AU727939B2

AU727939B2 - A method of treating cancer

Info

Publication number: AU727939B2
Application number: AU27221/97A
Authority: AU
Inventors: David C. Heimbrook; Allen I. Oliff; Steven M. Stirdivant
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1996-04-03
Filing date: 1997-03-31
Publication date: 2001-01-04
Anticipated expiration: 2017-03-31
Also published as: AU2722197A; EP0906099A1; JP2000504023A; EP0906099A4; WO1997036587A1; CA2250232A1

Description

WO 97/36587 PCT/US97/05328 -1- TITLE OF THE INVENTION A METHOD OF TREATING CANCER BACKGROUND OF THE INVENTION The present invention relates to a method of treating cancer using a combination of a compound which has Raf antagonist activity and a compound which has famesyl transferase inhibiting activity.

The Raf antagonist compounds used in the present invention demonstrate anti-cancer activity through antagonism of the kinase, Raf The raf genes code for a family of proteins which can be oncogenically activated through N-terminal fusion, truncation or point mutations. Raf is a member of the MAP Kinase cascade, which also includes MEK's and MAP Kinase (ERK). Raf can be activated and undergoes rapid phosphorylation in response to treatment of cells with PDGF, EGF, insulin, thrombin, endothelin, acidic FGF, CSFI or TPA, as well as in response to oncoproteins v-fms, v-src, v-sis, Hras and polyoma middle T antigen. Antisense constructs which reduce cellular levels of c-Raf, and hence Raf activity, inhibit the growth of oncogene-transformed rodent fibroblasts in soft agar, while exhibiting little or no general cytotoxicity. Since inhibition of growth in soft agar is highly predictive of tumor responsiveness in whole animals, these studies suggest that the antagonism of Raf is an effective means by which to treat cancers in which Raf plays a role.

Examples of cancers where Raf is implicated through overexpression include cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. More particularly, such examples include histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers. Additional examples include cancers in which overexpression or activation of Raf-activating oncogenes K-ras, erb-B) is observed. More particularly, such cancers include pancreatic and breast carcinoma.

The Ras protein is part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action WO 97/36587 PCT/US97/05328 -2indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP. Upon growth factor receptor activation, Ras is induced to exchange GDP for GTP and undergoes a conformational change. The 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. Biochem. 62:851-891 (1993)). Activation of Ras leads to activation of multiple intracellular signal transduction pathways, including the MAP Kinase pathway and the Rho/Rac pathway (Joneson et al., Science 271:810-812).

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

The Ras protein is one of several proteins that are known to undergo post-translational modification. Famesyl-protein transferase utilizes famesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad.

Sci USA, 87:7541-7545 (1990)).

Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane 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-Aaal-Aaa 2 -Xaa" box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)). Depending on the specific sequence, this motif serves as a signal sequence for the enzymes faresyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the WO 97/36587 PCT/US97/05328 -3- CAAX motif with a C 15 or C20 isoprenoid, respectively. Clarke., Ann. Rev. Biochem. 61:355-386 (1992); W.R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237 (1992)). However, direct inhibition of faresyl-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 famesylated proteins include the Ras-related GTPbinding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are famesylated proteins of unknown structure and function in addition to those listed above.

Inhibitors of famesyl-protein transferase (FPTase) have been described in two-general classes. The first class includes analogs of famesyl diphosphate (FPP), while the second is related to protein substrates Ras) for the enzyme. The peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the famesyl-protein transferase enzyme, or may be purely competitive inhibitors (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)).

Inhibition of farnesyl-protein transferase has been shown to block the growth of ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of famesyl-protein transferase selectively block the processing of the Ras oncoprotein intracellularly S 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 faresyl-protein transferase blocks the growth of rasdependent tumors in nude mice Kohl et al., Proc. Natl. Acad. Sci WO 97/36587 PCT/US97/05328 -4- 91:9141-9145 (1994) and induces regression of mammary and salivary carcinomas in ras transgenic mice Kohl et al., Nature Medicine, 1:792-797 (1995).

Indirect inhibition of famesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck Co., Rahway, NJ) and compactin (Hancock et al., ihid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Inhibition of famesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells.

A Raf antagonist compound and a farnesyl protein transferase inhibitor are used in the present invention to treat cancer, such as in tumor cells which are not particularly Raf or FPTase dependent. The Raf antagonist compound and a famesyl protein transferase inhibiting compound are used in combination.

SUMMARY OF THE INVENTION A method of treating cancer is disclosed which is comprised of administering to a mammalian patient in need of such treatment an effective amount of a Raf antagonist compound and an effective amount of a famesyl protein transferase inhibiting compound.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method of treating cancer which is comprised of admininstering to a mammalian patient in need of such treatment an effective amount of a Raf antagonist compound and an effective amount of a famesyl protein transferase inhibiting compound.

Any compound which antagonizes Raf and any compound which inhibits famesyl protein transferase can be used.

As used herein the term Raf antagonist is used in the general sense to relate to compounds which antagonize, inhibit or counteract the activity of the raf gene or the protein produced in response thereto.

WO 97/36587 PCT/US97/05328 The term farnesyl protein transferase inhibiting compound is likewise used in the general sense and refers to compounds which antagonize, inhibit or counteract the activity of the gene coding farnesyl protein transferase or the protein produced in response thereto.

Cancers which are treatable in accordance with the invention described herein include cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx, liver and lung. More particularly, such cancers include histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers. Additional examples include cancers in which overexpression or activation of Raf-activating oncogenes K-ras, erb-B) is observed. More particularly, such cancers include pancreatic, mammary and salivary carcinomas, colorectal carcinoma, exocrine pancreatic carcinoma and myeloid leukemias.

Examples of compounds which antagonize Raf are as follows: a compound represented by formula

N-

N (R')0-3 x HETCy (R)0- 3 -AR-X' N Rx (I-a) or a pharmaceutically acceptable salt thereof, wherein: AR represents an aromatic group containing 6-10 atoms; X and X' each independently represent -(CH2)m-Y-(CH2)n wherein m and n represent integers within the range of from 0 4, such that the sum of m and n is from 0 6; Y represents a member selected from the group consisting of: a direct bond; 0; S(O)y, with y equal to WO 97/36587 WO 9736587PCTJUS97/05328 -6- 0, 1 or 2; NRq', with RCI' as defined below; OC(O); C(0)O; SOxNRq t with x equal to I or 2 and Rq' as defined below; NRq'SOx; C(O)NRq' and NRq'C(O); HEy ET~y )represents a 4 to 10 membered non-aromatic heterocycle containing at least one N atom, and optionally containing 1-2 additional N atoms and 0-1 0 or S atom; Rx represents H, C1-6 alkyl(Rq) 3 OCI..6 alkyl(Rq) 3 or each R and R" independently represents a member selected from the group consisting of: halo; hydroxy;

CI..

6 alky1(Rq) 3 OC 1.-6 alkyl(Rq)3; C3-9 cycloalkyl(Rq)3; CN; CONH 2 CONC 1 6 alkyl(Rq) 3

CON(C

1 6 alky1(Rq)3)2;

NH

2

NHCI.

6 alky](Rq) 3 N(C-6 alky](Rq) 3 2 CO2H; CO2CI- 6 alkyl(Rq) 3

C(O)C.-

6 alkyl(Rq) 3 aryl(Rq) 3 heteroaryl(Rq) 3 CF3; SH; N02; SOYCI16 alkyl(Rq) 3 with y as defined above; SO2NH2; SO2NHCl.

6 alkyl(Rq) 3 SO2)N(CL..

6 alkyl(Rq) 3 2 NHSO2CI-6alkyl(Rq) 3 NHSO2aryl(Rq) 3 NHS02heteroary(Rq) 3 N(Rq')C(0)C- 6 alkyl(Rq) 3 NRq'C(O)NH (Ci -6 alkyl(Rq) 3 C2 4 alkenyl(Rq)2- 3 and C2-4 alkynyl(Rq) 1 3 each R' independently represents a member selected from the gTroup consisting of: CONH 2

CONHI-.

6 alkyl(Rq) 3 CON(CI -6 alky](Rq) 3 2

CONHC

3 8 cycloalkyl(Rq) 3

CON(C

3 cycloalky](Rq) 3 2

CO

2 H; C02C-6 alkyl(Rq) 3

C(O)C

1 -6 alkyl(Rq) 3 C0 2

C

3 8 cycloalkyl(Rq) 3 C(0)C 3 8 cycloalkyl(Rq) 3 -[C(O)(CH2)j-CR5R6-(CH 2 )k-NR7]p-R8; -C(0)C 3 -8 cycloalkyl(Rq) 3 -C(0)heterocyclyl(Rq)3;

CON[C

1 6alkyl(Rq) 3

][C

3 -8 cycloalky(Rcl) 3 C(0)aryl(Rq)3, C(0)heteroaryl(Rq) 3 WO 97/36587 PCT/US97/05328 -7wherein p represents 1, 2 or 3; j and k are integers independently selected from 0 3; each R 5 and R 6 independently represents H, aryl, C 1 -6 alkyl(Rq) 3 or each CR 5

R

6 taken in combination represents a 3, 4, or 6 membered cycloalkyl or heterocyclyl group, an aryl group or a heteroaryl group, wherein when p equals 1, at least one of j and k is 1, 2 or 3; each R 7 and R8 independently represents H, C1-6 alkyl or aryl; Rq represents a member selected from the group consisting of: Rq'; CN; CO2H; C02C1-4 alkyl; C(O)C 1 -4 alkyl aryl(Ra) 3 NH2; NHC1-6 alkyl(Ra)3; N(C1-6 alkyl(Ra)3)2; heteroaryl(Ra)3; CONH2 SH; S(O)y CI- 6 alkyl(Ra) 3

C(O)NHCI.

6 alkyl(Ra) 3

C(O)N(C

1

I

6 alkyl(Ra) 3 2 -heteroalkyl(Ra) 3 -NHC(O)NH2;

-NHC(NH)NH

2 (Ra) 3 an d N(Ra) 3 wherein N and independently represent mono or bicyclic ring systems, non-aromatic or partially aromatic, containing from 5-10 ring atoms, 1-4 of which are N and 0-1 of which are O or S(O)y, with y equal to 0, 1 or 2, optionally containing 1-2 carbonyl groups; each Ra independently represents a member selected from the group consisting of: H, C1-6 alkyl, OC]-6 alkyl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, aralkoxy, substituted WO 97/36587 WO 9736587PCTIUS97/05328 -8aralkoxy, halo, hydroxy, CN, CONI-2, CONHFC-6 alkyl, CON(C 1 6 alkyl)2, CO2H, C02C 1 6 alkyl, C(O)C 1 6 alkyl, phenyl, CF3, SH, N02, SOyCI-.

6 alkyl, with y as defined above; SO2NH 2 S02NHCI- 6 alkyl, NHLS 02 (substituted aryl), NHS 02(substituted heteroaryl), NHS02C I.6alkyl, NHSO2aryl, NHSO2heteroaryl, NI-2, NHC 1 6 alkyl, N(CI.6 alkyl)2, NHC(O)Cj- 6 alkyl, NHC(O)NE-(CI- 6 alkyl), C2-.4 alkenyl and C2-.4 alkynyl; and Rq' represents or C(O)C 1 4 alkyl; H, OH, C 1 -4 alkyl, -0CI.

4 alkyl, aryl a compound represented by formula (1-b)

(R)

03

-AR-X'

(1-b) or a pharmaceutically acceptable salt thereof, wherein: A R, X, x, Y, y, Rq', 3 __CN (RHa) 3 and are as defined above with respect to formula WO 97/36587 WO 9736587PCTIUS97/05328 -9each R' independently represents a member selected from the group consisting of: hydroxy; CI-6 alkyl(Rq)3; C3-8 cycloalkyI(Rq)3; OCI.6 alkyl(Rq)3; OC3-8 cycloalky1(Rq) 3 heterocyclyl(Rq)3; CN; NH(Rq"); NHC 1 6 alkyl(Rq) 3

N(C

1 6 alkyl(Rq) 3 2 NH-C3-8cycloalkyl(Rq)3; N(C3-8cycloalky1(Rq)3) 2 CF3; SH; N02; C2-4 alkenyl(Rq)2-3 aryI(Rq)3 heteroaryl(Rq) 3 C2-4 alkynyl(Rq)1.3 -OC(O) C3-8 cycloalkyl(Rq)3; SO2NI- 2 SO2NHCl.

6 alkyl(Rq)3; SO 2

N(C-

6 alkyl(Rq) 3 2 ;NHSO2Cl..

6 alkyl(Rq) 3 NHSO2aryl(Rq) 3 NHSO2heteroary(Rq) 3 -OC(O)heterocyclyl(Rq)3; N(Rq')C(O)C 1 6 alky1(Rq) 3 NRq'C(O)NH(C 1 -6 alkyl(Rq) 3 -OC(O)Cj 16 alkyl(Rq)3; -C(=Nq')NHC 1 -6 alkyl(Rq)3, -C(=Nq')N(C 1 6 alkyl(Rq)3) 2 (CH2)j-CR5R6- (CH 2 )kNR7:!-R8 p and -tENR7(CH2)krCRR

R

5 and R 6 are independently H, aryl, CI- 6 alkyl(Rq) 3 or

CR

5

R

6 in combination represents a 3, 4, 5 or 6 membered cycloalkyl or heterocyclyl group, an aryl group or a heteroaryl group; p represents 1, 2 or 3, with the proviso that when p represents 1, CR 5

R

6 represents a 3, 4, 5 or 6 membered cycloalkyl group or a heterocyclyl group, an aryl group or a heteroaryl group, and at least one of j and k is 1, 2 or 3;

R

9 represents H, a negative charge balanced by a positively 3 charged group or a protecting group; Rq represents a member selected from the group consisting of: Rq'; CN; CO2H; C02CI-4 alkyl; C(O)C 1 4 alkyl NH(Rq'); aryl(Ra)3; heteroaryl(Ra)3;

NHCI.

4 alkyl N(C 1 4 alkyl) 2

CONH

2 WO 97/36587 WO 9736587PCTIUS97/05328 SH; S(O)y C 1 6 alkyl(Ra) 3

C(O)NHC..

6 alkyl(Ra1) 3

C(O)N(C..

6 alkyl(Ra) 3 2

NHC(NH)NH

2 -heteroalkyl (R'1) 3

-NI-C(O)NH

2 Na 3

N(R)

3 and and Rq' represents H, OH or 0CI..4 alkyl, and a compound represented by formula R2 R,

N

R3 R4N (I-c) or a pharmaceutically acceptable salt thereof, wherein: R I is 4-pyridyl, pyrimidinyl, quinazolin-4-yl, quinolyl, isoquinolinyl, 1 -imidazolyl or 1 -benzimidazolyl which is optionally substituted with one or two substituents each of which is independently selected from Cl-4 alkyl, halogen, CI-.4 alkoxy, CI-4 alkylthio, NRlcjR20, or Nheterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR22; R2 is hydrogen, -(CR1I0R20)n OR 12, heterocyclyl, heterocyclyl C I- alkyl, C I 1 alkyl, halo-substituted C I -i1 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl CI1-10 alkyl, C5-7 cycloalkenyl, aryl, aryl CI-10 alkyl, heteroaryl, heteroaryl C I 10 alkyl, (CR1 I0R20)n'OR 13. (CR1 I0R20)n'S (CR1 0R20)n'NIIS(O)2R25, (CR1 0R20)n'NR8R9, (CR1 0R20)n'N02, (CR1 0R20)n'CN, (CR1 0R20)n'S(O)mNR8R9, (CR1 I0R20)n'C(Z)R 13, (CR1 0R20O)n'C(Z)OR 13, (CR 10R20)n'NRjI C(Z)NR8R9. (CRI 0R20)ntC(Z)NR 13 OR1I2, (CR1I 0R20)ntNR I OC(Z)R 13, (CR1 I0R20)n'NR 1 OC(Z)NR8R9, WO 97/36587 WO 9736587PCTIUS97/05328 (CR1 0R20)n'N(0R2l1)C(Z)NR8R9, (CR1 0R20)n'N(0R2l1)C(Z)R 13, (CR1 0R20)n'C(=NOR2lI)R 13, (CR1 0R20)n'NRlIOC(=NR27)NR gR9, (CR1 0R20)n'OC(Z)NR8R9, (CR1 0R20)n'NRI1OC(Z)NRgR9, (CR1 0R20)n'C(Z)OR 10, 5-(R25)- 1,2,4-oxadiazol-3-yl or 4-(R 12)- 5-(R 18R 1 )-4,5-dihydro-1I,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroary 1, heteroarylalkyl, heterocyclyl or heterocyclyalkyl moieties may be optionally substituted; n' is an integer having a value of 1 to m is 0 or the integer 1 or 2; R3 is Q-(YI)t; Q is an aryl or heteroaryl group; t is a number having a value of 1, 2 or 3; Z is oxygen or sulfur; n is 0 or an integer from I to Y I is independently selected from hydrogen, Ci1-5 alkyl, halosubstituted Ci1-5 alkyl, halogen, or -(CR I10R20)nY2; Y2 is -0R8, -N02, -S(O)m'RI 1, -SR8, -S(O))m'0R8, -S(O)mNR8R9, -NRgR9, -O(CR1IOR2O)nNR8R9, -C(O)R8, -CO02R8, -C02(CRI1 R20)n'CONRSR9, -ZC(O)R8, -CN, -C(Z)NR8R9, NR-NRIOC(Z)R8, -C(Z)NR8OR9, -NR1OC(Z)NR8R9, -NR IOS(O)mRi 11, -N(0R21I)C(Z)NR8R9, -N(0R2 I)C(Z)R8, -C(=N0R21 )R8, -NR I OC(=NR I 5)SR 11, -NR I 0C(=NR 1 5)NR8R9, -NR IOC(=CR 14R24)SR 11, -NR IOC(=CR 14R24)NR8R9, -NRI1OC(O)C(O)NR8R9, -NRI1OC(O)C(O)OR -C(=NR1I3)NR8R9, -C(=N0R I3)NR8R9, -C(=NR1I3)ZR1 11, -OC(Z)NR8R9, -NR 1 OS(O)mCF3, -NR I OC(Z)OR 10, 5-(R 1 8)- 1 ,2,4-oxadizaol-3-yI or 4-(R I I 8R I 9)-4,5-dihydro- 1,2,4oxadiazol-3-yl; m' is a number having a value of I or 2; R4 is phenyl, naphth- Il-yI or naphth-2-yI which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1I-yl or 5-naphth-1I-yl substituent, is halo, cyano,-C(Z)NR7 RI 7, -C(Z)0R23, -(CR1 0R20)m'"C0R36, SR5, -SOR5, 0R36, halo- substituted-Cl1 -4 WO 97/36587 PCT/US97/05328 -12alkyl, C -4 alkyl, -ZC(Z)R36, -NR1OC(Z)R23 or -(CR10R20)m'"NR10R20 and which, for other positions of substitution, is halo, cyano, -C(Z)NR16R26, -C(Z)ORS, -(CR1OR20)m"'COR8, -S(O)mR8, -ORS, halo-substituted-C -4 alkyl, C1-4 alkyl, -(CRIOR20)m"NRO1C(Z)R8, -NRIOS(O)m'Rl 1, -NR 10S(O)m'NR7R 17, -ZC(Z)R8 or -(CR10R20)m'NR 16R26; wherein m" is 0 to 5 and is 0 or 1; is hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the moieties -SR5 being -SNR7R17 and -SOR5 being

-SOH;

R6 is CI-4 alkyl, halo-substituted-C1-4 alkyl, Cl-4 alkenyl, C2-4 alkynyl or C3-5 cycloalkyl; R7 and R17 are each independently selected from hydrogen or C1-4 alkyl, or R7 and R17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR22; R8 is hydrogen, heterocyclyl, heterocyclylalkyl or R11; R9 is hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl or R8 and R9 may together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR12; R10 and R20 are each independently selected from hydrogen and C1-4 alkyl; R11 is C1-10 alkyl, halo-substituted Cl-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R12 is hydrogen, -C(Z)R13 or optionally substituted C1-4 alkyl, optionally substituted arylCl-4 alkyl or S(0)2R25; R13 is hydrogen, C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl C -10 alkyl, aryl, aryl C -10 alkyl, heteroaryl or heteroaryl CI-10 alkyl; WO 97/36587 PCTIUS97/05328 -13- R14 and R24 is each independently selected from hydrogen, alkyl, nitro or cyano; is hydrogen, cyano, C1-4 alkyl, C3-7 cycloalkyl or aryl; R16 and R26 is each independently selected from hydrogen or optionally substituted C1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR12; Rl8 and R19 is each independently selected from hydrogen, Cl-4 alkyl, substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl or together denote a oxygen or sulfur; R21 is hydrogen, a pharmaceutically acceptable cation, Cl-10 alkyl, C3-7 cycloalkyl, aryl, aryl Cl-4 alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl, or Cl-10 alkanoyl; R22 is R10 or C(Z)-C1-4 alkyl; R23 is C1-4 alkyl, halo-substituted-Cl-4 alkyl or C3-5 cycloalkyl; R36 is hydrogen or R23; is CI-10 alkyl, C3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-Cl-10 alkyl, heteroaryl or heteroarylalkyl; R27 is hydrogen, cyano, C1-4 alkyl, C3-7 cycloalkyl or aryl; or a pharmaceutically acceptable salt thereof.

Examples of famesyl protein transferase inhibiting compounds include the following: a compound represented by formula (II-a) through (II-c): WO 97/36587 WO 9736587PCTIUS97/05328 -14- (R 8)r V Al(CR1a 2 )nA 2 CR 1a 2 )n I (R t R 4 R (11-a) (R )r (R9~ -A A(CR 2)nA (CRla 2 )n (CF (It b N~ N-Z

R

3 r (R8)r V Al(CRla 2 )nA 2 (CRla 2 )n R9) R R 3 (CR Ib 2 N\

Z

(ti-c) wherein with respect to formula (11-a):

(R

8 )r V Al(CRla 2 )nA 2 (CRla 2 )n R9>-( '4

Y

R 4 R (11-a) or a pharmaceutically acceptable salt thereof, WO 97/36587 WO 9736587PCTIUS97/05328 Ri a and R I b are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 0 R I R I C(O)NR 10-, CN, N02, (R'O0)2N-C(NR 10-, R IOC(O)-, R I N3, 102,or R I I0C(O)NR c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocyclyl, C3 -Ci 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 0 R I IS(O)m-, R I C(O)NR 1 0

CN,

(R 1 0 )2N-C(NR R I R I N3, 102,or R I IOC(O)-NR 10-1

R

2 and R 3 are independently selected from: H; unsubstituted or substituted Ci1 -g alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, 'Ile or 0 0 wherein the 1) 2) 3) 4) substituted group is substituted with one or more of: aryl or heterocycle, unsubstituted or substituted with: a) C 1.-4 alkyl, b) (CH2)pOR 6 c) (CH2)pNR 6

R

7 d) halogen, C3-6 cycloalkyl,

OR

6

SR

6

S(O)R

6 S02R 6 WO 97/36587 WO 9736587PCT/US97/05328 -16- -NR 6 R 7 6) -N YR 7 0 7) 77 -N NR Ra 0 8) -0o NR 6 R 7 0 9) -0 Y0R 6 0 NR 6 R 7 0 11) -S0 2 -NR R 7 R 6 12) -N-S0 2

-R

13) R 6 or 0 14) -~-rOR 6 or 0

R

2 and R 3 are attached to the same C atom and are combined to form- (CH2) 1 wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(CORIO)-;- WO 97/36587 WO 9736587PCT1US97/05328 -17-

R

4 and R 5 are independently selected from H and CH3; and any two of R 2

R

3

R

4 and R 5 are optionally attached to the same carbon atom;

R

6

R

7 and R 7 a are independently selected from: H; C 1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) CI-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e)

Y-R

0 f) -S0 2

R

1 1 or g) N(R 10 or

R

6 and R 7 may be Joined in a ring;

R

7 and R 7 a may be joined in a ring; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, RI IS(O)m-, RIOC(O)NRIO-, CN, N02, R 10 2N-C(NRIO)-, R I R I N3, -N(R 10 or R I I 0C(O)NR 10-, and c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-CI10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R I IS(O)m-, WO 97/36587 WO 9736587PCT/US97/05328 R IOC(O)N1--, CN, H2N-C(NH)-, R IOC(O)-, R I 0C(O)-, N3, -N(RIO)2, or RIO0C(O)NH-; R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 R I IS(O)m-, R I C(O)NR 10-, CN, N02, (R 1 0 )2N-C-(NR R I R 1 I N3, -N(R 1 0)2, or R' I IC(O)NR 10-, and c) C I-C6 alkyl unsubstituted or substituted by perfiuoroalkyl, F, Cl, Br, R 10 R I IS(O)m-, R I C(O)NR 10-, CN, (Ri 0 )2N-C(NRI 10>, R I R I OOC(O)-, N3, -N(R 1 0)2, or R I I0C(O)NR R 1 0 is independently selected from hydrogen, C I-C6 alkyl, benzyl and aryl; R I I is independently selected from C I-C6 alkyl and aryl;

A

1 I and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NRIO-, -NRIOC(O)-, 0, -S(O)2N(RIO)-, -N(R 1O)S(O)2-, or S(O)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C I -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatomn selected from 0, S, and N, and C2-C2o alkenyl, provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A I is a bond, n is 0 and A 2 is S(O)m; WO 97/36587 WO 9736587PCTIUS97/05328 -19- W is a heterocycle; X is -CH2-, or S=m- Y is aryl, heterocycle, unsubstituted or substituted with one or more of: 1) C 1 -4 alkyl, unsubstituted or substituted with: a) C 1 -4 alkoxy, b) NR 6

R

7 0 c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR 6 or g) -C(O)NR 6

R

7 2) aryl or heterocycle, 3) halogen, 4) OR 6

NR

6

R

7 6) CN, N02, 8) CF3; 9) -S(O)mR 6

-C(O)NR

6

R

7 or 11) C3-C6 cycloalkyl; m is n is p is r is s is utis 1 or 2; 1, 2,3 or 4; 1, 2, 3 or 4; to 5, provided that r is 0 when V is hydrogen; or 1; or 1; and or with respect to formula (LI-b): WO 97/36587 WO 9736587PCTIUS97/05328 (R 8 )r V Al(CRla 2 )nA 2 (CRla 2 1n (R9 R 2

G

lb A (liR-b p N or a pharmaceutically acceptable salt thereof, RIa, Rib, RIO, RI 1 m, R 2

R

3

R

6

R

7 p, R.7a, u, R8, A 2 V, W, X, n, p, r, s, t and u are as defined above with respect to formula (11-a);

R

4 is selected from H and CH3; and any two of R 2

R

3 and R 4 are optionally attached to the same carbon atom; R9 is selected from: a) hydrogen, b) alkenyl. alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 0-, R I 1 R I C(O)NR 10-, CN, N02, (RI 102N-C-(NR R I R I OOC(O)-, N3, 102,or R I IOC(O)NR 10-, and c) ClI-C6 alkyl unsubstituted or substituted by peffluoroalkyl, F, Cl, Br, R 1 0 R I IS(O)mn-, R I C(O)NR 10-, CN, (R 1 0 )2N-C(NR R I R 1

I

0 N3, 102,or R I I0C(O)NR G is H2 or 0; Z is ary I, heteroaryl, arylmethyl, heteroarylmethyl, arylsu Ifonyl, heteroarylsu Ifonyl, unsubstituted or substituted with one or more of the following: 1) Cl1 4 alkyl, unsubstituted or substituted with: a) C 1 4 alkoxy, WO 97/36587 WO 9736587PCTIUS97/05328 -21b) NR 6

R

7 c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR 6 or g) -C(O)NR 6

R

7 2) aryl or heterocycle, 3) halogen, 4) OR 6 5) NR 6

R

7 6) CN, N02, 8) CF3; 9) -S(O)mR 6 10) -C(O)NR 6

R

7 or 11) C3-C6 cycloalkyl; with respect to formula (11-c): (R )r (R9 R R 3 VAl(CRla 2 )nA (CRla 2 )nXW -(CRlb 2

N\

or a pharmaceutically acceptable salt thereof, RIa, Rib, RIO, RI 1, mn, R 2

R

3

R

6

R

7 p, u, R 7 a, R8, Al, A 2 V, W, X, n, r and t are as defined above with respect to formula (11-a);

R

4 is selected from H and CH3; and any two of R 2

R

3 and R 4 are optionally attached to the same carbon atom; WO 97136587 WO 9736587PCTfUS97/05328 -22- G is 0; Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following: 1) Ci1 -4 alkyl, unsubstituted or substituted with: a) C 1-4 alkoxy, b) NR 6

R

7 2) aryl or heterocycle, 3) halogen, 4) OR 6

NR

6

R

7 6) CN, 7) N02, 8) CF3; 9) -S(O)mR 6

-C(O)NR

6

R

7 or 11) C3-C6 cycloalkyl; and sis 1; a compound represented by formula (11-d) through (11-g): WO 97/36587 WO 9736587PCT[US97/05328 -23- (R 8 )r V Al(CR1a 2 )nA 2 (CRla 2 )n

(R

8 )r V Al(CRla 2 )nA (CRla 2 )n

R

9

I)

(11-d)

OH

'OR'

(R

8 )r V A 1 (CRla 2 )nA 2 (CRl 2)n R9) 'H 0

OH

HOCH

2

(CH

2 )q (I I-f)

(R

8 )r R VAl(CR a 2 )nA (CRla 2 )n H 0 0 (11-g) wherein with respect to formula (ll-d): WO 97/36587 WO 9736587PCTIUS97/05328 -24- (R )r R R RH 4 4I Ill H A1(CRk (CR br 4

OH*

AlCl 2 )nA(Cla 2 )n OHW2) HA~ R 5 a R 5 b (11-d) R2,R2 or a pharmnaceutically acceptable salt thereof, Ri 1, V, W, m, n, p and r are as defined above with respect to formula (1I-a); R Ia and R Ib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R100-, RI IS(O)m-, RIOC(O)NR JO-, CN, N02, (Ri 0 )2N-C(NR RI RI OOC(O)-, N3, 102,or R I I0C(O)NR c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R1 00-, RIl R IOC(O)NR 10., CN, (RI 0 )2N-C(NRIO0>, RI 0 RI OOC(O)-, N3, 102,or R I I OC(O)-NR R2a and R2b are independently selected from: a) hydrogen, b) C I -C6 alkyl unsubstituted or substituted by C2-C6 atkenyl, R 10 RI IS R IOC(O)NR 10-, CN, N3, (RI 0 )2N-C(NR 10>-,R 0

R

1 OOC(O)-, -N(Rl 0)2, Or R I I OC(O)NR 1 0-, c) aryl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl,

R

10 RI IS(O)m-, RIOC(O)NRIO-, CN, N02, (RI 0 )2N-C(NRIO0>, RI R 0 N3, WO 97/36587 PCT/US97/05328 -N(R10)2, or R 1 1 OC(O)NR 0 and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-C10 cycloalkyl;

R

3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R1O)2, N02, R 10 Rl lS(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NRI0)-, R R N3, -N(R 10)2, R 1 1 0C(O)NR1O- 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 Cl-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, CF3, N(R1 0 N02, R 0 RI 1 S(O)m-, WO 97/36587 WO 9736587PCTIUS97/05328 -26-

R

1 I C(O)NR 1 0, CN, (R I %2N-C(NR Ri I R IOOC(O)-, N3, -N(R 10 R I IOC(O)NR 1 0- and C I -C20 alkyl, d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIlO cycloalkyl; or and R5b are combined to form (CH2)s wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(CORIO)-; x-Y is a) s~N 0

R

7 b b)N

C))

d)

S

H

e) ,or

H

f) -0H 2

-CH

2 R7a is selected from WO 97/36587 PCT/US97/05328 -27a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-CIO cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C 10 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, R1 0 0-, R 11S(O)m-, R 10 C(O)NR10-, CN, N02, R 10 RIOC(O)-, R 1 OOC(O)-, N3, -N(R 10 or R 1 1

C(O)NR

10 and WO 97/36587 WO 9736587PCTIUS97/05328 -28c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, RI IS(O)m-, RIOC(O)NH-, CN, H2N-C(NH)-, RIOC(O)-, RIO0C(O)-, N3, -N(R 1 0 or R IOOC(O)NH-; R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, RI IS(O)m-, RIOC(O)NRIO-, CN, N02, 0 )2N-C-(NR R 1 I R' I N3, -N(R102,or R I I OC(O)NR 10-, and c) C I -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, CI, Br, R 10 R I IS(O)m-, R I C(O)NR 10-, CN, (R 10 )2N-C(NR 10 R IOC(O)-, R I N3, 102,or R I IOC(O)NR R 10 is independently selected from H, C I-C6 alkyl, benzyl, substituted aryl and C I -C6 alkyl substituted with substituted aryl; A I and A 2 are independently selected from: a bond, -CH=CH-, _-iCC, or S(O)m; Z is independently H2 or 0; s is 4 or t is 3, 4or u is 0GorI-, with respect to formula (II-e): WO 97/36587 WO 9736587PCTIUS97/05328 -29-

(R

8 )r R9zR 3 R 4 0 -Al(CRI a 2 (CR Ia 2 C Ib2 4 (11-e) R 2 a (R2 or a pharmaceutically acceptable salt thereof, R 1,W, m, n, p and r are as defined above with respect to formula (IIa); R 1 a and R I b are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-CL10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 0 RI IS R I C(O)NR 1

CN,

N02, (Ri 0 )2N-C(NR 1 R I R I OOC(O)-, N3, 102,or R I I OC(O)NR C) ClI-C6 alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 R I IS(O)m-, R I C(O)NR 10

CN,

(R I 0 )2N-C(NR 1 R I R I OOC(O)-, N3, 102,or R I IOC(O)-NR R2a and R2b are independently selected from: a) hydrogen, b) ClI -C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, R 10 R I I R I C(O)NR 1 0 CN, N3, (Ri 0 )2N-C(NR RI RI OOC(O)-, -N(RI 0)2, or R I IOC(O)NR 1 0-, c) aryl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, R 1 0 0, R I IS(O)m-, R IOC(O)NR 10- CN, N02, (R'%02N-C(NR R IOC(O)-, R IOOC(O)-, N3, -N(R 10 or R I I0C(O)NR 1 and WO 97/36587 PCT/US97/05328 d) Cl-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 0 ii) methionine sulfone, c) substituted or unsubstituted C -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br,

N(R

10 N02, R1 0 R CN, (R 1 0 )2N-C(NR 10 RIOC(O)-, RIOOC(O)-, N3, -N(R 10 R 1 0C(O)NR10- and C1-C20 alkyl, and d) C -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and 0 C3-C10 cycloalkyl; or

R

3 and R 4 are combined to form (CH2)s and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, 0 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(R 10 N02, R 1 0 R S(O)m-, R 0C(O)NR 10-, CN, (R 10)2N-C(NR 10), R OC(O)-, WO 97/36587 PCT/US97/05328 -31- RIOOC(O)-, N3, -N(R 10

R

1 1 OC(O)NRIO- 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 and R5b are combined to form (CH2)s wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(COR10)

R

6 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(R 1)2, -OR 10, or b)

R

12 0 0 R 13 X-Y is WO 97/36587 PCT/US97/05328 -32- 7a a) N.

O 0 RI7b b) N c) m (0),m d)

H

e) I or

H

f) -CH 2

-CH

2 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-CIO cycloalkyl, and e) CI-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, WO 97/36587 WO 9736587PCTIUS97/05328 -33e) C I -C6 alkylI substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-ClO cycl oalkyl and C I -C6 alkyl substituted 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 C I -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1O cycloalkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, R I IS R I C(O)NR 1 0 CN, N02, R 10 2N-C(NR R I R I N3, -N(R 1 0 or R I IOC(O)NR 10-, and c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3 -C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R' IIS(O)m-, R I C(O)NH-, CN, H2N-C(NH)-, R IOC(O)-, R I 0C(O)-, N3, -N(R 10 or R I R9 is selected from: a) hydrogen, b) C2--C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, R 10 R I IS(O)m-, R I C(O)NR 10-, CN, N02, (RI 0 )2N-C-(NR R I R I OOC(O)-, N3, -N(R102,or R I IOC(O)NR 10 and WO 97136587 WO 9736587PCTIUS97/05328 -34c) C I -C6 alkyl unsubstituted or substituted by perfinoroalkyl, F, Cl, Br, R 1 0 R I IS(O)m-, R I C(O)NR 10-, CN, (R 1 0 )2N-C(NR 1 0Oy., R I R I OOC(O)-, N3, 102,or R I IOC(O)NR R 10 is independently selected from H, C1I-C6 alkyl, benzyl, substituted aryl and C I -C6 alkyl substituted with substituted aryl; R 12 is hydrogen or C I-C6 alkyl; R 13 is C I-C6 alkyl;

A

1 I and A 2 are independently selected from: a bond, -CH=CH-, -C7-C-, -C(O)NRIO-, -NRIOC(O)-, 0, -S(0)2N(RIO)-,

-N(R

1 0 or S(O)m; Z is independently H2 or 0; S is t is U is 4 or 3, 4 or 5; and 0 or 1; with respect to formula (11-f): (R")r V Al(CRla 2 )nA 2 (CRla 2 h, (R9

R

3 R

H

I b H V C pY OH UZ (Il-f) R 2 a R 2 b (CH 2 )qCH 2

OF

or a pharmaceutically acceptable salt thereof, R IV, W, m, n, p and r are as defined above with respect to formula (11- a); WO 97/36587 WO 9736587PCTIUS97/05328 R I a and R I b are independently selected from: a) hydrogen, b) aryl, heterocycle, C13-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 0 R I IS(O)m-, R I C(O)NR 10- CN, N02, (RI1 0 )2N-C(NR 1 R I R 1 I N3, -N R 1)2or R' IO0C(O)NR c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 R I IS(O)m-, R I C(O)NR 10- CN, (RI 0 )2N-C(NRI

R

1 R' OOC(O)-, N3, 102,or R' IIOC(O)-NR10--5 R2a and R2b are independently selected from: a) hydrogen, b) C I -C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, R 1 0 R I IS(O)m-, R I C(O)NR 10-, CN, N3, (Ri 0 )2N-C(NRI R 1 0

R

1 0 -N(Rl 0)2, or R I I0C(O)NR c) aryl, heterocycle, Ci3-C 10 cycloalkyl, C2-C6 alkenyl, R 1 0 R I IS(O)m-, R I C(O)NR 1 CN, N02, (RI 0 )2N-C(NR 1 RI R 1 OOC(O)-, N3, 102,or R' I IC(O)NR 10 and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-Cl 0 cycloalkyl; R3 and R 4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted CI-C20 alkyl, C2-C20 alkenyl, C3-C 10 cycloalkyl, aryl or heterocyclyl group, WO 97/36587 WO 9736587PCTIUS97/05328 -36wherein the substituent is selected from F, Cl, Br,

N(R

1 0 N02, RIO0-, RI IS(O)m-, RIOC(O)NR CN, (R 1 %2N-C(NR 1

R

1

R

1

OOC(O)-,

N3, -N(R 10 R I I0C(O)NR 1 0- and C I-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-CIO cycloalkyl; or

R

3 and R4 are combined to form (CH2)s x-Y is a) sNs 0

R

7 b b)N

C)

H

I o r

H

f) -CH 2 -0 H 2 R7a is selected from a) hydrogen, WO 97/36587 PCT/US97/05328 -37b) 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) Ci-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 C -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;

R

8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-,

RI

1 R10C(O)NR 10 CN, N02, R 10 2N-C(NR10)-, R 10

R

10 N3, -N(R 10 or R 10C(O)NR1O-, and WO 97/36587 WO 9736587PCT[US97/05328 -38c) C I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R I IS(O)m-, R IOC(O)N14-, CN, H2N-C(NH)-, R IOC(O)-, R I 0C(O)-, N3, -N(R 10 or R I 0C(O)NH-; R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfiuoroalkyl, F, Cl, B r, R 1 0 R I R I C(O)NR 1 0 CN, N02, (R I 02N-C-(NR R I R I OOC(O)-, N3, 102,or R I I0C(O)NR 10-, and C) C I -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 R I IS(O)m-, R I C(O)NR 10-, CN, (RIO)2N-C(NRIO)-, RIOC(O)-, RIO0C(O)-, N3, -N(R102,or R' IIOC(O)NR R 1 0 is independently selected from H, C I-C6 alkyl, benzyl, substituted aryl and C I-C6 alkyl substituted with substituted aryl; R 12 is hydrogen or ClI-C6 alkyl; R 1 3 is C I-C6 alkyl; A1 and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR 10-, -NR IOC(O)-, 0, -N(R -S(0)2N(R 10 -N(Rlo)S(O)2-, or S(O)m; Z is independently H2 or 0; q is 0,l1or 2; s81s 4 t is 3, 4or u is 0 or 1; WO 97/36587 WO 9736587PCTJUS97/05328 -39with respect to formula (11-g): (R8) (R9) -A A(CRla 2 )nA (CRla 2 )n- H 0 0 qN or a pharmaceutically acceptable salt thereof, R 11, V, W, m, n, p and r are as previously defined with respect to formula (11-a); R I a and R I b are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 R I 1 R I C(O)NR 10-, CN, N02, (RI 0 )2N-C(NR 1 R I R I OOC(O)-, N3, 102,or R I I OC(O)NR 1 0-, c) C I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10O-, R I IS(O)m-, R I C(O)NR 10-, CN, (RI %2N-C(NRIO0>, R R' OOC(O)-, N3, 102,or R I I0C(O)-NR R2a and R2b are independently selected from: a) hydrogen, b) C I -C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, R 10 R I IS(O)m-, R I C(O)NR 10-, CN, N3, (RI 0 )2N-C(NRIO0>, RI RI OOC(O)-, -N(RI 0)2, or R I I0C(O)NR 1 0-, c) aryl, heterocycle, C3-CIO cycloalkyl, C2-C6 WO 97/36587 WO 9736587PCTIUS97/05328 alkenyl, R 1 0 R I IS(O)m-, R I C(O)NR 10 CN, N02, (R I 0 )2N-C(NR 1 R I R I OOC(O)-, N3, -N(R 10)2 or R I IOC(O)NR 10-, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-CI10 cycloal-kyl; 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 occurrng amino acid which is: i) methionine sulfoxide, or ii) methionine suifone, c) substituted or unsubstituted C I-C20 alkyl, C2-C20 alkenyl, C3-ClO cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(RIO)2, N02, RIO0-, RI 1

RIOC(O)NRIO-,

CN, (R 10 )2N-C(NR R IOC(O)-, R IOOC(O)-, N3, -N(R 10 R I I0C(O)NR 1 0- and ClI-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-ClO cycloalkyl; or R3 and R4 are combined to form (CH2)s WO 97/36587 WO 9736587PCTfUS97/05328 -41x-Y is R 7 a a) Ns 0

R

7 b b)

NN

1

C))

H

,r

H

f) -0H 2

-CH

2 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) C I -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1O cycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, WO 97/36587 WO 9736587PCTfUS97/05328 -42d) unsubstituted or substituted C3-C 10 cycloalkyl, e) C I -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3 -C 10 cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted. or substituted group selected from aryl, heterocycle, C3-C cycloalkyl and C I -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 C I -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-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, RI IS(O)m-, RIOC(O)NRIO-, CN, N02, R 1 0 2N-C(NRIO)-, R IOC(O)-, R I N3, -N(R 10 or R I IOC(O)NR 10-, and c) C I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, RI IS(O)m-, R I CN, H2N-C(NH)-, R IOC(O)-, R I OC(O)-, N3, -N(R 10 or R I 0C(O)NH-; R9 is selected from: a) hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 R I 1 R I C(O)NR 1 0 CN, N02, (Ri 0 )2N-C-(NR 1

R

1 I R' I N3, 102,or R I IOC(O)NR 10-, and WO 97/36587 WO 9736587PCT/US97/05328 -43- C) ClI-C6 alkyl unsubstituted or substituted by peffluoroalkyl, F, Cl, Br, RIO0-, RI IS(O)m-, RIOC(O)NRIO-, CN, (RI 0 )2N-C(NR 1 R I Ri I N3, -N(R102,or R II OC(O)NR R 10 is independently selected from H, C I -C6 alkyl, benzyl, substituted aryl and C I -C6 alkyl substituted with substituted aryl; R 1 2 is hydrogen or ClI-C6 alkyl; R 13 is C1I-C6 alkyl; A and A 2 are independently selected from: a bond, -CH=CH-, -N(R 1 )S or S(O)m; Z is independently H2 or 0; q is 0,I1or 2; s is 4 or t is 3, 4or u is 0Oorl1; a compound represented by formula (11-h) through (1l-k): R9 R 5 I N N (C A

H

R 4 b (11-h)

R

WO 97/36587 WO 9736587PCT/US97/05328 -44- (R8)r V Al(CRla 2 2 (CRla 2 )n

IR

9 (Il-(C (R 8 )r V Al(CRla 2 )nA 2 (CRla 2 )n

IR

9 I (R9

R

V- Al(CRla 2 )nA (CRl9 2) -Wi (CR 2

J[

x

R'

(11-k) wherein with respect to formula (11-h):

(R

8 )r (R9 R 6 V -A'(CRla 2 )nA 2 CRla 2 -~j(CRlb 2 1 xR (11-h) or a pharmaceutically acceptable salt thereof, R 4 R 4 b WO 97/36587 PCT/US97/05328 Rla, Rib, R 8

R

9

R

0 R 1, A 1

A

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

R

2 and R 3 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 0 ii) methionine sulfone, and c) substituted or unsubstituted C l-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br,

N(R

10 N02, R 0 Rl 1

R

10 CN, (RL 0 )2N-C(NR 10), RIOC(O)-, R 0OC(O)-, N3, -N(R 10

R

1 1 0C(O)NRO0- and CI-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and D C3-C10 cycloalkyl; or

R

2 and R 3 are combined to form (CH2)s or R2 or R3 are combined with R 6 to form a ring such that R 6 N 1 2 R3

H

2 )t

SR

7 b R4a, R4b, R 7 a and R7b are independently selected from: a) hydrogen, WO 97/36587 WO 9736587PCT/US97/05328 -46b) C1I-C6 alkyl unsubstituted or substituted by alkenyl, R 100-, R I I R I C(O)NR 1 0 CN, N3, (R 10 )2N-C(NR RIOC(O)-, RIOOC(O)-, -N(RIO)2, or R 1 1 C(O)NR c) aryl, heterocycle, cycloalkyl, alkenyl, R 10 0-, R I IS(O)m-, R I C(O)NR 1 0 CN, N02, (Ri 0 )2N-C(NR 1 R I R I OOC(O)-, N3, -N(R 10 or R' IIOC(O)NR 10-, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-C 10 cycloatkyl; 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 C1I-C20 alkyl, C2-C20 alkenyl, cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R 10 N02, R 10 R I IS(O)m-, R I 0 C(O)NR 10 CN, (Rl I )2N-C(NR 1 R I R I OOC(O)-, N3, -N(R 10 R I IOC(O)NR 10- and C1I-C20 alkyl, d) ClI -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-ClO cycloalkyl; or and R5b are combined to form (CH2)s wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(CORIO)-; R6 is independently selected from hydrogen or ClI -C6 alkyl; WO 97/36587 PCT/US97/05328 -47- 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 tis u is 4 or 3, 4 or 5; and 0or 1; with respect to formula (II-i): (R8 R9 V- A'(CRa 2 )nA 2

(CR

1 2 (II-i) 0

R

4 b or a pharmaceutically acceptable salt thereof, wherein: Rla, Rib, R 8

R

9 RIO, R 1 1, Al, A 2 V, W, m, n, p and rare as previously defined with respect to formula (II-a);

R

2 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 CI-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, WO 97/36587 WO 9736587PCTIUS97/05328 -48wherein the substituent is selected from F, Cl, Br, N(RIO)2, N02, RIO0-, RI IS(O)m-, RIOC(O)NRIO- CN, (RI O)2N-C(NR 1 RI R' 0 0C(O)-, N3, -N(R 10 R I IOC(O)NR 10- and C I-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-ClO cycloalkyl; or

R

2 and R 3 are combined to form (CH2)s or R2or R 3 are combined with R 6 to form a ring such that Nis

(HA)

RA 3 R7aR 7 b R4a, R4b, R 7 a and R7b are independently selected from: a) hydrogen, b) C I-C6 alkyl unsubstituted or substituted by alkenyl, R 10 0-, R I IS(O)m-, R I C(O)NR 10-, CN, N3, (R 10 )2N-C(NR 1 R I R I -N(R 1 0 or R I I0C(O)NR c) aryl, heterocycle, cycloalkyl, alkenyl, R 1 0 R I IS(O)m-, R I C(O)NR 1 0 CN, N02, (R I 0 )2N-C(NR 1

R

1 I R I OOC(O)-, N3, 1)2or R I I OC(O)NR 1 and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-Cl 10 cycloalkyl; and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, WO 97/36587 PCTIUS97/05328 -49b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br,

N(R

1 0 N02, RO 0 Rl 1 CN, (R10)2N-C(NRIO)-, R R 1OOC(O)-, N3, -N(R 10 RI IOC(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: 0, S(O)m, and -N(CORI0)-; R6 is independently selected from hydrogen or C1-C6 alkyl;

R

12 is a) substituted or unsubstituted C -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(R 1)2, 4) -OR 10 or b)

R

13

O

R 14 O°l a R 1 3 is independently selected from hydrogen and CI-C6 alkyl; WO 97/36587 PCT/US97/05328

RI

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

R

V A'(CRa 2 )nA 2

(CR

1 a 2 n -W (CR 1 (II-j) or a pharmaceutically acceptable salt thereof,

R

1 a, Rib, R8, R 9 RIO, Rl 1, Al, A 2 V, W, m, n, p and r are as previously defined with respect to formula (II-a);

R

2 and R 3 a) b) are independently selected from: a side chain of a naturally occurring amino acid, an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and WO 97/36587 WO 9736587PCTIUS97/05328 -51 c) substituted or unsubstituted C1I-C20 alkyl, C2-C20 alkenyl, C3-CIO cycl oalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R 10 N02, R 10 R I 1 R I C(O)NR CN, (R 0 )2N-C(NRI10>, RIOC(O)-, R 1 0 0C(O)-, N3, -N(RIO)2, R 1 lOC(O)NR 10- and C1-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1O cycloalkyl; or

R

2 and R 3 are combined to form (CH2)s or R2or R3 are combined with R 6 to form a ring such that R 6 R 2

HA

7a, R)7 R4a, R4b, R 7 a and R7b are independently selected from: a) hydrogen, b) C I-C6 alkyl unsubstituted or substituted by alkenyl, R 10 0-, R I IS(O)m-, R IOC(O)NR 1 0 CN, N3, (R 1 02N-C(NR 1 0-, R IOC(O)-, R IOOC(O)-, -N(R 10 or R I I0C(O)NR c) aryl, heterocycle, cycloalkyl, alkenyl, R 10 R I IS(O)m-, R I C(O)NR 1 0 CN, N02, (Ri 0 )2N-C(NRI10>, R 1 0 R' OOC(O)-, N3, 1)2or R' IIOC(O)NR 10-, and d) C I -C6 alkyl substituted with an unsubstituted. or substituted group selected from aryl, heterocyclyl and C3-Cl10 cycloalkyl; R6 is independently selected from hydrogen or C I -C6 alkyl; WO 97/36587 PCT/US97/05328 -52- 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 tis 3, 4 or 5; and uis 0 or 1; with respect to formula (II-k): Z q q 0 (R)r 6 Y N K N z H V- A'(CRla 2 )nA 2 (CR1a 2 n CR1b 2

X

R

4 b (ll-k)

R

4 a or a pharmaceutically acceptable salt thereof, R a, Rib, R 8

R

9 R10, R 11

A

1

A

2 V, W, m, n, p, and r are as defined above 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-C10 cycloalkyl, aryl or heterocyclyl group, WO 97/36587 WO 9736587PCT1US97105328 -53wherein the substituent is selected from F, Cl, Br, N(RIO)2, N02, RIO0-, RI IS(0)m-, RIOC(0)NRIO-, CN, (Ri 0 )2N-C(NR 1 R I R I OOC(O)-, N3, -N(R 10 R I IC(0)NR 10- and C1I-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; or

R

2 and R3 are combined to form (CH2)s or R2or R3are combined with R 6 to form a ring such that

RH

2

R

3

R

7 a R 7 b R4a, R4b, R 7 a and R7b are independently selected from: a) hydrogen, b) C I -C6 alkyl unsubstituted or substituted by alkenyl, R 100>, R' IIS(0)m-, R I C(0)NR 1 0 CN, N3, (R 10 )2N-C(NR 1 R I R I -N(R 10 or R I I0C(0)NR 10 c) aryl, heterocycle, cycloalkyl, alkenyl, R 1 00-, R' IIS(0)m-, R I 0 C(0)NIR 10 CN, N02, (Ri 0 )2N-C(NR 1 R I R 1

I

0 0C(0)-, N3, -N(R 10 )2 or R I I0C(0)NR 10-, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl,'heterocyclyl and C3-C10 cycloalkyl;

R

6 is independently selected from hydrogen or C I-C6 alkyl; WO 97/36587 WO 9736587PCTIUS97/05328 -54- 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 0; q is 0,l1or 2; S is 4 or t is 3, 4or U is 0Oor 1; and a compound represented by formula (11-1) through (11-o):

(R

8 )rR9R6zR5 (r 1b N N V (CRla 2 )nA (CRla 2 h, -VW/ (CRl 2 4e_(I H 0 x R~a;

R

4 b

(R

8 )r (6 Z R 6

R

5

R

5 b 1 I K

N

V A(CRla 2 (CRlOn W (CR1b 2 q( 0 x 4a;3

R

4 b (I -r)R WO 97/36587 WO 9736587PCTIUS97/05328 HOC H 2 (C H2)q z (R )r R9R 6 YN

OH

V -A1(CR a 2 )nA2(OR a 2 )nKW) NC" H 0 R(R b 4aH R 4 b

(R

8 )r R6Y zq V- Al(CR a 2 )nA 2 CRla 2 1n (C R lb 2

N

x (11-0)R a i R4 wherein with respect to formula (11-1): (RB)r (R9 R 6 Y z N OH V -A A(C Rl 2 )nA (C Rl 2 )n W -(CR b 2 1 3 x or a pharmaceutically acceptable salt thereof: RIa, Rib, R 8

R

9 RIO RI 1, Al, A 2 V, W, m, n, p and r are as defined above with respect to formula (1l-a);

R

2 and R 3 are independently selected from: a) a side chain of a naturally occurring amino acid, WO 97/36587 WO 9736587PCTIUS97/05328 -56b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C I-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R 10 N02, R 1 0 R I IS(O)m-, R I C(O)NR CN, (Ri 0 )2N-C(NRIO0>, RI 0

R

1 0 0C(O)-, N3, -N(R 10 R I IOC(O)NR 10- and C1I-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 1O cycloalkyl; or

R

2 and R 3 are combined to form (CH2)s or R2or R3are combined with R 6 to form a ring such that R 6 N -is

H

2 )t R 2R aR 7 b R4a, R4b, R 7 a and R7b are independently selected from: a) hydrogen, b) ClI-C6 alkyl unsubstituted. or substituted by alkenyl, R 10 0-, R I IS(O)m-, R I C(O)NR 1 0 CN, N3, (R 10 )2N-C(NR 10 R I R IOOC(O)-, -N(R 1 0 or R I IOC(O)NR 1 0-, c) aryl, heterocycle, cycloalkyl, alkenyl, R 10 0-, ~R I IS(O)m-, R I C(O)NR 10 CN, N02,

(R

1 0 )2N-C(NR 1 RIOC(O)-, R 1 0 0C(O)-, N3, -N(R 10 )2 or R IIOC(O)NRi10-, and WO 97/36587 PCTIUS97/05328 -57d) 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 Cl-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br,

N(R

1 0 N02, RI 0

R

1 lS(O)m-, RIOC(O)NRIO-, CN, (RIO)2N-C(NR1O)-, RIOC(O)-, R 1 0

OC(O)-,

N3, -N(R 10

R

1 IOC(O)NRIO- and CI-C20 alkyl, d) CI-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; or and R5b are combined to form (CH2)s wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(CORIO)-

R

6 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 t is 3, 4 or 5; and WO 97/36587 PCT/US97/05328 -58u is Oor 1; with respect to formula (II-m): (R8)r R9 V A'(CRa 2 )nA 2 (CRa 2 )n-W

U

R

5 b

R

4 b (I1-m) or a pharmaceutically acceptable salt thereof, Ria, Rib, R8, R 9

R

10

R

11 Al, A 2 V, W, m, n, p and r are as defined above with respect to formula (II-a);

R

2 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, N02, R 1 0 RI 1 CN, (R1 0 )2N-C(NR 1 0 RIOC(O)-, R100C(O)-, N3, -N(R 10

R

1 1

OC(O)NR

1 O- and Ci-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 R 3 are combined to form (CH2)s or WO 97/36587 WO 9736587PCTIUS97/05328 -59- R2 or R3are combined with R 6 to form a ring such that

R

2 6

HA

R 7a,()R)7b R4a, R4b, R 7 a and R7b are independently selected from' a) hydrogen, b) ClI-C6 alkyl unsubstituted or substituted by alkenyl, R 1 0 0-, R I IS(O)m-, R I C(O)NR 1 0 CN, N3, (R 1 %2N-C(NR R IOC(O)-, R IOOC(O)-, N(R 10 or R I I0C(O)NR o c) aryl, heterocycle, cycloalkyl, alkenyl, RIOO-, R I IS(O)m-, RJ OC(O)NR 10 CN, N02, (Ri 102N-C(NR R I R I OOC(O)-, N3, -N(R 10 )2 or R I IOC(O)NR 10-, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-C 10 cycloalkyl; and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, o b) an oxidized form of a side chain of a naturally occurring amino acid which is: i methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C I -C20 alkyl, C2-C20 alkenyl, C3 -C 10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R 10)2, N02, R 1 0 R I IS(O)m-, R I C(O)NR 1 0 CN, (R 1 0 )2N-C(NR R I R I OOC(O)-, N 3, -N(R 10 R IIOC(O)NR 1 0 and C I-C20 alkyl, WO 97/36587 PCT/US97/05328 d) C -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: 0, S(O)m, and -N(COR 10 R6 is independently selected from hydrogen or Cl-C6 alkyl; R1 2 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(R 1)2, 4) -OR 10 or b)

R

13 0

R

13 is independently selected from hydrogen and C1-C6 alkyl;

R

14 is independently selected from Cl-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 WO 97/36587 WO 9736587PCTIUS97/05328 -61 t is 3, 4or u is 0 or 1; with respect to formula (11-n): (R )r R9R 6 V Al(CRla 2 )nA (CR a 2 )n (CR1b 2 ~'l 4 (11-n) or a pharmaceutically acceptable salt thereof: R 4 b Ria, Rib, R 8

R

9 RIO, RI 1, Al, A 2 V, W, m, n, p and r are as defined above with respect to formula (1I-a);

R

2 and R 3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized formn of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C I-C20 alkyl, C2-.C2 0 alkenyl, C3-CIO cycloalkyl, aryl or heterocyclyl group, 0 wherein the substituent is selected from F, Cl, Br, N(R 10 N02, R 10 R I IS(O)m-, R IOC(O)NR CN, (R 1 0 )2N-C(NR R I R I OOC(O)-, N3, -N(R'10)2, R I IOC(O)NRl10- and C I-C20 alkyl, and C I -C6 al-kyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; or WO 97/36587 PCT/US97/05328 -62- R2 and R3 are combined to form (CH2)s or R2 or R3 are combined with R 6 to form a ring such that R6 jje N^ is H 2tt R2 R 3 D7a."C -71 R4a, R4b, R 7 a and R7b are independently selected from: a) hydrogen, b) CI-C6 alkyl unsubstituted or substituted by alkenyl, R 10 0-, Rl lS(O)m-, R 1 OC(O)NR10-, CN, N3, (R10)2N-C(NR10)-,

R

10 RIOOC(O)-, -N(R 10 or R 1 1 c) aryl, heterocycle, cycloalkyl, alkenyl, R 10

O-,

RII R 1 C(O)NR 10-, CN, N02, (R I 0 )2N-C(NR 1 RIOC(O)-, R1OOC(O)-, N3, -N(R 10 or R 1 IOC(O)NR10-, and d) C -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-C10 cycloalkyl; R6 is independently selected from hydrogen or C -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 s is t is u is 0, 1 or 2; 4 or 3, 4 or 5; and 0or 1: WO 97/36587 PCT/US97/05328 -63and with respect to formula (II-o): R9) V A'(CRa 2 )nA 2 (CRla 2 n

(CR

(II-o)

R

6

Y

R

4 b or a pharmaceutically acceptable salt thereof: Rla, Rib, RS, R 9 RIO, R 11 Al, A 2 V, W, m, n, p and r are as defined above 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-C10 cycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R 10)2, N02, R 10 R l 1

R

1

OC(O)NR

10 CN, (R 10 )2N-C(NR10)-, R10C(O)-, N3, -N(R 1 0

R

1 1 OC(O)NR1O- and CI-C20 alkyl, and d) CI-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 R 6 to form a ring such that WO 97/36587 WO 9736587PCTIUS97/05328 -64is (HA) R 2 RaR 7 b R4a, R4b, R 7 a and R7b are independently selected from: a) hydrogen, b) ClI-C6 alkyl unsubstituted or substituted by alkenyl, R 1 0 0-, R' IIS(O)m-, R I C(O)NR 1 CN, N3, (R'1 0 )2N-C(NR'10)-, RIOC(O)-, RIO0C(O)-, -N(R' 0 or R' OC(O)NRIO-, c) aryl, heterocycle, cycloalkyl, alkenyl, R 1 0 0-, R I IS(O)m-, R IOC(O)NR 1 CN, N02, (R I 02N-C(NR R I R I OOC(O)-, N3, -N(R 10 )2 or R I IOC(O)NR 10-, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-ClO cycloalkyl;

R

6 is independently selected from hydrogen or CI-C6 alkyl; Q is a substituted or unsubstituted nitro gen-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 0; q is 0,l1or 2; s is 4or t is 3, 4or u is 0Oorl1.

Specific compounds which antagonize Raf include the following: WO 97/36587 WO 9736587PCTIUS97/05328 4- [5-(4-fluorophenyl)-4-pyridin-4-yI -1 H-imidazol-2-yl] -piperidine- 1 carboxylic acid tcrt-butyl ester; 4-[4-fluorophenyl)-3 -pyridin-yl- 1H-imidazol-2-yl] -1-acetyl-piperidine; 3- [5-(4-fluorophenyl)-4-pyridin-4-ylI1H -imidazol-2-yIl -piperidine- 1carboxylic acid tert-butyl ester; 3 [4 -fluorophenyl)-3 -pyri din -yl -I H-imidazol -2-yl] -1 -acetyl -piperidine; and 4-benzyl-[4-(4-fluorophenyl -pyridin-4-yl- 1H-imidazol-2-yl] piperidine-l1-carboxylic acid tert-butyl ester.

4-[15-(4-fluorophenyl)-4-pyridin-4-y 1-1H -imidazol-2-yl] -piperidine; 4-15-(4-fluorophenyl)-4-pyridin-4-yl- 1H-imidazol-2-yl]- 1-methylpiperidine; 4-[5-(4-fluorophenyl)-4-pyridin-4-yl- 1H-imidazol-2-yl]-lI-benzylpiperidine; -(4-fluorophenyl )-4-pyridin-4-yl- 1H-imidazol-2-yl] -1 -ethylpiperidine; 4-[5 ,4-dichlorophenyl)-4-pyridin-4-yl- I H-imidazolI-2-yl] -piperi dine; 4-15-(3,4-dichlorophenyl)-4-pyridin-4-yl- 1 H-imidazol-2-yl]- 1 -methylpiperidine; {4-[5-(3,4-dichlorophenyl)-4-pyridin-4-yl- 1 H-imidazol-2-yl]piperidin- Il-yl -butyl)-isoindole- I ,3-dione; -1 4[ 5-(3,4-di chilorophenylI)-4-pyri din-4-ylI- 1 H-imidazol-2-yI]piperidin- Il-yl I -pentyl)-isoindole- 1 ,3-dione; WO 97/36587 WO 9736587PCT/US97/05328 -66- 4-[5-(3,4-dichlorophenyl)-4-pyridin-4-yl- 1 H-imidazol-2-yl]piperidin- Il-yl I -hexyl)-isoindole- 1,3 -dione; ,4-dichlorophenyl)-4-pyridin-4-yl- I H-imidazol-2-y]- -1 -benzylpiperidine; ,4-dichlorophenyl)-4-pyridin-4-yl- I H-imidazol-2-yl]piperidin- Il-yI I -pentyl)-2,3-dihydro-isoindol- 1 -one ditrifluoroacetic acid salt; ,4-dichlorophenyl)-4-pyridin-4-y]I1H-imidazol-2-yl]piperidin- Il-yl -ethyl) -pyri dine; f ,4-dichlorophenyI)-4-pyridin-4-y1- 1 H-imidazol -2-yl] piperidin- Il-yl I -pentyl)- 1, 1 -dioxobenzo [d]isothiazol-3 -one; [5 -(3,4-di chl orophenylI)-4-pyri din -4-yJ 1 H-imidazol-2-yl]piperidin- Il-yl I -butyl)- 1, 1 -dioxobenzo[d] isothiazol-3 -one; 2-amino- I 5- [4-(3,4-dichlorophenyl)-4-pyri din -4-yl- 1 H-imidazol-2yJ]-piperidin- l-yi 1-ethanone dihydrochioride; 4 -[5-(3-hydroxyphenyl)-4-pyridin-4-yl- 1H-imidazol-2-yI]- 1-methylpiperidine; 3 -[5-(4-fluorophenyl)-4-pyridin-4-yl- IH-imidazol-2-yI]-piperidine- 1carboxylic acid tert-butyl ester; 3 -15-(4-fluorophenyl)-4-pyridin-4-ylI1H-imidazol-2-yl]-piperidine: 3 -[5-(4-fluorophenyl)-4-pyridin-4-yI- IH-imidazol-2-yl]- 1-methylpiperidine; WO 97/36587 WO 9736587PCTIUS97/05328 -67- 4- [5 -(4-fl uorophenyl)-4-pyri din 1 H-imidazol -1,4-dimethylpiperidine; 4-benzyl- 4 -(4-fiuorophenyl )-5-pyridin-4-yI- 1 H-imidazol-2-ylpiperidine-1I-carboxylic acid tert-butyl ester; 4-benzyl- 4 4 -fluorophenyl)-5-pyridin-4-yi- 1 H-imidazol-2-yi] pipe rid in e 4- f 5-(3,4-dichlorophenyl)-2-[ I-(2-phenylethyl)-piperidin.4yl] -1I Himidazol-4-yi I -pyridine; 5-(3,4-dichlorophenyl)-2-[

I-(

3 -phenylpropyl)-piperidin-4-.yly. I Himidazol-4-yl I -pyridine; 4- [5 ,4-dichl orophenyl)-4-pyridin-4-yI- 1 H-imidazol-2-yl] piperidin- Il-yl I -hexyl)- 1, 1 -dioxobenzo[dlisothiazol-3 -one; f 4- [5 ,4-di chiloropheny)-4-pyri din4.-ylI.- 1 H-imidazol-2-yI]piperidin- Il-ylI )-propyl)- 1, 1 -dioxobenzo[d]isothiazol.3.-one; f ,4-dichlorophenyI)-4-pyridin-4-y1 1 H-imidazol-2-yI]piperidin- 1 -yl-methyl I -imidazol- I -yi-methyl)-benzonitrile; 1-( 4 -benzyIoxybenzy1)-pipeidin4-yi...s(3 ,4-dichlorophenyl)- 1 Himidazol -4-yl -pyri dine; f 4 -[5-(3,4-dichloropheny)-4-pyridin4yl.. I H-imidazol-2-yI]piperidin- Il-yI I -propyl)-isoindole- 1 ,3-dione; 4-4(-loohnl--4prdliiao--lbnaioie 4-(lI -naphthyl)-2-.(4-.methylsu lfinylphenyl)-5-(4-pyridyl)imidazole; WO 97/36587 WO 9736587PCTIUS97/05328 -68- 4-(l1 -naphthyl 2 4 -methylthiophenyl)-5-(4-pyridyl)imidazole; 4 2 -naphthy)-2-(4-methylthiopheny)-5-(4-.pyridyl)imidazole; 4 2 -naphthyl)-2-(4-methylsulfinylphenyl)5-(4-.pyridyl)imidazole; 4-(4-flu orophenyl)-2-(3-thiophenyl)-5-(4-pyridyl)imidazole; 4 4 -fluorophenyl)-2-(2-thiophenyl)-5.(4-.pyridyl)imidazole; 4 4 -fluorophenyl)-2-(3-methylthiophenyl)>5-(4-pyridyl)imidazole; 4-4furpey)2(-ehlufnlhnl--4prdliiaoe 4-(4-fluorophenyl)-2-(3 -methylsulfonylphenyl)-5-(4-pyridyl)imidazole; 4 4 -fluorophenyl)-2-(2-methylthiophenyl)-s -(4-pyridyl)imidazole; 4 4 -fluorophenyl)-2-(2-methylsulfinylphenyl -(4-pyridyl)imidazole; 4 4 -fluorophenyl)-2-(2-methylsulfonylphenyl)>5(4-pyridyl)midazole; 4 4 -fluorophenyl)-2-(4-methoxyphenyl)5-(4-.pyridyl)imidazole; 4 4 -fluorophenyl)-2-(4-methylsulfinylphenyl). 1 -methyl-S -(4-pyridyl) imidazole; 4 4 -fluorophenyl)-2-(4-methylsulfinylphenyl)> 1 morpholinopropyl)-5-.(4-.pyridyl)imidazole; 4 4 -fluorophenyl)-2-(4-methylthiophenyl)- I 4 -pyridyl)imidazole; 4 4 -fluorophenyl)-2-(4-methylsulfonylphenyl)- 1 -(N-morpholino- WO 97/36587 WO 9736587PCTIUS97/05328 -69propyl) -5-(4-pyridyl)imidazole; 4 -(4-fluorophenyl)- I -(methylthio- 1 -propyl)-2-( [4-Nmorpholinomethyllphenyl)>5-.(4-pyridyl)injdazole; 4 4 -fluorophenyl)- I -(methylsulfinyl- I -propyl)-2-([4-Nmorpholinomethylpheny>s...(4-pyridy)rnjdazole; and 4 4 -fluorophenyl)- I -(methylsu ifonyl -1 -propyl)-2-([4-Nmorpholinomethyllphenyl).5 4 -pyridyl)imidazole.

Examples of compounds which antagonize or inhibit famesyl protein transferase include the following: 2(S)-B utyl- I 2 ,3-diaminoprop- I -yl)-lI -naphthoyl)piperazine; l-( 3 -Amino-2-(2-naphthylmethylamino)prop. 1 -yI)-2(S)-butyl-4-( 1naphthoyl)piperazine; 2(S)-Butyl- I I l-( 2 -naphthylmethyl)]-4,5-dihydroimidazo] )methyl-4- (I -naphthoyl)piperazine; 1- [5-(l1 -Benzylimidazol)methyl] -2(S)-butyl-4-( I -naphthoyl)piperazine; 1- 1 1-( 4 -nitrobenzyl)]imidazolylmeffiylI -2(S)-butyl-4-( 1naphthoyl)piperazine; 1 -Acetamidomethylthio-.2(R)-aminoprop- I -yI)-2(S)-butyl-4-( 1naphthoyl)piperazine; 2 (S)-Butyl-1 -imidazolyl)ethylsulfonyl4( 1 -naphthoyl)piperazine; 2(R)-Buty-I -imidazolyl-4-methyl-.4.(l -naphthoyl)piperazine; 2(S)-Butyl I -naphthoyl I -pyridylmethyl)piperazine; WO 97/36587 WO 9736587PCT/US97/05328 I -2(S)-butyl-(2(R)-(4-nitrobenzyl)amino-3 -hydroxypropyl)-4-(I1 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-( 1naphthoyl)piperazine; 1 -(2(R)-Amino-3-[3-(4-nitrobenzylthio)propyl])-2(S)-butyl-4-(1 naphthoyl)piperazine; 2(S )-Butyl- I -I(4-imidazolyl)ethyl] 1 -naphthoyl)piperazine; 2(S)-Butyl- 1 -I(4-imidazolyl)methyl]-4-( I -naphthoyl)piperazine; 2(S)-Butyl- 1 -naphth-2-ylmethyl)- 1 H-imidazol-5-yl)acetyl]-4-( 1naphthoyl)piperazine; 2(S)-Butyl- 1 -naphth-2-ylmethyl)- I H-imidazol-5-yl)ethyl] 1naphthoyl)piperazine; I -(2(R)-Amino-3 -hydroypropyl)-2(S )-buty 1 -naphthoyl)piperazine; I -(2(R)-Amino-4-hydroxybutyl )-2(S)-butyl I -naphthoyl)piperazine; 1 -(2-Amino-3-(2-benzyloxyphenyl)propyl)-2(S)-butyl-4-( 1naphthoyl)piperazine; I -(2-Amino-3-(2-hydroxyphenyl)propyl)-2(S)-butyl-4-( 1naphthoyl)piperazine; WO 97/36587 WO 9736587PCT[US97/05328 -71 1 -(4-imidazolyl)propyl] -2(8 )-butyi-4-( I -naphthoyi)-piperazine; 2(8 )-n-Butyl-4-(2,3 -dimethyiphenyl)- I -(4-imidazolylmethyl)- 2(S )-n-Butyl-I 1-[I -(4-cyanobenzyi)imidazol -5 -ylmethyl]-4-(2,3 -one; 1 1 4 -Cyanobenzyi)imidazol-5-ylmethy1]-4-(2,3-dimethylphenyl)> 2(8 )-(2-methoxyethyi)piperazin-5 -one; 2(S)-n-Butyl-4-(1 -naphthoyl)-l I- ylmethyl] -piperazine; 2(S)-n-Butyl-4-( I -naphthoyl)- 1 ylmethyl]I-piperazine; 2(8 )-n-Butyl- 1-ri1 -(4-cyanobenzyl)imidazol-5 -ylmethyl] 1naphthoyl)piperazine; 2(S)-n-Butyl- I1-[ I -(4-methoxybenzyl)imidazoi-5-ylmethyl]-4-( 1naphthoyl)piperazine; 2(S)-n-Butyl- I -Il -(3-methyl-2-butenyi)imidazol-5-ylmethyi] 1naphthoyl)piperazine; 2(S)-n-Butyl- 1 -rI -(4-fluorobenzyl)imidazol-5-ylmethyl] 1naphthoyl)piperazine; 2 -Butyl- I1-[ I -(4-chlorobenzyl)imidazoi-5-ylmethyl] 1naphthoyl)piperazine; WO 97/36587 WO 9736587PCTIUS97/05328 -72- [1 romobenzyl)imidazol-5-ylmethyl] -butyl-4-( 1 naphthoyl)piperazine; 2(S)-n -Butyl-4-( 1 -naphthoyl)- 1 -ri -(4-trifluoromethylbenzyl)imidazol-s ylmethyljl-piperazine; 2(S)-n-Butyl- 1 -[1I -(4-methylbenzyl)imidazol-5-ylmethyl-4.(1 naphthoyl)-piperazine; 2(S)-n-Butyl- 1 -rI -(3-methylbenzyilimidazol-5-ylmethyl]-4.(I naphtho yl) -pipe razine; 1-ri -(4-Phenylbenzyl)imidazol-5-ylmethyl] -2(S)-n-butyl-4-( 1naphthoyl)-piperazine; 2(S)-n-Butyl-4-( 1 -naphthoyl)- 1 I pipe razine; 2(S)-n-Butyl-4-( I -naphthoyl)- 1-ri1 yimethyllpiperazine; 1- I1 -(4-cyanobenzyl)- I H-imidazol-5-ylacetyl I -2(S)-n-butyl-4-( 1naphthoyi)piperazine; I-fI 5-ri -(4-nitrobenzyl)]imidazolylmethylI 1-2(S)-butyl-4-(1 naphthoyl)piperazine WO 97/36587 PTU9152 PCTIUS97/05328 -73- 0 2N O

N-

14-5-( -Benzylimidazol)methyl-2(S-butyI-4-(I -naphthoyl)piperazine N N \/N0 N J l-( 2 (R)-Amino-3-(3-benzylthio)propyl).2(S)-buty-4-(I1 naphthoyl)piperazine

~NH

2 0 7- I -(2(R)-Amino-3 3 4 -nitrobenzylthio)propyl I)-2(S)-butyl-4-(

I-

naphthoyl)piperazine WO 97/36587 WO 9736587PCTIUS97/05328 -74- 0 2

N

2(S)-n-Butyl- I-[l -(4-cyanobenzyl)imidazol-5-ylmethyl]-4-( 1naphthoyl)piperazine 0 NC

NN

N.

2(S)-n-Butyl-l1-[1 -(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3dimethyiphenyl )piperazin-5 -one

CH

3

NC

2(S)-n-Butyl- 141[ -(4-chlorobenzyl)imidazol-5-ylmethyl]-4.( I naphthoyl)piperazine WO 97/36587 WO 9736587PCTIUS97/05328

CI

N

[1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl]acetyl }-2(S)-n-butyl-4-( 1naphthoyl )piperazine 0

NC

NN N 0

N

-(4-Cyanobenzyl)imidazo] -5 -ylmetliyl] -dimethyiphenyl 2 (S)-(2-methoxyethyl)piperazin -5 -one

CH

3 0 NC

H

3 C

H

3 NC

N

0 1 4 -Lmidazoleacetyl)pyrrolidin-.2(S)yylmethyly.N-(I1 naphthylmethyl)glycylmethionine WO 97/36587 WO 9736587PCTIUS97/05328 -76- HNH

H

HNOH

0

SSCH

3 N- 4 -Imidazoleacetyl)pyrrolidin-2(S)-ylmethyl] I-naphthylmethyl)glycyl-methionine methyl ester; I 2 3 -Diaminopropionyl)pyrrolidin-2(S)-ylmethyl] 1naphthylmethyl)glycyl-methionine; 1-( 2 (S),3-Diaminopropionyl)pyrrolidin-2(S)-yh-nethyl] 1naphthylmethyl)glycyl-methionine methyl ester; N- -Aminopropionyl)pyrrolidin-2(S)-ylmethyl] 1naphthylmethyl)glycyl-methionine; 1 3 -Aminopropionyl)pyrrolidin-2(S)..ylmethyl]-N.( 1naphthylmethyl)glycyl-methionine methyl ester; I1 2 (S)-Amino -3 -benzyl oxy carbonylaminopropi onyl)pyrrol 1din ylmethyl]-N-( I-naphthylmethyl)glycyl-methionine; N- [1-(2(S)-Amino-3 -benzyloxycarbonylaminopropionyl)pyrrolidinylmethyl]-N-( 1 -naphthylmethyl)glycyl-methionine methyl ester; [1 -Amino 2 (S)-benzy loxycarbonylaminopropionyl)pyrroli dinylmethyl] 1-naphthylmethyl)glycyl -methi onine; N 1 -Amino- 2 (S)-benzy loxycarbonylaminopropionyl)pyrroli din ylmethyl] I -naphthylmethyl)glycyl-methionine methyl ester; WO 97/36587 WO 9736587PCTfUS97/05328 -77- N-El -(L-Glutaminyl)pyrrolidin-2(S)- ylmethyl] Inaphthylmethyl)glycyl-methionine; 1-(L-Glutaminyl)pyrrolidin-2(S)- ylmethyl] 1naphthylmethyl)glycyl-methionine methyl ester; I -(L-Histidyl)pyrrolidin-2(S)-ylmethyl]-N-(I naphthylmethyl)glycyl-methionine; I -(L-Histidyl)pyrrolidin-2(S)-ylmethyl]-N.( 1naphthylmethyl)glycyl-methionine methyl ester; I -(D-Histidyl)pyrrolidin-2(S)-ylmethyl]

I-

naphthylmethyl)glycyl-methionine; N-[El -(D-Histidyl)pyrrolidin-2(S)-ylmethyl]-N-(l naphthylmethyl )g lycyl-methionine methyl ester; 1 -(L-Pyroglutamyl)pyrrolidin-2(S)-ylmethyl].N.( 1naphthylmethyl)g lycyl-methionine; 1 -(L-Pyroglutamyl)pyrrolidin-2(S)-ylmethyl].N.( I naphthylmethyl)glycyl-methionine methyl ester; 2(S)-[El -(2(S)-Pyroglutamyl )pyrro Iidin-2(S )-ylmethyloxy] -3phenyipropionyl-methionine; 2(S)-ElI 2 (S)-Pyrog lutam yl)pyrroli din Imethyl ox yl- 3 phenyipropionyl -methionine methyl ester; 2(S)-El I-( 2 -Pyro glutamyl)pyrro li din- 2(S)-ylmethyl oxyy.-3 phenylpropionyl-methionine isopropyl ester; WO 97/36587 WO 9736587PCTIUS97/05328 -78- I H-Lmidazo l-4-ylacetyl)pyrrolidin-2(S)-ylmethyloxy] -3phenyipropionyl-methionine; I1 H-Imidazol-4-yl acetyl)pyrro li din -2(S)-ylmethyloxy] -3phenylpropionyl-methionine methyl ester; I 2 (S)-Pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy]-3pheny Ipropionyl -methionine sulfone; 2(S)-El 2 (S)-Pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy-3phenyipropionyl -methionine sulfone methyl ester; 2(S) [I -(Pyrid-3 -ylIcarboxy)pyrro li din -2(S)-ylmethyl oxy] 3..

phenyipropionyl-methionine; 1-(Pyrid-3-ylcarboxy)pyrrolidin-2(S)-ylmethyloxy]-3phenyipropionyl -methionine methyl ester; 1-(Naphth-2-yl)- 1H-imidazol-5-ylacetyllpyrrolidin-2(S)ylmethoxy) -3-phenyiprop ionyl-methionine; f 2-[lI -(Naphth-2-yl)- I H-imidazol-5-ylacetyllpyrrolidin-2(S>..

ylmethoxy )-3-phenyipropionyl-methionine methyl ester; I -(Pyrid-3-ylmethyl)pyrrolidin-2(S)yylmethyloxyy.3.

phenyipropionyl -methionine; 1 -(Pyrid-3 -ylmethyl)pyrrolidin-2(S )-ylmethyloxy] -3phenylpropionyl-methionine methyl ester; I-(1 H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]. N-(1 naphthylmethyl)glycyl-methi onine isopropyl ester; WO 97/36587 WO 9736587PCTIUS97/05328 -79- N- [I H-imidazol1-4-yl acetyl)pyrroli din- 2(S) -ylmethyl] N-(1 naphthylmethyl)glycyl-methionine sulfone isopropyl ester; 1-(1 H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl] 1naphthylmethyl)glycyl-methionine su ifone; 1-(Glycyl) pyrrolidin-2(S)-ylmethyll I-naphthylmethyl)glycyl methionine methyl ester; 1-(Glycyl) pyrrolidin-2(S)-ylmethyl]-N-( I-naphthylmethyl)glycylmethionine isopropyl ester; I-(Glycyl) pyrrolidin-2(S)-ylmethyl]-N-( I-naphthylmethyl)glycylmethionine; 1-(Glycyl) pyrrolidin-2(S)-ytmethyl] I-naphthylmethyl)glycylmethionine sulfone methyl ester N-[l -(Glycyl) pyrrolidin-2(S)-ylmethyI] 1-naphthylmethyl)glycyl methionine sulfone; I-(Sarcosyl) pyrrolidin-2(S)-ylmethyl]-N-( I-naphthylmethyl)glycyimethionine methyl ester; N- [1-(Sarcosyl) pyrrolidin-2(S )-ylmethyl] I-naphthylmethyl)glycylmethionine; 1-(N,N-Dimethylgiycyl) pyrrolidin-2(S)-ylmethyl]-N-( 1naphthylmethyl)glycyl-methionine methyl ester; 1-(N,N-Dimethylglycyl) pyrrolidin-2(S)-ylmethyl]-N.( 1naphthylmnethy l)glycyl -methionine; WO 97/36587 WO 9736587PCTIUS97/05328 -g0- N- H-imidazol-4-ylacetyl)pyrroidin-3(S)-ethyl-2(S)-ylmethyl]-

N-

(1 -naphthylmethyl)g lycyl -methionine methyl ester; N- [1 H-imi dazol-4-ylacetyl)pyrrolidin -3 -ethyl -2(S)-ylmethyl] N- (1 -naphthylmethyl)glycyl-methionine; N- [1-(Glycyl) pyrrolidin-3 (S)-ethyl-2(S)-ylmethyl] 1naphthylmethyl)glycyl -methionine methyl ester; N-[1I-(Glycyl) pyrrolidin-3(S)-ethyl-2(S)-ylmethyl]-N.( 1naphthylmethyl)g lycyl -methionine; N-[i -(4-Cyanobenzyl)- 1 H-imidazol-5-ylacetyl)pyrrolidin-2(S)ylmethyl]- N-(1 -naphthylmethyl)glycyl-methionine methyl. ester; N-f 1 -(4-Cyanobenzyl)- I H-imidazol-5-ylacetyl)pyrrolidin-2(S)ylmethyl]I- I-naphthylmethyl)glycyl -methi onine; N-[i I -(2-Acetylamino-3 benzyloxycarbonylaminopropionyl)pyrrolidin-2(S).ylmethyl] 1naphthylmethyl)glycyl-methionine; I -(2-Acetylamino-3 (S )-aminopropionyl)pyrrolidin-2(S )-ylmethyl] 1 -naphthylmnethyl)glycyl-methionine; N-4 I -(2-Amino-3 (S )-acetylaminopropionyl)pyrrolidin-2(S).ylmethyl] -naphthylmethyl)glycyl-methionine; 1 H-Imidazol-4-ylacetyl)pyrrolidin-3(S)ethyl2(Sy..

ylmethyloxy]-3-phenylpropionyl-methionine methyl ester; 2(S )4 1 H-imidazol -4-ylacetyl)pyrrolidin-3 (S )-ethyl-2(S ylmethyloxy] -3-phenyipropionyl -methionine; WO 97/36587 WO 9736587PCTIUS97/05328 -81- I I-(4-Cyanobenzyl)- 1 H-imidazol-5-ylacetyllpyrrolidin-2(S)ylmethoxy)I-3-phenyl prop ionyl -methi onine methyl ester; I 2-[I -(4-Cyanobenzyl)- 1 H-imidazol-5-ylacetyl]pyrrolidin-2(S)ylmethoxy -phenyl propionyl-methionine; I 2- [1-(4-Nitrobenzyl)- I H-imidazol -5-ylacetyllpyrrolidin-2(S ylmethoxy)}-3-phenyl prop ionyl -methi onine methyl ester; f 241 -(4-Nitrobenzyl)- I H-imidazol-5-ylacetyllpyrrolidin-2(S)ylmethoxy 1-3 -phenyl prop ionyl-methionine; 2- [1 -(4-Methoxybenzyl)- I H-imidazol -5 -ylacetyllpyrroli din ylmethoxy 1-3 -phenyl prop ionyl -methi onine methyl ester; -(4-Methoxybenzyl)- 1H-imidazol-5-ylacetyllpyrrolidin-2(S)ylmethoxy)I-3-phenyl prop ionyl1-methionine; 1-(4-Cyanobenzyl)- I H-imidazol-5-ylacetyllpyrrolidin-3(S)ethyl -ylmethox y I -3-phenyl propionyl-methionine methyl ester; I-(4-Cyanobenzyl)- 1 H-imidazol-5-ylacetyllpyrrolidin-3(S)ethyl-2(S)-ylmethoxy 1-3 -phenyl propionyl-methionine; 1-(1 H-imidazol-4-yacetyl)pyrrolidin-2(S..ylmethyl.. N-(1 naphthy lmethyl)glycyl-(f3-acetylamino)alanine methyl ester; 1-(1 H-imidazol-4-yIacetyI)pyrrolidin-2(S)-ylmethyl]-. N-(1 naphthytmethy1)glycyl-(P3-acetylamino)alanine; I-(Glycyl) pyrrolidin-2(S)-ylmethyl]-N-( 1-naphthylmethyl)glycyl- (f-acetylamino)alanine methyl ester; WO 97/36587 WO 9736587PCTIUS97/05328 -82- N-Li -(Glycyl) pyrrolidin-2(S)-ylmethyl]-N-( 1-naphthylmethyl)glycyl- (J-acetylamino)alanine; 1-(Seryl)pyrrolidin-2(S)-ylmethyl]- 1-naphthylmethyl)glycylmethionine methyl ester; N-[1I-(D-Alanyl) pyrrolidin-2(S)-ylmethyl]-N-( 1-naphthylmethyl)glycylmethionine methyl ester; 1-(1 H-imidazol-4-carbonyl)pyrrolidin-2(S)-ylmethyl]- 1naphthylmethyl)glycyl-methionine methyl ester; N-Il-(Isoasparagyl) pyrrolidin-2(S)-ylmethyl]-N-( 1naphthylmethyl )glycyl-methionine methyl ester; 1-(1 H-Imidazol-4-propionyl) pyrrolidin-2(S)-ylmethyl]- 1naphthylmethyl)g lycyl-methionine methyl ester; 1-(3-Pyridylacetyl) pyrrolidin-2(S)-ylmethyl]-N-( Inaphthylmethyl)glycyl-methionine methyl ester; 1-(2-Pyridylacetyl) pyrrolidin-2(S)-ylmethyl]-N-( 1naphthylmethyl)glycyl-methionine methyl ester; 1-(4-Pyridyiglycyl) pyrrolidin-2(S)-ylmethyl]-N-( 1naphthylmethyl )glycyl-methionine methyl ester; 1-(Seryl)pyrrolidin-2(S)-ylmethyl] 1-naphthylmethyl)glycylmethionine; 1-(D-A lanyl) pyrrolidin-2(S )-ylmethyl] -N -(1-naphthylmethyl)glycylmethionine; 1-(1 H-Imidazol-4-carbonyl)pyrrolidin-2(S)-ylmethyl] N-(I naphthylmethyl)glycyl-methionine WO 97/36587 WO 9736587PCTIUS97/05328 -83- 1-(Isoasparagyl) pyrrolidin-2(S)-ylmethyl] 1naphthylmethyl)g lycyl-methionine; 1-(1 H-Imidazol-4-propionyl) pyrrolidin-2(S)-ylmethyl]- 1naphthylmethyl)glycyl-methionine; 1-(3 -Pyridylacetyl) pyrrolidin-2(S)-ylmethyl] 1naphthylmethyl)glycylI-methionine; 1-(2-Pyridylacetyl) pyrrolidin-2(S)-ylmethyl] 1naphthylmethyl)glycyl -methionine; N-[1 -(4-Pyridyiglycyl) pyrrolidin-2(S)-ylmethyl]-N-(1 naphthylmethyl)glycyl-methionine; 1-(1 H-hnidazol-4-ylmethyl)pyrrolidin-2(S).ylmethyl] 1naphthylmethyl)glycyl-rnethionine; 1-( 2 -Aminoethyl)pyrrolidin-2(S)-ylmethyl]. 1naphthylmethyl)glycyl-methionine; 1-(Glycyl) pyrrolidin-2(S)-ylmethyl]-N-( I-naphthylmethyl)glycyl- 2 -thienyl)alanine; 1-(1 H-Imidazol 4 -ylacetyl)pyrrolidin-2(S)-ylmethyl] 1naphthylmethyl)glycy[-(trifluoromethyl)alanine; 1-(1 H-Lidazol-4-ylacetyl)pyrrolidin2(S)-ylmethyl]- 1naphthylmethyl)glycy[(2(S)-amino-4acetylamino)butyric acid; N-fl1-(1 H-Lmidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl.. 1naphthy Imethyl)gl ycy I-(N ,N-dimethy 1)glutamine; WO 97/36587 WO 9736587PCTIUS97/05328 -84- N- H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]

N-

(benzyl)g lycyl-methionine; N- [1-(GlycyI)pyrrolidin-2(S)-ylmethyl] N-(benzyl)glycyl-methionine; N- H-Lmidazol -4-ylacetyl )pyrrolidin-2(S)-ylmethyl]- methoxybenzyl )glycyl -methionine; 1-(Glycyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl]- N-(benzyl)glycylmethionine; 1-(1 H-Lmidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl]

N-

(benzyl)glycy 1-methionine; N-((4-Imidazolyl)methyl-(28)-pyrrolidinylmethyl)-N-(Inaphthylmethyl)glycyl-methionine methyl ester; N- [1-(Glycyl) pyrrolidin-2(S )-ylmethyl] 1-naphthylmethyl)glycyl (2-thienyl)alanine methyl ester; 1-(1 H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl] 1naphthylmethyl)glycyl-(N ,N-dimethyl)glutamine methyl ester; N- H-imidazol-4-ylacetyl)pyrrolidin-2(S )-ylmethyl] 1naphthylmethyi)gl ycyl -(trifluorome thy I)al anine methyl ester; 1-(1 H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]. N-(1 naphthylmethyl)glycyl-(2(S )-amino-4-acetylamino)butyric acid methyl ester; 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl].

N-

(benzyl)glycyl-methionine methyl ester; WO 97/36587 WO 9736587PCTIUS97/05328 N- [I-(Glycyl)pyrrolidin-2(S )-ylmethyl] N-(benzyl)glycyl-methionine methyl ester; N-[l H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl] -(4 methoxybenzyl)glycyl-methionine methyl ester; N- [1 H -Imidazol -4-ylacetyl)pyrrolidin-3 -ethyl -ylmethyl] N (benzyl)glycyl-methionine methyl ester; N-[1I-(Glycyl) pyrro li din- 3(S)-ethyl -2(S)-ylmethyl ]-N-(benzyl)glycylImethionine methyl ester; N-[l -(Glycyl) pyrrolidin-2(S)-ylmethyl] I-naphthylmethyl)glycyl methionine isopropyl ester; 1-(Glycyl) pyrrolidin-2(S)-ylmethyl]-N-( 1-naphthylmethyl)glycylmethionine cyclohexyl ester; 1-(Glycyl) pyrrolidin-2(S)-ylmethyl] 1-naphthylmethyl)glycyl methionine benzyl ester; I-(Glycyl) pyrrolidin-2(S)-ylmethyl]-N-( I-naphthylmethyl)glycylmethionine ethyl ester; N- [1-(Sarcosyl) pyrroildin-2(S)-ylmethyl] 1-naphthylmethyl)glycylmethionine isopropyl ester; N-[1I-(N,N-Dimethylglycyl) pyrrolidin-2(S)-ylmethyl]-N-( 1naphthylmethyl)gl ycyl-methionine isopropyl ester; N-[1I-(Glycyl) pyrrolidin-2(S)-ylmethyl]-N-( 1-naphthylmethyl)glycyl- Smethionine (2-pyridylmethyl) ester; N- [1-(Glycyl) pyrrolidin-2(S )-ylmethyl] 1-naphthylmethyl)glycyl methionine (1 -glyceryl) ester; WO 97/36587 WO 9736587PCTIUS97/05328 -86- 1 -L-Prolylpyrrolidin-2(S)-ylmethyl]-N-( 1naphthylmethyl)glycyl-methionine methyl ester; 1 -(L-Prolyl)pyrrolidin-2(S)-ylmethyl]-N-( 1naphthylmethyl)glycyl-methionine; 1 -Morpholinoacetyl)pyrrolidin-2(S)-ylmethylyN-( 1naphthylmethyl)glycyl-methionine methyl ester; 1 -Morpholinoacetyl)pyrrol idin-.2(S)-ylmethyl>N-( 1naphthylmethyl)g lycyl-methionine; I 4 -Piperidinecarbonyl)pyrrolidin-.2(S)yylmethyl] 1naphthylmethyl)glycyl-methionine methyl ester; N- [1I 4 -Piperi dinecarbonylI)pyrro11din -2(S..ylmethyl] 1naphthylmethyl)glycyl-methionine; 1 3 -Piperidinecarbonyl)pyrrolidin-2(S )-ylmethyl] 1naphthylmethyl )g lycylI-methi onine methyl ester; 1 -(Q 3 -Piperid ine carbonyl)pyrro lidin -2(S)-ylmethyl] 1naphthylmethyl)glycyl-methionine; I 2 -Pyri dylglycyl)pyrrolidin2(S).ylmethylpN-( 1naphthylmethyl )g lycy 1-methionine methyl ester; I 2 -Pyridylycyl)pyrrolidin-2(S)-ylmethyl].N-( 1naphthylmethy I)glycyl -methionine; 1 4 -Pyridyl,glycyl)pyrrolidin-2(S)-yfmethyl>N-( 1naphthylmethyl )glycyl-methionine methyl ester; WO 97/36587 WO 9736587PCTIUS97/05328 -87- I 4 -Pyridylglycyl)pyrrolidin-2(S)-ylmethyl]-N-(I1 naphthylmethy l)glycyl-methionine; [1 -(4-Pyridyl (N-methyl)glycyl)pyrrolidin-2(S).ylmethyl] 1naphthylmethyl)glycyl-methionine methyl ester; Il-( 4 -PyridyJ(N-methy)glycy)pyrroidin2(S)yylmethy-N.(I 1naphthylmethyl)glycyl-methionine; 1 H-Imidazol-4-ylpropionyl) pyrrolidin-2(S)-ylmethyl].N-( naphthylmethyl)glycyl-(P3..acetylamino)alanine; N-[11-(1 H-Imidazol-4-ylpropionyl) pyrrolidin-2(S)-ylmethyl]N( 1naphthylmethyI)glycyl-(P-acetylamino)alanine methyl ester; 1-( 4 -Pyridylglycyl) pyrrolidin-2(S)-ylmethyl]-N-( 1naphthylmethyl)glycyl..q3.acetylamino)alanine; N-[l I (4-Pyridyiglycyl) pyrrolidin-2(S)-ylmethyl]-N.( 1naphthylmethyl)glycyv.(f-acetylamino)alanine methyl ester; I-(Glycyl) pyrrolidin-2(S)-ylmethyl].N-( 1-naphthylmethyl)glycyl.

(0-acetylamino)alanine cyclohexyl ester; 1-(1 H-Imidazol-4-ylacetyI)pyrrolidin-2(S)-ylmethyl]. 1naphthylmethyl)glycyl -(N-methyl)glutamine; 1-(1 H-Lmidazol-4-ylacetyl)pyrrolidin2(S)-ylmethyl]- 1naphthylmethyl)glycyl -(N-methyl)glutamine methyl ester; 1-(1 H-Lidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethy1] 1naphthylmethy)glycyl.(3..methylcarbonylamin)aan 11 e; WO 97/36587 WO 9736587PCTIUS97/05328 -88- I H-Imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl]-N-( 1naphthylmethyl)glycyl-(fA-methylcarbonylamino)alanine methyl ester; 1-(1 H-Imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl]-N-( 1naphthylmethyl)glycyl-(f3-methylsulfonylamino)alanine; 1-(1 H-Imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl]-N-( 1naphthyhrnethyl)glycyl-(f3-methylsulfonylamino)alanine methyl ester; 1-(1 H-Imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl] 1naphthvlmethyl)glycyl- (f-propionylamino)alanine 1-(1 H-Imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl]-N-( 1naphthylmethy1)glycyI-(P3-propionylamino)alanine methyl ester; 1-(1 H-Imnidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl]-N-( 1naphthylmethy1)glycyI-(D3-pyrrolidinon- 1 -ylamino)alanine; 1 1H-Imidazol-4-ylacetyl) pyffolidin-2(S)-ylmethyl]-N-( 1naphthylmethyl)giycy1-(P3-pyrrolidinon- 1-ylamino)alanine methyl ester; 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)ylmethyl]. N-(3methoxybenzyl )glycyl -methionine; 1-(1 H-Lmidazol-4-ylacetyl)pyrrolidin-2(S>..ylmethyl]. N-(3methoxybenzyl)glycyl-methionine methyl ester; 1-(1 H-Lmidazol-4-ylacetyl)pyrrolidin-2(S).ylmethyl]. N-(2methoxvbenzyl)glycyl-methionine; 1-(1 H-Imidazo1-4-ylacetyl)pyrrolidin-2(S)-ylmethyl].. N-(2methoxybenzyl)glycyl-methionine methyl ester; WO 97/36587 WO 9736587PCTIUS97/05328 -89- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl]- N-(3-methoxybenzyl)glycylmethionine; 1-(Glycyl)pyrrolidin-2(S)-ylmethyl]- N-(3-methoxybenzyl)glycylmethionine methyl ester; I-(Glycyl)pyrrolidin-2(S)-ylmnethyl]- N-(2-methoxybenzyl)glycylmethioninie; I-(Glycyl)pyrrolidin-2(S)-ylmethyl] N-(2-methoxybenzyl)glycylmethionine methyl ester; 1-(1 H-Imidazol-4-ylpropionyl)pyrrolidin-2(S).ylmethyl]. N-(2methoxybenzyl)glycyl-methionine; 1-(1H -Imidazol-4-ylpropi onyl)pyrrolidin-2(S)-ylmethyl] N methoxybenzyl)glycyl-methionine methyl ester; 1-(1 H-Imnidazol-4-ylacetyl)pyrrolidin-2(Sy..ylmethyl]p N-(3cyanobenzyl)glycyl-mnethionine; 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(Sy..ylmethyl]- N-(3cyanobenzyl)glycyl-methionine methyl ester; 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)ylmethyl]. N-(4cyanobenzyl)glycyl -methionine; 1-(1 H-ImidazoI-4-ylacetyl)pyrrolidin..2(S)-ylmethyl]- cyanobenzyl)glycyl.methionine; 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(SY..ylmethyl]. N-(2cyanobenzyl)glycyl-methioiipne methyl ester; WO 97/36587 W09716587PCTIUS97/05328 N- [1-(Glycyl)pyrrolidin-2(S)-ylmethyl]- N-(2-cyanobenzyl)glycyl methionine; 1 -(GlycyI)pyrrolidin-2(S)-ylmethyl] N-(2-cyanobenzyl)glycyl methionine methyl ester; 1-(1 H-Jmidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl]y N-(2cyanobenzyl)glycyl-methi onine; 1-(1 H-Imidazol-4-ylpropionyl)pyrroldin-2(S)-ylmethyl]- cyanobenzyl)glycyl-methionine methyl ester; 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(2methylbenzyl )glycyl-methionine; 1-(1 H-Lidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(2methylbenzyl)glycyl -methionine methyl ester; N- H-lmidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl] -(2 trifluoromethylbenzyl)glycyl-methionine; 1-(1 1--Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- N-(2trifluoromethylbenzyl)glycyl-methionine methyl ester; 1-(1 H-Imnidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]. 1naphthylsulfonyl)glycyl-methionine; 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl] 1naphthylsulfonyl)glycyl-methionine methyl ester; 1-(Glycyl) pyrrolidin-2(S)-ylmethyl]-N-( I-naphthylmethyl)glycylmethionine 4-N-methylpiperidinyl ester; WO 97/36587 WO 9736587PCTIUS97/05328 -91 I-(Glycyl) pyrrolidin-2(S)-ylmethyil-N-( I-naphthylmethyl)glycylmethionine tert-butyl ester; I-(Glycyl) pyrrolidin-2(S)-ylmethyl] -naphthylmethyl)glycylmethionine 3-pentyl ester; I-(4-Pynidyiglycyl) pyrrolidin-2(S)-ylmethyl]-N-( 1naphthylmethyl)gl ycy I-methi onine isopropyl ester; 1 H-Lidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl] N-(I I1naphthylmethyl)glycyl -methionine isopropyl ester; I-(4-Imidazoleacetyl)pyrrolidin-2(S)-ylmethyl] 1naphthylmethyl)glycyl-methionine methyl ester 0 HN

H

OMe

SCH

3 1 4 Im idazoleacety I)pyrro lid in-2(S) -y Imethy N- (I 1naphthylmethyl)glycyl-methionine isopropyl ester N 0

HN

SCH

3 1 -(Glycyl)pyrrolidin-2(S)-ylmethyl]-N.( I -naphthylmethyl)glycylmethionine WO 97/36587 WO 9736587PCTIUS97/05328 -92- 0 SCH3 I1 -(Glycyl)pyrrolidin-2(S )-ylmethyl] 1 -naphthylmethyl)glycyl methionine methyl ester 0

H

2

H

0 OMe

VCH

3 I -(Glycyl)pyrrolidin-2(S)-ylmethyl]-N-(I -naphthylmethyl)glycylmethionine isopropyl ester 0

H

2 N-A

H

0 Y'Oi-Pr

SCH

3 N -[1I -(L-Pyroglutamyl)pyrrolidin-2(S)-ylmethyl] -N-(I1 naphthylmethyl)g lycyl-methi onine

'SCH

3 WO 97/36587 WO 9736587PCTIUS97/05328 -93- 1 (L-PyroglutamylI)pyrro li din -ylmethyl] 1naphthylmethyl)glycyl-methionine methyl ester 0 N sCH3 1 H-Imidazol-4-ylacetyl)pyrroildin-3(S)-ethy[-2(S).

ylmethyloxy] -3 -phenylpropionyl-methionine methyl ester H N

H

CH

3 0

-OCH

3

SCH

3 1 H-Imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-.2(S)ylmethyloxy] -3 -phenylpropionyl-methionine 00

OH

3 SCH 3 I -(Sarcosyl)pyrrolidin-2(S)-ylmethyl]-N-( I -naphthylmethyl)glycylmethionie WO 97/36587 WO 9736587PCT/US97/05328 -94- 0 H H 0

H

3 CHNA

N

N .N

OH

0 S SCH 3 [I -(Sarcosyl)pyrrolidin-2(S )-ylmethyli]-N-( 1 -naphthylmethyl)glycyl methionine methyl ester

H

3 CHN H HN _A OMe 0

SCH

3 l-(N,N-Dimethylglycyl)pyrrolidin-.2(s)-ylmethyl].N-(I naphthylmethyl )glycyl-methi onine

(H

3

C)

2 N H N OA0H 0

SOH

3 Il-(N,N-Dimethylg Iycy)pyrroi din2(S) ylmethyl] N- (1 naphthylmethyl )glycyl-methionine methyl ester 0I H H 0 (HC)N A N N OMe 0

SCH

3 WO 97/36587 WO 9736587PCTIUS97/05328 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- 1naphthylmethyl)g Iycyl -acetyl amino) alanine methyl ester HN H H

N

N N

OCH

3 00H 1-(1 H-Lidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl]- 1naphthylmethyl)glycyl-(3-acetylarnino)alanine H N

H

HH

NH

OH

~O~<CH

3 1-(Glycyl) pyrrolidin-2(S)-ylmethyl] I-naphthylmethyl)glycyl (f 3 -acetylamino)alanine cyclohexyl ester 0 H2Ni&N- '00 N-[1I-(Glycyl) pyrrolidin-2(S)-yfrnethyl]-N-( I-naphthylmethyl)glycyl- (1-acetylamirio)alanine WO 97/36587 WO 9736587PCTIUS97/05328 -96- 0

H

2 N

AN-

0

OH

OXH

3 I 4 -Pyridylglycyl)pyrrolidin-2(S)-ylmethyl]-N.(I1 naphthylmethy I)glycyl-methionine. isopropyl ester

H

0-<

SCH

3 1 -(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl].N.( 1naphthylmethyl )g lycyl-methionine H 0H N OH

SCH

3 1-(1 H-Imidazol-4-ylacetyl)pyrrolidin..2(S).ylmethyl]. N-(2methoxybenzyl)glycyl-methionine

H

I N3 WO 97/36587 WO 9736587PCT1US97/05328 -97- 1-(1 H-lmidazol-4-ylacetyl)pyrrolidin-2(S)-yhnethyl]- N-(2methoxybenzyl)glycyl -methionine methyl ester -0

NQ

1-(Glycyl)pyrrolidin-2(S)-ylmethyl]- N-(2-methoxybenzyl)glycylmethionine methyl ester S OCH 3 S/ 0 N K I OCH 3 1 -(Glycyl)pyrrolidin-2(S)-ylmethyl]methionine

-OCH

3 N- (2-methoxybenzyl)gl ycy I-

S

K OH

H

2

N

0 1 H-Lmidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl]- N-(2methoxybenzyl)glycyl.methionine methyl ester WO 97/36587 WO 9736587PCT/US97/05328 -98- 1 H-JImidazol1-4 -ylpropi onyl)pyrrolldin.-2(S) ylmethy 1] N-(2methoxybenzyl)glycyl-methionine

OCH

3 0 1-(1 H-Lmidazol-4-ylacetyl)pyrrolidin-.2(S).ylmethyl]. N-(2cyanobenzyl)glycyl-methionine CN N OH ixN N-[Il-(1 H-lmidazol-4-ylacetyl)pyrrolidin-2(S)ylmethyl]- N-(2cyanobenzyl)glycyl-methionine methyl ester WO 97/36587 WO 9736587PCTJUS97/05328 -99- 0 I-(Glycyl) pyrrolidin-2(S)-ylmethyl] I-naphthylmethyl)glycylmethionine 4-N -methylpiperidinyl ester 0

H

2

N")AN,

OH

3

SCH

3 1-(1 H-Lmidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl] naphthylmethyl)glycyl-methionine isopropyl ester 0 HN

N

H 0

N

N 0

SCH

3 N- H-imi dazol-4-ylacetyl-2(S )-amino)-3(S)-methylpentyl]- -1,2,3 ,4tetrahydro-3 (S)-isoquinolinecarbonyl-methionine methyl ester; 1 H-imidazol -4-ylacetyl-2(S)-amino)-3(S)-methylpentyly. 1,2,3,4tetrahydro-3(S)-isoquinolinecarbonyl-methionine; WO 97/36587 WO 9736587PCTJUS97/05328 -100- [1 H-imidazol -4-ylacetyl)-3 (S)-ethylpyrrolidin-2(S)-ylmethyl] prolyl-methionine methyl ester; 1-(1 H-iniidazol-4-ylacety1)-3(S)-ethylpyrrolidin-2(S)-ylmethy]prolyl-methionine; [1 -Glycylpyrrolidin-2(S)-ylmethyl] -3(S )-ethylpro lyl-methionine methyl ester; I-Glycylpyrrolidin-2(S)-ylmethyl] -3(S)-ethyiprolyl-methionine; N- rL-Pyroglutamyl amino -3 (S )-methylpentyl 1 1,2,3 ,4-tetrahydro )-isoquinolinecarbonyl -methionine

SCH

3 0

HN

00 N 0 0 N-[L-Pyroglutamy1-2(S-amino-3(S)-methylpentyly.1 ,2,3,4-tetrahydro- 3 (S)-isoquinolinecarbonyl-methionine methyl ester

SCH

3 0 H

OCH

3 WO 97/36587 WO 9736587PCTIUS97/05328 -101- 1 H-imidazoI-4-ylacetyI)-pyrroidin-.2(S)ylmefiyl].3(S)ethyiprolyl-methionine

SCH

3 ,N 0 N O HN H0 1 H-imidazoI-4-yacetyl)-pyrroidin2(S-)ylnmethyl]-3(S)ethylprolyl-methionine methyl ester

SCH

3 p~H

OCH

3 H N H0 N- H-imidazol-4-ylacety1-2(S)-amino)-3(S)-methylpentyl]yproyi-.

methionine methyl ester

SCH

3 0

HNN

N- H-imidazolI-4-ylacetyl -2(S )-amino)- 3(S) )-methylpentyl ]-prolIylmethionine WO 97/36587 WO 9736587PCT/US97/05328 -102-

SCH

3 H

OH

N 0

HNN

00 I H-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyly. 1,2,3,4tetrahydro-3 (S)-isoquinolinecarbonyl -methionine methyl ester 1H-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyly. 1,2,3,4tetrahydro-3 (S)-isoquinolinecarbonyl-methionine N- rL-Pyroglutamyl-2(S)-amino-3 (8)-methylpentyl] -1,2,3 ,4-tetrahydro- 3 (S)-isoquinolinecarbonyl-methionine methyl ester N- [L-Pyroglutamyl-2(S)-amino-3 (S)-methylpentyl] -1 ,2,3 ,4-tetrahydro- 3 (S )-isoquinolinecarbonyl-methionine N- H -imidazolI-4-yl acetyl -2(S )-amino)-3 (S )-methylpentyl]I -prol yl methionine methyl ester N- [(1H-imidazol-4-ylacetyl-2(S)-aminoy..3(S )-methylpentyl] -prolylmethionine 1 H-imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)yylmethyl].

prolyl-methionine methyl ester 1 H -imidazol 4 -yl acety1)- 3 (S)ethylpyrro li din 2(S)-ylmethyly -prolyl-methionine 1 H-imidazo-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]y3(S)ethyiprolyl-methionine methyl ester WO 97136587 WO 9736587PCTIUS97/05328 -103- 1 H-imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3(S)ethyiprolyl-methionine [1 -G lycylpyrrolidin-2(S )-ylmethyl] -3(S )-ethylprolyl-methionine methyl ester N-[i -Glycylpyrrolidin-2(S)-ylmethyl] -3(5 )-ethylprolyl-methionine 2(S)-Butyl- 1 -(2,3-diaminoprop- Il-yl)-lI -naphthoyl)piperazine 1- Q(-Amino (2-naphthylmethy lamin o)prop 1 -yI)-2(S)-butyl-4-( 1naphthoyl)piperazine 2(S)-Butyl- 1- I I-(2-naphthylmethyl)]-4,5-dihydroimidazol) methyl-4- (1 -naphthoyl)piperazine 1- [5 -Benzylimidazol)methyll -2(S)-butyl-4-( 1 -naphthoyl)piperazine 1- I 1-(4-nitrobenzyl)]imidazoiylmethyl I -2(S)-butyl-4-( 1naphthoyl)piperazine 1 -(3-Acetamidomethylthio-2(R)-aminoprop- 1 -yI)-2(S)-butyl-4-( 1naphthoyl )piperazine 2(S)-Butyl- 1 1 -midazolyl)ethyl] sulfonylI-4-( I -naphthoyi)piperazine 2(R)-Butyl- 1 -imidazolyl-4-methyl-4-( 1 -naphthoyl)piperaz ine 2(S)-Butyl-4-( I -naphthoyl 1 -pyidylmethyl)piperazine I 2 (S)-butyl-( 2 4 -nitrobenzyl)amino-3-hydroxypropyl)>4-( 1naphthoyl)piperazine WO 97/36587 WO 9736587PCTIUS97/05328 -104- I -(2(R)-Amino-3 -hydroxyheptadecyl)-2(S )-butyl-4-( I -naphthoyl piperazine 2(S )-Benzyl- I -imidazolyl-4-methyl-4-( I -naphthoyl)piperazine 1 -(2(R)-Amino-3-(3-benzylthio)propyl)-2(S)-butyl-4.( 1naphthoyl)piperazine I -(2(R)-Amino-3 -[3-(4-nitrobenzylthio)propyl] )-2(S)-butyl 1naphthoyl)piperazine 2(S)-Butyl--I- [(4-imidazoly 1)ethyl] I -naphihoyl )piperazine )-Butyl -I -[(4-imidazolyl)methyll 1 -naphthoyl)piperazine 2(S)-Butyl- I -naphth-2-ylmethyl)- 1 H-imidazol-5-yl)acetyl]-4-(1 naphthoyl)piperazine 2(S)-Butyl- 1 -naphth-2-ylmethyl)- 1 H-imidazol-5-yI)ethyl]-4-(

I-

naphthoyl)piperazine 1 -(2(R)-Amino-3 -hydroypropyl)-2(S)-butyl 1 -naphthoyl)piperazine 1 -(2(R)-Amino-4-hydroxybutyl)-2(S)-butyl 1 -naphthoyl)piperazine I 2 -Amino-3-(2-benzyloxyphenyl)propyl)y2(S)-butyl.4-(I naphthoyl)piperazine I 2 -Amino-3-(2-hydroxyphenyl)propyl>2(S)butyl4.(I

I-

naphthoyi)piperazine 1 -(4-imidazo IyI)propyl] -2(S )-butyl-4-( 1 -naphthoyl)-piperazine WO 97/36587 WO 9736587PCTIUS97/05328 -105- 2 (S)-n-Butyl-4-(2,3-dimethylphenyl)- 1 -(4-imidazolylmethyl)- 2(S)-n-Butyl- I1- I1 -(4-cyanobenzyl)imidazol -5 -ylmethyl] 1- [1-(4-Cyanobenzyl)imidazol-5 -ylmethyl] ,3 -dimethyiphenyl 2 (S)-(2-methoxyethyl)pipe 2(S)-n-Butyl-4-(l -naphthoyl)- I1- [I ylmethyl] -piperazine 2(S)-n-Butyl 1 -naphthoyl)- 1-I -(2-naphthylmethyl)imidazol ylmethyl] -piperazine 2(S)-n-Butyl- 1 1-(4-cyanobenzyl)imidazol -5-ylmethyl] 1naphthoyl)piperazine 2(S)-n-Butyl- -I -(4-methoxybenzyl)imidazol-5 -ylmethyl]-4-( 1naphthoyl)piperazine 2(S)-n-Butyl- 1 -[1I 3 -methyl-2-butenyl)imidazol-5...ylmethyl 4(l 1naphthoyl)piperazine 2(S)-n-Butyl- 1-[rI 4 -fluorobenzyl)imidazol-5-ylmethyl]-4-(l 1naphthoyl)piperazine 2(S)-n-Butyl- 1 1-( 4 -chlorobenzyl)imidazols...ylmethyl 4(l 1naphthoyl)piperazine 1-El1 4 -Bromobenzyl)imidazol-5..ylmethyl] -2(S)-n-butyl-4-(1 naphthoyl)piperazine WO 97/36587 PTU9/52 PCTIUS97/05328 -106- 2(S)-n -Butyl-4-( 1 -naphthoyl)- [1-(4-trifluoromethylbenzyl )imidazol-5 ylmethyl] -piperazine 2(S)-n-Butyl -(4-methylbenzyl)imidazo 1-5-ylmethyl] 1naphthoyl)-piperazine 2(S)-n-Butyl- 1 -(3-methylbenzyl)imidazol-5-ylmethyl]-4-(1 naphthoyl)-piperazine [1 -(4-Phenylbenzyl)imidazol-5 -ylmethyl] -2(5 )-n-butyl-4-( 1naphthoyl)-piperazine 2(S)-n-Butyl-4-( I -naphthoyl)- I1-[lI piperazine 2(S)-n-Butyl-4-( 1 -naphthoyl)- 1 -(4-trifluoromethoxy)imidazol-5 ylmethyl]piperazine 1- I -(4-cyanobenzyl)- I H-imidazo l-5-yl] acetyl)I -2(S)-n-butyl-4-( 1naphthoyl)piperazine I -Cyanobenzyl)- 1 H -imi dazol -5 -yl)acetyl11pyrro lidin -2(Sy.ylmethyly 3(S)-ethyl-prolyl methionine 1-Cyanobenzyl 1H-imidazol -5 -yl)acetyllpyrrolidin-2(S)-ylmethyl]- 3(S)-ethyl-prolyl methionine methyl ester I1 -Cyanobenzyl)- 1 H-imidazol-5 -yl)acetyl]pyrrolidin-2(S)-ylmethyl] 3 -ethyl -prolyl methionine isopropyl ester 1-(1 H-Lmidazol-4-propionyl) pyrrolidin-2(S)-ylmethyl]-N-(2methoxybenzy l)glycyl-methionine isopropyl ester Compounds which are useful in the present invention, and methods of synthesis thereof, can be found in the following patents, pending applications and publications: 107 U.S. Pat. No. 5,717,100; GB 2306108; WO 95/32987 published on 7 December 1995; U.S. Pat. No. 5,420,245; European Pat. Publ. O 618 221; WO 94/26723; WO 95/08542; WO 95/11917; WO 95/12612.

U.S. Pat. No. 5,238,922 granted on August 24, 1993; U.S. Pat. No. 5,340,828 granted on August 23, 1994; U.S. Pat. No. 5,352,705 granted on October 4, 1994; U.S. Pat. No. 5,326,773 granted on July 5, 1994; U.S. Pat. No. 5,504,212; U.S. Pat. No. 5,686,472; U.S. Pat. No. 5,736,539; U.S. Pat. No. 5,576,293 U.S. Pat. No. 5,585,359; U.S. Pat. No. 5,523,456; 20 U.S. Pat. No. 5,585,359; U.S. Pat. No. 5,661,161; U.S. Pat. No. 5,585,359; U.S. Pat. No. 5,631,280; U.S. Pat. No. 5,578,629; 25 WO 96/34010; U.S. Pat. No. 5,856,326; WO 96/37204; U.S. Pat. No. 5,756,528; U.S. Pat. No. 5,972,984; All patents, publications and pending patent applications identified are hereby incorporated by reference.

The Raf antagonists are described herein using the terms defined below unless otherwise specified.

.The term "alkyl" refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 15 carbon atoms unless otherwise defined. It may be straight, [R:\LIBAA]08314.doc:kww 108 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.

Alkyl also includes a straight or branched alkyl group which contains or is s interrupted by a cycloalkylene portion.

Examples include the following: o*e *o Ioooo WO 97/36587 PCT/US97/05328 -109-

-(CH

2 )x 7 2 (CH 2

-(CH

2 )w (CH 2 wherein: x and y from 0-10; and w and z from 0-9.

The alkylene and monovalent alkyl portion(s) of the alkyl group can be attached at any available point of attachment to the cycloalkylene portion.

When substituted alkyl is present, this 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 nonaromatic (non-resonating) carbon-carbon double bonds may be present. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, I-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As 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 is provided.

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 carboncarbon triple bonds may be present. Preferred alkynyl groups 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 substituted WO 97/36587 PCTIUS97/05328 -110when a substituted alkynyl group is provided.

Aryl refers to aromatic rings phenyl, substituted phenyl and like groups as well as rings which are fused, naphthyl and the like. Aryl thus contains at least one ring having at least 6 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms. The preferred aryl groups are phenyl and naphthyl.

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 farnesyl transferase 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 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 atoms, or a bicyclic aromatic 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 1 to 3 additional carbon atoms are optionally replaced by nitrogen 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, oxazine, pyrazole, tetrazole, imidazole, pyridine, pyrimidine, pyrazine and triazine. Examples of partially aromatic groups are tetrahydroimidazo[4,5-c]pyridine, phthalidyl and saccharinyl, as defined below.

With regard to the farnesyl transferase inhibitors, the term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7membered monocyclic or stable 8- to 11-membered bicyclic or stable 11-15 membered tricyclic heterocycle ring which is either saturated or WO 97/36587 PCT/US97/05328 -111unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, 0, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydro-benzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2oxopiperidinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide, pyridonyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolinyl N-oxide, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.

Preferably, heterocycle is selected from imidazolyl, 2-oxopyrrolidinyl, piperidyl, pyridyl and pyrrolidinyl.

Substituted alkyl, aryl and heteroaryl, and the substituted portions of aralkyl, aralkoxy, heteroaralkyl, heteroaralkoxy and like groups are substituted with from 1-3 groups selected from the group consisting of: halo, hydroxy, cyano, acyl, acylamino, aralkoxy, alkylsulfonyl, arylsulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, alkyl, alkoxy, aryl, aryloxy, aralkoxy, amino, alkylamino, dialkylamino, and sulfonylamino.

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 WO 97/36587 PCT/US97/05328 -112- 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(C1-C6 alkyl)2, N02, CN, (C1-C6 alkyl)O-, -OH, (C-C6 alkyl)S(O)m-, (CI-C6 alkyl)C(O)NH-, H2N-C(NH)-, (C1-C6 alkyl)C(O)-, (Cl-C6 alkyl)OC(O)-, N3,(C1-C6 alkyl)OC(O)NH- and C1-C20 alkyl.

The terms "heterocycloalkyl" and "heterocyclyl" refer to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S(O)y or N, and in which up to three additional carbon atoms may be replaced by said heteroatoms. When three heteroatoms are present in the heterocycle, they are not all linked together.

Examples of heterocyclyls are piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, imidazolinyl, piperazinyl, pyrolidine- 2-one, piperidine-2-one and the like.

Acyl as used herein refers to -C(O)C 1 -6 alkyl and aryl.

Acylamino refers to the group -NHC(O)C 1 6 alkyl and -NHC(O)aryl.

Aralkoxy refers to the group -OC1I-6 alkylaryl.

Alkylsulfonyl refers to the group -S02C1- 6 alkyl.

Alkylsulfonylamino refers to the group -NHSO2CI-6alkyl.

Arylsulfonylamino refers to the group -NHSO2aryl.

Alkylaminocarbonyl refers to the group -C(O)NHCI 6 alkyl.

Aryloxy refers to the group -O-aryl.

Aralkoxy refers to the group -O-CI-6 alkylaryl.

Sulfonylamino refers to the group -NHSO3H.

Halo means Cl, F, Br and I selected on an independent basis.

Within -[C(O)(CH2)j-CR5R6-(CH 2 )k-NR7]p-R 8 there may be from I to 3 groups -[C(0)(CH2)j-CR5R6-(CH2)k-NR7].

Thus, -[C(O)(CH2)j-CR5R6-(CH2)k-NR7]p-R8 with p equal to 1, 2 or 3 means the following: WO 97/36587 PCT/US97/05328 -113- -C(O)(CH2)j-CR 5

R

6 -(CH2)k-NR 7

-R

8 -C(O)(CH2)j-CR5R6-(CH2)k-NR7-C(O)(CH2)j-CR5R6-(CH2)k-NR7R8; and C(O)(CH2)jCR 5

R

6 (CH2)kNR 7 C(O)(CH2)jCR5R6(CH2)kNR7C()(CH 2 )jCR5R6(CH 2 )kNR7R 8 Within these groups, the variables are determined independently. For example, when more than one j is present, they may be the same or different. When CR 5

R

6 is taken in combination, it represents a 3, 4, or 6 membered cycloalkyl or heterocyclyl group, an aryl group or a heteroaryl group. Examples of suitable cycloalkylene attachment are as follows: iq 3 -0

U

In each of the patterns of attachment noted above, the ring may also be heterocyclic as defined above.

WO 97/36587 PCT/US97/05328 -114- SN (Ra) 3 ad (Ra) 3 Na and are optional substituents linked to the HETCy group.

and independently represent mono or bicyclic ring systems, non-aromatic or partially aromatic, containing from 5-10 ring atoms, 1-4 of which are N and 0-1 of which are O or S(O)y, with y equal to 0, 1 or 2, and when partially aromatic, the non-aromatic portion thereof optionally containing 1-2 carbonyl groups. Hence, these ring systems can be heteroaryl or heterocyclic as defined above.

-N

Sis linked to HETCy through a nitrogen atom contained in the ring system, either directly or through a linking group which is part of Examples include phthalidyl and saccharinyl, as further defined below.

is likewise linked to HETCy, but through a carbon atom contained in the ring system.

The term phthalidyl refers to the heteroaryl group: 0 0 The te saccharinyl refers to the heteroaryl group: The term saccharinyl refers to the heteroaryl group: WO 97/36587 PCTIUS97/05328 -115- In the present method, amino acids which are disclosed are identified both by conventional 3 letter and single letter abbreviations as indicated below: Alanine Ala A Arginine Arg R Asparagine Asn N Aspartic acid Asp D Asparagine or Aspartic acid Asx B Cysteine Cys C Glutamine Gin Q Glutamic acid Glu E Glutamine or Glutamic acid- Glx Z Glycine Gly G Histidine His H Isoleucine Ile I Leucine Leu L Lysine Lys K Methionine Met M Phenylalanine Phe F Proline Pro P Serine Ser S Threonine Thr T Tryptophan Trp W Tyrosine Tyr Y Valine Val V The compounds used in the present method may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. Unless otherwise WO 97/36587 PCT/US97/05328 -116specified, named amino acids are understood to have the natural "L" stereoconfiguration The following structure:

H

2 )t represents a cyclic amine moiety having 5 or 6 members in the ring, such a cyclic amine which may be optionally fused to a phenyl or cyclohexyl ring. Examples of such a cyclic amine moiety include, but are not limited to, the following specific structures: N N N k N It is also understood that substitution on the cyclic amine moiety by R2a and R2b may be on different carbon atoms or on the same carbon atom.

When R 3 and R 4 are combined to form (CH2)s cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to: When R5a and R 5 b are combined to form (CH2)s cyclic moieties as described hereinabove for R 3 and R 4 are formed.

In addition, such cyclic moieties may optionally include a heteroatom(s).

Examples of such heteroatom-containing cyclic moieties include, but are not limited to: WO 97/36587 PCT/US97/05328 -117- S" 0 S 0 S S S O H O N 0

COR

10 The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, from non-toxic inorganic or organic acids. For example, such conventional 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, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenyl-acetic, glutamic, benzoic, salicylic, sulfanilic, 2 -acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.

It is intended that the definition of any substituent or variable R10, Z, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, -N(R 10)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth below.

The pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base with stoichiometric amounts or with an excess of the desired salt- WO 97/36587 PCT/US97/05328 -118forming inorganic or organic acid in a suitable solvent or various combinations 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, in the following works: Schroeder et al., "The Peptides", Vol. I, Academic Press 1965, or Bodanszky et al., "Peptide Synthesis", Interscience Publishers, 1966, or McOmie "Protective Groups in Organic Chemistry", Plenum Press, 1973, or Barany et al., "The Peptides: Analysis, Synthesis, Biology" 2, Chapter 1, Academic Press, 1980, or Stewart et al., "Solid Phase Peptide Synthesis", Second Edition, Pierce Chemical Company, 1984. Also useful in exemplifying syntheses of specific unnatural amino acid residues are European Pat. Appl. No.

0 350 163 A2 (particularly page 51-52) and J. E. Baldwin et al.

Tetrahedron, 50:5049-5066 (1994). With regards to the synthesis of instant compounds containing a (P-acetylamino)alanine residue at the C-terminus, use of the commercially available Na-Z-L-2,3diaminopropionic acid (Fluka) as a starting material is preferred.

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

DBU

DMAP

DME

DMF

EDC

HOBT

Et3N EtOAc

FAB

Acetic anhydride; t-Butoxycarbonyl; 1,8-diazabicyclo[5.4.0]undec-7-ene; 4-Dimethylaminopyridine; 1,2-Dimethoxyethane; Dimethylformamide; l-(3-dimethylaminopropyl)-3-ethyl-carbodiimidehydrochloride; 1-Hydroxybenzotriazole hydrate; Triethylamine; Ethyl acetate; Fast atom bombardment; -119- HOOBT 3-Hydroxy- 1,2,2-benzotriazin-4(3H)-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 of formula and are prepared in accordance with U.S. Patent No. 5,717,100. Two general methods for preparation of the imidazole nucleus are outlined.

In the first, a suitably protected picolyl alcohol is deprotonated with a strong base such as n-butyl lithium or lithium diisopropyl amide and the resulting anion is reacted with an appropriate N,O-dimethylhydroxamide to give a protected alpha hydroxy ketone. The protected alpha hydroxy ketone is then condensed with a suitably functionalized and *t protected aminoaldehyde in the presence of ammonium acetate, acetic 20 acid and copper acetate.

The aldehydes typically used contain a suitably protected nitrogen atom. After the imidazole nucleus has been formed, the nitrogen is deprotected and then reacted with an appropriate electrophilic reagent to provide the final compounds.

25 In the second method, a suitably protected pidolyl alcohol is deprotonated with a strong base such as n-butyl lithium or lithium diisopropyl amide and the resulting anion is reacted with an appropriate aryl or alkyl aldehyde to give a mono-protected diol. The protecting group is removed and the resulting diol is oxidized (by the method of Swem or Moffat) to a dione. The dione is then condensed with a suitably functionalized and protected aminoaldehyde in the presence of ammonium acetate in acetic acid to give the imidazole.

In this same manner, the nitrogen is deprotected and then reacted with an appropriate electrophilic reagent to provide the Scompounds of formula I.

WO 97/36587 WO 9736587PCT/US97/05328 -120- Scheme 1

NN

TBDMSO

1.n-BuLi 0

/ON~

I

OTBDMS

Cu(OAc) 2

NH

4 OAc AcOH R= Boc or Cbz LiAIH 4

I+

N- j Electrophile

N

R ~IH WO 97/36587 WO 9736587PCTIUS97/05328 -121- Scheme 2

TBDMSO

1. n-BuLi

OH

NH

4 OAc HOAc SN-C bz 0

C

NR'

L~iAIH 4 I HBr Me WO 97/36587 WO 9736587PCT[US97/05328 -122- Scheme 3

TBDMSO

1. n-BuLi DMS

TBAF'

OH

0 HAy'OOM OMe

NH

4 OAc -N HOAc N-Cbz 0 H H0 LiAIH 4 N R HBr

N-

Me OMe HBr or B Br 3

OH

WO 97/36587 WO 9736587PCTJUS97/05328 -123- Scheme 4

NN

TBDMSO

1. n-BuLi

OTBDMS

0 R CI, OMe, or Cbz

FR

LiAIH 4

I+

IElectrophile N E N N R H WO 97/36587 WO 9736587PCTIUS97/05328 -124- Scheme EtO

LDAL

N, R-1 NaOH

H

Boo or Cbz 0 R Alkyl, Benzyl

EDO

NHMeOMe

LAH

0- Cu(OAC) 2

NH

4 OAc AcOH WO 97/36587 PCTIUS97/05328 -125-

N-

NR"

H

H+

R

LiAIH 4

N

N- K N

N-H

N N SN-Me RI'R Electrophile H

N

R

IH

RT H TBDMSO refers to t-butyldimethylsilyloxy, TFAA refers to trifluoroacetic anhydride, TBDMS refers to t-butyldimethylsilyl, TBAF refers to tetrabutyl ammonium fluoride, Cbz refers to carboxylbenzyl, Ac refers to acetyl, and LDA refers to lithium diisopropyl amide.

E represents an electrophile attached to the heterocyclic ring nitrogen atom. Examples of suitable electrophiles include alkyl halides, alkyl triflates, alkyl mesylates, benzyl halides, vinyl pyridine and the like. Hence, E represents alkyl, benzyl, vinyl and the like.

The compounds are useful in various pharmaceutically Sacceptable salt forms. The term "pharmaceutically acceptable salt" refers to those salt forms which would be apparent to the pharmaceutical chemist. those which are substantially non-toxic and which provide the desired pharmacokinetic properties, palatability, absorption, WO 97/36587 PCT/US97/05328 -126distribution, metabolism or excretion. Other factors, more practical in nature, which are also important in the selection, are cost of the raw 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 non-toxic salts or quarternary ammonium salts formed, 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, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods.

Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired saltforming inorganic or organic acid or base, in a suitable solvent or solvent combination.

Compounds of formula (1-c)

R

2 R

N

2

-R

3 (I-c) R4N S may be prepared using procedures described in PCT/US94/08297 published on 2 February 1995 and in U.S. Application No. 60/005,521 filed on October 13, 1995. Suitable procedures are also described in U.S. Patent Nos. 3,707,475 and 3,940,486.

WO 97/36587 PCT/US97/05328 -127- The Raf antagonists described herein are useful in various pharmaceutically acceptable salt forms. The term "pharmaceutically acceptable salt" refers to those salt forms which would be apparent to the pharmaceutical chemist, those which are substantially non-toxic and which provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion. Other factors, more practical in nature, which are also important in the selection, are cost of the raw 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.

The pharmaceutically acceptable salts can be synthesized by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base, in a suitable solvent or solvent combination.

The faresyl transferase inhibitors of formula (II-a) through (II-c) can be synthesized in accordance with reaction 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 substituents

R

2

R

3

R

4 and R 5 however their point of attachment to the ring is illustrative only and is not meant to be limiting.

WO 97/36587 PCT/US97/05328 -128- These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Reaction Schemes.

Synopsis of reaction Schemes 1-16: The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures, for the most part. In Scheme 1, 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 Organic Preparations and Proceedings Int., 1990, 22, 761-768. Boc-protected amino acids I, available commercially 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 as DCC (dicyclohexycarbodiimide) or EDC-HCI -ethyl- 3-(3-dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such as methylene chloride chloroform, dichloroethane, or in dimethylformamide. 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 as the Boc derivative V. The N-benzyl group can be cleaved under standard conditions of hydrogenation, 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 dehydrating conditions to furnish the carboxamides VII. A final acid deprotection step gives the intermediate VIII (Scheme Intermediate VIII can be reductively alkylated with a variety of aldehydes, such as IX, prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses, 1988, 67, 69-75, from the appropriate amino acid (Scheme The reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride WO 97/36587 PCT/US97/05328 -129or sodium cyanoborohydride, in a solvent such as dichloroethane, methanol or dimethylformamide. The product X can be deprotected to give the final compounds XI with trifluoroacetic acid in methylene chloride. The final product XI is isolated in the salt form, for example, as a trifluoroacetate, 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 XIII. Removal of the protecting group, and conversion to the cyclized product such as the dihydroimidazole XV, can be accomplished by literature procedures.

Alternatively, the protected piperazine intermediate VII can be reductively alkylated with other aldehydes such as 1-trityl-4carboxaldehyde or l-trityl-4-imidazolylacetaldehyde, to give products such as XVI (Scheme IV) (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 acylated or sulfonylated by standard techniques. The imidazole acetic acid XIX can be converted to the acetate XXI by standard procedures, and XXI can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XXII. Hydrolysis and reaction with piperazine VIII in 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 in Scheme 6, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 6, 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, 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 or tertiary amines.

WO 97/36587 PCT/US97/05328 -130- The protected amino alcohol XXVII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXXII (Scheme 8).

Treating XXVII with 1,1'-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 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 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 3-benzyl ester of aspartic acid, the intermediate diketopiperazine XLII (where n=1 and R=benzyl) is obtained, as shown in Scheme 10. 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 conditions, for example, sodium hydride in dimethylformamide or tetrahydrofuran. The resulting ether 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 bis -chloroethyl amine hydrochloride (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.

can be prepared as shown in Scheme 12.

Reductive amination of protected amino aldehydes XLIX (prepared from I as described previously) gives rise to compound L. This is then reacted with bromoacetyl bromide under Schotten-Baumann conditions.

Ring closure is effected with a base, such as sodium hydride, in a polar WO 97/36587 PCT/US97/05328 -131aprotic solvent, such as dimethylformamide, to give LI. The carbamate protecting group is removed under acidic conditions, such as trifluoroacetic acid in methylene chloride or hydrogen chloride gas in methanol or 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 arylcarboxamides LII and 2aminoglycinal diethyl acetal (LIII) can be reduced under a variety of conditions, including sodium triacetoxyborohydride in dichloroethane, to give the amine LIV. Amino acids 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 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, with trifluoroacetic acid, 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 described in Schemes 3-9.

Reaction Scheme 15 provides an example of the synthesis of compounds wherein the substituents R 2 and R 3 are combined to form (CH2)u For example, l-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 intermediate LXIX can be deprotected as before, and carried on to final products 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-substituents on the piperazine.

The aldehyde XLIX from Scheme 12 can also be reductively alkylated with an aniline as shown in Scheme 16. The WO 97/36587 PCT/US97/05328 -132product LXXI can be converted to a piperazinone by acylation with chloroacetyl chloride to give LXXII, followed by base-induced 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 solvolysis with a lower alkyl alcohol, such as methanol, or treatment with triethylsilane in methylene chloride in the presence of trifluoroacetic acid gives the final product LXXVII.

SCHEME 1 iO RaO H O Rb PhCH 2

NHCHCO

2

C

2

H

DCC, CH 2

CI

2 n_ I 0 Ra >O N N C0 2

C

2

H

H O Rb 1) HCI, CH 2

CI

2 2) NaHCO 3 Ra

O

HN N O Rb

III

LAH

THF, reflux

R

a HN N- Rb Boc 2

O

CH

2

CI

2 Ra

H"

0 10% Pd/C 0 SRb H2 CH 3 OH O Rb V VI WO 97/36587 WO 9736587PCTIUS97/05328 -133- SCHEME 2 Ra El BocN NH VI Rb BooN N4 R b ViI HCINN4 bo )C-HCI, HOBT

)MF

HCI, EtOAc WO 97/36587 WO 9736587PCT/IJS97/05328 -134- SCHEME 3

HOI

Boc NH I ix Boc NH CHO NaBH(OAc)3

EI

3 N CICH 2

CH

2 Ci Boc NH LcN N- NHBoc R b x C F 3 00 2

H

CH

2

CI

2

BOC

2 0 0H 2

CI

2

NH

2 BocNH N N-

NH

2 R

CI>CHO

'IN

NaBH(OAc)3 Et 3 N CICH 2

CH

2 Ci WO 97/36587 WO 9736587PCT/US97/05328 -135- SCHEME 3 (Cont.) BocNH N N NH R'

NH

2 N NR- NH Rb

XIV

CF

3

CO

2 H, CH 2

CI

2 NaHCO 3

NC

AgCN A~

R\/

N N N Rb WO 97/36587 WO 9736587PCT/US97/05328 -136- SCHEME 4

HOL

NaB H(OAC) 3 Et 3 N CICH 2

CH

2

CI

(C H 2 )nCHO

N

Tr 1) Ar CH 2 X, CH 3

CN

C12 2) CF 3

CO

2 H, CH 2 CI2 Cl 2

(C

2

H

5 3 SiH R b xv'

CF

3

CO

2 H, CH 2

(C

2

H

5 3 S1 H R b xvi'I 4a xv"'l WO 97136587 WO 9736587PCTIUS97/05328 -137- SCHEME

CH

3 0H

HO!

0- H 2 00 2

H

N

H

.HO!

XIX

(06 H 5 3 OBr 4-

(C

2

H

5 3 N N DMF Tr XXI Ar-- N CH 2 00 2

CH

3 2.

N XXI I

CH

2 00 2

H

N XXIII 31) ArCH 2 X OH 3

CN

ref lux 2) OH 3 OH, reflux 550C A r CH 2 00 2

H

N

Nxl HOJ-HN N4I Rb Vill EDO*- HCI HOBt

DMF

.H01 Ar"

XXIV

WO 97/36587 WO 9736587PCTIUS97/05328 -138- SCHEME 6 Ra E HCI N N- R b Vill BnO N N4':- NHI ocR Rb HO NN4 NHBoc Rb XX VII NaB H(OAC) 3 t 3 N CICH 2

CH

2

CI

BnOI BooN H CHO

XXV

20% Pd(OH) 2

H

2

CH

3 0H

CH

3

CO

2

H

cIcOCOCI DMSO

CH

2

CI

2

(C

2

H

5 3

N

1. R'MgX

(C

2

H

5 2 0 2. TFA, 0H 2 C1 2 XX VIII _4\b 0 R' NH 2 Rb

XXIX

WO 97/36587 WO 9736587PCT/US97/05328 -139- SCHEME 7 HO NHBoc R b

CF

3 00 2

H

CH

2 01 2 xxviI Ra \f

R'CHO

NaB H(OAc) 3

CICH

2

CH

2

CI

NH

2 R b xxx HO N N NH R b

R'CH

2

XXXI

WO 97/36587 WO 9736587PCTJUS97/05328 -140- SCHEME 8 HO N

NK

NHBoo R b XXVII N N- <Nr R b H XXXII H H 02 NaH, DMF 000

R'SH

(0 2

H

5 3 N

A

CH

3 0H

NH

2

XXXIII

WO 97/36587 WO 9736587PCT[US97/05328 -141- SCHEME 9 1) Boc 2 O, K 2 C0 3 TH F-H 2 0 2) CH 2

N

2 EtOAc

HO

BocNH

CO

2

CH

3

H

2

N

XXXIV

XXXV

LiAIH 4

THF

0-200C

HO

-I

BocNH CH 2 0H

R'CH

2

X

CS

2 00 3

DMF

XXXVI

R'CH

2

O,

pyridine

DMSO

(C 2

H

5 3

N

200C

R-CH

2

O

BocNH CHO

CH

2 0H

XXXVII

XXXVIII

WO 97/36587 WO 9736587PCT1US97/05328 -142- SCHEME 9 (continued) R'0H 2 0 BocNH CHO HCL-N N- Rb xxxv"'l NaB H(OAC) 3

CICH

2

CH

2

CI

R'C H 2 0'

HOI

ETOAc 1) 20% Pd(OH) 2

CH

3 OH, CH 3

CO/

2

H

2) HCI, EtOAc xxxix

'NH

2 R b WO 97/36587 WO 9736587PCTIUS97/05328 -143- C0 2

R

HN N 0b

XLII

1) LAH, Et 2

O

2) BoC 2 O0

XLIII

R 6 1 NaH, DMF0 0 SCHEME 11 Rb

XLVI

XLIV

ArNH 2

XLV

n butanol ref lux Ra R b ArN NH -HCI RaR b XL VII WO 97/36587 WO 9736587PCTIUS97/05328 -144- SCHEME 12 0 oN yOH

H

0 o

CH

3

NHOCH

3

-HG!

EDO. HC!, HOBT DMF, Et 3 N, pH 7 >Lo ON H-I N(CH 3

)OCH

3 H 0 XL VIII LAH, Et 2

O

0 Ra

H

0 o

XLIX

o N ),NHCH 2 Ar

H

L

ArCH 2

NH

2 NaB H(OAC) 3

CICH

2

CH

2

CI

pH 6 1) BrCH 2 C0Br EtOAc, H 2 0, NaHCO 3 2) NaH, THF, DMF O0)~ 1) TFA, CH 2

GI

2 HN N Ar 0 WO 97/36587 WO 9736587PCTIUS97/05328 -145- SCHEME 13 ArCHO NH 2

CH

2 CH(0C 2

H

5 2 NaBH(OAC) 3 Ar CH 2

NHCH

2 CH(0C 2

H

5 2

LIV

0c Ra N ,JOH I H 0 EDO. HOI, HOBT DMF, Et 3 N, pH 7 0 Ra r Ar 'kN KrN--CH(OCAH) 2 H 0 6N HOI

THF

Ar

H

2 1 O%Pd/C

CH

3 0H Ra 0 Ar

LVII

WO 97/36587 WO 9736587PCT/US97/05328 -146- SCHEME 14 R b v1) CF 3 00 2 H, CH 2

CI

2 2) NaHCO 3

-N

-N-

Ha NH ArCO 2

H

EDO*- HCI HOBT, DMF

LVIII

R b H- Ar Pd C

H

2 C H 3 0OH R b -j Ar WO 97/36587 WO 9736587PCTIUS97/05328 -147- SCHEME BocNH CO 2

H

PhCH 2

NHCH

2 00 2

C

2

H

DCC, CH 2

CI

2 BocNH N -C.-C 2 C0 0 LXII a) TFA, CH 2

CI

2 b) NaH 003 (C H 3 3

AI

CHCI

3

LXIII

HN N-b LiAIH 4

THF

LXIV

BoC 2

O

CH

2

CI

2 HN N

LXV

H

2 Pd/C

CH

3 0H

LXVI

WO 97/36587 WO 9736587PCTIUS97/05328 -148- SCHEME 15 (continued)

COD

BocN\-- NH NaHCO 3 EtOAc

LXVII

a) TFA, CH 2 01 2

U

0 0b) NaB H(OAc)., BocN N C(=O)H LXVIII N OP h 3 0 TFA CH 2

CI

2 N N /N

(C

2

H

5 3 SiH N CPh 3

LXIX

N N- N

N

H .2 TFA

LXX

WO 97/36587 WO 9736587PCTIUS97/05328 -149- SCHEME 16 R

H

AN H2BocNH _I N Ar BocNH ',CHO

XLIX

NaBH(UAc) 3

CICH

2

CH

2

CI

LXX I 0 CI-- c EtOAc

H

2 0 NaHCO 3

R

BocNH NA cf 0 LXXII NaH

DMF

BocN N-Ar LXXIII 0

HCI

EtOAc

R

HCFHN N-Ar 0

LXXIV

CHO

N.

C(Ph) 3 NaBH(OAc) 3

CICH

2

CH

2

CI

pH 5-6

R

N N-Ar

N

(Ph

LXXV

WO 97/36587 PCT/US97/05328 -150- Scheme 6 (Continued) ArCH 2

X

CH

3

CN

R

Ar- /N N-Ar N® X (Ph) (Ph)3 X

LXXVI

MeOH or TFA, CH 2

CI

(C

2

H

5 3 SiH

R

Ar-\ N N-Ar N L LXXV II The famesyl transferase inhibitors can be synthesized in accordance with the general reaction schemes in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Some key bond-forming and peptide modifying reactions are: Reaction A Amide bond formation and protecting group cleavage using standard solution or solid phase methodologies.

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

WO 97/36587 PCT/US97/05328 -151- 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.

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

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

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

-K

H

2 )t which can be substituted with R4a, R4b, R7a and R7b in accordance with structures (II-d) through These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Reaction Schemes.

WO 97/36587 WO 9736587PCTIUS97/05328 -152- REACTION SCHEME A Reaction A. COUnlirng of residues to form an amide bond 0KI R A H 0

RB

H

2 N

OR

0 0 EDO, HOBT or HOOBT Et 3 N, DMF HOI or

TFA

0 ko

A,

R A H 0

H

2 N -N 'ORC 0

RB

WO 97/36587 WO 9736587PCTIUS97/05328 -153- ALTERNATIVE REACTION SCHEME A FOR COMPOUNDS (1l-h) THROUGH (11-o) Coupling of residues to form an amide bond 0

RA

yOH 0 N H 0 R 4 b EDO, HOOT or HOOBT Et 3 N, DMF HCI or

TFA

R 0

R

4 b WO 97/36587 WO 9736587PCTIUS97/05328 -154- REACTION SCHEME B Preparation of reduced peptide subunits by reductive alkylation O

RA

O) N J

H

H 0

H

2 N yORC 0 NaCNBH 3 0 R AH N

N

H

0

RBORC

ALTERNATIVE REACTION SCHEME B FOR COMPOUNDS (11-h) THROUGH (I-o) Preparation of reduced peptide subunits by reductive alkylation O R A CO 2

R

0 N 1,rH

H

H (0Q 0 NaCNBH 3

H

O N 0 R 4b WO 97/36587 PCT/US97/05328 -155- REACTION SCHEME C Alkylation/reductive alkylation of reduced peptide subunits

SR

A

SR

7 bL, base 0 N N- ORC or H RB

O

I I RYCH, NaCNBH 3

R

A

R

7 b O N ORC

H

RB

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

WO 97/36587 WO 9736587PCT[US97/O5328 -156- ALTERNATIVE REACTION SCHEME C for-COMPOUNDS (11-h) THROUGH (11-o) Deprotection of reduced peptide subunits 0 2

R

0

H

2

NN

RA(

TFA or

HOI

R 4 b

CO

2

R

RA Q R 4a;: R 4 b REACTION SCHEME D Coupling of residues to form an amide bond

RHA

0 N jjOH H 0 EDO, HOBT or HOOBT Et 3 N, IDMVF

H

2

N'

RHA

0 jyH 0HCI or TFA N N 0 H 0 o

RHA

H 0

H

2 N N 0 WO 97/36587 WO 9736587PCTIUS97/05328 -157- ALTERNATIVE REACTION SCHEME D FOR COMPOUNDS (11-h) THROUGH (11-o) Coupling of residues to form an amnide bond EDC, HOET or HOOBT I I 0 Et 3 N, DMF R 4b 0 0 H 0

Q

R 4aT R4 HCI or TFA R 4b WO 97/36587 PCT/US97/05328 -158- REACTION SCHEME E Preparation of reduced dipeptides from peptides 0 RA 0 N ORc BH 3

THF

0 RB 0

O

R

A 0 N ORc

RB

ALTERNATIVE REACTION SCHEME E FOR COMPOUNDS (ll-h) THROUGH (11-o) Preparation of reduced dipeptides from peptides

H

ON

0

S'CO

2

R

RA

Q

4a 4 b R4a

BH

3

THF

All variables are as defined above.

Certain compounds wherein X-Y is an ethenylene or ethylene unit are prepared by employing the reaction sequences shown 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, WO 97/36587 PCT/US97/05328 -159ester hydrolysis, peptide coupling reaction, mesylation, cleavage of peptide protecting groups, reductive alkylation, etc., as may be known in the literature or exemplified in the Experimental Procedure. For simplicity, substituents R 2 a and R 2 b on the cyclic amine moiety are not shown. It is, however, understood that the reactions illustrated are also applicable to appropriately substituted cyclic amine compounds. The key reactions are: stereoselective reduction of the Boc-aminoenone to the corresponding syn aminoalcohol (Scheme F, Step B, Part and stereospecific boron triflouride or zinc chloride activated organomagnesio, organo-lithio, or organo-zinc copper(l) cyanide SN2' displacement reaction (Scheme F, Step Through the use of optically pure N-Boc amino acids as starting material and these two key reactions, the stereochemistry of the final products is well defined. In Step H of Scheme F, the amino terminus 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 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.

WO 97/36587 WO 9736587PCTIUS97/05328 -160- REACTION SCHEME F Boo O

AOH

CICO

2 i-Bu MeONHMe 2 B rM g Boo Step A 1. NaBH 4 2. AC 2 O, Py Step B 1. 03, Me 2

S

2. Ph 3

P=CHCO

2 Me Bo OAc Bo OAc

~~~CO

2 Me Step C WO 97/36587 WO 9736587PCTIUS97/05328 -161- REACTION SCHEME F (CONTD) Step D 1. LiOH Step E 2. EDO, HOBT amino acid (ester) E= OMe, Ell SMe El- Ell 0 H2)t 0 H 0

N"

MsCI, py Step F Boo c 0

F

1 R 3 Mg CuON CI BF 3 Step G Boo H 0 N

E

1. HO! 2. NaCNBH 3 RxCHO Step H RxCH 2

HH

N

wherein KR9 RX =(R 8 )r V Al(OR A 2 )A (ORl 2 )n (CRlb) a WO 97/36587 WO 9736587PCTIUS97/05328 -162- REACTION SCHEME F (CONT'D) NaOH RxCH 2 R 3 0

H

N

0 OH t 0El o r 1. HCI 0 11 2. RxCOH EDC, HOBT 0 Rx--\ Alternate Step H H 0

N

I NaOH 0 Rx--l HA 0 H 0

N

OH

I

WO 97/36587 WO 9736587PCTIUS97/05328 -163- REACTION SCHEME G Boo

OH

1. NaBH4 C'C0 2 '-Bu MeON HMe 2BrMg s-, Boc Boo 0 (2) 1. 03, Me 2

S

2. Ph 3

P=CHCO

2 Me 2. AC 2 O, py BoOAc 0 ~CO 2 Me

HN,,

H

2 )t K/L 1. LiGH 2. EDC, HOBT MsCI, py BoOH 0 WO 97/36587 WO 9736587PCTIUS97/05328 -164- REACTION SCHEME G (CONT'D) Boc OMS HO 00 1. R 3 MgCuCNCI*BF 3 2. H 2 5% Pd/C 1. HOI 2. NaCNBH 3

RKCHO

NaOH WO 97/36587 PCT/US97/05328 -165- REACTION SCHF.ME G (rnNT'D) REACTIONSCHEFP Q(CC)MT'Th'\ or 1. HCI 0 Rx 0

II

2. RXCOH EDC, HOBT NaOH 0 Rx

R

3 H2)t 0 0

OH

,,,OH

The oxa isostere compounds of this invention are prepared according to the route outlined in Scheme H. An aminoalcohol 1 is acylated with alpha-chloroacetyl chloride in the presence of trialkylamines to yield amide 2. Subsequent reaction of 2 with a deprotonation reagent 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 (1,2-dimethoxyethane) in the presence of a suitable base, preferably NaHMDS [sodium bis(trimethylsilyl)amide], affords 4, which is S retreated with NaHMDS followed by either protonation or the addition of an alkyl halide R4X to give 5a or 5b, respectively, as a enantiomeric mixture. Alternatively, 5a can be prepared from 3 via an aldol WO 97/36587 PCTIUS97/05328 -166condensation approach. Namely, deprotonation of 3 with NaHMDS followed by the addition of a carbonyl compound RYRzCO gives the adduct 6. Dehydration of 6 can be effected by mesylation and subsequent elimination catalyzed by DBU (1,8-diazabicyclo[5.4.0] undec-7-ene) or the direct treatment of 6 with phosphorus oxychloride in pyridine to give olefin 7. Then, catalytic hydrogenation of 7 yields (wherein -CHRYRz constitutes R 3 Direct hydrolysis of 5 with lithium hydrogen peroxide in aqueous THF, or aqueous HC1, produces acid 8a. Compound 8a is then derivatized with BOC-ON or BOC anhydride to give 8b. The peptide coupling of acid 8b with either an alpha-aminolactone homoserine lactone, etc.) or the ester of an amino acid is carried out under the conditions exemplified in the previously described references to yield derivative 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 H-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 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 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 [Ruth E.

TenBrink, J. Org. Chem., 52, 418-422 (1987)].

WO 97/36587 WO 9736587PCT/UJS97/05328 -167- SCHEME H C

I

base 0 0 N H 2 )t a Base

R

3

X

Base RyRzCO HO J 0~I

(H

2 )t 4 Base R 4 X or R 4

H

5.1: R 4 substituent 0

H

2 Pd/C

-H

2 0 WO 97/36587 WO 9736587PCTIUS97/05328 -168- SCHEME H (CONT'D) 1. LiOOH; or aq. HOI, n 2. BOC 2 0 a, Rw H b, R' BOO

EDC

HOBT

BocR

A

0

HCI

0 0 0 or N H,,

OR'

WO 97/36587 WO 9736587PCTIUS97/05328 -169- SCHEME H- I 0 11

CF

3

C)

2 0 O OH

CF

3

C""

(H

2 )t Ph-S-S-Ph nBU 3

P

0 SPh 11

CF

3 C~ 16 '1 HO

CO

2 Me AgCIO 4 SnCI 2 4A Mol. sieves N-ohio rosuccinimide O PhS 11

CF

3 C ~I

CO

2 Me Raney Ni WO 97/36587 PCTIUS97/05328 -170- SCHEME H-I (CONT'D)

O

II

I

19H2) 0 19

R

3 4

C

2 Me 2CO2Me 1. aq. HCI 2. BOC) 2 0 Boc

R

3 R4 O CO,2H H2)t

HCI-

HCI

H-A

EDC

HOBT

-CI H The thia, oxothia and dioxothia isostere compounds of this invention are prepared in accordance to the route depicted in Scheme I.

Aminoalcohol 1 is derivatized with BOC20 to give 25. Mesylation of 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-isopropylethylamine leads to lactam 27. Sequential alkylation of 27 with the alkyl halides R 3 X and R 4 X in THF/DME using NaHDMS as the deprotonation reagent produces 28. Hydrolysis of 28 in hydro-chloride to yield 29a which is derivatized with Boc anhydride to yield 29b. The coupling of 29b with an alpha-aminolactone homoserine lactone, etc.) or the ester of an amino acid is carried out under conventional conditions as WO 97/36587 PCT/US97/05328 -171exemplified in the previously described references to afford 30. Sulfide 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 gaseous hydrogen chloride.

SCHEME I

HO

BocN

(CH

2 )t 1)TFA

S

2) (i-Pr) 2

N

NEt 27 1) MsCI 2) Cs 2

CO

3

HSCH

2

CO

2

CH

3

"(CH

2 1 1) R 3

X,

Base 2) R 4

X,

Base

HCI

H

2 0 ;H2)t WO 97/36587 PCT/US97/05328 -172- SCHEME 1 (Continued) Rw

R

3

R

4 S

CO

2

H

H2)t 29 a, RW=H D BOC 2 0 b, RW=BOC' H-A, EDC

HOBT

Boc N^

R

3

R

4

A

0 0 NH,. O 0 q 0 or NH OR 6 R OR 6 Boc R R4 (0H2) t

O

C S(O)?

A

HCI

m=0, 30 m=2 31

MCPBA

HCI H R 3

R

4

(H

2 )t O 32 m 0 or 2 Reaction Schemes J R illustrate reactions wherein the nonsulfhydryl-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 WO 97/36587 PCT/US97/05328 -173that the reactions illustrated may also be performed on a simple cyclic amino acid, which may then be further elaborated utilizing reactions described in Reaction Schemes A- I to provide the instant compounds.

The intermediates whose synthesis are illustrated in Reaction Schemes A-I can be reductively alkylated with a variety of aldehydes, such as V, as shown in Reaction Scheme J. The aldehydes can be prepared by standard procedures, such as that described by O. P. 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 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 compounds VII. The final product VII is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine VII can further be selectively protected to obtain VIII, which can subsequently be reductively alkylated with a second aldehyde to obtain IX. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XI can be accomplished by literature procedures.

Alternatively, the protected cyclic aminopeptidyl intermediate can be reductively alkylated with other aldehydes such as l-trityl-4-carboxaldehyde or 1-trityl-4-imidazolylacetaldehyde, to give products such as XII (Reaction Scheme The trityl protecting group can be removed from XII to give XIII, or alternatively, XII can first be treated with an alkyl halide then subsequently deprotected to give the alkylated 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 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 WO 97/36587 PCT/US97/05328 -174intermediate in the presence of condensing reagents such as 1-(3dimethylaminopropyl)-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 hydroxyl group, such as XX in Reaction Scheme N, the protecting groups can be subsequently removed to unmask the hydroxyl group (Reaction Schemes N, 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 XXIV. In addition, the fully deprotected amino alcohol XXV can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXVI (Reaction Scheme or tertiary amines.

The Boc protected amino alcohol XXII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXVII (Reaction Scheme Treating XXII with 1,1'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXVII The aziridine may be reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ringopened product XXVIII.

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 XXXIV, as shown in Reaction Scheme R. When R' is an aryl group, XXXIV can first be hydrogenated to unmask 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.

WO 97/36587 WO 9736587PCTIUS97/05328 -175- REACTION SCHEME J Bo NH

V

Boo NH CHO R 4b NaBH(OAc)3 Et 3 N CCH 2

CH

2

CI

NH

2

R

NH

2

VII

R 4a~i R4 NHBoo Boc NHF

R

Q

VIR4a R 4b C F 3

CO

2

H

CH

2

CI

2 BoC 2

O

CH

2

CI

2

.NH

2 BocNH Vill

R

C

CHO

NaB H(OAc)3 Et 3 N, CICH 2

CH

2

CI

R 4b wherein

H

0 Nq WO 97/36587 WO 9736587PCT/US97/05328 -176- REACTION SCHEME J (continued)

R

BocNHf-.

Ix 4 b

CF

3

CO

2 H, CH 2

CI

2 NaHCO 3

NC

AgCNA R 4 b WO 97/36587 WO 9736587PCTIUS97/05328 -177- REACTION SCHEME K

(CH

2 )nCHO

N-

R 4 b Tr NaBH(OAc) 3 Et 3 N CICH 2

CH

2

CI

NNJ

CF

3

CO

2 H, CH 2

CI

2

(C

2

H

5 3 SiH R 4 b 1) Ar CH 2 X, CH 3

CN

2) CF 3

CO

2 H, CH 2

CI

2

(C

2

H

5 3 SiH R 4 b WO 97/36587 WO 9736587PCTIUS97/05328 -178- REACTION SCHEME L 0- H 2 00 2

H

N

H

CH

3 0H

HCI

.HCI

xvi

(C

6

H

5 3 CBr_

(C

2

H

5 3 N N DMF Tr Ar-"'\N-CH 2 00 2

CH

3

N

Ar--\N-CH 2 00 2

H

N

3H 3 1) ArCH 2 X CH 3

CN

ref lux-, 2) CH 3 OH, reflux HClaq 55 0

C

WO 97/36587 WO 9736587PCT/US97/05328 -179- REACTION-SCHEME M

R

Ar'\ N-CH 2 00 2 H l, N

Q

EDC-HCI

HOBt

DMF

0

R

N

Ar'-.J

Q

xix R i

R

4 b WO 97/36587 WO 9736587PCTIUS97/05328 REACTION SCHEME N NaBH(OAc) 3 Et 3 N, CICH 2

CH

2

CI

R 4 b BnOI BocN H CHO NHBoc

R

BnO

Q

XXI ~R 4a; 20% Pd(OH) 2

H

2 R 4b

CH

3 0H C H 3 00 2

H

CICOCOCI

DMS0 CH 2

CI

2

(C

2 H5)3N XXIIRb R 4b WO 97/36587 WO 9736587PCTIUS97/05328 -181- REACTION SCHEME N (continued) H NHBoc 0 R 1. R'MgX

(C

2

H

5 2 0 Q l-R4b2. TFA, CH 2

CI

2 XXIII R 4 a; R

HO

XXIV

R 4 b REACTION SCHEME P NHBoc H

,R

HO CF 3

CO

2

H

Q

CH

2

CI

2 XXIIR a b

R'CH

2

NH

2 HOR R'CHO HOf 0 NaBH(OAc) 3 xxv 4a2R 4 b CICH 2

CH

2 CIXXVI R 4 a R 4 b WO 97/36587 WO 9736587PCT/JS97/05328 -182- REACTION SCHEME Q NHBoc

HO

H H N~ -N 02

XXI

R 4 b NaH, DMF 0 0

C

H

N

R

XXVII a i R 4 b

R'SH

(C

2

H

5 3 N N

CH

3 0HA

NH

2

Q

xxvillR 4a~i R4 WO 97/36587 WO 9736587PCTIUS97/05328 -183- REACTION SCHEME R 1) Boc 2

K

2 00 3

THF-H

2 0 2) CH 2

N

2 EtOAc

HO

BocNH CO 2

CH

3

XXX

H

2 N" 'CO 2

H

XXIX

LiAIH 4

THF

0-20 0

C

HO

B cN H CH 2 0H

R'CH

2

X

CS

2

CO

3

DMF

XXXI

R'CH

2

O

pyride C DMS0

(C

2

H

5 3 N BocNH iCHO 0

C

XXXIII

BocNH'

XXXII

WO 97/36587 WO 9736587PCTIUS97/05328 -184- REACTION SCHEME R (continued)

R

NaBH(QAc) 3 BocNH -CHO xxxiII

CICH

2

CH

2

CI

XXXIV

1) 20% Pd(OH) 2

CH

3 OH, CH 3

CO

2

H

2) HCI, EtOAc

_/NH

2 HO, HC\IEtOAc

R'CH

2 O0,.

INH

2

R

R 4a, XXX

VI

XXXV R' The intermediates whose synthesis are illustrated in Reaction Schemes A and C can be reductively alkylated with a variety WO 97/36587 PCT/US97/05328 -185of aldehydes, such as I, as shown in Reaction Scheme F. The aldehydes can be prepared by standard procedures, such as that described by O. P.

Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses, 1988, 67, 69-75, from the appropriate amino acid (Reaction Scheme The reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloroethane, methanol or dimethylformamide. The product II can be deprotected to give the final compounds III with trifluoroacetic acid in methylene chloride.

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 subsequently be reductively alkylated with a second aldehyde to obtain V. Removal of the protecting group, and conversion to 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 aldehydes such as 1-trityl-4carboxaldehyde or 1-trityl-4-imidazolylacetaldehyde, to give products such as VIII (Alternative Reaction Scheme 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.

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 Hydrolysis and reaction with the protected dipeptidyl analog intermediate in the presence of condensing reagents such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) leads to acylated products such as XV.

If the protected dipeptidyl analog intermediate is reductively alkylated with an aldehyde which also has a protected WO 97/36587 PCT/US97/05328 -186hydroxyl group, such as XVI in Reaction Scheme I, the protecting groups can be subsequently removed to unmask the hydroxyl group (Reaction Schemes I, 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 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 or tertiary amines.

The Boc protected amino alcohol XVIII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXIII (Reaction Scheme 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 as those whose synthesis is illustrated in Reaction Schemes B E.

WO 97/36587 WO 9736587PCTIUS97/05328 -187- ALTERNATE REACTION SCHEME F FOR COMPOUNDS (11-h) THROUGH (11-o)

H

2

NK

P0 2

R

Boo NHI

I

Boo NH CHO NaBH(OAc)3 Et 3 N CICH 2

CH

2 CI R 4 b NHBoc

H

Boo NH/L

F

CF

3

CO

2

H

CH

2

CI

2 R 4 b

NH

2

NH

2 Boc 2 0

CH

2

CI

2 R 4 b ocr

CHO

NaBH(OAo)3 Et 3 N CICH 2

CH

2

CI

R

4 b WO 97/36587 WO 9736587PCTIUS97/05328 -188- ALTERNATE REACTION SCHEME F (continued)

H

BocNH/

N,,

4a/

H

NH,

2

N

RV

A

CF

3

CO

2 H, CH 2

CI

2 NaHCO 3 R 4 b AgCN L!\ R 4 b WO 97/36587 WO 9736587PCTIUS97/05328 -189- ALTERNATE REACTION SCHEME G FOR COMPOUNDS (11-h) THROUGH (11-o)

Y

H

2

RA

C0 2

R

NaBH(OAc) 3 Et 3 N

CICH

2

CH

2 CI-0.

(C H 2 )nCHO

N-

H y

CO

2

R

(C H 2

HA

NR Q TrI 1) ArCH 2 X, CH 3

CN

2) CF 3 00 2 H, CH 2

CI

2

(C

2

H

5 3 SiH

CF

3

CO

2 H, CH 2

CI

2 (02 H 5 3 Si H C0 2

R

ix R 4a H Y C 2

(CH

2 )n~l N HAR 4b N ~x R4a; WO 97/36587 WO 9736587PCTIUS97/05328 -190- ALTERNATE REACTION SCHEME H FOR COMPOUNDS (11-h) THROUGH (11-o) N-

CH

2 C0 2

H

xi

CH

3 0H

HCI

N CH 2 00 2

CH

3

N

H H01 (06 H 5 3 CBr

(C

2

H

5 3

N

DMF

N 0 H 2 C0 2 0H 3 1) ArCH 2 X CH, 3

CN

ref lux N 2) CH 3 OH, reflux

XIII

Ar-*'\N-CH 2 00 2

CH

3

N

N CH 2 00 2

H

N

HClaq 550C WO 97/36587 WO 9736587PCTIUS97/05328 -191- ALTERNATE REACTION SCHEME I FOR COMPOUNDS (11-h) THROUGH (11-o) N CH 2

CO

2

H

N

H

2 C 2

R

R4A R 4a;R4 EDO*- HOI HOBt

DMF

L\N C0 2

R

ArA xv R4a Q\ R 4 b WO 97/36587 WO 9736587PCTIUS97/05328 -192- ALTERNATE REACTION SCHEME J FOR COMPOUNDS (11-h) THROUGH (11-o)

H

2 N y C2 R 4a~i R4 NaB H(OAc) 3 Et 3 N ,CICH 2

CH

2

CI

BnOI BocNH CHO xv' R 20% Pd(OH) 2

H

2

CH

3 0H

CH

3

CO

2

H

R 4 b Xv"l NHBoc

N

HO0

H>

CICOCOC'

DMSO

CH

2

CI

2

(C

2

H

5 3

N

xvi' 4 R 4b WO 97/36587 WO 9736587PCTIUS97/05328 -193- ALTERNATIVE REACTIO SCHEME J (continued)

R

4 b 1. R'MgX

(C

2

H

5 2 0 2. TFA, CH 2 01 2 R 4 b WO 97/36587 WO 9736587PCTIUS97/05328 -194- ALTERNATE REACTION SCHEME K FOR COMPOUNDS (11-h) THROUGH (II-o) NHBoc 0 0 2

R

H:

XVIIIR a~ R 4 b

NH

2 y C0 2

R

x R 4a; \R4

CF

3 00 2

H

CH

2 C1 2

ROCHO

NaB H(OAC) 3 CI CH 2 C H 2

CI

R'CH

2

NH

N.

HO

H

XXII

WO 97/36587 WO 9736587PCTIUS97/05328 -195- ALTERNATE REACTION SCHEME L FOR COMPOUNDS (11-h) THROUGH (11-o) NHBoc H H y C0 2 R N==\N HO N XVIIIR4a R 4 b NaH, DMF OOC

H

N y 0RR'SH H A

(C

2

H

5 3 N A XXIIIR4a: R 4 b CH 3 0H

NH

2 00 2 R'S N R 4 b WO 97/36587 WO 9736587PCTIUS97/05328 -196- ALTERNATE REACTION SCHEME M FOR COMPOUNDS (11-h) THROUGH (II-o) 1) BoC 2 O, K 2 00 3

THF-H

2 0 2) CH 2

N

2 EtOAc

HO

BocNH C0 2 0H 3 xxvi

H

2 N_ _CO 2

H

XXV

LiAIH 4

THF

0-200C

R'CH

2 X a

CS

2

CO

3

DMF

ICH

2 0H

XXVII

pyridine

DMSO

(C 2

H

5 3

N

0

C

BocNH- CH 2

OH

XXVIII

BocNH -CHO Xxix WO 97/36587 WO 9736587PCTIUS97/05328 -197- ALTERNATE REACTION SCHEME M (CONT.)

R'CH

2

O.

I C0 2

R

H

2 N"k R A Q R 4a ~i R4

CHO

xxix NaB H(OAC) 3 010 H 2

CH

2

CI

R-CH

2 0 1) 20% Pd(O H) 2

CH

3 OH, CH 3 C0 2

H

2) HCI, EtOAc K~R

R

4 b HC\ EtOAc R 4 b xxx"i R 4 b WO 97/36587 PCT/US97/05328 -198- Certain compounds used in the invention are described below.

EXAMPLE 1 (S)-1-(3-chlorophenyl)-4-[ 1-(4-cyanobenzyl)-imidazolylmethyl]-5-[2- (methanesulfonvl)ethvll-2-piperazinone dihydrochloride Step A: 1-triphenvlmethyl-4-(hydroxvmethvl)-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 solid precipitated from the solution. Chlorotriphenylmethane (76.1 g, 273 mmol) in 500 mL of DMF was added dropwise. The reaction mixture was stirred for 20 hours, 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 which was sufficiently pure for use in the next step.

Step B: -triphenvlmethvl-4-(acetoxymethvl)-imidazole Alcohol from Step A (260 mmol, prepared above) was suspended in 500 mL of pyridine. Acetic anhydride (74 mL, 780 mmol) was added dropwise, and the reaction was stirred for 48 hours during which it became homogeneous. The solution was poured into 2 L of EtOAc, washed with water (3 x 1 5% aq. HCI 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 isolated as a white powder which was sufficiently pure for use in the next reaction.

Step C: 1-( 4 hydrobromide A solution of the product from Step B (85.8 g, 225 mmol) and a-bromo-p-tolunitrile (50.1 g, 232 mmol) in 500 mL of EtOAc was stirred at 60 0 C for 20 hours, during which a pale yellow precipitate WO 97/36587 PCT/US97/05328 -199formed. The reaction was cooled to room temperature and filtered to provide the solid imidazolium bromide salt. The filtrate was concentrated in vacuo to a volume 200 mL, reheated at 60 0 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 0 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, dissolved in 500 mL of methanol, and warmed to 60 0 C. After two hours, the solution was reconcentrated in vacuo 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 purification.

Step D: 1-(4-cyanobenzyl)-5-(hvdroxymethvl)-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 monohydrate (18.9 g, 450 mmol). After one hour, the reaction was concentrated in vacuo, diluted with EtOAc (3 and washed with water, sat. aq. NaHCO3 and brine. The solution was then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product as a pale yellow fluffy solid which was sufficiently pure for use in the next step without further purification.

Step E: 1-(4-cvanobenzvl)-5-imidazolecarboxaldehvde To a solution of the alcohol from Step D (21.5 g, 101 mmol) in 500 mL of DMSO at room temperature was added triethylamine (56 mL, 402 mmol), then S03-pyridine complex (40.5 g, 254 mmol). After 45 minutes, the reaction was poured into 2.5 L of EtOAc, washed with water (4 x 1 L) and brine, dried (Na2S04), filtered, and concentrated in vacuo to provide the aldehyde as a white powder which was sufficiently pure for use in the next step without further purification.

WO 97/36587 PCT/US97/05328 -200- Step F: (S)-2-(tert-butoxycarbonylamino)-N-methoxy-N-methyl-4- (methylthio)butanamide 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 0 C under nitrogen. More N,O-dimethylhydroxylamine hydrochloride (2.3 g, 23 mmol) was 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. NaHCO3 soln. The organic phase was washed with saturated sodium bicarbonate, water, 10% citric acid, and 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 mol) in ether (500 mL) was stirred at room temperature for one hour.

The solution was cooled to -50 0 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 was complete, the reaction was warmed to 5 0 C, then recooled to -45 0 C. Analysis by tic revealed incomplete reaction. The solution was rewarmed to 5 0 C, stirred for 30 minutes, then cooled to 0 C. A solution of potassium hydrogen sulfate (72 g, 0.529 mol) in 200 mL water was slowly added, maintaining the temperature below The mixture was wasmed to 5 0 C, filtered through Celite, and concentrated in vacuo to provide the title aldehyde.

Step H: (S)-2-(tert-butoxycarbonvlamino)-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 (27.8 mL, 487 mmol) in dichloroethane (250 mL) under nitrogen was added sodium triacetoxyborohydride (41.3 g, 195 mmol). The reaction was WO 97/36587 PCT/US97/05328 -201stirred overnight, then quenched with saturated sodium bicarbonate 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 ethyl acetate in hexane to obtain the title compound.

Step I: (S)-4-(tert-butoxvcarbonvl)- 1-(3-chlorophenvl)-5-[2- (methvlthio)ethvllpiperazin-2-one A solution of the product from Step H (22.0 g, 63.8 mmol) in ethyl acetate (150 mL) was vigorously stirred at 0°C with saturated sodium bicarbonate (150 mL). Chloroacetyl chloride (5.6 mL, 70.2 mmol) was added dropwise, and the reaction stirred at 0°C for 2h.

The layers were separated, and the ethyl acetate phase was washed with 10% citric acid and saturated brine, and dried over sodium sulfate.

After concentration in vacuo, the resulting crude product (27.6 g) was 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 days, allowing it to warm to room temperature. Another portion of cesium carbonate (10 g, 30 mmol) was added, and the reaction was stirred for 16 hours. The DMF was distilled in vacuo, and 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-butoxvcarbonvl)- 1 -(3-chlorophenvl)-5-[2- (methanesulfonyl)ethvl]piperazin-2-one A solution of the product from Step I (14.2 g, 37 mmol) in methanol (300 mL) was cooled to 0 oC, and a solution of magnesium monoperoxyphthalate (54.9 g, 111 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 was concentrated in vacuo to half the original volume, then quenched by WO 97/36587 PCT/US97/05328 -202the addition of 2N Na2S203 soln. The solution was poured into EtOAc and sat NaHCO3 solution, and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude sulfone. This material was chromatographed on silica gel with 60-100% ethyl acetate in hexane to obtain the titled compound.

Step K: (S)--(3-chlorophenyl)-5-[2- (methanesulfonyl)ethvllpiperazin-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 OC was bubbled anhydrous HCI gas. The saturated solution was stirred for 35 minutes, then concentrated in vacuo to provide the hydrochloride salt as a white powder. This material was suspended in EtOAc and treated with dilute aqueous NaHCO3 solution. The aqueous phase was extracted with EtOAc, and the combined organic mixture was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting amine was reconcentrated from toluene to provide the titled material suitable for use in the next step.

Step L: -(3-chlorophenyl)-4-f 1-(4cvanobenzvl)imidazolylmethyll-5-[2-(methanesulfonyl)ethyll-2-piperazinone dihydrochloride To a solution of the amine from Step K (898 mg, 2.83 mmol) and imidazole carboxaldehyde from Step E (897 mg, 4.25 mmol) in 15 mL of 1,2-dichloroethane was added sodium triacetoxyborohydride (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 CHC13. The combined organics were washed with brine, dried (Na2S04), filtered, and concentrated in vacuo. The resulting product was purified by silica gel chromatography (95:5:0.5-90:10:0 EtOAc:MeOH:NH4CI), and the resultant product was taken up in EtOAc/methanol and treated with 2.1 equivalents of 1 M HCl/ether WO 97/36587 PCTIUS97/05328 -203solution. After concentrated in vacuo, the product dihydrochloride was isolated as a white powder.

EXAMPLE 2 1-(3-chlorophenyl)-4-[ 1 -(4-cyanobenzyl)imidazolvl-methyll-2piperazinone 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 (80 mL, 320 mmol HC1). 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, 282 mmol) was heated under nitrogen atmosphere at 160'C for 10 hours, during which the solids melted, and gas evolution was observed. The reaction was allowed to cool, forming the crude diamine hydrochloride salt as a pale brown solid.

Step B: N-(tert-butoxycarbonyl)-N'-(3chlorophenyl)ethylenediamine The amine hydrochloride from Step A (ca. 282 mmol, crude material prepared above) was taken up in 500 mL of THF and 500 mL of sat. aq. NaHCO3 soln., cooled to 0°C, and di-tertbutylpyrocarbonate (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 further purification.

Step C: N-[2-(tert-butoxycarbamoyl)ethyl]-N-(3-chlorophenyl)- 2-chloroacetamide WO 97/36587 PCT/US97/05328 -204- A solution of the product from Step B (77 g, ca. 282 mmol) and triethylamine (67 mL, 480 mmol) in 500 mL of CH2C12 was cooled to 0°C. Chloroacetyl chloride (25.5 mL, 320 mmol) was added dropwise, and the reaction was maintained 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 with water, sat. aq. NH4Cl soln, sat. aq. NaHCO3 soln., and brine.

The solution was dried (Na2SO4), filtered, and concentrated in vacuo to provide the chloroacetamide as a brown oil which was used in the next step without further purification.

Step D: 4-(tert-butoxycarbonyl)- 1 -(3-chlorophenyl)-2piperazinone To a solution of the chloroacetamide from Step C (ca. 282 mmol) in 700 mL of dry DMF was added K2C03 (88 g, 0.64 mol).

The solution was heated in an oil bath at 70-75 0 C for 20 hours, cooled 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 concentrated in vacuo to provide the product as a brown oil. This material was purified by silica gel chromatography (25-50% EtOAc/hexane) to yield pure product, along with a sample of product (ca. 65% pure by HPLC) containing a less polar impurity.

Step E: l-(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 0 C was bubbled anhydrous HCI gas. The saturated solution was warmed to 0°C, and stirred for 12 hours. Nitrogen gas was bubbled through the reaction to remove excess HCI, and the mixture was warmed to room temperature.

The solution was concentrated in vacuo to provide the hydrochloride as a white powder. This material was taken up in 300 mL of CH2C12 and treated with dilute aqueous NaHC03 solution. The aqueous phase was extracted with CH2C12 (8 x 300 mL) until tic analysis indicated WO 97/36587 PCT/US97/05328 -205complete extraction. The combined organic mixture was dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled free amine as a pale brown oil.

Step F: 1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)imidazolylmethyl]- 2-piperazinone dihydrochloride To a solution of the amine from Step E (55.4 mmol, prepared above) in 200 mL of 1,2-dichloroethane at 0°C was added 4A powdered molecular sieves (10 followed by sodium triacetoxyborohydride (17.7 g, 83.3 mmol). The imidazole carboxaldehyde from Step E 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 backextracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was taken up in 500 mL of 5:1 benzene:CH2Cl2, and propylamine (20 mL) was added. The mixture was stirred for 12 hours, then concentrated in vacuo to afford a pale yellow foam. This material was purified by silica gel chromatography MeOH/CH2Cl2), and the 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.

EXAMPLE 3 N N 0 NH 0 N

SCH

3

H

3

COS

1-(1H-Imidazol-4-propionyl) pyrrolidin-2(S)-ylmethyl]-N-(2methoxvbenzyl)glycvI-methionine isopropvl ester

I

WO 97/36587 PCT/US97/05328 -206- Step A: 2-Methoxybenzylglycine methyl ester 2-Methoxybenzyl alcohol (53.5 g, 0.39 mol) was dissolved in CH2C12 (200 mL), treated with diisopropylethylamine (81 mL, 0.74 mol), cooled to 0°C. with stirring in an ice-CH3OH bath under Ar, and treated dropwise with methanesulfonyl chloride (33 mL, 0.43 mol). After 0.5 hr, the reaction mixture was left to warm to ambient temperature 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 The aqueous 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 (Si02, 1-5% CH30H/CH2CI2).

Step B: N-[(2S)-(t-Butoxycarbonylpyrrolidinyl-methyl)-N-(2methoxvbenzyl)glvcine methyl ester 2-Methoxybenzylglycine methyl ester (27.4 g, 0.131 mol) was dissolved in 1,2-dichloroethane (500 ml), 3A molecular sieves g) were added, and the pH of the reaction mixture adjusted to pH with acetic acid (7.5 mL, 0.131 mol). N-(t-Butoxycarbonyl)-L-prolinal (26.1 g, 0.131 mol) Org. Chem. (1994) 59, 6287-95) 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 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.

WO 97/36587 PCT/US97/05328 -207- Step C: N-[(2S)-(t-Butoxycarbonylpyrrolidinyl-methyl)-N-(2methoxvbenzvl)glycine N-[(2S)-(t-Butoxycarbonylpyrrolidinylmethyl)-N-(2methoxybenzyl)glycine methyl ester (7.0 g, 0.018 mol) was dissolved in CH30H (150 ml) and IN NaOH (71 ml, 0.071 mol) was added with cooling in an ice-water bath. The mixture was stirred at ambient temperature for 2 hr, neutralized with IN HC1 (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 foam.

Step D: Methionine isopropyl ester hydrochloride N-(t-Butoxycarbonyl)methionine (25 g, 0.1 mol), isopropyl alcohol (11.8 mL, 0.15 mol), EDC (21.1 g, 0.11 mol), and 4-dimethylaminopyridine (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 H20, the aqueous layer washed with EtOAc (2 x 50 mL), the 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).

N-(t-Butoxycarbonyl)methionine isopropyl ester (20.5 g, 0.07 mol) was dissolved in EtOAc (200 mL) with stirring and cooling to 0 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: hexane, 1:3) indicates loss 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.

WO 97/36587 PCTIUS97/05328 -208- Step E: N-[(2S)-(t-Butoxycarbonylpyrrolidinyl-methyl)-N- (2-methoxvbenzl)glyvcvl-methionine isopropyvl ester N-[(2S)-(t-Butoxycarbonylpyrrolidinylmethyl)-N- (2-methoxybenzyl)glycine (from step C) (5.98 g, 0.0158 mol), dissolved in CH2Cl2 (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 g, 0.019 mol). The pH was adjusted to 7.5 with Et3N (8.81 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 compound as a thick oil. This was used without further purification.

Step F: N-((2S)-Pyrrolidinylmethyl)-N-(2-methoxybenzyl)glvcl-methionine isopropyl ester bis hydrochloride N-[(2S)-(t-Butoxycarbonylpyrrolidinylmethyl)-N-(2methoxybenzyl)glycyl-methionine isopropyl ester (0.85 g, 1.54 mmol) was dissolved in EtOAc (25 mL) and cooled to 0 0 C. HCI was bubbled through the mixture until the soln was saturated, and it was stoppered and stirred for 3 hr. Argon was bubbled through the mixture to remove excess HCI and the mixture was then concentrated to give the title compound.

Step G: H-Imidazol-4-propionyl) pyrrolidin-2(S)ylmethyl]-N-(2-methoxybenzyl)glycyl-methionine isopropyl ester N-((2S)-Pyrrolidinylmethyl)-N-(2-methoxybenzyl)glycyl methionine isopropyl ester bis hydrochloride (0.800 g, 1.53 mmol), dissolved in DMF (30 mL), was treated with IH-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-methylmorpholine (0.756 mL, 6.89 mmol), and the mixture was stirred WO 97/36587 WO 9736587PCTf[US97/05328 -209at 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, 95:5 CH2Cl2/MeOH) to give the title compound as a foam.

I H NMR (CD3OD); 6 7.58 IH, J=1 Hz), 7.25-7.3 1 (in, 2H), 6.89- 7.00 (in, 2H), 6.81 1H), 5.00-5.06 (in, 11H), 4.49-4.56 (in, lH), 4.23- 4.30 (in, 3.91 IH, J=13 Hz), 3.86 3H), 3.54 IH, J=l3Hz), 3.30-3.41 (mn, 2H), 3.36 1H-, J=17 Hz), 3.15 1H, J=17 Hz), 2.85- 2.92 (in, 2H), 2.56-2.77 (in, 3H), 2.30-2.45 (in, 3H), 2.05-2.17 (in, lH), 2.04 3H), 1.69-1.86 (in, 5H), 1.24 6H, J=6 Hz).

Anal, calculated for C29H-43N505S 0.6 C, 59.59; H, 7.62; N, 11.98; Found: C, 59.58; H, 7.43; N, 12.02.

EXAMPLE 4 (N-[I1 -CyanobenzylI)- 1 H -imi dazol -5 -yl)acetyll pyrro li din -2(S)-vlinethyl I 3(S)-ethyl-prolyl methionine isoprop~yl ester

NC

SCH

3

HH

N 0 \L 0 Step A: Diethyl 1-Acetyl-5-hydroxy-3-ethylpyrrolidine-2,2dicarboxylate Sodium (4.02 g, 0. 175 moD) was dissolved in a stirred solution of diethyl acetainidoinalonate (235.4 g, 1. 19 mol) in abs EtOH WO 97/36587 PCT/US97/05328 -210- (1.4 L) at ambient temperature under argon. The reaction mixture was cooled to 0°C, and trans-2-pentenal (100 g, 1.08 mol) was added dropwise maintaining the reaction temperature at <5 0 C. After the addition, the reaction was allowed to warm to room temperature, stirred for 4 h, then quenched with acetic acid (28 mL). The solution was concentrated in vacuo, and the residue dissolved in EtOAc (1.5 washed with 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 On cooling, the title compound precipitated and was collected, mp 106 109 0 C. 1 H NMR (CD30D) 6 5.65 1H, J= 5 Hz), 4.1 4.25 4H), 2.7-2.8 1H), 2.21 3H), 2.10 (dd, 1H, J 6, 13, Hz),1.86- 1.97 2H), 1.27 3H, J= 7 Hz), 1.23 3H, J= 7 Hz), 1.1- 1.25 1H), 0.97 3H, J= 7 Hz).

Step B: Diethyl 1-Acetyl-3-ethvlpyrrolidine-2.2-dicarboxvlate To a solution of diethyl 1-acetyl-5-hydroxy-3-ethylpyrrolidine-2,2-dicarboxylate (287 g, 0.95 mol) and triethylsilane (228 mL, 1.43 mol) in CH2C12 (3 L) under argon was added trifluoroacetic 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 in vacuo, the residue diluted with CH2C12 (1.5 then treated with H20 (1 L) and solid Na2CO3 with vigorous stirring until the solution was basic. The organic layer was separated, dried (Na2SO4), filtered, then concentrated to give the title compound as a yellow oil which was used without further purification.

Step C: 3-Ethylproline hydrochloride (Cis:Trans Mixture) Diethyl 1-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 then concentrated in vacuo to give an oil which crystallized upon trituration with ether to give the title compound.

WO 97/36587 PCT/US97/05328 -211- 1 H NMR (D20) 8 4.23 1H, J= 8 Hz), 3.84 1H, J= 8 Hz), 3.15- 3.4 4H), 2.33- 2.44 1H), 2.19-2.4 1H), 2.02- 2.15 2H), 1.53- 1.72 3H), 1.23- 1.43 2H), 1.0- 1.15 1H), 0.75 0.83 6H).

Step D: N-[(tert-Butyloxy)carbonyl]-cis:trans-3-ethylproline methyl ester 3-Ethylproline hydrochloride (Cis:Trans Mixture) g, 0.11 mol) was dissolved in CH30H (200 mL), and the solution was saturated with HCI gas, then stirred at 23 0 C for 24 h. Argon was bubbled through the solution to remove excess HC1. The solution was treated with NaHCO3 (>84 g) to a pH of 8, then di-tert-butyl dicarbonate (25.1 g, 0.115 mol) dissolved in CH30H (20 mL) was 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-[(tert-Butyloxy)carbonyl]-trans-3-ethylproline and N- [(tert-Butyloxy)carbonyl]-cis-3-ethylproline methyl ester N-[(tert-Butyloxy)carbonyl]-cis,trans-3-ethylproline methyl ester (29.1 g, 0.113 mol) was dissolved in CH30H (114 mL) with cooling to 0°C, then treated with 1 N NaOH (114 mL). After stirring for 20 h at 23 0 C, the solution was concentrated to remove the and then extracted with EtOAc (3 The organic layers were combined, dried (MgSO4), filtered, and concentrated to give 12.8 g of N-[(tert-Butyloxy)carbonyl]-cis-3-ethylproline methyl ester as an oil.

The aqueous layer was acidified with solid citric acid and extracted with EtOAc (2 the organic layers combined, dried (MgSO4), filtered, and concentrated to give N-[(tert-Butyloxy)carbonyl]-trans-3-ethylproline as an oil. IH NMR (CD30D) 6 3.86 and 3.78 (2 d, 1H, J 6 Hz), 3.33 3.58 2H), 2.01 2.22 2H), 1.5 1.74 2H), 1.33 1.5 (m, 1H), 1.45 and 1.42 (2 s, 9H), 0.98 3H, J= 8 Hz).

WO 97/36587 PCT/US97/05328 -212- Step F: 3(S)-Ethyl-2(S)-proline hydrochloride N-[(tert-Butyloxy)carbonyl]-trans-3-ethylproline (15.5 g, 0.064 mol), S-a-methylbenzylamine (9.03 mL, 0.070 mol), HOBT (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-H20 bath, treated with EDC (13.4 g, 0.070 mol) stirred at 23 0 C for 48 h. The reaction mixture was partitioned between EtOAc and 10% citric acid solution, the organic layer washed with satd NaHCO3 solution, brine and dried (MgSO4), filtered, and concentrated to give an oil. This oil was dissolved in a minimum amount of ether (10 mL) to crystallize the desired S,S,S diastereomer (4.2 mp 118-121 C. A solution of this product in 8N HCI (87 mL) and glacial acetic acid (22 mL) was heated at reflux overnight. The solution was concentrated on a rotary evaporator, and the residue taken up in H20 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 a-methylbenzylamine.

3(S)-Ethyl-2(S)-proline containing a-methylbenzylamine g, 0.0128 mol) was dissolved in dioxane (10 mL) and H20 (10 mL) with stirring and cooling to 0°C. N,N-diisopropylethylamine (2.2 mL, 0.0128 mol) and di-tert-butyl-dicarbonate (2.79 g, 0.0128 mol) were added and stirring was continued at 23°C for 48 h. The reaction mixture was partitioned between EtOAc (60 mL) and H20 (30 mL), the organic layer washed with 0.5N NaOH (2 x 40 mL), the aqueous layers combined and washed with EtOAc 30 mL) and this layer back-extracted with 0.5 N NaOH (30 mL). The aqueous layers were combined and carefully acidified at 0°C with IN HCI to pH 3. This 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 was dissolved in EtOAc (50 mL) and the solution was saturated with HCI gas with cooling in an ice-H20 bath.

The solution was stoppered and stirred at 0°C. for 3 hr. Argon was WO 97/36587 PCT/US97/05328 -213bubbled through the solution to remove excess HC1, and the solution was 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 sieves (2 g) and KOAc (1.27 g, 0.013 mol) to adjust the pH of the reaction mixture to 4.5-5, then N-[(tert-Butyloxy)carbonyl-prolinal (Pettit et al., J. Org. Chem. (1994) 59, [21] 6287-95) (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 mL) and concentrated to dryness. The residue was extracted with CHC13. The extract was dried (MgSO4), filtered, and concentrated to give the title compound and inorganic salts.

Step H: N-(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)ethyl-prolyl methionine isopropyl ester N-(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]- 3(S)-ethyl-proline (2.4 g, 0.008 mol), methionine isopropyl ester hydrochloride (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 mL) at room temperature and treated with N-methylmorpholine (3 mL, 0.024 mol).

The reaction mixture was stirred overnight at room temperature, then concentrated and partitioned between EtOAc and H20. The organic layer was washed with aq 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]-3(S)-ethyl-prolyl methionine isopropyl ester.

WO 97/36587 PCT/US97/05328 -214isopropyl ester hydrochloride N-(t-butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)ethyl-prolyl methionine isopropyl ester (1.38 g, 0.0028 mol) was dissolved in EtOAc (40 mL), cooled to -20 0 C, saturated with HC1 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)-ethylprolyl methionine isopropyl ester hydrochloride.

Step J: Preparation of IH-Imidazole-4- acetic acid methyl ester hydrochloride A solution of IH-imidazole-4-acetic acid hydrochloride (4.00g, 24.6 mmol) in methanol (100 ml) was saturated with gaseous hydrogen chloride. The resulting solution was allowed to stand at room temperature (RT) for 18hr. The solvent was evaporated in vacuo to afford the title compound as a white solid.

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

Step K: Preparation of 1-(Triphenylmethyl)-lH-imidazol-4vlacetic acid methyl ester To a solution of lH-Imidazole-4- acetic acid methyl ester hydrochloride (24.85g, 0.141mol) in dimethyl formamide (DMF) (115ml) was added triethylamine (57.2 ml, 0.412mol) and triphenylmethyl bromide(55.3g, 0.171mol) and the suspension was stirred for 24hr. After this time, the reaction mixture was diluted with ethyl acetate (EtOAc) (1 1) and water (350 ml). The organic phase was washed with sat. aq. NaHCO3 (350 ml), dried (Na2SO4) and evaporated in vacuo.

The residue was purified by flash chromatography (Si02, 0-100% ethyl acetate in hexanes; gradient elution) to provide the title compound as a white solid.

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

WO 97/36587 PCT/US97/05328 -215- Step L: Preparation of [1-(4-Cyanobenzyl)-1H-imidazol-5-yllacetic acid methyl ester To a solution of 1-(Triphenylmethyl)-lH-imidazol-4ylacetic acid methyl ester (8.00g, 20.9mmol) in acetonitrile (70 ml) was added bromo-p-toluonitrile (4.10g, 20.92 mmol) and heated at 55 0

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 mixture was cooled to room temperature and evaporated in vacuo.

To the residue was added EtOAc (70 ml) and the resulting white precipitate collected by filtration. The precipitated imidazolium salts were combined, suspended in methanol (100 ml) and heated to reflux for 30min. After this time, the solvent was removed in vacuo, the resulting residue was suspended in EtOAc (75ml) and the solid isolated by filtration and washed (EtOAc). The solid was treated with sat 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 IHNMR(CDC13, 400 MHz) 8 7.65(1H, d, J=8Hz), 7.53(lH, 7.15(1H, d, J=8Hz), 7.04(1H, 5.24(2H, 3.62(3H, s) and 3.45(2H, s) ppm.

Step M: Preparation of [1-(4-cyanobenzyl)- acid A solution of [1-(4-cyanobenzyl)-1H-imidazol-5-yl] acetic acid methyl ester (4.44g, 17.4mmol in THF (100ml) and 1 M lithium hydroxide (17.4 ml, 17.4 mmol) was stirred at RT for 18 hr. 1 M HCI (17.4 ml) was added and the THF was removed by evaporation in vacuo. The aqueous solution was lyophilized to afford the title compound containing lithium chloride as a white solid.

1H NMR(CD30D, 400 MHz) 8 8.22(1H, 7.74(1H, d, J=8.4Hz), 7.36(1H, d, J=8.4Hz), 7.15(1H, 5.43(2H, s) and 3.49(2H, s) ppm.

WO 97/36587 PCT/US97/05328 -216- Step N: Preparation of yl)acetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl methionine isopropyl ester [1-(4-Cyanobenzyl)- 1 H-imidazol-5-yl]acetic acid LiC (0.416 g, 1.47 mmol), pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl methionine isopropyl ester hydrochloride (Step I) 0.63 g, 1.33 mmol), HOOBT (0.239 g, 1.47 mmol), and EDC (0.281 g, 1.47 mmol) were dissolved in degassed DMF (20 mL) with stirring 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 aq satd NaHCO3 solution. The aq layer was washed 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 CH2Cl2:CH30H, 95:5.

Anal. calcd for C33H46N604S 0.7 C, 62.38; H, 7.52; N, 13.23; Found: C, 62.40; H, 7.17; N, 13.11.

FAB MS 623 (M+1) EXAMPLE 2(S)-n-Butyl-l-[1 -(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3- WO 97/36587 PCTIUS97/05328 -217- 1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3-dimethylphenyl)- 2(S)-(2-methoxyethyl)piperazin-5-one ditrifluoroacetic acid salt Step A: N-Methoxy-N-methyl 4-benzyloxy-2(S)-(tertbutoxycarbonylamino)butanamide 4-Benzyloxy-2(S)-(tert-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-dimethylhydroxylamine 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)-(tert-butoxycarbonylamino) butanal The title compound was obtained by lithium aluminum hydride reduction of the product of Step A using the procedure described in Example 24, Step B.

Step C: N-(2,3-Dimethylphenyl)-4-(2-benzyloxyethyl)-2-(S)-(tertbutoxycarbonylamino)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 triacetoxyborohydride (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(S)-(2-Benzyloxyethyl)- 1 -tert-butoxycarbonyl-4-(2,3- 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 WO 97/36587 PCT/US97/05328 -218- 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- The product from Step D was dissolved in methanol mL) and 10% Pd/C was added (0.160 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 -tert-Butoxycarbonyl-4-(2,3-dimethylphenyl)-2(S)-(2methoxyethyl)piperazin 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 was quenched with water, and the 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-[4-(1- The product from Step F (0.113 g, 0.312 mmol) was 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 pH 5. Sodium triacetoxyborohydride (0.100 g, 0.468 mmol) and 1-triphenylmethyl- WO 97/36587 PCT/US97/05328 -219- 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 was washed with saturated brine and dried over magnesium sulfate. Silica gel chromatography using 5% methanol in chloroform as eluant yielded the title compound.

Step H: 1-[1 -(4-Cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3dimethylphenyl)-2(S)-(2-methoxyethyl)piperazin-5-one ditrifluoroacetic acid salt The product from Step G (0.182 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 salt with triethylsilane (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.

The title compound was isolated after lyophilization from water. FAB ms 458.

Anal. Calc. for C27H31N502 0.35 H20 2.0 TFA: C, 53.81; H, 4.91; N, 10.21.

Found: C, 53.83; H, 4.95; N, 10.29.

EXAMPLE 6 -(4-Cyanophenyl-methyl)-1 3(S)-methylpentyl]-N-l-naphthylmethyl-glycyl-methionine methyl ester WO 97/36587 PCT/US97/05328 -220-

CN

PH 0 N N N OMe N O 0

SCH

3 Preparation of N-[2(S)-N'-(-(4-Cyanophenylmethyl)-1H-imidazol-5ylacetyl)amino-3(S)-methylpentyl]-N-1-naphthylmethyl-glycylmethionine bis trifluoroacetate Step A: Preparation of 1-(Triphenylmethyl)- H-imidazol-4-ylacetic acid methyl ester (23) To a suspension of 1H-imidazole-4-acetic acid methyl ester hydrochloride 7.48, 42.4 mmol) in methylene chloride (200 ml) was added triethylamine (17.7 ml, 127 mmol) and triphenylmethyl bromide (16.4 g, 50.8 mmol) and stirred for 72 h. After this time, reaction mixture was washed with sat. aq. sodium bicarbonate (100 ml) and water (100 ml). The organic layer was evaporated in vacuo and purified by flash chromatography (30-100% ethyl acetate/hexanes gradient elution) to provide 23 as a white solid.

1 H NMR (CDC13, 400 MHz) 5 7.35 (1H, 7.31 (9H, 7.22 (6H, 6.76 (1H, 3.68 (3H, s) and 3.60 (2H, s) ppm.

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

C

for 16 h. After this time, the reaction was cooled to room temperature, treated with ethyl acetate (20 ml) and the resulting precipitate was filtered. The filtrate was concentrated to dryness in vacuo and the residue was redissolved in acetonitrile (4 ml) and heated to 65 0 C for WO 97/36587 PCTIUS97/05328 -221- 3 h. After this time, the reaction mixture was evaporated to dryness and combined with initial precipitate. This residue was dissolved in methanol (5 ml) and heated to reflux for 30 min. The resulting solution was evaporated in vacuo and the residue was purified by flash chromatography methanol/methylene chloride gradient elution to provide 16.

1 H NMR (CDC13, 400 MHz) 8 8.20 (2H, d, J=8.8 Hz), 7.53 (1H, s), 7.19 (2H, d, J=8.8 Hz), 7.03 (1H, 5.28 (2H, 3.61 (3H, s) and 3.44 (2H, s) ppm.

Step C: 1 -(4-Nitrophenylmethyl)-1H-imidazol-5-ylacetic acid hydrochloride 1 -(4-Nitrophenylmethyl)-1 H-imidazol-5-ylacetic acid methyl ester (0.115 g, 0.42 mmol was dissolved in 1.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.

1H NMR (CD30D, 400 MHz) 8 9.06 (1H, 8.27 (2H, d, J=8.8 Hz), 7.61 (1H, 7.55 (2H, d, J=8.8 Hz), 5.63 (2H, s) and 3.81 (2H, s) ppm.

Step D: N-[2(S)-N'-(l-(4-Nitrophenylmethyl)-lH-imidazol-5ylacetyl)amino-3(S)-methylpentyl]-N-1 -naphthylmethylglvcvl-methionine methyl ester bis trifluoroacetate To a solution of 1-(4-nitrophenylmethyl)- H-imidazolacid hydrochloride, N-[2(S)-amino-3(S)-methylpentyl]-Nnaphthylmethyl-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 pl, 1.57 mmol) and the mixture stirred overnight at room temperature. After this 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.

WO 97/36587 PCT/US97/05328 -222- EXAMPLE 7 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenvlpropionyl-methionine sulfone isopropvl ester

HS

H H 0 N NA 0

H

2 N O 0 2S\ The title compound is prepared in accordance with WO 94/10138 published on May 11, 1994, incorporated by reference.

BIOLOGICAL ASSAYS.

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

Raf kinase assay Raf kinase activity in vitro is measured by the phosphorylation of its physiological substrate MEK (Map/ERK kinase).

Phosphorylated MEK is subsequently trapped on a filter membrane and incorporation of radio-labeled phosphate is quantitated by scintillation counting.

WO 97/36587 PCT/US97/05328 -223-

MATERIALS

Activated Raf Produced in Sf9 insect cells coinfected with three different baculoviruses expressing epitope-tagged Raf, and the upstream activators Vall 2 -H-Ras, and Lck. The epitope sequence Glu-Tyr-Met- Pro-Met-Glu ("Glu-Glu") was fused to the carboxy-terminus of fulllength c-Raf.

MEK

Catalytically inactive MEK is produced in Sf9 cells infected with baculovirus expressing epitope-tagged MEK with a lysine 9 7 to alanine mutation (K97A). The epitope sequence Glu-Tyr-Met-Pro-Met- Glu ("Glu-Glu") was fused to the amino-terminus of full-length MEK1.

Anti "Glu-Glu" antibody A hybridoma cell line expressing an antibody specific for the "Glu-Glu" epitope was obtained from Gerot Walter, UCSD. Cells were grown and antibodies were purified as described (Grussenmeyer et al., Proc. Natl. Acad. Sci. 82, pp. 7952-7954, 1985).

Column buffer mM Tris, pH 8, 100 mM NaCI, 1 mM EDTA, 2.5 mM EGTA, 10 mM MgCl 2 2 mM DTT, 0.4 mM AEBSF, 0.1% n-octyl glucopyranoside, 1 nM okadeic acid, and 10 Ltg/ml each of benzamidine, leupeptin, pepstatin, and aprotinin (all SIGMA).

reaction buffer 125 mM HEPES pH=8.0, 25 mM MgCI 2 5 mM EDTA, mM Na 3

VO

4 100 gg/ml BSA Enzyme dilution buffer mM HEPES pH=8.0, 1 mM EDTA, 1 mM Na 3

VO

4 400 gg/ml BSA.

Stop solution 100 mM EDTA, 80 mM sodium pyrophosphate.

WO 97/36587 PCT/US97/05328 -224- Filter plates Millipore Multiscreen #SE3M078E3, Immobilon-P (PVDF).

METHOD

A. Protein purification 1. Sf9 insect cells were infected with baculovirus and grown as described (Williams et al., Proc. Natl. Acad. Sci. U.S.A., 89, pp. 2922-2926, 1992).

2. All subsequent steps were performed on ice or at 4 0

C.

Cells were pelleted and lysed by sonication in column buffer. Lysates were spun at 17,000x g for 20 min, followed by 0.22 [m filtration.

3. Epitope-tagged proteins were purified by chromatography over a GammaBind Plus (Pharmacia) affinity column to which "Glu-Glu" antibody had been coupled. Proteins were loaded on the column, followed by washes with two column volumes of column buffer, and eluted with 50 gg/ml of peptide antigen (Glu-Tyr-Met-Pro-Met-Glu) in column buffer.

B. Raf kinase assay 1. Add 10 gl of inhibitor or control in 10% DMSO to assay plate.

2. Add 30 gl of reaction mix containing 10 Rl 5x reaction buffer and 0.5 gl1 ImM 3 P-y-ATP (20 gCi/ml), 0.5 gl MEK (2.5 mg/ml), 1 pl 50 mM P-mercaptoethanol.

3. Start reaction by addition of 10 pl1 enzyme dilution buffer containing 1 mM DTT and an empirically determined amount of activated Raf that produces linear incorporation kinetics over the reaction time course.

4. Mix and incubate at room temperature for 90 min.

Stop reaction by addition of 50 pl stop solution.

6. Prewet filter plate with 70% ethanol and rinse with water.

WO 97/36587 PCT/US97/05328 -225- 7. Transfer 90 gl aliquots of stopped reaction to filter plate.

8. Aspirate and wash four times with 200 [l H 2 0.

9. Add 50 tl scintillation cocktail, seal plate, and count in Packard TopCount scintillation counter.

Mao Kinase Phosnhorvlation assay Inhibition of Raf kinase activity in intact cells is measured by determining the phosphorylation state of Map Kinase in TPAstimulated C-33a human epithelial cells. Phosphorylated Map Kinase is detected by "Western" blot using an anti-phospho-Map Kinase antibody.

Materials C33a Human Epithelial Cells The C33a cell line is obtained from the ATCC repository, catalog H TB31, and is maintained in DMEM (Mediatech) 10% fetal bovine serum penicillin/streptomycin (Gibco) according to the instructions provided.

Anti-phospho-MAP Kinase antibody The rabbit polyclonal anti-phospho-MAP kinase antibody is obtained from New England Biolabs (Beverly, MA) Secondary antibody The anti-rabbit antibody-alkaline phosphatase conjugate is obtained from New England Biolabs Acrylamide Gel Ten percent bis-acrylamide electrophoresis gels were obtained from Novex.

Blocking Buffer Ix Phosphate-buffered saline, 0.1% Tween-20, 5% nonfat dry milk.

WO 97/36587 PCT/US97/05328 -226- Antibody dilution buffer lx phosphate-buffered saline, 0.05% Tween-20, 5% bovine serum albumin Alkaline phosphatase substrate The chemiluminescent alkaline phosphatase substrate, CDP-StarTM, is obtained from New England Biolabs.

Assay Buffer 0.1 M diethanolamine, 1 mM MgCl2.

Method 1. C33a cells are grown to confluency in 24 well plates, then starved for 24 hr in DMEM 0.5 charcoal-stripped serum.

2. Compound to be tested, dissolved in DMSO at 1000x concentration, is added to each well.

3. One hour later, TPA (dissolved in DMSO at 1000x concentratrion) is added at a final concentration of 100 ng/ml.

4. Twenty minutes later, the media is removed from all wells, and 100 pl of boiling hot reducing Laemmli sample buffer is added to each well.

The plate is agitated, and the cell lysate is transferred to a 1.5 ml plastic microcentrifuge tube. Each lysate is then sonicated for 10 s, and placed in a boiling water bath for 5-10 minutes. Fifteen microliters of each sample is then loaded on a 10 Laemmli polyacrylamide gel (Novex), and the gel electrophoresed according to the manufacturer's instructions.

Proteins in the gel are electroblotted to a PVDF membrane, which is then rinsed in PBS and blocked with Blocking Buffer for approximately 1 hr at room temperature.

WO 97/36587 PCT/US97/05328 -227- 6. The PVDF membrane is rinsed in PBS. The anti-phospho-MapK antibody, diluted approximately 1:500 in antibody dilution buffer, is incubated with the PVDF membrane with gentle agitation overnight at 4 oC.

7. The PVDF membrane is rinsed 3 times for 5 minutes with Blocking Buffer, then incubated with the secondary antibody, diluted approximately 1 1000 in antibody dilution buffer, for 1 hr with gentle agitation at room temperature.

8. The PVDF membrane is rinsed 5 times for 5 minutes with Blocking Buffer, then incubated with the chemiluminescent alkaline phosphatase substrate dissolved in Assay Buffer for approximately 5 minutes. The membrane is then rinsed, wrapped in plastic, and exposed to x-ray film to detect blotted proteins.

In the Raf kinase inhibition assay, the IC50 ranges from about 0.001 tiM to about 1.5 RM.

In vitro inhibition of ras famesvl transferase Assays offarnesyl-protein transferase.

Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) were prepared as described by Schaber et al., J. Biol. Chem. 265:14701-14704 (1990), Pompliano, et al., Biochemistry 31:3800 (1992) and Gibbs et al., PNAS U.S.A.

86:6630-6634 (1989), respectively. Bovine FPTase was assayed in a volume of 100 l containing 100 mM N-(2-hydroxy ethyl) piperazine- N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCI2, 5 mM dithiothreitol (DTT), 100 mM 3 H]-famesyl diphosphate 3 H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 gtg/ml FPTase at 31 C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol. Precipitates were collected WO 97/36587 PCT/US97/05328 -228onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB 3-plate counter. The assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the 3 H]-FPP was utilized during the reaction period.

Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay. Percentage inhibition is measured by the amount of incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound.

Human FPTase was prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10 IM ZnCI 2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 gl of 30% trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.

The famesyl protein transferase inhibiting compounds are tested for inhibitory activity against human FPTase by the assay described above and the compounds can generally be found to have IC50 of approximately 50 pgM.

In vivo ras faresvlation assay The cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21. The assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is After 4 hours at 37 0 C, the cells are labelled in 3 ml methionine-free DMEM supplemeted with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[ 3 5 S]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer NP40/20 mM HEPES, pH 7.5/5 mM MgC12/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml mM PMSF) and the lysates cleared by centrifugation at WO 97/36587 PCT/US97/05328 -229- 100,000 x g for 45 min. Aliquots of lysates containing equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et al., J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at 4°C, 200 ml of a 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 7.5/1 mM EDTA/1% Triton X- 100.0.5% deoxycholate/0.1%/SDS/0.1 M NaCI) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to famesylated and nonfamesylated ras proteins are compared to determine the percent inhibition of famesyl transfer to protein.

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

Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 104 cells per plate (35 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer Both layers contain 0.1% methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay).

The cells are fed twice weekly with 0.5 ml of medium A containing 0.1% methanol or the concentration of the instant compound.

Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made.

Claims

1. A method of treating cancer, the method comprising administering to a mammalian patient in need of such treatment an effective amount of a RAF antagonist compound and an effective amount of a farnesyl protein transferase inhibiting compound.

2. A RAF antagonist compound and a farnesyl protein transferase inhibiting compound when used in the treatment of cancer.

3. The use of a RAF antagonist compound and a farnesyl protein transferase inhibiting compound for the manufacture of a medicament for the treatment of cancer.

4. A method in accordance with claim 1, a RAF antagonist compound and a farnesyl protein transferase inhibiting compound in accordance with claim 2 or use in accordance with claim 3 wherein the cancer is selected from the group consisting of: cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. A method in accordance with claim 1 or claim 4, a RAF antagonist compound and a farnesyl protein transferase inhibiting compound in accordance with claim 2 or claim 4 or use in accordance with claim 3 or claim 4 wherein the cancer is selected from the group consisting of: histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers.

6. A method in accordance with any one of claims 1, 4 or 5, a RAF antagonist compound and a farnesyl protein transferase inhibiting compound in accordance with any one of claims 2, 4 or or use in accordance with any one of claims 3 to 5 wherein the cancer is selected from the group consisting of: pancreatic and breast carcinoma. S7. A method in accordance with any one of claims 1 or 4 to 6, a RAF antagonist compound and a farnesyl protein transferase inhibiting compound in accordance with any one of claims 2 or 4 to 6, or use in accordance with any one of claims 3 to 6 wherein the RAF antagonist compound is selected from the group consisting of: 25 a compound represented by formula N X X X Rx (R')o-3 ,AR (1-a) or a pharmaceutically acceptable salt thereof, wherein: AR represents an aromatic group containing 6- 10 atoms; X and X' each independently represent -(CH 2 wherein m and n represent integers within the range of from 0-4, such that the sum of m and n is from 0-6; Y represents a member selected from the group consisting of: a direct bond; 0; S(O)y, with y equal to 0, 1 or 2; NRq', with Rq' as defined below; OC(O); C(0)O; SOxNRq' with x equal to 1 or 2 and Rq' as defined below; NRq'SOx; C(O)NRq' and NRq'C(O); represents a 4 to 10 membered non-aromatic heterocycle containing at least one N atom, and optionally containing 1-2 additional N atoms and 0-1 0 or S atom; Rx S represents H, Cl6alkyl(Rq)3, OCi- alkyl(Rq) 3 or C(O)C 1 )alkyl(R)3; each R and R" independently C04154 represents a member selected from the group consisting of: halo; hydroxy; C1-6alkyI(Rq) 3 OC1. 6 alkyl(Rq) 3 C 3 -8cycloalky(Rq)3; CN; CONH 2 CONHC 1 -6alky(Rq) 3 CON (C 1 -alkyl(R) 3 2 NH2; NHCj_ 6 alkyl(Rq) 3 N(Cl.6alkyl (Rq)3) 2 C0 2 H; CO 2 Cl 1 6alkyl(Rq) 3 C(O)C 1 -6alky(Rq) 3 aryl(Rq) 3 heteroary(Rq) 3 CF3; SH; NO 2 SOyCi-6alkyl(Rq)3, with y as defined above; SO 2 NH 2 SO 2 NHC-6alkyl(Rq) 3 S0 2 N(C 1 6alkyl(Rq)3)2; NHSO 2 Cl 1 6alkyl(Rq) 3 NHSO 2 aryl(Rq) 3 NHSO 2 heteroary(Rq)3, N(Rq')C(O)C i-alkyl(Rq) 3 N Rq'C(O)NH (Cl-6alkyl(Rq)3); C24alkenyl(Rq)2-3 and C24~alkynyl(Rq) 13; each R' independently represents a member selected from the group consisting of: CONH2; CONHC 1 e6alkyl(R)3; CON(Cl-6alkyl(Rq)3)2 CON HC3-8CYCloalkyl(Rq) 3 CON (C3-8CYCloal kyl(R)3)2; COAH C0 2 C1_6alkyl (Rq) 3 C(O)Ci-6alkyl(Rq) 3 CO2C3-8cycloalkyl(Rq) 3 C(O)C3-8cycloalkyl(Rq)3; -[C(O)(CH 2 )-CR 5 R 6 -(CH2)k-NR 7 ]p-R 8 -C(O)C 3 8CYCloalkyl(Rq)3-C(O)heterocyclyl(Rq) 3 CON [C1 -aakyl (R) 3 ][C 3 -8cycloalkyl(R)3; C(O)aryl(Rq) 3 C(0)heteroaryl(R) 3 wherein p represents 1, 2 or 3; j and k are integers independently selected from 0- 3; each R 5 and R 6 independently represents H, aryl, Cl-6alky(Rq) 3 or each CR 5 R 6 taken in combination represents a 3, 4, 5 or 6 membered cycloalkyl or heterocyclyl group, an aryl group or a heteroaryl group, wherein when p equals 1, at least one of j and k is 1, 2 or 3; each R 7 and R 8 independently represents H, Ci_6 alkyl or aryl; Rq represents a member selected from the group consisting of: Rq'; CN; C0 2 H; CO2C14talkyl; C(O)Cl4alkyl aryl(Ra)3; NH 2 NHC1i6alkyl(Ra) 3 N(Cl-6alkyl(Ra)3)2; heteroaryl(Ra)3; CON H2 SH; S(O)y; Cl-6alkyl(Ra)3 C(O)NHC1-6alkyl(Ra)3 C(O)N(Cl-6alkyl(Ra)3)2-heteroalkyl(Ra)3- (Ra) (Ra)A (Ra) N- N N2) NHC(O)NH 2 .NHC(NH)NH 2 and wherein and (Ra) 3 *.:independently represent mono or bicyclic ring systems, non-aromatic or partially C.2o aromatic, containing from 5-10 ring atoms, 14 of which are N and 0-1 of which are 0 or S(O)y, with y equal to 0, 1 or 2, optionally containing 1-2 carbonyl groups; each Ra independently represents a member selected from,~ the group consisting of: H, Ci-6alkyl, OCis6alkyl, aralkyl, substituted aralkyl, heteroaralkyl. substituted heteroaralkyl, aralkoxy, substituted aralkoxy, halo, hydroxy, CN, CONH 2 CONHC1i6alkyl, CON(Cl-6alkyl)2, CO 2 H, CO2CI-6alkyl, C(O)Ci-6alkyl, phenyl, CF 3 SH, NO 2 SOyC 1 .00 25 6alkyl, with y as defined above; SO 2 NH 2 SO 2 NHCi-6alkyl, NHSO 2 (Substituted aryl), NHS02(substituted heteroaryl), NHS0 2 C1. 6 alkyl, NHSO2aryl, NHSO2heteroaryl, NH 2 NHCi-6alkyl, N(Cl-6alkyl)2, NHC(O)Ci. 6alkyl, NHC(O)NH(Cl. 6 alkyl), C24alkenyl and C24alkynyl; and Rq' represents H, OH, C14LalkyI, -OCi. U 4alkyl, aryl or C(O)Ci4alkyl; a compound represented by formula N X, N Rx H rcy (R) 0 3 ,,AR (R) 0 3 (1-b) ~c3~ AQ~,or a pharmaceutically acceptable salt thereof, wherein: C04154 N Ra) 3 (Ra) 3 AR, X, x, Y, y, S Rx, R, j, k, R 7 R 8 and are as defined above with respect to formula (1 each R' independently represents a member selected from the group consisting of: hydroxy; Cl-6alkyl(Rq) 3 C 3 -8cycloalkyl(Rq)3; OCj-6alkyl(Rq) 3 003- 8cycloalkyl(Rq)3; .heterocyclyl(R)3; CN; NH(Rq") NHCj. 6 alkyl(Rq)3 N(Cli.6alkyl(R) 3 2 NHC3. 8cycloalkyl(Rq) 3 N(C 3 -8cycloalky(R)3)2; OF 3 SH; NO 2 C 2 A4alkenyl(R)2.3, aryl(Rq) 3 heteroaryl(Rq) 3 02- 4 alkynyI(Rq)1. 3 -OC(O)C 3 4 8cycloalkyl(Rq)3; SO 2 NH 2 SO 2 N HC 1 -6alkyl(Rq) 3 SO 2 N (Cl-6alkyl(R)3)2 NHSO 2 Cl.6alky(Rq) 3 N HSO 2 aryl(Rq)3, NHSO 2 heteroary(Rq)3, -OC(O)heterocyclyl(R)3; N(Rq')C(O)Cl_ 6 alkyl(Rq) 3 NRq'C(O)NH(Ci-6alkyl(R) 3 -OC(O)Ci-6alkyl(Rq) 3 -OC(O)aryl(R'j3; -OC(O)heteroaryl(R)3; C(=Nq R')NH 2 -C(=Nq')NHCiealkyl(Rq) 3 (Cl-alky(Rq)3)2; -O[C(O)-(CH 2 )j-CR 5 R 6 -(CH2)k-NR 7 ]p- i0 R 8 and -[NR 7 (CH2)k-CR 5 R 6 -(CH2)1-C(O)Ip-0R 9 R 5 and W 6 are independently H, aryl, Cl-6alkyl(Rq) 3 or CR 5 R 6 in combination represents a 3, 4, 5 or 6 membered cycloalkyl or heterocyclyl group, an aryl group or a heteroaryl group; p represents 1, 2 or 3, with the proviso that when p represents 1, CR 5 R 6 represents a 3, 4, 5 or 6 membered cycloalkyl group or a heterocyclyl group, an aryl group or a heteroaryl group, and at least one of j and k is 1, 2 or 3; R 9 represents H, a negative charge balanced by a positively charged group or a protecting group; Rq represents a member selected from the group consisting of: Rq; CN; 002H; CO2C1. 4 alkyl; C(O)Ol4alkyl; aryl(Ra)3; heteroaryl(Ra NHCi. 4alkyl N(Ci-4alkyl)2; CONH 2 SH; S(O)y; Cl.6alkyl(Ra)3 C(O)NHCl. 6 alkyl(Ra)3; C(O)N(C1l6alkyl(Ra)3)2; (Ra) 3 (Ra) 3 NHC(NH)NH. 2 -heteroalkyl(Ra)3; -NHC(O)NH2; _N and N and -Rq represents *9 9* 9 p 0 *0

9. 0 p 000 0 p 0 0 *00* H, OH or 00-4 alkyl; 20 and a compound represented by formula RN N (1 -c) or a pharmaceutically acceptable salt thereof, wherein: R 1 is 4-pyridyl, pyrimidinyl, quinazolin-4-yl, quinolyl, isoquinolinyl, 1-imidazolyl or 1-benzimidazolyl which is optionally substituted with one or two substituents each of which is independently selected 25 from C14alkyl, halogen, C1.4alkoxy, Cl4alkylthio, NRioR 2 0, or N-heterocyclyl ring which ring has from to 7 members and optionally contains an additional heteroatomn selected from oxygen, sulfur or NR22; R 2 is hydrogen, -(CRjoR 2 o)nOR1 2 heterocyclyl, heterocyclyl Cl-ioalkyl, Ci-loalkyl, halo-substituted C1_ loalkyl, C2-loalkenyl, C2.loalkynyl, C3- 7 cycloalkyl, C3-7cycloalkylCt-ioalkyl, C5-7cycloalkenyl, aryl, aryl C1_ ioalkyl, heteroaryl, heteroarylCitloalkyl, (CRloR2o)n'0R13, (CRoR 2 o)n'S(O)mR25, (CR 1 oR 2 0)n'N HS(O) 2 R 25 (CRioR 2 o)n'NR 8 Rq, (CRioR 2 o)n'NO 2 (CRloR2o)n'CN, (CRiOR 2 o)n'S(O)mNR 8 Rq, (CRoR 2 0)n'O(Z)Rl3, (CRioR 2 o)n'C(Z)OR 1 3 (ORjoR 2 0)n'N RjoC(Z)NNRR9, (CR 1 oR 2 0)n'C(Z)N R 1 3 0R 1 2 (CRoR 2 0)n'NRloO(Z)R 1 3, (CRjoR2o)n'NRjoC(Z)NRq, (CRioR 2 o)n'N(0R21)C(Z)NR8Rq, (CRloR 2 0)n'N(0R 2 1)C(Z)R13, (RRon'(0 2 1 ,(ioo'NRjoC(=NR27)NR8R9, (CRjoR 2 o)n'OC(Z)NR 8 Rq, C041 54 233 (CRioR 2 o)n'NRIoC(Z)NP8R 9 (CRioR 2 o)n'C(Z)ORio, 5-(R2 5 ,2,4-oxadiazol-3-yl or 4-(Rl2)-5-(Rl 8 Rl 9 dihydro-1 ,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclyalkyl moieties may be optionally substituted; n' is an integer having a value of 1 to 10; m is 0 or the integer 1 or 2; R3 is Q-(Yi)t; Q is an aryl or heteroaryl group; t is a number having a value of 1, 2 or 3; Z is oxygen or sulfur; n is 0 or an integer from 1 to 10; Y, is independently selected from hydrogen, C1_5alkyl, halo-substituted Cl-5alkyl, halogen, or-(CRoR2o)nY 2 Y 2 is-OR8, -NO 2 SR8, -S(O)m'0R 8 -S(O)mNR 8 R 9 -NR 8 Rg, 0O(CRioR 2 0)nNR 8 R9, -C(O)R8, -C0 2 R 8 C02(CRipR2o)n'CONR8R 9 -ZC(O)R 8 -CN, -C(Z)NR8R 9 NR-NRioC(Z)Ra, -C(Z)NR 8 OR9, NRioC(Z)NR8R9, -NRioS(O)mRii, -N(OR 2 i)C(Z)NR8R 9 -N(0R 2 1 )C(Z)R 8 -C(=N0R 21 )R 8 NRioC(=NR15)SRii, -NRloOC(=NR15)NR8R 9 -NRioC(=CR 1 4 R 24 )SR1i, -NRioC(=CR 1 4 R 2 4 )NR 8 R9, NRioC(O)C(O)NR8Rg, -NRioC(O)C(O)ORio, -C(=NRi4)NR8R9, -C(=NOR134NR 8 R 9 -C(=NR134ZR 11 OC(Z)NR8R 9 -NRioS(O)mCF 3 -NRioC(Z)ORio, 5-(R 1 8 ,2,4-oxadizaol-3-yl or 4-(R12)-5-(R18Rig)-4 dihydro-1,2,4-oxadiazol-3-yl; m' is a number having a value of 1 or 2; R 4 is pheny, naphth-1-yl or naphth-2-yl which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl or 5-naphth-1-yl substituent, is halo, cyano, C(Z)NR7Rl7, -C(Z)0R 2 3 -(CMoR 2 o0m"'C0R 36 SR 5 -SOR 5 0R36, halo-substituted-Cl~alkyl, C14alkyl, ZC(Z)R 3 6 -NRioC(Z)R 2 3 or-(CRioR 2 o)m"'NRioR 2 o and which, for other positions of substitution, is halo, cyano, -C(Z)N R 1 6 R 2 6 -C(Z)0R 8 -(CRioR 2 0)m"'COR 8 -S(O)mR 8 -OR8, halo-substituted-Cl~alkyl, C 1 4alkyl, -(CRioR2o)m"NRioC(Z)R5, -N RioS(O)m'Rii, -NRioS(O)m'NR7Ri 7 -ZC(Z)R8 or-(CRioR 2 0)m'NRisR 2 6; wherein m" is 0 to 5 and is 0 or 1; R5 is hydrogen, C14alkyl, C24alkenyl, C2..4alkynyl or NR 7 Rv7, *excluding the moieties-SR 5 being-SNR7RI7 and -SOR5 being-SOH; R 6 is C14alkyl, halo-substituted-Cl. 4alkyl, C14alkenyl, C24alkynyl or C3-5CYCloalkyl; R 7 and R 1 7 are each independently selected from hydrogen or C14alkyl, or R 7 and R 17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 2 2 R 8 is hydrogen, heterocyclyl, heterocyclylalkyl or Rij; R 9 is hydrogen, Ci- joalkyl, ,C2.ioalkenyl, C2-loalkynyl, C3-7cycloalkyl, C5_ 7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl or R8 and Rg may together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NRi 2 Rio and R 2 o are each independently selected from hydrogen and C14alkyl; Rii is Ci.ioalkyl, halo-substituted Cioalkyl, C2-loalkenyl, C2.ioalkynyl, C3-7cycloalkyl, C5-7cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R 12 is hydrogen, -C(Z)Rl 3 or optionally substituted C14 alkyl, optionally substituted arylC14 alkyl or S(O)2R2 5 R1 3 is hydrogen, Ci-loalkyl, C3-7cycloalkyl, heterocyclyl, heterocyclyl Ci-ioalkyl, aryl, aryl C1.1o alkyl, heteroaryl or heteroaryl Ci-ioalkyl; R14 and R 2 4 is each independently selected from hydrogen, alkyl, nitro or cyano; R 15 is hydrogen, cyano, C14alkyl, C3-cycloalkyl or aryl; R16 and R 26 is each independently selected from hydrogen or optionally substituted C1_4alkyl, optionally substituted aryl or optionally substituted aryl-C14alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatomn selected from oxygen, sulfur or NRi 2 R 18 and Rig is each RAndependently selected from hydrogen, C 1 4 alkyl, substituted alkyl, optionally substituted aryl, optionally susiue arylalkyl or together denote a oxygen or sulfur; R 21 is hydrogen, a pharmaceutically C041 54 acceptable cation, Ci-ioalkyl, C 37 CYCloalkyl, aryl, aryl Cl~alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl, or Ci-ioalkanoyl; R22 is Rio or C(Z)-Cl-4alkyl; R 2 3 is Cl-4alkyl, halo-substituted-Cl-4alkyl or C3- CYCloalkyl; R 3 6 is hydrogen or R23; R25 is Ci-loalkyl, Cai7cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-Cl-ioalkyl, heteroaryl or heteroaryl alkyl; R2 7 is hydrogen, cyano, Cl~alkyl, C3- 7 cycloalkyl or aryl. 8. A method in accordance with claim 1, a RAE antagonist compound and a farnesyl protein transferase inhibiting compound in accordance with claim 2, or use in accordance with claim 3 wherein the farnesyl transferase inhibiting compound is selected from the group consisting of: a compound represented by one of formulas (1l-a) through (Il-c): Ri R Ia Rib R 2 R ia R ia R ibI R R5 (1l-a) R 9 R 8 Rla Ria Ri R 2 G Ria Ria Rib NI R9 2 Ria Ria I Rib R 0Ria Ria Rib N~ 0S or a pharmaceuticaly acceptable salt thereof, wherein with respect to formula (Il-a): (i l Rib R 2 It RR s R(Il-a) Ria and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C 3 ilocycloalkyl, 02. 6aknl 260yy, 10,RS0mRO(0N10 N lCO- R10OC(O)-, N 3 -N(R 10 or Rl'OC(O)NRO-, c) Ci.6alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-iocycloalkyl, C2e6alkenyl, C2s6alkynyI, R 1 0 R 1 R 1 0 0(O)N R 10 ON, (R 1 0 2 N- RlOC(O)-, RiOOC(O)-, N 3 -N(RO) 2 or RiiOC(O)N Rio-, R 2 and R 3 are independently selected from: H; unsubstituted or substituted Ci-8alkyl, unsubstituted or substituted C2-8alkenyl, unsubstituted or substituted C248alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, R6 "R 0 or 0 wherein the substituted group is substituted with one or more of:1) arlor CD4154 heterocycle, unsubstituted or substituted with: a) Ci~alkyl, b) (CH 2 )pOR 6 c) (CH 2 )pNR 6 R7, d) halogen, R6 R6 _N 7 N NR7R7a Y Y 2) C3-6Cycloalkyl, 3) OR 6 4) SR 6 S(O)R 6 S02R 6 5)-NH 6 R 7 6) 0 0 R 6 -0 NR 6 R 7 -O OR 6 I Y N1 1 8) 0 0 ,10) 0 11)-S0 2 -NR 6 R7, 12) 13) R6 0 "R6 "Y 0 or 14) 0 ;'or R 2 and R 3 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: 0, and-N(CORO)-; R 4 and k 5 are independently selected from H and OH 3 and any two of R 2 R 3 R 4 and R 5 are optionally attached to the same carbon atom; R 6 R 7 and R7a are independently selected from: H; C1_4alkyl, CucycloalkyI, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Ci-salkoxy, b) aryl or heterocycle, c) halogen, d) R11 HO, e) 0 f)-SO 2 Rii, or g) N(RlO) 2 or R 6 and R 7 may be joined in a ring; R 7 and Rla may be joined in a ring; R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-iocycloalkyl, 02- 6alkenyl, C2-6alkynyl, pertluoroalkyl, F, Cl, Br, R' 0 RIIS(O)m-, R' 0 0(O)NR' 0 CN, NO 2 (R 10 )2N- C(NRO), RiOC(O)-, R'OOC(O)-, N 3 -N(RO) 2 Or RllOC(O)NRIO-, and c) Ci-6alkyl unsubstituted or substituted by aryl, heterocycle, C3-iocycloalkyl, C2e6alkenyl, C2-6alkynyl, perfluoroalkyl, F, Cl, Br, R' 0 0-, 15 RIOC(O)NH-, ON, H 2 R1OO(O)-, R'OOC(O)-, N 3 -N(RO) 2 or RlOOO(O)NH-; R 9 is selected from: a) hydrogen, b) C2-6alkenyl, C2s6alkynyl, perfuoroalkyl, F, Cl, Br, R1 0 R"S(O)m-, -RiOC(O)NRO-, ON, N02, (RlO) 2 RIOC(O)-, RlOOC(O)-, N 3 or RllOO(O)NRIO-, and c) Ci- go: ~6alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R' 0 R'OC(O)NR' 0 ON, 20(R10) 2 N-O(NR1O)-_, R10OC(O)-, N 3 or Ri'OC(O)NRO-; RIO is independently selected from 2ohydrogen, C1.6alkyl, benzyl and aryl; R"1 is independently selected from C1_6alkyl and aryl; A' and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR'O, -NRIOC(O)-, 0, -N(R' 0 S(O) 2 N(RIO), or S(O)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) Cl-2oalkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatomn selected from 0, S, and N, and e) 02- 2oalkenyl, provided that V is not hydrogen if A' is S(O)m and V is not hydrogen if A' is a bond, n isO and A 2 is S(O)m; W is a heterocycle; X is-CH2-, or-S(O)m-; Y is aryl, heterocycle, unsubstituted or so substituted with one or more of: 1) C1_4alkyl, unsubstituted or substituted with: a) ClAalkoxy, b) NR 6 R 7 C) C3-6CYCloalkyl, d) aryl or heterocycle, e) HO, f)-S(O)mR 6 or g)-O(O)NR 6 R 7 2) aryl or heterocycle, 3) halogen, 4) OR 6 5) NR 6 R 7 6) ON, 7) NO 2 8) OF 3 9)-S(O)mR 6 10)-C(O)NR 6 R 7 or 11) Cmcycloalkyl; 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 Oorl;tisoor1;anduis4or5; with respect to formula (1l-b): COA4154 Ria R alI Rib 2 G R8) AIA2*lV~J ljX R G R 1 8 Rla Rib N111~4 R PsF 4 z(I l-b) Ria, Rib, RIO, R" 1 R 2 R 3 R 6 R 7 p, Rla, u, R 8 A 2 V. W, X, n, p. r, s, t and -u are as defined above with respect to formula R 4 is selected from H and CH3; and any two of R 2 R3 and R 4 are optionally attached to the same carbon atom; R 9 is selected from; a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R' 0 R 10 C(O)NR 1 0 CN, N02, (RlO)2N-C(NRO)' R 1 0 N3, -N(RO) 2 or RliOC(O)NR'O) and c) Ci-6alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R' 0 R 11 RIOC(O)NRI0-, CN, (R 1 0 2 NC(NRIO)-, RIO0C(O)-, R 10 0C(O)- ,N 3 -N(RlO) 2 or RllOC(O)NRO-; G is H 2 or 0;Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following: 1) Ci- 4alkyI, unsubstituted or substituted with: a) ClAalkoxy, b) NR 6 R 7 C) C3-6cycloalkyl, d) aryl or heterocycle, e) HO, f)-S(O)mR 6 or g)-C(O)NR 6 R 7 2) aryl or heterocycle, 3) halogen, 4) OR6, 5) NR 6 R 7 6) CN, 7) NO 2 8) C17 3 9)-S(O)mR 6 1 0)-C(O)NR 6 R 7 or 11) C3e6cycloalkyl; with respect to formula (Il-c): R 9 2 Ria RialI Rib R Ria RiB Rib N1 0R Z RaG (Il-c) RiRib, RIO, R 1 1 m, R 2 R 3 R 6 R 7 p, u, R7a, R 8 A 1 A 2 V, W, X, n, r and t are as defined above with respect to formula R 4 is selected from H and CH 3 and any two of R 2 R 3 and R 4 are optionally attached to the. same carbon atom; G is 0; Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following: 1) C 1 4alkyl, unsubstituted or substituted with: a) Cl~alkoxy, b) NR 6 R 7 C) C3-6cycloalkyl, d) ary or 2o heterocycle, e) HO, f) -S(O)mR 6 or g) -C(O)NR 6 R 7 2) aryl or heterocycle, 3) halogen, 4) OR 6 :NR 6 R 7 6) CN, 7) NO 2 8) CF3; 9) -S(O)mR 6 10) -C(O)N R6R7, or 11) C3-6cycloalkyl; and s is 1; a compound represented by formula (lI-d) through OVS:H 0 3 R4 N OH 0SR 9 z 5b k5a R R) l a Ria 1I Rib IIY R 1 a. Ria Rib U FH 2 t R2a R2b (11-d) C041 54 H 0 R 3 R4 NOR R 9 Z sa R 5 b R 1 a Ria Rib H 2 1 R2a~\~ R2b (ll-e) H 0 R R R 9 Z R NO (R8)A1 Ria R 1 Ribz Ria R 1 a Rib 1 H 2 t R2a R2b (lf H 0 RPR R4 R KN R9 R~ Rla Rib H 2 1 R1 l-g) wherein with respect to formula (11-d):H 0 H 0@ 4R 3 R4 N V. OH R9 z 5 R :Ri Rib H) V t' R" V, W, m, n, p and r are as defined above with respect to formula RIa and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3.iocycloalkyl, C2.oalkenyl, C 26 alkynyl, aR' 0 0, R 11 R' 0 C(O)NRl 0 CN, NO 2 (R 10 2 N-C(NRIO)-, R 10 R1 0 N 3 or R"lOC(O)NRO-, c) Ci-6alkyl unsubstituted or substituted by aryl, heterocyclyl, C3ilocycloalkyl, C2- .,10 6alkenyl, C2-6alkynyl, R 10 R 11 R 10 C(O)NR' 0 CN, (R' 0 2 N-C(NR1 0 RIOC(O)-, R' 0 N 3 or RliOC(O)-NR'O-; R 2 a. and R2b are independently selected from: a) hydrogen, b) CI-6alkyl unsubstituted or substituted by C2.ralkenyl, R' 0 R"S(O)nr, RlOC(O)NR 1 CN, N 3 (R1o) 2 RlOOC(O)-, -N(RlO)2, or R11OC(O)NRO-, c) aryl, heterocycle, C3.1ocycloalkyl, C 2 -6alkenyl, R' 0 0, R 11 R 10 C(O)NR 10 CN, N02, (RO) 2 N-C(NRO)-, RlOC(O)-, RlOOC(O)-, N3, or R 11 00(O)NR'O-, and d) Ci-6 alkyl substituted with an unsubstituted or substituted group selected from ___aryl, heterocyclyl and C3-iocycloalkyl; R 3 andR 4 are independently selected from: a) a side chain of a C041 54 238 naturally occurrng amino'acid, b) an oxidized form of a side chain of a naturally occurning amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl-2oalkyl, C2-2oalkenyl, C3-locycloalkyI, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R 10 N02, R 1 0 RIIS(O)m-, R 1 0 C(O)NRIO-, CN, (R 1 0 2 N-C(NR 1 0 R' 0 R 10 N3, N(Rl 0 R 1 1 0C(O)NR 1 0 -and Cl-2oalkyI, and d) C1-6alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-iocycloalkyl; or R 3 and R 4 are combined to form-(CH2)s-; R~a and R~b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Ci.2oalkyl, C2.2oalkenyl, C3-locycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, CF 3 N(R 10 N02, R 1 0 0-, R 11 R 10 C(O)NR 10 CN, (R 1 0 2 N-C(NR 1 0 RIOC(O)-, R 1 0 N3, -N(R 10 R 11 0C(O)NRI 0 -and Cl- 2 oalkyl, d) C1-6alkyI substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3.iocycloalkyl; or R5, and R~b are combined to form-(CH2),wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, and-N(CORO)-; X-Y is a) R~a H MR7b o 0 b) e) H C2 CH 2 R 7 a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3.1ocycloalkyl, and e) C1-6alkyl substituted with f ~hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3.iocycloalkyl; R~b is selected from a) hydrogen, b) unsubstituted or substituted'aryl, c) unsubstituted or substituted 20 heterocycle, d) unsubstituted or substituted C3-locycloalkyl, e) Cio6alkyl substituted with hydrogen or an of0: *0 unsubstituted or substituted group selected from aryl, heterocycle and C3.iocycloalkyl, f) a carbonyl '00, group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3. of o:iocycloalkyl and Ci-6alkyl substituted with hydrogen or an unsubstituted or substituted group selected .0.25 from aryl, heterocycle and C3ilocycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted *1000* 25or substituted group selected from aryl, heterocycle, C3.1ocycloalkyl and CI.6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3.ibcycloalkyl; R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3aiocycloalkyl, C2-6 alkenyl, C 2 6alkynyl, perfluoroalkyl, F, Cl, Br, R 10 R 11 R' 0 C(O)NR 1 CN, NO 2 R 1 0 2 N-C(NR 1 RI 0 N3, -N(R 10 or R' 1 0C(O)NR 10 and c) Ci-6alkyl unsubstituted or substituted by aryl, 3o heterocycle, C3-iocycloalkyl, C26alkenyl, C2.ealkynyl, perfluoroalkyl, F, Cl, Br, RW 0 R 11 S(O)m-, RIOC(O)NH-, CN, H 2 R1 0 RIO0C(O)-, -N3, -N(R 10 orRlOOC(O)NH-; R 9 is selected from: a) hydrogen, b) C2s6alkenyl, C2o6alkynyl, perfiuoroalkyl, F, Cl, Br, R 1 0 R 11 S(O)m, R 1 GC(O)NR 10 CN, N02, (RIO) 2 C-(NR 1 0)-RIOC(O)-, R 10 N3, -N(R 10 or RllOC(O)NRO-, and c) Cis6alkyl unsubstituted or! substituted by pertluoroalkyl,F., Cl, Br, RI 0 R 1 1 S(O)m, R' 0 C(O)NR 10 CN,. (R 10 )2N- C(NRlO)-, RlOC(O)-, RIOOC(O)-, N3, or R'lOC(O)NRO-; RIO is independently selected from H, C,.salkyl, benzyl, substituted aryl and Ci-6alkyl substituted with substituted aryl; A' and A 2 are independently C04154 239 selected from: a bond, -CH=CH-, -C(O)NRO-, -NRlOC(O)-, 0, -N(R 1 0 -S(O) 2 N(Rl0)-, or S(O)m;Z is independently H 2 or 0; s is 4 or 5; t is 3, 4 or 5; and u is 0 or 1; with respect to formula (ll-e): H 0 R 3 R4 N OR R 9 Z >K 5 a R la Ribz Ria ia Rb H 2 R2ab Rb(le RI', W, m, n, p and r are as defined above with respect to formula Ria and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-iocycloalkyl, C2-6alkenyl, C2e6alkynyl, R1 0 0-, RS(O)m-, RlOC(O)NRO-, CN, N0 2 (Rlo) 2 N-C(NR10)-, RlOC(O)-, RIOOC(O)-, N 3 or R"OC(O)NRO-, c) C1-6alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-locycloalkyl, C2s6alkenyl, C2e6alkynyl, R1 0 R'OC(O)NR' 0 CN,-(R'O) 2 N-C(NRl), RlOC(O)-, R'OOC(O)-, N3, or R"OC(O)-NRO-; R 2 a and R2b are independently selected from: a) hydrogen, b) Ci-6alkyl unsubstituted or substituted by C2s6alkenyl, R1 0 RI 0 C(O)NR' 0 CN, N 3 (R'O) 2 N-C(NR' 0 Rl 0 R1 0 -N(R' 0 2 or R"OC(O)NR'O-, c) aryl, heterocycle, C3ilocycloalkyl, C26alkenyl, R1 0 0, R 11 R'OC(O)NR' 0 CN, NO 2 (R1O) 2 N-C(NR10), RlOC(O)-, R10OC(O)-, N 3 -N(R'O) 2 or R"OC(O)NRO-, and d) dv-6alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C 3 iocycloalkyl; R 3 and R 4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidised form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-2oalkyl, C2-2oalkenyl, C 3 got lacycloalkyl, aryl or heterocyclyll group, wherein the substituent is selected from F, Cl, Br, CN, (R'O) 2 N- '00 C(NR' 0 R'OOC(O)-, N 3 -N(Ro) 2 Rl"OC(O)NRO- and Ci-2oalkyl, and d) C1-alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-iocycloalkyl; or R 3 and R 4 are combined to form-(CH2)!,; R~a and R51) 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 C1-2oalkyl, C2. 2oalkenyl, C3.iocycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, CF3, NCR' 0 2 N02, R' 0 R"IS(O)m-, RlOC(O)NR10O., CN, (R1O) 2 N-C(NRO), RI 0 R'O0C(O)-, N3, *N(RlO)2, Ri'OC(O)NRO-and C1.2oalkyl, and d) Cisalkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-locycloalkyl; or R~a and R5b are combined to forrn-(CH2)s- wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and-N(CORl 0 RWis a) substituted or unsubstituted Cl.alkyl, substituted or unsubstituted 8cycloalkyl, 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) Ci-alkyl, 2) aryl, 3) C04154 N/_0 R7b heterocycle, 5) -OR 0 or b) X-Y is a) ,b) H c) ,d H ,)-CH 2 -CH2-; Ria is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-iocycloalkyl, and e) C1-6alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-locycloalkyl; Rib is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-locycloalkyl, e) C1-6alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and 03-iocycloalkyl, I) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, 03-locycloalkyl and C,-6alkyl l0 substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-iocycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-locycloalkyl and C1-6alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and -C3.locycloalkyl; R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3.iocycloalkyl, C2-6alkenyl, C2-6alkynyl, perfluoroalkyl, F, Cl, Br, R1 0 R'OC(O)NR' 0 CN, NO 2 R 1 0 2 N-C(NR1 0 R'OC(O)-, N 3 -N(R' 0 or Ri'OC(O)NRO-, and c) C1-6alkyl unsubstituted or substituted by aryl, C3-iocycloalkyl, C2-6alkenyl, C2s6alkynyl, perfluoroalkyl, F, Cl, Br, R' 0 R"S(O)m-, R'OC(O)NH-, CN, H 2 R10OC(O)-, N 3 -N(RO) 2 or Ri0OC(O)NH-; R 9 is selected *from: a) hydrogen, b) C2.6alkenyl, C2e6alkynyl, pertluoroalkyl, F, Cl, Br, R1 0 Ri0 C(O)NR'O.- CN, NO 2 (R' 0 2 RiOOC(O)-, N 3 or Rl1OC(O)NRO., and c) C,46alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R1 0 R"IS(O)m-, R'OC(O)NR' 0 CN, (Rlo)2N- RIOC(O)-, R'OOC(O)-, N 3 or R"OC(O)NRO-; R1 0 is independently selected from H, Ci-6alkyl, benzyl, substituted aryl and Ci-6alkyl substituted with substituted aryl; R1 2 is hydrogen or CI-6 alkyl; R1 3 is Cie6alkyl; A' and A 2 are independently selected from: a bond, -CH=CH-, or S(O)m; Z is independently H 2 or 0; sis 4or 5; tis 3, 4 or 5; and uis 0ori1; with respect to formula (11l-f): H 0 R3 R R4 N OH R 1 6 Ria IRib Ra Ra Rb 2) (I-f R1 V, W, m, n, p and r are as defined above with respect to formula Ria and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3vwcycloalkyl, C2.6alkenyl, C246alkynyl, C04154 241 WOO0-, R 11 R1OC(O)NRlO-, CN, N02, (R1O) 2 NC(NRO)) R 1 0 RIO0C(O)-, N 3 or R' 1 0C(O)NR' 0 c) C1.6alkyl unsubstituted or substituted by aryl, heterocyclyl, C3-locycloalkyl, C 2 6alkenyl, C2s6alkynyl, R 1 0 R 11 R' 0 C(O)NR' 0 CN, (R 10 2 N-C(NRIO)) RIOC(O)-, RlIcOC(O)-; N3, or R'IOC(O)-NR' 0 R~a and R2b are independently selected from: a) hydrogen, b) C1-6alkyl unsubstituted or substituted by C2o6alkenyl. R 1 0 R 11 R 10 C(O)NR 1 0 CN, N 3 (R 10 2 N-C(NRIOY, RlOOC(O)-, -N(R 10 or RIlOC(O)NR 10 c) aryl, heterocycle, C3-iocycloalkyl, C2-6alkenyI. RI 0 R 11 RI 0 C(O)NR' 0 CN, NO 2 (R'o) 2 N-C(NRO)) RI 0 R 10 N3, or R11OC(O)NRO-, and d) Cis6alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-iocycloalkyl; R 3 and R 4 are independenly 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 Ci-2oalkyl, C 22 oalkenyl, Ca-iocycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R 10 -N02, R' 0 R 1 1 R 1 0 C(O)NR 10 CN, (R1O) 2 NC(NRlO);, RIOC(O)-, R 10 N3, N(R 10 Rl 1 OC(O)NRI 0 and Cl-2oalkyl, and d) C1-6alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-locycloalky; or R 3 and R 4 are combined to form-(CH2)s., X- R~a H R7b M Y is a) 0 b) c) H .f-GH2- CH 2 V~ is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-iocycloalkyl, and e) Ci-6alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3aiocycloalkyl; R~h is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-iocycloalkyl, e) Cv-6alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C 3 0 cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3- iocycloalkyl and C1.6alkyl substituted with hydrogen or an unsubstituted or substituted group selected 25 from aryl, heterocycle and C3.1ocycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group* selected from aryl, heterocycle, C3-jocycloalkyl and Ci-6alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-IOCycloalkyl; R 8 is independenly selected from: a) hydrogen, b) aryl, heterocycle, C3.iocycloalkyl, C2s6alkenyl, C 2 6alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R 11 R 1 0 C(O)NR' 0 CN, N02, R1o 2 NC(NRIO)-, R 1 0 R 10 N3, -N(R 10 or R1IOC(O)NRIO., and c) Ci-alkyl unsubstituted or substituted by aryl, heterocycle, C3-iocycloalkyt, C2-6alkenyl, C2s6alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R 11 S(O)m,' R 10 C(O)NH-, CN, H 2 RlOOC(O)-, N3, -N(R 10 or RlOOC(O)NH-; R 9 is selected from: a) hydrogen, b) C2-6alkenyl, C2.6alkynyl, perfiuoroalkyl, F, Cl, Br, R 10 R 11 S(O)m, R'OC(O)NR 10 CN, N02, (R'O) 2 N-C-(NR1 0 R 10 N3, or RllOC(O)NRO-, and Cis6alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R' 0 R 1 0 C(O)NR 10 CN, (R 10 )2N- C(NRIO)-, RiOC(O)-, R10OC(O)-, N3, -N(R 10 or RI1OC(O)NRO-; R 1 0 is independenly selected from H, Ci-6alkyl, benzyl, substituted aryl and Cis6alkyl substituted with substituted aryl; R1 2 is hydrogen or Ci. 00 0 *0 000.. .09* 0.00 0 000 C04154 6alkyl; R 13 is Ci-6alkyl; A' and A 2 are independenly selected from: a. bond, -CH=CH-, C(O)NRO-, NR'OC(O)-, 0, -N(R' 0 .S(0)2N(RlO)-, -N(R' 0 or Z is independently H 2 or 0; q is 0, 1 or 2; s is 4or 5;t1is3, 4 or5; and u is 0 or 1; with respect to formula (11-g): R 3 R4 N J1 R 9 Z q R~ Ra jRb Ria Ria Rib H) R2b (lg R 1 1 V, m, n, p and r are as previously defined with respect to formula Ria and Rib are independently selected from a) hydrogen,b) aryl, heterocycle, C3-locycloalkyl, C2s6alkenyl, C2-6alkynyl, R' 0 RIIS(O)m-, R 10 C(0)NRI 0 CN, NO 2 (RI02N-C(NRO)-, R 10 RlOOC(O)-, N 3 -N(R' 0 or R'lOC(O)NR' 0 CI-6alkyl unsubstituted or substituted by aryl, heterocycle, C3-iocycloalkyl, C2- 6alkenyl, C2-6alkynyl, R1 0 R 11 R 1 0 C(0)NRIO-, CN, (R 1 0 2 N-C(NR 1 0 R 1 0 R 10 N3, -N(R 10 or RllOC(O)-NRO-; R 2 a and R 2 b are independently selected from: a) hydrogen, b) CI-6alkyl unsubstituted or substituted by C2s6alkenyl, R 1 0 R 11 R 10 C(0)NR' 0 CN, N3, (R 10 2 N-C(NR 1 0 RlOC(0)-, RlOOC(0)-, -N(R 10 or R'OC(0)NRO-, c) aryl, heterocycle, C3.1ocycloalkyl, C26alkenyl, R 1 0 0- R 11 R'OC(O)NRIO-, CN, NO 2 (R 10 2 N-C(NRIO), R 10 Rl 0 N 3 -N(R 10 2 or R'OC(O)NRO-, and d) C1-6alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-iocycloalkyI; R 3 and R 4 are independently selected from: a) a side chain of a naturally occur-ring amino acid, b) an oxidized form of a side chain of a naturally. occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Ci.2oalkyl, C 2 2oalkenyl, C3ijocycloalkyl, aryl. or heterocycle group, wherein the substituent is selected from F, Cl, Br, 2N(R' 0 2 N02, R 10 R 11 RIOC(0)NRIO, -CN, (R 1 0 2 N-C(NR 1 0 R 1 0 R1 0 N3, N(R'O) 2 RI'OC(0)NRO-, and Cl-2oalkyI, and d) Ci.6alkyl substituted with an unsubstituted or substituted .:group selected from aryl, heterocycle and C3-iocycloalkyl; or R 3 and R 4 are combined to form-(CH2),-; X- ~RR~ (a H R~b (0) Y is a) 0 b) kc) /Nd) H -CH2- CH 2 R 7 a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3.locycloalkyl, and e) C1-6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3ijocycloalkyl; R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3.iocycloalkyl, e) C1-6alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3aiocycloalkyl, f) a carbonyl 3o group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3- ~-~-~-..ocycloalkyl and CI-alkyl substituted with hydrogen or an unsubstituted or substituted group selected CZ4154 243 from aryl, heterocycle and C3.locycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-iocycloalkyl and Ci.6alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and 03.locycloalkyl; R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-locycloalkyl, C2-6alkenyl, C2. 6alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R 1 1 R 1 0 0(O)NR 1 0 CN, N0 2 R1O 2 NC(NR'0)-, R'OC(O)-, R 1 0 N 3 -N(RO) 2 or RI'OC(O)NRO-, and c) C1-6alkyl unsubstituted or substituted by aryl, heterocycle, C3.locycloalkyl, C2-6alkenyl, C2.6alkynyl, perfiuoroalkyl, F, C1, Br, R' 0 R 11 S(O)m-, RO(O)NH-, CN, H 2 RlOC(O)-, R'OOC(O)-, -N(R' 0 orR 10 00(O)NH-; R 9 is selected from: a) hydrogen, b) C2-6 alkenyl, C2-6alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R 11 S(O)mr, Rl 0 C(O)NR 10 CN, NO 2 (R10) 2 RIOC(O)-, RIOOC(O)-, N3, or R1OOC(O)NRlO-, and c) C1-6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 R 11 Ri 0 C(O)NR 10 ON, (Rlo) 2 N-C(NR 1 0 RiOOC(O)-, N3, -N(R 1 O)2, or R'lOO(O)NRO-; R 1 0 is independently selected from H, CI-6alkyl, benzyl, substituted aryl and Cl-6alkyl substituted with substituted aryl; R1 2 is hydrogen or Ci-6alkyl; R 1 3 is Ci-6alkyI; A' and A 2 are independently selected from: a bond, -CH=CH-, -C(0)NR' 0 NR'OC(O)-, 0, -N(RIO), -S(O) 2 N(Rl 0 -N(RIO)S(O) 2 or S(O)m; Z is independently H 2 or 0; q is 0, 1 or 2; s is 4 or 5: t is 3, 4 or 5;and u is 0 or 1: a compound represented by one of formulas (1l-h) through (11 R4a R4b R R9 I b Ri R2 R 3 Q Nl RRa aRI bb Ria Rla Rib KO Y OH N H* 0 %R4a ROb R 9 XR R3 Q Ria RIa 41Rib R n Un N I f H 0 U RO R4b O S R9 Ib xR 2 .R 3 *Ria Rla Rib R 6 y OH 20 H 0 R4a ROb R R 9 X 3 Q l 1 Ra I RibR R Ria Ria Rib RO Y 0 N TH 0 (lk C04 154 or a pharmaceutically acceptable salt thereof, wherein with respect to formula RaR R 9 X 2 R R 1 a RialI Rib" IR Q 3 Rl Rla RIb R 6 Y OH N H 0 Ilh Ria, Rib, R 8 R 9 R' 0 R 1 1 A 2 V, W, m, n, p and r are as previously defined with respect to formula (l R 2 and R 3 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 C1v2oalkyl, C2-2oalkenyl, C3.locycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, CI, Br, N(R 1 0 NO 2 R' 0 R 1 1 S(O)m-r, RiOC(O)NRO-, CN, (R'O) 2 N-C(NR10)-, RIOC(O)-, RIOOC(O)-, N3, -N(R' 0 R 1 'OC(O)NR10-and Ci-2oalkyl, and d) Ci-6alkyI substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-locycloalkyl; or R 2 and R 3 are combined to form-(CH2),-; or R 2 or R 3 are combined with ER 6 to form R 7 a (CH 2 )t a ring such that R R 3 is R7b ;R4a, ROb, Rla and R7b are independently selected from: a) hydrogen, b) Ci.6alkyl unsubstituted or substituted by alkenyl, R 1 0 R 1 1 S(O)m-r, R'OC(O)NRl 0 CN, N 3 (R'O) 2 N-C(NR10)-, RlOC(O)-, RIOOC(O)-, -N(RO) 2 or R"lOC(O)NRIO-, c) aryl, heterocycle, cycloalkyl,'alkenyl, R 1 0 R 11 R' 0 C(O)NR 10 ON, NO 2 (R1) 2 NC(NRlO)., R' 0 R 10 00(O)-, N 3 -N(R' 0 or R"lOC(O)NRO-, and d) Ci-6alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-iocycloalkyl; R~a 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_2oalkyl, C2-2oalkenyl, C3.iocycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R' 0 NO 2 R' 0 R' 1 RloC(O)NRlO-, ON, (R1O) 2 N..C(NRlO)-, RlOOC(O)-, N 3 -N(R 1 0 RliOC(O)NRO-and C1l2oalkyl, d) C1_6alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3.locycloalkyl; or Rsa and are combined, to form -(CH2)s- wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(CORO)-; R 6 is independently selected from hydrogen or Ci. Galkyl;,Q is a substituted or unsubstituted nitrogen-containing CO. mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5_7 saturated ring or a heterocycle; X, Y and Z are independently H 2 or 0; s is 4 or 5; t is 3, 4 or 5; and u is 0 or 1; with respect to formula (11-i): C04 154 Rla Rl 1 1 I Rb r~7VkT 'j1~NR 5 a Ria Ria Rib RO Y -2 N H 0 (li Ria, Rib, R 8 R 9 R 1 0 R 1 1 A 2 V, W, m, n, p and r are as previously defined with respect to formula R 2 and R 3 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 occur-ring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted CI-2oalkyl, C2-2oalkenyl, C3-iocycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R 10 NO 2 R 10 R' 1 S(O)m-, RIOC(O)NRlO-, CN, (R10) 2 N-C(NRO)-, RlOC(O), RlOOC(O)-, -N(R10) 2 Rl'OC(O)NRO- and Ci-2oalkyl, and d) C 1.6alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3.iocycloalkyl; or R 2 and R 3 are combined to form-(CH2)s.; or R 2 or R 3 are combined with R 6 to form R 6 Wa~c( H 2 a ring such that R 2 R 3 is R7b ROb, R7a and Rib are independently selected from: a) hydrogen, b) Ci-6alkyl unsubstituted or substituted by alkenyl, R' 0 R 11 R' 0 )C(O)NR 10 CN, N 3 (RlO) 2 N-C(NR10)-, RlOC(O)-, R 1 0 -N(R 10 or RllOC(O)NRO-, c) aryl. heterocycle, cycloalkyl, al *kenyl, R' 0 Rl'S(O)m-, R 10 C(O)NR 1 0 ON, N02, (R 1 O) 2 NC(NR 10 R' 0 R'O0C(O)-, N 3 -N(RO) 2 or RilOC(O)NRO-, and d) C1i6alkyl substituted with an unsubstituted or substituted group 15 selected from aryl, heterocyclyl and C3-locycloalkyl; R~a 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 Ci-2oalkyl, C2-2oalkenyl, C3-iocycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(RO) 2 N02, R1 0 R 1 1 S(O)m-,l RIOC(O)NR 1 0O, ON, (R' 0 2 N-C(NRl 0 RlOC(O)-, R'OOC(O)-, N3, -N(R 1 0 R11OC(O)NR10- and C1_2oalkyl, d) Ci-6alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-locycloalkyl; or R5a and are combined to form-(CH2),.wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, and-N(CORO)-; R 6 .is independently selected from hydrogen or C1_ 6alkyl; R 1 2 is a) substituted or unsubstituted C1_8alkyl or substituted or unsubstituted C- acycloalkyl, :25 wherein the substituent on the alkyl or cycloalkyl is selected from: 1) aryl, 2) heterocycle, 3) -N(R 1 1 4) R 1 3 -OR' 0 or b) ;R1 3 is independently selected from hydrogen and C1_6alkyl; R 14 is independently selected from CI-6alkyl; Q is a substituted or unsubstituted nitrogen-containing C4-9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-7 saturated ring or a heterocycle; X, Y and Z are independently H 2 or 0; s is 4 or 5; t is'3, 4 or 5; u is 0 or 1 with respect to formula (11-j): C041 54 R~a RO O R 9 X Rla RialI Rib R 2 R 3 2 N H~ 0l (U 1 Ri, ib 8 9 1 4 1 ,A;AV ,m ,padraea reiul eie ihrsett oml 2 ndR 3 ar ndpedetl sletd ro: sdechi o anaurll ocrrngamnoacdb anoxdiedf r of a iecano aual cuNgaiocdwhhisi)mtinesufier R~,Rib,(O)R,R9,RO, R 1 ,)ANC(N, V,-W,R'mC(On, R'nd C(Oa-e Na pr N(Rously deine ith NO andec tofrml aehind i-l su bsttued it an unsubstituted or substituted gr2akyC-oupy, 3i selected fro aryl heterocycle and C3-locycloalkyl; or R 2 and R 3 are combined to form-(CH2) or R 2 or R 3 are combined R 6 R~~a (CH 2 with R 6 to form a ring such that R 2 R 3 is Rib R4a, R4b, R7a and Rib are independently' selected from: a) hydrogen, b) C1_6alkyl unsubstituted or substituted by alkenyl, R' 0 0-, R 11 R'OC(O)NR10-, ON, N 3 (R10) 2 N-C(NRO)-, R1OC(O)-, R1POC(O)., -N(R' 0 or Rli'OC(O)NR'O-; c) aryl, heterocycle, c ycloalkyl, alkenyl, R' 0 R 11 RlOC(O)NR 1 0 ON, N02, or Rl'OC(O)NR 10 and d) Ci-6alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3.iocycloalkyl; R 6 is independently selected from hydrogen or CI-6alkyl; Q is a substituted or unsubstituted nitrogen-containing C4-9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C.,7 saturated ring or a heterocycle; X, Y and Z are independently H2 or0; q isO, 1 or 2; s is 4or 5; t is3, 4or 5; and u is 0or 1; with respect to formula (1l-k): R4a R4b R 9 X 2 R 3 Ria Rib"RQ *Rla Ria- Rib R 6 Y 0 20 H 0~ (1Il-k) Rla, Rib, R 8 R 9 RIO, R1 1 A 2 V. W, m, n, p, and r are as defined above with respect to formula (11- R 2 and R 3 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 suifone, and c) substituted or unsubstituted Clv2oalkyl, C 22 0alkenyl, C3-locycloalkyl, aryl or heterocyclyl group, wherein the substituent is selected from F, Cl, Br, N(R' 0 NO 2 R 10 R 11 IS(O)m-, RlOC(O)NRO-, ON, (RiO) 2 N-C(NR10)-, R'OOC(O)-, N 3 -N(R' 0 R11OC(O)NRO- and C1_2oalkyl, and d) CI-6alkyl substituted with an unsubstituted or substituted group selected. from aryl, heterocycle C041 54 and C3.locycloalkyl; or R 2 and R 3 are combined to form-(CH2)s-; or R 2 or R 3 are combined with R 6 to form R 6 'KR 7 a (OH 2 )t a ring such that R 2 R 3 is R7b a, ROb, Ria and Rib are independently selected from: a) hydrogen, b) Ci-6alkyl unsubstituted or substituted by alkenyl, R 1 0 0, R 11 S(O)m, RI 0 0(O)NRI 0 CN, N3, (Rlo) 2 N-C(NRlO)-, RlOC(O)-, R'OOC(O)-, -N(R 10 or R"lOC(O)NRO-, c)*aryl, heterocycle, cycloalkyl, alkenyl, R 1 0 R 11 RI 0 C(O)NR' 0 CN, N02, (R' 0 2 N-C(NR 1 0 RlaC(O)-, R' 0 0C(O)-, N3, -N(R 10 )2 or R'lOC(O)NR'O-, and d) Cio6alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclyl and C3-locycloalkyl; R 6 is independently selected from hydrogen or C 1 6alkyl; 0 is a substituted or unsubstituted nitrogen-containing C4.gmono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C 57 saturated ring or a heterocycle; X, Y and Zare independently H2 or; q is,or 2; sis 4or 5; tis 3, 4 or6;and uis 0orl1. 9. A method, RAF antagonist compound and a famesyl protein transferase inhibiting compound, or use in accordance with claim 7 wherein the RAF antagonist is a compound represented by formula N 6>x X N R. rcy (R) 0 3 selected from the group consisting of: 4-[5-(4-fluorophenyl)-4-pyndin-4-yl-1 H-imidazol-2-yl]-piperidine- 1-carboxylic acid tert-butyl ester; 4-[4-fluorophenyl)-3-pyridin-yl-lH-imidazol-2-yl]-i1-acetyl-piperidine; 3- [5-(4-fluorophenyl)-4-pyridin-4-yl-1 H-imidazol-2-yl]-piperidine-1 -carboxylic acid tert-butyl ester; fluorophenyl)-3-pyridin-yl-1 H-imidazol-2-yll-1 -acetyl-piperidine; and 4-benzyl-[4-(4-fluorophenyl)-5- pyridin-4-yl-1 H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester, or a pharmaceutically acceptable salt thereof.

10. A method, RAE antagonist compound and a farnesyl protein transferase inhibiting compound, or use in accordance with claim 7 wherein the RAF antagonist compound is a compound represented by formula N c3 x XXN R- rcy (R) 0 3 ',AR(-b (R) 0 3 (1b selected from the group consisting of: 4-[5-(4-fluorophenyl)4-pyidin4-yl-1 H-imnidazol-2-yl]-piperidine; 4-[5-(4-fluorophenyl)-4-pyidin-4-yl-1 H-imidazol-2-yl]-1 -methyl-piperidine; 4-[5-(4-fluorophenyi)-4- pyridin-4-yl-1 H-imidazol-2-yl]-1 -benzyl-piperidine; 4-[5-(4-fluorophenyl)-4-pyndin4-yl-1 H-imidazol-2-yI]- C04154 1 -ethyl-piperidine; 4-[5-(3,4-dichlorophenyl)-4-pyridin-4-y-1 H-imidazol-2-yI]-piperidine; dichlorophenyl)-4-pyidin-4-yI-1 H-imidazol-2-y]-1 -methyl-piperidine; 2-(4-{4-[5-(3,4-dichlorophenyl)-4- pyddin4-yl-l1H-imidazol-2-yl]-piperidin-1 -yl}-butyl)-isoindole-1 .3-dione; 2-(5-{4-[5-(3,4-dichiorophenyl)- 4-pyridin-4-yl-1 H-imidazol-2-:yl]-piperidin-1 -yl}-pentyl)-isoindole-1 ,3-dione; 2-(04-15-(3,4-dichloro phenyl)-4-pyridin-4-y-1 H-imidazoi-2-yl]-piperidin-1 -yI}-hexyl)-isoindole-1 ,3-dione; 4 -[5-(3,4-dichloro phenyl)-4-pyridin-4-yl-1 H-imidazol-2-ylI-1 -benzyl-piperidine; 2-(5-{4-[5-(3,4-dichlorophenyl)-4-pyridin-4- yl-1 H-imidazol-2-yl]-pipeddin-1 -y}-pentyl)-2,3-dihydro-isoindol-1 -one ditrifluoroacetic acid salt; [5-(3,4-dichlorophenyl)4-pyidin-4-y-1 H-imidazol-2-yIJ-pipeddin-1 -yl}-ethyl)-pyndine; dichlorophenyl)-4-pyidin-4-yl-1 H-imidazol-2-yl]-piperidin-1 -yI}-pentyl)-, 1 -dioxobenzo[dlisothiazol-3-one; 2-(4-{4-[5-(3,4-dichlorophenyl)4-pyidin4-yl-1 H-imidazol-2-yl]-pipendin-1 -yl}-butyl)-1, 1-dioxobenzoldl isothiazol-3-one; 2-amino- 1 -{5-[4-(3,4-dichlorophenyl)-4-pyndin4-yl-1 H-imidazol-2-yll-piperidin-1 -yl}- ethanone dihydrochioride; 4-[5-(3-hydroxyphenyl)-4-pyidin4-ylI-H-imidazol-2-yl]-1 -methyl-piperidine; 3-[5-(4-fluoropheny)-4-pyddin-4-y-1 H-imidazol-2-yI]-piperidine]-1 -carboxylic acid tert-butyl ester; (4-fluorophenyl)-4-pyridin-4-yl-1 H-imidazol-2-yI]-piperidine: 3-[5-(4-fluorophenyl)-4-pyidin-4-yl-1 H-. imidazol-2-ylJ-1 -methyl-piperidine; 4-[5-(4-fluorophenyl)4-pyidin4-yl-1 H-imidazol-2-yl]-1 ,4-dimethyl- piperidine; 4-benzyl-[4-(4-fluorophenyl)-5-pyidin-4-y-1 H-imidazol-2-yI]-piperidine-1 -carboxylic acid tert- butyl ester; 4-benzyl-E4-(4-fluorophenyl)-5-pyidin-4-ylI-H-imidazol-2-yl]-piperidine; 4-{5-(3,4-dichloro phenyl)-2-(1 -(2-phenylethyl)-pipeidin4-yl]-1 H -imidazol-4-yI}-pyridine; 4-{5-(3,4-dichlorophenyl)-2-[ 1-(3- phenylpropyl)-pipeidin-4-yl]-1 H-imidazol-4-yI-1 -pyridine; 2-(6-{4-[5-(3,4-dichlorophenyl)-4-pyridin-4-yl- 1 H-i mid azol-2-yl]-piperidin- 1 -ylI -hexyl)-1 1 Adioxobenzo[d]isothiazol-3-one; -2-(3-{4-[5-(3,4-dichloro phenyl)-4-pyridin-4-yl-1 H-imidazol-2-yI]-piperidin-1 -yI}-propyl)-1 ,1 -dioxobenzo[d]isothiazol-3-one; 4-(S- 4-[5-(3,4-dichlorophenyl)-4-pyidin-4-y-1 H-imidazol-2-yl]-piperidin-1 -yl-methyl, 1 -imidazol-1 -yl-methyl)- :benzonitrile; 4-12-11 -(4-benzyloxybenzy)-piperidin-4-yl-S-(3,4-dichlorophenyl)-1 H-imidazol-4-yl-pyridine; and 2-(3-{4-[5-(3,4-dichlorophenyl)4-pyridin4-yl-1 H-imidazol-2-yll-piperidin-1 -yl-1 -propyl)-isoindole- 25 1 ,3-dione, or a pharmaceutically acceptable salt thereof. *11. A method, RAF antagonist compound and a famesyl protein transferase inhibiting compound, or use in accordance with claim 7 wherein the RAF antagonist compound is a compound represented by formula (1 *1 2 R N N R4 (1 -c) selected from the group consisting of: 4-[4-(4-fluorophenyl)-5-(4-pyridyl)imidazol-2-yl]benzamidoxime; 4-(l1-naphthyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)imidazole; -naphthyl)-2-(4-methylthiophenyl)- 5-(4-pyridyl)imidazole; 4-(2-naphthyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)imidazole; 4-(2-naphthyl)-2-(4- methylsUlfinylphenyl)-5-(4-pyridyl)imidazole; 4-(4-fluorophenyl)-2-(3-thiophene)-5-.(4-pyridyl)imidazoe; 4-(4-fluorophenyl)-2-(2-thiophene)-5-(4-pyidyl)imidazole; 4-(4-fluorophenyl)-2-(3-methylthiophenyl)-5- (4-pyridyl)imidazole; 4-(4-fluorophenyl)-2-(3-methylsulfinylphenyl)-5-(4-pyridyl)imidazole; 4-(4-fluoro phenyl)-2-(3-methylsulfonylphenyl)-5-(4-pyidyl)imidazole; 4-(4-fluorophenyl)-2-(2-methylthiophenyl)-5- (4-pyridyl)imidazole; 4-(4-fluorophenyl)-2-(2-methylsulfinylphenyl)-5-(4-pyidyl)imidazole; 4-(4-fluoro C041 54 phenyl)-2-(2-methylsulfonylphenyl)-5-(4-pyridyl)imidazole; 4-(4-fluorophenyl)-2-(4-methoxyphenyl)-5-(4- pyridyl)imidazole; 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1 -methyl-5-(4-pyridyl)imidazole; 4-(4- fluorophenyl)-2-(4-methylsulfinylphenyl)-1 -(N-morpholinopropyl)-5-(4-pyridyl)imidazole; 4-(4-fluoro phenyl)-2-(4-methylthiophenyl)-1 -(N-morpholinopropyl)-5-(4-pyidyl)imidazole; 4-(4-fluorophenyl)-2-(4- methylsulfonylphenyl)-1 -(N-morpholino-propyl)-5-(4-pyridyl)imidazole; 4-(4-fluorophenyl)-1 -(methylthio- 1 -propyl)-2-([4-N-morpholinomethyl]phenyl)-5-(4-pyridyl)imidazole; 4-(4-fluorophenyl)-1 -(methylsulfinyl- 1 -propyl)-2-([4-N-morpholinomethyl]phenyl)-5-(4-pyridyl)imidazole; and 4-(4-fluorophenyl)-1 -(methyl sulfonyl-1 -propyl)-2-([4-N-morpholinomethyllpheny)-5-(4-pyidyl)imidazole, or a pharmaceutically acceptable salt thereof.

12. A method, RAE antagonist compound and a famesyl protein transferase inhibiting compound, or use in accordance with claim 8 wherein the famesyl transferase inhibiting compound is a compound represented by one of formulas (1l-a) through (1k): R 9 Ria la I Rib R 2 Ri Ria IRib IN (R),,,AlRia A2l Rib R2 G *n *t 2-I Ria RIa I Rib R R Ria Rib N* R z G (lc 0* selected from the group consisting of: 2(S)-butyl-1-(2,3-diaminoprop-1-yl)-1-(l-naphthoyl)piperazine; 1- (3-amino-2-(2-naphthylmethylamino)prop-1 -yI)-2(S)-butyl-4-(1 -naphthoyl)piperazine; 2(S)-butyl-l 45-fl (2-naphthylmethyl)]-4,5-dihydroimidazol~methyl-4-(1 -naphthoyl)piperazine; 1 -benzylimidazol) 20 ~methyl-2(S)-butyl-4-(1 -naphthoyl)piperazine; 1 45-fl -(4-nitrobenzyl)]imidazolylmethyl}-2(S)-butyI-4-(l 2naphthoyl)piperazine; 1 -(3-acetamidomethylthio-2(R)-aminoprop- -yl)-2(S)-butyl-4-(1 -naphthoyl) piperazine; 2(S)-butyl-1 -imidazolyl)ethyljsulfonyl-4-(1 -naphthoyl)piperazine; 2(R)-butyl-1 i mid azolyl-4-methyl-4-(l -naphthoyl)piperazine; 2(S)-butyl-4-(l -naphthoyl)-l -(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-(l -naphthoyl)-piperazine; 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; 2(S)-butyl-l -[(4-imidazolyl)methyl]-4-(l naphthoyl)piperazine; 2(S)-butyl-1 -naphth-2-ylmethyl)-1 H-imidazol-5-yI)acetyl]-4-(l -naphthoyl) 1 piperazine; 2(S)-butyl-1 -naphth-2-ylmethyl)-l H-imidazol-5-yl)ethyl1-4-(1 -naphthoyl)piperazine; 1- C041 54 (2(R)-amino-3-hydroypropyl)-2(S)-butyl-4-(l1-naphthoyl)piperazine; 1 -(2(R)-amino-4-hydroxybutyl)-2(S)- butyl-4-(l1-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)-butyl4-(1 -naphthoyl)piperazine; 1 .43-(4- imidazolyl)propylj-2(S)-butyl-4-(1 -naphthoyl)-piperazine; 2(S)-n-butyl-4-(2,3-dimethylphenyl)-1 imidazolylmethyl)-piperazin-5-one; 2(S)-n-butyl-1 -(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3- one; 1 -(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3-dimethylphenyl)-2(S)- 2(S)-n-butyl-4-(1 -naphthoyl)-1 methyl]-piperazine; 2(S)-n-butyl-4-(.1-naphthoyl)-1 piperazine; 2(S)-n-butyl-1 -(4-cyanobenzyl)imid azol-5-ylmethyl]-4-(1 -naphthoyl)piperazine; 2(S)-n- butyl-1 -(4-methoxybenzyl)imidazol-5-yl methyl]-4-'(1 -naphthoyl)piperazine; 2(S)-n-butyl-1 methyl-2-butenyl)imidazol-5-ylmethyl]-4-(1 -naphthoyl)piperazine; 2(S)-n-butyl-1 -(4-fluorobenzyl) imidazol-5-ylmethyll-4-(1 -naphthoyl)piperazine; 2(S)-n-butyl-1 1 -naphthoyl)piperazine; 1 -(4-bromobenzyl)imidazol-5-ylmethyUl-2(S)-n-butyl4-(1 -naphthoyl) piperazine; 2(S)-n-butyl-4-(1 -naphthoyl)-1 2(S)-n-butyl-1 -(4-methylbenzyl)imidazol-5-ylmethyl]4-(1 -naphthoyl)-piperazine; 2(S)-n-butyl-1 methylbenzyl)imidazol-5-ylmethyl]-4-(l1-naphthoyl)-piperazine; 1 methyll-2(S)-n-butyl-4-(1 -naphthoyl)-piperazine; 2(S)-n-butyl-4-(1 -naphthoyl)-1 -(2-phenylethyl) 2(S)-n-butyl-4-( 1 -naphthoyl)-1 ylmethyl]piperazine; 14-[1 -(4-cyanobenzyl)-1 H-imidazol-5-yllacetyl}-2(S)-n-butyl-4-( 1 -naphthoyl) piperazine; or a pharmaceutically acceptable salt thereof.

13. A method, RAF antagonist compound and a famesyt protein transferase inhibiting com pound, or use in accordance with claim 8 wherein the famesyl transferase inhibiting compound is a compound represented by one of formulas (11-d) through (11-g): .H 0 R 3 R4 R 9 Z ~aR OH Rl R 1 Rib R) A' 2 R 1 8 Ria Rib H 2 R~a R2b (11-d) C041 54 H 0 R3 R4 N R 9 Z O R 1 3 Rla 1 Rib RiaaRRab'bIl-f) H 0 R3IR4 Nj~ R 9 Z /R A Rla RA2 RiaI lb X -Y z R 1 a Ria RibH2 R~a R2b (Il-g) selected from the group consisting of: N-ji -(4-imidazoleacetyl)pyrrolidin-2(S)-ylmethyl]-N-(1 naphthylmethyl)glycylmethionine; N-ti -(4-imidazoleacetyl)pyrrolidin-2(S)-ylmethyl-N-(l1-naphthyl- methyl)glycyl-methionine methyl ester; N-ti -(2(S),3-diaminopropionyl)pyrrolidin-2(S)-ylmethyll-N-( 1- naphthylmethyl)glycyl-methionine; N-[l 1 3-diaminopropioriyl)pyrrolidin-2(S)-ylmethyl]-N-( naphthylmethyl)glycyl-methionine methyl ester; N-ti -(3-aminopropionyl)pyrrolidin-2(S)-yl'methyl-N-( 1- naphthylmethyl)glycyl-methionine; N-[i -(3-aminopropionyl)pyrrolidin-2(S)-ylmethyl-N-(1 -naphthyl methyl)glycyl-methionine methyl ester; N-ti -(2(S)-amino-3-benzyloxycarbonylaminopropionyl)pyrrolidin- 2(S)-ylmethyll-N-(i -naphthylmethyl)glycyl-methionine; N-ti -(2(S)-amino-3-benzyloxycarbonylamino propionyl)pyrrolidin-2(S)-ylmethyll-N-(i -naphthylmethyl)glycyl-methionine methyl ester; N-ti -(3-amino- 2(S)-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)-ylmethyl-N-(1 -naphthylmethyl)glycyl- methionine; N-ti -(3-amino-2(S)-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)-ylmethyl-N-(1 naphthylmethyl)glycyl-methionine mt se; N-ti -(L-glutaminyl)pyrrolidin-2(S)-ylmethyl]-N-(1l -nptyleh naphthylmethyl)glycyl-methionine mt se; N- ti -(L-glutaminyl)pyrrolidin-2(S)-ylmethyl]-N-( 1-ylehl glycyl-methionine methyl ester; N-[1 -(L-histidyl)pyrrolidin-2(S)-ylmethyl]-N-(i -naphthylmethyl)glycyl- :methionine; N-ti -(L-histidyl)pyrrolidin-2(S)-ylmethyl]-N-(i -naphthylmethyl)glycyl-methionine methyl ester; N-[i -(D-histidyl)pyrrolidin-2(S)-ylmethyl]-N-(i -naphthylmethyl)glycyl-methionine; N-[i histidyl)pyrrolidin-2(S)-ylmhethyl]-N-(i -naphthylmethyl)glycyl-methionine methyl ester; 'N-ti pyroglutamyl)pyrrolidin-2(S)-ylmethyl)N(1l -naphthylmethyl)glycyl-methionine; N-ti -(L-pyroglutamyl) **pyrrolidin-2(S)-ylmethyl]-N-( 1-naphthylmethyl)glycyl-methionine methyl ester; 2(S)-ti pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy]-3-phenylp ropionyl-methionine; -(2(S)-pyroglutamyl) pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine methyl ester; 2(S)-ti -(2(S)-pyroglutamyl) pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine isopropyl ester; 2(S)-ti H-imidazol-4- ylacetyl)pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine; 2(S)-ti H-imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine methyl ester; 2(S)-ti -(2(S)-pyroglutamyl) pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropionyl-methionine sulfone; -(2(S)-pyroglutamyl) pyrrolidin-2(S)-ylmethyloxy]-3-phenylpropI ,onyl-methionine sulfone methyl ester; 2(S)-ti -(pyrid-3- C04154 252 ylcarboxy)pyrrolidin-2(S)-ylmethyloxy-3-phelpropiofl-methioflife; 2(S)-ti -(pyrid-3-ylcarboxy) pyrrolidin-2(S)-ylmethyloxyI-3-phenylpropiony-methioflife methyl ester; -(naphth-2-yI)-i H- imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethoxy-1 -3-phenyipropionyl-methionine; 2(R)-{2-ti -(naphth-2-yI)- 1 H-imidazol-5-ylacetyllpyrrolidin-2(S)-ylmethoxy-1 -3-phenyipropionyl-methionine methyl ester; 2(S)-ti (pynd-3-ylmethyl)pyrrolidin-2(S)-ylmethyloxy]-3-phelylpropioflyl-methioflie; -(pyrid-3- ylmethyl)pyrrolidin-2(S)-ylmethyloxy-3-phelpropioflyl-methioflile methyl ester; N-[1 H-imidazol-4- ylacetyl)pyrrolidin-2(S)-ylmethyl]-N-(1 -naphthylmethyl)glycyl-methionine isopropyl ester; N-ti -(1H- imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyll-N-(1 -naphthylmethyl)glycyl-methionine sulfone isopropyl ester; N-ti H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylnmethylU-N-(i -naphthylmethyl)glycyl-methionine l0 sulfone; N-ti -(glycyl)pyrrolidin-2(S)-ylmethyl]-N-( 1-naphthylmethyl)glycyl-methionine methyl ester; N-ti (glycyl)pyrrolidin-2(S)-ylmethyl]-N-(i -naphthylmethyl)glycyl-methionifle isopropyl ester; N-ti (gliycyl)pyrrolidin-2(S)-ylmethyl-N-(1 -naphthylmethyl)glycyl-methionifle; N-ti -(glycyl)pyrrolidin-2(S)- ylmethyl]-N-(1 -naphthylmethyl)glycyl-methionine sulfone methyl ester; N-ti -(glycyl)pyrrolidin-2(S)- ylmethyl]-N-(i -naphthylmethyl)glycyl-methionine sulfone; N-ti -(sarcosyl)pyrrolidin-2(S)-ylmethyl]-N-(i naphthylmethyl)glycyl-methionine methyl ester; N-ti -(sarcosyl)pyrrolidin-2(S)-ylmethyl]-N-(i -naphthyl methyl)glycyl-methionine; N-ti ,N-dimethylglycyl)pyrrolidin-2(S)-ylmethyl]-N-(i -naphthylmethyl) glycyl-methionine methyl ester; N-ti ,N-dimethylglycyl)pyrrolidin-2(S)-ylmethyll-N-(l -naphthyl methyl)glycyl-methionine; N-l H-imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl]-N-( i naphthylmethyl)glycyl-methionine methyl ester; N-ti H-imidazol-4-ylacetyl)pyrrolidif-3(S)-e thyl-2(S)- ylmethyl]-N-(l1-naphthylmethyl)glycyl-methionine; N-ti -(glycyl)pyrrolidin-3(S)-ethyl-2(S)-ylnlethylll-N-( 1- naphthylmethyl)glycyl-methionine methyl ester; N-ti -(glycyl)pyrrolidin-3(S)-ethyl- 2(S)-ylmethyl]-N-(l naphthylmethyl)dlycyl-methionine; N-ti -(4-cyanobenzyl)-i H-imidazol-5-ylacetyl)pyrrolidin-2(S)-yl methyl]-N-(i -naphthylmethyl)glycyl-methionine methyl ester; N-ti -(4-cyanobenzyl)-i acetyl)pyrrolidin-2(S)-ylmethyl]-N-(i -naphthylmethyl)glycyl-methionine; N-ti -(2-acetylamino-3(S)-belzyl 25 oxycarbonylaminopropionyl)pyrrolidin-2(S)-ylmethyl]-N-(i -naphthylmethyl)gtycyl-methioflife; N-ti acetylamino-3(S)-aminopropionyl)pyrrolidin-2(S)-ylmethyl]-N-(i -naphthylmethyl)glycyl-methionine; N-ti (2-.amino-3(S)-acetylaminopropionyl)pyrrolidifl-2(S)-ylmethyl]-N-(i -naphthylmethyl)glycyl-methionile; :methyl ester; 2(S) i mi -(1laey yroii-()-ty-()-lehlxy--hnlpo inl methionine; -(4-cyanobenzyl)-limi o-5yaey~yrldi-()ymtoy3pey propionyl-methionine methyl ester; 2(R)-{2-ti -(4-cyanobenzyl)-i H-imidazol-5-ylacetylipyITolidifl-2(S)- ylmethoxy}-3-phenylpropionyl-methionine; 2(R)-{2-ti -(4-nitrobenzyl)-l 2(S)-ylmethoxy}-3-phenylpropionyl-methioflife methyl ester; 2(R)-{2-ti-(4-nitrobenzyl)-i acetyl]pyrrolidin-2(S)-ylmethoxy-3-phenylpropioflyl-methioflife; 2(R)-{2-ti -(4-mhethoxybenzyl)-i H- imidazol-5-ylacetyllpyrroidin.-2(S)-ylmethoxy}-3-phelylpropiofyl-methioflife methyl ester; methoxybenzyl)-limi o--lctlproii-()ymehxy-hnlrpoy-ehoie 2(R)- {2-ti -(4-cyanobenzyl)-limi o--lctlproii-()ehy-()ymtoy3peypoinl methionine methyl ester; 2(R)-{i-(4-cyanobenzyl)-i H-imidazol-5-ylacetylpyrrolidin-3(S)-ethyl- 2 ylmethoxy}-3-phenyl propionyl-methionine; N-ti -(limi o--laey~yrlii-()y ehl-1- _o naphthylmethyl)glycyl-(P-acetylamino)alanifle methyl ester; N-ti H-imidazol-4ylacetyl)pyrrolidifl- 2 CG4 154 ylmethyl]-N-(l -naphthylmethyl)glycyl-(3-acetylamiflo)alaflife; N-il -(glycyl)pyrrolidin-2(S -)-ylmethyl]-N-(l naphthylmethyl)glycyl-U3-acetylamiflo)alaflife methyl ester; N-il -(glycyl)pyrrolidin-2(S)-ylmethyl]-N-(l naphthylmethyl)glycyl-(3-acetylamiflo)alaflife; N-[l -(seryl)pyrrolidin-2(S)-ylmethyll-N-(l -naphthyl methyl)glycyl-methionine methyl ester; N-[l -(D-alanyl)pyrrolidin-2(S)-ylmethyll-N-(l -naphthylmethyl) glycyl-methionine methyl ester; N-il H-imidazol-4-carbony)pyrrolidin-2(S)-ylmfethyII-N-( 1 -naphthyl methyl)glycyl-methionine methyl ester; N-[l -(isoasparagyl)pyrrolidin-2(S)-ylmlethylI-N-(l -naphthyl methyl)glycyl-methionine methyl ester; N-il H-imidazol-4-propionyl)pyTolidifl-2(S)-ylmlethyI]-N-(l naphthylmethyl)glycyl-methionine methyl ester; N-[l -(3-pyridylacetyl)pyrrolidifl-2(S)-ylmethyl]-N-(l naphthylmethyl)glycyl-methionifle methyl ester; N-il -(2-pyridylacetyl)pyrrolidifl-2(S)-yflmethyl]-N-(l naphthylmethyl)glycy-methioflife methyl ester; N-il -(4-pyridylglycyl)pyrr~lidif-2(S)-ylmethyl]-N-(l naphthylmethyl)glycyl-methioflife methyl ester; N-Il -(seryl)pyrrolidin-2(S)-ylmethyl1-N-(l1-naphthyl methyl)glycyl-methioflife; N-il -(D-alanyl) pyrrolidin-2(S)-ylmethyl1-N-(l -naphthylmethyl)glycyl- methionine; N-il H-imidazol-4-carbonyl)pyrrolidifl-2(S)-ylmlethylI-N-(l -naphthylmethyl)glycyl- methionine; N-il -(isoasparagy)pyrrolidin-2(S)-ylmethyl1-N-(l -naphthylmethyl)glycyl-methioflife; N-il (1 H-iridazol-4-propionyl)pyrrolidifl-2(S)-ylmethylI-N-(l -naphthylmethyl)glycyl-methioflife; N-[l pyridylacetyl)pyrrolidin-2(S)-ylmethyl]-N-( 1 -naphthylmethy)glycyl-methioflife; N-[I-(2-pyddylacey) pyrrolidin-2(S)-ylmethylj-N-( 1-naphthylmethy)glycyl-methioflife; N-il -(4-pyndylglycyl)pyrrolidin-2(S)-yI methyl]-N-(l -naphthylmethy)glycyl-methioflife; N-il H-iridazol-4-ylmethyl)pyrrolidif-2(S)-ylmethyl]- 1 -naphthylmethy)glycyl-methioflife; N-[l -(2-aminoethyl)pyrrolidin-2(S)-ylmethylI-N-( 1 -naphthyl methyl)glycyl-methionine; N-il -(giycyl)pyrrolidin-2(S)-ylmethylJ-N-(l -naphthylmethyl)glycyl-(2-thienyl) alanine; N-il H-imidazoI-4-ylacety)pyrrolidifl-2(S)-ylmethyl]-N-(l -naphthylmethyl)glycyl-(tifluoro methyl)alanine; N-il H-i mid azol-4-ylacetyl)pyrrolid if-2(S)-ylmethylI-N-(l -naphthylmethyl)g lycyl-(2(S)-* amino-4-acetylamino)butyric acid; N-il H-imidazol-4-ylacetyl)pyrrolidif-2(S)-ylfl'ethyl]-N-(l naphthylmethyl)glycyl-(N ,N-dimethyl)glutamine; N-Il-Cl H-iridazol-4-ylacety)pyrTolidif-2(S)-ylmethyl]- N-(benzyl)glycyl-methionine; N-il (lclproii-(S-lehl--bnyigyy-ehoie N-Il (1 H-md~b--lctlproii-()ymthl--4mtoyezlgyy-ehoie N-il -(glycyl) pyrldn3S-ty*2S lehl--bnzlgyy-ehoie H-imidazol-4-ylacetyl)pyrrOlidifl- 3()ehl2S-lehl--(ezlgyy-ehoie N-((4-imidazolyl)methyl-(2S)-pyrrolidiflylmethyl)- N-(l1-naphthymethyl)glycyl-methioflife methyl ester; N-il -(glycyl)pyrrolidin-2(S)-ylmethyl]-N-(l -naphthyl methyl)glycyl-(2-thienyl)alanine mhethyl ester; N-il H-imidazol-4-ylacetyl)pyrrolidif-2(S)-ylmethyl]-N- (1 -naphthylmethyl)glycyl-(NN-dimethyl)gIutamifle methyl ester; N-[l H-imidazol-4-ylacetyl)pyrrolidifl- 99* 2(S)-ylmethylj-N-(l -naphthylmethyl)glycyl-(trifIuoromethyl)alaflife methyl ester; -imidazol-4- .ylacetyl)pyrrolidin-2(S)-ylmethyl]-N-(l ahhlehlgycl(()aio4actlmn~uyi acid methyl ester; N-il iiao--lcty~yrldn2S-ymtylN(ezl~lclmtinn methyl ester; N-il (lclproidn2S-lehylN(ezlglc mtinn methyl ester; N-il H-, imdzl4yaey~yrldn2S-iehl-ehxbny~lclmtinn methyl ester; N-il -(1H- i i zl4yaey~yrldn3S-ty-2S-lehl--bny~lclmt oin methyl ester; N-[i- (gyy~yrldn3S-ty-()ymtylN bny~lclmtinn methyl ester; N-[i-(glycyl) pyrrolidin-2(S)-ylmethyl]-N-(l -naphthylmethyl)glycyl-methionine isopropyl ester; N-il -(glycyl)pyrrolidin- ,T,(S)-ylmethyl-N-(l -naphthylmethyl)glycyl-niethioflife cyclohexyl ester; N-[i-(glycyl)pyrrolidin-2(S)- C04 154 ylmethyl]-N-(i -naphthylmethyl)glycyl-methioflife benzyl ester; N-ti -(glycyl)pyrrolidin-2(S)-ylmethyll-N- (1 -naphthylmethyl)glycyl-methioflife ethyl ester; N-[i -(sarcosyl)pyrrolidin-2(S)-ylmethyll-N-(1 -naphthyl methyl)glycyl-methionine isopropyl ester; N-[i ,N-dimethylglycyl)pyrrolidifl-2(S)-ylmethyl]-N-(l naphthylmethyl)glycyl-methioflife isopropyl ester; N-li -(glycyl)pyrrolidin-2(S)-ylmlethylI-N-(i -naphthyl methyl)glycyl-methioflife (2-pyridylmethyl) ester; N-[i -(glycyl)pyrrolidin-2(S)-ylmethyl]-N-(i -naphthyl methyl)glycyl-methioflife (1 -glyceryl) ester; N-ti -L-prolylpyrrolidin-2(S)-ylmethylU-N-(i -naphthylmethyl) glycyl-methionine methyl ester; N-ti -(L-prolyl)pyrrolidin-2(S)-ylmlethyl]-N-(i -naphthylmethyl)glycyl- methionine; N-ti -morpholinoacetyl)pyrrolidifl-2(S)-ylmlethylI-N-(i -naphthylmethyl)glycyl-methioflife methyl ester;. N-[i -morpholinoacetyl)pyrrolidil-2(S)-Ylmlethyl]-N-(i -naphthylmethy)glycyl-methioflife; N-[i -(4-piperidinecarbolyl)pyrrolidifl-2(S)-ylmethyl]-N-(l -naphthylmethyl)glycyl-methioflife methyl ester; N-li -(4-piperidinecarbonyl)pyrrolidifl-2(S)-ylmlethylI-N-(i -naphthylmethyl)glycyl-methioflife; N-ti (3-piperidinecarbonyl)pyrrolidifl-2(S)-ylmethylI-N-(i-naphthylmethyl)glycyl-methioflife methyl ester; N- [1 -(3-piperidinecarbonyl)pyrrolidifl-2(S)-ylmethyl-N-(i naphthylmethyl)glycyl-methioflife; N-ti -(2-pyddyl glycyl)pyrrolidin-2(S)-ylmethyl]-N-(l -naphthylmethyl)glycyl-methionline methyl ester; N-ti -(2-pyridyl glycyl)pyrrolidin-2(S)-ylmethyl]-N-(i -naphthylmethy)glycyl-methioflife; N-ti -(4-pyridylglycyl)pyTolidifl- 2(S)-ylmethyll-N-( 1-naphthylmethyl)glycyl-methioflife methyl ester; N-ti -(4-pyridylglycyl)pyrrolidin-2(S)- ylmethyll-N-(i -naphthylmethyl)glycyl-methioflile; N-[i -(4-pyridyl(N-methyl)glycyl)pyTolidifl-2(S)-yl methyll-N-(i -naphthylmethyl)glycyl-methioflife methyl ester; N-ti -(4-pyridyl(N-methyl)glycyl)pyrTolidifl- 2(S)-ylmethylF-N-(i -naphthylmethyl)glycyl-methioflife; N-ti H-imidazol-4-ylpropioflyl)pyrrolidifl-2(S)-y methyl]-N-( 1 naphthylmethyl)glycyl-(3-acetylamiflo)alaflile; N-[i H-imidazol-4-yipropionyl)pyrrolidifl- 2(S)-ylmethyl]-N-(i -naphthytmethyl)glycyl-(3-acetyamiflo)alaflife methyl ester; N-[i -(4-pyridyl glycyl)pyrrolidin-2(S)-ylmethyll-N-(i -naphthylmethyl)glycyl-(f3-acetylamiflo)alalife; N-ti -(4-pyridylglycyl) ~.:pyrrolidin-2(S)-ylmethyll-N-(l -naphthylmethy)glycyl-(3-acetyano)alaflife methyl ester; N-ti (glycyl)pyrrolidin-2(S)-ylmethyl]-N-(i -naphthylmethy)glycyl-(3-acetylamiflo)alaflife cyclohexyl ester; N- [i H-imidazol4-ylacetyI)pyrrolidifl-2(S)-ylmethyl]-N-(i -naphthylmethy)glycyl-(N-mfethyl)glutamifle; N- 1i H-i mid azol4-ylacetyl)pyrrolidifl-2(S)-ylmethyl]-N-(i -naphthylmethyl)glycyl-(N-methy)glutamifle methyl ester; N-ti H-imidazol-4Lylacetyl)pyrrolidifl-2(S)-ylmethylI-N-(i -naphthylmethyl)glycyl-f- methylcarbonylamino)alafline; N-ti H-imidazol4-ylacetyl)pyrrolidifl-2(S)-ylmethyl1-N-( i-naphthyl methyl)g lycyl-(P3-methycarbonylamino)alaflife methyl ester; N-ti H-imidazol-4-ylacetyl)pyrrolidifl- 30 2( S)-ylmethylj-N-(i -naphthylmethyl)glycyl-(f -methy5ulfoflylamiflo)alaflife; N-[i H-imidazol-4- ylacetyl)pyrrolidin-2(S)-ylmethyll-N-(li naphthymethy)glycyl(3flmethylsulfoflylamifo)alaflife methyl ester; N-ti H-imidazol-4-yacetyl)pyrrolidif-2(S)-ylmethyl-N-(1 -naphthylmethyl)glycyl-(P3-propioflyl -amino)alanine; N-ti H-imidazol-4-ylacetyl)pyrrolidif-2(S)-ylmethylI-N-(1 -naphthylmethyl)glydy-U 3 propionylamino)alanine methyl ester; N-[1 H-imidazol-4-ylacetyl)pyrrQlidifl-2(S)ylmethylFN-(1 naphthylmethy)glycyl-(P-pyrrolidiflof-i -ylamino)alanine; N-ti H-imidazol-4-y5cetyl)pyrrolidifl- 2 ylmethyl]-N-(i -naphthylmethyl)glycy-(3-pyrrolidiflof-1 -ylamino)alanine methyl ester; N-ti H-imidazol- 4-ylacety)pyrrolidin-2(S)-ylmethyl-methoxybelzyl)glycyl-methioflile; N-ti H-imidazol-4-ylacetyl) pyrrolidin-2(S)-ylmethyl]-methoxybelzyl)glycyl-methioflife methyl ester; N-ti H-imidazol-4- ylctlproii-()ymtylN-2mtoyezlgyy-ehoie N-ti H-imidazol-4-ylacetyl) yrldn2S-iehl--(-ehxbny~lclmtinn methyl ester; N-ti -(glycyl)pyrrolidifl- C04154 2(S)-ylmethyl-N-(3-methoxybenzy)glycyl-mfethioflife; N-Il -(glycyl)pyrrolidin-2(S)-ylmethylj-N-(3- methoxybenzyl)glycyl-methionine methyl ester; N-Il -(glycyl)pyrrolidin-2(S)-ylmethyl]-N-(2-methoxy benzyl)glycyl-methionine; N-[I (glycyl)pyrrolidin-2(S)-ylmethyl]-N-(2-methoxybelzyl)glycyl-methioflife methyl ester; N-Il H-imidazol-4-yIpropionyl)pyrrolidin-2(S)-ylmethyl]-N-(2-metho~xybelzyl)glycyl- methionine; N-Il H-imidazol-4-ylpropionyl)pyrrolidil-2(S)7Ylmethyl]-N-(2-methoxybelzyl)glycyl- methionine- methyl ester; N-Il H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylethyi-N-(3-cyalobelzyl) glycyl-methionine; N-I H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl-N-(3-CYalobelzyl)glycyl- methionine methyl ester; N-Il H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyll-N-(4-cyalobelzyl) glycyl-methionine; N-Il H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl-Cyalo belzy)glycy- lo methionine; N-[Il- zl4yaetlproii-(S-lehl--(-ynbny~lyy-ehoi methyl ester; N-[I-lycl roii-()yl~tylN(-ynbnzlgyy-ehoie N-Il -(glycyl) pyrrolidin-2(S)-ylmethyl]-N-(2-cyalobeflzyl)glycyI-methioflife methyl ester; N-Il H-imidazol-4-yl prpoy~yrldn2S-lehl--2caoezlgyy-ehoie N-Il H-imidazol-4-yl prpoy~yrldn2S-lehl-N(-ynbny~lclmtinn methyl ester; N-Il H-imidazol- 4-ylacetyl)pyrrolidin-2(S)-ylmethyl-methylbel)glycyl-mfethioflife; N-[1 H-imidazol-4-ylacey) pyrldn2S-lehl--2mtybny~lclmtinn methyl ester; H-imidazol-4-yl actlproii-()ymty]N(-dlooehlezlgyy-ehoie N-I H-imidazol-4-yl actlproii-()ymtylN(-tfurmtybny~lclmtinn methyl ester; N-[l -(1H- imidazol-4-ylacetyI)pyrrolidin-2(S)-ylmethyl]-N-(l -naphthylsulfony)glycyl-methioflife; N-Il H-imidazol- 4-ylacetyl)pyrrolidin-2(S)-ylmethy -naphthylsulfonyl)glycyl-methioflife methyl 'ester; N-Il (glycyl)pyrrolidin-2(S)-ylmethyl]-N-(l -naphthylmethyl)glycyl-methionine 4-N-methylpiperidinyl ester; N- 00 ~1-(glycyl)pyrrolidin-2(S)-ylmethyl]-N-(l -naphthylmethyl)glycyl-methionifle tert-butyl ester; N-Il -(glycyl) 2 pyrrolidin-2(S)-ylmethyll-N-(l -naphthylmethyl)glycyl-methionine 3-pentyl ester; N-l -(4-pyridylglycyl) pyrldn-()ymeh -ahhymty~gyy-etinn isopropyl ester; N-Il-(l H-imidazol-4- ylpropionyl)pyrrolidin-2(S)-ylmethyll-N-(l l-naphthylmethyl)glycyl-methionifle isopropyl ester; N-Il-(l H- 4-rpoylproidn2S-ymtyl--2mthxbny gyy-mtinn isopropyl ester OH 3 C H 3 0 H @040 @00N N N0 LIN H 0 H a pharmaceutically acceptable salt thereof.

14. A method,' RAF antagonist compound and a famesyl protein transferase inhibiting 130 compound, or use in accordance with claim 8 wherein the famesyl transferase inhibiting compound is a compound represented by one of formulas (1l-h) through (1l-k): C041 54 (1l-h) R4a ROb (R ,V 2 It R 5 a Rla RiB Rib R 6 yN H 0 (Ii RaROb OH Ra RR 9 bX R2 -r 3 Q Al RA2 Rib R 6 O Z N H 0 (1 I..j R4a R4b *R R 9 Rb X R2 R3 Q *RIB RIB Rib R 6 -0 N H 0 (lk selected from the group consisting of: N-(Hiiao4yaey-()aio-()mtypnyl 1,2 ,3,4-tetrahydro-3(S)-isoquinoilecarbofl-methioflife methyl ester; H-imidazol-4-ylacetyl-2(S)- amino)-3(S)-methylpentyl]-1 ,2,3,4-tetrahydro-3(S)isoquinolilecarboflyl-methioflife; N-[1 H-imidazol- 4-ylacetyI)-3(S)-ethylpyrroidin-2(S)-ylmethyl-proIly-mfethioflife methyl ester; N41 H-imidazol-4- ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ymethyl-prolyl-methioflife; N-[1 -glycylpyrrolidin-2(S)-ylmethyll-3(S)- lo1 ethylprolyl-methionine methyl ester; N-ri -glycylpyrrolidin-2(S)-ylmethyl]-3(S)-ethylprolyi-methioflife; N- [L-pyroglutamyl-2(S)-amino-3(S)-methylpefltyll-l ,2,3,4-tetrahydro-3(S)-isoquinolilecabofl-methiolifle CH 3 S0 H H 00 0 N 00 C04154 257 N-[L-pyroglutamyl-2(S)-amino-3(S)-methyIpeltyl)-l ,2,3,4-tetrahydro-3(S)-isoquiolilecarboflyl- methionine methyl ester o H 3 CH 3 0 0 00 o N 0 N-[1 H-mdzl4yaey)proii-()-lehl-()ehlrlimtinn C H 3 S OH 00 N 0 NH H-N H H N N-ri H-mdzl4vaev)ivrldn2S-lehl-()ehlrllmtinn methyl ester *5 S S S 555 S S. S S S 55 S S S 555 S 0-C H 3 H-i mid azol-4-ylacetyl-2(S)-amino)-3(S)-methylpelty]-prolyl-meth ioflife methyl ester C H 3 O-CH 3 H0-\ N 0 HH H-H H 0. C04154 1 H-imidazoi-4-ylacetyl-2(S)-ailo)-3(S)-methylpel]-prolIt-methioflife CH 3 S OH 0 ,,0 H F H H-N/ 0 -cyanobenzyl)-1 H-imidazol-5-yl)acetylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-proIyI methionine; N II CH3 S o OH O- 0 N 0 H N N N 5 (N-fl -cyanobenzyl)-1 H-imidazoI-5-yl)acetylpyrrolidin-2(S)-ylmethyII-3(S)-ethyI-proIyI methionine methyl ester; 4 C C O-CH 3 (N-fl -cyanobenzyl)-1 H-imidazol-5-yl)acetyllpyrrolidin-2(S)-ylmethYl]-3(S)-ethyl-proQI isopropyl ester, and methionine C04154 259 H CH 3 1 0 9 0 /N 0 H H N N or a pharmaceutically acceptable salt thereof. A method in accordance with claim 1, a RAF antagonist compound and a farnesyl protein transferase inhibiting compound in accordance with claim 2, or use in accordance with claim 3 wherein the farnesyl protein transferase inhibiting compound is selected from the group consisting of: chlorophenyl)-4-[1 -(4-cyanobenzyl)-imid azolylmethyl]-5-[2-(methanesuIfonyl)ethyl]-2-piperazi none dihydrochloride; 1 -(3-ch lorophenyl)-4-[1 -(4-cyanobenzyl) imid azolyl-methyl]-2-pi perazi none dihydrochloride; N-Il H -imid azol-4-propionyl) pyrrolid in-2(S)-yl methyl]-N-(2-methoxybenzyl)g lycyl- methionine isopropyl ester; 1 -cyanobenzyl)- 1 H-i mid azol-5-yI) acetyl] pyrrol id in-2(S)-yl methyl]-3(S)- ethyl-prolyl methionine isopropyl ester; 2(S)-n-butyl-1[1-(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3- di methylphenyl)piperazin-5-one; -(4-cyanophenyl-methyl)- 1 H-i mid azol-5-ylacetyl) am ino- 3 3(S)-methyl pentyl]-N 1-n aphthylmethyl-g lycyl-meth ion in e methyl ester; and 2(S)-[2(S)-[2(R)-amino-3- *mercaptolpropylamino-3(S)-methyl]-pentyloxy-3-pheny propionyl-meth ion ine s ulfone isopropyl ester, or a pharmaceutically acceptable salt thereof. 15 Dated 4 October 2000 MERCK CO., INC. Patent Attorneys for the Applicant/Nominated Person SPRUSON&F ERGUSON C04 154