, 1H), 8.06 (d, J= 8.3 Hz, 1H), 8.00 - 7.95 (m, 2H), 7.93 7.80 (m, 6H), 7.74 (s, 1H), 7.08 (d, J= 8.9 Hz, 2H), 4.66 (d, J= 5.6 Hz, 2H), 4.32 (dd, J= 10.7, 3.5 Hz, 1H), 4.17 (dd, J= 10.5, 8.4 Hz, 1H), 3.97 - 3.89 (m, 1H), 3.28 - 3.17 (m, 2H), 2.16-2.08 (m, 1H), 2.05-1.95 (m, 1H), 1.95-1.84 (m, 1H), 1.80-1.68 (m, 1H); LC-MS: 93.84%; 575.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.82 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity): 93.14%; (column; X-select CSH-C18 (150 x 4.6 mm, 3.5 pm); RT 5.83 min. 0.05% TFA (Aq) + 5% ACN: ACN + 5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: DMSO: ACN: water).

-480 Synthesis of 11135

Synthesis of (5)-27-((2-(4-(( 1-methylpyrrolidin-2-yl) methoxy) phenyl) thiazol-5-yl)methyl)-lloxo-10,11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5,5-dioxide (11135): To a stirring solution of 11029 (90 mg, 0.14 mmol) in MeOH (5 mL) under inert atmosphère were added paraformaldéhyde (22 mg, 0.73 mmol) and sodium cyanoborohydride (46 mg, 0.73 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with CH2CI2 (3 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2CI2 and 2 mL aqueous ammonia to afford 11135 (73 mg, 83%) as an off white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.6); *H NMR (DMSO-X 400 MHz): δ 11.51 (br s, 1H), 9.45 (t, J= 5.7 Hz, 1H), 8.06 (d,J=8.3 Hz, 1H), 8.02-7.95 (m, 2H), 7.92-7.78 (m, 6H), 7.72 (s, 1H), 7.02 (d, J= 8.7 Hz, 2H), 4.66 (d, J= 5.6 Hz, 2H), 4.02 (dd, J= 9.6, 5.5 Hz, 1H), 3.94-3.85 (m, 1H), 3.01-2.96 (m, 1H), 2.65-2.56 (m, 1H), 2.38 (br s, 3H), 2.27-2.16 (m, 1H), 2.01-1.92 (m, 1H), 1.76-1.55 (m, 3H); LC-MS: 96.81%; 589.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.83 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.00%; (column; X-select CSH-C18 (150 x 4.6 mm, 3.5 pm); RT 5.98 min. 0.05% TFA (Aq) + 5% ACN: ACN + 5% 0.05% TFA (Aq) ; 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of 11139

-481 -

Synthesis of (5)-pyrrolidin-3-ylmethanol TFA sait (691): To a stirring solution of terLbutyl (S)-3-(hydroxym ethyl) pyrrolidine-l-carboxylate 690 (2 g, 14.90 mmol) in CH2CI2 (30 mL) under inert atmosphère was added trifluoroacetic acid (30 mL) at 0 °C and stirred for 30 min.

The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with CH2CI2 (2 x 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 691 (2 g) as yellow syrup. TLC: 20% EtOAc/ hexanes (Rf 0.2).

Synthesis of benzyl (5)-3-(hydroxymethyl) pyrrolidine-l-carboxylate (692): To a stirring solution of compound 691 (2 g, 19.77 mmol) in THF: H2O (4: 1, 60 mL) was added potassium carbonate (5.4 g, 31.67 mmol) portion wise for 10 min at 0 °C; warmed to RTand stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 75 mL). The

-482 combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 692 (1.1 g, crude) as yellow syrup. TLC: 40% EtOAc/ hexanes (Rf 0.2); LC-MS: 67.76%; 236.0 (M⁺+l); (column; X Select CSH C-18, (50 x 3.0 mm, 2.5 pm); RT 2.12 min. 2.5 mM Aq. NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of benzyl (5)-3-(((methylsulfonyl) oxy) methyl) pyrrolidine-l-carboxylate (693): To a stirring solution of compound 692 (1.2 g, crude) in CH2Q2 (10 mL) under inert atmosphère were added triethylamine (2.11 mL, 15.31 mmol), methanesulfonyl chloride (0.67 mL, 7.65 mmol) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH2CI2 (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 693 (2 g) as brown liquid. TLC: 40% EtOAc/hexanes (Rf. 0.4); LC-MS: 80.20%; 313.9 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 1.27 min. 2.5 mM Aq. NH₄OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of benzyl (5)-3-((4-(5-(((ter/-butoxycarbonyl) amino) methyl) thiazol-2-yl) phenoxy) methyl) pyrrolidine-l-carboxylate (694): To a stirring solution of compound 693 (230 mg, 0.98 mmol) in DMF (3 mL) under inert atmosphère were added terZ-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl) carbamate 356 (200 mg, 0.65 mmol), césium carbonate (424 mg, 1.36 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 694 (300 mg) as yellow solid. TLC: 40% EtOAc/ hexanes (Rf 0.4); LC-MS: 63.70%; 524.5 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm,2.6 um); RT 1.27 min. 2.5 mM Aq. NH₄OAc: ACN, 0.8 mL/min).

- 483 Synthesis of benzyl (5)-3-((4-(5-(aminomethyl) thiazol-2-yl) phenoxy) methyl) pyrrolidine1-carboxylate hydrochloride (695): To a stirring solution of compound 694 (1.4 g, crude) in CH2CI2 (10 mL) was added 4 N HCl in 1, 4-dioxane (10 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with diethyl ether (5 mL), EtOAc (5 mL) and dried in vacuo to afford compound 695 (1 g, crude) as brown solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.1); LC-MS: 69.41%; 424.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.08 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of benzyl (5)-3-((4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) methyl) pyrrolidine-1-carboxylate (696): To a stirring solution of 92 (400 mg, 1.32 mmol) in DMF (5 mL) under inert atmosphère were added HOBt (356 mg, 2.64 mmol), EDCI.HC1 (506 mg, 2.64 mmol), diisopropyl ethyl amine (0.68 mL, 3.96 mmol) and compound 695 (722 mg, crude) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (2 x 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2% MeOH/ CH₂C1₂ to afford compound 696 (400 mg, 43%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.4); ‘H-NMR (DMSO-7₆, 400 MHz): δ 11.52 (s, 1H), 9.45 (t, J = 5.8 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.98 (td, J = 7.7, 1.3 Hz, 2H), 7.93-7.84 (m, 3H), 7.84-7.77 (m, 3H), 7.72 (s, 1H), 7.38-7.33 (m, 4H), 7.33-7.28 (m, 1H), 7.07-6.98 (m, 2H), 5.06 (s, 2H), 4.66 (d, J= 5.6 Hz, 2H), 4.13-3.93 (m, 2H), 3.61-3.41 (m, 2H), 3.40-3.34 (m, 1H), 3.25-3.13 (m, 1H), 2.71-2.60 (m, 1H), 2.12-1.96 (m, 1H), 1.83-1.68 (m, 1H); LC-MS: 84.44%; 709.2 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.98 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

P A513177/OA/5598087.1

-484 Synthesis of (S)-l l-oxo-A-((2-(4-(pyrrolidin-3-ylmethoxy) phenyl) thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (11139): To a stirring solution of compound 696 (200 mg, 0.28 mmol) in CH2CI2 (10 mL) was added trimethylsilyl iodide (0.03 mL, 0.21 Immol) under inert atmosphère at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with EtOAc (10 mL) and dried in vacuo to afford crude amine.

To the above crude amine (150 mg) in CH2CI2 (5 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (3 mL) at 0 °C and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with triturated with diethyether (10 mL) and dried in vacuo to afford crude compound HCl (140 mg) which was further purified by préparative HPLC purification to afford 11139 (89 mg, HCl sait, 36%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.2); 'H-NMR (DMSO-î/₆, 400 MHz): δ 11.51 (s, 1H), 9.45 (t,J=5.8Hz, 1H), 8.67 (br s, 2H), 8.05 (d, J= 8.2 Hz, 1H), 7.97 (td, J = 7.5, 1.3 Hz, 2H), 7.92-7.78 (m, 6H), 7.72 (s, 1H), 7.03 (d, J= 8.9 Hz, 2H), 4.65 (d, J = 5.6 Hz, 2H), 4.13-3.90 (m, 2H), 3.44-3.35 (m, 1H), 3.21-3.12 (m, 2H), 3.06- 2.98 (m, 1H), 2.78-2.70 (m, 1H), 2.19-1.98 (m, 1H), 1.83-1.66 (m, 1H); LC-MS: 98.88%; 575.1 (M⁺+l); (column; Ascentis Express Cl8, (50 ^χ 3.0 mm, 2.7 pm); RT 1.98 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 99.73%; (column; X-Select CSH-C-18 (150 x 4.6 mm, 3.5 pm); RT 5.61 min. 0.05% TFA (Aq) + 5% ACN: ACN + 5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: ACN: H₂O: DMSO).

-485 Synthesis of 11140

Synthesis of (Æ)-pyrrolidin-3-ylmethanol.TFA sait (698): To a stirring solution of teH-butyl (7?)-3-(hydroxymethyl) pyrrolidine-1 -carboxylate 697 (2 g, 9.95 mmol) in CH2CI2 (20 mL) was added trifluoroacetic acid (20 mL) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was triturated with diethylether (20 mL), n-hexane (30 mL) and dried under vacuum to afford crude compound 698 (1.8 g) as pale yellow sticky syrup. This crude material was taken to next step without further purification. TLC: 5% MeOH/ CH2C1₂ (Ry 0.1); LC-MS (Agilent 6310 Ion trap): 32.89%; 102.3 (M⁺+l); (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 um); RT 1.95 min. 2.5 mM Aq. NH4OAC: ACN; 1.0 mL/min).

Synthesis of benzyl (R)-3-(hydroxymethyl) pyrrolidine-l-carboxylate (699): To a stirring solution of compound 698 (1.8 g, crude) in a mixture of THF: H2O (1: 1, 60 mL) were added potassium carbonate (4.92 g, 35.64 mmol) and benzyl chloroformate (50% in toluene, 10.22 mL, 35.64 mmol) at 0 °C. The reaction mixture was gradually warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The

-486 crude was purified through silica gel column chromatography using 50% EtOAc/ hexanes to afford compound 699 (1.3 g) as pale yellow liquid. This material with minor impurity was taken to next step. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.3); *H NMR (500MHz, DMSO-î/ô): δ 7.447.25 (m, 5H), 5.05 (s, 2H), 4.66 (q, J= 4.6 Hz, 1H), 3.52-3.34 (m, 4H), 3.30-3.20 (m, 1H), 3.10-3.06 (m, 1H), 2.37-2.20 (m, 1H), 1.92-1.82 (m, 1H), 1.66-1.54 (m, 1H); LC-MS: 76.88%; 236.0 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 2.13 min. 2.5 mM NH4OOCH in water + 5% ACN: ACN + 5% 2.5 mM NH4OOCH in water, 0.8 mL/min).

Synthesis of benzyl (/?)-3-(((methylsulfonyl) oxy) methyl) pyrrolidine-l-carboxylate (700): To a stirring solution of compound 699 (1.3 g, 5.53 mmol) in CH₂C1₂ (30 mL) were added triethylamine (2.32 mL, 16.59 mmol) and methanesulfonyl chloride (0.51 mL, 6.64 mmol) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with CH₂C1₂ (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 700 (1.5 g) as pale yellow viscous syrup. This crude material was taken to next step without further purification. TLC: 50% EtOAc/hexanes (Rf 0.3); LC-MS: 81.89%; 313.9 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 2.64 min. 2.5 mM NH4OOCH in water + 5% ACN: ACN + 5% 2.5 mM NH4OOCH in water, 0.8 mL/min).

Synthesis of benzyl (À)-3-((4-(5-(((terLbutoxycarbonyl) amino) methyl) thiazol-2-yl) phenoxy) methyl) pyrrolidine-l-carboxylate (701): To a stirring solution of terLbutyl ((2-(4hydroxyphenyl) thiazol-5-yl) methyl) carbamate 356 (800 mg, 2.61 mmol) in DMF (15 mL) were added compound 700 (1.53 g, crude) and césium carbonate (1.7 g, 5.23 mmol) at RT in a sealed tube under inert atmosphère. The reaction mixture was heated to 70 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 150 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 701 (800 mg) as pale yellow viscous syrup. This crude material was taken to next step without

-487further purification. TLC: 5% MeOH/ CH₂Cl₂ (Rf. 0.6); LC-MS: 53.55%; 524.2 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 3.73 min. 2.5 mM NH4OOCH in water + 5% ACN: ACN + 5% 2.5 mM NH4OOCH in water, 0.8 mL/min).

Synthesis of benzyl (7?)-3-((4-(5-(aminomethyl) thiazol-2-yl) phenoxy) methyl) pyrrolidine1-carboxylate hydrochloride (702): To a stirring solution of compound 701 (500 mg, crude) in CH₂C1₂ (10 mL) was added 4 N HCl in 1, 4-dioxane (5 mL) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was triturated with diethyl ether (10 mL), n-pentanc (10 mL) and dried in vacuo to afford compound 702 (450 mg) as colorless sticky solid. This crude material was taken to next step without further purification. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.1); LC-MS (Agilent 6310 Ion trap): 66.70%; 424.3 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 3.53 min. 5mM Aq. NH₄OAc: ACN, 0.8 mL/min).

Synthesis of benzyl (R)-3-((4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b, fj [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenoxy) methyl) pyrrolidine-l-carboxylate (703): To a stirring solution of 1 l-oxo-10, 11-dihydrodibenzo [b, f] [1,4] thiazepine-8carboxylic acid 5, 5-dioxide 92 (250 mg, 0.82 mmol) in DMF (10 mL) were added compound 702 (419 mg, crude) and HOBt (167 mg, 1.24 mmol), EDCI.HC1 (238 mg, 1.24 mmol) followed by diisopropylethylamine (0.72 mL, 4.12 mmol) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 150 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was triturated with EtOAc (20 mL), CH₂C1₂ (20 mL), 77-pentane (20 mL) and dried under vacuum to afford compound 703 (230 mg) as colorless sticky solid. This crude material was taken to next step without further purification. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.5); ’H NMR (500MHz, DMSOd₆): δ 11.51 (br s, 1H), 9.45 (t, J=5.5Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.98 (t, J= 8.7 Hz, ' » Ύ' C ' ' : f* JAV '

-488 2H), 7.90 (t, J = 7.2 Hz, 1H), 7.87-7.78 (m, 6H), 7.72 (s, 1H), 7.38-7.29 (m, 4H), 7.03 (J= 8.1 Hz, 2H), 5.06 (s, 2H), 4.72-4.64 (m, 2H), 4.11-3.97 (m, 2H), 3.61-3.46 (m, 2H), 3.24-3.16 (m, 1H), 3.00-2.94 (m, 2H), 1.82-1.71 (m, 1H), 1.50-1.45 (m, 1H); LC-MS: 68.55%; 709.1 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.71 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (Λ)-1 l-oxo-A-((2-(4-(pyrrolidin-3-ylmethoxy) phenyl) thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b, f] [1,4] thiazepine-8-carboxamide 5, 5-dioxide (11140): To a stirring solution of compound 703 (230 mg, crude) in CH₂C1₂(5 mL) was added trimethylsilyl iodide (0.06 mL, 0.45 mmol) at 0 °C under inert atmosphère and stirred at the same température for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with CH₂C1₂ (30 mL) and washed with saturated sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography in basic A1₂O₃ using 10% MeOH/ CH₂C1₂ to afford 11140 (18 mg, 8%) as an off white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.1); 'H NMR (400MHz, DMSO-/: δ 9.45 (t, J= 5.5 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.78 (m, 6H), 7.72 (s, 1H), 7.02 (d, J= 8.8 Hz, 2H), 4.66 (d, J = 5.4 Hz, 2H), 4.00-3.89 (m, 2H), 3.46-3.37 (m, 1H), 3.03-2.89 (m, 2H), 2.83-2.80 (m, 1H), 2.73-2.66 (m, 1H), 1.95-1.84 (m, 1H), 1.53-1.45 (m, 1H); LC-MS: 96.04%; 575.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.82 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 95.84%; (column; X-Select CSH-C-18 (150 x 4.6 mm, 3.5 pm); RT 5.64 min. 0.05% TFA + 5% ACN : ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: ACN : H₂O).

98087.1

-489 Synthesis of 11103:

Synthesis of benzyl (5)-3-hydroxypyrrolidine-l-carboxyIate (705): To a stirring solution of (6)-pyrrolidin-3-ol 704 (1.5 g, 17.22 mmol) in CH2CI2 (50 mL) under inert atmosphère were added triethylamine (7.4 mL, 51.72 mmol), benzyl chloroformate (50% in toluene, 7.05 mL, 20.66 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion, the reaction mixture was poured into ice-cold water and extracted with CH2CI2 (2 x 60 mL). The combined organic extracts were washed dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 50% EtOAc/ hexanes to afford compound 705 (2 g, 53%) as pale yellow liquid. TLC: 60% EtOAc/ hexanes (Rf 0.5); ^lH NMR (DMSO-îZ₆,500 MHz): δ 7.38 - 7.32 (m, 4H), 7.32 - 7.27 (m, IH), 5.05 (s, 2H), 4.91 (br s, IH), 4.26-4.24 (m, IH), 3.42-3.27 (m, 3H), 3.24 - 3.13 (m, IH), 1.91-1.81 (m, IH), 1.78 - 1.70 (m, IH); LC-MS: 98.78%; 222.0

-490 - (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.85 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of benzyl (R)-3-(4-(5-(((teH-butoxycarbonyl) amino) methyl) thiazol-2-yl) phenoxy) pyrrolidine-l-carboxylate (706): To a stirring solution of ter/-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl) carbamate 356 (700 mg, 2.28 mmol) in diethyl ether (30 mL) under argon atmosphère were added benzyl (5)-3-hydroxypyrrolidine-l-carboxylate 705 (758 mg, 3.42 mmol), triphenylphosphine (1.19 g, 4.54 mmol), DIAD (0.906 mL, 4.57 mmol) at 0 °C; warmed to RT and stirred for 24 h. The reaction was monitored by TLC; after completion, the reaction mixture was poured into ice-cold water and extracted with EtOAc (2 x 75 mL). The combined organic extracts were washed dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 50% EtOAc/ hexanes to afford compound 706 (1.6 g, crude) as an off-white solid. TLC: 50% EtOAc/hexanes (Rf 0.5); LC-MS: 33.04%; 510.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.85 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). LC-MS shows 65.46%, TPPO as major impurity at RT 2.25.

Synthesis of benzyl (Æ)-3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) pyrrolidine-lcarboxylate hydrochloride (707): To a stirring solution of benzyl (R)-3-(4-(5-(((tertbutoxycarbonyl) amino) methyl) thiazol-2-yl) phenoxy) pyrrolidine-l-carboxylate 706 (1.6 g, crude) in CH2CI2 (30 mL) was added 4 N HCl in 1, 4-dioxane (3 mL) under argon atmosphère at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with diethyl ether (10 mL) and dried in vacuo to afford compound 707 (550 mg; HCl sait) as an off-white solid.TLC: 50% EtOAc/ hexanes (Rf. 0.1); 'H NMR (DMSO-rf₆,500 MHz): δ 8.54 (br s, 1H), 7.91 (s, 1H), 7.86 (d, J= 8.7 Hz, 1H), 7.40-7.32 (m, 1H), 7.09 (d, J= 8.7 Hz, 1H), 5.23 - 4.97 (m, 1H), 4.32 (q, J= 5.6 Hz, 1H), 3.80 - 3.31 (m, 1H), 2.29 - 2.05 (m, 1H); LC-MS: 99.37%; 432.0 (M⁺+Na); (column; Ascentis Express Cl 8, (50 x 3.0 mm, 2.7 pm); RT 1.93 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

-491 Synthesis ofbenzyl (R)-3-(4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) pyrrolidine-l-carboxylate (708): To a stirring solution of 92 (200 mg, 0.66 mmol) in DMF (15 mL) under inert atmosphère were added EDCI.HC1 (190 mg, 0.99 mmol), HOBt (135 mg, 0.99 mmol), benzyl (^)-3-(4-(5(aminomethyl) thiazol-2-yl) phenoxy) pyrrolidine-l-carboxylate hydrochloride 707 (299 mg, 0.66 mmol) and diisopropylethylamine (0.63 mL, 3.30 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice-cold water (50 mL) and extracted with EtOAc (2x60 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel (100-200 mesh) column chromatography using 5% MeOH/ CH2CI2 to afford compound 708 (300 mg, 67%) as an offwhite solid. TLC: 4% MeOH/ CH₂C1₂ (Rf 0.4); *H-NMR (DMSO-tZ₆, 500 MHz): δ 11.51 (s, 1H), 9.45 (t, .7= 5.8 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 8.01 -7.96 (m, 2H), 7.90 (td,J=7.5, 1.2 Hz, 1H), 7.87-7.79 (m, 5H), 7.73 (s, 1H), 7.42-7.26 (m, 5H), 7.04 (d, J= 8.7 Hz, 2H), 5.15 5.01 (m, 3H), 4.66 (br d, J= 5.8 Hz, 2H), 3.71 - 3.60 (m, 1H), 3.58 - 3.39 (m, 3H), 2.27 - 2.04 (m, 2H); LC-MS: 91.64%; 695.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.61 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (7?)-l l-oxo-A-((2-(4-(pyrrolidin-3-yloxy) phenyl) thiazol-5-yl) methyl)-10, 11dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (11103): To a stirring solution ofbenzyl (R)-3-(4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) pyrrolidine-l-carboxylate 708 (100 mg, 0.14 mmol) in t-butanol (10 mL) under inert atmosphère was added 10% Pd/C (50% wet, 200 mg), ammonium formate (180 mg, 2.88 mmol) at RT ; heated to 80 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were concentrated in vacuo to obtain the crude. The crude was purified through silica gel (100-200 mesh) column chromatography using 12% MeOH/ CH2CI2 to afford crude amine (30 mg).

Λ „ ·_;π Γ/.ΌΑ/5598087

-492 -

To the above crude amine (30 mg) in CH2CI2 (5 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (3 mL) at 0 °C and stirred for 30 min. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with triturated with EtOAc (5 mL) and dried in vacuo to afford 11103 (22 mg, 68.9%) as an off5 white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); 'H NMR (DMSO-4 400 MHz): δ 11.53 (s, 1H), 9.50 (t, J= 5.8 Hz, 1H), 9.41- 9.24 (m, 2H), 8.06 (d, J= 8.3 Hz, 1H), 7.98 (td, J= Ί.3, 1.5 Hz, 2H), 7.93-7.81 (m, 6H), 7.74 (s, 1H), 7.06 (d, J= 8.9 Hz, 2H), 5.21 (t, J= 4.4 Hz, 1H), 4.66 (d, J= 5.6 Hz, 2H), 3.40-3.22 (m, 4H), 2.29-2.09 (m, 2H); LC-MS: 92.21%; 561.1 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.81 min. 0.025%

Aq.TFA+ 5% ACN: ACN +5% 0.025% Aq TFA, 1.2 mL/min); HPLC (purity): 97.17%; (column; X-select CSH C-18 (150 x 4.66 mm, 3.5 pm); RT 5.28 min. ACN + 5% 0.05% TFA (Aq): 0.05% TFA (Aq) + 5% ACN; 1.0 mL/min, Diluent: ACN: water)

Synthesis of 11028 & 11134:

-493 -

Synthesis of benzyl (7î)-3-hydroxypyrrolidine-l-carboxyIate (710): To a stirring solution of (R)-pyrrolidin-3-ol 709 (1.5 g, 17.24 mmol) in CH2CI2 (50 mL) under inert atmosphère were added triethylamine (7.4 mL, 51.72 mmol), benzyl chloroformate (50% in toluene, 7.05 mL, 20.66 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion, the reaction mixture was poured into ice-cold water and extracted with CH2CI2 (2 x 60 mL). The combined organic ex tracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 50% EtOAc/ hexanes to afford compound 710 (1.5 g, 39%) as pale yellow liquid. TLC: 60% EtOAc/ hexanes (Rf. 0.5);*H NMR (DMSO-t/₆,500 MHz): δ 7.40-7.34 (m, 4H), 7.33-7.28 (m, 1H), 5.06 (s, 2H), 4.93 (br s, 1H), 4.26-4.24 (m, 1H), 3.42 - 3.30 (m, 3H), 3.23-3.17 (m, 1H), 1.93-1.82 (m, 1H), 1.80 - 1.71 (m, 1H); LC-MS: 99.47%; 222.0

-494(M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.86 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of benzyl ¢8)-3-(4-(5-(((tert-butoxycarbonyl) amino) methyl) thiazol-2-yl) phenoxy) pyrrolidine-l-carboxylate (711): To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl) carbamate 356 (700 mg, 2.28 mmol) in diethyl ether (30 mL) under argon atmosphère were added benzyl (R)-3-hydroxypyrrolidine-l-carboxylate 710 (758 mg, 3.43 mmol), triphenylphosphine (1.19 g, 4.57 mmol), DIAD (0.906 mL, 4.57 mmol) at 0 °C; warmed to RT and stirred for 48 h. The reaction was monitored by TLC; after completion, the reaction mixture was poured into ice-cold water and extracted with EtOAc (2 x 75 mL). The combined organic extracts were washed dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 50% EtOAc/ hexanes to afford compound 711 (1.6 g, crude) as an off-white solid. TLC: 50% EtOAc/hexanes (Ry 0.4); LC-MS: 42.16%; 510.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.86 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). LC-MS shows 53.36% TPPO as major impurity at RT 2.25.

Synthesis of benzyl (5)-3-(4-(5-(aminomethyl) thiazol-2-yI) phenoxy) pyrrolidine-lcarboxylate hydrochloride (712): To a stirring solution of benzyl (S)-3-(4-(5-(((tertbutoxycarbonyl) amino) methyl) thiazol-2-yl) phenoxy) pyrrolidine-l-carboxylate 711 (1.6 g, crude) in CH₂C1₂ (30 mL) was added 4 N HCl in 1, 4-dioxane (3 mL) under argon atmosphère at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with diethyl ether (10 mL) and EtOAc (2x5 mL) and dried in vacuo to afford compound 712 (510 mg; HCl sait) as an off-white solid. TLC: 50% EtOAc/ hexanes (Ry 0.1); ^XH NMR (DMSO-î/₆, 400 MHz): δ 8.50 (br s, 3H), 7.91 (s, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.43-7.25 (m, 5H), 7.09 (d, J= 8.9 Hz, 2H), 5.17 - 4.93 (m, 3H), 4.32 (q, J= 5.5 Hz, 2H), 3.74 - 3.61 (m, 1H), 3.60 - 3.36 (m, 3H), 2.29 - 2.05 (m, 2H); LC-MS: 93.90%; 432.0 (M⁺+Na); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.94 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

-495 Synthesis ofbenzyl (5)-3-(4-(5-((5,5-dioxido-l l-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) pyrrolidine-l-carboxylate (713): To a stirring solution of 92 (200 mg, 0.66 mmol) in DMF (15 mL) under inert atmosphère were added EDCI.HC1 (190 mg, 0.99 mmol), HOBt (135 mg, 0.99 mmol), benzyl (5)-3-(4-(5(aminomethyl) thiazol-2-yl) phenoxy) pyrrolidine-l-carboxylate hydrochloride 712 (294 mg, 0.66 mmol) and diisopropylethylamine (0.63 mL, 3.30 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion, the reaction mixture was poured into ice-cold water (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel (100-200 mesh) column chromatography using 4% MeOH/ CH2CI2 to afford compound 713 (220 mg, 49%) as an off-white solid. TLC: 4% MeOH/ CH2CI2 (Rf 0.4); LC-MS: 82.34%; 695.2 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.56 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (5)-l l-oxo-7V-((2-(4-(pyrrolidin-3-yloxy) phenyl) thiazol-5-yl) methyl)-10, 11dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide TFA sait (11028): To a stirring solution ofbenzyl (5)-3-(4-(5-((5,5-dioxido-l l-oxo-10, 11-dihydrodibenzo \b,f [1,4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) pyrrolidine-l-carboxylate 713 (100 mg, 0.14 mmol) in CH2CI2 (5 mL) under inert atmosphère was added trimethylsilyl iodide (0.02 mL, 0.014 mmol) at 0 °C; warmed to RT and stirred for 30 min. The reaction was monitored by TLC; after completion of the reaction, the volatiles were concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 10% MeOH/ CH2CI2 foliowed by préparative HPLC purification to afford 11028 (38 mg, 47%) as an offwhite solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); ’H NMR (DMSO-î/₆, 400 MHz): δ 11.52 (s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 9.06 (br s, 1H), 8.90 (br s, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.007.96 (m, 2H), 7.93-7.80 (m, 6H), 7.74 (s, 1H), 7.06 (d, J= 8.9 Hz, 2H), 5.21 (t, J= 4.7 Hz, 1H), 4.67 (d, J= 5.6 Hz, 2H), 3.51-3.43 (m, 2H), 3.39-3.26 (m, 2H), 2.27-2.21 (m, 1H), 2.18-2.10

-496 - (m, 1H); LC-MS: 98.35%; 561.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.83 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). HP LC (purity): 99.08%; (column; X-select CSH-C18 (150 x 4.6 mm, 3.5 pm); RT 5.73 min. 0.05% TFA (Aq) + 5% ACN: ACN + 5% 0.05% TFA (Aq): 1.0 mL/min, Diluent: ACN: water: DMSO).

Synthesis of (5)-N-((2-(4-((l-methylpyrrolidin-3-yl) oxy) phenyl)thiazol-5-yl) methyl)-11-oxo10, 11-dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxamide 5,5-dioxide (11134): To a stirring solution of 11028 (100 mg, 0.17 mmol) in MeOH (10 mL) under inert atmosphère were added paraformaldéhyde (55 mg, 0.89 mmol) and sodium cyanoborohydride (26 mg, 0.89 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with 10% MeOH/ CH2CI2 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel (100-200 mesh) column chromatography using 8% MeOH/ CH2CI2 to afford 11134 (35 mg, 34%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.4); ‘H NMR (DMSO-d₆,400 MHz): δ 11.53 (s, 1H), 9.48 (t, J = 5.8 Hz, 1H), 8.05 (d,J=8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.80 (m, 6H), 7.73 (s, 1H), 7.01 (d, J= 8.9 Hz, 2H), 5.11-5.05 (m, 1H), 4.66 (d, J= 5.5 Hz, 2H), 3.17-3.10 (m, 2H), 2.96-2.86 (m, 1H), 2.60 (s, 3H), 2.57-2.54 (m, 1H), 2.44-2.37 (m, 1H), 2.02-1.93 (m, 1H); LC-MS: 98.35%; 593.1 (M⁺+l); (Column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 1.89 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.0 mL/min); HP LC (purity): 97.97%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm);

RT 6.45 min. 0.05% TFA (Aq) + 5% ACN : ACN + 5% 0.5% TFA (Aq) ; 1.0 mL/min, Diluent: ACN: water).

Synthesis of 11026

-497-

Synthesis of benzyl 4-hydroxypiperidine-l-carboxylate (714): To a stirring solution of piperidin-4-ol 485 (1 g, 9.90 mmol) in CH2CI2 (10 mL) under argon atmosphère were added triethylamine (2.08 mL, 14.85 mmol), Cbz-Cl (50% in toluene) (3.4 mL, 11.88 mmol) at 0 °C;

warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (40 mL) and extracted with CH2CI2 (2 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL); dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 50% EtOAc/ hexanes to afford compound 714 (1.3 g, 56%) as colorless liquid. TLC: 70% EtOAc/ hexanes (Rf 0.3); 'H NMR (500 MHz, DMSO-rfé): δ 7.41-7.28 (m, 5H), 5.06 (s, 2H), 4.71 (d, J = 4.1 Hz, IH), 3.76-3.61 (m, 3H), 3.08-3.04 (m, 2H), 1.75-1.67 (m, 2H), 1.34-1.23 (m, 2H); LC-MS: 98.38%; 236.0 (M⁺+l); (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 1.96 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of benzyl 4-(4-(5-(((ter/-butoxycarbonyl) amino) methyl) thiazol-2-yl) phenoxy) piperidine-l-carboxylate (715): To a stirring solution of teH-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl) carbamate (356) (1 g, 3.26 mmol) in diethyl ether (30 mL) under argon atmosphère were added triphenylphosphine (2.56 g, 9.80 mmol), DIAD (1.98 g, 9.80 mmol)

-498 and benzyl 4-hydroxypiperidine-l-carboxylate 714 (921 mg, 3.92 mmol) at 0 °C; warmed to RT and stirred for 48 h. The reaction was monitored by LCMS; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20-30% EtOAc/ hexanes to afford compound 715 (2.2 g, impure) as pale yellow liquid. This material was taken to next step without further purification. TLC: 50% EtOAc/hexanes (Rf 0.5); LC-MS: 19.62%; 524.1 (M⁺+l); (column; Ascentis Express C-18 (50 x 3.0 mm, 2.7 pm); RT 3.00 min. 0.025% Aq.TFA + 5% ACN: ACN + 5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of benzyl 4-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) piperidine-l-carboxylate (716): To a stirring solution of compound 715 (2.2 g, crude. 4.20 mmol) in CH2CI2 (10 mL) was added 4 N HCl in 1, 4-dioxane (5 mL) under argon atmosphère at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with diethyl ether (5 mL) and EtOAc (5 mL) and dried in vacuo to afford compound 716 (420 mg, HCl sait) as white solid. TLC: 50% EtOAc/ hexanes (Rf 0.1);^ NMR (500 MHz, DMSOV): δ 8.44 (br s, 3H), 7.88 (s, 1H), 7.83 (d, J= 8.7 Hz, 2H), 7.39-7.29 (m, 5H), 7.09 (d, J= 8.7 Hz, 2H), 5.08 (s, 2H), 4.72-4.64 (m, 1H), 4.33-4.27 (m, 2H), 3.77-3.69 (m, 2H), 3.34-3.24 (m, 2H), 1.99-1.92 (m, 2H), 1.63-1.53 (m, 2H); LC-MS: 75.11%; 424 (M⁺+l); (column; Ascentis Express C-18 (50 x 3.0 mm, 2.7 pm); RT 2.04 min. 0.025% Aq.TFA + 5% ACN: ACN + 5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of benzyl 4-(4-(5-((5, 5-dioxido-1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy)piperidine-l-carboxylate (717): To a stirring solution of 92 (200 mg, 0.66 mmol) in DMF (6 mL) under inert atmosphère were added EDCI.HC1 (189 mg, 0.99 mmol), HOBt (135 mg, 0.99 mmol), diisopropyl ethyl amine (0.60 mL, 3.30 mmol) and compound 716 (333 mg, 0.72 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2x30 mL). The combined organic extracts were washed with water (30 mL) and brine (30 mL); dried over

-499 sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2% MeOH/ CH2CI2 to afford compound 717 (160 mg, 34%) as white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.6); *H NMR (500 MHz, DMSO-Ji): δ 11.51 (br s, 1 H), 9.44 (t,J=5.5 Hz, 1H), 8.06 (d,J=8.1 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.78 (m, 6H), 7.72 (s, 1H), 7.40-7.30 (m, 5H), 7.06 (d, J= 8.7 Hz, 2H), 5.09 (s, 2H), 4.69-4.64 (m, 3H), 3.75-3.69 (m, 2H), 1.98-1.89 (m, 2H), 1.63-1.52 (m, 2H), 1.31-1.15 (m, 2H);LC-MS: 96.50%; 709.2 (M⁺+l) (column; Ascentis Express C-18 (50 x 3.0 mm, 2.7 pm); RT 2.61 min. 0.025% Aq.TFA + 5% ACN: ACN + 5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of 1 l-oxo-/V-((2-(4-(pipendin-4-yloxy) phenyl) thiazol-5-yl) methyl)-10, 11dihydrodibenzo \b,J\ [1,4] thiazepine-8-carboxamide 5,5-dioxide (11026): To a stirring solution of compound 717 (140 mg, 0.19 mmol) in CH₂C1₂ (5 mL) was added trimethylsilyl iodide (0.02 mL, 0.19 mmol) under inert atmosphère at 0 °C; and stirred for 30 min. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water and basified to pH ~8 using saturated NaHCO₃solution The obtained solid was filtered and dried in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% MeOH/ CH2CI2 and 0.05 mL aqueous ammonia to afford compound 11026 (25 mg, 22%) as white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.1); ’H NMR (400 MHz, DMSO-t/₆): δ 9.45 (t, J= 5.8 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.98 (td, J= 7.6, 1.1 Hz, 2H), 7.92-7.84 (m, 3H), 7.84-7.76 (m, 3H), 7.72 (s, 1H), 7.03 (d, J= 8.8 Hz, 2H), 4.66 (d, J = 5.6 Hz, 2H), 4.53-4.47 (m, 1H), 3.02-2.96 (m, 2H), 2.69-2.60 (m, 2H), 2.00-1.90 (m, 2H), 1.56-1.45 (m, 2H); LC-MS: 97.84%; 589.1 (M⁺+l); (column;

Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 1.85 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min);HPLC (purity): 94.94%; (column; X select CSH ΟΙ 8 (150 x 4.6 mm, 3.5 pm); RT 5.74 min. 0.05% TFA + 5% ACN: ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: ACN: water: DMSO.

Synthesis of 1996

-500 -

Synthesis of (teri-butoxycarbonyl) proline (719): To a stirring solution of proline 718 (10 g, 86.96 mmol) in CH2CI2 (100 mL) were added triethyl amine (15.75 mL, 113.04 mmol) and di5 Z-butyl dicarbonate (29.93 mL, 130.43 mmol) in CH2CI2 (50 mL) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated citric acid solution (100 mL). The organic layer was separated, washed with water (100 mL) and concentrated in vacuo to afford compound 719 (13 g) as colorless liquid.

This crude material was taken to next step without further purification. TLC: 10% MeOH/ CH2CI2 (Rf 0.4); 'H NMR (500MHz, DMSO-J_d): δ 12.47 (br s, 1H), 4.08-4.00 (m, 1H), 3.363.21 (m, 2H), 2.22-2.07 (m, 1H), 1.87-1.73 (m, 3H), 1.45 (s, 9H).

-501 Synthesis of teri-butyl 2-(2-methoxy-2-oxoethyl) pyrrolidine-l-carboxylate (720) : To a stirring solution of compound 719 (5 g, crude) in THF (100 mL) were added 4Methylmorpholine (3.06 mL, 27.91 mmol) followed by isobutyl chloroformate (4.56 mL, 34.88 mmol) at -30 °C under inert atmosphère. The reaction mixture was allowed to stir at -30 °C for 1 h. Then freshly prepared CH2N2 solution (~75 mL) was added at -30 °C. The reaction mixture was gradually warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the excess of CH2N2 was quenched with acetic acid (2 mL) and the volatiles were concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was dissolved in methanol (75 mL) and Ag2Û (6.45 g, 27.91 mmol) was added in portion wise at 0 °C. The reaction mixture was stirred at RT for 2 h. Then CH2CI2 (30 mL) was added and filtered through a pad of celite. The filtrate was concentrated in vacuo and purified through flash column chromatography using 5% EtOAc/ hexanes to afford compound 720 (2 g, 37%) as colorless oily liquid. TLC: 10% EtOAc/ hexanes (Rf 0.2); *H NMR (400MHz, CDCI3): δ 4.254.03 (m, 1H), 3.67 (s, 3H), 3.43-3.30 (m, 2H), 2.98-2.75 (m, 1H), 2.31 (dd,J = 15.1, 9.7 Hz, 1H), 2.13-1.98 (m, 1H), 1.89-1.71 (m, 3H), 1.46 (s, 9H).

Synthesis of tert-butyl 2-(2-hydroxyethyl) pyrrolidine-l-carboxylate (721): To a stirring solution of compound 720 (200 mg, 0.82 mmol) in THF (50 mL) was added lithium aluminium hydride (38 mg, 0.99 mmol) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with 10% aqueous sodium hydroxide (2 mL) and stirred for 20 min, filtered through a pad of celite. The celite pad was eluted with EtOAc (30 mL). The filtrate was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 721 (180 mg, 97%) as colorless oily liquid. TLC: 20% EtOAc/ hexanes (Rf. 0.1); ^XH NMR (500MHz, DMSO-/: δ 4.36 (t, J= 4.9 Hz, 1H), 3.75-3.71 (m, 1H), 3.43-3.39 (m, 2H), 3.26-3.15 (m, 2H), 1.91-1.63 (m, 6H), 1.39 (s, 9H);

-502 -

LC-MS (Agilent 6310 Ion trap): 89.07%; 216.2 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 2.95 min. 2.5mM Aq. NH₄OAc: ACN, 0.8 mL/min).

Synthesis of tert-butyl 2-(2-((methylsulfonyl) oxy) ethyl) pyrrolidine-l-carboxylate (722): To a stirring solution of compound 721 (150 mg, 0.7 mmol) in CH2CI2 (10 mL) were added triethylamine (0.29 mL, 2.09 mmol) followed by methanesulfonyl chloride (0.11 mL, 1.39 mmol) drop wise over a period of 10 min, at 0 °C under inert atmosphère and allowed to stir at the same température for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (20 mL) and extracted with CH2CI2 (2x30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 722 (120 mg) colorless oily liquid. This crude material was taken to next step without further purification. TLC: 40% EtOAc/ hexanes (Rf 0.3).

Synthesis of tert-b\Ay\ 2-(2-(4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) ethyl) pyrrolidine-l-carboxylate (723): To a stirring solution of A-((2-(4-hydroxyphenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide 595 (500 mg, 1.02 mmol) in DMF (5 mL) were added compound 722 (900 mg, crude) and césium carbonate (1 g, 3.05 mmol) at 0 °C under inert atmosphère. The reaction mixture was heated to 70 °C and stirred for 18 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 60 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through flash column chromatography using 2-4% MeOH/ CH2CI2 to afford compound 723 (90 mg, 13%) as an off white solid. TLC: 5% MeOH/ CH2CI2 (Rf 0.4); 'HNMR (500MHz, DMSO-î/₆): δ 11.51 (s, IH), 9.44 (t, J = 5.5 Hz, IH), 8.06 (d,J = 8.1 Hz, IH), 8.01-7.96 (m, 2H), 7.90 (t, J= 7.0 Hz, IH), 7.88-7.78 (m, 5H), 7.72 (s, IH), 6.99 (d, J= 8.7 Hz, 2H), 4.66 (d, J= 5.8 Hz, 2H), 4.09-4.00 (m, 2H), 3.91-3.84 (m, IH), 3.26-3.22 (m, 2H), 2.17-2.05 (m, 2H), 1.95-1.80 (m, 2H), 1.80-1.71 (m, 2H), 1.35 (s, 9H); LC-MS:

ΡΛ513177/ΟΑ'Χ98ΰ57.-!

-503 -

93.56%; 589.2 (M⁺-Boc+1); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 3.47 min. 2.5 mM NH4OOCH in water + 5% ACN: ACN + 5% 2.5 mM NH4OOCH in water, 0.8 mL/min).

Synthesis of 11-oxo-A-((2-(4-(2-(pyrrolidin-2-yl) ethoxy) phenyl) thiazol-5-yl) methyl)-10, 11dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (1 996): To a stirring solution of compound 723 (80 mg, 0.12 mmol) in CH2Q2 (5 mL) was added 4 N HCl in 1, 4-dioxane (0.2 mL) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with CH2CI2 (15 mL), n-hexane (15 mL) and dried in vacuo to afford 1996 (50 mg, 73%, HCl sait) as an off white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.1); ’H NMR (400MHz, DMSO-^): δ 11.53 (s, 1H), 9.48 (t,J=5.8Hz, 1H), 9.04 (br s, 1H), 8.59 (br s, 1H), 8.06 (d,J=8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.90 (td, J= 7.5, 1.6 Hz, 1H), 7.87-7.80 (m, 5H), 7.73 (s, 1H), 7.04 (d, J= 8.9 Hz, 2H), 4.66 (d, J= 5.6 Hz, 2H), 4.19-4.08 (m, 2H), 3.64-3.56 (m, 1H), 3.26-3.08 (m, 2H), 2.22-2.06 (m, 3H), 1.98-1.82 (m, 2H), 1.67-1.57 (m, 1H); LC-MS: 99.79%; 589.1 (M⁺+l); (column; Ascentis Express Cl8, (50 ^x 3.0 mm, 2.7 pm); RT 1.84 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 96.60%; (column; X-Select CSH-C-18 (150 x 4.6 mm, 3.5 pm); RT 5.68 min. 0.05% TFA + 5% ACN: ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: ACN : H2O : DMSO).

-504-

Synthesis of methyl pyrrolidine-3-carboxylate hydrochloride (725): To a stirring solution of pyrrolidine-3-carboxylic acid 724 (4 g, 34.78 mmol) in methanol (60 mL) under inert atmosphère was added thionyl chloride (3.8 mL, 52.17 mmol) drop wise at 0 °C. The reaction mixture was heated to reflux température and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford compound 725 (4 g, HCl sait) as colorless syrup. This crude material was taken to next step without further purification. TLC: 10% MeOH/ CH2CI2 (Rf 0.3); *H NMR (400MHz, DMSO-dô): δ = 9.72-9.52 (m, 2H), 3.65 (s, 3H), 3.39-3.33 (m, 1H), 3.31-3.23 (m, 2H), 3.20-3.16 (m, 1H), 3.14-

3.11 (m, 1H), 2.24-2.11 (m, 1H), 2.08-1.95 (m, 1H).

Synthesis of methyl l-(3-(4-(5-(((tert-butoxycarbonyl) amino) methyl) thiazol-2-yl) phenoxy) 15 propyl) pyrrolidine-3-carboxylate (726): To a stirring solution of 3-(4-(5-(((ter tbutoxycarbonyl) amino) methyl) thiazol-2-yl) phenoxy) propyl methanesulfonate 386 (3 g, crude) in DMF (25 mL) under inert atmosphère were added compound 725 (1.67 g, crude),

-505 potassium carbonate (2.8 g, 20.31 mmol) at RT; heated to 80 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAC (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2CI2 to afford compound 726 (1.1 g, 34%) as colorless viscous syrup. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.5); ‘H NMR (500MHz, DMSO-î/₆): δ 7.81 (d,J=8.7Hz, 2H), 7.60 (s, 1H), 7.53 (br s, 1H), 7.02 (d, J = 8.7 Hz, 2H), 4.31 (d, J= 5.8 Hz, 2H), 4.06 (t, J= 6.4 Hz, 2H), 3.61 (s, 3H), 3.053.02 (m, 1H), 2.82-2.69 (m, 2H), 2.57-2.54 (m, 3H), 2.07-1.84 (m, 5H), 1.40 (s, 9H); LC-MS: 78.25%; 476.2 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 2.69 min. 2.5 mM NH4OOCH in water + 5% ACN: ACN + 5% 2.5 mM NH4OOCH in water, 0.8 mL/min).

Synthesis of methyl l-(3-(4-(5-(aminomethyl) thiazol-2-yI) phenoxy) propyl) pyrrolidine3-carboxylate hydrochloride (727): To a stirring solution of compound 726 (1.1 g, 2.31 mmol) in CH2CI2 (2.5 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (8 mL) drop wise at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with EtOAc (2x5 mL), diethylether (2x5 mL) and dried in vacuo to afford compound 727 (700 mg, HCl sait) as an off white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.1); LC-MS: 67.23%; 376.3 (M⁺+l); (column; Cortecs Cl8 (50 x 3.0 mm, 2.7 pm); RT 3.04 min. 2.5mM Aq. NH4HCO3 : ACN, 0.8 mL/min).

Synthesis of methyl 1-(3-(4-(5-((5, 5-dioxido-l 1-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) propyl) pyrrolidine-3-carboxylate (11107-A): To a stirring solution of 1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8carboxylic acid 5, 5-dioxide 92 (200 mg, 0.66 mmol) in DMF (20 mL) were added compound 727 (325 mg, 0.79 mmol), EDCI.HC1 (190 mg, 0.99 mmol), HOBt (136 mg, 0.99 mmol) followed by diisopropylethylamine (0.34 mL, 1.98 mmol) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 16 h. The reaction was monitored

-506 by TLC; after completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 5% MeOH/ CH2O2 to afford 11107-A (180 mg, 41%) as an off white solid. TLC: 10% MeOH/ CH₂C1₂ (Ry 0.7); *H NMR (400MHz, DMSO-ri₆): δ 11.52 (s, 1H), 9.45 (t, J = 5.7 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.00-7.95 (m, 2H), 7.93-7.84 (m, 3H), 7.83-7.77 (m, 3H), 7.72 (s, 1H), 7.01 (d, J= 8.9 Hz, 2H), 4.66 (d, J= 5.5 Hz, 2H), 4.06 (t, J= 6.3 Hz, 2H), 3.61 (s, 3H), 3.11-3.01 (m, 1H), 2.92-2.71 (m, 2H), 2.63-2.55 (m, 2H), 2.45-2.39 (m, 2H), 2.17-1.84 (m, 4H); LC-MS: 97.88%; 661.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.89 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 1-(3-(4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8carboxamido) methyl) thiazol-2-yl) phenoxy) propyl) pyrrolidine-3-carboxylic acid (11107): To a stirring solution of methyl 1-(3-(4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) propyl) pyrrolidine-3carboxylate 11107-A (90 mg, 0.13 mmol) in a mixture of THF: MeOH: H2O (2: 1: 1,8 mL) was added lithium hydroxide monohydrate (17 mg, 0.41 mmol) at 0 °C. The reaction mixture was gradually warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was acidified with 2 N HCl to pH ~5 and extracted with EtOAc (2x30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was triturated with diethylether (2x5 mL) and dried in vacuo to afford 11107 (30 mg, 34%) as an off white solid. TLC: 10% MeOH/ CH₂C1₂ (Ry 0.1); ‘H NMR (400MHz, DMSO-ri₆): δ 11.53 (br s, 1H), 9.50 (t, J= 5.8 Hz, 1H), 8.05 (d, J= 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.92-7.78 (m, 6H), 7.72 (s, 1H), 7.01 (d, J= 8.9 Hz, 2H), 4.66 (d, J = 5.6 Hz, 2H), 4.07 (t, J= 6.3 Hz, 2H), 3.02-2.96 (m, 2H), 2.85-2.78 (m, 1H), 2.77-2.63 (m, 4H), 2.03-1.92 (m, 4H); LC-MS: 96.27%; 647.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.84 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 94.30%;

-507 (column; X-Select CSH-C-18 (150 x 4.6 mm, 3.5 pm); RT 5.63 min. 0.05% TFA + 5% ACN: ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: ACN : H₂O : DMSO).

Synthesis of mr/butyl ((2-(4-(3-(2, 2, 2-trifluoroacetamido) propoxy) phenyl) thiazol-5-yl) methyl) carbamate (728): To a stirring solution of ZerLbutyl ((2-(4-(3-aminopropoxy) phenyl) thiazol-5-yl) methyl) carbamate 404 (250 mg, 0.68 mmol) in CH₂C1₂ (10 mL) under inert atmosphère was added triethylamine (0.29 mL, 2.06 mmol), followed by addition of trifluoroacetic anhydride (0.11 mL, 0.82 mmol) for 5 min at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with 10% H₂O/ MeOH (10 mL) and the volatiles were removed in vacuo to obtain the crude. The crude was triturated with diethylether (2x10 mL) and dried in vacuo to afford compound 728 (230 mg, 73%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.8); 'H

NMR (DMSOV, 500 MHz): δ 9.50 (t,/=5.2 Hz, 1H), 7.82 (d,/= 8.7 Hz, 2H), 7.61 (s, 1H), 7.53 (t, /= 5.5 Hz, 1H), 7.02 (d, J= 8.7 Hz, 2H), 4.31 (d, / = 5.8 Hz, 2H), 4.06 (t, /=6.1 Hz, 2H), 3.37 (q, /= 6.4 Hz, 2H), 1.96 (p, /= 6.5 Hz, 2H), 1.40 (s, 9H); LC-MS: 97.62%; 460.1

- 508 - (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.64 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of /V-(3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) propyl)-2, 2, 2trifluoroacetamide hydrochloride (729): To a stirring solution of compound 728 (230 mg, 0.50 mmol) in CH2CI2 (10 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (1 mL) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with EtOAc (2x10 mL), and dried in vacuo to afford compound 729 (180 mg, HCl sait) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.2); ‘H-NMR (DMSO4, 500 MHz): δ 9.53 (t, J = 5.8 Hz, 1H), 8.54 (br s, 3H), 7.90 (s, 1H), 7.86 (d, J= 8.7 Hz, 2H), 7.05 (d, J= 8.7 Hz, 2H), 4.31 (q, J= 5.6 Hz, 2H), 4.07 (t, J= 6.1 Hz, 2H), 3.42-3.33 (m, 2H), 1.97 (p, J =6.5 Hz, 2H);

Synthesis of 1 l-oxo-A-((2-(4-(3-(2, 2, 2-trifluoroacetamido) propoxy) phenyl) thiazol-5-yl) methyl)-10, 11-dihydrodibenzo \b,f [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (730): To a stirring solution of 92 (150 mg, 0.49 mmol) in DMF (10 mL) under inert atmosphère were added EDCI.HC1 (142 mg, 0.74 mmol), HOBt (100 mg, 0.74 mmol), diisopropylethylamine (0.72 mL, 2.47 mmol) and compound 729 (195 mg, 0.54 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2CI2 to afford compound 730 (180 mg, 57%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf. 0.8); ‘H-NMR (DMSO-ô/₆, 400 MHz): 11.51 (br s, 1H), 9.68-9.29 (m, 2H), 8.05 (d, J= 8.3 Hz, 1H), 8.00-7.95 (m, 2H), 7.93-7.78 (m, 6H), 7.72 (s, 1H), 7.01 (d, J= 8.9 Hz, 2H), 4.66 (d, J= 5.4 Hz, 2H), 4.05 (t, J= 6.0 Hz, 2H), 3.40-3.33 (m, 2H), 1.95 (p, J = 6.4 Hz, 2H); LC-MS: 94.34%; 654.1 (M⁺+l) (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.46 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

-509 Synthesis of A-((2-(4-(3-aminopropoxy) phenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo [b, f[ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (1988): To a stirring solution of compound 730 (140 mg, 0.21 mmol) in MeOH (10 mL) under inert atmosphère was added potassium carbonate (90 mg, 0.65 mmol) at RT; heated to 80 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% MeOH/ CH₂C1₂ (aqueous ammonia) to afford crude amine (200 mg).

To the above crude amine (200 mg) in CH₂C1₂ (10 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (4 mL) at 0 °C and stirred for 30 min. The reaction was monitored by TLC; after completion of the reaction, the volatiles were concentrated in vacuo to afford 1988 (85 mg, 63%) as white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); 'H-NMR (DMSO-î/₆, 400 MHz): δ 11.54 (s, 1H), 9.54 (t, J= 5.8 Hz, 1H), 8.14-8.07 (m, 2H), 8.05 (d, J= 8.2 Hz, 2H), 7.98 (td, J= 7.5, 1.1 Hz, 2H), 7.93-7.80 (m, 6H), 7.72 (s, 1H), 7.03 (d, J= 8.9 Hz, 2H), 4.66 (d, J= 5.5 Hz, 2H), 4.12 (t, J = 6.1 Hz, 2H), 3.00-2.88 (m, 2H), 2.05 (p, J = 6.7Hz, 2H); LC-MS: 96.04%; 549.1 (M'^r+1); (column; Ascentis Express Cl8, (50 ^x 3.0 mm, 2.7 pm); RT 1.80 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 95.01%; (column; X select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 5.85 min. 0.05% TFA + 5% ACN : ACN + 5% 0.05% TFA ; 1.0 mL/min, Diluent: DMSO:ACN: water).

- 510 -

Synthesis of tert-butyl ((2-(4-(3-(2, 2, 2-trifluoro-N-methylacetamido) propoxy) phenyl) thiazol-5-yl) methyl) carbamate (731): To a stirring solution of compound 380 (250 mg, 0.66 mmol) in CH2CI2 (10 mL) under inert atmosphère were added triethylamine (0.14 mL, 0.99 mmol), followed by dropwise addition of trifluoroacetic anhydride (0.14 mL, 0.99 mmol) for 5 min at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 2% MeOH/ CH2CI2 to afford compound 731 (150 mg, 47%) as thick syrup. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.8); LC-MS: 81.19%; 474.1 (M⁺+l)_; (column;

Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.72 min. 0.025% Aq. TFA + 5% ACN:

ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

-511 Synthesis of 7V-(3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) propyl)-2, 2, 2-trifluoro-A^rmethylacetamide hydrochloride (732): To a stirring solution of compound 731 (150 mg, 0.31 mmol) in CH₂C1₂ (10 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (2 mL) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude, which was triturated with EtOAc (2x5 mL), diethyl ether (5 mL) and dried in vacuo to afford compound 732 (100 mg, 77%; HCl sait) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.1); 'H-NMR (DMSO-<Z₆, 400 MHz): δ 8.55 (br s, 3H), 8.37 (s, 1H), 8.10 (s, 1H), 7.51 (d, 1H), 4.40 (q, J= 5.6 Hz, 2H); LC-MS: 88.64%; 374.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.72 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 1 l-oxo-A-((2-(4-(3-(2, 2, 2-trifluoro-/V-methylacetamido) propoxy) phenyl) thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (733): To a stirring solution of 92 (70 mg, 0.23 mmol) in DMF (8 mL) under inert atmosphère were added EDCI.HC1 (66 mg, 0.34 mmol), HOBt (47 mg, 0.34 mmol), diisopropylethylamine (0.12 mL, 0.69 mmol) and compound 732 (103 mg, 0.25 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 5% MeOH/ CH₂C1₂ to afford compound 733 (50 mg, 32%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.5); ‘H-NMR (DMSO-J₆, 400 MHz): δ 11.49 (br s, 1H), 9.42 (t, J= 5.7 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.98-7.92 (m, 2H), 7.90-7.76 (m, 6H), 7.70 (s, 1H), 6.98 (d, J = 9.0 Hz, 2H), 4.64 (d, J= 5.6 Hz, 2H), 4.11-3.96 (m, 2H), 3.64-3.51 (m, 2H), 2.97 (s, 3H), 2.08 - 1.94 (m, 2H);LC-MS: 95.56%; 659.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.48 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

= 77

-512 Synthesis ofM((2-(4-(3-(methylamino) propoxy) phenyl) thiazol-5-yl) methyl)-! 1-oxo-10, 11dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (1989): To a stirring solution of compound 733 (50 mg, 0.07 mmol) in MeOH (5 mL) under inert atmosphère was added potassium carbonate (52 mg, 0.37 mmol) in a sealed tube at RT; heated to 70 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the voaltiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using aqueous ammonia: MeOH: CH2CI2 (1: 1: 8) to afford 1989 (25 mg, 59%) as an off-white solid. TLC: 5% MeOH/ CH2CI2 (Rf 0.2'H NMR (DMSO-/400 MHz): δ 9.45 (t, J= 5.8 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 8.00-7.95 (m, 2H), 7.90 (td, J= 7.5,

1.4 Hz, 1H), 7.87-7.85 (m, 2H), 7.83-7.77 (m, 3H), 7.72 (s, 1H), 7.01 (d, J= 8.9 Hz, 2H), 4.66 (d, J= 5.6 Hz, 2H), 4.07 (t, J= 6A Hz, 2H), 2.66 (t, J= 6.9 Hz, 2H), 2.32 (s, 3H), 1.92-1.83 (m, 2H); LC-MS: 98.03%; 563.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.81 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.45%; (column; X select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 6.00 min.

0.05% TFA + 5% ACN : ACN + 5% 0.05% TFA ; 1.0 mL/min, Diluent: DMSO:ACN: water).

-513 Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) propan-l-ol hydrochloride (734): To a stimng solution of Zuri-butyl ((2-(4-(3-hydroxypropoxy) phenyl) thiazol-5-yl) methyl) carbamate 385 (1.2 g, 3.29 mmol) in CH2Q2 (20 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (4 mL) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude triturated with diethyl ether (10 mL) and dried in vacuo to afford compound 734 (1.2 g; HCl sait) as an off-white solid. TLC: 5% EtOAc/ hexanes (Rf. 0.1); LC-MS: 97.67%; 264.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.35 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of/7-((2-(4-(3-hydroxypropoxy) phenyl) thiazol-5-yl) methyl)-l l-oxo-10, 11dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (735): To a stirring solution of 92 (1 g, 3.30 mmol) in DMF (25 mL) under inert atmosphère were added HATU (1.87 g, 4.95 mmol), diisopropylethylamine (2.4 mL, 13.20 mmol) and 3-(4-(5-(aminomethyl) thiazol2-yl) phenoxy) propan-l-ol hydrochloride 734 (1.09 g, 3.62 mmol) at 0 °C warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the diluted with water (10 mL) and extracted with EtOAc (2 x 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3% MeOH/ CH2CI2 to afford compound 735 (1 g, 56%) as an off-white solid. TLC: 5% MeOH/ CH2CI2 (Rf 0.1); ’HNMR (DMSO-dô, 400 MHz): δ 11.51 (s, 1 H), 9.44 (t, 7= 5.8 Hz, 1H), 8.06 (d, 7=8.3 Hz, 1H), 8.01 - 7.95 (m, 2H), 7.93 - 7.84 (m, 3H), 7.84 - 7.78 (m, 3H), 7.72 (s, 1H), 7.01 (d, J= 8.9 Hz, 2H), 4.66 (d, 7= 5.6 Hz, 2H), 4.55 (t, 7= 5.1 Hz, 1H), 4.08 (t, 7= 6.4 Hz, 2H), 3.61 - 3.50 (m, 2H), 1.87 (p, 7= 6.3 Hz, 2H);

Synthesis of 3-(4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b,f\ [1,4] thiazepine-8carboxamido) methyl) thiazol-2-yl) phenoxy) propyl methanesulfonate (736): To a stirring solution of compound 735 (1.0 g, 1.82 mmol) in CH2CI2 (20 mL) under inert atmosphère were added triethylamine (0.5 mL, 3.62 mmol), methanesulfonyl chloride (0.15 mL, 1.82 mmol) at 0 ’ . . '=OA/i.tÆ30ü7.

- 514 - °C; warmed to RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with CH2CI2 (100 mL), washed with water (2 x 50 mL) The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was triturated with «-pentane (10 mL) and dried in vacuo to afford compound 736 (1 g, crude, mixture of mono and dimesylated compounds) as colorless sticky solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.4); LC-MS: 41.67%; 628.0 (M⁺+l) (monomesylated compound), 39.31%; 706.0 (M⁺+l) (dimesylated compound); (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 2.28 min (monomesylated compound), 2.44 min (dimesylated compound); 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis ofA'-((2-(4-(3-(ArZ-butylamino) propoxy) phenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo \b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide (1990): To a stirring solution of compound 736 (500 mg, crude) in MeOH (10 mL) under inert atmosphère were added potassium carbonate (330 mg, 2.39 mmol), 2-methylpropan-2-amine (0.42 mL, 3.98 mmol) in a sealed tube at RT; heated to 80 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with 10% MeOH/ CH2CI2 (2 x 75 mL). The combined organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude the voaltiles were removed in vacuo to obtain the crude. The crude was purified through basic alumnia column chromatography using 10% MeOH/ CH₂Cl₂to afford 1990 (50 mg, 9%, over 2 steps) as an offwhite solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.1, eluted twice); *H NMR (DMSO-d_6;400 MHz): δ 9.47 (t, J = 5.6 Hz, 1H), 8.36 - 8.29 (m, 1H), 8.05 (d, J= 8.2 Hz, 1H), 8.00-7.95 (m, 2H), 7.93 7.77 (m, 6H), 7.72 (s, 1H), 7.02 (br d, J= 8.7 Hz, 2H), 4.66 (br d, J= 5.3 Hz, 2H), 4.11 (t, J = 6.0 Hz, 3H), 2.81 (t, J= 7.0 Hz, 2H), 2.00 - 1.88 (m, 2H), 1.14 (s, 9H); LC-MS: 90.26%; 605.1 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.93 min. 0.025% Aq.

TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 91.83%; (column; X select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 6.37 min. 0.05% TFA + 5% ACN : ACN + 5% 0.05% TFA ; 1.0 mL/min, Diluent: ACN: water).

Synthesis of 11108

-515 -

Synthesis of terf-butyl ((2-(4-(3-bromopropoxy) phenyl) thiazol-5-yl) methyl) carbamate (737): To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl) carbamate 356 (1 g, 3.27 mmol) in acetone (50 mL) were added 1,3-dibromopropane 432 (1.7 mL, 16.35 mmol) and potassium carbonate (2.3 g, 16.35 mmol) at RT under inert atmosphère. The reaction mixture was heated to reflux température and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with EtOAc (60 mL), washed with water (40 mL) followed by brine (20 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 1 % MeOH/ CH2CI2 to afford compound 737 (1.1 g, 79%) as an off white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.8); ^XH NMR (400MHz, DMSO-î7₆): δ 7.82 (d, J= 8.8 Hz, 2H), 7.61 (s, 1H), 7.53 (t, J= 5.8 Hz, 1H), 7.05 (d, J= 8.9 Hz, 2H), 4.31 (d, J= 6.0 Hz, 2H), 4.14 (t, J= 6.0 Hz, 2H), 3.68 (t, J = 6.6 Hz, 2H), 2.30-2.24 (m, 2H), 1.40 (s, 9H).

Synthesis of (2-(4-(3-bromopropoxy) phenyl) thiazol-5-yl) methanamine hydrobromide (738): To a stirring solution of compound 737 (200 mg, 0.47 mmol) in CH2CI2 (5 mL) was added hydrobromic acid in acetic acid (0.6 mL, 2.34 mmol) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 4 h. The reaction was monitored

- 516 - by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was triturated with diethylether (2x10 mL) and dried in vacuo to afford compound 738 (200 mg, HBr sait) as an off white solid. TLC: 40% EtOAc/ hexanes (Rf 0.1); ‘H NMR (400MHz, DMSOV): δ 8.26 (br s, 3H), 7.90-7.83 (m, 3H), 7.09 (d, J= 8.9 Hz, 2H), 4.35 (q, J= 5.6 Hz, 2H), 4.16 (t, J = 6.0 Hz, 2H), 3.68 (t, J= 6.5 Hz, 2H), 2.31-2.24 (m, 2H).

Synthesis of7V-((2-(4-(3-bromopropoxy) phenyl) thiazol-5-yl) methyl)-!l-oxo-10,11dihydrodibenzo [b, f] [1,4] thiazepine-8-carboxamide 5, 5-dioxide (739): To a stirring solution of 1 l-oxo-10, 11-dihydrodibenzo [b, f] [1,4] thiazepine-8-carboxylic acid 5, 5-dioxide 92 (200 mg, 0.66 mmol) in acetonitrile (10 mL) were added compound 738 (216 mg, 0.66 mmol), Propylphosphonic anhydride (0.98 mL, 3.3 mmol) and A’-Mcthylmorpholinc (0.37 mL, 3.3 mmol) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with EtOAc (40 mL), washed with water (20 mL) followed by brine (20 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was triturated with diethylether (2 x 10 mL) and dried in vacuo to afford compound 739 (181 mg, 45%) as an off white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.4); ^lH NMR (500MHz, DMSOV): δ 11.52 (s, 1H), 9.45 (t, J= 5.5 Hz, 1H), 8.06 (d, J= 8.1 Hz, 1H), 8.01-7.96 (m, 2H), 7.92-7.79 (m, 6H), 7.73 (s, 1H), 7.04 (d, J= 8.7 Hz, 2H), 4.66 (d, J= 5.8 Hz, 2H), 4.14 (t, J = 5.8 Hz, 2H), 3.67 (t, J= 6.4 Hz, 2H), 2.29-2.24 (m, 2H).

Synthesis of 1-(3-(4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b, f] [1, 4] thiazepine-8carboxamido) methyl) thiazol-2-yl) phenoxy) propyl) quinuclidin-l-ium bromide (11108): To a stirring solution of compound 739 (50 mg, 0.08 mmol) in a mixture of THF/acetonitrile (1:1, 10 mL) was added Quinuclidine (9.5 mg, 0.08 mmol) at RT under inert atmosphère. The reaction mixture was heated to reflux température and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was triturated with diethylether (2x10 mL), CHsCN/MeOH (10%, 5 mL) and dried

-517 in vacuo. The obtained solid was dissolved in CH3CN/MeOH/H₂O (1:1:1,3 mL) and lyophilized for 16 h to afford 11108 (30 mg, 57%) as an off white solid. TLC: 10% MeOH/ CH₂C1₂ (/?/ 0.1); 'HNMR (400MHz, DMSO-î/₆): δ 11.55 (br s, 1H), 9.46 (t, J= 5.0 Hz, 1H), 8.03 (d, J= 8.3 Hz, 1H), 7.99-7.94 (m, 2H), 7.89 (td, J= 7.4, 1.2 Hz, 1H), 7.86-7.80 (m, 4H), 7.79-7.71 (m, 2H), 7.03 (d, J= 8.8 Hz, 2H), 4.66 (d, J= 5.5 Hz, 2H), 4.10 (t, J= 5.8 Hz, 2H), 3.46-3.38 (m, 6H), 3.27-3.23 (m, 2H), 2.22-2.12 (m, 2H), 2.10-2.05 (m, 1H), 1.90-1.82 (m, 6H); LC-MS: 92.59%; 643.2 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.90 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 90.14%; (column; X-Select CSH-C-18 (150 x 4.6 mm, 3.5 pm); RT 6.31 min. 0.05% TFA + 5% ACN: ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: ACN: H₂O).

Synthesis of 11108-B

Synthesis of N-((2-(4-(3-((3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)propoxy) phenyl)thiazol5-yl)methyl)-l l-oxo-10,1 l-dihydrodibenzo[b,f] [l,4]thiazepine-8-carboxamide 5,5-dioxide (11108-B): To a stirring solution of 1 l-oxo-10, 11-dihydrodibenzo [b, f] [1,4] thiazepine-8carboxylic acid 5, 5-dioxide 92 (200 mg, 0.66 mmol) in DMF (2 mL) were added HATU (376 mg, 0.99 mmol), diisopropylethylamine (0.36 mL, 1.98 mmol) and compound 738 (215 mg, 0.66 mmol) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2x5 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 4% MeOH/ CH₂C1₂ to afford 11108-B (50 mg, 12%) as an off white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.4); ‘H NMR (DMSO-î/_6>400 MHz): δ 11.52 (br s, 1H), 9.45 (t, J = 5.6 Hz, 1H), 8.80 (dd, J= 1.4, 4.4 Hz, 1H), 8.62 (dd, J= 1.3, 8.4 Hz, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.98 (dt,

-518 7=7.6, 1.1 Hz, 2H), 7.93-7.79 (m, 6H), 7.73 (s, IH), 7.58 (dd, J= 4.4, 8.4 Hz, IH), 7.05 (d, 7 = 8.8 Hz, 2H), 4.80 (t, J= 6.3 Hz, 2H), 4.66 (br d, J= 5.5 Hz, 2H), 4.32 (t, J = 62 Hz, 2H), 2.26 (p, J= 6.3 Hz, 2H); LC-MS: 94.98%; 668.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.37 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 5 1.2 mL/min); HPLC (purity): 94.02%; (column; X-select CSH-C18 (150 x 4.6 mm, 3.5 pm);

RT 10.06 min. 5mM Aq. NH4HCO3 : ACN ; 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of A-((2-(4-(3-chloro-2-hydroxypropoxy) phenyl) thiazol-5-yl) methyl)-!l-oxo10, 11-dihydrodibenzo [b, /] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (743):- A

Synthesis of tert-butyl ((2-(4-(oxiran-2-ylmethoxy) phenyl) thiazol-5-yl) methyl) carbamate (741): To a stirring solution of ter/-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl) carbamate 356 (2.5 g, 8.16 mmol) in DMF (50 mL) under inert atmosphère were added epichlorohydrin 740 (1.89 g, 20.42 mmol) and potassium carbonate (2.8 g, 20.42 mmol) at RT; heated to 70-80 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice-cold water (100 mL) and the precipitated solid was filtered and titurated with 15% EtOAc/hexanes and dried in vacuo to afford

- 519 compound 741 (1.9 g, 64%) as an off-white solid. TLC: 5% MeOH/ CH2CI2 (Rf 0.8); NMR (DMSO-4 400 MHz): δ 7.82 (d, J= 8.7 Hz, 2H), 7.61 (s, 1H), 7.53 (d, J= 5.0 Hz, 1H), 7.06 (d, J= 8.9 Hz, 2H), 4.40 (dd, J = 11.4, 2.7 Hz, 1H), 4.31 (br d, J= 5.6 Hz, 2H), 3.90 (dd, J = 11.4, 6.6 Hz, 1H), 3.38-3.33 (m, 1H), 2.87-2.84 (m, 1H), 2.73 (dd, J = 5.0, 2.6 Hz, 1H), 1.40 (s, 9H); LC-MS: 83.49%; 363.0 (M⁺+l); (column; Ascentis Express C18, (50 χ 3.0 mm, 2.7 pm); RT 2.42 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of l-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-3-chloropropan-2-ol hydrochloride (742): To a stirring solution of compound 741 (1.9 g, 5.24 mmol) in CH2CI2 (20 mL) was added 4 N HCl in 1, 4-dioxane (15 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with 50% EtOAc/ hexanes (5 mL) and dried in vacuo to afford compound 742 (1.5 g, 86%; HCl sait) as white solid. TLC: 5% MeOH/ CH2CI2 (Rf 0.1); 'H-NMR (DMSO-Jé, 400 MHz): δ 8.67 (br s, 3H), 7.92 (s, 1H), 7.86 (d, J = 9.0 Hz, 2H), 7.09 (br d, J= 9.0 Hz, 2H), 4.30 (q, J= 5.2 Hz, 2H), 4.06 (s, 2H), 3.79-3.66 (m, 3H), 3.56 (s, 2H); LC-MS: 90.32%; 298.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.50 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of A-((2-(4-(3-chloro-2-hydroxypropoxy) phenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (743): To a stirring solution of compound 742 (1.2 g, 3.96 mmol) and 92 (1.0 g, 3.30 mmol) in DMF (40 mL) under inert atmosphère were added HOBt (801 mg, 5.94 mmol), EDCI.HC1 (945 mg, 5.95 mmol), diisopropyl ethyl amine (2.1 mL, 11.88 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice-cold water (30 mL) and extracted with 10% MeOH/ CH2CI2 (2 x 250 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 4% MeOH/ CH2CI2 to afford compound 743 (1.1 g, 48%) as white solid. TLC: 7% MeOH/ CH2CI2 (Rf 0.8); ‘H NMR (DMSO-r7₆, 500 MHz): δ 11.51 (s, 1H), 9.45 (br t, J= 5.8

-520 Hz, 1H), 8.06 (d, J= 8.7 Hz, 1H), 7.98 (t, J = 8.4 Hz, 2H), 7.90 (td, J= 7.5, 1.2 Hz, 1H), 7.877.79 (m, 5H), 7.73 (s, 1H), 7.04 (d, J= 8.7 Hz, 2H), 5.58 (d, J= 4.6 Hz, 1H), 4.66 (br d, J = 5.8 Hz, 2H), 4.07-4.01 (m, 3H), 3.79-3.64 (m, 2H); LC-MS: 89.09%; 584.0 (M⁺+l); (column;

Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.22 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Préparation

Compound 743 was synthesized as mentioned above and converted to final products as HCl sait/ TFA sait/ free amine using commercially available amines employing typical procedures L and the results are captured in the Table 4:

Typical procedure L:

To a stirring solution of compound 743 (250 mg, 0.42 mmol) in EtOH (10 mL) in a sealed tube was added 33% ethanolic ammonia (10 mL) at 0 °C; heated to 50 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo and the residue washed with 20% EtOAc/ hexanes and dried in vacuo to obtain the crude which was purified by préparative HPLC purification/ triturated to afford the desired product.

Commercial amines used for the préparation

CH3NH2	Z HN	ΗΝ_χ		h₂n^
240	243	387	412	469

Table 4: Synthesis from compound 743 using various amines

						6H);
11087	θ'θ < ·Ζ—G \ / ( \ Ν Λ_/~Ο οη	L^c, 743, 412	31	621.1 (Μ⁺+1 )	620.18 for C31H32N4O 6§2	‘H-NMR (DMSO-îZ₆, 400 MHz): δ 11.51 (br s, 1H), 9.44 (t, J = 5.8 Hz, 1H), 8.05 (d, .7=8.1 Hz, 1H), 8.017.95 (m, 2H), 7.927.84 (m, 3H), 7.827.79 (m, 3H), 7.72 (s,

- 521 -

Example	Structure	Proced ure, Interm ediate, amine	Rx Yie Id (% )	Mass Spec. Found	Mass Spec. Calculated	’h-nmr
11084	0 ]^-ΝΗ O rt jyu _sh /¾. z~n à'o ^HHC‘ N L# ° OH	L, 743, 240	38	579.0 (M⁺+l )	614.11 for C₂₈H₂₇C1N₄ O₆S₂	‘H-NMR (DMSO-ri_ô, 400 MHz): δ 11.52 (s, 1H), 9.46 (t, J = 5.7 Hz, 1H), 8.498.42 (m, 1H), 8.06 (d, J= 8.2 Hz, 1H), 8.017.95 (m, 2H), 7.937.80 (m, 6H), 7.73 (s, 1H), 7.04 (d, J = 8.9 Hz, 2H), 5.99-5.82 (m, 1H), 4.66 (br d, J = 5.6 Hz, 2H), 4.174.10 (m, 1H), 4.02 (br d, J = 5.0 Hz, 3H), 3.19-3.10 (m, 1H), 3.06-2.96 (m, 1H), 2.61 (t, J = 5.4 Hz, 3H);
11085	O Vnh p CUO-K^ /V	L“, 743, 243	25	593.1 (M⁺+l )	592.15 for C29H₂₈N₄O 6^2	‘H-NMR (DMSO-î7₆, 400 MHz): δ 11.48 (m, 1H), 9.46 (t, J = 5.4, 1H), 8.06 (br d, J = 8.2 Hz, 1H), 7.98 (t, J = 7.8 Hz, 2H), 7.93-7.77 (m, 6H), 7.72 (s, 1H), 7.02 (br d, J = 8.4 Hz, 2H), 4.87 (br s, 1H), 4.66

- 523 -

						1H), 7.02 (d, J = 9.3 Hz, 2H), 4.75 (br s, 1H), 4.66 (br d, J = 5.2 Hz, 2H), 4.04 (dd, J = 9.9, 2.9 Hz, 1H), 3.96-3.82 (m, 2H), 2.75 (td, J = 13.2, 6.4 Hz, 1H), 2.34 (br d, J = 5.8 Hz, 1H), 2.31 (br d, J = 5.8 Hz, 1H), 2.18 (s, 3H), 0.92 (dd, J = 6.4, 2.9 Hz, 6H);
11088	0 Ο X-X ' N Vy ° OH	L^è, 743, 469	25	621.1 (M⁺+l )	734.17 for C33H33F3N6 O₈S₂	'H-NMR (DMSO-î/ô, 400 MHz): δ 11.53 (s, 1H), 9.47 (t, J = 5.8 Hz, 1H), 8.418.23 (m, 2H), 8.06 (d, J= 8.2 Hz, 1H), 8.017.96 (m, 2H), 7.93 7.80 (m, 6H), 7.73 (s, 1H), 7.06 (d, J = 9.0 Hz, 2H), 5.91 (d, J = 4.7 Hz, 1H), 4.66 (br d, J = 5.6 Hz, 2H), 4.16-4.09 (m, 1H), 4.08-4.05 (m, 2H), 3.22-3.06 (m, 1H), 3.01-2.89 (m, 1H), 1.29 (s, 9H);

L“: Dimethyl amine (2 M sol. In THF, 4 mL), 80 °C, 24 h. L^è: compd: 743 (100 mg), Diethyl amine (37 mg, 3 equiv), EtOH (5 mL), 80 °C, 24 h. L^c: compd: 743 (200 mg), Mmethylpropan19643

-5242-amine (75 mg, 3 equiv), EtOH (10 mL), 80 °C, 48 h in sealed tube

Synthesis of 3-((6-bromopyridin-3-yl) oxy) propan-l-ol (746): To a stirring solution of 6bromopyridin-3-ol (744) 1 g, 5.74 mmol) in DMF (10 mL) under inert atmosphère was added CS2CO3 (5.5 g, 17.22 mmol) at RT and stirred for 5 min. Then 3-bromo-l-propanol 745 (0.86 g, 6.32 mmol) was added and continued stirring at RT for 16h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2x20 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 40% EtOAc/ hexanes to afford compound 746 (700 mg, 53%) as colorless syrup. TLC: 50% EtOAc/ hexanes (Rf 0.2); ¹H NMR (DMSO-î^ 400 MHz): δ 8.11 (d, J= 3.2 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.38 (dd, J= 8.8, 3.1 Hz, 1H), 4.56 (t, J= 5.2 Hz,

-525 1H), 4.11 (t, J = 6.4 Hz, 3H), 3.57 - 3.52 (m, 2H), 1.86 (p, J= 6.3 Hz, 2H); LC-MS: 56.62%; 231.8 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.73 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 2-bromo-5-(3-((tetrahydro-2Æ-pyran-2-yl) oxy) propoxy) pyridine (747): To a stirring solution of compound 746 (700 mg, 3.03 mmol) in DCM (10 mL) under inert atmosphère were added dihydropyran (305 mg, 3.63 mmol) and p-toulenc sulfonic acid (5 mg) at 0-5 °C; stirred at RT for 16h. The reaction was monitored by TLC and LC-MS; after completion volatiles were evaporated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 30% EtOAc/ hexanes to afford compound 747 (700 mg, 73%) as colorless syrup. TLC: 30% EtOAc/ hexanes (Rf. 0.5); *H NMR (DMSO-î/î, 400 MHz): δ 8.12 (d, J= 2.9 Hz, 1H), 7.53 (d, J= 8.7 Hz, 1H), 7.40 (dd, J= 8.7, 3.2 Hz, 1H), 4.59-4.53 (m, 1H), 4.12 (t, J = 6.3 Hz, 2H), 3.81-3.65 (m, 2H), 3.48 (td, J = 9.9, 6.3 Hz, 1H), 3.44- 3.38 (m, 1H), 1.97 (p, J =6.3 Hz, 2H), 1.78 - 1.65 (m, 1H), 1.65 - 1.56 (m, 1H), 1.53 1.34 (m, 4H);

Synthesis of 5-(3-((tetrahydro-217-pyran-2-yl) oxy) propoxy)-2-tributyl stannyl) pyridine (748): To a stirring solution of compound 747 (1 g, 3.17 mmol) in dry THF (20 mL) under inert atmosphère was added n-BuLi (1.9 mL, 3.17 mmol) at -78 °C and stirred for 30min. Then tributyltin chloride (3 g, 9.52 mmol) was added at -78 °C and continued stirring for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ammonium chloride solution (30 mL) and extracted with EtOAc (2x30 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 748 (1.8 g, crude) as colorless syrup. TLC: 30% EtOAc/ hexanes (Rf 0.7); LC-MS: 39.52%; 528.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.60 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 1 l-oxo-A-((2-(5-(3-((tetrahydro-2Æ-pyran-2-yl) oxy) propoxy) pyridin-2-yl) thiazol-5-yl) methyl)-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (749): To a stirring solution of A-((2-chlorothiazol-5-yl) methyl)-! l-oxo-10, 1119643

-526 dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (535) (500 mg, 1.16 mmol) in 1, 4-dioxane (25 mL) under inert atmosphère were added compound 748 (1.8 g, 3.48 mmol) and Pd(dppf)Cl₂ (85 mg, 0.116 mmol) at RT and purged under argon atmosphère 30 min; heated to 110 °C and stirred for 16 h. The reaction was monitored by TLC; after completion the volatiles were removed in vacuo to obtain the crude. The crude was purified through combiflash column chromatography using 30% EtOAc/ hexanes to afford compound 749 (75 mg, 10%) as an off-white solid. TLC: 30% MeOH/ CH₂C1₂ (Rf. 0.4); 'H NMR (DMSO-d^yOO MHz): LC-MS: 94.65%; 635.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.51 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of A-((2-(5-(3-hydroxypropoxy) pyridin-2-yl) thiazol-5-yl) methyl)-! l-oxo-10, 11dihydrodibenzo \b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide (750): To a stirring solution of compound 749 (30 mg, 0.047 mmol) in MeOH (5 mL) under argon atmosphère was addedpToluenesulfonic acid (4 mg, 0.023 mmol) at RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (1 mL) and pH was neutralized with aqueous saturated Na₂CO₃ solution and extracted with 5% MeOH/ EtOAc (2 x 1 mL). The combined organic extarcts were dried over sodium sulfate and concentrated vacuo to afford compound 750 (20 mg, 76%) as an off-white solid. TLC: 10% MeOH/ EtOAc (Rf 0.5); Y NMR (DMSO-d_6; 400 MHz): δ 11.54 (br s, 1 H), 9.52-9.44 (m, 1H), 8.31 (d, J= 3.1 Hz, 1H), 8.09-7.97 (m, 3H), 7.95-7.77 (m, 4H), 7.54 (dd, J= 8.7, 2.9 Hz, 1H), 7.49 (d, J= 8.2 Hz, 2H), 7.18-7.07 (m, 2H), 4.69 (d, J= 5.5 Hz, 1H), 4.63-4.59 (m, 1H), 4.24 - 4.14 (m, 2H), 3.60-3.56 (m, 1H), 1.94-1.86 (m, 2H);

Synthesis of 3-((6-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo \b,f\ [1 ,4] thiazepine-8carboxamido) methyl) thiazol-2-yl) pyridin-3-yl) oxy) propyl methane sulfonate (751): To a stirring solution of compound 750 (220 mg, 0.40 mmol) in CH₂C1₂ (10 mL) under inert atmosphère were added triethylamine (0.11 mL, 0.80 mmol) and methanesulfonyl chloride (0.04 mL, 0.60 mmol) at 0-5 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with

-527 CH₂C1₂ (5 mL) and washed with water (2x5 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 751 (200 mg, crude) as an offwhite solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.3); LC-MS: 27.24%; 629.0 (M⁺+l); (column;

Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.21 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of A-((2-(5-(3-(dimethylamino) propoxy) pyridin-2-yl) thiazol-5-yl) methyl)-! l-oxo10, 11-dihydrodibenzo [b,f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (1 1011): To a stirring solution of compound 751 (200 mg, 0.31 mmol) under argon atmosphère was added dimethyl amine (7 mL) in a sealed tube. The reaction mixture was heated to 60 °C and stirred for 16h. The reaction was monitored by TLC; after completion the reaction the volatiles were removed in vacuo to obtain the crude. The crude was purified through basic aluminia column chromatography using 2% MeOH/ CH₂C1₂ to afford 11011 (20 mg, 11%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.1); ’H NMR (DMSO-^,400 MHz): δ 11.49 (br s, IH), 9.45 (t, J= 5.7 Hz, IH), 8.28 (d, J= 2.6 Hz, IH), 8.06 (d, J= 8.2 Hz, IH), 8.03-7.95 (m, 3H), 7.937.85 (m, 3H), 7.84-7.79 (m, IH), 7.77 (s, IH), 7.51 (dd, J = 8.8, 2.9 Hz, IH), 4.67 (d,J=5.6 Hz, 2H), 4.13 (t, J= 6.4 Hz, 2H), 2.40 (t, J= 7.1 Hz, 2H), 2.17 (s, 6H), 1.92-1.85 (m, 2H); LCMS: 98.18%; 578.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.78 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 96.44%; (column; X select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 5.39 min. 0.05% TFA + 5% ACN : ACN + 5% 0.05% TFA ; 1.0 mL/min, Diluent: ACN : Water).

Synthesis of 11006,11007,11007-A & 11067

- 528 -

Synthesis of m/Ÿ-butvl (3-bromopropyl) carbamate (753): To a stimng solution of 3bromopropan-1 -amine hydrobromide 752 (20 g, 91.35 mmol) in CH2CI2 (200 mL) under inert atmosphère were added added Boc-anhydride (39.80 g, 182.15 mmol), diisopropylethylamine (75 mL, 135.05 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (500 mL) and extracted with CH2CI2 (2 x 500 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 5-20% EtOAc/ hexanes to afford compound 753 (15 g, 68%) as colorless liquid. TLC: 30% EtOAc/ hexanes (Rf 0.8); ^XH NMR (DMSO-îZô,400 MHz): δ 6.88 (br s, 1H), 3.50 (t, J= 6.6 Hz, 2H), 3.09 - 2.98 (m, 2H), 1.91 (p, J= 6.7 Hz, 2H), 1.38 (s, 9H); LC-MS (Agilent 6310 Ion Trap): 91.42%; 138.4 (M⁺+l) (Des Boc) (Column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 3.78 min. 2.5 mM Aq.

NH₄OAc: ACN, 0.8 mL/min).

-529 -

Synthesis of S-(3-((teri-butoxycarbonyl) amino) propyl) ethanethioate (755): To a stirring solution of compound 753 (15 g, 63.29 mmol) in acetone (250 mL) under inert atmosphère was added potassium thioacetate 754 (7.2 g, 63.29 mmol) at RTand stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the the reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2 x 250 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 755 (10 g, crude) as colorless syrup. TLC: 30% EtOAc/ hexanes (Rf 0.2); 'H NMR (400 MHz, DMSOd₆): δ 6.82 (br s, 1H), 2.94 (q, J = 6.6 Hz, 2H), 2.80 (t, J= 7.2 Hz, 2H), 2.31 (s, 3H), 1.60 (p, J = 7.1 Hz, 2H), 1.37 (s, 9H);

Synthesis of teri-butyl (3-mercaptopropyl) carbamate (756): To a stirring solution of compound 755 (10 g, crude) in MeOH (100 mL) under inert atmosphère was added potassium carbonate (17.76 g, 128.57 mmol) portionwise for 15 min at 0 °C; warmed to RTand stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the the reaction mixture was diluted with fitered through celite. The filtrate was concentrated in vacuo to afford crude compound 756 (7 g) as pale brown syrup. The crude was carried forward for next step without further purification. TLC: 30% EtOAc/ hexanes (Rf. 0.7);

Synthesis of tert-butyl (3-((4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b, f\ [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenyl) thio) propyl) carbamate (11007-A): To a stirring solution of compound 538 (4 g, 7.21 mmol) in 1, 4-dioxane (40 mL) were added tert-butyl (3-mercaptopropyl) carbamate 756 (4.14 g, 21.64 mmol) césium carbonate (7.05 g, 21.66 mmol) and potassium iodide (1.19 g, 7.22 mmol) at RT and purged under argon atmosphère for 15 min. To this were added Pd2(dba)s (661 mg, 0.72 mmol), Xantphos (292 mg, 0.50 mmol) purged under argon atmosphère for 5 min; heated to 110 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite. The fitrate was concentrated in vacuo to obtain the crude. The crude was purified through silicagel flash column chromatography using 1-5% MeOH/ CH2CI2. The obtained compound was triturated with 5% MeOH/ CH2CI2 (2 mL), n-pentane (5 mL) and

- 530 - further purified by préparative HPLC purification to afford 11007-A (130 mg, 3%) as white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.4). ‘H-NMR (DMSO-V 400 MHz): δ 11.50 (br s, 1H), 9.46 (t, J= 5.7 Hz, 1H), 8.06 (d, J= 8.2 Hz, 1H), 7.98 (dd, J= 7.8, 1.2 Hz, 2H), 7.90 (td, J= 7.5, 1.4 Hz, 1H), 7.87-7.84 (m, 2H), 7.84-7.77 (m, 4H), 7.36 (d, J= 8.5 Hz, 2H), 6.89 (t, J= 4.7 Hz, 1H), 4.68 (d, 5.5 Hz, 2H), 3.07-2.96 (m, 4H), 1.70 (p, J = 6.9 Hz, 2H), 1.36 (s, 9H);

LC-MS: 95.07%; 663.1 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0mm, 2.6um); RT 3.28 min. 2.5 mM Aq. NH₄OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min); HPLC (purity): 95.22%; (column; X-select CSH-C18 (150 x 4.6 mm, 3.5 pm); RT 10.62 min. 0.05% TFA + 5% ACN: ACN: + 5% 0.05% ACN; 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of 77-((2-(4-((3-aminopropyl) thio) phenyl) thiazol-5-yl) methyl)-! l-oxo-10, 11dihydrodibenzo [b,f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (11007): To a stirring solution of 11007-A (200 mg, 0.30 mmol) in CH₂C1₂ (20 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (2 mL) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford 11007 (160 mg, 88%; HCl sait) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.1); 'H-NMR (DMSO-V 400 MHz): δ 11.53 (s, 1H), 9.50 (t, J = 5.7 Hz, 1H), 8.06 (d, J= 8.2 Hz, 1H), 7.98 (dd, J= 7.6, 1.1 Hz, 2H), 7.94-7.74 (m, 10H), 7.45-7.38 (m, 2H), 4.68 (d, J= 5.6 Hz, 2H), 3.12 (t, J= 7.2 Hz, 2H), 2.97-2.83 (m, 2H), 1.88 (p, J= 7.3 Hz, 2H); LC-MS: 95.89%; 566.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.88 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 96.17%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 5.95 min. 0.05% TFA (Aq) + 5% ACN : ACN + 5% 0.5% TFA (Aq) ; 1.0 mL/min, Diluent: ACN: water).

Synthesis of 77-((2-(4-((3-(dimethylamino) propyl) thio) phenyl)thiazol-5-yl) methyl)-1 l-oxo10, 11-dihydrodibenzo (b, f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide (11006): To a stirring solution of 11007 (130 mg, 0.21 mmol) in MeOH (10 mL) under inert atmosphère were added paraformaldéhyde (32 mg, 1.08 mmol) and sodium cyanoborohydride (68 mg, 1.08 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with 10%

-531 MeOH/ CH2CI2 (2x50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 1-4% MeOH/ CH₂C1₂. The compound obtained was titurated with 5% MeOH/ CH2CI2 (5 mL) to afford 11006 (20 mg, 15%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.4); 'H-NMR (DMSO-Vî, 400 MHz): δ 11.51 (br s, 1H), 9.46 (t, J= 5.4 Hz, 1H), 8.06 (d, J= 8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.84 (m, 3H), 7.84-7.77 (m, 4H), 7.38 (d, J = 8.5 Hz, 2H), 4.68 (d, J= 5.3 Hz, 2H), 3.03 (t, J = 7.2 Hz, 2H), 2.38 (t, J= 6.3 Hz, 2H), 2.16 (s, 6H), 1.73 (p, J= 6.9 Hz, 2H); LC-MS: 98.35%; 593.1 (M⁺+l); (Column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 1.89 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.0 mL/min); HPLC (purity): 97.97%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 6.45 min. 0.05% TFA (Aq) + 5% ACN : ACN + 5% 0.5% TFA (Aq) ; 1.0 mL/min, Diluent: ACN: water).

Synthesis of A-((2-(4-((3-acetamidopropyl) thio) phenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide (11067): To a stirring solution of 11007 (35 mg, 0.058 mmol) in THF: H2O (4: 2, 2 mL) were added sodium carbonate (30 mg, 0.29 mmol), acetyl chloride (0.012 mL, 0.17 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3% MeOH/ CH2C1₂ to afford 11067 (15 mg, 43%) as white solid. TLC: 5% MeOH/ CH2CI2 (Rf. 0.6); 'H-NMR (DMSO-4 400 MHz): δ 11.51 (br s, 1H), 9.46 (t, J= 5.6 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.98 (td J= 7.5, 1.1 Hz, 2H), 7.93-7.85 (m, 4H), 7.84-7.77 (m, 4H), 7.37 (d, J = 8.5 Hz, 2H), 4.68 (d, J= 5.5 Hz, 2H), 3.19-3.10 (m, 2H), 3.02 (t, J= 7.2 Hz, 2H), 1.79 (s, 3H), 1.71 (p, J= 6.9 Hz, 2H); LC-MS: 97.37%; 607.1 (M⁺+l); (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 2.14 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 98.83%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm);

- 532 RT 8.14 min. 0.05% TFA (Aq) + 5% ACN : ACN + 5% 0.5% TFA (Aq) ; 1.0 mL/min, Diluent: ACN: water).

Synthesis of 3-((4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8carboxamido) methyl) thiazol-2-yl) phenyl) thio) propyl methanesulfonate (757): To a stirring solution of 1 1063-A (500 mg, 0.88 mmol) in THF: CH2CI2 (1: 1, 20 mL) under inert atmosphère were added triethylamine (1.2 mL, 8.84 mmol), methanesulfonyl chloride (0.36 mL, 4.40 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with CH₂C1₂ (100 mL) and washed with 10% sodium bicarbonate solution (50 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford mixture of mono and di-compound

757 (1.4 g) as brown thick syrup. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.7, 0.8); LC-MS: 39.97%;

644.0 (M⁺+l) (monomesylated mass), 42.82%; 722.0 (M⁺+l) (dimesylated mass); (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT: 2.49, 0.58 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min);

-533 Synthesis of A-((2-(4-((3-(diethylamino) propyl) thio) phenyl) thiazol-5-yl) methyl)-l l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (11063): To a stirring solution of 3-((4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b, J} [1, 4] thiazepine-8carboxamido) methyl) thiazol-2-yl) phenyl) thio) propyl methanesulfonate 1 (120 mg, mixture of compounds) in THF (1 mL) in a sealed tube was added diethylamine 387 (1 mL, 8 vol) at RT and heated to 75 °C and stirred for 16 h. The reaction was monitored by TLC; after completion the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel (100-200 mesh) column chromatography using 4-5% MeOH/ CH₂C1₂ to afford 11063 (15 mg, 13%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.4); 'HNMR (DMSO-c/₆, 400 MHz): δ 11.51 (br s, 1 H), 9.46 (t, 5.6 Hz, 1H), 8.06 (d, J =8.2 Hz,

1H), 8.01-7.95 (m, 2H), 7.93-7.74 (m, 7H), 7.37 (d, J= 8.4 Hz, 2H), 4.68 (d, J= 5.4 Hz, 2H), 3.04 (t, J= 7.0 Hz, 2H), 2.52-2.40 (m, 6H), 1.70 (quin, J= 7.0 Hz, 2H), 0.94 (t, J= 7.1 Hz, 6H); LC-MS: 97.40%; 621.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.80 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity): 98.67%; (column; X select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 6.14 min. 0.05% TFA + 5% ACN : ACN + 5% 0.05% TFA ; 1.0 mL/min, Diluent: water: DMSO: ACN).

Synthesis of/V-((2-(4-((3-(im-butylamino) propyl) thio) phenyl) thiazol-5-yl) methyl)-1 l-oxo10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide TFA sait (11064): To a stirring solution of compound 757 (300 mg, mixture) in DMF (8 mL) under inert atmosphère was added potassium carbonate (128 mg, 0.93 mmol), 2-methylpropan-2-amine 469 (0.46 mL, 4.65 mmol) in a sealed tube at RT; heated to 80 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with

-534 water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2-5% MeOH/ CH2CI2 and further purified by préparative HPLC purification to afford 11064 (25 mg, 9%) as an off-white solid. TLC: 5% MeOH/ CH2CI2 (Rf. 0.3); ‘H-NMR (DMSO-A, 400 MHz): δ 11.52 (s, 1H), 9.47 (t, J = 5.8 Hz, 1H), 8.29-8.16 (m, 2H), 8.05 (d, J = 8.3 Hz, 1H), 8.00-7.94 (m, 2H), 7.89 (td, J= 7.5, 1.6 Hz, 1H), 7.87-7.77 (m, 5H), 7.42 (d, J= 8.7 Hz, 2H), 4.67 (d, J= 5.4 Hz, 2H), 3.13 (t, J= 7.2 Hz, 2H), 3.04 - 2.94 (m, 2H), 1.91-1.83 (m, 2H), 1.24 (s, 9H); LC-MS: 98.77%; 621.1 (M⁺+l); (column; Ascentis Express Cl8, (50 ^x 3.0 mm, 2.7 pm); RT 1.97 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 99.27%; (column; X select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 6.29 min. 0.05% TFA + 5% ACN : ACN + 5% 0.05% TFA ; 1.0 mL/min, Diluent: ACN: DMSO).

Synthesis of 11065:

Synthesis of 1 l-oxo-A-((2-(4-((3-(piperidin-l-yl) propyl) thio) phenyl) thiazol-5-yl) methyl)10, 11-dihydrodibenzo \b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide (11065): To a stirring solution of 3-((4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b, j} [1, 4] thiazepine-8carboxamido) methyl) thiazol-2-yl) phenyl) thio) propyl methanesulfonate 757 (300 mg, mixture of compounds) in THF (5 mL) in a sealed tube was added piperidine 472 (2 mL, 6.6 vol) at RT and heated to 70 °C and stirred for 16 h. The reaction was monitored by TLC; after completion the volatiles were removed in vacuo to obtain the crude. The crude was either purified through basic alumina column chromatography using 1 -2% MeOH/ CH2CI2 to obtain the crude. The crude was diluted with EtOAc (50 mL), washed with water (50 mL). The .-.3177/0^/=^=0^-7 '

- 535 - organic extract was dried over sodium sulfate, filtered and concentrated in vacuo and triturated with EtOAc (5 mL) to afford 11065 (20 mg, 7%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.4); *H-NMR (DMSO-t/₆, 400 MHz): δ 11.51 (br s, IH), 9.46 (t, J= 5.6 Hz, IH), 8.06 (d, J= 8.3 Hz, IH), 7.98 (td, J = 1.3, 7.5, 1.3 Hz, 2H), 7.90 (td, J=1A, 1.4 Hz, IH), 7.877.76 (m, 6H), 7.38 (d, J= 8.5 Hz, 2H), 4.68 (d, J= 5.6 Hz, 2H), 3.03 (t, J = 7.2 Hz, 2H), 2.422.21 (m, 6H), 1.81-1.69 (m, 2H), 1.77-1.72 (m, 2H), 1.52-1.44 (m, 4H), 1.42-1.29 (m, 2H); LC-MS: 98.99%; 633.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.98 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity): 96.51%; (column; X select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 6.17 min. 0.05% TFA + 5% ACN: ACN + 5% 0.05% TFA ; 1.0 mL/min, Diluent: water: DMSO: ACN).

Synthesis of 11066:

Synthesis of A-((2-(4-((3-morpholinopropyl) thio) phenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo \b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide (11066): To a stirring solution of 3-((4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8carboxamido) methyl) thiazol-2-yl) phenyl) thio) propyl methanesulfonate 757 (300 mg, mixture of compounds) in THF (5 mL) in a sealed tube was added morpholine (2 mL, 6.6 vol) at RT and heated to 70 °C and stirred for 16 h. The reaction was monitored by TLC; after completion the volatiles were removed in vacuo to obtain the crude. The crude was purified through basic alumina column chromatography using 1-2% MeOH/ CH₂C1₂ to obtain the crude. The crude was diluted with water (10 mL), washed with water (50 mL). The organic extract was dried over sodium sulfate and stirred for 16 h. The obtained solid was filtered, washed with w-pentane (5 mL) and dried in vacuo to afford 11066 (72 mg, 24%) as an off-white solid. TLC:

- 536 5% MeOH/ CH₂Cl₂ (Rf. 0.3); 'H-NMR (DMSO-î7₆, 400 MHz): δ 11.52 (s, 1H), 9.46 (t, J = 5.7 Hz, 1H), 8.06 (d, 7=8.3 Hz, 1H), 7.98 (td,7=7.5, 1.1 Hz, 2H), 7.93-7.84 (m, 3H), 7.84-7.76 (m, 4H), 7.38 (d, J = 8.4 Hz, 2H), 4.68 (d, J= 5.5 Hz, 2H), 3.55 (t, J = 4.6 Hz, 4H), 3.05 (t, J = 7.2 Hz, 2H), 2.32 (d, J= 4.0 Hz, 5H), 1.75 (p, J = 7.0 Hz, 2H); LC-MS: 99.08%; 635.1 (M⁺+l);

(column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.91 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity): 99.03%; (column; X select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 5.91 min. 0.05% TFA + 5% ACN : ACN + 5% 0.05% TFA ; 1.0 mL/min, Diluent: ACN: water).

Synthesis of 3-((4-bromophenyl) thio) propan-l-ol (759): To a stirring solution of 4bromobenzenethiol 758 (5 g, 26.45 mmol) in THF (100 mL) under argon atmosphère was

- 537 - added sodium hydride (60%, 1.9 g, 79.16 mmol) portion wise for 10 min at 0 °C; warmed to RT and stirred for 1 h. To this was added 3-bromopropan-l-ol 384 (4.3 g, 31.74 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (50 mL) and extracted with EtOAc (2 x 150 mL), washed with water (100 mL), brine (100 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 759 (4.5 g, 69%) as colorless thick syrup. TLC: 30% EtOAc/ hexanes (Rf 0.4); ’HNMR (DMSO-4 400 MHz): δ 7.48 (d, J= 8.1 Hz, 2H), 7.26 (d, J= 8.7 Hz, 2H), 4.55 (t, J = 5.2 Hz, 1H), 3.51-3.45 (m, 2H), 3.00 (t, J= 7.2 Hz, 2H), 1.70 (p, J= 6.7 Hz, 2H);

Synthesis of 3-((4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) phenyl) thio) propan-1ol (760) (SAP-MA1623-71): To a stirring solution of compound 759 (3 g, 12.14 mmol) in 1, 4dioxane (90 mL) under inert atmosphère were added bispinacolato diboron (4.17 g, 16.51 mmol), potassium acetate (3.6 g, 36.43 mmol) at RT and purged under argon atmosphère for 15 min; to this was added Pd(dppf)C12.CH2C12 (991 mg, 1.21 mmol) and purged under argon atmosphère for 5 min, heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10-30% EtOAc/ hexanes to afford compound 760 (4.7 g, 43%) as colorless syrup. TLC: 30% EtOAc/ hexanes (R_f: 0.3); ’H-NMR (DMSO-4 400 MHz): δ 7.56 (d, J= 8.3 Hz, 2H), 7.27 (d, J= 8.3 Hz, 2H), 4.55 (t, J = 5.2 Hz, 1H), 3.51 -3.45 (m, 2H), 3.01 (t, J= 7.3 Hz, 2H), 1.78-1.61 (m, 2H), 1.27 (s, 12H);

Synthesis of/V-((2-(4-((3-hydroxypropyl) thio) phenyl) thiazol-5-yl) methyl)-! l-oxo-10, 11dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (11063-A): To a stirring solution of A-((2-chlorothiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide 535 (2.5 g, 5.77 mmol) in 1, 4-dioxane: H2O (2: 1, 113 mL) were added 2 3-((4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) phenyl) thio) propanl-ol 760 (3.4 g, 11.54 mmol), sodium bicarbonate (1.94 g, 23.09 mmol) and purged under

- 538 - argon atmosphère for 30 min. To this was added Pd(PPh3)4 (560 mg, 0.48 mmol) and purged under argon atmosphère for 5 min at RT ; heated to 90 °C and stirred for 16 h. The reaction was monitored by TLC and LC-MS; after completion the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 1 -6% MeOH/ CH2CI2, triturated with 5% MeOH/CH2Cl₂ (10 mL), n-pentane (20 mL) and dried in vacuo to afford 11063-A (3 g, 43%) as an off-white solid. TLC: 5% MeOH/ CH2CI2 (Rf 0.4); ^]H NMR (DMSO-ri₆,400 MHz): δ 11.51 (s, 1H), 9.46 (t, .7=5.8 Hz, 1H), 8.06 (d, J= 8.3 Hz, 1H), 8.027.95 (m, 2H), 7.92-7.85 (m, 3H), 7.84-7.76 (m, 4H), 7.37 (d, J = 8.7 Hz, 2H), 4.68 (d, J= 5.6 Hz, 2H), 4.57 (t, J= 5.2 Hz, 1H), 3.54-3.47 (m, 2H), 3.09-3.02 (m, 2H), 1.78-1.70 (m, 2H); LC-MS: 94.81%; 566.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.30 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 98.73%; (column; X-Select CSH-C-18 (150 x 4.6 mm, 3.5 pm); RT 8.25 min. 0.05% TFA (Aq) + 5% ACN: ACN + 5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: ACN: DMSO).

Synthesis of A-((2-(4-((3-hydroxypropyl) sulfonyl) phenyl) thiazol-5-yl) methyl)-l l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (11063-B): To a stirring solution of 11063-A (200 mg, 0.35 mmol) in CH₂C1₂ (10 mL) under argon atmosphère was added m-chloro perbenzoic acid (73 mg, 0.42 mmol) at 0 °C; warmed to RT and stirred for 30 min. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL), aqueous ammonia (20 mL) and extracted with 10% MeOH/ CH2CI2 (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 1-5% MeOH/ CH2C12, triturated with 10% MeOH/ CH2Q2 and dried in vacuo to afford 11063-B (60 mg, 28%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.4); 'H NMR (DMSO-î/₆, 400 MHz): δ 11.65 (br s, 1H), 9.62 (t, .7=5.7 Hz, 1H), 8.24 (d, J= 8.7 Hz, 2H), 8.16 (d, J = 8.3 Hz, 1H), 8.11-8.04 (m, 4H), 8.03-7.90 (m, 5H), 4.82 (d, J = 5.5 Hz, 2H), 4.71 (t,J=5.3 Hz, 1H), 3.50 (q, J= 6.1 Hz, 2H), 3.46-3.42 (m, 2H), 1.83-1.73 (m,

- 539 -

2H); LC-MS: 98.25%; 596.1 (M-l)⁺; (column; Kinetex EVO C-18 (50 x 3.0 mm,2.6 um); RT 2.28 min. 2.5 mM Aq. NH₄OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min); HPLC (purity): 98.97%; (column; X-Select CSH-C-18 (150 x 4.6 mm, 3.5 pm); RT 8.25 min. 0.05% TFA (Aq) + 5% ACN: ACN + 5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: ACN: H₂O: DMSO).

Synthesis of 3-((4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b,j] [1, 4] thiazepine-8carboxamido) methyl) thiazol-2-yl) phenyl) sulfonyl) propyl methanesulfonate (761): To a stirring solution of /V-((2-(4-((3-hydroxypropyl) sulfonyl) phenyl) thiazol-5-yl) methyl)-l 1oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide 11063-B (350 mg, 0.58 mmol) in THF: CH2CI2 (1: 1, 16 mL) under inert atmosphère were added triethylamine (6 mL, 41.58 mmol), methanesulfonyl chloride (1.2 mL, 14.73 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with CH2CI2 (100 mL) and washed with water (75 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 761 (450 mg) as colorless liquid. The crude was carried forward for next step without further purification. TLC: 30% EtOAc/ hexanes (Rf 0.8);

Synthesis of A-((2-(4-((3-azidopropyl) sulfonyl) phenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo \b,j\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide (762): To a stirring solution of compound 761 (450 mg, crude) in DMF (5 mL) under inert atmosphère was added sodium azide (129 mg, 1.99 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (100 mL) washed with water (100 mL), brine (50 mL). The organic extract was dried over sodium sulphate, filtered and concentrated in vacuo to afford crude compound 762 (320 mg) as colorless sticky solid. The crude was carried forward for next step without further purification TLC: 20% EtOAc/ hexanes (Rf 0.4);

Synthesis of A-((2-(4-((3-aminopropyl) sulfonyl) phenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo [b, J] [1,4] thiazepine-8-carboxamide 5, 5-dioxide TFA sait (11032): To a stirring solution of compound 762 (320 mg, crude) in THF: H2O (4: 1, 10 mL) was added

-540 triphenyl phosphine (134 mg, 0.51 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction; the volatiles were removed in vacuo to obtain the crude amine (250 mg crude). The crude was purified by préparative HPLC purification to afford 11032 (15 mg, 4.6%) as an off-white solid. TLC: 5% MeOH/ CH2CI2 (Rf 0.3); ^XH NMR (DMSO/400 MHz): δ 11.53 (s, 1H), 9.53 (t, J= 5.8 Hz, 1H), 8.17 (d, J=8.7 Hz, 2H), 8.06 (d, J= 8.3 Hz, 1H), 8.00-7.89 (m, 6H), 7.88-7.79 (m, 3H), 7.63 (br s, 3H), 4.72 (d, J= 5.5 Hz, 2H), 3.50-3.44 (m, 2H), 2.91-2.83 (m, 2H), 1.87-1.80 (m, 2H); LC-MS: 99.29%; 597.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.79 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity): 98.76%; (column; X select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 5.50 min. 0.05% TFA + 5% ACN: ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of A-((2-(4-((3-(dimethylamino) propyl) sulfonyl) phenyl) thiazol-5-yl) methyl)-lloxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide TFA sait (11033): To a stirring solution of 3-((4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenyl) sulfonyl) propyl methanesulfonate 761 (250 mg, 0.37 mmol) in DMF (1 mL) in a sealed tube was added 2 M dimethylamine in THF (20 mL, 31.11 mmol) at RT and heated to 70 °C and stirred for 16 h. The reaction was monitored by TLC; after completion the volatiles were removed in vacuo to obtain the crude. The crude was either purified through silica gel column chromatography using 5-10% MeOH/ CH2CI2 and further purified by préparative HPLC purification. The compound obatained was lyophilized for 16 h to afford 11033 (20 mg, 9%) as an off-white solid. TLC: 5%

-541 MeOH/ CH₂C1₂ (Rf 0.3); ’HNMR (DMSO-î?₆, 400 MHz): δ 11.53 (s, 1H), 9.53 (t, J= 5.8 Hz, 1H), 9.29 (br s, 1H), 8.17 (d, J= 8.5 Hz, 2H), 8.06 (d, J= 8.3 Hz, 1H), 8.01-7.94 (m, 4H), 7.937.80 (m, 5H), 4.72 (d, J = 5.6 Hz, 2H), 3.47-3.42 (m, 2H), 3.11 (t, J= 6.8 Hz, 2H), 2.74 (s, 6H), 1.99-1.89 (m, 2H); LC-MS: 97.65%; 624.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.79 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity): 99.70%; (column; X select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 5.59 min. 0.05% TFA + 5% ACN: ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: DMSO: ACN: water)

Synthesis of tert-butyl (4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) benzyl) carbamate (763): To a stirring solution of teH-butyl (4-bromobenzyl) carbamate 762 (1 g, 3.49 mmol) in DMSO (20 mL) under inert atmosphère were added bispinacolato diboron (1.06 g, 4.19 mmol), potassium acetate (1.02 g, 10.48 mmol) at RT and stirred under argon atmosphère for 30 min, added Pd(dppf)₂C12 (255 mg, 0.35 mmol) and heated to 90-100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture

-542 - was diluted with water (100 mL) extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 763 (500 mg, 43%). TLC: 20% EtOAc/ hexanes (Rf 0.8); 'H NMR (DMSO-î/₆, 400 MHz): δ 7.62 (d, J= 7.8 Hz, 2H), 7.38 (t, J= 5.5 Hz, 1H), 7.24 (d, J = 7.9 Hz, 2H), 4.13 (d, J= 62 Hz, 2H), 1.39 (s, 9H), 1.28 (s, 12H).

Synthesis of teri-butyl (4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) benzyl) carbamate (764): To a stirring solution of compound 763 (150 mg, 0.34 mmol) in 1, 2 dimethoxy ethane: H2O (4: 1,5 mL) were added (4-hydroxyphenyl) boronic acid 762 (230 mg, 0.69 mmol), sodium carbonate (128 mg, 1.21 mmol) and purged under argon atmosphère for 30 min. To this was added Pd(PPh3)4 (40 mg, 0.034 mmol) at RT; heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion the reaction mixture was diluted with water (100 mL) and extracted with 10% MeOH/ CH2CI2 (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3% MeOH/ CH2CI2 to afford compound 764 (70 mg, 33%) as white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.3); 'H-NMR (DMSO-ri₆, 400 MHz): δ 11.52 (s, 1H), 9.47 (t,J=5.7Hz, 1H), 8.06 (d,J=8.3 Hz, 1H), 7.98 (dd,J=7.5, 1.5 Hz, 2H), 7.90 (td, 7.5, 1.5 Hz, 1H), 7.87-7.80 (m, 5H), 7.78 (s, 1H), 7.43 (t, J= 5.7 Hz, 1H), 7.32 (d, J = 8.3 Hz, 2H), 4.68 (d, J = 5.5 Hz, 2H), 4.15 (d, J = 6.1 Hz, 2H), 1.39 (s, 9H).

Synthesis of A-((2-(4-(aminomethyl) phenyl) thiazol-5-yl) methyl)-! l-oxo-10, 11dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (1654): To a stirring solution of compound 764 (65 mg, 0.10 mmol) in CH2Q2 (2 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (1 mL) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with EtOAc (2x5 mL) and dried in vacuo to afford 1654 (40 mg, 69%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf

- 543 0.2); 'H-NMR (DMSO-V 500 MHz): δ 11.54 (s, 1H), 9.53 (t,/=5.8 Hz, 1H), 8.31 (br s, 3H), 8.06 (d,/ = 8.1 Hz, 1H), 8.01-7.88 (m, 5H), 7.87-7.82 (m, 4H) 7.57 (d,/ = 8.1 Hz, 2H), 4.69 (d, /= 5.5 Hz, 2H), 4.07 (q, / = 5.8 Hz, 2H); LC-MS: 96.02%; 505.0 (M⁺+l); (column;

Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.78 min. 0.025% Aq. TFA + 5% ACN:

ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 96.27%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 5.43 min. ACN + 5% 0.05% TFA (Aq): 0.05% TFA (Aq) + 5% ACN; 1.0 mL/min, Diluent: ACN: water).

Synthesis of (2-bromophenethoxy) (tert-butyl) dimethylsilane (766): To a stirring solution of 2-(2-bromophenyl) ethan-l-ol 765 (2 g, 9.95 mmol) in CH2Q2 (50 mL) under inert atmosphère was added imidazole (1.35 g, 19.85 mmol) at 0 °C and stirred for 10 min, followed by addition of TBDMS-C1 (1.79 g, 11.93 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH2CI2 (3 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude.

-544The crude was purified through silica gel column chromatography using 2-5% EtOAc/ hexanes to afford compound 766 (3 g, 96%) as colorless liquid. TLC: 10% EtOAc/ hexanes (Rf 0.8); ’H-NMR (DMSO-î/₆, 500 MHz): δ 7.57 (d, J = 8.1 Hz, 1H), 7.36-7.28 (m, 2H), 7.16 (t, J = 7.5 Hz, 1H), 3.78 (t, J= 6.8 Hz, 2H), 2.90 (t, J= 6.7 Hz, 2H), 0.82 (s, 9H), 0.06 (s, 6H).

Synthesis of tert-butyldimethyI(2-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) phenethoxy) silane (767): To a stirring solution of compound 766 (1 g, 3.18 mmol) in 1,4dioxane (30 mL) under argon atmosphère were added bispinacolato diboron (1.20 g, 4.74 mmol), potassium carbonate (1.31 g, 9.49 mmol) at RT and purged argon atmosphère for 5 min, added Pd(dppf)C12 (232 mg, 0.31 mmol) and heated to reflux and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite. The fïltrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 5-20% EtOAc/ hexanes to afford compound 767 (300 mg, 26%) as pale yellow liquid. TLC: 2% EtOAc/ hexanes (Rf 0.5); LC-MS: 93.59%; 363.2 (M⁺+l); (column; X-select CSH C-18 (50 x 3.0 mm, 2.5 pm); RT 5.19 min. 2.5 mM NH₄OOCH (Aq) + 5% ACN: ACN + 5% 2.5 mM NH4OOCH (Aq); 0.8 mL/min).

Synthesis of V-((2-(2-(2-((fôA-butyldimethylsilyl) oxy) ethyl) phenyl) thiazol-5-yl) methyl)-lloxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (768): To a stirring solution of A-((2-chlorothiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide 535 (200 mg, 0.46 mmol) in 1, 2-dimethoxy ethane: H2O (3: 1, 26 mL) under inert atmosphère were added compound 767 (334 mg, 0.92 mmol), sodium carbonate (147 mg, 1.38 mmol) in a sealed tube at RT and purged under argon atmosphère for 15 min, added Pd(dppf)C12 (33.76 mg, 0.046 mmol) and purged under argon atmosphère for 10 min and heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the fïltrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 2% MeOH/ CH2CI2 to afford compound 768 (150 mg, crude) as pale yellow liquid. TLC: % MeOH/ CH2Q2 (Rf 0.4);

-545 Synthesis ofM((2-(2-(2-hydroxyethyl) phenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo \b,f [1,4] thiazepine-8-carboxamide 5, 5-dioxide (1839): To a stirring solution of compound 768 (150 mg, 0.23 mmol) in CH2CI2 (5 mL) under inert atmosphère was added trifluoroacetic acid (0.3 mL) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with washed with water (75 mL) and extracted with 5% MeOH/ CH2CI2 (3 x 50 mL), The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified by préparative HPLC purification to afford 1839 (80 mg, 33% over 2 steps) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.3); *H-NMR (DMSO-c/₆,

400 MHz): δ 11.51 (s, IH), 9.48 (t, J= 5.6 Hz, IH), 8.06 (d, J = 8.3 Hz, IH), 7.98 (td, J= 7.7,

1.1 Hz, 2H), 7.93-7.80 (m, 5H), 7.53 (d, J= 7.5 Hz, IH), 7.44-7.36 (m, 2H), 7.34-7.26 (m, IH), 4.71 (d, J = 5.6 Hz, 2H), 4.65-4.56 (m, IH), 3.56 (t, J= 7.0 Hz, 2H), 3.04 (t, J= 7.0 Hz, 2H); LC-MS: 95.17%; 520.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.14 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 95.97%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 7.82 min. 0.05% TFA (Aq) + 5% ACN: ACN + 5% 0.05% TFA (Aq): 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of 1842

-546 -

Synthesis of 2-(2-bromophenyl) ethan-l-amine (770): To a stirring solution of 2-(2bromophenyl) acetonitrile 769 (1 g, 5.10 mmol) in THF (25 mL) under inert atmosphère was added borane dimethyl sulfïde complex (3.06 mL, 15.30 mmol, 5.0 M) dropwise for 5 min at

RT and heated to 80 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with MeOH (5 mL). To this was added 2 N HCl (20 mL) and refluxed for 1 h. The reaction mixture was basified using 10% aqueous NaHCOs solution (50 mL) and extracted with EtOAc (2 xlOO mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 770 (750 mg, crude) as colorless oil. The crude was carried forward for next step without further purification. TLC: 5% MeOH/ CH2CI2 (Rf 0.1);

Synthesis of iert-butyl (2-bromophenethyl) carbamate (771): To a stirring solution of compound 770 (750 mg, 3.75 mmol) in THF: H2O (4: 1. 10 mL) were added NaHCOa (788 mg, 9.37 mmol) and Boc-anhydride (1.63 g, 7.50 mmol) at RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 100 mL). The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 771 (600 mg,

-547 53%) as thick syrup. TLC: 30% EtOAc/ hexanes (Rf 0.8). *H-NMR (DMSO-îZ₆, 500 MHz): δ 7.57 (d, J= 8.1 Hz, 1H), 7.35-7.26 (m, 2H), 7.19-7.12 (m, 1H), 6.91 (t, J= 5.5 Hz, 1H), 3.16 (q, J= 6.7 Hz, 2H), 2.82 (t, J= 7.2 Hz, 2H), 1.36 (s, 9H).

Synthesis of tert-butyi (2-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) phenethyl) carbamate (772): To a stirring solution of compound 771 (600 mg, 2.00 mmol) in 1, 4-dioxane (20 mL) under inert atmosphère were added bispinacolato diboron (556 mg, 2.20 mmol), potassium acetate (686 mg, 7.00 mmol) RT and purged argon atmosphère for 30 min, added Pd(dppf)C12 (146 mg, 0.20 mmol) and heated to 100 °C and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with EtOAc (2x50 mL). The filtrate was concentrated in vacuo to afford compound 772 (600 mg). TLC: 10% EtOAc/hexanes (Rf 0.8); LC-MS: 66.71%; 248.1 (M⁺+l) (Des Boc); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 3.17 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl (2-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenethyl) carbamate (773): To a stirring solution of ?/-((2-chlorothiazol-5-yl) methyl)-l l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide 535 (150 mg, 0.34 mmol) in 1, 2-dimethoxy ethane: H₂O (4:1, 10 mL) under inert atmosphère were added compound 772 (300 mg, 0.86 mmol), sodium carbonate (128 mg, 1.21 mmol) at RT and purged under argon atmosphère for 30 min; added Pd(dppf)Cl₂ (25 mg, 0.034 mmol) and heated to 110 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2% MeOH/ 0¾¾ to afford compound 773 (60 mg, 28%) as brown syrup. TLC: 2% MeOH/ CH₂C1₂ (Rf 0.4); ‘H-NMR (DMSO-t/₆, 500 MHz): δ 11.52 (s, 1H), 9.48 (t, J= 5.8 Hz, 1H), 8.06 (d, J= 8.1 Hz, 1H), 8.00-7.96 (m, 2H), 7.93-7.80 (m, 5H), 7.55 (d, J= 7.2 Hz, 1H), 7.41-7.37 (m, 1H), 7.35-7.28 (m, 2H), 6.83 (t, J = 4.6 Hz, 1H), 4.71 (d, J= 5.8 Hz, 2H), 3.14 (q, J = 6.3 Hz, 2H), 3.03-2.97 (m, 2H), 1.30 (s, 9H); LC-MS: 97.49%; 619.1

- 548 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.55 min. 0.025% Aq.

TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of A-((2-(2-(2-aminoethyl) phenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 115 dihydrodibenzo [b,J] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (1842): To a stirring solution of compound 773 (60 mg, 0.097 mmol) in CH2CI2 (5 mL) was added 4 N HCl in 1, 4-dioxane (1 mL) under argon atmosphère at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude washed with EtOAc (5 mL) and dried in vacuo to afford compound 1842 (35 mg, 65%; HCl sait) as white solid. TLC: 5% MeOH/ CH2CI2 (Rf. 0.1); *H-NMR (DMSO-rié, 400 MHz): δ 11.54 (s, 1H), 9.56 (t, J= 5.8 Hz, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.98 (td, J=!A, 1.3 Hz, 2H), 7.94-7.82 (m, 8H), 7.61 (dd, J= 7.6, 0.9 Hz, 1H), 7.50-7.35 (m, 3H), 4.72 (d, J= 5.6 Hz, 2H), 3.21-3.13 (m, 2H), 3.12-3.02 (m, 2H); LC-MS: 99.26%; 519.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.85 min. 0.025% Aq. TFA + 5% ACN:

ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity): 98.26%; (column; X-select CSHC18 (150 x 4.6 mm, 3.5 pm); RT 6.21 min. 0.05% TFA (Aq) + 5% ACN: ACN + 5% 0.05% TFA (Aq) ; 1.0 mL/min, Diluent: DMSO: ACN: water).

-549 Synthesis of 1841

Boc₂O

Et₃N, CH₂CI₂

bis(pinacolato) diboron

KOAc, Pd(dppf)CI₂1, 4-dioxane

774 775 776

Synthesis of fôrt-butyl (2-bromobenzyl) carbamate (775): To a stirring solution of (2bromophenyl) methanamine 774 (2 g, 10.75 mmol) in CH2CI2 (20 mL) under inert atmosphère were added triethylamine (2.29 mL, 16.13 mmol) and Boc-anhydride (2.81 g, 12.89 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH2CI2 (2 x 100 mL). The crude was purified through silica gel flash column chromatography using 5% EtOAc/ hexanes to afford compound 775 (2.8 g, 91%) as an off-white solid. TLC: 20% EtOAc/ hexanes (Rf. 0.8). 'H NMR (400 MHz, DMSO-/₆): δ 7.58 (dd, J= 1.0, 7.9 Hz, 1H), 7.43 (br t, /=5.6 Hz, 1H), 7.41-7.35 (m, 1H), 7.28 (br d,/= 7.4 Hz, 1H), 7.20 (td,/=7.6, 1.8 Hz, 1H), 4.16 (d,/= 6.1 Hz, 2H), 1.41 (s, 9H);

Synthesis of tcrt-butyl (2-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) benzyl) carbamate (776): To a stirring solution of compound 775 (1 g, 3.49 mmol) in 1, 4-dioxane (20

- 550 mL) under argon atmosphère were added bispinacolato diboron (1.06 g, 4.18 mmol), potassium acetate (1.03 g, 10.51 mmol) at RT and purged argon atmosphère for 15 min, added Pd(dppf)C12 (256 mg, 0.35 mmol) and heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 2-10% EtOAc/ hexanes to afford compound 776 (700 mg, 56%) as pale yellow liquid. TLC: 2% EtOAc/ hexanes (Rf 0.5); ¹H NMR (400 MHz, DMSO-/: δ 7.65 (dd, J= 7.3, 1.1 Hz, 1H), 7.44 (dt, J = 7.5, 1.1 Hz, 1H), 7.27-7.19 (m, 3H), 7.14 (br t, J= 6.0 Hz, 1H), 4.38 (br d, J= 6.1 Hz, 2H), 1.40 (s, 9H), 1.31 (s, 12H); LC-MS: 74.04%; 332.3 (M⁺+l); column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 3.09 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of tert-butyl (2-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) benzyl) carbamate (777): To a stirring solution of A-((2-chlorothiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo \b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide 535 (200 mg, 0.46 mmol) in 1, 2-dimethoxy ethane: H2O (4: 1, 25 mL) under inert atmosphère were added compound 776 (200 mg, 0.55 mmol), sodium carbonate (147 mg, 1.38 mmol) in a sealed tube at RT and purged under argon atmosphère for 15 min, added Pd(PPh3)₄ (53.30 mg, 0.046 mmol) and purged under argon atmosphère for 10 min and heated to 120 °C and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 2-5% MeOH/ CH2CI2 to afford compound 777 (150 mg, 54%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.2); LC-MS: 93.68%; 605.1 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.57 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of X-((2-(2-(aminomethyl) phenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo \b,f [1, 4] thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (1841): To a

-551 - stirring solution of compound 777 (150 mg, 0.24 mmol) in CH2CI2 (10 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (1 mL) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was triturated with diethyl ether (50 mL) and dried in vacuo to afford 1841 (65 g, 48%) as white solid. TLC: 5% EtOAc/ hexanes (Rf 0.2); ‘H NMR (DMSO-î/₆, 400 MHz): δ 11.48 (br s, 1H), 9.56 (t, J= 5.7 Hz, 1H), 8.33 (br s, 2H), 8.08 (d, J= 8.3 Hz, 1H), 8.02-7.96 (m, 2H), 7.94-7.78 (m, 6H), 7.64-7.59 (m, 1H), 7.58-7.52 (m, 2H), 4.73 (d, J = 5.5 Hz, 2H), 4.25 (s, 2H); LC-MS: 99.47%; 505.1 (M⁺+l); (column; Ascentis Express Cl 8, (50 x 3.0 mm, 2.7 pm); RT 1.84 min. 0.025% Aq. TFA + 5% ACN:

ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity): 99.71%; (column; X-select CSHC18 (150 x 4.6 mm, 3.5 pm); RT 6.10 min. 0.05% TFA (Aq) + 5% ACN: ACN + 5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of 11002-A, 11002 & 11004

-552 -

Synthesis of 4-(4-(5-(aminomethyI) thiazol-2-yI) phenyl) but-3-yn-l-ol hydrochloride (778): To a stirring solution of compound 464 (310 mg, 0.86 mmol) in CH₂C12(10 mL) was added 4 N HCl in 1, 4-dioxane (5 mL) under inert atmosphère at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was triturated with EtOAc (5 mL), diethylether (5 mL) and dried in vacuo to afford compound 778 (280 mg, quantitative; HCl sait) as an offwhite solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.1); LC-MS: 94.71%; 258.9 (M⁺+l); (column;

Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 1.48 min. 2.5 mM Aq. NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of A-((2-(4-(4-hydroxybut-l-yn-l-yl) phenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide (11002-A): To a stirring

- 553 solution of compound 92 (150 mg, 0.49 mmol) in CH₃CN (20 mL) under argon atmosphère was added, 1-propylphosphonic acid cyclic anhydride (50% solution in EtOAc, 0.89 mL, 1.48 mmol), 4-(4-(5-(aminomethyl) thiazol-2-yl) phenyl) but-3-yn-l-ol hydrochloride (160 mg, 0.54 mmol) at 0 °C; warmed to RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. The crude purified through silica gel column chromatography to afford 11002-A (130 mg, 48%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.5); ^lH NMR (400 MHz, DMSO-r/₆): δ 11.47 (brs , IH), 9.48 (t, J = 5.7 Hz, IH), 8.06 (d,J= 8.3 Hz, IH), 7.98 (dd, J= 7.5, 1.4 Hz, 2H), 7.90 (td, J= 7.5, 1.5 Hz, IH), 7.87-7.79 (m, 6H), 7.47 (d, J= 8.5 Hz, 2H), 4.90 (t, J= 5.6 Hz, IH), 4.69 (br d, J= 5.6 Hz, 2H), 3.64 - 3.54 (m, 2H), 2.57 (t, J = 6.8 Hz, 2H); LC-MS: 99.59%; 544.0 (M⁺+l); (column;

Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.17 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 98.71%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 8.43 min. 0.05% TFA (Aq) + 5% ACN : ACN + 5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of 4-(4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] thiazepine-8carboxamido) methyl) thiazol-2-yl) phenyl) but-3-yn-l-yl methanesulfonate (779): To a stirring solution of 1 1002-A (650 mg, 1.19 mmol) in CH2CI2 (50 mL) under inert atmosphère were added triethyl amine (0.2 mL, 2.39 mmol), methanesulfonyl chloride (0.11 mL, 1.43 mmol) at 0 °C; warmed to RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (50 mL) and extracted with CH2CI2 (2 x 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 779 (800 mg) as colorless thick syrup. TLC: 5% MeOH/CH₂Cl₂ (Rf 0.8); LC-MS: 52.47%; 622.0 (M⁺+l); 28.75%; 700.0 (M⁺+l) (Dimesylated compound); (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 2.38 min, 2.53 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min);

- 554Synthesis of/V-((2-(4-(4-azidobut-l-yn-l-yl) phenyl) thiazol-5-yl) methyl)-! l-oxo-10, 11dihydrodibenzo [b,f [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (780): To a stirring solution of compound 779 (800 mg, 1.27 mmol) in DMF (10 mL) under inert atmosphère was added sodium azide (100 mg, 1.54 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2CI2 to afford compound 780 (400 mg) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.6); *H NMR (400 MHz, DMSO-îZ₆): 11.51 (s, 1H), 9.48 (t,J=5.5Hz, 1H), 8.06 (d,J=8.1 Hz, 1H), 8.01 -7.96 (m, 2H), 7.94-7.78 (m, 7H), 7.48 (d, J= 8.1 Hz, 2H), 4.69 (br d, J= 5.8 Hz, 2H), 3.53 (t, J = 6.4 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H);

Synthesis of A-((2-(4-(4-aminobut-l-yn-l-yl) phenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo [b, J] [1,4] thiazepine-8-carboxamide 5, 5-dioxide (11002): To a stirring solution of compound 780 (430 mg, 0.75 mmol) in THF: H₂O (4: 1, 45 mL) was added triphenyl phosphine (238 mg, 0.90 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC and LC-MS; after completion of the reaction; the reaction mixture was quenched with water (50 mL) and extracted with 10% MeOH/ CH₂C1₂ (2 x 50 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through basic alumina column chromatography using NH4OH: MeOH: 11002 (80 mg, 19%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.1); ⁽H NMR (400 MHz, DMSO-t/₆): δ 9.48 (t, J= 5.7 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.98 (td, J = 7.3, 0.9 Hz, 2H), 7.94-7.75 (m, 7H), 7.48 (d, J = 8.4 Hz, 2H), 5.47 5.04 (m, 2H), 4.69 (d, J = 5.5 Hz, 2H), 2.75 (t, J= 6.8 Hz, 2H) 2.61 -2.50 (m, 1H), 2.49 - 2.41 (m, 1H);LC-MS: 96.45%; 543.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.85 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.99%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 6.10 min. 0.05% TFA (Aq) + 5% ACN : ACN + 5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: DMSO: ACN: water).

-555 Synthesis of A-((2-(4-(4-aminobutyl) phenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo [b,f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide hydrochloride sait (11004): To a stirring solution of 11002 (200 mg, 0.35 mmol) in MeOH (15 mL) under inert atmosphère was added 10% Pd/C (150 mg) at RT and stirred under hydrogen atmosphère (balloon pressure) at RT for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and eluted with 20% MeOH/ CH2CI2 (250 mL).

The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through basic alumina column chromatography using NH4OH: MeOH: CH2CI2 (1: 1: 8) to afford amine (25 mg, crude)

The above crude amine (25 mg, crude) was dissolved in THF (10 mL) under inert atmosphère was added Et2O.HCl (5 mL) at 0 °C; warmed to RT and stirred for 2 h. The volatiles were removed in vacuo and the obatained crude was triturated with EtOAc (5 mL), diethylether (5 mL) and dried in vacuo to afford 11004 (80 mg, 10% over 3 steps) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.4); ^XH NMR (400 MHz, DMSO-J₆): δ 11.51 (br s, 1H), 9.47 (t, J= 5.7 Hz, 1H), 8.06 (d,7=8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.90 (td,7=7.5, 1.5 Hz, 1H), 7.877.81 (m, 6H), 7.46 (d, 7= 8.4 Hz, 2H), 4.69 (d, 7= 5.5 Hz, 2H), 2.64 - 2.49 (m, 4H), 2.22 (s, 6H); LC-MS: 95.39%; 547.1 (M⁺+l); (column; Ascentis Express Cl8, (50 ^x 3.0 mm, 2.7 pm); RT 1.87 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 95.30%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 8.39 min. 0.05% TFA + 5% ACN: ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: DMSO : ACN).

Synthesis of 11003 & 11005

-556 -

Synthesis of 2V-((2-(4-(4-(dimethylamino) but-l-yn-l-yl) phenyl) thiazol-5-yl) methyl)-1 l-oxo10, 11-dihydrodibenzo [b,f\ [1,4] thiazepine-8-carboxamide 5, 5-dioxide (11003): To a stirring solution of 11002 (220 mg, 0.40 mmol) in MeOH (15 mL) under inert atmosphère were added paraformaldéhyde (60 mg, 2.02 mmol) and sodium cyanoborohydride (127 mg, 2.02 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with 10% MeOH/ CH2CI2 (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through basic alumina column chromatography using NH4OH: MeOH: CH2CI2 (1: 1: 8) to afford 11003 (140 mg, 60%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.4); *H NMR (400 MHz, DMSOd₆): δ 11.50 (s, 1H), 9.47 (t,/=5.6 Hz, 1H), 8.03 (d,/=8.4 Hz, 1H), 7.95 (t,/=7.4 Hz, 2H), 7.91-7.82 (m, 3H), 7.82-7.73 (m, 4H), 7.72-7.64 (m, 2H), 7.29 (d, J = 7.9 Hz, 2H), 4.65 (d, / = 5.3 Hz, 2H), 2.81 - 2.71 (m, 2H), 2.67- 2.56 (m, 2H), 1.67-1.44 (m, 4H); LC-MS: 96.66%; 571.1 (M⁺+l); (Column; X-select CSH C-18 (150 x 4.6 mm, 2.7 pm); RT 1.86 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.0 mL/min); HPLC (purity): 98.60%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 6.47 min. 0.05% TFA + 5% ACN: ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: DMSO : ACN).

-557 Synthesis of V-((2-(4-(4-(dimethylamino) butyl) phenyl) thiazol-5-yl) methyl)-11-oxo-10, 11dihydrodibenzo (b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (11005): To a stirring solution of 11003 (140 mg, 0.24 mmol) in MeOH (15 mL) under inert atmosphère was added 10% Pd/C (50 mg) at RT and stirred under hydrogen atmosphère (balloon pressure) at RT for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and eluted with 20% MeOH/ CH₂C1₂ (200 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through basic alumina column chromatography using 10% MeOH/ CH₂C1₂ to afford 11005 (15 mg, 10%). TLC:10% MeOH/ CH₂C1₂ (Ry 0.2); ‘H NMR (400 MHz, DMSO-ri₆): δ 1150 (br s, 1H), 9.46 (br t, J= 5.5 Hz, 1H), 8.06 (d, J= 8.2 Hz, 1H), 8.01 - 7.95 (m, 2H), 7.93-7.87 (m, 1H), 7.87 - 7.76 (m, 6H), 7.29 (d, J= 8.1 Hz, 2H), 4.68 (br d, J= 5.3 Hz, 2H), 2.61 (t, J= 7.6 Hz, 2H), 2.20 (t, J= 7.2 Hz, 2H), 2.09 (s, 5H), 1.65 - 1.51 (m, 2H), 1.44-1.36 (m, 2H); LC-MS: 95.02%; 575.1 (M⁺+l); (Column; X-select CSH C-18 (150 x 4.6 mm, 2.7 pm); RT 1.89 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.0 mL/min); HPLC (purity): 97.71%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 9.02 min. 5 mM NH₄OAc: ACN; 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of 11061

Synthesis of/V-((2-(4-(4-morpholinobut-l-yn-l-yl) phenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo [b, f] [1,4] thiazepine-8-carboxamide 5, 5-dioxide (11061): To a stirring solution of 4-(4-(5-((5, 5-dioxido-l l-oxo-10, 11-dihydrodibenzo b, f] [1, 4] thiazepine-8carboxamido) methyl) thiazol-2-yl) phenyl) but-3-yn-l-yl methanesulfonate 779 (330 mg, crude) in THF (15 mL) was added morpholine 302 (0.23 mL, 2.65 mmol) in a sealed tube at RT under inert atmosphère. The reaction mixture was heated to 70 °C and stirred for 16 h. The

- 558 reaction was monitored by TLC and LCMS; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 1-5% MeOH/ CH₂C1₂ followed by trituration with acetonitrile (2x2 mL) to afford 11061 (30 mg, 9%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.4); *H NMR (400MHz, DMSOV₆): δ 11.49 (br s, 1H), 9.48 (t, J= 5.6 Hz, 1H), 8.06 (d, J= 8.3 Hz, 1H), 8.01-7.96 (m, 2H), 7.93-7.79 (m, 7H), 7.46 (d, J = 8.4 Hz, 2H), 4.69 (d, J= 5.5 Hz, 2H), 3.61-3.55 (m, 4H), 2.64-2.55 (m, 4H), 2.45-2.39 (m, 4H); LC-MS: 93.38%; 613.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.87 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 93.71%; (column; X-Select CSH-C-18 (150 x 4.6 mm, 3.5 pm); RT 5.87 min. 0.05% TFA + 5% ACN: ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: ACN : H₂O : DMSO).

Synthesis of A-((2-(4-hydroxybenzyl) thiazol-5-yl) methyl)-! l-oxo-10, 11-dihydrodibenzo [b, J} [1,4] oxazepine-8-carboxamide (1835): To a stirring solution of A-((2-(4-methoxybenzyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] oxazepine-8-carboxamide (1835-A) (150 mg, 0.31 mmol) in CH₂C1₂ (10 mL) under inert atmosphère was added BBr₂(0.06 mL, 0.63 mmol) at 0 °C; warmed to RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold

- 559 water (10 mL) and the obtained solid was filtered, washed with 10% NaHCO₃ solution (100 mL). The obtained solid was dried in vacuo to obtain the crude which was titurated with EtOAc (10 mL) and dried in vacuo to afford 1835 (130 mg, 90%) as an off-white solid. TLC: 10% EtOAc/hexanes (Rf 0.4); 'H NMR (DMSO-rZ_d,400 MHz): δ 10.59 (s, 1H), 9.12-9.06 (m, 1H), 7.78 (dd, J=7.8, 1.6 Hz, 1H), 7.65-7.62 (m, 2H), 7.61-7.56 (m, 1H), 7.53 (s, 1H), 7.41-7.31 (m, 3H), 7.08 (d, J= 8.5 Hz, 2H), 6.69 (d, J= 8.4 Hz, 2H), 4.53 (d, J= 5.9 Hz, 2H), 4.10 (s, 2H); LC-MS: 94.88%; 458.1 (M+l)⁺; (column; Kinetex EVO C-18 (50 x 3.0 mm,2.6 um); RT 2.38 min. 2.5 mM Aq. NH₄OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min); HPLC (purity): 97.47%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 7.77 min. 0.05% TFA + 5% ACN : ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: DMSO: ACN : water).

Synthesis of A-((2-(4-hydroxy-3-methylphenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo \b,f\ [1, 4] oxazepine-8-carboxamide (1736): To a stirring solution of 1736-A (120 mg, 0.25 mmol) in CH2CI2 (10 mL) was added BBr₃ (0.048 mL, 0.50 mmol) at 0 °C;

warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (10 mL). The precipitated solid was filtered, washed with 10% NaHCO₃ solution (20 mL), water (10 mL), «-pentane (10 mL) and dried in vacuo to afford compound 1736 (110 mg, 95%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.2); ‘H-NMR (DMSO-î/₆, 500 MHz): δ 10.64 (s, 1H), 9.84 (s, 1H), 9.17 (t, J= 5.2 Hz, 1H), 7.78 (d, J= 6.9 Hz, 1H), 7.72-7.58 (m, 5H), 7.53 (d, J= 8.2 Hz, 1H), 7.42 (d,J=8.3 Hz, 1H), 7.38-7.31 (m, 2H), 6.83 (d,J=8.3 Hz, 1H), 4.62 (d, J = 5.1 Hz, 2H),

- 560 2.15 (s, 3H); LC-MS: 95.08%; 457.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.19 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.99%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 pm); RT 7.56 min. ACN + 5% 0.05% TFA (Aq): 0.05% TFA (Aq) + 5% ACN; 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of A-((2-(4-hydroxy-3, 5-dimethylphenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo \b,f\ [1,4] oxazepine-8-carboxamide (1738): To a stirring solution of 1738-A (120 mg, 0.24 mmol) in CH2CI2 (15 mL) was added BBr₃ (62 mg, 0.24 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with ice-cold water (5 mL) and the precipitated solid was filtered washed with 10% aqueous sodium carbonate solution and in vacuo to obtain the crude. The crude was titurated with MeOH (2 mL) and dried in vacuo to afford 1738 (100 mg, 86%) as an of-white solid. TLC: 5% MeOH/ CH2CI2 (Rf 0.1); *H NMR (DMSO-d₆,400 MHz): δ 10.64 (s, 1H), 9.18 (t, J= 5.8 Hz, 1H), 8.74 (br s, 1H), 7.78 (dd, J = Ί.Ί, 1.7 Hz, 1H), 7.69 (d, J= 2.0 Hz, 1H), 7.66-7.60 (m, 3H), 7.45 (s, 2H), 7.42 (d, J= 8.4 Hz, 1H), 7.38-7.31 (m, 2H), 4.62 (d, J= 5.6 Hz, 2H), 2.19 (s, 6H); LC-MS: 96.50%; 472.0 (M⁺+l); (column; Ascentis Express Cl 8, (50 ^x 3.0 mm, 2.7 pm); RT 2.23 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 98.22%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 8.70 min. ACN + 5% 0.05% TFA (Aq): 0.05% TFA (Aq) + 5% ACN; 1.0 mL/min, Diluent: DMSO: ACN: water).

-561 Synthesis of 1709

Synthesis of/V-((2-(2-hydroxypyrimidin-5-yl) thiazol-5-yl) methyl)-! l-oxo-10, 11dihydrodibenzo [b, f\ [1, 4] oxazepine-8-carboxamide (1709): To a stirring solution of/V-((2-(2methoxypyrimidin-5-yl) thiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] oxazepine-8-carboxamide 1709-A (50 mg, 0.10 mmol) in CH2CI2 (15 mL) was added BBrs (0.10 mL, 1.08 mmol) at 0 °C; warmed to RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with ice-cold water (10 mL) and stirred for 15 min. The obtained solid was filtered, washed with saturated soldium carbonate solution (5 mL) and water (10 mL) and dried in vacuo to obtain the crude. The crude was titurated with MeOH (2 mL), diethyl ether (2 mL) and pentane (5 mL) and dried in vacuo to afford 1709 (35 mg, 72%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.3); ^XH NMR (DMSO/400 MHz): δ 12.42 (s, 1H), 10.65 (s, 1H), 9.22 (t, J= 5.7 Hz, 1H), 8.70 (s, 2H), 7.78 (dd, J= Ί.Ί, 1.6 Hz, 1H), 7.72-7.68 (m, 2H), 7.66-7.59 (m, 2H), 7.42 (d, J= 8.4 Hz, 1H), 7.39-7.31 (m, 2H), 4.63 (d, J= 5.6 Hz, 2H); LC-MS: 97.71%; 445.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.84 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 94.09%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 5.87 min. ACN + 5% 0.05% TFA (Aq): 0.05% TFA (Aq) + 5% ACN; 1.0 mL/min, Diluent: ACN: water).

-562 -

Synthesis of methyl (5-((1 l-oxo-10, 11-dihydrodibenzo [b,f] [1, 4] oxazepine-8-carboxamido) methyl) thiazol-2-yl) glycinate (781): To a stimng solution of compound 149 (150 mg, 0.58 mmol) in DMF (5 mL) under inert atmosphère were added methyl (5-(aminomethyl) thiazol-2yl) glycinate hydrochloride 623 (139 mg, 0.58 mmol), EDCI.HC1 (212 mg, 1.17 mmol), HOBt (158 mg, 1.17 mmol) and diisopropylethylamine (0.5 mL, 2.94 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and the precipitated solid was filtered and dried in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 5-10% MeOH/ CH2CI2 to afford compound 781 (72 mg, 27%) as an offwhite solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.4); ‘H-NMR (DMSO-û?₆ 500 MHz): δ 10.61 (s, 1H), 8.97 (t, J= 5.5 Hz, 1H), 7.85-7.76 (m, 1H), 7.70-7.57 (m, 3H), 7.49-7.25 (m, 4H), 6.86 (s, 1H), 4.38 (d, J = 5.5 Hz, 2H), 3.99 (d, J= 6.1 Hz, 2H), 3.62 (s, 3H).

Synthesis of (5-((1 l-oxo-10,11-dihydrodibenzo [b,f\ [1, 4] oxazepine-8-carboxamido) methyl) thiazol-2-yl) glycine (1615): To a stirring solution of compound 781 (70 mg, 0.16 mmol) in THF: H₂O (1:1, 10 mL) was added lithium hydroxide monohydrate (38.4 mg, 0.80 mmol) at RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (30 mL), washed with EtOAc (2 x 25 mL). The pH of the aqueous layer was acidified with 4 N HCl to ~2. The precipitated solid was

-563 filtered and triturated with CH₃CN (2 mL), MeOH: CH₃CN (1:1, 1 mL), MeOH (1 mL) and dried in vacuo to afford 1615 (30 mg, 44%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.2); ’H-NMR (DMSO-4 400 MHz): δ 10.60 (s, 1H), 8.95 (t, J = 5.2 Hz, 1H), 7.77 (dd, J = 7.6, 1.4 Hz, 1H), 7.68-7.55 (m, 3H), 7.51 (br s, 1H), 7.43-7.28 (m, 3H), 6.85 (s, 1H), 4.36 (d, J= 5.6 Hz, 2H), 3.77 (d, J= 4.8 Hz, 2H); LC-MS: 93.23%; 424.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.86 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 93.86%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 5.54 min. 0.05% TFA (Aq): ACN; 1.0 mL/min).

Synthesis of methyl 2-((5-((1 l-oxo-10, 11-dihydrodibenzo [b,f [1, 4]oxazepine-8carboxamido) methyl) thiazol-2-yl) thio) acetate (782): To a stirring solution of compound 149 (150 mg, 0.59 mmol) in DMF (5 mL) under inert atmosphère were added EDCI.HC1 (224 mg, 1.18 mmol), HOBt (158 mg, 1.18 mmol) and diisopropylethylamine (0.30 mL, 1.81 mmol) and methyl 2-((5-(aminomethyl) thiazol-2-yl) thio) acetate hydrochloride 627 (139 mg, 0.65 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL); the obtained solid was filtered, triturated with CH₃CN (2 mL), diethyl ether (5 mL) and dried in vacuo to afford compound 782 (180 mg, 67%) as an off-white solid. TLC: 10% MeOH/ CH2C1₂ (Rf 0.5); ‘H-NMR (DMSO-^ 500 MHz): δ 10.60 (s, 1H), 9.13 (t, J =5.6 Hz, 1H), 7.76 (d, J =6.1

-564 Hz, IH), 7.67-7.54 (m, 4H), 7.40 (d, J = 8.4 Hz, 1H), 7.37-7.29 (m, 2H), 4.52 (d, J= 5.5 Hz, 2H), 4.10 (s, 2H), 3.62 (s, 3H).

Synthesis of 2-((5-((1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] oxazepine-8-carboxamido) methyl) thiazol-2-yl) thio) acetic acid (1616): To a stirring solution of compound 782 (150 mg, 0.33 mmol) in THF: H₂O (5: 1,6 mL) was added lithium hydroxide monohydrate (31.6 mg, 0.66 mmol) at RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL), washed with EtOAc (2 x 50 mL). The pH of the aqueous layer was acidified with 4 N HCl to ~2. The precipitated solid was filtered washed with CH₃CN (5 mL) and dried in vacuo to afford 1616 (90 mg, 62%) as an offwhite solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); ’H-NMR (DMSO-V 500 MHz): δ 12.98 (br s, 1H), 10.62 (s, 1H), 9.15 (t, J =5.6 Hz, 1H), 7.78 (dd,/=7.7, 1.3 Hz, 1H), 7.69-7.58 (m, 3H), 7.56 (s, 1H), 7.42 (d, /= 8.4 Hz, 1H), 7.38-7.31 (m, 2H), 4.54 (d, / = 5.5 Hz, 2H), 4.00 (s, 2H); LC-MS: 98.46%; 440.2 (M-l)⁺; (column; X-select Cl8, (50 x 3.0 mm, 2.5 pm); RT 2.64 min. 5 mM Aq. NH₄OAc + ACN; 0.8 mL/min); HPLC (purity): 96.34%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 p); RT 7.27 min. ACN : 0.05% TFA (Aq); 1.0 mL/min; Diluent: ACN: water).

- 565 -

Synthesis of A-((2-chlorothiazol-5-yl) methyl)-l l-oxo-10,11-dihydrodibenzo [b,j\ [1, 4] oxazepine-8-carboxamide (783): To a stirring solution of compound 149 (500 mg, 1.96 mmol) in DMF (10 mL) under inert atmosphère were added compound 223 (398 mg, 2.15 mmol), EDCI.HC1 (561 mg, 2.94 mmol), HOBt (397 mg, 2.94 mmol) and diisopropylethylamine (1.75 mL, 9.80 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold-water (50 mL), extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 8% MeOH/ CH2CI2 to afford compound 783 (390 mg, 52%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf. 0.4); 'H-NMR (DMSO-rf₆ 500 MHz): δ 10.63 (s, 1H), 9.23 (t, J= 5.6 Hz, 1H), 7.78 (dd, J= Ί.Ί, 1.6 Hz, 1H), 7.68 (s, 1H), 7.65-7.58 (m, 3H), 7.43 (d, J = 8.4 Hz, 1H), 7.397.31 (m, 2H), 4.56 (d, J= 5.8 Hz, 2H).

Synthesis of A-((2-(3-(dimethylamino) propoxy) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo [b,f\ [1,4] oxazepine-8-carboxamide (1691): To a stirring solution of 3(dimethylamino) propan-l-ol 364 (0.11 mL, 0.97 mmol) in THF (15 mL) under argon atmosphère was added sodium hydride (60%, 39 mg, 1.62 mmol) at 0 °C and stirred for 15 min. To this was added compound 783 (125 mg, 0.32 mmol) at 0 °C; heated to 60 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with water (5 mL) and the extracted with EtOAc (2x50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude compound was purified through silicagel column chromatography using 5% MeOH/ CH2CI2 to afford 1691 (15 mg, 10%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.4); 'H-NMR (DMSO-7₆, 400 MHz): δ 10.62 (br s, 1H), 9.07 (t, J = 5.3 Hz, 1H), 7.78 (dd, 7=7.8, 1.6 Hz, 1H), 7.68-7.56 (m, 3H), 7.41 (d,7=8.4 Hz, 1H), 7.38-7.31 (m, 2H), 7.05 (s, 1H), 4.44 (d, 7= 5.6 Hz, 2H), 4.32 (t, 7= 6.5 Hz, 2H), 2.28 (t, 7= 7.0 Hz, 2H), 2.11 (s, 6H), 1.88-1.79 (m, 2H); LC-MS: 95.08%; 453.1 (M⁺+l); (column; Ascentis Express Cl 8, (50 x 3.0 mm, 2.7 pm); RT 1.73 min. 0.025% Aq. TFA + 5% ACN: ACN + 5%

-566 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 93.73%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 pm); RT 5.64 min. ACN : 0.05% TFA (Aq); 1.0 mL/min).

Synthesis of A-((2-(3-(dimethylamino) propoxy) thiazol-5-yl) methyl)-A-methyl-l l-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] oxazepine-8-carboxamide (1687): To a stirring solution of 3(dimethylamino) propan-l-ol 364 (0.14 mL, 1.12 mmol) in THF (10 mL) under argon atmosphère was added sodium hydride (60%, 41 mg, 1.69 mmol) portion wise at 0 °C and stirred for 10 min. To this was added compound 784 (150 mg, 0.37 mmol) at 0 °C; heated to 60 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with water (0.5 mL) and the volatiles were removed in vacuo to obtain the crude. The crude compound was purified through basic alumina column chromatography using 2% MeOH/ CH2CI2 to afford 1687 (75 mg, 43%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.4); ¹ H-NMR (DMSO-î/₆, 400 MHz): δ 10.56 (br s, IH), 7.79 (dd, J=7.8, 1.6 Hz, IH), 7.64-7.60 (m, IH), 7.42-7.31 (m, 3H), 7.23-7.17 (m, 3H), 4.59 (br s, 2H), 4.35 (t, J= 6.5 Hz, 2H), 2.85 (s, 3H), 2.30 (t, J= 7.1 Hz, 2H), 2.12 (s, 6H), 1.88-1.81 (m, 2H); LC-MS: 97.53%; 467.1 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.75 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 96.51%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 5.80 min. 0.05% TFA (Aq): ACN; 1.0 mL/min).

- 567 -

Synthesis of W((2-(2-(dimethylamino) ethoxy) thiazol-5-yl) methyl)-! l-oxo-10, 11dihydrodibenzo [b,f] [1, 4] oxazepine-8-carboxamide (1614): To a stirring solution of 2(dimethylamino) ethan-l-ol 358 (70 mg, 0.77 mmol) in THF (10 mL) under argon atmosphère was added sodium hydride (60%, 28 mg, 1.16 mmol) at 0 °C and stirred for 10 min. To this was added V-((2-chlorothiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] oxazepine8-carboxamide 783 (150 mg, 0.38 mmol) at 0 °C; heated to reflux and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (5 mL) and the extracted with EtOAc (2x50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude compound was purified through silicagel column chromatography using 10% MeOH/ CH2CI2 and further purified by préparative HPLC purification to afford 1614 (35 mg, 20%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.4); *H-NMR (DMSO-X 500 MHz): δ 10.64 (s, 1H), 9.12 (t, J = 5.6 Hz, 1H), 7.78 (dd,J=7.7. 1.6 Hz, 1H), 7.69 (s, 1H), 7.65-7.58 (m, 2H), 7.41 (d, J= 8.4 Hz, 1H), 7.38-7.31 (m, 2H), 7.05 (s, 1H), 4.44 (d, J= 5.5 Hz, 2H), 4.37 (t, J= 5.6 Hz, 2H), 2.59 (t, J= 5.5 Hz, 2H), 2.16 (s, 6H); LC-MS: 99.24%; 439.0 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.95 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 98.60%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 pm); RT 5.65 min. 0.05% TFA (Aq): ACN; 1.0 mL/min).

- 568 -

Synthesis of V-((2-chlorothiazol-5-yl) methyl)-V-methyl-l l-oxo-10, 11-dihydrodibenzo \b,f\

[1,4] oxazepine-8-carboxamide (784): To a stirring solution of compound 149 (400 mg, 1.57 mmol) in DMF (5 mL) under argon atmosphère were added EDCI.HC1 (570 mg, 3.15 mmol), HOBt (425 mg, 3.15 mmol) at 0 °C RT and stirred for 10 min. To this were added compound 368 (280 mg, 1.73 mmol) and diisopropylethylamine (0.8 mL, 4.72 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (50 mL) and the obtained solid was filtered, triturated with CH₃CN: diethyl ether (1: 4, 10 mL) and dried in vacuo to afford compound 784 (520 mg, 89%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.3); ‘H-NMR (DMSO-ri₆, 500 MHz): δ 10.56 (br s, 1H), 7.79 (dd, 7.7, 1.0 Hz, 1H), 7.71 (br s, 1H), 7.66-7.61 (m, 1H), 7.42-7.31 (m, 3H), 7.27-7.20 (m, 2H), 4.70 (br s, 2H), 2.89 (s, 3H).

Synthesis of 7V-((2-(2-(dimethylamino) ethoxy) thiazol-5-yl) methyl)-V-methyl-l l-oxo-10, 11dihydrodibenzo \b,f\ [1, 4] oxazepine-8-carboxamide (1686): To a stirring solution of 2(dimethylamino) ethan-l-ol 358 (0.12 mL, 1.12 mmol) in THF (10 mL) under argon atmosphère was added sodium hydride (60%, 41 mg, 1.69 mmol) portion wise at 0 °C and

-569 stirred for 10 min. To this was added compound 784 (150 mg, 0.37 mmol) at 0 °C; heated to 60 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with water (0.5 mL) and the volatiles were removed in vacuo to obtain the crude. The crude compound was purified through basic alumina column chromatography using 2% MeOH/ CH2CI2 to afford 1686 (85 mg, 50%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.4); 'H-NMR (DMSO-c/₆, 500 MHz): δ 10.56 (br s, 1H), 7.79 (dd, J=7.8, 1.6 Hz, 1H), 7.66-7.60 (m, 1H), 7.42-7.31 (m, 3H), 7.24-7.16 (m, 3H), 4.59 (br s, 2H), 4.40 (t, J = 5.6 Hz, 2H), 2.85 (s, 3H), 2.62 (t, J= 5.6 Hz, 2H), 2.19 (s, 6H); LC-MS: 98.25%; 453.1 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 μm); RT 1.72 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.15%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 5.67 min. 0.05% TFA (Aq): ACN; 1.0 mL/min).

Synthesis of 2-((tetrahydro-2Æ-pyran-2-yl) oxy) ethan-l-ol (787): To a stirring solution of ethane-1, 2-diol 785 (20 g, 322.5 mmol) in CH₂C1₂ (250 mL) under inert atmosphère was added /2-toluene sulfonic acid (3 g, 0.16 mmol) and 3, 4-dihydro-2//-pyran 786 (13.5 g, 0.16 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the diluted with CH₂C1₂ (200 mL) and washed with water (100 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the

-570 crude. The crude was purified through silica gel column chromatography using 30% EtOAc/ hexanes to afford compound 787 (6 g, 13%) as colorless thick syrup. TLC: 50% EtOAc/ hexanes (Ry 0.4); *H-NMR (CDC1₃, 400 MHz): δ 4.74-4.53 (m, 1H), 3.98-3.61 (m, 5H), 3.593.48 (m, 1H), 1.91-1.68 (m, 2H), 1.66-1.48 (m, 5H).

Synthesis of 1 l-oxo-A-((2-(2-((tetrahydro-2/7-pyran-2-yl) oxy) ethoxy) thiazol-5-yl) methyl)10, 11-dihydrodibenzo [b,f] [1, 4] oxazepine-8-carboxamide (1613-A): To a stirring solution of compound 787 (19 mg, 0.12 mmol) in THF (4 mL) under argon atmosphère was added sodium hydride (60%, 4.5 mg, 0.18 mmol) at 0 °C and stirred for 30 min. To this was added A-((2chlorothiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo [b,f] [1, 4] oxazepine-8carboxamide 783 (25 mg, 0.06 mmol) at 0 °C; heated to 60 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated citric acid solution (1 mL) and the extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, fdtered and concentrated in vacuo. The crude compound was diluted with 10% MeOH/ CH₂C1₂ (20 mL), saturated citric acid solution (3 mL) and the organic extract was dried over sodium sulfate, fdtered and concentrated in vacuo to obtain the crude; which was triturated CH3OH (2x2 mL) and dried in vacuo to afford 1613-A (12 mg, 45%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Ry 0.4); *HNMR (DMSO-riô, 400 MHz): δ 10.62 (s, 1H), 9.09 (t, J= 5.7 Hz, 1H), 7.78 (dd, J=7.7, 1.7 Hz, 1H), 7.68-7.57 (m, 3H), 7.41 (d, J = 8.5 Hz, 1H), 7.38-7.31 (m, 2H), 7.05 (s, 1H), 4.91 (t, J = 5.5 Hz, 1H), 4.44 (d, J= 5.5 Hz, 2H), 4.30 (t, J = 5.2 Hz, 2H), 3.68 (q, J= 5.2 Hz, 2H); LCMS: 96.28%; 412.0 (M⁺+l); (column; X-Select CSH C-18, (50 x 3.0 mm, 2.5 pm); RT 2.46 min. 2.5 mM Aq. NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq. NH4OOCH, 1.2 mL/min); HPLC (purity): 96.02%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 8.39 min. 0.05% TFA (Aq): ACN; 1.0 mL/min).

-571 -

Synthesis of A^L((2-(6-methoxypyridin-3-yl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo \b,f\ [1, 4] oxazepine-8-carboxamide (1705): To a stirring solution of A-((25 chlorothiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo \b,f\ [1, 4] oxazepine-8carboxamide 783 (300 mg, 0.77 mmol) in 1, 2 dimethoxy ethane: H₂O (4: 1, 10 mL) were added (6-methoxypyridin-3-yl) boronic acid 582 (143 mg, 0.93 mmol), sodium carbonate (244 mg, 2.31 mmol) in a sealed tube and purged under argon atmosphère for 15 min. To this was added Pd(PPh₃)₄ (88 mg, 0.07 mmol) at RT; heated to 110 °C and stirred for 16 h. The reaction 10 was monitored by TLC; after completion the reaction mixture was diluted with water (50 mL) and extracted with CH₂C1₂ (2x30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2-8% MeOH/ CH₂C1₂ to afford 1705 (160 mg, 45%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.4); 'H-NMR (DMSO-î/₆, 500 MHz): δ 10.65 15 (s, 1H), 9.23 (t, J = 5.8 Hz, 1H), 8.68 (d, J= 2.0 Hz, 1H), 8.16 (dd, J = 8.7, 2.5 Hz, 1H), 7.807.76 (m, 2H), 7.70 (d, J= 2.0 Hz, 1H), 7.66-7.60 (m, 2H), 7.43 (d, J= 8.4 Hz, 1H), 7.39-7.29 (m, 2H), 6.92 (d, J = 8.7 Hz, 1H), 4.66 (d, J = 5.6 Hz, 2H), 3.90 (s, 3H); LC-MS: 98.15%;

459.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.26 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 99.44%;

-572(column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 8.52 min. ACN + 5% 0.05% TFA (Aq): 0.05% TFA (Aq) + 5% ACN; 1.0 mL/min, Diluent: ACN: water).

Synthesis of7V-((2-(6-hydroxypyridin-3-yl) thiazol-5-yl) methyl)-! l-oxo-10, 115 dihydrodibenzo \b,f\ [1, 4] oxazepine-8-carboxamide (1706): To a stirring solution of 1705 (100 mg, 0.21 mmol) in DMF (5 mL) under inert atmosphère were added lithium chloride (46 mg, 1.08 mmol) /?-toluenesulfonic acid (215 mg, 1.08 mmol) at RT in a sealed tube; heated to 120 °C and stirred for 16 h. The reaction was monitored by TLC and LC-MS; after completion the reaction mixture was diluted with water (50 mL) and the precipitate was filtered. The solid was suspended in EtOAc (10 mL), stirred for 5 h, filtered and dried in vacuo to afford 1706 (40 mg, 42%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.4); 'H-NMR (DMSOV, 500 MHz): δ 11.72 (br s, 1H), 10.62 (br s, 1H), 9.18 (t, J= 5.2 Hz, 1H), 7.92 (br s, 1H), 7.88 (d, J = 9.5 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.67 (d, J= 8.1 Hz, 2H), 7.64-7.59 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.37-7.30 (m, 2H), 6.41 (d, J = 9.5 Hz, 1H), 4.60 (d, J = 5.2 Hz, 2H); LC-MS:

94.14%; 445.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 1.90 min.

0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 93.67%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 6.06 min. ACN + 5% 0.05% TFA (Aq): 0.05% TFA (Aq) + 5% ACN; 1.0 mL/min, Diluent: DMSO: ACN: water).

- 573 -

Synthesis of 2-nitro-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) pyridine (789): To a stirring solution of 5-bromo-2-nitropyridine 788 (1 g, 4.95 mmol) in 1, 4-dioxane (20 mL) under inert atmosphère were added bispinacolato diboron (1.9 g, 7.42 mmol), potassium acetate (1.45 g, 14.85 mmol) at RT and purged under argon atmosphère for 15 min; to this was added Pd(dppf)Cl₂ (362 mg, 0.49 mmol) and purged under argon atmosphère for 5 min, heated to 100 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were concentrated in vacuo to obtain the crude. The crude was triturated with diethylether (20 mL) and dried in vacuo to afford compound 789 (980 mg, crude) as an brown sticky solid. TLC: 20% MeOH/ CH₂C1₂ (Rf 0.2);

Synthesis of A-((2-(6-nitropyridin-3-yl) thiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo ¹⁵ [b,f\ [1,4] oxazepine-8-carboxamide (790): To a stirring solution /V-((2-chlorothiazol-5-yl) methyl)-! l-oxo-10, 11-dihydrodibenzo \b,f\ [1,4] oxazepine-8-carboxamide 783 (300 mg,

-5740.77 mmol) in 1, 2-dimethoxy ethane: H₂O (4: 1, 20 mL) under inert atmosphère were added 2nitro-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) pyridine 789 (600 mg, crude) and sodium carbonate (248 mg, 2.33 mmol) at RT and purged under argon atmosphère for 15 min. To this was added Pd(dppf)Cl₂ (57 mg, 0.07 mmol) and heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 4% MeOH/ CH₂C1₂ to afford compound 790 (200 mg, 54%) as an offwhite solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.3). LC-MS: 47.25 %; 474.0 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.249 min. 0.025% Aq.TFA+ 5% ACN: ACN + 5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of A%(2-(6-aminopyiïdin-3-yl) thiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] oxazepine-8-carboxamide (1707): To a stirring solution of compound 790 (100 mg, 0.21 mmol) in EtOH: H₂O (1:1, 10 mL) under inert atmosphère were added iron powder (118 mg, 2.11 mmol), ammonium chloride (113 mg, 2.11 mmol) at RT; heated to 90 °C for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and washed with 5% MeOH/ CH₂C1₂ (30 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 5% MeOH/ CH₂C1₂, triturated with EtOAc (10 mL), MeOH (10 mL) and dried in vacuo to afford 1707 (20 mg, 21%) as an off-white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.2); *H NMR (DMSO/400 MHz): δ 10.63 (s, 1H), 9.17 (t, J= 5.8 Hz, 1H), 8.42 (d, J= 2.0 Hz, 1H), 7.85-7.76 (m, 2H), 7.71-7.59 (m, 4H), 7.42 (d, J= 8.3 Hz, 1H), 7.397.30 (m, 2H), 6.53-6.47 (m, 3H), 4.61 (d, J= 5.5 Hz, 2H); LC-MS: 98.86%; 444.0 (M⁺+l)_;(column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.76 min. 0.025% Aq.TFA+ 5% ACN: ACN +5% 0.025% Aq TFA, 1.2 mL/min). HPLC (purity): 96.35%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 5.61 min. 5% ACN + 5% 0.05% TFA (Aq): ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: ACN: water).

Synthesis of 1770,1770-A

-575 -

Synthesis of/V-((2-(4-cyanophenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1,4] oxazepine-8-carboxamide (1770-A): To a stirring solution of 149 (150 mg, 0.58 mmol) in DMF (7.5 mL) under inert atmosphère were added EDCI.HC1 (168 mg, 0.88 mmol), HOBt (119 mg, 0.88 mmol), 4-(5-(aminomethyl) thiazol-2-yl) benzonitrile hydrochloride 227 (148 mg, 0.58 mmol) and diisopropylethylamine (0.32 mL, 1.76 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted withl0% MeOH/ CH2CI2 (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silicagel column chromatography using 5% MeOH/ CH₂C12 to afford 1770-A (120 mg, 45%) as white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.5); *Η NMR (DMSO-î7₆,400 MHz): δ 10.65 (s, 1H), 9.27 (t, J = 5.6 Hz, 1H), 8.07 (d, J= 8.5 Hz, 2H), 7.97-7.88 (m, 3H), 7.78 (dd, J= 7.7, 1.6 Hz, 1H), 7.70 (s, 1H), 7.66-7.60 (m, 2H), 7.43 (d, J= 8.4 Hz, 1H), 7.39-7.31 (m, 2H), 4.69 (d, J= 5.6 Hz, 2H); LC-MS: 99.16%; 453.2 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.35 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). HP LC (purity): 98.94%; (column; X-Select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 8.92 min. ACN + 5% 0.05% TFA (Aq): 0.05% TFA (Aq): 5% ACN; 1.0 mL/min, Diluent: ACN: water).

Synthesis of A-((2-(4-carbamoylphenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1,4] oxazepine-8-carboxamide (1770): To a stirring solution of 1770-A (80 mg, 0.17

-576 mmol) in DMSO (3 mL) under inert atmosphère were added potassium carbonate (122 mg, 0.88 mmol), 30% hydrogen peroxide (0.16 mL, 1.41 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water and the precipitated solid was filtered, washed with MeOH: EtOAc (1: 1, 20 mL). The obtained solid was suspended in 50% n-pcntane/ diethylether (10 mL) and stirred for 16 h, the solvent was decanted and the solid was dried in vacuo to afford 1770 (25 mg, 30%) as white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf. 0.3); ^!H NMR (DMSO-î/ô, 500 MHz): δ 10.62 (br s, IH), 9.29 (br s, IH), 8.06 (br s, IH), 7.96-7.94 (m, 4H), 7.84 (s, IH), 7.74 (dd, J = 7.7, 1.5 Hz, IH), 7.69 (s, IH), 7.62-7.54 (m, 2H), 7.44 (br s, IH), 7.37 (d, J = 8.3 Hz, IH), 7.34-7.27 (m, 2H), 4.67 (s, 2H); LC-MS: 99.24%; 471.0 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.96 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 99.45%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 6.96 min. ACN + 5% 0.05% TFA (Aq): 0.05% TFA (Aq) + 5% ACN; 1.0 mL/min, Diluent: DMSO: ACN: water).

Synthesis of methyl 4-(5-((1 l-oxo-10, 11-dihydrodibenzo [b,f] [1,4] oxazepine-8carboxamido) methyl) thiazol-2-yl) benzoate (1612-A): To a stirring solution of compound 149 (150 mg, 0.58 mmol) in DMF (6 mL) under inert atmosphère were added EDCI.HC1 (167 mg, 0.88 mmol), HOBt (119 mg, 0.88 mmol), methyl 4-(5-(aminomethyl) thiazol-2-yl) benzoate

-577 hydrochloride 636 (183 mg, 0.64 mmol) and diisopropylethylamine (0.50 mL, 2.94 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice-cold water (50 mL) and stirred for 10 min. The precipitated solid was filtered and dried in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2% MeOH/ CH2CI2 to afford compound 1612-A (160 mg, 56%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.5); ^lH NMR (DMSO-X 500 MHz): δ 10.64 (s, 1H), 9.25 (t, J= 5.6 Hz, 1H), 8.04 (s, 4H), 7.88 (s, 1H), 7.78 (dd, J = 7.8, 1.4 Hz, 1H), 7.70 (s, 1H), 7.66-7.61 (m, 2H), 7.43 (d, J= 8.4 Hz, 1H), 7.39-7.31 (m, 2H), 4.69 (d, J= 5.8 Hz, 2H), 3.87 (s, 3H); LC-MS: 97.06%; 485.9 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 2.45 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.26%; (column; X-select CSH C-18 (150 x 4.6 mm, 3.5 pm); RT 9.55 min. ACN + 0.5% TFA (Aq): 0.5% TFA (Aq) + ACN; 1.0 mL/min, Diluent: ACN: water).

Synthesis of 4-(5-((1 l-oxo-10, 11-dihydrodibenzo [b,f] [1, 4] oxazepine-8-carboxamido) methyl) thiazol-2-yl) benzoic acid (1612): To a stirring solution of 1612-A (60 mg, 0.12 mmol) in THF: H₂O (4: 1,5 mL) was added lithium hydroxide monohydrate (11 mg, 0.24 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (10 mL) and the pH was adjusted to with 2 N HCl to ~4. The precipitated solid was filtered washed with water (20 mL) diethyl ether (5 mL), n-pentane (10 mL) and dried in vacuo to afford 1612 (50 mg, 86%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.2); ^lH NMR (DMSO-î/₆,400 MHz): δ 13.12 (br s, 1H), 10.64 (s, 1H), 9.26 (t, J= 5.7 Hz, 1H), 8.02-7.99 (m, 4H), 7.87 (s, 1H), 7.78 (dd, J= 7.7, 1.7 Hz, 1H), 7.70 (s, 1H), 7.66-7.60 (m, 2H), 7.43 (d, J= 8.4 Hz, 1H), 7.39-7.31 (m, 2H), 4.68 (d, J = 5.5 Hz, 2H); LC-MS: 96.31%; 472.0 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.21 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 96.41%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 pm); RT 6.86 min.

ACN + 5% 0.5% TFA (Aq): 0.5% TFA (Aq) + 5% ACN; 1.0 mL/min, Diluent: ACN: water).

Synthesis of 1620

-578 -

Synthesis of ethyl 2-(4-(5-((1 l-oxo-10, 11 -dihydrodibenzo[b,f\[1,4]oxazepine-8carboxamido)methyl)thiazol-2-yl)phenoxy)acetate (791): To a stirring solution of compound 149 (75 mg, 0.29 mmol) in DMF (5 mL) under inert atmosphère were added ethyl 2-(4-(5(aminomethyl) thiazol-2-yl) phenoxy) acetate hydrochloride 639 (96 mg, 0.29 mmol), EDCI.HC1 (84 mg, 0.44 mmol), HOBt (60 mg, 0.44 mmol), and diisopropylethylamine (0.27 mL, 1.47 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice-cold water (50 mL) and extracted with EtOAc (2 x 150 mL). The combined organic extracts were dried over sodium sulfate, fdtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3% MeOH/ CH2CI2 to afford compound 791 (60 mg, 39%) as white solid. TLC: 5% MeOH/ CH₂C1₂ (Rf 0.6); *H NMR (DMSO-d_6; 500 MHz): δ 10.63 (s, 1H), 9.19 (t, J= 5.8 Hz, 1H), 7.81 (d, 7=9.0 Hz, 2H), 7.78 (dd,7=7.8, 1.4 Hz, 1H), 7.73-7.69 (m, 2H), 7.65-7.61 (m, 2H), 7.42 (d, J= 8.4 Hz, 1H), 7.36 (d, J= 8.1 Hz, 1H), 7.35-7.31 (m, 1H), 7.01 (d, J= 9.0 Hz, 2H), 4.84 (s, 2H), 4.64 (d, J= 5.5 Hz, 2H), 4.17 (q, 7=7.2 Hz, 2H), 1.21 (t, 7 = 7.1 Hz, 3H).

Synthesis of 2-(4-(5-((1 l-oxo-10, 11-dihydrodibenzo [b,f] [1, 4] oxazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) acetic acid (1620): To a stirring solution of compound 791 (60 mg, 0.11 mmol) in THF: H₂O (4: 1,6 mL) was added lithium hydroxi de monohydrate (24 mg, 0.56 mmol) at RT and stirred for 2 h. The reaction was monitored by TLC; after completion of

-579 the reaction, the volatiles were removed in vacuo. The residue was diluted water (50 mL) and the pH was acidified with 2 N HCl to ~6. The precipitated solid was filtered and dried in vacuo to afford 1620 (50 mg, 88%) as white solid. TLC: 10% MeOH/ CH2CI2 (Rf 0.2); 'H-NMR (DMSO-4 500 MHz): δ 13.05 (br s, 1H), 10.63 (s, 1H), 9.20 (t,J= 5.8 Hz, 1H), 7.81 (d, J = 9.0 Hz, 2H), 7.78 (dd, J = 7.8, 1.7 Hz, 1H), 7.72-7.69 (m, 2H), 7.65-7.61 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.36 (d, J= 8.1 Hz, 1H), 7.35-7.31 (m, 1H), 7.00 (d, J = 9.0 Hz, 2H), 4.74 (s, 2H), 4.64 (d, J= 5.5 Hz, 2H); LC-MS: 98.03%; 501.9 (M⁺+l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 pm); RT 2.11 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 99.39%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 pm); RT 7.71 min; ACN + 0.5% TFA (Aq): 0.5% TFA (Aq) : 5% ACN; 1.0 mL/min, Diluent: ACN: water).

Synthesis of/V-((2-(4-(3-hydroxypropoxy) phenyl) thiazol-5-yl) methyl)-l l-oxo-10, 11dihydrodibenzo [b, f] [ 1, 4] oxazepine-8-carboxamide (792): To a stirring solution of 1 l-oxo10, 11-dihydrodibenzo [b, f] [1,4] oxazepine-8-carboxylic acid 149 (1 g, 3.94 mmol) in DMF (30 mL) were added 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) propan-l-ol hydrochloride 734 (1.3 g, 4.33 mmol), EDCI.HC1 (1.13 g, 5.9 mmol), HOBt (797 mg, 5.9 mmol) followed by diisopropylethylamine (3.43 mL, 19.68 mmol) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 16 h. The reaction was monitored by TLC and LCMS; after completion of the reaction, the reaction mixture was diluted with ice cold

- 580 water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 1-5% MeOH/ CH2CI2 followed by triturations with 5% MeOH/ CH2CI2 (2x5 mL) to afford compound 792 (800 mg, 41%) as an off white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf 0.5); *H NMR (400MHz, DMSO-7₆): δ 10.64 (s, 1H), 9.20 (t, J = 5.8 Hz, 1H), 7.83-7.76 (m, 3H), 7.72-7.68 (m, 2H), 7.66-7.60 (m, 2H), 7.43 (d, J= 8.4 Hz, 1H), 7.38-7.31 (m, 2H), 7.01 (d, J= 8.9 Hz, 2H), 4.63 (d, J= 5.6 Hz, 2H), 4.56 (t, J= 5.1 Hz, 1H), 4.08 (t, J= 6.3 Hz, 2H), 3.55 (q, J= 6.0 Hz, 2H), 1.91-1.82 (m, 2H); LC-MS: 95.30%; 502.2 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 2.49 min. 2.5 mM NH4OOCH in water + 5% ACN: ACN + 5% 2.5 mM NH4OOCH in water, 0.8 mL/min).

Synthesis of 3-(4-(5-((1 l-oxo-10, 11-dihydrodibenzo [b, f] [1, 4] oxazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) propyl methanesulfonate (793): To a stirring solution of compound 792 (200 mg, 0.4 mmol) in CH₂C1₂ (10 mL) were added triethylamine (0.33 mL, 2.39 mmol) followed by methanesulfonyl chloride (0.1 mL, 1.2 mmol) at 0 °C under inert atmosphère. The reaction mixture was gradually warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with CH₂C1₂ (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 793 (250 mg) as pale brown viscous syrup. This crude material was taken to next step without further purification. TLC: f0% MeOH/ CH₂C1₂ (Rf 0.6); LC-MS: 46.00%; 580.1 (M⁺+l); (column; Kinetex EVO C-18 (50 x 3.0 mm, 2.6 um); RT 2.85 min. 2.5 mM NH4OOCH in water + 5% ACN: ACN + 5% 2.5 mM NH4OOCH in water, 0.8 mL/min).

Synthesis of A-((2-(4-(3-morpholinopropoxy) phenyl) thiazol-5-yl) methyl)-! l-oxo-10, 11dihydrodibenzo [b, f] [1,4] oxazepine-8-carboxamide (11161): To a stirring solution of compound 793 (180 mg, crude) in THF (5 mL) was added morpholine (0.11 mL, 1.29 mmol) in a sealed tube at RT under inert atmosphère. The reaction mixture was heated to 70 °C and stirred for 16 h. The reaction was monitored by TLC and LCMS; after completion of the

- 581 reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2-10% MeOH/ CH₂C1₂ followed by trituration with 10% MeOH/ CH₂C1₂ (2x2 mL) to afford 11161 (80 mg, 32%) as an off-white solid. TLC: 10% MeOH/ CH₂C1₂ (Rf. 0.4); 'H NMR (400MHz, DMSOV): δ 10.64 (s, 1H), 9.19 (t, J= 5.8 Hz, 1H), 7.82-7.76 (m, 3H), 7.72-7.69 (m, 2H), 7.66-7.61 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.39-7.31 (m, 2H), 7.01 (d, J= 8.9 Hz, 2H), 4.63 (d, J= 5.6 Hz, 2H), 4.06 (t, J = 6.4 Hz, 2H), 3.56 (t, J= 4.6 Hz, 4H), 2.44-2.33 (m, 6H), 1.91-1.85 (m, 2H); LC-MS: 92.40%; 571.2 (M⁺+l); (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.85 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 94.04%; (column; X-Select CSHC-18 (150 x 4.6 mm, 3.5 pm); RT 5.75 min. 0.05% TFA + 5% ACN: ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: ACN : H₂O : DMSO).

Synthesis of 11160

Synthesis of 1 l-oxo-2V-((2-(4-(3-(piperidin-l-yl) propoxy) phenyl) thiazol-5-yl) methyl)-10, 11dihydrodibenzo [b,f [1, 4] oxazepine-8-carboxamide (11160): To a stirring solution of 3-(4-(5((1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] oxazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) propyl methanesulfonate 793 (250 mg, 0.43 mmol) in THF (5 mL) was added piperidine 472 (0.21 mL, 2.15 mmol) at RT under inert atmosphère. The reaction mixture was heated to 70 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction mixture was diluted with water (50 mL), and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography

-582 - using 1-6% MeOH/ CH2CI2 which was further triturated with 10% MeOH/CFLCF (2x5 mL) to afford 11160 (90 mg, 36%) as an off-white solid. TLC: 10% MeOH/CH2C12 (Rf. 0.3); *H NMR (400 MHz, DMSO-d₆): δ 10.65 (s, 1H), 9.22 (t, J= 5.7 Hz, 1H), 7.85-7.74 (m, 3H), 7.717.68 (m, 2H), 7.66-7.60 (m, 2H), 7.42 (d, J= 8.4 Hz, 1H), 7.38-7.28 (m, 2H), 7.02 (d, J= 8.9 Hz, 2H), 4.63 (d, J= 5.5 Hz, 2H), 4.08 (t, J= 6.1 Hz, 2H), 2.92-2.62 (m, 4H), 2.46-2.35 (m, 2H), 2.03-2.01 (m, 2H), 1.61-1.63 (m, 4H), 1.46-1.44 (m, 2H); LC-MS: 99.16%; 569.3 (M⁺+l); (column; Ascentis Express C-18, (50 * 3.0 mm, 2.7 pm); RT 1.87 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 99.01%; (column; X-Select CSH-C-18 (150 x 4.6 mm, 3.5 pm); RT 6.03 min. 0.05% TFA + 5% ACN: ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: DMSO: ACN).

Synthesis of A-((2-(4-(3-(diethylamino) propoxy) phenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo [b,f\ [1,4] oxazepine-8-carboxamide hydrochloride (11162): To a stirring solution of 3-(4-(5-((1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1,4] oxazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) propyl methanesulfonate 793 (200 mg, 0.34 mmol) in THF (10 mL) was added diethylamine hydrochloride 387 (1 mL, 1.04 mmol) at RT under inert atmosphère. The reaction mixture was heated to 80 °C and stirred for 16 h in a sealed tube. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH₂C1₂ to afford 11162 (80 mg, 41%) as an off white solid. TLC: 5% MeOH/CH₂Cl₂ (Rf. 0.2); ’H NMR (400 MHz, DMSO-d₆): δ 10.65 (s, 1H), 9.86 (br s, 1H), 9.23 (t, J= 5.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.78 (dd, J= Ί.Ί, 1.6 Hz, 1H), 7.71-7.69 (m, 2H), 7.64-7.61 (m, 2H), 7.43 (d, J= 8.4 Hz, 1H), 7.38-7.29 (m, 2H), 7.03 (d, J = 8.9 Hz, 2H), 4.63

- 583 (d, J= 5.6 Hz, 2H), 4.12 (t, J = 6.0 Hz, 2H), 3.20-3.11 (m, 6H), 2.12 (br s, 2H), 1.21 (br s, 6H); LC-MS: 95.66%; 557.1 (M⁺+l); (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 pm); RT 1.97 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.95%; (column; X-Select CSH-C-18 (150 x 4.6 mm, 3.5 pm); RT 5.94 min. 0.05%

TFA + 5% ACN: ACN + 5% 0.05% TFA; 1.0 mL/min, Diluent: H₂O: ACN).

Synthesis of terLbutyl (4-(5-((1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] oxazepine-810 carboxamido) methyl) thiazol-2-yl) benzyl) carbamate (795): To a stirring solution of A-((2chlorothiazol-5-yl) methyl)-1 l-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] oxazepine-8carboxamide 783 (150 mg, 0.38 mmol) in 1, 2 dimethoxy ethane: H₂O (4: 1,6 mL) were added tert-butyl (4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) benzyl) carbamate 794 (259 mg, 0.77 mmol), sodium carbonate (144 mg, 1.36 mmol) and purged under argon atmosphère for 15 min. To this was added Pd(PPh₃)₄ (45 mg, 0.039 mmol) at RT; heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion the reaction mixture was diluted with water (100 mL) and extracted with 10% MeOH/ CH₂C1₂ (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 4% MeOH/

- 584 -

CH2CI2 to afford compound 795 (150 mg, 69%) as white solid. TLC: 5% MeOH/ CH2CI2 (Ry 0.4); ‘H-NMR (DMSO-4 400 MHz): δ 10.77 (s, 1H), 9.35 (t, J= 5.6 Hz, 1H), 7.97 (d, J= 8.1 Hz, 2H), 7.94-7.89 (m, 2H), 7.84 (s, 1H), 7.80-7.74 (m, 2H), 7.59-7.54 (m, 2H), 7.52-7.43 (m, 4H), 4.79 (d, J = 5.5 Hz, 2H), 4.29 (d, J = 5.8 Hz, 2H), 1.53 (s, 9H); LC-MS: 94.24%; 557.1 (M⁺+l); (column; X Select CSH C-18, (50 x 3.0 mm, 2.5 pm); RT 3.19 min. 2.5 mM Aq. NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq.NH4OOCH, 0.8 mL/min).

Synthesis of V-((2-(4-(aminomethyl) phenyl) thiazol-5-yl) methyl)-1 l-oxo-10, 11dihydrodibenzo [b, J] [1, 4] oxazepine-8-carboxamide hydrochloride (1712): To a stirring solution of compound 795 (150 mg, 0.26 mmol) in CH₂C1₂ (3 mL) under inert atmosphère was added 4 N HCl in 1, 4-dioxane (1.5 mL) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with CH₂C1₂ (2x5 mL) and dried in vacuo to afford 1712 (95 mg, 72%) as white solid. TLC: 10% MeOH/ CH2C1₂ (Ry 0.2); ‘H-NMR (DMSO-riô, 400 MHz): δ 10.67 (s, 1H), 9.30 (t, J= 5.8 Hz, 1H), 8.40 (br s, 3 H), 7.93 (d, J= 8.4 Hz, 2H), 7.81 (s, 1H), 7.78 (dd, J= 7.7, 1.7 Hz, 1H), 7.71 (s, 1H), 7.67-7.60 (m, 2H), 7.57 (d, J= 8.4 Hz, 2H), 7.43 (d, J = 8.3 Hz, 1H), 7.38-7.30 (m, 2H), 4.66 (d, J= 5.6 Hz, 2H), 4.06 (q, J= 5.7 Hz, 2H); LC-MS: 99.11%; 457.0 (M⁺+l);. (column; Ascentis Express Cl8, (50 x 3.0 mm, 2.7 pm); RT 1.79 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity): 98.28%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 pm); RT 5.61 min. ACN + 5% 0.05% TFA (Aq): 0.05% TFA (Aq) + 5% ACN; 1.0 mL/min, Diluent: ACN: water).

Example 2: Assay Measuring Activity of Compounds on Viral Production in and on Viability of AD38 Cells

AD38 cells grown in a 175 cm flask with “Growth Medium” (DMEM/F12 (1:1) (cat# SH30023.01, Hyclone, IX Pen/step (cat#: 30-002-CL, Mediatech, Inc), 10% FBS (cat#: 101, Tissue Culture Biologics), 250 pg/mL G418 (cat#: 30-234-CR, Mediatech, Inc), 1 pg/mL Tétracycline (cat#: T3325, Teknova)) were detached with 0.25% trypsin. Tetracycline-free

- 585 “treatment medium” (15 mL DMEM/F12 (1:1) (cat# SH30023.01, Hyclone, Ix Pen/step (cat#: 30-002-CL, Mediatech, Inc), with 2% FBS, Tet-system approved (cat#: 631106, Clontech) were then added to mix and spun at 1300 rpm for 5 min. Pelleted cells were then resuspended/washed with 50 mL of IX PBS 2 times and 10 mL Treatment Medium one time. AD38 cells were then re-suspended with 10 mL of Treatment Medium and counted. Wells of a collagen coated 96-well NUNC microtiter plate were seeded at 50,000/well in 180 pL of Treatment Medium, and 20 pL of in treatment media with either 10% DMSO (Control) or a 10X solution of compound in 10% DMSO was added. Plates were incubated for 6 days at 37 °C.

Viral load production was assayed by quantitative PCR of the core sequence. Briefly, 5 pL of clarified supematant was added to a PCR reaction mixture that contained forward primers HBV-f 5'-CTGTGCCTTGGGTGGCTTT-3', Reverse primers HBV-r 5'AAGGAAAGAAGTCAGAAGGCAAAA-3' and Fluorescent TaqMan™ Probes HBV-probe 5'-FAM/AGCTCCAAA/ZEN/TTCTTTATAAGGGTCGATGTCCATG/3IABkFQ -3' in Quanta Biosciences PerfeCTa® qPCR Toughmix®, and was subsequently on an Applied Biosystems VIIA7 in a final volume of 20 pL. The PCR mixture was incubated at 45 °C for 5 minutes, then 95 °C for 10 min, followed by 40 cycles of 10 seconds at 95 °C and 20 seconds at 60 °C. Viral load was quantitated against known standards by using ViiA™ 7 Software. Viral load in the supematant from wells with treated cells were compared against viral load in supematant from DMSO control wells (> 3 per plate).

At the end of compound treatment period cell viability was assessed using a Promega CellTiterGlo protocol. Ail supematant was removed the previously treated 96-well microtiter plate, and 50 pL Tetracycline-free treatment medium (DMEM/F12 (1:1), lx Pen/step (cat#: 30-002-CL, Mediatech, Inc), with 2% FBS, Tet-system approved (cat#: 631106, Clontech), and 1% DMSO was added back to each well. Another 50 pL of CellTiter-Glo reagent solution (Promega, G7573) was then added at room température and the contents mixed for 2 minutes on an orbital shaker to induce cell lysis. This was followed by incubation at room température for 10 minutes to stabilize the luminescent signal. The luminescence was recorded for 0.2 seconds per well on a Tecan multimode platereader (Infinité Ml000 pro). The luminescent signal from each well

- 586 was normalized against that of untreated (DMSO) control wells. Ail results were reported percent viability (with Controls being 100%).

Table 5 - Compounds and Biological activity

Example	AD38 Viral Load (%) (VL with cmpd/VL in DMSO control) at 10 μΜ	AD38 Viability Normalized Resuit (cmpd/DMSO %) at 10 μΜ
1425	0.6	100
1432	21.8	101
1473	26.5	79
1496	9.6	57
1424	0.5	97
1431	5.5	103
1421	1.3	104
1525	0.2	104
1528	0.8	76
1526	0.8	94
1535	0.8	84
1546	2.2	97
1541	3.7	98
1544	2.6	88
1551	0.4	99
1557	0.6	98
1558	0.5	106
1548	0.4	97
1552	0.4	102
1559	0.7	87
1529	2.0	97
1553	0.5	107

-587 -

1562	0.9	97
1549	106.2	105
1556	1.6	105
1594	0.9	105
1592	1.3	99
1561	10.3	96
1566	0.6	95
1555	1.0	89
1595	0.3	109
1550	4.0	96
1584	1.4	101
1585	64.1	96
1589	80.0	98
1581	34.4	93
1587	2.8	99
1590	6.2	95
1596	3.8	25
1598	1.4	97
1606	3.0	91
1611	1.4	100
1618	1.9	100
1586	27.9	83
1599-A	50.9	98
1604	0.9	82
1605	0.7	96
1607	52.8	98
1612-A	12.4	101
1617	2.2	101
1619	1.3	95

- 588 -

1620	41.9	103
1583	1.0	0
1599	5.9	61
1603	32.8	108
1608	12.4	98
1612	6.9	105
1616	105.0	103
1621	25.9	81
1624	0.8	98
1602	59.8	97
1614	8.5	98
1615	54.9	103
1626	2.7	99
1629	3.2	107
1580	104.3	102
1625	51.9	96
1648	9.9	95
1661	45.2	90
1627	6.0	63
1628	21.8	95
1636	76.9	95
1650	58.8	82
1679	1.1	94
1698	2.7	91
1613-A	11.5	95
1637	2.3	101
1686	58.4	102
1687	49.2	102
1691	77.1	89

-589 -

1645	6.7	101
1645-B	77.8	100
1654	0.5	94
1660	86.8	102
1668	23.4	106
1694	61.1	91
1704	47.6	96
1732	18.8	100
1734	10.6	96
1645-A	0.3	98
1654-A	2.6	68
1680	15.0	94
1696	0.8	109
1664	0.6	99
1665	2.7	90
1673	3.2	105
1697	5.5	90
1703	3.1	93
1705	3.7	93
1712-1	5.2	97
1749	54.3	109
1752	29.8	98
1764	1.1	107
1770-A	29.8	100
1666	0.9	98
1670	0.9	102
1746	5.6	92
1747	3.0	95
1750	1.1	107

-590 -

1753	2.4	97
1758	3.8	15
1760	6.4	94
1761	10.7	97
1766	1.3	98
1770	32.5	77
1675	2.3	115
1677-A	2.3	103
1695	22.9	102
1701	2.1	94
1702	5.3	102
1735	3.1	92
1736-A	14.1	97
1738-A	1.8	104
1751	2.8	18
1754	1.6	93
1755	0.4	93
1667	0.5	93
1710	39.9	96
1711	6.5	96
1714-A	49.2	106
1736	6.8	94
1737	7.2	112
1738	2.9	93
1763	12.9	93
1769	43.3	101
1772	7.1	109
1653	65.4	108
1671-A	0.7	111

-591 -

1767	0.5	94
1669	13.1	104
1671	18.2	100
1677-B	2.4	89
1700	9.2	105
1706	57.5	103
1708	0.8	90
1709-A	29.5	106
1672	0.6	101
1674	0.3	121
1709	51.1	94
1768	0.4	94
1806-A	0.3	66
1707	10.7	88
1804-A	6.6	90
1805	0.6	97
1806	0.8	105
1804	0.5	103
1815	0.2	88
1814	0.9	92
1817	0.3	97
1826	11.8	91
1838	1.4	113
1819	0.5	118
1820	3.2	105
1831	3.8	112
1832	14.1	98
1911	0.4	111
1855	2.5	102

-592 -

1905	0.3	109
1910	19.0	94
1913	68.1	111
1915	15.7	100
1842	46.5	109
1857	1.5	107
1861	5.9	94
1862	19.9	107
1863	9.4	106
1917	1.1	108
1839	6.6	96
1840	3.2	107
1856	1.3	96
1860	7.5	98
1866	2.9	98
1877	0.2	96
1878	1.0	103
1914	120.4	77
1821	0.5	102
1833	67.4	102
1858	0.7	103
1859	2.7	89
1864	3.0	93
1904	0.5	89
1816	0.2	82
1835-A	0.3	89
1865	1.0	94
1921	1.2	101
1935	0.7	112

-593 -

1893	2.0	91
1907	0.5	85
1879-A	2.5	121
1942	3.0	106
1823-A	5.8	92
1835	12.3	94
1841	9.1	104
1879	7.2	104
1908	7.0	94
1916	15.5	103
1932	2.2	101
1974	15.3	103
1823	5.2	96
1920	48.8	85
1922	60.3	39
1930	23.8	91
1934	40.0	69
1936	13.5	94
1941	5.2	84
1975	1.0	63
1885-A	4.5	107
1909	1.3	95
1929	1.2	93
1931	8.5	97
1822	1.5	89
1951	1.8	101
1958	1.5	91
1971	7.0	87
1943	1.9	98

-594-

1944	2.5	93
1947	2.3	101
1949	2.9	99
1954	0.5	106
1957	1.5	94
1960	0.8	106
1880	6.7	104
1880-A	0.7	124
1886	1.5	106
1927	4.7	92
1959	5.0	92
1970	1.5	121
1993	0.5	96
1906	7.8	89
1992	5.0	89
11002-A	1.0	106
11016-A	6.7	103
11017-A	8.8	102
1952	0.8	106
1953	0.4	118
1956	2.3	88
11016	38.8	106
11017	21.0	86
11019	14.3	93
11019-A	1.0	95
1901-A	3.0	118
1901-B	69.4	108
1973	33.7	100
11004	5.5	94

- 595 -

11018	3.9	98
11018-A	0.6	104
11041	47.4	94
11042	0.8	109
1972	23.5	100
1981	0.2	105
11001	1.7	77
11002	0.9	90
11003	0.3	97
11007-A	0.9	75
11043	12.0	100
11044	5.1	124
1881	0.8	108
11006	1.3	97
11007	2.0	101
C38-02	0.5	94
11074	0.6	103
1995	16.3	103
11005	1.9	102
11032-A	12.9	110
11038	2.0	99
11067	2.5	99
11073	2.2	94
11078	45.7	96
1889	4.6	98
1995-A	2.4	107
11039	1.9	92
11040	1.9	104
11053	3.6	104

-596 -

11079	3.3	102
11082	1.2	95
11083	0.8	62
1882	1.0	103
1990	4.1	98
11054	14.1	102
11055	4.0	94
11056	0.8	96
1988	1.3	103
1991	2.0	98
11048	1.2	103
11051	1.2	103
11057	1.0	101
11077	0.9	90
1989	2.5	90
1994	0.9	92
11046	0.9	100
11047	1.4	96
11050	0.7	96
11080	1.4	84
11084	9.7	91
11086	4.7	88
1998	3.7	99
11011	5.3	98
11045	0.6	94
11085	3.4	88
11087	7.1	103
11088	17.9	100
11093	4.6	102

: : //<WtX8087 ³

-597 -

11094	0.6	94
11102	0.5	93
11104-A	0.9	74
C20-01	1.5	98
C20-02	0.5	95
C38-01	1.3	99
1888	1.2	100
11028	5.2	92
11029	5.3	105
11063	1.2	102
11063-A	0.4	104
11091	1.3	89
11103	2.5	102
11104	9.4	97
11116	0.9	97
11131	2.0	88
1997	9.7	104
11026	5.5	100
11049	0.8	89
11063-B	5.4	95
11065	1.2	66
11066	0.4	104
11092	0.5	101
11099	3.9	90
11101	1.9	85
11118	1.9	95
11134	1.4	90
11135	1.8	91
11106	3.3	97

- 598 -

11106-A	3.6	90
11137	3.6	96
11148	0.3	98
11149	0.2	100
11032	51.7	103
11033	17.1	95
11064	4.1	85
11100	6.8	102
11150	0.4	100
11152	1.6	96
C51-01	0.4	99
C51-02	0.2	98
11105	1.6	95
11107-A	7.7	100
11112	4.0	100
11117-A	0.3	110
11142	0.8	87
11158	6.4	100
11160	17.7	104
11162	8.7	104
11182	0.7	104
1996	17.4	100
11061	0.9	95
11107	6.4	96
11108	11.2	95
11108-B	0.8	101
11113	4.9	92
11138	1.0	96
11139	5.5	104

-599 -

11140	5.5	99
11161	1.7	104
C44-01	2.6	97

INCORPORATION BY REFERENCE

Ail publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for ail purposes as if each individual publication or 5 patent was specifically and individually incorporated by reference. In case of conflict, the présent application, including any définitions herein, will control.

EQUIVALENTS

While spécifie embodiments of the subject invention hâve been discussed, the above spécification is illustrative and not restrictive. Many variations of the invention will become 10 apparent to those skilled in the art upon review of this spécification. The full scope of the invention should be determined by reference to the daims, along with their full scope of équivalents, and the spécification, along with such variations.

Unless otherwise indicated, ail numbers expressing quantities of ingrédients, reaction conditions, and so forth used in the spécification and daims are to be understood as being 15 modified in ail instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this spécification and attached daims are approximations that may vary depending upon the desired properties sought to be obtained by the présent invention.

600

Claims

What is claimed is:

1. A compound represented by:

wherein

Y is S(O)_y, wherein y is 2;

R^z is H;

R^m and R^m are H, Ci_₆alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), and C2-6alkenyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl);

R^c is H;

R⁷⁷ is selected from the group consisting of H, halogen, cyano, and Ci^alkyl;

R⁷⁸ is selected from the group consisting of Ci^alkyl substituted with one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, and cyano; phenyl substituted with one, two, three or four substituents each independently selected 73 2 79 from the group consisting of R ; and X -Ci.6alkylene-R ;

X² is selected from the group consisting of S(O)_W (wherein w is 0,1, or 2), O, -C(O)and NR’;

R⁷⁹ is selected from the group consisting of H, hydroxyl, halogen, Ci-éalkyl, -C(O)-OCi-6alkyl, heterocycle (optionally substituted by one or more substituents selected from the group consisting of halogen, NR’R’, -C(O)-O-Ci-6alkyl, carboxy and Ci-ealkyl), -C(O)NR’R”, -C (=NH)-NR’R”, heteroaryl, phenyl (optionally substituted by one or more substituents selected from the group consisting of halogen, NR’R’, -C(O)-O-Ci_6alkyl, carboxy, Ci-6alkoxy, and Ci-ealkyl), C2-6alkenyl, C2-6alkynyl, C].6alkoxy, carboxy, NR’R”, -C(O)-Ci. ₆alkyl, C₃.₆cycloalkyl, -NR’-C(O)- C₁.₆alkyl, NR’-C(O)- O-Ci_₆alkyl, -S(O)_w-Ci.₆alkyl (where

601 w is 0, 1 or 2), -S(O)_W-NR’R” (where w is 0, 1 or 2), and -NR’-S(O)_W- Ci.₆alkyl (where w is 0, 1 or 2));

R⁷³ is selected from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, oxo, Ci-ealkyl, -C(O)-O-C]_6alkyl, heterocycle (optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, NR’R’, -C(O)-O-Ci. 6alkyl, carboxy and Ci.6alkyl), -C(O)-NR’-Ci-6alkyl, -C (=NH)-NR’R”, heteroaryl, phenyl, C2. galkenyl, C2.6alkynyl, Ci_6alkoxy, carboxy, oxo, NR’R”, -C(O)-Ci_6alkyl, - C3-6cycloalkyl, NR’-C(O)- Ci-ealkyl, NR’-C(O)- O-Ci-ealkyl, -S(O)w-Ci-6alkyl (where w is 0, 1 or 2), -S(O)WNR’R” (where w is 1, 2 or 3), -NR’-S(O)W- Ci/alkyl (where w is 0, 1 or 2), C(O)-NR’- Ci. 6alkyl, CCOj-C^alkylene-NR’- C(O)-O- Cj.6alkyl, X²- R⁷⁹; and X²-Ci.6alkylene-R⁷⁹;

R’ is selected, independently for each occurrence, from H, methyl, ethyl, cyclopropyl, cyclobutyl, and propyl;

R’ ’ is selected, independently for each occurrence, from H, methyl, ethyl, propyl, (optionally substituted by hydroxyl), butyl (optionally substituted by hydroxyl), -C(O)-methyl and -C(O)-ethyl, or R’ and R’ ’ taken together with the nitrogen to which they are_attached may--------form a 4-7 membered heterocycle optionally substituted by one, two or more substituents selected from the group consisting of halogen, hydroxyl, NH₂, -C(O)-O-Ci-3alkyl, -C(O)-Ci. ₃alkyl, carboxy, oxo, and Ci.₃alkyl;

each of moieties R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently selected for each occurrence from the group consisting of hydrogen, Ci^alkyl, Ci/alkoxy, C₂.₆alkynyl, C₂. ealkenyl, halogen, hydroxyl, nitro, cyano, and NR’R”;

wherein for each occurrence, Ci^alkyl, C₂.6alkenyl or C₂.6alkynyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C₃.6cycloalkyl, C₂.4alkenyl, C₂.4alkynyl, Ci.₃alkoxy, NR’R”, -NR’-S(O)_W- Ci_₂alkyl (where w is 0, 1 or 2), NR’-C(O)-Ci.₃alkyl, NR’-C(O)- O-Ci. ₃alkyl, and S(O)_w-NR’R”(where w is 0, 1 or 2); Ci-éalkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci.₃alkyl, NR’R”, -NR’-S(O)_W- Ci.₂alkyl (where w is 0, 1 or 2), and S(O)_W-NR’R” (where w is 0, 1 or 2); Ci.ôalkylene may be optionally substituted by a substituent selected from the group consisting of C₃.6cycloalkyl, hydroxyl, cyano, and halogen;

and pharmaceutically acceptable salts and N-oxides thereof.

602
2. The compound of claim 1, wherein R⁷⁸ is selected from the group consisting of CF₃, cyano, and phenyl substituted with one, two, three or four substituents each independently selected from the group consisting of R⁷³.
3. The compound of claim 1, wherein R⁷⁷ is selected from the group consisting of H, CH₃ and CF₃.
4. The compound of claim 1, wherein R⁷ is H or halogen.
5. The compound of claim 1, wherein R¹⁰ is H, halogen or methyl.
6. The compound of claim 1, wherein each of R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is H.
7. The compound of claim 1, wherein R is H.
8. A pharmaceutically acceptable composition comprising a compound of claim 1, and a pharmaceutically acceptable excipient.
9. A compound of claim 1 for use in a method of treating a hepatitis B infection in a patient in need thereof, the method comprising administering an effective amount of the compound to the patient.- _ _ — —--
10. A compound of claim 1 for use in a method of treating a hepatitis B infection in a patient in need thereof, the method comprising administering a first compound selected from a compound of claim 1, and optionally administering one or more additional compounds to the patient.
11. A compound of claim 1 for use in a method of treating a hepatitis B infection in a patient in need thereof, the method comprising administering an amount of the compound, and administering another HBV capsid assembly promoter to the patient.
12. A compound of claim 1 for use in a method of treating a hepatitis B infection in a patient in need thereof, the method comprising administering a first compound selected from a compound of claim 1, and one or more other HBV agents to the patient, wherein each of the HBV agents is selected from the group consisting of HBV capsid assembly promoters, HBF viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg sécrétion inhibitors, disruptors of nucleocapsid formation, cccDNA formation inhibitors, antiviral core protein mutant, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-7/9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinase inhibitors, and STING agonists.
13. A compound represented by

or pharmaceutically acceptable salts thereof.
14. A pharmaceutically acceptable composition comprising the compound of claim 13.
15. The compound of claim 13 for use in a method of treating a hepatitis B infection.

_ ABSTRACT__ _ __

The présent disclosure provides, in part, compounds having allosteric effector properties against Hepatitis B virus Cp. Also provided herein are methods of treating viral infections, such as hepatitis B, comprising administering to a patient in need thereof a disclosed

5 compound.