AU700175B2 - Thiol-free inhibitors of farnesyl-protein transferase - Google Patents

Description

Thiol-Free Inhibitors of Farnesyl-Protein Transferase Background of the Invention The Ras protein is part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP. Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTPbound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form Lowy and D.M. Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)).

Mutated ras genes are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.

Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane Slocalization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-Aaal-Aaa 2 -Xaa" box (Cys is 20 cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., SNature 310:583-586 (1984)). Depending on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C 15 or C 20 isoprenoid, respectively. Clarke., Ann. Rev. Biochem.

e 9, WO 96/10034 PCT/US95/12224 -2- 61:355-386 (1992); W.R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237 (1992)). The Ras protein is one of several proteins that are known to undergo post-translational famesylation. Other famesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also famesylated.

James, et al., have also suggested that there are famesylated proteins of unknown structure and function in addition to those listed above.

Inhibition of farnesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of famesyl-protein transferase selectively block the processing of the Ras oncoprotein intracellularly Kohl et al., Science, 260:1934-1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of famesyl-protein transferase blocks the growth of rasdependent tumors in nude mice Kohl et al., Proc. Natl. Acad. Sci U.SA., 91:9141-9145 (1994) and induces regression of mammary and salivary carcinomas in ras transgenic mice Kohl et al., Nature Medicine, 1:792-797 (1995).

It has recently been shown that famesyl-protein transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and thereapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7-112930).

Indirect inhibition of famesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck Co., Rahway, NJ) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including famesyl pyrophosphate. Famesyl-protein transferase utilizes famesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., 1 WO 96/10034 PCT/US95/12224 -3- Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA, 87:7541-7545 (1990)). Inhibition of famesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. However, direct inhibition of famesyl-protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis.

Inhibitors of famesyl-protein transferase (FPTase) have been described in two general classes. The first are analogs of famesyl diphosphate (FPP), while the second class of inhibitors is related to the protein substrates Ras) for the enzyme. The peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the famesyl-protein transferase enzyme, or may be purely competitive inhibitors Patent 5,141,851, University of Texas; N.E. Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)). In general, deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound. However, the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable.

It is, therefore, an object of this invention to develop tetrapeptide-based compounds which do not have a thiol moiety, and which will inhibit famesyl transferase and the post-translational functionalization of the oncogene Ras protein. It is a further object of this invention to develop chemotherapeutic compositions containing the compounds of this invention and methods for producing the compounds of this invention.

WO 96/10034 PCT/US95/12224 -4- SUMMARY OF THE INVENTION The present invention comprises analogs of the CAAX motif of the protein Ras that is modified by famesylation in vivo.

These CAAX analogs inhibit the famesylation of Ras. Furthermore, these CAAX analogues differ from those previously described as inhibitors of Ras famesyl transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thioldependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.

WO 96/10034 WO 9610034PTIUS95/12224 The compounds of this invention are illustrated by the formulae:

(R

8 )r

R

V A'C ')A2(R2n- W-

(R

8 )r

R

V AC2)A2(R2n-

W-

z

(CR

1 2

A

(R

8 )r V A(R2n C -WR9

HOCH

2

(CH

2 )q z

Y,,O

R 3 R 4 0 and

(R

8 )r

R

9 V A'(CR 1 2 )nA 2

(CR

1 2 )n W (CR 1 WO 96/10034 WO 9610034PCT1US95/12224 -6- DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention inhibit the farnesylation of Ras. In a first embodiment of this invention, the Ras farnesyl transferase inhibitors are illustrated by the formula 1: (R 8 )r

R

9 ZR 2 a R 2 b Z R 5 a R 5 b wherein: R I is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RIO0-, RI IS(O)m-, RIOC(O)NR 1 CN, N02, (R 10 )2N-C(NR RlI R I OOC(O)-, N3, 102,or R I IOC(O)NR c) ClI -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 1 00-., R I IS(O)m-, R IOC(O)NR 10-, CN, (R I 0 )2N-C(NR 1 0 RIOC(O)-, RIOOC(O)-, N3, -N(RIO)2, or R I IOC(O)NR R2a and R2b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C I -C20 alkyl, C2-C20 alkenyl, C3-Cl10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, RIO0-, RI IS(O)m-, RIOC(O)NRIO-,

CN,

WO 96/10034 PCT/US95/12224 -7-

(R

10 )2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, R110C(O)NRIO- and C1-C20 alkyl, and d) Ci-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C10 cycloalkyl; or R2a and R2b are combined to form (CH2)s R3 and R 4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R10)2, N02, R100-, R11S(O)m-, R 10 CN, (R10)2N-C(NR10)-, R10C(O)-,

R

10 N3, -N(R10)2, R 1OC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; or R3 and R 4 are combined to form (CH2)s and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, WO 96/10034 WO 9610034PCT/US95/12224 -8wherein the substituent is selected from F, Cl, Br, N(R 10 N02, R 1 0 R I S R I C(O)NR CN, (R I 0 )2N-C(NR 10 R I R I N 3,

-N(R

1 0

R

1 OC(O)NRIO-, -SO2N(R' 0 )2, R I IS02NR 10 and CI -C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; or R5a and R5b are combined to form (CH2)s wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(COR or or R5b are combined with R 14 to form a ring such that

R

5 a R 5 b R 14 O R 1 WO 96/10034 PCT/US95/12224 -9- X-Y is

R

7 a a)

N

0 R7b b)

N

C)

(0)m d)

S

H

e) Y ,or

H

f)

-CH

2

-CH

2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, WO 96/10034 PCTUS95/12224 c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R1 0 RI IS(O)m-, RIOC(O)NR 10-, CN, N02, R 10 2N-C(NR R1OC(O)-, R 1 0 N3, -N(R 10 or R1 1 0C(O)NR10-, and c) Ci -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R1 1 S(O)m-,

R

1 OC(O)NH-, CN, H2N-C(NH)-, RIOC(O)-,

R

1 0 N3, -N(R 10 or R 1 1

OC(O)NH-;

R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, RL R 10

C(O)NR

10 CN, N02, (R10)2N- WO 96/10034 PCT/US95/12224 11 R10C(O)-, R 10 N3, -N(R10)2, or R 1 0OC(O)NR10-, and c) C -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 R 1S(O)m-, R0OC(O)NR 10, CN, (R 10)2N-C(NR10)-,

R

10

R

1 0 N3, -N(R 10 or R11OC(O)NR10-;

R

10 is independently selected from hydrogen, C1-C6 alkyl and aryl; R 1 is independently selected from C1-C6 alkyl and aryl; R1 2 is independently selected from hydrogen and C1-C6 alkyl;

R

14 is independently selected from hydrogen,C1-C6 alkyl and benzyl;

R

15 is independently selected from hydrogen and C1-C6 alkyl; A1 and A 2 are independently selected from: a bond, -CH=CH-, O, -C(O)NR 10-, -NR I OC(O)-, -S(0)2N(R 10), -N(R 0)S(0)2- or S(O)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl; provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if A is a bond, n is 0 and A 2 is S(O)m or a bond; W is a heterocycle; WO 96/10034 WO 9610034PCTIUS95/12224 -12- Z is independently H2 or 0; m isO0, 1 or 2; n is 0, 1, 2,3or 4; pis 0, 1,2,3 or4; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 4 or 5; and t is 3, 4 or or the pharmaceutically acceptable salts thereof.

In a second embodiment of this invention the prodrugs of compounds of formula I are illustrated by the formula Hl: (R 8 )r R 9 Z R 2 a R 2 b Z R 5 a R 5 b V A (CR 1 2 )A (CR 2 W (CR 2 )p N1 R3 N ORR4 6 wherein: R 1 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 1 0 R I 1 S R I C(O)NR 10-, CN, N02, (Ri 0 )2N-C(NR 1 R I R I OOC(0)-, N3, -N('02,or RI IOC(0)NRIO-, c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RI 00.., RI I S R IOC(0)NR 10-, CN, (R 1 0 )2N-C(NR 10 R IOC(O)-, R IO0C(0)-, N3, -N(R 10)2, or R I0 C(0)NR R2a and R2b are independently selected from: a) a side chain of a naturally occurring amino acid, WO 96/10034 PCT/US95/12224 -13b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Ci -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 0

R

1 RIOC(O)NRIO-, CN,

(R

10 )2N-C(NR10)-, R LOC(O)-, R100 N3,

-N(R

1 0

R

11 OC(O)NR10- and Cl-C20 alkyl, and d) CI -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; or R2a and R2b are combined to form (CH2)s

R

3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1 -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R10)2, N02, R 10 R 11S(O)m-, R 10 CN, (R 10)2N-C(NR R 1 0

R

10 N3,

-N(R

1 0

R

1 1 OC(O)NR10- and C1-C20 alkyl, and d) C -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; or R3 and R 4 are combined to form (CH2)s WO 96/10034 PCTIUS95/12224 -14and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Ci-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br,

N(R

10 N02, R 10

R

1 lS(O)m-, R 10 CN, (R 10 )2N-C(NR10)-,

R

10

R

10 N3,

-N(R

10

R

1 1 OC(O)NRIO-, -SO2N(RO0)2,

R

1 1 S02NR 1 0 -and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl; or and R5b are combined to form (CH2)s wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(COR 10) or or R5b are combined with R 14 to form a ring such that

R

5 a R 5 b 2 5

V

is

HA

2 t

R

14

R

6 is a) substituted or unsubstituted Cl-C8 alkyl, wherein the substituent on the alkyl is selected from: 1) aryl, WO 96110034 WO 9610034PCT/US95/12224 2) heterocycle, 3) -N(R"1)2, 4) -OR 10, or b) 0'

R

13 x-Y is 10RI7 a) i 0

R

7 b b)

N

d) N

H

e) or

H

f) -CH 2 -0H 2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, WO 96/10034 PCT/US95/12224 -16d) unsubstituted or substituted cycloalkyl, and e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R1 0

R

1 S(O)m-, 10 CN, N02, R 10 2N-C(NR10)-, RIOC(O)-, R1OOC(O)-, N3, -N(R10)2, or

R

1 1

OC(O)NR

10 and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R1 0

R

1 1 S(O)m-, WO 96/10034 WO 9610034PCTIUS95/12224 17 R IOC(O)NH-, CN, H2N-C(NH)-, R IOC(O)-, R IOOC(O)-, N3, -N(R 10 or R I IOC(O)NH-,

R

9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 0-, RI IS(O)m-, RIOC(O)NRIO-, CN, N02, (R' 0 )2N- C(NRIO)-, RIOC(O)-, RIOOC(O)-, N3, -N(R 1 0 or R' IIOC(O)NR 10-, and C) C I -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br. R 10 RI IS R IOC(O)NR 1 CN, (R 10 )2N-C(NR R IOC(O)-, R IOOC(O)-, N3, -N(R 10)2, or R I IOC(O)NR R 10 is independently selected from hydrogen, C I -C6 alkyl and aryl; Ri I1 is independently selected from ClI-C6 alkyl and aryl; R 12 is independently selected from hydrogen and ClI-C6 alkyl; R1 3 is independently selected from Ci-C6 alkyl;

R

14 is independently selected from hydrogen,C 1 -C6 alkyl and benzyl; R 1 5 is independently selected from hydrogen and C I -C6 alkyl; A I and A 2 are independently selected from: a bond, -CH=CH-, -NR' -S(O)2N(R -N(Rl 0 or S(O)m; V is selected from: a) hydrogen, b) heterocycle, WO 96/10034 PCT/US95/12224 -18c) aryl, d) Cl-C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl; provided that V is not hydrogen if A is S(O)m and V is not hydrogen if A is a bond, n is 0 and A 2 is S(O)m or a bond; W is a heterocycle; Z is independently H2 or O; m is 0, I or 2; nis 0,1,2, 3 or4; pis O, 1,2,3 or4; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 4 or 5; and tis 3, 4 or or the pharmaceutically acceptable salts thereof.

In a third embodiment of this invention, the inhibitors of famesyl transferase are illustrated by the formula III:

HOCH

2

(CH

2 )q (R)r 9 Z R 2a

R

2 b Z I lix."O V A1(CR1nA2CR12) W (CR 1 2) N X 4 O H

R

3

R

4

O

III

wherein: R is independently selected from: WO 96/10034 WO 9610034PCTIUS95/12224 19 a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 10 R I IS(O)m-, R I C(O)NR 1 CN, N02, (R 10 )2N-C(NR R I R I OOC(0)-, N3, 102,or R I IOC(O)NR c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 1 00., R I S R I OC(O)NR CN, (R 1 I b2N-C(NR'1 0 R I R IOOC(0)-, N 3, -N (R 1 0 2, or R' IIOC(0)NR 1 0 R2a and R2b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C I -C20 alkyl, C2-C20 alkenyl, C3-Cl10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 1 0 R I IS(0)m-, R IOC(0)NR 10-, CN, (Ri I )2N-C(NR 1 R I R I OOC(0)-, N3,

-N(R

1 0

R

1 1 0C(0)NRIO- and CI-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; or R2a and R2b are combined to form (CH2)s R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or WO 96/10034 WO 9610034PCTIUS95/12224 ii) methionmne sulfone, and substituted or unsubstituted C I -C20 alkyl, C2-C20 alkenyl, C3-C 10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R 10)2, N02, R 1 0 R I IS(O)m-, R 1 I C(O)NR CN, (R 1 0 )2N-C(NRIO)-, RIOC(O)-, RIO0C(O)-, N3, -N(RIO)2, RI l0C(O)NRIO- and CI-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; or

R

3 and R 4 are combined to form -(CH2)s x-Y is 15RI7 a) YNs 0

R

7 b b)N

C)

d))

H

e) ,or

H

f) -CH 2

-CH

2 WO 96/10034 PCT/US95/12224 -21- R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;

R

8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0

R

1 S(O)m-,

R

10

C(O)NR

10 CN, N02, R 1 0 WO 96110034 WO 9610034PCT1US95/12224 -22 RIOC(0)-, RIOOC(0)-, N3, or R I IOC(0)NR 10-, and c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, peffluoroalkyl, F, Cl, Br, R 10 R I iS R IOC(0)NII-, CN, H2N-C(NH)-, R IOC(0)., R I N3, -N(R'1O)2, or R I IOC(0)N1-, R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 1 00.., RI IS R I C(0)NR 1 0 CN, N02, (R I 0 )2N- C(NR R IOC(0)-, R I N3, -N(R 10 or R I IOC(0)NR 10-, and C) C I-C6 alkyl unsubstituted or substituted by peffluoroalkyl, F, Cl, Br, R 100-, RI IS R I OC(O)NR 1 CN, (Ri 0 )2N-C(NR R I OC(O)-, R IOOC(0)-, N3, -N(R 10)2, or R I I0C(0)NR Ri10 is independently selected from hydrogen, C I -C6 alkyl and aryl; R I I s independently selected from C I -C6 alkyl and aryl; R 12 is independently selected from hydrogen and C I -C6 alkyl; R1 4 is independently selected from hydrogen,C 1 -C6 alkyl and benzyl; AlI and A 2 are independently selected from: a bond, -CH=CH-, -S (0)2N(R -N(Ri 0 or S (O)m; V is selected from: a) hydrogen, WO 96/10034 PCT/US95/12224 -23b) heterocycle, c) aryl, d) C -C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl; provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A l is a bond, n is 0 and A 2 is S(O)m or a bond; W is a heterocycle; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1,2, 3 or 4; pis 0, 1,2,3 or4; q is 0, 1 or 2; r is 0 to 5, provided that r is 0 when V is hydrogen; and s is 4 or or the pharmaceutically acceptable salts thereof.

In a fourth embodiment of this invention the prodrugs of compounds of formula III are illustrated by the formula IV: (R)r RZ

R

2 a R 2 b z V A'(CRnA2(CR1) n W (CR 1 2 )p N- X ON

R

3 R4

IV

wherein: R 1 is independently selected from: WO 96/10034 WO 9610034PCTIUS95/12224 24 a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RIO0-, RI IS(O)m-, RIOC(O)NR 10-, CN, N02, (R I 0 )2N-C(NR 1

R

1 I R I OOC(O)-, N3, -N(R 10 or R I I0C(O)NR 1 0-, c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 1 00., RI IS(O)m-, RIOC(0)NRIO-, CN, (R 10 )2N-C(NRIO)-, R I R 1

I

0 N3, -N(R 10 or R I I0C(0)NR 1 0-; R2a and R2b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C I -C20 alkyl, C2-C20 alkenyl, C3-CI10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 R I IS(0)m-, R I C(0)NR 10-, CN, (Ri 0 )2N-C(NR R I R I OOC(0)-, N3,

-N(R

1 0 RIIOC(0)NRIO- and Cl-C20 alkyl, and d) Ci -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; or R2a and R2b are combined to form (CH2)s R3 and R 4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or WO 96/10034 WO 9610034PCTIUS95112224 25 ii) methionine sulfone, and c) substituted or unsubstittited C I -C20 alkyl, C2-C20 alkenyl, C3-ClO cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R 10 N02, R 10 R' IIS(O)m-, R I C(O)NR CN, (R I 0 )2N-C(NR R I R I N3, -N(R 10 R I I0C(O)NR 1 0- and ClI-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl; or

R

3 and R 4 are combined to form -(CH2)s x-Y is 15RI7 a)N 0

R

7 b b) N~

C)

(Y)m d)S

H

e) ,or

H

f) -0H 2

-CH

2 WO 96/10034 PCT/US95/12224 -26- R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10-, Rl S(O)m-,

R

10

C(O)NR

10 CN, N02, R 10 2N-C(NR10)-, WO 96110034 WO 9610034PCTIUS95/12224 27 R IOC(O)-, R I N3, -N(R'1O)2, or R I IOC(O)NR 10-, and c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, peffluoroalkyl, F, Cl, Br, R 1 0 R II 1 S(O)m-, RIOC(O)N--, CN, H2N-C(NH)-,

RIOC(O)-,

R I N3, -N(R 1 0)2, or R I I0C(O)NH,;

R

9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, R I IS(O)m-, R I C(O)NR 10-, CN, N02, (RI 0 )2N- C(NR R IOC(O)-, R I 0 N3, -N(R'10)2, or R I I0C(O)NR 1 and c) C I -C6 alkyl unsubstituted or substituted by peffluoroalkyl, F, Cl, Br, R 1 0 R I IS(O)m-,

R

1 0

C(O)NR

1 CN, (Ri %2N-C(NRI0).., RI OC(O)-, R I N3, -N(R 10 or R I IOC(O)NR R 10 is independently selected from hydrogen, C I -C6 alkyl and aryl; Ri 1 is independently selected from C1I-C6 alkyl and aryl; R 12 is independently selected from hydrogen and Ci -C6 alkyl; R 14 is independently selected from hydrogen,C 1 -C6 alkyl and benzyl; *AI and A 2 are independently selected from: a bond, -CH=CH-, -S(0)2N(R -N(RI 0 or S(O)m; is selected from: a) hydrogen, WO 96/10034 PCTIUS9S/12224 -28b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl; provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m or a bond; W is a heterocycle; Z is independently H2 or O; m is 0, 1 or 2; nis 0, 1,2, 3 or 4; pis 0, 1,2, 3 or4; q is 0, 1 or 2; r is 0 to 5, provided that r is 0 when V is hydrogen; and s is 4 or or the pharmaceutically acceptable salts thereof.

In a more preferred embodiment of this invention, the Ras famesyl transferase inhibitors are illustrated by the formula I:

(R

8 )r

R

9 Z R2 R 2 b Z

R

V A'(CR2)A(CR W (CRR 12

N

R

3

R

4

O

wherein: R is independently selected from: a) hydrogen, WO 96/10034 PCT/US95/12224 -29b) aryl, heterocyclic, cycloalkyl, R 10

-N(R

10 )2 or alkenyl, c) C -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, R100-, or -N(R 10 )2; R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine; b) substituted or unsubstituted C -C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R100-, R 1 1 R10C(O)NR10-, CN,

(R

10 )2N-C(NR0)-, R 10C(O)-, R10OC(O)-, N3, -N(R10)2, Rl 1OC(O)NR10- and C1-C20 alkyl, and c) C l-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; and R2b is selected from hydrogen and CI-C6 alkyl; or R2a and R2b are combined to form (CH2)s R3 and R 4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C l-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 Rl lS(O)m-, R 10 C(O)NR10-, CN, WO 96/10034 PCT/US95/12224 (R10)2N-C(NR 10 R R 10OC(O)-, N3,

-N(R

10 R 1OC(O)NRIO- and Cl-C20 alkyl, and d) Ci-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C10 cycloalkyl; is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glutamine, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl -C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10

R

1 1

R

10 C(O)NR10-, CN, (R 0)2N-C(NR10)-, R R10OC(O)-, N3, -N(R10)2, R11OC(O)NRIO-, -SO2N(R10)2, R 1SO2NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; is selected from: a) hydrogen, and b) C1-C3 alkyl; or R5a or R5b are combined with R1 4 to form a ring such that WO 96/10034 WO 9610034PCT/US95/12224 -31

R

5 5 b x-Y is R 7 a a) Ns 0 R 7 b X N C)

O

H

d) o

H

e) -0H 2

-CH

2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C I -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; WO 96/10034 PCT/US95/12224 -32wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C 1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R8 is selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R 10 R10C(O)NR10-, CN, WO 96/10034 WO 9610034PCTfUS95/12224 33 N02, (RI O)2N-C(NRl RI RI OOC(0)-, -N(IO2,or RI IOC(0)NRIO-, and c) C I -C6 alkyl substituted by C I -C6 peffluoroalkyl, RI100., RIOC(0)NRIO-, (RIO)2N-C(NRIO)-, R IOC(0)-, R IOOC(0)-, -N(R 10 or R' IIOC(0)NR

R

9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, Cl, R 10 R I 1 S R I C(0)NR 10 CN, N02, (Ri 0 )2N-C(NR R 1 RI OOC(0)-, -N(Ri 0)2, or R I IOC(0)NR 10-, and C) C 1 -C6 alkyl unsubstituted or substituted by C I -C6 perfluoroalkyl, F, Cl, R 100-, R I IS(0)m-, R I OC(0)NR CN, (Ri 1 )2N-C(NR R I OC(0)-, R IOOC(0)-, -N(R 10)2, or R I OC(0)NR10- R 10 is independently selected from hydrogen, C I -C6 alkyl and aryl; R' I is independently selected from C I-C6 alkyl and aryl; R 12 is independently selected from hydrogen and CI -C6 alkyl; R 14 is independently selected from hydrogen and C I -C6 alkyl; R 1 5 is independently selected from hydrogen and CI -C6 alkyl; A I and A 2 are independently selected from: a bond, -CH=CH-, -S(0)2N(RIO)-, -N(RIO)S(0)2- or S(O)m; V is selected from: WO 96/10034 PCT/US95/12224 -34a) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, b) aryl, c) Ci -C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and d) C2-C20 alkenyl; provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if A is a bond, n is 0 and A 2 is S(O)m or a bond; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, piperidinyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; Z is independently H2 or O; m is 0, 1 or 2; nis 0, 1,2,3 or 4; pis 0,1,2,3 or4; r is 0 to 2; s is 4 or 5; and t is 3, 4 or or the pharmaceutically acceptable salts thereof.

In a second more preferred embodiment of this invention, the prodrugs of the preferred compounds of formula I are illustrated by the formula II: WO 96/10034 WO 9610034PCTfUS95/12224 35

(R

8 )r

R

9 Z R 2 a R 2 b Z R~ R 5 b 2 YK Y 6 V A 1 (CR' )A (CR 1 2 N XN R' R R wherein: RI is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, R 100-, -N(R 10 )2 or alkenyl, c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, R 10O-, or NR02 R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine; b) substituted or unsubstituted C I-C 10 alkyl, C2-C alkenyl, C3-ClO cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 1 0 R' IIS(O)m-, R I C(O)NR 10-, CN, (R'O)2N-C(NRI10)..,

R

1 R 0 N3, -N(R'1O)2, R I IOC(O)NR 1 0- and ClI-C20 alkyl, and C) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; and R2b) is selected from hydrogen and C I -C6 alkyl; or R2a and R2b are combined to form (CH2)s R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, WO 96/10034 PCT/US95/12224 36 b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted CI-C 10 alkyl, C2-C alkenyl, C3-CO10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10

R

1 1 R1 0 C(O)NR10-, CN, (R 10 )2N-C(NR R 10 R 10 N3,

-N(R

10

R

1 1 0C(O)NR10- and Cl-C20 alkyl, and d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; R5a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glutamine, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl -C10 alkyl, C2-C1O alkenyl, C3-CIO cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, R1 0 RI IS(O)m-, R 10 C(O)NR10-, CN,

(R

10 )2N-C(NR10)-, RIOC(O)-, R100C(O)-, N3,

-N(R

10 R 11OC(O)NR10-, -SO2N(R10)2, RI IS02NR 1 0 and C1-C20 alkyl, and d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; is selected from: WO 96/10034 WO 9610034PCT/US95/12224 37 a) hydrogen, and b) C1I-C3 alkyl; or or R5b are combined with R 14 to form a ring such that R 5 a R 5 b isf C

HA)

R

6 is a) substituted or unsubstituted C I -C8 alkyl, wherein the substituent on the alkyl is selected from: 1) aryl, 2) heterocycle, 3) -N(R 11 )2, 4) -OR 10 or R 2o 0z~

R

13 WO 96/10034 PCT/US95/12224 -38- X-Y is R7a a '-Ii

N

0

R

7 b b) c) 0

H

d) s.

or

H

e) -CH 2

-CH

2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C 1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R7b is selected from a) hydrogen, WO 96/10034 PCT/US95/12224 -39b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R8 is selected from: a) hydrogen, b) Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CI-C6 perfluoroalkyl, F, Cl, R1 0 ROC(O)NR10-, CN, N02, (RI 0 )2N-C(NR R -N(R10)2, or R 1 1

OC(O)NR

10 and c) C1-C6 alkyl substituted by C -C6 perfluoroalkyl, R 00-, R OC(0)NR1O-, (R 10 )2N-C(NR10)-, RIOC(O)-, RIOOC(O)-, -N(R 10)2, or R 1 1 0C(0)NR10_; R9 is selected from: a) hydrogen, WO 96/10034 WO 9610034PCTIUS9S/12224 b) C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfinoroalkyl, F, Cl, RlO0-, RIIS(O)m-, RIOC(O)NRIO-, CN, N02, (R I 02N-C(NR 1 Ri I R 1 I -N(R 10)2, or R' IIOC(O)NR 1 and c) C I -C6 alkyl unsubstituted or substituted by C I -C6 perfluoroalkyl, F, Cl, R 10 R' IIS(O)m-, R' I C(O)NR 1 CN, (R I 0 )2N-C(NR 1 R I OC(O)-, R IOOC(O)-, -N(R 10 or R I IOC(O)NR R 10 is independently selected from hydrogen, C I-C6 alkyl and aryl; R' 1 is independently selected from C1I-C6 alkyl and aryl; R 12 is independently selected from hydrogen and C I -C6 alkyl; R 1 3 is 1, 1-dimethylethyl; R 14 is independently selected from hydrogen and C I -C6 alkyl; R 1 5 is independently selected from hydrogen and C I -C6 alkyl; Al and A 2 are independently selected from: a bond, -CH=CH-, -N(Ri 0 or S (O)m; V is selected from: a) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, b) aryl, C) C I -C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom. selected from 0, S, and N, and d) C2-C20 alkenyl; WO 96/10034 PCTIUS95/12224 -41provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A 2 is S(O)m or a bond; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, piperidinyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; Z is independently H2 or O; m is 0, 1 or 2; nis 0, 1, 2, 3 or 4; pis 0, 1,2,3 or4; r is 0 to 2; s is 4 or 5; and t is 3, 4 or or the pharmaceutically acceptable salts thereof.

In a third more preferred embodiment of this invention, the inhibitors of farnesyl transferase are illustrated by the formula III:

HOCH

2

(CH

2 )q

(R

8 )r

R

9 Z R 2 a R2b z N X N OH V A (CR 1 2 )nA 2

(CR

1 2 n W (CR 1 2 )p R R R R 12 R 14 R3 R4

O

III

wherein: R1 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, R 10 -N(R 10)2 or alkenyl, WO 96/10034 PCT/US95/12224 -42c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, R 10 or -N(R10)2; R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine; b) substituted or unsubstituted CI-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R1 0 R 1S(O)m-, RIOC(O)NR 10-, CN, (R 0)2N-C(NR10)-, R10C(O)-, R 10C(O)-, N3,

-N(R

10

R

1 1 OC(O)NR10- and C1-C20 alkyl, and c) C -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; and R2b is selected from hydrogen and Ci-C6 alkyl; or R2a and R2b are combined to form (CH2)s

R

3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted CI-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10

R

1 1

R

10 C(O)NR10-, CN, (R 10 )2N-C(NR RIOC(O)-, R 10 N3,

-N(R

10

R

1 1 0C(O)NR 10 and C1-C20 alkyl, and WO 96/10034 PCT/US95/12224 -43d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; X-Y is R7a a) N N 0

R

7 b b) C) O

H

d) ,or

H

e) -CH 2

-CH

2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C -C6 alkyl substituted with hydrogen or an 0 unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- WO 96/10034 PCT/US95/12224 -44oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Ci-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R8 is selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R 10

R

10 C(O)NR10-, CN, N02, (R10)2N-C(NR10)-,

R

1 R -N(R10)2, or R11OC(O)NR 1 and WO 96/10034 WO 9610034PCrIUS95/12224 45 c) C I -C6 alkyl substituted by C I -C6 perfluoroalkyl, R 1 0 R IOC(O)NR 10 (R I 0 )2N-C(NR R IOC(O)- R I -N(R'1 0 or R I I0C(O)NR 1 0-;

R

9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, Cl, R 1 0 R I 1 R I C(O)NR 1 CN, N02, (R 1 0 )2N-C(NR R I R 1 I -N(R 10)2, or R I IOC(O)NR 10-, and c) C I -C6 alkyl unsubstituted or substituted by C I -C6 perfluoroalkyl, F, Cl, R 10 RI IS

R

1 I C(O)NR CN, (R 10 )2N-C(NRl R 1 I R I -N(R 10 or R' IIOC(O)NR R 1 0 is independently selected from hydrogen, C I -C6 alkyl and aryl; R II is independently selected from C I -C6 alkyl and aryl; R 12 is independently selected from hydrogen and C I -C6 alkyl; R 14 is independently selected from hydrogen and C I -C6 alkyl; Al and A 2 are independently selected from: a bond, -CH=CH-, -S(0)2N(R 1

-N(R

1 0 or S (O)m; V is selected from: a) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, b) aryl, WO 96/10034 PCT/US95/12224 -46c) C1-C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and d) C2-C20 alkenyl; provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m or a bond; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, o1 thiazolyl, pyridonyl, piperidinyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; Z is independently H2 or O; mis0, 1 or 2; nis 0, 1,2, 3 or 4; pis 0, 1,2,3 or4; q is 0, 1 or 2; r is 0 to 2; and sis 4 or the pharmaceutically acceptable salts thereof.

In a fourth more preferred embodiment of this invention, the prodrugs of the preferred compounds of formula III are illustrated by the formula IV:

(R

8 )r

R

9 Z R R 2 b Z I A X, oY 0

V-A(CR

2

)A

2

(CR

1 2 n (CR'2)p R2 4

R

3

R

4

O

IV

wherein: WO 96/10034 PCT/US95/12224 -47-

R

1 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, R 1 0 -N(R10)2 or alkenyl, c) C 1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, R100-, or -N(R10)2; R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine; b) substituted or unsubstituted C -C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 1 0 R11S(O)m-, R 10 C(O)NRO1-, CN, (R 0)2N-C(NR 10 R R 10C(O)-, N3, 2 R11OC(O)NR10- and C1-C20 alkyl, and c) C -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C10 cycloalkyl; and R2b is selected from hydrogen and C1-C6 alkyl; or R2a and R2b are combined to form (CH2)s R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, WO 96110034 WO 9610034PCTfUS95/12224 -48 wherein the substituent is selected from F, Cl, Br, N02, R 1 0 R I IS(O)m-, R I C(O)NR 10-, CN, (R 10 )2N-C(NR10).., R 0 R 1 0 N3, -N(R 10 R I IOC(O)NR 1 0- and C I-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- Ci1G cycloalkyl; X-Y is R7 a) N 0 R 7 b b) N I-

I

C) 0

H

d) or

H

e) -CH 2 -0H 2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and WO 96/10034 PCT/US95/12224 -49e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;

R

8 is selected from: a) hydrogen, WO 96/10034 WO 961004PCTIUJS9SI12224 b) C I -C6 ailkyl, C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, Cl, R 100-, R IOC(O)NR 10-, CN, N02, (R I %2N-C(NR R I R I OOC(O)-, -N('02,or RI IOC(O)NRIO-, and c) C I -C6 alkyl substituted by C I -C6 peffluoroalkyl, RI100., R 1 OC(0)NRIO0., (RIO)2N-C(NR10).., R IOC(0)-, R IOOC(O)-, -N(R 10 or R I I0C(O)NR R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1I-C6 perfluoroalkyl, F, Cl, R 10 R' IIS(0)m-, R I C(O)NR 1 0 CN, N02, (R 10 )2N-C(NR 1 R I R I O0C(0)-, -N(R 10)2, or R I IOC(0)NRl10-, and c) C I -C6 alkyl unsubstituted or substituted by C I -C6 perfluoroalkyl, F, Cl, R 10 R I IS(0)m-, R I OC(0)NRi CN, (R 10 )2N-C(NR R 1 I R IOOC(0)-, -N(R 10 or R I0 C(0)NR10-; R 1 0 is independently selected from hydrogen, C I -C6 alkyl and aryl; R 11 is independently selected from C I -C6 alkyl and aryl; Ri1 2 is independently selected from hydrogen and C I -C6 alkyl; Ri1 4 is independently selected from hydrogen and C I -C6 alkyl; AlI and A 2 are independently selected from: a bond, -CH=CH-, -S(O)2N(R' 0 -N(RIO)S(0)2- or S(O)m; V is selected from: WO 96/10034 PCT/US95/12224 -51a) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, b) aryl, c) C 1-C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and d) C2-C20 alkenyl; provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if A is a bond, n is 0 and A 2 is S(O)m or a bond; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, piperidinyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; Z is independently H2 or O; m is 0, 1 or 2; nis 0, 1,2,3 or 4; pis 0, 1,2,3or4; qis 0, 1 or2; r is 0 to 2; and s is 4 or or the pharmaceutically acceptable salts thereof.

The preferred compounds of this invention are as follows: -(Phenylmethyl)-1H-imidazol-4-ylacetyl)amino-3(S)methylpentyl]-N- 1 -naphthylmethyl-glycyl-methionine WO 96/10034 WO 9610034PCT21US95/12224 52 N- 1 -(Phenylmethyl)- 1 H-imidazol-4-yiacetyi)amino-3 (S methylpentyl] I -naphthylmethyl-giycyl-methionine methyl ester N- (1 -(Phenylmethyl)- I H-imidazol-5-ylacetyl)amino-3 (S methylpentyl] I -naphthylmethyl-glycyi-methionine N- 1 -(Phenylmethyl)- 1 H-imidazol-5-ylacetyl)-amnino-3(S)methylpentyl] -N-i -naphthylmethyl-glycyl-methionine methyl ester N- 1 -(4-Nitrophenyimethyl)- 1 H-imidazol-4-ylacetyl)amino-3(S)methylpentyl] -N-I -naphthylmethyl-glycyl-methionine N- [(2S I -(4-Nitrophenylmethyl)- 1 H-imidazol-4-ylacetyl)amino-3 methylpentyl] I -naplithylmethyl-glycyl-methionmne methyl ester N- 1 -(4-Nitrophenylmethyl)- 1 H-imidazol-5-ylacetyl)amino-3(S)methylpentyl] -N-i -naphthylmnethyl-glycyl-methionine N- 1 -(4-Nitrophenyl-methyl)- 1 H-imidazol-5 -ylacetyl)amino-3 methylpentyl]-N-lI -naphthylmethyl-glycyl-methionine methyl ester N- (1 -(2-Naphthylmethyl)- 1 H-iinidazol-5-ylacetyi)amino-3 methylpentyl]-N- I -naphthylmnethyl-glycyi-methionmne N- 1 -(2-Naphthylmethyl)- 1 H-imidazoi-5-ylacetyl)amino-3(S)methylpentyl] I -naphthylmethyl-glycyl-methionine methyl ester -Naphthylmethyl)-1IH-imidazol-5-yacetyl)amino-3(S..

methylpentyl] I -naphthylmethyl-glycyl-methionine -(I1-Naphthyimethyl)- 1H-imidazol-5-yiacetyl)amino-3(S)methylpentyl] I -naphthylmethyl-glycyl-methionine methyl ester WO 96/10034 WO 9610034PCTI1JS9S,12224 53 N- 1 -Famesyl- 1 H-imidazoi-5-ylacetyl)amino-3 (S)-methylpentyl] N- I -naplithylmethyl-glycyl-methionine N- 1 -Famesyl- 1 H-imidazol-5-ylacetyl)amino-3 (S)-methylpentyl] N- I -naphthyhmethyl-glycyl-methionine methyl ester N- 1 -Geranyl- 1 H-imidazol-5 -ylacetyl)amino-3 (S)-methylpentyll N- I -naphthylmethyl-glycyl-methionine N- 1 -Geranyl- 1 H-imidazol-5-ylacetyl)amino-3 (S)-methylpentyl] N- I -naphthylmethyl-glycyl -methionine methyl ester 4 -Pyridylmefiyl)- 1H-imidazol-4-ylacetyl)amnino-3(S)methyipentyl] I -naphthyimethyl-giycyl-methionine N- 1 -(4-Pyridylmethyl)- I H-imidazol-4-ylacetyl)amino-3 methylpentyl] I -naphthylmethyl-glycyl-methionine methyl ester N- 1 -(4-Pyridyimethyl)- 1 H-imidazol-5-ylacety)amino-.(3S).

methyipentyl] I -naphthyhriethyl-glycyi-methionine N- 1 -(4-Pyridyimethyl)- I H-imidazol-5-ylacetyl)amino-3 (S methylpentyl] I -naphthylmethyi-giycyi-methionine methyl ester N- -(4-Cyanophenylmethyl)- I H-imidazol-5-ylacetyi)amino-3(S)methyipentyl] I -naphthylmethyi-giycyi-methionmne N- 1 -(4-Cyanophenyimethyl)- 1 H-imnidazol-5-yiacetyi)amino-3 methyipentyl] -N-i -naphthylmethyl-glycyl-methionine methyl ester N- 1-(4-Methoxyphenyimethyl)- 3 (S)-methyipentyi] -N-i -naphthylmethyl-glycyl-methionmne WO 96/10034 WO 9610034PCTIUS95/12224 N- 1 -(4-Methoxyphenyknethyl)- 3 (S)-methylpentyl] I -naplithyimethyl-glycyl-methionine methyl ester N- 1 -(4-Quinolinylmethyl)- 1 H-imidazol-5-ylacetyl)amnino-3(S)methylpentyl] 1 -naphthylmnethyl-glycyl-methionine N- I -(4-Quinolinylmethyl)- 1 H-imidazol-5-ylacetyl)amino-3(S)methylpentyl] I -naphthylmnethyl-glycyl-methionine methyl ester 1 -(2-Naphthylmethyl)- 1 H-imidazol-5-ylacetyl)amino-3 methylpentyl] -N-i -phenylmethyl -glycyl-methionine 1 -(2-Naphthylmethyl)- 1 H-imidazol-5-ylacetyl)amino-3(S)methyipentyl] -N-i -phenylmethyl -glycyl-methionine methyl ester N- I-(2-Naphthylmethyl)- 1H-imidazol-5-ylethyl)amino-3 methylpentyl] -N-i -naphthylmethyl-glycyl-methionine N- 1-(2-Naphthylmethyl)- 1H-imidazol-5-ylethyl)amino-3 (S methyipentyl] -N-i -naphthylmethyl-glycyl-methionine methyl ester 1 -(2-Naphthyimethyl)- I H-imidazol-5-ylacetyl)amino-3(S)methyllpentyloxy-3-phenylpropionyl-methionine sulfone methyl ester I -(2-Naphthyimethyl)- 1 H-imidazol-5 -ylacetyl)amino-3 methyllpentyloxy-3-phenylpropionyl-methionine suifone 1-(2-Naplithyimethyl)- 1H-imidazol-5-ylethyl)amino-3 methyllpentyloxy-3-phenylpropionyl-methionine methyl ester 1-(2-Naphthylmethyl)- 1H-imidazol-5-ylethyl)amino-3 methyllpentyloxy-3-phenylpropionyl-methionine WO 96/10034 WO 9610034PCTIUS95/12224 55 N- 1-Methyl- I H-imidazol -4-ylacetyl)-amino-3 (S )-methylpentyl] 1-naphthylmethyl)-glycyl-methionine methyl ester N- 1-Methyl-i H-imidazol-4-ylacetyl)-amino -3 (S)-methylpentyl] 1 -naphthylmethyl)-glycyl-methionine N- [2(S)-N-(2-Naphthylmethyl)- 1 H-imidazol-5-ylacetyl] amino-(3 S)methylpentyl] -N-(cyclopropyhriethyl)-glycylmnethionine methyl ester N- [(2S)-N-(2-Naphthylmethyl)- 1 H-imidazol-5-ylacetyl]amino-(3S)methylpentyl] -N-(cyclopropylmethyl)-glycylmethionine N- [(5(R,S)-Methylpyroglutamyl)amino] -3 (S)-methylpentyl] 1naphthylmethyl)-glycylmnethionine methyl ester N- [(5(R,S)-Methylpyroglutamyl)amino] -3 (S)-methylpentyl]-N-( 1naphthylmethyl)-glycylmethionine N- 2 (S)-((N-Methylpyroglutamyl)amino)-3(S)-methylpentyl]N.(I 1naphthylmethyl)-glycyl-methionine N- 2 (S)-((N-Methylpyroglutamyl)-amino)-3 (S )-methylpentyl] 1naphthylmethyl)-glycyl-methionine methyl ester

N-[

2 (S)-(N-Fornylprolylamino)-3(S)-methylpentyl}-N.(l naphthylmethyl)-glycyl-methionine methyl ester N- [2(S)-(N-Formnylprolylamino)-3 (S )-methylpentyl] 1naphthylmnethyl)-glycyl-methionine N- '-(4-Nitrobenzyl)pyroglutamyl)-amino)-3 (S)-methylpentyl] N-(1 -naphthylmethyl)-glycyl-methionine methyl ester WO 96/10034 WO 9610034PCTIUS95/12224 56 N- -(4-Nitrobenzyl)pyroglutamyl)-amino)-3 (S)-methylpentyl] 1 -naphthylmethyl)-glycyl-methionine N- '-Benzylpyroglutamyl)amino)-3 (S)-methylpentyl] 1naphthylmethyl)-glycyl-methionine methyl ester N- -Benzylpyroglutamyl)amino)-3(S)-methylpentyl] 1naphthylmethyl)-glycyl-methionine 1 -(4-Fluorophenylmethyl)- 1 H-imidazol-5-ylacetyl)amino-3(S)methylpentyl] I -naphthylmethyl-glycyl-methionine methyl ester 1 -(4-Fluorophenylmethyl)- 1 H-imidazol-5-ylacetyl)amino-3 methylpentyl]-N- 1 -naphthylmethyl-glycyl-methionine N- 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] acetylamino)-3(S)methylpentyl] 1-naphthylmethyl)glycyl-methionine isopropyl ester N- 1 -(4-cyanobenzyl)- 1H-imidazol-5-yl] acetylamino)-3(S)methylpentyl]-N-( 1-naphthylmethyl)glycyl-methionine sulfone methyl ester N- 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] acetylamino)-3 methylpentyl] 1-naphthylmethyl)glycyl-methionine sulfone N- [1 -(4-cyanobenzyl)- 1H-imidazol-5-yl] acetylamino)-3(S methylpentyl] 1 -naphthyhmethyl)glycyl-(3 -acetylamino)alanine methyl ester N- 1-(4-cyanobenzyl)- 1H-imidazol-5-yl] acetylamino)-3(S)methylpentyl] 1 -naphthylmethyl)glycyl-(3 -acetylamino)alanine WO 96/10034 WO 9610034PCT1US95/12224 57 N- 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yllacetylamino)-3(S)methylpentyl] 1-naphthylmethyl)glycyl-2(RS) amino-3 -(2 thienyl)propionic acid methyl ester N- 1 -(4-cyanobenzyl)- 1H-imidazol-5-yl] acetylamino)-3(S)methylpentyl] 1 -naphthylmethyl)glycyl-2(RS)-amino-3-(2 thienyl)propionic acid N- 1-(4-cyanobenzyl)- 1H-imidazol-5-yl] acetylamino)-3(S)la methylpentyl] 1 -naphthylmethyl )glycyl-2(S) amino-4-sulfamylbutanoic acid methyl ester N- I-(4-cyanobenzyl)- 1H-imidazol-5-yl] acetylamino)-3(S)methylpentyl] 1-naphthylmethyl)glycyl-2(S) amino-4-sulfamnylbutanoic acid 1-(4-cyanobenzyl)- 1H-imidazol-5-yI] acetylamino)-3 methylpentyl] 1 -naphthylmethyl)glycyl-N-methyl methionine methyl ester I-(4-cyanobenzyl)- 1H-imidazol-5-yllacetylamino)-3(S)methylpentyl] 1 -naphthylmethyl)glycyl-N-methyl methionine N- 1-(4-cyanobenzyl)- 1H-imidazol-5-yl] acetylammno)-3(S)methylpentyl] 1-naphthylmethyl)glycyl-homoserine lactone N- I-(4-cyanobenzyl)- 1H-imidazol-5-yl] acetylamino)-3(S)methylpentyl] 1 -naphthylmethyl)glycyl-homoserine N- 1-(4-cyanobenzyl)- 1H-imidazol-5-yl] acetylamino)-3(S methylpentyl] 1 -naphthylmnethyl)glycyl-proline methyl ester N- 1-(4-cyanobenzyl)- 1H-imidazo 1-5 -yl] acetylamino)-3 methylpentyl]-N-( 1 -naphthylmethyl)glycyl-proline WO 96110034 WO 9610034PCTIUS95/12224 58 N- 1 -(4-cyanobenzyl)- 1 H-imidazol-5 -yl] acetylamino)-3(S)methylpentyl]-N-( 1 -naphthylmethyl)glycyl-D-proline methyl ester 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] acetylamino)-3(S)methylpentyl]-N-( 1 -naphthylmethyl)glycyl-D-proline I -(4-cyanobenzyl)- 1H-imidazol-5-yl]acetylamino)-3(S)methylpentyl] 1 -naphthylmethyl)glycyl-L- pipecolinic acid N- I -(4-carbomethoxybenzyl)- 1 3 (S)-methylpentyl] 1-naphthylmethyl)glycyl-methionine methyl ester N- 1 -(4-carbomethoxybenzyl)- 1 H-imidazol-5-yl] acetylammno)- 3 (S)-methylpentyl] I -naphthylmethyl)glycyl -methionine 1 -(2-naphthylmethyl)- 1 phenylalaninyl-methionine methyl ester 1 -(2-naphthylmethyl)- 1 phenylalaninyl-methionine or the pharmaceutically acceptable salts thereof.

Representative compounds of the invention are: N- (1 -(4-Nitrophenylmethyl)- 1 H-imidazol-5-ylacetyl)amino-3 methylpentyl]-N- 1 -naphthylmnethyl-glycyl-methionine WO 96/10034 WO 9610034PCTIUS95/12224 59 N0 2

(N

N 0 N- I -(4-Nitrophenyl-methyl)- 1 H-imidazol-5 -ylacetyl)amino-3 methylpentyl] I -naphthylmethyl-glycyl-methionine methyl ester

NO

2 Ny- 0 0

SCHS

N-112(S)-(1 -(4-Cyanophenylmethyl)- 1 H-imidazol-5-ylacetyl)amino-3(S)methylpentyl]-N- 1-naphthylmethyl-glycyl-methionine

ON

H H N N N

O

0 N 0O

SCH

3 WO 96/10034 WO 9610034PCTIUS95/12224 60 N- 1 -(4-Cyanophenyl-methyl)- 1 H-imidazol-5-ylacetyl)amino-3 (S methylpentyl] I -naplithylmethyl-glycyl-methionine methyl ester

ON

PH H0 (N N N e 0 0

SCH

3 N- 1-(4-Cyanophenyl-methyl)- 1H-imidazol-5-ylacetyl)amino-3 methylpentyll -N-i -naphthylmethyl-glycyl-methi onine isopropyl ester

ON

PH H 0 N N-N N N 0 N 01-Pr

H

3 N- 1-(4-Methoxyphenylmethyl)- 3 (S)-methylpentyl] I -naphthylmethyl-glycyl-methionine WO 96/10034 WO 9610034PCJ21US95/12224 -61- OMe

P~H

IN

N

N

H 0 O H

CH

3 1 -(4-Methoxyphenyl-methyl)- 1 3(S)-methylpentyl]-N- 1 -naphthylmethyl-glycyl-methionine methyl ester .OMe H 0

*OM.

SCH

3 1 -(2-Naphthylmethyl)- 1 H-imidazol-5-ylacetyl)amnino-3(S)methylpentyl] I -naphthylmethyl-glycyl-methionine WO 96/10034 WO 9610034PCTIUS95/12224 62 N R H H0 N OH N 0o

SCH

3 N- 1-(2-Naphthylphenyl-methyl)- 1 H-imidazol-5 -ylacetyl )amino- 3 (S)-methylpentyl] -N-i -naphthyhmethyl-glycyl-methionine methyl ester RH H0 N N N,_ N OMe N 0 0 ~jSH3 N- 1 -(4-Cyanophenyl-methyl)- 1 H-imidazol-5-ylacetyl)amino-3(S)methylpentyl] -N-i -naphthylmethyl-glycyl-methionine sulfone methyl ester WO 96/10034 WO 9610034PCTIUS95/12224 63 r H H 0 N N-N N N 0~ N 0 2

CH

3 N- 1-(4-Cyanophenyl-methyl)- 1H-imidazol-5-ylacetyl)amino-3(S)methylpentyl] -N-i -naphthylmethyl-glycyl-methionine sulfone

ON

N

N 0 H 0

N

0 OH

~SO

2

CH

3 N- 1 -(4-Cyanophenyl-methyl)- 1 H-imidazol-5-ylacetyl)amino-3(S)methylpentyl] I -naphthylmethyl-glycyl-2-(acetylamino)alanine methyl ester WO 96/10034 WO 9610034PCTIUS95/12224 64 N- 1 -(4-Cyanophenyl-methyl)- 1 H-imidazol-5-ylacetyl)amino-3 (S methylpentyl] I -naphthylmethyl-glycyl-2-(acetylamino)alanine methyl ester I H N N

N"

N 0 0 0

OH

0 OH 3 1 -(4-Cyanophenylmethyl)- 1 H-imidazol-5-ylacetyl)amino-3(S)methylpentyl] I -naphthylmethyl-glycyl-N-methyl-methionine

ON

H 0H 3 0 N N.y l'

OH

N 0 0 /\H3 N- [2(S)-(lI-(4-Cyanophenyl-methyl)- 1H-imidazol-5-ylacetyl)amino-3(S)methylpentyl] -N-i -naphthylmethyl-glycyl-N-methyl-methionine methyl ester WO 96/10034 PCT/US95/12224

CN

OH

3 0

HCH

\H I H N N OMe N O O SCH3 or the pharmaceutically acceptable salts thereof.

In the present invention, the amino acids which are disclosed are identified both by conventional 3 letter and single letter 1 abbreviations as indicated below: Alanine Ala A Arginine Arg R Asparagine Asn N Aspartic acid Asp

D

Asparagine or Aspartic acid Asx B Cysteine Cys C Glutamine Gin Q Glutamic acid Glu E Glutamine or Glutamic acid Glx Z Glycine Gly G Histidine His H Isoleucine Ile I Leucine Leu L Lysine Lys K Methionine Met M Phenylalanine Phe F Proline Pro P

II

WO 96/10034 PCT/US95/12224 -66- Serine Ser S Threonine Thr T Tryptophan Trp W Tyrosine Tyr Y Valine Val V The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.

As used herein, "cycloalkyl" is intended to include nonaromatic cyclic hydrocarbon groups having the specified number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

"Alkenyl" groups include those groups having the specified number of carbon atoms and having one or several double bonds. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2butenyl, isoprenyl, famesyl, geranyl, geranylgeranyl and the like.

As used herein, "aryl" is intended to include any stable monocyclic, bicyclic or tricyclic carbon ring(s) of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like.

The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11membered bicyclic or stable 11-15 membered tricyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the WO 96/10034 PCTIUS95/12224 -67group consisting of N, 0, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydro-benzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide, pyridonyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolinyl N-oxide, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.

As used herein, the terms "substituted aryl", "substituted heterocycle" and "substituted cycloalkyl" are intended to include the cyclic group which is substituted with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, NH2, N(C1-C6 alkyl)2, CF3, N02, (C1-C6 alkyl)O-, -OH, (C1-C6 alkyl)S(O)m-, (C1-C6 alkyl)C(O)NH-, H2N-C(NIl)-, (C1-C6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)-, N3, CN, (Cl-C6 alkyl)OC(O)NH- and alkyl.

WO 96/10034 PCT/US95/12224 -68- The following structure:

H

2 )t represents a cyclic amine moiety having 5 or 6 members in the ring, such a cyclic amine which may be optionally fused to a phenyl or cyclohexyl ring. Examples of such a cyclic amine moiety include, but are not limited to, the following specific structures:

N

When R 2 a and R2b and R 3 and R 4 are combined to form (CH2)s cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to: When R5a and R5b are combined to form (CH2)s cyclic moieties as described hereinabove for R2a and R2b and R 3 and R 4 are formed. In addition, such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include, but are not limited to: WO 96/10034 PCTIUS95/12224 -69- O

S

^LL4 %;sr o S N, N H 0 I S 0

COR'O

Preferably, RI is selected from: hydrogen, and Ci-C6 alkyl.

Preferably, R2a and R2b are independently selected from: a side chain of a naturally occurring amino acid and C1-C6 alkyl unsubstituted or substituted with an aryl group.

Preferably, R 3 and R 4 are independently selected from: a side chain of a naturally occurring amino acid and C1-C6 alkyl unsubstituted or substituted with a group selected from aryl, heterocycle and C3-C10 cycloalkyl.

Preferably, R5a and R5b are independently selected from: a side chain of a naturally occurring amino acid, methionine sulfoxide, methionine sulfone and unsubstituted or substituted C1-C6 alkyl.

Preferably, X-Y is selected from: 25

R

7 b and O.

Preferably, R7b C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted aryl group.

Preferably, R8 is selected from: hydrogen, perfluoroalkyl, F, Cl, Br, R 10 RI 1 CN, N02, R 1

R

10

OC(O)-,

-N(R10)2, R 1 OC(O)NR10- and C1-C6 alkyl.

Preferably, R 9 is hydrogen.

WO 96/10034 PCTIUS95/12224 Preferably, R 10 is selected from H, C1-C6 alkyl and benzyl.

Preferably, Al and A2 are a bond.

Preferably, V is selected from hydrogen, heterocycle and aryl.

Preferably, n, p and r are independently 0, 1, or 2.

Preferably t is 3.

The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, from non-toxic inorganic or organic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenyl-acetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.

It is intended that the definition of any substituent or variable R10, Z, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, -N(R10)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth below.

The pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base with stoichiometric amounts or with an excess of the desired saltforming inorganic or organic acid in a suitable solvent or various combinations of solvents.

WO 96/10034 PCT/US95/12224 -71 The compounds of the invention can be synthesized from their constituent amino acids by conventional peptide synthesis techniques, and the additional methods described below. Standard methods of peptide synthesis are disclosed, for example, in the following works: Schroeder et al., "The Peptides", Vol. I, Academic Press 1965, or Bodanszky et al., "Peptide Synthesis", Interscience Publishers, 1966, or McOmie "Protective Groups in Organic Chemistry", Plenum Press, 1973, or Barany et al., "The Peptides: Analysis, Synthesis, Biology" 2, Chapter 1, Academic Press, 1980, or Stewart et al., "Solid Phase Peptide Synthesis", Second Edition, Pierce Chemical Company, 1984. The teachings of these works are hereby incorporated by reference.

Abbreviations used in the description of the chemistry and in the Examples that follow are: Boc

DBU

DMAP

DME

DMF

EDC

HOBT

Et3N EtOAc

FAB

HOOBT

HPLC

MCPBA

MsCI NaHMDS Py

TFA

Acetic anhydride; t-Butoxycarbonyl; 1,8-diazabicyclo[5.4.0]undec-7-ene; 4-Dimethylaminopyridine; 1,2-Dimethoxyethane; Dimethylformamide; 1 -(3-dimethylaminopropyl)-3-ethyl-carbodiimidehydrochloride; 1 -Hydroxybenzotriazole hydrate; Triethylamine; Ethyl acetate; Fast atom bombardment; 3-Hydroxy-1,2,2-benzotriazin-4(3H)-one; High-performance liquid chromatography; m-Chloroperoxybenzoic acid; Methanesulfonyl chloride; Sodium bis(trimethylsilyl)amide; Pyridine; Trifluoroacetic acid; WO 96/10034 PCTIUS95/12224 -72- THF Tetrahydrofuran.

Compounds of this invention are prepared by employing the reactions shown in the following Reaction Schemes A-J, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Some key bondforming and peptide modifying reactions are: Reaction A. Amide bond formation and protecting group cleavage using standard solution or solid phase methodologies.

Reaction B. Preparation of a reduced peptide subunit by 1 reductive alkylation of an amine by an aldehyde using sodium cyanoborohydride or other reducing agents.

Reaction C. Alkylation of a reduced peptide subunit with an alkyl or aralkyl halide or, alternatively, reductive alkylation of a reduced peptide subunit with an aldehyde using sodium cyanoborohydride or other reducing agents.

Reaction D. Peptide bond formation and protecting group cleavage using standard solution or solid phase methodologies.

Reaction E. Preparation of a reduced subunit by borane reduction of the amide moiety.

These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Reaction Schemes.

REACTION SCHEME A Reaction A. Coupling of residues to form an amide bond WO 96/10034 WO 9610034PCTIUS95/12224 73 >L0 R A N )OH H 0

%RB

H

2 N A 0 EDO, HOBT or HOOBT EtAN DMF 0 O 'K RA H 0 O RB 0

RBOR

HOI or

TFA

RA

H

2 N 0 REACTION SCHEME B Reaction B. Preparation of reduced peptide subunits by reductive alkylation O R A H 0

H

2 N

YO

0 NaCNBH 3 0 RAH0 NN~ "OR H

RB

WO 96/10034 WO 9610034PCTIUS95/12224 -74 REACTION SCHEME C Reaction C. Alkylation/reductive alkylation of reduced peptide subunits 0RA H 0 0 N ~N -A.O0R H R 7 bXL, base or 0 11 RCCH, NaCNBH,

H

RB

REACTION SCHEME D Reaction D. Coupling of residues to form an amide bond 0

RA

%OH

EDO, HOBT or HOOBT Et 3 N, DMF HOI or TFA

H

RA 0

H

2 N Nk% 0 WO 96/10034 PCT/US95/12224 REACTION SCHEME E Reaction E. Preparation of reduced dipeptides from peptides

OR

H O Ra O N OR H

RB

where RA and RB are R2a, R2b, R 3 R4, R5a or R5b as previously defined; XL is a leaving group, Br-, I- or MsO-; and RCis defined such that R7b is generated by the reductive alkylation process.

Reaction Schemes A-E illustrate bond-forming and peptide modifying reactions incorporating acyclic peptide units. It is well understood that such reactions are equally useful when the NHC(RA) moiety of the reagents and compounds illustrated is replaced with the following moiety:

S-K

H

2 )t Certain compounds of this invention wherein X-Y is an ethenylene or ethylene unit are prepared by employing the reaction sequences shown in Reaction Schemes F and G. Reaction Scheme F outlines the preparation of the alkene isosteres utilizing standard manipulations such as Weinreb amide formation, Grignard reaction, acetylation, ozonolysis, Wittig reaction, ester hydrolysis, peptide WO 96/10034 PCT/US95/12224 -76coupling reaction, mesylation, cleavage of peptide protecting groups, reductive alkylation, etc., as may be known in the literature or exemplified in the Experimental Procedure. The key reactions are: stereoselective reduction of the Boc-amino-enone to the corresponding syn amino-alcohol (Scheme F, Step B, Part and stereospecific boron triflouride or zinc chloride activated organomagnesio, organo-lithio, or organo-zinc copper(l) cyanide SN2' displacement reaction (Scheme F, Step Through the use of optically pure N-Boc amino acids as starting material and these two key reactions, the stereo-chemistry of the final products is well defined. In Step H of Scheme F, Rx is incorporated using coupling reaction A and RICOOH; the alkylation reaction C using RxCHO and a reducing agent; or alkylation reaction C using RxCH2XL.

The alkane analogs are prepared in a similar manner by including an additional catalytic hydrogenation step as outlined in Reaction Scheme G.

REACTION SCHEME F

OH

BocNH2aOH R2a 1. CICO 2 i-Bu MeONHMe BrMg 0 BocNH l^ Step A 1. NaBH4 2. Ac20, Py Step B 1. 03, Me 2

S

2. Ph 3

P=CHCO

2 Me Step C OAc BocNH R2a OAc BocN O H.2

CO

2 Me WO 96/10034 WO 9610034PCTIUS95/12224 -77 REACTION SCHEME F (CONT'D) Step D 1. LiOH

OH

BocNH R 2a 0 Step E 2. EDO, HOBT amino acid (ester) W= OMe, Wit SMe Wi MsCI, py Step F OMs 0 BocN H Wit R 2a 0 wit BocNH N,.w R 2a 0 Wi t

R

3 Mg~uONCIBF 3 Step G 1. HG! 2. NaCNBH 3 RxCHO Step H H R3H 0 RxCH 2 N N Wi R a0 Wi WO 96/10034 WO 9610034PCTIUS95/12224 78 REACTION SCHEME F (CONTD) NaOH HR 3 H 0 RxCH 2 N N

OH

R 2 0wo 1. HCI 0 11 2. RxCOH EDO, HOBT R x 0 R 2a Alternate Step H

R

3 H 0 0 Wit aOH

NA

OH,

IN

Ax y'- 0 WO 96/10034 WO 9610034PCTIUS95112224 79 REACTION SCHEME G BocNHK

EOH

1. NaBH4

CICO

2 i-Bu MeONHMe Bo 2 B rM g CAc BocNH", 0 cN H," R 2a 1. 03, Me 2

S

2. Ph, 3

P=CHCO

2 Me 2. AC 2 O, py QAc0 B o cN 2,

CO

2 Me OH 0

HI

1. LiOH 2. EDC, HOOT MsCI, py WO 96/10034 WO 9610034PCTIUS95/12224 REACTION SCHEME G (CONT'D) OMs 0 BocNH H 0 -~0 1. R 3 MgCuCNCI*BF 3 2. H 2 5% Pd/C Step K R 2a 1. HOI 2. NaCNBH 3

AXOHO

RxCH 2

N

NaOH A R 3 H 0 RxCH 2 NHN.A

H

0O WO 96/10034 PCT/US95/12224 -81 REACTION SCHEME G (CONT'D) or

O

II

1. HCI 2. RXCOH

EDC,HOBT

0 R 3 0 RXCNH

N-

R2a 0 NaOH 0

R

3 0 RxCNH

OH

R

2 a 0 .OH The oxa isostere compounds of this invention are prepared according to the route outlined in Scheme H. An aminoalcohol H- is acylated with alpha-chloroacetyl chloride in the presence of trialkylamines to yield amide H-2. Subsequent reaction of H- 2 with a deprotonation reagent sodium hydride or potassium t-butoxide) in an ethereal solvent such as THF provides morpholinone H-3. The N-Boc derivative H-4 is then obtained by the treatment of H-3 with BOC anhydride and DMAP (4dimethylaminopyridine) in methylene chloride. Alkylation of H-4 with R3XL, where XL is a leaving group such as Br-, I- or Cl- in THF/DME (1,2-dimethoxyethane) in the presence of a suitable base, preferably NaHMDS [sodium bis(trimethylsilyl)amide], affords which is retreated with NaHMDS followed by either protonation or WO 96/10034 PCT/US95/12224 -82the addition of an alkyl halide R4X to give H-6a or H-6b, respectively. Alternatively, H-6a can be prepared from H-4 via an aldol condensation approach. Namely, deprotonation of H-4 with NaHMDS followed by the addition of a carbonyl compound RyRzCO gives the adduct H-7 (wherein RY and Rz are selected such that R 3 is eventually provided. Dehydration of H-7 can be effected by mesylation and subsequent elimination catalyzed by DBU (1,8diazabicyclo[5.4.0]undec-7-ene) or the direct treatment of H-7 with phosphorus oxychloride in pyridine to give olefin H-8. Then, catalytic hydrogenation of H-8 yields H-6a. Direct hydrolysis of H-6 with lithium hydrogen peroxide in aqueous THF will produce acid H- 9b. Sometimes, it is more efficient to carry out this conversion via a 2-step sequence, namely, hydrolysis of H-6 in hydrochloric acid to afford H-9a, which is then derivatized with BOC-ON or BOC anhydride to give H-9b. The peptide coupling of acid H-9b with either an alpha-aminolactone homoserine lactone, etc.) or the ester of an amino acid is carried out under the conditions exemplified in the previously described references to yield derivative Treatment of H-10 with gaseous hydrogen chloride gives H-ll, which undergoes reductive alkylation in the presence of an aldehyde RxCHO (H-12) and a reducing agent sodium cyanoborohydride); or acylation in the presence of RxCOOH (H-13) and a peptide coupling reagent affording the products H-14a and b.

Hydrolysis of compounds H-14 to the corresponding hydroxy acids and acids, respectively, is accomplished by standard methods such as treatment with NaOH in alcoholic or aqueous milieux followed by careful acidifcation with dilute HC1.

WO 96/10034 PTU9122 PCTfUS95/12224 83 SCHEME H

HO

H

2 N ,R 2 a c

I

0>01 Cl H 0 2a

H

base 0 R, 2 a

H

BOC

2 0

BOO

H-4 Base 0 Base RyRzCO

RZ

BOO

Base R 4 X or R 4 R 311, 0 2a 0 N R

I

BOC BOO H-5i H-6

-H

2 0

H

2 Pd/C

BOO

H-7 H-8 WO 96/10034 WO 9610034PCT1US95/12224 84- SCHEME H (CONTD) LiOOH; or aq. HOI, then BOC 2 0

R

3 R 4 a, R' H b, R' BOO EDO

RR

9 +H-A B 0OCN H A- HOBT 0~ HCI

R

3 R 4 HH CsINs 2/' 0 01 R 2a 0 H-1i1 WO 96/10034 PCT/US95/1224 SCHEME H (CONT'D) RXCHO, NaCNBH 3 R 4 H-12 RXCH 2 NH O A

R

2 a

O

H-14a RXCOOH, EDC, HOBT H-13 0 R 0 1 II NO

R

2a

O

H-14b

A=

0 o

NHJ

1 0 or NH

AOR

6 R a q The thia, oxothia and dioxothia isostere compounds of this invention are prepared in accordance to the route depicted in Scheme I. Aminoalcohol I-1 is derivatized with BOC20 to give 1-15.

Mesylation of 1-15 followed by reaction with methyl alphamercaptoacetate in the presence of cesium carbonate gives sulfide 1- 16. Removal of the BOC group in 1-16 with TFA followed by neutralization with di-isopropylethylamine leads to lactam 1-17. N- BOC derivative I-18 is obtained via the reaction of 1-17 with BOC anhydride in THF catalyzed by DMAP. Sequential alkylation of I-18 with the alkyl halides R 3 X and R 4 X in THF/DME using NaHDMS as the deprotonation reagent produces 1-19. Hydrolysis of 1-19 in hydro-chloride to yield I-20a, which is derivatized with Boc WO 96/10034 PCT/US95/12224 -86anhydride to yield I-20b. The coupling of I-20b with an alphaaminolactone homoserine lactone, etc.) or the ester of an amino acid is carried out under conventional conditions as exemplified in the previously described references to afford 1-21. Sulfide I-21 is readily oxidized to sulfone 1-22 by the use of MCPBA (mchloroperoxybenzoic acid). The N-BOC group of either 1-21 or 1-22 is readily removed by treatment with gaseous hydrogen chloride.

The resultant amine hydrochloride 1-23 undergoes reductive alkylation in the presence of an aldehyde RxCHO (1-12) and a reducing agent sodium cyanoborohydride); or acylation in the presence of RxCOOH (1-13) and a peptide coupling reagent to afford the products 1-24 and 1-25.

WO 96/10034 WO 9610034PCTIUS95/12224 87 SCHEME I HO 2

H

2 N R 2

BOC

2 0 HO 2 HN R 2 115 BOO 1) MsOI 2) 052003

HSCH

2 C0 2

CH

3 C0H r

S

30CHN R 2 a 1-16

BOO

1) TEA 2) (i-Pr) 2 NEt

I

H 1-17

BOC

2 0 O -1 N 1-18

BOO

1) R 3

X,

Base 2) R 4

X,

Base 0 N R 2 I1 O HCi

H

2 0

R

3 R 4 N H I NS C02H mw R 2 a H-A, EDO

HOBT

R 3

[R

4 BOCNH,, A R 0 1-21 a, Rw=H b, RW=BOC

BOC

2 0 0

NE%),

0 or N~IkOR' WO 96/10034 WO 9610034PCTfUS95/12224 88 SCHEME I (CONT'D)

R

3 R 4 BOCNH,'- S(O)m

A

R 2a 0

HOI

J m=2, 1-22

MCPBA

R 3 R 4

HCI-NH

2 5

A

-S(O)m R 2a 0 RxCH 2

NH

RxCHO 12 NaCNBH 3

R

3

A

R~a 0 1-24 m 0 or 2

R'COOH

EDO, HOBT 0

R

3 R~a 0 WO 96/10034 PCTIUS95/12224 -89- Reaction Schemes J M illustrate reactions wherein the nonsulfhydryl-containing moiety at the N-terminus of the compounds of the instant invention is attached to an acyclic peptide unit which may be further elaborated to provide the instant compounds. These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the reactions described in Reaction Schemes A

E.

The intermediates whose synthesis are illustrated in Reaction Schemes A and C can be reductively alkylated with a variety of aldehydes, such as V, as shown in Reaction Scheme J. The aldehydes can be prepared by standard procedures, such as that described by O. P.

1 Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses, 1988, 67, 69-75, from the appropriate amino acid (Reaction Scheme The reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloroethane, methanol or 2 dimethylformamide. The product VI can be deprotected to give the final compounds VII with trifluoroacetic acid in methylene chloride. The final product VII is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine VII can further be selectively protected to obtain VIII, which can subsequently be reductively alkylated with a second aldehyde to obtain IX. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XI can be accomplished by literature procedures.

Alternatively, the protected dipeptidyl analog intermediate can be reductively alkylated with other aldehydes such as 1-trityl-4carboxaldehyde or 1 -trityl-4-imidazolylacetaldehyde, to give products such as XII (Reaction Scheme The trityl protecting group can be removed from XII to give XIII, or alternatively, XII can first be treated with an alkyl halide then subsequently deprotected to give the alkylated WO 96/10034 PCTIUS95/12224 imidazole XIV. Alternatively, the dipeptidyl analog intermediate can be acylated or sulfonylated by standard techniques.

The imidazole acetic acid XV can be converted to the acetate XVII by standard procedures, and XVII can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XVIII. Hydrolysis and reaction with the protected dipeptidyl analog intermediate in the presence of condensing reagents such as 1-(3-dimethylaminopropyl)-3ethylcarbodiimide (EDC) leads to acylated products such as XIX.

Similar procedures as are illustrated in Reaction Schemes J- M may be employed using other peptidyl analog intermediates such as those whose synthesis is illustrated in Reaction Schemes B I.

WO 96/10034 PTU9122 PCTIUS95/12224 -91 REACTION SCHEME J RB Bo NH 1 v

H

2 N.KN OR Boc NH CHO H 0 NaBH(OAc)3

EI

3 N CICH 2

CH

2

CI

NHBoc -JH y~ RB OR

CF

3 00 2

H

Boo NHF NN)N. R H 2

I

NA HHC

HVI

NH

2 iFH Y

R"

NH2 N'AN ~OR RA 0 BoC 2

O

CH

2 01 2 NaBH(OAc)3 Et 3 N CICH 2

CH

2

CI

=ARA

H

WO 96/10034 WO 9610034PCTIUS9S/12224 92 REACTION SCHEME J (continued)

CF

3 00 2 H, 0H 2 C1 2 NaHCO 3 BocNH H 1

H

0

NHIA

H

NH

2

N

R

A

RB

NTOR

H 0

NC

Ag CN /1, WO 96110034 PTU9/22 PCTIUS95/12224 93 REACTION SCHEME K y R B H2N KN OR A H NaBH(OAc) 3 Et 3 N CICH 2

CH

2

CI

(CH

2 )nCHO

ZN

Tr

.OR

1) ArCH 2 X, CH 3

CN

2) CF 3

CO

2 H, 0H 2 01 2

(C

2

H

5 3 SiH

CF

3 C0 2 H, C2'

(C

2

H

5 3 Si H H

Y

OR

N

H XIII H Y

XIV

WO 96/10034 WO 9610034PCTfUS95/12224 94 REACTION SCHEME L N- 0H 2 00 2

H

N

H

xv

H

2 00 2 C H 3

CH

3 0H-

HOI

xv' (0 6

H

5 3 CBr

(C

2

H

5 3

N

DMF

N- 0H 2 00 2 0H 3 1) ArCH 2

X

N 2) CH 3

OH,

CH

3

CN

ref lux ref lux XV I

N-CH

2

CO

2

CH

3

N

2.5N HClaq_ 550C

XVIII

Ar--\N-CH 2 00 2

H

N

WO 96/10034 WO 9610034PCTIUS95/12224 95 RE.ACTION SCHEME M Ar--\N-CH 2 00 2

H

N

y R B

H

2

N

A

H

EDC -HOI HOBt

DMF

Hj RB N N~A OR Ar RA H xix WO 96/10034 PCT/US95/12224 -96- The compounds of this invention inhibit Ras farnesyl transferase which catalyzes the first step in the post-translational processing of Ras and the biosynthesis of functional Ras protein.

These compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias.

The compounds of this invention are also useful for inhibiting proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which the Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes neu, src, abl, lck, and fyn) may be inhibited by the compounds of this invention. Furthermore, arteriosclerosis and diabetic disturbance of blood vessels may be prevented or treated by use of the instant compounds to inhibit proliferation of vascular smooth muscle cells.

The compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

For oral use of a chemotherapeutic compound according to this invention, the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are WO 96/10034 PCT/US95/12224 -97commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic.

The present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, saline, at a pH level, 7.4. The solutions may be introduced into a patient's intramuscular blood-stream by local bolus injection.

When a compound according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.

In one exemplary application, a suitable amount of compound is administered to a mammal undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg of body weight to about 20 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 10 mg/kg of body weight per day.

The compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and WO 96/10034 PCT/US95/12224 -98quantity of farnesyl-protein transferase (FPTase) in a composition.

Thus the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to allow the FPTase to famesylate the substrate, the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.

It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain famesyl-protein transferase and quantitating the enzyme. Thus, potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract containing an unknown amount of famesyl-protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention. The concentration of a sufficiently potent inhibitor one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel) required to inhibit the enzymatic activity of the sample by is approximately equal to half of the concentration of the enzyme in that particular sample.

WO 96/10034 PCT/US95/12224 -99-

EXAMPLES

Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species and conditions are intended to be further illustrative of the invention and not limitative of the reasonable scope thereof.

The standard workup referred to in the examples refers to solvent extraction and washing the organic solution with citric acid, 10% sodium bicarbonate and brine as appropriate.

Solutions were dried over sodium sulfate and evaporated in vacuo on a rotary evaporator.

EXAMPLE 1 Preparation of N-[2(S)-(1-(Phenylmethyl)-1 H-imidazol-4-ylacetyl)amino-3(S)-methylpentyl]-N- 1 -naphthylmethyl-glycyl-methionine bis trifluoroacetate (13) and N-[2(S)-(1-(Phenylmethyl)-lH-imidazol-5ylacetyl)amino-3(S)-methylpentyl]-N- 1 -naphthylmethyl-glycylmethionine bis trifluoroacetate (14) Step A: Preparation of 1H-Imidazole-4-acetic acid methyl esterhydrochloride (1) Into a solution of 1H-imidazole-4-acetic acid hydrochloride (4 g, 24.6 mmol) in methanol (100 ml) was bubbled hydrogen chloride gas until saturated. This solution was allowed to stand for 18 h at room temperature and the solvent evaporated in vacuo to give as a white solid.

1 H NMR (CDC13, 400 MHz) 8 8.85 (1H, 7.45 (1H, 3.89 (2H, s) and 3.75 (3H, s) ppm.

Step B: Preparation of 1-(Phenylmethyl)-1 H-imidazol-4-ylacetic acid methyl ester and 1-(Phenylmethyl)- ylacetic acid methyl ester (3:1 mixture) WO 96/10034 PCTIUS95/12224 -100- To a solution of sodium hydride (37.3 mg, 1.56 mmol) in dimethylformamide (2 ml) cooled to 0°C (ice bath) was added, via cannula, a solution of 1 (115 mg, 0.707 mmol) in dimethylformamide (3 ml). This suspension was allowed to stir at 0°C for 15 min. To this suspension was added benzyl bromide (84 pgL, 0.707 mmol) and the mixture was stirred at room temperature for 2h. After this time, the mixture was quenched with sat. aq. sodium bicarbonate (15 ml) and water ml) and extracted with methylene chloride (2 x 50 ml). The combined extracts were washed with brine (20 ml), dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography eluting with acetonitrile to give a 3:1 mixture of 2 and 3.

1 H NMR (CDC13, 400 MHz) 8 7.53 (0.25H, 7.48 (0.75H, 7.35 7.18 (1.5H, d, J=7.4 Hz), 7.06 (0.5H, d, J=7.2 Hz), 7.00 (0.25H, 6.87 (0.75H, 5.16 (0.5H, 5.08 (1.5H, 3.72 (1.5H, 3.65 (2.25H, 3.63 (0.75H, s) and 3.48 (0.5H, s) ppm.

Step C: Preparation of 1-(Phenylmethyl)-1 H-imidazol-4-ylacetic acid hydrochloride and 1-(Phenylmethyl)- 1H-imidazol- 5-vlacetic acid hydrochloride (3:1 mixture) A solution of 2 and 3 (3:1 mixture, 106 mg) in 1.0 N HCI (3 ml) was heated to 45°C for 4 h. After this time, the solution was evaporated in vacuo to give a 3:1 mixture of 4 and 1H NMR (DMSO, 400 MHz) 5 9.26 (0.75H, 9.23 (0.25H, 7.60 (0.25H, 7.58 (0.75H, 7.45-7.26 (5H, 5.43 (0.5H, 5.41 3.77 (1.5H, 3.75 (0.5H, s) ppm.

Step D: Preparation of N-(2(S)-(t-butoxycarbonylamino)-3(S)methylpentvl)glycine methyl ester (6) Glycine methyl ester hydrochloride (4.41 g, 0.035 mol) was dissolved in 1,2-dichloroethane (50 mL) and DMF (5 mL) and treated with 3A molecular sieves (10 g) and N-t-butoxycarbonyl-isoleucinal (6.3 g, 0.029 mol) with stirring at 0°C. Sodium triacetoxyborohydride (9.27 g, 0.044 mol) was added, and the pH of the mixture was adjusted to 6 with triethylamine (3 mL, 0.022 mol). After stirring for 18 h the mixture WO 96/10034 PCT/US95/12224 -101was filtered, concentrated to a small volume and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2 x mL). The combined organic phase was washed with aqueous saturated NaHCO3 solution, brine, and dried (Na2SO4). Filtration and concentration afforded a residue which was purified by flash chromatography (SiO2, EtOAc:hexane, 1:3) to give 1 H NMR (CDC13) 8 4.69 (1H, 3.72 (3H, 3.48-3.62 (1H, 3.42 (2H, ABq), 2.65 (2H, d, J=6 Hz), 1.4-1.6 (2H, 1.48 (9H, 1.04-1.2 (1H, 0.85-0.95 (6H, m) ppm.

Step E: Preparation of N-[2(S)-(t-Butoxycarbonylamino)-3(S)methvlpentyll-N-(l -naphthylmethvl)glvcine methyl ester (7) N-[2(S)-(t-Butoxycarbonylamino)-3(S)-methyl-pentyl]glycine methyl ester 2.00 g, 6.97 mmol) was dissolved in 1,2dichloroethane (56 ml) and 3A molecular sieves were added followed by 1-naphthaldehyde (1.89 ml, 13.9 mmol) and sodium triacetoxyborohydride (6.65 g, 31.4 mmol). The mixture was stirred at ambient temperature for 16 h, and filtered through glass fiber paper and concentrated. The residue was partitioned between EtOAc and sat.

NaHCO3 (100 ml/25 ml). The aqueous layer was extracted with EtOAc (3x50 ml). The organic layers were combined, dried (Na2SO4), filtered, and concentrated to give 5.0 g of crude product which was purified by chromatography (SiO2, 15-33% ethyl acetate/hexane) to give 7.

1H NMR (CD30D) 5 8.44-8.38 (1H, d, J=6Hz), 7.88-7.77 (2H, 7.55-7.35 (4H, 6.34-6.27 (1H, 4.25 (2H, ABq), 3.66 (3H, s), 3.40-3.23 (1H, 2.90 (1H, dd, J=6 and 15Hz), 2.63 (1H, dd, J=6 and 1.57-1.46 (IH, 1.43 (9H, 1.34-1.18 (2H, 1.06-0.85 (1H, m) and 0.85-0.71 (6H, m) ppm.

Step F: Preparation of N-[2(S)-(t-Butoxycarbonylamino)-3(S)methvlpentvll-N-( -naphthylmethvyl)glycine (8) N-[2(S)-(t-Butoxycarbonylamino)-3(S)-methylpentyl]-N-( naphthylmethyl)glycine methyl ester 2.61 g, 6.10 mmol) was dissolved in MeOH (50 ml) and IN NaOH (24.4 ml, 24.4 mmol) was WO 96/10034 PCT/US95/12224 -102added. The mixture was stirred at ambient temperature for 4 h and concentrated. The resulting residue was dissolved in water (25 ml) and neutralized with IN HCI (24.4 ml). The aqueous layer was washed with EtOAc (3x50 ml). The organic layers were combined, dried with Na2SO4, filtered, and concentrated to give the product. 1 H NMR 5 8.43 (1H, d, J=6Hz), 7.97 (2H, t, J=6 Hz) 7.75-7.48 (4H, m), 4.96 (1H, d, J=12Hz), 4.72 (1H, d, J=12 Hz), 3.80-3.58 (3H, 3.49- 3.40 (1H, dd,, J=3 and 12 Hz), 3.03 (1H, dd, J=3 and 12 Hz), 1.42 (9H, 1.37-1.28 (2H, 1.80-1.00 (1H, 0.94-0.78 (6H, ppm.

Step G: Preparation of N-[2(S)-(t-Butoxycarbonylamino)-3(S)methylpentyl]-N-( -naphthylmethyl)glycine-methionine methyl ester (9) N- [2(S)-(t-Butoxycarbonylamino)-3 (S)-methylpentyl] naphthylmethyl)glycine 2.29g, 5.53 mmol), dissolved in DMF mL), was treated with HOBT (0.822 g, 6.08 mmol), EDC (1.17 g, 6.08 mmol), and methionine methyl ester hydrochloride (1.21 g, 6.08 mmol).

The pH was adjusted to 7.5 with Et3N (1.7 mL, 12 mmol) and the mixture was stirred at ambient temperature for 24 h. The mixture was concentrated, and the residue was partitioned between EtOAc (50 mL) and saturated NaHCO3 solution (25 mL). The aqueous layer was extracted with EtOAc (1x30 mL). The organic layers were combined, washed with brine (1x25 mL), dried (Na2SO4), filtered, and concentrated to give 3.2 g of crude product which was purified by chromatography (silica gel eluting with 1:3 to 1:2 ethyl acetate in hexane) to give pure product. 1 H NMR (CD30D) 8 8.33 (1H, d, J=6 Hz), 7.90 (1H, d, J=6 Hz), 7.82 (1H, d, J=6 Hz), 7.61-7.39 (4H, 6.60-6.52 (1H, 4.32- 4.06 (2H, 3.90-3.69 (1H, 3.65 (3H, 3.27-3.14 (2H, 2.93- 2.70 (2H, 2.19-1.78 (6H, 1.63-1.30 (13H, 1.19-1.05 (1H, m), 0.95-0.81 (6H, m) ppm.

Step H: Preparation of N-(2(S)-amino-3(S)-methylpentyl)-N-( 1naphthylmethyl)-glycyl-methionine methyl ester hydrochloride WO 96/10034 PCT/US95/12224 -103- N-[2(S)-(t-Butoxycarbonylamino)-3(S)-methylpentyl]-N-(1naphthylmethyl)-glycyl-methionine methyl ester 2.82 g, 5.04 mmol) was dissolved in EtOAc (50 mL) and cooled to -25 0 C. HCI was bubbled through the mixture until TLC (95:5 CH2CI2:MeOH) indicated complete reaction. Nitrogen was bubbled through the mixture to remove excess HCI and the mixture was then concentrated to give the title compound.

1 H NMR (CD30D) 5 8.31 (1H, d, J=6 Hz), 7.96 (2H, d, J=6 Hz), 7.83- 7.71 (1H, 7.68-7.49 (3H, 4.76-4.55 (4H, 3.84-3.75 (2H, m), 3.71 (3H, 3.70-3.59 (1H, 3.21-3.00 (2H, 2.57-2.38 (3H, m), 2.17-2.04 (4H, 1.97-1.81 (1H, 1.63-1.50 (1H, 1.39-1.20 (1H, 1.19-1.00 (1H, 0.95-0.79 (6H, m) ppm.

Step I: Preparation of -(Phenylmethyl)- 1 H-imidazol-4ylacetyl)amino-3(S)-methylpentyl]-N- -naphthylmethylgylycyl-methionine methyl ester bis trifluoroacetate (11) and 3(S)-methylpentyl] -naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate (12) To a solution of a 1-(phenylmethyl)- I H-imidazol-4-ylacetic acid hydrochloride and 1-(phenylmethyl)-1H-imidazol-5-ylacetic acid hydrochloride 3:1 mixture, 115 mg, 0.455 mmol), N-[2(S)-amino- 3(S)-methylpentyl] -N-1-naphthylmethyl-glycyl-methionine methyl ester bis hydrochloride (10, 244 mg, 0.455 mmol) and 3-hydroxy-1,2,3benzotriazin-4(3H)-one (HOOBT, 74 mg, 0.46 mmol) in dimethylformamide (5 ml) was added 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (EDC, 87 mg, 0.455 mmol) and triethylamine (190 pl, 1.36 mmol) and the solution stirred overnight.

After this time, sat. aq. sodium bicarbonate (20 ml) and water (25 ml) were added and the mixture was extracted with ethyl acetate (2 X 50 ml).

The combined extracts were washed with brine (5 ml) and the solvent evaporated in vacuo. The regioisomers were separated by Prep HPLC using a Nova Prep 5000 Semi preparative HPLC system and a Waters PrepPak cartridge (47 X 300mm, C18, 15 um, IOOA) eluting with 5 WO 96/10034 WO 9610034PCT/US95/12224 -104acetonitrile/water 1% TFA) at 100 mi/mmn (chromatography method A) to give after lyophilization pure 11 and 12.

11: H NMR (CD3OD, 400MHz) 8 8.95 (1H, 8.27 (lH, in), 7.96 (2H, in), 7.68 (1H, 7.60-7.37 (9H, in), 5.38 (2H, 5.0-4.8 (1H, in), 4.52 (I1H, t, J= 10.6 Hz), 4.42 (1 H, dd, J=4 and 6.6 Hz), 4.14 (1 H, mn), 3.92 (I1H, d, J= 13.3 Hz), 3.83 (1IH, d, J= 13.3 Hz), 3.70 (1 H, 3.64 (1 H, in), 3.54 (2H, mn), 3.22 (1 H, dd, J=7 and 8 Hz), 2.3 7 (1 H, mn), 2. 10 (1 H, in), 2.00 (3H, 1.98 (1 H, in), 1.79 (1 H, mn), 1.58 (1 H, in), 1.42 (1 H, in), 1. 17 (1 H, in) and 0.90 (6H, m) ppm.

Anal. Calcd for C37H47N504S-3.0 TFA*0. 15 H20: C, 51.5 1; H, 5.06; N, 6.98. Found: C, 51.52; H, 4.98; N, 7.18.

FAB HRMS exact mass calcd for C37H48N504S 658.342702 found 658.341278.

12: 1 H NMR (CD3OD, 400 MHz) 6 8.8 (1IH, 8.26 (1IH, in), 7.89 (2H, in), 7.66-7.24 (8H, in), 7.21 (2H, 5.36 (2H, in), 4.37 (3H, in), 4.09 (1H,br 3.66 (3H, 3.56 (3H, in), 3.50-2.90 (3H, in), 2.27 (1 H, br 2.20 (I H, br 1.96 (3H, 1.90 (1 H, br 1.68 (1 H, br 1.58 (1 H, br s), 1.40 (1 H, in), 1. 18 (1 H, in) and 0. 89 (6H, m) ppm.

Anal. Calcd for C37H47N504S* 1.85 TFA-0.10 H20: C, 56.15; H, 5.68; N, 8.04. Found: C, 56.14; H, 5.62; N, 8.44.

FAB HRMS exact mass calcd for C37H48N504S 658.342702 found 658.343754.

Step J: Preparation of N- [2(S 1-(Phenylinethyl)- 1 H-imidazol-4ylacetyl)amino-3 (S)-methylpentyl] I -naphthylmethylglycyl-inethionine bis trifluoroacetate (13) and 1- (Phenylmethyl)- 1 H-imidazol-5 -ylacetyl)amino-3 methylpentyl] I -naphthylmethyl-glycyl-inethionine bis trifluoroacetate (14) WO 96/10034 PCT/US95/12224 -105- To a solution of N-[2(S)-(1-(Phenylmethyl)-1H-imidazol-4ylacetyl)amino-3(S)-methylpentyl]-N-1 -naphthylmethyl-glycylmethionine methyl ester bis trifluoroacetate (11) and (phenylmethyl)-1H-imidazol-5-yl)acetyl)amino-3(S)-methylpentyl]-N-1naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate (12, 2:1 mixture, 50 mg, 0.057 mmol) in methanol 5 ml was added 1 .ON lithium hydroxide (570 p1, 0.547 mmol This solution was stirred for 4 h and treated with trifluoroacetic acid (100 pl). This mixture was purified by preparative HPLC using chromatography method A to give the title compounds.

13: 1 H NMR (CD30D, 400 MHz) 5 8.83 (1H, 8.21 (1H, d, J=9.5 Hz), 7.88 (2H, 7.54 (1H, d, J=6.9 Hz), 7.5 7.3 (9H, 5.32 (2H, 4.56 (1H, br d, J 10 Hz), 4.36 (2H, 4.09 (1H, 3.55 (4H, 3.17 (1H, br d, J 10 Hz), 2.98 (1H, t, J 10Hz), 2.29 (1H, 2.18 (1H, m), 1.96 (1H, 1.95 (3H, 1.67 (1H, 1.56 (1H, 1.37 (1H, m), 1.11 (1H, m) and 0.88 (6H, m) ppm.

Anal. Calcd for C36H45N504S-2.15 TFA: C, 54.45; H, 5.35; N, 7.88.

Found: C, 54.42; H, 5.30; N, 7.97.

FAB HRMS exact mass calcd for C36H46N504S 644.327052 found 644.326691.

14: 1 H NMR (CD30D, 400 MHz) 8 8.80 (1H, 8.29 (1H, 7.92 (2H, 7.61 (1H, br), 7.32-7.53 (7H, 7.21 (2H, br 5.37 (2H, 4.37 (2H, 4.08 (1H, 3.57 (4H, br 3.05 (2H, 2.29 (2H, 2.20 (1H, 1.96 (3H, 1.70 (1H, 1.62 (1H, 1.57 (1H, 1.39 (1H, 1.13 (1H, m) and 0.88 (6H, m) ppm.

FAB HRMS exact mass calcd for C36H46N504S 644.327052 found 644.327917.

WO 96/10034 PCTIUS95/12224 -106- EXAMPLE 2 Preparation of -(4-Nitrophenylmnethyl)- 1H-imidazol-4ylacetyl)amino-3(S)-methylpentyl] -N-i -naphthylmethyl-glycyl methionine bis trifluoroacetate (21) and Nitrophenylmethyl)- 1H-imidazol-5-ylacetyl)amino-3(S)-methylpentyl]- N- -naphthlmethl- lvcvl-methionine bis trifluoroacetate (22).

Step A: Preparation of 1-(4-Nitrophenylmethyl)- 1 H-imidazol-4ylacetic acid methyl ester (15) and 1-(4-Nitrophenylmethyl)acid methyl ester (16) (3:lmixture) To a solution of sodium hydride (60% in mineral oil, 99 mg, mmol) in dimethylformamide (2 ml) cooled to OoC was added, via cannula, a solution of 1H-imidazole-4-acetic acid methyl ester hydrochloride 200 mg, 1.13 mmol) in dimethylformamide (3 mi).

This suspension was allowed to stir at OoC for 15 min. To this suspension was added 4-nitrobenzyl bromide (244 mg, 1.13 mmol) and stirred at room temperature for 2 h. After this time, the mixture was quenched with sat. aq. sodium bicarbonate (15 ml) and water (20 ml) and extracted with methylene chloride (2 x 50 mi). The combined organic extracts were washed with brine (20 mi), dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography using acetonitrile as eluent to give the title compounds as a yellow oil.

1H NMR (CDCl3, 400 MHz) 8 8.20 (2H, d, J=8.5 Hz), 7.49 (1H, 7.27 (2H, d, J=8.5 Hz), 7.03 (0.25H, 6.87 (0.75H, 5.28 (0.5H, 5.18 3.70 (2.25H, 3.65 (1.5H, 3.61 (0.75H, s) and 3.44 s) ppm.

Step B: Preparation of 1-(4-Nitrophenylmethyl)- 1H-imidazol-4ylacetic acid hydrochloride (17) and 1-(4-Nitrophenylmethyl)-l H-imidazol-5-vlacetic acid (18) (3:1 mixture) To a solution of a mixture of 1-(4-Nitrophenylmethyl)-1Himidazol-4-ylacetic acid methyl ester (15) and 1-(4-Nitrophenylmethyl)- WO 96/10034 PCT/US95/12224 -107acid methyl ester (16, 3:lmixture, 216 mg, 0.785 mmol) in methanol (3 ml) and tetrahydrofuran (3 ml) under argon was added 1.0 M sodium hydroxide (1.18 ml, 1.18 mmol) and stirred for 18 h.

After this time, 1.0 N hydrochloric acid (2.36 ml, 2.36 mmol) was added and the mixture evaporated in vacuo to give the title compounds.

1 H NMR (CDC13, 400 MHz) 8 9.04 (0.75H, 8.83 (0.25H, 8.28 (2H, d, J=8.8 Hz), 7.61 (2H, d, J=8.8 Hz), 7.54 (0.75H, 7.43 (0.25H, 5.61 (0.5H, 5.58 (1.5H, 3.84 (0.5H, s) and 3.82 (1.5H, s) ppm.

Step C: Preparation of N-[(2S)-(1-(4-Nitrophenylmethyl)-1 Himidazol-4-ylacetyl)amino-3(S)-methylpentyl]-N- naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate (19) and N-[2(S)-(1-(4-Nitrophenyl-methyl)- 1 H-imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N- naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate To a solution of 1-(4-nitrophenylmethyl)- H-imidazol-4ylacetic acid hydrochloride (17) and 1-(4-nitrophenylmethyl)-lHacid hydrochloride (18, 3:1 mixture, 153 mg, 0.392 mmol), N-[2(S)-amino-3(S)-methylpentyl]-N-naphthylmethyl-glycylmethionine methyl ester bis hydrochloride (10, 209 mg, 0.392 mmol) and 3-hydroxy-l,2,3-benzotriazin-4(3H)-one (HOOBT, 64 mg, 0.39 mmol) in methylene chloride (10 ml) was added 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (EDC, 75.2 mg, 0.392 mmol) and triethylamine (219 tl, 1.57 mmol) and the mixture stirred overnight at room temperature. After this time, sat. aq. sodium bicarbonate (10 ml) was added and the mixture was extracted with methylene chloride. The combined extracts were washed with sat. aq. sodium bicarbonate (10 ml) and the solvent evaporated in vacuo. The.regioisomers were separated by preparative HPLC (chromatography method A to give after lyophilization 19 and mm WO 96/10034 WO 9610034PCTIUS95/12224 108 19: 1 H NMR (CD3OD, 400 MHz) 8 8.96 (1 H, 8.17 (1 H, in), 8.23 (2H, d, J=8.7 Hz), 7.92 (2H, d, J=8.9 Hz), 7.61 (1 H, d, J=6.9 Hz), 7.56 (2H, d, J=8.9 Hz), 7.50 (2H, in), 7.44 (2H, in), 5.52 (2H, 4.70 (1IH, d, J=9.4 Hz), 4.49 (1 H, d, J= 1.9 Hz), 4.3 8 (1 H, dd, J=4.7 and 8.9 Hz), 4.13 (1 H, in), 3.67 (3H, 3.65 (4H, in), 3.30 (1 H, mn), 3.06 (1 H, in), 2.31 (1 H, mn), 2.23 (1 H, in), 1.97 (3H, 1.94 (1 H, in), 1.71 (1 H, in), 1.57 (1 H, in), 1.42 (1IH, in), 1.17 (1 H, in), 0.90 (3H, d, J=6.9 Hz) and 0.87 (3H, t, J=7.4 Hz) ppm.

Anal. Calcd for C37H46N606S-2.40 TFA*0.25 H20: C, 5 1.18S; H,5.02; N, 8.57. Found: C, 51.17; H, 5.03; N, 8.80.

FAB MS calcd for C37H47N606S 703 found 703.

1 H NMR (CD3 OD, 400 MHz) 6 8.91 (1 H, 8.26 (1 H, d, J= 12.8 Hz), 8.21 (2H, d, J= 10.7 Hz), 7.91 (2H, in), 7.65-7.36 (7H, in), 5.51 (2H, s), 4.72-3.99 (4H, in), 3.66 (3H, 3.66-3.24 (411, in), 3.20-2.85 (2H, in), 2.29 (1H, in), 2.20 (1H, in), 1.96 (3H, 1.91 (1H, br 1.70 (1H, d, J= 16 Hz), 1.56 (1 H, in), 1.3 8 (1 H, in), 1. 13 (1IH, m) and 0. 88 (6H, m) ppm.

FAB HRMS exact mass calcd for C37H47N606S 703.32778 found 703.32852.

Step D: Preparation of N-[2(S 1-(4-Nitrophenylmethyl)- 1 Himidazol-4-ylacetyl)amino-3 (S)-inethylpentyl] -N-i nap~hthvlinethyl- glvcvl-inethionine bis trifluoroacetate (21) To a solution of N- 1-(4-nitrophenylinethyl)- 1Himidazol-4-ylacetyl)amino-3 (S )-methylpentyl] -N-i -naphthyhmethylglycyl-methionine methyl ester bis trifluoroacetate, (19, 21 ing, 0.023 mmol) in methanol (1 ml at room temperature was added 1LON lithium hydroxide (135 j.U, 0. 135 minol). This solution was stirred for 4 h and treated with trifluoro acetic acid (100 p1). This mixture was purified by preparative HPLC using chromatography method A to give 21.

WO 96/10034 PCTIUS95/12224 -109lH NMR (CD30D, 400 MHz) 8 8.86 (1H, 8.23 (2H, d, J= 8.8Hz), 8.22 (1H, 7.90 (2H, dd, J=7.3 Hz), 7.55 (2H, d, J=8.4 Hz), 7.44-7.28 5.50 (2H, 4.53 (1H, 4.35 (2H, 4.12 (1H, 3.79- 3.25 (4H, 3.26-2.86 (2H, 2.27 (1H, 2.18 (1H, 1.96 (3H, 1.9 (1H, 1.67 (1H, 1.57 (1H, 1.42 (1H, 1.15 (1H, m), 0.90 (3H, d, J=6.9 Hz) and 0.86 (3H, t, J=7.3 Hz) ppm.

FAB HRMS exact mass calcd for C36H45N606S 689.31213 found 689.31262.

Step E: Preparation of -(4-Nitrophenylmethyl)- I Himidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N-1naphthvlmethvl-glvcvl-methionine bis trifluoroacetate (22) To a solution of -(4-nitrophenylmethyl)-1Himidazol-5-ylacetyl)amino-3(S)-methylpentyl] -N-1 -naphthylmethylglycyl-methionine methyl ester bis trifluoroacetate (20, 29 mg, 0.031 mmol) in methanol (1 ml was added 1.ON lithium hydroxide (187 gl, 0.187 mmol This solution was stirred for 4 h and treated with trifluoroacetic acid (100 pl1). This mixture was purified by preparative HPLC using chromatography method A to give 22.

1H NMR (CD30D, 400 MHz) 6 8.89 (1H, 8.25 (1H, 8.21 (2H, d, J= 9.0Hz), 7.89 (2H, 7.64-7.34 (7H, 5.52 (2H, 4.59-3.88 (4H, 3.77-3.38 (4H, 3.18-2.75 (2H, 2.27 (1H, 2.18 (IH, m), 1.96 (3H, 1.9 (1H, 1.67 (IH, 1.57 (IH, 1.42 (IH, 1.15 (1H, 0.89 (6H, m) ppm.

FAB HRMS exact mass calcd for C36H45N606S 689.31213 found 689.31135.

EXAMPLE 3 Regioselective preparation of -(4-Nitrophenylmethyl)- 1Himidazol-5-ylacetyl)amino-3(S)-methylpentyl] -N-1 -naphthylmethylglvcyl-methionine methyl ester bis trifluoroacetate WO 96/10034 PCT/US95/12224 -110- Step A: Preparation of 1 -(Triphenylmethyl)-1 H-imidazol-4-ylacetic acid methyl ester (23) To a suspension of 1H-imidazole-4-acetic acid methyl ester hydrochloride 7.48, 42.4 mmol) in methylene chloride (200 ml) was added triethylamine (17.7 ml, 127 mmol) and triphenylmethyl bromide (16.4 g, 50.8 mmol) and stirred for 72 h. After this time, reaction mixture was washed with sat. aq. sodium bicarbonate (100 ml) and water (100 ml). The organic layer was evaporated in vacuo and purified by flash chromatography (30-100% ethyl acetate/hexanes gradient elution) to provide 23 as a white solid.

1H NMR (CDC13, 400 MHz) 6 7.35 (1H, 7.31 (9H, 7.22 (6H, m), 6.76 (1H, 3.68 (3H, s) and 3.60 (2H, s) ppm.

Step B: Preparation of 1-(4-Nitrophenylmethyl)-1H-imidazol-5vlacetic acid methyl ester (16) To a solution of 1 -(triphenylmethyl)-1 H-imidazol-4-ylacetic acid methyl ester (23, 274 mg, 0.736 mmol) in acetonitrile (10 ml) was added 4-nitrobenzylbromide (159 mg, 0.736 mmol) and heated to 55 0

C

for 16 h. After this time, the reaction was cooled to room temperature, treated with ethyl acetate (20 ml) and the resulting precipitate was filtered. The filtrate was concentrated to dryness in vacuo and the residue was redissolved in acetonitrile (4 ml) and heated to 65°C for 3 h. After this time, the reaction mixture was evaporated to dryness and combined with initial precipitate. This residue was dissolved in methanol (5 ml and heated to reflux for 30 min. The resulting solution was evaporated in vacuo and the residue was purified by flash chromatography methanol/methylene chloride gradient elution to provide 16.

1H NMR (CDC13, 400 MHz) 6 8.20 (2H, d, J=8.8 Hz), 7.53 (1H, 7.19 (2H, d, J=8.8 Hz), 7.03 (1H, 5.28 (2H, 3.61 (3H, s) and 3.44 (2H, s) ppm.

Step C: Preparation of 1-(4-Nitrophenylmethyl)-1H-imidazol-5ylacetic acid hydrochloride (18) WO 96/10034 WO 9610034PCTIUS95/12224 1 -(4-Nitrophenylmethyl)-l1H-imidazol-5 -ylacetic acid methyl ester 115 g, 0.42 mmol was dissolved in 1LON hydrochloric acid (10 ml and heated at 55'C for 3 h. The solution was evaporated in vacuo to give 18 as a white solid.

H NMR (CD3OD, 400 MHz) 8 9.06 (1H, 8.27 (2H, d, J=8.8 Hz), 7.61 (1H, 7.55 (2H, d, J=8.8 Hz), 5.63 (2H, s) and 3.81 (2H, s) ppm.

Step D: Preparation of N-112(S)-( 1 (4-NitrophenyTmethYl)- 1 H- -ylacetyl)amiflo- 3 (S)-methylpentyl] 1 naphthylmethyl-glycylbmethionine methyl ester bis trifluoroacetate Following the procedure described in Example 2, Step C, but using the 1 -(4-nitrophenylmethyl> 1 H-imidazo1-5-ylacetic acid hydrochloride, prepared as described in Step C provided the title compound.

EXAMPLE 4 Preparation of 1 (2-Naphthylmethyl)- 1H-imidazol-5 ylacetyl)amino- 3 (S)-methylpentyl] -N-i I naphthylmethyl-glycyl inethionine bis trifluoroacetate Step A: Preparation of 1-(2-Naphthylmethyl)- 1 H-imidazol- -ylacetyl)amino- 3 (S)-methylpentyl] -N-i -naphthylmethyl glycyl-methionine methyl ester bis trifluoroacetate Following the procedure described in Example 3, Steps B-D, but using 2-(bromomethyl)naphthlen~e in place of 4-nitrobenzylbromide provided the title compound.

IH NMR (CD3OD, 400 MHz) 8 8.89 (1H, 8.29 (1H, d, J=9 Hz), 7.92 (4H, in), 7.83 (lH, d, J=9 Hz), 7.68 (1H, 7.58-7.42 (7H, in), 7.33 (lH, d, J=9 Hz), 5.54 (2H, 4.90-4.50 (2H4, in), 4.38 (111, in), 4.05 (11, in), 3.93-3.32 (5H1, in), 3.65 (3H, 3.12 (1H, in), 2.24 (2H, in), 1.93 (3H, s), WO 96/10034 WO 9610034PCTIUS95/12224 -112- 1.87 (lH, br 1.72 (1H, br 1.52 (1H, br 1.38 (1H, br 1.13 (1H, br s) and 0.87 (6H, m) ppm.

Anal. Calcd for C41 H49N504S-3.20 TFA*O.75 H20: C, 52.4 1; H, 4.98; N, 6.45. Found: C, 52.40; H, 4.96; N, 6.63.

FAB HRMS exact mass calcd for C41H50N504S 708.358352 found 708.357618.

Step B: Preparation of N-[2(S)-(1-(2-Naphthylmethyl)4IH- 3 (S)-methylpentyl] -N-inaphthylmethyl- glycvl-methionine bis trifluoro acetate Following the procedure described in Example 2, Step E, but using the methyl ester prepared as described in Step A provided the title compound.

IH NMR (CD3OD, 400 MHz) 8 8.88 (1H, 8.28 (LH, d, J=9 Hz), 7.96-7.78 (5H, in), 7.67 (1H, 7.57-7.41 (7H, in), 7.32 (LH, d, J=9 Hz), 5.55 (2H, 4.81(1H, in), 4.56 (1H, in), 4.37 (1H, in), 4.06 (1H, in), 3.89-3.50 (4H, in), 3.42 (1H, in), 3.10 (LH, in), 2.28 (1H, in), 2.19 (1H, in), 2.03-1.86 (lH, in), 1.93 (3H, 1.90 (1H, in), 1.71 (1H, in), 1.52 (I1H, in), 1.37 (1 H, in) and 0.87 (6H, m) ppm.

Anal. Calcd for C40H47N504S-2.95 TFAO0.5 H20: C, 53.05; H, 4.94; N, 6.74. Found: C, 53.03; H, 4.95; N, 7.10.

FAB HRMS exact mass calcd for C40H48N504S 694.342702 found 694.342837.

EXAMPLE Preparation of N-[2(S (1 -Naphthylmethyl)- 1H-imidazol-5 ylacetyl)amino- 3 (8)-methylpentyl] -N-i -naphthylmethyl-glycyl methionine bis trifluoroacetate Step A: Preparation of -Naphthylinethyl)- 1 H-imidazol- -ylacetyl)amino- 3 (8)-methylpentyl] I -naphthylmethyl glycyl-inethionine methyl ester bis trifluoroacetate WO 96/10034 PCT/US95/12224 -113- Following the procedure described in Example 3, Steps A-D, but using 1-(bromomethyl)naphthlene in place of 4-nitrobenzylbromide provided the title compound.

IH NMR (CD30D, 400 MHz) 5 8.42 (1H, s) 8.31 (1H, d, J=8.9 Hz), 8.04-7.80 (5H, 7.69 (1H, 7.59-7.39 (7H, 7.20 (1H, d, J=8.2 Hz), 5.80 (2H, 5.0-4.5 (2H, 4.26 (1H, 4.13 (1H, 4.0-3.6 (4H, 3.64 (3H, 3.49 (1H, 3.18 (1H, 2.17 (2H, 1.91 (3H, 1.86 (1H, 1.67 (1H, 1.55 (1H, 1.41 (1H, 1.16 (1H, br and 0.88 (6H, m) ppm.

Anal. Calcd for C41H49N504S-3.10 TFAo0.55 H20: C, 52.92; H, 5.01; N, 6.54. Found: C, 52.90; H, 4.99; N, 6.59.

FAB HRMS exact mass calcd for C41H50N504S 708.358352 found 708.357618.

Step B: Preparation of N-[2(S)-(1-(1-Naphthylmethyl)-lH-imidazol- 3 (S)-methylpentyl] -N-1 -naphthylmethylglycvl-methionine bis trifluoroacetate Following the procedure described in Example 2, Step E, but using the methyl ester prepared as described in Step A provided the title compound.

1 H NMR (CD30D, 400 MHz) 5 8.41 (1H, 8.19 (1H, d, J=7.7 Hz), 7.99 (2H, 7.87 (3H, 7.64 (1H, 7.56 (1H, t, J=7 Hz), 7.46 (6H, 7.16 (1H, d, J=8 Hz), 5.79 (2H, 5.04-4.71 (1H, 4.61-4.38 (1H, 4.38-4.21 (1H, 4.14 (1H, 3.97-3.51 (4H, 3.51-3.21 (1H, 3.21-2.85 (1H, 2.21 (1H, 2.13 (1H, 1.98 (1H, 1.91 (3H, 1.66 (1H, 1.56 (1H, 1.40 (1H, 1.15 (1H, and 0.87 (6H, m) ppm.

Anal. Calcd for C40H47N504S-2.70 TFA*0.5 H20: C, 53.95; H, 5.06; N, 6.93. Found: C, 53.97; H, 5.06; N, 7.10.

FAB HRMS exact mass calcd for C40H48N504S 694.342702 found 694.342837.

WO 96/10034 PCT/US95/12224 -114- EXAMPLE 6 Preparation of N-[2(S)-(1-Famesyl-1H-imidazol-5-ylacetyl)amino-3(S)methylpentyl]-N-l -naphthylmethyl-glycyl-methionine bis trifluoroacetate Step A: Preparation of 1-Famesyl-1 H-imidazol-5-ylacetic acid methyl ester To a solution of 1-(triphenylmethyl)- 1H-imidazol-4-ylacetic acid methyl ester (200 mg, 0.523 mmol) in acetonitrile (5 ml) was added trans, trans-famesyl bromide (156 1il, 0.575 mmol) and heated at for 16 h. After this time, the reaction was heated at 80 0 C for 3 h and then the reaction mixture was evaporated in vacuo. The residue was dissolved in methanol (5 ml and heated to reflux for 30 min and then evaporated in vacuo. The residue was purified by flash chromatography (2-4% methanol/methylene chloride gradient elution) to provide the title compound.

1 H NMR (CDC13, 400 MHz) 8 7.50 (1H, 6.92 (1H, 5.24 (1H, t, J=5.9 Hz), 5.09 (2H, 4.49 (2H, d, J=6.9 Hz), 3.69 (3H, 3.60 (2H, 1.91-2.15 (8H, 1.72 (3H, 1.65 (3H, 1.59 (3H, s) and 1.57 (3H, s) ppm.

Step B: Preparation of N-[2(S)-(1-(1-Famesyl)-lH-imidazol-5ylacetyl)amino-3(S)-methylpentyl]-N-1 -naphthylmethylglycyl-methionine methyl ester bis trifluoroacetate Following the procedure described in Example 3, Steps C-D, but using 1-famesyl-lH-imidazol-5-ylacetic acid methyl ester described in Step A in place of 1-(4-nitrophenylmethyl)-lH-imidazol-5-ylacetic acid methyl ester provided the title compound.

1 H NMR (CD30D, 400 MHz) S 8.70 (1H, 8.26 (1H, 7.91 (2H, 7.52 (3H, 7.48 (1H, 7.37 (1H, 5.40 (1H, 5.08 (2H, m), 4.94-4.72 (3H, 4.71 (1H, 4.40 (1H, 4.13 (1H, 3.95-2.80 (6H, 3.68 (3H, 2.27 (1H, 2.21 (1H, 2.09 (8H, 1.97 WO 96/10034 PCT/US95/12224 -115- (3H, 1.92 (2H, 1.72 (3H, 1.65 (1H, 1.65 (3H, 1.60 (3H, 1.58 (3H, 1.42 (1H, 1.18 (1H, m) and 0.90 (6H, m) ppm.

FAB HRMS exact mass Calcd for C45H66N504S 772.483553 found 772.481709.

Step C: Preparation of -Farnesyl)-l ylacetyl] amino-3(S)-methylpentyl]-N-i -naphthylmethylglyvcvl-methionine bis trifluoroacetate Following the procedure described in Example 2, Step E, but using the methyl ester prepared as described in Step B provided the title compound.

1 H NMR (CD30D, 400 MHz) 8 8.68 (1H, 8.18 (1H, 7.90 (2H, 7.52 (3H, 7.44 (1H, t, J=7.5 Hz), 7.37 (1H, 5.29 (1H, br t, J=7 Hz), 5.08 (2H, 4.95-4.64 (1H, 4.73 (2H, 4.37 (2H, 4.12 (1H, 3.71 (2H, 3.47 (2H, 3.11 (1H, 2.95 (1H, 2.27 (1H, 2.23-2.01 (9H, 2.01-1.89 (1H, 1.97 (3H, 1.77-1.54 (2H, 1.71 (3H, 1.65 (3H, 1.60 (3H, 1.58 (3H, 1.42 (l H, 1.16 (1H, 0.91 (3H, t, J=7 Hz) and 0.87 (3H, d, J=7.5 Hz) ppm.

FAB HRMS exact mass calcd for C44H64N504S 758.467903 found 758.467591.

EXAMPLE 7 Preparation of -Geranyl-1 H-imidazol-5-ylacetyl)amino-3(S)methylpentyl]-N-1-naphthylmethyl-glycyl-methionine bis trifluoroacetate Step A: Preparation of N-[2(S)-(1-Geranyl- ylacetyl)amino-3(S)-methylpentyl]-N-1 -naphthylmnethylglycyl-methionine methyl ester bis trifluoroacetate Following the procedure described in Example 6, Steps A-B, but using trans-geranyl bromide in place of farnesyl bromide provided the title compound.

WO 96/10034 PTU9122 PCTfUS95/12224 -116- 1H NMR (CD3OD, 400 MHz) 8 8.67 (1 H, 8.27 (111, in), 7.92 (2H, in), 7.57 (1H, in), 7.53 (2H, mn), 7.46 (1H, dd, J=9 Hz), 7.36 (1H, 5.29 (I1H, t, J=6 Hz), 5.08 (1 H, t, J=6 Hz), 4.71 (1LH, in), 4.71-4.12 (1IH, in), 4.38 (1H, in), 4.12 (1H, in), 3.80-3.33 (4H, in), 3.68 (3H, 3.14 (LH, in), 2.96 01H, in), 2.29 (1 H, in), 2.21 (1 H, in), 2.12 (4H, in), 2.11 (1LH, in), 1.97 (3H, 1.97 (1H, mn), 1.70 (3H, 1.68 (3H, 1.65 (1H, mn), 1.60 (3H, 1.41 (1H, in), 1.15 (1H, in), 0.91 (3H, d, J=7 Hz) and 0.88 (3H, t, J=7.5 Hz) ppm.

Anal. Calcd for C4OH57N504S- 1. 80 TFA.0.25 H20: C, 57.3 1; H, 6.54; N, 7.66. Found: C, 57.28; H, 6.54; N, 7.90.

FAB HRMS exact mass calcd for C40H58N504S 704.420953 found 704.420223.

Step B: Preparation of N-112(S)-( 1-Geranyl- 1 ylacetyl)amino-3 (S)-inethylpentyll -N-i -naphthyhnethyl g-lycyl-methionine bis trifluoroacetate Following the procedure described in Example 2, Step E, but using the methyl ester prepared as described in Step A provided the title compound.

IH NMR (CD3OD, 400 MHz) 8 8.67 (1H, 8.27 (1H, in), 7.92 (2H, in), 7.59 (1H, in), 7.52 (2H, mn), 7.46 (1H, t, J=7.8 Hz), 7.38 (OH, 5.28 (OH, t, J=1 1.2 Hz), 5.04 (1H, in), 4.96-4.54 (1H, in), 4.72 (2H, 4.54- 4.31 (1 H, in), 4.39 (1IH, in), 4.13 (1 H, in), 3.82-3.3 1 (4H, in), 3.68 (2H, in), 3.31-2.79 (2H, in), 2.30 (1H, in), 2.12 (5H, in), 1.97 (3H, 1.97 (1H, in), 1.73 (1H, in), 1.71 (3H, 1.70 (3H, 1.60 (3H, 1.44 (1H, in), 1.18 (1 H, m) and 0.92 (3H, d, 1=6.8 Hz), and 0.90 (3H, t, J=7.5 Hz) ppm.

FAB HRMS exact mass calcd for C39H56N504S 690.405303 found 690.405157.

WO 96/10034 PCT/US95/12224 -117- EXAMPLE 8 Preparation of N-[2(S)-(1-(4-Pyridylmethyl)-1H-imidazol-4ylacetyl)amino-3(S)-methylpentyl]-N-1 -naphthylmethyl-glycylmethionine tris trifluoroacetate (28) and -(4-Pyridylmethyl)- 1 H-imidazol-5-ylacetyl)amino-(3S)-methylpentyl]-N-1 -naphthylmethylglvcvl-methionine tris trifluoroacetate (29) Step A: Preparation of 1-(4-Pyridylmethyl)-1H-imidazol-4-ylacetic acid methyl ester (24) and 1-(4-Pyridylmethyl)-1 H-imidazolacid methyl ester (25) (3:1 mixture) To a solution of sodium hydride (60% in mineral oil, 99 mg, mmol) in dimethylformamide (2 ml) cooled at 0°C over ice bath was added, via cannula, a solution of 1H-imidazole-4-acetic acid methyl ester hydrochloride 115 mg, 0.707 mmol) in dimethylformamide (2 ml).

The suspension was stirred at 0°C for 15 min. This suspension was added to a solution prepared by adding 4-picolyl chloride hydrochloride (185 mg, 0.707 mmol) to sodium hydride (60% in mineral oil, 45.2 mg, 1.13 mmol) in dimethylformamide (2 ml at 0°C. After the addition was complete, the mixture was stirred at 0°C for 15 min and then at room temperature for 1.5 h. After this time, the mixture was quenched with sat. aq. sodium bicarbonate (50 ml) and extracted with methylene chloride (2 X 50 ml). The combined organic extracts were washed with brine (50 ml), dried(MgSO4), filtered and the solvent evaporated in vacuo. The residue was purified by flash chromatography( 3-7% methanol/methylene chloride gradient elution) to give a 3:1 mixture of 24 and 1H NMR (CDCL3, 400MHz) 6 8.57 (1.5H, d, J=5 Hz), 8.56 (0.5H, d, J=7 Hz), 7.51 (0.25H, 7.46 (0.75H, 7.01 (0.25H, 6.99 (1.5H, d, J=5 Hz), 6.90 (0.5H, d, J=7 Hz), 6.86 (0.75H, 5.17 (0.5H, 5.08 3.69 (2.25H, 3.64 (1.5H, 3.58 (0.75H, s) and 3.43 s) ppm.

WO 96/10034 PTU9/22 PCT/US95/12224 -118- Step B: Preparation of N-112(S)-( 1-(4-Pyridylmethyl)- 1H-imidazol-4ylacetyl )amino-3 (S)-methylpentyl] -N-i -naphthylmethyl glycyl-methionine methyl ester tris trifluoro acetate (26) and N- (4-Pyridylmethyl)- ylacetyl)amino-3 (S)-methylpentyl] I -naphthylmethylglycyl-methionine methyl ester tris trifluoroacetate (27) Following the procedure described in Example 2, Steps B-C, but using the mixture of pyridylmethylimidazolylacetic acid from Step A provided the title compounds after preparative HPLC.

26: IH NMR (CD3OD, 400 MHz) 5 8.99 (1H, 8.65 (2H, d, J=4.9 Hz), 8.28 (1 H, d, J=9.4 Hz), 7.91 (2H, in), 7.69 (1 H, d, J=6.5 Hz), 7.61 7.44 (6H, in), 5.59 (2H, 4.90 (1 H, in), 4.68 (1 H, d, J= 13.4 Hz), 4.42 (I1H, mn), 4.16 (1 H, mn), 3.90 (1 H, d, J= 15.6 Hz), 3.82 (1 H, d, J= 15.6 Hz), 3.75-3.55 (2H, in), 3.69 (3H, 3.50 (1H, d, J=13.1 Hz), 3.20 (1H, mn), 2.37 (1 H, in), 2.29 (1 H, in), 1.99 (3H, 1.96 (1 H, in), 1.77 (1 H, mn), 1.58 (1H, in), 1.23 (1 H, in), 1. 19 (1 H, mn) and 0.91( 6H, m) ppm.

Anal. Calcd for C36H46N604S-4.95 TFA-2.2 H20: C, 43.65; H, 4.42; N, 6.65. Found: C, 43.65; H, 4.16; N, 6.68.

FAB HRMS exact mass calcd for C36H47N604S 659.337951 found 659.336943 27: 1 H NMR (CD3OD, 400 MHz) 5 9.01 (1 H, 8.63 (2H, in), 8.28 (I1H, in), 7.98 (2H, in), 7.70 (1 H, d, J=6.0 Hz), 7.52 (4H, in), 7.41 (2H, d, J=6.2 Hz), 5.62 (2H, 4.94 (1H, in), 4.72 (1H, in), 4.42 (1H, in), 4.07 (1H, in), 3.89 (2H, in), 3.68 (1H,in), 3.69 (3H, 3.55 (2H, in), 3.24 (1H, in), 2.39 (1 H, in), 2.31 (1 H, in), 2.00 (3H, 1.98 (1 H, in), 1.79 (1 H, in), 1.58 (1H, in), 1.42 (1H, in), 1.18 (1H, in) and 0.91 (6H, m) ppm.

FAB HRMS exact mass calcd for C36H47N6045 659.337951 found 659.336826.

Step C: Preparation of -(4-Pyridylmethyl)-1H-imidazol-4ylacetyl )amino-3 (S)-inethylpentyll -N-I -naplithylmethylglvcyl-inethionine methyl ester-tris trifluoroacetate (28) WO 96/10034 PCT/US95/12224 -119- Following the procedure described in Example 2, Step D, but using the methyl ester 26 prepared as described in Step B provided the title compound.

1 H NMR (CD30D, 400 MHz) 5 8.96 (1H, 8.55 (2H, d, J=5.2Hz), 8.21 (1H, d, J=7.2 Hz), 7.97 (2H, 7.69 (1H, d, J=7.2 Hz), 7.60-7.40 (6H, 5.58 (2H, 4.91 (1H, d, J=13.2 Hz), 4.69 (1H, d, J=13.2 Hz), 4.38 (1H, dd, J=4.6 and 8.8 Hz), 4.15 (1H, 3.89 (1H, d, J=16.1 Hz), 3.81 (1H, d, J=16.1 Hz), 3.71 (1H, d, J=17 Hz), 3.62 (1H, d, J=17 Hz), 3.50 (1H, dd, J=3.4 and 12 Hz), 3.21 (1H, 2.38 (1H, 2.27 (1H, 1.99 (1H, 1.99 (3H, 1.77 (1H, 1.58 (1H, 1.43 (1H, m), 1.16 (1H, and 0.88 (6H, m) ppm.

FAB HRMS exact mass calcd for C35H45N604S 645.322301 found 645.323649.

Step D: Preparation of N-[2(S)--(1-(4-Pyridylmethyl)-1H-imidazol- 5-ylacetyl)amino-3(S)-methylpentyl]-N-1-naphthylmethylglycyl-methionine tris trifluoroacetate (29) Following the procedure described in Example 2, Step E, but using the methyl ester 27 prepared as described in Step B provided the title compound.

1 H NMR (CD30D, 400 MHz) 5 8.97 (1H, 8.58 (2H, 8.27 (1H, m), 7.95 (2H, 7.64 (1H, 7.50 (4H, 7.31 (2H, d, J=4.4 Hz), 5.57 (2H, 4.63 (2H, 4.38 (1H, 4.09 (1H, 3.78 (2H, 3.60 (2H, 3.42 (1H, 3.15 (1H, 2.36 (1H, 2.15 (1H, 2.01 (1H, 1.98 (3H, 1.76 (1H, 1.55 (1H, 1.41 (1H, 1.15 (1H, m) and 0.88 (6H, m) ppm.

FAB HRMS exact mass calcd for C35H45N604 645.322301 found 645.321321.

WO 96/10034 PTU9/22 PCTIUS95/12224 -120- EXAMPLE 9 Preparation of N- 1-(4-Cyanophenylmethyl)- 1 H-imidazol-5 ylacetyl)amino-3 (S)-methylpentyl] -N-i -naplithylmethyl-glycyl methionine bis trifluoroacetate Step A: Preparation of N- 1-(4-Cyanophenylmethyl)- 1Himidazol-5-ylacetyl)amino-3(S)-methylpentyll-N- 1naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate Following the procedure described in Example 3, Steps B-D, but using a-bromno-p-tolunitrile in place of 4-nitrobenzylbromide provided the title compound.

IH NMR (CD3OD, 400 MHz) 5 8.92 (1H, 8.31 (1H, in), 8.01 (lH, d, J=8 Hz), 7.96 (1H, in), 7.75 (2H, d, J=8 Hz), 7.62 (1 H, 7.58-7.48 (3H, in), 7.45 (1H, mn), 7.41 (2H, d, J=8 Hz), 5.51 (2H, 4.97 (1 H, in), 4.76 (1H, in), 4.41 (1H, in), 4.10 (1H, m) 3.92 (2H, in), 3.75-3.47 (3H, in), 3.69 (3H, 3.25 (1H, in), 2.37 (1H, in), 2.30 (1H, in), 2.00 (3H, 1.97 (I1H,m), 1.79 (1 H, in), 1.58 (1 H, in), 1.43 (1 H, mn), 1. 19 (1 H, m) and 0.91 (6H, m) ppm.

Anal. Calcd for C38H46N604S*2.40 TFA- 1.90 H20: C, 51.89; H, 5.3 1; N, 8.48. Found: C, 51.88; H, 5.29; N, 8.72.

FAB HRMS exact mass calcd for C38H47N604S 683.337951 found 683.338437.

Stepj B: Preparation of 1-(4-Cyanophenylinethyl)- 1Himidazol-5-ylacetyl)amino-3 (S )-methylpentyl] I1naphthylinethvl-glycyl-methionine bis trifluoroacetate To a solution of N-[2(S)-(1-(4-cyanophenylmethyl)-1IHiinidazol-5 -ylacetyl)amino-3 (S)-inethylpentyl] I -naphthylmethylglycyl-methionine methyl ester bis trifluoroacetate (25.6 ing, 0.028 mmol) in methanol (1 ml was added 1LON sodium hydroxide (280 RI1, 0.280 iniol) and stirred for 2 h. After this time, the mixture was treated with trifluoroacetic acid (to pH and purified by preparative HPLC WO 96/10034 PCT/US95/12224 -121 (chromatography method A) to give after lyophilization, the title compound.

1 H NMR (CD30D, 400 MHz) 8 8.87 (1H, 8.27 (1H, d, J=9.2 Hz), 7.90 (2H, 7.73 (2H, d, J=8 Hz), 7.60 (1H, 7.46 (4H, 7.36 (2H, d, J=8 Hz), 5.48 (2H, 4.95-4.28 (2H, 4.36 (1H, 4.09 (1H, m), 3.59 (4H, 3.51-2.73 (2H, 2.29 (1H, 2.19 (1H, 2.03-1.85 (1H, 1.97 (3H, 1.70 (1H, 1.56 (1H, 1.39 (1H, 1.14 (1H, m) and 0.89 (6H, m) ppm.

Anal. Calcd for C37H44N604S-2.45 TFA-1.3 H20: C, 51.80; H, 5.09; N, 8.65. Found: C, 51.78; H, 5.07; N, 8.95.

FAB HRMS exact mass Calcd for C37H44N604S 669.322301 found 669.323148.

EXAMPLE Preparation of N-[2(S)-(1-(4-Methoxyphenylmethyl)- ylacetyl)amino-3(S)-methylpentyl]-N-1 -naphthylmethyl-glycylmethionine bis trifluoroacetate Step A: Preparation of N-[2(S)-(1-(4-Methoxyphenylmethyl)-1Himidazol-5-yl)acetyl)amino-3(S)-methylpentyl]-N-1naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate Following the procedure described in Example 3, Steps B-D, but using 4-methoxybenzyl chloride in place of 4-nitrobenzylbromide provided the title compound.

1 H NMR (CD30D, 400 MHz) 8 8.70 (1H, 8.27 (1H, 7.92 (2H, 7.70-7.35 (5H, 7.18 (2H, d, J=8.5 Hz), 6.92 (2H, d, J=8.5 Hz), 5.27 (2H, 4.60-4.00 (4H, 3.79 (3H, 3.67 (3H, 3.61 (4H, m), 3.40-2.75 (2H, 2.28 (1H, 2.19 (1H, 1.96 (3H, 1.91 (1H, 1.70 (1H, 1.60 (1H, 1.43 (1H, 1.18 (1H, m) and 0.91 (6H, m) ppm.

Anal. Calcd for C38H49N505S*1.75 TFA*1.75 H20: C, 54.45; H, 5.98; N, 7.67. Found: C, 54.44; H, 5.95; N, 7.85.

WO 96/10034 WO 9610034PCTfUS95/12224 -122- FAB HRMS exact mass calcd for C38H50N505S 688.353267 found 688.352186.

Step B: Preparation of -(4-Methoxyphenylmethyl)- 1Himidazol-5-ylacetyl)amino-3 (S)-methylpentyl] -N-inaphthyhmethvl-glvcyl-methionine bis trifluoroacetate Following the procedure described in Example 9, Step B, but substituting the methyl ester from Step A provided the title compound.

IH NMR (CD3OD, 400 MHz) 8 8.70 (1H, 8.27 (1H, in), 7.92 (2H, in), 7.63 (1H, 7.56-7.35 (4H, in), 7.18(2H, d, J=8.6 Hz), 6.93 (2H, d, J=8.6 Hz), 5.27 (2H, 4.93-4.29 (2H, in), 4.36 (1 H, in), 4.12 (1 H, in), 3.79 (3H, 3.63 (4H, in), 3.07 (2H, in), 2.28 (1IH, in), 2.19 (1 H, in), 2.02-1.88 (1H, in), 1.95 (3H, 1.70 (1H, in), 1.60 (1H, in), 1.43 (1H, in), 1. 18 (1 H, m) and 0.91 (6H, m) ppm.

FAB HRMS exact mass calcd for C37H48N505S 674.337617 found 674.338053.

EXAMPLE 11 Preparation of -(4-Quinolinylmethyl)- ylacetyl)amino-3 (S)-methylpentyl] -N-i -naphthylmethyl-glycyl methionine bis trifluoroacetate Step A: Preparation of N-[2(S)-(1-(4-Quinolinylmethyl)-1Himidazol-5-ylacetyl)ainino-3 (S)-inethylpentyl] -N-inaphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate Following the procedure described in Example 3, Steps B-D, but using 4-(bromomethyl)quinoline hydrochloride in place of 4nitrobenzylbromide provided the title compound.

IH NMR (CD3OD, 400 MHz) 8 8.88 (1H, 8.83 (1H, d, J=4.8 Hz), 8.28 (1H, in), 8.15 (lH, d, J=8.6 Hz), 7.99-7.85 (4H, in), 7.67 (2H, in), 7.57 (1H, 7.48 (3H, in), 6.96 (1H, in), 6.02 (2H, 4.90 (lH, in), 4.62 WO 96/10034 WO 9610034PCTIUS95/12224 -123- (ILH, in), 4. 18 (1iH, in), 4.07 (1 H, in), 3.94-3.50 (4H, in), 3.64 (3H, s), 3.45 (1H, in), 3.13 (1H, in), 2.28 (1H, in), 2.21 (1H, in), 1.95 (3H, s), 1.87 (1 H, in), 1.69 (1 H, in), 1.48 (1 H, in), 1.35 (1 H, in), 1. 11 (1 H, m) and 0.84 (6H, m) ppm.

FAB HRMS exact mass calcd for C40H49N604S 709.353601 (MIH+), found 709.353711.

Step B: Preparation of 1-(4-Quinolinylmethyl)- 1 Himnidazol-5-ylacetyl)amino-3 (S )-methylpentyl] -N-i naphthvlmethyl- glvcvl-methionine bis trifluoroacetate Following the procedure described in Example 9, Step B, but substituting the methyl ester from Step A provided the title compound.

IH NMR (CD3OD, 400 MHz) 8 8.87 (1H, 8.82 (1H, d, J=5 Hz), 8.28 01H, in), 8.15 01H, d, J=8.6 Hz),8.06-7.82 (4H, mn), 7.67 (2H, in), 7.58 (OH, 7.48 (3H, 6.96 (1H, in), 6.03 (2H, 4.93-4.57 (2H, in), 4.22 (I1H, in), 4.08 (1 H, in), 3.72 (4H, in), 3.47 (1 H, mn), 3.13 (1 H, in), 2.28 (1H, in), 2.21 (1H, in), 1,95 (3H, 1.87 (1H, in), 1.70 (1H, in), 1.48 (1H, in), 1.35 (1H, in), 1.09 (1H, m) and 0.84 (6H, m) ppm.

FAB HRMS exact mass calcd for C39H47N604S 695.33795 found 695.33893.

EXAMPLE 12 Preparation of N- 1-(2-Naphthylinethyl)- 1H-imidazol-5 ylacetyl)amino-3 (S)-inethylpentyl] -N-i -phenylmethyl-glycyl-methionine bis trifluoroacetate Step A: Preparation of N- [2(S 1-(2-Naphthylmethyl)- 1H-imidazol- 5-ylacetyl)amino-3(S)-methylpentyl]-N- 1 -phenylmethylglycyl-methionine methyl ester bis trifluoroacetate To a solution of 1 -(2-naphthylmethyl)-1H-imidazol-5ylacetic acid hydrochloride (prepared in Example 4, 75 mg, 0.25 inmol), N- [2(S)-ainino-3 (S)-methylpentyl] -N-phenylmnethyl-glycyl-methionine WO 96/10034 PCT/US95/12224 -124methyl ester bis hydrochloride (prepared analogously to 10, 112 mg, 0.248 mmol) and 3-hydroxy-l,2,3-benzotriazin-4(3H)-one (HOOBT, 44 mg, 0.27 mmol) in dimethylformamide (5 ml) was added 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 52 mg, 0.272 mmol) and triethylamine (171 til, 1.23 mmol) and the suspension stirred for 3 days. After this time, sat. aq. sodium bicarbonate (10 ml) and water (10 ml) was added and the mixture was extracted with ethyl acetate (2 x 50 ml). The combined extracts were washed with brine ml) and the solvent evaporated in vacuo. Purification by preparative HPLC (chromatography method A gave, after lyophilization, the title compound.

1 H NMR (CD30D, 400 MHz) 6 8.94 (1H, 7.93 (1H, d, J=8.5 Hz), 7.88 (2H, 7.81 (1H, 7.55 (5H, 7.43 (4H, 5.68 (2H, 4.60 (1H, 4.46 (1H, dd, J=4.5 Hz), 4.27 (1H, d, J=13 Hz), 4.14 (1H, m), 3.95 (1H, d, J=15.5 Hz), 3.85 (1H, d, J=15.5 Hz), 3.83 (2H 3.67 (3H, 3.48 (1H, d, J=13 Hz), 3.24 (1H, d, J=13 Hz), 2.40 (1H, 2.31 (1H, 2.00 (1H, 1.96 (3H, 1.85 (1H, 1.57 (1H, 1.44 (1H, m), 1.19 (1H, 0.93 (3H, d, J=6.7 Hz) amd 0.91 (3H, t, J=7 Hz) ppm.

Anal. Calcd for C37H47N504S*2.85 TFA.0.40 H20: C, 51.80; H, 5.16; N, 7.07. Found: C, 51.80; H, 5.14; N, 7.31.

Step B: Preparation of N-[2(S)-(1-(2-Naphthylmethyl)- H-imidazol- 5-ylacetyl)amino-3(S)-methylpentyl]-N-1 -phenylmethylglycyl-methionine bis trifluoroacetate Following the procedure described in Example 9, Steps B, but substituting the methyl ester from Step A provided the title compound.

1 H NMR (CD30D, 400 MHz) 6 8.92 (1H, 7.93 (1H, d, J=8.6 Hz), 7.87 (2H, 7.78 (1H, 7.55 (3H, 7.43 (2H, 7.39 (1H, d, J=8.4Hz), 7.35 (3H, 5.67 (2H, 4.46 (1H, dd, J=4.5 Hz), 4.41-3.90 (1H, 4.11 (1H, 4.00 (1H, 3.75 (2H, 3.64 (2H, 3.20 (1H, 2.98 (1H, 2.43 (1H, 2.35 (1H, 2.08 (1H, 1.97 (3H, 1.91 (1H, 1.54 (1H, 1.40 (1H, 1.15 (1H, m) and 0.89 (6H, m) ppm.

WO 96/10034 PCTfUS95/12224 -125- Anal. Calcd for C36H45N504S*2.70 TFA-0.70 H20: C, 51.57; H, 5.13; N, 7.26. Found: C, 51.54; H, 5.11; N, 7.43.

FAB HRMS exact mass calcd for C36H46N504S 644.327052 found 644.326203.

EXAMPLE 13 Preparation of (2-Naphthylmethyl)-1H-imidazol-5ylethyl)amino-3(S)-methylpentyl]-N-1 -naphthylmethyl-glycylmethionine bis trifluoroacetate Step A: Preparation of N-Methoxy-N-methyl- -(2-naphthylmethyl)- 1 To a solution of 1-(2-naphthylmethyl)-1H-imidazol-5ylacetic acid hydrochloride (prepared in Example 4, 0.819 mg, 2.70 mmol) in dimethylformamide (15 ml was added sequentially N, Odimethylhydroxylamine hydrochloride (293 mg, 3.0 mmol), 3-hydroxy- 1,2,3-benzotriazin-4(3H)-one (HOOBT, 489 mg, 3.0 mmol), 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 575 mg, 3.0 mmol) and triethylamine (1.67 ml, 12.0 mmol) and the resulting mixture stirred at room temperature for 18 h. Saturated aq. sodium bicarbonate (30 ml) and water (30 ml) were added and the mixture was extracted with methylene chloride (2 x 50 ml). The combined organic extracts were washed with brine (50 ml) and the solvent evaporated in vacuo. The residue was purified by flash chromatography (2-4% methanol/methylene chloride gradient elution) to provide the title compound as an oil.

1 H NMR (CDC13, 400 MHz) 6 7.80 (2H, 7.74 (1H, 7.56 (1H, s), 7.47 (3H, 7.22 (1H, d, J=8.6 Hz), 6.97 (1H, 5.37 (2H, 3.58 (2H, 3.51 (3H, s) and 3.12 (3H, s) ppm.

Step B: 1-(2-Naphthylmethyl)-1 H-imidazol-5-vlacetaldehyde To a suspension of lithium aluminum hydride (40.8 mg, 1.07 mmol) in tetrahydrofuran (5 ml) at -45 0 C was added a solution of N- WO 96/10034 PCT/US95/12224 -126methoxy-N-methyl-1 -(2-naphthylmethyl) (243 mg, 0.895 mmol) in tetrahydrofuran (5 ml) via cannula at such a rate to maintain the temperature at <-35 0 C. After the addition was complete, the reaction was allowed to warm to +5 0 C and then recooled to -35 0

C.

To this solution was added a solution of potassium bisulfate (272 mg) in water (1 ml). The mixture was stirred for 30 min at room temperature and then filtered through celite. The celite pad was washed with ethyl acetate (25 ml). The combined filtrates were washed with sat. sodium bicarbonate (10 ml) and then water (10 ml). The organic layer was dried(MgSO4), filtered and evaporated in vacuo to give 30 as a clear oil.

This material was used as is in the next step.

1 H NMR (CDC13, 400 MHz) 8 9.50 (1H, t, J=2 Hz), 7.85-7.70 (3H, m), 7.64 (1H, 7.53-7.40 (3H, 7.16 (1H, d, J=12 Hz), 7.06 (1H, 5.20 (2H, s) and 3.53 (2H, m) ppm.

Step C: Preparation of N-[2(S)-(1-(2-Naphthylmethyl)-1H-imidazol- 5-ylethyl)amino-3(S)-methylpentyl]-N-1 -naphthylmethylglycyl-methionine methyl ester bis trifluoroacetate To a solution of 1-(2-naphthylmethyl)-IH-imidazol-5ylacetaldehyde (116.8 mg, 0.465 mmol) and N-[2(S)-amino-3(S)methylpentyl]-N-naphthylmethyl-glycyl-methionine methyl ester bis hydrochloride (10, 297 mg, 0.558 mmol) in 1,2-dichloroethane (10 ml) and dimethylformamide (5 ml) was added 3A molecular sieves (500 mg) and sodium triacetoxyborohydride (473 mg, 2.23 mmol). This mixture was stirred at room temperature for 18 h. After this time, the mixture was filtered through a sintered glass funnel. The filtrate was diluted with methylene chloride (100 ml) and washed with sat. sodium bicarbonate ml). The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo. The residue was purified first by flash chromatography eluting with 2-5% methanol/methylene chloride and then by preparative HPLC (chromatography method A) to provide the title compound as a white foam.

1 H NMR (CD30D, 400 MHz) 8 9.05 (1H, 8.10 (1H, d, J=7.5 Hz), 8.02-7.79 (5H, 7.75 (1H, 7.65-7.27 (7H, 7.21 (1H, 5.59 WO 96/10034 WO 9610034PCTIUS95/12224 127 (2H, 4.65 (1 H, dd, J=4.7 and 9.4 Hz), 4.31 (1 H, d, J= 13 Hz), 4.17 (1 H, d, J= 13 Hz), 3.69 (3H, 3.65 (1 H, d, J= 17 Hz), 3.55 (1 H, d, J= 17 Hz), 3.00 (1H, dd, J=3.5 and 14 Hz), 2.93-2.42 (6H, in), 2.33 (1H, in), 2.23 (I1H, in), 2.13 (1 H, mn), 2.06 (3H, 1.96 (1 H, in), 1.41 (1 H, mn), 1.07 (2H, in), 0.75 (3H, d, J=6.5 Hz) and 0.70 (3H, t, J=7.5 Hz) ppm.

FAB HRMS exact mass calcd for C41 H52N503S 694.37909 found 694.37959.

Step D: Preparation of 1-(2-Naphthylmethyl)- 1 H-imidazol- 5-ylethyl)amino-3 (S )-methylpentyl] I -naphthylmethyl glycyl-methionine bis trifluoroacetate Following the procedure described in Example 2, Steps D, but substituting the methyl ester from Step C provided the title compound.

1 H NMR (CD3OD, 400 MHz) 8 8.95 (1 H, 8.09 (1 H, d, J=7.7 Hz), 7.94 (1 H, d, J=8.5 Hz), 7.93-7.78 (4H, in), 7.73 (1 H, 7.62-7.24 (7H, in), 7.17 (1 H, 5.56 (2H, 4.61 (1 H, dd, J=4.3 and 10 Hz), 4.31 (1 H, d, J= 13 Hz), 4.14 (1IH, d, J= 13 Hz), 3.65 (1 H, d, J= 17 Hz), 3.55 (1 H, d, 1= 17 Hz), 2.99 (1 H, d, J= 15 Hz), 2.91-2.43 (6H, in), 2.25-1.91 (4H, in), 2.06 (3H, 1.33 (1H, in), 1.01 (2H, in), 0.72 (3H, d, J=6.7 Hz) and 0.65 (3H, t, J=7.5 Hz) ppm.

FAB HRMS exact mass calcd for C40H50N503S 680.36344 found 680.36282 EXAMPLE 14 Preparation of [N-2(S I -(2-Naphthylinethyl)- I ylacetyl)amino-3 (S)-methyl Ipentyloxy-3 -phenyipropionyl-inethionine sulfone methyl ester hydrochloride Step A: Preparation of N-(ux-chloroacetyl)-L-isoleucinoI To a stirred solution of L-isoleucinol (20 g, 0.17 inol) and triethylamine (28.56 ml, 0.204 inol) in CH2C12 (500 ml) at -78'C was added chioroacetyl chloride (16.3 ml, 0.204 inol) over 5 minutes. The WO 96/10034 PCT/US95/12224 -128cooling bath was removed and the solution allowed to warm to -20 0

C.

The mixture was diluted with EtOAc and washed sequentially with 1 M HC1, and brine and dried (Na2SO4). Evaporation in vacuo afforded the title compound Rf 0.3 CH2Cl2: MeOH (95:5); 1H NMR (CDC13) 8 6.80 (1H, brd, J 5 Hz), 4.10 (2H, 3.84 (1H, m), 3.79 (2H, 2.65 (1H, brs), 1.72 (1H, 1.55 (1H, 1.17 (1H, m), 0.96 (3H, d, J 6Hz) 0.90 (3H,t, J=6 Hz).

Step B: Preparation of 5(S)-[1(S)-methyl]propyl-2,3,5,6-tetra-hydro- 4H-1 4-oxazin-3-one.

To a stirred solution of N-(a-chloroacetyl)-L-isoleucinol (68, 7.4 g, 0.038 mol) in THF (125 ml) under argon at 0°C was slowly added sodium hydride (2.2 g of a 60% dispersion in mineral oil, 0.055 mol) with concomitant gas evolution. After completing the addition, the mixture was warmed to room temperature and stirred for 16 hr.

Water (2.8 ml) was added and the solvents evaporated in vacuo. The residue was dissolved in CHC13 (70 ml) and washed with saturated NaCI solution. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed using silica gel eluting with CH2C12:MeOH (96:4) to afford the title compound as a white solid.

Rf 0.35 CH2C12:MeOH (95:5); 1H NMR (CDC13) 5 6.72 (1H, brs), 4.20 (1H, d, J 14.5 Hz), 4.10 (1H, d, J 14.5 Hz), 3.88 (1H, dd, J 9 and 3.5 Hz), 3.58 (1H, dd, J 9 and 6.5 Hz), 3.45 (1H, brqt, J 3.5 Hz), 1.70-1.45 (2H, 1.34 1.15 (1H, 0.96 (3H, t, J 6.5 Hz), 0.94 (3H, d, J 6.5 Hz).

Step C: Preparation of N-(tert-butoxycarbonyl)-5(S)-[1(S)methvl]propyl-2.3 5,6-tetrahvdro-4H-1,4-oxazin-3-one.

(S)-Methyl]propyl-2,3,5,6-tetrahydro 4H-1,4-oxazin- 3-one (12.2 g, 0.0776 mol) and DMAP (18.9 g, 0.155 mol) were dissolved in methylene chloride (120 ml) under argon at room temperature. Boc anhydride (33.9 g, 0.155 mol) was added to the stirred solution in one portion, with concomitant gas evolution and the mixture WO 96/10034 PCTIUS95/12224 -129was stirred at for 16 hr. The solvent was evaporated in vacuo and the residue was taken up in ethyl acetate and washed sequentially with citric acid, 50% NaHCO3 and finally brine. The organic extract was dried (Na2SO4) and evaporated in vacuo. Chromatography of the residue over silica gel eluting with 20% EtOAc in hexanes afforded the title compound as a white solid.

Rf 0.75 EtOAc:hexanes (20:80); mp 59-60°C Anal. Calcd for C13H2304N C, 60.68; H,9.01; N, 5.44. Found: C, 60.75; H, 9.01; N, 5.58.

1H NMR (CDC13) 8 4.25 (1H, d, J 15 Hz), 4.15 (1H, d, J 15 Hz), 4.15 4.00 (2H, 3.73 (1H, dd, J 10 and 2 Hz), 1.88 (1H, qt, J 6 Hz), 1.55 (9H, 1.50 1.36 (1H, 1.35 1.19 (1H, 1.00 (3H, d, J 6 Hz), 0.95 (3H, d, J 6.5 Hz).

Step D: Preparation of [1 (S)-methyl]propyl-2,3,5,6-tetrahydro-4H- 1,4-oxazin-3one A solution of N-(tert-butoxycarbonyl)-5(S)-[1(S)methyl]propyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-3-one (5.75 g, 22.3 mmol) in DME (100 ml) under argon was cooled to -60 0 C. The cold solution was transferred via canula to a second flask containing sodium bis(trimethylsilyl)amide (24.58 ml of a lM solution in THF, 24.58 mmol) at -78 0 C under argon. After stirring for 10 minutes, benzyl bromide (2.25 ml, 19.0 mmol) was added over 5 minutes and the resulting mixture was stirred at -78 0 C for 3 hours. After this time, the reaction mixture was transferred via cannula to another flask containing sodium bis(trimethylsilyl)amide (24.58 ml of a 1M solution in THF, 24.58 mmol) at -78 0 C, under argon. After stirring for a further 5 minutes, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution (24.6 ml) and allowed to warm to room temperature. This mixture was diluted with brine (50 ml) and water (20 ml) and then extracted with ethyl acetate (2 x 100 ml). The organic extracts were washed with brine (50 ml) and evaporated in vacuo to afford an oil.

Chromatography of the residue over silica gel (230-400 mesh, 300 g) WO 96/10034 PCTIUS95112224 -130eluting with 10-20% ethyl acetate in hexanes afforded the title compound as a clear oil.

Rf 0.25 EtOAc:Hexanes (20:80); IH NMR (CDC13) 8 7.35 7.15 (5H, 4.31 (1H, dd, J 6 and 2 Hz), 4.03 (1H, d, J 12 Hz), 3.88 (1H, dd, J 6 and 1 Hz), 3.66 (1H, dd, J 12 and 2 Hz), 3.29 (1H, dd, J 12 and 3 Hz), 1.54 (9H, 3.12 (1H, dd, J 12 and 7 Hz), 1.47 (1H, 1.25 (1H, 1.10 (1H, 0.83 (3H, d, J 6 Hz), 0.80 (3H, t, J 6 Hz).

Step E: Preparation of N-(tert-butoxycarbonyl)-2(S)-[2(S)-amino- 3(S)-methyl]pentyloxy-3-phenvl-propionic acid To a stirred solution of N-(tert-butoxycarbonyl)-2(S)-benzyl- 5(S)-[1(S)-methyl]-propyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-3-one (5.1 g, 14.7 mmol) in THF (150 ml) and water (50 ml) at 0°C was added hydrogen peroxide (15 ml of a 30% aqueous solution, 132 mmol) and lithium hydroxide (3.0 g, 63.9 mmol). After stirring for 30 minutes, the reaction was quenched with a solution of sodium sulfite (28.25 g, 0.224 mol) in water (70 ml). The THF was evaporated in vacuo and the aqueous phase was acidified to pH 3-4 by addition of 10% citric acid solution and extracted with EtOAc. The organic extracts were dried (Na2SO4), evaporated in vacuo and the residue purified by chromatography over silica gel eluting with 4% MeOH in CH2C12 to give 2(S)-benzyl-5(S)-[1(S)-methyl]propyl-2,3,5,6-tetrahydro-4H-1,4oxazin-3-one and then with 20% MeOH in CH2C12 to afford the title compound as a white solid (pet ether, mp 68-70 0

C).

Rf 0.4 MeOH:CH2Cl2 (5:95) 0.3% AcOH; 1H NMR (d6 DMSO) 5 7.35 7.10 (5H, 6.68 (1H, br, 3.75 (1H, dd, J 7.5 and 2.5 Hz) 3.54 (1H, 3.5 3.2 (2H, m) 2.99 (1H, dd, J 12.5 and 2.5 Hz), 2.75 (1H, dd, J 12.5 and 7.5 Hz), 1.50 1.35 (11H, 0.98 (1H, sept, J 6 Hz), 0.78 (3H, t, J 6 Hz), 0.65 (3H, d, J 6 Hz); FAB MS 366 266 (MH2+ CO2tBu).

WO 96/10034 PTU9/22 PCTIUS95/12224 131 Step F: Preparation of N-(tert-Butoxycarbonyl)-2(S )-112(S )-amino 3(S)-methyl] -pentyloxy-3 -phenyl-propionyl-methione sulfone methyl ester The title compound was prepared by EDC coupling of N- (tert-butoxycarbonyl)-2(S )-[12(S)-amino-3 (S)-methyl]pentyloxy-3 phenyipropionic acid with methionine sulfone methyl ester.

I H NMR (CD3OD) 8 0.80 (3H, d, J=6 Hz), 0.88 (3H, t, J=6 Hz), 1. 12 01H, in), 1.40-1.55 (1 1.47 (9H, 2. 10 (1 H, in), 2.3 2 (1IH, in), 2.80-3.10 (4H1,m), 2.93 (3H, 3.40 3.5-3.7 (2H, mn), 3.74 (3H, 4.01 in), 4.60 mn), 6.60 d, J=8 Hz), 7.25 (5H, in).

Step G: Preparation of [2(S)-Ainino-3 (S)-inethyllpentyloxy-3 phenyipropionyl-methionine sulfone methyl ester hydrochloride N-(tert-butoxycarbonyl-2(S)- [2(S)-amino-3 methyllpentyloxy-3 -phenyipropionyl-methionine sulfone, methyl ester was treated with HCI gas in ethyl acetate and the solvent was evaporated in vacuo to afford the title compound.

1 H NMR (CD3OD) 8 0.85 (3H, d, J=6 Hz), 0.94 (3H, t, J=6 Hz), 1.20 (1H, in), 1.52 (1H, in), 1.72 (1H, in), 2.14 (1H, in), 2.38 (lH, in), 2.98 (3H, 2.90-3.20 (4H, in), 3.25 (1 H, in), 3.57 (1 H, dd, J= 12 and 6 Hz), 3.73 (1H, dd, J=12 and 9 Hz), 3.78 (3H, 4.15 (1H, in), 4.63 (1H, d, Hz), 7.30 (5H, in).

Step H: Preparation of [N-2(S )-(lI-(2-Naphthylmethyl)- 1Himidazol-5-ylacetyl)ainino-3 (S)-methyllpentyloxy-3phenyipropionyl-methionine sulfone methyl ester hydrochloride To a solution of 1 -(2-Naphthylinethyl)- ylacetic acid hydrochloride (prepared in Example 4, 67 mg, 0.21 iniol), [2(S)-amino-3 (S)-inethyl]pentyloxy-3 -phenylpropionyl-inethionine sulfone methyl ester hydrochloride (100 mg, 0.209 inmol) and 3hydroxy-1,2,3-benzotriazin-4(3H)-one (HOOBT, 37.5 mng, 0.209 inmol) in diinethylformnamide (4 ml) was added 1 -(3-dimethylaminopropyl)-3- WO 96/10034 PCTIUS95/12224 -132ethylcarbodiimide hydrochloride (EDC, 44 mg, 0.21 mmol) and triethylamine (109 ul, 0.78 mmol) and the suspension stirred overnight.

After this time, sat. aq. sodium bicarbonate (7 ml) was added and the resulting precipitate filtered. The precipitate was partitioned between water (25 ml) and methylene chloride (50 ml). The organic extract was evaporated in vacuo. The residue was purified by flash chromatography eluting with 2-3% methanol/methylene chloride gradient to provide a gum. The gum was dissolved in methanol (5 ml) and treated with gaseous hydrogen chloride to pH=2 and the solution was evaporated in 1o vacuo. The resulting gum was dissolved in methanol (2 ml) and water ml) and lyophilized to give the title compoundas a white foam.

1 H NMR (CD30D, 400 MHz) 5 8.93 (1H, 8.35 (1H, d, J=8.7 Hz), 8.14 (1H, d, J=8.7 Hz), 7.94 (1H, d, J=8.6 Hz), 7.92-7.83 (2H, 7.77 (1H, 7.58-7.49 (3H, 7.38 (1H, d, J=8.4 Hz), 7.23-7.10 (5H, m), 5.62 (1H, d, J=15.5 Hz), 5.61 (1H, d, J=15.5 Hz), 4.56 (1H, 4.05 (1H, dd, J=4.0 and 7.4 Hz), 3.90 (1H, 3.70 (2H, 3.66 (3H, 3.57 (1H, dd, J=3.5 and 9.9 Hz), 3.47 (1H, dd, J=7.0 and 9.9 Hz), 3.04 (1H, dd, and 14.1 Hz), 2.96 (1H, 2.91 (1H, dd, J=7.5 and 14.1 Hz), 2.90 (3H, 2.80 (1H, 2.27 (1H, 2.09 (1H, 1.50 (1H, 1.43 (1H, 1.07 (1H, 0.84 (3H, t, J=7.4 Hz) and 0.77 (3H, d, J=6.7 Hz) ppm.

Anal. Calcd for C37H46N407S*2.3 HCI: C, 57.36; H,6.28; N, 7.23.

Found: C, 57.40; H, 6.20; N, 7.38.

FAB HRMS exact mass calcd for C37H47N407S 691.316547 found 691.316460.

EXAMPLE Preparation of 2(S)-[N-2(S)-(1-(2-Naphthylmethyl)-1H-imidazol-5ylacetyl)amino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methionine sulfone trifluoroacetate Following the procedure described in Example 9, Step B, but substituting the methyl ester from Example 14 provided the title compound.

WO 96/10034 WO 9610034PCT/US95112224 133 IH NMR (CD3OD, 400 MHz) 8 8.93 (1H, 8.27 (1H, d, J=8.3 Hz), 8. 10 (1 H, d, J=9.3 Hz), 7.94 (1 H, d, J=8.6 Hz), 7.92-7.8 3 (2H, in), 7.75 (1H, 7.57-7.52 (2H, in), 7.50 (1H, 7.37 (1H, d, J=8.6 Hz), 7.23- 7.11 (5H, mn), 5.60 (1 H, d, J= 15 Hz), 6.59 (1 H, d, J= 15 Hz), 4.54 (1 H, in), 4.03 (1 H, dd, J=4.1 and 7.9 Hz), 3.91 (1 H, in), 3.69 (1 H, d, J= 16.7 Hz), 3.66 (1H, d, J=16.7 Hz), 3.56 (1H, dd, J=3.4 and 10.3 Hz), 3.45 (1H, dd, and 9.7 Hz), 3.04 (1 H, dd, J=4.2 and 15.1 Hz), 3.00 (1 H, in), 2.94- 2.85 (OH, mn), 2.89 (3H, 2.80 (1H, in), 2.30 (1H, in), 2.09 (1H, in), 1.50 (1 H, in), 1.43 (1 H, in), 1.07 (1 H, in), 0.83 (3H, t, J=6.4 Hz) and 0.75 l0 (3H, d, J=6.7 Hz) ppm.

Anal. Calcd for C36H44N407S*2. 10 TFA*0.90 H20: C, 51.78; H,5. 18; N, 6.01. Found: C, 51.78; H, 5.17; N, 6.42.

FAB HRMS exact mass calcd for C36H45N407S 677.300897 found 677.299827.

EXAMPLE 16 Preparation of [N-2(S I-(2-Naphthylmethyl ylethyl)ainino-3 (S )-methyllpentyloxy-3-phenylpropionyl-methionine methyl ester bis trifluoroacetate Step A: Preparation of [2(S)-t-butoxycarbonylamino-3(S) inethyl]-pentyloxy-3-phenylpropionyl-inethionine methyl ester The title compound was prepared in the same fashion as that described in Example 14 Step F using inethionine methyl ester in place of methionine sulfone methyl ester.

NMR (CD3OD) 6 0.78 (3H, d, J=6 Hz), 0.89 (3H, t, J=6 Hz). 1.11 (IH, in), 1.40-1.60 (2H, in), 1.47 (9H, 1.90-2.10 2.06 (3H, s), 2.20-2.40 (2H, in), 2.90 (1 H, dd, J= 14.7 and 5.0 Hz), 3.05 (H,dd, J= 14.5 and 3.0 Hz), 3.38 (1H, dd, J=8.6 and 7.0 Hz), 3.50-3.60 (2H, in), 3.71 (3 H, 3.97 (1 H, dd, J=7.5 and 4.0 Hz), 4.60 (1 H, in), 6.60 (1 H, d, J= Hz), 7.24 (5H, in).

WO 96/10034 PCT/US95/12224 -134- Step B: Preparation of 2(S)-[2(S)-amino-3(S)-methyl]-pentyloxy-3phenvlpropionyl-methionine methyl ester hydrochloride The product of Step A was converted to the title compound using the method of Example 14, Step G.

1H NMR (CD30D) 5 0.84 (3H, d, J=6 Hz), 0.93 (3H, t, J=6 Hz), 1.20 (1H, 1.45-1.60 (1H, 1.70 (1H, 1.80-2.20 (2H, m) 2.08 (3H, s), 2.50-2.30 (2H, 2.98 (1H, dd, J=14.7 and 5 Hz), 3.11 (1H, dd, J=14.5 and 3.0 Hz), 3.20-3.30 (IH, 3.57 (1H, 3.70 (1H, 3.73 (3H, s), 4.12 dd, J=8.6 and 6.0 Hz), 4.60 (IH, 7.30 (5H, m).

Step C: Preparation of 2(S)-[N-2(S)-(1-(2-Naphthylmethyl)- 1Himidazol-5-ylethyl)amino-3(S)-methyl]pentyloxy-3phenylpropionyl-methionine methyl ester bis trifluoroacetate Following the procedure described in Example 13, Step C, but substituting 1-(2-naphthylmethyl)- 1H-imidazol-5-ylacetaldehyde and 2(S)-[2(S)-amino-3(S)-methyl]pentyloxy-3-phenylpropionylmethionine methyl ester hydrochloride, the title compound was obtained.

IH NMR (CD30D, 400 MHz) 8 8.95 (1H, 7.96 (1H, d, J=8.5 Hz), 7.89 (2H, 7.79 (IH, 7.55 (2H, 7.47 (1H, 7.38 (1H, d, 8.4 Hz), 7.21 (4H, 7.15 (1H, 5.65 (2H, s, 4.63 (1H, dd, J=4.4 and 19.5 Hz), 4.15 (1H, dd, J=4.3 and 18.7 Hz), 3.67 (3H, 3.57 (2H, m), 3.43-3.15 (2H, 3.11-3.00 (4H, 2.88 (1H, dd, J=9 and 14.4 Hz), 2.51 (1H, 2.40 (1H, 2.10 (1H, 2.03 (3H, 1.95 (1H, m), 1.68 (1H, 1.35 (1H, 1.09 (1H, 0.86 (3H, t, J=7.2 Hz) and 0.74 (3H, d, J=6.9 Hz) ppm.

Anal. Calcd for C37H48N404S*2.45 TFA: C, 54.45; H,5.50; N, 6.06.

Found: C, 54.37; H, 5.51; N, 6.15.

FAB HRMS exact mass calcd for C37H49N404S 645.34745 found 645.34518.

WO 96/10034 PCTIUS95/12224 -135- EXAMPLE 17 Preparation of 2(S)-[N-2(S)-(1-(2-Naphthylmethyl)- ylethyl)amino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methionine bis trifluoroacetate Following the procedure described in Example 2, Step D, but substituting the methyl ester from Example 16 provided the title compound.

1 H NMR (CD30D, 400 MHz) 8 8.89 (1H, 7.95 (1H, d, J=8.5 Hz), 7.93-7.84 (2H, 7.77 (1H, 7.58-7.51 (2H, 7.45 (1H, 7.37 (1H, dd, J=1.7 and 8.3 Hz), 7.26-7.17 (4H, 7.15 (1H, 5.65 (2H, 4.59 (1H, dd, J=4.5 and 9.4 Hz), 4.14 (1H, dd, J=3.8 and 8.9 Hz), 3.56 (2H, d, J=3.8 Hz), 3.37-2.96 (6H, 2.88 (1H, dd, J=8.8 and 14.2 Hz), 2.52 (1H, 2.41 (1H, 2.16 (1H, 2.03 (3H, 1.97 (1H, m), 1.66 (1H, 1.32 (1H, 1.08 (1H, 0.85 (3H, t, J=7.1 Hz) and 0.74 (3H, d, J=7.1 Hz) ppm.

Anal. Calcd for C36H46N404S*2.95 TFA*1.00 H20: C, 51.08; H,5.21; N, 5.69. Found: C, 51.07; H, 5.22; N, 5.83.

FAB MS calcd for C36H47N404S, 631 found 631.

EXAMPLE 18 Preparation of N-[2(S)-(1-methyl-imidazol-4-yl acetyl)amino-3(S)methylpentyl]-N-(1-naphthylmethyl)-glycyl-methionine methyl ester trifluoroacetate salt 1-Methyl-4-imidazole acetic acid (0.070 g, 0.395 mmol), dissolved in DMF (5 mL), was treated with HOBT (0.053 g, 0.040 mmol), EDC (0.075 g, 0.395 mmol), and N-[2(S)-amino-3methylpentyl)-N-(l-naphthylmethyl)-glycyl-methionine methyl ester hydrochloride (10, 0.175 g, 0.395 mmol). The pH was adjusted to with Et3N (0.055 mL, 0.395 mmol) and the mixture was stirred at ambient temperature for 72 h. The mixture was concentrated and the residue was partitioned between EtOAc (30 mL) and saturated NaHCO3 solution (25 mL). The aqueous layer was extracted with EtOAc (2x20 WO 96/10034 PCTIUS95/12224 -136mL). The combined organic layer was washed with brine (1x25 mL), dried (Na2SO4), and evaporated in vacuo to give a crude product which was purified by chromatography (silica gel, eluting with 99:1 to 97:3 CH2Cl2:MeOH) to give the amine. This material was converted to the trifluroracetate salt by dissolving in 0.1% TFA in H20 and lyophilization to give the title compound. 1 H NMR (CD30D) 8 8.72 (1H, 8.30- 8.20 (1H, 8.00-7.90 (2H, 7.45-7.70 (4H, 7.34 (1H, 4.80- 4.65 (1H, 4.60-4.40 (2H, m 4.20-4.10 (1H, m 3.86 (3H, s 3.70 (3H, s 3.85-3.50 (4H, m 3.40-3.30 (1H, 3.20-3.05 (1H, 2.40- 2.20 (2H, 2.00 (3H, s 2.00-1.90 (1H, 1.82-1.65(1H, 1.65- 1.52 (1H, 1.50-1.35 (1H, 1.25-1.07 (1H, 1.00-0.85 (6H, m).

Anal. Calcd for C31H43N504S*3 TFA: C, 48.10; H, 5.02; N, 7.58.

Found: C, 48.36; H, 5.30; N, 7.77.

EXAMPLE 19 Preparation of N-[2(S)-(1-methyl- H-imidazoleacetyl) amino methvlpentvll-N-( -naphthylmethyl)-glycyl-methionine N-[2(S)-(1-Methyl-4-imidazoleacetyl) amino-3(S)methylpentyl]-N-( 1 -naphthylmethyl)-glycyl-methionine methyl ester (prepared in Example 18, 0.081 g, 0.139 mmol) was dissolved in MeOH ml), cooled to 0°C, and IN NaOH (0.557 ml, 0.557 mmol) was added.

The mixture was stirred at ambient temperature for 4 h and evaporated in vacuo. The resulting residue was dissolved in H20 (5 ml) and neutralized with IN HCI (0.557 ml, 0.557 mmol). The aqueous layer was washed with EtOAc (3x10 ml). The organic layers were combined, dried (Na2SO4), and evaporated in vacuo to give a crude product. Purification by preparative HPLC (Vydac column eluting with acetonitrile/0.1% TFA in H20 gradient) and lyophilization gave the title compound. 1H NMR (CD30D) 5 8.72 (1H, 8.31-8.23 (1H, 8.02-7.90 (2H, 7.70- 7.45 (4H, 7.35 (1H, 4.93-4.74 (1H, 4.58 (1H, d, J=13 Hz), 4.45-4.36 (1H, 4.20-4.10 (1H, 3.89 (3H, 3.86-3.52 (4H, m), 3.45-3.30 (1H, 3.22-3.09 (1H, 2.45-2.20 (2H, 2.00 (3H, s), WO 96/10034 WO 9610034PCTIUS95/12224 137- 2.10-1.92 (1H, in), 1.83-1.68 (1H1, in), 1.68-1.52 (1H1, in), 1.52-1.37 (1H, in), 1.26-1.08 (1H, 1.00-0.85 (6H, m).

Anal. Calcd for C30H41N504S-2.75 CF3CO2H: C, 48.38; H, 5.00; N, 7.95.

Found: C, 48.53; H, 5.05; N, 8.11.

EXAMPLE Preparation of N- -(2-naphthylmethyl)- ylacetyl] amino-3 (S)-methylpentyl] -N-(cyclopropylmethyl glvcylmethionine methyl ester bis trifluoroacetate salt Step A: Preparation of N- [2(S )-t-Butoxycarbonylamino)-3methvlp~entvl] -N-(cvclop~ropvylmethvl) 2lvcine methyl ester N- [2(S)-t-Butoxycarbonylamino)-3 (S)-methylpentyl] glycine methyl ester 287.8 mg, 0.9980 mmnol) was dissolved in 1,2-dichioroethane (7.0 ml). 4A Molecular sieves (207 mg), cyclopropanecarboxaldehyde (75 ml, 1.0 mmol), and sodium triacetoxyborohydride (1.075 g, 5.072 mmol) were added. The mixture was stirred under argon at ambient temperature for 16 h and filtered. The filtrate was diluted with EtOAc (50 mL) and washed with saturated aq NaHCO3 (2 x 25 ml) and saturated aq NaCl (25 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo. The crude product was purified by chromatography (silica gel, 1: 19 to 1:9 EtOAc/CH2CI2) to give the title compound. 1

H

NMR (CDCI3, 400 MHz): 6 4.85 (1H,br 3.69 (3H, 3.64-3.54 (1H, in), 3.70 (1 H, d, J 18 Hz), 3.30 (1 H, d, J 18 Hz), 2.74 (1 H, dd, J 14 and 5 Hz), 2.57-2.42 (3H, in), 1.80-1.68 (1H1, in), 1.50-1.36 (1H, in), 1.44 (9H1, 1.15-1.02 (1 H, in), 0.91 (311, t, J=7 Hz), 0.86 (3H, d, J=7 Hz), 0.86-0.76 in), 0.54-0.43 (2H, in), 0.09 (2H, d, J=5 Hz).

Step B: Preparation of N-[2(S)-t-Butoxycarbonylamino)-3inethylp~entyll -N-(cvclopropylmethyl) glycine N- [2(S)-t-Butoxycarbonylamino)-3 -iethylpentyl] -N (cyclopropylmethyl)glycine methyl ester (268 mg, 0.783 inmol) was WO 96/10034 PCTIUS9/12224 -138dissolved in MeOH (40 ml). After cooling to 0°C under argon, IN aq LiOH (1.0 ml, 1.0 mmol) was added. After stirring at ambient temperature for 18 h, additional IN aq LiOH (1.0 ml, 1.0 mmol) was added. After stirring at ambient temperature for 6 h, additional IN aq LiOH (1.0 ml, 1.0 mmol) was added. After stirring for 18 h at ambient temperature, 1 N aq HCI (4.0 mL, 4 mmol) was added and the reaction was evaporated in vacuo. The resulting residue was dissolved in ml) and acidified with IN aq HCI to pH 2. Residual methanol was evaporated in vacuo and the remaining aqueous material lyophilized to give the title compound. 1 H NMR (CD30D, 400 MHz): 5 3.86-3.76 (2H, 3.62 (IH, d, J 15 Hz), 3.47 (1H, br 3.28-3.14 (2H, m), 3.12-3.03 (1H, 1.64-1.43 (2H, 1.47 (9H, 1.26-1.10 (2H, m), 0.98-0.90 (6H, 0.80-0.68 (2H, 0.51-0.41 (2H, m).

Step C: Preparation of N-[2(S)-t-Butoxycarbonylamino)-3methylpentyl]-N-(cyclopropylmethyl)glycylmethionine methyl ester The title compound was prepared in the same fashion as that described in Example 1 Step G but using the compound described in Step B.

1 H NMR (CDC13, 400 MHz): 6 8.02 (1H, br 4.78-4.68 (1H, 4.67 (1H, td, J 9 and 6 Hz), 3.75 (3H, 3.70-3.60 (1H, 3.31 (1H, d, J 17Hz), 3.18 (1H, d, J 17 Hz), 2.67 (1H, dd, J 9 and 4 Hz), 2.54 (2H, t, J 8 Hz), 2.54-2.44 (2H, 2.43-2.35 (1H, 2.30-2.20 (1H, 2.16- 2.06 (1H, 2.10 (3H, 1.63-1.52 (1H, 1.50-1.40 (1H, 1.44 (9H, 1.17-1.05 (1H, 0.93 (3H, d, J 8 Hz), 0.91 (3H, t, J 8 Hz), 0.90-0.80 (1H, 0.56-0.46 (2H, 0.15 (2H, d, J 6 Hz).

Step D: Preparation of N-[2(S)-Amino-3-methylpentyl)-N- (cyclopropylmethyl)glycylmethionine methyl ester hydrochloride N-[2(S)-t-Butoxycarbonylamino)-3-methylpentyl]-N- (cyclopropylmethyl)-glycylmethionine methyl ester (22.8 mg, 0.0481 mmol) was dissolved in EtOAc (1.5 mL) and cooled to 0°C. HCI was WO 96/10034 PCT/US95/12224 -139bubbled through the mixture until saturated. After 30 min, the mixture was evaporated in vacuo to give the title compound.

IH NMR (CD30D, 400 MHz): 6 4.68 (1H, dd, J 9 and 5 Hz), 4.28- 4.00 (2H, 3.74 (3H, 3.70-3.45 (2H, 3.40-3.00 (3H, 2.67- 2.51 (2H, 2.23-1.95 (2H, 2.10 (3H, br 1.87-1.86 (1H, 1.60- 1.49 (1H, 1.34-1.21 (1H, 1.20-1.10 (1H, 1.03 (3H, d, J 7 Hz), 1.01 (3H, t, J 7 Hz), 0.82-0.72 (2H, 0.50-0.40 (2H, m).

Step E: Preparation of N-[(2S)-1-(2-naphthylmethyl)-1H-imidazol- 5-ylacetyl]amino-(3S)-methylpentyl]-N-cyclopropylmethyl)glycylmethionine methyl ester bis trifluoroacetate salt The title compound was prepared in the same fashion as that described in Example 1 Step I, but using the compound prepared in Step D.

1H NMR (CD30D, 400 MHz): 8 8.93 (1H, 7.95 (1H, d, J 9 Hz), 7.93-7.85 (2H, 7.80 (1H, 7.60-7.53 (3H, 7.42 (1H, dd, J 9 and 2 Hz), 5.68 (2H, 4.69-4.45 (1H, 4.30-3.90 (3H, 3.90-3.80 (2H, 3.69 (3H, 3.60-3.45 (1H, 3.40-3.14 (3H, 2.60-2.40 (2H, 2.15-2.05 (1H, 2.03 (3H, 2.00-1.85 (1H, 1.60-1.52 (1H, 1.50-1.40 (1H, 1.25-1.15 (1H, 1.12-1.05 (1H, 0.98- 0.90 (6H, 0.80-0.68 (2H, 0.50-0.40 (2H, m).

FAB HRMS exact mass calcd for C34H48N504S: 622.342702 found 622.343884.

EXAMPLE 21 Preparation of N-[(2S)-1-(2-naphthylmethyl)-1H-imidazol-5ylacetyl]amino-(3S)-methylpentyl]-N-(cyclopropylmethyl)glycylmethionine bis trifluoroacetate salt N- [(2S)-N-(2-Napthylmethyl) 1 ylacetyl]amino-(3S)-methylpentyl]-N-(cyclopropylmethyl)glycylmethionine methyl ester (19.8 mg, 0.0319 mmol) was dissolved in MeOH (0.60 ml), cooled to 0°C under argon, and treated with 1.0 N aq LiOH (38 ml, 0.038 mmol). After stirring at ambient temperature for 16 WO 96/10034 PCTIUS95/12224 -140h, the reaction was diluted with MeOH (1.5 ml) and purified by preparative HPLC (chromatography method A) to give the title compound as its bis trifluoroacetate salt after lyophilization. 1H NMR 400 MHz): 5 8.95 (1H, 7.95 (IH, d, J 9 Hz), 7.94-7.85 (2H, 7.82 (1H, 7.62-7.52 (3H, 7.44 (1H, dd, J 9 and 1 Hz), 5.60 (2H, 4.65-4.50 (1H, 4.23-4.05 (2H, 4.01-3.93 (1H, m), 3.89 (1H, d, J 19 Hz), 3.82 (1H, d, J 19 Hz), 3.52 (1H, d, J 14 Hz), 3.30-3.05 (3H, 2.61-2.40 (2H, 2.20-2.10 (1H, 2.05 (3H, s), 2.00-1.89 (1H, 1.62-1.52 (1H, 1.50-1.40 (1H, 1.25-1.04 (2H, 0.97 (3H, d, J 7 Hz), 0.92 (3H, t, J 7 Hz), 0.79-0.65 (2H, m), 0.50-0.40 (2H, Anal. Calcd for C33H45N504S*2.70 TFA*0.45 C, 49.93; H, 5.30; N, 7.58. Found: C, 49.90; H, 5.29; N, 7.92.

FAB HRMS exact mass calcd for C33H46N504S: 608.327052 found 608.326603.

EXAMPLE 22 Preparation of N-[2(S)-[(5(R,S)-Methylpyroglutamyl)amino]-3(S)methylpentyl]-N-(1-naphthylmethyl)-glycylmethionine methyl ester trifluoroacetate salt-diastereomers A (31) and B (32) N-[2(S)-amino-3-methylpentyl)-N-( -naphthylmethyl)glycyl-methionine methyl ester hydrochloride (10, 186.1 mg, 0.349 mmol) was dissolved in methylene chloride (3 mL). pyrrolidone-2-carboxylic acid Pfister III, W. J. Leanza, J. P. Conbere, H. J. Becker, A. R. Matzuk, and E. F. Rogers, J. Am. Chem. Soc., 77:697- 700 (1955), 50.2 mg, 0.351 mmol) was added followed by triethylamine (270 mL, 1.94 mmol). The mixture was cooled to 0°C under argon and treated with bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-C1, 133.3 mg. 0.5236 mmol). The reaction was stirred for 18 h at ambient temperature, diluted with EtOAc (20 mL), washed with saturated aq NaHCO3 (20 mL), saturated aq NaCI (20 mL), dried (Na2SO4) and evaporated in vacuo to give the crude product as a mixture of diastereomers. Purification by chromatography (silica gel, 1:40 MeOH/CH2Cl2) gave the two diastereomeric products as an inseparable WO 96/10034 PCT/US95/12224 -141mixture. Separation of the diastereomers was accomplished through prep plate chromatographies (silica gel, 3-5% MeOH/CH2C2) to give the high Rf diastereomer (31) and the low Rf diastereomer (32) as colorless residues. Final purification of each diastereomer was accomplished by chromatography method A. Compounds 31 and 32 were obtained as the trifluoroacetate salts by lyophilization of appropriate column fractions.

31: 1 H NMR (CD30D, 400 MHz): 5 8.25-8.17 (1H, 7.95-7.82 (2H, 7.68-7.40 (4H, 5.10-2.80 (6H, 4.50-4.30 (1H, 4.10-3.95 (1H, 3.65 (3H, 2.60-0.90 (17H, 0.83 (3H, d, J 7 Hz), 0.78 (3H, t, J 8 Hz).

Anal. Calcd for C31H44N405S*1.10 TFA.0.10 H20: C, 56.01; H, 6.41; N, 7.87. Found: C, 56.02; H, 6.29; N, 8.04.

FAB HRMS exact mass calcd for C31H45N405S: 585.311068 found 585.311153.

32: 1 H NMR (CD30D, 400 MHz): 5 8.25-8.15 (1H, 7.95-7.81 (2H, 7.65-7.38 (4H, 5.00-2.80 (6H, 4.42-4.28 (1H, 4.05-3.95 (1H, 3.63 (3H, 2.70-1.00 (17H, 0.85 (3H, br d, J 7 Hz), 0.80 (3H, br t, J 7 Hz). Anal. Calcd for C31H44N405S-1.05 TFA-0.20 C, 56.14; H, 6.47; N, 7.91. Found: C, 56.17; H, 6.47; N, 8.12.

FAB HRMS exact mass calcd for C31H45N405S: 585.311068 found 585.311694.

EXAMPLE 23 Preparation of N-[2(S)-[(5(R,S)-methyl-pyroglutamyl)amino]-3(S)methylpentyl]-N-( 1 -naphthylmethyl)-glycylmethionine trifluoroacetate salt.

N-[2(S)-[(5(R,S)-Methyl-pyroglutamyl)amino]-3(S)methylpentyl]-N-(-naphthylmethyl)-glycyl-methionine methyl ester (31, 32.3 mg, 0.0552 mmol) was dissolved in MeOH (1.5 mL) under argon and treated with 1.0 N aq LiOH (66 gtL, 0.066 mmol). The reaction was stirred at ambient temperature for 18 h, treated with glacial acetic acid (2 drops), and purified by chromatography method A to give, after lyophilization, the title compound as a 2:1 mixture of diastereomers as WO 96/10034 PTU9/22 PCT/US95/12224 -142their trifluoroacetate salts. IH NMR (CD3OD, 400 MHz): 6 8.29 (IH, d, J 8 Hz), 8.00-7.89 (2H, in), 7.78-7.45 (4H, in), 5.00-2.80 (8H, mn), 2.60-1.00 (17H, in), 0.96-0.84 (6H, in).

Anal. Calcd for C30H42N405S-1.25 TFA.0.20 H20: C, 54.45; H, 6.14; N, 7.82. Found: C, 54.46; H, 6.14; N, 7.91.

FAB HRMS exact mass calcd for C30H43N405S: 571.295418 found 57 1.295373.

EXAMPLE 24 Preparation of [(5(R,S)-methylpyroglutamyl)amino] methylpentyl] 1 -naphthylmethyl)-glycylmethionine trifluoroacetate salt Following the procedure described in Example 23, but substituting the methyl ester 32 from Example 22, the title compound was prepared.

I H NMR (CD3OD, 400 MHz): 8 8.36-8.26 (1H, in), 7.97 (2H, br d, J= 8 Hz), 7.80-7.44 (4H, in), 5.00-3.00 (8H, in), 2.60-1.10 (17H, in), 0.99- 0.84 (6H, in).

Anal. Calcd for C30H42N405S* 1.40 TFA.0.15 H20: C, 53.74; H, 6.01; N, 7.64. Found: C, 53.73; H, 5.99; N, 7.74.

FAB HRMS exact mass calcd for C30H43N405S: 571.295418 found 571.29635 1.

EXAMPLE Preparation of N- [2(S)-((N-inethylpyroglutamyl)ainino)-3 methylpentyl]-N-( 1-naphthylmethyl)-glycyl-inethionine methyl ester trifluoroacetate salt N-methylpyroglutainate Hardegger and H. Ott, Helv.

Chim Acta, 38:3 12 (1955), 51 mng, 0.35 mmol)], dissolved in DMF ml), was treated with HOBT (48 mng, 0.35 inmol), EDC (8 1 ing, 0.42 mmol), N- [2(5 )-amino-3 (S )-methylpentyl)-N-( 1 -naphthylmnethyl)glycyl inethionine methyl ester hydrochloride (10, 150 mg, 0.28 nimol), and WO 96/10034 PCT/US95/12224 -143triethylamine (0.079 ml, 0.56 mmol). The mixture was stirred at room temperature for 24 hours. The mixture was partitioned between ethyl acetate and 10% citric acid solution and the organic phase was washed three times with saturated NaHCO3, brine, and dried (MgSO4). The solution was filtered through celite and evaporated in vacuo The crude product was chromatographed MeOH in EtOAc) and further purified by preparative HPLC (Waters PrepPak C-18 eluting with TFA in H20) to give, after lyophilization, the title compound.

1H NMR (CD30D) 5 8.35(1H,d), 8.0(2H,m), 7.7(4H,m), 5.1(1H,m), 4.75(1H,m), 4.55(lH,m), 4.05(4H,m), 3.75(3H,s), 3.60(1H,m), 3.20(1H,m), 2.70(3H,s), 2.30(6H,m), 2.00(4H,m), 1.85(1H,m), 1.65(1H,m), 1.45(1H,m), 1.25( 0.95(6H,m).

FAB MS calcd for C31H45N405S 585 found 585.

Anal. Calcd for C31H44N405S*1.35TFA*1.60H20: C, 52.73; H,6.38; N, 7.30.

Found: C, 52.75; H, 6.00; N, 7.70 EXAMPLE 26 Preparation of N-[2(S)-((N-methylpyroglutamyl)-amino)-3(S)methvlpentll-N-(1 -naphthlmethl)-2lcvl-methionine N-[2(S)-((N-Methylpyroglutamyl)-amino)-3(S)methylpentyl] -naphthylmethyl)-glycyl-methionine methyl ester trifluoroacetate salt (prepared in Example 25, 112 mg, 0.19 mmol) was dissolved in methanol (5 ml) and treated with 0.76 ml of IN LiOH. The mixture was stirred for 4 hours at room temperature, then treated with 0.76 ml of IN HCI. The solvent was evacuated in vacuo. The crude product was purified by preparative HPLC (Waters PrepPak C-18 eluting with CH3CN/O.1 TFA in H20) to give, after lyophilization, the title compound.

1 H NMR (CD30D) 8 8.35 8.00 7.65 5.10 4.75 4.50 4.05 3.60 3.25 2.70 2.30 2.05 1.85 1.60 1.45 1.20 0.95 (6H,m).

WO 96/10034 WO 9610034PCT1US95/12224 -144- FAB MS calcd for C30H143N405S: 571 found 57 1.

Anal. Calcd for C30H42N405S- 1.6OTFA.0.55H20: C, 52.25; H, 5.90; N, 7.34. Found: C, 52.27; H, 5.92; N, 7.71.

EXAMPLE 27 Preparation of N- [2(S)-(N-foninylprolylamino)-3 (S)-methylpentyl] 1nap~hthylmethvl)-glvcvl-methionine methyl ester trifluoroacetate salt N-formyl-L-proline [IT. Sawayama, et al, Chem. Pharm.

Bull., 38 529-531 (1990), 44.3 mg, 0.31 mmol], dissolved in DMF (3 ml), was treated with HOBT (46 mg, 0.34 mmol), EDC (81 mg, 0.42 mmol), N-112(S )-amino-3 -methylpentyl)-N-( 1 -naphthylmethyl)glycyl methionine methyl ester hydrochloride (10, 150 mg, 0.28 mmol), and triethylamine (0.079 ml, 0.56 mmol). The mixture was stirred at room temperature for 72 h, then partitioned between ethyl acetate and citric acid solution. The organic extract was washed with saturated NaHCO3 three times, then brine, and dried (MgSO4). After filtration through celite and evaporation of solvent in vacuo., the crude product was purified by preparative HPLC (Waters PrepPak C-i 18 eluting with CH3 CN/0.1I %TFA in H20) to give, after lyophi lization, the title compound. IH NMR (CD3OD) 8.35 8.20 8.00 (2H,m), 7.65 5.10 4.65 4.10 (411,m), 3.75 (3H1,s), 3.60 3.10 2.40 (2Hjm), 1.90 (8H1,m), 1.55 1.20 (I1Him), 0.90 (6H,m).

FAB MS calcd for C31IH45N405S 585 found 57 1.

Anal. Calcd for C31IH44N405S*1.4OTFA-0.20H20: C, 54.28; H, 6.11; N, 7.47.

Found: C, 54.25; H, 6.16; N, 7.69.

EXAMPLE 28 Preparation of N- [2(S )-(N-formylprolylamino)-3 (S)-methylpentyl] 1naphthylmethyl)-glvcyl-methionine WO 96/10034 PCT/US95/12224 -145- The procedure described in Example 26, substituting the methyl ester prepared in Example 27 was used to obtain the title compound.

FAB MS m/z 571 Anal. Calcd for C30H42N405S1*1.75 TFA: C, 52.24; H, 5.72; N, 7.27.

Found: C, 52.19; H, 5.82; N, 7.61.

EXAMPLE 29 Preparation of N-[2(S)-(N'-(4-nitrobenzyl)-pyroglutamyl)-amino)-3(S)methylpentyl]-N-(1-naphthylmethyl)-glycyl-methionine methyl ester hydrochloride salt() Step A: Preparation of (S)-N-(4-nitrobenzyl)pyroglutamic acid methyl ester (S)-Pyroglutamic acid methyl ester (0.200 g, 1.40 mmol) was dissolved in dry THF (5 ml) and NaH (0.061 g, 1.5 mmol) was added. After gas evolution ceased, 4-nitrobenzyl bromide (0.332 g, 1.54 mmol) was added and the mixture stirred for 1 h. The reaction was quenched with saturated NaHCO3 solution (40 mL) and extracted with EtOAc (2 x 50 ml). The organic layers were washed with water, brine, dried (MgSO4), filtered, and concentrated to give the title compoundas a solid. IH NMR (CDC13) 8 8.19 2H, J=8.6 Hz), 7.40 2H, J=8.6 Hz), 5.29 1H, J=15 Hz), 4.19 1H, J=15 Hz), 4.02 (dd, 1H, J=3,9 Hz), 3.79 3H), 2.54-2.67 1H), 2.42-2.51 1H), 2.27-2.39 (m, 1H), 2.11-2.21 1H).

Step B: Preparation of (S)-N-(4-nitrobenzyl)pyroglutamic acid (S)-N-(4-Nitrobenzyl)pyroglutamic acid methyl ester (0.365 g, 1.31 mmol) was dissolved in 10 ml MeOH, cooled to 0°C, and IN NaOH (5.2 ml, 5.2 mmol) was added. The reaction was stirred at room temperature for Ih. Water (50 ml) was added and the aqueous was washed with 2 x 50 ml EtOAc. The aqueous was acidified with 1N HCI and extracted with 3 x 40 ml EtOAc. The organic layers were dried (MgSO4), filtered, and concentrated to give the title compound as a solid.

WO 96/10034 PCTIUS95/12224 -146- 1H NMR (d6-DMSO) 6 8.19 2H, J=8.7 Hz), 7.51 2H, J=8.6 Hz), 4.86 IH, J=16 Hz), 4.19 1H, J=16 Hz), 4.02-4.10 1H), 3.30 (br s, 1H), 2.29-2.41 3H), 1.96-2.05 1H).

Step C: Preparation of Nitrobenzyl)pyroglutamyl)amino)-3(S)-methylpentyl] 1naphthylmethyl)-glycyl-methionine methyl ester hydrochloride salt (S)-N-(4-Nitrobenzyl)pyroglutamic acid (0.95 g, 0.36 mmol), N-[2(S)-amino-3-methylpentyl)-N-(1 -naphthylmethyl)-glycylmethionine methyl ester hydrochloride (10, 0.160 g, 0.300 mmol) and diisopropylethylamine (0.261 mL, 1.50 mmol) were dissolved in DMF (3 mL). BOP-CI (0.137 g, 0.539 mmol) was added and the mixture was stirred at ambient temperature for 24 h. The mixture was concentrated and the residue was partitioned between EtOAc (80 mL) and saturated NaHCO3 solution (25 mL). The aqueous layer was extracted with EtOAc (30 mL). The combined organic layer was washed with brine mL), dried (MgSO4), filtered, and concentrated to give a crude product which was purified by chromatography (silica gel, eluting with 98:2 CH2C12:MeOH). Further purification by preparative HPLC (Waters C- 18 Prep Pak eluting with acetonitrile/0.1% TFA in H20 gradient) gave the amine trifluoroacetate, which was converted to the hydrochloride salt by dissolving in EtOAc, bubbling HCI gas, filtering, and drying under vacuum to give the title compound. 1H NMR (CD30D) 8 8.29-8.41 (m, 1H), 8.17 2H, J=8 Hz), 7.92-8.08 2H), 7.64-7.76 2H), 7.48- 7.64 2H), 7.33-7.48 2H), 5.03-5.18 1H), 4.59-4.72 1H), 4.39-4.52 1H), 3.81-4.27 4H), 3.72 3H),3.14-3.28 1H), 2.50-2.73 1H), 2.19-2.50 6H), 1.85-2.13 4H), 2.01 3H), 1.67-1.85 IH), 1.41-1.53 1H), 1.24-1.38 1H), 1.02-1.19 (m, 1H), 0.72-0.94 6H).

Anal. Calcd for C37H46N507S*1.95 HC1.0.95 H20: C, 56.04; H, 6.34; N, 8.83.

Found: C, 56.07; H, 6.28; N, 8.71.

WO 96/10034 PCT/US95/12224 -147- EXAMPLE Preparation of N-[2(S)-((4-nitrobenzyl)pyroglutamyl)-amino)-3(S)methylpentyl]-N-( 1-naphthylmethyl)-glycyl-methionine trifluoroacetate salt N-[2(S)-((4-Nitrobenzyl)pyroglutamyl)amino)-3(S)methylpentyl]-N-(1-naphthylmethyl)-glycyl-methionine methyl ester (0.050 g, 0.071 mmol) was dissolved in MeOH (1 ml), cooled to 00, and IN NaOH (0.283 ml, 0.283 mmol) was added. The mixture was stirred at ambient temperature for 1h. The mixture was neutralized with IN HC1 (0.283 ml, 0.283 mmol). The aqueous layer was washed with EtOAc (3x10 ml). The organic layers were combined, dried with MgSO4, filtered, and concentrated to give a crude product. Preparative HPLC (Waters C-18 Prep Pak eluting with acetonitrile/0.1 TFA in gradient) gave the pure title compound. 1 H NMR (CD30D); 5 8.35 (d, 1H, J=8 Hz), 8.17 2H, J=8 Hz), 7.94-8.04 2H), 7.70-7.77 1H), 7.61 1H, J=8 Hz), 7.52-7.63 2H), 7.42 2H, J=8 Hz), 4.93-5.10 1H), 4.62-4.75 1H), 4.43-4.56 1H), 4.08-4.21 1H), 3.81- 4.21 4H), 3.45-3.61 1H), 3.10-3.26 2H), 2.28-2.53 6H), 1.95-2.19 3H), 2.03 3H) 1.76-1.92 1H), 1.41-1.54 1H), 1.24-1.38 1H), 1.03-1.17 IH), 0.77-0.94 6H).

Anal. Calcd for C36H44N507S*1.9 TFA.0.85 H20: C, 51.80; H, 5.20; N, 7.59.

Found: C, 51.81; H, 5.36; N, 7.53.

EXAMPLE 31 Preparation of N-[2(S)-((N'-benzylpyroglutamyl)amino)-3(S)methylpentyl]-N-(l-naphthylmethyl)-glycyl-methionine methyl ester trifluoroacetate salt Using the method of Example 29, substituting benzyl bromide for the p-nitrobenzyl bromide used therein, the title compound was obtained.

Anal. Calcd for C37H48N405S-1.65 TFA: C, 57.01; H, 5.89; N, 6.60.

WO 96/10034 PCT[US95/12224 -148- Found: C, 56.96; H, 5.94; N, 6.91.

EXAMPLE 32 Preparation of N-[2(S)-(N'-benzylpyro-glutamyl)amino)-3(S)methylpentyl]-N-(l -naphthylmethyl)-glycyl-methionine trifluoroacetate salt The product of Example 31 was converted to the title compound as described in Example FAB MS calcd for C36H47N405S 647 found 647 Anal. Calcd for C36H46N405S*1.5 TFA: C, 57.27; H, 5.85; N, 6.85.

Found: C, 57.17; H, 5.94; N, 6.79.

EXAMPLE 33 Preparation of I -(4-Fluorophenylmethyl)- I ylacetyl)amino-3 (S)-methylpentyl] I -naphthylmethyl-glycyl methionine Step A: Preparation of 1-(4-Fluorophenylmethyl)- viacetic acid The title compound was prepared as the hydrogen bromide salt using the procedures described in Example 3 steps B and C replacing 4-nitrobenzyl bromide with 4-fluorobenzyl bromide.

1H NMR(CD30D, 400 MHz) 8 8.89(1H, d, J=1.3Hz), 7.55(1H, 7.50- 7.30(2H, 7.17(2H, t, J=8.8Hz), 5.43(2H, s) and 3.82(2H, s) ppm.

Step B: Preparation of -(4-Fluorophenylmethyl)- 1Himidazol-5-ylacetyl)amino-3(S)-methylpentyl] -N-1naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate The title compound was prepared as the bis trifluoroacetate salt using the procedures described in example 2 step C using 1-(4acid.

WO 96/10034 WO 9610034PCT/US95/12224 -149- IH NMR(CD3OD, 400 MHz) 5 8.77(1H, 8.28(1H,m), 8.00- 7. 80(2H,m)), 7.65-7 .40(5H,m), 7.30-7.20(2H,m), 7.1 4(2H,t, J=8.6Hz),5.34(2H, m) 4.39(2H,m), 4.13(1H,m), 3.68(3H,s), 3.65- 3.40(4H,m), 2.95(1H,m), 2.40-2.15(2H,m), 1.97(3H,s), 1.95(1H,m), 1.70(1H,m), 1.60(1H,m), 1.43(1H,m), 1.07(1H,m), and 1.00-O.80(6H,m) ppm.

FAB Mass spectrum, m/z 676 Anal. calc'd for C37H46N504S O.45H20, 1.65TFA; C, 55.50 H, 5.61 N, 8.03. Found: C, 55.50; H, 5.60; N, 8.23.

StepC: Preparation of N-[2(S)-1I-(4-Fluorophenylmethyl)-1IHimnidazol-5-ylacetyl)amino-3 (S )-methylpentyl] Inaphthylmethyl-glvcvl-methionine bis trifluoroacetate.

The title compound was prepared as the bis trifluoro acetate salt using the procedure described in Example 2 step D.

IH NMR(CD3OD, 400 MHz) 6 8.79(1H, 8.30(1H,m), 8.00- 7.80(2H,m)), 7.65-7.40(5H,m), 7.30-7.20(2H,m), 7.1 3(2H,t, J=8.7Hz),5.35(2H, m) 4.38(2H,m), 4.13(1 3.80-3.40(4H,m), 3.10(1H,m), 2.40-2. 15(2H,m), 1 .97(3H,s), 1.95(1 1.70(1 H,m), 1.60(l1H,m), l.43(l 1.07(l1H,m), and 1.00-0.80(6H,m) ppm.

FAB Mass spectrum, m/z 662 Anal. calc'd for C36H44N504S 0.60H20, 2.3OTFA; C, 52.16 H, 5.12 N, 7.49. Found: C, 52.18; H, 5.13; N, 7.76.

EXAMPLE 34 Preparation of 1 -(4-cyanobenzyl)- 1 yl] acetylamino)-3 (S )-methylpentyl] 1 -naphthylmethyl)glycyl methionine isop~ropvyl ester Step A: Preparation of I1H-Imidazole-4- acetic acid methyl ester hydrochloride.

A solution of 1 H-imidazole-4-acetic acid hydrochloride 4 .00g, 24.6 mmol) in methanol (100 ml) was saturated with gaseous WO 96/10034 PCTIUS95/12224 -150hydrogen chloride. The resulting solution was allowed to stand at room temperature (RT) for 18hr. The solvent was evaporated in vacuo to afford the title compound as a white solid.

1 H NMR(CDCl3, 400 MHz) 8 8.85(1H, s),7.45(1H, 3.89(2H, s) and 3.75(3H, s) ppm.

Step B: Preparation of 1-(Triphenylmethyl)- 1H-imidazol-4-ylacetic acid methyl ester.

To a solution of the product from Step A (24.85g, 0.141mol) in dimethyl formamide (DMF) (115ml) was added triethylamine (57.2 ml, 0.412mol) and triphenylmethyl bromide(55.3g, 0.171mol) and the suspension was stirred for 24hr. After this time, the reaction mixture was diluted with ethyl acetate (EtOAc) (1 1) and water (350 ml). The organic phase was washed with sat. aq. NaHCO3 (350 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (Si02, 0-100% ethyl acetate in hexanes; gradient elution) to provide the title compound as a white solid.

1 H NMR (CDC13, 400 MHz) 8 7.35(1H, 7.31(9H, 7.22(6H, m), 6.76(1H, 3.68(3H, s) and 3.60(2H, s) ppm.

Step C: Preparation of [1-(4-cyanobenzyl)- acid methyl ester.

To a solution of the product from Step B (8.00g, 20.9mmol) in acetonitrile (70 ml) was added bromo-p-toluonitrile (4.10g, 20.92 mmol) and heated at 55°C for 3 hr. After this time, the reaction was cooled to room temperature and the resulting imidazolium salt (white precipitate) was collected by filtration. The filtrate was heated at for 18hr. The reaction mixture was cooled to room temperature and evaporated in vacuo. To the residue was added EtOAc (70 ml) and the resulting white precipitate collected by filtration. The precipitated imidazolium salts were combined, suspended in methanol (100 ml) and heated to reflux for 30min. After this time, the solvent was removed in vacuo, the resulting residue was suspended in EtOAc (75ml) and the solid isolated by filtration and washed (EtOAc). The solid was treated with sat WO 96/10034 WO 9610034PCTIIUS95/12224 151 aq NaHCO3 (300m1) and CH2Cl2 (300m1) and stirred at room temperature for 2 hr. The organic layer was separated, dried (MgSO4) and evaporated in vacuo to afford the title compound as a white solid IHNMR(CDC13, 400 MHz) 8 7.65(1H, d, J=8Hz), 7.53(0H, 7.15(1H, d, J=8Hz), 7.04(lH, 5.24(2H, 3.62(3H, s) and 3.45(2H, s) ppm.

Ste p D: Preparation of 1-(4-cyanobenzyl)- 1 H-imidazol-5-yl] acetic acid.

A solution of [1I -(4-cyanobenzyl)- 1 H-imidazol-5 -yl] acetic acid methyl ester (4.44g, 17.4mmol in THF (lO0mI) and 1 M lithium hydroxide (17.4 ml, 17.4 mmol) was stirred at RT for 18 hr. 1 MKHI (17.4 ml) was added and the THF was removed by evaporation in vacuo.

The aqueous solution was lyophilised to afford the title compound containing lithium chloride as a white solid.

IH NMR(CD3OD, 400 MHz) d 8.22(1H, 7.74(1H, d, J=8.4Hz), 7.36(lH, d, J=8.4Hz), 7.15(1H, 5.43(2H, s) and 3.49(2H, s) ppm.

Step E: Preparation of N-[2(S)-(amino)-3(S)-methylpentyl]-N-( 1naphthvlmethyl) glycine methyl ester hydrochl oride.

A solution of N-12(S)-(t-Butoxycarbonylamino)-3(S)methylpentyl]N( 1 -naphthylmethyl) glycine methyl ester from example 1 step B (5.90g, 13.8 mmol) in EtOAc (100 ml) was saturated with gaseous hydrogen chloride. The resulting solution was allowed to stand at room temperature for lhr. The solvent was evaporated in vacuo to afford the title compound as a white solid.

IH NMR(CD3OD 400 MHz) 6 8.26(1H, d, J=8.6Hz),7.92(1H, d, J=7.2Hz), 7.87(lH, d, J=8.6Hz), 7.63-7.42(4H,m), 4.34(1H,d, J=12.3Hz, 4.26(1H,d, J=12.3Hz), 3.68(3H,s), 3.13(1H, d, J=10.3Hz), 2.67- 2.55(2H,m); 1.46(1 1 .28(2H,m), 1.1 0-0.90(2H,m), O.84(3H,d,J=6.8Hz) and 0.77(3H,t, J=6.8Hz)ppm.

Step F: Preparation of N- [2(8 [1-(4-cyanobenzyl)- 1H-imidazolyl] acetylamino)-3 (S )-methylpentyl] 1narhthvlmethvl) glvcine methyl ester.

WO 96/10034 WO 9610034PCTfUS95/12224 -152- To a solution of [1I -(4-cyanobenzyl)- 1 H-imidazol-5-yl] acetic acid. (4.09g, 10.24 mmol), the amine hydrochloride salt from step E(5.07g, 10.24 mmol), HOOBT (1.67g, 10.24mmol), and Nmethylmorpholmne (2.36m1, 21 .5mmol) in DMF (50ml) at 0 0 C, was added EDC (2.16g, 11.26 mmol). The reaction was stirred at room temperature for 1 8hrs, diluted with EtOAc and the organic layer washed with sat. aq NaHCO3, brine, dried (Na2SO4), and the solvent evaporated in vacuo.

The residue was chromatographed (SiO2, 3-4% MeOH in CH2Cl2) to afford the title compound as a white solid.

IH NMR(CD3OD, 400 MHz) 8 8.30(l1H,d, J=8.4Hz), 7.84( 1H,d, J=8.OHz), 7.80(1H,t, J=4.5Hz), 7.68-7.38(3H,m), 7.48- 7.32(4H,m), 7. lO(2H,d, J=8.OHz), 6.87(1 5.24(1 H,d, J=1 6.7Hz), 5.1 8(1H,d,J=1 6.7Hz), 4.83(2H,s), 4.27( 1H,d, J=12.8Hz), 4. l0(1H,d, 1=12.8Hz), 3.97( 1H,m), 3.65(3H,s), 3.40-3.20(2H,m), 2.92(1 H,dd, J=13.3 and 4.3Hz), 2.60(1H,dd, J=13.3 and 10.0Hz), 1.48(1H,m), 1.25(1H,m), 0.98(1H,m), 0.78(3H,d, J=6.8Hz) and 0.77(3H,t, ppm.

Anal. calc'd for C33H37N503 1 .05H20, 2.85 TFA C, 51.90; H, 4.72; N, 7.82. Found: C, 51.90; H, 4.70; N, 8.18.

FAB Mass spectrum, m/z 552 Step G: Preparation of N-[2(S 1 -(4-cyanobenzyl)- 1 H-imidazolacetylamino)-3 (8)-methylpentyl] 1-naphthylmethyl) glycine.

A solution of the methyl ester from step F (2.32g, 4.2 immol) in MeOH(20m1) and I M lithium hydroxide (4.70 ml, 4.70 mmol) was stirred at RT for 6hr. The aqueous solution diluted with water (I15m1) and extracted with EtOAc (IlO0ml), dried (Mg2SO4), and the solvent evaporated in vacuo. The residue was chromatographed (SiO2, MeOH in CH2CI2) to afford the title compound as a white solid.

1 H NMR(CD3OD, 400 MHz) 8 8.33(LH, d,J=8.3Hz), 7.87(2H,d, 1=7.7Hz), 7.78(1 7.63(2H,d, J=6.6Hz), 7.57(1 H,d, J=6.4Hz), 7.50-7.38(4H,m), 7.17(1 H,d, J=8.3Hz), 6.96(1 5.32(1H,d, WO 96/10034 WO 9610034PCT1US95/12224 153 J= I16.6Hz), 5.25(l 1H,d,J=1I 6.6Hz), 4.64(l1H,d, J= 1 3.2Hz), 4.40(l1H,d, J=1I3.2Hz), 3.99(1 3.60-3.28(4H,m), 3.22(l1H,dd, J= 13.3 and 3.1lHz), 2.93(1H,dd, J=13.3 and 10.3Hz), 1.52(1H,m), 1.29(1H,m), 1.06(1H,m), 0.86-0.76(6H,m) ppm.

Anal. calc'd for C32H35N503 1.00H20, C, 69.17; H, 6.71 N, 12.60.

Found: C, 68.95; H, 6.37; N, 12.54.

FAB Mass spectrum, m/z 538 Step H: Preparation of -(4-cyanobenzyl)- 1 Himidazol-5-yl]acetylamino)-3 (S)-methylpentyl]-N-( 1nap~hthvlmethvP glvcvl-methionine isop~ropvyl ester To a solution of the acid from step G (1 00mg, 0. 1 6mmol) and methionmne isopropyl ester hydrochloride (42.4mg,0. 1 86mmol), HOOBT (30.4mg, 0. 1 86mmol) and triethylamine (0.077m1, 0.56mmol) in DMF (1 .Oml) was added EDC (37.5mg, 1 .96mmol). The reaction was stirred at room temperature for 1 8hrs, diluted with EtOAc and the organic layer washed with sat. aq NaHCO3 brine dried (Na2SO4), and the solvent evaporated in vaduo. The residue was chromatographed (SiO2, 5% MeOH in CH2CI2), evaporated to dryness and converted to the hydrochloride salt by treatment with aqueous HCl (O.32ml of a 1 M solution) and acetonitrile and lyophilisation, to afford the title compound as a white powder.

1 H NMR(CD3OD, 400 MHz) 8 9.00-8.90(1H, in), 8.38(1H, m),8.10- 7. 10(11 H,M),5.80-4.80 (4H, in), 4.60-3.30(l1 2.60-1 .70(8H,m), 1 .60(1H,m), 1 .42( 1H,m), 1.21 (6H,d, J=6.2Hz), 0.91 8(6H,br t, J=7.3Hz) ppm.

FAB HRMS exact mass calc'd for C40H5 1 N604S 711.36925 1 found 711367663.

Anal. calc'd for C40H50N604S 0.55H20 and 2.8OHCI C, 58.38; H, 6.60 N, 10.21. Found: C, 58.40; H, 6.60; N, 10.36.

WO 96/10034 WO 9610034PCTIUS95112224 -154- EXAMPLE Preparation of 1-(4-cyanobenzyl)- 1H- -yl] acetylamino)-3 (S)-methylpentyl] 1naphthvlmethvl)glvcyl-methionine sulfone methyl ester The title compound was prepared as the hydrogen chloride salt using the procedures described in Example 34 Steps H using methionine sulfone methyl ester hydrochloride.

IH NMR(CD3OD, 400 MHz) 8 8.93(1H, in), 8.39(1H, m),8.20- 7.15(l1H,m),5.50(2H,m), 5.40-3.00 (1 5H, in), 2.95(3H,s), 2.30(1 H,m), 2.05(1 1.60(1 1 .45(1H,m), 1 .22( 1H,m), 0.91 5(6H,m) ppm.

FAB HRMS exact mass calc'd for C38H47N606S 715.327781 found 7 15.327372.

calc'd for C38H47N606S 0.35H20 and 3.25HC1 C, 54.36; H, 6.00 N, 10.01. Found: C, 54.36; H, 5.99; N, 10.21.

EXAMPLE 36 Preparation of N- [2(5 1 -(4-cyanobenzyl)- yl] acetylamino)-3 (S)-methylpentyll 1 -naphthylmethyl)glycylmethionine sulfone A stirred solution of the methyl ester from Example (23.7mg, 0.O33nimol) in THF(0.20ml) and 1 M lithium hydroxide (0.033m1, 0.O33mmol)was allowed to warm from 0 0 C to room temperature over 1 8hrs. The reaction was quenched by the addition of trifluoroacetic acid and the solvent evaporated in vacuo. The residue was by preparative hplc to afford the title compound after yophilisation.

IH NMR(CD3OD, 400 MHz) 5 8.89(IH, in), 8.16(1H, mn), 7.85- 7.20(1 IH,m),5.38(2H,in), 4.31 4.00(1H,in), 3.60-3.30(7H,m), 3.00-2.90(3H,m), 2.81 2.1 4(1H,m), 1.94(1 1.43 1H,m), 1.29(IH,in), 1.04(1H,in), 0.78(6H,m) ppm.

WO 96/10034 WO 9610034PCTfUS95/12224 155 Anal. calc'd for C37H44N606S 0.45H20, 2.30 TFA C, 51.45; H, 4.90 N, 8.65. Found: C, 51.44 H, 4.89; N, 8.62.

FAB HRMS exact mass calc'd for C37H45N606S 701.3 12130(MH+), found 701.3 13179.

EXAMPLE 37 Preparation of 1-(4-cyanobenzyl)- 1H-imidazol-5 yl] acetylamino)-3 (S )-methylpentyl] -N -naphthylmethyl)glycyl-(3acetylamino)alanine methyl ester The title compound was prepared as the hydrochloride salt using the procedures described in Example 34 Step H using (S)-N t -acetyl diaminopropionic acid methylester hydrochloride.

IH NMR(CD3OD, 400 MHz) 6 8.90(1H, in), 8.38(1H, m),8.10- 7.20(1 1H,m), 5.60(2H,m), 5.20-3.00(1OH,m), 3.60(3H,s), 1.92(3H,s), 1 .83( 1H,s), 1 .57(1H,m), 1 .43(1H,m), 1 .19(1H,m), 0.90(6H,m) ppm.

FAB HRMS exact mass calc'd for C38H46N705 680.356043(MH+), found 680.356735.

calc'd for C38H45N705 0.35H20 and 3.05 HCl C, 57.24; H, 6.16 N, 12.30. Found: C, 57.26; H, 6.16; N, 12.40.

EXAMPLE 38 Preparation of 1 -(4-cyanobenzyl)- 1 yll acetylamino)-3 (S )-methylpentyl] 1 -naphthylmethyl)glycyl-(3acetylamino)alanine The title compound was prepared as the trifluoroacetate salt using the procedures described in Example 36 and the methyl ester prepared in Example 37 1 H NMR(CD3OD, 400 MHz) 6 8.82(1H, in), 8.40(1H, mn), 7.70(2H,m), 7.65(2H,d, J=8.OHz), 7.60-7.30(5H,m), 7.27(2H,d, J=8.OHz), .40(2H,in), WO 96/10034 WO 9610034PCTIUS95/12224 -156- 4.32(1H,m), 4.00(1H,m), 3.70-3. 10(1OH,m), 1 .75(3H,s), 1.48(1 H,s), 1 .33(1H,m), 1 .08( 1H,m), O.80(6H,m) ppm.

FAB HRMS exact mass calc'd for C37H44N705 666.340393(vli+), found 666.340627.

Anal. calc'd for C37H43N705 0.30H20 and2.35 TFA C, 53.33; H, 4.93 N, 10.44. Found: C, 53.33; H, 4.95; N, 10.22.

EXAMPLE 39 Preparation of N-112(S)-(I -(4-cyanobenzyl)- 1 yl] acetylamino)-3 (S )-methylpentyl] 1 -naphthylmethyl)glycyl-2(RS) amino-3-(2 thienvl)p2ropionic acid methyl ester The title compound was prepared as the trifluoroacetate salt using the procedures described in Example 34 Step H using 2(RS) amino- 3-(2 thienyl)propionic acid methyl ester hydrochloride.

I H NMR(CD3OD, 400 MHz) 8 8.8 1 (1 H, in), 8.19(l1H, d, 8.00-7.80(2H,m), 7.62(2H,d, J=8.OHz), 7.50-7.30(5H,m), 7.29(2H,d, J=8.OHz), 7.036(l1H,m), 6.71 8(l1H,s), 6.61 (1 5.39(2H,m), 204.60(1 4.40(1 3.98(1 3.60(3H,s), 3.60-3.30(7H,m), 3.20- 202.95(3H,m), 1.47(1H,m), 1.32(1H,m), 1.08(1H,m), 0.85(6H,m) ppm.

FAB HRMS exact mass calc'd for C40H45N604S 705.32230 1 found 705.321444.

Anal. calc'd for C40H44N6045 0.35H20 and 2.5OTFA C, 54.25; H, 4.78 N, 8.44. Found: C, 54.27; H, 4.77; N, 8.36.

EXAMPLE Preparation of N- 1 -(4-cyanobenzyl)- 1 yl] acetylamino)-3 (S )-methylpentyl] 1 -naphthylmethyl)glycyl-2(RS amino-3-(2 thienyl)prop~ionic acid The title compound was prepared as the trifluoroacetate salt using the procedures described in Example 36 and the methyl ester prepared in Example 39 WO 96/10034 WO 9610034PCTfUS95/12224 157 FAB HRMS exact mass calc'd for C39H42N604S 691.306651 found 691.306950.

EXAMPLE 41 Preparation of 1-(4-cyanobenzyl)- yl] acetylamino)-3 (S )-methylpentyl] 1 -naphthylmethyl)glycyl-2(S) amino-4-sulfamyl-butanoic acid methyl ester The title compound was prepared as the trifluoroacetate salt using the procedures described in Example 34 Step H using 2(S) ammno- 4-sulfamyl-butanoic acid methyl ester hydrochloride.

IH NMR(CD3OD, 400 MHz) 6 8.87(1H, in), 8.33(1H, in), 8.00- 7 .80(2H,m), 7 .73(2H,d, J=8.2Hz), 7.70-7 .40(5H,m), 7.3 5(2H,d, J=8.OHz), 5.42(2H,m), 4.40(1 4.1 0(1 3.70(3H,s), 3.60-3.20(7H,m), 3.00(3H,m),2.30(1H,m), 2.05(1 1 .55(1H,m), 1.40(1 H,m), 1.15(1H,m), 0.95(6H,m) ppm.

FAB HRMS exact mass calc'd for C37H46N7065 716.323030(MH+), found 7 16.323766.

Anal. calc'd for C37H45N706S 1 .20H20 and 3.OOTFA C, 47.84; H, 4.71 N, 9.08. Found: C, 47.84; H, 4.58; N, 9.26.

EXAMPLE 42 Preparation of N- [1-(4-cyanobenzyl)- 1H-imidazol-5 yl] acetylamino)-3 (S )-methylpentyl] 1 -naphthylmethyl)glycyl-2(S) amino-4-sulfamyl-butanoic acid The title compound was prepared as the trifluoroacetate salt the methyl ester prepared in Example 4 1.

H NMR(CD3OD, 400 MHz) 8 8.86(1H, in), 8.26(1H, in), 8.00- 7.80(2H,m), 7.73 (2H,d, J=8.2Hz), 7.70-7 .40(5H,m), 7 .35(2H,d, J=8.OHz), WO 96/10034 WO 9610034PCTIUS95/12224 -158- 5.47(2H,m), 4.42(1H,m), 4.08(1 3.60-3.20(7H,m), 3.00(3H,m), 2.30(1H,m), 2.05(1H,m), 1 .57(1H,m), 1 .38(1H,m), 1. 15(1H,m), 0.95(6H,m) ppm.

FAB HRMS exact mass calc'd for C36H44N706S 702.307379(MH+), found 702.308307.

Anal. calc'd for C36H43N706S 0.40H20 and 2.65TFA C, 49.06; H, 4.63 N, 9.70. Found: C, 49.03; H, 4.63; N, 9.99.

EXAMPLE 43 Preparation of I-(4-cyanobenzyl)- 1 yl] acetylamino)-3 (S )-methylpentyl] 1 -naphthylmnethyl)glycyl-Nmethyl methionine methyl ester The title compound was prepared as the trifluroacetate salt using the procedures described in Example 34 Step H using N-methyl methionine methyl ester hydrochloride.

IH NMR(CD3OD, 400 MHz) 5 8.93(1H, in), 8.34(1H, in), 8.04(IH,d, J=7.7Hz), 7.98(1H,m), 7.75(3H,m), 7.60-7.20(6H,m), 5.48(2H,m), 5.06(l1H,m), 4.40(l1H,m), 4. 10(1 3.66(3H,s), 3.80-3.20(9H,m), 2.85(3H,br 2.40-2.00(1 H,in),2.05(3H,s), 1 .95( 1H,m), 1.57(1 H,m), 1.45(1 1.1 0(1H,m), O.95(6H,m) ppm.

FAB HRMS exact mass calc'd for C39H49N604S 697.353601 found 697.353335.

Anal. calc'd for C39H48N604S 0.45H20 and 2.95TFA C, 51.79; H, 5.02 N, 8.07. Found: C, 51.79; H, 4.99; N, 8.15.

EXAMPLE 44 Preparation of N-r2S-([ 1-(4-cyanobenzyl)-l1H-imidazol-5 ylj acetylamino)-3 (S )-methylpentyl] 1 -naphthylmethyl)glycyl-Nmethyl methionine WO 96/10034 WO 9610034PCTIUS9S/12224 -159- The title compound was prepared as the trifluoroacetate salt using the procedures described in Example 36 and the methyl ester prepared in Example 43.

IH NMR(CD3OD, 400 MHz) 8 8.78(0.7H, m),8.76(0.3H,m), 8.24(lH, inm), 8.0- 7.00(1 lH,m), 5.37(2H,m), 5.00-3.00(lOH,m), 2.85(3H,br s), 2.40-2.00(4H,m),1 .93(0.9H,s), 1.90(2.1 1 .50(lH,m), 1.31(1 H,m), l.08(1H,m), 0.80(6H,m) ppm.

FAB HRMS exact mass calc'd for C36H47N604S 683.33795 1 found 683.337329.

Anal. calc'd for C36H46N604S 2.84TFA C, 52.11; H, 4.89 N, 8.35.

Found: C, 51.74; H, 5.02; N, 8.74.

EXAMPLE Preparation of 1 -(4-cyanobenzyl)- 1 yl] acetylamino)-3 (S )-methylpentyl] 1 -naphthylmethyl)glycylhomoserine lactone The title compound was prepared as the trifluoroacetate salt using the procedures described in Example 34 Step H using homoserine lactone hydrochloride.

IH NMR(CD3OD, 400 MHz) 5 8.9 1(1H, in), 8.30(1H, in), 8.05- 7 .90(2H, in), 7.74(2H,d, J=8.4Hz),7.70( 1H,d, J=6 .2Hz), 7.60- 7.50(4H,m), 7.53(2H,d, 8.0Hz), 5.50(2H,m), 4.70(2H,m), 4.39(1H,dd,J=10.9 and 8.9 Hz), 4.30(1H,t, J=7.9Hz), 4.21(1H,in), 4.05(2H,m), 4.00-3.40(5H,m), 2.30(1H,m), I .90(1H,m), 1.57(1 H,m), 1 .43(1H,m), 1.1 8(1H,m), 0.98-0.90(6H,in) ppm.

FAB HRMS exact mass calc'd for C36H41N604 621.3 18929(MHi+), found 621.3 17455.

Anal. calc'd for C39H48N6045 0.83H20 and 3.76TFA C, 49.11; H, 304.30 N, 7.90. Found: C, 49.11; H, 4.30; N, 8.35.

WO 96/10034 WO 9610034PCT/US95/12224 -160- EXAMPLE 46 Preparation of N- [2(S)-(I1-(4-cyanobenzyl)- 1H-imidazol-5 yl] acetylamino)-3 (S )-methylpentyl] -N -naphthylmethyl)glycylhomoserine The title compound was prepared as the lithium salt using the procedures described in Example 36 and the lactone prepared in Example FAB HRMS exact mass calc'd for C36H43N605 639.329494(MH+), found 639.328919.

EXAMPLE 47 Preparation of 1-(4-cyanobenzyl)- 1H-imidazol-5 yl] acetylamino)-3 (S )-methylpentyl] 1 -naphthylmethyl)glycyl-proline methyl ester The title compound was prepared as the trifluoroacetate salt using the procedures described in Example 34 Step H using L- proline methyl ester hydrochloride.

IH NMR(CD3OD, 400 MHz) 8 8.80(lH, 8.38-8.28(1H,m), 8.02(l1H, d, J=8.4Hz), 7.960lH, d, J=8.4Hz), 7.80-7.65(3H,m), 7.60- 7.30(6H,m), 5 .55-5.40(2H,m), 5.00(1 4.40-4.00(3H,m),3 .70(3H,m), 253.70-3.00(8H,m), 2.25-2.05(1H,m), 2.OO(2H,m), 1.95-1 .50(2H,m), 1.40( 1H,m), 1.1 7( 1H,m), 1 .00-0.80(6H,m)ppm.

FAB HRMS exact mass calc'd for C38H45N604 649.350229(MH+), found 649.35048 1.

Anal. calc'd for C38H44N604 1.75H20 and 3.OOTFA C, 51.69; H, 4.98N, 8.22. Found: C, 51.69; H, 4.79; N, 8.58.

WO 96/10034 WO 9610034PCTf[JS95/12224 161 EXAMPLE 48 Preparation of 1 -(4-cyanobenzyl)- 1 yl] acetylamino)-3 (S )-methylpentyl] 1 -naphthylmethyl)glycylp1roline The title compound was prepared as the trifluoroacetate salt using the procedures described in Example 36 and the methyl ester prepared in Example 47.

1 H NMR(CD3OD, 400 MHz) 8 8.85(0.8H, in), 8.80(O.2H,m), 8.32(l1H, d, J=8.4Hz), 8.04-7.90(2H,m), 7.80-7.64(3H,m), 7.60-7.28(6H,m),5.54- 5.36(2H,m), 4.40-4.00(2H,m), 3.85-3.O0(1OH,m), 2.20( 1H,m), 2.10- 1 .80(3H,m), 1.57(1 1.42(1 1.1 7( 1H,m), 0.98-0.82(6H,m) ppm.

FAB HRMS exact mass calc'd for C3'7H43N604 635.334579(MH+), found 635.332994.

Anal. calc'd for C3'7H42N604 0.80H20 and 2.8OTFA C, 52.83; H, 4.83N, 8.68. Found: C, 52.81; H, 4.81; N, 8.88.

EXAMPLE 49 Preparation of ([1I -(4-cyanobenzyl)- 1 yl] acetylamino)-3 (S )-methylpentyl] 1 -naphthylmethyl)glycyl-Dpro line methyl ester The title compound was prepared as the trifluoroacetate salt using the procedures described in Example 34 Step H using D- proline methyl ester hydrochloride.

H NMR(CD3OD, 400 MHz) 8 8.92(0.3H, 8.88(0.7H,s),8.08- 7.90(2H,m), 7.85-7.30(1 OH,m), 5 .46(2H,m), 5.00-4.40(1 H,m), 4.35(IH,m), 4.1 0-4.00(2H,m), 3.60(3H,s), 3.80-3 .20(8H,m), 2.20(1H,m), 2.00-1 .80(3H,m), 1.60(1 1.45(1 1.1 5(1H,m), 1.00- 0.80(6H,m)ppm.

WO 96/10034 PTU9/22 PCTIUS95/12224 -162- FAB HRMS exact mass calc'd for C38H45N604 649.350229(M1-+), found 649.35127 1.

Anal. calc'd for C38H44N604 2.20H20 and 3.OOTFA C, 51.28; H, 5.03N, 8.16. Found: C, 51.27; H, 4.71 N, 8.39.

EXAMPLE Preparation of N- [2(8 1-(4-cyanobenzyl)- yl] acetylamino)-3 (S )-methylpentyl] 1 -naphthylmethyl)glycylproline The title compound was prepared as the trifluoroacetate salt using the procedures described in Example 36 and the methyl ester prepared in Example 49.

1 H NMR(CD3OD, 400 MHz) 8 8.80-8.70(1H, in), 8.30-8.15(1H, in), 8.00-7.20(11 5.40(0.4H,s), 5.35(1 5.00-4.60(1H,m), 4.24(1 3.97(1 3.70-3.00(1 OH,m), 2.20-2.00(1 2.00- 1 .60(2H,m), 1 .50(1H,m), 1 .34(1H,m), 1 .08(1H,m), 1 .90-0.70(6H,m)ppm.

FAB HRMS exact mass calc'd for C37H43N604 635.334579(MH+), 635.333794.

calc'd for C37H42N604 0.50H20 and 2.55TFA C, 54.11 H, 4.91N, 8.99. Found: C, 54.11; H, 4.93; N, 8.95.

EXAMPLE 51 Preparation of N- 1-(4-cyanobenzyl)- 1H-imidazol-5 yl] acetylamino)-3 (S)-methylpentyl] 1 -naphthylmethyl)glycyl-Lp2ipecolinic acid The title compound was prepared as the trifluroacetate salt using the procedures described in Example 34 Step H using L-pipecolinic acid 1 H NMR(CD3OD, 400 MHz) 8 8.96-8.84(1H,m),8.36(1H,m), 8.10- 7.20(11 5 .45 5.20-4.40(1 4.40-4.00(3H,m), 4.00- 3 .00(9H,m), 2.20(2H,m), 1.80-1 .05(6H,m), 1 .00-0.80(6H,m)ppm.

WO 96/10034 WO 9610034PCTIUS95/12224 163 FAB HRMS exact mass calc'd for C38H45N604 649.350229(Mi-+), found 649.352801.

Anal. calc'd for C38H44N604 2.75TFA C, 54.29; H, 4.90N, 8.73.

Found: C, 54.22; H, 4.88 N, 8.89.

EXAMPLE 52 Preparation of 1-(4-carbomethoxybenzyl)- yl] acetylamino)-3 (S )-methylpentyl] 1 -naphthylmethyl)glycylmethionine methyl ester The title compound -as the trifluoroacetate salt- was isolated as a minor component of the reaction mixture prepared in Example 9 Step A.

H NMR(CD3OD, 400 MHz) 8 8.93(1H,s),8.30(1H,m), 8.05- 7.35(9Hjm), 7.31 (2H,d, J=8.2Hz), 5.48(2H,m), 5.00-4.40(1 H,m), 4.39( 1H,s), 4.05(1H,m), 3.90(3H,m), 4.0O-3.30(7H,m), 3.67(3H,m), 3. 17( 1H,m), 2.20-2.1 0(2H,m), 1 .98(3H,s), 1.75(1 1 .55( 1H,m), 1.40(1H,m), 1.1 1 .00-0.80(6H,m)ppm.

Anal. calc'd for C39H49N506S 0. 15H20, 2.L5TFA C, 53.96; H, 5.38; N, 7.27. Found: C, 53.96; H, 5.39 N, 7.59.

EXAMPLE 53 Preparation of 1-(4-carbomethoxybenzyl)- yl] acetylamino)-3 (S )-methylpentyl] 1 -naphthylmethyl)glycyl methionine The title compound was prepared as the trifluoroacetate salt using the procedures described in Example 36 and the methyl ester prepared in Example 52.

IH NMR(CD3OD, 400 MHz) 5 8.80(1H, in), 8.20(1H, mn), 8.00- 7.20(l1 5.40(2H,m), 5.00-4.60(1 4.3 2(1 4.05 (1 H,m), 3.80(3H,s), 3.70-3.00(7H,m), 2.40-2.00(3H,m), 1 .88(3H,s), 1 .75(1H,m), 1 .55( 1H,m), 1 .30( 1H,m), 1 .05(1H,m), 1 .0O-0.65(6H,m)ppm.

WO 96/10034 WO 9610034PCTIUS95/12224 -164- Anal. calc'd for C38H47N506S 0.15H20 and 2.85TFA C, 50.98 H, 4.91iN, 6.80. Found: C, 50.98; H, 4.89; N, 7.19.

EXAMPLE 54 Preparation of 1 -(2-naphthylmethyl)- 1 isoleucinyl- p2henvialaninyl-methionine methyl ester The title compound was prepared as the trifluoroacetate salt using the procedures described in Example 34 Step H and isoleucinylphenylalaninyl-methionine methyl ester hydrochloride.

I H NMR(CD3OD, 400 MHz) 6 8.89(IH, 8.39(1H,d, 1=8.0Hz), 8.1 9(2H,m), 8.00-7.90(3H,m), 7.67( 1H,s), 7.60-7.52(2H,m), 7.48(1 H,s), 7.36(1 H,d,J=8.OHz), 7.30-7.1 0(5H,m), 5.56( LH,d,J= 15.0Hz), 5.49(1 H,dJ= 15.0Hz), 4.69(1 4.52(1H,m), 4.20-4. 14( 1H,m), 3.54(1 H,d, J=1 8.0Hz), 3.66(1 H,d,J=1 8.0Hz), 3.66(3H,s), 3.14(l1H,dd,J= 15.0 and 6.0Hz), 2.91 (1 H,dd, J= 15.0 and 9.0Hz), 2.56- 2.1 6(2H,m), 2.06(1 2.04(3H,s), 1 .89( 1H,m), 1 .73(1H,m), 1.40(1 1.08(1 0.90-0.80(6H,m)ppm.

FAB HRMS exact mass calc'd for C37H46N505S 672.32 1967(MH+), found 672.321794.

Anal. calc'd for C37H45N505S 0. 10H20 and 2.3OTFA C, 57.87; H, 5.70N, 8.52. Found: C, 57.88; H, 5.61 N, 8.49.

EXAMPLE Preparation of 1 -(2-naphthylmethyl)- 1H-imidazol-5 -ylacetyl-isoleucinylphenylaianinyl-methionine The title compound was prepared as the trifluoroacetate salt using the procedures described in Example 36 and the methyl ester prepared in Example 54.

WO 96/10034 PCTIUS95/12224 165 1H NMR(CD30D, 400 MHz) 6 8.80(1H, 8.15(1H,d, 7.93(1H,d,J=8.OHz), 7.89(2H,m), 7.74(1H,m), 7.58-7.52(2H,m), 7.44(1H,s), 7.35(1H,dd, J=10.0 and 3Hz), 7.30-7.10(5H,m), 5.54(1lH,d,J=15.0Hz), 5.47(1H,d, J=15.OHz), 4.70(1H,m), 4.50(1H,m), 4.15(1H,m), 3.51(1H,d, J=17.0Hz), 3.66(1H,d,J=17.OHz), 3.18(1H,dd,J=15.0 and 2.92(1H,dd, J=15.0 and 9.0Hz), 2.56-2.40(2H,m), 2.10(1H,m), 2.05(3H,s), 1.92(1H,m), 1.73(1H,m), 1.40(1H,m), 1.08(1H,m), 0.90- 0.80(6H,m)ppm.

FAB HRMS exact mass calc'd for C36H44N505S 658.305448(MH+), found 658.306317.

EXAMPLE 56 In vitro inhibition of ras famesvl transferase Assays offarnesyl-protein transferase. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and RAS-CAIL) were prepared as described by Schaber et al., J. Biol. Chem. 265:14701-14704 (1990), Pompliano, et al., Biochemistry 31:3800 (1992) and Gibbs et al., PNAS U.S.A. 86:6630-6634 (1989), respectively. Bovine FPTase was assayed in a volume of 100 pl containing 100 mM N-(2-hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgC12, mM dithiothreitol (DTT), 100 mM 3 H]-famesyl diphosphate 3

H]-FPP;

740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and gg/ml FPTase at 31 0 C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol. Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB P-plate counter. The assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the 3 H]-FPP was utilized during the reaction period.

Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay. Percentage inhibition is measured by the amount of incorporation of famesyl in the presence of WO 96/10034 PCT/US95/12224 -166the test compound when compared to the amount of incorporation in the absence of the test compound.

Human FPTase was prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1 polyethylene glycol 20,000, 10 tM ZnCl2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 pl of 30% trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.

The compounds of the instant invention were tested for inhibitory activity against human FPTase by the assay described above and were found to have IC50 of 10 gM.

EXAMPLE 57 In vivo ras famesylation assay The cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21. The assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is After 4 hours at 37 0

C,

the cells are labelled in 3 ml methionine-free DMEM supple-meted with regular DMEM, 2% fetal bovine serum and 400 mCi[ 3 5 S]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml mM PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45 min. Aliquots of lysates containing equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et al., J. Virol. 43:294-304, (1982)).

Following a 2 hour antibody incubation at 4 0 C, 200 ml of a suspension of protein A-Sepharose coated with rabbit anti rat IgG is WO 96/10034 PCT/US95/12224 -167added for 45 min. The immunoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1% Triton X-100.0.5% deoxycholate/0.1%/SDS/0.1 M NaCI) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to farnesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of famesyl transfer to protein.

EXAMPLE 58 In vivo growth inhibition assay To determine the biological consequences of FPTase inhibition, the effect of the compounds of the instant invention on the anchorage-independent growth of Ratl cells transformed with either a vras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Raf and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation.

Ratl cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 10 4 cells per plate (35 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer Both layers contain 0.1% methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay). The cells are fed twice weekly with 0.5 ml of medium A containing 0.1 methanol or the concentration of the instant compound. Photomicrographs are taken 16 days after the cultures were seeded and comparisons are made.

Claims (7)

170- CN, (R 1 O)2N-C(NR' 0 RIOC(O)-, RIOOC(O)-, N3, -N(R 1 0 R 1 1 C(O)NRIO-, -S02N(R' 0 )2, R II 1 S02NR 10 and C 1-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl; or and R5b are combined to form (CH2)s wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(CORIO)-; or or R5b are combined with R 14 to form a ring such that R 5 a R 5 b N is H WO 96/10034 WO 9610034PCTfUS95/12224 171 x-Y is a) sN 0 R 7b b) C) (Y)m d)S H e) .js 1 Ior H f) -0H 2 -CH 2 R7a is selected from a) hydrogen, b) unsubstittited or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C I -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, WO 96/10034 PCT/US95/12224 -172- c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R1 0 R IS()m-, R10OC(O)NR10-, CN, N02, R 10 2N-C(NR 10 RIOC(O)-, RIOOC(O)-, N3, -N(R 10 or R 1 0OC(O)NR10-, and c) Ci -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 R 1 1 S(O)m-, RIOC(O)NH-, CN, H2N-C(NH)-, RIOC(O)-, RIOOC(O)-, N3, -N(R 10 or RI 1 0C(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R1 0 0-, RI R 0 IOC(O)NR 10 CN, N02, (R10)2N- WO 96/10034 PCT/US95/12224

173- C(NR 10 R10C(O)-, R 10 N3, -N(R 10 or R 1OC(O)NR 10 and c) C -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R100-, R11S(O)m-, RIOC(O)NR10-, CN, (R 10 )2N-C(NR 10 R1OOC(O)-, N3, -N(R 10 or R11OC(O)NR10-; is independently selected from hydrogen, C -C6 alkyl and aryl; R 1 1 is independently selected from Cl-C6 alkyl and aryl; R 12 is independently selected from hydrogen and C1-C6 alkyl; R 14 is independently selected from hydrogen,C1-C6 alkyl and benzyl; R 15 is independently selected from hydrogen and C1-C6 alkyl; A1 and A 2 are independently selected from: a bond, -CH=CH-, O, -N(R -C(O)NR10-, -S(0)2N(RO 1 -N(R10)S(0)2- or S(O)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl; provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A is a bond, n is 0 and A 2 is S(O)m or a bond; W is a heterocycle; WO 96/10034 WO 9610034PCIUS95/12224 -174- Z is independently H2 or 0; m isO0, 1 or 2; n is 0, 1,2, 3or 4; pis 0,l1,2,3 or4; r is 0 to 5, provided that r is 0 when V is hydrogen; sis 4 or5; and t is 3, 4or or a pharmaceutically acceptable salt thereof. 2. A prodrug of a compound of Claim I having the form-ula 11: (R 8 )r R 9 Z R 2 b Z R 5 a R 5 b R 3 R 4 0 wherein: RI1 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 100-, R I 1 S R IOC(0)NR 10-, CN, N02, (R 10)2N-C(NR R I Ri I N3, 102,or R I I0C(0)NR c) C I C6 alkyl. unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 100.., R I I 1 1 S R I C(O)NR 10-, CN, (R'I 0 )2N-C(NR R IOC(0)-, R I N3, -N(R 10 or R I I0C(0)NR R2a and R2b are independently selected from: a) a side chain of a naturally occurring amino acid, WO 96/10034 PCTIUS95/12224 -175- b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 R 1 1 R 10 C(O)NR 1 0 CN, (R IO)2N-C(NR10)-, R 1 R 100C(O)-, N3, -N(R 1 0)2, R 1 10C(O)NR 1 0 and C1-C20 alkyl, and d) CI -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO0 cycloalkyl; or R2a and R2b are combined to form (CH2)s R3 and R 4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R 10 N02, R 1 0 R 1 1 R 10 C(O)NRIO-, CN, (RIO)2N-C(NRIO)-, R1OC(O)-, RIOOC(O)-, N3, -N(R 10 R110 C(O)NR 1 0 and C1-C20 alkyl, and d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- cycloalkyl; or R 3 and R 4 are combined to form (CH2)s WO 96/10034 PCTIUS95/12224 -176- and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R 10 N02, R 10 R11S(O)m-, RIOC(O)NR 10 CN, (R10)2N-C(NR10)-, R10C(O)-, R1OOC(O)-, N3, -N(R 10)2, R1OC(O)NR 10 -SO2N(R 10 )2, R 1 1S 2NR 10 -and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- cycloalkyl; or and R5b are combined to form (CH2)s wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(COR0)- or or R5b are combined with R 14 to form a ring such that Rsa R 5 b N is H 2 t R 14 R R 6 is a) substituted or unsubstituted C1-C8 alkyl, wherein the substituent on the alkyl is selected from: 1) aryl, WO 96/10034 WO 9610034PCT1US95/12224 177 2) heterocycle, 3) -N(R 1 1 )2, 4) -OR 10 or b) ol 0) R 13 x-Y is 10RI7 a)N 0 R 7 b b) C) d)) H e) o H f) -0H 2 -CH 2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, WO 96/10034 PCT/US95/12224 -178- d) unsubstituted or substituted cycloalkyl, and e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R1 0 R 1 1 S(O)m-, RIOC(O)NR 10 CN, N02, R 10 2N-C(NR 10 R 1 R10OC(O)-, N3, -N(R 10 or R 1 1 OC(O)NR 10 and c) C -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 R 1 1 S(O)m-, WO 96/10034 WO 9610034PCTIUS95/12224 -179- RIOC(O)NII-, CN, H2N-C(M-I)-, RIOC(O)-, R IOOC(O)-, N3, -N(R 1 0 or R I I OC(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 100., RI IS(0)m-, RIOC(O)NRIO-, CN, N02, (R 1 0 )2N- C(NRIO)-, RIOC(O)-, RIO0C(O)-, N3, -N(R' 0 or R I IOC(0)NR 10-, and C) ClI -C6 alkyl unsubstituted or substituted by peffluoroalkyl, F, Cl, Br, R 1 0 R I 1 S R I OC(0)NR CN, (R I 0 )2N-C(NR 1 R I OC(0)-, R I N3, -N(R 10)2, or R I IOC(0)NR R 10 is independently selected from hydrogen, C I -C6 alkyl and aryl; RI I is independently selected from C I -C6 alkyl and aryl; R 12 is independently selected from hydrogen and C I -C6 alkyl; R 1 3 is independently selected from C1I-C6 alkyl; R 1 4 is independently selected from hydrogen,C 1 -C6 alkyl and benzyl; R 1 5 is independently selected from hydrogen and CI -C6 alkyl; A I and A 2 are independently selected from: a bond, -CH=CH-, -NRl -S(0)2N(Rl -N(Rl 0 or S (O)m; V is selected from: a) hydrogen, b) heterocycle, WO 96/10034 PCTIUS95/12224 -180- c) aryl, d) C1-C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl; provided that V is not hydrogen if A is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m or a bond; W is a heterocycle; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; pis 0,1,2,3or4; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 4 or 5; and tis 3, 4 or a pharmaceutically acceptable salt thereof. 3. A compound which inhibits Ras famesyl- transferase having the formula III: HOCH 2 (CH 2 )q (R 8 )r R 9 Z R 2a R 2 b Z I I Y OH V A'(CR'2)nA2(CR2) n W (CR 1 2 X R 3 R 4 O wherein: Ri is independently selected from: a) hydrogen, Wo 96/10034 WO 9610034PCT1US95112224 181 b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 10 R11S R I OC(0)NR 10-, CN, N02, (R 1 %)2N-C(NRl R I R I OOC(O)-, N3, -N(IO2,or RI IOC(0)NRIO-, c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 100.., R I S R I C(0)NR 10 CN, (R I O2N-C(NR'1 0 RIOC(0)-, RIO0C(0)-, N3, -N(R 1 0 or R 1 IIOC(0)NR10-; R2a and R2b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C I -C20 alkyl, C2-C20 alkenyl, C3-CIO cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 R I R I C(0)NR 1 0 CN, (R '(b2N-C(NR R I R I OOC(0)-, N3, -N(R 10 R I IOC(0)NR 1 0- and ClI-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; or R2a and R2b are combined to form (CH2)s R 3 and R 4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino aqcid which is: i) methionine sulfoxide, or ii) methionine sulfone, and WO 96/10034 WO 9610034PCTfUS95/12224 -182- c) substituted or unsubstituted C I -C20 alkyl, C2-C20 alkenyl, C3-ClO cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RIO)2, N02, RIO0-, RI IS(O)m-, RIOC(O)NRIO-, CN, (R 10 )2N.-C(NR 10 R I R IOOC(O)-, N3, -N(R 1 0 RIIOC(O)NRIO- and Cl-C20)alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; or R3 and R4 are combined to form -(CH2)s x-y is Ra)7 0 b) C) (Y)m H e) or f) -0H 2 -0H 2 WO 96/10034 PCT/US95/12224

183- R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 R 1 1 S(O)m-, RIOC(O)NR 10 CN, N02, R 0 2N-C(NR WO 96/10034PC2U9124 PCr/US95/12224

184- R IOC(O)-, R IOOC(O)-, N3, -N(R 10 or R I I0C(O)NR 10 and c) C 1 -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, B r, R 1 0 R II RIOC(O)NH-, CN, H2N-C(NI-)-, RlOC(O)-, R I N3, -N(R'1O)2, or R I IOC(O)N--; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 0-, R I IS(O)m-, R IOC(O)NR 1 CN, N02, (R I 0 )2N- C(NRIO)-, RIOC(O)-, RIOOC(O)-, N3, -N(R 1 0 or R I IOC(O)NR 10-, and c) C I -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 100-, R I IS(O)m-, R I OC(O)NR 1 CN, (R 1 0Q2N-C(NR R I OC(O)-, R IOOC(O)-, N3, -N(R 1 0 or R I IOC(O)NR R 10 is independently selected from hydrogen, C I -C6 alkyl and aryl; Ri I is independently selected from C I -C6 alkyl and aryl; R 1 2 is independently selected from hydrogen and C I -C6 alkyl; R1 4 is independently selected from hydrogen,C 1 -C6 alkyl and benzyl; AlI and A 2 are independently selected from: a bond, -CH=CH-, -S(0)2N(RI -N(Rl 0 or S(O)m; V is selected from: a) hydrogen, WO 96/10034 PCT/US95/12224 -185- b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl; provided that V is not hydrogen if A is S(O)m and V is not hydrogen if A is a bond, n is 0 and A 2 is S(O)m or a bond; W is a heterocycle; Z is independently H2 or O; mis 0, 1 or 2; nis 0,1,2, 3 or4; pis 0, 1,2,3 or4; q is 0, 1 or 2; r is 0 to 5, provided that r is 0 when V is hydrogen; and s is 4 or or a pharmaceutically acceptable salt thereof. 4. A prodrug of a compound of Claim 3 of the formula IV: (R 8 )r 9 R 2 a R 2 b Z V-ACRnA2( W (CR 1 2 )p N X N R 3 R 4 IV wherein: R 1 is independently selected from: WO 96/10034 WO 9610034PCTIUS95/12224

186- a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 1 0 RI IS R I C(0)NR 10 CN, N02, (RIO)2N-C(NRIO)-, RIOC(0)-, RIO0C(0)-, N3, -N(R 10 or R' IIOC(0)NR c) C 1 -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 1 00.., RI IS(0)m-, RIOC(0)NRIO-, CN, (RIO)2N-C(NR' 0 R I R IOOC(0)-, N3, -N(R 10 or R I IOC(O)NR 1 0-; R2a and R2b are independently selected from: a) a side chain of a naturally occurring ammno acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C I -C20 alkyl, C2-C20 alkenyl, C3 -C 10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 1 0 R' IIS(0)m-, R IOC(0)NR 1 0 CN, (R 1 0 )2N-C(NRIO)-, RIOC(0)-, RIO0C(0)-, N3, -N(R 1 0 RIIOC(0)NRIO- and C1-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; or R2a and R2b are combined to form (CH2)s R3 and R 4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or WO 96/10034 PTU9/22 PCT/US95/12224

187- ii) methionine sulfone, and c) substituted or unsubstituted C I -C20 alkyl, C2-C20 alkenyl, C3-C1O cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R 10 N02, R 1 0 R I 1 R I C(O)NR 1 0 CN, (R I )2N-C(NR 10 R IOC(O)-, R IOOC(O)-, N3, -N(R 10 R I IOC(O)NR 10 and C1I-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; or R 3 and R 4 are combined to form -(CH2)s X-Y is 15RI7 a) Ns 0 R 7 b b) N (Y)m d) S H e) -s o H f) -0H 2 -CH 2 WO 96/10034 PCT/US95/12224 -188- R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) CI-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R 1 S(O)m-, R I O C(O)NR 10 CN, N02, R 10 2N-C(NR10)-, WO 96/10034 WO 9610034PCTIUS95/12224 -189- R IOC(O)-, R IOOC(O)-, N3, -N(R 1 0)2, or R IIOC(O)NR 1 and C) C I -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, peffluoroalkyl, F, Cl, Br, RIO0-, RI IS(O)m-, RIOC(O)NR-, CN, H2N-C(NH)-, RlOC(O)-, R IOOC(O)-, N3, -N(R 10 or R I IOC(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyi, F, Cl, Br, R 10 0-, R I IS(O)m-, R I C(O)NR 10 CN, N02, (R 10 )2N- C(NR R IOC(O)-, R IOOC(O)-, N3, -N(R 10 or R I IOC(O)NR 10-, and c) C I -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 R IIS R I OC(O)NR 10-, CN, (Ri1 0 )2N-C(NR 1 R I OC(O)-, R IOOC(O)-, N3, -N(R 10 or R' IIOC(O)NR R 10 is independently selected from hydrogen, ClI -C6 alkyl and aryl; R 1 I s independently selected from C I -C6 alkyl and aryl; R 1 2 is independently selected from hydrogen and ClI -C6 alkyl; R 1 4 is independently selected from hydrogen,C 1 -C6 alkyl and benzyi; AlI and A 2 are independently selected from: a bond, -CH=CH-, -S (0)2N(RIO0>, -N(RI 0)S(0)2. or S(O)m; V is selected from: a) hydrogen, I~ -190- b) heterocycle, c) aryl, d) C -C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl; provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m or a bond; W is a heterocycle; Z is independently H2 or 0; m is 0, 1 or 2; n is 0, 1, 2,3 or 4; pis 0, 1,2,3 or4; q is 0, 1 or 2; r is 0 to 5, provided that r is 0 when V is hydrogen; and s is 4 or or a pharmaceutically acceptable salt thereof. 5. A compound having the formula I: 25 (R)r R9 Z R 2a R 2 b Z R 5 a R 5 b I I Y 01 V A (CR' 2 n A 2 (CR 2 )n W (CR 2 )p 12 X Y a. R'( R 3 R 4 0 S wherein: RI is independently selected from: a) hydrogen, WO 96/10034 PCT/US95/12224 -191 b) aryl, heterocyclic, cycloalkyl, R100-, -N(R10)2 or alkenyl, c) C -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, R 10 or -N(R10)2; R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine; b) substituted or unsubstituted Cl -C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 R1 R 10 C(O)NR10-, CN, (R 10 )2N-C(NR 10 R10C(O)-, R OOC(O)-, N3, -N(R 10 R1 1 OC(O)NRO1- and C1-C20 alkyl, and c) C -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl; and R2b is selected from hydrogen and C1-C6 alkyl; or R2a and R2b are combined to form (CH2)s R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 R 1 R 10 C(O)NR10-, CN, WO 96/10034 PCTIUS95/12224 -192- (R1O)2N-C(NR 10 R1OC(O)-, R OOC(O)-, N3, -N(R 10 R11OC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C10 cycloalkyl; is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glutamine, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C -Cl 0 alkyl, C2-Cl 0 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R100-, R 1S(O)m-, R10C(O)NR10-, CN, (R 0 )2N-C(NR 10 R1OC(O)-, R10OC(O)-, N3, -N(R 10 R11OC(O)NRO1-, -SO2N(R10)2, R 1 1 S02NR 10 and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C1O cycloalkyl; is selected from: a) hydrogen, and b) C1-C3 alkyl; or R5a or R5b are combined with R 14 to form a ring such that WO 96/10034 WO 9610034PCTIUS95/12224 -193- R 5 a R 5 b x-Y is R 7 a a)N 0 R 7 b b C) O H d) o H e) -CH 2 -CH 2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted. or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C I -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; WO 96/10034 PCT/US95/12224 -194- wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R8 is selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 10 RIOC(O)NR1O-, CN, WO 96/10034 PTU9122 PCT[US95/12224 195 N02, (RI 0 )2N-C(NR 1 RI RI OOC(0)-, 102,or R I IOC(0)NR 10-, and c) C I -C6 alkyl substituted by C I -C6 perfluoroalkyl, RI RIOC(0)NRIO-, (RIO)2N-C(NR'O)-, R I R IOOC(0)-, -N(R 10 or R I OC(0)NR R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroaikyl, F, Cl, R 10 R I 'S R 1 C(0)NR 10 CN, N02, (Ri 0 )2N-C(NR R I R IOOC(0)-, -N(R 10)2, or R I IOC(0)NR 10-, and C) C I -C6 alkyl unsubstituted or substituted by C I -C6 perfluoroalkyl, F, Ci, R 10 R 1 1 S RIOC(0)NRIO-, CN, (R 1 0 )2N-C(NR R 1 OC(0)-, R IOOC(0)-, -N(Ri10)2, or R I0 C(0)NRi10-; is independently selected from hydrogen, C1I-C6 alkyl and aryl; R I is independently selected from C I -C6 alkyl and aryl; R 1 2 is independently selected from hydrogen and C I -C6 alkyl; R 1 4 is independently selected from hydrogen and C I -C6 alkyl; Ri1 5 is independently selected from hydrogen and C I -C6 alkyl; A I and A 2 are independently selected from: a bond, -CH=CH-, -S (0)2N(R 1 N(RI O)S(0)2- or S(O)m; V is selected from: -196- a) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, b) aryl, c) C 1-C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and d) C2-C20 alkenyl; provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A is a bond, n is 0 and A 2 is S(O)m or a bond; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, piperidinyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; Z is independently H2 or O; m is 0, 1 or 2; 20 nis 0, 1,2,3 or 4; pis 0, 1,2,3 or4; ris0to2; s is 4 or 5; and t is 3, 4 or 9. io: *or a pharmaceutically acceptable salt thereof. 6. A compound having the formula II: e« *t WO 96/10034 WO 9610034PCT/US95/12224 -197- (R 8 )r R 9 ZR 2 a R 2 b Z R 5 a R 5 b V A 1 (C R' )A 2 (CR 1 N X wherein: N<OR R I is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, R 10 -N(R 1 0 )2 or alkenyl, C) C I -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, R 10 or NR02 R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine; b) substituted or unsubstituted C I -Cl10 alkyl, C2-C alkenyl, C3-ClO0 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 R I IS(O)m-, R I C(O)NR 10-, CN, (RI 0 )2N-C(NR 1 RIOC(O)-, R IOOC(O)-, N3, -N(RiO)2, RI IOC(O)NRIO- and Ci-C20 alkyl, and c) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; and R2b is selected from hydrogen and C I-C6 alkyl; or R2a and R2b) are combined to form- (CH2)s R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid,

198- b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C I-Ci1G alkyl, C2-Cl10 alkenyl, C3-ClO cycloalkyl, aryl or heterocyclic group, wherein the. substituent is selected from F, CI, Br, N02, RIO0-, RI IS(O)m-, RIOC(O)NRIO-, CN, (Ri 0 )2N-C(NR 1 R I R I O0C(O)-, N3, -N(R 10)2, R I I0C(O)NR 1 0- and C I-C20 alkyl, and d) C1I-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl; R5a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glutamine, an oxidized fomof a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C I-Ci10 alkyl, C2-Cl10 alkenyl, C3-ClO cycloalkyl, aryl or heterocyclic group, 25 wherein the substituent is selected from F, Cl, Br, N02, RIO0-, RI IS(O)m-, Rl 0 C(O)NRI'O-, CN, I 0 )2N-C(NR 1 R I R I OOC(O)-, N3, 5* -N(RIO)2, R 1 1 0C(O)NRIO-, -SO2N(RIO)2, RI IS 02NR 1 0 and C I-C20) alkyl, and d) C I-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- Cl1O cycloalkyl; is selected from: WO 96/10034 WO 9610034PCTIUS95/12224 -199- a) hydrogen, and b) C1I-C3 alkyl; or or R5b are combined with R 14 to form a ring such that R 5 a R R14 R 1 R 6 is a) substituted or unsubstituted C I -C8 alkyl, wherein the substituent on the alkyl is selected from: 1) aryl, 2) heterocycle, 3) -N(R 1 1 )2, 4) -OR 10, or b) R 12 0 1 0 13 WO 96/10034 PCTIUS95/12224 -200- X-Y is R7a a) N. 0 R 7 b c) v Oi1 H d) or H e) -CH 2 -CH 2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R7b is selected from a) hydrogen, WO 96/10034 PCT/US95/12224 -201- b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R8 is selected from: a) hydrogen, b) CI-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R100-, R10C(O)NR10-, CN, N02, (R10)2N-C(NR 1 RO1C(O)-, -N(R10)2, or Rl IOC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 0-, RO1C(O)NR10-, (R10)2N-C(NR10)_, R100C(O)-, -N(R 10 or R 110C(O)NR10-; R9 is selected from: a) hydrogen, WO 96/10034 WO 9610034PCT11JS95/12224 -202- b) C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, Cl, RIO0-, RI IS(O)m-, RIOC(O)NRIO-, CN, N02, (Ri 0 )2N-C(NR 1 R 1 R 1 OOC(O)-, 0)2, or R I IOC(O)NR 10-, and C) C I -C6 alkyl unsubstituted or substituted by C I -C6 perfluoroalkyl, F, Cl, R 1 0 R' IIS(O)m-, RIOOC(O)-, -N(R 1 0 or RI IOC(O)NRlO-; R 1 0 is independently selected from hydrogen, C I -C6 alkyl and aryl; R I is independently selected from C I -C6 alkyl and aryl; R 12 is independently selected from hydrogen and ClI -C6 alkyl; R 1 3 is 1, 1-dimethylethyl; R 14 is independently selected from hydrogen and CI -C6 alkyl; R 1 5 is independently selected from hydrogen and C I -C6 alkyl; A and A 2 are independently selected from: a bond, -CH=CH-, -S(O)2N(RIO)-, -N(R 1 0 or S(O)m; V is selected from: a) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, b) aryl, c) C I -C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from 0, S, and N, and d) C2-C20 alkenyl; 203 provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if 1 is a bond, n is 0 and A 2 is S(O)m or a bond; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, piperidinyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; Z is independently H2 or 0; m isO0, 1 or 2; n is 0, 1,2, 3or 4; pis 0, 1,2,3 or4; r is 0Oto 2; s is 4or t is 3, 4 or or a pharmaceutically acceptable salt thereof. 7. A compound having the formula III: HOCH 2 (CH 2 )q (R 8 r R92 b z I OHR V A 1 C( C R CR 1 2 W A N X Y K N O IIIRR12 R 1 4 o wherein: R I is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, R 10 -N(R 1 0 )2 or alkenyl, WO 96/10034 PCT/US95/12224 -204- c) CI -C6 alkyl unsubstituted or substitvtedftlyiyl, heterocyclic, cycloalkyl, alkenyl, R 10 or -N(R10)2; R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine; b) substituted or unsubstituted Ci -CO10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 RI lS(O)m-, R 10 C(O)NR10-, CN, (R IO)2N-C(NR RI0C(0)-, RIOOC(0)-, N3, -N(R 1 0 R 11 0C(O)NR 1 0- and Cl-C20 alkyl, and c) Ci -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- cycloalkyl; and R2b is selected from hydrogen and C1 -C6 alkyl; or R2a and R2b are combined to form (CH2)s R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted CI-C 10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R' 0 R 1 1 R 0 IOC(O)NRIO-, CN, (R 10 )2N-C(NR 10 R 10 R 1 OOC(O)-, N3, -N(R 10 RI IOC(O)NR 10O- and C1-C20 alkyl, and WO 96/10034 PCT/US95/12224 -205- d) C -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- cycloalkyl; X-Y is R7a O a) Y N 0 R 7 b b) \v 1. c) O. H d) or H e) -CH 2 -CH 2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- WO 96/10034 PCTIUJS95/12224 -206- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R8 is selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 10 R10C(O)NR 10 CN, N02, (R 10 )2N-C(NRIO)-, R1OC(O)-, -N(R10)2, or R 1 1 OC(O)NR 10 and WO 96/10034 WO 9610034PCT/US9SI12224 207 C) Ci -C6 alkyl substituted by CI -C6 peffluoroalkyl, RIO0-, RIOC(O)NRIO-, (R 1 0 )2N-C(NRIO)-, RIOC(O)- R IOOC(O)-, -N(R 10)2, or R' IIOC(O)NR R 9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, Cl, R 10 R I IS(O)m-, RIOC(O)NRIO-, CN, N02, (R 10 )2N-C(NR R 1 I R I OOC(O)-, -N(R 1 0)2, or R IIOC(O)NR 1 and c) C 1 -C6 alkyl unsubstituted or substituted by C I -C6 peffluoroalkyl, F, Cl, R 10 R' IIS(O)m-, R IOC(O)NR 1 CN, (R I 0 )2N-C(NR 1 R I OC(O)-, R I -N(R 10 or R I IOC(O)NR 1 0-; R 10 is independently selected from hydrogen, C I -C6 alkyl and aryl; R 1 I is independently selected from C I -C6 alkyl and aryl; R 12 is independently selected from hydrogen and C I -C6 alkyl; R 14 is independently selected from hydrogen and C I -C6 alkyl; A and A 2 are independently selected from: a bond, -CH=CH-, -S (0)2N(R -N(Rl 0)S(0)2- or S(O)m; V is selected from: a) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, b) aryl, -208- c) C 1-C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and d) C2-C20 alkenyl; provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m or a bond; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, piperidinyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; Z is independently H2 or O; m is 1 or 2; n is 0, 1, 2, 3 or 4; pis 0, 1,2,3 or4; q is 0, 1 or 2; ris 0to 2; and 20 s is 4 or or a pharmaceutically acceptable salt thereof. 8. A compound having the formula IV: IV R is independently selected from: Z R 2b V- A1(CR2)nA2(CR2) n W- (CR12)p 12 X N 14 30 R3 R" O IV wherein: R l is independently selected from: WO 96/10034 PCTIUS95/12224 -209- a) hydrogen, b) aryl, heterocyclic, cycloalkyl, R 1 00-, -N(R10)2 or alkenyl, c) C -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, R 10 or -N(R10)2; R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine; b) substituted or unsubstituted CI-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 R 1 S( O R 1 0 C(O)NR 10 CN, (R10)2N-C(NR10)-, RIOC(O)-, R10OC(O)-, N3, -N(R 10 R 1 1 0C(0)NR 10 and Cl-C20 alkyl, and c) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- cycloalkyl; and R2b is selected from hydrogen and C1-C6 alkyl; or R2a and R2b are combined to form (CH2)s R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R1 0 R 1 1 R 10 C(O)NR 10 CN, WO 96/10034 PTU9/22 PCTfUS95/12224 -210- (R'O)2N-C(NR' 0 RIOC(O)-, R IOOC(O)-, N3, -N(R 10 R I IOC(O)NR 1 0- and C1I-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl; x-y is a 0 R 7 b b) C) s0 s H d) -AI S I or H e) -CH 2 -CH 2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C I -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; WO 96/10034 PCT/US95/12224 -211- wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R8 is selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 10 R OC(O)NR10-, CN, WO 96/10034 PTU9/22 PCTfUS95/12224 -212- N02, (Ri O)2N-C(NRl R' RI OOC(O)-, 102,or R I IOC(O)NR 10-, and C) C I -C6 alkyl substituted by C I -C6 perfluoroalkyl, RIOO-, RIOC(O)NRIO-, (RIO)2N-C(NR'O1)-, R IOC(O)-, R IOOC(O)-, -N(R 10)2, or R' IIOC(O)NR R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, Cl, RIO0-, R I IS(O)m-, RIOC(O)NRI 0 CN, N02, (R 1 0 )2N-C(NR 1 R I R I OOC(O)-, -N(R 10)2, or R I I OC(O)NR 10-, and C) C I -C6 alkyl unsubstituted or substituted by C I -C6 perfluoroalkyl, F, Ci, R1 0 0, R I IS(O)m-, R I OC(O)NR CN, (RI 0 )2N-C(NR R I OC(O)-, R IOOC(O)-, -N(R 10)2, or R I IOC(O)NR R 1 0 is independently selected from hydrogen, C I -C6 alkyl and aryl; Ri 1 is independently selected from C I -C6 alkyl and aryl; R 1 2 is independently selected from hydrogen and C I -C6 alkyl; R 14 is independently selected from hydrogen and CI -C6 alkyl; A I and A 2 are independently selected from: a bond, -CH=CH-, -S(O)2N(RIO)-, -N(R 1 0 or S(O)m; V is selected from: a) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, b) aryl, WO 96/10034 PCT/US95/12224 -213- c) C -C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and d) C2-C20 alkenyl; provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if A is a bond, n is 0 and A 2 is S(O)m or a bond; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, piperidinyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; Z is independently H2 or O; mis0, 1 or 2; nis 0,1,2, 3 or4; pis O, 1,2, 3or4; q is 0, 1 or 2; r is 0 to 2; and s is 4 or or a pharmaceutically acceptable salt thereof. 9. A compound which inhibits famesyl-protein transferase which is: N-[2(S)-(1-(Phenylmethyl)-lH-imidazol-4-ylacetyl)amino-3(S)- methylpentyl]-N-1 -naphthylmethyl-glycyl-methionine 1 -(Phenylmethyl)-1 H-imidazol-4-ylacetyl)amino-3 methylpentyl]-N-l-naphthylmethyl-glycyl-methionine methyl ester N-[2(S)-(1-(Phenylmethyl)-1H-imidazol-5-ylacetyl)amino-3(S)- methylpentyl]-N-1 -naphthylmethyl-glycyl-methionine Wo 96/10034 WO 9610034PCTIUS95/12224 -214- N-112(S)-( 1 -(Phenylmethyl)- 1H-imnidazol-5 -ylacetyl)-amino-3(S)- methylpentyl] I -naphthylmethyl-glycyl-methionine methyl ester N- -(4-Nitrophenylmethyl)- 1 H-imidazol-4-ylacetyl)amino-3(S)- methylpentyl] I -naphthylmethyl-glycyl-methionine N- 1 -(4-Nitrophenylmethyl)- 1 H-imidazol-4-ylacetyl)amino-3 (S methylpentyl] I -naplithylmethyl-glycyl-methionine methyl ester N- 1 -(4-Nitrophenyimethyl)- 1 H-imidazol-5-ylacetyl)amino-3(S)- methylpentyl] I -naphthylmethyl-glycyl-methionine N- 1 -(4-Nitrophenyl-methyl)- 1 H-imnidazoi-5 -yiacetyl)amino-3 methylpentyl]-N-1I -naphthylmethyi-glycyl-methionine methyl ester 1 -(2-Naphthylmethyl)- 1 H-imidazol-5-ylacetyl)amino-3(S)- methylpentyl] I -naphthlethyl-glycyl-methionine 1 -(2-Naphthylmethyl)- 1 H-imidazol-5-ylacetyl)amino-3(S)- methylpentyl] I -naphthylmethyl-giycyl-methionine methyl ester 1 -Naplithyimnethyl)- 1 H-imnidazol-5-ylacetyl)amino-3(S)- methylpentyl] I -naphthylmethyl-glycyl-methionine -Naphthylmethyl)- 1 H-imidazol-5-ylacetyl)amino-3(S)- methylpentyl]-N- 1 -naphthylmethyi-glycyl-methionine methyl ester N- 1 -Famesyl- 1 H-imnidazol-5 -ylacetyl)amino-3 (S)-methylpentyl] N- I -naphthylmethyl-glycyl-methionine N- 1 -Farnesyl -I H-imidazol-5 -ylacetyl)amino-3 (S)-methylpentyl] N- I -naphthylmethyl-glycyl-methionine methyl ester WO 96/10034 PTU9/22 PCTIIJS95/12224 -215- N- 1 -Geranyl- 1 H-imidazol-5 -ylacetyl)amino-3 (S)-methylpentyl]j- N- I -naphthyimethyl-glycyl-methionine N- 1 -Geranyl- 1 H-imidazol-5 -ylacetyl)amino-3 (8)-methylpentyl] N- I -naphthylmethyl-glycyl-methionine methyl ester N- 1 -(4-Pyridyimethyl)- 1 H-imidazol-4-ylacetyl)amino-3(S)- methylpentyl] I -naphthylmethyl-glycyl-methionine 1 -(4-Pyridylmethyl)- 1 H-imidazol-4-ylacetyl)amino-3 methylpentyl] I -naphthylmethyl-glycyl-methionine methyl ester N- 1 -(4-Pyridylmethyl)- 1 H-imidazol-5-ylacetyl)amino-(3S)- methylpentyl] I -naphthylmethyl-giycyl-methionine N- 1 -(4-Pyridyimethyl)- 1 H-imidazoi-5-ylacetyl)amino-3(S)- methyipentyl] I -naphthylmethyl-giycyl-methionine methyl ester N- 1 -(4-Cyanophenyimethyl)- 1 H-imidazoi-5-yiacetyl)amino-3(S)- methylpentyl]-N- 1 -naphthylmethyl-giycyl-methionine 1 -(4-Cyanophenylmethyl)- 1 H-imidazol-5-ylacetyl)amino-3 methylpentyl] I -naphthylrmethyl-glycyl-methionine methyl ester N- 1 -(4-Methoxyphenylmnethyl)- 1 3 (S)-methylpentyl] I -naplithylmnethyl-glycyl-methionine N- I -(4-Methoxyphenylmethyl)- 1 3 (S)-methylpentyi] -N-i -naplithylmethyl-glycyl-methionine methyl ester N- 1-(4-Quinolinylmethyl)- 1H-imidazol-5-ylacetyl)amino-3(S)- methylpentyl] I -naphthyhmethyl-glycyl-methionine WO 96/10034 PTU9122 PCTIUS95/12224 -216- N- 1 -(4-Quinolinylmethyl)- I H-imidazol-5-ylacetyl)amnino-3(S methylpentyl]-N- 1 -naplithylmethyl-glycyl-methionine methyl ester -(2-Naphthylmethyl)-1IH-imidazol-5-ylacetyl)amino-3(S)- methyipentyl] I -phenyimethyl -glycyl-methionine 1 -(2-Naphthylmethyl)- 1 H-imidazol-5-ylacetyl)amino-3(S)- methylpentyl] -N-i -phenylmethyl-glycyl-methionine methyl ester N- 1 -(2-Naphthylmethyl)- 1 H-imidazol-5-ylethyl)amino-3(S)- methylpentyl] I -naphthylmnethyl-glycyl-methionine 1 -(2-Naphthylmethyl)- 1 H-imidazol-5-ylethyl)amino-3(S)- methyipentyl] -N-i -naphthylmethyl-glycyl-methionine methyl ester 1-(2-Naphthylmethyl)- 1H-imidazol-5-ylacetyl)amino-3 methyilpentyloxy-3-phenylpropionyl-methionine sulfone methyl ester [N-2(S 1-(2-Naphthylmethyl)- 1H-imidazol -5 -ylacetyl)amino-3 methyllpentyloxy-3 -phenyipropionyl-methionine sulfone 1-(2-Naphthylmethyl)- 1H-imidazol -5-ylethyl)amino-3 methyllpentyloxy-3 -phenyipropionyl-methionine methyl ester [N-2(S I-(2-Naphthylmethyl)- 1H-imidazol-5 -ylethyl)amino-3 methyllpentyloxy-3 -phenyipropionyl-methionine N- 1-Methyl-i H-imidazol -4-ylacetyl)-amino-3 (S)-methylpentyl] 1 -naphthylmethyl)-glycyl-methionine methyl ester N- 1-Methyl-i H-imidazol-4-ylacetyl)-amnino -3 (5)-methylpentyl] 1 -naphthylmethyl)-glycyl-methionmne WO 96/10034 WO 9610034PCTfUS95/12224 -217- N-[2(S -(2-Naplithylmethyl)- 1H-imidazol-5-ylacetyllamino-(3S)- methylpentyl]-N-(cyclopropylmethyl)-glycylmethionine methyl ester N- [(2S)-N-(2-Naphthylmethyl)-l1H-imidazol-5-ylacetyl] amino-(3 methylpentyl]-N-(cyclopropylmethyl)-glycylmethionine N- [(5(R,S)-Methylpyroglutamyl)amino] -3 (S)-methylpentyl] 1- naphthylmethyl)-glycylmethionine methyl ester (5(R,S)-Methylpyroglutamyl)amino] -3 (S)-methylpentyl] 1- naphthylmethyl)-glycylmethionine N-[2(S)-((N-Methylpyroglutamyl)amino)-3(S)-methylpentyl]-N-( 1- naphthylmnethyl)-glycyl-methionine N- [2(S)-((N-Methylpyroglutamyl)-amino)-3 (S )-methylpentyl] 1- naphthylmethyl)-glycyl-methionine methyl ester N-[2(S)-(N-Formnylprolylamino)-3(S)-methylpentyll-N-(1 naphthylmethyl)-glycyl-methionine methyl ester N-12(S)-(N-Formylprolylamino)-3(S)-methylpentyll-N-(I naphthyhnethyl)-glycyl-methionine N- -(4-Nitrobenzyl)pyroglutamyl)-amino)-3 (8)-methylpentyl] N- (1 -naphthylmethyl)-glycyl-methionine methyl ester N- '-(4-Nitrobenzyl)pyroglutamyl)-amrino)-3 (S)-methylpentyl] 1 -naphthylmethyl)-glycyl-methionine N- '-Benzylpyroglutamyl)amino)-3 (S)-methylpentyl] 1- naphthylmethyl)-glycyl-methionine methyl ester WO 96/10034 WO 9610034PCTIUS95/12224 218 N- -Benzylpyroglutamyl)amino)-3 (S)-methylpentyl] -N-(I1 naphthyimethyl)-glycyl-methionine 1 -(4-Fluorophenylmethyl)- 1 H-imidazol-5-ylacetyl)amino-3 methylpentyl] I -naphthyimethyl-glycyl-methionine methyl ester N- -(4-Fluorophenylmethyl)- 1 H-imidazol-5-ylacetyl)amino-3 (S methylpentyll -N-i -naphthylmethyl-glycyl-methionine N- 1 -(4-cyanobenzyl)- I H-imidazol-5-yl] acetylamino)-3(S)- methylpentyl] 1 -naphthylmethyl)glycyl-methionine isopropyl ester N- 1 -(4-cyanobenzyl)- I H-imidazol-5-yl] acetylamino)-3(S)- methylpentyl] 1 -naphthylmnethyl)glycyl-methionine sulfone methyl ester N- I -(4-cyanobenzyl)- 1 H-imidazol-5-yl] acetylamino)-3(S)- methylpentyl] 1 -naphthylmnethyl)glycyl-methionine sulfone N- i -(4-cyanobenzyl)- 1 H-imidazol-5-yl] acetylamino)-3 methylpentyl] 1 -naphthylmethyi)glycyl-(3 -acetylamino)alanine methyl ester N- 1-(4-cyanobenzyl)- 1H-imidazol-5-yl] acetylamino)-3 (S methyipentyl] 1 -naphthylmethyl)glycyl-(3-acetylamino)alanine N- 1 -(4-cyanobenzyl)- 1H-imidazol-5-yl] acetylamino)-3 methylpentyl] 1-naphthylmethyl)glycyl-2(RS) amino-3 -(2 thienyl)propionic acid methyl ester N- I -(4-cyanobenzyl)- 1H-imnidazol-5-yl] acetylamino)-3(S)- methylpentyl] 1 -naphthylmethyl)glycyl-2(RS)-amino-3 -(2 thienyl)propionic acid WO 96/10034 WO 96/10034PCTIUS95/12224 -219- N- 1 -(4-cyanobenzyl)- 1 H-imidazol-5-ylacetylamino)-3(S)- methylpentyl] 1-naphthylmethyl)glycyl-2(S) amino-4-sulfamyl- butanoic acid methyl ester 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] acetylamino)-3(S)- methylpentyl] 1-naphthylmethyl)glycyl-2(S) amino-4-sulfamyl- butanoic acid N- I -(4-cyanobenzyl)- 1H-imidazol-5-yl] acetylamino)-3 methylpentyl]-N-( 1-naphthylmethyl)glycyl-N-methyl methionine methyl ester N- 1 -(4-cyanobenzyl)- 1H-imidazol-5-yl] acetylamino)-3(S)- methylpentyl] 1 -naphthylmethyl)glycyl-N-methyl methionine N- 1-(4-cyanobenzyl)- 1H-imidazol-5-yl] acetylamino)-3(S)- methylpentyll 1-naphthylmnethyl)glycyl-homoserine lactone N- 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] acetylamino)-3(S methylpentyll 1 -naphthylmethyl )glycyl-homoserine N- 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] acetylamino)-3(S methylpentyl]-N-( 1 -naphthylmethyl)glycyl-proline methyl ester N- 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] acetylamino)-3(S)- methylpentyl] 1 -naphthylmethyl)glycyl-proline N- I -(4-cyanobenzyl)- 1 H-imidazol-5 -yll acetylamino)-3 methylpentyl] 1-naphthylmethyl)glycyl-D-proline methyl ester N- 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] acetylamino)-3(S)- methylpentyl] 1 -naphthylmethyl )glycyl-D-proline WO 96/10034 PTU9/22 PCTIUS95/12224 220 N- 1 -(4-cyanobenzyl)- 1H-imidazol-5-yl] acetylamino)-3 methylpentyll 1-naphthylmethyl)glycyl-L- pipecolinic acid N- 1 -(4-carbomethoxybenzyl)- 1 H-imidazol-5-yl] acetylamino)- 3(S)-methylpentyl]-N-( 1-naphthylmethyl)glycyl-methionine methyl ester I -(4-carbomethoxybenzyl)- 1 3 (S)-methylpentyl] 1 -naphthylmethyl)glycyl -methionine 1 -(2-naphthylmethyl)- 1 phenylalaninyl-methionine methyl ester 1 -(2-naphthylmethyl)- 1 H-imidazol -5 -ylacetyl-isoleucinyl phenylalaninyl-methionine or a pharmaceutically acceptable salt thereof. A compound according to Claim 9 which inhibits famnesyl-protein transferase which is: N- 1 -(4-Nitrophenylmethyl)- 1 H-imidazol-5-ylacetyl)amino methylpentyl]-N- I -naphthylmethyl-glycyl-methionine 25N0 H H 0 N N N 0H N OH0 SCH 3 or a pharmaceutically acceptable salt thereof. WO 96/10034 WO 9610034PCT1US95/12224 221 11. A compound according to Claim 9 which inhibits farnesyl-protein transferase which is: L2(S)-N -(4-Nitrophenyl-methyl) -1H-imidazol-5 -ylacetyl)amino- 3 (S)-methylpentyl] -N-i -naphthylmethyl-glycyl-methionine methyl ester N0 2 N N 0 H 0 N OMe -~SCH 3 or a pharmaceutically acceptable salt thereof. 12. A compound according to Claim 9 which inhibits famnesyl-protein transferase which is: N- 1 -(4-Cyanophenylmethyl)- 1 H-imidazol-5-ylacetyl)amino-3(S)- methylpentyl] I -naphthylmethyl-glycyl-methionine WO 96/10034 PTU9122 PCT/US95/12224 222 or a pharmaceutically acceptable salt thereof. 13. A compound according to Claim 9 which inhibits famnesyl-protein transferase which is: 1 -(4-Cyanophenyl-methyl)- IH-imnidazol-5-ylacetyl)amino-3(S)- methylpentyl] -N-i -naphthylmethyl-glycyl-methionine methyl ester <N N 0 H 0 -SCH 3 or a pharmaceutically acceptable salt thereof. 14. A compound according to Claim 9 which inhibits famnesyl-protein transferase which is: N- 1 -(4-Cyanophenyl-methyl)- 1H-imidazol-5-ylacetyl)amino-3(S)- methylpentyl] -N-i -naphthylmethyl -glycyl-methionine isopropyl ester 0 0i-Pr SCH3 WO 96/10034 WO 9610034PCTIUS95/12224 223 or a pharmaceutically acceptable salt thereof. A compound according to Claim 9 which inhibits farnesyl-protein transferase which is: N- 1 -(4-Methoxyphenylmethyl)-l1H-imidazol-5 -ylacetyl)amino- 3 (S)-methylpentyl] 1 -naphthylmethyl-glycyl-methionine N N 0 H 0 N 0H SCH 3 or a pharmaceutically acceptable salt thereof. WO 96/10034 WO 9610034PCTIUS95/12224 224 16. A compound according to Claim 9 which inhibits farnesyl-protein transferase which is: N- I-(4-Methoxyphenyl-methyl)- 1 H-imidazol-5 -ylacetyl)amino- 3 (S)-methylpentyl] -N-i -naphthylmethyl-glycyl-methionine methyl ester OMe H H NN N N_ OMe N 0 0 OCH 3 or a pharmaceutically acceptable salt thereof. 17. A compound according to Claim 9 which inhibits famnesyl-protein transferase which is: -(2-Naphthylmethyl)-1H-imnidazol-5-ylacetyl)amino-3(S)- methylpentyl] I -naphthyhmethyl-glycyl-methionine I H NN N 0 N OH ~SCH 3 WO 96/10034 PTU9122 PCTfUS95/12224 225 or a pharmaceutically acceptable salt thereof. 18. A compound according to Claim 9 which inhibits farnesyl-protein transferase which is: N- 1 -(2-Naphthylphenyl-methyl)- 1H-imidazol-5 -ylacetyl)amino- 3 (S)-methylpentyll I -naphthylmnethyl-glycyl-methionine methyl ester RH H 0 N Oe N 0 SCH 3 or a pharmaceutically acceptable salt thereof. 19. A compound according to Claim 9 which inhibits farnesyl-protein transferase which is: N- -(4-Cyanophenyl-methyl)- 1H-imidazol-5-ylacetyl)amino-3(S methylpentyl] -N-i -naphthylmethyl-glycyl-methionine sulfone methyl ester WO 96/10034 PCT/US95/12224 -226- 0 OMe SS0 2 CH 3 or a pharmaceutically acceptable salt thereof. A compound according to Claim 9 which inhibits farnesyl-protein transferase which is: N-[2(S)-(1-(4-Cyanophenyl-methyl)-1 H-imidazol-5-ylacetyl)amino-3(S)- methylpentyl]-N-l -naphthylmethyl-glycyl-methionine sulfone CN 0 HH N N N N N OH H SO2CH 3 or a pharmaceutically acceptable salt thereof. 21. A compound according to Claim 9 which inhibits farnesyl-protein transferase which is: WO 96/10034 PTU9/22 PCTfUS95/12224 227 N- 1 -(4-Cyanophenyl-methyl)- 1 H-imidazol-5-ylacetyl)amino-3 methylpentyll -N-i -naphthylmethyl-glycyl-(3-acetylamino)alanine methyl ester CN H H 0 N N N Oe N e N 0 0 N or a pharmaceutically acceptable salt thereof. 22. A compound according to Claim 9 which inhibits famnesyl-protein transferase which is: N- I-(4-Cyanophenyl-methyl)- 1H-imidazol-5-ylacetyl)amino-3(S methylpentyl] I -naphthyhmethyl -glycyl-(3 -acetylamino)alanine methyl ester ON HH 0 yN"O N 0 0 N b 0 OH 3 WO 96/10034 PTU9/22 PCTIVS95/12224 228 or a pharmaceutically acceptable salt thereof. 23. A compound according to Claim 9 which inhibits famnesyl-protein transferase which is: N- I -(4-Cyanophenylmethyl)- 1H-imidazol-5-ylacetyl)amino-3(S)- methylpentyl] I -naphthylmnethyl-glycyl-N-methyl-methionine (N N :r0 or a pharmaceutically acceptable salt thereof. 24. A compound according to famnesyl-protein transferase which is: Claim 9 which inhibits N- 1-(4-Cyanophenyl-methyl)- 1H-imidazol-5-ylacetyl)amino-3(S)- methylpentyl] I -naphthylmethyl-glycyl-N-methyl-methionine methyl ester 229 or a pharmaceutically acceptable salt thereof. A compound which inhibits Ras farnesyl-transferase, substantially as hereinbefore described with reference to any one of the Examples. 26. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of any one of claims 1 to 27. A method for inhibiting farnesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 25 or of a composition of claims 26. 28. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to or of a composition of claims 26. 29. The use of a compound of any one of claims 1 to 25 for the manufacture of a medicament for inhibiting farnesylation of Ras protein. S: '30. The use of a compound of any one of claims 1 to 25 for the manufacture of a medicament for treating cancer. 31. A compound of any one of claims 1 to 25 or a composition of claim 26 when used for inhibiting farnesylation of Ras protein. 20 32. A compound of any one of claims 1 to 25 or a composition of claim 26 when used for treating cancer. Dated 24 September, 1998 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON e* [n:\libc]01968:ABN I WO 96/10034 PCTfUS95/12224 -230- 31. A method for inhibiting famesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 26. 32. A method for inhibiting famesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 27. 33. A method for inhibiting famesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 28. 34. A method for inhibiting famesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 29. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 36. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 26. 37. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 27. 38. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 28. WO 96/10034 PCrTUS95/12224 -231- 39. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 29.