Inhibitors of prenyl-protein transferase

A compound of the formula A:

• wherein:
• R1a, R1b, R1c and R1d are independently selected from:
• a) hydrogen,
• b) aryl, heterocycle, C3-C10 cycloalkyl, R10O—, R11S(O)m—, R10C(O)NR10—, (R10)2N—C(O)—, CN, NO2, (R10)2N—C(NR10)—, R10C(O)—, R10C(O)—, —N(R10)2, or R11OC(O)NR10—,
• c) unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl or unsubstituted or substituted C2-C6 alkynyl, wherein the substituent on the substituted C1-C6 alkyl, substituted C2-C6 alkenyl or substituted C2-C6 alkynyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O—, R11S(O)m—, R10C(O)NR10—, (R10)2N—C(O)—, CN, (R10)2N—C(NR10)—, R10C(O)—, R10OC(O)—, —N(R10)2, and R11OC(O)—NR10—,
• or two R1as, two R1bs or two R1cs, on the same carbon atom may be combined to form —(CH2)t—;
• R2a, R2b, R3a and R3b are independently selected from H;
• unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle,
• wherein the substituted group is substituted with one or more of:
• 1) aryl or heterocycle, unsubstituted or substituted with:
• a) C1-4 alkyl,
• b) (CH2)pOR6,
• c) (CH2)pNR6R7,
• d) halogen,
• e) CN,
• 2) C3-6 cycloalkyl,
• 3) OR6,
• 4) SR4, S(O)R4, SO2R4,
• 5) —NR6R7
• 11) —SO2—NR6R7
• 15) N3, or
• 16) F;
• or
• R2a and R3a are attached to the same carbon atom and are combined to form —(CH2)u— wherein one of the carbon atoms is optionally replaced by a moiety selected from O, S(O)m, —NC(O)—, and —N(COR10)—;
• and
• R2a and R3a are optionally attached to the same carbon atom;
• R4 is selected from C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
• a) C1-4 alkoxy,
• b) aryl or heterocycle,
• c) halogen,
• d) HO,
• f) —SO2R11,
• g) N(R10)2, or
• h) C1-4 perfluoroalkyl;
• R5, R6 and R7 are independently selected from:
• 1) hydrogen,
• 2) R10C(O)—, or R10OC(O)—, and
• 3) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more substituents selected from:
• a) R10O—,
• b) aryl or heterocycle,
• c) halogen,
• d) R10C(O)NR10—,
• f) —SO2R11
• g) N(R10)2,
• h) C3-6 cycloalkyl,
• i) C1-C6 perfluoroalkyl,
• j) (R10)2N—C(NR10)—,
• k) R10OC(O)—,
• l) R11OC(O)NR10—,
• m) CN, and
• n) NO2;
• or
• R6 and R7 may be joined in a ring;
• and independently,
• R5 and R7 may be joined in a ring;
• R8 is independently selected from:
• a) hydrogen,
• b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Br, R12O—, R11S(O)m—, R10C(O)NR10—, (R10)2NC(O)—, R102N—C(NR10)—, CN, NO2, R10C(O)—, R10OC(O)—, —N(R10)2, or R11OC(O)NR10—, and
• c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Br, R10O—, R11S(O)m—, R10C(O)NH—, (R10)2NC(O)—, R102N—C(NR10)—, CN, R10C(O)—, R10OC(O)—, —N(R10)2, or R10OC(O)NH—;
• R9 is selected from:
• a) hydrogen,
• b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O—, R11S(O)m—, R10C(O)NR10—, (R10)2NC(O)—, R102N—C(NR10)—, CN, NO2, R10C(O)—, R10OC(O)—, —N(R10)2, or R11OC(O)NR10—, and
• c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, Br, R10O—, R11S(O)m—, R10C(O)NR10—, (R10)2NC(O)—, R102N—C(NR10)—, CN, R10C(O)—, R10C(O)—, —N(R10)2, or R11 OC(O)NR10—;
• R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
• R11 is independently selected from C1-C6 alkyl unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
• R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C3 perfluoroalkyl, unsubstituted or substituted benzyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, and C1-C6 alkyl substituted with unsubstituted or substituted aryl or unsubstituted or substituted heterocycle;
• A1 is selected from a bond, —C(O)—, —C(O)NR10—, —NR10C(O)—, O, —N(R10)—, —S(O)2N(R10)—, —N(R10)S(O)2—, and S(O)m;
• A2 is selected from a bond, —C(O)—, —C(O)NR10—, —NR10C(O)—, O, —N(R10)—, —S(O)2N(R10)—, —N(R10)S(O)2—, NR10 C(O)NR10—, S(O)m and —C(R1c)2—;
• G1, G2 and G3 are independently selected from H2 and O;
• W is heterocycle;
• V is selected from:
• a) heterocycle, and
• b) aryl;
• X is selected from:
• abond, —C(O)—, —C(O)NR10—, —NR10C(O)—, —NR10C(O)—O—, —O— C(O)NR10—, —NR10C(O)NR10—, O, —N(R10)—, —S(O)2N(R10)—, —N(R10)S(O)2— and S(O)m;
• X1 is selected from:
• a bond, —C(O)—, —NR10C(O)—, —N(R10)S(O)2— and S(O)2;
• Y is selected from a bond, —C(═O)—, —C(O)NR10—, —C(O)O—, or —S(═O)m;
• Z1 is selected from unsubstituted or substituted aryl and unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or more of:
• 1) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl, unsubstituted or substituted with:
• a) C1-4 alkoxy,
• b) NR6R7,
• c) C3-6 cycloalkyl,
• d) aryl or heterocycle,
• e) HO,
• f) —S(O)mR4,
• g) —C(O)NR6R7, or
• h) C1-4 perfluoroalkyl;
• 2) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
• 3) halogen,
• 4) OR6,
• 5) NR6R7,
• 6) CN,
• 7) NO2,
• 8) CF3;
• 9) —S(O)mR4,
• 10) —OS(O)2R4,
• 11) —C(O)NR6R7,
• 12) —C(O)OR6, or
• 13) C3-C6 cycloalkyl;
• Z2 is selected from a bond, unsubstituted or substituted aryl and unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or more of:
• 1) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl, unsubstituted or substituted with:
• a) C1-4 alkoxy,
• b) NR6R7,
• c) C3-6 cycloalkyl,
• d) aryl or heterocycle,
• e) HO,
• f) —S(O)mR4,
• g) —C(O)NR6R7, or
• h) C1-4 perfluoroalkyl;
• 2) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
• 3) halogen,
• 4) OR6,
• 5) NR6R7,
• 6) CN,
• 7) NO2,
• 8) CF3,
• 9) —S(O)mR4,
• 10) —OS(O)2R4,
• 11) —C(O)NR6R7,
• 12) —C(O)OR6, or
• 13) C3-C6 cycloalkyl;
• m is 0, 1 or 2;
• n is 0, 1, 2, 3 or 4;
• p is independently 0, 1, 2, 3 or 4;
• q is 1 or 2;
• r is 0 to 5;
• s is independently 0, 1, 2 or 3;
• t is 2, 3, 4, 5 or 6;
• and
• u is 4 or 5;
• or a pharmaceutically acceptable salt or stereoisomer thereof.