AU728477B2 - Inhibitors of protein farnesyltransferase - Google Patents

Description

WO 97/44350 PCT/US97/06591 -1- INHIBITORS OF PROTEIN FARNESYLTRANSFERASE The present invention relates to compounds that can be used in the medicinal field to treat, prophylactically or otherwise, uncontrolled or abnormal proliferation of human tissues. Specifically, the present invention relates to compounds that inhibit the farnesyl transferase enzyme, which has been determined to activate ras proteins that in turn activate cellular division and are implicated in cancer and restenosis.

BACKGROUND OF THE INVENTION Ras protein (or p21) has been examined extensively because mutant forms are found in 20% of most types of human cancer and greater than 50% of colon and pancreatic carcinomas (Gibbs Cell, 1991;65:1, Cartwright et al., Chimica. Oggi 1992;10:26).

These mutant ras proteins are deficient in the capability for feedback regulation that is present in native ras, and this deficiency is associated with their oncogenic action since the ability to stimulate normal cell division cannot be controlled by the normal endogenous regulatory cofactors. The recent discovery that the transforming activity of mutant ras is critically dependent on post-translational modifications (Gibbs et al., Microbiol. Rev., 1989;53:171) has unveiled an important aspect of ras function and identified novel prospects for cancer therapy.

In addition to cancer, there are other conditions of uncontrolled cellular proliferation that may be related to excessive expression and/or function of native ras proteins. Post-surgical vascular restenosis is such a condition. The use of various surgical WO 97/44350 PCT/US97/06591 -2revascularization techniques such as saphenous vein bypass grafting, endarterectomy, and transluminal coronary angioplasty are often accompanied by complications due to uncontrolled growth of neointimal tissue, known as restenosis. The biochemical causes of restenosis are poorly understood and numerous growth factors and protooncogenes have been implicated (Naftilan et al., Hypertension, 1989;13:706 and J. Clin. Invest., 83:1419; Gibbons et al., Hypertension, 1989;14:358; Satoh et al., Molec.

Cell. Biol., 1993;13:3706). The fact that ras proteins are known to be involved in cell division processes makes them a candidate for intervention in many situations where cells are dividing uncontrollably. In direct analogy to the inhibition of mutant ras related cancer, blockade of ras dependant processes has the potential to reduce or eliminate the inappropriate tissue proliferation associated with restenosis, particularly in those instances where normal ras expression and/or function is exaggerated by growth stimulatory factors.

Ras functioning is dependent upon the modification of the proteins in order to associate with the inner face of plasma membranes. Unlike other membraneassociated proteins, ras proteins lack conventional transmembrane or hydrophobic sequences and are initially synthesized in a cytosol soluble form.

Ras protein membrane association is triggered by a series of post-translational processing steps that are signaled by a carboxyl terminal amino acid consensus sequence that is recognized by protein farnesyl transferase (PFT). This consensus sequence consists of a cysteine residue located four amino acids from the carboxyl terminus, followed by two lipophilic amino acids, and the C-terminal residue. The sulfhydryl group of the cysteine residue is alkylated WO97/44350 PCT/US97/06591 -3by farnesylpyrophosphate in a reaction that is catalyzed by protein farnesyl transferase. Following prenylation, the C-terminal three amino acids are cleaved by an endoprotease and the newly exposed alphacarboxyl group of the prenylated cysteine is methylated by a methyl transferase. The enzymatic processing of ras proteins that begins with farnesylation enables the protein to associate with the cell membrane.

Mutational analysis of oncogenic ras proteins indicate that these post-translational modifications are essential for transforming activity. Replacement of the consensus sequence cysteine residue with other amino acids gives a ras protein that is no longer farnesylated, fails to migrate to the cell membrane and lacks the ability to stimulate cell proliferation (Hancock et al., Cell, 1989;57:1617, Schafer et al., Science, 1989;245:379, Casey Proc. Natl. Acad. Sci. USA, 1989;86:8323).

Recently, protein farnesyl transferases (PFTs, also referred to as farnesyl proteintransferases (FPTs) have been identified and a specific PFT from rat brain was purified to homogeneity (Reiss et al., Bioch.

Soc. Trans., 1992;20:487-88). The enzyme was characterized as a heterodimer composed of one alphasubunit (49kDa) and one beta-subunit (46kDa), both of which are required for catalytic activity. High level expression of mammalian PFT in a baculovirus system and purification of the recombinant enzyme in active form has also been accomplished (Chen et al., J. Biol. Chem., 1993;268:9675).

In light of the foregoing, the discovery that the function of oncogenic ras proteins is critically dependent on their post-translational processing provides a means of cancer chemotherapy through inhibition of the processing enzymes. The identification and isolation of a protein farnesyl

I

WO 97/44350 PCT/US97/06591 -4transferase that catalyzes the addition of a farnesyl group to ras proteins provides a promising target for such intervention. Ras farnesyl transferase inhibitors have been shown to have anticancer activity in several recent articles.

Ras inhibitor agents act by inhibiting farnesyl transferase, the enzyme that anchors the protein product of the ras gene to the cell membrane. The role of the ras mutation in transducing growth signals within cancer cells relies on the protein being in the cell membrane so with farnesyl transferase inhibited, the ras protein will stay in the cytosol and be unable to transmit growth signals: these facts are well-known in the literature.

A peptidomimetic inhibitor of farnesyl transferase B956 and its methyl ester B1086 at 100 mg/kg have been shown to inhibit tumor growth by EJ-1 human bladder carcinoma, HT1080 human fibrosarcoma and human colon carcinoma xenografts in nude mice (Nagasu, et al., Cancer Res., 1995;55:5310-5314). Furthermore, inhibition of tumor growth by B956 has been shown to correlate with inhibition of ras posttranslational processing in the tumor. Other ras farnesyl transferase inhibitors have been shown to specifically prevent 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 et al., Cancer Res., 1995;55:4243-4247), a ras farnesyl transferase inhibitor FTI276 has been shown to selectively block tumor growth in nude mice of a human lung carcinoma with K-ras mutation and p53 deletion. In yet another report, daily administration of a ras farnesyl transferase inhibitor L-744,832 caused tumor regression of mammary and salivary carcinomas in ras transgenic WO 97/44350 PCT/US97/06591 mice (Kohl et al., Nature Med., 1995;1(8):792-748).

Thus, ras farnesyl transferase inhibitors have benefit in certain forms of cancer, particularly those dependent on oncogenic ras for their growth. However, it is well-known that human cancer is often manifested when several mutations in important genes occurs, one or more of which may be responsible for controlling growth and metastases. A single mutation may not be enough to sustain growth and only after two of three mutations occur, tumors can develop and grow. It is therefore difficult to determine which of these mutations may be primarily driving the growth in a particular type of cancer. Thus, ras farnesyl transferase inhibitors can have therapeutic utility in tumors not solely dependent on oncogenic forms of ras for their growth. For example, it has been shown that various ras FT-inhibitors have antiproliferative effects in vivo against tumor lines with either wildtype or mutant ras (Sepp-Lorenzino, supra.). In addition, there are several ras-related proteins that are prenylated. Proteins such as R-Ras2/TC21 are rasrelated proteins that are prenylated in vivo by both farnesyl transferase and geranylgeranyl transferase I (Carboni, et al., Oncocene, 1995;10:1905-1913).

Therefore, ras farnesyl transferase inhibitors could also block the prenylation of the above proteins and therefore would then be useful in inhibiting the growth of tumors driven by other oncogenes.

With regard to the restenosis and vascular proliferative diseases, it has been shown that inhibition of cellular ras prevents smooth muscle proliferation after vascular injury in vivo (Indolfi C, et al., Nature Med., 1995;1(6):541-545). This report definitively supports a role for farnesyl transferase inhibitors in this disease, showing inhibition of S@cwnatc d pZoOzertjc of vasculswm@ SUWMay OF TMU niCr' SAccording to a first aspect, the present invention provides a compouncj having the Formula

I

A-N.

where in R21 is hydrogen. .or C, -c6 alkyl; I42 n 2) n

C

1

-C

6 alky! rC. C 6 alky2.

i A is o or 1; -CORa, -CO 2 Ra CONHa', -CSRa, -C ORa, 30-

I

-C N1a.

_SO

2 Ra, -CONRaRa' -CSRa, or

S

I aa -C-NRRa Ra, Ra', and Ra are independently Cl-C 6 alkyl, ~(OI2) m-cycloalkyl,

-(CH

2 )m-aryl, or -(CH2) Mhe teroaxyl; each a is detly 0 to 3; RI, R 2 and R4 are indeparxdently brydrogOn or lC alkyl; WO 97/44350 WO 9744350PCT[US97/06591 -7- Rb

R

3 is -(CH 2 m (CH 2 )m-heteroaryl,

-(C

2 )C (c 2 t CH 2 m-naphthyl,

-(CH

2 )m-(heteroaryl substituted with Rb), or

C

1

-C

6 alkyl; t is 2 to 6; Rb is -0-phenyl, -O-benzyl, halogen, C 1

-C

6 alkyl, hydrogen, -0-C 1

-C

6 alkyl, -NH 2 -NHRa, NRaRa,' 0 0

-CC-

1

-C-

6 alkyl, -C-aryl, -OH, -CF 3

-NO

2 0 0 -CO, -OC 1

C

6 alkyl, -CN, -0P0 3

H

2 0

-CH

2

PO

3

H

2 -C..aryl, -N 3

-CF

2

CF

3

-SO

2 Ra,

_SO

2 NRaRa,' -CHO, -OCOCH 3 or -O(CH 2 0 0 heteroaryl, -kCNRaRa NH-C-Ra, (CH 2 )yNRaRa'; -0 (CH 2 )m-cycloalkyl, (CH 2 )m-cycloalkyl, -0(CH 2 )m-aryl, -(CH 2 )m-aryl, or

(CH

2 )m-heteroarYl; y is 2 or 3;

R

5 is Tc T Ri N -C-C R

I

QRc Re

R

N I ;:R -8- Re R

Q

and Rh are independentl hydro halogen -C6 alkyl, C._C Y hdroenhalgen 002 I i -N h1-C Ra z'.3 1 b n y 0 1 -v(Ci2),NRa a _N-zaRa -or, 20 0 0 alkyl, 0 3, NO f 0 0 -CF6 -C C 1.O a k v l -CO aryl,

-N

3 -CF 2 3,

-SO

2 Ra _So or -OCOCE 3 aad ,a pd 3; Ed2RCO lRR ad R' are independent C-C all 2(C 2)m-Phe 2 ya hydroge. -CH .6 0 v1 ~(CF2)rrncycloalkyl Or -CN, E 0 the Pharmaceutically acceptable salts, esters, amides, and prodruos thereof "'ith the DrOVic^ 1, 2 1 i t e t e r eo a l a n d R a r e n o t a l l h y d r o g e n w h e n R 2 1 R 4 a n d 1 RCt Rtare roen.

In a preferred embodiment of the compounds of Formula

I

R1 is hydroge.

R

2 is hydrogen. R is hydrogen,

R

2 1 is hydrocgen or CH3. and 8a A is -c :I E 0 v or -C-N-CH2Q 0 c 1

-C

6 alkyl WO 97/44350 PCT/US97/06591 -9- In another preferred embodiment of the compound of Formula I

R

3 is Rb (CH2o -(CH 2 )m or -CH 2

-CH(CH

3 2

R

1 is hydrogen, R 2 is hydrogen, R 4 is hydrogen, and R 2 1 is hydrogen or CH 3 In another preferred embodiment of the compounds of Formula I WO 97/44350 WO 9744350PCTIUS97/06591

R

5 is -CH 2

CH

2

O-CH

2 K) -CH 2

CH

0lQ

N

CH

3

-CH

2 .or

-CH

2

CH

2 where R' is hydrogen, Cl, Br, F, or NH 2 -21- According to a second aspect, the invention provides a compound having the Formula 11 wherein C6alkyl R' is -0-benzyl, -NE-benzyl, or -N-benzyl; I2 1is hydrogen or methyl; R7 i s hydrogen or methyl; R8 is hnydrogen, halogen, C,-C6 alkyl, -O-benzy!,

-OC,-C

6 alkyl, -CF 3 H O(~ 2 ~prc~,o phenyl;

R

1 R, -3 and Ri 4 ar ndepe-ndentlyv hydr:Logen, C -C 6 alkyl, Or (CH 2 )m-phenyl; each n is independently 0 to 3; RI-2 4 I -S or k 2 Rk N ;and RRk, and Rlare independently hydrogen, halogen, -0C 1

-C

6 alkyl, -Cl-C 6 alkyl, -NaR, or NH2, and the pha rmaceuti cally acceptable salts, esters, amides, and prodrugs thereof.

-7 lla- R a is C, -C 6 alkyl, -(CH 2 -cycloalkyl, -(CH 2 or -(CH 2 ).,-heteroaryl.

with the proviso that R to R' are not all hydrogen when R1 0

R"

3 and R' 4 are all hydrogen.

In a preferred embodiment of the compounds of Formula 11, R" and R 1 4 are 12- In another preferred embodiment of the compounds for Formula I, R! is methyl or methoxy.

According to a third aspect, the invention provides a compound having the Formula III

R

1 6 H H X N N

N

O III HN, N 8

R

1 wherein X is NH, O, or -N(CH3)

R

1 5 is -0-benzyl, -CF 3 hydrogen, halogen, alkyl, phenyl, -0-(CH 2 )m-pyridyl, or

-C

1

-C

6 alkyl; m'is 0 to 3; and

R

1 6 is a phenyl, hydrogen, or C 1

-C

6 alkyl, and the pharmaceutically acceptable salts, esters, amides, an; prodrugs thereof.

According to a fourth aspect, the invention provides a compound having the Formula IV 21 R2 1 6

R

20 X-:C-NH C 0 r 16 IV

::R

IDOC

12a wherein X is NH, 0, or N(CH 3 R1 5 is -O-benzyl, -C3 hydrogen, halogen, Cl-C 6 alkyl, -0-C 1

-C

6 alkyl, phenyl, or (CH 2 )m-pyridyl; R1 and R 1 6 1 are C 1

-C

6 al1kyl; m is 0 to 3; and WO 97/44350 PCT/US97/06591 -13-

R

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

In another aspect, the present invention provides a pharmaceutically acceptable composition that comprises a compound of Formula I, II, III, or IV.

Also provided is a method of treating or preventing restenosis, the method comprising administering to a patient having restenosis or a risk of having restenosis a therapeutically effective amount of a compound of Formula I, II, III, or IV.

Also provided is 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.

Also provided is 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.

Also provided is a method of treating viral infection, the method of 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 more 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)-[l-[(4-Benzyloxy-benzyl)-(phenethyl-carbamoylmethyl)-carbamoyl]-2-(3H-imidazole-4-yl)-ethyl]carbamic acid benzyl ester; (S)-[l-[[2-Benzyloxy-ethylcarbamoyl]-methyl]-[4chlorobenzyl]-carbamoyl]-2-(1H-imidazole-4-yl)-ethyl]carbamic acid benzyl ester; WO 97/44350 PCTIUS97/06591 -14- [(4-Benzyloxy-benzyl) [(2-phenyl-propylcarbamoyl) -methyl) -carbarnoyl] (1H-imidazole-4-yl) ethyllcarbamic acid benzyl ester; (4-Benzyloxy-benzyl) 2-diphenylethylcarbamoyl) -methyl] -carbamoyl] (lH-imidazole-4yl)-ethyl]-carbamic acid benzyl ester; (4-Benzyloxy-benzyl) (3-benzyl-ureido) 3- C1H-imidazole-4-yl) 2 -phenyl-propylcarbamoyl) methyl] -prop ionamide; (S)-[l-{Biphenyl-4-ylmethyl-[ (2-methyl-2-phenylpropylcarbamoyl) -methyl] -carbamoyl)-2- (lH-imidazole- 4-yl)-ethyl]-carbamic acid benzyl ester; -[l-{Biphenyl-4-ylmethyl- [(2-phenylpropylcarbamoyl) -methyl) -carbamoyl) (lH-imidazole- 4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[l-((4-Benzyloxy-benzyl)-{[2-(2-fluorophenyl) -ethylcarbamoyl) -methyl}-carbamoyl) (liiimidazole-4-yl) -ethyl] -carbamic acid benzyl ester; [1-f (4-Benzyloxy-benzyl) (2-pyridin-2-ylethylcarbamoyl) -methyl] -carbamoyl) (1H-imidazole- 4-yl)-ethyl]-carbamic acid benzyl ester; (4-Benzyloxy-benzyl)-( (2-bromo-phenyl)ethylcarbamoyl] -methyll-carbamoyl) (1H-imidazole-4yl)-ethyl]-carbamic acid benzyl ester; (4-Benzyloxy-benzyl)- C-methyl-2-phenylethylcarbamoyl) -methyl] -carbamoyl) (lH-imidazole- 4-yl)-ethyl]-carbamic acid benzyl ester; (4-Benzyloxy-benzyl) (2-phenyl-2-pyridin- 2-yl-ethylcarbamoyl) -methyl) -carbamoyl)-2-(lHimidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (4-Chloro-benzyl) (2-phenylpropylcarbamoyl) -methyl] -carbamoyl) (1Himidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (4-Benzyloxy-benzyl)- [(2-phenylbutylcarbamoyl) -methyl] -carbamoyll (11--imidazole- 4-yl)-ethyl)-carbamic acid benzyl ester; WO 97/44350 WO 9744350PCTIUS97/06591 (4-Benzyloxy-benzyl) (lH-imidazole-4-yl) 2- (3-phenyl-propionylanino) -N-[(2-phenylpropylcarbamoyl) -methyl] -propionamide; (4-Fluoro-benzyl) (2-phenyl-propylcarbamoyl) -methyl] -carbamoyl)-2- (lH-imidazole-4yl)-ethyl]-carbamic acid benzyl ester; (lH-Imidazole-4-yl) -1-f(4-methyl-benzyl) [(2-phenyl-propylcarbamoyl) -methyl] -carbamoyl)ethyl)-carbamic acid benzyl ester; (S)-(2-(lH-Imidazole-4-yl) (4-rethoxy-benzyl) -phenyl-propylcarbamoyl) -methyl] -carbamoyl) ethyl)-carbamic acid benzyl ester; (2-Amino-phenyl) -propylcarbamoyl] methyl)- (4-benzyloxy-benzyl) -carbamoyl] (3Himidazole-4-yl)-ethyl]-carbamic acid benzyl ester; [1-f(4-Fluoro-benzyl) [(2-methyl-2-phenylpropylcarbamoyl) -methyl] -carbamoyl}--2- (lI--imidazole-4yl)-ethyl]-carbamic acid benzyl ester; -[l-{Benzyl- [(2-phenyl-propylcarbamoyl) methyl]-carbamoyl}-2-(lH-imidazole-4-yl)-ethyl]carbamic acid benzyl ester; (S)-[1-((4-Benzyloxy-benzyl)-{[2-(2-chlorophenyl) -2 -phenyl-ethylcarbamoyl] -methyl) -carbamoyl) 2- (lH-imidazole-4-yl) -ethyl] -carbamic acid benzyl ester; (4-Benzyloxy-benzyl)-[ (2-ethyl-2-phenylbutylcarbamoyl) -methyl] -carbamoyl) (3H-imidazole- 4-yl)-ethyl]-carbamic acid benzyl ester; (4-Benzyloxy-benzyl) (3-benzyl-ureido) -3- (lH-imidazole-4-yl) [(2-phenyl-propylcarbamoyl) methyl] -propionamide; (4-Benzyloxy-benzyl) (3-benzyl-ureido) -3- (lH-imidazole-4-yl) [(2-phenyl--butylcarbamoyl) methyl] -propionamide; WO 97/44350 WO 9744350PCT/US97/06591 -16- (2-Chloro-benzyl) (2-phenylpropylcarbamoyl) -methyl] -carbarnoyl) (1Himidazole-4-y1) -ethyl] -carbamic acid benzyl ester; (4-Bromo-benzyl) (2-phenylpropylcarbamoyl) -methyl] -carbamoyl 1-2- (1Himidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (3-Chloro-benzyl) (2-phenylpropylcarbamoyl) -methyl] -carbamoyl 1-2 (Himidazole-4-yl) -ethyl] -carbamic acid benzyl ester; (4-Chloro-benzyl)-[(2-methy1-2-phenylpropylcarbamoyl) -methyl] -carbarnoyl)-2- (1H-imidazole-4yl)-ethyl]-carbamic acid benzyl ester; ((4-Benzyloxy-beizyl) (2-chlorophenyl) -propylcarbamoyl] -methyl)-carbamoyl) (lHimidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-(2-(lH-Imidazole-4-yl) -1-f(2-methoxy-benzyl)- (2-phenyl-propylcarbamoyl) -methyl] -carbamoyl 1ethyl)-carbamic acid benzyl ester; (S)-(2-(1H-Imidazole-4-yl)-l-{ [(2-phenylpropylcarbamoyl) -methyl] (pyridin-4-ylmethoxy) benzyl] -carbamoyl) -ethyl) -carbamic acid benzyl ester; (S)-(2-(lH-Imidazole-4-yl)-1-{ (3-methoxy-benzyl)- [(2-phenyl-propylcarbamoyl) -methyl] -carbamoyl)-ethyl) carbamic acid benzyl ester; (S)-(2-(1H-Imidazole-4-yl)-l-f [(2-phenylpropylcarbamoyl) -methyl] (pyridin-3-ylmethoxy) benzyl] -carbamoyl) -ethyl) -carbanic acid benzyl ester; -(S)-(2-(lH-Imidazole-4-yl) -l-{naphthalen-lylmethyl- -phenyl-propylcarbamoyl) -methyl] carbamoyll-ethyl)-carbamic acid benzyl ester; (S)-(2-(1H-Imidazole-4-yl)-l- [[(2-phenylpropylcarbamoyl) -methyl] -(4-trifluoromethyl-benzyl) carbamoyl] -ethyll -carbamic acid benzyl ester; (lH-Imidazole-4-yl) [(2-methyl-2-phenylpropylcarbamoyl) -methyl] -pyridin-3-ylmethyl-carbamoyl} ethyl)-carbamic acid benzyl ester; WO 97/44350 WO 9744350PCT/US97/06591 -17- (S)-(2-(lH-Imidazole-4-yl)-.-{[ (2-methyl-2-phenylpropylcarbamoyl) -methyl] (pyridin-2-ylmethoxy) benzyl] -carbamoyl)-ethyl) -carbamic acid benzyl ester; El- (Benzyl- [(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(li-imidazole-4yl).

ethyl]-carbamic acid benzyl ester; (S)-(2-(lH-Imidazole-4-yl)-l-{ (2-methyl-benzyl)- 2 -phenyl-propylcarbamoyl) -methyl)I-carbamoyl} -ethyl) carbamic acid benzyl ester; (S)-(2-(lH-Imidazole-4-yl) -1-f(4-methoxy-benzyl)- 2 -methyl-2-phenyl-propylcarbamoyl) -methyl] carbamoyl) -ethyl) -carbamic acid benzyl ester; (4-Benzyloxy-benzyl)-[(2-cyano-2-phenylethylcarbamoyl) -methyl] -carbamoyl) (lH-imidazole- 4-yl)-ethyl]-carbamic acid benzyl ester; (S)-(2-(lH-Imidazole-4-yl)-l-( [(2-methyl-2-phenylpropylcarbamoyl) -methyl] -pyridin-2-ylmethyl-carbamoyl} ethyl)-carbanic acid benzyl ester; (S)-(2-(lH-Imidazole-4-yl)-1-{ (3-methyl-benzyl)- [(2-phenyl-propylcarbamoyl) -methyl] -carbamoyl) -ethyl) carbamic acid benzyl ester; [1-f (4-Dimethylamino-benzyl) -[E(2-phenylpropylcarbamoyl) -methyl] -carbamoyl 1-2- (lH-imidazole-4 yl)-ethyl]-carbanic acid benzyl ester; (S)-(2-(lH-Imidazole-4-yl)-l-{ [(2-methyl-2-phenylpropylcarbamoyl) -methyl] (pyridin-4-ylmethoxy) benzyl] -carbamoyl)-ethyl) -carbamic acid benzyl ester; (lH-Imidazole-4-yl) [(2-methyl-2-phenylpropylcarbamoyl) -methyl] (pyridin-3-ylmethoxy) benzyl] -carbamoyl) -ethyl) -carbamic acid benzyl ester; (l-H-imidazole-4-yl)-l-{isobutyl-[ (2-phenylpropylcarbamoyl) -methyl] -carbamoyl 1-ethyl) -carbamic acid benzyl ester; (4-Benzyloxy-benzyl)- [(2-methyl-2-phenylpropylcarbamoyl) -methyl] -carbamoyl}-2- (3H-imidazole- 4-yl)-ethyl]-carbamic acid benzyl ester; WO 97/44350 WO 9744350PCTIUS97/06591 -18- (3-Berzyl-3-methyl-ureido) (4-benzyloxybenzyl)-3-(1H-imidazole-4-yl) (2-methyl-2-phenylpropyilcarbamoyl) -methyl] -propionamide; {(4-Benzyloxy-benzyl) (2-hydroxy-2-phenylethylcarbamoyl) -methyl] -carbamoyl) (3H-imidazole-4yl) -ethyl] -carbamic acid benzyl ester; (lH-Imidazole-4-yl) -1-f (C4-methoxy-benzyl) [C2-phenyl-propylcarbamoy.) -methyl] -carbamoyll -ethyl) carbamic acid benzyl ester; (S)-[l-((4-Benzyloxy-benzyl)-{[2-(2-chlorophenyl) -ethylcarbamoyl] -methyl) -carbamoyl) (lHimidazole-4-yl)-ethyl]-carbamic acid benzyl ester; [1-f(4-Benzyloxy-benzyl)-[(2-methyl-2-phenylpropylcarbamoyl) -methyl] -carbamoyl)-2- (lH-imidazole-4yl)-ethyl]-carbamic acid thiophen-3-ylmethyl ester; (4-Chloro-benzyl) (2-rnethyl-2-phenylpropylcarbamoyl) -ethyl] -carbamoyl} (31-imidazole-4ylL)-ethyl]-carbamic acid benzyl ester; (lH-Imidazole-4-yl)-1-f{ (4-methyl-benzyl) [(2-methyl-2-phenyl-propylcarbanoyl) -methyl] carbamoyl) -ethyl) -carbamic acid benzyl ester; (S)-(2-(lH-Imidazole-4-yl) -1-f 2-methoxy-benzyl) (2-methyl-2-phenyl-propylcarbanoyl) -methyl] carbamoyl}-ethyl) -carbamic acid benzyl ester; (S)-2-(3-Benzyl-3-methyl-ureido)-N-(4-chlorobenzyl) (lH-imidazole-4-yl) -N-I (2-methyl-2-phenylpropylcarbamoyl) -methyl] -propionamide;I (S)-(2-(lH-Imidazole-4-yl)-l-f (3-methoxy-benzyl)- [(2-methyl-2-phenyl-propylcarbanoyl) -methyl] carbamoyl)-ethyl)-carbamic acid benzyl ester; (2-(lH-Imidazole-4-yl)-1-( [(2-methyl-2-phenylpropylcarbamoyl) -methyl] (pyridin-4-ylnethoxy) benzyl] -carbamoyl}-ethyl) -carbaiic acid benzyl ester; Cyclohexylmethyl- [(2-phenylpropylcarbamoyl) -methyl] -carbamoyl}-2- (3H-imidazole- 4-yl) -ethyl] -carbamic acid benzyl ester; WO 97/44350 WO 9744350PCTIUS97/06591 -19- (4-Benzyloxy-benzyl) (2-phenyl-pentylcarbamoyl) -methyl] -carbarnoyl)-2- (3H-imidazole-4yl)-ethylfl-carbamic acid benzyl ester; S)-[l-u[2-4-Benzyloxy-phenyl)-ethyl]-[(2-methyl.

2-phenyl-propylcarbamoyl) -methyl] -carbamoyll (3Himidazole-4-yl) -ethyl] -carbamic acid benzyl ester; (3H-Imidazole-4-yl) (4-methoxyphenyl) -ethyl] 2 -methyl-2-phenyl-propylcarbamoyl) methyl] -carbamoyll-ethyl) -carbamic acid benzyl ester; [2-(2-Amino-phenyl)-ethylcarbamoyl]methyl)- (4-benzyloxy-benzyl) -carbamoyl] (3Himidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (2-(lH-imidazol-4-yl)-l-(isobutyl-[ (2-phenylpropylcarbamoyl) -methyl] -carbamoyl}-ethyl) -carbamic acid benzyl ester; (4-Benzyloxy-benzyl) (2-methyl-2-pheiylpropylcarbamoyl) -methyl] -carbamoyl) (3H-imidazole- 4-yl)-ethyl]-methyl-carbamic acid benzyl ester; (4-Benzyloxy-benzyl) (2-methyl-2-phenylpropylcarbamoyl) -methyl] -carbamoyl)-2- (3-methyl-3Himidazole-4-yl)-ethyl]-carbamic acid benzy. ester; (4-Benzyloxy-benzyl) (2-methyl-2-phenylpropylcarbamoyl) -methyl] -carbamoyl)-2- (l-methyl-lHimidazole-4-yl)-ethyl]-carbanic acid benzyl ester; (4-Benzyloxy-benzyl)-[ (2-methyl-2-phenylpropylcarbamoyl) -methyl] -carbamoyl}-2- (3H-imidazole- 4-yl) -ethyl] -carbamic acid furan-2-ylmethyl ester; (4-Benzyloxy-benzyl) (2-methyl-2-phenylpropylcarbamoyl) -methyl] -carbamoyl)-2- (3H-imidazole- 4-yl)-ethyl]-carbamic acid thiophen-2-ylmethyl ester; (4-Benzyloxy-benzyl)-[ (2-methyl-2-phenylpropylcarbamoyl) -methyl] -carbamoyl) (3H-imidazole- 4-yl) -ethyl] -carbamic acid pyridin-3-ylmethyl ester; (4-Benzyloxy-benzyl)-[ (2-methyl-2-phenylpropylcarbamoyl) -methyl] -carbamoyl)-2- (3H-imidazole-4yl) -ethyl] -carbamic acid IH-imidazole-4-ylmethyl ester; (3-Benzyl-ureido) (4-chloro-benzyl) (3Himidazole-4-yl) (2-methyl-2-phenyl-propylcarbamoyl)methyl]I -propionamide; (4-Benzyloxy-benzyl) -[f(2-methyl-2-phenylpropylcarbamoyl) -methyl] -carbamoyl)-2- (3H-imidazole- 4-yl) -ethyl] -carbamic acid 4-methoxy-benzyl ester; (3-Benzyl-thioureido) (3H-imidazole- 4-yl) (4-methyl-benzyl) -N-f (2-methyl-2-phenylpropylcarbamoyl) -methyl] -propionamide; -2-Acetylamino-N- (4-benzyloxy-benzyl) (3Himidazole-4-yl) (2-methyl-2-phenyl-propycarbamoyl) methyl] -propionamide; (S)-(2-(3H-Imidazole-4-yl)-l-U[(2-methyl-2-phenylpropylcarbamoyl) -methyl] -pyridin-4-ylmethylcarbamoyl)-ethyl) -carbamic acid benzyl ester; (3H-Imidazole-4-yl) ((4-iodo-benzyl) (phenethylcarbamoyl -methyl) -carbamoyl] -ethyl) -carbarmic acid benzyl ester; (4 -Amino -benzyl) (2-methyl-2-phenylpropyl carbamoyl) -methyl] -carbamoyl} (3H-imidazole- 4-yl) -ethyl] -carbamic acid benzyl ester; -fl-f( (4-Ethoxy-benzyl) C (2-methyl-2-phenylpropylcarbanoyl) -methyl]I -carbamoyl) -2 (3H-imidazole- 4-yl)-ethyl]-carbamic acid benzyl ester; (2-Dimethylamino-ethoxy)-benzyl]-.(2me thyl1- 2 -phenyl1-propyl carbamoyl1) -me thyl]1 carbamoyl} -2 (3E-imidazole-4-yl) -ethyl] -carbanic acid benzyl ester; and 2-ohenyl-oropy. carbamoyl) -methyl] -carbamoyll -ethyl) ::car-bamic acid benzyl ester.

According to a fifth aspect, the invention provides a pharmaceutically acceptable composition that comprises a compound according to the first aspect.

According to a sixth aspect, the invention provides a pharmaceutically acceptable composition that comprises a compound according to the second aspect.

According to a seventh aspect, the invention provides a pharmaceutically acceptable composition that comprises a compound according to the second aspect wherein and R 1 4 are methyl.

According to an eighth aspect, the invention provides a method of treating or preventing restenosis, the method comprising administering to a patient having restenosis or at risk of having restenosis a therapeutically effective amount of a compound according to the first aspect.

According to a ninth aspect, the invention provides a method of treating or preventing restenosis, the method comprising administering to a patient having restenosis or at risk of having restenosis a therapeutically effective amount of a compound according to the second aspect.

.o According to a tenth aspect, the invention provides a method of treating or 9* preventing restenosis, the method comprising administering to a patient having *restenosis or at risk of having restenosis a therapeutically effective amount of a compound according to the second aspect wherein and R 14 are methyl.

1478-00.DOC According to an eleventh aspect. the invention provides a method of treatingz cancer. the method comprising administering to a patient having cancer a therapeutically effective amount of a compound according to the first aspect.

According to a twelfth aspect. the invention provides a method of treating cancer, Sthe method. comprising administering to a patient having cancer a therapeutically effective amount of a compound according to the second aspect.

Ac cording to a thirteenth aspect, the invention provides a method of treating cancer, the method comprising administering to a patient having cancer a therapeutically effective amount of a compound according to the second aspect wherein R' 1 and R 1 4 are methyl.

According to a fourteenth aspect. the invention provides the compounds E 4-Benzyloxy-beznzyl) (phenethylcarbamoyl-rnethyl) -carbamoylj (311-Imidazole-4yl)-etnyl)-carbamnic acid benzy. ester; 1 [1-f 2-Benzyloxy-ethycarbamoyl] -methyl] (4-chlorobenzyl] -carbanoyl) 111--imidazole-4-yl) ethyl] -carbamic acid benzyl ester; (4-Berizyl oxy -benzyl- (2 -phenyl Propyl-carbamoyl) -methyl I -carbaxnoyl]1 (1H- 20 imidazole-4-yl) -ethyl] carbamic acid berizyl ester; 1- E(4-Benzyloxy-benzyl) 2-diphenylethylcarbamoyl) -methyl)I -carbamoyl]1 imidazole-4-yl) -ethyl)l-carbamic acid b-erzyl ester; anid 25 (4-Benzyloxy-benzyl) (3-berizylureido) (1H-imidacjzole-4-yl) C (2-phenyl-propylcarbamoyl) -metbhyi -propionamide 20c According to a fifteenth aspect, the invention provides the compound 4-Bwnzyiax-bflZYl) (2-nethyl-2phenyl-jpropycxbaWWyl) -methyl I -caxbamayl) (331iidazole-4-yl) -etyl-cabmic acid benzyl ester.

According to a sixteenth aspect, the invention provides the compounds (BIp~henyl-4-ylmetbyl- (2-methyl-2phenyl -propylcarbamoyl) -methyl]I -carbamoyl) -2 (lIMirmidazole-4-yl) -ethyl] -carbamic acid benzyl ester; l- (Biphenyl-4-ylmethyl- (2-phenyl- Propylcarbamoyl) -methyl]I -carbamoyll -2 (1Himidazole-4-yl) -ethyl] -carbamic acid benzyl ester; 1- (4 (-Benzyloxy-benzyl) (1-methyl- 2-phenyl-ethylcarbamoyl) -methyl] -carbamoyl) 2-(lH-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; -E 1- -Benzyloxy-benzyl) (-methyl- 2-phenyl-et-hylcarbanoyl) -methyl]I -carbamoyl) 2-(lH-izidazole-4-yl -ethyl]-carbanic acid benzyl ester; 1 4l- (-Benzyl1oxy -ben zyl1) -pbeny 1butylcarbamoyl) -methyl]I -carbamoyl) (lH-imidazole 4 yl) -ethyl-c arbam-ic acid benzyl ester; (lH-Imidazole-4-yl) (4-methylbenzyl-) [(2-phenyl-propylcarbamoyl) -methyl] carbamoyl) -ethyl) -carbamic acid benzyl ester; (lH-Iznidazole-4-yl) 4-methoxybenzyl) (2 -phenyl-propylcarbar-oyl) -methyl] carbamoyl) -ethyl) -carbamic acid benzyl ester; (S0 1 4BnyOYbn~)-((-(-hoo (S-1(o-ezyoybnz1-(2(-hoo phernyl) -2 -pheriyl-ethylcarbaayllI -mwethyl) 21 DOC 20d carbanloy.1) (lH-ixnidazole-4-y1) -ethyl] -carbamj..c acid benzyl ester; 4 -BenzyoxY-benzyl).. (2-ethyl-2- Phenyl-butylcarbamoyl) -methyl -carbamoyl (3Himidazole-4yl).-ethyl] carbamic acid benzyl ester; propylcarbamoyl) -me thyl -carbaxnoyly -2 (Himidazole-4-yl) -ethyl] -~carbmc acid benzyl ester; 4 -Benzyloxy-benzyl).( 2 -(2-chlorophenyl) -propy2.carbamoyl I -methyl)l-carbamoyl) (111imdzl--l ehl crai acid benzyl ester; (2 (1H- Imidazole-4 -yl) 1- C (2 -methoxybenzyl) 2 -phenyl -propylcarbamoyl) -methyl cabmy)-thl crai acid benzyl ester; (2 (1H- Imidazole-4 -yl) -1I- f[ (2 -phenyl propylcarbamoy.) -methyl] 4- (pyridin- 4-yJlmethoxy) benzyl] -carbamoyl) -ethyl) -carbainic acid benzyl ester; (1H-I-midazole-4-yl) -1-f (2-phenylpropylcarbamoyl) -methyl] (pyridin-3-yalmehoxy) benzyl] -carbamoyl) -ethyl) -carbamic acid benzyl ester; (lH-itidaolee....yl)-.1-. (2-phenylpropylcarbamoyl) -methyl] 4 -trif luoromethylbenzyl) -carbamoyl]I -ethyl) -carbamic acid benzyl :ester; H-Iidzol-4-l)-1- C(2-methyl-2phenyl -propylcarbamoyl) -methyl] (pyridin-2 20 ylmethox-y) -benzyl] -carbalnoyll -ethyl) -carbamic acid benzyl ester; (1-{Benzyl-

C(

2 -methyl2.phnyl..propyl..

carbamoyl) -methyl] -carbamoyl) (1H-iznidazole-4- Yl) -ethyl] -carbamic acid benzyl ester; (1H-Imidazole-4-yl) -1-f (4-methoxy- ~Tf benzyl) 2 -methyl-2-pheny-proylcarbamoyl) 21..0 DOC 20e methyl] -carbamoyl) -ethyl) -car'bamic acid benzyl.

ester; C- (f(4-Benzyloxy-benzyl)- 2 -cyano-2phenyl-ethylcarbamoyl) -methyl] -carbanioyl) (21imdzl--l-tylcrai acid benzyl ester; (3-Benzyl-3-methyl-ureido) (4be-nzyloxy-benzyl) (lH-limidazole-4-yl) methyl-2-pheny1-propyicarbamoyl) -methyl] propionamide; (2-Amino-phenyl)propylcarbamoyl] -methyl)- (4-benzyloxy-benzyl) carbamoyl] (3H-ixidazole-4-yl) -ethyl] -carbami~c acid benzyl ester; (lH-Imidazole-4-yl) -1-f [(2-methyl-2phenyl-propylcarbanoyl) -methyl] (pyridin-4ylmethoxy) -benzyl] -carbamoyll -ethyl) -carbamic acid benzyl ester; S) (lH-Ixnidazole-4-yl) -1-f F(2-methyl-2- .00. phenyl-propylcarbamoyl)-mtyl[-prdn3 ylmethoxy) -benzyl] -carbamoyll -ethyl) -carbamic acid benzyl ester; and CS) -[l-{Cyclohexylmethyl-( (2-phenylpropylcarbamoyl) -methyl] -carbamoyl}-2- (3Himidazole-4-yl) -ethyl] -carbamic acid benzyl ester.

0 0 0 21473-0 DOC 20f According to a seventeenth aspect, the invention provides the compounds (8)El ((4-3minylmW-byl- -(112- 2 -fliao- PhOW1) -etbv~carbmy1 I -ast)yl) -cacbafOYl.) (2ijimidazole-4-yl) -etbyll -cazbmmic acid benzy ater, ((4-Benzyloxy-benzyl) C(2-pyzridin- 2 -yl-ethylcarbamoyl) -methyl] -abmy) (11-imidazole-4-yl) -ethyl] -carbamic acid benzyj ester; (4 -Benzyloxy-banzyl)- C 2- (2 -bromo- Phenyl) -ethylcarbamoyl]I -mthyl} -carbamoYl) 2- (11imidazole-4-yl) -ethyl] -carbamic acid benzyl ester; 2 DOC 20g (4-Benzyloxy-benzYl)-[ (2-phenyl-2pyridin-2-yl-ethylcarbamoyl) -methyl] -carbamoyl) -2- (lH-imidazole-4-yl) -ethyl] -carbamic acid benzyl ester; (4-Chloro-benzyl)-( (2-phenylprop ylcarbamoyl) -methyl] -carbamoyl)-2-(1H'imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (4-Benzyloxy-benzyl) (lH-imidazole-4yl) (3-phenyl-propionylamino) [(2-phenylpropylcarbamoyl) -methyl] -propionamide; (4-Fluoro-benzyl)-[ (2-phenyl-propylcarbamoyl) -methyl] -carboamoyl} (1H-imidazole-4yl)-ethyl].-carbamic acid benzyl ester; (4-Fluoro-benzyl) (2-methyl-2phenyl-propylcarbamoyl) -methyl] -carbanioyl 1-2- (1Himidazole-4-yl) -ethyl] -carbam.ic acid benzyl ester; Benzyl- [(2-phenyl-propylcarbamoyl) methyl] -carbamoyll-2- (lE-imidazole-4-yl) -ethyl] carbamic acid benzyl ester; (4-Benzyloxy-belzyl) (3-benzylureido)-3-(lH-imidazole-4-yl) -N-[((2-phenylpropylcarbamoyl) -methyl] -propionamide; (4-Benzyloxy-belzyl) (3-benzylureido) (1E-imidazole-4-yl) [(2-phenylbutylcarbamoyl) -methyl] -propionamide; (4-Bromo-beflzyl)-[ (2-phenylpropylcarbamoyl) -methyl] -carbamoyl)-2- (ilimidazole-4-yl) -ethyl] -carbarmic acid benzyl. ester; 20 (S)-E1-((3-Chloro-beflzyl)-[(2-phelylpropylcarbamoyl) -methyl] -carbaxnoyl 1-2- (lHimidazole-4-yl) -ethyl] -carbamic acid benzyl. ester; (4-Chloro-benzyl)-( (2-methyl-2phenyl-propylcarbamoyl) -methyl] -carbamoyl 1-2- imidazole-4-yl) -ethyl] -carbamic acid benzyl ester; 21473-) DOC 20h (lH-Ixidazole-4-yl) -methoxyben~iyl) [(C2-phenyl-propylcarbamfoyl) -methyl] carbamoyl) -ethyl) -carbamic acid benzyl ester; (2 (1H- Imidazole- 4 -Yl) -1I- {naphthalen-lylmethyl- (2 -phenyl-propylcarbamoyl) -methyl carbamoyl) -ethyl) -carbamic acid benzyl ester; ClH-Imidazole-4-Yl) (C2-methyl-2phenyl-propylcarbamoyl) -methyl)I -pyridin-3 ylmethyl-carbaxnoyl) 1-ethyl) -carbamic acid benzyl ester; (1H-ImidazoJle-4-yl) (2-methylbenzyl) i(2-phenyl-propy1carbamoyl) -methyl] carbamoyl) -ethyl) -carbamic acid benzyl ester; ClH-Imidazole-4-yl) -1-C (2-methyl-2phenyl-propylcarbamoyl) -methyl] -pyridin-2ylmethyl-carbaxnoYl)-ethyl) -carbamic acid benzyl ester; (S)-(2-(lH-Imidazole-4-Yl) -1-f(3-methylbenzyl) (2-phenyl-propylcarbamoyl) -methyl) carbamoyl} -ethyl) -carbamic acid benzyl ester; propylcarbamoyl) -methyl -carbamoyl) -2 (1Himidazole-4-yl) -ethyl) -carbaxnic acid benzyl ester; (4-Benzyloxy-belzyl)-[ (2-hydroxy-2phenyl -ethyl- carbamoyl) -methyl) -carbamoyl)-2- (3Himidazo-4-yl)-ethyl]-carbamic acid benzyl ester; -[1-C(4-Benzyloxy-belzyl) 2- (2-chlorophenyl) -ethylcarbamoyl)methyl)-carbamoyl)

CIH-

20 irmidazole-4-yl) -ethyl] -carbaLi1c acid benzyl ester; S) -[l-{(4-Benzyloxy-benzyl)-( (2-methyl- 2 phenyl-propylcarbamoyl) -methyl] -carbamoyl)- 2 C1Himidazole-4-yl) -ethyl) -carbaniic acid thiophel- 3-ylmethyl ester; Sphenyl-propylcarbamoyl) -ethyl]I -carbamoyl)-2- (3Mimidazole-4-yl) -ethyl) -carbamic acid benzyl ester; 21473-'A DCr 20i (1H-Imidazole-4-yl) (4-methylbenzyl) [(2-methyl-2-phenyl-propylcarbamoyl) methyl]I -carbamoyll -ethyl) -car-bamic acid benzyl ester; -(2-(1H-Imxidazole-4-yl) (2-methoxy- :benzyl) -E(2-methyl-2-phenyl-propylcarbamoyl) methylj-carbamoyl) -ethyl) -carbamic acid benzyl ester; (3-Benzyl-3-methyl-ureido) (4-chiorobenzyl) (lH-imidazole-4-yl) (2-methyl-2phenyl-propylcarbamoyl) -methyl] -propionamide; -(2-(lH-Imidazole-4-yl) ((3-methoxybenzyl) (2-methyl-2-phenyl-propylcarbanoyl) methyl]I -carbamoyl) -ethyl) -carbamic acid benzyl ester; (2 (1H-Imidazole-4-yl)-l1-( (2 -methyl-2 phenyl-propylcarbanoyl) -methyl] (pyridin-4ylmethoxy) -benzyl] -carbamoyll -ethyl) -carbamic acid benzyl ester; and (IH-Imidazol-4-yl) -1-{isobutyl- (2-phenylpropylcarbanoyl) -methyl]I -carbamoyl) -ethyl) carbamic acid benzyl ester.

2147"-O DOC 20j According to an eighteenth aspect, the invention provides the compounds [1-C (4-Benouy-by)- E (2-bmwpntyl-carbamoyl) -methyl)I -carbamayl) -2 (3HiadAzole-4-yl) -ethyl) -carbamic acid beuizyl ester; l- E2- (4-Benzyloxy-vhenyl) -ethyl] 1(2mthyl-2 -pheriyl-propylcarbamoyl) -methyl] cazbamoyl)-2 (3H-imidazole-4-yl) -ethyl]I -carbamic acid benzyl ester; (3H-Imidazole-4-yl) (4-methoxyto phenyl) -ethyl]I (2-methyl-2-phenyl-propylcarbamoyl) -methyl] -carbamoyl) -ethyl) -carbamic acid benzyl ester; 2147-,3,) DOC 20k methyl) (4 -benzyloxy-benzyl) -carbamoyl -2 (3H-* imidazole-4-yl) -ethyl] -carbamic acid benzyl ester; (4-Benzyloxy-benzyl)-( (2-methyl-2- ~phenyl-propylcarbamoyl) -methyl]I -carbamoyl) (3Hirmidazole-4-yl) -ethyl] -methyl-carbarmi'c acid benzyl ester; [1-f (4-Benzyloxy-benzyl)-[C (2-methyl-2phenyl -propylcarbamoyl) -methyl]I -carbainoyl) -2 (3 methyl-3H-imidazole4.yl) -ethyl] -carbaniic acid benzyl ester; (4-Benzyloxy-benzyl)-[ (2-methyl-2phenyl -propylcarbanoyl) -methyl]I -carbaznoyl) (1methyl-lH-imidazole-4-yl) -ethyl] -carbatic acid benzyl ester; (4-Benzylox-y-benzyl)-[ (2-methyl-2phenyl-propylcarbamoyl) -methyl] -carbamoyl 1-2- (3Himidazole-4-yl) -ethyl] -carbamic acid furan-2ylmethyl ester; (4-Benzyloxy-benzyl)-[ (2-methyl-2phenyl-propylcarbamoyl) -methyl] -carbamoyl) (3Mimidazole-4-yl) -ethyl] -carbamic acid thiophen-2ylmethyl ester; [1-f(4-Benzyloxy-benzyl)-[ (2-methyl-2phenyl-propylcarbamoyl) -methyl]I -carbamoyl 1-2- (3M.imidazole-4-yl) -ethyl] -carbamic acid pyridin-3ylmethyl ester; (1-f (4-Benzylox-y-benzyl) (2-methyl-2phenyl-propylcarbamoyl) -methyl]I -carbaznoyl 1-2- (3Mimidazole-4-yl) -ethyl] -carbauic acid lH-imidazole-4-ylmethy. ester; (3-Benzyl-ureido) (4-chloro-benzyl)- 3-(3Himidazole-4-yl) (2 -methyl-2-phenyl-propylcarbamoyl) -methyl]I -propionamide; 2147-00 DC 201 [1-f (4-Benzyloxy-benzyl) (2-methyl1-2- Phenyl-propylcarbamoyl) -methyl] -carbamoyl1-2- (3Himidazole-4-yl) -ethyl] -carbamic acid 4-methoxybenzyl ester; (3-Benzyl-tiiioureido) (3H-imridazole- -4 (4-methyl-benzyl) (2-methyl-2-phenylpropylcarbamoyl) -methyl) -propionamide; -2 -Acetylarmino-N- (4-benzyloxy-benzy.)- 3- (3H-imidazole-4-yl) 2 -methyl-2-phenylpropylcarbanoyl) -methyl] -propionamide; 2 (3H-Imidazole-4-yl) [(2-methyl-2phenyl -propylcarbamoyl) -me thyl]I -pyridin-4 ylmethyl-carbamoyl) -ethyl) -ca-rbamic acid benzyl ester; 2 -(3H-Imidazole-4-yl)-l- [(4-iodo-benzyl)- (phene thylcarbamoyl -methyl) -carbamoyl]I -ethyl) carbamic acid benzyl ester; (S)-[l(f(4-Amino-benzyl) 2 -methyl-2-phenylpropylcarbamoyl) -methyl]I -carbamoyl) -2 (3Himidazole-4-yl) -ethyl] -carbamic acid benzyl ester; phenyl-propylcarbamoyl) -methyl] -carbamoyl)-2- (3Himidazole-4-yl) -ethyl] -carbnjc acid benzyl ester; 99 (2-Dimethylamino-ethoxy) -benzyl] 99999 2 -methyl-2-phenyl-propylcarbamoyl) -methyl] carbamoyl) (3H-imidazole-4-yl) -ethyl] -carbamic acid berizyl ester; and (1H-imidazole-4-yl) -1-f isobutyl- 2 -methyl-2-phenyl-propyl carbamoyl) -methyl] carbamoyl) -ethyl) -carbamic acid benzyl ester.

21479-M~ DOC According to a nineteenth aspect, the invention provides 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 according to the first aspect.

According to a twentieth aspect, the invention provides 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 according to the second aspect.

According to a twenty-first aspect, the invention provides 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 according to the second aspect wherein R" I and R 14 are methyl.

According to an twenty-second aspect, the invention provides a method of treating psoriasis, the method comprising administering to a patient having psoriasis a i :X •therapeutically effective amount of a compound according to the first aspect.

According to a twenty-third aspect, the invention provides a method of treating S• 15 psoriasis, the method comprising administering to a patient having psoriasis a therapeutically effective amount of a compound according to the second aspect.

According to a twenty-fourth aspect, the invention provides a method of treating •psoriasis, the method comprising administering to a patient having psoriasis a therapeutically effective amount of a compound according to the second aspect wherein 2o R1aI d 14 20 RandR are methyl.

o,

'C,

21473-00DOC 20n According to a twenty-fifth aspect, the invention provides a pharmaceutically acceptable composition that comprises a compound according to the third aspect.

According to a twenty-sixth aspect, the invention provides a pharmaceutically acceptable composition that comprises a compound according to the fourth aspect.

According to a twenty-seventh aspect, the invention provides a method of treating or preventing restenosis, the method comprising administering to a patient having restenosis or at risk of having restenosis a therapeutically effective amount of a compound according to the third aspect.

According to a twenty-eighth aspect, the invention provides a method of treating or preventing restenosis, the method comprising administering to a patient having restenosis or at risk of having restenosis a therapeutically effective amount of a compound according to the fourth aspect.

S: According to a twenty-ninth aspect, the invention provides a method of treating go •cancer, the method comprising administering to a patient having cancer a therapeutically S: 15 effective amount of a compound according to the third aspect.

According to a thirtieth aspect, the invention provides a method of treating cancer, *the method comprising administering to a patient having cancer a therapeutically «*00 S• effective amount of a compound according to the fourth aspect.

According to a thirty-first aspect, the invention provides a method of treating a S 20 viral infection, the method comprising administering to a patient 21478-00.DOC having a viral infection a therapeutically effective amount of a compound according to the third aspect.

According to a thirty-second aspect, the invention provides 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 according to the fourth aspect.

According to a thirty-third aspect, the invention provides a method of treating psoriasis, the method comprising administering to a patient having psoriasis a therapeutically effective amount of a compound according to the third aspect.

According to a thirty-fourth aspect, the invention provides a method of treating psoriasis, the method comprising administering to a patient having psoriasis a therapeutically effective amount of a compound according to the fourth aspect.

According to a thirty-fifth aspect, the invention provides use of a compound according to the first aspect for the manufacture of a medicament for the treatment or prevention of restenosis.

According to a thirty-sixth aspect, the invention provides use of a compound according to the second aspect for the manufacture of a medicament for the treatment or prevention of reste.nosis.

According to a thirty-seventh aspect, the invention provides use of a compound according to the second aspect wherein R I I and R 14 are methyl for the manufacture of a medicament for the treatment or prevention of restenosis.

21478-00 DOC According to a thirty-eighth aspect, the invention provides use of a compound according to the third aspect for the manufacture of a medicament for the treatment or prevention of restenosis.

According to a thirty-ninth aspect, the invention provides use of a compound according to the fourth aspect for the manufacture of a medicament for the treatment or prevention of restenosis.

According to a fortieth aspect, the invention provides use of a compound according to the first aspect for the manufacture of a medicament for the treatment of cancer.

According to a forty-first aspect, the invention provides use of a compound according to the second aspect for the manufacture of a medicament for the treatment of cancer.

According to a forty-second aspect, the invention provides use of a compound II 14 according to the second aspect wherein R1 n and R 14 are methyl for the manufacture of a medicament for the treatment of cancer.

*ooo 15 According to a forty-third aspect, the invention provides use of a compound according to the third aspect for the manufacture of a medicament for the treatment of cancer.

o. According to a forty-fourth aspect, the invention provides use of a compound according to the fourth aspect for the manufacture of a medicament for the treatment of cancer.

Z1478-00.DOC According to a forty-fifth aspect, the invention provides use of a compound according to the first aspect for the manufacture of a medicament for the treatment of a viral infection.

According to a forty-sixth aspect, the invention provides use of a compound according to the second aspect for the manufacture of a medicament for the treatment of a viral infection.

According to a forty-seventh aspect, the invention provides use of a compound 11 1I4 according to the second aspect wherein RI and R4 are methyl for the manufacture of a medicament for the treatment of a viral infection.

According to a forty-eighth aspect, the invention provides use of a compound according to the third aspect for the manufacture of a medicament for the treatment of a viral infection.

•According to a forty-ninth aspect, the invention provides use of a compound according to the fourth aspect for the manufacture of a medicament for the treatment of a S. 15 viral infection.

According to a fiftieth aspect, the invention provides use of a compound according to the first aspect for the manufacture of a medicament for the treatment of psoriasis.

According to a fifty-first aspect, the invention provides use of a compound according to the second aspect for the manufacture of a medicament for the treatment of Sp s g: 20 psoriasis.

oo 21478-00.DOC 20r According to a fifty-second aspect, the invention provides use of a compound according to the second aspect wherein R n and R 14 are methyl for the manufacture of a medicament for the treatment of psoriasis.

According to a fifty-third aspect, the invention provides use of a compound according to the third aspect for the manufacture of a medicament for the treatment of psoriasis.

According to a fifty-fourth aspect, the invention provides use of a compound according to the fourth aspect for the manufacture of a medicament for the treatment of psoriasis.

According to a fifty-fifth aspect, the invention provides use of a compound according to the first aspect as a medicament.

According to a fifty-sixth aspect, the invention provides use of a compound e according to the second aspect as a medicament.

According to a fifty-seventh aspect, the invention provides use of a compound according to the second aspect wherein R I and R 14 are methyl as a medicament.

According to a fifty-eighth aspect, the invention provides use of a compound according to the third aspect as a medicament.

According to a fifty-ninth aspect, the invention provides use of a compound according to the fourth aspect as a medicament.

Unless the context clearly requires otherwise, throughout the description and the claims, the words 'comprise', 'comprising', and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".

21478-00.DOC WO 97/44350 WO 9744350PCTIUS97/06591 -21- DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound having the Formula I

R

2 1

R

4 I I

A-N,

wherein

R

21 is hydrogen or Cl-C 6 alkyl; RQ is

(CH

2 n

N

N

H

~(CH

2 n- C2n

N

,or N N

C

1

-C

6 alkyl alkyl n is 0 or 1; A is -CORa, -CO 2 Ra', -CONHRa,' -CSRa, -C(S)ORa', 0 -C(S)NHRa', -S0 2 Ra, -CONRaRa' ~C~~aor

S

Ra, Ral, and Ra' are independently C 1

-C

6 alkyl,

(CH

2 )m-cycloalkyl, (CH 2 )m-aryl,

(CH

2 )mr-he teroaryl; each m is independently 0 to 3; R R an&dR are independently hydrogen or lC alkyl; Rb R3is

-(CH

2 m cii I- (CH 2 )m-rheteroaryl, WO 97/44350 WO 9744350PCT/US97/06591 -22-

(C

2 )mC (CH 2 )t C 2 )m-naphthyl,

C

1

-C

6 alkyl, or

-(CH

2 )m-(heteroaryl substituted with Rb) t is 2 to 6; Rb is -0-phenyl, -O-benzyl, halogen, C 1

-C

6 alkyl, hydrogen, -0C 1

-C

6 alkyl, -NH 2 -NHRa, -NRaRa' O 0 11 11

-CC-C

6 alkyl, -C-aryl, -OH, -CF 3

-NO

2 O 0 -Ol, CC 1 alkyl, -CN, -0P0 3

H

2 0

-CH

2

PO

3

H

2 -CO0 aryl, -N 3

-CF

2

CF

3

-SO

2

R,

-SO

2 NRaRal, -CHO, -OCOCH 3

-O(CH

2 )m-heteroaryl, 0 0 11 11 NH-CRa -O-(CH 2 )YNRaRa', -0 (CH 2 )m-cYcloalkyl, or (CH 2 )m-heteroaryl; y is 2or 3;

R

5 is WO 97/44350 WO 9744350PCTIUS97/06591 -23yc e

R'

Rh N

R

i 0

N

NI ,or Re

Q

R

1 Rg, and Rh are independently hydrogen, halogen,

-OC

1

-C

6 alkyl, C 1

-C

6 alkyl, -CN, -0P0 3

H

2

-CH

2

PO

3

H

2 -O-phenyJ., -O-benzyl, -NH 2 -NHRa 0 0 .NRa, 1 -C alkyl, -tC1 -aryl -OH, -CF 3

-NO

2 0 0 tNH C (CH 2 )AyRaRa -COH -0 0 11 11 -COCu 1

-C

6 alkyl, -CO aryl, -N 3

-CF

2

CF

3

-SO

2 Ra

_SO

2 NRaRa, -CHO, or -OCOCH3; and RC, Rd, Re, and Rf are independently Cl-C 6 alkyl,

(CH

2 )m-phenyl, hydrogen,

(CH

2 mOH, (CH 2 )mNH 2

-(CH

2 )m-cycloalkyl, or -CN, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

WO 97/44350 WO 9744350PCT/US97/06591 -24- Also provided are compounds having the Formula II 7 0 R21H RIO 11 RK(N N 0 0 R 13

R

14

I

QN

R

8

H

where in

S

1

-C

6 alkyl

R

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

R

2 1 is hydrogen or methyl;

R

7 is hydrogen or methyl;

R

8 is hydrogen, halogen, C 1

-C

6 alkyl, -O-benzyl, -0C 1

-C

6 alkyl, -CF 3 -OH, -0-CH 2 -pyridyl, or phenyl;

R

10

R

1

R

13 and R are independently hydrogen,

C

1

-C

6 alkyl, or -(CH 2 )m-phenyl; each m is independently 0 to 3;

R

12 is Rk -OCHT-~~ Rk 3'or ;k and N ki Ri, Rk, and Rlare independently hydrogen, halogen, -0Cl-C 6 alkyl, -Cl-C 6 alkyl, or -NHRa, or NH 2 and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

Also provided are compounds having the Formula III WO 97/44350 PCT/US97/06591 O

R

16 SH H X N N N HN1N HN N

R

1 wherein X is NH, O, or -N(CH3);

R

15 is -O-benzyl, -CF 3 hydrogen, halogen, C 1

-C

6 alkyl,

-OC

1

-C

6 alkyl, -O-(CH 2 )m-pyridyl, or phenyl; m is 0 to 3; and

R

16 is a phenyl, hydrogen, or C 1

-C

6 alkyl, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

Also provided are compounds having the Formula IV 21 R R 1 6 0 0 II II X-C-NH C-N C-NH O R4 16

IV

HN

\,N

wherein X is NH, O, or -N(CH3);

R

15 is -O-benzyl, -CF 3 hydrogen, halogen, C 1

-C

6 alkyl,

-OC

1

-C

6 alkyl, phenyl, or -0-(CH 2 )m-pyridyl;

R

16 and R 16 are Cl-Cg alkyl; m is 0 to 3; and

R

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

The term "alkyl" means a straight or branched hydrocarbon having from 1 to 6 carbon atoms and WO 97/44350 PCT/US97/06591 -26includes, 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 ring which contains from 3 to 7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like.

The term "aryl" means an aromatic ring which is a phenyl, 5-fluorenyl, l-naphthyl, or 2-naphthyl group, unsubstituted or substituted by 1 to 3 substituents selected from 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 )mCO 2 H, (CH 2 )mCO 2 -alkyl, (CH 2 )mSO 3 H, (CH 2 )mPO 3

H

2

(CH

2 )mPO3(alkyl)2, (CH 2 )mSO 2

NH

2 and (CH 2 )mSO 2 NH-alkyl wherein alkyl is defined as above and m 0, 1, 2, or 3.

The term "heteroaryl" means a heteroaromatic ring which is a 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, or 4-pyridyl, imidazolyl, 3-, or 7-indoxyl group, unsubstituted or substituted by 1 or 2 substituents from the group of substituents described above for aryl.

The symbol means 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 when administered to a patient ameliorates a symptom of a viral infection, restenosis, cancer, atherosclerosis, psoriasis, endometriosis, or prevents restenosis or atherosclerosis. A therapeutically effective amount of a compound of the present invention can be easily determined by one skilled in the art by administering a quantity of a compound to a patient and observing the result. In addition, those skilled in the art are WO 97/44350 PCT/US97/06591 -27familiar with identifying patients having cancer, viral infections, restenosis, atherosclerosis, psoriasis, or endometriosis or who are at risk of having restenosis or atherosclerosis.

The term "cancer" includes, but is not limited to, the following cancers: breast; ovary; cervix; prostate; testis; esophagus; glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma; lung, epidermoid carcinoma, large cell carcinoma, adenocarcinoma; bone; colon, adenocarcinoma, adenoma; pancreas, adenocarcinoma; thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladder carcinoma; liver carcinoma and biliary passages; kidney carcinoma; myeloid disorders; lymphoid disorders, Hodgkins, hairy cells; buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx; small intestine; colon-rectum, large intestine, rectum; brain and central nervous system; and WO 97/44350 PCT/US97/06591 -28leukemia.

The term "pharmaceutically acceptable salts, esters, amides, and prodrugs" as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.

Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laureate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphtholate mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like.

These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic 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.

WO 97/44350 PCT/US97/06591 -29- Sci., 1977;66:1-19 which is incorporated herein by reference.) Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include C1-C6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C 7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.

Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C1-C6 alkyl amines and secondary C1-C6 dialkyl amines wherein the alkyl groups.are straight or branched chain. In the case of secondary amines the amine may also be in the form of a or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C 1

-C

3 alkyl primary amines and C1-C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.

The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference.

The compounds of the present invention can be administered to a patient alone or as part of a composition that contains other components such as excipients, diluents, and carriers, all of which are WO 97/44350 PCT/US97/06591 well-known in the art. The compositions can be administered to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments or drops), or as a buccal or nasal spray.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), Cremophor EL (a derivative of castor oil and ethylene oxide; purchased from 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 a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example 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 WO 97/44350 PCT/US97/06591 -31such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; humectants, as for example, glycerol; disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, solution retarders, as for example paraffin; absorption accelerators, as for example, quaternary ammonium compounds; wetting agents, as for example, cetyl alcohol and glycerol monostearate; adsorbents, as for example, kaolin and bentonite; and lubricants, as for example, 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 comprise buffering agents.

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

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well-known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if WO 97/44350 PCT/US97/06591 -32appropriate, 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 contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, Cremophor EL (a derivative of castor oil and ethylene oxide; purchased from Sigma Chemical Co., St. Louis, MO), polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

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

Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at WO 97/44350 PCT/US97/06591 -33body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.

Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component 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 contemplated as being within the scope of this invention.

The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 2,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is preferable. The specific dosage used, however, can vary. For example, the dosage can depended on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to those skilled in the art.

The compounds of the present invention can exist in different stereoisomeric forms by virtue of the presence of asymmetric centers- in the compounds. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of this invention.

In addition, the compounds of the present invention can exist in unsolvated as well as 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.

WO 97/44350 PCT/US97/06591 -34- The examples presented below are intended to illustrate particular embodiments of the invention, and are not intended to limit the scope of the specification or the claims in any way.

Scheme 1 shows a general method by which the compounds of the present invention can be prepared, by illustrating the synthesis of [1-[(4-benzyloxy-benzyl)- (phenethyl-carbamoyl-methyl)-carbamoyl]-2-(3Himidazole-4-yl)-ethyl]-carbamic acid benzyl ester (Example Reductive amination of 4benzyloxybenzaldehyde with glycine methyl ester hydrochloride was carried out in methylene chloride with sodium triacetoxyborohydride. The (4benzyloxybenzylamino)acetic acid methyl ester was then coupled to Cbz-His in dimethylformamide with 1hydroxybenzotriazole (HOBt) and dicyclohexylcarbodiimide (DCC) as coupling agents. The resulting product was 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.

The following abbreviations are used herein: Abbreviations Cbz or Z His Trt

TEA

HOAc Et20 tBu

TFA

ES-MS

FAB-MS

HOBt

DCC

Carbobenzoxy Histidine trityl Triethylamine Acetic acid Diethylether tert-Butyl Trifluoroacetic acid Electrospray Mass Spectrometry Fast Atom Bombardment Mass Spectrometry 1-Hydroxybenzotriazole Dicyclohexylcarbodiimide WO 97/44350 WO 9744350PCTIUS97/06591

THF

PyBOP DI EA

DMF

Et 3

N

QAc Et 2

O

Boc iBUOCOCi

NMM

DMSO

Te trahydro furan Benzotriazole-1-yl-oxy- tris-pyrrolidinophosphonium hexafluorophosphate Diisopropylethylamine Dimethylformamide Trie thylamine Acetate Diethyl ether tert-Butoxycarbonyl Isobutylchloro formate N-me thylmorpho line Dime thylsul foxide WO 97/44350 WO 9744350PCTIUS97/06591 -36- SCHEME 1 H2 HC1,

OCH

3

CHO

OBn NaBH(OAc 3 C11 2 C1 2 0 0 C to Room Temperature OH DCC/HOBt_

DMF

HN,, ,N N 0,,o

,OCH

3 LiOH THF

H

2 O0 00C OBn

N

2 N- .HC 1 OBn DCC! HOBt Et 3

N

DMF

OBn Bn is benzyl.

WO 97/44350 PCT/US97/06591 -37- Scheme 2 shows a method by which compounds of the present invention can be prepared, by illustrating the synthesis of Example 15, [1-{(4-benzyloxy-benzyl)-[(2methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2- (3H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester.

Reductive amination of 4-benzyloxy-benzaldehyde with glycine methyl ester was carried out in methylene chloride with sodium triacetoxyborohydride. The (4-benzyloxybenzylamino) acetic acid methyl ester was then coupled to Cbz-His-(trityl) in methylene chloride with benzotriazole-l-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP) as coupling agent in the presence of diisopropylethylamine (DIEA) as the base. The resulting product was saponified using lithium hydroxide at 0°C, followed by coupling with 3,P-dimethylphenethylamine hydrochloride in methylene chloride, with l-hydroxybenzotriazole (HOBt) and dicyclohexylcarbodiimide (DCC) as coupling agents, and triethylamine. The trityl group was removed in the presence of acetic acid in water, at reflux. The P,P-dimethylphenethylamine hydrochloride was prepared from benzyl cyanide, which was treated with 2 equivalents of sodium hydride in tetrahydrofuran (THF) and 2 equivalents of methyl iodide in THF followed by hydrogenation (H 2 Pd/C, ammonia) and treatment with HC1 to give the HC1 salt.

WO 97/44350 WO 9744350PCTIUS97/06591 -38- SCHEME 2

CHO

H

2 N Y OCH 3 NaBH(OAc)3 0 OBn OBn Z-His (Trt) DIEA, PyBOP Z-His (Trt) N,

OH

0 &OBri LiOH Z-His (Trt) NIyO 0 I&OBn 112N

TEA;

DCC;HOBt WO 97/44350 WO 9744350PCT/US97/06591 -39- SCHEME 2 (cont) HOAc Trt OBn

CH

3 01n Ol"

CN

0

C

2 x CH 3

I

2 x NAH 1

THF

H

2 /Pd

NH

3 2) Et 2 O/HC1 oHC1 WO 97/44350 PCT/US97/06591 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-Benzyloxy-benzyl)- [(2-pyridin-2-yl-ethyl-carbamoyl)-methyl]-carbamoyl}-2- (lH-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester.

Reductive amination of 4-benzyloxy benzaldehyde with glycine t-butyl ester was carried out in methylene chloride with sodium triacetoxyborohydride. The (4-benzyloxybenzylamino)acetic acid t-butyl ester was then coupled to Cbz-histidine-(trityl) in methylene chloride with PyBOP as coupling agent and DIEA as the base. The resulting product was deprotected by treatment with 50% trifluoroacetic acid in methylene chloride. Coupling with 2-pyridineethaneamine in methylene chloride was carried out with PyBOP as coupling agent, and diisopropylethylamine as the base.

WO 97/44350 WO 9744350PCTIUS97/06591 -41- SCHEME 3 H 2 N" OtBu .HC1+ 0 Cbz-HisCTrt)

C

DIEA, PyBOP CH0 0 OBn ~bz -His Trt NaBH (OAc)3- OBn .OBn Cbz 5001 TFA

CH

2 C1 2 OBn DIEA, PyBOP H Nl'I

H

2 0 2 'OBn WO 97/44350 PCT/US97/06591 -42- 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-Benzyloxy-benzyl)- {[2-(2-fluoro-phenyl)-ethylcarbamoyl]-methyl}carbamoyl)-2-(lH-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester. Boc-glycine was coupled to 2-fluorophenethylamine in tetrahydrofuran (THF) in the presence of isobutylchloroformate as coupling agent and N-methylmorpholine as the base. The Boc 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 was carried out in methylene chloride with sodium triacetoxyborohydride and potassium acetate as the base. The fluorophenyl)-ethyl]-Na-(4-benzyloxy-benzyl)glycinamide*HC1 was then coupled to Cbz-histidine- (trityl) in methylene chloride with benzotriazole-l-yloxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) as coupling agent and diisopropylethylamine as the base. The resulting product was deprotected by treatment with 50% trifluoroacetic acid in methylene chloride, with trisopropylsilane as the scavenger.

-a WO 97/44350 WO 9744350PCTIUS97/06591 -43- SCHEME 4 Boc-NH->< O 0

H

2 N--0

F

iBuOCOC 1

NMM

THF

Boc-NH,*> NH F 0

TFA

CH

2 Cl 2 0

*TFA

CHO

0 OBn NaBH(OAc) 3

K

2 C0 3

CH

2 C1 2 HN F0 0 0 *HC 1 Cbz-His (Trt) -OH PyBOP

DIEA

CH

2 C1 2 Cbz-His-N->(N F0 1 0 Trt IIOBn TFA Cbz-His--Nl'>(N F0

CH

2 C1 2 1(CH 3 2 CE13 SiH n WO 97/44350 PCT/US97/06591 -44- Scheme 5 shows a method by which the compounds of the present invention can be prepared, by illustrating the synthesis of Example 62, (2-(1H-imidazol-4-yl)l-{isobutyl-[(2-phenyl-propylcarbamoyl)-methyl]carbamoyl}-ethyl)-carbamic acid benzyl ester. Bocglycine was coupled to -methylphenethylamine in methylene chloride, in the presence of dicyclohexylcarbodiimide (DCC) and l-hydroxy-benzotriazole (HOBt) as coupling agents and diisopropylethylamine as the base. The boc group was then removed by treatment with TFA in methylene chloride for 2 hours and reductive amination of isobutyraldehyde in methylene chloride with sodium triacetoxyborohydride and sodium acetate as the base was carried out. The above product was then coupled to Cbz-histidine-(trityl) in methylene chloride with O-(7-azabenzotriazol-l-yl)-N,N,N',N'tetramethyluronium hexafluorophosphate (HATU) and l-hydroxy-7-azabenzotriazole(HOAt) as coupling agents and diisopropylethylamine as the base. The resulting product was deprotected by treatment with trifluoroacetic acid in methylene chloride.

WO 97/44350 WO 9744350PCTIUS97/06591 SCHEME Boc-NH_'N< O H N0 0 01-3

DCC/HOBL

DI EA

CH

2 Cl 2 Boc-NH

N

0

CH

3 3 0 0 TFA

CH

2 Cl 2

CHO

NaBH (OAc) 3 NaCOOCH 3

CH

2 Cl 2 Cbz -His (Trt) -OH

CH

3 HN< 0 0 H3 HATU/HOAt

DIEA

CH

2 Cl 2 Cbz -His N( 1 0 OH 3 Trt 3 0%O TFA

OH

2 Cl 2 Cbz-His-

CE

3 WO 97/44350 PCT/US97/06591 -46- EXAMPLE 1 F (Phenvlmethoxv) carbonyl -L-histidvl-N- 2- (phenvlmethoxv) ethyl -N 2 [r4- (phenvlmethoxv)phenyl methyl qlycinamide Step 1: (4-Benzyloxvbenzylamino)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 C12 (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 was added, and the mixture was stirred for 30 minutes. The aqueous layer was extracted three times with CH 2 C1 2 The combined organic extracts were washed with brine, dried over MgSO 4 and concentrated. Flash chromatography ethyl acetate/hexane) gave 1.98 g of the title compound as a white solid; mp 57-58 0

C.

Step 2: (Phenvlmethoxv)carbonll-L-histidvll- N-f 4- (Dhenvlmethoxv)phenyllmethyllcrlvcine 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 with CHC1 3 washed twice with saturated NaHCO 3 brine, dried over MgS0 4 and concentrated. Flash chromatography gave 1.68 g (72%) of the title compound as a white foam; ES-MS (electrospray mass spectrometry) 557 (m 1).

WO 97/44350 PCT/US97/06591 -47- Step 3: (Phenvlmethoxv)carbonvll-L-histidvl N-[[4-(phenvlmethoxv)phenvllmethyl Ilvcine To a solution of the ester from Step 2 (1.53 g, 2.75 mmol) in THF (tetrahydrofuran) (15 mL) and H 2 0 (5 mL) at 0°C was added LiOH hydrate (0.14 g, 3.30 mmol), and the solution was stirred 5 hours at 0°C. The solution was concentrated, the residue taken up in H 2 0, and the pH was adjusted to 4-5 with 1N HC1.

The resulting mixture was concentrated and dried in vacuo to afford 1.65 g of the title compound as a white solid; FAB-MS 543 (m 1).

Analysis calculated for C 30

H

30

N

4 0 6 -1.2 LiCl-2.0 H 2 0: C, 57.24; H, 5.44; N, 8.90.

Found: C, 57.35; H, 5.32; N, 8.62.

Step 4: (S)-N-F(Phenvlmethoxv)carbonvll-L-histidvl- N- 2-(phenvlmethoxy)ethvll-N 2 -[[4-(phenvlmethoxv)phenyllmethvl alvcinamide 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) followed by 2-benzyloxyethylamine hydrochloride (1.0 g, 5.33 mmol). Et 3 N (triethylamine) (0.82 mL, 5.86 mmol) was added, and the mixture was stirred overnight at room temperature. The mixture was filtered, and the filtrate was diluted with CHC1 3 washed twice with saturated NaHCO 3 brine, dried over MgSO 4 and concentrated. Flash chromatography Methanol/ CHC1 3 gave 2.25 g of the title compound as a white foam; ES-MS 676 (m 1).

EXAMPLE 2 (4-Benzvloxv-benzvl)-(phenethvl-carbamoylmethyl)-carbamovll-2-(3H-imidazole-4-vl)-ethyllcarbamic acid benzyl ester WO 97144350 WO 9744350PCTIUS97/06591 -48- [(4-Benzyloxy-benzyl) -(phenethyl-carbamoy.methyl) -carbanoyl] (3H-imidazole-4-yl) -ethyl] carbamic acid benzyl ester can be made according to Example 1, Step 4, by substituting phenethylamine for 2-benzyloxyethylamine hydrochloride. The title compound is obtained as a while solid; ES-MS 646 (m 1).

EXAMPLE 3 1-fF2-Benzvloxv-ethvlcarbamovll-methvll-f 4chlorobenzvl1 -carbamoyll (lH-imidazole-4-vl) -ethvll carbamic acid benzvl ester 2 -Benzyloxy-ethylcarbamoyl]-methyl] chlorobenzyl] -carbamoyl] (lH-imidazole-4-yl) -ethyl] carbamic acid benzyl ester can be made according to Example 1, Step 1, by substituting 4-chlorobenzaldehyde for 4-benxyloxybenzaldehyde. The title compound is obtained as a white solid; ES-MS 604 (m 1).

EXAMPLE 4 Fl-f(4-Benzvloxv-benzvl) -rF(2-D~henvl-Droipvlcarbamoyl) -methyll -carbamoyll (lH-imidazole-4-vl) ethyllcarbamic acid benzvl ester [(4-Benzyloxy-benzyl) (2-phenyl-propylcarbamoyl) -methyl] -carbamoyl] (1H-imidazole-4-yl) ethyllcarbamic acid benzyl ester can be prepared according to Example 1, Step 4, by substituting P-methylphenethylamine for 2 -benzyloxyethylamine hydrochloride. The title compound was obtained as a white solid; ES-MS 660 (m 1).

EXAMPLE -[1-F(4-Benzvloxv-benzvl) -rF(2, 2-di-phenylethvlcarbamoyl) -methyll -carbamovil (lH-imidazole-4vl)-ethvll-carbamic acid benzvl ester

II

WO 97/44350 PCT/US97/06591 -49- (S)-[l-[(4-Benzyloxy-benzyl)-[(2,2-diphenylethylcarbamoyl)-methyl]-carbamoyl]-2-(lH-imidazole-4yl)-ethyl]-carbamic acid benzyl ester can be prepared according to Example 1, Step 4, by substituting 2,2-diphenylethylamine for 2-benzyloxyethylamine hydrochloride. The title compound was obtained as a white powder; ES-MS 722 (m 1).

EXAMPLE 6 (S)-N-(4-Benzvloxv-benzvl)-2-(3-benzvl-ureido)- 3-(1H-imidazole-4-vl)-N- (2-phenvl-propylcarbamoyl)methyll-proDionamide The title compound can be prepared according to Example 1, Step 2, by substituting benzyl-ureahistidine (Steps 1 and 2) for Cbz-histidine. The title compound is obtained as a white solid; ES-MS 659 (m 1).

Step 1: Benzvl-urea-histidine 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 overnight at room temperature.

The solution was concentrated and the residue taken up in ethyl acetate. The solution was washed with water, saturated NaHCO 3 brine, dried over MgSO 4 and concentrated. The product was obtained as a white foam (1.09 g, 84%).

Step 2: Benzvl-urea-histidine To a solution of the ester from Step 1 (1.9 g, 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 overnight at room temperature.

The solution was added to IN HCl:ethyl acetate (30 mL WO 97/44350 PCT/US97/06591 each). The organic layer was separated and washed with IN HC1, brine, dried over MgSO 4 and concentrated. The product was obtained as a white foam (0.53 g, 53%); ES-MS 289 (m 1).

EXAMPLE 6a (S)-N-(4-Benzvloxv-benzvl)-2-(3-benzvl-ureido)- 3-(1H-imidazole-4-vl)-N- (2-phenvl-propylcarbamoyl)methyll-priopionamide The title compound can be prepared according to Example 1, Step 2, by substituting benzyl-ureahistidine-(trityl) (Steps 1 and 2) for Cbz-histidine and Step 4, by substituting P-methylphenethylamine for 2-benzyloxyethylamine hydrochloride. The title compound is obtained as a white solid; ES-MS 659 (m 1).

Step 1: Benzvl-urea-histidine-tritvl 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 overnight at room temperature.

The solution was concentrated and the residue taken up in ethyl acetate. The solution was washed with water, saturated NaHC0 3 brine, dried over MgSO 4 and concentrated. The product was obtained as a white foam (1.95 g, 83%).

Step 2: Benzvl-urea-histidine-(trityl)*HC1 To a solution of the ester from Step 1 (1.9 g, 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 overnight at room temperature.

The solution was added to 1N aqueous HC1:ethyl acetate mL each). The organic layer was separated and WO 97/44350 PCT/US97/06591 -51washed with IN HC1, brine, dried over MgSO 4 and concentrated. The product was obtained as a white foam g, ES-MS 531 (m 1).

EXAMPLE 7 -(S)-[l-((4-Benzvloxv-benzvl)-{[2-(2-fluoro-phenyl)ethylcarbamovll-methyl}-carbamoyl)-2-(lH-imidazole-4vl)-ethyll-carbamic acid benzyl ester Step 1: N-Boc-N-[2-(2-fluorophenvl)-ethyl qlvcinamide To a solution of Boc-glycine (1.75 g, 10 mmol) in THF (50 mL) at 0°C was added isobutylchloroformate (1.3 mL, 10 mmol), followed by N-methylmorpholine (1.1 mL, 10 mmol). The resulting suspension was stirred for 5 minutes at 0°C, then treated with fluorophenyl)-ethyl]-amine (10 mmol). The suspension was stirred at room temperature overnight. The reaction was treated with IN HCI and was extracted with diethyl ether (2 x 50 mL). The organic extracts were combined, washed successively with water, a saturated aqueous NaHCO 3 solution, and then water. The organic extracts were dried over MgSO 4 and concentrated. Flash chromatography methanol in methylene chloride) gave 1.93 g of the title compound as a white solid; CI-MS 297 (m 1).

Step 2: N-[2-(2-Fluorophenvl)-ethyll-qlvcinamide 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 (20 mL). The solution was stirred for 30 minutes, then concentrated. The residue was dissolved in methylene chloride and reconcentrated to give the title compound as an oil. This was used in the next reaction without characterization.

WO 97/44350 PCT/US97/06591 -52- Step 3: N-[2-(2-Fluorophenyl)-ethyl -Na-(4-benzvloxybenzvl)-qlycinamide hydrochloric salt To a suspension of the compound from Step 2 above (6.48 mmol), 4-benzyloxybenzaldehyde (1.38 g, 6.48 mmol) and potassium acetate (1.27 g, 12.96 mmol) in methylene chloride (50 mL), cooled to 0°C, was added sodium triacetoxyborohydride (1.79 g, 8.43 mmol). The reaction was allowed to warm to room temperature and was stirred for 3 hours. The reaction was treated with a saturated aqueous NaHCO 3 solution, 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 HC1 (8 mL). The precipitate was collected by filtration to give 1.46 g of the title compound as an offwhite solid; CI-MS 393 (m 1).

Step 4: rl-((Benzvloxv-benzyl)-{[2-(2-fluorophenyl)ethvl-carbamoyll-methyl}-carbamoyl)-2-(1tritvl-1H-imidazole-4-vl)-ethyll-carbamic acid benzyl ester To a solution of (S)-(2-benzyloxycarbonylamino- 3-(l-trityl)-lH-imidazole-4-yl)-propionic acid (Cbzhistidine-(trityl)) (Hudspeth Kaltenbronn J.S., Repine Roark Stier Renin Inhibitors III, United States Patent Number 4,735,933; 1988) (0.532 g, 1.0 mmol) in methylene chloride (20 mL) was added diisopropylethylamine (0.48 mL, 2.75 mmol) and benzotriazole-l-yl-oxy-tris-pyrrolidino-phosphonium 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 was treated with a saturated aqueous NaHCO 3 solution, and the layers were separated.

The aqueous layer was extracted with methylene chloride WO 97/44350 PCT/US97/06591 -53- (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 of the title compound as a white foam; ES-MS 906.5 (m 1).

Step 5: [l-((4-Benzvloxv-benzvl)-f[2-(2-fluorophenvl) -ethylcarbamoyl -methyl -carbamoyl) -2- (lH-imidazole-4-vl)-ethyll-carbamic acid benzyl ester To a solution of the trityl compound (0.49 g, 0.54 mmol) from Step 4 above in methylene chloride mL) was added TFA (5 mL) and triisopropylsilane (0.25 mL). The solution was stirred for 3 hours, then concentrated. The residue was partitioned between a saturated aqueous solution of 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 of the title compound as a white foam; ES-MS 664.4 (m 1).

EXAMPLE 8 (S)-[l-f(4-Benzvloxv-benzvl)-r(2-Dvridin-2-vlethylcarbamoyl)-methyll-carbamoyll-2-(lH-imidazole-4vl)-ethvll-carbamic acid benzyl ester Step 1: (4-Benzvloxvbenzvlamino) acetic acid t-butvl ester To a mixture of glycine t-butyl ester hydrochloride (0.84 g, 5 mmol), and 4-benzyloxybenzaldehyde (0.53 g, 2.5 mmol) in CH 2 C12 (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 was added, and the mixture was stirred for 30 minutes. The WO 97/44350 PCT/US97/06591 -54aqueous layer was extracted 3 times with CH 2 C12. The combined organic extracts were washed with brine, dried over MgS04, and concentrated. Flash chromatography (ethyl acetate) gave 0.38 g of the title compound as a white solid.

Step 2: N- N-[(Phenvlmethoxv)carbonvll-L-histidyltrityll-N-[[4- (phenvlmethoxv)phenyllmethyl qlycine t-butvl 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 mL, 3.9 mmol). The amine from Step 1 above (0.38 g, mmol) was then added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, the residue taken up in ethyl acetate, which was washed 3 times with saturated NaHC0 3 brine, dried over MgSO 4 and concentrated.

Flash chromatography gave 0.59 g of the title compound as a white foam; ES-MS 841 (m 1).

Step 3: N- N- (Phenvlmethoxv)carbonvll-L-histidyll-N- 4- (phenvlmethoxv) phenvl 1 methyl 1 qlycine To a solution of the ester from Step 2 (0.59 g, 0.76 mmol), 50% trifluoroacetic acid in methylene chloride (25 mL) was added. The reaction was stirred at room temperature for 3 hours. The solution was concentrated in vacuo. Cold diethyl ether was added to the residue, and the solution was left at overnight. A white precipitate was obtained, filtered, and dried; 0.33 g Step 4: fl-{(4-Benzvloxv-benzvl)-[(2-Dvridin-2-vlethvlcarbamovl)-methyll-carbamoyl}-2-(1Himidazole-4-yl)-ethvll-carbamic acid benzyl ester r' WO 97/44350 PCT/US97/06591 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 mL, 1.3 mmol) followed by 2-pyridineethaneamine hydrochloride (0.082 g, 0.67 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, the residue taken up in ethyl acetate, which was washed 3 times with saturated NaHC0 3 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)-[l-((4-Benzvloxv-benzvl)-f 2-(2-bromo-phenyl)ethvlcarbamovll-methyl)-carbamovl)-2-(1H-imidazole- 4-vl)-ethvll-carbamic acid benzyl ester The title compound can be prepared according to Example 8, Step 4, by substituting 2-bromophenethylamine (Steps 1 and 2) for 2-pyridineethaneamine*HCl. The title compound is obtained as a white foam ES-MS 725 (m 1).

Step 1: o-Bromo-nitrostyrene To a solution of o-bromo-benzaldehyde (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 of H 2 0. After 45 minutes, the precipitate was dissolved in 10 mL of H 2 0. The product precipitated out after the addition of 6N HC1. The product was recrystallized from ethanol; 0.312 g Step 2: 2-Bromo phenethylamine To the styrene of Step 1 (0.310 g, 1.3 mmol) in 5 mL of THF was added 1 M LiAlH 4 solution in THF (5.2 mL, 5.2 mmol) at 0°C. The solution was stirred WO 97/44350 WO 9744350PCTIUS97/06591 -56f or 1 hour. A concentrated KHS0 4 solution was added dropwise to destroy the excess of LiAlH 4 The solution was filtered over celite and the filtrate concentrated in vacuo to give a yellow oil; 150 mg EXAMPLE -1-f (4-Benzyloxv-benzyl)- r (-methyl-2-iphenylethvlcarbamoyl) -methyl] -carbamovl)-2- (1H-imidazole-4vl)-ethvll--carbamic acid benzvl ester The title compound can be prepared according to Example 15, Step 5, by substituting L-amphetamine for D,Df-dimethylphenethylamine hydrochloride. The title compound is obtained as a white foam ES-MS 660 (m 1).

EXAMPLE 11 (4-Benzvloxv-benzvl) (-methvl-2-Dphenvlethvlcarbamoyl) -methyll -carbamovl}-2- (lH-imidazole-4vl)-ethvll-carbamic acid benzyl ester The title compound can be prepared according to Example 15, Step 5, by substituting D-amphetamine for DP -dimethylphenethylamine hydrochloride. The title compound is obtained as a white foam; ES-MS 660 (m 1).

EXAMPLE 12 1- f (4-Benzvloxv-benzvl) r(2-phenvl-2-pyridin-2-vlethvlcarbamoyl) -methyll -carbamovl}-2- (1H-imidazole-4vl)-ethvll-carbamic acid benzvl ester The title compound can be prepared according to Example 8, Step 4, by substituting 2- (aminomethyl) benzyl]pyridine hydrochloride (Step 1) for 2-pyridineethane-amine*HC1. The title compound is obtained as a white foam ES-MS 723 (m 1).

WO 97/44350 WO 9744350PCTIUS97/06591 -57- Step 1: 2-rF0- (Aminomethyl )benzvll Dyridine hydrochloride (x-(2-Pyridyl)-phenylacetonitrile (97.1 g, 0.5 mol) was reduced with Raney cobalt (25 g) and triethylaxnine (25 niL) in toluene (500 rnL) The solution was filtered, and the filtrate was concentrated. The residue was dissolved in diethyl ether, and HCl was bubbled in. The hydrochloride salt precipitated out of the solution.

EXAMPLE 13 F1- f (4-Chloro-benzyl) 2-phenYl-Drorpylcarbamoyl) methyl] -carbamoyll-2- (lH-imidazole-4-vl) -ethyl] carbamic acid benzyl ester The title compound can be prepared according to Example 8, Step 4, by substituting P-methylphenethylamine for 2-pyridineethane-amine.HCl and in Step 1, by substituting p-chloro-benzaldehyde for 4-benzyloxy-benzaldehyde. The title compound is obtained as a white foam ES-MS 588 (m 1).

EXAMPLE 14 fl-f(4-Benzyloxy-benzvl) f(2-hydroxy-2-iphenylethylcarbamoyl) -methyl] -carbamovll-2- (3H-imidazole-4vl)-ethyll-carbamic acid benzvl ester The title compound can be prepared according to Example 15, Step 5, by substituting 2-amino-lphenylethanol for IP,P1-dimethylphenethylamine hydrochloride. The title compound is obtained as a white foam ES-MS 662 (m 1).

EXAMPLE (S)-rl-f (4-Benzyloxy-benzvl)-F (2-methyl-2-phenylpropylcarbamoyl) -methyll -carbamoyD (3H-imidazole-4vl)-ethyll-carbamic acid benzvl'ester WO 97/44350 PCT/US97/06591 -58- Step 1: (4-Benzyloxvbenzvlamino) acetic acid methyl ester To a mixture of glycine methyl ester hydrochloride (2.07 g, 16.5 mmol), and 4-benzyloxy-benzaldehyde (3.18 g, 15 mmol) in CH 2 Cl 2 (50 mL) at 0°C was added Ssodium triacetoxyborohydride (3.81 g, 18 mmol). The mixture was allowed to warm to room temperature and stirred overnight. Aqueous NaHCO 3 was added, and the mixture was stirred for 30 minutes. The aqueous layer was extracted 3 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 of the title compound as a white solid; mp 57-58 0

C.

Step 2: N-[N-[(Phenvlmethoxv)carbonyll-L-histidyltrityll-N-rr4-(phenvlmethoxv)phenyllmethyl]qlvcine 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, the residue taken up in ethyl acetate, which was washed 3 times with saturated NaHCO 3 brine, dried over MgSO 4 and concentrated.

Flash-chromatography gave 1.68 g of the title compound as a white foam; ES-MS 557 (m 1).

Step 3: N-[N-r(Phenvlmethoxv)carbonvll-L-histidyltrityll-N-f[4-(phenvlmethoxv)phenvll-methyllalvcine To a solution of the ester from Step 2 (1.53 g, 2.75 mmol) in THF (15 mL) and H 2 0 (5 mL) at 0°C was added LiOH hydrate (0.14 g, 3.30 mmol), and the WO 97/44350 PCT/US97/06591 -59solution was stirred 5 hours at 0°C. The solution was concentrated, the residue taken up in H 2 0, and the pH was adjusted to 4-5 with 1N HC1. The resulting mixture was concentrated and dried in vacuo to afford 1.65 g of the title compound as a white solid; FAB-MS 543 (m 1).

Step 4: D,J-Dimethylphenethvlamine hydrochloride Sodium hydride (60% in oil) (17 g, 0.43 mol) was suspended in THF (150 mL) and cooled to 0°C under nitrogen. Benzyl cyanide (22.2 g, 0.19 mol) in THF mL) was added dropwise, and the reaction was left to stir for 1 hour. Iodomethane (24.9 mL, 0.4 mol) in THF (20 mL) was added dropwise at 0°C. The reaction was stirred at room temperature overnight, under nitrogen. The solution was filtered and the filtrate removed in vacuo. The residue was taken up in ethyl acetate (100 mL) and washed 3 times with 10% NaHS0 3 saturated NaHC0 3 brine, and dried over MgSO 4 concentrated; 22.74 g Reduction of the above product was 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 HC1 was added dropwise to precipitate the desired product; 24.8 g Step 5: [1-{(4-Benzvloxv-benzvl)-[(2-methyl-2-phenylproDvlcarbamoyl)-methvll-carbamoyl-2- (3-tritvl-3H-imidazole-4-vl)-ethvll-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) followed by B, -dimethylphenethylamine hydrochloride WO 97/44350 PCT/US97/06591 (from Step 4) (0.99 g, 5.33 mmol). Triethylamine (0.82 mL, 5.86 mmol) was added, and the mixture was stirred overnight at room temperature. The mixture was filtered, and the filtrate was diluted with CHC1 3 washed twice with saturated NaHCO 3 brine, dried over MgS0 4 and concentrated. Flash chromatography methanol/CHCl 3 gave 2.25 g of the title compound; ES-MS 917 (m 1).

Step 6: (S)-rl-{(4-benzvloxv-benzvl)-r(2-methyl- 2-phenvl-propylcarbamoyl)-methyll-carbamovl1- 2-(3H-imidazole-4-yl)-ethyll-carbamic acid benzvl ester To a solution of the trityl compound from Step (2.25 g, 2.4 mmol) was added glacial acetic acid mL) and water (5 mL). The mixture was stirred at 0 C for 30 minutes, then cooled and concentrated. The residue was taken up in ethyl acetate. The organic solution was washed twice with saturated NaHCO3, brine, and dried over MgS04. The solution was concentrated and the compound purified by flash chromatography 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 (4-Benzvloxv-benzvl)-F(2-phenvlbutylcarbamoyl)-methyll-carbamovl)-2-(1H-imidazole-4vl)-ethvll-carbamic acid benzyl ester The title compound can be prepared according to Example 15, Step 5, by substituting P-ethylbenzeneethamine hydrochloride (Step 1) for P,P-dimethylphenethylamine hydrochloride. The title compound is obtained as a white foam ES-MS 674 (m 1).

Step 1: O-Ethvlbenzeneethamine hydrochloride WO 97/44350 PCT/US97/06591 -61- This compound is synthesized by catalytic reduction of 2-phenylbutyronitrile as exemplified in B.K. Trivedi, et al., J. Med. Chem., 1993;36:3300-3307.

EXAMPLE 17 (S)-N-(4-Benzvloxv-benzvl)-3-(1H-imidazole-4-vl)-2-(3phenyl-propionylamino)-N-F(2-phenyl-propvlcarbamoyl)methyll-Dropionamide The title compound can be prepared according to Example 15, Step 2, by substituting phenylpropionylhistidine-(trityl) (Steps 1 and 2) for Cbz-histidine- (trityl) and Step 5 by substituting p-methylphenethylamine for P-dimethylphenethylamine hydrochloride. The title compound is obtained as a white foam ES-MS 658 (m 1).

Step 1: Phenvlpropionvl-histidine-(tritvl) methyl ester To a solution of histidine-(trityl) methyl ester hydrochloride (2.0 g, 4.2 mmol) and methyl piperidine (1.07 mL, 8.8 mmol) in methylene chloride at 0°C was added slowly 3-phenylpropionyl chloride (0.62 mL, 4.2 mmol), and the solution was stirred overnight at room temperature. Ethyl acetate was added and washed twice with water, saturated NaHC0 3 brine, dried over MgSO 4 and concentrated. The product was obtained as a white foam; 2.0 g Step 2: Phenvlpropionvl-histidine-(trityl) To a'solution of the ester from Step 1 (2.0 g, 3.7 mmol) in THF:methanol (10 mL each) and water (2 mL) was added sodium hydroxide (0.44 g, 11 mmol), and the solution was stirred overnight at room temperature.

The solvent was removed in vacuo and 5 mL of H 2 0 was added, followed by 1N HC1, to obtain pH 3. The product was extracted with ethyl acetate. The organic was WO 97/44350 WO 9744350PCTIUS97/06591 -62washed with 1N HCl, brine, dried over MgSO 4 and concentrated. The product was obtained as a white foam (2.18 ES-MS 529 (m 1).

EXAMPLE 18 IS)-r1-f (4-Fluoro-benzvl) (2-iphenyl-propylcarbamoyl)methyll -carbamoyl)-2- (lH-imidazole-4-vl) -ethyll carbamic acid benzvl ester The title compound can be prepared according to Example 8, Step 4, by substituting f-methylphenethylamine for 2-pyridineethaneamine*HC1 and in Step 1, by substituting p-fluoro-benzaldehyde for 4-benzyloxy-benzaldehyde. The title compound is obtained as a white foam ES-MS 572 (m 1).

EXAMPLE 19 (S)-(2-(lH-Imidazole-4-yl)-l-f(4-methyl-benzvl)-r(2iphenyl-iproipylcarbamoyl) -methyl) -carbamoyl -ethyl) carbamic acid benzyl ester The title compound can be prepared according to Example 8, Step 4, by substituting 1-methylphenethylamine for 2-pyridineethaneamine*HCl and in Step 1, by substituting p-methyl-benzaldehyde for 4-benzyloxy-benzaldehyde. The title compound is obtained as a white foam ES-MS 568 (m 1).

EXAMPLE (S)-(2-(lH-Imidazole-4-vl)-l-f(4-methoxy-benzvl)-r(2p~henyl-propyvlcarbamoyl) -methyll -carbamoy1l -ethyl) carbamic acid benzyl ester The title compound can be prepared according to Example 8, Step 4, by substituting 1-methylphenethylamine for 2-pyridineethaneamine-HCl and in Step 1, by substituting p-methoxy-benzaldehyde for 4-benzyloxy-benzaldehyde. The title compound is obtained as a white foam ES-MS 583 (m 1).

WO 97/44350 WO 9744350PCTIUS97/06591 -63- EXAMPLE 21 [1-rFf2- (2-Amino-Dphenvl) -Dropyvlcarbamoyll -methyl]- (4-benzvloxv-benzyl) -carbamoyll (3H-irnidazole-4-vl) ethyll-carbamic acid benzyl ester The title compound can be prepared according to Example 8, Step 4, by substituting' 2-ainino-f3methyiphenethylamine (Step 1) for 2-pyridineethaneamine-HCl. The title compound is obtained as a- white foam ES-MS 675 (m 1).

Step 1: 2 -Axnino-0-rethlphenethylamine Reduction of 4-methyl-cinnoline (10 g, 69.5 mmol) in methanol (100 mL), using Raney nickel (3 The catalyst was removed and washed with methanol. The filtrate was treated with an excess of HCl in isopropanol; ether was then added and the solution cooled. The precipitate was filtered and dried; 9.4 g EXAMPLE 22 (4-Fluoro-benzvl)-F (2-methvl-2-phenvliprot~vlcarbamoyl) -methyll -carbamovl}-2- (lH-imidazole-4vl)-ethyll-carbamic acid benzvl ester The title compound can be prepared according to Example 15, Step 1, by substituting p-f luorobenzaldehyde for 4-benzyloxy benzaldehyde. The title compound is obtained as a white foam ES-MS 586 (M 1).

EXAMPLE 23 r1- (Benzvl- r (2-phenyl-rpro-pylcarbamoyl) -methyll carbamovl]-2- (lH-imidazole-4-vl) -ethyll -carbamic acid benzyl ester The title compound can be prepared according to Example 8, Step 4, by substituting f3-methylphenethylanine for 2-pyridineethaneamine*HC1 and in WO 97/44350 PCT/US97/06591 -64- Step 1, by substituting benzaldehyde for 4-benzyloxybenzaldehyde. The title compound is obtained as a white foam ES-MS 554 (m 1).

EXAMPLE 24 S(S)-[1-((4-Benzvloxv-benzvl)-{[ 2-(2-chloro-phenvl)-2phenvl-ethvlcarbamoyll-methvl)-carbamovl)-2-(1Himidazole-4-vl)-ethyll-carbamic acid benzvl ester The title compound can be prepared according to Example 8, Step 4, by substituting o-chloro-P-phenylphenethylamine hydrochloride (Steps 1 and 2) for 2-pyridineethaneamine.HCl. The title compound is obtained as a white foam ES-MS 756 (m 1).

Step 1: 2-Phenvl-3-(2-chloro-phenl) cyanide Bromine (2 mL) was added dropwise to 2-chlorobenzylcyanide (5 g, 32 mmol) at 90 0 C over 1 hour with stirring. Nitrogen was passed over the reaction to remove HBr. The reaction was heated for 15 minutes, and benzene (2 mL) was then added. This solution was added dropwise to a refluxing solution of AlC1 3 (4.2 g, 32 mmol) in benzene (15 mL) over 2 hours. The reaction was refluxed 1 hour. The reaction was cooled and poured onto ice (200 g) and concentrated HC1 (20 mL).

The aqueous layer was extracted with diethyl ether and diethyl ether:benzene The organic solution was washed twice with H 2 0, saturated NaHC0 3 brine, and dried over Na 2

SO

4 and concentrated to give an orange oil; 6.3 g Step 2: o-Chloro-0-phenvl-phenethvlamine hydrochloride Reduction of the product from Step 1 was 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 WO 97/44350 PCT/US97/06591 added to the residue. Concentrated HC1 was added slowly until pH 3. The volume of ethanol was reduced in vacuo to about 5 mL, and the HC1 salt was precipitated by the addition of diethyl ether; 1.84 g EXAMPLE (4-Benzvloxv-benzvl)-r(2-ethvl-2-phenvlbutvlcarbamoyl)-methyll-carbamovl}-2-(3H-imidazole-4vl)-ethvll-carbamic acid benzyl ester The title compound can be prepared according to Example 15, Step 5, by substituting P,P-diethylbenzeneethaneamine hydrochloride (Step 1) for 3, -dimethylphenethylamine hydrochloride. The title compound is obtained as a white foam ES-MS 702 (m 1).

Step 1: P,.-Diethvlbenzeneethaneamine hvdrochloride This compound is synthesized by diethylating phenylacetonitrile followed by catalytic reduction as exemplified in B.K. Trivedi, et al., J. Med. Chem., 1993;36:3300-3307.

EXAMPLE 26 (S)-N-(4-Benzvloxv-benzvl)-2-(3-benzvl-ureido)-3-(1Himidazole-4-vl)-N-[(2-phenvl-propylcarbamoyl)-methyllpropionamide The title compound can be prepared according to Example 15, Step 2, by substituting benzyl-ureahistidine-(trityl) (Steps 1 and 2, Example 6) for Cbzhistidine-(trityl), and Step 5, by substituting P-methyl-phenethylamine hydrochloride for 3, -dimethylphenethylamine hydrochloride. The title compound is obtained as a white foam ES-MS 659 (m 1).

WO 97/44350 WO 9744350PCTIUS97/06591 -66- EXAMPLE 27 (4-Benzvloxv-benzyl) (3 -benzvl-ureido) (lHimidazole-4-yl) -N-F (2-pohenyl-butvlcarbamoyl) -methyll ipropionamide The title compound can be prepared according to Example 15, Step 2, by substituting benzyl-ureahistidine-(trityl).HCl (Steps 1 and 2, Example 6) for Cbz-histidine-(trityl), and Step 5, by substituting P-ethylbenzeneethamine hydrochloride (Step 1, Example 16) for J,f-dimethylphenethylanine hydrochloride. The title compound is obtained as a white foam ES-MS 673 (m 1).

EXAMPLE 28 (2-Chloro-benzvl)-r (2-iphenyl-ipropyvlcarbamoyl)methyll1-carbamoyl 1-2- (lH-imidazole-4-yl) -ethyll1carbamic acid benzvl ester

I

The title compound can be prepared according to Example 8, Step 4, by substituting P-methylphenethylamine for 2-pyridineethaneamine.HC1 and in Step 1, by substituting o-chloro-benzaldehyde for 4 -benzyloxy-benzaldehyde. The title compound is obtained as a white foam ES-MS 588 (m 1).

EXAMPLE 29 Fl-f (4-Bromo-benzyl) -rF(2-phenyl-propyvlcarbamoyl) methyll -carbamovll-2- (lH-imidazole-4-vl) -ethyll carbamic acid benzvl ester The title compound can be prepared according to Example 8, Step 4, by substituting P-methy1phenethylamine for 2-pyridineethaneamine.HCl and in Step 1, by substituting p-bromo-benzaldehyde for 4-benzyloxy-benzaldehyde. The title compound is obtained as a white foam ES-MS 633 (m 1).

WO 97/44350 PCT/US97/06591 -67- EXAMPLE (3-Chloro-benzyl) r (2-Dhenyl-proDlcarbamol) methvll-carbamoyl}-2-(lH-imidazole-4-vl)-ethyllcarbamic acid benzyl ester The title compound can be prepared according to Example 8, Step 4, by substituting P-methylphenethylamine for 2-pyridineethaneamine.HC1 and in Step 1, by substituting m-chloro-benzaldehyde for 4-benzyloxy-benzaldehyde. The title compound is obtained as a white foam ES-MS 588 (m 1).

EXAMPLE 31 (S)-[l-{(4-Chloro-benzyl)-r(2-methvl-2-Dhenylpropylcarbamoyl)-methyll-carbamoyl}-2-(lH-imidazole-4vl)-ethyll-carbamic acid benzyl ester The title compound can be prepared according to Example 15, Step 1, by substituting p-chlorobenzaldehyde for 4-benzyloxy-benzaldehyde. The title compound is obtained as a white foam ES-MS 602 (m 1).

EXAMPLE 32 (S)-[l-((4-Benzyloxv-benzyl)-f{2-(2-chloro-phenyl)propylcarbamoyll-methyl}-carbamoyl)-2-(lH-imidazole-4yl)-ethyll-carbamic acid benzyl ester The title compound can be prepared according to Example 8, Step 4, by substituting o-chloro-P-mqthylphenethylamine hydrochloride (Steps 1 and 2) for 2-pyridineethaneamine.HC1. The title compound is obtained as a white foam ES-MS 694 (m 1).

Step 1: 2-Methvl-3-(2-chloro-phenyl) cyanide To a suspension of NaNH 2 powder (0.6 g, 15.5 mmol) in THF (15 mL), 2-chlorophenylacetonitrile (2 g, 13 mmol) in THF (10 mL) was added. The mixture was refluxed for 2 hours. A solution of methyl iodide WO 97/44350 PCTUS97/06591 -68- (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 was cooled and treated with H 2 0. The organic layer was separated and washed twice with Na 2

S

2 03, brine, dried over Na 2

SO

4 and concentrated; 1.93 g Step 2: o-Chloro-D-methyl Dhenethvlamine hydrochloride Reduction of the product from Step 1 was 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 HC1 was added dropwise to precipitate the compound; 1.06 g EXAMPLE 33 (S)-(2-(lH-Imidazole-4-yl)-l-f(2-methoxv-benzyl)-[(2phenyl-proyvlcarbamoyl)-methyll-carbamoyl}-ethyl)carbamic acid benzyl ester The title compound can be prepared according to Example 8, Step 4, by substituting P-methylphenethylamine for 2-pyridineethaneamine.HCl and in Step 1, by substituting o-methoxy-benzaldehyde for 4-benzyloxy-benzaldehyde. The title compound is obtained as a white foam ES-MS 584 (m 1).

EXAMPLE 34 (S)-(2-(lH-Imidazole-4-vl)-l-r{[(2-phenvl-propvlcarbamovl)-methyll-[4-(pyridin-4-ylmethoxy)-benzyllcarbamovl)-ethyl)-carbamic acid benzyl ester The title compound can be prepared according to Example 15, Step 1, by substituting 4-[(4-pyridyl)methyloxy)-benzaldehyde (Step 1) for 4-benzyloxybenzaldehyde and Step 5 by substituting P-methylphenethylamine for P,P-dimethylphenethylamine WO 97/44350 WO 9744350PCTIUS97/06591 -69hydrochloride. The title compound is obtained as a white foam ES-MS 661 (mn 1).

Step 1: 4-F (4-Pvridvl) -methvloxvl -benzaldehyde This compound is synthesized as exemplified in J. Het. Chem., 1988;25:129.

EXAMPLE 3 (lH-Imidazole-4-yl) -1-f(3-methoxy-benzvl) pohenyl-Droipylcarbamoyl) -methyl] -carbamoyll-ethyl) carbamic acid benzyl ester The title compound can be prepared according to Example 8, Step 4, by substituting j3-methylphenethylamine for 2-pyridineethaneamine-HC1 and in Step 1, by substituting m-methoxy-benzaldehyde for 4-benzyloxy-benzaldehyde. The title compound is obtained as a white foam ES-MS 584 (m 1).

EXAMPLE 36 (S)-(2-(lH-Imidazole-4-yl)-l-f[ (2-iphenylp~roipvlcarbamoyl) -methyl] (ipridin-3-ylmethoxy) benzvll -carbamoyl} -ethyl) -carbamic acid benzvl ester The title compound can be prepared according to Example 15, Step 1, by substituting 4-[(3-pyridyl)methyloxyl-benzaldehyde (Step 1) for 4-benzyloxybenzaldehyde and Step 5 by substituting P-methylphenethylamine for 03,0-dimethylphenethylamine hydrochloride. The title compound is obtained as a white foam ES-MS 661 (m 1).

Step 1: 4-f (3-Pyridyl) -methyloxyl benzaldehvde This compound is synthesized as exemplified in J. Het. Chem., 1988;25:129.

WO 97/44350 WO 9744350PCT/US97/06591 EXAMPLE 37 (lH-Imidazole-4-yl)-l-fnaphthalen-l-ylmethvl- (2-pohenyl-Dpropylcarbamoyl) -methyl] -carbamovl} -ethyl) carbamic acid benzvl ester The title compound can be prepared according to Example 15, Step 1, by substituting l-naphthalenecarboxaldehyde for 4-benzyloxy-benzaldehyde and Step by substituting J-methylphenethylamine for P,Of-dimethylphenethylaxnine hydrochloride. The title compound is obtained as a white foam ES-MS 604 (m 1).

EXAMPLE 38 (lH-Imidazole-4-yl) r(2-p~henylproipylcarbamoyl) -methl- (4-trifluoromethyl-benzvl) carbamovll -ethyll-carbamic acid benzvl ester The title compound can be prepared according to Example 8, Step 4, by substituting f-methylphenethylamine for 2-pyridineethaneamine*HCl and in Step 1, by substituting p-trifluoromethyl-benzaldehyde for 4-benzyloxy-benzaldehyde. The title compound is obtained as a white foam ES-MS 622 (m 1).

EXAMPLE 39 (S)-(2-(lH-Irnidazole-4-yl)-l-f [(2-methyl-2-p~henylproipylcarbamoyl) -methyl] -pyridin-3 -ylmethylcarbamovl) -ethyl) -carbamic acid benzvl ester The title compound can be prepared according to Example 15, Step 1 by substituting 3-pyridin-aldehyde for 4-benzyloxy-benzaldehyde. The title compound is obtained as a white foam ES-MS 569 (m 1).

EXAMPLE (S)-(2-(lH-Imidazole-4-yl)-1-(fr(2-methyl-2-iphenylpropylcarbamoyl) -methyl] (pyridin-2-ylmethoxy) benzvll -carbamoyl -ethyl) -carbamic acid benzyl ester WO 97/44350 PCT/US97/06591 -71- The title compound can be prepared according to Example 15, Step 1, by substituting 4-[(2-pyridyl)methyloxy]-benzaldehyde (Step 1) for 4-benzyloxybenzaldehyde. The title compound is obtained as a white foam ES-MS 675 (m 1).

Step 1: 4-[(2-Pyridyl)-methvloxvl-benzaldehvde This compound is synthesized as exemplified in J. Het. Chem., 1988;25:129.

EXAMPLE 41 (S)-2-(3-Benzyl-3-methvl-ureido)-N-(4-benzvloxvbenzvl)-3-(lH-imidazole-4-yl)-N-[(2-methyl-2-phenylpropvlcarbamoyl)-methyll-propionamide The title compound can be prepared according to Example 15, Step 2, by substituting N-methyl-N-benzylurea-histidine-(trityl) (Steps 1 and 2) for Cbzhistidine-(trityl). The title compound is obtained as a white foam ES-MS 687 (m 1).

Step 1: N-methyl-N-benzvl-urea-histidine-(trityl) methyl ester Histidine-(trityl) methyl ester hydrochloride g, 4.2 mmol) was suspended in methylene chloride (20 mL,) and the solution was washed twice with saturated NaHC0 3 and brine, dried over MgSO 4 and cooled to 0°C. Triethylamine (0.65 mL, 8.8 mmol) and 4-nitrophenyl chloroformate (0.93 g, 4.7 mmol) was added. The reaction was stirred at 0°C under nitrogen for 1.5 hours. N-benzyl-N-methylamine (1.14 mL, 8.8 mmol) in methylene chloride (10 mL) was then added slowly, and the reaction was stirred at room temperature overnight, under nitrogen. The solvent was removed, and ethyl acetate was added to the residue.

The organic solution was washed twice with saturated NaHC0 3 brine, and dried over MgSO 4 and WO 97/44350 PCTIUS97/06591 -72concentrated. Chromatography using 1:1 ethyl acetate: hexanes gave a foam; 1.19 g Step 2: N-methyl-N- benzvl-urea-histidine-(tritvl) The methyl ester from Step 1 (1.19 g, 2.1 mmol) was dissolved in THF:methanol (10 mL of each). 1N NaOH (6.3 mL, 6.3 mmol) was added, and the reaction was stirred overnight. The solvent was removed. 1N HC1 (6.3 mL) was added and extracted with ethyl acetate.

The organic solution was then washed twice with brine, dried over MgS0 4 and concentrated to give a white foam; 1.4 g.

EXAMPLE 42 (S)-[l-{Benzyl-[(2-methvl-2-phenvl-propylcarbamoyl)methvll-carbamoyl}-2-(1H-imidazole-4-vl)-ethyl carbamic acid benzyl ester The title compound can be prepared according to Example 8, Step 4, by substituting ,P-dimethylphenethylamine hydrochloride for 2-pyridineethaneamine-HCl and in Step 1, by substituting benzaldehyde for 4-benzyloxy-benzaldehyde. The title compound is obtained as a white foam ES-MS 568 (m 1).

EXAMPLE 43 (S)-(2-(1H-Imidazole-4-vl)-l-f(2-methvl-benzyl)-[(2phenyl-propylcarbamovl)-methyll-carbamoyl}-ethyl)carbamic acid benzyl ester The title compound can be prepared according to Example 8, Step 4, by substituting P-methylphenethylamine for 2-pyridineethaneamine-HC1 and in Step 1, by substituting o-methyl-benzaldehyde for 4 -benzyloxy-benzaldehyde. The title compound is obtained as a white foam ES-MS 568 (m 1).

WO 97/44350 WO 9744350PCTIUS97/06591 -73- EXAMPLE 44 (S)-(2-(lH-Imidazole-4-vl)-l-f(4-methoxv-benzvl)-F (2methvl-2-pohenyl-tropvylcarbamoyl) -methyll -carbamovl} ethvl)-carbanic acid-benzvl ester The title compound can be prepared according to Example 8, Step 4, by substituting P,f3-dimethylphenethylamine hydrochloride for 2 -pyridineethaneamine*HCl and in Step 1, by substituting p-methoxybenzaldehyde for 4-benzyloxy-benzaldehyde. The title compound is obtained as a white foam ES-MS 598 (mn 1).

EXAMPLE (S)-f1-f (4-Benzvloxv-benzvl)-f (2-cvano-2-phenvlethvlcarbamoyl) -methyll -carbamovll (1H-imidazole-4vl)-ethvll-carbamic acid benzvl ester The title compound can be prepared according to Example 15, Step 5, by substituting P-cyanophenethylamine hydrochloride (Step 1) for PP-dimethylphenethylamine hydrochloride. The title compound is obtained as a white foam ES-MS 671 (m 1).

Step 1: D-Cvano-phenethlanine hydrochloride This compound is synthesized according to the United States Patent No. 4,760,089, 1988, which is hereby incorporated by reference.

EXAMPLE 46 UH-Imidazole- 4-vl) 1-f r(2 -methyl -2 -rhenvl- D~roT~ylcarbamoyl) -methvll-pvridin-2-vlm-ethvlcarbamovl)-ethvl)-carbamic acid benzvl ester The title compound can be prepared according to Example 15, where Step 1 is carried out as shown below.

The title compound is obtained as a white foam ES-MS 569 (m 1).

WO 97/44350 PCT/US97/06591 -74- Step 1: f(2-Pvridvl)-methvlamino)1-acetic acid methyl ester 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). After stirring for 1 hour at room temperature, the solution was heated at reflux overnight. The solution was diluted with ethyl acetate and washed with saturated NaHCO 3 water, and brine, dried over MgS04, and concentrated.

Chromatography eluting with 3% methanol in chloroform gave 2.73 g of pure product, as an oil.

EXAMPLE 47 (S)-(2-(lH-Imidazole-4-vl)-1-f(3-methvl-benzvl)-[(2phenvl-Dropylcarbamoyl)-methyll-carbamoyl}-ethyl)carbamic acid benzyl ester The title compound can be prepared according to Example 8, Step 4, by substituting P-methylphenethylamine for 2-pyridineethaneamine.HC1 and in Step 1, by substituting m-methyl-benzaldehyde for 4-benzyloxy-benzaldehyde. The title compound is obtained as a white foam ES-MS 568 (m 1).

EXAMPLE 48 (S)-[l-{(4-Dimethvlamino-benzvl)-f(2-phenylpropylcarbamovl)-methyll-carbamovl}-2-(lH-imidazole- 4-vl)-ethyll-carbamic acid benzvl ester The title compound can be prepared according to Example 8, Step 4, by substituting P-methylphenethylamine for 2-pyridineethaneamine.HCl and in Step 1, by substituting p-dimethylamino-benzaldehyde for 4-benzyloxy-benzaldehyde. The title compound is obtained as a white foam ES-MS 597 (m 1).

WO 97/44350 WO 9744350PCTIUS97/06591 EXAMPLE 49 -(2-(lH-Imidazole-4-vl) -1-f r (2-methvl-2-YDhenylipropyvlcarbamoyl) -methyl]I f 4 (pvridin- 4-vlmethoxy) benzvll -carbamovJ) -ethyl) -carbamic acid benzyl ester The title compound can be prepared according to Example 15, Step 1, by substituting 4- [(4-pyridyl) methyloxy]-benzaldehyde (Step 1) for 4-benzyloxybenzaldehyde. The title compound is obtained as a white foam ES-MS 675 (m 1).

Step 1: 4- f(4-Pvridvl) -methyloxyl -benzaldehvde This compound is synthesized as exemplified in J. Het. Chem., 1988;25:129.

EXAMPLE -(2-(lH-Imidazole-4-vl)-1-( f r(2-methvl-2-phenylipropylcarbamoyl) -methyl]I r 4 (pvridin-3 -vlmethoxv) benzvll -carbamoyll-ethyl) -carbamic acid benzvl ester The title compound can be prepared according to Example 15, Step 1, by substituting 4-[(3-pyridyl)methyloxy]-benzaldehyde (Step 1) for 4-benzyloxybenzaldehyde. The title compound is obtained as a white foam ES-MS 675 (m 1).

Step 1: 4-F (3-Pyridyl) -methvloxvl -benzaldehyde This compound is synthesized as exemplified in J. Het. Chem., 1988;25:129.

EXAMPLE 51 1-f Biphenyl-4-ylmethvl-F (2-p~henylirolpvlcarbamovl) -methyl] -carbamoyl 1-2- (1Himidazole-4-yl)-ethyll-carbamic acid benzvl ester The title compound can be prepared according to Example 15, Step 1, by substituting p-phenylbenzaldehyde for 4-benzyloxy-benzaldehyde and in Step 5, by substituting P-methyl-phenethylamine WO 97/44350 PCT/US97/06591 -76hydrochloride for P,P-dimethyphenethylamine hydrochloride. The title compound was obtained as a white foam ES-MS 630 (m 1).

EXAMPLE 52 Biphenl-4-vlmethl-(2-methvl-2-Dhenvloroovlcarbamoyl)-methyll-carbamovl}-2-(iNimidazole-4-vl) -ethyll-carbamic acid benzvl ester The title compound can be prepared according to Example 15, Step 1, by substituting p-phenylbenzaldehyde for 4-benzyloxy-benzaldehyde. The title compound was obtained as a white foam ES-MS 644 (m 1).

EXAMPLE 53 (S)-[l-((4-Benzvlox-benzvl)-f 12-(2-chloro-ohenyl)ethvlcarbamoyll-methvl}-carbamoyl)-2-(lH-imidazole-4vl)-ethvll-carbamic acid benzvl ester The title compound can be prepared according to Example 7, Step 1, by substituting 2-chiorophenethylamine for 2-[(2-fluorophenyl)-ethyl]-amine.

The title compound is obtained as a white foam ES-MS 681 (m 1).

EXAMPLE 54 l-f (4-Benzvloxv-benzvl) r (2-methvl-2-n~henvloroo~vlcarbamoyl)-methyll-carbamovi}-2-(lH-imidazole- 4-vl)-ethyll-carbamic acid thiophen-3-vlmethvl ester The title compound can be prepared according to Example 15, Step 2, by substituting 3-thiophenemethyloxycarbonyl-histidine-(trityl) (Steps 1 and 2) for Cbz-histidine-(trityl). The title compound is obtained as a white foam ES-MS 680 (m 1).

WO 97/44350 PCT/US97/06591 -77- Step 1: 3-Thiophenemethvloxvcarbonyl-histidine- (tritvl) methyl ester 3-Thiophene methanol (0.43 mL, 4.6 mmol), triethylamine (0.64 mL, 4.6 mmol), and 4-nitrophenyl chloroformate (0.92 g, 4.6 mmol) were dissolved in methylene chloride (20 mL) and cooled to 0 0 C under nitrogen. After 1 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 was stirred overnight. The solvent was removed in vacuo. Ethyl acetate and water were added. The organic layer was washed with saturated NaHC0 3 brine, dried over MgSO 4 and concentrated to give a yellow oil. Flash chromatography (1:1 ethyl acetate:hexanes) yielded a white foam; 1.15 g Step 2: 3-Thiophenemethvloxvcarbonvl-histidine- (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 lN NaOH (6.3 mL, 6.3 mmol) and the solution was stirred overnight at room temperature. The solution was concentrated, 1N HC1 (6.3 mL) was added, and the product extracted with ethyl acetate, which was washed twice with brine, dried over MgSO 4 and concentrated to give a white foam; 1.12 g EXAMPLE (S)-[1-{(4-Chloro-benzvl)-1-(2-methyl-2-phenvlpropvlcarbamoyl)-ethyll-carbamoyl}-2-(3H-imidazole- 4 -yl)-ethyll-carbamic acid benzvl ester The title compound can be prepared according to Example 15, Step 1, by substituting alanine methyl ester hydrochloride for glycine methyl ester hydrochloride and in Step 2 by substituting WO 97/44350 WO 9744350PCTIUS97/06591 -78- 1-hydroxy-7-azabenzotriazole (HOAt) and 0- (7-azabenzotriazol-1-yl) 1, 3, 3-tetramethyluroniun hexafluorophosphate (HATJ) for PyBOB. The title compound is obtained as a white foam ES-MS 617 (m 1).

EXAMPLE 56 2 -(lH-Imidazole-4-vl)-l-f(4-methyl-benzvl)F(2methvl-2-iphenyl-propyvlcarbamoyl) -methyll -carbamol)~ethvl)-carbamic acid benzvl ester The title compound can be prepared according to Example 15, Step 1, by substituting 4-methylbenzaldehyde for 4-benzyloxy-benzaldehyde. The title compound is obtained as a white foam ES-MS 582 (m 1).

EXAMPLE 57 (S)-(2-(lH-Imidazole-4-vl)-l-{ (2-methoxv-benzvl)-[ (2methvl-2-phenvl-iDror~vlcarbamoyl) -methyll -carbamoyl}ethvl)-carbamic acid benzvl ester The title compound can be prepared according to Example 8, Step 1, by substituting 2-methoxybenzaldehyde for 4-benzyloxy-benzaldehyde and in Step 4, by substituting PP-dimethylphenethylamine (Example 15, Step 4) for 2-pyridine-ethaneamine hydrochloride. The title compound is obtained as a white foam ES-MS 598 (m 1).

EXAMPLE 58 (3-Benzvl-3-methyl-ureido)-N-(4-chloro-benzvl)- 3- (lH-imidazole-4-vl) -N-r[(2-methvl-2-phenyliororvlcarbamovl) -methyll1-propioiamide The title compound can be prepared according to Example 15, Step 1, by substituting 4-chlorobenzaldehyde for 4-be nzyloxy-benzaldehyde and in Step 2, by substituting N-methyl-N-benzyl-urea- WO 97/44350 WO 9744350PCTIUS97/06591 -79histidine-(trityl) (Example 41, Steps 1 and 2) for Cbz-histidine- (trityl). The title compound is obtained as a white foam ES-MS 616 (mn 1).

EXAMPLE 59 UH-Imidazole-4-yl)-1- f (3-methoxv-benzyl) -r (2methvl-2-iphenvl-Dproipvlcarbamovl) -methyll -carbamoyllethvl)-carbamic acid benzvl ester The title compound can be prepared according to Example 8, Step 1, by substituting 3-methoxybenzaldehyde for 4-benzyloxy-benzaldehyde and in Step 4, by substituting 0,0J-dimethylphenethylamine (Example 15, Step 4) for 2-pyridine-ethaneamine hydrochloride. The title compound is obtained as a white foam ES-MS 598 (m 1).

EXAMPLE (S)-(2-(lH-Imidazole-4-vl)-l-f r(2-methvl-2-iphenvlpr o~vlcarbamoyl) -methvll 2- (pvridin-4-vlmethoxv) benzvll-carbamovl}-ethvl)-carbamic acid benzyl ester The title compound can be prepared according to Example 15, Step 1, by substituting 2-[(4-pyridyl)methyloxy]-benzaldehyde (Step 1) for 4-benzyloxybenzaldehyde. The title compound is obtained as a white foam ES-MS 676 (m 1).

Step 1: 2- F(4-Pvridvl) -methvloxvl -benzaldehvde A solution of salicylaldehyde (5 g, 40.9 mmol) in DMSO (75 mL) was treated with crushed potassium hydroxide (5.4 g, 81.8 mnmol) and allowed to stir at room temperature for 1 hour. This was then treated with 4-picolyl chloride hydrochloride (6.8 g, 40.9 mmol) and the dark mixture 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 WO 97/44350 PCT/US97/06591 with water then with brine. Drying over MgSO 4 and removal of the solvent under reduced pressure gave the crude product. This was taken up in ethyl acetate, treated with charcoal, filtered, and the solvent removed under reduced pressure to give 5.42 g (62.1%) of the product as an oil; MS-CI 214 (M 1).

EXAMPLE 61 fl-(Cvclohexvlmethyl-[(2-phenyl-propylcarbamoyl)methyll-carbamoyl}-2-(3H-imidazole-4-yl)-ethyllcarbamic acid benzyl ester The title compound can be prepared according to Example 8, Step 1, by substituting cyclohexanecarboxaldehyde for 4-benzyloxy-benzaldehyde and in Step 4, by substituting P-methyl-phenethyl-amine for 2-pyridineethaneamine HC1. The title compound is obtained as a white foam MS-ES 559 (M H).

EXAMPLE 62 (S)-(2-(1H-Imidazol-4-vl)-l-(isobutvl-f(2-phenylproDylcarbamoyl)-methyll-carbamovl}-ethyl)-carbamic acid benzyl ester Step 1: N-Boc-N-f(2-phenyl-propylcarbamoyl)-methyl]qlycinamide To a solution of Boc-glycine (2.1 g, 12 mmol) in methylene chloride (100 mL) was added 3-methylphenethylamine (1.91 mL, 13.2 mmol), l-hydroxybenzotriazole (Hobt) (1.78 g, 13.2 mmol), dicyclohexylcarbodiimide (DCC) (0.5 M DCC in methylene chloride; 26 mL, 13.2 mmol) and diisopropylethylamine (4.17 mL, 24 mmol). The reaction was stirred at room temperature overnight. The reaction solution was filtered. The filtrate was washed 3 times with brine. The organic solution was dried over MgSO 4 and concentrated. Flash chromatography methanol in chloroform) gave 3.5 g r WO 97/44350 PCT/US97/06591 -81- (100%) of the title compound as a white solid; CI-MS 293 (m 1).

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

Step 3: N-[(2-Dhenvl-propvlcarbamoyl)-methyl]-Na- (4-benzvloxv-benzvl)-qlvcinamide hydrochloride salt To a suspension of the compound from Step 2 above (1.16 g, 6 mmol), isobutyraldehyde (0.274 mL, 3 mmol), and sodium acetate (0.59 g, 7.25 mmol) in methylene chloride (25 mL) were added. The solution was cooled to 0°C, and sodium triacetoxyborohydride (1.92 g, 9.1 mmol) was added. The reaction was allowed to warm to room temperature and was stirred overnight. The reaction was treated with a saturated aqueous NaHCO 3 solution, and the layers were separated. The aqueous layer was extracted with methylene chloride (2 x 20 mL). The organic layers were combined and washed 3 times with brine, dried over MgSO 4 and concentrated.

The product was purified by flash chromatography methanol in chloroform) to give 0.22 g of the title compound: CI-MS 249 (m 1).

WO 97/44350 PCT/US97/06591 -82- Step 4: 2 -(l-tritvl-1H-imidazole-4-vl)-l-(isobutvl- [(2-phenyl-provlcarbamoyl)-methyl carbamovl}-ethvl)-carbamic acid benzvl ester To a solution of (S)-(2-benzyloxycarbonylamino- 3 -(l-trityl)-1H-imidazole-4-yl)-propionic acid (Cbzhistidine-(trityl)) (Hudsspeth Kaltenbronn J.S.; Repine Roark Stier M.A. Renin Inhibitors III. United States Patent No. 4,735,933; 1988), (0.532 g, 1.0 mmol) in methylene chloride (50 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'tetramethyluronium hexafluorophosphate (HATU) (0.67 g, 1.7 mmol), l-hydroxy-7-azabenzotriazole (HOAt) (0.24 g, 1.7 mmol) and diisopropylethylamine (1.08 mL, 6.2 mmol). The mixture was then treated with amine (0.22 g, 0.88 mmol) from Step 3 above, and stirred overnight. The reaction solution was concentrated and the residue dissolved in ethyl acetate (25 mL). The organic solution was washed 3 times with 5% citric acid, 5% NaHCO 3 and brine, dried over MgS0 4 and concentrate. The product was used without further purification in the next step.

Step 5: 2 -(lH-imidazole-4-yl)-l-{isobutvl- 2 -phenvl-propvlcarbamoly)-methyllcarbamovll-ethvl)-carbamic acid benzvl ester To a solution of the trityl compound (0.64 g, 0.86 mmol) from Step 4 above in methylene chloride mL) was added TFA (25 mL). The solution was stirred for 3 hours, then concentrated. The residue was partitioned between a saturated aqueous solution of 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 MgS04, and concentrated. Purification by reversed-phase high pressure liquid chromatography (eluents: 0.1% TFA in water and 01% TFA in WO 97/44350 PCT/US97/06591 -83acetonitrile) was carried out and gave 0.060 g of the title compound: ES-MS 520 (m 1).

PFT Inhibitory Activity The protein:farnesyl transferase (PFT) or farnesyl protein transferase (FPT) inhibitory activity of compounds of the present invention were assayed in HEPES buffer (pH 7.4) containing 5 mM potassium phosphate and 20 pM ZnC1 2 The solution also contained 5 mM DTT (dithiothreitol), 5 mM MgCl 2 and 0.1% PEG 8000. Assays were performed in 96 well plates (Wallec) and employed solutions composed of varying concentrations of a compound of the present invention in 100% DMSO (dimethylsulfoxide). Upon addition of both substrates, radiolabeled farnesyl pyrophosphate ([1 3 specific activity 15-30 Ci/mmol, final concentration 134 nM) and (biotinyl)-Ahe-Thr-Lys-Cys- Val-Ile-Met ([3aS[3a alpha, 4 beta, 6a 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, Ile is isoleucine and Met is methionine) (final concentration 0.2 pM), the enzyme reaction was started by addition of SF9 affinity purified rat farnesyl protein transferase.

After incubation at 30 0 C for 30 minutes, the reaction was terminated by diluting the reaction 2.5-fold with a stop buffer containing 1.5 M magnesium acetate, 0.2 M

H

3

PO

4 0.5% BSA (bovine serum albumin), and strepavidin beads (Amersham) at a concentration of 1.3 mg/mL.

After allowing the plate to settle for 30 minutes at room temperature, radioactivity was quantitated on a microBeta counter (Model 1450, Wallec). The assay was also carried out without 5 mM potassium phosphate.

WO 97/44350 PCT/US97/06591 -84- Gel Shift Assay Twenty-four hours after planting 2 x 106 rastransformed cells per treatment condition, the farnesylation inhibitor is added at varying concentrations. Following an 18-hour incubation period, cells are lysed in phosphate-buffered saline containing 1% Triton X-100, 0.5% sodium deoxycholate, and 0.1% SDS (sodium dodecyl sulfate), pH 7.4 in the presence of several protease inhibitors (PMSF (phenylmethylsulfonylfluoride), antipain, leupeptin, pepstatin A, and aprotinin all at 1 pg/mL). Ras protein is immunoprecipitated from the supernatants by the addition of 3 pg v-H-ras Ab-2 (Y13-259 antibody from Oncogene Science). After overnight immunoprecipitation, 30 pL of a 50% protein G-Sepharose slurry (Pharmacia) is added followed by incubation. Pellets are resuspended in 2X tris-glycine loading buffer (Novex) containing 5% P-mercaptoethanol and then denatured by 5 minutes boiling prior to electrophoresis on 14% Tris-glycine SDS gels. Using Western transfer techniques, proteins are transferred to nitrocellulose membranes followed by blocking in blocking buffer. Upon overnight incubation with primary antibody (pan-ras Ab-2 from Oncogene Science), an antimouse HRP (horse radish peroxidase) conjugate secondary antibody (Amersham) is employed for detection of the ras protein. Blots are developed using ECL(enhanced chemiluminescence) techniques (Amersham).

Clonogenic Assay (6 well plates) Sometime previous to setting up an actual test: 1. Make up 1.5% Bacto Agar in Milli-Q water and autoclave.

2. Make up 500 mL 2X DMEM-HG without phenol red by combining the following:

I

WO 97/44350 PCT/US97/06591 1 bottle DMEM base powder (Sigma D-5030) g glucose 3.7 g sodium bicarbonate 0.11 g sodium pyruvate 20 mL of 200 mM L-glutamine (Sigma G-7513) 1 mL pen-strep (GibcoBRL No. 15140-023) Adjust pH to 7.1 with HCL; filter sterilize.

1. Set up makeshift water bath (beaker of water with thermometer, on hot plate) in the hood. Keep water temperature between 37 0 C to 43 0

C.

2. Autoclave 1.5% Bacto Agar for approximately 2 minutes on high, or until completely melted.

Then let it cool somewhat before using it. (You can keep it from resolidifying by setting the bottle on the hot plate.) 3. Bottom Layer agar) Top Layer aqar) 20% calf serum 20% calf serum 2X DMEM 50% 2X DMEM Bacto Agar 20% Bacto Agar sterile H 2 0 x uL cell suspension (to 5000 cells/well) (H61 cells: NIH transformed 3T3 H-ras cells) Depending on the volume of each layer needed, use either 50 mL conical tubes or 200 mL turnip tubes which can be floated in the "water bath".

4. Add 1 mL of bottom layer agar/medium to each well: deliver 1 mL warm agar/medium to a well; then using the tip of the pipet, spread the agar/medium around to completely cover the bottom. Repeat with next well. Do Not add the last mL in the pipet to a well, it leads to bubbles.

Ji WO 97/44350 PCT/US97/06591 -86- Allow the plates to set at room temperature for about 5 minutes until the bottom layer solidifies.

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

7. Aliquot 4 pL of DMSO or drug solution per 1 mL of agar/medium to appropriate tubes; then add the agar/medium/cells to each tube. Always add 1 mL more than will actually be needed. Mix up and down in the pipet (gently); then deliver 1 mL to the center of each well. The upper layer is less viscous, so it will generally spread out over the bottom layer unaided. If necessary, rotate the plane of the plate gently to spread the top layer evenly over the bottom layer.

8. Let plates set for 5 or 10 minutes at room temperature to solidify, then put into 5% C0 2 370C incubator.

9. On Day 13, add 0.5 mL of INT (tetrazolium 1 mg/mL in Milli-Q H 2 0, filter sterilized) and return plates to incubator.

Count colonies.

The data in the Table below shows farnesyl protein transferase inhibitory activity, and activity in the gel shift and clonogenic assays against ras protein of compounds of the present invention.

WO 97/44350 PCT/US97/06591 -87- Example IC50 (IM) IC 50 (pM) Gel Shift Clonogenic Assay No. Hepes 5 mM K 3 P0 4 -2 (PM) MED* IC 50

(PM)

7.7 2.84 (2.1) 3.1 (2.8) 5.8 (0.15) 1.73 (1.6) 0.2 (0.5) 9.8 7.8 0.58 1.1 1.4 1.6 0.12 0.29 2.8 2.8 1.26 0.16 1.2 1.6 0.20 0.93 0.15 0.12 2.6 0.26 0.024 (0.062) 0.97 (0.61) 0.0076 (0.005) 0.038 0.0022 (0.017) 0.36 0.30 0.36 0.018 0.082 0.062 0.022 0.066 0.007 0.007 0.086 0.061 0.015 0.017 0.008 0.016 0.022 0.014 0.032 0.009 0.014 0.043 1 0.1 0.25 0.05 0.2 (0.05) 0.2 0.1 0.2 0.2 0.01-0.05 0.2 0.2 0.2 0.05 0.01-0.05 0.01-0.05 0.2 0.2 0.05 0.05 0.05 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.1 0.1 0.1 0.05 0.05 0.05 0.2 20.05 20.2 0.2 2.7 (14.3) 9.2 (4.33) >1 >1 (0.31) 0.71 >1 >1 >1 >1 0.71 >1 >1 >1 >1 0.19 0.40 >1 >1 0.66 0.46 0.30 >1 >1 0.82 0.89 >1 >1 0.6 >1 >1 >1 0.36 0.36 0.14 >1 0.32 0.78 0.52 0.32 0.50 0.097 2.1 0.45 0.92 1.6 0.016 0.014 0.007 0.009 0.002 0.009 0.007 0.026 0.013 0.22 S1 WO 97/44350 PCT/US97/06591 -88- Example IC 50 (PM) IC 50 (pM) Gel Shift Clonogenic Assay No. Hepes 5 mM K 3 P0 4 -2 (pM) MED* IC 50

(PM)

0.12 0.009 0.60 3.9 0.30 0.35 1.98 0.62 0.060 0.089 0.88 0.48 10.6 0.20 0.86 0.32 0.38 0.029 0.52 0.14 0.66 2.6 0.10 0.001 0.004 0.005 0.038 0.002 0.0024 0.034 0.035 0.0029 0.009 0.0010 0.004 0.004 0.12 0.0012 0.014 0.012 0.0052 0.005 0.004 0.016 0.018 0.029 >0.2 0.01 0.05 0.05 0.2 0.02 0.05 1 0.05 0.05 0.05 0.05 >0.05 0.05 0.2 0.2 0.05 0.05 >1 0.19 0.04 0.51 >1 0.36 0.14 0.73 0.1 0.27 0.25 0.52 12.4 0.05 0.05 0.05 0.01 Numbers in parentheses indicate averages obtained by additional tests.

MED is minimal effective dose to observe inhibition of ras farnesylation.

In Vivo Assay The compound described in Example 15 was tested for its ability to inhibit the growth of H61 tumor cell xenografts in nude mice. H61 Cells are fibroblasts transformed to a malignant state by transfection with an activated mutant form of human h-ras. Ten to mg fragments of H61 tumors were inoculated SC (subcutaneously) in the axial region into female nude WO 97/44350 PCT/US97/06591 -89mice with a trocar needle on day zero of the experiment. The mice were randomized to treatment groups and were then given SC injections of the compound described in Example 15 suspended in cremofor/10% ethanol/80% water twice each day on Days 3-17 of the experiment. At Day 12 of the experiment, the median control tumor burden was 1958 mg as assessed by caliper measurements. The median tumor burden for animals treated with the compound described in Example 15 at 125 mg/kg/injection was 106 mg, indicating a 95% inhibition of tumor growth. The treatment regimen induced a tumor growth delay also consistent with significant inhibition of tumor growth at the 125 and 78 mg/kg/injection dose levels. These dose levels were well-tolerated with minimal or no host toxicity.

Claims (28)

1. A compound having the Formula I R 2 I R 4 A-N. where in R1is hydrogen or Cl-C 6 alkyl; RQ is (CH 2 n- N H CCH 2 )n -(C t/ ,o r N C 1 -C 6 alkyl ,H)n C 6 alkyl n is 0 or 1; 0 A is -CORa, -C0 2 Ra', -CONHRa', -CSRa, -C-SRa, -C(S)0Ra' C(S)NHRa', -S0 2 Ra, -CONRaRa' .or -C NRaRa; Ra, Ra', and R are independently Cl-C 6 alkyl, -(CH 2 )m-cycloalkyl, -(CH 2 )m-aryl, or (CH 2 )m-heteroarYl; each mn is independently 0 to 3; R 1 R 2 and R 4 ,are independently hydrogen or Cl-C 6 alkyl; Rb R 3 is -(CH2)m QI (CH- 2 )m-heteroaryl, -91- (CH 2 )m-(heteroaryl substituted with Rn), or CI-C 6 alkyl; t is 2 to 6; Rb is -O-pheriyl, -O-benzyl, halogen, Cj-C6 alkyl, hyd-rogen, -0CI-C 6 alkyl, -NH 2 -NH~a, 0 0 a I I Ra R C 1 6 akl Cal -OH, -CF 3 0 0 Nu2, -C ",-CC-C 6 alkyl, -CN, -OPO 3 H 2 0 -C11 2 p0 3 l- 2 -Cay,-N 3 -CF 2 CF 3 -SO 2 Ra, S0 2 NR.LRa, -CE-O, -OCOCH 3 550 0 -0 (CH 2 m-he t-eroaryl, NHCa -0-(CFH 2 ,NRaRa, (C 2 )mrl (CH 2 (CH 2 r,-het:roaryvl, -0i )m-cycloalkyJ.. Or (CM 2 ,-cycloal y;

5.s2 =3 -CR .09 IdJR N 29 *Id -If -92- N ,or ReRf O R9 and Rh are independently hydrogen, halogen, -0C 1 C 6 alkyl, cl-C 6 alkyl, -cN, -0P0 3 H 2 -CH 2 PO 3 H 2 -0-phenyl, -O-benzyl, 0 -NH-C-Ra, -NF2' NHRa, -NaRa, 0 0 -C 1 C 6 alkyl, -Cayl O(C 2 9 RaRa', -OH, 0 0 0 -CF 3 -NO, 2 -Coc 1 -C6 alkyl, -Co aryl, -N 3 -CF 2 C .S 2 Ra -S0 2 a -C1FO, or *-OCOCH 3 and RC, Rd, Re, and Rf are Indepenidently Cl-C 6 alkyl, 9 -(C2)..-phenyl, hydrogen, (CH2)rrn-OH, (CH,)m,-cycloalkyl, (CH 2 )mNH 2 or -CN, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, with the proviso o h 21 4c that R and R' are not all hydrogen when R R and Rc to Rr are all ~':hydrogen. 2. A compound in accordance with Claim 1 wherein R Iis hydrogen, R 2 is hydrogen. R 4 is hydrogen, R 2 1 is hydrogen or CH 3 and 92a A is 0 C C 2 -I H %J 0 or CH2 0I0 -93- 3. A comipound in accordance with Claim 1 wherein R 3 is -(CH2)n 0 (CH2) m 0 Rishydrogen, R 2 is hydrogen, R 4 is hydrogen, and R2.is hydrogen or 3 4. A comp~ound according to Claim 1 wherein R 5 is a. a a a 0 Q N C'H2 Ior WO 97/44350 WO 9744350PCT/US97/06591 -94- where R' is hydrogen, Cl, Br, F, or NH 2 A compound having the Formula II where in C 1 -C 6 alkyl R 6 is -o-benzyl, -NH-benzyl, or -Nbenzyl; R1is hydrogen or methyl; Ris hydrogen or methyl; R 8 is hydrogen, halogen, Cl-C 6 alkyl, -O-benzyl, -0C 1 C 6 alkyl, -CF 3 OH, or -O-(CH 2 )m-pyridyl, or phenyl; R 10 R 11 R' 3 and Rare independently hydrogen, Ci-C 6 alkyl, or -(CH2)m-phenyl; each m is independently 0 to 3; R2is -(Rk -CH Rk ;and Rk, and Rlare independently hydrogen, halogen, -0C 1 -C 6 alkyl or Cl-C 6 alkyl, -~NHRa, NH 2 and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof. Ra is C 1 -C 6 alkyl, -(CH 2 )m-cycloalkyl, -(CH 2 )m-aryl, or -(CH 2 )m-heteroaryl, with the proviso that R to R' are not all hydrogen when R 1 0 R R 1 3 and R 14 are all hydrogen.

6. A compound in accordance with Claim 5 wherein R' 1 and R 4 are methyl. A compound in accordance with Claim 5 wherein R is methyl or methoxy. 0 R 16 H H 1 R wherein X is NH, O, or -N(CH3); R" is -O-benzyl, -CF 3 hydrogen, halogen, -OC -C 6 alkyl, phenyl, -O-CH 2 -pyridyl, or CI-C 6 alkyl; R 8is a phenyl, hydrogen, or C-C 6 alkyl, cycloalkyl, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof. acceptable salts, esters, amides, and prodrugs thereof. 95a

9. A compound having the Formula IV R2 R Q 6 0 0-N R 1 6 I WO 97/44350 PCT/US97/06591 -96- wherein X is NH, O, or.-N(CH 3 R 15 is -O-benzyl, -CF 3 hydrogen, halogen, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, phenyl, or -O-(CH 2 m-pyridyl; R 1 6 and R 16 are C 1 -C 6 alkyl; m is 0 to 3; and R 21 is hydrogen or methyl, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof. A pharmaceutically acceptable composition that comprises a compound of Claim 1.

11. A pharmaceutically acceptable composition that comprises a compound of Claim

12. A pharmaceutically acceptable composition that comprises a compound of Claim 6.

13. A method of treating or preventing restenosis, the method comprising administering to a patient having restenosis or at risk of having restenosis a therapeutically effective amount of a compound of Claim 1.

14. A method of treating or preventing restenosis, the method comprising administering to a patient having restenosis or at risk of having restenosis a therapeutically effective amount of a compound of Claim A method of treating or preventing restenosis, the method comprising administering to a patient having restenosis or at risk of having restenosis WO 97/44350 PCT/US97/06591 -97- 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 Stherapeutically effective amount of a compound of Claim 1.

17. A method of treating cancer, the method comprising administering to a patient having cancer a therapeutically effective amount of a compound of Claim

18. A method of treating cancer, the method comprising administering to a patient having cancer a therapeutically effective amount of a compound of Claim 6.

19. The compounds (S)-[1-[(4-Benzyloxy-benzyl)-(phenethyl- carbamoyl-methyl)-carbamoyl]-2-(3H-imidazole-4- yl)-ethyl]-carbamic acid benzyl ester; (S)-[1-[[2-Benzyloxy-ethylcarbamoyl]-methyl]- [4-chlorobenzyl]-carbamoyl]-2-(1H-imidazole-4-yl)- ethyl]-carbamic acid benzyl ester; (S)-[l-[(4-Benzyloxy-benzyl)-[(2-phenyl- propyl-carbamoyl)-methyl]-carbamoyl]-2-(lH- imidazole-4-yl)-ethyl]carbamic acid benzyl ester; (S)-[l-[(4-Benzyloxy-benzyl)-[(2,2-diphenyl- ethylcarbamoyl)-methyl]-carbamoyl]-2-(1H- imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; and (S)-N-(4-Benzyloxy-benzyl)-2-(3-benzyl- S 15 ureido)-3-(1H-imidazole-4-yl)-N-[(2-phenyl-propyl- carbamoyl)-methyl]-propionamide. WO 97/44350 WO 9744350PCTIUS97/06591 -98- The method of Claim 16 wherein the cancer is lung cancer, colon cancer, pancreatic cancer, thyroid cancer, breast cancer, or bladder cancer.

21. The compound (4-Benzyloxy-benzyl)-[ (2-methyl-2- phenyl-propylcarbamoyl) -methyl] -carbamoyl 1-2- (3H- imidazole-4-yl)-ethyl]-carbamic acid benzyl ester.

22. The compounds -[l-{Biphenyl-4-ylmethyl- [(2-methyl-2- phenyl-propylcarbamoyl) -methyl] -carbamoyl) (1H- imidazole-4-yl) -ethyl] -carbamic acid benzyl ester; (S)-[l-{Biphenyl-4-ylmethyl-[ (2-phenyl- propylcarbamoyl) -methyl] -carbamoyl)-2- (1H- imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (4-Benzyloxy-benzyl) -(1-methyl- 2 -phenyl-ethylcarbamoyl) -methyl] -carbamoyl 1- 2- (lH-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[l-((4-Benzyloxy-benzyl)-[(R)-(l-methyl- 2-phenyl-ethylcarbamoyl) -methyl] -carbamoyl) 2- (lH-imidazole-4-yl) -ethyl] -carbamic acid benzyl ester; (4-Benzyloxy-benzyl) (2-phenyl- butylcarbamoyl) -methyl] -carbamoyl) (lH-imidazole -4-yl) -ethyl] -carbamic acid benzyl ester; (lH-Imidazole-4-yl) -1-f(4-methyl- benzyl) t(2-phenyl-propylcarbamoyl) -methyl] carbamoyl}-ethyl)-carbamic acid benzyl ester; (lH-Imidazole-4-yl) -1-f(4-methoxy- benzyl) [(2-phenyl-propylcarbamoyl) -methyl] carbamoyl) -ethyl) -carbamic acid benzyl ester; (S)-[l-((4-Benzyloxy-benzyl)-([2-(2-chloro- phenyl) -2-phenyl-ethylcarbamoyl] -methyl)- WO 97/44350 WO 9744350PCT[US97/06591 -99- carbamoyl) (lH-imidazole-4-yl) -ethyl] -carbamic acid benzyl ester; (4-Berizyloxy-benzyl) (2-ethyl-2- phenyl-butylcarbamoyl) -methyl) -carbamoyl}-2- (3H- imidazole-4-yl) -ethyl] -carbamic acid benzyl ester; C2-Chloro-benzyl)-[ (2-phenyl- propylcarbamoyl) -methyl] -carbamoyl} (lH- imidazole-4-yl) -ethyl] -carbamic acid benzyl ester; (S)-[l-((4-Benzyloxy-benzyl)-{[2-(2-chloro- phenyl) -propylcarbamoyl] -methyll-carbamoyl) (lii- imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-(2-(lH-Imidazole-4-yl)-l-{(2-methoxy- benzyl) -[I(2-phenyl-propylcarbamoyl) -methyl] carbamoyl}-ethyl)-carbamic acid benzyl ester; (1H-Imidazole-4-yl) [(2-phenyl- propylcarbamoyl) -methyl] -14- (pyridin-4-ylmethoxy) benzyl] -carbamoyll -ethyl) -carbamic acid benzyl ester; (S)-(2-(lH-Imidazole-4-yl)-l-{[(2-phenyl- propylcarbamoyl) -methyl] -14- (pyridin-3-ylmethoxy) benzyl] -carbamoyll -ethyl) -carbamic acid benzyl ester; (S)-{2-(lH-Imidazole-4-yl)-l-[ [(2-phenyl- propylcarbamoyl) -methyl] -(4-trifluoromethyl- benzyl) -carbamoyl] -ethyll-carbamic acid benzyl ester; (lH-Imidazole-4-yl) [(2-methyl-2- phenyl-propylcarbamoyl) -methyl] (pyridin-2- ylmethoxy) -benzyl] -carbamoyl)-ethyl) -carbamic acid benzyl ester; (S)-[l-{Benzyl-[ (2-methyl-2-phenyl-propyl- carbainoyl) -methyl] -carbamoyll-2- (lH-imidazole-4- yl)-ethyl]-carbamic acid benzyl ester; a 60 (S)-(2-(lH-Imidazole-4-yl)-1-{(4-methoxy- benzyl) -((2-methyl-2-phenyl-propylcarbamoyl) WO 97/44350 WO 9744350PCT/US97/06591 -100- methyl] -carbamoyl)-ethyl) -carbamic acid benzyl ester; (4-Benzyloxy-benzyl)-I(2-cyano-2- phenyl-ethylcarbamoyl) -methyl] -carbamoyll-2- (lH- imidazole-4-yl)-ethyl]-carbanic acid benzyl ester; (S)-2-(3-Benzyl-3-methyl-ureido)-N-(4- benzyloxy-benzyl) (lH-imidazole-4-yl) methyl-2 -phenyl-propylcarbamoyl) -methyl] propionamide; K (2-Amino-phenyl) propylcarbamoyl] -methyl)- (4 -benzyloxy-benzyl) carbamoyl] (3H-imidazole-4-yl) -ethyl] -carbamic acid benzyl ester; (S)-(2-(lH-Imidazole-4-yl)-l-([(2-methyl-2- phenyl-propylcarbamoyl) -methyl] (pyridin-4- ylmethoxy) -benzyl] -carbamoyl}-ethyl) -carbamic acid benzyl ester; (lH-Imidazole-4-yl) [(2-methyl-2- phenyl-propylcarbamoyl) -methyl) (pyridin-3- ylmethoxy) -benzyl] -carbamoyl) -ethyl) -carbamic acid benzyl ester; and {Cyclohexylmethyl- [(2-phienyl- propylcarbamoyl) -methyl] -carbamoyl 1-2 -(3H- imidazole-4-yl)-ethyl]-carbamic acid benzyl ester.

23. The compounds (4-Benzyloxy-benzyl)-{ [2-(2-fluoro- phenyl) -ethylcarbamoyl I-methyl) -carbamoyl) (1H- imidazole-4-yl) -ethyl] -carbamic acid benzyl ester; (4-Benzyloxy-benzyl) (2-pyridin- 2-yl--ethylcarbamoyl) -methyl] -carbamoyll- 2- (lH-imidazole-4-yl) -ethyl] -carbamic acid benzyl ester; (s)-[l-((4-Benzyloxy-benzyl)-{.[2-(2-bromo- phenyl) -ethylcarbamoyl]-methyl}-carbamoyl) (lH- imidazole-4-yl) -ethyl) -carbamic acid benzyl ester; WO 97/44350 WO 9744350PCT/US97/06591 -101- (S)-II1-{(4-Benzyloxy-benzyl)-[ (2-phenyl-2- pyridin-2-yl-ethylcarbamoyl).-methyl] -carbamoyl}-2- (1H-imidazole-4-yl) -ethyl] -carbarnic acid benzyl ester; (4-Chloro-benzyl)-[ (2-phenyl- propylcarbamoyl) -methyl] -carbamoyll (1H- imidazole-4-yl) -ethyl) -carbamic acid benzyl ester; (4-Benzyloxy-benzyl) (lH-imidazole-4- yl) (3-phenyl-propionylamino) [(2-phenyl- propylcarbamoyl) -methyl] -propionamide; (4-Fluoro-benzyl)-[ (2-phenyl-propyl- carbamoyl) -methyl] -carbamoyl)-2- (lH-imidazole-4- yl)-ethyl].-carbamic acid benzyl ester; (4-Fluoro-benzyl)-[ (2-methyl-2- phenyl-propylcarbanoyl) -methyl] -carbainoyl) (1H- imidazole-4-yl) -ethyl] -carbanic acid benzyl ester; -[l-{Benzyl- [(2-phenyl-propylcarbamoyl) methyl] -carbamoyl)-2- (1H-imidazole-4-yl) -ethyl] carbamic acid benzyl ester; (4-Benzyloxy-benzyl) (3-benzyl- ureido)-3-(lH-imidazole-4-yl)-N-t (2-phenyl- propylcarbamoyl) -methyl] -propionamide; (4-Benzyloxy-benzyl) (3-benzyl- ureido) (lH-imidazole-4-yl)-N- I(2-phenyl- butylcarbamoyl) -methyl] -propionamide; (s)-[1-{(4-Bromo-benzyl)-[ (2-phenyl- propylcarbanoyl) -methyl] -carbamoyl}-2- (1H- imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (3-Chloro-benzyl) (2-phenyl- propylcarbamoyl) -methyl] -carbaxnoyl) (lH- imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (4-Chloro-benzyl)-[ (2-methyl-2- phenyl-propylcarbamoyl) -methyl] -carbamoyl) (lH- imidazole-4-yl) -ethyl] -carbamic acid benzyl ester; WO 97/44350 PCTIUS97/06591 -102- (lH-Imidazole-4-yl) (3-methoxy- benzyl) -[I(2-phenyl-propylcarbamoyl) -methyl] carbamoyl)-ethyl) -carbamic acid benzyl ester; (lH-Imidazole-4-yl) -1-{naphthalen-l- ylmethyl- [(2-phenyl-propylcarbamoyl) -methyl] carbamoyl)-ethyl)-carbamic acid benzyl ester; (S)-(2-(lH-Imidazole-4-yl)-l-{[(2-methyl-2- phenyl-propylcarbamoyl) -methyl] -pyridin-3 ylmethyl-carbamoyl)-ethyl) -carbamic acid benzyl ester; (lH-Imidazole-4-yl) -1-f(2-methyl- benzyl) (2-phenyl-propylcarbamoyl) -methyl] carbamoyl)-ethyl)-carbamic acid benzyl ester; CS) (lH-Imidazole-4-yl) -l-{[[(2-methyl-2- phenyl-propylcarbamoyl) -methyl] -pyridin-2- ylmethyl-carbamoyl}-ethyl) -carbamic acid benzyl ester; (lH-Imidazole-4-yl) -1-f(3-methyl- benzyl) (2-phenyl-propylcarbamoyl) -methyl) carbainoyl)-ethyl)-carbamic acid benzyl ester; (4-Dimethylamino-benzyl) -[I(2-phenyl- propylcarbamoyl) -methyl] -carbamoyl)-2- (1H- imidazole-4-yl) -ethyl] -carbainic acid benzyl ester; CS) (4-Benzyloxy-benzyl) -[I(2-hydroxy-2- phenyl-ethyl-carbanoyl) -methyl] -carbamoyl)-2- (3H- imidazo-4-yl) -ethyl] -carbamic acid benzyl ester; C4-Benzyloxy-benzyl)-fI2-(2-chloro- phenyl) -ethylcarbamoyllmethyl)-carbamoyl) (lH- imidazole-4-yl) -ethyl) -carbamic acid benzyl ester; C4-Benzyloxy-benzyl)-I (2-methyl-2- phenyl-propylcarbamoyl) -methyl] -carbamoyll-2- (lH- imidazole-4-yl) -ethyl] -carbamic acid thiophen- 3-ylmethyl ester; (4-Chloro-benzyl)-I[l-(2-methyl-2- phenyl-propylcarbamoyl) -ethyl] -carbamoyl) (3H- imidazole-4-yl) -ethyl] -carbamic acid benzyl ester; I (A WO 97/44350 PCTIUS97/06591 -103- (S)-(2-(lH-Imidazole-4-yl)-l-{ (4-methyl- benzyl) (2-methyl-2-phenyl-propylcarbamoyl) methyl] -carbamoyl) -ethyl) -carbarnic acid benzyl ester; (S)-(2-(lH-Imidazole-4-yl)-l-{(2-methoxy- benzyl) (2-methyl-2-phenyl-propylcarbamoyl) methyl] -carbamoyl 1-ethyl) -carbamic acid benzyl ester; (3-Benzyl-3-methyl-ureido) -N-(4-chloro- benzyl) (lH-imidazole-4-yl) [(2-methyl-2- pheriyl-propylcarbamoyl) -methyl] -propionamide; (S)-(2-(lH-Imidazole-4-yl)-l-{ (3-methoxy- benzyl) (2-methyl-2-phenyl-propylcarbamoyl) methyl] -carbamoyll -ethyl) -carbamic acid benzyl ester; (lH-Imidazole-4-yl) {[(2-methyl-2- phenyl-propylcarbamoyl) -methyl] (pyridin-4- ylmethoxy) -benzyl] -carbamoyl) -ethyl) -carbamic acid 100 benzyl ester; and (2-(lH-Imidazol-4-yl)-1-(isobutyl-[ (2-phenyl- propylcarbamoyl) -methyl] -carbamoyl) -ethyl) carbainic acid benzyl ester.

24. The compounds (4-Benzyloxy-benzyl) -[t(2-phenyl- pentyl-carbamoyl) -methyl] -carbanoyll (3H- imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[l-{[2-(4-Benzyloxy-phenyl)-ethyl]-[(2- methyl-2-phenyl-propylcarbanoyl) -methyl] carbamoyl}-2- (3H-imidazole-4-yl) -ethyl] -carbamic acid benzyl ester; (S)-(2-(3H-Imidazole-4-yl)-l-([2-(4-methoxy- phenyl) -ethyl] [(2-methyl-2-phenyl-propyl- carbamoyl) -methyl] -carbamoyl)-ethyl) -carbainic acid benzyl ester; WO 97/44350 WO 9744350PCTIUS97/06591 -104- (2-Amino-phenyl) -ethylcarbamoyl] methyll- (4-benzyloxy-benzyl) -carbamoyl] (3H- imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (4-Benzyloxy-benzyl) -[(2-methyl-2- phenyl-propylcarbamoyl) -methyl] -carbamoyl}-2- (3H- imidazole-4-yl) -ethyl] -methyl-carbamic acid benzyl ester; (S)-[l-{(4-Benzyloxy-benzyl)-[(2-methyl-2- phenyl-propylcarbamoyl) -methyl] -carbamoyl) (3- methyl-3H-imidazole-4-yl) -ethyl] -carbanic acid benzyl ester; (4-Benzyloxy-benzyl)-[(2-methyl-2- phenyl-propylcarbamoyl) -methyl] -carbamoyl)-2- (1- methyl-lH--imidazole-4-yl) -ethyl] -carbamic acid benzyl ester; (4-Benzyloxy-benzyl)-[(2-methyl-2- phenyl-propylcarbamoyl) -methyl] -carbamoyll (3H- imidazole-4-yl) -ethyl] -carbamic acid furan-2- ylmethyl ester; (4-Benzyloxy-benzyl)-[(2-methyl-2- phenyl-propylcarbamoyl) -methyl] -carbamoyl)-2- (3H- imidazole-4-yl) -ethyl] -carbamic acid thiophen-2- ylmethyl ester; (4-Benzyloxy-benzyl)-[ (2-methyl-2- phenyl-propylcarbamoyl) -methyl] -carbamoyl) (3H- imidazole-4-yl) -ethyl] -carbamic acid pyridin-3- ylmethyl ester; (4-Benzyloxy-benzyl)-[ (2-methyl-2- phenyl-propylcarbamoyl) -methyl] -carbainoyl) (3H- imidazole-4-yl) -ethyl] -carbamic acid lH-imidazole-4-ylmethyl ester; (3-Benzyl-ureido) (4-chloro-benzyl) 3-(3H- imidazole-4-yl) (2-methyl-2-phenyl-propyl- carbamoyl) -methyl] -propionanide; WO 97/44350 WO 9744350PCTIUS97/06591 -105- (4-Benzyloxy-benzyl)-[ (2-methyl-2- phenyl-propylcarbamoyl) -methyl] -carbamoyl) (3H- imidazole-4-yl) -ethyl] -carbamic acid 4-methoxy- benzyl ester; (3-Benzyl-thioureido) (3H-irnidazole- 4-yl) (4-methyl-benzyl) [(2-methyl-2-phenyl- propylcarbamoyl) -methyl] -propionamide; -2-Acetylamino-N- (4-benzyloxy-benzyl) 3- (3H-imidazole-4-yl) -N-Il(2-methyl-2-phenyl- propylcarbamoyl) -methyl] -propionamide; (S)-(2-(3H-Imidazole-4-yl)-l-{[(2-methyl-2- phenyl-propylcarbamoyl) -methyl] -pyridin-4- ylrnethyl-carbamoyl} -ethyl) -carbamic acid benzyl ester; (3H-Imidazole-4-yl)-1-[ (4-iodo-benzyl)- (phenethylcarbamoyl-methyl) -carbamoyl] -ethyl) carbamic acid benzyl ester; (4-Amino-benzyl)-[1(2-methyl-2-phenyl- propylcarbamoyl) -methyl] -carbamoyl}-2- (3H- imidazole-4-yl) -ethyl] -carbamic acid benzyl ester; (4-Ethoxy-benzyl) (2-methyl-2- phenyl-propylcarbamoyl) -methyl] -carbamoyl) (3H- imidazole-4-yl) -ethyl] -carbamic acid benzyl ester; 14- (2-Dimethylamino-ethoxy) -benzyl] [1(2-methyl-2 -phenyl-propylcarbamoyl) -methyl] carbamoyl)-2- (3H-imidazole-4-yl) -ethyl] -carbamic acid benzyl ester; and (2-(lH-imidazole-4-yl)-l-{isobutyl- [(2-methyl-2-phenyl-propyl carbamoyl) -methyl] carbamoyl) -ethyl) -carbarnic acid benzyl ester. 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 Claim 1. -106-

26. 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 Claim

27. 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 Claim 6.

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 S. compound of Claim S: 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. -107-

31. A pharmaceutically acceptable composition that comprises a compound of claim 8.

32. A pharmaceutically acceptable composition that comprises a compound of claim 9.

33. A method of treating or preventing restenosis, the method comprising administering to a patient having restenosis or at risk of having restenosis a therapeutically effective amount of a compound of claim 8.

34. A method of treating or preventing restenosis, the method comprising administering to a patient having restenosis or at risk of having restenosis a therapeutically effective amount of a compound of claim 9. A method of treating cancer, the method comprising administering to a patient having cancer a therapeutically effective amount of a compound of claim 8.

36. A method of treating cancer, the method comprising administering to a patient So"' having cancer a therapeutically effective amount of a compound of claim 9.

37. 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 claim 8. -38. 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 claim 9.

39. A method of treating psoriasis, the method comprising administering to a patient having psoriasis a therapeutically effective amount of a compound of claim 8. A method of treating psoriasis, the method comprising administering to a patient having psoriasis a therapeutically effective amount of a compound of claim 9.

21478-00.DOC -108- 41. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment or prevention of restenosis. 42. Use of a compound according to claim 5 for the manufacture of a medicament for the treatment or prevention of restenosis. 43. Use of a compound according to claim 6 for the manufacture of a medicament for the treatment or prevention of restenosis. 44. Use of a compound according to claim 8 for the manufacture of a medicament for the treatment or prevention of restenosis. Use of a compound according to claim 9 for the manufacture of a medicament for the treatment or prevention of restenosis. 46. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of cancer. S 47. Use of a compound according to claim 5 for the manufacture of a medicament for the treatment of cancer. 15 48. Use of a compound according to claim 6 for the manufacture of a medicament for :the treatment of cancer. 49. Use of a compound according to claim 8 for the manufacture of a medicament for the treatment of cancer. ee 1 50. Use of.a compound according to claim 9 for the manufacture of a medicament for the treatment of cancer. 51. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of a viral infection. the treatment of a viral infection. 2147S-00.DOC 109- 52. Use of a compound according to claim 5 for the manufacture of a medicament for the treatment of a viral infection. 53. Use of a compound according to claim 6 for the manufacture of a medicament for the treatment of a viral infection. 54. Use of a compound according to claim 8 for the manufacture of a medicament for the treatment of a viral infection. Use of a compound according to claim 9 for the manufacture of a medicament for the treatment of a viral infection. 56. Use ofa compound according to claim 1 for the manufacture of a medicament for the treatment ofpsoriasis. 57. Use of a compound according to claim 5 for the manufacture of a medicament for the treatment of psoriasis. 58. Use of a compound according to claim 6 for the manufacture of a medicament for ee: the treatment of psoriasis. 15 59. Use of a compound according to claim 8 for the manufacture of a medicament for the treatment of psoriasis. 60. Use of a compound according to claim 9 for the manufacture of a medicament for the treatment of psoriasis. 61. A compound having the formula I, substantially as herein described with reference to one or more of the examples but excluding comparative examples. 62. A compound having the formula II, substantially as herein described with reference to one or more of the examples but excluding comparative examples. -110- 63. A compound having the formula III, substantially as herein described with reference to one or more of the examples but excluding comparative examples. 64. A compound having the formula IV, substantially as herein described with reference to one or more of the examples but excluding comparative examples. A pharmaceutically acceptable composition that comprises a compound of formula I, substantially as herein described with reference to one or more of the examples but excluding comparative examples. 66. A pharmaceutically acceptable composition that comprises a compound of formula o II, substantially as herein described with reference to one or more of the examples but excluding comparative examples. 67. A pharmaceutically acceptable composition that comprises a compound of formula III, substantially as herein described with reference to one or more of the examples but :o excluding comparative examples. oo o 68. A pharmaceutically acceptable composition that comprises a compound of formula IV, substantially as herein described with reference to one or more of the examples but excluding comparative examples. 69. A method of treating or preventing restenosis, substantially as herein described with reference to one or more of the examples but excluding comparative examples. 70. A method of treating cancer, substantially as herein described with reference to one or more of the examples but excluding comparative examples. 71. A method of treating a viral infection, substantially as herein described with reference to one or more of the examples but excluding comparative examples. -111- 72. A method of treating psoriasis, substantially as herein described with reference to one or more of the examples but excluding comparative examples. 73. Use of a compound having the Formula I, substantially as herein described with reference to one or more of the examples but excluding comparative examples. 74. Use of a compound having the Formula II, substantially as herein described with reference to one or more of the examples but excluding comparative examples. Use of a compound having the Formula III, substantially as herein described with reference to one or more of the examples but excluding comparative examples. 10 76. Use of a compound having the Formula IV, substantially as herein described with reference to one or more of the examples but excluding comparative examples. o DATED this 18th Day of October 2000 oor WARNER-LAMBERT COMPANY Attorney: IVAN A. RAJKOVIC Fellow Institute of Patent Attorneys of Australia of BALDWIN SHELSTON WATERS oeao°