INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE

Abstract: The present invention comprises analogs of the CA1A2X motif of the protein Ras that is modified by farnesylation in vivo. These CA1A2X analogs inhibit the farnesylation of Ras. Furthermore, these CA1A2X analogs differ from those previously described as inhibitors of Ras farnesly transferase in that they have a prolyl like moiety in the A1 position. 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-PROTEJN 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. 55:171 -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 farnesyl pyrophosphate (FPP) occurs in vivo on Cys to form a thioether linkage (Hancock etal., Cell 57:1167 (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 farnesyl acceptor (Gutierrez et al., EMBO J. ?:1093- 1098 (1989); Hancock et al., Cell 57:1167-1 177 (1989)). Ki-Ras lacks the palmitate acceptor Cys. The last 3 amino acids at the Ras C- terminal end are removed proteolytically, and methyl esterifϊcation 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); Farns worth et al., J. 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 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids and the farnesyl pyrophosphate precursor. It has been shown that a farnesyl- protein transferase using farnesyl 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, 57:7541-7545 (1990)). Inhibition of farnesyl-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. Farnesyl-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 farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group. Inhibition of farnesyl 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, 55:732-736 (1991)). Previously described CAi A2X-type FPTase inhibitors contain acyclic amino acids in the second position. Incorporation of proline in the Al position in such inhibitors has been shown to be the least well tolerated amino acid substitution in that position (Reiss et al., PNAS (1991)). Such inhibitors may inhibit while serving as altemate substrates for the Ras farnesyl-transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141,851, University of Texas). Recently, it has 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). Inhibitors of Ras farnesyl-protein transferase (FPTase) have been described in two general classes. The first are analogs of farnesyl diphosphate (FPP), while the second class of inhibitors is related to the protein 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). It is, therefore, an object of this invention to develop tetrapeptide-based compounds which incorporate a cyclic amino acid in the second position, 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 preferred inhibitors of Ras famesyl transferase in that they incorporate a cyclic amine moiety in the second amino acid position of the motif. Further contained in this invention are chemotherapeutic compositions containing these famesyl transferase inhibitors and methods for their production. The compounds of this invention are illustrated by the formulae: -5 10 20 30 IV 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: 5 wherein: Rl is selected from: a) hydrogen, b) R8S(0)2-, R 8 C(0)-, (R8)2NC(0)- or R9θC(0)-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, o heterocyclic, cycloalkyl, alkenyl, alkynyl, R8θ-, R 8 S(0)m-, R8C(0)NR8-, CN, (R8)2N-C(NR8)-, R8C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, or R9θC(0)NR8- ; R2a and R2b are independently selected from: 5 a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by alkenyl, R8θ-, R8S(0)πr, R 8 C(0)NR8_, CN, (R8)2N-C(NR8)-, R 8 C(0)-, R8θC(0)-, N3, -N(R 8 )2, or R9θC(0)NR8-, c) aryl, heterocycle, cycloalkyl, alkenyl, R8θ-, o R 8 S(0)m-, R8c(0)N -, CN, N02, (R 8 )2N- C(NR8)-, R8C(0)-, R80C(0)-, N3, -N(R 8 )2, or R90C(0)NR8_, and d) Cl-Cό alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; 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) substituted or unsubstituted C1 -C2O alkyl, C2-C2O alkenyl, C3-C1O cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R8)2, N02, R 0-, R8S(0) m -, R 8 C(0)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 ) 2 , R9θC(0)NR 8 - and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl;or R3 and R4 are combined to form - (CH2)s - . R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C2O alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R 8 )2, Nθ2, R 8 0-, R S(0)m-, R 8 C(0)NR 8 -, CN, (R8)2N-C(NR 8 )-, R C(0)-, R 8 OC(0)-, N3, -N(R )2, R9θC(0)NR 8 - and C1-C2O alkyl, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; 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 8 )- ; X-Y is Fj. 7a o R 7b f) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) Cl -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R7b i selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C 1 -C alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R 8 is independently selected from hydrogen, Cl-C6 alkyl and aryl; R9 is independently selected from -C6 alkyl and aryl; and Z^ are independently H2 or O, provided that Z^ is not O when X-Y is - C(0)N(R7a)_; m is 0, 1 or 2; s is 4 or 5; and t is 3, 4 or 5; or the pharmaceutically acceptable salts thereof. In a second embodiment of this invention the prodmgs of compounds of formula I are illustrated by the formula II: wherein: Rl is selected from: a) hydrogen, b) R 8 S(0)2-, R 8 C(0)-, (R 8 )2NC(0)- or R9θC(0)-, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 0-, R 8 S(0)m-, R 8 C(0)NR 8 -, CN, (R )2N-C(NR 8 )-, R C(0)-, R OC(0)-, N3, -N(R 8 )2, or R9θC(0)NR 8 -; R2a and R2b are independently selected from: a) hydrogen, b) C1-C alkyl unsubstituted or substituted by alkenyl, R 0-, R 8 S(0)m-. R 8 C(0)NR 8 -, CN, (R )2N-C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, or R9θC(0)NR 8 -, c) aryl, heterocycle, cycloalkyl, alkenyl, R 0-, R 8 S(0)m-, R 8 C(0)NR 8 -, CN, N02, (R 8 )2N- C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, or R90C(0)NR 8 -, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; 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 unsubstituted CJ-C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R )2, N02, R 8 0-, R 8 S(0) m -, R C(0)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(0)-, R OC(0)-, N3, -N(R )2, R9θC(0)NR 8 - and C1-C2O alkyl, and d) Cl -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; or R3 and R4 are combined to form - (CH2)s - ; R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1 -C2O alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R )2, N02, R 8 0-, R 8 S(0)m-, R 8 C(0)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, R9θC(0)NR 8 - and Cl -C20 alkyl, and d) C1-C alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 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 8 )- ; R6 IS a) substituted or unsubstituted C1-C8 alkyl, wherein the ! 0 substituent on the alkyl is selected from: D aryl, 4) -OR 8 , or 20 25 30 X-Y is R 7a 0 O 7 b) (P) m d) f) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R 8 is independently selected from hydrogen, C1-C6 alkyl and aryl; R9 is independently selected from Cl-C alkyl and aryl; RIO is independently selected from hydrogen and Cl -C6 alkyl; R ! 1 is independently selected from C1 -C6 alkyl; Zl and Z^ are independently H2 or O, provided that Z^ is not O when X-Y is - C(0)N(R7a). ; m is 0, 1 or 2; s is 4 or 5; and t is 3, 4 or 5; or the pharmaceutically acceptable salts thereof. In a third embodiment of this invention, the inhibitors of famesyl transferase are illustrated by the formula III: wherein: Rl is selected from: a) hydrogen, b) R 8 S(0)2-, R 8 C(0)-, (R 8 )2NC(0)- or R9θC(0)-, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 0-, R 8 S(0) -, R 8 C(0)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(0)-, R OC(0)-, N3, -N(R 8 )2, or R9θC(0)NR 8 -; R2a and R2b are independently selected from: a) hydrogen, b) Cl-Q) alkyl unsubstituted or substituted by alkenyl, R 8 0-, R S(0)m-, R 8 C(0)NR 8 -, CN, (R )2N-C(NR 8 )-, R 8 C(0)-, R OC(0)-, N3, -N(R 8 )2, or R9θC(0)NR 8 -, c) aryl, heterocycle, cycloalkyl, alkenyl, R 0-, R 8 S(0) m -, R 8 C(0)NR 8 -, CN, N02, (R 8 )2N- C(NR 8 )-, R C(0)-, R OC(0)-, N3, -N(R )2, or R9θC(0)NR 8 -, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; 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 unsubstituted Cl-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R 8 )2, N02, R 8 0-, R 8 S(0)m-, R 8 C(0)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, R90C(0)NR 8 - and C1-C2O alkyl, and d) C1-C alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; or R3 and R4 are combined to form - (CH2)s X-Y is (0) m f) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R 8 is independently selected from hydrogen, C1-C6 alkyl and aryl; R9 is independently selected from C1-C alkyl and aryl; I and Z2 are independently H2 or O, provided that Z* is not O when X-Y is - C(0)N(R7a)_; m is 0, 1 or 2; q is O, 1 or 2; s is 4 or 5; and t is 3, 4 or 5; or the pharmaceutically acceptable salts thereof. In a fourth embodiment of this invention the prodmgs of compounds of formula III are illustrated by the formula IV: wherein: Rl is selected from: a) hydrogen, b) R 8 S(0)2-, R 8 C(0)-, (R )2NC(0)- or R9θC(0)-, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 8 0-, R 8 S(0) m -, R C(0)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(0)-, R OC(0)-, N3, -N(R 8 )2, or R9θC(0)NR 8 -; R2a and R2b are independently selected from: a) hydrogen, b) C1 -C6 alkyl unsubstituted or substituted by alkenyl, R 8 0-, R 8 S(0) m -, R C(0)NR 8 -, CN, (R )2N-C(NR 8 )-, R 8 C(0)-, R OC(0)-, N3, -N(R )2, or R9θC(0)NR 8 -, c) aryl, heterocycle, cycloalkyl, alkenyl, R 0-, R 8 S(0)πr, R 8 C(0)NR 8 -, CN, N02, (R 8 )2N-C(NR 8 )-, R C(0)-, R OC(0)-, N3, -N(R )2, or R9θC(0)NR 8 -, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; 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, and c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R 8 )2, N02, R 8 0-, R S(0) m -, R 8 C(0)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, R9θC(0)NR 8 - and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl;or R3 and R4 are combined to form - (CH2)s - . X-Y is R 7b f) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R7b i selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R 8 is independently selected from hydrogen, Cl-C6 alkyl and aryl; R9 is independently selected from -C6 alkyl and aryl; Zl and Z are independently H2 or O, provided that Z^ is not O when X-Y is - C(0)N(R7a).; m is 0, 1 or 2; q is 0, 1 or 2; s is 4 or 5; and t is 3, 4 or 5; or the pharmaceutically acceptable salts thereof. h a more preferred embodiment of this invention, the Ras famesyl transferase inhibitors are illustrated by the formula I: wherein: is selected from: a) hydrogen, b) R 8 S(0)2-, R 8 C(0)-, (R )2NC(0)- or R9θC(0)-, and c) C1-C alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 8 0-, R 8 S(0) m -, R C(0)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(OK R 8 OC(OK N3, -N(R 8 )2, or R9θC(0)NR 8 -; R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine, norleucine, valine and norvaline; 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, R 8 0-, R 8 S(0) m -, R 8 C(0)NR 8 -, CN, (R )2N- C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, R9θC(0)NR 8 - and C1-C20 alkyl, and c) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; and R2b is selected from hydrogen and C1-C6 alkyl; 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, R 8 0-, R 8 S(0)m-, R 8 C(0)NR 8 -, CN, (R )2N- C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, R9θC(0)NR 8 - and C1-C2O alkyl, and d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 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 8 0-, R 8 S(0)m-, R 8 C(0)NR 8 -, CN, (R 8 )2N- C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, R9θC(0)NR 8 - and C1-C2O alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R5b is selected from: a) hydrogen, and b) Cl-C3 alkyl; X-Y is R 7a ») o b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) Cl -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle 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 heterocycle, d) unsubstituted or substituted cycloalkyl, e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R 8 is independently selected from hydrogen, C1 -C6 alkyl and aryl; R9 is independently selected from -C6 alkyl and aryl; ZS and Z2 are independently H2 or O, provided that 7} is not O when X-Y is - C(0)N(R7a)- ; m is 0, 1 or 2; and t is 3, 4 or 5; or the pharmaceutically acceptable salts thereof. In a second more preferred embodiment of this invention, the prodmgs of the preferred compounds of formula I are illustrated by the formula II: wherein: Rl is selected from: a) hydrogen, b) R S(0)2-, R 8 C(0)-, (R 8 )2NC(0)- or R9θC(0)-, and c) C1 -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 8 0-, CN, R 8 S(0)m-, R 8 C(0)NR 8 -, (R 8 )2N-C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, or R9θC(0)NR 8 -; R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine, norleucine, valine and norvaline; and 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, R 8 0-, R 8 S(0) m -, R 8 C(0)NR 8 -, CN, (R 8 )2N- C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, R90C(0)NR8- and C1-C2O alkyl, and c) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R2b is selected from hydrogen and C 1 -C6 alkyl; 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, R 8 0-, R S(0) m -, R 8 C(0)NR 8 -, CN, (R )2N-C(NR 8 )-, R C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, R 9 OC(0)NR 8 -, C1-C20 alkyl, or heterocycle; 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- o alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 8 0-, R S(0)m-, R 8 C(0)NR 8 -, CN, (R )2N- C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, R9θC(0)NR 8 - and Cl-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R5b is selected from: a) hydrogen, and b) Cl -C3 alkyl; X-Y is }7b b) \ s^ N }* e) -CH 2 -CH 2 - ; R° i IS a) substituted or unsubstituted C1-C8 alkyl, wherein the substituent on the alkyl is selected from: D aryl, 4) -OR 8 , or R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C l -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle 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 heterocycle, d) unsubstituted or substituted cycloalkyl, e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R 8 is independently selected from hydrogen, C1-C6 alkyl and aryl; R is independently selected from Cl -C6 alkyl and aryl; RIO is independently selected from hydrogen and -C alkyl; R 1 1 is 1 ,1-dimethylethyl; Z* and Z 2 are independently H2 or O, provided that 7x is not O when X-Y is - C(0)N(R7a)- ; m is 0, 1 or 2; and t is 3, 4 or 5; or the pharmaceutically acceptable salts thereof. In a third more preferred embodiment of this invention, the inhibitors of famesyl transferase are illustrated by the formula HI: wherein: Rl is selected from: a) hydrogen, b) R 8 S(0)2-, R 8 C(0)-, (R 8 )2NC(0)- or R9θC(0 , and c) C 1 -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 8 0-, R S(0)m-, R 8 C(0)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R8C(0)-, R8θC(0)-, N3, -N(R 8 )2, or R90C(0)NR 8 - ; R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine, norleucine, valine and norvaline; and b) substituted or unsubstituted C l -C 10 alkyl, C2-C 10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 8 0-, R 8 S(0)m-, R C(0)NR 8 -, CN, (R 8 )2N- C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, R9θC(0)NR 8 - and Cl -C20 alkyl, and c) C 1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R2b is selected from hydrogen and C 1 -C6 alkyl; 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, Nθ2, R 8 0-, R S(0)m-, R 8 C(0)NR 8 -, CN, (R 8 )2N- C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, R9θC(0)NR 8 - and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; X-Y is )7a a) o c) Y d > Y^ , or H Θ) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle 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 heterocycle, d) unsubstituted or substituted cycloalkyl, e) C l -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R 8 is independently selected from hydrogen, Cl-C6 alkyl and aryl; R is independently selected from -C6 alkyl and aryl; 7 and Z2 are independently H2 or O, provided that 7} is not O when X-Y is - C(0)N(R7a). ; m is 0, 1 or 2; q is 0, 1 or 2; and t is 3, 4 or 5; or the pharmaceutically acceptable salts thereof. In a fourth more preferred embodiment of this invention, the prodmgs of the preferred compounds of formula IE are illustrated by the formula IV: wherein: Rl is selected from: a) hydrogen, b) R S(0)2-, R C(0)-, (R 8 )2NC(0)- or R9θC(0)-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 0-, R 8 S(0)m-, R C(0)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, or R9θC(0)NR 8 -; R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine, norleucine, valine and norvaline; 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, R 8 0-, R 8 S(0)m-, R 8 C(0)NR 8 -, CN, (R 8 )2N- C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, R9θC(0)NR 8 - and C1-C20 alkyl, and c) C 1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C 10 cycloalkyl; R2b is selected from hydrogen and C1 -C6 alkyl; 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, R 8 0-, R 8 S(0)m-, R C(0)NR 8 -, CN, (R 8 )2N- C(NR 8 )-, R 8 C(0)-, R OC(0)-, N3, -N(R 8 )2, R9θC(0)NR 8 - and C1-C2O alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; X-Y is .7a a) Y o b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) Cl -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle 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 heterocycle, d) unsubstituted or substituted cycloalkyl, e) C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C l -C alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R 8 is independently selected from hydrogen, -C6 alkyl and aryl; R is independently selected from Cl-C6 alkyl and aryl; 7S and Z2 are independently H2 or O, provided that } is not O when X-Y is - C(0)N(R7a)- ; m is 0, 1 or 2; q is 0, 1 or 2; and t is 3, 4 or 5; or the pharmaceutically acceptable salts thereof. The preferred compounds of this invention are as follows: N-[l -(2(R)-amino-3-mercaptopropyl)-2(S)-pyrrolidinylme_hylJ-N-(l naphthylmethyl)glycyl-methionine N-[ 1 -(2(R)-amino-3-mercaptopropyl)-2(S)-pyrrolidinylmethyl]-N-( 1 ■ naphthylmethy glycyl -methionine methyl ester 2(S)-[[ 1 -[2(R)-Amino-3-mercaρtolpropyI]-2(S)-(pyrrolidinyl)- methyloxy]-3-phenylpropionyl-methionine 2(S)-[[l-[2(S)-Amino-3-mercapto]propyl]-2(S)-(pyrrolidinyl)- methyloxy]-3-phenylpropionyl-methionine or the pharmaceutically acceptable salts thereof. In the present invention, the amino acids which are disclosed are identified both by conventional 3 letter and single letter abbreviations as indicated below: The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. As used herein, "cycloalkyl" is intended to include non- aromatic cyclic hydrocarbon groups having the specified number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. "Alkenyl" groups include those groups having the specified number of carbon atoms and having one or several double bonds. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2- butenyl, isoprenyl, 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. The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 1 1- membered bicyclic or stable 11-15 membered tricyclic heterocycle ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable 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, thiamorpholinyl, thiamoφholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl. As used herein, the terms "substituted aryl", "substituted heterocycle" and "substituted cycloalkyl" are intended to include the cyclic group which is substituted with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Cl -C6 alkyl)2, N02, CN, (C1-C6 alkyl)0-, -OH, (C1-C6 alkyl)S(0)m-. (C1-C6 alkyl)C(0)NH-, H2N-C(NH)-, (C1-C6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)-, N3,(Ci-C6 alkyl)OC(0)NH- and C1 -C2O alkyl. The following stmcture: represents a cyclic amine moiety having 5 or 6 members in the ring, such a cyclic amine which may be optionally fused to a phenyl or cyclohexyl ring. Examples of such a cyclic amine moiety include, but are not limited to, the following specific structures: It is also understood that substitution on the cyclic amine moiety by R a and R b m ay be on different carbon atoms or on the same carbon atom. When R3 and R are combined to form - (CH2)s -. cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to: When R5a and R5b are combined to form - (CH2)s -, cyclic moieties as described hereinabove for 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 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 8 , Z, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, -N(R8)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 incoφorated by reference. Abbreviations used in the description of the chemistry and in the Examples that follow are: HOOBT 3-Hydroxy- 1 ,2,2-benzotriazin-4(3//)-one; HPLC High-performance liquid chromatography; 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 1 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, alternatively, reductive alkylation of a reduced peptide subunit with an aldehyde using sodium cyanoborohydride or other reducing agents. Reaction D. Peptide bond formation and protecting group cleavage using standard solution or solid phase methodologies. Reaction E. Preparation of a reduced subunit by borane reduction of the amide moiety. Reaction Schemes A-E illustrate bond-forming and peptide modifying reactions incoφorating acyclic peptide units. It is well understood that such reactions are equally useful when the - NHC(R ) - moiety of the reagents and compounds illustrated is replaced with the following moiety: These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Reaction Schemes. REACTION SCHEME A Reaction A. Coupling of residues to form an amide bond EDC, HOBT . 1 ft f A H ?\ or HOOBT > < N OR H ϋ = « Et 3 N, DMF REACΉON 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 y CH, NaCNBH 3 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 R3, R4, R5a or R5b as previously defined; XL is a leaving group, e.g., Br, I- or MsO-; and R v 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. For simplicity, substituents R2a and R2b 0 n the cyclic amine moiety are not shown. It is, however, understood that the reactions illustrated are also applicable to appropriately substituted cyclic amine compounds. 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 S 2' 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, the amino terminus sidechain, designated Rx is incoφorated using coupling reaction A and RxCOOH; the alkylation reaction C using RxCHO 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. REACΉON SCHEME F Step A REACTION SCHEME F (CONT'D) 1. HCI whe REACTION SCHEME F (CONT'D) NaOH or 10 1. HCI 3. TFA/Et 3 SiH Alternate O Step H II 2. proR x COH EDC, HOBT 30 REACTION SCHEME G REACTION SCHEME G (CONT'D^ 3 NaOH 25 30 REACTION SCHEME G (CONT'D) or O II 1. HCI 2. proR x COH EDC, HOBT 3. TFA/Et 3 SiH NaOH The oxa isostere compounds of this invention are prepared according to the route outlined in Scheme H. An aminoalcohol 1 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 moφholinone 3. Alkylation of 3 with R3χL, where XL is a leaving group such as Br, I- or Cl- in TΗF/DME ( 1 ,2-dimethoxyethane) in the presence of a suitable base, preferably NaHMDS [sodium bis(trimethylsilyl)amide], affords 4, which is retreated with NaHMDS followed by either protonation or the addition of an alkyl halide R4χ to give 5a or 5b, respectively. Alternatively, 5a can be prepared from 3 via an aldol condensation approach. Namely, deprotonation of 3 with NaHMDS followed by the addition of a carbonyl compound RyRzCO gives the adduct £. Dehydration of 6 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 with phosphoms oxychloride in pyridine to give olefin 7. Then, catalytic hydrogenation of 2 yields 5 (wherein -CHRyR z constitutes R3). Direct hydrolysis of 5 with lithium hydrogen peroxide in aqueous THF, or aqueous HCl, produces acid 8a. Compound 8a is then derivatized with BOC-ON or BOC anhydride to give £b. The peptide coupling of acid 8b 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 9. Treatment of 9 with gaseous hydrogen chloride gives JO, which undergoes reductive alkylation in the presence of a protected aldehyde proRxCHO (11) and a reducing agent (e.g., sodium cyanoboro-hydride); or acylation in the presence of proR*COOH (12) and a peptide coupling reagent affording, after removal of the trityl protecting group, the products 13 and .14. Hydrolysis of compounds J_3 and J_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. An alternative method for the preparation of the prolyl oxa isostere (compounds 23 and 24 ) is illustrated in Scheme H-l . Referring to Scheme H- 1 , the aminoalcohol 1 is protected with trifluoroacetic anhydride and the blocked compound L5 treated with diphenyl disulfide in the presence of tributylphosphine to provide the thioether 16. Chlorination of compound 16 provides compound 17 which can be reacted with the appropriate carboxylic acid alcohol in the presence of silver perchlorate and tin (II) chloride, to afford the mixed acetal 18. Removal of the phenylmercapto moiety with Raney nickel provides compound 19. Compound 19 is doubly deprotected, then selectively BOC protected to provide acid 20, which undergoes the steps previously described for incoφorating terminal amino acid. The appended free amine 22 then undergoes reductive alkylation in the presence of an aldehyde proRxCHO (11) and a reducing agent (e.g., sodium cyanoboro-hydride); or acylation in the presence of proRxCOOH (12) and a peptide coupling reagent affording, after removal of the trityl protecting group, the products 22. and 24- Hydrolysis of compounds 23 and 24 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 acidif cation with dilute HCl. Yet another alternative method for the preparation of the prolyl oxa isostere (compounds 23 and 24 ) is described in the literature [Ruth E. TenBrink, J. Org. Chem., 52:418-422 (1987)]. SCHEME H R y R z CO SCHEME H (CONT'D) a, R w = H b, R w = BOC SCHEME H (CONT'D) 14 A = SCHEME H-l SCHEME H-l (CONT'D) SCHEME H-1 (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 BOC2O to give 25. Mesylation of 25 followed by reaction with methyl alpha- mercaptoacetate in the presence of cesium carbonate gives sulfide 26. Removal of the BOC group in 26 with TFA followed by neutralization with di-isopropylethylamine leads to 27. Sequential alkylation of 27 with the alkyl halides R3χ and R χ in THF/DME using NaHDMS as the deprotonation reagent produces 28. Hydrolysis of 28 in hydro- chloride to yield 29a, which is derivatized with Boc anhydride to yield 29b. The coupling of 29b 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 30. Sulfide 30 is readily oxidized to sulfone 31 by the use of MCPB A (m-chloroperoxybenzoic acid). The N-BOC group of either 30 or 31 is readily removed by treatment with gaseous hydrogen chloride. The resultant amine hydrochloride 32 undergoes reductive alkylation in the presence of an aldehyde proRxCHO (12) and a reducing agent (e.g., sodium cyanoborohydride); or acylation in the presence of proRxCOOH (13) and a peptide coupling reagent to afford, following removal of the trityl group, the products 33 and 34. SCHEME I HCl m=0, 2D. " ^ CPBA m=2, 21 J 1. proR x COOH 2. TFA/Et 3 SiH EDC, HOBT 24 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, 10 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. χ 5 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 20 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 25 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 _ 0 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-[ 1 -(2(R)-amino-3-mercaptopropyl)-2(S)-pyrrolidinyl- methyl]- N-(l-naphthylmethyl)glycyl-methionine methyl ester tris trifluoroacetate salt Step A: Preparation of N-[(2S)-(t-Butoxycarbonylpyrrolidinyl- methyP-glycine methyl ester N-(t-Butoxycarbonyl)-L-prolinal (9.16 g, 0.046 mol) and glycine methyl ester hydrochloride salt (5.78 g, 0.046 mol) were 5 dissolved in MeOH (180 mL) at 0°C under nitrogen, treated with sodium cyanoborohydride (4.34 g, 0.069 mol), and stirred for 18 h. The mixture was concentrated, and the residue was partitioned between EtOAc (100 mL) and satd aq NaHCθ3 soln (100 mL). The basic layer was washed with EtOAc (2x 50 mL), the organics combined, washed with brine, and χ 0 dried over Na2S04). Filtration and concentration to dryness gave the title compound as a pale yellow oil. J H NMR (CDCI3) δ 3.7-3.9 (m, IH), 3.72 (s, 3H), 3.43 (s, 2H), 3.33 (s, 2H), 2.7-2.9 (m, IH), 2.5-2.65 (m, IH), 1.75-2.0 (m, 4H), 1.47 (s, 9H). 15 Step B: Preparation of N-[(2S)-(t-ButoxycarbonylpyπOlidinyl- methyl)-N-(l-naphthylmethyl) glycine methyl ester N-[(2S)-(t-Butoxycarbonylpyrrolidinylmethyl) glycine methyl ester (3.0 g, 0.011 mol) was dissolved in 1 ,2-dichloroethane (100 ml) and 3 A molecular sieves (3 g) were added followed by 1 - 0 naphthaldehyde (1.63 ml, 0.012 mol) and sodium triacetoxyborohydride (4.64 g, 0.022 mol). The mixture was stirred at ambient temperature for 5 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 5 were combined, dried with Na2Sθ4, filtered, and concentrated to give cmde product which was purified by chromatography (silica gel 1 :6 EtOAc/hexane) to give the title compound. H NMR (CDCI3) δ 8.24-8.4 (m, IH), 7.7-7.9 (m, 2H), 7.35-7.5 (m, 4H), 4.43 (d, IH, J= 12 Hz), 3.8- 4.1 (m, 2H). 3.68 (s, 3H), 3.15-3.5 (m, 4H), 2.94 (t, IH, J= 12 Hz), 2.44 0 (t, IH, J= 11 Hz), 1.7-1.8 (m, 2H), 1.5-1.7 (m, 2H), 1.47 (s, 9H). Step C: Preparation of N-[(2S)-(t-Butoxycarbonylpyrrolidinyl- methyl)- N-( 1 -naphthylmethyPglvcine N-[(2S)-(t-Butoxycarbony lpyrrolidinylmethyl)-N-( 1 - naphthylmethyl)glycine methyl ester (2.91 g, 7.10 mmol) was dissolved in MeOH (60 ml) and IN NaOH (21.3 ml, 21.3 mmol) was added. The mixture was stirred at ambient temperature for 5 h and concentrated. The resulting residue was dissolved in H2θ (25 ml) and neutralized with IN HCl (21.3 ml). The aqueous layer was washed with EtOAc (3x50 ml). The organic layers were combined, dried with Na2Sθ4, filtered, and concentrated to give product. H NMR (CD3OD); δ 8.57 (d, IH, J= 9 Hz), 7.5-8.0 (m, 6H), 5.13 (d, IH, J= 12 Hz), 4.71 (d, IH, J= 12 Hz), 4.05-4.15 (m, IH), 3.71 (ABq, 2H), 3.2- 3.4 (m, 3H), 3.0-3.1 (m, IH), 2.0-2.1 (m, IH), 1.6-1.75 (m, 2H), 1.5- 1.6 (m, IH), 1.30 (s, 9H). Step D: Preparation of N-[(2S)-(t-Butoxycarbonylpyrrolidinyl- methyl)-N-( 1 -naphthylmethyl)glycine-methionine methyl ester N-[(2S)-(t-Butoxycarbonylpyrrolidinylmethyl)-N-( 1 - naphthylmethyl) glycine (1.44 g, 3.6 mmol), dissolved in CH2CI2 (30 mL), was treated with HOBT (0.581 g, 4.3 mmol), EDC (0.831 g, 4.3 mmol), and methionine methyl ester hydrochloride (0.859 g, 4.3 mmol). The pH was adjusted to 7.5 with Et3N (1.1 mL, 7.9 mmol) and the mixture was stirred at ambient temperature for 18 h. The mixture was concentrated, and the residue was partitioned between CH2CI2 (50 mL) and saturated NaHC03 solution (25 mL). The aqueous layer was extracted with CH2CI2 (2 x 50 mL). The organic layers were combined, washed with brine (1x25 mL), dried (Na2S04), filtered, and concentrated to give crude product which was purified by chromatography (silica gel eluting with 1 :3 to 1 : 1 ethyl acetate in hexane) to give the title compound. iH NMR (CDCI3); δ 8.22 (d, IH, J= 9 Hz), 7.8-7.95 (m, 2H), 7.4-7.6 (m, 4H), 4.54 (d, IH, J= 16 Hz), 4.3-4.5 (m, 2H), 4.07-4.15 (m, IH), 3.7- 3.9 (m, 2H), 3.68 (s, 3H), 3.25-3.4 (m, 3H), 3.04-3.15 (m, IH), 2.85 -3.0 (m, IH), 2.4-2.5 (m, IH), 1.89 (s, 3H). 1.53-2.5 (m, 5H), 1.48 (s. 9H), 1.2-1.45 (m, 2H). Step E: Preparation of N-((2S)-pyrrolidinylmethyl)-N-(l - naphthyl-methyl)-glycyl-methionine methyl ester hvdrochloride N-[(2S)-(t-Butoxycarbony lpyrrolidinylmethyl)-N-( 1 - naphthylmethy -glycyl-methionine methyl ester (1.5 g, 2.76 mmol) was dissolved in EtOAc (50 mL) and cooled to 0°C. HCl was bubbled through the mixture until TLC (95:5 CH2Cl2:MeOH) indicated complete reaction. Argon was bubbled through the mixture to remove excess HCl and the mixture was then concentrated to give the title compound. *H NMR (CD3OD); δ 8.23 (d, IH, J = 8 Hz), 7.9-7.95 (m, 2H), 7.45-7.65 (m, 4H), 4.4-4.6 (m, 4H). 3.7-3.8 (m, IH), 3.71 (s, 3H), 3.5-3.7 (m, 2H), 3.12-3.28 (m, 2H), 2.9-3.05 (m, IH), 2.35-2.5 (m, 2H), 1.93-2.15 (m, 4H), 2.02 (s, 3H), 1.77-1.89 (m, IH), 1.6-1.7 (m, IH). Anal. Calcd for C24H33N303S-2 HC1-0.5 H2θ: C, 54.85; H, 6.90; N, 8.00 Found: C, 54.77; H, 6.72; N, 7.79 Step F: Preparation of N-[ 1 -(2(R)-(t-butoxycarbonyl)amino-3- triphenylmethylmercaptopropyl)-2(S)- pyrrolidinyl- methyl]- N-(l-naphthylmethyl)glycyl -methionine methyl ester N-((2S)-pyrrolidinylmethyl)-N-(l-naphthylmethyl)-glycyl- methionine methyl ester hydrochloride (0.20 g, 0.39 mmol) was dissolved in MeOH (10 mL) in an ice-H2θ bath, treated with KOAc (0.15 g, 2.3 mmol), N-(t-butoxycarbonyl)-S-triphenylmethyl cysteinal (0.26 g, 0.59 mmol) and sodium cyanoborohydride (0.074 g, 1.17 mmol) then stirred at ambient temperature under argon for 18 h. The reaction mixture was filtered through glass fiber paper, concentrated, and partitioned between EtOAc and 5% NH4OH soln (50 mL/ 50 mL). The aqueous layer was washed with EtOAc (50 mL), organics combined, washed with brine (50 mL) and dried over Na2Sθ4. Filtration and concentration to dryness gave the title compound after chromatography on silica gel (CH2CI2: MeOH, 98:2 ). *H NMR (CD3OD); δ 8.29 (d, IH, J= 9 Hz), 7.90 (d, IH, J= 9Hz), 7.81 (d, IH, J= 9 Hz), 7.3-7.55 (m, 19 H), 4.25-4.34 (m, 2H), 3.89 (d, IH, J = 16 Hz), 3.65 (s, 3H), 3.55-3.65 (m, IH), 3.0-3.2 (m, 2H), 2.55-2.85 (m, 4H), 2.25-2.45 (m, 4H), 2.05-2.15 (m, IH), 1.8-2.0 (m, 3H), 1.89 (s, 3H), 1.55-1.8 (m, 3H), 1.45 (s, 9H), 1.25-1.4 (m, 2H). Step G: Preparation of N-[ 1 -(2(R)-amino-3-mercaptopropyl)-2(S)- pyrrolidinylmethyl]- N-(l-naphthylmethyl)glycyl- methionine methyl ester tris trifluoroacetate salt N-[ 1 -(2(R)-(t-butoxycarbonyl)amino-3-triphenylmethyl mercaptopropyl)-2(S)-pyrrolidinylmethy 1]- N-( 1 -naphthylmethyl) glycyl-methionine methyl ester (0.129 g, 0.147 mmol) was dissolved in CH2CI2 (2 mL) and treated with trifluoroacetic acid (TFA) (1 mL) and triethylsilane (0.094 mL, 0.589 mmol) with stirring at ambient temperature. After 4 h the mixture was concentrated, triturated with hexane, and the residue dissolved in 0.1% TFA H2O and chromatographed by RP HPLC to give the title compound. iH NMR (CD3OD); δ 8.20 (d, IH, J= 9 Hz), 7.85-7.95 (m, 2H), 7.5- 7.65 (m, 4H), 4.62-4.68 (m,lH), 4.40 (ABq, 2H), 3.7-3.8 (m, IH), 3.73 (s, 3H), 3.35-3.6 (m, 4H), 3.0-3.3 (m, 6H), 2.8-2.9 (m,lH), 2.65-2.8 (m, IH), 2.4-2.6 (m, 2H), 2.06 (s, 3H), 1.85-2.2 (m, 4H), 1.62- .7 (m, IH). MS (M + 1) 533. EXAMPLE 2 Preparation of N-[l-(2(R)-amino-3-mercaptopropyl)-2(S)- pyrrolidinylmethyll- N-( 1 -naphthylmethyDglycyl-methionine Step A: Preparation of N-[ 1 -(2(R)-(t-butoxycarbonyl)amino-3- triphenylmemylmercaptopropyl)-2(S)-pyπOlidinyl- methyll- N-(l -naphthylmethvDglvcyl-methionine N-[ 1 -(2(R)-(t-butoxycarbonyl)amino-3-triphenylmethyl- mercaptopropyl)-2(S)- pyrrolidinylmethyl]-N-( 1 -naphthylmethyl)glycyl- methionine methyl ester from Example 1 , Step F (0.091 g, 0.104 mmol) was dissolved in MeOH (2.5 mL) and IN NaOH (0.416 mL, 0.416 mmol) with stirring at 0°C. After 6 h the mixture was concentrated, and the residue was partitioned between EtOAc and H2θ (25 mL/ 25 mL). The aqueous layer was washed with EtOAc (2 x 20 mL), the organics combined, washed with brine and dried over Na2S04. Filtration and concentration gave the product. J H NMR (CD3OD); δ 8.05-8.1 (m, IH), 7.75-7.90 ( m, 2H), 7.15-7.5 (m, 19H), 4.35 (d, IH, J = 16 Hz), 4.05-4.25 (m, 2H), 3.6-3.7 (m, IH), 3.44 (ABq, 2H), 2.93-3.05 (m, IH), 2.75-2.95 (m, 2H), 2.6-2.75 (m, 2H), 2.25-2.6 (m, 5H), 2.04 (s, 3H), 1.8-2.1 (m, 4H), 1.45-1.6 (m, IH), 1.44 (s, 9H). Step B: Preparation of N-[ 1 -(2(R)-amino-3-mercaptoρropy 1)-2(S)- pyrrolidinylmethyl]- N-(l -naphthylmethyl)glycyl- methionine tris trifluoroacetate salt N-[ 1 -(2(R)-(t-butoxycarbonyl)amino-3-triphenylmethyl mercaptopropyl) -2(S)- pyrrolidinylmethyl]-N-( 1 -naphthylmethyl)glycyl- methionine (0.089 g, 0.104 mmol) was deprotected as described in Example 1, Step G to give the title compound. l U NMR (CD3OD); δ 8.22 (d, IH, J = 9 Hz), 7.94 (d, IH, J = 8 Hz), 7.89 (d, IH, J = 8 Hz), 7.5- 7.63 (m, 4H), 4.59-4.64 ( m, IH), 4.42 (ABq, 2H), 3.7-3.84 (m, 2H), 3.4- 3.64 (m, 4H), 3.25-3.33 (m, IH), 3.1-3.2 (m, IH), 3.0-3.1 (m, 2H), 2.82- 2.9 (m, IH), 2.65-2.75 (m, IH), 2.42-2.6 (m, 2H), 2.07 (s, 3H), 1.86-2.2 (m, 4H), 1.62-1.7 (m, IH). MS (M + 1) 519. EXAMPLE 3 Preparation of 2(S)-[[1-[2(R or S)-Amino-3-mercapto]propyl]-2(S)- (pyrrolidinyl)methyloxy]-3-phenylpropionyl-methionine bis trifluoro- acetate - diastereomer A Step A: Preparation of N-Chloroacetyl-2(S)-hydroxy- methypyrrolidine To a solution of 2(S)-hydroxymethylpyrrolidine (25.32 g, 0.250 mol) in CH2CI2 (720 mL) under argon was added E_3N (38.0 mL, 0.273 mol). After cooling this mixture to -20°C, chloroacetyl chloride (20.0 mL, 0.251 mol) was added dropwise over 0.75 h maintaining the reaction temperature at -20 ± 3°C. The reaction was stirred at ambient temperature for 18 h and evaporated in vacua . An impurity which precipitated during concentration was removed by filtration. The cmde product was purified by chromatography (silica gel, 1 :39 to 1 :19 MeOH/CH2Cl2) to give the title compound as a yellow oil. H NMR (CDC13, 400 MHz): δ 4.37 (dd, J = 8, 3 Hz, IH), 4.22 (qd, J = 7, 3 Hz, IH), 4.08 (s, 2H), 3.71 (td, J = 8, 3 Hz, IH), 3.68-3.50 (m, 3H), 2.14-1.86 (m, 3H), 1.72-1.62 (m, lH). Step B: Preparation of 6(S)-2-Oxo- 1 -aza-4-oxabicyclo-[4.3.0]- nonane To a solution of N-chloroacetyl-2(S)-hydroxymethy- pyrrolidine (12.8 g, 0.072 mol) in THF (240 mL, distilled from Na/benzophenone) under argon at 0°C was added NaH (3.16 g of a 60% dispersion in mineral oil, 0.079 mol) slowly in several portions. After complete addition, the reaction was stirred at ambient temperature for 1 8 h, then quenched by adding glacial acetic acid (400 mL), diluted with toluene, and evaporated in vacuo to give a thick gray liquid. Water was cautiously added dropwise until no further gas evolution was observed. This mixture was diluted with MeOH and CH2CI2 and dried (Na2Sθ4). Since filtration was unsuccessful, silica gel (60 g) was added and the mixture was evaporated in vacuo. The cmde product was purified by chromatography (silica gel, 7:13 to 1:1 EtOAc/CH2θ2) to give the title compound as a white solid. ^H NMR (CDCI3, 400 MHz): δ 4.25 (d, J = 17 Hz, IH), 4.19 (dd, J = 12, 4 Hz, IH), 4.02 (d, J = 17 Hz, IH), 3.76- 3.64 (m, 2H), 3.50 (td, J = 10, 2.5 Hz, IH), 3.24 (dd, J = 12, 10 Hz, IH), 2.09-1.99 (m, 2H), 1.92-1.78 (m, IH), 1.39 (qd, J = 12, 8 Hz, IH). Step C: Preparation of 3(R),6(S)-2-Oxo-3-(phenylmethyl)-l - aza-4-oxabicyclo-[4.3.0]-nonane and 3(S),6(S)-2-Oxo- 3-(phenylmethyl)-l-aza-4-oxabicyclo-[4.3.0]-nonane (93:7 respectively) A solution of 6(S)-2-oxo-l-aza-4-oxabicyclo-[4.3.0J-nonane (6.013 g, 0.0426 mol) in THF (170 mL, distilled from Na/benzophenone) was cooled to -78 °C under argon and transferred via cannula to a second flask containing 1.0 M lithium bis(trimethylsilyl)amide in THF (52 mL, 0.052 mol) also at -78°C under argon. After stirring for 0.5h at -78°C, 10 benzyl bromide (7.20 mL, 0.0605 mol) was added dropwise over 5 min. The reaction was stirred for 1 h at -78°C followed by 1 h at -50°C then quenched by adding saturated aq NH4CI (60 mL) and warming to ambient temperature. The reaction was diluted with H2O (60 mL) and saturated aq NaCl (180 mL), and the layers were separated. The aqueous χ 5 layer was extracted twice with EtOAc (300, 200 mL). The organic extracts were washed in succession with saturated aq NaCl (150 mL), combined, dried (Na2Sθ4), and evaporated in vacuo. The cmde product was purified by chromatography (silica gel, 1 :4 EtOAc/CH2θ2) to give the title compound as a yellow oil. J H NMR (CDCI3, 400 MHz): δ 20 7.31-7.19 (m, 5H), 4.44 (dd, J = 10, 4 Hz, 0.07H), 4.27 (dd, J = 8, 4 Hz, 0.93H), 4.12 (dd, J = 12, 4 Hz, 0.93H), 3.94 (dd, J = 12, 5 Hz, 0.07H), 3.72-3.62 (m, IH), 3.54-3.18 (m, 4H), 3.01 (dd, J = 15, 8 Hz, 0.93H), 3.00 (dd, J = 14, 8 Hz, 0.07H), 2.04-1.91 (m, 2H), 1.83-1.69 (m, IH), 1.33 (qd, J = l l, 8 Hz, IH). 25 Step D: Preparation of 3(R),6(S)-2-Oxo-3-(phenylmethyl)- 1 -aza-4- oxabicyclo-[4.3.0]-nonane and 3(S),6(S)-2-Oxo-3- (phenylmethyl)-l -aza-4-oxabicyclo-[4.3.0]-nonane (2: 1 respectively) 30 A soln of 3(R,S),6(S)-2-oxo-3-(phenylmethyl)-l-aza- 4-oxabicyclo-[4.3.0]-nonane (8.818 g, o.o38 mol) in THF (170 mL, distilled from Na/benzophenone) was cooled to -78°C under argon and transferred via cannula to a second flask containing 1.0 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (57 mL, 0.057 mol) also at -78°C under argon. After stirring for 10 min at -78°C, the reaction was placed in an ice bath for 0.5 h. The reaction was again cooled to -78°C for 10 min, quenched by adding HO Ac (3.30 mL), and allowed to warm to ambient temperature. The reaction was diluted with H2θ (50 mL) and saturated aq NaCl (100 mL) and extracted twice with EtOAc (300, 200 mL). The organic extracts were combined, washed with saturated aq NaCl (200 mL), dried (Na2Sθ4), and evaporated in vacuo to give the title compound as a golden orange oil. *H NMR (CDCI3, 400 MHz) δ 7.34- 7.15 (m, 5H), 4.43 (dd, J = 10, 3 Hz, 0.33H), 4.27 (dd, J = 8, 3 Hz, 0.67H), 4.11 (dd, J = 11, 4 Hz, 0.67H), 3.94 (dd, J = 11, 4 Hz, 0.33H), 3.74-3.17 (m, 5H), 3.07 (dd, J = 14, 10 Hz, 0.33H), 3.01 (dd, J = 14, 8 Hz, 0.67H), 2.06-1.91 (m, 2H), 1.89-1.71 (m, IH), 1.39-1.24 (m, IH). Step E: Preparation of 2(R)-[2(S)-(Pyrrolidinyl)methyloxy]-3- phenylpropionic acid hydrochloride and 2(S)-[2(S)- (Pyrrolidinyl)methyloxy]-3-phenylpropionic acid hydro- chloride (2:1 respectively) 3(R,S),6(S)-2-Oxo-3-(phenylmethyl)- 1 -aza-4-oxabicyclo- [4.3.0]-nonane (8.569 g, 0.037 mol) was dissolved in 6N aq HCl (400 mL) and stirred at reflux under argon for 24 h. The reaction was cooled to ambient temperature, evaporated in vacuo, diluted with toluene, evaporated in vacuo, diluted with toluene, and evaporated in vacuo to give the title compound as an orange oil. H NMR (CD3OD, 400 MHz) δ 7.35-7.10 (m, 5H), 4.33-4.26 (m, IH), 3.84-3.53 (m, 3H), 3.30-3.09 (m, 3H), 3.05-2.96 (m, IH), 2.17-1.88 (m, 3H), 1.80-1.65 (m, IH). Step F: Preparation of 2(R)-[ 1 -(tert-Butoxycarbonyl)-2(S)-(pyrro- lidinyl)methyloxy]-3-phenylpropionic acid and 2(S)-[N- (tert-Butoxycarbonyl)-2(S)-(pyrrolidinyl)methyloxy]-3- phenylpropionic acid (2: 1 respectively) 2(R,S)-[2(S)-(Pyrrolidinyl)methyloxy]-3-phenylpropionic acid hydrochloride (9.48 g, 0.033 mol) was dissolved in H2O (70 mL) and neutralized with 1.0 N aq NaOH (approx. 40 mL). To this mixture was added a soln of Na2Cθ3 (7.304 g, 0.069 mol) in H2O (40 mL). The resulting mixture (pH = 11.5) was cooled to 0°C under argon; di-tert- butyl dicarbonate (8.2 mL, 0.036 mol) was added, followed by THF. The reaction was stirred at ambient temperature for 18 h, cooled to 0°C, acidified to pH = 3 with 10% aq citric acid, and extracted with EtOAc (2 x 250 mL). The organic extracts were washed in succession with saturated aq NaCl (250 mL), combined, dried (Na2Sθ4), and evaporated in vacuo to give the title compound as an orangish-brown oil. ^H NMR (CD3OD, 400 MHz) δ 7.29-7.17 (m, 5H), 4.05-3.99 (m, IH), 3.82-3.77 (m, IH), 3.69-3.59 (m, IH), 3.54-3.16 (m, 2H), 3.13-2.97 (m, 2H), 2.94- 2.85 (m, IH), 1.88-1.62 (m, 4H), 1.42 (s, 9H). Step G: Preparation of 2(S)-[N-(tert-Butoxycarbonyl)-2(S)- (py rrolidiny l)methy 1 oxy ] -3 -pheny lpropiony 1-methi onine methyl ester To a soln of 2(R,S)-[N-(tert-butoxycarbonyl)-2(S)- (pyrrolidinyl)methyloxy]-3-phenylpropionic acid (263.6 mg, 0.754 mmol) in DMF (8.0 mL) were added 3-hydroxy-l,2,3-benzotriazin- 4(3H)-one (HOOBT, 137 mg, 0.840 mmol), EDC (164 mg, 0.855 mmol), L-methionine methyl ester hydrochloride (176 mg, 0.881 mmol), and Et3N (0.35 mL, 2.5 mmol). The reaction was stirred under argon at ambient temperature for 18 h, diluted with EtOAc (70 mL), and washed with 10% aq citric acid (70 mL), saturated aq NaHC03 (40, 20 mL), and saturated aq NaCl (40 mL). The organic layer was dried (Na2Sθ4) and evaporated in vacuo. The diastereomeric cmde products were purified and separated by chromatography (silica gel, 1:19 to 1 :2 EtOAc/CH2Cl2) to give the title compound. *H NMR (CD3OD, 400 MHz) δ 7.35-7.17 (m, 5H), 4.63-4.55 (m, IH), 4.08-3.90 (m, 2H), 3.72 (s, 3H), 3.55-3.46 (m, 2H), 3.34-3.22 (m, IH), 3.09 (dd, J = 14, 4 Hz, IH), 2.91 (dd, J = 14, 7 Hz, IH), 2.38-2.20 (m, 2H), 2.10-2.00 (m, IH), 2.04 (br s, 3H), 1.97- 1.86 (m, 6H). 1.44 (s, 9H). Step H: Preparation of 2(S)-[(2(S)-(Pyrrolidinyl)methyloxy]-3- phenylpropionyl-methionine methyl ester hydrochloride 2(S)-[N-(tert-Butoxycarbonyl)-2(S)-(pyrrolidinyl)- methyloxy]-3-phenylpropionyl-methionine methyl ester (2.138 g, 4.322 mmol) was dissolved in EtOAc (80 mL). The mixture was cooled to 0°C and HCl gas was bubbled in until saturated. The mixture was stirred at ambient temperature for 1.25 h and evaporated in vacuo to give the title compound as a yellow foam which was used without further purification. iH NMR (CD3OD, 400 MHz) δ 7.35-7.20 (m, 5H), 4.67 (dd, J = 10, 5 Hz. IH), 4.21 (dd, J =8, 5 Hz, IH), 3.81-3.75 (m, 2H), 3.75 (s, 3H), 3.58 (q, J = 6 Hz, IH), 3.30-3.11 (m, 3H), 2.99 (dd, J = 14, 8 Hz, IH), 2.53- 2.36 (m, 2H), 2.19-2.10 (m, IH), 2.08 (s, 3H), 2.07-1.88 (m, 4H), 1.79- 1.68 (m, IH). Step I: Preparation of 2(S)-[[N-[2(R,S)-(tert-Butoxycarbonyl)- amino-3-triphenylmethylmercaptolpropyl]-2(S)-(pyrro- lidinyl)methy loxy] -3-phenylpropiony 1-methionine methyl ester - diastereomers A and B 2(S)-[(2(S)-(Pyrrolidinyl)methyloxy]-3-phenylpropionyl- methionine methyl ester hydrochloride (69.0 mg, 0.160 mmol) was dissolved in MeOH (1.40 mL). N-(t-Butoxycarbonyl)-S-triphenyl- methylcysteine aldehyde (95.6 mg, 0.214 mmol) was added followed by 4 A molecular sieves (0.26 g), KOAc (17.4 mg, 0.183 mmol) and 1.0 M sodium cyanoborohydride in THF (0.21 mL, 0.21 mmol). The mixture was stirred under argon at ambient temperature for 18 h and filtered. The filtrate was diluted with EtOAc (15 mL), and washed with saturated aq NaHCθ3 (15 mL) and saturated aq NaCl (15 mL). The organic layer was dried (Na2Sθ4) and evaporated in vacuo to give cmde material which was purified by chromatography (silica gel, 1 :4 EtOAc/CH2Cl2) to give the high Rf diastereomer (A) and the low Rf diastereomer (B) of the title compound. High Rf diastereomer (A): *H NMR (CD3OD, 400 MHz) δ 7.41 -7.35 (m, 6H), 7.30-7.16 (m, 14H), 4.59 (dd, J = 9, 5 Hz, IH), 3.96 (dd, J = 8, 4 Hz, IH), 3.75-3.54 (m, IH), 3.68 (s, 3H), 3.42-3.20 (m, 3H), 3.05 (dd, J = 13, 5 Hz, IH), 2.89 (dd, J = 14, 7 Hz, IH), 2.88-2.78 (m, IH), 2.68-2.54 (m, 2H), 2.40-2.14 (m, 5H), 2.10-1.96 (m, IH), 2.03 (s, 3H), 1.94-1.82 (m, IH), 1.82-1.70 (m, IH), 1.69-1.54 (m, 2H), 1.54-1.42 (m, IH), 1.45 (s, 9H). Low Rf diastereomer (B): J H NMR (CD3OD, 400 MHz) δ 7.43-7.36 (m, 6H), 7.33-7.15 (m, 14H), 4.59 (dd, J = 9, 5 Hz, IH), 3.99 (dd, J = 8, 4 Hz, IH), 3.74-3.60 (m, 2H), 3.65 (s, 3H), 3.47 (dd, J = 10, 5 Hz, IH), 3.14-2.70 ( m, 7H), 2.65-2.52 (m, 2H), 2.42-2.23 (m, 3H), 2.23-2.1 1 (m, IH), 2.03 (s, 3H), 1.98-1.85 ( m, IH), 1.82-1.55 (m, 3H), 1.45 (s, 9H). Step J: Preparation of 2(S)-[[N-[2(R,S)-(tert-Butoxy-carbonyl)- amino-3-triphenylmethylmercapto]propyl]-2(S)- (pyrrolidinyl)methyloxy]-3-phenylpropionyl-methionine - diastereomer A 2(S)-[[N-[2(R,S)-(tert-Butoxycarbonyl)-amino-3- triphenylmethylmercapto]propyl]-2(S)-(pyrrolidinyl)methyloxy]-3- phenylpropionyl-methionine methyl ester - diastereomer A (27.6 mg, 0.0334 mmol) was dissolved in MeOH (0.8 mL) under argon. 1.0 N aq LiOH (37 mL, 0.037 mmol) was added and the mixture was stirred at ambient temperature for 18 h. Additional 1.0 N aq LiOH (18 mL, 0.018 mmol) was added. After stirring for 3 h at ambient temperature, the reaction was evaporated in vacuo, diluted with MeOH (1 mL), neutralized with glacial acetic acid (1 drop), and evaporated in vacuo to give the title compound (cmde) which was used without further purification or characterization. Step K: Preparation of 2(S)-[[N-[2(R,S)-amino-3-mercapto]propyl]- 2(S)- (py rro lidiny l)methy loxy ] -3 -pheny lpropiony 1- methionine bis trifluoroacetate - diastereomer A 2(S)-[[N-[2(R,S)-(tert-Butoxycarbonyl)-amino-3- triphenylmethylmercapto]propyl]-2(S)-(pyrrolidinyl)methyloxy]-3- phenylpropionyl-methionine - diastereomer A (34.7 mg cmde, 0.0334 mmol), dissolved in CH2CI2 (1 mL) under argon was treated with TFA (0.5 mL) followed by triethylsilane (50 mL). The mixture was stirred at ambient temperature for 5 h. The mixture was evaporated in vacuo and the residue purified by preparative HPLC using a NovaPrep 5000 Semi Preparative HPLC System and a Waters PrepPak cartridge (47 x 300 mm, C18, 15 mm, 100 A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 100 mL/min to give the title compound. H NMR (CD3OD, 400 MHz) δ 7.32-7.20 (m, 5H), 4.61 (dd, J = 10, 5 Hz, IH), 4.25 (dd, J = 8, 5 Hz, IH), 3.83-3.74 (m, IH), 3.71 (dd, J = 12, 4 Hz, IH), 3.64 (dd, J = 12, 5 Hz, IH), 3.59-3.45 (m, 3H), 3.27-3.12 (m, 2H), 3.09-2.85 (m, 4H), 2.59- 2.39 (m, 2H), 2.23-1.90 (m, 5H), 2.09 (s, 3H), 1.87-1.75 (m, IH). FAB HRMS exact mass calc'd for 2H36N3O4S 2: 470.214726 (MH+); found 470.213392. Anal. Calc'd for C22H35N3O4S2-2.40 CF3CO2H-0.45 H2O: C, 42.84; H. 5.14; N, 5.59 Found: C, 42.82; H, 5.11 ; N, 5.79 EXAMPLE 4 Preparation of 2(S)-[[N-[2(R,S)-amino-3-mercapto]propyl]-2(S)- (pyrrolidinyl)methyloxy]-3-phenylpropionyl-methionine bis trifluoro- acetate - diastereomer B The title compound was prepared according to the methods of Example 3, Steps J and K, using the low Rf diastereomer (B) instead of the high Rf diastereomer (A) obtained from Step I. ^H NMR (CD3OD, 400 MHz) δ 7.34-7.21 (m, 5H), 4.60 (dd, J = 10, 5 Hz, IH), 4.22 (dd, J = 10, 5 Hz, IH), 3.78-3.66 (m, 2H), 3.64-3.56 (m, 2H), 3.50- 3.38 (m, 2H), 3.14 (dd, J = 14, 5 Hz, IH), 3.09-2.80 (m, 2H), 2.87 (br d, J = 6 Hz, 2H), 2.58-2.39 (m, 2H), 2.22-1.80 (m, 7H), 2.09 (s, 3H). FAB HRMS exact mass calc'd for C22H36N3O4S2: 470.214726 (MH+); found 470.214101. EXAMPLE 5 In vitro inhibition of ras fa esyl 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 57:3800 (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-/V'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM [3H]-farnesyl diphosphate ([3H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 μg/ml FPTase at 31 °C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol. Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB β-plate counter. The assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the [^H]-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 52:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1 % (w/v) polyethylene glycol 20,000, 10 μM ZnCl2 and 100 ΠM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 μl of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme. The compounds of the instant invention were tested for inhibitory activity against human FPTase by the assay described above and were found to have IC50 of < 10 μM. EXAMPLE 6 In vivo ras famesylation assay The cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21. T he 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 serum and 400 mCi[35S]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 mg/ml aρrotinen 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. 45:294-304, (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 7 In vivo growth inhibition assay To determine the biological consequences of FPTase inhibition, the effect of the compounds of the instant invention on the anchorage- independent growth of Ratl cells transformed with either a \-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. 10 Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 10^ 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 semm) over a bottom agarose layer (0.6%). Both layers contain 0.1 % methanol or an λ 5 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. 20 25 0

Claims: WHAT IS CLAIMED IS: 1. A compound which inhibits Ras farnesyl- transferase having the formula I: wherein: Rl is selected from: a) hydrogen, b) R 8 S(0)2-, R 8 C(0)-, (R8)2NC(0)- or R9θC(0)-, and c) C l -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R&0-, R 8 S(0) m -, R8C(0)NR8., CN, (R8)2N-C(NR8)-, R8C(0)-, R8θC(0)-, N3, -N(R8)2, or R90C(0)NR 8 -; R2a and R2b are independently selected from: a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by alkenyl, R8θ-, R8s(0)m-, R8C(0)NR8-, CN, (R8)2N-C(NR8)-, R8C(0)-, R8θC(0)-, N3, -N(R8)2, or R9θC(0)NR8-, c) aryl, heterocycle, cycloalkyl, alkenyl, R8θ-, R 8 S(0) m -, R8C(0)NR8-, CN, N02, (R 8 )2N- C(NR8 , R8C(0)-, R8θC(0)-, N3, -N(R 8 )2, or R9θC(0)NR8-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; 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 -C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R8)2, Nθ2, R 8 0-, R8S(0)m-, R 8 C(0)NR 8 -, CN, (R8)2N-C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, R9θC(0)NR 8 - and C1 -C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; or R3 and R4 are combined to form - (CH2)s - ; R^ a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R )2, Nθ2, R 8 0-, R 8 S(0) m -, R 8 C(0)NR 8 -, CN, (R )2N-C(NR 8 )-, R8C(0)-, R 8 OC(0)-, N3, -N(R8)2, R9θC(0)NR8. and C1-C2O alkyl, and d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; 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 8 )- ; X-Y is f) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C l -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R 8 is independently selected from hydrogen, Cl-C6 alkyl and aryl; R9 is independently selected from Cl-C6 alkyl and aryl; Zl and Z2 are independently H2 or O, provided that 7} is not O when X-Y is - C(0)N(R7a)_; m is 0, 1 or 2; s is 4 or 5; and t is 3, 4 or 5; or a pharmaceutically acceptable salt thereof. 2. A prodmg of a compound of Claim 1 having the formula II: wherein: Rl is selected from: a) hydrogen, b) R8S(0)2-, R8C(0)-, (R 8 )2NC(0)- or R9θC(0)-, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 0-, R 8 S(0) m -. R8C(0)NR8-, CN, (R 8 )2N-C(NR 8 )-, R 8 C(0)-, R OC(0)-, N3, -N(R 8 )2, or R9θC(0)NR 8 -; R2a and R2b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R 0-, R 8 S(0) m -, R8C(0)NR 8 -, CN, (R8) 2 N-C(NR8)-, R8C(0)-, R8θC(0)-, N3, -N(R8)2, or R9θC(0)NR8-, c) aryl, heterocycle, cycloalkyl, alkenyl, R8θ-, R 8 S(0) m -, R8C(0)NR8-, CN, Nθ2, (R 8 )2N- C(NR8)-, R8C(0)-, R8θC(0)-, N3, -N(R 8 )2, or R9θC(0)NR8. 5 and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; 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 unsubstituted C1 -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R 8 )2, N02, R 8 0-, R 8 S(0)πr, R 8 C(0)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, R9θC(0)NR 8 - and C1 -C2O alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl;or R3 and R4 are combined to form - (CH2)s - ' R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R 8 )2, N02, R 8 0-, R 8 S(0)m-, R 8 C(0)NR 8 -, CN, (R )2N-C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, R 9 OC(0)NR 8 - and C1-C2O alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; 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 8 )- ; R6 IS a) substituted or unsubstituted C1-C8 alkyl, wherein the substituent on the alkyl is selected from: D aryl, 4) -OR 8 , or X-Y is R 7a a) - N Y O V H ■ y or H f) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) Cl -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R is independently selected from hydrogen, Cl-C6 alkyl and aryl; Q R y is independently selected from Cl-C6 alkyl and aryl; RlO is independently selected from hydrogen and C1 -C6 alkyl; R! 1 is independently selected from C1-C6 alkyl; Zl and Z2 are independently H2 or O, provided that Z^ is not O when X-Y is - C(0)N(R7a)- ; m is 0, 1 or 2; s is 4 or 5; and t is 3, 4 or 5; or a pharmaceutically acceptable salt thereof. 3. A compound which inhibits Ras farnesyl- transferase having the formula III: wherein: Rl is selected from: a) hydrogen, b) R 8 S(0)2-, R8C(0)-, (R8)2NC(0)- or R9θC(0)-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R θ-, R8S(0) m -, R8C(0)NR8-, CN, (R8)2N-C(NR 8 )-, R C(0)-, R OC(0)-, N3, -N(R 8 )2, or R9θC(0)NR 8 -; R2a and R2b are independently selected from: a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by alkenyl, R 8 0-, R 8 S(0)m- . R 8 C(0)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R8C(0)-, R8θC(0)-, N3, -N(R8)2, or R9θC(0)NR8-, c) aryl, heterocycle, cycloalkyl, alkenyl, R 8 0-, R 8 S(0) m -, R8C(0)NR8-, CN, N02, (R 8 )2N- C(NR 8 )-, R C(0)-, R 8 OC(0)-, N3, -N(R 8 ) 2 , or R9θC(0)NR 8 -, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; 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 unsubstituted C1-C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R 8 )2, N02, R 8 0-, R 8 S(0) m -, R C(0)NR -, CN, (R8)2N-C(NR8)-, R8C(0)-, R90C(0)NR8. an C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; or R4 are combined to form - (CH2)s X-Y is f) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R 8 is independently selected from hydrogen, Cl-C6 alkyl and aryl; R9 is independently selected from C1-C6 alkyl and aryl; 7\ and Z2 are independently H2 or O, provided that Tλ is not O when X-Y is - C(0)N(R7a)- ; m is 0, 1 or 2; q is 0, 1 or 2; s is 4 or 5; and t is 3, 4 or 5; or a pharmaceutically acceptable salt thereof. A prodmg of a compound of Claim 3 of the formula IV: IV wherein: R is selected from: a) hydrogen, b) R S(0)2-, R 8 C(0)-, (R 8 )2NC(0)- or R9θC(0)-, and c) Cl -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 8 0-, R 8 S(0)m-, R 8 C(0)NR 8 -, CN, (R )2N-C(NR 8 )-, R C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, or R9θC(0)NR 8 -; R2a and R2b are independently selected from: a) hydrogen, b) Cl -C6 alkyl unsubstituted or substituted by alkenyl, R 8 0-, R S(0)m- . R 8 C(0)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, or R9θC(0)NR 8 -, c) aryl, heterocycle, cycloalkyl, alkenyl, R 8 0-, R 8 S(0) m -, R 8 C(0)NR 8 -, CN, N02, (R 8 )2N- C(NR8)-, R8C(0)-, R 8 OC(0)-, N3, -N(R )2, or R90C(0)NR 8 -, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; 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 unsubstituted C1-C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R 8 )2, N02, R 8 0-, R 8 S(0) m -, R C(0)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R8C(0)-, R8θC(0)-, N3, -N(R 8 )2, R9θC(0)NR 8 - and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; or e combined to form - (CH2)s - ; X-Y is R 7a o R 7b f) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R 8 is independently selected from hydrogen, Cl-C6 alkyl and aryl; R9 is independently selected from -C6 alkyl and aryl; Zl and Z2 are independently H2 or O, provided that Zl is not O when X-Y is - C(0)N(R7a)_; m is 0, 1 or 2; q is 0, 1 or 2; s is 4 or 5; and t is 3, 4 or 5; or a pharmaceutically acceptable salt thereof. 5. The compound according to Claim 1 which has the formula I: wherein: Rl is selected from: a) hydrogen, b) R 8 S(0)2-, R8C(0)-, (R 8 )2NC(0)- or R9θC(0)-, and c) Cl -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 8 0-, R 8 S(0)m-, R 8 C(0)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R8)2, or R90C(0)NR 8 -; R is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine, norleucine, valine and norvaline; and b) substituted or unsubstituted C l -C 10 alkyl , C2-C 10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, R O-, R8S(0)m-, R 8 C(0)NR 8 -, CN, (R 8 )2N- C(NR8)_. R8C(0)-, R8θC(0)-, N3, -N(R 8 )2, R9θC(0)NR 8 - and C1-C20 alkyl, and c) C1-C alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; and R2b is selected from hydrogen and C1-C6 alkyl; 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, R 8 0-, R 8 S(0) m -, R8C(0)NR8., CN, (R 8 )2N- C(NR8)-, R8c(0)-, R8θC(0)-, N3, -N(R8)2, R9θC(0)NR8- and -C20 alkyl, and d) C 1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 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 0-, R 8 S(0)m-, R 8 C(0)NR 8 -, CN, (R 8 )2N- C(NR 8 )-, R C(0 , R 8 OC(0)-, N3, -N(R 8 )2, R9θC(0)NR 8 - and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R5b is selected from: a) hydrogen, and b) Cl -C3 alkyl; X-Y is o e) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle 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 heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R 8 is independently selected from hydrogen, C1-C6 alkyl and aryl; R9 is independently selected from C1-C6 alkyl and aryl; Z and Z are independently H2 or O, provided that 7-- is not O when X-Y is - C(0)N(R7a)_; m is 0, 1 or 2; and t is 3, 4 or 5; or a pharmaceutically acceptable salt thereof. 6. The compound according to Claim 2 which has the formula I: wherein: Rl is selected from: a) hydrogen, b) R S(0)2-, R 8 C(0)-, (R 8 )2NC(0)- or R9θC(0)-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 8 0-, CN, R8S(0) m -, R 8 C(0)NR 8 -, (R 8 )2N-C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R )2, or R90C(0)NR 8 -; R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine, norleucine, valine and norvaline; b) substituted or unsubstituted -CiO alkyl, C2-C1O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, Nθ2, R 8 0-, R S(0)m-, R 8 C(0)NR8-, CN, (R8)2N- C(NR8)-, R8C(0)-, R8θC(0)-, N3, -N(R8)2, R9θC(0)NR8- and C1-C20 alkyl, and c) C 1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R2b is selected from hydrogen and C1 -C6 alkyl; 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, Nθ2, R 8 0-, R 8 S(0)m-, R 8 C(0)NR 8 -, CN, (R 8 )2N- C(NR 8 )-, R 8 C(0)-, R8θC(0)-, N3, -N(R8)2, R9θC(0)NR8- and C1-C2O alkyl, and d) Cl -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 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 8 0-, R 8 S(0)m-. R 8 C(0)NR 8 -, CN, (R 8 )2N- C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, R9θC(0)NR 8 - and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R5b is selected from: a) hydrogen, and b) Cl-C3 alkyl; X-Y is c) Oj, e) -CH 2 -CH 2 - ; R6 IS a) substituted or unsubstituted C1-C8 alkyl, wherein the substituent on the alkyl is selected from: D aryl, 4) -OR 8 , or R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle 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 heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R 8 is independently selected from hydrogen, C1-C6 alkyl and aryl; R is independently selected from C1-C6 alkyl and aryl; R 10 is independently selected from hydrogen and Cl -C6 alkyl; R 1 1 is 1,1-dimethylethyl; Zl and Z2 are independently H2 or O, provided that 7\ is not O when X-Y is - C(0)N(R7a). ; m is 0, 1 or 2; and t is 3, 4 or 5; or a pharmaceutically acceptable salt thereof. 7. The compound according to Claim 3 which has the formula I: H 2 OH wherein: Rl is selected from: a) hydrogen, b) R 8 S(0)2-, R 8 C(0)-, (R 8 )2NC(0)- or R9θC(0)-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 8 0-, R 8 S(0) m -, R 8 C(0)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, or R9θC(0)NR 8 -; R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine, norleucine, valine and norvaline; b) substituted or unsubstituted Cl -Clfj alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 8 0-, R 8 S(0)m-, R 8 C(0)NR 8 -, CN, (R8)2N- C(NR8)-, R8C(0)-, R8θC(0)-, N3, -N(R8)2, R9θC(0)NR8-, C1-C20 alkyl, and c) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C 10 cycloalkyl; R2b is selected from hydrogen and C1 -C6 alkyl; 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, R 8 0-, R8S(0)m-, R S C(0)NR8-, CN, (R 8 )2N- C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, R9θC(0)NR 8 - and Cl-Qo alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; X-Y is R 7a Y o e) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) Cl -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle 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 heterocycle, d) unsubstituted or substituted cycloalkyl, e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R 8 is independently selected from hydrogen, Cl-C6 alkyl and aryl; R9 is independently selected from C1-C6 alkyl and aryl; Zl and Z2 are independently H2 or O, provided that Zl is not O when X-Y is - C(0)N(R7a). ; m is 0, 1 or 2; q is O, 1 or 2; and t is 3, 4 or 5; or a pharmaceutically acceptable salt thereof. The compound according to Claim 4 which has the formula I: IV wherein: Rl is selected from: a) hydrogen, b) R 8 S(0)2-, R 8 C(0)-, (R 8 )2NC(0)- or R9θC(0)-, and c) C 1 -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 8 0-, R 8 S(0)m-, R 8 C(0)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R C(0)-, R OC(0)-, N3, -N(R 8 )2, or R9θC(0)NR 8 -; R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine, norleucine, valine and norvaline; and b) substituted or unsubstituted C l -C 10 alkyl, C2-C 10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 8 0-, R 8 S(0)m-, R 8 C(0)NR 8 -, CN, (R )2N- C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, R9θC(0)NR 8 - and C1-C20 alkyl, and c) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R2b is selected from hydrogen and Cl-C6 alkyl; 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, Nθ2, R 8 0-, R 8 S(0)m-, R 8 C(0)NR 8 -, CN, (R 8 )2N- C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, R9θC(0)NR 8 - and C1 -C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; X-Y is R 7a a) o e) -CH 2 -CH 2 - ; R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle 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 heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R 8 is independently selected from hydrogen, -C6 alkyl and aryl; R9 is independently selected from C1 -C6 alkyl and aryl; Zl and Z2 are independently H2 or O, provided that Zl is not O when X-Y is - C(0)N(R7a)_; m is 0, 1 or 2; q is 0, 1 or 2; and t is 3, 4 or 5; or a pharmaceutically acceptable salt thereof. 9. A compound which inhibits farnesyl-protein transferase which is: N-[ l-(2(R)-amino-3-mercaptopropyl)-2(S)-pyrrolidinylmethyl]- N- ( 1 -naphthylmethyl)glycyl-methionine N-[l-(2(R)-amino-3-mercaptopropyl)-2(S)-pyrrolidinylmethyl]- N-(l naphthylmethyl)glycyl-methionine methyl ester 2(S)-[[ 1 -[2(R)-Amino-3-mercapto]propyl]-2(S)-(pyrrolidinyl)- methyloxy]-3-phenylpropionyl-methionine; or SCH. 2(S)-[[ 1 -[2(S)- Amino-3-mercapto]propyl]-2(S)-(pyrrolidinyl)- methy loxy ] -3 -pheny lpropiony 1 -methionine ; or a pharmaceutically acceptable salt thereof. 10. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 1. 11. A phaimaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 2. 12. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 3. 13. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 4. 14. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 9. 15. A method for inhibiting famesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 10. 16. A method for inhibiting famesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 11. 17. A method for inhibiting famesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 12. 18. A method for inhibiting famesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 13. 19. A method for inhibiting famesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 14. 20. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 10. 21. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 11. 22. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12. 23. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 13. 24. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 14.

Inventors: ANTHONY NEVILLE J, DESOLMS S JANE, GRAHAM SAMUEL L, ANTHONY, NEVILLE, J., DESOLMS, S., JANE, GRAHAM, SAMUEL, L.
Applicants: ANTHONY NEVILLE J, DESOLMS S JANE, GRAHAM SAMUEL L, MERCK & CO INC, ANTHONY, NEVILLE, J., DESOLMS, S., JANE, GRAHAM, SAMUEL, L., MERCK & CO., INC.
Application year: 1995
Main classification: A61K31
IPC codes: A61K31, A61K38, A61P35, A61P43, C07D207, C07K5, C12N9