Pyrimidinones as factor XIa inhibitors
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.
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.