Spirocyclic 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, K, M and U are independently selected from the group consisting of —N(R54)—, —(CR1R2)—, —O—,
• —S—, —S(O)—, —S(O)2— and
• with the provisos that selection of A, E, G, J, K, M and U does not result in adjacent oxygen or sulfur atoms and that at least one carbon atom appear between said oxygen, nitrogen or sulfur atoms;
• each n is 0, 1 or 2 with the provisos that all n variables cannot be 0 and that the total of n variables cannot be greater than 7;
• 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;
• —OCHR6-phenyl;
• phenoxyalkyl;
• —NHCOR16;
• —NHSO2R16;
• biphenyl;
• —OC(R6)2COOR7;
• —OC(R6)2C(O)NR4R5;
• alkoxy substituted by alkyl, amino or —NHC(O)OR17;
• aryl;
• aryl substituted by 1 to 3 substituents independently selected from the group consisting of alkyl, halogen, alkoxy, methylenedioxy, carboxylic acid, carboxamide, amine, urea, amide, sulfonamide, —CN, —CF3, —OCF3, —OH, alkylamino-, di-(alkyl)amino-, —NR25R26alkyl-, hydroxyalkyl-, —C(O)OR17, —COR17, —NHCOR16, —NHS(O)2R16, —NHS(O)2CH2CF3, —C(O)NR25R26, —NR25—C(O)—NR25R26, —S(O)R16, —S(O)2R16 and —SR16;
• or alkyl optionally substituted with —NR1R2, —NR1COR2, —NR1CONR1R2, —NR1C(O)OR2, —NR1S(O)2R2, —NR1S(O)2NR1R2, —C(O)OH, —C(O)OR1, —CONR1R2heteroaryl, hydroxyalkyl, alkyl or —S(O)2-alkyl;—C(O)NR4R5 or heteroaryl;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
• 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;
• R6 is hydrogen, alkyl or phenyl;
• R7 is hydrogen or alkyl;
• each R13 is independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, halogen, —(CH2)n6NHC(O)OR16b, —(CH2)n6NHC(O)R16b, —(CH2)n6NHC(O)NR4R5, —(CH2)n6NHSO2R16, —(CH2)n6NHSO2NR4R5, and —(CH2)n6C(O)NR28R29, where n6 is 0-4;
• each R14 is independently selected from the group consisting of hydrogen, alkyl, —OH, alkoxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, —(CH2)n6NHC(O)OR16b, —(CH2)n6NHC(O)R16b, —(CH2)n6NHC(O)NR4R5, —(CH2)n6NHSO2R16, —(CH2)n6NHSO2NR4R5, and —(CH2)n6C(O)NR28R29 where n6 is 0-4;
• where 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;
• or
• R13 and R14 taken together form a spirocyclic or a heterospirocyclic ring of 3-6 ring atoms, wherein said heterospirocyclic ring contains 2 to 5 carbon ring atoms and 1 or 2 hetero ring atoms selected from the group consisting of O, S and N;
• 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;
• R16b is hydrogen, alkoxy, alkyl, alkoxyalkyl-, R22—O—C(O)-alkyl-, cycloalkyl, R21-aryl, R21-arylalkyl, haloalkyl, alkenyl, halo substituted alkenyl, alkynyl, halo substituted alkynyl, R21-heteroaryl, (R21-heteroaryl)-alkyl-, (R21-heterocycloalkyl)-alkyl-, R28R29N-alkyl-, R28R29N—C(O)-alkyl-, R28R29N—C(O)O-alkyl-, R28OC(O)N(R29)-alkyl-, R28S(O)2N(R29)-alkyl-, R28R29N—C(O)—N(R29)-alkyl-, R28R29N—S(O)2N(R29)-alkyl-, R28—C(O)N(R29)-alkyl-, R28R29N—S(O)2-alkyl-, HOS(O)2-alkyl-, (OH)2P(O)2-alkyl-, R28—S-alkyl-, R28-S(O)2-alkyl- or hydroxyalkyl;
• 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
• 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 —CONR4R5;
• or two adjacent R21 moieties can form a methylenedioxy group;
• R22 is hydrogen, alkyl, phenyl, benzyl, —COR16, —CONR18R19, —COR23, —S(O)R31, —S(O)2R31, —S(O2)N24R25 or —C(O)OR27;
• R23 is
• wherein R35 and R36 are independently selected from the group consisting of hydrogen, alkyl, and R37-substituted alkyl, wherein R37 is selected from the group consisting of HO—, HS—, CH2S—, —NH2, phenyl, p-hydroxyphenyl and indolyl;
• or R23 is alkyl;
• haloalkyl;
• alkenyl;
• haloalkenyl;
• alkynyl;
• cycloalkyl;
• cycloalkylalkyl;
• 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;
• aryl;
• aralkyl;
• heteroaryl;
• heterocycloalkyl;
• alkyl substituted with —NR1R2, —NR1COR2, —NR1CONR1R2, —NR1C(O)OR2, —NR1S(O2)R2, —NR1S(O2)NR1R2, —C(O)OH, —C(O)OR1, —CONR1R2 and —SO3H;
• R24, R25 and R26 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl, hydroxy and alkoxy;
• R27 is 1 to 3 moieties and each R27 is selected from the group consisting of hydrogen, alkyl, and cycloalkyl, wherein R27 is optionally substituted with —OH, —C(O)OH, halogen and alkoxy;
• R28 and R29 are independently selected from the group consisting of hydrogen, alkyl, alkoxy, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyalkyl, alkoxyalkyl, heterocyclyl, heterocyclylalkyl, and haloalkyl;
• or
• R28 and R29 taken together form a spirocyclic or a heterospirocyclic ring having 3-6 ring atoms;
• 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)NR44R45, —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);
• or R32 and R33 are combined to form a ring structure Q, below
• where
• R9 is hydrogen, OH, alkoxy, halogen or haloalkyl;
• Q is fused R-substituted aryl, R-substituted heteroaryl, R-substituted heterocyclic ring of 4-8 atoms containing 1-3 heteroatoms selected from O, S, S(O), S(O)2 and NR22 with the proviso that S and O cannot be adjacent to one another;
• or
• Q is
• 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 R10 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, —NR16CONR4R5, —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, —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;
• 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 subsituents selected from the group consisting of urea, sulfonamide, carboxamide, carboxylic acid, carboxylic ester and sulfonyl urea;
• and pharmaceutically acceptable salts thereof.