Factor IXa inhibitors

Patent metadata

Field	Value
Publication number	US-10189819-B2
Application number	US-201515534029-A
Country	US
Kind code	B2
Filing date	Dec 7, 2015
Priority date	Dec 10, 2014
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

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 unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels. The compounds are selective Factor IXa inhibitors.

First claim

What is claimed is:

1. A compound of Formula I:

wherein A is selected from:

R 1 is phenyl, which is optionally substituted with halo, R 5 , (C═O)OR 5 , (C═O)NR 5 R 6 or C 1-3 alkyl(C═O)OR 5 ; or heteroaryl, which is optionally substituted with one or two substituents independently selected from the group consisting of halo, oxo, R 5 , OR 5 , NR 5 R 6 and C 1-3 alkyl-NR 5 R 6 ;
R 2 is hydrogen or C 1-6 alkyl;
R 3 is heteroaryl, which is optionally substituted with one or two substituents independently selected from the group consisting of halo, oxo, cyclopropyl, R 5 , OR 5 , (C═O)OR 5 and CH 2 SO 2 CH 3 ;
each R 4 is independently selected from halo, R 5 or OR 5 ,
each R 5 is hydrogen or C 1-6 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxy;
R 6 is hydrogen, cyclopropyl or C 1-6 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxy;
R a is hydrogen, halo, C 1-6 alkyl or O(C 1-6 alkyl);
R b is hydrogen, halo, C 1-6 alkyl or O(C 1-6 alkyl);
R c is hydrogen, halo, C 1-6 alkyl or O(C 1-6 alkyl);
R d is hydrogen, halo, C 1-6 alkyl or O(C 1-6 alkyl);
R e is hydrogen, halo, C 1-6 alkyl or O(C 1-6 alkyl);
R f is hydrogen, halo, C 1-6 alkyl or O(C 1-6 alkyl);
R g is hydrogen, halo, C 1-6 alkyl or O(C 1-6 alkyl);
R h is hydrogen, halo, C 1-6 alkyl or O(C 1-6 alkyl);
n is an integer between zero and two;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein A is

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein R 1 is phenyl, which is optionally substituted with halo, (C═O)OR 5 , (C═O)NR 5 R 6 or C 1-3 alkyl(C═O)OR 5 , or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein R 1 is phenyl, which is optionally substituted with halo, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein R 2 is hydrogen, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 wherein R 4 is halo; n is 2; or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 wherein R 3 is 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazolyl, pyridazinyl, quinolinyl, triazolopyridinyl, triazolonyl, pyridinyl or benzoimidazolyl, wherein said groups are optionally substituted with halo, oxo, cyclopropyl, R 5 , OR 5 , (C═O)OR 5 or CH 2 SO 2 CH 3 , or a pharmaceutically acceptable salt thereof.

8. A compound selected from
(R)-2,6-Dichloro-N-(2-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)-4-(4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)benzamide;
(R)-2,6-dichloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-(1H-tetrazol-1-yl)benzamide;
(R)-2-chloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-[4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl]benzamide;
(R)-2-chloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-(3-methyl-1H-1,2,4-triazol-1-yl)-6-(trifluoromethyl)benzamide;
(R)-2-chloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-(4H-1,2,4-triazol-4-yl)-6-(trifluoromethyl)benzamide;
(R)-2,6-dichloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzamide;
(R)-2,6-dichloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-(4H-1,2,4-triazol-4-yl)benzamide;
(R)-2-chloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-6-methyl-4-(3-methyl-1,2,4-triazol-1-yl)benzamide;
(R)-2-chloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-6-methoxy-4-(4H-1,2,4-triazol-4-yl)benzamide;
(R)-2-chloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-6-fluoro-4-(4H-1,2,4-triazol-4-yl)benzamide;
(R)-2-chloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-6-methyl-4-(4H-1,2,4-triazol-4-yl)benzamide;
(R)-2-chloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-(1H-tetrazol-1-yl)benzamide;
(R)-2-chloro-N-[2-(6-chloro-1H-benzimidazol-2-yl)-2-(3-fluorophenyl)ethyl]-4-(3-methoxy-1H-1,2,4-triazol-1-yl)benzamide;
(R)-2-chloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-(4H-1,2,4-triazol-4-yl)-6-(trifluoromethoxy)benzamide;
(R)-2-chloro-N-[2-(6-chloro-4-methyl-1H-benzimidazol-2-yl)-2-(3-fluorophenyl)ethyl]-4-(3-methyl-4H-1,2,4-triazol-4-yl)benzamide;
(±)-4-(3,5-dichloro-4-{[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]carbamoyl}phenyl)pyridine-2-carboxylic acid;
(±)-2,6-dichloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-pyrimidin-5-ylbenzamide;
(±)-2,6-dichloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-{-[(methyl sulfonyl)methyl]-1H-pyrazol-4-yl}benzamide;
(±)-ethyl 4-(3,5-dichloro-4-{[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]carbamoyl}phenyl)pyridine-2-carboxylate;
(±)-2,6-dichloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)benzamide;
(±)-2,6-dichloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-[2-(2-fluoroethoxy)pyrimidin-5-yl]benzamide;
(±)-2,6-dichloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]benzamide;
(±)-methyl 5-(3,5-dichloro-4-{[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]carbamoyl}phenyl)pyridine-2-carboxylate;
(±)-2,6-dichloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-(7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)benzamide;
(±)-2,6-dichloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-quinolin-3-ylbenzamide;
(±)-5-(3,5-dichloro-4-{[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]carbamoyl}phenyl)pyridine-2-carboxylic acid;
(±)-2,6-dichloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-[1,2,4]triazolo[4,3-a]pyridin-6-ylbenzamide;
(±)-2,6-dichloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-[1,2,4]triazolo[1,5-a]pyridin-7-ylbenzamide;
(±)-2,6-dichloro-4-(2-cyclopropylpyrimidin-5-yl)-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]benzamide;
(±)-ethyl 4-(3-chloro-4-{[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]carbamoyl}phenyl)pyridine-2-carboxylate;
(±)-2,6-dichloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]benzamide;
(±)-2,6-dichloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-(1H-pyrazol-4-yl)benzamide;
(±)-4-(3-chloro-4-{[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]carbamoyl}phenyl)pyridine-2-carboxylic acid;
(±)-2,6-dichloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-[5-(hydroxymethyl)pyridin-3-yl]benzamide;
(±)-2,6-dichloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-[6-(hydroxymethyl)pyridin-3-yl]benzamide;
(±)-2,6-dichloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-[2-(hydroxymethyl)pyridin-4-yl]benzamide;
(R)-2-chloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-phenylethyl]-4-(4H-1,2,4-triazol-4-yl)benzamide;
(R)-2,6-dichloro-N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-(5-fluoropyridin-3-yl)ethyl]-4-(4H-1,2,4-triazol-4-yl)benzamide;
(±)-2,6-dichloro-N-[2-(6-chloro-1H-benzimida

Assignees

• Merck Sharp & Dohme
• Mochida Pharm Co Ltd
• Merck Sharp & Dohme
• Mochida Paraceuticals Co Ltd

Inventors

• Zhang Ting
• Chen Yi-Heng
• Guo Liangqin
• Hruza Alan
• Jian Tianying
• Li Bing
• Meng Dongfang
• Parker Dann L
• Sherer Edward C
• Wood Harold B
• Sakurada Isao

Classifications

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D413/12

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

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D401/12

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

• C07D417/12

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