Factor XIa inhibitors
The present invention provides a compound of Formula I and pharmaceutical compositions comprising one or more compounds of Formula I compounds, and methods for using the 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.
1 . A compound of the formula I:
wherein
R 1 is hydrogen, OCHF 2 , or a pyrazole optionally substituted with CF 3 ;
R 2 is chloro or fluoro;
R 3 is hydrogen or fluoro;
R 4 is hydrogen or C 1-3 alkyl;
X is CH or N;
or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 of the formula Ia:
wherein
R 2 is chloro or fluoro;
R 4 is hydrogen, CH 3 or CH 2 CH 3 ;
or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 1 of the formula Ib:
wherein
R 2 is chloro or fluoro;
R 4 is CH 3 or CH 2 CH 3 ;
X is CH or N;
or a pharmaceutically acceptable salt thereof.
4 . The compound of claim 3 of the formula Ic:
wherein
R 2 is chloro or fluoro;
R 4 is CH 3 or CH 2 CH 3 ;
or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 1 wherein X is CH; or a pharmaceutically acceptable salt thereof.
6 . The compound of claim 1 wherein X is N; or a pharmaceutically acceptable salt thereof.
7 . The compound of claim 1 wherein R 1 is OCHF 2 ; or a pharmaceutically acceptable salt thereof.
8 . The compound of claim 1 wherein R 4 is methyl or ethyl; or a pharmaceutically acceptable salt thereof.
9 . The compound of claim 1 wherein R 2 is fluoro; or a pharmaceutically acceptable salt thereof.
10 . The compound of claim 1 wherein R 2 is chloro; or a pharmaceutically acceptable salt thereof.
11 . The compound of claim 1 wherein R 3 is hydrogen; or a pharmaceutically acceptable salt thereof.
12 . The compound of claim 1 wherein R 3 is fluoro; or a pharmaceutically acceptable salt thereof.
13 . The compound of claim 1 selected from:
or a pharmaceutically acceptable salt thereof.
14 . A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
15 . A method for inhibiting thrombus formation in blood or treating thrombus formation in blood comprising administering a composition of claim 14 to a mammal in need of thereof.
16 . A method for preventing thrombus formation in blood comprising administering a composition of claim 14 to a mammal in need thereof.
17 . A method of treating venous thromboembolism and pulmonary embolism in a mammal comprising administering a composition of claim 14 to a mammal in need thereof.
18 . A method of treating deep vein thrombosis in a mammal comprising administering a composition of claim 14 to a mammal in need thereof.
19 . A method of treating thromboembolic stroke in a mammal comprising administering a composition of claim 14 to a mammal in need thereof.