Fused ring 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)n3—, —(CH2)—O—, —(CH2)S—, —(CH2)—NR6—, —C(O)NR6—, —NR6C(O)—,
• —(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 hydrogen, alkyl and halogen;
• A, E, G, J and M are independently selected from the group consisting of —N(R54)—, —(CR1R2)—, —O—, —C(O)—, —S—, —S(O)— and —S(O)2—;
• with the provisos that selection of A, E, G, J and M does not result in adjacent oxygen or sulfur atoms;
• each n is 0, 1 or 2 with the provisos that the sum of the n variables is 1, 2 or 3;
• X is —O—, —C(O)—, or —N(R15)—;
• Y is —C(O)— or —SO2—;
• 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, with the proviso that there are no adjacent oxygen or sulfur atoms present in the heteroaromatic group, wherein a ring nitrogen can form an N-oxide or a quaternary group with an 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 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;
• —OCHRE-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;
• wherein adjacent carbons on the Het ring can optionally form a ring with a methylenedioxy group;
• 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
• R1 and R2 when attached to nitrogen, taken together, form a mono or bicyclic heterocyclic ring of 4 to 10 atoms, with 1-3 heteroatoms selected from —O—, —N—, —S—, —S(O)—, —S(O)2— and —C(O)—, with the proviso that S and O ring atoms are not adjacent to each other, where said heterocyclic ring is unsubstituted or substituted with one or more groups selected from alkyl, halogen, hydroxy, alkoxy, aryloxy and arylalkoxy;
• R3 is H, optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
• n7 is 0 or 1;
• R6 is hydrogen, alkyl or phenyl;
• R7 is hydrogen or alkyl;
• R5 and R15 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
• R4 and R5 are independently selected from the group consisting of hydrogen, alkyl, phenyl, benzyl and cycloalkyl, or R4 and R5 together can form a ring with the nitrogen to which they are attached, wherein said ring formed by R4 and R5 is optionally substituted with ═O, OH, OR1 or —C(O)OH;
• R16 is independently selected from the group consisting of hydrogen, alkyl, phenyl and benzyl;
• R16a 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, heteroaryl, cycloalkyl, heterocyclyl, alkoxyalkyl, haloalkoxyalkyl, aryloxyalkyl, arylalkoxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, cycloalkyloxyalkyl, (heterocyclyl)alkyloxyalkyl, alkoxyalkyloxyalkyl, —S(O)2-alkyl, —C(NH)NR1R2 or alkyl substituted with one or two moieties selected from cycloalkyl, halogen, hydroxy, —NR1R2, —NR1C(O)R2, —NR1C(O)NR1R2, —NR1C(O)OR2, —NR1S(O)2R2, —NR1S(O)2NR1R2, —C(O)OH, —C(O)OR1 and —C(O)NR1R2;
• or
• R18 and R19 together with the nitrogen to which they are attached, form a mono or bicyclic heterocyclic ring of 4 to 10 atoms, having 1-3 hetero ring atoms selected from —O—, —N—, —S—, —S(O)—, —S(O)2- and —C(O)—, with the proviso that S and O atoms are not adjacent to each other, the ring being unsubstituted or substituted with one or more groups selected from alkyl, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy, —NR1R2, —NR1COR2, —NR1C(O)NR1R2, —NR1C(O)OR2, —NR1S(O)2R2, —NR1S(O2)NR1R2, —C(O)OR1, —CONR1R2 and alkyl substituted with —NR1R2, —NR1COR2, —NR1CONR1R2, —NR1C(O)OR2, —NR1S(O)2R2, —NR1S(O)2NR1R2, —C(O)OR1 or —CONR1R2;
• 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 —CONR4, R5;
• or two adjacent R21 moieties can form a methylenedioxy group;
• 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, 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)NR44R46, —NHS(O)2R43, —OC(O)NR43R44, R37-alkoxy, R37-alkenyloxy, R37-alkynyloxy, R40-heterocycloalkyloxy, R42-cycloalkyloxy, R42-cyclo-alkenyloxy, R42-cycloalkyl-NH—, —NHSO2NHR16 and —CH(═NOR17);
• where
• R9 is hydrogen, OH, alkoxy, halogen or haloalkyl;
• wherein R10 and R11 are independently selected from the group consisting of R1, fluoroalkoxy, difluoroalkoxy, trifluoroalkoxy, cycloalkyloxy, alkenyloxy, arylalkoxy, arylalkenyloxy, heteroarylalkoxy, heteroarylalkenyloxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aryloxy and thioalkoxy, provided that when ring Q is aromatic and the carbon atoms bearing R16 and R11 are connected by a double bond, R10 and R11 are absent;
• R is 1 to 5 moieties and each R is independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, amino, alkylamino, dialkylamino, alkoxy, —COR16, —C(O)OR17, —C(O)NR4R5, —SOR16, —S(O2)R16, —NR16COR16a, —NR16C(O)OR16a, —NR16CONR4R6, —NR16S(O2)NR4R5, fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl, alkenyl, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxyalkyl, aminoalkyl, aryl and thioalkyl;
• R34 is 1 to 3 moieties and each R34 is independently selected from the group consisting of hydrogen, halogen, —OH, alkoxy, R47-aryl, alkyl-C(O)—, alkenyl-C(O)—, alkynyl-C(O)—, heterocycloalkyl, R39-cycloalkyl, R39-cycloalkenyl, —OC(O)R43, —C(O)OR43, —C(O)R43, —C(O)NR43R44, —NR43R44, —NR43C(O)R44, —NR43C(O)NR44R45, —NHSO2R43, —OC(O)NR43R44, R39-alkenyloxy, R39-alkynyloxy, R40-heterocycloalkyloxy, R42-cycloalkyloxy, R42-cycloalkenyloxy, R42-cycloalkyl-NH—, —NHSO2NHR16 and —CH(═NOR17);
• 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;
• or two R38 groups on adjacent ring carbons form a fused methylenedioxy group;
• R39 is 1 to 3 moieties and each R39 is independently selected from the group consisting of hydrogen, halogen and alkoxy;
• 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;
• R47 is 1 to 3 moieties and each R47 is independently selected from the group consisting of hydrogen, alkyl, —OH, halogen, —CN, alkoxy, trihaloalkoxy, alkylamino, di(alkyl)amino, —OCF3, hydroxyalkyl, —CHO, —C(O)alkylamino, —C(O)di(alkyl)amino, —NH2, —NHC(O)alkyl and —N(alkyl)C(O)alkyl;
• 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, or R49 and R50 together are —(CH2)4—, —(CH2)5— or —(CH2)2—NR39—(CH2)2— and form a ring with the nitrogen to which they are attached;
• R51 and R52 are independently selected from the group consisting of hydrogen, alkyl, aralkyl, phenyl and cycloalkyl, or R51 and R52 in the group —NR39C(O)R40, together with the nitrogen atoms to which they are attached, form a cyclic lactam having 5-8 ring members;
• R53 is hydrogen, alkoxy, —SOR18, —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;
• and
• R54 is selected from the group consisting of hydrogen;
• alkyl;
• fluoroalkyl;
• difluoroalkyl;
• trifluoroalkyl;
• cycloalkyl;
• cycloalkyl substituted by 1 to 3 substituents selected from the group consisting of alkoxyalkyl, alkyl, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy, —NR1R2, —NR1C(O)R2, —NR1C(O)NR1R2, —NR1C(O)OR2, —NR1S(O)2R2, —NR1S(O)2NR1R2, —C(O)OH, —C(O)OR1 and —CONR1R2;
• alkenyl;
• alkoxy;
• arylalkyl;
• arylalkenyl;
• heteroarylalkyl;
• heteroarylalkenyl;
• hydroxy;
• alkoxy;
• hydroxyalkyl;
• alkoxyalkyl;
• aminoalkyl;
• aryl;
• heteroaryl;
• thioalkyl and alkyl substituted by 1 to 3 substituents selected from the group consisting of urea, sulfonamide, carboxamide, carboxylic acid, carboxylic ester and sulfonyl urea.