Factor XIIa inhibitors

1. A compound of the formula:

wherein X is

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 hydroxyl, cyano, halo, C 1-3 alkyl, O(C 1-3 alkyl), NR 10 R 11 , CH 2 NR 10 R 11 , (C═O)NR 10 R 11 or heteroaryl;

R 2 is (C═O)OR 6 , (C═O)CH 2 R 6 ,

R 3 is C 1-3 alkyl,

or C 3-7 cycloalkyl, which is optionally substituted with one or two substituents independently selected from the group consisting of R 6 , R 11 , NR 10 R 11 , (C═O)NR 10 R 11 and CH 2 NR 10 R 11 ;

R 4 is hydrogen or C 1-4 alkyl;

R 5 is

(a) hydrogen,

(b) (CH 2 ) m -cyclohexyl, which is optionally substituted with NR 10 R 11 or heterocyclyl,

(c) (CH 2 ) n -piperidinyl, which is optionally substituted with benzyl, R 11 , SO 2 R 10 , SO 2 R 6 , (C═O)R 6 , R 6 or (C═O)R 10 ,

(d) C 1-4 alkyl which is optionally substituted with R 6 , NR 10 R 11 or NHSO 2 CH 3 ;

each R 6 is independently aryl, heteroaryl, heterocyclyl or C 3-6 cycloalkyl, wherein said aryl and heteroaryl groups are optionally substituted with one to three substituents independently selected from the group consisting of hydroxyl, oxo, cyano, halo, C 1-3 alkyl, C 1-3 haloalkyl, O(C 1-3 alkyl), NR 10 R 11 , CH 2 NR 10 R 11 , CH 2 CN, (C═O)NR 10 R 11 and CH(NH 2 )(OCH 3 );

R 7 is hydrogen or C 1-3 alkyl;

R 8 is hydrogen or C 1-3 alkyl;

R 9 is hydrogen, C 1-3 alkyl, C 1-3 haloalkyl or phenyl, wherein said phenyl group is optionally substituted with halo, cyano, methyl or CH 2 NR 10 R 11 ;

each R 10 is independently hydrogen or C 1-5 alkyl;

each R 11 is independently hydrogen or C 1-3 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxyl;

R x is hydrogen or C 1-4 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, N + CH −3 R 10 R 11 and NR 10 R 1 ;

m is zero or one;

n is zero or one;

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 hydroxyl, cyano, halo, C 1-3 alkyl, O(C 1-3 alkyl), NR 10 R 11 , CH 2 NR 10 R 11 , (C═O)NR 10 R 11 or heteroaryl;

R 2 is (C═O)OR 6 , (C═O)CH 2 R 6 ,

R 3 is C 1-3 alkyl,

or C 3-7 cycloalkyl, which is optionally substituted with one or two substituents independently selected from the group consisting of R 6 , R 11 , NR 10 R 11 , (C═O)NR 10 R 11 and CH 2 NR 10 R 11 ;

R 4 is hydrogen or C 1-4 alkyl;

R 5 is

(a) hydrogen,

(b) (CH 2 ) m -cyclohexyl, which is optionally substituted with NR 10 R 11 or heterocyclyl,

(c) (CH 2 ) n -piperidinyl, which is optionally substituted with benzyl, R 11 , SO 2 R 10 , SO 2 R 6 , (C═O)R 6 , R 6 or (C═O)R 10 ,

(d) C 1-4 alkyl which is optionally substituted with R 6 , NR 10 R 11 or NHSO 2 CH 3 ;

each R 6 is independently aryl, heteroaryl, heterocyclyl or C 3-6 cycloalkyl, wherein said aryl and heteroaryl groups are optionally substituted with one to three substituents independently selected from the group consisting of hydroxyl, oxo, cyano, halo, C 1-3 alkyl, C 1-3 haloalkyl, O(C 1-3 alkyl), NR 10 R 11 , CH 2 NR 10 R 11 , CH 2 CN, (C═O)NR 10 R 11 and CH(NH 2 )(OCH 3 );

R 7 is hydrogen or C 1-3 alkyl;

R 8 is hydrogen or C 1-3 alkyl;

R 9 is hydrogen or phenyl, which is optionally substituted with halo, cyano, methyl or CH 2 NR 10 R 11 ;

each R 10 is independently hydrogen or C 1-5 alkyl;

each R 11 is independently hydrogen or C 1-3 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxyl;

m is zero or one;

n is zero or one;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein R 1 is phenyl, thiophenyl, indolyl or thienopyridinyl, wherein said phenyl, thiophenyl, indolyl or thienopyridinyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, O(C 1-3 alkyl), CH 2 NR 10 R 11 , (C═O)NR 10 R 11 or tetrazolyl; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein R 3 is C 1-3 alkyl,

or C 5-6 cycloalkyl, which is optionally substituted with one or two substituents independently selected from the group consisting of R 6 , NR 10 R 11 , (C═O)NR 10 R 11 and CH 2 NR 10 R 11 , or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein R 4 is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 wherein R 5 is

(a) CH 2 -cyclohexyl, or

(b) C 1-4 alkyl which is optionally substituted with R 6 , R 11 , NR 10 R 11 or NHSO 2 CH 3 , or a pharmaceutically acceptable salt thereof.

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

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

11. A method of treating venous thromboembolism and pulmonary embolism in a mammal comprising administering a composition of claim 8 to a mammal in need thereof.

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

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