INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE

Abstract: The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.

Description: TITLE OF THE INVENTION INHIBITORS OF FARNESYL-PROTELN TRANSFERASE BACKGROUND OF THE INVENTION The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP. Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M. Willumsen, ΛΛAZ. Rev. Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-rø_>, Ki4a-rα.s, Y Ab-ras and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defec¬ tive in their GTPase activity and constitutively transmit a growth stimulatory signal. Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-Aaa^Aaa-^-Xaa" box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al, Nature 570:583-586 (1984)). Depend¬ ing on the specific sequence, this motif serves as a signal sequence for the enzymes famesyl-protein transferase or geranylgerany I -protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 67 :355-386 (1992); W.R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-231 (1992)). The Ras protein is one of several proteins that are known to undergo post-translational famesylation. Other famesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also famesylated. James, et al., have also suggested that there are famesylated proteins of unknown structure and function in addition to those listed above. Inhibition of famesyl-protein transferase has been shown to block the growth of Ras -transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demon¬ strated that certain inhibitors of famesyl-protein transferase selectively block the processing of the Ras oncoprotein intracellularly (N.E. Kohl et al., Science, 260:1934-1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of famesyl-protein transferase blocks the growth of ras-dependent tumors in nude mice (N.E. Kohl et al., Proc. Natl. Acad. Sci U.S.A., 97 :9141 - 9145 (1994) and induces regression of mammary and salivary carcinomas in ras transgenic mice (N.E. Kohl et al., Nature Medicine, 1 :792-797 (1995). Indirect inhibition of famesyl-protein transferase i n vivo has been demonstrated with lovastatin (Merck & Co., Rahway, NJ) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:319 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including famesyl pyrophosphate. Famesyl-protein transferase utilizes famesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famesyl 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); Marine et al, Proc. Natl. Acad. Sci USA, 87:1541-7545 (1990)). Inhibition of famesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. However, direct inhibition of famesyl- protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis. Inhibitors of famesyl-protein transferase (FPTase) have been described in two general classes. The first are analogs of famesyl diphosphate (FPP), while the second class of inhibitors is related to the protein 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, 88:132-136 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the famesyl-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., /. Med. Chem., 37, 725 (1994)). In general, deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound. However, the thiol group potentially places limitations on the thera¬ peutic application of FPTase inhibitors with respect to pharmaco- kinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable. It has recently been reported that famesyl-protein transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7- 112930). It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516). Imidazole-containing inhibitors of famesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 Al). It is, therefore, an object of this invention to develop peptidomimetic compounds that do not have a thiol moiety, and that will inhibit famesyl-protein transferase and thus, the post-translational famesylation of proteins. It is a further object of this invention to develop chemotherapeutic compositions containing the compounds of this invention and methods for producing the compounds of this invention. SUMMARY OF THE INVENTION The present invention comprises peptidomimetic piperazine-containing compounds which inhibit the famesyl-protein transferase. The instant compounds lack a thiol moiety and thus offer unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these famesyl transferase inhibitors and methods for their production. The compounds of this invention are illustrated by the formulas A and B: V - A 1 (CR 1a 2 ) n A 2 (CR 1a 2 ) n ; DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention are useful in the inhibition of famesyl-protein transferase and the famesylation of the oncogene protein Ras. In a first embodiment of this invention, the inhibitors of famesyl-protein transferase are illustrated by the formula A: Z wherein: R la is selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOo-, Rl l S(0) m -, R10C(O)NR 10-, (RlO) 2 NC(0)-, R l0 2 N-C(NR lO)-, CN, NO2, R 10 C(O)-, N3, -N(RlO)2, or Rl lθC(O)NRl0-, c) unsubstituted or substituted C\ -Cβ alkyl wherein the substitutent on the substituted C1 -C alky] is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, R n S(0) m -, Rl0c(O)NRl0-, (RlO) 2 NC(0)-, RIO2N- C(NRlO)-, CN, R l c(O)-, N3, -N(Rl0)2, and R HoC(O)- NR10-; R^ and R3 are independently selected from: H; unsubstituted or substituted Cl -8 alkyl, unsubstituted or substituted C2- 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) Cl-4 alkyl, d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-Cl -4 alkyl, or h) SR6a, S(0)R 6 a, Sθ2R 6a , 2) C3-6 cycloalkyl, 3) OR6, 4) SR6a, S(0)R 6 a, or Sθ2R 6a , 6 D 7 5) * NR°R Ό. .NR 6 R 7 8) T o 9) -0. / OR 6 T o o 11 ) — S0 2 - NR 6 R 7 13) ^ R 6 o 15) N 3 , 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(0) m , -NC(O)-, and -N(CORlO)- ; R4 is selected from H and CH3; and any two of R2, R3 and R^ are optionally attached to the same carbon atom; R6, R7 and R7a are independently selected from: H; Cl-4 alkyl, C3- cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl_4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, f) — S0 2 R 11 , or g) N(Rl ) 2 ; or R6 and R7 may be joined in a ring; R7 and R^ may be joined in a ring; R6 is selected from: Cl -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(R lO) 2 ; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, R 1 ^(O -, RlOC(0)NRlO-, (RlO)2NC(0)-, R^N- C(NRlO)-, CN, N02, R 10 C(O)-, N3, -N(RlO) 2 , or RllOC(O)NRl0-, 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-, Rl lS(0) m -, Rl c(O)NH-, (Rl0) 2 NC(O)-, RI 2 N- C(NRlO)., CN, RlOC(O)-, N3, -N(RlO) 2 , 0 r R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0)m-, R!0C(O)NR10-, (Rl ) 2 NC(0)-, RK>2N- C(NRl )., CN, Nθ2, R 10 C(O)-, N3, -N(RlO) 2 , 0 r RllOC(O)N l0-,and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOo-, RllS(0) m -, R^C^NRlO., (RlO) 2 NC(0)-, Rl0 2 N-C(NRlO)-, CN, RlOC(O)-, N3, -N(Rl ) 2 , or Rl 1OC(O)NR10- ; Rio is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Al and A 2 are independently selected from: a bond, -CH=CH-, -C=C-, -C(O)-, -C(O)NRl0_, -NRlOC(O)-, O, -N(RlO)-, -S(O)2N(Rl0)-, -N(Rl0)S(O)2-, or S(0) m ; G is selected from H2 and O; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, provided that V is not hydrogen if A is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(0)m, W is a heterocycle; Z is selected from: a unsubstituted or substituted group selected from aryl or heteroaryl, wherein the substituted group is substituted with one or more of the following: a) Cl -4 alkyl, unsubstituted or substituted with: Cl-4 alkoxy, NR 6 R 7 , C3-6 cycloalkyl, aryl, heterocycle, HO, -S(0) m R 6a , or -C(0)NR6R7, or the pharmaceutically acceptable salts thereof. In a second embodiment of this invention, the inhibitors of famesyl-protein transferase are illustrated by the formula B: A 1 (CR 1a 2 ) n wherein: R a is selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, Rl l S(0) m -, R10C(O)NR 10-, (Rl0)2NC(O)-, Rl<>2N-C(NRl0)-, CN, Nθ2, R 10 C(O)-, N3, -N(Rl0)2, or R1 1 OC(O)NR 10_, c) unsubstituted or substituted Cj -C6 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 1 ^(O , R 10 C(0)NR10_, (Rl0) 2 NC(O)-, R IO 2 N- C(NRlO)-, CN, R lOC(O)-, N3, -N(R lO)2, and R π OC(0)- NRl _; R2 and R3 are independently selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, o wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) Cl -4 alkyl, d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-Cl -4 alkyl, or h) SR6a, S(0)R6a, Sθ2R 6a , 2) C3-6 cycloalkyl, 3) OR6, 4) SR6a, S(0)R 6a , or Sθ2R 6a , 5) — NR 6 R 7 * O^ .NR 6 R 7 8) T O 9) O^ .OR 6 T O 11 ) — SO 2 -NR 6 R 7 13) O 14) -η ∞ 6 O 15) N 3 , 16) F, or 17) perfluoro-C^-alkyl; or R 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(0) m , -NC(O)-, and -N(COR lO)- ; R4 is selected from H and CH3; and any two of R , R and R4 are optionally attached to the same carbon atom; R6, R7 and R7 are independently selected from: H; Cl -4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl -4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, f) — S0 2 R 1 1 , or g) N(Rl0) 2; O r R6 and R7 may be joined in a ring; R7 and R7a ma y be joined in a ring; R6a is selected from: Cl -4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) Cl -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) aryl, heterocycle, C3-C10 cycloalkyl, C2-C alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RllS(0)m-, Rl°C(O)NRl0-, (Rl0) 2 NC(O)-, Rl0 2 N- C(NRl )-, CN, N02, R 10 C(O)-, N3, -N(RlO)2, or RllOC(O)N l0-, 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, RlOO-, Rl lS(0)m-, Rl°C(0)NH-, (Rl0)2NC(O)-, RI 2N- C(NRlO)-, CN, RlOC(O)-, N3, -N(RlO)2, or Rl0θC(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RllS(0) m -, R1°C(0)NR10-, (RlO) 2 NC(0)-, RIO2N- C(NRl )-, CN, N02, Rl°C(0)-, N3, -N(Rl ) 2 , or RllOC(O)N l0-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, R10C(0)NR1 -, (RlO) NC(0)-, R!0 2 N-C(N 10)-, CN, RlOC(O)-, N3, -N(Rl )2, or Rl lθC(O)NRl0-; RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Al and A2 are independently selected from: a bond, -CH=CH-, -C≡C-, -C(O)-, -C(O)NRl0-, -NRlOC(O)-, O, -N(RlO)., -S(0)2N(R 1 )-, -N(R 10)S(O)2-, or S(0) m ; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C 1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A is S(0)m; W is a heterocycle; or the pharmaceutically acceptable salts thereof. In a preferred embodiment of this invention, the inhibitors of famesyl-protein transferase are illustrated by the formula A: - A 1 (CR 1 a 2 ) n A 2 (CR 1a 2 ) n - W N N N-Z R 3 R 4 A wherein: R la is independently selected from: hydrogen or Cl -C alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R l°0-, -N(R lO)2 or C2-C6 alkenyl, c) unsubstituted or substituted C l -C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, RlOO- and -N(RlO)2; R3 and R4 are independently selected from H and CH3; R2 is H; o or Cl -5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1 ) aryl, 2) heterocycle, 3) ORθ, 4) SR6a, Sθ2R 6a , or 5 ) ^ NR 6 R 7 T o : and any two of R , R , R4 5 anc ι R5 are optionally attached to the same carbon atom; R6, R7 and R7 are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) Cl-4 alkoxy, b) halogen, or c) aryl or heterocycle; R^ is selected from: Cl-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) Cl-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, RlOo-, R10C(O)NR10-, CN, Nθ2, (RlO) 2 N-C(NRlO)-, RlOC(O)-, -N(RlO)2, or RHθC(O)NRl0-,and c) C1-C alkyl substituted by -C6 perfluoroalkyl, Rl°0-, Rl0C(O)NRl0-, (RlO) 2 N-C(NRlO)-, RlOC(O)-, -N(Rl ) 2 , or Rl lOC(O)NRl0-; R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, Cl -Cό perfluoroalkyl, F, Cl, R OO-, Rl l S(0)m-, R I 0 C(O)NRl0-, CN, Nθ2, (R lO)2N-C(NR lO)-, RlOC(O)-, -N(RlO)2, or R1 1OC(O)N 10-, and c) C l -C6 alkyl unsubstituted or substituted by C l -C6 perfluoroalkyl, F, Cl, RlOO-, R l ! S(0) m -, R 10 C(O)NR l 0-, CN, (RlO)2N-C(NR O)-, RlOC(O)-, -N(RlO) 2 , or R1 10C(0)NR10-; RIO is independently selected from hydrogen, C1 -C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1 -C6 alkyl and aryl; A l and A are independently selected from: a bond, -CH=CH-, -C≡C-, -C(O)-, -C(O)NR l0-, O, -N(RlO)-, or S(0) m ; G is selected from H2 and O; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C 1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(0) m ; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; Z is mono- or bicyclic aryl, mono- or bicyclic heteroaryl, mono- or bicyclic arylmethyl, mono- or bicyclic heteroarylmethyl, mono- or bicyclic arylsulfonyl, mono- or bicyclic heteroarylsulfonyl, unsubstituted or substituted with one or two of the following: 1 ) Cl -4 alkyl, unsubstituted or substituted with: a) Cl -4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(0) m R 6 , or g) -C(0)NR6R7, u is 4 or 5; or the pharmaceutically acceptable salts thereof. In a more preferred embodiment of this invention, the inhibitors of famesyl-protein transferase are illustrated by the formula C: wherein: R3 and R^ are independently selected from H and CH3; R 2 is H; or Ci -5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1 ) aryl, 2) heterocycle, 3) OR6, 4) SR6a, Sθ2R 6a , or 5 ) \ .NR 6 R 7 T O ; and R2 and R3 are optionally attached to the same carbon atom; R6 and R7 are independently selected from: H; Cl -4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) Cl-4 alkoxy, b) halogen, or c) aryl or heterocycle; R oa is selected from: Cl -4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) Cl -4 alkoxy, b) halogen, or c) aryl or heterocycle; R8 is independently selected from: a) hydrogen, b) C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, R 0C(O)NR 10-, CN, Nθ2, (R lO)2N-C(NR lO)-, RlOc(O)-, -N(R l )2, or Rl lOC(O)NRl0-, and c) C 1 -C6 alkyl substituted by C l -C6 perfluoroalkyl, R 1 0 O-, RlOC(0)NRlO-, (R 10)2N-C(NR 10)-, RlOc(O)-, -N(RlO) 2 , or R lOC(O)NRl0-; RI is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; R l 1 is independently selected from C1 -C6 alkyl and aryl; Z is mono- or bicyclic aryl, mono- or bicyclic heteroaryl, mono- or bicyclic arylmethyl, mono- or bicyclic heteroarylmethyl, mono- or bicyclic arylsulfonyl, mono- or bicyclic heteroarylsulfonyl, unsubstituted or substituted with one or two of the following: or the pharmaceutically acceptable salts thereof. In a second more preferred embodiment of this invention, the inhibitors of famesyl-protein transferase are illustrated by the formula D: wherein: R2, R and R4 are independently selected from: hydrogen or C 1 -C6 alkyl; Z is mono- or bicyclic aryl, mono- or bicyclic heteroaryl, mono- or bicyclic arylmethyl, mono- or bicyclic heteroarylmethyl, mono- or bicyclic arylsulfonyl, mono- or bicyclic heteroarylsulfonyl, unsubstituted or substituted with one or two of the following: 1 ) Cl -4 alkyl, unsubstituted or substituted with: a) Cl -4 alkoxy, b) NR6R7 ( c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(0) m R 6 , or g) -C(0)NR6R7, 2) aryl or heterocycle, 3) halogen, 4) 0R6. 5) NR6R7, 6) CN, 7) N02, 8) CF3; 9) -S(0) m R6, 10) -C(0)NR 6 R7, or 1 1 ) C3-C6 cycloalkyl; m is 0, 1 or 2; and or the pharmaceutically acceptable salts thereof. The preferred compounds of this invention are as follows: 4-[ 1 -(4-methoxybenzyl)imidazol-2-ylJ-l -(2-chlorophenyl)-piperazin-2- one and 4-[3-(4-methoxybenzyl)pyrid-4-yl]-l-(2-chlorophenyl)-piperazin-2-one or the pharmaceutically acceptable salts or optical isomers thereof. The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. When any variable (e.g. aryl, heterocycle, Rl , R2 etc.) occurs more than one time in any constituent, its definition on each occurence is independent at every other occurence. Also, combinations of substituents/or variables 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, "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 1 1 - 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 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, be zothiopyranyl, 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, pyrrolidinyl, 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, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, and thienyl. As used herein in the definition of R and R^, the term "the substituted group" intended to mean a substituted Cl_8 alkyl, substituted C2-8 alkenyl, substituted C2-8 alkynyl, substituted aryl or substituted heterocycle from which the substitutent(s) R2 and R3 are selected. As used herein in the definition of R° R^a, R7 and R7a > the substituted Cl -8 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 substitutents in addition to the point of attachment to the rest of the compound. Preferably, such substitutents are selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Cl -C6 alkyl)2, N02, CN, ( -C6 alkyl)0-, -OH, (C1-C6 alkyl)S(0) m -, ( -Cό alkyl)C(0)NH-, H2N-C(NH)-, (C1 -C6 alkyl)C(O)-, (C1 -C6 alkyl)OC(O)-, N3,(Cι -C6 alkyl)OC(0)NH-, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl and C1 -C20 alkyl. When R and R^ 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-containing cyclic moieties include, but are not limited to: COR 10 Lines drawn into the ring systems from substituents (such as from R , R3, R4 e c .) indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms. Preferably, Rl is selected from: hydrogen, -N(RlO)2, R1°C(O)NR10- or unsubstituted or substituted Cl -C6 alkyl wherein the substituent on the substituted -C6 alkyl is selected from unsubstituted or substituted phenyl, -N(R l ) 2 , R l O- and R 1°C(O)NR 10-. Preferably, R2 is selected from: H, ^ ^- R 6 R 7 ( \^ R6 o o and an unsubstituted or substituted group, the group selected from Cl-8 alkyl, C2-8 alkenyl and C2-8 alkynyl; wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) Cl -4 alkyl, d) halogen, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6a, S(0)R6a, Sθ2R 6a , 5) — NR 6 R 7 R 7) ■ N NR 7 R 7a Y o Preferably, R3 is selected from: hydrogen and C1 -C6 alkyl. Preferably, R4 is hydrogen. Preferably, R6, R7 and R7 i s selected from: hydrogen, unsubstituted or substituted -C alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl. Preferably, R6a is unsubstituted or substituted -C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl. Preferably, R is hydrogen or methyl. Most preferably, R9 is hydrogen. Preferably, Rl° is selected from H, C1 -C6 alkyl and benzyl. Preferably, Al and A2 are independently selected from: a bond, -C(O)NRl0-, -NRI C(O)-, O, -N(R10)-, -S(0)2N(R 10)- and- Preferably, V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl. Preferably, Y is selected from unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted pyridyl, unsubstituted or substituted furanyl and unsubstituted or substituted thienyl. More preferably, Y is unsubstituted or substituted phenyl. Preferably, Z is selected from unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted pyridyl, unsubstituted or substituted furanyl and unsubstituted or substituted thienyl. More preferably, Z is unsubstituted or substituted phenyl. Preferably, W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyrrolidinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl. Preferably, n and r are independently 0, 1. or 2. Preferably s is 0. Preferably q is 1. Preferably, the moiety is selected from: It is intended that the definition of any substituent or variable (e.g., Rla, 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 materials. The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic 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 chromato graph y or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents. Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1-22, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Substituents R, R a and Rb, as shown in the Schemes, represent the substituents R2, R3, R4 a d R5; however their point of attachment to the ring is illustrative only and is not meant to be limiting. These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Schemes. Synopsis of Schemes 1-16: 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 suitably substi¬ tuted piperazines is outlined, and is essentially that described by J. S. Kiely and S. R. Priebe in Organic Preparations and Proceedings Int.. 1990, 22, 761-768. Boc-protected amino acids I, available commer¬ cially or by procedures known to those skilled in the art, can be coupled to N-aryl amino acid esters using a variety of dehydrating agents such as DCC (dicyclohexycarbodiimide) or EDC HC1 (l-ethyl-3-(3-dimethyl- aminopropyl)carbodiimide hydrochloride) in a solvent such as methyl- ene chloride , chloroform, dichloroethane, or in dimethylformamide. The product II is then deprotected with acid, for example hydrogen chloride in chloroform or ethyl acetate, or trifluoroacetic acid in methylene chloride, and cyclized under weakly basic conditions to give the diketopiperazine III. Reduction of UI with lithium aluminum hydride in refluxing ether gives the piperazine IV. Scheme 2 illustrates the incorporation of a hetercyclic moiety on the remaining unsubstituted nitrogen of the piperazine. Thus, intermediate IV is treated with the isothiocyanate V, followed by methylation provides the thioimidate VI. Displacement of the methyl thiol moiety with an appropriately substituted amine followed by cyclization provides the N-imidazolyl piperazine VIII. Scheme 2a illustrates incorporation of the preferred imidazolyl moiety on a nitrogen of a piperazinone. Thus, a suitably substituted aniline is N-alkylated sequentially with a protected acetaldehyde and a haloacetyl moiety. Reductive alkylation with an aminoimidazole, followed by base treatment provides the 1 -phenyl- 4-imidazolyl-piperazin-2-one. The imidazolyl can then be substituted with a suitably substituted benzyl moiety. Preparation of the corresponding N-pyridyl piperazine XII is illustrated in Scheme 3. A suitably substituted benzaldehyde is coupled to 4-chloropyridine to provide the pyridylphenylmethanol IX. Removal of the hydroxyl moiety followed by oxidation of the pyridinyl nitrogen provide intermediate X. Intermediate X is then reacted with the piperazine IV to provide the instant compound XII. Depending on the identity of the amino acid I, various side chains can be incorporated into the piperazine. For example when I is the Boc-protected β-benzyl ester of aspartic acid, the intermediate diketopiperazine XIII where n= 1 and R=benzyl is obtained, as shown in Scheme 4. Subsequent lithium aluminum hydride reduction reduces the ester to the alcohol XIV, which can then be reacted with a variety of alkylating agents such as an alkyl iodide, under basic conditions, for example, sodium hydride in dimethylformamide or tetrahydrofuran. The resulting ether XV can then be carried on to final products as described in Schemes 2 and 3. Reaction Scheme 5 provides an illustrative example the synthesis of compounds of the instant invention wherein the substituents R and R^ are combined to form - (CH2)u -• For example, 1-aminocyclohexane-l-carboxylic acid XVI can be converted to the spiropiperazine XVIII essentially according to the procedures outlined in Schemes 1. The piperazine intermediate XVIII can be carried on to final products as described in Schemes 2-3. Scheme 6 illustrates the use of an optionally substituted homoserine lactone XXI to prepare a Boc-protected piperazinone XXII. Intermediate XXII may be reduced, deprotected and reductively alkylated or acylated as illustrated in the previous Schemes. Alternatively, the hydroxyl moiety of intermediate XXiπ may be mesylated and displaced by a suitable nucleophile, such as the sodium salt of ethane thiol, to provide an intermediate XXIV. Intermediate XXπi may also be oxidized to provide the carboxylic acid on inter¬ mediate XXV, which can be utilized form an ester or amide moiety. Amino acids of the general formula XXVI which have a sidechain not found in natural amino acids may be prepared by the reactions illustrated in Scheme 18 starting with the readily prepared imine XXVII. SCHEME 1 II Z THF, reflux R HN N-Z R b IV SCHEME 2 Z HCI, isopropanol reflux SCHEME 2a SCHEME 2a (continued) 2. MeOH, reflux SCHEME 3 SCHEME 4 XIII XIV SCHEME 5 XVI XVII XVIII 42 SCHEME 5 (continued ) XVIII SCHEME 5 (continued) Ht -' 1 ' isopropanol reflux SCHEME 6 CICH 2 CH 2 CI HO sub O Cl BocNH N- Z EtOAc / H 2 0 NaHC0 3 Cl o HO sub NABH, Cs 2 CO Ξ BocN N-Z DMF O XXII SCHEME 6 (continued) BocN N-Ar \ / XXIV XXV SCHEME 7 P 2. 5% aqueous HCI |_J J XXVII 1. Boc 2 0, NaHC0 3 R 2 )-C0 2 H BocHN 2. LiAIH 4 , Et 2 0 XXVI The instant compounds are useful as pharmaceutical a gents 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, scr, abl, lck, fyn) or by other mechanisms. The compounds of the instant invention inhibit famesyl- protein transferase and the famesylation of the oncogene protein Ras. The instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575- 4580 (1995)). Such anti-angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization. The compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment. For example, a component of NF-1 is a benign proliferative disorder. The instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256:1331-1333 (1992). The compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1:541-545(1995). The instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al. American Journal of Pathology, 142: 1051 -1060 (1993) and B. Cowley, Jr. et dλ.FASEB Journal, 2:A3160 (1988)). The instant compounds may also be useful for the treatment of fungal infections. The compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combina¬ tion with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intra¬ muscular, intraperitoneal, subcutaneous, rectal and topical routes of administration. For oral use of a chemotherapeutic compound according to this invention, the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and com starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administra¬ tion in capsule form, useful diluents include lactose and dried com starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic. The 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 instant compounds may be useful in combination with known anti-cancer and cytotoxic agents. 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 compounds of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate. The present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutical ly effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacolo- gically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may be introduced into a patient's blood-stream by local bolus injection. As used herein, the term "composition" is intended to encompass a product comprising 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, and response of the individual patient, as well as the severity of the patient's symptoms. In one exemplary application, a suitable amount of compound is administered to a mammal undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg of body weight to about 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 are also useful as a component in an assay to rapidly determine the presence and quantity of famesyl-protein transferase (FPTase) in a composition. Thus the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to allow the FPTase to famesylate the substrate, the chemical content of the assay mixtures may be determined by well known immuno- logical, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested. It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain famesyl-protein transferase and quantitat- ing the enzyme. Thus, potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract containing an unknown amount of famesyl- protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention. The concentration of a sufficiently potent inhibitor (i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel) required to inhibit the enzymatic activity of the sample by 50% is approximately equal to half of the concentration of the enzyme in that particular sample. EXAMPLES Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species and conditions are intended to be further illustrative of the invention and not limitative of the reasonable scope thereof. EXAMPLE 1 Preparation of 4-[ l -(4-methoxybenzyl)imidazol-2-yl]-l-(2- chlorophenyl -piperazin-2-one. Step A: Synthesis of 4-[5-(4-memoxyphenyl)-2-thia-4-aza-pent-3- en-3-vn-l-(2-chlorophenyl -piperazin-2-one Modifying the method of Poisson, et al., (Tetrahedron Letters 32, 5325 (1991 )), p-methoxybenzyl isothiocyanate (1 molar equivalent) and 1 -(2-chlorophenyl)-piperazine-2-one are heated in toluene at 50°C for 6 h. Without purification the product is S-methyl- ated by treatment with methyl iodide (3 molar equivalents) to furnish the title compound. Step B: 4-[ 1 -(4-methoxybenzyl)-imidazol-2-yl J- 1 -(2-chlorophenyl)- piperazin-2-one. The product of step A is treated with aminoacetaldehyde dimethyl acetal (1.5 molar equivalents) in isopropanol. The intermediate guanidine is refluxed in isopropanol and hydrochloric acid to give the title compound. EXAMPLE 2 Preparation of 4-[3-(4-methoxybenzyl)pyrid-4-yl]- 1 -(2-chlorophenyl)- piperazin-2-one. Step A: 4-Chloro-3-(4-methoxybenzyl)pyridine. 4-Chloropyridine is treated sequentially with LDA (1.1 molar equivalents) and 4-methoxybenzaldehyde (1 molar equivalent). The resulting carbinol is isolated and deoxygenated with triethylsilane (10 molar equivalents) and 50% trifluoroacetic acid in methylene chloride to provide the title compound. Step B: 4-Chloro-3-(4-methoxybenzyl)pyridine-N-oxide The product of step A is oxidized to the title compound with m-chloroperoxybenzoic acid (1.1 molar equivalents). Step C: 4-[3-(4-methoxybenzyl)pyrid-4-yl]- 1 -(2-chlorophenyl)- piperazin-2-one. The product of step B is heated with 1 -(2-chIorophenyl)- piperazin-2-one (1 molar equivalent). The crude N-oxide of 4-[3-(4- methoxybenzyl)pyrid-4-yl]-l -(2-chlorophenyl)-piperazin-2-one is deoxygenated by treatment with triphenylphosphine (2 molar equivalents) to provide the title compound. EXAMPLE 3 In vitro inhibition of ras famesyl transferase Assays of farnesyl-protein transferase. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) were prepared as described by Schaber et aL, J. Biol. Chem. 265:14701 - 14704 (1990), Pompliano, et al, Biochemistry 31 :3800 (1992) and Gibbs et aJL, PNAS U.S.A. 86:6630-6634 (1989), respectively. Bovine FPTase was assayed in a volume of 100 μl containing 100 mM N-(2- hydroxy ethyl) piperazine- '-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM [ 3 H]-farnesyl diphosphate ( HJ-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 μg/ml FPTase at 31 °C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol. Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB β- plate counter. The assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the [^HI-FTP was utilized during the reaction period. Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay. Percentage inhibition is measured by the amount of incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound. Human FPTase was prepared as described by Omer et al.. Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1 % (w/v) polyethylene glycol 20,000, 10 μM ZnCl 2 and 100 ΠM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 μl of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme. The compounds of the instant invention are tested for inhibitory activity against human FPTase by the assay described above. EXAMPLE 4 In vivo ras famesylation assay The cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21. The assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51 :712-717. (1991 ). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 37°C, the cells are labelled in 3 ml methionine-free DMEM supple- meted with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[35S]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer (1 % NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45 min. Aliquots of lysates containing equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y 13-259 (Furth, M.E. et ah, J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at 4°C, 200 ml of a 25% suspension of protein A-Sepharose coated with rabbit anti rat IgG is added for 45 min. The immunoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1 % Triton X- 100.0.5% deoxycholate/0.1 %/SDS/0.1 M NaCl) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to famesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of famesyl transfer to protein. EXAMPLE 5 In vivo growth inhibition assay To determine the biological consequences of FPTase inhibition, the effect of the compounds of the instant invention on the anchorage-independent growth of Ratl cells transformed with either a \-ras, v-raf, or oncogene is tested. Cells transformed by v-Raf and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation. Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 10 4 cells per plate (35 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layers contain 0.1 % methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay). The cells are fed twice weekly with 0.5 ml of medium A containing 0.1 % methanol or the concentration of the instant compound. Photomicro¬ graphs are taken 16 days after the cultures are seeded and comparisons are made.

Claims: WHAT IS CLAIMED IS: 1. A compound which inhibits famesyl-protein transferase of the formula A: - A 1 (CR 1a 2 ) n A 2 (CR 1a 2 ) n - W l N-Z A R 3 R 4 wherein: Rla is selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R lOO-, Rl lS(0) m -, R !0C(O)NR 10-, (Rl ) 2 NC(0)-, Rl0 2 N-C(NRl )_, CN, NO2, R 10 C(O)-, N3, -N(RlO)2, or Rl lθC(O)NRl0-, c) unsubstituted or substituted C 1 -C alkyl wherein the substirutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, Rl lS(0)m-, Rl0C(O)NRl0-, (RlO) 2 NC(0)-, R10 2 N- C(NRl )-, CN, RlOC(O)-, N3, -N(RlO) 2 , and Rl lθC(O)- NRlO.; R and R3 are independently selected from: H; unsubstituted or substituted Cl-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) Cl-4 alkyl, d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-Cl -4 alkyl, or h) SR 6 a, S(0)R 6 a. S02R 6a , 2) C3-6 cycloalkyl, 3) OR6, 4) SR^a, S(0)R6a, 0 r Sθ2R 6a , 6 D 7 5) NR°R 9) -O^ .OR 6 T O 11) — S0 2 -NR 6 R 7 O 15) N 3 , 16) F, or 17) perfluoro-C-,. 4 -alkyl; or R2 and R 3 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(0) m , -NC(O)-, and -N(CORlO)- ; R4 is selected from H and CH3; and any two of R 2 , R and R^ are optionally attached to the same carbon atom; R 6 , R7 and R 7a are independently selected from: H; Cl -4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl -4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, O f) — S0 2 R 11 , or g) N(Rl ) 2 ; or R6 and R? may be joined in a ring; R7 and R? a may be joined in a ring; R6a is selected from: Cl -4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) Cl -4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, |11 o f) — S0 2 R 11 , or g) N(RlO) 2 ; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, R 1 •SiOm-, Rl0C(O)NRl -, (Rl0) 2 NC(O)-, RIO2 - C(NRlO)-, CN, N02, Rl°C(0)-, N3, -N(Rl ) , or RllOC(O)NRl0-,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, RlOO-, R n S(0) m -, Rl0C(O)NH-, (Rl ) 2 NC(O)-, RIO2N- C(NRlO)-, CN, RlOC(O)-, N3, -N(RlO) 2 , or Rl0θC(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R O-, Rl lS(0)m-, R 10 C(O)NRl0-, (Rl0)2NC(O)-, Rl0 2 N- C(NRlO)-, CN, N02, Rl°C(0)-, N3, -N(R1<>)2, or RllOC(O)NRl -,and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, Rl O-, Rl lS(0) m -, R1°C(0)NR10-, (RlO) 2 NC(0)-, Rlθ2N-C(NRlO)-, CN, Rl C(O)-, N3, -N(RlO)2, or Rl lOC(O)NRl0-; RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Al and A2 are independently selected from: a bond, -CH=CH-, -G^C-, -C(O)-, -C(O)NRl0-, -NRlOC(O)-, O, -N(R10)-, -S(O)2N(Rl0)-, -N(Rl0)S(O)2-, or S(0) m ; G is selected from H2 and O; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) Cl -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(0) m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(0) ; W is a heterocycle; Z is selected from: a unsubstituted or substituted group selected from aryl or heteroaryl, wherein the substituted group is substituted with one or more of the following: a) Cl -4 alkyl, unsubstituted or substituted with: Cl-4 alkoxy, NR 6 R 7 , C3-6 cycloalkyl, aryl, heterocycle, HO, -S(0) m R6a, 0 r -C(0)NR°R7, or a pharmaceutically acceptable salt thereof. 2. A compound which inhibits famesyl-protein transferase of the formula B : wherein: Rl is selected from: a) hydrogen, b) aryl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, RHS(0) m -, R!0C(O)NR10-, (Rl°)2NC(0)-, Rlθ2N-C(NRlO)-, CN, Nθ2, Rl°C(0)-, N3, -N(RlO)2, or Rl 10C(0)NR 10-, c) unsubstituted or substituted Cl -C6 alkyl wherein the substitutent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rl°0-, Rl lS(0) m -, Rl0C(O)NRl0-, (Rl0) 2 NC(O)-, Rl°2N- C(NRl )-, CN, RlOC(O)-, N3, -N(RlO)2, and R lθC(O)- NR10-; R and R^ are independently selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, ^ R6R7 OΓ y RB , O O wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) Cl-4 alkyl, d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-Cl -4 alkyl, or h) SR6 , S(0)R6a, Sθ2R 6a , 2) C3-6 cycloalkyl, 3) OR6, 4) SR6a, S(0)R6a, 0 r Sθ2R 6a , 5) — NR 6 R 7 8) "O γ NR°R 7 O 9) -O^ / OR 6 T O 11) — S0 2 -NR 6 R 7 15) N 3 , 16) F, or 17) perfluoro-C- | . 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(0) m , -NC(O)-, and -N(COR IO)- ; R4 is selected from H and CH3; and any two of R2, R and R^ are optionally attached to the same carbon atom; R 6 , R7 and R 7 are independently selected from: H; Cl -4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl -4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, , 11 e) ' o f) S0 2 R 1 1 or g) N(Rl ) 2 ; or R6 and R 7 may be joined in a ring; R 7 and R^ may be joined in a ring; R6a is selected from: Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) Cl -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) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, R 1 !S(0) m -, Rl°C(O)NRl0-, (Rl0) 2 NC(O)-, Rl0 2 N- C(NRlO)-, CN, N02, R 1 0 C(O)-, N3, -N(RlO)2, or Rl lOC(O)NRl0-, 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, RlOO-, R 1 !S(0) m -, Rl°C(0)NH-, (RlO) 2 NC(0)-, RIO2N- C(NRlO)-, CN, RlOC(O)-, N3, -N(RlO) 2 , or Rl0θC(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R lOO-, Rl lS(0)m-, R10C(0)NR 10-, (RlO) 2 NC(0)-, Rl°2N- C(NRlO)-, CN, N02, Rl°C(0)-, N3, -N(RlO) 2 , or R lOC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, R l l S(0) m -, R 1°C(0)NR10-, (Rl ) 2 NC(O)-, R l0 2 N-C(NR l )-, CN, RlOC(O)-, N3, -N(RlO)2, or Rl lθC(O)NR l0-; RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; R l 1 is independently selected from C 1 -C alkyl and aryl; Al and A are independently selected from: a bond, -CH=CH-, -C=C-, -C(O)-, -C(O)NRl0-, -NR lOc(O)-, O, -N(R 10)-, -S(O)2N(Rl0)-, -N(Rl0)S(O)2-, or S(0) m ; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(0)m; or a pharmaceutically acceptable salt thereof. 3. The compound according to Claim 1 of the formula A: A wherein: R la is independently selected from: hydrogen or C1 -C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, RlOO-, -N(RlO) 2 or C2-C6 alkenyl, c) unsubstituted or substituted C l -C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, RlOO- and -N(RlO) 2 ; R3 and R4 are independently selected from H and CH3; R2 is H; or Ci -5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1 ) aryl, 2) heterocycle, 3) OR 6 , 4) SR6 , Sθ2R 6a , or 5 ) \ .NR 6 R 7 T O : and any two of R2, R , R4 5 nd R5 are optionally attached to the same carbon atom; R6, R7 and R7 are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) Ci-4 alkoxy, b) halogen, or c) aryl or heterocycle; R6 is selected from: Cl-4 alkyl orC3_6 cycloalkyl, unsubstituted or substituted with: a) Cl-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, -C6 perfluoroalkyl, F, Cl, RlOO-, R10C(O)NR1 -, CN, NO2, (RlO) 2 N-C(NRl )-, Rl0c(O)-, -N(Rl ) 2 , or RllOC(O)NRl0-, and c) C1-C6 alkyl substituted by Cj -C6 perfluoroalkyl, RlOO-, Rl0C(O)NRl0-, (R10) 2 N-C(NR10)-, RlOC(O)-, -N(RlO)2, or Rl lOC(O)NRl0- ; R9 is selected from: a) hydrogen, b) C2-C alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Rl O-, Rl lS(0)m-, R 10 C(O)NRl0-, CN, Nθ2, (Rl )2N-C(NRl )-, Rl c(O)-, -N(RlO)2, or RllOC(O)NRl0-,and c) C l -C6 alkyl unsubstituted or substituted by C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, RllS(0) m -, R1°C(0)NR10-, CN, (RlO)2N-C(NRlO)-, R1 C(O)-, -N(RlO) , or RllOC(O)NRl0-; RIO is independently selected from hydrogen, -C6 alkyl, benzyl and aryl; Rl 1 is independently selected from Cl-C6 alkyl and aryl; Al and A are independently selected from: a bond, -CH=CH-, -C≡C-, -C(O)-, -C(O)NRl0-, O, -N(R10)-, or S(0) m ; G is selected from H2 and O; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C l -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if A 1 is a bond, n is 0 and A is S(0) m ; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; Z is mono- or bicyclic aryl. mono- or bicyclic heteroaryl, mono- or bicyclic arylmethyl, mono- or bicyclic heteroarylmethyl, mono- or bicyclic arylsulfonyl, mono- or bicyclic heteroarylsulfonyl, unsubstituted or substituted with one or two of the following: 1 ) Cl -4 alkyl, unsubstituted or substituted with: a) Cl -4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(0) m R 6 , or g) -C(0)NR6R7, or a pharmaceutically acceptable salt thereof. 4. The compound according to Claim 1 of the formula C: wherein: R3 and R ** * are independently selected from H and CH3; R2 is H; or C 1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1 ) aryl, 2) heterocycle, 3) OR 6 , 4) SR6a, Sθ2R 6a , or 5 ) \ ^NR 6 R 7 Y O ; and R and R^ are optionally attached to the same carbon atom; R6 and R 7 are independently selected from: H; Cl -4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) Cl -4 alkoxy, b) halogen, or c) aryl or heterocycle; R 6a is selected from: Cl-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) Cl-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, RlOO-, R!0C(O)NR10-, CN, Nθ2, (RlO)2N-C(NRlO)-, RlOc(O)-, -N(RlO)2, or RllOC(O)NRl0-, and c) C l -C6 alkyl substituted by C 1 -C6 perfluoroalkyl, R 1 0 O-, R!0C(O)NR10-, (R10) 2 N-C(NR1°)-, RlOc(O)-, -N(Rl )2, or Rl 10C(0)NR10- ; RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Z is mono- or bicyclic aryl, mono- or bicyclic heteroaryl, mono- or bicyclic arylmethyl, mono- or bicyclic heteroarylmethyl, mono- or bicyclic arylsulfonyl, mono- or bicyclic heteroarylsulfonyl, unsubstituted or substituted with one or two of the following: 1) Cl-4 alkyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, or a pharmaceutically acceptable salt thereof. 5. The compound according to Claim 1 of the formula D: wherein: R2, R3 nd R4 are independently selected from: hydrogen or -C6 alkyl; Z is mono- or bicyclic aryl, mono- or bicyclic heteroaryl, mono- or bicyclic arylmethyl, mono- or bicyclic or a pharmaceutically acceptable salt thereof. 6. A compound which inhibits famesyl-protein transferase which is: 4-[ 1 -(4-methoxybenzyI)imidazol-2-yl]- 1 -(2-chlorophenyI)-piperazin-2- one or 4-[3-(4-methoxybenzyl)pyrid-4-yl]- l -(2-chlorophenyl)-piperazin-2-one or a pharmaceutically acceptable salt or optical isomer thereof. 7. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 1. 8. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 2. 9. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 4. 10. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 6. 11. A method for inhibiting famesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 7. 12. A method for inhibiting famesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 8. 13. A method for inhibiting famesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 9. 14. A method for inhibiting famesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 10. 15. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 7. 16. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 8. 17. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 9. 18. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 10. 19. A method for treating neurofibromin benign proliferative disorder which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 7. 20. A method for treating blindness related to retinal vascularization which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 7. 21. A method for treating infections from hepatitis delta and related viruses which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 7. 22. A method for preventing restenosis which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 7. 23. 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 7. 24. A pharmaceutical composition made by combining the compound of Claim 1 and a pharmaceutically acceptable carrier. 25. A process for making a pharmaceutical composition comprising combining a compound of Claim 1 and a pharmaceutically acceptable carrier.

Inventors: GRAHAM SAMUEL L, WILLIAMS THERESA M, GRAHAM, SAMUEL, L., WILLIAMS, THERESA, M.
Applicants: GRAHAM SAMUEL L, MERCK & CO INC, WILLIAMS THERESA M, GRAHAM, SAMUEL, L., MERCK & CO., INC., WILLIAMS, THERESA, M.
Application year: 1997
Main classification: A61K31
IPC codes: A61K31, A61P9, A61P13, A61P27, A61P31, A61P35, A61P43, C07D401, C07D403