Pyrimidinones as factor XIa inhibitors

Patent metadata

Field	Value
Publication number	US-9453018-B2
Application number	US-201514872546-A
Country	US
Kind code	B2
Filing date	Oct 1, 2015
Priority date	Oct 1, 2014
Publication date	Sep 27, 2016
Grant date	Sep 27, 2016

Abstract

The present invention provides compounds of Formula (I):

or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.

First claim

What is claimed is:

1. A compound of Formula (VII):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
ring A is independently selected from

ring B is independently selected from

R 1 is independently selected from H and C 1-4 alkyl;
R 10 is independently selected from H, F, Cl, CF 3 , CHF 2 , and COOH;
R 3c is independently selected from H, CHF 2 , CD 3 , CH 3 , and

R 8b is independently selected from H and F; and
R 8c is independently selected from H, F, Cl, CH 3 , and OCH 3 .

2. A compound according to claim 1 , wherein R 10 is independently selected from F, Cl, CF 3 , and CHF 2 .

3. The compound of claim 1 , having Formula (VIII):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 1-4 alkyl;
R 10 is independently selected from F, Cl, CF 3 , CHF 2 , and COOH;
R 3c is independently selected from CHF 2 , CD 3 , and CH 3 ;
R 8b is H; and
R 8c is independently selected from F and Cl.

4. The compound of claim 1 , having Formula (IX):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 1-4 alkyl;
R 10 is independently selected from F, Cl, CF 3 , CHF 2 , and COOH;
R 3c is independently selected from CHF 2 , CD 3 , and CH 3 ;
R 8b is H; and
R 8c is independently selected from F and Cl.

5. The compound of claim 3 , having Formula (X):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
R 10 is independently selected from F, Cl, CF 3 , CHF 2 , and COOH; and
R 3c is independently selected from CHF 2 , CD 3 , and CH 3 .

6. A compound of claim 1 , selected from the group consisting of:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof.

7. A compound of claim 6 , having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof.

8. A compound of claim 6 , having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof.

9. A compound of claim 6 , having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof.

10. A compound of claim 6 , having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof.

11. A compound of claim 6 , having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof.

12. A compound of claim 6 , having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof.

13. A compound of claim 6 , having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof.

14. A compound of claim 6 , having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof.

15. A compound of claim 6 , having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof.

16. A compound of claim 6 , having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising one or more compounds according to claim 1 and a pharmaceutically acceptable carrier or diluent.

Assignees

• Bristol Myers Squibb Co

Inventors

• Dilger Andrew K
• Corte James R
• De Lucca Indawati
• Fang Tianan
• Yang Wu
• Wang Yufeng
• Pabbisetty Kumar Balashanmuga
• Ewing William R
• Zhu Yeheng
• Wexler Ruth R
• Pinto Donald J P
• Orwat Michael J
• Smith Ii Leon M

Classifications

• C07D471/08

  Bridged systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D487/08

  Bridged systems · CPC title

• C07D471/18 Primary

  Bridged systems · CPC title

• C07F7/0814

  said ring is substituted at a C ring atom by Si · CPC title