Nor-seco himbacine derivatives useful as thrombin receptor antagonists

A compound represented by the structural formula

• or a pharmaceutically acceptable salt thereof, wherein:
• Z is —CH2—;
• R1 is H, C1-C6 alkyl, fluoro(C1-C6)alkyl, difluoro(C1-C6)alkyl, trifluoro-(C1-C6)alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, aryl(C1-C6)alkyl, aryl(C2-C6)alkenyl, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, amino-(C1-C6)alkyl, aryl or thio(C1-C6)alkyl;
• R2 is H;
• R3 is H, hydroxy, C1-C6 alkoxy, —NR18R19, —SOR16, —SO2R17, —C(O)OR17, —C(O)NR18R19, C1-C6 alkyl, halogen, fluoro(C1-C6)alkyl, difluoro(C1-C6)alkyl, trifluoro(C1-C6)alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, aryl(C1-C6)alkyl, aryl(C2-C6)alkenyl, hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, aryl, thio(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl or (C1-C6)alkylamino(C1-C6)alkyl;
• Het is pyridyl, wherein the ring nitrogen can form an N-oxide or a quaternary group with a C1-C4 alkyl group, wherein Het is attached to B by a carbon atom ring member, and wherein the Het group is substituted by 1 to 4 substituents of W, wherein W is independently selected from the group consisting of H;
• C1-C6 alkyl;
• fluoro(C1-C6)alkyl;
• difluoro(C1-C6)alkyl;
• trifluoro-(C1-C6)-alkyl;
• C3-C7 cycloalkyl;
• C2-C6 alkenyl;
• R21-aryl(C1-C6)alkyl;
• R21-aryl-(C1-C6)-alkenyl;
• R21-aryloxy;
• R21-aryl-NH—;
• hydroxy(C1-C6)alkyl;
• dihydroxy(C1-C6)alkyl;
• amino(C1-C6)alkyl;
• (C1-C6)alkylamino-(C1-C6)alkyl;
• di-((C1-C6)alkyl)-amino-(C1-C6)alkyl;
• thio(C1-C6)alkyl;
• C1-C6 alkoxy;
• C2-C6 alkenyloxy;
• halogen;
• —NR4R5;
• —CN;
• —OH;
• —COOR17;
• —COR16;
• —OSO2CF3;
• —CH2OCH2CF3;
• (C1-C6)alkylthio;
• —C(O)NR4R5;
• —OCHR8-phenyl;
• phenoxy-(C1-C6)alkyl;
• —NHCOR16;
• —NHSO2R16;
• biphenyl;
• —OC(R6)2COOR7;
• —OC(R6)2C(O)NR4R5;
• (C1-C6)alkoxy:
• —C(═NOR17)R18;
• C1-C6 alkoxy substituted by (C1-C6)alkyl, amino, —OH, COOR17, —NHCOOR17, —CONR4R5, aryl, aryl substituted by 1 to 3 substutuents independently selected from the group consisting of halogen, —CF3, C1-C6 alkyl, C1-C6 alkoxy and —COOR17, —C(O)NR4R5;
• and R21-aryl;
• R4 and R5 are independently selected from the group consisting of H, C1-C6 alkyl, phenyl, benzyl and C3-C7 cycloalky;
• R6 is independently selected from the group consisting of H, C1-C6 alkyl, phenyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkyl and amino(C1-C6)alkyl;
• R7 is H or (C1-C6)alkyl;
• R8, R10 and R11 are each H;
• R9 is H, OH, C1-C6 alkoxy, halogen or halo(C1-C6)alkyl;
• B is —CH═CH—;
• R16 is C1-C6 lower alkyl, phenyl or benzyl;
• R17, R18 and R19 are independently selected from the group consisting of H, C1-C6 alkyl, phenyl, benzyl;
• R21 is 1 to 3 substutuents independently selected from the group consisting of hydrogen, CN, —CF3, —OCF3, halogen, —NO2, C1-C6 alkyl, C1-C6alkoxy, (C1-C6)alkylamino, di-((C1-C6)alkyl)amino, amino(C1-C6)alkyl, (C1-C6)-alkylamino(C1-C6)alkyl, di-((C1-C6)alkyl)-amino(C1-C6)alkyl, hydroxy-(C1-C6)alkyl, —COOR17, —COR17, —NHCOR16, —NHSO2R16, —NHSO2CH2CF3, or —C(═NOR17)R18;
• R22 and R23 are independently selected from the group consisting of hydrogen, R24—(C1-C10)alkyl, R24-(C2-C10)alkenyl, R24—(C2-C10)alkynyl, —R25-aryl, R25-aryl(C1-C6)alkyl, R29—(C3-C7)cycloalkyl, R29—(C3-C7)cyclo-alkenyl, —OH, —OC(O)R30, —C(O)OR30, —C(O)R30, —C(O)NR30R31, —NR30R31, —NR30C(O)R31, —NR30C(O)NR31R32, —NHSO2R30, —OC(O)NR30R31, R24—(C1-C10)alkoxy, R24—(C2-C10)-alkenyloxy, R24—(C2-C10)alkynyloxy, R29—(C3-C7)cycloalkyloxy, R29—(C3-C7)cyclo-alkenyloxy, R29—(C3-C7)cycloalkyl-NH—, —NHSO2NHR16 and —CH(═NOR17);
• or R22 and R10 together with the carbon to which they are attached, or R23 and R11 together with the carbon to which they are attached, independently form a R42-substituted carbocyclic ring of 3-10 atoms;
• R24 is 1, 2 or 3 substituents independently selected from the group consisting of hydrogen, halogen, —OH, (C1-C6)alkoxy, R35-aryl, (C1-C10)-alkyl-C(O)—, (C2-C10)-alkenyl-C(O)—, (C2-C10)alkynyl-C(O)—, R26—(C3-C7)cycloalkyl, R26—(C3-C7)cycloalkenyl, —OC(O)R30, —C(O)OR30, —C(O)R30, —C(O)NR30R31, —NR30R31, —NR30C(O)R31, —NR30C(O)NR31R32, —NHSO2R30, —OC(O)NR30R31, R29—(C3-C7)-cycloalkyloxy, R29—(C3-C7)cyclo-alkenyloxy, R29—(C3-C7)cycloalkyl-NH—, —NHSO2NHR16 and —CH(═NOR17);
• R25 is , 2 or 3 substituents independently selected from the group consisting of hydrogen. halogen, —COOR36, —CN, —C(O)NR37R38, —NR39C(O)R40, —OR36, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-C1-C6)alkyl, (C1-C6)alkyl(C3-C7)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl(C3-C7)cycloalkyl(C1-C6)alkyl, hydroxy(C1-C6)alkyl, and (C1-C6)alkoxy(C1-C6)alkyl;
• R26 is 1, 2, or 3 substituents independently selected from the group consisting of hydrogen, halogen and (C1-C6)alkoxy;
• R29 is 1, 2 or 3 substituents independently selected from the group consisting of hydrogen, (C1-C6)alkyl, —OH, (C1-C6)alkoxy and halogen;
• R30, R31 and R32 are independently selected from the group consisting of hydrogen, (C1-C10)-alkyl, (C1-C6)alkoxy(C1-C10)-alkyl, R25-aryl(C1-C6)-alkyl, R33—(C3-C7)cycloalkyl, R34-(C3-C7)cycloalkyl(C1-C6)alkyl, and R25-aryl;
• R33 is hydrogen, (C1-C6)alkyl, OH—(C1-C6)alkyl or (C1-C6)alkoxy;
• R35 is 1 to 4 substituents independently selected from the group consisting of hydrogen, (C1-C6)alkyl, —OH, halogen, —CN, (C1-C6)alkoxy, trihalo(C1-C6)alkoxy, (C1-C6)alkylamino, di((C1-C6)alkyl)amino, —OCF3, OH—(C1-C6)alkyl, —CHO, —C(O)(C1-C6)-alkylamino, —C(O)di((C1-C6)alkyl)amino, —NH2, —NHC(O)(C1-C6)alkyl and —N((C1-C6)alkyl)C(O)(C1-C6)alkyl;
• R36 is hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, dihalo(C1-C6)alkyl or trifluoro(C1-C6)alkyl,
• R37 and R38 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, aryl(C1-C6)alkyl, phenyl and (C3-C15)cycloalkyl;
• R39 and R40 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, aryl(C1-C6)alkyl, phenyl and (C3-C15)-cycloalkyl;
• and
• R42 is 1 to 3 substituents independently selected from the group consisting of hydrogen, —OH, (C1-C6)alkyl and (C1-C6)alkoxy.