SK161098A3 - Inhibitors of protein farnesyl transferase - Google Patents

Abstract

Novel inhibitors of protein farnesyl transferase enzymes are described, as well as methods for the preparation and pharmaceutical compositions of the same, which are useful in treating cancer, restenosis, psoriasis, endometriosis, atherosclerosis, or viral infections.

Description

Technical field

The present invention relates to compounds which can be used in medicine for the treatment, prophylaxis or otherwise uncontrolled or abnormal proliferation of human tissues. In particular, the present invention relates to compounds which inhibit farnesyltransferase enzyme, which has been found to activate ras proteins that re-activate cell division resulting in cancer and restenosis.

BACKGROUND OF THE INVENTION

Ras (or p21) protein has been widely studied because mutant forms have been found to be found in 20 Ϊ of most cancers in humans and more than 50% of colon and pancreatic cancer (Gibbs JB, Cell, 1991; 65: 1, Cartwright T. et al., Chimica Oggi., 1992; 10:26). These mutant ras proteins are deficient in the ability to regulate the feedback that is present in natural ras and this deficiency is associated with their oncogenic action, since the ability to stimulate normal cell division cannot be regulated by conventional endogenous regulatory factors. Recent discoveries that the conversion of mutant ras activity is critically dependent on post-translational modifications (Gibbs J. et al., Microbiol. Rev., 1989; 53: 171) have revealed an important aspect of ras function and identified new prospects for cancer therapy.

In addition to cancer, there are a number of conditions of uncontrolled cell proliferation that may be related to overexpression and / or function of ras proteins. Post-surgical vascular restenosis is such a condition. The use of various surgical revascularization techniques, such as saphenous vein bypass, transplantation, endarterectomy, and transluminal coronary angioplasty, are often accompanied by complications due to the uncontrolled growth of neointimal tissue known as restenosis. The biochemical causes of restenosis are difficult to understand and a number of growth factors and proto-oncogenes have been implicated (Naftilan AJ et al., Hypertension, 1989; 13: 706 and J. Clin. Invest., 83: 1419; Gibbons GH et al., Hypertension, 1989; 14: 358; Satoh T. et al., Molec. Cell. Biol., 1993; 13: 3706). The fact that ras proteins are known to be involved in cell division processes makes them candidates for intervention in a number of situations where cells divide uncontrolled. In direct analogy to the inhibition of mutant ras-related cancer, ras-dependent blockade or procedures have the potential to reduce or eliminate inappropriate tissue proliferation associated with restenosis, especially where the usual expression and / or function of ras is exacerbated by growth promoter factors.

The action of ras is dependent on the modification of proteins to associate with the inner surface of the plasma membrane. Unlike other membrane-associated proteins, ras proteins do not have conventional transmembrane or hydrophobic sequences and are initially synthesized in cytosolic soluble form. Membrane association of ras protein is activated by a number of post-translational processing steps, which are signaled by a carboxyl-terminated amino acid sequence recognized by protein farnesyltransferase (PFT).

This consensus sequence consists of a cysteine residue located four amino acids from the carboxyl terminus, followed by two lipophilic amino acids and a C-terminal residue. The sulfhydryl group of the cysteine residue is alkylated with farnesyl pyrophosphate in a reaction that is catalyzed by protein farnesyltransferase. Subsequent prenylation, the three C-terminal amino acids are cleaved by an endoprotease and the newly revealed alphacarboxyl group of the prenylated cysteine is methylated with methyltransferase. Enzymatic processing of ras proteins that begins with farnesylation will allow the protein to associate with the cell membrane. Mutational analysis of ras oncogenic proteins indicates that post-translational modifications are essential for transformation efficiency. Replacing the same cysteine residue sequence with other amino acids yields a protein that is no longer farnesylated, loses the ability to migrate into the cell membrane and does not have the ability to stimulate cell proliferation (Hancock, JF et al., Cell, 1989; 57: 1617; Schafer WR et al. , Science, 1989; 245: 379, Casey, PJ, Proc. Natl, Acad. Sci. USA, 1989; 86: 8323).

Recently, protein farnesyltransferases (PFTs), also referred to as farnesyl protein transferases (FPTs), have been identified and specific rat brain PFT has been purified to homogeneity (Reiss Y. et al., Bioch. Soc. Trans., 1922; 20: 48788). The enzyme was characterized as a heterodimer composed of one alpha-subunit (49kDa) and one beta-subunit (46kDa), both of which are desirable for catalytic activity. High levels of mammalian PFT expression in the baculovirus system and purification of the recombinant enzyme in active form have also been performed (Chen W. J. et al., J. Biol. Chem., 1993; 268: 9675).

*

The discovery that the function of ras oncogenic proteins is critically dependent on their posttranslational processing provides, in light of the above, methods of cancer chemotherapy by inhibiting process enzymes. The identification and isolation of a protein farnesyltransferase, which catalyzes the addition of a farnesyl group to ras proteins, provides promising targets for such intervention. Ras farnesyltransferase inhibitors have been reported to have anticancer activity in several previous articles.

Ras inhibitor agents act by inhibiting farnesyltransferase, an enzyme that anchors the protein product of the ras gene to the cell membrane. The role of ras mutation in changing growth signals in cancer cells relies on a protein that is in the cell membrane, so that together with the inhibited farnesyltransferase, the ras protein will remain in the cytosol and will be unable to transmit growth signals; these facts are well known in the literature.

The peptidomimetic farnesyltransferase inhibitor B956 and its methyl ester B1086 at 100 mg / kg are known to inhibit tumor growth with human mammary carcinoma EJ-1, human fibrosarcoma HT1080 and human colon carcinoma xenografts in nude mice (Nagasu, T. et al., Cancer Res 1995; 55: 5310-5314). Furthermore, it is known that inhibition of tumor growth with B596 correlates with inhibition of ras post-translational processing in the tumor. Other ras farnesyltransferase inhibitors are known to specifically protect ras processing and membrane localization and are effective in reversing the transformed phenotype of mutant ras containing cells (Sepp-Lorenzino L. et al., Cancer Res., 1995; 55: 5302-5309).

In another report (Sun J. et al., Cancer Res., 1995; 55: 4243-4247), the ras farnesyltransferase inhibitor FTI276 selectively blocks tumor growth in nude mice of human lung carcinoma with K-ras mutation and p53 deletion. In another report, daily administration of a ras farnesyltransferase inhibitor L-744,832 causes tumor regression of breast and salivary carcinomas in ras transgenic mice (Kohl et al., Nature Med., 1995; 1 (8); 792-748). Thus, ras farnesyltransferase inhibitors have had satisfactory results in certain forms of cancer, particularly those that are dependent on oncogenic races for their growth. However, it is well known that human cancer often manifests when several mutations occur in important genes, one or more of which are responsible for growth regulation and metastasis. A single mutation may not be sufficient to support growth, and only after two or three mutations does the tumor develop and grow. It is therefore difficult to determine which of these mutations are of primary importance in controlling growth in a particular type of cancer. Thus, ras farnesyltransferase inhibitors may have therapeutic utility in tumors dependent not only oncogenic ras for their growth. For example, various FT-ras inhibitors have been found to have antiproliferative effects in vivo against tumor-growing or mutant ras tumors (Sepp-Lorenzio, supra). Furthermore, there are several ras-dependent proteins that are prenylated. Proteins such as R-Ras2 / TC21 are dependent on ras, which are prenylated in vivo by both farnesyltransferase and geranylgeranyltransferase I (Karboni et al., Oncogone, 1955; 10: 1905-1913). Therefore, ras farnesyltransferase inhibitors could also block the prenylation of the aforementioned proteins and, as a result, could be useful in inhibiting the growth of cancer driven by other oncogenes.

With respect to restenosis and vascular proliferative diseases, inhibition of cell ras has been found to protect smooth muscle proliferation following vascular injury in vivo (Indolfi C. et al., Nature Med., 1995; 1 (6): 541-545). This report definitively supports the role of farnesyltransferase inhibitors in this disease, showing inhibition of vascular smooth muscle accumulation and proliferation.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I

where

R is hydrogen or C 1 -C 6 alkyl; rQ is _^(CH2> n

or ^(C 1-2 ⁾ n -C 1-6 alkyl

C 1 -C 6 alkyl n is 0 or i

A is -COR ^a , -CO 2 R ^a 'f -CONHR ^a ', -CSR ^a , -C (S) OR ^a ', -C (S) NHR ^a ',

O S

-SO ₂ R ^a , -CONR ^and R ^a '', -CSR ^a or -C-NR ^a R ^a '';

R ^a , R ^a 'and R ^a ''are independently C 1 -C 6 alkyl,

- (CH ₂ ) _m -cycloalkyl, - (CH ₂ ) _m -aryl, or - (CH ₂ ) _m -heteroaryl;

each m is independently 0 to 3;

R ¹ , R ² , and R ⁴ are independently hydrogen or C 1 -C 8 alkyl;

- (CH ₂ ) _m -heteroaryl, ^(CH 2 ⁾ m ' ^{naphthyl 1} '

-CH ₂ ) _m - (heteroaryl substituted with R ^b ) or C 1 -C 6 alkyl; t is 2 to 6;

R * ³ is -O-phenyl, -O-benzyl, halogen, C 1 -C 8 alkyl, hydrogen,

-OC ₁ -C 8 alkyl, -NH ₂ , -NHR ^a , NR ^and R ^a ', 0 0 II 1! -C 1 -C 6 alkyl, -C-aryl, -OH, 0-cf ₃ , -no ₂ , -COH, O -COC- _L -C 8 alkyl, -CN, OPO ₃ H ₂ , O II -CH ₂ PO ₃ H ₂ , -CO aryl, -CF ₂ CF ₃ , -SO ₂ R ^a , -SO ₂ NR ^a R ^a ', -CHO, -OCOCH ₃ , or O II aai-O (CH ₂ ) _m -heteroaryl, -CNR ^and R ^a O ' ^11a , -NH-CR ³ ,

-O- (CH ₂ ) y NR ^and R ^a ', -O- (CH ₂ ) _m -cycloalkyl,

- (CH ₂ ) _m -cycloalkyl, -O- (CH ₂ ) _m -aryl, - (CH ₂ ) _m -aryl or - (CH ₂ ) _m -heteroaryl;

y is 2 or 3;

R ⁵ is

R ¹ , R 5 and R ^h are independently hydrogen, halogen, -OC 1 -C 6 alkyl,

C 1 -C 8 alkyl, -CN, -OPO ₃ H ₂ ,

II _,

-NH-CR ^a , -CH ₂ PO ₃ H ₂ , -O-phenyl, -o-benzyl, -NH ₂ , -NHR ^a , -NR ^a R ^a ,

0

-O- (CH ₂ ) _y NR ^a R ^a ', -C ₁ -C 8 alkyl, -C-aryl, OH, CF ₃ ,

0 O

U II II

-NO ₂ , -COH, -COC-L-C 8 alkyl, -CO aryl, -N ₃ , -CF ₂ CF ₃ ,

-SO ₂ R ^a , -SO ₂ NR ^and R ^a ', -CHO or OCOCH 3 a

R ^c , R 6, R ^e and R 6 are independently C 1 -C 6 alkyl, - (CH ₂ ) _m -phenyl, hydrogen, - (CH ₂ ) _m -OH, - (CH ₂ ) _m NH ₂ , - ( CH ₂ ) _m -cycloalkyl or -CN, and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

In a preferred embodiment of the compounds of formula I

2 4 21

R is hydrogen, R is hydrogen, R is hydrogen, R j _is hydrogen or

3; and

And it is

In another preferred embodiment of the compounds of formula I

or -CH ₂ -CH (CH ₃ ) ₂ .

2 4 21

R is H, R is H, R is H, R J and _{E IN} Thanks

CH3.

In another preferred embodiment of the compounds of formula I

R ⁵ is

wherein R 1 is hydrogen, Cl, Br, F or NH ₂ .

The invention also provides compounds of formula II

where

Ci-Cgalkyl

I g

R is -O-benzyl, -NH-benzyl or -N-benzyl;

R is hydrogen or methyl;

R is hydrogen or methyl;

g

R is hydrogen, halogen, C 1 -C 6 alkyl, O-benzyl, -OC 1 -C 6 alkyl,

-CF ₃ , -OH, -O- (CH ₂ ) _m -pyridyl or phenyl; R, R ¹¹ _and R ¹³ j _e are independently hydrogen, Ci-Cgalkyl, or

- (0Η _{2) m} -phenyl;

each m is independently 0 to 3;

R ³

or

R ³

-R 1; and:

R ¹ ΐ k 1

_Ζ R R _and R is independently hydrogen, halogen, -OC Cgalkyl, £

C 1 -C 6 alkyl, NHR or NH 2 and pharmaceutically acceptable salts, esters, amides, prodrugs thereof.

In a preferred embodiment of the compounds of formula II, ¹ , ¹⁴ X 4. n

R _and ^R are methyl.

In another preferred embodiment of the compounds of formula (8), R is methyl or methoxy.

The invention also provides compounds of formula III

wherein X is NH, O or -N (CH 3);

R ¹⁵ is -O-benzyl, -CF 3, hydrogen, halogen, -OC 1 -C 6 alkyl, phenyl,

-O- (CH 2) n TPyridyl or C 1 -C 6 alkyl;

m is 0 to 3; and 16

R is phenyl, hydrogen, or C 1 -C 6 alkyl, and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

The invention also provides compounds of formula IV

wherein X is NH, O or -N (CH 3);

R is -O-benzyl, -CF 3, hydrogen, halogen, C 1 -C 6 alkyl, -O-C 1 -

C 6 alkyl, phenyl or -O- (CH 2) _m -pyridyl;

16 '

R and R is C 1 -C 6 alkyl;

m is 0 to 3; and 21

R is hydrogen or methyl, and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

Another aspect of the present invention are pharmaceutically acceptable compositions comprising a compound of Formula I, II, III or IV.

The invention also encompasses methods of treating or preventing restenosis, the method comprising administering to a patient having or at risk of restenosis a therapeutically effective amount of a compound of Formula I, II, III, or IV.

The invention further encompasses a method of treating cancer, the method comprising administering to a patient having cancer a therapeutically effective amount of a compound of Formula I, II, III, or IV.

The invention further includes a method of treating psoriasis, the method comprising administering to a patient having psoriasis a therapeutically effective amount of a compound of Formula I, II, III, or IV.

The invention further includes a method of treating a viral infection, the method comprising administering to a patient having a viral infection a therapeutically effective amount of a compound of Formula I, II, III, or IV.

In a preferred embodiment, the cancer is lung cancer, colon cancer, breast cancer, pancreatic cancer, thyroid cancer, or bladder cancer.

In a most preferred embodiment, the compounds of Formula I, II, III or IV are (S) - [1- (4-benzyloxybenzyl) - (phenethylcarbamoylmethyl) carbamoyl] -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester ;

(S) - [1 - [[2-Benzyloxyethylcarbamoyl] methyl] - [4-chlorobenzyl] carbamoyl] -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - [(4-Benzyloxybenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl] -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - [(4-Benzyloxybenzyl) - [(2,2-diphenylethylcarbamoyl) methyl] carbamoyl] -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) -N- (4-Benzyloxybenzyl) -2- (3-benzylureido) -3- (1H-imidazol-4-yl) -N - [(2-phenylpropylcarbamoyl) methyl] propionamide; (S) - [1- (Biphenyl-4-ylmethyl - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl] -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1- {Biphenyl-4-ylmethyl - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - ((4-Benzyloxybenzyl) - ([2- (2-fluorophenyl) ethylcarbamoyl] methyl] carbamoyl} -2- (1H-imidazol-4yl) ethyl) carbamic acid benzyl ester;

(S) - [1 - {(4-Benzyloxybenzyl) - [(2-pyridin-2-yl) ethylcarbamoyl] methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - ((4-Benzyloxybenzyl) - {[2- (2-bromophenyl) ethylcarbamoyl] methyl} carbamoyl) -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - {(4-Benzyloxybenzyl) - [(1-methyl-2-phenyl) ethylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - {(4-Benzyloxybenzyl) - [(2-phenyl-2-pyridin-2-ylethylcarbamoyl) methyl] carbamoyl] -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - {(4-Chlorobenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - {(4-Benzyloxybenzyl) - [(2-phenylbutylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) -N- (4-benzyloxybenzyl) -3- (lH-imidazol-4-yl) -2- (3-phenyl-propionylamino) -N - [(2-phenylpropylcarbamoyl) -methyl] -propionamide;

(S) - [1 - {(4-Fluorobenzylbenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl] -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - (2- (1H-Imidazol-4-yl) -1 - {(4-methylbenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester;

(S) - (2- (1H-Imidazol-4-yl) -1 - {(4-methoxybenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester;

(S) - [1 - [{(2- (2-Aminophenyl) propylcarbamoyl] methyl} - (4-benzyloxybenzyl) carbamoyl] -2H- (3H-imidazol-4-yl) ethyl] carbamate benzyl ester;

(S) - [1 - {(4-Fluorobenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl] -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1- (Benzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - ((4-Benzyloxybenzyl) - {[2- (2-chlorophenyl) -2-phenylethylcarbamoyl] methyl} carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - {(4-Benzyloxybenzyl) - [(2-ethyl-2-phenylbutylcarbamoyl) methyl} carbamoyl} -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) -N- (4-Benzyloxybenzyl) -2- (3-benzylureido) -3- (1H-imidazol-4-yl) -N - [(2-phenylpropylcarbamoyl) methyl] propionamide;

(S) -N- (4-Benzyloxybenzyl) -2- (3-benzylureido) -3- (1H-imidazol-4-yl) -N - [(2-phenylbutylcarbamoyl) methyl] propionamide;

(S) - [1 - {(2-Chlorobenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - {(4-Bromobenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - {(3-Chlorobenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - {(4-Chlorobenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - ((4-Benzyloxybenzyl) - {[2- (2-chlorophenyl) propylcarbamoyl) methyl] carbamoyl) -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - (2- (1H-Imidazol-4-yl) -1 - {(2-methoxybenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl] ethyl] carbamic acid benzyl ester;

(S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-phenylpropylcarbamoyl) methyl] - [4- (pyridin-4-ylmethoxy) benzyl] carbamoyl} ethyl] carbamic acid benzyl ester;

(S) - (2- (1H-Imidazol-4-yl) -1 - {(3-methoxy benzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester;

(S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-phenylpropylcarbamoyl) methyl] - [4- (pyridin-3-ylmethoxy) benzyl] carbamoyl} ethyl] carbamic acid benzyl ester;

(S) - (2- (1H-Imidazol-4-yl) -1- {naphthalen-1-ylmethyl - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester;

(S) - {2- (1H-Imidazol-4-yl) -1 - [[(2-phenylpropylcarbamoyl) methyl] - (4-trifluoromethylbenzyl) carbamoyl] ethyl] carbamic acid benzyl ester;

(S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-methyl-2-phenylpropylcarbamoyl) methyl] pyridin-3-ylmethylcarbamoyl} ethyl] carbamic acid benzyl ester;

(S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-methyl-2-phenylpropylcarbamoyl) methyl] - [4- (pyridin-2-ylmethoxy) benzyl] carbamoyl] ethyl] carbamic acid benzyl ester;

(S) - [1- {Benzyl - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - (2- (1H-Imidazol-4-yl) -1 - {(2-methylbenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester;

(S) - (2- (1H-Imidazol-4-yl) -1 - {(4-methoxybenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester;

(S) - [1 - {(4-Benzyloxybenzyl) - [(2-cyano-2-phenylethylcarbamoyl) methyl] carbamoyl] -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-methyl-2-phenylpropylcarbamoyl) methyl] pyridin-2-ylmethylcarbamoyl} ethyl] carbamic acid benzyl ester;

(S) - (2- (1H-Imidazol-4-yl) -1 - {(3-methylbenzyl - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl) carbamic acid benzyl ester;

(S) -1 - {(4-Dimethylaminobenzyl - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-methyl) benzyl ester

2-phenylpropylcarbamoyl) -methyl] - [4- (pyridin-4-ylmethoxy) -benzyl] -carbamoyl} -ethyl] -carbamic acid benzyl ester;

(2- (1-Imidazol-4-yl) -1- {isobutyl - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester (S) - [1 - {(4-benzyloxybenzyl - [(2) methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3H-imidazol-4-yl) ethyl] carbamate;

(S) -2- (3-Benzyl-3-methylureido) -N- (4-benzyloxybenzyl) -3- (1H-imidazol-4-yl) -N - [(2-methyl-2-phenylpropylcarbamoyl) methyl] propionamide;

(S) - [1 - {(4-Benzyloxybenzyl - [(2-hydroxy-2-phenylethylcarbamoyl) methyl] carbamoyl] -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - (2- (1H-Imidazol-4-yl) -1 - {(4-methoxy benzyl - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester;

(S) - [1 - ((4-Benzyloxybenzyl - {[2- (2-chlorophenylethylcarbamoyl) methyl) carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - {(4-Benzyloxybenzyl [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1Himidazol-4-yl) ethyl] carbamic acid thiophen-3-ylmethyl ester;

(S) - [1 - {(4-Chlorobenzyl- [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-methylbenzyl - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester;

(S) - (2- (1H-imidazol-4-yl) -1 - {(2-methoxybenzyl - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl) methyl] carbamate;

(S) -2- (3-benzyl-3-methyl-ureido) -N- (4-chlorobenzyl) -3- (1H-imidazol-4-yl) -N - [(2-methyl-2-phenylpropylcarbamoyl) -methyl] -propionamide;

(S) - (2- (1H-imidazol-4-yl) -1 - {(3-methoxy benzyl - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} methyl] carbamic acid benzyl ester;

(S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-methyl-2-phenylpropylcarbamoyl) methyl] - [2-pyridin-4-ylmethoxy) benzyl] carbamoyl} ethyl) carbamic acid benzyl ester ;

(S) - (1- {Cyclohexylmethyl - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - {(4-Benzyloxybenzyl - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - {[2- (4-Benzyloxyphenyl) ethyl] - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3H-imidazol-4-yl) ethyl] carbamate ;

(S) - (2- (3H-Imidazol-4-yl) -1 - {[4-methoxy-phenylethyl] - ((2-methyl-2-phenylpropylcarbamoyl) methyl) carbamoyl} ethyl) carbamic acid benzyl ester;

(S) - [1 - [{[2- (2-Amino-phenyl) -ethylcarbamoyl] -methyl} - (4-benzyloxy-benzyl) -carbamoyl] -2- (3H-imidazol-4-yl) -ethyl] -carbamic acid benzyl ester;

(2- (1H-Imidazol-4-yl) -1- {isobutyl - [(2-phenylpropylcarbamoyl) methyl] carbamoyl] ethyl) carbamic acid benzyl ester; (S) - [1 - {(4-Benzyloxybenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl] -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - {(4-Benzyloxybenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3-methyl-3Himidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - {(4-Benzyloxybenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1-methyl-1Himidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - {(4-Benzyloxybenzyl) [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl) -2- (3Himidazol-4-yl) ethyl] carbamic acid furan-2-ylmethyl ester;

(S) - [1 - {(4-Benzyloxybenzyl) [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3Himidazol-4-yl) ethyl] carbamic acid thiophen-2-ylmethyl ester;

(S) - [1 - {(4-Benzyloxybenzyl) [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3Himidazol-4-yl) ethyl] carbamic acid pyridin-3-ylmethyl ester;

(S) - [1 - {(4-Benzyloxybenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl) -2 (3H-imidazol-4-yl) ethyl] carbamic acid 1H-imidazol-4-ylmethyl ester ;

(S) -2- (3-Benzyl-3-methylureido) -N- (4-chlorobenzyl) -3- (3Himidazol-4-yl) -N - [(2-methyl-2-phenylpropylcarbamoyl) methyl] propionamide;

(S) - [1 - {(4-Benzyloxybenzyl) [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl) -2- (3Himidazol-4-yl) ethyl] carbamic acid 4-methoxybenzyl ester;

(S) -2- (3-Benzylthioureido) -3- (3H-imidazol-4-yl) -N- (4-methylbenzyl) -N - [(2-methyl-2-phenylpropylcarbamoyl) methyl] propionamide;

(S) -2-Acetylamino-N- (4-benzyloxybenzyl) -3- (3H-imidazol-4-yl) -N - [(2-methyl-2-phenylpropylcarbamoyl) methyl] propionamide;

(S) - (2- (3H-Imidazol-4-yl) -1 - {[(2-methyl) benzyl ester

2-phenylpropylcarbamoyl) -methyl] -pyridin-4-ylmethyl-carbamoyl} -ethyl] -carbamic acid benzyl ester;

(S) - {2- (3H-Imidazol-4-yl) -1 - [(4-iodobenzyl) - (phenethylcarbamoylmethyl) carbamoyl) ethyl] carbamic acid benzyl ester; (S) - [1 - {(4-Aminobenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - {(4-Ethoxybenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester;

(S) - [1 - {[4- (2-dimethylaminoethoxybenzyl) [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3Himidazol-4-yl) ethyl] carbamic acid benzyl ester; (2- (lH-imidazol-4-yl) -l- {isobutyl - [(2-methyl-2-phenylpropylcarbamoyl) -methyl] -carbamoyl} -ethyl] -carbamic acid benzyl ester.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds of Formula I

where

R ²¹ is hydrogen or C 1 -C 8 alkyl; R ^q is

- <™ 2> n

alkyl n is 0 or 1

A is -COR ^a , -CO ₂ R ^a ', -CONHR ^a ', -CSR ^a , -C (S) OR ^a ', -C (S) NHR ^and OS

-SO ₂ R ^a , -CONR ^and R ^a '', -CSR ^a or -il-NR ^a R ^a '';

R ^a , R ^a 'and R' ^a '' are independently C ₁ -C 8 alkyl,

- (CH ₂ ) _m -cycloalkyl, - (CH ₂ ) _m -aryl, or - (CH ₂ ) _m -heteroaryl;

each m is independently 0 to 3;

R ¹ , R ² , and R ⁴ are independently hydrogen or C 1 -C 6 alkyl;

R ³ is (CH ₉ )

2'm

- (CH ₂ ) _m -heteroaryl, (E ₂ H) _t o

, - (CH _{2) m} -naphthyl,

2 H _{CH2) m} - (heteroaryl substituted with R ^b) or C ^ Cg alkyl;

to 6; 0-phenyl, -O-benzyl, halogen, C 1 -C 8 alkyl , hydrogen, -O-C 1 -C ₆ alkyl, -NH ₂ , -NHR ^a , NR ^a R ^a ' / 0 0 0 II II II -CC- _L-C6 alkyl, -C-aryl, -OH, _-CF3, - no ₂ , COH. 0 II COC ^ -C alkyl, -CN, OPO ₃ H ₂ , -CH ₂ PO ₃ H ₂ , 0 II -CO aryl, -cf ₂ cf ₃ -SO ₂ R ^a , -SO ₂ NR ^a R ^a , -CHO, -OCOCH ₃ or -O (CH ₂ ) m - 0 = ¹¹ = t -heteroaryl, -CNR ^a R ^a, -NH 0 CR ^a ,

-O- (CH ₂ ) _y NR ^a R ^a ', -O- (CH ₂ ) _m -cycloalkyl,

- (CH ₂ ) _m -cycloalkyl, -O- (CH ₂ ) _m -aryl, - (CH ₂ ) _m -aryl or - (CH ₂ ) _m -heteroaryl;

y is 2 or 3;

R ⁵ is

or

Q

R ¹ , R ^g and R ^h are independently hydrogen, halogen, -OC 1 -C 8 alkyl, C 1 -C 8 alkyl, -CN, -OPO ₃ H ₂ ,

O ¹¹ a

-NH-CR, -CH ₂ PO ₃ H ₂ , -O-phenyl, -O-benzyl, -NH ₂ , -NHR ^a , O 0

-O- (CH ₂ ) y NR ^and R ^a ', -C-C 1 -C 8 alkyl, -C-aryl, OH, CF ₃ ,

0 O

II H II

-N0 _2, COH, -COCj -C alkyl, -CO aryl, -N _3, -CF ₂ CF _3, -SO ₂ R ^a, -SO 2 NR ^a R ^a ', -CHO, or OCOCH 3, and

R ^c , R ^d , R ^e and R ^f are independently C 1 -C 8 alkyl, - (CH ₂ ) _m -phenyl, hydrogen, - (CH ₂ ) _m -OH, - (CH ₂ ) _m NH ₂ , - (CH ₂ ) _m -cycloalkyl or -CN and their pharmaceutically acceptable salts, esters, amides and prodrugs.

NR ^and R ^a

The invention also provides compounds of formula II

where

Ci-Cgalkyl

I

R ⁶ is -O-benzyl, -NH-benzyl or -N-benzyl; 21

R is hydrogen or methyl; ⁷

R is hydrogen or methyl;

g

R is hydrogen, halogen, C 1 -C 6 alkyl, O-benzyl, -OC 1 -C 6 alkyl,

-CF ₃ , -OH, -O- (CH 2) _m -pyridyl or phenyl; R 10a is independently hydrogen, C 1 -C 6 alkyl or

- (CH 2) _m -phenyl;

each m is independently 0 to 3;

i k 1

^J R f R _and R is independently hydrogen, halogen, -OC Cgalkyl, and

C 1 -C 6 alkyl, -NI 1 R or NH 2 and pharmaceutically acceptable salts, esters, amides, prodrugs thereof.

The invention also provides compounds of formula III

wherein X is NH, O or -N (CH 3);

R is -O-benzyl, -CF 3, hydrogen, halogen, -OC 1 -C 6 alkyl, phenyl

-O- (CH ₂ ) m -pyridyl or C 1 -C 6 alkyl;

m is 0 to 3; and

R is phenyl, hydrogen or C 1 -C 6 alkyl, and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

The invention also provides compounds of formula IV

where

X is NH, O or -N (CH 3);

R! 5 j _e benzyl, -CF3, hydrogen, halogen, Cl-Cgalkyl, -Ο-Οχ-Οβalkyl, phenyl, or -O- (CH 2) m ^"pyridinium Idyla;

R and R is C 1 -C 6 alkyl;

m is 0 to 3; and 21

R is hydrogen or methyl, and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

The term "alkyl" denotes a straight or branched hydrocarbon radical having 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n- hexyl and the like.

The term "cycloalkyl" means a saturated hydrocarbon cyclic radical containing from 3 to 7 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl and the like.

The term "aryl" means an aromatic cyclic moiety such as phenyl, 5-fluorophenyl, 1-naphthyl or 2-naphthyl, unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of alkyl, O-alkyl and S-alkyl,

OH, SH, F, Cl, Br, I, CF _3, NO _2, NH _2, NHCH _3, N (CH _{3) 2,}

NHCO-alkyl, (CH ₂ ) _m CO ₂ H, (CH ₂ ) _m CO ₂ -alkyl, (CH ₂ ) _m SO ₃ H, (CH ₂ ) _m PO ₃ H ₂ , (CH ₂ ) _m PO ₃ ( alkyl) ₂ , (CH ₂ ) _m SO ₂ NH ₂ , and (CH ₂ ) _m SO ₂ NH-alkyl, _and alkyl _is as defined above _{and m} = 0, 1, 2 or 3.

The term "heteroaryl" means a heteroaromatic cyclic moiety such as 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, imidazolyl, 2-, 3-, 4- , 5-, 6-, or 7-indoxyl, unsubstituted or substituted with 1 or 2 substituents selected from the group of substituents described above for aryl.

The symbol "-" represents a bond.

The term "patient" means all animals, including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, and pigs.

A therapeutically effective amount is an amount of a compound of the present invention that upon administration to a patient ameliorates symptoms of viral infection, restenosis, cancer, atherosclerosis, psoriasis, endometriosis, or prevents restenosis or atherosclerosis. The therapeutic amount of a compound of the present invention can be readily determined by one skilled in the art by administering a certain amount of the compound to a patient and observing the result. Further, those skilled in the art are well versed in identifying patients with cancer, viral infections, restenosis, atherosclerosis, psoriasis or endometriosis, or who are at risk of restenosis or cancer.

The term "cancer includes, but is not limited to, the following cancers:

breast;

ovary;

throat;

prostate;

testicles;

esophagus;

glioblastoma;

neuroblastoma;

stomach;

skin, keratoacanthoma;

lung, epidermoid carcinoma, large cell carcinoma, adenocarcinoma;

bones;

colon, adenocarcinoma, pancreatic adenoma, adenocarcinoma t

thyroid gland, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma / seminoma;

melanoma;

sarcoma;

bladder cancer;

liver and biliary tract cancer;

renal cancer;

myeloid disorders;

limfoid disorders, Hodgkinson's;

buccal cavity and pharynx (oral), lips, tongue, mouth, pharynx;

small intestine;

colon-rectum, colon, rectum; urine and central nervous system; and leukemia.

The term "pharmaceutically acceptable salts, esters, amides, and prodrugs as used herein includes carboxylate salts, amino acid addition salts, esters, amides, or prodrugs of the compounds of the present invention, which are within the scope of medical opinion suitable for use in contact with tissues. patients without undesirable toxicity, irritation, allergic responses, and the like, at a proportional benefit / risk ratio and effective in the intended use, as well as both forms, where possible, of the compounds of the present invention. The term "salts" refers to the relatively nontoxic, inorganic and organic acid addition salts of the compounds of the invention. These salts can be prepared in situ during the final isolation and purification of the compounds or separately by reacting the pure compound in free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, mesylate , glucoheptonate, lactobionate and lauryl sulfate salts and the like. These salts include cations based on alkali metals and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium and the like. a cation as well as non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. (see, for example, S. M. Berge et al., "Pharmaceutical Salts, J. Pharm. Sci., 1997; 1-19, incorporated herein by reference.").

Examples of pharmaceutically acceptable nontoxic esters of the compounds of the invention include C 1 -C 6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable salts also include C5-C7cycloalkyl esters as well as arylalkyl esters such as, but not limited to, benzyl. C 1 -C 4 alkyl esters are preferred. Esters of the compounds of the invention are prepared by conventional methods.

Examples of pharmaceutically acceptable non-toxic amides of the compounds of the invention include amides derived from ammonia, primary C 1 -C 6 alkylamines and secondary C 1 -C 6 dialkylamines, wherein the alkyl group is straight or branched chain. In the case of secondary amines, the amine may be in the form of a 5- or 6-membered hetrocycle containing one nitrogen atom. Amides derived from ammonia, C 1 -C 3 alkyl primary amines and C 1 -C 2 dialkyl secondary amines are preferred. The amides of the compounds of the invention may be prepared by conventional methods.

The term "prodrug" refers to compounds that rapidly transform in vivo to the parent compound of the above formula by hydrolysis in blood. Discussion is given in "Prodrugs as Novel Delivery System, Volume 14 A.C.S. Syria Syndicate and Bioreversible Carriers in Drugs Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

The compounds of the invention may be administered to the patient alone or as part of a composition comprising other ingredients, such as excipients, diluents and carriers, all known in the art. All compositions can be administered to humans or animals orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, topically (powders, ointments or drops) or as a buccal or nasal spray.

Compositions suitable for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous or non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), Cremophor EL (castor oil derivatives and ethylene oxide); supplied by Sigma Chemical Co., St. Louis, MO) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by the maintenance of the desired particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying and dispersing agents. Protection against the action of microorganisms is achieved by the use of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to add isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is admixed with at least one inert conventional excipient (or carrier), such as sodium citrate and calcium phosphate, or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid. ; (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example glycerol; (d) disintegrating agents, for example agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) delay solutions, for example paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; wetting agents such as cetyl alcohol and glycerol monostearate; adsorbents such as kaolin and bentonite; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also include buffers.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

Solid dosage forms, such as tablets, dragees, capsules, pills, and granules, can also be prepared with coatings and shells, such as enteric coatings and other preparations well known in the art. They may contain opacifying agents and may be agents that release the active compound or compounds in a certain portion of the intestinal tract in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. The active compounds may be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may also contain inert diluents conventionally used in the art, such as water or other solvents, solubilizing agents and emulsifiers, for example ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofuryl alcohol, Cremophor EL (a derivative of castor oil and ethylene oxide); supplied by Sigma Chemical Co., St. Louis,

MO), polyethylene glycols and sorbitol fatty acid esters or mixtures thereof;

In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

The suspensions may contain, in addition to the active compounds, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these surfactants and the like.

Formulations for rectal administration are preferably suppositories which may be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as cocoa oil, polyethylene glycol or suppository wax that are solid at normal temperature but are liquid at body temperature and therefore they melt in the rectum or vaginal cavity and release the active ingredient.

Dosage forms for topical administration of the compounds of the invention include ointments, powders, sprays and inhalants. The active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders and solutions are also included in the present invention.

The compounds of the present invention may be administered to a patient in doses ranging from 0.1 to 2000 mg per day. A typical dose for normal adults weighing approximately 70 kilograms will be in the range of 0.01 to 100 mg / kg patient weight per day. However, the specific dose may vary. For example, the dosage will depend on a number of factors including the requirements of the patient, the severity of the condition to be treated and the pharmacological properties of the compound being used. Determination of the optimum dose for each patient is known to the person skilled in the art.

The compounds of the present invention may exist in various stereoisomeric forms based on the presence of asymmetric centers in the compound. All stereoisomeric forms of the compounds, mixtures thereof including racemic mixtures form part of the invention.

The compounds of the present invention may further exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

The following examples are given by way of illustration only and are not intended to limit the scope of the invention in any way.

Scheme 1 shows the general method by which the compounds of the present invention can be prepared by illustrating the synthesis of [1 - [(4-benzyloxybenzyl) (phenethylcarbamoylmethyl) carbamoyl] -2- (3H-imidazol-4-yl) ethyl] carbamate benzyl ester ( Example 2). Reductive amination of 4-benzyloxybenzaldehyde with glycine methyl ester hydrochloride is carried out in methylene chloride with triacetoxyborohydride. Then, (4-benzyloxybenzylamino) acetic acid methyl ester is coupled to Cbz-His in dimethylformamide with 1-hydroxybenzotriazole (HOBt) and dicycohalohexylcarbodiimide (DCC) as coupling reagents. The resulting product is saponified using lithium hydroxide at 0 ° C followed by coupling with phenethylamine hydrochloride in dimethylformamide with HOBt and DCC as coupling agents and in the presence of triethylamine.

In the present invention the following abbreviations are used:

ky: abbreviations: Cbz or Z carbobenzoxy His histidine Trt trityl TEA triethylamine HOAc acetic acid Et ₂ O diethyl ether TBU tert-butyl TFA trifluoroacetic acid ES-MS electrospray mass spectrometry FAB-MS fast atomic mass spectrometry HOBt bombing 1-hydroxybenzotriazole DCC dicyclohexylcarbodiimide THF tetrahydrofuran PyBOP benzotriazol-yloxytrispyrolidinofosfónium- DIEA hexafluorophosphate diisopropylethyleneamine DMF dimethylformamide Et ₃ N triethylamine OAc acetate Et ₂ O diethyl ether

Boe iBuOCOCl

NMM

DMSO tert-butoxycarbonyl isobutyl chloroformate N-methylmorpholine dimethylsulfoxide

Scheme 1

CHO

ABOUT

-HCl and ₃

OBn

Na ₃ H (OAc) ₃ ch ₂ or ₂₀ ^° C to moderate temperature

Bnjebenzyl

Scheme 2 shows a method by which compounds of the present invention can be prepared by illustrating the synthesis of Example 15, [1 - {(4-benzyloxybenzyl) -1- (2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3Himidazole-) benzyl ester 4-yl) -ethyl] -carbamic acid benzyl ester. Reductive amination of 4-benzyloxybenzaldehyde with glycine methyl ester is carried out in methylene chloride with sodium triacetoxyborohydride. (4-Benzyloxybenzylamino) acetic acid methyl ester is then coupled to CbzHis- (trityl) in methylene chloride with benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP) as a coupling reagent in the presence of diisopropylethyleneamine. The resulting product is saponified using lithium hydroxide at 0 ° C followed by coupling with β, β-dimethyl phenethylamine hydrochloride in methylene chloride with 1-hydroxybenzotriazole (HOBt) and dicyclohexylcarbodiimide (DCC) as coupling reagents and triethylamine. The trityl group is removed in the presence of acetic acid in water by heating to reflux. Β, β-dimethylphenethylamine hydrochloride was prepared from benzyl cyanide, which was treated with two equivalents of sodium hydride in tetrahydrofuran and two equivalents of methyl iodide in THF, followed by hydrogenation (H2, Pd / C, ammonia) and treatment with HCl to give the HCl salt.

Μ

Scheme 2

TEA;

DCC, HOBt

OBn

Scheme 2 (cont.)

HOAc _H2O

CN x CH ₃ I 2 x NaHTHF

1) _H2 / Pd

NH-

0 ^.

2) Et ₂ O / HCl • HCl

Scheme 3 shows a method by which the compounds of the present invention can be prepared by illustrating the synthesis of Example 8, [1 - {(4-benzyloxybenzyl) [(2-pyridin-2-ylethylcarbamoyl) methyl] carbamoyl} -2- (1Himidazole-) benzyl ester 4-yl) ethyl] carbamate. Reductive amination of 4-benzyloxybenzaldehyde with glycine tert-butyl ester is carried out in methylene chloride with sodium triacetoxyborohydride. (4-Benzyloxybenzylamino) acetic acid tert-butyl ester is then coupled to Cbz-His- (trityl) in methylene chloride with PyBOP as the coupling reagent and DIEA as the base. The resulting product is deprotected by treatment with 50% trifluoroacetic acid in methylene chloride. Coupling with 2-pyridinethenamine in methylene chloride is performed with PyBOP as coupling agent and diisopropylethylene amine as base.

w

Scheme 3

CHO

CBZ-His-:

Scheme 4 shows a method by which the compounds of the present invention can be prepared by illustrating the synthesis of Example 7, [1 - ((4-benzyloxybenzyl) {[2- (2-fluorophenyl) ethylcarbamoyl) methyl] carbamoyl} -2- (1H) benzyl ester Imidazol-4-yl) ethyl] carbamic acid. Boc-glycine is coupled to 2-fluorophenethylamine in tetrahydrofuran (THF) in the presence of isobutyl chloroformate as coupling agent and N-methylmorpholine as base. The Boe group was then removed by treatment with 50% TFA in methylene chloride for 30 minutes. Reductive amination of 4-benzyloxybenzaldehyde with N- [2- (2-fluorophenyl) ethyl] glycinamide TFA salt is carried out in methylene chloride with sodium triacetoxyborohydride and potassium acetate as the base. N- [2- (2-Fluorophenyl) ethyl] -N- (4-benzyloxybenzyl) glycinamide.HCl is then coupled to Cbz-histidine- (trityl) in methylene chloride with benzotriazol-1-yloxytrispyrrolidinophosphoniumhexafluorophosphate diisopropylethylene copolymer (PyBOP) as a copolymer (PyBOP) as a copolymer (PyBOP) as a copolymer. . The resulting product is deprotected by treatment with 50% trifluoroacetic acid in methylene chloride with triisopropylsilane as the scavenger.

Scheme 4

Cbz-His (Trc) -oh PyBOP

DIEA ch ₂ or ₂

O3n

Scheme 5 shows a method by which compounds of the present invention can be prepared by illustrating the synthesis of Example 62, (2- (1H-imidazol-4-yl) -1 {isobutyl - [(2-phenylpropylcarbamoyl) methyl] methyl] carbamoyl} benzyl ester Boc-glycine is coupled to β-methylphenethylamine / methylene chloride in the presence of dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt) as coupling reagents and diisopropylethylamine as a base. and the reductive amination of isobutyraldehyde in methylene chloride with sodium triacetoxyborohydride and sodium acetate as the base, and the above product is then coupled to Cbz-histidine- (trityl) in methylene chloride with O- (7-azabenzotriazol-1-yl) N, N, N, N, N, N, N'-tetramethyluronium hexafluorophosphate (HATU) and 1-hydroxy-7-azabenzotriazole (HOAt) as coupling agents and diisopropylethylamine as a base. protecting group with 50% trifluoroacetic acid.

Scheme 5

Boe-NH

Boe— ΝΉ

ABOUT

DCC / HOBt

DIEA

CH2Cl2

30% TFA ch ₂ or ₂

CHO

NaBH (OAc) ₃

NaCOOCH ₃ ch ₂ or ₂

DETAILED DESCRIPTION OF THE INVENTION

Example 1 (S) -N - [(Phenylmethoxy) carbonyl] -L-histidyl-N- [2- (phenylmethoxy) 2-ethyl] -N - [[4- (phenylmethoxy) phenyl] methyl] glycine amide

Step 1: (4-Benzyloxy-benzylamino) -acetic acid methyl ester

To a mixture of glycine methyl ester hydrochloride (2.07 g, 16.5 mmol) and 4-benzyloxybenzaldehyde (3.18 g, 15.0 mmol) in CH 2 Cl 2 (50 mL) at 0 ° C was added sodium triacetoxyborohydride (3.81 g, 18.0 mmol). The mixture was allowed to warm to room temperature and stirred for 4 hours. Aqueous NaHCO 3 solution was then added and the mixture was stirred for 30 minutes. The aqueous layer was extracted three times with CH 2 Cl 2. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated. Flash chromatography (75% ethyl acetate / hexane) gave 1.98 g (46%) of the title compound as a white solid; mp 57-58 ° C.

Step 2: N- [N- (phenylmethoxy) carbonyl] -L-histidyl-N - [[4- (phenylmethoxy) phenyl] methyl] glycine methyl ester

To a suspension of CBZ-histidine (1.22 g, 4.21 mmol) in DMF (dimethylformamide) (10 mL) was added HOBT (hydroxybenzotriazole) hydrate (0.77 g, 5.05 mmol) and DCC (dicyclohexylcarbodiimide) (1). , 04 g, 5.05 mmol). The amine from Step 1 above (1.20 g, 4.21 mmol) was then added and the mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was diluted

CHCl 3, washed twice with saturated NaHCO 3, dried over MgSO 4 and concentrated. Flash chromatography gave 1.68 g (72%) of the title compound as a white foam; ES-MS 557 (m + 1).

Step 3: N- [N- (Phenylmethoxy) carbonyl] -L-histidyl-N - [[4 (phenylmethoxy) phenyl] methyl] glycine

To a solution of the ester from step 2 (1.53 g, 2.75 mmol) in THF (tetrahydrofuran) (15 mL) and H 2 O (5 mL) was added LiOH hydrate (0.14 g, 3.30) at 0 ° C. mmol) and 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 4-5 with 1N HCl. The resulting mixture is concentrated and dried in vacuo to give 1.65 g of the title compound as a white solid;

FAB-MS (γη + D. Elementary analysis for C30H30N4O6.1,2 LÍCI.2,0 H2O: calculated: 57,24% C; H, 5.44; 8.90 % N. found: 57,35% C; H, 5.32; 8.62 % N.

Step 4: (S) -N - [(Phenylmethoxy) carbonyl] -L-histidyl-N- [22 (phenylmethoxy) ethyl] -N - [[4- (phenylmethoxy) phenyl] methyl] glycamide

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). ) and then 2-benzyloxyethylamine hydrochloride (1.0 g, 5.33 mmol). Et 3 N (triethylamine (0.82 mL, 5.86 mmol) was then added and the mixture was stirred at room temperature overnight.

The mixture was filtered and the filtrate was diluted with CHCl 3, washed twice with saturated NaHCO 3 solution, brine, dried over MgSO 4 and concentrated. Flash chromatography (2-5% methanol / CHCl 3) gave 2.25 g (63%) of the title compound as a white foam; ES-MS 676 (m. + 1)

Example 2

(S) - [1 - [(4-Benzyloxybenzyl) - (phenethylcarbamoylmethyl) carbamoyl] -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

(S) - [1 - [(4-Benzyloxybenzyl) (phenethylcarbamoylmethyl) carbamoyl] -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester was prepared according to Example 1, Step 4 by substituting phenethylamine for 2-benzyloxyethylamine hydrochloride. The title compound is obtained as a white solid; ES-MS 646 (m + 1).

Example 3

(S) - [1 - [[2-Benzyloxyethylcarbamoyl] methyl] - [4-chlorobenzyl] carbamoyl] -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

(S) - [1 - [[2-Benzyloxyethylcarbamoyl] methyl] - [4-chlorobenzyl] carbamoyl] -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester was prepared according to Example 1, step 1, sub by substitution with 4-chlorobezaldehyde for 4-benzyloxybenzaldehyde. The title compound is obtained as a white solid; ES MS 604 (m + 1).

Example 4

(S) - [1 - [(4-Benzyloxybenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl] -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

(S) - [1 - [(4-Benzyloxybenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl] -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester was prepared according to Example 1, Step 4, substituting β -phenylphenethylamine for 2-benzyloxyethylamine hydrochloride. The title compound is obtained as a white solid; ES-MS 660 (m + 1).

Example 5

(S) - [1 - ((4-Benzyloxybenzyl) - [(2,2-diphenylethylcarbamoyl) methyl] carbamoyl] -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

(S) - [1 - [(4-Benzyloxybenzyl) - [(2,2-diphenylethylcarbamoyl) methyl] carbamoyl] -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester was prepared according to Example 1, Step 4, substitution with 2,2-diphenylethylamine for 2-benzyloxyethylamine hydrochloride. The title compound is obtained as a white powder; ES-MS 722 (m + 1).

Example 6 (S) -N- (4-Benzyloxybenzyl) -2- (3-benzylureido) -3- (1H-imidazol-4-yl) -N - [(2-phenylpropylcarbamoyl) methyl] propionamide

The title compound was prepared according to Example 1, step 2, substituting benzylureahistidine (steps 1 and 2) for Cbz-histidine. The title compound is obtained as a white solid; ES-MS 659 (m + 1).

Step 1: Benzylureahistidine methyl ester

To a solution of histidine methyl ester hydrochloride (2.0 g, 4.3 mmol) in methylene chloride at 0 ° C was added benzyl isocyanate (0.58 mL, 0.63 g, 4.7 mmol) and triethylamine (1.32 mL, 9.5 mmol) and the solution was stirred at room temperature overnight. The solution was concentrated and the residue was taken up in ethyl acetate. The solution was washed with water, saturated NaHCO 3 solution, brine, dried over MgSO 4 and concentrated. Obtained as a white foam (1.09 g, 84%).

Step 2: Benzylureahistidine

To a solution of the ester from step 1 (1.9 g, 3.5 mmol) in THF: methanol (10 mL each) and water (2 mL) was added sodium hydroxide (0.4 g, 10 mmol) and the solution was stirred through night at room temperature. The solution was added to 1N HCl: ethyl acetate (30 mL of both). The organic layer was separated, washed with 1N HCl, brine, dried over MgSO 4 and concentrated. Obtained as a white foam (0.53 g, 53%); ES-MS 289 (m + 1).

Example 6a (S) -N- (4-Benzyloxybenzyl) -2- (3-benzylureido) -3- (1H-imidazol-4-yl) -N - [(2-phenylpropylcarbamoyl) methyl] propionamide

The title compound was prepared according to Example 1, step 2, substituting benzylureahistidine (steps 1 and 2) for Cbz-histidine and step 4, substituting β-methylphenethylamine for 2-benzyloxyethylamine hydrochloride. The title compound is obtained as a white solid; ES-MS 659 (m + 1).

Step 1: Benzylureahistidine trityl methyl ester

To a solution of histidine trityl methyl ester hydrochloride (2.0 g, 4.3 mmol) in methylene chloride at 0 ° C was added benzyl isocyanate (0.58 mL, 0.63 g, 4.7 mmol) and triethylamine (1.32 mL). (9.5 mmol) and the solution was stirred at room temperature overnight. The solution was concentrated and the residue was taken up in ethyl acetate. The solution was washed with water, saturated NaHCO 3 solution, brine, dried over MgSO 4 and concentrated. Obtained as a white foam (1.95 g, 83%).

Step 2: Benzylureahistidine- (trityl) .HCl

To a solution of the ester from step 1 (1.9 g, 3.5 mmol) in THF: methanol (10 mL each) and water (2 mL) was added sodium hydroxide (0.4 g, 10 mmol) and the solution was stirred through night at room temperature. The solution was added to 1N HCl: ethyl acetate (30 mL of both). The organic layer was separated, washed with 1N HCl, brine, dried over MgSO 4 and concentrated. Obtained as a white foam (1.0 g, 53%); ES-MS 531 (m + 1).

Example 7

(S) - [1 - ((4-Benzyloxybenzyl) - {[2- (2-fluorophenyl) ethylcarbamoyl] methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

Step 1: Na-Boc-N- [2- (2-fluorophenyl) ethyl] glycinamide

To a solution of Boc-glycine (1.75 g, 10 mmol) in THF (50 mL) at 0 ° C. Add isobutyl chloroformate (1.3 mL, 10 mmol) followed by N-methylmorpholine (1.1 mL, 10 mmol). The resulting suspension was stirred at 0 ° C for 5 min and then treated with 2 - [(2-fluorophenyl) ethyl] amine (10 mmol). The suspension was stirred at room temperature overnight. The reaction mixture was then treated with 1N HCl and extracted with diethyl ether (2 x 50 mL). The organic extracts were combined, washed sequentially with water, saturated NaHCO ₃ solution and then water. The organic extracts were dried over MgSO 4 and concentrated. Flash chromatography (5% methanol in methylene chloride) afforded 1.9 g (65%) of the title compound as a white solid;

CI-MS 297 (m + 1).

Step 2: N- [2- (2-Fluorophenyl) ethyl] glycinamide, trifluoroacetic acid salt

To a solution of the compound from Step 1 above (1.92 g, 6.48 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid. The solution was then stirred for 30 minutes and concentrated. The residue was dissolved in methylene chloride and concentrated again to give the title compound as an oil. This oil was used in the next reaction without characterization.

Step 3: N- [2- (2-Fluorophenyl) ethyl] -α- (4-benzyloxybenzyl) glycamide, hydrochloride salt

To a suspension of Step 2 compound (6.48 mmol), 4-benzyloxybezaldehyde (1.38 g, 6.48 mmol) and potassium acetate (1.27 g, 12.96 mmol) in methylene chloride (50 mL) cooled sodium triacetoxyborohydride (1.79 g, 8.43 mmol) was added to 0 ° C. The reaction mixture was allowed to warm to room temperature and then stirred for 3 hours. The mixture was then treated with saturated aqueous NaHCO 3 and the layers were separated. The aqueous layer was extracted with methylene chloride (2 x 20 mL). The organic layers were combined and concentrated. The residue was dissolved in diethyl ether and treated with 1N HCl (8 mL). The precipitate was collected by filtration to give 1.46 g (52%) of the title compound as an off-white solid; CI-MS 393 (m + 1).

Step 4: [1 - ((Benzyloxybenzyl) - {[2- (2-fluorophenyl) ethylcarbamoyl] methyl] carbamoyl} -2- (1-trityl-1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

To a solution of (S) - (2-benzyloxycarbonylamino-3- (1-trityl) -1H-imidazol-4-yl) propionic acid (Cbz-histidine (trityl)) (Hudspeth JP, Kaltenbronn JS, Repine JT, Roark WH, Stier MA) Renin Inhibitors III, US Patent 4,735,933; 1988) (0.532 g, 1.0 mmol) in methylene chloride (20 mL) was added diisopropylethylenediamine (0.48 mL, 2.75 mmol) and benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (0). , 520 g, 1.0 mmol). The mixture was then treated with the amine hydrochloride salt (0.429 g, 1.0 mmol) from step 3 above and stirred for 4 hours. The reaction mixture was then treated with saturated aqueous NaHCO 3 and the layers were separated. The aqueous layer was extracted with methylene chloride (2 x 30 mL). The organic layers were combined, dried over MgSO 4 and concentrated. Flash chromatography (2% methanol in methylene chloride) gave 0.501 g (55%) of the title compound as a white foam; ES-MS 906.5 (m + 1).

Step 5: [1 - ((4-Benzyloxybenzyl) - {[2 (2-fluorophenyl) ethylcarbamoyl] methyl] carbamoyl} -2 (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

To a solution of the trityl compound (0.49 g, 0.54 mmol) from step 4 above in methylene chloride (5 mL) was added TFA (5 mL) triisopropylsilane (0.25 mL). The solution was stirred for 3 hours and then concentrated. The residue was partitioned between saturated aqueous NaHCO 3 and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, dried over MgSO 4 and concentrated. Flash chromatography (10% methanol in methylene chloride) gave 0.248 g (37 of the title compound as a white foam; ES-MS 664.4 (m + 1)).

Example 8

(S) - [1 - {(4-Benzyloxybenzyl) - [(2-pyridin-2-yl) ethylcarbamoyl] methyl] carbamoyl} -2- (1H-imidazol-4yl) ethyl] carbamic acid benzyl ester

Step 1: (4-Benzyloxybenzylamino) acetic acid tert-butyl ester

To a mixture of glycine tert-butyl ester hydrochloride (0.84 g, 5 mmol) and 4-benzyloxybenzaldehyde (0.53 g, 2.5 mmol) in CH 2 Cl 2 (25 mL) at 0 ° C was added sodium triacetoxyborohydride (0.81 g). , 3.8 mmol). The mixture was allowed to warm to room temperature and stirred overnight. Aqueous NaHCO 3 solution was then added and the mixture was stirred for 30 minutes. The aqueous layer was extracted three times with CH 2 Cl 2. The combined organic extracts were washed with brine, dried over MgSO 4 and concentrated. Flash chromatography (ethyl acetate) gave 0.38 g (59%) of the title compound as a white solid.

Step 2: N- [N- (phenylmethoxy) carbonyl] -Histidyltrityl] -N - [[4- (phenylmethoxy) phenyl] methyl] glycine tert-butyl ester

To a suspension of Cbz-histidine- (trityl) (0.89 g, 1.7 mmol) in methylene chloride (25 mL) was added PyBOP (2.63 g, 5.05 mmol) and diisopropylethylamine (0.68 g, 3, 9 mmol). The amine from Step 1 (0.38 g, 1.5 mmol) was then added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was taken up in ethyl acetate, washed three times with saturated NaHCO 3 solution, brine, dried over MgSO 4 and concentrated. Flash chromatography gave 0.59 g (51%) of the title compound as a white foam;

ES-MS 841 (m + 1).

Step 3: N- [N- (Phenylmethoxy) carbonyl] -L-histidyl-N - [[4-phenylmethoxy) phenyl] methyl] glycine

To a solution of the ester from step 2 (0.59 g, 0.76 mmol) was added 50% trifluoroacetic acid in methylene chloride (25 mL). The reaction mixture was stirred at room temperature for 3 hours. The solution was then concentrated in vacuo. Cold diethyl ether was added to the residue and the solution was left at 4 ° C overnight. The resulting white precipitate was filtered and dried. Yield 0.33 g (80%).

Step 4: [1 - {(4-Benzyloxybenzyl) - [(2-pyridin-2-yl) ethylcarbamoyl] methyl] carbamoyl} -2- (1Himidazol-4-yl) ethyl] carbamic acid benzyl ester

To a solution of the acid from Step 3 (0.33 g, 0.61 mmol) in methylene chloride was added PyBOP (0.67 g, 1.3 mmol) and diisopropylethylamine (0.23 g, 1.3 mmol) followed by 2- pyridinethanamine hydrochloride (0.082 g, 0.67 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was taken up in ethyl acetate, which was washed three times with saturated NaHCO 3 solution, brine, dried over MgSO 4 and concentrated. Flash chromatography gave 0.156 g (37%) of the title compound as a white foam;

ES-MS 647 (m + 1).

Example 9

(S) - [1 - ((4-Benzyloxybenzyl) {[2- (2-bromophenyl) ethylcarbamoyl] methyl} carbamoyl) -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 4, Step 4, substituting 2-bromo-phenethylamine (Steps 1 and 2) for pyridine-ethanamine.HCl. The title compound is obtained as a white foam (10 L); ES-MS 725 (m + 1).

Step 1: o-Bromonitrostyrene

To a solution of o-bromobenzaldehyde (4 g, 21.6 mmol) and nitromethane (1.32 g, 21.6 mmol) in methanol (5 mL) was added NaOH (0. 908 g, 22.7 mmol) in 1 mL H? O. After 45 minutes, the precipitate was dissolved in 10 mL of H ₂ O. The product precipitated upon addition of 6N HCl. The product is recrystallized from ethanol; yield 0.312 g (6%).

Step 2: 2-Bromophenethylamine

To the styrene from step 1 (0.310 g, 1.3 mmol) in 5 mL of THF was added an IM solution of LiAlH ₄ in THF (5.2 mL, 5.2 mmol) at 0 ° C. The solution was stirred for 1 hour. A concentrated KHSO ₄ solution was then added dropwise to remove excess LiAlH. The solution was filtered through celite and the filtrate concentrated in vacuo to give a yellow oil; yield 150 mg (58%).

Example 10

(S) - [1 - {(4-Benzyloxybenzyl) - [(R) - (1-methyl-2-phenylethylcarbamoyl] methyl] carbamoyl} -2- (1H-imidazol-4yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 15, Step 5, substituting L-amphetamine for β, β-dimethylphenethylamine hydrochloride. The title compound is obtained as a white foam (90%); ES-MS 660 (m + 1).

Example 11

(S) - [1 - {(4-Benzyloxybenzyl) - [(S) - (1-methyl-2-phenylethylcarbamoyl] methyl] carbamoyl} -2- (1H-imidazol-4yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 5, Step 5, substituting D-amphetamine for β, β-dimethylphenethylamine hydrochloride. The title compound is obtained as a white foam (90%); ES-MS 660 (m + 1).

Example 12

(S) - [1 - {(4-Benzyloxybenzyl) - [(2-phenyl-2-pyridin-2-ylethylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 4, Step 4, substituting 2- [α- (aminomethyl) -benzyl] -pyridine hydrochloride (Step 1) for pyridinethanamine.HCl. The title compound was obtained as a white foam (64%); ES-MS 723 (m + 1).

Step 1: 2- [α- (Aminomethyl) benzyl] pyridine hydrochloride α- (2-Pyridyl) phenylacetonitrile (97.1 g, 0.5 mol) was reduced with Raney cobalt (25 g) and triethylamine (25 mL) in toluene (500 mL). The solution was filtered and the filtrate was concentrated. The residue was dissolved in diethyl ether and HCl was bubbled through. The hydrochloride salt precipitates in solution.

Example 13

(S) - [1 - {(4-Chlorobenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 4, Step 4, substituting β-methylphenethylamine for 2-pyridinethanamine.HCl, and Step 1, substituting p-chlorobenzaldehyde for 4-benzyloxybenzaldehyde. The title compound is obtained as a white foam (17%); ES-MS 588 (m + 1).

Example 14

(S) - [1 - {(4-Benzyloxybenzyl) - [2-hydroxy-2-phenylethylcarbamoyl] methyl] carbamoyl} -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 5, Step 5, substituting 2-amino-1-phenylethanol for β, β-dimethylphenethylamine hydrochloride. The title compound was obtained as a white foam (47%); ES-MS 662 (m + 1).

Example 15

(S) - [1 - {(4-Benzyloxybenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

Step 1: (4-Benzyloxy-benzylamino) -acetic acid methyl ester

To a mixture of glycine methyl ester hydrochloride (2.07 g, 16.5 mmol) and 4-benzyloxybenzaldehyde (3.18 g, 15 mmol) in CH 2 Cl 2 (50 mL) at 0 ° C was added sodium triacetoxyborohydride (3.81 g, 18 mmol). The mixture was allowed to warm to room temperature and stirred overnight. Aqueous NaHCO 3 solution was then added and the mixture was stirred for 30 minutes. The aqueous layer was extracted three times with CH 2 Cl 2. The combined organic extracts were washed with brine, dried over MgSO 4 and concentrated. Flash chromatography (ethyl acetate) gave 1.98 g (46%) of the title compound as a white solid; mp 57-58 ° C

Step 2: N- [N- (phenylmethoxy) carbonyl] -L-histidyltrityl] -N - [[4- (phenylmethoxy) phenyl] methyl] glycine methyl ester

To a suspension of Cbz-histidine- (trityl) (2.24 g, 4.21 mmol) in methylene chloride (25 mL) was added PyBOP (2.63 g, 5.05 mmol) and DIEA (1.46 mL, 8, 4 mmol). The amine from step 1 above (1.20 g, 4.21 mmol) was then added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was taken up in ethyl acetate, washed three times with saturated NaHCO 3 solution, brine, dried over MgSO 4 and concentrated. Flash chromatography gave 1.68 g (72%) of the title compound as a white foam;

ES-MS 557 (m + 1).

Step 3: N- [N- (Phenylmethoxy) carbonyl] -L-histidyltrityl] -N [[4-phenylmethoxy) phenyl] methyl] glycine

To a solution of the ester from Step 2 (1.53 g, 2.75 mmol) in THF (15 mL) and _H2O (5 mL) at 0 C was added LiOH ^much hydrate (0.14 g, 3.30 mmol ) and stirred at 0 ° C for 5 hours. The solution is concentrated, the residue is taken up in water and the pH is adjusted to 4-5 with 1N HCl. The resulting mixture was then concentrated and dried in vacuo to give 1.65 g of the title compound 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) and cooled under nitrogen to 0 ° C. Benzyl cyanide (22.2 g, 0.19) was added dropwise. mol) in THF (30 mL) and the reaction mixture was stirred for 1 hour. Iodomethane (24.9 mL, 0.4 mol) in THF (20 mL) was then added dropwise at 0 ° C. The reaction mixture was stirred at room temperature overnight under nitrogen. The solution was filtered and the filtrate was removed in vacuo. The residue was taken up in ethyl acetate (100 mL) and washed three times with 10% NaHCO 3, saturated solution

NaHCO 3, brine, dried over MgSO 4 and concentrated; yield 22.74 g (92%).

Reduction of the above product is carried out in the presence of Raney nickel in methanolic NH ₃ . The catalyst was removed and washed with methanol. The filtrate was concentrated and diethyl ether (100 mL) was added to the residue. HCl is then added dropwise and the desired product precipitates; 24.8 g (86%).

Step 5: [1 - {(4-Benzyloxybenzyl) - [(2-methyl-2-phenylpropylcarbamoyl] methyl] carbamoyl} -2 (3-trityl-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 was added HOBt hydrate (0.98 g, 6.39 mmol) and DCC (1.32 g, 6.39 mmol) then hydrochloride. β, β-dimethylphenethylamine (from step 4) (0.99 g, 5.33 mmol). Triethylamine (0.82 mL, 5.86 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was diluted with CHCl ₃ , washed twice with saturated NaHCO 3 solution, brine, dried over MgSO 4 and concentrated. Flash chromatography (2% -5% methanol / CHCl ₃ ) gave 2.25 g (63%) of the title compound; ES-MS 917 (m + 1).

Step 6: (S) - [1 - {(4-Benzyloxybenzyl) [(2-methyl-2-phenylpropylcarbamoyl] methyl] carbamoyl} 2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

To a solution of the trityl compound from Step 5 (2.25 g, 2.4 mmol) was added glacial acetic acid (20 mL) and water (5 mL). The mixture was stirred at 90 ° C for 30 min and then cooled and concentrated. The residue was taken up in ethyl acetate. The organic solution was washed twice with saturated NaHCO 3 solution, brine and dried over MgSO 4. The solution was concentrated and the compound purified by flash chromatography (0% to 8¾ methanol in methylene chloride) to give the title compound (1.5 g, 2.2 mmol, 93%) as a white foam; ES-MS 674 (m + 1).

Example 16

(S) - [1- (4-Benzyloxybenzyl) - [(2-phenylbutylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 15, Step 5, substituting β-ethylbenzenetamine hydrochloride (Step 1) for β, β-dimethylphenethylamine hydrochloride. The title compound was obtained as a white foam (55%); ES-MS 674 (m + 1).

Step 1: β-Ethylbenzenetamine hydrochloride

This compound is prepared by catalytic reduction of 2-phenylbutyronitrile as reported by B. K. Trivedi et al., J. Med. Chem., 1993; 36: 3300-3307.

Example 17 (S) -N- (4-Benzyloxybenzyl) -3- (1H-imidazol-4-yl) -2- (3-phenylpropionylamino) -N - [(2-phenylpropylcarbamoyl) methyl] propionamide

The title compound was prepared according to Step 2 of Example 15 by substituting phenylpropionylhistidine- (trityl) (steps 1 and 2) for Cbz-histidine- (trityl) and step 5 by substituting β-methylphenethylamine for β, β-dimethylphenethylamine hydrochloride. The title compound is obtained as a white foam (45%); ES-MS (m + 1).

Step 1: Phenylpropionylhistidine (trityl) methyl ester

To a solution of histidine (trityl) methyl ester hydrochloride (2.0 g, 4.2 mmol) and methylpiperidine (1.07 mL, 8.8 mmol) in methylene chloride is added slowly at 0 ° C 3-phenylpropionyl chloride (0, 62 ml) and the solution was stirred overnight at room temperature. Ethyl acetate was then added and washed twice with water, saturated NaHCO 3 solution, brine, dried over

MgSO4 and concentrated. This gives the product as a white foam; yield 2.0 g (88%).

Step 2: Phenylpropionylhistidine- (trityl)

To a solution of the ester from step 1 (2.0 g, 3.7 mmol) in a mixture of THF and methanol (both 10 mL) and water 2 mL) was added sodium hydroxide (0.44 g, 11 mmol) and the solution was stirred through night at room temperature. The solvent was removed in vacuo and 5 mL of water was added followed by 1N HCl to adjust the pH to 3. The product was extracted with ethyl acetate. The organic layer was washed with 1N HCl, brine, dried over MgSO 4 and concentrated. Obtained as a white foam (2.18 g); ES-MS 529 (m + 1).

Example 18

(S) - [1 - {(4-Fluorobenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure in Example 4, Step 4, substituting β-methylphenethylamine for 2-pyridinethanamine.HCl and Step 1, substituting p-fluorobenzaldehyde for 4-benzyloxybenzaldehyde. The title compound was obtained as a white foam (78%); ES-MS 572 (m + 1).

Example 19

(S) - (2- (1H-Imidazol-4-yl) -1 - {(4-methylbenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 4, Step 4, substituting β-methylphenethylamine for 2-pyridinethanamine.HCl, and, for Step 1, substituting p-fluorobenzaldehyde for 4-benzyloxybenzaldehyde. The title compound is obtained as a white foam (66%); ES-MS 568 (m + 1).

Example 20

(S) - (2- (1H-Imidazol-4-yl) -1 - {(4-methoxybenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 4, Step 4, substituting β-methylphenethylamine for 2-pyridinethanamine.HCl and Step 1, substituting p-methoxybenzaldehyde for 4-benzyloxybenzaldehyde. The title compound was obtained as a white foam (33%); ES-MS 583 (m + 1).

Example 21

(S) - [1 - [{[2- (2-Aminophenyl) propylcarbamoyl] methyl} - (4-benzyloxybenzyl) carbamoyl] -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 4, Step 4, substituting 2-amino-p-methylphenethylamine (Step 1) for 2-pyridinethane-amine.HCl. The title compound was obtained as a white foam (33%); ES-MS 675 (m + 1).

Step 1: 2-Amino-p-methylphenethylamine

Reduce 4-methylcinoline (10 g, 69.5 mmol) in methanol (100 mL) using Raney nickel (3 g). The catalyst was removed and washed with methanol. The filtrate was treated with excess HCl in isopropyl alcohol, ether was added and the solution was cooled. The precipitate was filtered off and dried; yield 9.4 g (60%).

Example 22

(S) - [1 - {(4-Fluorobenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 1, Step 1, substituting p-fluorobenzaldehyde for 4-benzyloxybenzaldehyde. The title compound is obtained as a white foam (87%); ES-MS 586 (m + 1).

Example 23

(S) - [1- (Benzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure in Example 4, Step 4, substituting β-methylphenethylamine for 2-pyridinethanamine.HCl, and Step 1, substituting benzaldehyde for 4-benzyloxybenzaldehyde. The title compound was obtained as a white foam (57%); ES-MS 524 (m + 1).

Example 24

(S) - [1 - ((4-Benzyloxybenzyl) - {[2- (2-chlorophenyl) -2-phenylethylcarbamoyl] methyl} carbamoyl} -2- (1Himidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure in Example 4, Step 4, substituting o-chloro-p-phenyl-phenethylamine hydrochloride (Steps 1 and 2) for 2-pyridine-ethanamine.HCl. The title compound was obtained as a white foam (37%); ES-MS 756 (m + 1).

Step 1: 2-Phenyl-3- (2-chlorophenyl) cyanide

At 90 ° C, bromine (2 mL) was added dropwise over 1 hour to 2-chlorobenzyl cyanide (5 g, 32 mmol) with stirring. Nitrogen was then passed through the reaction mixture to remove HBr. The reaction mixture was heated for 15 minutes and benzene (2 mL) was added. This solution is added dropwise over 2 hours to the refluxing solution of AlCl? (4.2 g, 32 mmol) in benzene (15 mL). The reaction mixture was heated at reflux for 1 hour. The reaction mixture was cooled and poured into ice (200 g) and concentrated HCl (20 mL). The aqueous layer was extracted with diethyl ether and a 1: 1 mixture of diethyl ether and benzene. The organic solution was washed twice with water, saturated NaHCO 3 solution, brine, dried over Na 2 SO 4 and concentrated. An orange oil is obtained; yield 6.3 g (86 $).

Step 2: o-Chloro-p-phenylphenethylamine hydrochloride

The reduction of the product of step 1 is carried out in the presence of Raney nickel in methanol / NH ₃ . The catalyst was removed and washed with methanol. The filtrate was concentrated and ethanol (100 mL) was added to the residue. Concentrated HCl is then slowly added to pH 3. The volume of ethanol is reduced in vacuo to approximately 5 ml and the HCl salt is precipitated by the addition of diethyl ether; yield 1.84 g (68%).

Example 25

(S) - [1 - {(4-Benzyloxybenzyl) - [(2-ethyl-2-phenylbutylcarbamoyl) methyl} carbamoyl} -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to Step 5 of Example 15, substituting β, β-diethylbenzenethanamine hydrochloride (step 1) for β, β-dimethylphenethylamine hydrochloride. The title compound is obtained as a white foam (52%); ES-MS 702 (m + 1).

Step 1: β, β-Diethylbenzenethanamine hydrochloride

This compound is prepared by diethylation of phenylacetonitrile followed by catalytic reduction as described by B. K. Trivedi et al., J. Med. Chem., 1993; 36: 3300-3307.

Example 26 (S) -N- (4-Benzyloxybenzyl) -2- (3-benzylureido) -3- (1H-imidazol-4-yl) -N - [(2-phenylpropylcarbamoyl) methyl] propionamide

The title compound was prepared according to Step 15, Example 15, substituting benzylureahistidine- (trityl) (steps 1 and 2) for Cbz-histidine- (trityl) and Step 5, substituting β-methylphenethylamine hydrochloride for β, β-dimethylphenethylamine hydrochloride. The title compound was obtained as a white foam (64%); ES-MS 659 (m + 1).

Example 27 (S) -N- (4-Benzyloxybenzyl) -2- (3-benzylureido) -3- (1H-imidazol-4-yl) -N - [(2-phenylbutylcarbamoyl) methyl] propionamide

The title compound was prepared according to Example 15, Step 2, substituting benzylureahistidine- (trityl) .HCl (steps 1 and 2, Example 6) with Cbz-histidine- (trityl) and Step 5, substituting β-ethylbenzenetamine hydrochloride (Step 1, Example 16). ) for β, β-dimethylphenethylamine hydrochloride. The title compound is obtained as a white foam (93 *); ES-MS 673 (m + 1).

Example 28

(S) - [1 - {(2-Chlorobenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure in Example 4, Step 4, substituting β-methylphenethylamine for 2-pyridinetanamine.HCl and Step 1, substituting o-chlorobenzaldehyde for 4-benzyloxybenzaldehyde. The title compound was obtained as a white foam (40%); ES-MS 588 (m + 1).

Example 29

(S) - [1 - {(4-Bromobenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 4, Step 4, substituting β-methylphenethylamine for 2-pyridinethanamine.HCl and Step 1, substituting o-bromobenzaldehyde for 4-benzyloxybenzaldehyde. The title compound was obtained as a white foam (91%); ES-MS 633 (m + 1).

Example 30

(S) - [1 - {(3-Chlorobenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 4, Step 4, substituting β-methylphenethylamine for 2-pyridinethanamine.HCl and Step 1, substituting o-chlorobenzaldehyde for 4-benzyloxybenzaldehyde. The title compound is obtained as a white foam (10%); ES-MS 588 (m + 1).

Example 31

(S) - [1- (4-Chlorobenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 1, Step 1, substituting p-chlorobenzaldehyde for 4-benzyloxybenzaldehyde. The title compound was obtained as a white foam (33%); ES-MS 602 (m + 1).

Example 32

(S) - [1 - ((4-Benzyloxybenzyl) - {[2- (2-chlorophenyl) propylcarbamoyl) methyl} carbamoyl) -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 4, Step 4, substituting o-chloro-4-methyl-phenethylamine hydrochloride (Steps 1 and 2) for 2-pyridine-ethanamine.HCl. The title compound was obtained as a white foam (41%); ES-MS 694 (m + 1).

Step 1: 2-Methyl-3- (2-chlorophenyl) cyanide

To a suspension of NaNH ₂ powder (0.6 g, 15.5 mmol) in THF (15 mL) was added 2-chlorophenylacetonitrile (2 g, 13 mmol) in THF (10 mL). The mixture was heated at reflux for 2 hours. Methyl iodide (2.18 g, 15.5 mmol) in THF (10 mL) was then added and the solution was refluxed for an additional 3 hours. The reaction mixture was cooled and treated with H _; The organic layer was separated and washed twice with 5% Na ₂ S ₂ O _{2 .} , brine, dried over Na ₂ SO ₄ and concentrated; yield 1.93 g (93%).

Step 2: O-Chloro-p-methylphenethylamine hydrochloride

The reduction of the product of step 1 is carried out in the presence of Raney nickel in methanol / NH ₃ . The catalyst was removed and washed with methanol. The filtrate was concentrated and diethyl ether (100 mL) was added to the residue. Concentrated HCl is then added dropwise and the compound precipitates; yield 1.06 g (44%) ·

Example 33

(S) - (2- (1H-Imidazol-4-yl) -1 - {(4-methoxybenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 4, Step 4, substituting β-methylphenethylamine for 2-pyridinethanamine.HCl, and, for Step 1, substituting o-methoxybenzaldehyde for 4-benzyloxybenzaldehyde. 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-phenylpropylcarbamoyl) methyl] - [4- (pyridin-4-ylmethoxy) benzyl] carbamoyl} ethyl] carbamic acid benzyl ester

The title compound was prepared according to Step 1 of Example 15 by substituting 4 - [(4-pyridyl) methoxy] benzaldehyde (Step 1) for 4-benzyloxybenzaldehyde and Step 5 by substituting β-methylphenethylamine for β, β-dimethyl-phenethylamine hydrochloride. The title compound was obtained as a white foam (67%); ES-MS 661 (m + 1).

Step 1: 4 - [(4-Pyridyl) methyloxy] benzaldehyde

This compound was prepared as described in J. Het. Chem., 1998; 25: 129th

Example 35

(S) - (2- (1H-Imidazol-4-yl) -1 - {(3-methoxybenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester

The title compound was prepared according to Step 4 of Example 8 by substitution of β-methylphenethylamine for 2-pyridinethanamine.HCl and Step 1 by substituting m-methoxybenzaldehyde for 4-benzyloxybenzaldehyde. The title compound is obtained as a white foam (14%); ES-MS 584 (m + 1).

Example 36

(S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-phenylpropylcarbamoyl) methyl] - [4- (pyridin-3-ylmethoxy) benzyl] carbamoyl} ethyl] carbamic acid benzyl ester

The title compound was prepared according to Step 1 of Example 15 by substituting 4 - [(3-pyridyl) methoxy] benzaldehyde (Step 1) for 4-benzyloxybenzaldehyde and Step 5 by substituting β-methylphenethylamine for β, β-dimethylphenethylamine hydrochloride. The title compound is obtained as a white foam (59%); ES-MS 661 (m + 1).

Step 1: 4 - [(3-Pyridyl) methyloxy] benzaldehyde

This compound was prepared as described in J. Het. Chem., 1998; 25: 129th

Example 37

(S) - (2- (1H-Imidazol-4-yl) -1- {naphthalen-1-ylmethyl - [(2-phenylpropylcarbamoyl) methyl] carbamoyl] ethyl] carbamic acid benzyl ester

The title compound was prepared according to Step 1 of Example 15 by substituting 1-naphthalenecarboxaldehyde for 4-benzyloxybenzaldehyde and Step 5 by substituting β-methylphenethylamine for β, β-dimethylphenethylamine hydrochloride. The title compound is obtained as a white foam (15%); ES-MS 661 (m + 1).

Example 38

(S) - {2- (1H-Imidazol-4-yl) -1 - [[(2-phenylpropylcarbamoyl) methyl] - (4-trifluoromethylbenzyl) carbamoyl] ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 4, Step 4, substituting β-methylphenethylamine for 2-pyridinethanamine.HCl, and Step 1, substituting p-trifluoromethylbenzaldehyde for 4-benzyloxybenzaldehyde. The title compound is obtained as a white foam (13%); ES-MS 622 (m + 1).

Example 39

(S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-methyl-2-phenylpropylcarbamoyl) methyl] pyridin-3-ylmethylcarbamoyl} ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 1, Step 1, substituting 3-pyridinaldehyde for 4-benzyloxybenzaldehyde. The title compound was obtained as a white foam (84%); ES-MS 569 (m + 1).

Example 40

(S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-methyl-2-phenylpropylcarbamoyl) methyl] - [4- (pyridin-2-ylmethoxy) benzyl] carbamoyl} ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 1, Step 1, substituting 4 - [(2-pyridyl) methyloxy] benzaldehyde (Step 1) for 4-benzyloxybenzaldehyde. The title compound was obtained as a white foam (62%); ES-MS 675 (m + 1).

Step 1: 4 - [(2-Pyridyl) methyloxy) benzaldehyde

This compound was prepared as described in J. Het. Chem., 1998; 25: 129th

Example 41 (S) -2- (3-Benzyl-3-methylureido) -N- (4-benzyloxybenzyl) -3- (1H-imidazol-4-yl) -N - [(2-methyl-2-phenylpropylcarbamoyl) methyl] propionamide

The title compound was prepared according to the procedure of Example 15, Step 2, substituting N-methyl-N-benzylureahistidine- (trityl) (steps 1 and 2) for Cbz-histidine- (trityl). The title compound was obtained as a white foam (79%); ES-MS (m + 1).

Step 1: N-Methyl-N-benzylureahistidine- (trityl) methyl ester

Histidine (trityl) methyl ester hydrochloride (2.0 g, 4.2 mmol) was suspended in methylene chloride (20 mL) and the solution was washed twice with saturated NaHCO 3 solution, brine, dried over MgSO 4 and cooled to 0 ° C. Then triethylamine (0.65 mL, 8.8 mmol) and 4-nitrophenyl chloroformate (0.93 g, 4.7 mmol) were added. The reaction mixture was stirred at 0 ° C under nitrogen for 1.5 hours. N-benzyl-N-methylamine (1.14 mL, 8.8 mmol) in methylene chloride was then added slowly and the reaction was stirred slowly under nitrogen overnight. The solvent was removed and ethyl acetate was added to the residue. The organic solution was washed twice with water, saturated NaHCO ₃ solution, brine, dried over MgSO 4 and concentrated. Chromatography using ethyl acetate / hexanes (1: 1) yields a foam; Yield 1.19 g (50%) ·

Step 2: N-Methyl-N-benzylureahistidine- (trityl)

Step 1 Methyl ester (1.19 g, 2.1 mmol) was dissolved in a mixture of THF and methanol (10 mL each). 1N NaOH (6.3 mL, 6.3 mmol) was then added and the reaction stirred overnight. The solvent was removed in vacuo. 1N HCl (6.3 mL) was then added and extracted with ethyl acetate. The organic solution was washed twice with brine and dried over MgSO 4 and concentrated. A white foam is obtained; yield 1.4 g.

Example 42

(S) -11- {Benzyl - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to Step 4 of Example 8, substituting β, β-dimethylphenethylamine hydrochloride for 2-pyridinethanamine.HCl, and, for Step 1, substituting benzaldehyde for 4-benzyloxybenzaldehyde. The title compound was obtained as a white foam (42%); ES-MS 568 (m + 1).

Example 43

(S) - (2- (1H-Imidazol-4-yl) -1 - {(2-methylbenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure in Example 4, Step 4, substituting β-methylphenethylamine for 2-pyridinethanamine.HCl, and Step 1, substituting o-methylbenzaldehyde for 4-benzyloxybenzaldehyde. The title compound was obtained as a white foam (49%); ES-MS 568 (m + 1).

Example 44

(S) - (2- (1H-Imidazol-4-yl) -1 - {(4-methoxybenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester

The title compound was prepared according to Step 4 of Example 8, substituting β, β-dimethylphenethylamine hydrochloride for 2-pyridinethane-amine.HCl, and Step 1, substituting p-methoxybenzaldehyde for 4-benzyloxybenzaldehyde. The title compound is obtained as a white foam (16%); ES-MS 598 (m + 1).

Example 45

(S) - [1 - {(4-Benzyloxybenzyl) - [(2-cyano-2-phenylethylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to Step 5 of Example 15, substituting β-cyanophenethylamine hydrochloride (step 1) for β, β-dimethylphenethylamine hydrochloride. The title compound was obtained as a white foam (47%); ES-MS 671 (m + 1).

Step 1: β-Cyanophenethylamine hydrochloride

This compound is prepared according to U.S. Pat. No. 4,760,089, incorporated herein by reference.

Example 46

(S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-methyl-2-phenylpropylcarbamoyl) methyl] pyridin-2-ylmethylcarbamoyl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to Step 1, Example 15, as follows. The title compound was obtained as a white foam (63%); ES-MS 569 (m + 1).

Step 1: [2-Pyridyl) -methyl-amino] -acetic acid methyl ester j

A solution of 2-aminomethylpyridine (5.0 g, 46.2 mmol) in acetonitrile (100 mL) was treated with methyl bromoacetate (4.3 mL, 46.2 mmol) and triethylamine (6.5 mL, 46.2 mmol). The mixture was stirred at room temperature for 1 hour and then heated at reflux overnight. The solution was diluted with ethyl acetate and washed with saturated NaHCO 3 solution, water, and brine, dried over MgSO 4 and concentrated. Chromatography eluting with 3% methanol in chloroform gave 2.73 g (33%) of the pure product as an oil.

Example 47

(S) - (2- (1H-Imidazol-4-yl) -1 - {(3-methylbenzyl - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester

The title compound was prepared according to Step 4 of Example 8 by substitution of β-methylphenethylamine for 2-pyridinethanamine.HCl and Step 1 by substituting m-methylbenzaldehyde for 4-benzyloxybenzaldehyde. The title compound is obtained as a white foam (52%); ES-MS 568 (m + 1).

Example 48

(S) -1 - {(4-Dimethylaminobenzyl - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to Step 4 of Example 8 by substituting β-methylphenethylamine for 2-pyridinethanamine.HCl and Step 1 by substituting p-dimethylaminobenzaldehyde for 4-benzyloxybenzaldehyde. The title compound is obtained as a white foam (36V); ES-MS 597 (m + 1).

Example 49

(S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-methyl-2-phenylpropylcarbamoyl) methyl] - [4- (pyridin-4-ylmethoxy) benzyl] carbamoyl} ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 15, Step 1, substituting 4 - [(4-pyridyl) methyloxy] benzaldehyde (Step 1) for 4-benzyloxybenzaldehyde. The title compound was obtained as a white foam (93%); ES-MS 675 (m + 1).

Step 1: 4 - [(4-Pyridyl) methyloxy] benzaldehyde

This compound is synthesized as described in J. Het. Chem., 1988; 25: 129th

Example 50

(S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-methyl-2-phenylpropylcarbamoyl) methyl] - [4- (pyridin-3-ylmethoxy) benzyl] carbamoyl] ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 15, Step 1, substituting 4 - [(3-pyridyl) methyloxy] benzaldehyde (Step 1) for 4-benzyloxybenzaldehyde. The title compound is obtained as a white foam (56%); ES-MS 675 (m + 1).

Step 1: 4 - [(3-Pyridyl) methyloxy] benzaldehyde

This compound is synthesized as described in J. Het. Chem., 1988; 25: 129th

Example 51

(S) - [1- (Biphenyl-4-ylmethyl - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to Example 15, Step 1, substituting p-phenylbenzaldehyde for 4-benzyloxybenzaldehyde and Step 5, substituting β-methylphenethylamine for β, β-dimethylphenethylamine hydrochloride. The title compound was obtained 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-imidazol-4-yl) -ethyl] -carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 1, Step 1, substituting p-phenylbenzaldehyde for 4-benzyloxybenzaldehyde. The title compound is obtained as a white foam (32%); ES-MS 644 (m + 1).

Example 53

(S) - [1 - ((4-Benzyloxybenzyl - {[2- (2-chlorophenylethylcarbamoyl) methyl) carbamoyl] -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 1 Step 1, substituting 2-chloro-phenethylamine for 2 - [(2-fluorophenyl) -ethyl] -amine. The title compound was obtained as a white foam (89%); ES-MS 681 (m + 1).

Example 54

(S) - [1 - ((4-Benzyloxybenzyl [2- (2-methyl-2-phenylpropylcarbamoyl) methyl) carbamoyl} -2- (1Himidazol-4-yl) ethyl] carbamic acid thiophen-3-ylmethyl ester

The title compound was prepared according to the procedure of Example 15, Step 2, substituting 3-thiophenomethyloxycarbonylhistidine (trityl) (steps 1 and 2) for Cbz-histidine- (trityl). The title compound was obtained as a white foam (40%); ES-MS 680 (m + 1).

Step 1: 3-Thiophenomethyloxycarbonylhistidine (trityl) methyl ester

3-Thiophenemethanol (0.43 mL, 4.6 mmol), triethylamine (0.64 mL, 6.4 mmol) and 4-nitrophenyl chloroformate (0.92 g, 4.6 mmol) were dissolved in methylene chloride (20 mL) and cooled to 0 ° C under nitrogen. After one hour, histidine- (trityl) methyl ester hydrochloride (2 g, 4.2 mmol) and triethylamine (1.28 mL, 9.2 mmol) in methylene chloride (10 mL) were added. The reaction mixture was stirred overnight. The solvent was removed in vacuo. Water and ethyl acetate were added. The organic layer was washed with saturated NaHCO 3 solution, brine, dried over MgSO 4 and concentrated to give a yellow oil. Flash chromatography (ethyl acetate: hexanes, 1: 1) gave a white foam; yield 1.15 g (50 a).

Step 2: 3-Thiophenomethyloxycarbonylhistidine- (trityl)

To a solution of the ester from step 1 (1.15 g, 2.1 mmol) in THF (10 mL) and methanol (10 mL) was added 1 N NaOH (6.3 mL, 6.3 mmol) and the solution was stirred overnight at room temperature. The solution was concentrated, 1N HCl (6.3 mL) was added and the product was extracted with ethyl acetate, which was then washed twice with brine, dried over MgSO 4 and concentrated to give a white foam; yield 1.12 g (99%).

Example 55

(S) - [1 - {(4-Chlorobenzyl- [1- (2-methyl-2-phenyl-propylcarbamoyl) -ethyl] -carbamoyl} -2- (3H-imidazol-4-yl) -ethyl] -carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 1, Step 1, substituting the alanine methyl ester hydrochloride for the glycine methyl ester hydrochloride, and the Step 2 substitution for 1-hydroxy-7-azabenzotriazole (HOAt) and O- (7-azabenzotriazoll-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate (HATU) for PyBOB. The title compound was obtained as a white foam (78%); ES-MS 617 (m + 1).

Example 56

(S) - (2- (1H-Imidazol-4-yl) -1 - ((4-methylbenzyl - [(2-methyl-2-phenylpropylcarbamoyl) methyl) carbamoyl} ethyl) carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 1, Step 1, substituting 4-methyl-benzaldehyde for 4-benzyloxy-benzaldehyde. The title compound was obtained as a white foam (74%); ES-MS 582 (m + 1).

Example 57

(S) - (2- (1H-Imidazol-4-yl) -1 - {(2-methoxybenzyl - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester

The title compound was prepared according to Example 1, Step 1, substituting 2-methoxybenzaldehyde for 4-benzyloxybenzaldehyde, and Step 4, substituting β, β-dimethylphenethylamine (Example 15, Step 4) for 2-pyridinethenamine hydrochloride. The title compound is obtained as a white foam (11%); ES-MS (m + 1).

Example 58 (S) -2- (3-Benzyl-3-methylureido) -N- (4-chlorobenzyl) -3- (1H-imidazol-4-yl) -N - [(2-methyl-2-phenylpropylcarbamoyl) methyl] propionamide

The title compound was prepared according to the procedure of Example 15, Step 1, substituting 4-chlorobenzaldehyde for 4-benzyloxybenzaldehyde and Step 2, substituting N-methyl-N-benzylureahistidine- (trityl) (Example 41, steps 1 and 2) for Cbz-histidine- (trityl) ). The title compound is obtained as a white foam (72 *); ES-MS 616 (m + 1).

Example 59

(S) - (2- (1H-Imidazol-4-yl) -1 - {(3-methoxybenzyl - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester

The title compound was prepared according to Example 15, Step 1, substituting 4-methoxybenzaldehyde for 4-benzyloxybenzaldehyde, and Step 4, substituting β, β-dimethylphenethylamine (Example 15, Step 4) for 2-pyridinethanamine hydrochloride. The title compound is obtained as a white foam (5%); ES-MS 598 (m + 1).

Example 60

(S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-methyl-2-phenylpropylcarbamoyl) methyl] - [2- (pyridin-4-ylmethoxy) benzyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 15, Step 1, substituting 2 - [(4-pyridyl) methoxy] benzaldehyde (Step 1) for 4-benzyloxybenzaldehyde. The title compound was obtained as a white foam (61%); ES-MS 676 (m + 1).

Step 1: 2 - [(4-Pyridyl) methoxy] benzaldehyde

A solution of salicylaldehyde (5 g, 40.9 mmol) in DMSO (75 mL) was treated with crushed potassium hydroxide (5.4 g, 81.8 mmol) and allowed to stir at room temperature for 1 hour. The solution was then treated with 4-picolyl chloride hydrochloride (6.8 g, 40.9 mmol) and the dark mixture was allowed to stir overnight. The mixture was poured into water and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with 5% NaOH, three times with water and then with brine. Drying over MgSO ₄ and removal of the solvent under reduced pressure gave the crude product. This product was taken up in ethyl acetate and treated with charcoal, filtered and the solvent was 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-phenylpropylcarbamoyl) methyl] carbamovl} -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester

The title compound was prepared according to the procedure of Example 1, Step 1, substituting cyclohexanecarboxaldehyde for 4-benzyloxybenzaldehyde and Step 4, substituting β-methylphenethylamine for 2-pyridinethanamine.HCl. The title compound is obtained as a white foam (16%); ES-MS 559 (m + 1).

Example 62

(S) - (2- (1H-Imidazol-4-yl) -1- {isobutyl [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester

Step 1: Na-Boc-N - [(2-phenylpropylcarbamoyl) methyl] glycamide

To a solution of Boc-glycine (2.1 g, 12 mmol) in methylene chloride (100 mL) was added β-methylphenethylamine (1.91 mL, 13.2 mmol), 1-hydroxybenzotriazole (Hobt) (1.78 g, 13 mmol). , 2 mmol), dicyclohexylcarbodiimide (DCC) (0.5 M DCC in methylene chloride; 26 mL, 13.2 mmol) and diisopropylethylamine (4.17 mL, 24 mmol). The reaction solution was filtered. The filtrate was washed three times with brine. The organic solution is dried over MgSO 4 and concentrated by flash chromatography (5 → methanol in chloroform) to give

3.5 g (100-) of the title compound as a white solid; CI-MS 293 (m + 1).

Step 2: [2-Phenylpropylcarbamoyl) methyl] glycamide trifluoroacetate salt

To a solution of the compound from Step 1 above (3.5 g, 12 mmol) in methylene chloride (35 mL) was added trifluoroacetic acid (15 mL). The solution was stirred for 2 hours and then concentrated. The residue was dissolved in methylene chloride and re-concentrated to give the title compound as an oil. This oil was used in the next reaction without characterization.

Step 3: N - [(2-Phenylpropylcarbamoyl) methyl] Na- (4-benzyloxybenzyl) glycamide hydrochloride

To a suspension of the compound of Step 2 above (1.16 g, 6 mmol) was added isobutyraldehyde (0.274 mL, 3 mmol) and sodium acetate (0.59 g, 7.25 mmol) in methylene chloride (25 mL). The solution was cooled to 0 ° C and sodium triacetoxyborohydride (1.92 g, 9.1 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was then treated with saturated aqueous NaHCO ₃ and the layers were separated.

The aqueous layer was extracted with methylene chloride (2 x 20 mL). The organic layers were combined and washed three times with brine, dried over MgSO ₄ and concentrated. The product was purified by flash chromatography (5% methanol in chloroform) to give 0.22 g (15%) of the title compound; CI-MS 249 (m + 1).

Step 4: (2- (1-Trityl-1H-imidazol-4-yl) -1- {isobutyl - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester

To a solution of (S) - (2-benzyloxycarbonylamino-3- (1-trityl) -1H-imidazol-4-yl) propionic acid (Cbz-histidine- (trityl)) (Hudsspeth JP, Kaltenbronn JS, Repine JT, Roark W.

H. Stier MA Renin Inhibitors III. U.S. Pat. 4,735,933; 1988), (0.532 g, 1.0 mmol) in methylene chloride (50 mL) is added O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethylammonium hexafluorophosphate (HATU) (0.67 g, 1.7 mmol), 1-hydroxy-7-azabenzotriazole (HOAt) (0.24 g, 1.7 mmol) and diisopropylethylamine (1.08 mL, 6.2 mmol). The mixture was then treated with the amine (0.22 g, 0.88 mmol) from step 3 above and stirred overnight. The reaction solution was concentrated and the residue was dissolved in ethyl acetate (25 mL). The organic solution was washed three times with 5% citric acid, 5% NaHCO ₃ and brine, dried over MgSO ₄ and concentrated. The product was used in the next step without further purification.

Step 5: (S) - (2- (1H-Imidazol-4-yl) -1 {isobutyl - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester

To a solution of the trityl compound (0.64 g, 0.86 mmol) from step 4 above in methylene chloride (25 mL) was added TFA (25 mL). The solution was stirred for 3 hours and then concentrated. The residue was partitioned and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, dried over MgSO 4 and concentrated. Purification by reverse-phase high-pressure liquid chromatography (eluents 0.1¾ TFA in water and 0.1¾ TFA in acetonitrile) gave 0.060 g (13%) of the title compound; ES-MS 520 (m + 1).

Inhibitory potency of PFT

Protein farnesyltransferase (PFT) or farnesylprotein transferase (FPT) inhibitory activity of the compounds of the present invention was tested in HEPES buffer (pH 7.4) containing 5 mM potassium phosphate and 20 μΜ ZnCl ₂ also containing 5 mM DTT (dithiothreitol). MgCl ₂ and 0.1¾ PEG 8000. Assays were performed in 96-well plates (Walec) and included solutions with various concentrations of the compound of the invention in 100% DMSO (dimethylsulfoxide). Upon addition of both substrates, radiolabeled farnesyl pyrophosphate ([1 ³ H], specific activity 15-30 Ci / mmol, final concentration 134 nM) and (biotinyl) -Ahe-Thr-Lys-Ile-CysV-Met ([3aS acid [ 3α alpha, 4β, 6α alpha] hexahydro-2-oxo-1H-thieno [3,4-d] imidazole-5-pentanoic acid - [7-aminoheptanoic acid] -Thr-Lys-Cys-Val-Ile-Met ) (Ahe is 7-aminoheptanoic acid, Thr is threonine, Lys is lysine, Cys is cysteine, Val is valine, clay is isoleucine and Met is methionine) (final concentration 0.2 μΜ), enzymatic reaction started by adding SF9 affinity purified rat ras farnesyl protein transferases. After incubation at 30 ° C for 30 minutes, the reaction was terminated by diluting the reaction with a 2.5-fold buffer containing 1.5 M magnesium acetate, 0.2 MH ₃ PO ₄ , 0.5% BSA (bovine serum albumin) and streptavidin beads. (Amersham) at a concentration of 1.3 mg / ml. The plate was then allowed to stand for 30 minutes at room temperature, and radioactivity was determined on a microBeta counter (Model 1450, Wallec). The assay is also performed with 5 mM potassium phosphate.

A gel shift assay hours after inoculation of 2 x 10 6 ras-transformed cells per assay condition, a farnesylation inhibitor is added at various concentrations. Following an 18-hour incubation period, cells are decomposed in phosphate buffered saline containing 1% Triton X-100, 0.5¾ sodium deoxycholate and 0.1% SDS (sodium dodecyl sulfate), pH 7.4 in the presence of several protease inhibitors ( PMSF (phenylmethylsulfonyl chloride), antipain, leupeptin, pepstatin A and aprotinin, all at 1 µg / ml). Ras protein is immunologically precipitated from the supernatants by the addition of 3 µg v-H-ras Ab-2 (Y13-259 from Oncogene Science). After immunological precipitation overnight, 30 μΐ of a 50% slurry of G-Sepharose protein (Pharmacia) is added followed by a 45 minute incubation. The pellets are resuspended in 2X tris-glycine buffer (Novex) containing 5% β-mercaptoethanol and then denatured by boiling for 5 minutes prior to electrophoresis on 14% tris-glycine SDS gels. Using Western transformation techniques, proteins are transferred to nitrocellulose membranes followed by blocking in blocking buffer. After overnight incubation with the primary antibody (pan-ras Ab-2 from Oncogene Science), a secondary antibody is used, which is an anti-mouse HRP (horseradish peroxidase) conjugate (Amersham) for the determination of ras protein. Spots are developed using the ECL (enhanced chemiluminescence) technique (Amersham).

Clonogenic assay (6-well plates)

1. Prepare 1.5% Bacto Agar in Milli-Q water and autoclave.

2. Prepare 500 ml of 2X DMEM-HG without phenol red following combination

bottle of DMEM powder (Sigma D-5030)

4.5 g glucose

3.7 g of sodium bicarbonate

0.11 g sodium pyruvate ml 200 mM L-glutamine (Sigma G-7513) ml pen-strep (GibcoBRL # 15140-023)

Adjust the pH to 7.1 with HCl; sterilize by filtration.

1. Prepare an operational water bath (beaker of water with a thermometer on a hot plate) in a fume cupboard. Keep water temperature between 37 ° C to 43 ^e C

2. 1.5% Bacto Agar autoclave at higher temperature until the charge melts. Then allow to cool before re-use. (You can prevent re-solidification by placing the bottle on a hot plate).

3. Bottom layer (0.6% agar) _ Top layer (0.3% agar)% calf serum 20% calf serum% 2X DMEM 50% 2X DMEM% Bacto Agar (1.5%) 20% Bacto Agar (1 , 5%)% sterile μ x μι, cell suspension (5000 cells / well) (H61 cells: 3T3H-ras cells transformed with NIH)

Depending on the volume of each layer required, either 50 ml conical tubes or 200 ml tubes may be used, which may float in the water bath.

4. Add 1 ml bottom of agar medium to each well; add 1 ml of hot agar medium to the well; then, using a pipette tip, spray the agar medium around to completely cover the bottom. Repeat with the next hole. Do not add the last ml in the pipette to the well, as bubbles form.

5. Allow the plates to stand at room temperature for 5 minutes until the layer solidifies at the bottom.

6. Label Falcon 2054 sterile tubes (12 x 75 mm) and add the appropriate volume of drug solutions.

7. Add aliquots of 4 μΐ of DMSO drug solution per ml of agar medium to the appropriate tubes; then add cell agar medium to each tube. Always add 1 ml more than the current need. Mix and carefully transfer to a pipette; then add 1 ml to the center of each well. The topsheet is less viscous and will therefore typically extend over the backsheet. If necessary, by gently rotating the plate surface, the top layer will spread over the bottom layer.

8. Allow the plates to set for 5 or 10 minutes at room temperature, then place in a 5% CO ₂ and 37 ° C incubator.

On day 13, add 0.5 ml INT (tetrazolium 1 mg / ml in MilliQ H ₂ O, filter sterilized) and place the plates in the incubator again.

10. Count the colonies.

The data presented in the table below show the farnesyl protein transferase inhibitory activity and the efficacy in goal shift and clonogenic assay against the ras protein of the compound of the invention.

Example no. IC ₅₀ (pM) HEPES IC ₅₀ (UM) 5 »MK ₃ PO ₄ -2 Gclovi slider. (pM) MED * ^: ClonogAn »IC ₅₀ (pM) 1 7.7 0.26 and 2.7 (14.3) 2 2.84 (2.1) 0.024 (0.062) 0.1 9.2 (4.33) 3 3.1 (2.8) 0.97 (0.61) 0.25 > 1 4 5.8 (0.15) 0.0076 (0.005) 0.05 > 1 (0,34) 5 1.73 (1.6) 0,038 0.2 (0.05) 0.71 (2.5) 6 0.2 (0.5) 0.0022 (0.017) 0.2 > 1 7 9.8 0.36 > 1 8 7.8 0.30 0.2 > 1 9 4.5 0.36 0.2 > 1 10 0.58 0,018 0.01-0.05 0.71 11 2.5 0,082 0.2 > 1 12 0,062 0.2 > 1 13 1.4 0,022 0.2 > 1 14 1.6 0,066 0.05 > 1 15 0.12 0,007 0.01-0.05 0.19 16 0.29 0,007 0.01-0.05 0.40 17 2.8 0,086 0.2 > 1 18 2.8 0,061 0.2 > 1 19 1.26 0,015 0.05 0.66 20 ^X > ⁵ 0,017 0.05 - L °, ⁴⁶ 21 0.16 0,008 0.05 0.30 22 1.2 0,016 0.2 > 1 23 1.6 0,022 0.2 > 1 24 0.20 0,014 0.2 0.82 25 0.93 0,032 0.2 0.89 26 0.15 0,009 0.2 > 1 27 0.12 0,014 0.2 > 1 28 2.6 0,043 0.2 0.6 29 0.1 > 1 30 0.78 0,016 0.1 > 1 31 0.52 0,014 0.1 > 1 32 0.32 0,007 0.05 0.36 33 0.50 0,009 0.05 0.36 34 0,097 0,002 0.05 0.14 35 2.1 0,009 0.2 > 1 36 0.45 0,007 20,05 0.32 37 '0.92 0,026 20.2 38 1.6 0,013 0.2 0.22

Example 'e. HQ _SQ (UM) Hepes IC ₅₀ (μΜ) 5 nM: <3? O ₄ -2 Gel sliding weave. (UM) MED * Clonogenic IC _S0 (UM) 39 9.5 0.10 > 0.2 > 1 40 0.12 0,001 0.01 0.19 41 0,009 0,004 0.05 0.04 42 0.60 0,005 0.05 0.51 43 ³ , ⁹ 0,038 0.2 > 1 44 0.30 0,002 0.02 0.36 45 0.35 0.0024 0.05 0.14 46 1.98 0,034 1 47 0.62 0,035 0.05 0.73 48 0.5 0.0029 0.05 49 0,060 0,009 0.05 0.1 50 0,089 0.0010 0.05 0.27 51 0.88 0,004 20,05 0.25 52 0.48 0,004 0.05 0.52 53 10.6 0.12 0.2 12.4 54 0.20 0.0012 0.2 55 0.86 0,014 0.05 56 0.32 0,012 0.05 57 0.38 0.0052 58 0,029 0,005 0.05 59 0.52 0,004 0.05 60 0.14 0,016 0.05 61 0.66 0,018 0.01 62 2.6 0,029

Numbers in brackets indicate the means obtained by another MED test is the minimum effective dose to observe inhibition of ras farnesylation

In vivo test

The compound described in Example 15 was tested for its ability to inhibit the growth of H61 cancer cells in nude mice. H61 are fibroblasts malignant by transfection with an activated mutant form of h-ras. Ten to 30 mg of H61 tumor fragments were inoculated SC (subcutaneously) in the axial region to female mice with a trocar needle on day 0 of the experiment. Mice were randomized into treatment groups and injected subcutaneously with the compound described in Example 15, suspended in 10% cremophor / 10% ethanol / 80% water, twice daily on days 3-17. On the twelfth day of the experiment, the mean tumor weight was 1958 mg as determined by caliper measurements. The mean tumor weight in animals treated with the compound of the invention described in Example 15 at 125 mg / kg / injection was 106 mg, indicated by 95% inhibition of tumor growth. The treatment regimen induced that tumor growth retardation and significant tumor growth inhibition occurred at dose levels of 125 and 78 mg / kg / injection. These doses were well tolerated with little or no toxicity.

Claims (28)

PATENT CLAIMS FROM 2Ιμ £ Λμ / | λΛζ 1 / StoééC.XzAx? MV / trCXX wherein, 21 is hydrogen or C1-C6 alkyl; rQ is or - (CH _O) ^2-pyrimidin ^ _/ ^Ci-Cg alkyl, N ^C 1 ^'C 6 ikyi ^and n is 0 or the A is -COR ^a , -CO ₂ R ^a ', -CONHR ^a ', -CSR ^a , -C (S) OR ^a ', -C (S) NHR ^a ', s II ABOUT II -SO ₂ R ^a , -CONR ^a R ^a , -CSR ^a or -C-NR ^a R ^a ; R ^a, R ^a and R ^La '' is independently a C -C alkyl, - (CH ₂ ) _m -cycloalkyl, - (CH ₂ ) _m -aryl, or - (CH ₂ ) _m -heteroaryl; each m is independently 0 to 3; R ¹ , R ² , and R ⁴ are independently hydrogen or C 1 -C 6 alkyl; ^{R 3 is} - (¾). - (CH _{2) m} -heteroaryl, - 100 - (CH (CH ₂ ) _m -naphthyl), -CH ₂ ) _m - (heteroaryl substituted with R ^b ) or C 1 -C 8 alkyl; t is 2 to 6; R ^b is -O-phenyl, -O-benzyl, halogen, C 1 -C 6 alkyl, hydrogen, -OC-Cg alkyl, -NH _2, -NHR ^a , NR ^and R ^a , 0 0 0 II II II -C ₁ -C ₈ alkyl, -C-aryl, -OH, -cf ₃ , -no ₂ COH. 0 0 || -COC-L-C8 alkyl, -CN, opo ₃ h ₂ , -ch ₂ after ₃ h ₂ , || -CO aryl, -CF ₂ CF ₃ , -SO ₂ R ^a , -SO ₂ NR ^and R ^a ', -CHO, -OCOCH ₃ , 0 0 ll -0 _{(CH2) m} -heteroaryl, || -CNR ^and R ^a in _A , -NH-CR ^and , -O- (CH ₂ ) _y NR ^a R ^a ', -O- (CH ₂ ) _m -cycloalkyl, - (CH ₂ ) _m -cycloalkyl, -O- (CH ₂ ) _m -aryl, - (CH ₂ ) _m -aryl or - (CH ₂ ) _m -heteroaryl; y is 2 or 3, · R ⁵ is - 101 R ¹ , R 4 and R 4 are independently hydrogen, halogen, -OC 1 -C 8 alkyl, C ₁ -C ₆ alkyl, -CN, -OPO ₃ H ₂ , ABOUT -NH-CR ^a , -CH ₂ PO ₃ H ₂ , -O-phenyl, -O-benzyl, -NH ₂ , -NHR ^a , -NR ^a R ^a OO -O- (CH ₂ ) y NR ^and R ^a , -C 1 -C 6 alkyl, -C-aryl, OH, CF ₃ , 0 0 0 -NO ₂ , -ίθΗ, -IOC-C 1-6 alkyl, -CO aryl, -N ₃ , -CF ₂ CF ₃ , -SO ₂ R ^a , -SO ₂ NR ^and R ^a ', -CHO or OCCH 3 a R ^c , R ^d , R ^e and R ^f are independently C 1 -C 8 alkyl, - (CH ₂ ) _m -phenyl, hydrogen, - (CH ₂ ) _m -OH, - (CH ₂ ) _m NH ₂ , - (CH ₂ ) _m -cycloalkyl or -CN and their pharmaceutically acceptable salts, esters, amides and prodrugs. A compound according to claim 1 ₍ of formula I) R ² is hydrogen, R is hydrogen, R ⁴ is hydrogen, R ² is H or CH _3; and A is C 1 -C 6 alkyl or A compound according to claim 1 of formula 1, R ³ is where - (CH ₂ ) m or _(CH2) m or -CH ₂ -CH (CH ₃ ) ₂ . R ¹ is hydrogen, R ² is hydrogen, R ⁴ is hydrogen and R ²¹ is hydrogen or ch ₃ . A compound according to claim 1 of formula I, wherein R ⁵ is 103 or wherein R * is hydrogen, Cl, Br, F or NH ₂ . 5.Compound of general formula, 12 II where Ci-Cgalkyl R is -O-benzyl, -NH-benzyl or -N-benzyl; R is hydrogen or methyl; R ⁷ is hydrogen or methyl; R is hydrogen, halogen, C 1 -C 6 alkyl, O-benzyl, -OC 1 -C 6 alkyl, -CF 3, -OH, -O- (CH ₂ ) _m -pyridyl or phenyl; '10' 11 '13' 14. . . . R, R, R, _and R are independently hydrogen, C 1 -C 6 alkyl or - (CHO) m-phenyl: 104 i k X F. _of R _and R is independently hydrogen, halogen, -OC 1 -C 6 alkyl,? C 1 -C 6 alkyl, NH NHR or NH 2, and pharmaceutically acceptable salts, esters, amides, prodrugs thereof. A compound according to claim 5 of formula II, wherein 11 14 F. _and ^R are methyl. A compound according to claim 5 of formula II, wherein F. is methyl or methoxy. wherein X is NH, O or -N (CH 3) 105 R is -O-benzyl, -CF 3, hydrogen, halogen, -OC 1 -C 6 alkyl, phenyl, -O- (CH 2) m Pyridyl or C 1 -C 6 alkyl; m is 0 to 3; and R is phenyl, hydrogen, or C 1 -C 6 alkyl, and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof. A compound of formula IV wherein X is NH, O or -N (CH 3); R is -O-benzyl, -CF3, hydrogen, halogen, C, -C6 alkyl, -O-CiCgalkyl, phenyl, or -O- (CH 2) m ^{- pyridinium} iclyl; 16 16 ' R and R is C 1 -C 6 alkyl; m is 0 to 3; and 21 R is hydrogen or methyl, and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof. A pharmaceutical acceptable composition comprising a compound according to claim 1. '_' 11 · Pharmaceutically acceptable composition, known— 106 comprising a compound of claim 5. 12. A pharmaceutically acceptable composition comprising a compound of claim 6. 13. A method of treating or preventing restenosis, the method comprising administering to a patient having or at risk of restenosis a therapeutically effective amount of a compound of claim 1. 14. A method of treating or preventing restenosis, the method comprising administering a therapeutically effective amount of a compound of claim 5 to a patient having or at risk of restenosis. 15. A method of treating or preventing restenosis, the method comprising administering to a patient having or at risk of restenosis a therapeutically effective amount of a compound of claim 6. 16. A method of treating cancer, the method comprising administering to a patient having cancer a therapeutically effective amount of a compound of claim 1. 17. A method of treating cancer, the method comprising administering therapeutically 107 an effective amount of a compound according to claim 5 to a patient having cancer. 18. A method of treating cancer, the method comprising administering to a patient having a cancer a therapeutically effective amount of a compound of claim 6. Compounds which are (S) - [1 - [(4-benzyloxybenzyl) - (phenethylcarbamoylmethyl) carbamoyl] -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1 - [[2-Benzyloxyethylcarbamoyl] methyl] - [4-chlorobenzyl] carbamoyl] -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1 - [(4-Benzyloxybenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl] -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1 - [(4-Benzyloxybenzyl) - [(2,2-diphenylethylcarbamoyl) methyl] carbamoyl] -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) -N- (4-Benzyloxybenzyl) -2- (3-benzylureido) -3- (1H-imidazol-4-yl) -N - [(2-phenylpropylcarbamoyl) methyl] propionamide. The method of claim 16, wherein the cancer is lung cancer, colon cancer, breast cancer, thyroid cancer, or bladder cancer. 21. A compound which is 108 (S) - [1 - {(4-Benzyloxybenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester. (S) - [1- {Biphenyl-4-ylmethyl - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1- (Biphenyl-4-ylmethyl - [(2-phenylpropylcarbamoyl) methyl] carbamoyl) -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1 - {(4-Benzyloxybenzyl) - [(S) - (1-methyl-2-phenyl) ethylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1 - {(4-Benzyloxybenzyl) - [(R) - (1-methyl-2-phenyl) ethylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1 - {(4-Benzyloxybenzyl) - [(2-phenylbutylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - (2- (1H-Imidazol-4-yl) -1 - {(4-methylbenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester; (S) - (2- (1H-Imidazol-4-yl) -1 - {(4-methoxybenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester; (S) - [1 - ((4-Benzyloxybenzyl) - {[2- (2-chlorophenyl) -2-phenylethylcarbamoyl] methyl} carbamoyl) -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; 109 (S) - [1 - {(4-Benzyloxybenzyl) - [(2-ethyl-2-phenylbutylcarbamoyl) methyl} carbamoyl} -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1 - {(2-Chlorobenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl] -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1 - ((4-Benzyloxybenzyl) - {[2- (2-chlorophenyl) propylcarbamoyl) methyl} carbamoyl) -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - (2- (1H-Imidazol-4-yl) -1 - ((2-methoxy benzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester; (S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-phenylpropylcarbamoyl) methyl] - [4- (pyridin-4-ylmethoxy) benzyl] carbamoyl} ethyl] carbamic acid benzyl ester; (S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-phenylpropylcarbamoyl) methyl] - [4- (pyridin-3-ylmethoxy) benzyl] carbamoyl} ethylcarbamic acid benzyl ester; (S) - {2- (1H-Imidazol-4-yl) -1 - [[(2-phenylpropylcarbamoyl) methyl] - (4-trifluoromethylbenzyl) carbamoyl] ethyl] carbamic acid benzyl ester; (S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-methyl-2-phenylpropylcarbamoyl) methyl] - [4- (pyridin-2-ylmethoxy) benzyl] carbamoyl} ethyl] benzyl ester butyl ester; (S) - [1- {Benzyl - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl) -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - (2- (1H-Imidazol-4-yl) -1 - {(4-methoxybenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester; 110 (S) - [1 - {(4-Benzyloxybenzyl) - [(2-cyano-2-phenylethylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) -2- (3-Benzyl-3-methylureido) -N- (4-benzyloxybenzyl) -3- (1H-imidazol-4-yl) -N - [(2-methyl-2-phenylpropylcarbamoyl) methyl] propionamide; (S) - [1 - [{(2- (2-Aminophenyl) propylcarbamoyl] methyl} - (4-benzyloxybenzyl) carbamoyl] -2H- (3H-imidazol-4-yl) ethyl] carbamate benzyl ester; (S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-methyl) benzyl ester 2-phenylpropylcarbamoyl) methyl] - [4- (pyridin-4-ylmethoxy) benzyl] carbamoyl} ethyl] carbamic; (S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-methyl) benzyl ester) 2-phenylpropylcarbamoyl) methyl] - [4-pyridin-3-ylmethoxy) benzyl] carbamoyl} ethyl) carbamic acid and (S) - (1- (cyclohexylmethyl - [(2-phenylpropylcarbamoyl) methyl) carbamoyl) methyl] carbamoyl} -2- ( 3H-imidazol-4-yl) -ethyl] -carbamic acid benzyl ester. (S) - [1 - ((4-Benzyloxybenzyl) - {[2- (2-fluorophenyl) ethylcarbamoyl] methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1 - {(4-Benzyloxybenzyl) - [(2-pyridin-2-yl) ethylcarbamoyl] methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1 - ((4-Benzyloxybenzyl) - {[2- (2-bromophenyl) ethylcarbamoyl] methyl} carbamoyl) -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; 111 (S) - [1 - {(4-Benzyloxybenzyl) - [(2-phenyl-2-pyridin-2-ylethylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazole benzyl ester) 4-yl) ethyl] carbamic; (S) - [1 - {(4-Chlorobenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) -N- (4-Benzyloxybenzyl) -3- (1H-imidazol-4-yl) -2- (3-phenylpropionylamino) -N - [(2-phenylpropylcarbamoyl) methyl] propionamide; (S) - [1 - ((4-Fluorobenzylbenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1 - {(4-Fluorobenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1- (Benzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) -N- (4-Benzyloxybenzyl) -2- (3-benzylureido) -3- (1H-imidazol-4-yl) -N - [(2-phenylpropylcarbamoyl) methyl] propionamide; (S) -N- (4-Benzyloxybenzyl) -2- (3-benzylureido) -3- (1H-imidazol-4-yl) -N - [(2-phenylbutylcarbamoyl) methyl] propionamide; (S) - [1 - {(4-Bromobenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1 - {(3-Chlorobenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1 - {(4-Chlorobenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; 112 (S) - (2- (1H-Imidazol-4-yl) -1 - {(3-methoxybenzyl) - [(2-phenylpropylcarbamoyl) methyl) carbamoyl) ethyl) carbamic acid benzyl ester; (S) - (2- {1H-Imidazol-4-yl) -1- (naphthalen-1-ylmethyl - [(2-phenylpropylcarbamoyl) methyl) carbamoyl} ethyl] carbamic acid benzyl ester; (S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-methyl) benzyl ester) 2-phenylpropylcarbamoyl) methyl] carbamoyl} pyridin-3-ylmethylcarbamoyl) ethyl] carbamic; (S) - (2- (1H-Imidazol-4-yl) -1 - {(2-methylbenzyl) - [(2-phenylpropylcarbamoyl) methyl] carbamoyl] ethyl] carbamic acid benzyl ester; (S) - (2- (1H-Imidazol-4-yl) -1 - {[2-methyl-2-phenylpropylcarbamoyl) methyl] pyridin-2-ylmethylcarbamoyl} ethyl] carbamic acid benzyl ester; (S) - (2- (1H-Imidazol-4-yl) -1 - {[3-methylbenzyl - [(2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl) carbamic acid benzyl ester; (S) -1 - {(4-dimethylaminobenzyl - [(2-phenylpropylcarbamoyl) methyl] carbamoyl] -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1 - {(4-benzyloxybenzyl - [(2-hydroxy) benzyl ester] 2-phenylethylcarbamoyl) methyl] carbamoyl} -2- (3H-imidazol-4-yl) ethyl] carbamic; (S) - [1 - ((4-Benzyloxybenzyl - {[2- (2-chloro-phenylethylcarbamoyl) methyl] carbamoyl) -2- (1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1 - {(4-Benzyloxybenzyl [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (1Himidazol-4-yl) ethyl] carbamic acid thiophen-3-ylmethyl ester; 113 (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-methylbenzyl - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester; (S) - (2- (1H-Imidazol-4-yl) -1 - {(2-methoxy benzyl - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl] carbamic acid benzyl ester; (S) -2- (3-Benzyl-3-methylureido) -N- (4-chlorobenzyl) -3- (1H-imidazol-4-yl) -N - [(2-methyl-2-phenylpropylcarbamoyl) methyl] propionamide; (S) - (2- (1H-Imidazol-4-yl) -1 - {(3-methoxy benzyl - ((2-methyl-2-phenylpropylcarbamoyl) methyl) carbamoyl} methyl) carbamic acid benzyl ester; (S) - (2- (1H-Imidazol-4-yl) -1 - {[(2-methyl) benzyl ester) 2-phenylpropylcarbamoyl) methyl] - [2-pyridin-4-ylmethoxy) benzyl] carbamoyl} ethyl] carbamic; and (2- (1-Imidazol-4-yl) -1- {isobutyl - [(2-phenylpropylcarbamoyl) methyl] carbamoyl] ethyl] carbamic acid benzyl ester. Compounds which are (S) - [1 - {(4-benzyloxybenzyl - [(2-phenylpentylcarbamoyl) methyl] carbamoyl] -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1 - {[2- (4-Benzyloxyphenyl) ethyl] - [{2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3H-imidazol-4-yl) ethyl] carbamate ; (S) - (2- (3H-Imidazol-4-yl) -1 - {[2- (4-methoxyphenyl) ethyl] - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} ethyl) carbamic acid benzyl ester; 114 (S) - [1 - [{[2- (2-Amino-phenyl) -ethylcarbamoyl] -methyl} - (4-benzyloxy-benzyl) -carbamoyl] -2- (3H-imidazol-4-yl) -ethyl] -carbamic acid benzyl ester; (S) - [1- (4-Benzyloxybenzyl - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3H-imidazol-4-yl) ethyl] methylcarbamic acid benzyl ester; (S) - {- ((4-Benzyloxybenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3-methyl-3Himidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1 - {(4-Benzyloxybenzyl) - ((2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl] -2- (1-methyl-1H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1 - {(4-Benzyloxybenzyl) [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3Himidazol-4-yl) ethyl] carbamic acid furan-2-ylmethyl ester; (S) - [1 - {(4-Benzyloxybenzyl) [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3Himidazol-4-yl) ethyl] carbamic acid thiophen-2-ylmethyl ester; (S) - [1 - {(4-Benzyloxybenzyl) [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3Himidazol-4-yl) ethyl] carbamic acid pyridin-3-ylmethyl ester; (S) - [1 - {(4-Benzyloxybenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl] -2- (3H-imidazol-4-yl) ethyl] carbamic acid 1H-imidazol-4-ylmethyl ester; (S) -2- (3-Benzylureido) -N- (4-chlorobenzyl) -3- (3H-imidazol-4-yl) -N - [(2-methyl-2-phenylpropylcarbamoyl) methyl] propionamide; 4-methoxybenzyl ester ( S) - [1 - {(4-benzyloxybenzyl) [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3Himidazol-4-yl) ethyl] carbamic; (S) -2- (3-Benzylthioureido) -3- (3H-imidazol-4-yl) -N- (4-methylbenzyl) -N - [(2-methyl-2-phenylpropylcarbamoyl) methyl] propionamide; 115 (S) -2-Acetylamino-N- (4-benzyloxybenzyl) -3- (3H-imidazol-4-yl) -N - [(2-methyl-2-phenylpropylcarbamoyl) methyl) propionamide; (S) - (2- (3H-Imidazol-4-yl) -1 - {[(2-methyl) benzyl ester 2-phenylpropylcarbamoyl) methyl-3-pyridin-4-ylmethylcarbamoyl} ethyl] carbamate; (S) - {2- (3H-Imidazol-4-yl) -1 - [(4-iodobenzyl) - (phenethylcarbamoylmethyl) carbamoyl) ethyl] carbamic acid benzyl ester; (S) - [1 - {(4-aminobenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl) carbamoyl} -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1 - ((4-Ethoxybenzyl) - [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3H-imidazol-4-yl) ethyl] carbamic acid benzyl ester; (S) - [1 - {[4- (2-dimethylaminoethoxybenzyl) [(2-methyl-2-phenylpropylcarbamoyl) methyl] carbamoyl} -2- (3Himidazol-4-yl) ethyl] carbamic acid benzyl ester; (2- (lH-imidazol-4-yl) -1- {isobutyl - [(2-methyl-2-phenylpropylcarbamoyl) -methyl] -carbamoyl) -ethyl] carbamate. 25. A method of treating a viral infection, which method comprises administering to a patient having a viral infection a therapeutically effective amount of a compound of claim 1. 26. A method of treating a viral infection, which method comprises administering to a patient having a viral infection a therapeutically effective amount of a compound according to claim 5. 27. A method of treating a viral infection, which method comprises administering a serum 116 a peutically effective amount of a compound according to claim 6 to a patient having a viral infection. 28. A method of treating psoriasis, the method comprising administering to a patient having psoriasis a therapeutically effective amount of a compound of claim 1. 29. A method of treating psoriasis, the method comprising administering to a patient having psoriasis a therapeutically effective amount of a compound of claim 5. 30. A method of treating psoriasis, the method comprising administering to a patient having psoriasis a therapeutically effective amount of a compound of claim 6.