Inhibitors of prenyl-protein transferase

A compound in accordance with formula I:

• wherein:
• R1 and R3 are independently selected from:
• a) hydrogen,
• b) R10O—, —N(R10)2, R10C(O)NR10—, R11OC(O)O— or R11OC(O)NR10—, and
• c) C1-C6 alkyl, unsubstituted or substituted by R10O—, —N(R10)2, R10C(O)NR10—, R11OC(O)O—, R11OC(O)NR10— or R11S(O)m—;
• R2 is selected from H;
• and C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
• 1) aryl,
• 2) heterocycle,
• 3) OR6,
• 4) SR5, SO2R5, or
• 5)
• R4 is selected from:
• a) hydrogen, and
• b) unsubstituted or substituted C1-C6 alkyl, wherein the substituent on the substituted C1-C6 alkyl is selected from one or more fluorines, R10O—, R11S(O)m—, R10C(O)NR10—, R10OC(O)O— and R11OC(O)—NR10—;
• R5 is selected from C1-4 alkyl and C3-6 cycloalkyl, unsubstituted or substituted with:
• a) C1-4 alkoxy,
• b) halogen, or
• c) aryl or heterocycle;
• R6 and R7 are independently selected from:
• a) hydrogen,
• b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10C(O)— or R10OC(O)— and
• c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O—, R10C(O)NR10—, (R10)2N—C(NR10)—, R10C(O)—, R10OC(O)—, —N(R10)2, or R11OC(O)NR10—;
• R8 is independently selected from:
• a) hydrogen,
• b) unsubstituted or substituted aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R12O—, R10C(O)NR10—, CN, NO2, (R10)2N—C(NR10)—, R10C(O)—, —N(R10)2, or R11OC(O)NR10—, and
• c) C1-C6 alkyl substituted by unsubstituted or substituted aryl, C1-C6 perfluoroalkyl, R10O—, R10C(O)NR10—, (R10)2N—C(NR10)—, R10C(O)—,—N(R10)2, or R11OC(O)NR10—;
• R10 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted with one or more fluorines, benzyl and unsubstituted or substituted aryl;
• R11 is independently selected from C1-C6 alkyl, C1-C6 alkyl substituted with one or more fluorines and unsubstituted or substituted aryl;
• R12 is independently selected from hydrogen, C1-C6 alkyl, unsubstituted or substituted benzyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, and C1-C6 alkyl substituted with one or more fluorines, unsubstituted or substituted aryl or unsubstituted or substituted heterocycle;
• A1 is O;
• V is phenyl;
• W is S(O)m or CH2;
• X is selected from:
• —C(O)—, —C(O)NR10—, —N(R10)—, —S(O)2N(R10)— and S(O)m;
• Y is selected from:
• a bond, —C(O)—, —NR10C(O)—, —N(R10)—, —N(R10)S(O)2—, and S(O)m;
• Z1 is selected from unsubstituted or substituted phenyl, wherein the substituted phenyl is substituted with one or two 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)mR5,
• g) —C(O)NR6R7, or
• h) one or more fluorines;
• 2) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
• 3) halogen,
• 4) OR6,
• 5) NR6R7,
• 6) CN,
• 7) NH2,
• 8) CF3,
• 9) —S(O)mR5,
• 10) —OS(O)2R5,
• 11) —C(O)NR6R7,
• 12) —C(O)OR6, or
• 13) C3-C6 cycloalkyl;
• m is 0, 1 or 2;
• p is 0, 1,2,3 or 4;
• q is 1 or 2;
• r is 0 to 5;
• s is independently 0, 1, 2 or 3;
• and
• t is 1, 2, 3 or 4;
• the term heterocycle represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring;
• or a pharmaceutically acceptable salt or stereoisomer thereof.