Preparation and use of 7a-amide 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 —[C(R a )(R b )] x —[C(R b )(R b )] y —C(O)NH 2 , or —N(H)—[(CH 2 )] z C(O)—NH 2 ,

where:

R a is independently H, —OH or —C 1 -C 3 -alkoxy,

R b is independently H or —C 1 -C 3 -alkyl;

R 2 is H or alkyl;

W is

x is 0 or 1;

y is 0, 1, 2 or 3; and

z is 1 or 2

provided that when R a is OH or —C 1 -C 3 -alkoxy, x is 1.

2. A compound as defined in claim 1 or a pharmaceutically acceptable salt thereof wherein

R 1 is —(CH 2 ) a —C(O)—NH 2 , —(NH)—[CH 2 ] Z —C(O)—NH 2 , —CH(CH 3 )—C(O)—NH 2 , —C(CH 3 )(CH 3 )—C(O)—NH 2 , —CH(OH)—C(O)—NH 2 , —CH(OCH 3 )—C(O)—NH 2 ;

a is 0 or 1; and

z is 1 or 2.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof which is:

(1R,3aR,6S,7R,7aS)-7-((E)-2-(5-(2-cyanophenyl)pyridin-2-yl)vinyl)-5,5-difluoro-1,6-dimethyl-3-oxooctahydroisobenzofuran-3a-carboxamide;

(1R,3aR,6S,7R,7aS)-7-((E)-2-(5-(2-cyanophenyl)-6-methylpyridin-2-yl)vinyl)-5,5-difluoro-1,6-dimethyl-3-oxooctahydroisobenzofuran-3a-carboxamide;

2-((1R,3aR,6S,7R,7aS)-7-((E)-2-(5-(2-cyanophenyl)pyridin-2-yl)vinyl)-5,5-difluoro-1,6-dimethyl-3-oxooctahydroisobenzofuran-3a-yl)acetamide;

2-((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)acetamide;

2-((1R,3aR,6S,7R,7aS)-7-((E)-2-(5-(2-cyanophenyl)pyridin-2-yl)vinyl)-5,5-difluoro-1,6-dimethyl-3-oxooctahydroisobenzofuran-3a-yl)propanamide;

R or S)-2-((1R,3aR,6S,7R,7aS)-7-((E)-2-(5-(2-cyanophenyl)pyridin-2-yl)vinyl)-5,5-difluoro-1,6-dimethyl-3-oxooctahydroisobenzofuran-3a-yl)propanamide;

(S or R)-2-((1R,3aR,6S,7R,7aS)-7-((E)-2-(5-(2-cyanophenyl)pyridin-2-yl)vinyl)-5,5-difluoro-1,6-dimethyl-3-oxooctahydroisobenzofuran-3a-yl)propanamide;

1R,3aR,6S,7R,7aS)-7-((E)-2-(2′-cyano-[3,3′-bipyridin]-6-yl)vinyl)-5,5-difluoro-1,6-dimethyl-3-oxooctahydroisobenzofuran-3a-carboxamide;

3-((1R,3aR,6S,7R,7aS)-7-((E)-2-(2′-cyano-[3,3′-bipyridin]-6-yl)vinyl)-5,5-difluoro-1,6-dimethyl 3-oxooctahydroisobenzofuran-3a-yl) propanamide;

2-((1R,3aR,6S,7R,7aS)-7-((E)-2-(2′-cyano-[3,3′-bipyridin]-6-yl)vinyl)-5,5-difluoro-1,6-dimethyl-3-oxooctahydroisobenzofuran-3a-yl)acetamide;

2-(((1R,3aS,6S,7R,7aS)-7-((E)-2-(5-(2-cyanophenyl)pyridin-2-yl)vinyl)-5,5-difluoro-1,6-dimethyl-3-oxooctahydroisobenzofuran-3a-yl)amino)acetamide;

(S and R)-2-((1R,3aR,6S,7R,7aS)-7-((E)-2-(5-(2-cyanophenyl)pyridin-2-yl)vinyl)-5,5-difluoro-1,6-dimethyl-3-oxooctahydroisobenzofuran-3a-yl)-2-methoxyacetamide;

(S and R)-2-((1R,3aR,6S,7R,7aS)-7-((E)-2-(5-(2-cyanophenyl)pyridin-2-yl)vinyl)-5,5-difluoro-1,6-dimethyl-3-oxooctahydroisobenzofuran-3a-yl)-2-hydroxyacetamide; or

2-((1R,3aR,6S,7R,7aS)-7-((E)-2-(5-(2-cyanophenyl)pyridin-2-yl)vinyl)-5,5-difluoro-1,6-dimethyl-3-oxooctahydroisobenzofuran-3a-yl)-2-methylpropanamide.

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 stroke or peripheral artery disease by administering a compound as defined in claim 3 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 .