Factor XIa inhibitors

Patent metadata

Field	Value
Publication number	US-10123995-B2
Application number	US-201615542948-A
Country	US
Kind code	B2
Filing date	Jan 15, 2016
Priority date	Jan 20, 2015
Publication date	Nov 13, 2018
Grant date	Nov 13, 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

What is claimed is:

1. A compound of the formula:

wherein X is (C═O)NH or —NH(C═O)—;
R 1 is aryl, heteroaryl or C 3-6 cycloalkyl, wherein said aryl, heteroaryl and cycloalkyl 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, hydroxy, halo or C 1-6 alkyl, wherein said alkyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, OR 4 or C 3-6 cycloalkyl;
R 3 is aryl, heteroaryl or C 3-10 cycloalkyl wherein said aryl, heteroaryl and cycloalkyl 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 and heteroaryl;
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 x is hydrogen, hydroxy or halo;
R z is hydrogen, hydroxy, methoxy or halo;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 of the formula:

wherein R 1 is phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo or heteroaryl which is optionally substituted with R 4 ;
R 2 is hydrogen, hydroxy, halo, or C 1-6 alkyl, wherein said alkyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, OR 4 or C 3-6 cycloakyl;
R 3 is phenyl or C 3-10 cycloalkyl, wherein said phenyl and cycloalkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, oxo, R 4 , OR 4 , (C═O)R 4 , (C═O)OR 4 and NH(C═O)R 4 ;
R 4 is hydrogen, or C 1-6 alkyl, which is optionally substituted with one to three groups of 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 x is hydrogen, hydroxy or halo;
R z is hydrogen, hydroxy, methoxy or halo;
or a pharmaceutically acceptable salt thereof.

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

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

5. The compound of claim 1 where in R 1 is phenyl, which optionally is substituted with three halo; or a pharmaceutically acceptable salt thereof.

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

7. The compound of claim 1 wherein R 3 is phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of (C═O)OR 4 and NH(C═O)R 4 ; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 wherein R 3 is phenyl, which is substituted with (C═O)OR 4 ; or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 selected from:

or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

11. A method for inhibiting thrombus formation in blood or treating thrombus formation in blood comprising administering a composition of claim 10 to a mammal in need of thereof.

12. A method of treating venous thromboembolism and pulmonary embolism in a mammal comprising administering a composition of claim 10 to a mammal in need thereof.

13. A method of treating deep vein thrombosis in a mammal comprising administering a composition of claim 10 to a mammal in need thereof.

14. A method of treating thromboembolic stroke in a human comprising administering a composition of claim 10 to a mammal in need thereof.

Assignees

• Merck Sharp & Dohme

Inventors

• Mertz Eric
• Liu Weiguo
• Edmondson Scott D
• Ali Amjad
• Gao Ying-Duo
• Neelamkavil Santhosh F
• So Sung-Sau
• Moningka Remond
• Sun Wanying
• Hruza Alan
• Brockunier Linda L

Classifications

• C07D401/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title

• C07D221/04

  Ortho- or peri-condensed ring systems · CPC title

• A61P7/02 Primary

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• A61K31/4375

  the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine · CPC title