Preparation and use of 7a-heterocycle substituted-6,6-difluoro bicyclic himbacine derivatives as PAR-1 receptor antagonists

1. A compound of the formula

or a pharmaceutically acceptable salt thereof

wherein:

R 1 is

W is

each R a is independently H or C 1 -C 4 alkyl;

R b is H; C 1 -C 4 alkyl; cycloalkyl; —N(R 3 )(R 4 ); or phenyl, which is optionally substituted once or twice by alkyl, haloalkyl, —OH, or alkoxy;

each R 2 is independently halo; —CN; alkyl; or haloalkyl;

R 3 is H or alkyl;

R 4 is H or alkyl;

R 5 is H, alkyl or —CN; and

a is 0, 1 or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein W is

3. A compound of claim 1 which is:

2-(6-((E)-2-((3R,3aS,4R,5S,7aR)-6,6-difluoro-3,5-dimethyl-1-oxo-7a-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)octahydroisobenzofuran-4-yl)vinyl)pyridin-3-yl) benzonitrile;

2-(6-((E)-2-((3R,3aS,4R,5S,7aR)-6,6-difluoro-3,5-dimethyl-1-oxo-7a-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)octahydroisobenzofuran-4-yl)vinyl)pyridin-3-yl)-6-methylbenzonitrile;

2-(6-((E)-2-((3R,3aS,4R,5S,7aR)-7a-(5-amino-1,3,4-oxadiazol-2-yl)-6,6-difluoro-3,5-dimethyl-1-oxooctahydroiso benzofuran-4-yl)vinyl)pyridin-3-yl)-6-methylbenzonitrile;

2-(6-((E)-2-((3R,3aS,4R,5S,7aR)-7a-(5-amino-1,3,4-oxadiazol-2-yl)-6,6-difluoro-3,5-dimethyl-1-oxooctahydroiso benzofuran-4-yl)vinyl)pyridin-3-yl) benzonitrile;

2-(6-((E)-2-((3R,3aS,4R,5S,7aR)-6,6-difluoro-3,5-dimethyl-7a-(5-methyl-1,3,4-oxadiazol-2-yl)-1-oxooctahydroisobenzofuran-4-yl)vinyl)pyridin-3-yl)-6-methylbenzonitrile;

2-(6-((E)-2-((3R,3aS,4R,5S,7aR)-7a-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6,6-difluoro-3,5-dimethyl-1-oxooctahydroisobenzofuran-4-yl)vinyl) pyridin-3-yl)-6-methylbenzonitrile;

2-(6-((E)-2-((3R,3aS,4R,5S,7aR)-6,6-difluoro-3,5-dimethyl-1-oxo-7a-(5phenyl -1,3,4-oxadiazol-2-yl) octahydroisobenzofuran-4-yl)vinyl)pyridin-3-yl)-6-ethylbenzonitrile;

5-((1R,3aR,6S,7R,7aS)-5,5-difluoro-7-((E)-2-(5-(3-fluorophenyl)pyridin-2-yl)vinyl)-1,6-dimethyl-3-oxooctahydroisobenzofuran-3a-yl)-1,3,4-oxadiazol-2(3H)-one;

2-(6-((E)-2-((3R,3aS,4R,5S,7aR)-7a-(5-(tert-butyl)-1H-pyrazol-3-yl)-6,6-difluoro-3,5-dimethyl-1-oxooctahydroisobenzofuran-4-yl)vinyl)pyridin-3-yl) benzonitrile;

2-(6-((E)-2-((3R,3aS,4R,5S,7aR)-7a-(5-(tert-butyl)- 1 -methyl- 1H-pyrazol-3-yl)-6,6-difluoro-3,5-dimethyl-1-oxooctahydroisobenzofuran-4-yl)vinyl) pyridin-3-yl)benzonitrile;

2-(6-((E)-2-((3R,3aS,4R,5S,7aR)-7a-(1,5-dimethyl-1H-pyrazol-3-yl)-6,6-difluoro-3,5-dimethyl-1-oxooctahydroiso benzofuran-4-yl)vinyl)pyridin-3-yl)benzonitrile;

2-(6-((E)-2-((3R,3aS,4R,5S,7aR)-6,6-difluoro-3,5-dimethyl-1-oxo-7a-(1H-pyrazol-3-yl)octa hydroisobenzofuran- 4-yl)vinyl)pyridin-3-yl)benzonitrile;

6′-((E)-2-((3R,3aS,4R,5S,7aR)-6,6-difluoro-3,5-dimethyl-1-oxo-7a-(1H-pyrazol-3-yl)octahydroisobenzofuran-4-yl)vinyl)-[3,3′-bipyridine]-2-carbonitrile;

or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising an effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition as defined in claim 4 , which further comprises a therapeutically effective amount of at least one additional cardiovascular agent.

6. The pharmaceutical composition as defined in claim 5 , wherein the at least one additional cardiovascular agent is aspirin or clopidogrel, wherein clopidogrel is a free base or pharmaceutically acceptable salt.

7. A pharmaceutical composition comprising an effective amount of a compound as defined in claim 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition as defined in claim 7 , which further comprises a therapeutically effective amount of at least one additional cardiovascular agent.

9. The pharmaceutical composition as defined in claim 8 , wherein the at least one additional cardiovascular agent is aspirin or clopidogrel, wherein clopidogrel is a free base or pharmaceutically acceptable salt.

10. A method for treating acute coronary syndrome or peripheral artery disease by administering a compound as defined in claim 1

or a pharmaceutically acceptable salt thereof

to a mammal in need of such treatment.

11. A method of inhibiting platelet aggregation comprising administering to a mammal an effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof.

12. A method for treating acute coronary syndrome or peripheral artery disease by administering a compound as defined in claim 3

or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment.

13. A method of inhibiting platelet aggregation comprising administering to a mammal an effective amount of a compound as defined in claim 3

or a pharmaceutically acceptable salt thereof.