INHIBITORS OF PRENYL-PROTEIN TRANSFERASE

Abstract: The present invention is directed to conformationally constrained compounds which inhibit prenyl-protein transferase and the prenylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting prenyl-protein transferase and the prenylation of the oncogene protein Ras.

Description: TITLE OF THE INVENTION INHIBITORS OF PRENYL-PROTEIN 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, Ann. Rev. Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-rαs, Ki4a- ras, Ki4b-ms and N-røs) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal. Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-Aaa -Aaa -Xaa" box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al, Nature 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 C 15 or C20 isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 62:355-386 (1992); W.R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237 (1992)). The Ras protein is one of several proteins that are known to undergo post-translational farnesylation. Other farnesylated 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 farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above. Inhibition of farnesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the Ras oncoprotein intracellularly (N.E. Kohl et al, Science, 260:1934-1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of ras- dependent tumors in nude mice (N.E. Kohl et al. , Proc. Natl. Acad. Sci U.S.A., 92:9141-9145 (1994) and induces regression of mammary and salivary carcinomas in ras transgenic mice (N.E. Kohl et al. , Nature Medicine, 1:792-797 (1995). Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck & Co., Rahway, NJ) and compactin (Hancock et; al., ibid; Casey et: al., ibid; Schafer et: al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et: al., Cell, 62:81-88 (1990); Schaber et: al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et: al., Science, 249:1133-1139 (1990); Manne et al, Proc. Natl. Acad. Sci USA, S7:7541- 7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. However, direct inhibition of farnesyl-protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis. Inhibitors of farnesyl-protein transferase (FPTase) have been described in two general classes. The first are analogs of farnesyl diphosphate (FPP), while the second class of inhibitors is related to the protein substrates (e.g., Ras) for the enzyme. The peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et: al., PNAS, 88:132-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141,851, University of Texas; N.E. Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)). In general, deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound. However, the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable. It has recently been reported that farnesyl-protein transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7-112930). It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516). Imidazole-containing inhibitors of farnesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 Al). Compounds containing piperazines, piperazinones, piperidines and piperidinones have also been observed to be inhibitors of FPTase (WO 97/37900, WO 97/36605, and WO 97/38665). It is, therefore, an object of this invention to develop compounds that do not have a thiol moiety, and that will inhibit prenyl- protein transferase and thus, the post-translational prenylation 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 conformationally constrained compounds that do not resemble peptides and which inhibit prenyl-protein transferase. Further contained in this invention are chemotherapeutic compositions containing these prenyl-protein transferase inhibitors and methods for their production. The compounds of this invention are illustrated by the formula I: A 1 (CR 1a 2 ) n A 2 (CR DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention are useful in the inhibition of prenyl-protein transferase and the prenylation of the oncogene protein Ras. In an embodiment of this invention, the inhibitors of prenyl-protein transferase are illustrated by the formula I: - A - wherein: Rla and BA" are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R O-, R9S(0) m -, R 8 C(O)NR 8 -, CN, NO2, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -, c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 O-, R 9 S(O) m -, R 8 C(O)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9OC(O)-NR 8 -; Rl and R2 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R 9 S(O) m -, R 8 C(O)NR 8 -, CN, NO2, R 8 2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -, and c) Ci-Cβ alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R 9 S(O) m -, R 8 C(O)NH-, CN, H2N-C(NH)-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R 8 OC(O)NH-; R3 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R9s(0) m -, R 8 C(O)NR 8 -, CN, NO2, (R 8 )2N-C-(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R 9 OC(O)NR 8 -, and c) Cl-Cβ alkyl, unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 8 O-, R9s(0) m -, R 8 C(O)NR 8 -, CN, (R 8 )2N- C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -; R4a, R4b. R4c and R5 independently are selected from: H, =O, unsubstituted or substituted Ci-8 alkyl, unsubstituted or substituted C2-8 alkenyl, 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 one or two groups selected from: a) C1-4 alkyl, d) halogen, e) Cl-4 perfluoroalkyl, 2) C3-6 cycloalkyl, 3) OR 6 , 4) SR6, S(0)R6, SO2R 6 , 5) NR°R 8) -O γ NR^ O 9) — O. .OR 6 T O 10) \ ^NR 6 R 7 O 11) — S0 2 -NR 6 R 7 14) ^OR 6 o 15) Cl-8 alkyl, 16) Cl-8 perfluoroalkyl, or 17) halo; either R^h and R° or R^ and _ ^°, when located on adjacent carbon atoms, may be joined to form a ring; R6, R7 and R' ?a are independently selected from: H, C 1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, Ci_4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from: a) Ci-4 alkoxy, b) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle, c) halogen, d) HO, g) -S(0) m R 9 , or h) N(R 8 )2; or R 6 and R" 7 may be joined in a ring; R' and R^ a may be joined in a ring; R 8 is independently selected from hydrogen, Ci-Cβ alkyl, benzyl, 2,2,2- trifluoroethyl and aryl; R9 is independently selected from C1-C6 alkyl and aryl; Al and A2 are independently selected from: a) a bond, b) HC=CH, c) C≡C, d) o, e) C=O, ) O=C, g) -C(O)NR 8 -, h) -NR 8 C(O)-, i) -N(R 8 )-, j) -S(O) 2 N(R 8 )-, k) -N(R 8 )S(O)2-, or 1) S(O) m ; χl, X^, χ3 ? χ4 and X^ are independently selected from: C(H) y , N(H) W , O, C=O, S(O)2,and PO(OMe); 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 Al is S(O) m and V is not hydrogen if Al is a bond, n is 0 and A^ is S(O) m ; provided that if V is hydrogen then Rl is absent; W is heterocycle; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; r is independently 0 to 5, provided that r is 0 when V is hydrogen; s is 1 or 2; t is 0 or 1; u is 0, 1 or 2; w is 0 or 1; and y is 1 or 2; dashed lines represent optional double bonds or the pharmaceutically acceptable salts or the optical isomers thereof. In a further embodiment of this invention, the inhibitors of prenyl-protein transferase are illustrated by the formula I: wherein Rla and Rl" are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 O-, R9S(O) m -, R 8 C(O)NR 8 -, CN, NO2, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -, c) Ci-Cβ alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 O-, R 9 S(O) m -, R C(O)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)-NR 8 -; Rl and R2 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R9S(O) m -, R 8 C(O)NR 8 -, CN, NO2, R 8 2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R 9 OC(O)NR 8 -, and c) Cl-Cβ alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R9s(O) m -, R 8 C(O)NH-, CN, H2N-C(NH)-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R 8 OC(O)NH-; R3 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, perfluoroalkyl, F, Cl, Br, R O-, R9s(0) m -, R 8 C(O)NR 8 -, CN, NO2, (R 8 )2N-C-(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -, and c) C1-C6 alkyl, unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 8 O-, R 9 S(O) m -, R 8 C(O)NR 8 -, CN, (R 8 )2N- C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -; R4a ; R4b, R4c and R5 independently are selected from: H, =O, unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C2-8 alkenyl, 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 one or two groups selected from: a) C1-4 alkyl, d) halogen, e) Ci-4 perfluoroalkyl, 2) C3-6 cycloalkyl, 3) OR 6 , 4) SR 6 , S(O)R 6 , SO2R 6 , 5) — NR 6 R 7 -0^ / NR 6 R 7 8) T O 9) ■ O^ / OR 6 T o o 11 ) — S0 2 -NR 6 R 7 13) ^Γ R6 o 14) ^-OR 6 o 15) Cl-8 alkyl, 16) C -8 perfluoroalkyl, or 17) halo; either R^ D and R^ or R^a and R^ ) when located on adjacent carbon atoms, may be joined to form a ring; R 6 , R *7 and R? a are independently selected from: H, C 1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, Ci-4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from: a) Ci-4 alkoxy, b) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle, c) halogen, d) HO, OR* f) Υ 0 0Rf 9) -S(0) m R ! or h) N(R 8 )2; or R 6 and R" 7 may be joined in a ring; R7 and R r?a may be joined in a ring; R 8 is independently selected from hydrogen, Ci-Cβ alkyl, benzyl, 2,2,2- trifluoroethyl and aryl; R9 is independently selected from Ci-Cβ alkyl and aryl; Al and A2 are independently selected from: a) a bond, b) HC=CH, c) C≡C, d) o, e) C=O, f) O=C, g) -C(O)NR 8 -, h) -NR 8 C(O)-, i) -N(R 8 )-, j) -S(O)2N(R 8 )-, k) -N(R 8 )S(O)2-, or 1) S(O) m ; χl, χ2, and X^ are independently selected from: C(H) y , N(H) W , O, C=O, S(O)2,and PO(OMe); χ3 is selected from N(H) W or O; χ5 is selected from C=O or C(H)y; V is selected from: a) hydrogen, b) heterocycle, selected from pyrrolidinyl, triazolyl, pyridyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, or isoquinolinyl; c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, provided that V is not hydrogen if Al is S(O) m and V is not hydrogen if A is a bond, n is 0 and A is S(O) ; provided that if V is hydrogen then Rl is absent; W is a heterocycle selected from pyrrolidinyl, triazolyl, imidazolyl, pyridyl, pyridinyl, thiazolyl, indolyl, quinolinyl, or isoquinolinyl; m is 0, 1 or 2; n is 0, 1, 2, 3 and 4; p is 0, 1, 2, 3 and 4; r is independently 0 to 5, provided that r is 0 when V is hydrogen; s is 1 or 2; t is 0 or 1; u is 0, 1 or 2; w is 0 or 1; and y is 1 or 2; dashed lines represent optional double bonds or the pharmaceutically acceptable salts or the optical isomers thereof. In another embodiment of this invention, the inhibitors of prenyl- protein transferase are illustrated by the formula II: wherein Rla and B 0 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 O-, R9S(O) m -, R 8 C(O)NR 8 -, CN, NO2, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R90C(0)NR 8 -, c) Cl-Cβ alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 O-, R9s(0) m -, R 8 C(O)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R 9 OC(O)-NR 8 -; Rl and R2 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R9S(O) m -, R 8 C(O)NR 8 -, CN, NO2, R 8 2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -, and c) Ci-Cβ alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R 9 S(O) m -, R 8 C(O)NH-, CN, H2N-CCNH)-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R 8 OC(O)NH-; R3 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R9S(O) m -, R 8 C(O)NR 8 -, CN, NO2, (R 8 )2N-C-(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R90C(0)NR 8 -, and c) Ci-Cβ alkyl, unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 8 O-, R 9 S(O) m -, R 8 C(O)NR 8 -, CN, (R 8 )2N- C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -; R4a ( R4b and R5 independently are selected from: H, =O, unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C2-8 alkenyl, 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 one or two groups selected from: a) C1-4 alkyl, b) (CH2) p OR 6 , c) (CH2) P NR 6 R' 7 , d) halogen, e) Ci-4 perfluoroalkyl, 2) C3-6 cycloalkyl, 3) OR 6 , 4) SR 6 , S(O)R 6 , SO2R 6 , 5) — NR 6 R 7 O^ . NR 6 R 7 8) Y 0 9) O^ .OR 6 T O o 11) — S0 2 -NR 6 R 7 13) ~A Rf o 14 > - 0R6 o 15) Cl-8 alkyl, 16) Cl-8 perfluoroalkyl, or 17) halo; either R^b and B or R^ a and R^h, when located on adjacent carbon atoms, may be joined to form a ring; R 6 , R' 7 and R^a are independently selected from: H, C -4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, Ci-4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from: a) Cl-4 alkoxy, b) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle, c) halogen, d) HO, R s O OR o g ) -S(0) m R 9 , or h) N(R 8 )2; or R 6 and R^ may be joined in a ring; R and R r?a may be joined in a ring; R 8 is independently selected from hydrogen, Cl-Cβ alkyl, benzyl, 2,2,2- trifluoroethyl and aryl; R 9 is independently selected from Ci-Cβ alkyl and aryl; Al and A2 are independently selected from: a) a bond, b) HC=CH, c) C≡C, d) o, e) C=O, f) O=C, g) -C(O)NR 8 -, h) -NR 8 C(O)-, i) -N(R 8 )-, j) -S(O)2N(R 8 )-, k) -N(R 8 )S(O)2-, or 1) S(O) m ; χl, χ , and X^ are independently selected from: C(H) y , N(H) W , O, C=O, S(O)2,and PO(OMe); χ3 is selected from N(H)w or O; X 5 is selectedd from C=O or C(H)y; V is selected from: a) hydrogen, b) heterocycle, selected from pyrrolidinyl, triazolyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, or isoquinolinyl; c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O) m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(O) ; provided that if V is hydrogen then Rl is absent; m is 0, 1 or 2; n is 0, 1, 2, 3 and 4; p is 0, 1, 2, 3 and 4; r is independently 0 to 5, provided that r is 0 when V is hydrogen; s is 1 or 2; u is 0, 1 or 2; w is 0 or 1; and y is 1 or 2; dashed lines represent optional double bonds or the pharmaceutically acceptable salts or the optical isomers thereof. In another embodiment of this invention, the inhibitors of prenyl-protein transferase are illustrated by the formula III: wherein: Rla and R b are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 O-, R9S(O) m -, R 8 C(O)NR 8 -, CN, NO2, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -, c) Cl-Cβ alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 O-, R 9 S(O) m -, R 8 C(O)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)-NR 8 -; Rl and R2 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R 9 S(O) m -, R 8 C(O)NR 8 -, CN, NO2, R 8 2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R 9 S(O) m -, R 8 C(O)NH-, CN, H2N-C(NH)-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R 8 OC(O)NH-; R3 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R9s(0) m -, R 8 C(O)NR 8 -, CN, NO2, (R 8 )2N-C-(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -, and c) Ci-Cβ alkyl, unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 8 O-, R9S(O) m -, R 8 C(O)NR 8 -, CN, (R 8 )2N- C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R90C(0)NR 8 -; R4a ; R4b and R5 independently are selected from: H, =0, unsubstituted or substituted Ci-8 alkyl, unsubstituted or substituted C2-8 alkenyl, 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 one or two groups selected from: a) C1-4 alkyl, d) halogen, e) Ci-4 perfluoroalkyl, 2) C3-6 cycloalkyl, 3) OR 6 , 4) SR 6 S(O)R 6 , SO2R 6 6 D 7 5) NR D R — O^NR 6 R 7 8) Y O 9) Y o o 11) — S0 2 -NR 6 R 7 13 ) ^R 6 O 1 4 > ^OR 6 O 15) Ci-8 alkyl, 16) Cl-8 perfluoroalkyl, or 17) halo; either R^b and R^ or R^ a and R^b, when located on adjacent carbon atoms, may be joined to form a ring; R 6 , R7 and R^a are independently selected from: H, C 1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, Ci-4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from: a) Ci-4 alkoxy, b) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle, c) halogen, d) HO, R* e) O OR ε f) O g) -S(0) m R y , or h) N(R 8 )2; or R 6 and Η may be joined in a ring; R7 and R^a m ay be joined in a ring; R 8 is independently selected from hydrogen, Cl-Cβ alkyl, benzyl, 2,2,2- trifluoroethyl and aryl; R9 is independently selected from C1-C6 alkyl and aryl; Al and A2 are independently selected from: a) a bond, b) HC=CH, c) C≡C, d) o, e) C=O, f) O=C, g) -C(O)NR 8 -, h) -NR 8 C(O)-, i) -N(R 8 )-, j) -S(O)2N(R 8 )-, k) -N(R 8 )S(O)2-, or 1) S(O) m ; χl, χ , and X^ are independently selected from: C(H) y , N(H) W , O, C=O, S(O)2,and PO(OMe); X^ is selected from N(H) W or O; X 5 is selectedd from C=O or C(H)y; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; r is independently 0 to 5; s is 1 or 2; u is 0, 1 or 2; w is 0 or 1; and y is 1 or 2; dashed lines represent optional double bonds or the pharmaceutically acceptable salts or the optical isomers thereof. In another embodiment of this invention, the inhibitors of prenyl-protein transferase are illustrated by formula IV: wherein Rla and Rib are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 O-, R9S(O) m -, R 8 C(O)NR 8 -, CN, NO2, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -, c) Ci-Cβ alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 O-, R9s(0) m -, R 8 C(O)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R90C(0)-NR 8 -; R2 is selected from: a) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R O-, R9S(0) m -, R 8 C(O)NR 8 -, CN, NO2, R 8 2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -, and b) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R9S(O) m -, R 8 C(O)NH-, CN, H2N-C(NH)-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R 8 OC(O)NH-; R3 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R 9 S(O) m -, R 8 C(O)NR 8 -, CN, NO2, (R 8 )2N-C-(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -, and c) C1-C6 alkyl, unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 8 O-, R9S(O) m -, R 8 C(O)NR 8 -, CN, (R 8 )2N- C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -; R4a, R4b and R5 independently are selected from: H, =O, unsubstituted or substituted Ci-8 alkyl, unsubstituted or substituted C2-8 alkenyl, 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 one or two groups selected from: a) C1-4 alkyl, d) halogen, e) Cl-4 perfluoroalkyl, 2) C3-6 cycloalkyl, 3) OR 6 , 4) SR 6 , S(O)R 6 , SO2R 6 , 6 D 7 5) NR°R — O^ NR 6 R 7 8) T O 9) -O^ / OR 6 T o DR7 11) — S0 2 -NR 6 R 7 13) R e o 14 > ^ 0R6 O 15) Ci-8 alkyl, 16) Cl-8 perfluoroalkyl, or 17) halo; either R^b and R^ or R^a and R^b, when located on adjacent carbon atoms, may be joined to form a ring; R 6 , R7 and R^ a are independently selected from: H, Ci-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, Cl-4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from: a) Cl-4 alkoxy, b) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle, c) halogen, d) HO, f » OR £ Ύ o g) -S(0) m R 9 , or h) N(R 8 )2; or R 6 and R^ may be joined in a ring; R^ and R^ a may be joined in a ring; R 8 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2- trifluoroethyl and aryl; R9 is independently selected from Ci-Cρ alkyl and aryl; Al and A2 are independently selected from: a) a bond, b) HC=CH, c) C≡C, d) o, e) C=O, f) O=C, g) -C(O)NR 8 -, h) -NR 8 C(O)-, i) -N(R 8 )-, j) -S(O)2N(R 8 )-, k) -N(R 8 )S(O)2-, or 1) S(O) m ; χl, χ , and X^ are independently selected from: C(H) y , N(H) W , O, C=O, S(O)2,and PO(OMe); X3 is NH or O; X is C=O or CH2; 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, 1, 2, 3 or 4; s is l or 2; u is 0, 1 or 2; w is 0 or 1; and y is l or 2; dashed lines represent optional double bonds or the pharmaceutically acceptable salts or the optical isomers thereof. Specific example of the compounds of the invention are: 4- [5-(4-Oxo- 1-phenyl- 1 ,3 ,8-triazaspiro [4.5] dec-8-ylmethyl)imidazol- 1 - ylmethyl]benzonitrile; 4-{5-[4-Oxo-l-(3-methylphenyl)-l,3,8-triazaspiro[4.5]dec-8- ylmethyl]imidazol-l-ylmethyl}benzonitrile; 4-{5-[4-Oxo-l-(4-methylphenyl)-l,3,8-triazaspiro[4.5]dec-8- ylmethyl]imidazol-l-ylmethyl}benzonitrile; 4-{5-[2,4-Dioxo-l-(3-methylphenyl)-l,3,8-triaza-spiro[4.5]dec-8- ylmethyl]imidazol-l-ylmethyl}benzonitrile; 4-{5-[2-Oxo-l-(3-methylphenyl)-l,3,8-triaza-spiro[4.5]dec-8- ylmethyl]imidazol-l-ylmethyl}benzonitrile; 4-{5-[2,2-Dioxo-l-(3-methylphenyl)-2-thia-l,3,8-triazaspiro[4.5]dec-8- ylmethyl]imidazol-l-ylmethyl}benzonitrile; 4-{5-[2,2-Dioxo-l-(4-chloro-3-methylphenyl)-2-thia-l,3,8- triazaspiro[4.5]dec-8-ylmethyl]imidazol-l-ylmethyl}benzonitrile; 4-{5-[2-Oxo-l-(3-methylphenyl)-3-oxa-l,8-diazaspiro[4.5]dec-8- ylmethyl]imidazol-l-ylmethyl}benzonitrile; 4-[5-(l-Oxo-3,4-benzo-2,9-diazaspiro[5.5]undec-9-ylmethyl)imidazol-l- ylmethyl]benzonitrile; 4-[5-(3,4-Benzo-8-azaspiro[4.5]-l-decen-8-ylmethyl)-imidazol-l- ylmethyl]benzonitrile; 4-[5-(4-Oxo-3-(3-trifluoromethoxybenzyl)-l-phenyl-l,3,8- triazaspiro[4.5]dec-8-ylmethyl)imidazol-l-ylmethyl]benzonitrile; 4- [5-(4-Oxo-3-(2-trifluoromethoxybenzyl)- 1-phenyl- 1,3,8- triazaspiro[4.5]dec-8-ylmethyl)imidazol-l-ylmethyl]benzonitrile; 4-[5-(2-Oxo-3-(3-trifluoromethoxybenzyl)-l-oxa-3,8-diaza-spiro[4.5]dec-8- ylmethyl)imidazol- 1 -ylm ethyl] benzonitrile ; 4-[5-(2-Oxo-3-(2-trifluoromethoxybenzyl)-l-oxa-3,8-diaza-spiro[4.5]dec-8- ylmethyl)imidazol-l-ylmethyl] benzonitrile; 4-[5-(2-Oxo-3-n-butyl-l-oxa-3,8-diaza-spiro[4.5]dec-8-ylmethyl)imidazol-l- ylmethyl]benzonitrile; 4-[5-(2-Oxo-3-(2,2,2-trifluoroethyl)-l-oxa-3,8-diaza-spiro[4.5]dec-8- ylmethyl)imidazol-l-ylmethyl]benzonitrile; 4-[5-(spiro[3H-indole-3,4'-piperidin]-2(lH)-on-l'-ylmethyl)imidazol-l- ylmethyl]benzonitrile; and 4-[5-(l,3-Dioxo-2-(3-trifluoromethoxybenzyl)-2,8-diaza-spiro[4.5]dec-8- ylmethyl)imidazol-l-ylmethyl]benzonitrile or the pharmaceutically acceptable salts thereof. Preferred examples of the compounds of the instant invention are: 4-{5-[4-Oxo-l-(3-methylphenyl)-l,3,8-triazaspiro[4.5]dec-8- ylmethyl]imidazol-l-ylmethyl}benzonitrile 4-{5-[2-Oxo-l-(3-methylphenyl)-l,3,8-triaza-spiro[4.5]dec-8- ylmethyl]imidazol-l-ylmethyl}benzonitrile 4-{5-[2,2-Dioxo-l-(3-methylphenyl)-2-thia-l,3,8-triazaspiro[4.5]dec-8- ylmethyl]imidazol-l-ylmethyl}benzonitrile 4-{5-[2,2-Dioxo-l-(4-chloro-3-methylphenyl)-2-thia-l,3,8- triazaspiro[4.5]dec-8-ylmethyl]imidazol-l-ylmethyl}benzonitrile 4- [5-(4-Oxo-3-(3-trifluoromethoxybenzyD- 1-phenyl- 1,3,8- triazaspiro [4.5] dec-8-ylmethyl)imidazol- 1 -ylmethyl] benzonitrile 4-[5-(4-Oxo-3-(2-trifluoromethoxybenzyl)-l-phenyl-l,3,8- triazaspiro [4.5] dec-8-ylmethyl)imidazol- 1 -ylmethyl] benzonitrile 4-[5-(2-Oxo-3-(3-trifluoromethoxybenzyl)-l-oxa-3,8-diaza-spiro[4.5]dec-8- ylmethyl)imidazol-l-ylmethyl] benzonitrile 4-[5-(l,3-Dioxo-2-(3-trifluoromethoxybenzyl)-2,8-diaza-spiro[4.5]dec-8- ylmethyl)imidazol-l -ylmethyl] benzonitrile or the pharmaceutically acceptable salts 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 a , R 6 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 monocyclic and bicyclic 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, 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 monocyclic and bicyclic 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, 2-oxopyrrolidinyl, 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 monocyclic and bicyclic heteroaryl 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, the terms "substituted aryl", "substituted heterocycle" and "substituted cycloalkyl" are intended to include the cyclic group containing from 1 to 3 substitutents in addition to the point of attachment to the rest of the compound. Such substitutents are preferably selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Ci-C6 alkyl)2, NO2, CN, (C1-C6 alkyDO-, -OH, (C1-C6 alkyl)S(O) m -, (Ci-Cβ alkyl)C(O)NH-, H 2 N-C(NH)-, (C1-C6 alkyl)C(O)-, (Cl-C 6 alkyl)OC(O)-, N3, (Cl-C 6 alkyl)OC(O)NH- and C1-C20 alkyl. Examples of the bicyclic moiety include, but are not limited to, When R^k and R^ or R^ and R^b are combined to form a ring, cyclic alkyl moieties are formed. Examples of such cyclic moieties include, but are not limited to, Examples of the bicyclic moiety when R^b and R^ or R^a and R^b are combined to form a ring include, but are not limited to: Specific examples of the tri cyclic moieties include, but are not limited to, When R 6 and R ' or B and R^ a are combined to form a ring, cyclic amine moieties are formed. Examples of such cyclic moieties include, but are not limited to: In addition, such cyclic moieties may optionally include another heteroatom(s). Examples of such heteroatom-containing cyclic amine moieties include, but are not limited to: Lines drawn into the ring systems from substituents (such as from R2, R4a ? R4b ? R5 ? e t c .) indicate that the indicated bond may be attached to any of the substitutable ring carbon or nitrogen atoms. Preferably, Rla and Rl" are independently selected from: hydrogen, -N(R 8 )2, R 8 C(O)NR 8 - or Ci-Cβ alkyl which is unsubstituted or substituted by -N(R 8 )2, R 8 O- or R 8 C(O)NR 8 -. Preferably, Rl and R2 is independently selected from: hydrogen, perfluoroalkyl, F, Cl, Br, R 8 O-, R9S(0) m -, CN, NO2, R 8 2N- C(NR 8 )-, R 8 C(O)-, N3, -N(R 8 )2, R9OC(O)NR 8 - and Ci-Cβ alkyl. Preferably, R3 is hydrogen or methyl. Preferably, R4a, R4b and R5 are independently selected from: a) Cl-8 alkyl, unsubstituted or substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: i) Ci-4 alkyl, iv) halogen, v) Cl-4 perfluoroalkyl, 2) OR 6 , 3) SR 6 S(O)R 6 , SO2R 6 , or ^ MR 6 R 7 b) c) aryl, unsubstituted or substituted with one or more of: 1) Ci-8 alkyl, 2) Cl-8 perfluoroalkyl, 3) halo, 4) OR 6 , 5) SR 6 , S(O)R 6 , SO2R 6 , or 6) d) -SO2R 6 More preferably, R4a, R4b or R5 is selected from unsubstituted or substituted phenyl. Preferably, R4c is hydrogen. Preferably, R^a s C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted aryl group. Preferably, R 8 is selected from H, C1-C6 alkyl and benzyl. Preferably, Al and A are independently selected from: a bond, -C(O)NR 8 -, -NR 8 C(O)-, O, -N(R 8 )-, -S(O)2N(R 8 )- and-N(R 8 )S(O)2-. Preferably, V is selected from hydrogen, heterocycle and aryl. More preferably, V is aryl or heterocycle. Most preferably, V is phenyl or pyridyl. Preferably, W is imidazolyl. Preferably, X2 is CH2, C=O or S(0)2. Preferably, X3 is NH or O. Preferably, Xδ is CH2 or C=O. Preferably, n, p and r are independently 0, 1, or 2. More preferably, r is 1. Preferably t is 1. Preferably, the moiety is selected from: Preferably, the moiety: is attached to the nitrogen atom of the piperidinyl ring. 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. It is intended that the definition of any substituent or variable (e.g., Rla, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, N(R 8 )2 represents -NH2, -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 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 stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents. Abbreviations used in the description of the chemistry and in the Examples that follow are: Ac2θ Acetic anhydride; Boc t-Butoxy carbonyl; CBz Carbobenzyloxy; DBU l,8-diazabicyclo[5.4.0]undec-7-ene; DMAP 4-Dimethylaminopyridine; DME 1 , 2 -Dim ethoxy ethane ; DMF Dimethylformamide; EDC l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride; Et3N Triethylamine; EtOAc Ethyl acetate; FAB Fast atom bombardment; HOBT 1-Hydroxybenzotriazole hydrate; HOOBT 3-Hydroxy-l,2,2-benzotriazin-4(3H)-one; HPLC High-performance liquid chromatography; MCPBA m-Chloroperoxybenzoic acid; MsCl Methanesulfonyl chloride; NaHMDS Sodium bis(trimethylsilyl)amide; Py Pyridine; TFA Trifluoroacetic acid: THF Tetrahy drofuran . The compounds of this invention are prepared by employing reactions as shown in Schemes 1-12, 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. While stereochemistry is shown in the Schemes, a person of ordinary skill in the art would understand that the illustrated compounds represent racemic mixtures which may be separated at a subsequent purification step or may be utilized as the racemic mixture. 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 reductive alkylation or acylation reactions described in the Schemes. Schemes 12-15 illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic strategies for preparing alkanols that incorporate other heterocyclic moieties for variable W are also well known in the art. SCHEME 1 A B SCHEME 1A D SCHEME IB SCHEME IC SCHEME ID CDI G SCHEME IE SCHEME IF H 2 0/THF SCHEME IG SCHEME IH SCHEME 2 iPr 2 NEt SCHEME 3 NaHMDS BocN COoEt SCHEME 4 SCHEME 4A SCHEME 5 2.5N HCI aq 55°C SCHEME 6 SCHEME 7 Et 3 N , CICH 2 CH 2 CI CF 3 C0 2 H, CH 2 CI 2 ; SCHEME 7 (CONTINUED) SCHEME 8 SCHEME 9 1. R'MgX SCHEME 10 1) SCHEME 11 Tr SCHEME 12 NaBH 4 (excess) SCHEME 13 SCHEME 14 SCHEME 15 In the above Schemes, it is understood that R is independently R4a ? R4b or R5 or a protected precursor thereof, R' is independently R2 or a protected precursor thereof, X, Y and Z are independently CH, CH2, N or NH; and Ar is an unsubstituted or substituted aryl. 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, scr, 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 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, the compounds are useful in the treatment of neurofibromatosis, which 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 81.FASEB Journal, 2:A3160 (1988)). The instant compounds may also be useful for the treatment of fungal infections. In a preferred embodiment of the instant invention the compounds of the invention are selective inhibitors of farnesyl-protein transferase. A compound is considered a selective inhibitor of farnesyl- protein transferase, for example, when its in vitro farnesyl-protein transferase inhibitory activity, as assessed by the assay described in Example 19, is at least 100 times greater than the in vitro activity of the same compound against geranylgeranyl-protein transferase-type I in the assay described in Example 20. Preferably, a selective compound exhibits at least 1000 times greater activity against one of the enzymatic activities when comparing geranylgeranyl-protein transferase-type I inhibition and farnesyl-protein transferase inhibition. It is also preferred that the selective inhibitor of farnesyl- protein transferase is further characterized by: b) an IC 0 (a measure of in vitro inhibitory activity) for inhibition of the prenylation of newly synthesized K-Ras protein more than about 100-fold higher than the ICgø for the inhibition of the farnesylation of hDJ protein. When measuring such IC5QS the assays described in Examples 24 and 25 may be utilized. It is also preferred that the selective inhibitor of farnesyl- protein transferase is further characterized by: c) an IC50 (a measurement of in vitro inhibitory activity) for inhibition of K4B-Ras dependent activation of MAP kinases in cells at least 100-fold greater than the IC50 for inhibition of the farnesylation of the protein hDJ in cells. It is also preferred that the selective inhibitor of farnesyl- protein transferase is further characterized by: d) an IC 0 (a measurement of in vitro inhibitory activity) against H- Ras dependent activation of MAP kinases in cells at least 1000 fold lower than the inhibitory activity (IC50) against H-røs-CVLL (SEQ.ID.NO.: 1) dependent activation of MAP kinases in cells. When measuring Ras dependent activation of MAP kinases in cells the assays described in Example 23 may be utilized. In another preferred embodiment of the instant invention the compounds of the invention are dual inhibitors of farnesyl-protein transferase and geranylgeranyl-protein transferase type I. Such a dual inhibitor may be termed a Class II prenyl-protein transferase inhibitor and will exhibit certain characteristics when assessed in in vitro assays, which are dependent on the type of assay employed. In a SEAP assay, such as described in Example 23, it is preferred that the dual inhibitor compound has an in vitro inhibitory activity (IC50) that is less than about 12μM against K4B-Ras dependent activation of MAP kinases in cells. The Class II prenyl-protein transferase inhibitor may also be characterized by: a) an ICg Q (a measurement of in vitro inhibitory activity) for inhibiting K4B-Ras dependent activation of MAP kinases in cells between 0.1 and 100 times the IC50 for inhibiting the farnesylation of the protein hDJ in cells; and b) an IC5 Q (a measurement of in vitro inhibitory activity) for inhibiting K4B-Ras dependent activation of MAP kinases in cells greater than 5-fold lower than the inhibitory activity (IC50) against expression of the SEAP protein in cells transfected with the pCMV-SEAP plasmid that constitutively expresses the SEAP protein. The Class II prenyl-protein transferase inhibitor may also be characterized by: a) an IC5 Q (a measurement of in vitro inhibitory activity) against H-Ras dependent activation of MAP kinases in cells greater than 2 fold lower but less than 20,000 fold lower than the inhibitory activity (IC50) against H-rαs-CVLL (SEQ.ID.NO.: 1) dependent activation of MAP kinases in cells; and b) an ICQQ (a measurement of in vitro inhibitory activity) against H-ras-CVLL dependent activation of MAP kinases in cells greater than 5-fold lower than the inhibitory activity (IC50) against expression of the SEAP protein in cells transfected with the pCMV-SEAP plasmid that constitutively expresses the SEAP protein. The Class II prenyl-protein transferase inhibitor may also be characterized by: a) an IC5 Q (a measurement of in vitro inhibitory activity) against H-Ras dependent activation of MAP kinases in cells greater than 10-fold lower but less than 2,500 fold lower than the inhibitory activity (IC50) against H-rαs-CVLL (SEQ.ID.NO.: 1) dependent activation of MAP kinases in cells; and b) an IC 0 (a measurement of in vitro inhibitory activity) against H-rαs-CVLL dependent activation of MAP kinases in cells greater than 5 fold lower than the inhibitory activity (IC50) against expression of the SEAP protein in cells transfected with the pCMV-SEAP plasmid that constitutively expresses the SEAP protein. A method for measuring the activity of the inhibitors of prenyl-protein transferase, as well as the instant combination compositions, utilized in the instant methods against Ras dependent activation of MAP kinases in cells is described in Example 23. In yet another embodiment, a compound of the instant invention may be a more potent inhibitor of geranylgeranyl-protein transferase-type I than it is an inhibitor of farnesyl-protein transferase. 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 specified amounts. The present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may be introduced into a patient's intramuscular blood-stream by local bolus injection. The compositions of the instant invention may alternatively or in addition comprise a farnesyl pyrophosphate-competitive inhibitor obtained by fermentation of cultures of novel organisms. In particular, the compounds disclosed in the following patents and publications may be useful as farnesyl pyrophosphate-competitive inhibitor component of the instant 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 comprise administering, simultaneously or sequentially or in any order, two or more of a protein substrate-competitive inhibitor and a farnesyl pyrophosphate-competitive inhibitor, such administration can be orally or parenterally, including intravenous, intramuscular, intraperitoneal, 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 farnesyl pyrophosphate-competitive inhibitor are administered sequentially, the administration of each can be by the same method or by different methods. The compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration. For oral use of a chemotherapeutic compound according to this invention, the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn 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, restinosis, polycystic kidney disease, infections of hepatitis delta and related viruses and fungal infections. 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 prenyl-protein transferase inhibitors and an antineoplastic agent. It is also understood that the instant combination of antineoplastic agent and inhibitor of prenyl-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-stabilising agents (such as paclitaxel (also known as Taxol®), docetaxel (also known as Taxotere®), or their derivatives); alkylating agents, anti-metabolites; epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes; biological response modifiers and growth inhibitors; 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, discodermolide, the pteridine family of drugs, diynenes and the podophyllotoxins. Particularly useful members of those classes include, for example, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, porfiromycin, trastuzumab (Herceptin™), 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo-phyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like. Other useful antineoplastic agents include estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, gemcitibine, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L- asparaginase, camptothecin, CPT-11, topotecan, pyridobenzoindole derivatives, interferons and interleukins. Preferably, the antineoplastic agent is paclitaxel. If formulated as a fixed dose, such combination products employ the combinations of this invention within the dosage range described 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 inappropriate. 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 an inhibitor of prenyl-protein transferase alone to treat cancer. Additionally, compounds of the instant invention may also be useful as radiation sensitizers, as described in WO 97/38697, published on October 23, 1997, and herein incorporated by reference. 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 farnesyl-protein transferase (FPTase) in a composition. Thus the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to allow the FPTase to farnesylate the substrate, the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested. It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain farnesyl-protein transferase and quantitating the enzyme. Thus, potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract containing an unknown amount of farnesyl-protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention. The concentration of a sufficiently potent inhibitor (i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel) required to inhibit the enzymatic activity of the sample by 50% is approximately equal to half of the concentration of the enzyme in that particular sample. EXAMPLES Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species and conditions are intended to be further illustrative of the invention and not limitative of the reasonable scope thereof. EXAMPLE 1 Preparation of 4-[5-(4-Oxo-l-phenyl-l,3,8-triazaspiro[4.5]dec-8- ylmethyl)imidazol-l-ylmethyl1benzonitrile Step A: Preparation of l-(4-Cyanobenzyl)-5-chloromethylimidazole hydrochloride salt A mixture of l-(4-cyanobenzyl)-5-hydroxymethylimidazole (10.8 g, 50.70 mmol) and thionyl chloride (70 mL, 960 mmol) was stirred at room temp, overnight under a calcium chloride drying tube. The resultant mixture was concentrated under vacuum, and residual thionyl chloride removed by co-evaporation with toluene. The residue was recrystallized from boiling methanol. After cooling to room temp., the white solid precipitated was obtained by filtration, and residual solvent removed under vacuum overnight. Alternate Step A: Substep I: p-Cyanobenzylamine * H. PO4 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 stirring 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. Phosphoric acid was gradually added over about 5 min to about 10 min, 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. Substep II: 4-Cyanobenzylamine Hydrochloride via Hexamethylene-tetrammonium salt NH 2 -HCI CN A 72 liter vessel was charged with 190 proof ethanol (14.4 L) followed by the addition of 4-cyanobenzylbromide (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 stirring. 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 HCI gas (2.20 kg) was sparged into the slurry over about 4 hours during 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 x 3 L). The solid was dried 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 stirring continued for about 15 min. The layers were allowed to settle and the lower organic layer was removed. The aqueous layer was extracted with methylene chloride (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 HCI 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 dried in vacuo at about 25 °C to provide the above-titled compound. IH 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. Substep III: l-(4-Cyanobenzyl)-2-Mercapto-5-Hydroxymethyl- imidazole 7% water in acetonitrile (50 mL) was added to a 250 L roundbottom flask. Next, an amine phosphate salt (12.49 g), as described above in Substep I, 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. Acetonitrile/water 93:7 (25 mL) was used to rinse 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 acetonitrile (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 dried in vacuo to obtain the above-identified compound. Substep IV: l-(4-Cyanobenzyl)-5-Hydroxymethylimidazole 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 described above in Substep III, 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 period, 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 dried with vacuum/N2 flow and the above-titled compound was obtained. IH NMR (250 MHz, CDCI3): δ 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). Substep V: l-(4-cyanobenzyl)-5-chloromethyl imidazole HCI salt l-(4-Cyanobenzyl)-5-hydroxymethylimidazole (1.0 kg), as described in above in Substep IV, was slurried with DMF (4.8 L) at 22 °C and then cooled to -5 °C. Thionyl chloride (390 mL) was added dropwise over 60 min during 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. 1 H NMR (250 MHz DMSO-dβ): 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. Substep VI: l-(4-Cyanobenzyl)-5-Chloromethyl Imidazole HCI salt via addition of Hydroxymethylimidazole to Vilsmeier Reagent To an ice cold solution of dry acetonitrile (3.2 L, 15 L/Kg hydroxymethylimidazole) was added 99% oxalyl chloride (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 stirring for about 5 to 10 min following the addition of DMF, solid hydroxymethylimidazole (213 g, 1.00 mol), as described above in Substep IV, 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 acetonitrile (400 mL displacement wash, 550 mL slurry wash, and a 400 mL displacement wash). The solid was maintained under a N 2 atmosphere during the filtration and washing to prevent hydrolysis of the chloride by adventitious H 2 O. This yielded the crystalline form of the chloromethylimidazole hydrochloride. *H NMR (250 MHz DMSO-dβ): 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. Substep VII: l-(4-Cyanobenzyl)-5-Chloromethyl Imidazole HCI salt via addition of Vilsmeier Reagent to Hydroxymethylimidazole To an ice cold solution of dry DMF (178 mL, 2.30 mol, 2.30 equiv.) in dry acetonitrile (2.56 L, 12 L/Kg Hydroxymethylimidazole) was added oxalyl chloride (101 L, 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 described above inSubstep IV, in dry acetonitrile (1.7 L, 8 L/Kg hydroxymethylimidazole). Additional dry acetonitrile (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 Tj < +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 acetonitrile (400 mL displacement wash, 550 mL slurry wash, and a 400 L displacement wash). The solid was maintained under a N 2 atmosphere during the filtration and washing to prevent hydrolysis of the chloride by adventitious H 2 O. This yielded the crystalline form of the chloromethylimidazole hydrochloride. Step B: Preparation of 4-[5-(4-Oxo-l-phenyl-l,3,8-triazaspiro[4.5]- dec-8-vlmethvl)imidazol-l-vlmethvl1benzonitrile A solution of l-phenyl-l,3,8-triazaspiro[4.5]decan-4-one (230 mg, 1 mmol), l-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt (265 mg, 1 mmol), and diisopropylethylamine (0.52 mL, 3 mmol) in anhydrous acetonitrile (5 mL) was stirred at room temp, for 2 days. The resulting mixture was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluting with 5% methanol in ethyl acetate. The appropriate fractions were collected and concentrated. The residue was triturated with diethyl ether, and the white solid precipitated was collected by filtration to provide the title compound. Anal. Calcd for C27H28N4θ3»0.25 Et2θ*0.7 H2O: C, 68.24; H, 6.59; N, 18.36. Found: C, 68.20; H, 6.33; N, 18.39. EXAMPLE 2 Preparation of 4-{ 5- [4-Oxo- l-(3-methylphenyl)- 1 ,3 ,8-triazaspiro [4.5] dec-8- ylmethyllimidazol-l-ylmethyllbenzonitrile Step A: Preparation of l-Benzyl-4-cyano-4-(3-methylphenylamino)- piperidine To a solution of l-benzyl-4-piperidone (18.9 g, 0.1 mol) and 3- methylaniline (10.7 g, 0.1 mol) in glacial acetic acid (100 mL), trimethylsilyl cyanide (6.7 mL, 0.1 mol; Journal of Organic Chemistry, vol. 55, page 4207, year 1990) was added dropwise with the temp, of the reaction maintained <40 °C with an ice-water bath. After addition was complete, the reaction mixture was stirred at room temp, for 30 min, and poured into a mixture of ice (140 g) and concentrated ammonium hydroxide (168 g). The resultant mixture was extracted with chloroform (3 times). The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residual oil was triturated with diisopropyl ether (300 mL) and stirred at room temp, overnight. The white solid precipitated was filtered to provide the title compound. Step B: Preparation of l-Benzyl-4-(3-methylphenylamino)- isonipecotamide A mixture of l-benzyl-4-cyano-4-(3-methylphenylamino)- piperidine (7.6 g) and 90% sulfuric acid (53 mL) was heated at 70 °C until all the solid dissolved (~ 1 h). The resultant mixture was stirred at the temp, for 30 min., and poured into a mixture of ice (80 g) and concentrated ammonium hydroxide (75 g). The solution was basified with ammonium hydroxide, and extracted with chloroform. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound. Step C: Preparation of 8-Benzyl-l-(3-methylphenyl)-l,3,8-triaza- spiro [4.51 dec-2-en-4-one To a mixture of l-benzyl-4-(3-methylphenylamino)- isonipecotamide (4.3 g, 13.5 mmol) and glacial acetic acid (1.0 mL) in toluene (20 mL) heated under reflux, triethyl orthoformate (2.0 g, 13.5 mmol) was added over a period of 3h using a syringe pump. The resultant mixture was refluxed for 38 h., and treated with a mixture of concentrated ammonium hydroxide (1.3 mL) and water (3.4 mL). The organic extract was isolated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to column chromatography on silica gel eluting with 5% methanol in chloroform. Collection and concentration of appropriate fractions provided the title compound. Step D: Preparation of l-(3-Methylphenyl)-l,3,8-triazaspiro[4.5]- decan-4-one A mixture of 8-benzyl-l-(3-methylphenyl)-l,3,8-triaza- spiro[4.5]dec-2-en-4-one (1.64 g, 4.9 mmol) and 10% palladium on charcoal (0.8 g) in a mixture of methanol (100 mL) and methanol saturated with anhydrous hydrochloride gas (5 mL) was shaken in a Parr hydrogenator at 55 psi for 24 h. The resultant mixture was filtered through a plug of Celite, and the filtrate concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 1:1 mixture of 10% methanol in chloroform and chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provide the title compound. Step E: Preparation of 4-{5-[4-Oxo-l-(3-methylphenyl)-l,3,8-triaza- spiro [4.51 dec-8-ylmethyll imidazol- 1 -ylmethyllbenzonitrile A solution of l-(3-methylphenyl)-l,3,8-triazaspiro[4.5]decan- 4-one (0.25 g, 0.94 mmol), l-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt (0.23 g, 0.94 mmol), and diisopropylethylamine (0.5 mL, 2.8 mmol) in absolute ethanol (5 mL) was heated under reflux overnight. The resulting mixture was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluting with 5% methanol in ethyl acetate. The appropriate fractions were collected and concentrated. The residue was triturated with diethyl ether, and the white solid precipitated was collected by filtration to provide the title compound. Anal. Calcd for C26H28N6O-0.55 MeOH: C, 69.60; H, 6.64; N, 18.34. Found: C, 69.60; H, 6.53; N, 18.11. EXAMPLE 3 Preparation of 4-{5-[4-Oxo-l-(4-methylphenyl)-l,3,8-triazaspiro[4.5]dec-8- ylmethyllimidazol-1-ylmethyllbenzonitrile The title compound was prepared using the protocol described in Example 2, Steps A - E, substituting 3-methylaniline with 4- methylaniline in Step A. Anal. Calcd for C26H28N6O: C, 70.89; H, 6.41; N, 19.08. Found: C, 70.62; H, 6.21; N, 18.88. EXAMPLE 4 Preparation of 4-{5-[2,4-Dioxo-l-(3-methylphenyl)-l,3,8-triaza- spiro \4.51 dec-8-ylm ethyl! imidazol- 1 -ylmethyllbenzonitrile Step A: Preparation of 8-Benzyl-l-(3-methylphenyl)-l,3,8-triaza- spiro [4.51 decan-2.4-dione To a solution of l-benzyl-4-cyano-4-(3-methylphenylamino)- piperidine (4.54 g, 14.86 mmol) as described above in Example 2, Step A) in dichloromethane (50 mL), a solution of chlorosulfonyl isocyanate (1.45 mL, 16.7 mmol; Journal of Organic Chemistry, vol. 55, page 4207, 1990) in dichloromethane (20 mL) was added slowly with the temperature of the reaction maintained between 20 - 30 °C. The resultant white slurry was stirred at room temp, for 30 min, and concentrated under vacuum. The residue was treated with hydrochloric acid (50 mL, 1 M) and heated under reflux for 1 h. The resultant mixture was cooled to 0 °C, and basified with aqueous sodium hydroxide (5 M) to pH 5.5. The solid precipitated was obtained by filtration, and further purified by column chromatography on silica gel eluting with 10% methanol in chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provided the title compound as white solid. Step B: Preparation of 4-{5-[2,4-Dioxo-l-(3-methylphenyl)-l,3,8- triaza-spiro [4.5] dec-8-ylm ethyl] imidazol- 1-ylmethyl}- benzonitrile The title compound was prepared using the protocol described in Example 2, Steps D - E, substituting 8-benzyl-l-(3- methylphenyl)-l,3,8-triaza-spiro[4.5]dec-2-en-4-one with 8-benzyl-l-(3- methylphenyl)-l,3,8-triaza-spiro[4.5]decan-2,4-dione in used Step D. Anal. Calcd for C26H26N6O2: C, 67.97; H, 5.94; N, 18.02. Found: C, 67.91; H, 5.79; N, 18.00. EXAMPLE 5 Preparation of 4-{5-[2-Oxo-l-(3-methylphenyl)-l,3,8-triaza-spiro[4.5]dec-8- ylmethvnimidazol-1-ylmethyllbenzonitrile Step A: Preparation of l-Benzyl-4-(3-methylphenylamino)-4- aminomethylpiperidine A mixture of l-benzyl-4-cyano-4-(3-methylphenylamino)- piperidine (4.0 g), as described above in Example 2, Step A, and 5% rhodium on alumina (4 g) in absolute ethanol (100 mL) treated with anhydrous ammonia gas (8 g) was hydrogenated at 55 psi at room temp. for 24 h. The resultant mixture was filtered through a plug of Celite, and the filtrate concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 1:1 mixture of 5% methanol in chloroform and chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provided the title triamine as clear, colorless, viscous oil. FAB MS m e 310 (M+l) Step B: Preparation of 8-Benzyl-l-(3-methylphenyl)-l,3,8-triaza- spiro [4.51 decan-2-one A mixture of l-benzyl-4-(3-methylphenyl)-4-aminomethyl- piperidine (0.52 g, 1.67 mmol) and l,l'-carbonyldiimidazole (0.41 g, 2.5 mmol) in dichloromethane (2 mL) was stirred at room temp, for 3 days. The resultant solution was concentrated and the residue subjected to column chromatography on silica gel eluting with a 1:1 mixture of chloroform and chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provide the title compound. FAB MS m/e 336 (M+l) Step C: Preparation of 4-{5-[2-Oxo-l-(3-methylphenyl)-l,3,8-triaza- spiro[4.51dec-8-ylmethynimidazol-l-ylmethyllbenzonitrile The title compound was prepared using the protocol described in Example 2, Steps D - E, substituting 8-benzyl-l-(3- methylphenyl)-l,3,8-triaza-spiro[4.5]dec-2-en-4-one with 8-benzyl-l-(3- methylphenyl)-l,3,8-triaza-spiro[4.5]decan-2-one used in Step D. Anal. Calcd for C26H28N6θ«0.1 Et2θ»0.2 H2O: C, 70.21; H, 6.56; N, 18.61. Found: C, 70.23; H, 6.59; N, 18.65. EXAMPLE 6 Preparation of 4-{5-[2,2-Dioxo-l-(3-methylphenyl)-2-thia-l,3,8- triazaspiro[4.51dec-8-ylmethyl1imidazol-l-ylmethyllbenzonitrile Step A: Preparation of 8-Benzyl-2,2-dioxo-l-(3-methylphenyl)-2-thia- 1.3.8-triazaspiro[4.51decane To a cold (-78 °C) solution of l-benzyl-4-(3-methylphenyl)-4- aminomethylpiperidine (0.51 g, 1.66 mmol) in dichloromethane (10 mL), sulfuryl chloride (0.19 mL, 2.3 mmol) was added and the reacting mixture was stirred at room temp, for 3 days. The resultant solution was concentrated and the residue subjected to column chromatography on silica gel eluting with a 1:1 mixture of 3% methanol in chloroform and chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provide the title compound. FAB MS m/e 372 (M+l) Step B: Preparation of 4-{5- [2,2-Dioxo- l-(3-methylphenyl)-2-thia- l,3,8-triazaspiro[4.5]dec-8-ylmethyl]imidazol-l- ylmethyllbenzonitrile The title compound was prepared using the protocol described in Example 2, Steps D - E, substituting 8-benzyl-l-(3- methylphenyl)- 1 ,3 ,8-triaza-spiro [4.5] dec-2-en-4-one with 8-benzyl-2 ,2- dioxo-l-(3-methylphenyl)-2-thia-l,3,8-triazaspiro[4.5]decane in Step D. The final product was subjected to high pressure liquid chromatography on C-18 stationary phase. Collection and lyophilization of appropriate fractions provided the title compound. Anal. Calcd for C25H28N6θ2S»2.25 TFA: C, 48.32; H, 4.16; N, 11.46. Found: C, 48.29; H, 4.13; N, 11.70. EXAMPLE 7 Preparation of 4-{5-[2,2-Dioxo-l-(4-chloro-3-methylphenyl)-2-thia-l,3,8- triazaspiro [4.51 dec-8-ylmethyll imidazol- 1 -ylmethyllbenzonitrile The title compound was isolated as a by-product during high pressure liquid chromatography purification of Example 6 in Step B. Anal. Calcd for C25H27N6θ2ClS«0.15 TFA»0.55 H2O: C, 45.93; H, 3.98; N, 10.97. Found: C, 45.94; H, 4.08; N, 10.80. EXAMPLE 8 Preparation of 4-{5-[2-Oxo-l-(3-methylphenyl)-3-oxa-l,8- diazaspiro[4.51dec-8-ylmethyl1imidazol-l-ylmethyllbenzonitrile Step A: Preparation of Ethyl l-Benzyl-4-(3-methylphenylamino)- piperidine-4-carboxylate A solution of l-benzyl-4-(3-methylphenylamino)- isonipecotamide (4.5 g, 13.9 mmol), as described above in Example 2, Step B, and potassium hydroxide (3.g, 53.5 mmol) in ethylene glycol (35 mL) was heated under reflux. The resulting mixture was diluted with water and neutralized with acetic acid. The white solid precipitated was filtered, washed with chloroform to provide l-benzyl-4-(3- methylphenylamino)piperidine-4-carboxylic acid. A mixture of l-benzyl-4-(3-methylphenylamino)piperidine-4- carboxylic acid (3.81 g, 11.7 mmol) and concentrated sulfuric acid (2 mL) in absolute ethanol (80 mL) was heated under reflux overnight. The resultant solution was concentrated under vacuum, and the residue was treated with chloroform saturated with ammonia gas. The mixture was filtered, and the filtrate concentrated. The residue was passed through a small plug of silica gel eluting with chloroform saturated with ammonia gas. Collection and concentration of the eluent under vacuum provided the title compound. Step B: Preparation of l-Benzyl-4-hydroxymethyl-4-(3- methylphenylamino)piperidine To a slurry of lithium aluminum hydride (330 mg, 8.7 mmol) in anhydrous diethyl ether (25 mL) at 0 °C, a solution of ethyl 1- benzyl-4-(3-methylphenylamino)piperidine-4-carboxylate (2.8 g, 7.94 mmol) in diethyl ether (10 mL) was added dropwise with the temp, of the reacting mixture maintained below 10 °C. The resulting mixture was stirred at 0 °C for 30 min, and quenched with successive addition of water (0.33 mL), 15% aqueous NaOH (0.33 mL), and water (1 mL). The resultant slurry was stirred at room temp, for 30 min., and was filtered through a small plug of Celite. The filtrate was washed brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title alcohol as white solid. Step C: Preparation of 8-Benzyl-l-(3-methylphenyl)-3-oxa-l,8- diazaspiro[4.51decan-2-one The title compound was prepared using the protocol described in Example 5, Step B substituting l-benzyl-4-aminomethyl-4-(3- methylphenyDpiperidine with l-benzyl-4-hydroxymethyl-4-(3- methylphenylamino)piperidine. The title compound was isolated by chromatography on silica gel. FAB MS m/e 337 (M+l). Step D: Preparation of 4-{5-[2-Oxo-l-(3-methylphenyl)-3-oxa-l,8- diazaspiro [4.5] dec-8-ylmethyl] imidazol- 1-ylmethyl} - benzonitrile The title compound was prepared using the protocol described in Example 2, Steps D - E, substituting 8-benzyl-l-(3- methylphenyl)-l,3,8-triaza-spiro[4.5]dec-2-en-4-one with 8-benzyl-l-(3- methylphenyl)-3-oxa-l,8-diazaspiro[4.5]decan-2-one used in Step D. FAB MS m/e 442 (M+l). EXAMPLE 9 Preparation of 4-[5-(l-Oxo-3,4-benzo-2,9-diazaspiro[5.51undec-9- ylmethyl)imidazol-l-ylmethyl1benzonitrile Step A: Preparation of Ethyl N-tert-butoxycarbonylpiperidine-4- carboxylate To a cold (0 °C) solution of ethyl isonipecotate (39.5g, 0.251 mol) and triethylamine (38.5 L, 0.276 mol) in dichloromethane (350 mL), a solution of di-tert-butyl dicarbonate (55.9 g, 0.256 mol) in dichloromethane (50 mL) was added over a period of 30 min. The reacting mixture was stirred at room temp, overnight. The product mixture was washed with aqueous potassium hydrogen sulfate (3 times), and brine (to pH 7). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound as clear, colorless, viscous oil. Step B: Preparation of Ethyl N-tert-butoxycarbonyl-4-(2- nitrobenzyl)piperidine-4-carboxylate To a cold (-78 °C) solution of ethyl N-tert-butoxycarbonyl- piperidine-4-carboxylate (7.5 g, 29 mmol) in anhydrous THF (75 mL), a solution of sodium bis(trimethylsilyl)amide (40 mL, 1M, 40 mmol) was added over a period of 30 min. The resultant mixture was stirred at -78 °C for 1 h., and a solution of 2-nitrobenzyl bromide (7.6 g, 35) in THF (10 mL) was added. The reacting mixture was allowed to warm up to room temp, and stirred overnight. The product mixture was concentrated, and the residue partition between water and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 20% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound. Step C: Preparation of 9-tert-Butoxycarbonyl-3,4-benzo-2,9- diazaspiro [5.51 undecan- 1-one A mixture of ethyl N-tert-butoxycarbonyl-4-(2-nitrobenzyl)- piperidine-4-carboxylate (0.85 g, 2.17 mmol) and 5% palladium on charcoal (0.06 g) in ethanol (100 mL) was hydrogenated at room temp, at 50 psi overnight. The resultant mixture was filtered through a plug of Celite, and the filtrate concentrated under vacuum to provide the title compound. Step D: Preparation of 9-tert-Butoxycarbonyl-3,4-benzo-2,9- diazaspiro [5.51 undecan- 1-one hydrochloride salt °\ H Hθι - H v A solution of 9-tert-butoxycarbonyl-3,4-benzo-2,9- diazaspiro[5.5]undecan-l-one (0.25 g) in dichloromethane (40 mL) at 0 °C was saturated with hydrogen chloride gas. The resultant solution was sealed with a rubber septum and stirred at room temp, for 1 h. The product solution was concentrated under vacuum to provide the title compound. Step E: Preparation of 4-[5-(l-Oxo-3,4-benzo-2,9-diazaspiro[5.5]- undec-9-ylmethyl)imidazol-l-ylmethyl1benzonitrile The title compound was prepared using the protocol described in Example 2, Step E substituting l-(3-methylphenyl)-l,3,8- triaza-spiro[4.5]dec-2-en-4-one hydrochloride salt with 9-tert- butoxycarbonyl-3 ,4-benzo-2 ,9-diazaspiro [5.5] undecan- 1-one hydrochloride salt. Anal. Calcd for C25H25NδO»0.1 CHCl3»0.65 H2O: C, 69.27; H, 6.12; N, 16.10. Found: C, 69.35; H, 6.15; N, 15.98. EXAMPLE 10 Preparation of 4-[5-(3,4-Benzo-8-azaspiro[4.5]-l-decen-8-ylmethyl)- irnidazol-1-vlmethvllbenzonitrile A mixture of spiro(lH-indene-l,4'-piperidine) (100 mg, 0.54 mmol (Journal of Medicinal Chemistry, vol. 35, p. 3919, (1992)), l-(4- cyanobenzyl)imidazole-5-carboxyaldehyde (171 mg, 0.81 mmol), and a small amount of 4A sieves in 1,2-dichloroethane (3 mL) was stirred at room temp, for 15 min. The resultant mixture was treated with sodium triacetoxyborohydride (230 mg, 1.08 mmol) and stirred at room temp. overnight. The product mixture was diluted with dichloromethane and washed with sodium bicarbonate and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 95:5:0.5 v/v/v mixture of EtOAc:methanol:NH 4 OH. Appropriate fractions were collected and concentrated under vacuum. The residual oil was dissolved in a 1:3 mixture of acetonitrile and water, and lyophilized to provide the title compound. Anal. Calcd for C25H24N4: C, 78.92; H, 6.36; N, 14.73. Found: C, 77.81; H, 6.43; N, 14.52. EXAMPLE 11 Preparation of 4- [5-(4-Oxo-3-(3-trifluoromethoxybenzyl)-l-phenyl-l,3,8- triazaspiro[4.5]dec-8-ylmethyl)imidazol-l-ylmethyl]benzonitrile dihydrochloride Step A: Preparation of l-phenyl-8-tert-butoxycarbonyl- 1,3,8- triazaspiro [4.51 -decan-4-one A solution of l-phenyl-l,3,8-triazaspiro[4.5]decan-4-one (693 mg, 3 mmol) and di-tert-butyl dicarbonate (780 mg, 3.6 mmol) in anhydrous methylene chloride (10 mL) was stirred at room temp, for 24 hours. The resulting solution was concentrated under vacuum, and the residue was triturated with diethyl ether. The white solid which precipitated was collected by filtration to provide the title compound, mp: 214-216°C. Step B: Preparation of l-phenyl-3-(3-trifluoromethoxybenzyl)-8-tert- butoxycarbonyl- 1.3.8-triazaspiro [4.51 -decan-4-one A solution of l-phenyl-8-tert-butoxycarbonyl-l,3,8-triaza- spiro[4.5]decan-4-one, as described above in Step A, (199 mg, 0.6 mmol) in anhydrous dimethyl-formamide (2 mL) was stirred at 50°C with 60% sodium hydride in mineral oil (40 mg, 1 mmol) for 15 minutes under an inert (argon) atmosphere. 3-Trifluoromethoxybenzyl bromide (0.12 mL, 0.75 mmol) was added to the reaction. The reaction was heated for an additional 1.5 hours. The cooled reaction mixture was diluted with ethyl acetate and the organic layer washed sucessively with sat'd. aqueous sodium bicarbonate and water (3X). The resulting solution was dried (anhyd. sodium sulfate), filtered, and concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluting with a 20-30% ethyl acetate/hexane gradient. Appropriate fractions were combined and the solvent evaporated to give the title compound as a viscous oil. Step C: Preparation of l-phenyl-3-(3-trifluoromethoxybenzyl) -1,3,8- triazaspiro [4.51 -decan-4-one A solution of l-phenyl-3-tert-butoxycarbonyl-8-tert- butoxycarbonyl-l,3,8-triaza-spiro[4.5]decan-4-one, as described above in Step B, (196 mg, 0.39 mmol) in anhydrous methylene chloride (6 mL) containing trifluoroacetic acid (0.5 mL) was stirred at ambient temp, for 20 hours. The solvent and excess TFA were removed under vacuum and the residue was redissolved in methylene chloride and washed with aqueous sat'd. sodium carbonate. The organic layer was dried (anhyd. sodium sulfate) ,filtered, and the solvent removed under vacuum to give the title compound as a viscous oil. Step D: Preparation of 4-{5-[4-Oxo-3-(3-trifluoromethoxybenzyl)-l- phenyl- 1 ,3 ,8-triazaspiro [4.5] -dec-8-ylm ethyl] imidazol- 1- ylmethyllbenzonitrile Dihvdrochloride A solution of l-phenyl-3-(3-trifluoromethoxybenzyl)-l,3,8- triazaspiro[4.5]decan-4-one, as described above in Step C, (159 mg, 0.39 mmol), l-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt, as described in Example 1, Alternate Step A, (121 mg, 0.45 mmol), and triethylamine (0.21 mL, 1.5 mmol) in anhydrous acetonitrile (3 mL) was stirred at room temp, for 7 hours. The resulting mixture was diluted with ethyl acetate and the solution washed with sat'd aqueous sodium carbonate, dried (anhyd. sodium sulfate), filtered and concentrated under vacuum. The resulting residue was subjected to column chromatography on silica gel eluting with a 1-4% methanol(sat'd with ammonia)/ ethyl acetate gradient. The appropriate fractions were collected and concentrated. The residue was dissolved in ethyl acetate and treated with two equivalents of 1M HCl/diethyl ether to afford the title compound as a dihydrochloride salt, mp: 240-241°C. Anal. Calcd for C33H3lF3N6θ2»2 HO0.25 H2O: C,58.45; H, 4.98; N, 12.39. Found: C, 58.44; H, 4.99; N, 12.30. MS (ES+) m/e 601.4 (m + 1) EXAMPLE 12 Preparation of 4- [5-(4-Oxo-3-(2-trifluoromethoxybenzyl)- 1-phenyl- 1,3, 8- triazaspiro [4.5] dec-8-ylmethyl)imidazol- 1 -ylmethyl] benzonitrile dihvdrochloride The title compound was prepared using the procedure described in Example 11, except substituting 2-trifluoromethoxybenzyl bromide for 3-trifluoromethoxybenzyl bromide in Step B to afford the dihydrochloride salt, mp:237-240°C. Anal. Calcd for C33H3lF3N6θ2»1.65 HCI: C, 59.98; H, 4.98; N, 12.72. Found: C, 60.01; H, 4.90; N, 12.62. MS (ES+) m/e 601.4 (m + 1) EXAMPLE 13 Preparation of 4-[5-(2-Oxo-3-(3-trifluoromethoxybenzyl)-l-oxa-3,8-diaza- spiro[4.5]dec-8-ylmethyl)imidazol-l-ylmethyl]benzonitrile dihydrochloride Step A: Preparation of l-Benzyl-4-hydroxy-4-aminom ethyl piperidine To neat l-benzyl-4-piperidone (2.22mL, 12 mmol) was added trimethylsilyl cyanide (1.95 mL, -15 mmol) and zinc iodide (~5 mg). The solution was stirred for 6 hours or until reaction was completed as indicated by tic. This oil was dissolved in diethyl ether (30 mL), filtered to remove some solid and added dropwise to a solution of diethyl ether (15 mL) containing 1M lithium aluminium hydride/di ethyl ether ( 30 mL). After stirring at ambient temp, for 2 hours, the reaction was carefully quenched with aqueous sat'd sodium sulfate. This suspension was diluted with more diethyl ether, filtered to remove solids, and the solvent evaporated under partial vacuum to give the crude title compound as an oil. Step B: Preparation of 8-Benzyl-l-oxa-3,8-diaza-spiro[4.5]decan-2- o ne To a solution of crude l-benzyl-4-hydroxy-4-aminomethyl piperidine, as described above in Step A, (-3.1 gm, 12 mmol) in acetonitrile (50 mL) containing triethyl amine ( 5.7 mL, 42 mmol) cooled in an ice bath was added in 1 mL portions 20% phosgene/toluene (9 mL) over a three hour period. The reaction mixture was stirred at ambient temp, for 15 hours and diluted with ethyl acetate. This solution was washed with water (2X) and the organic layer dried (anhyd. sodium sulfate), filtered, and the solvent removed under vacuum. The residue was triturated with diethyl ether and the title compound collected by filtration as a white solid, mp: 159-161°C. Step C: Preparation of l-Oxa-3,8-diaza-spiro[4.5]decan- 2-one acetate A solution of l-benzyl-l-oxa-3,8-diaza-spiro[4.5]decan-2-one, as described above in Step B, (496 mg, 2 mmol) in absolute ethanol (30 mL) containing acetic acid (2.4 mL) and 10% palladium carbon (165 mg) was hydrogenated at atmospheric pressure for three hours. The catalyst was removed by filtration and the solvent removed under vacuum. The residue was chased with toluene (2X) to give a solid. This material was triturated with diethyl ether to give the title compound as a white solid as the acetate salt. Step D: Preparation of 8-tert-Butoxycarbonyl-l-oxa-3,8-diaza- spiro[4.51deca-2-one Boc-N V ^ f \ / V-NH To a suspension of l-oxa-3,8-diazaspiro[4.5]decan-2-one acetate, as described above in Step C, (410 mg, 1.9 mmol) in anhydrous methylene chloride (10 mL) was added di-tert-butyl dicarbonate (520 mg, 2.38 mmol) and triethyl amine (0.35 mL, 2.5 mmol) and the mixture stirred at room temp, for 3 hours to give a homogeneous solution. The resulting solution was diluted with more methylene chloride and washed with aqueous sat'd sodium bicarbonate. The organic layer was dried (anhyd. sodium sulfate) and the solvent removed under vacuum. The residue was triturated with diethyl ether and collected to give the title compound as a white solid, mp: 175-176°C. Step E: Preparation of 3-(3-trifluoromethoxybenzyl)-8-tert- butoxycarbonyl-l-oxa-3.8-diaza-spiro[4.51deca-2-one A solution of 8-tert-butoxycarbonyl-l-oxa-3,8-diaza- spiro[4.5]deca-2-one, as described above in Step D, (154 mg, 0.6 mmol) in anhydrous dimethyl-formamide (2 mL) was stirred at 50°C with 60% sodium hydride in mineral oil (34 mg, 0.85 mmol) for 15 minutes under an inert (argon) atmosphere. 3-Trifluoromethoxybenzyl bromide (0.11 mL, 0.7 mmol) was added to the reaction and heated for an additional 2 hours. The cooled reaction mixture was diluted with ethyl acetate and the organic layer washed sucessively with sat'd. aqueous sodium bicarbonate and water (3X). The resulting solution was dried (anhyd. sodium sulfate), filtered, and concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluting with a 10-50% ethyl acetate/hexane gradient. Appropriate fractions were combined and the solvent evaporated to give the title compound as a viscous oil. Step F: Preparation of 3-(3-trifluoromethoxybenzyl)-l-oxa-3,8-diaza- spiro [4.51 deca-2-one A solution of 3-tert-butoxycarbonyl-8-tert-butoxycarbonyl-l- oxa-3,8-diazaspiro[4.5]deca-2-one, as described above in Step E, (220 mg, 0.51 mmol) in anhydrous methylene chloride (5 mL) containing trifluoroacetic acid (0.5 mL) was stirred at ambient temp, for 4 hours. The solvent and excess TFA was removed under vacuum and the residue was redissolved in methylene chloride and washed with aqueous sat'd. sodium carbonate. The organic layer was dried (anhyd. sodium sulfate) ,filtered, and the solvent removed under vacuum to give the title compound as a viscous oil. Step G: Preparation of 4-[5-(2-Oxo-3-(3-trifluoromethoxybenzyl)-l- oxa-3 ,8-diaza-spiro [4.5] dec-8-ylmethyl)imidazol- 1- ylmethyllbenzonitrile Dihydrochloride A solution of 3-(3-trifluoromethoxybenzyl)-l-oxa-3,8-diaza- spiro[4.5]deca-2-one, as described above in Step F, (164 mg, 0.50 mmol), 1- (4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt, as described in Example 1, Alternate Step A, (147 mg, 0.55 mmol), and triethylamine (0.21 mL, 1.5 mmol) in anhydrous acetonitrile (3 mL) was stirred at room temp, for 6 hours. The resulting mixture was diluted with ethyl acetate and the solution washed with sat'd aqueous sodium carbonate, dried (anhyd. sodium sulfate), filtered and concentrated under vacuum. The resulting residue was subjected to column chromatography on silica gel eluting with a 1-6% methanol (sat'd with ammonia)/ethyl acetate gradient. The appropriate fractions were collected and concentrated. The residue was dissolved in ethyl acetate and treated with two equivalents of 1M HCl/diethyl ether to afford the title compound as an amorphorous dihydrochloride salt. Anal. Calcd for C27H26F3N5θ3*2 HC 0.2 H2θ: C,53.83; H, 4.54; N, 11.70. Found: C, 54.14; H, 4.72; N, 11.70. MS (ES+) m/e 526.3 (m + 1) EXAMPLE 14 Preparation of 4-[5-(2-Oxo-3-(2-trifluoromethoxybenzyl)-l-oxa-3,8-diaza- spiro [4.5] dec-8-ylmethyl)imidazol- 1 -ylmethyl] benzonitrile dihydrochloride The title compound was prepared using the procedure described in Example 13, except substituting 2-trifluoromethoxybenzyl bromide for 3-trifluoromethoxybenzyl bromide in Step E to afford the dihydrochloride salt as an amorphorous solid. Anal. Calcd for C27H26 3Nδθ3*2 HC1»0.8 H2O: C,52.91; H, 4.87; N, 11.43. Found: C, 52.93; H, 4.96; N, 11.35. EXAMPLE 15 Preparation of 4-[5-(2-Oxo-3-n-butyl-l-oxa-3,8-diaza-spiro[4.5]dec-8- ylmethyl)imidazol-l-ylmethyl1benzonitrile dihydrochloride The title compound was prepared using the procedure described in Example 13, except substituting 1-bromobutane for 3- trifluoromethoxybenzyl bromide in Step E to afford the dihydrochloride salt as an amorphorous solid. Anal. Calcd for C23H29Nδθ2*2 HC1«0.5 H2O: C,56.44; H, 6.59; N, 14,31. Found: C, 56.38; H, 6.38; N, 14.51. MS(ES+) m/e 504.3 (m + 1) EXAMPLE 16 Preparation of 4-[5-(2-Oxo-3-(2,2,2-trifluoroethyl)-l-oxa-3,8-diaza- spiro [4.5] dec-8-ylmethyl)imidazol- 1-ylmethyl] benzonitrile dihydrochloride The title compound was prepared using the procedure described in Example 13, except substituting 2-iodo-l,l,l-trifluoroethane for 3-trifluoromethoxybenzyl bromide in Step E to afford the dihydrochloride salt as an amorphorous solid. Anal. Calcd for C2lH22F3Nδθ2*2 HCI: C,46.16; H, 5.08; N, 13.83. Found: C, 49.81; H, 4.78; N, 13.83 MS(ES+) m/e 434.2 (m + 1). EXAMPLE 17 Preparation of 4-[5-(spiro[3H-indole-3,4'-piperidin]-2(lH)-on-l'- ylmethyPimidazol- 1 -ylmethyl] benzonitrile Step A: Preparation of l'-tert-butoxycarbonyl-spiro[3H-indole-3,4'- piperidin1 -2( lH)-one To a solution of oxindole (1.33 gm, 10 mmol) in anhydrous tetrahydrofuran (8 mL) was added dropwise, with ice bath cooling, 1 M lithium bis(trimethylsilyl)amide/tetrahydrofuran (30 mL, 30 mmol) under an inert atmosphere (argon). After 15 minutes, this greenish- brown solution was added dropwise to a solution of N-tert-butoxy- carbonyl-bis(2-chloroethyl)amine (2.49 gm, 11 mmol) in anhydrous tetrahydrofuran (5 mL) which was also cooled in an ice bath under an inert atmosphere. This solution was stirred at ambient temp, over 20 hours. The reaction mixture was diluted with diethyl ether and acidified with 2 N HCI. The etheral layer was separated off and dried (anhyd. magnesium sulfate), filtered, and the solvent removed under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 20-50% ethyl acetate/hexane gradient. The appropriate fractions were combined and the solvents concentrated to give a residue which was triturated with 2:1 hexane /diethyl ether to give the title compound as an off-white solid, mp: 138-140°C. Step B: Preparation of spiro[3H-indole-3.4'-piperidin]-2(lH)-one A solution of l'-tert-butoxycarbonyl- spiro[3H-indole-3,4'- piperidin]-2(lH)-one, as described above in Step A, (551 mg, 1.70 mmol) in ethyl acetate saturated with HCI (5 mL) was stirred at ambient temp. for 3 hours as the product salt slowly crystallized out. This salt was collected by filtration and partitioned between methylene chloride and aqueous sat'd. sodium carbonate. The organic layer was separated off, dried (anhyd. sodium sulfate) ,filtered, and the solvent removed under vacuum. The residue was triturated with diethyl ether to give the title compound as a white solid, mp: 184-186°C. Step C: Preparation of 4- [5-(spiro [3H-indole-3 ,4'-piperidine] -2( 1H)- on-l'-ylmethyl)imidazol-l-ylmethyl1benzonitrile A solution of spiro[3H-indole-3,4'-piperidin]-2(lH)-one, as described above in Step B, (110 mg, 0.54 mmol), l-(4-cyanobenzyl)-5- chloromethylimidazole hydrochloride salt, as described in Example 1, Alternate Step A, (134 mg, 0.50 mmol), and triethylamine (0.21 mL, 1.5 mmol) in anhydrous acetonitrile (1.5 mL) was stirred at room temp, for 15 hours. The resulting mixture was diluted with ethyl acetate and the solution washed with sat'd aqueous sodium carbonate, dried (anhyd. sodium sulfate), filtered and concentrated under vacuum. The resulting residue was triturated with ethyl acetate to give a white solid which was collected to afford the title compound as a crystalline freebase, mp: 245- 247°C. Anal. Calcd for C26H23N5O •O.δ H2O: C,70.91; H, 5.95; N, 17.23. Found: C, 71.01; H, 6.00; N, 17.23. EXAMPLE 18 Preparation of 4-[5-(l,3-Dioxo-2-(3-trifluoromethoxybenzyl)-2,8-diaza- spiro[4.5]dec-8-ylmethyl)imidazol-l-ylmethyl]benzonitrile dihydrochloride The title compound was prepared using the procedure described in Example 13 , Steps C-G, except substituting 8-benzyl-2,8- diazaspiro[4.5]decan-l,3-dione [which can be prepared according to procedures described in Arch.Pharm., Vol. 294, 210-220(1961) and Swiss patent 383,968 (1965)] for 8-benzyl-l-oxa-3,8-diaza-spiro[4,5]decan-2-one in Step C to afford the dihydrochloride salt as an amorphorous solid. Anal. Calcd for C28H26F3Nδθ3*2 HCI: C,55.09; H, 4.62; N, 11.47. Found: C, 54.73; H, 4.32; N, 11.53. MS(ES+) m e 538.2 (m + 1) EXAMPLE 19 In vitro inhibition of ras farnesyl transferase Transferase Assays. Isoprenyl-protein transferase activity assays are carried out at 30 °C unless noted otherwise. A typical reaction contains (in a final volume of 50 μL): [ 3 H] farnesyl diphosphate, Ras protein , 50 mM HEPES, pH 7.5, 5 mM MgCl 2 , 5 mM dithiothreitol, 10 μM ZnCl 2 , 0.1% polyethyleneglycol (PEG) (15,000-20,000 mw) and isoprenyl-protein transferase. The FPTase employed in the assay is prepared by recombinant expression as described 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-equilibrating the assay mixture in the absence of enzyme, reactions are initiated by the addition of isoprenyl-protein transferase and stopped at timed intervals (typically 15 min) by the addition of 1 M HCI 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 described 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 described in the above Examples 1-18 were tested for inhibitory activity against human FPTase by the assay described above and were found to have IC50 of < 30 μM. EXAMPLE 20 Modified In vitro GGTase inhibition assay The modified geranylgeranyl-protein transferase inhibition assay is carried out at room temperature. A typical reaction contains (in a final volume of 50 μL): [ 3 H]geranylgeranyl diphosphate, biotinylated Ras peptide, 50 mM HEPES, pH 7.5, a modulating anion (for example 10 mM glycerophosphate or 5mM ATP), 5 mM MgCl 2 , 10 μM ZnCl 2 , 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 described in U.S. Pat. No. 5,470,832, incorporated by reference. The Ras peptide is derived from the K4B-Ras protein and has the following sequence: biotinyl- 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 described 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 KM concentrations. Enzyme and substrate concentrations for inhibitor IC 50 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 1-18 are tested for inhibitory activity against human GGTase type I by the assay described above. EXAMPLE 21 Cell-based in vitro ras farnesylation 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 labeled in 3 ml methionine-free DMEM supple-mented with 10% regular DMEM, 2% fetal bovine serum and 400 μCi[35S]methionine (1000 Ci mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45 min. Aliquots of lysates containing equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et al., J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at 4°C, 200 μL 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 farnesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein. EXAMPLE 22 Cell-based in 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 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 compound (dissolved in methanol at 1000 times the final concentration used in the assay). The cells are fed twice weekly with 0.5 ml of medium A containing 0.1% methanol or the concentration of the instant compound. Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made. EXAMPLE 23 Construction of SEAP reporter plasmid pDSElOO The SEAP reporter plasmid, pDSElOO was constructed by ligating a restriction fragment containing the SEAP coding sequence into the plasmid pCMV-RE-AKI. The SEAP gene is derived from the plasmid pSEAP2-Basic (Clontech, Palo Alto, CA). The plasmid pCMV-RE-AKI contains 5 sequential copies of the 'dyad symmetry response element' cloned upstream of a OAT-TATA' sequence derived 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 restriction fragment encoding the SEAP coding sequence was cut out of the plasmid pSEAP2-Basic using the restriction enzymes EcoRl 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 in an agarose gel and cutting out the 1694 base pair fragment. The vector plasmid pCMV-RE-AKI was linearized with the restriction 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 restriction fragment orientation. Properly oriented recombinant constructs were sequenced across the cloning junctions to verify 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 ligating a restriction fragment containing the SEAP coding sequence into the plasmid pCMV-RE-AKI. The SEAP gene is derived from plasmid P GEM7zf(-)/SEAP. The plasmid pDSElOl was constructed as follows: A restriction fragment containing part of the SEAP gene coding sequence was cut out of the plasmid pGEM7zf(-)/SEAP using the restriction 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 electrophoresing 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 described previously (Jones, R.E., Defeo-Jones, D., McAvoy, E.M., Vuocolo, G.A., Wegrzyn, R.J., Haskell, KM. 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 oligos. Sense strand N-terminal SEAP : 5' GAGAGGGAATTCGGGCCCTTCCTGCAT GCTGCTGCTGCTGCTGCTGCTGGGC 3' (SEQ.ID.NO.:3) Antisense strand N-terminal SEAP: 5' GAG AGAGC TC GAGGTT AAC C C GGGT GCGCGGCGTCGGTGGT 3' (SEQ.ID.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-terminal oligos (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 restriction sites at the ends. The Antisense N-terminal oligo (SEQ.ID.NO.: 4) introduces an internal translation STOP codon within the SEAP gene along with the Hpal site. The C-terminal oligos (SEQ.ID.NO.: 5 and SEQ.ID.NO.: 6) were used to amplify a 412 bp C-terminal PCR product containing Hpal and Hindlll restriction 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-terminal amplicon was digested with EcoRI and Hpal while the C-terminal amplicon was digested with Hpal and Hindlll. The two fragments comprising 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-ligated into the vector pGEM7zf(-) (Promega) which had been restriction 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 religated. The resulting plasmid is named pCMV- AKI. Next, the cytomegalovirus 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., NucAcids 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 oligos. Sense strand: 5' GGCAGAGCTCGTTTAGTGAACCGTCAG 3' (SEQ.ID.NO.: 7) Antisense strand: 5' GAGAGATCTCAAGGACGGTGACTGCAG 3' (SEQ.ID.NO.: 8) These two oligos generate a 991 base pair fragment with a Sad site incorporated by the sense oligo and a Bgl-II fragment incorporated by the antisense oligo. 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 (described 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 ligating the SEAP fragment into the pCMV-AKI-InA vector. Transformants were screened for the proper insert and then mapped for restriction fragment orientation. Properly oriented 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 intron A sequence and upstream of the bovine growth hormone poly-A sequence. The plasmid expresses SEAP in a constitutive manner when transfected into mammalian cells. Cloning of a Myristylated viral-H-rαs expression plasmid A DNA fragment containing viral-H-rαs 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 oligos. Sense strand: 5'TCTCCTCGAGGCCACCATGGGGAGTAGCAAGAGCAAGCCTAA GGACCCCAGCCAGCGCCGGATGACAGAATACAAGCTTGTGGTG G 3'. (SEQ.ID.NO.: 9) Antisense: 5'CACATCTAGATCAGGACAGCACAGACTTGCAGC 3'. (SEQ.ID.NO.: 10) A sequence encoding the first 15 aminoacids of the v-src gene, containing a myristylation site, is incorporated into the sense strand oligo. The sense strand oligo also optimizes the 'Kozak' translation initiation sequence immediately 5' to the ATG start site. To prevent prenylation at the viral-ras C-terminus, cysteine 186 would be mutated to a serine by substituting a G residue for a C residue in the C-terminal antisense oligo. The PCR primer oligos 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 transcribed from the CMV promoter of the pCI vector. Cloning of a viral-H-rαs-CVLL expression plasmid A viral-H-rαs clone with a C-terminal sequence encoding the amino acids CVLL can be cloned from the plasmid Η-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 oligos. Sense strand: 5'TCTCCTCGAGGCCACCATGACAGAATACAAGCTTGTGGTGG-3' (SEQ.ID.NO.: 11) Antisense strand: 5'CACTCTAGACTGGTGTCAGAGCAGCACACACTTGCAGC-3' (SEQ.ID.NO.: 12) The sense strand oligo optimizes the 'Kozak' sequence and adds an Xhol site. The antisense strand mutates serine 189 to leucine and adds an Xbal site. The PCR fragment can be trimmed 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 transcribed from the CMV promoter of the pCI vector. Cloning of c-H-ms-Leu61 expression plasmid The human c-H-rαs gene can be PCRed from a human cerebral cortex cDNA library (Clontech) using the following oligonucleotide primers. Sense strand: 5'-GAGAGAATTCGCCACCATGACGGAATATAAGCTGGTGG-3' (SEQ.ID.NO.: 13) Antisense strand: 5'-GAGAGTCGACGCGTCAGGAGAGCACACACTTGC-3' (SEQ.ID.NO.: 14) The primers will amplify a c-H-rαs encoding DNA fragment with the primers contributing an optimized 'Kozak' translation start sequence, an EcoRI site at the N-terminus and a Sal I stite at the C-terminal end. After trimming 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 glutamine-61 to a leucine 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-rαs-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 transcribe c-H-rαs-Leu61 from the CMV promoter of the pCI vector. Cloning of a c-N-rαs-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 primers. Sense strand: 5'-GAGAGAATTCGCCACCATGACTGAGTACAAACTGGTGG-3' (SEQ.ID.NO.: 16) Antisense strand: 5'-GAGAGTCGACTTGTTACATCACCACACATGGC-3' (SEQ.ID.NO.: 17) The primers will amplify a c-N-ras encoding DNA fragment with the primers contributing an optimized 'Kozak' translation start sequence, an EcoRI site at the N-terminus and a Sal I stite at the C-terminal end. After trimming 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 valine 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 transcribe c-N-ras-Val-12 from the CMV promoter of the pCI vector. Cloning of a c-K-rαs-VaI-12 expression plasmid The human c-K-ras gene can be PCRed from a human cerebral cortex cDNA library (Clontech) using the following oligonucleotide primers. Sense strand: 5'-GAGAGGTACCGCCACCATGACTGAATATAAACTTGTGG-3' (SEQ.ID.NO.: 19) Antisense strand: 5'-CTCTGTCGACGTATTTACATAATTACACACTTTGTC-3' (SEQ.ID.NO.: 20) The primers will amplify a c-K-ras encoding DNA fragment with the primers contributing an optimized 'Kozak' translation start sequence, a Kpnl site at the N-terminus and a Sal I site at the C-terminal end. After trimming 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 valine 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 glutamine + 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-rαs-CVLL are co-precipitated with the DSE- SEAP reporter construct. For 10cm plates 600μl of CaCl 2 -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, Glutamine and nonessential aminoacids). The CaPO4-DNA precipitate is added dropwise to the cells and the plate rocked gently to distribute. DNA uptake is allowed to proceed for 5-6 hrs at 37°C under a 5% CO2 atmosphere. Following the DNA incubation period, the cells are washed with PBS and trypsinized with 1ml of 0.05% trypsin. The 1 ml of trypsinized cells is diluted into 10ml of phenol red free DMEM + 0.2% charcoal stripped calf serum + IX (Pen/Strep, Glutamine 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 triplicate over a range of half-log steps. Incubation of cells and test compound is for 36 hrs at 37° under CO2- At the end of the incubation period, 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. Luminesence 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-CaPQ 4 precipitate for 10cm. plate of cells Ras expression plasmid (lμg/μl) lOμl DSE-SEAP Plasmid (lμg/μl) 2μl Sheared Calf Thymus DNA (lμg/μl) 8μl 2M CaCl 2 74μl dH 2 O 506μl 2X HBS Buffer 280mM NaCl lOmM KCl 1.5mM Na 2 HPO 4 2H 2 O 12mM dextrose 50mM HEPES Final pH = 7.05 Luminesence Buffer (26ml) Assay Buffer 20ml Emerald Reagent™ (Tropix) 2.5ml lOOmM homoarginine 2.5ml CSPD Reagent® (Tropix) 1.0ml Assay Buffer Add 0.05M Na 2 CO 3 to 0.05M NaHCO 3 to obtain pH 9.5. Make ImM in MgCl 2 EXAMPLE 24 The processing assays employed in this example and in Example 25 are modifications of that described by DeClue et al [Cancer Research 51, 712-717, 1991]. K4B-Ras processing inhibition assay PSN-1 (human pancreatic carcinoma) 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 cysteine-free/methionine-free DMEM supplemented with 0.035 ml of 200 mM glutamine (Gibco), 2% fetal bovine serum, respectively) containing the desired concentration of test compound, lovastatin 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-Mix (Amersham, cell labeling grade) is added. After introducing the label amino acid mixture, the cells are incubated at 37°C for an additional period 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 centrifugation (10,000 x g for 10 sec at room temperature), and lysed by vortexing 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 aprotinin, 2 μg/ml leupeptin and 2 μg/ml antipain). The lysate is then centrifuged at 15,000 x g for 10 min at 4°C and the supernatant saved. For immunoprecipitation of Ki4B-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 appropriate 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 Tris 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 brief centrifugation (15,000 x g for 30 sec. at room temperature). The supernatant is added to 1 ml of Dilution Buffer 0.1% Triton 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 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 Laemmli 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 centrifugation. The supernatant is subjected to SDS-PAGE on a 12% acrylamide gel (bis- acrylamide: acrylamide, 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 buffer 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 phosphorimager. 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 IC50 values are generated using 4-parameter curve fits in SigmaPlot software. EXAMPLE 25 K4B-Ras processing inhibition assay PSN-1 (human pancreatic carcinoma) cells are used for analysis of protein processing. Subconfluent cells in 150 mm dishes are fed with 20 ml of media (RPMI supplemented with 15% fetal bovine serum) containing the desired concentration of prenyl-protein transferase inhibitor 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%. The cells are incubated at 37°C for 24 hours, the media is then removed and the cells are washed twice with cold PBS. The cells are scraped into 2 ml of cold PBS, collected by centrifugation (10,000 x g for 5 min at 4°C) and frozen at -70 °C. Cells are lysed by thawing and addition of lysis buffer (50 mM HEPES, pH 7.2, 50 mM NaCl, 1% CHAPS, 0.7 μg/ml aprotinin, 0.7 μg/ml leupeptin 300 μg/ml pefabloc, and 0.3 mM EDTA). The lysate is then centrifuged at 100,000 x g for 60 min at 4°C and the supernatant saved. The supernatant may be subjected to SDS- PAGE, HPLC analysis, and/or chemical cleavage techniques. The lysate is applied to a HiTrap-SP (Pharmacia Biotech) column in buffer A (50 mM HEPES pH 7.2) and resolved by gradient in buffer A plus 1 M NaCl. Peak fractions containing Ki4B-Ras are pooled, diluted with an equal volume of water and immunoprecipitated with the pan Ras monoclonal antibody, Y13-259 linked to agarose. The protein/ antibody mixture is incubated at 4°C for 12 hours. The immune complex is washed 3 times with PBS , followed by 3 times with water. The Ras is eluted from the beads by either high pH conditions (pH>10) or by heating at 95°C for 5 minutes, after which the beads are pelleted by brief centrifugation. The supernatant may be subjected to SDS-PAGE, HPLC analysis, and/or chemical cleavage techniques. EXAMPLE 26 Rapl processing inhibition assay Protocol A: Cells are labeled, incubated and lysed as described in Example 25. 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 Tris 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 centrifugation (15,000 x g for 30 sec. at room temperature). The supernatant is added to 1 ml of Dilution Buffer (0.1% Triton X-100, 5 mM EDTA, 50 mM NaCl, 10 mM Tris pH 7.4) with 2 μg Rapl antibody, Rapl/Krevl (121) (Santa Cruz Biotech). The second protein/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 in Laemmli sample buffer. The Rapl is eluted from the beads by heating at 95°C for 5 minutes, after which the beads are pelleted by brief centrifugation. The supernatant is subjected to SDS-PAGE on a 12% acrylamide gel (bis- acrylamide:acrylamide, 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 6 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 (i.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 rinsed with 1ml PBS, and the PBS is aspirated. 180 μL SDS-PAGE sample buffer (Novex) containing 5% 2-mercaptoethanol 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 (Worthington Enzymes), 0.25 mg/ml Rnase A (Worthington Enzymes), 0.5M Tris-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-point 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 hours. 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% nonfat 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 Rap la 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 for 15 minutes per 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 phosphorimager 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 ECQQ for inhibition of processing of Rapla. The assay is run as described 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 Imagequant® 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 27 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 Ha-rαs 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 or compound treatment group. Animals are dosed subcutaneously starting on day 1 and daily for the duration of the experiment. Alternatively, the prenyl-protein transferase inhibitor may be administered by a continuous infusion pump. Compound 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.

Claims: WHAT IS CLAIMED IS: 1. A compound illustrated by the formula I: wherein: Rla and ΈV° are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 O-, R 9 S(O) m -, R 8 C(O)NR 8 -, CN, NO2, (R8) 2 N-C(NR 8 )-, R8C(0)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9OC(O)NR 8 -, c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 O-, R9S(0) m -, R 8 C(O)NR 8 -, CN, (R8) 2 N-C(NR8)-, R8c(0)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9OC(O)-NR 8 -; Rl and R are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R9S(0) m -, R 8 C(0)NR8-, CN, NO2, R 8 2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R8)2, or R90C(0)NR8-, and c) Cl-Cβ alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R 9 S(O) m -, R 8 C(O)NH-, CN, H2N-C(NH)-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R8)2, or R 8 OC(O)NH-; R3 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R9S(0) m -, R 8 C(O)NR 8 -, CN, NO2, (R 8 )2N-C-(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -, and c) Ci-Cβ alkyl, unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R O-, R9S(O) m -, R 8 C(O)NR 8 -, CN, (R 8 )2N- C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R 9 OC(O)NR 8 -; R4a s R4b, R4c and R5 independently are selected from: H, =O, unsubstituted or substituted Ci-8 alkyl, unsubstituted or substituted C2-8 alkenyl, 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 one or two groups selected from: a) Cl-4 alkyl, d) halogen, e) Cl-4 perfluoroalkyl, 2) C3-6 cycloalkyl, 3) OR 6 , 4) SR 6 , S(0)R6, SO2R 6 , — O^ .NR 6 R 7 8) T O 9) O^.OR 6 T O 11) — S0 2 -NR 6 R 7 13) A- R< O 15) Cl-8 alkyl, 16) Cl-8 perfluoroalkyl, or 17) halo; either R^b and R^ or R^ a and R^b, when located on adjacent carbon atoms, may be joined to form a ring; R 6 , R7 and R? a are independently selected from: H, Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, Cl-4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from: a) Cl-4 alkoxy, b) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle, c) halogen, d) HO, g) -S(0) m R 9 , or h) N(R 8 )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 8 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2- trifluoroethyl and aryl; R9 is independently selected from Ci-Cβ alkyl and aryl; Al and A2 are independently selected from: a) a bond, b) HC=CH, c) C≡C, d) o, e) C=O, f) O=C, g) -C(O)NR 8 -, h) -NR 8 C(O)-, i) -N(R 8 )-, j) -S(O) 2 N(R 8 )-, k) -N(R 8 )S(O)2-, or 1) S(O) m ; χl, χ2, χ3, χ4 and X^ are independently selected from: C(H) y , N(H) W , O, C=O, S(O)2,and PO(OMe); 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(O)m and V is not hydrogen if A^ is a bond, n is 0 and A is S(O)m; provided that if V is hydrogen then Rl is absent; W is heterocycle; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; r is independently 0 to 5, provided that r is 0 when V is hydrogen; s is 1 or 2; t is 0 or 1; u is 0, 1 or 2; w is 0 or 1; and y is 1 or 2; dashed lines represent optional double bonds or the pharmaceutically acceptable salts or the optical isomers thereof. 2. The compound according to Claim 1 of the formula I: wherein Rla and Rl" are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 O-, R9s(0) m -, R 8 C(O)NR 8 -, CN, NO2, (R8) 2 N-C(NR8)-, R8C(0)-, R80C(0)-, N3, -N(R8)2, or R90C(0)NR8-, c) Ci-Cβ alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R80-, R9S(O) m -, R 8 C(O)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R90C(0)-NR 8 -; Rl and R2 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R9S(O) m -, R 8 C(O)NR 8 -, CN, NO2, R 8 2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R90C(0)NR 8 -, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R 9 S(O) m -, R8C(O)NH-, CN, H2N-CCNH)-, R8C(O)-, R80C(0)-, N3, -N(R8)2, or R80C(0)NH-; R3 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, perfluoroalkyl, F, Cl, Br, R8O-, R9S(O) m -, R8C(O)NR8-, CN, NO2, (R8)2N-C-(NR8)-, RδC(O)-, R8θC(O)-, N3, -N(R 8 ) 2 , or R9OC(O)NR 8 -, and c) Cl-Cβ alkyl, unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R80-, R 9 S(O)m-, R 8 C(O)NR 8 -, CN, (R 8 ) 2 N- C(NR 8 )-, RδC(O)-, R 8 OC(O)-, N3, -N(R8) 2 , or R90C(0)NR 8 -; R4a 5 R4b 5 R4c and R5 independently are selected from: H, =0, unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C2-8 alkenyl, 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 one or two groups selected from: a) Cl-4 alkyl, d) halogen, e) Cl-4 perfluoroalkyl, 2) C3-6 cycloalkyl, 3) OR 6 , 4) SR 6 , S(O)R 6 , SO2R 6 5) — NR 6 R 7 ~ O^ . NR 6 R 7 8) T O o 13) AT* O 14 > - 0R6 o 15) Cl-8 alkyl, 16) Cl-8 perfluoroalkyl, or 17) halo; either R^h and R^ or R^a and R^b, when located on adjacent carbon atoms, may be joined to form a ring; R 6 , R7 and R^ a are independently selected from: H, Ci-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, Cl-4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from: a) Cχ_4 alkoxy, b) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle, c) halogen, d) HO, R* e) O OR 8 f) O g) -S(0) m R 9 s , or h) N(R8) 2 ; or R 6 and R^ may be joined in a ring; R and R^a m ay be joined in a ring; R is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2- trifluoroethyl and aryl; R is independently selected from Ci-Cβ alkyl and aryl; Al and A2 are independently selected from a) a bond, b) HC=CH, c) C≡C, d) o, e) C=O, f) O=C, g) -C(O)NR 8 -, h) -NR 8 C(O)-, i) -N(R 8 )-, j) -S(O) 2 N(R 8 )-, 1) S(O) m ; χl, χ , and X^ are independently selected from: C(H) y , N(H) W , O, C=O, S(O)2,and PO(OMe); χ3 is selected from N(H) or O; X^ is selected from C=O or C(H)y; V is selected from: a) hydrogen, b) heterocycle, selected from pyrrolidinyl, triazolyl, pyridyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, or isoquinolinyl; 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 A* is S(O) m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(O) m ; provided that if V is hydrogen then Rl is absent; W is a heterocycle selected from pyrrolidinyl, triazolyl, pyridyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, or isoquinolinyl; m is 0, 1 or 2; n is 0, 1, 2, 3 and 4; p is 0, 1, 2, 3 and 4; r is independently 0 to 5, provided that r is 0 when V is hydrogen; s is 1 or 2; t is 0 or 1; u is 0, 1 or 2; w is 0 or 1; and y is 1 or 2; dashed lines represent optional double bonds or the pharmaceutically acceptable salts or the optical isomers thereof. 3. The compound according to Claim 1 of the formula II: wherein Rla and Rl" are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 O-, R 9 S(O) m -, R 8 C(O)NR 8 -, CN, NO2, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R90C(0)NR 8 -, c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 O-, R9s(0) m -, R 8 C(O)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 ) 2 , or R9OC(O)-NR 8 -; Rl and R2 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O-, R9S(O) m -, R8C(O)NR8-, CN, NO2, R 8 2N-C(NR8)-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R9S(0) m -, R 8 C(O)NH-, CN, H2N-C(NH)-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R 8 OC(O)NH-; R3 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R9S(O) m -, R 8 C(O)NR 8 -, CN, NO2, (R 8 )2N-C-(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R90C(0)NR 8 -, and c) Ci-Cβ alkyl, unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 8 O-, R9s(O) m -, R 8 C(O)NR 8 -, CN, (R 8 ) N- C(NR 8 )-, R 8 C(O)-, R8θC(O)-, N3, -N(R8)2, or R90C(0)NR 8 -; R4a ; R4b a nd R5 independently are selected from: H, =O, unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C2-8 alkenyl, 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 one or two groups selected from: a) Ci-4 alkyl, d) halogen, e) Ci-4 perfluoroalkyl, 2) C3-6 cycloalkyl, 3) OR 6 , 4) SR 6 , S(O)R 6 , SO2R 6 , 5) — NR 6 R 7 8) ~ γ NR 6 R 7 0 9) 0^ / OR 6 T O 11) — S0 2 - NR 6 R 7 13 ) ^ R* O 15) Cl-8 alkyl, 16) Cl-8 perfluoroalkyl, or 17) halo; either R^b and R^ or R^a and R^b, when located on adjacent carbon atoms, may be joined to form a ring; R 6 , R' 7 and R' 7a are independently selected from: H, Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, Cl-4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from: a) Cl-4 alkoxy, b) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle, c) halogen, d) HO, g) -S(0) m R 9 , or h) N(R 8 )2; or R 6 and R^ may be joined in a ring; R7 and R^a a y be joined in a ring; R 8 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2- trifluoroethyl and aryl; R9 is independently selected from Ci-Cβ alkyl and aryl; Al and A2 are independently selected from: a) a bond, b) HC=CH, c) C≡C, d) o, e) C=O, f) O=C, g) -C(O)NR 8 -, h) -NR 8 C(O)-, i) -N(R 8 )-, j) -S(O)2N(R 8 )-, k) -N(R 8 )S(O)2-, or 1) S(O) m ; X l , χ , and X^ are independently selected from: C(H) y , N(H) W , O, C=O, S(O)2,and PO(OMe); χ3 is selected from N(H)w or O; X 5 is selectedd from C=O or C(H)y; V is selected from: a) hydrogen, b) heterocycle, selected from pyrrolidinyl, triazolyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, or isoquinolinyl; c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, provided that V is not hydrogen if A^ is S(O) m and V is not hydrogen if A^ is a bond, n is 0 and A2 is S(O) ; provided that if V is hydrogen then Rl is absent; m is 0, 1 or 2; n is 0, 1, 2, 3 and 4; p is 0, 1, 2, 3 and 4; r is independently 0 to 5, provided that r is 0 when V is hydrogen; s is 1 or 2; u is 0, 1 or 2; w is 0 or 1; and y is 1 or 2; dashed lines represent optional double bonds or the pharmaceutically acceptable salts or the optical isomers thereof. 4. The compound according to Claim 1 of the formula III : wherein: Rla and Rib are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 O-, R9S(O) m -, R 8 C(O)NR 8 -, CN, NO2, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -, c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 O-, R9s(0) m -, R 8 C(O)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)-NR 8 -; Rl and R2 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R9s(O) m -, R 8 C(O)NR 8 -, CN, NO2, R 8 2N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -, and c) Cl-Cβ alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R O-, R9S(O) m -, R 8 C(O)NH-, CN, H2N-C(NH)-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R 8 OC(O)NH-; R3 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R9S(O) m -, R 8 C(O)NR 8 -, CN, NO2, (R 8 )2N-C-(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R 9 OC(O)NR 8 -, and c) C1-C6 alkyl, unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 8 O-, R9S(O) m -, R 8 C(O)NR 8 -, CN, (R 8 )2N- C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -; R4a ; R4b and R5 independently are selected from: H, =O, unsubstituted or substituted Ci-8 alkyl, unsubstituted or substituted C2-8 alkenyl, 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 one or two groups selected from: a) Cl-4 alkyl, b) (CH 2 ) p OR 6 , c) (CH2) P NR 6 R' 7 , d) halogen, e) Cl-4 perfluoroalkyl, 2) C3-6 cycloalkyl, 3) OR 6 , 4) SR 6 , S(O)R 6 , SO2R 6 , 6 D 7 5) NR°R ^NR 6 R 7 8) T o 9) O. .OR 6 T o 11) — S0 2 -NR 6 R 7 13) R e o 14 > - 0R6 o 15) Cl-8 alkyl, 16) Cl-8 perfluoroalkyl, or 17) halo; either R^b and R^ or R^a a nd R^b when located on adjacent carbon atoms, may be joined to form a ring; R 6 , R7 and R^a are independently selected from: H, Ci-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, Cl-4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from: a) Ci-4 alkoxy, b) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle, c) halogen, d) HO, R fc e) O OR fc f) O g) -S(0) m R y , or h) N(R 8 )2; or R 6 and R^ may be joined in a ring; R 7 and R 7 a m ay be joined in a ring; R 8 is independently selected from hydrogen, Ci-Cβ alkyl, benzyl, 2,2,2- trifluoroethyl and aryl; R is independently selected from C1-C6 alkyl and aryl; Al and A are independently selected from: a) a bond, b) HC=CH, c) C≡C, d) o, e) C=O, f) O=C, g) -C(O)NR 8 -, h) -NR 8 C(O)-, i) -N(R 8 )-, j) -S(O) 2 N(R 8 )-, k) -N(R 8 )S(O)2-, or 1) S(O) m ; χl, χ2, and X^ are independently selected from: C(H) y , N(H) W , O, C=O, S(O)2,and PO(OMe); χ3 is selected from N(H) W or O; X 5 is selectedd from C=O or C(H)y; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; r is independently 0 to 5; s is 1 or 2; u is 0, 1 or 2; w is 0 or 1; and y is 1 or 2; dashed lines represent optional double bonds or the pharmaceutically acceptable salts or the optical isomers thereof. 5. The compound according to Claim 1 of the formula IV: wherein Rla and Ri are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 O-, R9S(O) m -, R8c(O)NR8-, CN, NO2, (R8) 2 N-C(NR8)-, R8C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(0)NR 8 -, c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 O-, R9S(O) m -, R 8 C(O)NR 8 -, CN, (R 8 )2N-C(NR 8 )-, R8c(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R90C(0)-NR 8 -; R2 is selected from: a) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R9s(0) m -, R8C(O)NR8-, CN, NO2, R8 2 N-C(NR 8 )-, R 8 C(0)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -, and b) Ci-Cβ alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R9s(0) m -, R 8 C(O)NH-, CN, H2N-C(NH)-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R 8 OC(O)NH-; R3 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R9S(O) m -, R 8 C(O)NR 8 -, CN, NO2, (R 8 )2N-C-(NR 8 )-, R 8 C(O)-, R 8 OC(0)-, N3, -N(R 8 )2, or R9θC(0)NR 8 -, and c) Ci-Cβ alkyl, unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 8 0-, R9S(O) m -, R8C(O)NR 8 -, CN, (R 8 )2N- C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N3, -N(R 8 )2, or R9θC(O)NR 8 -; 4a ? R4b and R5 independently are selected from: H, =O, unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C2-8 alkenyl, 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 one or two groups selected from: a) Cl-4 alkyl, d) halogen, e) Cl-4 perfluoroalkyl, 2) C3-6 cycloalkyl, 3) OR 6 , 4) SR 6 , S(O)R 6 SO2R 6 , 0-^ / NR 6 R 7 8) T o 9) — O^ ^ OR 6 Y o 11) — S0 2 -NR 6 R 7 13 ) ^R* O 14) ^OR 6 O 15) Cl-8 alkyl, 16) Cl-8 perfluoroalkyl, or 17) halo; either R^b and R^ or R^ a and R^b, when located on adjacent carbon atoms, may be joined to form a ring; R 6 , R7 and R 7 a are independently selected from: H, Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, Cl-4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from: a) Cl-4 alkoxy, b) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle, c) halogen, d) HO, 9) -S(0) m R 9 or h) N(R 8 )2; or R 6 and R^ may be joined in a ring; R 7 and R 7a may be joined in a ring; R 8 is independently selected from hydrogen, Ci-Cβ alkyl, benzyl, 2,2,2- trifluoroethyl and aryl; R is independently selected from Cl-Cβ alkyl and aryl; Al and A2 are independently selected from: a) a bond, b) HC=CH, c) C≡C, d) o, e) C=O, f O=C, g) -C(O)NR 8 -, h) -NR 8 C(O)-, i) -N(R 8 )-, j) -S(O) 2 N(R 8 )-, 1) S(O) m ; χl, χ2, and X^ are independently selected from: C(H) y , N(H) W , O, C=O, S(O)2,and PO(OMe); X3 is NH or 0; X 5 is C=O or CH2 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, 1, 2, 3 or 4; s is l or 2; u is 0, 1 or 2; w is 0 or 1; and y is l or 2; dashed lines represent optional double bonds or the pharmaceutically acceptable salts or the optical isomers thereof. 6. A compound selected from: 4- [5-(4-Oxo- 1-phenyl- 1 ,3 ,8-triazaspiro [4.5] dec-8-ylmethyl)imidazol- 1- ylmethyl] benzonitrile; 4-{5-[4-Oxo-l-(3-methylphenyl)-l,3,8-triazaspiro[4.5]dec-8- ylmethyl]imidazol-l-ylmethyl}benzonitrile; 4-{5-[4-Oxo-l-(4-methylphenyl)-l,3,8-triazaspiro[4.5]dec-8- ylmethyl]imidazol-l-ylmethyl}benzonitrile; 4-{5-[2,4-Dioxo-l-(3-methylphenyl)-l,3,8-triaza-spiro[4.5]dec-8- ylmethyl]imidazol-l-ylmethyl}benzonitrile; 4-{5-[2-Oxo-l-(3-methylphenyl)-l,3,8-triaza-spiro[4.5]dec-8- ylmethyl]imidazol-l-ylmethyl}benzonitrile; 4-{5-[2,2-Dioxo-l-(3-methylphenyl)-2-thia-l,3,8-triazaspiro[4.5]dec-8- ylmethyl]imidazol-l-ylmethyl}benzonitrile; 4-{5-[2,2-Dioxo-l-(4-chloro-3-methylphenyl)-2-thia-l,3,8- triazaspiro[4.5]dec-8-ylmethyl]imidazol-l-ylmethyl}benzonitrile; 4-{5-[2-Oxo-l-(3-methylphenyl)-3-oxa-l,8-diazaspiro[4.5]dec-8- ylmethyl]imidazol-l-ylmethyl}benzonitrile; 4-[5-(l-Oxo-3,4-benzo-2,9-diazaspiro[5.5]undec-9-ylmethyl)imidazol-l- ylmethyl]benzonitrile; 4-[5-(3,4-Benzo-8-azaspiro[4.5]-l-decen-8-ylmethyl)-imidazol-l- ylmethyl] benzonitrile; 4-[5-(4-Oxo-3-(3-trifluoromethoxybenzyl)-l-phenyl-l,3,8- triazaspiro[4.5]dec-8-ylmethyl)imidazol-l-ylmethyl]benzonitrile; 4- [5-(4-Oxo-3-(2-trifluoromethoxybenzyD- 1-phenyl- 1,3,8- triazaspiro[4.5]dec-8-ylmethyl)imidazol-l-ylmethyl]benzonitrile; 4-[5-(2-Oxo-3-(3-trifluoromethoxybenzyl)-l-oxa-3,8-diaza-spiro[4.5]dec-8- ylmethyl)imidazol-l-ylmethyl]benzonitrile; 4-[5-(2-Oxo-3-(2-trifluoromethoxybenzyl)-l-oxa-3,8-diaza-spiro[4.5]dec-8- ylmethyl)imidazol- 1 -ylmethyl] benzonitrile ; 4- [5-(2-Oxo-3-n-butyl- l-oxa-3 ,8-diaza-spiro [4.5] dec-8-ylmethyl)imidazol- 1- ylm ethyl] benzonitrile; 4-[5-(2-Oxo-3-(2,2,2-trifluoroethyl)-l-oxa-3,8-diaza-spiro[4.5]dec-8- ylmethyl)imidazol-l-ylmethyl]benzonitrile; 4- [5-(spiro[3H-indole-3 ,4'-piperidin] -2( lH)-on- l'-ylmethyl)imidazol- 1- ylmethyl] benzonitrile; and 4-[5-(l,3-Dioxo-2-(3-trifluoromethoxybenzyl)-2,8-diaza-spiro[4.5]dec-8- ylmethyl)imidazol-l -ylmethyl] benzonitrile or the pharmaceutically acceptable salts thereof. 7. The compound according to Claim 6 which is: 4-{5-[4-Oxo-l-(3-methylphenyl)-l,3,8-triazaspiro[4.5]dec-8- ylmethyl]imidazol-l-ylmethyl}benzonitrile or its pharmaceutically acceptable salts. 8. The compound according to Claim 6 which is: 4-{5-[2-Oxo-l-(3-methylphenyl)-l,3,8-triaza-spiro[4.5]dec-8- ylmethyl]imidazol-l-ylmethyl}benzonitrile or its pharmaceutically acceptable salts. 9. The compound according to Claim 6 which is: 4-{5-[2,2-Dioxo-l-(3-methylphenyl)-2-thia-l,3,8-triazaspiro[4.5]dec-8- ylmethyl]imidazol-l-ylmethyl}benzonitrile or its pharmaceutically acceptable salts. 10. The compound according to Claim 6 which is: 4-{5-[2,2-Dioxo-l-(4-chloro-3-methylphenyl)-2-thia-l,3,8- triazaspiro[4.5]dec-8-ylmethyl]imidazol-l-ylmethyl}benzonitrile or its pharmaceutically acceptable salts. 11. The compound according to Claim 6 which is: 4-[5-(4-Oxo-3-(3-trifluoromethoxybenzyl)-l-phenyl-l,3,8- triazaspiro[4.5]dec-8-ylmethyl)imidazol-l-ylmethyl]benzonitrile or its pharmaceutically acceptable salts. 12. The compound according to Claim 6 which is: 4-[5-(4-Oxo-3-(2-trifluoromethoxybenzyl)-l-phenyl-l,3,8- triazaspiro[4.5]dec-8-ylmethyl)imidazol-l-ylmethyl]benzonitrile or its pharmaceutically acceptable salts. 13. The compound according to Claim 6 which is: 4-[5-(2-Oxo-3-(3-trifluoromethoxybenzyl)-l-oxa-3,8-diaza-spiro[4.5]dec-8- ylmethyl)imidazol-l-ylmethyl]benzonitrile or its pharmaceutically acceptable salts. 14. The compound according to Claim 6 which is: 4-[5-(l,3-Dioxo-2-(3-trifluoromethoxybenzyl)-2,8-diaza-spiro[4.5]dec-8- ylmethyl)imidazol- 1 -ylmethyl] benzonitrile or its pharmaceutically acceptable salts. 15. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 1. 16. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 3. 17. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 4. 18. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 6. 19. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 15. 20. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 16. 21. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 17. 22. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 18. 23. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 15. 24. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 16. 25. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 17. 26. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 18. 27. 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 15. 28. 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 15. 29. 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 15. 30. A method for preventing restenosis which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 15. 31. 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 15. 32. A pharmaceutical composition made by combining the compound of Claim 1 and a pharmaceutically acceptable carrier. 33. A process for making a pharmaceutical composition comprising combining a compound of Claim 1 and a pharmaceutically acceptable carrier. 34. A method of conferring radiation sensitivity on a tumor cell using a therapeutically effective amount of a composition of Claim 15 in combination with radiation therapy. 35. A method of using a therapeutically effective amount of a composition of Claim 15 in combination with an antineoplastic to treat cancer. 36. A method according to Claim 35 wherein the antineoplastic is paclitaxel. SEQUENCE LISTING <110> Embrey, Mark W. Perlow, Debra S. ai , John S . Hoffman, Jacob M. <120> INHIBITORS OF PRENYL-PROTEIN TRANSFERASE <130> 19982Y <150> US 60/089,311 <151> 1998-06-15 <160> 21 <170> FastSEQ for Windows Version 3.0 <210> 1 <211> 4 <212> PRT <213> Homosapien <400> 1 Cys Val Leu Leu 1 <210> 2 <211> 15 <212> PRT <213> Homosapien <400> 2 Gly Lys Lys Lys Lys Lys Lys Ser Lys Thr Lys Cys Val lie Met 10 15 <210> 3 <211> 52 <212> DNA <213> Artificial Sequence <220> <223> completely synthesized <400> 3 gagagggaat tcgggccctt cctgcatgct gctgctgctg ctgctgctgg gc 52 <210> 4 <211> 41 <212> DNA <213> Artificial Sequence <220> <223> completely synthesized <400> 4 gagagagctc gaggttaacc cgggtgcgcg gcgtcggtgg t 41 <210> 5 <211> 42 <212> DNA <213> Artificial Sequence <220> <223> completely synthesized <400> 5 gagagagtct agagttaacc cgtggtcccc gcgttgcttc ct 42 <210> 6 <211> 43 <212> DNA <213> Artificial Sequence <220> <223> completely synthesized <400> 6 gaagaggaag cttggtaccg ccactgggct gtaggtggtg get 43 <210> 7 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> completely synthesized <400> 7 ggcagagctc gtttagtgaa ccgtcag 27 <210> 8 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> completely synthesized <400> 8 gagagatctc aaggacggtg actgcag 27 <210> 9 <211> 86 <212> DNA <213> Artificial Sequence <220> <223> completely synthesized 2 - <400> 9 tctcctcgag gccaccatgg ggagtagcaa gagcaagcct aaggacccca gccagcgccg 60 gatgacagaa tacaagcttg tggtgg 86 <210> 10 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> completely synthesized <400> 10 cacatctaga tcaggacagc acagacttgc age 33 <210> 11 <211> 41 <212> DNA <213> Artificial Sequence <220> <223> completely synthesized <400> 11 tctcctcgag gccaccatga cagaatacaa gcttgtggtg g 41 <210> 12 <211> 38 <212> DNA <213> Artificial Sequence <220> <223> completely synthesized <400> 12 cactctagac tggtgtcaga gcagcacaca cttgcagc 38 <210> 13 <211> 38 <212> DNA <213> Artificial Sequence <220> <223> completely synthesized <400> 13 gagagaattc gccaccatga cggaatataa gctggtgg 38 <210> 14 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> completely synthesized 3 - <400> 14 gagagtcgac gcgtcaggag agcaeacact tgc 33 <210> 15 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> completely synthesized <400> 15 ccgccggcct ggaggagtac ag 22 <210> 16 <211> 38 <212> DNA <213> Artificial Sequence <220> <223> completely synthesized <400> 16 gagagaattc gccaccatga ctgagtacaa actggtgg 38 <210> 17 <211> 32 <212> DNA <213> Artificial Sequence <220> <223> completely synthesized <400> 17 gagagtcgac ttgttacatc accacacatg gc 32 <210> 18 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> completely synthesized <400> 18 gttggagcag ttggtgttgg g 21 <210> 19 <211> 38 <212> DNA <213> Artificial Sequence <220> <223> completely synthesized <400> 19 gagaggtacc gccaccatga ctgaatataa acttgtgg 38 <210> 20 <211> 36 <212> DNA <213> Artificial Sequence <220> <223> completely synthesized <400> 20 ctctgtcgac gtatttacat aattacacac tttgtc 36 <210> 21 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> completely synthesized <400> 21 gtagttggag ctgttggcgt aggc 24 5 -

Inventors: EMBREY MARK W, HOFFMAN JACOB M, PERLOW DEBRA S, WAI JOHN S, EMBREY, MARK, W., HOFFMAN, JACOB, M., PERLOW, DEBRA, S., WAI, JOHN, S.
Applicants: EMBREY MARK W, HOFFMAN JACOB M, MERCK & CO INC, PERLOW DEBRA S, WAI JOHN S, EMBREY, MARK, W., HOFFMAN, JACOB, M., MERCK & CO., INC., PERLOW, DEBRA, S., WAI, JOHN, S.
Application year: 1999
Main classification: A61K31
IPC codes: C07D401, C07D471, C07D498, C07D513