Monocyclic and bicyclic himbacine derivatives useful as thrombin receptor antagonists

A compound represented by structural formula I:

• or a pharmaceutically acceptable salt of said compound, wherein
• represents a double bond or a single bond, as permitted by the valency requirement;
• with the proviso that R10 is absent when the carbon to which R10 is attached is part of a double bond;
• B is —(CH2)n4CR12═CR12a(CH2)n5— wherein n4 and n5 are independently 0-2, and R12 and R12a are independently selected from the group consisting of hydrogen, alkyl and halogen;
• G and J are independently —(CR1R2)—;
• Het is a pyridyl group wherein the pyridyl group is attached to B by a carbon atom ring member, and wherein the pyridyl group is substituted by 1 to 4 moieties, W, wherein each W is independently selected from the group consisting of hydrogen;
• alkyl;
• fluoroalkyl;
• difluoroalkyl;
• trifluoroalkyl;
• cycloalkyl;
• heterocycloalkyl;
• heterocycloalkyl substituted by alkyl or alkenyl;
• alkenyl;
• R21-arylalkyl;
• R21-aryl-alkenyl;
• heteroaryl;
• heteroarylalkyl;
• heteroarylalkenyl;
• hydroxyalkyl;
• dihydroxyalkyl;
• aminoalkyl;
• alkylaminoalkyl;
• di-(alkyl)-aminoalkyl;
• thioalkyl;
• alkoxy;
• alkenyloxy;
• halogen;
• —NR4R5;
• —CN;
• —OH;
• —C(O)OR17;
• —COR16;
• —OS(O2)CF3;
• —CH2OCH2CF3;
• alkylthio;
• —C(O)NR4R5;
• —OCHR6-phenyl;
• phenoxyalkyl;
• —NHCOR16;
• —NHC(O)OR16, —NHSO2R16;
• biphenyl;
• —OC(R6)2COOR7, —OC(R6)2C(O)NR4R5;
• alkoxy substituted by alkyl, amino or —NHC(O)OR17;
• R21-aryl;
• R21-heteroaryl;
• alkyl optionally substituted with —NR1R2, —NR1COR2, —NR1CONR1R2, —NR1C(O)OR2, —NR1S(O)2R2, —NR1S(O)2NR1R2, —C(O)OR1, —CONR1R2, heteroaryl, hydroxyalkyl or —S(O)2-alkyl;
• or —C(O)NR4R5;
• R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl, alkenyl, alkoxy, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl and thioalkyl;
• or
• R3 is R1, fluoroalkoxy, difluoroalkoxy, trifluoroalkoxy, cycloalkyloxy, alkenyloxy, alkoxy, arylalkoxy, arylalkenyloxy, heteroarylalkoxy, heteroarylalkenyloxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aryloxy or thioalkoxy;
• R4 and R5 are independently selected from the group consisting of hydrogen, alkyl, phenyl, benzyl and cycloalkyl;
• R8 is R34-alkyl, R34-alkenyl, R34-alkynyl, R40-heterocycloalkyl, R38-aryl, R38-aralkyl, R42-cycloalkyl, R42-cycloalkenyl, —OH, —OC(O)R43, —C(O)OR43, —C(O)R43, —C(O)NR43R44, —NR43R44, —NR43C(O)R44, —NR43C(O)OR44, —NR43C(O)NR44R45, —NHS(O)2R43, —OC(O)NR43R44, R37-alkoxy, R37-alkenyloxy, R37-alkynyloxy, R40-heterocycloalkyloxy, R42-cycloalkyloxy, R42-cyclo-alkenyloxy, R42-cycloalkyl-NH—, —NHSO2NHR16 or —CH(═NOR17);
• or R3 and R8 together are ═NOR17;
• R6 is hydrogen, alkyl or phenyl;
• R7 is hydrogen or alkyl;
• each R13 is independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, and halogen;
• each R14 is independently selected from the group consisting of hydrogen, alkyl, —OH and alkoxy;
• R16 is independently selected from the group consisting of hydrogen, alkyl, phenyl and benzyl;
• R17 is independently selected from the group consisting of hydrogen, alkyl, phenyl and benzyl;
• R18 and R19 are hydrogen, alkyl, aryl, R21-aryl and cycloalkyl;
• R21 is 1 to 3 moieties and each R21 is independently selected from the group consisting of hydrogen, —CN, —CF3, —OCF3, halogen, —NO2, alkyl, —OH, alkoxy, alkylamino-, di-(alkyl)amino-, —NR25R26alkyl-, hydroxyalkyl-, —C(O)OR17, —COR17, —NHCOR16, —NHS(O)2R16, —C(NH)—NH2, —NHS(O)2CH2CF3, —C(O)NR25R26, —NR25—C(O)—NR25R26, —S(O)R16, —S(O)2R16, —SR16;
• —SO2NR4R5 and —CONR4R5;
• R25 and R26 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl, hydroxy and alkoxy;
• R32 and R33 are independently selected from the group consisting of hydrogen, and R34-alkyl,
• or R32 and R33 are combined to form a ring structure Q, below
• where
• Q is
• R9 is hydrogen, OH, alkoxy, halogen or haloalkyl;
• R10 and R11 are independently selected from the group consisting of H or alkyl;
• R34 is 1 to 3 moieties and each R34 is independently selected from the group consisting of hydrogen, halogen, —OH and alkoxy;
• R37 selected from the group consisting of HO—, HS—, CH2S—, —NH2, phenyl, p-hydroxyphenyl and indolyl
• R38 is 1 to 3 moieties and each R38 is independently selected from the group consisting of hydrogen, heterocycloalkyl, halogen, —C(O)OR48, —CN, —C(O)NR49R50, —NR51C(O)R52, —OR48, cycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, haloalkylcycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, and R52-heteroaryl;
• R40 is 1 to 3 moieties and each R40 is independently selected from the group consisting of hydrogen, R41-alkyl, R41-alkenyl and R41-alkynyl;
• R41 is hydrogen, —OH or alkoxy;
• R42 is 1 to 3 moieties and each R42 is independently selected from the group consisting of hydrogen, alkyl, —OH, alkoxy and halogen;
• R43, R44 and R45 are independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, R38-arylalkyl, R46-cycloalkyl, R53-cycloalkylalkyl, R38-aryl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl and heteroarylalkyl;
• R46 is hydrogen, alkyl, hydroxyalkyl or alkoxy;
• R48 is hydrogen, alkyl, haloalkyl, dihaloalkyl or trifluoroalkyl;
• R49 and R50 are independently selected from the group consisting of hydrogen, alkyl, aralkyl, phenyl and cycloalkyl;
• R51 and R52 are independently selected from the group consisting of hydrogen, alkyl, aralkyl, phenyl and cycloalkyl;
• and
• R53 is hydrogen, alkoxy, —SOR16, —SO2R17, —C(O)OR17, —C(O)NR18R19, alkyl, halogen, fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl, alkenyl, aralkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxyalkyl, aminoalkyl, aryl, thioalkyl, alkoxyalkyl or alkylaminoalkyl.