WO2011045257A1 - Novel n-substituted-pyrrolidines as inhibitors of mdm2-p-53 interactions - Google Patents

Novel n-substituted-pyrrolidines as inhibitors of mdm2-p-53 interactions Download PDF

Info

Publication number
WO2011045257A1
WO2011045257A1 PCT/EP2010/065159 EP2010065159W WO2011045257A1 WO 2011045257 A1 WO2011045257 A1 WO 2011045257A1 EP 2010065159 W EP2010065159 W EP 2010065159W WO 2011045257 A1 WO2011045257 A1 WO 2011045257A1
Authority
WO
WIPO (PCT)
Prior art keywords
chloro
phenyl
fluoro
coch
dimethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2010/065159
Other languages
French (fr)
Inventor
David Joseph Bartkovits
Xin-Jie Chu
Jin-Jun Liu
Tina Morgan Ross
Zhuming Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Original Assignee
F Hoffmann La Roche AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to IN2487DEN2012 priority Critical patent/IN2012DN02487A/en
Priority to CN2010800461741A priority patent/CN102548963A/en
Priority to CA2774512A priority patent/CA2774512A1/en
Priority to JP2012533592A priority patent/JP2013507416A/en
Priority to MX2012003982A priority patent/MX2012003982A/en
Priority to AU2010305914A priority patent/AU2010305914A1/en
Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Priority to EP10768450A priority patent/EP2488491A1/en
Priority to BR112012008485A priority patent/BR112012008485A2/en
Publication of WO2011045257A1 publication Critical patent/WO2011045257A1/en
Priority to IL218018A priority patent/IL218018A0/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to pyrrolidine-2-carboxamide derivatives I which act as antagonists of mdm2 interactions and hence are useful as potent and selective anticancer agents.
  • p53 is a tumor suppresser protein that plays a central role in protection against development of cancer. It guards cellular integrity and prevents the propagation of permanently damaged clones of cells by the induction of growth arrest or apoptosis. At the molecular level, p53 is a transcription factor that can activate a panel of genes implicated in the regulation of cell cycle and apoptosis.
  • p53 is a potent cell cycle inhibitor which is tightly regulated by MDM2 at the cellular level. MDM2 and p53 form a feedback control loop.
  • MDM2 can bind p53 and inhibit its ability to transactivate p53-regulated genes.
  • MDM2 mediates the ubiquitin-dependent degradation of p53.
  • p53 can activate the expression of the MDM2 gene, thus raising the cellular level of MDM2 protein. This feedback control loop insures that both MDM2 and p53 are kept at a low level in normal proliferating cells.
  • MDM2 is also a co factor for E2F, which plays a central role in cell cycle regulation.
  • MDM2 to p53 The ratio of MDM2 to p53 (E2F) is dysregulated in many cancers. Frequently occurring molecular defects in the pl6INK4/pl9ARF locus, for instance, have been shown to affect MDM2 protein degradation. Inhibition of MDM2-p53 interaction in tumor cells with wild-type p53 should lead to accumulation of p53, cell cycle arrest and/or apoptosis. MDM2 antagonists, therefore, can offer a novel approach to cancer therapy as single agents or in combination with a broad spectrum of other antitumor therapies. The feasibility of this strategy has been shown by the use of different macromolecular tools for inhibition of MDM2-p53 interaction (e.g.
  • MDM2 also binds E2F through a conserved binding region as p53 and activates E2F-dependent transcription of cyclin A, suggesting that MDM2 antagonists might have effects in p53 mutant cells.
  • the present invention relates to pyrrolidine-2-carboxamide derivatives I which act as antagonists of mdm2 interactions and hence are useful as potent and selective anticancer agents.
  • the present compounds are of the general formula (I)
  • Another aspect of the present invention relates to a pharmaceutical formulation comprising at least one compound of the formulae (I), (IA), (IB) and (IC):
  • X, Y, R ls R 2 , R 3 , R 4 , and R 5 are as described herein and enantiomers and pharmaceutically acceptable salts and esters thereof for use as a medicament, preferably for use as a medicament in the treatment of cancer.
  • Cancer includes in particular solid tumors and more particularly breast, colon, lung and prostate tumors.
  • a further aspect of the present invention relates to the use of a compound of formula (I)
  • X, Y, R ls R 2 , R 3i R 4 , and R 5 are as described herein and enantiomers and pharmaceutically acceptable salts and esters thereof for the manufacture of medicaments for the treatment of cancer, in particular solid tumors, more particularly breast, colon, lung and prostate tumors.
  • Yet another aspect of the present invention relates to a process for the manufacture of the compound of formula (I)
  • a benzodioxyl group halogen, hydroxy, CN, CF 3 , NH 2 , N(H, lower-alkyl), N(lower-alkyl) 2 , amino carbonyl, carboxy, N0 2 , lower-alkoxy, thio-lower-alkoxy, lower-alkylsufonyl, aminosulfonyl, lower-alkylcarbonyl, lower-alkylcarbonyloxy, lower-alkoxycarbonyl, lower-alkyl-carbonyl-NH, fluoro-lower-alkyl, fluoro-lower-alkoxy, lower-alkoxy-carbonyl-lower-alkoxy, carboxy-lower-alkoxy, carbamoyl- lower-alkoxy, hydroxy- lower-alkoxy, NH 2 -lower-alkoxy, N(H, lower-alkyl)-lower-alkoxy, N(lower-alkyl) 2 -low
  • alkyl refers to straight- or branched-chain saturated hydrocarbon groups having from 1 to about 20 carbon atoms, including groups having from 1 to about 7 carbon atoms. In certain embodiments, alkyl substituents may be lower alkyl substituents. The term “lower alkyl” refers to alkyl groups having from 1 to 6 carbon atoms, and in certain
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.
  • cycloalkyl is intended to refer to any stable monocyclic or polycyclic system which consists of carbon atoms only, any ring of which being saturated
  • cycloalkenyl is intended to refer to any stable monocyclic or polycyclic system which consists of carbon atoms only, with at least one ring thereof being partially unsaturated.
  • cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, bicycloalkyls, including bicyclooctanes such as
  • cycloalkenyls include, but are not limited to, cyclopentenyl or cyclohexenyl.
  • alkenyl as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one double bond and having 2 to 6, preferably 2 to 4 carbon atoms.
  • alkenyl group examples include vinyl, ethenyl, allyl, isopropenyl, 1- propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-l-butenyl, 3-methyl-2- butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2- hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.
  • alkynyl as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one triple bond and having 2 to 6, preferably 2 to 4 carbon atoms.
  • alkynyl group examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3- hexynyl, 4-hexynyl and 5-hexynyl.
  • halogen as used in the definitions means fluorine, chlorine, bromine, or iodine, preferably fluorine and chlorine.
  • Aryl means a monovalent, monocyclic or bicyclic, aromatic carbocyclic hydrocarbon radical, preferably a 6-10 member aromatic ring system.
  • Preferred aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl.
  • Heteroaryl means an aromatic heterocyclic ring system containing up to two rings.
  • Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazole and tetrazolyl.
  • aryl or heteroaryl which are bicyclic it should be understood that one ring may be aryl while the other is heteroaryl and both being substituted or unsubstituted.
  • Heterocycle means a substituted or unsubstituted 5 to 8 membered, mono- or bicyclic, non-aromatic hydrocarbon, wherein 1 to 3 carbon atoms are replaced by a hetero atom selected from nitrogen, oxygen or sulfur atom. Examples include pyrrolidin-2-yl; pyrrolidin-3-yl;
  • Hetero atom means an atom selected from N, O and S.
  • Alkoxy, alkoxyl or lower alkoxy refers to any of the above lower alkyl groups attached to an oxygen atom. Typical lower alkoxy groups include methoxy, ethoxy, isopropoxy or propoxy, butyloxy and the like. Further included within the meaning of alkoxy are multiple alkoxy side chains, e.g. ethoxy ethoxy, methoxy ethoxy, methoxy ethoxy ethoxy and the like and substituted alkoxy side chains, e.g., dimethylamino ethoxy, diethylamino ethoxy, dimethoxy- phosphoryl methoxy and the like.
  • “Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
  • “Pharmaceutically acceptable salt” refers to conventional acid-addition salts or base- addition salts that retain the biological effectiveness and properties of the compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases.
  • Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, trifluoro acetic acid and the like.
  • Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide.
  • Chemical modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., Ansel et al, Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456- 1457.
  • Effective amount means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
  • IC 50 refers to the concentration of a particular compound required to inhibit 50% of a specific measured activity. IC 50 can be measured, inter alia, as is described subsequently. There are provided compounds of the formula
  • X is selected from the group consisting of H, F, CI, Br, I, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl and methoxy,
  • Y is one to four group(s) independently selected from the group consisting of H, F, CI, Br, I, CN, OH, nitro, lower alkyl, cycloalkyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aryl, heteroaryl, heterocycle, COOR', OCOR', CONR'R", NR'COR", NR"S0 2 R', S0 2 NR'R” and NR'R" wherein
  • R' and R" are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle and in the case of R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle, one of Ri and R 2 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloal
  • X is selected from the group consisting of F, CI and Br,
  • Y is one to two group(s) independently selected from the group consisting of H, F, CI, Br, I, CN, OH, nitro, lower alkyl, cycloalkyl and lower alkoxy,
  • Ri is hydrogen
  • one of R 2 and R 3 is selected from aryl, substituted aryl, heteroaryl or substituted heteroaryl and the other is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl,
  • R4 is hydrogen
  • R 5 is selected from the group consisting of lower alkyl, substituted lower alkyl,
  • R' and R" are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle and wherein R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle, m, n, and p are independently 0 to 6 and the pharmaceutically acceptable salts and esters and enantiomers thereof.
  • IB X is F, CI or Br
  • Y is a mono substituting group consisted of H or F
  • Z is F, CI or Br
  • W is H, F or CI, Ri is H,
  • R 5 is selected from the group consisting of lower alkyl, substituted lower alkyl,
  • R', R' and R" are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle and wherein R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle, m, n, and p are independently 0 to 6,
  • R 7 are both methyl, or linked to form cyclopropyl, cyclo butyl, cyclopentyl or cyclohexyl,
  • R 8 is (CH 2 ) q -R 9 , q is 0, 1 or 2,
  • Rg is selected from hydrogen, hydroxyl, lower alkyl, lower alkoxy, lower cycloalkyl, aryl, substituted aryl. heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle, and the pharmaceutically acceptable salts and esters and enantiomers thereof.
  • X is F, CI or Br
  • Y is a mono substituting group consisted of H or F, Z is F, CI or Br, W is H, F, Ri is H, R4 IS H,
  • R 5 is selected from the group consisting of -CO(CH 2 ) admir-R', -CO(CH 2 ) afford-NR'R",
  • n 0,1 or 2
  • R' and R" are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle, and wherein R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle, 5, R7 are both methyl, or linked to form cyclopropyl, cyclo butyl, cyclopentyl or cyclohexyl, R 8 is (CH 2 ) q -R 9 , q is 0, 1 or 2,
  • Rg is selected from hydrogen, hydroxyl, lower alkyl, lower alkoxy, cycloalkyl, aryl, substituted aryl. heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle, and the pharmaceutically acceptable salts and esters thereof.
  • the compounds of formula I and II as well as their salts that have at least one asymmetric carbon atom may be present as racemic mixtures or different stereoisomers.
  • the various isomers can be isolated by known separation methods, e.g., chromatography.
  • the compounds of the present invention are useful in the treatment or control of cell proliferative disorders, in particular oncological disorders. These compounds and formulations containing said compounds may be particularly useful in the treatment or control of solid tumors, such as, for example, breast, colon, lung and prostate tumors.
  • a therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
  • the therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art.
  • Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated.
  • the daily dosage can be administered as a single dose or in divided doses, or for parenteral administration; it may be given as continuous infusion.
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, as well as the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of a formula I compound which produces a therapeutic effect.
  • this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, sachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or nonaqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the present invention provides methods for the synthesis of N-substituted pyrrolidines.
  • the compounds of the invention can be prepared by processes known in the art. Suitable processes for synthesizing these compounds are provided in the examples.
  • An intermediate of formula III can be made from a base-catalyzed condensation reaction of appropriately selected substituted-phenyl acetonitrile and aldehyde or ketone. The reaction proceedes in a highly regioselective manner with Z-isomer as the major or exclusive product.
  • pyrrolidine of formula IV can be made from of intermediates Ila or lib, and III by a base catalized 1,3-dipolar cylcoaddition reaction.
  • the [2+3] cycloaddition reactions of azomethine ylides 1,3-dipoles with olefinic dipolarphiles to form pyrrolidine ring formation have been described in published procedures.
  • Formula IV is subsequently converted to a) formula VI either through intermediate V or by reacting with isocyanate; b) formula VII by amide formation with various acids using HATU as the coupling reagent; c) formula IX via intermediate VIII followed by amide formation with various amines (Scheme 4).
  • the amide formation from IV to VII or VIII to IX can also be achieved under other conditions using EDCI and HOBt or oxalyl chloride as the coupling reagent to activate the acid V.
  • Reagents and conditions are as follows: (a) COCI 2 /TEA/CH 2 CI 2 , rt, 5min; (b)
  • the pyrrolidine compounds I, VI, VII and IX are prepared initially as a racemic mixture and can be chirally separated using chiral Super Fluid Chromatography (SFC) or chiral HPLC or chiral column chromatography.
  • SFC Super Fluid Chromatography
  • racemic mixture of formula I can be readily resolved into two optically pure or enriched chiral enantiomers la and lb by separation using SFC. (Scheme 5).
  • Step C A suspension of (S)-4-(2-azido-ethyl)-2,2-dimethyl-[l,3]dioxolane as a yellow oil (18.7 g, 0.11 mol) and PtC"2 (2.5 g) in ethyl acetate (100 mL) was vigorously shaken in a Pan- under atmosphere of 3 ⁇ 4 (50 psi) for 18 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine as a colorless oil (14 g, 88%).
  • racemic product obtained above was further separated by SFC chiral column to give (4- ⁇ [(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino ⁇ -benzoic acid (16.5 mg) and 4- ⁇ [(2R,3R,4R)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino ⁇ -benzoic acid (10.5 mg).
  • (2S,3S,4S)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2- fluorophenyl)-4-neopentylpyrrolidine-3-carbonitrile 200 mg, 0.47 mmol
  • methyl 2- bromoacetate 159 mg, 1.04 mmol
  • K2CO3 58.3 mg, 1.04 mmol
  • CH2CI2 5 mL
  • reaction mixture was then purified by flash column to give rac-(2S,3S,4S)-2-(3- chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrrolidine-l-carboxylic acid (6-chloro-pyridin-3-ylmethyl)-amide (70.1 mg, 89.0 %).
  • ⁇ , ⁇ -dimethyl formamide (4.0 mL) was added ⁇ , ⁇ -carbonyldiimidazole (208.5 mg, 1.247 mmol, Aldrich) . After it was stirred at rt for 3 days under an argon atmosphere, a precipitate formed which was filtered, dissolved in EtOAc, washed with water, and saturated NaCl. The organic phase was separated, dried over Na 2 S0 4 , filtered and concentrated to give imidazole- 1- carboxylic acid ( 1 -methyl-2-oxo- 1 ,2-dihydro-pyridin-4-yl)-amide which was used without further purification.
  • reaction mixture was then purified by flash column to give 4- ⁇ [(2S,3S,4S)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino ⁇ -2-methyl-benzoic acid methyl ester (63.2 mg, 88 %).
  • the ability of the compounds to inhibit the interaction between p53 and MDM2 proteins was measured by an HTRF (homogeneous time-resolved fluorescence) assay in which recombinant GST-tagged MDM2 binds to a peptide that resembles the MDM2-interacting region of p53 (Lane et al). Binding of GST-MDM2 protein and p53-peptide (biotinylated on its N- terminal end) is registered by the FRET (fluorescence resonance energy transfer) between Europium (Eu)-labeled anti-GST antibody and streptavidin- conjugated Allophycocyanin (APC).
  • FRET fluorescence resonance energy transfer
  • Test is performed in black flat-bottom 384-well plates (Costar) in a total volume of 40 uL containing:90 nM biotinylate peptide, 160 ng/ml GST-MDM2, 20 nM streptavidin- APC (PerkinElmer Wallac), 2 nM Eu-labeled anti-GST-antibody (PerkinElmer Wallac), 0.2% bovine serum albumin (BSA), 1 mM dithiothreitol (DTT) and 20 mM Tris-borate saline (TBS) buffer as follows: Add 10 uL of GST-MDM2 (640 ng/ml working solution) in reaction buffer to each well.
  • BSA bovine serum albumin
  • DTT dithiothreitol
  • TBS Tris-borate saline

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

There are provided compounds of the formula (I) wherein X, Y, R1, R2, R3, R3, R4, and R5 are as described herein and enantiomers and pharmaceutically acceptable salts and esters thereof which are useful as anticancer agents.

Description

NOVEL N- SUB STITUTED-P YRROLIDINE S AS INHIBITORS OF MDM2-P-53
INTERACTIONS
FIELD OF THE INVENTION
The present invention relates to pyrrolidine-2-carboxamide derivatives I which act as antagonists of mdm2 interactions and hence are useful as potent and selective anticancer agents. p53 is a tumor suppresser protein that plays a central role in protection against development of cancer. It guards cellular integrity and prevents the propagation of permanently damaged clones of cells by the induction of growth arrest or apoptosis. At the molecular level, p53 is a transcription factor that can activate a panel of genes implicated in the regulation of cell cycle and apoptosis. p53 is a potent cell cycle inhibitor which is tightly regulated by MDM2 at the cellular level. MDM2 and p53 form a feedback control loop. MDM2 can bind p53 and inhibit its ability to transactivate p53-regulated genes. In addition, MDM2 mediates the ubiquitin-dependent degradation of p53. p53 can activate the expression of the MDM2 gene, thus raising the cellular level of MDM2 protein. This feedback control loop insures that both MDM2 and p53 are kept at a low level in normal proliferating cells. MDM2 is also a co factor for E2F, which plays a central role in cell cycle regulation.
The ratio of MDM2 to p53 (E2F) is dysregulated in many cancers. Frequently occurring molecular defects in the pl6INK4/pl9ARF locus, for instance, have been shown to affect MDM2 protein degradation. Inhibition of MDM2-p53 interaction in tumor cells with wild-type p53 should lead to accumulation of p53, cell cycle arrest and/or apoptosis. MDM2 antagonists, therefore, can offer a novel approach to cancer therapy as single agents or in combination with a broad spectrum of other antitumor therapies. The feasibility of this strategy has been shown by the use of different macromolecular tools for inhibition of MDM2-p53 interaction (e.g.
antibodies, antisense oligonucleotides, peptides). MDM2 also binds E2F through a conserved binding region as p53 and activates E2F-dependent transcription of cyclin A, suggesting that MDM2 antagonists might have effects in p53 mutant cells. SUMMARY OF THE INVENTION
The present invention relates to pyrrolidine-2-carboxamide derivatives I which act as antagonists of mdm2 interactions and hence are useful as potent and selective anticancer agents. The present compounds are of the general formula (I)
Figure imgf000003_0001
wherein X, Y, Rls R2, R3, R4, and R5 are as described herein and enantiomers and pharmaceutically acceptable salts and esters thereof.
Another aspect of the present invention relates to a pharmaceutical formulation comprising at least one compound of the formulae (I), (IA), (IB) and (IC):
Figure imgf000003_0002
wherein X, Y, Rls R2, R3, R4, and R5 are as described herein. Yet another aspect of the present invention relates to a compound of formula (I)
Figure imgf000004_0001
wherein X, Y, Rls R2, R3, R4, and R5 are as described herein and enantiomers and pharmaceutically acceptable salts and esters thereof for use as a medicament, preferably for use as a medicament in the treatment of cancer. Cancer includes in particular solid tumors and more particularly breast, colon, lung and prostate tumors.
A further aspect of the present invention relates to the use of a compound of formula (I)
Figure imgf000004_0002
wherein X, Y, Rls R2, R3i R4, and R5 are as described herein and enantiomers and pharmaceutically acceptable salts and esters thereof for the manufacture of medicaments for the treatment of cancer, in particular solid tumors, more particularly breast, colon, lung and prostate tumors.
Yet another aspect of the present invention relates to a process for the manufacture of the compound of formula (I)
Figure imgf000005_0001
I
wherein X, Y, Rl s R2, R3, R4, and R5 are as described herein, comprising the step of reacting a compound of formula (Ila) or (lib)
Figure imgf000005_0002
Ila lib with a compound of formula (III)
Figure imgf000005_0003
to give a compound of the formula (IV)
Figure imgf000005_0004
IV DETAILED DESCRIPTION OF THE INVENTION
In the specification where indicated the various groups may be substituted by 1-5 or, preferably, 1-3 substituents independently selected from the group consisting of lower alkyl, lower-alkenyl, lower-alkynyl, dioxo-lower-alkylene (forming e.g. a benzodioxyl group), halogen, hydroxy, CN, CF3, NH2, N(H, lower-alkyl), N(lower-alkyl)2, amino carbonyl, carboxy, N02, lower-alkoxy, thio-lower-alkoxy, lower-alkylsufonyl, aminosulfonyl, lower-alkylcarbonyl, lower-alkylcarbonyloxy, lower-alkoxycarbonyl, lower-alkyl-carbonyl-NH, fluoro-lower-alkyl, fluoro-lower-alkoxy, lower-alkoxy-carbonyl-lower-alkoxy, carboxy-lower-alkoxy, carbamoyl- lower-alkoxy, hydroxy- lower-alkoxy, NH2-lower-alkoxy, N(H, lower-alkyl)-lower-alkoxy, N(lower-alkyl)2-lower-alkoxy, benzyloxy-lower-alkoxy, mono- or di-lower alkyl substituted amino-sulfonyl and lower-alkyl which can optionally be substituted with halogen, hydroxy, NH2, N(H, lower-alkyl) or N(lower-alkyl)2.. Preferred substituents for the aryl, heteroaryl and heterocycle rings are halogen, lower alkoxy, lower alkyl and amino.
The term "alkyl" refers to straight- or branched-chain saturated hydrocarbon groups having from 1 to about 20 carbon atoms, including groups having from 1 to about 7 carbon atoms. In certain embodiments, alkyl substituents may be lower alkyl substituents. The term "lower alkyl" refers to alkyl groups having from 1 to 6 carbon atoms, and in certain
embodiments from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.
As used herein, "cycloalkyl" is intended to refer to any stable monocyclic or polycyclic system which consists of carbon atoms only, any ring of which being saturated, and the term "cycloalkenyl" is intended to refer to any stable monocyclic or polycyclic system which consists of carbon atoms only, with at least one ring thereof being partially unsaturated. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, bicycloalkyls, including bicyclooctanes such as
[2.2.2]bicyclooctane or [3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, and bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spiro compounds. Examples of cycloalkenyls include, but are not limited to, cyclopentenyl or cyclohexenyl. The term "alkenyl" as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one double bond and having 2 to 6, preferably 2 to 4 carbon atoms. Examples of such "alkenyl group" are vinyl, ethenyl, allyl, isopropenyl, 1- propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-l-butenyl, 3-methyl-2- butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2- hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.
The term "alkynyl" as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one triple bond and having 2 to 6, preferably 2 to 4 carbon atoms. Examples of such "alkynyl group" are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3- hexynyl, 4-hexynyl and 5-hexynyl.
The term "halogen" as used in the definitions means fluorine, chlorine, bromine, or iodine, preferably fluorine and chlorine.
"Aryl" means a monovalent, monocyclic or bicyclic, aromatic carbocyclic hydrocarbon radical, preferably a 6-10 member aromatic ring system. Preferred aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl.
"Heteroaryl" means an aromatic heterocyclic ring system containing up to two rings. Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazole and tetrazolyl. In the case of aryl or heteroaryl which are bicyclic it should be understood that one ring may be aryl while the other is heteroaryl and both being substituted or unsubstituted.
"Heterocycle" means a substituted or unsubstituted 5 to 8 membered, mono- or bicyclic, non-aromatic hydrocarbon, wherein 1 to 3 carbon atoms are replaced by a hetero atom selected from nitrogen, oxygen or sulfur atom. Examples include pyrrolidin-2-yl; pyrrolidin-3-yl;
piperidinyl; morpholin-4-yl and the like.
"Hetero atom" means an atom selected from N, O and S. "Alkoxy, alkoxyl or lower alkoxy" refers to any of the above lower alkyl groups attached to an oxygen atom. Typical lower alkoxy groups include methoxy, ethoxy, isopropoxy or propoxy, butyloxy and the like. Further included within the meaning of alkoxy are multiple alkoxy side chains, e.g. ethoxy ethoxy, methoxy ethoxy, methoxy ethoxy ethoxy and the like and substituted alkoxy side chains, e.g., dimethylamino ethoxy, diethylamino ethoxy, dimethoxy- phosphoryl methoxy and the like.
"Pharmaceutically acceptable," such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
"Pharmaceutically acceptable salt" refers to conventional acid-addition salts or base- addition salts that retain the biological effectiveness and properties of the compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, trifluoro acetic acid and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. Chemical modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., Ansel et al, Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456- 1457.
"Effective amount" means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
"IC50" refers to the concentration of a particular compound required to inhibit 50% of a specific measured activity. IC50 can be measured, inter alia, as is described subsequently. There are provided compounds of the formula
Figure imgf000009_0001
wherein
X is selected from the group consisting of H, F, CI, Br, I, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl and methoxy,
Y is one to four group(s) independently selected from the group consisting of H, F, CI, Br, I, CN, OH, nitro, lower alkyl, cycloalkyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aryl, heteroaryl, heterocycle, COOR', OCOR', CONR'R", NR'COR", NR"S02R', S02NR'R" and NR'R" wherein
R' and R" are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle and in the case of R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle, one of Ri and R2 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen, one of R3 and R4 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen,
Its is selected from the group consisting of lower alkyl, substituted lower alkyl,
-CH2(CH2)n-CHOH-R', -CH2(CH2)n-CHOH-CH2-(CH2)n-NR'R", -CH2(CH2)n-CO(CH2)nNR'R", -CO(CH2)n-R', -CO(CH2)n-NR'-(CH2)n-CHOH-R', -CO(CH2)n-NR'R", -(CH2)n-NR'S02R", -COCH2(CH2)n-COOH, -(CH2)n-COOR\ -(CH2)n-CONR'R", -CO(CH2)n-OR',
-COCH2(CH2)n-SR', -COCH2(CH2)n-SOR', -COCH2(CH2)n-S02R', -COCH2(CH2)n-COR', -COCH2(CH2)n-S03H, -COCH2(CH2)n-SONR'R", -COCH2(CH2)n-S02NR'R",
-COCH2(CH2CH20)m-(CH2)n-R', -COCH2(CH2CH20)m-(CH2)n-OH,
-COCH2(CH2CH20)m-(CH2)n-OR', -COCH2(CH2CH20)m-(CH2)n-NR'R",
-COCH2(CH2CH20)m-(CH2)n-NR'COR", -COCH2(CH2CH20)m-(CH2)n-NR'S02R",
-COCH2(CH2CH20)m-(CH2)n-COOH, -COCH2(CH2CH20)m-(CH2)n-COOR' ,
-COCH2(CH2CH20)m-(CH2)n-CONR'R", -COCH2(CH2CH20)m-(CH2)n-S02R',
-COCH2(CH2CH20)m-(CH2)n-COR', -COCH2(CH2CH20)m-(CH2)n-SONR'R",
-COCH2(CH2CH20)m-(CH2)n-S02NR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-R',
-COCH2(CH2)p- (CH2CH20)m-(CH2)n-OH, -COCH2(CH2)p-(CH2CH20)m-(CH2)n-OR' ,
-COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'COR", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'S02R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COOH, -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COOR', -COCH2(CH2)p-(CH2CH20)m-(CH2)n-CONR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-S02R' , -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COR' , -COCH2(CH2)p-(CH2CH20)m-(CH2)n-SONR'R",
-COCH2(CH2)p-(CH2CH20)m-(CH2)n-S02NR'R", -COCH2-COR', -COCH2-SOR' and
-COCH2S02R' wherein R' and R" are as above, m, n, and p are independently 0 to 6, and the pharmaceutically acceptable salts and esters thereof. Particular are compounds of formula I having a stereochemical structure as shown as formula IA
Figure imgf000011_0001
X is selected from the group consisting of F, CI and Br,
Y is one to two group(s) independently selected from the group consisting of H, F, CI, Br, I, CN, OH, nitro, lower alkyl, cycloalkyl and lower alkoxy,
Ri is hydrogen, one of R2 and R3 is selected from aryl, substituted aryl, heteroaryl or substituted heteroaryl and the other is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl,
R4 is hydrogen,
R5 is selected from the group consisting of lower alkyl, substituted lower alkyl,
-CH2(CH2)„-CHOH-R', -CH2(CH2)n-CHOH-CH2-(CH2)n-NR'R", -CH2(CH2)n-CO(CH2)nNR'R", -CO(CH2)n-R', -CO(CH2)n-NR'-(CH2)n-CHOH-R', -CO(CH2)n-NR'R", -(CH2)n-NR'S02R", -COCH2(CH2)n-COOH, -(CH2)n-COOR\ -(CH2)n-CONR'R", -CO(CH2)n-OR',
-COCH2(CH2)n-SR', -COCH2(CH2)n-SOR', -COCH2(CH2)n-S02R', -COCH2(CH2)n-COR', -COCH2(CH2)n-S03H, -COCH2(CH2)n-SONR'R", -COCH2(CH2)n-S02NR'R",
-COCH2(CH2CH20)m-(CH2)n-R', -COCH2(CH2CH20)m-(CH2)n-OH,
-COCH2(CH2CH20)m-(CH2)n-OR', -COCH2(CH2CH20)m-(CH2)n-NR'R",
-COCH2(CH2CH20)m-(CH2)n-NR'COR", -COCH2(CH2CH20)m-(CH2)n-NR'S02R",
-COCH2(CH2CH20)m-(CH2)n-COOH, -COCH2(CH2CH20)m-(CH2)n-COOR' ,
-COCH2(CH2CH20)m-(CH2)n-CONR'R", -COCH2(CH2CH20)m-(CH2)n-S02R', -COCH2(CH2CH20)m-(CH2)n-COR', -COCH2(CH2CH20)m-(CH2)n-SONR'R",
-COCH2(CH2CH20)m-(CH2)n-S02NR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-R',
-COCH2(CH2)p- (CH2CH20)m-(CH2)n-OH, -COCH2(CH2)p-(CH2CH20)m-(CH2)n-OR' ,
-COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'COR", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR' S02R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COOH, -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COOR', -COCH2(CH2)p-(CH2CH20)m-(CH2)n-CONR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-S02R' , -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COR' , -COCH2(CH2)p-(CH2CH20)m-(CH2)n-SONR'R",
-COCH2(CH2)p-(CH2CH20)m-(CH2)n-S02NR'R", -COCH2-COR', -COCH2-SOR' and
-COCH2S02R',
R' and R" are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle and wherein R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle, m, n, and p are independently 0 to 6 and the pharmaceutically acceptable salts and esters and enantiomers thereof.
Further particular are compounds shown as formula IB wherein:
Figure imgf000012_0001
IB X is F, CI or Br,
Y is a mono substituting group consisted of H or F, Z is F, CI or Br,
W is H, F or CI, Ri is H,
R4 IS H,
R5 is selected from the group consisting of lower alkyl, substituted lower alkyl,
-CH2(CH2)n-CHOH-R', -CH2(CH2)n-CHOH- CH2-(CH2)n-NR'R", -CH2(CH2)n-CO(CH2)nNR'R", -CO(CH2)n-R', -CO(CH2)n-NR'-(CH2)n-CHOH-R', -CO(CH2)n-NR'R", -(CH2)n-NR'S02R", -COCH2(CH2)n-COOH, -(CH2)n-COOR', -(CH2)n-CONR'R", -CO(CH2)n-OR',
-COCH2(CH2)n-SR', -COCH2(CH2)n-SOR', -COCH2(CH2)n-S02R', -COCH2(CH2)n-COR', -COCH2(CH2)n-S03H, -COCH2(CH2)n-SONR'R", -COCH2(CH2)n-S02NR'R",
-COCH2(CH2CH20)m-(CH2)n-R' , -COCH2(CH2CH20)m-(CH2)n-OH,
-COCH2(CH2CH20)m-(CH2)n-OR', -COCH2(CH2CH20)m-(CH2)n-NR'R",
-COCH2(CH2CH20)m-(CH2)n-NR'COR", -COCH2(CH2CH20)m-(CH2)n-NR'S02R",
-COCH2(CH2CH20)m-(CH2)n-COOH, -COCH2(CH2CH20)m-(CH2)n-COOR' ,
-COCH2(CH2CH20)m-(CH2)n-CONR'R", -COCH2(CH2CH20)m-(CH2)n-S02R',
-COCH2(CH2CH20)m-(CH2)n-COR', -COCH2(CH2CH20)m-(CH2)n-SONR'R",
-COCH2(CH2CH20)m-(CH2)n-S02NR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-R' ,
-COCH2(CH2)p- (CH2CH20)m-(CH2)n-OH, -COCH2(CH2)p-(CH2CH20)m-(CH2)n-OR' ,
-COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'COR", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'S02R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COOH, -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COOR', -COCH2(CH2)p-(CH2CH20)m-(CH2)n-CONR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-S02R', -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COR', -COCH2(CH2)p-(CH2CH20)m-(CH2)n-SONR'R",
-COCH2(CH2)p-(CH2CH20)m-(CH2)n-S02NR'R", -COCH2-COR', -COCH2-SOR' and
-COCH2S02R', R' and R" are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle and wherein R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle, m, n, and p are independently 0 to 6,
Re, R7 are both methyl, or linked to form cyclopropyl, cyclo butyl, cyclopentyl or cyclohexyl,
R8 is (CH2)q-R9, q is 0, 1 or 2,
Rg is selected from hydrogen, hydroxyl, lower alkyl, lower alkoxy, lower cycloalkyl, aryl, substituted aryl. heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle, and the pharmaceutically acceptable salts and esters and enantiomers thereof.
Other particular compounds are shown as formula IC
Figure imgf000014_0001
IC wherein
X is F, CI or Br,
Y is a mono substituting group consisted of H or F, Z is F, CI or Br, W is H, F, Ri is H, R4 IS H,
R5 is selected from the group consisting of -CO(CH2)„-R', -CO(CH2)„-NR'R",
-(CH2)n-CONR'R", -CH2(CH2)n-CHOH-R', -CH2(CH2)n-CHOH- CH2-(CH2)n-NR'R",
-CH2(CH2)n-CO(CH2)nNR'R", -CO(CH2)n-R', -CO(CH2)n-NR'-(CH2)n-CHOH-R', and
-CO(CH2)n-NR'R", n is 0,1 or 2,
R' and R" are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle, and wherein R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle, 5, R7 are both methyl, or linked to form cyclopropyl, cyclo butyl, cyclopentyl or cyclohexyl, R8 is (CH2)q-R9, q is 0, 1 or 2,
Rg is selected from hydrogen, hydroxyl, lower alkyl, lower alkoxy, cycloalkyl, aryl, substituted aryl. heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle, and the pharmaceutically acceptable salts and esters thereof.
Further particular compounds are compounds selected from the group consisting of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide,
(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid ((S)-3 ,4-dihydroxy-butyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid ((S)-3 ,4-dihydroxy-butyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid [ 1 -(2-hydroxy-2-methyl-propyl)- 1 H- pyrazo 1-3 -yl] -amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-4-(2,2- dimethyl-propyl)- 1 -(4-ethyl-piperazine- 1 -carbonyl)-pyrrolidine-3-carbonitrile,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (piperidin-4-ylmethyl)-amide,
rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-benzoic acid,
4-({[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino } -methyl)-benzoic acid,
rac-4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino} -benzoic acid,
4-{[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino } -benzoic acid, rac-3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino} -benzoic acid,
rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -benzoic acid,
rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -benzoic acid,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (4-chloro-phenyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine-l -carboxylic acid (4-fluoro-phenyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid 4-chloro-benzylamide,
rac-( 2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine-l -carboxylic acid [3-(lH-tetrazol-5-yl)-phenyl]-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (4-cyano-phenyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-l-(4-cyano- benzoyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine-l -carboxylic acid (4-carbamoyl-phenyl)-amide,
rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -benzamide,
rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-2-oxo-ethyl} -2-ethoxy-benzoic acid,
rac-4-{4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-4-oxo-butyl} -benzoic acid,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid 4-fluoro-benzylamide,
rac-4-{4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-3-oxo-propenyl} -benzoic acid,
rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-3-oxo-propionic acid, rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2- (2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetic acid tert-butyl ester,
rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2- (2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-acetic acid,
rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetylamino}-benzoic acid methyl ester,
rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-2-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-acetylamino} -benzoic acid,
rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-2-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-acetylamino} -benzamide,
rac-2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2- (2,2-dimethyl-propyl)-pyrrolidin-l-yl]-N-((S)-3,4-dihydroxy-butyl)-acetamide,
rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide,
rac-4-{[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 2-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-benzoic acid ethyl ester,
rac-4-{[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 2-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino} -benzoic acid,
rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2- (2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetic acid,
rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetylamino}-benzoic acid methyl ester,
rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-acetylamino} -benzoic acid,
rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetylamino}-methyl-benzoic acid methyl ester, rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetylamino}-methyl-benzoic acid,
rac-2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-N-((S)-3,4-dihydroxy-butyl)-acetamide,
rac-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetic acid ethyl ester, rac-( 2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid pyridin-4-ylamide,
rac-2-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-benzoic acid methyl ester,
rac- [(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-
(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-acetic acid,
2-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino } -benzoic acid,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine-l -carboxylic acid (4-fluoro-phenyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (3-methylsulfanyl-phenyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (3-methanesulfonyl-phenyl)-amid,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid pyridin-3-ylamide,
rac-4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-butyric acid ethyl ester,
rac-4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino} -butyric acid,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (3-carbamoyl-propyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (3-methylcarbamoyl-propyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid ( 1 -methanesulfonyl-piperidin-4-yl)-amide, rac-2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-acetamide,
rac-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-acetic acid ethyl ester,
rac-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino } -acetic acid, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid methylcarbamoylmethyl-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid carbamoylmethyl-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2- dimethyl-propyl)- 1 -(pyridine-3 -sulfonyl)-pyrro lidine-3 -carbonitrile,
rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid methyl ester,
rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2- dimethyl-propyl)- 1 -(6-morpho lin-4-yl-pyridine-3 -sulfonyl)-pyrro lidine-3 -carbonitrile,
rac-4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-2-methoxy-benzoic acid methyl ester, rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid, rac-3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-propionic acid ethyl ester,
rac-3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino} -propionic acid,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (2-methylcarbamoyl-ethyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine-l -carboxylic acid (2-dimethylcarbamoyl-ethyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (2-carbamoyl-ethyl)-amide,
rac-{l-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-piperidin-4-yl} -acetic acid ethyl ester,
rac-{l-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -piperidin-4-yl} -acetic acid,
rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidin- 1 -yl] -propionic acid, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (6-chloro-pyridin-3-ylmethyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (6-chloro-pyridin-3-yl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid ( 1 -methyl-2-oxo- 1 ,2-dihydro-pyridin-4-yl)- amide,
rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -sulfonyl] -benzoic acid,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-l-(6-chloro- pyridine-3-sulfonyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2- dimethyl-propyl)- 1 -(6-oxo- 1 ,6-dihydro-pyridine-3-sulfonyl)-pyrrolidine-3-carbonitrile,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-l-(6-chloro- pyridine-3-carbonyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2- dimethyl-propyl)- 1 -(6-oxo- 1 ,6-dihydro-pyridine-3-carbonyl)-pyrrolidine-3-carbonitrile,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2- dimethyl-propyl)- 1 -(1 -methyl-6-oxo- 1 ,6-dihydro-pyridine-3-carbonyl)-pyrrolidine-3-carbonitrile, rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid methyl ester,
rac-4-(((2S,3S,4S)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4- neopentylpyrrolidine- 1 -carboxamido)methyl)-2-methoxybenzoic acid,
rac-(2R,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine-l -carboxylic acid benzylamide,
rac N-[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonylj-benzamide,
chiral 4-({[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid, chiral 4-({[(2R,3R,4R)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid, 4-({[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid methyl ester,
rac 4-({[(2S,3S,4S)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid,
chiral 4-({[(2S,3S,4S)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid, chiral 4-({[(2R,3R,4R)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid and,
4-{[(2S,3S,4S)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino } -2-methyl-benzoic acid.
The compounds of formula I and II as well as their salts that have at least one asymmetric carbon atom may be present as racemic mixtures or different stereoisomers. The various isomers can be isolated by known separation methods, e.g., chromatography.
Compounds disclosed herein and covered by formula I and II above may exhibit tautomerism or structural isomerism. It is intended that the invention encompasses any tautomeric or structural isomeric form of these compounds, or mixtures of such forms, and is not limited to any one tautomeric or structural isomeric form depicted in the formulas above.
The compounds of the present invention are useful in the treatment or control of cell proliferative disorders, in particular oncological disorders. These compounds and formulations containing said compounds may be particularly useful in the treatment or control of solid tumors, such as, for example, breast, colon, lung and prostate tumors.
A therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art. The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art.
Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration; it may be given as continuous infusion.
Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, as well as the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of a formula I compound which produces a therapeutic effect.
Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, sachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or nonaqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste. The present invention provides methods for the synthesis of N-substituted pyrrolidines.
The compounds of the invention can be prepared by processes known in the art. Suitable processes for synthesizing these compounds are provided in the examples.
Compounds of this invention can be synthesized according to the following general schemes. The key transformation is a convergent [2+3] cylcoaddition of imine II and activated olefin III to generate pyrrolidine-3-carbonitrile compounds IV in a stereoselective manner.
The starting materials are either commercially available or can be synthesized by methods known to those of ordinary skill in the art. Preparations of intermediates II and III are illustrated in Scheme 1 and 2. In general an appropriately selected aldehyde or ketone can be reacted with methyl amine or C-trimethylsilanyl-methylamine in CH2CI2 to generate imines Ila or lib and were used as crude products without purification (Scheme 1).
heme 1
Figure imgf000025_0001
An intermediate of formula III can be made from a base-catalyzed condensation reaction of appropriately selected substituted-phenyl acetonitrile and aldehyde or ketone. The reaction proceedes in a highly regioselective manner with Z-isomer as the major or exclusive product.
Scheme 2
Figure imgf000025_0002
III
As illustrated in Scheme 3, pyrrolidine of formula IV can be made from of intermediates Ila or lib, and III by a base catalized 1,3-dipolar cylcoaddition reaction. The [2+3] cycloaddition reactions of azomethine ylides 1,3-dipoles with olefinic dipolarphiles to form pyrrolidine ring formation have been described in published procedures.
Scheme 3
Figure imgf000026_0001
Ila III
Figure imgf000026_0002
lib III jy
Formula IV is subsequently converted to a) formula VI either through intermediate V or by reacting with isocyanate; b) formula VII by amide formation with various acids using HATU as the coupling reagent; c) formula IX via intermediate VIII followed by amide formation with various amines (Scheme 4). The amide formation from IV to VII or VIII to IX can also be achieved under other conditions using EDCI and HOBt or oxalyl chloride as the coupling reagent to activate the acid V.
Scheme 4
Figure imgf000027_0001
Reagents and conditions are as follows: (a) COCI2/TEA/CH2CI2, rt, 5min; (b)
HNR5R6/TEA/CH2Cl2, rt, 30min; (c) R5N=C=0/CH2C12, rt, 2 hrs; (d)
R7COOH/HATU/iPr2NEt/CH2Cl2, rt 2 hrs, or
Figure imgf000027_0002
rt 2 hrs; (e)
BrCH2COOtBu/Cs2C03/DMF, rt, overnight; (f) TFA/CH2C12, rt, 3hrs; (g)
HNR5R6/HATU/iPr2NEt/CH2Cl2, rt, 30 min.
The pyrrolidine compounds I, VI, VII and IX are prepared initially as a racemic mixture and can be chirally separated using chiral Super Fluid Chromatography (SFC) or chiral HPLC or chiral column chromatography. For example, racemic mixture of formula I can be readily resolved into two optically pure or enriched chiral enantiomers la and lb by separation using SFC. (Scheme 5). Scheme 5
Figure imgf000028_0001
la lb
racemic mixture chiral chiral
EXAMPLES
The compounds of the present invention may be synthesized according to known techniques. The following examples and references are provided to aid the understanding of the present invention, the true scope of which is set forth in the appended claims.
Example la
Preparation of intermediate [l-(3-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-methyl- amine
Figure imgf000028_0002
M. W. I 71.6 CsHyFClN
A mixture of 3-chloro-2-fluoro-benzoaldehyde (Oakwood, 97%) (1.59 g, 10.0 mmol) and methyl amine (2.0 in THF, Aldrich, 7.5 mL, 15.0 mmol) in CH2CI2 (20 mL) was stirred at rt overnight. The reaction mixture was concentrated and the residue was dried under reduced pressure to afford [[l-(3-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-methyl-amine (1.72 g, 100%) as colorless oil which was used in the next step without further purification.
Example lb
Preparation of intermediate [l-(3-chloro- henyl)-meth-(E)-ylidene]-methyl-amine
Figure imgf000028_0003
M.W. 153.6 C8H8C1 A mixture of 3-chloro-benzoaldehyde (Aldrich, 97%) (4.21 g, 30.0 mmol) and methyl amine (2.0 M in THF, Aldrich, 22.5 mL, 45.0 mmol) in CH2C12 (50 mL) was stirred at rt overnight. The reaction mixture was concentrated and the residue was dried under reduced pressure to afford [[l-(3-chloro-phenyl)-meth-(E)-ylidene]-methyl-amine (4.60 g, 100%) as colorless oil which was used in the next step without further purification.
Example lc
Preparation of intermediate [l-(4-chloro- henyl)-meth-(E)-ylidene]-methyl-amine
Figure imgf000029_0001
M. W. I 71.6 CsHyFClN
A mixture of 4-chloro-2-fluoro-benzoaldehyde (Matrix Sci, 3.17 g, 20.0 mmol) and methyl amine (2.0 m THF, Aldrich, 15 mL, 15.0 mmol) in CH2C12 (20 mL) was stirred at rt overnight. The reaction mixture was concentrated and the residue was dried under reduced pressure to afford [[l-(4-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-methyl-amine (3.32 g, 97.0%)) as colorless oil which was used in the next step without further purification.
Example Id
Preparation of intermediate [l-(4-chloro- henyl)-meth-(E)-ylidene]-methyl-amine
Figure imgf000029_0002
M. W. 188.6 C8H7C12N
A mixture of 2,3-dichloro-benzoaldehyde (Aldrich, 3.50 g, 20.0 mmol) and methyl amine (2.0 M in THF, Aldrich, 15 mL, 15.0 mmol) in CH2C12 (20 mL) was stirred at rt overnight. The reaction mixture was concentrated and the residue was dried under reduced pressure to afford [[l-(4-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-methyl-amine (3.62 g, 96.3%) as colorless oil which was used in the next step without further purification.
Example le
Preparation of intermediate [3,3-dimethyl-but-(E)-ylidene]-trimethylsilanylmethyl-amine
Figure imgf000030_0001
M.W. 185.39 C10H23CI2NS1
To a solution of (aminomethyl)trimethylsilane (Fluka) (1.03 g, 10 mmol) in
dichloromethane (20 mL) was added 3,3-dimethyl-butyraldehyde (Aldrich) (1.0 g, 10 mmol). The reaction mixture was stirred at room temperature for 3 h. Water was added. The organic layer was separated, washed with brine, dried over MgS04, and concentrated to give [3,3- dimethyl-but-(E)-ylidene]-trimethylsilanylmethyl-amine as a colorless oil (1.8 g, 97%).
Example 2a
Preparation of intermediate (Z)-2-(4-chloro-2-fluoro-phenyl)-5,5-dimethyl-hex-2-
Figure imgf000030_0002
To a solution of 4-chloro-2-fluoro-benzyl cyanide (Oakwood) (1.70 g, 10.0 mmol) and 3,3-dimethyl-butyraldehyde (Aldrich) (1.0 g, 10.0 mmol) in iPrOH (20 mL) was added 2 N
NaOH (2.0 mL) drop wise at rt and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and the organic layer was separated, washed with water, brine, dried over Na2S04 and concentrated. The residue was dried overnight in vacuum to give (Z)-2- (4-chloro-2-fluoro-phenyl)-5,5-dimethyl-hex-2-enenitrile (2.52 g, 100%) as a colorless oil which was used in the next step without further purification.
Example 2b
Preparation of intermediate (Z)-2-(4-chloro-2-fluoro-phenyl)-4-cyclopropyl-but-2- enenitrile
Figure imgf000030_0003
Figure imgf000031_0001
To a solution of 4-chloro-2-fluro-benzyl cyanide (Oakwood) (3.39 g, 20.0 mmol) and cyclopropyl-acetaldehyde (Aldrich) (1.68.0 g, 20.0 mmol) in iPrOH (25 mL) was added 2 N NaOH (2.0 mL) drop wise at rt and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and the organic layer was separated, washed with water, brine, dried over Na2S04 and concentrated. The residue was dried overnight under reduced pressure to afford (Z)-2-(4-chloro-2-fluoro-phenyl)-4-cyclopropyl-but-2-enenitrile (2.36 g, 50.0%) as a colorless oil which was used in the next step without further purification. Example 2c
Preparation of intermediate (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro- phenyl)-acrylonitrile
Figure imgf000031_0002
M. W. 310.13 Ci5H7Cl2F2N
To a solution of 4-chloro-2-fluorophenylacetonitrile (Matrix) (5 g, 30 mmol) and 3- chloro-2-fluorobenzaldehyde (Oakwood) (5 g, 32 mmol) in methanol (200 mL) was slowly added a methanolic solution (Aldrich, 25 wt.%) of sodium methoxide (21 mL, 92 mmol). The reaction mixture was heated and stirred at 45 °C for 5 h. The mixture was cooled to room temperarure and filtered. The white precipitate was washed with water, cold methanol, and then dried under reduced pressure to afford (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro- phenyl)-acrylonitrile as a white powder (8 g, 86%).
Example 3a
Preparation of intermediate rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2- fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile
Figure imgf000032_0001
To a solution of [l-(3-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-methyl-amine (1.72 g,
10.00 mmol) and (Z)-2-(4-chloro-2-fluoro-phenyl)-5,5-dimethyl-hex-2-enenitrile (2.52 g, 10.00 mmol) in DMSO (10 mL) was added KOH powder (1.12 g, 20.00 mmol) in one portion. The mixture was stirred at rt overnight. The reaction mixture was diluted with water and extracted with EtOAc three times (3 x 50 mL). The combined organic layers were washed with water and brine and dried over Na2S04, and concentrated. The residue was purified by flash column (Si02, 1% - 15% of EtOAc in hexanes) after concentration to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro- phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (0.86 g,
20.3%; HRMS (ES+) m/z Caicd for C22H22CI2F2N2-;- H [(M÷H)+J: 423.1201 , found: 423.1 199) and rac (3S,4S,5S)-5-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl- propyl)pyrrolidine-3-carbonitrile (0.66 g, 15.6%); HRMS (ES ) m/z Ca!cd for C22H22CI2F2N2-;- H h Vs - i h j. 423.1201, found: 423.1202.
Example 3b
Preparation of intermediate rac-(2S,3S,4S)-2-(3-chloro-o-phenyl)-3-(4-chloro-2-fluoro- phenyl)-4-(2,2-dimethyl-propyl -pyrrolidine-3-carbonitrile
Figure imgf000032_0002
M.W. 405.4 C22H23CI2FN2
To a solution of [l-(3-chloro-phenyl)-meth-(E)-ylidene]-methyl-amine (0.77 g, 5.00 mmol) and (Z)-2-(4-chloro-2-fluoro-phenyl)-5,5-dimethyl-hex-2-enenitrile (1.72 g, 5.00 mmol) in DMSO (5 mL) was added KOH powder (0.56 g, 10.00 mmol) in one portion. The mixture was stirred at rt overnight. The reaction mixture was diluted with water and extracted with EtOAc three times (3 x 50 mL). The combined organic layers were washed with water and brine and dried over Na2S04, and concentrated. The residue was purified by flash column (S1O2, 1% - 15% of EtOAc in hexanes) after concentration to give rac-(2S,3S,4S)-2-(3-chloro-phenyl)-3-(4- chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (0.73 g, 36.1%);
HRMS (ES I m/z Calcd
Figure imgf000033_0001
{ M Π ) i. 405, 1295, found: 405.1292, ra - (2S,3S IR)-4~(4~c loro~2"fluoix p enyl)-2~(3-c lorO"plieiiyl)
pyrrolidine (0.0.42 g, 20.8%); HRMS (ES ;) m/z Calcd for C22H23CI2FN2+ H [(M+H)4]:
405. 1295, found: 405.1294, and (2S,3R,4R)-4-(4-chloro-2-fiuoro-phenyl)-2-(3-chloro-phenyl)-3- (2,2-dimethyl-propyl)-pyrrolidine (0.42 g, 20.8%); HRMS (ES ) m'z Calcd for C22H23CI2FN2+ e [(M+H)4]: 405.1295, found: 405.1294.
Example 3c
Preparation of intermediate rac-(2S,3S,4S)-2, 3-bis-(4-chloro-2-fluoro-phenyl)- 4-(2,2- dimethyl-propyl)-pyrrolidine-3-carbonitrile
Figure imgf000033_0002
M.W. 423.3 C22H22CI2F2N2
In a manner similar to the method described in Example 3a, [l-(4-chloro-2-fluoro- phenyl)-meth-(E)-ylidene]-methyl-amine (3.43 g, 20.00 mmol) reacted with (Z)-2-(4-chloro-2- fluoro-phenyl)-5,5-dimethyl-hex-2-enenitrile (5.03 g, 20.00 mmol) in DMSO (30 mL) in the presence of KOH powder (5.72 g, 56.11 mmol) to give rac-(2S,3S,4S)-2, 3-bis-(4-chloro-2- fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (1.12g 13.3%) and rac- ( 3S,4S,5S)-3,5-bis-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3- carbonitrile (1.66g 19.7%). HRMS (ES4) m z Calcd for C22H22CI2F2N2+ H [(M+H)4]: 423.1201, found: 423.1200.
Example 3d
Preparation of intermediate rac-(2S,3S,4S)-3-(4-chloro-2-fluoro-phenyl)-2-(2,3-dichloro- phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile
Figure imgf000034_0001
M.W. 439.8 C22H22CI3FN2
In a manner similar to the method described in Example 3a, [l-(2,3-dichloro-phenyl)- meth-(E)-ylidene]-methyl-amine (3.76 g, 20.00 mmol) reacted with (Z)-2-(4-chloro-2-fluoro- phenyl)-5,5-dimethyl-hex-2-enenitrile (5.03 g, 20.00 mmol) in DMSO (30 mL) in the presence of KOH powder (5.72 g, 56.11 mmol) to give rac-(2S,3S,4S)-3-(4-chloro-2-fiuoro-phenyl)-2- (2,3-dichloro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (1.85g 21.0%). LC-MS (ES+) m/z Calcd for C22H22CI3FN2+ H [(M+H)+]: 441, found: 441.
Example 3e
Preparation of intermediate rac (2S,3S,4S)-3-(4-chloro-2-fluoro-phenyl)-2-(2,4-dichloro Lenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile
Figure imgf000034_0002
M.W. 439.8 C22H22CI3FN2
In a manner similar to the method described in Example 3a, [l-(2,3-dichloro-phenyl)- meth-(E)-ylidene]-methyl-amine (3.76 g, 20.00 mmol) reacted with (Z)-2-(4-chloro-2-fluoro- phenyl)-5,5-dimethyl-hex-2-enenitrile (5.03 g, 20.00 mmol) in DMSO (30 mL) in the presence of KOH powder (5.72 g, 56.11 mmol) to give rac-(2S,3S,4S)-3-(4-chloro-2-fiuoro-phenyl)-2- (2,3-dichloro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (1.56g 17.7%). HRMS (ES+) m/z Calcd for C22H22CI3FN2+ H [(M+H)+]: 439.0906, found: 439.0905.
Example 3f
Preparation of intermediate rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2- fluoro-phenyl)-2-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile
Figure imgf000035_0001
M.W. 423.34 C22H22CI2F2N2
To a solution of (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)- acrylonitrile (1.2 g, 3.87 mmol) in hexamethylphosphoramide (20 mL) was added [3,3- dimethyl-but-(E)-ylidene]-trimethylsilanylmethyl-amine (1.1 g, 5.9 mmol), acetic acid (60 mg, 1 mmol) and H2O (0.1 g, 5.6 mmol) sequentially. The reaction mixture was stirred at room temperature for 18 h. Water was added. The mixture was extracted with ethyl acetate. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water twice, dried over MgSC^, then concentrated. The residue was purified by chromatography (EtOAc:hexanes = 1 :4, 1;3) to give rac-(2S,3R,4S)-4- (3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-pyrrolidine-3- carbonitrile as a white foam (0.4 g, 24%).
Example 4
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-
3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000035_0002
M.W. 554.54 C27H31CI2F2N2O3
To a mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (126.9 mg, 0.30 mmol) and triethylamine (TEA, 120.0 mg, 1.20 mmol) in CH2CI2 (10 mL) was added phosgene solution (Aldrich, 20% in toluene, 0.40 mL, 0.4 mmol) by injection, and the reaction mixture was stirred at rt for 20 min. 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine!i: (65.2 mg, 0.45 mmol) was then added. The reaction mixture was stirred at rt for another 30 min then concentrated to give the crude product (checked by LCMS) which was diluted with MeOH and treated with PPTS (cat.) at 120°C for 5 min with CEM microwave reactor. The reaction mixture was concentrated under reduced pressure and the residue was diluted with CH2CI2 and washed with water and brine. The organic phase was separated, filtered and dried over Na2S04. The mixture was then concentrated under reduced pressure and purified by RP-HPLC to give rac-(2S,3S,4S)-2-(3- chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrrolidine-l-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (62.5 mg, 39.5%, 2 steps) as a white amorphous. HRMS(ES+) m/z Calcd for C27H31CI2F2N3O3+ H [(M+H)+] : 554.1784; Found: 554.1787.
* Preparation of intermediate 2-((S -2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine
Figure imgf000036_0001
Step A. To a solution of (4S)-(+)-4-(2-hydroxyethyl)-2,2-dimethyl-l,3-dioxolane
(Aldrich) (21.1 g, 0.14 mol) and triethylamine (40 mL, 0.28 mol) in dichloromethane (250 mL) at 0 °C was added methanesulfonyl chloride (13.4 mL, 0.17 mol) dropwise. The reaction mixture was stirred at 0 °C for 1.5 h, then water was added. The organic layer was separated, washed with water, brine, dried over MgSC^, concentrated to give methanesulfonic acid 2-((S)-2,2- dimethyl-[l,3]dioxolan-4-yl)-ethyl ester as a yellow oil (31.7 g, 98%). Step B. To a solution of methanesulfonic acid 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)- ethyl ester (31.7 g, 0.14 mol) in N,N-dimethylformamide (200 mL) was added NaN3 (46 g, 0.71 mol). The reaction mixture was stirred at room temperature for 70 h. Then the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine several times, dried over MgSC^, concentrated to give (S)-4-(2-azido-ethyl)-2,2-dimethyl- [l,3]dioxolane as a yellow oil (21.3 g, 88%).
Step C. A suspension of (S)-4-(2-azido-ethyl)-2,2-dimethyl-[l,3]dioxolane as a yellow oil (18.7 g, 0.11 mol) and PtC"2 (2.5 g) in ethyl acetate (100 mL) was vigorously shaken in a Pan- under atmosphere of ¾ (50 psi) for 18 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine as a colorless oil (14 g, 88%). Preparation of (2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide and (2R,3R,4R)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid ((S)-3 ,4-dihydroxy-butyl)-amide
Figure imgf000037_0001
M.W. 554.54 C27H31CI2F2N2O3
The racemic product obtained above (Example 4, 60 mg) was further separated by SFC chiral column to give (2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (24.3 mg) and (2R,3R,4R)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l -carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (25.6 mg).
Example 5
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-
3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid [ 1 -(2-hydroxy-2-methyl-propyl)- 1 H-pyrazo 1-3 -yl] -amide
Figure imgf000037_0002
M. W. 604.5 C3oH33Ci2F2N502
In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2-(3-chloro-2- fluoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol) prepared in Example 3a was reacted with phosgene solution (Aldrich, 20% in toluene, 0.12 mL, 0.12 mmol), in the presence of triethylamine (TEA, 30.0 mg, 0.30 mmol) in CH2CI2 (2 mL) followed by reacting with l-(3-amino-pyrazol-l-yl)-2-methyl-propan-
2- ol (23.3 mg, 0.15 mmol) at rt for 30 min to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-
3- (4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid [ 1 - (2-hydroxy-2-methyl-propyl)-lH-pyrazo 1-3 -yl] -amide (7.8 mg, 13.0 %) as a white amorphous. HRMS (ES+) TB/Z Caicd for C30H33CI2F2N5O2+ H [( -t-H)'1 ]: 604.20538, found: 604.2056.
Example 6
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)- 1 -(4-eth l-piperazine- 1 -carbonyl)-pyrrolidine-3-carbonitrile
Figure imgf000038_0001
M. W. 563.5 C29H34CI2F2N4O
In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2-(3-chloro-2- fluoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol) was reacted with phosgene solution (Aldrich, 20% in toluene, 0.12 mL, 0.12 mmol), in the presence of triethylamine (TEA, 30.0 mg, 0.30 mmol) in CH2CI2 (2 mL) followed by reacting with 1-ethyl-piperazine (17.2 mg, 0.15 mmol) at rt for 30 min to give rac- (2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)- 1 -(4-ethyl-piperazine- l-carbonyl)-pyrrolidine-3-carbonitrile (20.6 mg, 30.4 %, as TFA salt) as a white amorphous. HRMS (ESI rn/z Caicd for C29H34CI2F2N4O + H | { 1 0 j: 563.2151, found: 563.2151 .
Example 7
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 3-cyano-4-(2,2-dimethyl-propyl)- rrolidine- 1 -carboxylic acid (piperidin-4-ylmethyl)-amide
Figure imgf000038_0002
M. W. 563.5 C29H34CI2F2N4O In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2-(3-chloro-2- fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol) was reacted with phosgene solution (Aldrich, 20% in toluene, 0.12 mL, 0.12 mmol), in the presence of triethylamine (TEA, 30.0 mg, 0.30 mmol) in CH2CI2 (2 mL) followed by reacting with 4-aminomethyl-piperidine-l-carboxylic acid tert-butyl ester (66.3 mg, 0.30 mmol) at rt for 30 min to give rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4- chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}- methyl)-piperidine-l-carboxylic acid tert-butyl ester (48.5 mg, 73.0 %) as a white amorphous. To a mixture of rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino } -methyl)-piperidine- 1 - carboxylic acid tert-butyl ester (35.0 mg, 0.05 mmol) in CH2CI2 (1.5 mL) was added TFA (aldrich, 97%, 1 mL) and the reaction mixture was stiired at rt for 2 firs. The reaction mixture was concentrated and the residure was diluted with CH2CI2 and washed with water, sat.NaHC03 and brine. The organic phase was separated, dried over Na2S04 and concentrated. The mixture was then concentrated and purified by flash column (1-60% of EtOAc in Hexanes) to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (piperidin-4-ylmethyl)- amide (27.3 mg, 91.9%). HRMS(ES+) m/z Calcd for C29H34Cl2F2N40+H [(M+H): 563.2151; Found: 563.2149.
Example 8
Preparation of rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl- ropyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-benzoic acid
Figure imgf000039_0001
M. W. 600.5 C3iH29Cl2F2N303
In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2-(3-chloro-2- fluoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (126.9 mg, 0.30 mmol) was reacted with phosgene solution (Aldrich, 20%> in toluene, 0.45 mL, 0.45 mmol), in the presence of triethylamine (TEA, 272.7 mg, 2.7 mmol) in CH2CI2 (10 mL) followed by reacting with 4-aminomethyl-benzoic acid methyl ester (90.7 mg, 0.45 mmol) at rt for 30 min to give rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-benzoic acid methyl ester (108.0 mg, 59.9 %) as a white amorphous which was used in the next step without further purification.
To a mixture of 4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-benzoic acid methyl ester (108.0 mg„ 0.18 mmol) in THF/MeOH (0.6 mL/0.2 mL) was added 4 N LiOH (0.2 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 N H2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2S04. The mixture was then concentrated to 4- ({[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-benzoic acid (101.2 mg, 95.9%). HRMS(ES+) m/z Calcd for C31H29CI2F2N3O3+H [(M+H): 600.1627; Found: 600.1629.
Preparation of 4-({[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-benzoic acid and 4-({[(2R,3R,4R)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-pro l)-pyrrolidine- 1 -carbonyl] -amino } -methyl)-benzoic acid
Figure imgf000040_0001
M. W. 600.5 C31H29CI2F2N3O3
The racemic product obtained above (90 mg) was further separated by SFC chiral column to give 4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-benzoic acid (42.0 mg) and 4- ({[(2R,3R,4R)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-benzoic acid (38.8 mg). Example 9
Preparation of rac-4- {[(2S, 3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino} -benzoic acid
Figure imgf000041_0001
M. W. 586.5 C30H27CI2F2N3O3
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (84.6 mg, 0.20 mmol)and 4-isocyanato- benzoic acid methyl ester (Aldrich, 53.1 mg, 0.30 mmol) in CH2CI2 (2 mL) was stirred at rt for 1 h. The reaction mixture was then concentrated and purified by flash column to give rac 4- {[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-benzoic acid methyl ester (89.7 mg, 74.7%) which was used in the next step without further purification.
To a mixture of 4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-benzoic acid methyl ester (85.0 mg, 0.14 mmol) in THF/MeOH (0.6 mL/0.2 mL) was added 2 N LiOH (0.2 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 N H2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2S04. The mixture was then concentrated to give rac-4- {[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino } -benzoic acid (83.0 mg, 100%). HRMS(ES+) m/z Calcd for C30H27CI2F2N3O3+H [(M+H): 586.1471; Found: 586.1474.
Preparation of 4- {[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-benzoic acid and 4- {[(2R,3R,4R)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino } -benzoic acid
Figure imgf000042_0001
M. W. 586.5 C30H27CI2F2N3O3
The racemic product obtained above (75 mg) was further separated by SFC chiral column to give (4- {[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-benzoic acid (16.5 mg) and 4- {[(2R,3R,4R)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-benzoic acid (10.5 mg).
Example 10
Preparation of rac-3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl- ropyl)-pyrrolidine-l-carbonyl]-amino} -benzoic acid
Figure imgf000042_0002
M. W. 586.5 C30H27CI2F2N3O3
In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2-(3-chloro-2- fluoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol) was reacted with phosgene solution (Aldrich, 20% in toluene, 0.12 mL, 0.12 mmol), in the presence of triethylamine (TEA, 30.0 mg, 0.30 mmol) in CH2CI2 (2 mL) followed by reacting with 3-amino-benzoic acid methyl ester (Aldrich, 45.0 mg, 0.30 mmol) at rt for 30 min to give rac-3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-benzoic acid methyl ester (38.1mg, 62.9 %) as a white amorphous which was used in the next step without further purification.
To a mixture of 3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-benzoic acid methyl ester (20.0 mg, 0.03 mmol) in THF/MeOH (0.6 mL/0.2 mL) was added 4 N LiOH (0.2 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 N H2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2S04. The mixture was then concentrated to give rac-3- {[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino }-benzoic acid (19.5 mg, 100%). HRMS(ES+) m/z Calcd for C30H27CI2F2N3O3+H [(M+H): 586.1471; Found: 586.1473.
Example 11
Preparation of rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl- ropyl)-pyrrolidine- 1 -carbonylj-benzoic acid
Figure imgf000043_0001
M. W. 571.5 C30H26CI2F2N2O3
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol), isophthalic acid (33.2 mg, 0.20 mmol), HATU (72.0 mg, 0.20 mmol)and iPr2NEt (0.1 mL) in CH2C12 (2 mL) was stirred at rt 2 hrs. The mixture was then diluted with CH2CI2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2S04. The mixture was then concentrated and the residue was purified by RP-HPLC to give rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro- phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l -carbonylj- benzoic acid (19.5 mg, 34.2%). HRMS(ES+) m/z Calcd for C30H26CI2 F2N203+H [(M+H): 571.1362; Found: 571.1364.
Example 12
Preparation of rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonylj-benzoic acid
Figure imgf000044_0001
M. W. 571.5 C30H26CI2F2N2O3
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol), terephthalic acid (33.2 mg, 0.20 mmol), HATU (72.0 mg, 0.20 mmol)and iPr2NEt (0.1 mL) in CH2C12 (2 mL) was stirred at rt 2 hrs. The mixture was then diluted with CH2CI2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2S04. The mixture was then concentrated and the residue was purified by RP-HPLC to give rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro- phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]- benzoic acid (21.5 mg, 37.6%). HRMS(ES+) m/z Calcd for C30H26CI2 F2N203+H [(M+H):
571.1362; Found: 571.1363.
Example 13
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)- 1 -(4-hydroxymethyl-benzoyl)-pyrrolidine-3-carbonitrile
Figure imgf000044_0002
M. W. 557.5 C30H28Cl2F2N2O2
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (100.0 mg, 0.23 mmol), 4-chlorocarbonyl- benzoic acid methyl ester (60.0 mg, 0.30 mmol), iPr2NEt (0.12 mL, 0.69 mmol) in CH2C12 (5 mL) was stirred at rt overnight. The mixture was then diluted with CH2CI2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2S04. The mixture was then concentrated and the residue was purified by flash column (1%-15% AcOEt in Hex) to give rac- 4-[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carbonyl]-benzoic acid methyl ester (132.0 mg, 98.0%). To a solution of rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fiuoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-benzoic acid methyl ester (130.0 mg, 0.222 mmol) in EtOH (1.0 mL) and THF (1.0 mL) was added NaBH4 (36.0 mg, 0.96 mmol) and LiCl (40.7 mg, 0.96 mmol). The reaction mixture was stirred at rt overnight. Work up and the residue was purified by RP-HPLC to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)- 3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-l-(4-hydroxymethyl-benzoyl)-pyrrolidine- 3-carbonitrile (5.7 mg, 4.6%). HRMS(ES+) m/z Calcd for C30H28CI2F2N2O2+H [(M+H):
557.1568; Found: 557.1569. Example 14
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (4-chloro-phenyl)-amide
Figure imgf000045_0001
. 576.9 C29H26CI3F2N3O
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-
4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol)and l-chloro-4- isocyanato-benzene (Aldrich, 45.0mg, 0.30 mmol) in CH2CI2 (2 mL) was stirred at rt for 1 h. The reaction mixture was then concentrated and purified by flash column to give rac-(2S,3S,4S)-2- (3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrrolidine- 1 -carboxylic acid (4-chloro-phenyl)-amide (35.9 mg, 59.3%) as a white amorphous. HRMS (ES+) m'z Calcd for C29H26CI2F2N3O ÷ B U VI - i h i : 576.1 183, found: 576, 1 183.
Example 15
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l -carboxylic acid 4-chloro-benzylamide
Figure imgf000045_0002
Figure imgf000046_0001
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol)and l-chloro-4- isocyanatomethyl-benzene (Aldrich, 20 mg, 0.12 mmol) in CH2CI2 (2 mL) was stirred at rt for 1 h. The reaction mixture was then concentrated and purified by flash column to give rac-
(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl- propyl)-pyrrolidine-l-carboxylic acid (4-chloro-phenyl)-amide (39.7 mg, 67.2%) as a white amorphous. HRMS (ESI rn/z Calcd for C30H28CI3F2N3O + H j{ Π ) i: 590. 1339, found: 590.1340
Figure imgf000046_0002
In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2-(3-chloro-2- fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol) was reacted with phosgene solution (Aldrich, 20% in toluene, 0.12 mL, 0.12 mmol), in the presence of triethylamine (TEA, 90 mg, 0.90 mmol) in CH2CI2 (2 mL) followed by reacting with 3-(lH-tetrazol-5-yl)-phenylamine (48.3 mg, 0.30 mmol) at rt for 30 min to give rac-( 2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carboxylic acid [3-(lH-tetrazol-5-yl)-phenyl]-amide (25.3 mg, 41.4 %) as a white amorphous. HRMS (ESI m/z Calcd for C30H27CI2F2N7O ÷ H [(M÷H) ]: 610.1695, found: 610.1695 Example 17
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)- 3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (4-cyano-phenyl)-amide
Figure imgf000047_0001
. 567.5 C30H26CI2F2N4O
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (84.6 mg, 0.20 mmol)and l-cyano-4- isocyanato-benzene (Aldrich, 34.7mg, 0.24 mmol) in CH2CI2 (2 mL) was stirred at rt for 1 h. The reaction mixture was then concentrated and triturated with EtOAt and the solid was collected to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l -carboxylic acid (4-cyano-phenyl)-amide (1st crop, 54.4 mg, 2nd crop, 60.3 mg: 100%;) as a white solid. FIRMS (ES ) miz CaScd for C30H26CI2F2N4O ÷ H j i VM h i: 567.1525, found: 567. 1526.
Example 18
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- l-(4-cyano-benzoyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile
Figure imgf000047_0002
. 552.5 C3oH25Cl2F2N30
In a manner similar to the method described in Example 11, rac-(2S,3S,4S)-2-(3-chloro- 2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3- carbonitrile (84.6 mg, 0.20 mmol) was reacted with 4-cyano-benzoic acid (Aldrich, 35.3 mg, 0.24 mmol), in the presence of HATU (72.0 mg, 0.20 mmol) and iPr2NEt (0.1 mL) in CH2C12 (2 mL) at rt for 2 hrs to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-l-(4-cyano-benzoyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (108.5 mg, 98.2 %). RMS (ES ;) m/z Calcd for C30H25CI2F2N3O■+■ H H 1 Π > i: 552.1417, found: 552.1416. Example 19
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-
3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (4-carbamoyl-phenyl)-amide
Figure imgf000048_0001
M. W. 585.5 C30H28CI2F2N4O2
To the mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (4-cyano-phenyl)-amide (56.8 mg, 0.10 mmol) and K2C03 (excess) in DMSO (2 mL) was added 30% H202 (1.0 mL, excess) and the reaction mixture was stirred at rt overnight. The reaction mixture was then diluted with EtOAc washed with sat NH4CI, water and brine. The solvent was removed and the crude product was triturated with EtOAc and the solid was collected to give rac-(2S,3S,4S)-2-(3- chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrrolidine-1 -carboxylic acid (4-carbamoyl-phenyl)-amide (55.9 mg, 95.5%). HRMS (ES ) to/z Calcd for (\UI U('1 >I'A .0 · H [(M÷Hf ]: 585.1630, found: 585. 1631.
Example 20
Preparation of rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-benzamide
Figure imgf000048_0002
M. W. 570.5 C3oH27Ci2F2N302
In a manner similar to the method described in Example 19, rac-(2S,3S,4S)-2-(3-chloro- 2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-l-(4-cyano-benzoyl)-4-(2,2-dimethyl-propyl)- pyrrolidine-3-carbonitrile (27.6 mg, 0.05 mmol) was reacted with 30%> H2O2 (1.0 mL, excess), K2CO3 (excess) in DMSO (2 mL) at rt overnight to give rac-4-[(2S,3S,4S)-2-(3-chloro-2-fiuoro- phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]- benzamide (15.3 mg, 56.7%). FIRMS (ES ) m/z Calcd for ( ,Ι Ι..-(Ί..Ι·'Λ' «0.. · M [(MH-H) ]: 570.1521 , found: 570.1523.
Example 21
Preparation of rac-4- {2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-2-oxo-ethyl} -2-ethoxy-benzoic acid
Figure imgf000049_0001
M. W. 629.5 C33H32CI2F2N2O4
In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2-(3-chloro-2- fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol) was reacted with 4-carboxymethyl-2-ethoxy-benzoic acid ethyl ester (Aldrich, 50.4 mg, 0.20 mmol), in the presence of HATU (91.0 mg, 0.24 mmol) and iPr2NEt (0.1 mL) in CH2C12 (2 mL) at rt for 2 hrs to give rac-4- {2-[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)- 3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-2-oxo-ethyl} -2- ethoxy-benzoic acid ethyl ester (52.6 mg, 37.6 %) which was used in the next step without further purification.
To a mixture of rac-4- {2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-2-oxo-ethyl} -2-ethoxy-benzoic acid ethyl ester (50.0 mg, 0.076 mmol) in THF/MeOH (1.2 mL/0.4 mL) was added 4 N LiOH (0.4 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 N H2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2S04. The mixture was then concentrated and the residue was purified by RP-HPLC to give rac-4- {2-[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4- chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-2-oxo-ethyl} -2- ethoxy-benzoic acid (24.4 mg, 50.9%). FIRMS (ES ) m/z Calcd for C33H32CI2F2N2O4 + H i ( I n i : 629.1780, found: 629.1782. Example 22
Preparation of rac-4- {4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fiuoro- phenyl)-3-cyano-4-(2,2-dimeth l-propyl)-pyrrolidin- 1 -yl]-4-oxo-butyl} -benzoic acid
Figure imgf000050_0001
. 599.5 C32H30CI2F2N2O3
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol), 4-(4-oxo-pentyl)- benzoic acid (58.3 mg, 0.30 mmol), HATU (114.0 mg, 0.30 mmol)and iPr2NEt (0.1 mL) in CH2C12 (2 mL) was stirred at rt 2 hrs. The mixture was then diluted with CH2C12 and washed with water, brine. The organic phase was separated, filtered and dried over Na2S04. The mixture was then concentrated and the residue was purified by RP-HPLC to rac-4- {4-[(2S,3S,4S)-2-(3- chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrrolidin-l-yl]-4-oxo-butyl} -benzoic acid (28.9 mg, 48.2 %). HRMS(ES+) m/z Calcd for C33H30CI2F2N2O3+H [(M+H):599.1675; Found: 599.1674.
Example 23
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 3-cyano-4-(2,2-dimethyl-propyl)- rrolidine- 1 -carboxylic acid 4-fluoro-benzylamide
Figure imgf000050_0002
. 574.5 C30H28CI2F3N3O
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (30 mg, 0.07 mmol)and l-fluoro-4- isocyanatomethyl-benzene (Aldrich, 16.1 mg, 0.11 mmol) in CH2CI2 (2 mL) was stirred at rt for 1 h. The reaction mixture was then concentrated and purified by flash column to give rac- (2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl- propyl)-pyrrolidine-l -carboxylic acid (4-fluoro-phenyl)-amide (18.9 mg, 59.3%) as a white amorphous. HRMS (ES+) m/z Calcd for C30H28CI2F3N3O + H [(M+H)+]: 574.1635, found:
574.1633
Example 24
Preparation of rac-4- {[(2S,3S,4S)-2, 3-bis-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino } -benzoic acid
Figure imgf000051_0001
M. W. 586.5 C30H27CI2F2N3O3
A mixture of rac-(2S,3S,4S)- 2, 3-bis (4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl- propyl)-pyrrolidine-3-carbonitrile (150.0 mg, 0.35 mmol)and 4-isocyanato-benzoic acid methyl ester (Aldrich, 86.0 mg, 0.53 mmol) in CH2CI2 (5 mL) was stirred at rt for 3 h. The reaction mixture was then concentrated and purified by flash column to give rac-4- {[(2S,3S,4S)-2, 3-bis- (4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}- benzoic acid methyl ester (141.6 mg, 66.6%) which was used in the next step without further purification.
To a mixture of rac-4- {[(2S,3S,4S)-2, 3-bis-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-benzoic acid methyl ester (142.6 mg, 0.24 mmol) in THF/MeOH (3.4 mL/0.8 mL) was added 4 N LiOH (1.4 mL), and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated and quenched with 2 N H2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2S04. The mixture was then concentrated to give rac-4- {[(2S,3S,4S)-2, 3-bis-(4-chloro- 2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino} -benzoic acid (111.6 mg, 80.6%). HRMS(ES+) m z Calcd for C30H27CI2F2N3O3+H [(M+H): 586.1471; Found: 586.1472.
Example 25
Preparation of rac- 4-({[(2S,3S,4S)-2,3-bis-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino } -methyl)-benzoic acid
Figure imgf000052_0001
. 600.5 C31H29CI2F2N3O3
In a manner similar to the method described in Example 4, rac-(2S,3S,4S)- 2, 3-bis (4- chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (126.9 mg, 0.30 mmol) was reacted with phosgene solution (Aldrich, 20% in toluene, 0.12 mL, 0.12 mmol), in the presence of triethylamine (TEA, 90 mg, 0.90 mmol) in CH2CI2 (2 mL) followed by reacting with 4-aminomethyl-benzoic acid methyl ester hydrochloride (90.7 mg, 0.45 mmol) at rt for 30 min to give rac- 4-({[(2S,3S,4S)-2,3-bis-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl- propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-benzoic acid methyl ester (110.5 mg, 60.9 %) as a white amorphous solid.
To a mixture of rac- 4-({[(2S,3S,4S)-2,3-bis-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-benzoic acid methyl ester (105.0 mg, 0.17 mmol) in THF/MeOH (1.8 mL/0.6 mL) was added 4 N LiOH (0.6 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 N H2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2S04. The mixture was then concentrated and purified by RP-HPLC to give rac- 4-({[(2S,3S,4S)-2,3-bis-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrrolidine- 1 -carbonyl] -amino }-methyl)-benzoic acid (100.1 mg, 97.6%). HRMS(ES+) m/z Calcd for C31H29CI2F2N3O3+H [(M+H): 600.1627; Found: 600.1628.
Example 26
Preparation of rac-4- {[(2S,3S,4S)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,3-dichloro- phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino } -benzoic acid
Figure imgf000053_0001
M. W. 602.9 C30H27CI3FN3O3
A mixture of rac-4- {[(2S,3S,4S)-3-(4-chloro-2-fluoro-phenyl)-2-(2,3-dichloro-phenyl)-4- (2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (88.0 mg, 0.20 mmol)and 4-isocyanato-benzoic acid methyl ester (Aldrich, 42.5 mg, 0.22 mmol) in CH2CI2 (2 mL) was stirred at rt for 1 h. The reaction mixture was then concentrated and purified by flash column to give rac-4- {[(2S,3S,4S)- 3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,3-dichloro-phenyl)-4-(2,2-dimethyl-propyl)- pyrrolidine-l-carbonyl]-amino}-benzoic acid methyl ester (98.6 mg, 79.9%) which was used in the next step without further purification.
To a mixture of rac-4-{[(2S,3S,4S)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,3- dichloro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino} -benzoic acid methyl ester (85.0 mg, 0.14 mmol) in THF/MeOH (0.6 mL/0.2 mL) was added 4 N LiOH (0.2 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 N H2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2S04. The mixture was then concentrated to give rac-4- {[(2S,3S,4S)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-2-(2,3-dichloro-phenyl)-4-(2,2-dimethyl- propyl)-pyrro lidine- 1 -carbonyl] -amino } -benzoic acid (54.3 mg, 65.4%). LC-MS(ES+) m/z Calcd for C30H27CI3FN3O3+H [(M+H): 604; Found: 604.
Example 27
Preparation of rac-4-({[(2S,3S,4S)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,3- dichloro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-benzoic acid
Figure imgf000053_0002
Figure imgf000054_0001
In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2-(2, 3- dichloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3- carbonitrile (88.0 mg, 0.20 mmol) was reacted with phosgene solution (Aldrich, 20% in toluene, 0.23 mL, 0.23 mmol), in the presence of triethylamine (TEA, 272.7 mg, 2.7 mmol) in CH2CI2 (3 mL) followed by reacting with 4-aminomethyl-benzoic acid methyl ester (AK-Scientific, 60.5 mg, 0.30 mmol) at rt for 2 hrs to give rac-4-({[(2S,3S,4S)-2-(2, 3-dichloro-phenyl)-3-(4-chloro- 2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)- benzoic acid methyl ester (126.0 mg, 43.8 %) as a white amorphous solid which was used in the next step without further purification.
To a mixture of rac-4-({[(2S,3S,4S)-2-(2, 3-dichloro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-benzoic acid methyl ester (44.2 mg„ 0.07 mmol) in THF/MeOH (0.6 mL/0.2 mL) was added 4 N LiOH (0.2 mL), and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated and quenched with 2 N H2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2S04. The mixture was then concentrated togive rac-4- ({[(2S,3S,4S)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-2-(2,3-dichloro-phenyl)-4-(2,2-dimethyl- propyl)-pyrro lidine- 1 -carbonyl] -amino }-methyl)-benzoic acid (43.0 mg, 99.6%). LC-MS(ES+/") m/z Calcd for C31H29CI3FN3O3: 617; Found: 617.
Example 28
Preparation of rac-4- {4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimeth l-propyl)-pyrrolidin- 1 -yl]-3-oxo-propenyl} -benzoic acid
Figure imgf000054_0002
M. W. 598.5 C32H28CI2F2N2O3
In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2-(3-chloro-2- fluoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (116 mg, 0.27 mmol) was reacted with 4-((E)-2-carboxyvinyl)-benzoic acid methyl ester* (84.7 mg, 0.41 mmol), in the presence of HATU (156.0 mg, 0.41 mmol) and iPr2NEt (146.0 mg, 1.15 mmol) in CH2C12 (5 mL) at rt for 2 hrs to give rac-4-{4-[(2S,3S,4S)-2-(3-chloro-2-fluoro- phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-3-oxo- propenyl} -benzoic acid methyl ester (120.2 mg, 71.5 %) which was used in the next step without further purification.
In a manner similar to the method described in Example 8, rac-4-{4-[(2S,3S,4S)-2-(3- chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrrolidin-l-yl]-3-oxo-propenyl} -benzoic acid methyl ester (88.1 mg, 0.14 mmol) was treated with 2 N LiOH (1.0 mL) in THF/MeOH (3 mL/1 mL) at rt for 3 hrs and purified by RP-HPLC to rac-4-{4-[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidin- 1 -yl]-3-oxo- propenyl} -benzoic acid (19.2 mg, 22.3 %). HRMS(ES ) m/z Calcd for C32H28C12F2N203+H [(M+H): 597.1518; Found: 597.1518.
* Pre aration of 4-((E)-2-carboxyvinyl)-benzoic acid methyl ester
Figure imgf000055_0001
To a solution of tert-butyl Ρ,Ρ-dimethylphosphonoacetate (Fluka, 1.43 g, 6.4 mmol) in THF (40 mL) was added NaH (Alderich, 60%, 536 mg, 13.4 mmol) portionwise at rt over 30 min. Methyl 4-formylbenzoate (Alderich, 1.0 g, 6.09 mmol) was then added and the reaction mixture was stirred at rt for 4 hrs. The reaction was quenched with water and extracted with EtOAc. The organic layer was separated, and dried over Na2S04. The mixture was then concentrated to give the crude 4-((E)-2-tert-butoxycarbonyl-vinyl)-benzoic acid methyl ester (1.89 g, 118%).
The crude 4-((E)-2-tert-butoxycarbonyl-vinyl)-benzoic acid methyl ester (1.00 g, 3.81 mmol) was then treated with 4N HCl in dioxane (Aldrich,.4 mL, 16.0 mmol) at rt for 2 hrs to give 4-((E)-2-carboxyvinyl)-benzoic acid methyl ester (0.43 g, 64.5 %>, 2 steps) after work up.
Example 29
Preparation of rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-3-oxo-propionic acid
Figure imgf000056_0001
M. W. 509.4 C25H24CI2F2N2O3
A mixture of methyl malonyl chloride (Aldrich, 127 mg, 0.93 mmol), DIPEA (Aldrich, 297.0 mg, 2.3 mmol) and rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fiuoro- phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (150 mg, 0.35 mmol) was stirred at rt overnight. The reaction mixture was concentrated and purified by RP-HPLC to give rac-3- [(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl- propyl)-pyrrolidin-l-yl]-3-oxo-propionic acid methyl ester (136.2 mg, 73.5%).
In a manner similar to the method described in Example 8, rac-3-[(2S,3S,4S)-2-(3-chloro-2- fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-3- oxo-propionic acid methyl ester (120 mg, 0.23 mmol) was treated with 2 N LiOH (1.0 mL) in THF/MeOH (3 mL/1 mL) at rt for 3 hrs and purified by RP-HPLC to rac-3-[(2S,3S,4S)-2-(3- chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrrolidin-l-yl]-3-oxo-propionic acid (21.2 mg, 18.2 %). HRMS(ES+) m/z Calcd for
C25H24CI2F2N2O3+H [(M+H): 509.1205; Found: 509.1207.
Example 30
Preparation of intermediate rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2- fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetic acid tert-butyl ester
Figure imgf000056_0002
M.W. 537.48 C28H32CI2F2N2O2
To a solution of rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-2-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (2.5 g, 5.9 mmol) in N,N- dimethylformamide (50 mL) was added tert-butyl bromoacetate (2.5 g, 12.8 mmol) and CS2CO3 (5 g, 15.4 mmol). The reaction mixture was stirred at room temperature for 66 h. Water was added. The mixture was extracted with ethyl acetate. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water twice, dried over MgSC^, then concentrated. The residue was purified by chromatography (EtOAc:hexanes = 1 : 10) to give rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2- fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetic acid tert-butyl ester as a white foam (2.1 g, 66%).
Example 31
Preparation of rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-acetic acid
Figure imgf000057_0001
M.W. 481.37 C24H24CI2F2N2O2
To a solution of rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetic acid tert-butyl ester (2.1 g, 3.9 mmol) in dichloromethane (20 mL) was added trifluoro acetic acid (10 mL). The reaction mixture was stirred at room temperature for 24 h. The mixture was concentrated, and water was added. The "pH" of the mixture was adjusted to 6-7 by saturated aqueous NaHC03 solution, then extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried over MgS04, then concentrated to give rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4- chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetic acid as a off- white solid (1.6 g, 85%). HRMS(ES+) m/z Calcd for C24H24CI2F2N2O2+H [(M+H): 481.1256; Found: 481.1254.
Example 32
Preparation of rac-4- {2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetylamino}-benzoic acid methyl ester
Figure imgf000058_0001
M.W. 614.52 C32H31CI2F2N3O3
A mixture of rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetic acid (0.5 g, 1.04 mmol), methyl 4- aminobenzoate (Aldrich) (0.3 g, 1.99 mmol), HATU (0.4 g, 1.05 mmol) and iPr2NEt (0.3 g, 2.33 mmol) in CH2C12 (30 mL) was stirred at room temperature for 20 h. The mixture was then diluted with CH2C12 and washed with water, brine. The organic phase was separated, filtered and dried over Na2S04. The mixture was then concentrated and purified by chromatography
(EtOAc:hexanes = 1 :5) to give rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2- fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-acetylamino} -benzoic acid methyl ester as a white solid (0.5 g, 81%).
Example 33
Preparation of rac-4- {2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-acetylamino} -benzoic acid
Figure imgf000058_0002
M.W. 600.50 C31H29CI2F2N3O3
To a solution of rac-4- {2-[(2S, 3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetylamino} -benzoic acid methyl ester (0.35 g, 0.57 mmol) in tetrahydrofuran (30 mL) was added an aqueous solution (1 N) of NaOH (10 mL, 10 mmol) and methanol (10 mL). The reaction mixture was stirred at room temperature for 24 h, and the "pH" of the solution was adjusted to 5-6 by aqueous HCl solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSC^, and concentrated to give rac-4- {2-[(2S,3R,4S)-4-(3-chloro-2- fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]- acetylamino} -benzoic acid as a white solid (0.33 g, 96%). HRMS(ES+) m/z Calcd for
C31H29CI2F2N3O3+H [(M+H): 600.1267; Found: 600.1628.
Example 34
Preparation of rac-4- {2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3 -cyano-2-(2,2-dimethyl-propyl)-pyrro lidin- 1 -yl] -acetylamino } -benzamide
Figure imgf000059_0001
M.W. 599.51 C31H30CI2F2N4O2
A mixture of rac-4- {2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetylamino}-benzoic acid (0.33 g, 0.55 mmol), a solution of ammonia (0.5 M in dioxane, Aldrich, 2 mL, 1 mmol), HATU (0.3 g, 0.79 mmol) and iP^NEt (0.3 g, 2.33 mmol) in CH2CI2 (20 mL) was stirred at room temperature for 20 h. The mixture was then diluted with CH2CI2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2S04. The mixture was then concentrated and purified by chromatography (EtOAc) to give rac-4- (2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl) 3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrro lidin- 1-yl] -acetylamino} - benzamide as a white solid (0.33 g, 100%).
Example 35
Preparation of rac-2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-N-((S)-3,4-dihydroxy-butyl)- acetamide
Figure imgf000059_0002
M.W. 568.50 C28H33CI2F2N3O3
A mixture of rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-
3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetic acid (0.2 g, 0.41 mmol), 2-((S)-2,2- dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.15 g, 1 mmol), HATU (0.23 g, 0.6 mmol) and iPr2NEt (0.29 mL, 1.68 mmol) in CH2C12 (30 mL) was stirred at room temperature for 20 h. The reaction mioxture was quenched with water was and the organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over Na2S04, and concentrated. The residue was dissolved into tetrahydroiuran (7 mL), and aqueous HCl solution (1 N, 3 mL, 3 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 0.5 h. The solvent was removed, and the residue was partitioned between ethyl acetate and saturated aqueous NaHC03 solution. The organic layer was separated, washed with water, brine, dried over Na2S04, and concentrated. The residue was purified by
chromatography (5% MeOH in EtOAc) to give rac-2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)- 3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-N-((S)-3,4- dihydroxy-butyl)-acetamide as an off-white solid (0.1 g, 42%). HRMS(ES+) m/z Calcd for C28H33C12F2N303+ H [(M+H)+]: 568.1940; Found: 568.1943.
Example 36
Preparation of intermediate rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2- fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl chloride
Figure imgf000060_0001
M.W. 485.79 C23H2iCl3F2N20
To a solution of rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-2-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile prepared in Example 3 (0.3 g, 0.71 mmol) in dichloromethane (5 mL) was added saturated aqueous NaHC03 solution (5 mL). The temperature of the mixture was lowered to 0 °C, and a solution of phosgene (Aldrich, 20% in toluene, 0.67 mL, 1.28 mmol) was added dropwise via a syringe. The reaction mixture was stirred at room temperature for 30 min, then diluted dichloromethane. The organic layer was separated, the aqueous layer was extracted with dichloromethane (2x). The combined organic layers were washed with water, brine, dried over MgS04, and concentrated to give crude rac- (2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl- propyl)-pyrrolidine-l -carbonyl chloride as a light yellow oil (0.34 g, 100%). Example 37
Preparation of rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-l-carboxylic acid ((S)-3,4-dihydroxy- butyl)-amide
Figure imgf000061_0001
M.W. 554.54 C27H31CI2F2N2O3
To a solution of rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl chloride (0.34 g, 0.7 mmol) in tetrahydrofuran (5 mL) was added 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.1 g, 0.71 mmol) and triethylamine (0.15 mL, 1 mmol). The reaction mixture was stirred at room temperature for 30 min. An aqueous HC1 solution (1 N, 5 mL, 5 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solvents were removed and the residue was partitioned between ethyl acetate and NaHC03 (sat.) solution. The organic layer was separated, washed with water, brine, dried over MgSC^, and concentrated. The residue was purified by column chromatography (EtOAc) to afford rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4- chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid ((S)-3,4- dihydroxy-butyl)-amide as a white solid (0.11 g, 28%). HRMS(ES+) m/z Calcd for
C27H3iCl2F2N303+ H [(M+H)+]: 554.1784; Found: 554.1785.
Example 38
Preparation of rac-4- {[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino} -benzoic acid ethyl ester
Figure imgf000061_0002
M.W. 614.52 C32H3iCl2F2N303 To a solution of rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-2-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile prepared in Example 3 (0.44 g, 1.04 mmol) in dichloromethane (5 mL) was added 4-isocyanato-benzoic acid ethyl ester (Aldrich, 0.22 g, 1.14 mmol) and triethylamine (0.22 mL, 1.56 mmol). The reaction mixture was stirred at room temperature for 30 min. Water was added, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSC^, and concentrated. The residue was purified by chromatography (25% EtOAc in hexanes) to give rac-4-{[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2- dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-benzoic acid ethyl ester as a white solid (0.59 g, 92%). HRMS(ES+) m/z Calcd for C32H31CI2F2N3O3+ H [(M+H)+]: 614.1784; Found:
614.1782.
Example 39
Preparation of rac-4- {[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-2-(2,2-dimethy -propyl)-pyrrolidine-l-carbonyl]-amino} -benzoic acid
Figure imgf000062_0001
M. W. 586.5 C30H27CI2F2N3O3
A mixture of rac-4- {[(2S, 3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino} -benzoic acid ethyl ester (0.2 g, 0.32 mmol) in methanol (5 mL) was added an aqueous solution (1 N) of NaOH (5 mL, 5 mmol). The reaction mixture was stirred at room temperature for 20 h. The "pH" of the mixture was adjusted to 5-6 by diluted aqueous HC1 solution. The mixture was partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (75%> EtOAc in hexanes) to give rac-4- {[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 2-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-benzoic acid as a white solid (0.1 g, 50%). HRMS(ES+) m z Calcd for C30H27CI2F2N3O3+H [(M+H): 586.1471; Found: 586.1473. Example 40
Preparation of intermediate rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2- fluoro-phenyl)-3-cyano-2-(2,2-dimeth l-propyl)-pyrrolidin-l-yl]-acetic acid methyl ester
Figure imgf000063_0001
M.W. 495.4 C25H26CI2F2N2O2
In a 10 mL round-bottomed flask, (2S,3S,4S)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2- fluorophenyl)-4-neopentylpyrrolidine-3-carbonitrile (200 mg, 0.47 mmol), methyl 2- bromoacetate (159 mg, 1.04 mmol), K2CO3 and KOH (58.3 mg, 1.04 mmol) were combined with CH2CI2 ( 5 mL) to give a brown suspension.
The reaction mixture was and stirred at rt for 3 h. The RM was dilute with CH2CI2, washed with water, brine, dried over Na2S04 and concentrated. The crude material was purified by flash chromatography (1-20 % of EtOA in hexanes) to give rac-[(2S,3R,4S)-4-(3-chloro-2- fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]- acetic acid methyl ester as a white amorphous solid (121.3 mg, 51.8%).
Example 41
Preparation of rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-2-(2,2-dimethyl-pro l)-pyrrolidin- 1 -yl]-acetic acid
Figure imgf000063_0002
M.W. 481.37 C24H24CI2F2N2O2
In a manner similar to the method described in Example 8, rac-[(2S,3R,4S)-4-(3-chloro- 2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]- acetic acid methyl ester (115 mg, 0.23 mmol) in THF/MeOH (1.8/0.6 mL) was treated with 2N KOH (0.6 mL) at rt overnight to give rac-[(2S,3R,4S)-4-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro- 2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetic acid (108.5 mg, 97.0 %).
Example 42
Preparation of rac-4- {2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetylamino} -benzoic acid methyl ester
Figure imgf000064_0001
M.W. 614.52 C32H31CI2F2N3O3
In a manner similar to the method described in Example 11, rac-[(2S,3R,4S)-4-(3-chloro-
2-fluoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]- acetic acid (48.2 mg, 0.10 mmol) was reacted with 4-amino-benzoic acid methyl ester (30.2 mg, 0.20 mmol), in the presence of HATU (57.0 mg, 0.15 mmol) and iPr2NEt (0.03 mL) in CH2C12 (2 mL) at rt for 2 hrs to give rac-4- {2-[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2- fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-acetylamino} -methyl-benzoic acid methyl ester as a white solid (39.6 mg, 64.5%).
Example 43
Preparation of rac-4- {2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl- ropyl)-pyrrolidin-l-yl]-acetylamino} -benzoic acid
Figure imgf000064_0002
M.W. 600.50 C3iH29Cl2F2N303
To a mixture of rac-4- {2-[(2S, 3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetylamino} -benzoic acid methyl ester (30.0 mg, 0.05 mmol) in THF/MeOH (0.6 mL/0.2 mL) was added 2 N LiOH (0.2 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 N H2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2S04. The mixture was then concentrated to give rac-4- {2-[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidin-l-yl]-acetylamino}-benzoic acid (29.0 mg, 98.9%). LC-MS(ES+) m/z Calcd for C31H29CI2F2N3O3+H [(M+H): 600.5; Found: 602.
Example 44
Preparation of rac-4- {2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetylamino}-methyl-benzoic acid methyl ester
Figure imgf000065_0001
M.W. 628.6 C33H33CI2F2N3O3
In a manner similar to the method described in Example 11, rac-[(2S,3R,4S)-4-(3-chloro- 2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]- acetic acid (48.2 mg, 0.10 mmol) prepared in Example 31 was reacted with methyl 4- (aminomethyl)benzoate hydrochloride (24.2mg, 0.12 mmol), in the presence of HATU (38.0 mg, 0.10 mmol) and iPr2NEt (0.04 mL, 0.24 mmol) in CH2C12 (2 mL) at rt for 2 hrs to give rac-4- {2- [(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl- propyl)-pyrrolidin-l-yl]-acetylamino}-methyl-benzoic acid methyl ester as a white amorphous
(59.5 mg, 94.7%). HRMS(ES+) m/z Calcd for C33H33CI2F2N3O3+H [(M+H): 628.1940; Found: 628.1939.
Example 45
Preparation of rac-4- {2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetylamino}-methyl-benzoic acid
Figure imgf000066_0001
M.W. 614.5 C32H31CI2F2N3O3
To a mixture of rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetylamino}-methyl-benzoic acid methyl ester (50.0 mg, 0.08 mmol) in THF/MeOH (0.6 mL/0.2 mL) was added 2 N LiOH (0.2 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 N H2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2S04. The mixture was then concentrated to give rac-4- {2-[(2S, 3S, 4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidin-l-yl]-acetylamino}-methyl-benzoic acid (48.8 mg, 99.8%). HRMS (ES+) m/z Calcd for C32H31CI2F2N3O3+H [(M+H): 614.1784; Found: 614.1783.
Example 46
Preparation of rac-2-[(2S, 3S, 4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-N-((S)-3,4-dihydroxy-butyl)- acetamide
Figure imgf000066_0002
M.W. 568.50/682.5 C28H33CI2F2N3O3/C2HF2O
In a manner similar to the method described in Example 11, rac-[(2S,3R,4S)-4-(3-chloro- 2-fluoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]- acetic acid (48.2 mg, 0.10 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)- ethylamine (Example 4, 87.1mg, 0.30 mmol), in the presence of HATU (72.0 mg, 0.20 mmol) and iPr2NEt (0.1 mL) in CH2C12 (2 mL) at rt for 2 hrs to give 2-[(2S,3S,4S)-2-(3-chloro-2- fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]- N-[2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethyl]-acetamide (58.2 mg, 95.7 %) which was used in the next step without further purification. 2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4- chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-N-[2-((S)-2,2- dimethyl-[l,3]dioxolan-4-yl)-ethyl]-acetamide ( 50 mg, 0.08mmol) was diluted with MeOH and treated with PPTS (cat.) at 120 °C for 5 min with CEM microwave reactor. The reaction mixture was concentrated and diluted with CH2CI2 and washed with water and brine. The organic phase was separated, filtered and dried over Na2S04. The mixture was then concentrated and purified by RP-HPLC to give 2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)- 3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-N-((S)-3,4-dihydroxy-butyl)-acetamide TFA salt (28.8 mg, 51.3%) as a white amorphous solid. HRMS(ES+) m/z Calcd for C28H33CI2F2N3O3+ H [(M+H)+]: 568.1940; Found: 568.1936.
Example 47
Preparation of rac-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetic acid ethyl ester
Figure imgf000067_0001
M.W. 509.43 C26H28CI2F2N2O2
To a solution of rac (2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.1 mg, 0.10 mmol) in DMF (3 mL) was added potassium carbonate (43.3 mg, 0.313 mmol) and the reaction mixture was stirred at rt under argon for 21 firs. The reaction mixture was diluted with ethyl acetate and washed with water (2X) and brine. The organic phase was separated, filtered and dried over Na2S04. The mixture was then concentrated and purified by flash chromatography to give rac [(2S,3S,4S)-2- (3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrrolidin-l-yl]-acetic acid ethyl ester (22.3 mg, 44.2%,) as a white amorphous solid.
HRMS(ES+) m/z Calcd for C26H28CI2F2N2O2+ H [(M+H)+]: 509.1569; Found: 509.1569.
Example 48
Preparation of rac-( 2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid pyridin-4-ylamide
Figure imgf000068_0001
M.W. 543.45 C28H26CI2F2N4O
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (39.4 mg, 0.093 mmol) and 4- isocyanatopyridine (Princeton, 27.8 mg, 0.231 mmol) in CH2CI2 (5 mL) was stirred at rt for 7.5 hrs then more 4-isocyanatopyridine (Princeton, 23.6 mg, 0.196 mmol) was added. After and additions 16 hrs, the reaction mixture was then concentraed and purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carboxylic acid pyridin-4-ylamide (45.3 mg, 89.5%). HRMS(ES+) m/z Calcd for C28H26CI2F2N4O + H [(M+H)+] : 543.1525; Found: 543.1525.
Example 49
Preparation of rac-2- {[(2S, 3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino} -benzoic acid methyl ester
Figure imgf000068_0002
M.W. 600.50 C31H29CI2F2N3O3
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (70.3 mg, 0.166 mmol) and methyl 2- isocyanatobenzoate (Aldrich, 150.7 mg, 0.851 mmol) in CH2CI2 (9mL) was stirred at rt for 18 hrs. The reaction mixture was then concentraed and purified by flash column to give rac-2- {[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-benzoic acid methyl ester (67.9 mg, 68.1%). HRMS(ES+) m/z Calcd for C31H29CI2F2N3O3 +Na [(M+Na): 622.1446; Found: 622.1449.
Example 50
Preparation of rac- [(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-acetic acid
Figure imgf000069_0001
M.W. 481.37 C24H24CI2F2N2O2
To a mixture of rac [(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetic acid ethyl ester (14.7 mg, 0.0288 mmol, Example CI) in THF (1.8 mL) was added a solution of LiOH (Aldrich, 8.5 mg, 0.02 mmol) in water (1.2 mL) and the reaction mixture was stirred at rt for 22 firs. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 4-5), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2SO The mixture was then concentrated to give rac- [(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4- chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetic acid (14.2 mg, 102%). HRMS(ES+) m z Calcd for C24H24CI2F2N2O2+ H [(M+H)+]: 481.1256; Found: 481.1255
Example 51
Preparation of 2- {[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino} -benzoic acid
Figure imgf000069_0002
M.W. 586.47 C30H27CI2F2N3O3 To a mixture of rac-2-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino} -benzoic acid methyl ester (53.0 mg, 0.0883 mmol, Example C3) in THF (3 mL) was added a solution of LiOH (Aldrich, 21.8 mg, 0.52 mmol) in water (2 mL) and the reaction mixture was stirred at rt for 23 firs. The reaction mixture was partly concentrated and quenched with 1 N HC1 (pH 4-5), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2S04. The mixture was then concentrated to give 2-{[(2S,3S,4S)-2-(3-chloro-2- fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l- carbonyl]-amino}-benzoic acid (49.1 mg, 95 %). HRMS(ES+) m/z Calcd for C30H27CI2F2N3O3+ H [(M+H)+]: 586.1471; Found: 586.1474.
Example 52
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 3-cyano-4-(2,2-dimethyl-propyl -pyrrolidine- 1 -carboxylic acid (4-fluoro-phenyl)-amide
Figure imgf000070_0001
M.W. 560.45 C29H26CI2F3N3O
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (43.1 mg, 0.102 mmol) and 4-fluorophenyl isocyanate (Aldrich, 71.0 mg, 0.512 mmol) in CH2C12 (5 mL) was stirred at rt for 24 firs. The reaction mixture was then concentrated and purified by flash column to give (2S,3S,4S)-2-(3- chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrrolidine-1 -carboxylic acid (4-fluoro-phenyl)-amide (45.6 mg, 79.8%). HRMS(ES+) m/z Calcd for C29H26CI2F3N3O + H [(M+H)+]: 560.1478; Found: 560.1479. Example 53
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (3-methylsulfanyl-phenyl)-amide
Figure imgf000071_0001
M.W. 588.55 C30H29CI2F2N3OS
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (59.9 mg, 0.142 mmol) and 3- methyl(thio)phenyl isocyanate (Aldrich, 117.0 mg, 0..711 mmol) in CH2CI2 (7 mL) was stirred at rt for 72 hrs. The reaction mixture was then concentrated and purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l -carboxylic acid (3-methylsulfanyl-phenyl)-amide (67.7 mg, 81%). HRMS(ES+) m/z Calcd for C30H29CI2F2N3OS + H [(M+H)+] : 588.1449; Found: 588.1452.
Example 54
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (3-methanesulfonyl-phenyl)- amid
Figure imgf000071_0002
M.W. 620.55 C30H29CI2F2N3O3S
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (3-methylsulfanyl-phenyl)-amide (Example 53) in CHCI3 (4 mL) was stirred at 0 °C for 30 min then at rt for 80 min. The reaction mixture was extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2S04. to give rac-(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3- (4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (3- methanesulfonyl-phenyl)-amide (67.7 mg, 81%). HRMS(ES+) m z Calcd for C30H29CI2F2N3O3S + H [(M+H)+]: 642.1167; Found: 642.1169. Example 55
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid pyridin-3-ylamide
Figure imgf000072_0001
M.W. 543.45 C28H26CI2F2N4O
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (40 mg, 0.095 mmol) and 3- isocyanatopyridine (Oakwood, 29.1 mg, 0.242 mmol) in CH2CI2 (5 mL) was stirred at rt for 17 hrs. The reaction mixture was then purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro- 2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l- carboxylic acid pyridin-3-ylamide (15.5 mg, 30 %). HRMS(ES+) m/z Calcd for C28H26CI2F2N4O + H [(M+H)+]: 543.1525; Found: 543.1527.
Example 56
Preparation of rac-4- {[(2S, 3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino} -butyric acid ethyl ester
Figure imgf000072_0002
M.W. 580.51 C29H33CI2F2N3O3
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (101 mg, 0.239 mmol) and ethyl 4- iaocyanatobutyrate (Aldrich, 196 mg, 1.25 mmol) in CH2CI2 (10 mL) was stirred at rt for 22 hrs. The reaction mixture was then purified by flash column to give rac-4-{[(2S,3S,4S)-2-(3-chloro- 2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l- carbonyl] -amino} -butyric acid ethyl Ester (121.8 mg, 87.8 %). HRMS(ES ) m/z Calcd for C29H33CI2F2N3O3 + H [(M+H)+]: 602.1759; Found: 602.1756.
Example 57
Preparation of rac-4- {[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3 -cyano-4-(2,2-dimeth -propyl)-pyrro lidine- 1 -carbonyl] -amino } -butyric acid
Figure imgf000073_0001
M.W. 552.45 C27H29CI2F2N3O3
To a mixture rac-4- {[(2S, 3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino} -butyric acid ethyl ester (98.6 mg, 0.170 mmol, Example CIO) in THF (6 mL) was added a solution of LiOH
(Aldrich, 47.1 mg, 1.12 mmol) in water (4 mL) and the reaction mixture was stirred at rt for 6 firs. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 4-5), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2S04. The mixture was then concentrated to give rac- 4-{[(2S,3S,4S)-2-(3-chloro-2- fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l- carbonyl]-amino}-butyric acid (93.9 mg, 100 %). HRMS(ES+) m/z Calcd for C27H29CI2F2N3O3+ H [(M+H)+]: 552.1627; Found: 552.1628.
Example 58
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 3-cyano-4-(2,2-dimethyl-prop -pyrro lidine- 1 -carboxylic acid (3-carbamoyl-propyl)-amide
Figure imgf000073_0002
M.W. 551.47 C27H30CI2F2N4O2
To a mixture rac- 4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-butyric acid (22.7 mg, 0.041 mmol, Example CI 1) in Ν,Ν-dimethyl formamide (2.5 mL) was added DIPEA (37.1 mg, 0.287 mmol) and HATU (25.1 mg, 0.066 mmol). After it was stirred at rt for 35 min, ground ammonium chloride (5.1 mg, 0.095 mmol,) was added. After 3 hrs the reaction mixture was extracted with EtOAc, and washed with water, 10% ammonium chloride, saturated sodium bicarbonate, water, and saturated NaCl. The organic phase was separated, and dried over Na2S04. The reaction mixture was then purified by flash column to give rac- (2S,3S,4S)-2-(3-chloro-2- fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l- carboxylic acid (3-carbamoyl-propyl)-amide (19.4 mg, 85.6 %). HRMS(ES ) m/z Calcd for C27H3oCl2F2N402+Na [(M+Na): 573.1606; Found: 573.1609.
Example 59
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (3-methylcarbamoyl-propyl)- amide
Figure imgf000074_0001
M.W. 565.50 C28H32Cl2F2N402
To a mixture rac-4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-butyric acid (24.0 mg, 0.043 mmol, Example 58) in Ν,Ν-dimethyl formamide (2.5 mL) was added DIPEA (48.2 mg, 0.373 mmol), HoBt (12.2 mg, 0.090 mmol), HBTU(30.7 mg, 0.081 mmol) and methylamine hydrochloride(9.6 mg, 0.142 mmol) . After it was stirred at rt for 5.5 hrs, the solvent was removed and the reaction mixture was extracted with EtOAc, and washed with IN sodium hydroxide (2X), water, and saturated NaCl. The organic phase was separated, and dried over Na2S04. The reaction mixture was then purified by flash column to give rac-(2S,3S,4S)-2-(3- chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrrolidine-1 -carboxylic acid (3-methylcarbamoyl-propyl)-amide (23.0 mg, 93.7 %). HRMS(ES ) m/z Calcd for C28H32Cl2F2N402+ H [(M+H)+] : 565.1943; Found: 565.1944. Example 60
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1-carboxylic acid (l-methanesulfonyl-piperidin-4- yl)-amide
Figure imgf000075_0001
M.W. 627.59 C29H34Cl2F2N403S
To a mixture of l-methanesulfonyl-piperidin-4-ylamine; compound with trifluoro-acetic acid (229.4 mg, 0.785 mmol, US20060014708) in Ν,Ν-dimethyl formamide (4.0 mL) was added TEA (101 mg, 1.004 mmol) and Ι,Γ-carbonyldiimidazole (Aldrich, 134 mg, 0.826 mmol) . After it was stirred at rt for 2 hrs, the solvent was removed and the reaction mixture was extracted with EtOAc, and washed with water (2X), and saturated NaCl. The organic phase was separated, dried over Na2S04, filtered and concentrated to give imidazole- 1-carboxylic acid (1- methanesulfonyl-piperidin-4-yl)-amide (150.7 mg, 70.5 %) which was used without further purification.
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (30.5 mg, 0.072 mmol) and imidazole- 1- carboxylic acid (l-methanesulfonyl-piperidin-4-yl)-amide (75.4 mg, 0.277 mmol) in CH2C12 (4 mL) was stirred at rt for 72 hrs. The reaction mixture was then purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine- 1-carboxylic acid (l-methanesulfonyl-piperidin-4-yl)-amide (15.7 mg, 34.7 %). HRMS(ES+) m/z Calcd for C29H34C12F2N403S + H [(M+H)+] : 627.1770; Found: 627.1770.
Example 61
Preparation of rac-2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- Lenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetamide
Figure imgf000076_0001
M.W. 480.39 C24H25Cl2F2N30
To a mixture rac- [(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetic acid (23.0 mg, 0.048 mmol, Example 51) in Ν,Ν-dimethyl formamide (2.5 mL) was added DIPEA (44.5 mg, 0.344 mmol) and HATU (29.6 mg, 0.078 mmol). After it was stirred at rt for 22 min, ground ammonium chloride (6.4 mg, 0.12 mmol,) was added. After 3 hrs the reaction mixture was extracted with EtOAc, and washed with water, 10% ammonium chloride, saturated sodium bicarbonate, water, and saturated NaCl. The organic phase was separated, and dried over Na2S04. The reaction mixture was then purified by flash column to give rac- 2-[(2S,3S,4S)-2-(3-chloro-2-fluoro- phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]- acetamide (3.7 mg, 16.1 %). HRMS(ES+) m/z Calcd for C24H25C12F2N30 +Na [(M+Na):
502.1235; Found: 502.1235.
Example 62
Preparation of rac- {[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-acetic acid ethyl ester
Figure imgf000076_0002
MW. 552.45 C27H29C12F2N303
In a manner similar to the method described in Example C3, rac-(2S,3S,4S)-2-(3-chloro- 2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3- carbonitrile (80 mg, 0.189 mmol) was reacted with isocyanato-acetic acid ethyl ester (122 mg, 0.945 mmol) to give rac- {[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-acetic acid ethyl ester (91.2 mg, 87%). HRMS(ES+) m z Calcd for C27H29CI2F2N3O3+ H [(M+H)+] : 552.1627; Found: 552.1629.
Example 63
Preparation of rac- {[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3 -cyano-4-(2,2-dimethy -propyl)-pyrro lidine- 1 -carbonyl] -amino } -acetic acid
Figure imgf000077_0001
M.W .524.40 C25H25Cl2F2N303
In a manner similar to the method described in Example 52, rac- {[(2S,3S,4S)-2-(3- chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrrolidine-l-carbonyl]-amino}-acetic acid ethyl ester (83 mg, 0.144 mmol, example C16) was reacted with lithium hydroxide hydrate (36 mg, 0.945 mmol, Aldrich) to give rac- {[(2S,3S,4S)- 2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrro lidine- 1 -carbonyl] -amino } -acetic acid (71 mg, 92%) HRMS(ES+) m z Calcd for
C25H25Cl2F2N303+ H [(M+H)+] : 524.1314; Found: 524.1315.
Example 64
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 3-cyano-4-(2,2-dimethyl-propyl)-pyrro lidine- 1 -carboxylic acid methylcarbamoylmethyl-amide
Figure imgf000077_0002
M.W .537.44 C26H28CI2F2N4O2
In a manner similar to the method described in Example 60, a mixture of rac- {[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-acetic acid (22.6 mg, 0.0432 mmole, example 64) was reacted with a solution of methylamine (0.04 mL, 2M in THF, 0.080 mmol, Aldrich ) to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carboxylic acid methylcarbamoylmethyl-amide (17.9 mg, 77%) as a white solid. HRMS (ES+) m/z Calcd for C26H28CI2F2N4O2+ H [(M+H)+] : 537.1630; Found: 537.1630.
Example 65
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid carbamoylmethyl-amide
Figure imgf000078_0001
M.W. 523.41 C25H26CI2F2N4O2
To a mixture rac-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-acetic acid (25.4 mg, 0.048 mmol, example 17) in Ν,Ν-dimethyl formamide (2.5 mL) was added DIPEA (44.5 mg, 0.344 mmol) and HATU (30.3 mg, 0.080 mmol). After it was stirred at rt for 22 min, ground ammonium chloride (6.6 mg, 0.12 mmol,) was added. After 3 firs the reaction mixture was extracted with EtOAc, and washed with water, 10% ammonium chloride, saturated sodium bicarbonate, water, and saturated NaCl. The organic phase was separated, and dried over Na2S04. The reaction mixture was then purified by flash column to give rac-2-[(2S,3S,4S)-2-(3-chloro-2- fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]- acetamide (16.3 mg, 64.3 %). HRMS(ES+) m/z Calcd for C25H26CI2F2N4O2 +Na [(M+Na):
545.1293; Found: 545.1294.
Example 66
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)- 1 -(pyridine-3-sulfonyl)-pyrrolidine-3-carbonitrile
Figure imgf000079_0001
M.W. 564.49 C27H25CI2F2N3O2S
To a mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (30.2 mg, 0.071 mmol) in CH2CI2 (3 mL) was added DIPEA (29.7 mg, 0.230 mmol) and pyridine-3-sulfonyl chloride hydrochloride (22.8 mg, 0.106 mmol, Acme Bioscience). It was stirred at rt for 3 hrs under argon. More DIPEA (29.7 mg, 0.230 mmol) and pyridine-3-sulfonyl chloride hydrochloride (Acme Bioscience, 25.2 mg, 0.118 mmol) were added. After 4 hrs the reaction mixture was extracted with EtOAc, washed with water, saturated sodium bicarbonate, water, and saturated NaCl. The organic phase was separated, and dried over Na2S04. The reaction mixture was then purified by flash column to give rac (2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2- dimethyl-propyl)-l-(pyridine-3-sulfonyl)-pyrrolidine-3-carbonitrile (20.3 mg, 50.4 %).
HRMS(ES+) m/z Calcd for
Figure imgf000079_0002
+ H [(M+H)+]: 564.1086; Found: 564.1087. Example 67
Preparation of rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3 -cyano-4-(2,2-dimethyl-propyl)-pyrro lidine- 1 -carbonyl] -amino } -methyl)- cyclohexanecarboxylic acid methyl ester
Figure imgf000079_0003
M.W. 620.57 C32H37CI2F2N3O3
To a mixture of 4-aminomethyl-cyclohexanecarboxylic acid methyl ester (1.008 g, 4.758 mmol, Astatech,) in Ν,Ν-dimethyl formamide (20.0 mL) was added TEA (617 mg, 6.098 mmol) and Ι,Γ-carbonyldiimidazole (810.3 mg, 4.997 mmol, Aldrich,) . After it was stirred at rt for 21 hrs under an argon atmosphere, the solvent was removed and the reaction mixture was extracted with EtOAc, and washed with water (2X), and saturated NaCl. The organic phase was separated, dried over Na2SC>4, filtered and concentrated to give 4-{[(imidazole-l-carbonyl)-amino]- methyl}cyclohexanecarboxylic acid methyl ester (1.184 g, 4.46 mmol, 93 %) which was used without further purification.
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (70.2 mg, 0.165 mmol) and 4- {[(imidazole- 1 - carbonyl)-amino]-methyl}cyclohexanecarboxylic acid methyl ester (509.6 mg, 1.921 mmol) in CH2C12 (9 mL) was stirred at rt for 17 hrs and at reflux for 7 hrs. The reaction mixture was then purified by flash column to give rac 4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2- fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)- cyclohexanecarboxylic acid methyl ester (87.7 mg, 85.1 %). HRMS(ES+) m/z Calcd for
C32H37Cl2F2N303 + H [(M+H)+]: 620.2253; Found: 620.2254. Example 68
Preparation of rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3 -cyano-4-(2,2-dimethyl-propyl)-pyrro lidine- 1 -carbonyl] -amino } -methyl)- cyclohexanecarboxylic acid
Figure imgf000080_0001
M.W. 606.55 C3iH35Cl2F2N303
To a mixture of rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3 -cyano-4-(2,2-dimethyl-propyl)-pyrro lidine- 1 -carbonyl] -amino } -methyl)- cyclohexanecarboxylic acid methyl ester (65.0 mg, 0.105 mmol, example 21) in THF (4 mL) was added a solution of LiOH (Aldrich, 31.5 mg, 0.75 mmol) in water (2 mL) and the reaction mixture was stirred at rt for 6.5 hrs then more THF (2mL) and water (1 mL) was added and stirred for 6 more hrs. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 5-6), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2S04. The mixture was then concentrated to rac- 4-({[(2S,3S,4S)-2- (3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrrolidine-l-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid (95.8 mg, 100 %).
HRMS(ES+) m z Calcd for Cs^C^^C^ H [(M+H)+]: 606.2097; Found: 606.2097.
Example 69
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)- 4-(2,2-dimethyl-propyl)- 1 -(6-mor ho lin-4-yl-pyridine-3 -sulfonyl)-pyrro lidine-3 -carbonitrile
Figure imgf000081_0001
M.W. 649.59 C31H32CI2F2N4O3S
To a mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (35.4 mg, 0.084 mmol) in CH2CI2 (3 mL) was added DIPEA (44.5 mg, 0.344 mmol) and 6-morpho lin-4-yl-pyridine-3-sulfonyl chloride (45.0 mg, 0.171 mmol, Maybridge). It was stirred at rt for 3.5 hrs under argon. More DIPEA (29.7 mg, 0.230 mmol) and 6-morpho lin-4-yl-pyridine-3-sulfonyl chloride (18.7 mg, 0.071 mmol, Maybridge) were added. After 1.75 hrs the reaction mixture was extracted with EtOAc, washed with water, saturated sodium bicarbonate, water, and saturated NaCl. The organic phase was separated, and dried over Na2S04. The reaction mixture was then purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)- 1 -(6-morpho lin-4-yl-pyridine-3 -sulfonyl)-pyrro lidine-3 -carbonitrile (19.4 mg, 35.7 %). HRMS(ES+) m/z Calcd for C31H32CI2F2N4O3S + H [(M+H)+]: 649.1613; Found: 649.1615.
Example 70
Preparation of rac-4- {[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-2-methoxy-benzoic acid methyl ester
Figure imgf000082_0001
M.W. 630.52 C32H31CI2F2N3O4
To a mixture of 4-amino-2-methoxy-benzoic acid methyl ester (1.000 g, 5.246 mmol, Maybridge) in Ν,Ν-dimethyl formamide (20.0 mL) was added 1,1 '-carbonyldiimidazole
(Aldrich, 919.8 mg, 5.502 mmol) . After it was stirred at rt for 21 hrs under an argon atmosphere, the solvent was removed and the reaction mixture was extracted with EtOAc, and washed with water (2X), and saturated NaCl. The organic phase was separated, dried over Na2S04, filtered and concentrated to give 4-[(imidazole-l-carbonyl)-amino]-2-methoxy-benzoic acid methyl ester (1.34 g, 4.87 mmol, 92.8 %) which was used without further purification.
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (50.5 mg, 0.119 mmol) and 4-[(imidazole-l- carbonyl)-amino]-2-methoxy-benzoic acid methyl ester (325.2 mg, 1.181 mmol) in CH2C12 (8 mL) was stirred at reflux for 16 hrs. The reaction mixture was then purified by flash column to give rac-4-{[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-2-methoxy-benzoic acid methyl ester (48.5 mg, 64.6 %). HRMS(ES+) m/z Calcd for C32H3iCl2F2N304 + H [(M+H)+] : 630.1733;
Found: 630.1738. Example 71
Preparation of rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro- phenyl)-3 -cyano-4-(2,2-dimethyl-propyl)-pyrro lidine- 1 -carbonyl] -amino } -methyl)- cyclohexanecarboxylic acid
Figure imgf000083_0001
M.W. 616.50 C31H29CI2F2N3O4
To a mixture of rac-4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-2-methoxy-benzoic acid methyl ester (26.5 mg, 0.042 mmol, Example 70) in THF (2.4 mL) was added a solution of LiOH (Aldrich, 12.9 mg, 0..307 mmol) in water (1.2 mL) and the reaction mixture was stirred at rt for 16 hrs then more THF (3mL) and water (1.5 mL) was added and stirred for 5 additonal hrs at 50 °C. The reaction mixture was partly concentrated and quenched with 1 N HC1 (pH 5-7), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2S04. The mixture was then concentrated to give rac- 4-({[(2S,3S,4S)-2-(3- chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrrolidine-l-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid (25.7 mg, 99.2 %).
HRMS(ES+) m/z Calcd for C31H29CI2F2N3O4+ H [(M+H)+]: 616.1576; Found: 616.1573.
Example 72
Preparation of rac-3- {[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino} -propionic acid ethyl ester
Figure imgf000083_0002
M.W .566.48, C28H31CI2F2N3O3
In a manner similar to the method described in Example 49, rac-(2S,3S,4S)-2-(3-chloro- 2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3- carbonitrile (100 mg, 0.236 mmol) was reacted with 3-isocyanato-propionic acid ethyl ester (168 mg, 1.174 mmol) to give rac- 3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino} -propionic acid ethyl ester (113.2 mg, 85%). HRMS(ES+) m/z Calcd for C28H31CI2F2N3O3+ H [(M+H)+]: 566.1784; Found: 566.1785.
Example 73
Preparation of rac-3- {[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimeth -propyl)-pyrrolidine-l-carbonyl]-amino} -propionic acid
Figure imgf000084_0001
M.W .538.43, C26H27CI2F2N3O3
In a manner similar to the method described in Example 8, rac- 3-{[(2S,3S,4S)-2-(3- chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrrolidine-l-carbonyl]-amino}-propionic acid ethyl ester (99 mg, 0.175 mmol, example 72) reacted with lithium hydroxide hydrate (44 mg, 1.047 mmol, Aldrich) to give rac- 3- {[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino } -propionic acid (94 mg, 99%). HRMS(ES+) m/z Calcd for C26H27CI2F2N3O3+ H [(M+H)+]: 538.1471; Found: 538.1470. Example 74
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (2-methylcarbamoyl-ethyl)- amide
Figure imgf000084_0002
M.W .551.47, C27H30CI2F2N4O2
In a manner similar to the method described in Example 59, a mixture of rac- 3- {[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-propionic acid (24 mg, 0.0446 mmole, example 73) was reacted with a solution of methylamine (0.05 mL, 2M in THF, 0.10 mmol, Aldrich) to give rac- (2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (2-methylcarbamoyl-ethyl)-amide (17.2mg, 70%) as a white solid. HRMS(ES+) m/z Calcd for C27H30CI2F2N4O2+ H [(M+H)+]: 551.1787; Found: 551.1789.
Example 75
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl) 3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (2-dimethylcarbamoyl-ethyl)- amide
Figure imgf000085_0001
M.W .565.50, C28H32CI2F2N4O2
In a manner similar to the method described in Example 59, a mixture of rac-3- {[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-propionic acid (24 mg, 0.0446 mmole, example 73) was reacted with a solution of dimethylamine (0.05 mL, 2M in THF, 0.10 mmol, Aldrich) to rac- (2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (2-dimethylcarbamoyl-ethyl)-amide (8.2mg, 32%) as a white solid. HRMS(ES+) m/z Calcd for C28H32CI2F2N4O2+ H [(M+H)+]: 565.1943; Found: 565.1944.
Example 76
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl) 3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (2-carbamoyl-ethyl)-amide
Figure imgf000086_0001
M.W .537.44, C26H28C12F2N402
In a manner similar to the method described in Example 63, a mixture of rac-3- {[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-propionic acid (25 mg, 0.0464 mmole, example 73), DIPEA (42 mg, 0.324 mmol) and HATU (26.4 mg, 0.069 mmol) in DMF was reacted with ammonium chloride (6.2 mg, 0.11 mmol) to give rac- (2S,3S,4S)-2-(3-chloro-2- fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l- carboxylic acid (2-carbamoyl-ethyl)-amide (14.1 mg, 57%). HRMS(ES+) m/z Calcd for
C26H28C12F2N402+ H [(M+H)+] : 537.1630; Found: 537.1630.
Example 77
Preparation of rac-{l-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl]-piperidin-4-yl} -acetic acid ethyl ester
Figure imgf000086_0002
M.W. 620.57 C32H37C12F2N303
To a mixture of 2-(piperidin-4-yl)-acetic acid ethyl ester (211.4 mg, 1.234 mmol, Oakwood,) in Ν,Ν-dimethyl formamide (5.0 mL) was added Ι,Γ-carbonyldiimidazole (216 mg, 1.332 mmol Aldrich) . After it was stirred at rt for 4 days under an argon atmosphere, the solvent was removed and the reaction mixture was extracted with EtOAc, and washed with water (2X), and saturated NaCl. The organic phase was separated, dried over Na2S04, filtered and concentrated to give [1 -(imidazole- l-carbonyl)-piperidin-4-yl]-acetic acid ethyl ester (293.3 mg, 1.10 mmol, 89.6 %) which was used without further purification.
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (51.6 mg, 0.122 mmol) and [ 1 -(imidazole- 1- carbonyl)-piperidin-4-yl]-acetic acid ethyl ester (293.3 mg, 1.10 mmol) in CH2CI2 (8 mL) was stirred at reflux for 16 hrs then lh at 140 °C in a microwave tube and finally at 160 °C for 1 hr.. The reaction mixture was then purified by flash column to give rac-{l-[(2S,3S,4S)-2-(3-chloro- 2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l- carbonyl]-piperidin-4yl} -acetic acid ethyl ester (40.4 mg, 53.4 %). HRMS(ES+) m/z Calcd for C32H37CI2F2N3O3 + H [(M+H)+]: 620.2253; Found: 620.2254.
Example 78
Preparation of rac-{l-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimeth l-propyl)-pyrrolidine- 1 -carbonyl]-piperidin-4-yl} -acetic acid
Figure imgf000087_0001
M.W. 592.52 C30H33CI2F2N3O3
To a mixture of rac-{l-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl]-piperidin-4-yl} -acetic acid ethyl ester (33.0 mg, 0.053 mmol) in THF (3 mL) was added a solution of LiOH (Aldrich, 15.7 mg, 0..374 mmol) in water (1.5 mL) and the reaction mixture was stirred at rt for 24 hrs. The reaction mixture was partly concentrated and quenched with 1 N HC1 (pH 6-7), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2S04. The mixture was then concentrated to give rac-{l-[(2S,3S,4S)-2-(3-chloro-2-fluoro- phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]- piperidin-4-yl} -acetic acid (29.5 mg, 93.6 %). HRMS(ES+) m/z Calcd for C30H33CI2F2N3O3+ H [(M+H)+]: 592.1940; Found: 592.1940. Example 79
Preparation of rac-3-[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl] -propionic acid
Figure imgf000088_0001
M.W. 495.40 C25H26CI2F2N2O2
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (30.6 mg, 0.0723 mmol), ethyl acrylate (73.7 mg, 0.728 mmol, Aldrich) and samarium(III) trifluoromethanesulfonate (34.9 mg, 0.0572 mmol) in THF (1.5 mL) were heated for 3h at 160 °C in a microwave tube. The reaction mixture was then diluted with CH2CI2, extracted with water, and saturated NaCl. The organic phase was separated, dried over Na2S04, and purified by flash column to give rac-3-[(2S,3S,4S)-2-(3- chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrrolidin-l-yl] -propionic acid ethyl ester (12.3 mg, 32.5 %).
To a mixture of rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-propionic acid ethyl ester (12.3 mg, 0.0235 mmol) in THF (2 mL) was added a solution of LiOH (Aldrich, 6.7 mg, 0.16 mmol) in water (1 mL) and the reaction mixture was stirred at rt for 22 firs. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 6-7), extracted with EtOAc, washed with water
(2X), and saturated NaCl. The organic phase was separated, and dried over Na2S04. The mixture was then concentrated to give rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4- chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-propionic acid (11 mg, 100%). HRMS(ES+) m/z Calcd for C25H26CI2F2N2O2+ H [(M+H)+]: 495.1412; Found: 495.1413.
Example 80
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (6-chloro-pyridin-3-ylmethyl)- amide
Figure imgf000089_0001
M.W. 591.92 C29H27CI3F2N4O
To a mixture of 5-aminomethyl-2-chloropyridine (194.5 mg, 1.323 mmol, Alfa Asear) in N,N-dimethyl formamide (5.0 mL) was added Ι,Γ-carbonyldiimidazole (236.5 mg, 1.415 mmol, Aldrich) . After it was stirred at rt for 18 hrs under an argon atmosphere, the solvent was removed and the reaction mixture was extracted with EtOAc, washed with water (4X), and saturated NaCl. The organic phase was separated, dried over Na2S04, filtered and concentrated to give [1 -(imidazole- l-carbonyl)-piperidin-4-yl]-acetic acid ethyl ester which was used without further purification.
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (56.5mg, 0.133 mmol) and [ 1 -(imidazole- 1- carbonyl)-piperidin-4-yl]-acetic acid ethyl ester (1.32 mmol) in CH2C12 (8 mL) was stirred at rt for 4 days. The reaction mixture was then purified by flash column to give rac-(2S,3S,4S)-2-(3- chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrrolidine-l-carboxylic acid (6-chloro-pyridin-3-ylmethyl)-amide (70.1 mg, 89.0 %).
HRMS(ES+) m/z Calcd for C29H27C13F2N40 + H [(M+H)+]: 591.1292; Found: 591.1293.
Example 81
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 3-cyano-4-(2,2-dimethyl-propyl -pyrrolidine- 1 -carboxylic acid (6-chloro-pyridin-3-yl)-amide
Figure imgf000089_0002
M.W. 577.89 C28H25Cl3F2N40 A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (60.8 mg, 0.144 mmol) and 2-chloro-5- isocyanatopyridine (109.1 mg, 0.144 mmol, Maybridge) in CH2CI2 (6mL) was stirred at rt for 16 hrs. The reaction mixture was then purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro- 2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 - carboxylic acid (6-chloro-pyridin-3-yl)-amide (59.1 mg, 71.1 %). HRMS(ES ) m/z Calcd for C28H25Cl3F2N40+ H [(M+H)+]: 577.1135; Found: 577.1135.
Example 82
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-
3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid ( 1 -methyl-2-oxo- 1 ,2-dihydro- pyridin-4-yl)-amide
Figure imgf000090_0001
M.W. 573.47 C29H28C12F2N402
To a mixture of 4-amino-l-methyl-pyrin-2-one (149.5 mg, 1.180 mmol, Mo IBridge) in
Ν,Ν-dimethyl formamide (4.0 mL) was added Ι,Γ-carbonyldiimidazole (208.5 mg, 1.247 mmol, Aldrich) . After it was stirred at rt for 3 days under an argon atmosphere, a precipitate formed which was filtered, dissolved in EtOAc, washed with water, and saturated NaCl. The organic phase was separated, dried over Na2S04, filtered and concentrated to give imidazole- 1- carboxylic acid ( 1 -methyl-2-oxo- 1 ,2-dihydro-pyridin-4-yl)-amide which was used without further purification.
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (15.8 mg, 0.0373 mmol) and imidazole-1- carboxylic acid (l-methyl-2-oxo-l,2-dihydro-pyridin-4-yl)-amide (76.3 mg, 0.105 mmol) in CH2C12 (1.5 mL) was stirred at rt for 1 day. The reaction mixture was then purified by flash column to rac (2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid ( 1 -methyl-2-oxo- 1 ,2-dihydro-pyridin-4-yl)- amide (19.7 mg, 92.1 %). HRMS(ES+) m/z Calcd for C29H28CI2F2N4O2+ H [(M+H)+] : 573.1630; Found: 573.1629.
Example 83
Preparation of rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -sulfonylj-benzoic acid
Figure imgf000091_0001
M.W .607.51, C29H26CI2F2N2O4S
To a mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (80 mg, 0.0189 mmol) and diisopropylethylamine (122mg, 0.942 mmol) in CH2CI2 (6 mL) was added p- (chlorosulfonyl)benzoic acid (70.0 mg, 0.283 mmol, Eastman) and the reaction mixture was stirred at room temp, for 6 hrs. The resulting mixture was diluted with EtOAc, washed with aqueous Na2C03, IN HC1 and brine, and concentrated to dryness to give rac-4-[(2S,3S,4S)-2-(3- chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrrolidine-1 -sulfonylj-benzoic acid (44.2 mg, 38%) as a white soild. HRMS(ES+) m/z Calcd for C29H26CI2F2N2O4S + H [(M+H)+]: 607.1031; Found: 607.1032.
Example 84
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- l-(6-chloro-pyridine-3-sulfonyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile
CI
Figure imgf000091_0002
M.W .598.93, C27H24CI3F2N3O2S
In a manner similar to the method described in Example 83, a mixture of rac-(2S,3S,4S)-
2- (3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-
3- carbonitrile (82 mg, 0.0195 mmol) was reacted with 6-chloropyridine-3-sulfonyl chloride (66 mg, 0.311 mmol, Enamine) to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2- fluoro-phenyl)-l-(6-chloro-pyridine-3-sulfonyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3- carbonitrile (116.6 mg, 97%) as a light yellow soild. HRMS(ES+) m/z Calcd for
C27H24CI3F2N3O2S + H [(M+H)+]: 598.0696; Found: 598.0696. Example 85
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)- 1 -(6-oxo- -dihydro-pyridine-3-sulfonyl)-pyrrolidine-3-carbonitrile
Figure imgf000092_0001
M.W .580.49, C27H25Ci2F2N303S
A suspension of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)- l-(6-chloro-pyridine-3-sulfonyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (24.4 mg, 0.041 mmol, example 37) in acetic acid (2 mL) and water (2 mL) was heated at 220 °C for 1 hr in microwave condition. The solvent was removed in vacuum and the residuer was taken up in EtOAc, washed with aqueous Na2C03 and brine, dried and evaporated. The crude product was purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2- fluoro-phenyl)-4-(2,2-dimethyl-propyl)- 1 -(6-oxo- 1 ,6-dihydro-pyridine-3-sulfonyl)-pyrrolidine- 3-carbonitrile (17.6 mg, 71%) as a white soild. HRMS(ES+) m/z Calcd for
Figure imgf000092_0002
+ H [(M+H)+]: 580.1035; Found: 580.1035. Example 86
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- l-(6-chloro-pyridine-3-carbonyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile
Figure imgf000093_0001
M.W .562.88, C28H24CI3F2N3O
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (53 mg, 0.125 mmol), diisopropylethylamine (64.7 mg, 0.50 mmol), dimethylaminopyridine (3mg, 0.024 mmol, Aldrich) in CH2CI2 (6 mL) and 6-chloro-nicotinoyl chloride (41.0 mg, 0.232 mmol, Aldrich) was stirred at room temp, for 2 hrs before diluted with EtOAc, washed with aqueous Na2C03, brine, and concentrated. The resiude was purified by by flash column to give rac- (2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3- (4-chloro-2-fluoro-phenyl)-l-(6-chloro-pyridine-3-carbonyl)-4-(2,2-dimethyl-propyl)- pyrrolidine-3-carbonitrile (58.3 mg, 83%) as a white soild. HRMS(ES+) m/z Calcd for
C28H24CI3F2N3O + H [(M+H)+]: 562.1026; Found: 562.1026
Example 87
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)- 1 -(6-oxo- 1 ,6-dihydro-pyridine-3-carbonyl)-pyrrolidine-3-carbonitrile
Figure imgf000093_0002
M.W .544.43, C28H25Cl2F2N302
A suspension of rac- (2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-l-(6-chloro-pyridine-3-carbonyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (63.9 mg, 0.113 mmol, example 39) in acetic acid (8 mL) and water (8 mL) was heated at 180 °C for 1 hr in microwave condition. The solvent was removed in vacuum and the residuer was taken up in EtOAc, washed with aqueous Na2C03 and brine, dried and evaporated. The crude product was purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2- fluoro-phenyl)-4-(2,2-dimethyl-propyl)- 1 -(6-oxo- 1 ,6-dihydro-pyridine-3-carbonyl)-pyrrolidine-
3- carbonitrile (61.4mg, 85%) as a white soild. HRMS(ES+) m/z Calcd for C28H25Cl2F2N302+ H [(M+H)+]: 544.1365; Found: 544.1364
Example 88
Preparation of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-
4- (2,2-dimethyl-propyl)- 1 -(1 -methyl-6-oxo- 1 ,6-dihydro-pyridine-3-carbonyl)-pyrrolidine-3- carbonitrile
Figure imgf000094_0001
M.W .558.46, C29H27Cl2F2N302
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)- 1 -(6-oxo- 1 ,6-dihydro-pyridine-3-carbonyl)-pyrrolidine-3-carbonitrile (15.1 mg, 0.0277 mmol, example 40), cesium carbonate (27 mg, 0.0829 mmol, Aldrich) in DMF (3 mL) and iodomethane was stirred at room temp, for 3 hrs before it was diluted with EtOAc, washed with water and brine, dried and concentrated. The resiude was purifed by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl- propyl)- 1 -( 1 -methyl-6-oxo- 1 ,6-dihydro-pyridine-3 -carbonyl)-pyrrolidine-3-carbonitrile (15.0 mg, 96%) as a white soild. HRMS(ES+) m/z Calcd for C29H27Cl2F2N302+ H [(M+H)+] : 558.1521; Found: 558.1520
Example 89
Preparation of rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-methoxy- benzoic acid methyl ester
Figure imgf000095_0001
M.W. 644.55 C33H33CI2F2N3O4
To a mixture of 4-cyano-2-methoxybenzoic acid (1.00 g, 5.648 mmol, Biogene) in methanol (15.0 mL) was added p-toluenesulfonic acid monohydrate (286 mg, 1.48 mmol, Aldrich) and it was heated to reflux under an argon atmosphere for 16 hrs. The solvent was removed and the reaction mixture was extracted with EtOAc, washed with saturated Na2CC"3, water, and saturated NaCl. The organic phase was separated, dried over Na2S04, filtered and concentrated to give 4-cyano-2-methoxy-benzoic acid methyl ester (1.04 g, 96.4%). A mixture of 4-cyano-2-methoxy-benzoic acid methyl ester (1.01 g, 5.28 mmol) in methanol (50 mL) was added to Raney-nickel 2800 slurry in water (a few grams washed with methanol to remove the water, Aldrich) and it was put under a 50 psi hydrogen atmosphere for 16 hrs. The mixture was filtered through Celite under an argon atmosphere and concentrated and then purified by flash chromatography to give 4-aminomethyl-2-methoxy-benzoic acid methyl ester (385.7 mg, 34.7%).
To a mixture of 4-aminomethyl-2-methoxy-benzoic acid methyl ester (149 mg, 0.763 mmol) in Ν,Ν-dimethyl formamide (4.0 mL) was added Ι,Γ-carbonyldiimidazole (Aldrich, 127 mg, 0.762 mmol) . After it was stirred at rt for 16 hrs under an argon atmosphere, the reaction mixture was extracted with EtOAc, and washed with water (2X), and saturated NaCl. The organic phase was separated, dried over Na2S04, filtered and concentrated to give 4- {[(imidazole-l-carbonyl)-amino]-methyl}-2-methoxy-benzoic acid methyl ester (224.3 mg, 101%) crude) which was used without further purification.
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (49.2 mg, 0.116 mmol) and 4- {[(imidazole- 1- carbonyl)-amino]-methyl}-2-methoxy-benzoic acid methyl ester (224.3 mg, 0.775 mmol) in CH2CI2 (8 mL) was stirred rt for 16 hrs. The reaction mixture was then purified by flash column to give rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid methyl ester (61.9 mg, 82.8 %). HRMS(ES+) m/z Calcd for C33H33CI2F2N3O4 : 644.1889; Found: 644.1888
Example 90
Preparation of rac-4-(((2S,3S,4S)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2- fluorophenyl)-3-cyano-4-neopentylpyrrolidine- 1 -carboxamido)methyl)-2-methoxybenzoic acid
Figure imgf000096_0001
M.W. 630.5 C30H33CI2F2N3O3
To a mixture of rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-methoxy- benzoic acid methyl ester (52.1mg, 0.0813 mmol, example 89) in THF (5 mL) was added a solution of LiOH (Aldrich, 25 mg, 0.595 mmol) in water (2.5 mL) and the reaction mixture was stirred at rt for 48 hrs. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 5), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2S04. The mixture was then concentrated to give rac-{l- [(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl- propyl)-pyrrolidine-l-carbonyl]-piperidin-4-yl} -acetic acid (16.2 mg, 31.6 %). LC-MS(ES+/") m/z Calcd for C30H33CI2F2N3O3+H [(M+H): 629; Found: 629.
Example 91
Preparation of rac-(2S,3S,4S)-2-(3-chloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000097_0001
M.W. 536.5 C27H32CI2FN2O3
To a mixture of rac-(2S,3S,4S)-2-(3-chloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2- dimethyl-propyl)-pyrrolidine-3-carbonitrile (40.5 mg, 0.10 mmol) and triethylamine (TEA, 20.0 mg, 0.20 mmol) in CH2CI2 (1 mL) was added phosgene solution (Aldrich, 20% in toluene, 0.12 mL, 0.12 mmol) by injection, and the reaction mixture was stirred at rt for 20 min. 2-((S)-2,2- dimethyl-[l,3]dioxolan-4-yl)-ethylamine (29.4 mg, 0.20 mmol) was then added. The reaction mixture was stirred at rt for another 30 min then concentrated to give the crude product (checked by LCMS) which was diluted with MeOH and treated with PPTS (cat.) at 120 °C for 5 min with CEM microwave reactor. The reaction mixture was concentrated and diluted with CH2CI2 and washed with water and brine. The organic phase was separated, filtered and dried over Na2S04. The mixture was then concentrated and purified by RP-HPLC to give rac-(2S,3S,4S)-2-(3- chloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l- carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (23.5 mg, 43.8%, 2 steps) as a white amorphous. HRMS(ES+) m/z Calcd for C27H32CI2FN3O3+ H [(M+H)+]: 536.1878; Found: 536.1879.
Example 92
Preparation of rac-(2R,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-pro l)-pyrrolidine- 1 -carboxylic acid benzylamide
Figure imgf000097_0002
M. W. 556.5 C30H29CI2F2N3O
A mixture of rac-(2R,3S,4S)-2-(4-chloro-3-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol) prepared in Example 3 and (isocyanatomethyl)benzene (Aldrich, 16.0 mg, 0.12 mmol) in CH2CI2 (2 mL) was stirred at rt for 1 h. The reaction mixture was then concentrated and purified by flash column to give rac-(2R,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carboxylic acid benzylamide (46.8 mg, 84.2%) as a white solid HRMS(ES+) m z Calcd for C30H29CI2F2N3O +H [(M+H): 556.1729; Found: 556.1725. Example 93
Preparation of rac N-[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-pro l)-pyrrolidine-l-carbonyl]-benzamide
Figure imgf000098_0001
M. W. 570.5 C30H27CI2F2N3O2
A mixture of rac-(2R,3S,4S)-2-(4-chloro-3-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-
3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol) prepared in Example 3 and benzoyl isocyanate (Aldrich, 17.6 mg, 0.12 mmol) in CH2CI2 (2 mL) was stirred at rt for 2 h. The reaction mixture was then concentrated and purified by flash column to give rac-(2R,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carboxylic acid benzylamide (52.1 mg, 91.4%) as a white solid. HRMS(ES+) m/z Calcd for C30H27CI2F2N3O2 +H [(M+H): 570.1521; Found: 570.1521.
Example 94
Preparation of chiral 4-({[(2S,3S,4S)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-methoxy- benzoic acid and chiral 4-({[(2R,3R,4R)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-methoxy- benzoic acid
Figure imgf000098_0002
MW 630.52, C32H31CI2F2N3O4
The mixture of rac- 4-({[(2S,3S,4S)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-methoxy- benzoic acid was separated by SFC, 30 % CH3OH on a Kromasil 5-CelluCoat OD prep column to give chiral 4-({[(2S,3S,4S)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid as a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 630.17, found: 630.2 and chiral 4- ({[(2R,3R,4R)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid as a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 630.17, found: 630.2
Example 95
Preparation of 4-({[(2S,3S,4S)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-fluoro- benzoic acid methyl ester
Figure imgf000099_0001
MW 632.52, C32H30CI2F3N3O3
Preparation of methyl 4-(aminomethyl)-2-fluorobenzoate: A solution of 4-cyano-2- fluorobenzoic acid (4.02 g, 24.36 mmol, Aldrich) in methanol (50 mL) was treated with p- toluenesulfonic acid monohydrate (0.46 g, 2.43 mmol) and heated to reflux overnight. The solvent was removed and the reaction residue was extracted with EtOAc, washed with saturated Na2C03, brine and dried over Na2S04 to give Methyl 4-cyano-2-fluorobenzoate (4.46 g, 95%). This Methyl ester (1.03 g, 5.77 mmol) was combined with methanol (60 mL) and Raney Ni (2 spatula tip fulls were added after washing with methanol under argon). It was then put under Hydrogen at 50 PSI on a PARR shaker for 18 firs. The reaction was filtered through celite and washed with methanol while being kept under N2. It was then purified by silica gel chromatography with methanol and methylene chloride to give methyl 4-(aminomethyl)-2- fluorobenzoate (247.6 mg, 23%) as off-white solid.
To a mixture of methyl 4-(aminomethyl)-2-fluorobenzoate (106.9 mg, 0.584 mmol) in Ν,Ν-dimethyl formamide (4.0 mL) was added 1,1 '-carbonyldiimidazole (Aldrich, 98.9 mg, 0.592 mmol) . After it was stirred at rt overnight under an argon atmosphere, the reaction mixture was extracted with EtOAc, and washed with water (2X), and saturated NaCl. The organic phase was separated, dried over Na2S04, filtered and concentrated to give 2-Fluoro-4- {[(imidazole-l-carbonyl)-amino]-methyl}-benzoic acid methyl ester (187.0 mg) which was used without further purification.
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (48.8 mg, 0.115 mmol) and 2-Fluoro-4- {[(imidazole-l-carbonyl)-amino]-methyl}-benzoic acid methyl ester (183.3 mg, 0.764 mmol) in CH2C12 (8 mL) was stirred rt for 16 hrs. The reaction mixture was then purified by flash column to give 4-({[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid methyl ester (64.5 mg, 88 %). HRMS(ES+) m/z Calcd C32H3oCl2F3N303+H(M+H): 632.1689; Found: 632.1686.
Example 96
Preparation of rac 4-({[(2S,3S,4S)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-fluoro- benzoic acid
Figure imgf000100_0001
MW 618.49, C3iH28Cl2F3N303
To a mixture of rac-4-({[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-fluoro- benzoic acid methyl ester (53.0 mg, 0.0838 mmol) in THF (6 mL) was added a solution of LiOH.H20 (Aldrich, 26 mg, 0.615 mmol) in water (3 mL) and the reaction mixture was stirred at rt overnight. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 5), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2S04. The mixture was then concentrated to give rac4-({[(2S,3S,4S)-2-(3- Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrrolidine- 1 -carbonyl] -amino }-methyl)-2-fiuoro-benzoic acid (38.9 mg, 75 %). HRMS(ES+) m/z Calcd C31H28CI2F3N3O3+H (M+H):618.1533; Found: 618.1532 Example 97
Preparation of chiral 4-({[(2S,3S,4S)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-fluoro- benzoic acid and
chiral 4-({[(2R,3R,4R)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3- cyan -4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino} -methyl)-2-fluoro-benzoic acid
Figure imgf000101_0001
MW 618.49, C31H28CI2F3N3O3
The mixture of rac-4-({[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fiuoro- phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-fluoro- benzoic acid was separated by SFC, 25 % CH3OH on a Diacel AD prep column to give chiral chiral- 4-({[(2S,3S,4S)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid as a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 617.15, found: 617.2 and chiral 4- ({[(2R,3R,4R)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid as a white lyophilized solid. MS (ES+) m z Calcd: [(M+H)+]: 617.15, Found: 617.2. Example 98
4-{[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carbon l] -amino } -2-methyl-benzoic acid
Figure imgf000102_0001
MW 600.50, C31H29CI2F2N3O3
To a mixture of methyl 4-amino-2-methylbenzoate (208.9 mg, 1.230 mmol) in N,N- dimethyl formamide (5 mL) was added Ι, -carbonyldiimidazole (Aldrich, 215 mg, 1.29 mmol) . After it was stirred at rt overnight under an argon atmosphere, the reaction mixture was extracted with EtOAc, and washed with water (2X), and saturated NaCl. The organic phase was separated, dried over Na2S04, filtered and concentrated to give 4-[(Imidazole-l-carbonyl)-amino]-2- methyl-benzoic acid methyl ester (342.0 mg) which was used without further purification.
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)- 4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (49.5 mg, 0.117 mmol) and 4-[(Imidazole-l- carbonyl)-amino]-2-methyl-benzoic acid methyl ester (342.4 mg, 1.32 mmol) in CH2C12 (8 mL) was stirred rt for 16 hrs. The reaction mixture was then purified by flash column to give 4- {[(2S,3S,4S)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-2-methyl-benzoic acid methyl ester (63.2 mg, 88 %).
This methyl ester (61.0 mg, 0.099 mmol) in THF (6 mL) was added a solution of
LiOH.H20 (Aldrich, 30 mg, 0.717 mmol) in water (3 mL) and the reaction mixture was stirred at rt overnight. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 5), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2S04. The mixture was then concentrated to give rac- 4-{[(2S,3S,4S)-2-(3- Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)- pyrrolidine- 1 -carbonyl] -amino } -2-methyl-benzoic acid (39 mg, 66 %). HRMS(ES+) m/z Calcd C31H29CI2F2N3O3+H [(M+H):600.1627; Found: 600.1626. Jti Vitro Activity Assay
The ability of the compounds to inhibit the interaction between p53 and MDM2 proteins was measured by an HTRF (homogeneous time-resolved fluorescence) assay in which recombinant GST-tagged MDM2 binds to a peptide that resembles the MDM2-interacting region of p53 (Lane et al). Binding of GST-MDM2 protein and p53-peptide (biotinylated on its N- terminal end) is registered by the FRET (fluorescence resonance energy transfer) between Europium (Eu)-labeled anti-GST antibody and streptavidin- conjugated Allophycocyanin (APC). Test is performed in black flat-bottom 384-well plates (Costar) in a total volume of 40 uL containing:90 nM biotinylate peptide, 160 ng/ml GST-MDM2, 20 nM streptavidin- APC (PerkinElmer Wallac), 2 nM Eu-labeled anti-GST-antibody (PerkinElmer Wallac), 0.2% bovine serum albumin (BSA), 1 mM dithiothreitol (DTT) and 20 mM Tris-borate saline (TBS) buffer as follows: Add 10 uL of GST-MDM2 (640 ng/ml working solution) in reaction buffer to each well. Add 10 uL diluted compounds (1 :5 dilution in reaction buffer) to each well, mix by shaking. Add 20 uL biotinylated p53 peptide (180 nM working solution) in reaction buffer to each well and mix on shaker. Incubate at 37°C for 1 h. Add 20 uL streptavidin- APC and Eu- anti-GST antibody mixture (6 nM Eu-anti-GST and 60 nM streptavidin- APC working solution) in TBS buffer with 0.2% BSA, shake at room temperature for 30 minutes and read using a TRF- capable plate reader at 665 and 615 nm (Victor , Perkin Elmer Wallac). If not specified, the reagents were purchased from Sigma Chemical Co.
Activity data for some of the Example compounds expressed as lCs<>:bsa:0.Q2% are as follows:
Example IC™:bsa:0.02%
4 0.269
5 1.317
6 3.591
7 1.596
8 0.049
9 0.089
10 0.469
11 0.811
12 0.644
16 3.228
19 2.28 Example IC™:bsa:0.02%
21 0.974
22 0.329
26 0.592
27 0.247
31 1.356
33 0.491
34 3.27
35 0.69
41 0.869
48 1.734
50 0.869
51 1.926
55 0.851
57 0.353
58 0.541
59 0.817
62 1.188
63 0.383
64 0.846
65 0.583
68 0.222
71 0.123
72 3.28
73 0.693
74 0.671
75 1.071
76 0.368
78 0.79
83 1
90 0.1
91 1.043
94 0.064
96 0.075
97 0.045
98 0.265

Claims

Claims
1. A compound of the formula (I)
Figure imgf000105_0001
wherein
X is selected from the group consisting of H, F, CI, Br, I, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl and methoxy,
Y is one to four group(s) independently selected from the group consisting of H, F, CI, Br,
I, CN, OH, nitro, lower alkyl, cycloalkyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aryl, heteroaryl, heterocycle, COOR', OCOR', CONR'R", NR'COR", NR"S02R',
S02NR'R" and NR'R" wherein
R' and R" are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle
and in the case of R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle,
one of Ri and R2 is selected from the group consisting of lower alkyl,
substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen,
one of R3 and R4 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen, R5 is selected from the group consisting of lower alkyl, substituted lower alkyl,
-CH2(CH2)n-CHOH-R', -CH2(CH2)n-CHOH-CH2-(CH2)n-NR'R", -CH2(CH2)n-CO(CH2)nNR'R", -CO(CH2)n-R', -CO(CH2)n-NR'-(CH2)n-CHOH-R', -CO(CH2)n-NR'R", -(CH2)n-NR'S02R", -COCH2(CH2)n-COOH, -(CH2)n-COOR', -(CH2)n-CONR'R", -CO(CH2)n-OR',
-COCH2(CH2)n-SR' , -COCH2(CH2)n-SOR' , -COCH2(CH2)n-S02R' , -COCH2(CH2)n-COR' , -COCH2(CH2)n-S03H, -COCH2(CH2)n-SONR'R", -COCH2(CH2)n-S02NR'R",
-COCH2(CH2CH20)m-(CH2)n-R' , -COCH2(CH2CH20)m-(CH2)n-OH,
-COCH2(CH2CH20)m-(CH2)n-OR', -COCH2(CH2CH20)m-(CH2)n-NR'R",
-COCH2(CH2CH20)m-(CH2)n-NR'COR", -COCH2(CH2CH20)m-(CH2)n-NR'S02R",
-COCH2(CH2CH20)m-(CH2)n-COOH, -COCH2(CH2CH20)m-(CH2)n-COOR',
-COCH2(CH2CH20)m-(CH2)n-CONR'R", -COCH2(CH2CH20)m-(CH2)n-S02R',
-COCH2(CH2CH20)m-(CH2)n-COR', -COCH2(CH2CH20)m-(CH2)n-SONR'R",
-COCH2(CH2CH20)m-(CH2)n-S02NR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-R',
-COCH2(CH2)p- (CH2CH20)m-(CH2)n-OH, -COCH2(CH2)p-(CH2CH20)m-(CH2)n-OR' ,
-COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'COR", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'S02R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COOH, -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COOR', -COCH2(CH2)p-(CH2CH20)m-(CH2)n-CONR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-S02R' , -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COR' , -COCH2(CH2)p-(CH2CH20)m-(CH2)n-SONR'R",
-COCH2(CH2)p-(CH2CH20)m-(CH2)n-S02NR'R", -COCH2-COR', -COCH2-SOR' and
-COCH2S02R' wherein R' and R" are as above,
m, n, and p are independently 0 to 6,
and the pharmaceutically acceptable salts and esters thereof.
2. A compound of claim 1 of the formula (IA)
Figure imgf000106_0001
wherein
X is selected from the group consisting of F, CI and Br, Y is one to two group(s) independently selected from the group consisting of H, F, CI, Br, I, CN, OH, nitro, lower alkyl, cycloalkyl and lower alkoxy,
Ri is hydrogen,
one of R2 and R3 is selected from aryl, substituted aryl, heteroaryl or substituted heteroaryl and the other is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl,
R4 is hydrogen,
R5 is selected from the group consisting of lower alkyl, substituted lower alkyl,
-CH2(CH2)n-CHOH-R', -CH2(CH2)n-CHOH-CH2-(CH2)n-NR'R", -CH2(CH2)n-CO(CH2)nNR'R", -CO(CH2)n-R', -CO(CH2)n-NR'-(CH2)n-CHOH-R', -CO(CH2)n-NR'R", -(CH2)n-NR'S02R", -COCH2(CH2)n-COOH, -(CH2)n-COOR\ -(CH2)n-CONR'R", -CO(CH2)n-OR',
-COCH2(CH2)n-SR', -COCH2(CH2)n-SOR', -COCH2(CH2)n-S02R', -COCH2(CH2)n-COR', -COCH2(CH2)n-S03H, -COCH2(CH2)n-SONR'R", -COCH2(CH2)n-S02NR'R",
-COCH2(CH2CH20)m-(CH2)n-R' , -COCH2(CH2CH20)m-(CH2)n-OH,
-COCH2(CH2CH20)m-(CH2)n-OR', -COCH2(CH2CH20)m-(CH2)n-NR'R",
-COCH2(CH2CH20)m-(CH2)n-NR'COR", -COCH2(CH2CH20)m-(CH2)n-NR'S02R",
-COCH2(CH2CH20)m-(CH2)n-COOH, -COCH2(CH2CH20)m-(CH2)n-COOR' ,
-COCH2(CH2CH20)m-(CH2)n-CONR'R", -COCH2(CH2CH20)m-(CH2)n-S02R',
-COCH2(CH2CH20)m-(CH2)n-COR', -COCH2(CH2CH20)m-(CH2)n-SONR'R",
-COCH2(CH2CH20)m-(CH2)n-S02NR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-R',
-COCH2(CH2)p- (CH2CH20)m-(CH2)n-OH, -COCH2(CH2)p-(CH2CH20)m-(CH2)n-OR' ,
-COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'COR", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR' S02R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COOH, -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COOR', -COCH2(CH2)p-(CH2CH20)m-(CH2)n-CONR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-S02R' , -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COR' , -COCH2(CH2)p-(CH2CH20)m-(CH2)n-SONR'R",
-COCH2(CH2)p-(CH2CH20)m-(CH2)n-S02NR'R", -COCH2-COR', -COCH2-SOR' and
-COCH2S02R',
R' and R" are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle
and wherein R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle,
m, n, and p are independently 0 to 6
and the pharmaceutically acceptable salts and esters and enantiomers thereof.
3. The compound of claim 2 of the formula (IB)
Figure imgf000108_0001
wherein
X is F, CI or Br,
Y is a mono substituting group consisted of H or F,
Z is F, CI or Br,
W is H, F or CI,
Ri is H,
R4 IS H,
R5 is selected from the group consisting of lower alkyl, substituted lower alkyl,
-CH2(CH2)„-CHOH-R', -CH2(CH2)n-CHOH-CH2-(CH2)n-NR'R", -CH2(CH2)n-CO(CH2)nNR'R", -CO(CH2)n-R', -CO(CH2)n-NR'-(CH2)n-CHOH-R', -CO(CH2)n-NR'R", -(CH2)n-NR'S02R", -COCH2(CH2)n-COOH, -(CH2)n-COOR\ -(CH2)n-CONR'R", -CO(CH2)n-OR',
-COCH2(CH2)n-SR', -COCH2(CH2)n-SOR', -COCH2(CH2)n-S02R', -COCH2(CH2)n-COR', -COCH2(CH2)n-S03H, -COCH2(CH2)n-SONR'R", -COCH2(CH2)n-S02NR'R",
-COCH2(CH2CH20)m-(CH2)n-R', -COCH2(CH2CH20)m-(CH2)n-OH,
-COCH2(CH2CH20)m-(CH2)n-OR', -COCH2(CH2CH20)m-(CH2)n-NR'R",
-COCH2(CH2CH20)m-(CH2)n-NR'COR", -COCH2(CH2CH20)m-(CH2)n-NR'S02R",
-COCH2(CH2CH20)m-(CH2)n-COOH, -COCH2(CH2CH20)m-(CH2)n-COOR' , -COCH2(CH2CH20)m-(CH2)n-CONR'R", -COCH2(CH2CH20)m-(CH2)n-S02R',
-COCH2(CH2CH20)m-(CH2)n-COR', -COCH2(CH2CH20)m-(CH2)n-SONR'R",
-COCH2(CH2CH20)m-(CH2)n-S02NR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-R',
-COCH2(CH2)p- (CH2CH20)m-(CH2)n-OH, -COCH2(CH2)p-(CH2CH20)m-(CH2)n-OR' ,
-COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'COR", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'S02R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COOH, -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COOR', -COCH2(CH2)p-(CH2CH20)m-(CH2)n-CONR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-S02R' , -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COR' , -COCH2(CH2)p-(CH2CH20)m-(CH2)n-SONR'R",
-COCH2(CH2)p-(CH2CH20)m-(CH2)n-S02NR'R", -COCH2-COR', -COCH2-SOR' and
-COCH2S02R',
R' and R" are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle,
and wherein R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle,
m, n, and p are independently 0 to 6,
Re, R7 are both methyl, or linked to form cyclopropyl, cyclo butyl, cyclopentyl or cyclohexyl,
R8 is (CH2)q-R9,
q is 0, 1 or 2
Rg is selected from hydrogen, hydroxyl, lower alkyl, lower alkoxy, lower cycloalkyl, aryl, substituted aryl. heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle,
and the pharmaceutically acceptable salts and esters and enantiomers thereof.
4. The compound of claim 2 having the formula (IC)
Figure imgf000110_0001
wherein
X is F, CI or Br,
Y is a mono substituting group consisted of H or F,
Z is F, CI or Br,
W is H or F,
Ri is H,
R4 IS H,
R5 is selected from the group consisting of -CO(CH2)„-R', -CO(CH2)„-NR'R",
-(CH2)n-CONR'R", -CH2(CH2)n-CHOH-R', -CH2(CH2)n-CHOH-CH2-(CH2)n-NR'R",
-CH2(CH2)n-CO(CH2)nNR'R", -CO(CH2)n-R', -CO(CH2)n-NR'-(CH2)n-CHOH-R', and
-CO(CH2)n-NR'R",
n is 0,1 or 2,
R' and R" are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle,
and wherein R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle,
R6, R7 are both methyl, or linked to form cyclopropyl, cyclo butyl, cyclopentyl or cyclohexyl ,
R8 is (CH2)q-R9,
q is 0, 1 or 2
R9 is selected from hydrogen, hydroxyl, lower alkyl, lower alkoxy, cycloalkyl, aryl, substituted aryl. heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle,
and the pharmaceutically acceptable salts and esters thereof.
5. A compound of claim 1 selected from the group consisting of:
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide,
(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid ((S)-3 ,4-dihydroxy-butyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2- dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid ((S)-3 ,4-dihydroxy-butyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid [ 1 -(2-hydroxy-2-methyl-propyl)- 1 H- pyrazo 1-3 -yl] -amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-4-(2,2- dimethyl-propyl)- 1 -(4-ethyl-piperazine- 1 -carbonyl)-pyrrolidine-3-carbonitrile,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine-l -carboxylic acid (piperidin-4-ylmethyl)-amide,
rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-benzoic acid,
4-({[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino } -methyl)-benzoic acid,
rac-4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino} -benzoic acid,
4-{[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino } -benzoic acid and
rac-3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino} -benzoic acid.
6. A compound of claim 1 selected from the group consisting of:
rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4 (2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -benzoic acid,
rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4 (2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -benzoic acid,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (4-chloro-phenyl)-amide, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (4-fluoro-phenyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid 4-chloro-benzylamide,
rac-( 2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-
(2,2-dimethyl-propyl)-pyrrolidine-l -carboxylic acid [3-(lH-tetrazol-5-yl)-phenyl]-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (4-cyano-phenyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-l-(4-cyano- benzoyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (4-carbamoyl-phenyl)-amide,
rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonylj-benzamide and
rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-2-oxo-ethyl} -2-ethoxy-benzoic acid.
7. A compound of claim 1 selected from the group consisting of:
rac-4-{4-[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-4-oxo-butyl} -benzoic acid,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid 4-fluoro-benzylamide,
rac-4-{4-[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-3-oxo-propenyl} -benzoic acid,
rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-3-oxo-propionic acid,
rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2- (2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetic acid tert-butyl ester,
rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2- (2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetic acid,
rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3- cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetylamino}-benzoic acid methyl ester, rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-2-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-acetylamino} -benzoic acid,
rac-4-{2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-2-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-acetylamino} -benzamide,
rac-2-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2- (2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-N-((S)-3,4-dihydroxy-butyl)-acetamide and
rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide.
8. A compound of claim 1 selected from the group consisting of:
rac-4-{[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 2-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-benzoic acid ethyl ester,
rac-4-{[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 2-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino} -benzoic acid ,
rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2- (2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-acetic acid,
rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetylamino}-benzoic acid methyl ester,
rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-acetylamino} -benzoic acid,
rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetylamino}-methyl-benzoic acid methyl ester, rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetylamino}-methyl-benzoic acid,
rac-2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidin-l-yl]-N-((S)-3,4-dihydroxy-butyl)-acetamide,
rac-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidin-l-yl]-acetic acid ethyl ester,
rac-( 2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine-l -carboxylic acid pyridin-4-ylamide and
rac-2-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-benzoic acid methyl ester.
9. A compound of claim 1 selected from the group consisting of:
rac- [(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-acetic acid,
2-{[(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino } -benzoic acid,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (4-fluoro-phenyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (3-methylsulfanyl-phenyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (3-methanesulfonyl-phenyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid pyridin-3-ylamide,
rac-4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-butyric acid ethyl ester,
rac-4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino} -butyric acid,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (3-carbamoyl-propyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine-l -carboxylic acid (3-methylcarbamoyl-propyl)-amide and rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid ( 1 -methanesulfonyl-piperidin-4-yl)-amide.
10. A compound of claim 1 selected from the group consisting of:
rac-2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidin- 1 -yl]-acetamide,
rac-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-acetic acid ethyl ester,
rac-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino } -acetic acid,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid methylcarbamoylmethyl-amide, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid carbamoylmethyl-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2- dimethyl-propyl)- 1 -(pyridine-3 -sulfonyl)-pyrro lidine-3 -carbonitrile,
rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid methyl ester,
rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2- dimethyl-propyl)- 1 -(6-morpho lin-4-yl-pyridine-3 -sulfonyl)-pyrro lidine-3 -carbonitrile,
rac-4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-2-methoxy-benzoic acid methyl ester and
rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid.
11. A compound of claim 1 selected from the group consisting of:
rac-3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-propionic acid ethyl ester,
rac-3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino} -propionic acid,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (2-methylcarbamoyl-ethyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (2-dimethylcarbamoyl-ethyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (2-carbamoyl-ethyl)-amide,
rac-{l-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-piperidin-4-yl} -acetic acid ethyl ester,
rac-{l-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -piperidin-4-yl} -acetic acid, rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidin- 1 -yl] -propionic acid,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (6-chloro-pyridin-3-ylmethyl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid (6-chloro-pyridin-3-yl)-amide,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carboxylic acid ( 1 -methyl-2-oxo- 1 ,2-dihydro-pyridin-4-yl)- amide and,
rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -sulfonyl] -benzoic acid.
12. A compound of claim 1 selected from the group consisting of:
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-l-(6-chloro- pyridine-3-sulfonyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile,
rac-(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-4-(2,2- dimethyl-propyl)- 1 -(6-oxo- 1 ,6-dihydro-pyridine-3-sulfonyl)-pyrrolidine-3-carbonitrile,
rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-l-(6-chloro- pyridine-3-carbonyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile,
rac-(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-4-(2,2- dimethyl-propyl)- 1 -(6-oxo- 1 ,6-dihydro-pyridine-3-carbonyl)-pyrrolidine-3-carbonitrile,
rac-(2S,3S,4S)-2-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-4-(2,2- dimethyl-propyl)- 1 -(1 -methyl-6-oxo- 1 ,6-dihydro-pyridine-3-carbonyl)-pyrrolidine-3-carbonitrile, rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid methyl ester,
rac-4-(((2S,3S,4S)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4- neopentylpyrrolidine- 1 -carboxamido)methyl)-2-methoxybenzoic acid,
rac-(2R,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine-l -carboxylic acid benzylamide,
rac N-[(2S,3S,4S)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonylj-benzamide, chiral 4-({[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid, chiral 4-({[(2R,3R,4R)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid,
4-({[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-fiuoro-benzoic acid methyl ester,
rac 4-({[(2S,3S,4S)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano- 4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-fiuoro-benzoic acid,
chiral 4-({[(2S,3S,4S)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-fiuoro-benzoic acid, chiral 4-({[(2R,3R,4R)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3- cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-l-carbonyl]-amino}-methyl)-2-fiuoro-benzoic acid and,
4-{[(2S,3S,4S)-2-(3-Chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4- (2,2-dimethyl-propyl)-pyrrolidine- 1 -carbonyl] -amino } -2-methyl-benzoic acid.
13. A pharmaceutical formulation comprising a compound of the formula (IA)
Figure imgf000117_0001
wherein
X is selected from the group consisting of F, CI and Br,
Y is one to two group(s) independently selected from the group consisting of H, F, CI, Br, I, CN, OH, nitro, lower alkyl, cycloalkyl and lower alkoxy,
Ri is hydrogen,
one of R2 and R3 is selected from aryl, substituted aryl, heteroaryl or substituted heteroaryl and the other is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl,
R4 is hydrogen,
R5 is selected from the group consisting of lower alkyl, substituted lower alkyl,
-CH2(CH2)n-CHOH-R', -CH2(CH2)n-CHOH-CH2-(CH2)n-NR'R", -CH2(CH2)n-CO(CH2)nNR'R", -CO(CH2)n-R', -CO(CH2)n-NR'-(CH2)n-CHOH-R', -CO(CH2)n-NR'R", -(CH2)n-NR'S02R", -COCH2(CH2)n-COOH, -(CH2)n-COOR', -(CH2)n-CONR'R", -CO(CH2)n-OR',
-COCH2(CH2)n-SR', -COCH2(CH2)n-SOR', -COCH2(CH2)n-S02R', -COCH2(CH2)n-COR', -COCH2(CH2)n-S03H, -COCH2(CH2)n-SONR'R", -COCH2(CH2)n-S02NR'R",
-COCH2(CH2CH20)m-(CH2)n-R', -COCH2(CH2CH20)m-(CH2)n-OH,
-COCH2(CH2CH20)m-(CH2)n-OR', -COCH2(CH2CH20)m-(CH2)n-NR'R",
-COCH2(CH2CH20)m-(CH2)n-NR'COR", -COCH2(CH2CH20)m-(CH2)n-NR'S02R",
-COCH2(CH2CH20)m-(CH2)n-COOH, -COCH2(CH2CH20)m-(CH2)n-COOR' ,
-COCH2(CH2CH20)m-(CH2)n-CONR'R", -COCH2(CH2CH20)m-(CH2)n-S02R',
-COCH2(CH2CH20)m-(CH2)n-COR', -COCH2(CH2CH20)m-(CH2)n-SONR'R",
-COCH2(CH2CH20)m-(CH2)n-S02NR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-R',
-COCH2(CH2)p-(CH2CH20)m-(CH2)n-OH, -COCH2(CH2)p-(CH2CH20)m-(CH2)n-OR',
-COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'COR", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'S02R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COOH, -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COOR', -COCH2(CH2)p-(CH2CH20)m-(CH2)n-CONR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-S02R' , -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COR' , -COCH2(CH2)p-(CH2CH20)m-(CH2)n-SONR'R",
-COCH2(CH2)p-(CH2CH20)m-(CH2)n-S02NR'R", -COCH2-COR', -COCH2-SOR' and
-COCH2S02R',
R' and R" are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle
and wherein R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle,
m, n, and p are independently 0 to 6, and the pharmaceutically acceptable salts and esters and enantiomers thereof together with a pharmaceutically acceptable excipient and/or carrier.
14. A compound according to claims 1 to 12 for use as a medicament.
15. A compound according to claims 1 to 12 for use as a medicament in the treatment of cancer, in particular solid tumors, more particularly breast, colon, lung and prostate tumors.
16. The use of a compound according to claims 1 to 12 for the manufacture of medicaments for the treatment of cancer, in particular solid tumors, more particularly breast, colon, lung and prostate tumors.
17. A process for the manufacture of the compound of formula (I)
Figure imgf000119_0001
I
wherein
X is selected from the group consisting of H, F, CI, Br, I, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl and methoxy,
Y is one to four group(s) independently selected from the group consisting of H, F, CI, Br, I, CN, OH, nitro, lower alkyl, cycloalkyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aryl, heteroaryl, heterocycle, COOR', OCOR', CONR'R", NR'COR", NR"S02R', S02NR'R" and NR'R" wherein
R' and R" are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle and in the case of R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle,
one of Ri and R2 is selected from the group consisting of lower alkyl,
substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen,
one of R3 and R4 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen,
R5 is selected from the group consisting of lower alkyl, substituted lower alkyl,
-CH2(CH2)n-CHOH-R', -CH2(CH2)n-CHOH-CH2-(CH2)n-NR'R", -CH2(CH2)n-CO(CH2)nNR'R", -CO(CH2)n-R', -CO(CH2)n-NR'-(CH2)n-CHOH-R', -CO(CH2)n-NR'R", -(CH2)n-NR'S02R", -COCH2(CH2)n-COOH, -(CH2)n-COOR' , -(CH2)n-CONR'R", -CO(CH2)n-OR' ,
-COCH2(CH2)n-SR', -COCH2(CH2)n-SOR', -COCH2(CH2)n-S02R', -COCH2(CH2)n-COR', -COCH2(CH2)n-S03H, -COCH2(CH2)n-SONR'R", -COCH2(CH2)n-S02NR'R",
-COCH2(CH2CH20)m-(CH2)n-R' , -COCH2(CH2CH20)m-(CH2)n-OH,
-COCH2(CH2CH20)m-(CH2)n-OR', -COCH2(CH2CH20)m-(CH2)n-NR'R",
-COCH2(CH2CH20)m-(CH2)n-NR'COR", -COCH2(CH2CH20)m-(CH2)n-NR'S02R",
-COCH2(CH2CH20)m-(CH2)n-COOH, -COCH2(CH2CH20)m-(CH2)n-COOR' ,
-COCH2(CH2CH20)m-(CH2)n-CONR'R", -COCH2(CH2CH20)m-(CH2)n-S02R',
-COCH2(CH2CH20)m-(CH2)n-COR', -COCH2(CH2CH20)m-(CH2)n-SONR'R",
-COCH2(CH2CH20)m-(CH2)n-S02NR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-R',
-COCH2(CH2)p- (CH2CH20)m-(CH2)n-OH, -COCH2(CH2)p-(CH2CH20)m-(CH2)n-OR',
-COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'COR", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-NR'S02R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COOH, -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COOR', -COCH2(CH2)p-(CH2CH20)m-(CH2)n-CONR'R", -COCH2(CH2)p-(CH2CH20)m-(CH2)n-S02R' , -COCH2(CH2)p-(CH2CH20)m-(CH2)n-COR' , -COCH2(CH2)p-(CH2CH20)m-(CH2)n-SONR'R",
-COCH2(CH2)p-(CH2CH20)m-(CH2)n-S02NR'R", -COCH2-COR', -COCH2-SOR' and
-COCH2S02R' wherein R' and R" are as above,
m, n, and p are independently 0 to 6, comprising the step of reacting a compound of formula (Ila) or (lib)
Figure imgf000121_0001
Ila lib with a compound of formula (III)
Figure imgf000121_0002
to give a compound of the formula (IV)
Figure imgf000121_0003
18. The novel compounds, processes, formulations and uses substantially as described herein before.
PCT/EP2010/065159 2009-10-14 2010-10-11 Novel n-substituted-pyrrolidines as inhibitors of mdm2-p-53 interactions Ceased WO2011045257A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
CN2010800461741A CN102548963A (en) 2009-10-14 2010-10-11 Novel N-substituted-pyrrolidines as inhibitors of MDM2-p53 interactions
CA2774512A CA2774512A1 (en) 2009-10-14 2010-10-11 Novel n-substituted-pyrrolidines as inhibitors of mdm2-p-53 interactions
JP2012533592A JP2013507416A (en) 2009-10-14 2010-10-11 Novel N-substituted pyrrolidines as inhibitors of MDM2-P53 interaction
MX2012003982A MX2012003982A (en) 2009-10-14 2010-10-11 Novel n-substituted-pyrrolidines as inhibitors of mdm2-p-53 interactions.
AU2010305914A AU2010305914A1 (en) 2009-10-14 2010-10-11 Novel N-substituted-pyrrolidines as inhibitors of MDM2-p-53 interactions
IN2487DEN2012 IN2012DN02487A (en) 2009-10-14 2010-10-11
EP10768450A EP2488491A1 (en) 2009-10-14 2010-10-11 Novel n-substituted-pyrrolidines as inhibitors of mdm2-p-53 interactions
BR112012008485A BR112012008485A2 (en) 2009-10-14 2010-10-11 compound, pharmaceutical formulation, use of a compound, process for the manufacture of compound of formula and compounds, processes, formulations and uses
IL218018A IL218018A0 (en) 2009-10-14 2012-02-09 Novel n-substituted-pyrrolidines as inhibitors of mdm2-p-53 interactions

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US25141309P 2009-10-14 2009-10-14
US61/251,413 2009-10-14
US34562610P 2010-05-18 2010-05-18
US61/345,626 2010-05-18

Publications (1)

Publication Number Publication Date
WO2011045257A1 true WO2011045257A1 (en) 2011-04-21

Family

ID=43567698

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2010/065159 Ceased WO2011045257A1 (en) 2009-10-14 2010-10-11 Novel n-substituted-pyrrolidines as inhibitors of mdm2-p-53 interactions

Country Status (12)

Country Link
US (1) US8017607B2 (en)
EP (1) EP2488491A1 (en)
JP (1) JP2013507416A (en)
KR (1) KR20120081210A (en)
CN (1) CN102548963A (en)
AU (1) AU2010305914A1 (en)
BR (1) BR112012008485A2 (en)
CA (1) CA2774512A1 (en)
IL (1) IL218018A0 (en)
IN (1) IN2012DN02487A (en)
MX (1) MX2012003982A (en)
WO (1) WO2011045257A1 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012076513A1 (en) * 2010-12-09 2012-06-14 F. Hoffmann-La Roche Ag 3-cyano-1-hydroxymethyl-2-phenylpyrrolidine derivatives as inhibitors of mdm2-p53 interactions useful for the treatment of cancer
US8629133B2 (en) 2011-03-10 2014-01-14 Daiichi Sankyo Company, Limited Dispiropyrrolidine derivatives
US8846657B2 (en) 2012-12-20 2014-09-30 Merck Sharp & Dohme Corp. Substituted imidazopyridines as HDM2 inhibitors
US9359368B2 (en) 2012-09-06 2016-06-07 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
WO2017201449A1 (en) 2016-05-20 2017-11-23 Genentech, Inc. Protac antibody conjugates and methods of use
WO2023056069A1 (en) 2021-09-30 2023-04-06 Angiex, Inc. Degrader-antibody conjugates and methods of using same
WO2024240858A1 (en) 2023-05-23 2024-11-28 Valerio Therapeutics Protac molecules directed against dna damage repair system and uses thereof

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK2118123T3 (en) * 2007-01-31 2016-01-25 Dana Farber Cancer Inst Inc Stabilized p53 peptides and uses thereof
US8592377B2 (en) 2007-03-28 2013-11-26 President And Fellows Of Harvard College Stitched polypeptides
US8354444B2 (en) * 2008-09-18 2013-01-15 Hoffmann-La Roche Inc. Substituted pyrrolidine-2-carboxamides
US20110118283A1 (en) * 2009-11-17 2011-05-19 Qingjie Ding Substituted Pyrrolidine-2-Carboxamides
ES2711526T3 (en) 2010-08-13 2019-05-06 Aileron Therapeutics Inc Peptidomimetic macrocycles
TW201806968A (en) 2011-10-18 2018-03-01 艾利倫治療公司 Peptidomimetic macrocycles
BR112014020103A2 (en) 2012-02-15 2018-10-09 Aileron Therapeutics, Inc. peptidomimetic macrocycles
EP2819688A4 (en) 2012-02-15 2015-10-28 Aileron Therapeutics Inc PEPTIDOMIMETIC MACROCYCLES CROSS-LINKED WITH TRIAZOLE AND THIOETHER
WO2014071241A1 (en) 2012-11-01 2014-05-08 Aileron Therapeutics, Inc. Disubstituted amino acids and methods of preparation and use thereof
AU2015320545C1 (en) 2014-09-24 2020-05-14 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and formulations thereof
EP3197478A4 (en) 2014-09-24 2018-05-30 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and uses thereof
WO2016154058A1 (en) 2015-03-20 2016-09-29 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and uses thereof
WO2017044633A1 (en) 2015-09-10 2017-03-16 Aileron Therapeutics, Inc. Peptidomimetic macrocycles as modulators of mcl-1

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060014708A1 (en) 2004-07-15 2006-01-19 Bartkovitz David J 2,6-Diaminopyridine derivatives
WO2006091646A2 (en) * 2005-02-22 2006-08-31 The Regents Of The University Of Michigan Small molecule inhibitors of mdm2 and uses thereof
WO2007082805A1 (en) * 2006-01-18 2007-07-26 F. Hoffmann-La Roche Ag Cis-4, 5-biaryl-2-heterocyclic-imidazolines as mdm2 inhibitors

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0947511A1 (en) 1998-03-30 1999-10-06 F. Hoffmann-La Roche Ag Derivatives of phenoxy acetic acid and of phenoxymethyl tetrazole having antitumor activity
HUP0203548A3 (en) 1999-07-21 2003-04-28 Astrazeneca Ab New spirooxindole derivatives, process for their preparation, pharmaceutical compositions containing them and their use
WO2005099687A2 (en) 2004-04-09 2005-10-27 President And Fellows Of Harvard College Analogs of salinosporamide a
BRPI0713119A2 (en) 2006-06-30 2012-04-17 Schering Corp Substituted piperidines that increase the activity of p53 and the uses of these
MY160424A (en) 2008-09-18 2017-03-15 Hoffmann La Roche Substituted pyrrolidine-2-carboxyamides.

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060014708A1 (en) 2004-07-15 2006-01-19 Bartkovitz David J 2,6-Diaminopyridine derivatives
WO2006091646A2 (en) * 2005-02-22 2006-08-31 The Regents Of The University Of Michigan Small molecule inhibitors of mdm2 and uses thereof
WO2007082805A1 (en) * 2006-01-18 2007-07-26 F. Hoffmann-La Roche Ag Cis-4, 5-biaryl-2-heterocyclic-imidazolines as mdm2 inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANSEL ET AL.: "Pharmaceutical Dosage Forms and Drug Delivery Systems", 1995, pages: 196,1456 - 1457

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012076513A1 (en) * 2010-12-09 2012-06-14 F. Hoffmann-La Roche Ag 3-cyano-1-hydroxymethyl-2-phenylpyrrolidine derivatives as inhibitors of mdm2-p53 interactions useful for the treatment of cancer
US8629133B2 (en) 2011-03-10 2014-01-14 Daiichi Sankyo Company, Limited Dispiropyrrolidine derivatives
US12545685B2 (en) 2011-03-10 2026-02-10 Daiichi Sankyo Company, Limited Dispiropyrrolidine derivatives
US9718830B2 (en) 2012-09-06 2017-08-01 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
US9540386B2 (en) 2012-09-06 2017-01-10 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
US9718831B2 (en) 2012-09-06 2017-08-01 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
US9359368B2 (en) 2012-09-06 2016-06-07 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
US9745315B2 (en) 2012-09-06 2017-08-29 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
US9884871B2 (en) 2012-09-06 2018-02-06 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
US10023578B2 (en) 2012-09-06 2018-07-17 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
US10030030B2 (en) 2012-09-06 2018-07-24 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
US8846657B2 (en) 2012-12-20 2014-09-30 Merck Sharp & Dohme Corp. Substituted imidazopyridines as HDM2 inhibitors
WO2017201449A1 (en) 2016-05-20 2017-11-23 Genentech, Inc. Protac antibody conjugates and methods of use
WO2023056069A1 (en) 2021-09-30 2023-04-06 Angiex, Inc. Degrader-antibody conjugates and methods of using same
WO2024240858A1 (en) 2023-05-23 2024-11-28 Valerio Therapeutics Protac molecules directed against dna damage repair system and uses thereof

Also Published As

Publication number Publication date
IN2012DN02487A (en) 2015-08-28
EP2488491A1 (en) 2012-08-22
BR112012008485A2 (en) 2019-09-24
KR20120081210A (en) 2012-07-18
US8017607B2 (en) 2011-09-13
AU2010305914A1 (en) 2012-03-08
MX2012003982A (en) 2012-05-08
CA2774512A1 (en) 2011-04-21
IL218018A0 (en) 2012-04-30
US20110086854A1 (en) 2011-04-14
JP2013507416A (en) 2013-03-04
CN102548963A (en) 2012-07-04

Similar Documents

Publication Publication Date Title
WO2011045257A1 (en) Novel n-substituted-pyrrolidines as inhibitors of mdm2-p-53 interactions
KR101380013B1 (en) Substituted pyrrolidine-2-carboxamides
KR101418191B1 (en) Spiroindolinone pyrrolidines
AU2011214506C1 (en) Substituted pyrrolidine-2-carboxamides
US8288431B2 (en) Substituted spiroindolinones
US20110118283A1 (en) Substituted Pyrrolidine-2-Carboxamides
RU2442779C2 (en) Derivants of 2, 4, 5-triphenylimidazoline as inactivators of interaction between p53 and mdm2 proteins designed for application as anticancer drugs
US8217044B2 (en) Spiroindolinone pyrrolidines
US20120149660A1 (en) Novel n-substituted 5-hydroxypyrollindes as inhibitors of mdm2-p53 interactions
CA2662838A1 (en) Oxindole derivatives
AU2013269798A1 (en) Substituted pyrrolidine-2-carboxamides
CN101679241B (en) Prolinamide derivatives as NK3 antagonists
EA014498B1 (en) Benzamide derivatives as antagonists of bradykinin receptors
CN101090888A (en) 4-aminopiperidine derivatives
EP2155719A1 (en) Azacyclylbenzamide derivatives as histamine-3 antagonists
HK1123789B (en) Azabicyclic derivatives, preparation method thereof and pharmaceutical compositions containing same

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201080046174.1

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10768450

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2010305914

Country of ref document: AU

Ref document number: 218018

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2010768450

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2010305914

Country of ref document: AU

Date of ref document: 20101011

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2774512

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2487/DELNP/2012

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: MX/A/2012/003982

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2012533592

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 20127012100

Country of ref document: KR

Kind code of ref document: A

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112012008485

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112012008485

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20120411