Thrombin receptor antagonists

A compound represented by the structural formula

• 160
• or a pharmaceutically acceptable salt thereof, wherein:
• 161
• wherein R10 is absent;
• or
• wherein R3 is absent;
• the single dotted line represents an optional double bond;
• the double dotted line represents an optional single bond;
• n is 0-2;
• 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;
• R34 is (H, R3), (H, R43), ═O or ═NOR17 when the optional double bond is absent;
• R34 is R44 when the double bond is present;
• Het is a mono-, bi- or tricyclic heteroaromatic group of 5 to 14 atoms comprised of 1 to 13 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, wherein a 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, W, 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;
• heterocycloalkyl;
• heterocycloalkyl substituted by C1-C6 alkyl, C2-C6 alkenyl, OH—(C1-C6)alkyl, or ═O;
• C2-C6 alkenyl;
• R21-aryl(C1-C6)alkyl;
• R21-aryl-(C2-C6)-alkenyl;
• R21-aryloxy;
• R21-aryl-NH—;
• heteroaryl(C1-C6)alkyl;
• heteroaryl(C2-C6)-alkenyl;
• heteroaryloxy;
• heteroaryl-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;
• —OCHR6-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, aryl wherein adjacent carbons form a ring with a methylenedioxy group, —C(O)NR4R5 or heteroaryl;
• R21-aryl;
• aryl wherein adjacent carbons form a ring with a methylenedioxy group;
• R41-heteroaryl;
• and heteroaryl wherein adjacent carbon atoms form a ring with a C3-C5 alkylene group or a methylenedioxy group;
• 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 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 optional double bond is present, R10 is absent;
• R9 is H, OH, C1-C6 alkoxy, halogen or halo(C1-C6)alkyl;
• B is —(CH2)n3—, —CH2—O—, —CH2S—, —CH2—NR6—, —C(O)NR6—, —NR6C(O)—,
• 162
• cis or trans —(CH2)n4CR12═CR12a(CH2)n5 or —(CH2)n4C≡C(CH2)n5—,
• wherein n3 is 0-5, n4 and n5 are independently 0-2, and R12 and R12a are independently selected from the group consisting of H, C1-C6 alkyl and halogen;
• X is —O—or —NR6— when the double dotted line represents a single bond, or X is H, —OH or —NHR20 when the bond is absent;
• Y is ═O, ═S, (H, H), (H, OH) or (H, C1-C6 alkoxy) when the double dotted line represents a single bond, or when the bond is absent, Y is ═O, ═NOR17, (H, H), (H, OH), (H, SH), (H, C1-C6 alkoxy) or (H, —NHR45);
• R15 is absent when the double dotted line represents a single bond;
• R15 is H, C1-C6 alkyl, —NR18R19 or —OR17 when the bond is absent;
• or Y is
• 163
• or
• 164
• and R15 is H or C1-C6 alkyl;
• 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;
• R20 is H, C1-C6 alkyl, phenyl, benzyl, —C(O)R6 or —SO2R6;
• R21 is 1 to 3 substutuents independently selected from the group consisting of hydrogen, —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 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, 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(O)NR30R31, —NR30R31, —NR30C(O)R31, —NR30C(O)NR31R32, —NHSO2R30, —OC(O)NR30R31, R24—(C1-C10)alkoxy, R24—(C1-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, or R23 and R11 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 —SO0-2—, provided that when R22 and R10 form a ring, the optional double bond is absent;
• 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)—, 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 substituents independently selected from the group consisting of hydrogen, 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-CC6)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 substituents independently selected from the group consisting of hydrogen, halogen and (C1-C6)alkoxy;
• R27 is 1, 2 or 3 substituents independently selected from the group consisting of hydrogen, R28—(C1-C10)alkyl, R28—(C2-C10)alkenyl, R28—(C2-C10)alkynyl,
• R28 is hydrogen, —OH or (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, R25-aryl, heterocycloalkyl, heteroaryl, heterocycloalkyl(C1-C6)alkyl and heteroaryl(C1-C6)alkyl;
• 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, 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 hydrogen, (C1-C6)alkyl, aryl(C1-C6)alkyl, phenyl and (C3-C1)-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 substituents independently selected from the group consisting of hydrogen, (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 substituents 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.