JP2000511527A - Inhibition of protein farnesyltransferase - Google Patents

Abstract

  (57) [Summary] Novel inhibitors of the protein farnesyltransferase, as well as methods of making the inhibitors and pharmaceutical compositions, are described which treat cancer, restenosis, psoriasis, endometriosis, atherosclerosis, or viral infections. Useful for

Description

DETAILED DESCRIPTION OF THE INVENTION           Inhibition of protein farnesyltransferase   The present invention provides for the prophylactic or other prevention of uncontrolled or abnormal growth of human tissue. The invention relates to compounds which can be used in the medical field for treating in a method. For details, Ming was confirmed to activate the ras protein and thus cell division. , And farnesyl transfer in cancer and restenosis A compound that inhibits the enzyme.                             Background of the Invention   Ras protein (or p21) has a mutant form that is 20% of most types of human cancer And is widely studied because it is found in more than 50% of colon and pancreatic cancers (Gibbs J.B.,Cell1991; 65: 1, Cartwright T., et al., Chimica. Oggi., 1992 10:26). These mutant Ras proteins are present in native ras There is a lack of feedback control, and this lack is associated with their oncogene action. Related. Because the ability to stimulate normal cell division is not This is because some factors cannot be controlled. Transform of mutant ras Recent discovery that gut activity is strictly dependent on post-translational modifications (Gibbs J., et al., Mic. robiol. Rev., 1989; 53: 171) reveals important aspects of the ras function, and A new perspective on cancer treatment was confirmed.   In connection with overexpression and / or function of raw ras protein in addition to cancer There are other conditions of uncontrolled cell growth that may be present. Is muscular vascular restenosis after surgery? It is in a state of being scared. Saphenous vein bypass graft, terminal arteriotomy, and transluminal (trans luminal) Various surgical revascularization techniques such as coronary angioplasty Surgery is a complication known as restenosis due to uncontrolled growth of neointimal tissue Often cause. Biochemistry of restenosis The underlying causes are poorly understood and have been linked to many growth factors and proto-oncogenes. (Naftilan A.J.,Hypertension, 1989; 13: 706, andJ . Clin. Inv est. 83: 1419; Gibbons G.H., outside,Hypertension, 1989; 14: 358; Sato T. et al. ,Molec . Cell. Biol.,1993 ; 13: 3706). ras protein is involved in the cell division process The fact that they are known to be linked can be attributed to many aspects of uncontrolled and dividing cells. And ask for ras protein intervention. From blocking cancer associated with mutant ras By direct analogy, blockade of a ras-dependent process is particularly important for normal ras expression and / or function. If exaggerated by growth stimulators, it may reduce inappropriate tissue growth associated with restenosis. May be reduced or eliminated.   The ras function relies on protein modifications to associate with the inner surface of the plasma membrane. Unlike other membrane-associated proteins, ras proteins are normally transmembrane or hydrophobic. Lacks rows and is initially synthesized in a cytosolic soluble form. ras protein membrane association Association is triggered by a series of post-translational processing steps, A signal is sent by the carboxyl terminal amino acid consensus sequence and the consensus sequence The rows are recognized by the protein farnesyltransferase (PFT). this The consensus sequence is the fourth from the carboxyl terminus followed by two lipophilic amino acids It consists of a cysteine residue located at an amino acid, and a C-terminal residue. Cysteine The sulfhydryl group of the residue is catalyzed by protein phanesyltransferase. In the reaction used, it is alkylated with farnesyl pyrophosphate. Pre Following nitration, the three C-terminal amino acids are cleaved by the endoprotease. The newly exposed alpha-carboxyl group of the prenylated cysteine Methylated by methyltransferase. Ras starting with farnesylation Enzymatic processing of proteins involves the association of proteins with cell membranes To be able to Mutation analysis of the oncogene ras protein Figure 4 shows that modification is essential for transforming activity. Common array system When the amino acid residue is replaced with another amino acid, it is no longer farnesylated and is transferred to the cell membrane. A ras protein is obtained that is immobile and lacks the ability to stimulate cell growth (Hanco ck J.F.Cell, 1989; 57: 1617, Schafer W.R., outside,Science ,1989; 245: 37 9, Casey P.J.,Proc . Natl. Acad. Sci. USA1989; 86: 8323).   Recently, protein farnesyltransferases (PFTs, farnesyltan Protein transferases (FPTs) have been identified in rat brain Specific PFTs were purified to homogeneity (Reiss Y., et al.Bioch . Soc. Trans., 1992; 20: 487-88). The enzyme consists of one alpha subunit (49 kDa) and one base. Is characterized as a heterodimer composed of a protein subunit (46 kDa) And both subunits are required for catalytic activity. Baculovirus strain High levels of expression of the milk PFT and purification of the active form of the recombinant enzyme were also achieved ( Chen W.-J., outside,J . Biol. Chem., 1993; 268: 9675).   In light of the above, the function of the oncogene ras protein is Discovery that it depends strictly on cancer chemotherapy by blocking processing enzymes Give the means. Catalyzes the addition of farnesyl group to ras protein Confirmation and isolation of the protein farnesyltransferase is the key to such intervention Give promising goals. ras farnesyltransferase inhibitor Several recent publications have shown that they have a tumor suppressive effect.   A ras inhibitor is an enzyme that fixes the protein product of the ras gene to the cell membrane. Acts by blocking certain farnesyltransferases You. The role of ras mutants in introducing growth signals into cancer cells Block farnesyltransferase because it depends on a protein That the ras protein remains in the cytosol and transmits growth signals Will not be able to. These facts are well known in the literature.   Peptides of farnesyltransferase B956 and its methyl ester B1086 Peptidomimetic inhibitor is 100 mg / kg, EJ-1 human bladder Xenograft of bladder cancer, HT1080 human fibrosarcoma and human colon cancer into nude mice Was shown to inhibit tumor growth (Nagas T. et al.,Cancer Res., 1995; 55:53. 10-5314). In addition, inhibition of tumor growth by B956 is associated with ras post-translational processing in tumors. It has been shown to be related to the prevention of Thing. Other ras farnesyl transferer Inhibitors specifically prevent ras processing and membrane localization, and Is effective in restoring the transformed phenotype of mutant ras-containing cells (Sepp-Lorenzino L., outside,Cancer Res., 1995; 55: 5302-5309).   In another report (Sun J. et al., Cancer Res. 1995; 55: 4243-4247), ras farnesi. Transtransferase inhibitor FTI276 deletes K-ras mutants and p53 deletions. Is shown to selectively inhibit tumor growth in nude mice with human lung cancer Was. In yet another report, ras farnesyltransferase inhibitor L-7 was reported. Administration of 44,832 daily resulted in breast cancer and salivary in ras transgenic mice. Caused tumor regression of salivary carcinomas (Kohl et al.,Nature Med., 1 995; 1 (8): 792-748). Therefore, ras farnesyltransferase inhibitor Is useful for some forms of cancer, especially those whose growth is dependent on the oncogene ras. You. However, human cancer is one of those that will be responsible for controlling growth and metastasis. Is more Often strengthened when mutations occur in some of the important genes. Sig The null mutation was not enough to sustain growth, and two of the three mutations occurred Only later does the tumor develop and grow. Which of these mutations is a particular type It is difficult to determine if it mainly induces growth in human cancers. Therefore, ras file Renesyltransferase inhibitors grow only on the ras oncogene form. Nonexistent tumors have therapeutic benefit. For example, various rasFT-inhibitors Tumors against tumor lines with either wild-type or mutant ras It was shown to have a growth inhibitory effect in vivo (in vivo) (Sepp-Lorenzino, su pra.). In addition, there are several ras-related proteins that are prenylated. R-Ras2 / Proteins such as TC21 are used in vivo to produce farnesyltransferase and gene. A ras-related protein prenylated by both Ranyltransferase I (Carboni, outside,Oncogene, 1995; 10: 1905-1913). Therefore, ras farnesi Lutransferase inhibitors also prevent prenylation of these proteins Therefore, it is useful for blocking the growth of tumors induced by other oncogenes. Would be for   With respect to restenosis and vascular proliferative diseases, inhibition of cellular ras can reduce vascular injury in vivo. It has been shown to inhibit smooth muscle proliferation after injury (Indolfi C, outside,Nature Med., 199 5; 1 (6): 541-545). This report describes farnesyl transfer in this disease. Crucially supports the role of the inhibitor and inhibits the accumulation and proliferation of vascular smooth muscle Is shown.                               Summary of the Invention   The present invention relates to compounds having the following formula I, and their pharmaceutically acceptable salts, Provides amides, amides, and prodrugs: here,   R^{twenty one}Is hydrogen or C₁~ C₆Alkyl;   R^QIs   n is 0 or 1;   A is -COR^a, -CO_TwoR^{a '}, -CONHR^{a '}, -CSR^a, -C (S) OR^{a '}, -C (S) NHR^{a '},   R^a, R^{a '}, And R^{a "}Is, independently, C₁~ C₆Alkyl,-(CH_Two)_m-Cycloalkyl ,-(CH_Two)_m-Aryl, or-(CH_Two)_m-Heteroaryl;   Each m is independently 0 to 3;   R¹, R^Two, And R^FourIs independently hydrogen or C₁~ C₆Alkyl;   R^ThreeIs-(CH_Two)_m-(R^bHeteroaryl substituted with) or C₁~ C₆Alkyl;   t is 2 to 6;   R^bIs -O-phenyl, -O-benzyl, halogen, C₁~ C₆Alkyl, water -O- (CH_Two)_yNR^aR^{a '};   -O- (CH_Two)_m-Cycloalkyl,-(CH_Two)_m-Cycloalkyl, -O- (CH_Two)_m-Ally ,-(CH_Two)_m-Aryl, or-(CH_Two)_m-Heteroaryl;   y is 2 or 3;   R^FiveIs   Rⁱ, R^g, And R^hIs independently hydrogen, halogen, -OC₁~ C₆Alkyl, Aryl, -N_Three, -CF_TwoCF_Three, -SO_TwoR^a, -SO_TwoNR^aR^{a '}, -CHO, or -OCOCH_Three; And ,   R^c, R^b, R^e, And R^fIs independently C₁~ C₆Alkyl,-(CH_Two)_m-Phenyl, water Element,-(CH_Two)_m-0H,-(CH_Two)_mNH_Two,-(CH_Two)_m-Cycloalkyl, or -CN, .   In a preferred embodiment of the compounds of formula I,   R¹Is hydrogen, R^TwoIs hydrogen, R^FourIs hydrogen, R^{twenty one}Is hydrogen or CH_Three; And   A is It is.   In another preferred embodiment of the compound of formula I,   R^ThreeIs Or -CH_Two-CH (CH_Three)_Two.   R¹Is hydrogen, R^TwoIs hydrogen, R^FourIs hydrogen, and R^{twenty one}Is hydrogen or CH_ThreeIt is.   In another preferred embodiment of the compound of formula I,   R^FiveIs Is;   Where RⁱIs hydrogen, Cl, Br, F, or NH_TwoIt is.   Compounds having the following formula II, and their pharmaceutically acceptable salts, esters, amides , And prodrugs are also provided:   here,   R^{twenty one}Is hydrogen or methyl;   R⁷Is hydrogen or methyl;   R⁸Is hydrogen, halogen, C₁~ C₆Alkyl, -O-benzyl, -OC₁~ C₆Alkyl, -CF_Three, -OH, -O- (CH_Two)_m-Pyridyl or phenyl; R^Ten, R¹¹, R¹³, And R¹⁴Is independently hydrogen, C₁~ C₆Alkyl, or-(CH_Two)_m -Phenyl;   Each m is independently 0 to 3;   R¹²Is And   R^j, R^k, And R¹Is independently hydrogen, halogen, -OC₁~ C₆Alkyl, -C₁~ C₆ Alkyl, -NHR^a, Or NH_Two,.   In a preferred embodiment of the compounds of formula II,¹¹And R¹⁴Is methyl.   In another preferred embodiment of the compounds of formula II, R⁸Is methyl or methoxy .   Compounds having the following formula III, and their pharmaceutically acceptable salts, esters, And prodrugs are also provided:here,   X is NH, O, or -N (CH_Three);   R¹⁵Is -O-benzyl, -CF_Three, Hydrogen, halogen, -OC₁~ C₆Alkyl, phenyl , -O- (CH_Two)_m-Pyridyl, or -C₁~ C₆Alkyl;   m is from 0 to 3; and   R¹⁶Is phenyl, hydrogen, or C₁~ C₆Alkyl.   Compounds having the following formula IV, and their pharmaceutically acceptable salts, esters, amides , And prodrugs are also provided:   here,   X is NH, O, or N (CH_Three);   R¹⁵Is -O-benzyl, -CF_Three, Hydrogen, halogen, C₁~ C₆Alkyl, -O-C₁~ C₆A Alkyl, phenyl, or -O- (CH_Two)_m-Pyridyl,   R¹⁶And R^{16 '}Is C₁~ C₆Alkyl;   m is from 0 to 3; and R^{twenty one}Is hydrogen or methyl.   In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I, II, III, or IV. To provide a composition that is acceptable.   Also provided is a method of treating or preventing restenosis, said method comprising: Treats patients at risk for restenosis with a therapeutically effective amount of Formula I, II, III, or I. Administering the compound of V.   Also provided is a method of treating cancer, wherein the method comprises treating a cancer patient with a therapeutically effective amount of Formula I, Administering a compound of II, III, or IV.   Also provided is a method of treating psoriasis, the method comprising providing a psoriatic patient with a therapeutically effective amount of Administering a compound of Formula I, II, III, or IV.   Also provided is a method of treating a viral infection, the method comprising administering to a patient infected with a virus. Administering a therapeutically effective amount of a compound of Formula I, II, III, or IV.   In a more preferred embodiment, the cancer is lung, colon, breast, pancreatic, instep. It is thyroid cancer or bladder cancer.   In a most preferred embodiment, the compound of Formula I, II, III, or IV is   (S)-[1-[(4-benzyloxy-benzyl)-(phenethyl-carbamoyl -Methyl) -carbamoyl] -2- (3H-imidazol-4-yl) -ethyl]- Carbamic acid benzyl ester;   (S)-[1-[[2-benzyloxy-ethylcarbamoyl] -methyl] -[4-Chlorobenzyl] -carbamoyl] -2- (1H-imidazole-4-i L) -ethyl] -carbamic acid benzyl ester;   (S)-[1-[(4-benzyloxy-benzyl)-[(2-phenyl-propyl -Carbamoyl) -methyl] -carbamoyl] -2- (1H-imidazole-4- Yl) -ethyl] -carbamic acid benzyl ester;   (S)-[1-[(4-benzyloxy-benzyl)-[(2,2-diphenyl-ethyl Rucarbamoyl) -methyl] -carbamoyl] -2- (1H-imidazole-4-i L) -ethyl] -carbamic acid benzyl ester;   (S) -N- (4-benzyloxy-benzyl) -2- (3-benzyl-ureido) -3- (1H-Imidazol-4-yl) -N-[(2-phenyl-propylcarba Moyl) -methyl] -propionamide;   (S)-[1- {biphenyl-4-ylmethyl-[(2-methyl-2-phenyl -Propylcarbamoyl) -methyl] -carbamoyl} -2- (1H-imidazole -4-yl) -ethyl] -carbamic acid benzyl ester;   (S)-[1- {biphenyl-4-ylmethyl-[(2-phenyl-propylca Rubamoyl) -methyl] -carbamoyl} -2- (1H-imidazol-4-yl) -Ethyl] -carbamic acid benzyl ester;   (S)-[1-((4-benzyloxy-benzyl)-{[2- (2-fluoro- Enyl) -ethylcarbamoyl] -methyl} -carbamoyl) -2- (1H-imidazol-4-yl) -ethyl] -carbamic acid benzyl ester;   (S)-[1-{(4-benzyloxy-benzyl)-[(2-pyridine-2-i [L-ethylcarbamoyl) -methyl] -carbamoyl} -2- (1H-imidazo Ru-4-yl) -ethyl] -carbamic acid benzyl ester;   (S)-[1-((4-benzyloxy-benzyl)-{[2- (2-bromo- Nil) -ethylcarbamoyl] -methyl} -carbamoyl) -2- (1H-imidazo 4-yl) -ethyl] -carbamic acid benzyl ester;   (S)-[1-{(4-benzyloxy-benzyl)-[(1-methyl-2-fe Nyl-ethylcarbamoyl) -methyl] -carbamoyl} -2- (1H-imidazo Ru-4-yl) -ethyl] -carbamic acid benzyl ester;   (S)-[1-{(4-benzyloxy-benzyl)-[(2-phenyl-2-pi Lysin-2-yl-ethylcarbamoyl) -methyl] -carbamoyl {-2- (1H -Imidazol-4-yl) -ethyl] -carbamic acid benzyl ester;   (S)-[1-{(4-chloro-benzyl)-[(2-phenyl-propylcarba Moyl) -methyl] -carbamoyl} -2- (1H-imidazol-4-yl) -d Tyl] -carbamic acid benzyl ester;   (S)-[1-{(4-benzyloxy-benzyl)-[(2-phenyl-butyl Carbamoyl) -methyl] -carbamoyl} -2- (1H-imidazol-4-yl ) -Ethyl] -carbamic acid benzyl ester;   (S) -N- (4-benzyloxy-benzyl) -3- (1H-imidazole-4- Yl) -2- (3-phenyl-propionylamino) -N-[(2-phenyl-pro Pyrcarbamoyl) -methyl] -propionamide;   (S)-[1-{(4-fluoro-benzyl)-[(2-phenyl-propyl-ca) Rubamoyl) -methyl] -carbamoyl} -2- (1H-imidazol-4-yl) -Ethyl] -carbamic acid benzyl ester;   (S)-(2- (1H-imidazol-4-yl) -1-{-(4-methyl-benzyl) -[(2-phenyl-propylcarbamoyl) -methyl] -carbamoyl} -ethyl L) -carbamic acid benzyl ester;   (S)-(2- (1H-imidazol-4-yl) -1-{-(4-methoxy-benzyl) )-[(2-Phenyl-propylcarbamoyl) -methyl] -carbamoyl} -e Tyl) -carbamic acid benzyl ester;   (S)-[1-[{[2- (2-amino-phenyl) -propylcarbamoyl]- Methyl {-(4-benzyloxy-benzyl) -carbamoyl] -2- (3H-i Midazol-4-yl) -ethyl] -carbamic acid benzyl ester;   (S)-[1-{(4-fluoro-benzyl)-[(2-methyl-2-phenyl- Propylcarbamoyl) -methyl] -carbamoyl {-2- (1H-imidazole- 4-yl) -ethyl] -carbamic acid benzyl ester;   (S)-[1- {benzyl-[(2-phenyl-propylcarbamoyl) -methyl] ] -Carbamoyl {-2- (1H-imidazol-4-yl) -ethyl] -carbami Acid benzyl ester; (S)-[1-((4-benzyloxy-benzyl)-｛ [2- (2-chloro-phenyl) -2-phenyl-ethylcarbamoyl] -methyl {-Carbamoyl) -2- (1H-imidazol-4-yl) -ethyl] -carbami Acid benzyl ester;   (S)-[1-{(4-benzyloxy-benzyl)-[(2-ethyl-2-fe Nyl-butylcarbamoyl) -methyl] -carbamoyl} -2- (3 H-Imidazol-4-yl) -ethyl] -carbamic acid benzyl ester;   (S) -N- (4-benzyloxy-benzyl) -2- (3-benzyl-ureido) -3- (1H-Imidazol-4-yl) -N-[(2-phenyl-propylcarba Moyl) -methyl] -propionamide;   (S) -N- (4-benzyloxy-benzyl) -2- (3-benzyl-ureido ) -3- (1H-Imidazol-4-yl) -N-[(2-phenyl-butylcarbamo Yl) -methyl] -propionamide;   (S)-[1-{(2-chloro-benzyl)-[(2-phenyl-propylcarba Moyl) -methyl] -rubamoyl} -2- (1H-imidazol-4-yl) -ethyl Ru] -carbamic acid benzyl ester;   (S)-[1-{(4-bromo-benzyl)-[(2-phenyl-propylcarba Moyl) -methyl] -carbamoyl} -2- (1H-imidazol-4-yl) -d Tyl] -carbamic acid benzyl ester;   (S)-[1-{(3-chloro-benzyl)-[(2-phenyl-propylcarba Moyl) -methyl] -carbamoyl {-2- (1H-imidazol-4-yl) ethyl ] -Rubamic acid benzyl ester;   (S)-[1-{(4-chloro-benzyl)-[(2-methyl-2-phenylop) Ropylcarbamoyl) -methyl] -carbamoyl} -2- (1H-imidazole-4 -Yl) -ethyl] -carbamic acid benzyl ester;   (S)-[1-((4-benzyloxy-benzyl)-{[2- (2-chloro-phen Nil) -propylcarbamoyl] -methyl} -carbamoyl) -2- (1H-imida Sol-4-yl) -ethyl] -carbamic acid benzyl ester;   (S)-(2- (1H-imidazol-4-yl) -1-{(2-methoxy- Ndyl)-[(2-phenyl-propylcarbamoyl) -methyl] -carbamoyl ｝ -Ethyl) -carbamic acid benzyl ester;   (S)-(2- (1H-imidazol-4-yl) -1-{[(2-phenyl-propyl Rucarbamoyl) -methyl]-[4- (pyridin-4-ylmethoxy) -benzyl ] -Carbamoyl {-ethyl) -carbamic acid benzyl ester;   (S)-(2- (1H-imidazol-4-yl) -1-{(3-methoxy-benzyl) )-[(2-Phenyl-propylcarbamoyl) -methyl] -carbamoyl} -e Tyl) -carbamic acid benzyl ester;   (S)-(2- (1H-imidazol-4-yl) -1-{[(2-phenyl-propyl Rucarbamoyl) -methyl]-[4- (pyridin-3-ylmethoxy) -benzyl] -Carbamoyl {-ethyl) -carbamic acid benzyl ester;   (S)-(2- (1H-imidazol-4-yl) -1- {naphthalen-1-ylme Tyl-[(2-phenyl-propylcarbamoyl) -methyl] -carbamoyl}- Ethyl) -carbamic acid benzyl ester;   (S)-{2- (1H-imidazol-4-yl) -1-[[(2-phenyl-propyl Rucarbamoyl) -methyl]-(4-trifluoromethyl-benzyl) -carbamo Yl] -ethyl} -carbamic acid benzyl ester;   (S)-(2- (1H-imidazol-4-yl) -1-{[(2-methyl-2-fe Nyl-propylcarbamoyl) -methyl] -pyridin-3-ylmethyl-carba Moyl {-ethyl) -carbamic acid benzyl ester;   (S)-(2- (1H-imidazol-4-yl) -1-{[(2-methyl-2-fe Nyl-propylcarbamoyl) -methyl]-[4- (pyridin-2-ylmethoxy) ) -Benzyl] -carbamoyl} -ethyl) -carbamic acid Benzyl ester;   (S)-[1- {benzyl-[(2-methyl-2-phenyl-propylcarbamo) Yl) -methyl] -carbamoyl} -2- (1H-imidazol-4-yl) -ethyl Ru] -carbamic acid benzyl ester;   (S)-(2- (1H-imidazol-4-yl) -1-{-(2-methyl-benzyl) -[(2-phenyl-propylcarbamoyl) -methyl] -carbamoyl} -ethyl L) -carbamic acid benzyl ester;   (S)-(2- (1H-imidazol-4-yl) -1-{-(4-methoxy-benzyl) )-[(2-Methyl-2-phenyl-propylcarbamoyl) -methyl] -carba Moyl {-ethyl) -carbamic acid benzyl ester;   (S)-[1-{(4-benzyloxy-benzyl)-[(2-cyano-2-fe Nyl-ethylcarbamoyl) -methyl] -carbamoyl} -2- (1H-imidazo Ru-4-yl) -ethyl] -carbamic acid benzyl ester;   (S)-(2- (1H-imidazol-4-yl) -1-{[(2-methyl-2-fe Nyl-propylcarbamoyl) -methyl] -pyridin-2-ylmethyl-carba Moyl {-ethyl) -carbamic acid benzyl ester;   (S)-(2- (1H-imidazol-4-yl) -1-{-(3-methyl-benzyl) -[(2-phenyl-propylcarbamoyl) -methyl] -carbamoyl} -ethyl L) -carbamic acid benzyl ester;   (S)-[1-{(4-dimethylamino-benzyl)-[(2-phenyl-propyl Rucarbamoyl) -methyl] -carbamoyl} -2- (1H-imidazole-4-i L) -ethyl] -carbamic acid benzyl ester;   (S)-(2- (1H-imidazol-4-yl) -1-{[(2-methyl-2-fe Nyl-propylcarbamoyl) -methyl]-[4- (pyridin-4-ylmethoxy) -Benzyl] -carbamoyl} -ethyl) -carbamic acid Benzyl ester;   (S)-(2- (1H-imidazol-4-yl) -1-{[(2-methyl-2-fe Nyl-propylcarbamoyl) -methyl]-[4- (pyridin-3-ylmethoxy) ) -Benzyl] -carbamoyl} -ethyl) -carbamic acid benzyl ester;   (2- (1-H-imidazol-4-yl) -1- {isobutyl-[(2-phenyl -Propylcarbamoyl) -methyl] -carbamoyl {-ethyl) -carbamine Acid benzyl ester;   (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-fe Nyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imidazo 4-yl) -ethyl] -carbamic acid benzyl ester;   (S) -2- (3-benzyl-3-methyl-ureido) -N- (4-benzyloxy C-benzyl) -3- (1H-imidazol-4-yl) -N-[(2-methyl-2- Phenyl-propylcarbamoyl) -methyl] -propionamide;   (S)-[1-{(4-benzyloxy-benzyl)-[(2-hydroxy-2- Phenyl-ethylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imida Sol-4-yl) -ethyl] -carbamic acid benzyl ester;   (S)-(2- (1H-imidazol-4-yl) -1-{-(4-methoxy-benzyl) )-[(2-Phenyl-propylcarbamoyl) -methyl] -carbamoyl} -e Tyl) -carbamic acid benzyl ester;   (S)-[1-((4-benzyloxy-benzyl)-{[2- (2-chloro-phen Nil) -ethylcarbamoyl] -methyl} -carbamoyl) -2- (1H-imidazol-4-yl) -ethyl] -carbamic acid benzyl ester;   (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-fe Nyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (1H-imidazo 4-yl) -ethyl] -carbamic acid thiophen-3-ylmethyl ester ;   (S)-[1-{(4-chloro-benzyl)-[1- (2-methyl-2-phenyl- Propylcarbamoyl) -ethyl] -carbamoyl} -2- (3H-imidazole- 4-yl) -ethyl] -carbamic acid benzyl ester;   (S)-(2- (1H-imidazol-4-yl) -1-{-(4-methyl-benzyl) -[(2-methyl-2-phenyl-propylcarbamoyl) -methyl] -Carbamoyl {-ethyl) -carbamic acid benzyl ester;   (S)-(2- (1H-imidazol-4-yl) -1-{(2-methoxy-begone Zyl)-[(2-methyl-2-phenyl-propylcarbamoyl) -methyl] -ca Rubamoyl {-ethyl) -carbamic acid benzyl ester;   (S) -2- (3-benzyl-3-methyl-ureido) -N- (4-chloro-ben (Zyl) -3- (1H-imidazol-4-yl) -N-[(2-methyl-2-phenyl -Propylcarbamoyl) -methyl] -propionamide;   (S)-(2- (1H-imidazol-4-yl) -1-{-(3-methoxy-benzyl) )-[(2-Methyl-2-phenyl-propylcarbamoyl) -methyl] -carba Moyl {-ethyl) -carbamic acid benzyl ester;   (S)-(2- (1H-imidazol-4-yl) -1-{[(2-methyl-2-fe Nyl-propylcarbamoyl) -methyl]-[2- (pyridin-4-ylmethoxy) -Benzyl] -carbamoyl} -ethyl) -carbamic acid benzyl ester;   (S)-[1- {cyclohexylmethyl-[(2-phenyl-propylcarbamo) Yl) -methyl] -carbamoyl} -2- (3H-imidazol-4-yl) -e Tyl] -carbamic acid benzyl ester;   (S)-[1-{(4-benzyloxy-benzyl)-[(2-phenyl-pentene -Carbamoyl) -methyl] -carbamoyl} -2- (3H-imidazole-4 -Yl) -ethyl] -carbamic acid benzyl ester;   (S)-[1-{[2- (4-benzyloxy-phenyl) -ethyl]-[(2-methyl Ru-2-phenyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (3 H-Imidazol-4-yl) -ethyl] -carbamic acid benzyl ester;   (S)-(2- (3H-Imidazol-4-yl) -1-{[2- (4-methoxy- Enyl) -ethyl]-[(2-methyl-2-phenyl-propylcarbamoyl) -meth Tyl] -carbamoyl {-ethyl) -carbamic acid benzyl ester;   (S)-[1-[{[2- (2-amino-phenyl) -ethylcarbamoyl] -methyl {-(4-benzyloxy-benzyl) -carbamoyl] -2- (3H-imidazole -4-yl) -ethyl] -carbamic acid benzyl ester;   (2- (1H-imidazol-4-yl) -1- {isobutyl-[(2-phenyl- Propylcarbamoyl) -methyl] -carbamoyl {-ethyl) -carbamic acid Benzyl ester;   (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-phenyl -Propylcarbamoyl) -methyl] -carbamoyl｝ -2- (3H-imidazo Ru-4-yl) -ethyl] -methyl-carbamic acid benzyl ester;   (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2 -Phenyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (3-meth Tyl-3H-imidazol-4-yl) -ethyl] -benzylcarbamate Le;   (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-fe Nyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (1-methyl- 1H-imidazol-4-yl) -ethyl] -carbamic acid benzyl ester;   (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-fe Nyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imidazo 4-yl) -ethyl] -carbamic acid furan-2-ylmethyl ester;   (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-fe Nyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imidazo 4-yl) -ethyl] -thiophen-2-ylmethylcarbamate Le;   (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-fe Nyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imidazo 4-yl) -ethyl] -carbamic acid pyridin-3-ylmethyl ester ;   (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-fe Nyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imidazo 4-Hyl) -ethyl] -carbamic acid 1H-imidazol-4-ylmethyl ester;   (S) -2- (3-benzyl-ureido) -N- (4-chloro-benzyl) -3- (3 H-imidazol-4-yl) -N-[(2-methyl-2-phenyl -Propylcarbamoyl) -methyl] -propionamide;   (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-fe Nyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imidazo 4-yl) -ethyl] -carbamic acid 4-methoxy-benzyl ester;   (S) -2- (3-benzyl-thioureido) -3- (3H-imidazole-4- Yl) -N- (4-methyl-benzyl) -N-[(2-methyl-2-phenyl-pro Pyrcarbamoyl) -methyl] -propionamide;   (S) -2-acetylamino-N- (4-benzyloxy-benzyl) -3- (3H -Imidazol-4-yl) -N-[(2-methyl-2-phenyl-propylcal Bamoyl) -methyl] -propionamide;   (S)-(2- (3H-imidazol-4-yl) -1-{[(2-methyl-2-fe Nyl-propylcarbamoyl) -methyl] -pyridin-4-ylmethyl-carba Moyl {-ethyl) -carbamic acid benzyl ester;   (S)-{2- (3H-imidazol-4-yl) -1-[(4-iodo-benzyl) -(Phenethylcarbamoyl-methyl) -carbamoyl] -ethyl} -carbamine Acid benzyl ester;   (S)-[1-{(4-amino-benzyl)-[(2-methyl-2-phenyl-p Ropylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imidazole-4 -Yl) -ethyl] -carbamic acid benzyl ester;   (S)-[1-{(4-ethoxy-benzyl)-[(2-methyl-2-phenyl- Propylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imidazole- 4-yl) -ethyl] -carbamic acid benzyl ester;   (S)-[1-{[4- (2-dimethylamino-ethoxy) -benzyl]-[(2- Methyl-2-phenyl-propylcarbamoyl) -methyl] -cal Bamoyl {-2- (3H-imidazol-4-yl) -ethyl] -bencarbamate A gill ester; and   (2- (1H-imidazol-4-yl) -1- {isobutyl-[(2-methyl-2 -Phenyl-propylcarbamoyl) -methyl] -carbamoyl {-ethyl) -ca It is rubamic acid benzyl ester.                           Detailed description of the invention   The present invention relates to compounds having the following formula I, and their pharmaceutically acceptable salts, Provides amides, amides, and prodrugs: here,   R^{twenty one}Is hydrogen or C₁~ C₆Alkyl;   R^QIs  n is 0 or 1;   A is -COR^a, -CO_TwoR^{a '}, -CONHR^{a '}, -CSR^a, -C (S) OR^{a '}, -C (S) NHR^{a '},   R^a, R^{a '}, And R^{a "}Is independently C₁~ C₆Alkyl,-(CH_Two)_m-Cycloa Lucil,-(CH_Two)_m-Aryl,-(CH_Two)_m-Heteroaryl;   Each m is independently 0 to 3;   R¹, R^Two, And R^FourIs independently hydrogen or C₁~ C₆Alkyl;   R^ThreeIs C₁~ C₆Alkyl or-(CH_Two)_m− (R^bHeteroaryl substituted with   t is 2 to 6;   R^bIs -O-phenyl, -O-benzyl, halogen, C₁~ C₆Alkyl, water(CH_Two)_yNR^aR^{a '}, -O- (CH_Two)_m-Cycloalkyl,-(CH_Two)_m-Cycloalkyl, -O- (CH_Two )_m-Aryl,-(CH_Two)_m-Aryl, or-(CH_Two)_m-Heteroaryl;   y is 2 or 3;   R^FiveIs   Rⁱ, R^g, And R^hIs independently hydrogen, halogen, -OC₁~ C₆Alkyl, C₁~ C₆A Lucil, -CN, -OPO_ThreeH_Two, -CH_TwoPO_ThreeH_Two, -O-phenyl, -O-benzyl , -N_Three, -CF_TwoCF_Three, -SO_TwoR^a, -SO_TwoNR^aR^{a '}, -CHO, or -OCOCH_ThreeAnd   R^c, R^d, R^eAnd R^fIs independently C₁~ C₆Alkyl,-(CH_Two)_m-Phenyl, hydrogen ,-(CH_Two)_m-OH,-(CH_Two)_mNH_Two,-(CH_Two)_m-Cycloalkyl, or -CN.   Compounds having the following formula II, and their pharmaceutically acceptable salts, esters, amides , And prodrugs are also provided: here,   R^{twenty one}Is hydrogen or methyl;   R⁷Is hydrogen or methyl;   R⁸Is hydrogen, halogen, C₁~ C₆Alkyl, -O-benzyl, -OC₁~ C₆Alkyl, -CF_Three, -OH, -O-CH_Two-Pyridyl or phenyl;   R^Ten, R¹¹, R¹³And R¹⁴Is independently hydrogen, C₁~ C₆Alkyl, or-(CH_Two)_m -Phenyl;   Each m is independently 0 to 3;   R¹²Is And   R^j, R^k, And R^lIs independently hydrogen, halogen, -OC₁~ C₆Alkyl, -C₁~ C₆A Lucil, or -NHR^a, Or NH_Two,.   Compounds having the following formula III, and their pharmaceutically acceptable salts, esters, And prodrugs are also provided: here,   X is NH, O, or -N (CH_Three);   R¹⁵Is -O-benzyl, -CF_Three, Hydrogen, halogen, C₁~ C₆Alkyl, -OC₁~ C₆A Lucil, -O- (CH_Two)_m-Pyridyl or phenyl;   m is from 0 to 3; and   R¹⁶Is phenyl, hydrogen, or C₁~ C₆Alkyl.   Compounds having the following formula IV, and their pharmaceutically acceptable salts, esters, amides , And prodrugs are also provided:here,   X is NH, O, or -N (CH_Three);   R¹⁵Is -O-benzyl, -CF_Three, Hydrogen, halogen, C₁~ C₆Alkyl, -OC₁ ~ C₆Alkyl, phenyl, or -O- (CH_Two)_m-Pyridyl;   R¹⁶And R^{16 '}Is C₁~ C₆Alkyl;   m is from 0 to 3; and   R^{twenty one}Is hydrogen or methyl.   The term "alkyl" refers to a straight or branched chain having 1 to 6 carbon atoms. Hydrocarbon means, for example, methyl, ethyl, n-propyl, isopropyl, n -Butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl Including sill etc.   The term "cycloalkyl" refers to a saturated carbon atom ring containing from 3 to 7 carbon atoms. Means, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl Includes xyl, adamantyl and the like.   The term “aryl” refers to phenyl, 5-fluorenyl, 1-naphthyl, or Or an aromatic ring which is a 2-naphthyl group, which is unsubstituted or alkyl, O-alkyl and S-alkyl, OH, SH, F, Cl, Br, I, CF_Three, NO_Two, NH_Two, N HCH_Three, N (CH_Three)_Two, NHCO-alkyl, (CH_Two)_mCO_TwoH, (CH_Two)_mCO_Two-Alkyl, (CH_Two)_mSO_Three H, (CH_Two)_mPO_ThreeH_Two, (CH_Two)_mPO_Three(Alkyl)_Two, (CH_Two)_mSO_TwoNH_Two, And (CH_Two)_mSO_TwoNH- Substituted with one to three substituents selected from alkyl (where alkyl Is defined as above and m = 0, 1, 2, or 3.)   The term "heteroaryl" refers to 2- or 3-thienyl, 2- or 3- Furanyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, imida Hetero which is a zolyl, 2-, 3-, 4-, 5-, 6- or 7-indoxyl group An aromatic ring, unsubstituted or as defined above for aryl Substituted with one or two substituents selected from the group of the above substituents.   The symbol "-" means a bond.   The term "patient" refers to all animals, including humans. patient Examples include those of humans, cows, dogs, cats, goats, sheep, and pigs.   "Therapeutically effective amount" means that when administered to a patient, a virus, restenosis, cancer, Improve the symptoms of atherosclerosis, psoriasis, endometriosis or restenosis Or the amount of a compound of the invention that prevents atherosclerosis. Therapeutically An effective amount of a compound of the invention may be administered to a patient in an amount and observed. This can be easily determined by those skilled in the art. Further, those skilled in the art Cancer, viral infection, restenosis, atherosclerosis, psoriasis or endometriosis Patients with or at risk for restenosis or atherosclerosis Familiar with identifying.   The term "cancer" includes, but is not limited to, the following cancers:   milk;   Ovaries;   neck;   prostate;   Testicles;   esophagus;   Glioblastoma;   Neuroblastoma;   stomach;   Cutaneous, keratoblastoma;   Lung, epidermoid carcinoma, large cell carcinoma, adenocarcinoma;   Bone;   Colon, adenocarcinoma, adenoma;   Pancreas, adenocarcinoma;   Thyroid, follicular, undifferentiated, papillary;   Seminoma   melanoma;   sarcoma;   Bladder cancer;   Liver cancer and bile duct;   Kidney cancer;   Bone marrow disorders;   Lymphatic disorder, Hodgson's disease, hairy cells;   Oral and pharyngeal (mouth), lips, tongue, mouth, pharynx;   Small intestine;   Colon-rectum, large intestine, rectum;   Brain and central nervous system; and   leukemia.   “Pharmaceutically acceptable salts, esters, amides, and prodrugs” as used herein The term is used to indicate that excessive toxicity, irritation, allergic reactions, etc. Suitable for use in contact with the patient's tissue, and deserves a reasonable benefit / risk ratio Carboxylic acid salts of the compounds of the present invention, which are effective for the intended use Acid addition salts, esters, amides, and prodrugs; Refers to zwitterionic forms of the compounds of the invention. The term “salt” refers to the relatively Non-toxic, inorganic and organic acid addition salts. These salts are the last components of the compound. The purified compound in situ during separation and purification, or in free base form, is treated with a suitable organic or Apart from inorganic acids And by separating the salt thus formed. Typical Salts include bromate, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, Phaseates, oleates, palmitates, stearate, laurate, borate Acid, benzoate, lactate, phosphate, tosylate, citrate, Oleate, fumarate, succinate, tartrate, naphtholate mesylate, Includes lucoheptone, lactobionate and lauryl sulfonate . These include sodium, lithium, potassium, calcium, magnesium, etc. Based on alkali and alkaline earth metals, and non-toxic ammonium Ammonium, quaternary ammonium and amine cations Lamethylammonium, tetraethylammonium, methylamine, dimethylamine It is not limited to min, trimethylamine, triethylamine, ethylamine and the like. (See, eg, S.M. Berge et al., "Pharmaceutical Sal, which is incorporated herein by reference. ts ”,J . Pharm. Sci., 1977; 66: 1-19. )   Examples of pharmaceutically acceptable non-toxic esters of compounds of the present invention include those wherein the alkyl group is linear or Is a branched chain C₁~ C₆Alkyl esters are included. Acceptable esters are C_Five~ C₇Shi Chloroalkyl esters, as well as (but not limited to) benzyl ) Also include arylalkyl esters. C₁~ C_FourAlkyl esters are preferred. Esters of the compounds of the present invention may be prepared by conventional methods.   Examples of pharmaceutically acceptable non-toxic amides of compounds of the present invention include ammonia, primary C₁~ C₆Alkylamine and secondary C₁~ C₆Amides derived from dialkylamines Included, wherein the alkyl group is straight or branched. For secondary amines, The amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. A Mononia, C₁~ C_ThreeAlkyl primary amine and C₁~ C_TwoAmides derived from dialkyl secondary amines are preferred. Compound of the present invention The product amide can be prepared by conventional methods.   The term “prodrug” is rapidly applied, for example, by hydrolysis in blood. Refers to a compound that is transformed in vivo to produce the parent compound of the above formula. A thorough study has Higuchi and V.S. Stella, “Pro-drugs as Novel Delivery  Systems ”, the A.C.S. Symposium Series Vol 14, and Bioreversible Carr iers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Associa and Pergamon Press, 1987, both of which are incorporated herein by reference. Can be   The compounds of the present invention may be used alone or in all excipients well known to those skilled in the art, Administered to the patient as part of a composition that includes other ingredients such as diluents and carriers be able to. The composition can be administered orally, rectally, parenterally (intravenously) to humans and animals. Intra, intramuscular or subcutaneous), intracapsular, intravaginal, intraperitoneal, intravesical, topical (powder, ointment) Or drip) or as a buccal or intranasal spray can do.   Compositions suitable for parenteral injection include sterile, physiologically acceptable aqueous or non-aqueous solutions Liquids, dispersions, suspensions or emulsions, and sterile injectable solutions or Include sterile powder for reconstitution into a powder. Suitable aqueous and non-aqueous carriers, dilution Examples of agents, solvents or vehicles include water, ethanol, polyol, (propylene Glycol, polyethylene glycol, glycerol, etc.), Cremophor EL (Hima Oil and derivatives of ethylene oxide; Sigma Chemical Co., St. Purchased from Louis, MO And appropriate mixtures thereof, vegetable oils (such as olive oil), and olive oil. Injectable organic esters such as ethyl oleate are included. The proper liquidity is For example, by using a coating such as lecithin, the required particle size in the case of a dispersion By maintaining And by the use of surfactants.   These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. It may also include. Prevention of the action of microorganisms is due to various antibacterial and antibacterial drugs, For example, paravin, chlorobutanol, phenol, sorbic acid, etc. Things. Contains isotonic agents, such as sugar, sodium chloride, etc. Would also be desirable. Absorption retardants, such as aluminum monostearate And gelatin can prolong absorption of injectable dosage forms. You.   Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules Is included. In such solid dosage forms, the active compound is sodium citrate Or at least one inert conventional excipient such as dicalcium phosphate (or Or carrier), or (a) a filler or bulking agent such as starch, lactose, Loose, glucose, mannitol, and silicic acid; (b) binders, such as Cimethylcellulose, alginate (alignates), gelatin, polyvinylpyro Lidon, sucrose, and acacia; (c) humectants, such as glycerol; (d) disintegrants such as agar-agar, calcium carbonate, potato or Pio starch, alginic acid, certain complex silicates, and sodium carbonate; (e) dissolution (F) absorption enhancers, such as quaternary ammonia compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite; and (i) lubricants such as ta Luk, calcium stearate, magnesium stearate, solid polyethylene It is mixed with glycol, sodium lauryl sulfate, or a mixture thereof. In the case of capsules, tablets and pills, the dosage form may also comprise a buffer.   Solid compositions of a similar type are also described as soft and hard-filled gelatin capsules. Lactose or lactose, as well as high molecular weight polyethylene It can be used with excipients such as recall and the like.   Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be Coatings and shells such as coatings and others well known to those skilled in the art. Can be manufactured together with shells. They may contain opacifying agents and also contain active compounds. It can also be a composition that releases it in a delayed manner to certain parts of the intestinal tract. Usable embedding Examples of compositions are polymeric substances and waxes. The active compound, if appropriate Micro-encapsulat with one or more of the above-mentioned excipients ed) It may be in a form.   Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions and suspensions , Syrups, and elixirs. Liquid dosage forms in addition to the active compound Include inert diluents commonly used in the art, such as water or other solvents, Agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, , Ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol Oil, 1,3-butylene glycol, dimethylformamide, oil, especially cottonseed oil, peanut Raw oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tet Lahydrofurfuryl alcohol, Cremophor EL (castor oil and ethylene oxide) Derivatives; Sigma Chemical Co., St. Louis, Mo), polyethylene glycol And sorbitan fatty acid esters, or mixtures of these substances, etc. Can be rare.   In addition to such inert diluents, the compositions can also contain wetting agents, emulsifying and suspending agents, sweetening agents. Adjuvants such as flavorings, flavors, and fragrances can also be included.   Suspensions include, in addition to the active compound, suspending agents, for example, ethoxylated isostearyl alcohol. Cole, polyoxyethylene sorbitol and sorbitan esters, microcrystalline Cellulose, meta aluminum hydroxide, bentonite, agar-aga and traga Cant, or a mixture of these substances, and the like.   Compositions for rectal administration are preferably combined with a compound of the invention and a suitable nonirritating agent. Excipient or carrier, for example cocoa butter, polyethylene glycol or suppository A suppository which can be produced by mixing Is solid but liquid at body temperature, thereby dissolving and active in the rectum or vaginal cavity. Releases sexual components.   Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays and powders. And inhalants. The active component is a sterile, physiologically acceptable carrier, and And, if necessary, preservatives, buffers, or propellants. Ophthalmic formulation, eye Ointments, powders, and solutions are also contemplated as being within the scope of this invention. You.   Compounds of the present invention can be administered to patients at dosage levels ranging from about 0.1 to about 2,000 mg per day. Can be administered. For a normal adult weighing about 70 kilograms a day Dosages in the range of about 0.01 to about 100 mg per kilogram of body weight per kilogram are preferred. However, the particular dosage used may vary. For example, the dose may be Many factors, including the severity of the condition being treated, and the pharmacological activity of the compound used May depend on child. Determination of the optimal dosage for a particular patient is well known to those of skill in the art. is there.   The compounds of the present invention may be in various stereoisomeric forms due to the presence of asymmetric centers in the compounds. Can exist. Including all stereoisomeric forms of the compounds, as well as mixtures of racemates These mixtures are also considered to form part of the present invention. Can be   In addition, the compounds of the present invention may be in unsolvated forms and as in water, ethanol and the like. It may exist in a solvated form with a pharmaceutically acceptable solvent. Generally, for the purposes of the present invention In solvates, solvated forms are considered equivalent to unsolvated forms.   The examples set forth below are intended to illustrate certain aspects of the present invention and are not Is not to limit the scope of the claims.   Scheme 1 shows that [1-[(4-benzyloxy-benzyl)-(phenethyl- Carbamoyl-methyl) -carbamoyl] -2- (3H-imidazole-4-i Il) -Ethyl] -carbamic acid benzyl ester (Example 2) Shows a general method for producing the compound of the present invention. 4-benzylo The reductive amination of xybenzaldehyde and glycine methyl ester hydrochloride Performed with sodium triacetoxyborohydride in methylene. (4- Benzyloxybenzylamino) acetic acid methyl ester and then dimethylforma In the amide, 1-hydroxybenzotriazole (HOBt) and To Cbz-His using dicyclohexylcarbodiimide (DCC) did. The product obtained is saponified with lithium hydroxide at 0 ° C. and then dimethyl Using HOBt and DCC as coupling agents in Coupling with Luamine hydrochloride.   The following abbreviations have been used in this application:Abbreviation Cbz or Z carbobenzoxy His histidine Trt Trityl TEA Triethylamine HOAc acetic acid Et_TwoO diethyl ether tBu tert-butyl TFA trifluoroacetic acid ES-MS Electrospray mass spectrometry FAB-MS high-speed atomic bombardment mass spectrometry HOBt 1-hydroxybenzotriazole DCC dicyclohexylcarbodiimide THF tetrahydrofuran PyBOP benzotriazol-1-yl-oxy-tris-pyrrolidine                  No-phosphonium hexafluorophosphate DIEA diisopropylethylamine DMF dimethylformamide Et_ThreeN triethylamine OAc acetate Et_TwoO diethyl ether Boc tert-butoxycarbonyl iBuOCOCl isobutyl chloroformate NMM N-methylmorpholine DMSO dimethyl sulfoxide                         Scheme 1Bn is benzyl.   Scheme 2 describes Example 15, [1-{(4-benzyloxy-benzyl)-[(2- Methyl-2-phenyl-propylcarbamoyl) -methyl] -carbamoyl｝- 2- (3H-Imidazol-4-yl) -ethyl] -carbamic acid benzyl ester Illustrates a method for preparing the compounds of the present invention by exemplifying the synthesis of G Reduction of 4-benzyloxybenzaldehyde using lysine methyl ester Nomination was performed using sodium triacetoxyborohydride in methylene chloride. did. (4-Benzyloxybenzylamino) acetic acid methyl ester and then chloride In methylene, benzotriazol-1-yl-oxy- as a coupling agent Tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) With Cbz- in the presence of diisopropylethylamine (DIEA) as base Coupling to His- (trityl). Using the resulting product with lithium hydroxide And saponified at 0 ° C., and then 1-hydroxybenzotri Azoles (HOBt) and dicyclohexylcarbodiimide (DCC), Β, β-dimethylphenethylamine salt in methylene chloride using ethylamine Coupling with acid salts. Trityl group was removed under reflux in the presence of acetic acid in water . β, β-dimethylphenethylamine hydrochloride is prepared from benzyl cyanide, It is added with 2 equivalents of sodium hydride in tetrahydrofuran (THF) and 2 equivalents in THF. Treat with an equivalent of methyl iodide, then hydrogenate (H_Two, Pd / C, ammonia ) And treatment with HCl to give the HCl salt.                           Scheme 2                  Scheme 2 (continued)  Scheme 3 describes Example 8, [1-{(4-benzyloxy-benzyl)-[(2 -Pyridin-2-yl-ethyl-carbamoyl) -methyl] -carbamoyl}- 2- (1H-imidazol-4-yl) -ethyl] -carbamic acid benzyl ester Illustrates a method for preparing the compounds of the present invention by exemplifying the synthesis of 4 Of benzyloxybenzaldehyde with glycine t-butyl ester Amination is performed using sodium triacetoxyborohydride in methylene chloride. Carried out. (4-benzyloxybenzylamino) acetic acid t-butyl ester, Next, in methylene chloride, use PyBOP as a coupling agent and DIEA as a base. To Cbz-histidine- (trityl). The resulting product is Deprotected by treatment with 50% trifluoroacetic acid in methylene chloride . Coupling with 2-pyridineethanamine in methylene chloride involves coupling Using PyBOP as the bulking agent and diisopropylethylamine as the base. gave.                           Scheme 3  Scheme 4 describes Example 7, [1-((4-benzyloxy-benzyl)-} [2 -(2-Fluoro-phenyl) -ethylcarbamoyl] -methyl} -carbamoyl ) -2- (1H-Imidazol-4-yl) -ethyl] -benzylcarbamate The preparation of the compounds of the present invention is illustrated by illustrating the synthesis of the compound. Boc− Glycine in tetrahydrofuran (THF) Isobutyl chloroformate as a coupling agent and N-methyl as a base Coupling to 2-fluoro-phenethylamine in the presence of tylmorpholine Was. The Boc group is then treated with 50% TFA in methylene chloride for 30 minutes. Removed. N- [2- (2-fluorophene) of 4-benzyloxybenzaldehyde Nyl) -ethyl] -glycinamide reductive amination with TFA salt was carried out using methylene chloride In sodium triacetoxyborohydride and potassium acetate as base Was carried out using N- [2- (2-fluorophenyl) -ethyl] -N^α− (4- Benzyloxy-benzyl) -glycinamide HCl is then added in methylene chloride, Benzotriazol-1-yl-oxy-tris-pyrroli as a coupling agent Dino-phosphonium hexafluorophosphate (PyBOP) was used as the base Coupling to Cbz-histidine- (trityl) using isopropylethylamine I did. The resulting product is purified using 50% trifluoroacetic acid in methylene chloride, Deprotected by treatment with triisopropylsilane as scavenger .                           Scheme 4  Scheme 5 illustrates the synthesis of (2- (1H-imidazol-4-yl) -1- {iso- Butyl-[(2-phenyl-propylcarbamoyl) -methyl] -carbamoyl -Ethyl) -carbamic acid benzyl ester Thus, a method for producing the compound of the present invention is shown. Boc-glycine , Dicyclohexylcarbodiimide as coupling agent in methylene chloride (DCC) and 1-hydroxy-benzotriazole (HoBt), and as a base Β-methylphenethylamine in the presence of diisopropylethylamine Pulled. The Boc group is then treated with 30% TFA in methylene chloride for 2 hours By reductive amination of isobutyraldehyde in methylene chloride. Using sodium triacetoxyborohydride and sodium acetate as bases It was carried out. The above product is then dissolved in methylene chloride as O.C. -(7-Azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluroni Hexafluorophosphate (HATU) and 1-hydroxy-7-azaben Using zotriazole (HOAt) and diisopropylethylamine as base And coupled to Cbz-histidine- (trityl). The resulting product is Deprotect by treating with 50% trifluoroacetic acid in methylene chloride. Was.                         Scheme 5Example 1(S) -N-[(phenylmethoxy) carbonyl] -L-histidyl-N- [2- (phenylmethoxy) ethyl] -N ² - [[4- (phenylmethoxy) phenyl ] -Methyl] glycinamide Step 1:(4-benzyloxybenzylamino) -acetic acid methyl ester   CH_TwoCl_TwoGlycine methyl ester hydrochloride (2.07 g, 16.5 mmol) in (50 mL) And 4-benzyloxybenzaldehyde (3.18 g, 15.0 mmol) at 0 ° C. To the mixture was added sodium triacetoxyborohydride (3.81 g, 18.0 mmol). Was added. The mixture was heated to room temperature and stirred for 4 hours. NaHCO_ThreeAdd aqueous solution Was added and the mixture was stirred for 30 minutes. CH_TwoCl_TwoThe aqueous layer was extracted three times with. Organic extraction The product was washed with brine and dried over MgSO_FourAnd concentrated. Flash chroma By chromatography (75% ethyl acetate / hexane), 1.98 g of the title compound (46% ) Was obtained as a white solid: mp 57-58 ° C. Step 2:N- [N-[(phenylmethoxy) carbonyl] -L-histidyl] -N-[[4- (phenylmethoxy) phenyl] methyl] Glycine methyl ester   CBZ-histidine (1.22 g, 4.21 ml) in DMF (dimethylformamide) (10 mL) HOBT (hydroxybenzotriazole) hydrate (0.77 g, 5 .05 mmol) and DCC (dicyclohexylcarbodiimide) (1.04 g, 5.05 mmol) Mol) was added. The amine from Step 1 (1.20 g, 4.21 mmol) was then added. Was added and the mixture was stirred at room temperature-overnight. The mixture was filtered and the filtrate was washed with CHCl_ThreeDiluted with Saturated NaHCO_Three, Washed twice with brine, dried over MgSO_FourAnd concentrated. Flat Chromatography gave 1.68 g (72%) of the title compound as a white foam. Obtained: ES-MS (electrospray mass spectrometry) 557 (m + 1). Step 3:N- [N-[(phenylmethoxy) carbonyl] -L-histidyl] -N-[[4- (phenylmethoxy) phenyl] methyl] glycine   THF (tetrahydrofuran) (15 mL) and H_TwoD from step 2 in O (5 mL) A solution of steal (1.53 g, 2.75 mmol) at 0 ° C was added to LiOH hydrate (0.14 g, 3.30 mi). Mmol) was added and the solution was stirred at 0 ° C. for 5 hours. The solution is concentrated and the residue is concentrated in H_Two O and the pH was adjusted to 4-5 with 1N HCl. Concentrate the resulting mixture and dry under vacuum Drying gave 1.65 g of the title compound as a white solid: FAB-MS 543 (m + 1).   C₃₀H₃₀N_FourO₆・ 1.2LiCl ・ 2.0H_TwoAnalytical value of O:     Calculated value: C, 57.24; H, 5.44; N, 8.90     Found: C, 57.35; H, 5.32; N, 8.62 Step 4:(S) -N-[(phenylmethoxy) carbonyl] -L-hithidyl -N-[2-(phenylmethoxy) - ethyl] -N ² - [[4- (phenylmethoxy) Phenyl] -methyl] glycinamide   To a solution of the acid from step 3 (2.9 g, 5.33 mmol) in DMF (15 mL) was added HOBt Hydrate (0.98 g, 6.39 mmol) and DCC (1.32 g, 6.39 mmol) were added. Then 2-benzyloxyethylamine hydrochloride (1.0 g, 5.33 mmol) was added. Was. Et_ThreeAdd N (triethylamine) (0.82 mL, 5.86 mmol) and mix Stirred at room temperature-overnight. The mixture was filtered and the filtrate was washed with CHCl_ThreeDiluted with saturated NaHCO_Three , Washed twice with brine, dried over MgSO_FourAnd concentrated. Flash chroma Torography (2-5% methanol / CHCl_Three) Gave 2.25 g of the title compound (63 %) Was obtained as a white foam: ES-MS 676 (m + 1). Example 2(S)-[1-[(4-benzyloxy-benzyl)-(phenethyl-carbamoy) -Methyl) -carbamoyl] -2- (3H-imidazol-4-yl) -ethyl] -Carbamic acid benzyl ester   (S)-[1-[(4-benzyloxy-benzyl)-(phenethyl-carbamoy -Methyl) -carbamoyl] -2- (3H-imidazol-4-yl) -ethyl]- The carbamic acid benzyl ester was prepared according to Example 1, Step 4 using 2-benzyl It can be produced by substituting phenethylamine for ruoxyethylamine hydrochloride. The title compound was obtained as a white solid; ES-MS646 (m + 1). Example 3(S)-[1-[[2-benzyloxy-ethylcarbamoyl] -methyl]-[ 4-chlorobenzyl] -carbamoyl] -2- (1H-imidazol-4-yl)- Ethyl] -carbamic acid benzyl ester   (S)-[1-[[2-benzyloxy-ethylcarbamoyl] -methyl]- [4-Chlorobenzyl] -carbamoyl] -2- (1H-imidazol-4-yl) -Ethyl] -carbamic acid benzyl ester was prepared according to Example 1, Step 1. 4-chlorobenzaldehyde instead of 4-benzyloxybenzaldehyde It can be manufactured instead. Title compound was obtained as white solid; ES-MS 604 (m + 1) ). Example 4(S)-[1-[(4-benzyloxy-benzyl)-[(2-phenyl-propyl -Carbamoyl) -methyl] -carbamoyl] -2- (1H-imidazole-4- Yl) -ethyl] -carbamic acid benzyl ester   (S)-[1-[(4-benzyloxy-benzyl)-[(2-phenyl- Propyl-carbamoyl) -methyl] -carbamoyl] -2- (1H-imidazole -4-yl) -ethyl] carbamic acid benzyl ester was prepared in Example 1, Step 4 According to the above, instead of 2-benzyloxyethylamine hydrochloride, Can be produced in place of tylamine. Title compound was obtained as white solid; ES-MS 66 0 (m + 1). Example 5(S)-[1-[(4-benzyloxy-benzyl)-[(2,2-diphenyl-e Tylcarbamoyl) -methyl] -carbamoyl] -2- (1H-imidazole-4- Yl) -ethyl] -carbamic acid benzyl ester   (S)-[1-[(4-benzyloxy-benzyl)-[(2,2-diphenyl-e Tylcarbamoyl) -methyl] -carbamoyl] -2- (1H-imidazole-4- Yl) -ethyl] -carbamic acid benzyl ester was prepared according to Example 1, step 4. 2,2-diphenylethyl instead of 2-benzyloxyethylamine hydrochloride Can be prepared in place of amine. Title compound was obtained as white powder; ES-MS 722 ( m + 1). Example 6(S) -N- (4-benzyloxy-benzyl) -2- (3-benzyl-ureido) -3- (1H-Imidazol-4-yl) -N-[(2-phenyl-propylcarba Moyl) -methyl] -propionamide   The title compound was benzylated with Cbz-histidine according to Example 1, Step 2. It can be produced by substituting ru-urea-histidine (steps 1 and 2). Title As a white solid; ES-MS 659 (m + 1). Step 1:Benzyl-urea-histidine methyl ester   Histidine methyl ester hydrochloride (2.0 g, 4.3 mmol) in methylene chloride Benzyl isocyanate (0.58 mL, 0.63 g, 4.7 mm Mol) and triethylamine (1.32 mL, 9.5 mmol) were added and the solution was brought to room temperature. And stirred overnight. The solution was concentrated and the residue was taken up in ethyl acetate. This solution The solution was washed with water, saturated NaHCO_Three, Washed with brine, MgSO_FourDried and concentrated . The product was obtained as a white foam (1.09 g, 84%). Step 2:Benzyl-urea-histidine   THF: ester from step 1 in methanol (10 mL each) and water (2 mL) (1.9 g, 3.5 mmol) to a solution of sodium hydroxide (0.4 g, 10 mmol). Was added and the solution was stirred overnight at room temperature. The solution is added to 1N HCl: ethyl acetate (30 mL each) Was added. The organic layer was separated and washed with 1N HCl, brine, MgSO_FourDry Dried and concentrated. The product was obtained as a white foam (0.53 g, 53%); ES-M S 289 (m + 1). Example 6a(S) -N- (4-benzyloxy-benzyl) -2- (3-benzyl-ureido) -3- (1H-Imidazol-4-yl) -N-[(2-phenyl-propylcarba Moyl) -methyl] -propionamide   The title compound was benzylated with Cbz-histidine according to Example 1, Step 2. Replace with ru-urea-histidine- (trityl) (steps 1 and 2) And add 2-benzyloxyethylamine hydrochloride to β-methyl It can be produced by replacing with netylamine. Obtain the title compound as a white solid; ES -MS 659 (m + l). Step 1:Benzyl-urea histidine-trityl methyl ester   Histidine-trityl methyl ester hydrochloride in methylene chloride (2.0 g, 4.3 M Benzyl isocyanate (0.58 mL, 0.63 g, 4.7 mm) Mol) and triethylamine (1.32 mL, 9.5 mmol) were added and the solution was brought to room temperature. And stirred overnight. The solution is concentrated and the residue is Taken during chill. This solution is combined with water, saturated NaHCO_Three, Washed with brine, MgSO_Fourso Dried and concentrated. The product was obtained as a white foam (1.95 g, 83%). Step 2:Benzyl-urea-histidine- (triethyl) HCl   THF: ester from step 1 in methanol (10 mL each) and water (2 mL) (1.9 g, 3.5 mmol) to a solution of sodium hydroxide (0.4 g, 10 mmol). Was added and the solution was stirred at room temperature-overnight. The solution was diluted with 1N HCl aqueous solution: ethyl acetate ( 30 mL each). The organic layer was separated and washed with 1N HCl, brine , MgSO_FourAnd concentrated. The product was obtained as a white foam (1.0 g, 53 %); ES-MS 531 (m + 1). Example 7(S)-[1-((4-benzyloxy-benzyl)-{[2- (2-fluoro- Enyl) -ethylcarbamoyl] -methyl} -carbamoyl) -2- (1H-imida Zol-4-yl) -ethyl] -carbamic acid benzyl ester Step 1:N ^α- Boc-N- [2- (2-fluorophenyl) -ethyl] -glyci Namide   To a solution of Boc-glycine (1.75 g, 10 mmol) in THF (50 mL) at 0 ° C. Isobutyl logate (1.3 g, 10 mmol) and then N-methylmorpholine (1.1 mmol) L, 10 mmol). The resulting suspension was stirred at 0 ° C. for 5 minutes, and Was treated with 2-[(2-fluorophenyl) -ethyl] -amine (10 mmol). Was. The suspension was stirred at room temperature for -night. The reaction was treated with 1N HCl, and And extracted with diethyl ether (2 × 50 mL). Combine the organic extracts and water, Saturated NaHCO_ThreeWashing successively with an aqueous solution and then with water. The organic extract was extracted with MgSO_FourDry with And concentrated. Flat Chromatography (5% methanol in methylene chloride) to give the title 1.93 g (65%) of the compound were obtained as a white solid: CI-MS 297 (m + 1). Step 2:N- [2- (2-fluorophenyl) -ethyl] -glycinamide Trifluoroacetate   Compound from Step 1 above (1.92 g, 6.48 ml) in methylene chloride (20 mL) Rim) was added trifluoroacetic acid (20 mL). Stir the solution for 30 minutes And then concentrated. The residue was dissolved in methylene chloride and re-concentrated, The title compound was obtained as an oil. Use this product for the next reaction without characterization Used. Step 3:N- [2- (2-fluorophenyl) -ethyl] -Nα- (4-ben (Diloxy-benzyl) -glycinamide hydrochloride   Compound from Step 2 above (6.48 mmol) in methylene chloride (50 mL) , 4-benzyloxybenzaldehyde (1.38 g, 6.48 mmol) and potassium acetate Triacetoxyl was added to a 0 ° C cooled suspension of lium (1.27 g, 12.96 mmol). Sodium borohydride (1.79 g, 8.43 mmol) was added. Bring the reaction to room temperature And stirred for 3 hours. The reaction was washed with saturated NaHCO_ThreeTreated with aqueous solution, and The layers were separated. The aqueous layer was extracted with methylene chloride (2 × 20 mL). Combine the organic layers And concentrated. The residue was dissolved in diethyl ether and 1N HCl (8 mL ). The precipitate was collected by filtration and 1.46 g (52.6%) of the title compound was added. Obtained as an off-white solid: CI-MS 393 (m + 1). Step 4:[1-((benzyloxy-benzyl)-{[2- (2-fluorophen Nil) -ethyl-carbamoyl] -methyl} -carbamoyl) -2- (1-triti 1H-Imidazol-4-yl) -ethyl] -carbamic acid benzyl ester   (S)-(2-benzyloxycarbonylamino-3) in methylene chloride (20 mL) -(1-Trityl) -1H-imidazol-4-yl) -propionic acid (Cbz-hist Gin- (trityl)) (Hudspeth J.P., Kaltenbronn J.S., Repine J.T., Roark W H., Stier M.A., Renin Inhibitors III, U.S. Patent No. 4,735,933; 1988) (0.532 g) , 1.0 mmol) in a solution of diisopropylethylamine (0.48 mL, 2.75 mmol) ) And benzotriazol-1-yl-oxy-tris-pyrrolidino-phospho Hexafluorophosphate (0.520 g, 1.0 mmol) was added. next The mixture was added to the amine hydrochloride salt obtained from step 3 above (0.429 g, 1.0 mmol). And stirred for 4 hours. The reaction was washed with saturated NaHCO_ThreeTreat with aqueous solution The layers were separated. The aqueous layer was extracted with methylene chloride (2 × 30 mL). Organic layer And MgSO_FourAnd concentrated. Flash chromatography ( (2% methanol in methylene chloride) to give 0.501 g (55%) of the title compound as white Obtained as a colored foam: ES-MS 906.5 (m + 1). Step 5:[1-((4-benzyloxy-benzyl)-{[2- (2-fluoro- Phenyl) -ethylcarbamoyl] -methyl} -carbamoyl) -2- (1H-imi Dazol-4-yl) -ethyl] -carbamic acid benzyl ester   The trityl compound obtained from step 4 above (0.49 g) in methylene chloride (5 mL) , 0.54 mmol) in a solution of TFA (5 mL) and triisopropylsilane (0.25 mmol). L) was added. The solution was stirred for 3 hours and concentrated. NaHCO saturated with residue_ThreePartitioned between aqueous solution and ethyl acetate. The layers are separated and the water The layers were extracted with ethyl acetate (2 × 20 mL). Combine the organic layers and add MgSO_FourDried in And concentrated. Flash chromatography (10% methanol in methylene chloride) To give 0.248 g (37%) of the title compound as a white foam Obtained as a solid: ES-MS 664.4 (m + 1). Example 8(S)-[1-{(4-benzyloxy-benzyl)-[(2-pyridine-2-i -Ethylcarbamoyl) -methyl] -carbamoyl} -2- (1H-imidazole -4-yl) -ethyl] -carbamic acid benzyl ester Step 1:( 4-benzyloxybenzylamino) acetic acid t-butyl ester   CH_TwoCl_TwoGlycine t-butyl ester hydrochloride (0.84 g, 5 mmol) in (25 mL) ) And 4-benzyloxy-benzaldehyde (0.53 g, 2.5 mmol) at 0 ° C. Sodium triacetoxyborohydride (0.81 g, 3.8 mmol) Was added. The mixture was warmed to room temperature and stirred overnight. NaHCO_ThreeAdd the aqueous solution, The mixture was then stirred for 30 minutes. CH water layer_TwoCl_TwoExtracted three times. Organic combined The extract was washed with brine and dried over MgSO_FourAnd concentrated. Flash black 0.38 g (59%) of the title compound was obtained as a white solid by chromatography (ethyl acetate). As obtained. Step 2:N- [N-[(phenylmethoxy) carbonyl] -L-histidyl- Trityl] -N-[[4- (phenylmethoxy) phenyl] methyl] -glycine t -Butyl ester   Cbz-histidine- (trityl) (0.89 g, 1.7 mmol) in methylene chloride (25 mL) PyBOP (2.63 g, 5.05 mmol) and diisopropyl Ethylamine (0.68 mL, 3.9 mmol) was added. Obtained from step 1 above Amine (0.38 g, 1.5 mmol) is then added and the mixture is stirred at room temperature overnight did. The reaction mixture is concentrated in vacuo, the residue is taken up in acetic acid and saturated NaHCO_Three, Wash three times with brine and wash with MgSO_FourAnd concentrated. Flash chromatography Chromatographically processed title compound 0.59 g (51%) was obtained as a white foam: ES-MS841 (m + 1). Step 3:N- [N-[(phenylmethoxy) carbonyl] -L-histidyl] -N-[[4- (phenylmethoxy) phenyl] methyl] glycine   Methylene chloride was added to a solution of the ester from Step 2 (0.59 g, 0.76 mmol). 50% trifluoroacetic acid in (25 mL) was added. The reaction was stirred at room temperature for 3 hours . The solution was concentrated in vacuo. Cool diethyl ether was added to the residue and the solution was C.-left overnight. A white precipitate was obtained, which was filtered and dried; 0.33 g (80%). Step 4:[1-{(4-benzyloxy-benzyl)-[(2-pyridine-2 -Yl-ethylcarbamoyl) -methyl] -carbamoyl} -2- (1H-imidazo 4-yl) -ethyl] -carbamic acid benzyl ester   A solution of the acid obtained from step 3 (0.33 g, 0.61 mmol) in methylene chloride In addition, PyBOP (0.67 g, 1.3 mmol) and diisopropylethylamine (0.23 mL) , 1.3 mmol) followed by 2-pyridineethanamine hydrochloride (0.082 g, 0.67 mmol). Mol) was added. The mixture was stirred at room temperature-overnight. Concentrate the reaction mixture in vacuo The residue was taken up in ethyl acetate and saturated NaHCO_Three, Washed 3 times with brine, Mg SO_FourAnd concentrated. Flash chromatography and title conversion 0.156 g (37%) of the compound were obtained as a white foam: ES-MS 647 (m + 1). Example 9(S)-[1-((4-benzyloxy-benzyl)-{[2- (2-bromo- Nil) -ethylcarbamoyl] -methyl} -carbamoyl) -2- (1H-imidazo 4-yl) -ethyl] -benzylcarbamate Le   The title compound was prepared according to Example 8, Step 4 using 2-pyridineethanamine. Made by replacing HCl with 2-bromo-phenethylamine (steps 1 and 2) it can. The title compound is obtained as a white foam (10%); ES-MS 725 (m + 1) ). Step 1:o-Bromo-nitrostyrene   O-Bromo-benzaldehyde (4 g, 21.6 mmol) in methanol (5 mL) ) And nitromethane (1.32 g, 21.6 mmol) in 1 mL of H_TwoNaOH in O (0.908 g, 22.7 mmol) was added. After 45 minutes, precipitate was washed with 10 mL of H_TwoDissolved in 0 Was. After addition of 6N HCl, the product precipitated. This product from ethanol Recrystallized; 0.312 g (6%). Step 2:2-bromophenethylamine   To the styrene from step 1 (0.310 g, 1.3 mmol) in 5 mL THF was added THF at 0 ° C. 1M LiAlH_FourA solution (5.2 mL, 5.2 mmol) was added. The solution was stirred for 1 hour . Concentrated KHSO_FourThe solution is added dropwise and excess LiAlH_FourDestroyed. Filter the solution through Celite And the filtrate was concentrated in vacuo to give a yellow oil; 150 mg (58%). Example 10(S) -1-{(4-benzyloxy-benzyl)-[(R)-(1-methyl-2- Phenyl-ethylcarbamoyl) -methyl] -carbamoyl} -2- (1H-imida Zol-4-yl) -ethyl] -carbamic acid benzyl ester   The title compound was prepared as in Example 15, Step 5, β, β-dimethylphenethylene. Luamine hydrochloride can be produced by replacing L-amphetamine. The title compound Obtained as a white foam (90%); ES-MS 660 (m + 1). Example 11(S) -1-{(4-benzyloxy-benzyl)-[(S)-(1-methyl-2- Phenyl-ethylcarbamoyl) -methyl] -carbamoyl} -2- (1H-imida Zol-4-yl) -ethyl] -carbamic acid benzyl ester   The title compound was prepared as in Example 15, Step 5, β, β-dimethylphenethylene. Luamine hydrochloride can be produced by replacing D-amphetamine. The title compound Obtained as a white foam; ES-MS 660 (m + 1). Example 12(S)-[1-{(4-benzyloxy-benzyl)-[(2-phenyl-2-pi Lysin-2-yl-ethylcarbamoyl) -methyl] -carbamoyl {-2- (1H -Imidazol-4-yl) -ethyl] -carbamic acid benzyl ester   The title compound was prepared according to Example 8, Step 4, 2-pyridineethane-amido. HCl is converted to 2- [α- (aminomethyl) -benzyl] pyridine hydrochloride (step 1). ). Obtain the title compound as a white foam (64%); ES -MS 723 (m + l). Step 1:2- [α- (aminomethyl) benzyl] pyridine hydrochloride   α- (2-Pyridyl) -phenylacetonitrile (97.1 g, 0.5 mol) Raney cobalt (25 g) and triethylamine (25 mL) in ene (500 mL) Reduced. The solution was filtered and the filtrate was concentrated. Residue in diethyl ether And HCl was bubbled through. The hydrochloride precipitated from solution. Example 13(S)-[1-{(4-chloro-benzyl)-[(2-phenyl-propylca Rubamoyl) -methyl] -carbamoyl} -2- (1H-imidazol-4-yl) -Ethyl] -carbamic acid benzyl ester   The title compound was prepared according to Example 8, Step 4, 2-pyridineethane-amido. Replace HCl with β-methyl-phenethylamine and in Step 1 , 4-benzyloxy-benzaldehyde into p-chloro-benzaldehyde It can be replaced and manufactured. Obtain the title compound as a white foam (17%); ES-MS588 (m + 1). Example 14(S)-[1-{(4-benzyloxy-benzyl)-[(2-hydroxy-2-f Enyl-ethylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imidazo 4-yl) -ethyl] -carbamic acid benzyl ester   The title compound was prepared as in Example 15, Step 5, β, β-dimethylphenethylene. Can be produced by replacing ruamine hydrochloride with 2-amino-1-phenylethanol . Obtain the title compound as a white foam (47%); ES-MS662 (m + 1). Example 15(S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-phenyl -Propylcarbamoyl) -methyl] -carbamoyl｝ -2- (3H-imidazo Ru-4-yl) -ethyl] -carbamic acid benzyl ester Step 1:( 4-benzyloxybenzylamino) acetic acid methyl ester   CH_TwoCl_TwoGlycine methyl ester hydrochloride (2.07 g, 16.5 mmol) in (50 mL) And 4-benzyloxy-benzaldehyde (3.18 g, 15 mmol) at 0 ° C. To the mixture was added sodium triacetoxyborohydride (3.81 g, 18 mmol). Added. The mixture was warmed to room temperature and stirred overnight. NaHCO_ThreeAn aqueous solution was added and the mixture was stirred for 30 minutes. CH water layer_TwoCl_TwoAt 3 Extracted times. The combined organic extracts were washed with brine and dried over MgSO_FourDry in and Concentrated. Flash chromatography (ethyl acetate) gives the title compound 1.98 g (46%) were obtained as a white solid; mp 57-58 ° C. Step 2:N- [N-[(phenylmethoxy) carbonyl] -L-histidyl- Trityl] -N-[[4- (phenylmethoxy) phenyl] methyl] -glycineme Chill ester   Cbz-histidine- (trityl) (2.24 g, 4.21 mmol) in methylene chloride (25 mL) Of PyBOP (2.63 g, 5.05 mmol) and diDIEA (1.46 mL, 8.4 mmol). Was added. The amine from Step 1 above (1.20 g, 4.21 mmol) was And the mixture was stirred at room temperature overnight. The reaction mixture is concentrated in vacuo, The residue was taken up in ethyl acetate and saturated NaHCO_Three, Washed three times with brine, and dried over MgSO_Four And concentrated. Flash chromatography to convert the title 1.68 g (72%) of the compound were obtained as a white foam: ES-MS 557 (m + 1). Step 3:N- [N-[(phenylmethoxy) carbonyl] -L-histidyl- Trityl] -N-[[4- (phenylmethoxy) phenyl] methyl] -glycine   THF (15 mL) and H_TwoEster from step 2 in O (5 mL) (1.53 g, 2.75 LiOH hydrate (0.14 g, 3.30 mmol) was added to a solution of The solution was stirred at 0 ° C. for 5 hours. The solution is concentrated, the residue is taken up in water and the pH is adjusted to 1 Adjusted to 4-5 with N HCl. The resulting mixture is concentrated and dried in vacuo, 1.65 g of the title compound were obtained as a white solid; FAB-MS 543 (m + 1). Step 4:β, β-dimethylphenethylamine hydrochloride   Sodium hydride (60% in oil) (17 g, 0.43 mol) was suspended in THF (150 mL) Then cooled to 0 ° C. under nitrogen. Benzyl cyanide in THF (30 mL) (22.2 g, 0.19 mol) was added dropwise and the reaction was stirred for 1 hour. Iodomethane (2 mL in THF (20 mL) 4.9 g, 0.4 mol) at 0 ° C. The reaction was stirred at room temperature under nitrogen for -night . The solution was filtered and the filtrate was removed in vacuo. The residue is taken up in ethyl acetate (100 mL) and 10% NaHSO_Three, Saturated NaHCO_Three, Brine And washed three times with MgSO_FourAnd concentrated; 22.74 g (92%).   The above product was converted to methanol / NH_ThreeIn the presence of Raney-nickel. The catalyst was removed and washed with methanol. The filtrate is concentrated and the residue is Ethyl ether (100 mL) was added. HCl is added dropwise to precipitate the desired product. 24.8 g (86%). Step 5:[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-f Enyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (3-triti -3H-Imidazol-4-yl) -ethyl] -carbamic acid benzyl ester   To a solution of the acid from Step 3 (2.9 g, 5.33 mmol) in methylene chloride , HOBt hydrate (0.98 g, 6.39 mmol) and DCC (1.32 g, 6.39 mmol), Β, β-dimethylphenethylamine hydrochloride (obtained from step 3) (0.99 g, 5 .33 mmol) was added. Triethylamine (0.82 mL, 5.86 mmol) was added. And the mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was washed with CHCl_Three Diluted with saturated NaHCO_Three, Washed twice with brine, dried over MgSO_FourDried and concentrated Was. Flash chromatography (2% -5% methanol / CHCl_Three) Process To give 2.25 g (63%) of the title compound: ES-MS 917 (m + 1). Step 6:(S) -1-{(4-benzyloxy-benzyl)-[(2-methyl -2-phenyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (3H -Imidazol-4-yl) -ethyl] -carbamic acid benzyl ester   Ice vinegar was added to the solution of the trityl compound (2.25 g, 2.4 mmol) obtained from Step 5. Acid (20 mL) and water (5 mL) were added. The mixture is stirred at 90 ° C. for 30 minutes, then And concentrated. The residue was taken up in ethyl acetate. NaCl saturated organic solution O_Three, Washed twice with brine, and washed with MgSO_FourAnd dried. The solution is concentrated and the compound is flash chromatographed (methylene chloride (0% -8% methanol in methanol) to give the title compound (1.5 g, 2.2 mmol, 9 3%) as a white foam: ES-MS 674 (m + 1). Example 16(S)-[1-{(4-benzyloxy-benzyl)-[(2-phenyl-butyl Carbamoyl) -methyl] -carbamoyl} -2- (1H-imidazol-4-yl ) -Ethyl] -carbamic acid benzyl ester   The title compound was prepared as in Example 15, Step 5, β, β-dimethylphenethylene. Luamine hydrochloride is converted to β-ethylbenzene-ethamine hydrochloride (step It can be manufactured by replacing 1). Obtain the title compound as a white foam (55%); ES-MS674 (m + 1). Step 1:β-ethylbenzene ethamine hydrochloride   This compound is described in B.K. Trivedi and others,J.Med . Chem., 1993; 36: 3300-3307 As shown, synthesized by catalytic reduction of 2-phenylbutyronitrile . Example 17(S) -N- (4-benzyloxy-benzyl) -3- (1H-imidazole- 4-yl) -2- (3-phenyl-propionylamino) -N-[(2-phenyl- Propylcarbamoyl) -methyl] -propionamide   The title compound was prepared according to Example 15, Step 2, Cbz-histidine- (tri Tyl) with phenylpropionyl-histidine- (trityl) (step 1 and 2) and according to step 5, β, β-dimethylphenethylamine The hydrochloride can be prepared by replacing β-methyl-phenethylamine. Compound of title Obtained as a white foam (45%); ES-MS 658 (m + 1). Step 1:Phenylpropionyl-histidine- (trityl) methyl ester   Histidine- (trityl) methyl ester hydrochloride in methylene chloride (2.0 g, 4. 2 mmol) and methylpiperidine (1.07 mL, 8.8 mmol) at 0 ° C. Slowly add 3-phenylpropionyl chloride (0.62 mL, 4.2 mmol) The solution was stirred at room temperature for -night. Ethyl acetate is added and water, saturated NaHCO_Three , Washed twice with brine, dried over MgSO_FourAnd concentrated. The product is a white foam 2.0 g (88%). Step 2:Phenylpropionyl-histidine- (trityl)   THF: ester from step 1 in methanol (10 mL each) and water (2 mL) (2.0 g, 3.7 mmol) in a solution of sodium hydroxide (0.44 g, 11 mmol) Was added and the solution was stirred overnight at room temperature. The solvent is removed in vacuo and 5 mL of H_TwoO, next The pH is then brought to 3 by adding 1N HCl. The product was extracted with acetate . The organics are washed with 1N HCl, brine and MgSO_FourAnd concentrated. Raw The product was obtained as a white foam (2.18 g): ES-MS 529 (m + 1). Example 18 (S)-[1-{(4-fluoro-benzyl)-[(2-phenyl-propylcal Bamoyl) -methyl] -carbamoyl {-2- (1H-imidazol-4-yl)- Ethyl] -carbamic acid benzyl ester   The title compound was prepared according to Example 8, Step 4, 2-pyridineethanamine • Replace HCl with β-methyl-phenethylamine and in step 1 4 Benzyloxy-benzaldehyde in p-fluoro-benzaldehyde It can be manufactured instead. Obtain the title compound as a white foam (78%); ES-MS 57 2 (m + 1). Example 19(S)-(2- (1H-imidazol-4-yl) -1-{(4-methyl-benzyl) -[(2-phenyl-propylcarbamoyl) -methyl] -carbamoyl} -ethyl Ru) -carbamic acid benzyl ester   The title compound was prepared according to Example 8, Step 4, 2-pyridineethanamine • Replace HCl with β-methyl-phenethylamine and in step 1 4 Replacing benzyloxy-benzaldehyde with p-methyl-benzaldehyde Can be manufactured. Obtain the title compound as a white foam (66%); ES-MS 568 ( m + 1). Example 20(S)-(2- (1H-imidazol-4-yl) -1-{(4-methoxy-benzyl) )-[(2-Phenyl-propylcarbamoyl) -methyl] -carbamoyl} -e (Tyl) -carbamic acid benzyl ester   The title compound was prepared according to Example 8, Step 4, 2-pyridineethanamine • Replace HCl with β-methyl-phenethylamine and in step 1 4 -Benzyloxy-benzaldehyde in p-methoxy-benzaldehyde It can be manufactured instead. The title compound was converted to a white foam (33 %); ES-MS583 (m + 1). Example 21(S)-[1-[{[2- (2-amino-phenyl) -propylcarbamoyl]- Methyl {-(4-benzyloxy-benzyl) -carbamoyl] -2- (3H-imi Dazol-4-yl) -ethyl] -carbamic acid benzyl ester   The title compound was prepared according to Example 8, Step 4, 2-pyridineethanamine • Replace HCl with 2-amino-β-methylphenethylamine (step 1) Can be manufactured. The title compound is obtained as a white foam (33%); ES-MS 675 (m + 1) ). Step 1:2-amino-β-methylphenethylamine   Add 4-methyl-cinnoline (10 g, 69.5 mmol) in methanol (100 mL) -Reduction using nickel (3 g). The catalyst was removed and washed with methanol. The filtrate was treated with excess HCl in isopropanol; ether was then added. The solution was cooled. The precipitate was filtered and dried; 9.4g (60%). Example 22(S)-[1-{(4-fluoro-benzyl)-[(2-methyl-2-phenyl- Propylcarbamoyl) -methyl] -carbamoyl {-2- (1H-imidazole- 4-yl) -ethyl] -carbamic acid benzyl ester   The title compound was prepared according to Example 15, Step 1 by adding 4-benzyloxybenz The aldehyde can be produced by substituting p-fluoro-benzaldehyde. Title The compound is obtained as a white foam (87%); ES-MS 586 (m + 1). Example 23 (S)-[1- {benzyl-[(2-phenyl-propylcarbamoyl) -methyl] -Carbamoyl {-2- (1H-imidazol-4-yl) -ethyl] -carbamine Acid benzyl ester   The title compound was prepared according to Example 8, Step 4, 2-pyridineethanamine • Replace HCl with β-methyl-phenethylamine and in step 1 4 -Can be produced by replacing benzyloxy-benzaldehyde with benzaldehyde. You. The title compound is obtained as a white foam (57%); ES-MS 554 (m + 1). Example 24(S)-[1-((4-benzyloxy-benzyl)-{[2- (2-chloro- Nyl) -2-phenyl-ethylcarbamoyl] -methyl} -carbamoyl) -2- (1H-Imidazol-4-yl) -ethyl] -carbamic acid benzyl ester   The title compound was prepared according to Example 8, Step 4, 2-pyridineethanamine HCl to o-chloro-β-phenyl-phenethylamine hydrochloride (step 1 and It can be manufactured by replacing 2). This affords the title compound as a white foam (37%); ES -MS 756 (m + l). Step 1:2-phenyl-3- (2-chloro-phenyl) cyanide   Bromine (2 mL) was added to 2-chloro-benzyl cyanide (5 g, 32 mmol) at 90 ° C. Add dropwise with stirring over 1 hour. Nitrogen is passed over the reactants to remove HBr. I left. The reaction was heated for 15 minutes, after which benzene (2 mL) was added. This solution AlCl in benzene (15 mL) over 2 hours_ThreeTo a refluxing solution of (4.2 g, 32 mmol) It was added dropwise. The reaction was refluxed for 1 hour. The reaction was cooled, ice (200 g) and concentrated HCl (20 mL). Dilute the aqueous layer with diethyl ether and diethyl ether: (1: 1). Yes Machine solution H_Two0, saturated NaHCO_Three, Washed twice with brine, Na_TwoSO_FourAnd dried, and Concentration gave an orange oil; 6.3 g (86%). Step 2:o-chloro-β-phenyl-phenethylamine hydrochloride   The reduction of the product obtained from step 1 is carried out with methanol / NH_ThreeRaneynicke in Performed in the presence of The catalyst was removed and washed with methanol. Concentrate the filtrate And ethanol (100 mL) was added to the residue. Add concentrated HCl until pH 3 It was added very well. Reduce the amount of ethanol in vacuo to about 5 mL and add HCl salt Was precipitated by the addition of diethyl ether; 1.84 g (68%). Example 25(S)-[1-{(4-benzyloxy-benzyl)-[(2-ethyl-2-fe Nyl-butylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imidazo Ru-4-yl) -ethyl] -carbamic acid benzyl ester   The title compound was prepared as in Example 15, Step 5, β, β-dimethylphenethylene. Luamine hydrochloride to β, β-diethylbenzeneethanamine hydrochloride (Step 1) Can be interchanged and manufactured. Obtain the title compound as a white foam (52%); ES-MS 702 (m + 1). Step 1:β, β-diethylbenzeneethanamine hydrochloride   This compound diethylates phenylacetonitrile and then B.K. OutsideJ.Med . Chem., 1993; 36: 3300-3307. Synthesized. Example 26(S) -N- (4-benzyloxy-benzyl) -2- (3-benzyl-ureido) -3- (1H-Imidazol-4-yl) -N-[(2-phenyl-propylcarba Moyl) -methyl] -propionamide   The title compound was prepared as described in Example 15, Step 2 using Cbz-histidine (trityl). ) With benzyl-urea-histidine- (trityl) (Steps 1 and 2, Examples 6) and according to step 5, β, β-dimethylphenethylamine The hydrochloride can be produced by replacing β-methyl-phenethylamine hydrochloride. Title As a white foam (64%); ES-MS 659 (m + 1). Example 27(S) -N- (4-benzyloxy-benzyl) -2- (3-benzyl-ureido) -3- (1H-Imidazol-4-yl) -N-[(2-phenyl-butylcarbamo Yl) -methyl] -propionamide   The title compound was prepared as described in Example 15, Step 2 using Cbz-histidine (trityl). ) With benzyl-urea-histidine- (trityl) .HCl (steps 1 and 2, Example 6) and according to step 5, β, β-dimethylphenethyl Mine hydrochloride was converted to β-ethylbenzeneethanamine hydrochloride (Step 1, Example 16) It can be manufactured by replacing with Obtain the title compound as a white foam (93%); ES-M S 673 (m + 1). Example 28(S)-[1-{(2-chloro-benzyl)-[(2-phenyl-propylcarba Moyl) -methyl] -carbamoyl} -2- (1H-imidazol-4-yl) -d Tyl] -carbamic acid benzyl ester   The title compound was prepared according to Example 8, Step 4, 2-pyridineethanamine • Replace HCl with β-methyl-phenethylamine and in step 1 Replacing benzyloxy-benzaldehyde with o-chloro-benzaldehyde Can be manufactured. The title compound is obtained as a white foam (40%); ES-MS 588 ( m + 1). Example 29(S)-[1-{(4-bromo-benzyl)-[(2-phenyl-propylcarba Moyl) -methyl] -carbamoyl} -2- (1H-imidazol-4-yl) -d Tyl] -carbamic acid benzyl ester   The title compound was prepared according to Example 8, Step 4, 2-pyridineethanamine • Replace HCl with β-methyl-phenethylamine and in step 1 Production by replacing jyloxy-benzaldehyde with p-bromo-benzaldehyde Can be built. Obtain the title compound as a white foam (91%); ES-MS 633 (m + 1) ). Example 30(S)-[1-{(3-chloro-benzyl)-[(2-phenyl-propylcarba Moyl) -methyl] -carbamoyl} -2- (1H-imidazol-4-yl) -d Tyl] -carbamic acid benzyl ester   The title compound was prepared according to Example 8, Step 4, 2-pyridineethanamine • Replace HCl with β-methyl-phenethylamine and in Step 1 Put 4-benzyloxy-benzaldehyde into m-chloro-benzaldehyde It can be manufactured instead. Title compound is obtained as white foam (10%); ES-MS 58 8 (m + 1). Example 31(S)-[1-{(4-chloro-benzyl)-[(2-methyl-2-phenyl-p) Ropylcarbamoyl) -methyl] -carbamoyl} -2- (1H-imidazole-4 -Yl) -ethyl] -carbamic acid benzyl ester   The title compound was prepared according to Example 15, Step 1 by adding 4-benzyloxybenz The aldehyde can be produced by replacing p-chloro-benzaldehyde. Title change The compound is obtained as a white foam (33%); ES-MS 602 (m + 1). Example 32(S)-[1-((4-benzyloxy-benzyl)-{[2- (2-chloro- Nil) -propylcarbamoyl] -methyl} -carbamoyl) -2- (1H-imida Zol-4-yl) -ethyl] -carbamic acid benzyl ester   The title compound was prepared according to Example 8, Step 4, 2-pyridineethanamine HCl to o-chloro-β-methyl-phenethylamine hydrochloride (steps 1 and 2) ). This gives the title compound as a white foam (41%); ES- MS 694 (m + l). Step 1:2-methyl-3- (2-chloro-phenyl) cyanide   NaNH in THF (15 mL)_TwoTo a suspension of powder (0.6 g, 15.5 mmol) in THF (10 mL) 2-Chlorophenylacetonitrile (2 g, 13 mmol) in was added. mixture The material was refluxed for 2 hours. Of methyl iodide (2.18 g, 15.5 mmol) in THF (10 mL) The solution was then added and the solution was refluxed for a further 3 hours. Allow the reaction to cool And H_TwoTreated with O. Separate the organic layer and add 5% Na_TwoS_TwoO_Three, Washed twice with brine And Na_TwoSO_FourAnd concentrated; 1.93 g (93%). Step 2:o-chloro-β-methylphenethylamine hydrochloride   The reduction of the product obtained from step 1 is carried out with methanol / NH_ThreeRaneynicke in Performed in the presence of The catalyst was removed and washed with methanol. Concentrate the filtrate And diethyl ether (100 mL) was added to the residue. Concentrated HCl is added dropwise The compound precipitated; 1.06 g (44%). Example 33(S)-(2-1H-imidazol-4-yl) -1-{(2-methoxy-benzyl) -[(2-phenyl-propylcarbamoyl) -methyl] -carbamo (Ill-ethyl) -carbamic acid benzyl ester   The title compound was prepared according to Example 8, Step 4, 2-pyridineethanamine • Replace HCl with β-methyl-phenethylamine and in step 1 4 Benzyloxy-benzaldehyde in o-methoxy-benzaldehyde It can be manufactured instead. The title compound is obtained as a white foam (15%); ES-MS 584 ( m + 1). Example 34(S)-(2- (1H-imidazol-4-yl) -1-{[(2-phenylpropyl Carbamoyl) -methyl]-[4- (pyridin-4-ylmethoxy) -benzyl] -Carbamoyl｝ -ethyl) -carbamic acid benzyl ester   The title compound was prepared according to Example 15, Step 1 by adding 4-benzyloxybenz The aldehyde is converted to 4-[(4-pyridyl) -methyloxy] -benzaldehyde (step 1) and according to step 5, β, β-dimethylphenethyl The amine hydrochloride can be produced by replacing β-methylphenethylamine. Title change The compound is obtained as a white foam (67%): ES-MS 661 (m + 1). Step 1:4-[(4-pyridyl) -methyloxy] -benzaldehyde   This compound is synthesized as exemplified in J. Het, Chem., 1988; 25; 129. You. Example 35(S)-(2- (1H-imidazol-4-yl) -1-{(3-methoxy-benzyl) -[(2-phenyl-propylcarbamoyl) -methyl] -carbamoyl} -ethyl Ru) -carbamic acid benzyl ester   The title compound was obtained in Example 8, Step 4 using 2-pyridineethanea. Replace min.HCl with β-methyl-phenethylamine and in step 1 Converts 4-benzyloxy-benzaldehyde to m-methoxy-benzaldehyde Can be interchanged and manufactured. Obtain the title compound as a white foam (14%); ES-MS 584 (m + 1). Example 36(S)-(2- (1H-imidazol-4-yl) -1-{[(2-phenyl-propyl Rucarbamoyl) -methyl]-[4- (pyridin-3-ylmethoxy) -benzyl ] -Carbamoyl} -ethyl) -carbamic acid benzyl ester   The title compound was obtained in Example 15, Step 1 using 4-benzyloxybenzure. The aldehyde was converted to 4-[(3-pyridyl) -methyloxy] -benzaldehyde (step Step 1), and in step 5, β, β-dimethylphenethylamine Can be prepared by replacing β-methylphenethylamine with hydrochloride. Title compound As a white foam (59%); ES-MS 661 (m + 1). Step 1:4-[(3-pyridyl) -methyloxy] -benzaldehyde   This compound is synthesized as exemplified in J. Met, Chem., 1988; 25: 129. You. Example 37(S)-(2- (1H-imidazol-4-yl) -1- {naphthalen-1-ylme Tyl-[(2-phenyl-propylcarbamoyl) -methyl] -carbamoyl}- Ethyl) -carbamic acid benzyl ester   The title compound was obtained in Example 15, Step 1 using 4-benzyloxybenz. The aldehyde is replaced with 1-naphthalene-carboxaldehyde and In Step 5, β, β-dimethylphenethylamine hydrochloride was added. It can be produced by replacing β-methylphenethylamine. White foam with title compound Obtained as a solid (15%); ES-MS 604 (m + 1). Example 38(S)-{2- (1H-imidazol-4-yl) -1-[[(2-phenyl-propyl Rucarbamoyl) -methyl]-(4-trifluoromethyl-benzyl) -carbamoy Ru] -Ethyl} -carbamic acid benzyl ester   The title compound was prepared according to Example 8, Step 4 using 2-pyridineethanamine. The HCl was replaced with β-methyl-phenethylamine and in step 1 4- Benzyloxy-benzaldehyde is converted to p-trifluoromethyl-benzaldehyde Can be manufactured by replacing the Obtain the title compound as a white foam (13%) ES-MS 622 (m + 1). Example 39(S)-(2- (1H-imidazol-4-yl) -1-{[(2-methyl-2-fe Nyl-propylcarbamoyl) -methyl] -pyridin-3-ylmethyl-carba Moyl｝ -ethyl) -carbamic acid benzyl ester   The title compound was prepared according to Example 15, Step 1 by adding 4-benzyloxybenz Aldehydes can be prepared by replacing 3-pyridine-aldehydes. Title compound As a white foam (84%); ES-MS 569 (m + 1). Example 40(S)-(2- (1H-imidazol-4-yl) -1-{[(2-methyl-2-fe Nyl-propylcarbamoyl) -methyl]-[4- (pyridin-2-ylmethoxy) -Benzyl] -carbamoyl} -ethyl) -carbamic acid benzyl ester   The title compound was prepared according to Example 15, Step 1 by adding 4-benzyloxybenz Converting the aldehyde to 4-[(2-pyridyl) -methyloxy] -benzal It can be manufactured by replacing the dehydration (step 1). The title compound was converted to a white foam (62 %); ES-MS 675 (m + l). Step 1:4-[(2-pyridyl) -methyloxy] -benzaldehyde   This compound is described in Het, Chem., 1988; synthesized as exemplified in 25: 129. I do. Example 41(S) -2- (3-benzyl-3-methyl-ureido) -N- (4-benzyloxy C-benzyl) -3- (1H-imidazol-4-yl) -N-[(2-methyl-2- Phenyl-propylcarbamoyl) -methyl] -propionamide   The title compound was prepared according to Example 15, Step 2, Cbz-histidine- (tri )) With N-methyl-N-benzyl-urea-histidine- (trityl) It can be manufactured by replacing the above steps 1 and 2). White foam (79%) of the title compound ES-MS 687 (m + 1). Step 1:N-methyl-N-benzyl-urea-histidine- (trityl) methyl Ruster   Histidine- (trityl) methyl ester hydrochloride (methylene chloride (20 mL) 2.0 g, 4.2 mmol) and suspend the solution with saturated NaHCO_Three, Washed twice with brine And MgSO_FourAnd cooled at 0 ° C. Triethylamine (0.65mL, 8.8mm Mol) and 4-nitrophenyl chloroformate (0.93 g, 4.7 mmol) Was added. The reaction was stirred at 0 ° C. under nitrogen for 1.5 hours. In methylene chloride (10 mL) N-benzyl-N-methylamine (1.14 mL, 8.8 mmol) is then slowly added The reaction was stirred overnight at room temperature under nitrogen. Remove solvent and remove ethyl acetate as residue Was added. Organic solution H_TwoO, saturated NaHCO_Three, Washed twice with brine, dried over MgSO_FourDry with And concentrated. A foam was obtained by chromatography using 1: 1 ethyl acetate: hexane; 1.19g (50%). Step 2:N-methyl-N-benzyl-urea-histidine- (trityl)   The methyl ester from Step 1 (1.19 g, 2.1 mmol) was added in THF: methanol (10 mL each). Add 1N NaOH (6.3 mL, 6.3 mmol) and add The reaction was stirred overnight. The solvent was removed. Add 1N HCl (6.3 mL) and add And extracted with ethyl acetate. The organic solution was then washed twice with brine and dried over MgSO_Four And concentrated to give a white foam; 1.4 g. Example 42(S)-[1- {benzyl-[(2-methyl-2-phenyl-propylcarbamo) Yl) -methyl] -carbamoyl} -2- (1H-imidazol-4-yl) -ethyl Ru] -carbamic acid benzyl ester   The title compound was prepared according to Example 8, Step 4, 2-pyridineethanamine Replace HCl with β, β-dimethyl-phenethylamine hydrochloride and In Step 1, 4-benzyloxy-benzaldehyde is replaced with benzaldehyde. Can be manufactured. The title compound is obtained as a white foam (42%); ES-MS 568 ( m + 1). Example 43(S)-(2- (1H-imidazol-4-yl) -1-{(2-methyl-benzyl) -[(2-phenyl-propylcarbamoyl) -methyl] -carbamoyl} -ethyl Ru) -carbamic acid benzyl ester   The title compound was prepared according to Example 8, Step 4, 2-pyridineethanamine • Replace HCl with β-methyl-phenethylamine and proceed to Step 1 Now converts 4-benzyloxy-benzaldehyde to o-methyl-benzaldehyde. Can be interchanged and manufactured. Obtain the title compound as a white foam (49%); ES-MS 568 (m + 1). Example 44(S)-(2- (1H-imidazol-4-yl) -1-{(4-methoxy-benzyl) )-[(2-Methyl-2-phenyl-propylcarbamoyl) -methyl] -carba Moyl｝ -ethyl) -carbamic acid benzyl ester   The title compound was prepared according to Example 8, Step 4, 2-pyridineethanamine Replace HCl with β, β-dimethyl-phenethylamine hydrochloride and In Step 1, 4-benzyloxy-benzaldehyde is converted to p-methoxy-benzaldehyde It can be manufactured by replacing the fold. Obtain the title compound as a white foam (16%) ES-MS 598 (m + 1). Example 45(S)-[1-{(4-benzyloxy-benzyl)-[(2-cyano-2-fe Nyl-ethylcarbamoyl) -methyl] -carbamoyl} -2- (1H-imidazo Ru-4-yl) -ethyl] -carbamic acid benzyl ester   The title compound was prepared as in Example 15, Step 5, β, β-dimethylphenethylene. Luamine hydrochloride replaced with β-cyano-phenethylamine hydrochloride (step 1) Can be manufactured. Obtain the title compound as a white foam (47%); ES-MS 671 ( m + 1). Step 1:β-cyano-phenethylamine hydrochloride   This compound is disclosed in U.S. Pat.No. 4,760,089, 1988, which is incorporated herein by reference. Synthesized according to year. Example 46(S)-(2- (1H-imidazol-4-yl) -1-{[(2-methyl-2 -Phenyl-propylcarbamoyl) -methyl] -pyridin-2-ylmethyl- Carbamoyl｝ -ethyl) -carbamic acid benzyl ester   The title compound can be prepared according to Example 15, where Step 1 is shown below. It is implemented as follows. The title compound is obtained as a white foam (63%); ES-M S 569 (m + 1). Step 1:[(2-pyridyl) -methylamino] -acetic acid methyl ester   2-Aminomethylpyridine (5.0 g, 46.2 mmol) in acetonitrile (100 mL) Solution of methyl bromoacetate (4.3 mL, 46.2 mmol) and triethylamido (6.5 mL, 46.2 mmol). After stirring for 1 hour at room temperature, the solution was Warm to reflux at night. Dilute the solution with ethyl acetate and add saturated NaHCO_ThreeTo, water and brine Washed with MgSO_FourAnd concentrated. With 3% methanol in chloroform Elution chromatography gave 2.73 g (33%) of pure product as an oil. I got it. Example 47(S)-(2- (1H-imidazol-4-yl) -1-{(3-methyl-benzyl) -[(2-phenyl-propylcarbamoyl) -methyl] -carbamoyl} -ethyl Ru) -carbamic acid benzyl ester   The title compound was prepared according to Example 8, Step 4, 2-pyridineethanamine • Replace HCl with β-methyl-phenethylamine and in step 1 4 Replacing benzyloxy-benzaldehyde with m-methyl-benzaldehyde Can be manufactured. The title compound is obtained as a white foam (52%); ES-MS 568 ( m + 1). Example 48(S)-[1-{(4-dimethylamino-benzyl)-[(2-phenyl-propyl Rucarbamoyl) -methyl] -carbamoyl} -2- (1H-imidazo Ru-4-yl) -ethyl] -carbamic acid benzyl ester   The title compound was prepared according to Example 8, Step 4, 2-pyridineethanamine • Replace HCl with β-methyl-phenethylamine and in step 1 Put the ziroxy-benzaldehyde in the -benzaldehyde of p-dimethylami It can be manufactured instead. Obtain the title compound as a white foam (36%); ES-MS 59 7 (m + 1). Example 49(S)-(2- (1H-imidazol-4-yl) -1-{[(2-methyl-2-fe Nyl-propylcarbamoyl) -methyl]-[4- (pyridin-4-ylmethoxy) ) -Benzyl] -carbamoyl} -ethyl) -carbamic acid benzyl ester   The title compound was prepared according to Example 15, Step 1 by adding 4-benzyloxy-benzene. The aldehyde is converted to 4-[(4-pyridyl) -methyloxy] -benzaldehyde (s It can be manufactured by replacing Step 1). Obtain the title compound as a white foam ( 93%): ES-MS 675 (m + 1). Step 1:4-[(4-pyridyl) -methyloxy] -benzaldehyde   This compound is synthesized as exemplified in J. Het., Chem., 1988; 25: 129. Is done. Example 50(S)-(2- (1H-imidazol-4-yl) -1-{[(2-methyl-2-fe Nyl-propylcarbamoyl) -methyl]-[4- (pyridin-3-yl-methoxy) Cis-benzyl] -carbamoyl} -ethyl) -carbamic acid benzyl ester   The title compound was prepared according to Example 15, Step 1 using 4-benzyloxy-benzene. The dialdehyde is converted to 4-[(3-pyridyl) -methyloxy] -benzure It can be manufactured by replacing with aldehyde (step 1). White foam on title compound (56%): ES-MS 675 (m + 1). Step 1:4-[(3-pyridyl) -methyloxy] -benzaldehyde   This compound is synthesized as exemplified in J. Het., Chem., 1988; 25: 129. Is done. Example 51(S)-[1- {biphenyl-4-ylmethyl-[(2-phenyl-propylca) Rubamoyl) -methyl] -carbamoyl} -2- (1H-imidazol-4-yl) -Ethyl] -carbamic acid benzyl ester   The title compound was prepared according to Example 15, Step 1 by adding 4-benzyloxy-benzene. Replacing the dialdehyde with p-phenyl-benzaldehyde and 5, the β, β-dimethylphenethylamine hydrochloride is converted to β-methyl-phenethyl It can be produced by replacing with amine hydrochloride. Obtain the title compound as a white foam (33%): ES-MS 630 (m + 1). Example 52(S)-[1- {biphenyl-4-ylmethyl-[(2-methyl-2-phenyl -Propylcarbamoyl) -methyl] -carbamoyl} -2- (1H-imidazole -4-yl) -ethyl] -carbamic acid benzyl ester   The title compound was prepared according to Example 15, Step 1 by adding 4-benzyloxy-benzene. It can be produced by replacing the dialdehyde with p-phenyl-benzaldehyde. Title (32%): ES-MS 644 (m + 1). Example 53(S)-[1-((4-benzyloxy-benzyl)-{[2- (2-chloro-phen Nil) -ethylcarbamoyl] -methyl} -carbamoyl) -2- (1H -Imidazol-4-yl) -ethyl] -carbamic acid benzyl ester   The title compound was prepared according to Example 7, Step 1 using 2-[(2-fluorophene). Nyl) -ethyl] -amine is replaced by 2-chloro-phenethylamine. Wear. Title compound is obtained as white foam (89%): ES-MS 681 (m + 1) ). Example 54(S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-phenyl -Propylcarbamoyl) -methyl] -carbamoyl} -2- (1H-imidazole -4-yl) -ethyl] -carbamic acid thiophen-3-ylmethyl ester   The title compound was prepared according to Example 15, Step 2, Cbz-histidine- (tri Tyl) is converted to 3-thiophenemethyl-oxycarbonyl-histidine- (trityl) ( It can be manufactured by replacing steps 1 and 2). Convert the title compound to a white foam (40%): ES-MS 680 (m + 1). Step 1:3-thiophenemethyloxycarbonyl-histidine- (trityl) Methyl ester   3-thiophene methanol (0.43 mL, 4.6 mmol), triethylamine (0.64 m L, 4.6 mmol) and 4-nitrophenyl chloroformate (0.92 g, 4.6 mmol) Was dissolved in methylene chloride (20 mL) and cooled to 0 ° C. under nitrogen. One hour later Histidine- (trityl) methyl ester hydrochloride (2 mL) in methylene chloride (10 mL) g, 4.2 mmol) and triethylamine (1.28 mL, 9.2 mmol) were added. . The reaction was stirred -night. The solvent was removed under vacuum. Add ethyl acetate and water did. NaHCO saturated organic layer_Three, Washed with brine, MgSO_FourDried and concentrated To give a yellow oil. White foam by flash chromatography (1: 1 ethyl acetate: hexane) Obtained: 1.15 g (50%). Step 2:3-thiophenemethyloxycarbonyl-histidine- (trityl)   Ester from step 1 in THF (10 mL) and methanol (10 mL) (1.15 g , 2.1 mmol), 1N NaOH (6.3 mL, 6.3 mmol) was added and the solution was Stirred at room temperature-night. The solution was concentrated, 1N HCl (6.3 mL) was added, and the The product was extracted with ethyl acetate. This is washed twice with brine and dried over MgSO_FourAt Dry and concentrate to give a white foam: 1.12 g (99%). Example 55(S)-[1-{(4-chloro-benzyl)-[1- (2-methyl-2-phenyl) -Propylcarbamoyl) -ethyl] -carbamoyl} -2- (3H-imidazole -4-yl) -ethyl] -carbamic acid benzyl ester   The title compound was the glycine methyl ester salt according to Example 15, Step 1. The salt to alanine methyl ester hydrochloride and in step 2 PyBOB to 1- Roxy-7-azabenzotriazole (HOAt) and 0- (7-azabenzotriazole Zol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate Can be replaced with HATU. Obtain the title compound as a white foam (78%): ES-MS 617 (m + 1). Example 56(S)-(2- (1H-imidazol-4-yl) -1-{(4-methyl-benzyl) -[2-methyl-2-phenyl-propylcarbamoyl) -methyl] -carbamo (Ill-ethyl) -carbamic acid benzyl ester   The title compound was prepared according to Example 15, Step 1 by using 4-benzyloxy. -Can be produced by replacing benzaldehyde with 4-methyl-benzaldehyde. Obtain the title compound as a white foam (74%): ES-MS 582 (m + 1). Example 57(S)-(2- (1H-imidazol-4-yl) -1-{(2-methoxy-benzyl) )-[(2-Methyl-2-phenyl-propylcarbamoyl) -methyl] -carba Moyl｝ -ethyl) -carbamic acid benzyl ester   The title compound was prepared according to Example 8, Step 1, 4-benzyloxy-benzene. Replacing the dialdehyde with 2-methoxy-benzaldehyde and step 4 To convert 2-pyridine-ethanamine hydrochloride to β, β-dimethylphenethylamine (actually Example 15 can be replaced with step 4) to manufacture. White foam on title compound (11%): ES-MS 598 (m + 1). Example 58(S) -2- (3-benzyl-3-methyl-ureido) -N- (4-chloro-ben (Zyl) -3- (1H-imidazol-4-yl) -N-[(2-methyl-2-phenyl -Propylcarbamoyl) -methyl] -propionamide   The title compound was prepared according to Example 15, Step 1 by adding 4-benzyloxy-benzene. The dialdehyde is converted to 4-chloro-benzaldehyde and in step 2 Cbz- Stidine- (trityl) is converted to N-methyl-N-benzyl-urea-histidine- (to (Example 41, Steps 1 and 2). Title change The compound is obtained as a white foam (72%): ES-MS 616 (m + 1). Example 59(S)-(2- (1H-imidazol-4-yl) -1-{(3-methoxy-benzyl) )-[(2-Methyl-2-phenyl-propylcarbamoyl) -methyl Ru] -carbamoyl} -ethyl) -carbamic acid benzyl ester   The title compound was prepared according to Example 8, Step 1, 4-benzyloxy-benzene. Replacing the dialdehyde with 3-methoxy-benzaldehyde and step 4 The 2-pyridine-ethanamine hydrochloride in β, β-dimethylphenethylamine (Example 15, Step 4) to produce the product. White foam with title compound (5%): ES-MS 598 (m + 1). Example 60(S)-(2- (1H-imidazol-4-yl) -1-{[(2-methyl-2-fe Nyl-propylcarbamoyl) -methyl]-[2- (pyridin-4-ylmethoxy) ) -Benzyl] -carbamoyl} -ethyl) -carbamic acid benzyl ester   The title compound was prepared according to Example 15, Step 1 by adding 4-benzyloxy-benzene. The aldehyde is converted to 2-[(4-pyridyl) -methyloxy] -benzaldehyde (s It can be manufactured by replacing Step 1). Obtain the title compound as a white foam ( 61%): ES-MS 676 (m + 1). Step 1:2-[(4-pyridyl) -methyloxy] -benzaldehyde   Grind a solution of salicylaldehyde (5 g, 40.9 mmol) in DMSO (75 mL) Treated with potassium hydroxide (5.4 g, 81.8 mmol) and stirred at room temperature for 1 hour. Stirred. This was then treated with 4-picolyl chloride hydrochloride (6.8 g, 40.9 mmol). And the dark mixture was stirred overnight. Pour the mixture into water and add ethyl acetate Extracted twice. Wash the combined ethyl acetate extracts with 5% NaOH, water and then Was washed three times with brine. MgSO_FourAnd remove the solvent under reduced pressure To give the crude product. Take this in ethyl acetate, treat with charcoal, filter, The solvent was then removed under reduced pressure to give 5.42 g (62.1%) of the product as an oil; MS -CI 214 (M + 1). Example 61[1- {cyclohexylmethyl-[(2-phenyl-propylcarbamoyl)-] Methyl] -carbamoyl {-2- (3H-imidazol-4-yl) -ethyl] -ca Rubamic acid benzyl ester   The title compound was prepared according to Example 8, Step 1, 4-benzyloxy-benzene. Replace the aldehyde with cyclohexane-carboxaldehyde and In Step 4, 2-pyridineethanamine HCl was replaced with β-methyl-phenethyl-amido. It can be replaced and manufactured. Obtain the title compound as a white foam (16%) : MS-ES 559 (M + H). Example 62(S)-(2- (1H-imidazol-4-yl) -1- {isobutyl-[(2-fe Nyl-propylcarbamoyl) -methyl] -carbamoyl {-ethyl) -carbami Acid benzyl ester Step 1:N ^α- Boc-N-[(2-phenyl-propylcarbamoyl) -methyl ] -Glycinamide   To a solution of Boc-glycine (2.1 g, 12 mmol) in methylene chloride (100 mL) was added β -Methyl-phenethylamine (1.91 mL, 13.2 mmol), 1-hydroxybenzo -Triazole (Hobt) (1.78 g, 13.2 mmol), dicyclohexyl-carbodi Imide (DCC) (0.5 M DCC in methylene chloride; 26 mL, 13.2 mmol); Sopropylethylamine (4.17 mL, 24 mmol) was added. Remove the reaction at room temperature Stirred at night. The reaction solution was filtered. The filtrate was washed three times with brine. Organic solvent MgSO 4_FourAnd concentrated. Flash chromatography (chloroform 3.5% (100%) of the title compound as a white solid Obtained: CI-MS 293 (m + 1). Step 2:N-[(2-phenyl-propylcarbamoyl) -methyl] -glyci Amide trifluoroacetate   Compound from step 1 above (3.5 g, 12 mmol) in methylene chloride (35 mL) To the solution of), trifluoroacetic acid (15 mL) was added. The solution is stirred for 2 hours and then Concentrated. The residue was dissolved in methylene chloride and re-concentrated to give the title compound Was obtained as an oil. This was used for the next reaction without characterization. Step 3:N-[(2-phenyl-propylcarbamoyl) -methyl] -Nα- (4-benzyloxy-benzyl) -glycinamide hydrochloride   To a suspension of the compound from Step 2 above (1.16 g, 6 mmol) was added methyl chloride. Isobutyraldehyde (0.274 mL, 3 mmol) and sodium acetate in ren (25 mL) Lithium (0.59 g, 7.25 mmol) was added. The solution is cooled to 0 ° C., and Sodium triacetoxyborohydride (1.92 g, 9.1 mmol) was added. The The reaction was warmed to room temperature and stirred overnight. The reaction was washed with saturated NaHCO_ThreeTreated with aqueous solution And the layers were separated. The aqueous layer was extracted with methylene chloride (2 × 20 mL). Said yes The organic layers were combined, washed three times with brine,_FourAnd concentrated.   Flash chromatography of the product (5% methanol in chloroform) Purification afforded 0.22 g (15%) of the title compound: CI-MS 249 (m + 1). Step 4:( 2- [1-trityl-1H-imidazol-4-yl) -1- {iso Butyl-[(2-phenyl-propylcarbamoyl) -methyl] -carbamoyl -Ethyl) -carbamic acid benzyl ester   (S)-(2-benzyloxycarbonylamino-3) in methylene chloride (50 mL) -(1-Trityl) -1H-imidazol-4-yl) -propionic acid (Cbz-hist Gin- (trityl)) (Hudsspeth J.P., Kaltenbronn J.S., Repine J.T., Roark W H., Stier M.A., Renin Inhibitors III, U.S. Patent No. 4,735,933; 1988) (0.53). 2 g, 1.0 mmol) in a solution of O- (7-azabenzotriazol-1-yl) -N , N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) (0.67 g, 1.7 mmol), 1-hydroxy-7-azabenzotriazole (N0At) (0.2 4 g, 1.7 mmol) and diisopropylethylamine (1.08 mL, 6.2 mmol) Was added. The mixture was then combined with the amine from step 3 above (0.22 g, 0.88 mmol). And stirred for -night. The reaction solution is concentrated and the residue is Dissolved in ethyl (25 mL). Organic solution is 5% citric acid, 5% NaHCO_ThreeAnd Bly Wash three times with MgSO_FourAnd concentrated. Further purification of the product Not used for next step. Step 5:( S)-(2- (1H-imidazol-4-yl) -1- {isobutyl- [(2-phenyl-propylcarbamoyl) -methyl] -carbamoyl} -ethyl ) -Carbamic acid benzyl ester   The trityl compound from step 4 above (0.64 g) in methylene chloride (25 mL) , 0.86 mmol) was added TFA (25 mL). The solution is stirred for 3 hours, And concentrated. NaHCO saturated with residue_ThreePartitioned between aqueous solution and ethyl acetate. Layers Separate and extract the aqueous layer with ethyl acetate (2 × 20 mL). Combine the organic layers, Mg SO_FourAnd concentrated. Reversed-phase high-pressure liquid chromatography (eluent: water 0.1% TFA in acetonitrile and 0.1% TFA in acetonitrile), and 0.060 g (13%) of product were obtained: ES-MS 520 (m + 1).PET Inhibitory activity   Protein: Farnesyltransferase (PET) of the compound of the present invention or Shows a farnesyl protein transferase (PET) inhibitory activity of 5 mmol Potassium phosphate and 20 micromolar ZnCl_TwoIn HEPES buffer solution (pH 7.4) And tested. This solution also contains 5 mM DTT (dithiothreitol), 5 mM MgCl_TwoAnd 0.1% PEG8000. The test is a 96-well plate (Walle Compound of the invention carried out in c) and in 100% DMSO (dimethylsulfoxide) Of different concentrations were used. Both substrates; radiolabeled farnesylpi Lophosphate ([1^ThreeH], specific activity 15-30 Ci / molole, final concentration 134 nM) and (bio (Thinyl) -Ahe-Thr-Lys-Cys-Val-Ile-Met ([3aS [3a alpha, 4 beta , 6aalpha])-Hexahydro-2-oxo-1H-thieno [3,4-d] imida Zol-5-pentanoic acid]-[7-aminoheptanoic acid] -Thr-Lyr-Cys-Val- Ile-Met) (where Ahe = 7-aminoheptanoic acid, Thr = threonine, Lys = lysine , Cys = cystine, Val = valine, Ile = isoleucine and Met = methionine. (Final concentration of 0.2 micromolar), the enzymatic reaction is SF9 affinity purified. Initiated by the addition of rat farnesyl protein transferase . After incubation at 30 ° C. for 30 minutes, 1.5M magnesium acetate, 0.2M H_ThreePO_Four, 0.5% BSA (bobbin serum albumin), and strepavidin beads (st repavidin beads) (Amersham) at a concentration of 1.3 mg / mL in a stop buffer. Stopped by diluting things 2.5-fold. Leave this plate at room temperature for 30 minutes After that, the radioactivity was quantified using a micro beta counter (Model 1450, Wallec). Was. This assay was performed without using 5 mM potassium phosphate.Gel shift test   2 × 10 of processing conditions⁶24 hours after transplanting the ras-transformed cells, Nesulation inhibitors were added at various concentrations. 18 hour incubation Following the period, 1% Triton X-100, 0.5% sodium deoxycholate and -Buffered salt containing 0.1% SDS (sodium sodium dodecyl sulfate), pH 7.4, in which several protease inhibitors (PMSF (phenylmethylsulfonylfur Oride), antipain, leupeptin, pepsta Tin (pepstatin) A, aprotinin, all of which are 1 microg / ML) in the presence of cells. 3 micrograms of v-H-ras Ab-2 (Onc ras-protein was added to the supernatant by addition of the Y13-259 antibody from ogene Science). From immunoprecipitation. After overnight immunoprecipitation, 30 μL (microliter) of 50% Add protein G-Sepharose slurry (Pharmacia), then incubate for 45 minutes. Was shocked. The pellet was washed with 2X Tris containing 5% β-mercaptoethanol. -Denature by resuspending in glycine loading buffer (Novex) and then boiling for 5 minutes Then, electrophoresis was performed using a 14% Tris-glycine SDS gel. Western (Western) Transfer protein to nitrocellulose membrane using transfer method, then Blocking was performed with a blocking buffer. Primary antibody (Oncogene Science During the overnight incubation using pan-ras Ab-2) from Anti-mouse HRP (horseradish peroxidase) conjugation for detection of protein A secondary antibody (Amersham) was used. ECL (chemiluminescence enhancement) method (Amersham) And expressed the blot.Clonogenic assay (6-well plate)   Before doing the actual test: 1. 1.5% Bact-aga (Ba) in Milli-Q water and autoclave cto Agar) was prepared. 2. Combine the following reagents and use 500mL of 2XDMEM-HG without phenol red. Prepared.       One bottle of DMEM base powder (Sigma D-5030)       4.5 g glucose       3.7 g sodium bicarbonate       0.11 g of sodium pyruvate       20 mL of 200 mmol L-glutamine (Sigma G-7513)       1 mL pen-strep (GibcoBRL No.15140-023)     The pH was adjusted to 7.1 with HCl; the filter was sterilized. ... 1. Replacement water bath in the hood (beaker with thermometer filled with water on hot plate) -) Is prepared. Maintain the water temperature between 37 ° C and 43 ° C. 2. 1.5% Bacto agar at elevated temperature for about 2 minutes or until completely dissolved Autoclaved. Then cool slightly before use. (This bot on a hot plate To prevent re-solidification. ) 3.Bottom layer (0.6% agar) Top layer (0.3% agar)     20% calf serum 20% calf serum     40% 2X DMEM 50% 2X DMEM     40% Bacto Agar (1.5%) 20% Bacto Agar (1.5%)                                  10% sterile H_TwoO × μL                                  Cell suspension (5000 cells / hole)                                  To) (H61 cells: NIH transformation 3T3H-ras                                  cell)     Floating in a “water bath” depending on the volume of each layer required Use a 50 mL triangular tube or a 200 mL round tube. 4. Add 1 mL bottom layer agar / medium to each well: 1 mL warm agar / medium Then spread the agar / medium around using the tip of a pipette to the bottom Cover completely. Repeat for the next hole. Pipette to avoid bubbles Do not add the last mL in. 5. The plate is brought to room temperature for about 5 minutes until the bottom layer solidifies. 6. Label a sterile Falcon 2054 (12 x 75 mm) tube and add the appropriate amount of drug Add the liquid. 7. Add 4 μL DMSO or drug solution per 1 ml agar / medium / cell Separate into tubes; add agar / medium / cells to each tube. Actually needed Always add 1 mL more than required. Mix up and down in the pipette (slowly ); Next, supply 1 mL to the center of each hole. The top layer is less viscous and therefore the bottom It is easy to spread naturally on the member layer. Rotate the surface of the board slowly if necessary to remove the bottom layer Spread the upper layer evenly on top. 8. The plate is allowed to solidify for 5 or 10 minutes at room temperature, then 5% CO2_TwoIncubation at 37 ℃ Put it in the heater. 9. On day 13, 0.5 mL of INT (1 mg / mL tetrazolium in Milli-Q, no filter Bacteria) and return the plate to the incubator. 10. Count the colonies.   The data in the table below shows the farnesyl protein transferase inhibitory activity and Shift and Chronogen Assay of Compounds of the Present Invention and ras Protein Shows the activity.   The numbers in parentheses indicate the average values obtained from the additional tests.   * MED is the minimum effective dose to observe inhibition of ras farnesylation.In vivo assays   The compound described in Example 15 was used for xenotransplantation of H61 tumor cells in nude mice. The ability to inhibit growth was tested. H61 cells activate human h-ras Transfection using a template to transform fibroblasts into a malignant state Replace. A 10-30 mg section of H61 tumor was SC (subcutaneous) in the axial area with a trocar needle. Was used to inoculate female nude mice on the first day of the experiment. Processing this nude mouse The compounds described in Example 15 were then randomized to 10% cremophor. SC injection of a suspension in (cremofor) / 10% ethanol / 80% water twice a day, Given on days 3-17 of the experiment. On the 12th day of the experiment, as verified by a caliper meter In addition, the median tumor burden was 1958 mg. Compound 12 described in Example 15 The median tumor load in animals treated with 5 mg / kg / injection was 106 mg, 95% of tumor growth Inhibition of Dosing regimens (regimen) that caused tumor growth delay were 125 and 78 Significant inhibition of tumor growth at mg / kg / injection dose. These dosage levels Animals were well tolerated or not host toxic.

──────────────────────────────────────────────────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 38/00 37/02 (81) Designated country 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 (GH, KE, LS, MW, SD, SZ, UG), EA (AM, AZ, BY, KG, KZ, MD, RU) , TJ, TM), AL, AU, BA, BB, BG, BR, CA, CN, CZ, EE, GE, GH, HU, IL, IS, JP, KR, LC, LK, L , LT, LV, MG, MK, MN, MX, NO, NZ, PL, RO, SG, SI, SK, TR, TT, UA, US, UZ, VN, YU (72) Inventor Kaltenbron, J. Aims. Stanley Michigan, USA 48103. Ann Arbor. Greenbrier Boulevard 3555. Apartment 70 Sea (72) Inventor Leonard, Daniel M. Michigan, USA 48103. Ann Arbor. Peters Road 2380 (72) Inventor McNamara, Dennis Gijosev Michigan, USA 48103. Ann Arbor. Linda Vista 304 (72) Inventor Sebalto-Liopoulde, Judeus Michigan, USA 48103. Ann Arbor. South Seventh Street 2020 (72) Inventor Schuyler, Keveon Earl Michigan, USA 48118. Chelsea. East Summit 146

Claims (1)

[Claims] 1. Having the following formula I:     here,     R^{twenty one}Is hydrogen or C₁~ C₆Alkyl;     R^QIs     n is 0 or 1;     R^a, R^a', And R^{a "}Is, independently, C₁~ C₆Alkyl,-(CH_Two)_m-Cycloal Kill,-(CH_Two)_m-Aryl, or-(CH_Two)_m-Heteroaryl;     Each m is independently 0 to 3;     R¹, R^Two, And R^FourIs independently hydrogen or C₁~ C₆Alkyl;     R^ThreeIs-(CH_Two)_m− (R^bHeteroaryl substituted with) or C₁~ C₆Alkyl;   t is 2 to 6;   R^bIs -O-phenyl, -O-benzyl, halogen, C₁~ C₆Alkyl, water (CH_Two)_yNR^aR^a',-(CH_Two)_m-Aryl, -O- (CH_Two)_m-Aryl,-(CH_Two)_m-Heteroa Reel, -O- (CH_Two)_m-Cycloalkyl, or-(CH_Two)_m-Cycloalkyl;   y is 2 or 3;   R^FiveIs     Rⁱ, R^g, And R^hIs independently hydrogen, halogen, -OC₁~ C₆Alkyl, C₁~ C₆ Alkyl, -CN, -OPO_ThreeH_Two, -CH_TwoPO_ThreeH_Two, -O-phenyl, -O-benzyl, , -N_Three, -CF_TwoCF_Three, -SO_TwoR^a, -SO_TwoNR^aR^a', -CHO, or -OCOCH_ThreeAnd     R^c, R^b, R^e, And R^fIs independently C₁~ C₆Alkyl,-(CH_Two)_m-Phenyl, Hydrogen,-(CH_Two)_m-OH,-(CH_Two)_m-Cycloalkyl- (CH_Two)_mNH_Two, Or -CN, And their pharmaceutically acceptable salts, esters, amides, and prodrugs. 2. R¹Is hydrogen, R^TwoIs hydrogen, R^FourIs hydrogen, R^{twenty one}Is hydrogen or CH_Three; And     A is   2. The compound of claim 1 which is: 3. R^ThreeBut,   Or -CH_Two-CH (CH_Three)_Two.     R¹Is hydrogen, R^TwoIs hydrogen, R^FourIs hydrogen, and R^{twenty one}Is hydrogen or CH_ThreeThe claim that is Compound of 1. 4. R^FiveBut,   Is;     Where RⁱIs hydrogen, Cl, Br, F, or NH_Two2. The compound of claim 1, which is 5. Compounds having the following Formula II, and their pharmaceutically acceptable salts, esters, And prodrugs:     here,     R^{twenty one}Is hydrogen or methyl;     R⁷Is hydrogen or methyl;     R⁸Is hydrogen, halogen, C₁~ C₆Alkyl, -O-benzyl, -OC₁~ C₆Alkyl , -CF_Three, -OH, or -O- (CH_Two)_m-Pyridyl or phenyl;     R^Ten, R¹¹, R¹³, And R¹⁴Is independently hydrogen, C₁~ C₆Alkyl, or-(CH_Two )_m-Phenyl;     Each m is independently 0 to 3;     R¹²Is And     R^j, R^k, And R¹Is independently hydrogen, halogen, -OC₁~ C₆Alkyl or C₁ ~ C₆Alkyl, -NHR^a, NH_Two,. 6. R¹¹And R¹⁴Is methyl. 7. R⁸Is a methyl or methoxy. 8. Compounds having the following formula III, and their pharmaceutically acceptable salts, esters, Mid, and prodrugs:     here,     X is NH, O, or -N (CH_Three);     R¹⁵Is -O-benzyl, -CF_Three, Hydrogen, halogen, -OC₁~ C₆Alkyl, Phenyl, -O-CH_Two-Pyridyl, or -C₁~ C₆Alkyl;     m is from 0 to 3; and     R¹⁶Is phenyl, hydrogen, or C₁~ C₆Alkyl, cycloalkyl, . 9. Compounds having the following formula IV, and their pharmaceutically acceptable salts, esters, And prodrugs:     here,     X is NH, O, or -N (CH_Three);     R¹⁵Is -O-benzyl, -CF_Three, Hydrogen, halogen, C₁~ C₆Alkyl, -OC₁~ C₆ Alkyl, phenyl, or -O- (CH_Two)_m-Pyridyl;     R¹⁶And R^{16 '}Is C₁~ C₆Alkyl;     m is from 0 to 3; and     R^{twenty one}Is hydrogen or methyl. Ten. A pharmaceutically acceptable composition comprising the compound of claim 1. 11． A pharmaceutically acceptable composition comprising the compound of claim 5. 12． A pharmaceutically acceptable composition comprising the compound of claim 6. 13. For patients with restenosis or at risk for restenosis, a therapeutically effective dose A method for treating or preventing restenosis, comprising administering the compound of claim 1. 14. For patients with restenosis or at risk for restenosis, a therapeutically effective dose A method for treating or preventing restenosis, comprising administering the compound of claim 5. 15． For patients with restenosis or at risk for restenosis, a therapeutically effective dose A method for treating or preventing restenosis, comprising administering the compound of claim 6. 16． Treating cancer, comprising administering to a cancer patient a therapeutically effective amount of a compound of claim 1. how to. 17． Treating cancer, comprising administering to a cancer patient a therapeutically effective amount of a compound of claim 5. how to. 18． Treating cancer, comprising administering to a cancer patient a therapeutically effective amount of a compound of claim 6. how to. 19. The following compounds:     (S)-[1-[(4-benzyloxy-benzyl)-(phenethyl-carbamo) Yl-methyl) -carbamoyl] -2- (3H-imidazol-4-yl) -ethyl ] -Carbamic acid benzyl ester;     (S)-[1-[[2-benzyloxy-ethylcarbamoyl] -methyl]-[ 4-chlorobenzyl] -carbamoyl] -2- (1H-imidazol-4-yl)- Ethyl] -carbamic acid benzyl ester;     (S)-[1-[(4-benzyloxy-benzyl)-[(2-phenyl-pro Pyr-carbamoyl) -methyl] -carbamoyl] -2- (1H-imidazole-4 -Yl) -ethyl] -carbamic acid benzyl ester;     (S)-[1-[(4-benzyloxy-benzyl)-[(2,2-diphenyl-e Tylcarbamoyl) -methyl] -carbamoyl] -2- (1H-imidazole-4- Yl) -ethyl] -carbamic acid benzyl ester;   and,     (S) -N- (4-benzyloxy-benzyl) -2- (3-benzyl-urey De) -3- (1H-Imidazol-4-yl) -N-[(2-phenyl-propylcal Bamoyl) -methyl] -propionamide. 20. The cancer is lung, colon, pancreatic, thyroid, breast, or bladder cancer. 16. The method according to 16. twenty one. The following compounds:     (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-f Enyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imida Sol-4-yl) -ethyl] -carbamic acid benzyl ester; twenty two. The following compounds:     (S)-[1- {biphenyl-4-ylmethyl-[(2-methyl-2-phenyl -Propylcarbamoyl) -methyl] -carbamoyl} -2- (1H-imidazole -4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-[1- {biphenyl-4-ylmethyl-[(2-phenyl-propyl Carbamoyl) -methyl] -carbamoyl} -2- (1H-imidazol-4-yl ) -Ethyl] -carbamic acid benzyl ester;     (S)-[1-{(4-benzyloxy-benzyl)-[(S)-(1-methyl- 2-phenyl-ethylcarbamoyl) -methyl] -carbamoyl {-2- (1H-i Midazol-4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-[1-{(4-benzyloxy-benzyl)-[(R)-(1-methyl- 2-phenyl-ethylcarbamoyl) -methyl] -carbamoyl {-2- (1H-i Midazol-4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-[1-{(4-benzyloxy-benzyl)-[(2-phenyl-butyi) Rucarbamoyl) -methyl] -carbamoyl} -2- (1H-imidazole-4-i L) -ethyl] -carbamic acid benzyl ester;     (S)-(2- (1H-imidazol-4-yl) -1-{-(4-methyl-benzyl) )-[(2-Phenyl-propylcarbamoyl) -methyl] -carbamoyl} -e Tyl) -carbamic acid benzyl ester;     (S)-(2- (1H-imidazol-4-yl) -1-{-(4-methoxy-benzyl) )-[(2-phenyl-propylcarbamoyl) -methyl] -carbamoyl}- (Ethyl) -carbamic acid benzyl ester;     (S)-[1-((4-benzyloxy-benzyl)-{[2- (2-chloro- Enyl) -2-phenyl-ethylcarbamoyl] -methyl} -carbamoyl) -2 -(1H-Imidazol-4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-[1-{(4-benzyloxy-benzyl)-[(2-ethyl-2-f Enyl-butylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imidazo 4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-[1-{(2-chloro-benzyl)-[(2-phenyl-propylcal Bamoyl) -methyl] -carbamoyl {-2- (1H-imidazol-4-yl)- Ethyl] -carbamic acid benzyl ester;     (S)-[1-((4-benzyloxy-benzyl)-{[2- (2-chloro- Enyl) -propylcarbamoyl] -methyl} -carbamoyl) -2- (1H-imi Dazol-4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-(2- (1H-imidazol-4-yl) -1-{-(2-methoxy-benzyl) )-[(2-phenyl-propylcarbamoyl) -methyl] -carba Moyl {-ethyl) -carbamic acid benzyl ester;     (S)-(2- (1H-imidazol-4-yl) -1-{[(2-phenyl-pro Pyrcarbamoyl) -methyl]-[4- (pyridin-4-ylmethoxy) -benzyl L] -carbamoyl} -ethyl) -carbamic acid benzyl ester;     (S)-(2- (1H-imidazol-4-yl) -1-{[(2-phenyl-pro Pyrcarbamoyl) -methyl]-[4- (pyridin-3-ylmethoxy) -benzyl L] -carbamoyl} -ethyl) -carbamic acid benzyl ester;     (S)-{2- (1H-imidazol-4-yl) -1-[[(2-phenyl- Ropylcarbamoyl) -methyl]-(4-trifluoromethyl-benzyl) -cal Bamoyl] -ethyl} -carbamic acid benzyl ester;     (S)-(2- (1H-imidazol-4-yl) -1-{[(2-methyl-2-f Enyl-propylcarbamoyl) -methyl]-[4- (pyridin-2-ylmethoxy) Cis) -benzyl] -carbamoyl} -ethyl) -carbamic acid benzyl ester;     (S)-[1- {benzyl-[(2-methyl-2-phenyl-propylcarba) Moyl) -methyl] -carbamoyl} -2- (1H-imidazol-4-yl) -d Tyl] -carbamic acid benzyl ester;     (S)-(2- (1H-imidazol-4-yl) -1-{-(4-methoxy-benzyl) )-[(2-methyl-2-phenyl-propylcarbamoyl) -methyl] -car Bamoyl {-ethyl) -carbamic acid benzyl ester;     (S)-[1-{(4-benzyloxy-benzyl)-[(2-cyano-2-fe Nyl-ethylcarbamoyl) -methyl] -carbamoyl} -2- (1H-imidazo Ru-4-yl) -ethyl] -carbamic acid benzyl ester;     (S) -2- (3-benzyl-3-methyl-ureido) -N- (4-benzylo Xy-benzyl) -3- (1H-imidazol-4-yl) -N-[(2-methyl-2 -Phenyl-propylcarbamoyl) -methyl] -propionamide;     (S)-[1-[{[2- (2-amino-phenyl) -propylcarbamoyl] -Methyl}-(4-benzyloxy-benzyl) -carbamoyl] -2- (3H-i Midazol-4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-(2- (1H-imidazol-4-yl) -1-{[(2-methyl-2-f Enyl-propylcarbamoyl) -methyl]-[4- (pyridin-4-ylmethoxy) Cis) -benzyl] -carbamoyl} -ethyl) -carbamic acid benzyl ester;     (S)-(2- (1H-imidazol-4-yl) -1-{[(2-methyl-2-f Enyl-propylcarbamoyl) -methyl]-[4- (pyridin-3-ylmethoxy) Cis) -benzyl] -carbamoyl} -ethyl) -carbamic acid benzyl ester; and,     (S)-[1- {cyclohexylmethyl-[(2-phenyl-propylcarba Moyl) -methyl] -carbamoyl} -2- (3H-imidazol-4-yl) -e Tyl] -carbamic acid benzyl ester. twenty three. The following compounds:     (S)-[1-((4-benzyloxy-benzyl)-{[2- (2-fluoro- Phenyl) -ethylcarbamoyl] -methyl} -carbamoyl) -2- (1H-imi Dazol-4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-[1-{(4-benzyloxy-benzyl)-[(2-pyridine- 2-yl-ethylcarbamoyl) -methyl] -carbamoyl} -2- (1H-imida Sol-4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-[1-((4-benzyloxy-benzyl)-{[2- (2-bromo- Enyl) -ethylcarbamoyl] -methyl} -carbamoyl) -2- (1H-imida Sol-4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-[1-{(4-benzyloxy-benzyl)-[(2-phenyl-2- Pyridin-2-yl-ethylcarbamoyl) -methyl] -carbamoyl} -2- ( 1H-imidazol-4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-[1-{(4-chloro-benzyl)-[(2-phenyl-propylcal Bamoyl) -methyl] -carbamoyl {-2- (1H-imidazol-4-yl)- Ethyl] -carbamic acid benzyl ester;   (S) -N- (4-benzyloxy-benzyl) -3- (1H-imidazole-4- Yl) -2- (3-phenyl-propionylamino) -N-[(2-phenyl-pro Pyrcarbamoyl) -methyl] -propionamide;     (S)-[1-{(4-fluoro-benzyl)-[(2-phenyl-propyl- Carbamoyl) -methyl] -carbamoyl} -2- (1H-imidazol-4-yl ) -Ethyl] -carbamic acid benzyl ester;     (S)-[1-{(4-fluoro-benzyl)-[(2-methyl-2-phenyl- Propylcarbamoyl) -methyl] -carbamoyl {-2- (1H-imidazole- 4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-[1- {benzyl-[(2-phenyl-propylcarbamoyl) -methyl] ] -Carbamoyl {-2- (1H-imidazol-4-yl) -ethyl] -carba Benzyl formate;     (S) -N- (4-benzyloxy-benzyl) -2- (3-benzyl-urey De) -3- (1H-Imidazol-4-yl) -N-[(2-phenyl-propylcal Bamoyl) -methyl] -propionamide;    (S) -N- (4-benzyloxy-benzyl) -2- (3-benzyl-ureido ) -3- (1H-Imidazol-4-yl) -N-[(2-phenyl-butylcarbamo Yl) -methyl] -propionamide;     (S)-[1-{(4-bromo-benzyl)-[(2-phenyl-propylcal Bamoyl) -methyl] -carbamoyl {-2- (1H-imidazol-4-yl)- Ethyl] -carbamic acid benzyl ester;     (S)-[1-{(3-chloro-benzyl)-[(2-phenyl-propylcal Bamoyl) -methyl] -carbamoyl {-2- (1H-imidazol-4-yl)- Ethyl] -carbamic acid benzyl ester;     (S)-[1-{(4-chloro-benzyl)-[(2-methyl-2-phenyl- Propylcarbamoyl) -methyl] -carbamoyl {-2- (1H-imidazole- 4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-(2- (1H-imidazol-4-yl) -1-{-(3-methoxy-benzyl) )-[(2-phenyl-propylcarbamoyl) -methyl] -carbamoyl}- (Ethyl) -carbamic acid benzyl ester;     (S)-(2- (1H-imidazol-4-yl) -1- {naphthalen-1-yl Methyl-[(2-phenyl-propylcarbamoyl) -methyl] -carbamoyl -Ethyl) -carbamic acid benzyl ester;     (S)-(2- (1H-imidazol-4-yl) -1-{[(2-methyl-2-f Enyl-propylcarbamoyl) -methyl] -pyridin-3-ylmethyl-cal Bamoyl {-ethyl) -carbamic acid benzyl ester;     (S)-(2- (1H-imidazol-4-yl) -1-{-(2-methyl-ben (Zyl)-[(2-phenyl-propylcarbamoyl) -methyl] -carbamoyl} -Ethyl) -carbamic acid benzyl ester;     (S)-(2- (1H-imidazol-4-yl) -1-{[(2-methyl-2-f Enyl-propylcarbamoyl) -methyl] -pyridin-2-ylmethyl-cal Bamoyl {-ethyl) -carbamic acid benzyl ester;     (S)-(2- (1H-imidazol-4-yl) -1-{-(3-methyl-benzyl) )-[(2-Phenyl-propylcarbamoyl) -methyl] -carbamoyl} -e Tyl) -carbamic acid benzyl ester;     (S)-[1-{(4-dimethylamino-benzyl)-[(2-phenyl-pro Pyrcarbamoyl) -methyl] -carbamoyl} -2- (1H-imidazole-4- Yl) -ethyl] -carbamic acid benzyl ester;     (S)-[1-{(4-benzyloxy-benzyl)-[(2-hydroxy-2 -Phenyl-ethylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imi Dazol-4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-[1-((4-benzyloxy-benzyl)-{[2- (2-chloro- Enyl) -ethylcarbamoyl] -methyl} -carbamoyl) -2- (1H-imida Sol-4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-f Enyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (1H-imida Sol-4-yl) -ethyl] -thiophen-3-ylmethyles-carbamate Tell;     (S)-[1-{(4-chloro-benzyl)-[1- (2-methyl-2-phenyl) -Propylcarbamoyl) -ethyl] -carbamoyl} -2- (3H- Imidazol-4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-(2- (1H-imidazol-4-yl) -1-{-(4-methyl-benzyl) )-[(2-Methyl-2-phenyl-propylcarbamoyl) -methyl] -Carbamoyl {-ethyl) -carbamic acid benzyl ester;     (S)-(2- (1H-imidazol-4-yl) -1-{-(2-methoxy-benzyl) )-[(2-methyl-2-phenyl-propylcarbamoyl) -methyl] -car Bamoyl {-ethyl) -carbamic acid benzyl ester;     (S) -2- (3-benzyl-3-methyl-ureido) -N- (4-chloro- Benzyl) -3- (1H-imidazol-4-yl) -N-[(2-methyl-2-phenyl Ru-propylcarbamoyl) -methyl] -propionamide;     (S)-(2- (1H-imidazol-4-yl) -1-{-(3-methoxy-benzyl) )-[(2-methyl-2-phenyl-propylcarbamoyl) -methyl] -car Bamoyl {-ethyl) -carbamic acid benzyl ester;     (S)-(2- (1H-imidazol-4-yl) -1-{[(2-methyl-2-f Enyl-propylcarbamoyl) -methyl]-[2- (pyridin-4-ylmethoxy) Cis) -benzyl] -carbamoyl} -ethyl) -carbamic acid benzyl ester; and,     (2- (1H-imidazol-4-yl) -1- {isobutyl-[(2-phenyl -Propylcarbamoyl) -methyl] -carbamoyl {-ethyl) -carbamic acid Benzyl ester. twenty four. The following compounds:     (S)-[1-{(4-benzyloxy-benzyl)-[(2-phenyl-pen Tyl-carbamoyl) -methyl] -carbamoyl} -2- (3H-imidazole-4 -Yl) -ethyl] -carbamic acid benzyl ester;     (S)-[1-{[2- (4-benzyloxy-phenyl) -ethyl]- [(2-Methyl-2-phenyl-propylcarbamoyl) -methyl] -carbamoy Benzyl-2- (3H-imidazol-4-yl) -ethyl] -benzylcarbamate Steal;     (S)-(2- (3H-imidazol-4-yl) -1-{[2- (4-methoxy- Phenyl) -ethyl]-[(2-methyl-2-phenyl-propylcarbamoyl) -Methyl] -carbamoyl {-ethyl) -carbamic acid benzyl ester;     (S)-[1-[{[2- (2-amino-phenyl) -ethylcarbamoyl]- Methyl {-(4-benzyloxy-benzyl) -carbamoyl] -2- (3H-imi Dazol-4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-f Enyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imida Sol-4-yl) -ethyl] -methyl-carbamic acid benzyl ester;     (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-f Enyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (2-methyl -3H-imidazol-4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-f Enyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (1-methyl -1H-imidazol-4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-f Enyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (3H-Imidazol-4-yl) -ethyl] -furan-2-ylmethacarbamate Luster;     (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-f Enyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imida Zol-4-yl) -ethyl] -thiophen-2-ylmethylcarbamate Tell;     (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-f Enyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imida Zol-4-yl) -ethyl] -pyridin-3-ylmethylesterate Le;     (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-f Enyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imida Zol-4-yl) -ethyl] -carbamic acid 1H-imidazol-4-ylmethyi Luster;     (S) -2- (3-benzyl-ureido) -N- (4-chloro-benzyl) -3- (3H-imidazol-4-yl) -N-[(2-methyl-2-phenyl-propyl Carbamoyl) -methyl] -propionamide;     (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-f Enyl-propylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imida Zol-4-yl) -ethyl] -carbamic acid 4-methoxy-benzyl ester ;     (S) -2- (3-benzyl-thioureido) -3- (3H-imidazole-4- Yl) -N- (4-methyl-benzyl) -N-[(2-methyl-2-phenyl-pro Pyrcarbamoyl) -methyl] -propionamide;   (S) -2-acetylamino-N- (4-benzyloxy-benzyl) -3 -(3H-imidazol-4-yl) -N-[(2-methyl-2-phenyl-propyl Carbamoyl) -methyl] -propionamide;     (S)-(2- (3H-imidazol-4-yl) -1-{[(2-methyl-2-f Enyl-propylcarbamoyl) -methyl] -pyridin-4-ylmethyl-cal Bamoyl {] ethyl) -carbamic acid benzyl ester;     (S)-{2- (3H-imidazol-4-yl) -1-[(4-iodo-benzyl) )-(Phenethylcarbamoyl-methyl) -carbamoyl] -ethyl} -carba Benzyl formate;     (S)-[1-{(4-amino-benzyl)-[(2-methyl-2-phenyl- Propylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imidazole- 4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-[1-{(4-ethoxy-benzyl)-[(2-methyl-2-phenyl -Propylcarbamoyl) -methyl] -carbamoyl} -2- (3H-imidazole -4-yl) -ethyl] -carbamic acid benzyl ester;     (S)-[1-{[4- (2-dimethylamino-ethoxy) -benzyl]-(2 -Methyl-2-phenyl-propylcarbamoyl) -methyl] -carbamoyl -2- (3H-Imidazol-4-yl) -ethyl] -benzylcarbamate And;     (2- (1H-imidazol-4-yl) -1- {isobutyl-[(2-methyl- 2-phenyl-propylcarbamoyl) -methyl] -carbamoyl {-ethyl)- Carbamate benzyl ester. twenty five. Administering a therapeutically effective amount of a compound of claim 1 to a patient having a viral infection. A method of treating a viral infection, comprising: 26. Administering a therapeutically effective amount of a compound of claim 5 to a patient having a viral infection. A method of treating a viral infection, comprising: 27. Administering a therapeutically effective amount of a compound of claim 6 to a patient having a viral infection. A method of treating a viral infection, comprising: 28. Treating psoriatic patients with a therapeutically effective amount of the compound of claim 1. How to treat. 29. Treating psoriatic patients with a therapeutically effective amount of the compound of claim 5; How to treat. 30. Treating psoriatic patients with a therapeutically effective amount of the compound of claim 6; How to treat.