Factor XIa inhibitors
View Patent ↗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.
1. A compound of Formula I
or a pharmaceutically acceptable salt thereof, where
A is
1) 6-membered monocyclic carbocycle unsubstituted or mono-substituted with R 3 or di-substituted with R 3 and R 4 , or
2) 10-membered bicyclic carbocycle unsubstituted or substituted with R 3 ;
R 1 is
1) C 1-6 alkyl, or
2) 6-membered monocyclic carbocycle unsubstituted or substituted with R 7 ;
R 1a is H or CH 3 ;
R 2 is benzimidazole, which is unsubstituted or substituted with R 16 , R 17 or R 18 ;
R 3 is tetrazole;
R 4 is
1) —C(NH)NH 2 ,
2) —NH 2 ,
3) Halogen,
4) —C 1-6 alkyl, unsubstituted or substituted with —OH, F or —NH 2 ;
5) —C(O)OC 1-6 alkyl,
6) —CF 3 ,
7) —NO 2 ,
8) —CN, or
9) —OC 1-6 alkyl;
R 7 is halogen, —CF 3 or —OCF 3 ;
R 10 is
4-6-membered carbocycle either unsubstituted or substituted with —NHC(O)OH;
R 14 is C 1-6 alkyl unsubstituted or substituted with —OH, —C 6 H 5 , or —((CH 2 ) n —O) m —CH 3 , where m is 1 or 2 and n is 1 or 2;
R 16 is and R 17 are each independently
1) 6-membered carbocycle unsubstituted or substituted with R 20 , or
2) 6-membered carbocycle unsubstituted or substituted with R 19 ;
R 18 is
1) —C(O)OC 1-6 alkyl,
2) —C(O)OH,
3) halogen,
4) —P(O)(OC 1-6 alkyl)(OC 1-6 alkyl),
5) —P(O)(OH) 2 ,
6) —SO 2 C 1-6 alkyl,
7) —CN,
8) —CF 3 ,
9) —C(O)NHR 10 ,
10) —NHC(O)OR 14 ,
11) —NHC(O)R 10 , or
12) —P(O)(NHC 1-6 alkyl)(NH C 1-6 alkyl);
R 19 and R 20 are each independently
1) halogen,
2) —SO 2 C 1-6 alkyl,
3) —CF 3 ,
4) —CN,
5) —OC 1-6 alkyl,
6) —OCF 3 ,
7) —C 1-6 alkyl,
8) —C(O)NHR 10 ,
9) —NHC(O)R 10 ,
10) —P(O)(OH) 2 ,
11) —P(O)(OC 1-6 alkyl)(OC 1-6 alkyl), or
12) —P(O)(NHC 1-6 alkyl)(NH C 1-6 alkyl).
2. A compound of claim 1 or a pharmaceutically acceptable salt thereof, where
A is
1) 6-membered monocyclic carbocycle unsubstituted or mono-substituted with R 3 or di-substituted with R 3 and R 4 , or
2) 10-membered bicyclic carbocycle unsubstituted or substituted with R 3 ;
R 1 is
1) C 1-6 alkyl, or
2) 6-membered monocyclic carbocycle unsubstituted or substituted with R 7 ;
R 1a is H or CH 3 ;
R 2 is benzimidazole, which is unsubstituted or substituted with R 18 ;
R 3 is tetrazole;
R 4 is
1) —C(NH)NH 2 ,
2) —NH 2 ,
3) Halogen,
4) —C 1-6 alkyl, unsubstituted or substituted with —OH, F or —NH 2 ,
5) —C(O)OC 1-6 alkyl,
6) —CF 3 ,
7) —NO 2 ,
8) —CN, or
9) —OC 1-6 alkyl;
R 7 is halogen, —CF 3 or —OCF 3 ;
R 10 is
4-6-membered carbocycle either unsubstituted or substituted with —NHC(O)OH;
R 14 is C 1-6 alkyl unsubstituted or substituted with —OH, —C 6 H 5 , or —((CH 2 ) n —O) m —CH 3 , where m is 1 or 2 and n is 1 or 2;
R 18 is
1) —C(O)OC 1-6 alkyl,
2) —C(O)OH,
3) halogen,
4) —P(O)(OC 1-6 alkyl)(OC 1-6 alkyl),
5) —P(O)(OH) 2 ,
6) —SO 2 C 1-6 alkyl,
7) —CN,
8) —CF 3 ,
9) —C(O)NHR 10 ,
10) —NHC(O)OR 14 ,
11) —NHC(O)R 10 , or
12) —P(O)(NHC 1-6 alkyl)(NH C 1-6 alkyl).
3. A compound of claim 2 of formula Ia
or a pharmaceutically acceptable salt thereof, where
A is
1) 6-membered monocyclic carbocycle unsubstituted or mono-substituted with R 3 or di-substituted with R 3 and R 4 , or
2) 10-membered bicyclic carbocycle unsubstituted or substituted with R 3 ;
R 1 is
1) C 1-6 alkyl, or
2) 6-membered monocyclic carbocycle unsubstituted or substituted with R 7 ;
R 2 is benzimidazole, which is unsubstituted or substituted with R 18 ;
R 3 is tetrazole;
R 4 is —NO 2 , C 1-6 alkyl, —CN, —NH 2 , or —OC 1-6 alkyl;
R 7 is halogen, —CF 3 or —OCF 3 ;
R 10 is
4-6-membered carbocycle either unsubstituted or substituted with —NHC(O)OH;
R 14 is C 1-6 alkyl unsubstituted or substituted with —OH, —C 6 H 5 , or —((CH 2 ) n —O) m —CH 3 , where m is 1 or 2 and n is 1 or 2;
R 18 is
1) —C(O)OC 1-6 alkyl,
2) —C(O)OH,
3) halogen,
4) —P(O)(OC 1-6 alkyl)(OC 1-6 alkyl),
5) —P(O)(OH) 2 ,
6) —SO 2 C 1-6 alkyl,
7) —CN,
8) —CF 3 ,
9) —C(O)NHR 10 ,
10) —NHC(O)OR 14 ,
11) —NHC(O)R 10 , or
12) —P(O)(NHC 1-6 alkyl)(NH C 1-6 alkyl).
4. A compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein
A is
R 1 is
R 2 is
R 3 is
R 4 is
—NO 2 , —CH 3 , —CN, —NH 2 , or —OCH 3 , or
R 7 is —Cl, F, or —OCF 3 ;
R 18 is —C(O)OCH 3 , —C(O)OCH 2 CH 3 , —C(O)OH, —F, —P(O)(OCH 2 CH 3 ) 2 , —P(O)(OH) 2 , —C(O)OC(CH 3 ) 3 , —CN or —P(O)(NHC 1-6 alkyl)(NHC 1-6 alkyl).
5. A compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein
A is
R 1 is
R 2 is
6. 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.
7. A composition for inhibiting thrombus formation in blood comprising a compound of claim 1 and a pharmaceutically acceptable carrier.