INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE

Abstract: The present invention comprises analogs of the CA<1>A<2>X motif of the protein Ras that is modified by farnesylation in vivo. These CA<1>A<2>X analogs inhibit the farnesyl-protein transferase and the farnesylation of certain proteins. Furthermore, these CA<1>A<2>X analogs differ from those previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. The compounds of the instant invention also incorporate a cyclic amine moiety in the A<2> position of the motif. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.

Description: ΉTLE OF THE INVENΉON INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE RELATED APPLICATION The present patent application is a continuation-in-part application of copending application Serial No. 08/412,626, filed March 29, 1995. BACKGROUND OF THE INVENTION The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP. Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M. Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-rαs, Ki4a-r_.,s, Ki4b-ra_ and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal. Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-Aaa^-Aaa^-Xaa" box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 570:583-586 (1984)). Depending on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 67:355-386 (1992); W.R. Schafer and J. Rine, Ann. Rev. Genetics 30:209- 237 (1992)). The Ras protein is one of several proteins that are known to undergo post-translational famesylation. Other famesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also famesylated. James, et al., have also suggested that there are famesylated proteins of unknown structure and function in addition to those listed above. Inhibition of farnesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the Ras oncoprotein intracellularly (N.E. Kohl et al, Science, 260:1934-1937 (1993) and G.L. James et al, Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of ras- dependent tumors in nude mice (N.E. Kohl et al, Proc. Natl. Acad. Sci U.S.A., 97:9141-9145 (1994) and induces regression of mammary and salivary carcinomas in ras transgenic mice (N.E. Kohl et al, Nature Medicine, 1:792-797 (1995). Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck & Co., Rahway, NJ) and compactin (Hancock et al, ibid; Casey et al, ibid; Schafer et al, Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al, Cell, 62:81-88 (1990); Schaber et al, J. Biol. Chem., 265:14701-14704 (1990); Schafer et al, Science, 249:1133-1139 (1990); Manne et al, Proc. Natl. Acad. Sci USA, 57:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. However, direct inhibition of farnesyl-protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis. Inhibitors of farnesyl-protein transferase (FPTase) have been described in two general classes. The first are analogs of farnesyl diphosphate (FPP), while the second class of inhibitors is related to the protein substrates (e.g., Ras) for the enzyme. The peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al, ibid; Reiss et. al, ibid; Reiss et al, PNAS, ? _.:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141,851, University of Texas; N.E. Kohl et al, Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)). In general, deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound. However, the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable. It has recently been reported that farnesyl-protein transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7- 112930). It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516). Imidazole-containing inhibitors of farnesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 Al). It is, therefore, an object of this invention to develop tetrapeptide-based compounds that do not have a thiol moiety, and that will inhibit farnesyl-protein transferase and thus, the post-translational famesylation of proteins. It is a further object of this invention to develop chemotherapeutic compositions containing the compounds of this invention and methods for producing the compounds of this invention. SUMMARY OF THE INVENTION The present invention comprises analogs of the CA^A^X motif of the protein Ras that is modified by famesylation in vivo. These CAlA^X analogs inhibit the farnesylprotein transferase. Furthermore, these C A 1 A-^X analogs differ from those previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol- dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. The compounds of the instant invention also incorporate a cyclic amine moiety in the AT- position of the motif. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production. The compounds of this invention are illustrated by the formulae: - A 1 (CR 1a 2 ) n A 2 (CR 1a 2 ) n V - A 1 (CR 1a 2 ) n A 2 (CR 1a 2 ) n DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention inhibit the famesyl-protein transferase. In a first embodiment of this invention, the famesyl-protein transferase inhibitors are illustrated by the formula I: wherein: Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, RlOO-, Rl lS(0) m -, R 10 C(O)NRl0-, CN, N02, (R 10 )2N- C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or R11OC(O)NR10-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, Rl^O-, R n S(0) m -, R 10 C(O)NRl0_, CN, (R10) N-C(NR10)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, or Rl lθC(O)- NR10-; R and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C2O alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RlO)2, Nθ2, R 10 O-, Rl lS(0)m-, R 10 C(O)NRl0-, CN, (RlO)2N-C(NRlO)-, RWCtO)-, RlOθC(O)-, N3, -N(Rl )2, Rl lθC(O)NRl . and C1-C20 alkyl, and d) C 1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R2 and R3 are combined to form - (CH2)s - ", or R2 or R3 are combined with R6 to form a ring such that R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) C 1 -C6 alkyl unsubstituted or substituted by alkenyl, R 1°0-, R n S(0)m-, R 10 C(O)NRl0-, CN, N3, (R10) 2 N-C(NR1 )-, Rl C(O)-, Rl θC(O)-, -N(RlO)2, or Rl 1OC(O)NR1 _, c) aryl, heterocycle, cycloalkyl, alkenyl, RI^O-, R π S(0)m-, R 10 C(O)NRl0-, CN, N02, (R 10 )2N- C(NRlO)-, RlOC(O)-, Rl θC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C2O alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, (Rl0) 2 NC(O)-, N02, R 10 O-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, (R10) 2 N-C(NR10)-, R10C(O)-, RlOθC(O)-, N3, -N(RlO) 2 , R11OC(O)NR10_ and Cl-C 2 0 alkyl, d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl ; or R5a and R5b are combined to form - (CH 2 )s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0)m » -NC(O)-, and -N(CORlO)- ; R6 is independently selected from hydrogen or Cl-Cβ alkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, N02, R 10 2N-C(NRlO)-, RIOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lθC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RHS(0) m -, Rl C(O)NH-, CN, H2N- C(NH)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl0θC(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 1°0-, R n S(0) m -, Rl°C(O)NRl0-, CN, Nθ2, (Rl°)2N-C- (NRlO)-, Rl C(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, and c) C 1 -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, R1 C(O)NR1 -, CN, (RlO) 2 N-C(NRl )-, RlOc(O)-, Rl θC(O)-, N3, -N(RlO)2, OΓ RHOC(O)NR10- ; RlO is independently selected from hydrogen, C . -C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Al and A^ are independently selected from: a bond, -CH-CH-, -CΞC-, -C(O)-, -C(O)NRl0-, -NRlOC(O)-, O, -N(R10)-, -S(0)2N(RlO)-, -N(Rl )S(O)2-, or S(0) m ; Q is a substituted or unsubstituted nitrogen-containing C6-C9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A is S(0)m and V is not hydrogen if A is a bond, n is 0 and A-2 is S(0)m; W is a heterocycle; X, Y and Z are independently H2 or O; or the pharmaceutically acceptable salts thereof. In a second embodiment of this invention the prodrugs of compounds of formula I are illustrated by the formula II: V - A 1 (CR 1 a 2 ) n A 2 (CR 1 a 2 ) n wherein: Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, RlOO-, R n S(0) m -, Rl0c(O)NRl0-, CN, Nθ2, (RlO)2N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, or Rl lOC(O)NRl0-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, Rl^O-, RUS(0) m -, Rl c(O)NRl0-, CN, (R10) 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, N3, -N(Rl )2, or RHθC(O)- NRlO-; R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RlO)2, N02, Rl°0-, Rl lS(0)m-, R1°C(0)NR1 -, CN, (RlO)2N-C(NRlO)-, R10C(O)-, RlOθC(O)-, N3, -N(RlO)2, Rl lOC(O)NRl0- and C1-C2O alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R2 and R3 are combined to form - (CH2)s - ; or R2 or R3 are combined with R6 to form a ring such that R4a 5 R4b, R7a and R7b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, Rl^O-, RHS(0)m-, Rl°C(O)NRl0-, CN, N3, (R10)2N-C(NR10)-, Rl C(O)-, RlOθC(O)-, -N(RlO) 2 , or Rl 10C(0)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, Rl^O-, Rl lS(0)m-, Rl°C(O)NRl0-, CN, N02, (R 10 )2N- C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, or Rl lOC(O)NRl0., and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C2O alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, (RlO) 2 NC(0)-, N02, Rl°0-, Rl lS(0)m-, Rl C(O)NRl0-, CN, (R1 ) 2 N-C(NR1 )-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, R11OC(O)NR10- and C1-C20 alkyl, d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R5a and R5b are combined to form - (CH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0)m, -NC(O)-, and -N(CORlO)- ; R6 is independently selected from hydrogen or C1-C6 alkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, N02, Rl°2N-C(NRlO)-, RlOC(O)-, Rl θC(O)-, N3, -N(RlO)2, or Rl lθC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RHS(0) m -, Rl°C(0)NH-, CN, H2N- C(NH)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, or Rl0θC(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, Rl°0-, Rl lS(0)m-, Rl°C(O)NRl0-, CN, NO2, (Rl°)2N-C- (NRl )-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, R1°C(0)NR1 -, CN, (RlO)2N-C(NRlO)-, R10C(O)-, RlOθC(O)-, N3, -N(RlO)2, or Rl lOC(O)NRl0- ; RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Rl2 is a) substituted or unsubstituted C 1-C8 alkyl, substituted or unsubstituted C5-C8 cycloalkyl, or substituted or unsubstituted cyclic amine, wherein the substituted alkyl, cycloalkyl or cyclic amine is substituted with 1 or 2 substituents independently selected from: 1) C1-C6 alkyl, 2) aryl, 5) -OR 0, or b) Rl3 is independently selected from hydrogen and C1-C6 alkyl; Rl4 is independently selected from C1-C6 alkyl; Al and A^ are independently selected from: a bond, -CH-CH-, -CHC-, -C(O)-, -C(O)NRl0-, -NRlOC(O)-, O, -N(RlO)-, -S(0)2N(RlO)-, -N(RlO)S(0)2-, or S(0) m ; Q is a substituted or unsubstituted nitrogen-containing C6-C9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A^ is S(0) m ; W is a heterocycle; X, Y and Z are independently H2 or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 4 or 5; t is 3, 4 or 5; and u is 0 or 1 ; or the pharmaceutically acceptable salts thereof. In a third embodiment of this invention, the inhibitors of farnesyl transferase are illustrated by the formula III: V - A 1 (CR 1a 2 ) n A 2 (CR 1 a 2 ) n wherein: Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, Rl^O-, Rl lS(0) m -, R1°C(0)NR10-, CN, Nθ2, (Rl°)2N- C(NRl )-, RlOC(O)-, RlOθC(O)-, N3, -N(Rl )2, or Rl lθC(O)NRl0-, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, Rl^O-, Rl lS(0)m-, R 10 C(O)NRl0_, CN, (R10) 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lθC(O)- NR10-; R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl-C 2 0 alkyl, C 2 -C 2 _ alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RlO) 2 , N0 2 , Rl O-, RHS(0)m-, R1°C(0)NR10-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , Rl lOC(O)NRl0- and Cl-C 2 0 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R2 and R3 are combined to form - (CH 2 )s - ; or R2 or R3 are combined with R6 to form a ring such that R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R 1^0-, R u S(0)m-, Rl°C(O)NRl0-, CN, N3, (R10)2N-C(NR10)-, RlOC(O)-, RlOθC(O)-, -N(RlO) 2 , or Rl 10C(0)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, Rl lS(0)m-, Rl°C(O)NRl0-, CN, N0 , (RlO)2N- C(NRlO)-, Rl C(O)-, RI OC(O)-, N3, -N(Rl ) 2 , or Rl lθC(O)NRl0-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C 10 cycloalkyl; R6 is independently selected from hydrogen or C1-C6 alkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, Rl O-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, N02, R1°2N-C(NR10)-, R10C(O)-, RlOθC(O)-, N3, -N(Rl ) 2 , or Rl lθC(O)NRl0-, and c) C 1 -C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, R lS(0) m -, Rl°C(0)NH-, CN, H 2 N- C(NH)-, RlOC(O)-, RlOθC(O)-, N3, -N(Rl ) 2 , or Rl0θC(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0)m-, Rl°C(O)NRl0-, CN, N0 2 , (RlO) 2 N-C- (NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, R1°C(0)NR10-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, Rl θC(O)-, N3, -N(Rl ) 2 , or Rl lOC(O)NRl0-; RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Al and A*2 are independently selected from: a bond, -CH-CH-, -C=C-, -C(O)-, -C(O)NRl0-, -NRlOC(O)-, O, -N(R10)-, -S(0)2N(RlO)-, -N(Rl0)S(O)2-, or S(0) m ; Q is a substituted or unsubstituted nitrogen-containing C6-C9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A^ is S(0)m; W is a heterocycle; X, Y and Z are independently H 2 or O; or the pharmaceutically acceptable salts thereof. In a fourth embodiment of this invention the prodrugs of compounds of formula III are illustrated by the formula IV: V - A 1 (CR 1a 2 ) n A 2 (CR 1a 2 ) n wherein: Rla and Ri are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, Rl^O-, R lS(0) m -, Rl0C(O)NRl0-, CN, N0 2 , (Rl°)2N- C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, or R11OC(O)NR10-, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, Rl^O-, R n S(0) m -, Rl0C(O)NRl0-, CN, (R10) 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lθC(O)- NRlO-; R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl-C20 alkyl, C2-C 2 0 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RlO) 2 , N0 2 , RlOO-, Rl lS(0)m-, R 10 C(O)NRl0_, CN, (RlO)2N-C(NRlO)-, RIOC(O)-, RlOθC(O)-, N3, -N(Rl°)2, R1 10C(0)NR10- and C1-C2O alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R2 and R3 are combined to form - (CH2)s - ; or R2 or R3 are combined with R6 to form a ring such that R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) C 1 -C6 alkyl unsubstituted or substituted by alkenyl, R 10θ-, Rl lS(0) m -, R 10 C(O)NRl0-, CN, N3, (R 10 )2N-C(NRlO)_. Rl C(O)-, RlOθC(O)-, -N(RlO)2, or Rl lθC(O)NRl0-, c) aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, R H S(0)m-, Rl°C(O)NRl0-, CN, N02, (Rl°)2N- C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R6 is independently selected from hydrogen or C1-C6 alkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, N02, Rlθ2N-C(NRlO)-, R10C(O)-, RlOθC(O)-, N3, -N(RlO)2, or Rl 10C(0)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl°C(0)NH-, CN, H2N- C(NH)-, RlOC(O)-, Rl0θC(O)-, N3, -N(RlO) 2 , or Rl0θC(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, Rl^O-, Rl lS(0)m-, Rl°C(O)NRl0-, CN, N0 2 , (RlO) 2 N-C- (NRlO)-, RlOc(O)-, Rl θC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, R1°C(0)NR10-, CN, (Rl ) 2 N-C(NRlO)-, RlOc(O)-, Rl θC(O)-, N3, -N(RlO) 2 , O Γ RHOC(O)NR10- ; RIO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Al and A^ are independently selected from: a bond, -CH=CH-, -C≡C-, -C(O)-, -C(O)NRl0-, -NRlOC(O)-, O, -N(R10)-, -S(O)2N(Rl0)-, -N(Rl0)S(O)2-, or S(0) m ; Q is a substituted or unsubstituted nitrogen-containing C6-C9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle; provided that V is not hydrogen if A is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A^ is S(0)m; or the pharmaceutically acceptable salts thereof. In a more preferred embodiment of this invention, the Ras farnesyl transferase inhibitors are illustrated by the Formula I: - A 1 (CR 1 a 2 ) n A 2 (CR 1 a 2 ) n wherein: Rla is independently selected from: hydrogen or Cl-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, Rl^O-, -N(RlO)2 or alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, Rl^O-, or -N(RlO) 2 ; R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C 1 -C 10 alkyl, C -C 10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N0 2 , Rl O-, Rl lS(0)m-, R 10 C(O)NRl0-, CN, (R10) 2 N-C(NR10)-, R10C(O)-, Rl0θC(O)-, N3, -N(RlO)2, RHOC(O)NR10- and Cl-C 2 0 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R2 and R3 are combined to form - (CH2)s - ; or R2 or R3 are combined with R6 to form a ring such that R4a and R7 are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, RlOO-, Rl lS(0)m-, R 10 C(O)NRl0_. CN, N3, (R10)2N-C(NR10)_, RlOC(O)-, RlOθC(O)-, -N(RlO)2, or Rl lθC(O)NRl0-, c) aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, R n S(0) m -, Rl0c(O)NRl0-, CN, Nθ2, (Rl°)2N- C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(Rl )2, or RHθC(O)NRl0-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- C 10 cycloalkyl; R4b and R 7 b are hydrogen; R5a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glutamine, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C 1 -C 10 alkyl, C2-C 10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, Nθ2, Rl°0-, Rl lS(0) m -, R10C(O)NR10-, (RlO)2NC(0)-, CN, (R10) 2 N-C(NR10)-, Rlθc(θ)-, RlOθC(O)-, N3, -N(RlO)2, RHOC(0)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl; R5b is selected from: a) hydrogen, and b) C1-C3 alkyl; R6 is independently selected from hydrogen or C1-C6 alkyl; R8 is independently selected from: a) hydrogen, b) C 1 -Cβ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C l -C6 perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR10-, CN, Nθ2, (R10) 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, -N(Rl )2, or Rl lOC(O)NRl0-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, Rl°0-, Rl0C(O)NRl0-, (R10) 2 N-C(NR10)-, RlOc(O)-, RlOθC(O)-, -N(RlO)2, or RHOC(O)NR10- ; R9 is selected from: a) hydrogen, b) C 2 -C6 alkenyl, C 2 -C6 alkynyl, C 1-C6 perfluoroalkyl, F, Cl, RIOO-, Rl lS(0)m-, R1°C(0)NR10-, CN, N0 2 , (RlO)2N- C(NRlO)-, RlOC(O)-, RlOθC(O)-, -N(RlO) 2 , or Rl lOC(O)NRl0-, and c) C 1 -C6 alkyl unsubstituted or substituted by C 1 -C6 perfluoroalkyl, F, Cl, R O-, Rl lS(0) m -, R!0C(O)NR10-, CN, (Rl ) N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, -N(RlO) 2 , or Rl lOC(O)NRl0-; R O is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl is independently selected from C1-C6 alkyl and aryl; Q is selected from: Al and A^ are independently selected from: a bond, -CH=CH-, -C≡C-, -C(O)-, -C(O)NRl0-, O, -N(RlO)-, or S(0) m ; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(0) m and V is not hydrogen if Al is a bond, n is 0 and A- is S(0)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H 2 or O; or the pharmaceutically acceptable salts thereof. In a second more preferred embodiment of this invention, the prodrugs of the preferred compounds of Formula I are illustrated by the Formula II: - A 1 (CR 1a 2 ) n A 2 (CR 1a 2 ) n wherein: Rla is independently selected from: hydrogen or Cl-C6 alkyl; Rib is independently selected from: a"> hydrogen, b) aryl, heterocycle, cycloalkyl, Rl^O-, -N(R 10) 2 or alkenyl, c) C 1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, or -N(RlO) 2 ; R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-ClO alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N0 2 , RlOO-, Rl lS(0)m-, R 10 C(O)NRl0-, CN, (RlO) 2 N-C(NRlO)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO) 2 , Rl lθC(O)NRl0- and Cl-Qo alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl; or R2 and R3 are combined to form - (CH 2 ) S - ; or R2 or R3 are combined with R6 to form a ring such that R4a and R^ are independently selected from: a) hydrogen, b) C 1 -C6 alkyl unsubstituted or substituted by alkenyl, R l^O-, Rl lS(0)m-, Rl°C(O)NRl0-, CN, N3, (R10)2N-C(NR10)-, RlOC(O)-, RlOθC(O)-, -N(RlO) 2 , or Rl lθC(O)NRl0-, c) aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, R n S(0)m-, Rl°C(O)NRl0-, CN, N0 , (Rl ) 2 N- C(NRlO)-, Rl C(O)-, RlOθC(O)-, N3, -N(RlO) , or RHOC(O)NRl0-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- ClO cycloalkyl; R4b and R^b are hydrogen; R5a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glutamine, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N0 2 , RlOO-, RHS(0)m-, R1°C(0)NR10-, (Rl0)2NC(O)-, CN, (RlO) 2 N-C(NRlO)-, R10C(O)-, RlOθC(O)-, N3, -N(Rl ) 2 , Rl lθC(O)NRl0- and Cl-C 2 0 alkyl, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; R5b is selected from: a) hydrogen, and b) C1-C3 alkyl; R6 is independently selected from hydrogen or C1-C6 alkyl; R8 is independently selected from: a) hydrogen, b) C 1 -C6 alkyl, C 2 -C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, R10C(O)NR10-, CN, Nθ2, (RlO)2N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, -N(RlO) 2 , or Rl lOC(O)NRl0-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, RlOO-, Rl0C(O)NRl0-, (Rl0) 2 N-C(NRl0)-, RlOC(O)-, RlOθC(O)-, -N(RlO) 2 , or R1 10C(0)NR10-; R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C l -Cβ perfluoroalkyl, F, Cl, RIOO-, Rl lS(0) m -, R 10 C(0)NR10_, CN, N02, (R 10 )2N- C(NRlO)-, RlOC(O)-, RlOθC(O)-, -N(RlO)2, or Rl lOC(O)NRl0-, and c) C 1 -C6 alkyl unsubstituted or substituted by C l -C6 perfluoroalkyl, F, Cl, RlOO-, Rl lS(0) m -, R 10 C(O)NRl0-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, -N(Rl ) 2 , or RHθC(O)NRl0-; R O is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Rl2 is a) substituted or unsubstituted C 1-C8 alkyl, substituted or unsubstituted C5-C8 cycloalkyl, or substituted or unsubstituted cyclic amine, wherein the substituted alkyl, cycloalkyl or cyclic amine is substituted with 1 or 2 substituents independently selected from: 1) C1-C6 alkyl, 2) aryl, 5) -ORlO, or Rl3 is independently selected from hydrogen and C1-C6 alkyl; Rl4 is independently selected from C1-C6 alkyl; Q is selected from: A! and A2 are independently selected from: a bond, -CH-CH-, -CΞC-, -C(O)-, -C(O)NRl0-, O, -N(RlO)-, or S(0) m ; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(0)m and V is not hydrogen if A is a bond, n is 0 and A2 is S(0)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; or the pharmaceutically acceptable salts thereof. In a third more preferred embodiment of this invention, the inhibitors of farnesyl transferase are illustrated by the formula III: - A 1 (CR 1a 2 ) n A 2 (CR 1 a 2 ) n wherein: Rla is independently selected from: hydrogen or Cl-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, RlOO-, -N(RlO)2 or alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, Rl^O-, or -N(RlO)2; R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-ClO alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, Nθ2, RlOO-, Rl lS(0) m -, R 10 C(O)NRl0_, CN, (Rl°)2N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, Rl lOC(O)NRl0- and C1-C2O alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl; or R2 and R3 are combined to form - (CH2)s - ; or R2 or R3 are combined with R6 to form a ring such that R4a and R7a are independently selected from: a) hydrogen, b) C 1-C6 alkyl unsubstituted or substituted by alkenyl, R 10θ-, Rl lS(0)m-, Rl°C(O)NRl0-, CN, N3, (R10) 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, -N(RlO)2, or Rl lθC(O)NRl0-, c) aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, Rl lS(0) m -, Rl°C(O)NRl0-, CN, N02, (Rl°)2N- C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(Rl )2, or RHθC(O)NRl0-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- ClO cycloalkyl; R4b and R 7b are hydrogen; R6 is independently selected from hydrogen or C1-C6 alkyl; R8 is independently selected from: a) hydrogen, b) C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C l -C6 perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR10-, CN, Nθ2, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, -N(RlO)2, or Rl lOC(O)NRl0-, and c) C 1 -C6 alkyl substituted by C 1 -C6 perfluoroalkyl, R 10θ-, Rl0C(O)NRl0-, (RlO)2N-C(NRlO)-, Rl C(O)-, RlOθC(O)-, -N(RlO)2, or R110C(0)NR10-; R is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, Rl lS(0)m-, R1°C(0)NR10-, CN, Nθ2, (Rl°)2N- C(NRlO)-, RlOC(O)-, RlOθC(O)-, -N(RlO)2, or RHθC(O)NRl0-, and c) C 1 -C6 alkyl unsubstituted or substituted by C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, Rl lS(0) m -, R1°C(0)NR10-, CN, (RlO)2N-C(NRlO)-, RlOc(O)-, RlOθC(O)-, -N(RlO)2, OΓ RHOC(O)NR10-; RlO is independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from Cl-C6 alkyl and aryl; Q is selected from: A and A2 are independently selected from: a bond, -CH-CH-, -C=C-, -C(O)-, -C(O)NRl0-, O, -N(RlO)-, or S(0) m ; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, and provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(0)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; or the pharmaceutically acceptable salts thereof. In a fourth more preferred embodiment of this invention, the prodrugs of the preferred compounds of Formula III are illustrated by the Formula IV: wherein: Rla is independently selected from: hydrogen or C . -C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, RI^O-, -N(RlO) 2 or alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, Rl^O-, or -N(RlO) 2 ; R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C 1 -C 10 alkyl, C2-C 10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, Rl lS(0)m-, R 10 C(O)NRl0-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(Rl ) 2 , Rl lθC(O)NRl0- and -Qo alkyl, and d) C l -Cβ alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R2 and R3 are combined to form - (CH 2 ) S - ; or R2 or R3 are combined with R6 to form a ring such that R4a and R7 are independently selected from: a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by alkenyl, R 0θ-, Rl lS(0) m -, Rl°C(O)NRl0-, CN, N3, (R1°)2N-C(NR10)-, RlOC(O)-, RlOθC(O)-, -N(RlO)2, or Rl 10C(0)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, Rl^O-, R π S(0) m -, Rl°C(O)NRl0-, CN, NO2, (R i0 )2N- C(NRlO)-, Rl0c(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- C 10 cycloalkyl; R4b and R7b are hydrogen; R6 is independently selected from hydrogen or C1-C6 alkyl; R8 is independently selected from: a) hydrogen, b) C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR10-, CN, N02, (RlO) 2 N-C(NRlO)-, RlOc(O)-, RlOθC(O)-, -N(RlO) 2 , or Rl lθC(O)NRl0-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, RlOO-, Rl0C(O)NRl0-, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, -N(RlO) 2 , or RHOC(O)NR10- ; R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, Rl lS(0)m-, R1°C(0)NR10-, CN, NO2, (Rl°)2N- C(NRlO)-, Rl C(O)-, RlOθC(O)-, -N(RlO) 2 , or Rl lOC(O)NRl0-, and c) C 1 -C6 alkyl unsubstituted or substituted by C 1 -C6 perfluoroalkyl, F, Cl, Rl O-, RHS(0) m -, R!0C(O)NR10-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, -N(RlO)2, or Rl lθC(O)NRl0-; RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Q is selected from: A and A2 are independently selected from: a bond, -CH-CH-, -C=C-, -C(O)-, -C(O)NRl0-, O, -N(RlO)-, or S(0) m ; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(0)m W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; or the pharmaceutically acceptable salts thereof. The preferred compounds of this invention are as follows: N-[(lH-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-l,2,3,4- tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester N-[(lH-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]- 1,2,3,4- tetrahydro-3(S)-isoquinolinecarbonyl-methionine N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-l,2,3,4-tetrahydro- 3(S)-isoquinolinecarbonyl-methionine methyl ester N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-l,2,3,4-tetrahydro- 3 (S Hsoquinolinecarbonyl-methionine N-[(lH-imidazol-4-ylpropionyl)-2(S)-amino-3(S)-methylpentyl]-l,2,3,4- tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester N-[(lH-imidazol-4-ylpropionyl)-2(S)-amino-3(S)-methylpentyl]- 1 ,2,3,4- tetxahydro-3(S)-isoquinolinecarbonyl-met onine N-[(l-(4-cyanobenzyl) lH-imidazol-5-yl)acetyl]-2(S)-amino-3(S)- methylpentyl]- 1 ,2,34-tetrahydro-3(S)-isoquinolinecarbonyl methionine methyl ester N-[(l-(4-cyanobenzyl)-lH-imidazol-5-yl)acetyl]-2(S)-amino-3(S)- methylpentyl]- 1 ,2,34-tetrahydro-3(S)-isoquinolinecarbonyl methionine N-[N-(4-cyanobenzyl)-L-pyroglutamyl-2(S)-amino-3(S)-methylpentyl]- l,2,3,4-tetrahyc_ro-3(S)-isoquinolinecarbonyl-methionine methyl ester N-[N-(4-cyanobenzyl)-L-pyroglutamyl-2(S)-amino-3(S)-methylpentyl]- l,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine or the pharmaceutically acceptable salts or optical isomer thereof. Specific examples of compounds of the invention are: N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-l,2,3,4-tetrahydro- 3(S)-isoquinolinecarbonyl-methionine N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]- 1 ,2,3,4-tetrahydro- 3(S)-isoquinolinecarbonyl-methionine methyl ester or the pharmaceutically acceptable salts or optical isomer thereof. In the present invention, the amino acids which are disclosed are identified both by conventional 3 letter and single letter abbreviations as indicated below: The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. As used herein, "cycloalkyl" is intended to include non- aromatic cyclic hydrocarbon groups having the specified number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. "Alkenyl" groups include those groups having the specified number of carbon atoms and having one or several double bonds. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like. As used herein, "aryl" is intended to include any stable monocyclic, bicyclic or tricyclic carbon ring(s) of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like. The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11- membered bicyclic or stable 11-15 membered tricyclic heterocycle 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. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydro- benzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide, pyridonyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolinyl N-oxide, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydro-quinolinyl, thiamoφholinyl, thiamoφholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl. As used herein, the terms "substituted aryl", "substituted heterocycle" and "substituted cycloalkyl" are intended to include the cyclic group which is substituted with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Cl- C6 alkyl)2, Nθ2, CN, (C1-Q3 alkyl)0-, -OH, (C1-C6 alkyl)S(0) m -, (Cl- C6 alkyl)C(0)NH-, H2N-C(NH)-, (C1-C6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)-, N3,(Cl-C6 alkyl)OC(0)NH- and C1-C2O alkyl. The following structure: represents a cyclic amine moiety having 5 or 6 members in the ring, such a cyclic amine which may be optionally fused to a phenyl or cyclohexyl ring. Examples of such a cyclic amine moiety include, but are not limited to, the following specific structures: It is also understood that substitution on the cyclic amine moiety by R^ a and R&b may be on different carbon atoms or on the same carbon atom. When R3 and R4 are combined to form - (CH2)s -• cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to: When R^ a and R^b are combined to form - (CH2)s -. cyclic moieties as described hereinabove for R3 and R^ are formed. In addition, such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include, but are not limited to: As used herein, the phrase "nitrogen containing C6-C9 bicyclic ring system wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle" which defines moiety "Q" of the instant invention includes but is not limited to the following ring systems: It is well understood by persons of ordinary skill in the art that the "side chain" of the naturally occurring amino acid glycine is a hydrogen moiety. The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenyl- acetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like. It is intended that the definition of any substituent or variable (e.g., RlO, Z, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, -N(RlO)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth below. Preferably, Rla and Rib are independently selected from: hydrogen, -N(R 8 )2, R 8 C(0)NR 8 - or C1-C6 alkyl unsubstituted or substituted by -N(R 8 )2, R 8 0- or R C(0)NR 8 -. Preferably, R2 is the sidechain of glycine (hydrogen). Preferably, R is selected from: a) a side chain of a naturally occurring amino acid, b) substituted or unsubstituted C 1-C20 alkyl, wherein the substituent is selected from F, Cl, Br, N(RlO)2, N02, R 10 O-, Rl lS(0) m -, R1°C(0)NR10-, CN, (R10) 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, RUOC(0)NR10- and C1-C2O alkyl, and c) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R3 is combined with R6 to form pyrrolidinyl ring. Preferably, R4a, R4b, R7a and R 7 b are independently selected from: hydrogen, -C6 alkyl, aryl and benzyl. Preferably, R^a and R-5b are independently selected from: a side chain of a naturally occurring amino acid, methionine sulfoxide, methionine sulfone and unsubstituted or substituted C1-C6 alkyl . Preferably, R6 is: hydrogen or is combined with R3 to form pyrrolidinyl ring. Preferably, R 8 is selected from: hydrogen, perfluoroalkyl, F, Cl, Br, RlOO-, RHS(0) m -, CN, N02, R1°2N-C(NR10)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl 10C(0)NR10- and C1-C6 alkyl. Preferably, R9 is hydrogen. Preferably, R 10 is selected from H, C 1 -Cβ alkyl and benzyl. Preferably, Rl2 is selected from C1-C6 alkyl and benzyl. Preferably, Al and A2 are independently selected from: a bond, -C(O)NRl0-, -NRIOC(O)-, O, -N(R10)-, -S(0) N(RlO)- and- Preferably, Q is a tetrahydroisoquinolinyl moiety. Preferably, V is selected from hydrogen, heterocycle and aryl. Preferably, n, p and r are independently 0, 1, or 2. Preferably t is 3. The pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety conventional chemical methods. Generally, the salts are prepared by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents. The compounds of the invention can be synthesized from their constituent amino acids by conventional peptide synthesis techniques, and the additional methods described below. Standard methods of peptide synthesis are disclosed, for example, in the following works: Schroeder et al, "The Peptides", Vol. I, Academic Press 1965, or Bodanszky et al, "Peptide Synthesis", Interscience Publishers, 1966, or McOmie (ed.) "Protective Groups in Organic Chemistry", Plenum Press, 1973, or Barany et al, "The Peptides: Analysis, Synthesis, Biology" 2, Chapter 1, Academic Press, 1980, or Stewart et al, "Solid Phase Peptide Synthesis", Second Edition, Pierce Chemical Company, 1984. The teachings of these works are hereby incoφorated by reference. Abbreviations used in the description of the chemistry and in the Examples that follow are: Compounds of this invention are prepared by employing the reactions shown in the following Reaction Schemes A-J, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Some key bond-forming and peptide modifying reactions are: Reaction A Amide bond formation and protecting group cleavage using standard solution or solid phase methodologies. Reaction B Preparation of a reduced peptide subunit by reductive alkylation of an amine by an aldehyde using sodium cyanoborohydride or other reducing agents. Reaction C Deprotection of the reduced peptide subunit Reaction D Peptide bond formation and protecting group cleavage using standard solution or solid phase methodologies. Reaction E Preparation of a reduced subunit by borane reduction of the amide moiety. Reaction Schemes A-E illustrate bond-forming and peptide modifying reactions incoφorating acyclic peptide units. It is well understood that such reactions are equally useful when the - NHC(RA) - moiety of the reagents and compounds illustrated is replaced with the following moiety: These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the reactions described in the Reaction Schemes. REACΉON SCHEME A Reaction A. Coupling of residues to form an amide bond REACπON SCHEME B Reaction B. Preparation of reduced peptide subunits by reductive alkylation REACTION SCHEME C Reaction C. Deprotection of reduced peptide subunits REACTION SCHEME D Reaction D. Coupling of residues to form an amide bond REACTION SCHEME E Reaction E. Preparation of reduced dipeptides from peptides where RA is R2, R3, R5a or R5b as previously defined; R4a and R4b are as previously defined; and R is an appropriate protecting group for the carboxylic acid. Reaction Schemes F - M illustrate reactions wherein the non- sulfhydryl-containing moiety at the N-terminus of the compounds of the instant invention is attached to an acyclic peptide unit which may be further elaborated to provide the instant compounds. It is well understood that such reactions are equally useful when the - NHC(RA) - moiety of the reagents and compounds illustrated is replaced with the following moiety: These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the reactions described in Reaction Schemes A - E. The intermediates whose synthesis are illustrated in Reaction Schemes A and C can be reductively alkylated with a variety of aldehydes, such as I, as shown in Reaction Scheme F. The aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses. 1988, 67, 69-75, from the appropriate amino acid (Reaction Scheme F). The reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloroethane, methanol or dimethylformamide. The product II can be deprotected to give the final compounds HI with trifluoroacetic acid in methylene chloride. The final product HI is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine III can further be selectively protected to obtain IV, which can subsequently be reductively alkylated with a second aldehyde to obtain V. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole VII can be accomplished by literature procedures. Alternatively, the protected dipeptidyl analog intermediate can be reductively alkylated with other aldehydes such as l-trityl-4- carboxaldehyde or l-trityl-4-imidazolylacetaldehyde, to give products such as VHI (Reaction Scheme G). The trityl protecting group can be removed from VHI to give IX, or alternatively, VHI can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole X. Alternatively, the dipeptidyl analog intermediate can be acylated or sulfonylated by standard techniques. The imidazole acetic acid XI can be converted to the acetate Xiπ by standard procedures, and XIII can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XIV. Hydrolysis and reaction with the protected dipeptidyl analog intermediate in the presence of condensing reagents such as l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDC) leads to acylated products such as XV. If the protected dipeptidyl analog intermediate is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XVI in Reaction Scheme I, the protecting groups can be subsequently removed to unmask the hydroxyl group (Reaction Schemes I, J). The alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as XX. In addition, the fully deprotected amino alcohol XXI can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXII (Reaction Scheme K), or tertiary amines. The Boc protected amino alcohol XVHI can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXUI (Reaction Scheme L). Treating XVIII with lj'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXUI . The aziridine reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product XXIV . In addition, the protected dipeptidyl analog intermediate can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXX, as shown in Reaction Scheme M. When R' is an aryl group, XXX can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XXXI. Alternatively, the amine protecting group in XXX can be removed, and O-alkylated phenolic amines such as XXXII produced. Similar procedures as are illustrated in Reaction Schemes F- M may be employed using other peptidyl analog intermediates such as those whose synthesis is illustrated in Reaction Schemes B - E. Reaction Schemes N-R illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic strategies for preparing alkanols that incoφorate other heterocyclic moieties for variable W are also well known in the art. REACTION SCHEME F REACTION SCHEME F (continued REACTION SCHEME G REACTION SCHEME H XIII XIV REACTION SCHEME I REACΗON SCHEME J XVI REACΗON SCHEME J (CONΉNUED REACTION SCHEME K REACTION SCHEME L REACΗON SCHEME M XXV XXVI XXVII XXVIII XXIX REACTION SCHEME M (continued) REACTION SCHEME N NaBH 4 (excess) REACTION SCHEME P REACΉON SCHEME O NaBH 4 (excess) REACTION SCHEME R excess NaBH 4 The instant compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors. Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras formation (i.e., neurofibromin (NF-1), neu, scr, abl, lck, fyn) or by other mechanisms. The compounds of the instant invention inhibit famesyl- protein transferase and the famesylation of the oncogene protein Ras. The instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575- 4580 (1995)). Such anti-angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization. The compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment. For example, a component of NF- 1 is a benign proliferative disorder. The instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256: 1331-1333 (1992). The compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1:541-545(1995). The instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al. American Journal of Pathology, 142: 1051-1060 (1993) and B. Cowley, Jr. et dλ.FASEB Journal, 2: A3160 (1988)). The compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration. For oral use of a chemotherapeutic compound according to this invention, the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and com starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents include lactose and dried com starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic. The present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may be introduced into a patient's intramuscular blood-stream by local bolus injection. When a compound according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms. In one exemplary application, a suitable amount of compound is administered to a mammal undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg of body weight to about 20 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 10 mg/kg of body weight per day. The compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and quantity of famesyl-protein transferase (FPTase) in a composition. Thus the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to allow the FPTase to farnesylate the substrate, the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested. It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain famesyl-protein transferase and quantitating the enzyme. Thus, potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract containing an unknown amount of famesyl-protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention. The concentration of a sufficiently potent inhibitor (i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel) required to inhibit the enzymatic activity of the sample by 50% is approximately equal to half of the concentration of the enzyme in that particular sample. EXAMPLES Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species and conditions are intended to be further illustrative of the invention and not limitative of the reasonable scope thereof. The standard workup referred to in the examples refers to solvent extraction and washing the organic solution with 10% citric acid, 10% sodium bicarbonate and brine as appropriate. Solutions were dried over sodium sulfate and evaporated in vacuo on a rotary evaporator. EXAMPLE 1 Preparation of N-[( lH-imidazol-4-ylacetyl-2(S)-amino)-3(S)- methylpentyl]-l,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester and N-[(lH-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-l,2,3,4- tetrahydro-3(S)-isoquinolinecarbonyl-methionine trifluoroacetate Step A: N-(t-Butoxycarbonyl)-isoleucinal This compound was synthesized by applying the procedure of Goel, Krolls, Stier, and Kesten [Organic Syntheses, 67, 69 (1988)] to N-(t-butoxycarbonyl-isoleucine. The compound was obtained as a colorless oil, which was used without purification. Step B: N-[(2S)-(t-Butyloxycarbonylamino)-3(S)-methylpentyl)- l,2,3,4-tetrahydro-3(S)-isoquinolinecarboxylic acid benzyl ester. N-(t-Butyloxycarbonyl)-isoleucinal (1.5 g, 0.0070 mol) and l,2,3,4-tetrahydro-3(S)-isoquinolinecarboxylic acid benzyl ester (2.23 g, 0.0084 mol) were dissolved in MeOH (30 mL) at ambient temperature under nitrogen and treated with 3A molecular sieves (3 g) and sodium cyanoborohydride (0.66 g, 0.0105 mol) with stirring. After 18 h the mixture was filtered, concentrated, and the residue was partitioned between EtOAc (50 mL) and satd aq NaHC03 solution (50 mL). The basic layer was washed with EtOAc (3 x 30 mL), the organics combined, washed with brine, and dried (Na 2 Sθ4). Filtration and concentration to dryness gave the title compound as a colorless oil after chromatography (Si0 2 , hexane: EtOAc, 6:1). iH NMR (CDCI3) 67.02-7.35 (m, 9H), 5.11 (s, 2H), 4.6-4.78 (m, IH), 3.98 (s, 2H), 3.84 (t, IH, J=5 Hz), 3.64- 3.75 (m, IH), 3.05-3.27 (m, 2H), 2.84 (dd, IH, J=5, 13 Hz), 2.59 (dd, IH, J=5, 13 Hz), 1.70-1.82 (m, IH), 1.40 (s, 9H), 1.26-1.37 (m, IH), 0.97- 1.13 (m, IH), 0.92 (d, 3H, J=7 Hz), 0.86 (t, 3H, J= 7 Hz). Step C: N-[(2S)-(t-Butyloxycarbonylamino)-3(S)-methylpentyl)- 1.2.3.4-tetrahydro-3(S)-isoquinolinecarboxylic acid N-[(2S)-(t-Butyloxycarbonylamino)-3(S)-methylpentyl)- l,2,3,4-tetrahydro-3(S)-isoquinolinecarboxylic acid benzyl ester (1.5 g, 0.0032 mol) was dissolved in methanol (50 mL) - EtOAc (50 mL), treated with 10% palladium on carbon (0.15 g) and hydrogenated under a balloon of hydrogen for 4 h. Filtration and concentration to dryness gave the title compound as a white solid which was used without further purification. Step D: N-[2(S)-(t-Butyloxycarbonylamino-3(S)-methylpentyl]- l,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester N-[(2S)-(t-Butyloxycarbonylamino)-3(S)-methylpentyl)- 1 ,2,3,4-tetrahydro-3(S)-isoquinolinecarboxylic acid (0.67 g, 0.00178 mol) was dissolved in DMF (10 mL) with stirring at ambient temperature and treated with EDC (0.376 g, 0.00196 mol), HOBT (0.265 g, 0.00196 mol), and methionine methyl ester hydrochloride (0.427 g, 0.00214 mol). The pH was adjusted to 7 with Et3N (0.546 mL, 0.00392 mol) and stirring was continued for 18 h. The reaction mixture was concentrated, then partitioned between EtOAc (50 mL) - H2θ (50 mL). The aq layer was washed with EtOAc (2 x 30 mL), the organics combined, washed with aq satd NaHCθ3 solution, brine, and dried (Na2Sθ4). Filtration and concentration gave the title compound after chromatography (Siθ2, CH2CI2: MeOH, 99.5:0.5). J H NMR (CD3OD) 67.05-7.2 (m, 4H), 4.43-4.52 (m, IH), 3.98 (d, IH, J=13 Hz), 3.68-3.82 (m, 2H), 4.87 (s, 3H), 3.55 (t, IH, J=6 Hz), 2.96-3.14 (m, 2H), 2.84 (dd, IH, J= 5, 13 Hz), 2.70 (dd. IH. J= 5,13 Hz), 1.88-2.14 (m, 2H), 1.95 (s, 3H), 1.32-1.57(m, 2H), 1.41 (s, 9H), 1.06-1.25 (m, IH), 0.84-0.96 (m, 6H). Step E: N-[2(S)-amino-3(S)-methylpentyl]-l ,2,3,4-tetrahydro-3(S)- isoquinolinecarbonyl-methionine methyl ester HCl gas was bubbled into a solution of N-[2(S)-(t- butyloxycarbonylamino-3(S)-methylpentyl]- 1 ,2,3,4-tetrahydro-3(S)- isoquinolinecarbonyl-methionine methyl ester (0.37 g, 0.71 mmol) in EtOAc (25 mL) with stirring at -20°C over 0.5 h. The solution was purged with argon for 0.5 h, then concentrated to give the title compound as a white solid which was used without further purification. Step F: N-[(lH-imidazol-4-ylacetyl-2(S)-amino)-3(S)- methylpentyl]-l,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl- methionine methyl ester trifluoroacetate lH-Imidazol-4-ylacetic acid (0.18 g, 1.11 mmol) was dissolved in DMF (10 mL) and treated with EDC (0.213 g, 1.11 mmol), HOBT (0.15 g, 1.11 mmol), and N-[2(S)-amino-3(S)-methylpentyl]- 1 ,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester (0.275 g, 0.556 mmol) with stirring at ambient temperature. Et3N (0.618 mL, 4.44 mol) was added to bring the pH of the solution to 8, and stirring was continued for 16 h. The reaction mixture was concentrated to remove the DMF, and the residue was partitioned between EtOAc (20 mL) and H2θ (30 mL). The aqueous layer was washed with EtOAc (3 x 20 mL), the organics combined, washed with brine and dried (Na2Sθ4). Filtration and concentration to dryness gave the title compound after preparative reverse phase chromatography (CH3CN: H2O gradient). iH NMR (CD3OD) 68.48 (s, IH), 7.07 (s, IH), 6.92-7.04 (m, 4H), 4.29 (d, IH, J= 14 Hz), 4.0-4.15 (m, 3H), 3.85-3.9 (m, IH), 3.45 (ABq, 2H), 3.35 (s, 3H), 2.9 - 3.2 (m, 4H), 2.05-2.2 (m, 2H), 1.72 (s, 3H), 1.55-1.7 (m, 2H), 1.2-1.35 (m, IH), 1.1 - 1.20 (m, IH), 0.8-0.9 (m, IH), 0.55 - 0.6 (m, 6H). FAB MS 530 (M + 1). Step G: N-[(lH-imidazol-4-ylacetyl)-2(S)-amino-3(S)- methylpentyl]- 1 ,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl- methionine trifluoroacetate N-[(lH-imidazol-4-ylacetyl-2(S)-amino)-3(S)- methylpentyl]-l,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester (0.037 g, 0.049 mmol) was dissolved in CH3OH (2 mL) in an ice-H2θ bath and treated with In NaOH (0.195 mL, 0.195 mmol) with stirring. After 3 h the reaction mixture was neutralized with IN HCl (0.195 mL, 0.195 mmol), then chromatographed on a preparative VYDAC reverse phase column, eluting with 0.1% TFA, H2O: 0.1% TFA, CH3CN 95:5 to 5:95 gradient to give the title compound. iH NMR (CD3OD) 68.81 (s, IH), 7.42 (s, IH), 7.2-7.4 (m, 4H), 4.52 (d, IH, J= 14 Hz), 4.25-4.45 (m, 3H), 4.15-4.25 (m, IH), 3.80 (ABq, 2H), 3.25 - 3.5 (m, 2H), 2.3-2.5 (m, 2H), 2.05 (s, 3H), 2.03 - 2.15 (m, IH), 1.9-2.0 (m, IH), 1.57 - 1.7 (m, IH), 1.42 -1.55 (m, IH), 1.1 - 1.23 (m, IH), 0.9 - 1.0 (m, 6H). FAB MS 516 (M + l). Using the methods outlined above, the following compounds are prepared: N-[(lH-imidazol-4-ylpropionyl)-2(S)-amino-3(S)-methylpentyl]-l,2,3,4- tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester N-[(lH-imidazol-4-ylpropionyl)-2(S)-amino-3(S)-methylpentyl]-l,2,3,4- tetrahydro-3(S)-isoquinolinecarbonyl-methionine EXAMPLE 2 Preparation of N-[(l-(4-Cyanobenzyl)-lH-imidazol-5-yl)acetyl]-2(S)- amino-3(S)-methylpentyl]-l,2,34-tetrahydro-3(S)-isoquinolinecarbonyl methionine methyl ester and N-[(l-(4-Cyanobenzyl)-lH-imidazol-5-yl)acetyl]-2(S)-amino-3(S)- methylpentyll- 1.2.34-tetrahydro-3(S)-isoquinolinecarbonyl methionine Step A: lH-Imidazole-4- acetic acid methyl ester hydrochloride A solution of lH-imidazole-4-acetic acid hydrochloride (4.00g, 24.6 mmol) in methanol (100 ml) was saturated with gaseous hydrogen chloride. The resulting solution was allowed to stand at room temperature (RT) for 18hr. The solvent was evaporated in vacuo to afford the title compound as a white solid. iH NMR(CDCl3, 400 MHz) 6 8.85(1H, s),7.45(lH, s), 3.89(2H, s) and 3.75(3H, s) ppm. Step B: l-(Triphenylmethyl)-lH-imidazol-4-ylacetic acid methyl ester To a solution of lH-imidazole-4- acetic acid methyl ester hydrochloride (24.85g, 0.141mol) in dimethyl formamide (DMF) (115ml) was added triethylamine (57.2 ml, 0.412mol) and triphenylmethyl bromide(55.3g, 0.171mol) and the suspension was stirred for 24hr. After this time, the reaction mixture was diluted with ethyl acetate (EtOAc) (1 1) and water (350 ml). The organic phase was washed with sat. aq. NaHCθ3 (350 ml), dried (Na2Sθ4) and evaporated in vacuo. The residue was purified by flash chromatography (Siθ2, 0-100% ethyl acetate in hexanes; gradient elution) to provide the title compound as a white solid. iH NMR (CDC13, 400 MHz) 67.35(1H, s), 7.31(9H, m), 7.22(6H, m), 6.76(1H, s), 3.68(3H, s) and 3.60(2H, s) ppm. Step C: [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] acetic acid methyl ester To a solution of l-(triphenylmethyl)-lH-imidazol-4-ylacetic acid methyl ester (8.00g, 20.9mmol) in acetonitrile (70 ml) was added bromo-p-toluonitrile (4.10g, 20.92 mmol) and heated at 55°C for 3 hr. After this time, the reaction was cooled to room temperature and the resulting imidazolium salt (white precipitate) was collected by filtration. The filtrate was heated at 55°C for 18hr. The reaction mixture was cooled to room temperature and evaporated in vacuo. To the residue was added EtOAc (70 ml) and the resulting white precipitate collected by filtration. The precipitated imidazolium salts were combined, suspended in methanol (100 ml) and heated to reflux for 30min. After this time, the solvent was removed in vacuo, the resulting residue was suspended in EtOAc (75ml) and the solid isolated by filtration and washed (EtOAc). The solid was treated with sat aq NaHCθ3 (300ml) and CH2CI2 (300ml) and stirred at room temperature for 2 hr. The organic layer was separated, dried (MgSθ4) and evaporated in vacuo to afford the title compound as a white solid : lHNMR(CDCl3, 400 MHz) 67.65(1H, d, J=8Hz), 7.53(1H, s), 7.15(1H, d, J=8Hz), 7.04(1H, s), 5.24(2H, s), 3.62(3H, s) and 3.45(2H, s) ppm. Step D: f 1 -(4-Cvanobenzyl)-lH-imidazol-5-ynacetic acid A solution of [l-(4-cyanobenzyl)-lH-imidazol-5-yl]acetic acid methyl ester (4.44g, 17.4mmol ) in THF (100ml) and 1 M lithium hydroxide (17.4 ml, 17.4 mmol) was stirred at RT for 18 hr. 1 M HCl (17.4 ml) was added and the THF was removed by evaporation in vacuo. The aqueous solution was lyophilized to afford the title compound containing lithium chloride as a white solid. iH NMR(CD3θD, 400 MHz) 6 8.22(1H, s), 7.74(1H, d, J=8.4Hz), 7.36(1H, d, J=8.4Hz), 7.15(1H, s), 5.43(2H, s) and 3.49(2H, s) ppm. Step E: N-[(l-(4-Cyanobenzyl)-lH-imidazol-5-yl)acetyl]-2(S)- amino-3(S)-methylpentyl]- 1 ,2,34-tetrahydro-3(S)- isoquinolinecarbonyl methionine methyl ester Using the method described in Example 1, Step F, but substituting [l-(4-cyanobenzyl)-lH-imidazol-5-yl]acetic acid for 1H- imidazol-4-ylacetic acid, the title compound is obtained. Step F: N-[(l-(4-Cyanobenzyl)-lH-imidazol-5-yl)acetyl]-2(S)- amino-3(S)-methylpentyl]- 1 ,2,34-tetrahydro-3(S)- isoquinolinecarbonyl methionine Using the method described in Example 1, Step G, the title compound is obtained. EXAMPLE 3 Preparation of N-[L-Pyroglutamyl-2(S)-aij__o-3(S)-methylpentyl]- 1.2.3.4-tetrahvdro- 3 (S Visoquinolinecarbonyl-methionine trifluoroacetate Step A: N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]- 1,2,3,4- tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester trifluoroacetate Following the methods described in Example 1, but using L- pyroglutamic acid in place of lH-imidazol-4-yl acetic acid, the title compound was prepared. Anal, calcd for C27H40N4O5S • 1.5 CF3CO2H: C, 51.20; H, 5.94; N, 7.96; Found: C, 51.01; H, 6.00; N, 8.23. Step B: N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]- 1,2,3,4- tetrahydro-3(S)-isoquinolinecarbonyl-methionine trifluoroacetate The title compound was prepared following the method dscribed in Example 1, Step G. FAB MS 519 (M + 1). EXAMPLE 4 Preparation of N-[N-(4-Cyanobenzyl)-L-Pyroglutamyl-2(S)-amino-3(S)- methylpentyl]-l,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester and N-[N-(4-Cyanobenzyl)-L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]- 1.2.3.4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine Step A: L-Pyro lutamic acid methyl ester L-Pyroglutamic acid (15.17 g, 0.1175 mol) was dissolved in CH3OH (100 mL), cooled to 0°C. under Ar and treated dropwise with thionyl chloride (18.9 mL, 0.259 mol) with stirring. The bath was removed and stirring was continued at ambient temperature for 3.5 h. Water (150 mL) and solid NaHCθ3 (60 g) were added, the CH3OH was removed on a rotary evaporator, and the residue extracted with CH 2 C1 2 (3 x 150 mL). The organic layers were combined, washed with brine, dried (MgSθ4), filtered and concentrated to dryness to give the title compound. Step B: N-(4-Cvanobenzyl)-L-pyroglutamic acid methyl ester L-Pyroglutamic acid methyl ester (1.36 g, 0.0095 mol) was dissolved in dry THF (20 mL) under Ar, treated with NaH (60% oil dispersion) (0.58 g, 0.0145 mol) with stirring for 5 min, then the mixture was cooled to 0°C. p-Cyanobenzylbromide (1.78 g, 0.0091 mol) was added, and the mixture left to slowly warm to ambient temperature. After 48 h the reaction mixture was partitioned between EtOAc and satd NaHCθ3 solution, the aqueous layer separated and washed with CH 2 C1 2 , the organic s combined, washed with brine and dried (MgSθ4). Filtration and concentration to dryness followed by trituration with ether gave the white solid product. iH NMR(CDCl3, 400 MHz) 67.62(2H, d, J=8 Hz) , 7.33(2H, d, J=8 Hz), 4.98(1H, d, J-15.4 Hz), 4.13(1H, d, J=15.4 Hz), 3.99(1H, dd, J=3, 9 Hz) and 2.5-2.6 (IH, m), 2.4-2.5 (IH, m), 2.2-2.45 (lH, m), 2.1-2.2 (lH, m) ppm. Step C: N-(4-Cyanobenzyl)-L-pyroglutamic acid N-(4-Cyanobenzyl)-L-pyroglutamic acid methyl ester (0.875 g, 0.0034 mol) was dissolved in THF:H2θ (3:1) (12 mL) and treated with LiOH (0.294 g, 0.007 mol) with stirring at ambient temperature. After stirring for 3 h, the solution was neutralized with 1 N HCl, and concentrated to dryness to give the title compound and 2.1 eq of LiCl which was used without further purification. Step D: N-[N-(4-Cyanobenzyl)-L-Pyroglutamyl-2(S)-amino-3(S)- me ylpentyl]-l,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl- methionine methyl ester Using the method described in Example 1, Step F, but substituting N-(4-Cyanobenzyl)-L-pyroglutamic acid for lH-imidazol-4- ylacetic acid, the title compound is obtained. Step E: N-[N-(4-Cyanobenzyl)-L-Pyroglutamyl-2(S)-amino-3(S)- methylpentyl]- 1 ,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl- methionine Using the method described in Example 1, Step G, the title compound is obtained. EXAMPLE 5 In vitro inhibition of ras farnesyl transferase Assays of farnesyl-protein transferase. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and RAS- CAIL) were prepared as described by Schaber et al, J. Biol. Chem. 265: 14701-14704 (1990), Pompliano, et al, Biochemistry 37:3800 (1992) and Gibbs et al, PNAS U.S.A. 56:6630-6634 (1989), respectively. Bovine FPTase was assayed in a volume of 100 μl containing 100 mM N- (2-hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM [3H]-farnesyl diphosphate ([3H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 μg/ml FPTase at 31°C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol. Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB β- plate counter. The assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the [3H]-FPP was utilized during the reaction period. Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay. Percentage inhibition is measured by the amount of incoφoration of radioactivity in the presence of the test compound when compared to the amount of incoφoration in the absence of the test compound. Human FPTase was prepared as described by Omer et al, Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10 μM ZnCl 2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 μl of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme. The compounds of the instant invention described in Examples 1, Step G, and Example 3, Step B, were tested for inhibitory activity against human FPTase by the assay described above and were found to have IC50 of < 10 μM. EXAMPLE 6 In vivo ras famesylation assay The cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21. The assay is performed essentially as described in DeClue, J.E. et al, Cancer Research 51:112-111, (1991). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 37°C, the cells are labelled in 3 ml methionine-free DMEM supple-meted with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[35S]methionine (1000 Ci mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/l M DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45 min. Aliquots of lysates containing equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et al, J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at 4°C, 200 ml of a 25% suspension of protein A-Sepharose coated with rabbit anti rat IgG is added for 45 min. The immunoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1% Triton X-100.0.5% deoxycholate/0.1%/SDS/0.1 M NaCl) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to famesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein. EXAMPLE 7 In vivo growth inhibition assay To determine the biological consequences of FPTase inhibition, the effect of the compounds of the instant invention on the anchorage-independent growth of Rat 1 cells transformed with either a v- ras, v-raf, or \-mos oncogene is tested. Cells transformed by v-Raf and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation. Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 10 4 cells per plate (35 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layers contain 0.1% methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay). The cells are fed twice weekly with 0.5 ml of medium A containing 0.1% methanol or the concentration of the instant compound. Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made.

Claims: WHAT IS CLAIMED IS: 1. A compound which inhibits Ras famesyl-transferase having the Formula I: - A 1 (CR 1a 2 ) n A 2 (CR 1a 2 ) n wherein: Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, Rl^O-, RHS(0)m-, Rl°C(O)NRl0-, CN, Nθ2, (RlO)2N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(Rl ) 2 , or Rl lOC(O)NRl0-, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, Rl^O-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, (R10) 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) , or Rl lθC(O)- NR10-; R and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C 1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RlO) 2 , N0 2 , RlOO-, Rl lS(0)m-, R1°C(0)NR10-, CN, (RlO) 2 N-C(NRlO)-, Rl C(O)-, RlOθC(O)-, N3, -N(RlO) 2 , Rl lOC(O)NRl0- and Cl-C 2 0 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R2 and R3 are combined to form - (CH2)s - ; or R2 or R3 are combined with R6 to form a ring such that R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) C 1-C6 alkyl unsubstituted or substituted by alkenyl, R l^O-, R π S(0) m -, Rl°C(O)NRl0-, CN, N3, (R10)2N-C(NR10)-, RlOC(O)-, RlOθC(O)-, -N(RlO) 2 , or Rl 10C(0)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, Rl^O-, Rl ^(O , Rl°C(O)NRl0-, CN, N02, (Rl°)2N- C(NRlO)-, Rl c(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or RHθC(O)NRl0-, and d) C1-C alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, (Rl0)2NC(O)-, Nθ2, Rl°0-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, (RlO)2N-C(NRlO)-, Rlθc(θ)-, RlOθC(O)-, N3, -N(Rl ) 2 , RHOC(O)NR10- and C1-C20 alkyl, d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R5a and R5b are combined to form - (CH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0)m- -NC(O)-, and -N(CORlO)- ; R6 is independently selected from hydrogen or C1-C6 alkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, Nθ2, Rl°2N-C(NRlO)-, R10C(O)-, Rl θC(O)-, N3, -N(Rl ) 2 , or Rl 10C(0)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0)m-, Rl0C(O)NH-, CN, H 2 N- C(NH)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl θC(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl°C(O)NRl -, CN, Nθ2, (Rl°)2N-C- (NRl )-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lOC(0)NRlO-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, R 10 C(O)NRl0-, CN, (RlO)2N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, or RHθC(O)NRl0-; RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Al and A2 are independently selected from: a bond, -CH-CH-, -CHC-, -C(O)-, -C(O)NRl0-, -NRl C(O)-, O, -N(R10)-, -S(0) 2 N(RlO)-, -N(RlO)S(0)2-, or S(0) m ; Q is a substituted or unsubstituted nitrogen-containing C6-C9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C 1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(0)m', W is a heterocycle; X, Y and Z are independently H 2 or O; or a pharmaceutically acceptable salt thereof. 2. A prodrug of the compound according to Claim 1 illustrated by the formula II: V - A 1 (CR 1a 2 ) n A 2 (CR 1a 2 ) n wherein: Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, Rl^O-, Rl lS(0)m-, Rl°C(O)NRl0-, CN, Nθ2, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or RHθC(O)NRl0-, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RlOO-, Rl lS(0)m-, Rl°C(O)NRl0-, CN, (R1 ) 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lθC(O)- NRlO-; R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Ci-C 2 0 alkyl, C 2 -C 2 0 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RlO) 2 , N0 2 , Rl O-, Rl lS(0)πr, R1°C(0)NR10-, CN, (RlO) N-C(NRl )-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) , Rl lOC(O)NRl0- and Cl-C 2 0 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl; or R2 and R3 are combined to form - (CH 2 ) S - ; or R2 or R3 are combined with R6 to form a ring such that R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) C 1 -C6 alkyl unsubstituted or substituted by alkenyl, R 1 OO-, R n S(0)m-, Rl°C(O)NRl0-, CN, N3, (R1°)2N-C(NR1 )-, R10C(O)-, RlOθC(O)-, -N(RlO) 2 , or Rl 10C(0)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, Rl lS(0) m -, Rl0C(O)NRl -, CN, N0 2 , (RlO) 2 N- C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-C 2 0 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, (RlO) 2 NC(0)-, N02, Rl°0-, Rl lS(0) m -, Rl C(O)NRl0-, CN, (R10) 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, RHOC(0)NR1 - and C1-C20 alkyl, d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R5a and R5b are combined to form - (CH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0)m» -NC(O)-, and -N(CORlO)- ; R6 is independently selected from hydrogen or C1-C6 alkyl; R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, Nθ2, Rl°2N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, or Rl lθC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RHS(0) m -, Rl0C(O)NH-, CN, H2N- C(NH)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl0θC(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RHS(0)m- > Rl°C(O)NRl0-, CN, N0 , (RlO) 2 N-C- (NRl )-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or RUθC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R OO-, Rl lS(0) m -, R1°C(0)NR10-, CN, (Rl ) 2 N-C(NRlO)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-; RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Rl2 is a) substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C5-C8 cycloalkyl, or substituted or unsubstituted cyclic amine, wherein the substituted alkyl, cycloalkyl or cyclic amine is substituted with 1 or 2 substituents independently selected from: 1) C1-C6 alkyl, 2) aryl, 5) -ORl°, or b) R 13 O O^ R 14 Rl3 is independently selected from hydrogen and Cl-C6 alkyl; Rl4 is independently selected from C1-C6 alkyl; Al and A2 are independently selected from: a bond, -CH=CH-, -C≡C-, -C(O)-, -C(O)NRl0-, -NRlOC(O)-, O, -N(R10)-, -S(O)2N(Rl0)-, -N(RlO)S(0)2-, or S(0) m ; Q is a substituted or unsubstituted nitrogen-containing C6-C9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C 2 -C 2 0 alkenyl, provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(0)m', W is a heterocycle; X, Y and Z are independently H 2 or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 4 or 5; t is 3, 4 or 5; and u is 0 or 1 ; or a pharmaceutically acceptable salt thereof. 3. A compound which inhibits Ras farnesyl-transf erase having the Formula III: V - A 1 (CR 1 a 2 ) n A 2 (CR 1 a 2 ) n wherein: Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, Rl^O-, RllS(0) m -, R10C(0)NR10-, CN, Nθ2, (Rl°)2N- C(NRl )-, RlOC(O)-, Rl θC(O)-, N3, -N(RlO)2, or Rl lθC(O)NRl0-, c) C 1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RlOO-, Rl lS(0)πr, R 10 C(O)NRl0-, CN, (R10) 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) , or RHθC(O)- NRlO-; R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C 1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RlO)2, N02, RlOO-, Rl lS(0) m -, R1°C(0)NR10-, CN, (RlO)2N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, RHOC(O)NR10- and C1-C2O alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R2 and R3 are combined to form - (CH2)s - ; or R2 or R3 are combined with R6 to form a ring such that R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) C 1 -C6 alkyl unsubstituted or substituted by alkenyl, R 1°0-, RHS(0)m-, Rl°C(O)NRl0-, CN, N3, (R1°)2N-C(NR10)-, Rl C(O)-, RlOθC(O)-, -N(Rl )2, or Rl 10C(0)NR1 -, c) aryl, heterocycle, cycloalkyl, alkenyl, Rl^O-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, Nθ2, (Rl°)2N- C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) , or RHθC(O)NRl0-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R6 is independently selected from hydrogen or C1-C6 alkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R OO-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, Nθ2, Rlθ2N-C(NRlO)-, R10C(O)-, RlOθC(O)-, N3, -N(RlO)2, or RHOC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, Rl O-, RHS(0) m -, Rl°C(0)NH-, CN, H2N- C(NH)-, Rl C(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl0θC(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0)m-, R 10 C(O)NRl0_, CN, N02, (Rl°)2N-C- (NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, or Rl lOC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, R1°C(0)NR10-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, or Rl lθC(O)NRl0- ; RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Al and A2 are independently selected from: a bond, -CH=CH-, -CHC-, -C(O)-, -C(O)NRl0-, -NRIOC(O)-, O, -N(R10)-, -S(O)2N(Rl0)-, -N(RlO)S(0)2-, or S(0) m ; Q is a substituted or unsubstituted nitrogen-containing C6-C9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, provided that V is not hydrogen if A is S(0) and V is not hydrogen if Al is a bond, n is 0 and A2 is S(0)m; W is a heterocycle; X, Y and Z are independently H2 or O; or a pharmaceutically acceptable salt thereof. 4. A prodrug of the compound according to Claim 3 illustrated by the formula IV: wherein: Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, RlOO-, R n S(0) m -, Rl°C(O)NRl0-, CN, N02, (Rl°)2N- C(NRlO)-, Rl C(O)-, RlOθC(O)-, N3, -N(RlO)2, or Rl lθC(O)NRl0-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, Rl^O-, R n S(0)m-, Rl°C(O)NRl0-, CN, (R10) 2 N-C(NR1 )-, R10C(O)-, RlOθC(O)-, N3, -N(RlO)2, or Rl lθC(O)- NR10-; R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RlO) 2 , Nθ2, Rl°0-, RHS(0) m -, R 10 C(O)NRl0-, CN, (RlO) 2 N-C(NRlO)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO)2, Rl lθC(O)NRl0- and -C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R2 and R3 are combined to form - (CH2)s - ; or R2 or R3 are combined with R6 to form a ring such that R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, Rl^O-, R π S(0) m -, Rl°C(O)NRl -, CN, N3, (R1°)2N-C(NR1 )-, RlOC(O)-, Rl0θC(O)-, -N(Rl0)2, or RHθC(O)NRl0-, c) aryl, heterocycle, cycloalkyl, alkenyl, Rl^O-, Rl lS(0) m -, Rl C(O)NRl0-, CN, N02, (R 10 )2N- C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, OΓ RHOC(O)NR10-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R6 is independently selected from hydrogen or C1-C6 alkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, Rl O-, R lS(0) m -, Rl C(O)NRl -, CN, Nθ2, R!°2N-C(NR10)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, or Rl lθC(O)NRl0-, and c) C 1 -C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl C(O)NH-, CN, H 2 N- C(NH)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl0θC(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, R lS(0) m -, Rl C(O)NRl0-, CN, N0 2 , (Rl°)2N-C- (NRl )-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl -, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, R1°C(0)NR10-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, Rl θC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-; RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Al and A are independently selected from: a bond, -CH=CH-, -C=C-, -C(O)-, -C(O)NRl -, -NRI C(O)-, O, -N(R10)-, -S(0)2N(RlO)-, -N(RlO)S(0)2-, or S(0) m ; Q is a substituted or unsubstituted nitrogen-containing C6-C9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(0)m; W is a heterocycle; X, Y and Z are independently H2 or O; or a pharmaceutically acceptable salt thereof. 5. The compound according to Claim 1 of the formula I: V - A 1 (CR 1 a 2 ) n A 2 (CR 1 a 2 ) n wherein: Rla is independently selected from: hydrogen or C1-C6 alkyl; Rlb is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R ^O-, -N(R10)2 or alkenyl, c) C 1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, Rl^O-, or -N(RlO)2; R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C l -C 10 alkyl, C2-C 10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, Rl lS(0)m-, R1°C(0)NR10-, CN, (Rl )2N-C(NRlO)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO)2, Rl lθC(O)NRl0- and -C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R2 and R3 are combined to form - (CH2)s - ; or R2 or R3 are combined with R6 to form a ring such that R4a and R7a are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, Rl^O-, R π S(0) m -, Rl°C(O)NRl0-, CN, N3, (R10)2N-C(NR10)-, RlOC(O)-, RlOθC(O)-, -N(RlO)2, or Rl 10C(0)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, Rl^O-, Rl lS(0)m-, Rl°C(O)NRl -, CN, N02, (Rl°)2N- C(NRl )-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO)2, or Rl lOC(O)NRl0-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- ClO cycloalkyl; R4b and R^b are hydrogen; R5a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glutamine, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl-ClO alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, Nθ2, Rl°0-, Rl lS(0) m -, R10C(O)NR10-, (RlO)2NC(0)-, CN, (R10)2N-C(NR10)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO)2, RHOC(0)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; R5b is selected from: a) hydrogen, and b) C1-C3 alkyl; R6 is independently selected from hydrogen or C1-C6 alkyl; R8 is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR10-, CN, Nθ2, (RlO)2N-C(NRlO)-, Rl C(O)-, RlOθC(O)-, -N(Rl )2, or Rl lOC(O)NRl0-, and c) C l -C6 alkyl substituted by C 1 -C6 perfluoroalkyl, R 1 OO-, Rl0C(O)NRl0-, (R10) 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, -N(Rl0)2, or Rl 10C(0)NR10- ; R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, RIOO-, Rl lS(0)m-, R1°C(0)NR10-, CN, N02, (Rl°)2N- C(NRlO)-, RlOC(O)-, Rl θC(O)-, -N(Rl )2, or Rl lOC(O)NRl0-, and c) C 1 -C6 alkyl unsubstituted or substituted by C 1 -C6 perfluoroalkyl, F, Cl, Rl O-, Rl lS(0) m -, R1°C(0)NR10-, CN, (Rl ) 2 N-C(NRlO)-, RlOc(O)-, RlOθC(O)-, -N(RlO)2, O Γ RHOC(O)NR1 - ; RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Q is selected from: Al and A2 are independently selected from: a bond, -CH-CH-, -C=C-, -C(O)-, -C(O)NRl0-, O, -N(RlO)-, or S(0) m ; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, and provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if A is a bond, n is 0 and A2 is S(0) m ; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; or a pharmaceutically acceptable salt thereof. 6. The compound according to Claim 2 of the formula II: V - A 1 (CR a 2 ) n A 2 (CR 1a 2 ) n wherein: Rla is independently selected from: hydrogen or Cl-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, Rl^O-, -N(R10) 2 or alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, Rl^O-, or -N(RlO) 2 ; R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C 1 -C 10 alkyl, C2-C 10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, Rl lS(0) m -, R10C(0)NR1 -, CN, (RlO)2N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, R11OC(O)NR10- and Cl-C 2 Q alkyl, and d) C 1 -Cβ alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl; or R2 and R3 are combined to form - (CH 2 )s - ", or R2 or R3 are combined with R6 to form a ring such that R4a and R 7a are independently selected from: a) hydrogen, b) C 1 -C6 alkyl unsubstituted or substituted by alkenyl, R OO-, Rl lS(0)m-, Rl°C(O)NRl0-, CN, N3, (R10) 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, -N(Rl ) 2 , or Rl 10C(0)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, Rl^O-, Rl lS(0)m-, Rl°C(O)NRl0-, CN, N0 , (RlO) 2 N- C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- C 10 cycloalkyl; R4b and R7b are hydrogen; R5a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glutamine, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl-ClO alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, Rl lS(0) m -, R10C(O)NR10-, (RlO)2NC(0)-, CN, (Rl0)2N-C(NRl0)-, Rlθc(θ)-, RlOθC(O)-, N3, -N(RlO) 2 , R11OC(O)NR10- and Cl-C 2 0 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; R5b is selected from: a) hydrogen, and b) C1-C3 alkyl; R6 is independently selected from hydrogen or C1-C6 alkyl; R8 is independently selected from: a) hydrogen, b) C 1 -C6 alkyl, C2-C6 alkenyl, C 2 -C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR10-, CN, Nθ2, (Rl ) N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, -N(RlO)2, or Rl lOC(O)NRl0-, and c) C1-C6 alkyl substituted by -C6 perfluoroalkyl, Rl°0-, Rl0C(O)NRl0-, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, -N(RlO)2, or R11OC(O)NR10-; R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, Rl lS(0)m-, R1°C(0)NR10-, CN, N02, (Rl°)2N- C(NRlO)-, RlOC(O)-, RlOθC(O)-, -N(RlO)2, or Rl θC(O)NRl0-, and - I l l - c) C 1 -C6 alkyl unsubstituted or substituted by C 1 -Cβ perfluoroalkyl, F, Cl, Rl O-, Rl lS(0) m -, R1°C(0)NR10-, CN, (RlO) 2 N-C(NRl )-, RlOc(O)-, RlOθC(O)-, -N(RlO)2, OΓ RHOC(O)NR10-; RIO is independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from Cl-C6 alkyl and aryl; Rl is a) substituted or unsubstituted Cl-C8 alkyl, substituted or unsubstituted C5-C8 cycloalkyl, or substituted or unsubstituted cyclic amine, wherein the substituted alkyl, cycloalkyl or cyclic amine is substituted with 1 or 2 substituents independently selected from: 1) C1-C6 alkyl, 2) aryl, 3) heterocycle, 5) -ORlO, or Rl3 is independently selected from hydrogen and C1-C6 alkyl; Rl4 is independently selected from C1-C6 alkyl; Q is selected from: Al and A2 are independently selected from: a bond, -CH-CH-, -C=C-, -C(O)-, -C(O)NRl0-, O, -N(R 10)-, or S(0) m ; V is selected from: a) hydrogen, b> heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, and provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if A is a bond, n is 0 and A2 is S(0) m ; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; or the pharmaceutically acceptable salts thereof. 7. The compound according to Claim 3 of the formula wherein: Rla is independently selected from: hydrogen or C1-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, Rl^O-, -N(R10) 2 or alkenyl, c) C 1 -C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, Rl^O-, or -N(RlO) 2 ; R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-ClO alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, Rl lS(0) m -, R10C(O)NR1 -, CN, (RlO) 2 N-C(NRl )-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO) 2 , Rl lOC(O)NRl0- and Cl-Qo alkyl, and d) C 1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- Clθ cycloalkyl; or R2 and R3 are combined to form - (CH2)s - ; or R2 or R3 are combined with R6 to form a ring such that R4a and R7a are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R!°0-, Rl lS(0)m-, Rl°C(O)NRl0-, CN, N3, (R10)2N-C(NR10)-, Rl C(O)-, RlOθC(O)-, -N(RlO)2, or Rl lθC(O)NRl0-, c) aryl, heterocycle, cycloalkyl, alkenyl, Rl^O-, R π S(0) m -, Rl°C(O)NRl0-, CN, N02, (Rl°)2N- C(NRlO)-, RlOC(O)-, RIOOC(O)-, N3, -N(Rl ) , or RHθC(O)NRl0-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- ClO cycloalkyl; R4b and R7b are hydrogen; R6 is independently selected from hydrogen or C1-C6 alkyl; R8 is independently selected from: a) hydrogen, b) C l -C6 alkyl, C 2 -C6 alkenyl, C 2 -Cβ alkynyl, C l -C6 perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR10-, CN, N0 2 , (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, -N(RlO) 2 , or Rl lOC(O)NRl0-, and c) C1-C6 alkyl substituted by Cl-C6 perfluoroalkyl, RlOO-, Rl0C(O)NRl0-, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, -N(RlO)2, or R11OC(O)NR10- ; R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, Rl lS(0) m -, R10C(O)NR10-, CN, NO2, (Rl°)2N- C(NRlO)-, RlOC(O)-, Rl θC(O)-, -N(Rl ) 2 , or Rl lOC(O)NRl0-, and c) C 1 -C6 alkyl unsubstituted or substituted by C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, RHS(0) m -, R 10 C(O)NRl0-, CN, (RlO)2N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, -N(RlO)2, or RHθC(O)NRl0-; R O is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Q is selected from: Al and A2 are independently selected from: a bond, -CH-CH-, -C=-C-, -C(O)-, -C(O)NRl0-, O, -N(R10)-, or S(0) m ; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A is S(0)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; or a pharmaceutically acceptable salt thereof. 8. The compound according to Claim 4 of the formula Formula IV: V - A 1 (CR 1 a 2 ) n A 2 (CR 1a 2 ) n wherein: Rla is independently selected from: hydrogen or Cl-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, Rl^O-, -N(RlO)2 or alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, or -N(RlO)2; R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-ClO alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, Nθ2, Rl°0-, Rl lS(0)m-, R1°C(0)NR10-, CN, (RlO)2N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, Rl lOC(O)NRl0- and C1-C2O alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R2 and R3 are combined to form - (CH2)s - ; or R2 or R3 are combined with R6 to form a ring such that R4a and R7a are independently selected from: a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by alkenyl, Rl^O-, Rl lS(0)m-, Rl°C(O)NRl0-, CN, N3, (R10)2N-C(NR10)-, RlOC(O)-, RlOθC(O)-, -N(RlO)2, or Rl 10C(0)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, R π S(0)m-, R1°C(0)NR10-, CN, N02, (Rl°)2N- C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, or Rl lOC(O)NRl0-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- C 10 cycloalkyl; R4b and R7b are hydrogen; R6 is independently selected from hydrogen or C1-C6 alkyl; R8 is independently selected from: a) hydrogen, b) C 1 -Cβ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C l -C6 perfluoroalkyl, F, Cl, RlOO-, R10C(O)NR10-, CN, N02, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, -N(RlO)2, or Rl lOC(O)NRl0-, and c) C 1 -C6 alkyl substituted by C 1 -C6 perfluoroalkyl, R IOO-, Rl0C(O)NRl0-, (R10)2N-C(NR10)-, RlOC(O)-, RlOθC(O)-, -N(RlO)2, or RHOC(O)NR10-; R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, Rl lS(0)m-, R1°C(0)NR10-, CN, N02, (Rl°)2N- C(NRl )-, RlOc(O)-, Rl θC(O)-, -N(Rl )2, or Rl lOC(O)NRl0-, and c) C 1 -C6 alkyl unsubstituted or substituted by C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, Rl lS(0) m -, R1°C(0)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, RlOθC(O)-, -N(RlO)2, or Rl lOC(O)NRl0-; R O is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl is independently selected from C1-C6 alkyl and aryl; Q is selected from: Al and A2 are independently selected from: a bond, -CH=CH-, -C=C-, -C(O)-, -C(O)NRl0-, O, -N(RlO)-, or S(0) m ; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C 1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, and provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(0)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; or a pharmaceutically acceptable salt thereof. 9. A compound which inhibits famesyl-protein transferase which is: N-[(lH-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-l,2,3,4- tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester N-[(lH-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-l,2,3,4- tetrahydro-3(S)-isoquinolinecarbonyl-methionine N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-l,2,3,4-tetrahydro- 3(S)-isoquinotinecarbonyl-methionine methyl ester N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]- 1 ,2,3,4-tetrahydro- 3(S)-isoquinolinecarbonyl-methionine N-[(lH-imidazol-4-ylpropionyl)-2(S)-amino-3(S)-methylpentyl]-l,2,3,4- tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester N-[( lH-imidazol-4-ylpropionyl)-2(S)-amino-3(S)-methylpentyl]- 1 ,2,3,4- tetrahydro-3(S)-isoquinolinecarbonyl-methionine N-[(l-(4-cyanobenzyl)-lH-imidazol-5-yl)acetyl]-2(S)-amino-3(S)- methylpentyl]- 1 ,2,34-tetrahydro-3(S)-isoquinolinecarbonyl methionine methyl ester N-[(l-(4-cyanobenzyl)-lH-imidazol-5-yl)acetyl]-2(S)-amino-3(S)- methylpentyll-l,2,34-tetrahydro-3(S)-isoquinolinecarbonyl memionine N-[N-(4-cyanobenzyl)-L-pyroglutamyl-2(S)-amino-3(S)-methylpentyl]- l,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester or N-[N-(4-cyanobenzyl)-L-pyroglutamyl-2(S)-amino-3(S)-methylpentyl]- 1 ,2,3 ,4-tetrahy dro- 3 (S )-isoquinolinecarbonyl-methionine or a pharmaceutically acceptable salt or optical isomer thereof. 10. The compound according to Claim 9 which inhibits famesyl-protein transferase which is: N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-l,2,3,4-tetrahydro- 3(S)-isoquinolinecarbonyl-methionine or a pharmaceutically acceptable salt or optical isomer thereof. 11. The compound according to Claim 9 which inhibits famesyl-protein transferase which is: N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]- 1 ,2,3,4-tetrahydro- 3(S)-isoquinolinecarbonyl-met_ιionine methyl ester or a pharmaceutically acceptable salt or optical isomer thereof. 12. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 2. 13. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 4. 14. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 9. 15. A method for inhibiting famesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 12. 16. A method for inhibiting famesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 13. 17. A method for inhibiting famesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 14. 18. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12. 19. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 13. 20. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 14. 21. A method for treating neurofibromin benign proliferative disorder which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12. 22. A method for treating blindness related to retinal vascularization which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12. 23. A method for treating infections from hepatitis delta and related viruses which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12. 24. A method for preventing restenosis which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12. 25. A method for treating polycystic kidney disease which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12.

Inventors: DESOLMS S JANE, DESOLMS, S., JANE
Applicants: DESOLMS S JANE, MERCK & CO INC, DESOLMS, S., JANE, MERCK & CO., INC.
Application year: 1996
Main classification: C07K
IPC codes: A61K38, C07K5