Factor XIa inhibitors

Patent metadata

Field	Value
Publication number	US-9809545-B2
Application number	US-201414778765-A
Country	US
Kind code	B2
Filing date	Mar 21, 2014
Priority date	Mar 27, 2013
Publication date	Nov 7, 2017
Grant date	Nov 7, 2017

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.

First claim

What is claimed is:

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)e

Assignees

• Merck Sharp & Dohme

Inventors

• Ogawa Anthony
• Edmondson Scott
• Erion Mark
• Neelamkavil Santhosh
• Guo Zhuyan
• Mal Rudrajit
• He Jiafang
• Liu Weiguo
• Vande Bunte Ellen K

Classifications

• C07F9/65583

  each of the hetero rings containing nitrogen as ring hetero atom · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D491/044

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• C07D413/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title