INHIBITORS OF PRENYL-PROTEIN TRANSFERASE

Abstract: The present invention comprises piperazine-containing compounds which inhibit the prenyl-protein transferases: farnesyl-protein transferase and geranylgeranyl-protein transferase type I. Such therapeutic compounds are useful in the treatment of cancer.

Description: TITLE OF THE INVENTION INHIBITORS OF PRENYL-PROTEIN TRANSFERASE BACKGROUND OF THE INVENTION The present invention relates to certain compounds that are useful for the inhibition of prenyl-protein transferases and the treatment of cancer. In particular, the invention relates to prenyl-protein transferase inhibitors which are efficacious in vivo as inhibitors of geranylgeranyl-protein transferase type I (GGTase-I) and that inhibit the cellular processing of both the H-Ras protein and the K4B-Ras protein. Prenylation of proteins by prenyl-protein transferases represents a class of post-translational modification (Glomset, J. A., Gelb, M. H., and Farnsworth, C. C. (1990). Trends Biochem. Sci. 15, 139-142; Maltese, W. A. (1990) FASEB J. 4, 3319- 3328). This modification typically is required for the membrane localization and function of these proteins Prenylated proteins share characteristic C-terminal sequences including CAAX (C, Cys; A, an aliphatic ammo acid; X, another ammo acid), XXCC, or XCXC. Three post-translational processing steps have been described for proteins having a C-terminal CAAX sequence: addition of either a 15 carbon (farnesyl) or 20 carbon (geranylgeranyl) isoprenoid to the Cys residue, proteolytic cleavage of the last 3 ammo acids, and methylation of the new C-terminal carboxylate (Cox, A. D. and Der, C. J. (1992a). Cπtical Rev. Oncogenesis 3:365-400; Newman, C. M. H. and Magee, A. I (1993). Biochim. Biophys Acta 1155:79-96). Some proteins may also have a fourth modification: palmitoylation of one or two Cys residues N-termmal to the farnesylated Cys. While some mammalian cell proteins terminating in XCXC are carboxymethylated, it is not clear whether carboxy methylation follows prenylation of proteins terminating with a XXCC motif (Clarke, S. (1992). Annu. Rev. Biochem. 61, 355-386). For all of the prenylated proteins, addition of the isoprenoid is the first step and is required for the subsequent steps (Cox, A. D. and Der, C. J. (1992a). Cπtical Rev. Oncogenesis 3:365-400; Cox, A. D. and Der, C. J. (1992b) Current Opinion Cell Biol. 4:1008-1016) Three enzymes have been descπbed that catalyze protein prenylation: farnesyl-protem transferase (FPTase), geranylgeranyl-protem transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase). These enzymes are found in both yeast and mammalian cells (Clarke, 1992; Schafer, W. R. and R e, J. (1992) Annu. Rev. Genet 30:209-237). Each of these enzymes selectively uses farnesyl diphosphate or geranyl-geranyl diphosphate as the isoprenoid donor and selectively recognizes the protein substrate. FPTase farnesylates CaaX-containing proteins that end with Ser, Met, Cys, Gin or Ala. For FPTase, CaaX tetrapeptides comprise the minimum region required for interaction of the protein substrate with the enzyme. The enzymological characterization of these three enzymes has demonstrated that it is possible to selectively inhibit one with little inhibitory effect on the others (Moores, S. L., Schaber, M. D., Mosser, S. D., Rands, E., OΗara, M. B., Garsky, V. M., Marshall, M. S., Pompliano, D. L., and Gibbs, J. B., J. Biol. Chem., 266: 17438 (1991), U.S. Pat. No. 5,470,832). The prenylation reactions have been shown genetically to be essential for the function of a variety of proteins (Clarke, 1992; Cox and Der, 1992a; Gibbs, J. B. (1991). Cell 65: 1-4; Newman and Magee, 1993; Schafer and Rine, 1992). This requirement often is demonstrated by mutating the CaaX Cys acceptors so that the proteins can no longer be prenylated. The resulting proteins are devoid of their central biological activity. These studies provide a genetic "proof of principle" indicating that inhibitors of prenylation can alter the physiological responses regulated by prenylated proteins. The Ras protein is part of a signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP. Upon growth factor receptor activation, Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M. Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). Activation of Ras leads to activation of multiple intracellular signal transduction pathways, including the MAP Kinase pathway and the Rho/Rac pathway (Joneson et al., Science 271:810-812). Mutated ras genes are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal. The Ras protein is one of several proteins that are known to undergo post-translational modification. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaber et al., J. Biol. Chem., 265: 14701-14704 (1990); Schafer et al, Science, 249: 1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA, 87:7541-7545 (1990)). Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-Aaa^- Aaa^-Xaa" box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)). Depending on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386 (1992); W.R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237 (1992)). Direct inhibition of farnesyl-protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis. Other famesylated proteins include the Ras-related GTP-binding proteins such as RhoB, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also famesylated. James, et al., have also suggested that there are famesylated proteins of unknown structure and function in addition to those listed above. Inhibitors of farnesyl-protein transferase (FPTase) have been described in two general classes. The first class includes analogs of farnesyl diphosphate (FPP), while the second is related to protein substrates (e.g., Ras) for the enzyme. The peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141,851, University of Texas; N.E. Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)). Mammalian cells express four types of Ras proteins (H-, N-, K4A-, and K4B-Ras) among which K4B-Ras is the most frequently mutated form of Ras in human cancers. The genes that encode these proteins are abbreviated H-ras, N-ras , K4A-ras and K4B-ras respectively. H-ras is an abbreviation for Harvey-ras. K4A-ras and K4B-ras are abbreviations for the Kirsten splice vaπants of ras that contain the 4A and 4B exons, respectively. Inhibition of farnesyl-protein transferase has been shown to block the growth of H-ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the H-Ras oncoprotein mtracellularly (N.E. Kohl et al., Science, 260:1934-1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of H-ras-dependent tumors in nude mice (N.E. Kohl et al., Proc. Natl. Acad Sci U.S.A., 91:9141-9145 (1994) and induces regression of mammary and salivary carcinomas in H-ras transgenic mice (N E Kohl et al., Nature Medicine, 1:792-797 (1995). Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck & Co., Rahway, NJ) and compactm (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. It has been disclosed that the lysme-nch region and terminal CVIM sequence of the C-terminus of K-RasB confer resistance to inhibition of the cellular processing of that protein by certain selective FPTase inhibitors. James, et al., J. Biol. Chem 270, 6221 (1995) Those FPTase inhibitors were effective in inhibiting the processing of H-Ras proteins. James et al., suggested that prenylation of the K4B-Ras protein by GGTase-I contπbuted to the resistance to the selective FPTase inhibitors. Selective inhibitors of GGTase-I have been previously disclosed (see for example U.S. Pat. No. 5,470,832, issued November 28, 1995). Other compounds have been descπbed as selective inhibitors of GGTase-I (see for example PCT Publication No. WO 96/21456). Combinations of a selective inhibitor of FPTase and a selective inhibitor of GGTase-I have been disclosed as useful in the treatment of cancer (PCT Publication No WO 97/34664). Several groups of scientists have recently disclosed compounds that are non-selective FPTase/GGTase-I inhibitors. (Nagasu et al. Cancer Research, 55 5310-5314 (1995); PCT application WO 95/25086). It is the object of the instant invention to provide a prenyl-prote transferase inhibitor which is efficacious in vivo as an inhibitor of geranylgeranyl- protein transferase type I (GGTase-I), also known as CAAX GGTase It is also the object of the present invention to provide a compound which inhibits the cellular processing of both the H-Ras protein and the K4B-Ras protein It is also the object of the present invention to provide a compound which is efficacious in vivo as an inhibitor of the growth of cancer cells charactenzed by a mutated K4B-Ras protein. A composition which compπses such an inhibitor compound is used in the present invention to treat cancer SUMMARY OF THE INVENTION The present invention compπses piperazine-containing compounds which inhibit prenyl-protem transferases Further contained this invention are chemotherapeutic compositions containing these prenyl transferase inhibitors and methods for their production. The compounds of this invention are illustrated by the formula A DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention are useful in the inhibition of prenyl- protem transferases and the prenylation of the oncogene protein Ras In a first embodiment of this invention, the inhibitors of prenyl-protem transferases are illustrated by the formula A A wherein: Rl a and Rl" are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 O-, R u S(0) m -, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NRl°)-, c) unsubstituted or substituted Cj-Cβ alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rl°O-, R^SIO , R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NR 10 )-, CN, R 10 C(O)-, N3, -N(R 10 )2, and RHOC^-NR 10 -; R2 and R^ are independently selected from: H; unsubstituted or substituted Ci-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, wherein the substituted group is substituted with one or more of: l)aryl or heterocycle, unsubstituted or substituted with: a) Cl-4 alkyl, d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-Ci-4 alkyl, h) SR6a S(O)R 6a , SO2R 6a , 2) C3-6 cycloalkyl, 3) OR 6 , 4) SR 6a , S(O)R 6a , or SO2R 6a , 5) — NR 6 R 7 9) — O^ ^ OR 6 T O 11) — S0 2 -NR 6 R 7 14) 0 15) N 3 , 16) F, or 17) perfluoro-Cι. 4 -alkyl; or R2 and R3 are attached to the same C atom and are combined to form -(CH2)u- wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , -NC(O)-, and -N(COR 10 )- ; R4 is selected from H and CH3; and any two of R^, R3 and R4 are optionally attached to the same carbon atom; R 6 , R7 and R^ a are independently selected from: H; Ci-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Ci-4 alkoxy, b) aryl or heterocycle, c) halogen, 1 f) — S0 2 R 11 , or g) N(RlO) 2; or R 6 and R^ may be joined in a ring; R7 and R^ a may be joined in a ring; R°a is selected from: Ci-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) Ci-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, R 11 e) o f) — S0 2 R 11 , or g) N(RlO) 2 ; R8 is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, Rl lS(O) m -, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NR 10 )-, CN, NO2, R 10 C(O)-, N3, -N(R 10 )2, or RHOC^NR 10 -, and c) C1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R 1 ^(OJm-, R 10 C(O)NH-, (R 10 )2NC(O)-, R 10 2N-C(NR 10 )-, CN, R 10 C(O)-, N3, -N(R 10 )2, or R 10 OC(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R u S(O) m -, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NR 10 )-, CN, NO2, R 10 C(O)-, N3, -N(R 10 )2, or RHoC^NR 10 -, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 O-, Rl lS(O) m -, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NR 10 )-, CN, R 10 C(O)-, N3, -N(R 10 )2, or R 1 Ϊ OC^NR 10 -; RlO is independently selected from hydrogen, C1-C alkyl, benzyl and aryl; RU is independently selected from C1-C6 alkyl and aryl; A* and A 2 are independently selected from: a bond, -CH=CH-, -C-≡C-, -C(O)-, -C(O)NR 10 -, -NR 10 C(O)-, O, -N(R 10 )-, -S(O)2N(R 10 )-, -N(R 10 )S(O)2-, or S(O) m ; A 3 is selected from: -C(O)-, -C(O)NR 10 -, -C(O)(CR l a )2-O-, -C(O)O- and S(O) m ; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A* is S(O) m and V is not hydrogen if h\ is a bond, n is 0 and /A is S(O) m ; W is a heterocycle; Z is unsubstituted or substituted C5-C10 alkyl, wherein the substituted C5-C10 alkyl is substituted with one or two moieties selected from the following: a) Ci-4 alkoxy, b) NR 6 R 7 , c) C3-6 cycloalkyl, d) -NR 6 C(O)R 7 , e) -OR 10 , f) -S(O) m R 6a , g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; q is 1 or 2; r is 0 to 5, provided that r is 0 when V is hydrogen; s is O or l; t is O or 1; u is 4 or 5; and v is 0, 1, 2 or 3; or the pharmaceutically acceptable salts thereof. In a preferred embodiment of this invention, the inhibitors of prenyl- protein transferase are illustrated by the formula A: wherein: Rl a is independently selected from: hydrogen or C1-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, Rl^O-, -N(RlO)2 or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R^O- and -N(R10)2; R and R^ are independently selected from H and CH3; \ .NR 6 R 7 R2 is H; Y O ; or C 1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 , 4) SR 6a , SO2R 6a , or and any two of R R } R4 a nd R^ are optionally attached to the same carbon atom; R 6 and R 7 are independently selected from: H; Ci-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) Ci-4 alkoxy, b) halogen, or c) aryl or heterocycle; R a is selected from: Ci-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) Ci -4 alkoxy, b) halogen, or c) aryl or heterocycle; R8 is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 10 O-, R 10 C(O)NRl°-, CN, NO2, (R 10 )2N-C(NR 10 )-, R 10 C(O)-, -N(R 10 )2, or RHOC^NR 10 -, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 O-, R 10 C(O)NR 10 -, (R 1 0) 2 N-C(NR 10 )-, R 10 C(O)-, -N(R 10 )2, or RH0C(0)NR 10 -; R is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 10 O-, R u S(0) m -, R 10 C(O)NR 10 -, CN, NO2, (R 10 )2N-C(NR 10 )-, R 10 C(O)-, -N(R!0)2, or RHoC(O)NR 10 -, and c) C1-C6 alkyl unsubstituted or substituted by C]-C6 perfluoroalkyl, F, Cl, R 10 O-, Rl lS(O) m -, R 10 C(O)NR 10 -, CN, (R 10 )2N-C(NR 10 )-, RiOC(O)-, R1° is independently selected from hydrogen, C]-C6 alkyl, benzyl and aryl; RI 1 is independently selected from C1-C6 alkyl and aryl, A 1 and A 2 are independently selected from: a bond, -CH=CH-, -C≡C-, -C(O)-, -C(O)NR 10 -, O, -N(R 10 )-, or S(O) m ; A 3 is selected from. -C(O)-, -C(O)NR 10 -, -C(O)(CR l a )2-O-, -C(O)O- and S(O) m> V is selected from: a) hydrogen, b) heterocycle selected from pyrro dmyl, lmidazolyl, pyπdinyl, thiazolyl, pyπdonyl, 2-oxopιpeπdιnyl, indolyl, qumo nyl, lsoqumohnyl, and thienyl, c) aryl, d) C1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1* is S(O) m and V is not hydrogen if A 1" is a bond, n is 0 and A 2 is S(O) m ; W is a heterocycle selected from pyrrohdinyl, lmidazolyl, pyπdinyl, thiazolyl, pyπdonyl, 2-oxopιpeπdmyl, mdolyl, qumohnyl, or isoquinolinyl, Z is unsubstituted or substituted C5-C10 alkyl, wherein the substituted C5-C10 alkyl is substituted with one or two moieties selected from the following: a) Cι_4 alkoxy, b) NR 6 R7, c) C3-6 cycloalkyl, d) -NR 6 C(O)R 7 , e) -ORlO, f) -S(O) m R 6a , g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; q is 1 or 2; r is 0 to 5, provided that r is 0 when V is hydrogen; s is O or 1; t is 0 or 1 ; and v is 0, 1, 2 or 3; or the pharmaceutically acceptable salts thereof. A preferred embodiment of the compounds of this invention are illustrated by the formula B: wherein: Rla and R' D are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 O-, -N(R 10 )2 or C2-C6 alkenyl, c) Ci-Cβ alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 O~, or -N(R 10 )2; R3 is selected from H and CH3; \ .NR 6 R 7 R 2 is selected from H; T O ; or Cι_5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 , 4) SR 6a , SO2R 6a , or and R 2 and R3 are optionally attached to the same carbon atom; R 6 and R 7 are independently selected from: H; Cι_4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) Ci-4 alkoxy, b) halogen, or c) aryl or heterocycle; R 6a is selected from: Ci-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) Ci-4 alkoxy, b) halogen, or c) aryl or heterocycle; R° is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C]-C6 perfluoroalkyl, F, Cl, R 10 O-, R 10 C(O)NR 10 -, CN, NO2, (R 10 )2N-C(NR 10 )-, RlOc(O)-, -N(R 10 )2, or RHOC^NR 10 -, and c) C1-C6 alkyl substituted by -C6 perfluoroalkyl, R 10 O-, R 10 C(O)NR 10 - (R 10 )2N-C(NR 10 )-, R 10 C(O)-, -N(R 10 )2, or Rl lθC(O)NR 10 -; R is hydrogen or methyl; R 0 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; R 11 is independently selected from C1-C6 alkyl and aryl; A 1 and A 2 are independently selected from: a bond, -CH=CH-, -C=C-, -C(O)-, -C(O)NR 10 -, O, -N(R 10 )-, or S(O) m ; A 3 is selected from: -C(O)-, -C(O)NR 10 -, -C(O)(CR la )2-O-, -C(O)O- or S(O) m ; V is selected from: a) hydrogen, b) heterocycle selected from pyπolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, ande) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ; Z is unsubstituted or substituted C5-C10 alkyl, wherein the substituted C5-C10 alkyl is substituted with one or two moieties selected from the following: a) Ci-4 alkoxy, b) NR R 7 , c) C3-6 cycloalkyl, d) -NR 6 C(O)R 7 , e) -OR 10 , f) -S(O) m R 6a , g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; and v is 0, 1, 2 or 3; or the pharmaceutically acceptable salts thereof. Another preferred embodiment of the compounds of this invention are illustrated by the formula C: wherein: R!a and R l rj are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 1 O-, -N(R 10 )2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 O-, or -N(R 10 )2; R 3 is selected from H and CH3; \ .NR 6 R 7 R 2 is selected from H; Y O or Ci-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 , 4) SR 6a , SO2R 6a or and R 2 and R 3 are optionally attached to the same carbon atom; R 6 and R 7 are independently selected from: H; C]-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) Ci-4 alkoxy, b) halogen, or c) aryl or heterocycle; R 6a is selected from: C1.4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) Cj-4 alkoxy, b) halogen, or c) aryl or heterocycle; R^ is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 . -C6 perfluoroalkyl, F, Cl, R 10 O-, R 10 C(O)NR 10 -, CN, NO2, (R 10 )2N-C(NR 10 )-, R 10 C(O)-, -N(R 10 )2, or R^OC^NR 10 -, and c) C1-C6 alkyl substituted by -C6 perfluoroalkyl, R 10 O-, R 10 C(O)NR 10 -, (R 10 )2N-C(NR 10 )-, R 10 C(O)-, -N(R 10 )2, or R n OC(O)NR 10 -; R i s hydrogen or methyl; R 10 is independently selected from hydrogen, Ci-C alkyl, benzyl and aryl; R 1 i is independently selected from C1-C6 alkyl and aryl; A 1 and A 2 are independently selected from: a bond, -CH=CH-, -C≡C-, -C(O)-, -C(O)NR 10 -, O, -N(R 10 )-, or S(O) m ; A 3 is selected from: -C(O)-, -C(O)NR 10 -, -C(O)(CR l a )2-O-, -C(O)O- or S(O) m ; V is selected from a) hydrogen, b) heterocycle selected from pyrrolidinyl, lmidazolyl, pyπdinyl, thiazolyl, pyridonyl, 2-oxopιpeπdmyl, mdolyl, qumohnyl, isoquinolmyl, and thienyl, c) aryl, d) C1 -C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, and provided that V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m , Z is unsubstituted or substituted C5-C10 alkyl, wherein the substituted C -C10 alkyl is substituted with one or two moieties selected from the following a) Ci-4 alkoxy, b) NR 6 R 7 , c) C3-6 cycloalkyl, d) -NR C(O)R 7 , e) -OR 10 , f) -S(O) m R a , g) halogen, or h) perfluoroalkyl, m is 0, 1 or 2, n is 0, 1, 2, 3 or 4, p is 2, 3 or 4, r is 0 to 5, provided that r is 0 when V is hydrogen, and or the pharmaceutically acceptable salts thereof A further embodiment of the compounds of this invention is illustrated by the formula D: wherein: R l a and R * 3 are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 0 O-, -N(R 1 )2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 O-, or -N(R 10 )2; R 3 IS selected from H and CH3; \ .NR 6 R 7 R 2 is selected from H, O or Cl .5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 , 4) SR 6a , SO2R 6a , or and R 2 and R are optionally attached to the same carbon atom; R 6 and R 7 are independently selected from: H; Cι_4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with, a) Ci-4 alkoxy, b) halogen, or c) aryl or heterocycle; R 6a selected from: Ci-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) Ci-4 alkoxy, b) halogen, or c) aryl or heterocycle; R° is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RlOo-, R 10 C(O)NR 10 -, CN, NO2, (R 10 )2N-C(NR 10 )-, R 10 C(O)-, -N(R 10 )2, or R 1 1 OC(O)NR 10 -, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 O-, R 10 C(O)NR 10 -, (R 10 )2N-C(NR 10 )-, R 10 C(O)-, -N(R 10 )2, or RHOC(O)NR 10 -; R is hydrogen or methyl; R 0 is independently selected from hydrogen, Ci-Cό alkyl, benzyl and aryl; R ! is independently selected from Ci -C6 alkyl and aryl; A 1 is selected from: a bond, -CH=CH-, -C≡C-, -C(O)-, -C(0)NR 10 -, O, -N(R 10 )-, or S(O) m ; A 3 is selected from: -C(O)-, -C(O)NR 10 - or -C(O)O-; V is selected from: a) heterocycle selected from pyridinyl and quinolinyl, and b) aryl; Z is unsubstituted or substituted C5-C10 alkyl, wherein the substituted C5-C10 alkyl is substituted with one or two moieties selected from the following: a) Cι_4 alkoxy, b) NR 6 R 7 , c) C3-6 cycloalkyl, d) -NR 6 C(O)R 7 , e) -OR 10 , f) -S(O) m R 6 , g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; or the pharmaceutically acceptable salts thereof. Another embodiment of the compounds of this invention is illustrated by the formula E: wherein: R l a and R 1 D are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 O-, -N(R 1 )2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 O-, or -N(R 10 )2; R3 is selected from H and CH3; \ .NR 6 R 7 R 2 is selected from H; Y O ; or C1.5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 , 4) SR 6a , SO2R 6a , or and R 2 and R3 are optionally attached to the same carbon atom; R 6 and R 7 are independently selected from: H; Ci-4 alkyl, C3_6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) Ci-4 alkoxy, b) halogen, or c) aryl or heterocycle; R 6a is selected from: C1-.4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) Ci-4 alkoxy, b) halogen, or c) aryl or heterocycle; R8 is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 10 O-, R 10 C(O)NR 10 -, CN, NO2, (R 10 )2N-C(NR 10 )-, R 10 C(O)-, -N(R 1 )2, or R 1 iOC^NR 10 -, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 O-, R 10 C(O)NR 10 -, (R 10 )2N-C(NR 10 )-, R 10 C(O)-, -N(R 10 )2, or R 1 1 OC(O)NR 10 -; R9a is hydrogen or methyl; R 0 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; R i is independently selected from C1-C6 alkyl and aryl, A 1 is selected from: a bond, -CH=CH-, -C≡C-, -C(O)-, -C(O)NR 10 -, O, -N(R 10 )-, or S(O) m ; A 3 is selected from. -C(O)-, -C(O)NR 10 - or -C(O)O-; V is selected from: a) heterocycle selected from pyπdinyl and qumohnyl, and b) aryl; Z is unsubstituted or substituted C5-C10 alkyl, wherein the substituted C5-C10 alkyl is substituted with one or two moieties selected from the following: a) C1 -.4 alkoxy, b) NR 6 R 7 , c) C3-6 cycloalkyl, d) -NR 6 C(O)R 7 , e) -OR 10 , f) -S(O) m R 6a , g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4, or the pharmaceutically acceptable salts thereof. A still further embodiment of the compounds of this invention is illustrated by the formula F: wherein: R 1 D is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 O-, -N(R 1 )2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 O-, or -N(R 1 )2; R 3 is selected from H and CH3; \ .NR 6 R 7 R 2 is selected from H; Y O ; or Ci -.5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 , 4) SR 6a , SO2R 6a , or and R 2 and R 3 are optionally attached to the same carbon atom; R 6 and R 7 are independently selected from: H; Ci-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) Ci-4 alkoxy, b) halogen, or c) aryl or heterocycle; R 6a is selected from: Ci-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with. a) Ci-4 alkoxy, b) halogen, or c) aryl or heterocycle; R8 IS independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 10 O-, R 10 C(O)NR 10 -, CN, NO2, (R 10 )2N-C(NR 10 )-, R 10 C(O)-, -N(R 10 )2, or R^OC^NR 10 -, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 O-, R 10 C(O)NR 10 - (R 10 )2N-C(NR 10 )-, R 10 C(O)-, -N(R 10 )2, or R 1 lθC(O)NRl°-; R9a is hydrogen or methyl; R 10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; R 1 is independently selected from C1-C alkyl and aryl; A 3 is selected from: -C(O)-, -C(O)NR 10 - or -C(O)O-; Z is unsubstituted or substituted C5-C10 alkyl, wherein the substituted C5-C10 alkyl is substituted with one or two moieties selected from the following: a) Ci-4 alkoxy, b) NR 6 R 7 , c) C3-6 cycloalkyl, d) -NR 6 C(O)R 7 , e) -OR 10 , f) -S(O) m R 6a , g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; p is 1, 2 or 3; r is 0 to 5, and v is 0, 1, 2 or 3; or the pharmaceutically acceptable salts thereof. Another further embodiment of the compounds of this invention is illustrated by the formula G: wherein: R l rj is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 O-, -N(R 10 )2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 O-, or -N(R 10 )2; R 3 is selected from H and CH3; \ .NR 6 R 7 R 2 is selected from H; Y O ; or C 1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 , 4) SR 6a , SO2R 6a , or and R 2 and R 3 are optionally attached to the same carbon atom; R 6 and R 7 are independently selected from: H; Cι_4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) Ci-4 alkoxy, b) halogen, or c) aryl or heterocycle; R a is selected from. Ci-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) Ci -4 alkoxy, b) halogen, or c) aryl or heterocycle; R° is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cj-Cό perfluoroalkyl, F, Cl, R 10 O-, R 10 C(O)NR 10 -, CN, NO2, (R 10 )2N-C(NR 10 )-, R 10 C(O)-, -N(R 10 )2, or R^OC^NR 10 -, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 O-, R 10 C(O)NR 10 -, (R 1 °)2N-C(NR ! °)-, R 2 °C(O)-, -N(R l °)2, or R 1 l OC(O)NR 1 °- ; R a ]s hydrogen or methyl; R 10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; R 1 1 is independently selected from C1-C6 alkyl and aryl; A 3 is selected from: -C(O)-, -C(O)NR 10 - or -C(O)O-; Z is unsubstituted or substituted C5-C10 alkyl, wherein the substituted C5-C10 alkyl is substituted with one or two moieties selected from the following: a) Cι_4 alkoxy, b) NR 6 R 7 , c) C3-6 cycloalkyl d) -NR 6 C(O)R 7 , e) -OR 10 , f) -S(O) m R 6a , g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; V is 0, 1, 2 or 3; or the pharmaceutically acceptable salts thereof. Specific examples of compounds of this invention are as follows: l-[l-(4 ' -Cyanobenzyl) ιmιdazol-5-ylrnethyl]pιperazιne-4-carboxylιc acιd-(3,3- dιmethyl)butyπc ester 1-[1 -(4' -Cyanobenzyl) ιmιdazol-5-ylmethyl]pιperazιne-4-(2-hydroxy-4,4- di meth y 1 ) val erami de 1-[1 -(4' -Cyanobenzyl) ιmιdazol-5-ylmethyl]pιperazιne-4-caιboxyhc acιd-(2,2- dιmethyl)propyl ester l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]-4-(2-ethylbutanecarbonyl) piperazine l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]-pιperazιne-4-carboxyhc acιd-(2-t- butoxy)ethyl ester l-(l-(4 -cyanobenzyl)ιmιdazol-5-ylmethyl)-4-(N-(l,l,3,3-tetramethyl)-butyl) carboxamidejpiperazine l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]-pιperazιne-4-carboxyhc acid (2,2,5,5- tetramethyl)hexyl ester l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]-pιperazme-4-carboxylιc acid (2,2- dιmethyl)pent-3-yl ester l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]-4-(2-methyl-2-ethylbutanoyl)pιperazme 4-[5-(4-Heptanoyl-pιperazm-l-ylmethyl)-ιmιdazol-l-ylmethyl]-benzonιtπle 4-[5-(4-Hexanoyl-pιperazιn-l-ylmethyl)-ιmιdazol-l-ylmethyl]-benzonιtπle 4-[5-(4-Octanoyl-pιperazιn-l-ylmethyl)-ιmιdazol-l-ylmethyl]-benzonιtπle 4-[5-(4-Nonanoyl-pιperazιn-l-ylmethyl)-ιmιdazol-l-ylmethyl]-benzonιtπle 4-[5-(4-Decanoyl-pιperazιn-l-ylmethyl)-ιmιdazol-l-ylmethyl]-benzonιtπle or the pharmaceutically acceptable salts or optical isomers thereof. In an embodiment of the instant invention, the specific examples of compounds of this invention are as follows 1-[1 -(4' -Cyanobenzyl) ιmιdazol-5-ylmethyl]pιperazιne-4-carboxylιc acιd-(3,3- dιmethyl)butyπc ester l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]pιperazιne-4-(2-hydroxy-4,4- dιmethyl)valeramιde l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]pιperazιne-4-carboxyhc acιd-(2,2- dimethyl)propyl ester 1-[1 -(4' -Cyanobenzyl) ιmιdazol-5-ylmethyl]-4-(2-ethylbutanecarbonyl) piperazine 1-[1 -(4' -Cyanobenzyl) ιmιdazol-5-ylmethyl]-pιperazme-4-carboxylιc acιd-(2-t- butoxy)ethyl ester l-(l-(4 -cyanobenzyl)ιmιdazol-5-ylmethyl)-4-(N-(l,l,3,3-tetramethyl)-butyl) carboxamidejpiperazine l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]-pιperazme-4-carboxyhc acid (2,2,5,5- tetramethyl)hexyl ester l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]-pιperazιne-4-carboxyhc acid (2,2- dιmethyl)pent-3-yl ester 1-[1 -(4' -Cyanobenzyl) ιmιdazol-5-ylmethyl]-4-(2-methyl-2-ethylbutanoyl)pιperazιne or the pharmaceutically acceptable salts or optical isomers thereof. The compounds of the instant invention differ from previously disclosed piperazinone-containing and piperazine-containing compounds, (PCT Publ. No. WO 96/30343 - October 3, 1996; U.S. Pat. No. 5,856,326 - January 5, 1999; PCT Publ. No WO 96/31501 - October 10, 1996; PCT Publ. No. WO 97/36593 - October 9, 1997, PCT Publ. No. WO 97/36592 - October 9, 1997) that were descπbed as inhibitors of farnesyl-protein transferase (FPTase), in that, among other things, the instant compounds are dual inhibitors of farnesyl -protein transferase and geranylgeranyl-protein transferase type I (GGTase-I) In one embodiment of the invention, the compounds are further characteπzed in that the inhibitory activity of the compounds against GGTase-I is greater than the inhibitory activity against FPTase. Preferably, the compounds of this embodiment of the instant invention inhibit FPTase in vitro (Example 16) at an IC 50 of less than 1 μM and inhibit GGTase-I in vitro (Example 17) at an IC 50 of less than 50 nM Also preferably, the compounds of this embodiment of the instant invention inhibit the cellular processing of the Rapl protein (Example 22, Protocol C) at an EC 50 of less than about 1 μM. More preferably, the compounds of this embodiment of the instant invention inhibit the cellular processing of the Rapl protein (Example 22, Protocol C) at an EC 50 of less than about 50 nM. Also more preferably, the ratio of the IC 50 of the compounds of this embodiment of the instant invention for in vitro inhibition of FPTase to the IC-; 0 of the compounds of the instant invention for in vitro inhibition of GGTase type I is greater than 25 Also more preferably, the ratio of the EC 50 of the compounds of this embodiment of the instant invention for inhibition of the cellular processing of the hDJ protein (Example 21) to the EC 50 of the compounds of the instant invention for inhibition of the cellular processing of the Rapl protein is about equal to or less than 1 In a second embodiment of the compounds of the instant invention, the compounds are further characteπzed in that the inhibitory activity of the compounds against FPTase is greater than the inhibitory activity against GGTase-I Preferably, the compounds of this second embodiment of the instant invention inhibit FPTase in vitro (Example 16) at an IC 50 of less than 100 nM and inhibit GGTase-I in vitro (Example 17) at an IC 50 of less than 5 μM Preferably, the compounds of this second embodiment of the instant invention inhibit the cellular processing of the hDJ protein (Example 21) at an EC 50 of less than about 250 nM Also preferably, the compounds of this second embodiment of the instant invention inhibit the cellular processing of the Rapl protein (Example 23, Protocol C) at an EC 50 of less than about 10 μM More preferably, the compounds of this second embodiment of the instant invention inhibit the cellular processing of the Rapl protein (Example 23, Protocol C) at an EC 50 of less than about 1 μM Also more preferably, the ratio of the IC 50 of the compounds of this embodiment of the instant invention for m vitro inhibition of GGTase type I to the IC 50 of the compounds of the instant invention for in vitro inhibition of FPTase is greater than 1 and less than 25 Also more preferably, the ratio of the EC 50 of the compounds of this second embodiment of the instant invention for inhibition of the cellular processing of the hDJ protein (Example 21) to the EC 30 of the compounds of the instant invention for inhibition of the cellular processing of the Rapl protein is between about 1 and about 100 The compounds of the present invention may have asymmetnc centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention When any vanable (e g aryl, heterocycle, R 1 , R 2 etc ) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence Also, combinations of substituents/or vaπables are permissible only if such combinations result in stable compounds As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. "Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo. As used herein, "cycloalkyl" is intended to include monocyclic saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of such cycloalkyl groups includes, but are not limited to, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl and cyclooctyl. As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The term heterocycle or heterocyclic, as used herein, includes heteroaryl moieties. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2- oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyπolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl. As used herein, "heteroaryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S. Examples of such heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnohnyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, lmidazolyl, indolinyl, mdolyl, isochromanyl, lsomdohnyl, isoquinolmyl, isothiazolyl, naphthyπdinyl, oxadiazolyl, pyndyl, pyraz yl, pyrazolyl, pyπdazinyl, pynmidmyl, pyrrolyl, qumazolinyl, qumohnyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinohnyl, thiazolyl, thienofuryl, thienothienyl, and thienyl As used herein in the definition of R 2 and R 3 , the term "the substituted group" intended to mean a substituted Cι_8 alkyl, substituted C2-8 alkenyl, substituted C2-8 alkynyl, substituted aryl or substituted heterocycle from which the substιtuent(s) R 2 and R 3 are selected As used herein in the definition of R 6 , R 6a , R 7 and R 7a , the substituted Cι_g alkyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroarylsulfonyl and substituted heterocycle include moieties containing from 1 to 3 substituents in addition to the point of attachment to the rest of the compound Preferably, such substituents are selected from the group which includes but is not limited to F, Cl, Br, CF 3 , NH , N(Cι-C6 alkyl)2, NO 2 , CN, (Ci-C 6 alkyl)O-, -OH, (C1-C6 alkyl)S(O) m - , (C1-C6 alkyl)C(O)NH-, H2N-C(NH)-, (C1-C6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)-, N3,(Cι-C6 alkyl)OC(O)NH-, phenyl, pyndyl, lmidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl and C1-C20 alkyl When R 2 and R 3 are combined to form -(CH2)u~, cyclic moieties are formed Examples of such cyclic moieties include, but are not limited to In addition, such cyclic moieties may optionally include a heteroatom(s) Examples of such heteroatom-contaming cyclic moieties include, but are not limited to The moiety formed when, in the definition of R 6 , R 7 and R , R6 and R 7 or R 7 and R 7 are joined to form a πng, is illustrated by, but not limited to, the following Lines drawn into the πng systems from substituents (such as from R 2 , R 3 , R4 etc.) indicate that the indicated bond may be attached to any of the substitutable πng carbon atoms. Preferably, R l a and R " are independently selected from: hydrogen, -N(R 10 )2, R 10 C(O)NR 10 - or unsubstituted or substituted -C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted phenyl, -N(R 10 )2, R 10 O- and R 10 C(O)NR 10 -. Preferably, R 2 is selected from: H, and an unsubstituted or substituted group, the group selected from Cι_8 alkyl, C2-8 alkenyl and C2-8 alkynyl; wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, 2) OR 6 , and 3) SR 6a , SO2R 6a Preferably, R 3 is selected from hydrogen and methyl. Preferably, R4 is hydrogen. Preferably, R 6 and R 7 are selected from: hydrogen, unsubstituted or substituted C]-C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted C3-C6 cycloalkyl. Preferably, R 6 is unsubstituted or substituted Cι-C6- Preferably, R9 is hydrogen or methyl. Preferably, R 10 is selected from H, C]-C6 alkyl and benzyl. Preferably, A 1 and A 2 are independently selected from: a bond, -C(O)NR 10 -, -NR 10 C(O)-, O, -N(R 10 )-, -S(O)2N(R 10 )- and -N(R 10 )S(O)2-. Most preferably, A 1 and A 2 are a bond. Preferably, A 3 is selected from: -C(O)-, -C(O)NR 10 - and -C(O)O-. Preferably, V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl. Preferably, W is selected from imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, or isoquinolinyl. More preferably, W is imidazolyl and pyridyl. Preferably, Z is selected from unsubstituted branched C5-C10 alkyl and substituted C5-C10 alkyl which is substituted with one, two or three selected from the following: a) Ci_4 alkoxy, b) NR°R 7 , c) C3-6 cycloalkyl, d) -NR 6 C(O)R 7 , e) HO, f) -S(O) m R 6a , g) halogen, or h) perfluoroalkyl. Preferably, n and r are independently 0, 1, or 2. Preferably p is 1, 2 or 3. Preferably s is 0. Preferably t is 1. Preferably v is 0, 1 or 2. Preferably, the moiety is selected from- 1 la 2 la Preferably, the moiety A (CR 2)n A (CR 2)n 1S not a bond- It is intended that the definition of any substituent or vaπable (e.g., R l a , R , n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule Thus, -N(R 10 )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, from readily available starting mateπals. 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 deπved from inorganic acids such as hydrochloπc, hydrobromic, sulfuπc, sulfamic, phosphoπc, nitπc and the like: and the salts prepared from organic acids such as acetic, propionic, succmic, glycohc, steaπc, lactic, malic, tartaπc, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfani c, 2-acetoxy-benzoιc, fumaπc, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, lsethionic, tπfluoroacetic and the like 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 either by ion exchange chromatography or by reacting the free base with stoichiometπc amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or vaπous combinations of solvents. Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1-20, 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 expeπmental procedures. Substituents R, R a and R D , as shown in the Schemes, represent the substituents R 2 , R 3 and R4; however their point of attachment to the πng is illustrative only and is not meant to be limiting. Substituent Z', as shown in the Schemes, represents the substiutent Z as defined heremabove or a protected precursor thereof . 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 descπbed in the Schemes. Synopsis of Schemes 1-20" The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures, for the most part. In Scheme 1, for example, the synthesis of 2-cycloalkylalkanoyl substituted piperazmes is outlined Boc -protected amino acids I, available commercially or by procedures known to those skilled in the art, can be coupled to N-benzyl amino acid esters using a variety of dehydrating agents such as DCC (dicyclohexycarbodπmide) or EDC-HC1 (l-ethyl-3- (3-dιmethylammopropyl)carbodιιmιde hydrochloπde) in a solvent such as methylene chloπde , chloroform, dichloroethane, or dimethylformamide The product II is then deprotected with acid, for example hydrogen chloπde in chloroform or ethyl acetate, or tπfluoroacetic acid in methylene chloride, and cychzed under weakly basic conditions to give the diketopiperazme III Reduction of III with lithium aluminum hydπde in refluxing ether gives the piperazine IV, which is protected as the Boc deπvative V The N-benzyl group can be cleaved under standard conditions of hydrogenation, e.g , 10% palladium on carbon at 60 psi hydrogen on a Parr apparatus for 24-48 h. The product VI can be ieacted with a suitably substituted carboxyhc acid to provide the piperazine VII; a final acid deprotection as previously descπbed gives the intermediate VIII (Scheme 2). The intermediate VIII can itself be reductively alkylated with a variety of aldehydes, such as IX The aldehydes can be prepared by standard procedures, such as that descπbed by O. P. Goel, U. Krolls, M. Stier and S Kesten in Organic Syntheses, 1988, 67, 69-75, from the appropπate ammo acid (Scheme 3). The reductive alkylation can be accomplished at pH 5-7 with a vaπety of reducing agents, such as sodium tπacetoxyborohydπde or sodium cyanoborohydπde in a solvent such as dichloroethane, methanol or dimethylformamide. The product X can be deprotected to give the final compounds XI with tπfluoroacetic acid m methylene chloπde. The final product XI is isolated in the salt form, for example, as a tπfluoroacetate, hydrochloπde or acetate salt, among others The product diamine XI can further be selectively protected to obtain XII, which can subsequently be reductively alkylated with a second aldehyde to obtain XIII. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XV can be accomplished by literature procedures. As shown in Scheme 4, the piperazine intermediate VIII can be reductively alkylated with other aldehydes such as l-tπtyl-4-ιmιdazolyl- carboxaldehyde or l-tπtyl-4-ιmιdazolylacetaldehyde, to give products such as XVI The tπtyl protecting group can be removed from XVI to give XVII. or alternatively, XVI can first be treated with an alkyl hahde then subsequently deprotected to give the alkylated lmidazole XVIII Alternatively, the intermediate VIII can be acylated or sulfonylated by standard techniques. Incorporation of a hydroxyl moiety on the sidechain carbon alpha to the amide carbonyl of compounds of the formula XVIII can be accomplished as illustrated in Scheme 5. A suitably substituted pπmary alcohol XIX undergoes a one carbon homologation, via a Swem oxidation, nitπle addition and hydrolysis, to provide the substituted hydroxyacetic acid XX. The tπfluoromethyl ketal is formed and reacted with the previously descπbed protected piperazine VI to provide, following deprotection, the intermediate XXI Intermediate XXI can undergo a vaπety of reactions at its unsubstituted nitrogen For example, treatment of XXI with a suitably substituted lmidazolylmethyl ha de to provide the instant compound XXII Scheme 6 illustrates incorporation of an alkoxycarbonyl moiety onto the piperazine nitrogen. Thus a suitably substituted alcohol XXIII is reacted with nitrophenylchloroformate to provide the intermediate XXIV, which is reacted with a suitably substituted piperazine to provide the instant compound XXV An analogous reaction sequence alternatively provides the corresponding aminocarbonyl substitution on the piperazine nitrogen, as shown in Scheme 7 Scheme 8 illustrates the preparation of compounds analogous to compound XXXI wherein the alcohol utilized in the first step is a suitably substituted alkyl alcohol The scheme also illustrates the incorporation of an mdole moiety for the substiutent W in place of the preferred benzy midazolyl moiety Scheme 9 illustrates synthesis of an instant compound wherein a non-hydrogen R b 1S incorporated in the instant compound Thus, a readily available 4-substιtuted imidazole XXVI may be selectively lodinated to provide the 5-ιodoιmιdazole XXVII That imidazole may then be protected and coupled to a suitably substituted benzyl moiety to provide intermediate XXVIII Attachment of the imidazolyl nitrogen via an ethyl linker to the piperazine nitrogen of intermediate XXI, descπbed above, provides the instant compound XXIX Compounds of the instant invention wherein the A (CR l a 2)nA (CR a 2)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 10 The suitably substituted phenol XXX may be reacted with methyl N-(cyano)methanιmιdate to provide the 4- phenoxyimidazole XXXI After selective protection of one of the imidazolyl nitrogens, the intermediate XXXII can undergo alkylation reactions as descπbed for the benzy midazoles in Scheme 9 If the piperazine VIII is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XXXIII in Scheme 11, the protecting groups can be subsequently removed to unmask the hydroxyl group The Boc protected amino alcohol XXXIV can then be utilized to synthesize 2- aziπdinylmethylpiperazines such as XXXV Reaction Scheme 12 provides an illustrative example of the synthesis of compounds of the instant invention wherein the substituents R 2 and R 3 are combined to form - (CH2)u - For example, 1-amιnocyclohexane-l-carboxylιc acid XLV can be converted to the spiropiperazme XL VI essentially according to the procedures outlined in Schemes 1 and 2 The piperazine intermediate XL VI can be deprotected as before, and earned on to final products as descπbed in Schemes 3-8 It is understood that reagents utilized to provide the lmidazolylalkyl substituent may be readily replaced by other reagents well known in the art and readily available to provide other N-substituents on the piperazine. Ammo acids of the general formula LI which have a sidechain not found in natural amino acids may be prepared by the reactions illustrated in Scheme 13 starting with the readily prepared lmine LII. Schemes 14-17 illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyndyl moiety. Similar synthetic strategies for prepaπng alkanols that incorporate other heterocyclic moieties for vaπable W are also well known in the art. For example, Scheme 18 illustrates the preparation of the coπesponding qumoline aldehyde. Scheme 19 depicts a general method for synthesizing a key intermediate useful in the preparation of a preferred embodiment of the instant invention wherein V is phenyl and W is imidazole. A piperazine moiety can be readily added to this benzyl-imidazole intermediate as set forth in Scheme 20 SCHEME 1 IV SCHEME 2 HCl, EtOAc VII SCHEME 3 CFCO H CH CI X XI SCHEME 3 (continued) SCHEME 4 SCHEME 5 (CHa) SCHEME 6 XXIII XXIV XXV SCHEME 7 SCHEME 8 su — alky intermediate A SCHEME 8 (continued) alkyl" sub SCHEME 9 XXVI XXVII SCHEME 9 (continued) Swern oxidation SCHEME 10 XXXI ii. MeOH, reflux XXXII SCHEME 11 VIII Et 3 N , CICH 2 CH 2 CI XXXIV XXXV SCHEME 12 XLV SCHEME 12 (continued) SCHEME 13 Lll SCHEME 14 NaBH 4 (excess) SCHEME 15 SCHEME 16 NaBH 4 (excess) SCHEME 17 SCHEME 18 NaBH 4 (excess) SCHEME 19 SCHEME 20 diisopropylethyl amine The instant compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors. Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity (i.e., neurofibromin (NF-1), neu, src, abl, lck, fyn) or by other mechanisms. The compounds of the instant invention inhibit prenyl-protein transferase and the prenylation of the oncogene protein Ras. The instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55: 4575-4580 (1995)). Such anti-angiogenesis properties of the instant compounds may also be useful m the treatment of certain forms of vision deficit related to retinal vascularization. The compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment. For example, a component of NF-1 is a benign proliferative disorder. The instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256: 1331-1333 (1992). The compounds of the instant invention are also useful m the prevention of restenosis after percutaneous translummal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1:541-545(1995). The instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al. American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)). The instant compounds may also be useful for the treatment of fungal infections. The instant compounds may also be useful as inhibitors of proliferation of vascular smooth muscle cells and therefore useful in the prevention and therapy of arteriosclerosis and diabetic vascular pathologies. The compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable earners, excipients or diluents, 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. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a water soluble taste masking material such as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate buryrate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene- oxycetanol, or condensation products of ethylene oxide with partial esteis deπved from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters deπved from fatty acids and hexitol anhydπdes, for example polyethylene sorbitan monooleate The aqueous suspensions may also contain one or more pieservatives, for example ethyl, or n- propyl p-hydroxybenzoate, one or more coloπng agents, one or more flavoring agents, and one or moie sweetening agents, such as sucrose, sacchaπn or aspartame Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol Sweetening agents such as those set forth above, and flavoπng agents may be added to provide a palatable oral preparation These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above Additional excipients, for example sweetening, flavoπng and coloring agents, may also be present These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these Suitable emulsifying agents may be naturally-occurπng phosphatides. for example soy bean lecithin, and esters or partial esters deπved from fatty acids and hexitol anhydπdes, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate The emulsions may also contain sweetening, flavouπng agents, preservatives and antioxidants Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose Such formulations may also contain a demulcent, a preservative, flavoπng and coloπng agents and antioxidant The pharmaceutical compositions may be in the form of a steπle injectable aqueous solutions. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloπde solution. The sterile injectable preparation may also be a sterile injectable oil-in- water microemulsion where the active ingredient is dissolved in the oily phase. For example, the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulation. The injectable solutions or microemulsions may be introduced into a patient's blood-stream by local bolus injection Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUS™ model 5400 intravenous pump. The pharmaceutical compositions may be in the form of a steπle injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a steπle injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. In addition, steπle, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglyceπdes. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Compounds of Formula A may also be administered in the form of a suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irntatmg excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glyceπnated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of vaπous molecular weights and fatty acid esters of polyethylene glycol For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula A are employed. (For purposes of this application, topical application shall include mouth washes and gargles.) The compounds for the present invention can be administered in intranasal form via topical use of suitable tranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. As used herein, the term "composition" is intended to encompass a product compπsing the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts. 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, sex and response of the individual patient, as well as the seventy 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 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day. The compounds of the instant invention may also be co- administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated For example, the compounds of the instant invention may also be co-administered with other well known cancer therapeutic agents that are selected for their particular usefulness against the condition that is being treated. Included in such combinations of therapeutic agents are combinations of the instant farnesyl-protein transferase inhibitors and an antineoplastic agent. It is also understood that such a combination of antineoplastic agent and inhibitor of farnesyl-protein transferase may be used in conjunction with other methods of treating cancer and/or tumors, including radiation therapy and surgery. Examples of an antineoplastic agent include, in general, microtubule- stabihzing agents ( such as pac taxel (also known as Taxol®), docetaxel (also known as Taxotere®), epothilone A, epothilone B, desoxyepothilone A, desoxyepothilone B or their denvatives); microtubule-disruptor agents; alkylating agents, anti-metabolites; epidophyllotoxm; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazme, mitoxantrone; platinum coordination complexes; biological response modifiers and growth inhibitors; hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors. Example classes of antineoplastic agents include, for example, the anthracycline family of drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, the taxanes, the epothilones, discodermo de, the pteπdine family of drugs, diynenes and the podophyllotoxms. Particularly useful members of those classes include, for example, doxorubicin, carmmomycin, daunorubic , aminoptenn, methotrexate, methopteπn, dichloro-methotrexate, mitomycin C, porfiromycin, 5-fluorouracιl, 6-mercaptopunne, gemcitabine, cytosine arabmoside, podophyllotoxin or podo-phyllotoxin denvatives such as etoposide, etoposide phosphate or teniposide, melphalan, v blastine, vincπstine, leurosidme, vindesine, leurosine, pachtaxel and the like. Other useful antineoplastic agents include estramustme, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, lfosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, tπmetrexate, dacarbazme, L-asparagmase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprohde, pyndobenzoindole denvatives, interferons and mterleukins. The preferred class of antineoplastic agents is the taxanes and the preferred antineoplastic agent is pachtaxel. Radiation therapy, including x-rays or gamma rays which are delivered from either an externally applied beam or by implantation of tiny radioactive sources, may also be used in combination with the instant inhibitor of farnesyl-protem transferase alone to treat cancer Additionally, compounds of the instant invention may also be useful as radiation sensitizers, as descnbed in WO 97/38697, published on October 23, 1997, and herein incoφorated by reference. The instant compounds may also be useful in combination with other inhibitors of parts of the signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Thus, the instant compounds may be utilized in combination with a compound which has Raf antagonist activity. The instant compounds may also be co-administered with a compounds that is a selective inhibitor of geranylgeranyl protein transferase type I, a selective inhibitor of farnesyl-protein transferase and/or a compound that is a dual inhibitor of geranylgeranyl protein transferase type I and farnesyl-protein transferase Such a selective inhibitor or dual inhibitor may be an inhibitor that is competitive with the binding of the CAAX-contaming protein substrate of farnesyl-protein transferase or may be a prenyl pyrophosphate compeptitive inhibitor. In particular, the compounds disclosed in the following patents and publications may be useful as farnesyl pyrophosphate-competitive inhibitor component of such a composition: U.S. Ser. Nos. 08/254,228 and 08/435,047. Those patents and publications are incorporated herein by reference. In practicing methods of this invention, which compπse administenng, simultaneously or sequentially or in any order, two or more of a protein substrate-competitive inhibitor and a prenyl pyrophosphate-competitive inhibitor, such administration can be orally or parenterally, including intravenous, intramuscular, intrapeπtoneal, subcutaneous, rectal and topical routes of administration. It is preferred that such administration be orally. It is more preferred that such administration be orally and simultaneously. When the protein substrate- competitive inhibitor and prenyl pyrophosphate-competitive inhibitor are administered sequentially, the administration of each can be by the same method or by different methods. The instant compounds may also be useful in combination with an integπn antagonist for the treatment of cancer, as descπbed in U.S. Ser. No. 09/055,487, filed Apnl 6, 1998, which is incorporated herein by reference. As used herein the term an integπn antagonist refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to an ιntegπn(s) that is involved in the regulation of angiogenisis, or in the growth and invasiveness of tumor cells In particular, the term refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ocvβ3 integπn, which selectively antagonize, inhibit or counteract binding of a physiological ligand to the αvβ5 integπn, which antagonize, inhibit or counteract binding of a physiological ligand to both the ocvβ3 integπn and the αvβ5 integπn, or which antagonize, inhibit or counteract the activity of the particular mtegπn(s) expressed on capillary endothelial cells The term also refers to antagonists of the αvβ6, αvβ8, lβl, α2βl, 5βl, α6βl and α6β4 integπns. The term also refers to antagonists of any combination of αvβ3, αvβ5, αvβ6, vβ8, αlβl, α2βl, α5βl, α6βl and α6β4 integπns The instant compounds may also be useful with other agents that inhibit angiogenisis and thereby inhibit the growth and invasiveness of tumor cells, including, but not limited to angiostatin and endostatin. Similarly, the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF-1, restenosis, polycystic kidney disease, infections of hepatitis delta and related viruses and fungal infections. If formulated as a fixed dose, such combination products employ the combinations of this invention within the dosage range descnbed below and the other pharmaceutically active agent(s) within its approved dosage range Combinations of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a multiple combination formulation is inappropnate. EXAMPLES Examples provided are intended to assist in a further understanding of the invention. Particular mateπals employed, species and conditions are intended to be further illustrative of the invention and not limitative of the reasonable scope thereof. EXAMPLE 1 Preparation Of l-(4-cyanobenzyl)-5-chloromethyl imidazole HCl salt Step 1 Preparation of 4-Cyanobenzylamιne Method 1 (Hydrochlonde salt) A 72 liter vessel was charged with 190 proof ethanol (14.4 L) followed by the addition of 4-cyanobenzylbromιde (2.98 kg) and HMTA (2 18 kg) at ambient temperature. The mixture was heated to about 72- 75°C over about 60 min. On warming, the solution thickens and additional ethanol (1.0 liter) was added to facilitate stirπng The batch was aged at about 72-75°C for about 30 min The mixture was allowed to cool to about 20°C over about 60 min, and HCl gas (2 20 kg) was sparged into the slurry over about 4 hours duπng which time the temperature rose to about 65 °C The mixture was heated to about 70-72°C and aged for about 1 hour The slurry was cooled to about 30°C and ethyl acetate (22.3 L) added over about 30 min The slurry was cooled to about -5°C over about 40 min and aged at about -3 to about -5°C for about 30 min. The mixture was filtered and the crystalline solid was washed with chilled ethyl acetate (3 3 L). The solid was dπed under a N2 stream for about 1 hour before charging to a 50 liter vessel containing water (5.5 L). The pH was adjusted to about 10-10.5 with 50% NaOH (4.0 kg) maintaining the internal temperature below about 30°C. At about 25 °C, methylene chloride (2.8 L) was added and stirnng continued for about 15 mm. The layers were allowed to settle and the lower organic layer was removed. The aqueous layer was extracted with methylene chlonde (2 x 2.2 L). The combined organic layers were dried over potassium carbonate (650 g). The carbonate was removed via filtration and the filtrate concentrated in vacuo at about 25°C to give a free base as a yellow oil. The oil was transferred to a 50 liter vessel with the aid of ethanol (1.8 L). Ethyl acetate (4.1 L) was added at about 25°C The solution was cooled to about 15°C and HCl gas (600 g) was sparged in over about 3 hours, while keeping batch temperature below about 40°C. At about 20-25°C, ethyl acetate (5 8 L) was added to the slurry, followed by cooling to about -5°C over about 1 hour. The slurry was aged at about -5°C for about 1 hour and the solids isolated via filtration. The cake was washed with a chilled mixture of EtOAc/EtOH (9:1 v/v) (1 x 3.8 L), then the cake was washed with chilled EtOAc (2 x 3.8 L). The solids were dned in vacuo at about 25 °C to provide the above-titled compound. »H NMR (250 MHz, CDCI3) δ 7.83-7.79 (d, 2H), 7.60-7.57 (d, 2H), 4.79 (s, 2H), 4.25 (s, 2H); 13 C NMR (62.9 MHz, CDCI3) δ 149.9, 139.8, 134.2, 131.2, 119.7, 113.4, 49.9, 49.5, 49.2, 48.8, 48.5, 48.2, 43.8. Method 2 (phosphate salt): A slurry of HMTA in 2.5 L EtOH was added gradually over about 30 min to about 60 min to a stirred slurry of cyanobenzyl- bromide in 3.5 L EtOH and maintained at about 48-53°C with heating & cooling in a 22L neck flask (small exotherm). Then the transfer of HMTA to the reaction mixture was completed with the use of 1.0 L EtOH. The reaction mixture was heated to about 68-73 °C and aged at about 68-73 °C for about 90 min. The reaction mixture was a slurry containing a granular precipitate which quickly settled when stirnng stopped. The mixture was cooled to a temperature of about 50°C to about 55°C. Propionic acid was added to the mixture and the mixture was heated and maintained at a temperature of about 50°C to about 55°C. Phosphonc acid was gradually added over about 5 min to about 10 mm, maintaining the reaction mixture below about 65°C to form a precipitate-containing mixture. Then the mixture was gradually warmed to about 65°C to about 70°C over about 30 min and aged at about 65°C to about 70°C for about 30 min. The mixture was then gradually cooled to about 20-25°C over about 1 hour and aged at about 20-25°C for about 1 hour. The reaction slurry was then filtered. The filter cake was washed four times with EtOH, using the following sequence, 2.5 L each time. The filter cake was then washed with water five times, using 300 mL each time. Finally, the filter cake was washed twice with MeCN (1.0 L each time) and the above identified compound was obtained. Step 2. Preparation of l-(4-Cyanobenzyl)-2-mercapto-5- hydroxymethylimidazole 7% water m acetonitπle (50 mL) was added to a 250 mL roundbottom flask. Next, an amine phosphate salt (12.49 g), as descπbed in Step 1, was added to the flask. Next potassium thiocyanate (6.04 g) and dihydroxyacetone (5.61 g) was added. Lastly, propionic acid (10.0 mL) was added. Acetonitπle/water 93:7 (25 mL) was used to nnse down the sides of the flask. This mixture was then heated to 60°C, aged for about 30 minutes and seeded with 1% thioimidazole. The mixture was then aged for about 1.5 to about 2 hours at 60°C. Next, the mixture was heated to 70°C, and aged for 2 hours. The temperature of the mixture was then cooled to room temperature and was aged overnight. The thioimidazole product was obtained by vacuum filtration. The filter cake was washed four times acetonitπle (25 mL each time) until the filtrates became nearly colorless. Then the filter cake was washed three times with water (approximately 25-50 mL each time) and dπed in vacuo to obtain the above-identified compound. Step 3: Preparation of l-(4-Cyanobenzyl)-5-hydroxymethylιmιdazole A IL flask with cooling/heating jacket and glass stirrer (Lab-Max) was charged with water (200 mL) at 25°C. The thioimidazole (90.27 g), as descnbed in Step 2, was added, followed by acetic acid (120 mL) and water (50 mL) to form a pale pink slurry. The reaction was warmed to 40°C over 10 minutes. Hydrogen peroxide (90.0 g) was added slowly over 2 hours by automatic pump maintaining a temperature of 35-45°C. The temperature was lowered to 25°C and the solution aged for 1 hour. The solution was cooled to 20°C and quenched by slowly adding 20% aqueous Na2SO3 (25 mL) maintaining the temperature at less than 25°C. The solution was filtered through a bed of DARCO G-60 (9.0 g) over a bed of SolkaFlok (1.9 g) in a sintered glass funnel. The bed was washed with 25 mL of 10% acetic acid in water. The combined filtrates were cooled to 15 °C and a 25% aqueous ammonia was added over a 30 minute peπod, maintaining the temperature below 25°C, to a pH of 9.3. The yellowish slurry was aged overnight at 23°C (room temperature). The solids were isolated via vacuum filtration. The cake (100 mL wet volume) was washed with 2 x 250 mL 5% ammonia (25%) in water, followed by 100 mL of ethyl acetate. The wet cake was dned with vacuum/N2 flow and the above- titled compound was obtained. ] H NMR (250 MHz, CDCI3): o 7.84-7.72 (d, 2H), 7.31-7.28 (d, 2H), 6.85 (s, IH), 5.34 (s, 2H), 5.14-5.11 (t, IH), 4.30-4.28 (d, 2H), 3.35 (s, IH). Step 4: Preparation of l-(4-cyanobenzyl)-5-chloromethyl imidazole HCl salt Method 1 : l-(4-Cyanobenzyl)-5-hydroxymethylιmιdazole (1.0 kg), as described in above in Step 3, was slurπed with DMF (4.8 L) at 22°C and then cooled to -5°C. Thionyl chloπde (390 mL) was added dropwise over 60 mm duπng which time the reaction temperature rose to a maximum of 9°C. The solution became nearly homogeneous before the product began to precipitate from solution. The slurry was warmed to 26°C and aged for 1 h. The slurry was then cooled to 5°C and 2-propanol (120 mL) was added dropwise, followed by the addition of ethyl acetate (4.8 L). The slurry was aged at 5°C for 1 h before the solids were isolated and washed with chilled ethyl acetate (3 x 1 L). The product was dried in vacuo at 40°C overnight to provide the above-titled compound. l H NMR (250 MHz DMSO-d6): δ 9.44 (s, IH), 7.89 (d, 2H, 8.3 Hz), 7.89 (s, IH), 7.55 (d, 2H, 8.3 Hz), 5.70 (s, 2H), 4.93 (s, 2H). 13 C NMR (75.5 MHz DMSO-dό)' δ c 139.7, 137.7, 132 7, 130.1, 128 8, 120.7, 118.4, 111.2, 48.9, 33.1 Method 2 To an ice cold solution of dry acetonitnle (3.2 L, 15 L/Kg hydroxymethylimidazole) was added 99% oxalyl chlonde (101 mL, 1.15 mol, 1.15 equiv.), followed by dry DMF (178 mL, 2 30 mol, 2 30 equiv.), at which time vigorous evolution of gas was observed. After stirnng for about 5 to 10 min following the addition of DMF, solid hydroxymethylimidazole (213 g, 1.00 mol), as descπbed above in Step 3, was added gradually After the addition, the internal temperature was allowed to warm to a temperature of about 23°C to about 25°C and stirred for about 1 to 3 hours. The mixture was filtered, then washed with dry acetonitnle (400 mL displacement wash, 550 mL slurry wash, and a 400 mL displacement wash). The solid was maintained under a N 2 atmosphere dunng the filtration and washing to prevent hydrolysis of the chloπde by adventitious H 2 O. This yielded the crystalline form of the chloromethylimidazole hydrochloπde. [ H NMR (250 MHz DMSO-d6): δ 9 44 (s, IH), 7.89 (d, 2H, 8.3 Hz), 7.89 (s, IH), 7.55 (d, 2H, 8.3 Hz), 5.70 (s, 2H), 4 93 (s, 2H) 13 C NMR (75.5 MHz DMSO-d6): δ c 139.7, 137.7, 132.7, 130.1, 128.8, 120.7, 118 4, 111.2, 48.9, 33.1 Method 3: To an ice cold solution of dry DMF (178 mL, 2.30 mol, 2.30 equiv.) in dry acetonitnle (2.56 L, 12 L/Kg Hydroxymethylimidazole) was added oxalyl chloride (101 mL, 1.15 mol, 1.15 equiv) The heterogeneous mixture in the reagent vessel was then transferred to a mixture of hydroxymethylimidazole (213 g, 1.00 mol), as descnbed above in Step 3, in dry acetonitnle (1 7 L, 8 L/Kg hydroxymethylimidazole). Additional dry acetonitnle (1.1 - 2.3 L, 5 - 11 L/Kg hydroxymethylimidazole) was added to the remaining solid Vilsmeier reagent in the reagent vessel This, now nearly homogenous, solution was transferred to the reaction vessel at T, < +6 °C. The reaction vessel temperature was warmed to a temperature of about 23°C to about 25°C and stirred for about 1 to 3 hours. The mixture was then cooled to 0°C and aged 1 h. The solid was filtered and washed with dry, ice cold acetonitnle (400 mL displacement wash, 550 mL slurry wash, and a 400 mL displacement wash). The solid was maintained under a N 2 atmosphere duπng the filtration and washing to prevent hydrolysis of the chloπde by adventitious H 2 O. This yielded the crystalline form of the chloromethylimidazole hydrochloπde. EXAMPLE 2 1 -IT -(4' -Cyanobenzyl) ιmιdazol-5-ylmethyllpιperazιne Step 1: l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl pιperazιne-4-carboxylιc acid benzyl ester To an acetonitnle solution of l-(4'-cyanobenzyl)-5- chloromethy midazole (7.45 mmol) prepared as descπbed in Example 1 and dnsopropylethyl amine (22.4 mmol) was added 1 -benzyl 1 -piperazine carboxylate (10.4mmol). This solution was stirred for 4.0 hour at 80°C. The product was isolated after silica column puπfication. 1H-NMR (CDC1 3 ): 7.65 (d, 2H); 7.55 (s, IH); 7.38 (m, 5H); 7.15 (d, 2H); 7.0 (s, IH); 5.3 (s, 2H), 5.1 (s, IH); 3.4 (m, 4H); 3.3 (s, 2H); 2.3 (m, 4H). Step 2: l-[l-(4' -Cyanobenzyl) ιmιdazol-5-ylmethyllpιperazιne The product from Step 1 (6.17 mmol) was dissolved in absolute ethanol followed by the introduction of 10% Pd/C catalyst then hydrogen under atmosphenc pressure. The catalyst was removed via filtration through filter-aid and the product was isolated by removing the solvent under reduced pressure. H-NMR (CD OD): 7.8 (s, IH); 7.75 (d, 2H); 7.3 (d, 2H); 6.9 (s, IH); 5.45 (s, 2H); 3.3 (m, 4H); 2.6 (s, 2H); 2.3 (m, 4H). EXAMPLE 3 l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]pιperazιne-4-carboxyhc acιd-(3,3- dimethyPbutync ester Step 1: 3,3-Dιmethyl-l-butyloxy-(4-nιtropheny)carbonate A THF: acetonitnle (7: 1, 2mL) solution of 4-nιtrophenyl chloroformate (2.41g, 11.95mmol) was added to a THF:acetonιtnle (7: 1, 2mL) solution of 3,3- dιmethyl-1-butanol (l.llg, 10.9mmol) at 25°C and then stirred for 0.25 hour. Pyπdine (11.95mmol) was then added dropwise over 4 minute. Stirnng was continued for 2 hours at 25°C and then the reaction was diluted with ethyl acetate and washed with water, a saturated sodium chloπde solution, dried with sodium sulfate and then evaporated to provide the title compound. H-NMR (CDC1 ) 8.3pρm (d, 2H); 7 4ppm (d, 2H); 4.4ppm (t, 2H), 1.7ρpm (t, 2H); l.Oppm (s, 9H) Step 2: 3,3-Dιmethylbutyl-l-pιperazιne carboxylate t-Butyl-1 -piperazine carboxylate (0.721g, 3.98mmol) was added to a dichloromethane solution of 3,3-Dιmethyl-l-butyloxy-(4-nιtropheny)carbonate prepared as descnbed Step 1 (23, l.Olg, 3.79mmol) and then dnsopropylethyl amine (4.17mmol) was added. Stirnng was continued for 3 hours then the reaction was washed with potassium hydrogen sulfate, sodium bicarbonate and bnne followed by drying with sodium sulfate then evaporation. The residue was punfied on a silica column and then dissolved in 3mL of tnfluoroacetic acid. After stirnng for 0.5 hour the tnfluoroacetic acid was evaporated under reduced pressuie. The residue was dissolved in dichloromethane and washed with dilute sodium carbonate, dried with sodium sulfate and evaporated under reduced pressure to provide the title compound 1H-NMR (CDC1 3 ) 4.2ppm (t, 2H); 3.4ppm (m, 4H); 2.8ppm (m, 4H); l.όppm (t, 2H); 0.95ppm (s, 9H). Step 3: l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]pιperazme-4-carboxylιc acιd-(3,3-dιmethyl)butync ester To an acetonitπle solution of 3,3-Dιmethylbutyl-l-pιperazιne carboxylate prepared as descnbed in Step 2 (0.319g, 1.49mmol) was added l-(4- cyanobenzyl)-5-chloromethyl)ιmιdazole prepared as descπbed in Example 1 (0.20g, 0.74mmol) and dnsopropylethyl amine (2.22mmol). This solution was stirred for 4.0 hours at 80°C. The title compound was isolated after preparative hplc punfication. FAB-MS: calc. 409.5 found: 410.3. Η-NMR (CD OD): 8.45ppm (s, IH); 7.8ppm (d, 2H); 7.4ppm (d, 2H); 7.3ppm (s, IH); 5.55ppm (s, 2H); 4.1ppm (t, 2H); 3.4ppm (s, 2H); 3.3ppm (m, 4H); 2.3ppm (m, 4H); 1.55ppm (t, 2H); 0.95ppm (s, 9H). EXAMPLE 4 l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]pιperazιne-4-(2-hydroxy-4,4- dimethvDvaleramide Step 1: 2-Hydroxy-4,4-dimethylvaleric acid Commercially available 3,3-dιmethylbutyraldehyde (9.9mmol) was treated as descπbed in J. Chem. Soc, Chem. Comm. 1973, 55-56 to provide 2- hydroxy-4,4-dιmethylvalenc acid. 1H-NMR (CDC1 3 ): 4.4ppm (t, IH); 1.8ppm (d, 2H); 0.95ppm (s, 9H). Step 2: [2,2-Bιs(tπfluoromethyl)-4-oxo-l,3-dιoxolan-5-yl] 2,2- dimethylpropane 2-Hydroxy-4,4-dιmethylvalenc acid prepared as descnbed in step 1 (2.23mmol) was treated as descnbed in J. Org. Chem., 1995, 60, 7641-7645 to provιde[2,2-Bιs(tπfluoromethyl)-4-oxo-l,3-dιoxolan-5-yl] 2,2-dιmethylpropane. H- NMR (CDC1 3 ): 4.25ppm (t, IH); 1.7ppm (d, 2H), 0.95ppm (s, 9H). Step 3: Piperazine- l-(2-hydroxy-4,4-dιmethyl)valeramιde Benzyl 1 -piperazine carboxylate (0.91 mmol) was added to an ether solution of [2,2-Bιs(tπfluoromethyl)-4-oxo-l,3-dιoxolan-5-yl] 2,2-dιmethylpropane prepared as described in step 2 (0.91mmol) and stirred at 25°C for 0.5 hour. The reaction was loaded directly onto a silica column and then the purified product was dissolved in absolute ethanol and treated with 10%Pd/C catalyst under a hydrogen atmosphere for 1.0 hour The catalyst was removed via filtration and the title compound was isolated after rotary evaporation. H-NMR (CDC1 3 ): 4.45ppm (m, IH); 3.75ppm (m, IH), 3.55pρm (m, IH); 3.35ppm (m, 2H); 2.9ppm (m, 4H); 1.4ppm (m, 2H); l.Oppm (s, 9H). Step 4: l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]pιperazιne-4-(2-hydroxy- 4,4-dιmethy)lvaleramιde To an acetonitnle solution of piperazine- l-(2-hydroxy-4,4- dιmethyl)valeramιde prepared as descnbed in step 3 (0.65mmol) was added l-(4' cyanobenzyl)-5-chloromethyhmιdazole prepared as descnbed in Example 1 (0.44mmol) and dnsopropylethyl amine (1.32mmol). This solution was stirred for 3.0 hour at 80°C. The title compound was isolated after preparative hplc purification. FAB-MS: calc: 409.5 found: 410.2. 1H-NMR (CD 3 OD): 8.45ppm (s, IH), 7.8ppm (d, 2H); 7.4ppm (d, 2H); 7.3ppm (s, IH); 5.6ppm (s, 2H); 4.5ppm (m, IH); 3.3-3.5ppm (m, 6H); 2.4ppm (m, 4H); 1.45ppm (m, 2H), 1.Oppm (s, 9H). EXAMPLE 5 l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl pιperazme-4-carboxylιc acιd-(2,2- dimethvDpropyl ester Step 1: l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl pιperazιne-4-carboxyhc acid- (2,2-dιmethvDpropyl ester To l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl piperazine prepared as described in EXAMPLE 2 (0.416 mmol) in methylene chlonde was added DIEA (0.832 mmol) and commercially available neopentyl chloroformate (0.499 mmol). This solution was stirred for 2 hours at 25°C and then the title compound was punfied on preparative hplc and isolated via lyophihzation. FAB-MS: calc: 395.5 found: 396.2. 1H-NMR (CD 3 OD): 8.9ppm (s, IH); 7.8ppm (d, 2H); 7.5ppm (s, IH); 7.45ppm (d, 2H); 5.65ppm (s, 2H); 3.8ppm (s, 2H); 3.45ppm (s, 2H); 3.3ppm ( , 4H); 2.3ppm (m, 4H); 0.95ppm (m, 9H). EXAMPLE 6 l-[l-(4'-Cyanobenzyl) imidazol-5-ylmethyll-4-(2-ethylbutanecarbonyl) piperazine Step 1: l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]~4-(2- ethylbutanecarbonvDpiperazme To 1 -(4' -Cyanobenzyl) ιmιdazol-5-ylmethyl piperazine prepared as descnbed in EXAMPLE 2 (0.356 mmol) in DMF was added commercially available 2-ethylbutyπc acid (0.356 mmol), HOBt (0.427 mmol), EDC (0.463 mmol) and N- methylmorpho ne (1.07 mmol). This solution was stirred for 18 hours at 25°C and then the crude product was isolated by partioning between ethyl acetate and potassium hydrogen sulfate, sodium bicarbonate and sodium chloride solutions. The title compound was punfied on preparative hplc and isolated via lyophihzation. FAB-MS" calc: 379.5 found: 380.3. 1H-NMR (CD 3 OD): 9.1ppm (s, IH); 7.8ppm (d, 2H); 7.75ppm (s, IH), 7.5ppm (d, 2H); 5.7ppm (s, 2H); 3.5-3.8ppm (m, 6H), 2.5-2.7ppm (m, 4H); l.όppm (m, 2H); 1.5ppm (m, 2H), 1.3ppm (s, IH); 0.85ppm (t, 6H). EXAMPLE 7 l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]-pιperazme-4-carboxyhc acιd-(2-t- butoxy)ethyl ester Step 1: 2-t-Butoxyethyl-(4-nιtrophenyl)carbonate A THF: acetonitπle (7:1, lOmL) solution of 4-nιtrophenyl chloroformate (6.71 mmol) was added to a THF:acetonιtπle (7:1, 20mL) solution of commercially available ethylene glycol mono-t-butyl ether (6.64 mmol) at 25°C and then stirred for 0.25 hour. Pyπdine (6.71 mmol) was then added dropwise over 4 minutes. Stirnng was continued for 2 hours at 25°C and then the reaction was diluted with ethyl acetate and washed with water, a saturated sodium chlonde solution, dπed with sodium sulfate and then evaporated to provide the title compound. H-NMR (CDCI3): δ 8.3 (d, 2H); 7.4 (d, 2H); 4.4 (t, 2H); 3 65 (t, 2H); 1.2 (s, 9H). Step 2: 1 -Piperazine carboxy c acιd-(2-t-butoxy)ethyl ester To 2-t-Butoxyethyl-(4-nιtrophenyl)carbonate prepared as descπbed in Step 1 (6.54 mmol) in methylene chloπde was added benzyl- 1 -piperazine carboxylate (6.86 mmol) and DIEA (7.19 mmol) with stirnng for 18 hours at 25°C. The reaction was diluted with more methyene chloπde and then washed with dilute potassium hydrogen sulfate, ammonium hydroxide (3x) and sodium chloπde then dπed with sodium sulfate and concentrated under reduced pressure. The residue was punfied on a silica column (ethyl acetate :hexane, 4:6) and then hydrogenated in absolute ethanol in the presence of 10% palladium on carbon. Filtration and evaporation provided the title compound. ' H-NMR (CDCI 3 ): δ 4.2 (t, 2H), 3.55 (t, 2H); 3.45 (m, 4H); 2.8 (m, 4H); 1.1 (s, 9H) Step 3: l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]-pιperazme-4-carboxyhc acιd-(2-t-butoxy)ethyl ester To 1 -piperazine carboxy c acιd-(2-t-butoxy)ethyl ester prepared as descnbed in step 2 (0.97 mmol) in dry acetonitnle was added l-(4'-cyanobenzyl)-5- chloromethyhmidazole prepared as described in Example 1 (0.75 mmol) and DIEA (2.25 mmol) with stimng for 1.5 hours at 80°C. The title compound was then purified via preparative hplc and isolated via lyophilization. FAB-MS: calc. 425.5 found' 426.3. 1H-NMR (CD 3 OD): δ 8.4 (s, IH); 7.8 (d, 2H); 7.4 (d, 2H); 7.3 (s, IH); 5.6 (s, 2H); 4.1 (t, 2H); 3.6 (t, 2H); 3.45 (s, 2H); 3.3 (m, 4H); 2.3 (m, 4H); 1.1 (s, 9H). EXAMPLE 8 1 -( 1 -(4 -cyanobenzyl)ιmιdazol-5-ylmethyl)-4-(N-( 1 , 1 ,3,3-tetramethyl)-butyl) carboxamidelpiperazine Dry methylene chlonde (1.0ml) was added to a round bottom flask along with "proton-sponge" [l,8-bιs(dιmethylamιno)naphthalene, N,N,N',N'- tetramethyl-l,8-naphthalenedιamιne] (428. Omg. 2.0mmol), and 1,1,3.3- tetramethylbutylamine (129.2mg, l.Ommol). The solution was cooled 5 C with an ice/water bath and phosgene (0.57ml, 1.1 mmol, 20% in toluene) added dropwise. The ice bath was removed and the reaction allowed to warm to Rt. over thirty five minutes. Cold dilute hydrochlonc acid solution (1.0ml, l.ON) was added and the mixture agitated. The aqueous layer was removed and the remaining methylene chlonde solution dned (MgSO 4 ). An aliquot (.05mmol) of this stock isocynate solution was then added to a tared test tube containing l-(l-(4- Cyanobenzyl)ιmιdazole-5-ylmethyl)pιperazιne prepared as descπbed in Example 2 (0.05mmol in DMF), ethyl acetate (1.0ml), and diisopropylamme (0.022ml, 0.13mmol). The reaction was allowed to stand for 48 hours. Ethyl acetate (1.5ml) along with water (0.5ml), and bnne (0.5ml) were added to the tube. The tube was shaken and the aqueous layer carefully removed. The test tube sample was concentrated in a rotary speed evaporator. The weight of the resulting pellet was then used to dilute the sample to standard concentrations for analytical and biological assays. Punty was checked using standard HPLC techniques and High res. Mass Spect. High res FAB MS: Theoretical Mass 437.3023, Measured Mass 437.3030 (C 25 H 36 N 6 O+H + ) EXAMPLE 9 Preparation of Carbamates from Alcohols To each of 14 previously tared screw cap test tubes was added approximately 1.25 equivalents of one of the 14 alcohols. After determining the weights of alcohols by difference the appropπate amount of p-nitrophenyl chloroformate (1.27 equivalents) was added to each of the tubes as a freshly made tetrahydrofuran. acetonitnle (7:1) solution. This was stirred for 10 minutes and then pyndme (1.37 equivalents) was added to each tube followed by stimng for 1.5 hours. Each tube was diluted with 1.5mL each of ethyl acetate and water. The aqueous was removed and the organic layer was rotary speed evaporated to a pellet. To each of the 14 tubes was added 1.0 mL of ethyl acetate:DCM:methanol (1:1:0.1) and 0.1 mmol of a stock DMF solution of l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl piperazine, prepared as described in Example 1 and 0.2 mmol DIEA. Stir for 18 hours. To each tube was added 1.0 mL of ethyl acetate then each tube was washed with 5x1 mL of l.ON NaOH. The organic layer was then rotary speed evaporated to a pellet. The resulting pellet was dissolved in 2.0 mL of DMSO and submitted for LC and HI-RES Mass spec analysis. The completeness of reaction was estimated by companng the AUC of each reaction against an independently prepared standard of known concentration that was also prepared in the library run. The following compounds were isolated using this procedure: l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]-pιperazιne-4-carboxyhc acid (2,2,5,5- tetramethyl)hexyl ester Hi-Res MS: calc 466.3176 found. 466.3172 l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]-pιperazιne- 4-carboxylιc acid (2,2- dιmethyl)pent-3-yl ester Hi-Res MS: 424 2708 calc. found. 424.2707 EXAMPLE 10 Preparation of Amides from Acids To each of twelve previously tared screw cap test tubes was added approximately 0.12 mmol of one of the acids. After determining this weight by difference, a DCM solution of 2,3-dιmethyl-2-fluoro-pyndmιum tosylate (1.2 equivalents vs. acid, 218 mg/mL) was added to each tube and then a DCM solution of tnethyl amine (1.2 equivalents vs. acid, 250 uL/mL DCM) was added. These solutions were stirred for 15 minutes and then a solution of 1 -(4 '-Cyanobenzyl) ιmιdazol-5-ylmethyl piperazine, prepared as descπbed in Example 1 (0.1 mmol in DMF) and DIEA (0.2 mmol) in DCM (0.5 mL) for a total volume of 0.615 mL was added to each tube and then stirred for 5 hours. Each tube was washed with 2x1 mL of 1% tπfluoroacetic acid The DCM layers were removed and then transferred to new pre-tared test tubes and then rotary speed evaporated to a pellet. The resulting pellet was dissolved in 2.0 mL of DMSO and submitted for LC and HI-RES Mass spec analysis. The completeness of reaction was estimated by companng the AUC of each reaction against an independently prepared standard of known concentration that was also prepared in the library run. The following compound was isolated using this procedure- l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]-4-(2-methyl-2-ethylbutanoyl)pιperazme Hi-Res MS- calc: 394.2605 found" 394.2601 EXAMPLE 11 4-[5-(4-Heptanoyl-pιperazιn-l-ylmethyl)-ιmιdazol-l-ylmethyl]-benzonιtnle To a solution of l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl piperazine, prepared as described in Example 1 (65 mg, 0.18 mmol), in 0.5 mL of dimethylformamide at room temperature was added heptanoic acid (0.028 mL, 0.2 mmol), 1-hydroxybenzotπazole (30 mg, 0.22 mmol), tπethylamine (0.10 mL, 0.72 mmol), and l-[3-(dιmethylamιno)propyl]-3-ethylcarbodnmιde hydrochloride (42 mg, 0.22 mmol). After stirring overnight, the solution was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and bnne, dπed with sodium sulfate, filtered, and concentrated in vacuo. Punfication by preparative HPLC was followed by conversion to the bis-hydrochloπde salt by exposure of a dichloromethane solution of the product to excess ethereal HCl Concentration in vacuo provided the titled product as a white powder (23 mg). MS found: 394 (M+H + ) EXAMPLE 12 4-[5-(4-Hexanoyl-pιperazm-l-ylmethyl)-ιmιdazol-l-ylmethyl]-benzonιtnle The titled product was prepared using the same procedure descπbed in Example 11, except that hexanoic acid was used in place of heptanoic acid Punfication by preparative HPLC was followed by conversion to the bis- hydrochloride salt by exposure of a dichloromethane solution of the product to excess ethereal HCl. Concentration in vacuo provided the titled product as a white powder MS: found: 380 (M+H + ) EXAMPLE 13 4-[5-(4-Octanoyl-pιperazm-l-ylmethyl)-ιmιdazol-l-ylmethyl]-benzonιtnle The titled product was prepared using the same procedure described in Example 11, except that octanoic acid was used in place of heptanoic acid. Punfication by preparative HPLC was followed by conversion to the bis- hydrochloπde salt by exposure of a dichloromethane solution of the product to excess ethereal HCl. Concentration in vacuo provided the titled product as a white powder. MS- found: 408 (M+H + ) EXAMPLE 14 4-[5-(4-Nonanoyl-pιperazιn-l-ylmethyl)-ιmιdazol-l-ylmethyl]-benzonιtπle The titled product was prepared using the same procedure descπbed in Example 11, except that nonanoic acid was used in place of heptanoic acid. Purification by preparative HPLC was followed by conversion to the bis- hydrochloπde salt by exposure of a dichloromethane solution of the product to excess ethereal HCl Concentration in vacuo provided the titled product as a white powder MS- found: 422 (M+H + ) EXAMPLE 15 4-[5-(4-Decanoyl-pιperazιn-l-ylmethyl)-ιmιdazol-l-ylmethyl]-benzonιtnle The titled product was prepared using the same procedure descnbed in Example 11, except that decanoic acid was used in place of heptanoic acid. Purification by preparative HPLC was followed by conversion to the bis- hydrochloπde salt by exposure of a dichloromethane solution of the product to excess ethereal HCl. Concentration m vacuo provided the titled product as a white powder MS: found: 436 (M+H + ) EXAMPLE 16 In vitro inhibition of ras farnesyl transferase Transferase Assays. Isoprenyl-protein transferase activity assays are earned out at 30 °C unless noted otherwise. A typical reaction contains (in a final volume of 50 μL) [^HJfarnesyl diphosphate, Ras protein , 50 mM HEPES, pH 7.5, 5 mM MgCl2, 5 mM dithiothreitol, 10 μM ZnCl2, 0.1% polyethyleneglycol (PEG) (15,000-20,000 mw) and isoprenyl-prote transferase. The FPTase employed in the assay is prepared by recombinant expression as descπbed in Omer, C.A., Krai, A.M., Diehl, R.E., Prendergast, G.C., Powers, S., Allen, CM., Gibbs, J.B. and Kohl, N.E (1993) Biochemistry 32:5167-5176. After thermally pre-equi brating the assay mixture in the absence of enzyme, reactions are initiated by the addition of lsoprenyl- protein transferase and stopped at timed intervals (typically 15 min) by the addition of 1 M HCl in ethanol (1 mL). The quenched reactions are allowed to stand for 15 m (to complete the precipitation process). After adding 2 mL of 100% ethanol, the reactions are vacuum-filtered through Whatman GF/C filters Filters are washed four times with 2 mL aliquots of 100% ethanol, mixed with scintillation fluid (10 mL) and then counted in a Beckman LS3801 scintillation counter For inhibition studies, assays are run as descnbed above, except inhibitors are prepared as concentrated solutions in 100% dimethyl sulfoxide and then diluted 20-fold into the enzyme assay mixture. Substrate concentrations for inhibitor IC50 determinations are as follows: FTase, 650 nM Ras-CVLS (SEQ.ID.NO.: 1), 100 nM farnesyl diphosphate. The compounds of the instant invention descπbed in the above Examples 3-15 were tested for inhibitory activity against human FPTase by the assay descnbed above and were found to have IC50 of <5 μM. EXAMPLE 17 Modifiedln vitro GGTase inhibition assay The modified geranylgeranyl-protein transferase inhibition assay is earned out at room temperature. A typical reaction contains (in a final volume of 50 μL). [^Hjgeranylgeranyl diphosphate, biotinylated Ras peptide, 50 mM HEPES, pH 7.5, a modulating anion (for example 10 mM glycerophosphate or 5mM ATP), 5 mM MgCl2, 10 μM ZnCl2, 0.1% PEG (15,000-20,000 mw), 2 mM dithiothreitol, and geranylgeranyl-protein transferase type I(GGTase). The GGTase-type I enzyme employed in the assay is prepared as descnbed in U.S. Pat. No. 5,470,832, incorporated by reference. The Ras peptide is denved from the K4B-Ras protein and has the following sequence: biotmyl-GKKKKKKSKTKCVIM (single amino acid code) (SEQ.ID.NO.: 2). Reactions are initiated by the addition of GGTase and stopped at timed intervals (typically 15 min) by the addition of 200 μL of a 3 mg/mL suspension of streptavidin SPA beads (Scintillation Proximity Assay beads, Amersham) in 0.2 M sodium phosphate, pH 4, containing 50 mM EDTA, and 0.5% BSA. The quenched reactions are allowed to stand for 2 hours before analysis on a Packard TopCount scintillation counter For inhibition studies, assays are run as descπbed above, except inhibitors are prepared as concentrated solutions in 100% dimethyl sulfoxide and then diluted 25-fold into the enzyme assay mixture. IC50 values are determined with Ras peptide near K concentrations Enzyme and substrate concentrations for inhibitor IC50 determinations are as follows- 75 pM GGTase-I, 1.6 μM Ras peptide, 100 nM geranylgeranyl diphosphate The compounds of the instant invention described in the above Examples 3-15 were tested for inhibitory activity against human GGTase type I by the assay descnbed above and were found to have IC50 of <5 μM. EXAMPLE 18 Cell-basedin vitro ras farnesylation assay The cell line used this assay is a v-ras line denved from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21. The assay is performed essentially as descπbed in DeClue, J.E. et al., Cancer Research 51:712-717, (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 labeled in 3 ml methionine-free DMEM supple-mented with 10% regular DMEM, 2% fetal bovine serum and 400 μCι[35s]methιomne (1000 Ci/mmol). After an additional 20 hours, the cells are lysed 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 mg/ml aprotmen/2 mg/ml leupeptιn/2 mg/ml antιpaιn/0.5 mM PMSF) and the lysates cleared by centπfugation at 100,000 x g for 45 mm. 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 Y 13-259 (Furth, M.E. et al., J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at 4°C, 200 μl of a 25% suspension of protein A-Sepharose coated with rabbit anti rat IgG is added for 45 min. The immuno-precipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1% Tπton X-100.0.5% deoxycholate/0.1%/SDS/0.1 M NaCl) boiled SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dπed and autoradiographed. The intensities of the bands corresponding to famesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein. EXAMPLE 19 Cell-basedin vitro growth inhibition assay To determine the biological consequences of FPTase inhibition, the effect of the compounds of the instant invention on the anchorage-independent growth of Ratl cells transformed with either a v-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Raf and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation. Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 10^ cells per plate (35 mm in diameter) in a 0 3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layers contain 0.1% methanol or an appropπate 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 compaπsons are made. EXAMPLE 20 Construction of SEAP reporter plasmid pDSElOO The SEAP reporter plasmid, pDSElOO was constructed by hgating a restnction fragment containing the SEAP coding sequence into the plasmid pCMV-RE-AKI. The SEAP gene is denved from the plasmid pSEAP2-Basιc (Clontech, Palo Alto, CA). The plasmid pCMV-RE-AKI was constructed by Deborah Jones (Merck) and contains 5 sequential copies of the 'dyad symmetry response element' cloned upstream of a 'CAT-TATA' sequence deπved from the cytomegalovirus immediate early promoter. The plasmid also contains a bovine growth hormone poly-A sequence. The plasmid, pDSElOO was constructed as follows. A restnction fragment encoding the SEAP coding sequence was cut out of the plasmid pSEAP2 -Basic using the restnction enzymes EcoRI and Hpal The ends of the linear DNA fragments were filled in with the Klenow fragment of E coli DNA Polymerase I The 'blunt ended' DNA containing the SEAP gene was isolated by electrophoresing the digest an agarose gel and cutting out the 1694 base pair fragment. The vector plasmid pCMV-RE-AKI was linearized with the restnction enzyme Bgl-II and the ends filled in with Klenow DNA Polymerase I The SEAP DNA fragment was blunt end ligated into the pCMV-RE-AKI vector and the ligation products were transformed into DH5-alpha E. coli cells (Gibco-BRL). Transformants were screened for the proper insert and then mapped for restnction fragment orientation. Properly oπented recombinant constructs were sequenced across the cloning junctions to venfy the correct sequence. The resulting plasmid contains the SEAP coding sequence downstream of the DSE and CAT-TATA promoter elements and upstream of the BGH poly-A sequence. Alternative Construction of SEAP reporter plasmid, pDSElOl The SEAP repotrer plasmid, pDSElOl is also constructed by hgating a restnction fragment containing the SEAP coding sequence into the plasmid pCMV- RE-AKI. The SEAP gene is deπved from plasmid pGEM7zf(-)/SEAP. The plasmid pDSElOl was constructed as follows: A restnction fragment containing part of the SEAP gene coding sequence was cut out of the plasmid pGEM7zf(-)/SEAP using the restnction enzymes Apa I and Kpnl. The ends of the linear DNA fragments were chewed back with the Klenow fragment of E. coli DNA Polymerase I. The "blunt ended" DNA containing the truncated SEAP gene was isolated by electrophoresmg the digest in an agarose gel and cutting out the 1910 base pair fragment. This 1910 base pair fragment was ligated into the plasmid pCMV-RE-AKI which had been cut with Bgl-II and filled in with E. coli Klenow fragment DNA polymerase. Recombinant plasmids were screened for insert orientation and sequenced through the ligated junctions. The plasmid pCMV-RE-AKI is derived from plasmid pCMVIE-AKI-DHFR (Whang , Y., Silberklang, M., Morgan, A., Munshi, S., Lenny, A.B., Ellis, R.W., and Kieff, E. (1987) J. Virol., 61, 1796- 1807) by removing an EcoRI fragment containing the DHFR and Neomycin markers. Five copies of the fos promoter serum response element were inserted as descnbed previously (Jones, R.E., Defeo- Jones, D., McAvoy, E.M., Vuocolo, G.A., Wegrzyn, R.J., Haskell, K.M. and Oliff, A. (1991) Oncogene, 6, 745-751) to create plasmid pCMV-RE-AKI. The plasmid pGEM7zf(-)/SEAP was constructed as follows. The SEAP gene was PCRed, in two segments from a human placenta cDNA library (Clontech) using the following o gos. Sense strand N-termmal SEAP : 5' GAGAGGGAATTCGGGCCCTTCCTGCAT GCTGCTGCTGCTGCTGCTGCTGGGC 3' (SEQ.ID.NO..3) Antisense strand N-terminal SEAP: 5' GAGAGAGCTCGAGGTTAACCCGGGT GCGCGGCGTCGGTGGT 3' (SEQ.-D.NO..4) Sense strand C-terminal SEAP: 5' GAGAGAGTCTAGAGTTAACCCGTGGTCC CCGCGTTGCTTCCT 3' (SEQ.ID.NO.:5) Antisense strand C-terminal SEAP: 5' GAAGAGGAAGCTTGGTACCGCCACTG GGCTGTAGGTGGTGGCT 3' (SEQ.ID.NO. :6) The N-termmal o gos (SEQ.ID.NO.: 4 and SEQ.ID.NO.: 5) were used to generate a 1560 bp N-terminal PCR product that contained EcoRI and Hpal restnction sites at the ends. The Antisense N-termmal oligo (SEQ.ID.NO.: 4) introduces an internal translation STOP codon withm the SEAP gene along with the Hpal site. The C-terminal o gos (SEQ.ID.NO.: 5 and SEQ.ID.NO.: 6) were used to amplify a 412 bp C-terminal PCR product containing Hpal and Hindlll restnction sites. The sense strand C-terminal oligo (SEQ.ID.NO.: 5) introduces the internal STOP codon as well as the Hpal site. Next, the N-termmal amphcon was digested with EcoRI and Hpal while the C-terminal amphcon was digested with Hpal and Hindlll. The two fragments compnsing each end of the SEAP gene were isolated by electrophoresing the digest in an agarose gel and isolating the 1560 and 412 base pair fragments. These two fragments were then co-hgated into the vector pGEM7zf(-) (Promega) which had been restnction digested with EcoRI and Hindlll and isolated on an agarose gel. The resulting clone, pGEM7zf(-)/SEAP contains the coding sequence for the SEAP gene from amino acids. Construction of a constitutively expressing SEAP plasmid pCMV-SEAP An expression plasmid constitutively expressing the SEAP protein was created by placing the sequence encoding a truncated SEAP gene downstream of the cytomegalovirus (CMV) IE-1 promoter. The expression plasmid also includes the CMV intron A region 5' to the SEAP gene as well as the 3' untranslated region of the bovine growth hormone gene 3' to the SEAP gene. The plasmid pCMVIE-AKI-DHFR (Whang et al, 1987) containing the CMV immediate early promoter was cut with EcoRI generating two fragments. The vector fragment was isolated by agarose electrophoresis and rehgated. The resulting plasmid is named pCMV-AKI Next, the cytomegalovnus intron A nucleotide sequence was inserted downstream of the CMV IE1 promter in pCMV-AKI. The intron A sequence was isolated from a genomic clone bank and subcloned into pBR322 to generate plasmid pl6T-286. The intron A sequence was mutated at nucleotide 1856 (nucleotide numbering as in Chapman, B.S , Thayer, R.M., Vincent, K A. and Haigwood, N.L , Nuc. Acids Res. 19, 3979-3986) to remove a Sad restriction site using site directed mutagenesis The mutated intron A sequence was PCRed from the plasmid pl6T-287 using the following ohgos Sense strand : 5' GGCAGAGCTCGTTTAGTGAACCGTCAG 3' (SEQ.ID.NO.: 7) Antisense strand : 5' GAGAGATCTCAAGGACGGTGACTGCAG 3' (SEQ.ID.NO.: 8) These two ohgos generate a 991 base pair fragment with a Sad site incoφorated by the sense oligo and a Bgl-II fragment incoφorated by the antisense ohgo The PCR fragment is trimmed with Sad and Bgl-II and isolated on an agarose gel The vector pCMV-AKI is cut with Sad and Bgl-II and the larger vector fragment isolated by agarose gel electrophoresis. The two gel isolated fragments are ligated at their respective Sad and Bgl-II sites to create plasmid pCMV-AKI-InA. The DNA sequence encoding the truncated SEAP gene is inserted into the pCMV-AKI-InA plasmid at the Bgl-II site of the vector. The SEAP gene is cut out of plasmid pGEM7zf(-)/SEAP (descnbed above) using EcoRI and Hindlll. The fragment is filled in with Klenow DNA polymerase and the 1970 base pair fragment isolated from the vector fragment by agarose gel electrophoresis The pCMV-AKI- InA vector is prepared by digesting with Bgl-II and filling in the ends with Klenow DNA polymerase The final construct is generated by blunt end hgatmg the SEAP fragment into the pCMV-AKI-InA vector Transformants were screened for the proper insert and then mapped for restnction fragment onentation Properly onented recombinant constructs were sequenced across the cloning junctions to verify the correct sequence. The resulting plasmid, named pCMV-SEAP, contains a modified SEAP sequence downstream of the cytomegalovirus immediately early promoter IE-1 and mtron A sequence and upstream of the bovme growth hormone poly-A sequence. The plasmid expresses SEAP in a constitutive manner when transfected into mammalian cells. Cloning of a Mynstylated viral-H-ras expression plasmid A DNA fragment containing viral-H-ras can be PCRed from plasmid "H-l" (Ellis R. et al. J. Virol. 36, 408, 1980) or "HB-11 (deposited in the ATCC under Budapest Treaty on August 27, 1997, and designated ATCC 209,218) using the following ohgos. Sense strand: 5'TCTCCTCGAGGCCACCATGGGGAGTAGCAAGAGCAAGCCTAAGGACCC CAGCCAGCGCCGGATGACAGAATACAAGCTTGTGGTGG 3'. (SEQ.ID.NO.: 9) Antisense: 5 ' C AC ATCTAGATC AGGAC AGC AC AGACTTGCAGC 3 ' . (SEQ.ID.NO.: 10) A sequence encoding the first 15 ammoacids of the v-src gene, containing a myπstylation site, is incoφorated into the sense strand ohgo. The sense strand ohgo also optimizes the 'Kozak' translation initiation sequence immediately 5' to the ATG start site. To prevent prenylation at the viral-ras C-termmus, cysteine 186 would be mutated to a seπne by substituting a G residue for a C residue in the C- terminal antisense ohgo. The PCR pπmer ohgos introduce an Xhol site at the 5' end and a Xbal site at the 3 'end. The Xhol-Xbal fragment can be ligated into the mammalian expression plasmid pCI (Promega) cut with Xhol and Xbal. This results in a plasmid in which the recombinant myr-viral-H-ras gene is constitutively transcπbed from the CMV promoter of the pCI vector. Cloning of a viral-H-ras-CVLL expression plasmid A viral-H-ras clone with a C-terminal sequence encoding the amino acids CVLL can be cloned from the plasmid "H-l" (Ellis R et al. J Virol. 36, 408, 1980) or "HB-11 (deposited in the ATCC under Budapest Treaty on August 27, 1997, and designated ATCC 209,218) by PCR using the following ohgos. Sense strand: 5 'TCTCCTCGAGGCCACCATGACAGAATACAAGCTTGTGGTGG-3 ' (SEQ.ID.NO.: 11) Antisense strand: 5'CACTCTAGACTGGTGTCAGAGCAGCACACACTTGCAGC-3' (SEQ.ID.NO.: 12) The sense strand ohgo optimizes the 'Kozak' sequence and adds an Xhol site. The antisense strand mutates seπne 189 to leucme and adds an Xbal site. The PCR fragment can be tnmmed with Xhol and Xbal and ligated into the Xhol- Xbal cut vector pCI (Promega). This results in a plasmid in which the mutated viral- H-ras-CVLL gene is constitutively transcπbed from the CMV promoter of the pCI vector Cloning of c-H-ras-Leu61 expression plasmid The human c-H-ras gene can be PCRed from a human cerebral cortex cDNA library (Clontech) using the following oligonucleotide primers. Sense strand: 5 ' -G AG AGA ATTCGCC ACC ATG ACGGAAT ATA AGCTGGTGG-3 ' (SEQ.ID.NO.: 13) Antisense strand: 5'-GAGAGTCGACGCGTCAGGAGAGCACACACTTGC-3' (SEQ.ID.NO.: 14) The pπmers will amplify a c-H-ras encoding DNA fragment with the pπmers contπbutmg an optimized 'Kozak' translation start sequence, an EcoRI site at the N-terminus and a Sal I stite at the C-termmal end. After tnmming the ends of the PCR product with EcoRI and Sal I, the c-H-ras fragment can be ligated ligated into an EcoRI -Sal I cut mutagenesis vector pAlter-1 (Promega). Mutation of glutamιne-61 to a leucme can be accomplished using the manufacturer's protocols and the following oligonucleotide: 5'-CCGCCGGCCTGGAGGAGTACAG-3' (SEQ.ID.NO.: 15) After selection and sequencing for the correct nucleotide substitution, the mutated c-H-ras-Leu61 can be excised from the pAlter-1 vector, using EcoRI and Sal I, and be directly ligated into the vector pCI (Promega) which has been digested with EcoRI and Sal I. The new recombinant plasmid will constitutively transcnbe c- H-ras-Leu61 from the CMV promoter of the pCI vector. Cloning of a c-N-ras-Val-12 expression plasmid The human c-N-ras gene can be PCRed from a human cerebral cortex cDNA library (Clontech) using the following oligonucleotide pπmers. Sense strand: 5'-GAGAGAATTCGCCACCATGACTGAGTACAAACTGGTGG-3' (SEQ.ID.NO.: 16) Antisense strand: 5'-GAGAGTCGACTTGTTACATCACCACACATGGC-3' (SEQ.ID.NO : 17) The pnmers will amplify a c-N-ras encoding DNA fragment with the pnmers contπbutmg an optimized 'Kozak' translation start sequence, an EcoRI site at the N-terminus and a Sal I stite at the C-terminal end. After tnmming the ends of the PCR product with EcoRI and Sal I, the c-N-ras fragment can be ligated into an EcoRI -Sal I cut mutagenesis vector pAlter-1 (Promega). Mutation of glycine- 12 to a vahne can be accomplished using the manufacturer's protocols and the following oligonucleotide: 5'-GTTGGAGCAGTTGGTGTTGGG-3' (SEQ.ID.NO.: 18) After selection and sequencing for the correct nucleotide substitution, the mutated c-N-ras-Val-12 can be excised from the pAlter-1 vector, using EcoRI and Sal I, and be directly ligated into the vector pCI (Promega) which has been digested with EcoRI and Sal I. The new recombinant plasmid will constitutively transcπbe c- N-ras-Val-12 from the CMV promoter of the pCI vector Cloning of a c-K-ras-Val-12 expression plasmid The human c-K-ras gene can be PCRed from a human cerebral cortex cDNA library (Clontech) using the following oligonucleotide pπmers. Sense strand: 5'-GAGAGGTACCGCCACCATGACTGAATATAAACTTGTGG-3' (SEQ.ID.NO • 19) Antisense strand- 5'-CTCTGTCGACGTATTTACATAATTACACACTTTGTC-3' (SEQ.ID.NO.: 20) The pπmers will amplify a c-K-ras encoding DNA fragment with the pnmers contπbutmg an optimized 'Kozak' translation start sequence, a Kpnl site at the N-termmus and a Sal I stite at the C-terminal end. After tnmming the ends of the PCR product with Kpn I and Sal I, the c-K-ras fragment can be ligated into a Kpnl - Sal I cut mutagenesis vector pAlter-1 (Promega). Mutation of cysteine- 12 to a vahne can be accomplished using the manufacturer's protocols and the following oligonucleotide 5'-GTAGTTGGAGCTGTTGGCGTAGGC-3' (SEQ.ID.NO.: 21) After selection and sequencing for the correct nucleotide substitution, the mutated c-K-ras-Val-12 can be excised from the pAlter-1 vector, using Kpnl and Sal I, and be directly ligated into the vector pCI (Promega) which has been digested with Kpnl and Sal I The new recombinant plasmid will constitutively transcribe c-K- ras-Val-12 from the CMV promoter of the pCI vector SEAP assay Human C33A cells (human epitheial carcenoma - ATTC collection) are seeded in 10cm tissue culture plates in DMEM + 10% fetal calf serum + IX Pen/Strep + IX glutamme + IX NEAA Cells are grown at 37°C in a 5% CO2 atmosphere until they reach 50 -80% of confluency. The transient transfection is performed by the CaPO4 method (Sambrook et al., 1989). Thus, expression plasmids for H-ras, N-ras, K-ras, Myr-ras or H-ras-CVLL are co-precipitated with the DSE-SEAP reporter construct For 10cm plates 600μl of CaCl2 -DNA solution is added dropwise while vortexing to 600μl of 2X HBS buffer to give 1.2ml of precipitate solution (see recipes below). This is allowed to sit at room temperature for 20 to 30 minutes While the precipitate is forming, the media on the C33A cells is replaced with DMEM (minus phenol red, Gibco cat # 31053-028)+ 0.5% charcoal stripped calf serum + IX (Pen/Strep, Glutamme and nonessential aminoacids) The CaPO4-DNA precipitate is added dropwise to the cells and the plate rocked gently to distnbute. DNA uptake is allowed to proceed for 5-6 hrs at 37°C under a 5% CO2 atmosphere. Following the DNA incubation penod, the cells are washed with PBS and trypsinized with 1ml of 0.05% trypsin The 1 ml of trypsmized cells is diluted into 10ml of phenol red free DMEM + 0.2% charcoal stπpped calf serum + IX (Pen/Strep, Glutamme and NEAA ). Transfected cells are plated in a 96 well microtiter plate (lOOμl/well) to which drug, diluted in media, has already been added in a volume of lOOμl. The final volume per well is 200μl with each drug concentration repeated in tnphcate over a range of half-log steps Incubation of cells and drugs is for 36 hrs at 37°C under CO2- At the end of the incubation penod, cells are examined microscopically for evidence of cell distress. Next, lOOμl of media containing the secreted alkaline phosphatase is removed from each well and transferred to a microtube array for heat treatment at 65°C for 1 hr to inactivate endogenous alkaline phosphatases (but not the heat stable secreted phosphatase). The heat treated media is assayed for alkaline phosphatase by a luminescence assay using the luminescence reagent CSPD® (Tropix, Bedford, Mass.) A volume of 50 μl media is combined with 200 μl of CSPD cocktail and incubated for 60 minutes at room temperature Lum esence is monitored using an ML2200 microplate luminometer (Dynatech) Luminescence reflects the level of activation of the fos reporter construct stimulated by the transiently expressed protein DNA-CaPO4 precipitate for 10cm. plate of cells Ras expression plasmid (lμg/μl) lOμl DSE-SEAP Plasmid (lμg/μl) 2μl Sheared Calf Thymus DNA ( 1 μg/μl) 8μl 2M CaCl2 74μl dH2θ 506μl 2X HBS Buffer 280mM NaCl lOmM KC1 1.5mM Na2HPO4 2H2O 12mM dextrose 50mM HEPES Final pH = 7.05 Lummesence Buffer (26ml) Assay Buffer 20ml Emerald Reagent™ (Tropix) 2.5ml lOOmM homoarginine 2.5ml CSPD Reagent® (Tropix) 1.0ml Assay Buffer Add 0.05M Na2CO3 to 0.05M NaHCO3 to obtain pH 9.5 EXAMPLE 21 The processing assays employed are modifications of that descπbed by DeClue et al [Cancer Research 51, 712-717, 1991]. K4B-Ras processing inhibition assay PSN-1 (human pancreatic carcinoma) or vιral-K4B-ras-transformed Ratl cells are used for analysis of protein processing. Subconfluent cells in 100 mm dishes are fed with 3.5 ml of media (methionine-free RPMI supplemented with 2% fetal bovine serum or cysteme-free/methionme-free DMEM supplemented with 0.035 ml of 200 mM glutamme (Gibco), 2% fetal bovine serum, respectively) containing the desired concentration of test compound, lovastatm or solvent alone Cells treated with lovastatin (5-10 μM), a compound that blocks Ras processing in cells by inhibiting a rate-limiting step in the isoprenoid biosynthetic pathway, serve as a positive control. Test compounds are prepared as lOOOx concentrated solutions in DMSO to yield a final solvent concentration of 0.1%. Following incubation at 37°C for two hours 204 μCi/ml [35s]Pro-Mιx (Amersham, cell labeling grade) is added. After introducing the label amino acid mixtuie, the cells are incubated at 37°C for an additional penod of time (typically 6 to 24 hours). The media is then removed and the cells are washed once with cold PBS. The cells are scraped into 1 ml of cold PBS, collected by centnfugation (10,000 x g for 10 sec at room temperature), and lysed by vortex g in 1 ml of lysis buffer (1% Nonidet P-40, 20 mM HEPES, pH 7.5, 150 mM NaCl, 1 mM EDTA, 0.5% deoxycholate, 0.1% SDS, 1 mM DTT, 10 μg/ml AEBSF, 10 μg/ml aprotimn, 2 μg/ml leupeptin and 2 μg/ml antipain). The lysate is then centπfuged at 15,000 x g for 10 min at 4°C and the supernatant saved. For immunoprecipitation of Kι4B-Ras, samples of lysate supernatant containing equal amounts of protein are utilized. Protein concentration is determined by the bradford method utilizing bovine serum albumin as a standard. The appropπate volume of lysate is brought to 1 ml with lysis buffer lacking DTT and 8 μg of the pan Ras monoclonal antibody, Y13-259, added. The protein/antibody mixture is incubated on ice at 4°C for 24 hours The immune complex is collected on pansorbin (Calbiochem) coated with rabbit antiserum to rat IgG (Cappel) by tumbling at 4°C for 45 minutes. The pellet is washed 3 times with 1 ml of lysis buffer lacking DTT and protease inhibitors and resuspended in 100 μl elution buffer (10 mM Tπs pH 7.4, 1% SDS). The Ras is eluted from the beads by heating at 95°C for 5 minutes, after which the beads are pelleted by bnef centnfugation (15,000 x g for 30 sec. at room temperature) The supernatant is added to 1 ml of Dilution Buffer 0.1% Tπton X- 100, 5 mM EDTA, 50 mM NaCl, 10 mM Tris pH 7.4) with 2 μg Kirsten-ras specific monoclonal antibody, c-K-ras Ab-1 (Calbiochem). The second protein/antibody mixture is incubated on ice at 4°C for 1-2 houis The immune complex is collected on pansorbin (Calbiochem) coated with rabbit antiserum to rat IgG (Cappel) by tumbling at 4°C for 45 minutes. The pellet is washed 3 times with 1 ml of lysis buffer lacking DTT and protease inhibitors and resuspended in Laemmh sample buffer. The Ras is eluted from the beads by heating at 95°C for 5 minutes, after which the beads are pelleted by brief centnfugation. The supernatant is subjected to SDS- PAGE on a 12% acrylamide gel (bιs-acrylamιde:acrylamιde, 1:100), and the Ras visualized by fluorography. hDJ processing inhibition assay PSN-1 cells are seeded in 24-well assay plates. For each compound to be tested, the cells are treated with a minimum of seven concentrations in half-log steps. The final solvent (DMSO) concentration is 0.1% A vehicle-only control is included on each assay plate. The cells are treated for 24 hours at 37°C / 5% CO 2 The growth media is then aspirated and the samples are washed with PBS. The cells are lysed with SDS-PAGE sample buffei containing 5% 2- mercaptoethanol and heated to 95°C for 5 minutes. After cooling on ice for 10 minutes, a mixture of nucleases is added to reduce viscosity of the samples. The plates are incubated on ice for another 10 minutes. The samples are loaded onto pre -cast 8% acrylamide gels and electrophoresed at 15 mA/gel for 3-4 hours. The samples are then transferred from the gels to PVDF membranes by Western blotting. The membranes are blocked for at least 1 hour in buffer containing 2% nonfat dry milk The membranes are then treated with a monoclonal antibody to hDJ- 2 (Neomarkers Cat. # MS-225), washed, and treated with an alkaline phosphatase- conjugated secondary antibody. The membranes are then treated with a fluorescent detection reagent and scanned on a phosphoπmager. For each sample, the percent of total signal corresponding to the unprenylated species of hDJ (the slower-migrating species) is calculated by densitometry. Dose-response curves and EC50 values are generated using 4- parameter curve fits in SigmaPlot software EXAMPLE 22 Rapl processing inhibition assay Protocol A- Cells are labeled, incubated and lysed as descπbed in Example 21 For immunoprecipitation of Rapl, samples of lysate supernatant containing equal amounts of protein are utilized. Protein concentration is determined by the bradford method utilizing bovine serum albumin as a standard The appropriate volume of lysate is brought to 1 ml with lysis buffer lacking DTT and 2 μg of the Rapl antibody, Rapl/Krevl (121) (Santa Cruz Biotech), is added. The protein/antibody mixture is incubated on ice at 4°C for 1 hour. The immune complex is collected on pansorbin (Calbiochem) by tumbling at 4°C for 45 minutes. The pellet is washed 3 times with 1 ml of lysis buffer lacking DTT and protease inhibitors and resuspended in 100 μl elution buffer (10 mM Tns pH 7.4, 1% SDS). The Rapl is eluted from the beads by heating at 95°C for 5 minutes, after which the beads are pelleted by brief centnfugation (15,000 x g for 30 sec. at room temperature). The supernatant is added to 1 ml of Dilution Buffer (0.1% Tnton X- 100, 5 mM EDTA, 50 mM NaCl, 10 mM Tns pH 7.4) with 2 μg Rapl antibody, Rapl/Krevl (121) (Santa Cruz Biotech). The second prote /antibody mixture is incubated on ice at 4°C for 1-2 hours. The immune complex is collected on pansorbin (Calbiochem) by tumbling at 4°C for 45 minutes. The pellet is washed 3 times with 1 ml of lysis buffer lacking DTT and protease inhibitors and resuspended m Laemmh sample buffer. The Rapl is eluted from the beads by heating at 95°C for 5 minutes, after which the beads are pelleted by bnef centnfugation. The supernatant is subjected to SDS-PAGE on a 12% acrylamide gel (bιs-acrylamιde:acrylamιde, 1:100), and the Rapl visualized by fluorography. Protocol B PSN-1 cells are passaged every 3-4 days in 10cm plates, splitting near- confluent plates 1:20 and 1:40. The day before the assay is set up, 5x 10 cells are plated on 15cm plates to ensure the same stage of confluency in each assay. The media for these cells is RPMI 1640 (Gibco), with 15% fetal bovine serum and lx Pen/Strep antibiotic mix. The day of the assay, cells are collected from the 15cm plates by trypsinization and diluted to 400,000 cells/ml in media. 0.5ml of these diluted cells are added to each well of 24-well plates, for a final cell number of 200,000 per well The cells are then grown at 37°C overnight. The compounds to be assayed are diluted in DMSO in 1/2-log dilutions The range of final concentrations to be assayed is generally 0.1-100μM. Four concentrations per compound is typical The compounds are diluted so that each concentration is lOOOx of the final concentration (1 e., for a lOμM data point, a lOmM stock of the compound is needed). 2μL of each lOOOx compound stock is diluted into 1ml media to produce a 2X stock of compound A vehicle control solution (2μL DMSO to 1ml media) is utilized 0 5 ml of the 2X stocks of compound are added to the cells After 24 hours, the media is aspirated from the assay plates Each well is πnsed with 1ml PBS, and the PBS is aspirated 180μL SDS-PAGE sample buffer (Novex) containing 5% 2-mercapto-ethanol is added to each well. The plates are heated to 100 » C for 5 minutes using a heat block containing an adapter for assay plates The plates are placed on ice. After 10 minutes, 20μL of an RNAse/ DNase mix is added per well. This mix is lmg/ml DNasel (Worth gton Enzymes), 0 25mg/ml Rnase A (Worthmgton Enzymes), 0 5M Tns-HCl pH8 0 and 50mM MgCl 2 The plate is left on ice for 10 minutes Samples are then either loaded on the gel, or stored at -70°C until use. Each assay plate (usually 3 compounds, each in 4-poιnt titrations, plus controls) requires one 15-well 14% Novex gel. 25μl of each sample is loaded onto the gel The gel is run at 15mA for about 3 5 houis It is important to run the gel far enough so that there will be adequate separation between 21kd (Rapl) and 29kd (Rab6). The gels are then transferred to Novex pre-cut PVDF membranes for 1.5 hours at 30V (constant voltage) Immediately after transferring, the membranes are blocked overnight in 20ml Western blocking buffer (2% nontat dry milk in Western wash buffer (PBS + 0 1 % Tween-20). If blocked over the weekend, 0.02% sodium azide is added The membranes are blocked at 4°C with slow rocking The blocking solution is discarded and 20ml fresh blocking solution containing the anti Rapla antibody (Santa Cruz Biochemical SC1482) at 1.1000 (diluted in Western blocking buffer) and the anti Rab6 antibody (Santa Cruz Biochemical SC310) at 1 5000 (diluted in Western blocking buffer) are added The membranes are incubated at room temperature for 1 hour with mild rocking The blocking solution is then discarded and the membrane is washed 3 times with Western wash buffer foi 15 minutes pei wash 20ml blocking solution containing 1 1000 (diluted in Western blocking buffer) each of two alkaline phosphatase conjugated antibodies (Alkaline phosphatase conjugated Anti-goat IgG and Alkaline phosphatase conjugated anti-rabbit IgG [Santa Cruz Biochemical]) is then added. The membrane is incubated for one hour and washed 3x as above About 2ml per gel of the Amersham ECF detection reagent is placed on an overhead transparency (ECF) and the PVDF membranes are placed face- down onto the detection reagent. This is incubated for one minute then the membrane is placed onto a fresh transparency sheet. The developed transparency sheet is scanned on a phosphoπmager and the Rapla Minimum Inhibitory Concentration is determined from the lowest concentration of compound that produces a detectable Rapla Western signal. The Rapla antibody used recognizes only unprenylated/unprocessed Rapla, so that the precence of a detectable Rapla Western signal is indicative of inhibition of Rapla prenylation Protocol C This protocol allows the determination of an EC50 for inhibition of processing of Rapla. The assay is run as descπbed in Protocol B with the following modifications. 20 μl of sample is run on pre -cast 10-20% gradient acrylamide mini gels (Novex Inc ) at 15 mA/gel for 2.5-3 hours. Prenylated and unprenylated forms of Rapla are detected by blotting with a polyclonal antibody (Rapl/Krev-1 Ab#121; Santa Cruz Research Products #sc-65), followed by an alkaline phosphatase- conjugated anti-rabbit IgG antibody. The percentage of unprenylated Rapla relative to the total amount of Rapla is determined by peak integration using Imagequant7 software (Molecular Dynamics). Unprenylated Rapla is distinguished from prenylated protein by virtue of the greater apparent molecular weight of the prenylated protein Dose-response curves and EC50 values are generated using 4- parameter curve fits in SigmaPlot software EXAMPLE 23 In vivo tumor growth inhibition assay (nude mouse) In vivo efficacy as an inhibitor of the growth of cancer cells may be confirmed by several protocols well known in the art. Examples of such in vivo efficacy studies are described by N. E. Kohl et al. (Nature Medicine, 1:792-797 (1995)) and N. E. Kohl et al. (Proc. Nat. Acad. Sci. U.S.A., 91:9141-9145 (1994)). Rodent fibroblasts transformed with oncogenically mutated human Haras or Ki-ras (10 cells/animal in 1 ml of DMEM salts) are injected subcutaneously into the left flank of 8-12 week old female nude mice (Harlan) on day 0. The mice in each oncogene group are randomly assigned to a vehicle, compound or combination treatment group. Animals are dosed subcutaneously starting on day 1 and daily for the duration of the expeπment Alternatively, the farnesyl-protein transferase inhibitor may be administered by a continuous infusion pump. Compound, compound combination or vehicle is delivered in a total volume of 0.1 ml. Tumors are excised and weighed when all of the vehicle-treated animals exhibited lesions of 0.5 - 1.0 cm in diameter, typically 11-15 days after the cells were injected. The average weight of the tumors in each treatment group for each cell line is calculated Cell Radiotracer Assay of Farnesyl Transferase Inhibitors (CRAFTI ) This assay measures the competition between a farnesyl transferase inhibitor (FTI) and a radiolabeled FTI for binding to high affinity sites (presumably farnesyl transferase) in living cells and is descπbed in detail in PCT Pat. Publ WO 99/00654 (1/7/99). Fresh radiotracer [123τ](g)-i-(3-,odo-phenyl)-4-[l-(4-cyanobenzyl)-5- ιmιdazolylmethyl]-5-[2-(methanesulfonyl)ethyl]-2-pιperazιnone dihydrochlonde, prepared as descπbed in Example 3 of PCT Pat Publ. WO 99/00654 (1/7/99) is synthesized monthly, with a specific activity of -350-1400 Ci/mmole. CRAFTI is run routinely using a Ratl fibroblast line transformed by v-Ha-ras (Hras/ratl) CRAFTI is performed by growing cells under anchorage-dependent conditions in 24 - well tissue culture plates overnight, to achieve near confluent monolayers of cells. Radiotracer is diluted in cell growth media to a concentration of ~1 nM (-1 mCi/ml), and vehicle or test FTI (in log dilutions, 6 point titration) is added to the diluted tracer. The growth media is removed from the cell monolayers, and 0.65 ml of the diluted radiotracer/test FTI mixture is applied. After 4 hr incubation, the tracer is removed by aspiration, the monolayers are rinsed quickly with 2 ml PBS, and the cells are trypsinized and transferred to tubes for gamma counting. Dose-inhibition curves and IC 50 's are determined by curve-fitting the equation: Radiotracer Bound = A 0 - A 0 *[I 0 ]/([I 0 ) + IC 50 ) + NS, where A 0 is the count-rate of radiotracer in the absence of inhibitor, I 0 is the concentration of added FTI, IC 50 is the concentration of FTI that inhibits 50% of radiotracer binding and NS is the extent of non-specific binding.

Claims: WHAT IS CLAIMED IS: 1. A compound which is: - A 1 (CR 1a 2 ) n A 2 (CR 1a 2 ) n wherein: Rl a and R lb are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 O-, Rl lS(O) m -, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NR 10 )-, CN, NO2, R 10 C(O)-, N3, -N(R 10 )2, or R π OC(O)NR 10 -, c) unsubstituted or substituted Ci-Cβ alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, R n S(O) m -, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NR 10 )-, CN, R 10 C(O)-, N3, -N(R 10 )2, and R 1 !θC(O)-NR 10 -; R2 and R^ are independently selected from: H; unsubstituted or substituted Cι_8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C 1-4 alkyl, c) (CH 2 ) P NR6R7, d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C 1-4 alkyl, h) SR 6a , S(O)R 6a , SO2R 6a , 2) C3-6 cycloalkyl, 3) OR 6 , 4) SR 6a , S(O)R 6a , or SO2R 6a , 5) — NR 6 R 7 β) -°γ NR6R7 o 1 °) \ ^NR 6 R 7 O 11) — S0 2 -NR 6 R 7 14) OR fc o 15) N 3J 16) F, or 17) perfluoro-C^-alkyl; or R2 and R^ are attached to the same C atom and are combined to form - (CH2)u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , -NC(O)-, and -N(COR 10 )- ; R4 is selected from H and CH3; and any two of R^, R3 and R4 are optionally attached to the same carbon atom; R 6 , R7 and R^a are independently selected from: H; Ci-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Ci-4 alkoxy, b) aryl or heterocycle, c) halogen, f) — S0 2 R 11 , or g) N(RlO) 2 ; or R 6 and R 7 may be joined in a ring;R and R ' a ma y be joined in a ring; R^a is selected from: C j-4 alkyl. C3-6 cycloalkyl. heterocycle. aryl. unsubstituted or substituted with: a) Ci-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, f) — S0 2 R 11 , or g) N(RlO) 2 ; R8 is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R π S(0) m -, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NR 10 )-, CN, NO2, R 10 C(O)-, N3, -N(R 10 )2, or RϋOC OjNR 10 -, and c) C[-C alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle. C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, Rl lS(O)m-, R 10 C(O)NH-, (R 10 )2NC(O)-, R 10 2N-C(NR 10 )-, CN, RlOC(O)-, N3, -N(R 10 )2, or R 10 OC(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R^S m-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-. R 10 2N-C(NR 10 )-, CN, NO2, R l0 C(O)-, N3, -N(R 10 )2, or R 1 iOC^NR 10 -, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 O-. R 1 ^(OJm-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NR 10 )-, CN, R 10 C(O)-, N3, -N(Rl°)2, or R 1 1 OC(O)NR 1 0-; RIO is independently selected from hydrogen, C 1-C6 alkyl, benzyl and aryl; RU is independently selected from C -C6 alkyl and aryl; A^ and A- are independently selected from: a bond. -CH=CH-. -C≡C-, -C(O)-, -C(O)NR 10 -, -NRiOcrø)-, O, -N(R 10 )-. -S(O)2N(R 10 )-, -N(R 10 )S(O)2-, or S(O) m , A 3 is selected from: -C(O)-, -C(O)NR 10 -, -C(O)(CR l a )2-O-, -C(O)O- and S(O) m ; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A^ is S(O) m and V is not hydrogen if A^ is a bond, n is 0 and A- is S(O) m ; W is a heterocycle; Z is unsubstituted or substituted C5-C10 alkyl, wherein the substituted C5-C10 alkyl is substituted with one or two moieties selected from the following: a) Ci-4 alkoxy, b) NR°R 7 , c) C3-6 cycloalkyl, d) -NR 6 C(O)R 7 , e) -OR 10 , f) -S(O) m R6a, g) halogen, or h) perfluoroalkyl, m is 0, 1 or 2; p is 0, 1 , 2, 3 or 4, r is 0 to 5, provided that r is 0 when V is hydrogen or a pharmaceutically acceptable salt thereof. 2. The compound according to Claim 1 of the formula B: wherein: Rla and R 0 are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R1°O-, -N(R 10 )2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 O-. or -N(R 10 )2; R 3 IS selected from H and CH3; .NR 6 R 7 R2 is selected from H; O or Cj -.5 alkyl, unbranched or branched. unsubstituted or substituted with one or more of: 1) aryl. 2) heterocycle, 3) OR 6 . 4) SR 6a . SO2R 6a . or and R- and R 3 are optionally attached to the same carbon atom: R 6 and R 7 are independently selected from: H; Ci-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle. unsubstituted or substituted with: a) Ci-4 alkoxy, b) halogen, or c) aryl or heterocycle; R 6a is selected from: Ci-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) Ci-4 alkoxy, b) halogen, or c) aryl or heterocycle; R° is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R IOQ-, R!0C(O)NR 10 -, CN, NO2, (R 10 )2N-C(NR 10 )-, R 10 C(O)-, -N(R 10 )2, or R 1 1 OC(O)NR 10 -, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 O-, R 10 C(O)NR 10 -. (Ri0)2N-C(NR 10 )-, R 10 C(O)-, -N(R 10 )2, or R 1 lθC(O)NR 10 -; R^a is hydrogen or methyl; R 10 is independently selected from hydrogen, C -C6 alkyl, benzyl and aryl; RI ! is independently selected from C1-C6 alkyl and aryl; A 1 and A- are independently selected from: a bond. -CH=CH-, -C≡C-, -C(O)-, -C(O)NR 10 -, O. -N(R 10 )-, 01 S(O) m . A 3 is selected from -C(O)-, -C(O)NR 10 -, -C(O)(CR l a )2-O-, -C(O)O- 01 S(O) m , V is selected from a) hydrogen, b) heterocycle selected from pyrro dinyl, imidazolyl, pyπdinyl, thiazolyl, pyπdonyl, 2-oxopιpeπdιnyl, indolyl. qumohnyl, isoquinolmyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m , Z is unsubstituted or substituted C5-C10 alkyl, wherein the substituted C5-C10 alkyl is substituted with one or two moieties selected from the following- a) Ci-4 alkoxy, b) NR 6 R 7 , c) C3-6 cycloalkyl, d) -NR 6 C(O)R 7 , e) -OR 10 f) -S(O) m R 6 , g) halogen, or h) perfluoroalkyl, n is 0, 1, 2, 3 or 4, p is 0, 1, 2, 3 or 4, r is 0 to 5, piovided that r is 0 when V is hydrogen, and or a pharmaceutically acceptable salt thereof 3 The compound according to Claim 1 of the formula C wherein: Rla and R 1 " are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, Rl°O-, -N(R i0 )2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 O-, or -N(R 10 )2; R 3 is selected from H and CH3; \ .NR 6 R 7 R^ is selected from H; T O ; or Ci-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 , 4) SR 6a , SO2R 6a , or and R^ and R 3 are optionally attached to the same carbon atom; R 6 and R 7 are independently selected from: H; Ci-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) C -4 alkoxy, b) halogen, or c) aryl or heterocycle, R a is selected from: Ci-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with- a) Ci-4 alkoxy, b) halogen, or c) aryl or heterocycle; R8 is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RIOO-, Rl0c(O)NR 10 -, CN, NO2, (R 10 )2N-C(NRl0)-, R 10C(O)-, -N(R 1 0) 2 , or R HOCCOJNR 10 -, and c) Ci-Ct, alkyl substituted by C1-C6 perfluoroalkyl, R 10 O-, R^C^NRiO-, (R 10 )2N-C(NR 10 )-, R 10 C(O)-, -N(R 10 )2, or R 1 lθC(O)NR 10 -; R^ is hydrogen or methyl; RIO IS independently selected from hydrogen, Ci-Cό alkyl, benzyl and aryl; RU IS independently selected from Ci-Cβ alkyl and aryl; A 1 and A- are independently selected from: a bond, -CH=CH-, -G=C-, -C(O)-, -C(O)NR 10 -, O, -N(R 10 )-, or S(O) m , A 3 is selected from: -C(O)-, -C(O)NR 10 -, -C(O)(CR l a )2-O-, -C(O)O- or S(O) m , V is selected from: a) hydrogen, b) heterocycle selected from pyrrohdinyl, imidazolyl, pyπdinyl, thiazolyl, pyπdonyl. 2-oxopιpeπdιnyl, indolyl, qumohnyl, isoquinolinyl, and thienyl, c) aryl, d) C 1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C?-C20 alkenyl. and provided that V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A~ is S(O) m , Z is unsubstituted or substituted C5-C10 alkyl, wherein the substituted C5-C10 alkyl is substituted with one or two moieties selected from the following a) Ci-4 alkoxy, b) NR 6 R 7 , c) C3-6 cycloalkyl, d) -NR 6 C(O)R 7 , e) -OR 10 , 0 -S(O) m R6a g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; p is 2, 3 or 4; πs 0 to 5, provided that r is 0 when V is hydrogen; and or a pharmaceutically acceptable salt thereof. The compound according to Claim 2 of the formula D: wherein: R l a and R 1 ^ are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 O-, -N(R 10 )2 or C2-C6 alkenyl, c) C 1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 O-. or -N(R 10 )2; R 3 is selected from H and CH3; .NR 6 R 7 R^ is selected from H; O or C -5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 , 4) SR 6a , SO2R 6a or and R2 and R 3 are optionally attached to the same carbon atom; R 6 and R 7 are independently selected from: H; C1-.4 alkyl, C3-6 cycloalkyl, aryl, heterocycle. unsubstituted or substituted with: a) C -4 alkoxy, b) halogen, or c) aryl or heterocycle; R 6a selected from: Ci-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) Cj-4 alkoxy, b) halogen, or c) aryl or heterocycle; R° is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 10Q-. R 10 C(O)NR 10 -, CN, NO2, (R 10 )2N-C(NR 10 )-, R 10 C(O)-, -N(R 10 )2, or R 1 1 OC(O)NR 10 -. and c) C1-C6 alkyl substituted by Cj-C6 perfluoroalkyl. R 10 O-. R 10 C(O)NR 10 -, (R 10 )2N-C(NR 10 )-, R 10 C(O)-, -N(R 10 )2, or R 1 1 OC(O)NR 10 -: R^a is hydrogen or methyl; R 10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; R 1 1 is independently selected from C1-C6 alkyl and aryl; A 1 is selected from: a bond, -CH=CH-. -C≡C-, -C(O)-, -C(O)NR 10 -, O, -N(R 10 )-, or S(O) m ; A 3 is selected from: -C(O)-, -C(O)NR 10 - or -C(O)O-; V is selected from: a) heterocycle selected from pyridinyl and quinolinyl, and b) aryl; Z is ' unsubstituted or substituted C5-C 10 alkyl, wherein the substituted C5-C10 alkyl is substituted with one or two moieties selected from the following: a) Ci-4 alkoxy, b) NR 6 R 7 , c) C3-6 cycloalkyl, d) -NR 6 C(O)R 7 , e) -OR 10 , 0 -S(O) m R 6 , g) halogen, or h) perfluoroalkyl; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; V I S 0. 1, 2 or 3: or a pharmaceutically acceptable salt thereof. The compound according to Claim 3 of the formula E: wherein: R l a and R 1 ^ are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 O-, -N(R 10 )2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 O-, or -N(R 10 )2; R 3 is selected from H and CH3; \ .NR 6 R 7 R2 is selected from H; Y O ; or Cj-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 , 4) SR 6a , SO2R 6a , or and R- and R 3 are optionally attached to the same carbon atom: R 6 and R 7 are independently selected from: H; C[_4 alkyl, C3-6 cycloalkyl, aryl. heterocycle, unsubstituted or substituted with: a) Ci-4 alkoxy. b) halogen, or c) aryl or heterocycle; R 6a is selected from: Cι_4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) Ci-4 alkoxy, b) halogen, or c) aryl or heterocycle; R° is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 10 O-, R 10 C(O)NR 10 -, CN, NO2, (R 10 )2N-C(NR 10 )-, R 10 C(O)-, -N(R 10 )2, or R^OC^NR 1 -, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 O-, R 10 C(O)NR 10 -, (R 1 )2N-C(NR 10 )-, R 10 C(O)-, -N(R 10 )2, or R H0C(0)NR 10 -; R^a is hydrogen or methyl; R 10 is independently selected from hydrogen, C1-C6 alkyl. benzyl and aryl, R 1 1 is independently selected from C1-C6 alkyl and aryl; A 1 is selected from: a bond, -CH=CH-, -C≡C-, -C(O)-, -C(O)NR 10 -. O. -N(R 10 )-, or S(O) m , A 3 is selected from: -C(O)-, -C(O)NR 10 - or -C(O)O-, V is selected from- a) heterocycle selected from pyπdinyl and qumohnyl. and b) aryl. Z is unsubstituted or substituted C5-C10 alkyl, wherein the substituted C5-C 10 alkyl is sul bstituted with one or two moieties selected from the following- a) C i-4 alkoxy, b) NR 6 R 7 , c) C3-6 cycloalkyl, d) -NR 6 C(O)R 7 , e) -OR 10 , f) -S(O) m R , ς) halogen, or h) perfluoroalkyl; m is 0, l or 2; n is 0, 1, 2, 3 or 4; p is 2, 3 or 4; V is 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof. 6. A compound which is selected from: l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]pιperazιne-4-carboxylιc acιd-(3,3- dιmethyl)butyπc ester 1-[1 -(4' -Cyanobenzyl) ιmιdazol-5-ylmethyl]pιperazme-4-(2-hydroxy-4.4- dιmethyl)valeramιde l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]pιperazιne-4-carboxyhc acιd-(2,2- dιmethyl)propyl ester l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]-4-(2-ethylbutanecarbonyl) piperazine l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]-pιperazιne-4-carboxyhc acιd-(2-t- butoxy)ethyl ester l-(l-(4 -cyanobenzyl)ιmιdazol-5-ylmethyI)-4-(N-(l,l,3,3-tetramethyl)-butyl) carboxamιde]pιperazme l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]-pιperazιne-4-carboxyhc acid (2,2,5,5- tetramethyl)hexyl ester l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]-pιperazme-4-carboxylιc acid (2,2- dιmethyl)pent-3-yl ester 1-[1 -(4' -Cyanobenzyl) ιmιdazol-5-ylmethyl]-4-(2-methyl-2-ethylbutanoyl)pιperazιne 4-[5-(4-Heptanoyl-pιperazιn-l-ylmethyl)-ιmιdazol-l-ylmethyl]-benzonιtπle 4-[5-(4-Hexanoyl-pιperazιn-l-ylmethyl)-ιmιdazol-l-ylmethyl]-benzonιtnle 4-[5-(4-Octanoyl-pιperazιn-l-ylmethyl)-ιmιdazol-l-ylmethyl]-benzonιtπle 4-[5-(4-Nonanoyl-pιperazιn-l-ylmethyl)-ιmιdazol-l-ylmethyl]-benzonιtπle 4-[5-(4-Decanoyl-pιperazιn-l-ylmethyl)-ιmιdazol- l-ylmethyl]-benzonιtπle or a pharmaceutically acceptable salt or optical isomer thereof. 7. The compound according to Claim 6 which is selected from: l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]pιperazιne-4-carboxyhc acιd-(3,3- dιmethyl)butyπc ester l-[l-(4' -Cyanobenzyl) ιmιdazol-5-ylmethyl]pιperazιne-4-(2-hydroxy-4.4- dιmethyl)valeramιde 1-[1 -(4' -Cyanobenzyl) ιmιdazol-5-ylmethyl]pιperazme-4-carboxylιc acιd-(2,2- dimethyl)propyl ester 1-[1 -(4 " -Cyanobenzyl) ιmιdazol-5-ylmethyl]-4-(2-ethylbutanecarbonyl) piperazine l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]-pιperazme-4-carboxyhc acιd-(2-t- butoxy ethyl ester l-(l-(4 -cyanobenzyl)ιmιdazol-5-ylmethyl)-4-(N-(l,l,3,3-tetramethyl)-butyl) carboxamιde]pιperazιne l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]-pιperazιne-4-carboxylιc acid (2,2,5,5- tetramethyl)hexyl ester l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]-pιperazιne-4-carboxyhc acid (2,2- dιmethyl)pent-3-yl ester l-[l-(4'-Cyanobenzyl) ιmιdazol-5-ylmethyl]-4-(2-methyl-2-ethylbutanoyl)pιperazme or a pharmaceutically acceptable salt or optical isomer thereof. 8 A pharmaceutical composition compnsing a pharmaceutical earner, and dispersed therein, a therapeutically effective amount of a compound of Claim 1. 9. A pharmaceutical composition compnsing a pharmaceutical earner, and dispersed therein, a therapeutically effective amount of a compound of Claim 6 10 A method for inhibiting farnesyl-protein transferase and geranylgeranyl-protein transferase type I which compπses administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 8 11 A method for inhibiting farnesyl-protein transferase and geranylgeranyl-protein transferase type I which compnses administenng to a mammal in need thereof a therapeutically effective amount of a composition of Claim 9. 12. A method for treating cancer which compnses administeπng to a mammal in need thereof a therapeutically effective amount of a composition of Claim 8. 13. A method according to Claim 12 wherein the cancer is characteπzed by a mutated K4B-Ras protein. 14. A method for treating cancer which compnses administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 9. 15. A method according to Claim 14 wherein the cancer is charactenzed by a mutated K4B-Ras protein. 16. A method for treating neurofibromin benign proliferative disorder which compπses administenng to a mammal in need thereof a therapeutically effective amount of a composition of Claim 8. 17 A method for treating blindness related to retinal vasculanzation which compnses administenng to a mammal in need thereof a therapeutically effective amount of a composition of Claim 8. 18. A method for treating infections from hepatitis delta and related viruses which compπses administeπng to a mammal in need thereof a therapeutically effective amount of a composition of Claim 8 19. A method for preventing restenosis which compπses administeπng to a mammal in need thereof a therapeutically effective amount of a composition of Claim 8. 20. A method for treating polycystic kidney disease which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 8. 21. A pharmaceutical composition made by combining the compound of Claim 1 and a pharmaceutically acceptable caπier. 22. A process for making a pharmaceutical composition compnsing combining a compound of Claim 1 and a pharmaceutically acceptable earner.

Inventors: BERGMAN JEFFREY M, DINSMORE CHRISTOPHER J, LUMMA WILLIAM C JR, SISKO JOHN T, SMITH ANTHONY M, TUCKER THOMAS J, BERGMAN, JEFFREY, M., DINSMORE, CHRISTOPHER, J., LUMMA, WILLIAM, C., JR., SISKO, JOHN, T., SMITH, ANTHONY, M., TUCKER, THOMAS, J.
Applicants: BERGMAN JEFFREY M, DINSMORE CHRISTOPHER J, LUMMA WILLIAM C JR, MERCK & CO INC, SISKO JOHN T, SMITH ANTHONY M, TUCKER THOMAS J, BERGMAN, JEFFREY, M., DINSMORE, CHRISTOPHER, J., LUMMA, WILLIAM, C., JR., MERCK & CO., INC., SISKO, JOHN, T., SMITH, ANTHONY, M., TUCKER, THOMAS, J.
Application year: 2000
Main classification: A61K31
IPC codes: A61K31, A61P9, A61P13, A61P27, A61P31, A61P35, C07D233