JP2019532052A5 - - Google Patents
Download PDFInfo
- Publication number
- JP2019532052A5 JP2019532052A5 JP2019515428A JP2019515428A JP2019532052A5 JP 2019532052 A5 JP2019532052 A5 JP 2019532052A5 JP 2019515428 A JP2019515428 A JP 2019515428A JP 2019515428 A JP2019515428 A JP 2019515428A JP 2019532052 A5 JP2019532052 A5 JP 2019532052A5
- Authority
- JP
- Japan
- Prior art keywords
- sulfonyl
- pyrrolidine
- hydroxymethyl
- hydroxy
- chloro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 125000000217 alkyl group Chemical group 0.000 claims description 76
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 39
- 125000001153 fluoro group Chemical group F* 0.000 claims description 31
- -1 -OH Chemical group 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 14
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 10
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 125000001246 bromo group Chemical group Br* 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- 150000003222 pyridines Chemical class 0.000 claims description 6
- 239000002464 receptor antagonist Substances 0.000 claims description 6
- 229940044551 receptor antagonist Drugs 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 5
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
- 229940125715 antihistaminic agent Drugs 0.000 claims description 4
- 239000000739 antihistaminic agent Substances 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 4
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 108090000312 Calcium Channels Proteins 0.000 claims description 3
- 102000003922 Calcium Channels Human genes 0.000 claims description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 3
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 claims description 3
- 239000000674 adrenergic antagonist Substances 0.000 claims description 3
- 239000002170 aldosterone antagonist Substances 0.000 claims description 3
- 229940083712 aldosterone antagonist Drugs 0.000 claims description 3
- 239000002876 beta blocker Substances 0.000 claims description 3
- 229940097320 beta blocking agent Drugs 0.000 claims description 3
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 claims description 3
- 239000000496 cardiotonic agent Substances 0.000 claims description 3
- 230000003177 cardiotonic effect Effects 0.000 claims description 3
- 239000002934 diuretic Substances 0.000 claims description 3
- 229940030606 diuretics Drugs 0.000 claims description 3
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 3
- 239000003149 muscarinic antagonist Substances 0.000 claims description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 3
- 239000002571 phosphodiesterase inhibitor Substances 0.000 claims description 3
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 claims description 3
- 239000002461 renin inhibitor Substances 0.000 claims description 3
- 229940086526 renin-inhibitors Drugs 0.000 claims description 3
- 230000003637 steroidlike Effects 0.000 claims description 3
- ANMOCXJIWTUCIZ-DZGCQCFKSA-N (3R,4S)-1-(2,4-dichlorophenyl)sulfonyl-3-(hydroxymethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]sulfonylpyrrolidin-3-ol Chemical compound ClC1=C(C=CC(=C1)Cl)S(=O)(=O)N1C[C@@]([C@H](C1)S(=O)(=O)C=1C=NC(=NC=1)C(F)(F)F)(O)CO ANMOCXJIWTUCIZ-DZGCQCFKSA-N 0.000 claims description 2
- QPAMCINKTNHHRX-GOEBONIOSA-N (3R,4S)-1-(2,4-dichlorophenyl)sulfonyl-3-(hydroxymethyl)-4-[5-(trifluoromethyl)pyridin-2-yl]sulfonylpyrrolidin-3-ol Chemical compound ClC1=C(S(=O)(=O)N2C[C@@H]([C@](O)(CO)C2)S(=O)(=O)C2=NC=C(C(F)(F)F)C=C2)C=CC(Cl)=C1 QPAMCINKTNHHRX-GOEBONIOSA-N 0.000 claims description 2
- REZAGHQSTJAQBB-JKSUJKDBSA-N (3R,4S)-1-(2,4-dichlorophenyl)sulfonyl-3-(hydroxymethyl)-4-[6-(trifluoromethyl)pyridin-3-yl]sulfonylpyrrolidin-3-ol Chemical compound ClC1=C(C=CC(=C1)Cl)S(=O)(=O)N1C[C@@]([C@H](C1)S(=O)(=O)C=1C=NC(=CC=1)C(F)(F)F)(O)CO REZAGHQSTJAQBB-JKSUJKDBSA-N 0.000 claims description 2
- JNLWUMKYPBFKIY-DLBZAZTESA-N (3R,4S)-1-(2,4-dichlorophenyl)sulfonyl-4-(3,4-dichlorophenyl)sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=C(C=CC(=C1)Cl)S(=O)(=O)N1C[C@@]([C@H](C1)S(=O)(=O)C1=CC(=C(C=C1)Cl)Cl)(O)CO JNLWUMKYPBFKIY-DLBZAZTESA-N 0.000 claims description 2
- KIHLXIWRTRLYFG-DLBZAZTESA-N (3R,4S)-1-(2,4-dichlorophenyl)sulfonyl-4-(3,4-difluorophenyl)sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=C(C=CC(=C1)Cl)S(=O)(=O)N1C[C@@]([C@H](C1)S(=O)(=O)C1=CC(=C(C=C1)F)F)(O)CO KIHLXIWRTRLYFG-DLBZAZTESA-N 0.000 claims description 2
- XSNUTFHJGMIWAF-DLBZAZTESA-N (3R,4S)-1-(2,4-dichlorophenyl)sulfonyl-4-(4-fluorophenyl)sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=C(S(=O)(=O)N2C[C@@H]([C@](O)(CO)C2)S(=O)(=O)C2=CC=C(F)C=C2)C=CC(Cl)=C1 XSNUTFHJGMIWAF-DLBZAZTESA-N 0.000 claims description 2
- PTLVPDPCSNZKNX-FUHWJXTLSA-N (3R,4S)-1-[2-chloro-4-(difluoromethyl)phenyl]sulfonyl-4-(4-chlorophenyl)sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=C(C=CC(=C1)C(F)F)S(=O)(=O)N1C[C@@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)Cl)(O)CO PTLVPDPCSNZKNX-FUHWJXTLSA-N 0.000 claims description 2
- STAOPFDANLGETD-ZWKOTPCHSA-N (3R,4S)-1-[2-chloro-4-(fluoromethyl)phenyl]sulfonyl-4-(4-chlorophenyl)sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=C(C=CC(=C1)CF)S(=O)(=O)N1C[C@@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)Cl)(O)CO STAOPFDANLGETD-ZWKOTPCHSA-N 0.000 claims description 2
- OBUCPEQOUPIOSM-FUHWJXTLSA-N (3R,4S)-1-[4-chloro-2-(difluoromethyl)phenyl]sulfonyl-4-(4-chlorophenyl)sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=CC(=C(C=C1)S(=O)(=O)N1C[C@@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)Cl)(O)CO)C(F)F OBUCPEQOUPIOSM-FUHWJXTLSA-N 0.000 claims description 2
- GSTYRNAIWRLWND-DLBZAZTESA-N (3R,4S)-4-(4-chloro-3-fluorophenyl)sulfonyl-1-(2,4-dichlorophenyl)sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=C(C=C(C=C1)S(=O)(=O)[C@@H]1[C@](CN(C1)S(=O)(=O)C1=C(C=C(C=C1)Cl)Cl)(O)CO)F GSTYRNAIWRLWND-DLBZAZTESA-N 0.000 claims description 2
- OKXWVBCXBOPICS-DLBZAZTESA-N (3R,4S)-4-(4-chlorophenyl)sulfonyl-1-(2,4-dichlorophenyl)sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)[C@@H]1[C@](CN(C1)S(=O)(=O)C1=C(C=C(C=C1)Cl)Cl)(O)CO OKXWVBCXBOPICS-DLBZAZTESA-N 0.000 claims description 2
- CQBTVINTBADUGP-WMLDXEAASA-N (3R,4S)-4-(4-chlorophenyl)sulfonyl-1-[2-(difluoromethoxy)pyridin-3-yl]sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)[C@@H]1[C@](CN(C1)S(=O)(=O)C=1C(=NC=CC=1)OC(F)F)(O)CO CQBTVINTBADUGP-WMLDXEAASA-N 0.000 claims description 2
- AEIKJQLTWFSJIE-DLBZAZTESA-N (3R,4S)-4-(4-chlorophenyl)sulfonyl-1-[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=C(C=CC(=C1)C(F)(F)F)S(=O)(=O)N1C[C@@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)Cl)(O)CO AEIKJQLTWFSJIE-DLBZAZTESA-N 0.000 claims description 2
- JNLWUMKYPBFKIY-IRXDYDNUSA-N (3S,4S)-1-(2,4-dichlorophenyl)sulfonyl-4-(3,4-dichlorophenyl)sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=C(C=CC(=C1)Cl)S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC(=C(C=C1)Cl)Cl)(O)CO JNLWUMKYPBFKIY-IRXDYDNUSA-N 0.000 claims description 2
- GSTYRNAIWRLWND-IRXDYDNUSA-N (3S,4S)-4-(4-chloro-3-fluorophenyl)sulfonyl-1-(2,4-dichlorophenyl)sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=C(C=C(C=C1)S(=O)(=O)[C@@H]1[C@@](CN(C1)S(=O)(=O)C1=C(C=C(C=C1)Cl)Cl)(O)CO)F GSTYRNAIWRLWND-IRXDYDNUSA-N 0.000 claims description 2
- SOZGHDCEWOLLHV-UHFFFAOYSA-N 2-(trifluoromethyl)benzonitrile Chemical compound FC(F)(F)C1=CC=CC=C1C#N SOZGHDCEWOLLHV-UHFFFAOYSA-N 0.000 claims description 2
- UWTJDYHOXXQPKF-ZWKOTPCHSA-N 2-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-[4-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound O[C@]1(CN(C[C@@H]1S(=O)(=O)C1=CC=C(C=C1)C(F)(F)F)S(=O)(=O)C1=C(C#N)C=CC=C1)CO UWTJDYHOXXQPKF-ZWKOTPCHSA-N 0.000 claims description 2
- WSLYBDGLOOWRKV-ZWKOTPCHSA-N 2-[(3R,4S)-4-(3,4-difluorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl-5-(trifluoromethyl)benzonitrile Chemical compound FC=1C=C(C=CC=1F)S(=O)(=O)[C@@H]1[C@@](CN(C1)S(=O)(=O)C1=C(C#N)C=C(C=C1)C(F)(F)F)(CO)O WSLYBDGLOOWRKV-ZWKOTPCHSA-N 0.000 claims description 2
- NYSOYBHHKXZKAL-ZWKOTPCHSA-N 2-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl-5-(trifluoromethyl)benzonitrile Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)[C@@H]1[C@@](CN(C1)S(=O)(=O)C1=C(C#N)C=C(C=C1)C(F)(F)F)(CO)O NYSOYBHHKXZKAL-ZWKOTPCHSA-N 0.000 claims description 2
- FIUMIWMDAREBLP-ZWKOTPCHSA-N 2-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)[C@@H]1[C@@](CN(C1)S(=O)(=O)C1=C(C#N)C=CC=C1)(CO)O FIUMIWMDAREBLP-ZWKOTPCHSA-N 0.000 claims description 2
- DPLMOBXRUYGQCI-RBUKOAKNSA-N 2-[5-chloro-2-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylphenyl]acetonitrile Chemical compound C1(CC#N)=C(S(=O)(=O)N2C[C@@H]([C@](O)(CO)C2)S(=O)(=O)C2=CC=C(Cl)C=C2)C=CC(Cl)=C1 DPLMOBXRUYGQCI-RBUKOAKNSA-N 0.000 claims description 2
- LLOZHKBBVRPYFI-ZWKOTPCHSA-N 2-chloro-4-[(3S,4R)-1-[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound ClC1=C(C#N)C=CC(=C1)S(=O)(=O)[C@H]1CN(C[C@]1(CO)O)S(=O)(=O)C1=C(C=C(C=C1)C(F)(F)F)Cl LLOZHKBBVRPYFI-ZWKOTPCHSA-N 0.000 claims description 2
- LLOZHKBBVRPYFI-ROUUACIJSA-N 2-chloro-4-[(3S,4S)-1-[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound ClC1=C(C#N)C=CC(=C1)S(=O)(=O)[C@H]1CN(C[C@@]1(CO)O)S(=O)(=O)C1=C(C=C(C=C1)C(F)(F)F)Cl LLOZHKBBVRPYFI-ROUUACIJSA-N 0.000 claims description 2
- FSNDSLDYIRAFSN-ZWKOTPCHSA-N 2-chloro-5-[(3S,4R)-1-(2,4-dichlorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound ClC1=C(C#N)C=C(C=C1)S(=O)(=O)[C@H]1CN(C[C@]1(CO)O)S(=O)(=O)C1=C(C=C(C=C1)Cl)Cl FSNDSLDYIRAFSN-ZWKOTPCHSA-N 0.000 claims description 2
- SFFRVAPGBGVILI-RBUKOAKNSA-N 2-fluoro-4-[(3S,4R)-4-hydroxy-4-(hydroxymethyl)-1-[2-methyl-4-(trifluoromethyl)phenyl]sulfonylpyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound FC1=C(C#N)C=CC(=C1)S(=O)(=O)[C@H]1CN(C[C@]1(CO)O)S(=O)(=O)C1=C(C=C(C=C1)C(F)(F)F)C SFFRVAPGBGVILI-RBUKOAKNSA-N 0.000 claims description 2
- JAIRADVACRBDQL-PKOBYXMFSA-N 3-(difluoromethyl)-4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-[4-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound FC(C=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)C(F)(F)F)(CO)O)F JAIRADVACRBDQL-PKOBYXMFSA-N 0.000 claims description 2
- VQECCCDKLOYTPX-DLBZAZTESA-N 3-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylpyridine-2-carbonitrile Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)[C@@H]1[C@@](CN(C1)S(=O)(=O)C=1C(=NC=CC=1)C#N)(CO)O VQECCCDKLOYTPX-DLBZAZTESA-N 0.000 claims description 2
- LPRYGAJXDSKREY-DLBZAZTESA-N 3-bromo-4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-[6-(trifluoromethyl)pyridin-3-yl]sulfonylpyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound BrC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C=1C=NC(=CC=1)C(F)(F)F)(CO)O LPRYGAJXDSKREY-DLBZAZTESA-N 0.000 claims description 2
- QFSCTDUWWDFTPR-ZWKOTPCHSA-N 3-bromo-4-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound BrC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)Cl)(CO)O QFSCTDUWWDFTPR-ZWKOTPCHSA-N 0.000 claims description 2
- CBMYAGOITHXBFI-DZGCQCFKSA-N 3-chloro-4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-(1,3-thiazol-2-ylsulfonyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C=1SC=CN=1)(CO)O CBMYAGOITHXBFI-DZGCQCFKSA-N 0.000 claims description 2
- JZGRQLRHWWZWLY-LEWJYISDSA-N 3-chloro-4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-(4-propan-2-ylphenyl)sulfonylpyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)C(C)C)(CO)O JZGRQLRHWWZWLY-LEWJYISDSA-N 0.000 claims description 2
- DTDUDPJQNDVLRF-LEWJYISDSA-N 3-chloro-4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-(4-propylphenyl)sulfonylpyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)CCC)(CO)O DTDUDPJQNDVLRF-LEWJYISDSA-N 0.000 claims description 2
- IVGDETGKDIXXTN-GOEBONIOSA-N 3-chloro-4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]sulfonylpyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C=1C=NC(=NC=1)C(F)(F)F)(CO)O IVGDETGKDIXXTN-GOEBONIOSA-N 0.000 claims description 2
- HTTGTURMCLWJTN-ZWKOTPCHSA-N 3-chloro-4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-[4-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)C(F)(F)F)(CO)O HTTGTURMCLWJTN-ZWKOTPCHSA-N 0.000 claims description 2
- LVILWSRKTWZYMY-DOTOQJQBSA-N 3-chloro-4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-[5-(trifluoromethyl)pyridin-2-yl]sulfonylpyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=NC=C(C=C1)C(F)(F)F)(CO)O LVILWSRKTWZYMY-DOTOQJQBSA-N 0.000 claims description 2
- NAZBDWWLJWHYMF-DLBZAZTESA-N 3-chloro-4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-[6-(trifluoromethyl)pyridin-3-yl]sulfonylpyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C=1C=NC(=CC=1)C(F)(F)F)(CO)O NAZBDWWLJWHYMF-DLBZAZTESA-N 0.000 claims description 2
- FTRZGPXZCAQDIT-ZWKOTPCHSA-N 3-chloro-4-[(3R,4S)-4-(4-chloro-3-fluorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC(=C(C=C1)Cl)F)(CO)O FTRZGPXZCAQDIT-ZWKOTPCHSA-N 0.000 claims description 2
- TUADROHZTJLERW-ZWKOTPCHSA-N 3-chloro-4-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)Cl)(CO)O TUADROHZTJLERW-ZWKOTPCHSA-N 0.000 claims description 2
- OCGZBKOXQIVIBD-RBUKOAKNSA-N 3-chloro-4-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-[(2,2,2-trifluoroethylamino)methyl]pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)Cl)(CNCC(F)(F)F)O OCGZBKOXQIVIBD-RBUKOAKNSA-N 0.000 claims description 2
- SDNLCTDHVZERAD-RBUKOAKNSA-N 3-chloro-4-[(3R,4S)-4-(4-cyano-3-fluorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC1=C(S(=O)(=O)N2C[C@@H]([C@](O)(CO)C2)S(=O)(=O)C2=CC=C(C(=C2)F)C#N)C=CC(C#N)=C1 SDNLCTDHVZERAD-RBUKOAKNSA-N 0.000 claims description 2
- OUYMKZPBVOUUOB-RBUKOAKNSA-N 3-chloro-4-[(3R,4S)-4-(4-cyanophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)C#N)(CO)O OUYMKZPBVOUUOB-RBUKOAKNSA-N 0.000 claims description 2
- IZJPABZLKVAUDI-VQTJNVASSA-N 3-chloro-4-[(3R,4S)-4-(4-ethylphenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)CC)(CO)O IZJPABZLKVAUDI-VQTJNVASSA-N 0.000 claims description 2
- GZYAXDICQLQUQT-DOTOQJQBSA-N 3-chloro-4-[(3R,4S)-4-(5-chloropyridin-2-yl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound OC[C@]1(O)CN(C[C@@H]1S(=O)(=O)c1ccc(Cl)cn1)S(=O)(=O)c1ccc(cc1Cl)C#N GZYAXDICQLQUQT-DOTOQJQBSA-N 0.000 claims description 2
- AXYMMJGNAINGBL-SWLSCSKDSA-N 3-chloro-4-[(3R,4S)-4-[(5-chloro-1,3-thiazol-2-yl)sulfonyl]-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C=1SC(=CN=1)Cl)(CO)O AXYMMJGNAINGBL-SWLSCSKDSA-N 0.000 claims description 2
- TUADROHZTJLERW-ROUUACIJSA-N 3-chloro-4-[(3S,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)Cl)(CO)O TUADROHZTJLERW-ROUUACIJSA-N 0.000 claims description 2
- GTAKMFSILLVNEH-OALUTQOASA-N 3-chloro-4-[(3S,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(methylaminomethyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)Cl)(CNC)O GTAKMFSILLVNEH-OALUTQOASA-N 0.000 claims description 2
- SDNLCTDHVZERAD-OALUTQOASA-N 3-chloro-4-[(3S,4S)-4-(4-cyano-3-fluorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC1=C(C=CC(=C1)C#N)S(=O)(=O)N1C[C@@H]([C@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C=C1)F SDNLCTDHVZERAD-OALUTQOASA-N 0.000 claims description 2
- GZYAXDICQLQUQT-RDJZCZTQSA-N 3-chloro-4-[(3S,4S)-4-(5-chloropyridin-2-yl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@@]([C@H](C1)S(=O)(=O)C1=NC=C(C=C1)Cl)(CO)O GZYAXDICQLQUQT-RDJZCZTQSA-N 0.000 claims description 2
- VBCCMDFPDDJZNJ-LEWJYISDSA-N 3-cyclopropyloxy-4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-[4-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound C1(CC1)OC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)C(F)(F)F)(CO)O VBCCMDFPDDJZNJ-LEWJYISDSA-N 0.000 claims description 2
- TVOGDPWVBCCZIN-ZWKOTPCHSA-N 4-[(3R,4S)-3-(aminomethyl)-4-(4-chlorophenyl)sulfonyl-3-hydroxypyrrolidin-1-yl]sulfonyl-3-chlorobenzonitrile Chemical compound NC[C@]1(CN(C[C@@H]1S(=O)(=O)C1=CC=C(C=C1)Cl)S(=O)(=O)C1=C(C=C(C#N)C=C1)Cl)O TVOGDPWVBCCZIN-ZWKOTPCHSA-N 0.000 claims description 2
- AVVFJEZVPHMSAF-ZWKOTPCHSA-N 4-[(3R,4S)-3-(aminomethyl)-4-(4-chlorophenyl)sulfonyl-3-hydroxypyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound NC[C@]1(CN(C[C@@H]1S(=O)(=O)C1=CC=C(C=C1)Cl)S(=O)(=O)C1=CC=C(C#N)C=C1)O AVVFJEZVPHMSAF-ZWKOTPCHSA-N 0.000 claims description 2
- WLVZWRUVPREQAW-DOTOQJQBSA-N 4-[(3R,4S)-3-(aminomethyl)-4-(5-chloropyridin-2-yl)sulfonyl-3-hydroxypyrrolidin-1-yl]sulfonyl-3-chlorobenzonitrile Chemical compound NC[C@]1(CN(C[C@@H]1S(=O)(=O)C1=NC=C(C=C1)Cl)S(=O)(=O)C1=C(C=C(C#N)C=C1)Cl)O WLVZWRUVPREQAW-DOTOQJQBSA-N 0.000 claims description 2
- JEBCCMTXPLKGHB-RBUKOAKNSA-N 4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-[4-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]sulfonyl-3-methoxybenzonitrile Chemical compound O[C@]1(CN(C[C@@H]1S(=O)(=O)C1=CC=C(C=C1)C(F)(F)F)S(=O)(=O)C1=C(C=C(C#N)C=C1)OC)CO JEBCCMTXPLKGHB-RBUKOAKNSA-N 0.000 claims description 2
- LMRYYYAOZLUANZ-DLBZAZTESA-N 4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-[6-(trifluoromethyl)pyridin-3-yl]sulfonylpyrrolidin-1-yl]sulfonyl-3-(trifluoromethyl)benzonitrile Chemical compound O[C@]1(CN(C[C@@H]1S(=O)(=O)C=1C=NC(=CC=1)C(F)(F)F)S(=O)(=O)C1=C(C=C(C#N)C=C1)C(F)(F)F)CO LMRYYYAOZLUANZ-DLBZAZTESA-N 0.000 claims description 2
- UOLCQJALMSULDJ-ZWKOTPCHSA-N 4-[(3R,4S)-4-(4-bromophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl-3-chlorobenzonitrile Chemical compound BrC1=CC=C(C=C1)S(=O)(=O)[C@@H]1[C@@](CN(C1)S(=O)(=O)C1=C(C=C(C#N)C=C1)Cl)(CO)O UOLCQJALMSULDJ-ZWKOTPCHSA-N 0.000 claims description 2
- XWWXAXPFKCSTCT-PKOBYXMFSA-N 4-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl-3-(difluoromethyl)benzonitrile Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)[C@@H]1[C@@](CN(C1)S(=O)(=O)C1=C(C=C(C#N)C=C1)C(F)F)(CO)O XWWXAXPFKCSTCT-PKOBYXMFSA-N 0.000 claims description 2
- IOTUXRBCFFEFQD-ZWKOTPCHSA-N 4-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl-3-(trifluoromethyl)benzonitrile Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)[C@@H]1[C@@](CN(C1)S(=O)(=O)C1=C(C=C(C#N)C=C1)C(F)(F)F)(CO)O IOTUXRBCFFEFQD-ZWKOTPCHSA-N 0.000 claims description 2
- WAOCGEXSWRBBAK-LEWJYISDSA-N 4-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl-3-cyclopropyloxybenzonitrile Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)[C@@H]1[C@@](CN(C1)S(=O)(=O)C1=C(C=C(C#N)C=C1)OC1CC1)(CO)O WAOCGEXSWRBBAK-LEWJYISDSA-N 0.000 claims description 2
- ANYGWCNXKAHNPD-VQTJNVASSA-N 4-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl-3-ethoxybenzonitrile Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)[C@@H]1[C@@](CN(C1)S(=O)(=O)C1=C(C=C(C#N)C=C1)OCC)(CO)O ANYGWCNXKAHNPD-VQTJNVASSA-N 0.000 claims description 2
- MICKGXNXBATLIV-VQTJNVASSA-N 4-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl-3-ethylbenzonitrile Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)[C@@H]1[C@@](CN(C1)S(=O)(=O)C1=C(C=C(C#N)C=C1)CC)(CO)O MICKGXNXBATLIV-VQTJNVASSA-N 0.000 claims description 2
- AHSPTXYKWPCGJF-ZWKOTPCHSA-N 4-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl-3-fluorobenzonitrile Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)[C@@H]1[C@@](CN(C1)S(=O)(=O)C1=C(C=C(C#N)C=C1)F)(CO)O AHSPTXYKWPCGJF-ZWKOTPCHSA-N 0.000 claims description 2
- YUJTYBDLQGOXPQ-RBUKOAKNSA-N 4-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl-3-methoxybenzonitrile Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)[C@@H]1[C@@](CN(C1)S(=O)(=O)C1=C(C=C(C#N)C=C1)OC)(CO)O YUJTYBDLQGOXPQ-RBUKOAKNSA-N 0.000 claims description 2
- JLEAWYRBJIZQBA-RBUKOAKNSA-N 4-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl-3-methylbenzonitrile Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)[C@@H]1[C@@](CN(C1)S(=O)(=O)C1=C(C=C(C#N)C=C1)C)(CO)O JLEAWYRBJIZQBA-RBUKOAKNSA-N 0.000 claims description 2
- HFHFGSWWOZIHDF-VQTJNVASSA-N 4-[(3R,4S)-4-(4-cyano-3-fluorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl-3-methylbenzonitrile Chemical compound C(#N)C1=CC(=C(C=C1)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C=C1)F)C HFHFGSWWOZIHDF-VQTJNVASSA-N 0.000 claims description 2
- BZVUOGHVUJKCCG-DOTOQJQBSA-N 4-[(3R,4S)-4-(5-bromopyridin-2-yl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl-3-chlorobenzonitrile Chemical compound BrC=1C=CC(=NC=1)S(=O)(=O)[C@@H]1[C@@](CN(C1)S(=O)(=O)C1=C(C=C(C#N)C=C1)Cl)(CO)O BZVUOGHVUJKCCG-DOTOQJQBSA-N 0.000 claims description 2
- MHKZHEOHDLHROZ-ZWKOTPCHSA-N 4-[(3S,4R)-1-(2,4-dichloro-5-fluorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-2-fluorobenzonitrile Chemical compound ClC1=C(C=C(C(=C1)Cl)F)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C=C1)F MHKZHEOHDLHROZ-ZWKOTPCHSA-N 0.000 claims description 2
- YFMZBDZZLQCOEJ-ZWKOTPCHSA-N 4-[(3S,4R)-1-(2,4-dichloro-5-fluorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound ClC1=C(C=C(C(=C1)Cl)F)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC=C(C#N)C=C1 YFMZBDZZLQCOEJ-ZWKOTPCHSA-N 0.000 claims description 2
- MBOKWXSQDMUDLG-ZWKOTPCHSA-N 4-[(3S,4R)-1-(2,4-dichlorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-2,5-difluorobenzonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C=C1F)F MBOKWXSQDMUDLG-ZWKOTPCHSA-N 0.000 claims description 2
- JYOSLWOOCLLKSB-ZWKOTPCHSA-N 4-[(3S,4R)-1-(2,4-dichlorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-2,6-difluorobenzonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C(=C1)F)F JYOSLWOOCLLKSB-ZWKOTPCHSA-N 0.000 claims description 2
- RYDOPOXKOPOTSC-ZWKOTPCHSA-N 4-[(3S,4R)-1-(2,4-dichlorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-2-fluorobenzonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C=C1)F RYDOPOXKOPOTSC-ZWKOTPCHSA-N 0.000 claims description 2
- UHEHCPQUIPNCEE-ZWKOTPCHSA-N 4-[(3S,4R)-1-(2,4-dichlorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-3-fluorobenzonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=C(C=C(C#N)C=C1)F UHEHCPQUIPNCEE-ZWKOTPCHSA-N 0.000 claims description 2
- SWZJRWKRFKLVKK-ZWKOTPCHSA-N 4-[(3S,4R)-1-(2,4-dichlorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC=C(C#N)C=C1 SWZJRWKRFKLVKK-ZWKOTPCHSA-N 0.000 claims description 2
- XEKCJGISXPWGKF-ZWKOTPCHSA-N 4-[(3S,4R)-1-(2-bromo-4-chlorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound BrC1=C(C=CC(=C1)Cl)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC=C(C#N)C=C1 XEKCJGISXPWGKF-ZWKOTPCHSA-N 0.000 claims description 2
- XFPOFQCBDWTJTL-ZWKOTPCHSA-N 4-[(3S,4R)-1-(2-bromo-4-fluorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound BrC1=C(C=CC(=C1)F)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC=C(C#N)C=C1 XFPOFQCBDWTJTL-ZWKOTPCHSA-N 0.000 claims description 2
- JPGKXYAOPFHGBP-RBUKOAKNSA-N 4-[(3S,4R)-1-(2-bromo-4-methoxyphenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound BrC1=C(C=CC(=C1)OC)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC=C(C#N)C=C1 JPGKXYAOPFHGBP-RBUKOAKNSA-N 0.000 claims description 2
- CWBMDHWZAZTIAO-ZWKOTPCHSA-N 4-[(3S,4R)-1-(2-bromophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound BrC1=C(C=CC=C1)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC=C(C#N)C=C1 CWBMDHWZAZTIAO-ZWKOTPCHSA-N 0.000 claims description 2
- GKIPSWGBCAWVFH-ZWKOTPCHSA-N 4-[(3S,4R)-1-(2-chloro-4-fluorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-2-fluorobenzonitrile Chemical compound ClC1=C(C=CC(=C1)F)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C=C1)F GKIPSWGBCAWVFH-ZWKOTPCHSA-N 0.000 claims description 2
- WPDDOIFYDLBQPK-ZWKOTPCHSA-N 4-[(3S,4R)-1-(2-chloro-4-fluorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound ClC1=C(C=CC(=C1)F)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC=C(C#N)C=C1 WPDDOIFYDLBQPK-ZWKOTPCHSA-N 0.000 claims description 2
- ZLTUGVYBROGBCR-RBUKOAKNSA-N 4-[(3S,4R)-1-(2-chloro-4-methylphenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-2-fluorobenzonitrile Chemical compound ClC1=C(C=CC(=C1)C)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C=C1)F ZLTUGVYBROGBCR-RBUKOAKNSA-N 0.000 claims description 2
- UHFBMUAHSSJYCK-RBUKOAKNSA-N 4-[(3S,4R)-1-(2-chloro-4-methylphenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound ClC1=C(C=CC(=C1)C)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC=C(C#N)C=C1 UHFBMUAHSSJYCK-RBUKOAKNSA-N 0.000 claims description 2
- RZFNYGDTBWMKNF-ZWKOTPCHSA-N 4-[(3S,4R)-1-(2-chlorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-2-fluorobenzonitrile Chemical compound ClC1=C(C=CC=C1)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C=C1)F RZFNYGDTBWMKNF-ZWKOTPCHSA-N 0.000 claims description 2
- CHGZFXRPUQCTND-ZWKOTPCHSA-N 4-[(3S,4R)-1-(4-bromo-2-chlorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound BrC1=CC(=C(C=C1)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC=C(C#N)C=C1)Cl CHGZFXRPUQCTND-ZWKOTPCHSA-N 0.000 claims description 2
- CYZYMVVPOMCONK-RBUKOAKNSA-N 4-[(3S,4R)-1-(4-bromo-2-methoxyphenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound BrC1=CC(=C(C=C1)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC=C(C#N)C=C1)OC CYZYMVVPOMCONK-RBUKOAKNSA-N 0.000 claims description 2
- BUDDEEIVQCSBIC-RBUKOAKNSA-N 4-[(3S,4R)-1-(4-chloro-2-methoxyphenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound ClC1=CC(=C(C=C1)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC=C(C#N)C=C1)OC BUDDEEIVQCSBIC-RBUKOAKNSA-N 0.000 claims description 2
- KLDORZKBRAMSGC-ZWKOTPCHSA-N 4-[(3S,4R)-1-[2-bromo-4-(trifluoromethyl)phenyl]sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound BrC1=C(C=CC(=C1)C(F)(F)F)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC=C(C#N)C=C1 KLDORZKBRAMSGC-ZWKOTPCHSA-N 0.000 claims description 2
- YZXUWCAJCXQEQM-PKOBYXMFSA-N 4-[(3S,4R)-1-[2-chloro-4-(difluoromethyl)phenyl]sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound ClC1=C(C=CC(=C1)C(F)F)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC=C(C#N)C=C1 YZXUWCAJCXQEQM-PKOBYXMFSA-N 0.000 claims description 2
- IGNIHCLXWKJWHX-RBUKOAKNSA-N 4-[(3S,4R)-1-[2-chloro-4-(fluoromethyl)phenyl]sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound ClC1=C(C=CC(=C1)CF)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC=C(C#N)C=C1 IGNIHCLXWKJWHX-RBUKOAKNSA-N 0.000 claims description 2
- RVBNPRFWFFYKFN-ZWKOTPCHSA-N 4-[(3S,4R)-1-[2-chloro-4-(trifluoromethoxy)phenyl]sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-2-fluorobenzonitrile Chemical compound ClC1=C(C=CC(=C1)OC(F)(F)F)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C=C1)F RVBNPRFWFFYKFN-ZWKOTPCHSA-N 0.000 claims description 2
- SGQZXHGBJZOIKQ-ZWKOTPCHSA-N 4-[(3S,4R)-1-[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-2,6-difluorobenzonitrile Chemical compound ClC1=C(C=CC(=C1)C(F)(F)F)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C(=C1)F)F SGQZXHGBJZOIKQ-ZWKOTPCHSA-N 0.000 claims description 2
- RIIRSYQSUSJVQL-ZWKOTPCHSA-N 4-[(3S,4R)-1-[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-2-fluorobenzonitrile Chemical compound ClC1=C(C=CC(=C1)C(F)(F)F)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C=C1)F RIIRSYQSUSJVQL-ZWKOTPCHSA-N 0.000 claims description 2
- AGFDILFTPCPVRN-RBUKOAKNSA-N 4-[(3S,4R)-1-[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-2-methylbenzonitrile Chemical compound ClC1=C(C=CC(=C1)C(F)(F)F)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C=C1)C AGFDILFTPCPVRN-RBUKOAKNSA-N 0.000 claims description 2
- VWSBHJZBCFFWAR-ZWKOTPCHSA-N 4-[(3S,4R)-1-[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound ClC1=C(C=CC(=C1)C(F)(F)F)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC=C(C#N)C=C1 VWSBHJZBCFFWAR-ZWKOTPCHSA-N 0.000 claims description 2
- JWWXOVKRDMRSIL-ZWKOTPCHSA-N 4-[(3S,4R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound FC1=C(C=CC(=C1)C(F)(F)F)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC=C(C#N)C=C1 JWWXOVKRDMRSIL-ZWKOTPCHSA-N 0.000 claims description 2
- FWOCJLFVQULDHX-ZWKOTPCHSA-N 4-[(3S,4R)-1-[4-bromo-2-(trifluoromethyl)phenyl]sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound BrC1=CC(=C(C=C1)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC=C(C#N)C=C1)C(F)(F)F FWOCJLFVQULDHX-ZWKOTPCHSA-N 0.000 claims description 2
- YPFXUGUPNYZMPQ-ZWKOTPCHSA-N 4-[(3S,4R)-1-[4-chloro-2-(trifluoromethyl)phenyl]sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound ClC1=CC(=C(C=C1)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC=C(C#N)C=C1)C(F)(F)F YPFXUGUPNYZMPQ-ZWKOTPCHSA-N 0.000 claims description 2
- JROYPEPGQNHMNP-ZWKOTPCHSA-N 4-[(3S,4R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound FC1=CC(=C(C=C1)S(=O)(=O)N1C[C@@H]([C@@](C1)(CO)O)S(=O)(=O)C1=CC=C(C#N)C=C1)C(F)(F)F JROYPEPGQNHMNP-ZWKOTPCHSA-N 0.000 claims description 2
- RTJFFTRLEGEYNZ-ZWKOTPCHSA-N 4-[(3S,4R)-4-hydroxy-4-(hydroxymethyl)-1-[2-(trifluoromethyl)phenyl]sulfonylpyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound O[C@@]1([C@H](CN(C1)S(=O)(=O)C1=C(C=CC=C1)C(F)(F)F)S(=O)(=O)C1=CC=C(C#N)C=C1)CO RTJFFTRLEGEYNZ-ZWKOTPCHSA-N 0.000 claims description 2
- CORVAEADVOGRMJ-RBUKOAKNSA-N 4-[(3S,4R)-4-hydroxy-4-(hydroxymethyl)-1-[2-methyl-4-(trifluoromethyl)phenyl]sulfonylpyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound O[C@@]1([C@H](CN(C1)S(=O)(=O)C1=C(C=C(C=C1)C(F)(F)F)C)S(=O)(=O)C1=CC=C(C#N)C=C1)CO CORVAEADVOGRMJ-RBUKOAKNSA-N 0.000 claims description 2
- WHRUOODKQGORGW-RBUKOAKNSA-N 4-[(3S,4R)-4-hydroxy-4-(hydroxymethyl)-1-[4-methoxy-2-(trifluoromethyl)phenyl]sulfonylpyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound O[C@@]1([C@H](CN(C1)S(=O)(=O)C1=C(C=C(C=C1)OC)C(F)(F)F)S(=O)(=O)C1=CC=C(C#N)C=C1)CO WHRUOODKQGORGW-RBUKOAKNSA-N 0.000 claims description 2
- MHKZHEOHDLHROZ-ROUUACIJSA-N 4-[(3S,4S)-1-(2,4-dichloro-5-fluorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-2-fluorobenzonitrile Chemical compound ClC1=C(C=C(C(=C1)Cl)F)S(=O)(=O)N1C[C@@H]([C@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C=C1)F MHKZHEOHDLHROZ-ROUUACIJSA-N 0.000 claims description 2
- MBOKWXSQDMUDLG-ROUUACIJSA-N 4-[(3S,4S)-1-(2,4-dichlorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-2,5-difluorobenzonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)S(=O)(=O)N1C[C@@H]([C@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C=C1F)F MBOKWXSQDMUDLG-ROUUACIJSA-N 0.000 claims description 2
- RYDOPOXKOPOTSC-ROUUACIJSA-N 4-[(3S,4S)-1-(2,4-dichlorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-2-fluorobenzonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)S(=O)(=O)N1C[C@@H]([C@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C=C1)F RYDOPOXKOPOTSC-ROUUACIJSA-N 0.000 claims description 2
- GKIPSWGBCAWVFH-ROUUACIJSA-N 4-[(3S,4S)-1-(2-chloro-4-fluorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-2-fluorobenzonitrile Chemical compound ClC1=C(C=CC(=C1)F)S(=O)(=O)N1C[C@@H]([C@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C=C1)F GKIPSWGBCAWVFH-ROUUACIJSA-N 0.000 claims description 2
- ZLTUGVYBROGBCR-OALUTQOASA-N 4-[(3S,4S)-1-(2-chloro-4-methylphenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-2-fluorobenzonitrile Chemical compound ClC1=C(C=CC(=C1)C)S(=O)(=O)N1C[C@@H]([C@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C=C1)F ZLTUGVYBROGBCR-OALUTQOASA-N 0.000 claims description 2
- RZFNYGDTBWMKNF-ROUUACIJSA-N 4-[(3S,4S)-1-(2-chlorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-2-fluorobenzonitrile Chemical compound ClC1=C(C=CC=C1)S(=O)(=O)N1C[C@@H]([C@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C=C1)F RZFNYGDTBWMKNF-ROUUACIJSA-N 0.000 claims description 2
- RVBNPRFWFFYKFN-ROUUACIJSA-N 4-[(3S,4S)-1-[2-chloro-4-(trifluoromethoxy)phenyl]sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-2-fluorobenzonitrile Chemical compound ClC1=C(C=CC(=C1)OC(F)(F)F)S(=O)(=O)N1C[C@@H]([C@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C=C1)F RVBNPRFWFFYKFN-ROUUACIJSA-N 0.000 claims description 2
- RIIRSYQSUSJVQL-ROUUACIJSA-N 4-[(3S,4S)-1-[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-2-fluorobenzonitrile Chemical compound ClC1=C(C=CC(=C1)C(F)(F)F)S(=O)(=O)N1C[C@@H]([C@](C1)(CO)O)S(=O)(=O)C1=CC(=C(C#N)C=C1)F RIIRSYQSUSJVQL-ROUUACIJSA-N 0.000 claims description 2
- VWSBHJZBCFFWAR-ROUUACIJSA-N 4-[(3S,4S)-1-[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound ClC1=C(C=CC(=C1)C(F)(F)F)S(=O)(=O)N1C[C@@H]([C@](C1)(CO)O)S(=O)(=O)C1=CC=C(C#N)C=C1 VWSBHJZBCFFWAR-ROUUACIJSA-N 0.000 claims description 2
- TVOGDPWVBCCZIN-ROUUACIJSA-N 4-[(3S,4S)-3-(aminomethyl)-4-(4-chlorophenyl)sulfonyl-3-hydroxypyrrolidin-1-yl]sulfonyl-3-chlorobenzonitrile Chemical compound NC[C@@]1(CN(C[C@@H]1S(=O)(=O)C1=CC=C(C=C1)Cl)S(=O)(=O)C1=C(C=C(C#N)C=C1)Cl)O TVOGDPWVBCCZIN-ROUUACIJSA-N 0.000 claims description 2
- AVVFJEZVPHMSAF-ROUUACIJSA-N 4-[(3S,4S)-3-(aminomethyl)-4-(4-chlorophenyl)sulfonyl-3-hydroxypyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound NC[C@@]1(CN(C[C@@H]1S(=O)(=O)C1=CC=C(C=C1)Cl)S(=O)(=O)C1=CC=C(C#N)C=C1)O AVVFJEZVPHMSAF-ROUUACIJSA-N 0.000 claims description 2
- WLVZWRUVPREQAW-RDJZCZTQSA-N 4-[(3S,4S)-3-(aminomethyl)-4-(5-chloropyridin-2-yl)sulfonyl-3-hydroxypyrrolidin-1-yl]sulfonyl-3-chlorobenzonitrile Chemical compound NC[C@@]1(CN(C[C@@H]1S(=O)(=O)C1=NC=C(C=C1)Cl)S(=O)(=O)C1=C(C=C(C#N)C=C1)Cl)O WLVZWRUVPREQAW-RDJZCZTQSA-N 0.000 claims description 2
- UOLCQJALMSULDJ-ROUUACIJSA-N 4-[(3S,4S)-4-(4-bromophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl-3-chlorobenzonitrile Chemical compound BrC1=CC=C(C=C1)S(=O)(=O)[C@@H]1[C@](CN(C1)S(=O)(=O)C1=C(C=C(C#N)C=C1)Cl)(CO)O UOLCQJALMSULDJ-ROUUACIJSA-N 0.000 claims description 2
- BZVUOGHVUJKCCG-RDJZCZTQSA-N 4-[(3S,4S)-4-(5-bromopyridin-2-yl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl-3-chlorobenzonitrile Chemical compound BrC=1C=CC(=NC=1)S(=O)(=O)[C@@H]1[C@](CN(C1)S(=O)(=O)C1=C(C=C(C#N)C=C1)Cl)(CO)O BZVUOGHVUJKCCG-RDJZCZTQSA-N 0.000 claims description 2
- LGYWSNCVXQFPGN-DLBZAZTESA-N 5-chloro-2-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-[6-(trifluoromethyl)pyridin-3-yl]sulfonylpyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=CC(=C(C#N)C=1)S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C=1C=NC(=CC=1)C(F)(F)F)(CO)O LGYWSNCVXQFPGN-DLBZAZTESA-N 0.000 claims description 2
- CMZUBDHMHFQVFV-ZWKOTPCHSA-N 5-chloro-2-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=CC(=C(C#N)C=1)S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)Cl)(CO)O CMZUBDHMHFQVFV-ZWKOTPCHSA-N 0.000 claims description 2
- ZMDZJAAMFDJBFF-RBUKOAKNSA-N 5-chloro-2-[(3R,4S)-4-(4-cyanophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=CC(=C(C#N)C=1)S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)C#N)(CO)O ZMDZJAAMFDJBFF-RBUKOAKNSA-N 0.000 claims description 2
- 102000003567 TRPV4 Human genes 0.000 claims description 2
- 101150098315 TRPV4 gene Proteins 0.000 claims description 2
- 102000030619 alpha-1 Adrenergic Receptor Human genes 0.000 claims description 2
- 108020004102 alpha-1 Adrenergic Receptor Proteins 0.000 claims description 2
- 239000005557 antagonist Substances 0.000 claims description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 claims description 2
- 102000012740 beta Adrenergic Receptors Human genes 0.000 claims description 2
- 108010079452 beta Adrenergic Receptors Proteins 0.000 claims description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 2
- 229940095102 methyl benzoate Drugs 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 108091006073 receptor regulators Proteins 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 20
- 125000004043 oxo group Chemical group O=* 0.000 claims 17
- 206010011224 Cough Diseases 0.000 claims 16
- 206010030113 Oedema Diseases 0.000 claims 12
- 208000002551 irritable bowel syndrome Diseases 0.000 claims 12
- 125000001072 heteroaryl group Chemical group 0.000 claims 10
- 125000003118 aryl group Chemical group 0.000 claims 9
- 206010007559 Cardiac failure congestive Diseases 0.000 claims 8
- 125000003545 alkoxy group Chemical group 0.000 claims 8
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims 6
- 208000002193 Pain Diseases 0.000 claims 6
- 208000003251 Pruritus Diseases 0.000 claims 6
- 230000000968 intestinal effect Effects 0.000 claims 6
- 208000005264 motor neuron disease Diseases 0.000 claims 6
- SBUKLPSBNFWJCU-UHFFFAOYSA-N ClIBr Chemical compound ClIBr SBUKLPSBNFWJCU-UHFFFAOYSA-N 0.000 claims 5
- 206010019280 Heart failures Diseases 0.000 claims 5
- 208000004852 Lung Injury Diseases 0.000 claims 5
- 206010069363 Traumatic lung injury Diseases 0.000 claims 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims 5
- 231100000515 lung injury Toxicity 0.000 claims 5
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims 4
- 206010048962 Brain oedema Diseases 0.000 claims 4
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims 4
- 206010069351 acute lung injury Diseases 0.000 claims 4
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims 4
- 208000006752 brain edema Diseases 0.000 claims 4
- 208000013116 chronic cough Diseases 0.000 claims 4
- 208000024827 Alzheimer disease Diseases 0.000 claims 3
- 201000001320 Atherosclerosis Diseases 0.000 claims 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims 3
- 208000015943 Coeliac disease Diseases 0.000 claims 3
- 206010010774 Constipation Diseases 0.000 claims 3
- 208000011231 Crohn disease Diseases 0.000 claims 3
- 208000026292 Cystic Kidney disease Diseases 0.000 claims 3
- 201000004624 Dermatitis Diseases 0.000 claims 3
- 206010012735 Diarrhoea Diseases 0.000 claims 3
- 201000009273 Endometriosis Diseases 0.000 claims 3
- 206010016807 Fluid retention Diseases 0.000 claims 3
- 208000010412 Glaucoma Diseases 0.000 claims 3
- 208000035202 High altitude pulmonary edema Diseases 0.000 claims 3
- 206010020772 Hypertension Diseases 0.000 claims 3
- 206010062016 Immunosuppression Diseases 0.000 claims 3
- 206010021639 Incontinence Diseases 0.000 claims 3
- 206010061218 Inflammation Diseases 0.000 claims 3
- 201000010538 Lactose Intolerance Diseases 0.000 claims 3
- 208000019695 Migraine disease Diseases 0.000 claims 3
- 208000008589 Obesity Diseases 0.000 claims 3
- 206010033645 Pancreatitis Diseases 0.000 claims 3
- 208000017442 Retinal disease Diseases 0.000 claims 3
- 206010038923 Retinopathy Diseases 0.000 claims 3
- 206010040047 Sepsis Diseases 0.000 claims 3
- 208000005392 Spasm Diseases 0.000 claims 3
- 208000006011 Stroke Diseases 0.000 claims 3
- 230000001154 acute effect Effects 0.000 claims 3
- 230000002491 angiogenic effect Effects 0.000 claims 3
- 208000006673 asthma Diseases 0.000 claims 3
- 210000000988 bone and bone Anatomy 0.000 claims 3
- 230000001684 chronic effect Effects 0.000 claims 3
- 208000019425 cirrhosis of liver Diseases 0.000 claims 3
- 206010009887 colitis Diseases 0.000 claims 3
- 201000003146 cystitis Diseases 0.000 claims 3
- 206010012601 diabetes mellitus Diseases 0.000 claims 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 3
- 208000035475 disorder Diseases 0.000 claims 3
- 230000004064 dysfunction Effects 0.000 claims 3
- 208000003906 hydrocephalus Diseases 0.000 claims 3
- 230000001506 immunosuppresive effect Effects 0.000 claims 3
- 230000004054 inflammatory process Effects 0.000 claims 3
- 208000037805 labour Diseases 0.000 claims 3
- 201000010901 lateral sclerosis Diseases 0.000 claims 3
- 208000019423 liver disease Diseases 0.000 claims 3
- 208000030159 metabolic disease Diseases 0.000 claims 3
- 206010027599 migraine Diseases 0.000 claims 3
- 201000006417 multiple sclerosis Diseases 0.000 claims 3
- 230000003387 muscular Effects 0.000 claims 3
- 235000020824 obesity Nutrition 0.000 claims 3
- 201000008482 osteoarthritis Diseases 0.000 claims 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims 3
- 230000002980 postoperative effect Effects 0.000 claims 3
- 208000005069 pulmonary fibrosis Diseases 0.000 claims 3
- 208000002815 pulmonary hypertension Diseases 0.000 claims 3
- 206010039083 rhinitis Diseases 0.000 claims 3
- 201000009890 sinusitis Diseases 0.000 claims 3
- 230000009885 systemic effect Effects 0.000 claims 3
- 230000005760 tumorsuppression Effects 0.000 claims 3
- 206010003445 Ascites Diseases 0.000 claims 2
- 208000026372 Congenital cystic kidney disease Diseases 0.000 claims 2
- 206010052139 Eye oedema Diseases 0.000 claims 2
- 241000282412 Homo Species 0.000 claims 2
- 206010020751 Hypersensitivity Diseases 0.000 claims 2
- 230000003187 abdominal effect Effects 0.000 claims 2
- 208000026935 allergic disease Diseases 0.000 claims 2
- 230000003247 decreasing effect Effects 0.000 claims 2
- 230000009610 hypersensitivity Effects 0.000 claims 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 2
- 230000001575 pathological effect Effects 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 230000004044 response Effects 0.000 claims 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims 1
- 208000019693 Lung disease Diseases 0.000 claims 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 229910021419 crystalline silicon Inorganic materials 0.000 claims 1
- 230000000694 effects Effects 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 150000002617 leukotrienes Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 208000007232 portal hypertension Diseases 0.000 claims 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 4
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 4
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 4
- NGNJLTRNLNSMJQ-UHFFFAOYSA-N CC(C)(OC1)OC1(CN(C1)C(O)=O)C1S(C(C=C1)=CC=C1C#N)(=O)=O Chemical compound CC(C)(OC1)OC1(CN(C1)C(O)=O)C1S(C(C=C1)=CC=C1C#N)(=O)=O NGNJLTRNLNSMJQ-UHFFFAOYSA-N 0.000 description 2
- 239000003199 leukotriene receptor blocking agent Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- BJCWKEUJFNATJV-PKOBYXMFSA-N 3-chloro-4-[[(4S,5R)-4-(5-chloropyridin-2-yl)sulfonyl-6-oxa-2,9-diazaspiro[4.5]decan-2-yl]sulfonyl]benzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]2([C@H](C1)S(=O)(=O)C1=NC=C(C=C1)Cl)OCCNC2 BJCWKEUJFNATJV-PKOBYXMFSA-N 0.000 description 1
- UCTWMZQNUQWSLP-UHFFFAOYSA-N Adrenaline Natural products CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 1
- 102000004136 Vasopressin Receptors Human genes 0.000 description 1
- 108090000643 Vasopressin Receptors Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662397008P | 2016-09-20 | 2016-09-20 | |
| US62/397,008 | 2016-09-20 | ||
| US201762482300P | 2017-04-06 | 2017-04-06 | |
| US62/482,300 | 2017-04-06 | ||
| PCT/IB2017/055702 WO2018055526A1 (en) | 2016-09-20 | 2017-09-20 | Trpv4 antagonists |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2019532052A JP2019532052A (ja) | 2019-11-07 |
| JP2019532052A5 true JP2019532052A5 (enExample) | 2021-02-12 |
| JP7106528B2 JP7106528B2 (ja) | 2022-07-26 |
Family
ID=60084021
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2019515428A Active JP7106528B2 (ja) | 2016-09-20 | 2017-09-20 | Ｔｒｐｖ４拮抗薬 |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US11260049B2 (enExample) |
| EP (1) | EP3515888B1 (enExample) |
| JP (1) | JP7106528B2 (enExample) |
| KR (1) | KR20190049865A (enExample) |
| CN (1) | CN109790116B (enExample) |
| AU (1) | AU2017330620A1 (enExample) |
| CA (1) | CA3036933A1 (enExample) |
| ES (1) | ES2877763T3 (enExample) |
| RU (1) | RU2019110821A (enExample) |
| WO (1) | WO2018055526A1 (enExample) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10590077B2 (en) | 2016-09-20 | 2020-03-17 | Glaxosmithkline Intellectual Property Development Limited | TRPV4 antagonists |
| TW201825458A (zh) | 2016-09-20 | 2018-07-16 | 英商葛蘭素史克智慧財產（第二）有限公司 | Ｔｒｐｖ４拮抗劑 |
| TWI878266B (zh) | 2019-02-15 | 2025-04-01 | 愛爾蘭商博士倫愛爾蘭有限公司 | 治療眼表痛之方法 |
| JP6994061B2 (ja) | 2019-02-15 | 2022-01-14 | ノバルティス アーゲー | ４－（７－ヒドロキシ－２－イソプロピル－４－オキソ－４ｈ－キナゾリン－３－イル）－ベンゾニトリルの製剤 |
| CN110407721A (zh) * | 2019-08-13 | 2019-11-05 | 上海毕得医药科技有限公司 | 一种4-氰基-3-(三氟甲基)苯-1-磺酰氯的合成方法 |
| CA3180132A1 (en) | 2020-04-30 | 2021-10-30 | Raqualia Pharma Inc. | Pyrimidin-4(3h)-one derivatives as trpv4 antagonists |
| CN115776890A (zh) | 2020-07-16 | 2023-03-10 | 拉夸里亚创药株式会社 | 作为眼病治疗剂的trpv4抑制剂 |
| CN112500419A (zh) * | 2020-11-23 | 2021-03-16 | 浙大城市学院 | 一种环氧稠合的2-亚甲基吡咯烷类化合物及其制备方法 |
| CN114058694A (zh) * | 2021-11-29 | 2022-02-18 | 上海市普陀区中心医院 | Trpv1在筛选或制备预防、缓解和/或治疗肝脏疾病的药物中的应用 |
Family Cites Families (38)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CY1308A (en) | 1979-12-06 | 1985-12-06 | Glaxo Group Ltd | Device for dispensing medicaments |
| ATE23272T1 (de) | 1981-07-08 | 1986-11-15 | Draco Ab | Pulverinhalator. |
| PT77471B (en) | 1982-10-08 | 1986-08-19 | Glaxo Group Ltd | Devices for administering medicaments to patients |
| US4778054A (en) | 1982-10-08 | 1988-10-18 | Glaxo Group Limited | Pack for administering medicaments to patients |
| GB2169265B (en) | 1982-10-08 | 1987-08-12 | Glaxo Group Ltd | Pack for medicament |
| CA1272917A (en) | 1985-07-30 | 1990-08-21 | Paul Kenneth Rand | Devices for administering medicaments to patients |
| GB9004781D0 (en) | 1990-03-02 | 1990-04-25 | Glaxo Group Ltd | Device |
| HU213221B (en) | 1990-03-02 | 1997-03-28 | Glaxo Group Ltd | Inhalation device and medicine packet for device |
| US6536427B2 (en) | 1990-03-02 | 2003-03-25 | Glaxo Group Limited | Inhalation device |
| ES2201318T3 (es) | 1996-08-28 | 2004-03-16 | THE PROCTER & GAMBLE COMPANY | Inhibidores de metaloproteasas de aminas ciclicas substituidas. |
| GB9700226D0 (en) | 1997-01-08 | 1997-02-26 | Glaxo Group Ltd | Inhalation device |
| WO2003050154A2 (en) | 2001-12-06 | 2003-06-19 | Cornell Research Foundation, Inc. | Catalytic carbonylation of three and four membered heterocycles |
| GB0201677D0 (en) | 2002-01-25 | 2002-03-13 | Glaxo Group Ltd | Medicament dispenser |
| JP4969238B2 (ja) | 2003-03-27 | 2012-07-04 | サイトキネティクス・インコーポレーテッド | 化合物、組成物および方法 |
| GB0317374D0 (en) | 2003-07-24 | 2003-08-27 | Glaxo Group Ltd | Medicament dispenser |
| PL1730676T3 (pl) | 2004-02-16 | 2014-04-30 | Glaxo Group Ltd | Licznik do stosowania z dozownikiem leku |
| AR048523A1 (es) | 2004-04-07 | 2006-05-03 | Kalypsys Inc | Compuestos con estructura de aril sulfonamida y sulfonilo como moduladores de ppar y metodos para tratar trastornos metabolicos |
| CN101103027A (zh) | 2004-04-28 | 2008-01-09 | 默克公司 | 3,3-二取代四氢吡喃基环戊基酰胺趋化因子受体活性调节剂 |
| EP1758884A2 (en) | 2004-05-20 | 2007-03-07 | Elan Pharmaceuticals, Inc. | N-cyclic sulfonamido inhibitors of gamma secretase |
| CN1329374C (zh) | 2004-06-09 | 2007-08-01 | 上海靶点药物有限公司 | 作为ccr5拮抗剂的化合物 |
| US20080064736A1 (en) | 2004-07-12 | 2008-03-13 | Bayer Cropscience Ag | Substituted 2-Pyrrolidone Derivatives as Fungicides and Insecticides |
| GB0418278D0 (en) | 2004-08-16 | 2004-09-15 | Glaxo Group Ltd | Medicament dispenser |
| DOP2006000010A (es) | 2005-01-10 | 2006-07-31 | Arena Pharm Inc | Procedimiento para preparar eteres aromáticos |
| GB0515584D0 (en) | 2005-07-28 | 2005-09-07 | Glaxo Group Ltd | Medicament dispenser |
| AR058289A1 (es) | 2005-12-12 | 2008-01-30 | Glaxo Group Ltd | Colector para ser usado en dispensador de medicamento |
| AR058558A1 (es) | 2005-12-21 | 2008-02-13 | Schering Corp | Derivados de anilina sustituida utiles como antagonistas de la histamina h3 |
| US20090012011A1 (en) * | 2006-01-11 | 2009-01-08 | Smithkline Beecham Corporation | Novel Compounds |
| BRPI0713119A2 (pt) | 2006-06-30 | 2012-04-17 | Schering Corp | piperidinas substituìdas que aumentam a atividade de p53 e os usos destas |
| US20080176861A1 (en) | 2007-01-23 | 2008-07-24 | Kalypsys, Inc. | Sulfonyl-substituted bicyclic compounds as ppar modulators for the treatment of non-alcoholic steatohepatitis |
| US20110046199A1 (en) | 2008-01-17 | 2011-02-24 | Purdue Research Foundation | Small molecule inhibitors of hiv proteases |
| MX2010013876A (es) | 2008-06-20 | 2011-03-04 | Metabolex Inc | Agonistas de arilo grpr119 y sus usos . |
| SG11201503556PA (en) | 2012-11-16 | 2015-06-29 | Bristol Myers Squibb Co | Dihydropyrazole gpr40 modulators |
| EP2970121B1 (en) | 2013-03-15 | 2017-12-13 | Araxes Pharma LLC | Covalent inhibitors of kras g12c |
| AU2014230122A1 (en) | 2013-03-15 | 2015-08-06 | AbbVie Deutschland GmbH & Co. KG | Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy |
| JP6272832B2 (ja) | 2013-04-04 | 2018-01-31 | 武田薬品工業株式会社 | 複素環化合物 |
| BR112017002001B1 (pt) | 2014-07-31 | 2022-10-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Compostos e composição farmacêutica |
| US10590077B2 (en) | 2016-09-20 | 2020-03-17 | Glaxosmithkline Intellectual Property Development Limited | TRPV4 antagonists |
| TW201825458A (zh) | 2016-09-20 | 2018-07-16 | 英商葛蘭素史克智慧財產（第二）有限公司 | Ｔｒｐｖ４拮抗劑 |
-
2017
- 2017-09-20 AU AU2017330620A patent/AU2017330620A1/en not_active Abandoned
- 2017-09-20 RU RU2019110821A patent/RU2019110821A/ru not_active Application Discontinuation
- 2017-09-20 CA CA3036933A patent/CA3036933A1/en active Pending
- 2017-09-20 JP JP2019515428A patent/JP7106528B2/ja active Active
- 2017-09-20 WO PCT/IB2017/055702 patent/WO2018055526A1/en not_active Ceased
- 2017-09-20 KR KR1020197010953A patent/KR20190049865A/ko not_active Withdrawn
- 2017-09-20 EP EP17784401.6A patent/EP3515888B1/en active Active
- 2017-09-20 US US16/334,400 patent/US11260049B2/en active Active
- 2017-09-20 ES ES17784401T patent/ES2877763T3/es active Active
- 2017-09-20 CN CN201780057911.XA patent/CN109790116B/zh active Active
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2019532052A5 (enExample) | ||
| JP2019529443A5 (enExample) | ||
| JP2019532054A5 (enExample) | ||
| RU2019111882A (ru) | Антагонисты trpv4 | |
| HRP20171913T1 (hr) | Aminopirimidinilni spojevi kao inhibitori jak | |
| JP2018510857A5 (enExample) | ||
| JP2017511794A5 (enExample) | ||
| JP2013523710A5 (enExample) | ||
| JP2010518026A5 (enExample) | ||
| RU2015139590A (ru) | ИНГИБИРУЮЩЕЕ Trk СОЕДИНЕНИЕ | |
| JP2016526576A5 (enExample) | ||
| RU2019110821A (ru) | Антагонисты trpv4 | |
| JP7701473B2 (ja) | Ｌｐａ受容体アンタゴニスト及びそれらの使用 | |
| JP6353530B2 (ja) | キナーゼ阻害剤として有用なカルバゾールカルボキサミド化合物 | |
| JP2017515844A5 (enExample) | ||
| JP2017125037A (ja) | イミダゾピロリジノン化合物 | |
| JP2014500322A5 (enExample) | ||
| JP2020506171A5 (enExample) | ||
| JP2019505541A5 (enExample) | ||
| JP2008222557A (ja) | ピロロ［３，２−ｄ］ピリミジン誘導体及びこれを有効成分とする医薬組成物 | |
| AU2024202860A1 (en) | Metalloenzyme inhibitor compounds | |
| JP2013519724A5 (enExample) | ||
| RU2009133846A (ru) | Новые производные гидантоина в качестве ингибиторов металлопротеиназ | |
| JP2013523814A5 (enExample) | ||
| JP2017519023A5 (enExample) |