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US 9,809,545 B2Granted
Factor XIa inhibitors
AssigneeMerck Sharp & Dohme Corp.
InventorsAnthony Ogawa, Scott Edmondson, Mark Erion, Santhosh Neelamkavil, Zhuyan Guo, Rudrajit Mal, Jiafang He, Weiguo Liu, Ellen K. Vande Bunte
Life of this patent
Estimating the term…
Abstract
The present invention provides a compound of Formula (I) and pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing thromboses, embolisms, hypercoaguability or fibrotic changes.
Claims7
A compound of Formula I
- or a pharmaceutically acceptable salt thereof, where
- A is
- 1) 6-membered monocyclic carbocycle unsubstituted or mono-substituted with R3 or di-substituted with R3 and R4, or
- 2) 10-membered bicyclic carbocycle unsubstituted or substituted with R3;
- R1 is
- 1) C1-6 alkyl, or
- 2) 6-membered monocyclic carbocycle unsubstituted or substituted with R7;
- R1a is H or CH3;
- R2 is benzimidazole, which is unsubstituted or substituted with R16, R17 or R18;
- R3 is tetrazole;
- R4 is
- 1) —C(NH)NH2,
- 2) —NH2,
- 3) Halogen,
- 4) —C1-6 alkyl, unsubstituted or substituted with —OH, F or —NH2;
- 5) —C(O)OC1-6 alkyl,
- 6) —CF3,
- 7) —NO2,
- 8) —CN, or
- 9) —OC1-6 alkyl;
- R7 is halogen, —CF3 or —OCF3;
- R10 is
- 4-6-membered carbocycle either unsubstituted or substituted with —NHC(O)OH;
- R14 is C1-6 alkyl unsubstituted or substituted with —OH, —C6H5, or —((CH2)n—O)m—CH3, where m is 1 or 2 and n is 1 or 2;
- R16 is and R17 are each independently
- 1) 6-membered carbocycle unsubstituted or substituted with R20, or
- 2) 6-membered carbocycle unsubstituted or substituted with R19;
- R18 is
- 1) —C(O)OC1-6 alkyl,
- 2) —C(O)OH,
- 3) halogen,
- 4) —P(O)(OC1-6 alkyl)(OC1-6 alkyl),
- 5) —P(O)(OH)2,
- 6) —SO2C1-6 alkyl,
- 7) —CN,
- 8) —CF3,
- 9) —C(O)NHR10,
- 10) —NHC(O)OR14,
- 11) —NHC(O)R10, or
- 12) —P(O)(NHC1-6 alkyl)(NH C1-6 alkyl);
- R19 and R20 are each independently
- 1) halogen,
- 2) —SO2C1-6 alkyl,
- 3) —CF3,
- 4) —CN,
- 5) —OC1-6 alkyl,
- 6) —OCF3,
- 7) —C1-6 alkyl,
- 8) —C(O)NHR10,
- 9) —NHC(O)R10,
- 10) —P(O)(OH)2,
- 11) —P(O)(OC1-6 alkyl)(OC1-6 alkyl), or
- 12) —P(O)(NHC1-6 alkyl)(NH C1-6 alkyl).
50 more elements
A compound, or a pharmaceutically acceptable salt thereof, which is
- tert-butyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate,
- (S)-tert-butyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate,
- (R)-tert-butyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate,
- (S)-2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylic acid,
- methyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate,
- 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylic acid,
- 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(5-fluoro-1H-benzo[d]imidazol-2-yl)-2-(4-fluorophenyl)ethyl)pyridin-2(1H)-one,
- (S)-methyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate,
- (S)-ethyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazole-5-carboxylate,
- (S)-2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazole-5-carboxylic acid,
- (S)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(5-fluoro-1H-benzo[d]imidazol-2-yl)-2-(4-fluorophenyl)ethyl)pyridin-2(1H)-one,
- (S)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(5-bromo-1H-benzo[d]imidazol-2-yl)-2-(4-fluorophenyl)ethyl)pyridin-2(1H)-one,
- (R)-methyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylate,
- (R)-2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxylic acid,
- (R)-ethyl 2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazole-5-carboxylate,
- (R)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(5-fluoro-1H-benzo[d]imidazol-2-yl)-2-(4-fluorophenyl)ethyl)pyridin-2(1H)-one,
- (S)-diethyl (2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazol-5-yl)phosphonate,
- (S)-(2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazol-5-yl)phosphonic acid.
15 more elements
Dependencies are inferred from the claim text.