JP2013507416A - Ｍｄｍ２−ｐ５３相互作用の阻害剤として新規なｎ−置換ピロリジン - Google Patents

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Publication number

JP2013507416A

JP2013507416A JP2012533592A JP2012533592A JP2013507416A JP 2013507416 A JP2013507416 A JP 2013507416A JP 2012533592 A JP2012533592 A JP 2012533592A JP 2012533592 A JP2012533592 A JP 2012533592A JP 2013507416 A JP2013507416 A JP 2013507416A

Authority

JP

Japan

Prior art keywords

phenyl

chloro

fluoro

coch

propyl

Prior art date

2009-10-14

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

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• -1 N-substituted pyrrolidines Chemical class 0.000 title claims description 582
• 230000003993 interaction Effects 0.000 title description 6
• 239000003112 inhibitor Substances 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 73
• 150000003839 salts Chemical class 0.000 claims abstract description 20
• 150000002148 esters Chemical class 0.000 claims abstract description 16
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 10
• 239000000203 mixture Substances 0.000 claims description 131
• 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 118
• 238000002360 preparation method Methods 0.000 claims description 74
• 125000000217 alkyl group Chemical group 0.000 claims description 73
• 125000001072 heteroaryl group Chemical group 0.000 claims description 65
• 125000000623 heterocyclic group Chemical group 0.000 claims description 61
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 51
• 125000003342 alkenyl group Chemical group 0.000 claims description 49
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 47
• 125000003118 aryl group Chemical group 0.000 claims description 39
• 229910052739 hydrogen Inorganic materials 0.000 claims description 37
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 33
• 229910052731 fluorine Inorganic materials 0.000 claims description 30
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 26
• 125000003107 substituted aryl group Chemical group 0.000 claims description 26
• 229910052801 chlorine Inorganic materials 0.000 claims description 24
• 239000005711 Benzoic acid Substances 0.000 claims description 23
• 229910052794 bromium Inorganic materials 0.000 claims description 21
• 239000001257 hydrogen Substances 0.000 claims description 18
• 125000003545 alkoxy group Chemical group 0.000 claims description 17
• 238000000034 method Methods 0.000 claims description 15
• 206010028980 Neoplasm Diseases 0.000 claims description 13
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
• 125000004122 cyclic group Chemical group 0.000 claims description 10
• 229910052740 iodine Inorganic materials 0.000 claims description 9
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 9
• SHNLZFBEQAPIJR-JJZKUNFFSA-N 4-[[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino]benzoic acid Chemical compound C1([C@H]2N(C[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)C(=O)NC=2C=CC(=CC=2)C(O)=O)=CC=CC(Cl)=C1F SHNLZFBEQAPIJR-JJZKUNFFSA-N 0.000 claims description 8
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 7
• 238000009472 formulation Methods 0.000 claims description 7
• 125000005842 heteroatom Chemical group 0.000 claims description 7
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
• RSSFCGHOFLWWST-VWQFJMCTSA-N 2-[(2s,3r,4s)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-2-(2,2-dimethylpropyl)pyrrolidin-1-yl]acetic acid Chemical compound C1([C@H]2CN(CC(O)=O)[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)=CC=CC(Cl)=C1F RSSFCGHOFLWWST-VWQFJMCTSA-N 0.000 claims description 6
• KCHLDNLIJVSRPK-UHFFFAOYSA-N 3-methylsulfanylaniline Chemical compound CSC1=CC=CC(N)=C1 KCHLDNLIJVSRPK-UHFFFAOYSA-N 0.000 claims description 6
• PYMXYOCBMHHCBC-QDSGMSMLSA-N 4-[[[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino]methyl]benzoic acid Chemical compound C1([C@H]2N(C[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)C(=O)NCC=2C=CC(=CC=2)C(O)=O)=CC=CC(Cl)=C1F PYMXYOCBMHHCBC-QDSGMSMLSA-N 0.000 claims description 6
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
• 125000001424 substituent group Chemical group 0.000 claims description 6
• PIOJBQYSLLLCKB-OSDUOIJGSA-N 2-[1-[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]piperidin-4-yl]acetic acid Chemical compound C1([C@H]2N(C[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)C(=O)N2CCC(CC(O)=O)CC2)=CC=CC(Cl)=C1F PIOJBQYSLLLCKB-OSDUOIJGSA-N 0.000 claims description 5
• GLAVWTBVMORNAA-SNMFSRKCSA-N 4-[[[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino]methyl]-2-fluorobenzoic acid Chemical compound C1([C@H]2N(C[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)C(=O)NCC=2C=C(F)C(C(O)=O)=CC=2)=CC=CC(Cl)=C1F GLAVWTBVMORNAA-SNMFSRKCSA-N 0.000 claims description 5
• RXAITFMEUYISKV-LRUBMJKJSA-N 4-[[[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino]methyl]cyclohexane-1-carboxylic acid Chemical compound C1([C@H]2N(C[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)C(=O)NCC2CCC(CC2)C(O)=O)=CC=CC(Cl)=C1F RXAITFMEUYISKV-LRUBMJKJSA-N 0.000 claims description 5
• KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 claims description 5
• 208000026310 Breast neoplasm Diseases 0.000 claims description 5
• 125000000304 alkynyl group Chemical group 0.000 claims description 5
• 210000000481 breast Anatomy 0.000 claims description 5
• 201000011510 cancer Diseases 0.000 claims description 5
• 210000001072 colon Anatomy 0.000 claims description 5
• 208000029742 colonic neoplasm Diseases 0.000 claims description 5
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
• XTQQSHXNTAMSFT-FLFAQTGJSA-N ethyl 2-[[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino]acetate Chemical compound C1([C@@H]2[C@](C#N)([C@H](CC(C)(C)C)CN2C(=O)NCC(=O)OCC)C=2C(=CC(Cl)=CC=2)F)=CC=CC(Cl)=C1F XTQQSHXNTAMSFT-FLFAQTGJSA-N 0.000 claims description 5
• PJCQBRDHXCFPPD-ZSRPKCNMSA-N ethyl 3-[[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino]propanoate Chemical compound C1([C@@H]2[C@](C#N)([C@H](CC(C)(C)C)CN2C(=O)NCCC(=O)OCC)C=2C(=CC(Cl)=CC=2)F)=CC=CC(Cl)=C1F PJCQBRDHXCFPPD-ZSRPKCNMSA-N 0.000 claims description 5
• 210000004072 lung Anatomy 0.000 claims description 5
• 208000037841 lung tumor Diseases 0.000 claims description 5
• 208000023958 prostate neoplasm Diseases 0.000 claims description 5
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 5
• ALVADNUZHVYQQH-DTQNUGEQSA-N (2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-n-[(3s)-3,4-dihydroxybutyl]-4-(2,2-dimethylpropyl)pyrrolidine-1-carboxamide Chemical compound C1([C@H]2N(C[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)C(=O)NCC[C@H](O)CO)=CC=CC(Cl)=C1F ALVADNUZHVYQQH-DTQNUGEQSA-N 0.000 claims description 4
• XPARFBOWIYMLMY-UHFFFAOYSA-N (6-chloropyridin-3-yl)methanamine Chemical compound NCC1=CC=C(Cl)N=C1 XPARFBOWIYMLMY-UHFFFAOYSA-N 0.000 claims description 4
• YLFWBYYEIGTMTF-UHFFFAOYSA-N 2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-4-(2,2-dimethylpropyl)-1-(6-oxo-1h-pyridine-3-carbonyl)pyrrolidine-3-carbonitrile Chemical compound C=1C=C(Cl)C=C(F)C=1C1(C#N)C(CC(C)(C)C)CN(C(=O)C2=CNC(=O)C=C2)C1C1=CC=CC(Cl)=C1F YLFWBYYEIGTMTF-UHFFFAOYSA-N 0.000 claims description 4
• AVFVBBGUKJGEOG-FUEHQLCJSA-N 2-[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidin-1-yl]acetamide Chemical compound C1([C@H]2N(CC(N)=O)C[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)=CC=CC(Cl)=C1F AVFVBBGUKJGEOG-FUEHQLCJSA-N 0.000 claims description 4
• UUACNRASSWGEJL-UQSXEEQZSA-N 2-[[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino]acetic acid Chemical compound C1([C@H]2N(C[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)C(=O)NCC(O)=O)=CC=CC(Cl)=C1F UUACNRASSWGEJL-UQSXEEQZSA-N 0.000 claims description 4
• CTJZMRMMDSWRIQ-KNJFRBFSSA-N 2-[[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino]benzoic acid Chemical compound C1([C@H]2N(C[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)C(=O)NC=2C(=CC=CC=2)C(O)=O)=CC=CC(Cl)=C1F CTJZMRMMDSWRIQ-KNJFRBFSSA-N 0.000 claims description 4
• FLGISLVJQPPAMV-UHFFFAOYSA-N 3-(2h-tetrazol-5-yl)aniline Chemical compound NC1=CC=CC(C2=NNN=N2)=C1 FLGISLVJQPPAMV-UHFFFAOYSA-N 0.000 claims description 4
• CENUAQYYKNQUJJ-MIBARKHLSA-N 3-[[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino]propanoic acid Chemical compound C1([C@H]2N(C[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)C(=O)NCCC(O)=O)=CC=CC(Cl)=C1F CENUAQYYKNQUJJ-MIBARKHLSA-N 0.000 claims description 4
• NJLYXKKGYFFTEX-YDIMZXDKSA-N 4-[[(2s,3r,4s)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-2-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino]benzoic acid Chemical compound C1([C@H]2CN([C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)C(=O)NC=2C=CC(=CC=2)C(O)=O)=CC=CC(Cl)=C1F NJLYXKKGYFFTEX-YDIMZXDKSA-N 0.000 claims description 4
• NVOJQMAVJVYBIW-FLFAQTGJSA-N 4-[[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino]butanoic acid Chemical compound C1([C@H]2N(C[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)C(=O)NCCCC(O)=O)=CC=CC(Cl)=C1F NVOJQMAVJVYBIW-FLFAQTGJSA-N 0.000 claims description 4
• GLAVWTBVMORNAA-UEVBBWJISA-N 4-[[[(2r,3r,4r)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino]methyl]-2-fluorobenzoic acid Chemical compound C1([C@@H]2N(C[C@@H]([C@@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)C(=O)NCC=2C=C(F)C(C(O)=O)=CC=2)=CC=CC(Cl)=C1F GLAVWTBVMORNAA-UEVBBWJISA-N 0.000 claims description 4
• NRYDHRPCHWVEDU-KFTYYEIZSA-N 4-[[[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino]methyl]-2-methoxybenzoic acid Chemical compound C1=C(C(O)=O)C(OC)=CC(CNC(=O)N2[C@@H]([C@](C#N)([C@H](CC(C)(C)C)C2)C=2C(=CC(Cl)=CC=2)F)C=2C(=C(Cl)C=CC=2)F)=C1 NRYDHRPCHWVEDU-KFTYYEIZSA-N 0.000 claims description 4
• AJINJXIRMANQBT-YFCBNTRVSA-N ethyl 4-[[(2s,3r,4s)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-2-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1NC(=O)N1[C@@H](CC(C)(C)C)[C@](C#N)(C=2C(=CC(Cl)=CC=2)F)[C@@H](C=2C(=C(Cl)C=CC=2)F)C1 AJINJXIRMANQBT-YFCBNTRVSA-N 0.000 claims description 4
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
• WUOFJTSVPNJJHP-RCYFZCHXSA-N methyl 4-[[[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino]methyl]cyclohexane-1-carboxylate Chemical compound C1CC(C(=O)OC)CCC1CNC(=O)N1[C@H](C=2C(=C(Cl)C=CC=2)F)[C@@](C#N)(C=2C(=CC(Cl)=CC=2)F)[C@H](CC(C)(C)C)C1 WUOFJTSVPNJJHP-RCYFZCHXSA-N 0.000 claims description 4
• 229920002554 vinyl polymer Polymers 0.000 claims description 4
• YMVFJGSXZNNUDW-UHFFFAOYSA-N (4-chlorophenyl)methanamine Chemical compound NCC1=CC=C(Cl)C=C1 YMVFJGSXZNNUDW-UHFFFAOYSA-N 0.000 claims description 3
• IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 claims description 3
• QTMFWQYTTCWLLT-UHFFFAOYSA-N 1-(3-aminopyrazol-1-yl)-2-methylpropan-2-ol Chemical compound CC(C)(O)CN1C=CC(N)=N1 QTMFWQYTTCWLLT-UHFFFAOYSA-N 0.000 claims description 3
• SUBAFJXQKOELMZ-UHFFFAOYSA-N 2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-1-(4-cyanobenzoyl)-4-(2,2-dimethylpropyl)pyrrolidine-3-carbonitrile Chemical compound C=1C=C(Cl)C=C(F)C=1C1(C#N)C(CC(C)(C)C)CN(C(=O)C=2C=CC(=CC=2)C#N)C1C1=CC=CC(Cl)=C1F SUBAFJXQKOELMZ-UHFFFAOYSA-N 0.000 claims description 3
• BYHQVMDIDMNIPM-UHFFFAOYSA-N 2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-4-(2,2-dimethylpropyl)-1-(1-methyl-6-oxopyridine-3-carbonyl)pyrrolidine-3-carbonitrile Chemical compound C1=CC(=O)N(C)C=C1C(=O)N1C(C=2C(=C(Cl)C=CC=2)F)C(C#N)(C=2C(=CC(Cl)=CC=2)F)C(CC(C)(C)C)C1 BYHQVMDIDMNIPM-UHFFFAOYSA-N 0.000 claims description 3
• HWLHXTTVEJAUOD-UHFFFAOYSA-N 2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-4-(2,2-dimethylpropyl)-1-(6-morpholin-4-ylpyridin-3-yl)sulfonylpyrrolidine-3-carbonitrile Chemical compound C=1C=C(Cl)C=C(F)C=1C1(C#N)C(CC(C)(C)C)CN(S(=O)(=O)C=2C=NC(=CC=2)N2CCOCC2)C1C1=CC=CC(Cl)=C1F HWLHXTTVEJAUOD-UHFFFAOYSA-N 0.000 claims description 3
• XQEMDTJMNKAECS-FUEHQLCJSA-N 2-[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidin-1-yl]acetic acid Chemical compound C1([C@H]2N(CC(O)=O)C[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)=CC=CC(Cl)=C1F XQEMDTJMNKAECS-FUEHQLCJSA-N 0.000 claims description 3
• UUYDPHCMCYSNAY-UHFFFAOYSA-N 2-amino-n-methylacetamide Chemical compound CNC(=O)CN UUYDPHCMCYSNAY-UHFFFAOYSA-N 0.000 claims description 3
• KMWJIUUVZAGJHS-ZFNFVVQQSA-N 3-(4-chloro-2-fluorophenyl)-2-(3-chlorophenyl)-3-cyano-n-[(3s)-3,4-dihydroxybutyl]-4-(2,2-dimethylpropyl)pyrrolidine-1-carboxamide Chemical compound C=1C=C(Cl)C=C(F)C=1C1(C#N)C(CC(C)(C)C)CN(C(=O)NCC[C@H](O)CO)C1C1=CC=CC(Cl)=C1 KMWJIUUVZAGJHS-ZFNFVVQQSA-N 0.000 claims description 3
• SVKVOIGLRQQTND-LBEFLKDASA-N 3-[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidin-1-yl]-3-oxopropanoic acid Chemical compound C1([C@H]2N(C[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)C(=O)CC(O)=O)=CC=CC(Cl)=C1F SVKVOIGLRQQTND-LBEFLKDASA-N 0.000 claims description 3
• ZYPGRMHSHJRQCR-GKLUMCFYSA-N 3-[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidin-1-yl]propanoic acid Chemical compound C1([C@H]2N(CCC(O)=O)C[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)=CC=CC(Cl)=C1F ZYPGRMHSHJRQCR-GKLUMCFYSA-N 0.000 claims description 3
• CPGQLEJKDXXCIW-UQKGSUGDSA-N 3-[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]benzoic acid Chemical compound C1([C@H]2N(C[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)C(=O)C=2C=C(C=CC=2)C(O)=O)=CC=CC(Cl)=C1F CPGQLEJKDXXCIW-UQKGSUGDSA-N 0.000 claims description 3
• JNDIDJUNNCBHTI-UHFFFAOYSA-N 3-amino-n,n-dimethylpropanamide Chemical compound CN(C)C(=O)CCN JNDIDJUNNCBHTI-UHFFFAOYSA-N 0.000 claims description 3
• BFJOJIJWHRDGQO-UHFFFAOYSA-N 3-amino-n-methylpropanamide Chemical compound CNC(=O)CCN BFJOJIJWHRDGQO-UHFFFAOYSA-N 0.000 claims description 3
• CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 claims description 3
• MBNPJRQKQLLRIS-UHFFFAOYSA-N 3-methylsulfonylaniline Chemical compound CS(=O)(=O)C1=CC=CC(N)=C1 MBNPJRQKQLLRIS-UHFFFAOYSA-N 0.000 claims description 3
• QIKYZXDTTPVVAC-UHFFFAOYSA-N 4-Aminobenzamide Chemical compound NC(=O)C1=CC=C(N)C=C1 QIKYZXDTTPVVAC-UHFFFAOYSA-N 0.000 claims description 3
• JGNUKPMTVPHSKR-UQKGSUGDSA-N 4-[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]benzamide Chemical compound C1([C@H]2N(C[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)C(=O)C=2C=CC(=CC=2)C(N)=O)=CC=CC(Cl)=C1F JGNUKPMTVPHSKR-UQKGSUGDSA-N 0.000 claims description 3
• AACJNVZEBPLKEZ-UQKGSUGDSA-N 4-[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]benzoic acid Chemical compound C1([C@H]2N(C[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)C(=O)C=2C=CC(=CC=2)C(O)=O)=CC=CC(Cl)=C1F AACJNVZEBPLKEZ-UQKGSUGDSA-N 0.000 claims description 3
• NCJGKNPUFHQWRG-JSSHLTTDSA-N 4-[2-[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidin-1-yl]-2-oxoethyl]-2-ethoxybenzoic acid Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N2[C@@H]([C@](C#N)([C@H](CC(C)(C)C)C2)C=2C(=CC(Cl)=CC=2)F)C=2C(=C(Cl)C=CC=2)F)=C1 NCJGKNPUFHQWRG-JSSHLTTDSA-N 0.000 claims description 3
• VZJWFOLUOITSOO-CCTXPWOESA-N 4-[4-[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidin-1-yl]-4-oxobutyl]benzoic acid Chemical compound C1([C@H]2N(C[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)C(=O)CCCC=2C=CC(=CC=2)C(O)=O)=CC=CC(Cl)=C1F VZJWFOLUOITSOO-CCTXPWOESA-N 0.000 claims description 3
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• HACXOVHECSPDLA-PNXLVOQQSA-N 4-[[2-[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidin-1-yl]acetyl]amino]benzoic acid Chemical compound C([C@H]([C@]([C@H]1C=2C(=C(Cl)C=CC=2)F)(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)N1CC(=O)NC1=CC=C(C(O)=O)C=C1 HACXOVHECSPDLA-PNXLVOQQSA-N 0.000 claims description 3
• NRYDHRPCHWVEDU-WZLZLLLYSA-N 4-[[[(2r,3r,4r)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino]methyl]-2-methoxybenzoic acid Chemical compound C1=C(C(O)=O)C(OC)=CC(CNC(=O)N2[C@H]([C@@](C#N)([C@@H](CC(C)(C)C)C2)C=2C(=CC(Cl)=CC=2)F)C=2C(=C(Cl)C=CC=2)F)=C1 NRYDHRPCHWVEDU-WZLZLLLYSA-N 0.000 claims description 3
• CRGNLDFNDMPVBN-UHFFFAOYSA-N 4-amino-1-methylpyridin-2-one Chemical compound CN1C=CC(N)=CC1=O CRGNLDFNDMPVBN-UHFFFAOYSA-N 0.000 claims description 3
• IJUCBGPQWGGYBV-UHFFFAOYSA-N 4-amino-n-methylbutanamide Chemical compound CNC(=O)CCCN IJUCBGPQWGGYBV-UHFFFAOYSA-N 0.000 claims description 3
• YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 claims description 3
• WCVPFJVXEXJFLB-UHFFFAOYSA-N 4-aminobutanamide Chemical compound NCCCC(N)=O WCVPFJVXEXJFLB-UHFFFAOYSA-N 0.000 claims description 3
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• QAJYCQZQLVENRZ-UHFFFAOYSA-N 6-chloropyridin-3-amine Chemical compound NC1=CC=C(Cl)N=C1 QAJYCQZQLVENRZ-UHFFFAOYSA-N 0.000 claims description 3
• RSDOASZYYCOXIB-UHFFFAOYSA-N beta-alaninamide Chemical compound NCCC(N)=O RSDOASZYYCOXIB-UHFFFAOYSA-N 0.000 claims description 3
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
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• GHAKQXXJLXLAHQ-RJEVLRCPSA-N ethyl 2-[1-[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]piperidin-4-yl]acetate Chemical compound C1CC(CC(=O)OCC)CCN1C(=O)N1[C@H](C=2C(=C(Cl)C=CC=2)F)[C@@](C#N)(C=2C(=CC(Cl)=CC=2)F)[C@H](CC(C)(C)C)C1 GHAKQXXJLXLAHQ-RJEVLRCPSA-N 0.000 claims description 3
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
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• ZZQNOWXIHUWSHD-CXUYDDCUSA-N methyl 4-[[[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino]methyl]-2-methoxybenzoate Chemical compound C1=C(OC)C(C(=O)OC)=CC=C1CNC(=O)N1[C@H](C=2C(=C(Cl)C=CC=2)F)[C@@](C#N)(C=2C(=CC(Cl)=CC=2)F)[C@H](CC(C)(C)C)C1 ZZQNOWXIHUWSHD-CXUYDDCUSA-N 0.000 claims description 3
• LTEKQAPRXFBRNN-UHFFFAOYSA-N piperidin-4-ylmethanamine Chemical compound NCC1CCNCC1 LTEKQAPRXFBRNN-UHFFFAOYSA-N 0.000 claims description 3
• RXHKYVIDEHAEEA-FPUALCIBSA-N tert-butyl 2-[(2s,3r,4s)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-2-(2,2-dimethylpropyl)pyrrolidin-1-yl]acetate Chemical compound C1([C@H]2CN(CC(=O)OC(C)(C)C)[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)=CC=CC(Cl)=C1F RXHKYVIDEHAEEA-FPUALCIBSA-N 0.000 claims description 3
• GVOQPISYQGYLLT-UHFFFAOYSA-N 2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)-n-(1-methylsulfonylpiperidin-4-yl)pyrrolidine-1-carboxamide Chemical compound C=1C=C(Cl)C=C(F)C=1C1(C#N)C(CC(C)(C)C)CN(C(=O)NC2CCN(CC2)S(C)(=O)=O)C1C1=CC=CC(Cl)=C1F GVOQPISYQGYLLT-UHFFFAOYSA-N 0.000 claims description 2
• NPLXQGYXOFMMFA-UHFFFAOYSA-N 2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-4-(2,2-dimethylpropyl)-1-(4-ethylpiperazine-1-carbonyl)pyrrolidine-3-carbonitrile Chemical compound C1CN(CC)CCN1C(=O)N1C(C=2C(=C(Cl)C=CC=2)F)C(C#N)(C=2C(=CC(Cl)=CC=2)F)C(CC(C)(C)C)C1 NPLXQGYXOFMMFA-UHFFFAOYSA-N 0.000 claims description 2
• XANGTOWFMYRPQT-UHFFFAOYSA-N 2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-4-(2,2-dimethylpropyl)-1-[(6-oxo-1h-pyridin-3-yl)sulfonyl]pyrrolidine-3-carbonitrile Chemical compound C=1C=C(Cl)C=C(F)C=1C1(C#N)C(CC(C)(C)C)CN(S(=O)(=O)C2=CNC(=O)C=C2)C1C1=CC=CC(Cl)=C1F XANGTOWFMYRPQT-UHFFFAOYSA-N 0.000 claims description 2
• IJXJYCXFZPXHKR-UHFFFAOYSA-N 2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-4-(2,2-dimethylpropyl)-1-pyridin-3-ylsulfonylpyrrolidine-3-carbonitrile Chemical compound C=1C=C(Cl)C=C(F)C=1C1(C#N)C(CC(C)(C)C)CN(S(=O)(=O)C=2C=NC=CC=2)C1C1=CC=CC(Cl)=C1F IJXJYCXFZPXHKR-UHFFFAOYSA-N 0.000 claims description 2
• BJZHXHVDACPRNF-RBJPJBLUSA-N 4-[[2-[(2s,3r,4s)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-2-(2,2-dimethylpropyl)pyrrolidin-1-yl]acetyl]amino]benzoic acid Chemical compound N1([C@H]([C@]([C@@H](C=2C(=C(Cl)C=CC=2)F)C1)(C#N)C=1C(=CC(Cl)=CC=1)F)CC(C)(C)C)CC(=O)NC1=CC=C(C(O)=O)C=C1 BJZHXHVDACPRNF-RBJPJBLUSA-N 0.000 claims description 2
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• IEJITTCGXVYJBB-YFCBNTRVSA-N methyl 4-[[2-[(2s,3r,4s)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-2-(2,2-dimethylpropyl)pyrrolidin-1-yl]acetyl]amino]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1NC(=O)CN1[C@@H](CC(C)(C)C)[C@](C#N)(C=2C(=CC(Cl)=CC=2)F)[C@@H](C=2C(=C(Cl)C=CC=2)F)C1 IEJITTCGXVYJBB-YFCBNTRVSA-N 0.000 claims description 2
• JAOFFPWNRPOIMQ-JSSHLTTDSA-N methyl 4-[[2-[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidin-1-yl]acetyl]amino]-2-methylbenzoate Chemical compound C1=C(C)C(C(=O)OC)=CC=C1NC(=O)CN1[C@H](C=2C(=C(Cl)C=CC=2)F)[C@@](C#N)(C=2C(=CC(Cl)=CC=2)F)[C@H](CC(C)(C)C)C1 JAOFFPWNRPOIMQ-JSSHLTTDSA-N 0.000 claims description 2
• MBBLQJNEOGCOMD-UXSLQZLDSA-N methyl 4-[[2-[(2s,3s,4s)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidin-1-yl]acetyl]amino]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1NC(=O)CN1[C@H](C=2C(=C(Cl)C=CC=2)F)[C@@](C#N)(C=2C(=CC(Cl)=CC=2)F)[C@H](CC(C)(C)C)C1 MBBLQJNEOGCOMD-UXSLQZLDSA-N 0.000 claims description 2
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