WO2011098398A1 - Substituted pyrrolidine-2-carboxamides - Google Patents

Substituted pyrrolidine-2-carboxamides Download PDF

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Publication number
WO2011098398A1
WO2011098398A1 PCT/EP2011/051619 EP2011051619W WO2011098398A1 WO 2011098398 A1 WO2011098398 A1 WO 2011098398A1 EP 2011051619 W EP2011051619 W EP 2011051619W WO 2011098398 A1 WO2011098398 A1 WO 2011098398A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
chloro
fluoro
cyano
pyrrolidine
Prior art date
Application number
PCT/EP2011/051619
Other languages
French (fr)
Inventor
David Joseph Bartkovitz
Xin-Jie Chu
Qingjie Ding
Nan Jiang
Jin-Jun Liu
Tina Morgan Ross
Jing Zhang
Zhuming Zhang
Original Assignee
F. Hoffmann-La Roche Ag
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Filing date
Publication date
Priority to MX2012009186A priority Critical patent/MX2012009186A/en
Priority to CA2788236A priority patent/CA2788236C/en
Priority to DK11702449.7T priority patent/DK2534132T3/en
Priority to SG2012055752A priority patent/SG182763A1/en
Priority to BR112012019672-3A priority patent/BR112012019672B1/en
Priority to EP11702449.7A priority patent/EP2534132B1/en
Priority to SI201131222T priority patent/SI2534132T1/en
Priority to ES11702449.7T priority patent/ES2629439T3/en
Priority to KR1020127023297A priority patent/KR101461298B1/en
Priority to NZ601422A priority patent/NZ601422A/en
Application filed by F. Hoffmann-La Roche Ag filed Critical F. Hoffmann-La Roche Ag
Priority to JP2012552343A priority patent/JP5612710B2/en
Priority to LTEP11702449.7T priority patent/LT2534132T/en
Priority to RS20170658A priority patent/RS56163B1/en
Priority to RU2012138257/04A priority patent/RU2564022C2/en
Priority to CN2011800089274A priority patent/CN102753522B/en
Priority to AU2011214506A priority patent/AU2011214506C1/en
Priority to UAA201210421A priority patent/UA107954C2/en
Publication of WO2011098398A1 publication Critical patent/WO2011098398A1/en
Priority to HK12112287.3A priority patent/HK1171452A1/en
Priority to HRP20170903TT priority patent/HRP20170903T1/en
Priority to CY20171100673T priority patent/CY1119049T1/en

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    • 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
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • 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.
  • 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 cofactor 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.
  • 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.
  • 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, hetereoaryl, hetereocycle, 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, hetereoaryl, substituted hetereoaryl, hetereocycle, or substituted hetereocycle.
  • 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,
  • 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, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen or lower alkyl,
  • R 3 is H or lower alkyl
  • R4 and R 5 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
  • R 6 and R 7 are selected from the group consisting of (CH 2 ) n -R', (CH 2 ) n -NR'R", (CH 2 ) n - NR'COR", (CH 2 ) admir-NR'S0 2 R", (CH 2 ) dislike-COOH, (CH 2 ) dislike-COOR', (CH 2 ) dislike-COOR', (CH 2 ) dislike-COOR', (CH 2 ) dislike-COOR', (CH 2 ) dislike-COOR', (CH 2 ) dislike-COOR', (CH 2
  • n and p are independently 0 to 6
  • 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, hetereoaryl, hetereocycle, 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, hetereocycle, or substituted hetereocycle,
  • 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,
  • Ri is selected from the group consisting of lower alkyl
  • R 2 is hydrogen or lower alkyl
  • R 3 is H or lower alkyl
  • R 5 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 6 and R 7 are selected from the group consisting of (CH 2 ) n -R', (CH 2 ) n -NR'R", (CH 2 ) n -
  • n, and p are independently 0 to 6
  • X is F, CI or 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, lower alkoxy, lower alkenyl, lower cycloalkenyl and lower alkynyl,
  • Ri 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,
  • R 2 is hydrogen
  • R 3 is H
  • R 5 is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl,
  • R4 is hydrogen
  • R 6 and R 7 are selected from the group consisting of (CH 2 ) n -R', (CH 2 ) n -NR'R", (CH 2 ) n - NR'COR", (CH 2 ) n -NR'S0 2 R", (CH 2 ) deliberately-COOH, (CH 2 ) favor-COOR', (CH 2 ) resort-CONR'R", (CH 2 ) admir-OR', (CH 2 ) n -SR ⁇ (CH 2 ) n -SOR ⁇ (CH 2 ) n -S0 2 R ⁇ (CH 2 ) n -COR ⁇ (CH 2 ) n -S0 3 H, (CH 2 ) n -SONR'R", (CH 2 ) n -S0 2 NR'R", (CH 2 CH 2 0) m -(CH 2 ) n -R ⁇ (CH 2 CH 2 0) m -(CH 2 ) n -OH, (CH
  • NR'S0 2 R (CH 2 CH 2 0) m -(CH 2 ) n -COOH, (CH 2 CH 2 0) m -(CH 2 ) n -COOR', (CH 2 CH 2 0) m -(CH 2 ) n - CONR'R", (CH 2 CH 2 0) m -(CH 2 ) n -S0 2 R', (CH 2 CH 2 0) m -(CH 2 ) n -COR ⁇ (CH 2 CH 2 0) m -(CH 2 ) n - SONR'R", (CH 2 CH 2 0) m -(CH 2 ) n -S0 2 NR'R", (CH 2 ) p -(CH 2 CH 2 0) m -(CH 2 ) n -R', (CH 2 ) P - (CH 2 CH 2 0) m -(CH 2 ) n -OH, (
  • 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, hetereocycle, or substituted hetereocycle,and wherein R and R may also 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,
  • n and p are independently 0 to 6
  • X is F, CI or Br
  • Y is a mono-substituting group selected from H or F and
  • Ri is selected from the group consisting of lower alkyl
  • substituted lower alkyl lower alkenyl, substituted lower alkenyl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl.
  • Ri is a substituted lower alkyl selected from:
  • n 0, 1 or 2
  • R11 is selected from hydrogen, hydroxyl, lower alkyl, lower alkoxy, aryl, substituted aryl. hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle, R 2 is H,
  • R 3 is H
  • R 5 is a substituted p
  • W is F, CI or Br
  • V is H or F
  • R4 is hydrogen
  • R 6 and R 7 are hydrogen and the other is (CH 2 ) n -R',
  • n 0 or 1
  • R' is selected from aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle.
  • the present invention is directed to the compounds of the formula Ila
  • R' is Cyclohexyl, or a 5 to 10 membered, mono- or bicyclic aromatic hydrocarbon wherein 1 or 2 carbon atoms may be replaced by N, S or O, and wherein any of the aforementioned cyclohexyl or aromatic hydrocarbon can be substituted once or twice with a group independently selected from lower alkyl, lower-alkenyl, lower-alkynyl, dioxo-lower- alkylene (forming e.g.
  • a benzodioxyl group halogen, hydroxy, CN, CF 3 , NH 2 , N(H, lower-alkyl), N(lower-alkyl) 2 , aminocarbonyl, carboxy, N0 2 , lower-alkoxy, thio- lower-alkoxy, lower-alkylsufonyl, aminosulfonyl, lower-alkylcarbonyl, lower- alkylcarbonyloxy, lower-alkoxycarbonyl, lower-alkyl-carbonyl-NH, fluoro-lower- alkyl, fiuoro-lower-alkoxy, lower-alkoxy-carbonyl-lower-alkoxy, carboxy-lower- alkoxy, carbamoyl-lower-alkoxy, hydro xy-lower-alkoxy, NH 2 -lower-alkoxy, N(H, lower-alkyl)-lower-alkoxy, N(lower-alkyl)
  • n O or l .
  • R' is phenyl, pyridinyl, pyrazinyl or pyrimidinyl which can be each unsubstituted or once or twice substituted with a substituent independently selected from halogen, CI -6 alkoxy, CI -6 alkyl, hydroxycarbonyl, carboxy, carboxy CI -6 alkoxy, oxo and CN; and
  • n 0.
  • the compounds of formula Ila selected from rac-4-( ⁇ [(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino ⁇ -methyl)-cyclohexanecarboxylic acid methyl ester,
  • a benzodioxyl group halogen, hydroxy, CN, CF 3 , NH 2 , N(H, lower-alkyl), N(lower-alkyl) 2 , aminocarbonyl, carboxy, N0 2 , lower-alkoxy, thio-lower-alkoxy, lower-alkylsufonyl, amino sulfonyl, 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, hydro xy-lower-alkoxy, NH 2 -lower-alkoxy, N(H, lower-alkyl)-lower-alkoxy, N(lower- alkyl)
  • Preferred substituents for the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle rings are halogen, lower alkoxy, lower alkyl, hydro xycarbonyl, carboxy, carboxy lower alkoxy, oxo and CN.
  • Preferred substituents for alkyl are alkoxy and N(lower alkyl) 2 .
  • 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.
  • 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.
  • 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.
  • 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- 1- 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. Where the aryl group is bicyclic a preferred group is l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl group.
  • 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 substituted or unsubstituted triazolyl and substituted or unsubstituted tetrazolyl.
  • Heterocycle or “heterocyclic ring”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 which in turn can be substituted.
  • 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.
  • the compounds of formula I and II (or Ila) 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 (or Ila) 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.
  • compositions comprising a compound of formula I, II or Ila together with pharmaceutically acceptable excipients.
  • 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.
  • 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 non-aqueous 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.
  • 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. IC 5 o can be measured, inter alia, as is described subsequently.
  • the present invention provides methods for the synthesis of pyrrolidine-2-carboxamide.
  • 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.
  • R is tert-butyl or methyl
  • Rl or R2 is H, CH2C12, room temperature, overnight;
  • An intermediate of formula III can be made from a base-catalyzed condensation reaction of appropriately selected substituted-phenyl acetonitrile and aldehyde The reaction proceedes in a highly stereoselective manner with Z-isomer as the major or exclusive product.
  • R 5 is H, aq. NaOH, iPrOH, room temperature, 5 min or NaOMe, MeOH, 50 °C, 3 h
  • pyrrolidine of formula IV can be made from intermediates II and III by a convergent 1,3-dipolar cylcoaddition reaction mediated by lewis acid AgF and triethylamine.
  • 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 including
  • R is tert-butyl, cone. H 2 S0 4 ; or TFA, CH 2 C1 2 , rt, 18 h;
  • R is methyl, NaOH or LiOH, H 2 0 and MeOH and THF, rt, 18 h;
  • the pyrrolidine compounds I, IV, V 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 compound la and la' can be readily resolved into two optically pure or enriched chiral enantiomers by separation using chiral Super Fluid Chromatography (SFC). (Scheme 4).
  • Example le The racemic product obtained above (Example le, 45 mg) was further separated by SFC chiral column to give-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (13.1 mg, 29.1%) and (2S,3S,4S,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethylpropyl)-pyrrolidine-2-carboxylic acid (2 ⁇ ⁇ 1 ⁇ -4 ⁇ 1- ⁇ 1) ⁇ (14.6 mg, 32.4%).
  • Example 2 Example 2
  • 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 NaN 3 (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.
  • Step C A suspension of (S)-4-(2-azido-ethyl)-2 ,2 -dimethyl- [1, 3 Jdioxolane as a yellow oil (18.7 g, 0.11 mol) and Pt0 2 (2.5 g) in ethyl acetate (100 mL) was vigorously shaken in a Parr under atmosphere of H 2 (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%).
  • the mixture was then diluted with CH 2 C1 2 and washed with water, brine.
  • the organic phase was separated, filtered and dried over Na 2 S0 4 .
  • the mixture was then concentrated and the residue was treated with PPTS (cat) in MeOH (20 mL) at 120 °C for 5 min with CEM microwave reactor.
  • the reaction mixture was concentrated and the residue was diluted with EtOAc and washed with water, brine.
  • the organic phase was separated, filtered and dried over Na 2 S0 4 .
  • Example Id (61.0 mg, 0.14 mmol) prepared in Example Id was reacted with l-morpholin-4-yl-2-piperazin- 1-yl-ethanone (65.0 mg, 0.30 mmol), HATU (106.0 mg, 0.28 mmol) and iPr 2 NEt (38.8 mg, 0.30 mmol) in CH 2 C1 2 (2 mL) at rt overnight to give rac-(2S,3R,4R,5R)-4-(3-chloro-phenyl)-3-(4- chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-l- carbonyl]-pyrrolidine-3-carbonitrile (45.5 mg, 51.9 %).
  • Example 26b rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 26b (0.8 g, 1.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.9 g, 100%).
  • glycine tert-butyl ester (1.31 g, 10 mmol) was reacted with 3-chlorobenzaldehyde (Aldrich) (1.4 g, 10 mmol) in CH2CI2 at room temperature for 18 h to give ⁇ [l-(3-chloro-phenyl)-meth-(E)-ylidene]-amino ⁇ -acetic acid tert- butyl ester as a plae yellow oil (2.4 g, 95%).
  • 3-chlorobenzaldehyde Aldrich
  • Example 32a ⁇ [l-(3-chloro-phenyl)-meth-(E)- ylidene]-amino ⁇ -acetic acid tert-butyl ester prepared in Example 32a (2.6 g, 11 mmol) was reacted with (Z)-2-(4-chloro-phenyl)-5,5-dimethyl-hex-2-enenitrile (2 g, 7.9 mmol) prepared in Example 32b, AgF (1.3 g, 10 mmol), and triethylamine (2.2 g, 22 mmol) in 1,2-dichloroethane (100 mL) at room temperature for 24 h to give rac-(2R,3R,4R,5S)-5-(3-Chloro-phenyl)-4-(4- chloro-phenyl)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid
  • Example 34d rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-arboxylic acid tert-butyl ester prepared in Example 34b (0.4 g, 0.77 mmol) was reacted with trifiuoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-arboxylic acid trifiuoroacetic acid as a off white solid (0.5 g, 100%).
  • Example 34d Example 34d
  • Example 32a ⁇ [l-(3-Chloro-phenyl)-meth-(E)- ylidene]-amino ⁇ -acetic acid tert-butyl ester prepared in Example 32a (2 g, 7.6 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (0.55 g, 2 mmol) prepared in Example lb, AgF (1.3 g, 10 mmol), and triethylamine (1.9 g, 19 mmol) in dichloromethane (30 mL) at 50 °C for 20 h to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro- phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-buty
  • Example 43b rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(l -ethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 43b (1.1 g, 2.3 mmol) was reacted with trifiuoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4- chloro-phenyl)-4-cyano-5-(l-ethyl-propyl)-pyrrolidine-2-carboxylic acid trifiuoroacetic acid as a white solid (1.2 g, 98%).
  • glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with cyclohexanecarbaldehyde (Aldrich) (0.6 g, 5 mmol) in CH2CI2 at room temperature for 20 h to give ⁇ [1 -eye lohexyl-meth-(E)-ylidene]-amino ⁇ -acetic acid tert-butyl ester as a colorless oil (1.2 g, 100%).
  • Example 50a ⁇ [l-cyclohexyl-meth-(E)-ylidene]- amino ⁇ -acetic acid tert-butyl ester prepared in Example 50a (1.2 g, 5.3 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (1 g, 3.7 mmol) prepared in Example lb, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)- 4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam
  • Example 55b rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 55b (1.6 g, 3.3 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.7 g, 94%).
  • Example 55d Example 55d
  • Step A A mixture of 4-chloro-2-methylbenzyl alcohol (Aldrich) (5 g, 32 mmol) in thionyl chloride (20 mL) was heated at refluxing (100 °C) for 30 min. The mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous NaHC0 3 solution, water, brine, dried over MgS0 4 , and concentrated to give 4-chloro-2- methylbenzyl chloride as a light yellow oil (5.2 g, 93%).
  • Step C In a manner similar to the method described in Example lb, 4-chloro-2-methylbenzyl cyanide (3.5 g, 21 mmol) was reacted with 3-chloro-2-fiuorobenzaldehyde (5 g, 32 mmol), methanolic solution (25 wt%) of sodium methoxide (15 mL, 66 mmol) in methanol (100 mL) at 50 °C for 5 h to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-methyl-phenyl)- acrylonitrile as a white powder (4 g, 62%>).
  • Step A In a manner similar to the method described in Example 57 Step A, 4-chloro-2- methoxybenzyl alcohol (Aldrich) (4.9 g, 28 mmol) was reacted with thionyl chloride (20 mL) to give 4-chloro-2-methoxybenzyl chloride as a white solid (5.1 g, 95%).
  • Step B In a manner similar to the method described in Example 57 Step B, 4-chloro-2- methoxybenzyl chloride (5.1 g, 27 mmol) was reacted with NaCN (3 g, 61 mmol) in ethanol (40 mL) and water (20 mL) at 100 °C for 8 h to give 4-chloro-2 -methoxybenzyl cyanide as a colorless oil (1.8 g, 36%)
  • Step C In a manner similar to the method described in Example lb, 4-chloro-2 -methoxybenzyl cyanide (1.8 g, 10 mmol) was reacted with 3-chloro-2-fiuorobenzaldehyde (2 g, 13 mmol), methanolic solution (25 wt%) of sodium methoxide (15 mL, 66 mmol) in methanol (50 mL) at 50 °C for 2 h to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-methoxy-phenyl)- acrylonitrile as a white powder (2.1 g, 65%).
  • glycine tert-butyl ester (1.3 g, 10 mmol) was reacted with 2-cyclohexylacetaldehyde (Betapharma) (1.3 g, 10 mmol) in CH 2 C1 2 at room temperature for 5 h to give [2-cyclohexyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (2.3 g, 96%).
  • Example 60c rac-(2S,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 60a (0.4 g, 0.75 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fiuoro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.46 g, 100%).
  • Example 60c Example 60c
  • Example 61a AgF (1.7 g, 13 mmol), and triethylamine (2.8 g, 28 mmol) in dichloromethane (100 mL) at room temperature for 24 h to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)- 4-(4-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.8 g, 60%).
  • Example 61b rac-(2S,3R,4R,5S)-4-(4-chloro-2- methoxy-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 61b (2 g, 3.9 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy- phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.2 g, 98%).
  • Example 61d Example 61d
  • Example 62a AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-3-(2,3-difiuoro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.8 g, 44%).
  • rac-(2R,3R,4R,5S)-4-(4-chloro-2- fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 64b (1 g, 2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fiuoro- phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.88 g, 79%).

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Abstract

There are provided compounds of the formula (I) wherein X, Y, R1, R2, R3, R3, R4, R5, R6 and R7 are as described herein and enantiomers and pharmaceutically acceptable salts and esters thereof. The compounds are useful as anticancer agents.

Description

SUBSTITUTED PYRROLIDINE-2-CARBOXAMIDES Background of the Invention 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 cofactor 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. Detailed Description of the Invention
There are provided compounds of the formula
Figure imgf000003_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, hetereoaryl, hetereocycle, 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, hetereoaryl, substituted hetereoaryl, hetereocycle, or substituted hetereocycle.
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 or lower alkyl,
R3 is H or lower alkyl,
one of R4 and R5 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, R6 and R7 are selected from the group consisting of (CH2)n-R', (CH2)n-NR'R", (CH2)n- NR'COR", (CH2)„-NR'S02R", (CH2)„-COOH, (CH2)„-COOR', (CH2)„-CONR'R", (CH2)„-OR', (CH2)n-SR', (CH2)n-SOR', (CH2)n-S02R\ (CH2)n-COR', (CH2)n-S03H, (CH2)n-SONR'R", (CH2)n-S02NR'R", (CH2CH20)m-(CH2)n-R\ (CH2CH20)m-(CH2)n-OH, (CH2CH20)m-(CH2)n- OR', (CH2CH20)m-(CH2)n-NR'R", (CH2CH20)m-(CH2)n-NR'COR", (CH2CH20)m-(CH2)n- NR'S02R", (CH2CH20)m-(CH2)n-COOH, (CH2CH20)m-(CH2)n-COOR\ (CH2CH20)m-(CH2)n- CONR'R", (CH2CH20)m-(CH2)n-S02R', (CH2CH20)m-(CH2)n-COR', (CH2CH20)m-(CH2)n- SONR'R", (CH2CH20)m-(CH2)n-S02NR'R", (CH2)p-(CH2CH20)m-(CH2)n-R', (CH2)P- (CH2CH20)m-(CH2)n-OH, (CH2)p-(CH2CH20)m-(CH2)n-OR', (CH2)p-(CH2CH20)m-(CH2)n- NR'R", (CH2)p-(CH2CH20)m-(CH2)n-NR'COR", (CH2)p-(CH2CH20)m-(CH2)n-NR'S02R", (CH2)p-(CH2CH20)m-(CH2)n-COOH, (CH2)p-(CH2CH20)m-(CH2)n-COOR', (CH2)P- (CH2CH20)m-(CH2)n-CONR'R", (CH2)p-(CH2CH20)m-(CH2)n-S02R', (CH2)p-(CH2CH20)m- (CH2)n-COR', (CH2)p-(CH2CH20)m-(CH2)n-SONR'R", (CH2)p-(CH2CH20)m-(CH2)n-S02NR'R", -COR', -SOR' and S02R' wherein R' and R" are as above,
m, n and p are independently 0 to 6
and the pharmaceutically acceptable salts and esters thereof.
Preferred are compounds of fo tructure as shown as formula II
Figure imgf000004_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, hetereoaryl, hetereocycle, 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, hetereocycle, or substituted hetereocycle,
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,
Ri 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, R2 is hydrogen or lower alkyl,
R3 is H or lower alkyl,
R5 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,
R6 and R7 are selected from the group consisting of (CH2)n-R', (CH2)n-NR'R", (CH2)n-
NR'COR", (CH2)„-NR'S02R", (CH2)n-COOH, (CH2)n-COOR\ (CH2)n-CONR'R", (CH2)n-OR\ (CH2)n-SR\ (CH2)n-SOR\ (CH2)n-S02R\ (CH2)n-COR\ (CH2)n-S03H, (CH2)n-SONR'R", (CH2)n-S02NR'R", (CH2CH20)m-(CH2)n-R\ (CH2CH20)m-(CH2)n-OH, (CH2CH20)m-(CH2)n- OR', (CH2CH20)m-(CH2)n-NR'R", (CH2CH20)m-(CH2)n-NR'COR", (CH2CH20)m-(CH2)n- NR'S02R", (CH2CH20)m-(CH2)n-COOH, (CH2CH20)m-(CH2)n-COOR', (CH2CH20)m-(CH2)n- CONR'R", (CH2CH20)m-(CH2)n-S02R', (CH2CH20)m-(CH2)n-COR', (CH2CH20)m-(CH2)n- SONR'R", (CH2CH20)m-(CH2)n-S02NR'R", (CH2)p-(CH2CH20)m-(CH2)n-R', (CH2)P- (CH2CH20)m-(CH2)n-OH, (CH2)p-(CH2CH20)m-(CH2)n-OR', (CH2)p-(CH2CH20)m-(CH2)n- NR'R", (CH2)p-(CH2CH20)m-(CH2)n-NR'COR", (CH2)p-(CH2CH20)m-(CH2)n-NR'S02R", (CH2)p-(CH2CH20)m-(CH2)n-COOH, (CH2)p-(CH2CH20)m-(CH2)n-COOR', (CH2)P-
(CH2CH20)m-(CH2)n-CONR'R", (CH2)p-(CH2CH20)m-(CH2)n-S02R', (CH2)p-(CH2CH20)m- (CH2)n-COR', (CH2)p-(CH2CH20)m-(CH2)n-SONR'R", (CH2)p-(CH2CH20)m-(CH2)n-S02NR'R", -COR', -SOR' and S02R'
wherein R' and R" are as above,
m, n, and p are independently 0 to 6
and the pharmaceutically acceptable salts and esters thereof.
Especially preferred are compounds of formula II wherein
X is F, CI or 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, lower alkoxy, lower alkenyl, lower cycloalkenyl and lower alkynyl,
Ri 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,
R2 is hydrogen,
R3 is H,
R5 is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl,
R4 is hydrogen,
R6 and R7 are selected from the group consisting of (CH2)n-R', (CH2)n-NR'R", (CH2)n- NR'COR", (CH2)n-NR'S02R", (CH2)„-COOH, (CH2)„-COOR', (CH2)„-CONR'R", (CH2)„-OR', (CH2)n-SR\ (CH2)n-SOR\ (CH2)n-S02R\ (CH2)n-COR\ (CH2)n-S03H, (CH2)n-SONR'R", (CH2)n-S02NR'R", (CH2CH20)m-(CH2)n-R\ (CH2CH20)m-(CH2)n-OH, (CH2CH20)m-(CH2)n- OR', (CH2CH20)m-(CH2)n-NR'R", (CH2CH20)m-(CH2)n-NR'COR", (CH2CH20)m-(CH2)n-
NR'S02R", (CH2CH20)m-(CH2)n-COOH, (CH2CH20)m-(CH2)n-COOR', (CH2CH20)m-(CH2)n- CONR'R", (CH2CH20)m-(CH2)n-S02R', (CH2CH20)m-(CH2)n-COR\ (CH2CH20)m-(CH2)n- SONR'R", (CH2CH20)m-(CH2)n-S02NR'R", (CH2)p-(CH2CH20)m-(CH2)n-R', (CH2)P- (CH2CH20)m-(CH2)n-OH, (CH2)p-(CH2CH20)m-(CH2)n-OR', (CH2)p-(CH2CH20)m-(CH2)n- NR'R", (CH2)p-(CH2CH20)m-(CH2)n-NR'COR", (CH2)p-(CH2CH20)m-(CH2)n-NR'S02R", (CH2)p-(CH2CH20)m-(CH2)n-COOH, (CH2)p-(CH2CH20)m-(CH2)n-COOR\ (CH2)P- (CH2CH20)m-(CH2)n-CONR'R", (CH2)p-(CH2CH20)m-(CH2)n-S02R',
(CH2)p-(CH2CH20)m-(CH2)n-COR', (CH2)p-(CH2CH20)m-(CH2)n-SONR'R", (CH2)P- (CH2CH20)m-(CH2)n-S02NR'R", -COR', -SOR' and S02R' 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, hetereocycle, or substituted hetereocycle,and wherein R and R may also 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 thereof. Further preferred are compounds of formula II wherein:
X is F, CI or Br,
Y is a mono-substituting group selected from H or F and
Ri is selected from the group consisting of lower alkyl,
substituted lower alkyl, lower alkenyl, substituted lower alkenyl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl.
Further preferred Ri is a substituted lower alkyl selected from:
Figure imgf000007_0001
where Rs, R9 are both methyl, or linked to form a cyclopropyl, cyclobutyl, cyclopentyl or acyclohexyl group,
Rio is (CH2)m-R„,
m is 0, 1 or 2,
R11 is selected from hydrogen, hydroxyl, lower alkyl, lower alkoxy, aryl, substituted aryl. hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle, R2 is H,
R3 is H,
R5 is a substituted p
Figure imgf000008_0001
W is F, CI or Br,
V is H or F,
R4 is hydrogen,
one of R6 and R7 is hydrogen and the other is (CH2)n-R',
n is 0 or 1 and
R' is selected from aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle.
In yet another embodiment, the present invention is directed to the compounds of the formula Ila
Figure imgf000008_0002
wherein R6 and all variables and substituents mentioned in the definitions for R6 have the meanings given for formula II above. In still another embodiment, there are provided the compounds of formula Ila, wherein R6 is -(CH2)n-R\ and
R' is Cyclohexyl, or a 5 to 10 membered, mono- or bicyclic aromatic hydrocarbon wherein 1 or 2 carbon atoms may be replaced by N, S or O, and wherein any of the aforementioned cyclohexyl or aromatic hydrocarbon can be substituted once or twice with a group independently selected from 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, aminocarbonyl, carboxy, N02, lower-alkoxy, thio- lower-alkoxy, lower-alkylsufonyl, aminosulfonyl, lower-alkylcarbonyl, lower- alkylcarbonyloxy, lower-alkoxycarbonyl, lower-alkyl-carbonyl-NH, fluoro-lower- alkyl, fiuoro-lower-alkoxy, lower-alkoxy-carbonyl-lower-alkoxy, carboxy-lower- alkoxy, carbamoyl-lower-alkoxy, hydro xy-lower-alkoxy, NH2-lower-alkoxy, N(H, lower-alkyl)-lower-alkoxy, N(lower-alkyl)2-lower-alkoxy, lower-alkyl- 1 -oxiranyl- lower-alkoxy-lower-alkyl, 2-oxo-pyrrolidin-l-yl, (l,l-dioxo)-2-isothiazolidine, 3- lower-alkyl sulfmyl, a substituted or unsubstituted heterocyclic ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heteroaryl ring, trifiuoro-lower- alkylsulfonylamino-aryl, lower-alkyl sulfonylaminocarbonyl, lower-alkyl sulfonylaminocarbonyl-aryl, hydroxycarbamoyl-phenyl, 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; and
n is O or l .
In still another preferred embodiment there are provided the compounds of formula Ila, wherein R6 is -(CH2)„-R', and
R' is phenyl, pyridinyl, pyrazinyl or pyrimidinyl which can be each unsubstituted or once or twice substituted with a substituent independently selected from halogen, CI -6 alkoxy, CI -6 alkyl, hydroxycarbonyl, carboxy, carboxy CI -6 alkoxy, oxo and CN; and
n is 0.
Especially preferred are the compounds of formula Ila, selected from rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid methyl ester,
rac- 4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-cyclohexanecarboxylic acid, rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-2-methoxy-benzoic acid methyl ester,
rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-2-methoxy-benzoic acid, rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-2-fluoro-benzoic acid methyl ester,
rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-2-fluoro-benzoic acid, chiral 5-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-pyridine-2-carboxylic acid methyl ester,
chiral 5-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-pyridine-2-carboxylic acid, chiral 6-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-nicotinic acid ethyl ester, chiral 6-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-nicotinic acid,
rac 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-ethoxy-benzoic acid,
chiral (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydrazinocarbonyl-phenyl)-amide, chiral [2-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-ethyl]-carbamic acid tert-butyl ester, chiral (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-amino-ethyl)-phenyl]-amide, chiral 5-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazine-2-carboxylic acid,
chiral 4-(((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)methyl)-2-methoxybenzoic acid,
chiral-4-({[(2S,3R,4S,5R)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid, chiral methyl 3-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2-fluorophenyl)-4- cyano-5 -neopentylpyrrolidine-2-carboxamido)phenyl)propanoate,
chiral 3-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2 -fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)phenyl)propanoic acid,
chiral- 4-(((2S,3R,4S,5R)-3-(3-chloro-2 -fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)methyl)-2-fluorobenzoic acid,
chiral 4-(((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)methyl)-2-fluorobenzoic acid,
chiral (2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(2- morpholinopyrimidin-5-yl)-5-neopentylpyrrolidine-2-carboxamide,
chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentyl-N-(pyrimidin-5-yl)pyrrolidine-2-carboxamide,
chiral (2S,3R,4S,5R)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-dimethylaminomethyl-phenyl)-amide, (2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-dimethylaminomethyl-phenyl)-amide, chiral methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fiuorophenyl)-4- cyano-5-neopentylpyrrolidine-2-carboxamido)-lH-benzo[d]imidazole-2-carboxylate,
chiral-5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fiuorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)-lH-benzo[d]imidazole-2-carboxylic acid,
chiral-methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fiuorophenyl)-4- cyano-5 -neopentylpyrrolidine-2-carboxamido)benzofuran-2-carboxylate, chiral-5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)benzofuran-2-carboxylic acid,
chiral- methyl 4-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4- cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)butanoate,
chiral- 4-(4-((2R,3S,4R,5S)-3-(3-chloro-2 -fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)phenyl)butanoic acid,
chiral methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4- cyano-5-neopentylpyrrolidine-2-carboxamido)benzo[d]oxazole-2-carboxylate,
chiral- 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)benzo[d]oxazole-2-carboxylic acid,
chiral- (2R,3S,4R,5S)-N-(benzo[d]oxazol-5-yl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamide,
rac-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzyl)-carbamic acid tert-butyl ester, rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-aminomethyl-phenyl)-amide,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(methanesulfonylamino-methyl)-phenyl]- amide,
l-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-piperidine-4-carboxylic acid ethyl ester,
l-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-piperidine-4-carboxylic acid, rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-dimethylaminomethyl-phenyl)-amide, rac-5-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-pyrrolidin- 1 -yl-benzoic acid, rac-4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -4-methyl-piperidine-l -carboxylic acid tert-butyl ester, rac- (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-rluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methyl-piperidin-4-yl)-amide,
rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ( 1 -methanesulfonyl-4-methyl-piperidin-4-yl)- amide,
methyl l-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano- 5 -neopentylpyrro lidine -2 -c arboxamido)phenyl)pyrrolidine -2 -c arboxylate ,
l-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)phenyl)pyrrolidine-2-carboxylic acid,
chiral 5- {[(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -lH-pyrrole-2-carboxylic acid, chiral 5- {[(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -lH-pyrrole-2-carboxylic acid ethyl ester, chiral (i?)-2-(4- {[(2i?,35,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-butyric acid, chiral (5)-2-(4- {[(2i?,35,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-butyric acid, chiral (S)-2- { [(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-thiazol-4-yl-propionic acid methyl ester,
chiral (5,)-2- {[(25,,3i?,45,,5i?)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-thiazol-4-yl-propionic acid methyl ester,
chiral (S)-2- { [(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-thiazol-4-yl-propionic acid, chiral (5,)-2- {[(25,,3i?,45,,5i?)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-thiazol-4-yl-propionic acid, chiral 4- {[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -lH-indole-2-carboxylic acid,
rac (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrro lidine -2-carboxylic acid (5-iodo-pyridin-2-yl)-amide, 2-chloro-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-
5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid,
6- {[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -nicotinic acid,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid pyridin-2-ylamide,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid pyridin-4-ylamide,
5- {[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -pyridine-2-carboxylic acid,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid pyridin-3-ylamide,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-iodo-3 ,5dimethyl-phenyl)-amide,
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2 fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-fluoro-benzoic acid tert-butyl ester, 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2 fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-fluoro-benzoic acid,
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2 fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-fluoro-benzoic acid,
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-trifluoromethyl-benzoic acid,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-iodo-2-trifluoromethoxy-phenyl)-amide, 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-trifluoromethoxy-benzoic acid methyl ester, 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-trifluoromethoxy-benzoic acid,
6- {[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -nicotinic acid, 6-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -nicotinic acid methyl ester ,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-iodo-pyridin-3-yl)-amide,
5-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyridine-2-carboxylic acid methyl ester, 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid methyl ester,
4- {[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-methoxy-benzoic acid,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-carbamoyl-naphthalen-2-yl)-amide, (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-3-chloro-phenyl)-amide, (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-3-trifluoromethyl-phenyl)-amide,
5- {[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyridine-2-carboxylic acid,
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-fluoro-benzoic acid methyl ester,
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-nuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-chloro-benzoic acid methyl ester,
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-nuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-chloro-benzoic acid,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-2-fluoro-phenyl)-amide, (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-2-methoxy-phenyl)-amide, 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-nuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2,5-difluoro-benzoic acid methyl ester, 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2,5-difluoro-benzoic acid ,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3,5-difluoro-4-iodo-phenyl)-amide,
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2,6-difluoro-benzoic acid,
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-hydroxy-benzoic acid,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-3-methoxy-phenyl)-amide, (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-3-trifluoromethoxy-phenyl)-amide, (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-3-fluoro-phenyl)-amide,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-2-chloro-phenyl)-amide,
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-fluoro-5-methoxy-benzoic acid methyl ester ,
4- {[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-fluoro-5-methoxy-benzoic acid,
2-(4-{[(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-4-methyl-pentanoic acid,
chiral 2-(4-{[(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-
5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-2-methyl-propionic acid methyl ester,
chiral 2-(4-{[(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-2-methyl-propionic acid, chiral (25,,3i?,45,,5i?)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(l-methyl-l-methylcarbamoyl-ethyl)-phenyl]- amide, chiral (25',3i?,45,,5i?)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid {4-[l -(3-hydroxy-propylcarbamoyl)- 1 -methyl- ethyl] -phenyl} amide, and
chiral (25',3i?,45,,5i?)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(l -carbamoyl- l-methyl-ethyl)-phenyl]-amide.
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, aminocarbonyl, carboxy, N02, lower-alkoxy, thio-lower-alkoxy, lower-alkylsufonyl, amino sulfonyl, 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, hydro xy-lower-alkoxy, NH2-lower-alkoxy, N(H, lower-alkyl)-lower-alkoxy, N(lower- alkyl)2-lower-alkoxy, lower-alkyl- 1-oxiranyl-lower-alkoxy-lower-alkyl, 2-oxo-pyrrolidin-l-yl, (l,l-dioxo)-2-isothiazolidine, 3-lower-alkyl sulfinyl, a substituted or unsubstituted heterocyclic ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heteroaryl ring, trifluoro-lower-alkylsulfonylamino-aryl, lower-alkyl sulfonylaminocarbonyl, lower-alkyl sulfonylaminocarbonyl-aryl, hydroxycarbamoyl-phenyl, 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 cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle rings are halogen, lower alkoxy, lower alkyl, hydro xycarbonyl, carboxy, carboxy lower alkoxy, oxo and CN. Preferred substituents for alkyl are alkoxy and N(lower alkyl)2.
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- 1- 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. Where the aryl group is bicyclic a preferred group is l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl group. "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 substituted or unsubstituted triazolyl and substituted or unsubstituted 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" or "heterocyclic ring"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 which in turn can be substituted.
"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.
The compounds of formula I and II (or Ila) 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 (or Ila) 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. Consequently, in a further embodiment of the present invention there are provided the compounds of formula I, II or Ila for use as a medicament, in particular for use as a medicament for the treatment of cancer, more particularly solid tumors such as breast, colon, lung and prostate tumors. The present invention is also directed to pharmaceutical compositions comprising a compound of formula I, II or Ila together with pharmaceutically acceptable excipients. 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 non-aqueous 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. "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. IC5o can be measured, inter alia, as is described subsequently.
Synthetic Methods
The present invention provides methods for the synthesis of pyrrolidine-2-carboxamide. 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 emine II and activated olefin III to generate pyrrolidine-3-carbonitrile compounds IV in a stereoselective and efficient 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 ketonecan be reacted with glycine tert-butyl ester or glycine methyl ester to generate imine II and were used as a crude product (Scheme 1).
Figure imgf000023_0001
Reagents and conditions: R is tert-butyl or methyl
(1) If Rl or R2 is H, CH2C12, room temperature, overnight;
(2) If Rl and R2 are both not H, ethanol, 100 oC, 48 h;
Scheme 1
An intermediate of formula III can be made from a base-catalyzed condensation reaction of appropriately selected substituted-phenyl acetonitrile and aldehyde The reaction proceedes in a highly stereoselective manner with Z-isomer as the major or exclusive product.
Figure imgf000023_0002
Ill
Reagents and conditions:
If R5 is H, aq. NaOH, iPrOH, room temperature, 5 min or NaOMe, MeOH, 50 °C, 3 h
Scheme 2
As illustrated in Scheme 3, pyrrolidine of formula IV can be made from intermediates II and III by a convergent 1,3-dipolar cylcoaddition reaction mediated by lewis acid AgF and triethylamine. 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 including
Jorgensen, K. A. et al {Org. Lett. 2005, Vol 7, No. 21, 4569-4572), Grigg, R. et al {Tetrahedron, 1992, Vol 48, No. 47, 10431-10442; Tetrahedron, 2002, Vol 58, 1719-1737), Schreiber, S. L. et al (J. Am. Chem. Soc, 2003, 125, 10174-10175), and Carretero, J. C. et al {Tetrahedron, 2007, 63, 6587-6602). . Compounds IV is subsequently converted to acid V followed by amide formation with various amines using HATU as the coupling reagent to give the compounds of formula I. The amide formation from V to I can also be achieved under other conditions using EDCI and HOBt or oxalyl chloride as the coupling reagent to activate the acid V.
Figure imgf000024_0001
Reagents and conditions:
a. AgF, NEt3, CH2C12 or C1CH2CH2C1, rt, 18 h;
b. 1) If R is tert-butyl, cone. H2S04; or TFA, CH2C12, rt, 18 h;
or 2) If R is methyl, NaOH or LiOH, H20 and MeOH and THF, rt, 18 h;
c. HNR6R7, HATU, iPr2NEt, CH2C12, rt, 18 h
Scheme 3
The pyrrolidine compounds I, IV, V 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 compound la and la' can be readily resolved into two optically pure or enriched chiral enantiomers by separation using chiral Super Fluid Chromatography (SFC). (Scheme 4).
Figure imgf000025_0001
Scheme 4
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. Examples 1 to 378 are disclosed herein as Reference Examples.
Example la
Preparation of intermediate [3,3-dimethy -but-(E)-ylideneamino]-acetic acid tert-butyl ester
Figure imgf000026_0001
A mixture of glycine tert-butyl ester (Alfa) (2.71 g, 20.0 mmol) and 3,3-dimethyl-butyraldehyde (Alfa) (2.21 g, 21.0 mmol) in CH2CI2 (50 mL) was stirred at rt overnight. The reaction mixture was concentrated and the residue was dried in vacuo to give [3,3-dimethyl-but-(E)- ylideneamino]-acetic acid tert-butyl ester
(4.29 g, 100%) as colorless oil which was used in the next step without further purification.
Example lb
Preparation of intermediate (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile
Figure imgf000026_0002
M. W. 274.2 Ci5H9Cl2N Method A To a solution of 4-chlorobenzyl cyanide (5.62 g, 4.00 mmol) and 3-chloro- benzaldehyde (Aldrich) (6.06 g, 4.00 mmol) in iPrOH (250 mL) was added 4 N NaOH (5 mL) dropwise at rt and the reaction mixture was stirred at rt for 10 min to give a white suspension. The solid was filtered and washed with water and iPrOH and then dried overnight in vacuum to give (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (9.33 g, 85.1%) as a white powder which was used in the next step without further purification.
Method B To a solution of 4-chlorobenzyl cyanide (Aldrich) (4.5 g, 30 mmol) and 3-chloro- benzaldehyde (Aldrich) (4 g, 29 mmol) in methanol (150 mL) was slowly added a methanolic solution (Aldrich, 25 wt.%) of sodium methoxide (10 mL, 44 mmol). The reaction mixture was heated and stirred at 50 °C for 3 h. The mixture became cloudy, and was cooled to room temperarure and filtered. The white precipitate was washed with water, cold methanol, and then dried in vacu to give the first batch of desired product (5.5 g). The filtrate was concentrated, diluted with water, neutralized by aqueous HC1 solution to "pH" 7, then extracted with ethyl acetate. The organic layer was separated, dried over MgSC>4, and concentrated. The residue was purified by chromatography (EtOAc;hexanes = 1 ;20, then 1 : 10) to give the second batch of the desired product (1.6 g).The two batches were combined to give (Z)-3-(3-chloro-phenyl)-2-(4- chloro-phenyl)-acrylonitrile as a white powder (7.1 g, 88%).
HRMS (ES+) m/z Calcd for Ci5H9Cl2N [M+]: 273.0112, found: 273.0113.
Example lc
Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phi cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000027_0001
M. W. 487.5 C27H32CI2N2O2
To a solution of [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (4.26 g, 20.00 mmol) and (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (5.48 g, 20.00 mmol) in C1CH2CH2C1 (100 mL) were added triethyl amine (4.2 g, 40.00 mmol) and AgF (2.53 g, 20.00 mmol) in one portion. The mixture was stirred at rt overnight. The mixture was then quenched with sat. NH4CI and extracted with CH2CI2. The organic phase was separated, filtered through Celite and dried overNa2S04. The mixture was then separated and concentrated. The residue was triturated with EtOAc and nHexane, and the precipitates were collected by filtration and the mother liquid was concentrated and further purified by flash column (S1O2, 1-20% of EtOAc in hexanes) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (6.65 g, 68.2%; HRMS (ES+) m/z Calcd for C27H32CI2N2O2 + H [(M+H)+]: 487.1914, found: 487.1910) and rac-(2R,3R,4R,5R)-3- (3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid tert-butyl ester (0.86 g, 8.8%).
HRMS (ES+) m/z Calcd for C27H32CI2N2O2 + H [(M+H)+]: 487.1914, found: 487.1910).
Example Id
Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbox lic acid
Figure imgf000028_0001
M. W. 431.4 C23H24CI2N2O2
A solution of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (3.78 g, 7.75 mmol) in cone. H2SO4 (20 mL) was stirred at rt for 2 hrs. The mixture was then poured into ice and extracted with EtOAc. The organic phase was separated, dried overNa2S04, and concentrated. The residue was then triturated with EtOAc and nHexane and the precipitates were collected by filtration and washed with ether to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine -2 -carboxylic acid (3.60 g, 100%) as a white solid which was used in the next step without further purification: HRMS (ES ) m/z Calcd for C23H24CI2N2O2 + H [(M+H)+]: 431.1288, found: 431.1287.
Example le Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide
Figure imgf000029_0001
M. W. 543.5 C29H36CI2N4O2
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol), 2-ηιοφ1ιο1ίη-4-γ1- ethylamine (36.0 mg, 0.28 mmol), 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 106.0 mg, 0.28 mmol) and iP^NEt (38.8 mg, 0.30 mmol) in CH2CI2 (2 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 purified by S1O2 flash column (20-100% of EtOAc in
Hexanes) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (60.5 mg, 86.4%o) as a white amorphous.
HRMS (ES+) m/z Calcd for C29H36CI2N4O2 + H [(M+H)+]: 543.2288, found: 523.2284.
Example If
Preparation of (2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl- propyl)-pyrrolidine-2-carboxylic acid (2^οφ1ιο1ίη-4^1-εί1^1)^ηιίάε
Figure imgf000029_0002
M. W. 543.5 C29H36C12N402
The racemic product obtained above (Example le, 45 mg) was further separated by SFC chiral column to give-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (13.1 mg, 29.1%) and (2S,3S,4S,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethylpropyl)-pyrrolidine-2-carboxylic acid (2^ο ηο1ίη-4^1-ε^1)^ηιίάε (14.6 mg, 32.4%). Example 2
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid dimethylamide
Figure imgf000030_0001
M. W. 458.4 C25H29Cl2N302
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example Id was reacted with dimethylamine (1.0 M in THF, 2 mL), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid dimethyl amide (57.8 mg, 90.0 %).
HRMS (ES+) m/z Calcd for C25H29C12N302 + H [(M+H)+]: 458.1761, found: 458.1757. Example 3a
Preparation of intermediate 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine
Figure imgf000030_0002
M. W. 145.20 C7Hi5N02
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>4, 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 MgS04, 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- [1, 3 Jdioxolane as a yellow oil (18.7 g, 0.11 mol) and Pt02 (2.5 g) in ethyl acetate (100 mL) was vigorously shaken in a Parr under atmosphere of H2 (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%).
Example 3 b
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy-butyl)-amide
Figure imgf000031_0001
M. W. 518.5 C27H33C12N303
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (431.4 mg, 1.00 mmol) prepared in Example Id, 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (217.5 mg, 1.5 mmol), HATU (570.30 mg, 1.50 mmol) and iPr2NEt (258.6 mg, 2.00 mmol) in CH2C12 (20 mL) was stirred at rt for 1 hour. 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 treated with PPTS (cat) in MeOH (20 mL) at 120 °C for 5 min with CEM microwave reactor. The reaction mixture was concentrated and the residue was diluted with EtOAc and washed with water, brine. The organic phase was separated, filtered and dried over Na2S04. The mixture was then concentrated and purified by Si02 flash column (5% of MeOH in EtOAc) to give rac- (2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (450.0 mg, 86.7%>) as a white amorphous. HRMS (ES ) m/z Calcd for C27H33CI2N3O3+ H [(M+H)+]: 518.1972, found: 518.1970.
Example 3 c
Preparation of (2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl- propyl)-pyrrolidine-2-carboxylic acid -3,4-dihydroxy-butyl)-amide
Figure imgf000032_0001
M. W. 518.5 C27H33CI2N3O3
The racemic product obtained above (Example 3b, 450.0 mg) was further separated by SFC chiral column to give (2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (178.6 mg, 34.4%) and (2S,3S,4S,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl- propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (159.8 mg, 30.8%).
Example 4
Preparation of rac-(2S,3R,4R,5R)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl- propyl)-5-[4-(2-mo holin-4-yl-2-oxo-eth l)-piperazine-l-carbonyl]-pyrrolidine-3-carbonitrile
Figure imgf000032_0002
M. W. 626.6 C35H4iCl2N503
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid
(61.0 mg, 0.14 mmol) prepared in Example Id was reacted with l-morpholin-4-yl-2-piperazin- 1-yl-ethanone (65.0 mg, 0.30 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2S,3R,4R,5R)-4-(3-chloro-phenyl)-3-(4- chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-l- carbonyl]-pyrrolidine-3-carbonitrile (45.5 mg, 51.9 %).
HRMS (ES+) m/z Calcd for C35H4iCl2N503+ H [(M+H)+]: 626.2659, found: 626.2654. Example 5
Preparation of rac-(2S,3R,4R,5R)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl- propyl)-5-[4-(2-oxo-2-pyrrolidin-l-yl-eth l)-piperazine-l-carbonyl]-pyrrolidine-3-carbonitrik
Figure imgf000033_0001
M. W. 610.6 C33H4iCl2N5O2
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example Id was reacted with 2-piperazin-l-yl-l-pyrrolidin-l- yl-ethanone (65.0 mg, 0.33 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2S,3R,4R,5R)-4-(3-Chloro-phenyl)-3-(4- chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-[4-(2-oxo-2-pyrrolidin- 1 -yl-ethyl)-piperazine- 1 - carbonyl]-pyrrolidine-3-carbonitrile (60.5 mg, 70.8 %).
HRMS (ES+) m/z Calcd for C33H4iCl2N502+ H [(M+H)+]: 610.2710, found: 610.2708.
Example 6
Preparation of rac-(2S,3R,4R,5R)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl- propyl)-5-[4-(2-hydroxy-ethyl)-piperazine-l-carbon l]-pyrrolidine-3-carbonitrile
Figure imgf000033_0002
M. W. 543.5 C29H36C12N402
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example Id was reacted with 2-piperazin-l-yl-ethanol (65.0 mg, 0.50 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2S,3R,4R,5R)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2- dimethyl-propyl)-5-[4-(2-hydroxy-ethyl)-piperazine- 1 -carbonyl]-pyrrolidine-3-carbonitrile (48.3 mg, 63.5 %).
HRMS (ES+) m/z Calcd for C29H36CI2N4O2+ H [(M+H)+]: 543.2288, found: 543.2284.
Example 7
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbox lic acid (4-hydroxy-butyl)-amide
Figure imgf000034_0001
M. W. 502.4 C27H33CI2N3O2
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example Id was reacted with 4-methylamino-butan-l-ol (44.5 mg, 0.50 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2CI2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydroxy-butyl)-amide (30.5 mg, 43.4 %). HRMS (ES+) m/z Calcd for C27H33CI2N3O2+H [(M+H)+]: 502.2023, found: 502.2020.
Example 8
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-pyrrolidin- 1 -yl-ethyl)-amide
Figure imgf000034_0002
M. W. 527.5 C29H36CI2N4O
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (82.2 mg, 0.20 mmol) prepared in Example Id was reacted with 2-pyrrolidin-l-yl-ethylamine (34.2 mg, 0.30 mmol), HATU (76.0 mg, 0.20 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2C12 (2 niL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-pyrrolidin-l -yl-ethyl)- amide (50.6 mg, 64.0 %). HRMS (ES+) m/z Calcd for C29H36C12N40 +H [(M+H)+]: 527.2339, found: 527.2338.
Example 9
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-piperazin- 1 -yl-ethyl)-amide
Figure imgf000035_0001
M. W. 542.6 C29H37C12N50
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (82.2 mg, 0.20 mmol) prepared in Example Id was reacted with 2-piperazin-l-yl-ethylamine (38.7 mg, 0.30 mmol), HATU (76.0 mg, 0.20 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-piperazin- 1-yl-ethyl)- amide (45.9 mg, 58.0 %). HRMS (ES+) m/z Calcd for C29H37C12N50 +H [(M+H)+]: 542.2448, found: 542.2445.
Example 10a
Preparation of (S)-2-{[(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbon l]-amino}-3-methyl-butyric acid tert-butyl ester
Figure imgf000035_0002
M. W. 586.6 C32H4iCl2N303 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (215.7 mg, 0.50 mmol) prepared in Example Id was reacted with (S)-2-amino-3-methyl-butyric acid tert-butyl ester (125.4 mg, 0.60 mmol), HATU (210.1.0 mg, 0.60 mmol) and iPr2NEt (129.3 mg, 1.00 mmol) in CH2C12 (5 mL) at rt overnight to give (S)-2-{[(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}- 3 -methyl-butyric acid tert-butyl ester (95.0 mg, 32.4 %) after column separation. HRMS (ES+) m/z Calcd for C32H41CI2N3O3+H [(M+H)+]: 586.2602, found: 586.2598. Example 10b
Preparation of (S)-2-{[(2S,3S,4S,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbon l]-amino}-3-methyl-butyric acid tert-butyl ester
Figure imgf000036_0001
M. W. 586.6 C32H41CI2N3O3
Column separation from the above example (Example 10a) gave (S)-2-{[(2S,3S,4S,5R)-3-(3- chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]- amino} -3 -methyl-butyric acid tert-butyl ester (98.0 mg, 33.4 %).
HRMS (ES+) m/z Calcd for C32H41CI2N3O3+H [(M+H)+]: 586.2601, found: 586.2598. Example 10c
Preparation of (S)-2-{[(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino -3-methyl-butyric acid methyl ester
Figure imgf000036_0002
M. W. 544.5 C29H35Cl2N303
Column separation from the above example (Example 10a) gave a mixture of (S)-2- {[(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid tert-butyl ester and (S)-2- {[(2S,3S,4S,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid tert-butyl ester (45.8 mg, 15.6 %). The mixture was treated with 2N H2S04 (catalytic) in MeOH (1 mL) at 120°C for 10 min using CEM microwave reactor to give after purification by PR-HPLC: (S)-2-{[(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}- 3 -methyl-butyric acid methyl ester (15.5 mg, 36.5%).
HRMS (ES+) m/z Calcd for C29H35C12N303+H [(M+H)+]: 544.2128, found: 544.2127. Example lOd
Preparation of (S)-2-{[(2S,3S,4S,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl -amino}-3-methyl-butyric acid methyl ester
Figure imgf000037_0001
M. W. 544.5 C29H35C12N303
Column separation from the above example (Example 10a) gave a mixture of (S)-2-
{[(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid tert-butyl ester and (S)-2- {[(2S,3S,4S,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid tert-butyl ester (45.8 mg, 15.6 %). The mixture was treated with 2N H2S04 (catalytic) in MeOH (1 mL) at 120°C for 10 min using CEM microwave reactor to give after purification by reverse phase chromatography (20-95% of MeCN/water): (S)-2-{[(2S,3S,4S,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid methyl ester (13.5 mg, 31.8%).
HRMS (ES+) m z Calcd for C29H35C12N303+H [(M+H)+]: 544.2128, found: 544.2126.
Example 11 Preparation of (S)-2-{[(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl -amino}-3-methyl-butyric acid
Figure imgf000038_0001
M. W. 530.5 C28H33CI2N3O3
A mixture of (S)-2-{[(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid tert-butyl ester (86.0 mg, 0.15 mmol) prepared in Example 10a and 2 N H2SO4 (0.5 mL) in MeCN (1 mL) was heated to 120 °C for 10 min with CEM microwave reactor. The mixture was then concentrated and the residue was purified by reverse phase chromatography (20-95% of MECN/water) to give: (S)-2- {[(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid (45.1 mg, 58.0%).
HRMS (ES+) m z Calcd for C28H33CI2N3O3+H [(M+H)+]: 530.1972, found: 530.1971.
Example 12
Preparation of (S)-2-{[(2S,3S,4S,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino -3-methyl-butyric acid
Figure imgf000038_0002
M. W. 530.5 C28H33CI2N3O3
A mixture of (S)-2-{[(2S,3S,4S,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3 -methyl-butyric acid tert-butyl ester (90 mg, 0.15 mmol) prepared in Example 10b and 2 N H2SO4 (0.5 mL) in MeCN (1 mL) was heated to 120 °C for 10 min with CEM microwave reactor. The mixture was then concentrated and the residue was purified by reverse phase chromatography (20-95%) of MeCN/water) to give: (S)-2- {[(2S,3S,4S,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid (45.8 mg, 56.3%).
HRMS (ES+) m z Calcd for C28H33CI2N3O3+H [(M+H)+]: 530.1972, found: 530.1971. Example 13
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ( 1 -hydroxymethyl-cyclopropylmethyl)-amide
Figure imgf000039_0001
M. W. 514.50 C28H33CI2N3O2
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol) prepared in Example Id, (l-aminomethyl-cyclopropyl)-methanol (30.3 mg, 0.3 mmol), HATU (76.0 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2C12 and washed with water, brine. The organic phase was separated, filtered and dried overNa2S04. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of MeCN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid (l-hydroxymethyl-cyclopropylmethyl)-amide (23.9 mg, 24.7 %) as a white powder.
HRMS (ES+) m/z Calcd for C28H33CI2N3O2 + H [(M+H)+]: 514.2023, found: 514.2024.
Example 14
Preparation of rac-(2R,3R,4R,5S)-3-(3-Chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbox lic acid ( 1 -h droxymethyl-cyclobutylmethyl)-amide
Figure imgf000039_0002
M. W. 528.53 C29H35Cl2N302 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example Id was reacted with (1-aminomethyl-cyclobutyl)- methanol (34.5 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-hydroxymethyl- cyclopropylmethyl)-amide (11.2 mg, 10.6 %).
HRMS (ES+) m/z Calcd for C29H35CI2N3O2 + H [(M+H)+]: 528.2179, found: 528.2179.
Example 15
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbox lic acid 4-tert-butyl benzylamide
Figure imgf000040_0001
M. W. 576.62 C34H39CI2N3O
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example Id was reacted with 4-teri-butylbenzylamine (48.98 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid 4-tert-butyl-benzylamide (41.8 mg, 36.25 %). HRMS (ES+) m/z Calcd for C34H39CI2N3O + H [(M+H)+]: 576.2543, found: 576.2541.
Example 16
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl) pyrrolidine -2 -carboxylic acid (3,3-dimethyl-butyl)-amide
Figure imgf000041_0001
M. W. 514.54 C29H37CI2N3O
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example Id was reacted with 3,3-dimethylbutylamine (30.36 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl) pyrrolidine -2 -carboxylic acid (3,3-dimethyl-butyl)-amide (30.4 mg, 29.5 %). HRMS (ES+) m/z Calcd for C29H37CI2N3O + H [(M+H)+]: 514.2387, found: 514.2384.
Example 17
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbox lic acid (2,2-dimethyl-propyl)-amide
Figure imgf000041_0002
M. W. 500.52 C28H35C12N30
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example Id was reacted with 2,2-dimethyl-propylamine (34.2 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2,2-dimethyl-propyl)-amide (24.6 mg, 24.6 %). HRMS (ES+) m/z Calcd for C28H35C12N30 + H [(M+H)+]: 500.2230, found: 500.2229.
Example 18 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbox -trifiuoro-ethyl)-amide
Figure imgf000042_0001
M. W. 512.41 C25H26CI2F3N3O
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example Id, 2,2,2-trifiuoroethylamine (29.7 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 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 concentrated then purified by flash column (Si02, 1-20% of EtOAc in Heptane) to afford rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (2,2-dimethyl-propyl)-amide (48.1 mg, 46.9 %).
HRMS (ES+) m/z Calcd for C25H26CI2F3N3O + H [(M+H)+]: 512.1478, found: 512.1478.
Example 19a
Preparation of (2R,3S,4S,5S)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)- 5-((S)-2-hydroxymethyl-pyrrolidine-l-carbon l)-pyrrolidine-3-carbonitrile
Figure imgf000042_0002
M. W. 514.494 C28H33CI2N3O2
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example Id was reacted with (S)-l-pyrrolidin-2-yl-methanol (30.3 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight. 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 reverse phase chromatography (30-95% of MeCN/water) to give (2R,3S,4S,5S)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-((S)-2- hydroxymethyl-pyrrolidine-l-carbonyl)-pyrrolidine-3-carbonitrile (12.0 mg, 11.7 %).
HRMS (ES+) m/z Calcd for C28H33CI2N3O2 + H [(M+H)+]: 514.2023, found: 514.2023.
Example 19b
Preparation of (2S,3R,4R,5R)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)- 5-((S)-2-hydroxymethyl-pyrrolidine-l-carbon l) pyrrolidine-3-carbonitrile
Figure imgf000043_0001
M. W. 514.494 C28H33CI2N3O2
Reverse phase chromatography separation from the above example (Example 19a) gave (2S,3R,4R,5R)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-((S)-2- hydroxymethyl-pyrrolidine-l-carbonyl) pyrrolidine-3-carbonitrile (18.1 mg, 17.6 %).
HRMS (ES+) m/z Calcd for C28H33CI2N3O2 + H [(M+H)+]: 514.2023, found: 514.2023.
Example 20
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-(3 ,4-dimethoxy-phenyl)-ethyl]-methyl-amide
Figure imgf000043_0002
M. W. 608.606 C34H39CI2N3O3
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol) prepared in Example Id was reacted with [2-(3,4-dimethoxy-phenyl)- ethyl]-methyl-amine (58.6 mg, 0.3 mmol), HATU (76.0 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-(3,4-dimethoxy- phenyl)-ethyl]-methyl-amide (57.3 mg, 48.26 %) as a white powder.
HRMS (ES+) m/z Calcd for C34H39CI2N3O3 + H [(M+H)+]: 608.2441, found: 608.2437.
Example 21
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid 2-(3,4-dimethoxy-phenyl)ethyl amide
Figure imgf000044_0001
M. W. 594.579 C33H37CI2N3O3
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example Id was reacted with 2-(3,4-dimethoxy-phenyl)ethyl amine (30.3 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2CI2 (2 mL) to at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 2-(3,4-dimethoxy- phenyl)ethyl amide (53.6 mg, 45.07 %).
HRMS (ES+) m/z Calcd for C33H37CI2N3O3 + H [(M+H)+]: 594.2285, found: 594.2283.
Example 22
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid 3 -chloro-2-fluoro-benzylamide
Figure imgf000045_0001
M. W. 572.936 C30H29CI3FN3O
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example Id was reacted with 3-chloro-2-fiuoro-benzyl amine (47.9 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 3-chloro-2-fiuoro-benzylamide (24.5 mg, 21.4 %).
HRMS (ES+) m/z Calcd for C30H29CI3FN3O + H [(M+H)+]: 572.1433, found: 572.1431.
Example 23a
Preparation of (2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl- propyl)-pyrrolidine-2-carboxylic acid ((R)-l-h droxymethyl-3-methyl-butyl)-amide
Figure imgf000045_0002
M. W. 530.54 C29H37CI2N3O2
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example Id, (R)-2-amino-4-methyl-pentan-l-ol (35.16 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 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 purified by reverse phase chromatography (30-95% of MeCN/water) to give (2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid ((R)-l-hydroxymethyl-3-methyl-butyl)-amide (26.2 mg, 24.7%). HRMS (ES+) m/z Calcd for C29H37CI2N3O2 + H [(M+H)+]: 530.2336, found: 530.2333.
Example 23b
Preparation of (2S,3S,4S,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl- propyl)-pyrrolidine-2-carboxylic acid R)-l-hydrox meth l-3-methyl-butyl)-amide
Figure imgf000046_0001
M. W. 530.54 C29H37CI2N3O2
Reverse phase chromatography separation from the above example (Example 23a) gave (2S,3S,4S,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid ((R)-l-hydroxymethyl-3-methyl-butyl)-amide (23.3 mg, 21.9 %). HRMS (ES+) m/z Calcd for C29H37CI2N3O2 + H [(M+H)+]: 530.2336, found: 530.2336.
Example 24
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethylpropyl)-pyrrolidine-2-carboxylic acid 3,4-difluoro-benzylamide
Figure imgf000046_0002
M. W. 556.49 C30H29CI2F2N3O
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example Id was reacted with 3, 4-difluoro-benzyl amine (42.94 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 3, 4-difluoro-benzyl amide (53.5 mg, 48.1 %).
HRMS (ES+) m/z Calcd for C30H29CI2F2N3O + H [(M+H)+]: 556.1729, found: 556.1728.
Example 25a
Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phi
cyano-5-(2,2-dimethyl-propyl)-p rrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000047_0001
M. W. 431.37 C23H24CI2N2O2 .C2HF3O2
To a solution of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example lc (2 g, 4.12 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 18 h, and concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried under reduced pressure to give rac- (2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.1 g, 94%)
HRMS (ES+) m/z Calcd for C23H24CI2N2O2 + H [(M+H)+]: 431.1288, found: 431.1287.
Example 25b
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy-propyl)-amide
Figure imgf000048_0001
M. W. 488.46 C26H31CI2N3O2
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 25a (0.5 g, 1.1 mmol) was reacted with 3 -amino- 1- propanol (Aldrich) (0.4 g, 5.3 mmol), HATU (0.5 g, 1.31 mmol) and iPr2NEt (1 g, 7.7 mmol) in CH2C12 (30 mL) at room temperature for 24 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4- (4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy- propyl)-amide as a white solid (0.56 g, 93%).
HRMS (ES+) m/z Calcd for C26H31CI2N3O2 + H [(M+H)+]: 488.1866, found: 488.1864.
Example 26a
Preparation of intermediate (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile
Figure imgf000048_0002
In a manner similar to the method described in Example lb, 4-chlorobenzyl cyanide (8.9 g, 59 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (Oakwood) (10 g, 63 mmol), methanolic solution (25 wt%) of sodium methoxide (15 mL, 66 mmol) in methanol (300 mL) at 40 °C for 5 h to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile as a white powder (16 g, 92%).
Example 26b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000049_0001
M. W. 505.46 C27H31CI2FN2O2
In a manner similar to the method described in Example lc, [3,3-dimethyl-but-(E)- ylideneamino]-acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (2.3 g, 7.9 mmol) prepared in Example 26a, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in 1,2- dichloroethane (130 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2.7 g, 68%).
Example 26c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro- phenyl)-4-cyano-5-(2,2-dimethyl- ropyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000049_0002
M. W. 449.36 C23H23CI2FN2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 26b (0.8 g, 1.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.9 g, 100%).
HRMS (ES+) m/z Calcd for C23H23CI2FN2O2+ H [(M+H)+]: 449.1194, found: 449.1194. Example 26d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-(cis-2,6-dimethyl-morpholin-4-yl)-ethyl]- amide
Figure imgf000050_0001
M. W. 589.58 C31H39CI2FN4O2
In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.20 g, 0.36 mmol) was reacted with 4-(2- aminoethyl)-cis-2,6-dimethylmo holine (Oakwood) (0.20 g, 1.2 mmol), HATU (0.3 g, 0.78 mmol) and iP^NEt (0.60 g, 4.6 mmol) in CH2CI2 (20 mL) at room temperature for 20 hrs to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl- propyl)-pyrrolidine-2-carboxylic acid [2-(cis-2,6-dimethyl-mo holin-4-yl)-ethyl]-amide as a white solid (0.20 g, 94%). HRMS (ES+) m/z Calcd for C31H39CI2FN4O2+ H [(M+H)+]: 589.2507, found: 589.2507.
Example 27
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-cyclopropyl-ethyl)-amide
Figure imgf000050_0002
M. W. 498.50 C28H33CI2N3O
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 25a (0.16 g, 0.37 mmol) was reacted with 2- cyclopropylethylamine (Bridge Organics) (0.1 g, 1.1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2 mmol) in CH2C12 (20 mL) at room temperature for 20 h to give rac- (2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid (2-cyclopropyl-ethyl)-amide as a white solid (0.11 g, 37%).
HRMS (ES+) m/z Calcd for C28H33C12N30 + H [(M+H)+]: 498.2074, found: 498.2075.
Example 28
Preparation of rac-(3-{[(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbon l]-amino}-propyl)-carbamic acid tert-butyl ester
Figure imgf000051_0001
M. W. 587.59 C3iH40Cl2N4O2
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid prepared in Example 25a (1 g, 1.8 mmol) was reacted with N-Boc-l,3-diaminopropane
(Aldrich) (0.7 g, 4 mmol), HATU (1.4 g, 3.7 mmol) and iPr2NEt (2.8 g, 21 mmol) in CH2C12 (100 mL) at room temperature for 60 h to give rac-(3-{[(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4- chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -propyl)- carbamic acid tert-butyl ester as a white solid (0.92 g, 87%).
HRMS (ES+) m/z Calcd for C3iH40Cl2N4O2 + H [(M+H)+]: 587.2550, found: 587.2551.
Example 29
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbox lic acid (3-amino-propyl)-amide
Figure imgf000051_0002
M. W. 487.47 C26H32C12N40 To a solution of rac-(3-{[(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester prepared in Example 28 (0.9 g, 1.5 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 1 h, and concentrated. The residue was then neutralized with saturated aqueous NaHC03 solution, and then extracted with ethyl acetate. The organic layer was separated, dried over MgS04, concentrated, dried under reduced pressure to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-amino-propyl)-amide as a white solid (0.8 g, 100%)
HRMS (ES+) m/z Calcd for C26H32C12N40+ H [(M+H)+]: 487.2026, found: 487.2027.
Example 30
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(l-acetyl-piperidin-4-ylamino)-propyl]-amide
Figure imgf000052_0001
M. W. 640.65 C34H43C12N503
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3- amino-propyl)-amide prepared in Example 29 (0.18 g, 0.37 mmol) was reacted with 1- acetylpiperidine-4-carboxylic acid (Lancaster) (0.7 g, 0.58 mmol), HATU (0.3 g, 0.78 mmol) and iPr2NEt (0.5 g, 3.9 mmol) in CH2C12 (20 mL) at room temperature for 20 h to give rac- (2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid [3-(l-acetyl-piperidin-4-ylamino)-propyl]-amide as a white solid (0.16g, 67%).
HRMS (ES+) m/z Calcd for C34H43C12N503 + H [(M+H)+]: 640.2816, found: 640.2818.
Example 31a
Preparation of intermediate [3-Methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester
Figure imgf000053_0001
M. W. 199.16 C11H21NO2
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with isovaleraldehyde (Alfa) (0.43 g, 5 mmol) in CH2CI2 at room temperature for 18 h to give [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil
(0.98 g, 98%).
Example 31b
Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-ph(
cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000053_0002
M. W. 473.45 C26H30CI2N2O2
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example 31a (2 g, 10 mmol) was reacted with (Z)-3-(3- chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (2 g, 7.3 mmol) prepared in Example lb, AgF (1.3 g, 10 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.7 g, 20%).
Example 31c
Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-ph(
cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000053_0003
M. W. 417.34 C22H22CI2N2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 31b (0.4 g, 0.85 mmol) was reacted with trifiuoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4- chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifiuoroacetic acid as a off white solid (0.4 g, 89%).
HRMS (ES+) m/z Calcd for C22H22CI2N2O2+ H [(M+H)+]: 417.1131 , found: 417.1131.
Example 3 Id
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl- pyrrolidine-2-carboxylic acid (3-hydrox -propyl)-amide
Figure imgf000054_0001
M. W. 474.43 C25H29CI2N3O2
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifiuoroacetic acid prepared in Example 31c (0.6 g, 1.1 mmol) was reacted with 3-amino-l-propanol (Aldrich) (0.4 g, 5.3 mmol), HATU and iP^NEt in CH2CI2 at room temperature to give rac- (2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2- carboxylic acid (3-hydroxy-propyl)-amide as a white solid (0.21 g, 40%).
HRMS (ES+) m/z Calcd for C25H29CI2N3O2 + H [(M+H)+]: 474.1710, found: 474.1710.
Example 32a
Preparation of intermediate {[l-(3-Chloro-phenyl)-meth-(E)-ylidene]-amino} -acetic acid butyl ester
Figure imgf000055_0001
M. W. 253.73 C13H16CINO2
In a manner similar to the method described in Example la, glycine tert-butyl ester (1.31 g, 10 mmol) was reacted with 3-chlorobenzaldehyde (Aldrich) (1.4 g, 10 mmol) in CH2CI2 at room temperature for 18 h to give {[l-(3-chloro-phenyl)-meth-(E)-ylidene]-amino} -acetic acid tert- butyl ester as a plae yellow oil (2.4 g, 95%).
Example 32b
Preparation of intermediate (Z)-2- 4-chloro-phenyl)-5,5-dimethyl-hex-2-enenitrile
Figure imgf000055_0002
In a manner similar to the method described in Example lb, 4-chlorobenzyl cyanide (4.5 g, 30 mmol) was reacted with 3,3-dimethyl-butyraldehyde (Aldrich) (3 g, 30 mmol), methanolic solution (25 wt%)of sodium methoxide (7 mL, 30 mmol) in methanol (130 mL) at room temperature for 3 h to give (Z)-2-(4-chloro-phenyl)-5,5-dimethyl-hex-2-enenitrile as a colorless oil (5 g, 71%).
Example 32c
Preparation of intermediate rac-(2R,3R,4R,5S)-5-(3-Chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000056_0001
M. W. 487.47 C27H32CI2N2O2
In a manner similar to the method described in Example lc, {[l-(3-chloro-phenyl)-meth-(E)- ylidene]-amino} -acetic acid tert-butyl ester prepared in Example 32a (2.6 g, 11 mmol) was reacted with (Z)-2-(4-chloro-phenyl)-5,5-dimethyl-hex-2-enenitrile (2 g, 7.9 mmol) prepared in Example 32b, AgF (1.3 g, 10 mmol), and triethylamine (2.2 g, 22 mmol) in 1,2-dichloroethane (100 mL) at room temperature for 24 h to give rac-(2R,3R,4R,5S)-5-(3-Chloro-phenyl)-4-(4- chloro-phenyl)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.2 g, 31 %).
HRMS (ES+) m/z Calcd for C27H32CI2N2O2+ H [(M+H)+]: 487.1914, found: 487.1912.
Example 32d
Preparation of intermediate rac-(2R,3R,4R,5S)-5-(3-Chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-3-(2,2-dimethyl- ropyl)-pyrrolidine-2-carboxylic acid trifiuoroacetic acid
Figure imgf000056_0002
M. W. 431.37 C23H24CI2N2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-5-(3-Chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert- butyl ester prepared in Example 32c (1.2 g, 2.5 mmol) was reacted with trifiuoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-5-(3-Chloro-phenyl)-4-(4- chloro-phenyl)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifiuoroacetic acid as a yellow solid (1.0 g, 76%).
HRMS (ES+) m/z Calcd for C23H24CI2N2O2+ H [(M+H)+]: 431.1288, found: 431.1288. Example 32e
Preparation of rac-(2R,3R,4R,5R)-5-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-3-(2,2- dimethyl-propyl)-pyrrolidine-2-carbox lic acid (3-hydroxy-propyl)-amide
Figure imgf000057_0001
M. W. 488.46 C26H31CI2N3O2
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5R)-5-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 32d (0.6 g, 1.1 mmol) was reacted with 3-amino-l- propanol (Aldrich) (0.6 g, 8 mmol), HATU and iP^NEt in CH2CI2 at room temperature to give rac-(2R,3R,4R,5R)-5-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-3-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid (3-hydroxy-propyl)-amide as a yellow solid (0.12 g, 22%).
HRMS (ES+) m/z Calcd for C26H31CI2N3O2+ H [(M+H)+]: 488.1866, found: 488.1864.
Example 33a
Preparation of intermediate (S)-2-[3,3-Dimethyl-but-(E)-ylideneamino]-propionic acid tert-butyl ester
Figure imgf000057_0002
A mixture of L-alanine tert-butyl ester hydrochloride (Bachem) (1.8 g, 10 mmol) and MgSC>4 in CH2CI2 (100 mL) was added triethylamine (1.5 g, 15 mmol). The mixture was stirred at room temperature for 1 h, and 3,3-dimethyl-butyraldehyde (1 g, 10 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The mixture was filtered, and the filtrate was washed with water, brine, and concentrated. The residue was dried under reduced pressure to give (S)-2-[3,3-dimethyl-but-(E)-ylideneamino]-propionic acid tert-butyl ester as colorless oil (2,3 g, 100%) which was used without further purification. Example 33b
Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-Chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000058_0001
M. W. 501.50 C28H34CI2N2O2
In a manner similar to the method described in Example lc, (S)-2-[3,3-dimethyl-but-(E)- ylideneamino]-propionic acid tert-butyl ester prepared in Example 33a (2.4 g, 11 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (2.4 g, 8.8 mmol) prepared in Example lb, AgF (1.6 g, 13 mmol), and triethylamine (2.4 g, 24 mmol) in 1,2- dichloroethane (150 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-Chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2.4 g, 54%).
HRMS (ES+) m/z Calcd for C28H34CI2N2O2+ H [(M+H)+]: 501.2070, found: 501.2066. Example 33c
Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-2-meth l-pyrrolidine-2-carboxylic acid trifiuoroacetic acid
Figure imgf000058_0002
M. W. 445.39 C24H26CI2N2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 33b (1 g, 2 mmol) was reacted with trifiuoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4- (4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid trifiuoroacetic acid as a white solid (1.1 g, 98%). HRMS (ES ) m/z Calcd for C24H26CI2N2O2+ H [(M+H)+]: 445.1444, found: 445.1443.
Example 33d
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-2-methyl-pyrrolidine-2-carbox lic acid (3-hydroxy-propyl)-amide
Figure imgf000059_0001
M. W. 502.48 C27H33CI2N3O2
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 33c (0.4 g, 0.7 mmol) was reacted with 3-amino-l - propanol (Aldrich) (0.4 g, 5.3 mmol), HATU (0.5 g, 1.3 mmol) and iP^NEt (1 g, 7.7 mmol) in CH2CI2 (30 mL) at room temperature for 24 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4- (4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid (3- hydroxy-propyl)-amide as a white solid (0.21 g, 60%).
HRMS (ES+) m/z Calcd for C27H33CI2N3O2 + H [(M+H)+]: 502.2023, found: 502.2021.
Example 34a
Preparation of intermediate [2-Cyclopentyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester
Figure imgf000059_0002
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.7 g, 5 mmol) was reacted with 2-cyclopentylacetaldehyde (Betapharma) (0.9 g, 8 mmol) in CH2CI2 at room temperature for 20 h to give [2-cyclopentyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1 g, 90%).
Example 34b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro- phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-arboxylic acid tert-butyl ester
Figure imgf000060_0001
M. W. 517.48 C28H31CI2FN2O2
In a manner similar to the method described in Example lc, [2-cyclopentyl-eth-(E)- ylideneamino]-acetic acid tert-butyl ester prepared in Example 34a (1 g, 4.4 mmol) was reacted with (Z)-3-(3-chloro-2-fiuoro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (0.9 g, 3 mmol) prepared in Example 26a, AgF (1.3 g, 10 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (150 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)- 4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-arboxylic acid tert-butyl ester as a white foam (0.4 g, 26%).
Example 34c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro- phenyl)-4-cyano-5-cyclopentylmeth l-pyrrolidine-2-arboxylic acid trifiuoroacetic acid
Figure imgf000060_0002
M. W. 461.37 C24H23CI2FN2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-arboxylic acid tert-butyl ester prepared in Example 34b (0.4 g, 0.77 mmol) was reacted with trifiuoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-arboxylic acid trifiuoroacetic acid as a off white solid (0.5 g, 100%). Example 34d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5- cyclopentylmethyl-pyrrolidine-2-car xylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000061_0001
M. W. 548.48 C28H32CI2FN3O3
In a manner similar to the method described in Example 3b, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-arboxylic acid trifluoroacetic acid prepared in Example 34c (0.4 g, 0.71 mmol) was reacted with 2-((S)-2,2- dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.2 g, 1.4 mmol), HATU (0.4 g, 1.1 mmol) and iPr2NEt (0.6 g, 4.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2- carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.14 g, 36%).
HRMS (ES+) m/z Calcd for C28H32CI2FN3O3+ H [(M+H)+]: 548.1878, found: 548.1880.
Example 35
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-car xylic acid (2 -hydroxy- 1 , 1 -dimethyl-ethyl)-amide
Figure imgf000061_0002
M. W. 520.47 C27H32CI2FN3O2
In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.2 g, 0.36 mmol) was reacted with 2-amino- 2-methyl-l-propanol (Fluka) (0.2 g, 2.2mmol), HATU (0.3 g, 0.78 mmol) and iPr2NEt (0.5 g, 3.8 mmol) in CH2CI2 (10 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-hydroxy-l,l-dimethyl-ethyl)-amide as a white solid (0.17 g, 91%).
HRMS (ES+) m/z Calcd for C27H32CI2FN3O2+ H [(M+H)+]: 520.1929, found: 590.1929.
Example 36
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy-2,2-dimethyl-propyl)-amide
Figure imgf000062_0001
M. W. 534.5 C28H34CI2FN3O2
In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.2 g, 0.36 mmol) was reacted with 3-amino- 2,2-dimethyl-l-propanol (TCI-US) (0.2 g, 2 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.2 g, 1.6 mmol) in CH2CI2 (20 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid (3-hydroxy-2,2-dimethyl-propyl)-amide as a white solid (0.16 g, 83%).
HRMS (ES+) m/z Calcd for C28H34CI2FN3O2+ H [(M+H)+]: 534.2085, found: 534.2084.
Example 37
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbox lic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide
Figure imgf000062_0002
M. W. 536.47 C27H32CI2FN3O3 In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.3 g, 0.54 mmol) was reacted with 2-(2- aminoethyl)ethanol (Aldrich) (0.15 g, 1.4 mmol), HATU (0.3 g, 0.75 mmol) and iPr2NEt (0.6 g, 4.8 mmol) in CH2C12 (20 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide as a white solid (0.18 g, 62%).
HRMS (ES+) m/z Calcd for C27H32CI2FN3O3+ H [(M+H)+]: 536.1878, found: 536.1877. Example 38
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-acetylamino-ethyl)-amide
Figure imgf000063_0001
M. W. 533.47 C27H31CI2FN4O2
In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.3 g, 0.54 mmol) was reacted with N- acetylethylenediamine (Aldrich) (0.15 g, 1.5 mmol), HATU (0.3 g, 0.75 mmol) and iPr2NEt (0.6 g, 4.8 mmol) in CH2C12 (20 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid (2-acetylamino-ethyl)-amide as a white solid (0.24 g, 83%).
HRMS (ES+) m/z Calcd for C27H31CI2FN4O2+ H [(M+H)+]: 533.1881 , found: 533.1882. Example 39
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-imidazol-l -yl-propyl)-amide
Figure imgf000064_0001
M. W. 556.51 C29H32C12FN50
In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.2 g, 0.36 mmol) was reacted with l-(3- aminopropopyl)imidazole (Aldrich) (0.15 g, 1.2 mmol), HATU (0.3 g, 0.75 mmol) and iPr2NEt (0.5 g, 3.6 mmol) in CH2C12 (20 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid (3-imidazol-l -yl-propyl)-amide as a white solid (0.19 g, 94%).
HRMS (ES+) m/z Calcd for C29H32C12FN50 + H [(M+H)+]: 556.2041, found: 556.2040. Example 40
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-4-hydroxy-3-methyl-butyl)-amide
Figure imgf000064_0002
M. W. 534.5 C28H34C12FN302
In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine -2 -carboxylic acid trifluoroacetic acid prepared in Example 26c (0.16 g, 0.29 mmol) was reacted with (R)-4- amino-2-methyl-l-butanol (TCI-US) (0.1 g, 1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2 mmol) in CH2C12 (20 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid ((R)-4-hydroxy-3-methyl-butyl)-amide as a white solid (0.1 g, 65%).
HRMS (ES+) m/z Calcd for C28H34CI2FN3O2+ H [(M+H)+]: 534.2085, found: 534.2084.
Example 41
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2- ar xylic acid cyclopropylmethoxy-amide
Figure imgf000065_0001
M. W. 518.46 C27H30CI2FN3O2
In a manner similar to the method described in Example le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.15 g, 0.27 mmol) was reacted with O- cyclopropylmethylhydroxyamine (HUHU Tech) (0.1 g, 1.1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2 mmol) in CH2CI2 (20 mL) at room temperature for 20 h to give rac- (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl- propyl)-pyrrolidine-2-carboxylic acid cyclopropylmethoxy-amide as a white solid (30 mg, 21%). HRMS (ES+) m/z Calcd for C27H30CI2FN3O2+ H [(M+H)+]: 518.1772, found: 518.1773.
Example 42a
Preparation of intermediate rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000065_0002
M. W. 527.88 C28H25C13N202
In a manner similar to the method described in Example lc, {[l-(3-Chloro-phenyl)-meth-(E)- ylidene]-amino} -acetic acid tert-butyl ester prepared in Example 32a (2 g, 7.6 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (0.55 g, 2 mmol) prepared in Example lb, AgF (1.3 g, 10 mmol), and triethylamine (1.9 g, 19 mmol) in dichloromethane (30 mL) at 50 °C for 20 h to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro- phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.45 g, 44%). HRMS (ES+) m/z Calcd for C28H25CI3N2O2 + H [(M+H)+]: 527.1055, found: 527.1051.
Example 42b
Preparation of intermediate rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000066_0001
M. W. 471.77 C24Hi7Cl3N202.C2HF302
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3,5-bis-(3- chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 42a (0.45 g, 0.85 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4- chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.49 g, 98%).
HRMS (ES+) m/z Calcd for C24Hi7Cl3N202+ H [(M+H)+]: 471.0429, found: 471.0429.
Example 42c
Preparation of rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano- pyrrolidine-2-carboxylic acid [2-((S -2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethyl]-amide
Figure imgf000066_0002
M. W. 598.96 C3iH30Cl3N3O3 In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3,5-bis-(3- chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifiuoroacetic acid prepared in Example 42b (0.3 g, 0.5 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan- 4-yl)-ethylamine (0.3 g, 2 mmol), HATU (0.3 g, 0.75 mmol) and iPr2NEt (0.6 g, 4 mmol) in CH2C12 (30 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl- [l,3]dioxolan-4-yl)-ethyl]-amide as a off white solid (0.25 g, 83%).
HRMS (ES+) m/z Calcd for C31 H30CI3N3O3+ H [(M+H)+]: 598.1426, found: 598.1424.
Example 42d
Preparation of rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano- pyrrolidine-2-carboxylic acid ((S)-3 4-dihydroxy-butyl)-amide
Figure imgf000067_0001
M. W. 558.89 C28H26Cl3N303
To a solution of rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano- pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 42c (0.4 g, 0.66 mol) in tetrahydrofuran (10 mL) was added aqueous HC1 solution (IN, 10 mL). The reaction mixture was stirred at room temperature for 2 h, then concentrated. Then the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, aqueous saturated NaHC03, brine, dried over MgSC>4, concentrated, dried under reduced pressure to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro- phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.2 g, 89%).
HRMS (ES+) m/z Calcd for C28H26C13N303+ H [(M+H)+]: 558.1113, found: 558.1110.
Example 43a
Preparation of intermediate [2-ethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester
Figure imgf000068_0001
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with 2-ethylbutyraldehyde (Aldrich) (0.55 g, 5 mmol) in CH2CI2 at room temperature for 18 h to give [2-ethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1 g, 94%).
Example 43b
Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-(l-ethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000068_0002
M. W. 487.5 C27H32CI2N2O2
In a manner similar to the method described in Example lc, [2-ethyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example 43a (1 g, 4.7 mmol) was reacted with (Z)-3-(3- chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (0.91 g, 3.3 mmol) prepared in Example lb, AgF (1.5 g, 12 mmol), and triethylamine (1.9 g, 19 mmol) in 1,2-dichloroethane (50 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)- 4-cyano-5-(l-ethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.1 g, 68%).
Example 43 c
Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phi
cyano-5-(l-ethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000069_0001
M. W. 431.37 C23H24CI2N2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(l -ethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 43b (1.1 g, 2.3 mmol) was reacted with trifiuoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4- chloro-phenyl)-4-cyano-5-(l-ethyl-propyl)-pyrrolidine-2-carboxylic acid trifiuoroacetic acid as a white solid (1.2 g, 98%).
HRMS (ES+) m/z Calcd for C23H24CI2N2O2+ H [(M+H)+]: 431.1288, found: 431.1286.
Example 43 d
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(l -ethyl- propyl)-pyrrolidine-2-carboxylic ac -3,4-dihydroxy-butyl)-amide
Figure imgf000069_0002
M. W. 518.48 C27H33CI2N3O3
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3- chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(l-ethyl-propyl)-pyrrolidine-2-carboxylic acid trifiuoroacetic acid prepared in Example 43c (0.55 g, 1 mmol) was reacted with 2-((S)-2,2- dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.2 g, 1.3 mmol), HATU (0.4 g, 1.1 mmol) and iPr2NEt (0.2 g, 1.5 mmol) in CH2CI2 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3- chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(l-ethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.5 g, 96%).
HRMS (ES ) m/z Calcd for C27H33CI2N3O3+ H [(M+H)+]: 518.1972, found: 518.1970. Example 44a
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4- (2,2-dimethyl-propyl)-pyrrolidine-2-carbox lic acid ((S)-3 ,4-dihydroxy-butyl)-amide
Figure imgf000070_0001
M. W. 536.47 C27H32CI2FN3O3
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 26c (0.25g, 0.44 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.2 g, 1.3 mmol), HATU (0.3 g, 0.79 mmol) and iPr2NEt (0.5 g, 3.9 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)- 3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine- 2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.21g, 89%).
HRMS (ES+) m/z Calcd for C27H32CI2FN3O3+ H [(M+H)+]: 536.1878, found: 536.1875.
Example 44b
Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrroli dine -2-carbox lic acid ((S)-3 ,4-dihydroxy-butyl)-amide
Figure imgf000070_0002
M. W. 536.47 C27H32CI2FN3O3
Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl- propyl)-pyrrolidine -2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (0.19 g) was separated by chiral SFC chromatography to provide chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4- chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine -2-carboxylic acid ((S)-3,4- dihydroxy-butyl)-amide as a white solid (85 mg, 45%>) and chiral-(2S,3R,4SR,5R)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (81 mg, 43%).
Example 45
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl- pyrrolidine-2-carboxylic acid ((S)-3 4-dihydroxy-butyl)-amide
Figure imgf000071_0001
M. W. 504.46 C26H31CI2N3O3
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3- chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 31c (0.4 g, 0.75 mmol) was reacted with 2-((S)-2,2- dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.25 g, 1.6 mmol), HATU (0.4 g, 1.1 mmol) and iPr2NEt (1 g, 7.8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid ((S)-3,4- dihydroxy-butyl)-amide as a white solid (0.4 g, 95%).
HRMS (ES+) m/z Calcd for C26H31CI2N3O3+ H [(M+H)+]: 504.1815, found: 504.1815.
Example 46a
Preparation of intermediate rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000071_0002
M. W. 473.45 C26H30CI2N2O2
In the preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5- isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester as described in Example 31b, rac- (2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2- carboxylic acid tert-butyl ester was obtained as the second product: white powder, Yield: 0.82 g, 24%.
HRMS (ES+) m/z Calcd for C26H30CI2N2O2+ H [(M+H)+]: 473.1757, found: 473.1756.
Example 46b
Preparation of intermediate rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-isobutyl-pyrrolidine-2-carbox lic acid trifluoroacetic acid
Figure imgf000072_0001
M. W. 417.34 C22H22CI2N2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5R)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 46a (0.6 g, 1.3 mmol) was reacted with trifluoroacetic acid in
dichloromethane at room temperature to give rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4- chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.6 g, 89%).
Example 46c
Preparation of rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl- pyrrolidine-2-carboxylic acid ((S)-3 4-dihydroxy-butyl)-amide
Figure imgf000072_0002
M. W. 504.46 C26H31CI2N3O3
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5R)-3-(3- chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 46b (0.6 g, 1.1 mmol) was reacted with 2-((S)-2,2- dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.3 g, 2 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (1.2 g, 9.3 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5R)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid ((S)-3 ,4- dihydroxy-butyl)-amide as a white solid (0.6 g, 95%).
HRMS (ES+) m/z Calcd for C26H31CI2N3O3+ H [(M+H)+]: 504.1815, found: 504.1816.
Example 47a
Preparation of intermediate rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5 -( 1 -ethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000073_0001
In the preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(l- ethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as described in Example 43b, rac- (2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(l-ethyl-propyl)-pyrrolidine- 2-carboxylic acid tert-butyl ester was obtained as the second product: white foam, Yield, 0.26 g,
16%.
Example 47b
Preparation of intermediate rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phi
cyano-5 -(l-ethyl-propyl)-pyrrolidine-2-carbox lic acid trifluoroacetic acid
Figure imgf000073_0002
M. W. 431.37 C23H24CI2N2O2.C2HF3O2 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5R)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(l -ethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 47a (0.25 g, 0.5 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4- chloro-phenyl)-4-cyano-5-(l-ethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.2 g, 73%).
HRMS (ES+) m/z Calcd for C23H24CI2N2O2+ H [(M+H)+]: 431.1288, found: 431.1285.
Example 47c
Preparation of rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(l-ethyl- propyl)-pyrrolidine-2-carboxylic aci -3,4-dihydroxy-butyl)-amide
Figure imgf000074_0001
M. W. 518.48 C27H33CI2N3O3
In a manner similar to the method described in Example 42e, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(l -ethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 47b (0.27 g, 0.5 mmol) was reacted with 2-((S)-2,2- dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.2 g, 1.3 mmol), HATU (0.4 g, 1.1 mmol) and iPr2NEt (0.4 g, 3 mmol) in CH2CI2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5R)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(l-ethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4- dihydroxy-butyl)-amide as a white solid (0.23 g, 88%).
HRMS (ES+) m/z Calcd for C27H33CI2N3O3+ H [(M+H)+]: 518.1972, found: 518.1971.
Example 48a
Preparation of intermediate (l-ethyl-propylideneamino)-acetic acid tert-butyl ester
Figure imgf000075_0001
M. W. 199.16 C11H21NO2
A mixture of glycine tert-butyl ester (Alfa) (0.66 g, 10 mmol) and 3-pentanone (6 g, 70 mmol) in ethanol (6 mL) was heated at 110 °C in a sealed tube for 48 h. The reaction mixture was concentrated and dried in vacu to give crude (1 -ethyl -propylideneamino)-acetic acid tert-butyl ester as a colorless oil (1.0 g). The crude product contains unreacted glycine tert-butyl ester and was used without further purification.
Example 48b
Preparation of intermediate rac-(2R,3R,4R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano- 5,5-diethyl-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000075_0002
M. W. 473.45 C26H30CI2N2O2
In a manner similar to the method described in Example lc, crude (1-ethyl-propylideneamino)- acetic acid tert-butyl ester prepared in Example 48a (1.2 g, 6 mmol) was reacted with (Z)-3-(3- chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (0.7 g, 2.5 mmol) prepared in Example lb, AgF (1.9 g, 15 mmol), and triethylamine (2.5 g, 25 mmol) in 1,2-dichloroethane (130 mL) at room temperature for 10 h to give rac-(2R,3R,4R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a yellow gum (0.33 g, 28%).
Example 48c
Preparation of intermediate rac-(2R,3R,4R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano- 5,5-diethyl-pyrrolidine-2-carboxylic acid trifiuoroacetic acid
Figure imgf000076_0001
M. W. 417.34 C22H22CI2N2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 48c (0.33 g, 0.7 mmol) was reacted with trifluoroacetic acid in
dichloromethane at room temperature to give rac-(2R,3R,4R)-3-(3-chloro-phenyl)-4-(4-chloro- phenyl)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white foam (0.35 g, 96%).
HRMS (ES+) m/z Calcd for C22H22CI2N2O2+ H [(M+H)+]: 417.1131.0429, found: 417.1132.
Example 48d
Preparation of rac-(2R,3R,4R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5,5-diethyl- pyrrolidine-2-carboxylic acid ((S)-3 4-dihydroxy-butyl)-amide
Figure imgf000076_0002
M. W. 504.46 C26H31CI2N3O3
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 48c (0.33 g, 0.62 mmol) was reacted with 2-((S)-2,2-dimethyl- [l,3]dioxolan-4-yl)-ethylamine (0.15 g, 1 mmol), HATU (0.34 g, 0.89 mmol) and iPr2NEt (1 g, 7.8 mmol) in CH2CI2 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R)-3-(3-chloro-phenyl)-4-(4- chloro-phenyl)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)- amide as a off white solid (0.4 g, 95%).
HRMS (ES+) m/z Calcd for C26H31CI2N3O3+ H [(M+H)+]: 504.1815, found: 504.1815. Example 49a
Preparation of intermediate [2-methyl-pro -(E)-ylideneamino]-acetic acid tert-butyl ester
Figure imgf000077_0001
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with isobutyraldehyde (Aldrich) (0.4 g, 5 mmol) in CH2CI2 at room temperature for 20 h to give [2-methyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.9 g, 97%).
Example 49b
Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-isopropyl-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000077_0002
M. W. 459.42 C25H28Cl2N202
In a manner similar to the method described in Example lc, [2-methyl-prop-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example 49a (1 g, 5.4 mmol) was reacted with (Z)-3-(3- chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (0.85 g, 3.1 mmol) prepared in Example lb, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-isopropyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.64 g, 45%>).
Example 49c
Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-isopropyl-pyrrolidine-2-carboxylic acid trifiuoroacetic acid
Figure imgf000078_0001
M. W. 403.31 C21H20CI2N2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 49b (0.64 g, 1.4 mmol) was reacted with trifiuoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4- chloro-phenyl)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid trifiuoroacetic acid as a off white solid (0.7 g, 100%).
HRMS (ES+) m/z Calcd for C21H20CI2N2O2+ H [(M+H)+]: 403.0975, found: 403.0974.
Example 49d
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isopropyl- pyrrolidine-2-carboxylic acid ((S)-3 4-dihydroxy-butyl)-amide
Figure imgf000078_0002
M. W. 490.43 C25H29Cl2N303
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3- chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid trifiuoroacetic acid prepared in Example 49c (0.5 g, 0.97 mmol) was reacted with 2-((S)-2,2- dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.25 g, 1.7 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (1 g, 7.8 mmol) in CH2CI2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid ((S)-3,4- dihydroxy-butyl)-amide as a white solid (0.25 g, 52%).
HRMS (ES+) m/z Calcd for C25H29Cl2N303+ H [(M+H)+]: 490.1659, found: 490.1657. Example 50a
Preparation of intermediate {[1 -eye lohexyl-meth-(E)-ylidene]-amino} -acetic acid tert-butyl ester
Figure imgf000079_0001
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with cyclohexanecarbaldehyde (Aldrich) (0.6 g, 5 mmol) in CH2CI2 at room temperature for 20 h to give {[1 -eye lohexyl-meth-(E)-ylidene]-amino} -acetic acid tert-butyl ester as a colorless oil (1.2 g, 100%).
Example 50b
Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000079_0002
M. W. 499.49 C28H32CI2N2O2
In a manner similar to the method described in Example lc, {[l-cyclohexyl-meth-(E)-ylidene]- amino}-acetic acid tert-butyl ester prepared in Example 50a (1.2 g, 5.3 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (1 g, 3.7 mmol) prepared in Example lb, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)- 4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.69 g, 38%).
Example 50c Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid trifiuoro acetic acid
Figure imgf000080_0001
M. W. 443.38 C24H24CI2N2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 50b (0.69 g, 1.4 mmol) was reacted with trifiuoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4- chloro-phenyl)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid trifiuoroacetic acid as a off white solid (0.8 g, 100%).
HRMS (ES+) m/z Calcd for C24H24CI2N2O2+ H [(M+H)+]: 443.1288, found: 443.1286.
Example 50d
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5- cyclohexyl-pyrrolidine-2-carboxylic acid S)-3,4-dihydroxy-butyl)-amide
Figure imgf000080_0002
M. W. 530.49 C28H33CI2N3O3
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3- chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid trifiuoroacetic acid prepared in Example 50c (0.5 g, 0.76 mmol) was reacted with 2-((S)-2,2- dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.3 g, 2 mmol), HATU (0.4 g, 1.1 mmol) and iP^NEt (0.9 g, 7 mmol) in CH2CI2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4- (4-chloro-phenyl)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy- butyl)-amide as a white solid (0.25 g, 62%). HRMS (ES ) m/z Calcd for C28H33CI2N3O3+ H [(M+H)+ ]: 530.1972, found: 530.1971.
Example 51a
Preparation of intermediate [2,2-dimethyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester
Figure imgf000081_0001
M. W. 199.16 C11H21NO2
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with trimethylacetaldehyde (Aldrich) (0.42 g, 5 mmol) in CH2CI2 at room temperature for 20 h to give [2,2-dimethyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.0 g, 100%).
Example 51b
Preparation of intermediate rac-(2R,3S,4R,5S)-5-tert-butyl-3-(3-chloro-2-fiuoro-phenyl)-4-(4- chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000081_0002
M. W. 491.44 C26H29CI2FN2O2
In a manner similar to the method described in Example lc, [2,2-dimethyl-prop-(E)- ylideneamino]-acetic acid tert-butyl ester prepared in Example 51a (1 g, 5 mmol) was reacted with (Z)-3-(3-chloro-2-fiuoro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (0.8 g, 2.7 mmol) prepared in Example 26a, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (50 mL) at room temperature for 24 h to give (2R,3S,4R,5S)-5-tert-Butyl-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.4 g, 30%).
Example 51c Preparation of intermediate rac-(2R,3S,4R,5S)-5-tert-butyl-3-(3-chloro-2-fiuoro-phenyl)-4-(4- chloro-phenyl)-4-cyano-pyrrolidine-2-carbox lic acid trifiuoro acetic acid
Figure imgf000082_0001
M. W. 435.33 C22H21CI2FN2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-tert-Butyl-3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 51b (0.3 g, 0.6 mmol) was reacted with trifiuoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-5-tert-Butyl-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifiuoroacetic acid as a off white solid (0.4 g, 100%).
HRMS (ES+) m/z Calcd for C22H21CI2FN2O2+ H [(M+H)+]: 435.1037, found: 435.1036.
Example 51d
Preparation of rac-(2R,3S,4R,5S)-5-tert-butyl-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-phenyl)- 4-cyano-pyrrolidine-2-carboxylic acid S)-3,4-dihydroxy-butyl)-amide
Figure imgf000082_0002
M. W. 522.45 C26H30CI2FN3O3
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifiuoroacetic acid prepared in Example 51c (0.4 g, 0.73 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.2 g, 1.3 mmol), HATU (0.3 g, 0.79 mmol) and iP^NEt (0.6 g, 4.7 mmol) in CH2CI2 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)- 5-tert-butyl-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.22 g, 58%). HRMS (ES ) m/z Calcd for C26H30CI2FN3O3+ H [(M+H)+ ]: 522.1721 , found: 522.1719.
Example 52a
Preparation of intermediate (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)- acrylonitrile
Figure imgf000083_0001
M. W. 310.13 Ci5H7Cl2F2N
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (5 g, 30 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (5 g, 32 mmol), methanolic solution (25 wt%) of sodium methoxide (21 mL, 92 mmol) in methanol (200 mL) at 45 °C for 5 h to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (9 g, 97%).
Example 52b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000083_0002
M. W. 523.46 C27H3oCl2 F2N202
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example la (2.3 g, 11 mmol) was reacted with (Z)-3-(3- chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.5g, 8 mmol) prepared in Example 52a, AgF (0.7 g, 5.5 mmol), and triethylamine (2.9 g, 29 mmol) in dichloromethane (200 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)- 4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (3 g, 64%). Example 52c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifiuoroacetic acid
Figure imgf000084_0001
M. W. 467.35 C23H22CI2F2N2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid tert-butyl ester prepared in Example 52b (0.4 g, 0.8 mmol) was reacted with trifiuoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifiuoroacetic acid as a white solid (0.5 g, 100%).
HRMS (ES+) m/z Calcd for C23H22CI2F2N2O2+ H [(M+H)+]: 467.1099, found: 467.1098.
Example 52d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000084_0002
M. W. 554.46 C27H31CI2F2N3O3
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifiuoroacetic acid prepared in Example 52c (0.4 g, 0.69 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.25 g, 1.7 mmol), HATU (0.35 g, 0.92 mmol) and iP^NEt (0.75 g, 5.8 mmol) in CH2CI2 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.26 g, 84%).
HRMS (ES+) m/z Calcd for C27H31CI2F2N3O3+ H [(M+H)+]: 554.1784, found: 554.1783.
Example 52e
Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrr lidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000085_0001
M. W. 554.46 C27H31CI2F2N3O3
Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (0.3g) was separated by chiral SFC chromatography to provide chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro- phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (120 mg, 40%) and chiral-(2S,3R,4S,5R)- 3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (121 mg, 40%>).
Example 53a
Preparation of intermediate rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000085_0002
M. W. 523.46 C27H30CI2F2N2O2 In preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as described in Example 52b, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester was obtained as the second product: a white foam (0.98 g, 21%).
Example 53b
Preparation of intermediate rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifiuoroacetic acid
Figure imgf000086_0001
M. W. 467.35 C23H22CI2F2N2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2S,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid tert-butyl ester prepared in Example 53a (0.4 g, 0.8 mmol) was reacted with trifiuoroacetic acid in dichloromethane at room temperature to give rac-(2S,3S,4R,5S)-3-(3- Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifiuoroacetic acid as a white solid (0.5 g, 100%).
HRMS (ES+) m/z Calcd for C23H22CI2F2N2O2+ H [(M+H)+]: 467.1099, found: 467.1099.
Example 53 c
Preparation of rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbox lic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000086_0002
M. W. 554.46 C27H31CI2F2N3O3 In a manner similar to the method described in Examples 42c, 42d, rac-(2S,3S,4R,5S)-3-(3- Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 53b (0.3 g, 0.5 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.15 g, 1 mmol), HATU (0.3 g, 0.79 mmol) and iPr2NEt (0.4 g, 3.1 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac- (2S,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.26 g, 94%).
HRMS (ES+) m/z Calcd for C27H31CI2F2N3O3+ H [(M+H)+]: 554.1784, found: 554.1782.
Example 54a
Preparation of intermediate (Z)-2-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-phenyl)-acrylonitrile
Figure imgf000087_0001
M. W. 336.59 Ci5H8BrClFN
In a manner similar to the method described in Example lb, 4-bromophenylacetonitrile (Aldrich) (4.5 g, 23 mmol) was reacted with 3-chloro-2-fiuorobenzaldehyde (5.2 g, 33 mmol), methanolic solution (25 wt%) of sodium methoxide (15 mL, 66 mmol) in methanol (150 mL) at 50 °C for 3 h to give (Z)-2-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (7.8 g, 100%).
Example 54b
Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-bromo-phenyl)-3-(3-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000088_0001
M. W. 549.92 C27H3iBrClFN202
In a manner similar to the method described in Example lc, [3,3-dimethyl-but-(E)- ylideneamino]-acetic acid tert-butyl ester prepared in Example la (1.1 g, 5 mmol) was reacted with (Z)-2-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-phenyl)-acrylonitrile (1.2 g, 3.6 mmol) prepared in Example 54a, AgF (1.3 g, 10 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 3 h to give rac-(2R,3S,4R,5S)-4-(4-bromo- phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.1 g, 56%).
Example 54c
Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-bromo-phenyl)-3-(3-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl- ropyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000088_0002
M. W. 493.81 C23H23BrClFN202.C2HF302
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-4-(4-bromo- phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 54b (1.1 g, 2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-4-(4-bromo-phenyl)-3- (3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (1.2 g, 99%).
HRMS (ES+) m/z Calcd for C23H23BrClFN202+ H [(M+H)+]: 493.0688, found: 493.0689. Example 54d
Preparation of rac-(2R,3S,4R,5S)-4-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- (2,2-dimethyl-propyl)-pyrrolidine-2-carbox lic acid ((S)-3 ,4-dihydroxy-butyl)-amide
Figure imgf000089_0001
M. W. 580.92 C27H32BrClFN303
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-4-(4- bromo-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 54c (0.3 g, 0.49 mmol) was reacted with 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 (0.4 g, 3.1 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)- 4-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine- 2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.18 g, 63%).
HRMS (ES+) m/z Calcd for C27H32BrClFN303+ H [(M+H)+]: 580.1373, found: 580.1372
Example 55a
Preparation of intermediate (Z)-3-(3-chloro-2-fiuoro-phen l)-2-(4-fiuoro-phenyl)-acrylonitrile
Figure imgf000089_0002
In a manner similar to the method described in Example lb, 4-fluorophenylacetonitrile (Aldrich) (3.5 g, 26 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (5.3 g, 34 mmol), methanolic solution (25 wt%) of sodium methoxide (15 mL, 66 mmol) in methanol (200 mL) at 50 °C for 3 h to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-fluoro-phenyl)-acrylonitrile as a white powder (5.7 g, 80%). Example 55b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000090_0001
M. W. 489.01 C27H31CIF2N2O2
In a manner similar to the method described in Example lc, [3,3-dimethyl-but-(E)- ylideneamino]-acetic acid tert-butyl ester prepared in Example la (1.1 g, 5 mmol) was reacted with (Z)-3-(3-chloro-2-fiuoro-phenyl)-2-(4-fiuoro-phenyl)-acrylonitrile (1.25 g, 4.5 mmol) prepared in Example 55a, AgF (1.6 g, 13 mmol), and triethylamine (1.6 g, 16 mmol) in dichloromethane (100 mL) at room temperature for 5 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.6 g, 72%).
Example 55c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-4-(4-fluoro-phen l)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000090_0002
M. W. 432.90 C23H23CIF2N2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 55b (1.6 g, 3.3 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.7 g, 94%). Example 55d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl- propyl)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy-butyl)-amide
Figure imgf000091_0001
M. W. 520.02 C27H32CIF2N3O3
In a manner similar to the method described in Example 42e, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 55c (0.4 g, 0.73 mmol) was reacted with 2-((S)- 2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.2 g, 1.4 mmol), HATU (0.3 g, 0.8 mmol) and iPr2NEt (0.6 g, 4.6 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-4-(4-fluoro-phenyl)-pyrrolidine-2- carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.21 g, 55%).
HRMS (ES+) m/z Calcd for C27H32CIF2N3O3+ H [(M+H)+]: 520.2173, found: 520.2175.
Example 56a
Preparation of intermediate (Z)-3-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dichloro-phenyl)- acrylonitrile
Figure imgf000091_0002
In a manner similar to the method described in Example lb, 2, 4-dichlorobenzyl cyanide (6 g, 32 mmol) was reacted with 3-chloro-2-fiuorobenzaldehyde (6 g, 38 mmol), methanolic solution (25 wt%) of sodium methoxide (30 mL, 131 mmol) in methanol (200 mL) at 50 °C for 3 h to give (Z)-3-(3-chloro-2-fiuoro-phenyl)-2-(2,4-dichloro-phenyl)-acrylonitrile as a white powder (7 g, 67%). Example 56b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-4-(2,4- dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000092_0001
M. W. 539.91 C27H30CI3FN2O2
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(3- chloro-2-fluoro-phenyl)-2-(2,4-dichloro-phenyl)-acrylonitrile (2.2 g, 6.7 mmol) prepared in Example 56a, AgF (2 g, 16 mmol), and triethylamine (5 g, 50 mmol) in dichloromethane (200 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-4-(2,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2.4 g, 66%).
Example 56c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-4-(2,4- dichloro-phenyl)-5-(2,2-dimethyl- ropyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000092_0002
M. W. 483.80 C23H22CI3FN2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-cyano-4-(2,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid tert-butyl ester prepared in Example 56b (2.4 g, 7.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-cyano-4-(2,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid as a white solid (2.7 g, 100%). Example 56d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-4-(2,4-dichloro-phenyl)- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbox lic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000093_0001
M. W. 570.92 C27H3iCl3FN303
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-cyano-4-(2,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 56c (0.6 g, 1 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.3 g, 2 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (0.9 g, 7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-cyano-4-(2,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.5 g, 88%).
HRMS (ES+) m/z Calcd for C27H3iCl3FN303+ H [(M+H)+]: 570.1488, found: 570.1487.
Example 56e
Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-4-(2,4-dichloro-phenyl)-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbox lic acid ((S)-3 ,4-dihydroxy-butyl)-amide
Figure imgf000093_0002
M. W. 570.92 C27H3iCl3FN303
Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-cyano-4-(2,4-dichloro-phenyl)-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (0.5 g) was separated by chiral SFC chromatography to provide chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro- phenyl)-4-cyano-4-(2,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (200 mg, 40%) and chiral-(2S,3R,4S,5R)-3-(3- chloro-2-fluoro-phenyl)-4-cyano-4-(2,4-dic^^
carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (220 mg, 44%).
Example 57a
Preparation of intermediate (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-methyl-phenyl)- acrylonitrile
Figure imgf000094_0001
M. W. 306.17 Ci6HioCl2FN
Step A A mixture of 4-chloro-2-methylbenzyl alcohol (Aldrich) (5 g, 32 mmol) in thionyl chloride (20 mL) was heated at refluxing (100 °C) for 30 min. The mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous NaHC03 solution, water, brine, dried over MgS04, and concentrated to give 4-chloro-2- methylbenzyl chloride as a light yellow oil (5.2 g, 93%). Step B To a solution of 4-chloro-2-methylbenzyl chloride (5.2 g, 30 mmol) in ethanol (40 mL) was added an aqueous solution (30 mL) of KCN (5 g, 77 mmol) at room temperature. The reaction mixture was then heated at 100 °C for 2 h. The mixture was cooled to room temperarure and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, concentrated. The residue was purifed by chromatography (EtOAc:hexanes=l;10, then 1 :4) to give 4-chloro-2-methylbenzyl cyanide as a yellow oil (3.5 g, 66%).
Step C In a manner similar to the method described in Example lb, 4-chloro-2-methylbenzyl cyanide (3.5 g, 21 mmol) was reacted with 3-chloro-2-fiuorobenzaldehyde (5 g, 32 mmol), methanolic solution (25 wt%) of sodium methoxide (15 mL, 66 mmol) in methanol (100 mL) at 50 °C for 5 h to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-methyl-phenyl)- acrylonitrile as a white powder (4 g, 62%>).
Example 57b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000095_0001
M. W. 519.49 C28H33CI2FN2O2
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(3- chloro-2-fluoro-phenyl)-2-(4-chloro-2-methyl-phenyl)-acrylonitrile (2.3 g, 7.5 mmol) prepared in Example 57a, AgF (1.3 g, 10 mmol), and triethylamine (2.8 g, 28 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)- 4-(4-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.9 g, 49%).
Example 57c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000095_0002
M. W. 463.38 C24H25Cl2FN202.C2HF302
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid tert-butyl ester prepared in Example 57b (1.9 g, 3.7 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.1 g, 98%).
Example 57d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-methyl-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000096_0001
M. W. 550.50 C28H34CI2FN3O3
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 57c (0.4 g, 0.69 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.2 g, 1.4 mmol), HATU (0.4 g, 1.1 mmol) and iPr2NEt (0.8 g, 6.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac- (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-methyl-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.29 g, 76%).
HRMS (ES+) m/z Calcd for C28H34CI2FN3O3+ H [(M+H)+]: 550.2034, found: 550.2036.
Example 58a
Preparation of intermediate (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-methoxy-phenyl)- acrylonitrile
Figure imgf000096_0002
M. W. 322.17 Ci6Hi0Cl2FNO
Step A In a manner similar to the method described in Example 57 Step A, 4-chloro-2- methoxybenzyl alcohol (Aldrich) (4.9 g, 28 mmol) was reacted with thionyl chloride (20 mL) to give 4-chloro-2-methoxybenzyl chloride as a white solid (5.1 g, 95%). Step B In a manner similar to the method described in Example 57 Step B, 4-chloro-2- methoxybenzyl chloride (5.1 g, 27 mmol) was reacted with NaCN (3 g, 61 mmol) in ethanol (40 mL) and water (20 mL) at 100 °C for 8 h to give 4-chloro-2 -methoxybenzyl cyanide as a colorless oil (1.8 g, 36%)
Step C In a manner similar to the method described in Example lb, 4-chloro-2 -methoxybenzyl cyanide (1.8 g, 10 mmol) was reacted with 3-chloro-2-fiuorobenzaldehyde (2 g, 13 mmol), methanolic solution (25 wt%) of sodium methoxide (15 mL, 66 mmol) in methanol (50 mL) at 50 °C for 2 h to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-methoxy-phenyl)- acrylonitrile as a white powder (2.1 g, 65%).
Example 58b
Preparation of intermediate rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000097_0001
M. W. 535.49 C28H33CI2FN2O3
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(3- chloro-2-fluoro-phenyl)-2-(4-chloro-2-methoxy-phenyl)-acrylonitrile (1.8 g, 5.6 mmol) prepared in Example 58a, AgF (1.7 g, 13 mmol), and triethylamine (2.8 g, 28 mmol) in dichloromethane (100 mL) at room temperature for 24 h to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)- 4-(4-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.8 g, 60%>). Example 58c
Preparation of intermediate rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000098_0001
M. W. 479.38 C24H25CI2FN2O3.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2S,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid tert-butyl ester prepared in Example 58b (1.3 g, 2.4 mmol) was reacted with trifluoro acetic acid in dichloromethane at room temperature to give rac-(2S,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifluoro acetic acid as a white solid (1.5 g, 100%).
Example 58d
Preparation of rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-methoxy-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrr lidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000098_0002
M. W. 566.50 C28H34CI2FN3O4
In a manner similar to the method described in Examples 42c, 42d, rac-(2S,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifluoro acetic acid prepared in Example 58c (0.4 g, 0.67 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.25 g, 1.7 mmol), HATU (0.4 g, 1.1 mmol) and iP^NEt (0.6 g, 4.7 mmol) in CH2CI2 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac- (2S,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.23 g, 61%).
HRMS (ES+) m/z Calcd for C28H34CI2FN3O4+ H [(M+H)+]: 566.1983, found: 566.1983. Example 59a
Preparation of intermediate [2-cyclohexyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester
Figure imgf000099_0001
M. W. 239.36 Ci4H25N02
In a manner similar to the method described in Example la, glycine tert-butyl ester (1.3 g, 10 mmol) was reacted with 2-cyclohexylacetaldehyde (Betapharma) (1.3 g, 10 mmol) in CH2C12 at room temperature for 5 h to give [2-cyclohexyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (2.3 g, 96%).
Example 59b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro- phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000099_0002
M. W. 531.50 C29H33C12FN202
In a manner similar to the method described in Example lc, [2-cyclohexyl-eth-(E)- ylideneamino]-acetic acid tert-butyl ester prepared in Example 59a (2.3 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fiuoro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (1.9 g, 6.5 mmol) prepared in Example 26a, AgF (1.7 g, 13 mmol), and triethylamine (2.6 g, 26 mmol) in dichloromethane (100 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro- 2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.9 g, 55%).
Example 59c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro- phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid trifiuoroacetic acid
Figure imgf000100_0001
M. W. 475.39 C25H25Cl2FN202.C2HF302
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 59b (1.9 g, 3.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)- 4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.1 g, 99%).
Example 59d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5- cyclohexylmethyl-pyrrolidine-2-car xylic acid ((S)-3 ,4-dihydroxy-butyl)-amide
Figure imgf000100_0002
M. W. 562.51 C29H34C12FN303
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 59c (0.6 g, 1 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.3 g, 2 mmol), HATU (0.6 g, 1.6 mmol) and iPr2NEt (0.9 g, 7 mmol) in CH2CI2 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2- carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.4 g, 71%).
HRMS (ES+) m/z Calcd for C29H34C12FN303+ H [(M+H)+]: 562.2034, found: 562.2033. Example 60a
Preparation of intermediate rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)- 4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000101_0001
M. W. 531.50 C29H33CI2FN2O2
In preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano- 5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester as described in Example 59b, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5- cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester was obtained as the second product: a white foam, Yield, 1 g, 29%.
Example 60b
Preparation of intermediate rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)- 4-cyano-5-cyclohexylmethyl-p rrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000101_0002
M. W. 475.39 C25H25Cl2FN202.C2HF302
In a manner similar to the method described in Example 25a, rac-(2S,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 60a (0.4 g, 0.75 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fiuoro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.46 g, 100%). Example 60c
Preparation of rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)
cyclohexylmethyl-pyrrolidine-2-carbox lic acid ((S)-3 ,4-dihydroxy-butyl)-amide
Figure imgf000102_0001
M. W. 562.51 C29H34CI2FN3O3
In a manner similar to the method described in Example 42e, rac-(2S,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 60b (0.45 g, 0.75 mmol) was reacted with 2-((S)-2,2- dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.23 g, 1.6 mmol), HATU (0.45 g, 1.2 mmol) and iPr2NEt (0.9 g, 7 mmol) in CH2CI2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2S,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.4 g, 95%).
HRMS (ES+) m/z Calcd for C29H34CI2FN3O3+ H [(M+H)+]: 562.2034, found: 562.2033.
Example 61a
Preparation of intermediate (Z)-2-(4-chloro-2-methoxy-phenyl)-3-(3-chloro-phenyl)-acrylonitrile
Figure imgf000102_0002
M. W. 304.18 Ci6HiiCl2NO
In a manner similar to the method described in Example lb, 4-chloro-2-methoxybenzyl cyanide (2 g, 10 mmol) prepared in Example 58a Step B was reacted with 3-chlorobenzaldehyde (2 g, 14 mmol), methanolic solution (25 wt%) of sodium methoxide (15 mL, 66 mmol) in methanol (50 mL) at 50 °C for 5 h to give (Z)-2-(4-chloro-2-methoxy-phenyl)-3-(3-chloro-phenyl)- acrylonitrile as a white powder (1.9 g, 63%). Example 61b
Preparation of intermediate rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-phenyl)-3-(3-chloro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000103_0001
M. W. 517.50 C28H34CI2N2O3
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-2-(4- chloro-2-methoxy-phenyl)-3-(3-chloro-phenyl)-acrylonitrile (1.8 g, 5.9 mmol) prepared in
Example 61a, AgF (1.7 g, 13 mmol), and triethylamine (2.8 g, 28 mmol) in dichloromethane (100 mL) at room temperature for 24 h to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)- 4-(4-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.8 g, 60%).
Example 61c
Preparation of intermediate rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-phenyl)-3-(3-chloro- phenyl)-4-cyano-5-(2,2-dimethyl- ropyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000103_0002
M. W. 461.39 C24H26CI2N2O3.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2S,3R,4R,5S)-4-(4-chloro-2- methoxy-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 61b (2 g, 3.9 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy- phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.2 g, 98%). Example 61d
Preparation of rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-phenyl)-3-(3-chloro-phenyl)-4- 5-(2,2-dimethyl-propyl)-pyrrolidine-2- arboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000104_0001
M. W. 548.51 C28H35Cl2N304
In a manner similar to the method described in Examples 42c, 42d, rac-(2S,3R,4R,5S)-4-(4- chloro-2-methoxy-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 61c (0.2 g, 0.35 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.15 g, 1.0 mmol), HATU (0.24 g, 0.63 mmol) and iPr2NEt (0.3 mL, 1.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac- (2S,3R,4R,5S)-4-(4-chloro-2-methoxy-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl- propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.15 g, 84%).
HRMS (ES+) m/z Calcd for C28H35C12N304+ H [(M+H)+]: 548.2078, found: 548.2077.
Example 62a
Preparation of intermediate (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(2,3-difluoro-phenyl)- acrylonitrile
Figure imgf000104_0002
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (4.5 g, 26 mmol) was reacted with 2,3-difluorobenzaldehyde (Aldrich) (4.5 g, 32 mmol), methanolic solution (25 wt%) of sodium methoxide (6.3 g, 29 mmol) in methanol (135 mL) at 50 °C for 3 h to give (Z)-2-(4-chloro-2-fiuoro-phenyl)-3-(2,3-difiuoro-phenyl)-acrylonitrile as a white powder (6.85 g, 88%).
Example 62b
Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(2,3- difluoro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000105_0001
M. W. 507.00 C27H30CIF3N2O2
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-2-(4- chloro-2-fluoro-phenyl)-3-(2,3-difluoro-phenyl)-acrylonitrile (2.3 g, 8 mmol) prepared in
Example 62a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-3-(2,3-difiuoro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.8 g, 44%).
Example 62c
Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(2,3- difluoro-phenyl)-5-(2,2-dimeth l-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000105_0002
M. W. 450.89 C23H22CIF3N2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-3-(2,3-difluoro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid tert-butyl ester prepared in Example 62b (1.8 g, 3.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-3-(2,3-difl^
carboxylic acid trifluoroacetic acid as a white solid (2 g, 100%).
HRMS (ES+) m/z Calcd for C23H22CIF3N2O2+ H [(M+H)+]: 451.1395, found: 451.1394.
Example 62d
Preparation of rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(2,3-difluoro-phenyl)- 5-(2,2-dimethyl-propyl)-pyrrolidine -2 -carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000106_0001
M. W. 538.01 C27H31CIF3N3O3
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-3-(2,3-difluoro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 62c(0.47 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.49 mmol) and iP^NEt (0.72 mL, 4.2 mmol) in CH2CI2 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac- (2R,3S,4R,5S)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-3-(2,3-difiuoro-phenyl)-5-(2,2-dimethyl- propyl)-pyrrolidine -2 -carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.26 g, 58%).
HRMS (ES+) m/z Calcd for C27H31CI2F2N3O3+ H [(M+H)+]: 538.2079, found: 538.2077.
Example 62e
Preparation of (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(2,3-difiuoro-phi (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy-butyl)-amide
Figure imgf000106_0002
M. W. 538.01 C27H31CIF3N3O3 Rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(2,3-difluoro-phenyl)-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (0.22 g) was separated by chiral SFC chromatography to provide chiral-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-3-(2,3-difluoro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (87 mg, 40%) and chiral-(2S,3R,4S,5R)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-3-(2,3-difluoro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (87 mg, 40%).
Example 63a
Preparation of intermediate (Z)-3-(3-bromo-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)- acrylonitrile
Figure imgf000107_0001
M. W. 354.58 Ci5H7BrClF2N
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (1.39 g, 8.2 mmol) was reacted with 3-bromo-2-fluorobenzaldehyde (Apollo)(2 g, 9.9 mmol), methanolic solution (25 wt%) of sodium methoxide (2 g, 9 mmol) in methanol (40 mL) at 50 °C for 3 h to give (Z)-3-(3-bromo-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (2.3 g, 79%).
Example 63b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2 -carboxylic acid tert-butyl ester
Figure imgf000107_0002
M. W. 567.91 C27H30BrClF2N2O2 In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(3- bromo-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.3 g, 6.5 mmol) prepared in Example 63a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-phenyl)- 4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2 g, 54%).
Example 63 c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifiuoroacetic acid
Figure imgf000108_0001
M. W. 511.80 C23H22BrClF2N202.C2HF302
In a manner similar to the method described in Example Id, rac-(2R,3S,4R,5S)-3-(3-bromo-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid tert-butyl ester prepared in Example 63b (2 g, 3.5 mmol) was reacted with trifiuoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3- bromo-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifiuoroacetic acid as a white solid (2.1 g, 95%).
HRMS (ES+) m/z Calcd for C23H22BrClF2N202+ H [(M+H)+]: 511.0594, found: 511.0595.
Example 63 d
Preparation of rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000109_0001
M. W. 598.91 C27H31B1-CIF2N3O3
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3- bromo-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifluoro acetic acid prepared in Example 63c (0.51 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.49 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.2 g, 40%).
HRMS (ES+) m/z Calcd for C27H3iBrClF2N303+ H [(M+H)+]: 598.1278, found: 598.1278.
Example 63 e
Preparation of (2R,3S,4R,5S)-3-(3-bromo-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000109_0002
M. W. 598.91 C27H3iBrClF2N303
Rac-(2R,3S,4R,5S)-3-(3-bromo-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (0.15 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-bromo-2-fiuoro- phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (66 mg, 44%) and chiral (2S,3R,4S,5R)-3- (3-bromo-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (70 mg, 47%). Example 64a
Preparation of intermediate (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-acrylonitrile
Figure imgf000110_0001
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (4.5 g, 26 mmol) was reacted with 3-chlorobenzaldehyde (Aldrich) (4.4 g, 32 mmol), methanolic solution (25 wt%) of sodium methoxide (6.6 mL, 29 mmol) in methanol (150 mL) at 50 °C for 3 h to give (Z)-2-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-phenyl)-acrylonitrile as a white powder (6.5 g, 84%).
Example 64b
Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000110_0002
M. W. 505.46 C27H3iCl2FN202
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-2-(4- chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-acrylonitrile (2.3 g, 8 mmol) prepared in Example 64a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3- chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.02 g, 25%).
Example 64c Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000111_0001
M. W. 449.36 C23H23CI2FN2O2.C2HF3O2
In a manner similar to the method described in Example Id, rac-(2R,3R,4R,5S)-4-(4-chloro-2- fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 64b (1 g, 2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fiuoro- phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.88 g, 79%).
HRMS (ES+) m/z Calcd for C23H23CI2FN2O2+ H [(M+H)+]: 449.1194, found: 449.1194.
Example 64d
Preparation of rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-4- (2,2-dimethyl-propyl)-pyrrolidine-2- arboxylic acid ((S)-3 ,4-dihydroxy-butyl)-amide
Figure imgf000111_0002
M. W. 536.47 C27H32CI2FN3O3
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-4-(4- chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 64c (0.46 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iP^NEt (0.72 mL, 4.2 mmol) in CH2CI2 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac- (2R,3R,4R,5S)-4-(4-chloro-2-fiuoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2 -dimethyl- - I l l - propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.21 g, 48%).
HRMS (ES+) m/z Calcd for C27H32CI2FN3O3+ H [(M+H)+]: 536.1878, found: 5361877. Example 64e
Preparation of (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carb xylic acid ((S)-3 ,4-dihydroxy-butyl)-amide
Figure imgf000112_0001
M. W. 536.47 C27H32CI2FN3O3
Rac-(2R,3R,4R,5S)-4-(4-chloro-2-fiuoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl- propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (0.15 g) was separated by chiral SFC chromatography to provide chiral (2R,3R,4R,5S)-4-(4-chloro-2-fiuoro-phenyl)-3-(3- chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4- dihydroxy-butyl)-amide
as a white solid (71 mg, 47%) and chiral-(2S,3S,4S,5R)-4-(4-chloro-2-fiuoro-phenyl)-3-(3- chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4- dihydroxy-butyl)-amide as a white solid (70 mg, 47%).
Example 65a
Preparation of intermediate (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3-fluoro-phenyl)-acrylonitrile
Figure imgf000112_0002
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (3.27 g, 19 mmol) was reacted with 3-fluorobenzaldehyde (Aldrich) (2.87 g, 23 mmol), methanolic solution (25 wt%) of sodium methoxide (4.83 mL, 21 mmol) in methanol (90 mL) at 50 °C for 3 h to give (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3-fluoro-phenyl)-acrylonitrile as a white powder (5.2 g, 98%).
Example 65b
Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000113_0001
M. W. 489.01 C27H31CIF2N2O2
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-2-(4- chloro-2-fluoro-phenyl)-3-(3-fluoro-phenyl)-acrylonitrile (2.2 g, 8 mmol) prepared in Example 65a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.02 g, 26%).
Example 65c
Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-3-(3-fluoro-phen l)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000113_0002
M. W. 432.90 C23H23CIF2N2O2.C2HF3O2
In a manner similar to the method described in Example Id, rac-(2R,3R,4R,5S)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 65b (1 g, 2.1 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid trifiuoro acetic acid as a white solid (1 g, 88%).
HRMS (ES+) m/z Calcd for C23H23CIF2N2O2+ H [(M+H)+]: 433.1489, found: 433.1487. Example 65d
Preparation of rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl- propyl)-3-(3-fluoro-phenyl)-pyrroli ine-2-carboxylic acid ((S)-3 ,4-dihydroxy-butyl)-amide
Figure imgf000114_0001
M. W. 520.02 C27H32CIF2N3O3
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5 S)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-3-(3-fluoro-phenyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 65c (0.46 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iP^NEt (0.72 mL, 4.2 mmol) in CH2CI2 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-
(2R,3R,4R,5S)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-3-(3-fiuoro- phenyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.21 g, 48%).
HRMS (ES+) m/z Calcd for C27H32CIF2N3O3+ H [(M+H)+]: 520.2173, found: 520.2171.
Example 66a
Preparation of intermediate (Z)-3-(3-bromo-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile
Figure imgf000114_0002
M. W. 336.59 Ci5H8BrClFN In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (1.9 g, 1 1 mmol) was reacted with 3-bromobenzaldehyde (Aldrich) (1.57 mL, 13.4 mmol), methanolic solution (25 wt%) of sodium methoxide (2.8 mL, 12 mmol) in methanol (50 mL) at 50 °C for 3 h to give (Z)-3-(3-bromo-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (2.3 g, 60%).
Example 66b
Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
M. W. 549.92 C27H3iBrClFN202
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(3- bromo-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2 g, 5.9 mmol) prepared in Example 66a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.3 g, 40%).
Example 66c
Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimeth l-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000115_0002
M. W. 493.81 C23H23BrClFN202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-bromo- phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 66b (1.2 g, 2.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4- (4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.1 g, 83%).
HRMS (ES+) m/z Calcd for C23H23BrClFN202+ H [(M+H)+]: 493.0688, found: 493.0688.
Example 66d
Preparation of rac-(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2- arboxylic acid ((S)-3 ,4-dihydroxy-butyl)-amide
Figure imgf000116_0001
M. W. 580.92 C27H32BrClFN303
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3- bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 66c (0.5 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.49 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac- (2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl- propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.26 g, 55%).
HRMS (ES+) m/z Calcd for C27H32BrClFN303+ H [(M+H)+]: 580.1373, found: 580.1372.
Example 67a
Preparation of intermediate rac-(2S,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000117_0001
M. W. 549.92 C27H3iBrClFN202
In preparation of rac-(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as described in Example 66b, rac-(2S,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester was obtained as the second product: a white foam (1.2 g, 37%).
Example 67b
Preparation of intermediate rac-(2S,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000117_0002
M. W. 493.81 C23H23BrClFN202.C2HF302
In a manner similar to the method described in Example 25a, rac-(2S,3R,4R,5S)-3-(3-bromo- phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 67a (1.3 g, 2.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3R,4R,5S)-3-(3-bromo-phenyl)-4- (4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.2 g, 83%).
HRMS (ES+) m/z Calcd for C23H23BrClFN202+ H [(M+H)+]: 493.0688, found: 493.0689.
Example 67c
Preparation of rac-(2S,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy-butyl)-amide
Figure imgf000118_0001
M. W. 580.92 C27H32BrClFN303
In a manner similar to the method described in Examples 42c, 42d, rac-(2S,3R,4R,5S)-3-(3- bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 67b (0.5 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.49 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac- (2S,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl- propyl)-pyrrolidine -2 -carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.21 g, 44%).
HRMS (ES+) m/z Calcd for C27H32BrClFN303+ H [(M+H)+]: 580.1373, found: 580.1372.
Example 68a
Preparation of intermediate (Z)-2-(4-Chloro-2-fluoro-phenyl)-3-(3,4-dichloro-phenyl)- acrylonitrile
Figure imgf000118_0002
In a manner similar to the method described in Example lb, 4 -chloro -2 -fluorophenyl acetonitrile (4.5 g, 26 mmol) was reacted with 3,4-dichlorobenzaldehyde (Aldrich) (5.5 g, 32 mmol), methanolic solution (25 wt%) of sodium methoxide (6.6 mL, 29 mmol) in methanol (150 mL) at 50 °C for 3 h to give (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3,4-dichloro-phenyl)-acrylonitrile as a white powder (6.5 g, 76%). Example 68b
Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(3,4- dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000119_0001
M. W. 539.91 C27H30CI3FN2O2
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-2-(4- chloro-2-fluoro-phenyl)-3-(3,4-dichloro-phenyl)-acrylonitrile (2.6 g, 8 mmol) prepared in
Example 68a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fiuoro-phenyl)- 4-cyano-3-(3,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.7 g, 39%).
Example 68c
Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(3,4- dichloro-phenyl)-5-(2,2-dimeth l-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000119_0002
M. W. 483.80 C23H22CI3FN2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-3-(3,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid tert-butyl ester prepared in Example 68b (1.7 g, 3.1 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-3-(3,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid as a white solid (1.8 g, 96%). Example 68d
Preparation of rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(3,4-dichloro- phenyl)-5-(2,2-dimethyl-propyl)-p rrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000120_0001
M. W. 570.92 C27H31CI3FN3O3
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-3-(3,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 68c (0.5 g, 0.84 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac- (2R,3R,4R,5S)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-3-(3,4-dichloro-phenyl)-5-(2,2-dimethyl- propyl)-pyrrolidine -2 -carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.28 g, 59%).
HRMS (ES+) m/z Calcd for C27H31CI3FN3O3+ H [(M+H)+]: 570.1488, found: 570.1489.
Example 69a
Preparation of intermediate (Z)-3-(3-chloro-4-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)- acrylonitrile
Figure imgf000120_0002
M. W. 308.99 Ci5H7Cl2F2N
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (3.3 g, 19 mmol) was reacted with 4-chloro-3-fluoro-benzaldehyde (Aldrich) (3.65 g, 23 mmol), methanolic solution (25 wt%) of sodium methoxide (4.8 mL, 21 mmol) in methanol (90 mL) at 50 °C for 3 h to give (Z)-3-(3-chloro-4-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (3 g, 50%).
Example 69b
Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000121_0001
M. W. 523.46 C27H30CI2F2N2O2
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(3- chloro-4-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 69a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-4-fiuoro-phenyl)- 4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1 g, 24%).
Example 69c
Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifiuoroacetic acid
Figure imgf000121_0002
M. W. 467.35 C23H22CI2F2N2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-4- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid tert-butyl ester prepared in Example 69b (1 g, 1.9 mmol) was reacted with trifluoro acetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3- chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifluoro acetic acid as a white solid (1 g, 90%).
Example 69d
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrr lidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000122_0001
M. W. 554.46 C27H31CI2F2N3O3
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3- chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifluoro acetic acid prepared in Example 69c (0.28 g, 0.48 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.21 g, 1.44 mmol), HATU (0.33 g, 0.87 mmol) and iPr2NEt (0.42 mL, 2.4 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.18 g, 77%).
HRMS (ES+) m/z Calcd for C27H31CI3FN3O3+ H [(M+H)+]: 554.1784, found: 554.1785.
Example 69e
Preparation of (2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (S)-3,4-dihydroxy-butyl)-amide
Figure imgf000122_0002
M. W. 554.46 C27H31CI2F2N3O3 Rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-nuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (0.14 g) was separated by chiral SFC chromatography to provide chiral (2R,3R,4R,5S)-3-(3-chloro-4-fluoro- phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (61 mg, 44%) and chiral-(2S,3S,4S,5R)-3- (3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (61 mg, 44%).
Example 70a
Preparation of intermediate (Z)-3-(4-bromo-thiophen-2-yl)-2-(4-chloro-2-fiuoro-phenyl)- acrylonitrile
r
Figure imgf000123_0001
M. W. 342.62 Ci3H6BrClFNS
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (4.05 g, 24 mmol) was reacted with 4-bromo-2-thiophenecarboxaldehyde (Aldrich) (6.08 g, 29 mmol), methanolic solution (25 wt%) of sodium methoxide (6 mL, 26 mmol) in methanol (90 mL) at 50 °C for 3 h to give (Z)-3-(4-bromo-thiophen-2-yl)-2-(4-chloro-2-fluoro-phenyl)- acrylonitrile as a light yellow solid (5.2 g, 64%).
Example 70b
Preparation of intermediate rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-yl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
M. W. 555.94 C25H29BrClFN202S In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(4- bromo-thiophen-2-yl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.7 g, 8 mmol) prepared in Example 70a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-yl)-4- (4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert- butyl ester as a white foam (0.9 g, 20%).
Example 70c
Preparation of intermediate rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-yl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimeth l-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000124_0001
M. W. 499.83 C2iH2iBrClFN202S.C2HF302
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(4-bromo- thiophen-2-yl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid tert-butyl ester prepared in Example 70b (0.9 g, 1.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(4- bromo-thiophen-2-yl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifluoroacetic acid as a light blue solid (0.9 g, 92%).
Example 70d
Preparation of rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-yl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbox lic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000124_0002
M. W. 586.95 C25H30BrClFN3O3 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(4- bromo-thiophen-2-yl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 70c (0.2 g, 0.33 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.14 g, 1 mmol), HATU (0.22 g, 0.58 mmol) and iPr2NEt (0.28 mL, 1.63 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-yl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.15 g, 80%).
HRMS (ES+) m/z Calcd for C25H3oBrClFN303+ H [(M+H)+]: 586.0937, found: 586.0935.
Example 71a
Preparation of intermediate (Z)-2-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-4-trifluoromethyl- phenyl)-acrylonitrile
Figure imgf000125_0001
M. W. 360.14 Ci6H7Cl2F4N
Step A A mixture of 3-chloro-4-(trifluoromethyl)benzyl alcohol (Synquest) (4.77 g, 23 mmol) and activated Mn02 (19.5 g, 230 mmol) in 1,2-dichlorethane (80 mL) was heated and stirred at 80 °C for 3 h. The mixture was cooled to room temperature and filtered through a short pad of celite. The celite was washed with dichloromethane, and ethyl acetate. The filtrates were combined, concentrated, dried under reduced pressure to give 3-chloro-4- (trifluoromethyl)benzaldehyde as a light yellow oil (2.8 g, 60%).
Step B In a manner similar to the method described in Example lb, 4-chloro-2-methylbenzyl cyanide (1.9 g, 11 mmol) was reacted with 3-chloro-4-(trifluoromethyl)benzaldehyde (2.8 g, 14 mmol), methanolic solution (25 wt%) of sodium methoxide (2.8 mL, 12 mmol) in methanol (50 mL) at 50 °C for 5 h to give (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-4-trifluoromethyl- phenyl)-acrylonitrile as a yellow solid (2.45 g, 61%>). Example 71b
Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-4- trifiuoromethyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert- butyl ester
Figure imgf000126_0001
M. W. 573.46 C28H30CI2F4N2O2
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-2-(4- chloro-2-fluoro-phenyl)-3-(3-chloro-4-trifluoromethyl-phenyl)-acrylonitrile (2.5 g, 6.9 mmol) prepared in Example 71a, AgF (1 g, 8 mmol), and triethylamine (2.4 mL, 17 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-4-(4-chloro- 2-fluoro-phenyl)-3-(3-chloro-4-trifiuoromethyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.2 g, 30%).
Example 70c
Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-4- trifiuoromethyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifiuoro acetic acid
Figure imgf000126_0002
M. W. 517.35 C24H22CI2F4N2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-4-(4-chloro-2- fluoro-phenyl)-3-(3-chloro-4-trifluoromethyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 70b (1.2 g, 2.1 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac- (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-4-trifluoromethyl-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifiuoroacetic acid as solid (1.1 g, 83%).
Example 71d
Preparation of (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-4-trifluoromethyl- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy- butyl)-amide
Figure imgf000127_0001
M. W. 604.47 C28H31CI2F4N3O3
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5 S)-4-(4- chloro-2-fluoro-phenyl)-3-(3-chloro-4-trifluoromethyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifiuoroacetic acid prepared in Example 71c (0.22 g, 0.35 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.15 g, 1.05 mmol), HATU (0.24 g, 0.63 mmol) and iPr2NEt (0.3 mL, 1.74 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-trifluoromethyl-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.14 g, 73%).
HRMS (ES+) m/z Calcd for C28H31CI2F4N3O3+ H [(M+H)+]: 604.1752, found: 604.1748.
Example 72a
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (R)-3,4-dihydroxy-butyl)-amide
Figure imgf000127_0002
M. W. 554.46 C27H31CI2F2N3O3 Step A In a manner similar to the method described in Example 3a Step A to C, (4R)-(-)-4-(2- hydroxyethyl)-2,2-dimethyl-l,3-dioxolane (Aldrich) (4.91 g, 33.6 mmol) was reacted with methanesulfonyl chloride (3.12 mL, 40.3 mmol) and triethylamine (9.34 mL, 67 mmol) in dichloromethane, then reacted with NaN3 (10.7 g, 0.16 mol) in Ν,Ν-dimethylformamide, then treated with Pt02 and H2 (50 psi) in ethyl acetate to give 2-((R)-2,2-dimethyl-[l,3]dioxolan-4- yl)-ethylamine as a brown oil (4.4 g, 90% for three steps).
Step B In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)- 3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 69c (0.2 g, 0.48 mmol) was reacted with 2-((R)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.15 g, 1.0 mmol), HATU (0.23 g, 0.62 mmol) and iPr2NEt (0.3 mL, 1.72 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-4-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.11 g, 74%).
HRMS (ES+) m/z Calcd for C27H3iCl3FN303+ H [(M+H)+]: 554.1784, found: 554.1786.
Example 72b
Preparation of (2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (R)-3,4-dihydroxy-butyl)-amide
Figure imgf000128_0001
M. W. 554.46 C27H3iCl2F2N303
Rac-(2R,3R,4R,5S)-3-(3-chloro-4-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide (80 mg) was separated by chiral SFC chromatography to provide chiral (2R,3R,4R,5S)-3-(3-chloro-4-fiuoro- phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (35 mg, 44%) and chiral (2S,3S,4S,5R)-3- (3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (35 mg, 44%).
Example 73a
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide
Figure imgf000129_0001
M. W. 554.46 C27H3iCl2F2N303
In a manner similar to the method described in Example 72a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 53b (0.44 g, 0.769 mmol) was reacted with 2-((R)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.33 g, 2.3 mmol), HATU (0.52 g, 1.36 mmol) and iPr2NEt (0.66 mL, 3.8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac- (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.29 g, 68%).
HRMS (ES+) m/z Calcd for C27H3iCl2F2N303+ H [(M+H)+]: 554.1784, found: 554.1783.
Example 73b
Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrr lidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide
Figure imgf000129_0002
M. W. 554.46 C27H3iCl2F2N303
Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide (0.28 g) was separated by chiral SFC chromatography to provide chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro- phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (109 mg, 39%) and chiral-(2S,3R,4S,5R)- 3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (109 mg, 39%>).
Example 74
Preparation of rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2- arboxylic acid ((R)-3 ,4-dihydroxy-butyl)-amide
Figure imgf000130_0001
M. W. 536.47 C27H32C12FN303
In a manner similar to the method described in Example 72a, rac-(2R,3R,4R,5S)-4-(4-chloro-2- fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid (0.2 g, 0.36 mmol) was reacted with 2-((R)-2,2-dimethyl-[l,3]dioxolan- 4-yl)-ethylamine (0.15 g, 1.07 mmol), HATU (0.24 g, 0.64 mmol) and iPr2NEt (0.31 mL, 1.78 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro- phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 54%).
HRMS (ES+) m/z Calcd for C27H32C12FN303+ H [(M+H)+]: 536.1878, found: 5361880.
Example 75
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2- arboxylic acid ((R)-3 ,4-dihydroxy-butyl)-amide
Figure imgf000130_0002
M. W. 536.47 C27H32C12FN303 In a manner similar to the method described in Example 72a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid (0.2 g, 0.36mmol) was reacted with 2-((R)-2,2-dimethyl-[l ,3]dioxolan- 4-yl)-ethylamine (0.15 g, 1.07 mmol), HATU (0.24 g, 0.64 mmol) and iPr2NEt (0.31 g, 1.78 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 54%).
HRMS (ES+) m/z Calcd for C27H32C12FN303+ H [(M+H)+]: 536.1878, found: 536.1880.
Example 76
Preparation of rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-phenyl)-3-(3-chloro-phenyl)-4- 5-(2,2-dimethyl-propyl)-pyrrolidine- - arboxylic acid ((R)-3,4-dihydroxy-butyl)-amide
Figure imgf000131_0001
M. W. 548.51 C28H35C12N304
In a manner similar to the method described in Example 72a, rac-(2S,3R,4R,5S)-4-(4-chloro-2- methoxy-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid (0.2 g, 0.35 mmol) was reacted with 2-((R)-2,2-dimethyl-[l,3]dioxolan- 4-yl)-ethylamine (0.15 g, 1.0 mmol), HATU (0.24 g, 0.63 mmol) and iPr2NEt (0.3 mL, 1.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy- phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 57%).
HRMS (ES+) m/z Calcd for C28H35C12N304+ H [(M+H)+]: 548.2078, found: 548.2074.
Example 77 Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3 ,4-dihydroxy-butyl)-amide
Figure imgf000132_0001
M. W. 518.48 C27H33CI2N3O3
In a manner similar to the method described in Example 72a, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifiuoro acetic acid (0.2 g, 0.37 mmol) was reacted with 2-((R)-2,2-dimethyl-[l ,3]dioxolan-4-yl)- ethylamine (0.159 g, 1.1 mmol), HATU (0.25 g, 0.66 mmol) and iPr2NEt (0.32 mL, 1.8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.15 g, 81%).
HRMS (ES+) m/z Calcd for C27H33CI2N3O3+ H [(M+H)+]: 518.1972, found: 518.1972. Example 78a
Preparation of intermediate [3,3,4-trimethyl-pent-(E)-ylideneamino]- acetic acid tert-butyl ester
Figure imgf000132_0002
Step A To a solution of ethyl 3,3-dimethylacrylate (Aldrich) (6.98 g, 54 mmol) in anhydrous tetrahydrofuran (60 mL) was added chlorotrimethylsilane (12 mL, 70 mmol), Cul (1.5 g, 8 mmol) under nitrogen. The mixture was stirred and the temperature was cooled to -20 °C. To the stirring mixture was slowly added a tetrahydrofuran solution (2 N) if isopropylmagnesium chloride (40 mL, 80 mmol) during a period of 30 min while maitining the temperature below -10 °C. After the addition was finished, the reaction mixture was gradually warmed to 0 °C and stirred at 0 °C for 3 h. Aqueous saturated NH4C1 solution was added to quench the reaction, and the mixture was extracted with ethyl acetate and ethyl ether. The organic layers were combined, concentrated. The residue was purifed by chromatography (EtOAc:hexanes=l;20, 1;10) to give 3,3,4-trimethyl-pentanoic acid ethyl ester as a colorless oil (7 g, 75%).
Step B To a solution of 3,3,4-trimethyl-pentanoic acid ethyl ester (7 g, 41 mmol) in anhydrous ethyl ether (100 mL) at 0 °C was added a ethyl ether solution (1 M) of LiAlH4 (67 mL, 67 mmol) under nitrogen. The reaction mixture was stirred at 0 °C for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgS04, and concentrated to give 3,3,4-trimethyl- pentan-l-ol as a colorless oil (5.4 g, 100%).
Step C To a solution of 3,3,4-trimethyl-pentan-l-ol (5.4 g, 41 mmol) in dichloromethane (100 mL) was added Dess-Martin periodinane (22 g„ 52 mmol) The reaction mixture was stirred at room temperature for 3 h. Aqueous Na2S03 solution was added to quench the reaction. The organic layers were separated, washed with saturated NaHC03, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=l :30) to give 3,3,4- trimethyl-pentanal as a colorless oil (Yield: 1.1 g, 21%). Step D In a manner similar to the method described in Example la, glycine tert-butyl ester (1 g, 7.7 mmol) was reacted with 3,3,4-trimethyl-pentanal (1.1 g, 8 mmol) in CH2C12 at room temperature for 5 h to give [3,3,4-trimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.5 g, 80%>).
Example 78b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000133_0001
M. W. 555.51 C29H34CI2F2N2O2
In a manner similar to the method described in Example lc, [3,3,4-trimethyl-pent-(E)- ylideneamino]-acetic acid tert-butyl ester prepared in Example 78a (1.5 g, 6.2 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.1 g, 3.5 mmol) prepared in Example 52a, AgF (1.2 g, 9.5 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (150 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)- pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.1 g, 56%).
Example 78c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000134_0001
M. W. 495.40 C25H26Cl2F2N202.C2HF302
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2- carboxylic acid tert-butyl ester prepared in Example 78b (1.1 g, 2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)- pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (1.1 g, 91%).
Example 78d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000135_0001
M. W. 582.52 C29H35Cl2F2N303
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)- pyrrolidine-2-carboxylic acid trifluoro acetic acid prepared in Example 78c (0.55 g, 0.9 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.39 g, 2.7 mmol), HATU (0.62 g, 1.6 mmol) and iPr2NEt (0.78 mL, 4.5 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2,3- trimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.32 g, 62%).
HRMS (ES+) m/z Calcd for C29H35Cl2F2N303+ H [(M+H)+]: 582.2097, found: 582.2095.
Example 78e
Preparation of (2R,3S,4R,5S)-3-(3-chloro-2 -fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000135_0002
M. W. 582.52 C29H35Cl2F2N303
Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2,3- trimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (0.25 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro- phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 40%) and chiral (2S,3R,4S,5R)-3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)- pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 40%>). Example 79a
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide
Figure imgf000136_0001
M. W. 582.52 C29H35C12F2N303
In a manner similar to the method described in Example 72a rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 78c (0.55 g, 0.9 mmol) was reacted with 2-((R)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.39 g, 2.7 mmol), HATU (0.62 g, 1.6 mmol) and iPr2NEt (0.78 mL, 4.5 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac- (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2,3- trimethyl-butyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.3 g, 58%).
HRMS (ES+) m/z Calcd for C29H35C12F2N303+ H [(M+H)+]: 582.2097, found: 582.2094.
Example 79b
Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide
Figure imgf000136_0002
M. W. 582.52 C29H35C12F2N303
Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2,3- trimethyl-butyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide (0.29 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro- phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxyH acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.12 g, 41%) and chiral (2S,3R,4S,5R)-3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)- pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.12 g, 41%).
Example 80a
Preparation of intermediate [3,3-dimethyl-pent-4-en-(E)-ylideneamino]-acetic acid tert-butyl ester
Figure imgf000137_0001
Step A To a solution of methyl 3,3-dimethyl-4-pentenoate (Aldrich) (6.1 g, 43 mmol) in anhydrous ethyl ether (100 mL) at 0 °C was added a tetrahydrofuran solution (2 M) of L1AIH4 (32 mL, 64 mmol) under nitrogen. The reaction mixture was stirred at 0 °C for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSC>4, and concentrated to give 3,3-dimethyl-pent-4-en-l-ol as a colorless oil (4.8 g, 98%>).
Step B To a solution of oxalyl chloride (5.9 g, 46 mmol) (Aldrich) in dichloromethane (60 mL) at -78 °C was added the solution of dimethyl sulfoxide (6.6 mL, 92 mmol) in dichloromethane dropwise. After 5 mins, the solution of 3,3-dimethyl-pent-4-en-l-ol (4.8 g, 42 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 15 min. Triethylamine (21 mL, 0.15 mol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. The water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10%> of HC1, saturated NaHC03, brine, dried over MgSC>4, and concentrated to give 3,3-dimethyl-pent-4-enal as a colorless oil (Yield: 3.2 g, 68%>). Step C. In a manner similar to the method described in Example la, glycine tert-butyl ester (1.3 g, 10 mmol) was reacted with 3,3-dimethyl-pent-4-enal (1.2 g, 11 mmol) in CH2CI2 at room temperature for 18 h to give [3,3-dimethyl-pent-4-en-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (2.1 g, 93%).
Example 80b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000138_0001
M. W. 535.47 C28H30CI2F2N2O2
In a manner similar to the method described in Example lc, [3,3-dimethyl-pent-4-en-(E)- ylideneamino]-acetic acid tert-butyl ester prepared in Example 80a (2.1 g, 9.3 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fiuoro-phenyl)-acrylonitrile (2 g, 6.4 mmol) prepared in Example 52a, AgF (0.9 g, 7.1 mmol), and triethylamine (1.5 g, 15 mmol) in dichloromethane (150 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)- pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.98 g, 56%).
Example 80c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid trifiuoroacetic acid
Figure imgf000138_0002
M. W. 479.36 C24H22CI2F2N2O2.C2HF3O2 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2- carboxylic acid tert-butyl ester prepared in Example 80b (1.0 g, 1.7 mmol) was reacted with trifluoro acetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)- pyrrolidine-2-carboxylic acid trifluoro acetic acid as a white solid (1.0 g, 91%).
Example 80d
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine -2 -carboxylic acid [2-((S)-2,2- dimethyl-[l ,3]dioxolan-4-yl)-ethyl]-ami
Figure imgf000139_0001
M. W. 606.55 C3lH35Cl2F2N303
In a manner similar to the method described in Example 42c, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 80c (1.0 g, 1.69 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.73 g, 5.0 mmol), HATU (1.15 g, 3 mmol) and iPr2NEt (1.46 mL, 8.4 mmol) in CH2C12 at room temperature for 20 h to give rac- (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)- ethyl]-amide as a white solid (0.82 g, 80%).
Example 80e
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)- amide
Figure imgf000140_0001
M. W. 566.47 C28H31CI2F2N3O3
In a manner similar to the method described in Example42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2- carboxylic acid [2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 80d (0.36 g, 0.59 mmol) was reacted with aqueous HC1 solution (1 N, 1 mL) in tetrahydrofuran (10 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2 -carboxylic acid ((S)- 3,4-dihydroxy-butyl)-amide as a white solid (0.32 g, 95%).
HRMS (ES+) m/z Calcd for C28H31CI2F2N3O3+ H [(M+H)+]: 566.1784, found: 566.1786.
Example 81a
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-butyl)-pyrrolidine -2 -carboxylic acid [2-((S)-2,2- dimethyl-[l ,3]dioxolan-4-yl)-ethyl]-amide
Figure imgf000140_0002
M. W. 608.56 C31H37CI2F2N3O3
A suspension of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl- [l,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 80d (0.4 g, 0.65 mmol) and PtC>2 (0.2 g) in ethyl acetate (15 mL) was vigorously shaken under ¾ atomosphere (30 psi) for 1 h. The mixture was filtered through a short pad of celite, and the filtrate was concentrated to give rac- (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-butyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethyl]- amide as a white gum (0.33 g, 83%). Example 81b
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000141_0001
M. W. 568.49 C28H33CI2F2N3O3
In a manner similar to the method described in Example 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-butyl)-pyrrolidine-2- carboxylic acid [2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 81a (0.41 g, 0.67 mmol) was reacted with aqueous HC1 solution (1 N, 1 mL) in tetrahydrofuran (10 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-butyl)-pyrrolidine -2 -carboxylic acid ((S)-3,4- dihydroxy-butyl)-amide as a white solid (0.38 g, 99%).
HRMS (ES+) m/z Calcd for C28H33CI2F2N3O3+ H [(M+H)+]: 568.1940, found: 568.1942.
Example 82a
Preparation of intermediate [3-methyl-3-phenyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester
Figure imgf000141_0002
M. W. 275.39 Ci7H25N02
Step A To a solution of 3-methyl-3-phenylbutanoic acid (ChemBridge) (4.46 g, 25 mmol) in anhydrous tetrahydrofuran (150 mL) at 0 °C was added a tetrahydrofuran solution (1 M) of BH3.THF (Aldrich, 50 mL, 50 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 3 h, then concentrated. The residue was partitoned between ethyl acetate and water. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgS04, and concentrated to give 3-methyl-3-phenyl-butan-l-ol as a colorless oil (4.1 g, 100%). Step B To a solution of oxalyl chloride (1.7 g, 13 mmol) (Aldrich) in dichloromethane (50 mL) at -78 °C was added the solution of dimethyl sulfoxide (1.9 mL, 27 mmol) in dichloromethane (10 mL) dropwise. After 5 mins, the solution of 3 -methyl-3 -phenyl-butan-l-ol (2 g, 12 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 15 min. Triethylamine (6.1 mL, 44 mol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. The water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHC03, brine, dried over MgSC>4, and concentrated to give 3 -methyl-3 -phenyl -butyraldehyde as a colorless oil (Yield: 1.8 g, 90%).
Step C In a manner similar to the method described in Example la, glycine tert-butyl ester (1.3 g, 10 mmol) was reacted with 3 -methyl-3 -phenyl-butyraldehyde (1.8 g, 11 mmol) in CH2CI2 at room temperature for 18 h to give [[3-methyl-3-phenyl-but-(E)-ylideneamino]-acetic acid tert- butyl ester as a colorless oil (2.3 g, 93%>).
Example 82b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000142_0001
M. W. 585.53 C32H32C12F2N202
In a manner similar to the method described in Example lc, [[3 -methyl-3 -phenyl-but-(E)- ylideneamino]-acetic acid tert-butyl ester prepared in Example 82a (2.3 g, 8.3 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.4 g, 7.7 mmol) prepared in Example 52a, AgF (0.7 g, 5.5mmol), and triethylamine (2.1 g, 21 mmol) in dichloromethane (150 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenyl-propyl)- pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1 g, 22%).
Example 82c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine -2-carboxylic acid
trifiuoro acetic acid
Figure imgf000143_0001
M. W. 529.42 C28H24CI2F2N2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine- 2-carboxylic acid tert-butyl ester prepared in Example 82b (1.0 g, 1.7 mmol) was reacted with trifiuoro acetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenyl-propyl)- pyrrolidine-2-carboxylic acid trifiuoro acetic acid as a white solid (1.0 g, 91%). Example 82d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5 -(2-methyl-2-phenyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy-butyl)- amide
Figure imgf000143_0002
M. W. 616.53 C32H33CI2F2N3O3 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2 -phenyl-propyl)- pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 82c (0.35 g, 0.54 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.24 g, 1.62 mmol), HATU (0.37 g, 0.98 mmol) and iPr2NEt (0.47 mL, 2.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac- (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2 -methyl- 2-phenyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.21 g, 66%).
HRMS (ES+) m/z Calcd for C32H33CI2F2N3O3+ H [(M+H)+]: 616.1940, found: 616.1939.
Example 83a
Preparation of intermediate (Z)-3-(3-chloro-5-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)- acrylonitrile
Figure imgf000144_0001
M. W. 308.99 Ci5H7Cl2F2N
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (3.4 g, 20 mmol) was reacted with 3-chloro-5-fluoro-benzaldehyde (Aldrich) (3.77 g, 24 mmol), methanolic solution (25 wt%) of sodium methoxide (4.99 mL, 22 mmol) in methanol (90 mL) at 50 °C for 3 h to give (Z)-3-(3-chloro-5-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (5.5 g, 90%).
Example 83b
Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000145_0001
M. W. 523.46 C27H30CI2F2N2O2
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-(3- chloro-5-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 83a, AgF (1.0 g, 8 mmol), and triethylamine (2.8 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-5-fiuoro-phenyl)- 4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.2 g, 29%).
Example 83 c
Preparation of intermediate rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifiuoroacetic acid
Figure imgf000145_0002
M. W. 467.35 C23H22CI2F2N2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-5- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid tert-butyl ester prepared in Example 83b (1.2 g, 2.2 mmol) was reacted with trifiuoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3- chloro-5-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifiuoroacetic acid as a white solid (1.3 g, 97%).
Example 83 d Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000146_0001
M. W. 554.46 C27H3 iCl2F2N303
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3- chloro-5-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 83c (0.4 g, 0.69 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.3 g, 2.06 mmol), HATU (0.47 g, 1.24 mmol) and iPr2NEt (0.6 mL, 3.44 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac- (2R,3R,4R,5S)-3-(3-chloro-5-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.13 g, 35%).
HRMS (ES+) m/z Calcd for C27H3iCl3FN303+ H [(M+H)+]: 554.1784, found: 554.1782.
Example 84a
Preparation of intermediate (Z)-3- {2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro- phenyl} -2-(4-chloro-2-fiuoro-phenyl)-acr lonitrile
Figure imgf000146_0002
M. W. 466.46 C23H26C12FN 02Si
Step A To a solution of 5-chlorosalicylaldehyde (2 g, 12.8 mmol) (Aldrich) in N,N- dimethylformamide (40 mL) was added K2C03 (5.3 g, 38 mmo), and (2-bromo-ethoxy)-tert- butyl-dimethyl-silane (3.67 g, 15 mmol, Aldrich). The reaction mixture was heated at 60 °C for 18 h. The crude was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, concentrated, and the residue was purified by
chromatography (EtOAc:Hexanes=l :8, then 1 :4) to give 2-[2-(tert-butyl-dimethyl-silanyloxy)- ethoxy]-5-chloro-benzaldehyde as a brown oil (Yield 3.8 g, 91%).
Step B In a manner similar to the method described in Example lb, 4-chloro-2- fluorophenylacetonitrile (1.7 g, 10 mmol) was reacted with 2-[2-(tert-butyl-dimethyl-silanyloxy)- ethoxy]-5-chloro-benzaldehyde (3.8 g, 12.5 mmol), methanolic solution (25 wt%) of sodium methoxide (2.5 mL, 11 mmol) in methanol (60 mL) at 50 °C for 3 h to give (Z)-3-{2-[2-(tert- butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl}-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a yellow oil (4.5 g, 80%).
Example 84b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]- 5-chloro-phenyl} -4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid tert-butyl ester
Figure imgf000147_0001
M. W. 679.78 C35H49Cl2FN204Si
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example la (2.1 g, 10 mmol) was reacted with (Z)-3-{2- [2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl}-2-(4-chloro-2-fluoro-phenyl)- acrylonitrile (3.7 g, 8 mmol) prepared in Example 84a, AgF (1.0 g, 8 mmol), and triethylamine (2.8 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac- (2R,3S,4R,5S)-3-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl}-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.0 g, 18%).
Example 84c
Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-[5-chloro-2-(2- hydroxy-ethoxy)-phenyl]-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifiuoro acetic acid
Figure imgf000148_0001
M. W. 509.47 C25H27Cl2FN204.C2HF302
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-{2-[2-(tert- butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl}-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 84b (1.0 g, 1.5 mmol) was reacted with trifiuoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-[5-chloro-2-(2-hydroxy-ethoxy)- phenyl]-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifiuoroacetic acid as a white solid (0.9 g, 98%).
Example 84d
Preparation of rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-[5-chloro-2-(2-hydroxy- ethoxy)-phenyl]-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4- dihydroxy-butyl)-amide
Figure imgf000148_0002
M. W. 596.53 C29H36C12FN305 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-4-(4- chloro-2-fluoro-phenyl)-3-[5-chloro-2-(2-hydroxy-ethoxy)-phenyl]-4-cyano-5-(2,2-dimethyl- propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 84c (0.4 g, 0.64 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.28 g, 1.93 mmol), HATU (0.44 g, 1.15 mmol) and iPr2NEt (0.56 mL, 3.21 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-[5-chloro-2-(2-hydroxy-ethoxy)-phenyl]-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (50 mg, 13%).
HRMS (ES+) m/z Calcd for C29H36C12FN305+ H [(M+H)+]: 596.2089, found: 596.2087.
Example 85a
Preparation of intermediate (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)- acrylonitrile
Figure imgf000149_0001
M. W. 322.17 Ci6HioCl2FN O
In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (2.8 g, 16.6 mmol) was reacted with 5-chloro-2-methoxybenzaldehyde (Matrix) (3.4 g, 19.9 mmol), methanolic solution (25 wt%) of sodium methoxide (4.17 mL, 18 mmol) in methanol (100 mL) at 50 °C for 3 h to give (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy- phenyl)-acrylonitrile as a white solid (2.0 g, 37%).
Example 85b
Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2- methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000150_0001
M. W. 535.49 C28H33CI2FN2O3
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example la (1.1 g, 5 mmol) was reacted with (Z)-2-(4- chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-acrylonitrile (1.28 g, 4 mmol) prepared in Example 85a, AgF (0.76 g, 6 mmol), and triethylamine (1.38 mL, 10 mmol) in
dichloromethane (100 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-4-(4-chloro- 2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine- 2-carboxylic acid tert-butyl ester as a white foam (0.3 g, 14%).
Example 85c
Preparation of intermediate rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2- methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000150_0002
M. W. 479.38 C24H25Cl2FN203.C2HF302
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-4-(4-chloro-2 fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid tert-butyl ester prepared in Example 85b (0.3 g, 0.56 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-4-(4- chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.32 g, 97%).
Example 85d Preparation of rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000151_0001
M. W. 566.51 C28H34CI2FN3O4
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-4-(4- chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 85c (0.32 g, 0.54 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.23 g, 1.62 mmol), HATU (0.37 g, 0.98 mmol) and iP^NEt (0.47 mL, 2.7 mmol) in CH2CI2 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac- (2R,3S,4R,5S)-4-(4-chloro-2-fiuoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (65 mg, 21%).
HRMS (ES+) m/z Calcd for C28H34CI2FN3O4+ H [(M+H)+]: 566.1983, found: 566.1984.
Example 86
Preparation of rac(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbox lic acid (quinolin-3-ylmethyl)-amide
Figure imgf000151_0002
M. W. 571.56 C33H32CI2N4O
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol) prepared in Example Id was reacted with quinolin-3-yl-methylamine (47.5 mg, 0.3 mmol), HATU (76.0 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) at rt overnight, to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (quinolin-3-ylmethyl)-amide (54.4 mg, 47.5 %) as a white powder.
HRMS (ES+) m/z Calcd for C33H32CI2N4O + H [(M+H)+]: 571.2026, found: 571.2027.
Example 87
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid 4-trifluoromethyl-benzylamide
Figure imgf000152_0001
M. W. 588.498 C31H30CI2F3N3O
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example Id was reacted with 4-trifiuoromethylbenzyl amine (52.5 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 4-trifluoromethyl-benzylamide (58.1 mg, 58.04 %).
HRMS (ES+) m/z Calcd for C31H30CI2F3N3O + H [(M+H)+]: 588.1791 , found: 588.1788.
Example 88
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2- arboxylic acid 3-trifluoromethyl-benzyl amide
Figure imgf000152_0002
M. W. 588.498 C31H30CI2F3N3O In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example Id was reacted with 3-trifluoromethylbenzyl amine (52.55 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 3-trifluoromethyl-benzyl amide (26.2 mg, 26.2 %).
HRMS (ES+) m/z Calcd for C31H30CI2F3N3O + H [(M+H)+]: 588.1791 , found: 588.1788.
Example 89
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid 4-hydroxy-benzylamide
Figure imgf000153_0001
M. W. 536.51 C30H31CI2N3O2
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example Id was reacted with 4-hydroxybenzyl amine (36.9 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 4-hydroxy-benzylamide (45.1 mg, 45.0 %). HRMS (ES+) m/z Calcd for C30H31CI2N3O2 + H [(M+H)+]: 536.1866, found: 536.1866.
Example 90
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid 3 -iodo-benzylamide
Figure imgf000154_0001
M. W. 646.393 C30H30CI2IN3O
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example Id was reacted with 3-iodobenzyl amine (68.92 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 3-iodo-benzylamide (44.1 mg, 34.1 %). HRMS (ES+) m/z Calcd for C30H30CI2IN3O + H [(M+H)+]:646.0884, found: 646.0881.
Example 91
Preparation of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-ethyl-butyl)-amide
Figure imgf000154_0002
M. W. 514.54 C29H37CI2N3O
In a manner similar to the method described in Example le, rac-(2R,3R,4R,5S)-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example Id was reacted with 2-ethyl butyl amine (30.3 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight to rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-
(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-ethyl-butyl)-amide (34 mg, 33.04 HRMS (ES+) m/z Calcd for C29H37CI2N3O + H [(M+H)+]:514.2387, found: 514.2385. Example 92
Preparation of rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl^ropyl)-pyrrolidine-2-carbonyl]-amino} -piperidine-l- carboxylic acid tert-butyl ester
Figure imgf000155_0001
M. W. 649.61 C33H40CI2F2N4O3
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 52c (1.8 g, 3.1 mmol) was reacted with 4-Amino-piperidine-l -carboxylic acid tert-butyl ester(Aldrich, 931 mg, 4.65 g, 4.65 mmol), HATU (2.12 g, 0.92 mmol) and iPr2NEt (2.7 mL, 15.5 mmol) in CH2C12 at room temperature overnight, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give a white solid (0.758 g, 38%).
HRMS (ES+) m/z Calcd for C33H40CI2F2N4O3+ H [(M+H)+]: 649.2519, found: 649.2518.
Example 93
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifluoroacetic acid
Figure imgf000155_0002
M. W. 549.49 C28H32CI2F2N4O. C2HF3O2 To a stirred solution of a mixture of TFA/CH2C12 (5 niL/10 niL), rac-4-{[(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino}-piperidine-l-carboxylic acid tert-butyl ester (example 92, 510 mg, 0.79 mmol) was added and the mixture was stirred at rt for 15 min. The solvent was removed and the residue dried to give a white solid after precipation from methylene chloride and ethyl acetate. 492 mg.
HRMS (ES+) m/z Calcd for C28H32C12F2N40 + H [(M+H)+]: 549.1994, found: 549.1994.
Example 94
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (l-methanesulfonylpiperidin-4-yl)- amide
Figure imgf000156_0001
M. W. 627.58 C29H34C12F2N403S
To a stirred solution of (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifiuoro acetic acid (80 mg, 0.10 mmol) in methylene chloride (10 mL), methanesulfonyl chloride (14 uL, 0.18 mmol) and triethylamine (84 uL, 0.61 mmol) were added and the misture was stirred at rt for 1 hr. The reaction was quenched with water and the organic layer was separated and dried with sodium sulfate. Removal of solvent gave the crued which was chromatographied on an ISCO machine (0-10% EtOAc/CH2Cl2) to give a white solid. 53 mg. HRMS (ES+) m/z Calcd for C29H34C12F2N403S+ H [(M+H)+]: 627.1770, found: 627.1766.
Example 95
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (l-methyl-carbonyl-piperidin-4-yl)- amide
Figure imgf000157_0001
M. W. 591.53 C30H34CI2F2N4O3
To a stirred solution of (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifiuoro acetic acid (80 mg, 0.10 mmol) in methylene chloride (10 mL), acetic anhydride (18 uL, 0.18 mmol) and triethylamine (84 uL, 0.61 mmol) were added and the misture was stirred at rt for 1.5 hr. The reaction was quenched with water and the organic layer was separated and dried with sodium sulfate. Removal of solvent gave the crued which was chromatographied on an ISCO machine (0-10% EtOAc/CH2Cl2) to give a white solid. 58 mg.
HRMS (ES+) m/z Calcd for C3oH34Cl2F2N403+ H [(M+H)+]: 591.2100, found: 591.2099.
Example 96
Preparation of rac-(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbox lic acid (l-benzoyl-piperidin-4-yl)-amide
Figure imgf000157_0002
M. W. 653.59 C35H36C12F2N402
To a stirred solution of (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifiuoro acetic acid (80 mg, 0.10 mmol) in methylene chloride (10 mL), benzoyl chloride (21 uL, 0.18 mmol) and triethylamine (84 uL, 0.61 mmol) were added and the misture was stirred at rt for 1 hr. The reaction was quenched with water and the organic layer was separated and dried with sodium sulfate. Removal of solvent gave the crued which was chromatographied on an ISCO machine (0-10% EtOAc/CH2Cl2) to give a white solid. 36 mg. HRMS (ES ) m/z Calcd for C35H36C12F2N402 + H [(M+H)+]: 653.2256, found: 653.2253.
Example 97
Preparation of rac-4-{ [(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2 -fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -piperidine-l- carboxylic acid isopropylamide
Figure imgf000158_0001
M. W. 634.60 C32H39C12F2N502
To a stirred solution of (2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifiuoro acetic (80 mg, 0.10 mmol) in methylene chloride (10 mL), 2-propyl isocyante (18 uL, 0.18 mmol) and triethylamine (84 uL, 0.61 mmol) were added and the misture was stirred at rt for 1 h. The reaction was quenched with water and the organic layer was separated and dried with sodium sulfate. Removal of solvent gave the crued which was chromatographied on an ISCO machine (0-10% EtOAc/CH2Cl2) to give a white solid.
HRMS (ES+) m/z Calcd for C32H39C12F2N502 + H [(M+H)+]: 634.2520, found: 634.2522
Example 98a
Preparation of intermediate (Z)-3-(5-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)- acrylonitrile
Figure imgf000158_0002
M. W. 310.13 Ci5H7Cl2F2N In a manner similar to the method described in Example lb, 4-chloro-2-fluorophenylacetonitrile (2.8 g, 16.6 mmol) was reacted with 5-chloro-2-fluorobenzaldehyde (Alfa) (3.2 g, 19.9 mmol), methanolic solution (25 wt%) of sodium methoxide (4.17 mL, 18 mmol) in methanol (100 mL) at 50 °C for 3 h to give (Z)-2-(4-chloro-2-fiuoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)- acrylonitrile as a off white solid (3.5 g, 68.6%).
Example 98b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000159_0001
M. W. 523.46 C27H30CI2F2N2O2
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example la (2.2 g, 10 mmol) was reacted with (Z)-2-(4- chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-acrylonitrile (2.46 g, 8 mmol) prepared in Example 98a, AgF (1.52 g, 12 mmol), and triethylamine (2.78 mL, 20 mmol) in
dichloromethane (1500 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(5-chloro- 2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid tert-butyl ester as a white foam (1.1 g, 26%). Example 98c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2 -carboxylic acid trifiuoroacetic acid
Figure imgf000159_0002
M. W. 467.35 C23H22CI2F I2N2O2.C2HF3O2 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(5-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid tert-butyl ester prepared in Example 98b (1.1 g, 2.1 mmol) was reacted with trifiuoro acetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(5- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifiuoro acetic acid as a white solid (1.1 g, 90%).
Example 98d
Preparation of rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrr lidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000160_0001
M. W. 554.46 C27H3 iCl2F2N303
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(5- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 98c (0.4 g, 0.68 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.3 g, 2.06 mmol), HATU (0.47 g, 1.24 mmol) and iPr2NEt (0.6 mL, 3.44 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac- (2R,3S,4R,5S)-3-(5-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.36 g, 80%).
HRMS (ES+) m/z Calcd for C27H3iCl2F2N303+ H [(M+H)+]: 554.1784, found: 554.1782.
Example 99a
Preparation of intermediate [3-cyclopropyl-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester
Figure imgf000161_0001
M. W. 239.36 Ci4H25N02
Step A To a suspension of Cul (7.61 g, 40 mmol) in anhydrous tetrahydrofuran (100 mL) at -50 °C was added cyclopropylmagnesium bromide (0.5 M, 160 mL, 80 mmol) during a period of 15 min. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 20 min. Then the temperature of the mixture was lowered to -50 °C, a tetrahydrofuran solution (50 mL) of diethyl isopropylidenemalonate (Aldrich) (4 g, 20 mmol) was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 3 h. Aqueous saturated NH4C1 solution was added to quench the reaction. The mixture was filtered, and the filtrate was concentrated to remove most of tetrahydrofuran. The residue was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was purifed by chromatography (EtOAc:hexanes=l;20, 1;10) to give 2-(l-cyclopropyl-l-methyl- ethyl)-malonic acid diethyl ester as a colorless oil (4.3 g, 89%). Step B To a solution of 2-(l-cyclopropyl-l-methyl-ethyl)-malonic acid diethyl ester (4.3 g, 17.8 mmol) in DMSO (30 mL) was added LiCl (1.5 g, 35.6 mmol) and H20 (0.3 mL, 17.8 mmol). The reaction mixture was heated at 170 °C for 4 h, then poured into a ice-water, extracted with ethyl acetate. The organic layer were separated, washed with water, brine, dried over MgS04, and concentrated to give 3-cyclopropyl-3-methyl-butyric acid ethyl ester as a colorless oil (2 g, 66%).
Step C To a solution of 3 -cyclopropyl-3 -methyl-butyric acid ethyl ester (2 g, 11.75 mmol) in anhydrous tetrahydrofuran (40 mL) at 0 °C was added a tetrhydrofuran solution (1 M) of LiAlH4 (23.5 mL, 23.5 mmol) under nitrogen. The reaction mixture was stirred at 0 °C for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HCl solution, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (EtOAc:hexanes = 1;10, 1 :5) to give 3-cyclopropyl- 3-methyl-butan-l-ol as a colorless oil (0.7 g, 46%>). Step D To a solution of oxalyl chloride (0.75 g, 5.9 mmol) (Aldrich) in dichloromethane (30 mL) at -78 °C was added the solution of dimethyl sulfoxide (0.84 mL, 11.8 mmol) in
dichloromethane (5 mL) dropwise. After 5 mins, the solution of 3-cyclopropyl-3-methyl-butan- l-ol (0.69 g, 5.4 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 15 min. Triethylamine (2.7 mL, 19.4 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHC03, brine, dried over MgSC>4, and concentrated to give 3-cyclopropyl-3-methyl- butyraldehyde as a light yellow oil (Yield: 0.68 g, 98%).
Step E In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with 3-cyclopropyl-3-methyl-butyraldehyde (0.68 g, 5.3 mmol) in CH2CI2 at room temperature for 5 h to give [3-cyclopropyl-3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester as a colorless oil (0.9 g, 75%).
Example 99b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000162_0001
M. W. 507.41 C26H26CI2F2N2O2
To a solution of [3-cyclopropyl-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 99a (0.9 g, 3.76 mmol) and (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro- 2-fluoro-phenyl)-acrylonitrile (1.16 g, 3.76 mmol) prepared in Example 52a in dichloromethane (100 mL) were added triethylamine (0.76 g, 7.5 mmol) and AgF (0.47 g, 3.76 mmol), in one portion. The mixture was stirred at room temperature for overnight. The mixture was then quenched with sat. NH4C1 and extracted with CH2CI2. The organic phase was separated, filtered through celite and dried overNa2S04, and concentrated. The residue was dissolved into methanol (40 mL), and DBU (3 mL) was added. The mixture was heated at 100 °C for 5 h, then cooled to room temperature, and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer were separated, dried over MgS04, and concentrated. The residue was purified by chromatography (EtOAc:hexanes = 1;5, 1 :3) to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-cyclopropyl-2-methyl- propyl)-pyrrolidine-2-carboxylic acid methyl ester as a white foam (0.95 g, 50%).
Example 99c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2-cyclopro l-2-methyl-propyl)-pyrrolidine-2-carboxylic acid
Figure imgf000163_0001
M. W. 493.39 C25H24Cl2F2N202
To rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2- cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid methyl ester prepared in Example 99b (0.95 g, 1.87 mmol) in tetrahydrofuran (40 mL) was added an aqueous solution (20 mL) of NaOH (0.15 g, 3.7mmol) and methanol (20 mL). The reaction mixture was stirred at room temperature for 18 h. The "pH" of the mixture was adjusted to 5 by aqueous HC1 solution. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgS04, concentrated, and trituated with dichloromethane and hexanes to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro- phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2- carboxylic acid as a white solid (0.78 g, 80%)
Example 99d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5 -(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy- butyl)-amide
Figure imgf000164_0001
M. W. 580.51 C29H33CI2F2N3O3
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-cyclopropyl-2-methyl- propyl)-pyrrolidine-2-carboxylic acid prepared in Example 99c (0.41 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iPr2NEt (0.43 mL, 2.5 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac- (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2- cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.33 g, 70%).
HRMS (ES+) m/z Calcd for C29H33CI2F2N3O3+ H [(M+H)+]: 580.1940, found: 580.1936.
Example 99e
Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5 -(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy- butyl)-amide
Figure imgf000164_0002
M. W. 580.51 C29H33CI2F2N3O3
Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2- cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (0.3 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-cyclopropyl-2-methyl- propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.11 g, 37%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5 -(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy- butyl)-amide as a white solid (0.11 g, 37%).
HRMS (ES+) m/z Calcd for C29H33CI2F2N3O3+ H [(M+H)+]: 580.1940, found: 580.1941.
Example 100a
Preparation of intermediate (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-3-methyl-phenyl)- acrylonitrile
Figure imgf000165_0001
M. W. 306.17 Ci6HioCl2FN
Step A In a manner similar to the method described in Example 57 Step A, 4-chloro-2- methylbenzyl alcohol (PLATTE) (1.69 g, 11 mmol) was reacted with thionyl chloride (20 mL) to give 4-chloro-2-methylbenzyl chloride as a colorless oil (1.83 g, 97%).
Step B In a manner similar to the method described in Example 57 Step B, 4-chloro-2- methylbenzyl chloride (1.83 g, 10 mmol) was reacted with KCN (1.76 g, 27 mmol) in ethanol (13 mL) and water (10 mL) at 100 °C for 1 h to give 4-chloro-2-methylbenzyl cyanide as a yellow oil (1.2 g, 69%)
Step C In a manner similar to the method described in Example lb, 4-chloro-2-methylbenzyl cyanide (1.2 g, 7.2 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (1.38 g, 8.7 mmol), methanolic solution (25 wt%) of sodium methoxide (1.82 mL, 8 mmol) in methanol (50 mL) at 50 °C for 3 h to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-3-methyl-phenyl)- acrylonitrile as a white solid (2.0 g, 91%).
Example 100b Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3- methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000166_0001
M. W. 519.49 C28H33CI2N2O2
To a solution of [3-cyclopropyl-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example la (0.93 g, 7.3 mmol) and To a solution of [3-cyclopropyl-3-methyl-but- (E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 99a (1.6 g, 7.3 mmol) and (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.5 g, 4.9 mmol) prepared in Example 100a in dichloromethane (100 mL) were added triethylamine (1.7 g, 12 mmol) and AgF (0.9 g, 7.3mmol), in one portion. The mixture was stirred at room temperature for 18 h. The mixture was then quenched with sat. NH4CI and extracted with CH2CI2. The organic phase was separated, filtered through celite and dried over Na2S04, and concentrated. The residue was dissolved into tert-butanol (30 mL), and DBU (5 mL) was added. The mixture was heated at 100 °C for 18 h, then cooled to room temperature, and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer were separated, dried over MgS04, and concentrated. The residue was purified by chromatography (EtOAc:hexanes = 1;10, 1 :5) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-3-methyl-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2 g, 80%).
Example 100c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3- methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000167_0001
M. W. 463.38 C24H25Cl2FN202.C2HF302
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-3-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid tert-butyl ester prepared in Example 100b (2.0 g, 3.8 mmol) was reacted with trifluoro acetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-3-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifluoro acetic acid as a white solid (1.88 g, 85%).
Example lOOd
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-methyl-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrr lidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000167_0002
M. W. 550.50 C28H34C12FN303
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-3-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifluoro acetic acid prepared in Example 100c (0.44 g, 0.76 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.33 g, 2.3 mmol), HATU (0.52 g, 1.37 mmol) and iP^NEt (0.66 mL, 3.8 mmol) in CH2CI2 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-methyl-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.26 g, 64%).
HRMS (ES+) m/z Calcd for C28H34C12FN303+ H [(M+H)+]: 550.2034, found: 550.2034. Example 101a
Preparation of intermediate [2-(tetrahydro-pyran-4-yl)-eth-(E)-ylideneamino]-acetic acid tert- butyl ester
Figure imgf000168_0001
In a manner similar to the method described in Example la, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with (tetrahydro-pyran-4-yl)-acetaldehyde (Pharmacore) (0.64 g, 5 mmol) CH2CI2 at room temperature for 5 h to give [2-(tetrahydro-pyran-4-yl)-eth-(E)-ylideneamino]- acetic acid tert-butyl ester
as a colorless oil (0.43 g, 33%).
Example 101b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000168_0002
M. W. 551.47 C28H30CI2F2N2O3
In a manner similar to the method described in Example 100b, [2-(tetrahydro-pyran-4-yl)-eth- (E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 100a (0.43 g, 1.8 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fiuoro-phenyl)-acrylonitrile (0.31 g, 1 mmol) prepared in Example 52a, AgF (0.19 g, 1.5 mmol), and triethylamine (0.46 g, 4.5 mmol) in dichloromethane (50 mL) at room temperature for 18 h, followed by reaction with DBU in tert-butanol at 100 °C for 8 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4- (4-chloro-2-fluoro-phenyl)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxyl acid tert-butyl ester as a white solid (0.45 g, 82%).
Example 101c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000169_0001
M. W. 495.36 C24H22CI2F2N2O3.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)- pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 101b (0.45 g, 0.81 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac- (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5- (tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid
(0.4 g, 80%).
Example 101 d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)- amide
Figure imgf000169_0002
M. W. 582.47 C28H31CI2F2N3O4
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)- pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 101c (0.15 g, 0.25 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.11 g, 0.74 mmol), HATU (0.17 g, 0.44 mmol) and iPr2NEt (0.21 mL, 1.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5- (tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.25 g, 80%).
HRMS (ES+) m/z Calcd for C28H31CI2F2N3O4+ H [(M+H)+]: 582.1733, found: 582.1731.
Example 102a
Preparation of intermediate [2-(l-methyl-cyclohexyl)-eth-(E)-ylideneamino]-acetic acid tert- butyl ester
Figure imgf000170_0001
M W. 253.39 Ci5H27N02
Step A To a suspension of NaH (60%, 3 g, 74 mmol) in DME (100 mL) was added methyl
(dimethoxyphosphonyl)acetate (Aldrich) (1 1.3 g, 61.8 mmol). The mixture was stirred at room temperature for 40 min, then cyclohexanone (6.07 g, 61.8 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. Aqueous saturated NH4CI solution was added and the mixture was extracted with ethyl acetate twice. The organic layers were combined, dried over MgSC>4, concentrated. The residue was purifed by chromatography (EtOAc:hexanes=l;10) to give cyclohexylidene-acetic acid methyl ester as a colorless oil (6.4 g, 67%>).
Similar transformation was reported by Bruckner, R. et al in Eur. J. Org. Chem. 2006, 2119- 2133 and the described procedures were used without modification. Step B To a suspension of Cul (7.61 g, 40 mmol) in anhydrous ethyl ether (20 mL) at 0 °C was added an ethyl ether solution (1.6 M) of MeLi (50 mL, 80 mmol) The reaction mixture was stirred at 0 °C for 10 min. The solvent was evaporated under reduced pressure, then
dichloromethane (20 mL) was added under nitrogen at 0 °C. The mixture was stirred for 5 min. The solvent was evaporated again. To the residue was added dichlormethane (20 niL), and the temperature of the mixture was lowered to -78 °C. To the mixture was added
chlorotrimethylsilane (4.3 g, 40 mmol) and a dichloromethane solution (20 mL) of
cyclohexylidene-acetic acid methyl ester (3.1 g, 20 mmol). The reaction mixture was allowed to slowly warmed to 0 °C and stirred for 1 h. Aqueous saturated NH4C1 solution was added to quench the reaction. The mixture was extracted with ethyl ether twice. The organic layers were combined, dried over MgSC>4, concentrated. The residue was purifed by chromatography (EtOAc:hexanes=l ;5) to give (l-methyl-cyclohexyl)-acetic acid methyl ester as a colorless oil (3.3 g, 97%).
Similar transformation was reported by Yamamoto, Y. et al in Tetrahedron Letter 44 (2003), 4265-4266 and the described procedures were used without modification.
Step C To a solution of (l-methyl-cyclohexyl)-acetic acid methyl ester (3.3 g, 19.4 mmol) in anhydrous tetrahydrofuran (50 mL) at 0 °C was added a tetrhydrofuran solution (1 M) of L1AIH4 (29 mL, 29 mmol) under nitrogen. The reaction mixture was stirred at 0 °C for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSC>4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes = 1 :4) to give 2-(l-methyl- cyclohexyl)-ethanol as a colorless oil (2.2 g, 80%).
Step D To a solution of oxalyl chloride (2.18 g, 17.2 mmol) (Aldrich) in dichloromethane (12 mL) at -78 °C was added the solution of dimethyl sulfoxide (2.44 mL, 34.3 mmol) in
dichloromethane (8 mL) dropwise. After 5 mins, the solution of 2-(l-methyl-cyclohexyl)- ethanol (2.2 g, 15.6 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 15 min. Triethylamine (7.8 mL, 56mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHC03, brine, dried over MgSC>4, and concentrated to give (1-methyl-cyclohexyl)- acetaldehyde as a light yellow oil (Yield: 2 g, 91%>). Step E In a manner similar to the method described in Example la, glycine tert-butyl ester (1.87 g, 14.3 mmol) was reacted with (l-methyl-cyclohexyl)-acetaldehyde (2.9 g, 14.3 mmol) in CH2CI2 at room temperature for 18 h to give [2-(l-methyl-cyclohexyl)-eth-(E)-ylideneamino]- acetic acid tert-butyl ester
as a colorless oil (3.4 g, 95%).
Example 102b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(l-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000172_0001
M. W. 563.52 C30H34CI2F2N2O2
In a manner similar to the method described in Example 100b, [2-(l-methyl-cyclohexyl)-eth- (E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 101a (2.55 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fiuoro-phenyl)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 52a, AgF (1.55 g, 12.3 mmol), and triethylamine (2.8 mL, 20 mmol) in dichloromethane (150 mL) at room temperature for 18 h, followed by the reaction with DBU (10 ml) in tert-butanol (50 mL) at 100 °C for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(l-methyl-cyclohexylmethyl)- pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow solid (3 g, 66%).
Example 102c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(l-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid trifiuoro acetic acid
Figure imgf000172_0002
M. W. 507.41 C26H26Cl2F2N202.C2HF302
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(l-methyl-cyclohexylmethyl)- pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 102b (3 g, 5.3 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-
(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(l-methyl- cyclohexylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (3.3 g, 100%). Example 102d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5 -( 1 -methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy-butyl)- amide
Figure imgf000173_0001
M. W. 594.53 C3oH35Cl2F2N303
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(l-methyl-cyclohexylmethyl)- pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 102c (0.5 g, 0.8 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.35 g, 2.41 mmol), HATU (0.55 g, 1.45 mmol) and iPr2NEt (0.70 mL, 4.0 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5- (l-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.22 g, 46%).
HRMS (ES+) m/z Calcd for C30H35Cl2F2N3O3+ H [(M+H)+]: 594.2097, found: 594.2094.
Example 102e Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5 -( 1 -methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy-butyl)- amide
Figure imgf000174_0001
M. W. 594.53 C3oH35Cl2F2N303
Rac-(2R,3S,4R,5S)- 3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(l- methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (0.18 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)- 3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(l-methyl-cyclohexylmethyl)- pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (78 mg, 71%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(l- methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (80 mg, 73%).
HRMS (ES+) m/z Calcd for C30H35Cl2F2N3O3+ H [(M+H)+]: 594.2097, found: 594.2094.
Example 103a
Preparation of intermediate 4-[(E)-tert-butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid benzyl ester
Figure imgf000174_0002
Step A A mixture of 2,2-dimethylbutyrolactone (6.84 g, 60 mmol) and KOH (3.36 mmol) in H2O (60 mL) was heated at reflux for 2 h. The solution was cooled to room temperature and concentrated to dryness to give 4-hydroxy-2,2-dimethyl-butanoic acid monopotassium salt as a white solid (10.2 g, 100%). Step B To the mixture of 4-hydroxy-2,2-dimethyl-butanoic acid monopotassium salt (60 mmol) and benzyl bromide (8.55 mL, 72 mmol) were added Nal (10.8 g, 72 mmol) and K2C03 (8.29 g, 60 mmol). The reaction mixture was stirred at reflux for 18 h. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by flash column chromatography
(EtOAc: hexanes=l :2) to give 4-hydroxy-2,2-dimethyl-butyric acid benzyl ester as a colorless oil (9 g, 67%)
The same transformations were reported in EP246529 and the described procedures were used without modification.
Step C To a solution of oxalyl chloride (2.8 mL, 22 mmol) (Aldrich) in dichloromethane (40 mL) at -78 °C was added the solution of dimethyl sulfoxide (3.1 mL, 44 mmol) in
dichloromethane (5 mL) dropwise. After 5 mins, the solution of 4-hydroxy-2,2 -dimethyl-butyric acid benzyl ester (4.5 g, 20 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 15 min. Triethylamine (10 mL, 72 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHC03, brine, dried over MgS04, and concentrated to give 2,2-dimethyl-4-oxo- butyric acid benzyl ester as a colorless oil (Yield: 2.9 g, 66%).
Step D In a manner similar to the method described in Example la, glycine tert-butyl ester (1.72 g, 13.2 mmol) was reacted with 2,2-dimethyl-4-oxo-butyric acid benzyl ester (4.1 g, 13.2 mmol) in CH2C12 at room temperature for 18 h to give 4-[(E)-tert-butoxycarbonylmethylimino]-2,2- dimethyl-butyric acid benzyl ester as a colorless oil (4.1 g, 93%>).
Example 103b
Preparation of intermediate rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbonyl-2-methyl-propyl)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert- butyl ester
Figure imgf000176_0001
M. W. 643.56 C34H34CI2F2N2O4
In a manner similar to the method described in Example 100b, 4-[(E)-tert- butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid benzyl ester prepared in Example 103a (4.1 g, 12.3 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro- phenyl)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 52a, AgF (1.55 g, 12.3 mmol), and triethylamine (2.5 g, 24 mmol) in dichloromethane (150 mL) at room temperature for 18 h, followed by the reaction with DBU (4 ml) in tert-butanol (40 mL) at 100 °C for 4 h to give rac- (2R,3S,4R,5S)-5-(2-benzyloxycarbonyl-2-methyl-propyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow gum (0.98 g, 19%).
Example 103 c
Preparation of intermediate rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbonyl-2-methyl-propyl)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000176_0002
M. W. 587.46 C30H26CI2F2N2O4.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-(2- benzyloxycarbonyl-2-methyl-propyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 103b (0.98 g, 1.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac- (2R,3S,4R,5S)-5-(2-benzyloxycarbonyl-2-methyl-propyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white gum (0.94 g, 86%).
Example 103 d
Preparation of rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbonyl-2-methyl-propyl)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4- dihydroxy-butyl)-amide
Figure imgf000177_0001
M. W. 674.57 C34H35C12F2N305
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-5-(2- benzyloxycarbonyl-2-methyl-propyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 103c (0.94 g, 1.34 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.58 g, 4.0 mmol), HATU (0.92 g, 2.41 mmol) and iPr2NEt (1.17 mL, 6.7 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbonyl-2-methyl-propyl)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.2 g, 22%).
HRMS (ES+) m/z Calcd for C34H35C12F2N305+ H [(M+H)+]: 674.1995, found: 674.1991.
Example 104a
Preparation of intermediate 4-[(E)-tert-butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid methyl ester
Figure imgf000177_0002
Figure imgf000178_0001
Step A A mixture of 2,2-dimethylbutyrolactone (6.84 g, 60 mmol) and KOH (3.36 g) in H20 (60 mL) was heated at reflux for 2 h. The solution was cooled to room temperature, and acidified to "pH" 5 with aqueous HC1 solution. The mixture was then extracted with ethyl acetate three times The combined organic layers wer washed with brine, dried over MgS04, concentrated under reduced pressure to give 4-hydroxy-2,2-dimethyl-butanoic acid as a colorless oil (4 g, 51%).
Step B To the mixture of 4-hydroxy-2,2-dimethyl-butanoic acid (2.2 g, 16.6 mmol) in ethyl ether (16 mL) and methanol (24 mL) at 0 °C was added a hexane solution (2.0 M) of
trimethylsilyldiazomethane (Aldrich) (12.5 mL, 25mmol). The reaction mixture was stirred at 0 °C for 1 h. The solvents were evaporated. The residue was taken up in ethyl acetate, washed with diluted aqueous HC1 solution, saturated aqueous NaHC03 solution, brine, dried over MgSC>4, and concentrated to give 4-hydroxy-2,2 -dimethyl-butyric acid methyl ester as a colorless oil (1.5 g, 62%).
Step C To a solution of oxalyl chloride (1.09 mL, 12.5 mmol) (Aldrich) in dichloromethane (20 mL) at -78 °C was added the solution of dimethyl sulfoxide (1.77 mL, 25 mmol) in
dichloromethane (5 mL) dropwise. After 5 mins, the solution of 4-hydroxy-2,2 -dimethyl-butyric acid methyl ester (1.5 g, 11.3 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 15 min. Triethylamine (5.7 mL, 41 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10%) of HC1, saturated NaHC03, brine, dried over MgSC>4, and concentrated to give 2,2- dimethyl-4-oxo-butyric acid methyl ester as a light yellow oil (Yield: 1.2 g, 81 %).
Step D In a manner similar to the method described in Example la, glycine tert-butyl ester (1.09 g, 8.32 mmol) was reacted with 2,2-dimethyl-4-oxo-butyric acid methyl ester (1.2 g, 8.32 mmol) in CH2C12 at room temperature for 18 h to give 4-[(E)-tert-butoxycarbonylmethylimino]-2,2- dimethyl-butyric acid methyl ester as a colorless oil (2.1 g, 100%>). Example 104b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2-methoxycarbonyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000179_0001
M. W. 567.47 C28H30CI2F2N2O4
In a manner similar to the method described in Example 100b, 4-[(E)-tert- butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid methyl ester prepared in Example 104a (2.1 g, 8.3 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro- phenyl)-acrylonitrile (2.05 g, 6.7 mmol) prepared in Example 52a, AgF (1.27 g, 10 mmol), and triethylamine (2.3 mL, 17 mmol) in dichloromethane (150 mL) at room temperature for 18 h, followed by the reaction with DBU (2 ml) in tert-butanol (10 mL) at 100 °C for 2 h to give rac- (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2- methoxycarbonyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (0.75 g, 20%).
Example 104c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2-methoxycarbonyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid trifiuoro acetic acid
Figure imgf000179_0002
M. W. 511.36 C24H22CI2F2N2O4.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methoxycarbonyl-2-methyl-propyl)- pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 104b (0.7 g, 1.23 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac- (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2- methoxycarbonyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.75 g, 97%).
Example 104d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5 -(2-methoxycarbonyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4- dihydroxy-butyl)-amide
Figure imgf000180_0001
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenoxycarbonyl- propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 104c (0.75 g, 1.26 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.52 g, 3.6 mmol), HATU (0.82 g, 2.16 mmol) and iPr2NEt (1.04 mL, 6 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenoxycarbonyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.45 g, 56%).
HRMS (ES+) m/z Calcd for C28H3iCl2F2N305+ H [(M+H)+]: 598.1682, found: 598.1679.
Example 105a
Preparation of intermediate [4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-(E)- ylideneamino]-acetic acid tert-butyl ester
Figure imgf000181_0001
M. W. 343.59 C18H37NO3S1
Step A A mixture of 2,2-dimethyl-propane-l,3-diol (Aldrich) (10 g, 96 mmol) and imidazole (9.8 g, 140 mmol) in dichloromethane (200 mL) was added tert-butyldimethylchlorosilane (15.9 g, 10.6 mmol). The reactiom mixture was stirred at room temperature for 0.5 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with dichloromethane. The combined organic layers wer washed with brine, dried over MgS04, concentrated to give 3- (tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propan-l-ol as a colorless oil (20.4 g, 97%). Step B To the solution of 3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propan-l-ol (20.4 g, 93 mmol) and triethylamine (26 g, 186 mmol) in dichloromethane (200 mL) at 0 °C was added a dichlormethane solution (20 mL) of methanesulfonyl chloride (Aldrich) (8.69 mL, 112 mmol). The reaction mixture was stirred at 0 °C for 2 h. Water was added. Organic layer was separated, the aqueous layer was extracted with dichlormethane. The combined organic layers were washed with diluted aqueous HC1 solution, saturated aqueous NaHC03 solution, brine, dried over
MgS04, and concentrated to give methanesulfonic acid 3-(tert-butyl-dimethyl-silanyloxy)-2,2- dimethyl-propyl ester as a yellow oil (24 g, 87%).
Step C To the solution of methanesulfonic acid 3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl- propyl ester (5 g, 16.8 mmol) in anhydrous dimethyl sulfoxide (50 mL) was added KCN (2.85 g, 44 mmol). The reaction mixture was heated at 120 °C for 16 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHC03 solution, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (EtOAc:hexanes = 1;4) to give 4- (tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butyronitrile as a yellow oil (2.2 g, 57%). Step D To a solution of 4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butyronitrile (2.2 g, 9.67 mmol) (Aldrich) in dichloromethane (20 niL) at -78 °C was added a toluene solution (1 M) of DIBAL (10.6 mL, 10.6 mmol) dropwise. The reaction mixture was stirred at 0 °C for 3 h. The mixture was poured into aqueous saturated NH4C1 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgS04, and concentrated. The residue was purifed by
chromatography (EtOAc:hexanes=l :4) to give 4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl- butyraldehyde as a colorless oil (Yield: 0.84 g, 38%). Step E In a manner similar to the method described in Example la, glycine tert-butyl ester (0.52 g, 3.64 mmol) was reacted with 4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butyraldehyde (0.84 g, 3.64 mmol) in CH2CI2 at room temperature for 18 h to give [4-(tert-butyl-dimethyl- silanyloxy)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.25 g, 100%).
Example 105b
Preparation of intermediate rac-(2R,3S,4R,5S)-5-[3-(tert-butyl-dimethyl-silanyloxy)-2,2- dimethyl-propyl]-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano- pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000182_0001
M. W. 653.72 C33H44Cl2F2N203Si
In a manner similar to the method described in Example 100b, [4-(tert-butyl-dimethyl- silanyloxy)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 105a (1.25 g, 3.64 mmol) was reacted with (Z)-3-(3-chloro-2-fiuoro-phenyl)-2-(4-chloro-2- fluoro-phenyl)-acrylonitrile (0.93 g, 3 mmol) prepared in Example 52a, AgF (0.57 g, 4.5 mmol), and triethylamine (1.05 mL, 7.5 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (3.6 ml) in tert-butanol (15 mL) at 100 °C for 2 h to give rac-(2R,3S,4R,5S)-5-[3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propyl]-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (1.2 g, 61%).
Example 105c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000183_0001
M. W. 483.35 C23H22CI2F2N2O3.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-[3-(tert- butyl-dimethyl-silanyloxy)-2,2-dimethyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 105b (l .lg, 1.68 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5- (3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1 g, 100%).
Example 105d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy- butyl)-amide
Figure imgf000183_0002
M. W. 570.46 C27H31CI2F2N3O4 In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl- propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 105c (1 g, 1.67 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.73 g, 5 mmol), HATU (1.14 g, 3 mmol) and iPr2NEt (1.46 mL, 8.4 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3- hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.3 g, 64%).
HRMS (ES+) m/z Calcd for C27H31CI2F2N3O4+ H [(M+H)+]: 570.1733, found: 570.1731.
Example 105e
Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy- butyl)-amide
Figure imgf000184_0001
M. W. 570.46 C27H31CI2F2N3O4
Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(3- hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (0.24 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl- propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (102 mg 43%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy- butyl)-amide as a white solid (93 mg, 39%>).
HRMS (ES+) m/z Calcd for C27H31CI2F2N3O4+ H [(M+H)+]: 570.1733, found: 570.1730.
Example 106a Preparation of intermediate [3,3-diethy -pent-(E)-ylideneamino]-acetic acid tert-butyl ester
Figure imgf000185_0001
M. W. 255.40 Ci5H29N02
Step A To a solution of dimethyl malonate (10 g, 75mmol), 3-pentanone (6.5 g, 75 mmol) and pyridine (7.9 g, 100 mmol) in anhydrous tetrahydrofuran (300 mL) at 0 °C was added a dichloromethane solution (1 M) of TiCl4 (100 mL, 100 mmol) during a period of 1 h. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 18 h. Water was added to quench the reaction. The mixture was extracted with ethyl ether. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, concentrated. The residue was purifed by chromatography
(EtOAc:hexanes=l ;20) to give 2-(l-ethyl-propylidene)-malonic acid dimethyl ester as a light yellow oil (7 g, 46%).
Step B To a suspension of Cul (7.61 g, 40 mmol) in anhydrous tetrahydrofuran (100 mL) at -50 °C was added ethylmagnesium chloride (2 M, 40 mL, 80 mmol) during a period of 15 min. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 20 min. Then the temperature of the mixture was lowered to -50 °C, a tetrahydrofuran solution (50 mL) of 2-(l-ethyl-propylidene)-malonic acid dimethyl ester (3.5 g, 17.5 mmol) was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 3 h. Aqueous saturated NH4C1 solution was added to quench the reaction. The mixture was filtered, and the filtrate was concentrated to remove most of tetrahydrofuran. The residue was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was purifed by chromatography (EtOAc:hexanes=l;30) to give 2-(l,l-diethyl-propyl)-malonic acid dimethyl ester as a colorless oil (2.6 g, 57%).
Step C To a solution of 2-(l,l-diethyl-propyl)-malonic acid dimethyl ester (2.5 g, 11 mmol) in DMSO (30 mL) was added LiCl (0.91 g, 21.6 mmol) and H20 (0.19 mL, 11 mmol). The reaction mixture was heated at 170 °C for 4 h, then poured into a ice-water, extracted with ethyl acetate. The organic layer were separated, washed with water, brine, dried over MgSC>4, and concentrated to give 3,3-diethyl-pentanoic acid methyl ester as a yellow oil (1.9 g, 100%).
Step D To a solution of 3,3-diethyl-pentanoic acid methyl ester (1.9 g, 11 mmol) in anhydrous tetrahydrofuran (50 mL) at 0 °C was added a tetrhydrofuran solution (2 M) of L1AIH4 (9 mL, 18 mmol) under nitrogen. The reaction mixture was stirred at 0 °C for 1 h, then poured into a ice- water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSC>4, and concentrated to give 3,3- diethyl-pentan-l-ol as a yellow oil (1.4 g, 90%).
Step E To a solution of oxalyl chloride (0.86 mL, 9.9 mmol) (Aldrich) in dichloromethane (20 mL) at -78 °C was added the solution of dimethyl sulfoxide (1.4 mL, 19.8 mmol) in
dichloromethane (5 mL) dropwise. After 5 mins, the solution of 3,3-diethyl-pentan-l-ol (1.3 g, 9 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 15 min. Triethylamine (4.5 mL, 32 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with
dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHC03, brine, dried over MgSC>4, and concentrated to give 3,3-diethyl-pentanal as a yellow oil (Yield: 1 g, 78%).
Step F In a manner similar to the method described in Example la, glycine tert-butyl ester (0.92 g, 7 mmol) was reacted with 3,3-diethyl-pentanal (1 g, 7 mmol) in CH2CI2 at room temperature for 5 h to give [3,3-diethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.8 g, 100%).
Example 106b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-diethyl-butyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000187_0001
M. W. 507.41 C26H26CI2F2N2O2
In a manner similar to the method described in Example 100b, [3,3-diethyl-pent-(E)- ylideneamino]-acetic acid tert-butyl ester prepared in Example 106a (1.8 g, 7 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.74 g, 5.6 mmol) prepared in Example 52a, AgF (1.1 g, 8.6mmol), and triethylamine (1.95 mL, 14 mmol) in dichloromethane (150 mL) at room temperature for 18 h, followed by the reaction with DBU (7 ml) in tert-butanol (30 mL) at 100 °C for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-diethyl-butyl)-pyrrolidine-2- carboxylic acid tert-butyl ester as a white gum (1.8 g, 57%).
Example 106c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dieth l-butyl)-pyrrolidine -2 -carboxylic acid trifluoroacetic acid
Figure imgf000187_0002
M. W. 509.43 C26H28CI2F2N2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-diethyl-butyl)-pyrrolidine-2- carboxylic acid tert-butyl ester prepared in Example 106b (1.8 g, 3.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-diethyl-butyl)-pyrrolidine- 2-carboxylic acid trifluoroacetic acid as a light yellow solid (2 g, 100%).
Example 106d Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-diethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000188_0001
M. W. 596.54 C30H37CI2F2N3O3
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-diethyl-butyl)-pyrrolidine-
2- carboxylic acid trifluoroacetic acid prepared in Example 106c (0.5 g, 0.8 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.35 g, 2.4 mmol), HATU (0.55 g, 1.4 mmol) and iP^NEt (0.7 mL, 4 mmol) in CH2CI2 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-
3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-diethyl-butyl)- pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.33 g, 70%). HRMS (ES+) m/z Calcd for C30H37CI2F2N3O3+ H [(M+H)+]: 596.2253, found: 596.2254.
Example 107a
Preparation of intermediate [3-ethyl-3-methyl-pent-(E)-ylid
mino]-acetic acid tert-butyl ester
Figure imgf000188_0002
Step A To a suspension of Cul (5.7 g, 30 mmol) in anhydrous tetrahydrofuran (100 mL) at -50 °C was added methylmagnesium chloride (3 M, 20 mL, 60 mmol) during a period of 15 min. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 20 min. Then the temperature of the mixture was lowered to -50 °C, a
tetrahydrofuran solution (20 mL) of 2-(l-ethyl-propylidene)-malonic acid dimethyl ester (3 g, 15 mmol) prepared in Example 106a Step A was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 1 h. Aqueous saturated NH4C1 solution was added to quench the reaction. The mixture was filtered, and the filtrate was concentrated to remove most of tetrahydrofuran. The residue was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was purifed by chromatography
(EtOAc:hexanes=l ;30) to give 2-(l-ethyl-l-methyl-propyl)-malonic acid dimethyl ester as a colorless oil (3 g, 93%).
Step B To a solution of 2-(l -ethyl- 1 -methyl-propyl)-malonic acid dimethyl ester (3 g, 14 mmol) in DMSO (30 mL) was added LiCl (1.2 g, 28 mmol) and H20 (0.25 mL, 14 mmol). The reaction mixture was heated at 170 °C for 3 h, then poured into a ice-water, extracted with ethyl acetate. The organic layer were separated, washed with water, brine, dried over MgS04, and concentrated to give 3-ethyl-3-methyl-pentanoic acid methyl ester as a yellow oil (1.5 g, 68%).
Step C To a solution of 3-ethyl-3-methyl-pentanoic acid methyl ester (1.5 g, 9.4 mmol) in anhydrous tetrahydrofuran (30 mL) at 0 °C was added a tetrhydrofuran solution (2 M) of LiAlH4 (5 mL, 10 mmol) under nitrogen. The reaction mixture was stirred at 0 °C for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgS04, and concentrated to give 3- ethyl-3-methyl-pentan-l-ol as a yellow oil (1.3 g, 100%>).
Step D To a solution of oxalyl chloride (0.96 mL, 11 mmol) (Aldrich) in dichloromethane (20 mL) at -78 °C was added the solution of dimethyl sulfoxide (1.56 mL, 22 mmol) in
dichloromethane (5 mL) dropwise. After 5 mins, the solution of 3-ethyl-3-methyl-pentan-l-ol (1.3 g, 10 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 15 min. Triethylamine (5 mL, 36 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHC03, brine, dried over MgS04, and concentrated to give 3-ethyl-3-methyl-pentanal as a light yellow oil (Yield: 1 g, 78%). Step E In a manner similar to the method described in Example la, glycine tert-butyl ester (1.0 g, 7.8 mmol) was reacted with 3-ethyl-3-methyl-pentanal (1 g, 7.8 mmol) in CH2CI2 at room temperature for 5 h to give [3-ethyl-3-methyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.9 g, 100%).
Example 107b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2-ethyl-2-methyl-butyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000190_0001
M. W. 551.51 C29H34CI2F2N2O2
In a manner similar to the method described in Example 100b, [3-ethyl-3-methyl-pent-(E)- ylideneamino]-acetic acid tert-butyl ester prepared in Example 107a (1.9 g, 7.8 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fiuoro-phenyl)-acrylonitrile (1.9 g, 6.2 mmol) prepared in Example 52a, AgF (1.2 g, 9.4 mmol), and triethylamine (2.1 mL, 15 mmol) in dichloromethane (150 mL) at room temperature for 18 h, followed by the reaction with DBU (7 ml) in tert-butanol (30 mL) at 100 °C for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-ethyl-2-methyl-butyl)-pyrrolidine-2- carboxylic acid tert-butyl ester as a light yellow gum (2.5 g, 74%).
Example 107c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2-ethyl-2-methyl-butyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000190_0002
M. W. 495.40 C25H26Cl2F2N202.C2HF302 In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-ethyl-2-methyl-butyl)-pyrrolidine-2- carboxylic acid tert-butyl ester prepared in Example 107b (1.8 g, 3.2 mmol) was reacted with trifluoro acetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-ethyl-2-methyl-butyl)- pyrrolidine-2-carboxylic acid trifluoro acetic acid as a light yellow solid (2.5 g, 91%).
Example 107d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2-ethyl-2-methyl-butyl)-p rrolidine -2 -carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000191_0001
M. W. 582.52 C29H35C12F2N303
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-ethyl-2-methyl-butyl)- pyrrolidine-2-carboxylic acid trifluoro acetic acid prepared in Example 106c (0.6 g, 1 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.43 g, 3 mmol), HATU (0.67 g, 1.8 mmol) and iPr2NEt (0.86 mL, 4.9 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac- (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2-ethyl-2- methyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.3 g, 53%).
HRMS (ES+) m/z Calcd for C29H35C12F2N303+ H [(M+H)+]: 582.2097, found: 582.2096.
Example 108a
Preparation of intermediate (Z)-2-(4-chloro-2,6-difluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)- acrylonitrile
Figure imgf000192_0001
M. W. 328.12 Ci5H6Cl2F3N
Step A To the solution of 4-chloro-2,6-difluorobenzyl bromide (Alfa) (2.5 g, 10 mmol) in ethanol (13 mL) and H20 (10 mL) was added KCN (1.75 g, 27 mmol). The reaction mixture was heated at 100 °C for 1 h. The mixture was cooled, and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHC03 solution, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (EtOAc:hexanes = 1;4) to give (4-chloro-2,6-difluoro-phenyl)-acetonitrile as a yellow oil (1.1 g, 57%). Step B In a manner similar to the method described in Example lb, (4-chloro-2,6-difiuoro- phenyl)-acetonitrile (1.1 g, 6 mmol) was reacted with 2-fiuoro-3-chlorobenzaldehyde (1.2 g, 7mmol), methanolic solution (25 wt%) of sodium methoxide (1.5 mL, 7 mmol) in methanol (40 mL) at 50 °C for 3 h to give (Z)-2-(4-chloro-2,6-difluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)- acrylonitrile as a white solid (1.5 g, 75%).
Example 108b
Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-phenyl)-3-(3-chloro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000192_0002
M. W. 505.46 C27H CI2FN2O2
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example la (1 g, 5 mmol) was reacted with (Z)-2-(4- chloro-2,6-difluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-acrylonitrile (1.3 g, 4mmol) prepared in Example 109a, AgF (0.77 g, 6 mmol), and triethylamine (1.4 mL, 10 mmol) in
dichloromethane (120 mL) at room temperature for 18 h, followed by the reaction with DBU (4.8 ml) in tert-butanol (20 mL) at 100 °C for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,6- difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxyl acid tert-butyl ester as a white gum (0.9 g, 41%).
Example 108c
Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-phenyl)-3-(3-chloro- phenyl)-4-cyano-5-(2,2-dimeth l-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000193_0001
M. W. 467.35 C23H22CI2F2N2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-4-(4-chloro- 2,6-difiuoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid tert-butyl ester prepared in Example 108b (0.9 g, 1.7 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4- chloro-2,6-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid as a white solid (0.9 g, 91%).
Example 108d
Preparation of rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-phenyl)-3-(3-chloro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrr lidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000193_0002
M. W. 572.45 C27H30CI2F2N3O3
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-4-(4- chloro-2,6-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 108c (0.4 g, 0.67 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.29 g, 2 mmol), HATU (0.46 g, 1.2 mmol) and iPr2NEt (0.58 mL, 3.3 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac- (2R,3R,4R,5S)-4-(4-chloro-2,6-difiuoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2 -dimethyl- propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.3 g, 77%).
HRMS (ES+) m/z Calcd for C27H30CI2F2N3O3+ H [(M+H)+]: 572.1689, found: 572.1691.
Example 109a
Preparation of intermediate (Z)-2-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)- acrylonitrile
Figure imgf000194_0001
M. W. 328.12 Ci5H6Cl2F3N
Step A To the solution of 4-chloro-2,5-difluorobenzoic acid (Oakwood) (6.08 g, 31 mmol) in anhydrous tetrahydrofuran (75 mL) at 0 °C was added a solution of BH3.THF (1 M, 62 mL, 62 mmol). The reaction mixture was stirred at room temperature for 18 h. Aqueous HC1 solution was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHC03 solution, brine, dried over MgS04, and concentrated to give (4-chloro-2,5-difiuoro-phenyl)-methanol as a colorless oil (5.5 g, 98%).
Step B A mixture of (4-chloro-2,5-difluoro-phenyl)-methanol (5.5 g, 32 mmol) in thionyl chloride (25 mL) was heated at refluxing (100 °C) for 30 min. The mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous NaHC03 solution, water, brine, dried over MgSC>4, and concentrated to give l-chloro-4- chloromethyl-2,5-difluoro-benzene as a yellow oil (2.1 g, 34%>).
Step C To the solution of l-chloro-4-chloromethyl-2,5-difluoro-benzene (2.1 g, 11 mmol) in ethanol (13 mL) and ¾0 (10 mL) was added KCN (1.8 g, 28 mmol). The reaction mixture was heated at 100 °C for 1 h. The mixture was cooled, and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHC03 solution, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (EtOAc:hexanes = 1;4) to give 4- chloro-2,5-difluoro-phenyl)-acetonitrile as a light yellow oil (1.0 g, 50%).
Step D In a manner similar to the method described in Example lb, 4-chloro-2,5-difluoro- phenyl)-acetonitrile (1.0 g, 5 mmol) was reacted with 2-fiuoro-3-chlorobenzaldehyde (1.0 g, 6 mmol), methanolic solution (25 wt%) of sodium methoxide (1.3 mL, 5.9 mmol) in methanol (40 mL) at 50 °C for 3 h to give (Z)-2-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)- acrylonitrile as a white solid (1.3 g, 75%).
Example 109b
Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000195_0001
M. W. 505.46 C27H31CI2FN2O2
In a manner similar to the method described in Example lc, [3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester prepared in Example la (5 mmol) was reacted with give (Z)-2-(4- chloro-2,5-difluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-acrylonitrile (1.3 g, 3 mmol) prepared in Example 109a, AgF (0.77 g, 6 mmol), and triethylamine (1.4 mL, 10 mmol) in
dichloromethane (120 mL) at room temperature for 18 h, followed by the reaction with DBU (4.8 ml) in tert-butanol (20 mL) at 100 °C for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,5- difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow gum (1.5 g, 69%>).
Example 109c
Preparation of intermediate rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000196_0001
M. W. 467.35 C23H22CI2F2N2O2.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-4-(4-chloro- 2,5-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid tert-butyl ester prepared in Example 109b (1.5 g, 2.8 mmol) was reacted with trifluoro acetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4- chloro-2,5-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid as a off white solid (1.5 g, 91%).
Example 109d
Preparation of rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000196_0002
M. W. 572.45 C27H30CI2F2N3O3
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5 S)-4-(4- chloro-2,5-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 108c (0.5 g, 0.84 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iP^NEt (0.73 mL, 4.2 mmol) in CH2CI2 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-
(2R,3R,4R,5S)-4-(4-chloro-2,5-difiuoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl- propyl)-pyrrolidine -2 -carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.3 g, 50%).
HRMS (ES+) m/z Calcd for C27H30CI2F2N3O3+ H [(M+H)+]: 572.1689, found: 572.1689. Example 110a
Preparation of intermediate [4-methoxy-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert- butyl ester
Figure imgf000197_0001
M. W. 243.35 Ci3H25N03
Step A A mixture of 2,2-dimethyl-propane-l,3-diol (Aldrich) (5 g, 48 mmol) in anhydrous ethyl ether (100 mL) at 0 °C was added thionyl chloride (8.7 mL, 120 mmol). The reactiom mixture was stirred at 0 °C for 2 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with ethyl ether. The combined organic layers wer washed with saturated aqueous NaHC03 solution, brine, dried over MgS04, concentrated to give 5,5-dimethyl- [l,3,2]dioxathiane 2-oxide as a light pink oil (4.8 g, 82%).
Step B To the solution of 5,5-dimethyl-[l ,3,2]dioxathiane 2-oxide (4.8 g, 39 mmol) in anhydrous dimethyl sulfoxide (50 mL) was added NaCN (5.8 g, 118 mmol). The reaction mixture was heated at 120 °C for 5 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHC03 solution, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (EtOAc:hexanes = 1;4) to give 4-hydroxy-3,3-dimethyl-butyronitrile as a yellow oil (1.6 g, 38%).
Step C To the solution of 4-hydroxy-3,3-dimethyl-butyronitrile (0.8 g, 7 mmol) in anhydrous dimethylformamide (5 mL) was added NaH (60%, 0.42 g, 11 mmol). The mixture was stirred at room temperature for 15 min, then iodomethane (0.88 mL, 14 mmol) was added. The mixture was stiired at room temperature for 1 h. Water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over MgS04, and concentrated to give 4-methoxy-3,3-dimethyl-butyronitrile as a yellow oil (0.85 g, 94%). Step D To a solution of 4-methoxy-3,3-dimethyl-butyronitrile (0.85 g, 6.7 mmol) in dichloromethane (20 mL) at -78 °C was added a toluene solution (1 M) of DIBAL (7.4 mL, 7.4 mmol) dropwise. The reaction mixture was stirred at 0 °C for 1 h. The mixture was poured into aqueous saturated NH4C1 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgS04, and concentrated to give 4-methoxy-3,3-dimethyl-butyraldehyde as a colorless oil (Yield: 0.3 g, 34%).
Step E In a manner similar to the method described in Example la, glycine tert-butyl ester (0.3 g, 2.3 mmol) was reacted with 4-methoxy-3,3-dimethyl-butyraldehyde (0.3 g, 2.3 mmol) in CH2CI2 at room temperature for 18 h to give [4-methoxy-3,3-dimethyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester as a colorless oil (0.56 g, 100%).
Example 110b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert- butyl ester
Figure imgf000198_0001
M. W. 553.48 C28H32CI2F2N2O3
In a manner similar to the method described in Example 100b, [4-methoxy-3,3-dimethyl-but- (E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 110a (3.8 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fiuoro-phenyl)-acrylonitrile (0.94 g, 3 mmol) prepared in Example 52a, AgF (0.58 g, 4.6 mmol), and triethylamine (1.06 mL, 7.6 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (3.6 ml) in tert-butanol (20 mL) at 100 °C for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow solid (1 g, 59%>). Example 110c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifiuoro acetic acid
Figure imgf000199_0001
M. W. 497.37 C24H24CI2F2N2O3.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 105b (1.0 g, 1.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-
(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(3- methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow solid (0.9 g, 82%).
Example HOd
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy- butyl)-amide
Figure imgf000199_0002
M. W. 584.49 C28H33CI2F2N3O4
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl- propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 110c (0.45 g, 0.74 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.32 g, 2.2 mmol), HATU (0.5 g, 1.3 mmol) and iP^NEt (0.64 mL, 3.7 mmol) in CH2CI2 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)- 3,4-dihydroxy-butyl)-amide as a white solid (0.28 g, 65%).
HRMS (ES+) m/z Calcd for C28H33CI2F2N3O4+ H [(M+H)+]: 584.1889, found: 584.1890.
Example llOe
Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy- butyl)-amide
Figure imgf000200_0001
M. W. 584.49 C28H33CI2F2N3O4
Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(3- methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (0.24 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl- propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (114 mg, 48%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy- butyl)-amide as a white solid (114 mg, 48%>).
HRMS (ES+) m/z Calcd for C28H33CI2F2N3O4+ H [(M+H)+]: 584.1889, found: 584.1892.
Example 111a
Preparation of intermediate 3-(tert-butyl-dimethyl-silanyloxymethyl)-3-ethyl-pent-(E)- ylideneamino]-acetic acid tert-butyl ester
Figure imgf000201_0001
M. W. 371.64 C20H41NO3S1
Step A A mixture of 2,2-diethyl-propane-l,3-diol (Aldrich) (5.5 g, 40 mmol) in anhydrous ethyl ether (100 mL) at 0 °C was added thionyl chloride (10.6 g, 90 mmol). The reactiom mixture was stirred at 0 °C for 2 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with ethyl ether. The combined organic layers wer washed with saturated aqueous NaHC03 solution, brine, dried over MgSC>4, concentrated to give 5,5-diethyl-[l ,3,2]dioxathiane 2-oxide as a colorless oil (7 g, 98%). Step B To the solution of 5,5-diethyl-[l ,3,2]dioxathiane 2-oxide (7 g, 39 mmol) in anhydrous dimethyl sulfoxide (40 mL) was added NaCN (3.9 g, 80mmol). The reaction mixture was heated at 120 °C for 20 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHC03 solution, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (EtOAc:hexanes = 1;2) to give 3-ethyl-3-hydroxymethyl-pentanenitrile as a yellow oil (1.7 g, 31%).
Step C To the solution of 3-ethyl-3-hydroxymethyl-pentanenitrile (1.7 g, 12 mmol) and imidazole (1.2 g, 18 mmol) in dichloromethane (80 mL) was added tert- butyldimethylchlorosilane (2 g, 13 mmol). The reactiom mixture was stirred at room temperature for 2 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with dichloromethane. The combined organic layers wer washed with brine, dried over MgS04, concentrated to give 3-(tert-butyl-dimethyl-silanyloxymethyl)-3-ethyl-pentanenitrile as a colorless oil (2.28 g, 74%). Step D To a solution of 3-(tert-butyl-dimethyl-silanyloxymethyl)-3-ethyl-pentanenitrile (2.28 g, 8.9 mmol) in dichloromethane (20 mL) at -78 °C was added a toluene solution (1 M) of DIBAL (9.8 mL, 9.8 mmol) dropwise. The reaction mixture was stirred at 0 °C for 1 h. The mixture was poured into aqueous saturated NH4C1 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSC>4, and concentrated to give 3-(tert-butyl-dimethyl-silanyloxymethyl)-3-ethyl- pentanal as a colorless oil (Yield: 1.5 g, 65%).
Step E In a manner similar to the method described in Example la, glycine tert-butyl ester (0.78 g, 5.8 mmol) was reacted with 3-(tert-butyl-dimethyl-silanyloxymethyl)-3-ethyl-pentanal (1.5 g, 5.8 mmol) in CH2CI2 at room temperature for 18 h to give [4-methoxy-3,3-dimethyl-but-(E)- ylideneamino]-acetic acid tert-butyl ester as a colorless oil (2.2 g, 100%).
Example 111b
Preparation of intermediate rac-(2R,3S,4R,5S)-5-[2-(tert-butyl-dimethyl-silanyloxymethyl)-2- ethyl-butyl]-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-pyrrolidine-2- carboxylic acid tert-butyl ester
Figure imgf000202_0001
M. W. 681.77 C35H48Cl2F2N203Si
In a manner similar to the method described in Example 100b, give [4-(tert-butyl-dimethyl- silanyloxy)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 111a (2.2 g, 5.8 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro- phenyl)-acrylonitrile (1.43 g, 4.6 mmol) prepared in Example 52a, AgF (0.89 g, 7 mmol), and triethylamine (1.6 mL, 12 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (7 ml) in tert-butanol (20 mL) at 100 °C for 2 h to give rac- (2R,3S,4R,5S)-5-[2-(tert-butyl-dimethyl-silanyloxymethyl)-2-ethyl-butyl]-3-(3-chloro-2-fiuoro- phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow solid (1.8 g, 58%).
Example 111c Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2-ethyl-2-hydroxymethyl-butyl)-pyrrolidine-2-carboxylic acid trifiuoro acetic acid
Figure imgf000203_0001
M. W. 511.40 C25H26Cl2F2N203.C2HF302
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-[2-(tert- butyl-dimethyl-silanyloxymethyl)-2-ethyl-butyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 111b (1.8 g, 2.6 mmol) was reacted with trifiuoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5- (2-ethyl-2-hydroxymethyl-butyl)-pyrrolidine-2-carboxylic acid trifiuoroacetic acid as a light yellow solid (1.5 g, 94%).
Example llld
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5 -(2-ethyl-2-hydroxymethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy- butyl)-amide
Figure imgf000203_0002
M. W. 598.51 C29H35Cl2F2N304
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-ethyl-2-hydroxymethyl- butyl)-pyrrolidine-2-carboxylic acid trifiuoroacetic acid prepared in Example 111c (1.1 g, 1.8 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.78 g, 5 mmol), HATU (1.2 g, 3 mmol) and iP^NEt (1.6 mL, 9 mmol) in CH2CI2 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2- ethyl-2-hydroxymethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.11 g, 10%).
HRMS (ES+) m/z Calcd for C29H35Cl2F2N304+ H [(M+H)+]: 598.2046, found: 598.2045.
Example 112a
Preparation of intermediate [2-(3-methyl-oxetan-3-yl)-eth-(E)-ylideneamino]-acetic acid tert- butyl ester
Figure imgf000204_0001
M. W. 227.31 Ci2H2iN03
Step A To a solution of 3-methyl-3-oxetanemethanol (Aldrich) (3.5 g, 34 mmol) and
triethylamine (10 g, 103 mmol) in dichloromethane (100 mL) at 0 °C was added a
dichlormethane solution (20 mL) of methanesulfonyl chloride (Aldrich) (5.08 g, 45 mmol). The reaction mixture was stirred at 0 °C for 2 h. Water was added. Organic layer was separated, the aqueous layer was extracted with dichlormethane. The combined organic layers were washed with diluted aqueous HC1 solution, saturated aqueous NaHC03 solution, brine, dried over MgS04, and concentrated to give methanesulfonic acid 3-methyl-oxetan-3-ylmethyl ester as a yellow oil (6 g, 97%).
Step B To the solution of methanesulfonic acid 3-methyl-oxetan-3-ylmethyl ester (6 g, 33 mmol) in anhydrous dimethyl sulfoxide (30 mL) was added NaCN (3.2 g, 67 mmol). The reaction mixture was heated at 130 °C for 3 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHC03 solution, brine, dried over MgS04, and concentrated to give (3- methyl-oxetan-3-yl)-acetonitrile as a yellow oil (2.5 g, 68%). Step C To a solution of (3-methyl-oxetan-3-yl)-acetonitrile (2.5 g, 22.5 mmol) in dichloromethane (30 niL) at -78 °C was added a toluene solution (1 M) of DIBAL (24.7 niL, 24.7 mmol) dropwise. The reaction mixture was stirred at 0 °C for 3 h. The mixture was poured into aqueous saturated NH4C1 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgS04, and concentrated to give (3-methyl-oxetan-3-yl)-acetaldehyde as a colorless oil (Yield: 0.8 g, 31%).
Step D In a manner similar to the method described in Example la, glycine tert-butyl ester (0.92 g, 7 mmol) was reacted with (3-methyl-oxetan-3-yl)-acetaldehyde (0.8 g, 7 mmol) in CH2CI2 at room temperature for 18 h to give [2-(3-methyl-oxetan-3-yl)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester
as a colorless oil (1.6 g, 100%). Example 112b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000205_0001
M. W. 537.44 C27H28CI2F2N2O3
In a manner similar to the method described in Example 100b[2-(3-methyl-oxetan-3-yl)-eth-(E)- ylideneamino]-acetic acid tert-butyl ester prepared in Example 112a (1.6 g, 7 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fiuoro-phenyl)-acrylonitrile (1.7 g, 5.6 mmol) prepared in Example 52a, AgF (1.1 g, 8.5 mmol), and triethylamine (1.9 mL, 14 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (6.7 ml) in tert-butanol (20 mL) at 100 °C for 2 h to rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)- pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow gum (1.0 g, 33%). Example 112 c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000206_0001
M. W. 481.33 C23H20CI2F2N2O3.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)- pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 112b (1.0 g, 1.9 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac- (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methyl- oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1 g, 91%).
Example 112d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)- amide
Figure imgf000206_0002
M. W. 568.45 C27H29CI2F2N3O4
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)- pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 112c (0.5 g, 0.84 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iPr2NEt (0.73 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3- methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.23 g, 48%).
HRMS (ES+) m/z Calcd for C27H29C12F2N304+ H [(M+H)+]: 568.1576, found: 568.1579.
Example 113 a
Preparation of intermediate [2-(3-ethyl-oxetan-3-yl)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester
Figure imgf000207_0001
Step A In a manner similar to the methods described in Example 112a Step A. Step B., and
Step C, 3-ethyl-3-oxetanemethanol (TCI-US) (3.5 g, 30 mmol) was reacted with triethylamine (6.6 g, 60 mmol) and treated with NaCN (2.2 g, 46mmol) in anhydrous dimethyl sulfoxide at 130 °C, followed by the reaction with DIBAL (1 M in heptane, 27 mL, 27 mmol) in dichloromethane at 0 °C to give (3-ethyl-oxetan-3-yl)-acetaldehyde as a light yellow oil (Yield: 2.5 g, 26% for three steps). Step B In a manner similar to the method described in Example la, glycine tert-butyl ester (1 g, 7.8 mmol) was reacted with (3-ethyl-oxetan-3-yl)-acetaldehyde (1 g, 7.8 mmol) in CH2C12 at room temperature for 18 h to give [2-(3-ethyl-oxetan-3-yl)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a yellow oil (1.9 g, 100%>). Example 113 b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000208_0001
M. W. 551.41 C28H30CI2F2N2O3
In a manner similar to the method described in Example 100b, [2-(3-ethyl-oxetan-3-yl)-eth-(E)- ylideneamino]-acetic acid tert-butyl ester prepared in Example 113a (1.9 g, 7.8 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.9 g, 6.2 mmol) prepared in Example 52a, AgF (1.2 g, 9.5 mmol), and triethylamine (2.2 mL, 16 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (7.5 ml) in tert-butanol (10 mL) at 100 °C for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine- 2-carboxylic acid tert-butyl ester
as a white solid (2 g, 58%).
Example 113 c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine -2-carboxylic acid
trifiuoro acetic acid
Figure imgf000208_0002
M. W. 495.36 C24H22CI2F2N2O3.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine- 2-carboxylic acid tert-butyl ester prepared in Example 113b (2 g, 3.6 mmol) was reacted with trifiuoro acetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)- pyrrolidine-2-carboxylic acid trifiuoro acetic acid as a white solid (2 g, 91%). Example 113 d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(3-ethyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)- amide
Figure imgf000209_0001
M. W. 582.47 C28H3 iCl2F2N304
In a manner similar to the method described in Examples 42c and 42d rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-ethyl-oxetan-3-ylmethyl)- pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 105c (1 g, 1.6 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.7 g, 5 mmol), HATU (1.1 g, 3 mmol) and iPr2NEt (1.4 mL, 8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac- (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(3-ethyl- oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.56 g, 58%).
HRMS (ES+) m/z Calcd for C28H3iCl2F2N304+ H [(M+H)+]: 582.1733, found: 582.1732.
Example 114a
Preparation of intermediate [2-[l-(tert-tutyl-dimethyl-silanyloxymethyl)-cyclopropyl]-eth-(E)- ylideneamino]-acetic acid tert-butyl
Figure imgf000209_0002
M. W. 341.57 Ci8H35N03Si
Step A In a manner similar to the methods described in Example 111a Step A. Step B., Step C, and Step D., l ,l-bis(hydroxymethyl)-cyclopropane (Aldrich) (4 g, 39 mmol) was reacted with thionyl chloride (14 g, 126 mmol) in anhydrous ethyl ether at 0 °C, then reacted with NaCN (2.4 g, 49 mmol) in anhydrous dimethyl sulfoxide 120 °C for 18 h, then treated with tert- butyldimethylchlorosilane (1.4 g, 9 mmol) and imidazole (0.85 g, 13 mmol) in dichloromethane at room temperature, follone by the reaction with DIBAL (1 M in heptane, 8.3 mL, 8.3 mmol) at 0 °C to give [l-(tert-butyl-dimethyl-silanyloxymethyl)-cyclopropyl]-acetaldehyde as a colorless oil (Yield: 1.3 g, 15% for four steps).
Step B In a manner similar to the method described in Example la, glycine tert-butyl ester (0.75 g, 5.7 mmol) was reacted with [l-(tert-butyl-dimethyl-silanyloxym
ethyl)-cyclopropyl]-acetaldehyde (1.3 g, 5.7 mmol) in CH2CI2 at room temperature for 18 h to give [2-[l -(tert-tutyl-dimethyl-silanyloxymethyl)-cyclopropyl]-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.9 g, 100%).
Example 114b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(l-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000210_0001
M. W. 537.44 C27H28CI2F2N2O3
In a manner similar to the method described in Example 100b, [2-[l-(tert-tutyl-dimethyl- silanyloxymethyl)-cyclopropyl]-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 114a (1.9 g, 5.7 mmol) was reacted with (Z)-3-(3-chloro-2-fiuoro-phenyl)-2-(4- chloro-2-fluoro-phenyl)-acrylonitrile (1.4 g, 4.6 mmol) prepared in Example 52a, AgF (0.89 g, 7.1 mmol), and triethylamine (1.6 mL, 12 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (5 ml) in tert-butanol (20 mL) at 100 °C for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)- 4-cyano-5-(l-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (0.4 g, 30%). Example 114c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(l-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid trifiuoro acetic acid
Figure imgf000211_0001
M. W. 481.33 C23H20CI2F2N2O3.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(l-hydroxymethyl-cyclopropylmethyl)- pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 114b (0.4 g, 0.74 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac- (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(l- hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.4 g, 91%).
Example 114d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phi cyano-5 -( 1 -hydro xymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4- dihydroxy-butyl)-amide
Figure imgf000211_0002
M. W. 568.45 C27H29CI2F2N3O4
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(l-hydroxymethyl- cyclopropylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 114c (0.4 g, 0.67 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.29 g, 2 mmol), HATU (0.46 g, 1.2 mmol) and iPr2NEt (0.58 niL, 3.4 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(l-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.15 g, 40%).
HRMS (ES+) m/z Calcd for C27H29C12F2N304+ H [(M+H)+]: 568.1576, found: 568.1578.
Example 114e
Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl) cyano-5 -( 1 -hydro xymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4- dihydroxy-butyl)-amide
Figure imgf000212_0001
M. W. 568.45 C27H29C12F2N304
Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(l- hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy-butyl)- amide (0.12 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(l-hydroxymethyl- cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (46 mg, 38%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(l-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid ((S)- 3,4-dihydroxy-butyl)-amide as a white solid (48 mg, 40%>).
HRMS (ES+) m/z Calcd for C27H29C12F2N304+ H [(M+H)+]: 568.1576, found: 568.1578.
Example 115a
Preparation of intermediate [2-[l-(tert-tutyl-dimethyl-silanyloxymethyl)-cyclobutyl]-eth-(E)- ylideneamino]-acetic acid tert-butyl ester
Figure imgf000213_0001
M. W. 355.60 C19H37NO3S1
Step A In a manner similar to the methods described in Example 111a Step A. Step B., Step C, and Step D., l ,l-bis(hydroxymethyl)-cyclobutane (Waterstone) (3.8 g, 33 mmol) was reacted with thionyl chloride (8 g, 72 mmol) in anhydrous ethyl ether at 0 °C, then reacted with NaCN (2 g, 41 mmol) in anhydrous dimethyl sulfoxide 120 °C for 18 h, then treated with tert- butyldimethylchlorosilane (1 g, 6 mmol) and imidazole (1 g, 15 mmol) in dichloromethane at room temperature, follone by the reaction with DIBAL (1 M in heptane, 6.4 mL, 6.4 mmol) at 0 °C to give [l-(tert-butyl-dimethyl-silanyloxym
ethyl)-cyclobutyl]-acetaldehyde as a colorless oil (Yield: 0.48 g, 6% for four steps).
Step B In a manner similar to the method described in Example la, glycine tert-butyl ester (0.26 g, 2 mmol) was reacted with [l-(tert-butyl-dimethyl-silanyloxym
ethyl)-cyclobutyl]-acetaldehyde (0.48 g, 2 mmol) in CH2CI2 at room temperature for 18 h to give [2-[l-(tert-tutyl-dimethyl-silanyloxymethyl)-cyclopropyl]-eth-(E)-ylideneamino]-acetic acid tert- butyl ester as a colorless oil (0.71 g, 100%).
Example 115b
Preparation of intermediate rac-(2R,3S,4R,5S)-5-[l -(tert-butyl-dimethyl-silanyloxymethyl)- cyclobutylmethyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano- pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000213_0002
M. W. 665.73 C34H44CI2F2N2O3S1 In a manner similar to the method described in Example 100b, [2-[l-(tert-tutyl-dimethyl- silanyloxymethyl)-cyclopropyl]-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 115a (0.71 g, 2 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro- 2-fluoro-phenyl)-acrylonitrile (0.49 g, 1.6 mmol) prepared in Example 52a, AgF (0.3 g, 2.4 mmol), and triethylamine (0.55 mL, 4 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (1 ml) in tert-butanol (15 mL) at 100 °C for 2 h to give rac-(2R,3S,4R,5S)-5-[l-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutylmethyl]-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert- butyl ester as a yellow gum (0.7 g, 67%).
Example 115c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(l-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid trifiuoro acetic acid
Figure imgf000214_0001
M. W. 495.36 C24H22CI2F2N2O3.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-[l-(tert- butyl-dimethyl-silanyloxymethyl)-cyclobutylmethyl]-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro- 2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 115b (0.7 g, 1 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(l-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.6 g, 100%). Example 115d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5 -( 1 -hydro xymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy- butyl)-amide
Figure imgf000215_0001
M. W. 582.48 C28H31CI2F2N3O4
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(l-hydroxymethyl- cyclobutylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 115c (0.6 g, 1 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.43 g, 3 mmol), HATU (0.67 g, 1.8 mmol) and iPr2NEt (0.86 mL, 4.9 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(l-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.32 g, 56%).
HRMS (ES+) m/z Calcd for C28H31CI2F2N3O4+ H [(M+H)+]: 582.1733, found: 582.1733.
Example 115e
Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5 -( 1 -hydro xymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy- butyl)-amide
Figure imgf000215_0002
M. W. 582.48 C28H31CI2F2N3O4
Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(l- hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy-butyl)- amide (0.25 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(l-hydroxymethyl- cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (104 mg, 41%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(l-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (103 mg, 41%).
HRMS (ES+) m/z Calcd for C28H31CI2F2N3O4+ H [(M+H)+]: 582.1733, found: 582.1733.
Example 116a
Preparation of intermediate [5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pent-(E)- ylideneamino]-acetic acid methyl ester
Figure imgf000216_0001
M. W. 315.53 Ci6H33N03Si
Step A To the solution of 3,3-dimethylglutaric acid (Aldrich) (5.1 g, 32 mmol) in anhydrous tetrahydrofuran (100 niL) at 0 °C was added a solution of BH3.THF (1 M, 100 mL, 100 mmol). The reaction mixture was stirred at room temperature for 18 h. Aqueous HCl solution was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHC03 solution, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (EtOAc) to give 3,3-dimethyl-pentane-l ,5-diol as a colorless oil (1.5 g, 34%).
Step B A mixture of 3,3-dimethyl-pentane-l,5-diol (1.5 g, 11 mmol) and imidazole (1.4 g, 20 mmol) in dichloromethane (50 mL) was added tert-butyldimethylchlorosilane (1.7 g, 1 1 mmol). The reactiom mixture was stirred at room temperature for 2 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with dichloromethane. The combined organic layers wer washed with brine, dried over MgS04, concentrated to give 5-(tert-butyl- dimethyl-silanyloxy)-3,3-dimethyl-pentan-l-ol as a colorless oil (2.7 g, 100%). Step C To a solution of oxalyl chloride (0.97 mL, 11 mmol) (Aldrich) in dichloromethane (20 mL) at -78 °C was added the solution of dimethyl sulfoxide (1.6 mL, 22 mmol) in
dichloromethane (5 mL) dropwise. After 5 mins, the solution of 5-(tert-butyl-dimethyl- silanyloxy)-3,3-dimethyl-pentan-l-ol (2.5 g, 10 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 15 min. Triethylamine (5 mL, 36mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHC03, brine, dried over MgSC^, and concentrated to give 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentanal as a light yellow oil (Yield: 1.75 g, 71%).
Step D In a manner similar to the method described in Example la, glycine methyl ester hydrochloride (0.9 g, 7.2 mmol) was reacted with 5-(tert-butyl-dimethyl-silanyloxy)-3,3- dimethyl-pentanal (1.75 g, 7.2 mmol) and triethylamine (1.49 mL, 11 mmol) in CH2CI2 at temperature for 18 h to give [4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-(E)- ylideneamino]-acetic acid methyl ester as a colorless oil (2.3 g, 100%>). Example 116b
Preparation of intermediate rac-(2R,3S,4R,5S)-5-[4-(tert-tutyl-dimethyl-silanyloxy)-2,2- dimethyl-butyl]-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-pyrrolidine- 2-carboxylic acid methyl ester
Figure imgf000217_0001
M. W. 625.66 C31H40CI2F2N2O3S-
In a manner similar to the method described in Example lc, [5-(tert-butyl-dimethyl-silanyloxy)- 3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid methyl ester prepared in Example 116a (6.4 mmol) was reacted with (Z)-3-(3-chloro-2-fiuoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)- acrylonitrile (1.58 g, 5.1 mmol) prepared in Example 52a, AgF (lg, 7.8 mmol), and
triethylamine (1.8 mL, 13 mmol) in dichloromethane (100 mL) at room temperature for 48 h to give rac-(2R,3S,4R,5S)-5-[4-(tert-tutyl-dimethyl-silanyloxy)-2,2-dimethyl-butyl]-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine -2-carboxylic acid methyl ester as a yellow gum (1.6 g, 50%>). Example 116c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(4-hydrox -2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid
Figure imgf000218_0001
M. W. 483.35 C23H22CI2F2N2O3
To rac-(2R,3S,4R,5S)-5-[4-(tert-mtyl-dimethyl-silanyloxy)-2,2-dimethyl-butyl]-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid methyl ester prepared in Example 116b (0.7 g, 1.1 mmol) in tetrahydrofuran (10 mL) was added
tetrahydrofuran solution (1 M, Aldrich) of TBAF (1.34 mL, 1.3 mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated, the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over MgSC>4, and concentrated. The residue was dissolved into tetrahydrofuran (10 mL), and an aqueous solution (1 M) of LiOH (10 mL, 10 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The "pH" of the mixture was adjusted to -4-5 by aqueous HCl solution. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgS04, concentrated to give intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid
as a light yellow solid (0.3 g, 54%)
Example 116d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy- butyl)-amide
Figure imgf000218_0002
M. W. 584.49 C28H33CI2F2N3O4
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl- butyl)-pyrrolidine-2-carboxylic acid
prepared in Example 116c (0.18 g, 0.36 mmol) was reacted with 2-((S)-2,2-dimethyl-
[l,3]dioxolan-4-yl)-ethylamine (0.16 g, 1 mmol), HATU (0.25 g, 0.65 mmol) and iPr2NEt (0.07 mL, 0.43 mmol) in CH2CI2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro- phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2- carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 54%).
HRMS (ES+) m/z Calcd for C28H33CI2F2N3O4+ H [(M+H)+]: 584.1889, found: 584.1889.
Example 116e
Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy- butyl)-amide
Figure imgf000219_0001
M. W. 584.49 C28H33CI2F2N3O4
Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(4- hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)- amide(0.35 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl- butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (157 mg, 45%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy- butyl)-amide as a white solid (155 mg, 44%>).
HRMS (ES+) m/z Calcd for C28H33CI2F2N3O4+ H [(M+H)+]: 584.1889, found: 584.1891. Example 117a
Preparation of intermediate [2-[l-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enyl]-eth- (E)-ylideneamino]-acetic acid tert-butyl ester
Figure imgf000220_0001
M. W. 381.64 C21H39NO3S1
Step A In a manner similar to the methods described in Example 111a Step A. Step B., Step C, and Step D., 3-cyclohexene-l ,l-dimethanol (Aldrich) (5.3 g, 37 mmol) was reacted with thionyl chloride (15 g, 135 mmol) in anhydrous ethyl ether at 0 °C, then reacted with NaCN (3 g, 61 mmol) in anhydrous dimethyl sulfoxide 120 °C for 18 h, then treated with tert- butyldimethylchlorosilane (3.9 g, 26 mmol) and imidazole (2.4 g, 36 mmol) in dichloromethane at room temperature, follone by the reaction with DIBAL (1 M in heptane, 26 mL, 26 mmol) at 0 °C to give l-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enecarbaldehyde as a light yellow oil (Yield: 6 g, 64% for four steps).
Step B In a manner similar to the method described in Example la, glycine tert-butyl ester (1.2 g, 9 mmol) was reacted with l-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3- enecarbaldehyde (2.5 g, 9 mmol) in CH2CI2 at room temperature for 18 h to give [2-[l-(tert- butyl-dimethyl-silanyloxymethyl)-cyclohex-3 -enyl]-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a light yellow oil (3.5 g, 100%).
Example 117b
Preparation of intermediate rac-(2R,3S,4R,5S)-5-[l -(tert-butyl-dimethyl-silanyloxymethyl)- cyclohex-3-enylmethyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano- pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000221_0001
M. W. 691.77 C36H46Cl2F2N203Si
In a manner similar to the method described in Example 100b, [2-[l-(tert-butyl-dimethyl- silanyloxymethyl)-cyclohex-3-enyl]-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 117a (3.5 g, 9 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4- chloro-2-fluoro-phenyl)-acrylonitrile (2.3 g, 7 mmol) prepared in Example 52a, AgF (1.4 g, 11 mmol), and triethylamine (2.6 mL, 19 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (9 ml) in tert-butanol (10 mL) at 100 °C for 2 h to give rac-(2R,3S,4R,5S)-5-[l-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enylmethyl]-3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (2.6 g, 51%).
Example 117c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(l-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000221_0002
M. W. 521.40 C26H24C12F2N203.C2HF302
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-[l-(tert- butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enylmethyl]-3-(3-chloro-2-fiuoro-phenyl)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in
Example 117b (2.6 g, 3.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(l-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.2 g, 92%). Example 117d
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(l-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethyl]-amide
Figure imgf000222_0001
M. W. 648.58 C33H37C12F2N304
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(l -hydro xymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid trifiuoroacetic acid prepared in Example 117c (1 g, 1.6 mmol), HATU (1.07 g, 2.8 mmol) and iPr2NEt (1.37 mL, 7.8 mmol) in CH2C12 (10 mL) was stirred at room temperature for 18 h. The mixture was then diluted with CH2C12 and washed with water, brine. The organic layer was separated, the aqueous layer was extracted with CH2C12. The organic layers were combined, and concentrated. The residue was dissolved into tetrahydrofuran (5 mL), and aqueous saturated K2C03 (5 mL) was added. The mixture was stirred at room temperature for 30 min, then partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSC>4 and concentrated. The residue was purified by flash chromatography (EtOAc) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(l- hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl- [1 ,3]dioxolan-4-yl)-ethyl]-amide as a white solid (0.48 g, 47%)
Example 117e
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(l -hydro xymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4- dihydroxy-butyl)-amide
Figure imgf000223_0001
M. W. 608.51 C30H33CI2F2N3O4
In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(l-hydroxymethyl-cyclohex-3- enylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 117d (0.2 g, 0.3 mmol) was reacted with aqueous HCl solution (1 N, ImL, 1 mol) in tetrahydrofuran (9 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(l-hydroxymethyl-cyclohex-3- enylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.14 g, 75%).
HRMS (ES+) m/z Calcd for C30H33CI2F2N3O4+ H [(M+H)+]: 608.1889, found: 608.1888.
Example 118a
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(l-hydroxymethyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2 ,2-dimethyl- [ 1 ,3 ]dioxolan- -yl)-ethyl] -amide
Figure imgf000223_0002
M. W. 650.60 C33H39CI2F2N3O4
To a solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(l -hydro xymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2- dimethyl-[l ,3]dioxolan-4-yl)-ethyl]-amide (0.28 g, 0.43 mmol) prepared in Example 117d in ethyl acetate (10 mL) was added PtC (0.1 g). The suspension was shaken vigorously under H2 atmosphere (50 psi) for 1 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(l -hydroxymethyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)- 2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethyl]-amide as a white solid (0.27 g, 96%)
Example 118b
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(l-hydroxymethyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy- butyl)-amide
Figure imgf000224_0001
M. W. 610.51 C3oH35Cl2F2N304
In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(l-hydroxymethyl-cyclohexylmethyl)- pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 118a (0.27 g, 0.4 mmol) was reacted with aqueous HC1 solution (1 N, lmL, 1 mol) in tetrahydrofuran (9 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(l-hydroxymethyl-cyclohexylmethyl)- pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.23 g, 91%). HRMS (ES+) m/z Calcd for C3oH35Cl2F2N304+ H [(M+H)+]: 610.2046, found: 610.2042.
Example 119a
Preparation of intermediate [5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pent- (E)-ylideneamino]-acetic acid tert-butyl ester
Figure imgf000224_0002
M. W. 401.67 C2iH43N04Si Step A To the solution of 3,3-dimethyl-pentane-l,5-diol (1.5 g, 11 mmol) prepared in Example 116a Step A. in anhydrous dimethylformamide (15 mL) was added NaH (60%, 0.68 g, 17 mmol). The mixture was stirred at room temperature for 15 min, then (2-bromoethoxy)-tert- butyldimethylsilane (3.3 g, 14 mmol) was added. The mixture was stiired at room temperature for 1 h. Water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over MgS04, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=l :3) to give 5-[2-(tert-butyl-dimethyl-silanyloxy)- ethoxy]-3,3-dimethyl-pentan-l-ol as a yellow oil (0.3 g, 9%>). Step B To a solution of oxalyl chloride (0.1 mL, 1 mmol) (Aldrich) in dichloromethane (5 mL) at -78 °C was added the solution of dimethyl sulfoxide (0.16 mL, 2.2 mmol) in dichloromethane (1 mL) dropwise. After 5 mins, the solution of 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]- 3,3-dimethyl-pentan-l-ol (0.3 g, 1 mmol) in dichloromethane (1 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 15 min. Triethylamine (0.5 mL, 3.6 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10%) of HC1, saturated NaHC03, brine, dried over MgSC>4, and concentrated to give 5-[2- (tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pentanal as a yellow oil (Yield: 0.27 g, 94%).
Step C In a manner similar to the method described in Example la, glycine tert-butyl ester (0.13 g, 1 mmol) was reacted with 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pentanal (0.27 g, 1 mmol) in CH2CI2 at room temperature for 18 h to give [5-[2-(tert-butyl-dimethyl- silanyloxy)-ethoxy]-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.4 g, 100%).
Example 119b
Preparation of intermediate rac-(2R,3S,4R,5S)-5-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]- 2,2-dimethyl-butyl}-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano- pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000226_0001
M. W. 711.80 C36H5oCl2F2N204Si
In a manner similar to the method described in Example 100b, [5-[2-(tert-butyl-dimethyl- silanyloxy)-ethoxy]-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 119a (0.4 g, 1 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro- 2-fluoro-phenyl)-acrylonitrile (0.3 g, 1 mmol) prepared in Example 52a, AgF (0.2 g, 1.5 mmol), and triethylamine (0.3 mL, 2.4 mmol) in dichloromethane (50 mL) at room temperature for 18 h, followed by the reaction with DBU (1 ml) in tert-butanol (2 mL) at 100 °C for 2 h to give rac- (2R,3S,4R,5S)-5-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2,2-dimethyl-butyl} -3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert- butyl ester as a white gum (0.49 g, 60%).
Example 119c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-{2,2-dimethyl-4-[2-(2,2,2-trifiuoro-acetoxy)-ethoxy]-butyl}- pyrrolidine-2-carboxylic acid trifiuoro acetic acid
Figure imgf000226_0002
M. W. 483.35 C23H22C12F2N203.C2HF302
To a solution of rac-(2R,3S,4R,5S)-5-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2,2- dimethyl-butyl}-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-pyrrolidine- 2-carboxylic acid tert-butyl ester prepared in Example 119b (0.49 g, 0.55 mmol) in
dichloromethane (3 mL) at room temperature was added trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-{2,2-dimethyl-4-[2-(2,2,2-trifluoro-acetoxy)-ethoxy]-butyl}-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow oil (0.37 g, 97%).
Example 119d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-[4-(2-hydroxy-ethoxy)-2,2-dimethyl-butyl]-pyrrolidine-2-carboxylic acid ((S)-3,4- dihydroxy-butyl)-amide
Figure imgf000227_0001
M. W. 628.54 C3oH37Cl2F2N305
In a manner similar to the method described in Examples 117d and 117e, rac-(2R,3S,4R,5S)-3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-{2,2-dimethyl-4-[2-(2,2,2- trifiuoro-acetoxy)-ethoxy]-butyl} -pyrrolidine -2 -carboxylic acid trifluoroacetic acid prepared in Example 119c (0.37 g, 0.58 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)- ethylamine (0.25 g, 1.7 mmol), HATU (0.4 g, 1 mmol) and iPr2NEt (0.5 mL, 2.9 mmol) in CH2C12 at room temperature for 20 h, then treated with aqueous saturated K2C03 solution in tetrahydrofuran, followed by reaction with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-[4-(2-hydroxy-ethoxy)-2,2-dimethyl-butyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a light yellow solid (90 mg, 25%).
HRMS (ES+) m/z Calcd for C30H37Cl2F2N3O5+ H [(M+H)+]: 628.2151, found: 628.2150.
Example 120a
Preparation of intermediate [5-azido-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester
Figure imgf000228_0001
Step A To the solution of 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentan-l-ol (1.1 g, 5 mmol) prepared in Example 116a Step B. and triethylamine (1.39 mL, 10 mmol) in
dichloromethane (50 mL) at 0 °C was added a dichlormethane solution (10 mL) of
methanesulfonyl chloride (Aldrich) (0.46 mL, 6mmol). The reaction mixture was stirred at 0 °C for 1 h. Water was added. Organic layer was separated, the aqueous layer was extracted with dichlormethane. The combined organic layers were washed with diluted aqueous HC1 solution, saturated aqueous NaHC03 solution, brine, dried over MgS04, and concentrated to give methanesulfonic acid 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentyl ester as a yellow oil (1.48 g, 99%).
Step B To the solution of methanesulfonic acid 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl- pentyl ester (1.48 g, 4.96 mmol) in anhydrous dimethylformamide (10 mL) was added NaN3 (1.6 g, 25 mmol). The reaction mixture was heated at 60 °C for 18 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHC03 solution, brine, dried over MgSC o give (5-azido-3,3-dimethyl-pentyloxy)-tert-butyl-dimethyl-silane as a yellow oil (0.8 g, 67%). Step C To a solution of (5-azido-3,3-dimethyl-pentyloxy)-tert-butyl-dimethyl-silane (0.8 g, 3 mmol) in tetrahydrofuran (5 mL) was added tetrahydrofuran solution (1 M, Aldrich) of TBAF (4.9 mL, 4.9 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over MgSC>4, and concentrated. The residue was purified by
chromatography (EtOAc:hexanes=l :3) to give 5-azido-3,3-dimethyl-pentan-l-ol as a colorless oil (Og, 76%) Step D To a solution of oxalyl chloride (0.24 mL, 2.7 mmol) (Aldrich) in dichloromethane (12 mL) at -78 °C was added the solution of dimethyl sulfoxide (0.38 mL, 5.5 mmol) in
dichloromethane (1 mL) dropwise. After 5 mins, the solution of 5-azido-3,3-dimethyl-pentan-l- ol (0.39 g, 2.5 mmol) in dichloromethane (1 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 15 min. Triethylamine (1.2 mL, 9 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHC03, brine, dried over MgSC>4, and concentrated to give 5-azido-3,3-dimethyl-pentanal as a yellow oil (Yield: 0.38 g, 99%).
Step C In a manner similar to the method described in Example la, glycine tert-butyl ester (0.32 g, 2.45 mmol) was reacted with 5-azido-3,3-dimethyl-pentanal (0.38 g, 2.45 mmol) in CH2CI2 at room temperature for 18 h to give [5-azido-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert- butyl ester as a yellow oil (0.65 g, 100%).
Example 120b
Preparation of intermediate rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-butyl)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester
Figure imgf000229_0001
N
M. W. 578.49 C28H31CI2F2N5O2
In a manner similar to the method described in Example 100b, [5-azido-3,3-dimethyl-pent-(E)- ylideneamino]-acetic acid tert-butyl ester prepared in Example 120a (0.65 g, 2.45 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fiuoro-phenyl)-acrylonitrile (0.76 g, 2.45 mmol) prepared in Example 52a, AgF (0.47 g, 3.7 mmol), and triethylamine (0.55 mL, 6 mmol) in dichloromethane (80 mL) at room temperature for 18 h, followed by the reaction with DBU (3 ml) in tert-butanol (3 mL) at 100 °C for 2 h to give rac-(2R,3S,4R,5S)-5-(4-azido-2,2- dimethyl-butyl)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-pyrrolidine- 2-carboxylic acid tert-butyl ester as a yellow gum (0.5 g, 36%).
Example 120c
Preparation of intermediate rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-butyl)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine -2-carboxylic acid
trifiuoro acetic acid
Figure imgf000230_0001
M. W. 522.39 C24H23Cl2F2N503.C2HF302
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-(4-azido-2,2- dimethyl-butyl)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-pyrrolidine- 2-carboxylic acid tert-butyl ester prepared in Example 120b (0.5 g, 0.86 mmol) was reacted with trifiuoro acetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-5-(4- azido-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano- pyrrolidine-2-carboxylic acid trifiuoro acetic acid as a yellow solid (0.54 g, 96%).
Example 120d
Preparation of intermediate rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-butyl)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine -2-carboxylic acid [2-((S)-2,2- dimethyl-[l ,3]dioxolan-4-yl)-ethy -amide
Figure imgf000230_0002
M. W. 649.57 C31H36CI2F2N6O3
In a manner similar to the method described in Examples 42c, rac-(2R,3S,4R,5S)-5-(4-azido- 2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano- pyrrolidine-2-carboxylic acid trifluoro acetic acid prepared in Example 120c (0.54 g, 0.85 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.37 g, 2.54 mmol), HATU (0.58 g, 1.5 mmol) and iPr2NEt (0.74 mL, 4.2 mmol) in CH2C12 at room temperature for 20 h, to give rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-butyl)-3-(3-chloro-2-fiuoro-phenyl)-4- (4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl- [l,3]dioxolan-4-yl)-ethyl]-amide as a light yellow solid (0.5 g, 91%).
Example 120e
Preparation of rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)- 4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)- amide
Figure imgf000231_0001
M. W. 609.50 C28H32C12F2N603
In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-5-(4-azido- 2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano- pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 120d (40 mg, 0.06 mmol) was reacted with aqueous HCl solution (1 N, 3 mL, 3 mol) in tetrahydrofuran (7 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-(4-azido-2,2- dimethyl-butyl)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-pyrrolidine- 2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (29 mg, 79%).
HRMS (ES+) m/z Calcd for C28H32C12F2N603+ H [(M+H)+]: 609.1954, found: 609.1954.
Example 121a
Preparation of intermediate rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-butyl)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine -2-carboxylic acid [2-((S)-2,2- dimethyl-[l ,3]dioxolan-4-yl)-ethyl]-amide
Figure imgf000232_0001
M. W. 623.58 C31H38CI2F2N4O3
In a manner similar to the method described in Examples 118a, rac-(2R,3S,4R,5S)-5-(4-azido- 2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano- pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 120d (0.5 g, 0.77 mmol) was treated with Pt02 and H2 in ethyl acetate to give rac- (2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-butyl)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)- ethyl]-amide as a black gum (0.47 g, 98%)
Example 121b
Preparation of rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-butyl)-3-(3-chloro-2-fiuoro-phenyl)- 4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)- amide
Figure imgf000232_0002
M. W. 583.50 C28H34CI2F2N4O3
In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-5-(4-amino- 2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano- pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 121a (50 mg, 0.08 mmol) was reacted with aqueous HCl solution (1 N, 3 mL, 3 mol) in tetrahydrofuran (7 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-(4-amino- 2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano- pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (29 mg, 62%). HRMS (ES+) m/z Calcd for C28H34CI2F2N4O3+ H [(M+H)+]: 583.2049, found: 583.2047. Example 122a
Preparation of intermediate rac-(2R,3S,4R,5S)-5-(4-acetylamino-2,2-dimethyl-butyl)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2- ((S)-2,2-dimethyl-[l,3]dioxolan-4- -ethyl]-amide
Figure imgf000233_0001
M. W. 665.61 C33H40CI2F2N4O4
To a solution of rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-butyl)-3-(3-chloro-2-fiuoro- phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2- dimethyl-[l ,3]dioxolan-4-yl)-ethyl]-amide (60 mg, 0.096 mmol) prepared in Example 121a and triethylamine (0.033 mL, 0.24 mmol) in tetrahydrofuran (3 mL) was added acetyl chloride (0.08 mL, 0.11 mmol). The reaction mixture was stirred at room temperature for 30 min, then water was added. The mixture was partitioned between ethyl acetate and water. Organic layer was separated, washed with water, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (2% MeOH in EtOAc) to give rac-(2R,3S,4R,5S)-5-(4-acetylamino- 2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano- pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethyl]-amide as a off white gum (60 mg, 94%)
Example 122b
Preparation of rac-(2R,3S,4R,5S)-5-(4-acetylamino-2,2-dimethyl-butyl)-3-(3-chloro-2-fiuoro- phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy- butyl)-amide
Figure imgf000233_0002
M. W. 625.54 C30H36CI2F2N4O4 In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-5-(4- acetylamino-2,2-dimethyl-butyl)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 122a (60 mg, 0.09 mmol) was reacted with aqueous HCl solution (1 N, 1 mL, 1 mol) in tetrahydrofuran (5 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5- (4-acetylamino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (50 mg, 89%).
HRMS (ES+) m/z Calcd for C30H36CI2F2N4O4+ H [(M+H)+]: 625.2155, found: 625.2151.
Example 123
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(4-methanesulfonylamino-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4- dihydroxy-butyl)-amide
Figure imgf000234_0001
M. W. 661.59 C29H36Cl2F2N405S
In a manner similar to the method described in Examples 122a and 122b, rac-(2R,3S,4R,5S)-5- (4-amino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethyl]-amide (60 mg, 0.096 mmol) prepared in Example 121a
was reacted with triethylamine and methane sulfonyl chloride (13 mg, 0.11 mmol) in
dichloromethane, followed by the reaction with aqueous HCl solution in tetrahydrofuran to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(4- methanesulfonylamino-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy- butyl)-amide as a off white solid (57 mg, 90%)
HRMS (ES+) m/z Calcd for C29H36Cl2F2N405S+ H [(M+H)+]: 661.1825, found: 661.1821.
Example 124 Preparation of rac-(2R,3S,4R,5S)-5-(4-benzoylamino-2,2-dimethyl-butyl)-3-(3-chloro-2-fiuoro- phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy- butyl)-amide
Figure imgf000235_0001
M. W. 687.61 C35H38Cl2F2N404
In a manner similar to the method described in Examples 122a and 122b, rac-(2R,3S,4R,5S)-5- (4-amino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethyl]-amide (80 mg, 0.13 mmol) prepared in Example 121a
was reacted with triethylamine and benzoyl chloride (22 mg, 0.16 mmol) in tetrahydrofuran, followed by the reaction with aqueous HC1 solution in tetrahydrofuran to give rac- (2R,3S,4R,5S)-5-(4-benzoylamino-2,2-dimethyl-butyl)-3-(3-chloro-2-fiuoro-phenyl)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (57 mg, 90%)
HRMS (ES+) m/z Calcd for C35H38Cl2F2N404+ H [(M+H)+]: 687.2311, found: 687.2308
Example 125a
Preparation of intermediate [3-methyl-3-(5-methyl-furan-2-yl)-but-(E)-ylideneamino]-acetic acid tert-butyl ester
Figure imgf000235_0002
M. W. 279.38 Ci6H25N03
Step A To a solution of dimethyl malonate (6.5 g, 49 mmol), 2-acetyl-5-methylfuran (6.1 g, 49 mmol) and pyridine (16 g, 200 mmol) in anhydrous tetrahydrofuran (300 mL) at 0 °C was added a dichloromethane solution (1 M) of TiCl4 (100 mL, 100 mmol) during a period of 1 h. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 18 h. Water was added to quench the reaction. The mixture was extracted with ethyl ether. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, concentrated. The residue was purifed by chromatography (EtOAc:hexanes=l ;10) to give 2-[l-(5-methyl-furan-2-yl)-ethylidene]-malonic acid dimethyl ester as a yellow oil (3.7 g, 32%).
Step B To a suspension of Cul (7.61 g, 40 mmol) in anhydrous tetrahydrofuran (100 mL) at -50 °C was added methylmagnesium chloride (3 M, 27 mL, 80 mmol) during a period of 15 min. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 20 min. Then the temperature of the mixture was lowered to -50 °C, a
tetrahydrofuran solution (50 mL) of 2-[l-(5-methyl-furan-2-yl)-ethylidene]-malonic acid dimethyl ester (3.7 g, 15.5 mmol) was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 3 h. Aqueous saturated NH4C1 solution was added to quench the reaction. The mixture was filtered, and the filtrate was concentrated to remove most of tetrahydrofuran. The residue was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was purifed by chromatography (EtOAc:hexanes=l :20, 1 :10) to give 2-[l-methyl-l-(5-methyl-furan-2-yl)-ethyl]-malonic acid dimethyl ester as a colorless oil (2.5 g, 63%).
Step C To a solution of 2-[l-methyl-l-(5-methyl-furan-2-yl)-ethyl]-malonic acid dimethyl ester (2.5 g, 9.8 mmol) in DMSO (30 mL) was added LiCl (1 g, 23.7 mmol) and H20 (0.17 mL, 9.8 mmol). The reaction mixture was heated at 170 °C for 3 h, then poured into a ice-water, extracted with ethyl acetate. The organic layer were separated, washed with water, brine, dried over MgS04, and concentrated. The residue was purifed by chromatography (EtOAc:hexanes=l :20, 1 :20) to give 3-methyl-3-(5-methyl-furan-2-yl)-butyric acid methyl ester as a colorless oil (1.5 g, 78%).
Step D To a solution of 3-methyl-3-(5-methyl-furan-2-yl)-butyric acid methyl ester (1.5 g, 7.8 mmol) in anhydrous tetrahydrofuran (50 mL) at 0 °C was added a tetrhydrofuran solution (1 M) of LiAlH4 (10 mL, 10 mmol) under nitrogen. The reaction mixture was stirred at 0 °C for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgS04, and concentrated to give 3-methyl-3-(5-methyl-furan-2-yl)-butan-l-ol as a yellow oil (1.2 g, 77%).
Step E To a solution of oxalyl chloride (0.91 g, 7.1 mmol) (Aldrich) in dichloromethane (20 mL) at -78 °C was added the solution of dimethyl sulfoxide (1 mL, 14.3 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 3-methyl-3-(5-methyl-furan-2-yl)-butan-l-ol (1.2 g, 7.1 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at - 78 °C for 15 min. Triethylamine (3.6 mL, 26 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHC03, brine, dried over MgSC>4, and concentrated to give 3-methyl-3-(5-methyl-furan-2-yl)- butyraldehyde as a yellow oil (Yield: 1 g, 83%).
Step F In a manner similar to the method described in Example la, glycine tert-butyl ester (0.79 g, 6 mmol) was reacted with 3-methyl-3-(5-methyl-furan-2-yl)-butyraldehyde (1 g, 6 mmol) in CH2CI2 at room temperature for 5 h to give [3-methyl-3-(5-methyl-furan-2-yl)-but-(E)- ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.7 g, 100%).
Example 125b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5 - [2-methyl-2 -(5 -methyl-furan-2 -yl)-propyl]-pyrrolidine-2 -carboxylic acid tert-butyl ester
M. W. 589.52 C3iH32Cl2F2N203
In a manner similar to the method described in Example 100b, [[3-methyl-3-(5-methyl-furan-2- yl)-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 125a (1.7 g, 6 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.48 g, 4.8 mmol) prepared in Example 52a, AgF (0.9 g, 7 mmol), and triethylamine (1.7 mL, 12 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (5.7 ml) in tert-butanol (10 mL) at 100 °C for 2 h to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2- yl)-propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester as a yellow solid (1.3 g, 46%).
Example 125c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dieth l-butyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid
Figure imgf000238_0001
M. W. 533.41 C27H24CI2F2N2O3.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-yl)- propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 125b (1.3 g, 2.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac- (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-[2-methyl- 2-(5-methyl-furan-2-yl)-propyl]-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a brown solid (1.3 g, 92%).
Example 125d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-[2-methyl-2-(5-methyl-furan-2-yl)-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4- dihydroxy-butyl)-amide
Figure imgf000238_0002
M. W. 620.52 C31H33CI2F2N3O4
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2- yl)-propyl]-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 125c (0.6 g, 0.93 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.4 g, 2.8 mmol), HATU (0.6 g, 1.7 mmol) and iPr2NEt (0.8 mL, 4.6 mmol) in CH2C12 at room
temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5 - [2-methyl-2 -(5 -methyl-furan-2 -yl)-propyl]-pyrrolidine-2 -carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.16 g, 29%).
HRMS (ES+) m/z Calcd for C31H33CI2F2N3O4+ H [(M+H)+]: 620.1889, found: 620.1889.
Example 126a
Preparation of intermediate [4-(4-methoxy-phenyl)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid methyl ester
Figure imgf000239_0001
Step A Under Argon, a mixture of NaOH (2.8 g, 70 mmol),tetrabutylammonium iodide (0.6 g, 1.6 mmol) in benzene (8 mL) and H2O (2.8 mL) was heated at 70 °C to form a homogeneous mixture. A mixture of 4-methoxybenzyl chloride (Aldrich) (10 g, 64 mmol) and
isobutyraldehyde (5.76 g, 80 mmol) in benzene (22 mL) was added dropwise. The resulting reaction mixture was heated at 70 °C for 3 h. The mixture was cooled, extracted with ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, concentrated. The residue was purifed by chromatography (EtOAc:hexanes=l ;30) to give 2-(4-methoxy-phenyl)-2-methyl-propionaldehyde as a colorless oil (4.1 g, 33%). Step B To a mixture of methoxymethyl triphenylphosphonium chloride (14.6 g, 42 mmol) in anhydrous tetrahydrofuran (60 mL) at 0 °C was a tetrahydrofuran solution (Aldrich, 1 M) of LiHMDS (42 mL, 42 mmol) dropwise. After the addition was finished, the reaction mixture was stirred at 0 °C for 20 min. Then a tetrahydrofuran solution (40 mL) of 2-(4-methoxy-phenyl)-2- methyl-propionaldehyde (4.1g, 21 mmol) was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 1 h. Water was added to quench the reaction. The mixture was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was purifed by chromatography (EtOAc:hexanes=l :30, 1 :20) to give a yellow oil (3.5 g). The oil was dissolved into a solution of aqueous HC1 solution (2 N, 50 mL, 100 mmol) and tetrahydrofuran (50 mL). The reaction mixture was heated at reflux for 1 h, then cooled to room temperature and concentrated. The residue partitioned between ethyl acetate and water. The organic layer was separated, concentrated. The residue was purified by
chromatography (EtOAc:hexanes=l :10,l :5) to give 3-(4-methoxy-phenyl)-3-methyl- butyraldehyde as a colorless oil (2.1 g, 47%).
Similar transformations have been reported in US6531494 and the procedures described were used without modifications.
Step C In a manner similar to the method described in Example la, glycine methyl ester hydrochloride (1.25 g, 10 mmol) was reacted with 3-(4-methoxy-phenyl)-3-methyl- butyraldehyde (2.1 g, 10 mmol) and triethylamine (2.2 g, 20 mmol) in CH2CI2 at room temperature for 5 h to give [4-(4-methoxy-phenyl)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid methyl ester as a colorless oil (2.7 g, 97%). Example 126b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-[3-(4-methoxy-phenyl)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000241_0001
M. W. 587.50 C31H30CI2F2N2O3
In a manner similar to the method described in Example lc, [4-(4-methoxy-phenyl)-3,3- dimethyl-but-(E)-ylideneamino]-acetic acid methyl ester prepared in Example 126a (2.7 g, 9.7 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)- acrylonitrile (3.1 g, 10 mmol) prepared in Example 52a, AgF (1.27 g, 10 mmol), and triethylamine (6 g, 60 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-[3-(4- methoxy-phenyl)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid methyl ester as a yellow solid (4 g, 70%).
Example 126c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-[3-(4-methoxy-phenyl)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid
Figure imgf000241_0002
M. W. 573.47 C30H28CI2F2N2O3
To rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[3- (4-methoxy-phenyl)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid
methyl ester prepared in Example 126b (4 g, 6.8 mmol) in tetrahydrofuran (60 mL) was added an aqueous solution (1 N) of NaOH (20 mL, 20 mmol) and methanol (20 mL). The reaction mixture was stirred at room temperature for 3 h. The "pH" of the mixture was adjusted to ~4-5 by aqueous HC1 solution. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgS04, concentrated to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-[3-(4-methoxy-phenyl)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid as a light yellow solid (4 g, 100%)
Example 126d
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-[3-(4-methoxy-phenyl)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4- dihydroxy-butyl)-amide
Figure imgf000242_0001
M. W. 660.59 C34H37CI2F2N3O4
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[3-(4-methoxy-phenyl)-2,2- dimethyl-propyl]-pyrrolidine-2-carboxylic acid
prepared in Example 126c (0.5 g, 0.87 mmol) was reacted with 2-((S)-2,2-dimethyl- [l,3]dioxolan-4-yl)-ethylamine (0.25 g, 1.7 mmol), HATU (0.6 g, 1.7 mmol) and iPr2NEt (0.45 mL, 2.6 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)- 4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[3-(4-methoxy-phenyl)-2,2-dimethyl-propyl]- pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.16 g, 29%). HRMS (ES+) m/z Calcd for C34H37CI2F2N3O4+ H [(M+H)+]: 660.2202, found: 660.2198.
Example 127a
Preparation of intermediate [3-(l -benzyl- l,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-but-(E)- ylideneamino]-acetic acid tert-butyl ester
Figure imgf000242_0002
Figure imgf000243_0001
Step A To a tetrahydrofuran solution (Aldrich, 1.8 M) of LDA (60 mL, 109 mmol) at -50 °C was added isobutyric acid ethyl ester (Alfa) (12.2 mL, 91 mmol) dropwise. The reaction mixture was stirred -50 °C for 1 h, then a tretrahydrofuran solution (10 mL) of l-benzyl-piperidin-4-one (12 mL, 68 mmol) was added dropwise. The reaction mixture was warmed up to room temperature and stirred for 18 h. Aqueous saturated NH4CI was added to quench the reaction. The mixture was extracted with ethyl ether. The organic layer was separated, and the aqueous layer was extracted with ethyl ether. The organic layers were combined, washed with brine, water, dried over MgS04, and concentrated to give 2-(l-benzyl-4-hydroxy-piperidin-4-yl)-2-methyl- propionic acid ethyl ester as an orange oil (18.5 g, 89%).
Step B To a solution of 2-(l-benzyl-4-hydroxy-piperidin-4-yl)-2-methyl-propionic acid ethyl ester (18.5 g, 61 mmol) in chloroform (75 mL) was added thionyl chloride (8.9 mL, 120 mmol) and dimethylformamide (0.17 mL). The reaction mixture was heated at 100 °C for 18 h, then cooled to room temperature and concentrated. To the resulting residue was added aqueous NaOH solution (10 N) to adjust the "pH" of the mixture to basic. The mixture was then extracted with ethyl ether twice. The combined organic extracts were washed with water, brine, dried over MgS04, and concentrated to give 2-(l-benzyl-l ,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl- propionic acid ethyl ester as a brown oil (13 g, 75%).
Step C To a solution of 2-(l-benzyl-l ,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propionic acid ethyl ester (6 g, 21 mmol) in anhydrous tetrahydrofuran 75 mL) at 0 °C was added a
tetrhydrofuran solution (1 M) of L1AIH4 (84 mL, 84 mmol) under nitrogen. The reaction mixture was heated at reflux for 3 h, then cooled to room temperature. Water and aqueous NaOH solution (2N) was added. The mixture was filtered to remove the precipitate, and the filtrate was concentrated. Water was added, and the mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgS04, and concentrated to give 2-(l-benzyl-l ,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propan-l-ol as a brown oil (4.73 g, 77%). Step D To a solution of oxalyl chloride (2.46 mL, 28 mmol) (Aldrich) in dichloromethane (150 mL) at -78 °C was added the solution of dimethyl sulfoxide (4 mL, 56 mmol) in dichloromethane (25 mL) dropwise. After 5 mins, the solution of 2-(l-benzyl-l ,2,3,6-tetrahydro-pyridin-4-yl)-2- methyl-propan-l-ol (6.3 g, 25.6 mmol) in dichloromethane (25 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 15 min. Triethylamine (12.8 mL, 92 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HC1, saturated NaHC03, brine, dried over MgSC>4, and concentrated to give 2-(l- benzyl-l,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propionaldehyde as a brown oil (Yield: 5.6 g, 89%).
Step E To a mixture of methoxymethyl triphenylphosphonium chloride (12.6 g, 37 mmol) in anhydrous tetrahydrofuran (50 mL) at 0 °C was a tetrahydrofuran solution (Aldrich, 1 M) of LiHMDS (46 mL, 46 mmol) dropwise. After the addition was finished, the reaction mixture was stirred at 0 °C for 20 min. Then a tetrahydrofuran solution (40 mL) of 2-(l-benzyl-l,2,3,6- tetrahydro-pyridin-4-yl)-2-methyl-propionaldehyde (5.6 g, 23 mmol) was added. The reaction mixture was stirred at 0 °C for 2 h. Water was added to quench the reaction. The mixture was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was dissolved into a solution of aqueous HC1 solution (2 N, 50 mL, 100 mmol) and
tetrahydrofuran (50 mL). The reaction mixture was heated at reflux for 30 min, then cooled to room temperature and concentrated. The residue partitioned between ethyl acetate and water. The organic layer was separated, concentrated. The residue was purified by chromatography (EtOAc:hexanes=l :3) to give 3-(l-benzyl-l ,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl- butyraldehyde as a yellow oil (1.65 g, 28%).
Step F In a manner similar to the method described in Example la, glycine tert-butyl ester (0.84 g, 6.4 mmol) was reacted with 3-(l-benzyl-l,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl- butyraldehyde (1.65 g, 6.4 mmol) in CH2CI2 at room temperature for 5 h to give [3-(l-benzyl- l,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a yellow oil (2.4 g, 100%). Example 127b
Preparation of intermediate rac-(2R,3S,4R,5S)-5-[2-(l-benzyl-l,2,3,6-tetrahydro-pyridin-4-yl)-2- methyl-propyl]-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine- 2-carboxylic acid tert-butyl ester
Figure imgf000245_0001
M. W. 680.67 C38H41CI2F2N3O3
In a manner similar to the method described in Example 100b, [3-(l-benzyl-l,2,3,6-tetrahydro- pyridin-4-yl)-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 127a (2.4 g, 6.4 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro- phenyl)-acrylonitrile (1.8 g, 6.4 mmol) prepared in Example 52a, AgF (1.3 g, 10 mmol), and triethylamine (2 mL, 14.5 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (7 ml) in tert-butanol (30 mL) at 100 °C for 2 h to give rac- (2R,3S,4R,5S)-5-[2-(l-benzyl-l,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propyl]-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine -2-carboxylic acid tert-butyl ester as a light yellow solid (3.2 g, 81%).
Example 127c
Preparation of intermediate rac-(2R,3S,4R,5S)-5-[2-(l-benzyl-l,2,3,6-tetrahydro-pyridin-4-yl)-2- methyl-propyl]-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine- 2-carboxylic acid trifluoroacetic acid
Figure imgf000245_0002
M. W. 626.58 C34H35Cl2F2N303.C2HF302
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-[2-(l-benzyl- l,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 127b (1.5 g, 2.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-5-[2-(l-benzyl-l ,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propyl]-3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow solid (1.6 g, 98%).
Example 127d
Preparation of intermediate rac-(2R,3S,4R,5S)-5-[2-(l-benzyl-l,2,3,6-tetrahydro-pyridin-4-yl)-2- methyl-propyl]-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine- 2-carboxylic acid [2-((S)-2,2-dim thyl-[l,3]dioxolan-4-yl)-ethyl]-amide
Figure imgf000246_0001
M. W. 751.75 C4iH46Cl2F2N403
In a manner similar to the method described in Examples 42c, rac-(2R,3S,4R,5S)-5-[2-(l- benzyl-l,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 127c (1.6 g, 2.2 mmol) was reacted with 2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)- ethylamine (0.94 g, 6.5 mmol), HATU (2.5 g, 6.5 mmol) and iPr2NEt (2.3 mL, 13 mmol) in CH2C12 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-5-[2-(l-benzyl-l ,2,3,6- tetrahydro-pyridin-4-yl)-2-methyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-pyrrolidine -2-carboxylic acid [2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethyl]- amide as a light yellow gum (1 g, 83%).
Example 127e
Preparation of rac-(2R,3S,4R,5S)-5-[2-(l-benzyl-l,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl- propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2- carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide
Figure imgf000247_0001
M. W. 711.68 C38H42CI2F2N4O3
In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-5-[2-(l- benzyl-l,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-
[l,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 127d (1 g, 1.3 mmol) was reacted with aqueous HC1 solution (1 N, 5 mL, 5 mol) in tetrahydrofuran (5 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-[2-(l-benzyl-l ,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propyl]-3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.3 g, 32%).
HRMS (ES+) m/z Calcd for C38H42CI2F2N4O3+ H [(M+H)+]: 711.2675, found: 711.2675.
Example 128
Preparation of rac-(2R,3S,4R,5S)-5-[2-(l-benzyl-piperidin-4-yl)-2-methyl-propyl]-3-(3-chloro- 2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4- dihydroxy-butyl)-amide
Figure imgf000247_0002
M. W. 713.69 C38H44CI2F2N4O3
In a manner similar to the method described in Examples 118a, rac-(2R,3S,4R,5S)-5-[2-(l- benzyl-l,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide prepared in Example 127e (60 mg, 0.08 mmol) was treated with PtC>2 and ¾ in ethyl acetate to give rac-(2R,3S,4R,5S)-5-[2-(l-benzyl-piperidin-4-yl)-2-methyl-propyl]-3-(3-chloro-2-fluoro- phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy- butyl)-amide as a off white solid (15 mg, 25%)
HRMS (ES+) m/z Calcd for C38H44CI2F2N4O3+ H [(M+H)+]: 713.2832, found: 713.2837.
Example 129a
Preparation of intermediate [3-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-but-(E)-ylideneamino]- acetic acid tert-butyl ester
Figure imgf000248_0001
Step A To a hexane solution (Aldrich, 2 M) of LDA (78 mL, 160 mmol) in tetrahydrofuran (100 mL) at -50 °C was added a solution of isobutyric acid ethyl ester (Alfa) (17 mL, 127 mmol) in tetrahydrofuran (20 mL) dropwise. The reaction mixture was stirred -50 °C for 1 h, then a tretrahydrofuran solution (10 mL) of tetrahydro-pyran-4-one (Aldrich) (9.8 g, 98 mmol) was added dropwise. The reaction mixture was warmed up to room temperature and stirred for 18 h. Aqueous saturated NH4C1 was added to quench the reaction. The mixture was extracted with ethyl ether. The organic layer was separated, and the aqueous layer was extracted with ethyl ether. The organic layers were combined, washed with brine, water, dried over MgSC>4, and concentrated to give 2-(4-hydroxy-tetrahydro-pyran-4-yl)-2-methyl-propionic acid ethyl ester as a yellow oil (19.5 g, 92%).
Step B To a solution of 2-(4-hydroxy-tetrahydro-pyran-4-yl)-2-methyl-propionic acid ethyl ester (19.5 g, 90 mmol) in chloroform (100 mL) was added thionyl chloride (13.3 mL, 180 mmol) and dimethylformamide (0.28 mL). The reaction mixture was heated at 100 °C for 18 h, then cooled to room temperature and concentrated. To the resulting residue was added aqueous NaOH solution (10 N) to adjust the "pH" of the mixture to basic. The mixture was then extracted with ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSC>4, and concentrated to give 2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propionic acid ethyl ester as a brown oil (17.6 g, 99%).
Step C To a solution of 2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propionic acid ethyl ester (6 g, 30 mmol) in anhydrous tetrahydrofuran (75 mL) at 0 °C was added a tetrhydrofuran solution (1 M) of L1AIH4 (100 mL, 100 mmol) under nitrogen. The reaction mixture was heated at reflux for 3 h, then cooled to room temperature. Water and aqueous NaOH solution (2N) was added. The mixture was filtered to remove the precipitate, and the filtrate was concentrated. Water was added, and the mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HC1 solution, brine, dried over MgSC>4, and concentrated to give 2- (3,6-dihydro-2H-pyran-4-yl)-2-methyl-propan-l-ol as a brown oil (4.63 g, 98%).
Step D To a solution of oxalyl chloride (2.84 mL, 33 mmol) (Aldrich) in dichloromethane (150 mL) at -78 °C was added the solution of dimethyl sulfoxide (4.6 mL, 65 mmol) in
dichloromethane (25 mL) dropwise. After 5 mins, the solution of 2-(3,6-dihydro-2H-pyran-4- yl)-2-methyl-propan-l-ol (4.6 g, 29 mmol) in dichloromethane (25 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 15 min. Triethylamine (14.8 mL, 110 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10%) of HC1, saturated NaHC03, brine, dried over MgSC>4, and concentrated to give 2 -(3,6- dihydro-2H-pyran-4-yl)-2-methyl-propionaldehyde as a brown oil (Yield: 5.6 g, 89%>).
Step E To a mixture of methoxymethyl triphenylphosphonium chloride (31.3 g, 91 mmol) in anhydrous tetrahydrofuran (150 mL) at 0 °C was a tetrahydrofuran solution (Aldrich, 1 M) of LiHMDS (110 mL, 110 mmol) dropwise. After the addition was finished, the reaction mixture was stirred at 0 °C for 20 min. Then a tetrahydrofuran solution (40 mL) of 2-(3,6-dihydro-2H- pyran-4-yl)-2-methyl-propionaldehyde (4.4 g, 28.5 mmol) was added. The reaction mixture was stirred at 0 °C for 1 h. Water was added to quench the reaction. The mixture was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was dissolved into a solution of aqueous HC1 solution (2 N, 50 mL, 100 mmol) and tetrahydrofuran (50 mL). The reaction mixture was heated at reflux for 30 min, then cooled to room temperature and concentrated. The residue partitioned between ethyl acetate and water. The organic layer was separated, concentrated. The residue was purified by chromatography (EtOAc:hexanes=l :3) to give 3-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-butyraldehyde as a brown oil (2.61 g, 54%).
Step F In a manner similar to the method described in Example la, glycine tert-butyl ester (2 g, 15.5 mmol) was reacted with 3-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-butyraldehyde (2.6 g, 15.5 mmol) in CH2CI2 at room temperature for 5 h to give [3-(3,6-dihydro-2H-pyran-4-yl)-3- methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a yellow oil (4.3 g, 100%).
Example 129b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propyl]-pyrrolidine-2- carboxylic acid tert-butyl ester
Figure imgf000250_0001
M. W. 591.53 C31H34CI2F2N2O3
In a manner similar to the method described in Example 100b, [3-(3,6-dihydro-2H-pyran-4-yl)- 3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 129a (4.3 g, 15.5 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)- acrylonitrile (3.8 g, 12.4 mmol) prepared in Example 52a, AgF (2.4 g, 19 mmol), and triethylamine (4.3 mL, 31mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (19 ml) in tert-butanol (18 mL) at 100 °C for 2 h to give rac- (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-[2-(3,6- dihydro-2H-pyran-4-yl)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester as a yellow gum(5.5 g, 75%). Example 129c
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propyl]-pyrrolidine-2- carboxylic acid trifluoroacetic acid
Figure imgf000251_0001
M. W. 535.42 C27H26CI2F2N3O3.C2HF3O2
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-yl)-2- methyl-propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 129b (5.5 g, 9.29 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5- [2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a dark solid (6 g, 99%).
Example 129d
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propyl]-pyrrolidine-2- carboxylic acid [2-((S)-2,2-dimethyl- l ,3]dioxolan-4-yl)-ethyl]-amide
Figure imgf000251_0002
M. W. 662.61 C34H39CI2F2N3O4
In a manner similar to the method described in Examples 42c, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-yl)-2- methyl-propyl]-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 129c (0.8 g, 1.2 mmol) was reacted with 2-((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethylamine (0.36 g, 2.5 mmol), HATU (0.84 g, 2.2 mmol) and iPr2NEt (0.64 mL, 3.7 mmol) in CH2C12 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-5-[2-(l-benzyl-l ,2,3,6-tetrahydro-pyridin-4-yl)- 2-methyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano- pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethyl]-amide as a off white gum (0.6 g, 74%). Example 129e
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-[2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid ((S)- 3 ,4-dihydroxy-butyl)-amide
Figure imgf000252_0001
M. W. 622.54 C3iH35Cl2F2N304
In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-yl)-2- methyl-propyl]-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-ethyl]- amide prepared in Example 129d (0.6 g, 0.9 mmol) was reacted with aqueous HCl solution (1 N, 3 mL, 3 mol) in tetrahydrofuran (7 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-
3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-
4- yl)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.52 g, 93%).
HRMS (ES+) m/z Calcd for C3 iH35Cl2F2N304+ H [(M+H)+]: 622.2046, found: 622.2046.
Example 130
Preparation of rac-(2R,3S,4R,5S)-3-(3-hloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5 -[2-methyl-2-(tetrahydro-pyran-4-yl)-propyl]-pyrrolidine-2-carboxylic acid ((S)-3 ,4- dihydroxy-butyl)-amide
Figure imgf000253_0001
M. W. 624.55 C31H37CI2F2N3O4
In a manner similar to the method described in Examples 118a, rac-(2R,3S,4R,5S)-3-(3-chloro- 2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-yl)-2- methyl-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide prepared in
Example 127e (0.28 g, 0.45 mmol) was treated with Pt02 and H2 in ethyl acetate to give rac- (2R,3S,4R,5S)-3-(3-hloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-[2-methyl- 2-(tetrahydro-pyran-4-yl)-propyl]-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy-butyl)-amide as a off white solid (0.15 g, 54%)
HRMS (ES+) m/z Calcd for C31H37CI2F2N3O4+ H [(M+H)+]: 624.2202, found: 624.2207.
Example 131a
Preparation of intermediate 2-((S)-2,2,5,5-ttramethyl-[l ,3]dioxolan-4-yl)-ethylamine
Figure imgf000253_0002
Step A To a suspension of L-(-)-malic aicd (Aldrich) (10.3 g, 77 mmol) in 2,2- dimethoxypropane (20 mL) was added p-toluenesulfonic acid monohydrate (0.4 g). The reaction mixture was stirred at room temperature for 30 min. The mixture was partitioned between water and dichloromethane. The organic layer was separated, the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with water, brine, dried over
MgSC>4, and concentrated to give ((S)-2,2-dimethyl-5-oxo-[l,3]dioxolan-4-yl)-acetic acid as a white solid (10.1 g, 75%).
Step B To the solution of ((S)-2,2-dimethyl-5-oxo-[l ,3]dioxolan-4-yl)-acetic acid (10.1 g, 58 mmol) in anhydrous tetrahydrofuran (20 mL) at 0 °C was added a solution of BH3.THF (1 M, 70 mL, 70 mmol). The reaction mixture was stirred at room temperature for 2 h. Aqueous HC1 solution was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHC03 solution, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (EtOAc) to give (S)-5-(2-hydroxy- ethyl)-2,2-dimethyl-[l,3]dioxolan-4-one as a colorless oil (6.8 g, 72%).
Step C A mixture of (S)-5-(2-hydroxy-ethyl)-2,2-dimethyl-[l,3]dioxolan-4-one (6.8 g, 42 mmol) and imidazole (7.5 g, 107 mmol) in dimethylformamide (40 mL) was added tert- butyldimethylchlorosilane (7 g, 45 mmol). The reactiom mixture was stirred at room temperature for 18 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with ethyl acetate twice. The combined organic layers wer washed with brine, dried over MgSC>4, concentrated to give (S)-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2,2-dimethyl- [l,3]dioxolan-4-one as a colorless oil (8.6 g, 74%).
Step D To a solution of (S)-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2,2-dimethyl- [l,3]dioxolan-4-one (8.5 g, 31 mmol) in diethyl ether (200 mL) at 0 °C was added a diethyl ether (1.6 M) solution of methyllithium (50 mL, 78 mmol) dropwise. The reaction mixture was stirred at 0 °C for 30 min. The mixture was poured into aqueous saturated NH4C1 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSC>4, and concentrated to give (S)-5-(tert- butyl-dimethyl-silanyloxy)-2-methyl-pentane-2,3-diol as a yellow oil (Yield: 6.8 g, 88%).
Step E To a suspension of (S)-5-(tert-butyl-dimethyl-silanyloxy)-2-methyl-pentane-2,3-diol (6.8 g, 27 mmol) in 2,2-dimethoxypropane (35 mL) was added p-toluenesulfonic acid monohydrate (0.2g). The reaction mixture was stirred at room temperature for 30 min. The mixture was partitioned between water and dichloromethane. The organic layer was separated, the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with water, brine, dried over MgSC>4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=l :20) to give tert-butyl-dimethyl-[2-((S)-2,2,5,5-tetramethyl-[l,3]dioxolan-4- yl)-ethoxy]-silane as a yellow oil (4.56 g, 58%). Step F To the solution of tert-butyl-dimethyl-[2-((S)-2,2,5,5-tetramethyl-[l ,3]dioxolan-4-yl)- ethoxy]-silane (4.56 g, 15.8 mmol) in tetrahydrofuran (20 mL) at 0 °C was added a solution of tetrabutylammonium fluoride (1 M, 20 mL, 20 mmol). The reaction mixture was stirred at room temperature for 1 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHC03 solution, brine, dried over MgSC>4, and concentrated to give 2-((S)-2,2,5,5-tetramethyl-[l,3]dioxolan-4-yl)-ethanol as a yellow oil (2.7 g, 100%).
Step G To a solution of 2-((S)-2,2,5,5-tetramethyl-[l ,3]dioxolan-4-yl)-ethanol (2.7 g, 15.8 mol) and triethylamine (4.6 g, 45 mmol) in dichloromethane (100 mL) at 0 °C was added
methane sulfonyl chloride (2.7 g, 24 mmol) 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>4, concentrated to give methanesulfonic acid 2-((S)-2 ,2,5,5 -tetramethyl- [l,3]dioxolan-4-yl)-ethyl ester as a yellow oil (2.5 g, 62%).
Step H To a solution of methanesulfonic acid 2-((S)-2,2,5,5-tetramethyl-[l,3]dioxolan-4-yl)- ethyl ester (2.5 g, 9.9 mmol) in N,N-dimethylformamide (50 mL) was added NaN3 (6 g, 70 mmol). The reaction mixture was heated at 95 °C for 4 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>4, concentrated to give (S)-5-(2-azido-ethyl)-2,2,4,4-tetramethyl- [l,3]dioxolane as a yellow oil (1.6 g, 80%>).
Step I A suspension of (S)-5-(2-azido-ethyl)-2,2,4,4-tetramethyl-[l,3]dioxolane (1.6 g, 8 mmol) and Pt02 (0.32 g) in ethyl acetate (15 mL) was vigorously shaken in a Parr under atmosphere of H2 (50 psi) for 18 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give 2-((S)-2,2,5,5-tetramethyl-[l ,3]dioxolan-4-yl)-ethylamine as a colorless oil (1.3 g, 94%).
Example 131b Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4- methyl-pentyl)-amide
Figure imgf000256_0001
M. W. 598.51 C29H35C12F2N304
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl- propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in
Example 105c (0.82 g, 1.37 mmol) was reacted with 2-((S)-2,2,5,5-tetramethyl-[l,3]dioxolan-4- yl)-ethylamine prepared in Example 131a (0.5 g, 2.88 mmol), HATU (0.94 g, 2.5 mmol) and iPr2NEt (1.2 mL, 6.9 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl- propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-pentyl)-amide as a white solid (0.53 g, 70%).
HRMS (ES+) m/z Calcd for C29H35Cl2F2N304+ H [(M+H)+]: 598.2046, found: 598.2047.
Example 131c
Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4- methyl-pentyl)-amide
Figure imgf000256_0002
M. W. 598.51 C29H35C12F2N304 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-rluoro-phenyl)-4-cyano-5-(3- hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl- pentyl)-amide (0.47 g) was separated by chiral SFC chromatography to provide chiral
(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3- hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl- pentyl)-amide as a white solid (0.18 g, 38%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro- phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid ((S)-3,4-dihydroxy-4-methyl-pentyl)-amide as a white solid (0.18 g, 38%). HRMS (ES+) m/z Calcd for C29H35Cl2F2N304+ H [(M+H)+]: 598.2046, found: 598.2045
Example 132a
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl- pentyl)-amide
Figure imgf000257_0001
M. W. 582.52 C29H35Cl2F2N303
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 52c (0.67 g, 1.15 mmol) was reacted with 2-((S)-2,2,5,5-tetramethyl-[l,3]dioxolan-4-yl)-ethylamine prepared in Example 131a (0.4 g, 2.3 mmol), HATU (0.79 g, 2.1 mmol) and iPr2NEt (1 mL, 5.8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4- methyl-pentyl)-amide as a white solid (0.29 g, 43%>).
HRMS (ES+) m/z Calcd for C29H35Cl2F2N303+ H [(M+H)+]: 582.2097, found: 582.2098.
Example 132b Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl- pentyl)-amide
Figure imgf000258_0001
M. W. 582.52 C29H35Cl2F2N303
Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy-4-methyl-pentyl)-amide (0.25 g) was separated by chiral SFC chromatography to provide chiral-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-pentyl)-amide as a white solid (103 mg, 41%) and chiral-(2S,3R,4S,5R)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl- pentyl)-amide as a white solid (114 mg, 45%).
HRMS (ES+) m/z Calcd for C29H35Cl2F2N303+ H [(M+H)+]: 582.2097, found: 582.2098.
Example 133 a
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5 -( 1 -methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy-4- methyl-pentyl)-amide
Figure imgf000258_0002
M. W. 622.58 C32H39C12F2N303
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(l-methyl-cyclohexylmethyl)- pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 102c (0.72 g, 1.15 mmol) was reacted with 2-((S)-2,2,5,5-tetramethyl-[l,3]dioxolan-4-yl)-ethylamine prepared in Example 131a (0.4 g, 2.3 mmol), HATU (0.79 g, 2.1 mmol) and iPr2NEt (1 niL, 5.8 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(l-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4- dihydroxy-4-methyl-pentyl)-amide as a white solid (0.25 g, 42%).
HRMS (ES+) m/z Calcd for C32H39C12F2N303+ H [(M+H)+]: 622.2410, found: 622.2411.
Example 133 b
Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5 -( 1 -methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy-4- methyl-pentyl)-amide
Figure imgf000259_0001
M. W. 622.58 C32H39C12F2N303
Rac-(2R,3S,4R,5S)- 3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(l- methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4-dihydroxy-4-methyl-pentyl)- amide (0.2 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)- 3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(l-methyl- cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-pentyl)-amide as a white solid (61 mg, 32%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro- 2-fluoro-phenyl)-4-cyano-5-(l -methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3 ,4- dihydroxy-4-methyl-pentyl)-amide as a white solid (78 mg, 39%>).
HRMS (ES+) m/z Calcd for C32H39Cl2F2N303+ H [(M+H)+]: 622.2410, found: 622.2412.
Example 134
Preparation of rac-(2S,3R,4S,5R)-4-(3-cloro-2-fiuoro-phenyl)-3-(4-chloro-2-fluoro-phi
(2,2-dimethyl-propyl)-5-(3-hydroxy-azetidine-l-carbonyl)-pyrrolidine-3-carbonitrile
Figure imgf000260_0001
M. W. 522.42 C26H27CI2F2N3O2
In a manner similar to the method described in Examples le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 52c (0.25 g, 0.43 mmol) was reacted with azetidin-3-ol hydrochloride (Matrix) (0.25 g, 2.7 mmol), HATU (0.4 g, 1 mmol) and iPr2NEt (0.6 g, 4.6 mmol) in CH2C12 at room temperature for 20 h to give rac-(2S,3R,4S,5R)-4- (3-cloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-5-(3-hydroxy- azetidine-l-carbonyl)-pyrrolidine-3-carbonitrile as a white solid (0.2 g, 89%).
HRMS (ES+) m/z Calcd for C26H27CI2F2N3O2+ H [(M+H)+]: 522.1521, found: 522.1520.
Example 135a
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [l-(2-hydroxy-2- methyl-propyl)-lH-pyrazol-3-yl]-amide
Figure imgf000260_0002
M. W. 620.53 C3oH33Cl2F2N503
In a manner similar to the method described in Examples le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 105c (0.55 g, 0.92 mmol) was reacted with l-(3-amino-pyrazol-l-yl)-2-methyl-propan-2-ol (0.17 g, 1.1 mmol), EDCI (0.26 g, 1.38 mmol), HOBT(0.19 g, 1.4 mmol) and NEt3 (0.26 mL, 1.8 mmol) in CH2C12 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1 -(2- hydroxy-2-methyl-propyl)-lH-pyrazol-3-yl]-amide as a white solid (0.11 g, 20%).
HRMS (ES+) m/z Calcd for C3oH33Cl2F2N503+ H [(M+H)+]: 620.2002, found: 620.1997.
Example 135b
Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [l-(2-hydroxy-2- methyl-propyl)-lH-pyrazol-3-yl]-amide
Figure imgf000261_0001
M. W. 620.53 C3oH33Cl2F2N503
Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(3- hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [l-(2-hydroxy-2-methyl-propyl)- lH-pyrazol-3-yl] -amide (0.11 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(3- hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (([1 -(2-hydroxy-2-methyl-propyl)- lH-pyrazol-3-yl] -amide as a white solid (40 mg, 36%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid [l-(2-hydroxy-2-methyl-propyl)-lH-pyrazol-3-yl]-amide as a white solid (39 mg, 35%).
HRMS (ES+) m/z Calcd for C30H33Cl2F2N5O3+ H [(M+H)+]: 620.2002, found: 620.1999.
Example 136a
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid [l-(2-hydroxy-2-methyl- propyl)- 1 H-pyrazol-3 -yl] -amide
Figure imgf000262_0001
M. W. 634.55 C31H35CI2F2N5O3
In a manner similar to the method described in Examples le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)- pyrrolidine-2-carboxylic acid
prepared in Example 116c (0.48 g, 0.78 mmol) was reacted with l-(3-amino-pyrazol-l-yl)-2- methyl-propan-2-ol (0.15 g, 0.9 mmol), HATU (0.6 g, 1.6 mmol) and iPr2NEt (0.41 mL, 2.4 mmol) in CH2CI2 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro- phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2- carboxylic acid [l-(2-hydroxy-2-methyl-propyl)-lH-pyrazol-3-yl]-amide as a white solid (0.27 g, 55%).
HRMS (ES+) m/z Calcd for C3 iH35Cl2F2N503+ H [(M+H)+]: 634.2158, found: 634.2153.
Example 136b
Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid [1 -(2-hydroxy-2-methyl- propyl)- 1 H-pyrazol-3 -yl] -amide
Figure imgf000262_0002
M. W. 634.55 C3iH35Cl2F2N503 Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(4- hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid [l-(2-hydroxy-2-methyl-propyl)-lH- pyrazol-3-yl]-amide (0.25 g) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(4- hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid [l-(2-hydroxy-2-methyl-propyl)-lH- pyrazol-3-yl]-amide as a white solid (105 mg, 42%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)- pyrrolidine-2-carboxylic acid [l-(2-hydroxy-2-methyl-propyl)-lH-pyrazol-3-yl]-amide as a white solid (105 mg, 42%).
HRMS (ES+) m/z Calcd for C3 iH35Cl2F2N503+ H [(M+H)+]: 634.2158, found: 634.2157.
Example 137
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbox lic acid amide
Figure imgf000263_0001
M. W. 466.36 C23H23C12F2N30
In a manner similar to the method described in Examples le, rac-(2R,3S,4R,5S)-3-(3-chloro-2 fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 52c (0.5 g, 0.86 mmol) was reacted with a dioxane solution (0.5 M) of ammonia (2 mL, 1 mmol), HATU (0.38 g, 1 mmol) and iPr2NEt (0.6 g, 4.6 mmol) in CH2C12 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3 (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid amide as a white solid (0.3 g, 75%).
HRMS (ES+) m/z Calcd for C23H23Cl2F2N30 + H [(M+H)+]: 466.1259, found: 466.1259. Example 138
Preparation of rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -nicotinic acid methyl ester
Figure imgf000264_0001
M. W. 601.48 C3QH28C12F2N403
In a manner similar to the method described in Examples le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 52c (0.5 g, 0.86 mmol) was reacted with 6-amino-nicotinic acid methyl ester (Aldrich) (0.3 g, 2 mmol), HATU (0.38 g, 1 mmol) and iPr2NEt (0.6 g, 4.6 mmol) in CH2C12 at room temperature for 20 h to give rac-6- {[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -nicotinic acid methyl ester as a white solid (0.3 g, 58%).
HRMS (ES+) m/z Calcd for C3oH28Cl2F2N403 + H [(M+H)+]: 601.1580, found: 601.1578.
Example 139
Preparation of rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -N-(2 -hydroxy- 1 ,1 - dimethyl-ethyl)-nicotinamide
Figure imgf000265_0001
M. W. 658.57 C33H35Cl2F2N503
To a solution of rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -nicotinic acid methyl ester prepared in Example 138 (0.2 g, 0.33 mmol) in tetrahydrofuran (3 mL) was added an aqueous solution (1 N) of NaOH (1 mL, 1 mmol) and methanol (1 mL). The reaction mixture was stirred at room temperature fro 20 h, and the "pH" of the solution was adjusted to 5-6 by aqueous HC1 solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgS04, and concentrated to give rac-6- {[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid as a white foam (0.12 g).
In a manner similar to the method described in Examples le, rac-6-{[(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino} -nicotinic acid (0.12 g, 0.2 mmol) was reacted with 2-amino-2- methyl- 1 -propanol (Aldrich) (0.1 g, 1.1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2.3 mmol) in CH2C12 at room temperature for 20 h to give rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carbonyl]-amino}-N-(2-hydroxy-l ,l-dimethyl-ethyl)-nicotinamide as a white solid (30 mg, 22%). HRMS (ES+) m/z Calcd for C33H35Cl2F2N503 + H [(M+H)+]: 658.2158, found: 658.2155.
Example 140
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-acetylamino-pyridin-3-yl)-amide
Figure imgf000266_0001
M. W. 600.49 C30H29CI2F2N5O2
In a manner similar to the method described in Examples le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 52c (0.16 g, 0.28 mmol) was reacted with N-(5-amino-pyridin-2-yl)-acetamide (Aldrich) (0.12 g, 0.79 mmol), HATU (0.1 g, 0.26 mmol) and iP^NEt (0.2 g, 1.5 mmol) in CH2CI2 at room temperature for 20 h to give rac- (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-acetylamino-pyridin-3-yl)-amide as a white solid (0.15 g, 89%).
HRMS (ES+) m/z Calcd for C30H29CI2F2 5O2 +H [(M+H)+]: 600.1739, found: 600.1739.
Example 141a
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl) cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (l-methyl-2-oxo-l,2-dihydro- pyridin-4-yl)-amide
Figure imgf000266_0002
M. W. 573.47 C29H28CI2F2N4O2
In a manner similar to the method described in Examples le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 52c (0.2 g, 0.43 mmol) was reacted with 4-amino-l -methyl- lH-pyridin-2-one (Molbridge)(0.11 g, 0.86 mmol), HATU (0.29 g, 0.77 mmol) and iPr2NEt (0.15 mL, 0.86 mmol) in CH2C12 at room temperature for 20 h to give rac- (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (l-methyl-2-oxo-l ,2-dihydro-pyridin-4-yl)- amide as a white solid (35 mg, 14%).
HRMS (ES+) m/z Calcd for C29H28C12F2N402+ H [(M+H)+]: 573.1630, found: 573.1633.
Example 141b
Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (l-methyl-2-oxo-l,2-dihydro- pyridin-4-yl)-amide
Figure imgf000267_0001
M. W. 573.47 C29H28C12F2N402
Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (l-methyl-2-oxo-l ,2-dihydro-pyridin-4-yl)- amide (68 mg) was separated by chiral SFC chromatography to provide chiral-(2R,3S,4R,5S)-3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid (l-methyl-2-oxo-l,2-dihydro-pyridin-4-yl)-amide as a white solid (16 mg, 24%) and chiral-(2S,3R,4S,5R)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (l-methyl-2-oxo-l ,2- dihydro-pyridin-4-yl)-amide as a white solid (16 mg, 24%).
HRMS (ES+) m/z Calcd for C29H28C12F2N402+ H [(M+H)+]: 573.1630, found: 573.1626. Example 142
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [5-((S)-l ,2-dihydroxy-ethyl)- pyrazin-2 -yl] - amide
Figure imgf000268_0001
M. W. 604.48 C29H29CI2F2N5O3
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 52c (0.1 g, 0.2 mmol) was reacted with 5-((S)-2,2-dimethyl-[l ,3]dioxolan-4-yl)-pyrazin-2-ylamine (46 mg, 0.24 mmol), T3P (Aldrich) (0.32 mL, 0.53 mmol) and iPr2NEt (0.11 mL, 0.64 mmol) in CH2C12 at room temperature for 20 h, then reacted with aqueous HC1 solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [5-((S)-l,2-dihydroxy- ethyl)-pyrazin-2-yl]-amide as a white solid (14 mg, 1 1%).
HRMS (ES+) m/z Calcd for C29H29Cl2F2N503+ H [(M+H)+]: 604.1689, found: 604.1687.
Example 143
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid (l-methyl-2-oxo-l,2- dihydro-pyridin-4-yl)-amide
Figure imgf000269_0001
M. W. 603.49 C30H30CI2F2N4O3
In a manner similar to the method described in Examples le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)- pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 116c (0.5 g, 0.8 mmol) was reacted with 4-amino-l -methyl- lH-pyridin -2 -one (Molbridge)(0.18 g, 1.5 mmol), HATU (0.62 g, 1.6 mmol) and iP^NEt (0.71 mL, 4.1 mmol) in CH2CI2 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5- (4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid (1 -methyl-2-oxo-l ,2-dihydro- pyridin-4-yl)-amide as a white solid (25 mg, 5.1 %).
HRMS (ES+) m/z Calcd for C30H30CI2F2N4O3+ H [(M+H)+]: 603.1736, found: 603.1739.
Example 144
Preparation of rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -furan-2-carboxyl acid methyl ester
Figure imgf000269_0002
M. W. 590.45 C29H27CI2F2N3O4
To a solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl) cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.5 g, 1.07 mmol) in
dichloromethane (5 mL) at 0 °C was added oxalyl chloride (0.11 mL, 1.28 mmol) and DMF (0.03 niL). Thereaction mixture was stirred at 0 °C for 3 h, then concentrated. The residue was dissolved into dichloromethane (5 mL), triethylamine (0.45 mL, 3.2 mmol) and DMAP (20 mg, 0.14 mmol) were added, followed by the addtion of methyl 5-amino-2-furoate (Lancaster) (0.38 g, 2.7 mmol). The reaction mixture was stirred at room temperature for 4 h. Water was added, and the mixture was extracted with dichloromethane twice. The organic layers were combined, washed with water, brine, dried over MgSC>4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=l :3) to give rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro- phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]- amino}-furan-2-carboxylic acid methyl ester as a off white solid (0.1 g, 16%).
HRMS (ES+) m/z Calcd for C29H27CI2F2N3O4+ H [(M+H)+]: 590.1420, found: 590.1418.
Example 145
Preparation of rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl^ropyl)-pyi olidine-2-carbonyl]-amino} -furan-2-carboxyl acid
Figure imgf000270_0001
M. W. 576.43 C28H25Cl2F2N304
To a solution of rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl^ropyl)-pyi olidine-2-carbonyl]-amino} -furan-2-carboxylic acid methyl ester prepared in Example 144 (80 mg, 0.14 mmol) in tetrahydrofuran (2 mL) was added an aqueous solution (2 mL) of LiOH (32 mg, 1.35 mmol). The reaction mixture was stirred at room temperature for 66 h, and the "pH" of the solution was adjusted to 5-6 by aqueous HC1 solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgS04, and concentrated to give rac-5- {[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl^ropyl)-pyrrolidine-2-carbonyl]-amino}-furan-2-carboxylic acid as a yellow solid (60 mg, 74%).
HRMS (ES+) m/z Calcd for C28H25Cl2F2N304+ H [(M+H)+]: 576.1263, found: 576.1264. Example 146
Preparation of rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl^ropyl)-pyrrolidine-2-carbonyl]-amino} -furan-2-carboxylic acid amide
Figure imgf000271_0001
M. W. 575.44 C28H26Cl2F2N403
To a solution of rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl^ropyl)-pyrrolidine-2-carbonyl]-amino} -furan-2-carboxylic acid prepared in Example 145 (60 mg, 0.1 mmol) in N,N-dimethylformamide (2 mL) was added NH4C1 (28 mg, 0.5 mmol), EDCI (40 mg, 0.2 mmol), HOBT(28 mg, 0.2 mmol) and NEt3 (0.029 mL, 0.2 mmol). The reaction mixture was heated at 75 °C for 20 h. The mixture was cooled to room temperature, and partitioned between ethyl acetate 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 (EtOAc) to give rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro- phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]- amino}-furan-2-carboxylic acid amide as a white solid (30 mg, 50%).
HRMS (ES+) m/z Calcd for C28H26Cl2F2N403+ H [(M+H)+]: 575.1423, found: 575.1425.
Example 147
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-chloro-pyridazin-3-yl)-amide
Figure imgf000272_0001
M. W. 578.88 C27H24Cl3F2N50
In a manner similar to the method described in Examples le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 52c (0.3 g, 0.51 mmol) was reacted with 3-amino-6-chloro-pyridazine (Alfa) (0.15 g, 1.2 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.6 g, 4.6 mmol) in CH2C12 at room temperature for 48 h to give rac-(2R,3S,4R,5S)-3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid (6-chloro-pyridazin-3-yl)-amide as a yellow solid (0.15 g, 51%).
Example 148
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-methyl-pyridin-3-yl)-amide
Figure imgf000272_0002
M. W. 557.47 C29H28C12F2N40
In a manner similar to the method described in Examples le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 52c (0.3 g, 0.52 mmol) was reacted with 3-amino-2-methyl-pyridine (Aldrich) (0.11 g, 1.1 mmol), HATU (0.36 g, 0.94 mmol) and iPr2NEt (0.27 g, 1.6 mmol) in CH2C12 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid (2-methyl-pyridin-3-yl)-amide as a yellow solid (0.16 g, 55%). HRMS (ES+) m/z Calcd for C29H28CI2F2N4O+ H [(M+H)+]: 557.1681 , found: 557.1677.
Example 149a
Preparation of intermediate 2-(4-amin -phenoxy)-ethanol
Figure imgf000273_0001
M. W. 153.18 C8HiiN02
A suspension of 2-(4-nitrophenoxy)ethanol (Aldrich) (2 g, 10.9 mmol) and Pd/C (Aldrich, 10%>, 0.2 g) in methanol (50 mL) was vigorously shaken in a Parr under atmosphere of ¾ (50 psi) for 1 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give 2-(4-amino-phenoxy)-ethanol as a light yellow solid (1.6 g, 96%>).
Example 149b
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-hydroxy-ethoxy)-phenyl]- amide
Figure imgf000273_0002
M. W. 602.51 C31H31CI2F2N3O3
In a manner similar to the method described in Examples le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid (0.4 g, 0.86 mmol) was reacted with 2-(4-amino-phenoxy)-ethanol (0.24 g, 1.5 mmol), HATU (0.58 g, 1.5 mmol) and iPr2NEt (0.3 mL, 1.7 mmol) in CH2C12 (20 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2 -carboxylic acid [4-(2-hydroxy- ethoxy)-phenyl]-amide as a white solid (0.4 g, 78%).
HRMS (ES+) m/z Calcd for C31H31CI2F2N3O3+ H [(M+H)+]: 602.1784, found: 602.1783.
Example 149c
Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-hydroxy-ethoxy)-phenyl]- amide
Figure imgf000274_0001
M. W. 602.51 C31H31CI2F2N3O3
Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-hydroxy-ethoxy)-phenyl]-amide (0.25 g) was separated by chiral SFC chromatography to provide chiral-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid [4-(2-hydroxy-ethoxy)-phenyl]-amide as a white solid (94 mg, 37%) and chiral- (2S,3R,4S,5R)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-hydroxy-ethoxy)-phenyl]-amide as a white solid (100 mg, 40%).
HRMS (ES+) m/z Calcd for C31H31CI2F2N3O3+ H [(M+H)+]: 602.1784, found: 602.1784. Example 150
Preparation of rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -thiophene-2- carboxylic acid methyl ester
Figure imgf000275_0001
M. W. 606.52 C29H27CI2F2N3O3S
In a manner similar to the method described in Examples 144, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid (0.3 g, 0.64 mmol) was reacted with oxalyl chloride (0.12 mL, 1.4 mmol), triethylamine (0.22 mL, 1.6 mmol), DMAP (5 mg), and 5-amino-2-thiophene-carboxylate
(Princeton) (0.14 g, 0.96 mmol) to give rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-
(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}- thiophene -2 -carboxylic acid methyl ester as a yellow solid (0.11 g, 28%).
HRMS (ES+) m/z Calcd for C29H27CI2F2N3O3S+ H [(M+H)+]: 606.1191 , found: 606.1191.
Example 151a
Preparation of rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -thiophene-2- carboxylic acid
Figure imgf000275_0002
M. W. 592.49 C28H25CI2F2N3O3S
To a solution of rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl^ropyl)-pyrrolidine-2-carbonyl]-amino} -thiophene-2- carboxylic acid methyl ester prepared in Example 150 (90 mg, 0.15 mmol) in tetrahydrofuran (3 mL) was added an aqueous solution (3 niL) of LiOH (36 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 66 h, and the "pH" of the solution was adjusted to 5 by aqueous HC1 solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSC>4, and concentrated to give rac-5- {[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -thiophene-2-carboxylic acid as a yellow solid (60 mg, 74%).
HRMS (ES+) m/z Calcd for C28H25Cl2F2N303S+ H [(M+H)+]: 592.1035, found: 592.1035.
Example 151b
Preparation of 5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-thiophene-2-carboxylic acid
Figure imgf000276_0001
M. W. 592.49 C28H25CI2F2N3O3S
Rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-thiophene-2-carboxylic acid (50 mg) was separated by chiral SFC chromatography to provide chiral 5-{[(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carbonyl]-amino}-thiophene-2-carboxylic acid as a white solid (12 mg, 24%) and chiral 5- {[(2S,3R,4S,5R)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-thiophene-2-carboxylic acid as a white solid (12 mg, 24%). HRMS (ES ) m/z Calcd for C28H25Cl2F2N303S+ H [(M+H)+ ]: 592.1035, found: 592.1035.
Example 152
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbox lic acid (2-methoxy-pyridin-4-yl)-amide
Figure imgf000277_0001
M. W. 573.47 C29H28CI2F2N4O2
In a manner similar to the method described in Examples le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid (0.4 g, 0.75 mmol) was reacted with 2-methoxy-pyridin-4-ylamine (Oakwood) (0.1 g, 0.9 mmol), HATU (0.51 g, 1.35 mmol) and iPr2NEt (0.33 mL, 1.9 mmol) in CH2C12 at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-methoxy-pyridin-4- yl)-amide as a white solid (0.2 g, 47%).
HRMS (ES+) m/z Calcd for C29H28CI2F2N4O2+ H [(M+H)+]: 573.1630, found: 573.1633.
Example 153
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbox lic acid (2-hydroxy-pyridin-4-yl)-amide
Figure imgf000277_0002
M. W. 559.44 C28H26CI2F2N4O2 In a manner similar to the method described in Examples le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid (0.49 g, 1.1 mmol) was reacted with 4-amino-pyridin-2-ol (Molbridge) (0.14 g, 1.3 mmol), HATU (0.72 g, 1.9 mmol) and iPr2NEt (0.46 mL, 2.6 mmol) in CH2C12 at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-hydroxy-pyridin-4- yl)-amide as a off white solid (20 mg, 3.4%).
HRMS (ES+) m/z Calcd for C28H26C12F2N402+ H [(M+H)+]: 559.1474, found: 559.1477.
Example 154
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phi cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-acetyl-phenyl)-amide
Figure imgf000278_0001
M. W. 584.49 C3iH29Cl2F2N302
In a manner similar to the method described in Examples le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid (0.35 g, 0.75 mmol) was reacted with 1 -(4-amino-phenyl)-ethanone (Aldrich) (0.12 g, 0.9 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (0.33 mL, 2.6 mmol) in CH2C12 at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-acetyl-phenyl)-amide as a white solid (0.12 g, 27%).
HRMS (ES+) m/z Calcd for C3iH29Cl2F2N302+ H [(M+H)+]: 584.1678, found: 584.1680. Example 155
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbox lic acid [4-(2-bromo-acetyl)-phenyl]-amide
Figure imgf000279_0001
M. W. 663.39 C3iH28BrCl2F2N302
In a manner similar to the method described in Examples le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid (0.35 g, 0.75 mmol) was reacted with l-(4-amino-phenyl)-2-bromo-ethanone (Astatech) (0.17 g, 0.9 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (0.33 mL, 2.6 mmol) in CH2C12 at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2- bromo-acetyl)-phenyl]-amide as a white solid (36 mg, 7%).
HRMS (ES+) m/z Calcd for C3iH28BrCl2F2N302+ H [(M+H)+]: 662.0783, found: 662.0782.
Example 156
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl) cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2- dimethylamino-acetyl)- phenyl]-amide
Figure imgf000279_0002
M. W. 627.56 C33H34C12F2N402 To the solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-bromo-acetyl)-phenyl]- amide (30 mg, 0.045 mmol) in tetrahydrofuran (1 mL) was added a tetrahydrofuran solution (2 M) of dimethylamine (0.057 mL, 0.11 mmol). The reaction mixture was stirred at room temperature for 30 min. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSC>4, and concentrated to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro- 2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2- dimethylamino-acetyl)-phenyl]-amide as a yellow solid (10 mg, 35%)
HRMS (ES+) m/z Calcd for C33H34CI2F2N4O2+ H [(M+H)+]: 627.2100, found: 627.2102.
Example 157
Preparation of 4-chloro-3-fluoro-phen l)-acetonitrile
Figure imgf000280_0001
To a solution of 4-bromo-l-chloro-2-fluoro-benzene in diisopropl ether (50 mL) at -78°C was added t-butyllithium maintaining the temperature below -70°C. A white precipitate formed. After 30 minutes, zinc chloride was added, maintaining the temperature below -50°C. The resulting mixture was added to a solution of bromoacetonitrile (0.8 mL, 12.1 mmol),
nickel(II)acetylacetonate (0.1485 g, 0.578 mmol), and tri-o-tolylphosphine (0.1787 g, 0.578 mmol) in THF (100 mL) and the reaction heated under reflux for 2 hours with pentane removed by distillation. The reaction was concentrated under reduced pressure and partitioned between ethyl acetate and 2N aqueous sodium hydroxide solution. The organic layer was retained and the aqueous layer re-extracted with ethyl acetate. The organic portions were combined, washed with brine, dried over MgS04, filtered and concentrated under reduced pressure to give a brown oil. Purification by column chromatography, 40 g silica column, (1 to 100% EtOAc/heptane) to yield 4-chloro-3-fluoro-phenyl)-acetonitrile, 0.47 g, 33.6 %>. Example 158
Preparation of (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-3-fiuoro-phenyl)-acrylonitrile
Figure imgf000281_0001
A mixture of 4-chloro-3-fluorobenzylcyanide (1.0 g, 5.92 mmol), 3-chloro-2-fiuorobenzaldehyde (0.938 g, 5.92 mmol), 2 N NaOH (4 mL) and isopropyl alcohol were stirred at rt. The mixture was stirred for 10 min. to afford a solid ppt that was collected by filtration with multiple water washes. The solid was dried ON under reduced pressure to afford a white solid (Z)-3-(3-chloro- 2-fiuoro-phenyl)-2-(4-chloro-3-fiuoro-phenyl)-acrylonitrile, 1.62 g, 89.3%; HRMS (ES+) m/z Calcd for Ci5H7Cl2F2N+ H [(M+H)+]: 308.9924, found: 308.9926.
Example 159
Preparation of rac-(25',35,,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-3-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester and rac- (2i?,35,,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-3-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbox lic acid tert-butyl ester
Figure imgf000281_0002
M. W. 523.46 C27H3oCl2F2N202
To a solution of (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-3-fiuoro-phenyl)-acrylonitrile and [3,3-dimethyl-but-(Z)-ylideneamino]-acetic acid tert-butyl ester in dichloroethane (20 mL) was added TEA (1.46 mL, 10.44 mmol), AgF (0.661 g, 5.22 mmol) and stirred at RT overnight. The mixture was then quenched with NH4C1 (satd) solution and extracted with CH2C12. The organic phase was separated, filtered through celite and dried over Na2S04. the solvent was removed by reduced pressure to yield crude oil that was purified with silica column chromatography (1-20 % EtO Ac/heptane) to yield two products; rac-(25',35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4- chloro-3-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert- butyl ester (0.410 g, 15 %) as a yellow solid. HRMS (ES ) m/z Calcd for C27H30CI2F2N2O2 + H [(M+H)+]: 523.1725, found: 523.1725 and rac-(2i?,35,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4- chloro-3-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert- butyl ester (0.92 g, 33.7 %) as an yellow solid. HRMS (ES+) m/z Calcd for C27H30CI2F2N2O2 + H [(M+H)+]: 523.1725, found: 523.1722.
Example 160
Preparation of rac-(2i?,35',4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbox lic acid
Figure imgf000282_0001
M. W. 467.35 C23H22CI2F2N2O2
A mixture of rac-(2i?,35',4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (0.6 g, 1.15 mmol) was cooled to 0°C, then cone. H2S04 (2 mL) was added slowly. The reaction was stirred at RT for 2 hours. The mixture was then poured into ice and extracted with EtO Ac. The organic phase was separated, dried over Na2S04, filtered and solvent was removed under reduced pressure to yield a residue that was triturated with ethyl acetate/ heptane and the precipitates were collected by filtration and washed with ether to yield the product rac-(2i?,35',4i?,55)-3-(3-chloro-2-fluoro- phenyl)-4-(4-chloro-3-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.526 g, 98.1%) as a white solid. HRMS (ES+) m/z Calcd for C23H22CI2F2N2O2 + H
[(M+H)+]: 467.1099, found: 467.1097. Example 161
Preparation of rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[l ,3]dioxolan- 4-yl)-ethyl]-amide
Figure imgf000283_0001
M.W. 594.53 C3oH35Cl2F2N303
A mixture rac-(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-3-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (125 mg, 0.267 mmol), 2-((5)-2,2- dimethyl-[l ,3]dioxolan-4-yl)-ethylamine (0.2 mg, 1.3 mmol), 2-(7-azabenzotriazol-l -yl)- η,η,η',η'-tetramethyluronium hexafluorophosphate (HATU, 1 14.1 mg, 0.3 mmol) and iP^NEt (0.3 mL, 3.22 mmol) in CH2CI2 (2 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 purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2i?,35,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-3- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2- dimethyl-[l ,3]dioxolan-4-yl)-ethyl]-amide (101 mg, 63.5 %) as an off-white powder. HRMS (ES+) m/z Calcd for C30H35Cl2N3O3 + H [(M+H)+]: 594.2097, found: 594.2096.
Example 162
Preparation of rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide and rac-(25,,3i?,45,,5i?)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((5)-3,4-dihydroxy-butyl)-amide
Figure imgf000284_0001
M.W. 554.47 C27H31CI2F2N3O3
A mixture of rac-(2i?,3i?,4i?,55)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [l-((R)-2,2-dimethyl-[l,3]dioxolan-4-ylmethyl)- lH-pyrazol-3-yl] -amide (81 mg, 0.133 mmol), pyridinium p-toluene sulfonic acid (5 mg, 0.0198 mmol) and methanol (4 mL) was microwaved at 120°C for 5 min. Solvent evaporated and purified by reverse phase chromatography (20-95% of ACN/water) to rac-(2i?,35',4i?,55)-3-(3- Chloro-2-fiuoro-phenyl)-4-(4-chloro-3-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid ((5)-3,4-dihydroxy-butyl)-amide ( 20.7 mg, 22 %) as a white powder. HRMS (ES+) m/z Calcd for C27H31CI2F2N3O3 + H [(M+H)+]: 554.1784, found:
554.1780. rac-(2«S,3i?,4,S,5i?)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-3-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (18.8 mg, 20 %) as a white powder. HRMS (ES+) m/z Calcd for C27H31CI2F2N3O3 + H
[(M+H)+]: 554.1784, found: 554.1781
Example 163
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [l-(2-hydroxy-2-methyl-propyl)- lH-pyrazol-3-yl] -amide
Figure imgf000284_0002
M. W. 604.526 C30H33Cl2F2N5O2
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), l-(3-amino- pyrazol-l-yl)-2-methyl-propan-2-ol ( 62 mg, 0.3 mmol), 2-(7-azabenzotriazol-l-yl)-n,n,n',n'- tetramethyluronium hexafiuorophosphate (HATU, 114.06 mg, 0.3 mmol) and iPr2NEt (0.1 mL, 0.6 mmol) in CH2C12 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2C12 and washed with water, brine. The organic phase was separated, dried over Na2S04 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (20- 95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [l-(2-hydroxy-2- methyl-propyl)-lH-pyrazol-3-yl]-amide ( 23.1 mg, 20.8 %) as an off-white powder. HRMS (ES+) m/z Calcd for C3oH33Cl2F2N502 + H [(M+H)+]: 604.2052, found: 604.2052.
Example 164
Preparation of chiral 2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [l-(2-hydroxy-2-methyl-propyl)- lH-pyrazol-3-yl] -amide and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro- phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [ 1 -(2 -hydrox -2 -methyl-propyl)- 1 H-pyrazol-3 -yl] -amide
Figure imgf000285_0001
M. W. 604.526 C30H33Cl2F2N5O2
The racemate 2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [l-(2-hydroxy-2-methyl-propyl)-lH- pyrazol-3-yl]-amide (0.25 g) was submitted for SFC purification (30% methanol/water, lOOpsi) to afford of chiral 2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [l-(2-hydroxy-2-methyl-propyl)- lH-pyrazol-3-yl] -amide ( 117 mg, 21 %) as an off-white powder. HRMS (ES ) m/z Calcd for C30H33CI2F2N5O2 + H [(M+H)+]: 604.2052, found: 604.2051 and chiral (2S,3R,4S,5R)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid [l-(2-hydroxy-2-methyl-propyl)-lH-pyrazol-3-yl]-amide ( 110 mg, 19.8 %) as an off-white powder. HRMS (ES+) m/z Calcd for C3oH33Cl2F2N502+ H [(M+H)+]: 604.2052, found: 604.2052.
Example 165
Preparation of 1 -(3-amino-pyrazol-l -yl)-2-methyl-propan-2-ol
Figure imgf000286_0001
M. W. 155.22 C8Hi5N20
A mixture of 2-methyl-l-(3-nitro-pyrazol-l -yl)-propan-2-ol (0.3 g, 1.6 mmol), Zn dust( 0.42 g, 6.5 mmol), ammonium chloride (0.85 g, 16 mmol) and methanol (2 mL) was microwaved at 120°C for 10 min. The resulting suspension was filtered through celite with methanol and THF washes. Solvent was removed under reduced pressure to yield crude product.that was triterated with ethyl acetate and filtered again to get rid of ammonium chloride salt. Product 1 -(3-amino- pyrazol-l -yl)-2-methyl-propan-2-ol was a yellow solid (233 mg, 94%). Example 166
Preparation of 2-methyl- 1 -(3 -nitro-pyrazol- 1 -yl)-propan-2-ol
Figure imgf000286_0002
A mixture of 3-nitro-lH-pyrazole (10.0 g, 88.43 mmol), 2,2-dimethyl-oxirane ( 15.7 mL, 176.9 mmol), potassium carbonate (18.2 g, 132 mmol) and DMF (100 mL) was stirred at 100°C for lh, then stirred ON at rt. The mixture was then diluted with ethyl acetate and water, the organic layer was separated, dried over Na2S04, and filtered. The resulting mixture was concentrated under reduced pressure to yield the crude product that was purified (50% EtO Ac/heptane) to yield the product 2-methyl-l-(3-nitro-pyrazol-l-yl)-propan-2-ol as a waxy solid (4.88 g, 30%).
Example 167
Preparation of 1 -[2-methyl-2-((R)- 1 -oxiranylmethoxy)-propyl]-3-nitro- lH-pyrazole
Figure imgf000287_0001
M. W. 241.25 CioHi5N304
A mixture of 2-methyl-l-(3-nitro-pyrazol-l-yl)-propan-2-ol (1.31 g, 7.07 mmol), and DMF (60 mL) was stirred at 0°C for 5 min, then NaH (60%> dispersion in oil, 0.85 g, 21.2 mmol) was added and stirred 20 min at 0°C. R-(-)-glycidyl-3-nitrobenzenesulfonate ( 2.75 g, 10.6 mmol) was added and stirred at 0°C for lh then warmed to rt for 14h. The mixture was then diluted with NH4Cl(s), ethyl acetate, the organic phase was separated, washed with NaHC03(satd) dried with Na2S04, and filtered. The mixture was then concentrated and purified by column
chromatography (40-240 g Analogix column, 70% EtoAc/heptane to yield the product l-[2- methyl-2-((i?)-l-oxiranylmethoxy)-propyl]-3-nitro-lH-pyrazole as a white solid (0.7 g, 41 %).
Example 168
Preparation of l-[2-methyl-2-((i?)-l-oxiranylmethoxy)-propyl]-lH-pyrazol-3yl amine
Figure imgf000287_0002
M. W. 211.27 CioHi7N302 A mixture of l-[2-methyl-2-((i?)-l-oxiranylmethoxy)-propyl]-3-nitro-lH-pyrazole (0.3 g, 1.24 mmol), and ethyl acetate (15 mL), ethanol (15 mL) was subjected to the H-Cube (Thales Nano) at 1 mL/min at 10°C, 10 psi hydrogen. The first time through not completely reduced.
Resubjected and complete reduction of nitro group by NMR. Solvent was removed under reduced pressure to afford l-[2-methyl-2-((i?)-l-oxiranylmethoxy)-propyl]-lH-pyrazol-3ylamine as an oil (0.27 g, 100%).
Example 169
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {l-[2-methyl-2-((R)-l- oxiranylmethoxy)-propyl]- -pyrazol-3-yl} -amide
Figure imgf000288_0001
M. W. 660.589 C33H37C12F2N503
A mixture of rac-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.56 g, 1.2 mmol), l-[2-methyl-2- ((i?)-l-oxiranylmethoxy)-propyl]-lH-pyrazol-3ylamine ( 0.27 g, 1.12 mmol), 2-(7- azabenzotriazol-l-yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (HATU, 0.912 g, 2.4 mmol) and iPr2NEt (1.5 mL, 8.4 mmol) in CH2C12 (50 mL) was stirred at rt overnight. 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 column chromatography (25-80 g Analgix column, 1-100% ethyl acetate/heptane) to give rac- (2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethylpropyl)-pyrrolidine-2-carboxylic acid { 1 -[2-methyl-2-((i?)- 1 -oxiranylmethoxy)-propyl]- lH-pyrazol-3-yl} -amide ( 222 mg, 28 %) as an off-white solid. HRMS (ES+) m/z Calcd for C33H37C12F2N503 + H [(M+H)+]: 660.2315, found: 660.2312.
Example 170 Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid { l-[2-((i?)-3-amino-2-hydroxy- propoxy)-2-methyl-propyl -lH-pyrazol-3-yl} -amide
Figure imgf000289_0001
M. W. 677.63 C33H40CI2F2N6O3
A mixture of rac-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {l-[2-methyl-2-((i?)-l- oxiranylmethoxy)-propyl]-lH-pyrazol-3-yl}-amide ( 43.6 mg, 0.066 mmol), isopropyl alcohol ( 2 mL), and ammonium hydroxide (1 mL) was microwaved at 130°C for 15 min. 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 reverse phase chromatography (20-95% of ACN/water) to give rac-(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro- phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid { l-[2-((i?)-3-amino-2-hydroxy-propoxy)-2-methyl-propyl]-lH-pyrazol-3-yl}-amide ( 11.4 mg, 26 %) as an off-white solid. HRMS (ES+) m/z Calcd for C33H40CI2F2N6O3 + H [(M+H)+]: 677.2580, found: 677.2576.
Example 171
Preparation of rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (l-{2-[(i?)-2-hydroxy-3-(3- hydroxy-propylamino)-propoxy]-2-methyl-propyl} - 1 H- pyrazol-3 -yl)-amide
Figure imgf000289_0002
M. W. 735.699 CseH^C^NeC^ A mixture of rac-(2i?,35',4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {l-[2-methyl-2-((i?)-l- oxiranylmethoxy)-propyl]-lH-pyrazol-3-yl}-amide ( 43.6 mg, 0.066 mmol), isopropyl alcohol ( 2 mL), diisopropylethyl amine (0.1 mL, 0.56 mmol) and 3-amino-l-propanol (0.1 mL, 1.3 mmol) was micro waved at 130°C for 15 min. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2i?,35',4i?,55)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid (l-{2-[(i?)-2-hydroxy-3-(3-hydroxy-propylamino)-propoxy]-2-methyl-propyl} - 1H- pyrazol-3-yl)-amide ( 10.1 mg, 20.8 %) as an off-white powder. HRMS (ES+) m/z Calcd for C36H46CI2F2N6O4 + H [(M+H)+]: 735.2999, found: 735.2998.
Example 172
Preparation of rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (l-{2-[(i?)-2-hydroxy-3-(2- hydroxy-l-hydroxymethyl-ethylamino)-propoxy]-2-methyl-propyl} -lH-pyrazol-3-yl)-amide
Figure imgf000290_0001
A mixture of rac-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethylpropyl)-pyrrolidine -2 -carboxylic acid {l-[2-methyl-2-((i?)-l- oxiranylmethoxy)-propyl]-lH-pyrazol-3-yl}-amide ( 43.6 mg, 0.066 mmol), isopropyl alcohol ( 2 mL), diisopropylethyl amine (0.1 mL, 0.56 mmol) and serinol (0.1 mL, 1.09 mmol) was microwaved at 130°C for 15 min. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro- phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2 ,2 -dimethyl-propyl)-pyrrolidine -2 -carboxylic ac id ( 1 - {2 - [(i?) -2 -hydroxy-3 -(2 -hydroxy- 1 -hydroxymethyl-ethylamino)-propoxy] -2 -methyl- propyl}-lH-pyrazol-3-yl)-amide ( 14.2 mg, 28.6 %) as an off-white powder. HRMS (ES ) m/z Calcd for C36H46CI2F2N6O5 + H [(M+H)+]: 751.2948, found: 751.2943.
Example 173
Preparation of rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {l-[2-methyl-2-((5')-l- oxiranylmethoxy)-propyl]- -pyrazol-3-yl} -amide
Figure imgf000291_0001
A mixture of rac-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.12 g, 0.28 mmol), l-[2-methyl-
2- ((5)-l-oxiranylmethoxy)-propyl]-lH-pyrazol-3ylamine (52.4 mg, 0.248 mmol), 2-(7- azabenzotriazol-l-yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (HATU, 0.212 g, 0.56 mmol) and iPr2NEt (0.25 mL, 1.4 mmol) in CH2C12 (3 mL) was stirred at rt overnight. 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 column chromatography (4 g column, 1-100% ethyl acetate/heptane) to give rac-(2i?,35',4i?,55)-
3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)- pyrrolidine-2-carboxylic acid { 1 -[2-methyl-2-((5)- 1 -oxiranylmethoxy)-propyl]- 1 H-pyrazol-3- yl} -amide ( 58 mg, 35.4 %) as an off-white solid. HRMS (ES+) m/z Calcd for CSSHSTC^NJOS + H [(M+H)+]: 660.2315, found: 660.2316.
Example 174
Preparation of rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid { l-[2-((5)-3-amino-2-hydroxy- propoxy)-2-methyl-propyl]-lH-pyrazol-3-yl} -amide
Figure imgf000292_0001
M. W. 677.63 C33H40CI2F2N6O3
A mixture of rac-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {l-[2-methyl-2-((5)-l- oxiranylmethoxy)-propyl]-lH-pyrazol-3-yl}-amide ( 203 mg, 0.307 mmol), isopropyl alcohol ( 2 mL), and ammonium hydroxide (2.5 mL) was microwaved at 130°C for 15 min. 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 reverse phase chromatography (20-95% of ACN/water) to give rac- (2i?,35',4i?,55)-3-(3-chloro-2-fiuoro- phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid { l-[2-((5')-3-amino-2-hydroxy-propoxy)-2-methyl-propyl]-lH-pyrazol-3-yl} -amide ( 50.2 mg, 24.1 %) as an white powder. HRMS (ES+) m/z Calcd for C33H40CI2F2N6O3 + H [(M+H)+]: 677.2580, found: 677.2577. Example 175
Preparation of rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid { l-[2-((5)-2,3-dihydroxy-propoxy)- 2 -methyl-propyl] - 1 H-pyraz 1-3 -yl } -amide
Figure imgf000292_0002
M. W. 678.242 C33H39Cl2F2N504
A mixture of rac-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {l-[2-methyl-2-((5')-l- oxiranylmethoxy)-propyl]-lH-pyrazol-3-yl}-amide ( 51.2 mg, 0.078 mmol), water ( 2 mL), and acetone (10 mL) was cooled to 0°C, then a solution of 35% perchloric acid (0.1 mL) was added dropwise. The reaction was stirred an additional 0.5 h. Then an additional 1 mL of the 35% perchloric acid solution was added at 0°C, the reaction was allowed to warm to rt for 12 h. The mixture was then diluted with ethyl acetate and washed with sodium bicarbonate (sat'd). The organic phase was separated, dried over Na2S04 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (20-95%) of ACN/water) to give rac- (2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid { l-[2-((S)-2,3-dihydroxy-propoxy)-2-methyl- propyl]-lH-pyrazol-3-yl}-amide ( 22.1 mg, 42 %) as an white powder. HRMS (ES+) m/z Calcd for C33H39CI2F2N5O4 + H [(M+H)+]: 678.2420, found: 678.2416; C33H39Cl2F2N504 + [(Na+H)+]: 700.2239, found: 700.2235.
Example 176
Preparation of rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl) cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid { l-[2-((5)-3-dimethylamino-2- hydroxy-propoxy)-2-meth l-propyl]- 1 H-pyrazol-3-yl)-amide
Figure imgf000293_0001
M. W. 705.674 C35H44Cl2F2N603
A mixture of rac-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {l-[2-methyl-2-((5')-l- oxiranylmethoxy)-propyl]-lH-pyrazol-3-yl}-amide ( 87.5 mg, 0.133 mmol), isopropyl alcohol ( 2 mL), and dimethylamine (0.133 mL, 0.266 mmol, 2 M in dioxane) was microwaved at 130°C for 15 min. The mixture was extracted with dichloromethane and water. The organic layer was separated and the solvent evaporated under reduced pressure. The resulting oil was purified by reverse phase chromatography (20-95%) of ACN/water) to give rac(2i?,35',4i?,55)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid {l-[2-((5')-3-dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-lH-pyrazol- 3-yl)-amide ( 20.6 mg, 20.8 %) as a white powder. HRMS (ES ) m/z Calcd for Cssi^C^NeOs + H [(M+H)+]: 705.2890, found: 705.2893.
Example 177
Preparation of rac-{(5)-3-[2-(3-{[(2i?,35,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -pyrazol- 1 -yl)- l,l-dimethyl-ethoxy]-2-hydroxy-propylamino} -acetic acid
A mixture of rac-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {l-[2-methyl-2-((5')-l- oxiranylmethoxy)-propyl]-lH-pyrazol-3-yl}-amide (85.8 mg, 0.133 mmol), isopropyl alcohol ( 2 mL), and t-butyl glycine (35 mg, 0.266 mmol) was microwaved at 130°C for 15 min. The solvent evaporated under reduced pressure. The resulting oil was dissolved in dichloromethane (2 mL) and cooled to 0°C; then TFA (1 mL) was slowly added and stirred for 4h. The mixture was concentrated under reduced pressure and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-{(5)-3-[2-(3-{[(2i?,35,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro- 2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -pyrazol-l- yl)-l,l-dimethyl-ethoxy]-2-hydroxy-propylamino}-acetic acid ( 18.1 mg, 19 %) as an off-white powder. HRMS (ES+) m/z Calcd for
Figure imgf000294_0002
+ H [(M+H)+]: 735.2635, found:
735.2631
Example 178
Preparation of rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phi cyano-5-(2,2-dimethyl-propyl)pyrrolidine-2-carboxylic acid {l-[2-((5')-2-hydroxy-3- methylamino-propoxy)-2-methyl-propyl]-lH-pyrazol-3-yl } -amide
Figure imgf000295_0001
M. W. 691.647 C34H42CI2F2N6O3
A mixture of rac-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {l-[2-methyl-2-((5)-l- oxiranylmethoxy)-propyl]-lH-pyrazol-3-yl}-amide ( 87.5 mg, 0.133 mmol), isopropyl alcohol ( 2 mL), and methylamine (1.0 mL, 2 mmol, 2 M in methanol; old bottle) was microwaved at 130°C for 15 min. The solvent evaporated under reduced pressure. The resulting oil was purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2i?,35',4i?,55)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl- propyl)pyrrolidine-2-carboxylic acid {l-[2-((5)-2-hydroxy-3-methylamino-propoxy)-2-methyl- propyl]-lH-pyrazol-3-yl }-amide ( 14.9 mg, 16.2 %) as an off-white powder. HRMS (ES+) m/z Calcd for C34H42CI2F2N6O3 + H [(M+H)+]: 691.2737, found: 691.2731.
Example 179
Preparation of rac-(2i?,35',^i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid { l-[2-((i?)-3-dimethylamino-2- hydroxy-propoxy)-2-meth l-propyl]- 1 H-pyrazol-3-yl)-amide
Figure imgf000295_0002
M. W. 705.674 CssF^C^NeOs
A mixture of rac-(2i?,35',4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {l-[2-methyl-2-((i?)-l- oxiranylmethoxy)-propyl]-lH-pyrazol-3-yl}-amide ( 0.69 g, 1.04 mmol), isopropyl alcohol ( 2 mL), and dimethylamine (1.04 mL, 2.08 mmol, 2 M in THF) was micro waved at 130°C for 15 min. The mixture was extracted with dichloromethane and water. The organic layer was separated and the solvent evaporated under reduced pressure. The resulting oil was purified by column chromatography (50% ethyl acetate/heptane) to give rac-(2i?,35',4i?,55)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid {l-[2-((i?)-3-dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-lH-pyrazol- 3-yl)-amide ( 147.2 mg, 20.05 %) as a white powder. HRMS (ES+) m/z Calcd for
C35H44Cl2F2N603 + H [(M+H)+]: 705.2893, found:705.2893.
Example 180
Preparation of rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid { l-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-lH- pyrazol-3-yl} -amide
Figure imgf000296_0001
M. W. 654.76 C34H45Cl2N502Si
A mixture of rac-(2i?,3i?,4i?,55)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), l-[2-(tert-Butyl-dimethyl- silanyloxy)-ethyl]-lH-pyrazol-3-ylamine (72.42 mg, 0.3 mmol), 2-(7-azabenzotriazol-l-yl)- η,η,η',η'-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iP^NEt (0.1 mL, 0.55 mmol) in CH2CI2 (2 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 purified by reverse phase chromatography (20- 95% of ACN/water) to give rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid { l-[2-(tert-butyl-dimethyl- silanyloxy)-ethyl]-lH-pyrazol-3-yl} -amide ( 77.3mg, 59 %) as an off-white powder. HRMS (ES+) m/z Calcd for C34H45CI2N5O2 + H [(M+H)+]: 654.2793, found: 654.2790.
Example 181
Preparation ofrac- (2i?,3i?,4i?,55)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [l-((i?)-2,2-dimethyl-[l,3]dioxolan-4-ylmethyl)- lH-pyrazol-3-yl] -amide
Figure imgf000297_0001
M. W. 610.59 C32H37C12N503
A mixture of rac-(2i?,3i?,4i?,55)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), l-(2,2-Dimethyl- [l,3]dioxolan-4-ylmethyl)-lH-pyrazol-3-ylamine (59.14 mg, 0.3 mmol), 2-(7-azabenzotriazol-l- yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iP^NEt (0.1 mL, 0.55 mmol) in CH2CI2 (2 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 purified by reverse phase chromatography (20-95% of ACN/water) to give rac- (2i?,3i?,4i?,55)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [l-((i?)-2,2-dimethyl-[l ,3]dioxolan- 4-ylmethyl)-lH-pyrazol-3-yl]-amide (91.2mg, 74.68 %) as an off-white powder. HRMS (ES+) m/z Calcd for C34H45C12N502 + H [(M+H)+]: 610.2346, found: 610.2345. Example 182
Preparation of rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbo
xylic acid ((S)-2,3-dihydroxy-propyl)-amide and rac- (25,,35',45,,5i?)-3-(3-chloro-phenyl)-4-(4- chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((5)-2,3- dihydroxy-propyl)-amide
Chiral Chiral
Figure imgf000298_0001
M.W. 504.455 C26H31CI2N3O3
A mixture of rac-(2i?,3i?,4i?,55)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.86, 2.0 mmol), (S)-3-amino-propane-l ,2-diol (0.27 g, 3.0 mmol), 2-(7-azabenzotriazol-l-yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (HATU, 0.76 g, 2.0 mmol) and iPr2NEt (1.0 mL, 5.5 mmol) in CH2C12 (40 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 to yield a product that was purified by silica column chromatography ( 1 - 100% EtO Ac/heptane) to give 1.09g, 100% two diasteroisomers. The mixture was sent SFC to be separated (35 % CH3OH, 100 barr, 30°C) to give rac-(2i?,3i?,4i?,55)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((5)-2,3-dihydroxy-propyl)-amide (187.6 mg, 21.7 %) as an off-white powder. HRMS (ES+) m/z Calcd for C26H31CI2N3O3 + H [(M+H)+]: 504.455, found: 504.455 and rac- (2«S,35,4,S,5i?)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-2,3-dihydroxy-propyl)-amide (188.1 mg, 74.68 %) as an off-white foam. HRMS (ES+) m/z Calcd for C26H31CI2N3O3 + H
[(M+H)+]: 504.1815, found: 504.1815. Example 183
Preparation of rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbox lic acid [ 1 -(2-hydroxy-ethyl)- 1 H-pyrazol-3 -yl]-amide
Figure imgf000299_0001
M. W. 540.50 C28H3iCl2N502
A mixture of rac-(2i?,3i?,4i?,55)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid { l-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-lH- pyrazol-3-yl} -amide (65.2 mg, 0.0995 mmol), acetic acid (2.0 mL, 31 mmol), water (1 mL) and stirred at RT over the weekend (48 h). Reaction complete by 50%. The mixture was then diluted with EtOAc and washed with NaHC03(s). The organic phase was separated, filtered and dried over Na2S04. The mixture was then concentrated under reduced vacuum and purified by reverse phase chromatography (20-95%) of ACN/water) to give rac-(2i?,3i?,4i?,5S)-3-(3-chloro-phenyl)- 4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [l-(2- hydroxy-ethyl)-lH-pyrazol-3-yl]-amide ( 21.6 mg, 40.22 %) as awhite powder. HRMS (ES+) m/z Calcd for C28H3iCl2N502+ H [(M+H)+]: 540.1928, found: 540.1926.
Example 184
Preparation of rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1 -((i?)-2 ,3 -dihydroxy-propyl)- 1 H-pyrazol-3 -yl]- amide
Figure imgf000300_0001
M. W. 570.52 C29H33C12N503
A mixture of rac-(2i?,3i?,4i?,55)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [l-((i?)-2,2-dimethyl-[l,3]dioxolan-4-ylmethyl)- lH-pyrazol-3-yl] -amide (81 mg, 0.133 mmol), pyridinium p-toluene sulfonic acid (5 mg, 0.0198 mmol) and methanol (4 mL) was microwaved at 120°C for 5 min. Solvent evapoarated and purified by reverse phase chromatography (20-95% of ACN/water) to rac-(2i?,3i?,4i?,55)-3-(3- chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [l-((i?)-2,3-dihydroxy-propyl)-lH-pyrazol-3-yl]-amide ( 26.5 mg, 35 %) as an off-white powder. HRMS (ES+) m/z Calcd for C29H33Cl2N503 + H [(M+H)+]: 570.2033, found: 570.2032.
Example 185
Preparation of rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid 2-trifluoromethyl-benzylamide
Figure imgf000300_0002
M. W. 588.498 C31H30CI2F3N3O
A mixture of rac-(2i?,3i?,4i?,55)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 2-trifiuoromethyl-benzyl amine (52.55 mg, 0.3 mmol), 2-(7-azabenzotriazol-l-yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight. 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 reverse phase chromatography (20-95% of ACN/water) to give rac rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl- propyl)-pyrrolidine-2-carboxylic acid 2-trifluoromethyl-benzylamide (38 mg, 32.3 %) as an off- white powder. HRMS (ES+) m/z Calcd for C3iH3oCl2F3N30 + H [(M+H)+]: 588.1791 , found: 588.1795.
Example 186
Preparation of rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid 4-(2-oxo-pyrrolidin- 1 -yl)-benzylamide
Figure imgf000301_0001
M. W. 603.59 C34H36C12N402
A mixture of rac-(2i?,3i?,4i?,55)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 4-aminomethyl phenyl pyrrolidin-2-one (42.94 mg, 0.3 mmol), 2-(7-azabenzotriazol-l-yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight. 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 reverse phase chromatography (20-95% of ACN/water) to give rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid 4-(2-oxo-pyrrolidin-l-yl)-benzylamide (48.9 mg, 40.5 %) as an off-white powder. HRMS (ES+) m/z Calcd for C34H36C12N402 + H [(M+H)+]: 603.2288, found: 603.2289.
Example 187
Preparation of rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide
Figure imgf000302_0001
M. W. 528.52 C29H35Cl2N302
A mixture of rac-(2i?,3i?,4i?,55)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 4-aminomethyl tetrahydropyran (34.5 mg, 0.3 mmol), 2-(7-azabenzotriazol-l-yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iP^NEt (0.1 mL, 0.55 mmol) in CH2CI2 (2 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 purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (10.8 mg, 10.2 %) as an off- white powder. HRMS (ES+) m z Calcd for C29H35C12N302 + H [(M+H)+]: 528.2179, found: 528.2180. Example 188
Preparation of rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbox lic acid (3-hydroxy-2-hydroxymethyl-propyl)-amide
Figure imgf000302_0002
M. W. 504.46 C26H3iCl2N303
A mixture of rac-(2i?,3i?,4i?,55)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 2-aminomethyl-propane- 1,3-diol (31.5 mg, 0.3 mmol), 2-(7-azabenzotriazol-l-yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iP^NEt (0.1 mL, 0.55 mmol) in CH2CI2 (2 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 purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid (3-hydroxy-2-hydroxymethyl-propyl)-amide (31.2 mg, 30.9%) as an off-white powder. HRMS (ES+) m/z Calcd for C26H31CI2N3O3 + H [(M+H)+]: 504.455, found: 504.1815.
Example 189
Preparation of rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbox lic acid [2-(2-amino-ethoxy)-ethyl]-amide
Figure imgf000303_0001
M. W. 517.498 C27H34C12N402
A mixture of rac-(2i?,3i?,4i?,55)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 2,2'-oxybis(ethylamine) (31.3 mg, 0.3 mmol), 2-(7-azabenzotriazol-l-yl)-n,n,n',n'-tetramethyluronium
hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2C12 (2 mL) was stirred at rt overnight. 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 reverse phase chromatography (20-95% of ACN/water) to give rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid [2-(2-amino-ethoxy)-ethyl]-amide (20.3 mg, 19.6%) as an off- white powder. HRMS (ES+) m/z Calcd for C27H34C12N402 + H [(M+H)+]: 517.2132, found: 517.2133
Example 190
Preparation of rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methanesulfonyl-propyl)-amide
Figure imgf000304_0001
M. W. 550.548 C27H33CI2N3O3S
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methylsulfanyl-propyl)-amide (119.2 mg, 0.23 mmol) and dichloromethane (2 mL) was added to a solution of refluxing acetic acid (5 mL, 79.4 mmol) and 30% hydrogen peroxide (2 mL) for 5 min. The reaction mixture was cooled to room temperature and stored in the freezer overnight. The mixture was diluted with water and dichloromethane, the organic layer was separated and solvent removed under reduced pressure. The resulting oil was carried directly to the next step by adding acetic acid (5 mL, 79.4 mmol) and zinc dust (0.85 g, 13 mmol). After stirring at room temperature for 3 h, an additional amount of zinc dust (0.85 g, 13 mmol) was added and stirred for an additional 3h at room temperature. Reaction worked up by filtration through celite, washing with dichloromethane (50 mL). The filtrate was washed with water (2x) and the organic layer was separated, dried with MgSC>4, filtered and the solvent evaporated under reduced pressure to yield crude oil. Purification by reverse phase chromatography (20-95% of ACN/water) to give rac-(2i?,3i?,4i?,55')-3-(3-chloro- phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3- methanesulfonyl-propyl)-amide (36.5 mg, 28.8 %) as an off-white powder. HRMS (ES+) m/z Calcd for C27H33CI2N3O3S + H [(M+H)+]: 550.1693, found: 550.1692.
Example 191
Preparation of rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-methanesulfonyl-ethyl)-amide
Figure imgf000304_0002
M. W. 536.521 C26H31CI2N3O3S
A mixture of rac-(2i?,3i?,4i?,55)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 2-methanesulfonyl- ethylamine (54.6 mg, 0.3 mmol), 2-(7-azabenzotriazol-l-yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iP^NEt (0.1 mL, 0.55 mmol) in CH2CI2 (2 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 purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid (3-hydroxy-2-hydroxymethyl-propyl)-amide (65.2 mg, 60.8 %) as a white powder. HRMS (ES+) m z Calcd for C26H31CI2N3O3S + H [(M+H)+]: 536.1536, found: 536.1536.
Example 192
Preparation of rac-4-{ [(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2 -fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -cyclohexylamino-l- carboxylic acid tert-butyl ester
Figure imgf000305_0001
Molecular Weight =663.64
Molecular Formula =C34H42CI2F2N4O3 In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 52c (582 mg, 1 mmol) was reacted with 4-Amino- cyclohexylamino-l-carboxylic acid tert-butyl ester(APAC, 429 mg, 2 mmol), HATU (Aldrich, 760.4 mg, 2 mmol) and iPr2NEt (Aldrich, 350 uL, 2 mmol) in CH2C12 at room temperature for 1.5 hr. The solvent was reduced and the residue was loaded on 40 g silica gel column and eluted with MeOH/CH2Cl2 (2-5%) to give a white foam. 783 mg
HRMS (ES+) m/z Calcd for C34H42CI2F2N4O3+ H [(M+H)+]: 663.2675, found: 663.2675. Example 193
Preparation of rac-4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -trans- cyclohexylamine trifluoroacetic acid salt
Figure imgf000306_0001
Molecular Weight =563.52
Molecular Formula =C29H34CI2F2N4O C2HF3O2
To a stirred solution of trifluoroacetic acid in methylene chloride(3 mL/7 mL) at rt., rac-4- {[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -cyclohexylamino-l-carboxylic acid tert-butyl ester (760 mg) was added and the mixture was stirred for 30 min.. The solvent was removed and the residue was treated with ether/hexane. The solid was filtered and washed with hexane to give a white solid. 860 mg. [(M+H)+]: 563. Example 194
Preparation of rac-4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl^ropyl)-pyrrolidine-2-carbonyl]-amino} -trans-cyclohexyl-N- methanesulfonamide
Figure imgf000307_0001
Molecular Weight =641 .61
Molecular Formula =C30H36CI2F2N4O3S
To a stirred solution of rac-4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -trans- cyclohexylamine trifluoroacetic acid salt (80 mg, 0.1 mmol) in methylene chloride (5 mL), Methane sulfonyl chloride (Aldrich, 11.6 uL, 0.15 mmol) was added followed by the addition of triethylamine( 70 uL, 0.50 mmol). The mixture was stirred at rt for 1 hr and the reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was chromatographied on ISCO machine (column, 12g, eluent 5% MeOH/CH2C12) to give a white solid. 44 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 641.1926, found: 641.1926. Example 195
Preparation of rac-4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl^ropyl)-pyrrolidine-2-carbonyl]-amino} -trans-cyclohexyl-N- methanesulfonamide
Figure imgf000308_0001
Molecular Weight =605.56
Molecular Formula =C31 H36CI2F2N4O2
To a stirred solution of rac-4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -trans- cyclohexylamine trifluoroacetic acid salt (80 mg, 0.1 mmol) in methylene chloride (5 mL), Acetic anhydride (Aldrich, 16 uL, 0.15 mmol) was added followed by the addition of triethylamine( 70 uL, 0.50 mmol). The mixture was stirred at rt for 30 min. and the reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was chromatographied on ISCO machine (column, 12g, eluent 5% MeOH/CH2C12) to give a white solid. 30 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 605.2256, found: 605.2259 Example 196
Preparation of rac-4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -trans-cyclohexyl-(l ,1 - dioxo)-2-isothiazolidine
Figure imgf000309_0001
Molecular Weight =667.65
Molecular Formula =C32H38CI2F2N4O3S
To a stirred solution of rac-4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -trans- cyclohexylamine trifluoroacetic acid salt (200 mg, 0.253 mmol) in methylene chloride (5 mL), 3- chloro-n-propyl sulfonyl chloride (Aldrich, 40 uL, 0.328 mmol) was added followed by the addition of triethylamine( 176 uL, 1.265 mmol). The mixture was stirred at rt for 4 hrs and the reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was chromatographied on ISCO machine (column, 12g, eluent 5% MeOH/CH2C12) to give a white solid. 122 mg.
The white solid (80 mg, 0.114 mmol) was dissolved in acetonitrile/water( 3 :1 , 1 mL) and KI (10 mg) and KOAc (55 mg, 0.56 mmol) were added and the mixture was heated on a microwave for 30 min. at 150°C. The mixture was cooled and water was added. The resulting mixture was extracted with ethyl acetate (3 x 8 niL). The extracts were dried with magnesium sulfate and concentrated. The residue was chromatorgraphied (5% MeOH/CE^Cb) to give a solid. 46 mg. HRMS (ES+) m/z Calcd: [(M+H)+]: 667.2083, found: 667.2084.
Example 197
Preparation of rac-4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -trans-cyclohexyl-
Figure imgf000310_0001
Molecular Weight =606.55
Molecular Formula =C30H35CI2F2N5O2
To a stirred solution of rac-4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -trans- cyclohexylamine trifluoroacetic acid salt (100 mg, 0.126 mmol) in 1 ,4-dioxane (5 mL), N- trimethylsilyl isocyanate (Aldrich, 42 uL, 0.316 mmol) was added followed by the addition of triethylamine( 44 uL, 0.316 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC to give a white solid. 39 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 606.2209, found: 606.2209 Example 198
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid N-[l-(2-hydroxy ethyl)-piperidin- 4-yl]amide
Figure imgf000311_0001
Molecular Weight =593.55
Molecular Formula =C30H36CI2F2N4O2
To a stirred solution of rac-4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -trans- cyclohexylamine trifluoroacetic acid salt (80 mg, 0.103 mmol) in ethanol (5 mL), 2- bromoethanol (Aldrich,l 1 uL, 0.15 mmol) was added followed by the addition of sodium carbonate( 106 mg, 1 mmol). The mixture was stirred at reflux overnight. The reaction was quenched with addition of water. The mixture was extracted with EtOAc (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a ISCO machine (12g column, eluent, 5 MeOH/CH2Cl2) to give a white solid. 22 mg. HRMS (ES+) m/z Calcd: [(M+H)+]: 593.2256, found: 593.2256.
Example 199
Preparation of rac-4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl^ropyl)-pyrrolidine-2-carbonyl]-amino} -piperidine-l -sulfonic acid amide
Figure imgf000312_0001
Molecular Weight =628.57
Molecular Formula =C28H33CI2F2N5O3S
To a stirred solution of rac-4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -trans- cyclohexylamine trifluoroacetic acid salt (50 mg, 0.091 mmol) in THF (3 mL), sulfamide (Aldrich, 40 mg, 0.416 mmol) was added and the mixture was stirred at 110°C for 25 min. on microwave oven. The reaction was quenched with addition of water. The mixture was extracted with EtOAc (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC(25-90, acetonitrile/water) to give a white solid. 49 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 678.1722, found: 678.1728.
Example 200
Preparation of rac 3-{ 4-[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2 ,2 -dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-l-yl} -acetic acid
Figure imgf000313_0001
Molecular Weight =593.5062
Molecular Formula =C29H32CI2F2N4O3
To a stirred solution of rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid salt (475 mg, 0.871 mmol) in methylene chloride (5 mL), HATU (Aldrich, 490 mg, 1.29 mmol) was added followed by the addition of DIPEA( 0.9 mL, 5.2 mmol) and piperazin-l-yl-acetic acid tert- butyl ester (352 mg, 1.29 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40g column, eluent, 50% EtOAc/hexanes) to give a white solid. 525 mg.
The solid (500 mg) was dissolved in 30% TFA/methylene chloride and the solution was stirred for 2hrs at rt. The solvent was removed at reduced pressure and the residue was triturated with ether and hexane to give a white solid. 560 mg
HRMS (ES+) m/z Calcd: [(M+H)+]: 592.1820, found: 592.1819
Example 201
Preparation of rac 3-{ 4-[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-l-yl}- N,N-bis-(2- methoxy-ethyl)-acetamide
Figure imgf000314_0001
Molecular Weight =708.6828
Molecular Formula =C35H45CI2F2N5O4
To a stirred solution of rac 3-{ 4-[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-l-yl} -acetic acid (80 mg, 0.113 mmol) in methylene chloride (5 mL), HATU (Aldrich, 65 mg, 0.17 mmol) was added followed by the addition of DIPEA( 0.06 mL, 0.34 mmol) di-(2-methoxy)-ethylamine (Aldrich, 35 uL, 0.17 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (12g column, eluent, 20% EtOAc/methylene chloride) to give a white solid. 70 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 708.2890, found: 708.2887
Example 202
Preparation of rac 3-{ 4-[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-l-yl}- N,N-bis-(2- hydroxy-ethyl)-acetamide
Figure imgf000315_0001
Molecular Weight =680.6286
Molecular Formula =C33H41 CI2F2N5O4
To a stirred solution of rac 3-{ 4-[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-l-yl} -acetic acid (80 mg, 0.113 mmol) in methylene chloride (5 mL), HATU (Aldrich, 65 mg, 0.17 mmol) was added followed by the addition of DIPEA( 0.06 mL, 0.34 mmol) di-(2-hydroxy)-ethylamine (Across, 35 uL, 0.17 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reversed HPLC (10-90%) to give a white solid. 30 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 680.2577, found: 680.2575
Example 203
Preparation of rac 3-{ 4-[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-l-yl}- N-( 3- methoxy-propyl)-acetamide
Figure imgf000316_0001
Molecular Weight =664.6292
Molecular Formula =C33H41 CI2F2N5O3
To a stirred solution of rac 3-{ 4-[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-l-yl} -acetic acid (80 mg, 0.113 mmol) in methylene chloride (5 mL), HATU (Aldrich, 65 mg, 0.17 mmol) was added followed by the addition of DIPEA( 0.06 mL, 0.34 mmol) and 3-methoxy- propylamine (Aldrich, 0.17 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a ISCO machine (12g column, eluent, 20% EtOAc/methylene chloride) to give a white solid. 80 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 664.2628, found: 664.2625
Example 204
Preparation of rac 2- {4-[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-pipera
zin- 1 -yl} -acetamide
Figure imgf000317_0001
Molecular Weight =592.5215
Molecular Formula =C29H33CI2F2N5O2
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80 mg, 0.138 mmol) in methylene chloride (5 mL), HATU (Aldrich, 79 mg, 0.21 mmol) was added followed by the addition of DIPEA( 0.145mL, 0.83 mmol) and 2-piperazin-l-yl-acetamide (Chembridge, 45 mg, 0.21 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a ISCO machine (12g column, eluent, 20% EtOAc/methylene chloride) to give a white solid. 87 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 592.2052, found: 592.2054
Example 205
Preparation of rac (2S,3R,4S,5R)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2- (2,2-dimethyl-propyl)-5-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazi
ne - 1 -c arbonyl] -pyrro lidine -3 -c arbonitrile
Figure imgf000318_0001
Molecular Weight =662.6133
Molecular Formula =C33H39CI2F2N5O3
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80 mg, 0.138 mmol) in methylene chloride (5 mL), HATU (Aldrich, 79 mg, 0.21 mmol) was added followed by the addition of DIPEA( 0.145mL, 0.83 mmol) and l-morpholin-4-yl-2-piperazin-l-yl-ethanone (Oakwood, 44 mg, 0.21 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a ISCO machine (12g column, eluent, 20% EtOAc/methylene chloride) to give a white solid. 63 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 662.2471 , found: 662.2471
Example 206
Preparation of rac 2- {4-[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-l-yl}-N-[2-((S)-2,2- dimethyl-[l ,3]dioxolan-4-yl)-ethyl]-acetamide
Figure imgf000319_0001
Molecular Weight =720.6940
Molecular Formula =C36H45CI2F2N5O4
To a stirred solution of rac 3-{ 4-[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-l-yl} -acetic acid (80 mg, 0.113 mmol) in methylene chloride (5 mL), HATU (Aldrich, 86 mg, 0.23 mmol) was added followed by the addition of DIPEA( 0.06 mL, 0.34 mmol) and 2-((S)-2,2-dimethyl- [l,3]dioxolan-4-yl)-ethylamine (Prepared before, 33 mg, 0.23 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC (eluent, 40-90% ACN/Water) to give a white solid. 27 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 720, found: 720
Example 207
Preparation of rac 2- {4-[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro
2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-pipera
zin- 1 -yl} -N-((S)-3 ,4-dihydroxy-butyl)-acetamide
Figure imgf000320_0001
Molecular Weight =680.6286
Molecular Formula =C33H41 CI2F2N5O4
To a stirred solution of rac 2-{4-[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-l-yl} -N-[2- ((S)-2,2-dimethyl-[l,3]dioxolan-4-yl)-ethyl]-acetamide (32 mg, 0.0445 mmol) in 1 ,4-dioxane (5 mL), 4 M HC1 (2 mL) was added and the mixture was stirred at rt for 4 hrs.. The mixture was concentrated and the residue was dissolved in a mixture of 1 ,4-dioxane and freeze dried to give a white solid. 31 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 680, found: 680. Example 208
Preparation of rac { 1 -[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2 ,2 -dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl} -acetic acid methyl ester
Figure imgf000321_0001
Molecular Weight =606.5457
Molecular Formula =C31 H35CI2F2N3O3
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (581mg, 1 mmol) in methylene chloride (10 mL), HATU (Aldrich, 500 mg, 1.3 mmol) was added followed by the addition of DIPEA( 0.35mL, 2.2 mmol) and piperidin-4-yl-acetic acid methyl ester (Oakwood, 205 mg, 1.3 mmol). The mixture was stirred at rt for 3 hrs. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a ISCO machine (12g column, eluent, 20% EtOAc/methylene chloride) to give a white solid. 586 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 606.2097, found: 606.2096.
Example 209
Preparation of rac { 1 -[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl} -acetic acid hydrochloride salt
Figure imgf000322_0001
Molecular Weight =592.5186
Molecular Formula =C30H33CI2F2N3O3 HCl
To a stirred solution of rac {l-[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl} -acetic acid methyl ester (556 mg, 0.92 mmol) in methanol (8 mL), LiOH.H20(Aldrich, 80 mg) in 1 mL of water was added. The mixture was stirred at 60°C overnight. The reaction was quenched with addition of water. The mixture was filtered and the filtrate was concentrated to removed methanol. The aqueous layer was washed with EtOAc (2x5 mL) and acidified with 3N HCl .
The mixture was then extracted with EtOAc(3x6 mL). The extracts were combined and dried over sodium sulfate and concentrated to give a white solid. 649 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 592.1940, found: 592.1939.
Example 210
Preparation of rac 2- { 1 -[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl}-acetamide
Figure imgf000323_0001
Molecular Weight =591.5339
Molecular Formula =C30H34CI2F2N4O2
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80 mg, 0.138 mmol) in methylene chloride (10 mL), HATU (Aldrich, 79 mg, 0.21 mmol) was added followed by the addition of DIPEA( 0.145 mL, 0.83 mmol) and piperidin-4-yl-acetamide (Chembridge, 41 mg, 0.21 mmol). The mixture was stirred at rt for 3 hrs then overnight after the addition of 3 mL of DMF. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (12g column, eluent, 20% EtOAc/methylene chloride) to give a white solid. 21 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 591.2100, found: 591.2100
Example 211
Preparation of rac 2- { 1 -[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperi
din-4-yl}-N,N-bis-(2-hydroxy-ethyl)-acetamide
Figure imgf000324_0001
Molecular Weight =679.6410
Molecular Formula =C34H42CI2F2N4O4
To a stirred solution of rac {l-[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl} -acetic acid hydrochloride salt (80 mg, 0.127 mmol) in methylene chloride (5 mL), HATU (65 mg, 0.17 mmol) and DIPEA (80 uL, 0.339 mmol) were added followed by 2-(2-hydroxy-ethylamine)- ethanol (Across, 16 uL, 0.17 mmol) and the mixture was stirred at rt overnight. The reaction was quenched with water and the mixture was extracted with methylene chloride(3xl0 mL) and the extracts were combined and dried over sodium sulfate. The solvent was removed and the residue was chromatographied on a reverse phase HPLC (acetonitrile/water, 25-85%) to give a white solid. 45 mg.
MS (ES+) m z Calcd: [(M+H)+]: 679, found: 679.
Example 212
Preparation of rac 2-{l-[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro 2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperi
din-4-yl}-N-(2-hydroxy-ethyl)-N-methyl-acetamide
Figure imgf000325_0001
Molecular Weight =649.6146
Molecular Formula =C33H40CI2F2N4O3
To a stirred solution of rac {l-[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl} -acetic acid hydrochloride salt (80 mg, 0.127 mmol) in methylene chloride (5 mL), HATU (77 mg, 0.28 mmol) and DIPEA (94 uL, 0.54mmol) were added followed by 2-hydroxy-ethyl-methyl amine (Oakwood, 20mg, 0.27 mmol) and the mixture was stirred at rt overnight. The reaction was quenched with water and the mixture was extracted with methylene chloride(3xl0 mL) and the extracts were combined and dried over sodium sulfate. The solvent was removed and the residue was chromatographied on a reverse phase HPLC (acetonitrile/water, 25-85%) to give a white solid. 46 mg.
HRMS (ES+) m z Calcd: [(M+H)+]: 649.2519, found: 645.2518
Example 213
Preparation of rac 2- { 1 -[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl}-N-(2-hydroxy- propyl)-acetamide
Figure imgf000326_0001
Molecular Weight =649.6146
Molecular Formula =C33H40CI2F2N4O3
To a stirred solution of rac {l-[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl} -acetic acid hydrochloride salt (80 mg, 0.127 mmol) in methylene chloride (5 mL), HATU (77 mg, 0.28 mmol) and DIPEA (94 uL, 0.54mmol) were added followed by 2-hydroxy-2-methyl-ethylamine (Aldrich, 20mg, 0.27 mmol) and the mixture was stirred at rt for hers. The reaction was quenched with water and the mixture was extracted with methylene chloride(3xl0 mL) and the extracts were combined and dried over sodium sulfate. The solvent was removed and the residue was chromatographied on a reverse phase HPLC (acetonitrile/water, 25-85%) to give a white solid. 48 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 649.2519, found: 645.2519
Example 214
Preparation of rac {[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -acetic acid tert-butyl ester
Figure imgf000327_0001
Molecular Weight =580.5075
Molecular Formula =C29H33CI2F2N3O3
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (515 mg, 1.11 mmol) in methylene chloride (10 mL), HATU (Aldrich, 422 mg, 1.11 mmol) was added followed by the addition of DIPEA( 0. 5 mL) and 2-amino-t-butyl-acetate (Aldrich, 145 mg, 1.11 mmol). The mixture was stirred at rt for 2 hrs. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40g column, eluent, 30% EtOAc/hexanes chloride) to give a white solid. 510 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 579.1867, found: 579.1866.
Example 215
Preparation of rac {[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -acetic aid trifluoro acetic acid salt.
Figure imgf000328_0001
Molecular Weight =524.3991 , 1 14
Molecular Formula =C25H25CI2F2N3O3. C2HF3O2
To a stirred solution of {[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -acetic acid tert-butyl ester (500 mg) in methylene chloride (7 mL), TFA (3 mL ) was added and the mixture was stirred at rt overnight. The solvent was removed under reduced pressure to give a white solid.
508 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 524, found: 524.
Example 216
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propy -pyrrolidine-2-carboxylic acid carbamoylmethyl-amide
Figure imgf000328_0002
Molecular Weight =523.4144
Molecular Formula =C25H26CI2F2N4O2 To a stirred solution of rac {[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -acetic aid trifiuoro acetic acid salt. (100 mg, 0.19 mmol) in methylene chloride (10 mL), HATU (Aldrich, 95 mg, 0.25 mmol) was added followed by the addition of DIPEA( 0. 5 mL) and 4N ammonia in methanol (0.2 mL). The mixture was stirred at rt for 2 hrs. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (3X7 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40g column, eluent, 50% EtOAc/hexanes) to give a white solid. 34 mg. MS (ES+) m/z Calcd: [(M+H)+]: 523, found: 523.
Example 217
Preparation of {[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -acetic aid trifluoro acetic acid salt.
Figure imgf000329_0001
Molecular Weight =524.3991
Molecular Formula =C25H25CI2F2N3O3.
rac {[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4 cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -acetic aid trifluoro acetic acid salt was separate on a sfc machine (30% MeOH, 100 Bar, 30°C) give the desired enantiomer.
MS (ES+) m/z Calcd: [(M+H)+]: 524, found: 524. Example 218
Preparation of rac 3-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid ethyl ester
Figure imgf000330_0001
Molecular Weight =614.5250
Molecular Formula =C32H31 CI2F2N3O3
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.258 mmol) was added followed by the addition of DIPEA( 90 uL, 0.52 mmol) and 3-aminobenzoic acid ethyl ester (Aldrich, 43 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24g column, eluent, 10% EtOAc/methylene chloride) to give a white solid. 55 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 614.1784, found: 614.1783
Example 219
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-carbamoyl-phenyl)-amide
Figure imgf000331_0001
Molecular Weight =585.4861
Molecular Formula =C30H28CI2F2N4O2
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.258 mmol) was added followed by the addition of DIPEA( 90 uL, 0.52 mmol) and 3-amino benzamide (Oakwood, 35 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24g column, eluent, 30% EtOAc/methylene chloride) to give a white solid. 58 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 585.1630, found: 585.1629
Example 220
Preparation of rac 3-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid tert-butyl ester
Figure imgf000332_0001
Molecular Weight =642.5792
Molecular Formula =C34H35CI2F2N3O3
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.258 mmol) was added followed by the addition of DIPEA( 90 uL, 0.52 mmol) and 3-amino benzoic acid t-butyl ester (Aldrich, 50 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24g column, eluent, 5% EtOAc/methylene chloride) to give a white solid. 80 mg. HRMS (ES+) m/z Calcd: [(M+H)+]: 642.2097, found: 642.2101
Example 221
Preparation of rac 3-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2 ,2 -dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid
Figure imgf000333_0001
Molecular Weight =586.4708
Molecular Formula =C30H27CI2F2N3O3
rac 3-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid t-butyl ester (20 mg, 0.031 mmol) was treated with 30 % TFA/methylene chloride (10 mL) overnight . Removal of solvent and freeze drying of the residue give a white powder. 12 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 586.1471 , found: 586.1467
Example 222
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxymethyl-phenyl)-amide
Figure imgf000333_0002
Molecular Weight =572.4873
Molecular Formula =C30H29CI2F2N3O2
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 104 mg, 0.27 mmol) was added followed by the addition of DIPEA( 80 uL,) and 3-amino benzyl alcohol (Aldrich, 80 uL). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified reverse phase HPLC (24g column, eluent, ACN/water, 20-90) to give a white solid. 40 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 572.1678, found: 572.1679
Example 223
Preparation of rac (3-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} - propyl)-carbamic acid tert-butyl ester
Figure imgf000334_0001
Molecular Weight =623.5763
Molecular Formula =C31 H38CI2F2N4O3
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (800 mg, 1.74 mmol) in methylene chloride (10 mL), HATU (Aldrich, 662 mg, 1.74 mmol) was added followed by the addition of DIPEA( 1.74 mmol) and (3-amino-propyl)-carbamic acid tert-butyl ester (Aldrich, 1.74 mmol). The mixture was stirred at rt for 1 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24g column, eluent, EtOAc/Hexanes, 20%) to give a white solid. 810 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 623, found: 623 Example 224
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phi cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-amino-propyl)-amide
Figure imgf000335_0001
Molecular Weight =523.4580 1 14.0243
Molecular Formula =C26H30CI2F2N4O . C2HF3O2
Rac (3-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}- propyl)-carbamic acid tert-butyl ester (815 mg) was treated with 30 % TFA/methylene chloride (10 mL) overnight . Removal of solvent and freeze drying of the residue give a white powder. 800 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 523, found: 523
Example 225
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(aminosulfonyl-amino)-propyl)- amide
Figure imgf000336_0001
Molecular Weight =602.5355
Molecular Formula =C26H31 CI2F2N5O3S
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-amino-propyl)-amide (100 mg) in DMF (3 niL), sulfamide (Aldrich, 62 mg) and potassium carbonate (50 mg) were added and the mixture was stirred at 100°C for 6 hrs. The solvent was removed under reduced pressure and the residue was portioned between EtOAc and water. The organic layer was separated and dried with sodium sulfate. The solvent was removed and the residue was chromatographied on an ISCO machine (70-100% EtOAc/ Hexanes) to give a white solid. 25 mg.
MS (ES+) m z Calcd: [(M+H)+]: 602, found: 602
Example 226
Preparation of rac 2-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid tert-butyl ester
Figure imgf000337_0001
Molecular Weight =642.5792
Molecular Formula =C34H35CI2F2N3O3
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (120 mg, 0.21 mmol) in methylene chloride (10 mL), HATU (Aldrich, 157 mg, 0.41 mmol) was added followed by the addition of DIPEA( 1 10 uL, 0.62 mmol) and 2-amino benzoic acid t-butyl ester (Aldrich, 80 mg, 0.41 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40g column, eluent, 20% EtOAc/hexanes) to give a white solid. 71 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 642.2100, found: 642.2009
Example 227
Preparation of rac 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid tert-butyl ester
Figure imgf000338_0001
Molecular Weight =642.5792
Molecular Formula =C34H35CI2F2N3O3
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (120 mg, 0.21 mmol) in methylene chloride (10 mL), HATU (Aldrich, 157 mg, 0.41 mmol) was added followed by the addition of DIPEA( 1 10 uL, 0.62 mmol) and 4-amino benzoic acid t-butyl ester (Aldrich, 80 mg, 0.41 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40g column, eluent, 20% EtOAc/hexanes) to give a white solid. 55 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 642.2097, found: 642.2100
Example 228
Preparation of rac 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid ethyl ester
Figure imgf000339_0001
Molecular Weight =614.5250
Molecular Formula =C32H31 CI2F2N3O3
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA( 90 uL, 0.52 mmol) and 4-amino benzoic acid ethyl ester (43 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40g column, eluent, 20% EtOAc/hexanes) to give a white solid. 37 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 614.1784, found: 614.1786
Example 229
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-carbamoyl-phenyl)-amide
Figure imgf000340_0001
Molecular Weight =585.4861
Molecular Formula =C30H28CI2F2N4O2
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA( 90 uL, 0.52 mmol) and 2-amino benzamide (Aldrich, 35 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40g column, eluent, 20% EtOAc/hexanes) to give a white solid. 30 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 585.1630, found: 585.1628
Example 230
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-phenyl)-amide
Figure imgf000341_0001
Molecular Weight =585.4861
Molecular Formula =C30H28CI2F2N4O2
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA( 90 uL, 0.52 mmol) and 4-amino benzamide (Aldrich, 35 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40g column, eluent, 20% EtOAc/hexanes) to give a white solid. 30 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 585, found: 585
Example 231
Preparation of rac 2-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} benzoic acid ethyl ester
Figure imgf000342_0001
Molecular Weight =614.5250
Molecular Formula =C32H31 CI2F2N3O3
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA( 90 uL, 0.52 mmol) and 2-amino benzoic acid ethyl ester (Aldrich, 43 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40g column, eluent, 20% EtOAc/hexanes) to give a white solid. 13 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 614.1784, found: 614.1787
Example 232
Preparation of rac 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2 ,2 -dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid
Figure imgf000343_0001
Molecular Weight =586.4708
Molecular Formula =C30H27CI2F2N3O3
rac 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-rluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid t-butyl ester (35 mg, 0.031 mmol) was treated with 30 % TFA/methylene chloride (10 mL) overnight . Removal of solvent and freeze drying of the residue give a white powder. 31 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 586.1471 , found: 586.1470
Example 233
Preparation of rac 2-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid
Figure imgf000343_0002
Molecular Weight =586.4708
Molecular Formula =C30H27CI2F2N3O3
rac 2-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid t-butyl ester (50 mg, 0.031 mmol) was treated with 30 % TFA/methylene chloride (10 mL) overnight . Removal of solvent and freeze drying of the residue give a white powder. 15 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 586.1471 , found: 586.1473
Example 234
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-cyano-phenyl)-amide
Figure imgf000344_0001
Molecular Weight =567.4707
Molecular Formula =C30H26CI2F2N4O
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (250 mg, 0.54 mmol) in methylene chloride (10 mL), HATU (Aldrich, 247 mg, 0.65 mmol) was added followed by the addition of DIPEA(0.65 mmol) and 3-amino benzonitrile(Aldrich, 77 mg, 0.65 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40g column, eluent, 35-50% EtOAc/hexanes) to give a white solid. 84 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 567, found: 567
Example 235
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl) cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-hydroxy-2-methyl-propyl)- amide
Figure imgf000345_0001
Molecular Weight =538.4698
Molecular Formula =C27H31 CI2F2N3O2
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80 mg, 0.14 mmol) in methylene chloride (10 mL), HATU (Aldrich,105 mg, 0.28 mmol) was added followed by the addition of DIPEA(0.34 mmol) and 2-hydroxy-2-methyl-propylamine(Matrix, 25 mg, 028 mmol). The mixture was stirred at rt lhr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40g column, eluent, 35-50% EtOAc/hexanes) to give a white solid. 50 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 538.1834, found: 538.1834
Example 236
Preparation of rac 3-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid 2- hydroxy-2-methyl-propyl ester
Figure imgf000346_0001
Molecular Weight =657.5938
Molecular Formula =C34H36CI2F2N4O3
To a stirred solution rac 3-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid (80 mg, 0.14 mmol) in methylene chloride (10 mL), HATU (Aldrich,104 mg, 0.27 mmol) was added followed by the addition of DIPEA(0.41 mmol) and 2-hydroxy-2-methyl-propylamine(Matrix, 24 mg, 027 mmol). The mixture was stirred at rt lhr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40g column, eluent, 35-50% EtOAc/hexanes) to give a white solid. 75 mg. MS (ES+) m/z Calcd: [(M+H)+]: 657.2206, found: 657.2208
Example 237
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methanesulfonylamino-phenyl)- amide
Figure imgf000347_0001
Molecular Weight =635.5654
Molecular Formula =C30H30CI2F2N4O3S
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.22 mmol) in methylene chloride (10 mL), HATU (Aldrich, 83 mg, 0.22 mmol) was added followed by the addition of DIPEA(0.20 mL) and 3-aminophenyl-methanesulfonamide(Aldrich, 0.25 mmol). The mixture was stirred at rt lhr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40g column, eluent, 35-80% EtOAc/hexanes) to give a white solid. 64 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 634, found: 634
Example 238
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5 -(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ( 1 H-tetrazol-5 -ylmethyl)-amide
Figure imgf000348_0001
Molecular Weight =548.4271
Molecular Formula =C25H25CI2F2N7O
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.22 mmol) in methylene chloride (10 mL), HATU (Aldrich, 83 mg, 0.22 mmol) was added followed by the addition of DIPEA(0.20 mL) and lH-tetrazol-5-yl-methylamine hydrobromide (Aldrich, 54 mg, 0.3 mmol). The mixture was stirred at rt 4.5hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC to give a white solid. 47 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 548, found: 548
Example 239
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-ureado-propyl)-amide
Figure imgf000349_0001
Molecular Weight =566.4832
Molecular Formula =C27H31 CI2F2N5O2
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-amino-propyl)-amide (100 mg) in DMF (3 niL), N-trimethylsilyl isocyanate (Aldrich, 0.13 mmol) and
isopropylethylamine (Aldrich, 0.15 niL) were added and the mixture was stirred at rt for 2 hrs. The solvent was removed under reduced pressure and the residue was partioned between EtOAc and water. The organic layer was separated and dried with sodium sulfate. The solvent was removed and the residue was chromatographied on an ISCO machine (4-9% MeOH/EtOAc) to give a white solid. 52 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 566, found: 566
Example 240
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methylsulfanyl-phenyl)-amide
Figure imgf000350_0001
Molecular Weight =588.5519
Molecular Formula =C30H29CI2F2N3OS
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (250 mg, 0.44 mmol) in methylene chloride (10 mL), HATU (Aldrich, 332 mg, 0.88 mmol) was added followed by the addition of DIPEA(0.230 mL, 1.31 mmol) and 3-amino-phenyl methyl sulfide (Aldrich, 122 mg, 0.88 mmol). The mixture was stirred at rt for 2 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (50g column, eluent EtOAc/Hexanes, 5-10% )to give a white solid. 178 mg. HRMS (ES+) m/z Calcd: [(M+H)+]: 588.1449, found: 588.1450.
Example 241
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methanesulfonyl-phenyl)-amide
Figure imgf000351_0001
Molecular Weight =620.5507
Molecular Formula =C30H29CI2F2N3O3S
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methylsulfanyl- phenyl)-amide(32 mg, 0.0544 mmol) in methylene chloride (5 mL) at rt, McPBA (Aldrich, 77%, 20.6 mg, 0.12 mmol) was added and the mixture was stirred for 2 hrs. The reaction was quenched with aqueous sodium thiosulfate and the layers were separated. The organic layer was washed with 10%> sodium carbonate (10 mL) and dried with sodium sulfate. The solvent was removed and the residue was loaded onto a silica gel column (12g, 10%> EtOAc/methylene chloride) to give a white solid. 28 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 620.1348, found: 620.1347
Example 242
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methanesulfmyl-phenyl)-amide
Figure imgf000352_0001
Molecular Weight =604.5513
Molecular Formula =C30H29CI2F2N3O2S
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methylsulfanyl- phenyl)-amide(12 mg, 0.02mmol) in methylene chloride (5 mL) at rt, McPBA (Aldrich, 77%, 6 mg, 0.026 mmol) was added and the mixture was stirred for 1.5 hrs. The reaction was quenched with aqueous sodium thiosulfate and the layers were separated. The organic layer was washed with 10% sodium carbonate (10 mL) and dried with sodium sulfate. The solvent was removed and the residue was loaded onto a silica gel column (12g, 10%> EtOAc/methylene chloride) to give a white solid. 6 mg.
HRMS (ES+) m/z Calcd: [(M+H)], 604.1399, found: 604.1399
2 mg of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methanesulfonyl-phenyl)-amide was also obtained.
Example 243
Preparation of 3-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phi cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid
Figure imgf000353_0001
Molecular Weight =586.4708
Molecular Formula =C30H27CI2F2N3O3
rac 3-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid t-butyl ester (26 mg, 0.411 mmol) was treated with 50 % TFA/methylene chloride (10 mL) overnight . Removal of solvent and freeze drying of the residue give a white powder. 250 mg. The solid was resolved on a Berger SFC system on a Whelk column under 100 bar, 30°C, and 45% of methanol to give two peaks: Peak 1, undesired enantiomer, 78 mg; Peak 2, 77 mg as white solid.
HRMS (ES+) m/z Calcd: [(M+H)+]: 586.1471 , found: 586.1467
Example 244
Preparation of (2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-carbamoyl-phenyl)-amide
Figure imgf000354_0001
Molecular Weight =585.4861
Molecular Formula =C30H28CI2F2N4O2
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.258 mmol) was added followed by the addition of DIPEA( 90 uL, 0.52 mmol) and 3-amino benzamide (Oakwood, 35 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24g column, eluent, 30% EtOAc/methylene chloride) to give a white solid. 58 mg. The solid was resolved on a Berger SFC system on a Whelk column under 100 bar, 30°C, and 35% of methanol to give two peaks: Peak 1 , undesired enantiomer, 19 mg; Peak 2, 21 mg as white solid. HRMS (ES+) m/z Calcd: [(M+H)+]: 585.1630, found: 585.1629
Example 245
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2 -fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(lH-tetrazol-5-yl)-phenyl]- amide
Figure imgf000355_0001
Molecular Weight =610.4988
Molecular Formula =C30H27CI2F2N7O
To a stirred solution ofrac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 130 mg, 0.344 mmol) was added followed by the addition of DIPEA( 90 uL, 0.52 mmol) and 3-(lH-tetrazol-5-yl)-phenylamine (Alfa, 55 mg, 0.344 mmol). The mixture was stirred at rt for 2 hrs. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC (24g column, eluent, 30% EtOAc/methylene chloride) to give a yellow solid. 21 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 610.1695, found: 610.1698
Example 246
Preparation ofrac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2 -fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(lH-tetrazol-5-yl)-phenyl]- amide
Figure imgf000356_0001
Molecular Weight =610.4988
Molecular Formula =C30H27CI2F2N7O
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 130 mg, 0.344 mmol) was added followed by the addition of DIPEA( 90 uL, 0.52 mmol) and 4-(lH-tetrazol-5-yl)-phenylamine (Alfa, 55 mg, 0.344 mmol). The mixture was stirred at rt for 2 hrs. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC (24g column, eluent, 30% EtOAc/methylene chloride) to give a yellow solid. 21 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 610.1695, found: 610.1696
Example 247
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-amino-phenyl)-amide
Figure imgf000357_0001
Molecular Weight =557.4755
Molecular Formula =C29H28CI2F2N4O
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (300 mg, 0.66 mmol) in methylene chloride (10 mL), HATU (Aldrich, 266 mg, 0.66 mmol) was added followed by the addition of DIPEA( 0.30 mL) and 4-amino-aniline (Aldrich, 143 mg, 1.32 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24g column, eluent, 40-85% EtOAc/hexanes) to give an off-white solid. 298 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 557, found: 557
Example 248
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl- ropyl)-pyrrolidine-2-carboxylic acid (4-acetylamino-phenyl)-amide
Figure imgf000357_0002
Molecular Weight =599.5132
Molecular Formula =C31 H30CI2F2N4O2 To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-amino-phenyl)-amide (40 mg, 0.072 mmol) in methylene chloride (5 mL), acetic anhydride (0.072 mmol) was added at room temperature followed by triethylamine (0.10 mL). The mixture was stirred at for 1 hr. and then chromatographied on an ISCO machine (12g, 40-85% EtOAc/Hexanes) to give a white solid. 34 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 599, found: 599
Example 249
Preparation of rac 2-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -thiazole-4-carboxyl acid ethyl ester
Figure imgf000358_0001
Molecular Weight =621 .5383
Molecular Formula =C29H28CI2F2N4O3S
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.22 mmol) in methylene chloride (10 mL), HATU (Aldrich, 83 mg, 0.25 mmol) was added followed by the addition of DIPEA( 100 uL) and 2-amino-thiazole-4-carboxylic acid ethyl ester (Oakwood, 43 mg, 0.25 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24g column, eluent, 40-80%) EtOAc/hexanes) to give a solid. 32 mg. MS (ES+) m/z Calcd: [(M+H)+]: 621, found: 621
Example 250
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (l,3-dioxo-2,3-dihydro-lH- isoindol-5-yl)-amide
Figure imgf000359_0001
Molecular Weight =61 1.4807
Molecular Formula =C31 H26CI2F2N4O3
To a stirred solution of thionyl chloride (2 mL), rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro- phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (110 mg, 0.24 mmol) was added and the mixture was stirred at rt for 2hrs. The excess thionyl chloride was removed and the residue was dissolved in methylene chloride (5 mL) and 5- amino-isoindole-l,3-dione( Aldrich, 0.30 mmol) was added followed by the addition of triethylamine (0.2 mL). The mixture was stirred overnight. The solvent was removed and the residue was purified on an ISCO machine (24g column, eluent, 40-80% EtOAc/hexanes) to give a pale yellow solid. 10 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 611, found: 611
Example 251
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-oxo-l ,6-dihydro-pyridin-3-yl)- amide
Figure imgf000360_0001
Molecular Weight =559.4478
Molecular Formula =C28H26CI2F2N4O2
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.44 mmol) in methylene chloride (8 mL), HATU (Aldrich, 166 mg, 0.50 mmol) was added followed by the addition of DIPEA( 200 uL) and 5-amino-2-pyridinone (Alfa, 97 mg, 0.88 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24g column, eluent, 40-80% EtOAc/hexanes) to give a solid. 168 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 559, found: 559
Example 252
Preparation of (2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-oxo-l ,6-dihydro-pyridin-3-yl)- amide
Figure imgf000361_0001
Molecular Weight =559.4478
Molecular Formula =C28H26CI2F2N4O2
(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-oxo-l ,6-dihydro-pyridin-3-yl)-amide(168 mg) was resolved on a Berger SFC machine under 100 bar, 30°C with 40 % of methanol at a rate of 2 mL/min give two separated peaks. Peak 1, 62 mg, peak 2, 64 mg (desired).
MS (ES+) m/z Calcd: [(M+H)+]: 559, found: 559
Example 253
Preparation of rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-pro l)-pyrrolidine-2-carboxylic acid (4-methylsulfanyl-phenyl)-amide
Figure imgf000361_0002
Molecular Weight =588.5519
Molecular Formula =C30H29CI2F2N3OS
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (250 mg, 0.44 mmol) in methylene chloride (10 mL), HATU (Aldrich, 332 mg, 0.88 mmol) was added followed by the addition of DIPEA(0.230 mL, 1.31 mmol) and 4-amino-phenyl methyl sulfide (Aldrich, 122 mg, 0.88 mmol). The mixture was stirred at rt for 2 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (50g column, eluent EtOAc/Hexanes, 5-10% ) to give a white solid. 135 mg. HRMS (ES+) m/z Calcd: [(M+H)+]: 588.1449, found: 588.1452.
Example 254
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methanesulfonyl-phenyl)-amide
Figure imgf000362_0001
Molecular Weight =620.5507
Molecular Formula =C30H29CI2F2N3O3S
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methylsulfanyl- phenyl)-amide(41 mg, 0.085 mmol) in methylene chloride (5 mL) at rt, MCPBA (Aldrich, 77%, 32 mg, 0.187 mmol) was added and the mixture was stirred for 2 hrs. The reaction was quenched with aqueous sodium thiosulfate and the layers were separated. The organic layer was washed with 10%> sodium carbonate (10 mL) and dried with sodium sulfate. The solvent was removed and the residue was loaded onto a silica gel column (12g, 10%> EtOAc/methylene chloride) to give a white solid. 38 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 620.1348, found: 620.1348
Example 255
Preparation of 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid tert-butyl ester
Figure imgf000363_0001
Molecular Weight =642.5792
Molecular Formula =C34H35CI2F2N3O3
Racemic 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2 -dimethyl-propyl)-pyrrolidine -2 -carbonyl]-amino} -benzoic acid tert-butyl ester (670 mg) was resolved on a Berger SFC system under 30°C, 100 Bar, 20% MeOH on a O.D. column to give two peaks. Peak 1, desired, 267 mg, white solid; Peak 2, the other enantiomer, undesired, 267 mg, white solid;
HRMS (ES+) m/z Calcd: [(M+H)+]: 42, found: 642
Example 256
Preparation of 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid
Figure imgf000363_0002
Molecular Weight =586.4708
Molecular Formula =C30H27CI2F2N3O3
4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid t-butyl ester (255 mg, 0.397 mmol) was treated with 50 % TFA/methylene chloride (10 mL) overnight. Removal of solvent and treating the residue with acetonitrile and water gave a white solid after filtration and drying. 236 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 586.1471 , found: 586.1467
Example 257
Preparation of 4-{[(2S,3R,4S,5R)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid
Figure imgf000364_0001
Molecular Weight =586.4708
Molecular Formula =C30H27CI2F2N3O3
4-{[(2S,3R,4S,5R)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid t-butyl ester (made above, 255 mg, 0.397 mmol) was treated with 50 % TFA/methylene chloride (10 mL) overnight . Removal of solvent and treating the residue with acetonitrile and water gave a white solid after filtration and dying. 239 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 586.1471 , found: 586.1467
Example 258
Preparation of (2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-phenyl)-amide
Figure imgf000365_0001
Molecular Weight =585.4861
Molecular Formula =C30H28CI2F2N4O2
Rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-nuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-phenyl)-amide(475 mg) was resolved on Berger SFC system under 30°C, 100 Bar, 35% MeOH on a O.D. Column to give two peaks. Peak 1, desired, 38 mg white solid; Peak 2, undesired, 38 mg white solid;
MS (ES+) m/z Calcd: [(M+H)+]: 585, found: 585
Example 259
Preparation of (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimeth -propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-phenyl)-amide
Figure imgf000365_0002
Molecular Weight =585.4861
Molecular Formula =C30H28CI2F2N4O2
Rac (2S,3R,4S,5R)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-phenyl)-amide(475 mg) was resolved on Berger SFC system under 30°C, 100 Bar, 35%> MeOH on a O.D. Column to give two peaks. Peak 1, undesired, 38 mg white solid; Peak 2, desired, 38 mg white solid; MS (ES ) mix Calcd: [(M+H)+ ]: 585, found: 585
Example 260
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methanesulfonylamino-phenyl)- amide
Figure imgf000366_0001
Molecular Weight =635.5654
Molecular Formula =C30H30CI2F2N4O3S
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-amino-phenyl)-amide (made above, 40 mg, 0.072 mmol) in methylene chloride (5 mL), methanesulfonic anhydride (Aldrich, 0.072 mmol) was added at room temperature followed by triethylamine (0.10 mL). The mixture was stirred at for 1 hr. and then chromatographied on an ISCO machine (12g, 40- 85% EtOAc/Hexanes) to give a white solid. 31 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 635, found: 635
Example 261
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-trifluoro-methanesulfonylamino- phenyl)-amide
Figure imgf000367_0001
Molecular Weight =689.5367
Molecular Formula =C30H27CI2F5N4O3S
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-amino-phenyl)-amide (80 mg, 0.15 mmol) in methylene chloride (5 mL) at 0°C, trifluoromethanesulfonic anhydride (Aldrich, 0.15 mmol) was added at room temperature followed by triethylamine (0.10 mL). The mixture was stirred at for 1 hr. and then chromatographied on an ISCO machine (12g, 40-85% EtOAc/Hexanes) to give a white solid. 64 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 689, found: 689 Example 262
Preparation of rac (2R,3R,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3 -(1 -methyl- lH-tetrazol-5-yl)- phenyl]-amide
Figure imgf000368_0001
Molecular Weight =624.5259
Molecular Formula =C31 H29CI2F2N7O
To a stirred solution of rac (2R,3R,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(lH-tetrazol-5-yl)- phenyl]-amide (44 mg, 0.172 mmol) in acetone(5 mL), sodium bicarbonate (84 mg, 1 mmol) and dimethyl sulfate (30 uL, 0.22 mmol) was added and the mixture was stirred at rt for 5 hrs. The solvent was removed and the residue was suspended in 3 mL of methylene chloride. The mixture was filtered and the filtrate was loaded on a silica gel column. Eluting with 35-70% EtOAc/Hexanes on an ISCO machine gave the desired product (12 mg) and the other regioisomer (26 mg).
MS (ES+) m/z Calcd: [(M+H)+]: 624, found: 624
Example 263
Preparation of rac (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(2-methyl-lH-tetrazol-5-yl)- phenyl]-amide
Figure imgf000369_0001
Molecular Weight =624.5259
Molecular Formula =C31 H29CI2F2N7O
To a stirred solution of rac (2R,3R,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(lH-tetrazol-5-yl)- phenyl]-amide (44 mg, 0.172 mmol) in acetone(5 mL), sodium bicarbonate (84 mg, 1 mmol) and dimethyl sulfate (30 uL, 0.22 mmol) was added and the mixture was stirred at rt for 5 hrs. The solvent was removed and the residue was suspended in 3 mL of methylene chloride. The mixture was filtered and the filtrate was loaded on a silica gel column. Eluting with 35-70% EtOAc/Hexanes on an ISCO machine gave the desired product (26 mg) and the other regioisomer(12 mg).
MS (ES+) m/z Calcd: [(M+H)+]: 624, found: 624
Example 264
Preparation of (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-oxo-l ,6-dihydro-pyridin-3-yl)- amide
Figure imgf000370_0001
Molecular Weight =559.4478
Molecular Formula =C28H26CI2F2N4O2
Rac (2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-oxo-l ,6-dihydro-pyridin-3-yl)-amide(168 mg) was resolved on a Berger SFC machine under 100 bar, 30°C with 40 % of methanol at a rate of 2 mL/min give two separated peaks. Peak 1, 62 mg(desired), peak 2, 64 mg (undesired).
MS (ES+) m/z Calcd: [(M+H)+]: 559, found: 559
Example 265
Preparation of (2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2 -fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(lH-tetrazol-5-yl)-phenyl]- amide
Figure imgf000370_0002
Molecular Weight =610.4988
Molecular Formula =C30H27CI2F2N7O Rac (2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2 -fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(lH-tetrazol-5-yl)-phenyl]-amide (522 mg)was resolved on a Berger SFC machine under 100 bar, 30°C with 35 % of methanol on an O.D. column gave two separated peaks. Peak 1 , 186 mg (desired), peak 2, 185 mg (undesired). MS (ES+) m/z Calcd: [(M+H)+]: 610, found: 610
Example 266
Preparation of (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2 -fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(lH-tetrazol-5-yl)-phenyl]- amide
Figure imgf000371_0001
Molecular Weight =610.4988
Molecular Formula =C30H27CI2F2N7O
Rac (2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2 -fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(lH-tetrazol-5-yl)-phenyl]-amide (522 mg)was resolved on a Berger SFC machine under 1000 bar, 30°C with 35 % of methanol on an O.D. column gave two separated peaks. Peak 1 , 186 mg(undesired), peak 2, 185 mg (desired). MS (ES+) m/z Calcd: [(M+H)+]: 610, found: 610
Example 267
Preparation of rac (2R,3R,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2 -methyl- lH-tetrazol-5-yl)- phenyl]-amide
Figure imgf000372_0001
Molecular Weight =624.5259
Molecular Formula =C31 H29CI2F2N7O
To a stirred solution of rac (2R,3R,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(lH-tetrazol-5-yl)- phenyl]-amide (32 mg, 0.0524 mmol) in acetone(5 niL), sodium bicarbonate (45 mg, 0.6 mmol) and dimethyl sulfate(0.11 mmol) was added and the mixture was stirred at rt for 5 hrs. The solvent was removed and the residue was suspended in 3 mL of methylene chloride. The mixture was filtered and the filtrate was loaded on a silica gel column. Eluting with 35-70% EtOAc/Hexanes on an ISCO machine gave the desired product (18 mg) and the other regioisomer (3 mg).
MS (ES+) m/z Calcd: [(M+H)+]: 624, found: 624
Example 268
Preparation of rac (2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(l -methyl- lH-tetrazol-5-yl)- phenyl]-amide
Figure imgf000373_0001
Molecular Weight =624.5259
Molecular Formula =C31 H29CI2F2N7O
To a stirred solution of rac (2R,3R,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(lH-tetrazol-5-yl)- phenyl]-amide (32 mg, 0.0524 mmol) in acetone(5 mL), sodium bicarbonate (45 mg, 0.6 mmol) and dimethyl sulfate(0.11 mmol) was added and the mixture was stirred at rt for 5 hrs. The solvent was removed and the residue was suspended in 3 mL of methylene chloride. The mixture was filtered and the filtrate was loaded on a silica gel column. Eluting with 35-70% EtOAc/Hexanes on an ISCO machine gave the desired product (3 mg) and the other regioisomer (18 mg).
MS (ES+) m/z Calcd: [(M+H)+]: 624, found: 624
Example 269
Preparation of rac 5-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-fluoro-benzoic acid ethyl ester
Figure imgf000374_0001
Molecular Weight =632.5154
Molecular Formula =C32H30CI2F3N3O3
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA(0.150 mL, 0.855 mmol) and 5-amino-2-fluoro-benzoic acid ethyl ester (Oakwood, 63 mg, 0.34 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (50g column, eluent EtOAc/Hexanes, 5-20% ) to give a white solid. 64 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 632, found: 632
Example 270
Preparation of (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2 -fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(lH-tetrazol-5-yl)-phenyl]- amide
Figure imgf000375_0001
Molecular Weight =610.4988
Molecular Formula =C30H27CI2F2N7O
Rac (2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2 -fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(lH-tetrazol-5-yl)-phenyl]-amide (690 mg)was resolved on a Berger SFC machine under 100 bar, 30°C with 10 % of methanol on an O.D. column gave two separated peaks. Peak 1 , 256 mg (desired), peak 2, 186 mg (undesired). MS (ES+) m/z Calcd: [(M+H)+]: 610, found: 610
Example 271
Preparation of (2S,3R,4S,5R)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2 -fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(lH-tetrazol-5-yl)-phenyl]- amide
Figure imgf000376_0001
Molecular Weight =610.4988
Molecular Formula =C30H27CI2F2N7O
Rac (2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2 -fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(lH-tetrazol-5-yl)-phenyl]-amide (690 mg)was resolved on a Berger SFC machine under 100 bar, 30°C with 10 % of methanol on an O.D. column gave two separated peaks. Peak 1 , 256 mg(undesired), peak 2, 186 mg (desired). MS (ES+) m/z Calcd: [(M+H)+]: 610, found: 610
Example 272
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-3-chloro-phenyl)- amide
Figure imgf000376_0002
Molecular Weight =619.931 1
Molecular Formula =C30H27CI3F2N4O2 To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA(0.150 mL, 0.855 mmol) and 4-amino-2-chloro -benzamide(Chembridge, 58 mg, 0.34 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC to give a white solid. 6 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 619, found: 619
Example 273
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-chloro-4-(lH-tetrazol-5-yl)- phenyl]-amide
Figure imgf000377_0001
Molecular Weight =644.9438
Molecular Formula =C30H26CI3F2N7O
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA(0.150 mL, 0.855 mmol) and 3-chloro-4-(lH-tetrazol-5-yl) aniline(made below, 67 mg, 0.34 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC to give a white solid. 52 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 644, found: 644
Example 274
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimeth l-propyl)-pyrrolidine-2-carboxylic acid (4-fiuoro-phenyl)-amide
Figure imgf000378_0001
Molecular Weight =560.4513
Molecular Formula =C29H26CI2F3N3O
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA(0.150 mL, 0.855 mmol) and 4-fluoro-aniline(Aldrich, 38 mg, 0.32 mmol).
The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine
(20 g column, 0-10% EtOAc/methylene chloride) to give a white solid. 67 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 560, found: 560
Example 275
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phi cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-fiuoro-phenyl)-amide
Figure imgf000379_0001
Molecular Weight =560.4513
Molecular Formula =C29H26CI2F3N3O
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA(0.150 mL, 0.855 mmol) and 3-fluoro-aniline(Aldrich, 38 mg, 0.32 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (20 g column, 0-10% EtOAc/methylene chloride) to give a white solid. 60 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 560, found: 560
Example 276
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-chloro-phenyl)-amide
I
Figure imgf000379_0002
Molecular Weight =576.9059
Molecular Formula =C29H26CI3F2N3O To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA(0.150 mL, 0.855 mmol) and 3-chloro-aniline(Aldrich, 44 mg, 0.32 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (20 g column, 0-10% EtOAc/methylene chloride) to give a white solid. 48 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 576, found: 576
Example 277
Preparation of rac (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrr lidine-2-carboxylic acid (5-iodo-pyridin-2-yl)-amide
Figure imgf000380_0001
Molecular Weight =669.3449
Molecular Formula =C28H25CI2F2IN40
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid, TFA salt (200 mg, 0.34mmol) in methylene chloride (3 mL), HATU (Aldrich, 235 mg, 0.62 mmol) was added followed by the addition of DIPEA (0.3 mL, 1.72 mmol) and 5-Iodo-pyridin-2-ylamine (Aldrich, 138 mg, 0.69 mmol). The mixture was stirred at RT overnight. The reaction was quenched with water . The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with sodium sulfate. The solvent was removed and the residue was purified by flash chromatography (0-8% EtOAc/methylene chloride) to give the title compound as a white solid (95 mg, 41% yield).
MS (ES+) m/z Calcd: [(M+H)+]: 669, found: 669 Example 278
Preparation of rac 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl^ropyl)-pyrrolidine-2-carbonyl]-amino} -2-fluoro-benzoic acid tert-butyl ester
Figure imgf000381_0001
Molecular Weight =660.5696
Molecular Formula =C34H34CI2F3N3O3
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.26 mmol) in methylene chloride (10 mL), HATU (Aldrich,147 mg, 0.39 mmol) was added followed by the addition of DIPEA(0.225 mL, 1.29 mmol) and 4-amino-2-flouro-benzoic acid t-butyl ester(Aldrich , 44 mg, 0.32 mmol). The mixture was stirred at rt for 5.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 0-15% EtOAc/hexanes) to give a white solid. 19 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 660, found: 660
Example 279
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-ethylcarbamoyl-phenyl)-amide
Figure imgf000382_0001
Molecular Weight =613.5402
Molecular Formula =C32H32CI2F2N4O2
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.26 mmol) in methylene chloride (10 mL), HATU (Aldrich,147 mg, 0.39 mmol) was added followed by the addition of DIPEA(0.225 mL, 1.29 mmol) and 4-amino-ethyl-benzamide(made by reducing the corresponding nitro precursor, 56mg, 0.34 mmol). The mixture was stirred at rt for overnight.
The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 0-15%
EtOAc/hexanes) to give a white solid. 42 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 613, found: 613
Example 280
Preparation of rac 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-fluoro-benzoic acid
Figure imgf000383_0001
Molecular Weight =604.4612
Molecular Formula =C30H26CI2F3N3O3
rac 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2
-fiuoro-benzoic acid tert-butyl ester(35 mg, 0.053 mmol) was treated with 50 % TFA/methylene chloride (10 mL) overnight . Removal of solvent and treating the residue with acetonitrile and water gave a white solid after filtration and dying. 29 mg.
HRMS (ES+) m/z Calcd: [(M+H)+]: 604.1376, found: 604.1376
Example 281
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-methoxy-pyridin-3-yl)-amide
Figure imgf000383_0002
Molecular Weight =573.4749
Molecular Formula =C29H28CI2F2N4O2
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.217 mmol) in methylene chloride (10 mL), HATU (Aldrich,l 18 mg, 0.31 mmol) was added followed by the addition of DIPEA(0.15 mL, 0.86 mmol) and 3-amino-6-methoxy-pyridine(Aldrich, 43 mg, 0.34 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 0-5% MeOH/methylene chloride) to give a white solid. 73 mg. MS (ES+) m/z Calcd: [(M+H)+]: 573.1630, found: 573.1630
Example 281
Preparation of rac 3-({[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} - methyl)-benzoic acid methyl ester
Figure imgf000384_0001
Molecular Weight =614.5250
Molecular Formula =C32H31 CI2F2N3O3
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.26 mmol) in methylene chloride (10 mL), HATU (Aldrich,177 mg, 0.46 mmol) was added followed by the addition of DIPEA(0.36 mL, 2.06 mmol) and 3-aminomethyl-benzoic acid methyl ester hydrochloride salt(Aldrich, 104 mg, 0.52 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15% EtOAc/hexanes) to give a white solid. 118 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 614, found: 614
Example 282
Preparation of rac 4-({[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-benzoic acid methyl ester
Figure imgf000385_0001
Molecular Weight =614.5250
Molecular Formula =C32H31 CI2F2N3O3
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.26 mmol) in methylene chloride (10 mL), HATU (Aldrich,177 mg, 0.46 mmol) was added followed by the addition of DIPEA(0.36 mL, 2.06 mmol) and 4-aminomethyl-benzoic acid methyl ester hydrochloride salt (Aldrich, 104 mg, 0.52 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15%
EtOAc/hexanes) to give a white solid. 119 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 614, found: 614
Example 283 Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phi cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-chloro-phenyl)-amide
Figure imgf000386_0001
Molecular Weight =576.9059
Molecular Formula =C29H26CI3F2N3O
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.34 mmol) in methylene chloride (10 mL), HATU (Aldrich, 234 mg, 0.62 mmol) was added followed by the addition of DIPEA(0.30 mL, 1.71 mmol) and 4-chloro-aniline (Aldrich, 88 mg, 0.68 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15% EtOAc/hexanes) to give a white solid. 105 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 576, found: 576
Example 284
Preparation of (2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-chloro-phenyl)-amide
Figure imgf000387_0001
Molecular Weight =576.9059
Molecular Formula =C29H26CI3F2N3O
rac (2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-chloro-phenyl)-amide (lOOmg) was separated on a Berger SFC machine under 100 bar, 30°C, and 45% of MeOH through a Whelk column to give a white solid (peak 2, 41 mg)
MS (ES+) m/z Calcd: [(M+H)+]: 576, found: 576
Example 285
Preparation of (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-chloro-phenyl)-amide
Figure imgf000387_0002
Molecular Weight =576.9059
Molecular Formula =C29H26CI3F2N3O
rac (2S,3R,4S,5R)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-chloro-phenyl)-amide (lOOmg) was separated on a Berger SFC machine under 100 bar, 30°C, and 45% of MeOH through a Whelk column to give a white solid (peak 1 , 40 mg) MS (ES ) mix Calcd: [(M+H)+]: 576, found: 576
Example 286
Preparation of rac 4- {[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2
-methoxy-benzoic acid methyl ester
Figure imgf000388_0001
Molecular Weight =630.5244
Molecular Formula =C32H31 CI2F2N3O4
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich,l 18 mg, 0.31 mmol) was added followed by the addition of DIPEA(0.15 mL, 0.86 mmol) and 4-amino-2-methoxy-benzoic acid (Avocado, 62 mg, 0.34 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15% EtOAc/methylene chloride) to give a white solid. 29 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 630.1733, found: 630.1732
Example 287
Preparation of rac 3-({[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-benzoic acid
Figure imgf000389_0001
Molecular Weight =600.4979
Molecular Formula =C31 H29CI2F2N3O3
rac 3-({[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-benzoic acid methyl ester (40 mg) was dissolved in MeOH (10 mL) with help of slight heating. To the stirred solution was added NaOH ( IN, 2 mL) and the mixture was stirred for 1.5 hrs. The solvent was removed and the residue was treated with 1 N HC1 to make the mixture acidic. The white suspension was extracted with EtOAc (3 x10 mL) and the extracts combined and dried with sodium sulfate. The solvent was removed and the residue was freeze dried to give a white powder. 38 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 600, found: 600
Example 288
Preparation of rac 4-({[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-benzoic acid
Figure imgf000390_0001
Molecular Weight =600.4979
Molecular Formula =C31 H29CI2F2N3O3
rac 4-({[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-benzoic acid methyl ester (40 mg) was dissolved in MeOH (10 mL) with help of slight heating. To the stirred solution was added NaOH( IN, 2 mL) and the mixture was stiired for 1.5 hrs. The solvent was removed and the residue was treated with 1 N HC1 to make the mixture acidic. The white suspension was extracted with EtOAc (3 x10 mL) and the extracts combined and dried with sodium sulfate. The solvent was removed and the residue was freeze dried to give a white powder. 38 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 600, found: 600
Example 289
Preparation of (2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl- ropyl)-pyrrolidine-2-carboxylic acid (4-acetylamino-phenyl)-amide
Figure imgf000390_0002
Molecular Weight =599.5132
Molecular Formula =C31 H30CI2F2N4O2 rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-acetylamino-phenyl)-amide (360mg) was separated on a Berger SFC machine under 100 bar, 30°C, and 45% of MeOH through an OJ column to give a white solid (peak 1 , 103 mg)
MS (ES+) m/z Calcd: [(M+H)+]: 599, found: 599
Example 290
Preparation of (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-prop l)-pyrrolidine-2-carboxylic acid (4-acetylamino-phenyl)-amide
Figure imgf000391_0001
Molecular Weight =599.5132
Molecular Formula =C31 H30CI2F2N4O2
rac (2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-acetylamino-phenyl)-amide (360mg) was separated on a Berger SFC machine under 100 bar, 30°C, and 45% of MeOH through a OJ column to give a white solid (peak 2, 100 mg)
MS (ES+) m/z Calcd: [(M+H)+]: 599, found: 599
Example 291
Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methanesulfonyl-phenyl)-amide
Figure imgf000392_0001
Molecular Weight =620.5507
Molecular Formula =C30H29CI2F2N3O3S
rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methanesulfonyl-phenyl)-amide(165mg) was separated on a Berger SFC machine under 100 bar, 30°C, and 20% of MeOH to give a white solid (peak 1 , 90 mg)
MS (ES+) m/z Calcd: [(M+H)+]: 620, found: 620
Example 292
Preparation of (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methanesulfonyl-phenyl)-amide
Figure imgf000392_0002
Molecular Weight =620.5507
Molecular Formula =C30H29CI2F2N3O3S
rac (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methanesulfonyl-phenyl)-amide(165mg) was separated on a Berger SFC machine under 100 bar, 30°C, and 20% of MeOH to give a white solid (peak 2, 90 mg) MS (ES+) m/z Calcd: [(M+H)+]: 620, found: 620
Example 293
Preparation of rac 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-methoxy-benzoic acid
Figure imgf000393_0001
Molecular Weight =616.4973
Molecular Formula =C31 H29CI2F2N3O4
rac 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-methoxy-benzoic acid ester (40 mg) was dissolved in MeOH (10 mL) with help of slight heating. To the stirred solution was added NaOH (IN, 2 mL) and the mixture was stirred for 4hrs at 50°C. The solvent was removed and the residue was treated with 1 N HC1 to make the mixture acidic. The white suspension was extracted with EtOAc (3 x10 mL) and the extracts combined and dried with sodium sulfate. The solvent was removed and the residue was freeze dried to give a white powder. 27 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 616, found: 616
Example 294
Preparation of rac 5-bromo-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]- amino} -2-methoxy-benzoic acid methyl ester
Figure imgf000394_0001
Molecular Weight =709.4204
Molecular Formula =C32H30BrCI2F2N3O4
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro- phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.34 mmol) in methylene chloride (10 mL), HATU (Aldrich, 235 mg, 0.62 mmol) was added followed by the addition of DIPEA(0.30 mL, 1.72 mmol) and 4-amino-5-bromo-2- methoxy-benzoic acid (Aldrich, 179 mg, 0.69 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15%
EtOAc/methylene chloride) to give a white solid. 7.3 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 709, found: 709
Example 295
Preparation of rac 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-methyl-benzoic acid methyl ester
Figure imgf000395_0001
Molecular Weight =614.5250
Molecular Formula =C32H31 CI2F2N3O3
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.34 mmol) in methylene chloride (10 mL), HATU (Aldrich, 235 mg, 0.62 mmol) was added followed by the addition of DIPEA(0.30 mL, 1.72 mmol) and 4-amino-2 -methyl-benzoic acid (Aldrich, 114 mg, 0.69 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15% EtOAc/methylene chloride) to give a white solid. 102 mg. MS (ES+) m/z Calcd: [(M+H)+]: 614, found: 614
Example 296
Preparation of 4-amino-2-chlorobenzoic acid methyl ester.
Figure imgf000395_0002
A solution of 4-nitro-2-chlorobenzoic acid methyl ester (Aldrich, 700 mg, 3.24 mmol) in ethyl acetate (50 mL) was treated with 10% Pd/C (50 mg) and hydrogenated at 1 atmosphere for 3 hrs. The mixture was filtered and concentrated to give a light yellow solid which was directly used for the next step. Example 297
Preparation of rac 2-Chloro-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester
Figure imgf000396_0001
Molecular Weight =634.9429
Molecular Formula =C31 H28CI3F2N3O3
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.34 mmol) in methylene chloride (10 mL), HATU (Aldrich, 235 mg, 0.62 mmol) was added followed by the addition of DIPEA(0.30 mL, 1.72 mmol) and 4-amino-2-chloro-benzoic acid (made above, 128 mg, 0.69 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15% EtOAc/methylene chloride) to give a white solid. 74 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 634, found: 634
Example 298
Preparation of 4-amino-2-trifiuoromethyl benzoic acid methyl ester.
Figure imgf000397_0001
A solution of 4-nitro-2-trifluoromethyl benzoic acid methyl ester (Aldrich, 700 mg, 3.24 mmol) in ethyl acetate (50 mL) was treated with 10% Pd/C (50 mg) and hydrogenated at 1 atmosphere for 3 hrs. The mixture was filtered and concentrated to give a light yellow solid which was directly used for the next step.
Example 299
Preparation of rac 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl^ropyl)-pyrrolidine-2-carbonyl]-amino} -2-trifiuoromethyl- benzoic acid methyl ester
Figure imgf000397_0002
Molecular Weight =668.4963
Molecular Formula =C32H28CI2F5N3O3
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (166 mg, 0.29 mmol) in methylene chloride (10 mL), HATU (Aldrich,195 mg, 0.54 mmol) was added followed by the addition of DIPEA(0.25 mL, 1.425 mmol) and 4-amino-2-trifiuoromethyl-benzoic acid (made above, 125 mg, 0.57 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15% EtOAc/methylene chloride) to give a white solid. 40 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 668, found: 668
Example 300
Preparation of rac 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimeth l-propyl)-pyrrolidine-2-carbonyl]-amino} -2-methyl-benzoic acid
Figure imgf000398_0001
Molecular Weight =600.4979
Molecular Formula =C31 H29CI2F2N3O3
rac 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-methyl-benzoic acid methyl ester (82 mg) was dissolved in MeOH (10 mL) with help of slight heating. To the stirred solution was added NaOH ( IN, 2 mL) and the mixture was stirred for 3hrs at 50°C. The solvent was removed and the residue was treated with 1 N HC1 to make the mixture acidic. The white suspension was extracted with EtOAc (3 xlO mL) and the extracts combined and dried with sodium sulfate. The solvent was removed and the residue was freeze dried to give a white powder. 67 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 600, found: 600
Example 301
Preparation of rac 2-Chloro-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid
Figure imgf000399_0001
Molecular Weight =620.9158
Molecular Formula =C30H26CI3F2N3O3
rac 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-rluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-chloro-benzoic acid methyl ester (54 mg) was dissolved in MeOH (10 mL) with help of slight heating. To the stirred solution was added NaOH ( IN, 2 mL) and the mixture was stirred for lhrs at 55°C. The solvent was removed and the residue was treated with 1 N HC1 to make the mixture acidic. The white suspension was extracted with EtOAc (3 xlO mL) and the extracts combined and dried with sodium sulfate. The solvent was removed and the residue was freeze dried to give a white powder. 40 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 620, found: 620
Example 302
Preparation of 4-nitro-benzimidic acid methyl ester hydrochloride
Figure imgf000399_0002
Molecular Weight =180.1646 36.4610
Molecular Formula =C8H8N2O3 . HCI To a stirred solution of 4-nitro-benzonitrile(Aldrich, 17 g) in methanol (200 mL) was added 0.53 g of sodium methoxide. The solution was stirred for 12 hrs and another 1.5 g of sodium methoxide was added and the mixture was stirred for 6 hrs. The solution was cooled to 0°C and HCl gas was bubbled in until a white solid forms. The solvent was reduced to about 100 mL and the solid was filtered and dried under vacuum to give a white solid. 12.1 g.
Example 303
Preparation of 5-(4-nitro-phenyl)-lH-[l ,2,4]triazole
Figure imgf000400_0001
Molecular Weight =190.1626
Molecular Formula =C8H6N4O2
4-Nitro-benzimidic acid methyl ester hydrochloride (635 mg, 2.93 mmol) was suspended in pyridine (7 mL)and formic hydrazide (Aldrich, 178 mg, 2.95 mmol) was added and the mixture was stirred at rt for 1 hr. The solvent was removed and the residue was dissolved in toluene ( 10 mL) and the mixture was stirred at reflux for 1.5 hrs. the mixture was cooled and water was added. The organic layer was separated and dried over sodium sulfate. The solvent was removed and the residue was suspended in 25% EtOAc/Hexanes and the solid was filtered to give a solid. 510 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 191, found: 191
Example 304
Preparation of 5-(4-amino-phenyl)-lH-[l ,2,4]triazole
Figure imgf000401_0001
Molecular Weight =160.1798
Molecular Formula =C8H8N4
5-(4-Nitro-phenyl)-lH-[l,2,4]triazole (510 mg) was suspended in 50 mL of ethyl acetate and 56 mg of 10% Pd/C was added. The mixture was hydrogenated under 50 Psi for 100 min.. The mixture was filtered and the filtrate was concentrate to give a solid. 497 mg
MS (ES+) m/z Calcd: [(M+H)+]: 161, found: 161
Example 305
Preparation of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2H-[l ,2,4]triazol-3-yl)-phenyl]- amide
Figure imgf000401_0002
Molecular Weight =609.51 12
Molecular Formula =C31 H28CI2F2N6O
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.32 mmol) methylene chloride (5 mL), HATU (Aldrich,152 mg, 0. 4 mmol) was added followed by the addition of DIPEA(0.1 mL) and 5-(4-amino-phenyl)-lH-[l,2,4]triazole (made above, 64 mg, 0.4 mmol). The mixture was stirred at rt for 2 hrs. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 70% EtOAc/hexanes) to give a white solid. 140 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 609, found: 609
Example 306
Preparation of N'-[imino-(4-nitro-phenyl)-methyl]-hydrazinecarboxylic acid tert-butyl ester
Figure imgf000402_0001
Molecular Weight =280.2857
Molecular Formula =C12H16N4O4
To a stirred solution of 4-nitro-benzimidic acid methyl ester hydrochloride (500 mg, 2.31 mmol) in ethanol ( 8 mL), hydrazinecarboxylic acid tert-butyl ester (305 mg, 2.31 mmol) was added followed by triethylamine. The mixture was stirred at rt over night . The solvent was removed and the residue was suspended in methylene chloride (10 mL). The mixture was filtered and the filtrate was concentrated to about 4 mL and loaded on a 20 g silica gel column. Eluting with 40- 90% EtOAc/Hexanes on an ISCO machine gave a yellow solid. 410 mg. Which was directly used for the next step. Example 307
Preparation of 5-(4-Nitro-phenyl)-l ,2-dihydro-[l ,2,4]triazol-3-one
Figure imgf000403_0001
Molecular Weight =206.1620
Molecular Formula =C8H6N4O3
N'-[Imino-(4-nitro-phenyl)-methyl]-hydrazinecarboxylic acid tert-butyl ester ( made above, 410 mg) was suspended in 3 mL of acetonitrile and the mixture was heated at 200°C for 5 min.. The mixture was cooled and the solid was filtered and dried. 341 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 207, found: 207
Example 308
Preparation of 5-(4-amino-phenyl)-l,2-dihydro-[l,2,4]triazol-3-
Figure imgf000403_0002
Molecular Weight =176.1792
Molecular Formula =C8H8N4O
5-(4-amino-phenyl)-l,2-dihydro-[l,2,4]triazol-3-one ( made above, 340 mg) was suspended in a mixture of THF and EtOAc( 10 mL each). 10% Pd/C (100 mg ) was added and the mixture was hydrogenated under 50 psi for 4 hrs. Filtered and the filtrate was concentrated to give a white solid. 217 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 177, found: 177.
Example 309
Preparation of rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(5- oxo-2,5-dihydro-lH-[l ,2,4]triazol-3-yl)-phenyl]-amide
Figure imgf000404_0001
Molecular Weight =625.5106
Molecular Formula =C31 H28CI2F2N6O2
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (264 mg, 0.56 mmol) in DMF (5 mL), HATU (Aldrich, 213 mg, 0. 56 mmol) was added followed by the addition of DIPEA(0.1 mL) and 5-(4-amino-phenyl)-l,2-dihydro-[l,2,4]triazol-3-one (made above, 100 mg, 0.56 mmol). The mixture was stirred at rt for 4 hrs. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5% MeOH/methylene chloride) to give a white solid. 47 mg. MS (ES+) m/z Calcd: [(M+H)+]: 625, found: 625
Example 310
Preparation of 3-chloro-4-(lH-tetrazol-5-yl)-phenylamine
Figure imgf000405_0001
Molecular Weight =195.6124
Molecular Formula =C7H6CIN5
To a stirred solution of 4-amino-2-chloro-benzonitrile (Aldrich, 765 mg, 5 mmol) in toluene (10 mL), sodium azide (423 mg, 6.5 mmol) and triethylamine hydrochloride (895 mg, 6.5 mmol) was added and the mixture was stirred vigorously at 115°C overnight. The mixture was cooled and poured into water. The aqueous layer was adjusted to PH =5 by the addition of 6 N HCl and the solid formed was filtered and dried. 175 mg,
MS (ES+) m/z Calcd: [(M+H)+]: 196, found: 196
Example 311
Preparation of rac-(5-{[(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -4H-[l,2,4]triazol-3- yl)-acetic acid
Figure imgf000405_0002
M. W. 591.45 C27H26CI2F2N6O3
A mixture of rac- (5-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -4H-[l,2,4]triazol-3- yl)-acetic acid methyl ester (20 mg, 0.033 mmol) was dissolved in THF (0.6 mL) and methanol (0.2 mL), then 2N LiOH (0.2 mL) was added and stirred at room temperature for 3 hours. The mixture was concentrated and diluted with water and ethyl acetate. The organic phase was separated then concentrated to yield rac-(5-{[(2i?,35',4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl^ropyl)-pyrrolidine-2-carbonyl]-amino}-4H- [l,2,4]triazol-3-yl)-acetic acid ( 6.7 mg, 34 %) as an off-white powder. HRMS (ES ) m/z Calcd for C27H26CI2F2N6O3 + H [(M+H)+]: 591.1485, found: 591.1483.
Example 312
Preparation of rac-(3-{[(2i?,35,,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -pyrazol-l-yl)-acetic acid
Figure imgf000406_0001
M. W. 590.46 C28H27Cl2F2N503
A mixture of rac-(3-{[(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -pyrazol-l-yl)-acetic acid tert- butyl ester (25 mg, 0.039 mmol) was chilled to OoC. Then concentrated sulfuric acid (1 mL) was added and the reaction was stirred for 2 hours. Ice and water added all at once, crystals filtered and washed with water. The crystals were azeotroped three times with toluene then treated to high vacuum overnight to yield rac-(3-{[(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} - pyrazol-l-yl)-acetic acid as an off white powder (12.1 mg, 53 %). HRMS (ES ) m/z Calcd for C28H27Cl2F2N503 + H [(M+H)+]: 590.1532, found: 590.1532.
Example 313
Preparation of rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (lH-imidazol-4-ylmethyl)-amide
Figure imgf000406_0002
M. W. 545.44 C27H26Cl2F2N50
A mixture of rac-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), 1H- (imidazoyl-4-yl) methylamine (62 mg, 0.64 mmol), 2-(7-azabenzotriazol-l-yl)-n,n,n',n'- tetramethyluronium hexanuorophosphate (HATU, 243.3 mg, 0.64 mmol) and iP^NEt (0.22 mL, 1.2 mmol) in CH2CI2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2CI2 and washed with water, brine. The organic phase was separated, dried over Na2S04 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (15- 95% of ACN/water) to rac-(2i?,35,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (lH-imidazol-4- ylmethyl)-amide ( 6.2 mg, 2.6 %) as an off-white powder. HRMS (ES ) m/z Calcd for
C27H26CI2F2N5O + H [(M+H)+]: 546.1634, found: 546.1632.
Example 314
Preparation of rac-(25',3i?,45,,5i?)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fiuoro-phenyl)-2- (2,2-dimethyl-propyl)-5-(2-oxa-6-aza-s iro[3.3]heptane-6-carbonyl)-pyrrolidine-3-carbonitrile
Figure imgf000407_0001
M. W. 548.47 C28H29CI2F2N3O2
A mixture of rac-(2i?,35',4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), 2-oxa-6- aza-spiro[3.3] heptane oxylate salt (123 mg, 0.65 mmol), 2-(7-azabenzotriazol-l-yl)-n,n,n',n'- tetramethyluronium hexanuorophosphate (HATU, 243.3 mg, 0.64 mmol) and iP^NEt (0.22 mL, 1.2 mmol) in CH2CI2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2CI2 and washed with water, brine. The organic phase was separated, dried over Na2S04 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (20- 95% of ACN/water) to rac-(25,3i?,45,5i?)-4-(3-chloro-2-fiuoro-phenyl)-3-(4-chloro-2-fluoro- phenyl)-2-(2,2-dimethyl-propyl)-5-(2-oxa-6-aza-spiro[3.3]heptane-6-carbonyl)-pyrrolidine-3- carbonitrile ( 78 mg, 33.3 %) as an off-white powder. HRMS (ES ) m/z Calcd for C28H29CI2F2N3O2 + H [(M+H)+]: 548.1678, found: 548.1678.
Example 316
Preparation of rac- 1 -[(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-azetidine3-carboxylic acid
Figure imgf000408_0001
M. W. 550.44 C27H27CI2F2N3O3
A mixture of rac-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), azetidine-3- carboxylate methyl ester hydrochloride (200 mg, 1.32 mmol), 2-(7-azabenzotriazol-l-yl)- η,η,η',η'-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iP^NEt (0.22 mL, 1.2 mmol) in CH2CI2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2CI2 and washed with water, brine. The organic phase was separated, dried over Na2S04 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to yield
l-[(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-azetidine-3-carboxylic acid methyl ester (26 mg, 10.7 %). The ester was taken direcly to the hydrolysis step by dissolved in THF (0.6 mL) and methanol (0.2 mL), then 2N LiOH (0.2 mL) was added and stirred at room temperature for 3 hours. The mixture was concentrated and diluted with water and ethyl acetate. The organic phase was separated then concentrated to rac-l-[(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4- (4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-azetidine3- carboxylic acid ( 11.8 mg, 46.6 %) as an off-white powder. HRMS (ES+) m/z Calcd for
C27H27CI2F2N3O3 + H [(M+H)+]: 550.1471, found: 550.1471. Example 317
Preparation of rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-[l ,2,3]triazol-l -yl-ethyl)-amide
Figure imgf000409_0001
M. W. 561.47 C27H28CI2F2N6O
A mixture of rac-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), 2- [l,2,3]triazol-l-yl ethylamine (200 mg, 1.78 mmol), 2-(7-azabenzotriazol-l-yl)-n,n,n',n'- tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iP^NEt (0.22 mL, 1.2 mmol) in CH2CI2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2CI2 and washed with water, brine. The organic phase was separated, dried over Na2S04 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (15- 95% ofACN/water) rac-(2i?,35,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-[l,2,3]triazol-l-yl- ethyl)-amide ( 83.7 mg, 34.7 %) as an off-white powder. HRMS (ES+) m/z Calcd for
C27H28CI2F2N6O + H [(M+H)+]: 561.1743, found: 561.1741.
Example 318
Preparation of rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1 -carbamoylmethyl- 1 H-pyrazol-3 - yl)-amide
Figure imgf000409_0002
M. W. 589.48 C28H28CI2F2N6O2 A mixture of rac-(3-{[(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazol-l-yl)-acetic acid (85 mg, 0.144 mmol), ammonia (0.57 mL, 0.288 mmol, 0.5 M in dioxane), 2-(7-azabenzotriazol-l- yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (HATU, 109 mg, 0.288mmol) and iPr2NEt (0.1 mL, 0.43 mmol) in CH2C12 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2C12 and washed with water, brine. The organic phase was separated, dried over Na2S04 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) rac-(2i?,35,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-[l,2,3]triazol-l-yl- ethyl)-amide ( 12.3 mg, 14.5 %) as an off-white powder. HRMS (ES+) m/z Calcd for
C28H28CI2F2N6O2 + H [(M+H)+]: 589.1692, found: 589.1693.
Example 319
Preparation of rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [ 1 -(2-hydroxy-2-methyl-propyl)- 1 H-pyrazol-3 - yl]-amide
Figure imgf000410_0001
M. W. 568.545 C3oH35Cl2N502
A mixture of rac-(2i?,3i?,4i?,55)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), l-(3-amino-pyrazol-l-yl)- 2-methyl-propan-2-ol (93.12 mg, 0.3 mmol), 2-(7-azabenzotriazol-l-yl)-n,n,n',n'- tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iP^NEt (0.1 mL, 0.55 mmol) in CH2CI2 (2 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 purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [ 1 -(2-hydroxy-2-methyl-propyl)- 1 H-pyrazol-3 - yl]-amide (54.1 mg, 47.6 %) as an off-white powder. HRMS (ES ) m/z Calcd for C3oH35Cl2N502 + H [(M+H)+]: 568.2241 , found: 568.2246.
Example 320
Preparation of rac-(2i?,3i?,4i?,55')-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methanesulfonylamino-propyl)-amide
Figure imgf000411_0001
M. W. 565.563 C27H34C12N403S
A mixture of rac (2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-amino-propyl)-amide (120 mg, 0.24 mmol), methane sulfonyl chloride (49 μί, 0.6 mmol) and dimethylaminopyridine (97.6 mg, 0.8 mmol) in CH2C12 (8 mL) was stirred for 5h at rt. The mixture was then extracted with NaHC03(s), water and the organic layer dried with MgS04, filtered and the solvent was evaporated under reduced pressure, diluted with CH2C12 and washed with water, brine. The organic phase was separated, filtered and dried over Na2S04. The mixture was then purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2i?,3i?,4i?,55)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methanesulfonylamino-propyl)- amide (112.1 mg, 80.5 %) as an off-white powder. HRMS (ES+) m/z Calcd for C27H34C12N403S + H [(M+H)+]: 565.1802, found: 565.1800.
Example 321
Preparation of chiral (2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid { 1 -[2-((5)-3-dimethylamino-2- hydroxy-propoxy)-2-methyl-propyl]-lH-pyrazol-3- yl} -amide and chiral 2S,3R,4S,5R)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid { 1 -[2-((5)-3-dimethylamino-2-hydroxy-propoxy)-2-methyl- propyl]-lH-pyrazol-3- yl} -amide
Figure imgf000412_0001
M. W. 705.674 C35H44CI2F2N6O3 M. W. 705.674 C35H44CI2F2N6O3
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), (5)-l-[2-(3- amino-pyrazol-l-yl)-l,l-dimethyl-ethoxy]-3-dimethylamino-propan-2-ol ( 370 mg, 1.44 mmol),
2- (7-azabenzotriazol-l-yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (HATU, 950 mg, 2.5 mmol) and iP^NEt (1.4 mL, 8 mmol) in CH2CI2 (50 mL) was stirred at rt overnight. The mixture was then diluted with CH2CI2 and washed with water, brine. The organic phase was separated, dried over Na2S04 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (15-95% of ACN/water) to give rac-(2i?,35',4i?,55)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid {l-[2-((5')-3-dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-lH-pyrazol-
3- yl} -amide ( 255 mg, 18 %) as an off-white powder. The racemate mixture was submitted for SFC purification to of chiral (2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {l-[2-((5)-3- dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-lH-pyrazol-3- yl}-amide ( 85.1 mg, 6.1 %) as an white powder. HRMS (ES+) m z Calcd for C35H44CI2F2N6O3 + H [(M+H)+]:
705.2893, found: 705.2891 and chiral (2«S,3i?,4,S,5i?)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro- 2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine -2 -carboxylic acid {l-[2-((5)-3- dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-lH-pyrazol-3- yl}-amide( 23.1 mg, 20.8 %) as an off-white powder. HRMS (ES+) m z Calcd for C35H44CI2F2N6O3+ H [(M+H)+]: 705.2893, found: 705.2889. Example 322
Preparation of (5)-l-[2-(3-Amino-pyrazol-l-yl)-l ,l-dimethyl-ethoxy]-3-dimethylamino-propan-
2-ol
Figure imgf000413_0001
M. W. 286.33 C12H22N4O4
Compound (5')-l-dimethylamino-3-[l,l-dimethyl-2-(3-nitro-pyrazol-l-yl)-ethoxy]-propan-2-ol was prepared by reacting l-[2-methyl-2-((5)-l-oxiranylmethoxy)-propyl]-3-nitro-lH-pyrazole ( 0.39 g, 1.62 mmol), isopropyl alcohol ( 6 niL), and dimethylamine (3 niL, 6 mmol, 2 M in dioxane) under microwave conditions at 130°C for 15 min. The mixture was extracted with dichloromethane and water. The organic layer was separated and the solvent evaporated under reduced pressure to yield (5)-l-dimethylamino-3-[l,l-dimethyl-2-(3-nitro-pyrazol-l-yl)-ethoxy]- propan-2-ol (0.4 g, 87 %). This compound was reduced under the following conditions- The mixture of (5')-l-dimethylamino-3-[l,l-dimethyl-2-(3-nitro-pyrazol-l-yl)-ethoxy]-propan-2- ol (0.39 g, 1.66 mmol), ethyl acetate (30 mL), ethanol (30 mL) was added to a Parr bottle with 10% Pd/C (0.22 g) and subjected hydrogen gas (20 psi) for 2 h under the Parr Shaker Apparatus conditions. Work up by filtration via a glass membrane filter paper, solvent was removed under reduced pressure to afford (S)-l-[2-(3-amino-pyrazol-l-yl)-l ,l-dimethyl-ethoxy]-3- dimethylamino-propan-2-ol as an oil (0.37 g, 97.5 %). Example 323
Preparation of 1 -[2-methyl-2-((5')- 1 -oxiranylmethoxy)-propyl]-3 -nitro- 1 H-pyrazole
Figure imgf000413_0002
M. W. 241.25 CioHi5N304 A mixture of 2-methyl-l-(3-nitro-pyrazol-l-yl)-propan-2-ol (0.64 g, 3.46 mmol), and DMF (30 mL) was stirred at 0°C for 5 min, then NaH (60% dispersion in oil, 0.415 g, 17.3 mmol) was added and stirred 20 min at 0°C. 5'-(+)-glycidyl-3-nitrobenzenesulfonate (1.79 g, 6.92 mmol) was added and stirred at 0°C for 1 h then warmed to 25°C for 3h. The mixture was then diluted with NH4Cl(s), ethyl acetate, the organic phase was separated, washed with NaHC03(satd) dried with Na2S04, and filtered. The mixture was then concentrated and purified by column
chromatography (40-120 g Analogix column, 80% EtO Ac/heptane to yield the product l-[2- methyl-2-((5)-l-oxiranylmethoxy)-propyl]-3-nitro-lH-pyrazole as a white solid (0.36 g, 43.1 %). Example 324
Preparation of chiral-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid and chiral (25,,3i?,45',5i?)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbox lic acid
Figure imgf000414_0001
M. W. 467.35 C23H22C12F2N202 M. W. 467.35 C23H22C12F2N202
A mixture of rac-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid was synthesized by the Synthesis group (Lot# 40476-42-2, 84 g). A portion was submitted (20.5g, 40526-055-1) for SFC
Separation CH#3978; AD column method #05200916, 2 mL/min; 10% methanol, 100 bar, 30°C to afford chiral-(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid as a white solid (10.12 g)
HRMS(ES+) m/z Calcd C23H22C12F2N202+H [(M+H):467.1099; Found:467.1099
and chiral (25,,3i?,45,,5i?)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid as a white solid (9.6 g) HRMS(ES+) m/z Calcd C23H22C12F2N202+H [(M+H):467.1099; Found:467.1099.
Example 325 Preparation of rac-l-{[(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-p rrolidine-2-carbonyl]-amino} -cyclopropane carboxylic acid
Figure imgf000415_0001
M. W. 550.43 C27H27CI2F2N3O3
A mixture of rac-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), 1-amino- cyclopropanecarboxylic acid methyl ester hydrochloride (100 mg, 0.86 mmol), 2-(7- azabenzotriazol-l-yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iP^NEt (0.22 mL, 1.2 mmol) in CH2CI2 (20 mL) was stirred at rt overnight. The mixture was then diluted with CH2CI2 and washed with water, brine. The organic phase was separated, dried over Na2S04 and filtered. The mixture was then concentrated and purified flash column chromatography (1-100% ethyl acetate/heptane) to afford rac-l-j^ i^^^^^-S-iS- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino} -cyclopropanecarboxylic acid methyl ester as a white powder (120 mg, 49.6 %). HRMS (ES+) m/z Calcd for C28H29CI2F2N3O3 + H [(M+H)+]: 564.1627, found: 564.1627.
The ester was taken directly to the hydrolysis step by dissolved in THF (3 mL) and methanol (1 mL), then 2N LiOH (1 mL) was added and stirred at room temperature for 3 hours. The mixture was diluted with water and ethyl acetate, the organic phase was separated then concentrated under reduced pressure to rac-l-{[(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} - cyclopropanecarboxylic acid ( 65.2 mg, 67.2 %) as an off-white powder. HRMS (ES ) m/z Calcd for C27H27CI2F2N3O3 + H [(M+H)+]: 550.1471, found: 550.1471. Example 326
Preparation of rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phei cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [l-(4-hydroxy-piperidin-4- ylmethyl)-lH-pyrazol-3-yl]-amide
Figure imgf000416_0001
M. W. 645.578 C32H36CI2F2N6O2
A mixture of rac-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (500 mg, l .Ommol), 4-(3-amino- pyrazol-l-ylmethyl)-4-hydroxy-piperidine-l-carboxylic acid tert-butyl ester (592 mg, 2.0 mmol), 2-(7-azabenzotriazol-l-yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (HATU, 593 mg, 1.5 mmol) and iPr2NEt (0.718 mL, 4 mmol) in CH2C12 (50 mL) was stirred at rt overnight. The mixture was then diluted with CH2C12 and washed with water, brine. The organic phase was separated, dried over Na2S04 and filtered. The mixture was then concentrated and purified flash column chromatography (1-100% ethyl acetate/heptane) to afford rac- 4-(3-{[(2R,3S,4R,5S)-3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino}-pyrazol-l-ylmethyl)-4-hydroxy-piperidine-l-carboxylic acid tert-butyl ester as a white powder (480 mg, 64.4 %).
The compound was taken directly to the deprotection step by dissolved in a solution of 30%> TFA in dichloromethane (3 mL) and stirred at room temperature for 3 hours. The mixture was diluted with NaHC03(s) and dichloromethane and the organic phase was separated then concentrated under reduced pressure to afford an oil that was purified via triteration with ethyl acetate and heptane to afford a white foam rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1 -(4- hydroxy-piperidin-4-ylmethyl)-lH-pyrazol-3-yl]-amide ( 370 mg, 64.3 %). HRMS (ES+) m/z Calcd for C32H36Cl2F2N602 + H [(M+H)+]: 645.2318, found: 645.2315. Example 327
Preparation of rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-acetyl-thiophen-3-yl)-amide
Figure imgf000417_0001
M. W. 590.52 C29H27CI2F2N3O2S
A mixture of rac-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), l-(3- aminothiophen-2-yl) ethanone (140 mg, 0.98 mmol), 2-(7-azabenzotriazol-l-yl)-n,n,n',n'- tetramethyluronium hexafiuorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.3 mL, 1.67 mmol) in CH2C12 (5 mL) was stirred at rt overnight. The mixture was then diluted with
CH2C12 and washed with water, brine. The organic phase was separated, dried over Na2S04 and filtered. The mixture was then concentrated and purified flash column chromatography (1-100% ethyl acetate/heptane) to afford rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-acetyl- thiophen-3-yl)-amide as a off white powder (40 mg, 15.8 %). HRMS (ES ) m/z Calcd for C29H27CI2F2N3O2S + H [(M+H)+]: 590.1242, found: 590.1244.
Example 328
Preparation of rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-carbamoyl-thiophen-3-yl)-amide
Figure imgf000418_0001
M. W. 591.507 C28H26CI2F2N4O2S
A mixture of rac-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), 3- aminothiophene-2-carboxylic acid amide (160 mg, 1.1 mmol), 2-(7-azabenzotriazol-l-yl)- η,η,η',η'-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iP^NEt (0.3 mL, 1.67 mmol) in CH2CI2 (5 mL) was stirred at rt overnight. The mixture was then diluted with CH2CI2 and washed with water, brine. The organic phase was separated, dried over Na2S04 and filtered. The mixture was then concentrated and purified flash column chromatography (1- 100% ethyl acetate/heptane) to afford rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2- carbamoyl-thiophen-3-yl)-amide as a off white powder (15.8 mg, 6.2 %). HRMS (ES ) m/z Calcd for C28H26CI2F2N4O2S + H [(M+H)+]: 591.1195, found: 591.1191.
Example 329
Preparation of rac- (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro-ph cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [l-((S)-3-dimethylamino-2 hydroxy-propyl)- 1 H-pyrazol-3 - l]-amide
Figure imgf000418_0002
M. W. 633.57 C31H36CI2F2N6O2
A mixture of rac-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), (5)-l-(3- amino-pyrazol-l-yl)-3-dimethylamino-propan-2-ol (158 mg, 0.86 mmol), 2-(7-azabenzotriazol- l-yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.3 mL, 1.67 mmol) in CH2C12 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2C12 and washed with water, brine. The organic phase was separated, dried over Na2S04 and filtered. The mixture was then concentrated and purified flash column chromatography (1-100% ethyl acetate/heptane) to afford rac- (2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid [l-((S)-3-dimethylamino-2-hydroxy-propyl)-lH-pyrazol-3-yl]-amide as an off white powder (63.2 mg, 43.6 %). HRMS (ES+) m/z Calcd for C3iH36Cl2F2N602 + H [(M+H)+]: 633.2318, found: 633.2313.
Example 330
Preparation of (5)-l-(3-amino-pyrazol-l-yl)-3-dimethylamino-propan-2-ol
Figure imgf000419_0001
M. W. 184.24 C8Hi6N40
Compound ((5)-l-dimethylamino-3-(3-nitro-pyrazol-l-yl)-propan-2-o 1 was prepared by reacting 3-nitro-l-(R)-l-oxiranylmethyl-lH-pyrazole ( 0.8 g, 4.73 mmol), isopropyl alcohol ( 6 mL), and dimethylamine (4 mL, 8 mmol, 2 M in dioxane) under microwave conditions at 130°C for 15 min. The mixture was extracted with dichloromethane and water. The organic layer was separated and the solvent evaporated under reduced pressure to yield (5)-l-dimethylamino-3- [l,l-dimethyl-2-(3-nitro-pyrazol-l-yl)-ethoxy]-propan-2-ol (0.76 g, 75.2 %). This compound was reduced under the following conditions-
The mixture of (5')-l-dimethylamino-3-[l,l-dimethyl-2-(3-nitro-pyrazol-l-yl)-ethoxy]-propan-2- ol (0.76 g, 3.54 mmol), ethyl acetate (30 mL), ethanol (30 mL) was added to a Parr bottle with 10% Pd/C (0.14 g) and subjected hydrogen gas (20 psi) for 2 h under the Parr Shaker Apparatus conditions. Work up by filtration via a glass membrane filter paper, solvent was removed under reduced pressure to afford (^-^(S-amino-pyrazol-l-y^-S-dimethylamino-propan^-ol as an oil (0.62 g, 96.1 %). Example 331
Preparation of 3 -nitro- 1 -(R)- 1 -oxira
Figure imgf000420_0001
A mixture of 3 -nitro- 1 H-pyrazole (0.76g, 6.72 mmol), (S)-(+)-glycidyl-3-nitrobenzenesulfonate (2 g, 7.72 mmol), cesium carbonate (5.6 g, 17.16 mmol) and DMF (30 mL) were stirred at 25°C for 16 hours. The mixture was then diluted with ethyl acetate and water(3x), the organic phase was separated, washed with NaHC03(satd) dried with Na2S04, and filtered. The mixture was then concentrated and purified by column chromatography (40-120 g Analogix column, 1-100 % EtO Ac/heptane to yield the product 3 -nitro- 1 -(R)- 1 -oxiranylmethyl- 1 H-pyrazole as a waxy off- white solid (0.89 g, 78.8 %).
Example 332
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydroxycarbamoyl-phenyl)- amide
Figure imgf000420_0002
M. W. 601.48 C3oH28Cl2F2N403
To a solution of rac 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid prepared in Example 232 (50 mg, 0.09 mmol) in N,N-dimethylformamide (2 mL) was added NH2OH.HCl (18 mg, 0.26 mmol), EDCI (33 mg, 0.17 mmol), HOBT(21 mg, 0.15 mmol) and NEt3 (0.036 mL, 0.26 mmol). The reaction mixture was heated at 80 °C for 48 h. The mixture was cooled to room temperature, and partitioned between ethyl acetate 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 MgSC>4, and concentrated. The residue was purified by prep-HPLC to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydroxycarbamoyl- phenyl)-amide as a white solid (24 mg, 47%).
HRMS (ES+) m/z Calcd for C30H28CI2F2N4O3+ H [(M+H)+]: 601.1580, found: 601.1577. Example 333
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methanesulfonylaminocarbonyl- phenyl)-amide
Figure imgf000421_0001
M. W. 663.57 C3iH3oCl2F2N404S
A solution of rac 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid prepared in
Example 232 (0.14 g, 0.24 mmol) and CDI (97 mg, 0.6 mmol) in N,N-dimethylformamide (5 mL) was heated at 60 °C for 2 h, then to this solution was added a mixture of
methanesulfonamide (0.14 g, 1.43 mmol) and NaH (60% in mineral oil, 63 mg, 1.58 mmol), which had been stirred at room temperature for 2 h. The resulting mixture was stirred at room temperature for 1 h, then poured into water. The mixture was acidifed to "pH" 1-2 by addition of aqueous HC1 solution, then partitioned between ethyl acetate 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 MgSC>4, and concentrated. The residue was purified by chromatography (EtOAc) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4- (4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4- methanesulfonylaminocarbonyl-phenyl)-amide as a white solid (11 mg, 7%).
HRMS (ES+) m/z Calcd for C31H30CI2F2N4O4S+ H [(M+H)+]: 663.1406, found: 663.1407.
Example 336
Preparation of rac-4-{[(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester
Figure imgf000422_0001
M. W. 600.50 C31H29CI2F2N3O3
In a manner similar to the method described in Examples le, rac-(2R,3S,4R,5S)-3-(5-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 98c (0.5 g, 0.89 mmol) was reacted with methyl 4-aminobenzoate (0.24 g, 1.6 mmol), HATU (0.61 g, 1.6 mmol) and iP^NEt (0.39 mL, 2.2 mmol) in CH2CI2 at room temperature to give rac-4-{[(2R,3S,4R,5S)-3-(5-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carbonyl]-amino} -benzoic acid methyl ester as a white solid (0.14 g, 27%).
HRMS (ES+) m/z Calcd for C31H29CI2F2N3O3+ H [(M+H)+]: 600.1627, found: 600.1626.
Example 337
Preparation of rac-4-{[(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2 ,2 -dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid
Figure imgf000423_0001
M. W. 586.46 C30H27CI2F2N3O3
To a solution of rac-4-{[(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester prepared in Example 336 (125 mg, 0.21 mmol) in tetrahydrofuran (3 mL) was added an aqueous solution (1 N) of NaOH (3 mL, 3 mmol) and methanol (1 mL). The reaction mixture was heated at 80 °C for 2 h, and the "pH" of the solution was adjusted to 5 by aqueous HC1 solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgS04, and concentrated to give rac-4-{[(2R,3S,4R,5S)-3- (5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino} -benzoic acid as a white solid (90 mg, 73%).
HRMS (ES+) m/z Calcd for C30H27CI2F2N3O3+ H [(M+H)+]: 586.1471, found: 586.1473.
Example 338
Preparation of rac-4-{[(2R,3R,4R,5S)-3-(3-chloro-4-fiuoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester
Figure imgf000423_0002
M. W. 600.50 C31H29CI2F2N3O3
In a manner similar to the method described in Examples le, rac-(2R,3R,4R,5S)-3-(3-chloro-4- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid trifluoroacetic acid prepared in Example 69c (0.25 g, 0.43 mmol) was reacted with methyl 4-aminobenzoate (0.12 g, 0.8 mmol), HATU (0.29 g, 0.43 mmol) and iPr2NEt (0.19 mL, 1.1 mmol) in CH2C12 at room temperature to give rac-4-{[(2R,3R,4R,5S)-3-(3-chloro-4- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carbonyl]-amino} -benzoic acid methyl ester as a white solid (0.125 g, 48%).
HRMS (ES+) m/z Calcd for C31H29CI2F2N3O3+ H [(M+H)+]: 600.1627, found: 600.1627.
Example 339
Preparation of rac-4-{[(2R,3R,4R,5S)-3-(3-chloro-4-fiuoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2 ,2 -dimethyl-propyl -pyrrolidine-2-carbonyl]-amino} -benzoic acid
Figure imgf000424_0001
M. W. 586.46 C30H27CI2F2N3O3
To a solution of rac-4-{[(2R,3R,4R,5S)-3-(3-chloro-4-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester prepared in Example 338 (0.11 g, 0.18 mmol) in tetrahydrofuran (9 mL) was added an aqueous solution (1 N) of NaOH (9 mL, 9 mmol) and methanol (3 mL). The reaction mixture was heated at 80 °C for 2 h, and the "pH" of the solution was adjusted to 5 by aqueous HC1 solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgS04, and concentrated to give rac-4-{[(2R,3R,4R,5S)-3- (3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino} -benzoic acid as a white solid (0.1 g, 94%).
HRMS (ES+) m/z Calcd for C30H27CI2F2N3O3+ H [(M+H)+]: 586.1471, found: 586.1472.
Example 340
Preparation of rac-4-{[(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester
Figure imgf000425_0001
M. W. 626.95 C31H30B1-CIFN3O3
In a manner similar to the method described in Examples le, rac-(2R,3R,4R,5S)-3-(3-bromo- phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 66c (0.44 g, 0.74 mmol) was reacted with methyl 4-aminobenzoate (0.1 g, 1.32 mmol), HATU (0.3 g, 0.4 mmol) and iPr2NEt (0.32 mL, 1.8 mmol) in CH2C12 at room temperature to give rac-4-{[(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro- 2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester as a white solid (0.17 g, 37%).
HRMS (ES+) m/z Calcd for C3iH3oBrClFN303+ H [(M+H)+]: 626.1216, found: 626.1218.
Example 341
Preparation of rac-4-{[(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbon l]-amino} -benzoic acid
Figure imgf000425_0002
M. W. 612.92 C30H28B1-CIFN3O3
To a solution of rac-4-{[(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester prepared in Example 340 (0.15 g, 0.25 mmol) in tetrahydrofuran (9 mL) was added an aqueous solution (1 N) of NaOH (9 mL, 9 mmol) and methanol (3 mL). The reaction mixture was heated at 80 °C for 2 h, and the "pH" of the solution was adjusted to 5 by aqueous HC1 solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSC>4, and concentrated to give rac-4-{[(2R,3R,4R,5S)-3-(3-bromo- phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]- amino} -benzoic acid as a white solid (90 mg, 60%).
HRMS (ES+) m/z Calcd for C3oH28BrClFN303+ H [(M+H)+]: 612.1060, found: 612.1062.
Example 342
Preparation of rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbon l]-amino} -benzoic acid methyl ester
Figure imgf000426_0001
M. W. 582.5 C3iH30Cl2FN3O3
In a manner similar to the method described in Examples le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.38 g, 0.55 mmol)was reacted with methyl 4-aminobenzoate (0.33 g, 2.2 mmol), HATU (0.38 g, 1 mmol) and iPr2NEt (0.29 mL, 1.7 mmol) in CH2C12 at room temperature to give rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4- chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester as a white solid (0.11 g, 34%).
HRMS (ES+) m/z Calcd for C3iH30Cl2FN3O3+ H [(M+H)+]: 582.1721 , found: 582.1721.
Example 343
Preparation of rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid
Figure imgf000426_0002
M. W. 568.47 C30H28CI2FN3O3
To a solution of rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester prepared in Example 342 (95 mg, 0.16 mmol) in tetrahydrofuran (6 mL) was added an aqueous solution (1 N) of NaOH (6 mL, 6 mmol) and methanol (2 mL). The reaction mixture was heated at 80 °C for 2 h, and the "pH" of the solution was adjusted to 5 by aqueous HC1 solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSC>4, and concentrated to give rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]- amino} -benzoic acid as a white solid (80 mg, 86%).
HRMS (ES+) m/z Calcd for C30H28CI2FN3O3+ H [(M+H)+]: 568.1565, found: 568.1561.
Example 344
Preparation of rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(l -methyl-cyclohexylmethyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester
Figure imgf000427_0001
M. W. 640.56 C34H33CI2F2N3O3
In a manner similar to the method described in Examples le, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(l-methyl-cyclohexylmethyl)- pyrrolidine-2-carboxylic acid trifiuoro acetic acid prepared in Example 102c (0.41 g, 0.66 mmol) was reacted with methyl 4-aminobenzoate (0.2 g, 1.3 mmol), HATU (0.45 g, 1.2 mmol) and iPr2NEt (0.29 mL, 1.7 mmol) in CH2C12 at room temperature to give rac-4-{[(2R,3S,4R,5S)-3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(l-methyl- cyclohexylmethyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester as a white solid
(0.17 g, 41%). HRMS (ES ) m/z Calcd for C34H33CI2F2N3O3+ H [(M+H)+ ]: 640.1940, found: 640.1938.
Example 345
Preparation of rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(l -methyl-cyclohex lmethyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid
Figure imgf000428_0001
M. W. 626.53 C33H31CI2F2N3O3
To a solution of rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(l -methyl-cyclohexylmethyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester prepared in Example 344 (0.16 g, 0.24 mmol) in tetrahydrofuran (3 mL) was added an aqueous solution (1 N) of NaOH (3 mL, 3 mmol) and methanol (1 mL). The reaction mixture was heated at 80 °C for 2 h, and the "pH" of the solution was adjusted to 5 by aqueous HC1 solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSC>4, and concentrated to give rac-4-{[(2R,3S,4R,5S)-3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(l -methyl- cyclohexylmethyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid as a white solid (0.14 g, 90%). HRMS (ES+) m/z Calcd for C33H31CI2F2N3O3+ H [(M+H)+]: 626.1784, found: 626.1788.
Example 346
Preparation of rac-[4-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -pyrazol-l-ylmethy 4-hydroxy-piperidin- 1 -yl]-acetic acid
Figure imgf000429_0001
M. W. 703.62 C34H38CI2F2N6O4
A mixture of rac-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [l-(4-hydroxy-piperidin-4- ylmethyl)-lH-pyrazol-3-yl]-amide (80 mg, 0.12 mmol) was dissolved in DMF (3 mL) with cesium carbonate (100 mg, 0.31 mmol) then t-butyl acetate (0.1 mL, 0.677 mmol) was added stirred 16 hours at 25°C. The reaction mixture was diluted with ethyl acetate and separated with water (3x), the organic layer was dried with Na2S04, filtered and concentrated under reduced pressure. The mixture was purified by reverse phase column chromatography (20-95% acetonitrile/ water) to yield compound rac-[4-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)- 4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}- pyrazol-l-ylmethyl)-4-hydroxy-piperidin-l-yl] -acetic acid tert-butyl ester (68 mg, 74.7%).
The compound was taken directly to the deprotection step by dissolved in a solution of 30%> TFA in dichloromethane (3 mL) and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure then taken up in ethyl acetate and NaHC03(s), separated the organic layer, concentrated under reduced pressure to yield compound rac-[4-(3- {[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -pyrazol- 1 -ylmethyl)-4-hydroxy-piperidin- 1 - yl]-acetic acid as an off-white foam ( 41.2 mg, 65.4 %). HRMS (ES+) m/z Calcd for
C34H38C12F2N604 + H [(M+H)+]: 703.2373, found: 703.2376. Example 347
Preparation of 2-(4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)- rrolidine-2-carbonyl]-amino}-phenyl)-butyric acid
Figure imgf000430_0001
M. W. 628.54 C33H33CI2F2N3O3
A mixture of 2-(4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-butyric acid methyl ester (23 mg, 0.036 mmol) was dissolved in THF (0.9 mL) and methanol (0.3 mL), then 2N LiOH (1 mL) was added and stirred at room temperature for 2 hours. The mixture was diluted with water and ethyl acetate. The organic phase was separated then concentrated to yield 2-(4- {[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-butyric acid (16.4 mg, 72.9 %) as an off-white powder. HRMS (ES+) m/z Calcd for C33H33CI2F2N3O3 + H [(M+H)+]:628.1940, found: 628.1939.
Example 348
Preparation of chiral (4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-acetic acid
Figure imgf000430_0002
M. W. 600.50 C31H29CI2F2N3O3
A mixture of (4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-acetic acid methyl ester (72 mg, 0.117 mmol) was dissolved in THF (3 mL) and methanol (1 mL), then 2N LiOH (1 mL) was added and stirred at room temperature for 2 hours. The mixture was concentrated and diluted with water and ethyl acetate. The organic phase was separated then concentrated to yield chiral (4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-acetic acid (37 mg, 52.6 %) as an white powder. HRMS (ES+) m/z Calcd for C31H29CI2F2N3O3 + H [(M+H)+]:600.1627, found: 600.1626.
Example 349
Preparation of chiral (4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-acetic acid methyl ester
Figure imgf000431_0001
M. W. 614.51 C32H31CI2F2N3O3
A mixture of chiral-(2i?,35,,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (228 mg, 0.488 mmol), methyl 2- (4-aminophenyl)acetate (200 mg, 1.21 mmol), 2-(7-azabenzotriazol-l-yl)-n,n,n',n'- tetramethyluronium hexafiuorophosphate (HATU, 241 mg, 0.634 mmol) and iP^NEt (0.4 mL, 2.29 mmol) in CH2CI2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2CI2 and washed with water, brine. The organic phase was separated, then concentrated and purified by column chromatography (1-100% of EtO Ac/heptane, 12 g Analogix column) to afford chiral (4-{[(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-acetic acid methyl ester (209 mg, 69.7 %) as an white powder. LCMS (ES+) m/z Calcd for C32H31CI2F2N3O3 + H
[(M+H)+]: 613.17, found: 614.2.
Example 350
Preparation of 2-(4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-butyric acid methyl ester
Figure imgf000432_0001
M. W. 642.56 C34H35Cl2F2N303
A mixture of chiral (4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-acetic acid methyl ester (22 mg, 0.036 mmol) was dissolved in THF (1 mL) and cooled to -78°C, then LHMDS (1 mL, 1M in THF) was added and the mixture stirred 15 min at -78°C. Ethyl iodide (0.1 mL, 0.107 mmol) was added and stirred for lh at -78°C, then warmed to lh at room temperature. The mixture was diluted with sat'd ammonium chloride solution extracted with ethyl acetate, the organic layer was separated then concentrated under reduced pressure to afford an oil that was purified by silica colun chromatography (4g Analogix column, 1-100%
EtOAc/eptane) to afford 2-(4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-butyric acid methyl ester as a light yellow foam (12.4 mg, 53.9%). LCMS (ES+) m/z Calcd for
C34H35Cl2F2N303 + H [(M+H)+]:641.20, found: 642.2.
Example 351
Preparation of (4-nitro-phenyl)-acetic acid methyl ester
Figure imgf000432_0002
To a mixture of 2-(4-nitrophenyl)acetic acid (1 g, 5.52 mmol) dissolved in methanol (100 mL) cooled to 0°C, was added thionyl chloride (1.31 mL, 11 mmol) dropwise slowly. The mixture was stiired at 0°C for 30 min then 25°C for lh. TLC Rf = 0.5 PDT (50% EtO Ac/heptane; Rf = 0.2 for SM). The mixture was concentrated under reduced pressure to afford (4-nitro-phenyl)- acetic acid methyl ester (1.1 g, 100 %). !H NMR (CDC13) δ 8.2 (d, IH), 7.5 (d, IH), 3.79 (s, 2H), 3.78 (s, 3H). Example 352
Preparation of (4-amino-phenyl)-acetic acid meth l ester
Figure imgf000433_0001
(4-Nitro-phenyl)-acetic acid methyl ester (1.08 g, 5.52 mmol) was dissolved in methanol (50 mL) and EtOAc (50 mL), then added to a Parr bottle containing 10% Pd/C (0.42 g), the vessel was subjected to hydrogen atmosphere (40 psi) for 2h under the Parr Shaker Apparatus conditions. Workup with filtration via a glass membrane filter paper, solvent was removed under reduced pressure to afford (4-amino-phenyl)-acetic acid methyl ester as an oil (0.9 g, 98.7%). !H NMR (CDCI3) δ 7.05 (d, 1H), 6.62 (d, 1H), 3.63 (s, 3H), 3.6 (bs, 2H) 3.5 (s, 2H).
Example 353
Preparation of 2-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2-fluorophenyl)-4- cyano-5-neopentylpyrrolidine-2-carboxamido)thiazole-5-carboxylic acid triethylamine salt.
Figure imgf000433_0002
Molecular Weight =593.4841 102.201 1
Molecular Formula =C27H24CI2F2N4O3S . C6H16N
Racemic 2-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)thiazole-5-carboxylic acid was separated on a Berger SFC machine under 2ml/m of 40%> MeOH+TEAM, 100 bar at 30°C with a Whelko column to give the desired product (peak 1) as a white solid. 32 mg. MS (ES+) m/z Calcd: [(M+H)+]: 593, found: 593. Example 354
Preparation of rac 6-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4- cyano-5 -neopentylpyrrolidine-2-carboxamido)-2-naphthoic acid
Figure imgf000434_0001
Molecular Weight =636.5313
Molecular Formula =C34H29CI2F2N3O3
To a stirred solution of methyl 6-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-naphthoate (120 mg, 0.184 mmol) in methylene chloride 10 ml), aluminum bromide (295 mg, 1.11 mmol) and dimethyl sulfide (150 ul, 2.03 mmol) were added and the mixture was stirred at rt for overnight. LC/mass indicates complete reaction.
The solvent was removed and the residue was suspended in 6 ml of acetonitrile, 15 ml of water was added and the mixture was extracted with ethyl acetate (3x10ml). The extracts were combined and dried with sodium sulfate. Removal of solvent at reduced presure gave a white solid, 111 mg. MS (ES+) m z Calcd: [(M+H)+]: 636, found: 636.
Example 355
Preparation of rac 6-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4- cyano-5-neopentylpyrrolidine-2-carboxamido)-2-naphthoic acid methyl ester
Figure imgf000435_0001
Molecular Weight =650.5584
Molecular Formula =C35H31 CI2F2N3O3
(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-nuorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxylic acid (233.5 mg, 0.50 mmol), HATU (190 mg, 0.50 mmol), methyl 6-amino-2-naphthoate (208 mg, 1 mmol) and DIPEA ( 0.2 mL) were combined with methylene chloride (10 ml) and the mixture was stirred at rt overnight.
The solvent was reduced to 4 ml and the residue was loaded onto a silica gel column (40 g) and eluted with 15-34% EtOAC/Hexanes to give a wite solid. 210 mg. MS (ES+) m/z Calcd: [(M+H)+]: 650, found: 650.
Example 356
Preparation of rac methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methylbenzoate
Figure imgf000435_0002
Molecular Weight =614.5250
Molecular Formula =C32H31 CI2F2N3O3
In a round bottom flask containing (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid(133 mg) was combined with methylene chloride (10 ml), methyl 4-amino-3-methylbenzoate and DiPea. The mixture was stirred at rt for 2 hrs and another 100 mg of (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4- chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid was added and the mixture was stirred for another 2 hrs. The mixture was parti oned between water(10 ml) and methylene chloride (10 ml) and the organic layer was dried and concentrated to give a solid, which was treated with 3 ml of acetonitrile. The mixture was stirred and filtered, the solid was dried to give a white solid, 102 mg as the desired product. The filtrate was chromatographied on a reverse phase column (40 g, 30-100% acetonitrile) to give another 34 mg of desired product after removal of solvent, combined product: 102+34=136 mg. MS (ES+) m/z Calcd: [(M+H)+]: 614, found: 614.
Example 357
Preparation of rac 1 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fiuorophenyl)- 4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methylbenzoic acid
Figure imgf000436_0001
Molecular Weight =600.4979
Molecular Formula =C31 H29CI2F2N3O3
To a stirred solution of methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methylbenzoate (26 mg, 42.3 μηιοΐ) in methylene chloride (10 ml) at rt, aluminum bromide (100 mg,375 μηιοΐ) was added followed by dimethyl sulfide (60 mg, 966 μηιοΐ) and the mixture was stirred at rt overnight.
LC/Mass indicated complete reaction. The reaction was quenched with 1 N HC1(6 ml) and the mixture was extracted with methylene chloride (4x8 ml). The extractes were combined and dried with sodium sulfate. Removal of solvent gave a white solid. 11 mg. MS (ES ) m/z Calcd: [(M+H)+]: 600, found: 600.
Example 358 Preparation of rac (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-iodo-3,5-dimethyl-phenyl)- amide
Figure imgf000437_0001
Molecular Weight =696.41 15
Molecular Formula =C31 H30CI2F2IN3O
To a stirred solution of 3 ml CH2C12 at r.t. was added 100 mg of the (2R,3S,4R,5S)-4-(4-Chloro-
2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid, TFA salt and 1/3 amount of DIPEA under nitrogen. To this was added all of 4- iodo-3,5-dimethylaniline (0.255 g, 1.03 mmol), followed by 128 mg of HATU . The reaction was stirred for 30 minutes. To the reaction was added another 0.15 ml of the DIPEA, followed by a solid mixture of 100 mg of the starting acid and 128 mg of the HATU. This was stirred for 30 minutes and then the rest of the starting material and the reagents were added the same way. The reaction was stirred for overnight. LCMS (z9808672/ZQ) indicated clean Rxn. The reaction was diluted with CH2C12 (10 ml), washed with 0.5 N aqueous HC1 solution, dried with MgSO^., filtered and concentrated to give a yellow oil and this was purified by a 40 g flash silica gel column, eluted with a stepwise gradient of Hexanes to 25% EtOAc/Hexanes. Obtained the product as a white solid. 60 mg. MS (ES+) m z Calcd: [(M+H)+]: 696, found: 696
Example 359
Preparation of rac 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2,6-dimethyl-benzoic acid
Figure imgf000438_0001
Molecular Weight =614.5250
Molecular Formula =C32H31 CI2F2N3O3
In a 50 ml pressure tube, (2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-N-(5-iodopyridin-2-yl)-5-neopentylpyrrolidine-2-carboxamide (60 mg, 86.2 μηιοΐ, Eq: 1.00) was combined with DMF (3 ml) and water (200 μΐ). potassium carbonate (23.8 mg, 172 μηιοΐ, Eq: 2) was added. The mixture was bubbled with nitrogen and then palladium(II) acetate (3 mg, 12.9 μηιοΐ, Eq: 0.15) was added. The tube was subjected to CO atmosphere at 50 PSI and stirred for 3 hours at 70 °C. LCMS (z9809424, 50% ACN) indicated little desired product (RT 1.41, M+l 614), reduction product (RT 2.21 , 570), and sm (RT 2.62, 696). The reaction was continued for 5 days.
The reaction was filtered through celite, washed with DMF, water and EtOAC. The filtrate was acidified with 0.5N HC and was extracted with EtOAC 3x. The EtOAC solution washed with water, dried over Na2S04, and concentrated to give a residue. The residue was dissolved in DMSO and ACN and was purified by preparative HPLC (60-100% ACN/water). The first peak was concentrated and freezed dried to give a white foam, 2.2 mg desired product. MS (ES+) m z Calcd: [(M+H)+]: 614, found: 614
Example 360
Preparation of 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-methoxy-benzoic acid
Figure imgf000439_0001
Molecular Weight =616.4973
Molecular Formula =C31 H29CI2F2N3O4
Racemic 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2
-methoxy-benzoic acid was separated on a SFC machine with whelk column under a flow rate of 50%(MeOH) to give two products. The desired isomer came out as the second peak.
MS (ES+) m/z Calcd: [(M+H)+]: 616, found: 616
Example 361
Preparation of rac 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fluoro- phenyl)-4-cyano5(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-trifluoromethyl- benzoic acid
Figure imgf000439_0002
Molecular Weight =654.4692
Molecular Formula =C31 H26CI2F5N303
Rac 4 {[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-trifluoromethyl-benzoic acid methyl ester (36 mg) was dissolved in MeOH (10 mL). To the stirred solution was added NaOH ( IN, 3 mL) and the mixture was stirred at 50 °C for 3 hrs. The solvent was removed and the residue was treated with 1 N HC1 to make the mixture acidic. The white suspension was filtered to collect the white solid as the title compound (29 mg, 82% yield).
HRMS (ES+) m/z Calcd for C3iH26Cl2F5N303+ H [(M+H)+]: 654.1344, found: 654.1343
Example 362
Preparation of rac (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl) cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-bromo-2-methoxy-phenyl)- amide
Figure imgf000440_0001
Molecular Weight =651 .3834
Molecular Formula =C30H28BrCI2F2N3O2
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid, TFA salt (300 mg, 0.52 mmol) in methylene chloride (3 mL), HATU (Aldrich,352 mg, 0.93 mmol) was added followed by the addition of DIPEA(0.360 mL, 2.07 mmol) and 4-Bromo-2-methoxy-phenylamine (Oakwood, 210 mg, 1.04 mmol). The mixture was stirred at rt for 1.5 h. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified by flash chromatography ( 0-20% EtOAc/hexanes) to give the title compound as a white solid (295 mg, 88% yield).
MS (ES+) m/z Calcd: [(M+H)+]: 650, found: 650
Example 363
Preparation of rac (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-dimethylcarbamoyl-phenyl)- amide
Figure imgf000441_0001
Molecular Weight =613.5402
Molecular Formula =C32H32CI2F2N402
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid, TFA salt (150 mg, 0.26 mmol) in methylene chloride (3 mL), HATU (Aldrich,176 mg, 0.46 mmol) was added followed by the addition of DIPEA(0.225 mL, 1.29 mmol) and 4-Amino-N,N-dimethyl-benzamide (Alfa, 85 mg, 0.52 mmol). The mixture was stirred at rt for 3 h. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified by flash chromatography ( 0-5% MeOH/ CH2CI2) and recrystalized from CH2CI2 /Hexanes/EtOAc to give the title compound as a white solid (50.5 mg, 32% yield).
MS (ES+) m/z Calcd: [(M+H)+]: 613, found: 613
Example 364
Preparation of 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phi cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbon l]-amino}-2-methyl-benzoic acid
Figure imgf000441_0002
Molecular Weight =600.4979
Molecular Formula =C31 H29CI2F2N303 Rac 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-methyl-benzoic acid (65 mg) was resolved on a Berger SFC machine using whelk column under 100 bar, 30°C with 50 % of methanol at a rate of 2 mL/min to give two separated peaks. Peak 1 (20 mg, 31% yield) (RO5488609-000) and peak 2, (desired product, 20 mg , 31 % yield) (RO5488610-000) MS (ES+) m/z Calcd: [(M+H)+]: 600, found: 600
Example 365
Preparation of intermediate rac (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-iodo-2,5- dimethyl-phenyl)-amide
Figure imgf000442_0001
Molecular Weight =696.41 15
Molecular Formula =C31 H30CI2F2IN3O
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid, TFA salt (250 mg, 0.43 mmol) in methylene chloride (3 mL), HATU (Aldrich, 294 mg, 0.77 mmol) was added followed by the addition of DIPEA(0.375 mL, 2.15 mmol) and 4-Iodo-2,5-dimethyl-phenylamine (Spectra Group, 248 mg, 0.86 mmol). The mixture was stirred at RT for 1 h. The reaction was quenched with addition of IN HC1 (1.5 ml). The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified by flash chromatography (0-15% EtOAc/Hexanes) to give the title compound as a light yellow solid (175 mg, 63%> pure, 37 % yield).
MS (ES+) m/z Calcd: [(M+H)+]: 696, found: 696 Example 366
Preparation of rac 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2,5-dimethyl-be acid
Figure imgf000443_0001
Molecular Weight =614.5250
Molecular Formula =C32H31 CI2F2N303
To a solution of rac (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-iodo-2,5-dimethyl-phenyl)- amide (Example 365, 149 mg, 0.214 mmol) in DMF (5 ml) was added water (0.2 ml), and potassium carbonate (60 mg, 0.428 mmol). The mixture was bubbled with nitrogen and palladium acetate (5 mg, 0.021 mmol) was added. The mixture was subjected to carbon monoxide atmosphere at 50 psi and was heated at 70 °C for 3 h. The mixture was then filtered through celite, acidified with HOAc and extracted with EtOAc (3x10 ml). The organic solution was concentrated and was purified by reverse phase HPLC using acetonitrile and water.
Obtained the title compound as a white powder, (45 mg, 35% yield).
MS (ES+) m/z Calcd: [(M+H)+]: 614, found: 614
Example 367
Preparation of intermediate rac (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-flu oro-4-iodo-phenyl)-amide
Figure imgf000444_0001
Molecular Weight =686.3477
Molecular Formula =C29H25CI2F3IN30
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid, TFA salt (250 mg, 0.43 mmol) in methylene chloride (3 mL), HATU (Aldrich, 294 mg, 0.77 mmol) was added followed by the addition of DIPEA(0.375 mL, 2.15 mmol) and 2-Fluoro-4-iodo-phenylamine (Aldrich, 204 mg, 0.86 mmol). The mixture was stirred at RT for 5 h. The reaction was quenched with 0.5 N HC1 (2 ml). The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified by flash chromatography (0-20% EtOAc/Hexanes) to give the title compound as a white solid (100 mg, 60% pure, 20 % yield).
MS (ES+) m/z Calcd: [(M+H)+]: 686, found: 686
Example 368
Preparation rac 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-fiuoro-benzoic acid
Figure imgf000444_0002
Molecular Weight =604.4612
Molecular Formula =C30H26CI2F3N3O3 To a solution of rac (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-fiuoro-4-iodo-phenyl)-amide (Example 367, 95 mg, 0.138 mmol) in DMF (3 ml) was added water (0.2 ml), and potassium carbonate (38 mg, 0.27 mmol). The mixture was bubbled with nitrogen and palladium acetate (3 mg, 0.014 mmol) was added. The mixture was subjected to carbon monoxide atmosphere at 50 psi and was heated at 70 °C for 3 h. The mixture was then filtered through celite. The filtrate was acidified with HOAc and was extracted with EtOAc (3x10 ml). The organic solution was concentrated and purified by reverse phase HPLC using acetonitrile and water. Obtained the title compound as a white solid (28 mg, 34% yield).
MS (ES+) m/z Calcd: [(M+H)+]: 604, found: 604
Example 369
Preparation of rac (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbox lic acid (6-iodo-pyridin-3-yl)-amide
Figure imgf000445_0001
Molecular Weight =669.3449
Molecular Formula =C28H25CI2F2IN40
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid, TFA salt (200 mg, 0.34mmol) in methylene chloride (3 mL), HATU (Aldrich, 235 mg, 0.62 mmol) was added followed by the addition of DIPEA(0.3 mL, 1.72 mmol) and 6-Iodo-pyridin-3-ylamine
(Lancaster, 138 mg, 0.69 mmol). The mixture was stirred at RT for 4 h. The reaction was quenched with water . The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with sodium sulfate. The solvent was removed and the residue was purified by flash chromatography (0-8% EtOAc/methylene chloride) to give the title compound as a white solid (95 mg, 41% yield).
MS (ES+) m/z Calcd: [(M+H)+]: 669, found: 669 Example 370
Preparation of 2-Chloro-4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid methyl ester
Figure imgf000446_0001
Molecular Weight =634.9429
Molecular Formula =C31 H28CI3F2N303
To a stirred solution of (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid, TFA salt (200 mg, 0.34mmol) in methylene chloride (3 mL), HATU (Aldrich, 235 mg, 0.62 mmol) was added followed by the addition ofDIPEA(0.3 mL, 1.72 mmol) and 4-Amino-2-chloro-benzoic acid methyl ester (Example 296, 128 mg, 0.69 mmol). The mixture was stirred at RT for 2 h. The reaction was quenched with water . The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with sodium sulfate. The solvent was removed and the residue was purified by flash chromatography (0-25% EtOAc/Hexanes) to give the title compound as a white solid (72 mg, 33% yield).
MS (ES+) m/z Calcd: [(M+H)+]: 634, found: 634
Example 371
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-trifluoromethyl-phenyl)-amide
Figure imgf000446_0002
M. W. 610.45 C3oH26Cl2F5N30
In a manner similar to the method described in Examples le, rac-(2i?,35',4i?,55)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid (0.2 g, 0.43 mmol)was reacted with 4-aminobenzotrifluoride (Alfa)(0.14 g, 0.86 mmol), HATU (0.29 g, 0.77 mmol) and iPr2NEt (0.15 mL, 0.86 mmol) in CH2C12 at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-trifiuoromethyl- phenyl)-amide as a white solid (38 mg, 15%).
HRMS (ES+) m/z Calcd for C30H26Cl2F5N3O + H [(M+H)+]: 610.1446, found: 610.1448.
Example 372a
Preparation of intermediate l-(4-amino-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-ethanone
Figure imgf000447_0001
M. W. 265.43 Ci4H23N02Si
Step A To a solution of 2-hydroxy-l-(4-nitrophenyl)ethanone (1 g, 5.52 mmol) in DMF (25 ml) was added imidazole (564 mg, 8.28 mmol), followed by the addition of tert- butylchlorodimethylsilane (915 mg, 6.07 mmol). The reaction mixture was stirred at room temperature for 3h. The mixture was poured into H20 (25 mL) and extracted with ethyl acetate (3 x 25 mL). The organic layers were combined, washed with H20 (5 x 25 mL), brine (1 x 25 mL), dried over MgS04 and concentrated in vacuo to give 2-(tert-butyldimethylsilyloxy)-l-(4- nitrophenyl)ethanone as ayellow solid (1.6 g, 98%).
Step B To a solution of 2-(tert-butyldimethylsilyloxy)-l-(4-nitrophenyl)ethanone (0.54 g, 1.83 mmol) in methanol (60 mL) was added an aqueous solution (15 mL) of ammonium chloride (0.98 g, 18.3 mmol), followed by the addition of Zinc (1.2 g, 18.3 mmol). The reaction mixture was stirred at room temperature for 1 h . The mixture was filtered through a short pad of celite. The filtrate was concentrated to a small volume, then hen partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgS04, and concentrated to give l-(4-amino-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-ethanone as a white foam (0.4 g, 82%)
Example 372b
Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-hydroxy-acetyl)-phenyl]- amide
Figure imgf000448_0001
M. W. 600.49 C31H29CI2F2N3O3
To a solution of rac-(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.35 g, 0.749 mmol) in
dichloromethane (25 ml) was added iPr2NEt (242 mg, 1.87 mmol) was added, followed by the addition of HATU (513 mg, 1.35 mmol) and l-(4-aminophenyl)-2-(tert- butyldimethylsilyloxy)ethanone (398 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into H20 (50 mL) and extracted with dichloromethane (3 x 25 mL). The organic layers were combined, washed with H20 (1 x 50 mL), brine (50 mL), dried over MgSC>4 and concentrated in vacuo. The residue was dissolved in THF (25 mL) and then an aqueous solution (1 N) of HC1 (10 mL) was added. The reaction mixture was stirred at room temperature for 30 min. The mixture was concentrated in vacuo. The residue was poured into 20 mL saturated aqueous NaHC03 and extracted with ethyl acetate (3 x 25 mL). The organic layers were combined, washed with H20 (25 mL), brine (25 mL), dried over MgSC>4 and concentrated. The residue was purified by flash chromatography (silica gel, 40 g, 20% to 100% EtOAc in hexanes) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4- (4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2- hydroxy-acetyl)-phenyl]-amide as a light yellow solid (0.17 g, 38%>).
LCMS (ES+) m/z Calcd for C3iH29Cl2F2N303+ H [(M+H)+]: 600, found: 600. Example 373
Preparation of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methanesulfonylaminocarbonyl- phenyl)-amide
Figure imgf000449_0001
M. W. 663.57 C31H30CI2F2N4O4S
Rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methanesulfonylaminocarbonyl-phenyl)- amide (63 mg) was separated by chiral SFC chromatography to provide chiral (2R,3S,4R,5S)-3- (3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid (4-methanesulfonylaminocarbonyl-phenyl)-amide as a white solid (25 mg, 40%) and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4- methanesulfonylaminocarbonyl-phenyl)-amide as a white solid (24 mg, 38%).
Example 374a
Preparation of intermediate 4-amino- 1 -[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]- 1 H-pyridin-2- one
Figure imgf000449_0002
M. W. 268.43 C13H24N2O2S1
To a solution of 4-aminopyridin-2(lH)-one (Molbridge)(0.9 g, 8.17 mmol) in DMF (30 mL) was added NaH (60%, 490 mg, 12.3 mmol). The mixture was stirred at room temperature for 30 min before (2-bromoethoxy)(tert-butyl)dimethylsilane (2.15 g, 8.99 mmol) was added. The reaction mixture was heated at 78 °C for 15 h. The mixture was cooled and poured into H2O (100 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with H20 (5 x 50 mL), brine (50 mL), dried over MgS04 and concentrated. The residue was purified by flash chromatography (silica gel, 40+S, 0% to 10% MeOH in EtOAc) to give 4-amino-l-[2- (tert-butyl-dimethyl-silanyloxy)-ethyl]-lH-pyridin-2-one as a white solid (0.9 g, 41%).
Example 374b
Preparation of intermediate rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid { 1 -[2-(tert-butyl- dimethyl-silanyloxy)-ethyl]-2-oxo-l ,2-dihydro-pyridin-4-yl)-amide
Figure imgf000450_0001
M. W. 717.77 C36H44Cl2F2N403Si
To a mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.2 g, 0.428 mmol) in
dichloromethane (20 mL) was added iPr2NEt (138 mg, 1.07 mmol), followed by the addition of diphenylphosphinic chloride (Aldrich)(203 mg, 0.856 mmol). The mixture was stirred at room temperature for 30 min, then 4-amino-l-(2-(tert-butyldimethylsilyloxy)ethyl)pyridin-2(lH)-one (115 mg, 428 μηιοΐ) was added. The reaction mixture was stirred at room temperature for 3 h, then concentrated. The residue was purified by flash chromatography (silica gel, 40 g, 5% to 80% EtOAc in hexanes) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid { 1 -[2-(tert-butyl- dimethyl-silanyloxy)-ethyl]-2-oxo-l ,2-dihydro-pyridin-4-yl)-amide as a white solid (35 mg,
11%).
Example 374c Preparation of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [l-(2-hydroxy-ethyl)-2-oxo-l,2- dihydro-pyridin-4-yl] -amide
Figure imgf000451_0001
M. W. 603.49 C3oH3oCl2F2N403
To a solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid { 1 -[2-(tert-butyl-dimethyl- silanyloxy)-ethyl]-2-oxo-l ,2-dihydro-pyridin-4-yl)-amide (35 mg, 0.049 mmol) in THF (5 ml) was added an aqueous solution (I N) of HC1 (5 mL). The reaction mixture was stirred at room temperature for 30 min. The mixture was concentrated and the residue was partitioned between aqueous saturated Na2SC> and ethyl acetate. The organic layer was collected and washed with
H20 (25 mL), brine (25 mL), dried over MgS04 and concentrated. The residue was purified by flash chromatography (silica gel, 12 g, 20% to 100% EtOAc in hexanes) to give rac- (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [l-(2-hydroxy-ethyl)-2-oxo-l ,2-dihydro-pyridin- 4-yl]-amide as a white solid (12 mg, 41%).
Example 375
Preparation of 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phi cyano-5-(l-methyl-cyclohexylmethyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid
Figure imgf000451_0002
M. W. 626.53 C33H31CI2F2N3O3
Rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-nuoro-phenyl)-4-cyano-5- (l-methyl-cyclohexylmethyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid (110 mg) was separated by chiral SFC chromatography to provide chiral 4-{[(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(l-methyl-cyclohexylmethyl)- pyrrolidine-2-carbonyl]-amino} -benzoic acid as a white solid (48 mg, 44%) and chiral 4- {[(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(l- methyl-cyclohexylmethyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid as a white solid (48 mg 44%).
Example 376
Preparation of chiral 5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -lH-indole-2- carboxylic acid
Figure imgf000452_0001
M. W. 625.49 C32H28CI2F2N4O3
A chiral 5-{[(2R,3S,4R,5S)-3-(3-chloro-2 -fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -lH-indole-2-carboxylic acid ethyl ester (33 mg, 0.051 mmol) was dissolved in ethanol (15 mL), then 2N KOH (5 mL) was added and stirred 2 hours @ 50°C, then the temperature was warmed to 65°C for 2h, after cooling to 25°C, the reaction was diluted with water and extracted with ethyl acetate (3x). The organic phase was separated then concentrated under reduce pressure to chiral 5-{[(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carbonyl]-amino}-lH-indole-2-carboxylic acid (24 mg, 76%) as a white powder. HRMS (ES+) m/z Calcd for C32H28CI2F2N4O3 + H [(M+H)+]:625.1580, found: 625.1580.
Example 377 Preparation of chiral 5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -lH-indole-2- carboxylic acid ethyl ester
Figure imgf000453_0001
M. W. 653.55 C34H32CI2F2N4O3
A mixture of chiral-(2i?,35,,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.321 mmol), ethyl 5- amino-lH-indole-2-carboxylate (114 mg, 0.558 mmol), 2-(7-azabenzotriazol-l-yl)-n,n,n',n'- tetramethyluronium hexafiuorophosphate (HATU, 159 mg, 0.417 mmol) and iPr2NEt (0.4 mL, 2.29 mmol) in CH2C12 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2C12 and washed with water, brine. The organic phase was separated, then concentrated and purified by RP-HPLC chromatography (20-95% acetonitrile/water) to afford 5-{[(2R,3S,4R,5S)- 3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl- propyl)pyrrolidine-2-carbonyl]-amino}-lH-indole-2-carboxylic acid ethyl ester (37 mg, 17.6 %) as an off-white powder. LCMS (ES+) m/z Calcd for C34H32CI2F2N4O3+ H [(M+H)+]: 652.18, found: 653.2.
Example 378
Preparation of 5-Amino-lH-indole-2-carboxylic acid ethyl ester
Figure imgf000453_0002
5-Amino-lH-indole-2-carboxylic acid ethyl ester (150 mg, 0.64 mmol) was dissolved in ethanol (10 mL) and EtOAc (10 mL), then subjected to the H-Cube (ThalesNano) with a 10% Pd/C cartridge at the 10°C setting at 10 psi. The solution was concentrated under reduced pressure to afford 5-amino-lH-indole-2-carboxylic acid ethyl ester as a yellow solid (0.114 g, 87.2 %). 1H NMR (DMSO-de) δ 11.4 (bs, IH), 7.18 (d, IH), 6.8 (s, IH), 6.62 (m, 2H), 34.65(bs, 2H), 4.3 (q, 2H), 1.3 (t, 3H).
Example 379
Preparation of rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl^ropyl)-pyrrolidine-2-carbonyl]-amino} -methyl)- cyclohexanecarboxylic acid methyl ester
Figure imgf000454_0001
M.W. 620.57 C32H37C12F2N303
To a stirred solution of rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61 mg, 0.13 mmol) in Ν,Ν-dimethyl formamide (5 mL) was added diisopropylethylamine (126.1 mg, 0.976 mmol), HOBt (35.3 mg, 0.262 mmol), HBTU (97.8 mg, 0.258 mmol) and methyl-trans-4-aminomethyl- cyclohexane carboxylic acid HCl (56.2 mg, 0.256 mmol, AK Scientific). After it was stirred at rt for 2.5 hrs, the solvent was removed and the reaction mixture was extracted with EtOAc and washed with IN NaOH (2X), water, and saturated NaCl. The organic phase was separated and dried over Na2SC>4. The reaction mixture was then purified by flash column to give rac 4- ({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-cyclohexanecarboxylic acid methyl ester (64.0 mg, 79%) and a white solid foam. HRMS(ES+) m/z Calcd C32H37C12F2N303+H
[(M+H): 620.2253; Found: 620.2253.
Example 380
Preparation of rac- 4-({ [(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)- cyclohexanecarboxylic acid
Figure imgf000455_0001
M.W. 606.55 C3iH35Cl2F2N303
To a solution of rac 4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)- cyclohexanecarboxylic acid methyl ester (54.3 mg, 0.0875 mmol, example XC-1) in THF (5mL) was added a solution of LiOH (27.8 mg, 0.662 mmol, Aldrich) in water (2.5 mL) and the reaction mixture was stirred at rt for 22 hrs. The reaction mixture was partly concentrated and quenched with 1 N HC1 (pH 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 give rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid (52.1 mg, 98%). HRMS(ES+) m/z Calcd C3iH35Cl2F2N303+H [(M+H): 606.2097; Found: 606.2097. Example 381
Preparation of rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-2-methoxy- benzoic acid methyl ester
Figure imgf000455_0002
M.W. 644.55 C33H33C12F2N304 A solution of 4-cyano-2-methoxy benzoic acid (1.0 g, 5.65 mmol, Biogene) in methanol was reacted with / toluenesulfonic acid monohydrate (285.6 mg, 1.479 mmol) and heated to reflux for 16 hrs. The solvent was removed and the reaction residue was extracted with EtOAc, and washed with saturated sodium carbonate, water, and saturated NaCl, and dried over Na2S04 to give 4-Cyano-2-methoxy-benzoic acid methyl ester (1.04 g, 96%). This ester (1.01 g, 5.28 mmol) in methanol (50 mL) was reacted with Raney Ni (3 spatula tips full, exact amount unknown, Aldrich) under 50 psi H2 in a Parr apparatus for 16 hrs. After filtering through Celite and concentrating, the crude mixture was purified by silica gel chromatography using methanol and methylene chloride to give 4-aminomethyl-2-methoxy-benzoic acid methyl ester (385.7 mg, 37%).
In a manner similiar to the method described in Example 379, rac-(2R,3S,4R,5S)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid (64 mg, 0.137 mmol) and 4-aminomethyl-2-methoxy-benzoic acid methyl ester (55 mg, 0.282 mmol) in Ν,Ν-dimethyl formamide (5 mL) were reacted with DIPEA (1 11.3 mg, 0.861 mmol), HOBt (38.8 mg, 0.287 mmol) and HBTU (107.6 mg, 0.284 mmol) at room temperature to give rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-2-methoxy- benzoic acid methyl ester (91.8 mg, -100%). HRMS (ES+) m/z Calcd Csst^Cl^NsC^+H
[(M+H): 644.1889; Found: 644.1885.
Example 382
Preparation of rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-pheny^
phenyl)-4-cyano-5-(2,2-dimethyl^ropyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-2-methox benzoic acid
Figure imgf000457_0001
M.W. 630.52 C32H31CI2F2N3O4
In a manner similiar to the method described in Example 380, rac-4-({[(2R,3S,4R,5S)-4-(4- chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid methyl ester (75.2 mg, 0.117 mmol), was combined with THF (7 ml) and lithium hydroxide hydrate (33.5 mg, 0.798 mmol) in water (3.5 mL). It was stirred at room temperature to give rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro- 2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carbonyl]-amino}-methyl)-2-methoxy-benzoic acid as a white lyophilized solid (66.6 mg, 89%). HRMS (ES+) m/z Calcd C32H31CI2F2N3O4+H [(M+H): 630.1733; Found: 630.1729.
Example 383
Preparation of rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-2-fluoro- benzoic acid methyl ester
Figure imgf000457_0002
M.W. 632.52 C32H30CI2F3N3O3
Preparation of methyl 4-(aminomethyl)-2-fluorobenzoate: A solution of 4-cyano-2-fiuorobenzoic acid (4.02 g, 24.36 mmol, Aldrich) in methanol (50 mL) was treated with / 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-fiuorobenzoate (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 hrs. 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-fiuorobenzoate (247.6 mg, 23%) as off-white solid.
In a manner similiar to the method described in Example 379, rac-(2i?,35',4i?,55)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid (66.1 mg, 0.141 mmol) and methyl 4-(aminomethyl)-2-fluorobenzoate (51.0 mg, 0.278 mmol in Ν,Ν-dimethyl formamide (5 mL) were reacted with DIPEA (1 11 mg, 0.857 mmol), HOBt (37.6 mg, 0.277 mmol) and HBTU (104.9 mg, 0.275 mmol) at room temperature to give rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid methyl ester
(88.5 mg, 98%). HRMS(ES+) m/z Calcd C32H30CI2F3N3O3+H [(M+H):632.1689; Found:
632.1692.
Example 384
Preparation of rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2 -fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-2-fluoro- benzoic acid
Figure imgf000459_0001
M.W. 618.49 C31H28CI2F3N3O3
In a manner similiar to the method described in Example 380, rac-4-({[(2R,3S,4R,5S)-4-(4- chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino} -methyl)-2-fluoro-benzoic acid methyl ester (80.3 mg, 0.127 mmol) in THF (9 ml) was reacted with lithium hydroxide hydrate (37.6 mg, 0.896 mmol) in water (4.5 mL) to give rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-2- fluoro-benzoic acid as a white lyophilized solid (76.5 mg, 97%). HRMS(ES+) m/z Calcd C31H28CI2F3N3O3+H [(M+H): 618.1533; Found: 618.1533.
Example 385
Preparation of chiral 5-({ [(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-pyridine-2- carboxylic acid methyl ester
Figure imgf000459_0002
M.W. 615.51 C31H30CI2F2N4O3
Ethyl 5-cyanopicolinate 1.0387 g, 5.9 mmol, BioNet) 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 50PSI on a PARR shaker for 18 hrs. 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 (738. lmg, 69%) as an off-white solid which was used immerdiately. In a manner similiar to the method described in Example 379, a mixture of (2i?,35',4i?,55)-3-(3- chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid (59.2 mg, 0.127 mmol) and methyl 5-(aminomethyl)picolinate (64.4 mg, 0.388 mmol) in Ν,Ν-dimethyl formamide (5 mL) were treated with DIPEA (119mg, 0.916 mmol), HOBt (34.2 mg, 0.253 mmol) and HBTU (96.1 mg, 0.253 mmol) at room temperature to give 5-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-pyridine-2- carboxylic acid methyl ester
(30.7 mg, 39%). HRMS(ES+) m/z Calcd C31H30CI2F2N4O3+H [(M+H): 615.1736; Found:
615.1731.
Example 386
Preparation of chiral 5-({ [(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-pyridine-2- carboxylic acid
Figure imgf000460_0001
M.W.601.49 C30H28CI2F2N4O3
In a manner similiar to the method described in Example 380, chiral 5-({[(2R,3S,4R,5S)-4-(4- Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino}-methyl)-pyridine-2-carboxylic acid methyl ester (24.9 mg, 0.0405 mmol) in THF (3 ml) was treated with lithium hydroxide hydrate (12.0 mg, 0.286 mmol) in water (1.5 mL). It was stirred at room temperature to give chiral 5-({[(2R,3S,4R,5S)-4-(4- Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino}-methyl)-pyridine-2-carboxylic acid as a white lyophilized solid (25.4 mg, 100). RMS(ES+) m/z Calcd C30H28CI2F2N4O3+H [(M+H):601.1580; Found: 601.1579.
Example 387
Preparation of chiral 6-({ [(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-nicotinic acid ethyl ester
Figure imgf000461_0001
M.W. 629.54 C32H32CI2F2N4O3
In a manner similiar to the method described in Example 379, chiral 2i?,35',4i?,55)-3-(3-chloro- 2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid (60.9 mg, 0.130 mmol) in Ν,Ν-dimethyl formamide (5 mL) were reacted with DIPEA (134 mg, 1.03 mmol), 5-(ethoxycarbonyl)pyridin-2-yl)methanaminium chloride (68.5 mg, 0.316 mmol, Chem-Impex), HOBt (34.0 mg, 0.252 mmol) and HBTU (93.5 mg, 0.247 mmol) at room temperature to give chiral 6-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)- nicotinic acid ethyl ester as a white solid, (81.3 mg, 99%). HRMS(ES+) m/z Calcd
C32H32CI2F2N4O3+H [(M+H): 629.1893; Found: 629.1896. Example 388
Preparation of chiral 6-({ [(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl^ acid
Figure imgf000462_0001
M.W.601.49 C30H28CI2F2N4O3
In a manner similiar to the method described in Example 380, chiral 6-({[(2R,3S,4R,5S)-4-(4- Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino}-methyl)-nicotinic acid ethyl ester (73.8 mg, 0.117 mmol) in THF (8 ml) was combined with lithium hydroxide hydrate (35.9 mg, 0.855 mmol) in water (4 mL). It was stirred at room temperature to give chiral 6-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro- phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]- amino}-methyl)-nicotinic acid as a white lyophilized solid (71.3 mg, 100%). HRMS(ES+) m/z Calcd C30H28CI2F2N4O3+H [(M+H): 601.1580; Found: 601.1581. Example 389
Preparation of rac 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-ethoxy-benzoic acid
Figure imgf000462_0002
M.W.630.52 C32H31CI2F2N3O4 A solution of 2-ethoxy-4-nitrobenzoic acid (2.035 g, 9.45 mmol, Aldrich) in methanol (40 ml) was treated with p-toluenesulfonic acid monohydratr (583.3 mg, 3.07 mmol) and heated at reflux under argon for 17 hrs. The solvent was removed and the residue was dissolved in ethyl acetate, washed with saturated Na2C03, water and saturated NaCl and dried over Na2S04, filtered and concentrated to give methyl 2-ethoxy-4-nitrobenzoate (2.15g, 101%) as a yellow solid.
A mixture of methyl 2-ethoxy-4-nitrobenzoate (2.038 g, 9.05 mmol) and palladium on carbon (583 mg, 10 wt %, Aldrich) in methanol (62 ml) was reacted with hydrogen at 40 psi for 18 hrs on the PARR shaker. It was filtered through celite and washed with methanol under N2 and the filtrate was concentrated to give methyl 4-amino-2-ethoxybenzoate (1.672 g, 94 %) as a light brown solid.
To a solution of rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (60.8 mg, 0.13 mmol) in dicholoromethane (3 mL) were added DIPEA (89.0 mg, 0.69 mmol), methyl 4-amino-2- ethoxybenzoate (50.9 mg, 0.26 mmol) and HATU (90.8 mg, 0.24 mmol). (The acid, DIPEA, and HATU were added in thirds at 20 min intervals). After 90 min, the reaction was diluted with dichloromethane, washed with water and saturated sodium chloride and purified by silica gel chromatography with ethyl acetate and hexanes to give racemic methyl 4-((2R,3S,4R,5S)-3-(3- chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2- carboxamido)-2-ethoxybenzoate (90 mg, with minor impurity) as a light brown oil.
In a manner similiar to the method described in Example 380, a solution of the above methyl 4- ((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine -2 -carboxamido)-2 -ethoxybenzoate (89.7 mg, -0.13 mmol) in THF (8 ml) was treated with lithium hydroxide hydrate (40.9 mg, 0.974 mmol) in water (4 mL) and heated at 70 °C for 3 hrs and then stirred at room temperature to give rac 4-{[(2R,3S,4R,5S)-4-(4- Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino}-2-ethoxy-benzoic acid as a white lyophilized solid (33.5 mg., 38%) after HPLC purification.
HRMS(ES+) m/z Calcd C32H3iCl2F2N304+H [(M+H): 630.1733; Found: 630.1733. Example 390
Preparation of chiral (2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydrazinocarbonyl-phenyl)- amide
Chiral
Figure imgf000464_0001
M.W.600.50 C3oH29Cl2F2N502
To a solution of chiral-(2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (52.7 mg, 0.113 mmol) in dicholoromethane (3 mL) were added DIPEA (71.2 mg, 0.55 mmol), 4-aminobenzhydrazide
(33.1 mg, 0.22 mmol, Aldrich) and HATU (72.3 mg, 0.19 mmol). (The acid, DIPEA, and HATU were added in thirds at 20 min intervals). After 90 minutes the reaction was diluted with dichloromethane, washed with water and saturated sodium chloride and purified by HPLC with acetonitrile and water (with TFA 0.1% V/V) to give chiral (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro- phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydrazinocarbonyl-phenyl)-amide (45.7 mg., 67.5%) as a white solid. HRMS(ES ) m/z Calcd C3oH29Cl2F2N502+H [(M+H): 600.1739; Found: 600.1737.
Example 391
Preparation of chiral [2-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-ethyl]- carbamic acid tert-butyl ester
Figure imgf000465_0001
M.W.685.65 C36H40CI2F2N4O3
To a solution of chiral (2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (51.1 mg, 0.11 mmol) in dicholoromethane (3 niL) were added DIPEA (71.2 mg, 0.55 mmol), [2-(4-AMINO-PHE YL)- ETHYLJ-CARBAMIC ACID TERT-BUTYL ESTER (52.3 mg., 0.22 mmol, Chem-Impex) and HATU (77.8 mg, 0.20 mmol) (The acid, DIPEA, and HATU were added in thirds at 20 min intervals). After 90 mins, the reaction was diluted with dichloromethane, washed with water and saturated sodium chloride and purified by silica gel chromatography with ethyl acetate and n- hexanes to give chiral [2-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-ethyl]- carbamic acid tert-butyl ester (40.6 mg., 54.2%) as a white lyophilized solid. HRMS(ES+) m/z Calcd C36H40CI2F2N4O3+H [(M+H): 685.2519; Found: 685.2517.
Example 392
Preparation of chiral (2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phen 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-amino-ethyl)-phenyl]- amide
Figure imgf000465_0002
M.W.585.53 C31H32CI2F2N4O
A solution of tert-butyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenethylcarbamate (77.3 mg, 0.113 mmol) in dichloromethane (3 ml) was treated with trifluoroacetic acid (2.23 g, 19.6 mmol) and stirred under argon. After 1.5 hrs, the reaction mixture was concentrated and the residue diluted with ethyl acetate, washed with saturated sodium carbonate, water and brine to give chiral (2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-amino-ethyl)-phenyl]-amide (40.6 mg, 54.2%) as a white lyophilized solid.
MS (ES+) m/z Calcd: [(M+H)+]: 585.19, found: 585.1
Example 393
Preparation of chiral 5-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -pyrazine-2-carboxylic acid
Chiral
Figure imgf000466_0001
M.W.588.45 C28H25Cl2F2N503
A solution of rac-(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (79.9 mg, 0.171 mmol) in dichloromethane (3 ml) was treated with DIPEA (89.0 mg, 0.685 mmol) and
DIPHENYLPHOSPHINIC CHLORIDE (103 mg, 0. 428 μπιοΐ, Aldrich) and stirred for 30 mins under argon before 5 -AMINO -P YRAZINE-2 -C ARB OXYLIC ACID ETHYL ESTER (30.4 mg, 0.173 mmol, Ark Pharm) was added and the reaction was stirred overnight. The reaction mixture was diluted with dichloromethane and extracted with H20. The organic layer was washed with sat NaHC03, ¾0, and sat NaCl and purified by flash chromatography using ethyl acetate and n- hexanes to give ethyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)pyrazine-2-carboxylate (27.6 mg, 26%) which was used in the next step.
To a solution of ethyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)pyrazine-2-carboxylate (27.6 mg, 0.0448 mmol) in dichloromethane (2 ml) were added DIMETHYL SULFIDE (846 mg, 0.0136 mmol) and ALUMINUM BROMIDE (64.5 mg, 0. 242 mmol). The mixture was stirred under argon for 5 hrs. The reaction mixture was diluted with acetonitrile (2ml), EtOAc (10 ml) and water (10 ml) and stirred for several minutes. After more ethyl acetate (50 ml) was added, the organic layer was separated and washed with saturated ammonium chloride (10 ml), water (10 ml) and sat. sodium chloride (10 ml). The organic layers were dried overNa2SC>4 and concentrated and purified by silica gel chromatography with methanol and dichloromethane to give chiral 5-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazine-2-carboxylic acid as an off-white lyophilized solid (19.7 mg,74%). MS (ES+) m/z Calcd: [(M+H)+]: 588.13, found: 588.0
Example 394
Preparation of chiral 4-(((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)methyl)-2-methoxybenzoic acid and chiral-4-({[(2S,3R,4S,5R)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano- -(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid
Figure imgf000467_0001
M.W.630.52, C32H31CI2F2N304 M.W 630.52, C32H31 CI2F2N304
The mixture of rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-2-methoxy- benzoic acid (60 mg. 0.095 mmol) was separated by SFC, 25 % CH3OH on a Diacel AD prep column to give chiral 4-(((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)methyl)-2-methoxybenzoic acid (24.1 mg., 40.2%) as a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 630.17, found: 630.2 and chiral-4-({ [(2S,3R,4S,5R)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid (23.5 mg., 39.2%) as a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]:630.17, found: 630.2 Example 395
Preparation of chiral methyl 3-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)propanoate
Figure imgf000468_0001
M.W.628.55, C33H33CI2F2N3O3
Thionyl chloride (2.5 mL, 4.08 g, 34.3 mmol) was added to stirred anhydrous methanol (10 mL) at 0° C. After 20 mins, 3-(4-AMINOPHE YL)PROPIONIC ACID (1.7 g, 10.3 mmol, Trans World Chemicals) was added and the mixture was stirred at rt for 16 hrs. The reaction mixture was concentrated and the residue dissolved in ethyl acetate, washed with sat. NaHC03, water, and sat. NaCl, dried over Na2S04 and concentrated to give methyl 3-(4-aminophenyl)propanoate (1.80 g, 97%) as a light brown solid.
To a solution of chiral (2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80.6 mg, 0.172 mmol) in dichloromethane (3 ml) were added DIPEA (89.0 mg, 0.685 mmol) and
DIPHENYLPHOSPHINIC CHLORIDE (106 mg, 0.437 mmol). The mixture was stirred for 20 mins under argon before methyl 3-(4-aminophenyl)propanoate (33.4 mg, 0.186 mmol) was added. After 2 hrs, the reaction mixture was diluted with dichloromethane, washed with sat. NaHC03, water and brine. After drying over Na2S04 the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes to give chiral methyl 3-(4-((2R,3S,4R,5S)- 3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2- carboxamido)phenyl)propanoate (104.2 mg, 96%) as a white solid. MS (ES+) m/z Calcd:
[(M+H)+]: 628.19, found: 628.1
Example 396
Preparation of chiral 3-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)propanoic acid
Figure imgf000469_0001
M.W. 614.52 C32H31CI2F2N3O3
A solution of chiral methyl 3-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)propanoate (58.8 mg, 0.0936 mmol) in THF (5 ml) was treated with LITHKJM HYDROXIDE MONOHYDRATE (15.7 mg, 0.374 mmol) in water (2.5 ml) and stirred at rt overnight. The mixture was then treated with 1 N HC1 to pH 3-4, extracted with ethyl acetate. The organic extracts were washed with water and brine, dried over sodium sulfate and concentrated to give chiral 3-(4-((2R,3S,4R,5S)- 3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2- carboxamido)phenyl)propanoic acid (57.7 mg, 100 %) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 614.17, found: 614.2 Example 397
Preparation of chiral- 4-(((2S,3R,4S,5R)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)methyl)-2-fiuorobenzoic acid and chiral 4-(((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2-fiuorophenyl)-4-cyano-5- neopent lpyrrolidine-2-carboxamido)methyl)-2-fluorobenzoic acid
Figure imgf000470_0001
M.W. 618.49 C3iH28Cl2F3N303
The mixture 4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid (71.1 mg. 0.115 mmol) was separated by SFC, 40 % CH3OH on a Whelk-01 R,R prep column to give chiral- 4-(((2S,3R,4S,5R)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2-fiuorophenyl)-4- cyano-5-neopentylpyrrolidine-2-carboxamido)methyl)-2-fluorobenzoic acid (29.4 mg., 41.4%) as a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 618.15, found: 618.2 and chiral 4- (((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2-fiuorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)methyl)-2-fluorobenzoic acid (29.7 mg., 41.8%) as a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 618.15, found: 618.2.
Example 398
Preparation of chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluoroph( cyano-N-(2-mo holinopyrimidin-5-yl)-5-neopentylpyrrolidine-2-carboxamide
Figure imgf000470_0002
M.W. 629.54 C31H32CI2F2N6O2
A solution of chiral (2i?,35,,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (59.9 mg, 0.128 mmol) in dichloromethane (3 ml) was treated with DIPEA (66.8 mg, 0.514 mmol) and
DIPHENYLPHOSPHINIC CHLORIDE (75.8 mg, 0.314 mmol) and stirred for 20 min under argon. 2-MORPHOLIN-4-YLPYRIMIDIN-5-AMINE (23.4 mg, 0.130 mmol, Atlantic Research) was added. After stirred 2.5 hrs, the reaction mixture was diluted with dichloromethane, washed with sat. NaHC03, water and brine. After dried over Na2S04, the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes to give chiral (2R,3S,4R,5S)-3-(3- chloro-2-fluorophenyl)-4-(4-chloro-2-fiuorophenyl)-4-cyano-N-(2-morpholinopyrimidin-5-yl)-5- neopentylpyrrolidine-2-carboxamide (78.4 mg., 97.2%) as a white solid. MS (ES ) m/z Calcd: [(M+H)+]: 629.19, found: 629.2.
Example 399
Preparation of chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4- cyano-5-neopentyl-N-(pyrimidin-5-yl)pyrrolidine-2-carboxamide
Chiral
Figure imgf000471_0001
M.W.544.44, C27H25Cl2F2N50
A solution of chiral-(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (39.4 mg, 84.3 mmol) in dichloromethane (3 ml) was reacted with DIPEA (44.5 mg, 0.343 mmol) and
DIPHENYLPHOSPHINIC CHLORIDE (49.7 mg, 0.210 mmol) and stirred for 20 min under argon. PYRIMIDIN-5 -AMINE (8.3 mg, 0.0829 mmol, Ark Pharm) was added and stirred 2.5 hrs. The reaction mixture was diluted with dichloromethane, washed with water then with sat.
NaHC03, water, and sat. NaCl . After drying over Na2S04 the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes giving chiral (2R,3S,4R,5S)-3-(3- chloro-2-fluorophenyl)-4-(4-chloro-2-fiuorophenyl)-4-cyano-5-neopentyl-N-(pyrimidin-5- yl)pyrrolidine-2-carboxamide (35.7 mg., 77%) as a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 544.14, found: 544.0.
Example 400
Preparation of chiral (2S,3R,4S,5R)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-dimethylaminomethyl- phenyl)-amide and (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-dimethylaminomethyl-phenyl)- amide
Chiral
Figure imgf000472_0001
M.W. 544.44 C32H34CI2F2N4O
The mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2-fluorophenyl)-4- cyano-N-(4-((dimethylamino)methyl)phenyl)-5-neopentylpyrrolidine-2-carboxamide (41 mg. 0.0684 mmol) was separated by SFC, 55 % CH3OH on a Whelk-01 R,R prep column to give chiral (2S,3R,4S,5R)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-dimethylaminomethyl-phenyl)-amide (17.3 mg., 42.2%) as a light yellow lyophilized solid, MS (ES+) m/z Calcd: [(M+H)+]: 599.21, found: 599.2 and (2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-dimethylaminomethyl-phenyl)- amide (15.9 mg., 38.8%) as a light yellow lyophilized solid, MS (ES+) m/z Calcd: [(M+H)+]: 599.21, found: 599.2. Example 401
Preparation of chiral methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-lH-benzo[d]imidazole-2- carboxylate
Chiral
Figure imgf000473_0001
M.W. 640.52 C32H29Cl2F2N503
A solution of chiral (2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (60.3 mg, 0.129 mmol) in dichloromethane (3 ml) was reacted with DIPEA (66.8 mg, 0.514 mmol) and
DIPHENYLPHOSPHINIC CHLORIDE (75.7 mg, 0.320 mmol) and stirred for 20 min under argon. 5 -AMINO - 1 H-BENZOEVQD AZOLE-2 -C ARB OXYLIC ACID METHYL ESTER (25.7 mg, 0.134 mmol, Biofine) was added and stirred 2.5 hrs. The reaction mixture was diluted with dichloromethane and extracted with water then with sat'd NaHC03, water, and brine. After drying over Na2S04the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes giving a white lyophilized solid, chiral methyl 5-((2R,3S,4R,5S)-3-(3- chloro-2-fluorophenyl)-4-(4-chloro-2-fiuorophenyl)-4-cyano-5-neopentylpyrrolidine-2- carboxamido)-lH-benzo[d]imidazole-2-carboxylate (43 mg, 52%). MS (ES+) m/z Calcd:
[(M+H)+]: 640.16, found: 640.1. Example 402
Preparation of chiral-5-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-lH-benzo[d]imidazole-2- carboxylic acid
Figure imgf000474_0001
M.W. 626.50 C3iH27Cl2F2N503
A solution of chiral methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-lH-benzo[d]imidazole-2- carboxylate (84.4 mg, mmol) in THF (6 ml) was reacted with .LITHIUM HYDROXIDE
MONOHYDRATE (22.9 mg, 0.545mmol) in water (3 ml) and stirred at rt overnight. The reaction mixture was treated with 1 N HCl (0.37 ml, pH 3-4) and extracted with ethyl acetate. The organic extratct was washed with water and brine, dried with sodium sulfate, filtered and lyophilized to give chiral-5-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-lH-benzo[d]imidazole-2- carboxylic acid (36 mg, 43.6 %) a a white solid, MS (ES+) m/z Calcd: [(M+H)+]: 626.15, found:
626.0.
Example 403
Preparation of chiral-methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzofuran-2-carboxylate
Chiral
Figure imgf000474_0002
M.W. 640.52 C33H29CI2F2N3O4
A solution of chiral-(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phi cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (60.9 mg, 0.130 mmol) in dichloromethane (3 ml) was reacted with DIPEA (66.8 mg, 0.517 mmol) and
DIPHENYLPHOSPHINIC CHLORIDE (75.8 mg, 0.320 mmol) and stirred for 20 min under argon. 5 -AMINO -BENZOFURAN-2 -C ARB OXYLIC ACID METHYL ESTER (26.0 mg, 0.136 mmol, Biofine,) was added and stirred 2.5 hrs. The reaction mixture was diluted with
dichloromethane and washed with water, sat. NaHC03 and brine. After drying over Na2S04 the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes giving chiral-methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2-fiuorophenyl)-4- cyano-5-neopentylpyrrolidine-2-carboxamido)benzofuran-2-carboxylate (46.2 mg., 55.4%) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 640.15, found: 640.0.
Example 404
Preparation of chiral-5-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzofuran-2-carboxylic acid
Chiral
Figure imgf000475_0001
M.W. 626.49 C32H27C12F2N304
A solution of chiral methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzofuran-2-carboxylate (80.7 mg, 0.126 mmol) in THF (6 ml) was reacted with LITHIUM HYDROXIDE MONOHYDRATE (222.3 mg, 0.531 mmol) in water (3 ml) and stirred at rt for 3 hrs. The reaction treated with 1 N HCl (pH 3-4) and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried with sodium sulfate, filtered and lyophilized to give chiral-5-((2R,3S,4R,5S)-3-(3- chloro-2-fluorophenyl)-4-(4-chloro-2-fiuorophenyl)-4-cyano-5-neopentylpyrrolidine-2- carboxamido)benzofuran-2-carboxylic acid (74.3 mg, 94.1 %) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 626.13, found: 626.2. Example 405
Preparation of chiral methyl 4-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)butanoate
Chiral
Figure imgf000476_0001
M.W. 642.58, C34H35Cl2F2N303
Thionyl chloride (2.5 mL, 4.08 g, 34.3 mmol) was added to stirred anhydrous methanol (10 mL) at 0° C. After 20 mins, 4-(4-AMINOPHE YL)BUTYRIC ACID (1.85 g, 10.3 mmol, Aldrich) was added and the mixture was stirred at rt for 16 hrs. The reaction mixture was concentrated and the residue dissolved in ethyl acetate, washed with sat. NaHC03, water, and sat. NaCl, dried over Na2S04 and concentrated to give methyl 4-(4-aminophenyl)butanoate (1.88 g, 94%) as a light brown solid.
A solution of chiral (2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (60.9 mg, 0.130 mmol) in dichloromethane (3 ml) were added DIPEA (66.8 mg, 0.514 mmol) and
DIPHENYLPHOSPHINIC CHLORIDE (78.2 mg, 0.324 mmol). The mixture was stirred for 20 mins under argon before methyl 4-(4-aminophenyl)butanoate (24.7 mg, 0.128 mmol) was added. After 2 hrs, the reaction mixture was diluted with dichloromethane and extracted with water then with sat. NaHC03, water, and sat. NaCl . After drying over Na2S04 the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes giving chiral methyl 4-(4- ((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2-fiuorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)phenyl)butanoate (79.2 mg., 96%) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 642.2, found: 642.1 Example 406
Preparation of chiral- 4-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)butanoic acid
Chiral
Figure imgf000477_0001
M.W. 628.55 C33H33CI2F2N3O3
A solution of chiral methyl 4-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)butanoate (70.5 mg, 0.110 mmol) in THF (5 ml) was treated with LITHIUM HYDROXIDE MONOHYDRATE (18.5 mg, 0.441 mmol) in water (2.5 ml) and stirred at rt for 16 hrs. The reaction was treated with 1 N HC1 (pH 5) and extracted with ethyl acetate, washed with with water then sat'd sodium chloride, dried with sodium sulfate, filtered and lyophilized to give chiral- 4-(4-((2R,3S,4R,5S)-3-(3-chloro-2- fluorophenyl)-4-(4-chloro-2-fiuorophenyl)-4-cyano-5-neopentylpyrrolidine-2- carboxamido)phenyl)butanoic acid (67 mg, 97.2 %) as a white lyophilized solid. MS (ES ) m/z Calcd: [(M+H)+]: 628.19, found: 628.1
Example 407
Preparation of chiral methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzo[d]oxazole-2-carboxylate
Chiral
Figure imgf000477_0002
M.W.641.51 , C32H28CI2F2N4O4 A solution of chiral (2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (59.8 mg, 0.128 mmol) in dichloromethane (3 ml) was treated with DIPEA (66.8 mg, 0.517 mmol) and
DIPHENYLPHOSPHINIC CHLORIDE (80.7 mg, 0.341 mmol) and stirred for 20 min under argon. 5-AMINO-BENZOOXAZOLE-2-CARBOXYLIC ACID METHYL ESTER (25.8 mg, 134 μηιοΐ, JW PharmLab) was added and stirred 2 hrs. The reaction mixture was diluted with dichloromethane and washed with water, sat'd NaHC03, water and brine. After drying over Na2S04the crude material was purified by silica gel chromatography with ethyl acetate and n- hexanes giving chiral methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzo[d]oxazole-2-carboxylate (73.7 mg., 89.8%) as a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 641.15, found: 641.2.
Example 408
Preparation of chiral- 5-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzo[d]oxazole-2-carboxylic acid and chiral- (2R,3S,4R,5S)-N-(benzo[d]oxazol-5-yl)-3-(3-chloro-2-fiuorophenyl)-4-(4- chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamide
Chiral
Figure imgf000478_0001
M.W. 627.48 C3iH26Cl2F2N404 M.W. 583.47 C3oH26Cl2F2N402
A solution of chiral methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzo[d]oxazole-2-carboxylate (64.5 mg, 0.101 ηιμηιοΐ) in THF (5 ml) was reacted with LITHIUM HYDROXIDE
MONOHYDRATE (17.1 mg, 0.407 mmol) in water (2.5 ml) and stirred at rt for 4.5 hrs. The reaction mixture was treated with 1 N HCl (pH 5-6) and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried with sodium sulfate, filtered and purified by silica gel chromatography with methylene chloride and methanol to give chiral- 5-((2R,3S,4R,5S)-3- (3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2- carboxamido)benzo[d]oxazole-2-carboxylic acid (7.8 mg., 12.4%) a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 627.13, found: 627.2 and chiral (2R,3S,4R,5S)-N-(benzo[d]oxazol- 5-yl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine- 2-carboxamide (38.3 mg., 65.3%) as a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 583.14, found: 583.2.
Example 409
Preparation of rac-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2 -fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzyl)-carbamic acid tert-butyl ester
Figure imgf000479_0001
M.W .671 .62, C35H38CI2F2N4O3
To a stirred solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) in dichloromethane (5 ml) were added Ν,Ν-DIISOPROPYLETHYL AMINE (33 mg) and tert-butyl 4- aminobenzylcarbamate (57.0 mg, 0.256 mmol, Array) followed by N,N,N',N'-tetramethyl-0-(7- aza-benzotriazol-l-yl)uranium hexafiuorophosphate (HATU) (29 mg, Chem-Impex) and the reaction mixture was stirred for 30 min; Another portion of N,N- DIISOPROPYLETHYL AMINE (33 mg), rac-(2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4- chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) and HATU (29 mg) was added and stirring was contiued for 30 min before the addition of the last portion of N,N-DIISOPROPYLETHYL AMINE (33 mg), (2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4- chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) and HATU (29 mg). 1 hr later, the reaction mixture was diluted with CH2C12 (80 mL), washed with sat Na2C03 (2x15 mL), water (2x15 mL) and evaporated.The crude material was purified by flash chromatography (silica gel, 4 g, 4% to 50% EtOAc in hexanes) to give rac-(4-{[(2R,3S,4R,5S)- 4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino}-benzyl)-carbamic acid tert-butyl ester as off-white solid (82.8mg, 96%). HRMS (ES+) m/z Calcd for C35H39C12F2N403 [(M+H)+]: 671.2362, found: 671.2360
Example 410
Preparation of rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-aminomethyl-phenyl)-amide
Figure imgf000480_0001
M.W .571.50, C30H30CI2F2N4O
To a solution of rac tert-butyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzylcarbamate (64 mg, exampleXC31) in CH2C12 (4 ml) was added TRIFLUORO ACETIC ACID (5.92 g, 4 mL) and the reactiob was stirred at 0 C for 1.5 hrs . The crude reaction mixture was concentrated in vacuo and the taken up in CH2C12 (80 mL) and wahsed with sat Na2C03 (2x15 mL), water (2x15 mL) and concentrated to give rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3- chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4- aminomethyl-phenyl)-amide as a white solid (54.3 mg, 99%). HRMS (ES+) m/z Calcd for C30H31C12F2N4O [(M+H)+]: 571.1838, found: 571.1837
Example 411
Preparation of (2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(methanesulfonylamino- methyl)-phenyl]-amide
Figure imgf000481_0001
M .W .649.59, C31 H32CI2F2N403S
To a solution of rac-(2R,3S,4R,5S)-N-(4-(aminomethyl)phenyl)-3-(3-chloro-2-fluorophenyl)-4- (4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamide (21.0 mg, 0.0367 mmol, example XJ-2) in CH2C12 (4 ml) was treated with METHANESULFONYL CHLORIDE (8.5 mg, 5.78 μΐ, 0.0742 μηιοΐ) and the reaction was stirred at 0 C for 1 hr. The reaction mixture was diluted with CH2C12 (80 mL), washed with sat Na2C03 (2x15 mL), water (2x15 mL) and evaporated. The crude material was purified by flash chromatography (silica gel, 4 g, 1% to 10% MeOH/CH2C12) to give rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4- (methanesulfonylamino-methyl)-phenyl]-amide as off-white solid (17.6 mg, 73%). MS (ES+) m/z Calcd: [(M+H)+]: 649, found: 649
Example 412
Preparation of l-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-piperidine-4- carboxylic acid ethyl e
Figure imgf000481_0002
M.W .697.66, C37H40CI2F2N4O3
To a stirred solution of (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2 -fluorophenyl) 4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) in dichloromethane (5 ml) were added N,N-DIISOPROPYLETHYLAMINE (33 mg) and ethyl l-(4-aminophenyl)piperidine-4- carboxylate (63.8 mg, 0.257 mmol, Bionet Research Intermediates) followed by Ν,Ν,Ν',Ν'- tetramethyl-0-(7-aza-benzotriazol-l-yl)uranium hexafluorophosphate (HATU) (29 mg, Chem- Impex) and the reaction mixture was stirred for 30 min; Another portion of N,N- DIISOPROPYLETHYL AMINE (33 mg), (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4- chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) and HATU (29 mg) was added and stirring was contiued for 30 min before the addition of the last portion of N,N-DIISOPROPYLETHYL AMINE (33 mg), (2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4- chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) and HATU (29 mg). 1 hr later, the reaction mixture was diluted with CH2C12 (80 mL), washed with sat Na2C03 (2x15 mL), water (2x15 mL) and evaporated.The crude material was purified by flash chromatography (silica gel, 4 g, 4% to 50% EtOAc in hexanes) to give l-(4-{[(2R,3S,4R,5S)-4- (4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino}-phenyl)-piperidine-4-carboxylic acid ethyl ester as off-white solid (86.9 mg, 97%). MS (ES+) m/z Calcd: [(M+H)+]: 697, found: 697
Example 413
Preparation of l-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-piperidine-4- carboxylic acid
Figure imgf000482_0001
M.W .669.60, C35H36CI2F2N4O3
To a solution of ethyl l-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)piperidine-4-carboxylate (75 mg, 0.108 mmol) in THF (4mL) was added a solution of LITHIUM HYDROXIDE monohydrate (19.2 mg, 0.458 mmol) in Water (2 mL) dropwise. The reaction mixture was stirred at rt for 2 hrs before it was neutralized with IN HC1. it was then diluted with EtOAc, washed with water (2x10 mL), brine (2x10 niL), dried and evaporated to give l-(4-{[(2R,3S,4R,5S)-4- (4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carbonyl]-amino}-phenyl)-piperidine-4-carboxylic acid as a white solid(76 mg, 100%). MS (ES+) m/z Calcd: [(M+H)+]: 669, found: 669
Example 414
Preparation of rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-dimethylaminomethyl-phenyl)- amide
Figure imgf000483_0001
M .W .599.56, C32H34CI2F2N40
To a stirred solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (60 mg, 0.128 mmol) in dichloromethane (5.00 ml) were added Ν,Ν-DIISOPROPYLETHYL AMINE (100 mg) and 4- ((dimethylamino)methyl)aniline (29.8 mg, 0.198 mmol) followed by N,N ,Ν',Ν'-tetramethyl-O- (7-aza-benzotriazol-l-yl)uranium hexafluorophosphate (HATU) (90.3 mg,0.237 mmol, Chem- Impex) and the reaction mixture was stirred for 1 hr. The reaction mixture was diluted with CH2C12 (80 mL), washed with sat Na2C03 (2x15 mL), water (2x15 mL) and evaporated.The crude material was purified by flash chromatography (silica gel, 4 g, 4% to 50% EtOAc in hexanes) to give rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-dimethylaminomethyl- phenyl)-amide as white solid (54.1 mg, 70%). MS (ES+) m/z Calcd: [(M+H)+]: 599, found: 599
Example 415
Preparation of rac-5-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-pyrrolidin-l-; benzoic acid
Figure imgf000484_0001
M .W .655.58, C34H34CI2F2N403
To a stirred solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (60 mg, 0.128 mmol) in dichloromethane (5.00 ml) were added Ν,Ν-DIISOPROPYLETHYLAMINE (99.6mg,0.770 mmol) and N,N,N',N'-tetramethyl-0-(7-aza-benzotriazol-l-yl)uranium hexafluorophosphate (HATU) (90.3 mg,0.237 mmol, Chem-Impex) followed by 5-amino-2-(pyrrolidin-l-yl)benzoic acid (38.5 mg, 0.187 mmol, Array). The reaction mixture was stirred for 2 hr. The reaction mixture was diluted with CH2C12 (80 mL), washed with sat Na2C03 (2x15 mL), water (2x15 mL) and evaporated.The crude material was purified by flash chromatography (silica gel, 8g, 0.5% to 5% Me OH in CH2C12) to give rac-5-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3- (3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2- pyrrolidin-l-yl-benzoic acid as white solid (14.6 mg, 15.4%). MS (ES+) m/z Calcd: [(M+H)+]: 655, found: 655. Example 416
Preparation of rac-4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -4-methyl-piperidine- 1-carboxylic acid tert-butyl ester
Figure imgf000484_0002
M.W .663.64, C34H42CI2F2N4O3 To a stirred solution of racemic-(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (48.2 mg, 0.103 mmol) in dichloromethane (8 ml) were added N,N-DIISOPROPYLETHYLAMINE (72.7 mg, 98.3 μΐ, 563 μηιοΐ, Eq: 6) and N,N,N',N'-tetramethyl-0-(7-aza-benzotriazol-l-yl)uranium
hexafluorophosphate (HATU) (64.2 mg, 0.169 mmol) followed by tert-butyl 4-amino-4- methylpiperidine-l-carboxylate (20.1mg, 0.0938 mmol, Astatech). The reaction mixture was stirred from 2:00PM for 2hrs. The reaction mixture was diluted with CH2C12 (80 mL), washed with sat Na2C03 (15 mL), water (2x15 mL) and evaporated.The crude material was purified by flash chromatography (silica gel, 4 g, 5% to 70% EtOAc in hexanes) to give rac-4- {[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -4-methyl-piperidine- 1 -carboxylic acid tert- butyl ester as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 663, found: 663.
Example 417
Preparation of rac- (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methyl-piperidin-4-yl)-amide
Figure imgf000485_0001
M.W.563.52, C29H34CI2F2N4O
To a stirred solution of racemic tert-butyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4- chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-4-methylpiperidine-l- carboxylate (27.0 mg, 0.0407 mmol, example 386) in dichloromethane (3mL) was added TRIFLUORO ACETIC ACID (4.44 g, 3 mL) and the reaction mixture was stirred at 0-5 C for 2.5 hrs. The solvent was removed in vacuum and residue was dissolved in CH2C12 (80mL), washed with sat Na2C03 (15 mL), water (2x15 mL) and evaporated to give rac-(2R,3S,4R,5S)- 4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid (4-methyl-piperidin-4-yl)-amide as a white solid. MS (ES ) m/z Calcd: [(M+H)+]: 563, found: 563.
Example 418
Preparation of rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (l-methanesulfonyl-4-methyl- piperidin-4-yl)-amide
Figure imgf000486_0001
M .W .641 .61 , C30 H36CI2 F2N4O3S
A solution of racemic (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fiuorophenyl)- 4-cyano-N-(4-methylpiperidin-4-yl)-5-neopentylpyrrolidine-2-carboxamide (20.5 mg, 0.0364 μηιοΐ, example 387) was treated with TRIETHYLAMINE (24.8 mg, 0.245 mmol) followed by METHANESULFO YL CHLORIDE (8.5 mg, 0.0742 mmol). The reaction was stirred at 0 C for 2hrs. The reaction mixture was diluted with CH2C12 (80 mL), washed with sat. Na2C03 (2x15 mL), water (2x15 mL) and evaporated.The crude material was purified by flash chromatography (silica gel, 4 g, 10% to 100% EtOAc/hexane) to give rac-(2R,3S,4R,5S)-4-(4- Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)- pyrrolidine-2-carboxylic acid (l-methanesulfonyl-4-methyl-piperidin-4-yl)-amide a white solid(20.5 mg, 88%). MS (ES+) m/z Calcd: [(M+H)+]: 641, found: 641. Example 419
Preparation of methyl l-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)pyrrolidine-2-carboxylate
Figure imgf000487_0001
M .W .669.60, C35H36CI2F2N403
To a stirred solution of (2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2-fluorophenyl)- 4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (60 mg, 0.128 mmole) in dichloromethane (6 ml) were added Ν,Ν-DIISOPROPYLETHYL AMINE (104 mg, 140 μΐ, 0.802 mmol) and methyl l-(4-aminophenyl)pyrrolidine-2-carboxylate hydrochloride (50.2 mg, 0.196 mmol, Beta Pharma) followed by N,N,N',N'-tetramethyl-0-(7-aza-benzotriazol-l -yl)uranium hexafluorophosphate (HATU) (90.3 mg, 0237 mmole, Chem-Impex) and the reaction mixture was stirred at rt for 1 hr. The reaction mixture was diluted with CH2C12 (80 mL), washed with sat Na2C03 (2x15 mL), water (2x15 mL) and evaporated. The crude material was purified by flash chromatography (silica gel, 4 g, 5% to 100% EtOAc in hexanes) to give methyl l-(4-((2R,3S,4R,5S)-3-(3-chloro- 2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2- carboxamido)phenyl)pyrrolidine-2-carboxylate (72.4 mg, 84%) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 669, found: 669.
Example 420
Preparation of l-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fiuorophi cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)pyrrolidine-2-carboxylic acid
Figure imgf000487_0002
M.W .655.58, C34H34CI2F2N4O3 To a solution of methyl l-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)pyrrolidine-2-carboxylate (61.2 mg, 0.091.4 mmol, example 11) in THF (4.00 ml) was added a solution of LITHIUM HYDROXIDE monohydrate (22.6 mg, 0.539 mmol) in Water (2.00 ml) dropwise. The reaction mixture was stirred at rt for 2 hrs before it was neutralized with IN HCl. it was then diluted with EtOAc, washed with water (2x10 mL), brine (2x10 mL), dried and evaporated to give l-(4- ((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2-fiuorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)phenyl)pyrrolidine-2-carboxylic acid as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 655, found: 655.
Example 421
Preparation of chiral 5-{[(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -lH-pyrrole-2- carboxylic acid
Figure imgf000488_0001
M. W. 575.45 C28H26CI2F2N4O3
A mixture of chiral 5-{[(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -lH-pyrrole-2- carboxylic acid ethyl ester (38 mg, 0.036 mmol) was dissolved in EtOH (4 mL) and 2N KOH (2 mL) was added and stirred 3 hours at 60°C, then increased heat to 80°C for 12 h. The mixture was diluted with water and ethyl acetate. The organic phase was separated then concentrated under reduced pressure. The compound was purified by RP-HPLC (20%-95% of
acetonitrile/water) to afford chiral 5-{[(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro- 2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -lH-pyrrole- 2-carboxylic acid trifluoroacetate salt (5 mg, 13.8 %) as an off-white powder. HRMS (ES+) m/z Calcd for C28H26CI2F2N4O3 + H [(M+H)+]:575.1423, found: 575.1427. Example 422
Preparation of chiral 5-{[(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -lH-pyrrole-2- carboxylic acid ethyl ester
Figure imgf000489_0001
M. W. 603.50 C30H30CI2F2N4O3
A mixture of chiral-(2i?,35,,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.428 mmol), ethyl 5- amino-lH-pyrrole-2-carboxylate (180 mg, 1.17 mmol), 2-(7-azabenzotriazol-l-yl)-n,n,n',n'- tetramethyluronium hexafiuorophosphate (HATU, 200 mg, 0.526 mmol) and iPr2NEt (0.4 mL, 2.29 mmol) in CH2C12 (4 mL) and THF (4 mL) was stirred at 25°C for 16 hours. The mixture was then diluted with CH2C12 and washed with water. The organic phase was separated, then concentrated under reduced pressure. The compound was purified by RP-HPLC (20%-95% of acetonitrile/water) to afford chiral 5-{[(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro- 2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyiTolidine-2-carbonyl]-amino} -lH-pyrrole- 2-carboxylic acid ethyl ester (42 mg, 16.3 %) as an off-white powder. HRMS (ES+) m/z Calcd for C30H30CI2F2N4O3 + H [(M+H)+]: 603.1736, found: 603.1736.
Example 423
Preparation of chiral (i?)-2-(4-{[(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-butyric acid and chiral (5,)-2-(4-{[(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-butyric acid
Figure imgf000490_0001
M. W. 628.55 C33H33CI2F2N3O3
A mixture of diasteromeric 2-(4- {[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-butyric acid methyl esters (370 mg, 0.576 mmol) was dissolved in THF (15 mL) and methanol (5 mL), then 2N LiOH (5 mL) was added and stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate (2x). The organic phase was separated then concentrated under reduced pressure to afford crude product. Purified by SFC (30% MeOH, 100 bar, 30°C, 2 mL/min) to afford chiral (i?)-2-(4-{[(2i?,35,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4- (4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} - phenyl)-butyric acid as a off-white solid (80.5 mg, 22.2%) HRMS (ES+) m/z Calcd for
C33H33CI2F2N3O3 + H [(M+H)+]:628.1940, found: 628.1942
and chiral (S)-2-(4- { [(2i?,35,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-butyric acid (50.1 mg, 16.0 %) as an off-white powder. HRMS (ES+) m/z Calcd for C33H33CI2F2N3O3 + H
[(M+H)+]:628.1940, found: 628.1944.
Example 424
Preparation of chiral (5)-2-{ [(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-thiazol-4-yl- propionic acid methyl ester and chiral (5)-2-{ [(25',3i?,45,,5i?)-3-(3-chloro-2-fiuoro-phenyl)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3- thiazol-4-yl-propionic acid methyl ester Chiral
Figure imgf000491_0001
M. W. 635.56 C30H30CI2F2N4O3S
Regeant (5)-methyl 2-amino-3-(thiazol-4-yl)propanoate (655 mg, 2.94 mmol), was dissolved in dichloromethane (30 mL) then iPr2NEt (2.41 mL, 13.9 mmol) was added and stirred at 25°C. In three portions racemic (2i?,35,,4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-
4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (701 mg, 1.5 mmol) and 2-(7- azabenzotriazol-l -yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (HATU, 741 mg, 1.95 mmol) was added in 30 min intervals. The reaction mixture was stirred at 25°C for 14 hours. The mixture was then diluted with CH2C12 and washed with water. The organic phase was separated, then concentrated under reduced pressure. The diasteromers were purified by RP-HPLC (20%- 95% acetonitrile/water) to afford chiral (5)-2- {[(2i?,35,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3- thiazol-4-yl-propionic acid methyl ester trifluoroacetate salt as a white powder (122 mg, 12.8%) HRMS (ES+) m/z Calcd for C30H30CI2F2N4O3S+ H [(M+H)+]:635.1457, found: 635.1456 and chiral (S)-2- { [(25,,3i?,45',5i?)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-
5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-thiazol-4-yl-propionic acid methyl ester trifluoroacetate salt as a white powder (37 mg, 4%>). HRMS (ES+) m/z Calcd for
C30H30CI2F2N4O3S+ H [(M+H)+]:635.1457, found: 635.1456.
Example 425
Preparation of chiral (5)-2-{ [(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-thiazol-4-yl- propionic acid
Figure imgf000492_0001
M. W. 621.533 C29H28CI2F2N4O3S
A mixture of chiral (5)-2-{ [(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-thiazol-4-yl- propionic acid methyl ester trifluoroacetate salt (1 12 mg, 0.176 mmol) was dissolved in THF (3 mL) and methanol (1 mL), then 2N LiOH (1 mL) was added and stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate (2x), the organic phase was separated then concentrated under reduced pressure to afford the crude product that was purified by RP-HPLC (20-95% acetonitrile/water). The solvent was evaporated under reduced pressure to afford chiral (5)-2-{ [(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4- chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3- thiazol-4-yl-propionic acid trifluoroacetate salt as a white powder (41 mg, 37.9 %). HRMS (ES ) m/z Calcd for C29H28CI2F2N4O3S + H [(M+H)+]:621.1300, found: 621.1298. Example 426
Preparation of chiral (5)-2-{ [(25',3i?,45,,5i?)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-thiazol-4-yl- propionic acid
Figure imgf000492_0002
M. W. 621.533 C29H28CI2F2N4O3S
A mixture of chiral (5)-2-{ [(25',3i?,45,,5i?)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-thiazol-4-yl- propionic acid methyl ester trifluoroacetate salt (31 mg, 0.48.8 mmol) was dissolved in THF (1.5 mL) and methanol (0.5 mL), then 2N LiOH (0.5 mL) was added and stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate (2x), the organic phase was separated then concentrated under reduced pressure to afford crude product that was purified by RP-HPLC (20-95% acetonitrile/water) solvent evaporated from pure fraction under reduced pressure to afford the trifluoroacetate salt. This was free based with EtOAc and NaHC03(s), the organic layer was separated and concentrated under reduced pressure to afford chiral (5)-2-{[(25',3i?,45,,5i?)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-thiazol-4-yl- propionic acid
as a white powder (21 mg, 68.3 %). HRMS (ES+) m/z Calcd for C29H28Cl2F2N403S + H
[(M+H)+]:621.1300, found: 621.1298.
Example 427
Preparation of chiral 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -lH-indole-2- carboxylic acid
chiral
Figure imgf000493_0001
M. W. 625.5078 C32H28C12F2N403
A mixture of chiral 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -lH-indole-2- carboxylic acid ethyl ester (168 mg, 0.257 mmol) was dissolved in EtOH (4 mL) and 2N KOH (2 mL) was added and stirred 3 hours at 70°C, then cooled to 25°C. The mixture was diluted with water and ethyl acetate. The organic phase was separated then concentrated under reduced pressure. The compound was purified by RP-HPLC (20%>-95%> of acetonitrile/water) to afford the trifluoroacetate salt. Compound was very insoluble, used iPA with EtOAc and NaHC03(s) to free base, the organic layer was separated and concentrated under reduced pressure to afford chiral 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-lH-indole-2-carboxylic acid (84.5 mg, 52.6 %) as an off-white solidr. HRMS (ES+) m/z Calcd for C32H28CI2F2N4O3 + H
[(M+H)+]:625.1580, found: 625.1580.
Example 428
Preparation of rac (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (5-iodo-pyridin-2-yl)-amide
Figure imgf000494_0001
Molecular Weight =669.3449
Molecular Formula =C28H25CI2F2IN4O
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid, TFA salt (200 mg, 0.34 mmol ) in methylene chloride (3 mL), HATU (Aldrich, 235 mg, 0.62 mmol) was added followed by the addition of DIPEA (0.3 mL, 1.72 mmol) and 6-Iodo-pyridin-3-ylamine (Lancaster, 138 mg, 0.69 mmol). The mixture was stirred at RT for 4 h. The reaction was quenched with water. The mixture was extracted with methylene chloride (2X10 mL) and the extracts were dried with sodium sulfate. The solvent was removed and the residue was purified by flash chromatography (0-8% EtOAc/methylene chloride) to give the title compound as a white solid (95 mg, 41% yield).
MS (ES+) m/z Calcd: [(M+H)+]: 669, found: 669
Example 429
Preparation of 2-chloro-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2 ,2 -dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid
Figure imgf000495_0001
Molecular Weight =620.9158
Molecular Formula =C30H26C13F2N3O3
4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-chloro-benzoic acid methylester (54 mg) was dissolved in MeOH (10 mL) with help of slight heating. To the stirred solution was added NaOH ( IN, 2 mL) and the mixture was stirred for lhr. at 55°C. The solvent was removed and the residue was treated with 1 N HC1 to make the mixture acidic. The white suspension was extracted with EtOAc (3 xlO mL) and the extracts combined and dried with sodium sulfate. The solvent was removed and the residue was freeze dried to give a white powder. 40 mg. MS (ES+) m/z Calcd: [(M+H)+]: 620, found: 620
Example 430
Preparation of 6-{[(2R,3S,4R,5S)-4-(4-chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phi cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -nicotinic acid
Figure imgf000495_0002
Molecular Weight =587.4584
Molecular Formula =C29H26CI2F2N4O3
In a 50 ml pressure tube, (2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-N-(5-iodopyridin-2-yl)-5-neopentylpyrrolidine-2-carboxamide (87 mg, 130 μηιοΐ, Eq: 1.00) was combined with DMF (3.48 ml) and water (174 μΐ). Potassium carbonate (35.9 mg, 260 μηιοΐ, Eq: 2) was added. The mixture was bubbled with nitrogen and then palladium (II) acetate (3.48 mg, 15.5 μηιοΐ, Eq: 0.119) was added. The tube was subjected to CO atmosphere at 40 PSI and stirred for 3 hours at 70 °C.
The mixture was cooled to rt and filtered through celite. The filtrate was acidified with INHCl to PH 5 and was extracted with 5 ml EtOAc three times. The combined organic was dried over Na2S04, concentrated to give a residue.
The residue was dissolved in DMSO and was purified by HPLC using acetonitrile/Water. The peak one was concentrated and freeze dried to give an off-white foam, 8.7 mg, MS (ES+) m/z Calcd: [(M+H)+]: 587, found: 587
Example 431
Preparation of (2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fluoro-phi cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid pyridin-2-ylamide
Figure imgf000496_0001
Molecular Weight =543.4484
Molecular Formula =C28H26CI2F2N4O
In a 50 ml pressure tube, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-N-(5-iodopyridin-2-yl)-5-neopentylpyrrolidine-2-carboxamide (87 mg, 130 μηιοΐ, Eq: 1.00) was combined with DMF (3.48 ml) and water (174 μΐ). Potassium carbonate (35.9 mg, 260 μηιοΐ, Eq: 2) was added. The mixture was bubbled with nitrogen and then palladium (II) acetate (3.48 mg, 15.5 μηιοΐ, Eq: 0.119) was added. The tube was subjected to CO atmosphere at 40 PSI and stirred for 3 hours at 70 °C.
The mixture was cooled to rt and filtered through celite. The filtrate was acidified with INHCl to PH 5 and was extracted with 5 ml EtOAc three times. The combined organic was dried over Na2S04, concentrated to give a residue. The residue was dissolved in DMSO and was purified by HPLC using acetonitrile/Water. The peak two was concentrated and freeze dried to give an off- white foam, 13.8 mg, MS (ES+) m/z Calcd: [(M+H)+]: 543, found: 543 Example 432
Preparation of (2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid pyridin-4-ylamide
Figure imgf000497_0001
Molecular Weight =543.4484
Molecular Formula =C28H26CI2F2N4O
To 2 ml of CH2C12 at r.t. was added 1/3 amount of the (2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro- phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid, TFA salt (66.67 mg) and 1/3 amount of DIPEA (lOOuL) under nitrogen. To this was added 1/3 amount of HATU (80 mg). A solution of 4-amionpyridine in DCM 1 ml/DMF 0.5 ml was then added. The reaction was stirred for 30 minutes. To the reaction was added 1/3 of the DIPEA (lOOuL), followed by a solid mixture of 1/3 amount of the starting acid (66.67 mg) and 1/3 amount of the HATU (80 mg). The mixture was stirred for 30 minutes and then the rest of the starting material and the reagents were added the same way. The reaction was stirred for overnight. The reaction was then diluted with CH2CI2 (10 ml), dried with MgSO^., filtered and concentrated to give a residue. The residue was dissolved in DMSO (10 ml) and was purified by RP HPLC using 50-100% acetonitrile/water. 44.3 mg
MS (ES+) m/z Calcd: [(M+H)+]: 543, found: 543
Example 433
Preparation of 5-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyridine-2-carboxylic acid
Figure imgf000498_0001
Molecular Weight =587.4584
Molecular Formula =C29H26CI2F2N4O3
In a 50 ml pressure tube, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-N-(5-iodopyridin-2-yl)-5-neopentylpyrrolidine-2-carboxamide (100 mg, 149 μηιοΐ, Eq: 1.00) was combined with DMF (4 ml) and water (200 μΐ). Potassium carbonate (41.3 mg, 299 μηιοΐ, Eq: 2) was added. The mixture was bubbled with nitrogen and then palladium(II) acetate (4 mg, 17.8 μηιοΐ, Eq: 0.119) was added. The tube was subjected to CO atmosphere at 40 PSI and stirred overnight at 70 °C.
The reaction was filtered through celite. The filtrate diluted with water and was extracted with EtOAc ( 2x10 mL). The aqueous layer was acidified with IN HC1 to PH 5 to give a light suspension. This was filtered to give an orange solid. The EtOAc wash still contained the desired product. This was dried over Na2S04, concentrated to give a residue. The solid and the residue were combined and the mixture was dissolved in DMSO and was purified by HPLC using 50- 100% ACETONITRILE/Water. The clean fraction was concentrated and freeze dried to give a white foam, 8.7 mg, MS (ES+) m/z Calcd: [(M+H)+]: 587, found: 587
Example 434
Preparation of (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phi cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid pyridin-3-ylamide
Figure imgf000499_0001
Molecular Weight =543.4484
Molecular Formula =C28H26CI2F2N4O
In a 25 niL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid compound with 2,2,2- trifluoro acetic acid (1 :1) (200 mg, 344 μηιοΐ, Eq: 1.00), was combined with CH2CI2 (3 ml) to give a colorless solution. DIPEA (240 μΐ, 1.38 mmol, Eq: 4) and diphenylphosphinic chloride (244 mg, 1.03 mmol, Eq: 3) were added and the reaction was stirred at RT for 20 minutes. 3- Amino-pyridine (38.9 mg, 413 μηιοΐ, Eq: 1.2) was added and the reaction mixture was stirred at RT overnight. The crude reaction mixture was concentrated in vacuum. The crude material was purified by flash chromatography (silica gel, 40 g, 2% to 5% MeOH in DCM) to give a white solid as the product. 185 mg. MS (ES+) m/z Calcd: [(M+H)+]: 543, found: 543
Example 435
Preparation of (2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-iodo-3,5dimethyl-phenyl)-amide
Figure imgf000499_0002
Molecular Weight =696.41 15
Molecular Formula =C31 H30CI2F2IN3O
To 3 ml of CH2CI2 at r.t. was added 1/3 amount of the (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro- phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic 1) under nitrogen. To□ acid, TFA salt (100 mg) and 1/3 amount of DIPEA (111 this was added all of 4-iodo-3,5-dimethylaniline (0.255 g, 1.03 mmol), followed by 1/3 amount of HATU (1 17.7 mg) . The reaction was stirred for 30 minutes. To 1), followed by a solidDthe reaction was added another 1/3 of the DIPEA (111 mixture of 1/3 amount of the starting acid (100 mg) and 1/3 amount of the HATU (117.7 mg). This was stirred for 30 minutes and then the rest of the starting material and the reagents were added the same way. The reaction was stirred for overnight. The reaction was diluted with CH2CI2 (10 ml), washed with 0.5 N aqueous HC1 solution, dried with MgS0 , filtered and concentrated to give a yellow oil and this was purified by a 40 g flash silica gel column, eluted with a stepwise gradient of Hexanes to 25% EtOAc/Hexanes. Obtained was the product as a white solid. 60 mg. MS (ES+) m/z Calcd: [(M+H)+]: 696, found: 696.
Example 436
Preparation of 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2 fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-fluoro-benzoic acid tert-butyl ester
Figure imgf000500_0001
Molecular W eight =660.5696
Molecular Form ula =C34H34CI2F3N303
In a 25 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid compound with 2,2,2- trifluoro acetic acid (1 :1) (200 mg, 344 μηιοΐ, Eq: 1.00), was combined with CH2C12 (4.5 ml) to give a yellow solution. DIPEA (178 mg, 1.38 mmol, Eq: 4) and diphenylphosphinic chloride (244 mg, 1.03 mmol, Eq: 3) were added and the reaction was stirred at RT for 20 minutes. Tert- butyl 4-amino-2-fluorobenzoate (72.7 mg, 344 μηιοΐ, Eq: 1.00) was added and the reaction mixture was stirred at RT overnight. The crude reaction mixture was concentrated under vacuum. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 20% EtOAc in hexanes) to give a white solid as the product. 215 mg. MS (ES+) m/z Calcd: [(M+H)+]: 660, found: 660. Example 437
Preparation of 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2 fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-fiuoro-benzoic acid
Figure imgf000501_0001
Molecular Weight =604.4612
Molecular Formula =C30H26CI2F3N3O3
In a 50 mL round-bottomed flask, tert-butyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4- chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-fiuorobenzoate (170 mg, 257 μηιοΐ, Eq: 1.00) was combined with CH2CI2 (3 mL) to give a colorless solution. TFA (3 ml) was added and the reaction was stirred for 6 hours. The crude reaction mixture was concentrated in vacuum, added DCM and concentrated again. Recrystallization from diethyl ether and hexanes afforded a white solid (148 mg, 93% yield). MS (ES+) m/z Calcd: [(M+H)+]: 604, found: 604.
Example 438
Preparation of 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2 fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-fiuoro-benzoic acid
Figure imgf000501_0002
Molecular Weight =604.4612
Molecular Formula =C30H26CI2F3N3O3 In a 50 ml pressure tube, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-N-(5-iodopyridin-2-yl)-5-neopentylpyrrolidine-2-carboxamide (100 mg, 149 μηιοΐ, Eq: 1.00) was combined with DMF (4 ml) and water (200 μΐ). Potassium carbonate (41.3 mg, 299 μηιοΐ, Eq: 2) was added. The mixture was bubbled with nitrogen and then palladium(II) acetate (4 mg, 17.8 μηιοΐ, Eq: 0.119) was added. The tube was subjected to CO atmosphere at 40 PSI and stirred for 3 hours at 60 °C. The reaction temperature was raised to 70 °C, charged CO to 50 psi, stirred for 5 hours, and another 5 hours.
The reaction was filtered through celite. The filtrate diluted with 5% Na2C03 solution and was extracted with EtOAc (3x). The EtOAc solution was acidified with 0.5N HCl, washed with water, dried over Na2S04, and concentrated to give a residue. The residue was dissolved in methylene chloride and was purified by a 23 g silica gel column, eluted with methylene chloride to 5% MeOH in methylene chloride. The clean fraction was concentrated and the residue recrystallized from DCM/ether/hexanes. Obtained was desired product as a white solid, 165 mg.
MS (ES+) m/z Calcd: [(M+H)+]: 604, found: 604.
Example 439
Preparation of 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl^ropyl)-pyrrolidine-2-carbonyl]-amino}-2-trifluoromethyl-benzoic acid
Figure imgf000502_0001
Molecular Weight =654.4692
Molecular Formula =C31 H26CI2F5N303
In a 50 mL round-bottomed flask, methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4- chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2- (trifluoromethyl)benzoate (290 mg, 434 μηιοΐ, Eq: 1.00) was combined with THF (8 ml) and MeOH (8.00 ml) to give a colorless solution. 1.5 M NaOH (3 ml, 4.5 mmol, Eq: 10.4) was added. The reaction mixture was heated to 50 °C and stirred for 3 h. The reaction mixture was acidified with IN HC1 and was extracted with EtOAc (3 x 15 mL). The organic layers were combined, washed with saturated NaCl (1 x 10 mL), dried over Na2S04 and concentrated in vacuum.
The crude material was dissolved in DMSO and purified by preparative HPLC (70-100%
ACETONITRILE/water). Obtained was a white solid (130 mg, 46% yield). MS (ES+) m/z Calcd: [(M+H)+]: 654, found: 654.
Example 440
Preparation of (2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-iodo-2-trifiuoromethoxy- phenyl)-amide
Figure imgf000503_0001
Molecular W eight =752.3551
Molecular Form u la =C30 H25CI2F5IN3O2
In a 25 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid compound with 2,2,2- trifiuoro acetic acid (1 :1) (200 mg, 344 μηιοΐ, Eq: 1.00), was combined with CH2C12 (5 ml) to give a clear solution. DIPEA (178 mg, 1.38 mmol, Eq: 4) and diphenylphosphinic chloride (244 mg, 1.03 mmol, Eq: 3) were added and the reaction was stirred at RT for 30 minutes. 4-Iodo-2- (trifluoromethoxy) aniline (136 mg, 447 μηιοΐ, Eq: 1.3) was added and the reaction mixture was stirred at RT overnight. The crude reaction mixture was concentrated in vacuum. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 20% EtOAc/Hexanes) to give the desired product as a white solid. 255 mg. (ES+) m/z Calcd: [(M+H)+]: 752, found: 752.
Example 441 Preparation 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2^^ acid methyl ester
Figure imgf000504_0001
M o lecu lar W eig ht =684.4957
M o lecu lar Form u la =C32 H 28C I2 F5 N 304
In a 25 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid compound with 2,2,2- trifluoro acetic acid (1 :1) (300 mg, 516 μηιοΐ, Eq: 1.00), was combined with CH2CI2 (8 ml) to give a clear solution. DIPEA (267 mg, 361 μΐ, 2.06 mmol, Eq: 4) and diphenylphosphenic chloride (366 mg, 1.55 mmol, Eq: 3) were added and the reaction was stirred at RT for 20 minutes. Methyl 4-amino-2-(trifluoromethyl) benzoate (136 mg, 619 μηιοΐ, Eq: 1.2) was added and the reaction mixture was stirred at RT overnight.
The crude reaction mixture was concentrated in vacuum. The crude material was purified by flash chromatography (silica gel, 40 g, 5% to 25% EtOAc/Hexanes) to give the desired product as a white solid (340 mg, 98.6% yield). (ES+) m/z Calcd: [(M+H)+]: 684, found: 684.
Example 442
Preparation 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-trifluoromethoxy-benzoic acid
Figure imgf000505_0001
M olecu lar W e ig ht =670.4686
M olecu lar Form u la =C31 H 26C I2 F5 N 304
In a 50 ml pressure tube, (2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-N-(4-iodo-2-(trifluoromethoxy)phenyl)-5-neopentylpyrrolidine-2- carboxamide (200 mg, 266 μηιοΐ, Eq: 1.00) was combined with DMF (5 ml) and water (0.5 ml) to give a colorless solution. Potassium carbonate (83 mg, 601 μηιοΐ, Eq: 2.26) was added. The mixture was bubbled with nitrogen and then palladium (II) acetate (10 mg, 44.5 μηιοΐ, Eq: 0.168) was added. The tube was subjected to CO atmosphere at 50 PSI and stirred for
overnight at 70 °C.
The reaction was filtered through celite, washed with DMF, water and EtOAc. The filtrate was acidified with 1 N HC and was extracted with EtOAc ( 3x8ml ). The combined EtOAc solution was washed with water, dried over M^SO^., and concentrated to give a white solid. This was triturated with diethyl ether (2x15 ml) to give a white solid as desired product (172 mg, 97% yield). (ES+) m/z Calcd: [(M+H)+]: 670, found: 670.
Example 443
Preparation of 6-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -nicotinic acid
Figure imgf000506_0001
Molecular Weight =587.4584
Molecular Formula =C29H26CI2F2N4O3
In a 50 niL round-bottomed flask, methyl 6-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4- chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)nicotinate (25 mg, 41.6 μmol, Eq: 1.00) was dissolved in methylene chloride (8 ml) to give a colorless solution.
Aluminum bromide (66.5 mg, 249 μηιοΐ, Eq: 6) and dimethyl sulfide (25.8 mg, 30.7 μΐ, 416 μηιοΐ, Eq: 10) were added and the mixture was stirred at rt for overnight. The solvent was removed and the residue was suspended in 3 ml of acetonitrile, 3 ml of water was added and the mixture was extracted with ethyl acetate ( 3x8ml ). The extracts were combined and dried with sodium sulfate. Removal of solvent at reduced pressure gave a yellow solid, 30 mg.
The crude material was purified by preparative HPLC, (60-100% ACETONITRILE/water). The product peak was concentrated and freeze dried to give the desire product as a white foam. (10.1 mg, 41% yield ). (ES+) m z Calcd: [(M+H)+]: 587, found: 587.
Example 444
Preparation of 6-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -nicotinic acid methyl ester
Figure imgf000506_0002
Molecular Weight =601 .4855
Molecular Form ula =C30H28CI2F2N4O3 In a 50 ml pressure tube, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-N-(5-iodopyridin-2-yl)-5-neopentylpyrrolidine-2-carboxamide (185 mg, 276 μηιοΐ, Eq: 1.00) and DIPEA (0.29 ml, 1.67 mmol) were combined with DMF (5 ml) and MeOH (3.96 g, 5 ml, 124 mmol, Eq: 447) to give a colorless solution. The mixture was bubbled with nitrogen and palladium(II) acetate (6.21 mg, 27.7 mmol) was added. The tube was subjected to CO atmosphere at 50 PSI and stirred for overnight at 70 °C.
The reaction was filtered through celite, concentrated somewhat to remove MeOH. The mixture was acidified with IN HC1 (3 ml) and was extracted with EtOAc (3x5 ml). The EtOAc solution was washed with water, dried over Na2S04, and concentrated. The crude material was purified by flash chromatography (silica gel, 24g, 5% to 15% EtOAc in DCM). Obtained was a white solid as desired product (1 13 mg, 68% yield). (ES+) mix Calcd: [(M+H)+]: 601 , found: 601.
Example 445
Preparation of (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-prop l)-pyrrolidine-2-carboxylic acid (6-iodo-pyridin-3-yl)-amide
Figure imgf000507_0001
Molecular Weight =669.3449
Molecular Formula =C28H25CI2F2IN4O
In a 25 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (300 mg, 642 μηιοΐ, Eq: 1.00), was combined with CH2C12 (8 ml) to give a clear solution. DIPEA (332 mg, 448 μΐ, 2.57 mmol, Eq: 4) and diphenylphosphinic chloride (456 mg, 368 μΐ, 1.93 mmol, Eq: 3) were added and the reaction was stirred at RT for 30 minutes. 5-Amino-2-iodopyridine (141 mg, 642 μηιοΐ, Eq: 1) was added and the reaction mixture was stirred at RT overnight. The crude reaction mixture was concentrated in vacuum. The crude material was purified by flash chromatography (silica gel, 40 g, 5% to 20% EtOAc/CH2Cl2 ) to give the desired product as a white solid ( 409 mg, 93% yield). (ES+) m/z Calcd: [(M+H)+]: 669, found: 669.
Example 446
Preparation of 5-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyridine-2-carboxylic acid methyl ester
Figure imgf000508_0001
Molecular Weight =601.4855
Molecular Formula =C30H28CI2F2N4O3
In a 50 ml pressure tube, (2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-N-(6-iodopyridin-3-yl)-5-neopentylpyrrolidine-2-carboxamide (358 mg, 535 μηιοΐ, Eq: 1.00) and DIPEA (0.29 ml, 1.67 mmol) were combined with DMF (10 ml) and MeOH (10 ml) to give a colorless solution. The mixture was bubbled with nitrogen and palladium(II) acetate (25 mg, 111 μηιοΐ, Eq: 0.208) was added. The tube was subjected to CO atmosphere at 50 PSI and stirred for two days at 70 °C.
The reaction mixture was filtered through celite, concentrated somewhat to remove MeOH and was extracted with EtOAc (3x5 ml). The EtOAc solution was washed with water, dried over Na2S04, and concentrated. The crude material was purified by flash chromatography (silica gel, 40g, 5% to 25% EtOAc in DCM). obtained was a white solid as desired product (265 mg, 82% yield). (ES+) m/z Calcd: [(M+H)+]: 601, found: 601 Example 447
Preparation of 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-methoxy-benzoic acid methyl ester
Figure imgf000509_0001
Molecular Weight =630.5244
Molecular Formula =C32H31 CI2F2N3O4
In a 25 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (250 mg, 535 μmol), was combined with CH2CI2 (5 ml). DIPEA (277 mg, 374 μΐ, 2.14 mmol) and dipenylphospenic chloride (380 mg, 306 μΐ, 1.6 mmol) were added and the reaction was stirred at RT for 20 minutes. Methyl 4-amino-3-methoxybenzoate (100 mg, 552 μηιοΐ) was added and the reaction mixture was stirred at RT overnight.
The crude reaction mixture was concentrated in vacuum. The crude material was purified by flash chromatography (silica gel, 40 g, 5% to 25% EtOAc/Hexanes) to give the desired product as a white solid (275 mg, 81%> yield).
Example 448
Preparation of 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl^ropyl)-pyrrolidine-2-carbon l]-amino}-3-methoxy-benzoic acid
Figure imgf000510_0001
Molecular Weight =616.4973
Molecular Formula =C31 H29CI2F2N304
In a 25 mL round-bottomed flask, methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4- chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate
(150 mg, 238 μηιοΐ, Eq: 1.00) was combined with CH2CI2 (2 ml) to give a colorless solution.
Aluminum bromide (Aldrich, 254 mg, 952 μηιοΐ, Eq: 4) and dimethyl sulfide (1.69 g, 2 mL, 27.2 mmol, Eq: 114) were added. The reaction mixture was stirred for overnight.
The reaction mixture was diluted with CH3CN (6 ml), EtOAc (10 ml) and water (10 ml), stirred and layers separated. The aqueous layer was extracted with EtOAc (2 x 10 mL). The organic layers were combined, washed with saturated NaCl (1 x 15 mL), dried over MgS04 and concentrated in vacuum.
The crude material was dissolved in DMSO (4 ml) and was purified by preparative HPLC (70- 100% ACETONITRILE/water). The fractions were combined, concentrated and freeze dried to give a white powder as desired product (75 mg, 51% yield). (ES+) m/z Calcd: [(M+H)+]: 616, found: 616.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.95 (s, 9 H) 1.24 (d, J=13.90 Hz, 1 H) 1.62 (dd, J=14.10, 9.87 Hz, 1 H) 3.90 (s, 3 H) 3.91 - 3.99 (m, 1 H) 4.38 (br. s., 1 H) 4.51 - 4.62 (m, 2 H) 7.28 - 7.44 (m, 3 H) 7.47 - 7.61 (m, 4 H) 7.71 (t, J=6.85 Hz, 1 H) 8.35 (d, J=8.86 Hz, 1 H) 10.46 (s, 1 H) 12.86 (s, 1 H) Alternatively, the title compound could be prepared by the following method.
In a 500 mL round-bottomed flask, methyl 4-((2R,3S,4R,5 S)-3-(3-chloro-2-fluorophenyl)-4-(4- chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (3.74 g, 5.93 mmol, Eq: 1.00) was combined with THF (140 ml) and MeOH (160 ml) at 50°C to give a colorless solution. 1 N NaOH (23.7 ml, 23.7 mmol, Eq: 4) was added. The reaction mixture was stirred at 40 °C for 18 hrs.
The reaction mixture was concentrated to remove about 1/2 of the solvent, filtered to removed the insoluble, acidified with IN HC1 to PH = 4-5 and the resulting solid was collected by filtration and was washed with water, small amount of MeOH and diethyl ether. It was then dried in vacuum oven (60 °C) overnight. Obtained was a white solid as the desired product (2.96 g, 80.5% yield). H'NMR and LC/MASS data were the same as that in the above procedure. Example 449
Preparation of (2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-carbamoyl-naphthalen-2-yl)- amide
Figure imgf000511_0001
Molecular Weight =635.5466
Molecular Formula =C34H30CI2F2N4O2
To a stirred solution of 6-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-naphthoic acid (58 mg, 0.091 mmol) in methylene chloride (8 ml), HATU (35 mg, 0.091 mmol) was added followed by DIPEA (0. 15 ml). The solution was stirred for 5 minutes and then ammonia in methanol (2M in methanol, 1.0 ml) was added and the mixture was stirred at rt for 3 hrs. The solvent was reduced to 4 ml and loaded onto a silica gel column and eluted with 5% Methanol/methylene chloride on a combifalsh machine to give a white solid. 49 mg, 84.5%. (ES+) mix Calcd: [(M+H)+]: 635, found: 635.
Example 450
Preparation (2R,3 S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-3-chloro-phenyl)-amide
Figure imgf000512_0001
Molecular W eight =61 9.931 1
Molecular Form u la =C30H27CI3 F2N4O2
In a 25 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (150 mg, 321 μηιοΐ, Eq: 1.00), was combined with CH2CI2 (5 ml) to give a clear solution. DIPEA (145 mg, 196 μΐ, 1.12 mmol, Eq: 3.5) and diphenylphospenic chloride (Aldrich, 190 mg, 153 μΐ, 802 μηιοΐ, Eq: 2.5) were added and the reaction was stirred at RT for 20 minutes. 4-Amino-2-chlorobenzamide (53.1 mg, 31 1 μηιοΐ, Eq: 0.97) was added and the reaction mixture was stirred at RT overnight. The crude reaction mixture was concentrated under vacuum. The crude material was purified by preparative HPLC (70-100% ACETONITRILE/water) to give the desired product as a white solid (62 mg, 31% yield). (ES+) m/z Calcd: [(M+H)+]: 619, found: 619.
Example 451
Preparation of (2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-3-trifluoromethyl- phenyl)-amide
Figure imgf000513_0001
Molecu lar Weight =653.4844
Molecu lar Form ula =C31 H27CI2F5N402
In a 25 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-(trifluoromethyl)benzoic acid (42 mg, 64.2 μηιοΐ, Eq: 1.00) was combined with DMF (2.50 ml) to give a colorless solution. HATU (36.6 mg, 96.3 μιηοΐ, Eq: 1.5) and DIPEA (41.5 mg, 56.0 μΐ, 321 μιηοΐ, Eq: 5) were added. The reaction was stirred for 5 minutes and ammonia hydrochloride (34.3 mg, 642 μηιοΐ, Eq: 10) was added. The reaction mixture was stirred for overnight.
The reaction mixture was poured into 10 mL of H20 and extracted with EtOAc (3 x 10 mL). The organic layers were combined, washed with H20 (1 x 10 mL), saturated NaCl (1 x 10 mL), dried over Na2S04 and concentrated in vacuum. The crude material was purified by preparative HPLC (65-100% ACETONITRILE/water). The fractions were combined and freeze dried and triturated with CH2Cl2/hexanes to give a white foam (12 mg, 26% yield). (ES+) m z Calcd: [(M+H)+]: 653, found: 653.
Example 452
Preparation of 5-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl- ropyl)-pyrrolidine-2-carbonyl]-amino}-pyridine-2-carboxylic acid
Figure imgf000513_0002
Molecular Weight =587.4584
Molecular Formula =C29H26CI2F2N4O3 In a 25 niL round-bottomed flask, methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4- chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido) picolinate (230 mg, 382 μηιοΐ, Eq: 1.00) was combined with CH2CI2 (Mel) to give a colorless solution. Aluminum bromide (408 mg, 1.53 mmol, Eq: 4) and dimethyl sulfide (1.69 g, 2 ml, 27.2 mmol, Eq: 71.1) were added. The reaction mixture was stirred for overnight.
The reaction mixture was diluted with ACETONITRILE (5 ml), EtOAc (10 ml) and water (10 ml), stirred and layers separated. The aqueous layer was extracted with EtOAc (2 x 10 mL). The organic layers were combined, washed with H20 (1 x 15 mL), sat NaCl (1 x 15 mL), dried over Na2S04 and concentrated under vacuum.
The crude material was purified by preparative HPLC (with TFA). Obtained was a white solid after freeze drying (16.3 mg, 7% yield). (ES+) m/z Calcd: [(M+H)+]: 587, found: 587.
Example 453
Preparation of 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4 cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-fluoro-benzoic acid methyl ester
Figure imgf000514_0001
Molecular Weight =618.4883
Molecular Formula =C31 H28CI2F3N303
In a 50 ml pressure tube, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-N-(2-fluoro-4-iodophenyl)-5-neopentylpyrrolidine-2-carboxamide (1.42 g, 2.07 mmol, Eq: 1.00) and DIPEA (0.29 ml, 1.67 mmol) were combined with DMF (15 ml) and
MeOH (11.9 g, 15 ml, 371 mmol, Eq: 179) to give a colorless solution. The mixture was bubbled with nitrogen and palladium(II) acetate (40 mg, 178 μηιοΐ, Eq: 0.0861) was added. The tube was subjected to CO atmosphere at 50 PSI and stirred for two days at 70 °C. The reaction mixture was filtered through celite, concentrated somewhat to remove MeOH and was extracted with EtOAc (3x5 ml). The EtOAc solution was washed with water, dried over Na2SC> , and concentrated. The crude material was purified by flash chromatography (silica gel, 40g, 5% to 25% EtOAc in hexanes). Obtained was a white solid as desired product (845 mg, 65% yield). (ES+) m/z Calcd: [(M+H)+]: 618, found: 618.
Example 454
Preparation of 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-chloro-benzoic acid methyl ester
Figure imgf000515_0001
Molecular Weight =634.9429
Molecular Formula =C31 H28CI3F2N303
In a 25 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (150 mg, 321 μηιοΐ, Eq: 1.00), was combined with CH2CI2 (5 ml) to give a clear solution. DIPEA (145 mg, 196 μΐ, 1.12 mmol,
Eq: 3.5) and diphenyphophenic chloride (Aldrich, 190 mg, 153 μΐ, 802 μηιοΐ, Eq: 2.5) were added and the reaction was stirred at RT for 10 minutes. Methyl-4-amino-3-chloro-benzoate
(62.6 mg, 337 μηιοΐ, Eq: 1.05) was added and the reaction mixture was stirred at RT overnight.
The crude reaction mixture was concentrated under vacuum. The crude material was purified by flash chromatography (silica gel, 40 g, 8%> to 20%> EtOAc in hexanes) to give a white solid which still contains the aniline. The mixture was purified again by flash chromatography (silica gel, 40 g, 10% to 18% EtOAc in hexanes) to give the desired product as a white solid (60 mg, 30%> yield). (ES+) m/z Calcd: [(M+H)+]: 634, found: 634.
Example 455
Preparation of 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phi cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-chloro-benzoic acid
Figure imgf000516_0001
Molecular Weight =620.9158
Molecular Formula =C30H26CI3F2N3O3
To a stirred solution of aluminum bromide (250 mg, 937 μηιοΐ, Eq: 7.00) in
dimethyl sulfide (1.01 g, 1.2 ml, 16.2 mmol, Eq: 121) was added a solution of methyl 3-chloro-4- ((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fiuorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)benzoate (85 mg, 134 μηιοΐ, Eq: 1.00) in CH2CI2 (2 ml). The reaction mixture was stirred for 3 hours. The reaction mixture was diluted with CH3CN (3 ml), EtOAc (6 ml) and water (6 ml), stirred and layers separated. The aqueous layer was extracted with EtOAc (2 x6 ml). The organic layers were combined, washed with water (1x6 ml), sat NaCl (1 x 8 ml), dried over MgS04 and concentrated under vacuum. The crude material was purified by flash chromatography (silica gel, 12 g, 3% to 5% MeOH in DCM). The fractions were combined, concentrated, and was triturated with CE^CVhexanes to give a white powder as desired product (52 mg, 56% yield). (ES+) m/z Calcd: [(M+H)+]: 620, found: 620. Example 456
Preparation of (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-2-fluoro-phenyl)- amide
Figure imgf000517_0001
Molecular Weight =603.4765
Molecular Formu la =C30H27CI2 F3N4O2
In a 10 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-fluorobenzoic acid (70 mg, 116 μηιοΐ, Eq: 1.00) was combined with CH2CI2 (5.43 ml) to give a suspension. DIPEA (18.0 mg, 24.3 μΐ, 139 μηιοΐ, Eq: 1.2) and HATU (48.4 mg, 127 μηιοΐ, Eq: 1.1) were added. The reaction was stirred for 2 minutes and 2M ammonia (290 μΐ, 579 μηιοΐ, Eq: 5) in Methanol was added. The reaction mixture was stirred for overnight.
The crude material was purified by flash chromatography (silica gel, 40 g, 2% to 5% MeOH in DCM). The fractions were combined and concentrated to give a white solid (68 mg, 95% yield). (ES+) m/z Calcd: [(M+H)+]: 603, found: 603.
Example 457
Preparation of (2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-2-methoxy-phenyl)- amide
Figure imgf000518_0001
Molecular W eight =61 5.5125
Molecular Form ula =C31 H30CI2F2N4O 3
In a 10 niL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (200 mg,
324 μηιοΐ, Eq: 1.00) was combined with CH2CI2 (5.43 ml) to give a suspension. DIPEA (50.3 mg, 68.0 μΐ, 389 μηιοΐ, Eq: 1.2) and HATU (136 mg, 357 μηιοΐ, Eq: 1.1) were added. The reaction was stirred for 2 minutes and 2M ammonia (811 μΐ, 1.62 mmol, Eq: 5) in methanol was added.
The reaction mixture was stirred for 4h.
The crude material was dissolved in Ct^C /methanol, purified by flash chromatography (silica gel, 40 g, 2% to 30% EtOAc in DCM). The pure fractions were combined and triturated with
CH2Cl2/Hexanes to give a white solid (66 mg). Some later fractions were combined and purified by HPLC to give a white foam (14.9 mg). 81 mg. yield, 40.5%. (ES+) m/z Calcd: [(M+H)+]: 615, found: 615. Example 458
Preparation of 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2,5-difluoro-benzoic acid methyl ester
Figure imgf000519_0001
Molecular W eight =636.4787
Molecular Form u la =C31 H27CI2 F4N303
To a stirred solution of (2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2-fluorophenyl)- 4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (300 mg, 0.64 mmol) in methylene chloride (5 mL), DIPEA (Aldrich, 2.57 mmol, 0.45 ml) was added followed by diphenylphophinic chloride (Aldrich, 1.93 mmol, 0.37 ml). The mixture was stirred for 5 min. and 4-amino-2,5-difluoro- benzoic acid methyl ester ( Prepared by methylation of the corresponding acid. 201 mg, 0.76 mmol) was added and the mixture was stirred overnight. The reaction was quenched with 10% sodium carbonate (6 mL) and the mixture was stirred for 15 min.. The organic layer was separated and the solvent was reduced to about 3 ml. The solution was loaded onto a 40 g silica gel column and eluted with 2% EtOAc/CH2Cl2 to give a mixture of the desired product and aniline. The crude was again chromatographied on a reverse phase column and eluted with 50- 95% acetonitrile/water to give a white solid. 82 mg. (ES+) m/z Calcd: [(M+H)+]: 636, found: 636. Example 459
Preparation of 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2,5-difiuoro-benzoic acid
Figure imgf000519_0002
Molecular Weight =622.4516
Molecular Formula =C30H25CI2F4N3O3 To a stirred solution of methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2,5-difiuorobenzoate (75 mg, 0.118 mmol) in methylene chloride (10 ml), AlBr3 (Aldrich, 59 mg, 0.94 mmol) was added followed by dimethyl sulfide (Aldrich , 0.2 ml, 0.63 mmol). The mixture was stired at rt for 2 hrs. The solvent was removed and the residue was treated with 3 ml of acetonitrile and 10 ml of water. The mixture was then extracted with ethyl acetate. Removal of solvent gave an off white solid. 72 mg. (ES+) m/z Calcd: [(M+H)+]: 622, found: 622.
Example 460
Preparation of (2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3,5-difiuoro-4-iodo-phenyl)-amide
Figure imgf000520_0001
Molecular Weight =704.3381
Molecular Formula =C29H24CI2F4IN3O
In a 25 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid, 2,2,2-trifluoroacetic acid salt (1 :1) (400 mg, 688 μηιοΐ, Eq: 1.00) was combined with CH2C12 (3 ml) to give a clear solution. N-ethyl-N-isopropylpropan-2-amine (Aldrich, 356 mg, 479 μΐ, 2.75 mmol, Eq: 4) and diphenylphosphinic chloride (Aldrich, 407 mg, 328 μΐ, 1.72 mmol, Eq: 2.5) were added and the reaction was stirred at RT for 5 minutes. 3,5-Difiuoro-4-iodoaniline (Aldrich, 175 mg, 688 μηιοΐ, Eq: 1.00) was added and the reaction mixture was stirred at RT overnight.
The reaction mixture was diluted with DCM (10 ml), washed with 0.5 M HC1 (2x5 ml) and sat. NaHC03 (1 xlO ml), dried over Na2S04 and concentrated under vacuum. The crude material was purified by flash chromatography (silica gel, 40g, 5% to 25% EtOAc/Hexanes). The pure fractions were combined to give the desired product as a white solid (345 mg, 71% yield). (ES+) m/z Calcd: [(M+H)+]: 704, found: 704.
Example 461
Preparation of 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2,6-difiuoro-benzoic acid
Figure imgf000521_0001
Molecu lar W eight =622.451 6
Molecu lar Form ula =C30H25CI2F4N3O 3
In a 100 mL round-bottomed flask, methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4- chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2,6-difiuorobenzoate (270 mg, 424 μηιοΐ, Eq: 1.00) was combined with THF (5 ml) and MeOH (5.00 ml) to give a colorless solution. NaOH (1.06 ml, 2.12 mmol, Eq: 5) was added. The reaction mixture was heated to 40 °C and stirred for 3 h.
The crude reaction mixture was concentrated under vacuum to remove half of the solvent and the residue was diluted with water. Some solid came out and was removed by filtration (dimer,
M+l=899). The filtrate was acidified with IN HC1 to pH 2-3 and was extracted with EtOAc (3 x 10 mL). The organic layers were dried overNa2SC>4 and concentrated under vacuum to give a yellow foam. This was re crystallized from DCM/Hexanes to give a white solid as desired product ( 27 mg, 10% yield). (ES+) m/z Calcd: [(M+H)+]: 622, found: 622.
Example 462
Preparation of 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-hydroxy-benzoic acid
Figure imgf000522_0001
Molecu lar W eight =602.4702
Molecu lar Form ula =C30H27CI2F2N3O4
In a 25 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (200 mg, 324 μηιοΐ, Eq: 1.00) was combined with CH2CI2 (5 ml) to give a suspension. Boron tribromide (Aldrich, 1.3 ml, 1.3 mmol, Eq: 4) was added dropwise to give a brown solution. The reaction mixture was stirred for overnight (72% conversion after 4 hours) at rt.
To the reaction mixture was added CH3CN (3 mL). Then were added CH2CI2 (10 ml ) and water (10 ml) with stirring. Layers were separated, the aqueous layer was extracted with CH2C122 (2x10 ml). The organic layers were combined, washed with H2O (1 x 15 mL), sat NaCl (1 x 15 mL), dried over Na2S04 and concentrated under vacuum. To it was added DCM (3 mL). The solid was collected by filtration and washed with DCM. Obtained was a white solid as desired product (140 mg, 72% yield). (ES+) m/z Calcd: [(M+H)+]: 602, found: 602.
Example 463
Preparation of (2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-3-methoxy-phenyl)- amide
Figure imgf000522_0002
Molecular Weight =615.5125
Molecular Formula =C31 H30CI2F2N4O3 To a stirred solution of 4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-methoxybenzoic acid (250 mg, 0.41 mmol) in methylene chloride (8 ml), HATU (154 mg, 0.41 mmol) and DIPEA (0.1 ml, 0.57 mmol) were added. The mixture was stirred for 5 min. at rt and ammonia in methanol (2N, 2 ml) was added and the mixture was stirred overnight. The solvent was reduced to 3 ml and loaded onto a slica gel column, eluted with 3% methanol and methylene chloride to give 230 mg desired product. (ES+) m/z Calcd: [(M+H)+]: 615, found: 615.
Example 464
Preparation of (2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-3-trifluoromethoxy- phenyl)-amide
Figure imgf000523_0001
Molecu lar Weight =669.4838
Molecu lar Form ula =C31 H27CI2F5N403
In a 20 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-(trifluoromethoxy)benzoic acid (80 mg, 119 μηιοΐ, Eq: 1.00) was combined with CH2CI2 (7 ml) to give a suspension.
DIPEA (20.0 mg, 27.1 μΐ, 155 μηιοΐ, Eq: 1.3) and HATU (49.9 mg, 131 μηιοΐ, Eq: 1.1) were added. The reaction was stirred for 5 minutes and 2M ammonia (298 μΐ, 597 μηιοΐ, Eq: 5) in methanol was added. The reaction mixture was stirred for overnight.
The crude material was dissolved in Ct^C /methanol, purified by flash chromatography (silica gel, 24g, 2% to 5% MeOH in DCM). The pure fractions were combined and concentrated and triturated with 15% EtOAc/Hexanes to give a white solid as desired product (75 mg, 91% yield). (ES+) m/z Calcd: [(M+H)+]: 669, found: 669. Example 465
Preparation of (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-3-fluoro-phenyl)- amide
Figure imgf000524_0001
Molecular Weight =603.4765
Molecular Formula =C30H27CI2F3N4O2
In a 20 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-fluorobenzoic acid (60 mg, 99.3 μηιοΐ, Eq: 1.00) was combined with CH2CI2 (5 ml) to give a suspension. DIPEA (16.7 mg, 22.5 μΐ, 129 μηιοΐ, Eq: 1.3) and HATU (42 mg, 110 μηιοΐ, Eq: 1.11) were added. The reaction was stirred for 5 minutes and 2M ammonia (248 μΐ, 496 μηιοΐ, Eq: 5) in Methanol was added. The reaction mixture was stirred for overnight.
The crude material was dissolved in CELC /methanol, purified by flash chromatography (silica gel, 24g , 2% to 5% MeOH in DCM). The pure fractions were combined and concentrated and triturated with 15% EtOAc/Hexanes to give a white solid as desired product (54 mg, 88% yield). (ES+) m/z Calcd: [(M+H)+]: 603, found: 603.
Example 466
Preparation of (2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-2-chloro-phenyl)- amide
Figure imgf000525_0001
Molecular Weight =619.931 1
Molecular Formula =C30H27CI3F2N4O2
In a 20 niL round-bottomed flask, 3-chloro-4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4- chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzoic acid (215 mg, 346 μmol, Eq: 1.00) was combined with CH2CI2 (8 ml) to give a suspension. DIPEA (58.2 mg, 78.6 μΐ, 450 μηιοΐ, Eq: 1.3) and HATU (145 mg, 381 μηιοΐ, Eq: 1.1) were added. The reaction was stirred for 5 minutes and 2M ammonia (866 μΐ, 1.73 mmol, Eq: 5) in methanol was added. The reaction mixture was stirred over weekend.
The crude material was dissolved in CE^C /methanol, purified by flash chromatography (silica gel, 24g, 2% to 5% MeOH in DCM). The pure fractions were combined and concentrated to give a white solid as desired product (155 mg, 71% yield). (ES+) m/z Calcd: [(M+H)+]: 619, found: 619.
Example 467
Preparation of 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-fluoro-5-methoxy-benzoic acid methyl ester
Figure imgf000526_0001
Molecular Weight =648.5148
Molecular Formula =C32H30CI2F3N3O4
In a 15 niL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (250 mg, 535 μηιοΐ, Eq: 1.00), was combined with CH2CI2 (3 ml) to give a clear solution. DIPEA (242 mg, 327 μΐ, 1.87 mmol, Eq: 3.5) and diphenylphosphenic chloride (316 mg, 255 μΐ, 1.34 mmol, Eq: 2.5) were added and the reaction was stirred at RT for 5 minutes. Methyl 4-amino-2-fluoro-5-methoxybenzoate (107 mg, 535 μηιοΐ, Eq: 1.00) was added and the reaction mixture was stirred at RT overnight.
The crude reaction mixture was diluted with CH2CI2 and washed with 0.5 M HC1 (1x5 ml), dried over MgSC>4, filtered and concentrated to give a yellow oil.
The oil was dissolved in CH2CI2, purified by flash chromatography (silica gel, 24 g, 5% to 20% EtOAc in hexanes). The fractions were combined, concentrated and triturated with
CH2Cl2/Hexanes. Obtained was an off white solid (220 mg, 63% yield). (ES+) m/z Calcd: [(M+H)+]: 648, found: 648.
Example 468
Preparation of 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-fluoro-5-methoxy-benzoic acid
Figure imgf000527_0001
Molecular Weight =634.4877
Molecular Formula =C31 H28CI2F3N304
In a 25 niL round-bottomed flask, methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4- chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-fluoro-5- methoxybenzoate (80 mg, 123 μηιοΐ, Eq: 1.00) was combined with THF (2 ml) and MeOH (4
o
ml) at 45 C to give a colorless solution. 1 N NaOH (0.5 ml, 1.00 mmol, Eq: 8.11) was added. The reaction mixture was stirred at 40 °C for 2 hr.
The reaction mixture was concentrated to remove about 1/2 of the solvent, acidified with IN HCl to PH 2-3, diluted with water (10ml ) and EtOAc (15 ml). The layers were separated and the aqueous was extracted with EtOAc (2x15 ml). The organic layers were combined, washed with sat NaCl (1 x 15 mL), dried over MgS04 and concentrated under vacuum. Triturating with CH2C12 gave a white solid (60 mg, 73% yield). (ES+) m/z Calcd: [(M+H)+]: 634, found: 634.
Example 469
Preparation of 2-(4-{[(2i?,35,,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-4-methyl-pentanoic acid
Figure imgf000528_0001
M. W. 656.61 C35H37Cl2F2N303
A mixture of 2-(4-{[(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl^ropyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-4-methyl-pentanoic acid methyl ester (14 mg, 0.0209 mmol) was dissolved in THF (15 mL) and methanol (5 mL), then 2N LiOH (5 mL) was added and stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate (2x). The organic phase was separated then concentrated under reduced pressure to afford the crude mixture. The compound was purified by RP-HPLC (20%-95% acetonitrile/water) to afford of 2-(4-{[(2i?,35,4i?,55)-3-(3-chloro-2-fiuoro- phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]- amino}-phenyl)-4-methyl-pentanoic acid trifiuoroacetate salt (8.2 mg, 51.0 %) as a light brown solid. HRMS (ES+) m/z Calcd for C35H37Cl2F2N303 + H [(M+H)+]:656.2253, found: 656.2254.
Example 470
Preparation of chiral 2-(4-{[(2S,3R,4S,5R)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-2-methyl- propionic acid methyl ester
Figure imgf000528_0002
M. W. 642.58 C34H35Cl2F2N303 Methyl 2-(4-aminophenyl)-2 -methyl propanoate hydrochloride (100 mg, 0.435 mmol) was dissolved in dichloromethane (30 mL) then iPr2NEt (0.5 mL, 2.86 mmol) was added and stirred at 25°C. In three portions chiral (2i?,35',4i?,55,)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.214 mmol) and 2-(7-azabenzotriazol-l-yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (HATU, 106 mg, 0.278 mmol) was added in 30 min intervals. The reaction mixture was stirred at 25°C for 5 hours. Reaction not complete by LCMS, additional methyl 2-(4-aminophenyl)-2-methyl propanoate hydrochloride (30 mg, 0.13 mmol) was added to the reaction and stirred an additional 1 hr. The mixture was diluted with CH2C12 and washed with water. The organic phase was separated, then concentrated under reduced pressure. The compound was purified by column chromatography (8 g silica column, Analogix, 1-100% EtO Ac/heptane) to afford chiral 2-(4- {[(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-2-methyl-propionic acid methyl ester as a light yellow foam (26 mg, 18.9%) LCMS (ES+) m/z Calcd for C34H35C12F2N303+ H
[(M+H)+]:642.58, found: 642.1
Example 471
Preparation of chiral 2-(4-{[(2i?,35',4i?,55,)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-2-methyl- propionic acid
Chiral
Figure imgf000529_0001
M. W. 628.54 C33H33C12F2N303
A mixture of chiral 2-(4-{[(2i?,35',4i?,55,)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fluoro- phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-2-methyl- propionic acid methyl ester (21 mg, 0.0327 mmol) was dissolved in THF (3 mL) and methanol (1 mL), followed by 2N LiOH (1 mL). The reaction mixture was stirred at room temperature for 14 hours. The mixture was diluted with water and extracted with ethyl acetate (2x). The organic phase was separated then concentrated under reduced pressure to afford crude product. The compound was purified by RP-HPLC (30%-95% of acetonitrile/water) to afford of chiral 2-(4- {[(2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-2-methyl-propionic acid (12 mg, 58.4 %) as an off-white solid. HRMS (ES+) m/z Calcd for C33H33CI2F2N3O3+ H
[(M+H)+]:628.1940, found: 628.1937.
Example 472
Preparation of chiral (25,,3i?,45,,5i?)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(l -methyl- 1 - methylc arbamoyl-ethyl)-phen l] -amide
Figure imgf000530_0001
M. W. 641.59 C34H36CI2F2N4O2
Reagant 2-(4-amino-phenyl)-N-methyl-isobutyramide (130 mg, 0.676 mmol) was dissolved in dichloromethane (4 mL) then iPr2NEt (0.375 mL, 2.15 mmol) was added and stirred at 25°C. In three portions chiral (2i?,35',4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.214 mmol) and 2-(7- azabenzotriazol-l-yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (HATU, 106 mg, 0.278 mmol) was added in 30 min intervals. The reaction mixture was stirred at 25°C for 5 hours, complete by LCMS. The mixture was then diluted with CH2C12 and washed with water. The organic phase was separated, then concentrated under reduced pressure. The compound was purified by RP-HPLC (30-95% acetonitrile/water) to afford chiral (2S,3i?,4S,5i?)-3-(3-chloro-2- fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2- carboxylic acid [4-(l -methyl- l-methylcarbamoyl-ethyl)-phenyl]-amide as an off-white solid (56 mg, 40.8%) HRMS (ES ) m/z Calcd for C34H36CI2F2N4O2+ H [(M+H)+]:641.2256, found:
641.2256.
Example 473
Preparation of chiral (25,,3i?,45,,5i?)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {4-[l-(3-hydroxy- propylcarbamoyl)- 1 -methyl-ethyl]-phenyl} amide
Figure imgf000531_0001
M. W. 685.648 C36H40CI2F2N4O3
Reagent 2-(4-aminophenyl)-N-(3-hydroxylpropyl)-2-propanamide (130 mg, 0.550 mmol) was dissolved in dichloromethane (4 mL) then iPr2NEt (0.375 mL, 2.15 mmol) was added and stirred at 25°C. In three portions chiral (2i?,35',4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2- fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.214 mmol) and 2-(7-azabenzotriazol-l-yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (HATU, 106 mg, 0.278 mmol) was added in 30 min intervals. The reaction mixture was stirred at 25°C for 5 hours. The mixture was then diluted with CH2C12 and washed with water. The organic phase was separated, then concentrated under reduced pressure. The compound was purified by RP-HPLC (30-95% acetonitrile/water) to afford chiral (25,3i?,45,5i?)-3-(3-chloro-2-fiuoro- phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {4-[l-(3-hydroxy-propylcarbamoyl)-l-methyl-ethyl]-phenyl} amide as an off-white solid (75 mg, 51.1%) HRMS (ES+) m/z Calcd for C36H40CI2F2N4O3+ H [(M+H)+]:685.2519, found: 685.2523. Example 474
Preparation of chiral (25,,3i?,45,,5i?)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)- 4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(l -carbamoyl- 1 -methyl-ethyl)- phenyl]-amide
Chiral
Figure imgf000532_0001
M. W. 627.57 C33H34C12F2N402
Reagant 2-(4-amino-phenyl)isobutyramide (80 mg, 0.171 mmol) was dissolved in
dichloromethane (5 mL) then iPr2NEt (0.1 mL, 0.573 mmol) was added and stirred at 25°C. Chiral (2i?,35,,4i?,55)-3-(3-chloro-2-fiuoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (50 mg, 0.107 mmol) and 2-(7-azabenzotriazol- l-yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (HATU, 60 mg, 0.158 mmol) was added and the reaction mixture was stirred at 25°C for 2 hours. The mixture was then diluted with CH2C12 and washed with water. The organic phase was separated, then concentrated under reduced pressure. The compound was purified by RP-HPLC (30-95% acetonitrile/water) to afford chiral (25,,3i?,45,,5i?)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fiuoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(l -carbamoyl- l-methyl-ethyl)-phenyl]- amide [4-(l-methyl-l-methylcarbamoyl-ethyl)-phenyl]-amide as an solid (32.5 mg, 48.4%) LCMS (ES+) m/z Calcd for C33H34C12F2N402+ H [(M+H)+]: 627.2, found: 627.0. Example 475
In 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 fiat -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
(PerkinElmerWallac), 2 nM Eu-labeled anti-GST-antibody (PerkinElmerWallac), 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 5, Perkin ElmerWallac). If not specified, the reagents were purchased from Sigma Chemical Co.
Activity data for the Example compounds expressed as IC5o :bsa:0.02%> are as follows ( in
[μΜ]):
Ex.-No. IC50 | μΜ] Ex.-No. IC50 ΓμΜΙ Ex.-No. IC50 | μΜ]
379 2.939 421 0.042 467 0.057
380 0.027 422 0.072 468 0.02
381 3.812 423 0.04 469 0.309
382 0.088 423 0.046 470 0.749
383 3.75 424 1.376 471 0.047
384 0.092 424 10 472 0.155
385 0.675 425 0.132 473 0.106
386 0.049 426 2.698
387 1.526 427 0.094
388 0.058 428 0.01
389 0.053 429 0.003
390 0.129 430 0.066
391 0.439 431 0.353
392 0.083 432 0.165
393 0.05 433 0.053
394 0.051 434 0.104
394 0 435 1.272
395 0.1 436 0.435
396 0.023 437 0.022
397 #N/A 438 0.027
398 .231 439 0.029
399 0.075 440 0.064
400 8.374 442 0.494
400 0.085 444 0.082
401 0.049 445 0.063
402 0.044 447 0.05
403 0.138 448 0.017
404 0.023 449 0.049
405 0.243 450 0.089
406 0.03 451 0.136
407 0.042 452 0.03
408 0.027 453 0.123
408 0.067 454 0.098
409 1.025 455 0.038
410 0.14 456 0.05
411 0.186 457 0.031
412 0.52 458 0.118
413 0.038 459 0.044
414 0.147 460 0.281
415 0.107 461 0.053
416 10 462 0.028
417 0.691 463 0.028
418 10 464 0.06
419 0.465 465 0.032
420 0.057 466 0.041

Claims

Claims compounds of the formula
Figure imgf000535_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, hetereoaryl, hetereocycle, COOR', OCOR', CONR'R", NR'COR", NR"S02R', S02NR'R" and NR'R" wherein
R' and R" is independently selected from H or substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetereoaryl or substituted or unsubstituted hetereocycle,
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 or lower alkyl,
R3 is H or lower alkyl, one of R4 and R5 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,
R6 and R7 are selected from the group consisting of (CH2)n-R', (CH2)n-NR'R", (CH2)n-
NR'COR", (CH2)„-NR'S02R", (CH2)n-COOH, (CH2)n-COOR', (CH2)n-CONR'R", (CH2)n-OR\ (CH2)„-SR', (CH2)n-SOR', (CH2)n-S02R', (CH2)n-COR', (CH2)n-S03H, (CH2)n-SONR'R", (CH2)n-S02NR'R", (CH2CH20)m-(CH2)n-R', (CH2CH20)m-(CH2)n-OH, (CH2CH20)m-(CH2)n- OR', (CH2CH20)m-(CH2)n-NR'R", (CH2CH20)m-(CH2)n-NR'COR", (CH2CH20)m-(CH2)n- NR'S02R", (CH2CH20)m-(CH2)n-COOH, (CH2CH20)m-(CH2)n-COOR', (CH2CH20)m-(CH2)n- CONR'R", (CH2CH20)m-(CH2)n-S02R', (CH2CH20)m-(CH2)n-COR', (CH2CH20)m-(CH2)n- SONR'R", (CH2CH20)m-(CH2)n-S02NR'R", (CH2)p-(CH2CH20)m-(CH2)n-R', (CH2)P- (CH2CH20)m-(CH2)n-OH, (CH2)p-(CH2CH20)m-(CH2)n-OR', (CH2)p-(CH2CH20)m-(CH2)n- NR'R", (CH2)p-(CH2CH20)m-(CH2)n-NR'COR", (CH2)p-(CH2CH20)m-(CH2)n-NR'S02R", (CH2)p-(CH2CH20)m-(CH2)n-COOH, (CH2)p-(CH2CH20)m-(CH2)n-
COOR', (CH2)p-(CH2CH20)m-(CH2)n-CONR'R", (CH2)p-(CH2CH20)m-(CH2)n-S02R', (CH2)P- (CH2CH20)m-(CH2)n-COR', (CH2)p-(CH2CH20)m-(CH2)n-SONR'R", (CH2)p-(CH2CH20)m- (CH2)n-S02NR'R", -COR', -SOR' and S02R' wherein R' and R" are the same definitions as above,
m, n and p are independently 0 to 6
and the pharmaceutically acceptable salts and esters thereof.
2. The compounds of claim 1 of the formula
R7
Figure imgf000536_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, hetereoaryl, hetereocycle, COOR', OCOR', CONR'R", NR'COR", NR"S02R', S02NR'R" and NR'R" wherein
R' and R" are independently selected from H or substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted hetereoaryl or substituted or unsubstituted hetereocycle,
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,
Ri 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,
R2 is hydrogen or lower alkyl,
R3 is H or lower alkyl,
R5 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,
R6 and R7 are selected from the group consisting of (CH2)n-R', (CH2)n-NR'R", (CH2)n-
NR'COR", (CH2)„-NR'S02R", (CH2)n-COOH, (CH2)n-COOR\ (CH2)n-CONR'R", (CH2)n-OR\ (CH2)n-SR\ (CH2)n-SOR\ (CH2)n-S02R\ (CH2)n-COR\ (CH2)n-S03H, (CH2)n-SONR'R", (CH2)n-S02NR'R", (CH2CH20)m-(CH2)n-R\ (CH2CH20)m-(CH2)n-OH, (CH2CH20)m-(CH2)n- OR', (CH2CH20)m-(CH2)n-NR'R", (CH2CH20)m-(CH2)n-NR'COR", (CH2CH20)m-(CH2)n- NR'S02R", (CH2CH20)m-(CH2)n-COOH, (CH2CH20)m-(CH2)n-COOR\ (CH2CH20)m-(CH2)n- CONR'R", (CH2CH20)m-(CH2)n-S02R\ (CH2CH20)m-(CH2)n-COR\ (CH2CH20)m-(CH2)n- SONR'R", (CH2CH20)m-(CH2)n-S02NR'R", (CH2)p-(CH2CH20)m-(CH2)n-R', (CH2)P- (CH2CH20)m-(CH2)n-OH, (CH2)p-(CH2CH20)m-(CH2)n-OR' , (CH2)p-(CH2CH20)m-(CH2)n- NR'R", (CH2)p-(CH2CH20)m-(CH2)n-NR'COR", (CH2)p-(CH2CH20)m-(CH2)n- NR'S02R", (CH2)p-(CH2CH20)m-(CH2)n-COOH, (CH2)p-(CH2CH20)m-(CH2)n-COOR', (CH2)P- (CH2CH20)m-(CH2)n-CONR'R", (CH2)p-(CH2CH20)m-(CH2)n-S02R', (CH2)p-(CH2CH20)m- (CH2)n-COR', (CH2)p-(CH2CH20)m-(CH2)n-SONR'R", (CH2)p-(CH2CH20)m-(CH2)n-S02NR'R", -COR', -SOR' and S02R'
wherein R' and R" are the same definitions as above,
m, n, and p are independently 0 to-6
and the pharmaceutically acceptable salts and esters thereof.
3. The compounds according to claim 2 of the formula Ila
Figure imgf000538_0001
wherein R6 and all variables and substituents mentioned in the definitions for R6 have the meanings given for formula II above.
4. The compounds according to claim 3, wherein
R6 is -(CH2)„-R', and
R' is Cyclohexyl, or
a 5 to 10 membered, mono- or bicyclic aromatic hydrocarbon wherein 1 or 2 carbon atoms may be replaced by N, S or O, and wherein any of the aforementioned cyclohexyl or aromatic hydrocarbon can be substituted once or twice with a group independently selected from 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, aminocarbonyl, 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, hydro xy-lower-alkoxy, NH2-lower-alkoxy, N(H, lower-alkyl)-lower-alkoxy, N(lower-alkyl)2-lower-alkoxy, lower-alkyl- 1 -oxiranyl- lower-alkoxy-lower-alkyl, 2-oxo-pyrrolidin-l-yl, (l,l-dioxo)-2-isothiazolidine, 3- lower-alkyl sulfinyl, a substituted or unsubstituted heterocyclic ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heteroaryl ring, trifluoro-lower- alkylsulfonylamino-aryl, lower-alkyl sulfonylaminocarbonyl, lower-alkyl sulfonylaminocarbonyl-aryl, hydroxycarbamoyl-phenyl, 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; and
n is 0 or 1.
5. The compounds according to claim 3 or 4, wherein
R6 is -(CH2)n-R', and
R' is phenyl, pyridinyl, pyrazinyl or pyrimidinyl which can be each unsubstituted or once or twice substituted with a substituent independently selected from halogen, CI -6 alkoxy, CI -6 alkyl, hydro xycarbonyl, carboxy, carboxy CI -6 alkoxy, oxo and CN; and
n is 0.
6. The compounds selected from the group of
rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-cyclohexanecarboxylic acid methyl ester,
rac- 4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid, rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid methyl ester, rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid, rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-2-fluoro-benzoic acid methyl ester,
rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid, chiral 5-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-pyridine-2-carboxylic acid methyl ester,
chiral 5-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-pyridine-2-carboxylic acid, chiral 6-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-nicotinic acid ethyl ester, chiral 6-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -methyl)-nicotinic acid,
chiral (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydrazinocarbonyl-phenyl)-amide, chiral [2-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-ethyl]-carbamic acid tert-butyl ester,
chiral (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-amino-ethyl)-phenyl]-amide, chiral 4-(((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)methyl)-2-methoxybenzoic acid,
chiral-4-({[(2S,3R,4S,5R)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid, chiral methyl 3-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2-fluorophenyl)-4- cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)propanoate,
chiral 3-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fiuorophenyl)-4-(4-chloro-2 -fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)phenyl)propanoic acid, chiral- 4-(((2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)methyl)-2-fluorobenzoic acid,
chiral 4-(((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)methyl)-2-fluorobenzoic acid ,
chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(2- morpholinopyrimidin-5-yl)-5-neopentylpyrrolidine-2-carboxamide,
chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentyl-N-(pyrimidin-5-yl)pyrrolidine-2-carboxamide,
chiral (2S,3R,4S,5R)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-dimethylaminomethyl-phenyl)-amide, (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-dimethylaminomethyl-phenyl)-amide, chiral methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4- cyano-5-neopentylpyrrolidine-2-carboxamido)-lH-benzo[d]imidazole-2-carboxylate, chiral-5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)-lH-benzo[d]imidazole-2-carboxylic acid,
chiral-methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4- cyano-5-neopentylpyrrolidine-2-carboxamido)benzofuran-2-carboxylate,
chiral-5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)benzofuran-2-carboxylic acid,
chiral- methyl 4-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4- cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)butanoate,
chiral- 4-(4-((2R,3S,4R,5S)-3-(3-chloro-2 -fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)phenyl)butanoic acid,
chiral methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4- cyano-5-neopentylpyrrolidine-2-carboxamido)benzo[d]oxazole-2-carboxylate,
chiral- 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)benzo[d]oxazole-2-carboxylic acid,
chiral- (2R,3S,4R,5S)-N-(benzo[d]oxazol-5-yl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamide, rac-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzyl)-carbamic acid tert-butyl ester, rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-aminomethyl-phenyl)-amide,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(methanesulfonylamino-methyl)-phenyl]- amide,
l-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl^ropyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-piperidine-4-carboxylic acid ethyl ester,
l-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-piperidine-4-carboxylic acid, rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-dimethylaminomethyl-phenyl)-amide, rac-5-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-pyrrolidin- 1 -yl-benzoic acid, rac-4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -4-methyl-piperidine-l -carboxylic acid tert-butyl ester,
rac- (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methyl-piperidin-4-yl)-amide,
rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid ( 1 -methanesulfonyl-4-methyl-piperidin-4-yl)- amide,
methyl l-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano- 5 -neopentylpyrro lidine -2 -c arboxamido)phenyl)pyrrolidine -2 -c arboxylate ,
l-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine -2 -carboxamido)phenyl)pyrrolidine -2 -carboxylic acid,
chiral 5-{[(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-lH-pyrrole-2-carboxylic acid, chiral 5- {[(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -lH-pyrrole-2-carboxylic acid ethyl ester, chiral (i?)-2-(4- {[(2i?,35,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-butyric acid, chiral (S)-2 -(4- {[(2i?,35,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4- cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-butyric acid, chiral (S)-2- { [(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-thiazol-4-yl-propionic acid methyl ester,
chiral (S)-2- { [(25,,3i?,45,,5i?)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-thiazol-4-yl-propionic acid methyl ester,
chiral (S)-2- { [(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-thiazol-4-yl-propionic acid, chiral (S)-2- { [(25,,3i?,45,,5i?)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-thiazol-4-yl-propionic acid, chiral 4- {[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -lH-indole-2-carboxylic acid,
rac (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (5-iodo-pyridin-2-yl)-amide,
2-chloro-4- {[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-
5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -benzoic acid,
6- {[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -nicotinic acid,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid pyridin-2-ylamide,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid pyridin-4-ylamide,
5- {[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-nuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -pyridine-2-carboxylic acid, (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid pyridin-3-ylamide,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-iodo-3 ,5dimethyl-phenyl)-amide,
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2 fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-fluoro-benzoic acid tert-butyl ester, 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2 fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-fluoro-benzoic acid,
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2 fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-fluoro-benzoic acid ,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-iodo-2-trifluoromethoxy-phenyl)-amide,
4- {[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-trifluoromethoxy-benzoic acid methyl ester, 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-trifluoromethoxy-benzoic acid,
6-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -nicotinic acid,
6-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -nicotinic acid methyl ester ,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-iodo-pyridin-3-yl)-amide ,
5- {[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyridine-2-carboxylic acid methyl ester, 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid methyl ester, (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-carbamoyl-naphthalen-2-yl)-amide,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-3-chloro-phenyl)-amide, (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-3-trifluoromethyl-phenyl)-amide, 5-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -pyridine-2-carboxylic acid ,
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-fluoro-benzoic acid methyl ester,
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-chloro-benzoic acid methyl ester,
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -3-chloro-benzoic acid,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-2-fluoro-phenyl)-amide,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-2-methoxy-phenyl)-amide, 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2,5-difluoro-benzoic acid methyl ester, 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2,5-difluoro-benzoic acid,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3,5-difluoro-4-iodo-phenyl)-amide,
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2,6-difluoro-benzoic acid,
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-hydroxy-benzoic acid,
(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-3-methoxy-phenyl)-amide, (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-3-trifluoromethoxy-phenyl)-amide, (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-3-fluoro-phenyl)-amide, (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-2-chloro-phenyl)-amide,
4- {[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-fluoro-5-methoxy-benzoic acid methyl ester, 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-fluoro-5 -methoxy-benzoic acid,
2-(4-{[(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-4-methyl-pentanoic acid,
chiral 2-(4-{[(2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano- 5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-2-methyl-propionic acid methyl ester,
chiral 2-(4-{[(2i?,35,,4i?,55)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-
5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -phenyl)-2-methyl-propionic acid, chiral (25,,3i?,45,,5i?)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-( 1 -methyl- 1 -methylcarbamoyl-ethyl)-phenyl]- amide,
chiral (25,,3i?,45,,5i?)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid {4-[l -(3-hydroxy-propylcarbamoyl)- 1 -methyl- ethyl] -phenyl} amide, and
chiral (25',3i?,45,,5i?)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-( 1 -carbamoyl- 1 -methyl-ethyl)-phenyl]-amide .
7. The compound according to claim 3,
rac 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-nuoro-phenyl)-4-cyano-5- (2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino} -2-ethoxy-benzoic acid
8. The compound according to claim 3,
5-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-nuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazine-2-carboxylic acid.
9. The compound according to claim 3,
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid.
10. The compound according to claim 3,
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fiuoro-phenyl)-3-(3-chloro-2-fiuoro-phenyl)-4-cyano-5-(2,2- dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-trifiuoromethyl-benzoic acid.
11. A pharmaceutical preparation comprising a compound according to any one of claims 1 to 10 together with pharmaceutically acceptable excipients or carriers.
12. A compound according to any one of claims 1 to 10 for use as a medicament.
13. A compound according to any one of claims 1 to 10 for the use as a medicament for the treatment of cancer, in particular solid tumors, more particularly breast, colon, lung and prostate tumors.
14. The use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment of cancer, in particular solid tumors, more particularly .
15. The novel compounds, methods and uses substantially as described herein before.
***
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