Factor XI activation inhibitors

Patent metadata

Field	Value
Publication number	US-12304899-B2
Application number	US-202017613988-A
Country	US
Kind code	B2
Filing date	May 26, 2020
Priority date	May 30, 2019
Publication date	May 20, 2025
Grant date	May 20, 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 , OR 4 , R 6 and NO 2 ;
R 2 is piperidinyl, NR 4 R 5 or NR 4 R 6 , wherein said piperidinyl group is optionally substituted with one to three halo;
R 3 is heterocyclyl, which may be monocyclic or bicyclic, or NHC(CH 3 ) 2 R 6 , wherein said heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, R 4 , OR 4 , R 6 , CONR 4 R 5 , NR 4 COR 5 , (C 1-3 alkyl) R 6 and SO 2 R 4 ,
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;
R x is hydrogen, halo or C 1-6 alkyl;
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 benzoimidazolyl, benzoisoxazolyl, benzooxadiazolyl, benzooxazolyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, dihydroindazolyl, dihydroisobenzofuranyl, imidazopyridinyl, phenyl, pyrazolopyridinyl, pyridinyl or pyrrolyl wherein said groups are optionally substituted with one or two substituents independently selected from the group consisting of methyl, chloro, fluoro, oxo, cyano, NO 2 , CF 3 , OCHF 2 , OCF 3 and OCH 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, piperazinyl, azaspiroocatnyl or pyrrolidinyl, wherein said groups are optionally substituted with one or two substituents independently selected from the group consisting of methyl, fluoro, hydroxyl, cyano, pyrazolyl, phenyl, triazolyl, piperidinyl, CONH 2 , NHCOCH 3 , CH 2 CF 3 , CH(CH 3 )CF 3 , CH 2 CHF 2 , and SO 2 CH 3 ; or a pharmaceutically acceptable salt thereof.

5. 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 methyl, fluoro, hydroxyl, cyano, pyrazolyl, phenyl, triazolyl, piperidinyl, CONH 2 , NHCOCH 3 , CH 2 CF 3 , CH(CH 3 )CF 3 , CH 2 CHF 2 , and SO 2 CH 3 ; or a pharmaceutically acceptable salt thereof.

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

7. A 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 pharmaceutical composition of claim 8 to a mammal in need of thereof.

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

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

13. A method of treating thromboembolic stroke in a mammal comprising administering a pharmaceutical composition of claim 8 to a mammal in need thereof.

Assignees

• Merck Sharp & Dohme Llc

Inventors

• Hicks Jacqueline D
• Debenham John S
• Ali Amjad
• Wei Lan
• Jian Tianying
• Yang Dexi
• Ogawa Anthony K
• Fu Wenlang
• Lombardo Matthew
• Kuang Rongze
• Yang Meng
• So Sung-Sau
• Ellsworth Kenneth
• Nizner Peter
• Tatosian Daniel A
• Wilkening Robert R
• Wang Jun

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07D401/06

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