JP2000500502A - Farnesyl-protein transferase inhibitor - Google Patents

Abstract

  (57) [Summary] The present invention provides compounds that inhibit farnesyl-protein transferase (FTase) and suppress farnesylation of the oncogene protein Ras. The present invention further provides a chemotherapeutic composition containing the compound of the present invention, and a method for inhibiting farnesyl-protein transferase and suppressing farnesylation of the oncogene protein Ras.

Description

DETAILED DESCRIPTION OF THE INVENTIONTitle of invention Farnesyl-protein transferase inhibitorsBackground of the Invention   The protein Ras is a cell surface growth factor receptor and a nuclear signal that initiates cell proliferation. It forms part of the signal path connecting the null. Of biological and biochemical studies of the action of Ras As shown, Ras functions like a G-regulatory protein. In the inactive state Indicates that Ras is bound to GDP. Upon activation of the growth factor receptor, Ras is G DP is exchanged for GTP and the conformation is changed. R As a GTP-bound form of as, the growth stimulatory signal causes the protein Ras to Until terminated by Ras endogenous GTPase activity returning to DP-bound form (D.R. Lowy and D.M. Willumsen) , Ann. Rev .. Biochem. 62, pp. 851-891, 1 993). Many humans, including colorectal cancer, exocrine pancreatic cancer, and myeloid leukemia In cancer, a mutated ras gene is found. The gene Protein products lack their GTPase activity and constitutively transmit growth stimulus signals I do.   Ras is localized to the plasma membrane in both normal and oncogene function Should be. At least three post-translational modifications are involved in the membrane localization of Ras, All modifications occur at the C-terminus of Ras. The C-terminus of Ras is "CAA X ”or“ Cys-Aaaa ”¹-Aaaa^Two-Xaa "box (Cys is a system Aaa is an aliphatic amino acid, and Xaa is any amino acid). Have a chief (Willumsen et al., Nature 310, pp. 58) 3-586, 1984). This motif depends on the specific sequence, farnesyl -A protein transferase enzyme or geranylgeranyl-protein tiger Function as a signal sequence for the phosphatase enzyme, wherein the two enzymes are CAAX C of cysteine residue of motif₁₅And C₂₀Alkylation with isoprenoids Respectively catalyze (S. Clarke, Ann. Rev. Biochem.   61 pp. 355-386, 1992; R. Schafer and And J. Line, Ann. Rev .. Genetics 30, pp. 209-237, 1 992). Protein Ras is known to undergo post-translational farnesylation Is one of several proteins that exist. Other Tampas Farnesylated Proteins include Ras-related GTP-binding proteins such as Rho, fungal mating factors, and nuclei. Lamin and the gamma subunit of transducin are included. James and others J. Biol. Chem. 269, p. 14182, 1994 To identify peroxisome-related protein Pxf, which is also farnesylated did. James et al. Also have files with unknown structures and functions other than those listed above. This suggests the presence of a farnesylated protein.   Inhibiting farnesyl-protein transferase causes Ras Can prevent the transformed cells from growing on soft agar and Modifying other aspects of the transformed phenotype of the cells It turns out that you can. Also, certain farnesyl-protein transfections Erase inhibitors selectively block the processing of the oncoprotein Ras in cells (NE Kohl et al., Science 26). 0, pp. 1934-1937, 1993; L. James Etc., S science 260, pp. 1937-1942, 1993). Recently, Inhibitors of farnesyl-protein transferase are ras-dependent in nude mice. Blocking the growth of resident tumors (NE Kohl et al., Proc. Na tl. Acad. Sci. USA 91 pp. 9141-9145,   1994), and breast cancer and salivary glands of ras transgenic mice (sal ivary) Inducing regression of cancer (NE Kohl et al., Natur e Medicine 1, pp. 792-797, 1995) .   Indirect inhibition of farnesyl-protein transferase in vivo The harm was lovastatin (Merck & Co., Rahway, NJ) and Compactin (Hancock et al., Cell 57, pp. 1167-117). 7, 1989; Casey et al., Proc. Natl. Acad. S ci. USA 86, p. 8323, 1989; Schaffer et al., S. science 245, p. 379, 1989). The above drugs are used to produce polyisoprenoids including farnesyl pyrophosphate Inhibits HMG-CoA reductase, which is the rate-limiting enzyme. Farnesyl-tan The protein transferase uses farnesyl pyrophosphate to produce Ras CAA. The Cys thiol group of the X box is modified by covalent bonding to a farnesyl group (R eiss, et al., Cell 62, pp. 100-200. 81-88, 1990; Schab er et al. Biol. Chem. 265 pp. 1470-147 04, 1990; Schaffer et al., Science 249, pp. 1133-1139, 1990; Manne et al., Proc. Natl.   Acad. Sci. USA 87 pp. 7541-7545, 19 90). The inhibition of farnesyl pyrophosphate by inhibition of HMG-CoA reductase Suppressing biosynthesis can block Ras membrane localization in cultured cells. But, Direct inhibition of farnesyl-protein transferase is a normal isoprene production It can be more specific and requires less Only with no side effects.   Farnesyl-protein transferase (FP) published in various literatures Inhibitors of Tase) fall into roughly two classes. First class blockage Pests are analogs of farnesyl diphosphate (FPP), while a second class of inhibitors. The harmful agent is yeast Associated with a native protein substrate (eg, Ras). Pep published in the literature Inhibitors derived from tide are usually CAAX moti which are signals of protein prenylation. Is a cysteine-bearing molecule that is associated with   Reiss et al., The same journal; Reiss et al., PNAS 88, pp. 732 -736, 1991). Such inhibitors suppress protein prenylation. An alternative substrate for farnesyl-protein transferase enzyme Can function as a purely competitive inhibitor (Universi No. 5,141,851 to Ty of Texas; E. FIG. Ko hl, et al., Science 260, pp. 1934-1937, 1993 Graham et al., J .; Med. Chem. 37, p. 725 1994). Usually, when a CAAX derivative lacks a thiol, The power has been found to drop dramatically. However, thiol groups have pharmacokinetic and And therapeutic potential of FPTase inhibitors in terms of pharmacodynamics and toxicity Restrict. Therefore, it is desirable to substitute the function of the thiol with something.   Recently, farnesyl-protein transferase inhibitors Is a substance that inhibits the proliferation of vascular smooth muscle cells, and is therefore arteriosclerotic and diabetic. It has been found to be useful for the prevention and treatment of vascular disorders (JP-A-7-112) No. 930). Also, certain tricyclic compounds optionally having a piperidine moiety are FP It has also recently been disclosed that it is an inhibitor of Tase (WO 95/10). No. 514, No. 95/10515 and No. 95/10516).   Therefore, the present invention provides a novel peptide-like (peptido) having no thiol moiety. minesic) compounds, which are farnesyl-protein transferers Develop compounds that inhibit lysine, that is, suppress post-translational farnesylation of proteins The porpose is to do. The invention further provides a chemotherapeutic composition comprising a compound of the invention. Another object of the present invention is to develop a product and a method for producing the compound of the present invention.Summary of the Invention   The present invention relates to peptides that inhibit farnesyl-protein transferase Piperidine, 1,4-dihydropyridine and 1,2,3,4-tetrahydropi Lysine compounds. These compounds are farnesyl-protein trans Feller A farnesyl-protein transferase Heterocyclic compounds published in the literature as inhibitors and the position of substituents on the nitrogen-bearing ring In terms of location. The present invention relates to the farnesyltransferase inhibition of the present invention. Also included are chemotherapeutic compositions containing agents and methods for producing the inhibitors.   The compounds of the present invention have the formula A Is represented byDetailed description of the invention   The compounds of the present invention inhibit farnesyl-protein transferase, It is useful for suppressing farnesylation of the oncogene protein Ras. Departure In the first embodiment, Akira is of the formula A (In the formula R^1a, R^1bAnd R^1cIs a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C_Three~ C_TenShiku Lower alkyl, C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, R⁸O-, R⁹S (O)_m -, R⁸C (O) NR⁸-, CN, NO_Two, (R⁸)_TwoNC (NR⁸)-, R⁸C ( O)-, R⁸OC (O)-, N_Three, -N (R⁸)_TwoOr R⁹OC (O) NR⁸−, c) unsubstituted or unsubstituted or substituted aryl, heterocyclic, C_Three~ C_TenCycloalkyl, C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, R⁸O-, R⁹ S (O)_m-, R⁸C (O) NR⁸−, CN, (R⁸)_TwoNC (NR⁸)-, R⁸C (O)-, R⁸OC (O)-, N_Three, -N (R⁸)_Two Or R⁹OC (O) -NR⁸C substituted with-₁~ C⁶Alkyl Independently selected from among R^TwoIs H, unsubstituted or substituted C₁~ C₈Alkyl, unsubstituted or substituted C_Two~ C₈Al Phenyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, And -S (O)_TwoR⁶Selected from     The substituted group may have one or more     1) not substituted or         a) C₁~ C_FourAlkyl,         b) (CH_Two)_pOR⁶,         c) (CH_Two)_pNR⁶R⁷,         d) halogen, and         e) C₁~ C_FourPerfluoroalkyl         Aryl substituted with one or two groups selected from Heterocycle,     2) C_Three~ C₆Cycloalkyl,     3) OR⁶,     4) SR⁶, S (O) R⁶, SO_TwoR⁶,    15) C₁~ C₈Alkyl, or     16) C₁~ C₈Perfluoroalkyl     Has been replaced by R^ThreeIs H, Selected from R^FourIs a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C_Three~ C_TenShiku Lower alkyl, C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, perfluoroalkyl , F, Cl, Br, R⁸O-, R⁹S (O)_m-, R⁸C (O) NR⁸-, CN, N O_Two, (R⁸)_TwoNC (NR⁸)-, R⁸C (O)-, R⁸OC (O)-, N_Three, − N (R⁸)_TwoOr R⁹OC (O) NR⁸−, And c) unsubstituted or aryl, heterocyclic, C_Three~ C_TenCycloalkyl , C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, perfluoroalkyl, F, Cl , Br, R⁸O -, R⁹S (O)_m-, R⁸C (O) NH-, CN, H_TwoN—C (NH) —, R⁸C (O)-, R⁸OC (O)-, N_Three, -N (R⁸)_TwoOr R⁸OC (O) NH- C substituted with₁~ C₆Alkyl Independently selected from among R^FiveIs a) hydrogen, b) C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, C_Three~ C₆Cycloalkyl, per Fluoroalkyl, F, Cl, Br, R⁸O-, R⁹S (O)_m-, R⁸C (O) N R⁸-, CN, NO_Two, (R⁸)_TwoNC (NR⁸)-, R⁸C (O)-, R⁸OC ( O)-, N_Three, -N (R⁸)_TwoOr R⁹OC (O) NR⁸−, And c) unsubstituted or perfluoroalkyl, F, Cl, Br, R⁸ O-, R⁹S (O)_m-, R⁸C (O) NR⁸−, CN, (R⁸)_TwoNC (NR⁸) -, R⁸C (O)-, R⁸OC (O)-, N_Three, -N (R⁸)_TwoOr R⁹OC (O ) NR⁸C substituted with-₁~ C₆Alkyl Independently selected from among R⁶, R⁷And R^7aIs H and unsubstituted or         a) C₁~ C_FourAlkoxy,         b) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,         c) halogen,         d) HO,         h) N (R⁸)_Two Substituted with one or two substituents selected from₁~ C_FourAlkyl, C_Three ~ C₆Cycloalkyl, heterocycle, aryl and C₁~ C_FourPerfluoroalkyl Independently selected from inside, or R⁶And R⁷Can form a ring together with R⁷And R^7aCan form a ring together with R⁸Is hydrogen, C₁~ C₆Alkyl, benzyl, 2,2,2-tri Independently selected from fluoroethyl and aryl; R⁹Is C₁~ C₆Independently selected from alkyl and aryl; R^TenIs H, R⁸C (O)-, R⁹S (O)_m-, Unsubstituted or substituted C₁~ C_FourArchi , Unsubstituted or substituted C_Three~ C₆Cycloalkyl, unsubstituted or substituted heterocycle, unsubstituted Substituted or substituted aryl, substituted aroyl, unsubstituted or substituted heteroaroyl, substituted Selected from arylsulfonyl and unsubstituted or substituted heteroarylsulfonyl Where the substituted group is         a) C₁~ C_FourAlkoxy,         b) aryl or heterocycle,         c) halogen,         d) HO,        h) N (R⁸)_Two,as well as         i) C_Three~ C₆Cycloalkyl A is substituted with one or two substituents selected from¹And A^TwoIs In the case, -CH = CH-, -C≡C-, -C (O)-, -C (O) NR⁸-, -NR⁸ C (O)-, O, -N (R⁸)-, -S (O)_TwoN (R⁸)-, -N (R⁸) S (O )_Two-And S (O)_mIndependently selected from among V is a) hydrogen, b) heterocycle, c) aryl, d) 0-4 carbon atoms are replaced by heteroatoms selected from O, S and N C₁~ C₂₀Alkyl, and e) C_Two~ C₂₀Alkenyl , But A¹Is S (O)_mAnd A¹Is a bond, n is 0 and A^TwoIs S (O)_mIs V is not hydrogen, W is a heterocyclic ring, X is a bond, -C (= O) NR^Ten-, -NR^TenC (= O)-, -S (O)_m−, − NR^Ten-, O or -C (= O)-, m is 0, 1 or 2; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; r is 0 to 5, provided that when V is hydrogen, r is 0; s is 1 or 2, t is 0 or 1, The dashed line indicates an optional double bond]. Syl-protein transferase inhibitor or optical isomer or pharmaceutical thereof To provide an acceptable salt.   A preferred specific example of the compound of the present invention has the following formula: (In the formula R^1aAnd R^1cIs hydrogen, C_Three~ C_TenCycloalkyl, R⁸O-, -N (R⁸)_Two, F and And C₁~ C₆Independently selected from alkyl, R^1bIs a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C_Three~ C₆Cyclo Alkyl, R⁸O-, -N (R⁸)_TwoOr C_Two~ C₆Alkenyl, c) unsubstituted or unsubstituted or substituted aryl, heterocyclic, C_Three~ C₆Cycloalkyl, C_Two~ C₆Alkenyl, R⁸O- or -N (R⁸)_TwoReplace with Done C₁~ C₆Alkyl Independently selected from among R^TwoIs a) unsubstituted or one or more     1) not substituted or         i) C₁~ C_FourAlkyl,         ii) (CH_Two)_pOR⁶,         iii) (CH_Two)_pNR⁶R⁷,         iv) halogen,         v) C₁~ C_FourPerfluoroalkyl         An aryl or heterocyclic ring substituted with     2) OR⁶,     3) SR⁶, SO_TwoR⁶Or     C substituted with₁~ C₈Alkyl, b) c) unsubstituted or one or more     1) C₁~ C₈Alkyl,     2) C₁~ C₈Perfluoroalkyl,     3) OR⁶,     4) SR⁶, SO_TwoR⁶Or     Aryl substituted with d) -SO_TwoR⁶,as well as e)Selected from R^ThreeIs H, Selected from R^FourIs a) hydrogen, b) C₁~ C₆Alkyl, C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, C₁~ C₆Pe Fluoroalkyl, F, Cl, R⁸O-, R⁸C (O) NR⁸-, CN, NO_Two, (R⁸)_TwoNC (NR⁸)-, R⁸C (O)-, R⁸OC (O)-, N (R⁸)_TwoMa Or R⁹OC (O) NR⁸−, And c) C₁~ C₆Perfluoroalkyl, R⁸O-, R⁸C (O) NR⁸−, (R⁸)_Two NC (NR⁸)-, R⁸C (O)-, R⁸OC (O)-, -N (R⁸)_TwoOr R⁹ OC (O) NR⁸C substituted with-₁~ C₆Alkyl Independently selected from among R^FiveIs a) hydrogen, b) C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, C_Three~ C₆Cycloalkyl, C₁ ~ C₆Perfluoroalkyl, F, Cl, R⁸O-, R⁹S (O)_m-, R⁸C (O ) NR⁸-, CN, NO_Two, (R⁸)_TwoNC (NR⁸)-, R⁸C (O)-, R⁸O C (O)-, -N (R⁸)_TwoOr R⁹OC (O) NR⁸−, And c) unsubstituted or C₁~ C₆Perfluoroalkyl, F, Cl, R⁸ O-, R⁹S (O)_m-, R⁸C (O) NR⁸−, CN, (R⁸)_TwoNC (NR⁸) -, R⁸C (O)-, R⁸OC (O)-, -N (R⁸)_TwoOr R⁹OC (O) N R⁸C substituted with-₁~ C₆Alkyl Selected from R⁶, R⁷And R^7aIs H and unsubstituted or         a) C₁~ C_FourAlkoxy,         b) halogen, or         c) substituted or unsubstituted aryl or substituted or Unsubstituted heterocycle C substituted with₁~ C_FourAlkyl, C_Three~ C₆Cycloalkyl, aryl and heterocycle Independently selected from among R⁸Is hydrogen, C₁~ C₆Alkyl, benzyl, 2,2,2-trifluoroethyl and And aryl are independently selected from R⁹Is C₁~ C₆Independently selected from alkyl and aryl; R^TenIs H, R⁸C (O)-, R⁹S (O)_m-, Unsubstituted or substituted C₁~ C_FourArchi , Unsubstituted or substituted C_Three~ C₆Cycloalkyl, unsubstituted or substituted heterocycle, unsubstituted Substituted or substituted aryl, substituted aroyl, unsubstituted or substituted heteroaroyl, substituted Selected from arylsulfonyl and unsubstituted or substituted heteroarylsulfonyl Where the substituted group is         a) C₁~ C_FourAlkoxy,         b) aryl or heterocycle,         c) halogen,         d) HO,         h) N (R⁸)_Two,as well as         i) C_Three~ C₆Cycloalkyl A is substituted with one or two substituents selected from¹And A^TwoIs In the case, -CH = CH-, -C≡C-, -C (O)-, -C (O) NR⁸-, O,- N (R⁸)-And S (O)_mIndependently selected from among V is a) pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- Of oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl and thienyl A heterocyclic ring selected from among, and b) aryl Selected from W is pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, Pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl and isoquinolinyl A heterocyclic ring selected from nil, X is a bond, -C (= O) NR^Ten-, -NR^TenC (= O)-, -S (O)_m-Again Is -NR^Ten- m is 0, 1 or 2; n is 0, 1, 2, 3, or 4; p is 1, 2 or 3; q is 0 or 1, r is 0 to 5, provided that when V is hydrogen, r is 0; s is 1 or 2, t is 1] or an optical isomer or pharmaceutical thereof It is an acceptable salt.   Another preferred embodiment of the compounds of the present invention is represented by formula B(In the formula R^1aAnd R^1cIs hydrogen, C_Three~ C_TenCycloalkyl, R⁸O-, -N (R⁸)_Two, F and And C₁~ C₆Independently selected from alkyl, R^1bIs a) hydrogen, b) aryl, heterocycle, C_Three~ C_TenCycloalkyl, R⁸O-, -N (R⁸)_Two, F Or C_Two~ C₆Alkenyl, c) unsubstituted or unsubstituted or substituted aryl, heterocyclic, C_Three~ C_TenCycloalkyl, C_Two~ C₆Alkenyl, R⁸O- and -N (R⁸)_TwoFrom within C substituted with a selected substituent₁~ C₆Alkyl Independently selected from among R^TwoIs H, unsubstituted or substituted C₁~ C₈Alkyl, unsubstituted or substituted C_Two~ C₈Al Phenyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, And -S (O)_TwoR⁶Selected from     The substituted group may have one or more     1) not substituted or         a) C₁~ C_FourAlkyl,         b) (CH_Two)_pOR⁶,         c) (CH_Two)_pNR⁶R⁷,         d) halogen, and         e) C₁~ C_FourPerfluoroalkyl         Aryl substituted with one or two groups selected from Heterocycle,     2) C_Three~ C₆Cycloalkyl,     3) OR⁶,     4) SR⁶, S (O) R⁶, SO_TwoR⁶,     15) C₁~ C₈Alkyl, or     16) C₁~ C₈Perfluoroalkyl     Has been replaced by R^ThreeIs H, Selected from R^FourIs a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C₁~ C₆Alkyl, C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, C₁~ C₆Perfluoroalkyl, F, C l, R⁸O-, R⁸C (O) NR⁸-, CN, NO_Two, (R⁸)_TwoNC (NR⁸)- , R⁸C (O)-, -N (R⁸)_TwoOr R⁹OC (O) NR₈−, And c) C₁~ C₆Perfluoroalkyl, R⁸O-, R⁸C (O) NR⁸−, (R⁸)_Two NC (NR⁸)-, R⁸C (O)-, -N (R⁸)_TwoOr R⁹OC (O) NR⁸− C substituted with₁~ C₆Alkyl Independently selected from among R^5aAnd R^5bIs independently hydrogen, C₁~ C₆Alkyl, cyclopro Pill, trifluoromethyl or halogen; R⁶, R⁷And R^7aIs H and unsubstituted or         a) C₁~ C_FourAlkoxy,         b) halogen, or         c) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle C substituted with₁~ C_FourAlkyl, C_Three~ C₆Cycloalkyl, aryl and heterocycle Independently selected from among R⁸Is hydrogen, C₁~ C₆Alkyl, 2,2,2-trifluoroethyl, benzyl and And aryl are independently selected from R⁹Is C₁~ C₆Independently selected from alkyl and aryl; R^TenIs H, R⁸C (O)-, R⁹S (O)_m-, Unsubstituted or substituted C₁~ C_FourArchi , Unsubstituted or substituted C_Three~ C₆Cycloalkyl, unsubstituted or substituted heterocycle, unsubstituted Substituted or substituted aryl, substituted aroyl, unsubstituted or substituted heteroaroyl, substituted Selected from arylsulfonyl and unsubstituted or substituted heteroarylsulfonyl Where the substituted group is         a) C₁~ C_FourAlkoxy,         b) aryl or heterocycle,         c) halogen,         d) HO,        h) N (R⁸)_Two,as well as         i) C_Three~ C₆Cycloalkyl A is substituted with one or two substituents selected from¹And A^TwoIs In the case, -CH = CH-, -C≡C-, -C (O)-, -C (O) NR⁸-, O,- N (R⁸)-And S (O)_mIndependently selected from among V is a) hydrogen, b) pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, Pyridonyl, 2-oxopiperidinyl, oxazolyl, indolyl, quinolinyl A heterocyclic ring selected from the group consisting of: isoquinolinyl, triazolyl and thienyl; c) aryl, d) 0-4 carbon atoms are replaced by heteroatoms selected from O, S and N C₁~ C₂₀Alkyl, and e) C_Two~ C₂₀Alkenyl , But A¹Is S (O)_mAnd A¹Is a bond, n is 0 and A^TwoIs S (O)_mIs V is not hydrogen, X is a bond, -C (= O) NR^Ten-, -NR^TenC (= O)-, -S (O)_m-Again Is -NR^Ten- m is 0, 1 or 2; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; q is 0 or 1, r is from 0 to 5, provided that when V is hydrogen, r is 0. Or an optical isomer or a pharmaceutically acceptable salt thereof.   Another preferred embodiment of the compounds of the present invention is a compound of formula C (In the formula R^1aAnd R^1cIs hydrogen, C_Three~ C_TenCycloalkyl, R⁸O-, -N (R⁸)_Two, F and And C₁~ C₆Independently selected from alkyl, R^1bIs a) hydrogen, b) aryl, heterocycle, C_Three~ C_TenCycloalkyl, R⁸O-, -N (R⁸)_Two, F Or C_Two~ C₆Alkenyl, c) unsubstituted or unsubstituted or substituted aryl, heterocyclic, C_Three~ C_TenCycloalkyl, C_Two~ C₆Alkenyl, R⁸O- and -N (R⁸)_TwoFrom within C substituted with a selected substituent₁~ C₆Alkyl Independently selected from among R^TwoIs H, unsubstituted or substituted C₁~ C₈Alkyl, unsubstituted or Substitution C_Two~ C₈Alkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle , And -S (O)_TwoR⁶Selected from     The substituted group may have one or more     1) not substituted or         a) C₁~ C_FourAlkyl,         b) (CH_Two)_pOR⁶,         c) (CH_Two)_pNR⁶R⁷,         d) halogen, and         e) C₁~ C_FourPerfluoroalkyl         Aryl substituted with one or two groups selected from Heterocycle,     2) C_Three~ C₆Cycloalkyl,     3) OR⁶,     4) SR⁶, S (O) R⁶, SO_TwoR⁶,    15) C₁~ C₈Alkyl, or     16) C₁~ C₈Perfluoroalkyl     Has been replaced by R^ThreeIs H,Selected from R^FourIs a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C₁~ C₆Alkyl, C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, C₁~ C₆Perfluoroalkyl, F, C l, R⁸O-, R⁸C (O) NR⁸-, CN, NO_Two, (R⁸)_TwoNC (NR⁸)- , R⁸C (O)-, -N (R⁸)_TwoOr R⁹OC (O) NR⁸−, And c) C₁~ C₆Perfluoroalkyl, R⁸O-, R⁸C (O) NR⁸−, (R⁸)_Two NC (NR⁸)-, R⁸C (O)-, -N (R⁸)_TwoOr R⁹OC (O) NR⁸− C substituted with₁~ C₆Alkyl Independently selected from among R^5aAnd R^5bIs independently hydrogen, C₁~ C₆Alkyl, cyclopro Pill, trifluoromethyl or halogen; R⁶, R⁷And R^7aIs H and unsubstituted or         a) C₁~ C_FourAlkoxy,         b) halogen, or         c) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle C substituted with₁~ C_FourAlkyl, C_Three~ C₆Cycloalkyl, aryl and heterocycle Independently selected from among R⁸Is hydrogen, C₁~ C₆Alkyl, 2,2,2-trifluoroethyl, benzyl and And aryl are independently selected from R⁹Is C₁~ C₆Independently selected from alkyl and aryl; R^TenIs H, R⁸C (O)-, R⁹S (O)_m-, Unsubstituted or substituted C₁~ C_FourArchi , Unsubstituted or substituted C_Three~ C₆Cycloalkyl, unsubstituted or substituted heterocycle, unsubstituted Substituted or substituted aryl, substituted aroyl, unsubstituted or substituted heteroaroyl, substituted Selected from arylsulfonyl and unsubstituted or substituted heteroarylsulfonyl Where the substituted group is         a) C₁~ C_FourAlkoxy,         b) aryl or heterocycle,         c) halogen,         d) HO,         h) N (R⁸)_Two,as well as         i) C_Three~ C₆Cycloalkyl A is substituted with one or two substituents selected from¹And A^TwoIs In the case, -CH = CH-, -C≡C-, -C (O)-, -C (O) NR⁸-, O,- N (R⁸)-And S (O)_mIndependently selected from among V is a) hydrogen, b) pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, Pyridonyl, 2-oxopiperidinyl, oxazolyl, indolyl, quinolinyl A heterocyclic ring selected from the group consisting of: isoquinolinyl, triazolyl and thienyl; c) aryl, d) 0-4 carbon atoms are replaced by heteroatoms selected from O, S and N C₁~ C₂₀Alkyl, and e) C_Two~ C₂₀Alkenyl , But A¹Is S (O)_mAnd A¹Is a bond, n is 0 and A^TwoIs S (O)_mIs V is not hydrogen, X is a bond, -C (= O) NR^Ten-, -NR^TenC (= O)-, -S (O)_m-Again Is -NR^Ten- m is 0, 1 or 2; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4, wherein X is a bond, -NR⁸-Or 0 p is not 0, q is 0 or 1, r is from 0 to 5, provided that when V is hydrogen, r is 0. Or an optical isomer or a pharmaceutically acceptable salt thereof.   The present invention provides in a further preferred embodiment thereof a compound of formula D (In the formula R^1aAnd R^1cIs hydrogen, C_Three~ C_TenCycloalkyl and C₁~ C₆From the alkyl Independently selected, R^1bIs a) hydrogen, b) aryl, heterocycle, C_Three~ C_TenCycloalkyl, R⁸O-, -N (R⁸)_Two, F Or C_Two~ C₆Alkenyl, c) unsubstituted or aryl, heterocyclic, C_Three~ C_TenCycloalkyl , C_Two~ C₆Alkenyl, R⁸O- or -N (R⁸)_TwoC substituted with₁~ C₆A Lequil Independently selected from among R^TwoIs H, unsubstituted or substituted C₁~ C₈Alkyl, unsubstituted or substituted aryl, And -S (O)_TwoR⁶Selected from     The substituted group may have one or more     1) not substituted or         a) C₁~ C_FourAlkyl,         b) (CH_Two)_pOR⁶,         c) (CH_Two)_pNR⁶R⁷,         d) halogen, and         e) C₁~ C_FourPerfluoroalkyl         Aryl substituted with one or two groups selected from Heterocycle,     2) C_Three~ C₆Cycloalkyl,     3) OR⁶,     4) SR⁶, S (O) R⁶, SO_TwoR⁶,    15) C₁~ C₈Alkyl, or     16) C₁~ C₈Perfluoroalkyl     Has been replaced by R^ThreeIs H, Selected from R^FourIs a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C₁~ C₆Alkyl, C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, C₁~ C₆Perfluoroalkyl, F, C l, R⁸O-, R⁸C (O) NR⁸-, CN, NO_Two, (R⁸)_TwoNC (NR⁸)- , R⁸C (O)-, -N (R⁸)_TwoOr R⁹OC (O) NR⁸−, And c) C₁~ C₆Perfluoroalkyl, R⁸O-, R⁸C (O) NR⁸−, (R⁸)_Two NC (NR⁸)-, R⁸C (O)-, -N (R⁸)_TwoOr R⁹OC (O) NR⁸− C substituted with₁~ C₆Alkyl Independently selected from among R^5aAnd R^5bIs independently hydrogen, ethyl, cyclopropyl or Methyl, R⁶, R⁷And R^7aIs H and unsubstituted or         a) C₁~ C_FourAlkoxy,         b) halogen, or         c) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle C substituted with₁~ C_FourAlkyl, C_Three~ C₆Cycloalkyl, aryl and heterocycle Independently selected from among R⁸Is hydrogen, C₁~ C₆Alkyl, 2,2,2-trifluoroethyl, benzyl and And aryl are independently selected from R⁹Is C₁~ C₆Independently selected from alkyl and aryl; R^TenIs H, R⁸C (O)-, R⁹S (O)_m-And unsubstituted or substituted C₁~ C_FourAl Selected from kills, where the substituted alkyl group is         a) C₁~ C_FourAlkoxy,         b) aryl or heterocycle,         c) halogen,         d) HO,        h) N (R⁸)_Two,as well as         i) C_Three~ C₆Cycloalkyl A is substituted with one or two substituents selected from¹Is a bond,- C (O)-, O, -N (R⁸)-And S (O)_mSelected from X is a bond, -C (= O) NR^Ten-, -NR^TenC (= O)-, -S (O)_m-Again Is -NR^Ten- n is 0 or 1, provided that A¹Is a bond, O, -N (R⁸)-Or S (O)_m N is not 0, m is 0, 1 or 2; p is 0, 1, 2, 3, or 4; q is 0 or 1]. Provide a ferase inhibitor or an optical isomer or a pharmaceutically acceptable salt thereof .   In another more preferred embodiment, the present invention provides compounds of formula E (In the formula R^1aAnd R^1cIs hydrogen, R⁸O-, -N (R⁸)_Two, F, C_Three~ C_TenCycloalkyl and And C₁~ C₆Independently selected from alkyl, R^1bIs a) hydrogen, b) aryl, heterocycle, C_Three~ C_TenCycloalkyl, R⁸O-, -N (R⁸)_Two, F Or C_Two~ C₆Alkenyl, c) unsubstituted or aryl, heterocyclic, C_Three~ C_TenCycloalkyl , C_Two~ C₆Alkenyl, R⁸O- or -N (R⁸)_TwoC substituted with₁~ C₆A Lequil Independently selected from among R^TwoIs H, unsubstituted or substituted C₁~ C₈Alkyl, unsubstituted or substituted aryl, And -S (O)_TwoR⁶Selected from     The substituted group may have one or more     1) not substituted or         a) C₁~ C_FourAlkyl,         b) (CH_Two)_pOR⁶,         c) (CH_Two)_pNR⁶R⁷,         d) halogen, and         e) C₁~ C_FourPerfluoroalkyl         Aryl substituted with one or two groups selected from Heterocycle,     2) C_Three~ C₆Cycloalkyl,     3) OR⁶,     4) SR⁶, S (O) R⁶, SO_TwoR⁶,    15) C₁~ C₈Alkyl, or     16) C₁~ C₈Perfluoroalkyl     Has been replaced by R^ThreeIs H, Selected from R^FourIs a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C₁~ C₆Alkyl, C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, C₁~ C₆Perfluoroalkyl, F, C l, R⁸O-, R⁸C (O) NR⁸-, CN, NO_Two, (R⁸)_TwoNC (NR⁸)- , R⁸C (O)-, -N (R⁸)_TwoOr R⁹OC (O) NR⁸−, And c) C₁~ C₆Perfluoroalkyl, R⁸O-, R⁸C (O) NR⁸−, (R⁸)_Two NC (NR⁸)-, R⁸C (O)-, -N (R⁸)_TwoOr R⁹OC (O) NR⁸− C substituted with₁~ C₆Alkyl Independently selected from among R^5aAnd R^5bIs independently hydrogen, ethyl, cyclopropyl or Methyl, R⁶, R⁷And R^7aIs H and unsubstituted or         a) C₁~ C_FourAlkoxy,         b) halogen, or         c) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle C substituted with₁~ C_FourAlkyl, C_Three~ C₆Cycloalkyl, aryl and heterocycle Independently selected from among R⁸Is hydrogen, C₁~ C₆Alkyl, 2,2,2-trifluoroethyl, benzyl and And aryl are independently selected from R⁹Is C₁~ C₆Independently selected from alkyl and aryl; R^TenIs H, R⁸C (O)-, R⁹S (O)_m-And unsubstituted or substituted C₁~ C_FourAl Selected from kills, where the substituted alkyl group is         a) C₁~ C_FourAlkoxy,         b) aryl or heterocycle,         c) halogen,         d) HO,        h) N (R⁸)_Two,as well as         i) C_Three~ C₆Cycloalkyl Is substituted with one or two substituents selected from X is a bond, -C (= O) NR^Ten-, -NR^TenC (= O)-, -S (O)_m-Again Is -NR^Ten- n is 0 or 1, m is 0, 1 or 2; p is 0, 1, 2, 3, or 4, wherein X is a bond, -NR⁸-Or O p is not 0, q is 0 or 1]. Provide a ferase inhibitor or an optical isomer or a pharmaceutically acceptable salt thereof .   In yet another embodiment, the present invention provides a compound of formula F (In the formula R^1aAnd R^1cIs hydrogen, C_Three~ C_TenCycloalkyl and C₁~ C₆From the alkyl Independently selected, R^1bIs a) hydrogen, b) aryl, heterocycle, C_Three~ C_TenCycloalkyl, R⁸O-, -N (R⁸)_TwoAlso Is F, c) unsubstituted or aryl, heterocyclic, C_Three~ C_TenCycloalkyl , R⁸O- or -N (R⁸)_TwoC substituted with₁~ C₆Alkyl Independently selected from among R^TwoIs H, unsubstituted or substituted C₁~ C₈Alkyl, unsubstituted or substituted aryl, And -S (O)_TwoR⁶Selected from     The substituted group may have one or more     1) not substituted or         a) C₁~ C_FourAlkyl,         b) (CH_Two)_pOR⁶,         c) (CH_Two)_pNR⁶R⁷,         d) halogen, and         e) C₁~ C_FourPerfluoroalkyl         Aryl substituted with one or two groups selected from Heterocycle,     2) C_Three~ C₆Cycloalkyl,     3) OR⁶,     4) SR⁶, S (O) R⁶, SO_TwoR⁶,    15) C₁~ C₈Alkyl, or     16) C₁~ C₈Perfluoroalkyl     Has been replaced by R^ThreeIs H, Selected from R^5aAnd R^5bIs independently hydrogen, ethyl, cyclopropyl or methyl; R⁶, R⁷And R^7aIs H and unsubstituted or         a) C₁~ C_FourAlkoxy,         b) halogen, or         c) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle C substituted with₁~ C_FourAlkyl, C_Three~ C₆Cycloalkyl, aryl and heterocycle Independently selected from among R⁸Is hydrogen, C₁~ C₆Alkyl, 2,2,2-trifluoroethyl, benzyl and And aryl are independently selected from R⁹Is C₁~ C₆Independently selected from alkyl and aryl; R^TenIs H, R⁸C (O)-, R⁹S (O)_m-And unsubstituted or substituted C₁~ C_FourAl Selected from the kills and replaced Alkyl group         a) C₁~ C_FourAlkoxy,         b) aryl or heterocycle,         c) halogen,         d) HO,         h) N (R⁸)_Two,as well as         i) C_Three~ C₆Cycloalkyl Is substituted with one or two substituents selected from X is a bond, -C (= O) NR^Ten-, -NR^TenC (= O)-, -S (O)_m-Again Is -NR^Ten- m is 0, 1 or 2; p is 0, 1, 2, 3, or 4; q is 0 or 1]. Ferrase inhibitor or its optical isomer if Or a pharmaceutically acceptable salt.   In yet another embodiment, the present invention provides a compound of formula G (In the formula R^1aAnd R^1cIs hydrogen, R⁸O-, -N (R⁸)_Two, F, C_Three~ C_TenCycloalkyl and And C₁~ C₆Independently selected from alkyl, R^1bIs a) hydrogen, b) aryl, heterocycle or C_Three~ C_TenCycloalkyl, c) unsubstituted or aryl, heterocyclic, C_Three~ C_TenCycloalkyl , C_Two~ C₆Alkenyl, R⁸O- or -N (R⁸)_TwoC substituted with₁~ C₆A Lequil Independently selected from among R^TwoIs H, unsubstituted or substituted C₁~ C₈Alkyl, unsubstituted or substituted aryl, And -S (O)_TwoR⁶Selected from     The substituted group may have one or more     1) not substituted or         a) C₁~ C_FourAlkyl,         b) (CH_Two)_pOR⁶,         c) (CH_Two)_pNR⁶R⁷,         d) halogen, and         e) C₁~ C_FourPerfluoroalkyl         Aryl substituted with one or two groups selected from Heterocycle,     2) C_Three~ C₆Cycloalkyl,     3) OR⁶,     4) SR⁶, S (O) R⁶, SO_TwoR⁶,    15) C₁~ C₈Alkyl, or     16) C₁~ C₈Perfluoroalkyl     Has been replaced by R^ThreeIs H,Selected from R^5aAnd R^5bIs independently hydrogen, ethyl, cyclopropyl or methyl; R⁶, R⁷And R^7aIs H and unsubstituted or         a) C₁~ C_FourAlkoxy,         b) halogen, or         c) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle C substituted with₁~ C_FourAlkyl, C_Three~ C₆Cycloalkyl, aryl and heterocycle Independently selected from among R⁸Is hydrogen, C₁~ C₆Alkyl, 2,2,2-trifluoroethyl, benzyl and And aryl are independently selected from R⁹Is C₁~ C₆Independently selected from alkyl and aryl; R^TenIs H, R⁸C (O)-, R⁹S (O)_m-And unsubstituted or substituted C₁~ C_FourAl Selected from the kills and replaced Alkyl group         a) C₁~ C_FourAlkoxy,         b) aryl or heterocycle,         c) halogen,         d) HO,         h) N (R⁸)_Two,as well as         i) C_Three~ C₆Cycloalkyl A is substituted with one or two substituents selected from¹Is a bond,- C (O)-, O, -N (R⁸)-And S (O)_mSelected from X is a bond, -C (= O) NR^Ten-, -NR^TenC (= O)-, -S (O)_m-Again Is -NR^Ten- m is 0, 1 or 2; n is 0 or 1, p is 1, 2 or 3; q is 0 or 1]. Provide a ferase inhibitor or an optical isomer or a pharmaceutically acceptable salt thereof .   Preferred compounds of the invention are 1- (t-butoxycarbonyl) -cis-3-methoxycarbonyl-5- [N -(1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carba Moyl] piperidine, 1-phenethyl-cis-3-methoxycarbonyl-5- [N- (1- (4-cy Anobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidi , 1- (1-naphthylmethyl) -cis-3-methoxycarbonyl-5- [N- ( 1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoy Le] piperidine, 1-benzyl-cis-3-methoxycarbonyl-5- [N- (1- (4-sia Nobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine , 1-methyl-cis-3-methoxycarbonyl-5- [N- (1- (4-cyanobe Ndyl) -1H-imidazole-5-ylethyl Le) carbamoyl] piperidine, 1- (2-Indanyl) -cis-3-methoxycarbonyl-5- [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] Piperidine, 1- (2-diphenylethyl) -cis-3-methoxycarbonyl-5- [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamo Il] piperidine, 1- (3-phenylpropyl) -cis-3-methoxycarbonyl-5- [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamo Il] piperidine, 1- (2-methylpropyl) -cis-3-methoxycarbonyl-5- [N- ( 1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoy Le] piperidine, 1-phenethyl-cis-3-carboxyl-5- [N- (1- (4-cyanobe) Undyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1-phenethyl-cis-3- [N- (1-morpholinyl) carbamyl] -5 [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) ca Rubamoyl] piperidine, 1-phenethyl-cis-3- [N- (benzyl) carbamyl] -5- [N- ( 1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoy Le] piperidine, 1-phenethyl-cis-3- [N- (cyclopropyl) carbamyl] -5- [ N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) cal Bamoyl] piperidine, 1-phenethyl-cis-3- [N- (t-butyl) carbamyl] -5- [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamo Il] piperidine, 1- (2,2-diphenylethyl) -cis-3- [N- (1-morpholinyl) Carbamyl] -5- [N- (1- (4-cyanobenzyl) -1H-imidazole- 5-ylethyl) carbamoyl] piperidine, 1- (2,2-diphenylethyl) -cis-3- [N- (t-butyl) carba Mill] -5- [N- (1- (4-cyanobenzyl) -1H-imidazole-5-i Ruethyl) carbamoyl] piperidine, N- [1-phenethyl-cis-5- (N '-(4-cyanobenzyl-1-imi Dazol-5-ylethyl) carbamyl) pipe Lysine-3-carbonyl] methionine methyl ester, N- [1-phenethyl-cis-5- (N '-(4-cyanobenzyl-1-imi Dazol-5-ylethyl) carbamyl) piperidine-3-carbonyl] methioni , 1- (t-butoxycarbonyl) -cis-3-methoxycarbonyl-5- [N -(1- (4-cyanobenzyl) -1H-imidazol-5-ylacetyl) amido No] piperidine, 1-phenethyl-cis-3-methoxycarbonyl-5- [N- (1- (4-cy Anobenzyl) -1H-imidazol-5-ylacetyl) amino] piperidine, 1-diphenylacetyl-cis-3-methoxycarbonyl-5- [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] Piperidine, 1- (t-butoxycarbonyl) -trans-3-methoxycarbonyl-5- [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) ca Rubamoyl] piperidine, 1- (2,2-diphenylethyl) -3- [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Jyl) -1H-imidazol-5-ylacetyl) amino] piperidine, 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Jyl) -1H-imidazol-5-ylpropionyl) amino] piperidine, 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Zyl) -1H-imidazol-5-ylcarbonyl) amino] piperidine, 1- (phenylacetyl) -3 (S)-[N- (1- (4-cyanobenzyl)- 1H-imidazol-5-ylethyl) carbamoyl] piperidine; 1- (diphenylacetyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (3-chlorobenzoyl) -3 (S)-[N- (1- (4-cyanobenzyl) ) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine; 1- (2- (3-chlorophenyl) -2-phenylethyl)- 3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-yl Ethyl) carbamoyl] piperidine, 1- (dibenzylsuberylmethyl) -3 (S)-[N- (1- (4-cyanoben) Jill) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (2- (3-methylphenyl) -2-phenylethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imisol-5-ylethyl) carbamoy Le] piperidine, 1- (2- (3-trifluoromethylphenyl) -2-phenylethyl) -3 ( S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl Le) carbamoyl] piperidine, 1- (2- (2-chlorophenyl) -2-phenylethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamo Il] piperidine, 1- (2- (4-chlorophenyl) -2-phenylethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamo Il] piperidine, 1- (2- (3-aminomethylphenyl) -2-phenylethyl ) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazole-5 -Ylethyl) carbamoyl] piperidine, 1- (2-phenethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1 H-Imidazol-5-ylethyl) carbamoyl] piperidine; 1- (2-phenethyl) -3 (R)-[N- (1- (4-cyanobenzyl) -1 H-Imidazol-5-ylethyl) carbamoyl] piperidine; 1- (3-phenylpropyl) -3 (S)-[N- (1- (4-cyanobenzyl) ) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine; 1- (2-benzyl) -3- [N- (1- (4-cyanobenzyl) -1H-imi Dazol-5-ylethyl) carbamoyl] piperidine, 1- (2-chlorobenzyl) -3- [N- (1- (4-cyanobenzyl) -1H -Imidazol-5-ylethyl) carbamoyl] piperidine; 1- (3-chlorobenzyl) -3- [N- (1- (4-cyanobenzyl) -1H -Imidazol-5-ylethyl) carbamoy Le] piperidine, 1- (3-chlorobenzyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (2,2-diphenyl-2-hydroxyethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] Piperidine, 1- (3-methoxybenzyl) -3 (S)-[N- (1- (4-cyanobenzyl) ) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine; 1- (3,5-dichlorobenzyl) -3 (S)-[N- (1- (4-cyanoben) Jill) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (3-trifluoromethoxybenzyl) -3 (S)-[N- (1- (4-si Anobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidi , 1- (2,5-dimethylbenzyl) -3 (S)-[N- (1- (4-cyanoben) Jill) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (3-trifluoromethylbenzyl) -3 (S)-[N- (1- (4-sia Nobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine , 1- (3-bromobenzyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (3-methylbenzyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1-isobutyl-3 (S)-[N- (1- (4-cyanobenzyl) -1H-imi Dazol-5-ylethyl) carbamoyl] piperidine, 1- (2-methyl-2-phenylethyl) -3- [N- (1- (4-cyanoben) Jill) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (2- (1-morpholinyl) -2-phenylethyl) -3 (S)-[N- ( 1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoy Le] piperidine, 1- (2- (1-piperidinyl) -2-phenylethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylue Tyl) carbamoyl] piperidine, 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Zyl) -2-methyl-1H-imidazol-5-ylethyl) carbamoyl] pipe lysine, 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-methoxy Undyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (diphenylmethyl) -3 (S)-[N- (1- (4-cyanobenzyl)- 1H-imidazol-5-ylethyl) carbamoyl] piperidine; 1- (3-methoxyphenethyl) -3 (S)-[N- (1- (4-cyanobenzy) Ru) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (1-naphthylethyl) -3 (S)-[N- (1- (4-methoxybenzyl) ) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine; 1- (3-chlorophenethyl) -3 (S)-[N- (1- (4-cyanobenzyl) ) -1H-Imidazol-5-ylethyl) ca Rubamoyl] piperidine, 1- (α-methylbenzyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (diphenylmethyl) -3 (S)-[N- (1- (4-cyanobenzyl)- 2-methyl-1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (α-toluenesulfonyl) -3 (S)-[N- (1- (4-cyanobenzy) Ru) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (benzenesulfonyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (1-naphthylenesulfonyl) -3 (S)-[N- (1- (4-cyanoben) Jill) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (3-chlorobenzenesulfonyl) -3 (S)-[N- (1- (4-cyano Benzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine; 1- (3,5-dichlorobenzenesulfonyl) -3 (S)-[N- (1- (4- Cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperi gin, 1- (α-toluenesulfonyl) -3 (R)-[N- (1- (4-cyanobenzy) Ru) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (α-toluenesulfonyl) -cis-3-methoxycarbonyl-5- [N -(1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carba Moyl] piperidine, 1- (methanesulfonyl) -3 (S)-[N- (1- (4-cyanobenzyl)- 1H-imidazol-5-ylethyl) carbamoyl] piperidine; 1- (diphenylcarbamoyl) -3 (S)-[N- (1- (4-cyanobenzy Ru) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (phenylcarbamoyl) -3 (S)-[N- (1- (4-cyanobenzyl) ) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine; 1- [2- (2-pyridyl) -2-phenyl-2-hydroxy Ethyl] -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazole -5-ylethyl) carbamoyl] piperidine, 1- (2-pyridylethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1-phenyl-3 (S)-[N- (1- (4-cyanobenzyl) -1H-imida Sol-5-ylethyl) carbamoyl] piperidine; 1- (3-methylphenyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (2,2-diphenylethyl) -3 (S)-[2- (1- (4-cyanoben) Jyl) -1H-imidazol-5-yl) ethylthiomethyl] piperidine, 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Jyl) -1H-imidazol-5-yl) ethylsulfonylmethyl] piperidine, 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) -N-methyl- Carbamoyl] piperidine, 1- (3-bromobenzyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-Imidazol-5-ylethyl) -N-methyl-carbamoyl] piperidi , 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Jill) -1H-imidazol-5-ylethyl) aminomethyl] piperidine, 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Jill) -1H-imidazol-5-ylethyl) -N-acetyl-aminomethyl] Piperidine, 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Jil) -2-methyl-1H-imidazol-5-ylethyl) -N-acetyl-a Minomethyl] piperidine, 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Jill) -1H-imidazol-5-ylethyl) -N-cyclopropylmethyl-a Minomethyl] piperidine, 1- (2,2-diphenylethyl) -3 (S)-[N- (2-methyl-1H-i Midazol-4-ylethyl) -N- (4-si Anobenzoyl) aminomethyl] piperidine, 1- (2,2-diphenylethyl) -3 (S)-[5- (4-cyanobenzyl) -1H-imidazol-1-ylmethyl] piperidine; 1- (2,2-diphenylethyl) -3 (S)-[5- (4-cyanobenzyl) -1H-imidazol-1-ylethylcarbamoyl] piperidine; Or their optical isomers or pharmaceutically acceptable salts.   In specific examples of the compound of the present invention, 1-phenethyl-cis-3- [N- (1-morpholinyl) carbamyl] -5 [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) ca Lubamoyl] piperidine: 1- (2-diphenylethyl) -cis-3- [N- (1-morpholinyl) cal Bamyl] -5- [N- (1- (4-cyanobenzyl) -1H-imitazol-5 Ilethyl) carbamoyl] piperidine: N- [1-phenethyl-5- (N '-(4-cyanobenzyl-1-imidazole- 5-ylethyl) carbamyl) piperidine-cis-3-carbonyl] methioni N: 1- (2-diphenylethyl) -3-methoxycarbonyl-5- [N- (1- ( 4-cyanobenzyl) -1H-imidazole-cis-5-ethyl) carbamoy Le] piperidine:1- (2,2-diphenylethyl) -cis-3- [N- (1 -(4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl ] Piperidine: 1- (3-chlorobenzyl) -3- [N- (1- (4-cyanobenzyl) -1H -Imidazol-5-ylethyl) carbamoyl] piperidine:1- (2- (1-morpholinyl) -2-phenylethyl) -3 (S)-[N- ( 1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoy Le] piperidine: 1- (diphenylmethyl) -3 (S)-[N- (1- (4-cyanobenzyl)- 2-Methyl-1H-imidazol-5-yl-ethyl) carbamoyl] piperidine :1- (3-methylphenyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine: 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) -N-acetyl -Aminomethyl] piperidine:1- (benzenesulfonyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine: Alternatively, there are optical isomers or pharmaceutically acceptable salts thereof.   The compounds of the present invention have asymmetric centers and can be used as racemates and racemic mixtures. Can exist as individual diastereomers and include all possible Isomers are included in the present invention. Any variable (eg, ant) in a component , Heterocycle, R^1a, R^Four)), The definition of the variable part is Individually independent. Combinations of substituents or variables may also result in stable compounds. You can only use what brings.   The term "alkyl," as used herein, refers to a branch having the specified number of carbon atoms. It is intended to include both linear and linear saturated aliphatic hydrocarbon groups. "Arco The term "xy" refers to an alkyl having the indicated number of carbon atoms attached through an oxygen bridge. Means a kill group. The term “halogen” or “halo” as used herein Means fluoro, chloro, bromo and iodo.   As used herein, the term "aryl" means that each ring is 7 members or less, Any one ring includes any stable monocyclic, bicyclic or tricyclic carbocycle that is an aromatic ring Shall be. Examples of mono- and bicyclic aryl elements include phenyl, naphthyl, tetra Hydronaphthyl, indanyl, biphenyl, phenanthryl, antri Or acenaphthyl. Examples of tricyclic aryl elements include 10,11-di Hydro-5H-dibenzo [a, d] cyclohepten-5-yl (dibenzyl 9-fluorenyl and 9,10-dihydroanthracese -9-yl. Preferably, "aryl" is a monocyclic or bicyclic carbocyclic ring is there.   As used herein, the term "heterocycle" refers to carbon atoms as well as N, O, and S A saturated or unsaturated stable 5-7 compound consisting of 1-4 heteroatoms selected from Membered monocyclic, stable 8- to 11-membered bicyclic, or stable 13- to 15-membered tricyclic heterocyclic Means that one of the heterocycles thus defined is fused to a benzene ring Also included are any bicyclic groups. Heterocycle can be any hetero atom that creates a stable structure. Bond at a carbon atom or a carbon atom. Examples of monocyclic and bicyclic heterocyclic elements include aze Pinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, Nzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzo Thienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzof Ryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzo Thiopyranyls Rufone, frill, imidazolidinyl, imidazolinyl, imidazolyl, indori Nil, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, iso Thiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthy Lysinyl, oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl , 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidyl, piperazini , Pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyr Midinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalini , Tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinini Le, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolyl Phenyl, thienofuryl, thienothienyl and thienyl. Three rings Examples of heterocyclic elements include 6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridine, 9,10-dihydro-4H-3-thiabenzo [f] a Includes, without limitation, dulen-4-yl and 9-xanthenyl. 6,11-Jihi The dro-5H-benzo [5,6] cyclohepta [1,2-b] pyridine moiety is Having a structure. Preferably, "heterocycle" is a mono- or bicyclic moiety.   The term "heteroaryl" as used herein refers to a compound in which at least one ring is aromatic. Heteroatoms which are aromatic and have 1 to 4 carbon atoms selected from N, O and S Any stable mono-, bi- or tricyclic carbocyclic ring of up to 7 members in each ring substituted with Shall mean. Examples of mono- and bicyclic heteroaryl elements include benzimid Dazolyl, benzoisoxazolyl, benzofurazanyl, benzopyranyl, ben Zothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoo Xazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydroben Zothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfo , Furyl, imidazolyl, indolinyl, indolyl, isochromanyl, iso Indolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadia Zolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, Loryl, quinazolinyl, quinolinyl, quinoxalinyl, Tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienov Ryl, thienothienyl and thienyl are included without limitation. Tricyclic heteroaryl Examples of elements include 6,11-dihydro-5H-benzo [5,6] cyclohepta [1, 2-b] pyridine is included without limitation. Preferably, "heteroaryl" is simply A ring or bicyclic moiety.   As used herein, "substituted aryl", "substituted heterocycle" and "substituted cycloal The term "kill" refers to one to three substituents other than the site of attachment to the rest of the compound. Is included. The substituent is preferably F, Cl, Br , CF_Three, NH_Two, N (C₁~ C₆Alkyl)_Two, NO_Two, CN, (C₁~ C₆Alkyl ) O-, -OH, (C₁~ C₆Alkyl) S (O)_m−, (C₁~ C₆Alkyl) C (O) NH-, H_TwoNC (NH)-, (C₁~ C₆Alkyl) C (O)-, (C₁ ~ C₆Alkyl) OC (O)-, N_Three, (C₁~ C₆Alkyl) OC (O) NH— and And C₁~ C₂₀It is selected from the group including, but not limited to, alkyl.   R⁶And R⁷Or R⁷And R^7aAnd together form a ring, the cyclic amine moiety is It is formed. Examples of the annular portion include: Are included without limitation.   In addition, the cyclic moiety optionally has another (one or more) heteroatoms. obtain. Examples of such heteroatom-bearing cyclic amine moieties include:Are included without limitation.   Substituent (R^Two, R^Three, R^FourEtc.) into the ring system indicate that the bond shown is It shows that it is feasible at any of the possible ring carbon atoms.   Preferably, R^1aAnd R^1bIs hydrogen, -N (R⁸)_Two, R⁸C (O) NR⁸−, And Unsubstituted or -N (R⁸)_Two, R⁸O- or R⁸C (O) NR⁸C substituted with-₁~ C₆Germany out of alkyl Is selected.   Preferably, R^TwoIs a) unsubstituted or one or more     1) not substituted or         i) C₁~ C_FourAlkyl,         ii) (CH_Two)_pOR⁶,         iii) (CH_Two)_pNR⁶R⁷,         iv) halogen,         v) C₁~ C_FourPerfluoroalkyl         An aryl or heterocyclic ring substituted with     2) OR⁶,     3) SR⁶, SO_TwoR⁶Or     C substituted with₁~ C₈Alkyl, b) c) unsubstituted or one or more     1) C₁~ C₈Alkyl,     2) C₁~ C₈Perfluoroalkyl,     3) OR⁶,     4) SR⁶, SO_TwoR⁶Or     Aryl substituted with d) -SO_TwoR⁶ Is selected from   Preferably, R^TwoContains at least one unsubstituted or substituted phenyl.   Preferably, R^FourIs hydrogen, perfluoroalkyl, F, Cl, Br, R⁸O-, R⁹S (O)_m-, CN, NO_Two, (R⁸)_TwoNC (NR⁸)-, R⁸C (O)-, N_Three, -N (R⁸)_Two, R⁹OC (O) NR⁸-And C₁~ C₆Select from alkyl Is done.   Preferably, R^FiveIs hydrogen.   Preferably, R^7bIs hydrogen or C substituted by an unsubstituted or substituted aryl group₁ ~ C₆Alkyl.   Preferably, R⁸Is H, C₁~ C₆Selected from alkyl and benzyl.   Preferably, A¹And A^TwoIs a bond, -C (O) NR⁸-, -NR⁸C (O)-, O , -N (R⁸)-, -S (O)_TwoN (R⁸)-And -N (R⁸) S (O)_TwoFrom within Independently selected.   Preferably, V is selected from hydrogen, heterocycle and aryl.   Preferably, W is imidazolyl.   Preferably, X is a bond, -C (= O) NR^Ten-, -NR^TenC (= O)-or -NR^Ten-.   Preferably, n, p and r are independently 0, 1 or 2.   Preferably, t is 1.   Pharmaceutically acceptable salts of the compounds of the present invention include, for example, non-toxic non-toxic salts of the compounds of the present invention. Includes the usual non-toxic salts formed from organic or organic acids. Such normal non-toxic Examples of salts include hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like. Salts derived from inorganic acids, and acetic, propionic, succinic, glycolic, Thearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, Maleic acid, hydroxymaleic acid, Phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetate Toxibenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedi Manufactured from organic acids such as sulfonic, oxalic, isethionic and trifluoroacetic acids Salts included.   Any substituents or variables (eg, R^1a, Z, n, etc.) The definition at one position shall be independent of the definition at other positions in the molecule . That is, -N (R⁸)_TwoIs -NH_Two, -NHCH_Three, -NHC_TwoH_FiveAnd so on. The present invention Substituents and substitution patterns of compounds of formula I Chemically stable compounds that can be easily synthesized by known techniques and the methods described below It is understood that the choice to obtain is possible for a person skilled in the art.   A pharmaceutically acceptable salt of a compound of the present invention is a compound of the present invention having a basic moiety. Can be synthesized by ordinary chemical methods. Salt is usually ion exchange chromatography Or with the free base in stoichiometric or excess amounts to form the desired salt. React with inorganic or organic acids in suitable solvents or various solvent combinations Manufactured by   The abbreviations used in the description of the chemical operations and in the examples described below are as follows. is there.   Ac_TwoO Acetic anhydride   Boct-butoxycarbonyl   CBz carbobenzyloxy   DBU 1,8-diazabicyclo [5.4.0] undec-7-e                     In   DMAP 4-dimethylaminopyridine   DME 1,2-dimethoxyethane   DMF dimethylformamide   EDC 1- (3-dimethylaminopropyl) -3-ethyl-cal                     Bodiimide hydrochloride   Et_ThreeN triethylamine   EtOAc ethyl acetate   FAB fast atom bombardment   HOBT 1-hydroxybenzotriazole hydrate   HOOBT 3-hydroxy-1,2,2-benzotriazine-4 (3                     H) -ON   HPLC high-performance liquid chromatography   MCPBA m-chloroperoxybenzoic acid   MsCl methanesulfonyl chloride   NaHMDS sodium bis (trimethylsilyl) amide   Py pyridine   TFA trifluoroacetic acid   THF tetrahydrofuran   The compounds of the invention are known from the references or Ester hydrolysis, cleavage of protecting groups, etc. In addition to the other standard operations, the reactions shown in Reaction Schemes 1 to 21 are used. Therefore, it is manufactured. The stereochemistry is shown in the scheme, but the compound shown in the formula is racemic mixed That can be separated in a subsequent purification step or used as a racemic mixture It will be appreciated by those skilled in the art that   The above reaction can be used sequentially to obtain the compounds of the present invention, or In the latter case, the fragments are later combined with each other as shown in the reaction scheme. It is linked by a primary alkylation or acylation reaction.Overview of Reaction Schemes 1-8   Some of the required intermediates are commercially available, and most are described in references. It can be manufactured by the operation described. For example, in Reaction Schemes 1-3, 1,3,5- The synthesis of the trisubstituted piperidine is described, but the reaction shown in the above scheme is protected appropriately. Applies to commercially available nipecotic acid or nipecotamide , Thereby R^ThreeIt is also possible to obtain compounds of the invention in which is hydrogen.   As shown in Reaction Scheme 1, pyridine dicarboxylic acid Catalytic hydrogenation followed by N protection affords piperidine diester mixture 1. It is. Thereafter, the protected piperidine is partially hydrolyzed to give 3,5-cis- And a trans-isomeric racemic mixture can be obtained, Separable by chromatography. The rest of Reaction Scheme 1 and Reaction Schemes 2 and 3 and 3 show the operation performed on a racemic mixture of cis-isomers. Chemistry shown here Manipulation is applied to the racemic mixture of the trans-isomer and thereby to the other inventions It is well understood by those skilled in the art that it is also possible to obtain a compound of the formula Furthermore, on The procedure described above entails enantiomerically pure isomers (ie (+)-cis-isomer or (-) -Cis-isomer). The trans-isomer is converted to sodium carbonate It is possible to epimerize to the cis-isomer by treatment with any base. You. If the final racemate is separated on a chiral preparative HPLC column, The individual diastereomers are obtained.   Monocarboxylic acid 2 in the presence of a suitable coupling reagent such as EDC / HOBT To give 5-carboxynipecotamide 3 when treated with an appropriately substituted amine. Can be. Next, the appropriately substituted 5-carboxynipecotamide is deprotected and then Piperidi Intermediate 4 is obtained by reductive alkylation of the nitrogen of the compound. Remaining ester moiety And then similarly functionalized with an appropriately substituted amine Lysine 5 is obtained.   Reaction Scheme 2 shows another synthesis starting from carboxynipecotamide 3 to compound 5. Shows the synthesis route.   As shown in Reaction Scheme 3, monocarboxylic acid 2 can be contacted by Curtius rearrangement. After reduction, piperidine 6 can be obtained. Subsequent amide formation provides intermediate 7 The obtained intermediate is subjected to the reaction procedure shown in Reaction Scheme 1 to obtain Compound 8 of the present invention. .   The present invention relates to a 1,4-dihydropiperidine compound of the piperidine compound whose synthesis has been described above. Also encompasses lysine and 1,2,3,4-tetrahydropyridine analogs. Reaction scheme 4 leads to intermediates 11 and 13 corresponding to the saturated ring intermediate 2 shown in Scheme 1. 1 shows a synthesis route. That is, N-alkylation of an appropriately substituted pyridine gives a quaternary intermediate. An interstitial body 9 is obtained. Subsequently, the intermediate is reduced to give 1,4-dihydropyridine 1 0, which can be selectively hydrolyzed to give the important intermediate 11. Alternatively, in other cases, the 1,4-dihydropyridine 10 is further reduced To give an enantiomeric mixture 12 of tetrahydropyridine. This mixture is important if it is hydrolyzed and separated by chromatography. Intermediate 13 (and enantiomer not shown) can be obtained. Intermediate obtained The bodies 11 and 13 can be subjected to the various synthetic procedures shown in Reaction Schemes 1-3 above.   Reaction schemes 5 to 7 show that the 1,3-disubstituted pi of the present invention wherein moiety X is other than an amide moiety. 1 shows the synthesis of peridine. The reaction procedure described here must be performed in a suitable manner well known to those skilled in the art. Modified with protecting groups and reagents, thereby providing the 1,3,5-trisubstituted piper of the invention. It is possible to get gin.   In reaction scheme 5, X is -S- or -SO_Two-The synthesis of the compound of the invention Show. Racemic nipecotate 14 is resolved by selective crystallization of chiral tartrate Possible, reductive alkylation after resolution gives ester 15. Middle Isomer 15 is reduced to alcohol 16, which is activated and To give thioester 17. After that, thiol is formed, which is Killing and, optionally, oxidation provides compounds 18 and 19 of the present invention. You.   Intermediate 16 obtained by reduction is selectively oxidized again to aldehyde. This aldehyde was appropriately substituted Use in reductive alkylation of amines gives compounds 20 of the present invention . The 20 secondary amines can be further functionalized as shown schematically. is there.   As shown in Reaction Scheme 7, the imidazolyl substituted appropriately for the activated alcohol To thereby obtain a compound of the present invention wherein X is a bond. is there.   Reaction Scheme 8 shows that R^TwoShows the synthesis of compounds of the present invention where is an aryl moiety.Reaction scheme 1 Reaction scheme 2 Reaction scheme 3 Reaction scheme 3(Continued) Reaction Scheme 4 Reaction scheme 5 Reaction scheme 5(Continued) Reaction scheme 6 Reaction scheme 7 Reaction scheme 8   In reaction schemes 1 to 8, R^SaAnd R^SdIs Or a protected precursor thereof, R^ScCH_Two− Is R^TwoOr a protected precursor thereof, R^Sb− Is R⁶Or a protected precursor thereof, R- is a "substituent" or a protected precursor thereof Is understood.   The above reactions involve the side chain moiety R^SaAnd R^SdCommercially available having (C = O), or A variety of amines and acids that can be readily synthesized by reactions well known to those skilled in the art can be used. It is understood that. In Reaction Schemes 9 to 21, the side chain moiety R^SaAnd R^Sd(C = O) 2 shows specific reactions that can produce the following intermediates. Reaction Schemes 9-21 show protected intermediates And the preparation of both the unprotected intermediate and the intermediate obtained. Later, in reactions such as shown in Reaction Schemes 1-8, protection of any intermediate moiety; It will be appreciated by those skilled in the art that deprotection may be necessary in some cases. Can be   The selectively protected intermediates 20 used in the synthesis shown in Reaction Scheme 9 include 21 and the like. Can be reductively alkylated with various aldehydes. Aldehydes are O.D. P. Goel, U.S.A. Krolls, M .; Stier and S.M. Kesten Is described in Organic Synthesis. 67, pp. 69-75, 1988 It can be manufactured by standard operations as described in The reductive alkylation is Triacetate in a solvent such as loethane, methanol or dimethylformamide Various reducing agents such as sodium xylborohydride and sodium cyanoborohydride At pH 5-7. Ester product 22 is triflicated in methylene chloride. Deprotection with fluoroacetic acid gives the substituted diamine 23. Diamine 23 Is isolated, for example, in the form of a salt, in particular as a trifluoroacetate, hydrochloride or acetate I can do it. The diamine 23 formed is further selectively protected and is protected with a second aldehyde. Similar tertiary amines can be obtained by reductive alkylation. Or also Zia Min 23 is cyclized by procedures known from the literature, whereby dihydroimidazo It is also possible to obtain intermediates such as The resulting ester 24 is It can be used in a reaction as shown in Reaction Scheme 3, or via an azide intermediate 25 26. Amine 26 can be used in a reaction as shown in Scheme 1.   Reaction scheme 10 shows aralkyl imida which can be used for the reaction as shown in reaction scheme 3. 2 shows the preparation of zolyl intermediate 31. That is, imidazole acetic acid 27 can be used for standard operation. Thus, it can be converted to the protected acetate 29, where 29 is first alkylhalogenated. And then treated with refluxing methanol to give regiospecific alkylation. Thus, imidazole acetate 30 can be obtained. Acetic acid by hydrolysis 31 is obtained.   Alternatively, as shown in Reaction Scheme 11, intermediate 31 is azide intermediate 33 Can be converted to the homologous amine 34 via This amine is shown in Scheme 1. Can be used for various reactions.   Schemes 12 and 13 illustrate the preparation of amine intermediates with mixed heteroatom substitution. Show. That is, the protected serine 35 can be reduced to alcohol 36, Is subjected to a Mitsunobu reaction operation to obtain a phthalimidyl intermediate 37. Deprotection and selective reprotection give alcohol 39, which is converted to an acid Upon conversion, aldehyde 40 is obtained. Aldehyde 40 Can be subsequently alkylated and finally deprotected to give the amine intermediate 41. You.   Using Boc-protected phthalimidyl alcohol 39, 2-aziri such as 43 It is also possible to synthesize dinylmethylamine (Scheme 13). 39 1,1'-sulfonyldiimidazole and hydrogen in a solvent such as tylformamide When treated with sodium iodide, aziridine 42 is produced. This aziridine When the reaction is carried out in the presence of a nucleophile such as 43 is obtained.   In addition, amines such as 48 derived from amino acids such as O-alkylated tyrosine Can also be prepared according to the standard procedure shown in Scheme 14. Shown here Is an operation to obtain the amine moiety from an intermediate azide such as 47.   Scheme 15 of the present invention wherein the variable W is present as a pyridyl moiety in Reaction Schemes 15-18. 2 shows the synthesis of an appropriately substituted alkanol useful in the synthesis of compounds. like this The hydroxyl moiety of the intermediate is converted to the corresponding amine as shown in Scheme 15. Or a suitable leaving group as shown in Scheme 17. Variable part Production of alkanols having other heterocyclic moieties as component W Similar synthetic methods are well known to those skilled in the art.   A¹(CR^1a _Two)_nA^Two(CR^1a _Two)_nCompounds of the invention wherein the linker is a substituted methylene The compound can be synthesized by the method shown in Reaction Scheme 19. That is, N-protected iodide The imidazolyl 50 is reacted with the appropriately protected benzaldehyde under Grignard conditions. In response, alcohol 51 is obtained. Previously shown in other reaction schemes (especially reaction scheme 7) Acylation, followed by alkylation, provides compound 52 of the present invention. Pond substituent R¹If desired, the acetyl moiety can be substituted as shown in Reaction Scheme 19. And can be processed.   Reaction Scheme 20 shows that non-hydrogen R^5b1 shows the synthesis of compounds of the present invention having That is Selectively iodinating readily available 4-substituted imidazole 53 to give 5-iodo It may be doimidazole 54. Next, the resulting imidazole is protected and Coupling to an optionally substituted benzyl moiety gives intermediate 55. In this Intermediate 55 may be subjected to the above-described alkylation reaction operation.   A¹(CR¹ _Two)_nA^Two(CR¹ _Two)_nCompounds of the present invention wherein the linker is oxygen are, for example, Those skilled in the art as shown in Reaction Scheme 21 Can be synthesized by a known method. The appropriately substituted phenol 56 is replaced with methyl N- (cyano ) Reaction with methanimidate gives 4-phenoxyimidazole 57 . Intermediate 58 obtained by selectively protecting one imidazolyl nitrogen was added to The alkylation reaction procedure described for dilimidazole can be performed.Reaction scheme 9 Reaction scheme 9(Continued) Reaction scheme 10 Reaction Scheme 11 Reaction Scheme 12 Reaction Scheme 12(Continued)[Where R 'is R^1aOr a protected precursor thereof].Reaction Scheme 13 [Wherein R ′ is (R^Four)_r-V- or a protected precursor thereof].Reaction Scheme 14 Reaction Scheme 14(Continued) [Wherein R′CH_Two− Is R⁸Or a protected precursor thereof].Reaction Scheme 15 Reaction scheme 16 Reaction scheme 17 Reaction scheme 18 Reaction Scheme 19 Reaction Scheme 19(Continued) Reaction Scheme 20 Reaction Scheme 21   The compounds of the present invention are useful as drugs for mammals, especially for humans. Of the present invention The compound may be administered to a patient for use in treating cancer. Can be treated with a compound of the present invention. Examples of some types of cancer include colorectal cancer, exocrine pancreatic cancer, myeloid leukemia and nervous system tumors. Tumors include, but are not limited to. Tumors such as those described above have mutations in the ras gene itself, A protein capable of regulating Ras activity [ie, neurofibromin (neurof ibromin) (NF-1), Neu, Src, Abl, Lck, Fyn] It can be caused by mutations or other mechanisms.   The compounds of the present invention inhibit farnesyl-protein transferase and Inhibits farnesylation of tumor gene protein Ras. The compounds of the present invention also Inhibit tumor angiogenesis and thereby affect tumor growth (J. Rak et al., Cancer Research 55, pp. 4575-45 80, 1995). This anti-angiogenic property of the compounds of the present invention May also be useful in the treatment of some forms of blindness associated with   The compound of the present invention is characterized in that the protein Ras binds a gene other than ras to an oncogene. Abnormally activated as a result of mutation (Ie the ras gene itself is activated by mutation to the oncogene form) Not only) to control other proliferative disorders, benign or malignant, Said suppression comprises administering to a mammal in need of such treatment an effective amount of a compound of the present invention. It is realized by giving. For example, one of the proteins belonging to NF-1 is good. Induces sexual proliferative disorders.   The compounds of the present invention are useful in the treatment of several viral infections, in particular the hepatitis delta virus and related May also be useful in the treatment of infections with streptoviruses (JS Glenn et al., Science 256, pp. 1331-1333, 1992).   The compounds of the present invention may be used in neointima formati. on), the percutaneous transluminal (percutaneous transl) (Uminal) is also useful in preventing restenosis after coronary angioplasty (C.   Indolfi et al., Nature medicine 1, pp. 541 -545, 1995).   Compounds of the invention may also be useful for treating and preventing polycystic kidney disease (D . L. Schaffner et al., American Journal of   Pathology 1 42, pp. 1051-1060, 1993; Cowley, Jr. Et al., FASEB Journal 2, A3160, 1988).   The compounds of the present invention may also be useful for treating fungal infections.   The compounds of the present invention may be administered to mammals, preferably humans, alone or preferably Pharmaceutically acceptable carriers or diluents according to standard pharmaceutical preparation methods, and In the form of a pharmaceutical composition in combination with a known adjuvant such as alum. Can give. The compounds of the invention may be administered orally, or intravenously, intramuscularly, intraperitoneally, subcutaneously, Parenteral administration, including rectal and topical administration, is possible.   If the chemotherapeutic compound according to the invention is to be used orally, the selected compound may be used. For administration in the form of tablets or capsules, or aqueous solutions or suspensions I can do it. For tablets for oral use, commonly used carriers are lactose and Contains starch, and usually contains lubricants such as magnesium stearate Is done. Diluents useful for oral administration in capsule form include lactose and dry Contains corn starch. If an aqueous suspension is required for oral use The active ingredient is mixed with emulsifying and suspending agents. If desired, any sweeteners and And / or flavoring agents may be added. Intramuscular, intraperitoneal, subcutaneous and intravenous use For this purpose, a sterile solution of the active ingredient is usually prepared, but the pH of this solution may be adjusted and adjusted accordingly. Should be buffered. For intravenous use, the total solute concentration should be used to make the formulation isotonic. Should be controlled as follows.   The present invention relates to treatment with or without a pharmaceutically acceptable carrier or diluent. A pharmaceutical composition useful for treating cancer comprising administering a therapeutically effective amount of a compound of the present invention is also included. Include. Suitable compositions of the present invention include a compound of the present invention and a pH level, e.g. . And an aqueous solution containing a pharmaceutically acceptable carrier such as a saline solution. You. This solution was used for local bolus injection. ion) into the patient's intramuscular bloodstream.   As used herein, the term "composition" refers to a preparation containing specific ingredients in specific amounts. And a preparation obtained directly or indirectly from the combination of specific components in specific amounts. Cut off.   When administering the compounds according to the invention to human subjects, the daily dose is usually This dose is usually determined by the prescribing physician, but may vary depending on the age, weight and response of the individual patient. Answer and the severity of the patient's symptoms Varies according to severity.   In one example of application, a mammal receiving treatment for cancer is administered an appropriate amount of the compound. The daily dosage is from about 0.1 to about 60 mg / kg of body weight, preferably 0.1 mg / kg. 5 to about 40 mg.   The compounds of the invention may be used in compositions to produce farnesyl-protein transferase. As a component of an assay to quickly identify the presence and amount of FPTase Is also useful. That is, the composition to be tested is divided and the two parts are Known substrates of ases (eg tetrapeptides with cysteine at the amine terminus) And a mixture containing farnesyl pyrophosphate. The light compound is added. The assay mixture can be prepared using an FPTase, After incubation for a time sufficient for farnesylation of the substrate, The chemical content of the assay mixture is determined by well-known immunological, radiochemical or chromatographic Confirm by fee utilization technology. Compounds of the invention selectively inhibit FPTase Substrate, the substrate is present in the assay mixture without the compound of the invention. No longer exists or is quantitatively reduced while containing the compound of the present invention. (B) No change occurs in the substrate present in the mixture Is an indicator of the presence of FPTase in the test composition.   Assay as described above contains farnesyl-protein transferase It is readily apparent to those of skill in the art that it is useful for identifying tissue samples to be It will be clear. That is, the compound of the present invention, which is a potent inhibitor, is characterized by the amount of enzyme in the sample. Can be used in an active site titration assay to measure Unknown amount of farnesyl-protein Aliquot of tissue extract containing cytoplasmic transferase and excess FPT A known substrate of the enzyme (eg, a tetrapeptide having a cysteine at the amine end) , A series of samples consisting of farnesyl pyrophosphate and various concentrations of the compounds of the invention. Incubate for the appropriate time in the presence of the substance. A sufficiently potent inhibitor (ie, An inhibitor having a Ki substantially less than the concentration of the enzyme in the vessel). The concentration required to suppress elementary activity by 50% is approximately half that of the enzyme in the sample. equal.Example   Examples are provided to further understand the present invention. Specific use substances, compounds and The conditions are employed to further explain the present invention, and the reasonable scope of the present invention Is not limited. In each of Examples 1 to 24 below, HPLC Or mosquito Purification by ram chromatography was performed.Example 1 1- (t-butoxycarbonyl) -cis-3-methoxycarbonyl-5- [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carba Of Moyl] piperidine Step A:Preparation of pyridine-3,5-dicarboxylic acid methyl ester hydrochloride   Pyridine-3,5-dicarboxylic acid (5.00 g, 29.9 mmol) was added to CH_Three Stir in OH (100 mL), cool in an ice bath and add thiochloride dropwise. Nil (17.45 mL, 239.2 mmol). 0.5 hours later, The reaction mixture was refluxed for 48 hours. Concentrate to dryness and title as an off-white solid The compound was obtained. Step B:Piperidine-cis, trans-3,5-dicarboxylic acid methyl ester salt Preparation of acid salt   Pyridine-3,5-dicarboxylic acid methyl ester hydrochloride (7.07 g, 30. 5 mmol) was dissolved in acetic acid (75 mL) and platinum (IV) oxide (100 mg, 0.44 mmol) and overnight at 50 psi on a Parr apparatus Shake. The reaction mixture was filtered through celite and concentrated to dryness, The title compound was obtained. Step C:1- (t-butoxycarbonyl) piperidine-cis and trans-3, Preparation of 5-dicarboxylic acid methyl ester   Piperidine-3,5-dicarboxylic acid methyl ester hydrochloride (7.11 g, 29 . 9 mmol) in THF (60 mL) and H_TwoDissolved in O (60 mL). Heavy coal Sodium acid (13.81 g, 0.164 mol) was added followed by di-dicarbonate. Tert-butyl (9.79 g, 44.9 mmol) was added. This mixture Stir at ambient temperature for 5 hours. The THF was removed under reduced pressure and the solution was_TwoCl_Two(3x 100 mL). CH together_TwoCl_TwoWash the layers with saline and dry Dried (MgSO4_Four). Filter, concentrate to dryness and chromatographic ( After silica gel, 10% ethyl acetate / hexane), racemic 1- (t-butoxy) Carbonyl) piperidine-cis-3,5-dicarboxylic acid methyl ester and racemic Mimic 1- (t-butoxycarbonyl) piperidine-trans-3,5-dicarbo Acid methyl ester was obtained. Step D:1- (t-butoxycarbonyl) -cis-3-methoxycarbonyl-pi Preparation of peridine-5-carboxylic acid   1- (t-butoxycarbonyl) piperidine-cis-3,5-dicarboxylic acid The butyl ester (0.761 g, 2.52 mmol) was added to DME (6 mL) and H_Two Dissolved in O (6 mL) followed by LiOH-H_TwoO (0.106 g, 2.52 m mol) was added. The mixture was stirred overnight at ambient temperature. DME under reduced pressure Remove, take up in EtOAc and water, acidify to pH 3 and add EtOAc (10x). The EtOAc layers were combined, dried (MgSO_Four),filtration And concentrated to dryness and chromatographed (silica gel, 1-3% MeO H / CH_TwoCl_TwoThe title compound was obtained later. Step E:Preparation of 3- (4-cyanobenzyl) histamine   Nγ-pivaloyloxymethyl-N^αPhthaloylhistamine (4.55 g, 12.8 mmol) was previously described (JC Emmett, FH. Holloway and J.M. L. Turner, J.M. Chem. Soc. , Per Kin Trans. 1, 1341, (1979)). α -Bromo-p-tolunitrile (3.77 g, 19.2 mmol) was added to acetonitrile. Dissolved in ril (70 mL). Heat this solution at 55 ° C for 4 hours and cool to room temperature And then filter A white solid was removed. Acetonitrile (30 mL) was reduced to 1/2 its volume under reduced pressure. And the solution was heated at 55 ° C. overnight. The solution was cooled, filtered and white A colored solid was obtained. The volume of the filtrate was reduced to 10 mL, and the solution was Heat then cool to room temperature, dilute with EtOAc (25 mL), filter and add An additional white solid was obtained. Combine the solids, dry and use without further purification did.   1-pivaloyloxymethyl-3- (4-cia) in methanol (100 mL) Nobenzyl) -4- (2-phthalimidoethyl) imidazolium bromide (6. 13g, 11.1 mmol) with ammonia while maintaining the temperature below 30 ° C. The gas was saturated. The solution was stirred for 1 hour, concentrated to dryness, and CH_Two Cl_Two(3 × 200 mL), dried (MgSO 4)_Four), Concentrate and chromatograph Chromatography (silica gel, 10: 90: 1 MeOH / CH)_TwoCl_Two/ NH_FourOH) Treatment with 4-cyanobenzyl-N^α-Phthaloylhistamine was obtained.   3- (4-cyanobenzyl) -N^α-Phthaloylhistamine (1.64 g, 4 . 61 mmol) and hydrazine (1.46 mL, 46.1 mmol) in anhydrous E Dissolved in tOH (70 mL) I understand. The solution was concentrated after 1 hour and filtered to give a white precipitate, which was The material was washed several times with EtOH. The filtrate is concentrated and the residue is chromatographed (silica). Kagel, 10: 90: 1 MeOH / CH_TwoCl_Two/ NH_FourOH) Treat and title Compound was obtained. Step F:1- (t-butoxycarbonyl) -cis-3-methoxycarbonyl-5 -[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl ) Preparation of carbonyl] -piperidine   1-t-butoxycarbonyl-cis-3-methoxycarbonyl-piperidine- 5-carboxylic acid (1.45 g, 5.06 mmol), 3- (4-cyanobenzyl) ) Histamine (1.14 g, 5.06 mmol), HOBT (0.72 g, 5.0). 31 mmol), EDC (1.02 g, 5.31 mmol), Et_ThreeN (0.6 3mL, 4.55mmol) were dissolved in DMF (20mL). This solution Stir overnight, concentrate, and EtOAc (300 mL) and saturated NaHCO_Threesolution (200 mL). The organics are washed with brine, dried (MgS O_Four), Filter, concentrate to dryness and chromatograph (silica gel, 1 ~ 2% MeOH / CHCl_TwoThe title compound was obtained later.¹ H NMR (CDCl_Three): Δ 7.64 (d, 2H, J = 8 Hz), 7.52 (S, 1H), 7, 14 (d, 2H, J = 8 Hz), 6.90 (s, 1H), 6 . 12 (br s, 1H), 5.21 (s, 2H), 4.10-4.33 (m, 2H), 3.69 (s, 3H), 3.32-3.46 (m, 2H), 2.71- 2.92 (m, 2H), 2.54-2.68 (m, 2H), 2.39-2.50 (M, 1H), 2.12-2.28 (m, 2H), 1.78-1.92 (m, 1 H), 1.45 (s, 9H). FAB MS 496 (M + 1) Analysis, C₂₆H₃₃N_FiveO_Five・ 0.3H_TwoCalculated value for O: C, 62.34; H, 6.76; N, 13.98; Found: C, 62.32; H, 6.61; N, 13.89.   1- (t-butoxycarbonyl) piperidine-cis-3,5 used in step D -Dicarboxylic acid methyl ester was prepared as described in Step C 1- ( (t-butoxycarbonyl) piperidine-trans-3,5-dicarboxylate methyl 1- (t-butoxy) according to the method of Steps DF, except replacing with an ester. Carbonyl) -trans-3-methoxycarbonyl-5- [N- (1- (4- Anobenzyl) -1H-imidazo [Ru-5-ylethyl) carbamoyl] -piperidine.                                 Example 2 1-phenethyl-cis-3-methoxycarbonyl-5- [N- (4-cyanoben Preparation of Jil-1-imidazol-5-ylethyl) carbonyl] piperidine Step A:Cis-3-methoxycarbonyl-5- [N- (1- (4-cyanobenzy) L) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine   1- (t-butoxycarbonyl) -cis-3-methoxycarbonyl-5- [N -(1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) cal Bamoyl] piperidine (1.14 g, 2.30 mmol) in CH_TwoCl_Two(12 mL). Trifluoroacetic acid (6 mL) was added and the solution was allowed to reach ambient temperature. And stirred for 3 hours. The solution was concentrated to dryness to give the title compound. Step B:1-phenethyl-cis-3-methoxycarbonyl-5- [N- (1- ( 4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl Preparation of piperidine   Cis-3-methoxycarbonyl-5- [N- (1- (4-si Anobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperi Gin (59.0 mg, 0.149 mmol) was dissolved in MeOH (2 mL). Was. Phenylacetaldehyde (52.3 uL, 0.447 mmol) was added. Followed by sodium cyanoborohydride (28.1 mg, 0.447 mmol) Was added. The solution was stirred overnight at ambient temperature. The MeOH was removed under reduced pressure and Chromatography (silica gel, 1-2% MeOH / CH_TwoCl_Two/ NH_FourOH) Gave the title compound as a white solid.¹ H NMR (CDCl_Three): Δ 7.62 (d, 2H, J = 8 Hz), 7.50 (S, 1H), 7.08-7.37 (m, 7H), 6.88 (s, 1H), 6. 46 (br s, 1H), 5.22 (s, 2H), 3.64 (s, 3H), 27-3.19 (m, 1H), 3.03-3.20 (m, 1H), 2.86-3 . 00 (m, 1H), 2.73-2.85 (m, 3H), 2.44-2.70 ( m, 5H), 2.26-2.41 (m, 2H), 1.98-2.10 (m, 2H) ), 1.80-1.95 (m, 1H). FAB MS 500 (M + 1)   Substitute phenylacetaldehyde with the required aldehyde in step B The following compounds were prepared using the method described in Example 2, except for .1- (1-naphthylmethyl) -cis-3-methoxycarbonyl-5- [N- (1 -(4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoy Le] piperidine FAB MS 536 (M + 1)1-benzyl-cis-3-methoxycarbonyl-5- [N- (1- (4-cyano Benzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine FAB MS 486 (M + 1)1-methyl-cis-3-methoxycarbonyl-5- [N- (1- (4-cyanobe Ndyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine FAB MS 410 (M + 1)1- (2-Indanyl) -cis-3-methoxycarbonyl-5- [N- (1- ( 4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl Piperidine FAB MS 512 (M + 1) Analysis, C₃₀H₃₃N_FiveO_Three・ 0.15H_TwoO-0.5CHCl_Three Calculated value for: C, 63.82; H, 5.94; N, 12.20; Found: C, 63.83; H, 5.95; N, 12.16.1- (2,2-diphenylethyl) -cis-3-methoxycarbonyl-5- [N -(1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) cal Bamoyl] piperidine FAB MS 576 (M + 1) Analysis, C₃₅H₃₇N_FiveO_Three・ 0.9H_TwoCalculated value for O: C, 71.02; H, 6.61; N, 11.83; Found: C, 71.08; H, 6.35; N, 11.71.   Hexane / 0.2% DEA: 1-propanol, eluted with 55:45, Kira Dialysis of this compound on a Chiralcel OD HPLC column The following materials were obtained by separation of the teleomers.1- (2,2-diphenylethyl) -cis-3 (S) -methoxycarbonyl-5 -(R)-[N- (1- (4-cyanobenzyl) -1H-imidazole-5-i Ruethyl) carbamoyl] piperidine FAB MS 576 (M + 1) Analysis, C₃₅H₃₇N_FiveO_Three・ 0.9H_TwoCalculated value for O: C, 71.02; H, 6.61; N, 11.83; Found: C, 71.08; H, 6.35; N, 11.71.1- (2,2-diphenylethyl) -cis-3- (R) -methoxycarbonyl- 5- (S)-[N- (1- (4-cyanobenzyl) -1H-imidazole-5- Ilethyl) carbamoyl] piperidine FAB MS 576 (M + 1) Analysis, C₃₅H₃₇N_FiveO_Three・ 0.9H_TwoCalculated value for O: C, 71.02; H, 6.61; N, 11.83; Found: C, 71.08; H, 6.35; N, 11.71.1- (3-phenylpropyl) -cis-3-methoxycarbonyl-5- [N- ( 1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamo Il] piperidine FAB MS 514 (M + 1) Analysis, C₃₀H₃₅N_FiveO_Three・ 0.8H_TwoCalculated value for O: C, 68.24; H, 6.99; N, 13.26; Found: C, 68.20; H, 6.69; N, 13.14.1- (2-methylpropyl) -cis-3-methoxycarbonyl-5- [N- (1 -(4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoy Le] piperidine FAB MS 452 (M + 1) Analysis, C_{twenty five}H₃₃N_FiveO_Three・ 0.75H_TwoCalculated value for O: C, 64.57; H, 7.48; N, 15.06; Found: C, 64.61; H, 7.19; N, 14.68.                                 Example 3 1-phenethyl-cis-3-carboxy-5- [N- (1- (4-cyanobenzy L) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine   1-phenethyl-cis-3-methoxycarbonyl-5- [N- (1- (4-cy Anobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperi Gin (43.1 mg, 0.086 mmol) in THF (4 mL) and H_TwoO ( 1 mL). LiOH ・ H_TwoO 1N solution (86.2 uL, 0.08 6 mmol) was added and the solution was stirred overnight at ambient temperature. This solution is WATERS PrepPak column (CH_ThreeCN 0.1% TFA in: H_TwoPurification with 0.1% TFA in O, 5: 95-95: 5 gradient) afforded the title compound. Obtained.¹ H NMR (CD_ThreeOD): δ 8.72 (s, 1H), 7.78 (d, 2H, J = 8 Hz), 7.43 (d, 2H, J = 8 Hz), 7.20-7.40 (m, 6H), 5.55 (s, 2H), 3.75 (d, 1H, J = 11 Hz), 3.5 8 (d, 1H, J = 11 Hz), 3.30-3.46 (m, 3H), 2.83- 3.16 (m, 6H), 2.77 (t, 2H, J = 7 Hz), 2.30 (d, 1 H, J = 13 Hz), 1.65-1.80 (m, 1H), 1.37 (d, 1H, J = 6 Hz). FAB MS 486 (M + 1)                                 Example 4 1-phenethyl-cis-3- [N- (1-morpholinyl) carbamoyl] -5 [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) Of carbamoyl] piperidine   1-phenethyl-cis-3-carboxy-5- [N- (1- (4-cyanoben Jyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine Titanium salt (55.2 mg, 0.112 mmol), morpholine (11.7 μL, 0.134 mmol), H OOBT (21.9 mg, 0.134 mmol), EDC (25.8 mg, 0.1%). 134 mmol) and Et_ThreeN (14.0 μL, 0.101 mmol) was added to DM Dissolved in F (2 mL). The solution was stirred overnight at ambient temperature. Reduce this solution Concentrate under pressure and chromatograph the residue (silica gel, 1-3% MeOH / N H_FourOH-containing CH_TwoCl_Two) To give the title compound.¹ H NMR (CDCl_Three): Δ 7.63 (d, 2H, J = 8 Hz), 7.52 (S, 1H), 7.06-7.33 (m, 7H), 6.90 (s, 1H), 5. 89 (br s, 1H), 5.21 (s, 2H), 3.55-3.76 (m, 6 H), 3.43-3.53 (m, 2H), 3.28-3.40 (m, 2H), 3 . 09 (d, 1H, J = 11 Hz), 2.91 (d, 1H, J = 11 Hz), 2 . 71-2.86 (m, 3H), 2.53-2.70 (m, 4H), 2.36- 2.46 (m, 1H), 2.25 (t, 1H, J = 11 Hz), 2.15 (t, 1H, J = 11 Hz), 2.71-2.93 (m, 2H). FAB MS 55 5 (M + 1) Analysis, C₃₂H₃₈N₆O_Three・ 0.30H_TwoO0.30CHCl_ThreeCalculated value for: C, 65.10; H, 6.58; N, 14.10; Found: C, 65.16; H, 6.59; N, 13.86.   The following compounds were prepared using the methods described in Examples 2 and 4.1-phenethyl-cis-3- [N- (benzyl) carbamoyl-5- [N- (1 -(4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoy Le] piperidine FAB MS 575 (M + 1) Analysis, C₃₅H₃₈N₆O_Two・ 0.2H_TwoO0.35CH_TwoCl_TwoCalculated value for: C, 69.83; H, 6.48; N, 13.82; Found: C, 69.82; H, 6.46; N, 13.53.1-phenethyl-cis-3- [N- (cyclopropyl) carbamoyl] -5- [ N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) ca Lubamoyl] piperidine FAB MS 524 (M + 1) Analysis, C₃₁H₃₆N₆O_Two・ 0.5H_TwoO. 0.25 EtOAc Calculated value for: C, 69.17; H, 7.07; N, 15.12; Found: C, 69.22; H, 6.86; N, 15.12.1-phenethyl-cis-3- [N- (t-butyl) carbamoyl] -5- [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carba Moyl] piperidine FAB MS 541 (M + 1) Analysis, C₃₂H₄₀N₆O_Two・ 0.2H_TwoO ・ 0.25CH_TwoCl_TwoCalculated value for: C, 68.49; H, 7.29; N, 14.86; Found: C, 68.48; H, 7.27; N, 14.51.1- (2,2-diphenylethyl) -cis-3- [N- (t-butyl) carbamo Yl] -5- [N- (1- (4-cyanobenzyl) -1H-imidazole-5- Ilethyl) carbamoyl] piperidine FAB MS 617 (M + 1) Analysis, C₃₈H₄₄N₆O_Two・ 1.05H_TwoCalculated value for O: C, 71.80; H, 7.31; N, 13.22; Found: C, 71.76; H, 7.34; N, 12.83.1- (2,2-diphenylethyl) -cis-3- [N- (1-morpholinyl) ca Rubamoyl] -5- [N- (1- (4-cyanobenzyl) -1H-imidazole -5-ylethyl) carbamoyl] piperidine FAB MS 631 (M + 1) Analysis, C₃₈H₄₂N₆O_Three・ 0.4H_TwoCalculated value for O.0.4 EtOAc: C, 70.65; H, 6.89; N, 12.48; Found: C, 70.63; H, 6.63; N, 12.46.   Chiral cell eluting with hexane / 0.1% DEA: ethanol, 55:45 Separation of diastereomers of this compound on an OD HPLC column gave The substance described above was obtained.1- (2,2-diphenylethyl) -cis-3- (R)-[N- (1-morpholine Nil) carbamoyl] -5- (S)-[N- (1- (4-cyanobenzyl) -1 H-Imidazol-5-ylethyl) carbamoyl] piperidine FAB MS 576 (M + 1) Analysis, C₃₅H₃₇N_FiveO_Three・ 0.9H_TwoCalculated value for O: C, 71.02; H, 6.61; N, 11.83; Found: C, 71.08; H, 6.35; N, 11.71.1- (2,2-diphenylethyl) -cis-3- (S)-[N- (1-morpholine Nil) carbamoyl] -5- (R)-[N- (1- (4-cyanobenzyl) -1 H-Imidazol-5-ylethyl) carbamoyl] piperidine FAB MS 576 (M + 1) Analysis, C₃₅H₃₇N_FiveO_Three・ 0.9H_TwoCalculated value for O: C, 71.02; H, 6.61; N, 11.83; Found: C, 71.08; H, 6.35; N, 11.71.                                 Example 5 N- [1-phenethyl-cis-5- (N '-(1- (4-cyanobenzyl) -1 H-Imidazol-5-ylethyl) carbamoyl) piperidine-3-carboni Of methionine methyl ester   1-phenethyl-cis-3-carboxy-5- [N- (1- (4-cyanoben Jyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine Tium salt (90.0 mg, 0.183 mmol), methionine (43.8 mg, 0.219 mmol), HOOBT (35.8 mg, 0.219 mmol) l), EDC (42.1 mg, 0.219 mmol) and Et_ThreeN (60 uL, 0.430 mL) was dissolved in DMF (2 mL). Above solution at ambient temperature Stirred overnight. The solution is concentrated under reduced pressure and the residue is chromatographed (silica Gel, 1-2.5% MeOH / NH_FourOH-containing CH_TwoCl_Two) Process and title compound I got something.¹ H NMR (CDCl_Three): Δ 7.63 (d, 2H, J = 8 Hz), 7.51 (S, 1H), 7.10-7.33 (m, 7H), 6.90 (s, 1H), 6. 50-6.63 (m, 1H), 6.11-6.36 (m, 1H), 5.21 (s , 2H), 4.65-4.75 (m, 1H), 3.75 (s, 3H), 3.25. -3.48 (m, 2H), 2.95-3.11 (m, 2H), 2.73-2.8 3 (m, 2H), 2.53-2.71 (m, 4H), 2.45-2.52 (m, 3H), 2.35-2.44 (m, 1H), 1.93-2.33 (m, 5H), 2.09 (s, 3H), 1.67-1.85 (m, 1H). FAB MS 63 1 (M + 1) Analysis, C₃₄H₄₂N₆O_FourS0.30CH_TwoCl_TwoCalculated value for: C, 62.46; H, 6.52; N, 12.72; Found: C, 62.45; H, 6.53; N, 12.53.                                 Example 6 N- [1-phenethyl-cis-5- (N '-(1- (4-cyanobenzyl-1- Imidazol-5-ylethyl) carbamoyl) piperidine-3-carbonyl] Preparation of methionine   N- [1-phenethyl-cis-5- (N '-(4-cyanobenzyl-1-imi) Dazol-5-ylethyl) carbamoyl) piperidine-3-carbonyl] methyl Onine methyl ester (19 mg, 0.030 mmol) was added to THF (2 mL) and And H_TwoDissolved in O (1 mL). LiOH-H_TwoO 1N solution (30.1 μL, 0.030 mmol) was added and the solution was stirred overnight at ambient temperature. This solution With an RP HPLC VYDAC column (CH_Three0.1% TFA in CN: H_TwoIn O 0.1% TFA, 5: 95-95: 5 gradient), freeze-dried and cisdia The title compound was obtained as a stereomer. Diastereomer A:¹H NMR (CD_ThreeOD): δ 8.99 (s, 1H), 7.80 (d, 2H, J = 8 Hz), 7.51 (s, 1H), 7.47 (d, 2 H, J = 8 Hz), 7. 20-7.37 (m, 5H), 5.61 (s, 2H), 4.26-4.57 (m , 1H), 3.60-3.75 (m, 2H), 3.44-3.55 (m, 1H). , 3.30-3.43 (m, 3H), 2.90-3.15 (m, 6H), 2.7 5-2.85 (m, 2H), 2.48-2.70 (m, 2H), 2.09-2. 28 (m, 2H), 2.09 (s, 3H), 1.90-2.08 (m, 1H), 1.61-1.75 (m, 1H). FAB MS 617 (M + 1) Diastereomer B:¹H NMR (CD_ThreeOD): δ 9.02 (s, 1H), 7.81 (d, 2H, J = 8 Hz), 7.53 (s, 1H), 7.51 (d, 2 H, J = 8 Hz), 7.22-7.39 (m, 5H), 5.62 (s, 2H), 4.29-4.59 (m, 1H), 3.76 (d, 1H, J = 8 Hz), 3.6 8 (d, 1H, J = 10 Hz), 3.33-3.52 (m, 4H), 2.95- 3.20 (m, 6H), 2.79-2, 87 (m, 2H), 2.50-2.68 (M, 2H), 2.05-2.13 (m, 2H), 2.09 (s, 3H), 1. 93-2.08 (m, 1H), 1.70-1.82 (m, 1H). FAB MS = 617 (M + 1)Example 7 1- (t-butoxycarbonyl) -cis-3-methoxycarbonyl-5- [N- (1- (4-cyanobenzyl) -1H-imidazol-5-yl) acetylamido No] Preparation of piperidine Step A:1- (t-butoxycarbonyl) -cis-3-methoxycarbonyl-5 Preparation of-(benzyloxycarbonyl) aminopiperidine   1- (t-butoxycarbonyl) -cis-3-methoxycarbonyl-piperidi -5-carboxylic acid (1.87 g, 6.51 mmol), benzyl alcohol ( 1.68 mL, 16.3 mmol), diphenylphosphoryl azide (1.47 m L, 6.83 mmol) and Et_ThreeN (0.95 mL, 6.83 mmol) Dissolved in toluene (50 mL). The solution was heated at 90 ° C. for 4 hours. this The solution is diluted with EtOAc and saturated NaHCO_ThreeWash with solution, water and saline did. Dry the organics (MgSO 4_Four), Filter and concentrate without further purification. The title compound was obtained. Step B:1- (t-butoxycarbonyl) -cis-3-methoxycarbonyl-5 -Preparation of aminopiperidine   1- (t-butoxycarbonyl) -cis-3-methoxycarbonyl-5- (beta Ndyloxycarbonyl) aminopiperidine (2.55 g, 6.51 mmol) Was dissolved in EtOAc (75 mL) and treated with Pd / C (510 mg). And shaken overnight at 45 psi on a Parr apparatus. The reaction mixture was filtered through celite. Filtered, concentrated and chromatographed (silica gel, 2% MeOH / NH_Four OH-containing CH_TwoCl_Two) To give the title compound. Step C:Preparation of 1H-imidazole-4-acetic acid methyl ester hydrochloride   1H-imidazole-4-acetic acid hydrochloride (4.0 mL) in methanol (100 mL). (0 g, 24.6 mmol) was saturated with gaseous hydrogen chloride. The resulting solution The solution was left at room temperature (RT) for 18 hours. Evaporate the solvent in vacuo to a white solid To give the title compound.¹ H NMR (CDCl_Three, 400 MHz): δ 8.85 (1H, s), 7.4 5 (1H, s), 3.89 (2H, s) and 3.75 (3H, s) ppm. Step D:Methyl 1- (triphenylmethyl) -1H-imidazol-4-ylacetate Preparation of Luster   1H-imidazole-4 in dimethylformamide (DMF) (115 mL) -To a solution of methyl acetate hydrochloride (24.85 g, 0.141 mol) Triethylamine (57.2 mL, 0.412 mol) and triphenylmethylbutane Lomid (55.3 g, 0.171 mol) is added and the suspension is stirred for 24 hours did. After this time, the reaction mixture was washed with ethyl acetate (EtOAc) (1 L) and water ( (350 mL). Organic phase is saturated NaHCO_ThreeWash with aqueous solution (350mL) Clean, dry (Na_TwoSO_Four), Evaporated in vacuo. Flash chromatography of the residue Graphy (SiO_Two, 0-100% ethyl acetate in hexane, gradient elution). Purification afforded the title compound as a white solid.¹ H NMR (CDCl_Three, 400 MHz): δ 7.35 (1H, s), 7.3 1 (9H, m), 7.22 (6H, m), 6.76 (1H, s), 3.68 (3 H, s) and 3.60 (2H, s) ppm. Step E:[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetic acid Preparation of methyl ester   1- (Triphenylmethyl) -1H-imida in acetonitrile (70 mL) Solution of methyl -4-yl acetic acid (8.00 g, 20.9 mmol) To this was added bromo-p-toluonitrile (4.10 g, 20.92 mmol). At 55 ° C. for 3 hours. After this time, the reaction was cooled to room temperature and the resulting The midazolium salt (white precipitate) was collected by filtration. 18 hours at 55 ° C. For a while. The reaction mixture was cooled to room temperature and evaporated in vacuum. To this residue EtOAc (70 mL) was added and the resulting white precipitate was collected by filtration . Combine the precipitated imidazolium salt and suspend in methanol (100 mL). And heated under reflux for 30 minutes. After this time, the solvent was removed in vacuo and the resulting The residue was suspended in EtOAc (75 mL) and the solid was isolated by filtration and washed. Purified (EtOAc). The solid is saturated with NaHCO_ThreeAqueous solution (300 mL) and CH_Two Cl_Two(300 mL) and stirred at room temperature for 2 hours. Separate the organic layer , Dried (MgSO 4)_Four), Evaporated in vacuo to give the title compound as a white solid Was.¹ H NMR (CDCl_Three, 400 MHz): δ 7.65 (1H, d, J = 8H) z), 7.53 (1H, s), 7.15 (1H, d, J = 8 Hz), 7.04 ( 1H, s), 5.24 (2H, s), 3.62 (3H, s) and 3.45 (2H , S) ppm. Step F:[1- (4-cyanobenzyl) -1H-imidazol-5-yl] acetic acid Preparation of   THF (100 mL) and 1 M lithium hydroxide (17.4 mL, 17.4 mm [1- (4-cyanobenzyl) -1H-imidazol-5-yl] vinegar A solution of acid methyl ester (4.44 g, 17.4 mmol) at RT for 18 h Stirred. Add 1M HCl (17.4 mL) and evaporate in vacuo Therefore, THF was removed. The aqueous solution is lyophilized to form a white solid The title compound containing the compound was obtained.¹ H NMR (CD_ThreeOD, 400 MHz): δ 8.22 (1H, s), 7.7 4 (1H, d, J = 8.4 Hz), 7.36 (1H, d, J = 8.4 Hz), 7 . 15 (1H, s), 5.43 (2H, s) and 3.49 (2H, s) ppm. Step G:1- (t-butoxycarbonyl) -cis-3-methoxycarbonyl-5 -[N- (1- (4-cyanobenzyl) -1H-imidazol-5-yl) acetate Preparation of [Cylamino] piperidine   1- (t-butoxycarbonyl) -cis-3-methoxycarbonyl-5-amido Nopiperidine (134 mg, 0.520 mmol), [1- (4-cyanobenzide) Ru) -1H-Imidazol-5-yl] acetic acid (147 mg, 0.520 mmol ), HOBT (73.8 mg, 0.546 mmol), EDC (104 mg, 0 . 546 mmol) and Et_ThreeN (65.2 uL, 0.468 mmol) was added to D Dissolved in MF (4 mL) and stirred overnight at ambient temperature. Concentrate this solution under reduced pressure And the residue is chromatographed (silica gel, 0.5-2% MeOH / NH_FourO H-containing CH_TwoCl_Two) To give the title compound.¹ H NMR (CDCl_Three): Δ 7.64 (d, 2H, J = 8 Hz), 7.52 (S, 1H), 7.19 (d, 2H, J = 8 Hz), 6.90-7.05 (m, 1H), 6.98 (s, 1H), 5.22-5.35 (m, 2H), 3.78- 3.91 (m, 2H), 3.69 (s, 3H), 3,57-3.64 (M, 1H), 3.45-3.56 (m, 1H), 3.34 (s, 2H), 3. 05-3.30 (m, 1H), 2.55-2.68 (m, 1H), 2.05-2 . 13 (m, 1H), 1.55-1.70 (m, 1H), 1.42 (s, 9H) . FAB MS 482 (M + 1) Analysis, C_{twenty five}H₃₁N_FiveO_Five・ 0.90H_TwoCalculated value for O: C, 60.32; H, 6.64; N, 14.07; Found: C, 60.38; H, 6.36; N, 13.78.                                 Example 8 1-phenethyl-cis-3-methoxycarbonyl-5- [N- (1- (4-sia Nobenzyl) -1H-imidazol-5-yl) acetylamino] piperidine Preparation Step A:Cis-3-methoxycarbonyl-5- [N- (1- (4-cyanobenzy) Preparation of l) -1H-Imidazol-5-yl) acetylamino] piperidine   1- (t-butoxycarbonyl) -3-methoxycarbonyl-5- [N- (1 -(4-cyanobenzyl) -1H-imidazol-5-yl) acetylamino] Piperidine (44.6 mg, 0.093 mmol) was added to CH_TwoCl_Two(6mL) in Dissolved in Was. Trifluoroacetic acid (3 mL) was added and the solution was stirred at ambient temperature for 4 hours. Was. The solution was concentrated under reduced pressure to give the title compound without further purification. Step B:1-phenethyl-cis-3-methoxycarbonyl-5- [N- (1- ( 4-cyanobenzyl) -1H-imidazol-5-yl) acetylamino] pipe Preparation of lysine   Cis-3-methoxycarbonyl-5- [N- (1- (4-cyanobenzyl)- 1H-Imidazol-5-yl) acetylamino] piperidine (35.3 mg, 0.093 mmol), benzaldehyde (32.5 uL, 0.278 mmol) ) And sodium cyanoborohydride (17.5 mg, 0.278 mmol) in M Dissolved in MeOH (2 mL) and stirred at ambient temperature overnight. The solution is concentrated under reduced pressure. Chromatography (silica gel, 0.5-2% MeOH / NH_FourOH included Yes CH_TwoCl_Two) To give the title compound.¹ H NMR (CDCl_Three): Δ 7.62 (d, 2H, J = 8 Hz), 7.52 (S, 1H), 7.11-7.31 (m, 7H), 6.99 (s, 1H), 6. 25 (br s, 1H), 5.24 (s, 2H), 3.86-3.96 (m, 1 H), 3. 65 (s, 3H), 3.29 (s, 2H), 2.48-2.83 (m, 8H), 2.13-2.24 (m, 1H), 1.83-1.95 (m, 1H), 1.50 -1.65 (m, 1H). FAB MS 486 (M + 1) Analysis, C₂₈H₃₁N_FiveO_Three・ 0.30H_TwoO ・ 0.25CHCl_ThreeCalculated value for: C, 65.15; H, 6.16; N, 13.45; Found: C, 65.18; H, 6.15; N, 13.46.   In Example 7, Step A, 1- (t-butoxycarbonyl) -cis-3-methoxy Rubonyl piperidine-5-carboxylic acid is converted to 1- (t-butoxycarbonyl-piper Gin-3 (S) -carboxylic acid and in Example 8, Step B, phenyla Example 7 and Example 7 except that cetaldehyde was replaced with diphenylacetaldehyde. The following compounds were prepared using the methods described in paragraphs 8 and 8. 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Zyl) -1H-imidazol-5-ylacetyl) amino] piperidine Analysis, C₃₂H₃₃N_FiveO0.30H_TwoCalculated value for O: C, 75.50; H, 6.65; N, 13.62; Found: C, 75.51; H, 6.79; N, 13.76. FAB MS (M + 1) 504   In Example 7, Step C, 1H-imidazole-4-acetic acid was replaced with 1H-imidazole-4. -Using the method described for Examples 7 and 8, but replacing with propionic acid. The following compounds were prepared.1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Jil) -1H-Imidazol-5-ylpropionyl) amino] piperidine Analysis, C₃₃H₃₅N_FiveO ・ 0.55H_TwoCalculated value for O: C, 75.13; H, 6.90; N, 13.72; Found: C, 75.15; H, 6.89; N, 13.40. FAB MS (M + 1) 518   In Example 7, Step C, 1H-imidazole-4-acetic acid was replaced with 1H-imidazole-4. Using the method described for Examples 7 and 8, but replacing with carboxylic acid Thus, the following compound was prepared.1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Zyl) -1H-imidazol-5-ylcarbonyl) amino] piperidine FAB MS (M + 1) 490                                 Example 9 1- (diphenylacetyl) -cis-3-methoxycarbonyl-5- [N- (1 -(4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoy Preparation of piperidine   Cis-3-methoxycarbonyl-5- [N- (1- (4-cyanobenzyl)- 1H-Imidazol-5-ylethyl) carbamoyl] piperidine (86.8m g, 0.219 mmol) (Example 2, Step A), diphenylacetic acid (302 mg) , 1.42 mmol), HOOBT (54.3 mg, 0.328 mmol), E DC (63 mg, 0.328 mmol) and Et_ThreeN (392 uL, 5.34 m mol) was dissolved in DMF (4 mL) and stirred at ambient temperature for 5 days. This solution Concentrate the liquid and take the residue up in EtOAc and add saturated NaHCO_ThreeSolutions, water and saline And washed. Dry the organics (MgSO 4_Four), Concentrate and chromatograph Lycagel, 0.5-2% MeOH / NH_FourO H-containing CH_TwoCl_Two) To give the title compound. FAB MS = 590 (M + 1) Analysis, C₃₅H₃₅N_FiveO_Four・ 0.35CHCl_Three・ 0.20H_TwoCalculated value for O: C, 66.86; H, 5.67; N, 11.03; Found: C, 66.86; H, 5.67; N, 11.01.   3 (S)-[N- (1- (4-cyanobenzyl) -1H-imid Dazol-5-ylethyl) carbamoyl] piperidine (Example 11, Step E) And preparing the following compound using the above procedure except replacing with the required acid did.1- (phenylacetyl) -3 (S)-[N- (1- (4-cyanobenzyl)- 1H-Imidazol-5-ylethyl) carbamoyl] piperidine FAB MS (M + 1) 4561- (diphenylacetyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₃₃H₃₃N_FiveO_Two・ 0.45CH_TwoCl_Two・ 0.10H_TwoCalculated value for O : C, 70.28; H, 6.01; N, 12.25; Found: C, 70.24; H, 5.91; N, 12.09.1- (3-chlorobenzoyl) -3 (S)-[N- (1- (4-cyanobenzyl) ) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₂₆H₂₆N_FiveO_TwoCalculated value for Cl: C, 64.03; H, 5.64; N, 14.36; Found: C, 64.09; H, 5.39; N, 14.12. FAB MS (M + 1) 476                                Example 10 1- (2,2-diphenylethyl) -3- [N- (1- (4-cyanobenzyl) 1H-Imidazol-5-ylethyl) carbamoyl] piperidine Step A:Preparation of 1- (2,2-diphenylethyl) -3-carboxypiperidine   Nipecotic acid (300 mg, 2.38 mmol), diphenylacetoaldehyde (1.26 mL, 7.13 mmol), sodium cyanoborohydride (448 mg, 7.13 mmol) and HOAc (204 uL, 3.57 mmol) MeOH (20 mL) and stirred overnight at ambient temperature. The solution is concentrated under reduced pressure , Ether and 1N NaOH, extracted with ether (3 ×), and the aqueous layer Acidified with N HCl and extracted with EtOAc (3 ×). EtOAc layer Dry (MgSO 4_Four), And concentrated to give the title compound without further purification. Step B:1- (2,2-diphenylethyl) -3- [N- (1- (4-cyanobe) Undyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine Preparation   1- (2,2-diphenylethyl) -3-carboxypiperidine (472 mg , 1.52 mmol), 3- (4-cyanobenzyl) histamine (456 mg, 1.52 mmol) (Example 1, Step E), HOBT (216 mg, 1.60 m) mol), EDC (307 mg, 1.60 mmol) and Et_ThreeN (637uL , 4.57 mmol) in DMF (10 mL) and stirred overnight at ambient temperature did. The solution is concentrated under reduced pressure and chromatographed (silica gel, 0.5-0.5%). 2% MeOH / NH_FourOH-containing CH_TwoCl_Two) To give the title compound.¹ H NMR (CDCl_Three): Δ 7.96 (brs, 1H), 7.60 d, 2H, J = 8 Hz), 7.46 (s, 1H), 7.09-7.3 7 (m, 12H), 6, 74 (s, 1H), 5.20 (s, 2H), 4.26 ( t, 1H, J = 8 Hz), 3.05-3.17 (m, 2H), 2.93-3.0 4 (m, 1H), 2.78-2.91 (m, 2H), 2.49-2, 61 (m, 1H), 22.40-2.47 (m, 1H), 2.15-2.30 (m, 2H). , 1.95-2.14 (m, 2H), 1.86 (d, 1H, J = 12 Hz), 1 . 29-1.55 (m, 3H). FAB MS 518 (M + 1) Analysis, C₃₃H₃₅N_FiveO₁・ 0.35CHCl_Three・ 0.10H_TwoCalculated value for O: C, 71.37; H, 6.38; N, 12.48; Found: C, 71.41; H, 6.32; N, 12.36.                                Example 11 1- (2- (3-chlorophenyl) -2-phenylethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carba Of Moyl] piperidine Step A:Preparation of S-(-)-ethyl nipecotate   Racemic ethyl nipecotate (122.5 g, 0.78 mo l), The method described by Magnus et al. (J. Org. m. 95% EtOH (1991, 56, 1166-1170). 611 mL) with D-tartaric acid (117 g, 0.78 mol) Thus, ethyl S-(-)-nipecotate was obtained. Step B:Ethyl 1- (t-butoxycarbonyl) piperidine-3 (S) -cal Preparation of boxylate   Ethyl S-(-)-nipecotate (20.0 g, 0.127 mol) was added to TH F (250mL) -H_TwoO (250 mL) at ambient temperature, NaHCO_Three( 32.0 g, 0.381 mol) and di-tert-butyl dicarbonate (43.8 m L, 0.190 mol). After stirring for 16 hours, the reaction mixture was concentrated The THF was removed and extracted with EtOAc (2 × 200 mL). Organic matter Combine, wash with brine, dry (MgSO 4)_Four), Filter, concentrate and title Compound was obtained. Step C:1- (tert-butoxycarbonyl) piperidine-3 (S) -carbo Preparation of acid   Ethyl 1- (t-butoxycarbonyl) piperidine-3 (S) -carboxy Rate (35.9 g, 0.099 mol) Was dissolved in anhydrous EtOH (70 mL) and 0.5N NaOH (418 mL, 0.209 mol) and heated at reflux for 0.75 hours. This reaction mixture Was cooled and extracted with EtOAc. Cool the aqueous basic layer with ice and add 3N HCl Carefully acidify (pH 3), CH_TwoCl_Two(3 × 100 mL). Organic Combine and dry (MgSO 4)_Four), Filtered and concentrated to give the title compound. Step D:1- (tert-butyloxycarbonyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl Preparation of piperidine   1- (tert-butoxycarbonyl) piperidine-3 (S) -carboxylic acid ( 5.06 g, 0.022 mol) and 3- (4-cyanobenzyl) histamine ( Example 1, Step E) (6.6 g, 0.022 mol) was added at ambient temperature to DMF (3 0 mL), EDC (5.07 g, 0.026 mol), HOBT (3 . 58 g, 0.26 mol) and N-methylmorpholine (12.12 mL, 0.1 g). 11 mol). After stirring for 18 hours, the reaction mixture was washed with EtOAc ( 500 mL)-saturated NaHCO_ThreePartition between aqueous solutions, separate the organic layer and add saturated N a HCO_ThreeSolution, H_TwoO, washed with brine, dried (MgSO_Four), Filter and concentrate This provided the title compound, which was used without further purification. Step E:3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazole -5-Ethyl) carbamoyl] piperidine dihydrochloride   1- (tert-butyloxycarbonyl) -3 (S)-[N- (1- (4- Cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] pipe Lysine (9.25 g, 0.021 mol) was stirred in an ice-water bath at 0 ° C. Dissolved in EtOAc (500 mL). HCl gas through this solution for 5 minutes Bubble, stopper the flask and stir the solution for 1 hour. This solution is_Twoso Purge and then concentrate to dryness to give the title compound.¹ H NMR (CD_ThreeOD): δ 9.02 (s, 1H), 7.80 (d, 2H, J = 8 Hz), 7.52 (s, 1H), 7.48 (d, 2H, J = 8 Hz), 5 . 62 (s, 2H), 3.42 (td, 2H, J = 3.7 Hz), 3.00-3 . 26 (m, 4H), 2.80 (t, 2H, J = 7 Hz), 2.67-2. 78 (m, 1H), 1.65-2.0 (m, 4H). FAB MS 338 (M +1) Step F:Preparation of 2- (3-chlorophenyl) -2-phenyloxirane   In a 250 mL round bottom flask, NaH (60% dispersion in mineral oil) (1.92 g, 0 . 048 mol), washed with petroleum ether and then N 2_TwoDry DMSO under (40 mL). To this reaction mixture is added trimethylsulfoxonium iodide. (10.56 g, 0.048 mol) through a solid addition funnel over 15 minutes. Was added. After stirring for 0.5 h, 3-chlorobenz in DMSO (15 mL) A solution of zophenone (8.66 g, 0.04 mol) was added dropwise and the mixture was added. Was heated at 55 ° C. for 2 hours. The mixture was added to ice-water and ether (3 × 10 0 mL), combine the organics, dry (MgSO 4)_Four), Filter and concentrate To give the title compound. Step G:Preparation of 2- (3-chlorophenyl) -2-phenylcarboxaldehyde Made   2- (3-chlorophenyl) -2-phenyloxirane (10.19 g, 0.1. 04 mol) in dry benzene (250 mL) Dissolved in BF_ThreeTreated with etherate (0.2 mL) And stirred at ambient temperature for 1 hour. Benzene, the aqueous layer is no longer acidic Until H_TwoO, then concentrated to dryness and chromatographed (Si O_TwoThe title compound was obtained after (5% EtOAc / hexane).¹H NMR (CDC l_Three): Δ 9.95 (s, 1H), 7.1-7.5 (m, 9H), 4.85 ( s, 1H). Step H:1- (2- (3-chlorophenyl) -2-phenylethyl) -3 (S) -[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl ) Preparation of carbamoyl] piperidine   3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazole-5 Ilethyl) carbamoyl] piperidine dihydrochloride (0.256 g, 0.623 m mol) was dissolved in MeOH (10 mL) and Et._ThreeAdjust pH to 5 with N And 2- (3-chlorophenyl) -2-phenylcarboxaldehyde ( 0.427 g, 1.87 mmol) and NaCNBH_Three(0.078 g, 1.2 5 mmol) was added. After stirring at ambient temperature for 18 hours, the reaction mixture is tOAc and saturation NaHCO_ThreePartitioned between the solutions, the organic layer was separated and H 2_TwoO, washed with saline solution and dried (MgSO_Four), Filter and concentrate to dryness, 3% MeOH / NH_FourOH included Yes CH_TwoCl_TwoEluted with SiO_TwoThe title compound was obtained after the above chromatography .¹ H NMR (CD_ThreeOD): δ 7.88 (brs, 1H), 7.60 (d, 2H, J = 8 Hz), 7.47 (s, 1H), 7.07-7.36 (m, 11H ), 6.76 (d, 1H, J = 2.7 Hz), 5.21 (s, 2H), 4.24 (Td, 1H, J = 2.8 Hz), 2.80-3.13 (m, 5H), 2.50 -2.65 (m, 1H), 2.44 (s, 1H), 2.0-2.3 (m, 4H) , 1.86 (d, 1H, J = 12 Hz), 1.3-1.55 (m, 3H). FA B MS 552 (M + 1) Analysis, C₃₃H₃₄N_FiveOCl.0.40H_TwoCalculated value for O: C, 70.87; H, 6.27; N, 12.52; Found: C, 70.84; H, 6.31; N, 12.39.   Using the method described above, but replacing the required ketone in Step F, The following compounds were prepared.1- (dibenzylsuberylmethyl) -3 (S)-[N- (1- (4-cyanoben) Jil) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₃₅H₃₇N_FiveO ・ 0.45H_TwoCalculated value for O: C, 76.18; H, 6.92; N, 12.69; Found: C, 76.15; H, 6.84; N, 12.49.1- (2- (3-methylphenyl) -2-phenylethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carba Moyl] piperidine Analysis, C₃₄H₃₇N_FiveO ・ 0.40H_TwoCalculated value for O: C, 75.78; H, 7.07; N, 13.00; Found: C, 75.81; H, 7.01; N, 13.20.1- (2- (3-trifluoromethylphenyl) -2-phenylethyl) -3 ( S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylue Tyl) carbamoyl] piperidine Analysis, C₃₄H₃₄N_FiveOF_Three・ 0.20H_TwoCalculated value for O: C, 69.30; H, 5.88; N, 11.88; Found: C, 69.32; H, 5.84; N, 12.04.1- (2- (2-chlorophenyl) -2-phenylethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carba Moyl] piperidine Analysis, C₃₃H₃₄N_FiveOCl 0.50H_TwoCalculated value for O: C, 70.64; H, 6.29; N, 12.48; Found: C, 70.67; H, 6.16; N, 12.50.1- (2- (4-chlorophenyl) -2-phenylethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carba Moyl] piperidine Analysis, C₃₃H₃₄N_FiveCalculated value for OCl: C, 70.98; H, 6.26; N, 12.54; Found: C, 71.02; H, 6.22; N, 12.40.1- (2- (3-aminomethylphenyl) -2-phenylethyl) -3 (S)- [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) Carbamoyl] piperidine Analysis, C₃₄H₃₈N₆O ・ 4.25CF_ThreeCO_TwoH ・ 0.45H_TwoCalculated value for O : C, 49.11; H, 4.18; N, 8.09; Found: C, 49.11; H, 4.16; N, 8.15.   2- (3-chlorophenyl) -2-phenylcarboxyalde in Step H Using the method described above, but replacing the hide with a commercially available aldehyde, A compound was prepared.1- (2-phenethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1 H-Imidazol-5-ylethyl) carbamoyl] piperidine FAB MS (M + 1) 4421- (2-phenethyl) -3 (R)-[N- (1- (4-cyanobenzyl) -1 H-Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₂₇H₃₁N_FiveO ・ 2.0HCl ・ 1.60H_TwoCalculated value for O: C, 59.69; H, 6.72; N, 12.89; Found: C, 59.72; H, 7.18; N, 11.91. FAB MS (M + 1) 4421- (3-phenylpropyl) -3 (S)-[N- (1- (4-cyanobenzyl) ) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₂₈H₃₃N_FiveO ・ 2.75CF_ThreeCO_TwoH · 0.75 H_TwoCalculated value for O: C, 51.14; H, 4.80; N, 8.95; Found: C, 51.42; H, 4.78; N, 9.00. FAB MS (M + 1) 4561- (2-benzyl) -3- [N- (1- (4-cyanobenzyl) -1H-imi Dazol-5-ylethyl) carbamoyl] piperidine Analysis, C₂₆H₂₉N_FiveO ・ 2.80CF_ThreeCO_TwoH ・ 0.70H_TwoCalculated value for O : C, 49.98; H, 4.41; N, 9.22; Found: C, 49.98; H, 4.39; N, 9.67. FAB MS (M + 1) 4281- (2-chlorobenzyl) -3- [N- (1- (4-cyanobenzyl) -1H -Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₂₆H₂₈N_FiveOCl 3.25CF_ThreeCO_TwoH ・ 0.50H_TwoTotal for O Arithmetic: C, 46.38; H, 3.86; N, 8.32; Found: C, 46.39; H, 3.82; N, 8.54. FAB MS (M + 1) 4621- (3-chlorobenzyl) -3- [N- (1- (4-cyanobenzyl) -1H -Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₂₆H₂₈N_FiveOCl ・ 2.75CF_ThreeCO_TwoH ・ 0.40H_TwoTotal for O Arithmetic: C, 48.33; H, 4.06; N, 8.95; Found: C, 48.30; H, 4.06; N, 9.16. FAB MS (M + 1) 4621- (3-chlorobenzyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₂₆H₂₈N_FiveOCL 0.45H_TwoCalculated value for O: C, 66.43; H, 6.20; N, 14.90; Found: C, 66.43; H, 6.07; N, 14.97.1- (2,2-diphenyl-2-hydroxyethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl ] Piperidine Analysis, C₃₃H₃₅N_FiveO_Two・ 0.25H_TwoCalculated value for O: C, 73.65; H, 6.65; N, 13.01; Found: C, 73.69; H, 6.79; N, 12.84. FAB MS (M + 1) 5341- (3-methoxybenzyl) -3 (S)-[N- (1- (4-cyanobenzyl) ) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine FAB MS (M + 1) 4581- (3,5-dichlorobenzyl) -3 (S)-[N- (1- (4-cyanoben) Jil) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₂₆H₂₇N_FiveOCI_Two・ 0.40H_TwoCalculated value for O: C, 62.01; H, 5.56; N, 13.91; Found: C, 61.98; H, 5.55; N, 13.57.1- (3-trifluoromethoxybenzyl) -3 (S)-[N- (1- (4-si Anobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperi gin Analysis, C₂₇H₂₈N_FiveO_TwoF_Three・ 2.0HCl ・ 1.85H_TwoCalculated value for O: C, 52.49; H, 5.50; N, 11.34; Found: C, 52.50; H, 5.72; N, 11.34.1- (2,5-dimethylbenzyl) -3 (S)-[N- (1- (4-cyanoben) Jil) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₂₈H₃₃₈N_FiveO ・ 0.40H_TwoCalculated value for O: C, 72.67; H, 7.36; N, 15.13; Found: C, 72.67; H, 7.27; N, 14.77.1- (3-trifluoromethylbenzyl) -3 (S)-[N- (1- (4-sia Nobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidi N Analysis, C₂₇H₂₈N_FiveOF_Three・ 0.15H_TwoCalculated value for O: C, 65.09; H, 5.73; N, 14.06; Found: C, 65.14; H, 5.83; N, 14.01.1- (3-bromobenzyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₂₆H₂₈N_FiveOBr ・ 2.0HCl ・ 1.0H_TwoCalculated value for O: C, 52.28; H, 5.40; N, 11.72; Found: C, 52.33; H, 5.51; N, 11.26.1- (3-methylbenzyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₂₇H₃₁N_FiveO ・ 2.0HCl ・ 1.30H_TwoCalculated value for O: C, 60.54; H, 6.70; N, 13.07; Found: C, 60.58; H, 6.68; N, 12.22.1-isobutyl-3 (S)-[N- (1- (4-cyanobenzyl) -1H-imi Dazol-5-ylethyl) carbamoyl] piperidine Analysis, C_{twenty three}H₃₁N_FiveO · 2.3HCl-0.95H_TwoCalculated value for O: C, 55.87; H, 7.17; N, 14.16; Found: C, 55.91; H, 7.38; N, 14.01. FAB MS (M + 1) 3941- (2-methyl-2-phenylethyl) -3- [N- (1- (4-cyanoben) (Jill) -1H-imidazol-5-ylethyl Ru) carbamoyl] piperidine Analysis, C₃₄H₃₇N_FiveO ・ 0.40H_TwoCalculated value for O: C, 75.78; H, 7.07; N, 13.00; Found: C, 75.81; H, 7.01; N, 13.20. FAB MS (M + 1) 532   In Step H, 1-morpholinyl-α-phenylacetaldehyde or 1-morpholinyl-α-phenylacetaldehyde Piperidinyl-α-phenylacetaldehyde (L. Duhamel, P. Du Hamel, P .; Siret,Bull Soc. Chim. Fr., [7-8 ], Pp. 2460-2466 (1973). The following compounds were prepared using the method described above, but replacing1- (2- (1-morpholinyl) -2-phenylethyl) -3 (S)-[N- ( 1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamo Yl] piperidine-diastereomer A Analysis, C₃₁H₃₈N₆O_Two・ 0.80H_TwoCalculated value for O.0.25 EtOAc : C, 68.25; H, 7.45; N, 14.92; Found: C, 68.27; H, 7.13; N, 14.92.1- (2- (1-morpholinyl) -2-phenylethyl) -3 (S)-[N- ( 1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamo Yl] piperidine-diastereomer B Analysis, C₃₁H₃₈N₆O_Two・ 0.65H_TwoCalculated value for O: C, 69.16; H, 7.36; N, 15.61; Found: C, 69.15; H, 7.31; N, 15.48.1- (2- (1-piperidinyl) -2-phenylethyl) -3 (S)-[N- ( 1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamo Il] piperidine FAB MS (M + 1) 525   Except that the starting material in Example 1, Step E was replaced with 2-methylhistamine The following compounds were prepared using the methods described in Examples 11 and 1.1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Zyl) -2-methyl-1H-imidazol-5-ylethyl) carbamoyl] pi Peridine Analysis, C₃₄H₃₇N_FiveO ・ 0.45H_TwoCalculated value for O: C, 75.65; H, 7.08; N, 12.97; Found: C, 75.65; H, 6.93; N, 12.68.   The 4-cyanobenzyl bromide in Example 1, Step E was Using the method described in Examples 11 and 1, except replacing with Rubromide, The following compounds were prepared.1- (2,2-diphenylethyl) -3 (S) -N- (1- (4-methoxybenz) Jil) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₃₃H₃₈N_FourO_Two・ 2.0HCl ・ 1.40H_TwoCalculated value for O: C, 63.84; H, 6.95; N, 9.02; Found: C, 63.91; H, 7.33; N, 9.45.                                Example 12 1- (diphenylmethyl) -3 (S)-[N- (1- (4-cyanobenzyl)- Preparation of 1H-Imidazol-5-ylethyl) carbamoyl] piperidine   3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazole-5 Ilethyl) carbamoyl] piperidine dihydrochloride (Example 11, Step E) (0. 203g, 0.494mm ol) was dissolved in DMF (10 mL) and K_TwoCO_Three(0.503 g, 1.97 6 mmol) and bromodiphenylmethane (0.134 g, 0.543 mmol) ) And stirred at ambient temperature for 48 hours. The reaction mixture was concentrated and extracted with EtOA c in saturated NaHCO_ThreeAqueous solution, H_TwoO, washed with brine, dried (Mg SO_Four), Filter and concentrate to 0-3% MeOH: NH_FourOH-containing CH_TwoCl_TwoDissolved in Release SiO_TwoThe title compound was obtained after chromatography. Analysis, C₃₂H₃₃N_FiveO 0.75H_TwoCalculated value for O: C, 74.31; H, 6.72; N, 13.54; Found: C, 74.37; H, 6.48; N, 13.37. FAB MS (M + 1) 504   Except that bromodiphenylmethane was replaced with the required bromide or mesylate The following compounds were prepared using the methods described above.1- (3-methoxyphenethyl) -3 (S)-[N- (1- (4-cyanobenzy) L) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₂₈H₃₃N_FiveO_Two・ 2HCl ・ 1.95H_TwoCalculated value for O: C, 58.02; H, 6.76; N, 12.08; Found: C, 58.01; H, 7.03; N, 11.99. FAB MS (M + 1) 4721- (1-naphthylethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₃₁H₃₃N_FiveO 0.90H_TwoCalculated value for O: C, 73.32; H, 6.91; N, 13.79; Found: C, 73.32; H, 7.04; N, 13.46.1- (3-chlorophenethyl) -3 (S)-[N- (1- (4-cyanobenzyl) ) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₂₇H₃₀N_FiveOCl.2HCl.1.65H_TwoCalculated value for O: C, 56.04; H, 6.15; N, 12.10; Found: C, 56.09; H, 6.43; N, 11.77.1- (α-methylbenzyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₂₇H₃₁N_FiveO ・ 0.45H_TwoCalculated value for O: C, 72.12; H, 7.15; N, 15.57; Found: C, 71.80; H, 6.81; N, 15.96. FAB MS (M + 1) 442   Except that the starting material in Example 1, Step E was replaced with 2-methylhistamine The following compounds were prepared using the methods described in Examples 12 and 1.1- (2-diphenylmethyl) -3 (S)-[N- (1- (4-cyanobenzyl) ) -2-Methyl-1H-imidazol-5-ylethyl) carbamoyl] piper gin Analysis, C₃₃H₃₅N_FiveCalculated value for 0.40 EtOAc: C, 75.11; H, 6.96; N, 12.66; Found: C, 75.15; H, 7.24; N, 12.60. FAB MS (M + 1) 518                                Example 13 1- (α-toluenesulfonyl) -3 (S)-[N- (1- (4-cyanobenzy) L) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine   3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazole-5 Ilethyl) carbamoyl] piperidine dihydrochloride (Example 11, Step E) (0. 210 g, 0.512 mmol) in CH_TwoCl_Two(6 mL) and Et_Three N (0.285 mL, 2.046 mmol) and α-toluenesulfonyl chloride (0.195 g, 1.023 mmol) and stir at ambient temperature for 2 hours. Was. The reaction mixture was concentrated to dryness, EtOAc and sat._Threesolution And the organic layer was separated, washed with brine and dried (MgSO 4)._Four) . 0.1% TFA / H by filtration and concentration to dryness_Two0: 0.1% T FA / CH_ThreeWaters Prep Pack eluting with CN, 95: 5 to 5:95 The title compound was obtained after purification by filtration.¹ H NMR (CD_ThreeOD): δ 8.80 (s, 1H), 8.02-8.12 ( m, 1H), 7.78 (d, 2H, J = 8 Hz), 7.34-7.5 (m, 7H ), 5.54 (s, 2H), 4.32 (s, 2H), 3.2-3.56 (m, 4 H), 2.65-2.95 (m, 4H), 2.25-2.4 (m, 1H), 1. 4-1.8 (m, 4H). FAB MS492 (M + 1)   The following compounds were prepared using this method except replacing with sulfonyl chloride did.1- (benzenesulfonyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine FAB MS (M + 1) 4781- (1-naphthylenesulfonyl) -3 (S)-[N- (1- (4-cyanoben) Jil) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₂₉H₂₉N_FiveO_ThreeS · 1.50CF_ThreeCO_TwoH0.10H_TwoTotal for O Arithmetic: C, 54.87; H, 4.42; N, 10.00; Found: C, 54.84; H, 4.31; N, 10.19.1- (3-chlorobenzenesulfonyl) -3 (S)-[N- (1- (4-cyano Benzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C_{twenty five}H₂₆N_FiveO_ThreeSCl ・ 0.55H_TwoCalculated value for O: C, 57.53; H, 5.23; N, 13.42; Found: C, 57.51; H, 5.20; N, 13.28.1- (3,5-dichlorobenzenesulfonyl) -3 (S)-[N- (1- (4- Cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] pipe lysine Analysis, C_{twenty five}H_{twenty five}N_FiveO_ThreeSCl 0.30H_TwoCalculated value for O: C, 54.41; H, 4.68; N, 12.69; Found: C, 54.43; H, 4.82; N, 12.49.1- (α-toluenesulfonyl) -3- (R)-[N- (1- (4-cyanoben) Jil) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₂₆H₂₉N_FiveO_ThreeS ・ 0.35H_TwoCalculated value for O: C, 62.72; H, 6.01; N, 14.07; Found: C, 62.73; H, 5.85; N, 13.84.1- (α-toluenesulfonyl) -cis-3-methoxycarbonyl-5- [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carba Moyl] piperidine FAB MS (M + 1) 5501- (methanesulfonyl) -3 (S)-[N- (1- (4-cyanobenzyl)- 1H-Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₂₀H_{twenty five}N_FiveO_ThreeS ・ 0.25CH_TwoCl_TwoCalculated value for: C, 55.68; H, 5.89; N, 16.04; Found: C, 56.04; H, 5.89; N, 15.70. FAB MS (M + 1) 416                                Example 14 1- (diphenylcarbamoyl) -3 (S)-[N- (1- (4-cyanobenzy L) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine   3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazole-5 Ilethyl) carbamoyl] piperidine dihydrochloride (Example 11, step E) (0. 346 g, 0.843 mmol) in CH_TwoCl_Two(10 mL), and Et_Three N (0.587 g, 4.2 mmol) and diphenylcarbamoyl chloride (0.390 g, 1.686 mmol) and stirred at ambient temperature for 1 hour. The reaction mixture is concentrated to dryness, EtOAc and saturated NaHCO_ThreeSolution and partitioned, the organic layer was separated, brine And dried (MgSO 4)_Four). By filtration and concentration to dryness, 0 ~ 2% MeOH / CH_TwoCl_TwoAfter purification on a silica gel column eluted with Compound was obtained. Analysis, C₃₂H₃₂N₆O_Two・ 0.95H_TwoCalculated value for O: C, 69.91; H, 6.22; N, 15.29; Found: C, 69.97; H, 6.15; N, 14.80. FAB MS (M + 1) 533   Use phenyl isocyanate instead of diphenylcarbamoyl chloride. 1- (phenylcarbamoyl) -3 (S)-[N- (1- (4-cyano Benzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine I got Analysis, C₂₆H₂₈N₆O_Two・ 0.45H_TwoCalculated value for 0.45 EtOAc : C, 66.21; H, 6.50; N, 16.66; Found: C, 66.18; H, 6.56; N, 16.71. FAB MS (M + 1) 457Example 15 1- [2- (2-pyridyl) -2-phenyl-2-hydroxyethyl] -3 (S )-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl L) carbamoyl] piperidine Step A:1- [2- (2-pyridyl) -2-phenyl-2-hydroxyethyl] Preparation of ethyl piperidine-3 (S) -carboxylate   2- (2-pyridyl) -2-phenyloxy in EtOH (0.90 mL) Run (prepared according to the method of Example 11, Step F) (0.106 g, 0.53 7 mmol) and ethyl S-(-)-nipecotate (0.093 g, 0.591 mmol) was heated at 50 ° C. for 24 hours with stirring in a sealed tube. this The reaction mixture was dissolved in EtOAc, washed with brine, dried (Na_TwoSO_Four), Filtration And concentrated to dryness to give the title compound. Step B:1- [2- (2-pyridyl) -2-phenyl-2-hydroxyethyl] Preparation of piperidine-3 (S) -carboxylic acid   1- [2- (2-pyridyl) -2-phenyl-2-hydroxy [Ethyl] piperidine-3 (S) -carboxylate (0.187 g, 0.52 7 mmol) was dissolved in EtOH (5 mL) and 1N NaOH (0.791 m L, 0.791 mmol) and H_TwoO (5 mL) was added and the reaction mixture was reconstituted. Heated under flowing for 3 hours. Neutralize with 1N HCl (to pH of 6) and dry Concentration to afford the title compound, which was used without further purification. Step C:1- [2- (2-pyridyl) -2-phenyl-2-hydroxyethyl] -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazole-5 Preparation of [Ilethyl) carbamoyl] piperidine   1- [2- (2-pyridyl) -2-phenyl-2-hydroxyethyl] piperi Gin-3 (S) -carboxylic acid (0.172 g, 0.527 mmol) was added to DMF (5 mL), EDC (0.106 g, 0.553 mmol), HO Treat with BT (0.068 g, 0.501 mmol), then adjust the pH to 7 With N-methylmorpholine and 4- (4-cyanobenzyl) Treated with stamin dihydrochloride (0.158 g, 0.527 mmol). ring N at ambient temperature_TwoBelow 18 Stir for hours and concentrate the reaction mixture with CH_TwoCl_TwoAnd H_TwoPartition between O and organic Phase is saturated NaHCO_ThreeAqueous solution, brine, and dried (Na_TwoSO_Four). filtration And 0.1% TFA / H by concentration to dryness._TwoO: 0.1% TFA / CH_ThreeCN in a Waters Prep Pack eluting at 95: 5 to 5:95 After purification by RP HPLC, the title compound was obtained. FAB MS (M + 1 ) 535 Analysis, C₃₂H₃₄N₆O_Two・ 3.0HCl ・ 2.10H_TwoCalculated value for O: C, 56.37; H, 6.09; N, 12.33; Found: C, 56.36; H, 6.14; N, 11.54.                                Example 16 1- (2-pyridylethyl) -3 (S)-[N- (1- (4-cyanobenzyl) 1H-Imidazol-5-ylethyl) carbamoyl] piperidine Step A:Ethyl 1- (2-pyridylethyl) piperidine-3 (S) -carboxylate Preparation of   Ethyl S-(-)-nipecotinate (0.650 g, 4.14 mmol) and 2 -Vinyl pyridine (0.670 mL, 6.2 1 mmol) in n-butanol (50 mL) with stirring under Ar. And heated under reflux for 18 hours. The reaction mixture is concentrated and the residue is washed with CH_TwoCl_Two: MeOH, SiO eluting with 95: 5 to 9: 1_TwoChromatography on To give the title compound.¹ H NMR (CDCl_Three): Δ 8.52 (dd, 1H, J = 1, 4 Hz), 7 . 58 (td, 1H, J = 1.8, 8 Hz), 7.26 (s, 1H), 7.18 (D, 1H, J = 8 Hz), 7.106 (dd, 1H, J = 4.6 Hz), 4. 12 (q, 2H, J = 7 Hz), 3.07 (d, 1H, J = 10 Hz), 2.9 5-3.03 (m, 2H), 2.737-2.88 (m, 3H), 2.52-2 . 62 (m, 1H), 2.28 (t, 1H, J = 10 Hz), 2.11 (td, 1H, J = 3, 10 Hz), 1.9-2.0 (m, 1H), 1.4-1.8 (m , 4H), 1.25 (t, 3H, J = 7 Hz). Step B:Preparation of 1- (2-pyridylethyl) piperidine-3 (S) -carboxylic acid   The title compound was prepared according to the method of Example 15, Step B. Step C:1- (2-pyridylethyl) -3 (S)-[N- (1- (4-cyanobe) Undyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine Preparation   The title compound was prepared according to the method of Example 15, Step C. FAB MS (M + 1) 413                                Example 17 1-phenyl-3 (S)-[N- (1- (4-cyanobenzyl) -1H-imida Preparation of Zol-5-ylethyl) carbamoyl] piperidine Step A:Preparation of ethyl 1-phenyl- (S) -piperidinecarboxylate   CH_TwoCl_TwoEthyl S-Nipecotinate (0.3 g, 1.91 m) in (20 mL) mol), triphenylbismuth (1.68 g, 3.82 mmol), Copper acetate (0.52 g, 2.86 mmol) and Et_ThreeN (0.39 mL, 2.8 6 mmol) was added. The resulting mixture was stirred at 25 C for 18 hours. Reactant To CH_TwoCl_Two(50 mL) and saturated NaHCO_Three(30 mL). The organic layer was washed with brine (30 mL) and dried (MgSO_Four). Filtration and vacuum The concentration in SiOx eluting with 95: 5 xanthane: ethyl acetate_TwoAfter chromatography, the standard The title compound was obtained. Step B:Preparation of 1-phenyl- (S) -piperidinecarboxylic acid   The title compound was prepared according to the method of Example 15, Step B. Step C:1-phenyl-3 (S)-[N- (1- (4-cyanobenzyl) -1H -Imidazol-5-ylethyl) carbamoyl] piperidine   The title compound was prepared according to the method of Example 15, Step C. Purification is 0.1 % TFA / H_TwoO: 0.1% TFA / CH_ThreeEluting with CN, 95: 5 to 5:95 Performed on a RP HPLC Waters Prep Pack. Analysis, C_{twenty five}H₂₇N_FiveO ・ 3.1CF_ThreeCO_TwoH · 0.8H_TwoCalculated value for O: C, 47.96; H, 4.09; N, 8.96; Found: C, 47.94; H, 4.12; N, 8.97.   Other than replacing triphenylbismuth with tri-3-methylphenylbismuth The following compounds were prepared using the methods described above.1- (3-methylphenyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine Analysis, C₂₆H₂₉N_FiveO ・ 2.9CF_ThreeCO_TwoH · 0.8H_TwoCalculated value for O: C, 49.44; H, 4.37; N, 9.06; Found: C, 49.43; H, 4.35; N, 9.15.                                Example 18 1- (2,2-diphenylethyl) -3 (S)-[2- (1- (4-cyanoben) Preparation of Jill) -1H-Imidazol-5-yl) ethylthiomethyl] piperidine Step A:1- (2,2-diphenylethyl) -3 (S) -piperidinecarboxylic acid Preparation of ethyl   After using ethyl 3 (S) -piperidinecarboxylate instead of nipecotic acid Except for this, the title compound was prepared according to the method abbreviated to Example 10, Step A. Step B:1- (2,2-diphenylethyl) -3 (S) -hydroxymethyl pipe Preparation of lysine   1- (2,2-diif) dissolved in dry ether (40 mL) Enylethyl) -3 (S) -piperidinecarboxylate (4.90 g, 0.0 14 mol) with lithium aluminum hydride (40 mL) in dry ether (40 mL). (1.93 g, 0.051 mol). When the starting material is Reflux until consumed, then saturated sodium potassium tartrate solution (100 m L) and stirred for 2 hours. Separate the layers and extract the aqueous layer with ether (2 ×). Issued. The combined organic extracts were dried (MgSO 4_Four), Concentrate and purify further The title compound was obtained without. Step C:1- (2,2-diphenylethyl) -3 (S) -tosyloxymethylpi Preparation of peridine   1- (2,2-diphenylethyl) -3 (S) -hydroxymethylpiperidine (1.01 g, 3.41 mmol) in dry pyridine (25 mL) Tosyl chloride (0.684 g, 3.58 mmol) was added to this solution. Environmental temperature After stirring at 18 ° C for 18 hours, the solution was concentrated and the residue was taken up in EtOAc and saturated Na HCO_ThreeSolution, H_TwoO, washed with brine and dried (MgSO_Four). Filtration and concentration Afforded the title compound without further purification. Step D:1- (2,2-diphenylethyl) -3 (S) -acetylthiomethylpi Preparation of peridine   1- (2,2-diphenylethyl) -3 (S) -tosyloxymethylpiperidi (1.35 g, 3.23 mmol), potassium thioacetate (1.47 g, 1 2.9 mmol) and DMF (30 mL) were heated at 100 ° C. for 4 hours. this The solution was poured into ice and the resulting green precipitate was dissolved in EtOAc. organic matter To H_TwoO (2x), saturated NaHCO_ThreeSolution, brine, dried (MgSO 4)_Four ), And concentrated to give the title compound without further purification. Step D:1- (2,2-diphenylethyl) -3 (S) -mercaptomethyl pipe Preparation of Lysine Disulfide   1- (2,2-diphenylethyl) -3 (S) -acetylthiomethylpiperidi (0.523 g, 1.47 mmol), EtOH (20 mL) and NaOH ( (0.5N, 20 mL) was refluxed for 3 hours. Concentrate this solution and remove ethanol Removed and the remaining aqueous solution was decanted from the green oil. Add this oil to water (2 The sample was washed with x) and decanted. The oil is dried under reduced pressure for further purification. The title compound was obtained without. Step E:1- (2,2-diphenylethyl) -3 (S) -mercaptomethyl pipe Preparation of lysine   This disulfide (0.10 g, 0.161 mmol) was added to acetone (15 mL). ) And 10% aqueous MeOH (10 mL). Tributylphosphine (0.261 mL, 0.322 mmol). The solution was stirred for 2 hours and concentrated. And the residue is taken up in EtOAc and saturated NaHCO_ThreeAnd dried (Mg SO_Four). Filtration and concentration provided the title compound without further purification. Step F:Preparation of 1-triphenylmethyl-4- (hydroxymethyl) imidazole Made   4- (Hydroxymethyl) imidazo in dry DMF (250 mL) at ambient temperature To a solution of toluene hydrochloride (35.0 g, 260 mmol) was added Et._ThreeN (90.6 mL , 650 mmol) was added. A white solid precipitated from this solution. DMF (5 Chlorotriphenylmethane (76.1 g, 273 mmol) in It was added dropwise. The reaction mixture was stirred for 20 hours, poured onto ice, filtered And washed with ice water. The product obtained is slurried with cold dioxane, filtered and filtered. Dry in the air, white Obtained the title compound as a solid, which was sufficiently pure to use in the next step . Step G:Preparation of 1-triphenylmethyl-4- (acetoxymethyl) imidazole Made   1-triphenylmethyl-4- (hydroxymethyl) imidazole (260 m mol) were suspended in pyridine (500 mL). Acetic anhydride (74 mL, 7 80 mmol) was added dropwise and the reaction was stirred for 48 hours, during which time It became homogeneous. Pour this solution into EtOAc, and sequentially add water, 5% HCl aqueous solution , Saturated NaHCO_ThreeWashed with aqueous solution and brine. The organic extract is dried (Na_TwoS O_Four), Concentrated in vacuo to give the product as a white powder, which was used in the next step It was pure enough to do. Step H:1- (4-cyanobenzyl) -5- (acetoxymethyl) imidazole Preparation of hydrobromide   1-Triphenylmethyl-4- (acetoxime in EtOAc (500 mL) Tyl) imidazole (85.8 g, 225 mmol) and 4-cyanobenzylbu Lomide (50.1 g, 232 mmol) was stirred at 60 ° C. for 20 hours, during which time Pale yellow sun An artifact was formed. The reaction was cooled to room temperature, filtered and solid imidazo Lithium bromide salt was obtained. The filtrate is concentrated in vacuo to a volume (200 mL), Reheated at 2 ° C. for 2 hours, cooled to room temperature and filtered again. The volume of the filtrate (100 m Concentrate in vacuo to L), reheat at 60 ° C. for a further 2 hours, cool to room temperature and add Concentration in air gave a pale yellow solid. After bringing all of the solid material together, (500 mL) and warmed to 60 ° C. After 2 hours, the solution is evacuated In water to obtain a white solid that is triturated with hexane to remove solubles did. Removal of the residual solvent in vacuo afforded the title product as a white solid. The hydrobromide salt was obtained and used in the next step without further purification. Step I:1- (4-cyanobenzyl) -5- (hydroxymethyl) imidazole Preparation of   1- (4-cyanobenzyl) -5 in 1.5 L THF / water at 0 ° C. (Acetoxymethyl) imidazole hydrobromide (50.4 g, 150 mmol) ) Was added lithium hydroxide monohydrate (18.9 g, 450 mmol). 1 After time, the reaction was concentrated in vacuo, diluted with EtOAc (3 L), water, Saturated NaHCO_ThreeWashed with aqueous solution and brine. The solution is then dried (N a_TwoSO_Four), Filtered and concentrated in vacuo to give crude as light yellow fluffy solid Product, which is sufficiently pure to be used in the next step without further purification there were. Process J:Preparation of 1- (4-cyanobenzyl) -5- (chloromethyl) imidazole Made   1- (4-cyanobenzyl) -5- (hydroxy) in thionyl chloride (5 mL) A solution of (methyl) imidazole (1.0 g, 4.70 mmol) was added at 70 ° C. for 16 hours. Stirred for hours. The solvent is evaporated in vacuo and the resulting solid is CH_TwoCl_TwoSuspended in And collected by filtration and dried in vacuo. This material should not be further purified. Pure enough to use well.¹ H NMR (CD_ThreeOD): δ 9.06 (1H, s), 7.83 (2H, d, J = 8.0 Hz), 7.77 (1 H, s), 7.55 (2 H, d, J = 8.0 H) z), 5.67 (2H, s) and 4.78 (2H, s) ppm. Step K:1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-si Anobenzyl) -1H-imidazol-5-ylethylthiomethyl] piperidine Preparation of   1- (2,2-diphenylethyl) -3 (S) -mercaptomethyl-piperidi (0.322 mmol), 1- (4-cyanobenzyl) -5- (chloromethyl ) -Imidazole (0.117 g, 0.386 mmol) and diisopropyl Tylamine (0.168 mL, 0.966 mmol) was added to CH 2_TwoCl_Two(10mL ) And refluxed overnight. Concentrate the solution and take up the residue in EtOAc. And saturated NaHCO_Three, Water and brine. Dry the organics (MgSO 4_Four) , Concentrated and chromatographed (0-3% MeOH, CH_TwoCl_Two, NH_FourOH) Treated and prep HPLC (100: 0 to 5:95 H_TwoO: CH_ThreeCN w / 0. 1% TFA), remove the base, and acidify with a 1N HCl solution in ether. To give the title compound.¹ H NMR (CD_ThreeOD): δ 9.03 (s, 1H), 7.80 (D, 2H, J = 8 Hz), 7.65 (s, 1H), 7.50-7.33 (m, 10H), 7 . 26 (D, 2H, J = 8 Hz), 5.64 (s, 2H), 4.68 (t, 1H) , J = 7 Hz), 3.98-3.88 (m, 2H), 3.72 (s, 2H), 3 . 59-3.56 (m, 1H), 3.51-3.47 (M, 1H), 2.87-2.83 (m, 1H), 2.64 (t, 1H, J = 1 2Hz), 2.49-2.42 (m, 1H), 2.35-2.27 (m, 1H) , 2.02 (brs, 1H), 1.90-1.77 (m, 3H), 1.19- 1.12 (m, 1H). FAB MS 507 (M + 1) Analysis, C₃₂H₃₄N_FourS ・ 2.5HCl ・ 1.65H_TwoCalculated value for O: C, 61.24; H, 6.69; N, 8.93; Found: C, 61.20; H, 5.93; N, 8.72.                                Example 19 1- (2,2-diphenylethyl) -3 (S)-[2- (1- (4-cyanoben) Zyl) -1H-imidazol-5-yl) ethylsulfonylmethyl] piperidine Preparation of   1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanobe) Undil) -1H-imidazol-5-ylethylthiomethyl] piperidine (0. 050 g, 0.087 mmol) in MeOH (1 mL) and H_TwoO (1 mL) And dissolved in Oxone (0.106 g, 0.173 mmol) Treated and stirred at ambient temperature for 1 hour. Concentrate this solution And the residue was taken up in EtOAc and washed with water and brine. Dry the organics (M gSO_Four), Chromatography (RP HPLC Waters Prep Pack) H, 100: 0 to 5: 95H_TwoO: CH_ThreeCN w / 0.1% TFA) The title compound was obtained as the TFA salt. FAB MS 539 (M + 1) Analysis, C₃₂H₃₄N_FourO_TwoS ・ 3.70CF_ThreeCO_TwoH 0.90H_TwoTotal for O Arithmetic: C, 48.44; H, 4.08; N, 5.74; Found: C, 48.43; H, 4.06; N, 5.96.                                Example 20 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Jill) -1H-Imidazol-5-ylethyl) -N-methyl-carbamoyl] Preparation of piperidine Step A;1- (tert-butyloxycarbonyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) -N-methyl Of carbamoyl] piperidine   1- (tert-butyloxycarbonyl) -3 (S)-[N -(1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) cal Bamoyl] piperidine (Example 11, Step D) (0.100 g, 0.228 mm ol) was dissolved in dry DMF (5 mL) and cooled in an ice bath. NaH (0. 011 g, 0.274 mmol) and CH_ThreeI (0.023 mL, 0.365 m mol) was added and the mixture was stirred at 0 ° C. for 1.5 hours. Quench the reaction with water And extracted with EtOAc to remove organics from H_TwoWash with O (3x), dry (Mg SO_Four) And concentrated to give the title compound. Step B:1-3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazo -5-Ethyl) -N-methylcarbamoyl] piperidine   The title compound was prepared according to the method outlined in Example 11, Step E. Step C:1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-si Anobenzyl) -1H-imidazol-5-ylethyl) -N-methylcarbamo Of [Il] piperidine   The title compound was prepared according to the method outlined in Example 11, Step H. FAB   MS (M + 1) 532 Analysis, C₃₄H₃₇N_FiveO ・ 2.70CF_ThreeCO_TwoH ・ 1.60H_TwoCalculated value for O : C, 54.50; H, 4.98; N, 8.06; Found: C, 54.49; H, 4.97; N, 7.99.   The following compounds were prepared using the methods described above.1- (3-bromobenzyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-Imidazol-5-ylethyl) -N-methyl-carbamoyl] piperi gin FAB MS (M + 1) 520                                Example 21 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Preparation of jyl) -1H-imidazol-5-ylethyl) aminomethyl] piperidine Made Step A:1- (2,2-diphenylethyl) -3 (S) -piperidinecarboxy Preparation of aldehyde   1- (2,2-diphenylethyl) -3 (S) -hydroxymethyl-piperidi (Example 18, Step B) (2.10 g, 7.10 mmol) and Et_ThreeN (2 . 97 mL, 21.3 mmol) in dry DMSO (40 mL) and ice Cooling in the bath did. Pyridine SO_ThreeSlowly add the complex (3.39 g, 21.3 mmol) The solution was stirred for 1 hour while warming to room temperature. Put this solution in ice water Pour, CH_TwoCl_Two(2 ×) and combine the combined organics with saturated NaHCO 3_ThreeDissolution Liquid, H_TwoO, washed with brine and dried (MgSO_Four). By filtration and concentration, The title compound was obtained without further purification. Step B:1- (2,2-diphenylethyl) -3 (S)-[N- (1- (cyano Benzyl) -1H-imidazol-5-ylethyl) aminomethyl] piperidine Preparation of   1- (2,2-diphenylethyl) -3 (S) -piperidinecarboxyalde Hyd (0.575 g, 1.96 mmol), 3- (4-cyanobenzyl) hista Min dihydrochloride (0.388 g, 1.30 mmol) and NaCNBH_Three(0.1 23 g, 1.96 mmol) in MeOH (15 mL) at ambient temperature Stirred overnight. The solution is concentrated, the residue is taken up in EtOAc and saturated NaHCO_Three Solution, H_TwoWashed with O and brine. Dry the organics, concentrate and chromatograph (0-4% MeOH / CH_TwoCl_Two/ NH_FourOH) to give the title compound This was isolated as the Tris HCl salt.¹ H NMR (CD_ThreeOD): δ 9.05 (s, 1H), 7.81 (d, 2H, J = 8 Hz), 7.68 (s, 1H), 7.54 (d, 2H.J = 8 Hz), 7 . 49-7.25 (m, 10H), 5.67 (s, 2H), 4.76-7.74 (M, 1H), 4.05-3.88 (m, 3H), 3.54-3.47 (m, 1 H), 3.33-3.30 (m, 1H), 3.19-3.15 (m, 2H), 3 . 02-3.00 (m, 2H), 2.92-2.90 (m, 2H), 2.42 ( br s, 1H), 1.99-1.91 (m, 2H), 1.82-1.78 (m , 1H), 1.31-1.28 (m, 2H). FAB MS 504 (M + 1) Analysis, C₃₃H₃₇N_Five・ 3.0HCl ・ 0.90H_TwoCalculated value for O: C, 62.99; H, 6.70; N, 11.13; Found: C, 63.04; H, 6.83; N, 11.05.                                Example 22 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) (Jill) -1H-imidazol-5-ylethyl) -N-acetyl-aminomethyl Preparation of piperidine   1-diphenylethyl-3 (S)-[N-1- (4-cyanobenzyl) -1H -Imidazol-5-ylethylaminomethyl] piperidine (0.151 g, 0 . 246 mmol) and Et_ThreeN (0.154 mL, 1.10 mmol) Dry CH_TwoCl_Two(15 mL) and cooled in an ice bath. CH_TwoCl_Two(1mL ), A solution of acetyl chloride (0.026 mL, 0.369 mmol) in The reaction was stirred for 18 hours while warming to room temperature. Add this solution to EtOAc Diluted with saturated NaHCO_ThreeSolution, H_TwoWashed with O and brine. Dry organic matter (MgSO_Four) And concentrated to give the title compound.¹ H NMR (CDCl_Three): Δ 7.59 (d, 2H, J = 8 Hz), 7.52 (S, 1H), 7.49-7.04 (m, 12H), 6.87 (s, 1H), 5 . 29 (s, 2H), 4.17 (t, 1H, J = 7 Hz), 3.32-3.25 (M, 1H), 3.21-3.13 (m, 1H), 3.04-2.96 (m, 4 H), 2.68-2.49 (m, 4H), 2.24-2.20 (m, 1H), 1 . 91-1.73 (m, 6H), 1.56-1.50 (m, 1H), 1.46- 1.43 (m, 1H), 0,96-0.92 (m, 1H). FAB MS 54 6 (M +1). Analysis, C₃₅H₃₉N_FiveO 0.70H_TwoCalculated value for O: C, 75.29; H, 7.29; N, 12.54; Found: C, 75.25; H, 7.26; N, 12.06.   The amines required in Example 21, Step B and the acyls required in Example 22 The procedure described in Examples 21 and 22 was repeated except that the The following compounds were prepared using the method.1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) (Jill) -2-methyl-1H-imidazol-5-ylethyl) -N-acetyl- Aminomethyl] piperidine Analysis, C₃₆H₄₁N_FiveO ・ 0.35H_TwoCalculated value for O: C, 76.39; H, 7.43; N, 12.37; Found: C, 76.39; H, 7.13; N, 12.32. FAB MS (M + 1) 5601- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Jill) -1H-imidazol-5-ylethyl) -N-cyclopropylmethyl- Aminomethyl] piperidine Analysis, C₃₇H₄₃N_Five・ 3.0HCl ・ 0.95H_TwoO 0.6 0CH_TwoCl_TwoCalculated value for: C, 62.41; H, 6.73; N, 9.53; Found: C, 62.42; H, 7.02; N, 9.43. FAB MS (M + 1) 5581- (2,2-diphenylethyl) -3 (S)-[N- (2-methyl-1H-i Midazol-4-ylethyl) -N- (4-cyanobenzoyl) aminomethyl] Piperidine Analysis, C₃₄H₃₇N_FiveO ・ 2.95CF_ThreeCO_TwoH ・ 1.00H_TwoCalculated value for O : C, 54.08; H, 4.77; N, 7.90; Found: C, 54.06; H, 4.74; N, 7.91. FAB MS (M + 1) 532                                Example 23 1- (2,2-diphenylethyl) -3 (S)-[5- (4-cyanobenzyl) -1H-Imidazol-1-ylmethyl] piperidine bistrifluoroacetate Preparation of Step A:Preparation of 1-trityl-4- (4-cyanobenzyl) -imidazole   Activated zinc dust (3.57 g, 5 in THF (50 mL)) 4.98 mmol) in dibromomethane (0.315 mL, 3.60 m3). mol) was added and the reaction was stirred at 20 ° C. under argon for 45 minutes. This suspension Cool the solution to 0 ° C. and add α-bromo-p-tolunitrile in THF (100 mL) (Toluinitrile) (9.33 g, 47.6 mmol) for 10 minutes And added dropwise. The reaction was then stirred at 20 ° C. for 6 hours and the bis (tri Phenylphosphine) nickel II chloride (2.40 g, 3.64 mmol) ) And iodotrityl imidazole (15.95 g, 36.6 mmol) in part Min. The resulting mixture is stirred at 20 ° C. for 16 hours and then saturated NH 4_FourC quenched by the addition of 1 solution (100 mL) and the mixture Stirred. Saturated NaHCO_ThreeAn aqueous solution was added to reach a pH of 8 and the solution was Extract with OAc (2 × 250 mL), dry (MgSO 4_Four), Evaporate the solvent in vacuum Fired. The residue was chromatographed (silica gel, CH_TwoCl_TwoMedium 0-20% E tOAc) treatment afforded the title compound as a white solid.¹ H NMR (CDCl_Three, 400 Mz): δ 7.54 (2H, d, J = 7.9) Hz), 7.38 (1H, s), 7.36 −7.29 (11H, m), 7.15-7.09 (6H, m), 6.58 (1H , S) and 3.93 (2H, s) ppm. Step B:1- (2,2-diphenylethyl) -3 (S)-[5- (4-cyanobe Ndyl) -1H-imidazol-1-ylmethyl] piperidine / bistrifluoro Preparation of roacetate bistrifluoroacetate   CH_TwoCl_Two1- (2,2-diphenylethyl) -3 (S)-in (7 mL) Hydroxymethylpiperidine (Example 18, Step B) (0.271 g, 0.91 7 mmol) and 1-trityl-4- (4-cyanobenzyl) imidazole (0 . 390 g, 0.917 mmol) in a solution of N_TwoUnder diisopropylethyla Min (0.639 mL, 3.67 mmol) was added. This mixture is -78 ° C And cooled to trifluoromethanesulfonic anhydride (0.154 mL, 0.91 mL). 7 mmol) was added dropwise from a syringe. Remove the cooling bath and remove the reaction Stirred at 5 ° C. for 18 hours. The reaction was evaporated in vacuo and the residue was methanol (20 mL) and heated to reflux for 1 hour. After cooling, the mixture is Evaporate in air and remove the residue with EtOAc (50 mL) and saturated NaHCO_Three(30mL Between) And the organic layer was separated, washed with brine (30 mL) and dried (MgSO4). O_Four). Filtration and concentration in vacuo gave the title compound, which was converted to CH_TwoCl_Two: Chromatography on silica gel using MeOH, 98: 2, followed by And purified by preparative HPLC on a Waters C-18 Delta-Pak column. . Analysis, C₃₁H₃₂N_Four・ 3.10CF_ThreeCO_TwoH ・ 0.75H_TwoCalculated value for O: C, 53.98; H, 4.46; N, 6.77; Found: C, 54.02; H, 4.47; N, 6.75.                                Example 24 1- (2,2-diphenylethyl) -3 (S)-[5- (4-cyanobenzyl) 1H-Imidazol-1-ylethylcarbamoyl] piperidine Step A:5- (4-cyanobenzyl) -1H-imidazol-1-ylethylf Preparation of Talimide   2-hydroxyethylphthalimide (3.23 g, 16.9 mmol) was added to N_Two CH below_TwoCl_Two(50 mL) and Et_ThreeN (3.92 mL, 28.2 mmol) Dissolved in. Reactants Cool to −78 ° C. and add trifluoromethanesulfonic anhydride (2.85 mL, 1 6.9 mmol) was added dropwise from a syringe. Stirred at 0 ° C. for 0.5 hour Afterwards, the reaction was cooled to -20 ° C and CH_TwoCl_Two1-trityl in (20 mL) Add 4- (4-cyanobenzyl) imidazole (2.4 g, 5.64 mmol). And stirred at 25 ° C. for 18 hours. Vacuum the reaction to dryness Concentrate and dissolve the residue in MeOH (75 mL) and heat to reflux for 2 hours . After cooling and evaporating in vacuo, the residue was washed with EtOAc (100 mL) and saturated N aHCO_Three(30 mL). Wash the organic layer with brine (30 mL) Cleaned and dried (MgSO_Four). By concentration in vacuo, CH_TwoCl_Two: MeO H: NH_FourOH, 95: 5: 0.5 (3 L), 90: 10: 1.0 (2 L), 8 After chromatography on silica gel eluting with 5: 15: 1.5 (3 L), The title compound was obtained. Step B:5- (4-cyanobenzyl) -1- (2-aminoethyl) -1H-imi Preparation of dazole   5- (4-cyanobenzyl) -1H-imidazo in anhydrous EtOH (75 mL) 1-ylethyl phthalimide (3.2 g, 9.2 mmol) in a solution of hydrazine (0.72 mL, 23.0 mmol). ) Was added and the mixture was refluxed for 18 hours. Add this mixture to dimethyl phthalate (7.59 mL, 46 mmol) was added and reflux continued for 4 hours. Cool the reaction Cooled in the freezer for 18 hours. The solid formed was filtered and washed with water. In a vacuum By evaporation of CH_TwoCl_Two: MeOH: NH_FourOH, 95: 5: 0.5 (2 L ), 90: 10: 1.0 (2 L), 85: 15: 1.5 (2 L) The title compound was obtained after chromatography on Kagel. Step C:1- (2,2-diphenylethyl) -3 (S)-[5- (4-cyanobe Undyl) -1H-imidazol-1-ylethylcarbamoyl] piperidine Made   1- (2,2-diphenylethyl) -3 (S) -carboxypiperidine and above Using the amine from Step B above, according to the method outlined in Example 10, Step B, The title compound was prepared. Analysis, C₃₃H₃₅N_FiveO ・ 0.60H_TwoCalculated value for O: C, 74.99; H, 6.90; N, 13.25; Found: C, 74.99; H, 6.98; N, 13.19.Example 25 In vitro inhibition of ras farnesyltransferase   Assay for farnesyl-protein transferase. Partially purified Bovine FPTase and Ras peptide (Ras-CVLS, Ras-CVIM and And Ras-CAIL), respectively, by Schaber et al.J. Biol. Chem . 265: 14701-14704 (1990); Pompliano et al.B iochemistr   31: 3800 (1992) and Gibbs et al.PN AS   U. S. A. 86: 6630-6634 (1989). Prepared as described. Bovine FPTase is 100 mM N- (2-hydrogen). Roxyethyl) piperazine-N ′-(2-ethanesulfonic acid) (HEPES), pH 7.4, 5 mM MgCl_Two5 mM dithiothreitol (DTT), 10 0 mM [^ThreeH] -farnesyl diphosphate ([[^ThreeH] -FPP; 740 CBq / m mol) New England Nuclea (New England Nuc) learn)), 650 nM Ras-CVLS and 10 μg / mL FPT The assay was performed at 31 ° C. for 60 minutes in a volume of 100 μL containing ze. The reaction is FP Starting with Tase, 1 Quenched with mL of 1.0 M HCl in ethanol. Remove the precipitate from Tom Tech Ma Filter using a Tom Tec Mach II cell harvester -Collect on mat, wash with 100% ethanol, dry and LKB β- Counting was performed with a plate counter. This assay uses both substrates, FPT Linear with respect to enzyme level and time, with less than 10% [^ThreeH ]-FPP was used. The purified compound was treated with 100% dimethyl sulfoxide ( DMSO) and diluted 20-fold for the assay. The percent inhibition is When compared to the amount of inclusion in the absence of the test compound. As determined by the amount of radioactivity in the presence of the test compound.   Human FPTase has been described by Omer et al.Biochemistry  32: 516 7-5176 (1993). Human FPTase activity was 0.1% (w / v) polyethylene glycol 20,000 , 10 μM ZnCl_TwoAnd 100 nM Ras-CVIM added to reaction mixture Except as described above, the assay was performed as described above. The reaction was run for 30 minutes and 100 μL 30% (v / x) in ethanol Stop with lichloroacetic acid (TCA) and treat as above for bovine enzyme. Was.   The compounds of the present invention described in Examples 1 to 24 were tested for human F Tested for inhibitory activity against PTase, <10 μM IC₅₀Having Was found.                                Example 26 In vivo ras farnesylation assay   The cell line used in this assay was R-R, which represents the virus Ha-rasp21. It is a v-ras system derived from at1 or NIH3T3 cells. This assay Are essentially DeClue, J. et al. E. FIG. Et al.,Cancer Research  5 1: 712-717 (1991). Congestion Cells in a 10 cm dish at 50-75% confluency are tested with the test compound. (The final concentration of the solvent methanol or dimethyl sulfoxide is 0.1% ). After 4 hours at 37 ° C., cells were harvested with 10% regular DMEM, 2% Fetal bovine serum and 400 mM Ci [³⁵S] methionine (1000 Ci / mmol ) Is labeled in 3 mL DMEM without methionine supplemented. After another 20 hours The cells, lysis buffer Solution (1% NP40 / 20 mM HEPES, pH 7.5 / 5 mM MgCl_Two/ 1 mM DTT / 10 mg / mL aprotinen / 2 mg / ML leupeptin / 2mg / mL antipine / 0.5mM PMSF) 1m Lysate by dissolving in L and centrifuging at 100,000 xg for 45 minutes. Was made transparent. Aliquots of the lysate containing equal numbers of acid precipitation counts were Make up to 1 mL with buffer (lysis buffer without DTT) and add ras-specific Lonal antibody Y13-259 (Furth, ME et al.,J. Virol.43 : 294-304 (1982)). Antibody ink at 4 ° C for 2 hours After incubation, protein A-sepha coated with rabbit anti-rat IgG Add 200 mL of a 20% suspension of the loin for 45 minutes. This immunoprecipitate is treated 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 Na Cl) four times, boil in SDS-PAGE sample buffer, and add 13% Load on acrylamide. When the dye front reaches the bottom, fix the gel Immersed in Enlightening, Dry and autoradiograph. Farnesylated ras protein and non-fu By comparing the intensities of the bands corresponding to the arnsylated ras protein, The percent inhibition of farnesyl transfer to quality is determined.                                Example 27 In vivo growth inhibition assay   To determine the biological consequences of FPTase inhibition, v-ras, v-raf Or anchorage-independent synthesis of Rat1 cells transformed by the v-mos oncogene The effect of the compounds of the invention on length is tested. Formed by v-Raf and v-Mos The transformed cells are specific for the compounds of the invention for Ras-induced cell transformation. Will be included in the analysis to assess   Rat1 cells transformed with v-ras, v-raf or v-mos Medium A (supplemented with 10% fetal bovine serum) on top of the bottom agarose layer (0.6%) 0.3% top of Dulbecco's modified Eagle's medium) 1 × 10 per plate (35 mm diameter) in agarose layer^FourContact at cell density To seed. In both layers, 0.1% methanol or a suitable concentration of the compound of the invention (Of the final concentration used in the assay 1000 times dissolved in methanol). Cells include 1 Medium containing 0.1% methanol or a compound of this invention at this concentration twice a week A 0.5 mL is supplied. Photomicrographs taken 16 days after inoculation of the culture Make a comparison.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 35/00 A61K 31/00 635 43/00 643D A61K 31/454 31/445 614 31/5377 31/535 606 (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, LS, MW, SD, SZ, UG), UA (AM, AZ, BY, KG) , KZ, MD, RU, TJ, TM), AL, AM, AU, AZ, BA, BB, BG, BR, BY, CA, CN, CU, CZ, EE, GE, HU, I L, IS, JP, KG, KR, KZ, LC, LK, LR, LT, LV, MD, MG, MK, MN, MX, NO, NZ, PL, RO, RU, SG, SI, SK, TJ Graham, TM, TR, TT, UA, US, UZ, VN Samuel El-El, United States, New Jersey 07065, Lowway, East Lincoln Ave. 72) Inventor Situkarone, Terence M. New Jersey 07065, United States, Lowway East linker down, Abeniyu-126

Claims (1)

[Claims] 1. Formula A that inhibits farnesyl-protein transferase (In the formula R^1a, R^1bAnd R^1cIs a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C_Three~ C_TenShiku Lower alkyl, C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, R⁸O-, R⁹S (O)_m -, R⁸C (O) NR⁸-, CN, NO_Two, (R⁸)_TwoNC (NR⁸)-, R⁸C ( O)-, R⁸OC (O)-, N_Three, -N (R⁸)_TwoOr R⁹OC (O) NR⁸−, c) unsubstituted or unsubstituted or substituted aryl, heterocyclic, C_Three~ C_TenCycloalkyl, C_Two~ C₆Alkene Le, C_Two~ C₆Alkynyl, R⁸O-, R⁹S (O)_m-, R⁸C (O) NR⁸-, C N, (R⁸)_TwoNC (NR⁸)-, R⁸C (O)-, R⁸OC (O)-, N_Three, -N (R⁸)_TwoOr R⁹OC (O) -NR⁸C substituted with-₁~ C₆Alkyl Independently selected from among R^TwoIs H, unsubstituted or substituted C₁~ C₈Alkyl, unsubstituted or substituted C_Two~ C₈Al Phenyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, And -S (O)_TwoR⁶Selected from     The substituted group may have one or more     1) not substituted or         a) C₁~ C_FourAlkyl,         b) (CH_Two)_pOR⁶,         c) (CH_Two)_pNR⁶R⁷,         d) halogen, and         e) C₁~ C_FourPerfluoroalkyl         Aryl substituted with one or two groups selected from Heterocycle,     2) C_Three~ C₆Cycloalkyl,     3) OR⁶,     4) SR⁶, S (O) R⁶, SO_TwoR⁶,     15) C₁~ C₈Alkyl, or     16) C₁~ C₈Perfluoroalkyl     Has been replaced by R^ThreeIs H, Selected from R^FourIs a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C_Three~ C_TenShiku Lower alkyl, C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, perfluoroalkyl , F, Cl, Br, R⁸O-, R⁹S (O)_m-, R⁸C (O) NR⁸-, CN, N O_Two, (R⁸)_TwoNC (NR⁸)-, R⁸C (O)-, R⁸OC (O)-, N_Three, − N (R⁸)_TwoOr R⁹OC (O) NR⁸−, And c) unsubstituted or aryl, heterocyclic, C_Three~ C_TenCycloalkyl , C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, perfluoroalkyl, F, Cl , Br, R⁸O-, R⁹S (O)_m-, R⁸C (O) NH-, CN, H_TwoNC (N H)-, R⁸C (O)-, R⁸OC (O)-, N_Three, -N (R⁸)_TwoOr R⁸OC (O) NH-substituted C₁~ C₆Alkyl Independently selected from among R^FiveIs a) hydrogen, b) C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, C_Three~ C₆Cycloalkyl, per Fluoroalkyl, F, Cl, Br, R⁸O-, R⁹S (O)_m-, R⁸C (O) N R⁸-, CN, NO_Two, (R⁸)_TwoNC (NR⁸)-, R⁸C (O)-, R⁸OC ( O)-, N_Three, -N (R⁸)_TwoOr R⁹OC (O) NR⁸−, And c) unsubstituted or perfluoroalkyl, F, Cl, Br, R⁸ O-, R⁹S (O)_m-, R⁸C (O) N R⁸−, CN, (R⁸)_TwoNC (NR⁸)-, R⁸C (O)-, R⁸OC (O)-, N_Three, -N (R⁸)_TwoOr R⁹OC (O) NR⁸C substituted with-₁~ C₆Archi Le Independently selected from among R⁶, R⁷And R^7aIs not substituted as in H, or         a) C₁~ C_FourAlkoxy,         b) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,         c) halogen,         d) HO,         h) N (R⁸)_Two Substituted with one or two substituents selected from₁~ C_FourAlkyl, C_Three ~ C₆Cycloalkyl, heterocycle, aryl and C₁~ C_FourPerfluoroalkyl Independently selected from among Or R⁶And R⁷Can form a ring together with R⁷And R^7aCan form a ring together with R⁸Is hydrogen, C₁~ C₆Alkyl, benzyl, 2,2,2-trifluoroethyl and And aryl are independently selected from R⁹Is C₁~ C₆Independently selected from alkyl and aryl; R^TenIs H, R⁸C (O)-, R⁹S (O)_m-, Unsubstituted or substituted C₁~ C_FourArchi , Unsubstituted or substituted C_Three~ C₆Cycloalkyl, unsubstituted or substituted heterocycle, unsubstituted Substituted or substituted aryl, substituted aroyl, unsubstituted or substituted heteroaroyl, substituted Selected from arylsulfonyl and unsubstituted or substituted heteroarylsulfonyl Where the substituted group is         a) C₁~ C_FourAlkoxy,         b) aryl or heterocycle,         c) halogen,         d) HO,         h) N (R⁸)_Two,as well as         i) C_Three~ C₆Cycloalkyl A is substituted with one or two substituents selected from¹And A^TwoIs In the case, -CH = CH-, -C≡C-, -C (O)-, -C (O) NR⁸-, -NR⁸ C (O)-, O, -N (R⁸)-, -S (O)_TwoN (R⁸)-, -N (R⁸) S (O )_Two-And S (O)_mIndependently selected from among V is a) hydrogen, b) heterocycle, c) aryl, d) 0-4 carbon atoms are replaced by heteroatoms selected from O, S and N C₁~ C₂₀Alkyl, and e) C_Two~ C₂₀Alkenyl , But A¹Is S (O)_mAnd A¹Is a bond, n is 0 and A^TwoIs S (O)_m, V is not hydrogen, W is a heterocyclic ring, X is a bond, -C (= O) NR^Ten-, -NR^TenC (= O)-, -S (O)_m−, − NR^Ten-, O or -C (= O)-, m is 0, 1 or 2; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; r is 0 to 5, provided that when V is hydrogen, r is 0; s is 1 or 2, t is 0 or 1, The dotted line indicates a double bond present in some cases) Body or pharmaceutically acceptable salts. 2. Formula A (In the formula R^1aAnd R^1cIs hydrogen, C_Three~ C_TenCycloalkyl, R⁸O-, -N (R⁸)_Two, F and And C₁~ C₆Independently selected from alkyl, R^1bIs a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C_Three~ C₆Cyclo Alkyl, R⁸O-, -N (R⁸)_TwoOr C_Two~ C₆Alkenyl, c) unsubstituted or unsubstituted or substituted aryl, heterocyclic, C_Three~ C₆Cycloalkyl, C_Two~ C₆Alkenyl, R⁸O- or -N (R⁸)_TwoReplace with Done C₁~ C₆Alkyl Independently selected from among R^TwoIs a) unsubstituted or one or more     1) not substituted or         i) C₁~ C_FourAlkyl,         ii) (CH_Two)_pOR⁶,         iii) (CH_Two)_pNR⁶R⁷,         iv) halogen,         v) C₁~ C_FourPerfluoroalkyl         An aryl or heterocyclic ring substituted with     2) OR⁶,     3) SR⁶, SO_TwoR⁶Or     C substituted with₁~ C₈Alkyl, b) c) unsubstituted or one or more     1) C₁~ C₈Alkyl,     2) C₁~ C₈Perfluoroalkyl,     3) OR⁶,     4) SR⁶, SO_TwoR⁶Or     Aryl substituted with d) -SO_TwoR⁶ Selected from R^ThreeIs H, Selected from R^FourIs a) hydrogen, b) C₁~ C₆Alkyl, C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, C₁~ C₆Pe Fluoroalkyl, F, Cl, R⁸O-, R⁸C (O) NR⁸-, CN, NO_Two, (R⁸)_TwoNC (NR⁸)-, R⁸C (O)-, R⁸OC (O)-, -N (R⁸)_Two Or R⁹OC (O) NR⁸−, And C) C₁~ C₆Perfluoroalkyl, R⁸O-, R⁸C (O) NR⁸−, (R⁸)_Two NC (NR⁸)-, R⁸C (O)-, R⁸OC (O)-, -N (R⁸)_TwoOr R⁹ OC (O) NR⁸C substituted with-₁~ C₆Alkyl Independently selected from among R^FiveIs a) hydrogen, b) C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, C_Three~ C₆Cycloalkyl, C₁ ~ C₆Perfluoroalkyl, F, Cl, R⁸O-, R⁹S (O)_m-, R⁸C (O ) NR⁸-, CN, NO_Two, (R⁸)_TwoNC (NR⁸)-, R⁸C (O)-, R⁸O C (O)-, -N (R⁸)_TwoOr R⁹OC (O) NR⁸−, And c) unsubstituted or C₁~ C₆Perfluoroalkyl, F, Cl, R⁸ O-, R⁹S (O)_m-, R⁸C (O) NR⁸−, CN, (R⁸)_TwoNC (NR⁸) -, R⁸C (O)-, R⁸OC (O)-, -N (R⁸)_TwoOr R⁹OC (O) N R⁸C substituted with-₁~ C₆Alkyl Selected from R⁶, R⁷And R^7aIs H and unsubstituted or         a) C₁~ C_FourAlkoxy,         b) halogen, or         c) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle C substituted with₁~ C_FourAlkyl, C_Three~ C₆Cycloalkyl, aryl and heterocycle Independently selected from among R⁸Is hydrogen, C₁~ C₆Alkyl, benzyl, 2,2,2-trifluoroethyl and And aryl are independently selected from R⁹Is C₁~ C₆Independently selected from alkyl and aryl; R^TenIs H, R⁸C (O)-, R⁹S (O)_m-, Unsubstituted or substituted C₁~ C_FourArchi , Unsubstituted or substituted C_Three~ C₆Cycloalkyl, unsubstituted or substituted heterocycle, unsubstituted Substituted or substituted aryl, substituted aroyl, unsubstituted or substituted heteroaroyl, substituted Selected from arylsulfonyl and unsubstituted or substituted heteroarylsulfonyl Where the substituted group is         a) C₁~ C_FourAlkoxy,         b) aryl or heterocycle,         c) halogen,         d) HO,        h) N (R⁸)_Two,as well as         i) C_Three~ C₆Cycloalkyl A is substituted with one or two substituents selected from¹And A^TwoIs In the case, -CH = CH-, -C≡C-, -C (O)-, -C (O) NR⁸-, O,- N (R⁸)-And S (O)_mIndependently selected from among V is a) pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- Of oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl and thienyl A heterocyclic ring selected from among, and b) aryl Selected from W is pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- Select from oxopiperidinyl, indolyl, quinolinyl and isoquinolinyl Heterocyclic ring, X is a bond, -C (= O) NR^Ten-, -NR^TenC (= O)-, -S (O)_m-Again Is -NR^Ten- m is 0, 1 or 2; n is 0, 1, 2, 3, or 4; p is 1, 2 or 3; q is 0 or 1, r is 0 to 5, provided that when V is hydrogen, r is 0; s is 1 or 2, t is 1]. 2. The compound according to claim 1, which inhibits ferase, or an optical isomer or a pharmaceutical thereof. Pharmaceutically acceptable salts. 3. Formula B (In the formula R^1aAnd R^1cIs hydrogen, C_Three~ C_TenCycloalkyl, R⁸O-, -N (R⁸)_Two, F and And C₁~ C₆Independently selected from alkyl, R^1bIs a) hydrogen, b) aryl, heterocycle, C_Three~ C_TenCycloalkyl, R⁸O-, -N (R⁸)_Two, F Or C_Two~ C₆Alkenyl, c) unsubstituted or unsubstituted or substituted aryl, heterocyclic, C_Three~ C_TenCycloalkyl, C_Two~ C₆Alkenyl, R⁸O- and -N (R⁸)_TwoFrom within C substituted with a selected substituent₁~ C₆Alkyl Independently selected from among R^TwoIs H, unsubstituted or substituted C₁~ C₈Alkyl, unsubstituted or substituted C_Two~ C₈Al Phenyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, And -S (O)_TwoR⁶Selected from     The substituted group may have one or more     1) not substituted or         a) C₁~ C_FourAlkyl,         b) (CH_Two)_pOR⁶,         c) (CH_Two)_pNR⁶R⁷,         d) halogen, and         e) C₁~ C_FourPerfluoroalkyl         Aryl substituted with one or two groups selected from Heterocycle,     2) C_Three~ C₆Cycloalkyl,     3) OR⁶,     4) SR⁶, S (O) R⁶, SO_TwoR⁶,    15) C₁~ C₈Alkyl, or     16) C₁~ C₈Perfluoroalkyl     Has been replaced by R^ThreeIs H, Selected from R^FourIs a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C₁~ C₆Alkyl, C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, C₁~ C₆Perfluoroalkyl, F, C l, R⁸O-, R⁸C (O) NR⁸-, CN, NO_Two, (R⁸)_TwoNC (NR⁸)- , R⁸C (O)-, -N (R⁸)_TwoOr R⁹OC (O) NR⁸−, And c) C₁~ C₆Perfluoroalkyl, R⁸O-, R⁸C (O) NR⁸−, (R⁸)_Two NC (NR⁸)-, R⁸C (O)-, -N (R⁸)_TwoOr R⁹OC (O) NR⁸− C substituted with₁~ C₆Alkyl Independently selected from among R^5aAnd R^5bIs independently hydrogen, C₁~ C₆Alkyl, cyclopro Pill, trifluoromethyl or halogen; R⁶, R⁷And R^7aIs H and unsubstituted or         a) C₁~ C_FourAlkoxy,         b) halogen, or         c) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle C substituted with₁~ C_FourAlkyl, C_Three~ C₆Cycloalkyl, aryl and heterocycle Independently selected from among R⁸Is hydrogen, C₁~ C₆Alkyl, 2,2,2-trifluoroethyl, benzyl and And aryl are independently selected from R⁹Is C₁~ C₆Independently selected from alkyl and aryl; R^TenIs H, R⁸C (O)-, R⁹S (O)_m-, Unsubstituted or substituted C₁~ C_FourArchi , Unsubstituted or substituted C_Three~ C₆Cycloalkyl, unsubstituted or substituted heterocycle, unsubstituted Substituted or substituted aryl, substituted aroyl, unsubstituted or substituted heteroaroyl, substituted Selected from arylsulfonyl and unsubstituted or substituted heteroarylsulfonyl Where the substituted group is         a) C₁~ C_FourAlkoxy,         b) aryl or heterocycle,         c) halogen,         d) HO,         h) N (R⁸)_Two,as well as         i) C_Three~ C₆Cycloalkyl A is substituted with one or two substituents selected from¹And A^TwoIs In the case, -CH = CH-, -C≡C-, -C (O)-, -C (O) NR⁸-, O,- N (R⁸)-And S (O)_mIndependently selected from among V is a) hydrogen, b) pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, Pyridonyl, 2-oxopiperidinyl, oxazolyl, indolyl, quinolinyl A heterocyclic ring selected from the group consisting of: isoquinolinyl, triazolyl and thienyl; c) aryl, d) 0-4 carbon atoms are replaced by heteroatoms selected from O, S and N C₁~ C₂₀Alkyl, and e) C_Two~ C₂₀Alkenyl , But A¹Is S (O)_mAnd A¹Is a bond, n is 0 and A^TwoIs S (O)_mIs V is not hydrogen, X is a bond, -C (= O) NR^Ten-, -NR^TenC (= O)-, -S (O)_m-Again Is -NR^Ten- m is 0, 1 or 2; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; q is 0 or 1, r is from 0 to 5, with the proviso that when V is hydrogen, r is 0]. 2. The method of claim 1, which inhibits farnesyl-protein transferase. A compound or an optical isomer or a pharmaceutically acceptable salt thereof. 4. Formula C (In the formula R^1aAnd R^1cIs hydrogen, C_Three~ C_TenCycloalkyl, R⁸O-, -N (R⁸)_Two, F and And C₁~ C₆Independently selected from alkyl, R^1bIs a) hydrogen, b) aryl, heterocycle, C_Three~ C_TenCycloalkyl, R⁸O-, -N (R⁸)_Two, F Or C_Two~ C₆Alkenyl, c) unsubstituted or unsubstituted or substituted aryl, heterocyclic, C_Three~ C_TenCycloalkyl, C_Two~ C₆Alkenyl, R⁸O- and -N (R⁸)_TwoFrom within C substituted with a selected substituent₁~ C₆Alkyl Independently selected from among R^TwoIs H, unsubstituted or substituted C₁~ C₈Alkyl, unsubstituted or Substitution C_Two~ C₈Alkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle , And -S (O)_TwoR⁶Selected from     The substituted group may have one or more     1) not substituted or         a) C₁~ C_FourAlkyl,         b) (CH_Two)_pOR⁶,         c) (CH_Two)_pNR⁶R⁷,         d) halogen, and         e) C₁~ C_FourPerfluoroalkyl         Aryl substituted with one or two groups selected from Heterocycle,     2) C_Three~ C₆Cycloalkyl,     3) OR⁶,     4) SR⁶, S (O) R⁶, SO_TwoR⁶,    15) C₁~ C₈Alkyl, or     16) C₁~ C₈Perfluoroalkyl     Has been replaced by R^ThreeIs H,Selected from R^FourIs a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C₁~ C₆Alkyl, C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, C₁~ C₆Perfluoroalkyl, F, C l, R⁸O-, R⁸C (O) NR⁸-, CN, NO_Two, (R⁸)_TwoNC (NR⁸)- , R⁸C (O)-, -N (R⁸)_TwoOr R⁹OC (O) NR⁸−, And c) C₁~ C₆Perfluoroalkyl, R⁸O-, R⁸C (O) NR⁸−, (R⁸)_Two NC (NR⁸)-, R⁸C (O)-, -N (R⁸)_TwoOr R⁹OC (O) NR⁸− C substituted with₁~ C₆Alkyl Independently selected from among R^5aAnd R^5bIs independently hydrogen, C₁~ C₆Alkyl, cyclopro Pill, trifluoromethyl or halogen; R⁶, R⁷And R^7aIs H and unsubstituted or         a) C₁~ C_FourAlkoxy,         b) halogen, or         c) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle C substituted with₁~ C_FourAlkyl, C_Three~ C₆Cycloalkyl, aryl and heterocycle Independently selected from among R⁸Is hydrogen, C₁~ C₆Alkyl, 2,2,2-trifluoroethyl, benzyl and And aryl are independently selected from R⁹Is C₁~ C₆Independently selected from alkyl and aryl; R^TenIs H, R⁸C (O)-, R⁹S (O)_m-, Unsubstituted or substituted C₁~ C_FourArchi , Unsubstituted or substituted C_Three~ C₆Cycloalkyl, unsubstituted or substituted heterocycle, unsubstituted Substituted or substituted aryl, substituted aroyl, unsubstituted or substituted heteroaroyl, substituted Selected from arylsulfonyl and unsubstituted or substituted heteroarylsulfonyl Where the substituted group is         a) C₁~ C_FourAlkoxy,         b) aryl or heterocycle,         c) halogen,         d) HO,         h) N (R⁸)_Two,as well as         i) C_Three~ C₆Cycloalkyl A is substituted with one or two substituents selected from¹And A^TwoIs In the case, -CH = CH-, -C≡C-, -C (O)-, -C (O) NR⁸-, O,- N (R⁸)-And S (O)_mIndependently selected from among V is a) hydrogen, b) pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, Pyridonyl, 2-oxopiperidinyl, oxazolyl, indolyl, quinolinyl A heterocyclic ring selected from the group consisting of: isoquinolinyl, triazolyl and thienyl; c) aryl, d) 0-4 carbon atoms are replaced by heteroatoms selected from O, S and N C₁~ C₂₀Alkyl, and e) C_Two~ C₂₀Alkenyl , But A¹Is S (O)_mAnd A¹Is a bond, n is 0 and A^TwoIs S (O)_mIs V is not hydrogen, X is a bond, -C (= O) NR^Ten-, -NR^TenC (= O)-, -S (O)_m-Again Is -NR^Ten- m is 0, 1 or 2; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4, wherein X is a bond, -NR⁸-Or O p is not 0, q is 0 or 1, r is from 0 to 5, with the proviso that when V is hydrogen, r is 0]. 2. The method of claim 1, which inhibits farnesyl-protein transferase. A compound or an optical isomer or a pharmaceutically acceptable salt thereof. 5. Formula D (In the formula R^1aAnd R^1cIs hydrogen, C_Three~ C_TenCycloalkyl and C₁~ C₆From the alkyl Independently selected, R^1bIs a) hydrogen, b) aryl, heterocycle, C_Three~ C_TenCycloalkyl, R⁸O-, -N (R⁸)_Two, F Or C_Two~ C₆Alkenyl, c) unsubstituted or aryl, heterocyclic, C_Three~ C_TenCycloalkyl , C_Two~ C₆Alkenyl, R⁸O- or -N (R⁸)_TwoC substituted with₁~ C₆A Lequil Independently selected from among R^TwoIs H, unsubstituted or substituted C₁~ C₈Alkyl, unsubstituted or substituted aryl, And -S (O)_TwoR⁶Selected from     The substituted group may have one or more     1) not substituted or         a) C₁~ C_FourAlkyl,         b) (CH_Two)_pOR⁶,         c) (CH_Two)_pNR⁶R⁷,         d) halogen, and         e) C₁~ C_FourPerfluoroalkyl         Aryl substituted with one or two groups selected from Heterocycle,     2) C_Three~ C₆Cycloalkyl,     3) OR⁶,     4) SR⁶, S (O) R⁶, SO_TwoR⁶,    15) C₁~ C₈Alkyl, or     16) C₁~ C₈Perfluoroalkyl     Has been replaced by R^ThreeIs H,Selected from R^FourIs a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C₁~ C₆Alkyl, C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, C₁~ C₆Perfluoroalkyl, F, C l, R⁸O-, R⁸C (O) NR⁸-, CN, NO_Two, (R⁸)_TwoNC (NR⁸)- , R⁸C (O)-, -N (R⁸)_TwoOr R⁹OC (O) NR⁸−, And c) C₁~ C₆Perfluoroalkyl, R⁸O-, R⁸C (O) NR⁸−, (R⁸)_Two NC (NR⁸)-, R⁸C (O)-, -N (R⁸)_TwoOr R⁹OC (O) NR⁸− C substituted with₁~ C₆Alkyl Independently selected from among R^5aAnd R^5bIs independently hydrogen, ethyl, cyclopropyl or Methyl, R⁶, R⁷And R^7aIs H and unsubstituted or         a) C₁~ C_FourAlkoxy,         b) halogen, or         c) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle C substituted with₁~ C_FourAlkyl, C_Three~ C₆Cycloalkyl, aryl and heterocycle Independently selected from among R⁸Is hydrogen, C₁~ C₆Alkyl, 2,2,2-trifluoroethyl, benzyl and And aryl are independently selected from R⁹Is C₁~ C₆Independently selected from alkyl and aryl; R^TenIs H, R⁸C (O)-, R⁹S (O)_m-And unsubstituted or substituted C₁~ C_FourAl Selected from kills, where the substituted alkyl group is         a) C₁~ C_FourAlkoxy,         b) aryl or heterocycle,         c) halogen,         d) HO,         h) N (R⁸)_Two,as well as         i) C_Three~ C₆Cycloalkyl A is substituted with one or two substituents selected from¹Is a bond,- C (O)-, O, -N (R⁸)-And S (O)_mSelected from X is a bond, -C (= O) NR^Ten-, -NR^TenC (= O)-, -S (O)_m-Again Is -NR^Ten- n is 0 or 1, provided that A¹Is a bond, O, -N (R⁸)-Or S (O)_m N is not 0, m is 0, 1 or 2; p is 0, 1, 2, 3, or 4; q is 0 or 1]. 4. The compound according to claim 3, which inhibits transferase, or an optical isomer thereof. Or a pharmaceutically acceptable salt. 6. Formula E(In the formula R^1aAnd R^1cIs hydrogen, R⁸O-, -N (R⁸)_Two, F, C_Three~ C_TenCycloalkyl and And C₁~ C₆Independently selected from alkyl, R^1bIs a) hydrogen, b) aryl, heterocycle, C_Three~ C_TenCycloalkyl, R⁸O-, -N (R⁸)_Two, F Or C_Two~ C₆Alkenyl, c) unsubstituted or aryl, heterocyclic, C_Three~ C_TenCycloalkyl , C_Two~ C₆Alkenyl, R⁸O- or -N (R⁸)_TwoC substituted with₁~ C₆A Lequil Independently selected from among R^TwoIs H, unsubstituted or substituted C₁~ C₈Alkyl, unsubstituted or substituted aryl, And -S (O)_TwoR⁶Selected from     The substituted group may have one or more     1) not substituted or         a) C₁~ C_FourAlkyl,         b) (CH_Two)_pOR⁶,         c) (CH_Two)_pNR⁶R⁷,         d) halogen, and         e) C₁~ C_FourPerfluoroalkyl         Aryl substituted with one or two groups selected from Heterocycle,     2) C_Three~ C₆Cycloalkyl,     3) OR⁶,     4) SR⁶, S (O) R⁶, SO_TwoR⁶,    15) C₁~ C₈Alkyl, or     16) C₁~ C₈Perfluoroalkyl     Has been replaced by R^ThreeIs H,Selected from R^FourIs a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C₁~ C₆Alkyl, C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, C₁~ C₆Perfluoroalkyl, F, C l, R⁸O-, R⁸C (O) NR⁸-, CN, NO_Two, (R⁸)_TwoNC (NR⁸)- , R⁸C (O)-, -N (R⁸)_TwoOr R⁹OC (O) NR⁸−, And c) C₁~ C₆Perfluoroalkyl, R⁸O-, R⁸C (O) NR⁸−, (R⁸)_Two NC (NR⁸)-, R⁸C (O)-, -N (R⁸)_TwoOr R⁹OC (O) NR⁸− C substituted with₁~ C₆Alkyl Independently selected from among R^5aAnd R^5bIs independently hydrogen, ethyl, cyclopropyl or Methyl, R⁶, R⁷And R^7aIs H and unsubstituted or         a) C₁~ C_FourAlkoxy,         b) halogen, or         c) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle C substituted with₁~ C_FourAlkyl, C_Three~ C₆Cycloalkyl, aryl and heterocycle Independently selected from among R⁸Is hydrogen, C₁~ C₆Alkyl, 2,2,2-trifluoroethyl, benzyl and And aryl are independently selected from R⁹Is C₁~ C₆Independently selected from alkyl and aryl; R^TenIs H, R⁸C (O)-, R⁹S (O)_m-And unsubstituted or substituted C₁~ C_FourAl Selected from kills, where the substituted alkyl group is         a) C₁~ C_FourAlkoxy,         b) aryl or heterocycle,         c) halogen,         d) HO,         h) N (R⁸)_Two,as well as         i) C_Three~ C₆Cycloalkyl Is substituted with one or two substituents selected from X is a bond, -C (= O) NR^Ten-, -NR^TenC (= O)-, -S (O)_m-Again Is -NR^Ten- n is 0 or 1, m is 0, 1 or 2; p is 0, 1, 2, 3, or 4, wherein X is a bond, -NR⁸-Or O p is not 0, q is 0 or 1]. 5. The compound according to claim 4, which inhibits transferase, or an optical isomer thereof. Or a pharmaceutically acceptable salt. 7. Formula F(In the formula R^1aAnd R^1cIs hydrogen, C_Three~ C_TenCycloalkyl and C₁~ C₆From the alkyl Independently selected, R^1bIs a) hydrogen, b) aryl, heterocycle, C_Three~ C_TenCycloalkyl, R⁸O-, -N- (R⁸)_TwoMa Or F, c) unsubstituted or aryl, heterocyclic, C_Three~ C_TenCycloalkyl , R⁸O- or -N (R⁸)_TwoC substituted with₁~ C₆Alkyl Independently selected from among R^TwoIs H, unsubstituted or substituted C₁~ C₈Alkyl, unsubstituted or substituted aryl, And -S (O)_TwoR⁶Selected from     The substituted group may have one or more     1) not substituted or         a) C₁~ C_FourAlkyl,         b) (CH_Two)_pOR⁶,         c) (CH_Two)_pNR⁶R⁷,         d) halogen, and         e) C₁~ C_FourPerfluoroalkyl         Aryl substituted with one or two groups selected from Heterocycle,     2) C_Three~ C₆Cycloalkyl,     3) OR⁶,     4) SR⁶, S (O) R⁶, SO_TwoR⁶,     15) C₁~ C₈Alkyl, or     16) C₁~ C₈Perfluoroalkyl     Has been replaced by R^ThreeIs H, Selected from R^5aAnd R^5bIs independently hydrogen, ethyl, cyclopropyl or methyl; R⁶, R⁷And R^7aIs H and unsubstituted or         a) C₁~ C_FourAlkoxy,         b) halogen, or         c) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle C substituted with₁~ C_FourAlkyl, C_Three~ C₆Cycloalkyl, aryl and heterocycle Independently selected from among R⁸Is hydrogen, C₁~ C₆Alkyl, 2,2,2-trifluoroethyl, benzyl and And aryl are independently selected from R⁹Is C₁~ C₆Independently selected from alkyl and aryl; R^TenIs H, R⁸C (O)-, R⁹S (O)_m-And unsubstituted or substituted C₁~ C_FourAl Selected from the kills and replaced Alkyl group         a) C₁~ C_FourAlkoxy,         b) aryl or heterocycle,         c) halogen,         d) HO,        h) N (R⁸)_Two,as well as         i) C_Three~ C₆Cycloalkyl Is substituted with one or two substituents selected from X is a bond, -C (= O) NR^Ten-, -NR^TenC (= O)-, -S (O)_m-Again Is -NR^Ten- m is 0, 1 or 2; p is 0, 1, 2, 3, or 4; q is 0 or 1]. The method according to claim 5, which inhibits transferase. Or a pharmaceutically acceptable salt thereof. 8. Formula G (In the formula R^1aAnd R^1cIs hydrogen, R⁸O-, -N (R⁸)_Two, F, C_Three~ C_TenCycloalkyl and And C₁~ C₆Independently selected from alkyl, R^1bIs a) hydrogen, b) aryl, heterocycle or C_Three~ C_TenCycloalkyl, c) unsubstituted or aryl, heterocyclic, C_Three~ C_TenCycloalkyl , C_Two~ C₆Alkenyl, R⁸O- or -N (R⁸)_TwoC substituted with₁~ C₆A Lequil Independently selected from among R^TwoIs H, unsubstituted or substituted C₁~ C₈Alkyl, unsubstituted or substituted aryl, And -S (O)_TwoR⁶Selected from     The substituted group may have one or more     1) not substituted or         a) C₁~ C_FourAlkyl,         b) (CH_Two)_pOR⁶,         c) (CH_Two)_pNR⁶R⁷,         d) halogen, and         e) C₁~ C_FourPerfluoroalkyl         Aryl substituted with one or two groups selected from Heterocycle,     2) C_Three~ C₆Cycloalkyl,     3) OR⁶,     4) SR⁶, S (O) R⁶, SO_TwoR⁶,    15) C₁~ C₈Alkyl, or     16) C₁~ C₈Perfluoroalkyl     Has been replaced by R^ThreeIs H,Selected from R^5aAnd R^5bIs independently hydrogen, ethyl, cyclopropyl or methyl; R⁶, R⁷And R^7aIs H and unsubstituted or         a) C₁~ C_FourAlkoxy,         b) halogen, or         c) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle C substituted with₁~ C_FourAlkyl, C_Three~ C₆Cycloalkyl, aryl and heterocycle Independently selected from among R⁸Is hydrogen, C₁~ C₆Alkyl, 2,2,2-trifluoroethyl, benzyl and And aryl are independently selected from R⁹Is C₁~ C₆Independently selected from alkyl and aryl; R^TenIs H, R⁸C (O)-, R⁹S (O)_m-And unsubstituted or substituted C₁~ C_FourAl Selected from the kills and replaced Alkyl group         a) C₁~ C_FourAlkoxy,         b) aryl or heterocycle,         c) halogen,         d) HO,         h) N (R⁸)_Two,as well as         i) C_Three~ C₆Cycloalkyl A is substituted with one or two substituents selected from¹Is a bond,- C (O)-, O, -N (R⁸)-And S (O)_mSelected from X is a bond, -C (= O) NR^Ten-, -NR^TenC (= O)-, -S (O)_m-Again Is -NR^Ten- m is 0, 1 or 2; n is 0 or 1, p is 1, 2 or 3; q is 0 or 1]. 7. The compound according to claim 6, which inhibits transferase, or an optical isomer thereof. Or a pharmaceutically acceptable salt. 9. 1- (t-butoxycarbonyl) -cis-3-methoxycarbonyl-5 -[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) Carbamoyl] piperidine, 1-phenethyl-cis-3-methoxycarbonyl-5- [N- (1- (4-cy Anobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidi , 1- (1-naphthylmethyl) -cis-3-methoxycarbonyl-5- [N- ( 1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoy Le] piperidine, 1-benzyl-cis-3-methoxycarbonyl-5- [N- (1- (4-sia Nobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine , 1-methyl-cis-3-methoxycarbonyl-5- [N- (1- (4-cyanobe Undyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (2-Indanyl) -cis-3-methoxycarbonyl-5- [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] Piperidine, 1- (2-diphenylethyl) -cis-3-methoxycarbonyl-5- [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamo Il] piperidine, 1- (3-phenylpropyl) -cis-3-methoxycarbonyl-5- [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamo Il] piperidine, 1- (2-methylpropyl) -cis-3-methoxycarbonyl-5- [N- ( 1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoy Le] piperidine, 1-phenethyl-cis-3-carboxyl-5- [N- (1- (4-cyanobe) Undyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1-phenethyl-cis-3- [N- (1-morpholinyl) carbamyl] -5 [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) ca Rubamoyl] piperidine, 1-phenethyl-cis-3- [N- (benzyl) carbamyl] -5- [N- (1- (4-cyanobenzyl) -1H-imidazole-5-ylethyl Le) carbamoyl] piperidine, 1-phenethyl-cis-3- [N- (cyclopropyl) carbamyl] -5- [ N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) cal Bamoyl] piperidine, 1-phenethyl-cis-3- [N- (t-butyl) carbamyl] -5- [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamo Il] piperidine, 1- (2,2-diphenylethyl) -cis-3- [N- (1-morpholinyl) Carbamyl] -5- [N- (1- (4-cyanobenzyl) -1H-imidazole- 5-ylethyl) carbamoyl] piperidine, 1- (2,2-diphenylethyl) -cis-3- [N- (t-butyl) carba Mill] -5- [N- (1- (4-cyanobenzyl) -1H-imidazole-5-i Ruethyl) carbamoyl] piperidine, N- [1-phenethyl-cis-5- (N '-(4-cyanobenzyl-1-imi Dazol-5-ylethyl) carbamyl) piperidine-3-carbonyl] methioni Methyl ester, N- [1-phenethyl-cis-5- (N '-(4-cyanobenzyl-1-imi Dazol-5-ylethyl) carbamyl) piperidine-3-carbonyl] methioni , 1- (t-butoxycarbonyl) -cis-3-methoxycarbonyl-5- [N -(1- (4-cyanobenzyl) -1H-imidazol-5-ylacetyl) amido No] piperidine, 1-phenethyl-cis-3-methoxycarbonyl-5- [N- (1- (4-cy Anobenzyl) -1H-imidazol-5-ylacetyl) amino] piperidine, 1-diphenylacetyl-cis-3-methoxycarbonyl-5- [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] Piperidine, 1- (t-butoxycarbonyl) -trans-3-methoxycarbonyl-5- [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) ca Rubamoyl] piperidine, 1- (2,2-diphenylethyl) -3- [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylacetyl) amino] pipe lysine, 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Jyl) -1H-imidazol-5-ylpropionyl) amino] piperidine, 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Zyl) -1H-imidazol-5-ylcarbonyl) amino] piperidine, 1- (phenylacetyl) -3 (S)-[N- (1- (4-cyanobenzyl)- 1H-imidazol-5-ylethyl) carbamoyl] piperidine; 1- (diphenylacetyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (3-chlorobenzoyl) -3 (S)-[N- (1- (4-cyanobenzyl) ) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine; 1- (2- (3-chlorophenyl) -2-phenylethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imi Dazol-5-ylethyl) carbamoyl] piperidine, 1- (dibenzylsuberylmethyl) -3 (S)-[N- (1- (4-cyanoben) Jill) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (2- (3-methylphenyl) -2-phenylethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamo Il] piperidine, 1- (2- (3-trifluoromethylphenyl) -2-phenylethyl) -3 ( S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl Le) carbamoyl] piperidine, 1- (2- (2-chlorophenyl) -2-phenylethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamo Il] piperidine, 1- (2- (4-chlorophenyl) -2-phenylethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamo Il] piperidine, 1- (2- (3-aminomethylphenyl) -2-phenylethyl) -3 (S)- [N- (1- (4-cyanobenzyl) -1H] -Imidazol-5-ylethyl) carbamoyl] piperidine; 1- (2-phenethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1 H-Imidazol-5-ylethyl) carbamoyl] piperidine; 1- (2-phenethyl) -3 (R)-[N- (1- (4-cyanobenzyl) -1 H-Imidazol-5-ylethyl) carbamoyl] piperidine; 1- (3-phenylpropyl) -3 (S)-[N- (1- (4-cyanobenzyl) ) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine; 1- (2-benzyl) -3- [N- (1- (4-cyanobenzyl) -1H-imi Dazol-5-ylethyl) carbamoyl] piperidine, 1- (2-chlorobenzyl) -3- [N- (1- (4-cyanobenzyl) -1H -Imidazol-5-ylethyl) carbamoyl] piperidine; 1- (3-chlorobenzyl) -3- [N- (1- (4-cyanobenzyl) -1H -Imidazol-5-ylethyl) carbamoyl] piperidine; 1- (3-chlorobenzyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (2,2-diphenyl-2-hydroxyethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] Piperidine, 1- (3-methoxybenzyl) -3 (S)-[N- (1- (4-cyanobenzyl) ) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine; 1- (3,5-dichlorobenzyl) -3 (S)-[N- (1- (4-cyanoben) Jill) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (3-trifluoromethoxybenzyl) -3 (S)-[N- (1- (4-si Anobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidi , 1- (2,5-dimethylbenzyl) -3 (S)-[N- (1- (4-cyanoben) Jill) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (3-trifluoromethylbenzyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamo Il] piperidine, 1- (3-bromobenzyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (3-methylbenzyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1-isobutyl-3 (S)-[N- (1- (4-cyanobenzyl) -1H-imi Dazol-5-ylethyl) carbamoyl] piperidine, 1- (2-methyl-2-phenylethyl) -3- [N- (1- (4-cyanoben) Jill) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (2- (1-morpholinyl) -2-phenylethyl) -3 (S)-[N- ( 1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoy Le] piperidine, 1- (2- (1-piperidinyl) -2-phenylethyl) -3 (S)-[N- ( 1- (4-cyanobenzyl) -1H-imida Sol-5-ylethyl) carbamoyl] piperidine; 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Zyl) -2-methyl-1H-imidazol-5-ylethyl) carbamoyl] pipe lysine, 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-methoxy Undyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (diphenylmethyl) -3 (S)-[N- (1- (4-cyanobenzyl)- 1H-imidazol-5-ylethyl) carbamoyl] piperidine; 1- (3-methoxyphenethyl) -3 (S)-[N- (1- (4-cyanobenzy) Ru) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (1-naphthylethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (3-chlorophenethyl) -3 (S)-[N- (1- (4-cyanobenzyl) ) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine; 1- (α-methylbenzyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (diphenylmethyl) -3 (S)-[N- (1- (4-cyanobenzyl)- 2-methyl-1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (α-toluenesulfonyl) -3 (S)-[N- (1- (4-cyanobenzy) Ru) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (benzenesulfonyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (1-naphthylenesulfonyl) -3 (S)-[N- (1- (4-cyanoben) Jill) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (3-chlorobenzenesulfonyl) -3 (S)-[N- (1- (4-cyano Benzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine; 1- (3,5-dichlorobenzenesulfonyl) -3 (S)-[N -(1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carba Moyl] piperidine, 1- (α-toluenesulfonyl) -3 (R)-[N- (1- (4-cyanobenzy) Ru) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (α-toluenesulfonyl) -cis-3-methoxycarbonyl-5- [N -(1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carba Moyl] piperidine, 1- (methanesulfonyl) -3 (S)-[N- (1- (4-cyanobenzyl)- 1H-imidazol-5-ylethyl) carbamoyl] piperidine; 1- (diphenylcarbamoyl) -3 (S)-[N- (1- (4-cyanobenzy Ru) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (phenylcarbamoyl) -3 (S)-[N- (1- (4-cyanobenzyl) ) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine; 1- [2- (2-pyridyl) -2-phenyl-2-hydroxyethyl] -3 (S )-[N- (1- (4-cyanobenzyl)- 1H-imidazol-5-ylethyl) carbamoyl] piperidine; 1- (2-pyridylethyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1-phenyl-3 (S)-[N- (1- (4-cyanobenzyl) -1H-imida Sol-5-ylethyl) carbamoyl] piperidine; 1- (3-methylphenyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine, 1- (2,2-diphenylethyl) -3 (S)-[2- (1- (4-cyanoben) Jyl) -1H-imidazol-5-yl) ethylthiomethyl] piperidine, 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Jyl) -1H-imidazol-5-yl) ethylsulfonylmethyl] piperidine, 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) (Jill) -1H-imidazol-5-ylethyl Ru) -N-methyl-carbamoyl] piperidine, 1- (3-bromobenzyl) -3 (S)-[N- (1- (4-cyanobenzyl) -1H-Imidazol-5-ylethyl) -N-methyl-carbamoyl] piperidi , 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Jill) -1H-imidazol-5-ylethyl) aminomethyl] piperidine, 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Jill) -1H-imidazol-5-ylethyl) -N-acetyl-aminomethyl] Piperidine, 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Jil) -2-methyl-1H-imidazol-5-ylethyl) -N-acetyl-a Minomethyl] piperidine, 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-cyanoben) Jill) -1H-imidazol-5-ylethyl) -N-cyclopropylmethyl-a Minomethyl] piperidine, 1- (2,2-diphenylethyl) -3 (S)-[N- (2-methyl-1H-i Midazol-4-ylethyl) -N- (4-cyanobenzoyl) aminomethyl] pi Peridine, 1- (2,2-diphenylethyl) -3 (S)-[5- (4-cyanobenzyl) -1H-imidazol-1-ylmethyl] piperidine, or 1- (2,2-diphenylethyl) -3 (S)-[5- (4-cyanobenzyl) -1H-Imidazol-1-ylethylcarbamoyl] piperidine A compound that inhibits farnesyl-protein transferase, or An optical isomer or a pharmaceutically acceptable salt thereof. 10. 1-phenethyl-cis-3- [N- (1-morpholinyl) carbamyl ] -5- [N- (4-cyanobenzyl-1-imidazole-5-ethyl) carba Mill] piperidine: The compound according to claim 9 or light thereof. Isomers or pharmaceutically acceptable salts. 11. 1- (2-diphenylethyl) -cis-3- [N- (1-morpholini L) carbamyl] -5- [N- (4-cyanobenzyl-1-imidazole-5 Ethyl) carbamyl] piperidine:The compound according to claim 9 or an optical isomer thereof or Pharmaceutically acceptable salts. 12. N- [1-phenethyl-5- (N '-(4-cyanobenzyl-1-imi Dazol-5-ethyl) carbamyl) piperidine-3-carbonyl] methionine : The compound according to claim 9 or an optical isomer thereof or Pharmaceutically acceptable salts. 13. 1- (2-diphenylethyl) -3-methoxycarbonyl-5- [N- (4-cyanobenzyl-1-imidazole-5-ethyl) carbamyl] piperidi N:The compound according to claim 9 or an optical isomer thereof or Pharmaceutically acceptable salts. 14． 1- (2,2-diphenylethyl) -cis-3- [N- (1- (4- Cyanobenzyl) -1H-imidazol-5-ylethyl) carbamoyl] piperi gin: The compound according to claim 9 or an optical isomer thereof or Pharmaceutically acceptable salts. 15. 1- (3-chlorobenzyl) -3- [N- (1- (4-cyanobenzyl) ) -1H-Imidazol-5-ylethyl) carbamoyl] piperidine:The compound according to claim 9 or an optical isomer thereof or Pharmaceutically acceptable salts. 16. 1- (2- (1-morpholinyl) -2-phenylethyl) -3 (S)- [N- (1- (4-cyanobenzyl) -1H-imidazol-5-ylethyl) ca Lubamoyl] piperidine: The compound according to claim 9 or an optical isomer thereof or Pharmaceutically acceptable salts. 17． 1- (diphenylmethyl) -3 (S)-[N- (1- (4-cyanoben) Zyl) -2-methyl-1H-imidazol-5-ylethyl) carbamoyl] pipe lysine:The compound according to claim 9 or an optical isomer thereof or Pharmaceutically acceptable salts. 18. 1- (3-methylphenyl) -3 (S)-[N- (1- (4-cyanobe) Undyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine: The compound according to claim 9 or an optical isomer thereof or Pharmaceutically acceptable salts. 19. 1- (2,2-diphenylethyl) -3 (S)-[N- (1- (4-si Anobenzyl) -1H-imidazol-5-ylethyl) -N-acetyl-amino Methyl] piperidine:The compound according to claim 9 or an optical isomer thereof or Pharmaceutically acceptable salts. 20. 1- (benzenesulfonyl) -3 (S)-[N- (1- (4-cyanobe) Undyl) -1H-imidazol-5-ylethyl) carbamoyl] piperidine: The compound according to claim 9 or an optical isomer thereof or Pharmaceutically acceptable salts. 21. 2. A pharmaceutical carrier and a therapeutically effective amount dispersed in said carrier according to claim 1. A pharmaceutical composition comprising a compound as described above. 22. 6. A pharmaceutical carrier and a therapeutically effective amount dispersed in said carrier according to claim 5. A pharmaceutical composition comprising a compound as described above. 23. Pharmaceutical carrier and therapeutically effective dispersed in the carrier A pharmaceutical composition comprising an amount of the compound of claim 6. 24. 10. A pharmaceutical carrier and a therapeutically effective amount dispersed in said carrier according to claim 9. A pharmaceutical composition comprising a compound as described above. 25. A method for inhibiting farnesyl-protein transferase, comprising: 22. The composition of claim 21, in a therapeutically effective amount for a mammal in need of such inhibition. Administering a substance. 26. A method for inhibiting farnesyl-protein transferase, comprising: 23. The composition of claim 22, wherein said inhibitor is a therapeutically effective amount in a mammal in need thereof. Administering a substance. 27. A method for inhibiting farnesyl-protein transferase, comprising: 24. The composition of claim 23, wherein said mammal is in need of such inhibition in a therapeutically effective amount. Administering a substance. 28. A method for inhibiting farnesyl-protein transferase, comprising: 25. The composition of claim 24, a therapeutically effective amount in a mammal in need of such inhibition. Administering a substance. 29. A method of treating cancer, comprising treating a mammal in need of such treatment. 22. A method comprising administering a therapeutically effective amount of the composition of claim 21. 30. A method of treating cancer, comprising treating a mammal in need of such treatment. 23. A method comprising administering a therapeutically effective amount of the composition of claim 22. 31. A method of treating cancer, comprising treating a mammal in need of such treatment. 24. A method comprising administering a therapeutically effective amount of the composition of claim 23. 32. A method of treating cancer, comprising treating a mammal in need of such treatment. 25. A method comprising administering a therapeutically effective amount of the composition of claim 24. 33. A method of treating a neurofibromin-induced benign proliferative disorder, comprising: 22. A composition according to claim 21 in a mammal in need of such treatment in a therapeutically effective amount. Administering to the subject. 34. A method of treating blindness associated with retinal neovascularization, comprising treating such blindness. Administering to a mammal in need thereof a therapeutically effective amount of the composition of claim 21. A method that includes 35. Those who treat hepatitis delta virus and related virus infections 22. A method according to claim 21, wherein said mammal is in need of such treatment. A method comprising administering a composition as described. 36. A method for preventing restenosis, comprising a mammal in need of such prevention 22. A method comprising administering to the animal a therapeutically effective amount of the composition of claim 21. 37. A method of treating polycystic kidney disease that requires such treatment 22. A method comprising administering to a mammal a therapeutically effective amount of the composition of claim 21. . 38. Combining the compound of claim 1 with a pharmaceutically acceptable carrier. A pharmaceutical composition prepared by 39. Combining the compound of claim 1 with a pharmaceutically acceptable carrier. A method for preparing a pharmaceutical composition comprising: