INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE

Abstract: The present invention comprises analogs of the CAAX motif of the protein Ras that is modified by farnesylation in vivo. These CAAX analogs inhibit the farnesylation of Ras. Furthermore, these CAAX analogs differ from those previously described as inhibitors of Ras farnesyl 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. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.

Description: TITLE OF THE INVENTION INHIBITORS OF FARNES YL-PROTEIN TRANSFERASE BACKGROUND OF THE INVENTION The Ras gene is found activated in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein, since Ras must be localized in the plasma membrane and must bind with GTP in order to transform cells (Gibbs, J. et al., Microbiol. Rev. 53: 171 -286 (1989). Forms of Ras in cancer cells have mutations that distinguish the protein from Ras in normal cells. 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 (Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al.. Nature 570:583-586 (1984)). Other proteins having this motif include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. Famesylation of Ras by the isoprenoid famesyl pyrophosphate (FPP) occurs in vivo on Cys to form a thioether linkage (Hancock et al., Cell 57: 1 167 (1989); Casey et al, Proc. Natl. Acad. Sci. USA 56:8323 (1989)). In addition, Ha-Ras and N-Ras are palmitoylated via formation of a thioester on a Cys residue near a C- terminal Cys famesyl acceptor (Gutierrez et al., EMBO J. 5:1093- 1098 (1989); Hancock et al, Cell 57:1 167-1 177 (1989)). Ki-Ras lacks the palmitate acceptor Cys. The last 3 amino acids at the Ras C- terminal end are removed proteolytically, and methyl esterification occurs at the new C-terminus (Hancock et al, ibid). Fungal mating factor and mammalian nuclear lamins undergo identical modification steps (Anderegg et al, J. Biol Chem. 265:18236 (1988); Farnsworth et al. . Biol. Chem. 264:20422 (1989)). Inhibition of Ras famesylation 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 245:319 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids and the famesyl pyrophosphate precursor. It has been shown that a farnesyl- protein transferase using famesyl pyrophosphate as a precursor is responsible for Ras famesylation. (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, 87:1541 -1545 (1990)). Inhibition of famesyl-protein transferase and, thereby, of famesylation of the Ras protein, blocks the ability of Ras to transform normal cells to cancer cells. The compounds of the invention inhibit Ras famesylation and, thereby, generate soluble Ras which, as indicated infra, can act as a dominant negative inhibitor of Ras function. While soluble Ras in cancer cells can become a dominant negative inhibitor, soluble Ras in normal cells would not be an inhibitor. A cytosol-localized (no Cys-Aaa^-Aaa^-Xaa box membrane domain present) and activated (impaired GTPase activity, staying bound to GTP) form of Ras acts as a dominant negative Ras inhibitor of membrane-bound Ras function (Gibbs et al. , Proc. Natl Acad. Sci. USA 56:6630-6634(1989)). Cytosollocalized forms of Ras with normal GTPase activity do not act as inhibitors. Gibbs et al, ibid, showed this effect in Xenopus oocytes and in mammalian cells. Administration of compounds of the invention to block Ras famesylation not only decreases the amount of Ras in the membrane but also generates a cytosolic pool of Ras. In tumor cells having activated Ras, the cytosolic pool acts as another antagonist of membrane-bound Ras function. In normal cells having normal Ras, the cytosolic pool of Ras does not act as an antagonist. In the absence of complete inhibition of famesylation, other famesylated proteins are able to continue with their functions. Famesyl-protein transferase activity may be reduced or completely inhibited by adjusting the compound dose. Reduction of farnesyl-protein transferase enzyme activity by adjusting the compound dose would be useful for avoiding possible undesirable side effects resulting from interference with other metabolic processes which utilize the enzyme. These compounds and their analogs are inhibitors of farnesyl-protein transferase. Farnesyl-protein transferase utilizes famesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famesyl group. Inhibition of famesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in vivo and inhibits Ras function. Inhibition of farnesyl-protein transferase is more specific and is attended by fewer side effects than is the case for a general inhibitor of isoprene biosynthesis. Previously, it has been demonstrated that tetrapeptides containing cysteine as an amino terminal residue with the CAAX sequence inhibit Ras famesylation (Schaber et al, ibid; Reiss et. al, ibid; Reiss et al, PNAS, 88:132-136 (1991)). Such inhibitors may inhibit while serving as alternate substrates for the Ras farnesyl- transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141 ,851 , University of Texas). It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of 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 rαs-dependent tumors in nude mice (N.E. Kohl et al, Proc. Natl. Acad. Sci U.S. A., 97 :9141 -9145 (1994) . Inhibitors of Ras farnesyl-protein transferase (FPTase) have been described in two general classes. The first are analogs of famesyl diphosphate (FPP), while the second class of inhibitors is related to the protein substrate for the enzyme, Ras. Almost all of the peptide derived inhibitors that have been described are cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. The exception to this generalization is a class of natural products known as the pepticinnamins (Omura, et al, J. Antibiotics 46:222 (1993). In general, deletion of the thiol from a CAAX derivative dramatically reduces the inhibitory potency of these compounds. 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. With the exception of the pepticinnamins, non-thiol FPTase inhibitors that are competitive with the Ras substrate have not been described and are the subject of this invention. It is, therefore, an object of this invention to develop tetrapeptide-based compounds which do not have a thiol moiety, and which will inhibit famesyl transferase and the post-translational functionalization of the oncogene Ras protein. 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 CAAX motif of the protein Ras that is modified by famesylation in vivo. These CAAX analogs inhibit the famesylation of Ras. Furthermore, these CAAX analogues differ from those previously described as inhibitors of Ras famesyl 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. Further contained in this invention are chemotherapeutic compositions containing these famesyl transferase inhibitors and methods for their production. 5 - The compounds of this invention are illustrated by the formulae: and DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention inhibit the famesylation of Ras. In a first embodiment of this invention, the Ras famesyl transferase inhibitors are illustrated by the formula I: wherein: Rla is selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, (RlO) 2 N-C(NRlO)-, RlOC(O)-, or Rl θC(O)-, and 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, (RlO) 2 N-C(NRlO)-, RlOc(O)-, RI OC(O)-, N3, -N(RlO)2, or Rl lθC(O)NRl0-; Rib i independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, (RlO) 2 N-C(NRlO)-, RIOC(O)-, or RlOoC(O)-, and c) C l -C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, RlOO-, Rl lS(0) m -. R 10C(O)NR 10_, CN, (RlO) 2 N-C(NRlO)-, RlOC(OK Rl0θC(O)-, N3, Rl lθC(O)NRl0-; provided that R lb is not Rl0C(O)NR 10 - when R 1 ^ is alkenyl, V is hydrogen and X-Y is -C(0)NR7a. ; R2a and R2b 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-C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 O-, Rl -ISCOJnr, R 10 C(O)NRl0-, 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 R2a and R2b are combined to form - (CH2)s - ; R3 and R4 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 -C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 O-, R 1 ^(Ovm-, Rl0c(O)NRl0-, CN, (R lO)2N-C(NR -lO)-, RlOC(0)-, R 10oC(O)-, N3, -N(R lO)2, R 1 iOC^NR 10 - and C1-C2O alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; R3 and R4 are combined to form - (CH2)s - ; R5a and R5b 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 -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 O-, Rl lS(0) m -, Rl0C(O)NRl0-, CN (RlO)2N-C(NRlO)-, RlOc(O)-, R lOθC(O)-, N3, -N(RlO)2, R 1 !OC(O)NRl0- and C1-C2O alkyl, and d) C1-Q alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl; or R5 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(COR lO)- ; X-Y is (?) m f) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOo-, Rl lS(0) m -, Rl0C(O)NRl0-, CN? Nθ2 , Rl0 2 N-C(NRlO)-, Rl°C(0)-, R 10 OC(O)-, N3, -N(RlO)2, or Rl lθC(O)NRl0., and c) C1 -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, R 1 l S(0) m -, R 10 C(O)NH-, CN, H2N- C(NH)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lOC(0)NH-; R9 is selected from: hydrogen , C1-C6 alkyl , RlOo-, Rl lS(0) m -, Rl0C(O)NRi0_, CN, Nθ2, N3, -N(R 10 )2, and Rl lOC(O)NRl0-; provided that R9 is not Rl c(O)NRl0. w hen Rla i s alkenyl, V is hydrogen and X-Y is -C(0)NR7a. ; RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1 -C6 alkyl and aryl; R 12 is hydrogen or C1-C6 alkyl; V is selected from: a) aryl; b) heterocycle; or c) hydrogen; W is -S(0)m-, -0-, -NHC(O)-, -C(0)NH-, -NHSO2-, -SO2NH-, -N(R7a). or -N[C(0)R7a]. ; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4, provided that n ≠ 0 when V is hydrogen and W is -S(0)m- ; p is 0, 1 , 2, 3 or 4, provided that p ≠ 0 when R9 is not hydrogen or C1-C6 lower alkyl ; r is 0 or 1 ; s is 4 or 5; and t is 0, 1 or 2, provided that t = 0 when V is hydrogen; 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: wherein: Rla is selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, (Rl ) 2 N-C(NRlO)-, RlOc(O)-, or RlOθC(O)-, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, Rl^O-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lθC(O)NRl0-; R ib is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, (R10) 2 N-C(NR10)-, R 10C(O)-, or R lOθC(O)-, and c) C l -C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, RlOO-, RHS(0) m -, R10C(0)NR10-, CN, (RlO) 2 N-C(NRlO)-, R10C(O)-, Rl°OC(0)-, N3, -N(RlO)2, or RHθC(0)NRlO-; provided that Rib is not R 1°C(0)NR 10- when Rl is alkenyl, V is hydrogen and X-Y is -C(0)NR7a. ; R2a and R2b 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 -C20 alkyl, C2-C20 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)NR1 -, CN, (RlO)2N-C(NRlO)-, RlOC(O)-, R lOθC(O)-, N3, -N(R l0)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 R2a and R2b are combined to form - (CH2)s - ; R4 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-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RlO)2, N02, R 10 O-, Rl l S(0)m-, Rl0C(O)NRl0-, CN, (R lO)2N-C(NR lO)-, R 10C(O)-, RlOθC(O)-, N3, -N(R lO)2, R1 1 OC(O)NR 10- and C1-C20 alkyl, and d) Cl - ) alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R3 and R4 are combined to form - (CH2)s - ; R5a and R5b 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, C 2 -C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, R lS(0) m -, R 10C(0)NR10-, CN, (RlO)2N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, Rl lOC(O)NRl0- and C1-C20 alkyl, and 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(CORIO)- ; a) substituted or unsubstituted Cl-CR alkyl, wherein the substituent on the alkyl is selected from: D aryl, 2) heterocycle, 3) -N(Rl l )2, 4) -OR 10, or b) R 12 O O R ' 3 X-Y is R 7a * -γV O >7b b) Yv jS (O)m ) f) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C l -Cβ alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, N02, R !°2N-C(NR 10)-, RlOC(O)-, RlOθC(O)-, N3, -N(R lO) 2 , or Rl lOC(0)NRl°-, and c) Cl -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, Rl°0-, Rl lS(0) m -, Rl0C(O)NH-, CN, H 2 N- C(NH)-, R lOC(O)-, R lOθC(O)-, N3, -N(RlO) 2 , or R l lOC(0)NH-; R9 is selected from: hydrogen , Cl -C6 alkyl , Rl°0-, Rl l S(0) m -, Rl0C(O)NRl0-, CN, N02, N3, -N(RlO) 2 , and R 1 1QC(O)NR10-; provided that R9 is not R10C(0)NR10- when Rla is alkenyl, V is hydrogen and X-Y is -C(0)NR7a. ; R O is independently selected from hydrogen, C1 -C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1 -C6 alkyl and aryl; R 12 is independently selected from hydrogen and Cl -C6 alkyl; Rl3 is C1 -C6 alkyl; V is selected from: a) aryl; b) heterocycle; or c) hydrogen; W is -S(0)m-, -0-, -NHC(O)-, -C(0)NH-, -NHS02-, -SO2NH-, -N(R7a). or -NfC(0)R7a]. ; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4, provided that n ≠ 0 when V is hydrogen and W is -S(0)m- ; p is 0, 1, 2, 3 or 4, provided that p ≠ 0 when R9 is not hydrogen or C1 -C6 lower alkyl ; r is 0 or 1 ; s is 4 or 5; and t is 0, 1 or 2, provided that t = 0 when V is hydrogen; or the pharmaceutically acceptable salts thereof. In a third embodiment of this invention, the inhibitors of famesyl transferase are illustrated by the formula ID: wherein: Rla is selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, (RlO) 2 N-C(NRlO)-, Rl0c(O)-, or RlOθC(O)-, and c) Cl -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, Rl^O-, Rl lS(0) m -, RlOC(0)NRlO., CN, (R10) 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, N3, -N(R lO)2, or Rl lOC(O)NRl0-; Rib is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, (R10) 2 N-C(NR 10)-, Rlθc(θ)-, or RlOθC(O)-, and c) C 1 -Cβ alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, RlOO-, Rl lS(0) m -, R!0C(O)NR10-, CN, (RlO) 2 N-C(NRlO)-, RlOC(0)-, Rl0θC(O)-, N3, Rl lOC(O)NRl0-; provided that Rib is not R!0C(O)NR10- when Rla is alkenyl, V is hydrogen and X-Y is -C(0)NR7a.; R2a and R2b 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-C2O 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(O)NR 10-, CN, (R 10)2N-C(NR 10)-, R lOC(O)-, R 10OC(O)-, N3, -N(R lO)2, R l lθC(O)NRl0- and C1 -C2O alkyl, and d) Cl - ) alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R2a and R b are combined to form - (CH 2 )s - ; R3 and R4 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 -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, Rl l S(0)m-, R!0C(O)NR1 -, CN, (R l0)2N-C(NR l°)-, Rl°C(0)-, R !°OC(0)-, N3, -N(R 10)2, R 11 OC(0)NR 10- and C 1 -C20 alkyl, and d) Cl -Q) alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R3 and R4 are combined to form - (CH2)s - ; X-Y is R 7a a) O f) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) Cl -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C l -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, Rl O-, R l lS(0) m -, R!0C(O)NR 10-, CN, N02, R 10 2N-C(NRl0)-, R lOC(O)-, RlOθC(O)-, N3, -N(R lO) 2 , or Rl lOC(O)NRl0-, and c) Cl -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R l O-, Rl l S(0)m-, Rl°C(0)NH-, CN, H2N- C(NH)-, Rl C(O)-, RlOθC(O)-, N3, -N(RlO)2, or Rl lOC(0)NH-; R9 is selected from: hydrogen , C1-C6 alkyl , RlOO-, Rl lS(0)m-, Rl0C(O)NRl0-, CN, N02, N3, -N(RlO) 2 , and Rl lOC(O)NRl0-; provided that R9 is not R! C(O)NR10- when Rla is alkenyl, V is hydrogen and X-Y is -C(0)NR7a. ; 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 hydrogen or C1-C6 alkyl; V is selected from: a) aryl; b) heterocycle; or c) hydrogen; W is -S(0)m-, -0-, -NHC(O)-, -C(0)NH-, -NHSO2-, -SO2NH-, -N(R7a). or -N[C(0)R7a]. ; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1 , 2, 3 or 4, provided that n ≠ 0 when V is hydrogen and W is -S(0)m-; p is 0, 1 , 2, 3 or 4, provided that p ≠ 0 when R9 is not hydrogen or C1-C6 lower alkyl ; q is 0, 1 or 2; r is 0 or 1 ; s is 4 or 5; and t is 0, 1 or 2, provided that t = 0 when V is hydrogen; or the pharmaceutically acceptable salts thereof. In a fourth embodiment of this invention the prodmgs of compounds of formula HI are illustrated by the formula IV: - (CR i 1ιaa 22 )) nn -- WW -- IV wherein: Rla is selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, (RlO)2N-C(NRlO)-, RlOC(O)-, or RlOθC(O)-, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, Rl^O-, R 1 ^(O)™-, Rl0C(O)NRl0-, CN, (R10)2N-C(NR10)-, RlOC(O)-, R10OC(O)-, N3, -N(RlO)2, or R l lθC(O)NRl0-; R 1 b is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, (R10)2N-C(NRH))-, R 10C(O)-, or R IOOC(O)-, and c) C l -C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, RlOO-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, (R !0)2N-C(NR 1°)-, RlOC(O)-, RlOθC(O)-, N3, -N(R I 0 )2, or Rl lθC(O)NRl0-; provided that R ib is not R10C(O)NR1°- when R a is alkenyl, V is hydrogen and X-Y is -C(0)NR7a. ; R2a and R2b 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 -C20 alkyl, C2-C20 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(Rl0)2, RHθC(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 R2a and R2b are combined to form - (CH2)s - ; R3 and R4 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 heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, Rl lS(0)πr, R10C(O)NR10-, CN, (RlO)2N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, Rl 10C(0)NR10. and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C10 cycloalkyl;or R3 and R4 are combined to form - (CH2)s - ; X-Y is (0) m R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, R l0C(O)NR l°-, 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 aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R lOO-, Rl lS(0) m -, Rl0C(O)NH-, CN, H2N- C(NH)-, Rl C(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or Rl lOC(0)NH-; R9 is selected from: hydrogen , C1 -C6 alkyl , RlOO-, Rl lS(0)πr, Rl0C(O)NRl0-, CN, N02, N3, -N(Rl ) 2 , and Rl lOC(O)NRl0-; provided that R9 is not R 0C(0)NR10- when Rl is alkenyl, V is hydrogen and X-Y is -C(0)NR7a. ; RlO is independently selected from hydrogen, -C6 alkyl, benzyl and aryl; R l 1 is independently selected from C1-C6 alkyl and aryl; Rl2 is hydrogen or C1 -C6 alkyl; V is selected from: a) aryl; b) heterocycle; or c) hydrogen; W is -S(0) m -, -0-, -NHC(O)-, -C(0)NH-, -NHSO2-, -SO2NH-, -N(R7a). or -N[C(0)R7a]. ; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1 , 2, 3 or 4, provided that n ≠ 0 when V is hydrogen and W is -S(0) m - ; p is 0, 1, 2, 3 or 4, provided that p ≠ 0 when R9 is not hydrogen or C1 -C6 lower alkyl ; q is 0, 1 or 2; r is 0 or 1 ; s is 4 or 5; and t is 0, 1 or 2, provided that t = 0 when V is hydrogen; or the pharmaceutically acceptable salts thereof. In a more preferred embodiment of the invention, the Ras famesyl transferase inhibitors are illustrated by the formula I: wherein: R la is selected from: a) hydrogen, and b) Cl-C6 alkyl; R lb is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl or cycloalkyl, and c) C 1 -C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine; b) 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-, R 10 C(O)NRl0-, CN, (Rl0) 2 N-C(NRl0)-, RIO O)-, Rl θC(O)-, N3, -N(R 10)2, R 11 OC(0)NR 0- and C 1 -C20 alkyl, and c) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; and R2b is selected from hydrogen and C1 -Q3 alkyl; or R2a and R2b are combined to form - (CH2)s - ; R3 and R4 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-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, Rl lS(0) m -, R 0C(O)NR10-, CN, (Rl0) 2 N-C(NRl0)-, RlOc(O)-, RlOθC(O)-, N3, -N(R lO)2, R l lOC(O)NRl0- and C1-C20 alkyl, and d) C1 -Q3 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; 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, 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, R 10 O-, Rl lS(0)m-, R10C(O)NR10_, CN, (R10) 2 N-C(NR10)-, RlOc(O)-, Rl θC(O)-, N3, -N(RlO)2, Rl lθC(O)NRl0- 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) Cl-C3 alkyl; or X-Y is e) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R8 is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl -C6 perfluoroalkyl, F, Cl, R O-, R10C(0)NR10-, CN, N02, (Rl ) 2 N-C(NRl )-, RlOC(O)-, Rl θC(O)-, -N(RlO) 2 , or Rl lOC(O)NRl0-, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, RlOO-, Rl0C(O)NRl0-, (R 10) 2 N-C(NR10)-, RlOc(O)-, RlOθC(O)-, -N(RlO) 2 , or R HOC(O)NR10-; R9 is selected from: hydrogen , -C6 lower alkyl , RlOO-, and -N(Rl ) ; RIO is independently selected from hydrogen, Cl -C6 alkyl, benzyl and aryl; R l 1 is independently selected from Cl-C6 alkyl and aryl; Rl2 is hydrogen or Cl-C6 alkyl; V is selected from: a) aryl; b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; and c) hydrogen; W is -S(0)m-, -0-, -NHC(O)-, -C(0)NH-, -NHS02-, -S02NH-, -N(R7a). 0 r -N[C(0)R7a]. ; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1 , 2, 3 or 4, provided that n ≠ 0 when V is hydrogen and W is -S(0) m - ; p is 0, 1, 2, 3 or 4, provided that p ≠ 0 when R is not hydrogen or Cl-Cό lower alkyl ; r is 0 or 1 ; s is 4 or 5; and t is 0 or 1 , provided that t = 0 when V is hydrogen; or the pharmaceutically acceptable salts thereof. In a second more preferred embodiment of the invention, the prodmgs of the Ras famesyl transferase inhibitors of the formula I are illustrated by the formula II: II wherein: R la is selected from: a) hydrogen, and b) Cl -C6 alkyl; Rib is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl or cycloalkyl, and c) C l -C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, Rl0θ- or -N(Rl0) 2; R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine; b) 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)πr, R1 C(0)NR10-, CN, (Rl ) 2 N-C(NRlO)-, RlOc(O)-, RlOθC(O)-, N3, -N(Rl )2, Rl lθC(O)NRl0- and C1-C2O alkyl, and c) C 1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; and R2b is selected from hydrogen and C1-C6 alkyl; or R2a and R2b are combined to form - (CH2)s - ; R3 and R4 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- o alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, Rl lS(0)m-, R!0C(O)NR10-, CN, (Rl ) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(Rl ) 2 , Rl lθC(0)NRlO- and -C20 alkyl, and d) C1-Q3 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; 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, 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 -, R 10 C(O)NRl0-, CN, (R10)2N-C(NR10)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, RHOC(O)NR10- and -Qo 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) Cl -C3 alkyl; or R6 is a) substituted of unsubstituted C1 -C8 alkyl, wherein the substituent on the alkyl is selected from: l) aryl, 4) -OR 1 , or b) R 12 O Y . -o n - Rni; 3 X-Y is a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R8 is independently selected from: a) hydrogen, b) C1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C6 perfluoroalkyl, F, Cl, Rl°0-, R10C(O)N 10-, CN, NO2, (R10) 2 N-C(NR10)-, RlOc(O)-, Rl°OC(0)-, -N(RlO)2, or RHθC(O)NRl0-, and c) C1 -C6 alkyl substituted by C1-C6 perfluoroalkyl, RlOO-, Rl0c(O)NR l0-, (R10)2N-C(NR10)-, RlOc(O)-, RlOθC(O)-, -N(RlO)2, or Rl 10C(0)NR10- ; R9 is selected from: hydrogen , C1-C6 lower alkyl , RlOO-, and -N(RlO) 2 ; RlO is independently selected from hydrogen, -C6 alkyl, benzyl and aryl; Rl 1 is independently selected from Cl -C6 alkyl and aryl; Rl2 is independently selected from hydrogen and Cl-C6 alkyl; Rl3 is C1 -C6 alkyl; V is selected from: a) aryl; b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; and c) hydrogen; W is -S(0)m-, -0-, -NHC(O)-, -C(0)NH-, -NHS02-, -SO2NH-, -N(R7a). or -N[C(0)R7a]. ; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4, provided that n ≠ 0 when V is hydrogen and W is -S(0)m- ; p is 0, 1 , 2, 3 or 4, provided that p ≠ 0 when R9 is not hydrogen or C1 -C6 lower alkyl ; r is 0 or 1 ; s is 4 or 5; and t is 0 or 1 , provided that t = 0 when V is hydrogen; or the pharmaceutically acceptable salts thereof. In a third more preferred embodiment of the invention, the Ras famesyl transferase inhibitors are illustrated by the formula πi: wherein: Rla is selected from: a) hydrogen, and b) Cι -C6 alkyl; Rib are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl or cycloalkyl, and c) C l -Cβ alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine; b) 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-, R 10C(0)NR10-, CN, (RlO) 2 N-C(NR O)-, RlOC(O)-, RlOθC(O)-, N3, -N(R lO)2, Rl lθC(O)NRl0- and C1 -C2O alkyl, and c) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; and R2b is selected from hydrogen and Cl -C6 alkyl; or R2a and R2b are combined to form - (CH2)s - ; R3 and R 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-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, Rl lS(0)m-, R 10 C(O)NRl0-, CN, (R 10) 2 N-C(NR10)-, RlOC(O)-, Rl°OC(0)-, N3, -N(R l0)2, RHθC(O)NRl0- and -C20 alkyl, and d) C 1 -Q) alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; X-Y is R 7a ») O d) - . or H e) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) Cl -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R8 is independently selected from: a) hydrogen, b) C1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C6 perfluoroalkyl, F, Cl, R l°0-, R!0C(O)NR10-, CN, N02, (R10) 2 N-C(NR10)-, R 10C(O)-, RlOθC(O)-, -N(RlO)2, or RHθC(O)NRl0-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, RlOo-, R!0C(O)NR1 -, (R10) 2 N-C(NR10)-, RlOc(O)-, R l0θC(O)-, -N(R l0) 2 , or R l lθC(O)NRl0- ; R9 is selected from: hydrogen , C1-C6 lower alkyl , Rl°0-, and -N(Rl°)2; 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 hydrogen or C1 -C6 alkyl; V is selected from: a) aryl; b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; and c) hydrogen; W is -S(0)m-, -0-, -NHC(O)-, -C(0)NH-, -NHSO2- -SO2NH-, -N(R7a). or -N[C(0)R7a]. ; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1 , 2, 3 or 4, provided that n ≠ 0 when V is hydrogen and W is -S(0)m- ; p is 0, 1 , 2, 3 or 4, provided that p ≠ 0 when R9 is not hydrogen or C1 -C6 lower alkyl ; q is 0, 1 or 2; r is 0 or 1 ; s is 4 or 5; and t is 0 or 1 , provided that t = 0 when V is hydrogen; or the pharmaceutically acceptable salts thereof. In a fourth more preferred embodiment of the invention, the prodmgs of the Ras famesyl transferase inhibitors of the formula III are illustrated by the formula IV: IV wherein: Rla is selected from: a) hydrogen, and b) Cl-C6 alkyl; Rib are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl or cycloalkyl, and c) C 1 -C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, RlOO- or -N(RlO) 2 ; R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine; b) 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)πr, R !0C(O)NR10., CN, (R10) N-C(NR 10)., R 10C(O)-, RlOθC(O)-, N3, -N(RlO)2, Rl 1 QC(O)NR10- and C1-C20 alkyl, and c) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; and R2b is selected from hydrogen and Cl -Cβ alkyl; or R2a and R2b are combined to form - (CH2)s - ; R3 and R4 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 heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, Rl l S(0) m -, R1°C(0)NR10-, CN, (R lO) 2 N-C(NRlO)-, RlOc(O)-, R IOOC(O)-, N3, -N(R lO)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; X-Y is >7a o R 7b b) \ V^ N 5 e) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) Cj-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl -Cβ alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R8 is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1 -C6 perfluoroalkyl, F, Cl, Rl°0-, R10C(0)NR10-, CN, Nθ2, (R 10) 2 N-C(NR10)-, RlOc(O)-, Rl θC(O)-, -N(RlO)2, or R l lOC(O)NRl0-, and c) C1 -C6 alkyl substituted by C1-C6 perfluoroalkyl, RlOO-, RlOC(0)NRlO-, (R10)2N-C(NR10)., RlOc(O)-, Rl θC(O)-, -N(Rl0)2, or Rl lOC(O)NRl0-; R9 is selected from: hydrogen , C1-C6 lower alkyl , Rl°0-, and -N(Rl )2; RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from Cl -C6 alkyl and aryl; Rl is hydrogen or C1-C6 alkyl; V is selected from: a) aryl; b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; and c) hydrogen; W is -S(0)m-, -0-, -NHC(O)-, -C(0)NH-, -NHSO2-, -SO2NH-, -N(R7a). or -N[C(0)R7a]. ; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4, provided that n ≠ 0 when V is hydrogen and W is -S(0)m- ; p is 0, 1 , 2, 3 or 4, provided that p ≠ 0 when R9 is not hydrogen or C 1 -C6 lower alkyl ; q is 0, 1 or 2; r is 0 or 1 ; s is 4 or 5; and t is 0 or 1 , provided that t = 0 when V is hydrogen; or the pharmaceutically acceptable salts thereof. The preferred compounds of this invention are as follows: N-{2(S)-[(4-Nitrobenzylthio)acetamido]-3(S)-methylpentyl}-N-(l- naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(4-Nitrobenzylthio)acetamido]-3(S)-methylpentyl}-N-(l- naphthylmethyl)-glycyl-methionine N- { 2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl } -N-(l - naphthylmethyl)-glycyl-methionine N- { 2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl } -N-(l - naphthylmethyl)-glycyl-methionine methyl ester N-{ 2(S)-[(Phenylthio)acetamido]-3(S)-methylpentyl }-N-(l- naphthylmethy l)-glycyl-methionine N- { 2(S)-[(Phenylthio)acetamido]-3(S)-methylpentyl } -N-(l - naphthylmethyl)-g]ycyl-methionine methyl ester N- { 2(S)-[(3-Nitrobenzylthio)acetamido]-3(S)-methylpentyl } -N-(l - naphthylmethyl)-glycyl-methionine N-{2(S)-[(3-Nitrobenzylthio)acetamido]-3(S)-methylpentyl}-N-(l - naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(2-Nitrobenzylthio)acetamido]-3(S)-methylpentyl } -N-(l - naphthylmethyl)-glycyl-methionine N-{2(S)-[(2-Nitrobenzylthio)acetamido]-3(S)-methylpentyl }-N-(l - naphthylmethy -glycyl-methionine methyl ester N- { 2(S)-[(4-Cyanobenzylthio)acetamido]-3(S)-methylpentyl } -N-( 1 ■ naphthylmethyl)-glycyl-methionine N- { 2(S)-[(4-Cyanobenzylthio)acetamido]-3(S)-methylpentyl } -N-( 1 - naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(4-Trifluoromethylbenzylthio)acetamido]-3(S)-methyl- penty 1 } -N-( 1 -naphthylmethyl)-glycy 1-methionine N- { 2(S)-[(4-Trifluoromethylbenzylthio)acetamido]-3(S)-methyl- pentyl}-N-(l-naphthylmethyl)-glycyl-methionine methyl ester N-{ 2(S)-[(4-Methoxybenzylthio)acetamido]-3(S)-methylρentyl}-N- ( 1 -naphthylmethy -glycyl-methionine N- { 2(S)-[(4-Methoxybenzylthio)acetamido]-3(S)-methylpentyl } -N- (l-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(4-Methylsulfonylbenzylthio)acetamido]-3(S)-methyl- pentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[(4-Methylsulfonylbenzylthio)acetamido]-3(S)-methyl- pentyl}-N-(l-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(4-Phenylbenzylthio)acetamido]-3(S)-methylpentyl } -N-( 1 ■ naphthylmethyl)-glycyl-methionine N- {2(S)-[(4-Phenylbenzylthio)acetamido]-3(S)-methylpentyl}-N-(l - naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(4-( 1 - /-Tetrazol-5-yl)benzylthio)acetamido]-3(S)-methyl- penty 1 } -N-( 1 -naphthylmethyl)-glycy 1-methionine N- { 2(S)-[(4-( 1 -/7-Tetrazol-5-yl)benzylthio)acetamido]-3(S)-methyl- pentyl}-N-(l -naphthylmethyl)-glycyl-methionine methyl ester N- {2(S)-[(4-Methylbenzylthio)acetamido]-3(S)-methylpentyl}-N-(l- naphthylmethyl)-glycyl-methionine N- { 2(S)-[(4-Methylbenzylthio)acetamido]-3(S)-methylpentyl } -N-( 1 - naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(8-Chloronaphth-l -ylthio)acetamido]-3(S)-methylpentyl }- N-( 1 -naphthylmethy l)-glycyl-methionine N-{2(S)-[(8-Chloronaphth-l-ylthio)acetamido]-3(S)-methylpentyl }- N-( 1 -naphthylmethyl)-glycyl-methionine methyl ester N-{ 2(S)-[((2-Methylindol-3-yl)thio)acetamido]-4-methylpentyl }-N- ( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[((2-Methylindol-3-yl)thio)acetamido]-4-methylpentyl } -N- (1 -naphthylmethy -glycyl-methionine methyl ester N- { 2(S)-[(4-Pyridylthio)acetamido]-3(S)-methylpentyl } -N-( 1 - naphthylmethy l)-glycy 1-methionine N-{ 2(S)-[(4-Pyridylthio)acetamido]-3(S)-methylpentyl}-N-(l - naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(4-Picolinylthio)acetamido]-3(S)-methylpentyl } -N-(l - naphthylmethyl)-glycyl-methionine N-{ 2(S)-f(4-Picolinylthio)acetamido]-3(S)-methylpentyl}-N-(l - naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[3-(Benzylthio)propionamido]-3(S)-methylpentyl } -N-( 1 • naphthylmethyl)-glycyl-methionine N- { 2(S)-[(Benzyloxy)acetamido]-3(S)-methylpentyl } -N-(l - naphthylmethyl)-glycyl-methionine N- { 2(S)-[(Benzyloxy)acetamido]-3(S)-methylpentyl } -N-( 1 - naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(N , -Benzylglycyl)amino]-3(S)-methylpentyl } -N-( 1 - naphthylmethyl)-glycyl-methionine N- { 2(S)-[(N'-Benzylglycyl)amino]-3(S)-methylpentyl }-N-( 1 - naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(N-Acetyl-N'-benzylglycyl)amino]-3(S)-methylpentyl } -N- ( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[(N'-Acetyl-N-benzylglycyl)amino]-3(S)-methylpentyl } -N- ( 1 -naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(N'-Benzyl-N'-t-butoxycarbonylglycyl)amino]-3(S)- methylpentyl } -N-( 1 -naphthylmethy l)-glycyl-methionine N-{ 2(S)-[(N'-Benzyl-N'-t-butoxycarbonylglycyl)amino]-3(S)-methyl- pentyl }-N-(l -naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(Benzylthio-S-oxide)acetamido]-3(S)-methylpentyl}-N-(l- naphthylmethyl)-glycyl-methionine N-{2(S)-[(Benzylthio-S-oxide)acetamido]-3(S)-methylpentyl}-N-(l- naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(Benzylthio-S,S-dioxide)acetamido]-3(S)-methylpentyl } -N- ( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[(Benzylthio-S,S-dioxide)acetamido]-3(S)-methylpentyl } -N- (l-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl } -N-(l - naphthylmethyl)-glycyl-methionine sulfone N- { 2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl } -N-(l - naphthylmethyl)-glycyl-methionine sulfone methyl ester N-{2(S)-[(N'-4-Nitrobenzoylglycyl)amino]-3(S)-methylpentyl }-N-(l - naphthylmethyl)-glycyl-methionine N-{2(S)-[(N'-4-Nitrobenzoylglycyl)amino]-3(S)-methylpentyl}-N-(l - naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(N'-Methyl-N'-4-nitrobenzoylglycyl)amino]-4-methyl- penty 1 } -N-( 1 -naphthylmethyl)-glycyl -methionine N- { 2(S)-[(N'-Methyl-N'-4-nitrobenzoylglycyl)amino]-4-methyl- pentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(S-BenzyI-L-cysteinyl]-3(S)-methylpentyl }-N-(l - naphthylmethyl)-glycyl-methionine N- { 2(S)-[S-Benzyl-L-cysteinyl]-3(S)-methylpentyl } -N-(l -naphthyl- methyl)-glycyl-methionine methyl ester N- { 2(S)-[S-Benzyl-D-cysteinyl]-3(S)-methylpentyl } -N-( 1 -naphthyl- methyl)-glycyl-methionine N-{2(S)-[S-Benzyl-D-cysteinyl]-3(S)-methylpentyl}-N-(l-naphthyl- methyl)-glycyl-methionine methyl ester 3-Benzylthiopropionyl-valyl-isoleucyl-methionine N-[2(S)-(2(S),3-Diaminoρropionyl)amino-3(S)-methylpentyl]-N-(l- naphthylmethyl)glycyl-methionine N-[2(S)-(2(S),3-Diaminopropionyl)amino-3(S)-methylpentyl]-N-(l- naphthylmethyl)glycyl-methionine methyl ester N-[2(S)-(3-Aminopropionyl)amino-3(S)-methylpentyl]-N-(l- naphthylmethyl)glycyl-methionine N-[2(S)-(3-Aminopropionyl)amino-3(S)-methylpentyl]-N-(l - naphthylmethy glycyl-methionine methyl ester N-(2(S)-L-Glutaminylamino-3(S)-methylpentyl)-N-( 1 -naphthyl- methyl)glycyl-methionine N-(2(S)-L-Glutaminylamino-3(S)-methylpentyl)-N-( 1 -naphthyl- methy glycyl-methionine methyl ester N-[2(S)-(l,l-Dimethylethoxycarbonylamino)-3S)-methylpentyl]-N- (1 -naphthylmethy l)glycyl-methionine N-[2(S)-( 1 , 1 -Dimethylethoxycarbonylamino)-3S)-methylpentyl]-N- ( 1 -naphthylmethyl)glycyl-methionine methyl ester N-[2(S)-(l,l-Dimethylethoxycarbonylamino)-3(S)-methylpentyl]-N- benzylglycyl-methionine N-[2(S)-(l,l-Dimethylethoxycarbonylamino)-3(S)-methylpentyl]-N- benzylglycyl-methionine methyl ester N- { [ 1 -(4-Nitrobenzy lthio)acety lamino]cyclopent- 1 -y lmethyl } -N-( 1 - naphthylmethyl)-glycyl-methionine N- { [ 1 -(4-Nitrobenzylthio)acetylamino]cyclopent- 1 -ylmethyl } -N-( 1 - naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[2-(4-Nitrophenyl)ethylcarbamoylamino]-4-methylpentyl } - N-(l-naphthylmethyl)-glycyl-methionine N- { 2(S)-[2-(4-Nitrophenyl)ethylcarbamoylamino]-4-methylpenty 1 } - N-(l -naphthylmethy l)-glycyl-methionine methyl ester N-{2(S)-[(3(S)-tetrahydrofuryloxy)carbonylamino]-3(S)- methylpentyl } -N-(l -naphthylmethyl)-glycyl-methionine N- { 2(S)-[(3(S)-tetrahydrofuryloxy)carbonylamino]-3(S)- ethylpenty 1 } -N-( 1 -naphthylmethyl)-glycy 1-methionine methyl ester N-{2(S)-[(cis-4-benzyloxytetrahydromr-3-yloxy)carbonylamino]- 3(S)-methylpentyl }-N-(l -naphthylmethyl)-glycyl -methionine N-{2(S)-[(cis-4-benzyloxytetrahydrofur-3-yloxy)carbonylamino]- 3(S)-methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(N'-Methyl-N'-4-nitrophenylacetylglycyl)amino]-4- methylpenty 1 } -N-( 1 -naphthylmethyl)-glycyl-methionine N-{2(S)-[(N-Methyl-N'-4-nitrophenylacetylglycyl)amino]-4- methylpentyl }-N-(l -naphthylmethyl)-glycyl-methionine methyl ester or the pharmaceutically acceptable salts thereof. The most preferred compounds of the invention are: N-{ 2(S)-[(4-Methoxybenzylthio)acetamido]-3(S)-methylpentyl }-N- ( 1 -naphthylmethy l)-glycyl-methionine N- { 2(S)-[(4-Methoxybenzylthio)acetamido]-3(S)-methylpentyl } -N- (l-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(4-Cyanobenzylthio)acetamido]-3(S)-methylpentyl } -N-( 1 ■ naphthylmethyl)-glycyl-methionine N- { 2(S)-[(4-Cyanobenzylthio)acetamido]-3(S)-methylpentyl } -N-( 1 naphthylmethyl)-glycyl-methionine methyl ester N-(2(S)-L-Glutaminylamino-3(S)-methylpentyl)-N-( 1 -naphthyl- methy glycyl-methionine N-(2(S)-L-Glutaminylamino-3(S)-methylpentyl)-N-( 1 -naphthyl- methyl)glycyl-methionine methyl ester N- { 2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl } -N-(l - naphthylmethy l)-glycyl-methionine sulfone N- { 2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl } -N-(l - naphthylmethyl)-glycyl-methionine sulfone methyl ester or the pharmaceutically acceptable salts thereof. 10 15 20 25 30 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, ally 1, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2- butenyl, famesyl, 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. When R2a and R b and R and R are combined to form - (CH2)s -, cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to: When R 5a and R 5b are combined to form - (CH2)s -, cyclic moieties as described hereinabove for R2 and R b and R3 and R4 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: 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 1 1-15 membered tricyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable stmcture. 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, thiamo holinyl, 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, NH 2 , N(Cl-C6 alkyl)2, N02, CF3, (C1-C6 alkyl)0-, -OH, (C1-C6 alkyl)S(0)m-, (C1-C6 alkyl)C(0)NH-, CN, H2N-C(NH)-, (C1-C6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)-, N3 C1-C6 alkyl)OC(0)NH- and C1 -C20 alkyl. 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., R 1 , Z, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, -N(Rl)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. The pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared 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 incorporated by reference. Abbreviations used in the description of the chemistry and in the Examples that follow are: MCPBA m-Chloroperoxybenzoic acid; MsCl Methanesulfonyl chloride; NaHMDS Sodium bis(trimethylsilyl)amide; Py Pyridine; TFA Trifluoroacetic acid; THF Tetrahydrofuran. 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. Alkylation of a reduced peptide subunit with an alkyl or aralkyl halide or, altematively, reductive alkylation of a reduced peptide subunit with an aldehyde using sodium cyanoborohydride or other reducing agents. Reaction P. 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. 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 alkylation reactions described in the Reaction Schemes. REACTION SCHEME A Reaction A. Coupling of residues to form an amide bond REACΗON SCHEME B Reaction B. Preparation of reduced peptide subunits by reductive alkylation NaCNBH 3 REACTION SCHEME C Reaction C. Alkylation/reductive alkylation of reduced peptide subunits R A R 7b H I R B 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 and RB are R2a, R2b, R3, R4, R5a or R5b as previously defined; XL is a leaving group, e.g., Br, I- or MsO-, and RC is defined such that R7b is generated by the reductive alkylation process. Certain compounds of this invention wherein X-Y is an ethenylene or ethylene unit are prepared by employing the reaction sequences shown in Reaction Schemes F and G. Reaction Scheme F outlines the preparation of the alkene isosteres utilizing standard manipulations such as Weinreb amide formation, Grignard reaction, acetylation, ozonolysis, Wittig reaction, ester hydrolysis, peptide coupling reaction, mesylation, cleavage of peptide protecting groups, reductive alkylation, etc., as may be known in the literature or exemplified in the Experimental Procedure. The key reactions are: stereoselective reduction of the Boc-amino-enone to the corresponding syn amino-alcohol (Scheme F, Step B, Part 1), and stereospecific boron triflouride or zinc chloride activated organo- magnesio, organo-lithio, or organo-zinc copper(l) cyanide SN ' displacement reaction (Scheme F, Step G). Through the use of optically pure N-Boc amino acids as starting material and these two key reactions, the stereo-chemistry of the final products is well defined. In Step H of Scheme F, Rx, which represents the amino terminus side chain substituent of the instant invention, is incorporated using coupling reaction A and R*COOH; the alkylation reaction C using R*CHO and a reducing agent; or alkylation reaction C using R CH2XL. The alkane analogs are prepared in a similar manner by including an additional catalytic hydrogenation step as outlined in Reaction Scheme G. REACTION SCHEME F BocN H Step A 1.NaBH 4 OAc BocNH, 2. Ac 2 0, Py )2a StepB 1.0 3 , Me 2 S OAc 2. Ph 3 P=CHC0 2 Me BocNH, ' COoMe StepC R 2a REACTION SCHEME F (CONT'D) BocNH R 3 MgCuCNCIBF 3 StepG 1.HCI 2. NaCNBH 3 R x CHO StepH W" wherein R x is: R 8 -V-(CR 1 2 )n-W-(CR 1 2 )p(CR 1 R 9 ) r REACTION SCHEME F fCONT'D NaOH or 1. HCl Alternate Step H O II 2. R x COH EDC, HOBT REACTION SCHEME G 2. Ac 2 0, py Ξ > 2a 2 _ Ph p =C HCO o Me OAc O B0CNH ^-^C0 2 Me ♦ H2N '" ^^ R2a L 3 2. EDC, HOBT BocNH REACTION SCHEME G (CONT'D) BocNH 1. R 3 MgCuCNCI « BF 3 2. H 2 , 5% Pd/C Step K 10 15 1. HCl 2. NaCNBH 3> R x CHO 30 REACTION SCHEME G (CONT'D) or o 1. HCI 2. R x COH EDC, HOBT NaOH R The oxa isostere compounds of this invention are prepared according to the route outlined in Scheme H. An aminoalcohol i is acylated with alpha-chloroacetyl chloride in the presence of trialkylamines to yield amide 2. Subsequent reaction of 2 with a deprotonation reagent (e.g., sodium hydride or potassium t- butoxide) in an ethereal solvent such as THF provides morpholinone 3 . . The N-Boc derivative 4 is then obtained by the treatment of 3 with BOC anhydride and DMAP (4-dimethylaminopyridine) in methylene chloride. Alkylation of 4 with R3χL, where XL is a leaving group such as Br, I- or Cl- in THF/DME (1,2-dimethoxyethane) in the presence of a suitable base, preferably NaHMDS [sodium bis(trimethylsilyl)amide], affords 5, which is retreated with NaHMDS followed by either protonation or the addition of an alkyl halide R4χ to give 6a or 6b, respectively. Altematively, 6a can be prepared from 4 via an aldol condensation approach. Namely, deprotonation of 4 with NaHMDS followed by the addition of a carbonyl compound RyRzCO gives the adduct 7. Dehydration of 7 can be effected by mesylation and subsequent elimination catalyzed by DBU (1,8- diazabicyclo[5.4.0]undec-7-ene) or the direct treatment of 7 with phosphorus oxychloride in pyridine to give olefin 8. Then, catalytic hydrogenation of 8 yields (5a. Direct hydrolysis of 6 with lithium hydrogen peroxide in aqueous THF will produce acid 9b. Sometimes, it is more efficient to carry out this conversion via a 2-step sequence, namely, hydrolysis of 6 in hydrochloric acid to afford 9a, which is then derivatized with BOC-ON or BOC anhydride to give 9b. The peptide coupling of acid 9b with either an alpha-aminolactone (e.g., homoserine lactone, etc.) or the ester of an amino acid is carried out under the conditions exemplified in the previously described references to yield derivative 10. Treatment of .10 with gaseous hydrogen chloride gives jj_, which undergoes reductive alkylation in the presence of an aldehyde RxCHO (12) and a reducing agent (e.g., sodium cyanoboro-hydride); or acylation in the presence of RxCOOH (13) and a peptide coupling reagent affording the products J_4a and b. Hydrolysis of compounds \4 to the corresponding hydroxy acids and acids, respectively, is accomplished by standard methods such as treatment with NaOH in alcoholic or aqueous milieux followed by careful acidifcation with dilute HCl. SCHEME H 4 7 8 SCHEME H (CONT'D a, R w = H b, R w = BOC + H-A 1Q 11 SCHEME H (CONT'D) A = The thia, oxothia and dioxothia isostere compounds of this invention are prepared in accordance to the route depicted in Scheme I. Aminoalcohol 1 is derivatized with BOC20 to give 15. Mesylation of JJ5 followed by reaction with methyl alpha- mercaptoacetate in the presence of cesium carbonate gives sulfide 16. Removal of the BOC group in 16 with TFA followed by neutralization with di-isopropylethylamine leads to lactam J . N-BOC derivative J_8 is obtained via the reaction of 17 with BOC anhydride in THF catalyzed by DMAP. Sequential alkylation of 18 with the alkyl halides R3χ and R4χ in THF/DME using NaHDMS as the deprotonation reagent produces 19. Hydrolysis of J_9 in hydro- chloride to yield 20a. which is derivatized with Boc anhydride to yield 20b. The coupling of 20b with an alpha-aminolactone (e.g., homoserine lactone, etc.) or the ester of an amino acid is carried out under conventional conditions as exemplified in the previously described references to afford 2L Sulfide 21 is readily oxidized to sulfone 22 by the use of MCPB A (m-chloroperoxybenzoic acid). The N-BOC group of either 21 or 22 is readily removed by treatment with gaseous hydrogen chloride. The resultant amine hydrochloride 23 undergoes reductive alkylation in the presence of an aldehyde RxCHO (12) and a reducing agent (e.g., sodium cyanoborohydride); or acylation in the presence of RxCOOH (13) and a peptide coupling reagent to afford the products 24 and 25. SCHEME I 13. 17 18 19 20 21 SCHEME I (CONT'D) m=0, 20. ~ ) CPBA m=2, 22 J 22. NaCNBH 3 24 m = 0 or 2 R x COOH EDC, HOBT 23 The compounds of this invention inhibit Ras famesyl transferase which catalyzes the first step in the post-translational processing of Ras and the biosynthesis of functional Ras protein. These 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, and myeloid leukemias. 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 farnesyl-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 famesyl 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 famesylate 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 farnesyl-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 farnesyl-protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl 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- { 2(S)-[(4-Nitrobenzylthio)acetamido]-3-methylpentyl } ■ N-(l-Naphthylmethyl)-glycyl-methionine methyl ester Step A: Preparation of N-(2(S)-t-butoxycarbonylamino)-3- methylpentvDglvcine methyl ester Glycine methyl ester hydrochloride (23.1 g, 0.18mol) was dissolved in methanol (700 mL) and treated with N-t- butoxycarbonyl-isoleucinal (40 g, 0.18 mol) with stirring at 0°C. Sodium cyanoborohydride (17.3 g, 0.28 mol) was added, and the pH of the mixture was adjusted to 7 with HOAc . After stirring for 3 h, aqueous saturated NaHC03 (50 mL) was added to the mixture which was then concentrated to 250 mL. The solution was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with aqueous saturated NaHC03 solution, brine, and dried (MgSθ4). Filtration and concentration provided the title compound after purification by chromatography (Siθ2, EtOAc: hexane, 1 :3). iH NMR (CDC13); δ 4.69 (m, IH), 3.72 (s, 3H), 3.48-3.62 (m, IH), 3.42 (ABq, 2H), 2.65 (d, 2H, J=6Hz), 1.4-1.6 (m, 2H), 1.48 (s, 9H), 1.04- 1.2 (m, IH), 0.85-0.95 (m, 6H). Step B: Preparation of N-[2(S)-t-Butoxycarbonylamino)-3- methylpentyll-N-d -naphthylmethy Dglvcine methyl ester N-[2(S)-t-Butoxycarbonylamino)-3-methylpentyl]glycine methyl ester (2.00 g, 6.97 mmol) was dissolved in 1 ,2-dichloroethane (56 ml) and 3 A molecular sieves were added followed by 1- naphthaldehyde (1.89 ml, 13.9 mmol) and sodium triacetoxy- borohydride (6.65 g, 31.4 mmol). The mixture was stirred at ambient temperature for 16 h, and filtered through glass fiber paper and concentrated. The residue was partitioned between EtOAc and sat. NaHCθ3 (100 ml/25 ml). The aqueous layer was washed with EtOAc (3x50 ml). The organic layers were combined, dried with Na2S04, filtered, and concentrated to give cmde product which was purified by chromatography (silica gel 1 :6 to 1 :3 ethyl acetate in hexane) to provide the title compound. *H NMR (CD3OD); 5 8.44-8.38 (d, IH, J=6Hz), 7.88-7.77 (m, 2H), 7.55-7.35 (m, 4H), 6.34-6.27 (m, IH), 4.25 (ABq, 2H), 3.66 (s, 3H), 3.40-3.23 (m, IH), 2.95-2.85 (dd, IH, J=6, 15Hz), 2.68-2.57 (dd, IH, J=6, 15Hz), 1.57-1.46 (m, IH), 1.43 (s, 9H), 1.34-1.18 (m, 2H), 1.06-0.85 (m, IH), 0.85-0.71 (m, 6H). Step C: Preparation of N-[2(S)-t-Butoxycarbonylamino)-3- methylpentyll-N-( 1 -naphthylmethyDglycine N-[2(S)-t-Butoxycarbonylamino)-3-methylpentyl]-N-(l - naphthylmethyl)glycine methyl ester (2.61 g, 6.10 mmol) was dissolved in MeOH (50 ml) and IN NaOH (24.4 ml, 24.4 mmol) was added. The mixture was stirred at ambient temperature for 4 h and concentrated. The resulting residue was dissolved in H2θ (25 ml) and neutralized with IN HCl (24.4 ml). The aqueous layer was washed with EtOAc (3x50 ml). The organic layers were combined, dried with Na2Sθ4, filtered, and concentrated to provide the title compound. ^H NMR (CD3OD); δ 8.48-8.39 (d, IH. J=6Hz), 8.03-7.91 (t, 2H, J=6Hz), 7.75-7.48 (m, 4H), 5.00-4.93 (d, IH, J=12Hz), 4.78-4.66 (d, IH, J=12Hz), 3.80-3.58 (m, 3H), 3.49-3.40 (dd, IH, J=3, 12Hz), 3.09- 2.98 (dd, IH, J=3, 12Hz), 1.42 (s, 9H), 1.37-1.28 (m, 2H), 1.80-1.00 (m, IH), 0.94-0.78 (m, 6H). Step D: Preparation of N-[2(S)-t-Butoxycarbonylamino)-3- methylpentyl] -N-( 1 -naphthylmethy l)glycine -methionine methyl ester N-[2(S)-t-Butoxycarbonylamino)-3-methylpentyl]-N-(l - naphthylmethyl)glycine (2.29 g, 5.53 mmol), dissolved in DMF (20 mL). was treated with HOBT (0.822 g, 6.08 mmol), EDC ( 1.17 g, 6.08 mmol). and methionine methyl ester hydrochloride (1.21 g, 6.08 mmol). The pH was adjusted to 7.5 with Et3N (1.7 mL, 12 mmol) and the mixture was stirred at ambient temperature for 24 h. The mixture was concentrated, and the residue was partitioned between EtOAc (50 mL) and saturated NaHC03 solution (25 mL). The aqueous layer was extracted with EtOAc (1x30 mL). The organic layers were combined, washed with brine (1x25 mL), dried (Na2S04), filtered, and concentrated to give cmde product which was purified by chromatography (silica gel eluting with 1 :3 to 1 :2 ethyl acetate in hexane) to provide the title compound. iH NMR (CD3OD); δ 8.36- 8.29 (d, IH, J=6Hz), 7.93-7.86 (d, IH, J=6Hz), 7.85-7.80 (d, IH, J=6Hz), 7.61-7.39 (m, 4H), 6.60-6.52 (m, IH), 4.32-4.06 (m, 2H), 3.90-3.69 (m, IH), 3.65 (s, 3H), 3.27-3.14 (m, 2H), 2.93-2.70 (m, 2H), 2.19-1.78 (m, 6H), 1.63-1.30 (m, 13H), 1.19-1.05 (m, IH), 0.95-0.81 (m, 6H). Step E: Preparation of N-[2(S)-amino-3-methylpentyl)-N-( 1 - naphthylmethyl)-glycyl-methionine methyl ester hvdrochloride N-[2(S)-(t-Butoxycarbonylamino)-3-methylpentyl]-N-(l- naphthylmethy -glycyl-methionine methyl ester (2.82 g, 5.04 mmol) was dissolved in EtOAc (50 mL) and cooled to -25°C. HCl was bubbled through the mixture until TLC (95:5 CH2Cl2:MeOH) indicated complete reaction. Nitrogen was bubbled through the mixture to remove excess HCl and the mixture was then concentrated to provide the title compound. iH NMR (CD3OD); δ 8.34-8.28 (d, IH, J=6Hz), 8.00-7.92 (d, 2H, J=6Hz), 7.83-7.71 (m, IH), 7.68-7.49 (m, 3H), 4.76-4.55 (m, 4H), 3.84-3.75 (m, 2H), 3.71 (s, 3H), 3.59-3.70 (m. IH), 3.21 -3.00 (m, 2H), 2.57-2.38 (m, 3H), 2.17-2.04 (m, 4H), 1.97-1.81 (m, IH). 1.63- 1.50 (m, IH), 1.39-1.20 (m, IH), 1.19-1.00 (m, IH), 0.95-0.79 (m, 6H). Step F: Preparation of (4-nitrobenzylthio)acetic acid 4-Nitrobenzyl chloride (2.5 g, 15 mmol) was added to a solution of mercaptoacetic acid (80% in H2O, 1 mL, ~ 12 mmol) in aqueous sodium hydroxide (2.75 N, 10 mL) and THF (10 mL) with stirring at 50°C. After 1 hour, the reaction was cooled to ambient temperature, diluted with water (30 mL) and extracted with Et2θ to remove excess halide. The aqueous layer was distributed between EtOAc and 5% citric acid and the organic extract then washed with H2θ, dried (MgS04) and evaporated to give the title compound as a pale yellow solid, m.p. 101 -104°C [lit. m.p. 114°C]. *H NMR (CDC13); δ 3.10 (s, 2H), 3.94 (s, 2H), 5.37 (d, 2H, J = 8.7 Hz), 8.21 (d, 2H, J = 8.7 Hz). Step G: Preparation of N-{ 2(S)-[(4-Nitrobenzylthio)acetamido]- 3(S)-methylρenty 1 } -N-( 1 -naphthylmethyl)-glycyl- methionine methyl ester (4-Nitrobenzylthio)acetic acid (68 mg, 300 μmol), dissolved in DMF (4 mL), was treated with HOBT (51 mg, 300 μmol), EDC (65 mg, 300 μmol), and N-[2(S)-amino-3-methylpentyl)- N-( 1 -naphthylmethyl)-glycyl-methionine methyl ester hydrochloride (133 mg, 250 μmol). The pH was adjusted to 7.5 with Et3N (1 10 μL, 250 μmol) and the mixture was stirred at ambient temperamre for 16 h. The mixture was concentrated and the residue was partitioned between EtOAc (100 mL) and H2O (100 mL). The organic layer was washed with H2O (2x50 mL), dried (MgS04), filtered, and concentrated to give a cmde product which was purified by chromatography (silica gel, eluting with 1 : 1 to 1 :2 hexane : EtOAc) to provide the title compound. iH NMR (CDCI3); δ 0.89 (t, 3H, J = 7.5 Hz), 0.91 (d, 3H, J = 6.9 Hz), 1.02- 1.19 (m, 1 H), 1.37- 1.6 (m, 2H), 1.67-1.79 (m, IH), 1.85-1.98 (m, IH), 1.95 (s, 3H), 2.0-2.1 (m, 3H), 2.74 (dd, IH, J = 3, 12 Hz), 2.86-3.01 (m, 3H), 3.21 (d, IH, J = 14 Hz), 3.29 (d, IH, 14 Hz), 3.69 (s, 3H), 3.74 (d, IH, J = 12 Hz), 3.8 (d, IH, J = 12 Hz), 3.83-3.94 (m, IH), 4.05 (d, IH, J = 9 Hz), 4.18 (d, IH, J = 9 Hz), 4.41-4.49 (m, IH), 6.7 (d, IH, J = 8 Hz), 7.39-7.53 (m, 7H), 7.8-7.9 (m, 2H), 8.14-8.22 (m, 2H). Anal. Calcd for C34.H44N4O6S2-O. i5 EtOAc C, 60.92: H, 6.68; N, 8.21 C, 60.64; H, 6.65; N, 8.23 EXAMPLE 2 N-{ 2(S)-[(4-Nitrobenzylthio)acetamido]-3(S)-methylpentyl }-N-(l - naphthylmethyP-glycyl-methionine N- { 2(S)-[(4-Nitrobenzylthio)acetamido]-3(S)- methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine methyl ester (from Example 1 ; 100 mg, 150 μmol) was dissolved in MeOH (1 mL) and 1.ON NaOH (300 μL, 300 μmol) was added. The mixture was stirred at 45°C under argon for 45 minutes then the solution was partitioned between EtOAc (100 mL) and 5% citric acid (50 mL). The organic layer was washed with H2θ (2x50 mL), dried (MgSθ4), filtered and evaporated to give the title compound. -^H NMR; δ 0.84 (t, 3H, J = 7.5 Hz), 0.88 (d, 3H, J = 7 Hz), 0.91-1.0 (m, IH), 1.0-1.2 (m, IH), 1.2-2.1 (m, 5H), 1.90 (s, 3H), 2.8-2.86 (m, 2H), 3.0-3.3 (m, 4H), 3.90 (s, 2H), 3.91-4.22 (m, 4H), 7.37-7.56 (m, 6H), 7.78-7.88 (m, 2H), 8.15 (d, 2H, J = 8Hz), 8.27 (d, IH, J = 8.3 Hz). Anal. Calcd for C33H42N4O6S2O.25 CHC13-L0 CH3OH C, 57.39; H, 6.50; N, 7.82 C, 57.71 ; H, 6.42; N, 7.46 EXAMPLE 3 The following acids were prepared according to the procedure described for Example 1 , Step F or were obtained commercially: (Benzylthio)acetic acid (3-Nitrobenzylthio)acetic acid (2-Nitrobenzylthio)acetic acid (4-Cyanobenzylthio)acetic acid (4-Trifluoromethylbenzylthio)acetic acid (4-Methoxybenzylthio)acetic acid (4-Methylsulfonylbenzylthio)acetic acid (4-Phenylbenzylthio)acetic acid (4-Methylbenzylthio)acetic acid (8-Chloronaphth-l -ylthio)acetic acid (2-Methylindol-3-ylthio)acetic acid 3-(Benzylthio)propionic acid (4-Picolinylthio)acetic acid (4-Pyridylthio)acetic acid EXAMPLE 4 The following compounds were prepared using the procedure described for Example 1 , Step G, but substituting the appropriate acid from Example 3 for (4-nitrobenzylthio)acetic acid, and, in some cases, substituting N-t-butoxycarbonylleucinal for N-t- butoxycarbonyl-isoleucinal in Step A in the preparation of the intermediate. N-{2(S)-[(Benzylmio)acetamido]-3(S)-methylpentyl}-N-(l- naphthylmethyD-glycyl-methionine methyl ester FAB mass spectrum m/z = 624 (M+l). Anal. Calcd for C34H45N3O4S2O.3O TFA-0.95 H2θ C, 55.70; H, 6.16; N, 5.32 C, 55.72; H, 6.17; N, 5.30 N-{2(S)-[(3-Nitrobenzylthio)acetamido]-3(S)-methylpentyl}-N-(l - naphthylmethyD-glycyl-methionine methyl ester Anal. Calcd for C34H44N4O6S2O.2 EtOAc C, 60.88; H, 6.70; N, 8.16 C. 60.52; H, 6.63; N, 8.31 N-{ 2(S)-[(2-Nitrobenzylthio)acetamido]-3(S)-methylpentyl}-N-(l - naphthylmethvD-glvcyl-methionine ethyl ester Anal. Calcd for C34H44N4O6S2O.2 EtOAc C, 60.88; H, 6.70; N, 8.16 C, 60.44; H, 6.67; N, 8.19 N-{ 2(S)-[(4-Cyanobenzylthio)acetamido]-3(S)-methylpentyl}-N-(l- naphthylmethyO-glycyl-methionine methyl ester Anal. Calcd for C35H44N4O4S2O.5 EtOAc C, 64.13; H, 6.98; N, 8.09 C, 63.85; H, 6.91; N, 8.17 N-{2(S)-[(4-Trifluoromethylbenzylthio)acetamido]-3(S)-methylpentyl}- N-(l -naphthylmethyl)-glvcyl-methionine methyl ester Anal. Calcd for C35H44F3N3O4S2O.4 EtOAc- 1.0 H2O C, 58.99; H, 6.66; N, 5.64 C, 58.97; H, 6.37; N, 5.61 N- { 2(S)-[(4-MethoxybenzyIthio)acetamido]-3(S)-methylpentyl } -N-(l - naphthylmethyO-glycyl-methionine methyl ester Anal. Calcd for C35H47N3O5S2O.6 EtOAc-0.35 H2O C, 62.99; R 7.42; N, 5.89 C, 62.64; H, 7.17; N, 6.29 N- { 2(S)-[(4-Methylsulfonylbenzylthio)acetamido]-3(S)-methylρentyl } - N-(l -naphthylmethy P-glvcyl-methionine methyl ester Anal. Calcd for C35H47N3O6S3 C, 59.89; H, 6.75; N, 5.99 C, 60.14; H, 6.90; N, 5.96 N-{2(S)-[(4-Phenylbenzylthio)acetamido]-3(S)-methylpentyl}-N-(l - naphthylmethvD-glvcyl-rnethionine methyl ester FAB mass spectmm m/z = 700 (M+l). N- { 2(S)-[(4-Methylbenzylthio)acetamido]-3(S)-methylpentyl }-N-(l - naphthylmethvD-glvcyl-methionine methyl ester FAB mass spectmm m/z = 638 (M+l). N- { 2(S)-[(8-Chloronaphth-l -ylthio)acetamido]-3(S)-methylpentyl } - N-(l-naphthylmethyl)-glvcyl-methionine methyl ester Anal. Calcd for C37H44CIN3O4S2O.5 EtOAc C, 63.43; H, 6.55; N, 5.69 C, 63.33; H, 6.35; N, 6.07 N- { 2(S)-[((2-Methy lindol-3-yl)thio)acetamido]-4-methylpentyl } -N- ( 1 -naphthylmethvD-glvcyl-methionine methyl ester Anal. Calcd for C36H46N4O4S2O.35 EtOAc C, 64.74; H, 7.09; N, 8.08 C, 64.73; H, 6.93; N, 8.32 N- { 2(S)-[(4-Pyridylthio)acetamido]-3(S)-methylpentyl } -N-( 1 - naphthylmethyD-glycyl-methionine methyl ester Anal. Calcd for C32H42N4θ4S2'2.0 TFA-0.75 H2O C, 50.72; H, 5.38; N, 6.57 C, 50.84; H, 5.28; N, 6.56 N- { 2(S)-[(4-Picolinylthio)acetamido]-3(S)-methylpentyl } -N-(l - naphthylmethyD-glycyl-methionine methyl ester Anal. Calcd for C33H44N4θ4S2 « 2.0 TFA-0.75 H2O C, 51.29; H, 5.53; N, 6.47 C, 51.27; H, 5.35; N, 6.70 N- { 2(S)-[3-(Benzylthio)propionamido]-3(S)-methylpentyl } -N-(l - naphthylmethvD-glvcyl-methionine methyl ester !H NMR (CDC13); δ 0.84 (t, 3H), 0.88 (d, 3H), 1.08 (m, IH), 1.40 (m, 2H), 1.66-2.0 (m,7H), 2.33 (m, 2H), 2.7 (m, 3H), 2.99 (dd, IH), 3.21 (s, 2H), 3.68 (s, 3H), 3.7 (m, 3H), 4.4 (m, IH), 6.33 (d, IH), 7.2- 7.4 (m, 10H), 7.7-7.9 (m, 4H), 8.19 (m, IH). EXAMPLE 5 N- { 2(S)-[(Phenylthio)acetamido]-3(S)-methylpentyl } -N-(l - naphthylmethyD-glycyl-methionine methyl ester To solution of N-(2(S)-amino-3(S)-methylpentyl)-N-(l- naphthylmethy l)-gly cy 1-methionine methyl ester hydrochloride ( 125 mg, 0.23 mmol) and Et3N (65.5 μL, 0.47 mmol) in THF (2.5 mL) at room temperature was added bromo acetylbromide (24 μL, 0.28 mmol). After 10 minutes, thiophenol (29 μL, 0.28 mmol) and Et3N (49 μL, 0.35 mmol) were added and the mixture was stirred for 4 hours. The solution was poured into saturated aqueous NaHC03, extracted with EtOAc (x3), washed with brine, dried (MgS04) and evaporated. Purification of the residue by column chromatography (silica gel; hexane/EtOAc 3:2) gave the title compound as an oil. FAB mass spectmm m/z = 610 (M+ 1 ). Anal. Calcd for C33H43N3O4S2O.5 TFA-1.15 H2O C, 53.94; H, 5.88; N, 5.24 C, 53.93; H, 5.91 ; N, 5.1 1 EXAMPLE 6 N-{ 2(S)-[(4-(l-/ -Tetrazol-5-yl)benzylthio)acetamido]-3(S)- methylpentyl )-N-(l -naphthylmethyP-glycyl-methionine methyl ester Step A: Preparation of I4-(lH-tetrazol-5-yl)benzylthio1acetic acid (4-Cyanobenzylthio)acetic acid (from Example 3; 207 mg, 1 mmol) was added to a stirred solution of trimethylsilylazide (400 μL, 3 mmol) and dibutyltin oxide (25 mg, 100 μmol) in toluene (0.5 mL) at 1 10°C. After 6 hours, the reaction was quenched with MeOH (1 mL) and evaporated. The residue was purified by flash chromatography (silica gel; 1000: 100:3 to 1000:100:13 CHCl3/MeOH/HOAc) to give the title compound. Rf (silica; 1000:100:6 CHCl3/MeOH/HOAc) = 0.2 compared to the nitrile starting material of Rf = 0.67. iH NMR (d° DMSO); δ 3.15 (s, 2H), 3.88 (s, 2H), 7.51 (d, 2H, J = 8.1 Hz), 7.99 (d, 2H, J = 8.1 Hz). FAB mass spectmm m/z = 251 (M+l). Step B: N-{ 2(S)-[(4-(l- /-Tetrazol-5-yl)benzylthio)acetamido]- 3(S)-methylpenty 1 } -N-( 1 -naphthylmethyl)-glycyl- methionine methyl ester Following the procedure described for Example 1 , Step G, [4-(lH-tetrazol-5-yl)benzylthio]acetic acid was coupled with N- (2(S)-amino-3(S)-methylpentyl)-N-( 1 -naphthylmethyl)-glycyl- methionine methyl ester hydrochloride to give the title compound. Anal. Calcd for C35H45N7O4S2O.8 TFA C, 51.67; H, 5.26; N, 10.93 C, 51.66; H, 5.26; N, 10.84 EXAMPLE 7 N- { 2(S)-[(Benzyloxy)acetamido]-3(S)-methylpentyl } -N-( 1 - naphthylmethvP-glvcyl-methionine methyl ester The title compound was prepared from N-[2(S)-amino-3- methylpenty l)-N-( 1 -naphthylmethyl)-glycyl-methionine methyl ester hydrochloride (Example 1 , Step E) and benzyloxyacetyl chloride (Aldrich) under standard conditions. FAB mass spectmm m/z = 608 (M+l ). EXAMPLE 8 N-{2(S)-[(N'-Benzyl-N-t-butoxycarbonylglycyl)amino]-3(S)- methylpentyl ) -N-( 1 -naphthylmethvP-glvcyl-methionine methyl ester Step A: Preparation of N-benzyl-N-t-butoxycarbonylglycine N-Benzylglycine ethyl ester hydrochloride was converted to N-benzyl-N-t-butoxycarbonylglycine ethyl ester using di-t-butyl dicarbonate under standard conditions. The ethyl ester was saponified using sodium hydroxide in methanol to give the title compound. Step B: Preparation of N- { 2(S)-[(N'-benzyl-N'-t- butoxycarbonylglycyl)amino]-3(S)-methylpentyl }-N-(l - naphthylmethyP-glvcyl-methionine methyl ester The glycine derivative prepared in Step A was converted to the title compound using the method of Example 1 , Step G. Anal. Calcd for C39H54N4O6S-0.5 H2O C, 65.42; H, 7.74; N, 7.83 C, 65.31; H, 7.33; N, 8.01 EXAMPLE 9 N- { 2(S)-[(N'-Benzylglycyl)amino]-3(S)-methylpentyl } -N-( 1 - naphthylmethyP-glvcyl-methionine methyl ester The t-butoxycarbonyl group of N-{2(S)-[(N'-benzyl-N'-t- butoxycarbonylglycyl)amino]-3(S)-methylpentyl } -N-( 1 -naphthyl- methyl)-glycyl-methionine methyl ester. Example 8, was cleaved using the method of Example 1, Step E to provide the title compound. Anal. Calcd for C34H46N4θ4S » 2.0 HC1-0.75 H2O C, 58.90; H, 7.20; N, 8.08 C, 59.07; H, 6.88; N, 7.87 EX AMPLE 10 N-{2(S)-[(N'-Acetyl-N'-benzylglycyl)amino]-3(S)-methylpentyl}-N- (l-naphthylmethyl)-glvcyl-methionine methyl ester A solution of N-{ 2(S)-[(N'-benzylglycyl)amino]-3(S)- methylpentyl}-N-(l-naphthylmethyl)-glycyl-methionine methyl ester from Example 9 (200 mg, 0.3 mmol) was dissolved in CH2CI2 (4 mL). Acetic anhydride (0.1 1 mL) and N,N-diisopropylethylamine (0.31 mL) were added and the mixture was stirred for 48 hours. The mixture was concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried and evaporated to give a residue which was purified by silica gel chromatography (1-3% MeOH in CH2CI2) to give the title compound. Anal. Calcd for C36H48N4θ5S » 0.5 H2O C, 65.72; H, 7.51; N, 8.52 C, 65.87; H, 7.23; N, 8.69 EXAMPLE 1 1 N- { 2(S)-[(Benzylthio-S-oxide)acetamido]-3(S)-methy naphthylmethyP-glycyl-methionine methyl ester Step A: Preparation of (benzylthio)acetic acid S-oxide Benzylthioacetic acid was converted to the known title compound (Lindstrom and Mark, US Patent 4,637,833) by oxidation with sodium periodate in methanol. Step B: N- { 2(S)-[(Benzylthio-S-oxide)acetamido]-3(S)- methylpenty 1 } -N-( 1 -naphthylmethyl)-glycyl-methionine methyl ester The sulfoxide derivative from Step A was converted to the title compound using the method of Example 1, Step G. FAB mass spectmm m/z = 640 (M+l). EXAMPLE 12 N-{2(S)-[(Benzylthio-S,S-dioxide)acetamido]-3(S)-methylpentyl }-N- ( 1 -naphthylmethvP-glvcyl-methionine methyl ester Step A: Preparation of (benzylthio)acetic acid S,S-dioxide Benzylthioacetic acid was converted to the known title compound (Lindstrom and Mark, US Patent 4,637,833) by oxidation with Oxone in methanol. Step B: N- { 2(S)-[(Benzylthio-S,S-dioxide)acetamido]-3(S)- methylpenty 1 } -N-( 1 -naphthylmethy l)-glycyl-methionine methyl ester The sulfone derivative from Step A was converted to the title compound using the method of Example 1 , Step G. FAB mass spectmm m/z = 656 (M+l). EXAMPLE 13 N-{ 2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl}-N-(l- naphthylmethvP-glycyl-methionine sulfone methyl ester Using the method of Example 1 , but substituting methionine sulfone and benzylthioacetic acid as appropriate, the title compound was prepared. FAB mass spectmm m/z = 656 (M+l). EXAMPLE 14 N-{2(S)-[(N'-4-Nitrobenzoylglycyl)amino]-3(S)-methylpentyl}-N-(l* naphthylmethvP-glycvI-methionine methyl ester Following the procedure described for Example 1 , Step G, but substituting (4-nitrobenzylthio)acetic acid with N-(4- nitrobenzoyl)glycine (Aldrich) the title compound was obtained. Anal. Calcd for C34H43N5O7SO.8 H2O C, 60.03; H, 6.61 ; N, 10.30 C, 59.99; H, 6.32; N, 10.28 EXAMPLE 15 N- { 2(S)-[( -Methyl-N'-4-nitrobenzoylglycyl)amino]-4-methyl- pentyl )-N-(l -naphthylmethvP-glvcyl-methionine methyl ester Following the procedure described for Example 1, but substituting (4-nitrobenzylthio)acetic acid with N-(4- nitrobenzoyl)sarcosine (A. Morgan et al, J. Med. Chem., 34:2126 (1991)) and N-t-butoxycarbonylleucinal for N-t- butoxycarbonylisoleucinal the title compound was obtained. Anal. Calcd for C35H45N5O7SO.35 EtOAc C, 61.51 ; H, 6.78; N, 9.86 C, 61.13; H, 6.69; N, 10.1 1 EXAMPLE 16 N-{ 2(S)-[S-Benzyl-L-cysteinyl]-3(S)-methylpentyl }-N-(l - naphthylmethyP-glycyl-methionine methyl ester S-Benzyl-N-t-butoxycarbonyl-L-cysteine (Bachem) was coupled with N-[2(S)-amino-3-methylpentyl)-N-(l -naphthylmethyl)- glycyl-methionine methyl ester hydrochloride according to the procedure described for Example 1 , Step G. The product thus obtained was deprotected using TFA in CH2CI2 to give the title compound. FAB mass spectmm m/z = 653 (M+l). Anal. Calcd for C35H48N4θ4S2'2.8 TFA-0.1 H2O C, 50.07; H, 5.28; N, 5.75 C, 50.07; H, 5.32; N, 5.98 EXAMPLE 17 N- { 2(S)-[S-benzyl-D-cysteinyl]-3(S)-methylpentyl } -N-( 1 - naphthylmethvP-glvcyl-methionine methyl ester S-Benzyl-N-t-butoxycarbonyl-D-cysteine (Bachem) was coupled with N-[2(S)-amino-3-methylpentyl)-N-(l-naphthylmethyl)- glycyl-methionine methyl ester hydrochloride according to the procedure described for Example 1 , Step G. The product thus obtained was deprotected using TFA in CH2CI2 to give the title compound. FAB mass spectrum m/z = 653 (M+l). Anal. Calcd for C35H48N4θ4S2'2.3 TFA-0.5 H2O C, 51.47; H, 5.60; N, 6.06 C, 51.49; H, 5.57; N, 6.33 EXAMPLE 18 The following compounds were prepared from the corresponding esters (Examples 3-17) using the procedure described for Example 2. N- { 2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl } -N-( 1 - naphthylmethyP-glvcyl-methionine FAB mass spectmm m/z = 610 (M+l). Anal. Calcd for C33H43N3O4S2O.O5 TFA- 1.05 H2O C, 56.32; H, 6.22; N, 5.61 C, 56.32; H, 5.99; N, 6.01 N-{ 2(S)-[(Phenylthio)acetamido]-3(S)-methylpentyl }-N-(l* naphthylmethvP-glvcyl-methionine FAB mass spectmm m/z = 596 (M+l). Anal. Calcd for C32H41N3O4S2O.25 TFA-0.75 H2O C, 55.11; H, 5.87; N, 5.59 C, 55.14; H, 5.86; N, 5.46 N- { 2(S)-[(3-Nitrobenzylthio)acetamido]-3(S)-methylpentyl } -N-(l ■ naphthylmethvP-glvcyl-methionine Anal. Calcd for C33H42N4θ6S2« 2 H2O-0.5 EtOAc C, 58.34; H, 6.77; N, 7.78 C, 58.34; H, 6.54; N, 7.51 N-{ 2(S)-[(2-Nitrobenzylthio)acetamido]-3(S)-methylpentyl }-N-(l ■ naphthylmethyP-glycyl-methionine Anal. Calcd for C33H42N406S2* 1 H2O-0.5 EtOAc C, 58.34; H, 6.77; N, 7.78 C, 58.34; H, 6.51; N, 7.63 N-{ 2(S)-[(4-Cyanobenzylthio)acetamido]-3(S)-methylpentyl}-N-(l naphthylmethvP-glvcyl-methionine Anal. Calcd for C34H42N4O4S2O.3 CHCI3 C, 61.42; H, 6.36; N, 8.35 C, 61.73; H, 6.31; N, 8.41 N- { 2(S)-[(4-Trifluoromethylbenzylthio)acetamido]-3(S)- methylpentyl ) -N-( 1 -naphthylmethyP-glycy 1-methionine Anal. Calcd for C34H42F3N3O4S2O.5 EtOAc C, 59.89; H, 6.42; N, 5.82 C, 59.60; H, 6.25; N, 5.82 N-{ 2(S)-[(4-Methoxybenzylthio)acetamido]-3(S)-methylpentyl }-N- ( 1 -naphthylmethvP-glvcyl-methionine Anal. Calcd for C34H45N3O5S2O.5 EtOAc C, 63.22; H, 7.22; N, 6.14 C, 63.22; H, 7.03; N, 6.19 N- { 2(S)-[(4-Methylsulfonylbenzylthio)acetamido]-3(S)- methylpentyl ) -N-( 1 -naphthylmethyP-glycyl-methionine Anal. Calcd for C34H45N3O6S3-0.3 H2O C, 58.89; H, 6.63; N, 6.06 C, 58.85; H, 6.64; N, 6.00 N-{ 2(S)-[(4-Phenylbenzylthio)acetamido]-3(S)-methylpentyl }-N-(l - naphthylmethyP-glycyl-methionine Anal. Calcd for C39H47N3O4S2O.5 TFA-0.5 H2O C, 58.25; H, 5.76; N, 4.85 C, 58.26; H, 5.67; N, 4.87 N-{ 2(S)-[(4-Methylbenzylthio)acetamido]-3(S)-methylpentyl}-N-(l * naphthylmethvP-glvcyl-methionine Anal. Calcd for C34.H45N3O4S2-O.25 H2O C, 64.98; H, 7.30; N, 6.69 C, 64.95; H, 7.17; N, 6.66 N- { 2(S)-[(8-Chloronaphth-l -ylthio)acetamido]-3(S)-methylpentyl } - N-( 1 -naphthy l ethyP-glycyl-methionine Anal. Calcd for C36H42C1N3O4S2- 0 EtOAc- 1.0 H2O C, 61.08; H, 6.66; N, 5.34 C, 61.09; H, 6.94; N, 5.38 N- { 2(S)-[((2-Methylindol-3-yl)thio)acetamido]-4-methylpentyl } -N- ( 1 -naphthylmethvP-gl vcyl-methionine Anal. Calcd for C35H44N4O4S2-0.5 EtOAc-0.5 H2θ C, 63.30; H, 7.04; N, 7.98 C, 63.17; H, 6.77; N, 7.98 N- { 2(S)-[(4-Pyridylthio)acetamido]-3(S)-methylpentyl } -N-( 1 - naphthylmethvP-glvcyl-methionine FAB mass spectmm m/z = 579 (M+l). N- { 2(S)-[(4-Picolinylthio)acetamido]-3(S)-methylpentyl } -N-( 1 - naphthylmethyP-glycyl-methionine Anal. Calcd for C32H42N4O4S2-2.0 TFA- 1.7 H2O C, 49.72; H, 5.49; N, 6.44 C, 49.51; H, 5.10; N, 6.57 N- { 2(S)-[3-(Benzylthio)propionamido]-3(S)-methylpentyl } -N-( 1 ■ naphthylmethvP-glvcyl-methionine FAB mass spectmm m/z = 624 (M+l). Anal. Calcd for C34H45N3O4S2-L0TFA C, 58.60; H, 6.28; N, 5.69 C, 58.63; H, 6.29; N, 5.92 N- { 2(S)-[(Benzyloxy)acetamido]-3(S)-methylpentyl } -N-( 1 - naphthylmethvP-glvcyl-methionine FAB mass spectmm m/z = 594 (M+l ). N- { 2(S)-[(N'-Benzylglycyl)amino]-3(S)-methylpentyl } -N-( 1 - naphthylmethvP-glvcyl-methionine Anal. Calcd for C33H44N4O4S-2.0 TFA- 1.0 H2O C, 52.97; H, 5.77; N, 6.68 C, 52.91 ; H, 5.61 ; N, 6.63 N- { 2(S)-[(N'-Acetyl-N'-benzylglycyl)amino]-3(S)-methylpentyl } -N- ( 1 -naphthylmethyP-glycyl-methionine Anal. Calcd for C35H46-N4O5S-1.0 TFA-0.75 H2θ C, 58.29; H, 6.41; N, 7.35 C, 58.13; H, 6.19; N, 7.68 N- { 2(S)-[(Benzylthio-S-oxide)acetamido]-3(S)-methylpentyl } -N-( 1 - naphthylmethyP-glycyl-methionine FAB mass spectmm m/z = 626 (M+l ). N-{ 2(S)-[(Benzylthio-S,S-dioxide)acetamido]-3(S)-methylpentyl }-N- ( 1 -naphthylmethvP-gl vcyl-methionine FAB mass spectmm m/z = 642 (M+l). N- { 2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl } -N-(l - naphthylmethvP-glvcyl-methionine sulfone The i H-NMR was consistent with the titled stmcture. N- { 2(S)-[(N'-4-Nitrobenzoylglycyl)amino]-3(S)-methylpentyl } -N-( 1 - naphthylmethvP-glvcyl-methionine Anal. Calcd for C33H4l N5θ7S*0.5 H2O C, 59.98: H, 6.41 ; N, 10.60 C, 59.84; H, 6.31 ; N, 10.22 N- { 2(S)-[(N'-Methyl-N'-4-nitrobenzoylglycyl)amino]-4- methylpenty 11 -N-( 1 -naphthylmethyP-glycy 1-methionine Anal. Calcd for C34H43N5O7SO.6 EtOAc-0.5 H2O C, 60.08; H, 6.76; N, 9.62 C, 60.06; H, 6.45; N, 9.60 N- ( 2(S)-[(S-Benzyl-L-cysteinyl]-3(S)-methylpentyl } -N-( 1 - naphthylmethvP-glvcyl-methionine FAB mass spectmm m/z = 639 (M+l). Anal. Calcd for C34H46N404S2-2.4 TFA-0.7 H2O C, 50.37; H, 5.43; N, 6.06 C, 50.34; H, 5.39; N, 6.14 N- { 2(S)-[S-Benzyl-D-cysteinyl]-3(S)-methylpentyl } -N-( 1 - naphthylmethvP-glvcyl-methionine FAB mass spectmm m/z = 639 (M+l). Anal. Calcd for C34H46N404S2-2.9 TFA-0.5 H2O C, 48.85; H, 5.14; N, 5.73 C, 48.82; H, 5.12; N, 5.84 EXAMPLE 19 3-Benzylthiopropionyl-valyl-isoleucyl-methionine This compound was synthesized using standard techniques of solution phase peptide synthesis starting from methionine methyl ester and other commercially available materials. Anal. Calcd for C26H41N3O5S2 C, 57.86; H, 7.66; N, 7.79 C, 57.54; H, 7.58; N, 7.81 EXAMPLE 20 N- { 2(S)-[(4-( 1 -tf-Tetrazol-5-yl)benzylthio)acetamido]-3(S)- methylpentyl ) -N-( 1 -naphthylmethvP-glvcyl-methionine sodium salt The sodium salt of N-{ 2(S)-[(4-(l-//-tetrazol-5-yl)- benzylthio)acetamido]-3(S)-methylpentyl } -N-( 1 -naphthylmethyl)- glycyl-methionine was prepared from the corresponding methyl ester (2.1 mg) in 200 μL of MeOH treated with 150 μL of 0.1 N NaOH and the solution diluted to 1 mL for assay. EXAMPLE 21 N- { 2(S)-[(N'-Benzyl-N'-t-butoxycarbonylglycyl)amino]-3(S)- methylpentyl )-N-(l -naphthylmethyP-glycyl-methionine sodium salt The sodium salt of N-{ 2(S)-[(N'-benzyl-N'-t-butoxy- carbonylglycyl)amino]-3(S)-methylpenty 1 } -N-( 1 -naphthylmethyl)- glycyl-methionine was prepared in situ by hydrolysis of the corresponding methyl ester (2.2 mg) in 0.3 mL of MeOH with 6.2 μL of IN NaOH to give a 10 mM solution for assay. EXAMPLE 22 N- { [ 1 -(4-Nitrobenzylthio)acety lamino]cyclopent- 1 -ylmethyl } -N-( 1 - naphthylmethyP-glycyl-methionine methyl ester Step A: Preparation of l-tert-(butyloxy)carbonylaminocyclopentane- 1 -carboxaldehvde The title compound was prepared by a Swern oxidation (3 equivalents of pyridine-sulfurtrioxide complex and excess triethyl amine in DMSO/CH2CI2) of BOC protected 1 -amino- 1 - hydroxymethyl-cyclopentane (Aldrich). Step B : Preparation of N- { [ 1 -(4-Nitrobenzy lthio)acetylamino] - cyclopent- 1 -ylmethyl } -N-( 1 -naphthylmethyl)-glycyl- methionine methyl ester Following the procedure described in Example 1, but substituting the l-tert-(butyloxy)carbonylaminocyclopentane- 1 -carboxaldehyde from Step A for N-t-butoxycarbonylisoleucinal provided the title compound. C34H42N4O6S2 FAB mass spectmm, m/e 667 (M+l). EXAMPLE 23 N- { [ 1 -(4-Nitrobenzylthio)acety laminojcyclopent- 1 -ylmethyl } -N-( 1 - naphthylmethvP-glvcyl-methionine Following the procedure described in Example 2, but substituting the ester from Example 22 provided the title compound. C33H40N4O6S2 FAB mass spectmm, m/e 653 (M+l). EXAMPLE 24 N- { 2(S)-[2-(4-Nitrophenyl)ethylcarbamoylamino]-4-methylpenty 1 } -N- (l -naphthylmethyl)-glvcyl-methionine methyl ester 2-(4-Nitrophenyl)ethylamine (0.5 mmol) and p- nitrophenylchloroformate (0.5 mmol) were allowed to react in the presence of triethylamine (1 mmol) in 5 ml of DMF to provide 2-(4- nitrophenyPethyl isocyanate. Without isolation, the isocyanate was mixed with N-(2(S)-amino-4-methylpentyl)-N-(l-naphthylmethyl)- glycyl-methionine methyl ester dihydrochloride (0.4 mmol) and triethylamine (1 mmol) in 4 mL of DMF to provide the title compound. C34H45N5O6S-0.15 hexane Anal. Calcd for C26H41N3O5S2 C, 63.05; H, 7.14; N, 10.54 C, 63.10; H, 7.09; N, 10.16 EXAMPLE 25 N-{2(S)-[2-(4-Nitrophenyl)ethylcarbamoylamino]-4-methylpentyl }-N- ( 1 -naphthylmethvP-glvcyl-methionine Following the procedure described in Example 2, but substituting the ester from Example 24 provided the title compound. C33H43N5θ6S-EtOAc C, 61.22; H, 7.08; N, 9.65 C, 61.32; H, 6.72; N, 9.73 EXAMPLE 26 N-{2(S)-[(3(S)-tetrahydrofuryloxy)carbonylamino]-3(S)-methylpentyl}- N-(l -naphthylmethvP-glvcyl-methionine methyl ester The succinimidyl carbonate of 3(S)-hydroxytetrahydrofuran, was prepared as described by Ghosh, et al, (J. Med. Chem. 1993, 56:292). The carbonate (46 mg, 0.20 mmol) and N-(2(S)-amino-3(S)- methylpentyl)-N-( l-naphthylmethyl)-glycyl-methionine methyl ester dihydrochloride (106 mg, 0.20 mmol) were dissolved in 3 mL of methylene chloride and 56 μL (0.40 mmol) of triethylamine was added. After stirring overnight the mixture was diluted with ethyl acetate and washed successively with 10% citric acid, 10% sodium bicarbonate and brine. After drying, the solvent was evaporated and the residue was chromatographed on silica (1.5% methanol in methylene chloride) to provide N-{ 2(S)-[(3(S)-tetrahydrofuryloxy)-carbonylamino]-3(S)- methylpentyl } -N-( 1 -naphthylmethyl)-glycy 1-methionine methyl ester. EXAMPLE 27 N- { 2(S)-[(3(S)-tetrahydrofuryloxy)carbonylamino]-3(S)-methylpentyl } • N-( 1 -naphthylmethvP-gl vc yl-methionine Following the procedure described in Example 2, but substituting the ester from Example 26 provided the title compound. C29H41 N306S-CF3C02H-2.1 H2O C, 52.32; H, 6.54; N, 5.91 C, 51.85; H, 6.01 ; N, 6.34 EXAMPLE 28 N-{ 2(S)-f(cis-4-benzyloxytetrahydrofur-3-yloxy)carbonylamino]-3(S)- methylpentyl ) -N-( 1 -naphthylmethyP-glycyl-methionine methyl ester Following the procedure described in Example 26, but substituting the succinimidyl carbonate of racemic -4-benzyloxy-3- hydroxytetrahydrofuran (prepared as described by Vacca, et al, (Can. Pat. 2,084,800, June 17, 1993)) provided a 1 :1 mixmre of diastereomers of N- { 2(S)-[(cis-4-benzyloxytetrahydrofur-3-yloxy)carbonylamino]-3(S)- methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine methyl ester which were inseparable by HPLC chromatography. EXAMPLE 29 N-{ 2(S)-[(cis-4-benzyloxytetrahydrofur-3-yloxy)carbonylamino]-3(S)- methylpentyl)-N-( 1 -naphthylmethyP-glycyl-methionine Following the procedure described in Example 2, but substituting the ester from Example 28 provided the title compound as a mixmre of diastereomers that were separated by reverse phase HPLC chromatography. Isomers A and B, C36H47N3O7S gave FAB MS m/e = 666 (M+l). EXAMPLE 30 N- { 2(S)-(t-butoxycarbonylamino)-3(S)-methylpentyl } -N-(l - naphthylmethvP-glvcyl-methionine Using the procedure described in Example 2, N-[2(S)-(t- butoxycarbonylamino)-3(S)-methylpentyl]-N-(l -naphthylmethyl)-glycyl- methionine methyl ester (prepared in Example 1 , Step B, was converted to the title compound. C29H43N3O5S-0.4 H2O C, 62.99; H, 7.98; N, 7.60 C, 62.98; H, 7.83; N, 7.62 EX AMPLE 31 In vitro inhibition of ras famesyl 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.SΛ. 56:6630-6634 (1989). Bovine FPTase was assayed in a volume of 100 μl containing 100 mM N-(2-hydroxy ethyl) piperazine-7V'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM [3H]-farnesyl diphosphate ([-^HJ-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 incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation 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 mixmre. 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 were tested for inhibitory activity against human FPTase by the assay described above and were found to have IC50 of < 10 μM. EXAMPLE 32 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 57 :712-717, (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 semm 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/lmM 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 nonfamesylated ras proteins are compared to determine the percent inhibition of famesyl transfer to protein. EXAMPLE 33 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 Ratl cells transformed with either a v- ras, v-raf, or 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 farnesyl- transf erase having the formula I: wherein: Rla is selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, (Rl ) 2 N-C(NRlO)-, Rl c(O)-, or RlOθC(O)-, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RlOO-, Rl lS(0)m-, R 10 C(O)NRl0-, CN, (R10) 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or RllθC(O)NRl0-; Rib is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, (R10) 2 N-C(NR10)-, RIO O)-, or RlOθC(O)-, and c) C l -C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, RlOO-, Rl lS(0) m -, R!0C(O)NR10-, CN, (R10) 2 N-C(NR10)-,R10C(0)-, Rl θC(O)-, N3, -N(RlO)2, or Rl lθC(O)NRl0-; provided that Rib is not RIOC(O)NRK)- when Rla is alkenyl, V is hydrogen and X-Y is -C(0)NR7a. ; R2a and R2b 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-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 O-, Rl lS(0) m -, RlOC(0)NRlO-, CN, (R lO)2N-C(NRlO)-, RlOC(O)-, RlOoC(O)-, N3, -N(R lO)2, Rl !OC(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 R2a and R2b are combined to form - (CH2)s - ; R3 and R4 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) substimted or unsubstituted C 1 -C20 alkyl, C2-C2O 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 !°C(O)NR10-, CN, (R lO)2N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(R l0)2, R l lOC(O)NRl0- and C1-C20 alkyl, and d) C1 -Q5 alkyl substimted with an unsubstituted or substimted group selected from aryl, heterocycle and C3- ClO cycloalkyl;or R3 and R4 are combined to form - (CH2)s - ; R5a and R5b 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-C2O 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 10C(O)NR 0-, CN, (RlO)2N-C(NRlO)-, RlOc(O)-, RlOoC(O)-, N3, -N(RlO)2, R 1 lOC(O)NRl0- and C1-C2O alkyl, and d) C 1 -Q) alkyl substimted with an unsubstituted or substimted 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)- ; X-Y is (0) m d) \ f) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstimted or substimted aryl, c) unsubstituted or substimted heterocyclic, d) unsubstimted or substimted cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstimted or substimted aryl, c) unsubstituted or substimted heterocyclic, d) unsubstimted or substimted cycloalkyl, e) C1-C6 alkyl substimted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstimted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1 -C6 alkyl substituted with hydrogen or an unsubstimted or substimted group selected from aryl, heterocyclic and cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, R ] S(0) m -, R l0C(O)NRl0-, CN, Nθ2, Rl°2N-C(NRlO)-, Rl C(O)-, R lOθC(O)-, N3, -N(RlO)2, or Rl lOC(O)NRl0-, and c) Cl -Cβ alkyl unsubstituted or substimted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, R l l S(0)m-, Rl0C(O)NH-, CN, H2N- C(NH)-, RlOC(O)-, R lOθC(O)-, N3, -N(R lO)2, or Rl lOC(0)NH-; R9 is selected from: hydrogen , -C6 alkyl , RlOO-, RHS(0) m -, R l0C(O)NRl0-, CN, N02, N3, -N(RlO) 2 , and R 1 1OC(O)NR10-; provided that R9 is not R10C(0)NR10- when Rla is alkenyl, V is hydrogen and X-Y is -C(0)NR7a. ; 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 hydrogen or C1 -C6 alkyl; V is selected from: a) aryl; b) heterocycle; or c) hydrogen; W is -S(0) m -, -O-, -NHC(O)-, -C(0)NH-, -NHSO2-, -SO2NH-, -N(R7a). or -N[C(0)R7a]. ; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1 , 2, 3 or 4, provided that n ≠ 0 when V is hydrogen and W is -S(0) m - ; p is 0, 1 , 2, 3 or 4, provided that p ≠ 0 when R9 is not hydrogen or C1 -C6 lower alkyl ; r is 0 or 1 ; s is 4 or 5; and t is 0, 1 or 2, provided that t = 0 when V is hydrogen; or a pharmaceutically acceptable salt thereof. 2. A prodmg of a compound of Claim 1 having the formula II: wherein: Rla is selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl. alkynyl, (R O) 2 N-C(NRlO)-, Rl0c(O)-, or RlOθC(O)-, and c) Cl-C6 alkyl unsubstimted or substimted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RlOO-, RllS(0) m -, Rl0C(O)NRl0-,CN,(Rl0)2N-C(NRl0)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, or R1 OC(O)NR10. ; Rib i independently selected from: a) hydrogen, b) unsubstimted or substimted aryl, cycloalkyl, alkenyl, alkynyl, (R10) 2 N-C(NR10)-, R10C(O)-, or RlOθC(O)-, and c) C l -C6 alkyl unsubstimted or substimted by unsubstituted or substimted aryl, cycloalkyl, alkenyl, alkynyl, RlOO-, Rl lS(0) m -, R10C(0)N 1 -, CN, (RlO)2N-C(NRlO)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO)2,orRllOC(0)NRlO.; provided that Rib i not R1°C(0)NR1°- when Rla is alkenyl, V is hydrogen and X-Y is -C(0)NR 7a - ; R2a and R2b 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) substimted or unsubstimted C l -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 O-, Rl lS(0)m-, R10C(O)NR 0-, CN, (RlO) 2 N-C(NR lO)-, Rl C(O)-, RlOθC(O)-, N3, -N(R lO)2, R H θC(0)NRlO- and C1 -C2O alkyl, and d) C1 -C6 alkyl substituted with an unsubstituted or substimted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R2a and R2b are combined to form - (CH2)s - ; R4 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) substimted or unsubstimted 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, N02, Rl°0-, Rl lS(0)m-, R 10 C(O)NRl0-, CN, (R lO)2N-C(NR lO)-, R l0c(O)-, RlOθC(O)-, N3, -N(R l0)2, R U OC(O)NR l0- and Cl -C20 lkyl,and d) C 1 -Cβ alkyl substimted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R3 and R4 are combined to form - (CH2)s - ; R5a and R5b 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 heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 O-, Rl l S(0)m-, R 1°C(0)NR10-, CN, (RlO)2N-C(NRlO)-, RlOc(O)-, RlOθC(O)-, N3, -N(RlO)2, R l lOC(O)NRl0- and C1 -C2O alkyl, and d) Cl -Q) 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(COR IO)- ; R6 is a) substituted or unsubstituted C1-C8 alkyl, wherein the substituent on the alkyl is selected from: D aryl, 2) heterocycle, 3) -N(R l l )2, 4) -OR 10, or X-Y is (0) m f) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstituted or substimted aryl, c) unsubstituted or substimted heterocyclic, d) unsubstimted or substimted cycloalkyl, and e) Cl -C6 alkyl substimted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substimted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstimted or substimted cycloalkyl, e) C l -Cβ alkyl substituted with hydrogen or an unsubstituted or substimted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C l -C6 alkyl substituted with hydrogen or an unsubstimted or substimted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstimted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl -C6 alkyl substituted with hydrogen or an unsubstimted or substimted group selected from aryl, heterocyclic and cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R lOO-, R HS(0) m -, Rl°C(O)NRl0-, CN, N02, R 1°2N-C(NR 10)-, R lOC(O)-, RlOθC(O)-, N3, -N(R lO)2, or Rl lθC(O)NRl0-, and c) Cl-C6 alkyl unsubstimted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R lOO-, R l lS(0) m -, Rl0C(O)NH-, CN, H2N- C(NH)-, R lOC(O)-, Rl°OC(0)-, N3, -N(R lO)2, or R l lθC(0)NH-; R9 is selected from: hydrogen , C 1 -C6 alkyl , R lOO-, RHS(0) m -, R l°C(0)NR l°-, CN, N02, N3, -N(RlO) 2 , and R1 1 OC(O)NR 10-; provided that R9 is not Rl0C(O)NRl - when Rla is alkenyl, V is hydrogen and X-Y is -C(0)NR7a. ; RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1 -C6 alkyl and aryl; R 12 is independently selected from hydrogen and Cl -Cβ alkyl; Rl3 is C1 -C6 alkyl; V is selected from: a) aryl; b) heterocycle; or c) hydrogen; W is -S(0)m-, -0-, -NHC(O)-, -C(0)NH-, -NHSO2-, -SO2NH-, -N(R7a). or -N[C(0)R7a]. ; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4, provided that n ≠ 0 when V is hydrogen and W is -S(0)m- ; p is 0, 1 , 2, 3 or 4, provided that p ≠ 0 when R is not hydrogen or C1 -C6 lower alkyl ; r is 0 or 1 ; s is 4 or 5; and t is 0, 1 or 2, provided that t = 0 when V is hydrogen; or a pharmaceutically acceptable salt thereof. 3. A compound which inhibits Ras farnesyl- transferase having the formula HI: wherein: Rla is selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, (RlO) 2 N-C(NRlO)-, Rl C(O)-, or RlOθC(O)-, and c) C l -C6 alkyl unsubstituted or substimted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RlOO-, Rl lS(0)m-, Rl0C(O)NRl0-, CN, (R10) 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO)2, or RllθC(O)NRl0.; Rib is independently selected from: a) hydrogen, b) unsubstimted or substituted aryl, cycloalkyl, alkenyl, alkynyl, (Rl0)2N-C(NRl0)-,Rl0c(O)-, or RlOθC(O)-, and c) Cl-C6 alkyl unsubstituted or substimted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, RlOO-, Rl lS(0) m -, R10C(0)NR10-, CN, (RlO)2N-C(NRiO)-, R10C(O)-, RlOθC(O)-, N3, -N(RlO)2, or Rl lθC(O)NRl0-; provided that Rib is not R10C(O)NR10- when Rl is alkenyl, V is hydrogen and X-Y is -C(0)NR7a. ; R2a and R2b 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 unsubstimted C1-C2O alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 O-, Rl l S(0) m -, R1°C(0)NR10-, CN, (R lO)2N-C(NRl )-, RlOc(O)-, R lOθC(O)-, N3, -N(R lO)2, Rl !OC(O)NRl0- and C1-C2O alkyl, and d) C1 -C6 alkyl substimted with an unsubstituted or substimted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R2a and R2b are combined to form - (CH2)s - ; R and R4 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-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R ! °0-. R 1 1 S(0) m -, R 10C(O)NR 10-, CN, (RlO)2N-C(NR lO)-, RlOC(O)-, RlOθC(O)-, N3, -N(R lO)2, R 1 l OC(O)NRl0- and C1-C20 alkyl, and d) C1 -Q3 alkyl substimted with an unsubstituted or substimted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R3 and R4 are combined to form - (CH2)s - ; X-Y is >7a o ( ) m d) f) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstimted or substituted aryl, c) unsubstituted or substimted heterocyclic, d) unsubstimted or substimted cycloalkyl, and e) C l -C6 alkyl substimted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstimted or substimted aryl, c) unsubstituted or substimted heterocyclic, d) unsubstimted or substimted cycloalkyl, e) C l -Cβ alkyl substimted with hydrogen or an unsubstituted or substimted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substimted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstimted or substituted group selected from aryl, heterocyclic, cycloalkyl and C 1 -Cβ alkyl substituted with hydrogen or an unsubstituted or substimted group selected from aryl, heterocyclic and cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, Rl O-, Rl lS(0) m -, R !0C(O)NR 10-, CN, Nθ2, R 10 2N-C(NRlO)., R lOC(O)-, R lOθC(O)-, N3, -NCR 1 0)2, or R l lOC(O)NRl0-, and c) C l -Q) alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R lOO-, Rl l S(0) m -, Rl0C(O)NH-, CN, H2N- C(NH)-, RlOC(O)-, RlOθC(O)-, N3, -N(R lO) 2 , or R l lOC(0)NH-; R9 is selected from: hydrogen , -C6 alkyl , RlOO-, Rl lS(0) m -, R l0c(O)NR l0-, CN, N02, N3, -N(Rl0)2, and R l lθC(O)NRl0-; provided that R9 is not R ! C(O)NR1 - when R!a is alkenyl, V is hydrogen and X-Y is -C(0)NR7a. ; RlO is independently selected from hydrogen, C1-Q3 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; R 1 is hydrogen or C l -Cβ alkyl; V is selected from: a) aryl; b) heterocycle; or c) hydrogen; W is -S(0)m-, -0-, -NHC(O)-, -C(0)NH-, -NHSO2-, -SO2NH-, -N(R7a)_ or -N[C(0)R7a]. ; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1 , 2, 3 or 4, provided that n ≠ 0 when V is hydrogen and W is -S(0)m-; p is 0, 1 , 2, 3 or 4, provided that p ≠ 0 when R is not hydrogen or C1 -Q5 lower alkyl ; q is 0. 1 or 2; r is 0 or 1 ; s is 4 or 5; and t is 0, 1 or 2, provided that t = 0 when V is hydrogen; or a pharmaceutically acceptable salt thereof. 4. A prodrug of a compound of Claim 3 of the formula IV: IV wherein: Rla is selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, (R 10) 2 N-C(NR 10)-, R 1 °C(0)-, or R 10θC(O)-, and c) Cl-Q) alkyl unsubstituted or substimted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RlOO-, Rl lS(0)m-, R!0C(O)NR10-, CN, (R10) 2 N-C(NR10)-, RlOC(O)-, RlOθC(O)-, N3, -N(RlO) 2 , or RllθC(O)NRl0- ; R lb is independently selected from: a) hydrogen, b) unsubstimted or substituted aryl, cycloalkyl, alkenyl, alkynyl, (R10) 2 N-C(NR10)-, RlOc(O)-, or RlOθC(O)-, and c) C l -Cβ alkyl unsubstituted or substimted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, RlOO-, Rl lS(0) m -, R!0C(O)NR10-, CN, (R10) 2 N-C(NR10)-,R10C(O)-, Rl0θC(O)-,N3, -N(R 10)2, or Rl lθC(O)NRl0- ; provided that Rib is not R1°C(0)NR10- when Rla is alkenyl, V is hydrogen and X-Y is -C(0)NR7a. ; R2a and R2b 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-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 O-, Rl lS(0) m -, R !0C(O)NR10-, CN, (RlO) 2 N-C(NRlO)-, RlOc(O)-, Rl θC(O)-, N3, -N(R lO)2, Rl lOC(O)NRl0- and C1 -C20 alkyl, and d) Cl-Q alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R2a and R2b are combined to form - (CH2)s - ; R3 and R4 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 unsubstimted Cl -C20 alkyl, C2-C20 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 10C(O)NR10-, CN, (Rl ) 2 N-C(NRl0)-, RlOc(O)-, RlOθC(O)-, N3, -N(R 1 )2, R 11 OC(0)NR 10 . and C 1 -C20 alkyl, and d) C 1 -Q alkyl substituted with an unsubstituted or substimted group selected from aryl, heterocycle and C3- ClO cycloalkyl; or R3 and R4 are combined to form - (CH2)s - ; X-Y is (θ) m d) f) -CH 2 -CH 2 - R7a is selected from a) hydrogen, b) unsubstimted or substimted aryl, c) unsubstituted or substimted heterocyclic, d) unsubstituted or substimted cycloalkyl, and e) C l -Cβ alkyl substimted with hydrogen or an unsubstituted or substimted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstimted or substimted aryl, c) unsubstituted or substimted heterocyclic, d) unsubstimted or substituted cycloalkyl, e) C 1 -Q) alkyl substituted with hydrogen or an unsubstituted or substimted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstimted or substimted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstimted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstimted or substimted group selected from aryl, heterocyclic and cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R lOO-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, N02, R l°2N-C(NRlO)-, R l C(O)-, RlOθC(O)-, N3, -N(R l0)2, or R l lθC(O)NR l0-, and c) Cl-Q > alkyl unsubstimted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, R l l S(0) m -, Rl0c(O)NH-, CN, H2N- C(NH)-, RlOC(O)-, R lOθC(O)-, N3, -N(R lO) 2 , or Rl lOC(0)NH-; R9 is selected from: hydrogen , Cj -C6 alkyl , RlOO-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, Nθ2, N3, -N(RlO) 2 , and Rl lθC(O)NRl0- ; provided that R9 is not R !0C(O)NR10- when Rla is alkenyl, V is hydrogen and X-Y is -C(0)NR7a. ; R lO is independently selected from hydrogen, C1 -C6 alkyl, benzyl and aryl; R l 1 is independently selected from C1 -C6 alkyl and aryl; Rl2 is hydrogen or C1 -Q3 alkyl; V is selected from: a) aryl; b) heterocycle; or c) hydrogen; W is -S(0)m-, -0-, -NHC(OK -C(0)NH-, -NHSO2-, -SO2NH-, -N(R7a). or -N[C(0)R7a]. ; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1 , 2, 3 or 4, provided that n ≠ 0 when V is hydrogen and W is -S(0)m- ; p is 0, 1 , 2, 3 or 4, provided that p ≠ 0 when R is not hydrogen or Cl -Q lower alkyl ; q is 0, 1 or 2; r is 0 or 1 ; s is 4 or 5; and t is 0, 1 or 2, provided that t = 0 when V is hydrogen; or a pharmaceutically acceptable salt thereof. 5. The compound according to Claim 1 having the formula I: wherein: Rla is selected from: a) hydrogen, and b) Cl -C6 alkyl; Rib is independently selected from: a) hydrogen, b) unsubstimted or substimted aryl or cycloalkyl, and c) C l -C6 alkyl unsubstimted or substimted by unsubstituted or substimted aryl, cycloalkyl, alkenyl, R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine; b) substituted or unsubstimted 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 -, RlOC(0)NRlO-, CN, (RlO) N-C(NRlO)-, RlOc(O)-, R 10 OC(O)-, N3, -N(RlO)2, R l lθC(O)NRl0- and C1 -C20 alkyl, and c) Cl-Qs alkyl substituted with an unsubstituted or substimted group selected from aryl, heterocycle and C3- Cio cycloalkyl; and R2b is selected from hydrogen and Cl -Q3 alkyl; or R2a and R2b are combined to form - (CH2)s - ; R3 and R4 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) substimted or unsubstimted Cl-ClO alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, R 10 O-, Rl l S(0)m-, R 10 C(O)NRl0-, CN, (RlO) 2 N-C(NR lO)-, RlOc(O)-, RlOθC(O)-, N3, -N(R lO) 2 , Rl lOC(0)NR lO- and C1 -C20 alkyl, and d) C1 -Q3 alkyl substituted with an unsubstituted or substimted group selected from aryl, heterocycle and C3- ClO cycloalkyl; 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 -, R 10 C(O)NRl0., CN, (R lO)2N-C(NRlO)-, RlOc(O)-, RlOθC(O)-, N3, -N(R lO)2, Rl lθC(O)NRl0- and -C20 alkyl, and d) Cl-Q alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; R5b is selected from: a) hydrogen, and b) Cl-C3 alkyl; or X-Y is c) unsubstituted or substimted heterocyclic, d) unsubstimted or substimted cycloalkyl, and e) C l -C6 alkyl substimted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R7b is selected from a) hydrogen, b) unsubstimted or substimted aryl, c) unsubstituted or substimted heterocyclic, d) unsubstimted or substimted cycloalkyl, e) C 1 -Cβ alkyl substituted with hydrogen or an unsubstituted or substimted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-Q3 alkyl substituted with hydrogen or an unsubstimted or substimted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1 -Q3 alkyl substituted with hydrogen or an unsubstituted or substimted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R8 is independently selected from: a) hydrogen, b) C1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1 -C6 perfluoroalkyl, F, Cl, Rl O-, R10C(O)NR10-, CN, N02, (RlO)2N-C(NRl )-, RlOc(O)-, Rl θC(O)-, -N(RlO)2, or Rl lOC(O)NRl0-, and c) C1-C6 alkyl substimted by C1-C6 perfluoroalkyl, RlOO-, R l0C(O)NRl -, (R10) 2 N-C(NR10)-, R 10 C (O)-, Rl θC(O)-, -N(RlO)2, or Rl 10C(0)NR10-; R9 is selected from: hydrogen , C1-C6 lower alkyl , R lOO-, and -N(R!0)2; R lO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-Q3 alkyl and aryl; Rl2 is hydrogen or C1 -C6 alkyl; V is selected from: a) aryl; b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; and c) hydrogen; W is -S(0)m-, -0-, -NHC(O)-, -C(0)NH-, -NHSO2-, -SO2NH-, -N(R7a)- 0 r -N[C(0)R7a]-; Z is independently H2 or O; m is 0, 1 or 2; n is 0, l , 2, 3 or 4, provided that n ≠ 0 when V is hydrogen and W is -S(0) m - ; p is 0, 1 , 2, 3 or 4, provided that p ≠ 0 when R9 is not hydrogen or Cl -C6 lower alkyl ; r is 0 or 1 ; s is 4 or 5; and t is 0 or 1 , provided that t = 0 when V is hydrogen; or a pharmaceutically acceptable salt thereof. 6. The compound according to Claim 2 having the formula II: wherein: R la is selected from: a) hydrogen, and b) Cl -C6 alkyl; Rib i independently selected from: a) hydrogen, b) unsubstituted or substituted aryl or cycloalkyl, and c) Cl -Q, alkyl unsubstimted or substimted by unsubstituted or substimted aryl, cycloalkyl, alkenyl, R l0θ- or -N(Rl0) 2 ; R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine; b) substituted or unsubstimted Cl-ClO alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 O-, Rl lS(0)m-, R 10 C(O)NRl0_, CN, (R 10) 2 N-C(NR 10)_, RlOc(O)-, RlOθC(O)-, N3, -N(RlO) 2 , Rl lOC(O)NRl0. and C1-C2O alkyl, and c) C1 -C6 alkyl substimted with an unsubstituted or substimted group selected from aryl, heterocycle and C3- ClO cycloalkyl; and R2b is selected from hydrogen and Cl -Cβ alkyl; or R2a and R2b are combined to form - (CH2)s - ; R3 and R4 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 ϋ) methionine sulfone, c) substimted or unsubstimted Cl -ClO alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, Rl lS(0)m-, R l0c(O)NRl0-, CN, (R 10)2N-C(NR 10)-, R lOc(O)-, R l0θC(O)-, N3, -N(R lO)2, Rl l θC(O)NR l0- and -C20 alkyl, and d) Cl -Q) alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- Cl O cycloalkyl; R5a i selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and εlutamine, 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) substimted or unsubstimted Cl-ClO alkyl, C2- 0 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 O-, R lS(0)m-, Rl0c(O)NRl0_, CN, (Rl0) 2 N-C(NRl0)-, Rl c(O)-, RlOθC(O)-, N3, -N(RlO) 2 ,RllOC(0)NRl -and C1-C2O alkyl, and d) C 1 -Q alkyl substimted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; R5b is selected from: a) hydrogen, and b)Cl-C3 alkyl; or R6is a) substimted or unsubstituted Cl-CR alkyl, wherein the substituent on the alkyl is selected from: Daryl, 2) heterocycle, 3)-N(Rll)2, 4) -OR 10, or b) X-Y is R 7a e) -CH 2 -CH 2 - ; R7a i selected from a) hydrogen, b) unsubstimted or substituted aryl, c) unsubstituted or substimted heterocyclic, d) unsubstituted or substimted cycloalkyl, and e) C 1 -Q > alkyl substimted with hydrogen or an unsubstituted or substimted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R7b is selected from a) hydrogen, b) unsubstimted or substimted aryl, c) unsubstituted or substimted heterocyclic, d) unsubstimted or substimted cycloalkyl, e) C1-C6 alkyl substimted with hydrogen or an unsubstituted or substimted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C 1 -C6 alkyl substituted with hydrogen or an unsubstimted or substimted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstimted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstimted or substimted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R8 is independently selected from: a) hydrogen, b) Cl -Q alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1 -C6 perfluoroalkyl, F, Cl, R l O-, R 10C(0)NR 10-, CN, Nθ2, (R 10) 2 N-C(NR 10)-, R10C(O)-, R lOθC(O)-, -N(RlO)2, or R HθC(O)NRl0-, and c) Cl -Q) alkyl substimted by Cl-Cό perfluoroalkyl, RlOO-, R !0C(O)NR10-, (RlO) 2 N-C(NRlO)-, RlOc(O)-, R l0θC(O)-, -N(Rl0) 2 , or Rl lθC(O)NRl0-; R9 is selectedd ffrroomm:: hydrogen , Q -C6 lower alkyl , RlOO-, and -N(RlO) ; RlO is independently selected from hydrogen, C1-Q3 alkyl, benzyl and aryl; Rl 1 is independently selected from Cl -Cό alkyl and aryl; Rl2 is independently selected from hydrogen and C1 -C6 alkyl; R l3 is C1-C6 alkyl; V is selected from: a) aryl; b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; and c) hydrogen; W is -S(0) m -, -0-, -NHC(O)-, -C(0)NH-, -NHSO2-, -SO2NH-, -N(R7a or -N[C(0)R7a]. ; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4, provided that n ≠ 0 when V is hydrogen and W is -S(0) m - ; p is 0, 1, 2, 3 or 4, provided that p ≠ 0 when R9 is not hydrogen or Cl -Q) lower alkyl ; r is 0 or 1 ; s is 4 or 5; and t is 0 or 1 , provided that t = 0 when V is hydrogen; or a pharmaceutically acceptable salt thereof. 7. The compound according to Claim 3 having the formula ID: - (CR 1 a 2 ) n - W (CR 1b 2 ) p (C wherein: R la is selected from: a) hydrogen, and b) Cl-Q alkyl; R ib are independently selected from: a) hydrogen, b) unsubstimted or substimted aryl or cycloalkyl, and c) Cl-Q, alkyl unsubstimted or substimted by unsubstituted or substimted aryl, cycloalkyl, alkenyl, R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine; b) substimted or unsubstimted 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-, R l0C(O)NRl0-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlOθC(O)-, N3, -N(R l )2, R l lOC(O)NR l0- and C1-C20 alkyl, and c) C l -C6 alkyl substimted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; and R2b is selected from hydrogen and C1 -C6 alkyl; or R2a and R2b are combined to form - (CH2)s - ; R3 and R4 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) substimted or unsubstimted C l -ClO alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, Rl lS(0)m-, R!0C(O)NR -, CN, (RlO)2N-C(NR O)-, RlOc(O)-, RlOθC(O)-, N3, -N(R l0)2, R l lOC(O)NRl0- and C1-C2O alkyl, and d) Cl -Q alkyl substimted with an unsubstituted or substimted group selected from aryl, heterocycle and C3- ClO cycloalkyl; X-Y is R 7a >7b b) \ y^N^. e) -CH 2 -CH 2 - ; 7a is selected from a) hydrogen, b) unsubstituted or substimted aryl, c) unsubstituted or substimted heterocyclic, d) unsubstimted or substimted cycloalkyl, and e) C l -Qs alkyl substimted with hydrogen or an unsubstituted or substimted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R7b is selected from a) hydrogen, b) unsubstimted or substimted aryl, c) unsubstituted or substimted heterocyclic, d) unsubstimted or substimted cycloalkyl, e) Cl-Q) alkyl substimted with hydrogen or an unsubstituted or substimted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substimted group selected from aryl, heterocyclic, cycloalkyl and Cl -C6 alkyl substituted with hydrogen or an unsubstimted or substimted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstimted or substituted group selected from aryl, heterocyclic, cycloalkyl and C l -C6 alkyl substituted with hydrogen or an unsubstimted or substimted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R8 is independently selected from: a) hydrogen, b) Cl -Q alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R lOO-, R10C(O)NR 1 -, CN, N02, (RlO) 2 N-C(NRlO)-, R10C(O)-, Rl°OC(0)-, -N(RlO)2, or R HθC(O)NRl0-, and c) Cl -Q) alkyl substimted by Cl - ) perfluoroalkyl, R lOo-, R l0c(O)NRl0-, (R 10) 2 N-C(NR 10)-, RlOc(O)-, R lOθC(O)-, -N(RlO)2, or R HθC(0)NRlO-; R9 is selected from: hydrogen , -C6 lower alkyl , RlOO-, and -N(RlO)2; RlO is independently selected from hydrogen, C1 -C6 alkyl, benzyl and aryl; R 1 is independently selected from Cl -C6 alkyl and aryl; Rl2 is hydrogen or Cl -Cβ alkyl; V is selected from: a) aryl; b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; and c) hydrogen; W is -S(0)m-, -0-, -NHC(O)-, -C(0)NH-, -NHSO2-, -SO2NH-, -N(R7a). or -N[C(0)R7a]. ; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1 , 2, 3 or 4, provided that n ≠ 0 when V is hydrogen and W is -S(0) m - ; p is 0, 1 , 2, 3 or 4, provided that p ≠ 0 when R9 is not hydrogen or Cl -Q) lower alkyl ; q is 0, 1 or 2; r is 0 or 1 ; s is 4 or 5; and t is 0 or 1 , provided that t = 0 when V is hydrogen; or a pharmaceutically acceptable salt thereof. 8. The compound according to Claim 4 having the formula IV: IV wherein: Rla is selected from: a) hydrogen, and b) Cl-Q alkyl; R ib are independently selected from: a) hydrogen, b) unsubstimted or substimted aryl or cycloalkyl, and c) C 1 -C6 alkyl unsubstimted or substimted by unsubstituted or substimted aryl, cycloalkyl, alkenyl, Rl0θ- or -N(R 0) 2 ; R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine; b) substituted or unsubstimted 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 -, R 10 C(O)NRl0-, CN, (R l0) 2 N-C(NR l0)-, R lOc(O)-, RlOθC(O)-, N3, -N(R l0)2, Rl l OC(O)NRl0- and C1-C2O alkyl, and c) C1 -Q5 alkyl substimted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl; and R2b is selected from hydrogen and C1 -C6 alkyl; or R2a and R2b are combined to form - (CH2)s - ; R3 and R4 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) substimted or unsubstimted Cl -ClO alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, Rl lS(0)m-, Rl°C(O)NRl0-, CN, (R lO) 2 N-C(NR lO)-, RlOc(O)-, RlOθC(O)-, N3, -N(R lO)2, R l lOC(O)NRl0- and C1-C20 alkyl, and d) Cl -Cβ alkyl substimted with an unsubstituted or substimted group selected from aryl, heterocycle and C3- ClO cycloalkyl; X-Y is e) -CH 2 -CH 2 - ; R7a i s selected from a) hydrogen, b) unsubstituted or substimted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C 1 -Q) alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R7b i selected from a) hydrogen, b) unsubstimted or substimted aryl, c) unsubstituted or substimted heterocyclic, d) unsubstimted or substimted cycloalkyl, e) C1-Q5 alkyl substimted with hydrogen or an unsubstituted or substimted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substimted group selected from aryl, heterocyclic, cycloalkyl and C1 -C6 alkyl substituted with hydrogen or an unsubstimted or substimted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstimted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1 -C6 alkyl substituted with hydrogen or an unsubstimted or substimted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; 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)NR 10-, CN. N02, (R lO) 2 N-C(NR lO)-, R lOc(O)-, RlOθC(O)-, -N(Rl )2, or RHθC(O)NRl0-, and c) C1 -C6 alkyl substimted by C1 -C6 perfluoroalkyl, R lOO-, R !0C(O)NR 10-, (R 10) 2 N-C(NR 10)-, RlOc(O)-, R lOθC(O)-, -N(R l0)2, or Rl lOC(O)NRl0- ; R9 is selected from: hydrogen , C1-C6 lower alkyl , RlOO-, and -N(RlO)2; R lO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; R 1 is independently selected from Cl -Cβ alkyl and aryl; R is hydrogen or C1-C6 alkyl; V is selected from: a) aryl; b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; and c) hydrogen; W is -S(0)m-, -0-, -NHC(O)-, -C(0)NH-, -NHSO2-, -SO2NH-, -N(R7a). or -N[C(0)R7a]. ; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1 , 2, 3 or 4, provided that n ≠ 0 when V is hydrogen and W is -S(0) m - ; p is 0, 1, 2, 3 or 4, provided that p ≠ 0 when R is not hydrogen or Ci-Q, lower alkyl ; q is 0, 1 or 2; r is 0 or 1 ; s is 4 or 5; and t is 0 or 1 , provided that t = 0 when V is hydrogen; or a pharmaceutically acceptable salt thereof. 9. A compound which inhibits farnesyl-protein transferase which is: N-{ 2(S)-[(4-Nitrobenzylthio)acetamido]-3(S)-methylpentyl}-N-(l- naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(4-Nitrobenzylthio)acetamido]-3(S)-methylpentyl }-N-(l - naphthylmethyl)-glycyl-methionine N- { 2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl } -N-(l - naphthylmethyl)-glycyl-methionine N-{ 2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl}-N-(l- naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(Phenylthio)acetamido]-3(S)-methylpentyl } -N-(l - naphthylmethyl)-glycyl-methionine N-{ 2(S)-[(Phenylthio)acetamido]-3(S)-methylpentyl }-N-(l- naphthylmethyl)-glycyl-methionine methyl ester N-{ 2(S)-[(3-Nitrobenzylthio)acetamido]-3(S)-methylpentyl}-N-(l - naphthylmethyl)-glycyl-methionine N- { 2(S)-[(3-Nitrobenzylthio)acetamido]-3(S)-methylpentyl } -N-( 1 - naphthylmethyI)-glycyl-methionine methyl ester N- { 2(S)-[(2-Nitrobenzylthio)acetamido]-3(S)-methylpentyl }-N-(l - naphthylmethyl)-glycyl-methionine N- { 2(S)-[(2-Nitrobenzylthio)acetamido]-3(S)-methylpentyl } -N-( 1 - naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(4-Cyanobenzylthio)acetamido]-3(S)-methylpentyl } -N-( 1 ■ naphthylmethy -glycyl-methionine N- { 2(S)-[(4-Cyanobenzylthio)acetamido]-3(S)-methylpentyl } -N-( 1 - naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(4-Trifluoromethylbenzylthio)acetamido]-3(S)- methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[(4-Trifluoromethylbenzylthio)acetamido]-3(S)-methyl- pentyl }-N-(l-naphthylmethyl)-glycyl-methionine methyl ester N-{ 2(S)-[(4-Methoxybenzylthio)acetamido]-3(S)-methylpentyl }-N- ( 1 -naphthylmethyl)-glycyl-methionine N-{ 2(S)-[(4-Methoxybenzylthio)acetamido]-3(S)-methylpentyl }-N- (l-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(4-Methylsulfonylbenzylthio)acetamido]-3(S)-methyl- penty 1 } -N-( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[(4-Methylsulfonylbenzylthio)acetamido]-3(S)-methyl- pentyl }-N-(l-naphthylmethyl)-glycyl-methionine methyl ester N-{ 2(S)-[(4-Phenylbenzylthio)acetamido]-3(S)-methylpentyl }-N-(l naphthylmethyl)-glycyl-methionine N- { 2(S)-[(4-Phenylbenzylthio)acetamido]-3(S)-methylpentyl }-N-(l * naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(4-( 1 -//-Tetrazol-5-yl)benzylthio)acetamido]-3(S)-methyl- penty 1 } -N-( 1 -naphthylmethyl)-glycyl-methionine N-( 2(S)-[(4-(l - -Tetrazol-5-yl)benzylthio)acetamido]-3(S)-methyl- pentyl }-N-(l-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(4-Methylbenzylthio)acetamido]-3(S)-methylpentyl } -N-( 1 naphthylmethyl)-glycyl-methionine N-{ 2(S)-[(4-Methylbenzylthio)acetamido]-3(S)-methylpentyl}-N-(l * naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(8-Chloronaphth-l -ylthio)acetamido]-3(S)-methylpentyl }- N-( 1 -naphthylmethy l)-glycyl-methionine N-{ 2(S)-[(8-Chloronaphth-l-ylthio)acetamido]-3(S)-methylpentyl }- N-(l -naphthylmethyl)-glycyl-methionine methyl ester N-{ 2(S)-[((2-Methylindol-3-yl)thio)acetamido]-4-methylpentyl }-N- ( 1 -naphthylmethyl)-glycyl-methionine N-{ 2(S)-[((2-Methylindol-3-yl)thio)acetamido]-4-methylpentyl}-N- (l -naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(4-Pyridylthio)acetamido]-3(S)-methylpentyl }-N-(l- naphthylmethy l)-glycyl-methionine N- { 2(S)-[(4-Pyridylthio)acetamido]-3(S)-methy lpentyl } -N-( 1 - naphthylmethyl)-glycyl-methionine methyl ester N-{ 2(S)-[(4-Picolinylthio)acetamido]-3(S)-methylpentyl }-N-(l - naphthylmethyl)-glycyl-methionine N- { 2(S)-[(4-Picolinylthio)acetamido]-3(S)-methylpentyl } -N-(l - naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[3-(Benzylthio)propionamido]-3(S)-methylpentyl } -N-( 1 naphthylmethyl)-glycyl-methionine N- { 2(S)-[(Benzyloxy)acetamido]-3(S)-methylpentyl } -N-(l - naphthylmethyl)-glycyl-methionine N- { 2(S)-[(Benzyloxy)acetamido] -3(S)-methylpentyl } -N-(l - naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(N'-Benzylglycyl)amino]-3(S)-methylpentyl } -N-( 1 - naphthylmethyl)-glycyl-methionine N- { 2(S)-[(N-Benzylglycyl)amino]-3(S)-methylpentyl } -N-( 1 - naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(N'-Acetyl-N'-benzylglycyl)amino]-3(S)-methylpentyl } -N- ( 1 -naphthylmethy -glycyl-methionine N- { 2(S)-[(N'-Acetyl-N'-benzylglycyl)amino]-3(S)-methylpentyl } -N- (l-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(N'-Benzyl-N'-t-butoxycarbonylglycyl)amino]-3(S)- methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N-{ 2(S)-[(N'-Benzyl-N'-t-butoxycarbonylglycyl)amino]-3(S)-methyI- pentyl } -N-(l-naphthylmethyl)-glycyl-methionine methyl ester N-{ 2(S)-[(Benzylthio-S-oxide)acetamido]-3(S)-methylpentyl }-N-(l - naphthylmethyl)-glycyl-methionine N- { 2(S)-[(Benzylthio-S-oxide)acetamido]-3(S)-methylpentyl } -N-( 1 - naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(Benzylthio-S,S-dioxide)acetamido]-3(S)-methylpentyl } -N- ( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[(Benzylthio-S,S-dioxide)acetamido]-3(S)-methylpentyl } -N- (1 -naphthylmethy l)-glycyl-methionine methyl ester N- { 2(S)-[(Benzylthio)acetamido] -3(S)-methylpentyl } -N-(l - naphthylmethyl)-glycyl-methionine sulfone N- { 2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl }-N-(l- naphthylmethyl)-glycyl-methionine sulfone methyl ester N- { 2(S)-[(N-4-Nitrobenzoylglycyl)amino]-3(S)-methylpentyl } -N-( 1 - naphthylmethyl)-glycyl-methionine N- { 2(S)-[(N'-4-Nitrobenzoy lglycyl)amino]-3(S)-methylpentyl } -N-( 1 - naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(N'-Methyl-N'-4-nitrobenzoylglycyl)amino]-4-methyl- pentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N-{ 2(S)-[(N'-Methyl-N'-4-nitrobenzoylglycyl)amino]-4-methyl- pentyl }-N-(l -naphthylmethy l)-glycyl-methionine methyl ester N- { 2(S)-[(S-Benzyl-L-cysteinyl]-3(S)-methylpentyl } -N-( 1 - naphthylmethyl)-glycyl-methionine N- { 2(S)-[S-Benzyl-L-cy steiny 1] -3(S)-methy lpentyl } -N-( 1 - naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[S-Benzyl-D-cysteinyl]-3(S)-methylpentyl } -N-( 1 - naphthylmethyl)-glycyl-methionine N- { 2(S)-[S-Benzyl-D-cysteinyl]-3(S)-methy lpentyl } -N-( 1 - naphthylmethyl)-glycyl-methionine methyl ester 3-Benzylthiopropionyl-valyl-isoleucyl-methionine N-[2(S)-(2(S),3-Diaminopropionyl)amino-3(S)-methylpentyl]-N-(l- naphthylmethyl)glycyl-methionine N-[2(S)-(2(S),3-Diaminopropionyl)amino-3(S)-methylpentyl]-N-(l - naphthylmethyl)glycyl-methionine methyl ester N-[2(S)-(3-Aminopropionyl)amino-3(S)-methylpentyl]-N-(l - naphthylmethyl)glycyl-methionine N-[2(S)-(3-Aminopropionyl)amino-3(S)-methylpentyl]-N-(l - naphthylmethy glycyl-methionine methyl ester N-(2(S)-L-Glutaminylamino-3(S)-methy lpentyl)-N-( 1 -naphthyl- methy glycyl-methionine N-(2(S)-L-Glutaminylamino-3(S)-methy lpenty l)-N-( 1 -naphthyl- methyl)glycyl-methionine methyl ester N-[2(S)-(1 ,1 -Dimethylethoxycarbonylamino)-3S)-methylpentyl]-N- ( 1 -naphthylmethyl)glycyl-methionine N-[2(S)-( 1 , 1 -Dimethylethoxycarbonylamino)-3S)-methylpentyl]-N- (l -naphthylmethyl)glycyl-methionine methyl ester N-[2(S)-(l ,l -Dimethylethoxycarbonylamino)-3(S)-methylpentyl]-N- benzylglycyl-methionine N-[2(S)-(1 , 1 -Dimethylethoxycarbonylamino)-3(S)-methylpentyl]-N- benzylglycyl-methionine methyl ester N- { [ 1 -(4-Nitrobenzy lthιo)acety laminojcyclopent- 1 -ylmethyl } -N-( 1 - naphthylmethyl)-glycyl-methionine N- { [ 1 -(4-Nitrobenzy lthio)acety laminojcyclopent- 1 -ylmethyl } -N-( 1 - naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[2-(4-Nitrophenyl)ethylcarbamoylamino]-4-methylpentyl } - N-( 1 -naphthylmethy l)-glycyl-methionine N- { 2(S)-[2-(4-Nitrophenyl)ethylcarbamoylamino]-4-methylpentyl }- N-(l-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(3(S)-tetrahydrofuryloxy)carbonylamino]-3(S)- methylpenty 1 } -N-( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[(3(S)-tetrahydrofuryloxy)carbonylamino]-3(S)- methylpentyl } -N-( 1 -naphthylmethyl)-glycy 1-methionine methyl ester N- { 2(S)-[(cis-4-benzyloxytetrahydrofur-3-yloxy)carbonylamino]- 3(S)-methylpenty 1 } -N-( 1 -naphthylmethyl)-glycyl -methionine, N- { 2(S)-[(cis-4-benzyloxytetrahydrofur-3-yloxy)carbonylamino]- 3(S)-methylpentyl } -N-(l -naphthylmethy l)-glycyl -methionine methyl ester N-{ 2(S)-[(N'-Methyl-N'-4-nitrophenylacetylglycyl)amino]-4- methylpentyl } -N-( 1 -naphthylmethyl)-glycy 1-methionine or N-{ 2(S)-[(N'-Methyl-N'-4-nitrophenylacetylglycyl)amino]-4- methylpentyl }-N-( 1 -naphthylmethyl)-glycyl-methionine methyl ester or a pharmaceutically acceptable salt thereof. 10. A compound which inhibits farnesyl-protein transferase which is: N- { 2(S)-[(4-Methoxybenzylthio)acetamido]-3(S)-methy lpentyl } -N- ( 1 -naphthylmethyl)-glycyl-methionine or the pharmaceutically acceptable salts thereof. 11. A compound which inhibits farnesyl-protein transferase which is: N- { 2(S)-[(4-Methoxybenzylthio)acetamido]-3(S)-methylpentyl } -N- (l -naphthylmethyl)-glycyl-methionine methyl ester or a pharmaceutically acceptable salt thereof. 12. A compound which inhibits farnesyl-protein transferase which is: N- { 2(S)-[(4-Cyanobenzylthio)acetamido]-3(S)-methylpentyl } -N-( 1 ■ naphthylmethyl)-glycyl-methionine or a pharmaceutically acceptable salt thereof. 13. A compound which inhibits farnesyl-protein transferase which is: N- { 2(S)-[(4-Cyanobenzylthio)acetamido]-3(S)-methylpentyl } -N-( 1 ■ naphthylmethyl)-glycyl-methionine methyl ester or a pharmaceutically acceptable salt thereof. 14. A compound which inhibits farnesyl-protein transferase which is: N-(2(S)-L-Glutaminylamino-3(S)-methylpentyl)-N-( 1 -naphthyl- methyl)glycyl-methionine or a pharmaceutically acceptable salt thereof. 15. A compound which inhibits farnesyl-protein transferase which is: N-(2(S)-L-Glutaminylamino-3(S)-methylpentyl)-N-( 1 -naphthyl- methy glycyl-methionine methyl ester or a pharmaceutically acceptable salt thereof. 16. A compound which inhibits farnesyl-protein transferase which is: N- { 2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl } -N-( 1 - naphthylmethyl)-glycyl-methionine sulfone or a pharmaceutically acceptable salt thereof. 17. A compound which inhibits farnesyl-protein transferase which is: N- { 2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl } -N-( 1 - naphthylmethyl)-glycyl-methionine sulfone methyl ester or a pharmaceutically acceptable salt thereof. 18. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 1. 19. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 2. 0 20. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 3. 5 21. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 4. 22. A pharmaceutical composition comprising a o pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 9. 23. A method for inhibiting famesylation of Ras protein which comprises administering to a mammal in need thereof a 5 therapeutically effective amount of the composition of Claim 18. 24. 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 19. 0 25. 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 20. 26. 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 21. 27. 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 22. 28. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 18. 29. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 19. 30. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 20. 31. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 21. 32. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 22.

Inventors: BRESLIN MICHAEL J, DESOLMS S JANE, GRAHAM SAMUEL L, HUTCHINSON JOHN H, STOKKER GERALD E, BRESLIN, MICHAEL, J., DESOLMS, S., JANE, GRAHAM, SAMUEL, L., HUTCHINSON, JOHN, H., STOKKER, GERALD, E.
Applicants: BRESLIN MICHAEL J, DESOLMS S JANE, GRAHAM SAMUEL L, HUTCHINSON JOHN H, MERCK & CO INC, STOKKER GERALD E, BRESLIN, MICHAEL, J., DESOLMS, S., JANE, GRAHAM, SAMUEL, L., HUTCHINSON, JOHN, H., MERCK & CO., INC., STOKKER, GERALD, E.
Application year: 1995
Main classification: A61K38
IPC codes: A61K38, A61P35, A61P43, C07C229, C07C237, C07C255, C07C323, C07K5