Factor XIa inhibitors
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 XIa inhibitors or dual inhibitors of Factor XIa and plasma kallikrein.
1. A compound of the formula:
wherein R 1 is aryl or heteroaryl, wherein said aryl and heteroaryl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, nitro, cyano, oxo, R 4 , OR 4 , C(O)R 4 , C(O)OR 4 , NR 4 R 5 , C 1-3 alkyl-NR 4 R 5 , NHC(O)R 4 , NHC(O)OR 4 , C 3-6 cycloalkyl and heteroaryl (which is optionally substituted with halo, cyano, C(O)NR 4 R 5 or R 4 );
R 2 is hydrogen or CH(R 2a )(R 2b );
R 2a is C 1-6 alkyl, aryl, heteroaryl, C 3-6 cycloalkyl or heterocyclyl, wherein said alkyl group is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano and OR 4 , and wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, nitro, cyano, oxo, R 4 and OR 4 ;
R 2b is hydrogen or C 1-6 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxy and cyano;
R 3 is aryl, heteroaryl, C 3-10 cycloalkyl or heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, nitro, cyano, oxo, R 4 , OR 4 , C(O)R 4 , C(O)OR 4 , C(O)NR 4 R 5 , NR 4 R 5 , NHC(O)R 4 , NHC(O)OR 4 , NHC(O)C 1-4 alkyl-OR 4 and heteroaryl;
R 4 is hydrogen or C 1-6 alkyl, which is optionally substituted with one to three groups independently selected from the group consisting of halo and hydroxy;
R 5 is hydrogen or C 1-6 alkyl, which is optionally substituted with one to three groups independently selected from the group consisting of halo and hydroxy;
R 6 is hydrogen, cyano, halo, R 4 or OR 4 ;
R 7 is hydrogen, cyano, halo, R 4 or OR 4 ;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 of the formula:
wherein R 1 is aryl or heteroaryl, wherein said aryl and heteroaryl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, nitro, cyano, oxo, R 4 , OR 4 , C(O)R 4 , C(O)OR 4 , NR 4 R 5 , C 1-3 alkyl-NR 4 R 5 , NHC(O)R 4 , NHC(O)OR 4 , C 3-6 cycloalkyl and heteroaryl (which is optionally substituted with R 4 );
R 2a is C 1-6 alkyl, aryl, heteroaryl, C 3-6 cycloalkyl or heterocyclyl, wherein said alkyl group is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano and OR 4 , and wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, nitro, cyano, oxo, R 4 and OR 4 ;
R 2b is hydrogen or C 1-6 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxy and cyano;
R 3 is aryl, heteroaryl, C 3-10 cycloalkyl or heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, nitro, cyano, oxo, R 4 , OR 4 , C(O)R 4 , C(O)OR 4 , C(O)NR 4 R 5 , NR 4 R 5 , NHC(O)R 4 , NHC(O)OR 4 , NHC(O)C 1-4 alkyl-OR 4 and heteroaryl;
R 4 is hydrogen or C 1-6 alkyl, which is optionally substituted with one to three groups independently selected from the group consisting of halo and hydroxy;
R 5 is hydrogen or C 1-6 alkyl, which is optionally substituted with one to three groups independently selected from the group consisting of halo and hydroxy;
R 6 is hydrogen, cyano, halo, R 4 or OR 4 ;
R 7 is hydrogen, cyano, halo, R 4 or OR 4 ;
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 wherein R 1 is phenyl, which optionally is substituted with one to three substituents independently selected from the group consisting of chloro, fluoro, C 3-6 cycloalkyl and heteroaryl (which is optionally substituted with R 4 ); or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 wherein R 1 is phenyl, which optionally is substituted with two or three substituents independently selected from the group consisting of chloro and tetrazolyl; or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 wherein R 2a is phenyl, which optionally is substituted with one to three halo, and R 2b is hydrogen; or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 wherein R 3 is aryl or heteroaryl, wherein said aryl and heteroaryl groups are optionally substituted with one to three substituents independently selected from the group consisting of C(O)OR 4 , C(O)NR 4 R 5 , NR 4 R 5 , NHC(O)OR 4 , NHC(O)C 1-4 alkyl-OR 4 ; or a pharmaceutically acceptable salt thereof.
7. The compound of claim 6 wherein R 3 is phenyl, thiophenyl or indazolyl, wherein said phenyl, thiophenyl and indazolyl groups are optionally substituted with C(O)OR 4 , C(O)NR 4 R 5 , NR 4 R 5 , NHC(O)OR 4 , NHC(O)C 1-4 alkyl-OR 4 ; or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 selected from:
or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
10. A method for inhibiting thrombus formation in blood or treating thrombus formation in blood comprising administering a composition of claim 9 to a mammal in need of thereof.