Constrained himbacine analogs as thrombin receptor antagonists

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 R10 and R34 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—;
• R15 is H, or C1-C6 alkyl;
• Y is (O), (S), (H, H), (H, OH) or (H, C1-C6 alkoxy);
• Z is selected from the group consisting of —CH2—and —O—;
• n1 is 1 or 2;
• n2 is 0;
• n3 is 1;
• n4 is 0, 1 or 2;
• R is 1 to 3 substituents independently selected from the group consisting of H, C1-C6 alkyl, halogen, hydroxy, amino, (C1-C6) alkyl-amino, (C1-C6)dialkylamino, (C1-C6)alkoxy, —COR16, —COOR17, —SOR16, —SO2R16, —NR16COR16a, —NR16COOR16a, —NR16CONR4R5, fluoro-(C1-C6)alkyl, difluoro(C1-C6)alkyl, trifluoro(C1-C6)alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, aryl(C1-C6)alkyl, aryl(C2-C6)alkenyl, heteroaryl(C1-C6)-alkyl, heteroaryl(C2-C6)alkenyl, hydroxy(C1-C6)alkyl, amino(C1-C6)-alkyl, aryl and thio(C1-C6)alkyl;
• R1 and R2 are 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, aryl(C1-C6)alkyl, aryl(C2-C6)alkenyl, heteroaryl(C1-C6)alkyl, heteroaryl(C2-C6)alkenyl, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, amino-(C1-C6)alkyl, aryl and thio(C1-C6)alkyl;
• or R1 and R2 together form a ═O group;
• 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, heteroaryl(C1-C6)alkyl, heteroaryl(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, —O-aryl, N3, NO2, C(═NR1)NR1R2, N═C(R1)NR1R2, NR18COR19, NR18CONR18R19, NR18C(O)OR19, NR18S(O)2R19, NR18S(O)2NR18R19, NHNR18R9, NR18NR18R19 or NR18R19;
• 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;
• R4 and R5 are independently selected from the group consisting of H, C1-C6 alkyl, phenyl, benzyl and C3-C7 cycloalkyl, or R4 and R5 together are —(CH2)4—, —(CH2)5— or —(CH2)2NR7—(CH2)2— and form a heterocyclyl ring with the nitrogen to which they are attached;
• 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 independently selected from the group consisting of R1 and —OR1, provided that when the single-dashed line is a double bond, R10 is absent;
• R9 is H, OH, C1-C6 alkoxy, halogen or halo(C1-C6)alkyl;
• R16 and R16a are independently selected from the group consisting of 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;
• R20 is H, C1-C6 alkyl, phenyl, benzyl, —C(O)R6 or —SO2R6;
• R21 is 1 to 3 moieties independently selected from the group consisting of H, —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, heteroaryl, —C(═NOR17)R18, NR25R26alkyl-, hydroxy-alkyl-, —C(O)OR17, —COR17, —NHCOR16, —NHS(O)2R16, —NHS(O)2CH2CF3, —C(O)NR25R26—NR25—C(O)—NR25R26, —S(O)R13, —S(O)2R13 and —SR13;
• R22 is selected from the group consisting of H, R24—(C1-C10)alkyl, R24—(C2-C10)alkenyl, R24(C2-C10)alkynyl, R27-hetero-cycloalkyl, R25-aryl, R25-aryl(C1-C6)alkyl, R29—(C3-C7)cycloalkyl, R29—(C3-C7)cycloalkenyl, —OH, —OC(O)R30, —C(O)OR30, —C(O)R30, —C(C)NR30R31, —NR30R31, —NR30C(O)R31, —NR30C(O)NR31R32, NHSO2R30, —OC(O)NR30R31, R24—(C1-C10)alkoxy, R24—(C2-C10)-alkenyloxy, R24—(C2-C10)alkynyloxy, R27-heterocycloalkyloxy, 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, independently form a R42-substituted carbocyclic ring of 3-10 atoms, or a R42-substituted heterocyclic ring of 4-10 atoms wherein 1-3 ring members are independently selected from the group consisting of —O—, —NH— and —SOn2-, provided that when R22 and R10 form a ring, the single-dashed line represents an absent bond;
• R24 is 1, 2 or 3 moieties independently selected from the group consisting of H, halogen, —OH, (C1-C6)alkoxy, R35-aryl, (C1-C10)-alkyl-C(O)—, (C2-C10)-alkenyl-C(O)—, (C2-C10)alkynyl-C(O), heterocycloalkyl, 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, R24—(C2-C10)-alkenyloxy, R24—(C2-C10)alkynyloxy, R27-heterocycloalkyloxy, R29—(C3-C7)-cycloalkyloxy, R29—(C3-C7)cyclo-alkenyloxy, R29—(C3-C7)cycloalkyl-NH—, —NHSO2NHR16 and —CH(═NOR17);
• R25 is 1, 2 or 3 moieties independently selected from the group consisting of H, heterocycloalkyl, 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, (C1-C6)alkoxy(C1-C6)alkyl, and R41-heteroaryl;
• or two R25 groups on adjacent ring carbons form a fused methylenedioxy group;
• R26 is 1, 2, or 3 moieties independently selected from the group consisting of H, halogen and (C1-C6) alkoxy;
• R27 is 1, 2 or 3 moieties independently selected from the group consisting of H, R28—(C1-C10)alkyl, R28—(C2-C10)alkenyl, and R28—(C2-C10)alkynyl;
• R28 is H, —OH or (C1-C6) alkoxy;
• R29 is 1, 2 or 3 moieties independently selected from the group consisting of H, (C1-C6)alkyl, —OH, (C1-C6)alkoxy and halogen;
• R30, R31 and R32 are independently selected from the group consisting of H, (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, R25-aryl, heterocycloalkyl, heteroaryl, heterocycloalkyl(C1-C6)alkyl and heteroaryl(C1-C6)alkyl;
• R33 is H, (C1-C6)alkyl, OH—(C1-C6)alkyl or (C1-C6)alkoxy;
• R34 is (H, R3), (H, R43), (O) or (NOR17) when the single-dashed line is a single bond;
• R34 is R44 when the single-dashed line is a double bond;
• R35 is 1 to 4 moieties independently selected from the group consisting of H, (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 H, (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 H, (C1-C6)alkyl, aryl(C1-C6)alkyl, phenyl and (C3-C15)cycloalkyl;
• or R37 and R38 together are —(CH2)4—, —(CH2)5— or —(CH2)2—NR39—(CH2)2— and form a ring with the nitrogen to which they are attached;
• R39 and R40 are independently selected from the group consisting of H, (C1-C6)alkyl, aryl(C1-C6)alkyl, phenyl and (C3-C15)-cycloalkyl;
• or R39 and R40 in the group —NR39C(O)R40, together with the carbon and nitrogen atoms to which they are attached, form a cyclic lactam having 5-8 ring members;
• R41 is 1 to 4 moieties independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylamino, di((C1-C6)alkyl)amino, —OCF3, OH—(C1-C6)alkyl, —CHO and phenyl;
• R42 is 1 to 3 moieties independently selected from the group consisting of hydrogen, —OH, (C1-C6)alkyl and (C1-C6)alkoxy;
• R43 is —NR30R31, —NR30C(O)R31, —NR30C(O)NR31R32, —NHSO2R30 or —NHCOOR17;
• R44 is H, C1-C6 alkoxy, —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, heteroaryl(C1-C6)alkyl, heteroaryl(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;
• and
• R45 is H, C1-C6 alkyl, —COOR16 or —SO2.