Constrained himbacine analogs as thrombin receptor antagonists

1. A compound represented by the structural formula

or a pharmaceutically acceptable salt or solvate thereof, wherein:

the single-dashed line

 between the ring carbons to which R 10 and R 34 are attached represents either a single bond or a double bond;

the double-dashed line

between X and the carbon to which Y is

attached represents a single bond;

X is —O—;

R 15 is H, or C 1 -C 6 alkyl;

Y is (O), (S), (H, H), (H, OH) or (H, C 1 -C 6 alkoxy);

Z is selected from the group consisting of —CH 2 —and —O—;

n 1 is 1 or 2;

n 2 is 0;

n 3 is 1;

n 4 is 0, 1 or 2;

R is 1 to 3 substituents independently selected from the group consisting of H, C 1 -C 6 alkyl, halogen, hydroxy, amino, (C 1 -C 6 ) alkyl-amino, (C 1 -C 6 )dialkylamino, (C 1 -C 6 )alkoxy, —COR 16 , —COOR 17 , —SOR 16 , —SO 2 R 16 , —NR 16 COR 16a , —NR 16 COOR 16a , —NR 16 CONR 4 R 5 , fluoro-(C 1 -C 6 )alkyl, difluoro(C 1 -C 6 )alkyl, trifluoro(C 1 -C 6 )alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, aryl(C 1 -C 6 )alkyl, aryl(C 2 -C 6 )alkenyl, heteroaryl(C 1 -C 6 )-alkyl, heteroaryl(C 2 -C 6 )alkenyl, hydroxy(C 1 -C 6 )alkyl, amino(C 1 -C 6 )-alkyl, aryl and thio(C 1 -C 6 )alkyl;

R 1 and R 2 are independently selected from the group consisting of H, C 1 -C 6 alkyl, fluoro(C 1 -C 6 )alkyl, difluoro(C 1 -C 6 )alkyl, trifluoro-(C 1 -C 6 )alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, aryl(C 1 -C 6 )alkyl, aryl(C 2 -C 6 )alkenyl, heteroaryl(C 1 -C 6 )alkyl, heteroaryl(C 2 -C 6 )alkenyl, hydroxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, amino-(C 1 -C 6 )alkyl, aryl and thio(C 1 -C 6 )alkyl; or R 1 and R 2 together form a ═O group;

R 3 is H, hydroxy, C 1 -C 6 alkoxy, —NR 18 R 19 , —SOR 16 , —SO 2 R 17 , —C(O)OR 17 , —C(O)NR 18 R 19 , C 1 -C 6 alkyl, halogen, fluoro(C 1 -C 6 )alkyl, difluoro(C 1 -C 6 )alkyl, trifluoro(C 1 -C 6 )alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, aryl(C 1 -C 6 )alkyl, aryl(C 2 -C 6 )alkenyl, heteroaryl(C 1 -C 6 )alkyl, heteroaryl(C 2 -C 6 )alkenyl, hydroxy(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, aryl, thio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl or (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, —O-aryl, N 3 , NO 2 , C(═NR 1 )NR 1 R 2 , N═C(R 1 )NR 1 R 2 , NR 18 COR 19 , NR 18 CONR 18 R 19 , NR 18 C(O)OR 19 , NR 18 S(O) 2 R 19 , NR 18 S(O) 2 NR 18 R 19 , NHNR 18 R 9 , NR 18 NR 18 R 19 or NR 18 R 19 ; Het is pyridyl,

wherein the Het group is optionally substituted by W, wherein W is selected from the group consisting of aryl optionally substituted by halo or CN;

R 4 and R 5 are independently selected from the group consisting of H, C 1 -C 6 alkyl, phenyl, benzyl and C 3 -C 7 cycloalkyl, or R 4 and R 5 together are —(CH 2 ) 4 —, —(CH 2 ) 5 — or —(CH 2 ) 2 NR 7 —(CH 2 ) 2 — and form a heterocyclyl ring with the nitrogen to which they are attached;

R 6 is independently selected from the group consisting of H, C 1 -C 6 alkyl, phenyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl and amino(C 1 -C 6 )alkyl;

R 7 is H or (C 1 -C 6 )alkyl;

R 8 , R 10 and R 11 are independently selected from the group consisting of R 1 and —OR 1 , provided that when the single-dashed line is a double bond, R 10 is absent;

R 9 is H, OH, C 1 -C 6 alkoxy, halogen or halo(C 1 -C 6 )alkyl;

R 16 and R 16a are independently selected from the group consisting of C 1 -C 6 lower alkyl, phenyl or benzyl;

R 17 , R 18 and R 19 are independently selected from the group consisting of H, C 1 -C 6 alkyl, phenyl, benzyl;

R 20 is H, C 1 -C 6 alkyl, phenyl, benzyl, —C(O)R 6 or —SO 2 R 6 ;

R 21 is 1 to 3 moieties independently selected from the group consisting of H, —CN, —CF 3 , —OCF 3 , halogen, —NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (C 1 -C 6 )alkylamino, di-((C 1 -C 6 )alkyl)amino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )-alkylamino(C 1 -C 6 )alkyl, di-((C 1 -C 6 )alkyl)-amino(C 1 -C 6 )alkyl, hydroxy-(C 1 -C 6 )alkyl, —COOR 17 , —COR 17 , —NHCOR 16 , —NHSO 2 R 16 , —NHSO 2 CH 2 CF 3 , heteroaryl, —C(═NOR 17 )R 18 , NR 25 R 26 alkyl-, hydroxy-alkyl-, —C(O)OR 17 , —COR 17 , —NHCOR 16 , —NHS(O) 2 R 16 , —NHS(O) 2 CH 2 CF 3 , —C(O)NR 25 R 26 —NR 25 —C(O)—NR 25 R 26 , —S(O)R 13 , —S(O) 2 R 13 and —SR 13 ;

R 22 is selected from the group consisting of H, R 24 —(C 1 -C 10 )alkyl, R 24 —(C 2 -C 10 )alkenyl, R 24 (C 2 -C 10 )alkynyl, R 27 -hetero-cycloalkyl, R 25 -aryl, R 25 -aryl(C 1 -C 6 )alkyl, R 29 —(C 3 -C 7 )cycloalkyl, R 29 —(C 3 -C 7 )cycloalkenyl, —OH, —OC(O)R 30 , —C(O)OR 30 , —C(O)R 30 , —C(C)NR 30 R 31 , —NR 30 R 31 , —NR 30 C(O)R 31 , —NR 30 C(O)NR 31 R 32 , NHSO 2 R 30 , —OC(O)NR 30 R 31 , R 24 —(C 1 -C 10 )alkoxy, R 24 —(C 2 -C 10 )-alkenyloxy, R 24 —(C 2 -C 10 )alkynyloxy, R 27 -heterocycloalkyloxy, R 29 —(C 3 -C 7 )cycloalkyloxy, R 29 —(C 3 -C 7 )cyclo-alkenyloxy, R 29 —(C 3 -C 7 )cycloalkyl-NH—, —NHSO 2 NHR 16 and —CH(═NOR 17 );

or R 22 and R 10 together with the carbon to which they are attached, independently form a R 42 -substituted carbocyclic ring of 3-10 atoms, or a R 42 -substituted heterocyclic ring of 4-10 atoms wherein 1-3 ring members are independently selected from the group consisting of —O—, —NH— and —SOn 2 -, provided that when R 22 and R 10 form a ring, the single-dashed line represents an absent bond;

R 24 is 1, 2 or 3 moieties independently selected from the group consisting of H, halogen, —OH, (C 1 -C 6 )alkoxy, R 35 -aryl, (C 1 -C 10 )-alkyl-C(O)—, (C 2 -C 10 )-alkenyl-C(O)—, (C 2 -C 10 )alkynyl-C(O), heterocycloalkyl, R 26 —(C 3 -C 7 )cycloalkyl, R 26 —(C 3 -C 7 )cycloalkenyl, —OC(O)R 30 , —C(O)OR 30 , —C(O)R 30 , —C(O)NR 30 R 31 , —NR 30 R 31 , —NR 30 C(O)R 31 , —NR 30 C(O)NR 31 R 32 , —NHSO 2 R 30 , —OC(O)NR 30 R 31 , R 24 —(C 2 -C 10 )-alkenyloxy, R 24 —(C 2 -C 10 )alkynyloxy, R 27 -heterocycloalkyloxy, R 29 —(C 3 -C 7 )-cycloalkyloxy, R 29 —(C 3 -C 7 )cyclo-alkenyloxy, R 29 —(C 3 -C 7 )cycloalkyl-NH—, —NHSO 2 NHR 16 and —CH(═NOR 17 );

R 25 is 1, 2 or 3 moieties independently selected from the group consisting of H, heterocycloalkyl, halogen, —COOR 36 , —CN, —C(O)NR 37 R 38 , —NR 39 C(O)R 40 , —OR 36 , (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl-C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkyl-(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, and R 41 -heteroaryl; or two R 25 groups on adjacent ring carbons form a fused methylenedioxy group;

R 26 is 1, 2, or 3 moieties independently selected from the group consisting of H, halogen and (C 1 -C 6 ) alkoxy;

R 27 is 1, 2 or 3 moieties independently selected from the group consisting of H, R 28 —(C 1 -C 10 )alkyl, R 28 —(C 2 -C 10 )alkenyl, and R 28 —(C 2 -C 10 )alkynyl;

R 28 is H, —OH or (C 1 -C 6 ) alkoxy;

R 29 is 1, 2 or 3 moieties independently selected from the group consisting of H, (C 1 -C 6 )alkyl, —OH, (C 1 -C 6 )alkoxy and halogen;

R 30 , R 31 and R 32 are independently selected from the group consisting of H, (C 1 -C 10 )-alkyl, (C 1 -C 6 )alkoxy(C 1 -C 10 )-alkyl, R 25 -aryl(C 1 -C 6 )—alkyl, R 33 —(C 3 -C 7 )cycloalkyl, R 34 —(C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, R 25 -aryl, heterocycloalkyl, heteroaryl, heterocycloalkyl(C 1 -C 6 )alkyl and heteroaryl(C 1 -C 6 )alkyl;

R 33 is H, (C 1 -C 6 )alkyl, OH—(C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy;

R 34 is (H, R 3 ), (H, R 43 ), (O) or (NOR 17 ) when the single-dashed line is a single bond; R 34 is R 44 when the single-dashed line is a double bond;

R 35 is 1 to 4 moieties independently selected from the group consisting of H, (C 1 -C 6 )alkyl, —OH, halogen, —CN, (C 1 -C 6 )alkoxy, trihalo(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylamino, di((C 1 -C 6 )alkyl)amino, —OCF 3 , OH—(C 1 -C 6 )alkyl, —CHO, —C(O)(C 1 -C 6 )-alkylamino, —C(O)di((C 1 -C 6 )alkyl)amino, —NH 2 , —NHC(O)(C 1 -C 6 )alkyl and —N((C 1 -C 6 )alkyl)C(O)(C 1 -C 6 )alkyl;

R 36 is H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, dihalo(C 1 -C 6 )alkyl or trifluoro(C 1 -C 6 )alkyl;

R 37 and R 38 are independently selected from the group consisting of H, (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, phenyl and (C 3 -C 15 )cycloalkyl;

or R 37 and R 38 together are —(CH 2 ) 4 —, —(CH 2 ) 5 — or —(CH 2 ) 2 —NR 39 —(CH 2 ) 2 — and form a ring with the nitrogen to which they are attached;

R 39 and R 40 are independently selected from the group consisting of H, (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, phenyl and (C 3 -C 15 )-cycloalkyl;

or R 39 and R 40 in the group —NR 39 C(O)R 40 , together with the carbon and nitrogen atoms to which they are attached, form a cyclic lactam having 5-8 ring members;

R 41 is 1 to 4 moieties independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylamino, di((C 1 -C 6 )alkyl)amino, —OCF 3 , OH—(C 1 -C 6 )alkyl, —CHO and phenyl;

R 42 is 1 to 3 moieties independently selected from the group consisting of hydrogen, —OH, (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy;

R 43 is —NR 30 R 31 , —NR 30 C(O)R 31 , —NR 30 C(O)NR 31 R 32 , —NHSO 2 R 30 or —NHCOOR 17 ;

R 44 is H, C 1 -C 6 alkoxy, —SOR 16 , —SO 2 R 17 , —C(O)OR 17 , —C(O)NR 18 R 19 , C 1 -C 6 alkyl, halogen, fluoro(C 1 -C 6 )alkyl, difluoro(C 1 -C 6 )alkyl, trifluoro(C 1 -C 6 )alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, aryl(C 1 -C 6 )alkyl, aryl(C 2 -C 6 )alkenyl, heteroaryl(C 1 -C 6 )alkyl, heteroaryl(C 2 -C 6 )alkenyl, hydroxy(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, aryl, thio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl or (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl; and

R 45 is H, C 1 -C 6 alkyl, —COOR 16 or —SO 2 .

2. A compound of claim 1 wherein W is phenyl.

3. A compound of claim 2 wherein W is substituted by fluoro.

4. A compound of claim 2 wherein W is substituted by —CN.

5. A compound of claim 1 wherein Z is —CH 2 — and n 1 is 1.

6. A compound of claim 1 wherein Z is —O— and n 1 is 1.

7. A compound of claim 1 wherein Z is —O— and n 1 is 1.

8. A compound of claim 1 wherein R1 is methyl, and R 2 , R 8 , R 9 , R 10 , R 11 are all H.

9. A compound of claim 1 wherein R 3 is H.

10. A compound of claim 1 wherein R 3 is —OH.

11. A compound of claim 1 wherein R 22 is methyl.

12. A compound of claim 1 wherein Y is O.

13. A compound of claim 1 wherein the single-dashed line represents a single bond.

14. A pharmaceutical composition comprising at least one compound of claim 1 and a pharmaceutically acceptable carrier.

15. A compound represented by a structural formula selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.