CA2251955A1 - A method of treating cancer - Google Patents

Abstract

The present invention relates to a method of treating cancer which comprises administering to a mammalian patient an effective amount of a combination of geranylgeranyl-protein transferase-type I inhibitor and a farnesyl protein transferase inhibitor. The invention further relates to a method of treating cancer which comprises administering to a mammalian patient an effective amount of a combination of a selective geranylgeranyl-protein transferase-type I inhibitor and a selective farnesyl protein transferase inhibitor. The figure shows the autoradiograph of the immunoprecipates from assay set No. 1 of the in vivo prenylation inhibition by a combination by a selective of FPTase inhibitor and a selective geranylgeranyl-protein transferase-type I inhibitor.

Description

CA 022~19~ 1998-10-16 TITLE OF THE INVENTION
A METHOD OF TREATING CANCER

BACKGROUND OF THE ~NVENTION
The present invention relates to a method of treating cancer using a combination of a compound which is a inhibitor of geranylgeranyl-protein transferase-type I and a compound which is a inhibitor of farnesyl-protein transferase. The invention further relates to a method of treating cancer using a combination of a 10 compound which is a selective inhibitor of geranylgeranyl-protein transferase-type I and a compound which is a selective inhibitor of farnesyl-protein transferase.
Prenylation of proteins by intermediates of the isoprenoid biosynthetic pathway represents a new clas~s of post-translational 15 modification (Glomset, J. A., Gelb, M. H., and Farnsworth, C. C.
(1990). Trends Biochem. Sci. 15, 139-142; Maltese, W. A. (1990).
FASEB J. 4, 3319-3328). This modification typically is required for the membrane localization and function of these proteins. Prenylated proteins share characteristic C-terminal sequences including CaaX (C, 20 Cys; a, usually aliphatic amino acid; X, another amino acid), XXCC, or XCXC. Three post-translational proces,sing .step,s have been described for proteins having a C-terminal CaaX sequence: addition of either a 15 carbon (farnesyl) or 20 carbon (geranylgeranyl) isoprenoid to the Cys relsidue, proteolytic cleavage of the last 3 amino acids, and methylation 25 of the new C-terminal carboxylate (Cox, A. D. and Der, C. J. (1992a).
Critical Rev. Oncogene~is 3:365-400; Newman, C. M. H. and Magee, A. I. (1993). Biochim. Bi(~phy~. Acta 1155:79-96). Some proteins may also have a fourth modification: palmitoylation of one or two Cys residues N-terminal to the farnesylated Cys. Proteins terminating with 30 a XXCC or XCXC motif are modified by geranylgeranylation on the Cys residues and do not require an endoproteolytic processing step.
While some m~mm~lian cell protein,s terminating in XCXC are - carboxymethylated, it i,s not clear whether carboxymethylation follows prenylation of protein~s terminating with a XXCC motif (Clarke, S.

CA 022~19~ 1998-10-16 (1992). Annu. Rev. Biochem. 61, 355-3~6). For all of the prenylated proteins, addition of the isoprenoid is the first step and is required for the subsequent steps (Cox, A. D. and Der, C. J. (1992a). Critical Re~.
Oncogenesis 3:365-400; Cox, A. D. and Der, C. J. (1992b) Current 5 Opinion Cell Biol. 4:1008-1016).
Three enzyme~ have been described that catalyze protein prenylation: farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase). These 10 enzymes are found in both yeast and mammalian cell.s (Clarke, 1992;
Schafer, W. R. and Rine, J. (1992) An~lu. Rev. Gen~l. 30:209-237).
FPTase and GGPTase-I are oc/,~ heterodimeric enzymes that share a common oc subunit; the ,B subunits are distinct but share approximately 30% amino acid similarity (Brown, M. S. and Goldstein, J. L. (1993).
15 Nature 366, 14-15; Zhang, F. L., Diehl, R. E., Kohl, N. E., Gibbs, J.
B., Giros, B., Casey, P. J., and Omer, C. A. (1994). J. Biol. Chenn 269, 3175-3180). GGPTase-II has different oc and ~ subunits and complexes with a third component (REP, Rab Escort Protein) that presents the protein substrate to the o~/~ catalytic subunits. Each of these enzymes 20 selectively uses farnesyl diphosphate or geranylgeranyl diphosphate as the isoprenoid donor and selectively recognizes the protein substrate.
FPTase farnesylates CaaX-containing proteins that end with Ser, Met, Cys, Gln or Ala. GGPTase-I geranylgeranylates CaaX-containing proteins that end with Leu or Phe. For FPTase and GGPTase-I, CaaX
25 tetrapeptides comprise the minimum region required for interaction of the protein substrate with the enzyme. GGPTase-II modifies XXCC and XCXC proteins; the interaction between GGPTase-II and its protein substrates is more complex, requiring protein sequences in addition to the C-terminal amino acids for recognition. The enzymological 30 characterization of these three enzymes has demonstrated that it is possible to selectively inhibit one with little inhibitory effect on the others (Moores, S. L., Schaber, M. D., Mosser, S. D., Rands, E., O'Hara, M. B., Garsky, V. M., Marshall, M. S., Pompliano, D. L., CA 022~19~ 1998-10-16 and Gibbs, J. B., J. Biol. Chem., 266:17438 (1991), U.S. Pat. No.
5,470,832).
The characterization of protein prenylation biology and - enzymology has opened new areas for the development of inhibitors 5 which can modify physiological processes. The prenylation reactions have been shown genetically to be essential for the function of a variety of proteins (Clarke, 1992; Cox and Der, 1992a; Gibbs, J. B. (1991).
Cell 65: 1-4; Newman and Magee, 1993; Schafer and Rine, 1992). This requirement often is demonstrated by mutating the CaaX Cys acceptors 10 so that the proteins can no longer be prenylated. The resulting proteins are devoid of their central biological activity. These studies provide a genetic "proof of principle" indicating that inhibitors of prenylation can alter the physiological responses regulated by prenylated proteins.
The Ras protein is part of a .signalling pathway that links 15 cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ra.s 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 20 change. The GTP-bound 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 (D.R.
Lowy and D.M. Willumsen, Ann. Rev. Bio~hem. ~2 :~S5 l -89 l (1993)).
Activation of Ras leads to activation of multiple intracellular signal 25 transduction pathways, including the MAP Kinase pathway and the Rho/Rac pathway (Joneson et al., Science 2 71 :810-~ 12).
Mutated ~as genes are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these gene~s are defective in 30 their GTPase activity and constitutively transmit a growth stimulatory - signal.
The Ras protein is one of several proteins that are known to undergo post-translational modification. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cy.s thiol group CA 022~19~ 1998-10-16 of the Ra.s CAAX box with a farnesyl group (Reiss et al., Cell, 62~ 8 (1990); Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad.
Sci USA, ~7:7541-7545 (1990)).
Ras must be localized to the plasma membrane for both normal and oncogenic functions. At lea.st 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-Aaa1-Aaa2-Xaa"
box (Cy.s is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willum.sen et al., Nature 310:583-SX6 (19~4)). Depend-ing on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transfera~se or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a Cls or C20 isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386 (1992); W.R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237 (1992)). It has been shown that the N-Ras and K-Ras proteins' sequences do not exhibit the absolute substrate specificity for farnesyl-protein transferase that i,s found for the H-Ras C-terminus sequence, which allows N-Ras and K-Ras proteins to be processed bygeranylgeranyl-protein transferase as well (Moores, S. L.
et al., J. Biol. Chem., 266:1743~ (1991) and Jame,s, G. et al., J. Biol.
Chem., 270:6221-6226 (1995)). However, direct inhibition of farnesyl-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.
Other farne~sylated proteins include the Ras-related GTP-binding proteins such a.s RhoB, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol.
Chem. 269, 141~2 (1994) have identified a peroxi~some associated protein Pxf which is also farnesylated. James, et al., have also ,suggested that there are farne~sylated proteins of unknown structure and function in addition to those listed above.

CA 022~19~ 1998-10-16 Protein geranylgeranyltransferase type-I (GGTase-I) transfers a geranylgeranyl group from the prenyl donor geranylgeranyl diphosphate to the cysteine residue of substrate protein.s containing a C-terminal CAAX-motif in which the "X" re,sidue is leucine or phenyl-alanine (Clark, 1992; Newman and Magee, 1993). Known targets of GGTase-I include the gamrna subunits of brain heterotrimeric G proteins and Ras-related small GTP-binding proteins such as RhoA, RhoB, RhoC, CDC42Hs, Racl, Rac2, R-Ras, TC21, RaplA and RaplB
(Newman and Magee, 1993; Cox and Der, 1992a). The proteins RhoA, RhoB, RhoC, Racl, Rac2 and CDC42Hs have roles in the regulation of cell shape (Ridley, A. J. and Hall, A. (1992). Cell 70:3~s9-399; Ridley, A. J., Paterson, H. F., Johnston, C. L., Keikm~nn, D., and Hall, A.
(1992). Cell 70:401-410; Bokoch, G. M. and Der, C. J. (1993). FASEB
J. 7:750-759). Rac and Rap proteins have roles in neutrophil activation (Bokoch and Der, 1993).
Activation of growth factor function and Ra,s function can cause tumor formation. Recently, it was demonstrated that the Rho and Rac proteins transmit intracellular signals initiated by growth factors and by Ras protein (Prendergast, G. C. and Gibbs, J. B. (1993). Adv.
Canc~)~ Res. 62, 19-64; Ridley and Hall, 1992; Ridley et al., 1992).
Specifically, experiment.s demonstrated that the function of Rho and Rac proteins was required by Ras and growth factor,s to change cell shape, a biological parameter indicative of cellular transformation and cancer.
Activated forms of Rho and Rac proteins have also been shown to cau.se cellular transformation in cell culture (Symons, M., Current Opinit)n Biotechnology, 6:668-674 (1995)). Since Rho and Rac proteins require geranylgeranylation for function, an inhibitor of GGPTase-I would block the function,s of these proteins and be u,seful as an anticancer agent.
Inhibitors of farnesyl-protein transferase (FPTase) have been described in two general classes. The first clas~s includes analogls of farnesyl diphosphate (FPP), while the second is related to protein sub,strates (e.g., Ras) for the enzyme. The peptide derived inhibitor,s that have been described are generally cysteine containing molecules that CA 022~19~ 1998-10-16 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 farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. 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)).
M~mm~lian cells express four types of Ra.s proteins (H-, N, K4A-, and K4B-Ras) among which K-Ras4B is the most frequently mutated form of Ras in human cancers. Inhibition of farnesyl-protein transferase has been shown to block the growth of H-ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitor~s of farnesyl-protein transferase selectively block the processing of the H-Ras oncoprotein intracellularly (N.E. 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 farnesyl-protein transferase blocks the growth of H-ras-dependent tumors in nude mice (N.E. Kohl et al., Proc. Natl. Acad. Sci U.S.A., 91:9141-9145 (1994) and induces regression of mamrnary and salivary carcinomas in H-7 as transgenic mice (N.E. Kohl et al., Natu~ e Medicine, 1 :792-797 (1995).
In vivo inhibition of K-Ras4B processing using a non-selective inhibitor of FPTase and GGTase has recently been demon~strated (E.C. Lerner et al., J. Biol. Chemistry 270:26770-26773 (1995)).
Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck & Co., Rahway, NJ) and compactin (Hancock et al., ihid; Casey et al., ihid; Schafer et al., Science 245:379 (19~9)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids includ-ing farnesyl pyrophosphate. Inhibition of farne,syl pyropho~sphate biosynthesis by inhibiting HMG-CoA reductase blocks Ra,s membrane localization in cultured cell,s.
A pharrnaceutically effective combination of geranylgeranyl-protein transferase-type I inhibitor and a farnesyl-CA 022~19~ 1998-10-16 protein transferase inhibitor are used in the pre,sent invention to treat cancer, such as in tumor cells that are le.ss su.sceptable to treatment by one of the selective inhibitors when administered alone.

S SUMMARY OF THE INVENTION
A method of treating cancer is disclosed which is comprised of admini,stering to a mamm~lian patient in need of such treatment an effective amount of a combination of a geranylgeranyl-protein transferase-type I inhibitor and a farnesyl protein transferalse 10 inhibitor. Preferably a selective geranylgeranyl-protein transferase-type I inhibitor and a selective farne,syl protein tran,sfera.se inhibitor are used in such a combination.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1. Autoradiograph of the 13% acrylamide gel chromatography of the immunoprecipitates from A~say Set No. 1.
Assays that are illustrated include in vivo prenylation inhibition by a selective F~PTase inhibitor (Compound 5), a selective geranylgeranyl-20 protein transferase-type I inhibitor (Compound 1) and a non-selective inhibitor (Compound 7). The intensities of the bands corresponding to prenylated and nonprenylated Ras protein,s are compared to determine the percent inhibition of prenyl transfer to protein.

Figure 2. Autoradiograph of the 13% acrylamide gel chromatography of the immunoprecipitates from Assay Set No. 2, which include~s in vivo prenylation inhibition by a combination of a selective FPTase inhibitor (Compound 5) and a selective geranylgeranyl-protein transfera,se-type I inhibitor (Compound 1). The inten,sities of the bands corresponding to prenylated and nonprenylated Ras proteins are compared to determine the percent inhibition of prenyl transfer to protein.

CA 022~19~ 1998-10-16 Figure 3. Autoradiograph of the 13% acrylamide gel chromatography of the immunoprecipitates from Assay Set No.
3, which includes in vivo prenylation inhibition by a consecutive combination of a selective FPTase inhibitor (Compound 3) and a 5 selective geranylgeranyl-protein transferase-type I inhibitor (Compound 1). The intensities of the bands corresponding to prenylated and nonprenylated Ras proteins are compared to determine the percent inhibition of prenyl transfer to protein.

The present invention relates to a method of treating cancer which is comprised of a-lmininstering to a mammalian patient in need of such treatment an effective amount of a combination of a geranylgeranyl-protein transferase-type I inhibitor and a farnesyl-15 protein transferase inhibitor. The present method of treating cancerby simultaneously inhibiting farnesyl-protein transferase and geranylgeranyl-protein transfera,se-type I offers advantages over previously disclosed methods utilizing prenyl-protein transferase inhibitors, in that the inhibitory activity of the instant combination of 20 inhibitors against FPTase and/or GGTase can be varied by formulation depending on the nature of the cancer cells to be treated. In particular, such variable inhibitory potency combinations are useful in treatment of human cancers associated with the K-Ra~s4B and N-Ras mutated form.s of Ras whose processing are not blocked by a potent selective FPTa~se 2~S inhibitor alone. Any compound which inhibits geranylgeranyl-protein transferase-type I and any compound which inllibits farnesyl protein transferase can be used in the in,stant method. Preferably the compounds utilized in the instant combination are a selective geranylgeranyl-protein transferase-type I inhibitor and a selective 30 farnesyl-protein transferase inhibitor.
As used herein the term geranylgeranyl-protein transferase-type I inhibiting compound refers to compounds which antagonize, inhibit or counteract the activity of the gene coding geranylgeranyl-protein transferase-type I or the protein produced in response thereto.

.

CA 022~19~ 1998-10-16 The term farnesyl protein transferase inhibiting compound likewise refers to compounds which antagonize, inhibit or counteract the activity of the gene coding farnesyl-protein transferase or the protein produced in response thereto.
S In general, a geranylgeranyl-protein transferase-type I
inhibitor may be distinquished from a farnesyl-protein transferase inhibitor by having greater inhibitory activity against geranylgeranyl-protein transferase-type I than against farnesyl-protein transferase. In general, a farnesyl-protein transferase inhibitor may be distinc~uished from a geranylgeranyl-protein tran,sferase-type I inhibitor by having greater inhibitory activity against farnesyl-protein transferase than against geranylgeranyl-protein transferase-type I.
The term selective as used herein refers to the inhibitory activity of the particular compound again,st geranylgeranyl-protein transferase-type I activity when compared to the inhibitory activity of the compound against farnesyl-protein transferase activity. A
compound is considered a selective inhibitor of geranylgeranyl-protein transferase-type I, for example, when its in vitro activity, as alsseslsed by the assay described in Example 16, is at least 10 times greater that the in vitro acitivity of the same compound a~ainst farnesyl-protein transferase in that assay. ~ compound is considered a selective inhibitor of farnesyl-protein transferase, for example, when its in vitro farnesyl-protein transferase inhibitory activity, as assessed by the assay described in Example 16, is at least 10 times greater that the in vitro acitivity of the same compound against geranylgeranyl-protein transferase-type I in that assay. Prei'erably, a selective compound exhibits at least 20 times greater activity against one of the enzymatic activities when comparing geranylgeranyl-protein transferase-type I inhibition and farnesyl-protein transferase inhibition. More preferably the selectivity is at least 100 times or more. It is understood that the greater the selectivity of a geranylgeranyl-protein transferase-type I inhibitor or farnesyl-protein transferase inhibitor, the more preferred such a compound is in the instant combination.

CA 022~19~ 1998-10-16 The extent of selectivity of the two inhibitors that comprise the method of the instant invention effects the advantages that the method of treatment claimed herein offers over previously disclosed non-selective inhibitors of prenyl-transferase enzymes. In particular, 5 use of two independent inhibitor components that have complementary, essentially non-overlapping inhibitory activities allows the person utilizing the instant method of treatment to independently and accurately vary the inhibitory activity of the combination without having to synthesize a single drug having a particular GGTa.se-type I/FPTase 10 inhibitory profile.
Cancers which are treatable in accordance with the invention described herein include cancers of the brain, breast, colon, genitourinary tract, lymphatic system,pancreas, rectum, stomach, larynx, liver and lung, and chronic myelogenous Ieukemia. More 15 particularly, such cancers include histiocytic Iymphoma, lung adenocarcinoma, pancreatic carcinoma, colo-rectal carcinoma and small cell lung cancers.
The pharmaceutical composition of this invention may be a(lmini.stered to m~mm~ls, preferably humans, either alone or, 20 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, 25 rectal and topical routes of administration.
For oral use of a chemotherapeutic combination according to this invention, the selected combination or compounds may be administered, for example, in the form of tablets or capsule.s, or as an aqueous solution or suspension. In the case of tablets for oral 30 use, carriers which are commonly 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 su.spensions are required for oral use, the active ingredients are combined with emulsifying and CA 022~19~ 1998-10-16 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 5 buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic.
The combinations of the instant invention may also be co-a-lministered with other well known therapeutic agents that are selected for their particular usefulness against the condition that i~i being treated.
10 For example, the instant combination~s may be useful in combination with other known anti-cancer and cytotoxic agents.
If i~ormulated as a fixed dose, such combination products employ the combinations of this invention within the dosage range described below and the other pharmaceutically active agent(s) within 15 its approved dosage range. Combinations of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a multiple combination formulation is inappropriate.
The present invention also encompasse~; a pharmaceutical 20 composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the combinations of thi,s invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous solution.s comprising compounds of this invention and pharmacolo-25 gically acceptable carrier.s, e.g., saline, at a pH level, e.g., 7.4. Thesolutions may be introduced into a patient's blood-lstream by local bolu.s injection.
When a combination according to thi~s invention is administered into a human subject, the daily dosage will normally be 30 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 a geranylgeranyl-protein transferase-type I inhibitor and d fdrIleSyl-CA 022~19~ 1998-10-16 protein transferase inhibitor are ~lministered to a m~mmal undergoing treatment for cancer. Administration occurs in an amount of each type of inhibitor of between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of S body weight to about 40 mg/kg of body weight per day.
Examples of geranylgeranyl-protein transferase-type I
inhibiting compounds and in particular selective geranylgeranyl-protein transferase-type I inhibiting compounds, have been described in U.S.
Pat. No. 5,470,832 (Merck) and include the following:
H H R Z R~
H2N ~< N 1X-Y J~ N ~f H H
HS ~ R2 0 wherein:
R l and R2 are independently selected from:
a) C2 - C8 alkyl;
b) C2 - C8 alkenyl;
c) C2 - C8 alkynyl;
d) substituted Cl - C~ alkyl;
e) aryl;
f) substituted aryl;
g) heteroaryl;
h) substituted heteroaryl; and i) the side chain of a naturally occurring amino acid;

R3 is selected from alkyl, alkenyl and alkynyl of 1 to 6 carbon atoms, either branched or straight chain, which is unsubstituted or substituted 2~ with a phenyl group;

X-Y is H

a) 'Sss~N~s5s b) ~sSs~o~ss or c) H

H

and Z is H2 or 0;
5 or the pharmaceutically acceptable salts or disulfides thereof.

Examples of farnesyl protein transferase inhibiting compounds and in particular selective farnesyl protein transferase inhibiting compounds include the following:
(a) a compound represented by formula (II-~) through (II- c):

V A1(CR1a2)nA2(CR1a2)n -(W~- (CR1b2)p\ /N\ /

(Il-a) R4 R5 V - A~(CRla2)nA2(CR1a2)n ~W~- (CR 2)p\K,~--Z

(l 8)r /R~ R2 R3 V - A (CR 2)nA2(CR1a2)n ~W¦- (CR1b ) ~ ~
(I ~-c) /~G

wherein with respect to formula (II-a):

V A1(cR1a2)nA2(cR1a2)n (w) (CR1b2)p\ ~\ /

(Il-a) or a pharmaceutically acceptable salt thereof, Rla and Rlb are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, R 10O, R 1 1 S(O)m-~ R10C(O)NR 10, CN, NO2, (R10)2N-c(NRlo)-~ R10C(O)-~ Rl0Oc(o)- N3 -N(R 1~)2, or R 1 1 OC(O)NR 10, c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-Clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, R 1 0O-, R 1 1 S(O)m-~ R 1 0C(O)NR 10, CN, (R 1 0)2N-C(NR 10), R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R10)2, or Rl 1OC(O)-NR10-;

20 R2 and R3 are independently ~selected from: H; unsubstituted or substituted Cl ~ alkyl, unsubstituted or .substituted C2 ~ alkenyl, unsubstituted or substituted C2 ~ alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, WO 97t38664 PCTIUS97/06248 ~NR6R7 or ~oR6 O O
wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsub~tituted or sub~tituted with:
a) CI 4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, 2) C3-6 cycloalkyl, 3) oR6 4) SR6, S(O)R6, S02R6 5) --N R6R7 ~6 6) --N~ R7 --N~ N R 7R7a 8) --0~ NR6R7 O

9) --o~OR6 O
10) ~ NR6R7 O

CA 022~19~ 1998-10-16 11 ) --SO2--NR6R7 12) --N-SO2--R7 13) ~R6 , or o 14) ~r OR6 ; or 5 R2 and R3 are attached to the same C atom and are combined to form -(CH2)U - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

10 R4 and R5 are independently selected from H and CH3;

and any two of R2, R3, R4 and R5 are optionally attached to the same carbon atom;

15 R6, R7 and R7a are independently selected from: H; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, o f) --SO2R1 ~ , or g) N(R 1~)2; or CA 022~19~ 1998-10-16 R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

R~ is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R1 lS(O)m, R10C(O)NR10-~ CN, NO2, R102N-C(NR10)-, R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R 1~)2, or R11OC(O)NR10-, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0O-, R 1 1 S(O)m-R 1 0C(o)NH-, CN, H2N-C(NH)-, R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R 1~)2, or R 1 0OC(o)NH-;

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0O , R 1 1 S(O)m-~ R 1 0C(o)NR 10 , CN, NO2, (R 1 0)2N C (NR 10), R 1 ~C(O)-, R l ~OC(O)-? N3, -N(R 1~)2, or R 1 lOC(O)NR 10 , and c) C I -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, Rl lS(O)m-, R10C(o)NR10-, CN, (R 1 0)2N C(NR 10), R 1 ~C(O)-, R I ~OC(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10;

R10 is independently selected from hydrogen, Cl-c6 alkyl, benzyl and aryl;
Rl 1 is independently selected from Cl-c6 alkyl and aryl;

CA 022~19~ 1998-10-16 Al and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR 10 , -NR 1 ~C(O)-, O, -N(R 10) -S(O)2N(R 10 -N(R10)S(O)2-, or S(O)m;

5 V is selected from:
a) hydrogen, b) heterocycle, c) aryl, d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V i.s not hydrogen if A1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(O)m;
W is a heterocycle;

X is -CH2-, -C(=O)-, or -S(=O)m-;

20 Y is aryl, heterocycle, unsubstituted or substituted with one or more of:
I ) Cl 4 alkyl, unsubstituted or substituted with:
a) C 1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR6, or g) -C(o)NR6R7, 2) aryl or heterocycle, 3 ) halogen, 4) oR6, 5) NR6R7, 6) CN, .. . ..

7) NO2, 8) CF3;

9) -S(O)mR6, 10) -C(o)NR6R7, or 11) C3-C6 cycloalkyl;

mis 0, 1 or2;
nis 0, 1, 2, 3 or4;
pis 0, 1, 2, 3 or4;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 0 or I ;
t is 0 or 1; and u is 4 or 5;
15 with respect to formula (II-b):
( l 8)r !1 ~ Rj,~G
V - A1(CR1a2)nA2(CR1a2)n \W~- (CR1b2)p~ /N~ N--Z

(I l-b) or a pharmaceutically acceptable salt thereof, Rla, Rlb, Rl(), Rl 1, m, R2, R3, R6, R7, p, R7a, u, R~, Al, A2, V, W, X, 20 n, p, r, s, t and u are as defined above with respect to formula (II-a);

R4 is selected from H and CH3;

and any two of R2, R3 and R4 are optionally attached to the same 25 carbon atom;

R9 is selected from:
a) hydrogen, CA 022~19~ 1998-10-16 b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R 1 1 S(O)m-~ R 1 OC(O)NR 1 0-, CN, NO2, R 1 0)2N C (NR 1 0) , R l ~C(O)-, R l ~OC(O)-, N3, N (R 10)2, or R 1 l OC(O)NR l 0 ~ and c) Cl-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F Cl Br R1OO, Rlls(o)m, R1OC(O)NR10-, CN, (R 1 0)2N C(NR 1 0), R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R10)2, or Rl 1OC(O)NR10-;

G is H2 or O;

Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, un.substituted or substituted with one or more of the following:
1 ) C1 4 alkyl, unsubstituted or substituted with:
a) C 1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR6, or g) -C(o)NR6R7, 2) aryl or heterocycle, 3) halogen, 4) oR6, 5 ) NR6R7, 6) CN, 7) NO2, 8) CF3;
9) -S(O)mR6, l O) -C(o)NR6R7, or l l ) C3-C6 cycloalkyl;

with respect to formula (II-c):
( l 8)r !1 ~ b V Al(CR1a2) A2(CR1a2)n ~W~- (CR 2)p\X~N~ ~ Z
(Il-c) R4 or a pharmaceutically acceptable salt thereof, Rla Rlb, Rl(), Rl 1, m, R2, R3, R6, R7, p, u, R7a~ R~, Al, A2, V, W, X, n, r and t are as defined above with respect to formula (II-a);

R4 is selected from H and CH3;
and any two of R2, R3 and R4 are optionally attached to the same carbon atom;

Gi'i O;
Z i,s aryl, heteroaryl, arylmethyl, heteroarylmethyl, aryl.sulfonyl, heteroaryllsulfonyl, unsubstituted or substituted with one or more of the following:
I) Cl 4 alkyl, unsubstituted or substituted with:
a) Cl 4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR6, or g) -C(o)NR6R7, 2) aryl or heterocycle, 3 ) halogen, 4) oR6, S) NR6R7, 6) CN, 7) N02, S ~) CF3;
9) -S(O)mR6, 10) -C(o)NR6R7, or 1 1 ) C3-C6 cycloalkyl;

10and sis l;

(b) a compound represented by formula (II-d) through (II-g):

V A1 (C R 1 a2)nA2(c R l a2)n -(W~- (C R 1 b2)~ ~ OH

(I l-d) R2a R2b V - A (CR z)nA (CR 2)n -(W)- (CR ~ ~ R5à Rs V A1 (C R ~ a2)nA2(C R l a2)n -(W~- (C R 1 b2)~ ~H

(Il-f) R2a R2b HOCH2(CH2)q V A1 (C R l a2)nA2(CR ~ a2)n (W~)- (C R 1 b ~ J

(11-9) R2a R2b wherein with respect to formula (II-d):
s V Al (C Rl a2)nA2(CR 1 a2)n -(w)- (CR1b2~ ~Rsb R2a R2b (I l-d) or a pharmaceutically acceptable salt thereof, Rl ~, V, W, m, n, p and r are as defined above with respect to formula 10 (II-a);

Rla and ~lb are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, R 1 00-, R l l S(O)m-, R I OC(O)NR l ~-~ CN, N02, CA 022~19~ 1998-10-16 (Rlo)2N-c(NRlo)-~Rloc(o)-~ R100C(o),N3, -N(R10)2,orRllOC(O)NR10-, c) Cl-c6 alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-Clo cycloalkyl, C2-c6 alkenyl, C2-C6 S alkynyl, R 10o- Rlls(o)m-~Rloc(o) (R10)2N-c(NRlo)-~Rloc(o)-~ Rl0OC(o)-,N3, -N(R10)2, or Rl 1OC(O)-NR10-;

R2a and R2b are independently selected from:
10 a) hydrogen, b) C 1 -C6 alkyl unsubstituted or substituted by C2-C6 alkenyl7 R10O-, R 1 1 S(O)m-~ R 1 OC(O)NR 10, CN,N3,(R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or RllOC(O)NR10-15 c) aryl, heterocycle, C3-Clo cycloalkyl, C2-C~, alkenyl, R100,R1 lS(O)m-, R1OC(O)NR10-, CN, NO2, (R10)2N-C(NR10), R10C(o)-, R100C(o)-,N3,-N(Rl0)2~ or RllOC(O)NRl0-, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-CIo cycloalkyl;

R3 and R4 are independently selected from:
a) a side chain of a naturally occurring amino acid, 25 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 -c20 alkyl, C2-c2o alkenyl, C3-Clo cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R 1 0)2, N02, R 1 00-, R l l S(O)m-, R l OC(O)NR l o-CN,(R10)2N-C(NR10),R10C(o)~ Rl0Oc(o)-CA 022~19~ 1998-10-16 N3, -N(R10)2, Rl lOC(O)NR10- and Cl-C20 alkyl, and d) Cl-C6 alkyl ,substituted with an unsubstituted or substituted group selected from aryl, heterocycle and S C3- Clo cycloalkyl; or R3 and R4 are combined to fo~n - (CH2)S -;

R5a and Rsb 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-CIo cycloalkyl, aryl or heterocycle group, wherein the substituent i.s selected from F, Cl, Br, CF3, N(R 1 0)2, NO2, R 1 0O-, R l l S(O)m R 1 0C(O)NR 10, CN, (R 1 0)2N-C(NR 10), R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R 1~)2, R 1 1 OC(O)NR 10 and Cl-C20 alkyl, d) Cl -C6 alkyl substituted with an un.substituted or substituted group selected from aryl, heterocycle and C3-C l o 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: O, S(O)m, -NC(O)-, and -N(COR 10) ;

CA 022',19',', 1998-10-16 X-Y is ~7a a) ~555~f N~ss o R7b b) \5ss~N~sss c) ~ ~~sS

(ol )m d) \sss~s'sss e) ~555~555~ , or f) -CH2-CH2-;

5 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or sub,stituted C3-Clo cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-CIo cycloalkyl;

R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-Clo cycloalkyl, CA 022~19~ 1998-10-16 e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C1o cycloalkyl and Cl-C6 alkyl sub.stituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-Clo cycloalkyl and Cl-C6 alkyl ~ubstituted with hydrogen or an unsubstituted or ~ubstituted group selected from aryl, heterocycle and C3-CIo cycloalkyl;

1~ Rg is independently ~elected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R100-, R 1 1 S(O)m-, R 1 0C(o)NR 10, CN, NO2, R 1 02N-C(NR 10), R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) Cl-C6 alkyl unsub,~tituted or sub~tituted by aryl, heterocycle, C3-Clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, Rl lS(O)m-, R 1 0C(o)NH-, CN, H2N-C(NH)-, R I ~C(O)-, R 1 ~OC(O)-, N3, -N(R10)2, or R10OC(o)NH-;

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br R10O-, Rl lS(o)m, Rl0C(o)NR10-, CN, NO2, (R 1 0)2N C (NR 10), R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R 1~)2, or R I 1 OC(O)NR 10, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R100-, Rlls(o)m-~ RlOC(O)NR1O-, CN, (R 1 0)2N-C(NR 10) , R 1 ~C(O)-, R I ~OC(O)-, N3, -N(R10)2, or R1 1OC(O)NR10-;

R10 is independently selected from H, Cl-c6 alkyl, benzyl, substituted aryl and Cl-c6 alkyl substituted with substituted aryl;

A1 and A2 are independently .selected from: a bond, -CH=CH-, -C~
-C(O)-, -C(O)NR 10, -NR 1 ~C(O)-, O, -N(R 10) -S(0)2N(R 10) -N(R10)S(0)2-, or S(O)m;

Z is independently H2 or 0;

sis 40r5;
tis 3, 4 or5; and uis Oorl;

with respect to formula (II-e):

V Al(CR1a2)~A2(CR1a2)n-(w~-(cR1b2~ " Sb 2a 2b (Il-e) R

or a pharmaceutically acceptable salt thereof, R I I, W, m, n, p and r are a~ defined above with respect to formula 25 (II-a);

R 1 a and R 1 b are independently selected from:
a) hydrogen, CA 022~19~ 1998-10-16 b) aryl, heterocycle, C3-CIo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, Rl 1S(O)m-, R10C(O)NR10-, CN, NO2, (R 1 0)2N C(NR 10), R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R10)2, or Rl 1OC(O)NR10-, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R I I S(O)m-, R 1 0C(o)NR 10, CN, (R 1 0)2N C(NR 10), R 1 ~C(O)-, R 1 ~OC(O)-. N3, -N(R 1 0)2, or R 1 1 OC(O)-NR 1 0-;

R2a and R2b are independently selected from:
a) hydrogen, b) C1-C6 alkyl unsubstituted or .substituted by C2-C6 alkenyl, R 1 0o-, R I I S(O)m-, R 1 0C(o)NR 10-, CN, N3, (R10)2N-C(NR10)-, R10C(o)-, R10OC(o)-, -N(R10)2~ or R 1 1 OC(O)NR 10 c) aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R10O-, Rl lS(o)m, Rl0C(o)NR10-, CN, NO2, (R 1 0)2N-C(NR 10), R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10, and d) Cl-C6 alkyl substituted with an un,substituted or substituted group selected from aryl, heterocyclyl and C3-Clo cycloalkyl;
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 i,s:
i) methionine ,sulfoxide, or ii) methionine sulfone, c) ~ubstituted or unsubstituted Cl-c2o alkyl, C2-C20 alkenyl, C3-Clo cycloalkyl, aryl or heterocyclyl group, CA 022~19~ 1998-10-16 wherein the substituent is selected from F, Cl, Br, N(R10)2~ NO2, R10O-, R1 lS(O)m-, R10C(O)NR10-~
CN, (R 1 0)2N-C(NR 10), R l ~C(O)-, R l ~OC(O)-, N3, -N(R 1~)2, R 1 1 OC(O)NR 10 and C 1 -C20 alkyl, S and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C I o cycloalkyl; or 10 R3 and R4 are combined to form - (CH2)s -;

RSa 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 lS amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl -C20 alkyl, C2-C20 alkenyl, C3-C1o cycloalkyl, aryl or heterocycle group, wherein the sub~tituent is selected from F, Cl, Br, CF3, N(R1~)2, NO2, R10O , R 1 1 S(O)m R10C(O)NR10, CN, (R10)2N-C(NR10)-, R10C(O)-, R 1 ~OC(O)-, N3, -N(R 1~)2, R 1 1 OC(O)NR 10 and Cl-C2o alkyl, and 25 d) Cl-C6 alkyl substituted with an unsubstituted or substituted group ~elected from aryl, heterocycle and C3-C l o cycloalkyl; or R5a and R5b are combined to form - (CH2)S - wherein one of the 30 carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR 1 0)-;

__. . ~.

R6 is a) substituted or unsubstituted Cl-Cg alkyl, substituted or unsubstituted C5-Cg cycloalkyl, or substituted or unsubstituted cyclic amine, wherein the substituted alkyl, cycloalkyl or cyclic amine is substituted with 1 or 2 substituents independently selected from:
1) Cl-C6 alkyl, 2) aryl, 3 ) heterocycle, 4) -N(Rl 1)2, 5) -OR10, or b) R12 o ~lo~ R13;

15 X-Y is ~7a a) ~sss~N~ss o F~7b b) \5ss~ N~ss c) ~ o~ss CA 022~19~ 1998-10-16 (~)m d) ~S5s~s~ss e) 55s~S5s~ , or f) -CH2-CH2-;

R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C 10 cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1 o cycloalkyl;

R7b is selected from a) hydrogen, b) unsub~stituted or substituted aryl, c) unsubstituted orsubstitutedheterocycle, d) unsubstituted or substituted C3-C1o cycloalkyl, e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group .selected from aryl, heterocycle and C3-Clo cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-Clo cycloalkyl and Cl-c6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1o cycloalkyl? and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-Clo CA 022~19~ 1998-10-16 cycloalkyl and Cl-c6 alkyl substituted with hydrogen or an unsubstituted or sub~stituted group selected from aryl, heterocycle and C3-C1o cyclo~lkyl;

5 R~ is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R 1 1 S(O)m-~ R 1 0C(o)NR 10, CN, NO2, R 1 02N-C(NR 10), R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) C1-C6 alkyl un,sub,stituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, Rl 1S(O)m-R 1 0C(o)NH-, CN, H2N-C(NH)-, R 1 ~C(O)-, R I ~OC(O)-, N3, -N(R10)2, or R10OC(o)NH-;

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-c6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(o)NR10-, CN, NO2, (R 1 0)2N-C-(NR 10), R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R 1 ~)2, or R l 1 OC(O)NR 10, and c) C1-C6 alkyl un.substituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, Rl1s(o)m-~ R10C(o)NR10-, CN, (R 1 0)2N C(NR 10), R 1 ~C(O)-, R I ~OC(O)-, N3, -N(R10)2, or R1 1OC(O)NR10-;

R 1 0 is independently selected from H, C I -C6 alkyl, benzyl, substituted 30 aryl and Cl-C6 alkyl substituted with substituted aryl;

R12 is hydrogen or Cl-C6 alkyl;

R13 is Cl-C6 alkyl;

A l and A2 are independently selected from: a bond, -CH=CH-, -C--C-, -C(O)-, -C(O)NR l 0, -NR l ~C(O)-, O, -N(R l0) -S(O)2N(R l 0 -N(R l ~)S(O)2-, or S(O)m;

Z is independently H2 or O;

s is 4 or 5;
tis 3, 4 orS; and l0 uis 0 or l;
with respect to formula (II-f):

R3 ~R4 O

(I 8)r ~ y~ OH
V - A1(CR1a2)nA2(CR1a2)n -\wJ- (CR1b2)p ~N Z

R2a~2)~ (cH2)qcH2oH
(Il-f) 15 or a pharmaceutically acceptable ,~ialt thereof, R l l, V, W, m, n, p and r are as defined above with respect to folmula (II-a);
Rla and Rlb are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, R l 0O-, R l I S(O)m-1 R 1 0C(O)NR l 0-, CN, NO2, (R l 0)2N-C(NR l ~)-~ R l ~C(O)-, R l ~OC(O)- N3 -N(Rl0)2 or Rl lOC(O)NR10-c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-Clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, R l 0O , R l l S(O)m-~ R l 0C(O)NR l 0 , CN, (R l 0)2N-C(NR l 0), R l ~C(O)-, R l ~OC(O)-, N3, -N(R 1~)2, or R l 1 OC(O)-NR l 0;

CA 022~19~ 1998-10-16 R2a and R2b are independently selected from:
a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, R1OO-, Rlls(o)m-~ RlOC(O)NR10-, CN, N3 (R10)2N C(NRlO), RlOC(O)-~ RlOOC(O)-, -N(R10)2, or RllOC(O)NR10-, c) aryl, heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl Rloo-~Rlls(O)m-,Rloc(o)NRlO,CN, (R10)2N C(NR10),R10C(O)-, R10OC(o)-, N3, -N(R10)2, or RllOC(O)NR10-, and d) Cl-C6 alkyl substituted with an un~substituted or substituted group selected from aryl, heterocyclyl and C3-Clo cycloalkyl;
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, and c) sub,stituted or unsub.stituted C l -c20 alkyl, C2-C20 alkenyl, C3-Clo cycloalkyl, aryl or heterocyclyl group, wherein the substituent is ~selected from F, Cl, Br, N(RlO)2~ NO2, RlOO, Rl lS(O)m-, RlOC(O)NRlO-, CN,(R10)2N-C(NR10),R10C(o), Rl0Oc(o)-N3, -N(R10)2,RllOC(o)NRlo- and C l -C20 alkyl, and d) Cl-C6 alkyHsub~stituted with an un~ub~stituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl; or R3 and R4 are combined to form - (CH2)s-;

WO 97138664 rCT/US97/06248 X-Y is ~7a a) ~sss~N~ss o R7b b) \sSS~ N~sS

c) \SsS~0~5s ( 1~)m d) \5sS~SSsS

e) ~555~ , or f) -CH2-CH2-;

R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C1o cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsub~stituted or substituted group selected from aryl, heterocycle and C3-C1o cycloalkyl;

R7b i~s .selected from a) hydrogen, b) unsub~stituted or substituted aryl, c) unsubstituted or substituted heterocycle, CA 022~19~ 1998-10-16 d) unsubstituted or sub~stituted C3-Clo cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected ~rom aryl, heterocycle and C3-Clo cycloalkyl, f) a carbonyl group which is bonded to an unsub~tituted or substituted group selected from aryl, heterocycle, C3-C1o cycloalkyl and Cl-C6 alkyl ~substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1n cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or _stituted group selected from aryl, heterocycle, C3-Clo cycloalkyl and Cl-c6 alkyl substituted with hydrogen or an un.substituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl;
R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, pertluoroalkyl, F, Cl, Br, Rl0O-, Rl lS(o)m, R10C(O)NR10-, CN, NO2, Rlo2N-c(NRlo) R l ~C(O)-, R I ~OC(O)-, N3, -N(R ~ ~)2, or R I l OC(O)NR 10-, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl, C2-c6 alkenyl, C2-c6 alkynyl, perfluoroalkyl, F, Cl, Br, Rl0O-, Rl I S(O)m-, R l 0C(o)NH-, CN, H2N-c(NH)-~ R l ~C(O)-, R I ~OC(O)-, N3, -N(R 1~)2, or R 1 0OC(o)NH-;

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, Rl lS(o)m-~ R10c(o)NRlo- CN NO2 (R l 0)2N-C-(NR 10)-, R l ~C(O)-, R I ~OC(O)-, N3, -N(R 1~)2, or R l l OC(O)NR 10, and - 3~ -c) Cl-c6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R1OO-, R1 1S(O)m-, R1OC(O)NR10-, CN, (R 1 0)2N C(NR 1 0), R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R1 0)2, or R 1 l OC(O)NR 1 0-;

R10 is independently selected from H, Cl-c6 alkyl, benzyl, substituted aryl and Cl-C6 alkyl substituted with substituted aryl;

R 1 2 is hydrogen or C 1 -C6 alkyl;
~0 R13 is Cl-C6 alkyl;

Al and A2 are independently selected from: a bond, -CH=CH-, -C-C-, -C(O)-, -C(O)NR 10, -NR 1 ~C(O)-, O, -N(R 10) -S(O)2N(R 10) 15 -N(R10)S(O)2-, or S(O)m;
Z is independently H2 or O;

qis 0, 1 or2;
20 sis 4 or 5;
tis 3, 4 or5; and u is 0 or 1;
with respect to formula (II-g):

V A1(CR1a2)nA2(CRla2)n (W~- (CR1b ~

(11-9) R2a R2b or a pharmaceutically acceptable salt thereof, CA 022~19~ 1998-10-16 Rl ~, V, W, m, n, p and r are as previously defined with respect to formula (II-a);

Rla and Rlb are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m ~ R10C(o)NR10 CN, NO2, (R 10)2N-C(NR 10), R 1 ~C(O)-, R 1 ~OC(O)-N3, -N(R10)2, or Rl lOC(O)NR10-, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl R 1 0O-, R 1 1 S(O)m-~ R 1 0C(o)NR 10, CN, (R 1 0)2N C(NR 10), R 1 ~C(O)-, R I ~OC(O)-, N3, -N(R10)2, or Rl 1OC(O)-NR10-;
R2a and R2b are independently selected from:
a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, R 1 0O- R 1 1 S(O)m-~ R 1 0C(o)NR 10, CN, N3, (R 1 0)2N-C(NR 10) R 1 ~C(O)-, R 1 ~OC(O)-, -N(R 1~)2, or R I 1 OC(O)NR 10 c) aryl, heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, R10O-, Rl lS(O)m-~ R10C(o)NRl0-, CN, NO2, (Rlo)2N-c(NRlo)-~ RlOc(o)-~ RlOoC(o)- N3 N(Rl{~)2 or R 1 1 OC(O)NR 10, and d) Cl-c6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-Clo cycloalkyl;
~0 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 Cl-c2o alkyl, C2-C20 alkenyl, C3-C1o cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, R10O-, R1 1S(O)m-, R10C(O)NR10-, CN, (R 1 0)2N-C(NR 10) , R 1 ~C(O)-, R 1 ~OC(O)-N3, -N(R 1 0)2, R 1 1 OC(O)NR 1 0- and C l -C20 alkyl, and d) Cl-C6 alkyl substituted with an un~substituted or substituted group selected from aryl, heterocycle and C3 -C l o cycloalkyl; or R3 and R4 are combined to form - (CH2)s -;

15 X-Yi~s ~7a a) ~5ss~N~SS
o ~7b b) \s s~/N~sS

c) \5sS~O~ss (~)m d) \sss~S~sss e) ~SsS~ , or f) -CH2-CH2-;

CA 022~19~ 1998-10-16 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsub,stituted or substituted C3-clo cycloalkyl, and e) Cl-c6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl;

10 R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or ,substituted C3-C1o cycloalkyl, e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1o cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-CIo cycloalkyl and Cl-c6 alkyl sub.stituted with hydrogen or an unsubstituted or substituted group .selected from aryl, heterocycle and C3-CIn cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-CIo cycloalkyl and Cl-c6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-CIo cycloalkyl;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R 1 I S(O)m-~ R I OC(O)NR 10, CN, NO2, R 1 02N-C(NR 10), CA 022~19~ 1998-10-16 R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl, C2-c6 alkenyl, C2-C6 S alkynyl, perfluoroalkyl, F, Cl, Br, R10O-~ Rl 1S(o)m R 1 0C(o)NH-, CN, H2N-c(NH)-~ R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R10)2, or R10OC(O)NH-;

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, pelfluoroalkyl, F, Cl, Br, R 1 0O-, R 1 1 S(O)m-~ R 1 0C(o)NR 1 0-, CN, NO2, (R 1 0)2N C (NR 10) , R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R 1~)2, or R ~ 1 OC(O)NR 10, and c) Cl-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, Rl lS(O)m-, R10C(O)NR10-~ CN, (R 1 0)2N C(NR 10), R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R10)2, or Rl 1OC(O)NR10-;

20 R10 is independently selected from H, Cl-c6 alkyl, benzyl, substituted aryl and Cl-C6 alkyl substituted with substituted aryl;

R12 is hydrogen or Cl-C6 alkyl;

25 R13 i,s Cl-C6 alkyl;

Al and A2 are independently ,selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR 10, -NR 1 ~C(O)-, O, -N(R 10) -S(O)2N(R 10 -N(R 1 ~)S(O)2-, or S(O)m;
Z i.s independently H2 or O;

qis 0, 1 or2;
s is 4 or 5;

WO 97/38664 PCTtUS97tO6248 tis 3, 4 orS; and u is O or 1, (c) a compound represented by formula (Il-h) through (II-k):

R5a R5b (IR ), /~19~ J~NXT/
V - A1(CR1a2)nA2(CR1a2)n ~W~~ (CR1b2)~N~H O

(Il-h) R4a R4b R5a R5b V A (CR 2)nA2(CR1~2)n -(W)- (CR1b2)~f N ~ORl2 (I l-i) R4a R4b HOCH2(CH2)q V A~(cR1a2)nA2(cR1a2)n-(w)-(cRlb2~N~ R

V A1(CRla2)nA2(CR1a2)n -(w)- (cR~b2~ ~

(~I-k) R4a R4b wherein with respect to formula (Il-h):

V A1(cR1a2)nA~(cR1a2)n (W)- (CR1b2~

(Il-h) R4a R4b or a pharmaceutically acceptable salt thereof, Rla Rlb, R8, R9, R10, Rl 1, Al~ A2, V, W, m, n, p and r are as previously defined with re,spect to formula (II-a);

R2 and R3 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, and lS c) substituted or un~ubstituted Cl-C20 alkyl, C2-C20 alkenyl, C3-C1o cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R10)2, N02, R100-, Rl lS(O)m-, RlOC(O)NR10-CN, (R 1 0)2N-C(NR 10), R I ~C(O)-, R 1 ~OC(O)-, N3, -N(R1~)2, R1 1OC(O)NR10 and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C l o cycloalkyl; or R2 and R3 are combined to form - (CH2)S -; or R2 or R3 are combined with R6 to form a ring ,such that CA 022~19~ 1998-10-16 ~N~, R7a~ 9F,7b R4a, R4b, R7a and R7b are independently selected from:
a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by alkenyl, R10O-, R 1 1 S(O)m-~ R 1 0C(O)NR 10, CN, N3, (R 1 0)2N-C(NR 10), R10C(o)-, R10OC(O)-~ -N(Rlo)2~ or Rl loc(o)NRlo-c) aryl, heterocycle, cycloalkyl, alkenyl, R10O-, R I 1 S(O)m-, R 1 0C(O)NR 10, CN, NO2, (R 1 0)2N-C(NR 10) , R I ~C(O)-, R 1 ~OC(O)-, N3, -N(R 1~)2, or R I I OC(O)NR 10, and d) Cl-C6 alkyl substituted with an unsubstituted or ,~ubstituted group ~elected from aryl, heterocyclyl and C3-CIo cycloalkyl;
RSa and Rsb 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-c2o alkyl, C2-c2o alkenyl, C3-Clo cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, R10O-, Rl lS(O)m-, R10C(o)NR10-, CN, (R10)2N-C(NR10)-, R10C(o)-, Rl0OC(o)-N3, -N(R 1 0)2, R l l OC(O)NR 1 0- and C l -C20 alkyl, d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C l o cycloalkyl; or WO 97t38664 PCTtUS97/06248 R5a and R5b are combined to form - (cH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR 1 ~)-;
5 R6 is independently selected from hydrogen or Cl-c6 alkyl;

Q is a substituted or unsubstituted nitrogen-containing C4-Cg mono or bicyclic ring .system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
X, Y and Z are independently H2 or 0;

s is 4 or 5;
15 tis 3,40r5;and uis Oor 1;
with respect to formula (II-i):

V A1(CRla2)nAZ(cR1a2)n (W~ (CR1bz~

(Il-i) R4a R4b or a pharmaceutically acceptable salt thereof, wherein:

25 Rla, R1b, R~, R'), Rl(), R11, Al, A2, V, W, m, n, p and r are a~s previoulsly defined with respect to formula (II-a);

R2 and R3 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, and c) substituted or unsubstituted Cl -C20 alkyl, C2-C20 alkenyl, C3-Clo cycloalkyl, aryl or heterocyclyl group, wherein the substituent is ,selected from F, Cl, Br, N(R10)2, N02, R100-, Rl lS(O)m-, RlOC(O)NR10-, CN, (R 1 0)2N-C(NR 10), R 1 ~C(O)-, R 1 ~OC(O)-N3, -N(R 1~)2, R 1 1 OC(O)NR 10 and C 1 -C20 alkyl, and d) Cl-C6 alkyl substituted with an unlsubstituted or substituted group selected from aryl, heterocycle and C3-C l o cycloalkyl; or R2 and R3 are combined to form - (CH2)S -; or R2 or R3 are combined with R6 to forrn a ling such that ~ 2~ is "~ ~ RJ

R4a~ R4b, R7a and R7b are independently selected from:
a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R10O-, Rl lS(O)m, R10C(O)NR10-~ CN, N3, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(Rlo)2~ or Rl lOC(O)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, R10O-, Rl lS(o)m, Rloc(o)NRlo-~ CN, NO2, (R 1 0)2N C(NR 10), R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R 1~)2 or R 1 1 OC(O)NR 10 , and CA 022~19~ 1998-10-16 - 4P~ -d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-C1o cycloalkyl;

5 R5a 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 I -c20 alkyl, C2-C20 alkenyl, C3-CIo cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R10)2~ NO2, R10O-, R1 1S(O)m-, R10C(O)NR10-~
CN, (R 1 0)2N-c(NR 10) , R 1 ~C(O)-, R 1 ~OC(O)-N3, -N(R 1~)2, R 1 1 OC(O)NR 10 and C 1 -C20 alkyl, d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3 -C 1 o 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: O, S(O)m, -NC(O)-, and -N(COR10)-;

R6 is independently selected from hydrogen or Cl-c6 alkyl;

R12 i~
a) substituted or unsubstituted Cl-cx alkyl or substituted or unsubstituted C5-C~ cycloalkyl, wherein the substituellt on the alkyl or cycloalkyl is selected from:
1) aryl, 2) heterocycle, 3) -N(R1 1)2, 4) -OR10, or b) oJ~ R 14 R 13 is independently selected from hydrogen and Cl-C6 alkyl;

R14 is independently selected from Cl-C6 alkyl;

Q is a substituted or unsubstituted nitrogen-containing C4-Cg mono or bicyclic ring system, wherein the non-nitrogen containin~ ring may be 10 an aromatic ring, a Cs-C7 saturated ring or a heterocycle;

X, Y and Z are independently H2 or 0;

15 sis 40r5;
t is 3, 4 or 5; and ui,s Oor l;

with respect to formula (IIj):
HOC H2((~H2)q V ~ Al(CRl~2)nA2(cR1a2)n (W~- (CR1b2~ X~ H--X ~Q ~
(Il-j) ~R4b 20R4a or a pharmaceutically acceptable salt thereof, R~a, Rlb, Rx, R~, Rl(), Rl 1, Al, A2, V, W, m, n, p and r are as 25 previously defined with respect to formula (II-a);

CA 022~19~ 1998-10-16 R2 and R3 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 S amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl-c2n alkyl, C2-C20 alkenyl, C3-Clo cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(Rl0)2 NO2, R10O-, Rl lS(O)m-, R10C(O)NR10-~
CN, (R 1 0)2N-C(NR 10) , R 1 ~C(O)-, R 1 ~OC(O)-N3, -N(R 1~)2, R 1 1 OC(O)NR 10 and C I -C20 alkyl, and 15 d) Cl-c6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Cl o cycloalkyl; or R2 and R3 are combined to form - (CH2)S -; or R2 or R3 are combined with R6 to forrn a ring such that R6 ~
~,,,N~ is ~ (~H2)t;
R2 R3 R7a~l R7b 25 R4a, R4b, R7a and R7b are independently selected from:
a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by alkenyl, R10O-, Rl lS(o)m, Rl0c(o)NRlo-~ CN, N3, (R10)2N-C(NR10)-, R I ~C(O)-, R 1 ~OC(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10 c) aryl, heterocycle, cycloalkyl, alkenyl, R10O-, R1 I S(O)m-~ R10C(o)NR10-, CN, NO2, (R 10)2N-C(NR 10), R 1 ~C(O)-, R l ~OC(O)-, N3, -N(R 1~)2 or R 1 1 OC(O)NR I 0-, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-CIo cycloalkyl;

R6 is independently selected from hydrogen or Cl-C6 alkyl;

Q is a substituted or unsubstituted nitrogen-containing C4-Cg mono or lO bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;

X, Y and Z are independently H2 or 0;

15 q is 0, l or 2;
s is 4 or 5;
t is 3, 4 or 5; and uis Oorl;

20 with respect to formula (II-k):

R~ Y ~N~
V - A1(CR1a2)nA2(CR1a2)n -\W - (CR1b2)p~N~ H O

(Il-k) R4a~R

or a phannaceutically acceptable salt thereof, 25 R~a~ Rlb, RX, R~, Rl(), Rl l, Al, A2, V, W, m, n, p, and r are as defined above with respect to formula (II-a);

R2 and R3 are independently selected from:

CA 022~19~ 1998-10-16 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 S ii) methionine sulfone, and c) sub~tituted or unsubstituted Cl -C20 alkyl, C2-C20 alkenyl, C3-Clo cycloalkyl, aryl or heterocyclyl group, wherein the substituent is ~elected from F, Cl, Br, N(R10)2, N02, R100-, Rl lS(O)m-, RlOC(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-~
N3, -N(R 1~)2, R 1 1 OC(O)NR 10 and C 1 -C20 alkyl, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group ~elected from aryl, heterocycle and C3 -C l o cycloalkyl; or R2 and R3 are combined to form - (cH2)s -; or R2 or R3 are combined with R6 to form a ring such that R~ R7aJ~ >I R7~

R4a, R4b, R7a and R7b are independently selected from:
a) hydro~en, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R10O-, R 1 1 S(O)m ~ R 1 0C(O)NR 10, CN, N3, (R 1 0)2N-C(NR 10) , R10C(o)-, R10OC(o)-, -N(Rlo)2~ or Rl lOC(O)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, R10O-, R 1 I S(O)m-~ R 1 0C(o)NR 1 0-, CN, NO2, (R 1 0)2N-C(NR 10) , R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R 1~)2 or R 1 1 OC(O)NR 10 , and . , .. . ~

d) C1-C6 alkyl substituted with an unsubstituted or substituted group .selected from aryl, heterocyclyl and C3-Clo cycloalkyl;

5 R6 is independently .selected from hydrogen or Cl-C6 alkyl;

Q is a substituted or unsubstituted nitrogen-containing C4-Cg mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
X, Y and Z are independently H2 or 0;

qis 0, 1 or2;
s is 4 or S;
lS tis 3,40rS;and u is 0 or 1 ;

(d) a compound represented by formula (II-I):
R2 o R1NH N~T N~ RC
- H 3~"" H
HS R

20 wherein Rc is selected from:
~, ~~ and ~,~0 Rl is hydrogen, an alkyl group, an aralkyl group, an acyl group, an aracyl group, an aroyl group, an alkylsulfonyl group, CA 022~19~ 1998-10-16 aralkylsulfonyl group or arylsulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms;

S R2andR3are the side chains of naturally occurring amino acids, including their oxidized forms which may be methionine sulfoxide or methionine sulfone, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imid~zolyl or ,saturated chain,s of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substitutents may be substituted with an aromatic or heteroaromatic ring;
R4 is hydrogen or an alkyl group, wherein the alkyl group comprises ,straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms;

R5 is selected from:
a) a side chain of naturally occurrhlg amino acids, b) an oxidized form of a ~side chain of naturally occurring amino acids selected from methionine ,sulfoxide and methionine sulfone, c) substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl, or saturated chains of 2 to ~s carbon atoms which may be branched or unbranched, wherein the aliphatic substituent is optionally substituted with an aromatic or heteroaromatic ring, and d) -CH2CH2OH or-CH2CH2CH2OH;

R6 is a substituted or unsubstituted aliphatic, aromatic or heteroaromatic group such as saturated chains of 1 to CA 022~19~ 1998-10-16 carbon atoms, which may be branched or unbranched, wherein the aliphatic substituent may be substituted with an aromatic or heteroaromatic ring;

T is O or S(O)m;
mis 0, 1 or2;
nis 0, 1 or2;

and the pharmaceutically acceptable salts and disulfides thereof.

Examples of compounds that selectively inhibit geranylgeranyl-protein transferase-type I include the following:

15 N-(2(R)-amino-3-mercaptopropyl)-valyl-isoleucyl-leucine (Compound 2);

N-(2(R)-amino-3-mercaptopropyl)-valyl-isoleucyl-leucine methyl ester (Compound 1);
N-[2(S)-(2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyloxy)-3-methylbutanoyll-leucine; and N-L2(S)-(2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-25 methylpentyloxy)-3-methylbutanoyl]-leucine methyl ester, and the pharmaceutically acceptable salts and di,sulfide,s thereof.
Example~s of compounds which selectively inhibit farne.syl protein 30 tran,sferase include the following:

2(S)-Butyl- I -(2,3-diaminoprop- 1 -yl)- 1-( I -naphthoyl)piperazine;

I -(3-Amino-2-(2-naphthylmethylamino)prop- 1 -yl)-2(S)-butyl-4-( 1-35 naphthoyl)piperazine;

CA 022~19~ 1998-10-16 2(S)-Butyl- 1 - ~ 5-[1 -(2-naphthylmethyl)] -4 ,5 -dihydroimidazol 3 methyl-4-( 1 -naphthoyl)piperazine;

1-[5-(1 -Benzylimidazol)methyl]-2(S)-butyl-4-( 1 -naphthoyl)piperazine;

1- { 5-L 1 -(4-nitrobenzyl)~imidazolylmethyl } -2(S)-butyl-4-( 1-naphthoyl)piperazine;

10 1-(3-Acetamidomethylthio-2(R)-aminoprop- 1 -yl)-2(S)-butyl-4-( 1-naphthoyl)piperazine;

2(S)-Butyl- 1 -[2-(1 -imidazolyl)ethyl]sulfonyl-4-( 1 -naphthoyl)piperazine;

2(R)-Butyl- 1 -imidazolyl-4-methyl-4-( 1 -naphthoyl)piperazine;

2(S )-Butyl-4-( 1 -naphthoyl)- 1 -(3 -pyridylmethyl)piperazine;

1 -2(S)-butyl-(2(R)-(4-nitrobenzyl)amino-3-hydroxypropyl)-4-( 1-20 naphthoyl)piperazine;

1 -(2(R)-Amino-3-hydroxyheptadecyl)-2(S)-butyl-4-( 1 -naphthoyl)-piperazine;

25 2(S)-Benzyl-l-imidazolyl-4-methyl-4-(1-naphthoyl)piperazine;

1 -(2(R)-Amino-3-(3-benzylthio)propyl)-2(S)-butyl-4-( 1-naphthoyl)piperazine;

1-(2(R)-Amino-3-[3-(4-nitrobenzylthio)propyl])-2(S)-butyl-4-(1-naphthoyl)piperazine;

2(S)-Butyl- 1 -[(4-imidazolyl)ethyl]-4-( 1 -naphthoyl)piperazine;

CA 022~19~ 1998-10-16 2(S)-Butyl-1 -[(4-imidazolyl)methyl 1-4-(1 -naphthoyl)piperazine;

2(S)-Butyl- 1-~ naphth-2-ylmethyl)- 1 H-imidazol-S-yl)acetyl]-4-(1-- naphthoyl)piperazine;

2(S)-Butyl- 1-[( I -naphth-2-ylmethyl)- 1 H-imidazol-5-yl)ethyl]-4-(1-naphthoyl)piperazine;

I -(2(R)-Amino-3 -hydroypropyl)-2(S)-butyl-4-( 1 -naphthoyl)piperazine;
1 -(2(R)-Amino-4-hydroxybutyl)-2(S )-butyl -4-(1 -naphthoyl)piperazine;

1 -(2-Amino-3-(2-benzyloxyphenyl)propyl)-2(S)-butyl-4-( 1 -naphthoyl)piperazine;
1 -(2-Amino-3 -(2-hydroxyphenyl)propyl)-2(S ) -butyl -4-(1-naphthoyl)piperazine;

I -[3-(4-imidazolyl)propyl]-2(S)-butyl-4-( 1 -naphthoyl)-piperazine;
2(S)-n-Butyl-4-(2,3-dimethylphenyl)- 1 -(4-imidazolylmethyl)-plperazln-;S-one;

2(S)-n-Butyl- I -[ I -(4-cyanobenzyl)imidazol-5-ylrnethyl]-4-(2,3-25 dimethylphenyl)piperazin-5-one;

1-[ 1 -(4-Cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3-dimethylphenyl)-2(S)-(2-methoxyethyl)piperazin-5-one;

30 2(S)-n-Butyl-4-( 1 -naphthoyl)- 1-1 I -(1 -naphthylmethyl)imidazol-5-ylmethyl]-piperazine;

2(S)-n-Butyl-4-( 1 -naphthoyl)- I -L 1 -(2-naphthylmethyl)imidazol-5-ylmethyl] -piperazine;

CA 022~19~ 1998-10-16 WO 97/38664 PCTtUS97/06248 2(S)-n-Butyl- 1- [ 1 -(4-cyanobenzyl)imidazol-5 -ylmethyl] -4-( l -naphthoyl)piperazine;

5 2(S)-n-Butyl- 1-1 1 -(4-methoxybenzyl)imidazol-5-ylmethyl 1-4-(1-naphthoyl)piperazine;

2(S)-n-Butyl-1 -[ 1 -(3-methyl-2-butenyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine;
2(S)-n-Butyl- 1-[1 -(4-fluorobenzyl)imidazol-5-ylmethyl]-4-( 1-naphthoyl)piperazine;

2(S)-n-Butyl- 1-[ I -(4-chlorobenzyl)imidazol-5-ylmethyl]-4-( 1-1 5 naphthoyl)piperazine;

1-[1 -(4-Bromobenzyl)imidazol-5-ylmethyll-2(S)-n-butyl-4-(1 -naphthoyl)piperazine;

20 2(S)-n-Butyl-4-( 1 -naphthoyl)- I -[1 -(4-trifluoromethylbenzyl)imidazol-5-ylmethyl]-piperazine;

2(S)-n-Butyl- 1- [1 -(4-methylbenzyl)imidazol-5 -ylmethyl] -4-( 1-naphthoyl)-piperazine;
2(S)-n-Butyl- 1-[1 -(3-methylbenzyl)imidazol-5-ylmethyl] -4-(1 -naphthoyl)-piperazine;

1-[1 -(4-Phenylbenzyl)imidazol-5-ylmethyl 1-2(S)-n-butyl-4-( 1-30 naphthoyl)-piperazine;

2(S)-n-Butyl-4-( 1-naphthoyl)-1-[1 -(2-phenylethyl)imidazol-5-ylmethyll-piperazine;

2(S)-n-Butyl-4-( 1 -naphthoyl)- 1-[1 -(4-trifluoromethoxy)imidazol-5 -ylmethyllpiperazine;

1-{ [1-(4-cyanobenzyl)-lH-imidazol-S-yl]acetyl~-2(S)-n-butyl-4-(1-S naphthoyl)piperazine;

1-{ 5-[1 -(4-nitrobenzyl)]imidazolylmethyl }-2(S)-butyl-4-(1-naphthoyl)piperazine 02N~ ~ N

N~ ~?

1-[5-(1 -Benzylimidazol)methyll-2(S)-butyl-4-(1 -naphthoyl)piperazine ~0 ~ N~ / ~

1 -(2(R)-Amino-3-(3-benzylthio)propyl)-2(S)-butyl-4-( 1-naphthoyl)piperazine ~S ~N N~

I -(2(R)-Amino-3-[3-(4-nitrobenzylthio)propyl])-2(S)-butyl-4-(1 -naphthoyl)piperazine ~l~s ~N N~

5 2(S)-n-Butyl- 1-[ I -(4-cyanobenzyl)imidazol-5-ylmethyll-4-( 1-naphthoyl)piperazine ~0 N

2(S)-n-Butyl- I -[ I -(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(2~3-dimethylphenyl)piperazin-5-one ~ H3C CH3 NC ~ ~N N~

N O
2(S)-n-Butyl~ 1-(4-chlorobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine Cl~ ~N N~

1- { [ 1 -(4-cyanobenzyl)-1 H-imidazol-5-yl lacetYI ) -2(S)-n-butyl-4-( 1-naphthoyl)piperazine <N~-- ~

1-[ 1 -(4-Cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3-dimethylphenyl)-1 0 2(S)-(2-methoxyethyl)piperazin-5-one CA 022~19~ 1998-10-16 o <\~ O
N

N-[ 1 -(4-Imidazoleacetyl)pyrrolidin-2(S)-ylmethyl]-N-( 1-5 naphthylmethyl)glycylmethionine /=N O H O
HN,~'N~-- ~ ;

~3 SCH3 N-[ 1 -(4-Imidazoleacetyl)pyrrolidin-2(S)-ylmethyl]-N-( ] -naphthyl-methyl)glycyl-methionine methyl ester;
N-[ I -(2(S),3-Diaminopropionyl)pyrrolidin-2(S)-ylmethyl]-N-( I -naphthylmethyl)glycyl-methionine;

N-~ 1 -(2(S),3-Diaminopropionyl)pyrrolidin-2(S)-ylmethyl]-N-( 1-15 naphthylmethyl)glycyl-methionine methyl ester;

N-[ 1 -(3-Aminopropionyl)pyrrolidin-2(S)-ylmethyl]-N-( 1-naphthylmethyl)glycyl-methionine;

20 N-[1-(3-Aminopropionyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;

CA 022~19~ 1998-10-16 N-[ 1 -(2(S)-Amino-3-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)- ylmethyl]-N-(I-naphthylmethyl)glycyl-methionine;

5 N-[1-(2(S)-Amino-3-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)- ylmethyl]-N-(I-naphthylmethyl)glycyl-methionine methyl ester;

N-[ l -(3-Amino-2(S)-benzyloxycarbonylaminopropionyl)pyrrolidin-10 2(S)- ylmethyl]-N-( 1 -naphthylmethyl)glycyl-methionine;

N-[ 1 -(3-Amino-2(S)-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)- ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;
N-[ 1 -(L-Glutaminyl)pyrrolidin-2(S)- ylmethyl] -N-( l -naphthylmethyl)glycyl-methionine;

N-[ 1 -(L-Glutaminyl)pyrrolidin-2(S)- ylmethyl~-N-( l -20 naphthylmethyl)glycyl-methionine methyl ester;

N-[ 1 -(L-Histidyl)pyrrolidin-2(S)-ylmethyl]-N-( I -naphthylmethyl)glycyl-methionine;

25 N-[1-(L-Histidyl)pyrrolidin-2(S)-ylmethyl]-N-(l-naphthylmethyl)glycyl-methionine methyl e~ter;

N-[ l -(D-Histidyl)pyrrolidin-2(S)-ylmethyl]-N-( I -naphthylmethyl)glycyl-methionine;
N-[ 1 -(D-Histidyl)pyrrolidin-2(S)-ylmethyl~-N-( I -naphthylmethyl)glycyl-methionine methyl ester;

CA 022~19~ 1998-10-16 W O 97/38664 PCTrUS971~6248 N-[1 -(L-Pyroglutamyl)pyrrolidin-2(S)-ylmethyl]-N-(l -naphthylmethyl)glycyl-methionine;

N-[ 1 -(L-Pyroglutamyl)pyrrolidin-2(S)-ylmethyl]-N-( 1-5 naphthylmethyl)glycyl-methionine methyl e~ster;

2(S)-L 1 -(2(S)-Pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy] -3-phenylpropionyl-methionine;

10 2(S)-1 1-(2(S)-Pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine methyl ester;

2(S)-[ 1 -(2(S)-Pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine i.sopropyl ester;
2(S)-[ I -(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine;

2(S)-[ 1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyloxy]-3-20 phenylpropionyl-methionine methyl ester;

2(S)-[ 1 -(2(S)-Pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine sulfone;

25 2(S)-[ 1 -(2(S)-Pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine sulfone methyl ester;

2(S)-[ 1 -(Pyrid-3-ylcarboxy)pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine;
2(S)-[ 1 -(Pyrid-3-ylcarboxy)pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine methyl ester;

CA 022~19~ 1998-10-16 WO 97/38664 PCTtUS97/06248 2(R)-~2-[1-(Naphth-2-yl)-lH-imidazol-5-ylacetyl~pyrrolidin-2(S)-ylmethoxy ) -3-phenylpropionyl-methionine;

2(R)- ( 2-[1 -(Naphth-2-yl)- 1 H-imidazol-5 -ylacetyl Ipyrrolidin-2(S)-5 ylmethoxy ) -3-phenylpropionyl-methionine methyl ester;

2(S)-[ 1 -(Pyrid-3-ylmethyl)pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine;

10 2(S)-~ l-(Pyrid-3-ylmethyl)pyrrolidin-2(S)-ylmethyloxy~-3-phenylpropionyl-methionine methyl ester;

N-l 1 -(lH-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(l -naphthylmethyl)glycyl-methionine isopropyl ester;
N-[ 1-(1 H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl~ - N-( 1-naphthylmethyl)glycyl-methionine sulfone isopropyl ester;

N-[ 1-(1 H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyll- N-(1-20 naphthylmethyl)glycyl-methionine sulfone;

N-[l-(Glycyl) pyrrolidin-2(S)-ylmethyl]-N-(I-naphthylmethyl)glycyl-methionine methyl ester;

25 N- [ 1 -(Glycyl) pyrrolidin-2(S)-ylmethyl] -N-( 1 -naphthylmethyl)glycyl-methionine isopropyl ester;

N-L 1 -(Glycyl) pyrrolidin-2(S)-ylmethyll-N-( 1 -naphthylmethyl)glycyl-methionine;
N-[l-(Glycyl) pyrrolidin-2(S)-ylmethyl]-N-(l-naphthylmethyl)glycyl-methionine sulfone methyl e,ster;

CA 022~19~ 1998-10-16 N-[ 1 -(Glycyl) pyrrolidin-2(S)-ylmethyl]-N-( I -naphthylmethyl)glycyl-methionine sulfone;

N-[1-(Sarcosyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-5 methionine methyl ester;

N-[ 1 -(Sarcosyl) pyrrolidin-2(S)-ylmethyl]-N-( 1 -naphthylmethyl)glycyl-methionine;

10 N-[ 1 -(N,N-Dimethylglycyl) pyrrolidin-2(S)-ylmethyl~-N-( 1-naphthylmethyl)glycyl-methionine methyl ester;

N-[ 1 -(N,N-Dimethylglycyl) pyrrolidin-2(S)-ylmethyl] -N-( 1-naphthylmethyl)glycyl-methionine;
N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl]- N-(1-naphthylmethyl)glycyl-methionine methyl ester;

N-[1-(lH-imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl~- N-20 ( 1 -naphthylmethyl)glycyl-methionine;

N-[l-(Glycyl) pyrrolidin-3(S)-ethyl-2(S)-ylmethyl~-N-(I-naphthylmethyl)glycyl-methionine methyl ester;

25 N-[ 1 -(Glycyl) pyrrolidin-3(S)-ethyl-2(S)-ylmethyl] -N-( 1-naphthylmethyl)glycyl-methionine;

N-~ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(l-naphthylmethyl)glycyl-methionine methyl ester;
N-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(l-naphthylmethyl)glycyl-methionine;

CA 022~19~ 1998-10-16 N-[ 1 -(2-Acetylamino-3(S)-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)-ylmethyl]- N-(l-naphthylmethyl)glycyl-methionine, S N-[ 1 -(2-Acetylamino-3(S)-aminopropionyl)pyrrolidin-2(S)-ylmethyl]-N-( 1 -naphthylmethyl)glycyl-methionine;

N-l 1-(2-Amino-3(S)-acetylaminopropionyl)pyrrolidin-2(S)-ylmethylJ-N-( 1 -naphthylmethyl)glycyl-methionine;
2(S)-[ I -(1 H-Imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine methyl ester;

2(S)-[ 1-(1 H-imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-15 ylmethyloxy]-3-phenylpropionyl-methionine;

2(R)- ~ 2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl~cetyl Ipyrrolidin-2(S)-ylmethoxy)-3-phenyl propionyl-methionine methyl e.ster;

20 2(R)- ( 2-[1 -(4-Cyanobenzyl)- I H-imidazol-5-ylacetyllpyrrolidin-2(S)-ylmethoxy}-3-phenyl propionyl-methionine;

2(R)- ~ 2-l 1 -(4-Nitrobenzyl)- 1 H-imidazol-5-ylacetyl lPYrrolidin-2(S)-ylmethoxy~-3-phenyl propionyl-methionine methyl e,ster;
2(R)-~ 2-[1 -(4-Nitrobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethoxy ) -3-phenyl propionyl-methionine;

2(R)- ~ 2-[1 -(4-Methoxybenzyl)-1 H-imidazol-5-ylacetyl]pyrrolidin-2(S)-30 ylmethoxy ) -3-phenyl propionyl-methionine methyl ester;

2(R)- ~ 2-[1 -(4-Methoxybenzyl)-1 H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethoxy)-3-phenyl propionyl-methionine;

CA 022~19~ 1998-10-16 2(R)-{2-[1-(4-Cyanobenzyl)-lH-imidazol-5-ylacetyl]pyrrolidin-3(S)-ethyl-2(S)-ylmethoxy)-3-phenyl propionyl-methionine methyl ester;

2(R)- ~ 2-[1 -(4-Cyanobenzyl)- 1 H-imidazol-5-ylacetyl]pyrrolidin-3(S)-5 ethyl-2(S)-ylmethoxy } -3 -phenyl propionyl-methionine;

N-~l-(lH-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(1-naphthylmethyl)glycyl-(,~-acetylamino)alanine methyl ester;

10 N-[ 1-(1 H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl~ - N-(l -naphthylmethyl)glycyl-(~-acetylamino)alanine;

N-[l-(Glycyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-(~-acetylamino)alanine methyl ester;
N-[ 1 -(Glycyl) pyrrolidin-2(S)-ylmethyl l-N-( 1 -naphthylmethyl)glycyl-(,B-acetylamino)alanine;

N-[ 1 -(Seryl)pyrrolidin-2(S)-ylmethyl]- N-( 1 -naphthylmethyl)glycyl-20 methionine methyl ester;

N-[ 1 -(D-Alanyl) pyrrolidin-2(S)-ylmethyl]-N-( 1 -naphthylmethyl)glycyl-methionine methyl ester;

25 N-[ 1-(1 H-imidazol-4-carbonyl)pyrrolidin-2(S)-ylmethyl]- N-( 1-naphthylmethyl)glycyl-methionine methyl ester;

N-[ 1 -(Isoasparagyl) pyrrolidin-2(S)-ylmethyl]-N-( 1-naphthylmethyl)glycyl-methionine methyl ester;
N-[1-(1H-Imidazol-4-propionyl) pyrrolidin-2(S)-ylmethyl]- N-(1-naphthylmethyl)glycyl-methionine methyl ester;

N-[1-(3-Pyridylacetyl) pyrrolidin-2(S)-ylmethyll-N-(1-35 naphthylmethyl)glycyl-methionine methyl ester;

CA 022~19~ 1998-10-16 N-[ 1 -(2-Pyridylacetyl) pyrrolidin-2(S)-ylmethyl] -N-( 1-naphthylmethyl)glycyl-methionine methyl e~ter;

5 N-[1 -(4-Pyridylglycyl) pyrrolidin-2(S)-ylmethyl]-N-( 1-naphthylmethyl)glycyl-methionine methyl ester;

N-l1-(Seryl)pyrrolidin-2(S)-ylmethyl]- N-(l-naphthylmethyl)glycyl-methionine;
N-[ l -(D-Alanyl) pyrrolidin-2(S)-ylmethyl l-N-( I -naphthylmethyl)glycyl-methionine;

N-[l-(lH-Imidazol-4-carbonyl)pyrrolidin-2(S)-ylmethyl]- N-(1-15 naphthylmethyl)glycyl-methionine;

N-[ 1 -(Isoasparagyl) pyrrolidin-2(S)-ylmethyl] -N-( 1-naphthylmethyl)glycyl-methionine;

20 N-[1-(lH-Imidazol-4-propionyl) pyrrolidin-2(S)-ylmethyl]- N-(l-naphthylmethyl)glycyl-methionine;

N-L 1 -(3-Pyridylacetyl) pyrrolidin-2(S)-ylmethyl~-N-( I -naphthylmethyl)glycyl-methionine;
N-[1-(2-Pyridylacetyl) pyrrolidin-2(S)-ylmethyl]-N-(l-naphthylmethyl)glycyl-methionine;

N- [ 1 -(4-Pyridylglycyl) pyrrolidin-2(S)-ylmethyl] -N-( 1 -30 naphthylmethyl)glycyl-methionine;

N-[ 1-(1 H-lmidazol-4-ylmethyl)pyrrolidin-2(S)-ylmethyl]- N-( I -naphthylmethyl)glycyl-methionine;

CA 022~19~ 1998-10-16 N-l 1 -(2-Aminoethyl)pyrrolidin-2(S)-ylmethyl] - N-( 1-naphthylmethyl)glycyl-methionine;

N- [ 1 -(Glycyl) pyrrolidin-2(S)-ylmethyl] -N-( 1 -naphthylmethyl)glycyl -5 (2-thienyl)alanine;

N-[l-(lH-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(1-naphthylmethyl)glycyl-(tri~uoromethyl)alanine;

10 N-[ 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(1-naphthylmethyl)glycyl-(2(S)-amino-4-acetylamino)butyric acid;

N-[ 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethylJ- N-( 1-naphthylmethyl)glycyl-(N,N-dimethyl)glllt~mine;
N-[ 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl~- N-(benzyl)glycyl-methionine;

N-[l-(Glycyl)pyrrolidin-2(S)-ylmethyl]- N-(benzyl)glycyl-methionine;
N-L1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(4-methoxybenzyl)glycyl-methionine;

N-[1-(Glycyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl]- N-(benzyl)glycyl-25 methionine;

N-L1-(1H-lmidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl]- N-(benzyl)glycyl-methionine;

30 N-((4-Imidazolyl)methyl-(2S)-pyrrolidinylmethyl)-N-( 1-naphthylmethyl)glycyl-methionine methyl ester;

N-[ 1 -(Glycyl) pyrrolidin-2(S)-ylmethylJ-N-( 1 -naphthylmethyl)glycyl-(2-thienyl)alanine methyl ester;

CA 022~19~ 1998-10-16 N- L 1-(1 H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(1 -naphthylmethyl)glycyl-(N,N-dimethyl)glutamine methyl ester;

5 N-~ 1-(1 H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl] - N-( 1-naphthylmethyl)glycyl-(trifluoromethyl)alanine methyl ester;

N-[ 1-(1 H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyll- N-(l -naphthylmethyl)glycyl-(2(S)-amino-4-acetylamino)butyric acid methyl 1 0 ester;

N-[ 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl~- N-(benzyl)glycyl-methionine methyl ester;

15 N-l 1-(Glycyl)pyrrolidin-2(S)-ylmethyl]- N-(benzyl)glycyl-methionine methyl ester;

N-[1-(lH-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl~- N-(4-methoxybenzyl)glycyl-methionine methyl ester;
N-[ 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl] - N-(benzyl)glycyl-methionine methyl ester;

N-[l-(Glycyl) pyrrolidin-3(S)-ethyl-2(S)-ylmethyl]-N-(benzyl)glycyl-25 methionine methyl ester;

N-[ 1 -(Glycyl) pyrrolidin-2(S)-ylmethyl l-N-( I -naphthylmethyl)glycyl-methionine isopropyl ester;

30 N-L 1 -(Glycyl) pyrrolidin-2(S)-ylmethyl]-N-( I -naphthylmethyl)glycyl-methionine cyclohexyl ester;

N-[l-(Glycyl) pyrrolidin-2(S)-ylmethyl]-N-(l-naphthylmethyl)glycyl-methionine benzyl ester;

CA 022~19~ 1998-10-16 N-[1-(Glycyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine ethyl ester;

N- L 1 -(Sarcosyl) pyrrolidin-2(S)-ylmethyl l-N-( 1 -naphthylmethyl)glycyl-5 methionine isopropyl ester;

N-[ 1 -(N,N-Dimethylglycyl) pyrrolidin-2(S)-ylmethyl] -N-( 1-naphthylmethyl)glycyl-methionine isopropyl ester;

10 N-[ 1 -(Glycyl) pyrrolidin-2(S)-ylmethyl]-N-( 1 -naphthylmethyl)glycyl-methionine (2-pyridylmethyl) ester;

N-[ 1 -(Glycyl) pyrrolidin-2(S)-ylmethyl l-N-( 1 -naphthylmethyl)glycyl-methionine (l-glyceryl) ester;

N-[ 1 -L-Prolylpyrrolidin-2(S)-ylmethyl]-N-( 1-naphthylmethyl)glycyl-methionine methyl ester;

N-[ 1 -(L-Prolyl)pyrrolidin-2(S)-ylmethyl]-N-(1-20 naphthylmethyl)glycyl-methionine;

N-[ 1-(1 -Morpholinoacetyl)pyrrolidin-2(S)-ylmethyl]-N-( 1-naphthylmethyl)glycyl-methionine methyl ester;

25 N-[ 1-(1 -Morpholinoacetyl)pyrrolidin-2(S)-ylmethyl]-N-( 1-naphthylmethyl)glycyl-methionine;

N - [ 1 -(4-Piperidinecarbonyl)pyrrolidin-2(S)-ylmethyl] -N-( 1 -naphthylmethyl)glycyl-methionine methyl ester;
N-[ 1 -(4-Piperidinecarbonyl)pyrrolidin-2(S)-ylmethyl]-N-( 1-naphthylmethyl)glycyl-methionine;

N-[ 1 -(3-Piperidinecarbonyl)pyrrolidin-2(S)-ylmethyl] -N-( 1-35 naphthylmethyl)glycyl-methionine methyl ester;

CA 022~19~ 1998-10-16 N~ (3-Piperidinecarbonyl)pyrrolidin-2(S)-ylmethyl~-N-(1-naphthylmethyl)glycyl-methionine;

5 N-l 1-(2-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl]-N-(l-naphthylmethyl)glycyl-methionine methyl ester;

N-[ l -(2-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl]-N-( 1-naphthylmethyl)glycyl-methionine;
N-[ 1 -(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl] -N-( I -naphthylmethyl)glycyl-methionine methyl ester;

N-[ 1 -(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl] -N-( 1-1 5 naphthylmethyl)glycyl-methionine;

N- [ 1 -(4-Pyridyl(N-methyl)glycyl)pyrrolidin-2(S )-ylmethyl] -N-( l -naphthylmethyl)glycyl-methionine methyl ester;

20 N-[ 1 -(4-Pyridyl(N-methyl)glycyl)pyrrolidin-2(S)-ylmethyl]-N-( 1-naphthylmethyl)glycyl-methionine;

N-[ 1-( I H-Imidazol-4-ylpropionyl) pyrrolidin-2(S)-ylmethyl]-N-( 1-naphthylmethyl)glycyl-(~-acetylamino)alanine;
N-[ 1-(1 H-Imidazol-4-ylpropionyl) pyrrolidin-2(S)-ylmethyll-N-( 1-naphthylmethyl)glycyl-(~-acetylamino)alanine methyl ester;

N-[1-(4-Pyridylglycyl) pyrrolidin-2(S)-ylmethyl]-N-(l-30 naphthylmethyl)glycyl-(,B-acetylamino)alanine;

N-L 1 -(4-Pyridylglycyl) pyrrolidin-2(S)-ylmethyl] -N-( 1-naphthylmethyl)glycyl-(~-acetylamino)alanine methyl ester;

CA 022~19~ 1998-10-16 N-~ 1 -(Glycyl) pyrrolidin-2(S)-ylmethyl]-N-( 1 -naphthylmethyl)glycyl-(~-acetylamino)alanine cyclohexyl ester;

N- [ 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl] - N-( 1-5 naphthylmethyl)glycyl-(N-methyl)glutamine;

N-L 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl] - N-( 1-naphthylmethyl)glycyl-(N-methyl)glutamine methyl ester;

10 N-[ 1-(1 H-Imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl]-N-( 1-naphthylmethyl)glycyl-(~-methylcarbonylamino)alanine;

N-Ll-(1H-Imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl]-N-(l-naphthylmethyl)glycyl-(~-methylcarbonylamino)alanine methyl ester;
N-~ 1-(1 H-Imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl] -N-( 1-naphthylmethyl)glycyl-(~-methylsulfonylamino)alanine;

N-[ 1-(1 H-Imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl]-N-(l -20 naphthylmethyl)glycyl-(~-methylsulfonylamino)alanine methyl ester;

N-[ 1-(1 H-Imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl]-N-( 1-naphthylmethyl)glycyl-(~-propionylamino)alanine;

25 N-[ 1-(1 H-Imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl]-N-( I -naphthylmethyl)glycyl-(~-propionylamino)alanine methyl ester;

N-~ 1-(1 H-Irnidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl] -N-( 1-naphthylmethyl)glycyl-(~-pyrrolidinon- 1 -ylamino)alanine;
N-l l-(lH-Imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl]-N-(l-naphthylmethyl)glycyl-(~-pyrrolidinon-1-ylamino)alanine methyl ester;

CA 022~19~ 1998-10-16 N-[1-(1H-Irnidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl~- N-(3-methoxybenzyl)glycyl -methionine;

N- 1 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl] - N-(3-5 methoxybenzyl)glycyl-methionine methyl ester;

N-~ 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(2-methoxybenzyl)glycyl-methionine;

10 N-L 1 -(lH-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(2-methoxybenzyl)glycyl-methionine methyl ester;

N-[l-(Glycyl)pyrrolidin-2(S)-ylmethyl]- N-(3-methoxybenzyl)glycyl-methionine;
N-[1-(Glycyl)pyrrolidin-2(S)-ylmethyll- N-(3-methoxybenzyl)glycyl-methionine methyl ester;

N-[ l -(Glycyl)pyrrolidin-2(S)-ylmethyl 1- N-(2-methoxybenzyl)glycyl-20 methionine;

N-[l-(Glycyl)pyrrolidin-2(S)-ylmethyl]- N-(2-methoxybenzyl)glycyl-methionine methyl ester;

25 N-[ 1-(1 H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl] - N-(2-methoxybenzyl)glycyl-methionine;

N-[ I -(lH-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl 1- N-(2-methoxybenzyl)glycyl-methionine methyl ester;
N-[ 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl 1- N-(3-cyanobenzyl)glycyl-methionine;

CA 022~19~ 1998-10-16 N-[1-(lH-lmidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(3-cyanobenzyl)glycyl-methionine methyl ester;

N-[1-(lH-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(4-5 cyanobenzyl)glycyl-methionine;

N- [ 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl] - N-(2-cyanobenzyl)glycyl-methionine;

10 N-[ 1-( l H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(2-cyanobenzyl)glycyl-methionine methyl ester;

N-[1-(Glycyl)pyrrolidin-2(S)-ylmethyl]- N-(2-cyanobenzyl)glycyl-methionine;
N-[l-(Glycyl)pyrrolidin-2(S)-ylmethyl]- N-(2-cyanobenzyl)glycyl-methionine methyl ester;

N-[1-(1H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl]- N-(2-20 cyanobenzyl)glycyl-methionine;

N-[ 1-(1 H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl] - N-(2-cyanobenzyl)glycyl-methionine methyl ester;

25 N-[ 1 -(lH-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(2-methylbenzyl)glycyl-methionine;

N-[ 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(2-methylbenzyl)glycyl-methionine methyl ester;
N-[ 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(2-trifluoromethylbenzyl)glycyl-methionine;

CA 022~19~ 1998-10-16 W O 97~38664 PCTrUS97/06248 N-[ I -(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(2-trifluoromethylbenzyl)glycyl-methionine methyl ester;

N-[l-(lH-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyll- N-(l-5 naphthylsulfonyl)glycyl-methionine;

N-[l-(lH-Irnidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl1- N-(l-naphthylsulfonyl)glycyl-methionine methyl ester;

10 N-[ 1 -(Glycyl) pyrrolidin-2(S)-ylmethyl]-N-( 1 -naphthylmethyl)glycyl-methionine 4-N-methylpiperidinyl e.ster;

N-[l-(Glycyl) pyrrolidin-2(S)-ylmethyl~-N-(l-naphthylmethyl)glycyl-methionine tert-butyl ester;
N-[ 1 -(Glycyl) pyrrolidin-2(S)-ylmethyl ]-N-( 1 -naphthylmethyl)glycyl-methionine 3-pentyl ester;

N-[1-(4-Pyridylglycyl) pyrrolidin-2(S)-ylmethyll-N-(l-20 naphthylmethyl)glycyl-methionine isopropyl ester;

N-L 1-(1 H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl] - N-( 1 1 -naphthylmethyl)glycyl-methionine isopropyl ester;

2~ N-[ 1 -(4-Imidazoleacetyl)pyrrolidin-2(S)-ylmethyl]-N-( 1-naphthylmethyl)glycyl-methionine methyl ester /=N O H O
HN~ ~N~N ~'~ OMe ~ O ~ 3 N-[ 1 -(4-Imidazoleacetyl)pyrrolidin-2(S)-ylmethyl] -N-( I -naphthylmethyl)glycyl-methionine isopropyl ester /=N O O
HN~I'N N~NH~Jl~oi Pr ~3 SC H3 N-[ 1 -(Glycyl)pyrrolidin-2(S)-ylmethyll-N-(1 -naphthylmethyl)glycyl-5 methionine 2 J~N~N 1~ ;

~3 SCH3 N-[ 1 -(Glycyl)pyrrolidin-2(S)-ylmethyl~-N-(l -naphthylmethyl)glycyl-methionine methyl ester 2 J~N~ N~ N Jl'OMe ~ SCH3 10 N-[ 1 -(Glycyl)pyrrolidin-2(S)-ylmethyl]-N-( 1 -naphthylmethyl)glycyl-methionine isopropyl ester .. . . _ .

H NJ~ H N~NJ~Oi-Pr N-L 1 -(L-Pyroglutamyl)pyrrolidin-2(S)-ylmethyll-N-( 1-naphthylmethyl)glycyl-methionine ~ N~ ~H

S N- ~ 1 -(L-Pyroglutamyl)pyrrolidin-2(S)-ylmethylJ -N-( I -naphthylmethyl)glycyl-methionine methyl ester ~ ~ ~ N~ ~Me 2(S)-[ 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine methyl ester ~3 /=N o /~/
HN~ H J~NH~J~
~ O ~

C H3 SC H~

2(S)-[ 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyloxy] -3 -phenylpropionyl -methionine HN~ N~ o NJ~OH

~ -N-l l-(Sarcosyl)pyrrolidin-2(S)-ylmethyl]-N-(l-naphthylmethyl)glycyl-methionine H3CHN--J~N~N~
~' 3' N-[ 1 -(Sarcosyl)pyrrolidin-2(S)-y]methyl]-N-( 1 -naphthylmethyl)glycyl-methionine methyl ester O H H O
H3cHNJ~N~/\N~ J~OMe ~ ~3 SCH3 10 N-[ 1 -(N,N-Dimethylglycyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine ~ 81 -(H3C)2NRN N~

~3 SC H3 N-[ 1 -(N,N-Dimethylglycyl)pyrrolidin-2(S)-ylmethyl] -N-( 1-naphthylmethyl)glycyl-methionine methyl ester (H3C)~N RN~N~ ~Me S N-[ 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl] - N-( 1-naphthylmethyl)glycyl-(,B-acetylamino)alanine methyl ester /=N O H H O
HN ~N~ ,~f OCH3 \NH

N-[ 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-( 1-naphthylmethyl)glycyl-(~-acetylamino)alanine ~N O H O
HN,~I~ N/\l~ OH

~ O~CH3 WO 97138664 PC~/US97/06248 - ~2 -N-[ 1 -(Glycyl) pyrrolidin-2(S)-ylmethyll-N-( 1 -naphthylmethyl)glycyl-(,B-acetylamino)alanine cyclohexyl ester H2NJ~'N J ,_ N-[ 1 -(Glycyl) pyrrolidin-2(S)-ylmethyll-N-( 1 -naphthylmethyl)glycyl-(,~-acetylamino)alanine H2NJ~"'~N~N J~OH

~ N~CH3 N- [ 1 -(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl] -N-( 1-naphthylmethyl)glycyl-methionine isopropyl ester 3~N~ ~ ~N~ ;'~O~

10 N-[ 1 -(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl]-N-(I -naphthylmethyl)glycyl-methionine - ~3 -"'~N~OH

N-l 1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(2-methoxybenzyl)glycyl-methionine ,~OCH3 S

N3~_ N~

N-[1-(lH-lmidazol-4-yl~cetyl)pyrrolidin-2(S)-ylmethyl]- N-(2-methoxybenzyl)glycyl-methionine methyl e.ster ~C~C 5/

N3~N2 N

N-[l-(Glycyl)pyrrolidin-2(S)-ylmethyl]- N-(2-methoxybenzyl)glycyl-methionine methyl ester H2N ~Ir N~

N-[l-(Glycyl)pyrrolidin-2(S)-ylmethyl]- N-(2-methoxybenzyl)glycyl-methionine ~OCH3 S

NH

H2N--~f N~

5 N-[ 1-(1 H-lmidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl] - N-(2-methoxybenzyl)glycyl-methionine methyl e~ter ~OCH3 S/

<~ N 'b--OCH3 HN N~
o N-[ 1-(1 H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyll - N-(2-methoxybenzyl)glycyl-methionine N ' --J~NH

H ~
o N-[ 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyll - N-(2-cyanobenzyl)glycyl-methionine ~CN S/
~ ~ ~
- H
N~N~
NH

5 N-~ 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(2-cyanobenzyl)glycyl-methionine methyl ester ,~CN S /

- O
N~ N~
NH

N-[l-(Glycyl) pyrrolidin-2(S)-ylmethyl]-N-(I-naphthylmethyl)glycyl-methionine 4-N-methylpiperidinyl ester CA 022~19~ 1998-10-16 H2NJ~ '' ~N~O{~N-CH3 N-~ 1-(1 H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyll - N-( 1-naphthylmethyl)glycyl-methionine i.sopropyl ester HN~

SCH ~

N-[( 1 H-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl e~ter;

10 N-~(lH-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3 (S)-isoquinolinecarbonyl-methionine;

N-[l-(lH-imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-prolyl-methionine methyl e~ter;
N-[ I -(1 H-imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-prolyl-methionine;

N-[ 1 -Glycylpyrrolidin-2(S)-ylmethyl]-3(S)-ethylprolyl-methionine 20 methyl ester;

N-[ 1 -Glycylpyrrolidin-2(S)-ylmethyl]-3(S)-ethylprolyl-methionine;

N-[L-Pyroglutamyl-2(S)-amino-3 (S)-methylpentyl] - I ~2?3 ,4-tetrahydro-25 3(S)-i~oquinolinecarbonyl-methionine ~ ~NH OH
O I N O
~/~ ~

N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]- 1 ,2,3,4-tetrahydro-3(S)-i~oquinolinecarbonyl-methionine methyl ester ~CH3 ~ ~N OCH3 O (~N ~
0/~ ~

S N-[ 1 -(lH-imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethylprolyl-methionine /= N O H ~\~ N
HN~N~--N~ O

N-L 1 -(I H-imidazol-4-ylacetyl)-pyrrolidin-2(S-)ylmethyl~-3(S)-ethylprolyl-methionine methyl ester ~ _ O
r N~ '~N~oCH3 ~/ ~
N-[(1 H-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-prolyl-methionine methyl ester o f H ~N~oCH3 HN/~/ 1~>
/~

5 N-[( 1 H-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-prolyl-methionine H '~ NH ~OH

H N /~/ ~>
\= N O /~

N-[(lH-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-1 ,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester N-~(lH-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-1 ,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine CA 022~19~ 1998-10-16 N-l L-Pyroglutamyl-2(S)-amino-3 (S)-methylpentyl 1- I ,2,3 ,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester 5 N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl 1-1 ,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine N-[(lH-imidazol-4-ylacetyl-2(S)-~mino)-3(S)-methylpentyl]-prolyl-methionine methyl ester N-[(l H-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentylJ-prolyl-methionine N-[ 1-(1 H-imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-15 prolyl-methionine methyl ester N-[ 1-( I H-imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl] -prolyl-methionine 20 N-[l-(lH-imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethylprolyl-methionine methyl ester N-[ 1-(1 H-imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethylprolyl-methionine N-[ 1 -Glycylpyrrolidin-2(S)-ylmethyl]-3(S)-ethylprolyl-methionine methyl ester N-[ 1 -Glycylpyrrolidin-2(S)-ylmethyl]-3(S)-ethylprolyl-methionine 30 2(S)-Butyl- 1 -(2,3-diaminoprop- 1 -yl)- 1-(1 -naphthoyl)piperazine 1 -(3-Amino-2-(2-naphthylmethylamino)prop- 1 -yl)-2(S)-butyl-4-( 1-naphthoyl)piperazine CA 022~19~ 1998-10-16 2(S)-Butyl- 1- { 5-L 1 -(2-naphthylmethyl)] -4,5-dihydroimidazol ) methyl-4-( 1 -naphthoyl)piperazine 1- [5 -( l -Benzylimidazol)methyl I -2(S)-butyl-4-( l -naphthoyl)piperazine s 1-{ 5-L l -(4-nitrobenzyl)]imidazolylmethyl }-2(S)-butyl-4-(1-naphthoyl)piperazine l -(3-Acetamidomethylthio-2(R)-aminoprop- l -y])-2(S)-butyl-4-( 1-1 0 naphthoyl)piperazine 2(S)-Butyl-l -[2-(1-imidazolyl)ethyl].~iulfonyl-4-(1 -naphthoyl)piperazine 2(R)-Butyl- 1 -imidazolyl-4-methyl-4-( l -naphthoyl)piperazine 2(S)-Butyl-4-( 1 -naphthoyl)- 1 -(3-pyridylmethyl)piperazine l -2(S)-butyl-(2(R)-(4-nitrobenzyl)amino-3-hydroxypropyl)-4-( 1-naphthoyl)piperazine 1 -(2(R)-Amino-3-hydroxyheptadecyl)-2(S)-butyl-4-( 1 -naphthoyl)-piperazine 2(S)-Benzyl- l -imidazolyl-4-methyl-4-( l -naphthoyl)piperazine 1 -(2(R)-Amino-3 -(3 -benzylthio)propyl)-2(S )-butyl -4-( l -naphthoyl)piperazine 1 -(2(R)-Amino-3-[3-(4-nitrobenzylthio)propyl])-2(S)-butyl-4-(l -30 naphthoyl)piperazine 2(S)-Butyl- l -[(4-imidazolyl)ethyl]-4-( 1 -naphthoyl)piperazine 2(S)-Butyl-1 -[(4-imidazolyl)methyl]-4-(l -naphthoyl)piperazine CA 022~19~ 1998-10-16 2(S)-Butyl- 1-[(1 -naphth-2-ylmethyl)- 1 H-imidazol-5-yl)acetyl] -4-(1-naphthoyl)piperazine 5 2(S)-Butyl-l-[(l-naphth-2-ylmethyl)-lH-imidazol-5-yl)ethyl]-4-(1-naphthoyl)piperazine 1 -(2(R)-Amino-3-hydroypropyl)-2(S)-butyl-4-( 1 -naphthoyl)piperazine 1 -(2(R)-Amino-4-hydroxybutyl)-2(S)-butyl-4-( 1 -naphthoyl)piperazine 1 -(2-Amino-3-(2-benzyloxyphenyl)propyl)-2(S)-butyl-4-(1 -naphthoyl)piperazine 1 -(2-Amino-3-(2-hydroxyphenyl)propyl)-2(S)-butyl-4-( 1 -naphthoyl)piperazine 1 -[3-(4-imidazolyl)propyl] -2(S)-butyl-4-( 1 -naphthoyl)-piperazine 20 2(S)-n-Butyl-4-(2,3-dimethylphenyl)- 1 -(4-imidazolylmethyl)-piperazin-5-one 2(S)-n-Butyl- 1-1 1 -(4-cyanobenzyl)imidazol-5-ylmethyl 1-4-(2,3-dimethylphenyl)piperazin-5-one 1-[ 1 -(4-Cyanobenzyl)imidazol-5-ylmethyl]-4-(2, 3-dimethylphenyl)-2(S)-(2-methoxyethyl)piperazin-5-one 2(S)-n-Butyl-4-( 1 -naphthoyl)- 1-[1-(1 -naphthylmethyl)imidazol-5-30 ylmethyl]-piperazine 2(S)-n-Butyl-4-( 1 -naphthoyl)- 1-[1 -(2-naphthylmethyl)imidazol-5 -ylmethyl~ -piperazine CA 022~19~ 1998-10-16 2(S)-n-Butyl- 1-[ I -(4-cyanobenzyl)imidazol-5-ylmethyl]-4-( 1-naphthoyl~piperazine 2(S)-n-Butyl- 1-[ I -(4-methoxybenzyl)imidazol-5-ylmethyl]-4-( 1-5 naphthoyl)piperazine 2(S)-n-Butyl-1-[ 1 -(3-methyl-2-butenyl)imidazol-5-ylmethyl]-4-( 1-naphthoyl)piperazine 10 2(S)-n-Butyl- 1-[1 -(4-fluorobenzyl)imidazol-5-ylmethyl}-4-( 1-naphthoyl)piperazine 2(S)-n-Butyl-1-1 1-(4-chlorobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine I -L 1 -(4-B romobenzyl)imidazol-5-ylmethyl] -2(S)-n-butyl-4-( 1-naphthoyl)piperazine 2(S)-n-Butyl-4-( 1 -naphthoyl)- 1-[1 -(4-trifluoromethylbenzyl)imidazol-5-20 ylmethyl]-piperazine 2(S)-n-Butyl-1-[1 -(4-methylbenzyl)imidazol-5-ylmethyl]-4-(1 -naphthoyl)-piperazine 25 2(S)-n-Butyl-1-[1-(3-methylbenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)-piperazine 1-[1 -(4-Phenylbenzyl)imidazol-5-ylmethyl]-2(S)-n-butyl-4-( 1-naphthoyl)-piperazine 2(S)-n-Butyl-4-( 1 -naphthoyl)- 1-[1 -(2-phenylethyl)imidazol-5-ylmethyl] -plperazlne CA 022~19~ 1998-10-16 2(S)-n-Butyl-4-( 1 -naphthoyl)- 1-[1 -(4-trifluoromethoxy)imidazol-5-ylmethyl]piperazine 1- ~1 1 -(4-cyanobenzyl)-lH-imidazol-5-yl]acetyl } -2(S)-n-butyl-4-(1-5 naphthoyl)piperazine (N-[ 1 -Cyanobenzyl)- 1 H-imidazol-5-yl)acetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl methionine (N-[ 1 -Cyanobenzyl)- 1 H-imidazol-5-yl)acetyl]pyrrolidin-2(S)-ylmethyl]-10 3(S)-ethyl-prolyl methionine methyl ester (N-[ 1 -Cyanobenzyl)- 1 H-imidazol-5-yl)acetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl methionine isopropyl ester N-[1-(1~I-Irnidazol-4-propionyl) pyrrolidin-2(S)-ylmethyl]-N-(2-15 methoxybenzyl)glycyl-methionine isopropyl ester;

2(S)-1 2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl] -pentyloxy-3-phenylpropionyl-homo,serine lactone (Compound 3), 20 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserine (Compound 4), 2(S)-1 2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl~pentyloxy-2-methyl-3-phenylpropionyl-homoserine lactone, 2(S)-L2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy -2-methyl-3 -phenylpropionyl -homo.serine, 2(S)-L2(S)-[2(R)-Amino-3-mercapto)propylamino-3(S)-30 methyl]pentyloxy-4-pentenoyl-homo.serine lactone, 2(S)-~2(S)-L2(R)-Amino-3-mercapto]propylamino-3(S)-methyl~-pentyloxy-4-pentenoyl -homo~erine, CA 022~19~ 1998-10-16 2(S)-1 2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxypentanoyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylaniino-3(S)-5 methyl]pentyloxypentanoyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercaptolpropylamino-3(S)-methyl]5-pentyloxy-4-methylpentanoyl-homoserine lactone, 10 2(S)-[2(S)-[2(R)-Amino-3-mercaptolpropylamino-3(S)-methyl]pentyloxy-4-methylpentanoyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercaptolpropylamino-3(S)-methyllpentyloxy-3-methylbutanoyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-methylbutanoyl -homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-20 methylJpentyloxy-3-phenylbutanoyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3 -phenylbutanoyl-homoserine, 25 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentylthio-2-methyl-3-phenylpropionyl-homoserine lactone, 2(S)-[2(S)-L2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentylthio-2-methyl-3 -phenylpropionyl-homoserine, 2(S)-1 2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentylsulfonyl-2-methyl-3-phenylpropionyl-homo.serine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-.....

CA 022~19~ 1998-10-16 pentylsulfonyl-2-methyl-3 -phenylpropionyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylaniino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine methyl ester, s 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methionine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto3propylamino-3(S)-10 methyl]pentyloxy-3-phenylpropionyl-methionine sulfone methyl ester (Compound 5), 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methionine sulfone (Compound 6), 2(S)-[2(S)-L2(R)-Amino-3-mercapto]propylamino-3(S)-methyl] -pentyloxy-3-phenylpropionyl-methionine sulfone isopropyl ester, 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyll -20 pentyloxy-3-naphth-2-yl-propionyt-methionine sulfone methyl ester, 2-(S)-~2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl] -pentyloxy-3-naphth-2-yl-propionyI-methionine .sulfone, 25 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-naphth-1-yl-propionyl-methionine sulfone methyl e.ster, 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-30 methyl]pentyloxy-3-naphth- 1 -yl-propionyl-methionine sulfone, 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyllpentyloxy-3-methybutanoyl-methionine methyl ester.

CA 022~19~ 1998-10-16 2-(S)-L2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3 -methybutanoyl-methionine, Disulphide of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-~S 3(S)methyl3pentyloxy-3-phenylpropionyl-homoserine lactone, Disulphide of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyI-homoserine, 10 Disulphide of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)methyl}pentyloxy-3-methylbutanoyl-methionine methyl ester and the pharrnaceutically acceptable salts, disulfides or optical i.somers thereof.
Compounds which are useful in the pre,sent invention, and methods of synthesis thereof, can be found in the following patents, pending applications and publications:
WO 95/32987 published on 7 December 1995.
U. S. Pat. No. 5,420,245;
20 European Pat. Publ. 0 618 221;
WO 94/26723;
WO 95/08542;
WO 95/11917;

12.
U. S. Pat. No. 5,238,922 granted on August 24, 1993;;

U. S. Pat. No. 5,340,82X granted on August 23, 1994;;

30 U. S. Pat. No. 5,480,893 granted on January 2, 1996;;

U. S. Pat. No. 5,352,705 granted on October 4, 1994;

U. S. Pat. No. 5,504,115 granted on April 2, 1996;
U. S. Pat. No. 5,326,773 granted on July 5, 1994;

CA 022~19~ 1998-10-16 U. S. Pat. No. 5,504,212 granted on April 2, 1996;;

U. S. Pat. No. 5,439,918 granted on August 8, 1995;

USSN 08/968,025 filed on October 29, 1992 and USSN 08/143,943 filed on October 27, 1993;

USSN 08/080,028 filed on June 1~, 1993 and USSN 0~/237,586 filed on 10 Mayll,1994;

USSN 08/314,987 filed on September 29, l9g4 USSN 0~/315,171 filed on September 29, 1994 USSN 08/315,046 filed on September 29, 1994;

USSN 08/315,161 filed on September 29, 1994; USSN 08/399,282 filed on March 6, 1995; USSN 472,077 filed on June 6, 1995 and 20 USSN 08/527,972 filed on September 14, 1995 U. S. Pat. No. 5,491,164 granted on February 13, 1996;;

USSN 08/314,974 filed on September 29, 1994 USSN 08/412,621 filed on March 29, 1995 and USSN 08/448,865 filed on May 24, 1995;

USSN 08/413,137 filed on March 29, 1995;;
USSN 08/412,828 filed on March 29, 1995;

USSN 08/412,829 filed on March 29, 1995; and USSN 0X/470,690 filed on June 6, 1995; and USSN 08/600,728 filed on February 2~, 1996;
USSN 08/412,830 filed on March 29, 1995;

CA 022~19~ 1998-10-16 USSN 08/449,038 filed on May 24, 1995;; and USSN 08/468,160 filed on June 6, 1995.;
s All patents, publications and pending patent applications identified are hereby incorporated by reference.
The term "alkyl" refers to a monovalent alkane (hydrocarbon) derived radical cont~ining from 1 to 15 carbon atoms unless otherwilse defined. It may be straight, branched or cyclic.
Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopentyl and cyclohexyl.
When substituted alkyl is present, thi.s refers to a straight, branched or cyclic alkyl group as defined above, .substituted with 1-3 groups as defined with respect to each variable.
Heteroalkyl refers to an alkyl group having from 2-15 carbon atoms, and interrupted by from 1-4 heteroatoms selected from O, S and N.
The term "alkenyl" refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 15 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic (non-resonating) carbon-carbon double bonds may be present. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. A~s described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted when a substituted alkenyl group i~s provided.

CA 022~19~ 1998-10-16 99 _ The term "alkynyl" refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 15 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be pre,sent. Preferred alkynyl groups S include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be sub,stituted when a substituted alkynyl group is provided.
Aryl refers to aromatic rings e.g., phenyl, substituted 10 phenyl and like groups as well as rings which are fu~sed, e.g., naphthyl and the like. Aryl thus contains at lea.st one ring having at least 6 atoms, with up to two such rings being present, containing up to lO atom,s therein, with alternating (resonating) double bonds between adjacent carbon atoms. The preferred aryl groups are phenyl and naphthyl.
15 Aryl groups may likewise be substituted as defined below. Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups. With regard to the farne,syl tranlsferase inhibitors, "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 20 aromatic. Examples of aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like.
The term "heteroaryl" refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atom,s, or a bicyclic aromatic 25 group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S, and in which from l to 3 additional carbon atoms are optionally replaced by nitrogen 30 heteroatoms. The heteroaryl group is optionally ~substituted with up to three groups.
Heteroaryl thus includes aromatic and partially aromatic groups which contain one or more heteroatoms. Examples of this type are thiophene, purine, imidazopyridine, pyridine, oxazole, thiazole, CA 022~19~ 1998-10-16 oxazine, pyrazole, tetrazole, imidazole, pyridine, pyrimidine, pyrazine and triazine. Examples of partially aromatic groups are tetrahydro-imidazo[4,5-clpyridine, phthalidyl and saccharinyl, as defined below.
With regard to the farnesyl transferase inhibitors, the term S heterocycle or heterocyclic, as used herein, represents a stable S- to 7-membered monocyclic or stable ~- to l l-membered bicyclic or stable 11-15 membered tricyclic heterocycle ring which is either saturated or uns~turated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fu.sed 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, 2-oxoazepinyl, 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, tetrahydrofilryl, tetrahydroi.soquinolinyl, tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl .sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.
Preferably, heterocycle is selected from imidazolyl, 2-oxopyrrolidinyl, piperidyl, pyridyl and pyrrolidinyl.
With regard to the farnesyl transferase inhibitors, the terms "substituted aryl", "substituted heterocycle" and "substituted cycloalkyl"
are intended to include the cyclic group which is substituted with I or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(cl-c6 alkyl)2~ NO2, CN, (Cl-C6 alkyl)O-, -OH, (Cl-C6 alkyl)s(o)m-~ (cl-c6 alkyl)C(O)NH-, H2N-C(NH)-, (Cl-C6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)-, N3,(Cl-C6 alkyl) OC(O)NH- and C1-C20 alkyl.
In the present method, amino acids which are disclosed are identified both by conventional 3 letter and single letter abbreviations a.
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 Gln Q
Glutamic acid Glu E
Glutamine or Glutamic acid Glx Z
Glycine Gly G
Histidine His H
Isoleucine Ile Leucine Leu L
Lysine Lys K
Methionine Met M
Phenylalanine Phe F
Proline Pro P
Serine Ser S
Threonine Thr T
Tryptophan Trp W
Tyrosine Tyr Y
Valine Val V

CA 022~19~ 1998-10-16 The compounds used in the present method may have a~symmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. Unless other~,vise 5 specified, named amino acids are understood to have the natural "L"
stereoconfiguration The following structure:

,N~
( 7H2), represents a cyclic amine moiety having 5 or 6 members in the ring, lO such a cyclic amine which may be optionally fused to a phenyl or cyclohexyl rin~. Example,s of .such a cyclic amine moiety include, but are not limited to, the following specific structures:

It is also understood that substitution on the cyclic amine moiety by R2a 15 and R2b may be on different carbon atoms or on the same carbon atom.
When R3 and R4 are combined to form - (cH2)s -, cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to:
(~
20When R5a and R5b are combined to form - (CH2)S -, cyclic moieties as described hereinabove for R3 and R4 are formed.

. .

CA 022~19~ 1998-10-16 In addition, ,such cyclic moieties may optionally include a heteroatom(s).
Examples of such heteroatom-containing cyclic moieties include, but are not limited to:

~ ~J ~OJ ~S J

O ' H O NJ
~ COR10 The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as forrned, e.g., from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids Isuch a.s 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, meth~nesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
It is intended that the definition of any substituent or variable (e.g., 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, -NHc2Hs~ etc. It is understood that substituents and substitution patterns on the compound~ 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 salt~i of the compounds of this invention can be synthesized from the compounds of this invention CA 022~19~ 1998-10-16 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 salt-forming inorganic or organic acid in a .suitable solvent or various combinations 5 of solvents.
The compounds of formulas (II-a) through (II-k) 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, 10 in the following works: Schroeder et al., "The Peptides", Vol. I, Academic Press 1965, or Bodanszky et al., "Peptifle Synthesis", Interscience Publishers, 1966, or McOmie (ed.) "P~-otective G~ oups in Organic Chemistry", Plenum Press, 1973, or Barany et al., "The Peptides: Analysis, Synthesis, Biology" 2, Chapter 1, Academic Press, 15 l 9P~0, or Stewart et al., "Solid Phase Peptid~ Synthesi.~ ", Second Edition, Pierce Chemical Company, 19~S4. Also useful in exemplifying synthe.ses of specific unnatural amino acid re,ciidues are European Pat. Appl.
No. 0 350 163 A2 (particularly page 51-52) and J. E. Baldwin et al.
Tetrahed10n, 50:5049-5066 (1994). With regards to the ~ynthesis 20 of instant compounds containing a (~-acetylamino)alanine residue at the C-terminus, use of the commerci~lly available No~-Z-L-2,3-diaminopropionic acid (Fluka) as a starting material is preferred.
Abbreviations used in the description of the chemistry and in the Examples that follow are:
Ac2O Acetic anhydride;
Boc t-Butoxycarbonyl;
DBU 1,X-diazabicyclo[5.4.0~undec-7-ene;
DMAP 4-Dimethylaminopyridine;
DME 1,2-Dimethoxyethane;
DMF Dimethylformamide;
EDC 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide-hydrochloride;
HOBT 1 -Hydroxybenzotriazole hydrate;

CA 022~19~ 1998-10-16 Et3N Triethylamine;
EtOAc Ethyl acetate;
FAB Fast atom bombardment;
- HOOBT 3-Hydroxy- 1 ,2,2-benzotriazin-4(3~)-one;
HPLC High-performance liquid chromatography;
MCPBA m-Chloroperoxybenzoic acid;
MsCI Methanesulfonyl chloride;
NaHMDS Sodium bis(trimethylsilyl)amide;
Py Pyridine;
TFA Trifluoroacetic acid;
THF Tetrahydrofuran.
The compounds are useful in various pharmaceutically acceptable salt forms. The term "pharmaceutically acceptable salt"
15 refers to those salt forms which would be apparent to the pharma-ceutical chemist. i.e., tho,se which are .substantially non-toxic and which provide the desired pharmacokinetic properties, palatability, absorption, distribution, metaboli,sm or excretion. Other factors, more practical in nature, which are also important in the selection, are cost of the raw 20 materials, ease of crystallization, yield, stability, hygroscopicity and flowability of the resulting bulk drug. Conveniently, pharmaceutical compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers.
Pharmaceutically acceptable salts include conventional 25 non-toxic salts or ~luarternary ammonium salts formed, e.g., from non-toxic inorganic or organic acids. Non-toxic 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, 30 glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, i.sethionic, trifluoroacetic and the like.
The pharmaceutically acceptable salts of the present 35 invention c~n be ,synthesized by conventional chemical methods.

CA 022~19~ 1998-10-16 Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forrning inorganic or organic acid or base, in a suitable solvent or solvent combination.
The farnesyl transfera~se inhibitors of formula (II-a) through (II-c) can be synthesized in accordance with Schemes 1-16, 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. Substituents Ra and Rb, as shown in the Schemes, represent the substituent.s R2, R3, R4, and R5;
however their point of attachment to the ring is illustrative only and is not meant to be limiting.
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 Schemes.

Synopsi.s of Schemes l - l 6:
The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures, for the most part. In Scheme I, for example, the synthesis of 2-alkyl substituted piperazines is outlined, and is essentially that described by J. S. Kiely and S. R. Priebe in Or~anic Preparations and Proceedin~s Int., 1990, 22, 761-768. Boc-protected amino acids I, available cornrnercially or by procedures known to those skilled in the art, can be coupled to N-benzyl amino acid esters using a variety of dehydrating agents such a.s DCC (dicyclohexycarbodiimide) or EDC HCI (I-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such as methylene chloride, chloroform, dichloroethane, or in dimethyl-formamide. The product II is then deprotected with acid, for example hydrogen chloride in chloroform or ethyl acetate, or trifluoroacetic acid in methylene chloride, and cyclized under weakly basic conditions to give the diketopiperazine III. Reduction of III with lithium aluminum hydride in refluxing ether gives the piperazine IV, which is protected CA 022~19~ 1998-10-16 as the Boc derivative V. The N-benzyl group can be cleaved under standard conditions of hydrogenation, e.g., 10% palladium on carbon at 60 psi hydrogen on a Parr apparatus for 24-48 h. The product VI can be treated with an acid chloride, or a carboxylic acid under standard 5 dehydrating conditions to furnish the carboxamides vn. A final acid deprotection step gives the intermediate VIII (Scheme 2). Intermediate VIII can be reductively alkylated with a variety of aldehydes, such as IX, prepared by standard procedure,s, such a~s that described by O. P.
Goel, U. Krolls, M. Stier and S. Kesten in Or~anic Syntheses, 1988, 10 67, 69-75, from the appropriate amino acid (Scheme 3). The reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoboro-hydride, in a solvent such as dichloroethane, methanol or dimethyl-formamide. The product X can be deprotected to give the final 15 compounds XI with trifluoroacetic acid in methylene chloride. The final product XI is isolated in the salt form, for example, as a trifluoro-acetate, hydrochloride or acetate salt, among others. The product diamine XI can further be selectively protected to obtain XII, which can subsequently be reductively alkylated with a second aldehyde to obtain 20 XIII. Removal of the protecting group, and conversion to the cyclized product such as the dihydroimidazole XV, can be accompli.shed by literature procedures.
Alternatively, the protected piperazine intermediate VII
can be reductively alkylated with other aldehyde.s such a~s l-trityl-4-25 carboxaldehyde or 1-trityl-4-imidazolylacetaldehyde, to give products such as XVI (Scheme 4) (Tr = trityl). The trityl protecting group can be removed from XVI to give XVII, or alternatively, XVI can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole XVIII. Alternatively, the intermediate VIII can be 30 acylated or sulfonylated by standard techniques. The imidazole acetic acid XIX can be converted to the acetate XXI by standard procedure.s, and XXI can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid e~ster XXII. Hydroly~is and reaction with piperazine VIII in CA 022~19~ 1998-10-16 - 10~ -the presence of condensing reagents such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) leads to acylated products such as XXIV.
If the piperazine VIII is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XXV
5 in Scheme 6, the protecting groups can be subsequently removed to nm~k the hydroxyl group (Schemes 6, 7). The alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as XXIX. In addition, 10 the fully deprotected amino alcohol XXX can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain .secondary amines, such as XXXI (Scheme 7), or tertiary amines.
The protected amino alcohol XXVII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXXII (Scheme 8).
15 Treating XXVII with l,l'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide leads to the formation of aziridine XXXII. The aziridine reacts in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product XXXIII.
Piperazine VIII can be reacted with an aldehyde derived 20 from an amino acid, such as an O-alkylated tyrosine, to obtain compounds such as XXXIX. When R' is an aryl group, XXXIX can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XL. Alternatively, the amine protecting group in XXXIX can be removed, and O-alkylated phenolic 2~ amines such as XLI produced.
Depending on the identity of the amino acid I, various side chains can be incorporated onto the piperazine. For example, when I
is a protected ~-benzyl ester of aspartic acid, the intermediate diketo-piperazine XLII (where n=l and R=benzyl) is obtained, as shown in 30 Scheme lO. Subsequent reduction reduces the ester to the alcohol XLIII, which can then be reacted with a variety of alkylating agents such as an alkyl iodide, under basic condition~s, for example, sodium hydride in dimethylformamide or tetrahydrofuran. The resulting ether CA 022~19~ 1998-10-16 XLIV can then be carried on to final products as described in Schemes 3-9.
N-Aryl piperazines can be prepared as described in Scheme 11. An aryl amine XLV is reacted with bi~ -chloroethyl amine hydro-S chloride (XLVI) in refluxing n -butanol to furnish compounds XLVII.
The resulting piperazines XLVII can then be carried on to final products as described in Schemes 3-9.
Piperazin-5-ones can be prepared as shown in Scheme 12.
Reductive amination of protected amino aldehydes XLIX (prepared 10 from I as described previously) gives rise to compound L. This is then reacted with bromoacetyl bromide under Schotten-B;~um~nn conditions.
Ring closure is effected with a ba,se, such as sodium hydride, in a polar aprotic solvent, such as dimethylformamide, to give LI. The carbamate protecting group is removed under acidic conditions, such as trifluoro-15 acetic acid in methylene chloride or hydrogen chloride gas in methanolor ethyl acetate, and the resulting piperazine can then be carried on to final products as described in Schemes 3-9.
The isomeric piperazin-3-ones can be prepared as described in Scheme 13. The imine formed from arylcarboxamide.s LII and 2-20 aminoglycinal diethyl acetal (LIII) can be reduced under a variety ofconditions, including ~iodium triacetoxyborohydride in dichloroethane, to give the amine LIV. Amino acid,s I can be coupled to amines LIV
under standard conditions, and the resulting amide LV when treated with aqueous acid in tetrahydrofuran can cyclize to the unsaturated 25 LVI. Catalytic hydrogenation under standard conditions gives the requisite intermediate LVII, which is elaborated to final products as described in Schemes 3-9.
Access to alternatively substituted piperazines is described in Scheme 14. Following deprotection, e.g., with trifluoroacetic acid, 30 the N-benzyl piperazine V can be acylated with an aryl carboxylic acid.
The resulting N-benzyl aryl carboxamide LIX can be hydrogenated in the presence of a catalyst to give the piperazine carboxamide LX which can then be carried on to final products as de,scribed in Schemes 3-9.
Reaction Scheme 15 provides an example of the synthesi~

CA 022~19~ 1998-10-16 of compounds wherein the substituents R2 and R3 are combined to form - (CH2)U -. For example, 1-aminocyclohexane-1-carboxylic acid LXI
can be converted to the spiropiperazine LXVI essentially according to the procedures outlined in Schemes 1 and 2. The piperazine inter-5 mediate LXIX can be deprotected as before, and carried on to finalproducts as described in Schemes 3-9. It is understood that reagents utilized to provide the substituent Y which is 2-(naphthyl) and the imidazolylalkyl substituent may be readily replaced by other reagents well known in the art and readily available to provide other N-10 substituents on the piperazine.
The aldehyde XLIX from Scheme 12 can also bereductively alkylated with an aniline as shown in Scheme 16. The product LXXI can be converted to a piperazinone by acylation with chloroacetyl chloride to give LXXII, followed by base-induced 15 cyclization to LXXIII. Deprotection, followed by reductive alkylation with a protected imidazole carboxaldehyde leads to LXXV, which can be alkylation with an arylmethylhalide to give the imidazolium salt LXXVI. Final removal of protecting groups by either solvoly.sis with a lower alkyl alcohol, such as methanol, or treatment with triethylsilane in 20 methylene chloride in the presence of trifluoroacetic acid gives the final product LXXVII.

O Ra Rb >~O N~ PhCH2NHCHCO2C2H5 H O
DCC, CH2CI2 >~O~N 1~N'~ÇCO2C2H5 ) HC CH2CI2 Ra Ra O \ Boc20 )~ LAH ~ HN N~2cl2 III IV

Ra Ra o )--~ 10% Pd/C ~~ )--\
_~o~ N ~N~H2 CH30H ~0 y V VI

a EDC-HCI, HOBT Ra /=\
R ~_~ DMF )~
BocN NH ~CO2H BocN N~

Vl Vl I

HCI, EtOAc )~ _~
HCI N N

~~Rb ~
Vlll Boc NHl IX

Ra'~ ~ ~3 Boc NH CHO
HCI N N NaBH(OAc)3 YRb Et3N, CICH2CH2CI
Vlll Ra $~ C F3CO2H
Boc NH ~N N CH2CI2 NHBoc R

Ra ~ Boc20 NH2 rN N
Y '~ o CH2CI2 NH2 Rb Xl Ra _~ ~CHo BocNH ~ NyN NaBH(OAc)3 NH2 Rb Et3N, CICH2CH2CI
Xll CA 022519C.C. 1998-10-16 SCHEMF 3 (Cont.) ~, BocNH N N~/ CF3CO2H. CH2C12;
\~ ~~ O NaHCO3 NH Rb Ra e~
NH~N N~ ~NC

~=~ NH Rb AgCN
XIV

Ra ~3 rN N
/~\ --< b ~
~3 XV

a /=\ NaBH(OAc)3 ~Et3N, CICH2CH2CI
HCI N <N~ N~(CH2)nCHO

Vlll NTr ~\ 6 ~(CH2)n+1 <

N, XV I
Tr 1 ) Ar CH2X, CH3CN
Cl 2) CF3CO2H, CH2CI~
(c2H5)3siH (C2H5)3siH

2)n+ ( H ) N N~3 N~ Rb N XVIII

~N~ CH30H ~N~

XIX XX
CH2CO2CH31 ) ArCH2X CH3CN
(C6H5)3cBr ~ reflux, (C2Hs)3N N 2) CH30H, reflux DMF Tr XXI

SS~C
XXII XXIII

Ar~\N~CH2C02H Ra ~3 N + HCI H N N

XXIII Rb Vlll HCI

EDC HCI Ar~ Ra _~3 HOBt ~N ~N N
DMF N~' ~~Rb XXIV

NaBH(OAc)3 R~ ~3Et3N, CICH2CH2CI
HCI N N~ BnOl Rb BocNH CHO
Vlll XXV

BnO Ra ~ 20% Pd(OH)2 H2 \~ \~ O CH30H
NHBoc Rb CH3CO2H
XXVI

SCHEME 6 (CONTINUED) HO Ra ~3 CICOCOCI

NHBoc Rb (C2Hs)3N
XXVII

O~ N N $~3 2. TFA
H NHBoc Rb CH2C12 XXVIII

R8~
HO~N N
R' NH2 Rb XXIX

Ra _~3 CF3CO2H
HO~N N CH2CI2 NHBoc Rb XXVII

Ra~ ~ ~ R'CHO

HO~ ~N~N NaBH(OAc)3 NH2 Rb CICH2CH2 XXX

Ra ~3 HO ~N N
NH Rb R~C H2 XXXI
s SCHEME ~¢

H H

Ra ~ ~2 H0 rN N
NaH, DMF0~C
NHBoc Rb XXVII

Ra~ R'SH
rN N~ \=/ CH30H

XXXII

R'S rN N~
~ ~< O
NH2 Rb XXXIII

CA 022',19',', 1998-10-16 WO 97/38664 PCT,rUS97/06248 HO~ 1) Boc2O, K2C~3 HO~

~/ THF-H20 J~ 2) CH2N2, EtOAC ,1~
H2N C02H BocNH CO2CH3 XXXIV
XXXV

LiAlH4 H ~ 3 R'CH2X
TH F Cs2CO3 0-20~C BocNH CH2OH DMF

XXXVI

R'C H20 R'C H20 ~, ,~ DMSO
BocNH CH2OH 20~C BocNH CHO
XXXVII XXXVIII

SCHEME 9 (continued) R'CH~,3 Ra _~

HCI N N
BocNH CHO \ <Rb XXXVIII Vlll NaBH(OAc)3 ~a~

NHBoc Rb 1) 20% Pd(~H)2 / XXXIX \ HCI
CH30H, CH3C02H/ \ ETOAC

,~ )~
R'C H20 N N ~
~ Ra ~3 NH2 Rb HO/~ N N XLI
NH2 Rb XL

n( S~~ 1) LAH, Et20 HN N 2) Boc2O
0~ ~
XLII

HO

O n ~ NaH, DMF ~N N~

XL IV
XLIII

WO 97138664 PCT/~S97/06248 Rb ArNH2 + Cl ~' )2NH HCI
XLV Ra XLVI

Ra Rb n- butanol ArN NH HCI
reflux >~
Ra Rb XLVII

R Ra CH3NHOCH3 HCI
O N J~ EDC . HCI, HOBT
H o DMF, Et3N, pH 7 O Ra ~OJ~N~N(CH3)0CH3 LAH, Et20 XLVIII

>~O N ~ NaBH(OAc~3 H o CICH2CH2CI
pH 6 XLIX
R 1 ) BrCH2COBr H 2) NaH, THF, DMF

R~ 1 ) TFA, CH2CI2 R ~ '~

~0 ~~ Ar \~ Ar O O

CA 0225l955 l998- l0- l6 NaB H (OAc)3 ArCHO + NH2CH2CH(OC2H5)2 Lll Llll ~ Ra Ar CH2NHCH2CH(Oc2Hs)2 >~0 N ~
LIV EDC . HCI, HOBT
Dl\/IF, Et3N, pH 7 O R ~ 6N HCI
>~o~N~N~cH(oc2H5)2 THF r H o LV

Ra O H2 1 0%Pd/C

~N~=~N~ CH30H
~0 Ar LVI
Ra o / ~
~0 Ar LVII

CA 02251955 l99X- 10-16 Rb 1~ CF3CO2H, CH2C12. N NH ArCO2H
2) NaHCO3 ~ y EDC- HCI
Ra HOBT, DMF
LVIII

Rb Rb N N~ 10% Pd / C ~ HN N~
Ar H2 C H30 H y Ar Ra Ra ~b LIX LX

~ PhcH2NHcH2co2c2H5 BocNH C02H DCC, CH2CI2 LXI
a) TFA, CH2CI2 BocNH~N~C02C2Hs b) NaHCO

~1 H N~N~Co2c2Hs CHCI3 LXIII
~~
HN N~ 4, HN N
0~/ ~ TH F

LXIV / \ LXV
,f1~, Boc20 BocN N H2 Pd/C
CH2CI2 \ J ~ CH30H

LXVI

SCHEME 15 (continued) / \ COCI

BocN NH NaHCO3 EtOAc LXVII
~u~
~ \ a) TFA, CH2C12 BocN N~ /=\ b) NaBH(OAc)3 LXVI ll ~ ~C(=O)H
~ CPh3 ~ u ~
/ \ O
r / ~ A TFA CH2CI2 (C2H5)3siH

CPh3 LXIX

LXX

.....

BocNH CHO NaBH(OAc)3 N ~Ar XLIX LXXI

O R~ ~
C~ cl BocNH N-Ar EtOAc / H20 ~
NaHCO3 Cl O
LXXII

NaH ) \ HCI
~ BocN N- Ar DMF ~ EtOAc o LXXIII

SCHEME 16 (continued) CHO
N ~ R

HCI HN~N-Ar C(Ph)3 ~ ~N~
O NaBH(OAc)3 N
LXXIV pH 5-6 (Ph)3C

LXXV

Ar~ N N- Ar ArC H2X N ~ \~
CH3CN l~ )~ O
,N ~3 ~3 (Ph)3C X

LXXVI

MeOH )~
or Ar~ r N N- Ar N, \~
TFA, CH2CI N O
(C2Hs)3S; H
LXXVII
The geranylgeranyl-protein transferase-type I inhibitor,s and certain of the farnesyl transferase inhibitors can be synthesized in accordance with general Reaction Scheme,s A-E in addition to other 5 ,standard manipulation.s such as ester hydroly,sis, cleavage of protecting groups, etc., a,s may be known in the literature or exemplified in the CA 022~19~ 1998-10-16 W O 97/38664 PCTrUS97/06248 experimental procedures. Some key bond-forming and peptide modifying reaction,s 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 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.

Reaction Schemes A-E illu~strate bond-forming and peptide modifying reactions incorporating acyclic peptide units. Such reactions are equally u.seful when the - NHC(RA) - moiety of the reagents and 25 compounds illustrated is replaced with the following moiety:

~N~
( ~ H2)t which can be sub.stituted with R4a, R4b, R7a and R7b in accordance with structures (II-d) through (II-k). These reaction.s may be employed in a linear sequence to provide the compound.s of the invention or they may CA 022519C,C, 1998-10-16 be used to synthesi~e 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 OH + H2N~

or HOOBT >lo N N '~ORc Et3N, DMF ~ RB

HClor RA H ~
TFA ,H2N ~ N ~J~ORC

ALTERNATIVE RFACTION SCHFME A FOR
COMPOUNDS (Il-h) THROUGH (Il-k,~
Coupling of residues to form an amide bond >~OJ~N~OH +
~ ~R4b R4a EDC, HOBT ~0~NJ~ CO2R
or HOOBT R4a~

TFA , H2NJ~ <

RA ~ Q ~
>~R4b R4a REACTION SCHEME B
Preparation of reduced peptide subunits by reductive alkylation O RA RB

>lOJ~N H + H N~f~RC

>I'oJ~ Nl~ N Jl'oRc RB

Al TERNATIVF RFACTION SCHEMF B FOR COMPOUNDS
(Il-h) THROUGH (Il-k~
Preparation of reduced peptide subunits by reductive alkylation >~O N~ +

R4a R4b N~CNBH ~ ~O~ N
O R
~R4b R4a REACTION SCHEME C
Alkylation/reductive alkylation of reduced peptide subunits >~O N ~ORc or H RB o Il RYCH, NaCNBH3 RA R7b >~O N ~ORc RB

where RA and RB are R3, R4, R5a or R5b as previously defined; RC is 5 R6 as previously defined or a carboxylic acid protecting group; XL is a leaving group, e.g., Br-, I- or MsO-; and RY is defined ,such that R7b ils generated by the reductive alkylation process.

CA 0225l955 l998- l0- l6 WO 97/38664 PCTtUS97tO6248 - 136 ~

ALTERNATIVE REACTION SCHEME C for COMPOUNDS
(Il-h) THROUGH (Il-k) Deprotection of reduced peptide subunits >,O~fN ~ < TFA or O R ~ Q ~
>~ R4b HCI
R4a H2N~ CO2R

RA ~ Q ~
4a~ R4b R

REACTION SCHEME D
Coupling of residues to form an amide bond RA EDC, HOBT
O ~ I or HOOBT

>I'OJ~N~~H + H2N~ Et3N, DMF
RA

>~OJ~N NJ~ HCI orTFA
H O -~J

~A

H N~ N J~O
O -,,J

ALTERNATIVE REACTION SCHEMF D FOR COMPOUNDS
(Il-h) THROUGH (Il-k) Coupling of residues to form an amide bond ~ EDC, HOBT
2 + H N~O >

R4a R4b ~ ,~ ~~~ H O

~ Q ~
~R4b R4a ~ ~
H ~H~
\~

~R4b R4a REACTION SCHEME E
Preparation of reduced dipeptides from peptides ~ H N ~ORc BH3 THF

O RA O
>~oJ~ N N JI~oRc RB

CA 022~l9~ l998- l0- l6 ALTERNATIVE REACTION SCHEME E FOR COMPOUNDS
(Il-h) THROUGH (Il-o) Preparation of reduced dipeptides from peptides ~ < BH3 THF

O RA ~Q ~
~R4b R4a/

~0~ N ~02R

R4b R4a All variables are as defined above.
Certain compounds wherein X-Y is an ethenylene or ethylene unit are prepared by employing the reaction se4uences shown 5 in Reaction Schemes F and G. 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 coupling reaction, mesylation, cleavage of peptide protecting groups, reductive alkylation, etc., as may be known 10 in the literature or exemplified in the Experimental Procedure. For simplicity, substituent.s R2a and R2b on the cyclic amine moiety are not shown. It is, however, understood that the reactions illustrated are al~so applicable to appropriately substituted cyclic amine compounds as well as for acyclic amine moieties. The key reactions are: stereoselective 15 reduction of the Boc-aminoenone to the corresponding syn aminoalcohol (Scheme F, Step B, Part l), and stereospecific boron triflouride or zinc chloride activated organo-magnesio, organo-lithio, or organo-zinc copper(l) cyanide SN2' displacement reaction (Scheme F, Step G).
Through the use of optically pure N-Boc amino acids as starting 20 material and these two key reactions, the stereochemistry of the final products is well defined. In Step H of Scheme F, the amino terrninus sidechain, designated Rx is incorporated using coupling reaction A and RXCOOH; the alkylation reaction C using RXCHO and a reducing agent;
or alkylation reaction C using RxcH2xL. Such reactions as described 5 in Step H are described in more detail in Reaction Schemes J-X
hereinbelow.
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

MeONHMe Boc C~H2)t 2 ~ H2)t Step A

1. NaBH4 Boc OAc 2. Ac20, PY ( ~H2)t Step B

1. 03, Me2S B OAc 2. Ph3P=CHCO2Me oc ~~CO2Me Step C ( ~H2)t REACTION SCHFME F lCONT'D) Step D
1. LiOH Boc ~ NJI~ MsCI, py Step E - Step F
2. EDC, HOBT (5~H2)t ~ ~
amino acid (ester) ~ E"
E' = OMe, E" = SMe E'- E"=O

Boo OM6 /~ E'R MgCuCNClBF3 C~H2)t ~ ~ Step G

1. HCI
Boc R3 H ~ 2. NaCNBH3 E~ RXCHO
)t ~ ~ Step H
E"

Rxc~ E~

(~H2)t ~ E~

/R 9\
wherein ¦
RX = (R8)r - V - A1(CR1a2)nA2(CR1a2)n \W/- (CR1b2)p REACTION SCHEME F (CONT'D) NaOH

RXCH2 R3 H ~

OH
z)t ~ E~
or 1. HCI Alternate 1~l Step H
2. RXCOH
EDC, HOBT

RX ~ E~

C~H2)t ~
E"
NaOH

RX ~ OH
C~H2h ~ E"

REACTTON SCHEME G

Boc J~1 CMCoON-HBM Boc ~
~N . OH , ~JI~l, ~H2)t 2 ~\ ~H2)t 1. NaBH4 Boc ~ 1 03, Me2S

2.Ac20, PY ~H2)t 2. Ph3P=CHCO2Me B OAc o oc - CO Me + H2N""~ 1. LiOH

)t ~/ 2. EDC, HOBT

Boc OH H ~
~ ~, N ~
(J~H2)t ~ - /~ MsCI, py .

REACTION SCHEME G (CONT'D) Boc OMs H ~
f~ ~0 2)t ~
1. R3 MgCuCNCl-BF3 2. H2, 5% Pd/C

Boc R3 H ~
N

2)t ~

1. HC~2. NaCNBH3, RXCHO

RXCH2 R3 H ~
, N J~

2)t ~

NaOH

RXCH2 R3 H ~

N OH
~H2)t ~ - OH

CA 022~19~ 1998-10-16 REACTION SCHEME G (CONT'D) or O
Il 1. HCI 2. RXCOH
EDC, HOBT

N ~ ~o C,~,c H2)t 0 ---NaOH

RX ~ ~'OH
(~H2)t ~ OH

The oxa isostere compounds of thi~ invention are prepared according to the route outlined in Scheme H. An aminoalcohol I is 5 acylated with alpha-chloroacetyl chloride in the presence of trialkyl-amines to yield amide 2. Subsequent reaction of 2 with a deprotonation reagent (e.g., sodium hydride or potassium t-butoxide) in an ethereal solvent such as THF provides morpholinone 3. Alkylation of 3 with R3XL, where XL is a leaving group such as Br-, I- or Cl- in THF/DME
10 (1,2-dimethoxyethane) in the presence of a suitable base, preferably NaHMDS [sodium bis(trimethylsilyl)amide], al'fords 4, which is retreated with NaHMDS followed by either protonation or the addition of an alkyl halide R4X to give Sa or 5b, respectively, as a enantiomeric mixture. Alternatively, 5a can be prepared from 3 via an aldol 15 condensation approach. Namely, deprotonation of 3 with NaHMDS

CA 022~19~ 1998-10-16 W O 97/38664 PCTrUS97/06248 followed by the addition of a carbonyl compound RYRZCO gives the adduct 6. Dehydration of 6 can be effected by mesylation and subsequent elimin~tion catalyzed by DBU (l,~-diazabicyclol5.4.0]undec-7-ene) or the direct treatment of 6 with phosphorus oxychloride in S pyridine to give olefin 7. Then, catalytic hydrogenation of 7 yields Sa (wherein -CHRYRZ constitutes R3). Direct hydrolysis of 5 with lithium hydrogen peroxide in aqueous THF, or a~ueou~ HCI, produces acid 8a.
Compound ~a is then derivatized with BOC-ON or BOC anhydride to give 8b. The peptide coupling of acid ~Sb with either an alpha-10 aminolactone (e.g., homoserine lactone, etc.) or the ester of an aminoacid is carried out under the conditions exemplified in the previously de~scribed references to yield derivative 9. Treatment of 9 with gaseous hydrogen chloride gives 10, which undergoes further elaboration as described in Reaction Schemes J- hereinbelow.
An alternative method for the preparation of the prolyl oxa isostere (compounds 23 and 24 ) is shown in Scheme ~-1.
Referring to Scheme H- 1, the aminoalcohol 1 is protected with trifluoroacetic anhydride and the blocked compound 15 treated with diphenyl disulfide in the presence of tributylphosphine to provide the 20 thioether 16. Chlorination of compound 16 provides compound 17 which can be reacted with the appropriate carboxylic acid alcohol in the presence of silver perchlorate and tin (II) chloride? to afford the mixed acetal 18. Removal of the phenylmercapto moiety with Raney nickel provides compound 19. Compound 19 is doubly deprotected, then 25 selectively BOC protected to provide the acid 20, which undergoes the steps previously described for incorporating terminal amino acid. Still another alternative method for the preparation of the prolyl oxa isostere (compounds 23 and 24 ) is described in the literature l'Ruth E.
TenBrink, J. Org. Chem., 52, 41X-422 (1987)~.

SCHFME H
H0 Cl Cl H0 H~cH2)t ~ Cl O~ 3H ) base ~ ~"

3 (~

R~0~ R ~ ~

3 Base ~ Base ~ H2)t Base RYRZC0 ~: R4= H
5b: R4 = substituent H~~o~ -H20- RZ~0~ 2 ~ ~C H2)t ~ H2)t SCHFME H (CONT'D) 1. LiOOH;
oraq. HCI, Rw ~R3R4 2. BOC20 ~ N ~ ~ CO2H
(~C H2)t a RW=H
b, Rw = BOC

EDC Boc R3 R4 8 + H-A ~ N/' ~,A
HOBT ~ - ~ ll 2)t ~

HCI HCI H ~R R4 ~ 0 (JCH2)t ~

NH or NH Jl~ 6 ~ ~q SCHEME H-l ~OH CF3C' ,J' H( 1~H2)t ~,9H2)t nBu3P

oSPh N-chloro- o Cl ,SPh / succinimide 11 ~J

l~R o PhS ol CO2Me AgC104 , CF3C ~ ~
SnCI2 ~N (C~ H2)t Raney Ni 4A Mol. sieves J

SCHEME H-l (CONT'D) o Il CF3 l l3~R4 1 . aq. HCI
~~o CO2Me (~H2)t 2. BOC)20 /~CO2H H BT ' ~~ ~

HCI H
HCI ~N
(J&H2h o The thia, oxothia and dioxothia isostere compounds of this 5 invention are prepared in accordance to the route depicted in Scheme I.
Aminoalcohol 1 is derivatized with BOC20 to give 25. Mesylation of 25 followed by reaction with methyl alpha-mercaptoacetate in the presence of cesium carbonate gives sulfide 26. Removal of the BOC
group in 26 with TFA followed by neutralization with di-isopropyl-10 ethylamine leads to lactam 27. Sequential alkylation of 27 with the alkylhalides R3X and R4X in THF/DME ulsing NaHDMS as the deprotonation reagent produces 2~. Hydrolysis of 2~ in hydro-chloride to yield 29a, which is derivatized with Boc anhydride to yield 29b. The coupling of 29b with an alpha-aminolactone (e.g., homo~serine lactone, etc.) or 15 the e.ster of an amino acid is carried out under conventional conditions as exemplified in the previously described references to afford 30.
Sulfide 30 is readily oxidized to sulfone 31 by the use of MCPBA
(m-chloroperoxybenzoic acid). The N-BOC group of either 30 or 31 is readily removed by treatment with g~seous hydrogen chloride.
SCHEME I
HO HO
1 ) MsCI
~H ) BOC20 Boc~H2)t 2) Cs2CO3 S

3 2 ~ ' (C H2) B~C~v ~ (~

1 ) R3X, R3~S~ HCI

4 ' ~NJ''' (cH ) H20 28 ( ) SCHEME I (CONT'D) RW R3 R4 Boc R3 R4 --S CO2H H-A, EDC ~I S~
~H2)~ HOBT W~H2)t ~
2~ 30 a, RW=H ~ BOC20 A- O O
b, RW=BOC NH~V~ or NHJloR6 R
rJq BocR3 R4 ~N S(O)m~A HCI
2)t ~

m=O, 30 ~ MCPBA
m=2, 31 ~J

HCI H R ~, /R
~_N S(~)m V~H2)t ~

m=Oor2 Reaction Schemes J - R illustrate reactions wherein the non-sulfhydryl-containing moiety at the N-terminus of the compounds of the instant invention is attached to the fully elaborated cyclic amino peptide unit, prepared as described in Reaction Schemes A-I. It is understood 10 that the reactions illustrated may also be performed on a simple cyclic CA 022~19~ 1998-10-16 amino acid, which may then be further elaborated utilizing reactions described in Reaction Schemes A- I to provide the instant compounds.
The intermediates who,se synthesis are illustrated in Reaction Schemes A-I can be reductively alkylated with a variety of S aldehydes, such as V, as shown in Reaction Scheme J. The aldehydes can be prepared by standard procedures, such as that described by 0. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses, 1988, 67, 69-75, from the appropriate amino acid (Reaction Scheme F).
The reductive alkylation can be accomplished at pH 5-7 with a variety 10 of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloroethane, methanol or dimethylformamide. The product VI can be deprotected with trifluoroacetic acid in methylene chloride to give the final compound.s VII. The final product VII is isolated in the salt form, for example, lS 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 conver-~sion to cyclized products such as the dihydroimidazole XI can be 20 accomplished by literature procedures.
Alternatively, the protected cyclic aminopeptidyl intermediate can be reductively alkylated with other aldehyde~s such as 1-trityl-4-carboxaldehyde or l-trityl-4-imidazolylacetaldehyde, to give product.s such as XII (Reaction Scheme K). The trityl protecting group 25 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 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 30 protected 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-CA 022~19~ 1998-10-16 dimethylaminopropyl)-3-ethylcarbodiimide (EDC) leads to acylated products such as XIX.
If the protected dipeptidyl analog intermediate is reductively alkylated with an aldehyde which also has a protected 5 hydroxyl group, such as XX in Reaction Scheme N, the protecting groups can be subsequently removed to unma,sk the hydroxyl group (Reaction Schemes N, P). The alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain 10 secondary alcohol,s such as XXIV. In addition, the fully deprotected amino alcohol XXV can be reductively alkylated (under conditions described previously) with a variety of aldehyde~s to obtain secondaly amines, such as XXVI (Reaction Scheme P), or tertiary amines.
The Boc protected amino alcohol XXII can al~o be utilized 15 to synthesize 2-aziridinylmethylpiperazine~ ,such as XXVII (Reaction Scheme Q). Treating XXII with l,l'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXVII . The aziridine may be reacted in the prelsence of a nucleophile, such as a thiol, in the presence of base to yield the ring-20 opened product XXVIII .
In addition, the protected dipeptidyl analog intermediatecan be reacted with aldehydes derived from amillo acids such as O-alkylated tyrosines, according to ~tandard procedures, to obtain compounds such as XXXIV, as shown in Reaction Scheme R. When 25 R' is an aryl group, XXXIV can first be hydrogenated to unma~sk the phenol, and the amine group deprotected with acid to produce XXXV.
Alternatively, the amine protecting group in XXXIV can be removed, and O-alkylated phenolic amines such as XXXVI produced.

RF~CTION SCHEME J

R BocNH~ V NHBoc H~ < Boc NH 1CHO Boc NH ~ R
~Q
4bNaBH(OAc)3 ~ Q ~
R4a R Et3N, CICH2CH2CI R4a~R4b CF3CO2H NH2/~ R Boc20 CH2CI2 R4a~ CH2CI2 ~2 ~ ~ ~CHO

BocN H J "
,~1 \ NaBH(OAc)3 Vlll ~R4b Et3N, CICH2CH2CI
R4a wherein R = ~ X ~N' J~OR6 or ~2,' Y~ ~0 Z R5a R5b Z --~

REACTION SCHFME J (continued) ~, NH
~ CF3CO2H, CHZC12;
BocNH ,~ < NaHCO3 IX ~ R4b R4a e~, NH ~ NC

NH2 ,N--< AgCN

R4a~ R4b N--~ ~ R

~ fl ~

Qd Xl REACTION SCHEME K
H~ < (CH2)nCHO NaBH(OAc)3 R4a~ ~ Et3N, CICH2CH2CI

~CH2)n+1 R
T~ R4a~

Xll 1 ) Ar CH2X, CH3CN
2) CF3CO2H, CH2CI~
(C2H5)3siH
CF3CO2H, CH2CI2 (C2H5)3SiH

(,CH2)\ R
' ~ ~ R4b Xlll Ar~ (C H2)n+1 R

X V R4a W O 97138664 PCTrUS97/06248 REACTION SCHEME L

N~ 2CO2H CH OH N~CH2CO2CH3 HN HCI NH . HCI
XV XVI
CH2CO2CH3 1) ArCH2X CH3CN
(c6H5)3cBr ~ reflux (C2Hs)3N IN 2) CH30H, reflux DMF Tr XVII

Ar~\N~cH2co2cH3 2.5N HClaq ~N 55~C

XVIII

Ar~\N ~CH2c02H

N

REACTION SCHEME M

Ar~\N~CH2CO2H n~ R4b EDC HCI
HOBt DMF

Ar ~<
~Q ~
XIX ~ R4b R4a REACTION SCHEME N
N HBoc / < R
H NaBH(OAc)3 BnO

~ BnO 4a~R4b R4a BocNH CHO XXI
XX

NHBoc /~ R
HO _ < CICOCOCI
20% Pd(~H)2 H2 ~ 4b(C2H5)3N

CH3CO2H R4a H NHBoc R 1. R'MgX

/~ (C2H5)20 Q ~) 2. TFA, CH2C12 \/ ~ ~. 4b XXIII R4a~

R' NH2 ~ R
HO ,~

~ Q ~
XXIV ~ R4b R4a WO g7/38664 PCT/US97/06248 REACTION SCHEME P

NHBoc CF3CO2H
/~ R
HO ~_< CH2CI2 ~ Q ~
R4a~ R4b NH2 R'CHO
~ R
HO \ < NaBH(OAc)3 ~ Q ~ CICH2CH2CI
R4a~ R4b R'CH2~
NH

R4a R4b REACTION SCHEME Q

NHBoc H H
/~ R N =\ r N
HO ~ ~ 82 XXI ~ R4b NaH, DMF 0~C

H R4a <N

R R'SH
~ Q (c2H5)3N A
R4a R4b CH30H

/~ R
R'S ~ <

XXV I I I ~_~ R4b REACTION SCHEME R

~ ~3 THF-H20 ,)~

H2NCO2H2) CH2N2, EtOAc XXIX XXX

HO~
LiAlH4 ~ R'CH2X
TH F ~1~ Cs2CO3 0-20~C BocNH CH2OH DMF

XXXI

R'C H20~ R'C H20 DMSO ,~
BocNH CH2OH 20~C BocNH CHO
XXXII XXXIII

, REACTION SCHEME R (continued) R'CH20~ R
~ H~

BocNH CHO R4a~R4b XXXill NaBH(OAc)3 N H Boc XXXIV R4a 1) 20% Pd(OH)2 / HC~EtOAc CH30HI CH3CO2H/ ~ NH2 2) HCI, EtOAc R'CH2O

NH2 R4a R4b HO~_~R4b XXXVI

XXXV R4a The intermediates who.se synthesis are illustrated in Reaction Schemes A and C can be reductively alkylated with a variety CA 022~19~ 1998-10-16 of aldehydes, such as I, as shown in Reaction Scheme F. The aldehydes can be prepared by standard procedures, such a,s that described by O. P.
Goel7 U. Krolls, M. Stier and S. Kesten in Or~anic Syntheses, 1988, ~7, 69-75, from the appropriate amino acid (Reaction Scheme F). The S 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 dimethylformamide. The product II can be deprotected to give the final compounds III with trifluoroacetic acid in methylene chloride.
10 The final product III is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine III can further be selectively protected to obtain IV, which can sub.sequently be reductively alkylated with a second aldehyde to obtain V. Removal of the protecting group, and conversion to 1~ cyclized products such as the dihydroimidazole VII can be accomplished by literature procedures.
Alternatively, the protected dipeptidyl analog intermediate can be reductively alkylated with other aldehyde,s such as l-trityl-4-carboxaldehyde or l-trityl-4-imidazolylacetaldehyde, to give products 20 such as VIII (Alternative Reaction Scheme G). The trityl protecting group can be removed from VIII to give IX, or alternatively, VIII
can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole X. Alternatively, the dipeptidyl analog intermediate can be acylated or sulfonylated by standard techniques.
2~ The imidazole acetic acid XI can be converted to the acetate XIII by standard procedures, and XIII can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XIV
(Alternative Reaction Scheme H). Hydrolysis and reactio1l with the 30 protected dipeptidyl analog intermediate in the presence of condensing reagents such a,s 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) lead~s to acylated products such a~s XV.
If the protected dipeptidyl analog intermediate i~s reductively alkylated with an aldehyde which also ha~s a protected CA 022~19~ 1998-10-16 hydroxyl group, such as XVI in Reaction Scheme I, the protecting groups can be subsequently removed to llnm~.sk the hydroxyl group (Reaction Schemes I, J). The alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety 5 of organometallic reagents such as Grignard reagents, to obtain secondary alcohols ,such as XX. In addition, the fully deprotected amino alcohol XXI can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXII (Reaction Scheme K), or tertiary amines.
The Boc protected amino alcohol XVIII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXIII
(Reaction Scheme L). Treating XVIII with 1,1'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXIII . The aziridine reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product XXIV .
In addition, the protected dipeptidyl analog intermediate can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXX, as shown in Reaction Scheme M. When R' is an aryl group, XXX can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XXXI.
Alternatively, the amine protecting group in XXX can be removed, and O-alkylated phenolic amines such as XXXII produced.
Similar procedures as are illustrated in Reaction Schemes F-M may be employed using other peptidyl analog intermediates such a.s those whose synthesis is illustrated in Reaction Schemes B - E.

ALTERNATF RFACTION SCHEME F FOR
COMPOUNDS (Il-h) THROUGH (Il-o) Boc NH~
2 JA J' CO2R Boc NH CHO

(~ ) NaBH(OAc)3 R4a~ R4b Et3N, CICH2C H2CI

N H Boc Boc NH/~HN~ll~ CO2R CF3CO2H
~ < CH2CI2 R ~ Q \

R4a~ R4b NH~ < Boc20 RA l/~ Q \ CH2CI2 R4a/~ R4b ~ H2 y C02R ~CHO

BocN H N~
RA ~O NaBH(OAc)3 ~ Et3N, CICH2CH2CI
R4a~_ R4b ALTERNATE RFACTION SCHEME F (continued) e~
NH CF3CO2H. CH2C12;
~( H Y CO2R
BocNH \ N~ < NaHCO3 RA ~ Q ~

/=\ R 4a~ R 4b ~3, NH
NC

RA ~ O ~ AgCN
4b Vl R4a R

NH~,~ CO2R

/~ RA l~Q ~
N~vN~ R4b J~ R4a Vll ALTERNATE REACTION SCHEME G FOR
COMPOUNDS (Il-h) THROUGH (Il-o) H2N~ CO2R NaBH(OAc)3 RA /~~<Et3N, CICH2CH2CI

R4a~ R4b ~(CH2)nCHO

Tr H2)n+1 _ ~<
R /~ 0 R4a Tr Vlll 1 ) Ar CH2X, CH3CN
2) CF3CO2H, CH2 CF3CO2H, CH2CI2 (C2H5)3SiH
(C2H5)3SiH

(CH )~N CO2R

N~ RA ~, R4b Ar ~CH2) ~ 4b WO 97t38664 PCT/US97/06248 ALTERNATE REACTION SCHEME H FOR
COMPOUNDS (II-h) THROUGH (II-o) N~ 2 2H CH O N~CH2CO2CH3 H HCI HN . HCI
Xl Xll CH2CO2CH31 ) ArCH2X CH3CN
(C6H5)3CBr ~ reflux (C2Hs)3N N 2) CH30H, re~lux DMF Tr Xlll Ar~\N~C H2CO2C H3 Ar~\N C H2CO2H
N 2.5N HClaq, <~;~
55~C
XIV

ALTERNATE REACTION SCHEME I FOR
COMPOUNDS (Il-h) THROUGH (II-o) Ar~\N~CH2CO2H + H2N ~~

EDC HCI R4a HOBt DMF

Ar~ ~
XV R4b R4a ALTERNATE REACTION SCHEME J FOR
COMPOUNDS (II-h! THROUGH (II-o) NaBH(OAc)3 H2N~ <02R Et3N, CICH2CH2CI

RA ~Q ~ ~
~ R4b BocNH CHO
R4a XVI

NHBoc y BnO/~H\J~ ~< Cl 130H
R ~ Q ~ CH3CO2H
XVII ~ R4b R4a NHBoc ~N~I~ CO2R CICOCOCI
HO H ,1~1--< DMSO CH2C12 RA~ O ~ (C2Hs)3N
4b XVIII ~ R
R4a wo 97/38664 ALTERNATIVE REACTION SCHFMF J (continued) H NHBoc y ~N~I~ C02R 1. R'MgX .
~ H ,N~\ (C2H5)20 R ~ Q ~ 2. TFA, CH2C12 XIX >C >~R4b R4a R' NH2 y HO)~--HN--~I~ <02R

RA ~Q ~
XX ~ R4b R4a ALTERNATE REACTION SC~EME K FOR
COMPOUNDS (Il-h) THROUGH (Il-o N HBoc HO/~--HN~I~ < CF3CO2H
RA ~ ~R4b CH2CI2 R4a HO/~H ~< R'CHO
R ~ Q \ NaBH(OAc)3 XXI R4a~ R4bCICH2CH2CI

R'CH2~
NH y HO/~HJ~ CO2R
RA /~Q \
XXII ~ R4b R4a ALTERNATE REACTION SCHEME L FOR
COMPOUNDS (II-h) THROUGH (Il-o) NHBoc y H H
HO/~--N~ 02R l~\N N

XVIII ~R4b NaH, DMF0~C

R4a <~H J~ < R'SH

XXIII '~ R4b CH30H
R4a NH2 y R'S/~H--. J' CO2R
RA //J~ Q
R4a R4b ALTERNATE REACTION SCHEME M FOR
COMPOUNDS (Il-h! THROUGH (II-o) HO~ 1) Boc2O, K2C~3 HO~

~/ THF-H20 ~/
~ 2) CH2N2, EtOAc J~
H2NCO2H BocNH CO2CH3 XXV XXVI

HO,~
LiAlH4 ~J R'CH2X
THF 1 Cs2CO3 0-20~C BocNH CH2OH DMF

XXVI I

R'C H20 R'C H20 ~ pyrldine SO3 ~

BocNH CH2OH 20~C BocNH CHO
XXVIII XXIX

ALTERNATF REACTION SCHFME M (CONT.) R'CH2~~3 RA f Q ~
BocNH CHO R4a~ R4b XXIX NaBH(OAc)3 NHBoc R'CH20~-'H~2R4b R 4a R

1) 20% Pd(OH)2 ~ HC~OAc CH30H, CH3CO2H
2) HCI, EtOAc / NH2~ CO2R

RA ~ca~

_N~ CO2R

R4a R4b CA 022~19~ 1998-10-16 WO 97/38664 PCT/USg7106248 Certain compounds used in the invention are described below.
EXAMPLES
s Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, specie,s 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 10% citric acid, 10% sodium bicarbonate and brine as appropriate. Solutions were dried over .sodium sulfate and evaporated in vacuo on a rotary evaporator.

(S)- 1-(3 -chlorophenyl)-4-[ 1 -(4-cyanobenzyl)-imidazolylmethyl 1 -S-[2-(methanesulfonyl)ethyll-2-piperazinone dihydrochloride Step A: 1 -triphenylmethyl-4-(hydroxymethyl)-imidazole To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260 mmol) in 250 mL of dry DMF at room temperature was added triethylamine (90.6 mL, 650 mmol). A white 25 solid precipitated from the solution. Chlorotriphenylmethane (76.1 g, 273 mmol) in S00 mL of DMF was added dropwise. The reaction mixture wa.s stirred for 20 hour~, poured over ice, filtered, and washed with ice water. The resulting product was slurried with cold dioxane, filtered, and dried in vacuo to provide the titled product as a white ,solid 30 which wa.s sufficiently pure for u,se in the next ~step.

Step B: I-triphenylmethvl-4-(acetoxymethyl)-imidazole Alcohol from Step A (260 mmol, prepared above) was suspended in 500 mL of pyridine. Acetic anhydride (74 mL, 720 35 mmol) was added dropwise, and the reaction was stirred for 4~ hours CA 022~l9~ l998- l0- l6 during which it became homo~eneous. The ~olution was poured into 2 L of EtOAc, washed with water (3 x 1 L), 5~o aq. HCl soln. (2 x 1 L), sat. aq. NaHCO3, and brine, then dried (Na2so4)~ filtered, and concentrated in vacuo to provide the crude product. The acetate was 5 i,solated as a white powder which was sufficiently pure for use in the next reaction.

Step C: 1-(4-cyanobenzyl)-5-(acetoxymethyl)-imidazole hydrobromide A solution of the product from Step B (85.~s g, 225 mmol) and ~-bromo-p-tolunitrile (50.1 g, 232 mmol) in 500 mL of EtOAc was stirred at 60~C for 20 hour~, during which a pale yellow precipitate formed. The reaction was cooled to room temperature and filtered to provide the solid imidazolium bromide salt. The filtrate was concen-15 trated in vacuo to a volume 200 mL, reheated at 60~C for two hours, cooled to room temperature, and filtered again. The filtrate was concentrated in vacuo to a volume 100 mL, reheated at 60~C for another two hours, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, 20 dissolved in 500 mL of methanol, and warmed to 60~C. After two hours, the solution was reconcentrated in va~uo to provide a white solid which was triturated with hexane to remove soluble materials. Removal of residual solvents in vacuo provided the titled product hydrobromide as a white solid which was used in the next step without further 25 purification.

Step D: 1 -(4-cyanobenzyl)-5-(hydroxymethyl)-imidazole To a solution of the acetate from Step C (50.4 g, 150 mmol) in 1.5 L of 3:1 THF/water at 0~C was added lithium hydroxide 30 monohydrate (1~.9 g, 450 mmol). After one hour, the reaction was concentrated in vacuo, diluted with EtOAc (3 L), and washed with water, sat. aq. NaHCO3 and brine. The solution was then dried (Na2S04), filtered, and concentrated in vCl~ uo to provide the crude CA 022~19~ 1998-10-16 - 17g -product as a pale yellow fluffy ,solid which was sufficiently pure for use in the next step without further purification.

Step E: I -(4-cyanobenzyl)-5-imidazolecarboxaldehyde To a solution of the alcohol from Step D (21.5 g, 101 mmol) in 500 mL of DMSO at room temperature was added triethyl-amine (56 mL, 402 mmol), then SO3-pyridine complex (40.5 g, 254 mmol). After 45 minute.s, the reaction was poured into 2.5 L of EtOAc, washed with water (4 x 1 L) and brine, dried (Na2so4)~ filtered, and 10 concentrated in va~uo to provide the aldehyde a~ a white powder which was sufficiently pure for u~e in the next step without further purification.

Step F: (S)-2-(te1-t-butoxycarbonylamino)-N-methoxy-N-methyl-4-(methylthio)but~n~mide L-N-Boc-methionine (30.0 g, 0.120 mol), N,O-dimethylhydroxylamine hydrochloride (14.1 g, 0.144 mol), EDC
hydrochloride (27.7 g, 0.144 mol) and HOBT (19.5 g, 0.144 mol) were stirred in dry DMF (300 mL) at 20~C under nitrogen. More N,O-20 dimethylhydroxylamine hydrochloride (2.3 g, 23 mmol) wa~ added to obtain pH 7-8. The reaction was stirred overnight, the DMF distilled to half the original volume under high vacuum, and the residue partitioned between ethyl acetate and sat. l~aHCO3 soln. The organic phase was washed with saturated sodium bicarbonate, water, 10% citric acid, and 25 brine, and dried with sodium sulfate. The solvent was removed in vacuo to give the title compound.

Step G: (S)-2-(tert-butoxycarbonylamino)-4-(methylthio)butanal A suspension of lithium aluminum hydride (5.02 g, 0.132 30 mol) in ether (500 mL) was stirred at room temperature for one hour.
The solution was cooled to -50~C under nitrogen, and a solution of the product from Step F (39.8 g, ca. 0.120 mol) in ether (200 mL) was added over 30 min, maintaining the temperature below -40~C. When the addition wa.s complete, the reaction was warmed to 5~C, then CA 022~19~ 1998-10-16 recooled to -45~C. Analysis by tlc revealed incomplete reaction. The solution was rewarmed to 5 ~C, stirred for 30 minutes, then cooled to -50~C. A solution of potas.sium hydrogen sulfate (72 g, 0.529 mol) in 200 mL water was slowly added, maintaining the temperature below 5 -20~C. The mixture was wasmed to 5 ~C, filtered through Celite, and concentrated in vacuo to provide the title aldehyde.

Step H: (S)-2-(tert-butoxycarbonylamino)-N-(3-chlorophenyl)-4-(methylthio)butanamine To a solution of 3-chloroaniline (10.3 mL, 97.4 mmol), the product from Step G (23.9 g, 97.4 mmol), and acetic acid (27.~
mL, 487 mmol) in dichloroethane (250 mL) under nitrogen was added sodium triacetoxyborohydride (41.3 g, 195 rnrnol). The reaction wa~s stirred overnight, then quenched with saturated sodium bicarbonate 15 solution. The solution was diluted with CHC13, and the organic phase was washed with water, 10% citric acid and brine. The solution was dried over sodium sulfate and concentrated in vacuo to provide the crude product (34.8 g) which was chromatographed on silica gel with 20% ethyl acetate in hexane to obtain the title compound .
Step I: (S)-4-(te~ t-butoxycarbonyl)- 1 -(3-chlorophenyl)-s-l 2 (methylthio)ethyl Ipiperazin-2-one A solution of the product from Step H (22.0 g, 63.~ mmol) in ethyl acetate (150 mL) was vigorously stirred at 0~C with saturated 25 sodium bicarbonate (150 mL). Chloroacetyl chloride (5.6 mL, 70.2 mmol) was added dropwi,se, and the reaction stirred at 0~C for 2h. The layers were separated, and the ethyl acetate phase wa,s wa,shed with 10%
citric acid and saturated brine, and dried over sodium sulfate. After concentration i~l vacuo, the resulting crude product (27.6 g) was 30 dissolved in DMF (300 mL) and cooled to 0~C under argon. Cesium carbonate (63.9 g, 196 mmol) was added, and the reaction was stirred for two day,s, allowing it to warm to room temperature. Another portion of cesium carbonate (10 g, 30 mmol) wa,s added, and the reaction was stirred for 16 hours. The DMF was distilled in vacuo, and CA 022~19~ 1998-10-16 the residue partitioned between ethyl acetate and water. The organic phase was washed with saturated brine, and dried over sodium sulfate.
The crude product was chromatographed on silica gel with 20-25%
ethyl acetate in hexane to obtain the title compound.

Step J: (S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-12-(methane~sulfonyl)ethyllpiperazin-2-one A solution of the product from Step I (14.2 g, 37 mmol) in methanol (300 mL) was cooled to 0 ~C, and a solution of magnesium 10 monoperoxyphthalate (54.9 g, 11 I mmol) in 210 mL MeOH was added over 20 minutes. The ice bath was removed, and the solution was allowed to warm to room temperature. After 45 minutes, the reaction wa.s concentrated in vacuo to half the original volume, then quenched by the addition of 2N Na2s2o3 soln. The solution was poured into EtOAc 15 and sat NaHCO3 solution, and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude sulfone. Thi.s material was chromatographed on silica gel with 60-100% ethyl acetate in hexane to obtain the titled compound.

20 Step K: (S)-1-(3-chlorophenyl)-5-12-(methane,sulfonyl)ethyllpiperazin-2-one Through a solution of Boc-protected piperazinone from Step J (1.39 g, 3.33 mmol) in 30 mL of EtOAc at 0 ~C was bubbled anhydrous HCl gas. The saturated .solution was stirred for 35 minutes, 25 then concentrated in vacuo to provide the hydrochloride salt as a white powder. This material was su.spended in EtOAc and treated with dilute aqueous NaHCO3 solution. The aqueous phase wa.s extracted with EtOAc, and the combined organic mixture was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting amine was 30 reconcentrated from toluene to provide the titled material suitable for use in the next step.

CA 022~19~ 1998-10-16 Step L: (S)-1-(3-chlorophenyl)-4-l 1-(4-cyanobenzyl)imidazolylmethyl 1-5-1 2-(methanesulfonyl)-ethyll-2-piperazinone dihydrochloride To a solution of the amine from Step K (89~ mg, 2.83 5 mmol) and imidazole carboxaldehyde from Step E (897 mg, 4.25 mmol) in 15 mL of 1,2-dichloroethane was added sodium triacetoxyboro-hydride (1.21 g, 5.7 mmol). The reaction was stirred for 23 hours, then quenched at 0 ~C with sat. NaHCO3 solution. The solution was poured into CHC13, and the aqueous layer was back-extracted with 10 CHC13. The combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated iM vacuo. The resulting product was purified by silica gel chromatography (95:~:0.5-90:10:0 EtOAc:MeOH:NH4CI), and the resultant product was taken up in EtOAc/methanol and treated with 2.1 equivalents of 1 M HCl/ether 15 solution. After concentrated in vaCuo, the product dihydrochloride was isolated as a white powder.

1-(3-chlorophenyl)-4-1 1-(4-cyanobenzyl)imidazolyl-methyll-2-piperazinone dihydrochloride Step A: N-(3-chlorophenyl)ethylenediamine hydrochloride To a solution of 3-chloroaniline (30.0 mL, 284 mmol) in 500 mL of dichloromethane at 0 ~C was added dropwise a solution of 4 N HCI in 1,4-dioxane (~0 mL, 320 mmol HCI). The solution was warmed to room temperature, then concentrated to dryness in vacuo to provide a white powder. A mixture of this powder with 2-oxazolidinone (24.6 g, 2~s2 mmol) was heated under nitrogen atmosphere at 160 ~C for 10 hours, during which the solids melted, ~ and gas evolution wa.s ob.served. The reaction was allowed to cool, forming the crude diamine hydrochloride salt as a pale brown solid.

CA 022~19~ 1998-10-16 Step B: N-(te)-t-butoxycarbonyl)-N'-(3-chlorophenyl)ethylenediamine The amine hydrochloride from Step A (ca. 2~2 mmol, crude material prepared above) was taken up in 500 mL of THF and 5 500 mL of sat. aq. NaHCO3 soln., cooled to 0~C, and di-tert-butylpyrocarbonate (61.6 g, 282 mmol) was added. After 30 h, the reaction was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled carbamate as a brown oil which was used in the next step without 10 further purification.

Step C: N-[2-(te~t-butoxycarbamoyl)ethyl]-N-(3-chlorophenyl)-2-chloroacetamide A solution of the product from Step B (77 g, ca. 282 mmol) 15 and triethylamine (67 mL, 4~0 mmol) in 500 mL of CH2C12 was cooled to 0~C. Chloroacetyl chloride (25.5 mL, 320 mmol) was added drop-wise, and the reaction was m~int:lined at 0~C with stirring. After 3 h, another portion of chloroacetyl chloride (3.0 mL) was added dropwise.
After 30 min, the reaction was poured into EtOAc (2 L) and washed 20 with water, sat. a~. NH4CI soln, sat. ac~. NaHCO3 soln., and brine. The solution was dried (Na2so4)~ filtered, and concentrated in vacuo to provide the chloroacetamide as a brown oil which was u.sed in the next step without further purification.
~5 Step D: 4-(te) t-butoxycarbonyl)- 1 -(3-chlorophenyl)-2-piperazinone To a solution of the chloroacetamide from Step C (ca. 2~2 mmol) in 700 mL of dry DMF w~s added K2co3 (~8 g, 0.64 mol).
The solution was heated in an oil bath at 70-75 ~C for 20 hours, coo}ed 30 to room temperature, and concentrated in vacuo to remove ca. 500 mL
of DMF. The remaining material was poured into 33% EtOAc/hexane, washed with water and brine, dried (Na2so4)~ filtered, and concen-trated in vac uo to provide the product as a brown oil. This material was purified by silica gel chromatography (25-50% EtOAc/hexane) to yield WO 97t38664 PCT/US97/06248 - 1~3 -pure product, along with a sample of product (ca. 65~ pure by HPLC) cont~inin~ a less polar impurity.

CA 022~19~ 1998-10-16 Step E: 1 -(3-chlorophenyl)-2-piperazinone Through a solution of Boc-protected piperazinone from Step D (17.19 g, 55.4 mmol) in 500 mL of EtOAc at -78~C was bubbled anhydrous HCI gas. The saturated solution was warmed to 0~C, and S stirred for 12 hours. Nitrogen gas was bubbled through the reaction to remove excess HCl, and the mixture was warmed to room temperature.
The solution was concentrated in vaCuo to provide the hydrochloride a~s a white powder. This material was taken up in 300 mL of CH2C12 and treated with dilute aqueous NaHCO3 solution. The aqueous phase was 10 extracted with CH2C12 (~ x 300 mL) until tlc analysi.s indicated complete extraction. The combined organic mixture was dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled free amine as a pale brown oil.

15 Step F: 1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)imidazolylmethyl]-2-piperazinone dihydrochloride To a solution of the amine from Step E (55.4 mrnol, prepared above) in 200 mL of 1,2-dichloroethane at 0~C was added 4A
powdered molecular sieves (10 g), followed by sodium triacetoxyboro-20 hydride (17.7 g, 83.3 mmol). The imidazole carboxaldehyde from StepE of Example 1 (11.9 g, 56.4 mmol) was added, and the reaction was stirred at 0~C. After 26 hours, the reaction was poured into EtOAc, washed with dilute aq. NaHCO3, and the aqueous layer was back-extracted with EtOAc. The combined organics were washed with brine, 25 dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was taken up in 500 mL, of 5:1 benzene:CH2C12~ and propyl-amine (20 mL) was added. The mixture was stirred for 12 hours, then concentrated i71 vacuo to afford a pale yellow foam. This material was purified by silica gel chromatography (2-7% MeoHlcH2cl2)~ and the 30 resultant white foam was taken up in CH2C12 and treated with 2.1 equivalents of 1 M HCl/ether solution. After concentrated in vacuo, the product dihydrochloride was isolated as a white powder.

CA 022~19~ 1998-10-16 O H H O
N ~--~N~N~ ~ol ~N H ~ O -~
~ SCH3 H3CO~

N-[ l -(1 H-Imidazol-4-propionyl) pyrrolidin-2(S)-ylmethyl l-N-(2-methoxybenzyl)~lycyl-methionine isopropyl ester Step A: 2-Methoxybenzyl~lycine methyl ester 2-Methoxybenzyl alcohol (53.5 g, 0.39 mol) was dis~solved in CH2C12 (200 mL), treated with diisopropylethylamine (~Sl mL, 0.74 mol), cooled to 0~C. with stirring in an ice-CH30H bath under Ar, and treated dropwise with methane,sulfonyl chloride (33 mL, 0.43 mol).
After 0.5 hr, the reaction mixture was left to warm to ambient temper-ature and stirred for 4 hr. This solution and diisopropylethylamine (202.5 mL, 1.16 mol) were added alternately portionwise with to a slurry of glycine methyl ester hydrochloride (146.5 g, 1.17 mol) in DMF (250 mL) with stirring at 0~C. The reaction mixture was left to ~stir and warm to room temperature overnight. The DMF was removed under reduced pressure, and the residue was partitioned between EtOAc (1 L) and satd NaHCO3 solution (1 L). The a~lueous layer was washed with EtOAc (2 x 600 mL), the organics combined, washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound after chromatography (sio2~ 1-5~ CH3OH/CH2C12).

Step B: N-L(2S)-(t-Butoxycarbony~pyrrolidinyl-methyl)-N-(2-methoxybenzyl)~lycine methyl ester 2-Methoxybenzylglycine methyl ester (27.4 g, 0.131 mol) was dissolved in 1,2-dichloroethane (500 ml), 3A molecular sieves (20 g) were added, and the pH of the reaction mixture adjusted to pH 5 with acetic acid (7.5 mL, 0.131 mol). N-(t-Butoxycarbonyl)-L-prolinal CA 022~19~ 1998-10-16 (26.1 g, 0.131 mol) (J. Org. Chem. (1994) 59, [21], 62~S7-95) was added followed by sodium triacetoxyborohydride (33.2 g, 0.157 mol).
The mixture was stirred at ambient temperature for 18 h, filtered through celite and concentrated. The residue was partitioned between S EtOAc and sat. NaHCO3 (500 ml/100 ml). The aqueous layer was washed with EtOAc (3x100 ml). The organic layers were combined, dried with Na2SO4, filtered, and concentrated to give the title compound.

10 Step C: N-[(2S)-(t-Butoxycarbonylpyrrolidinyl-methyl)-N-(2-methoxybenzyl)~lycine N-[(2S)-(t-Butoxycarbonylpyrrolidinylmethyl)-N-(2-methoxybenzyl)~lycine methyl ester (7.0 g, 0.01X mol) was dissolved in CH30H (150 ml) and lN NaOH (71 ml, 0.071 mol) was added with l;S cooling in an ice-water bath. The mixture was stirred at ambient temperature for 2 hr, neutralized with lN HCI (71 ml, 0.071 mol), concentrated to remove the CH30H, and the residue extracted with EtOAc (3x200 mL). The organic layers were combined, dried with Mg2SO4, filtered, and concentrated to give the title compound as a 20 foam.

Step D: Methionine ilsopropyl ester hydrochloride N-(t-Butoxycarbonyl)methionine (25 g, 0.1 mol), isopropyl alcohol (l l.~ mL, 0.15 mol), EDC (21.1 g, 0.11 mol), and 4-dimethyl-25 aminopyridine (DMAP) (1.22 g, 0.01 mol) were dissolved in CH2C12 (400 mL) with stirring in an ice-water bath. After 2 h the bath was removed, and the solution was left to stir o.n. at RT. The reaction mixture was concentrated to dryness, then partitioned between EtOAc and H2O, the aqueous layer washed with EtOAc (2 x 50 mL), the 30 organics combined, washed with NaHCO3 soln, brine, and dried (Na2SO4). Filtration and concentration to dryness gave a yellow oil after chromatography (flash silica gel column, hexane: EtOAc, 6:1 to 5:1).

CA 022~19~ 1998-10-16 - 1~7 -N-(t-Butoxycarbonyl)methionine isopropyl ester (20.5 g, 0.07 mol) was dissolved in EtOAc (200 mL) with stirring and cooling to -20~C in a dry ice- acetone bath. HCI gas was bubbled into the solution for 10 min, the flask was stoppered and stirred for 1 h. Tlc (EtOAc:
5 hexane, 1:3) indicates lo.ss of starting material. Argon was bubbled through the soln for 5 min, then it was concentrated to dryness to give the title compound as a white solid.

Step E: N-~(2S)-(t-Butoxycarbonylpyrrolidinyl-methyl)-N-(2-methoxybenzyl)~lycyl-methionine i.sopropyl ester N-[(2S)-(t-Butoxycarbonylpyrrolidinylmethyl)-N-(2-methoxybenzyl)glycine (from step C) (5.98 g, 0.0158 mol), dissolved in CH2C12 (100 mL), was treated with HOBT (2.57 g, 0.019 mol), EDC
(4.54 g, 0.024 mol), and methionine isopropyl ester hydrochloride (4.33 15 g, 0.019 mol). The pH was adjusted to 7.5 with Et3N (8.8~ mL, 0.063 mol) and the mixture was stirred at ambient temperature for 18 h. The mixture was diluted with EtOAc (150 mL) and washed sequentially with 10% citric acid soln, saturated NaHCO3 solution, brine, and dried (MgSO4). Filtration and concentration to dryness gave the title 20 compound as a thick oil. This was used without further purification.

Step F: N-((2S)-Pyrrolidinylmethyl)-N-(2-methoxybenzyl)-~lycyl-methionine isopropyl ester bis hydrochloride N-L(2S)-(t-Butoxycarbonylpyrrolidinylmethyl)-N-(2-25 methoxybenzyl)glycyl-methionine isopropyl ester (0.X:S g, 1.54 mmol) was dissolved in EtOAc (25 mL) and cooled to 0~C. HCI was bubbled through the mixture until the soln was saturated, and it was ~stoppered and stirred for 3 hr. Argon wa,s bubbled through the mixture to remove excess HCI and the mixture was then concentrated to give the 30 title compound.

CA 022~19~ 1998-10-16 - 18g -Step G: N-[l -(1 H-Imidazol-4-propionyl) pyrrolidin-2(S)-ylmethyl] -N-(2-methoxybenzyl)glycyl -methionine isopropvl ester N-((2S)-Pyrrolidinylmethyl)-N-(2-methoxybenzyl)glycyl 5 methionine isopropyl ester bis hydrochloride (0.800 g, 1.53 mmol), dissolved in DMF (30 mL), was treated with lH-imidazol-4-propionic acid (0.43 g, 3.05 mmol) (prepared by catalytic hydrogenation of urocanic acid in 20% acetic acid with Pd on carbon), and BOP reagent (1.35 g, 3.05 mmol). The pH was adjusted to 7.5 with N-methyl-10 molpholine (0.756 mL, 6.89 mmol), and the mixture was stirredat ambient temperature for 18 h. The mixture was concentrated to dryness, diluted with EtOAc (100 mL), washed with 5% Na2CO3 solution, brine, and dried (MgSO4). Filtration and concentration to dryness gave an oil which was purified by chromatography (silica gel, 15 95:5 CH2C12/MeOH) to give the title compound as a foam.
lH NMR (CD30D); â 7.58 (d, lH, J=1 Hz), 7.25-7.31 (m, 2H), 6.89-7.00 (m, 2H), 6.81 (s, lH), 5.00-5.06 (m, IH), 4.49-4.56 (m, lH), 4.23-4.30 (m, lH), 3.91 (d, lH, J=13 Hz), 3.~S6 (s, 3H), 3.54 (d, lH, J=13Hz), 3.30-3.41 (m, 2H), 3.36 (d, lH, J=17 Hz), 3.15 (d, IH, J=17 Hz), 2.85-20 2.92 (m, 2H), 2.56-2.77 (m, 3H), 2.30-2.45 (m, 3H), 2.05-2.17 (m, lH), 2.04 (s, 3H), 1.69-1.86 (m, SH), 1.24 (d, 6H, J=6 Hz).
Anal. calculated for C2gH43N5O5S ~ 0-6 H2O:
C, 59.59; H, 7.62; N, 11.98;
Found: C, 59.58; H, 7.43; N, 12.02.

CA 022~l9~ l998- l0- l6 (N-L 1 -Cyanobenzyl)- 1 H-imidazol-5-yl)~cetyl]pyrrolidin-2(S)-ylmethyll -3(S)-ethyl-prolyl methionine isopropyl ester N~ SCH3 N~ H ~N ~~/

StepA: Diethyl l-Acetyl-5-hydroxy-3-ethylpyrrolidine-2,2-dicarboxylate Sodium (4.02 g, 0.175 mol) was dissolved in a stirred solution of diethyl acetamidomalonate (235.4 g, 1. ] 9 mol) in abs 10 EtOH (1.4 L) at ambient temperature under argon. The reaction mixture wa~ cooled to 0~C, and trans-2-penten~l (100 g, 1.08 mol) was added dropwise maintaining the reaction temperature at <5~C.
After the addition, the reaction wa.s allowed to warrn to room temperature, stirred for 4 h, then 4uenched with acetic acid (28 mL).
15 The solution was concentrated in vacuo, and the residue dissolved in EtOAc (1.5 L), washed with 10% NaHCO3 solution (2 x 300 mL), brine, and dried (MgSO4). The solution was filtered and concentrated to 700 mL, then heated to reflux and treated with hexane (1 L). On cooling, the title compound precipitated and was collected, mp 106 -20 109~C. IH NMR (CD30D) ~ 5.65 (d, lH, J= 5 Hz), 4.1 - 4.25 (m, 4H), 2.7-2.X (m, lH), 2.21 (s, 3H), 2.10 (dd, lH, J = 6, 13, Hz),1.86- 1.97 (m, 2H), 1.27 (t, 3H, J= 7 Hz), 1.23 (t, 3H, J= 7 Hz), 1.1- 1.25 (m, lH), 0.97 (t, 3H, J= 7 Hz).

CA 022~19~ 1998-10-16 Step B: Diethvl l-Acetyl-3-ethylpyrrolidine-2.2-dicarboxylate To a solution of diethyl l-acetyl-S-hydroxy-3-ethyl-pyrrolidine-2,2-dicarboxylate (287 g, 0.95 mol) and triethylsilane (22 mL, 1.43 mol) in CH2cl2 (3 L) under argon was added trifluoroacetic S acid (735 mL, 9.53 mol) dropwise with stirring while maintaining the internal temperature at 25 ~C by means of an ice bath. After stirring for 3 h at 23~C, the ,solution was concentrated i~l vacuo,, the residue diluted with CH2cl2 (l.S L), then treated with H2O (1 L) and solid Na2CO3 with vigorous stirring until the solution was basic. The 10 organic layer was separated, dried (Na2so4)~ filtered, then concentrated to give the title compound a.s a yellow oil which was used without further purification.

Step C: 3 -Ethylproline hydrochloride (Ci,s :Tran~ Mixture) Diethyl l-acetyl-3-ethylpyrrolidine-2,2-dicarboxylate (373 g, 0.95 mol) was suspended in 6N HCI (2 L) and HOAc (500 mL) and heated at reflux for 20 h. The reaction mixture was cooled, washed with EtOAc (lL), then concentrated in vacuo to give an oil which crystallized upon trituration with ether to give the title compound.
20 lH NMR (D2O) ~ 4.23 (d, lH, J= ~ Hz), 3.X4 (d, lH, J= ~ Hz), 3.15-3.4 (m, 4H), 2.33- 2.44 (m, lH), 2.19-2.4 (m, lH), 2.02- 2.15 (m, 2H), 1.53- 1.72 (m, 3H), 1.23- 1.43 (m, 2H), 1.0- 1.15 (m, lH), 0.75 - 0.~3 (m, 6H).

25 Step D: N-[(te~ t-Butyloxy)carbonyl]-cis:trans-3-ethylproline methyl e.ster 3-Ethylproline hydrochloride (Cis:Trans Mixture) (20 g, 0.11 mol) was dis.solved in CH30H (200 mL), and the solution was saturated with HCI gas, then stirred at 23~C for 24 h. Argon was 30 bubbled through the solution to remove excess HCI. The solution was treated with NaHCO3 (>X4 g) to a pH of ~¢, then di-tel~t-butyl dicarbonate (25.1 g, 0. l l S mol) dissolved in CH30H (20 mL) was CA 022~19~ 1998-10-16 added slowly. After stirring for 18 h at 23~C, the mixture was filtered, the filtrate concentrated, and the residue triturated with EtOAc, filtered again, and concentrated to give the title compound as an oil.

Step E: N-[(te1t-Butyloxy)carbonyl]-t~an~-3-ethylproline and N-~(tert-Butvloxy)carbonyll-cis-3-ethvlproline methyl este N-~(tert-Butyloxy)carbonyll-cis,tran~-3-ethylproline methyl ester (29.1 g, 0.113 mol) was dis,solved in CH30H (114 mL) with 10 cooling to 0~C, then treated with 1 N NaOH (114 mL). After stirring for 20 h at 23~C, the solution was concentrated to remove the CH30H
and then extracted with EtOAc (3 x). The organic layer~s were combined, dried (MgSO4), filtered, and concentrated to give 12.8 g of N-[(tert-Butyloxy)carbonyl l-cis-3-ethylproline methyl ester as an oil.
15 The aqueous layer was acidified with solid citric acid and extracted with EtOAc (2 x), the organic layers combined, dried (MgSO4), filtered, and concentrated to give N-~(tert-Butyloxy)carbonyl]-hans-3-ethylproline as an oil. lH NMR (CD30D) ~ 3.86 and 3.7~ (2 d, IH, J = 6 Hz), 3.33 -3.58 (m, 2H), 2.01 - 2.22 (m, 2H), 1.5 - 1.74 (m, 2H), 1.33 - 1.5 (m, 20 lH), 1.45 and 1.42 (2 s, 9H), 0.98 (t, 3H, J= 8 Hz).

Step F: 3(S)-Ethyl-2(S)-proline hydrochloride N-[(te7t-Butyloxy)carbonyl]-trans-3-ethylproline (15.5 g, 0.064 mol), S-(x-methylbenzyl~mine (9.03 mL, 0.070 mol), HOBT
25 (10.73 g, 0.70 mol), and N-methylmorpholine (8 mL, 0.076 mol) were dissolved in CH2C12 (150 mL) with sitrring in an ice-H2O bath, treated with EDC (13.4 g, 0.070 mol) stirred at 23~C for 48 h. The reaction mixture wa~s partitioned between EtOAc and 10% citric acid solution, the organic layer washed with satd NaHCO3 solution, brine and dried 30 (MgSO4), filtered, and concentrated to give an oil. This oil was dissolved in a minimum amount of ether (10 mL) to cry,stallize the desired S,S,S dia.stereomer (4.2 g), mp 118-121~C. A solution of thi,s product in 8N HCI (87 mL) and glacial acetic acid (22 mL) was heated at reflux overnight. The solution was concentrated on a rotary CA 022~19~ 1998-10-16 evaporator, and the residue taken up in H2O and extracted with ether.
The aqueous layer was concentrated to dryness to give a 1:1 mixture of 3(S)-ethyl-2(S)-proline hydrochloride and cx-methylbenzylamine.
3(S)-Ethyl-2(S)-proline containing o~-methylbenzylamine (2.0 g, 0.0128 mol) was dissolved in dioxane (10 mL) and H2O (10 mL) with stirling and cooling to 0~C. N,N-diisopropylethylamine (2.2 mL, 0.0128 mol) and di-tert-butyl-dicarbonate (2.79 g, 0.012g mol) were added and stirring was continued at 23~C for 4~ h. The reaction mixture wa~ partitioned between EtOAc (60 mL) and H2O (30 mL), the organic layer washed with 0.5N NaOH (2 x 40 mL), the aqueous layer.s combined and washed with EtOAc ( 30 mL) and this layer back extracted with 0.5 N NaOH (30 mL). The aqueous layer~s were combined and carefully acidified at 0~C with 1 N HCl to pH 3. Thi.s mixture was extracted with EtOAc (3 x 40 mL), the organics combined, dried (MgSO4), filtered and concentrated to give N-[(tert-Butyloxy) carbonyl-3(S)-ethyl-2(S)-proline as a colorless oil. N-[(tert-Butyloxy) carbonyl-3(S)-ethyl-2(S)-proline wa,s dissolved in EtOAc (50 mL) and the solution was saturated with HCl gas with cooling in an ice-H2O bath.
The solution was stoppered and stirred at 0~C. for 3 hr. Argon was bubbled through the solution to remove excess HCl, and the solution wa,s concentrated to dryness to give 3(S)-ethyl-2(S)-proline hydrochloride.

Step G: N-(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-proline 3(S)-Ethyl-2(S)-proline hydrochloride (2.33 g, 0.013 mol) was dissolved in CH30H (20 mL), treated with 3A molecular sieve~s (2 g) and KOAc (1.27 g, 0.013 mol) to adju.st the pH of the reaction mixture to 4.5-5, then N-[(tert-Butyloxy)carbonyl-prolinal (Pettit et al., J. Org. Chem. (1994) 59, 1211 62~7-95) (3.36 g, 0.017 mol) was added, and the mixture was stirred for 16 hrs at room temperature.
The reaction mixture was filtered, quenched with aq satd NaHCO3 (S mL) and concentrated to dryness. The residue was extracted with CHC13. The extract wa.s dried (MgS04), filtered, and concentrated to give the title compound and inorganic salts.

CA 022~19~ 1998-10-16 Step H: N-(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyll-3(S)-ethyl-prolyl methionine i.sopropyl ester N-(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl] -3(S)-5 ethyl-proline (2.4 g, 0.008 mol), methionine isopropyl ester hydro-chloride (2.21 g, 0.0097 mol), HOBT (1.49 g, 0.0097 mol) and EDC
(1.86 g, 0.0097 mol) were dissolved in DMF (15 m~) at room temperature and treated with N-methylmorpholine (3 mL, 0.024 mol). The reaction mixture was stirred overnight at room temperature, 10 then concentrated and partitioned between EtOAc and H2O. The organic layer was wa.shed with a4 satd NaHCO3 solution, brine, and dried (MgSO4). The crude product was chromatographed on a flash silica gel column eluting with hexane: EtOAc, 7:3 to give N-(t-butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl 1-3(S)-ethyl-prolyl 15 methionine isopropyl ester.

Step I: Pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl methionine i,sopropyl ester hydrochloride N-(t-butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl] -3(S)-20 ethyl-prolyl methionine isopropyl ester (1.38 g, 0.0028 mol) was dissolved in EtOAc (40 mL), cooled to -20~C, saturated with HCI gas, and stirred at 0~C. for 1.25 hr, and room temperature for 0.25 hr.
Concentration to dryness gave pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl methionine isopropyl ester hydrochloride.
Step J: Preparation of lH-Imidazole-4- acetic acid methyl ester hydrochloride A solution of lH-imidazole-4-acetic acid hydrochloride (4.00g, 24.6 mmol) in methanol (100 ml) was saturated with gaseous 30 hydrogen chloride. The resulting solution was allowed to stand at room temperature (RT) for lP~hr. The solvent was evaporated in vacuo to afford the title compound as a white solid.
lH NMR(CDCl3, 400 MHz) ~ 5(1H, s),7.45(1H, s), 3.89(2H, s) and 3.75(3H, s) ppm.

CA 022~19~ 1998-10-16 Step K: Preparation of 1 -(Triphenylmethyl)- 1 H-imidazol-4-ylacetic acid methyl ester To a solution of lH-Imidazole-4- acetic acid methyl ester 5 hydrochloride (24.85g, 0.141mol) in dimethyl formamide (DMF) (115ml) was added triethylamine (57.2 ml, 0.412mol) and triphenyl-methyl 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 wa.s washed with 10 sat. aq. NaHCO3 (350 ml), dried (Na2so4) and evaporated in vacuo.
The residue was purified by flash chromatography (sio2~ 0-100% ethyl acetate in hexanes; gradient elution) to provide the title compound as a white solid.
1H NMR (CDCl3, 400 MHz) ~ 7.35(1H, s), 7.31(9H, m), 7.22(6H, m), 15 6.76(1H, s), 3.68(3H, s) and 3.60(2H, s) ppm.

Step L: Preparation of [1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yllacetic acid methyl ester To a solution of l-(Triphenylmethyl)-lH-imidazol-4-20 ylacetic acid methyl ester (P~.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 55~C for 18hr. The reaction 25 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 30 residue was suspended in EtOAc (75ml) and the solid isolated by filtration and washed (EtOAc). The solid was treated with sat aq NaHCO3 (300ml) and CH2C12 (300ml) 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:

CA 022~19~ 1998-10-16 lHNMR(CDC13, 400 MHz) ~ 7.65(1H, d, J=~SHz), 7.53(1H, s), 7.15(1H, d, J=8Hz), 7.04(1H, s), 5.24(2H, s), 3.62(3H? s) and 3.45(2H, s) ppm.

Step M: Preparation of [1-(4-cyanobenzyl)-lH-imidazol-5-yllacetic acid A solution of [1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetic acid methyl ester (4.44g, 17.4mmol ) in THF (lOOml) and 1 M lithium hydroxide (17.4 ml, 17.4 mmol) wa.s stirred at RT for 1~ hr. 1 M HCI
(17.4 ml) was added and the THF wa.s removed by evaporation in vacuo. The aqueous .solution was Iyophilized to afford the title compound containing lithium chloride a~ a white ~olid.
lH NMR(CD30D, 400 MHz) ~ ~s.22(1H, s), 7.74(1H, d, J=P~.4Hz), 7.36(1H, d, J=~.4Hz), 7.15(1H, s), 5.43(2H, s) and 3.49(2H, s) ppm.

Step N: Preparation of N-[(1-(4-Cyanobenzyl)-lH-imidazol-5-yl)acetyl]pyrrolidin-2(S)-ylmethyl~ -3(S)-ethyl-prolyl methionine i.sopropyl e.ster [1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl]acetic acid ~ LiCI
(0.416 g, 1.47 mmol), pyrrolidin-2(S)-ylmethyl~-3(S)-ethyl-prolyl methionine isopropyl e.ster hydrochloride (Step 1) ( 0.63 g, 1.33 mmol), HOOBT (0.239 g, 1.47 mmol), and EDC (0.2~1 g, 1.47 mmol) were dissolved in degassed DMF (20 mL) with ~itirring at room temperature, N-methylmorpholine (0.8 mL, 5.32 mmol) was added to achieve a pH of 7, and .stirring was continued overnight. The reaction mixture was concentrated to remove most of the DMF, and the residue was partitioned between EtOAc and acl satd NaHCO3 ~iolution. The aq layer wa~ walshed with EtOAc, the organics combined, washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound after chromatography on silica gel eluting with CH2C12:CH3OH, 95:5.
Anal. calcd for C33H46N6O4S ~ 0.7 H2O:
C, 62.3X; H, 7.52; N, 13.23;
Found: C, 62.40; H, 7.17; N, 13.11.
FAB MS 623 (M+1) CA 022~19~ 1998-10-16 2(S)-n-Butyl- 1-[1 -(4-cyanobenzyl)imidazol-5 -ylmethyl] -4-(2,3-dimethylphenyl)piperazin-5-one ~ H3C CH3 N~
1-[ 1 -(4-Cyanobenzyl)imidazol-5-ylmethyll-4-(2,3-dimethylphenyl)-2(S)-(2-methoxyethyl)piperazin-5-one ditrifluoroacetic acid salt Step A: N-Methoxy-N-methyl 4-benzyloxy-2(S)-(te)~t-butoxycarbonylamino)butanamide 4-Benzyloxy-2(S)-(te~t-butoxycarbonylamino)butanoic acid (1.00 g, 3.23 mmol) was converted to the title compound following the procedure described in Example 24, Step A, using EDC HCI (0.680 g, 3.55 mmol). HOBT (0.436 g, 3.23 mmol) and N,O-dimethylhydroxyl-amine hydrochloride (0.473 g, 4.85 mmol) in DMF (50 mL) at pH 7.
After workup, the title compound was obtained as a clear gum.

Step B: 4-(1 -Benzyloxyethyl)-2(S)-(te~ t-butoxycarbonylamino) butanal The title compound was obtained by lithium aluminum hydride reduction of the product of Step A using the procedure de.scribed in Example 24, Step B.

CA 022~19~ 1998-10-16 Step C: N-(2,3-Dimethylphenyl)-4-(2-benzyloxyethyl)-2-(S)-(te) t-butoxycarbonylamino)butanamine The title compound was prepared from the product of Step C according to the procedure described in Example 24, Step C, using 2,3-dimethylaniline (0.505 mL, 4.14 mmol), sodium triacetoxyboro-hydride (1.20 g, 5.65 mmol) and crushed molecular sieves (1 g) at pH
5 in dichloroethane (20 mL). The title compound was obtained after purification on silica gel, eluting with 15% ethyl acetate in hexane.

Step D: 2(5)-(2-Benzyloxyethyl)-l-tert-butoxycarbonyl-4-(2,3-dimethylphenyl)piperazin-5 -one The title compound was prepared from the product of Step C according to the procedure described in Example 24, Step D, using chloroacetyl chloride (0.21 mL, 2.57 mmol) in 60 mL 1:1 ethyl acetate:saturated sodium bicarbonate, followed by reaction of the crude product with ,sodium hydride (0.373 g, 60% dispersion in oil, 9.32 mmol) in DMF (30 mL). After workup, the crude product was chromatographed on silica gel with 30% ethyl acetate in hexane to obtain the title compound.
Step E: 1 -tert-Butoxycarbonyl-4-(2,3-dimethylphenyl)-2(S)-(2-hydroxyethyl)piperazin-5-one The product from Step D wa,s dissolved in methanol (40 mL) and 10% Pd/C was added (0.160 g). The reaction was shaken under 60 psi hydrogen overnight. The catalyst was removed by filtration, and the solvent evaporated to give the title compound.

Step F: 1-te7 t-Butoxycarbonyl-4-(2,3-dimethylphenyl)-2(S)-(2-methoxyethyl)piperazin-5 -one The product from Step E (0.241 g, 0.688 mmol) was dissolved in DMF (10 mL) containing methyl iodide (0.21 mL, 3.44 mmol) and the stirred solution cooled to 0~C under nitrogen. Sodium hydride (0.070 g, 60% dispersion in oil, 1.72 mmol) was added and the reaction stirred for lh. The reaction wa,s ~luenched with water, and the CA 022~19~ 1998-10-16 DMF removed under vacuum. The residue was partitioned between ethyl acetate and water, and the organic phase washed with saturated brine and dried over magnesium sulfate. The crude product was chromatographed on silica gel with 40% ethyl acetate in hexane to give the title compound.

Step G: 4-(2,3-Dimethylphenyl)-2(S)-(2-methoxyethyl)- 1 -L4-(1 -triphenylmethylimidazolyl )methyl lpiperazin-5 -one The product from Step F (0.113 g, 0.312 mmol) was 10 converted to the title compound according to the procedure described in Example 24, Step E, except using 30% trifluoroacetic acid in dichloromethane (10 mL) for 1 h for the initial deprotection. The volatiles were removed in vacuo, and the residue dissolved in dichloroethane. Triethylamine was added to obtain p~I 5. Sodium 15 triacetoxyborohydride (0.100 g, 0.468 mmol) and l-triphenylmethyl-4-imidazolylcarboxaldehyde (0.1164 g, 0.343 mmol) was added. The reaction was stirred overnight at 20~C then poured into saturated sodium bicarbonate solution. The organic phase wa.s washed with saturated brine and dried over magnesium sulfate. Silica gel 20 chromatography using 5% methanol in chloroform as eluant yielded the title compound.

Step H: 1-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3-dimethylphenyl)-2(S)-(2-methoxyethyl)piperazin-5 -one ditrifluoroacetic acid salt The product from Step G (0.1 ~2 g, 0.312 mmol) was converted to the title compound according to the procedure described in Example 25, using 4-cyanobenzylbromide (0.061 g, 0.312 mmol) in acetonitrile (10 mL), followed by reaction of the crude imidazolium 30 salt with triethyl~silane (0.13 mL) and trifluoroacetic acid (2 mL) in dichloromethane (6 mL). Purification was accomplished by reverse phase preparative HPLC with a mixed gradient of 0%-70%
acetonitrile/0.1% TFA; 100%-30% 0.1% aqueous TFA over 60 min.

CA 022~19~ 1998-10-16 WO 97/38664 rCT/US97/06248 The title compound was isolated after Iyophilization from water. FAB
ms (m+1) 458.
Anal. Calc. for C27H3lN5o2 ~ 0.35 H2O ~ 2.0 TFA:
C, 53.gl; H, 4.91; N, 10.21.
5 Found: C, 53.83; H, 4.95; N, 10.29.

N-[2(S)-N'-(1 -(4-Cyanophenyl-methyl)-lH-imidazol-5-ylacetyl)amino-10 3(S)-methylpentyl l-N- 1 -naphthylmethyl-glycyl-methionine methyl ester ~CN

H H
~N~f N N/~ N J~OMe N O ~ ~3 SCH3 Preparation of N-[2(S)-N'-(1 -(4-Cyanophenylmethyl)- 1 H-imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N- 1 -naphthylmethyl-glycyl-15 methionine bis trifluoroacetate Step A: Preparation of 1 -(Triphenylmethyl)- 1 H-imidazol-4-ylacetic acid methyl ester (23) To a suspension of lH-imidazole-4-acetic acid methyl ester 20 hydrochloride (1, 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.~ mmol) and stirred for 72 h. After thi~s time, reaction mixture was wa,shed with sat. aq. ~sodium bic~rbonate (100 ml) and water (100 ml). The organic layer was evaporated in vacuo and 25 purified by flash chromatography (30-100% ethyl acetate~exanes gradient elution) to provide 23 as a white solid.

CA 022~19~ 1998-10-16 1H NMR (CDC13, 400 MHz) ~ 7.35 (lH, ,s), 7.31 (9H, m), 7.22 (6H, m), 6.76 (lH, s), 3.6~ (3H, s) and 3.60 (2H, s) ppm.

Step B: Preparation of 1 -(4-Nitrophenylmethyl)-lH-imidazol-5-S ylacetic acid methyl ester (16) To a solution of l-(triphenylmethyl)-lH-imidazol-4-ylacetic acid methyl ester (23, 274 mg, 0.736 mmol) in acetonitrile (10 ml) wa.s added 4-nitrobenzylbromide (159 mg, 0.736 mmol) and heated to 55~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 dryne,ss in vacuo and the re.sidue 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 (2-5% methanol/methylene chloride gradient elution ) to provide 16.
lH NMR (CDC13, 400 MHz) â ~.20 (2H, d, J=~.8 Hz), 7.53 (lH, s), 7.19 (2H, d, J=8.~ Hz), 7.03 (lH, s), 5.2~ (2H, .s), 3.61 (3H, s) and 3.44 (2H, s) ppm.

Step C: 1-(4-Nitrophenylmethyl)-lH-imidazol-5-ylacetic acid hydrochloride 1-(4-Nitrophenylmethyl)-lH-imidazol-5-ylacetic acid methyl ester (0.115 g, 0.42 mmol ) was di~solved in l .ON hydrochloric acid (10 ml ) and heated at 55~C for 3 h. The solution was evaporated in vacuo to give the compound as a white .solid.
lH NMR (CD30D, 400 MHz) ~ 9.06 (lH, s), ~.27 (2H, d, J=8.~ Hz), 7.61 (IH, s), 7.55 (2H, d, J=~.~ Hz), 5.63 (2H, s) and 3.~1 (2H, s) ppm.

CA 022~19~ 1998-10-16 Step D: N-L2(S)-N'-(1 -(4-Nitrophenylmethyl)- 1 H-imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N- I -naphthylmethyl-~lycyl-methionine methyl ester bis trifluoroacetate To a solution of 1-(4-nitrophenylmethyl)-lH-imidazol-5-ylacetic acid hydrochloride, N-L2(S)-amino-3(S)-methylpentyl]-N-naphthylmethyl-glycyl-methionine methyl ester bis hydrochloride (209 mg, 0.392 mmol) and 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (HOOBT, 64 mg, 0.39 mmol) in methylene chloride (10 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 75.2 mg, 0.392 mmol) and triethylamine (219 ,ul, 1.57 mmol) and the mixture stirred overnight at room temperature. After thi.s time, satd.
aq. sodium bicarbonate (10 ml) was added and the mixture was extracted with methylene chloride. The combined extracts were washed with satd. aq. ,sodium bicarbonate (10 ml) and the solvent evaporated in vacuo.

Preparation of N-(2(R)-amino-3-mercaptopropyl)-valyl-isoleucyl-leucine methyl ester (Compound 1) Step A. Preparation of N-(2(R)-t-butoxycarbonyl-amino-3-triphenyl-methylmercaptopropyl)-valyl-isoleucyl-leucine methyl ester The tripeptide ester valyl-isoleucyl-leucine methyl ester was synthesized using conventional solution phase peptide ,synthesis methods.
The trifluoroacetate salt of this tripeptide (360 mg, 0.77 mmol) was dissolved in 5 mL of methanol with 147 mg (1.5 mmol) of potassium acetate and 670 mg (1.5 mmol) of N-Boc-S-tritylcysteinal (prepared using the procedure of Goel, Krolls, Stier, and Kesten Org. Syn. 67:
69-74 (198~) for the preparation of N-Boc-leucinal) was added. Sodium cyanoborohydride (47 mg, 0.75 mmol) wa,s added and the mixture was stirred overnight. The mixture was diluted with ether and washed with water, 5% ammonium hydroxide and brine. The solution was dried CA 022~19~ 1998-10-16 (.sodium sulfate) and evaporated to give a white foam which was purified by chromatography (1-15% acetone in methylene chloride).
The title compound was obtained as an oily material.

5 StepB. Preparation of N-(2(R)-amino-3-mercaptopropyl)-valyl-isoleucyl-leucine methyl ester A ,sample of the protected p.seudopeptide prepared as described in Step A (728 mg, 0.92 mmol) was dissolved in 100 mL
of methylene chloride, 50 mL of TFA was added and the resulting 10 yellow solution was treated immediately with 0.~0 mL (S mmol) of triethylsilane. After 45 min, the solvents were evaporated and the residue was partitioned between hexane and 0.1 % aqueous TFA. The aqueous solution was Iyophilized. This material was further purified by reverse phase HPLC (5-95% acetonitrile/0.1% TFA/water) to afford the 15 title compound. IH NMR (CD30D) ~ ~.65 (lH, d), 4.45 (lH, m), 4.3 (lH, d), 3.7 (3H, s), 3.4 (lH, m), 3.15 (lH, d), 2.75-2.9~ (m), 0.~-1.05 (l~S H, m). FAB mass spectrum, m/z = 447 (M + 1).
Anal. Calcd for C21 H42N4O4S ~ 1.8 TFA:
C, 45.24; H, 6.75; N, ~.56.
20 Found: C, 45.26; H, 6.77; N. 8.50.

EXAMPLE ~s N-(2(R)-amino-3-mercaptopropyl)-valyl-isoleucyl-leucine (Compound 25 2) Step A. Preparation of N-(2(R)-t-butoxycarbonylamino-3-triphenylmethylmercaptopropyl)-valyl-i~soleucyl-leucine The product of Example 7, Step A (60 mg, 0.076 mmol) 30 wa.s dissolved in I mL of methanol and 150 ,uL of 1 N NaOH was added.
After stirring overnight, the Isolution was acidified with 150 ,uL of 10%
citric acid and the product was extracted with ether. The ether ,solution was washed with water and brine and dried (sodium sulfate).
Evaporation provided the title compound as a solid.

CA 022~19~ 1998-10-16 Step B. Preparation of N-(2(R)-amino-3-mercaptopropyl)-valyl-i.soleucyl-leucine Using the method of Example 7, Step B, the protecting groups were removed with TFA and triethylsilane to provide the title 5 compound. FAB mass spectrum, m/z = 433 (M+l).
Anal. Calcd for C20H4oN4o4s ~ 2 TFA:
Ct 43.63; H, 6.41; N, ~.4~.
Found: C, 43.26; H, 6.60; N. 8.49.

Preparation of 2(S)-[2(S)-[2(R)-Amino-3-merc~pto~-propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserine lactone (Compound 3) and 2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-15 methvl~pentyloxy-3 -phenyl-propionyl-homoserine (Compound 4) Step A: Preparation of N-((x-chloroacetyl)-L-isoleucinol To a stirred solution of L-isoleucinol (20 g, 0.17 mol) and triethylamine (28.56 ml, 0.204 mol) in CH2cl2 (500 ml) at -7~~C was 20 added chloroacetyl chloride (16.3 ml, 0.204 mol) over 5 minutes. The cooling bath was removed and the solution allowed to warm to -20~C.
The mixture was diluted with EtOAc and wa~shed sequentially with 1 M
HCI, and brine and dried (Na2so4). Evaporation in vacuo afforded the amide title compound (35 g, 100%).
25 Rf=0.3 CH2C12: MeOH (95:5);
lH NMR (CDC13) â 6.~0 (lH, brd, J = 5 Hz), 4.10 (2H, s), 3.~4 (lH, m), 3.79 (2H~ m), 2.65 (lH, brs), 1.72 (lH, m), 1.55 (IH, m), 1.17 (IH,m),0.96(3H,d,J=6Hz)0.90(3H,t,J=6Hz).

30 Step B: Preparation of 5(S)-~ I (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 (7.4 g, 0.03~ mol) in THF (125 ml) under argon at 0~C was slowly added sodium hydride (2.2 g of a 60% dispersion ill mineral oil, 0.055 CA 022~19~ 1998-10-16 mol) with concomitant gas evolution. After completing the addition, the mixture was warmed to room temperature (R.T.) 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 water saturated 5 NaCI solution. The organic layer was dried (Na2so4) and evaporated ~n vacuo. The residue was chromatographed using silica gel eluting with CH2C12:MeOH (96:4) to afford the lactam title compound (4.35 g, 72%) as a white solid.
Rf = 0.35 CH2C12:MeOH (95:5);
1H NMR ~ (CDC13) 6.72 (lH, brs), 4.20 (lH, d, J = 14.5 Hz), 4.10 (lH, d, J = 14.5 Hz), 3.88 (lH, dd, J = 9 and 3.5 Hz), 3.5~ (lH, dd, J = 9 and 6.5 Hz), 3.45 (lH, brqt, J = 3.5 Hz), 1.70-1.45 (2H, m), 1.34 - 1.15 (lH, m), 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)-[l(S)-methyllpropyl-2~3~5~6-tetrahydro-4H- 1 ~4-oxazin-3-one 5(S)-[1 (S)-Methyl]propyl-2,3,5,6-tetrahydro 4H- 1,4-oxazin-3-one (12.2 ~, 0.0776 mol) and DMAP (1~.9 ~, 0.155 mol) were dissolved in methylene chloride (120 ml) under argon at R.T. Boc anhydride (33.9 g, 0.155 mol) was added to the stirred solution in one portion, with concomitant gas evolution and the mixture was stirred at R.T. for 16 hr. The solvent was evaporated in vacuo and the residue was taken up in ethyl acetate and washed sequentially with 10% citric acid, 50% NaHCO3 and finally brine. The organic extract wa~s dried (Na2SO4) and evaporated in vacuo. Chromatography of the residue over silica gel eluting with 20% EtOAc in hexanes afforded the title compound (14.1 g, 71%) as a white solid.
Rf = 0.75 EtOAc:hexanes (20:~0); mp 59-60~C
Anal. Calc'd. for C 13H23~4N:
C, 60.6~s; H,9.01; N, 5.44.
Found: C, 60.75; H, 9.01; N, 5.5P~.
lH NMR (CDC13) o 4.25 (lH, d, J = 15 Hz), 4.15 (lH, d, J = 15 Hz), 4.15 - 4.00 (2H, m), 3.73 (lH, dd, J = 10 and 2 Hz), 1.~ (lH, qt, J = 6 CA 022~19~ 1998-10-16 Hz), 1.55(9H,s), 1.50- 1.36(1H,m), 1.35 - l.l9(1H,m) 1.00(3H,d, J=6Hz)0.95(3H,d,J=6.5Hz).

- StepD: Preparation of N-(tert-Butoxycarbonyl)-2(S)-benzyl-5(S)-[1 (S)-methyl]propyl-2,3,5,6-tetrahydro-4H- 1,4-oxazin-3-one 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, 22.34 mmol) in DME (100 ml) under argon was cooled to -60~C. The cold solution was transferred via canula to a second flask cont~ining sodium bis(trimethylsilyl)amide (24.58 ml of a IM solution in THF, 24.5~
mmol) at -78~C under argon. After stirring for 10 minute~, benzyl bromide (2.25 ml, 18.99 mmol) was added over 5 minutes and the resulting mixture was stirred at -78~C for 3 hour.s. After this time, the reaction mixture was tr~nsferred via cannula to another flask containing .sodium bis(trimethylsilyl)amide (24.58 ml of a I M solution in THF, 24.58 mmol) at -78~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 wa,s 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) eluting with 10-20% ethyl acetate in hexane,s afforded the title compound (5.12 g, 67%) as a clear oil.
Rf = 0.25 EtOAc:Hexanes (20:80);
lH NMR (CDC13) â 7.35 - 7.15 (5H, m), 4.31 (IH, dd, J = 6 and 2 Hz), 4.03 (IH, d, J = 12 Hz), 3.88 (lH, dd, J = 6 and I Hz), 3.66 (lH, dd, J =
12 and 2 Hz), 3.29 (lH, dd, J = 12 and 3 Hz), 1.54 (9H, s), 3.12 (lH, dd, J = 12 and 7 Hz), 1.47 (lH, m), 1.25 (lH, m), 1.10 (IH, m), 0.83 (3H, d, J = 6 Hz), 0.80 (3H, t, J = 6 Hz).

CA 022~19~ 1998-10-16 Step E: Preparation of N-(tert-butoxycarbonyl)-2(S)-[2(S)-amino-3(S)-methyllpentyloxy-3-phenyl-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-5 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 10 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 the lactam 2(S)-benzyl-5(S)-[1 (S)-methyl]propyl-2,3,5,6-15 tetrahydro-4H-1,4-oxazin-3-one (0.~2 g 22%) and then with 20% MeOH
in CH2C12 to afford the title compound (4.03 g, 75%) a~s a viscous oil.
Rf = 0.4 MeOH:CH2C12 (5:95) + 0.3% AcOH;
lH NMR (d6 DMSO) ~ 7.35 - 7.10 (5H, m), 6.6~ (lH, br, s), 3.75 (lH, dd, J = 7.5 and 2.5 Hz) 3.54 (lH, m), 3.5 - 3.2 (2H, m) 2.99 (lH, dd, J
20 = 12.5 and 2.5 Hz), 2.75 (lH, dd, J = 12.5 and 7.5 Hz), 1.50 - 1.3~S
(llH,m),0.9~(lH,sept,J=6Hz),0.7X(3H,t,J=6Hz),0.65(3H,d, J = 6 Hz);
FAB MS 366 (MH+) 266 (MH2+ - CO2tBu).
~5 Step F: Preparation of N-(tert-butoxycarbonyl)-2(S)-L2(S)-amino-3(S)-methyl] -pentyloxy-3 -phenyl -propionyl-homoserine lactone To a stirred solution of N-(tert-butoxycarbonyl)-2(S)-[2(S)-amino-3(S)-methyl]-pentyloxy-3-phenylpropionic acid (0.53 g, 1.45 30 mmol) and 3-hydroxy-1,2,3,-benzotriazin-4(3H)-one (HOOBT) (0.26 g, 1.6 mmol) in DMF (15 ml) at room temperature was added EDC (0.307 g, 1.6 mmol) and L-homoserine lactone hydrochloride (0.219 g, 6.0 mmol). The pH was adjusted to pH= 6.5 by addition of NEt3 (the pH
was monitored by application of an aliquot of the reaction mixture to a CA 022~19~ 1998-10-16 moist strip of pH paper). After stirring at room temperature for 16 hr, the reaction was diluted with EtOAc and washed with saturated NaHCO3 and then brine and dried (NaSO4). Evaporation in vacuo (sufficient to remove DMF) and chromatography over silica gel eluting with 5%
5 acetone in CH2C12 afforded the title compound (520 mg, 80%) as a white solid, mp 115-117~C.
Rf = 0.3 Acetone: CH2C12 (5:95)-IH NMR (CDC13) ~ 7.73 (lH, brd, J=5 Hz), 7.40-7.15 (5H, m), 4.68 (lH, dt, J=9 and 7.5 Hz), 4.65-4.35 (2H, m), 4.33-4.18 (lH, m), 4.20 10 (lH, dd, J=7 and 3 Hz), 3.78 (lH, m), 3.49 (lH, dd, J=7.5 and 4.0 Hz), 3.37 (lH, dd, J=7.5 and 6.5 Hz), 3.15 (lH, dd, J=l 1.5 and 2 Hz), 2.86 (lH, dd, J=1 1.5 and 7.5 Hz), 2.68 (lH, m) 2.11 (IH, q, J=9 Hz), 1.55-1.30 (1 lH, m), 1.07 (IH, m), 0.87 (3H, t, J=6.3 Hz), 0.79 (3H, d, J=6 Hz).
Step G: Preparation of 2(S)-12(S)-amino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-homo~erine lactone hydrochloride Anhydrous HCl ga~ wa~ bubbled through a cold (0~C) ~olution of N-(tert-butoxycarbonyl)-2(S)-[2(S)-amino-3(S)-methyl]
pentyloxy-3-phenylpropionyl-homoserine lactone (3.0 g, 6.7 mmol) in ethyl acetate (120 ml) until a ~aturated solution wa,~ obtained. The resulting mixture wa~ ~tirred at 0~C for 1 hr. The solution wa~ purged with nitrogen and the mixture concentrated in vacuo to afford the title compound as a sticky foam which was used without further purification.
lH NMR (d6 DMSO) ~ 8.60 (lH, d, J=7 Hz), 8.08 (3H, br~), 7.35-7.15 (SH, m), 4.60 (lH, qt, J=8 Hz), 4.36 (lH, t J=7.5 Hz), 4.22 (lH, q, J=7.5 Hz), 4.15-3.95 (2H, m), 3.64 (lH, dd, J=9 and 2.5 Hz), 3.15-3.00 (2H, m), 2.92 (lH, dd, J=12.5 and 5.0 Hz), 2.40-2.15 (2H, m), 1.65 (lH, m), 1.43 (lH, m), 1.07 (lH, m), 0.82 (3H, t, J=6 Hz), 0.72 (3H, d, J=6.0 Hz).

CA 022~19~ 1998-10-16 WO 97/38664 rCTlUS97/06248 Step H: Preparation of 2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)-amino-3 -triphenylmethy~mercap-to]propylamino-3(S)-methyll-pentyloxy-3-phenylpropionyl-homoserine lactone 2(S)-[2(S)-Amino-3(S)-methyl]pentyloxy-3-phenyl-propionyl-homoserine hydrochloride (6.7 mmol) and N-(tert-butoxy-carbonyl)-S-triphenylmethylcysteine aldehyde (0.74 g, 7.5 mmol) (prepared from N-(tert-butoxycarbonyl)-S-triphenylmethylcysteine by the procedure of Goel, O.P.; Krolls, U.; Stier, M.; Keston, S. ~g. Syn.
1988, 67, 69.) and potassium acetate (3.66 g, 8.2 mmol) were dissolved in methanol (48 ml). Activated 4A molecular sieves (6g) and then Na(CN)BH3 (0.70 g, 10.7 mmol) were added and the resulting ~slurry was stirred under argon at room temperature for 16 hr. The solids were removed by filtration and the filtrate evaporated in vacuo. The residue was dissolved in EtOAc and washed sequentially with saturated aqueous NaHCO3 and brine and then dried (Na2so4). Evaporation in vacuo afforded an oil which was purified by chromatography over silica gel eluting with a gradient of 30-50% EtOAc in hexane to afford the title compound (2.34 g, 45%) contaminated with a small amount of the corresponding methyl ester.
lH NMR (CD30D) ~ 7.60-7.05(20H, m), 4.64 (IH, d, J=9.OHz), 4.39 (lH, br t, J=9Hz), 4.25(1H, m), 3.93 (lH, m), 3.75-3.60(1H, m), 3.55 (lH, dd, J=9.0 and 2Hz), 3.20 (lH, dd, J=9.0 and 6.0 Hz), 3.04 (lH, dd, J=15.0 and 5.0 Hz), 2.X5 (lH, dd, J=15.0 and 9.0 Hz), 2.60 (lH, dd, J=12.0 and 5.0 Hz), 2.50-2.15 (7H, m), 1.45 (9H, s), 1.40-1.20 (lH, m), 1.07 (lH, m), 0.g7 (3H, t, J=6 Hz), 0.67 (3H, d, J=6.0 Hz).

Step I: Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homo~serine lactone To a stirred solution of 2(S)-12(S)-[2(R)-(tert-butoxy-carbonyl)amino-3-triphenylmethylmercapto] -propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserine lactone (2.72 g, 3.49 mmol) in CH2C12 (90 ml) was added HSiEt3 (2.16 ml, 13.5 mmol) and TFA (43.2 ml, 0.56 mol) and the ,solution was stirred at R.T. under CA 022~19~ 1998-10-16 argon for 2 hrs. The solvent was evaporated in vacuo and the residue partitioned between 0.1% aqueous TFA (200 ml) and hexanes (100 ml).
The aqueou.s layer was separated and washed with hexanes (20 ml) and then Iyophilised. The resulting white lyophilate wa~s chromatographed S in S equal portions over a Waters Prepak cartridge (C-lg, 15-20 mM
100 A) eluting with a gradient of 95:5 to 5:95 0.1% TFA in H20: 0.1%
TFA in CH3CN at 100 ml/min over 60 min. The desired compound eluted after 19 min. The CH3CN was evaporated in vacuo and the aqueous solution Iyophilised to afford the title compound (1.95 g, 77%) 10 as the TFA salt.
The salt is hygro,scopic and is prone to disulphide formation if left in solution and exposed to air.
lH NMR ~ (CD30D) 7.40-7.15 (5H~m), 4.55-5.40 (2H, m), 4.33 (lH, m), 4.1~ (lH, m), 3.90-3.62 (3H, m), 3.53 (lH, dd, J=10.5 and 4.0 Hz), 15 3.37 (lH, dd, J=10.5 and 6.0 Hz), 3.23 (lH, m), 3.15-2.95 (2H, m), 2.f~ (lH, dd, J=12.5 and 5.0 Hz), 2.55-2.25 (2H, m), 1.92 (lH, m), 1.49 (lH, m), 1.23 (lH, m), 0.94 (3H, t, J=6 Hz), 0.90 (3H, d, J=6Hz).
FAB MS ~73 (2M-H+) 438 (MH+) 361 (MH~Ph) Anal. calc'd for C22H36O4N3S 2.6 TFA:
C, 43.58; H, 5.25; N, 5,82.
Found: C, 43.62; H, 5.07; N, 5.80.

Step J: Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3 (S)-methyl]pentyloxy -3-phenylpropionyl-homo,serine 2(S)-L2(S)-[2(R)-Amino-3-mercapto]propyl-amino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserine lactone (0.00326 mmol) was dissolved in methanol (0.0506 ml) and lN sodium hydroxide (0.0134 ml) was added followed by methanol (0.262 ml). The 30 conversion of the lactone to the hydroxy-acid w~,s confirmed by HPLC
analy.sis and NMR.

CA 022~19~ 1998-10-16 Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyllpentyloxy-3 -phenylpropionyl -methionine Step A: Preparation of 2(S)-[2(S)-[2(R)-(tert-butoxy-carbonyl)-amino-3-triphenyl-methylmercapto] -propylamino-3(S)-methyllpentyloxy-3-phenyl -propionyl-methionine To a solution of 2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)-10 amino-3-triphenylmethylmercapto] -propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine methyl ester (120 mg, 0.143 mmol) in methanol (4 ml) wa~; added sodium hydroxide (lN, 0.57 ml, 0.57 mmol) and the resulting mixture was stirred at room temperature for 3 hours. Another portion of ,sodium hydroxide (lN, 0.25 ml) was 15 added and stirring continued for 0.5 hours. The reaction mixture wa,s concentrated and the residue was dissolved in a minimum amount of water and neutralized with hydrochloric acid (lN, 0.87 ml). The aqueous solution was extracted with ethyl acetate three times. The combined extracts were dried (Na2so4) and concentrated to yield the 20 title compound (110 mg, 0.133 mmol, 93%). NMR (CD30D) ~ 0.70 (3H, d, J=6Hz), 0.80 (3H, t, J=6Hz), 1.05 (H, m), 1.34 (9H, s), 1.60 (H, m), 1.95 (3H, S), 2.7~2.9 (3H, m), 2.95~3.1 (2H, m), 3.95 (H, d of d, J=8, 4Hz), 4.27 (H, d of d, J=8.6Hz), 7.1~7.4 (20H, m).
~5 Step B: Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3 (S)-methyl]pentyloxy-3 -phenylpropionyl-methionine The title compound was prepared in the ~same manner as that described in Example 9, Step I, but using 2(S)-[2(S)-[2(R)-(tert-30 butoxycarbonyl)-amino-3-triphenylmethylmercapto 1-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine in place of 2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)-amino-3-triphenylmethylmercapto]-propylamino-3(S)-methyl] -pentyloxy-3-phenylpropionyl-homo~;erine lactone. NMR (CD30D) ~ 0.~S2 (3H, d, J=6Hz), 0.95 (3H, t, J=6Hz), CA 022~19~ 1998-10-16 1.20 (H, m), 1.40 (H, m), 1.85 (H, m), 2.10 (3H, s), 2.4~2.6 (2H, m), 3.1~3.2 (2H, m), 3.35 (H, d of d, J=14, 6Hz), 3.55 (H, d of d, J=14, 5Hz), 4.20 (H, d of d, J=10, 5Hz), 4.63 (H, d of d, J=10.6Hz), 7.27 (5H, m).
Anal. Calcd for C23H39N3o4s2-2cF3co2H-2H2o:
C, 43.25; H, 6.05; N, 5.60.
Found: C~ 43.09; H, 6.01; N, 5.46.

Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl~pentyloxy-3-phenylpropionyl-methionine sulfone methyl ester (Compound 5) Step A: Preparation of Methionine sulfone methyl e~ster Thionyl chloride (2.63 ml, 36 mmol) was added dropwi.se to a stirred solution of N-Boc-Met .sulfone (5 g, 1 ~ mmol) in methanol (40 ml) cooled at 0~C. After the completion of the addition, the resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was recooled to 0~C and slowly treated with solid sodium bicarbonate to adjust the pH to 7. The mixture was concentrated in vacuo to remove methanol and the residue was dis.solved in a minimum amount of water (solution pH ca. 10) and extracted with ethyl acetate four times. The combined extracts were dried (Na2SO4) and concentrated to give the title compound (1.~ g). NMR (CD30D) 2.04 (H, m), 2.21 (H, m), 2.9~ (3H, s), 3.23 (2H, t, J=7Hz), 3.63 (H, d of d, ~=~.6Hz), 3.77 (3H, ,s).

Step B: Preparation of N-(tert-Butoxycarbonyl)-2(S)-12(S)-amino-3(S)-methyl]-pentyloxy-3-phenyl-propionyl-methionine ,sulfone methyl e.ster The title compound was prepared in the same fashion as that described in Example 9, Step F, but using methionine sulfone methyl ester in place of homoserine lactone hydrochloride. NMR

CA 022~19~ 1998-10-16 (CD30D) ~ 0.80 (3H, d, J=6Hz), 0.~ (3H, t, J=6Hz), 1.12 (H, m), 1.47 (9H, s), 2.10 (H, m), 2.32 (H, m), 2.93 (3H, s), 3.5~3.7 (2H, m), 3.74 (3H, s), 4.01 (H, d of d, J=7.4Hz), 4.60 (H, d of d, J=9.5Hz), 6.60 (H, d, J=~sHz), 7.25 (SH, m).

Step C: Preparation of 2(s)-l2(s)-Amino-3(s)-methyl]-pentyloxy-3 phenylpropionyl-methionine sulfone methyl ester hydrochloride The title compound was prepared in the same fashion as that described in Example 9, Step G, but using N-(tert-butoxycarbonyl)-2(S)-[2(S)-amino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methionine sulfone methyl ester in place of N-(tert-butoxycarbonyl)-2(S)-[2(S)-amino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserine lactone.
NMR (CD30D) ~ 0.85 (3H, d, J=6Hz), 0.94 (3H, t, J=6Hz), 1.20 (H, m), 1.52 (H, m), 1.72 (H, m), 2.14 (H, m), 2.3~s (H, m), 2.9~ (3H, s), 3.57 (H, d of d, J=12, 6Hz), 3.73 (H, d of d, J=12, 9Hz), 3.7~s (3H, s), 4.15 (H, d of d, J=~s.6Hz), 4.63 (H, d of d, J=~.5Hz), 7.30 (5H, m).

Step D: Preparation of 2(S)-[2(S)-[2(R)-(tert-Butoxy-carbonyl)-amino-3-triphenylmethylmercapto]-propylamino-3(S)-methyl]pentyloxy-3-phenyl-propionyl-methionine sulfone methyl ester The title compound was prepared in a similar fashion as that de.scribed in Example 9, Step H, but using 2(S)-[2(S)-amino-3(S)-methyl]pentyloxy-3-phenyl-propionyl-methionine sulfone methyl ester hydrochloride in place of 2(S)-[2(S)-amino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserine lactone hydrochloride. NMR (CD30D) ~
0.70 (3H, d, J=6Hz), O.X~ (3H, t, J=6Hz), 1.10 (H, m), 1.47 (9H, s), 2.15 (H, m), 2.67 (H, m), 2.92 (3H, s), 3.67 (H, m), 4.6~ (H, d of d, J=10, 6Hz), 7.15~7.45 (20H, m).

CA 022~19~ 1998-10-16 Step E: Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methionine sulfone methyl ester The title compound was prepared in a similar fashion as 5 that described in Example 9, Step I, but using 2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)amino-3-triphenylmethylmercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropiony}-methionine sulfone methyl ester in place of 2(S)-[2(S)-[2(R)-(tert-butoxy-carbonyl)-amino-3-triphenyl-methylmercapto]propylamino-3(S)-methyl]pentyloxy-3-phenyl-10 propionyl-homoserine lactone. NMR (CD30D) ~ 0.~S3 (3H, d, J=6Hz), 0.93 (3H, t, J=6Hz), 1.20 (H, m), 1.51 (H, m), l.~sO (H, m), 2.22 (H, m), 2.43 (H, m), 3.00 (3H, s), 3.78 (3H, s), 4.20 (H, d of d, J=~.4Hz), 4.72 (H,dofd,J=10,6Hz),7.30(5H,m).
FABMS m/z 532 (MH+).

Preparation of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine sulfone (Compound 20 6) Step A: Preparation of 2(S)-[2(S)-[2(R)-(tert-Butoxy-carbonyl)-amino-3 -triphenylmethylmercapto] -propylamino-3(S)-methyllpentyloxy-3-phenyl-propionyl-methionine sulfone 'rhe title compound was prepared in a ~imilar fashion as that described in Example lO, Step A, but using 2(S)-[2(S)-~2(R)-(tert-butoxycarbonyl)amino-3-triphenylmethylmercapto3 -propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine sulfone methyl ester in place of 2(S)-[2(S)-[2(R)-(tert-hutoxycarbonyl)amino-3-triphenyl-30 methylmercapto3propylamino-3(S)-methyl]pentyloxy-methionine methyl ester. NMR (CD30D) ~ 0.79 (3H, d, J=6Hz), 0.90 (3H, t, J=6Hz), 1.47 (9H, s), 2.92 (3H, s), 4.0~ (H, m), 4.32 (H, m), 7.15~7.35 (20H, m).

CA 022~19~ 1998-10-16 Step B: Preparation of 2(S)-~2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl] -pentyloxy-3 -phenylpropionyl -methionine sulfone The title compound was prepared in a similar fashion as 5 that described in Example 9, Step I, but using 2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)amino-triphenylmethylmercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine sulfone in place of 2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)amino-3-triphenylmethyl-mercapto]propylamino-3(S)-methyl] -pentyloxy-3 -phenylpropionyl-10 3(S)-methyllpentyloxy-3-phenylpropionyl-homoserine lactone. NMR
(CD30D) o 0.~4 (3H, d, J=6Hz), 0.94 (3H, t, J=6Hz), 1.21 (H, m), 1.50 (H, m), 1.82 (H, m), 2.24 (H, m), 2.47 (H, m), 2.9~ (3H, s), 3.6~3.75 (3H, m), 4.20 (H, d of d, J=9.5Hz), 4.64 (H, d of d, J=9.6~z), 7.30 (5H, m).~5 Anal. Calcd for C23H39N3O6S2-3CF3CO2H:
C, 40.51; H, 4.92; N, 4.89.
Found: C, 40.47; H, 5.11; N, 4.56.

Preparation of 2(S)-12(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine sulfone isopropyl e,ster H S "0 H N N o o <
~ ~
o2s\

The title compound was prepared using methods A-E from Example l l, except for Method A. Methionine sulfone isopropyl ester was prepared by coupling t-butyloxycarbonyl-methionine sulfone with i~opropyl alcohol using dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) followed by deprotection with HCI in EtOAc. NMR (CD30D) â 0.83 (3H, d, J = 6 Hz), 0.94 (3H, t, J = 6 S Hz), 1.11-1.56 (2H, m), 1.28 (6H, d, J = 6 Hz), 1.~-1.96 (lH, m), 2.12-2.27 (lH, m), 2.89-3.0 (2H, m), 3.01 (3H, ,s), 3.06-3.3 (4H, m), 3.42 (lH, dd, J = 6, 13 Hz), 3.65 (lH, dd, J = 6,13 Hz), 3.68-3.91 (3H, m), 4.2-4.27 (lH, m), 4.61-4.7 (lH, m), 4.96-5.12 (2H, m), 7.19-7.44 (SH, m).
10 Anal. Calc'd. for C26H4sN3o6s2 ~ 2 CF3CO2H:
C~ 44.07; H, 5.67; N, 4.97;
Found: C, 44.35; H, 5.68; N, 5.23 N-(2(R)-amino-3-mercaptopropyl)-valyl-i~oleucyl-methionine methyl e~ter (Compound 7);

HS \J

NJ~N N~ll~oCH3 o S\CH3 The title compound i.~ prepared in accordance with U.S.
Pat. No. S,23~922~ incorporated by reference.

N-(2(R)-amino-3-mercaptopropyl)-valyl-i~oleucyl-methionine (Compound ~);

CA 022~19~ 1998-10-16 HS \,J

H2N N J~ N N

O
S\CH3 The title compound is prepared in accordance with U.S.
5 Pat. No. 5,23~,922, incorporated by reference.

BIOLOGICAL ASSAYS.
The ability of compounds of the present invention to inhibit cancer can be demonstrated using the following assays.

In vitro inhibition T7ansfe)a.~e Assays. Isoprenyl-protein transferase activity 15 assays were carried out at 30 ~C unless noted otherwi,se. A typical reaction contained (in a final volume of 50 ~L): [3H]farnesyl diphosphate or [3H]geranylgeranyl diphosphate, Ras protein, 50 mM
HEPES, pH 7.5, 5 mM MgCI27 5 mM dithiothreitol and isoprenyl-protein tran~sferase. The FPTa,se employed in the assay was prepared by 20 recombinant expression as de.scribed in Omer, C.A., Kral, A.M., Diehl, R.E., Prendergast, G.C., Powers, S., Allen, C.M., Gibbs, J.B. and Kohl, N.E. (1993) Biochemist7y 32:5167-5176. The geranylgeranyl-protein transferase-type I employed in the assay was prepared as described in U.S. Pat. No. 5,470,~s32, incorporated by reference. After thermally 25 pre-equilibrating the assay mixture in the absence of enzyme, reactions were initiated by the addition of isoprenyl-protein transferase and ~stopped at timed interval,s (typically 15 min) by the addition of 1 M HCI
in ethanol (1 mL). The quenched reaction~s were allowed to stand for 15 CA 022~19~ 1998-10-16 m (to complete the precipitation process). After adding 2 mL of 100%
ethanol, the reactions were vacuum-filtered through Whatman GF/C
filters. Filter.s were wa,shed four times with 2 mL aliquots of 100%
ethanol, mixed with scintillation fluid (10 mL) and then counted in a 5 Beckrnan LS3801scintillation counter .
For inhibition studies, assays were run as described above, except inhibitor,s were prepared as concentrated ,solution,s in 100%
dimethyl sulfoxide and then diluted 20-fold into the enzyme assay mixture. ICso values were determined with both transferase substrate~
10 near KM concentrations. Nonsaturating sub,strate conditions for inhibitor IC50 determinations were as follows: FTa~e, 650 nM Ra~-CVLS, 100 nM farnesyl diphosphate; GGPTase-I, 500 nM ~a,s-CAIL, 100 nM geranylgeranyl dipho,sphate.

TABLE I

Inhibition of RAS farnesylation by compound.s of thi~s invention IC50 (nM!*
Compound FPTase GGTase-I
Compound 6 l.~s 3000 Compound 4 2.7 7~S00 Compound 8 7 28 Compound 2 ~00 1.9 *(IC50 is the concentration of the te~st compound which gives 50%
30 inhibition of FTase or GGTa,se-type I under the described assay conditions.

CA 022~19~ 1998-10-16 - 21~ -In vivo ras prenylation assay The cell lines used in this assay consist of either Ratl or 5 NIH3T3 cells transformed by either viral Ha-ras; an N-ras chimeric gene in which the C-te~ninal hypervariable region of v-Ha-ra.s was substituted with the corresponding region from the N-ras gene; or ras-CVLL, a v-Ha-ras mutant in which the C-terminal exon encodes leucine instead of serine, making the encoded protein a substrate for 10 geranylgeranylation by GGPTase I. The assay can also be performed using cell lines transformed with human Ha-ras, N-ras or Ki4B-ras.
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(.s) (final concentration of 15 solvent, methanol or dimethyl .sulfoxide, is 0.1%). After 4 hours at 37~C, the cells are labelled in 3 ml methionine-free DMEM supple-mented with 10% regular DMEM, 2% fetal bovine serum, 400 !lCi[35S]methionine (1000 Ci/mmol) and test compound(s). Cells treated with lova.statin, a compound that blocks Ras processing in 20 cells by inhibiting the rate-limiting step in the i.soprenoid biosynthetic pathway (Hancock, J.F. et al. Cell, 57:1167 (19X9); DeClue, J.E.
et al. Cancer Res., 51:712 (1991); Sinensky, M. et al. J. Biol. Chem., 265:19937 (1990))7 serve as a positive control in this assay. After an additional 20 hours, the cells are Iy.sed in 1 ml Iysis buffer (1% NP40/20 25 mM HEPES, pH 7.5/5 mM MgC12/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the Iysates cleared by centrifugation at 100,000 x g for 45 min. Alternatively, four hours after the additon of the labelling media, the media is removed, the cells washed, and ~ ml of media containing the same or a different test 30 compound added. Following an additional 16 hour incubation, the Iysis is carried out as above. Ali4uots of Iysates containing equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (Iysis buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et al., J. Virol. 43:294-304, (19~2)).
35 Following a 2 hour antibody incubation at 4~C, 200 ~1 of a 25%

CA 022~19~ 1998-10-16 suspension of protein A-Sepharose coated with rabbit anti rat IgG is added for 45 min. The immunoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/l mM EDTA/1% Triton X-100Ø5%
deoxycholate/0. 1 %/SDS/0. I M NaCl) boiled in SDS-PAGE sample 5 buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel i~s fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to prenylated and nonprenylated Ras proteins are compared to determine the percent inhibition of prenyl transfer to protein.

v-ras N-ras ras-C~lLL
Assay Set No. l 100 !lM Compound 5 +++ +
200 ~M Compound 7 +++ ++ ++
100 ~M Compound 1 + - ++
Assay Set No. 2 100 ~M Compound l ++ + +++
l0 ~M Compound 5 +++ +
Compound l + Compound 5 ++ +++ +++
added simultaneously Assay Set No. 3 100 IlM Compound 3/wash/ +++ +
MeOH
100 ~M Compound 3/wash/ +++ +
Compound 3 100 ~M Compound 3/wash/ +++ ++ +/-Compound l Groups of in Vil'O ras prenylation experiments are separated in Table 2 according to direct comparison of assay results on acrylamide gel 15 chromatography plates. Legend: +++, > 90% of Ras protein unprocessed; ++, 60 - 90% unprocessed; +, 30 - 60% unprocessed; +/-, 10 - 30% unprocessed; -, < 10% unproce,ssed.

CA 022~19~ 1998-10-16 In vivo growth inhibition assay S 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 v-ras, v-raf, or v-mos oncogene is tested. Cell line.s transformed with human Ha-ras, N-ras or Ki4B-ras can also be utilized. Cells 10 transformed by v-Raf and v-Mos may be included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation.
Rat 1 cell,s transformed with either v-ra.s~ v-raf~ or v-mos are seeded at a density of 1 x 104 cell.s per plate (35 mm in diameter) in 15 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 (0.6%). 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).
20 The cells are fed twice weekly with 0.5 ml of medium A containing 0.1% methanol or the concentration of the instant compound. Photo-micrographs are taken 16 days after the cultures are seeded and comparisons are made.

Claims (21)

WHAT IS CLAIMED IS:

1. A method of treating cancer comprising admininstering to a mammalian patient in need of such treatment a therapeutically effective amount of combination of a selective geranylgeranyl-protein transferase-type I inhibitor and a selective farnesyl protein transferase inhibitor.

2. A method of treating cancer in accordance with claim 1 wherein the cancer is selected from the group consisting of:
cancers of the brain, colon, genitourinary tract, lymphatic system, rectum, stomach, larynx and lung, and chronic myelogenous leukemia.

3. A method of treating cancer in accordance with claim 1 wherein the cancer is selected from the group consisting of:
histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers.

4. A method of treating cancer in accordance with claim 1 wherein the cancer is selected from the group consisting of:
pancreatic and breast carcinoma.

5. A method of treating cancer in accordance to Claim 1 wherein a selective geranylgeranyl-protein transferase-type I inhibitor compound is at least 10 times more active against geranylgeranyl-protein transferase-type I in vitro than the compound is active against farnesyl-protein transferase in vitro.

6. A method of treating cancer in accordance to Claim 1 wherein a selective farnesyl-protein transferase inhibitor compound is at least 10 times more active against farnesyl-protein transferase in vitro than the compound is active against geranylgeranyl-protein transferase-type I in vitro.

7. A method of treating cancer in accordance to Claim 1 wherein a selective geranylgeranyl-protein transferase-type I inhibitor compound is at least 20 times more active against geranylgeranyl-protein transferase-type I in vitro than the compound is active against farnesyl-protein transferase in vitro.

8. A method of treating cancer in accordance to Claim 1 wherein a selective farnesyl-protein transferase inhibitor compound is at least 20 times more active against farnesyl-protein transferase in vitro than the compound is active against geranylgeranyl-protein transferase-type I in vitro.

9. A method of treating cancer in accordance to Claim 1 wherein a selective geranylgeranyl-protein transferase-type I inhibitor compound is at least 100 times more active against geranylgeranyl-protein transferase-type I in vitro than the compound is active against farnesyl-protein transferase in vitro.

10. A method of treating cancer in accordance to Claim 1 wherein a selective farnesyl-protein transferase inhibitor compound is at least 100 times more active against farnesyl-protein transferase in vitro than the compound is active against geranylgeranyl-protein transferase-type I in vitro.

11. A method of treating cancer in accordance with Claim 1 wherein the selective geranylgeranyl-protein transferase-type I
inhibitor compound is selected from a compound of the formula I:

wherein:
R1 and R2 are independently selected from:
a) C2 - C8 alkyl;
b) C2 - C8 alkenyl;
c) C2 - C8 alkynyl;
d) substituted C1 - C8 alkyl;
e) aryl;
f) substituted aryl;
g) heteroaryl;
h) substituted heteroaryl; and i) the side chain of a naturally occurring amino acid;

R3 is selected from alkyl, alkenyl and alkynyl of 1 to 6 carbon atoms, either branched or straight chain, which is unsubstituted or substituted with a phenyl group;
X-Y is , , or and Z is H2 or O;
or a pharmaceutically acceptable salt or disulfide thereof.

12. A method of treating cancer in accordance with claim 1 wherein the farnesyl transferase inhibiting compound is selected from the group consisting of:

(a) a compound represented by one of formulas (II-a) through (II-c):

or a pharmaceuticaly acceptable salt thereof, wherein with respect to formula (II-a):

R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(o)NR10-, CN, NO2, (R10)2N-C(NR10), R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10),- R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)-NR10-;

R2 and R3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, or , wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl, b) (CH2)p OR6, c) (CH2)p NR6R7, d) halogen, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6, S(O)R6, SO2R6, 5) ~NR6R7 , , , , , , 11 ) ~SO2-NR6R7 , , , or or ;

R2 and R3 are attached to the same C atom and are combined to form -(CH2)u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R4 and R5 are independently selected from H and CH3;

and any two of R2, R3, R4 and R5 are optionally attached to the same carbon atom;
R6, R7 and R7a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, f) ~SO2R11 , or g) N(R10)2; or R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, R10 2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, CN, H2N-C(NH)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R10OC(O)NH-;

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NRl0-, CN, NO2, (R10)2N-C-(NR-10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-;

R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;

R11 is independently selected from C1-C6 alkyl and aryl;

A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10, -NR10C(O)-, O, -N(R10)-, -S(O)2N(R10)-, -N(R10)S(O)2-, or S(O)m;

V is selected from:
a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a 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 A1 is a bond, n is 0 and A2 is S(O)m;

W is a heterocycle;

X is -CH2-, -C(=O)-, or -S(=O)m-;

Y is aryl, heterocycle, unsubstituted or substituted with one or more of:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)m R6, or g) -C(O)NR6R7, 2) aryl or heterocycle, 3) halogen, 4) OR6, 5) NR6R7, 6) CN, 7) NO2, 8) CF3;
9) -S(O)m R6, 10) -C(O)NR6R7, or 11) C3-C6 cycloalkyl;

m is 0, 1 or2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 0 or 1;
t is 0 or 1; and u is 4 or 5;
with respect to formula (II-b):

R1a, R1b, R10, R11, m, R2, R3, R6, R7, p, R7a, R8, A1, A2, V, W, W, n, p, r, s, t and u are as defined above with respect to formula (II-a);

R4 is selected from H and CH3;

and any two of R2, R3 and R4 are optionally attached to the same carbon atom;

R9 is selected from:
a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C-(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10), R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-;

G is H2 or O;

Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)m R6, or g) -C(O)NR6R7, 2) aryl or heterocycle, 3) halogen, 4) OR6, 5) NR6R7, 6) CN, 7) NO2, 8) CF3;
9) -S(O)m R6, 10) -C(O)NR6R7, or 11) C3-C6 cycloalkyl;
with respect to formula (II-c):

R1a, R1b, R10, R11, m, R2, R3, R6, R7, p, u, R7a, R8, A1, A2, V, W, X, n, r and t are as defined above with respect to formula (II-a);

R4 is selected from H and CH3;

and any two of R2, R3 and R4 are optionally attached to the same carbon atom;
G is O;

Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)m R6, or g) -C(O)NR6R7, 2) aryl or heterocycle, 3) halogen, 4) OR6, 5) NR6R7, 6) CN, 7) NO2, 8) CF3;
9) -S(O)m R6, 10) -C(O)NR6R7, or 11) C3-C6 cycloalkyl;
and s is 1;

(b) a compound represented by formula (II-d) through (II-g):

wherein with respect to formula (II-d):

R11, V, W, m, n, p and r are as defined above with respect to formula (II-a);

R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2 (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10, CN, (R10)2N-C(NR10), R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)-NR10-;

R2a and R2b are independently selected from:
a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, N3, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, c) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10), R10C(O)-, R10OC(O)-, N3, -N(Rl0)2, or R11OC(O)NR10-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-C10 cycloalkyl;

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, and c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)- R10OC(O)-, N3, -N(R10)2, 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; or R3 and R4 are combined to form - (CH2)s -;

R5a 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, CF3, N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl, d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C10 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: O, S(O)m, -NC(O)-, and -N(COR10)-;

X-Y is , , , , , or f) -CH2-CH2- ;

R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl;

R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10, CN, NO2, R10 2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and C) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R11S(O)m-, R10C(O)NH-, CN, H2N-C(NH)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R10OC(O)NH-;

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C-(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R1))2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or sub.stituted by perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-;

R10 is independently selected from H, C1-C6 alkyl, benzyl, substituted aryl and C1-C6 alkyl substituted with substituted aryl;

A1 and A2 are independently .selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, -S(O)2N(R10)-, -N(R10)S(O)2-, or S(O)m;
Z is independently H2 or O;

s is 4 or 5;
t is 3, 4 or 5; and u is 0 or 1;
with respect to formula (II-e):

R11, W, m, n, p and r are as defined above with respect to formula (II-a);

R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2,(R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)-NR10-;

R2a and R2b are independently selected from:
a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, R10O-,R11S(O)m-, R10C(O)NR10-, CN, N3, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, c) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-C10 cycloalkyl;

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-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O), R10OC(O)-, N3, -N(R10)2, 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; or R3 and R4 are combined to form -(CH2)8-;

R5a 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, CF3, N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, 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; or R5a and R5b are combined to form - (CH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R6 is a) substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C5-C8 cycloalkyl, or substituted or unsubstituted cyclic amine, wherein the substituted alkyl, cycloalkyl or cyclic amine is substituted with 1 or 2 substituents independently selected from:
1) C1-C6 alkyl, 2) aryl, 3) heterocycle, 4) -N(R11)2, 5) -OR10, or ;

X-Y is , , , , , or f) -CH2-CH2- ;

R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl;

R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl;

R8 independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, R102N-C(NR10) R10C(O), R10OC(O), N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, CN, H2N-C(NH)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R10OC(O)NH-;

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10- CN, NO2, (R10)2N-C-(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F Cl Br R10O-, R11S(O)m, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10OC(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-;

R10 is independently selected from H, C1-C6 alkyl, benzyl, substituted aryl and C1-C6 alkyl substituted with substituted aryl;
R12 is hydrogen or C1-C6 alkyl;
R13 is C1-C6 alkyl;

A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, -S(O)2N(R10)-, -N(R10)S(O)2-, or S(O)m;
Z is independently H2 or O;

s is 4 or 5;
t is 3, 4 or 5; and u is 0 or 1;
with respect to formula (II-f):
R11, V, W, m, n, p and r are as defined above with respect to formula (II-a);
R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2(R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2 or R11OC(O)NR10-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)-NR10-;

R2a and R2b are independently selected from:
a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, N3, (R10)2NC(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, c) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-C10 cycloalkyl;

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, and c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10), R10C(O)-, R10OC(O)-N3, -N(R10)2, R11OC(O)NR 10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or R3 and R4 are combined to form -(CH2)s -;

X-Y is , , , , , or f) -CH2-CH2-;

R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl;

R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, R102N-C(NR10)-, R10C(O)-, R100C(o)-, N3, -N(R10)2, or R 1 1 OC(O)NR 10, and c) C 1 -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R100-, R 1 lS(o)m R 1 0C(O)NH-, CN, H2N-c(NH)-~ R 1 °C(O)-, R 1 °OC(O)-N3, -N(R 1°)2, or R 1 00C(o)NH-;

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-c6 alkynyl, perfluoroalkyl, F, Cl Br R100-, R11S(O)m, R10C(O)NR10-~ CN, NO2, (R 1 0)2N C (NR 10) , R 1 °C(O)-, R 1 °OC(O)-, N3, -N(R 1°)2, or R 1 1 OC(O)NR 10, and c) Cl-C6 alkyl unsubstituted or sub.stituted by perfluoroalkyl, F, Cl, Br, R100-, R1 1S(O)m-, R10c(o)NRlo-~ CN, (R10)2N C(NR10), R10c(o)-~ R J 00C(o)-, N3, -N(R10)2, or R1 1oC(O)NR10-;

R10 i.s independently selected from H, Cl-c6 alkyl, benzyl, substitutedaryl and Cl-C6 alkyl substituted with sub.stituted aryl;

R12 is hydrogen or C1-C6 alkyl;

R13 is Cl-C6 alkyl;

A1 and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR 10, -NR 1 °C(O)-, O, -N(R 10) -S(0)2N(R 10 -N(R10)S(0)2-, or S(O)m;

Z is independently H2 or O;

qis 0, 1 or2;
s is 4 or 5;

t is 3,4 or 5; and u is 0 or 1 ;
with respect to formula (II-g):
R11, V, W, m, n, p and r are as previously defined with respect to formula (II-a);

R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, R10)2N-C(NR10), R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)-NR10-;

R2a and R2b are independently selected from:
a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, N3, (R10)2N-C(NR10), R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, c) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10), R10C(O)-, R10OC(O)-, N3, -N(R10)2 or R11OC(O)NR10-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-C10 cycloalkyl;

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-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R10)2, N02, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10), R10C(O)-, R10OC(O)-, N3, -N(R10)2, 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; or R3 and R4 are combined to form -(CH2)s -;

X-Y is , , , , , or f) -CH2-CH2-;
R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl;

R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or Substituted C3-C10 cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, R102N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O, R11S(O)m-, R10C(O)NH-, CN, H2N-C(NH)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R10OC(O)NH-;

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10), R10C(O)-, R10OC(O)-. N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F Cl Br R10O-, R11S(O)m, R10C(O)NR10-, CN, (R10)2N-C(NR10), R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-;

R10 is independently selected from H, C1-C6 alkyl, benzyl, substituted aryl and C1-C6 alkyl sub,stituted with substituted aryl;

R12 is hydrogen or C1-C6 alkyl;

R13 is C1-C6 alkyl;

A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10) -S(0)2N(R10)-, -N(R10)S(O)2-, or S(O)m;

Z is independently H2 or O;

q is 0, 1 or 2;
s is 4 or 5;
t is 3, 4 or 5; and u is 0 or 1 ;

(c) a compound represented by one of formulas (II-h) through (II-k):

or a pharmaceutically acceptable salt thereof, wherein with respect to formula (II-h):

R1a, R1b, R8, R9, R10, R11, A1, A2, V, W, m, n, p and r are as previously defined with respect to formula (II-a);

R2 and R3 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, and c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR 10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, 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; or R2 and R3 are combined to form - (CH2)s -; or R2 or R3 are combined with R6 to form a ring such that is ;

R4a, R4b, R7a and R7b are independently selected from:
a) hydrogen, b) C1-C6 alkyl unsubstituted or,substituted by alkenyl, R10O-, R11S(O)m, R10C(O)NR10-, CN, N3, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10, c) aryl, heterocycle, cycloalkyl, alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-C10 cycloalkyl;

R5a 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(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10), R10C(O)-, R10OC(O)-, N3, -N(R10)2, R11OC(O)NR10- and C 1-C20 alkyl, d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 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: O, S(O)m, -NC(O)-, and -N(COR10)-;
R6 is independently selected from hydrogen or C1-C6 alkyl;

Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;

X, Y and Z are independently H2 or O;

s is 4 or 5;
t is 3, 4 or 5; and u is 0 or 1;
with respect to formula (II-i):

R1a, R1b, R8, R9, R10, R11, A1, A2, V, W, m, n, p and r are as previously defined with respect to formula (II-a);

R2 and R3 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, and c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN (R10)2N-C(NR10), R10C(O)-, R10OC(O)-, N3, -N(R10)2, 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; or R2 and R3 are combined to form - (CH2)s-; or R2 or R3 are combined with R6 to form a ring such that is R4a, R4b, R7a and R7b are independently selected from:
a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R10O-, R11S(O)m, R10C(O)NR10-, CN, N3, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10O-, c) aryl, heterocycle, cycloalkyl, alkenyl, R10O-, R11S(O)m, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2 or R11OC(O)NR10-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-C10 cycloalkyl;

R5a 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 sub,stituent is selected from F, Cl, Br, N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl, d) C1-C6 alkyl substituted with an unsubstituted or substituted group ,selected from aryl, heterocycle and C3-C10 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: O, S(O)m, -NC(O)-, and -N(COR10)-;

R6 is independently selected from hydrogen or C1-C6 alkyl;
R12 is a) substituted or unsubstituted C1-C8 alkyl or substituted or unsubstituted C5-C8 cycloalkyl, wherein the substituent on the alkyl or cycloalkyl is selected from:
1) aryl, 2) heterocycle, 3) -N(R11)2, 4) -OR10, or b) ;

R13 is independently selected from hydrogen and C1-C6 alkyl;
R14 is independently selected from C1-C6 alkyl;
Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
X, Y and Z are independently H2 or O;
s is 4 or 5;
t is 3, 4 or 5; and u is 0 or 1;
with respect to formula (II-j):

R1a, R1b, R8, R9, R10, R11, A1, A2, V, W, m, n, p and r are as previously defined with respect to formula (II-a);

R2 and R3 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, and c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, 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; or R2 and R3 are combined to form -(CH2)s-; or R2 or R3 are combined with R6 to form a ring such that is R4a, R4b, R7a and R7b are independently selected from:
a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, N3, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2 or R11OC(O)NR10-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-C10 cycloalkyl;
R6 is independently selected from hydrogen or C1-C6 alkyl;

Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
X, Y and Z are independently H2 or O;
q is 0, 1 or 2;
s is 4 or 5;
t is 3, 4 or 5; and u is 0 or 1;
with respect to formula (II-k):

R1a, R1b, R8, R9, R10, R11, A1, A2, V, W, m, n, p, and r are as definedabove with respect to formula (II-a);

R2 and R3 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, and c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, 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; or R2 and R3 are combined to form -(CH2)s-; or R2 or R3 are combined with R6 to form a ring such that is R4a, R4b, R7a and R7b are independently selected from:
a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, N3, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2 or R11OC(O)NR10-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-C10 cycloalkyl;
R6 is independently selected from hydrogen or C1-C6 alkyl;
Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;

X, Y and Z are independently H2 or O;
q is 0, 1 or 2;
s is 4 or 5;
t is 3, 4 or 5; and u is 0 or 1;
(d) a compound represented by formula (II-I):

or a pharmaceuticaly acceptable salt or disulfide thereof, wherein with respect to formula (II-I):
Rc is selected from:

and R1 is hydrogen, an alkyl group, an aralkyl group, an acyl group, an aracyl group, an aroyl group, an alkylsulfonyl group, aralkylsulfonyl group or arylsulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms;

R2 and R3 are the side chains of naturally occurring amino acids, including their oxidized forms which may be methionine sulfoxide or methionine sulfone, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substitutents may be substituted with an aromatic or heteroaromatic ring;
R4 is hydrogen or an alkyl group, wherein the alkyl group comprises straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms;
R5 is selected from:
a) a side chain of naturally occurring amino acids, b) an oxidized form of a side chain of naturally occurring amino acids selected from methionine sulfoxide and methionine sulfone, c) substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl, or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substituent is optionally substituted with an aromatic or heteroaromatic ring, and d) -CH2CH2OH or -CH2CH2CH2OH;
R6 is a substituted or unsubstituted aliphatic, aromatic or heteroaromatic group such as saturated chains of 1 to 8 carbon atoms, which may be branched or unbranched, wherein the aliphatic substituent may be substituted with an aromatic or heteroaromatic ring;
T is O or S(O)m;
m is 0, 1 or 2; and n is 0, 1 or 2.

13. A method of treating cancer in accordance with claim 5 wherein the selective geranylgeranyl-protein transferase-type I
inhibitor is selected from:
N-(2(R)-amino-3-mercaptopropyl)-valyl-isoleucyl-leucine;
N-(2(R)-amino-3-mercaptopropyl)-valyl-isoleucyl-leucine methyl ester;
N-[2(S)-(2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyloxy)-3-methylbutanoyl]-leucine; and N-[2(S)-(2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyloxy)-3-methylbutanoyl]-leucine methyl ester, or a pharmaceutically acceptable salt thereof.

14. A method of treating cancer in accordance with claim 6 wherein the farnesyl transferase inhibiting compound is (a) a compound represented by one of formulas (II-a) through (II-c):

selected from the group consisting of:
2(S)-butyl-1-(2,3-diaminoprop-1-yl)-1-(1-naphthoyl)piperazine;
1-(3-amino-2-(2-naphthylmethylamino)prop-1-yl)-2(S)-butyl-4-(1-naphthoyl)piperazine;
2(S)-butyl-1-{5-[1-(2-naphthylmethyl)]-4,5-dihydroimidazol}methyl-4-(1-naphthoyl)piperazine;
1-[5-(1-benzylimidazol)methyl]-2(S)-butyl-4-(1-naphthoyl)piperazine;
1-{5-[1-(4-nitrobenzyl)]imidazolylmethyl}-2(S)-butyl-4-(1-naphthoyl)piperazine;
1-(3-acetamidomethylthio-2(R)-aminoprop-1-yl)-2(S)-butyl-4-(1-naphthoyl)piperazine;

2(S)-butyl-1-[2-(1-imidazolyl)ethyl]sulfonyl-4-(1-naphthoyl)piperazine;
2(R)-butyl-1-imidazolyl-4-methyl-4-(1-naphthoyl)piperazine;
2(S)-butyl-4-(1-naphthoyl)-1-(3-pyridylmethyl)piperazine;
1-2(S)-butyl-(2(R)-(4-nitrobenzyl)amino-3-hydroxypropyl)-4-(1-naphthoyl)piperazine;
1-(2(R)-amino-3-hydroxyheptadecyl)-2(S)-butyl-4-(1-naphthoyl)-piperazine;
2(S)-benzyl-1-imidazolyl-4-methyl-4-(1-naphthoyl)piperazine;
1-(2(R)-amino-3-(3-benzylthio)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine;
1-(2(R)-amino-3-[3-(4-nitrobenzylthio)propyl])-2(S)-butyl-4-(1-naphthoyl)piperazine;
2(S)-butyl-1-[(4-imidazolyl)ethyl]-4-(1-naphthoyl)piperazine;
2(S)-butyl-1-[(4-imidazolyl)methyl]-4-(1-naphthoyl)piperazine;
2(S)-butyl-1-[(1-naphth-2-ylmethyl)-1H-imidazol-5-yl)acetyl]-4-(1-naphthoyl)piperazine;
2(S)-butyl-1-[(1-naphth-2-ylmethyl)-1H-imidazol-5-yl)ethyl]-4-(1-naphthoyl)piperazine;
1-(2(R)-amino-3-hydroypropyl)-2(S)-butyl-4-(1-naphthoyl)piperazine;
1-(2(R)-amino-4-hydroxybutyl)-2(S)-butyl-4-(1-naphthoyl)piperazine;

1-(2-amino-3-(2-benzyloxyphenyl)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine;
1-(2-amino-3-(2-hydroxyphenyl)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine;
1-[3-(4-imidazolyl)propyl]-2(S)-butyl-4-(1-naphthoyl)-piperazine;
2(S)-n-butyl-4-(2,3-dimethylphenyl)-1-(4-imidazolylmethyl)-piperazin-5-one;
2(S)-n-butyl-1-[1-(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3-dimethylphenyl)piperazin-5-one;
1-[1-(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3-dimethylphenyl)-2(S)-(2-methoxyethyl)piperazin-5-one;
2(S)-n-butyl-4-(1-naphthoyl)-1-[1-(1-naphthylmethyl)imidazol-5-ylmethyl]-piperazine;
2(S)-n-butyl-4-(1-naphthoyl)-1-[1-(2-naphthylmethyl)imidazol-5-ylmethyl]-piperazine;
2(S)-n-butyl-1-[1-(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine;
2(S)-n-butyl-1-[1-(4-methoxybenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine;
2(S)-n-butyl-1-[1-(3-methyl-2-butenyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine;
2(S)-n-butyl-1-[1-(4-fluorobenzyl)imidazol-5-ylmethyll-4-(1-naphthoyl)piperazine;

2(S)-n-butyl-1-[1-(4-chlorobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine;
1-[1-(4-bromobenzyl)imidazol-5-ylmethyl]-2(S)-n-butyl-4-(1-naphthoyl)piperazine;
2(S)-n-butyl-4-(1-naphthoyl)-1-[1-(4-trifluoromethylbenzyl)imidazol-5-ylmethyl]-piperazine;
2(S)-n-butyl-1-[1-(4-methylbenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)-piperazine;
2(S)-n-butyl-1-[1-(3-methylbenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)-piperazine;
1-[1-(4-phenylbenzyl)imidazol-5-ylmethyl]-2(S)-n-butyl-4-(1-naphthoyl)-piperazine;
2(S)-n-butyl-4-(1-naphthoyl)-1-[1-(2-phenylethyl)imidazol-5-ylmethyl]-piperazine;
2(S)-n-butyl-4-(1-naphthoyl)-1-[1-(4-trifluoromethoxy)imidazol-5-ylmethyl]piperazine;
1-{[1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetyl}-2(S)-n-butyl-4-(1-naphthoyl)piperazine;
or a pharmaceutically acceptable salt thereof.

15. A method of treating cancer in accordance with claim 6 wherein the farnesyl transferase inhibiting compound is (b) a compound represented by one of formulas (II-d) through (II-g):

selected from the group consisting of:

N-[1-(4-imidazoleacetyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycylmethionine N-[1-(4-imidazoleacetyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthyl-methyl)glycyl-methionine methyl ester;
N-[1-(2(S),3-diaminopropionyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;
N-[1-(2(S),3-diaminopropionyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;
N-[1-(3-aminopropionyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;
N-[1-(3-aminopropionyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;
N-[1-(2(S)-amino-3-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;
N-[1-(2(S)-amino-3-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;
N-[1-(3-amino-2(S)-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;
N-[1-(3-amino-2(S)-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;
N-[1-(L-glutaminyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;

N-[1-(L-glutaminyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;
N-[1-(L-histidyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;
N-[1-(L-histidyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;
N-[1-(D-histidyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;
N-[1-(D-histidyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;
N-[1-(L-pyroglutamyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;
N-[1-(L-pyroglutamyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;
2(S)-[1-(2(S)-pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine;
2(S)-[1-(2(S)-pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine methyl ester;
2(S)-[1-(2(S)-pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine isopropyl ester;
2(S)-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine;

2(S)-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine methyl ester;
2(S)-[1-(2(S)-pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine sulfone;
2(S)-[1-(2(S)-pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine sulfone methyl ester;
2(S)-[1-(pyrid-3-ylcarboxy)pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine;
2(S)-[1-(pyrid-3-ylcarboxy)pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine methyl ester;
2(R)-{2-[1-(naphth-2-yl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethoxy}-3-phenylpropionyl-methionine;
2(R)-{2-[1-(naphth-2-yl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethoxy}-3-phenylpropionyl-methionine methyl ester;
2(S)-[1-(pyrid-3-ylmethyl)pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine;
2(S)-[1-(pyrid-3-ylmethyl)pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine methyl ester;
N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine isopropyl ester;
N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine sulfone isopropyl ester;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine sulfone;
N-[1-(glycyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;
N-[1-(glycyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine isopropyl ester;
N-[1-(glycyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;
N-[1-(glycyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine sulfone methyl ester;
N-[1-(glycyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine sulfone;
N-[1-(sarcosyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;
N-[1-(sarcosyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;
N-[1-(N,N-dimethylglycyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;
N-[1-(N,N-dimethylglycyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;
N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;
N-[1-(glycyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;
N-[1-(glycyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;
N-[1-(4-cyanobenzyl)-1H-imidazol-5-ylacetyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;
N-[1-(4-cyanobenzyl)-1H-imidazol-5-ylacetyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;
N-[1-(2-acetylamino-3(S)-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;
N-[1-(2-acetylamino-3(S)-aminopropionyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;
N-[1-(2-amino-3(S)-acetylaminopropionyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;
2(S)-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine methyl ester;
2(S)-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyloxyl]-3-phenylpropionyl-methionine;
2(R)-{2-[1-(4-cyanobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethoxy}-3-phenyl propionyl-methionine methyl ester;

2(R)-{2-[1-(4-cyanobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethoxy}-3-phenyl propionyl-methionine;
2(R)-{2-[1-(4-nitrobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethoxy)-3-phenyl propionyl-methionine methyl ester;
2(R)-{2-[1-(4-nitrobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethoxy}-3-phenyl propionyl-methionine;
2(R)-{2-[1-(4-methoxybenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethoxy}-3-phenyl propionyl-methionine methyl ester;
2(R)-{2-[1-(4-methoxybenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethoxy}-3-phenyl propionyl-methionine;
2(R)-{2-[1-(4-cyanobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-3(S)-ethyl-2(S)-ylmethoxy}-3-phenyl propionyl-methionine methyl ester;
2(R)-{2-[1-(4-cyanobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-3(S)-ethyl-2(S)-ylmethoxy}-3-phenyl propionyl-methionine;
N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-(.beta.-acetylamino)alanine methyl ester;
N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-(.beta.-acetylamino)alanine;
N-[1-(glycyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-(.beta.-acetylamino)alanine methyl ester;
N-[1-(glycyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-(.beta.-acetylamino)alanine;

N-[1-(seryl)pyrrolidin-2(S)-ylmethyl]- N-(1-naphthylmethyl)glycyl-methionine methyl ester;

N-[1-(D-alanyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;

N-[1-(1H-imidazol-4-carbonyl)pyrrolidin-2(S)-ylmethyl]
-N-(1-naphthylmethyl)glycyl-methionine methyl ester;

N-[1-(isoasparagyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;

N-[1-(1H-imidazol-4-propionyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;

N-[1-[3-pyridylacetyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;

N-[1-(2-pyridylacetyl) pyrrolidin-2(S)-ylmethyl] -N-(1-naphthylmethyl)glycyl-methionine methyl ester;

N-[1-(4-pyridylglycyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;

N-[1-(seryl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;

N-[1-(D-alanyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;

N-[1-(1H-imidazol-4-carbonyl)pyrrolidin-2(S)-ylmethyl]- N-(1-naphthylmethyl)glycyl-methionine;

N-[1-(isoasparagyl) pyrrolidin-2(S)-ylmethy]]-N-(1-naphthylmethyl)glycyl-methionine;

N-[1-(1H-imidazol-4-propionyl) pyrrolidin-2(S)-ylmethyl]- N-(1-naphthylmethyl)glycyl-methionine;

N-[1-(3-pyridylacetyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;

N-[1-(2-pyridylacetyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;

N-[1-(4-pyridylglycyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;

N-[1-(1H-imidazol-4-ylmethyl)pyrrolidin-2(S)-ylmethyl]- N-(1-naphthylmethyl)glycyl-methionine;

N-[1-(2-aminoethyl)pyrrolidin-2(S)-ylmethyl]- N-(1-naphthylmethyl)glycyl-methionine;

N-[1-(glycyl) pyrrolidin-2(S)-ylmethyl] -N-(1-naphthylmethyl)glycyl-(2-thienyl)alanine;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(1-naphthylmethyl)glycyl-(trifluoromethyl)alanine;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl] - N-(1-naphthylmethyl)glycyl-(2(S)-amino-4-acetylamino)butyric acid;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(1-naphthylmethyl)glycyl-(N,N-dimethyl)glutamine;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(benzyl)glycyl-methionine;

N-[1-(glycyl)pyrrolidin-2(S)-ylmethyl]- N-(benzyl)glycyl-methionine;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl] - N-(4-methoxybenzyl)glycyl-methionine;

N-[1-(glycyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl]- N-(benzyl)glycyl-methionine;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl -2(S)-ylmethyl] - N-(benzyl)glycyl-methionine;

N-((4-imidazolyl)methyl-(2S)-pyrrolidinylmethyl)-N-(1-naphthylmethyl)glycyl-methionine methyl ester;

N-[1-(glycyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-(2-thienyl)alanine methyl ester;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(1-naphthylmethyl)glycyl-(N,N-dimethyl)glutamine methyl ester;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl] - N-(1-naphthylmethyl)glycyl-(trifluoromethyl)alanine methyl ester;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(1-naphthylmethyl)glycyl-(2(S)-amino-4-acetylamino)butyric acid methyl ester;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(benzyl)glycyl-methionine methyl ester;

N-[1-(glycyl)pyrrolidin-2(S)-ylmethyl]- N-(benzyl)glycyl-methionine methyl ester;

N-[ 1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyll- N-(4-methoxybenzyl)glycyl-methionine methyl ester;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl]- N-(benzyl)glycyl-methionine methyl ester;

N-[1-(glycyl) pyrrolidin-3(S)-ethyl-2(S)-ylmethyl]-N-(benzyl)glycyl-methionine methyl ester;

N-[1-(glycyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine isopropyl ester;
N-[1-(glycyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine cyclohexyl ester;

N-[1-(glycyl) pyrrolidin-2(S)-ylmethyl] -N-(1-naphthylmethyl)glycyl-methionine benzyl ester;

N-[1-(glycyl) pyrrolidin-2(S)-ylmethyl] -N-(1-naphthylmethyl)glycyl-methionine ethyl ester;

N-[1-(sarcosyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine isopropyl ester;

N-[1-(N,N-dimethylglycyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine isopropyl ester;

N-[1-(glycyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine (2-pyridylmethyl) ester;

N-[1-(glycyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine (1-glyceryl) ester;

N-[1-L-prolylpyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;

N-[1-(L-prolyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;

N-[1-(1-morpholinoacetyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;

N-[1-(1-morpholinoacetyl)pyrrolidin-2(S)-ylmethyl] -N-(1-naphthylmethyl)glycyl-methionine;

N-[1-(4-piperidinecarbonyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;

N-[1-(4-piperidinecarbonyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;

N-[1-(3-piperidinecarbonyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;

N-[1-(3-piperidinecarbonyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;

N-[1-(2-pyridylglycyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;

N-[1-(2-pyridylglycyl)pyrrolidin-2(S)-ylmethyll-N-(1-naphthylmethyl)glycyl-methionine;

N-[1-(4-pyridylglycyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;

N-[1-(4-pyridylglycyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;

N-[1-(4-pyridyl(N-methyl)glycyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester;

N-[1-(4-pyridyl(N-methyl)glycyl)pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine;

N-[1-(1H-imidazol-4-ylpropionyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-(.beta.-acetylamino)alanine;

N-[1-(1H-imidazol-4-ylpropionyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-(.beta.-acetylamino)alanine methyl ester;

N-[1-(4-pyridylglycyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-(.beta.-acetylamino)alanine;

N-[1-(4-pyridylglycyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-(.beta.-acetylamino)alanine methyl ester;

N-[1-(glycyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-(.beta.-acetylamino)alanine cyclohexyl ester;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(1-naphthylmethyl)glycyl-(N-methyl)glutamine;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(1-naphthylmethyl)glycyl-(N-methyl)glutamine methyl ester;

N-[1-(1H-imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl] -N-(1-naphthylmethyl)glycyl-(.beta.-methylcarbonylamino)alanine;

N-[1-(1H-imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-(.beta.-methylcarbonylamino)alanine methyl ester;

N-[1-(1H-imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl] -N-(1-naphthylmethyl)glycyl-(.beta.-methylsulfonylamino)alanine;

N-[1-(1H-imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-(.beta.-methylsulfonylamino)alanine methyl ester;

N-[1-(1H-imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-(.beta.-propionylamino)alanine;

N-[1-(1H-imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-(.beta.-propionylamino)alanine methyl ester;

N-[1-(1H-imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-(.beta.-pyrrolidinon- 1 -ylamino)alanine;

N-[1-(1H-imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-(.beta.-pyrrolidinon-1-ylamino)alanine methyl ester;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(3-methoxybenzyl)glycyl-methionine;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(3-methoxybenzyl)glycyl-methionine methyl ester;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(2-methoxybenzyl)glycyl-methionine;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(2-methoxybenzyl)glycyl-methionine methyl ester;

N-[1-(glycyl)pyrrolidin-2(S)-ylmethyl]- N-(3-methoxybenzyl)glycyl-methionine;

N-[1-(glycyl)pyrrolidin-2(S)-ylmethyl]- N-(3-methoxybenzyl)glycyl-methionine methyl ester;

N-[1-(glycyl)pyrrolidin-2(S)-ylmethyl]- N-(2-methoxybenzyl)glycyl-methionine;

N-[1-(glycyl)pyrrolidin-2(S)-ylmethyl]- N-(2-methoxybenzyl)glycyl-methionine methyl ester;

N-[1-(1H-imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl] - N-(2-methoxybenzyl)glycyl-methionine;

N-[1-(1H-imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl]- N-(2-methoxybenzyl)glycyl-methionine methyl ester;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl] - N-(3-cyanobenzyl)glycyl-methionine;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl] - N-(3-cyanobenzyl)glycyl-methionine methyl ester;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(4-cyanobenzyl)glycyl-methionine;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(2-cyanobenzyl)glycyl-methionine;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(2-cyanobenzyl)glycyl-methionine methyl ester;

N-[1-(glycyl)pyrrolidin-2(S)-ylmethyl]- N-(2-cyanobenzyl)glycyl-methionine;

N-[1-(glycyl)pyrrolidin-2(S)-ylmethyl]- N-(2-cyanobenzyl)glycyl-methionine methyl ester;

N-[1-(1H-imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl]- N-(2-cyanobenzyl)glycyl-methionine;

N-[1-(1H-imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl]- N-(2-cyanobenzyl)glycyl-methionine methyl ester;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(2-methylbenzyl)glycyl-methionine;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl] - N-(2-methylbenzyl)glycyl-methionine methyl ester;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(2-trifluoromethylbenzyl)glycyl-methionine;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(2-trifluoromethylbenzyl)glycyl-methionine methyl ester;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl] - N-(1-naphthylsulfonyl)glycyl-methionine;

N-[1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl] - N-(1-naphthylsulfonyl)glycyl-methionine methyl ester;

N-[1-(glycyl) pyrrolidin-2(S)-ylmethyl] -N-(1-naphthylmethyl)glycyl-methionine 4-N-methylpiperidinyl ester;

N-[1-(glycyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine tert-butyl ester;

N-[1-(glycyl) pyrrolidin-2(S)-ylmethyl]-N-(1-naphthylmethyl)glycyl-methionine 3-pentyl ester;

N-[1-(4-pyridylglycyl) pyrrolidin-2(S)-ylmethyl] -N-(1-naphthylmethyl)glycyl-methionine isopropyl ester;

N-[1-(1H-imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl]- N-(11-naphthylmethyl)glycyl-methionine isopropyl ester;

N-[1-(1H-Imidazol-4-propionyl) pyrrolidin-2(S)-ylmethyl]-N-(2-methoxybenzyl)glycyl-methionine isopropyl ester or a pharmaceutically acceptable salt thereof.

15. A method of treating cancer in accordance with claim 6 wherein the farnesyl transferase inhibiting compound is (c) a compound represented by one of formulas (II-h) through (II-k):

selected from the group consisting of:
N-[(1H-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester;

N-[(1H-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine;

N-[1-(1H-imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-prolyl-methionine methyl ester;

N-[1-(1H-imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-prolyl-methionine;

N-[1-glycylpyrrolidin-2(S)-ylmethyl]-3(S)-ethylprolyl-methionine methyl ester;

N-[1-glycylpyrrolidin-2(S)-ylmethyl]-3(S)-ethylprolyl-methionine;

N-[L-pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine N-[L-pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester N-[1-(1H-imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethylprolyl-methionine N-[1-(1H-imidazol-4-ylacetyl)-pyrrolidin-2(S-)ylmethyl]-3(S)-ethylprolyl-methionine methyl ester N-[(1H-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-prolyl-methionine methyl ester and N-[(1H-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-prolyl-methionine (N-[1-cyanobenzyl)-1H-imidazol-5-yl)acetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl methionine;

(N-[1-cyanobenzyl)-1H-imidazol-5-yl)acetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl methionine methyl ester;

(N-[1-cyanobenzyl)-1H-imidazol-5-yl)acetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl methionine isopropyl ester, and or a pharmaceutically acceptable salt thereof.

16. A method in accordance with claim 1 wherein the farnesyl protein transferase inhibiting compound is selected from the group consisting of:

(S)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-imidazolylmethyl]-5-[2-(methanesulfonyl)ethyll-2-piperazinone dihydrochloride;

1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)imidazolyl-methyl]-2-piperazinone dihydrochloride;

N-[1-(1H-Imidazol-4-propionyl) pyrrolidin-2(S)-ylmethyl]-N-(2-methoxybenzyl)glycyl-methionine isopropyl ester;

(N-[1-Cyanobenzyl)-1H-imidazol-5-yl)acetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl methionine isopropyl ester;

2(S)-n-Butyl-1-[1-(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3-dimethylphenyl)piperazin-5-one; and N-[2(S)-N'-(1-(4-Cyanophenyl-methyl)-1H-imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N-1-naphthylmethyl-glycyl-methionine methyl ester.

17. A method of treating cancer in accordance with claim 6 wherein the farnesyl transferase inhibiting compound is (d) a compound represented by formula (II-I):

selected from the group consisting of:

2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-2-methyl-3-phenylpropionyl-homoserine lactone, 2(S)-L2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-2-methyl-3-phenylpropionyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto)propylamino-3(S)-methyl]pentyloxy-4-pentenoyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-4-pentenoyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxypentanoyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylaniino-3(S)-methyl]pentyloxypentanoyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]5-pentyloxy-4-methylpentanoyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-4-methylpentanoyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-methylbutanoyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-methylbutanoyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylbutanoyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylbutanoyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentylthio-2-methyl-3-phenylpropionyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino -3(S)-methyl]pentylthio-2-methyl-3-phenylpropionyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentylsulfonyl-2-methyl-3-phenylpropionyl-homoserine lactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentylsulfonyl-2-methyl-3-phenylpropionyl-homoserine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine methyl ester, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methionine, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methionine sulfone methyl ester, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methionine sulfone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine sulfone isopropyl ester, 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-naphth-2-yl-propionyl-methionine sulfone methyl ester, 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-naphth-2-yl-propionyl-methionine sulfone, 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-naphth-1-yl-propionyl-methionine sulfone methyl ester, 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-naphth-1-yl-propionyl-methionine sulfone, 2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-methybutanoyl-methionine methyl ester.

2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-methybutanoyl-methionine, Disulfide of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)methyl]pentyloxy-3-phenylpropionyl-homoserine lactone, Disulfide of 2(S)-[2(S)-[2(R)-Amino-3-mercaptolpropylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserine, and Disulfide of 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)methyl]pentyloxy-3-methylbutanoyl-methionine methyl ester or a pharmaceutically acceptable salt, disulfide or optical isomer thereof.

18. A method in accordance with claim 1 wherein the farnesyl protein transferase inhibiting compound is selected from the group consisting of:

2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-homoserine lactone and 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methionine sulfone methyl ester;
or a pharmaceutically acceptable salt thereof;

and the geranylgeranyl-protein transferase-type I inhibiting compound iS
N-(2(R)-amino-3-mercaptopropyl)-valyl-isoleucyl-leucine methyl ester;

or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of combination of a selective geranylgeranyl-protein transferase-type I inhibitor and a selective farnesyl protein transferase inhibitor.

20. A method of treating cancer comprising admininstering to a mammalian patient in need of such treatment a therapeutically effective amount of combination of a geranylgeranyl-protein transferase-type I inhibitor and a farnesyl protein transferase inhibitor.

21. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of combination of a geranylgeranyl-protein transferase-type I
inhibitor and a farnesyl protein transferase inhibitor