Factor XIa inhibitors

Patent metadata

Field	Value
Publication number	US-9868727-B2
Application number	US-201515329634-A
Country	US
Kind code	B2
Filing date	Jul 23, 2015
Priority date	Jul 28, 2014
Publication date	Jan 16, 2018
Grant date	Jan 16, 2018

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, hypercoagulability or fibrotic changes. The compounds are selective Factor XIa inhibitors or dual inhibitors of Factor XIa and plasma kallikrein.

First claim

The invention claimed is:

1. A compound of the formula:

wherein

is a 5 or 6 membered heteroaryl ring, wherein said heteroaryl ring is optionally substituted with one to three substituents independently selected from the group consisting of nitro, cyano, oxo, R a , (C═O)R 4 , (C═O)OR 4 , NR 4 R 5 , NH(C═O)R 4 , NH(C═O)OR 4 , SO 2 R 4 , SO 2 NR 4 R 5 , NR 4 SO 2 R 5 and PO 3 R 4 ;
R 1 is aryl, heteroaryl, C 3-6 cycloalkyl or heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, nitro, cyano, oxo, R 4 , OR 4 , (C═O)R 4 , (C═O)OR 4 , NR 4 R 5 , NH(C═O)R 4 , NH(C═O)OR 4 , C 3-6 cycloalkyl and heteroaryl which is optionally substituted with R 4 ;
R 2 is hydrogen or CH(R 2a )(R 2b );
R 2a is hydrogen, C 1-6 alkyl, aryl, heteroaryl, C 3-6 cycloalkyl, heterocyclyl or (C═O)NR 4 R 5 , wherein said alkyl group is optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxy and cyano, and wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, nitro, cyano, oxo, R 4 and OR 4 ;
R 2b is hydrogen or C 1-6 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxy and cyano;
R 3 is halo, cyano, (C═O)OR 4 or R 6 ;
R 4 is hydrogen or C 1-6 alkyl, which is optionally substituted with one to three groups independently selected from the group consisting of halo and hydroxy;
R 5 is hydrogen or C 1-6 alkyl, which is optionally substituted with one to three groups independently selected from the group consisting of halo and hydroxy;
R 6 is aryl, heteroaryl, C 3-10 cycloalkyl or heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, nitro, cyano, oxo, R 4 , OR 4 , (C═O)R 4 , (C═O)OR 4 , (C═O)NR 4 R 5 , NR 4 R 5 , NH(C═O)R 4 , NH(C═O)OR 4 , SO 2 R 4 , SO 2 NR 4 R 5 , NR 4 SO 2 R 5 and PO 3 R 4 ;
R a is hydrogen, halo, R 4 or OR 4 ;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 of the formula:

wherein R 1 is aryl, heteroaryl, C 3-6 cycloalkyl or heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, nitro, cyano, oxo, R 4 , OR 4 , (C═O)R 4 , (C═O)OR 4 , NR 4 R 5 , NH(C═O)R 4 , NH(C═O)OR 4 , C 3-6 cycloalkyl and heteroaryl which is optionally substituted with R 4 ;
R 2a is hydrogen, C 1-6 alkyl, aryl, heteroaryl, C 3-6 cycloalkyl, heterocyclyl or (C═O)NR 4 R 5 , wherein said alkyl group is optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxy and cyano, and wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, nitro, cyano, oxo, R 4 and OR 4 ;
R 2b is hydrogen or C 1-6 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxy and cyano;
R 3 is halo, cyano, (C═O)OR 4 or R 6 ;
R 4 is hydrogen or C 1-6 alkyl, which is optionally substituted with one to three groups independently selected from the group consisting of halo and hydroxy;
R 5 is hydrogen or C 1-6 alkyl, which is optionally substituted with one to three groups independently selected from the group consisting of halo and hydroxy;
R 6 is aryl, heteroaryl, C 3-10 cycloalkyl or heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, nitro, cyano, oxo, R 4 , OR 4 , (C═O)R 4 , (C═O)OR 4 , (C═O)NR 4 R 5 , NR 4 R 5 , NH(C═O)R 4 , NH(C═O)OR 4 , SO 2 R 4 , SO 2 NR 4 R 5 , NR 4 SO 2 R 5 and PO 3 R 4 ;
R a is hydrogen, halo, C 1-3 alkyl or O(C 1-3 alkyl);
or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein R 1 is aryl, which optionally is substituted with one to three substituents independently selected from the group consisting of halo, cyano, R 4 , OR 4 and heteroaryl which is optionally substituted with R 4 ; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein R 1 is phenyl, which optionally is substituted with one to two substituents independently selected from the group consisting of halo and tetrazolyl; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein R 2a is aryl, which optionally is substituted with one to three halo groups; or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 wherein R 2a is phenyl, which optionally is substituted with halo; or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 wherein R 2b is hydrogen; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 wherein R 2a is cyclopropyl; or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 wherein R 3 is R 6 , which optionally is substituted with halo, (C═O)OR 4 or NH(C═O)OR 4 , or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 selected from:

Assignees

• Merck Sharp & Dohme

Inventors

• Liu Weiguo
• Edmondson Scott D
• Guo Zhuyan
• So Sung-Sau
• Ogawa Anthony K
• Kuang Rongze
• Wu Heping
• Ali Amjad
• Gao Ying-Duo
• Jiang Yu
• Li Chunsing
• Yu Tingting

Classifications

• C07D401/06

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

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D409/14 Primary

  containing three or more hetero rings · CPC title