Factor XI activation inhibitors

Patent metadata

Field	Value
Publication number	US-12428397-B2
Application number	US-202117920943-A
Country	US
Kind code	B2
Filing date	May 7, 2021
Priority date	May 12, 2020
Publication date	Sep 30, 2025
Grant date	Sep 30, 2025

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 XI activation inhibitors.

First claim

What is claimed is:

1. A compound of the formula:

wherein
R 1 is phenyl or heteroaryl, which may be monocyclic or bicyclic, wherein said phenyl and heteroaryl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, oxo, cyano, R 4 and OR 4 ;
R 2 is piperidinyl or NR 4 R 5 , wherein said piperidinyl group is optionally substituted with one to three halo;
R 3 is heterocyclyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R 4 , OR 4 and R 6 ;
R 4 is hydrogen or C 1-6 alkyl, which is optionally substituted with one to three halo;
R 5 is hydrogen or C 1-6 alkyl, which is optionally substituted with one to three halo;
R 6 is phenyl, C 3-6 cycloalkyl, heterocyclyl or heteroaryl, wherein said heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkyl and halo;
n is an integer from one to three;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein R 1 is selected from benzothiazolyl, phenyl or pyridinyl wherein said groups are optionally substituted with one or two substituents independently selected from the group consisting of chloro, cyano and CF 3 ; or a pharmaceutically acceptable salt thereof.

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

4. The compound of claim 1 wherein R 3 is piperidinyl, which is optionally substituted with one or two substituents independently selected from the group consisting of cyano, pyrazolyl, methylpyrazolyl, phenyl and triazolyl; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein R 3 is piperidinyl, which is optionally substituted with cyano and phenyl; or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 wherein n is one; or a pharmaceutically acceptable salt thereof.

7. The compound selected from

or a pharmaceutically acceptable salt thereof.

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

9. A method for inhibiting thrombus formation in blood or treating thrombus formation in blood comprising administering a composition of claim 8 to a mammal in need of thereof.

10. A method for preventing thrombus formation in blood comprising administering a composition of claim 8 to a mammal in need thereof.

11. A method of treating venous thromboembolism or pulmonary embolism in a mammal comprising administering a composition of claim 8 to a mammal in need thereof.

12. A method of treating deep vein thrombosis in a mammal comprising administering a composition of claim 8 to a mammal in need thereof.

13. A method of treating thromboembolic stroke in a mammal comprising administering a composition of claim 1 to a mammal in need thereof.

Assignees

• Merck Sharp & Dohme Llc

Inventors

• Hicks Jacqueline D
• Debenham John S
• Ali Amjad
• Gao Ying-Duo
• Wei Lan
• Yang Dexi
• Kuang Rongze
• Hruza Alan
• Nizner Peter
• Tatosian Daniel A

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61P7/02 Primary

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title