AU706495B2

AU706495B2 - Inhibitors of farnesyl-protein transferase

Info

Publication number: AU706495B2
Application number: AU25548/97A
Authority: AU
Inventors: Dong D. Wei; Theresa M. Williams
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1996-04-03
Filing date: 1997-03-27
Publication date: 1999-06-17
Anticipated expiration: 2017-03-27
Also published as: EP0921801A1; JP2000507582A; CA2249599A1; WO1997036593A1; AU2554897A

Description

WO 97/36593 PCT/US97/05144 -1- TITLE OF THE INVENTION INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE BACKGROUND OF THE INVENTION The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP.

Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTPbound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form Lowy and D.M. Willumsen, Ann. Rev. Biochern. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.

Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane 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-Aaa -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 farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 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)). The Ras protein is one of several proteins that are known to undergo post-translational WO 97/36593 PCT/US97/05144 -2famesylation. 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.

Inhibition of famesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of famesyl-protein transferase selectively block the processing of the Ras oncoprotein intracellularly Kohl et al., Science, 260:1934-1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of faresyl-protein transferase blocks the growth of rasdependent tumors in nude mice Kohl et al., Proc. Natl. Acad. Sci 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., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Faresyl-protein transferase utilizes farnesyl 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)). Inhibition of faresyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. However, direct inhibition of farnesylprotein transferase would be more specific and attended by fewer side WO 97/36593 PCT/US97/05144 -3effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis.

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

Patent 5,141,851, University of Texas; N.E. Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).

In general, deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound.

However, the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable.

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

It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516).

Imidazole-containing inhibitors of farnesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 Al).

It is, therefore, an object of this invention to develop peptidomimetic compounds that do not have a thiol moiety, and that will inhibit famesyl-protein transferase and thus, the post-translational farnesylation of proteins. It is a further object of this invention to WO 97/36593 PCT/US97/05144 -4develop chemotherapeutic compositions containing the compounds of this invention and methods for producing the compounds of this invention.

SUMMARY OF THE INVENTION The present invention comprises peptidomimetic piperazine- or piperazinone-containing compounds which inhibit the famesyl-protein transferase. The instant compounds lack a thiol moiety and thus offer unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these famesyl transferase inhibitors and methods for their production.

The compounds of this invention are illustrated by the formulae A and B:

(R

8 )r

R

3

R

4

(R

8

R

A

)r (R

R

2

R

3 V A(CRRla 2 )nA 2 (CR a 2 )n W (CRlb 2 -Z t

X

R

4 B

R

WO 97/36593 WO 9736593PCT/US97/05144 DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention are useful in the inhibition of famnesyl-protein transferase and the famnesylation of the oncogene protein Ras. In a first embodiment of this invention, the inhibitors of famnesyl-protein transferase are illustrated by the formula A:

(R

8 )r (R 9 qR2

G

V -A A(CRla 2 )nA (CRla 2 )n W Rl 2 )p, 7

N

A

wherein: R Ia and R Ib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, R 1 0 R I IS(O)m-, R I C(O)NR 1 0 CN(R I 0 R 10 2N-C(NR 10 CN, N02, R IOC(O)-, N3, -N(R 10 or R I IOC(O)NR c) unsubstituted or substituted C I -C6 alkyl wherein the substitutent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlO0-, R' IIS(O)m-, R I C(O)NR 10 (R 1 R 10 2N- C(NRIO)-, CN, RIOC(O)-, N3, -N(R' 0 and R 1 1

C(O)-

R

2 and R 3 are independently selected from: H; unsubstituted or substituted Ci1 -8 alkyl, unsubstituted or substituted C2-8 alkenyl, WO 97/36593 WO 9736593PCTfUS97/05144 -6unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, R 6

R

7 R 6 unsubstituted or substituted heterocycle, 0 0 wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C 1 4 alkyl, b) (CH2)pOR 6 c) (CH2)pNR 6

R

7 d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-Cl1 -4 alkyl, h) SR 6 a, S(O)R 6 a, SO2R 6 a, 2) C3-6 cycloalkyl, 3) OR 6 4) SR 6 a, S(O)R 6 a, or SO2R 6 a,

-NR

6 R 7 R 6 6) -N A 7

R

0 -N YNR 7 R 7 a 0 WO 97/36593 WO 9736593PCTf(US97/05144 -7- 8) -0o NR 6 R 7 0 9) -0 OR 6 0 y NR 6R' 0 11) -S0 2

-NR

6

R'

R

6 12) -NS R6 13) rR 6 0 14) rOR 6 0

N

3 16) F, or 17) perfluoro-Cl-4-alkyI; 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, S(O)m, and -N(CORIO)-

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 97/36593 WO 9736593PCTIUS97/05144 -8-

R

6

R

7 and R 7 a are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e)

"YR

0 f) -S0 2

R

11 ,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;

R

6 a is selected from: C 1 4 alkyl, C3-.6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e)

YR

0 f) -S0 2

R

11 ,or g) N(R 10 )2; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-ClO cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R I IS(O)m-, WO 97/36593 PCTJUS97/05144 -9-

R

1 I C(O)NRl 10, (Ri 0 R' 0 2N-C(NR 1

CN,

N02, R IOC(O)-, N3, -N(R 1 0 or R I I0C(O)NR 1 and c) ClI-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-CI0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, RI IS(O)m-, RIOC(O)NH-, (RIO)2NC(O)-,

R

10 2N- C(NR 1 CN, R IOC(O)-, N3, -N(R 1 0 or RI OOC(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfiuoroalkyl, F, Cl, Br, R 1 0 0-, RI IS(O)m-, R 1 OC(O)NRIO0, (R 1 0 R 10 2N- C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RIO)2, or R IIOC(O)NR 10-, and C) CjI -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 R' IIS(O)m-, R IOC(O)NR (Ri 0 Ri 0 2N-C(NRIO0>, CN, Rl 0 N3, -N(R 10)2, or R I IOC(O)NR R 1 0 is independently selected from hydrogen, ClI -C6 alkyl, benzyl and aryl; R Iis independently selected from C I -C6 alkyl and aryl; AlI and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR 10-, -NR IOC(O)-, 0, -N(R 10 -S(O)2N(R -N(Rl I 0 or S(O)m; G is H2 orO0; V is selected from: a) hydrogen, b) heterocycle, WO 97/36593 PCT/US97/05144 c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X is -CH2-, or Z is unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C3-C6 cycloalkyl or substituted C3-C6 cycloalkyl,wherein the substituted C1-C6 alkyl and substituted C3-C6 cycloalkyl is substituted with one or two of the following: a) C1-4 alkoxy, b) NR 6

R

7 c) C3-6 cycloalkyl, d) -NR 6

C(O)R

7 e) HO, f) -S(O)mR 6 a, g) halogen, or h) perfluoroalkyl; m is n is p is qis r is s is t is u is 0, 1 or 2; 0, 1, 2, 3 or 4; 0, 1, 2, 3 or 4; 1 or 2; 0 to 5, provided that r is 0 when V is hydrogen; Oor 1; 0 or 1; and 4 or WO 97/36593 WO 9736593PCTIUS97105144 -1I1 or the pharmaceutically acceptable salts thereof.

In a second embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula B:

(R

8 )r

(R

9 )q

RH

2

R

3 -A A(CRla 2 )nA (CRl 2 )n W (CRlb 2 N\ Nt x

G

B

wherein: R Ia and R Ib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-Cl10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, R 10 R I IS(O)m-, R I C(O)NR (R 1 0 R I 0 2N-C(NR CN, N02, R IOC(O)-, N3, -N(R 10 or R I I0C(O)NR c) unsubstituted or substituted C I -C6 alkyl wherein the substitutent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 0 0-, R I IS(O)m-, R I C(O)NR 1 (R 1 R 10 2N- C(NR 1 CN, R IOC(O)-, N3, -N(R 10 and R I IOC(O)-

R

2 and R 3 are independently selected from: H; unsubstituted or substituted Cl1 -8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, "e R R 7 or

HR

6 unsubstituted or substituted heterocycle, 0 0 WO 97/36593 WO 9736593PCTIUS97/05144 12 wherein the 1) 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, e) CN, f) aryl or heteroaryl, g) perfluoro-Ci1 -4 alkyl, h) SR 6 a, S(O)R 6 a, SO2R 6 a, C3-6 cycloalkyl,

OR

6

SR

6 a, S(O)R 6 a, or SO2R 6 a, -NR 6R 7 -N YR 7 0 R 6 -N YNR Ra 0 WO 97/36593 WO 9736593PCTIUS97/05144 13 8) -0 NR 6

R

7 0 9) -0O OR 6 0 0 11) -S0 2 -NR 6 R 7 R 6 12) -N-S0 2 -R 6 a 13) R 6 0 14) r R6 0

N

3 16) F, or 17) perfluoro-Cl- 4 -alkyl; 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, S(O)m, and -N(COR 1

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 97/36593 PCTfJS97IO5144 14

R

6

R

7 and R7a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e)

YR

0 f) -S0 2

R

1 or g) N(R 1 0 or

R

6 and R 7 may be joined in a ring;

R

7 and R 7 a may be joined in a ring;

R

6 a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) CI-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e)

R

0 f) -S0 2

R

11 or g) N(R 1 0 )2; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, perfluoroalkyl, F, CI, Br, R 1 0 R I IS(O)m-, WO 97136593 WO 9736593PCT/US97/05144 15

R

1 0 C(O)NRIO0, (Ri 0

R

10 2N-C(NRIO0>, CN, N02, R IOC(O)-, N3, -N(R 10)2, or R I I0C(O)NR 1 and c) ClI-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, peffluoroalkyl, F, Cl, Br, RI 0 0-, RI IS(O)m-, RIOC(O)NH-, (RI 0

R

10 2N- C(NR CN, R IOC(O)-, N3, -N(R 10)2, or

R

1

OOC(O)NH-;

R9 is selected from: a hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfinoroalkyl, F, Cl, Br, R 100-, R I R I OC(O)NR 10-, (R I 0 )2NC(O)-, R 10 2N-C(NR CN, N02, R IOC(O)-, N3, N(R 10 or R IIOC(O)NR 10-, and c) C I-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RIO0-, RI IS(O)m-, RI 0

C(O)NRIO-,

(R I 0 Ri 0 2N-C(NR 1 CN, R I N3, -N(R 10)2, or R I IOC(O)NR R 10 is independently selected from hydrogen, C I -C6 alkyl, benzyl and aryl1; Ri is independently selected from C I -C6 aikyl and aryl;' A I and A 2 are independently selected from: a bond, -CH=CH-,

-C(O)NR

1 -NRI 0, -S(0)2N(R 10>, -N(R I 0 or S(O)m; G is 0; V is selected from: a) hydrogen, b) heterocycle, WO 97/36593 WO 9736593PCT/IJS97/05144 -16 c) aryl, d) C I -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 I is S(O)m and V is not hydrogen if A 1 I is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X is -CH2-, or Z is unsubstituted Cl-C6 alkyl, substituted Cl-C6 alkyl, unsubstituted C3-C6 cycloalkyl or substituted C3-C6 cycloalkyl, wherein the substituted C1I-C6 alkyl and substituted C3-C6 cycloalkyl is substituted with one or two of the following: a) C 1-4 alkoxy, b) NR 6

R

7 c) C3-.6 cycloalkyl, d) -NR 6

C(O)R

7 e) HO, f) -S(O)mR 6 a, g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1,2, 3or 4; q is I or 2; r is 0 to 5, provided that r is 0 when V is hydrogen; s t is 0Oor1; and u is 4 WO 97/36593 PCT/US97/05144 17or the pharmaceutically acceptable salts thereof.

In a preferred embodiment of this invention, the inhibitors of famesyl-protein transferase are illustrated by the formula A: (Rr r R9

R

2

G

V A'(ACRa 2 )nA 2 (CR a 2 n (CRb 2 N N-Z

R

3

R

4

A

wherein: Ria is independently selected from: hydrogen or C -C6 alkyl;

R

l b is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 100-, -N(R 10)2 or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C -C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R 10 0- and -N(R10)2;

R

3 and R 4 are independently selected from H and CH3;

SNR

6

R

7

R

2 is H; O or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 4) SR 6 a, SO2R6a, or WO 97136593 PCT/US97/05144 18 NR 6 R 7 0 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, aryl, heterocycle, unsubstituted or substituted with: a) C1 -4 alkoxy, b) halogen, or c) aryl or heterocycle;

R

6 a is selected from: Cl1 4 alkyl or C3 -6 cycloalkyl, unsubstituted or substituted with: a) C 1 alkoxy, b) halogen, or c) aryl or heterocycle;

R

8 is independently selected from: a) hydrogen, b) ClI-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1-C6 perfluoroalkyl, F, Cl, R 10 RlIOC(O)NRl10-, CN, N02, (R I 0 )2N-C(NR Ri I -N(Rl 0)2, or R I I0C(O)NR 10-, and c) C1I-C6 alkyl substituted by C I-C6 perfluoroalkyl, R 100-, Ri I C(O)NR 1 (Ri 0 )2N-C(NR R I OC(O)-, -N(R 10)2, or R I IOC(O)NR

R

9 is selected from: a) hydrogen, b) C2)-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroaikyi,

F,

C1. R 1 0 R1 1 R I 0 C(O)NR 10-, CN, N02,

M

WO 97136593 PCT/US97/05144 19 (RI 0 )2N-C(NR R I -N(Rl 0)2, or R I I0C(O)NR 1 and C) C I -C6 alkyl unsubstituted or substituted by C I -C6 perfluoroalkyl, F, Cl, R 10 R I IS(O)m-, R I C(O)NR CN, (R'0)2N-C(NRIO)-, RIOC(O)-, -N(RiO)2, or R I I0C(O)NR R 10 is independently selected from hydrogen, C I -C6 alkyl, benzyl and aryl;

R

1 is independently selected from C I-C6 alkyl and aryl; AI and A 2 are independently selected from: a bond, -CH=CH-,

-CE-C-,

-C(O)NR 10-, 0, -N(R or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C I -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A I is S(O)m and V is not hydrogen if AIis a bond, n isO0 and A 2 is S(O)m; G is H2 orO0; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl. indolyl, quinolinyl, or isoquinolinyl; WO 97/36593 PCTJUS97/05144 X is -CH2- Z is unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C3-C6 cycloalkyl or substituted C3-C6 cycloalkyl,wherein the substituted C -C6 alkyl and substituted C3-C6 cycloalkyl is substituted with one or two of the following: a) C1-4 alkoxy, b) NR 6

R

7 c) C3-6 cycloalkyl, d) -NR 6

C(O)R

7 e) HO, f) -S(O)mR 6 a, g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 0 or 1; t is 0 or 1; and u is 4 or provided that when G is H2 and W is imidazolyl, then the substitutent

(R

8 V Al(CRla2)nA 2 (CR1a2)n is not H and provided that when X is or then t is 1 and the substitutent

(R

8 V AI(CRla2)nA 2 (CR a2)n is not H; or the pharmaceutically acceptable salts thereof.

A preferred embodiment of the compounds of this invention are illustrated by the formula C: WO 97/36593 WO 9736593PCT/UJS97/05144 21

(R

8 )r R 9 V Al(C Rl 2 )flA (C RlaP)- N\N (CRlb 2 )p C R 2 R 3 wherein: R Ia is selected from: hydrogen or C1I-C6 alkyl; R Ib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 1 0 -N(R 1 0)2 or C2-C6 alkenyl, c) C1I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 1 0 or 02

R

3 is selected from H and CH3; rNR 6 R 7

R

2 is selected from H; 0 or Ci1.- alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 4) SR6a, SO2R 7 a, or ~NR 6 R 7 0 and R 2 and R 3 are optionally attached to the same carbon atom;

R

6 and R 7 are independently selected from: H; Ci1A- alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) C 1 4 alkoxy, WO 97/36593 WO 9736593PCTIUS97/05 144 22 b) halogen, or c) aryl or heterocycle;

R

6 a is selected from: C 1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) Ci1 -4 alkoxy, b) halogen, or c) aryl or heterocycle;

R

8 is independently selected from: a) hydrogen, b) C1I-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, ClI-C6 perfluoroalkyl, F, Cl, R 10 R I C(O)NR 1 CN, N02, (R'1 0 )2N-C(NR R I -N(R 10 or R I I0C(O)NR 10-, and c) C I -C6 alkyl substituted by C I -C6 perfluoroalkyl, R 1 00-,

R

1 I C(O)NR 1 (R I 0 )2N-C(NR

R

1 I 102,or R I I0C(O)NR

R

9 a is hydrogen or methyl; R 10 is independently selected from hydrogen, C1I-C6 alkyl, benzyl and aryl; R I I is independently selected from C I-C6 alkyl and aryl; A and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR 10-, 0, -N(R or S(O)m; V is selected from: a) hydrogen, WO 97/36593 PCT/US97/05144 -23 b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A is a bond, n is 0 and A 2 is S(O)m; X is -CH2- or Z is unsubstituted Cl-C6 alkyl, substituted Cl-C6 alkyl, unsubstituted C3-C6 cycloalkyl or substituted C3-C6 cycloalkyl,wherein the substituted C1-C6 alkyl and substituted C3-C6 cycloalkyl is substituted with one or two of the following: a) C1-4 alkoxy, b) NR 6

R

7 c) C3-6 cycloalkyl, d) -NR 6

C(O)R

7 e) HO, f) -S(O)mR 6 a, g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; nis 0, 1, 2, 3 or 4; pis O, 1, 2, 3 or 4; and r is 0 to 5, provided that r is 0 when V is hydrogen; or the pharmaceutically acceptable salts thereof.

WO 97/36593 PCTJUS97/05144 -24 In a more preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula

D:

H

IN

R

8 (CR b 2 )p -xY

O

N N-Z

R

2

R

3 wherein: Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl,

R

10 -N(R10)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 or -N(R10)2;

R

3 is selected from H and CH3;

NR

6

R

7

R

2 is selected fr branched, 1) 2) 3) 4) om H; u or C1-5 alkyl, unbranched or unsubstituted or substituted with one or more of: aryl, heterocycle,

OR

6

SR

6 a, SO2R 7 a, or

NR

6

R

7 0 and R 2 and R 3 are optionally attached to the same carbon atom;

R

6 and R 7 are independently selected from: WO 97/36593 PCTIUS97/05144 25 H; CI-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) C1 -4 alkoxy, b) halogen, or c) aryl or heterocycle;

R

6 a is selected from: CI1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) C 1 4 alkoxy, b) halogen, or c) aryl or heterocycle; R8 is independently selected from: a) hydrogen, b) C I -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, Cl, R 10 R I 0 C(O)NR 10-, CN, N02, (Ri 0 )2N-C(NR 1 R I 0 -N(R 10)2, or R I I0C(O)NR 10-, and c) C I-C6 alkyl substituted by C I -C6 perfinoroalkyl, R 1 0 0-, RI 0 C(O)NR (RIO)2N-C(NRIO0>,

R

1 0 -N(R 10)2, or R I R 10 is independently selected from hydrogen, C I -C6 alkyl, benzyl and aryl;

R

1 I s independently selected from C I -C6 alkyl and aryl; X is -CH2- or Z is unsubstituted C I -C6 alkyl, substituted C I -C6 alkyl, unsubstituted C3-C6 cycloalkyl or substituted C3-C6 cycloalkyl, wherein the substituted C I -C6 alkyl and WO 97/36593 PCT/US97/05144 -26substituted C3-C6 cycloalkyl is substituted with one or two of the following: a) C1-4 alkoxy, b) NR 6

R

7 c) C3-6 cycloalkyl, d) -NR 6

C(O)R

7 e) HO, f) -S(O)mR 6 a, g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; and pis 0, 1, 2, 3 or 4; or the pharmaceutically acceptable salts thereof.

In a second more preferred embodiment of this invention, the inhibitors of famesyl-protein transferase are illustrated by the formula E:

H

NN0 .N N-Z (CRb2) X

R

2

R

3 NC E wherein:

R

1 b is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl,

R

10 -N(R0O)2 or C2-C6 alkenyl, WO 97/36593 PCT/US97/05144 -27 c) Ci-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R1 0 or -N(R10)2;

R

2 and R 3 are independently selected from: hydrogen or C1-C6 alkyl;

R

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

R

1 is independently selected from C -C6 alkyl and aryl; X is -CH2- or Z is unsubstituted C -C6 alkyl, substituted C -C6 alkyl, unsubstituted C3-C6 cycloalkyl or substituted C3-C6 cycloalkyl,wherein the substituted C1-C6 alkyl and substituted C3-C6 cycloalkyl is substituted with one or two of the following: a) C1-4 alkoxy, b) NR 6

R

7 c) C3-6 cycloalkyl, d) -NR 6

C(O)R

The preferred compounds of this invention are as follows: WO 97/36593 PCT/US97/05144 -28 2(S)-n-Butyl- 1-[1 -(4-cyanobenzyl)-5-imidazolylmethyl]-4-(2,2,2dihydrochloride 2(S)-n-Butyl-1-[1 -(4-cyanobenzyl)-5-imidazolylmethyl]-4-[ 1-(3,3,3trifluoropropyl)] -piperazin-5-one dihydrochloride 2(S)-n-Butyl- 1-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-4dihydrochi oride and 2(S)-n-Butyl- 1 -[3-(4-cyanobenzyl)pyridin-4-yl]-4-(2,2,2dihydrochloride or the pharmaceutically acceptable salts thereof.

Specific examples of the compounds of the invention are: 2(S)-n-Butyl-1-[1 -(4-cyanobenzyl)-5-imidazolylmethyl]-4-(2,2,2dihydrochloride NC N N-CH2CF3 NO~\ N 200

N

or the pharmaceutically acceptable salts thereof.

The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. When any variable aryl, heterocycle, R1, R 2 etc.) occurs more than one time in any constituent, its definition on each occurence is independent at every other occurence. Also, combinations of substituents/or variables are permissible only if such combinations result in stable compounds.

WO 97/36593 PCTIUS97/05144 -29- As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. "Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.

As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.

The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11membered bicyclic heterocyclic ring which is either saturated or unsaturated, 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, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2 -oxopiperdinyl, 2 -oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.

WO 97/36593 PCT/US97/05144 As used herein, "heteroaryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, 0, and S. Examples of such heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, and thienyl.

As used herein in the definition of R 2 and R 3 the term "the substituted group" intended to mean a substituted Cl-8 alkyl, substituted C2-8 alkenyl, substituted C2-8 alkynyl, substituted aryl or substituted heterocycle from which the substitutent(s) R 2 and R 3 are selected.

As used herein in the definition of R 6 R6a, R 7 and R7a, the substituted C1-8 alkyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroarylsulfonyl and substituted heterocycle include moieties containing from 1 to 3 substitutents in addition to the point of attachment to the rest of the compound.

When R 2 and R 3 are combined to form (CH2)u cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to: WO 97/36593 PCT/US97/05144 31 In addition, such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include, but are not limited to: N

N

00 H 0

COR

10 Lines drawn into the ring systems from substituents (such as from R 2

R

3

R

4 etc.) indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.

Preferably, Rla and Rlb are independently selected from: hydrogen, -N(R10)2, R10C(O)NRI0- or unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted phenyl, -N(RlO)2, R 10 0- and 1

O-.

Preferably, R 2 is selected from: H,

R

6

R

7

R-R

6 0 0 and an unsubstituted or substituted group, the group selected from Cl-8 alkyl, C2-8 alkenyl and C2-8 alkynyl; wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) Cl-4 alkyl, b) (CH2)pOR 6 c) (CH2)pNR 6

R

7 d) halogen, 2) C3-6 cycloalkyl, 3) OR 6 WO 97/36593 PCT/US97105144 32 4) SR 6 a, S(O)R 6 a, SO2R6a, -NR 6

R'

R 6 6) 0

R

6 7) 7I7 -N yNR Ra 0 8) -0o NR 6

R'

0 9) 0 O6 0 >'yNR 6R 7 0 11) -S0 2 -NR 6 R 7 R 6 12) %_NSO 2 j 1 WO 97/36593 PCT/US97/05144 -33 13)

R

6 0 O 14)

OR

6

N

3 or 16) F.

Preferably, R3 is selected from: hydrogen and C1-C6 alkyl.

Preferably, R 4 and R 5 are hydrogen.

Preferably,

R

6

R

7 and R7a is selected from: hydrogen, unsubstituted or substituted Cl-C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl.

Preferably, R6a is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl.

Preferably, R 9 is hydrogen or methyl. Most preferably, Ra is hydrogen.

Preferably, R 10 is selected from H, Cl-C6 alkyl and benzyl.

Preferably, Al and A 2 are independently selected from: a bond, -C(O)NR1O-,

-NR

1 0, -S(0)2N(RlO)- and-

N(RO

1 Preferably, V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.

Preferably, Z is unsubstituted or substituted C -C6 alkyl.

Preferably, W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl.

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

Preferably p is 1, 2 or 3.

Preferably s is 0.

Preferably t is 1.

WO 97/36593 PCT/US97/05144 -34- It is intended that the definition of any substituent or variable Ria, R 9 n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, -N(R10)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.

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, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.

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 either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.

Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1-21, 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 R, Ra and Rb, as shown in the Schemes, represent the substituents R 2

R

3

R

4 and WO 97/36593 PCT/US97/05144 however their point of attachment to the ring is illustrative only and is not meant to be limiting. Substituent as shown in the Schemes, represents an alkyl moiety or a substitutent on an alkyl moiety such that Z'CH2- is the substiutent Z as defined hereinabove.

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

Synopsis of Schemes 1-21: 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 (1-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 reductively alkylated with a suitably substituted aldehyde to provide the protected piperazine VII; a final acid deprotection as previously described gives the intermediate VIII (Scheme The intermediate VIII can itself be reductively alkylated with a variety of aldehydes, such as IX. The aldehydes can be prepared WO 97/36593 PCT/US97/05144 -36by 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 or 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 cyclized products such as the dihydroimidazole XV can be accomplished by literature procedures.

Alternatively, the piperazine intermediate VIII can be reductively alkylated with other aldehydes such as l-trityl-4-imidazolylcarboxaldehyde or 1-trityl-4-imidazolylacetaldehyde, to give products such as XVI (Scheme 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)-3ethylcarbodiimide (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 WO 97/36593 PCT/US97/05144 -37 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.

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

In addition, the piperazine VIII can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, 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 into the piperazine. For example when I is the Boc-protected 3-benzyl ester of aspartic acid, the intermediate diketopiperazine XLII (where n= and R=benzyl) is obtained, as shown in Scheme 10. Subsequent lithium aluminum hydride 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 1-9.

N-Alkyl piperazines can be prepared as described in Scheme 11. An alkyl 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.

WO 97/36593 PCT/US97/05144 38 can be prepared as shown in Scheme 12.

Reductive amination of Boc-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 aprotic 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.

Reaction Scheme 14 provides an illustrative example the synthesis of compounds of the instant invention wherein the substituents

R

2 and R 3 are combined to form (CH2)u For example, 1aminocyclohexane-1-carboxylic acid LVIII can be converted to the spiropiperazine LXVI essentially according to the procedures outlined in Schemes 1 and 2. The piperazine intermediate LXVI 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 imidazolylalkyl substituent may be readily replaced by other reagents well known in the art and readily available to provide other Nsubstituents on the piperazine.

The aldehyde XLIX from Scheme 12 can also be reductively alkylated with an alkyl amine as shown in Scheme 15. The product LXVIII can be converted to a piperazinone by acylation with WO 97/36593 PCT/US97/05144 -39chloroacetyl chloride to give LXIX, followed by base-induced cyclization to LXX. Deprotection, followed by reductive alkylation with a protected imidazole carboxaldehyde leads to LXXH, which can be alkylation with an arylmethylhalide to give the imidazolium salt LXXIII. 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 LXXIV.

Scheme 16 illustrates the use of an optionally substituted homoserine lactone LXXV to prepare a Boc-protected piperazinone LXXVIII. Intermediate LXXVIII may be deprotected and reductively alkylated or acylated as illustrated in the previous Schemes.

Alternatively, the hydroxyl moiety of intermediate LXXVIII may be mesylated and displaced by a suitable nucleophile, such as the sodium salt of ethane thiol, to provide an intermediate LXXIX. Intermediate LXXVIII may also be oxidized to provide the carboxylic acid on intermediate LXXXX, which can be utilized form an ester or amide moiety.

Amino acids of the general formula LXXXI which have a sidechain not found in natural amino acids may be prepared by the reactions illustrated in Scheme 17 starting with the readily prepared imine LXXXII.

Schemes 18-21 illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic strategies for preparing alkanols that incorporate other heterocyclic moieties for variable W are also well known in the art.

WO 97/36593 PCTIIJS97/05144 40 SCHEME I 0 yOH 0 R b PhCH 2

NHCHCO

2

C

2

H

DCC, CH 2

CI

2 Oo N TyN yC0 2

C

2

H

H 0 R b 11 1) HCI, CH 2 CI1 2 2) NaHCO 3 HN N- 0 R b

LAH

THF, reflux Ha HN N- Rb 80020_ 0H 2 C1 2 10% Pd/C0

H

2

CH

3 0H ->0 WO 97136593 WO 9736593PCTIUS97/05144 -41 SCHEME 2 Ra BocN N H RRb BooN "XN-CH 2 z' N aB H(OAC) 3 010 H 2 C H 2 C1 11 0 HOI, EtOAc HCl-N N-0H Z' Vill WO 97/36593 WO 9736593PCTIUS97/05144 42 SCHEME 3 HCI-N

N-CH

2

Z'

R b Vill Boo NH I ix Boo NH CHO NaBH(OAo)3 Et 3 N ,ClCH 2

CH

2

CI

Boo NH N \-<N-CH 2 Z'

CF

3 00 2

H

NHBoc R b

C

2 x

NHL

2 j N N-CH 2

Z'

NH

2 R b B0020

CH

2

CI

2 BocNH cN N-CH 2

Z'

NH

2 R b

~CHO

NaBH (OAc)3 Et 3 N ,ClGH 2

CH

2

CI

WO 97/36593 WO 9736593PCT/US97/05144 43 SCHEME 3 (continued) Ra BocNH N N-CH 2

Z'

NH Rb 7p xiii

CF

3

CO

2 H, CH 2

CI

2 NaHCO 3

RNC

NH

2 N N-CH 2

Z'

NH R b AgON xiv Ha r -N N-OH 2

Z'

N N Rb WO 97136593 PCTIUS97/05144 44 SCHEME 4 HOI-N

\<N-CH

2

Z'

R b Vill NaB H (GA) 3 Et 3 N CICH 2

CH

2

CI

(C H 2 )nC HO

N-

N

Tr N N-CH Z' R b

XVI

CF

3

CO

2 H, CH 2

CI

2

(C

2

H

5 3 SiH 1) Ar CH 2 X, CH 3

CN

2) CF 3 00 2 H, CH- 2

CI

2

(C

2

H

5 3 Si H Ha -N N-CH Z' 1 R b xviI Ar-\ xviII WO 97/36593 WO 9736593PCTIUS97/05144 45 SCHEME N CH 2 00 2

H

N

H

XIX

(C

6

H

5 3 CBr

(C

2

H

5 3

N

DMF

CH

3 0H

HCI

N CH 2 00 2

CH

3

N

H HOI x 3 1) ArCH 2 X CH 3

CN

ref lux_ 2) CH 3 0H, refiux Xxi Ar- -0H 2 00 2 0H 3

N

Nxi 2.5N HClaq 550C Ar-\ NSOH 2

CO

2

H

N

N xl WO 97/36593 PTU9/54 PCT/US97105144 46 SCHEME 5 (continued)

CH

2

CO

2

H

N,7

N

xxiII HCLH N\__N-CH 2

Z'

R b Vill EDC -HOI HOBt

DMF

Ar

R

N N N-~CH 2

Z'

N

RXIV

WO 97/36593 PCTfJS97/05144 47 SCHEME 6 BnOI xxv HCILN N-0H 2

Z'

R b Vill BocNH

CHO

NaBH(OAc) 3 Et 3 N ,CICH 2

CH

2

CI

BnO N N-CH 2

Z'

NH~oc Rb 20% Pd(OH) 2

H

2

CH

3 0H

CH

3 C0 2

H

xxv' HO N N-CH 2

Z'

N H oc R b xxvii cicococ'

CH

2 01 2 (02

H

5 3

N

WO 97/36593 PCTIUS97/05144 48 SCHEME 6 (CONTINUED) Ra 1 -R'MgX 0 N N-CH 2

Z'

H N H oc Rb (02 H 5 2 0 2. TFA,

CH

2 01 2 xxviii HO

N,

Rv NH 2

CH

2

Z'

xxix WO 97/36593 PCTIUS97/05144 49 SCHEME 7 HO N

N-CH

2

Z'

NHJBoc R b xxv ii C F 3 00 2

H

CH

2 01 2 HO N NCH 2 Z' 'CHO H O '11 N H 2Z 'N aB H (O A 3 NH 2 R b

CICH

2

CH

2

CI

xxx HO N, -N-CH 2

Z'

NH R b

R'CH

2 xxxi WO 97/36593 WO 9736593PCTIUS97/05144 50 SCHEME 8 HO N

N-CH

2

Z'

NHBoc R b

XXVII

N N- CH 2

Z'-

<N Rb Boc

XXXII

H'S N N-C H 2

Z'

NHBoc R b XXXI II H H N ~-N NaH, DMF 0 0

C

R'SH

(C

2

H

5 3 N

A

CH

3 0H

TFA

CH

2 01 2 Ha R'SX N N- CH 2

Z'

NH

2 R b WO 97/36593 PCTJUS97IO5144 -51 SCHEME 9 1) BoC 2 O, K 2 C0 3

THF-H

2 0 2) CH 2

N

2 EtOAc oN BocNH 0 2

CH

3

H

2

N

XXXIV

XXXV

LiAJH 4

THF

0-200C

R'CH

2

X

CS

2

CO

3

DMF

BocNHK 'CH 2

OH

XXXVI

R'CH

pyridine

-SO

3

DMSO

(C

2

HE;)

3

N

200C

CH

2 0H BocNH' NOHO

XXXVII

XXXVIII

WO 97/36593 PCTIUS97/05144 52 SCHEME 9 (continued) R0CH 2 0 BocNH

CHO

xxxviI' HCI N

N-CH

2

Z'

Rb NaB H(OAc)3 Vl

CICH

2

CH

2

CI

\JN-CH

2

Z'

NHBoc XXXX HI ETOAc 1) 20% Pd(O H) 2

CH

3 OH, CH 3 C0 2

H

2) HCI, EtOAc RO H 2 0 N- GH 2

Z'

R b

XLI

CH

2

Z'

NH

2 WO 97/36593 PCT/US97/05 144 53 SCHEME C0 2

R

0 HN N- 0

XLII

1) LAH, Et 2

O

2) BOC 2 0

HO

R 6 1 n( )NaH,

DMF

0N

XLIII

XLIV

WO 97/36593 WO 9736593PCTIUS97/05144 54 SCHEME 11

Z-NH

2

XLV

R b O CIH

XLVI

n butanol ref lux Ha Rb Z-N HNH -HCI a R b

XLVII

WO 97/36593 PCT/US97/05144 55 SCHEME 12 0 N yOH

H

0 o

CH

3

NHOCH

3

-HCI

EDO. HCI, HOBT DMF, Et 3 N, pH 7 O Ra >O N yN(CH,)OCH,

H

0 o

XLVIII

LAH, Et 2

O

0 '0'kN

H

yH 0

Z-NH

2 NaBH(OAc) 3

CICH

2

CH

2

CI

pH 6

XLIX

O N N H-Z 1) BrCH 2 00Br EtOAc, H 2 0, NaHCO, 2) NaH, THF, DMF WO 97/36593 PCT[US97/05144 56 SCHEME 12 (CONT'D) N N-Z 0 1) TFA, CH 2 C1 2 HN N-Z 0 WO 97/36593 PCTIUS97/05144 57 SCHEME 13

Z'-CHO

L11I

NH

2

CH

2 CH(0C 2

H

5 2 NaB H(OAC) 3

LIN

Z'-CH

2

NHCH

2 OH(0C 2

H

5 2

LIV

O Ra ON,

OH

H H 0 EDC. HOI, HOBT DMF, Et 3 N, pH 7 0 0 yNl-,CH(OC 2

H

5 2 0 6N HOI

THF

H

2 10% Pd/C

CH

3 0H 0

RO

N\-

N N

LVII

WO 97/36593 PCTIUS97/05144 58 SCHEME 14 BocNH CO 2

H

LVIII

PhCH 2

NHCH

2 00 2

C

2

H

DCC, CH 2 C1 2 BocNH

N"-CO

2

C

2

H

0 LXIX a) TFA, CH 2

CI

2 b) NaHCO 3 (C H 3 3

AI

CHCI

3

LXX

LiAIH 4 TH F HN N b

LXII

H

2 Pd/C

CH

3 0H BoC 2 0

CH

2

CI

2 BocN

N

LXI!I

WO 97/36593 PTU9/54 PCTIUS97/05144 59 SCHEME 14 (continued) NaBH (OAo) 3

CICH

2

CH

2

CI

BooN NH

LXIV

BooN \-jN-CH 2

Z'

LXV

C -H a) TFA, 0H 2 01 2 b) NaBH(OAc) 3 C(=0)H

N

CPh, N N-H 2 Z' TFA CH 2

CI

2 N NCH2Z'

(C

2

H

5 3 SiH

N\

CPh 3

LXVI

CH

2

Z'

N

H .2 TFA

LXVII

WO 97/36593 PCTIUS97/05144 60 SCHEME R R H BocNH ',CHO Z-NH 2 BoNI Nlz NaBH(OAC) 3 BoNz

CICH

2

CH

2

CI

XLIX

LXVIII

0 CI,

C

EtOAc

H

2 0 NaHC0 3

R

BocNH N-Z 01 0

LXIX

NaH

DMF

R

BocN N-Z 0

HOI

EtOAc

LXX

WO 97/36593 PCTIUS97/05144 61 SCHEME 15 (continued)

R

HCIHNN- Z 0

LXXI

CHO

N

C(Ph) 3 NaB H(OAc) 3 g

CICH

2

CH

2

CI

pH 5-6

R

-N N-Z

N

(Ph) 3 c

LXXII

ArCH 2

X

CH

3

CN

R

N N-Z

N

(Ph) 3 C

X

LXXI IfI MeOH

R

Ar-\N N-Z

N

TFA,

CH

2

CI

(C

2

H

5 3 Si H

LXXIV

WO 97/36593 PCT[US97/05144 62 SCHEME 16 sub BoC 2 O, i-P r 2 EtN 2. DIBAL

HCI

OH

LXXV OH sub

Z-NH

2 NaBH(OAC) 3 -BocNH CIG H 2 C H 2

CJ

LXX VI 0 Cl c EtOAc

H

2 0 NaHCO 3 HO sub BocNH N- Z CI 0

LXXVII

CS

2

CO

3

DMF

HO sub BocN N-Z

LXXVIII

WO 97/36593 PCTIUS97/05144 63 SCHEME -16- (continued) BooN N- Z 1 (r, 1. MsCI, iPr 2 NEt 2. NaSEt,/DMF EtS sub BocN N-Z 0 LXXVIII

DI

0C1)2, Et 3

N

mAso 2. NaCIO 2 t-BuOH 2-Me-2-butene NaH 2

PO

4 HO sub 0 A BocN N-Z LXXIX

LX

LXXX

WO 97/36593 WO 9736593PCT[US97/05144 64 SCH4EME 17 1. KOtBu, THF R 2

X

2. 5% aqueous HCI

CO

2 Et Ph R 2 -C0 2 Et

H

2

N

HOI

LXXX I Boc 2 O, NaHCO 3 2. LiAIH 4 Et 2

Q

)-C02

H

BocHN

LXXXII

WO 97/36593 WO 9736593PCTIUS97/05144 65 REACTION SCHEME 18

OH

3

H

2 N- N 1) HNO 2 ,Br 2 2) KMnO 4 3) MeOH,H+ MgCI Br- N-

ICO

2

CH

3 ZnCI 2 ,NiCI 2 (Ph 3

P)

2 NaBH 4 (excess) S0 3 'Py, Et 3

N

DMSO

WO 97/36593 WO 9736593PCTIUS97/05144 66 REACTION SCHEME 19 1. EtO(CO)CI Br C0 2

CH

3

N

Zn, CuCN 3. S, xylene, heat NaBH 4 (excess) R 6 S03-Py, Et 3

N

C H 2 0H DMSO

NI

R 6

CHO

N'

Br CC 3 N ZnCI 2 Ni01 2 (Ph 3

P)

2

CO

2

CH

3 NaBH 4 (excess)

SO

3 -Py, Et 3

N

,CH

2

OH

DMSO

,CHO

WO 97/36593 WO 9736593PCTIUS97/05144 67 REACTION SCHEME

N

1. LDA, 002 2. MeCH, H+

RH

6 I rMgCI ZnCI 2 NiCI 2 (Ph 3

P)

2 NaB H 4 (excess)

CH

2 0H S03'Py, Et 3

N

DMSO

WO 97/36593 PCTIUS97/05144 68 REACTION SCHEME 21 IN Br 1. LDA, 002 C0 2 0H 3 Br 2. (CH 3 3 SiCHN 2 R 6 Br Zn, NiCI 2 (Ph 3 p) 2 N C0 2

CH

3 excess NaBH 4 R 6 N CH 2 0H

SO

3 -Py, Et 3

N

DMSO

WO 97/36593 PCT/US97/05144 -69- The instant compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors.

Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity neurofibromin neu, scr, abl, Ick, fyn) or by other mechanisms.

The compounds of the instant invention inhibit faresylprotein transferase and the faresylation of the oncogene protein Ras.

The instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors Rak et al. Cancer Research, 55:4575- 4580 (1995)). Such anti-angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization.

The compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment. For example, a component of NF-1 is a benign proliferative disorder.

The instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses Glenn et al. Science, 256:1331-1333 (1992).

The compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation Indolfi et al. Nature medicine, 1:541-545(1995).

The instant compounds may also be useful in the treatment and prevention of polycystic kidney disease Schaffner et al.

WO 97/36593 PCT/US97/05144 American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)).

The instant compounds may also be useful for the treatment of fungal infections.

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

For oral use of a chemotherapeutic compound according to this invention, the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents.

If desired, certain sweetening and/or flavoring agents may be added.

For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic.

The compounds of the instant invention may also be coadministered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.

For example, the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents. Similarly, the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF-1, restinosis, polycystic kidney WO 97/36593 PCT/US97/05144 -71 disease, infections of hepatitis delta and related viruses and fungal infections.

If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.

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

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

In one exemplary application, a suitable amount of compound is administered to a mammal undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.

The compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and quantity of famesyl-protein transferase (FPTase) in a composition.

Thus the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine WO 97/36593 PCT[US97/05144 72terminus) and famesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to allow the FPTase to farnesylate the substrate, the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques.

Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.

It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain famesyl-protein transferase and quantitating the enzyme. Thus, potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract containing an unknown amount of famesyl-protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention. The concentration of a sufficiently potent inhibitor one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel) required to inhibit the enzymatic activity of the sample by 50% is approximately equal to half of the concentration of the enzyme in that particular sample.

EXAMPLES

Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species WO 97/36593 PCT/US97/05144 -73 and conditions are intended to be further illustrative of the invention and not limitative of the reasonable scope thereof.

EXAMPLE 1 2(S)-n-Butyl-1 1 4 -cyanobenzyl)-5-imidazolylmethylj-4-(2,2,2dihydrochloride NC N N-CH 2

CF

3 100

N

L-786,017 Step A: N-Methoxy-N-methyl 2 (S)-(tert-butoxycarbonylamino)hexanamide 2 (S)-Butoxycarbonylaminohexanoic acid (24.6 g, 0.106 mol), N,O-dimethylhydroxylamine hydrochloride (15.5 g, 0.15 mol), EDC hydrochloride 22.3 g, 0.117 mol) and HOBT (14.3 g, 0.106 mol) were stirred in dry, degassed DMF (300 mL) at 20 0 C under nitrogen.

N-Methylmorpholine was added to obtain pH 7. The reaction was stirred overnight, the DMF distilled under high vacuum, and the residue partitioned between ethyl acetate and 2% potassium hydrogen sulfate.

The organic phase was washed with saturated sodium bicarbonate, water, and saturated brine, and dried with magnesium sulfate. The solvent was removed in vacuo to give the title compound.

Step B: 2(S)-(tert-Butoxvcarbonvlamino)hexanal A mechanically stirred suspension of lithium aluminum hydride (5.00 g, 0.131 mol) in ether (250 mL) was cooled to under nitrogen. A solution of the product from Step A (28.3 g, 0.103 mol) in ether (125 mL) was added, maintaining the temperature below WO 97/36593 PCT/US97/05144 -74- When the addition was complete, the reaction was warmed to then recooled to -45 0 C. A solution of potassium hydrogen sulfate (27.3 g, 0.200 mol) in water was slowly added, maintaining the temperature below After quenching, the reaction was stirred at room temperature for 1h. The mixture was filtered through Celite, the ether evaporated, and the remainder partitioned between ethyl acetate and 2% potassium hydrogen sulfate. After washing with saturated brine, drying over magnesium sulfate and solvent removal, the title compound was obtained.

Step C: N-( 2 ,2,2,-Trifluoroethyl)-2(S)-(tertbutoxycarbonylamino)-hexanamine 2 ,2,2-Trifluoroethylamine hydrochloride (0.407 g, mmol) was dissolved in dichloroethane under nitrogen. N-Methyl morpholine (0.330 mL, 3.0 mmol) was added to obtain pH 5-6, and sodium triacetoxyborohydride (0.795 g, 3.75 mmol) was added. A solution of the product from Step B (0.573 g, 2.5 mmol) in dichloroethane (80 mL) was added slowly dropwise at 20 0 C. The reaction was stirred overnight, then quenched with saturated sodium bicarbonate solution. The aqueous layer was removed, the organic phase washed with saturated brine and dried over magnesium sulfate.

The title compound was obtained as an oil.

Step D: 1 -tert-Butoxycarbonyl-2(S)-n-butyl-4-(2,2,2- A solution of the product from Step C (0.590 g, 1.98 mmol) in ethyl acetate (30 mL) was vigorously stirred at 0°C with saturated sodium bicarbonate (30 mL). Chloroacetyl chloride (0.315 mL, 3.96 mmol) was added, and the reaction stirred at 0°C for 1 h.

The layers were separated, and the ethyl acetate phase was washed with saturated brine, and dried over magnesium sulfate. The crude product was dissolved in DMF (15 mL) and cooled to 0°C under nitrogen.

Cesium carbonate (1.67 g, 5.12 mmol) was added and the reaction stirred 1 h at 0°C, then at room temperature overnight. The reaction WO 97/36593 PCT/US97/05144 was quenched with amminium chloride, and partitioned between ethyl acetate and water. The organic phase was washed with water, saturated brine, and dried over magnesium sulfate. The title compound was obtained as a colorless oil.

Step E: -Triphenvlmethyl-4-(hvdroxvmethyl)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 F: I-Triphenvlmethvl-4-(acetoxvmethyl)-imidazole Alcohol from Step E (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 G: 1-( 4 hvdrobromide A solution of the product from Step F (85.8 g, 225 mmol) and a-bromo-p-tolunitrile (50.1 g, 232 mmol) in 500 mL of EtOAc was stirred at 60 °C for 20 hours, during which a pale yellow precipitate formed. The reaction was cooled to room temperature and filtered to provide the solid imidazolium bromide salt. The filtrate was WO 97/36593 PCT/US97/05144 -76concentrated in vacuo to a volume 200 mL, reheated at 60 °C for two hours, cooled to room temperature, and filtered again. The filtrate was concentrated in vacuo to a volume 100 mL, reheated at 60 °C for another two hours, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in 500 mL of methanol, and warmed to 60 OC.

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 H: 1-(4-Cvanobenzyl)-5-(hydroxvmethyl)-imidazole To a solution of the acetate from Step G (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 I: 1-( 4 To a solution of the alcohol from Step H (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 (Na2SO4), 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.

Step J: 2(S)-n-Butyl-l-[1-( 4 -cyanobenzyl)-5-imidazolylmethyl]-4- (22,2-trifluoroethyl)-piperazin-5-one dihydrochloride WO 97/36593 PCT/US97/05144 -77- A solution of the product from Step D (0.578 g, 1.71 mmol) was stirred in 30% trifluoroacetic acid in methylene chloride for 1 h. The volatiles were removed in vacuo, and the residue dissolved in dichloroethane (5 mL). The pH was adjusted to 5-6 with Nmethylmorpholine. Sodium triacetoxyborohydride (0.544 g, 2.57 mmol) and 1-( 4 -cyanobenzyl)imidazolyl-5-carboxaldehyde from Step I (0.361 g, 1.71 mmol) was added. The reaction was stirred overnight at 0 C then poured into saturated sodium bicarbonate solution. The organic phase was washed with saturated brine and dried over magnesium sulfate. The crude product was purified by preparative HPLC on a 40 X 100 mm Waters PrepPak® reverse phase HPLC column (Delta-PakTM C18 15 pm, 100 A) using a gradient elution of TFA in acetonitrile), 75% TFA in water) progressing to 45% TFA in acetonitrile), 55% TFA in water) over min. Pure fractions were combined, concentrated, and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate. The purified product was converted to the hydrochloride salt with HC1 in dichloromethane. The title compound was obtained as a white solid.

FAB ms 434. Anal. Calc. for C22H26F3N50 2.0 HCI: C, 52.18; H, 5.57; N, 13.83. Found: C, 52.41; H, 5.60; N, 13.65.

EXAMPLE 2 2(S)-n-Butyl-l-[1 4 -cyanobenzyl)-5-imidazolylmethyl]-4-[1-(3,3,3dihydrochloride NC .N N CH 2

CH

2

CF

3

N

N 0

_M

WO 97136593 PCT1US97105144 78 Step A: N- I -(3,3,3-Trifluoropropy)-2(S)(tet-.

butoxvcarbonylamino)-hexanamine The title compound is prepared according to the procedure described in Example 1, Step C, except using 1-(3,3,3trifluoropropyl)amine hydrochloride in place of 2,2,2trifl uoro ethyl amine hydrochloride.

Step B: 1 -ter-t-Butoxycarbonyl-2(S-nbutyl4[ 1-(3,3,3- -one The title compound is prepared according to the procedure described in Example 1, Step D, except using N- 1-(3,3,3trifluoropropy1l-2(S)-(ter-t-butoxycarbonylamino)hexanamine in place of N-( 2 ,2,2,-trifluoroethyl)-2(S)-(te-tbutoxycarbonyl amino)hexanamine.

Step C: 2(S)-n-Butyl- 141[ 4 1 -trifluoropropvl)]piperazin-5 one dihydrochioride The title compound is prepared according to the procedure described in Example 1, Step J, except using 1 -tei-t-butoxycarbonyl- 2(S) -n-butyl 3 3 -trifluoropropyl) ]piperazin-5 -one in place of Iter-t-butoxycarbonyl-2(S -butyl-4-(2 2- one. The purified product is converted to the hydrochloride salt with HC1 in dichioromethane.

EXAMPLE 3 2(S)-n-Butyl-l1-[1 4 -cyanobenzyl)-5-imidazolylmethylj -4- (cyclojpropylmethyl)piperazin...sone dihydrochoride N

N'

WO 97/36593 WO 9736593PCT[US97/05144 79 Step A N-(Cyclopropylmethyl)-2(S)-(tert-butoxycarbonylamino)hexanamine The title compound is prepared according to the procedure described in Example 1, Step C, except using cyclopropylmethylamine hydrochloride in place of 2,2,2-trifluoroethylamine hydrochloride.

Step B: 1 -ter-t-Butoxycarbonyl-2(S)-n -butyl-4- (cvclop~ropv lmethyl)p2iperazin-5 -one The title compound is prepared according to the procedure described in Example 1, Step D, except using N-(cyclopropylmethyl)- 2 (S)-(ter-t-butoxycarbonylamino)hexanamine in place of N- trifluoroethyl)-2(S )-(te7-t-butoxycarbonyllamino)hexanamine.

Step C: 2(S)-n-Butyl- I 1 4 -cyanobenzyl)-5-imidazolylmethyl]-4- -one dihydrochi oride The title compound is prepared according to the procedure described in Example 1, Step J, except using 1 -ter-t-butoxycarbonyl- 2(S)-n -butyl-4- (cyclopropylmethyl)piperazin-5 -one in place of I -tertbutoxycarbonyl-2(S -ni-butyl-4-(2,2 ,2-trifluoroethyl )piperazin-5 -one to obtain the title compound. The purified product is converted to the dihydrochioride salt with HCI in dichioromethane.

EXAMPLE 4 2(S)-n-Butyl- 1 3 4 -cyanobenzyl)pyridin-4-yl]-4-(2,2,2- -one dihydrochioride NC-N N- CH 2

CF

3 0 WO 97/36593 PCT/US97/05144 Step A: 3-(4-Cvanobenzyl)pyridin-4-carboxvlic acid methyl ester A solution of 4-cyanobenzyl bromide (0.625 g, 3.27 mmol) in dry THF (4 mL) was added slowly over -3 min to a suspension of activated zinc (dust; 0.250 g) in dry THF (2 mL) at 0°C under an argon atmosphere. The ice-bath was removed and the slurry was stirred at room temperature for a further 30 min. Then 3-bromopyridin-4carboxylic acid methyl ester (0.540 g. 2.5 mmol) followed by dichlorobis(triphenylphosphine)nickel (II) (50 mg). The resultant reddish-brown mixture was stirred for 3 h at -40-45 0 C. The mixture was cooled and distributed between ethyl acetate (100 ml) and aqueous citric acid (50 mL). The organic layer was washed with water (2X50 mL), dried with Na 2

SO

4 After evaporation of the solvent the residue was purified on silica gel, eluting with 35% ethyl acetate in hexane to give 0.420 g as a clear gum. FAB ms 253.

Step B: 3-(4-Cvanobenzyl)-4-(hydroxvmethyl)pyridine The title compound was obtained by sodium borohydride (300 mg) reduction of the ester from Step A (0.415 g) in methanol mL) at room temperature. After stirring for 4 h the solution was evaporated and the product was purified on silica gel, eluting with 2% methanol in chloroform to give the title compound. FAB ms (M+1) 225.

Step C: 3-(4-Cvanobenzyl)-4-pyridinal The title compound was obtained by activated manganese dioxide (1.0 g) oxidation of the alcohol from Step B (0.240 g, 1.07 mmol) in dioxane (10 mL) at reflux for 30 min. Filtration and evaporation of the solvent provided title compound, mp 80-83 0

C.

Step D: 3(S)-n-Butyl-l-[3-(4-cyanobenzyl)pyridin-4-yl]-4-(2,2,2dihydrochloride The title compound is prepared according to the procedure described in Example 1. Step J, except using 3-(4-cyanobenzyl)-4- WO 97/36593 PCT/US97/05144 81 pyridinal from Step C in place of 1-(4-cyanobenzyl)imidazolyl-5carboxaldehyde. The purified product is converted to the dihydrochloride salt with HCI in dichloromethane.

EXAMPLE In vitro inhibition of ras famesvl transferase Assays of farnesyl-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 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 ptl containing 100 mM N-(2hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 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 gg/ml FPTase at 31 0 C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol.

Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB 3plate 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 .M ZnCl2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., WO 97/36593 PCT/US97/05144 82stopped with 100 gl of 30% trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.

The compounds of the instant invention described in the above Examples and in the Tables hereinafter were tested for inhibitory activity against human FPTase by the assay described above and were found to have IC50 of <50 gM.

EXAMPLE 6 In vivo ras farnesylation 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 MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml mM PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45 min. Aliquots of lysates containing equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et al., J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at 4 0 C, 200 ml of a suspension of protein A-Sepharose coated with rabbit anti rat IgG is 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 WO 97/36593 PCTIUS97/05144 83 farnesylated and nonfanesylated ras proteins are compared to determine the percent inhibition of famesyl transfer to protein.

EXAMPLE 7 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

10-, and c) C I -C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 aikynyl, perfluoroalkyl, F, Cl, Br, RIO0-, RI IS(O)mn-, RIOC(O)NH-, (RIO)2NC(O)-, R 10 2N- C(NR CN, R I N3, -N(R 10 or R 1 0 0C(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, aikynyl, perfluoroalkyl, F, Cl, Br, R 1 0 0-, C(NR 1 CN, N02, R I N3, -N(R 10)2, 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 1 R I C(O)NR (Ri 0 R' 0 2N-C(NR 1 CN, R I N3, 102,or R I I OC(O)NR R 1 0 is independently selected from hydrogen, C I -C6 alkyl, benzyl and aryl1; R I Iis independently selected from C I -C6 alkyl and aryl; A I and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NRI 10, -NRl I 0, -N(R -S (O)2N(R -N(Rl I 0 )S or S(O)m; G is H2 orO0; V is selected from: a) hydrogen, b) heterocycle. WO 97/36593 WO 9736593PCT/US97/05144 -89 c) aryl, d) C 1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 I is S(O)m and V is not hydrogen if A 1 I is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X is -CH2-, or Z is unsubstituted CI-C6 alkyl, substituted CJ-C6 alkyl, unsubstituted C3-C6 cycloalkyl or substituted C3-C6 cycloalkyl,wherein the substituted C I -C6 alkyl and substituted C3-C6 cycloalkyl is substituted with one or two of the following: a) C 1-4 alkoxy, b) NR 6 R 7 c) C3-6 cycloalkyl, d) -NR 6 C(O)R 7 e) HO, f) -S(O)mR 6 a, g) halogen, or h) perfluoroalkyl; m is n is P is q is r is s is t is u 1s I or 2; 1, 2, 3 or 4; 1, 2, 3 or 4; or 2; to 5, provided that r is 0 when V is hydrogen; or 1; or 1; and or WO 97/36593 PCT[US97/05 144 90 provided that when G is H2 and W is imidazolyl, then the substitutent (R 8 V AlI(CR Ia2)flA 2 (CRlIa2)fl is not H and provided that when X is or then t is I and the substitutent (R 8 V AlI(CRlIa2)nA 2 (CRlIa2)n is not H; or a pharmaceutically acceptable salt thereof. 0 2. A compound which inhibits famnesyl-protein transferase of the formula B: (R 8 )r (R 9 )q R2 R 3 A' -A(CRla 2 )A 2 (CRla 2 )n w (C Rl 2 )pN N\ BR4 wherein: R Ia and R Ib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, R 10 R I IS(O)m-, R I C(O)NR (R 10 R 1 0 2N-C(NR 1 CN, N02, R I OC(O)-, N3, -N(R 10 or R I I0C(O)NR 1 c) unsubstituted or substituted C1I-C6 alkyl wherein the substitutent on the substituted C I-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 0 0-, R' IIS(O)m-, R I C(O)NRJ10-, (R 10 R 1 0 2N- C(NR CN, R IOC(O)-, N3, -N(R 1 0 and R I I0C(O)- WO 97/36593 PCT/US97/05144 91 R 2 and R 3 are independently selected from: H; unsubstituted or substituted Ci1 -8 alkyl, unsubstituted or substituted C2 -8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, RRor -VOR 6 unsubstituted or substituted heterocycle, 0 0 wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C 1-4 alkyl, b) (CH2)pOR 6 c) (CH2)pNR 6 R 7 d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C 1 -4 alkyl, h) SR&1, S(O)R 6 a, SO2R 6 a, 2) C3-.6 cycloalkyl, 3) OR 6 4) SR 6 a, S(O)R 6 a, or SO2R 6 a, -NR 6 R 7 R 6 -N R 7 0 -N YNR 7 R 7 a 0 WO 97/36593 PCT/US97/O5144 -92- 8) NR 6 R 7 0 9) -0 O.OR 6 0 NR 6 O 11) -SO 2 -NR 6 R 7 R 6 12) -N-SO- R 6a 13) R 6 O 14) OR 6 N 3 16) F, or 17) perfluoro-C 1 .4-alkyl; 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, S(O)m, and -N(CORIO)-; R 4 is selected from H and CH3; 0 and any two of R 2 R 3 and R 4 are optionally attached to the same carbon atom; WO 97/36593 PCT/US97/05144 93 R 6 R 7 and R 7 a are independently selected from: H; Ci1 -4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, aryisulfonyl, heteroarylsuifonyl, unsubstituted or substituted with: a) Ci -4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) YR 0 f) -S0 2 R 1 1 or g) N(R 10)2; or R 6 and R 7 may be joined in a ring; R 7 and R7a may be joined in a ring; R 6 a is selected from: Ci-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) CI 4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) "YR 0 f) -S0 2 R 1 1 ,or g) N(RIO)2; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 R I I S(O)m-, WO 97/36593 PCT[US97/O5 144 94 R I OC(O)NR 1 0, (R 1lQ2NC(O)-, Rl 0 2N-C(NR CN, N02, R IOC(O)-, N3, -N(R 10 or R I I0C(O)NR 10-, and c) C I-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 0-, R I 1 R IOC(O)NH-, (R I 02NC(O)-, R 10 2N- C(NR CN, R IOC(O)-, N3, -N(R 10)2, or Ri I 0C(O)NH-; R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 2N-C(NR CN, N02, R IOC(O)-, N3, -N(R 1 0)2, or R I 10C(O)NR and C) C1I-C6 alkyl unsubstituted or substituted by per-fluoroalkyl, F, Cl, Br, RIOO-, RI IS(O)rn-, RIOC(O)NRIO-, (Ri 0 Ri 0 2N-C(NR 1 CN, R I N3, -N(R'10)2, or R I I OC(O)NR R 10 is independently selected from hydrogen, C I-C6 alkyl, benzyl and aryl; Ri is independently selected from C I -C6 alkyl and aryl; A I and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NRIO-, -NRIOC(O)-, 0, -N(RIO)-, -S(0)2N(RIO)-, -N(RIO)S(O)2-, or S(O)m; G is 0; V is selected from: a) hydrogen, b) heterocycle, WO 97/36593 WO 9736593PCTIUS97/05144 95 c) aryl, d) C I -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if A 1 I is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X is -CH2-, or Z is unsubstituted C I -C6 alkyl, substituted CjI -C6 alkyl, unsubstituted C3-C6 cycloalkyl or substituted C3-C6 cycloalkyl, wherein the substituted C I -C6 alkyl and substituted C3-C6 cycloalkyl is substituted with one or two of the following: a) C 1-4 alkoxy, b) NR 6 R 7 c) C3-.6 cycloalkyl, d) -NR 6 C(O)R 7 e) HO, f) -S(O)mR 6 a, g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0,1, 2 3or 4; q is Ilor 2; r is 0 to 5, provided that r is 0 when V is hydrogen; S'is I1; t is 0Oor1; and u is 4 WO 97/36593 PCT/US97/05144 -96- or a pharmaceutically acceptable salt thereof. 3. The compound according to Claim 1 of the formula A: 1(Ra2R1ba)p N\ N-Z V- A'(CRa2)nA2(CR a2) n -W (CR 2)pN-Z R 3 R 4 A wherein: Ria is independently selected from: hydrogen or C1-C6 alkyl; R b is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 1 0 -N(R10)2 or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R 10 0- and -N(R 10)2; R 3 and R 4 are independently selected from H and CH3; SNR 6 R 7 R 2 is H; O or C 1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 4) SR 6 a. SO2R6a, or WO 97/36593 WO 9736593PCT[US97/05144 97 NR 6 R 7 0 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; CI -4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) Ci 1 4 alkoxy, b) halogen, or c) aryl or heterocycle; R 6 a is selected from: C 1 4 alkyl or C3..-6 cycloalkyl, unsubstituted or substituted with: a) Ci 1 4 alkoxy, b) halogen, or c) aryl or heterocycle; R 8 is independently selected from: a) hydrogen, b) C I -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, Cl, R 1 0 R IOC(O)NR 10-, CN, N02, (Ri 0 )2N-C(NRl 10), R I -N(R 10)2, or R I I0C(O)NR 10-, and c) Cl1-C6 alkyl substituted by C I-C6 perfinoroalkyl, R 1 0 0-, R I OC(O)NR (R I 0)2N-C(NR R I OC(O)-, -N(R 10)2, or R I I0C(O)NR R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C I-C6 perfluoroalkyl, F, Cl, R 10 R I IS(O)m-, R I C(O)NR 1 CN, N02, WO 97/36593 PCTIUS97/05144 98 (R 1 0 )2N-C(NR R IOC(O)-, -N(R 10)2, or R I IOC(O)NR 1 and C I -C6 alkyl unsubstituted or substituted by C I -C6 perfluoroalkyl, F, Cl, R 100-, RI I S R IOC(O)NR CN, (R I )2N-C(NR R IOC(O)-, -N(R'10)2, or R I IOC(O)NR R 1 0 is independently selected from hydrogen, C I -C6 alkyl, benzyl and aryl; RI is independently selected from ClI-C6 alkyl and aryl; AI and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR 10-, 0, -N(R or S (O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C I -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatorn selected from 0, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 I is S(O)m and V is not hydrogen if A I is abond, n is 0and A 2 is S()m; G is H2 orO; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; WO 97/36593 PCTJUS97/05144 -99- X is -CH2- or Z is unsubstituted C1-C6 alkyl, substituted Ci-C6 alkyl, unsubstituted C3-C6 cycloalkyl or substituted C3-C6 cycloalkyl,wherein the substituted C] -C6 alkyl and substituted C3-C6 cycloalkyl is substituted with one or two of the following: a) C1-4 alkoxy, b) NR 6 R 7 c) C3-6 cycloalkyl, d) -NR 6 C(O)R 7 e) HO, f) -S(O)mR 6 a, g) halogen, or h) perfluoroalkyl; 0, 1 or 2; 0, 1,2, 3 or 4; 0, 1, 2, 3 or 4; 0 to 5, provided that r is 0 when V is hydrogen; 0or 1; 0 or 1; and 4 or m is n is p is r is s is t is u is provided that when G is H2 and W is imidazolyl, then the substitutent (R 8 V Al(CRa2)nA 2 (CRla2)n is not H and provided that when X is or then t is 1 and the substitutent (R 8 V AI(CRla2)nA 2 (CR a2)n is not H; or a pharmaceutically acceptable salt thereof. 4. The compound according to Claim 1 of the formula WO 97/36593 PCTIUS97/05144 100 (R 8 )r R9 2 la V Al(CRla 2 )nA (CRla 2 )n-N N 0 R 2 R 3 wherein: R Ia is selected from: hydrogen or C I-C6 alkyl; R Ib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 -N(R 1 0)2 or C2-C6 alkenyl, c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 1 0 or -N(R 10)2; R 3 is selected from H and CH3; 'YNR 6 R 7 Kz- is selected from H; 0 or C 1 5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: I) aryl, 2) heterocycle, 3) OR 6 4) SR 6 a, SO2R 7 a, or >NR 6 R 7 0 and R 2 and R 3 are optionally attached to the same carbon atom; R 6 and R 7 are independently selected from: H; Ci1 -4 alkyl, C3-.6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) C 1-4 alkoxy, WO 97/36593 PCTIUS97/05144 -101 b) halogen, or c) aryl or heterocycle; R 6 a is selected from: C 1-4 alkyl or C3 -6 cycloalkyl, unsubstituted or substituted with: a) C 1 -4 alkoxy, b) halogen, or c) aryl or heterocycle; R 8 is independently selected from: a) hydrogen, b) ClI-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, Cl, R 1 0 RlIOC(O)NR 10-, CN, N02, (Rl 0 )2N-C(NR R 1 I -N(R 10)2, or R I I0C(O)NR 10-, and C) C I-C6 alkyl substituted by C I-C6 perfluoroalkyl, R 10 0-, R 1 I C(O)NRl 10., (RI 0 )2N-C(NRl 10>, R I OC(O)-, 102,or R I I0C(O)NR R9a is hydrogen or methyl; R 10 is independently selected from hydrogen, C I-C6 alkyl, benzyl and aryl; R 1 is independently selected from C I -C6 alkyl and aryl; AI and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR 10-, 0, -N(R or S(O)m; V is selected from: a) hydrogen, WO 97/36593 PTU9/54 PCTfUS97/05144 102 b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2 -oxopiperidinyl, indolyl, qumnolinyl, isoquinolinyl, and thienyl, c) aryl, d) C I -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(O)rn and V is not hydrogen if A 1 I is a bond, n is 0 and A 2 is S(O)m; X is CH2- or Z is unsubstituted C I -C6 alkyl, substituted C1I-C6 alkyl, unsubstituted C3-C6 cycloalkyl or substituted C3-C6 cycloalkyl, wherein the substituted C I -C6 alkyl and substituted C3-C6 cycloalkyl is substituted with one or two of the following: a) C 1 4 alkoxy, b) NR 6 R 7 0) C3-.6 cycloalkyl, d) -NR 6 C(0)R 7 e) HO, f) -S(0)mR 6 a, g) halogen, or h) perfluoroalkyl; mnis 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1,2, 3or 4;and r is 0 to 5, provided that r is 0 when V is hydrogen; provided that when X is or then t is I and the substitutent (RO)r- V AlI(CRlIa2)nA 2 (CR Ia2)n is not H; WO 97/36593 PCT/US97/05144 103 or a pharmaceutically acceptable salt thereof. The compound according to Claim 1 of the formula D: H N N-Z X N R 2 R R 8 D wherein: Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, RI 0 -N(R' 0 )2 or C2-C6 alkenyl, c) Ci-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 or -N(R10)2; R 3 is selected from H and CH3; "i NR 6 R 7 R 2 is selected from H; O or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle, 3) OR 6 4) SR 6 a, SO2R 7 a, or N NR 6 R 0 and R 2 and R 3 are optionally attached to the same carbon atom; and R2 and R3 are optionally attached to the same carbon atom; WO 97/36593 WO 9736593PCTIUS97/0i5144 -104- R 6 and R 7 are independently selected from: H; Ci1 -4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) C 1 4 alkoxy, b) halogen, or c) aryl or heterocycle; R 6 a is selected from: C1-4 alkyl or C3 -6 cycloalkyl, unsubstituted or substituted with: a) Cl1 -4 alkoxy, b) halogen, or c) aryl or heterocycle; R 8 is independently selected from: a) hydrogen, b) C1I-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1I-C6 peifluoroalkyl, F, Cl, R 1 0 R I C(O)NR 1 CN, N02, (R 1 0 )2N-C(NR 1 R IOC(O)-, -N(R 1 0 or R I IOC(O)NR 10-, and c) ClI-C6 alkyl substituted by ClI-C6 perfluoroalkyl, R 10 0-, R' I C(O)NR 1 0, (Ri 1%2N-C(NR 1 R I OC(O)-, 102,or R' IIOC(O)NR R 10 is independently selected from hydrogen, ClI -C6 alkyl, benzyl and aryl; R 1 I s independently selected from C I -C6 alkyl and aryl; X is -C112- or Z is unsubstituted CI-C6 alkyl, substituted Cl-C6 alkyl, unsubstituted C3-C6 cycloalkyl or substituted C3-C6 WO 97/36593 PCT/US97/05144 105 cycloalkyl,wherein the substituted C1-C6 alkyl and substituted C3-C6 cycloalkyl is substituted with one or two of the following: a) C1-4 alkoxy, b) NR 6 R 7 c) C3-6 cycloalkyl, d) -NR 6 C(O)R 7 e) HO, f) -S(O)mR 6 a, g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; and pis 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof. 6. The compound according to Claim 1 of the formula E: H N N-Z R 2 R 3 NC E wherein: Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 -N(R 10 )2 or C2-C6 alkenyl, WO 97/36593 WO 9736593PCTIUS97/05144 106 c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 1 00-, or -N(R 1 0)2; R 2 and R 3 are independently selected from: hydrogen or C I -C6 alkyl; R 10 is independently selected from hydrogen, C1I-C6 alkyl, benzyl and aryl1; R 1 is independently selected from ClI-C6 alkyl and aryl; X is -CH2- or Z is unsubstituted C I-C6 alkyl, substituted C I-C6 alkyl, unsubstituted C3-C6 cycloalkyl or substituted C3-C6 cycl oalkyl, wherein the substituted CI -C6 alkyl and substituted C3-C6 cycloalkyl is substituted with one or two of the following: a) Ci1 -4 alkoxy, b) NR 6 R 7 c) C3-6 cycloalkyl, d) -NR 6 C(O)R 7 e) HO, f) -S(O)mR 6 a, g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; and p is 0, 1,2, 3or 4; or a pharmaceutically acceptable salt thereof. 7. A compound which inhibits farnesyl-protein transferase which is: 2(S)-n-butyl-1-[1-( 4 -cyanobenzyl)-5-imidazolylmethyl]-4-(2,2,2-trifluoroethyl)piperazin-5-one dihydrochloride; 2(S)-n-butyl-1-[1-( 4 -cyanobenzyl)-5-imidazolylmethyl]-4-(3,3,3-trifluoropropyl)piperazin- dihydrochloride; 2(S)-n-butyl-1-[1-( 4 -cyanobenzyl)-5-imidazolylmethyl]-4- dihydrochloride; and 2(S)-n-butyl-1-[1-( 4 -cyanobenzyl)pyridin-4-yl]- 4 2 2 2 -trifluoroethyl)piperazin-5-one dihydrochloride or a pharmaceutically acceptable salt or optical isomer thereof. 8. The compound according to claim 7 which is: 2 (S)-n-butyl-1-[1-(4-cyanobenzyl)-5- imidazolylmethyl]- 4 -(2,2,2-trifluoroethyl)piperazin-5-one dihydrochloride N O F or a pharmaceutically acceptable salt or optical isomer thereof. 9. A compound which inhibits farnesyl protein transferase, substantially as hereinbefore described with reference to any one of the examples. S, 10. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, S a therapeutically effective amount of a compound of any one of claims 1 to 9. 15 11. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 9 or of a composition of claim

12. A compound of any one of claims 1 to 9 or a composition of claim 10 when used in inhibiting farnesyl-protein transferase.

13. The use of a compound of any one of claims 1 to 9 for the manufacture of a medicament for inhibiting farnesyl-protein transferase.

14. A method for treating cancer which comprises administering to a mammal in need thereof S a therapeutically effective amount of a compound of any one of claims 1 to 9 or of a composition of claim

15. A compound of any one of claims 1 to 9 or a composition of claim 10 when used in treating cancer.

16. The use of a compound of any one of claims 1 to 9 for the manufacture of a medicament for treating cancer.

17. A method for treating neurofibromin benign proliferative disorder which comprises 30 administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 9 or of a composition of claim

18. A compound of any one of claims 1 to 9 or a composition of claim 10 when used in treating neurofibromin benign proliferative disorder.

19. The use of a compound of any one of claims 1 to 9 for the manufacture of a medicament for treating neurofibromin benign proliferative disorder. C04212 A method for treating blindness related to retinal vascularisation which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 9 or of a composition of claim

21. A compound of any one of claims 1 to 9 or a composition of claim 10 when used in treating blindness related to retinal vascularisation.

22. The use of a compound of any one of claims 1 to 9 for the manufacture of a medicament for treating blindness related to retinal vascularisation.

23. A method for treating infections from hepatitis delta and related viruses which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 9 or of a composition of claim

24. A compound of any one of claims 1 to 9 or a composition of claim 10 when used in treating infections from hepatitis delta and related viruses. The use of a compound of any one of claims 1 to 9 for the manufacture of a medicament for treating infections from hepatitis delta and related viruses.

26. A method for preventing restenosis which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 9 or of a composition of claim

27. A compound of any one of claims 1 to 9 or a composition of claim 10 when used in preventing restenosis. **20 28. The use of a compound of any one of claims 1 to 9 for the manufacture of a medicament for preventing restenosis.

29. A method for treating polycystic kidney disease which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 9 or of a composition of claim

30. A compound of any one of claims 1 to 9 or a composition of claim 10 when used in treating polycystic kidney disease.

31. The use of a compound of any one of claims 1 to 9 for the manufacture of a medicament for treating polycystic kidney disease.

32. A method for inhibiting farnesyl-protein transferase which comprises administering to a 30 mammal in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of the formula A: (R9) q (R 8 )r R 1 A 2 R1a W R1b X R 2 G (Rt)r V N S1 N-Z P R3 R R4 wherein: Ria and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-locycloalkyl, C2-6alkenyl, C2-6alkynyl, R 1 oO-, R 11 RoC(O)NRio-, CN(R 1 0 2 R 10 2 N-C(NRi)-, CN, NO 2 RA,/ R1OC(O)-, N 3 -N(R10) 2 or R1iOC(O)NRO-, c) unsubstituted or substituted Ci-6alkyl wherein the C04212 substituent on the substituted Ci-6alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3.iocycloalkyl, C2-6alkenyI, C2-6alkynyl, R 10 R11S(O)m-, RloC(O)NR10-, (R 10 2 RlO2N.(NR1O)-, ON, R 1 0 N 3 -N(RO) 2 and RllOC(O)-NRO-; R 2 and R 3 are independently selected from: H; unsubstituted or substituted Ci-8alkyl, unsubstituted or substituted 02-8alkenyl, unsubstituted or substituted C2-8alkynyl, unsubstituted or substituted aryl, "'rNR6R 7 OR 6 unsubstituted or substituted heterocycle, 0 or 0 ,wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) Cl4alkyl, b) (CH2)pOR6, c) (CH 2 )pNR 6 R7, d) halogen, e) ON, f) aryl or heteroaryl, g) perfluoroCi~alkyl, h) SR 6 a, -N R 7 S(O)R 6 a, SO2R 6 a, 2) C3-6cycloalkyl, 3) OR 6 4) SR6a, S(O)R6a, or SO 2 R 6 a, 5) -NR 6 R 7 6) 0 -N Y NR7R 7 a -0 NR 6 R7 -Oy OR 6 NR 6 R7 lol7) 0 0 9) 0 ,10) 011 *R 6 'YR 6 'YOR 6 @555a SO 2 -NR 6 R 7 12 -N-S0 2 13) 0 14) 0 15) N 3 16) F, or 17) perfluoroCl~alkyl; 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, S(O)mr, and -N(COR10)-; R 4 is selected from H and OH 3 and any two of R 2 R 3 and R 4 are optionally attached to the same carbon atom; R 6 R 7 and R7a are independently selected from: H; C14alkyl, C3-6Cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C1l4alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) f -SO 2 R' 1 or g) N(R 10 or R 6 and R 7 may be joined in a ring; R 7 and R7a may be joined in a ring; R6a is selected from: C14alkyl, 03- cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) C14alkoxy, b) aryl or heterocycle, c) So 2o halogen, d) HO, e) 0 )-S0 2 R 11 or g) N(RO) 2 R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3.locycloalkyl, C2-6alkenyl, C2-6alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 0-, R 1 R 1 0 C0)NR 1 (R 1 0 2 R 1 0 2 N-(NR10)-, ON, NO 2 R1OC(O)-, N 3 -N(RO) 2 or RllOC(O)NRO-, and c) C1-6alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3- locycloalkyl, C2-6alkenyl, C2-6alkynyl, perfluoroalkyl, F, Cl, Br, R 10 R 11 R 10 C(O)NH-, (R 1 0 RlO 2 N-(NR10)-, ON, R 1 0 N 3 -N(RO) 2 or R 1 0 0C0)NH-; R 9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R100-, R 1 1 RlOC(O)NRO-, (R 10 2 NC(O)-, R 10 2 N-(NR10)-, ON, NO 2 R 1 0 N 3 -N(Rl0) 2 Or R 11 0C0()NR 1 and C) C1l6alkyl unsubstituted or C04212 -substituted by perfluoroalkyl, F, Cl, Br, RlOO-, R 11 RlOC(0)NRO, (R 10 2 R1O 2 N-(NRC)-, ON, Rl0C(O)-, N 3 -N(R1O) 2 or RllOC(O)NR0-; RIO is independently selected from hydrogen, Cl-6alkyl, benzyl and aryl; R 1 1 is independently selected from C1-6alkyl and aryl; A' and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NRO-, -NRlOC(0)-, 0, -S(O) 2 N(RlO)S(O) 2 or S(O)m G is H 2 V is selected from: a) hydrogen, b) heterocycle, c) aryl; d) C1l2oalkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from 0, S, and N, and e) C2- 2oalkenyl, provided that V is not hydrogen if A' is S(0)m and V is not hydrogen if A' is a bond, n is 0 and A 2 is S(O)m; W is imidazolyl; X is -H 2 or Z is unsubstituted Ci-6alkyl, substituted Cj- 6alkyl, unsubstituted C3-6cycloalkyl or substituted C3-6cycloalkyl, wherein the substituted Cl-6alkyl and io substituted C3-6cycloalkyl is substituted with one or two of the following: a) C1-4alkoxy, b) NR 6 R7, C) C3_ 6cycloalkyl, d) -NR 6 C(O)R7, e) HO, f) -S(O)mR6a, g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; q is 1 or 2; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 0 or 1;t is 1; and u is 4 or 5; provided that the substituent (R 8 )r-V-Al(CRia 2 )nA2(CRla2)n. is H; or a pharmaceutically acceptable salt thereof.

33. A compound of the formula A: (R9)q RSr A, Rt A 2 Ria W R1ib X R2 G VN t N-Z R1. n J Ra nRib RS R Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3ilocycloalkyl, C2-6alkenyl, C2-6alkynyl, R 1 0 R 1 1 RiOC(O)NR10-, CN(R 10 2 Rio 2 N-C(NRo)-, CN, NO 2 R 1 0 N 3 -N(R10) 2 or RllOC(O)NR0-, c) unsubstituted or substituted Ci-6alkyl wherein the substituent on the substituted Cie6alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3ilocycloalkyl, C2-6alkenyl, C2-6akynyl, R 1 0 R 1 1 RiOC(O)NRO-, (R 1 0 2 Rio 2 N-(NRIO)-, ON, R1OC(O)-, N 3 -N(RO) 2 and RliOC(O)-NR0-; R 2 and R 3 are independently selected from: H; unsubstituted or substituted Ci.8alkyl, unsubstituted or substituted C2-8alkenyl, unsubstituted or substituted C2B8alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted Y NR 6 R 7 OR 6 0000 heterocycle, or ,wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) Ci-4alkyl, b) (CH 2 )pOR6, c) (CH2)pNR6R7, d) halogen, e) CN, f) aryl or heteroaryl, g) perfiuoroCi-4alkyl, h) SR 6 a, S(O)R 6 a, SO2R 6 a, 2) C3- -NyR7 -NYNR7R 7 a, 6CYCloaikyl, 3) OR 6 4) SR 6 a, S(O)R6a, or SO 2 R6a, 5) -NR 6 R 7 6) 0 7) 0 -0 NR 6 R7 -OyOR 6 YNR 6 R7 8) 0 9) 0 10) 0 -S0 2 -NR 6 R 7 12 C04212 R6S& 'Y R6 'YOR 6 0 04 *e"l 6 0 4 4 13) J ,14) U 15) N 3 16) F, or 17) perfluoroCi-4alkyl; or R 2 and R 3 are attached to the same C atom and are combined to form -(CH 2 wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(CORO)-; R 4 is selected from H and OH 3 and any two of R 2 R 3 and R 4 are optionally attached to the same carbon atom; R 6 R 7 and R~a are independently selected from: H; C1-4alkyl, C3-6CYCloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Ci4alkoxy, b) aryl or heterocycle, c) YR11 halogen, d) HO, e) 0' f) -SO 2 Rl 1 or g) N(RO) 2 or R 6 and R 7 may be joined in a ring; R 7 and R7a may be joined in a ring; R6a is selected from: Ci~alkyl, C3-6CYCloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) C14alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) 0 f) -SO 2 R 11 or g) N(R 10 2 R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3- uocycloalkyl, C2s6alkenyl, C2-6alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R 1 1 RlOC(O)NRO-, (R 1 0 2 NC0)-, RlO 2 N-4NR10)-, ON, NO 2 R 1 0 N 3 -N(R10) 2 or RllOC(O)NR10-, and c) C1l6alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-locycloalkyl, C2-6alkenyl, C2-6alkynyl, "perfluoroalkyl, F, Cl, Br, R 1 0 R 11 S(O)m, R 1 0 C(O)NH-, (R' 0 2 Rlo 2 N-(NR10)-, ON, RIOC(O)-, N 3 -N(RO) 2 or R 10 00(O)NH-; R 9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R 11 RlOC(O)NR0-, (R 10 2 R 1 0 2 N-(NRIO)-, ON, NO 2 R1OC(O)-, N 3 -N(RO) 2 or and c) C1-6alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 1 0 0-, :R 11 S(O)m, Rl 0 C(O)NR1O, (R 1 0 2 RlO 2 N-4NRl0)-, ON, R1OC(O)-, N 3 -N(RO) 2 or RllOC(O)NRO-; R 1 0 is independently selected from hydrogen, Cl-6alkyl, benzyl and aryl; R 1 1 is independently selected from C1u6alk'yl and aryl; A' and A 2 are independently selected from: a bond, -CH=CH-, C(O)NRO-, -NRlOC(O)-, 0, -N(R' 0 -S(O) 2 N(RlO)-, -N(Rlo)S(O) 2 or S(O)m; G is H 2 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) O2-2oalkenyl, provided that V is not hydrogen if A' is S(O)m, and V is not hydrogen if A' is a bond, n isO0 and A 2 is W is imidazolyl; X is -H 2 or Z is unsubstituted C1-6alkyl, substituted C1-6alkyl, unsubstituted O3-6cycloalkyl or substituted C3-6CYCloalkyl, wherein the substituted Cl-6alkyl and substituted C3-6cycloalkyl is substituted with one or two of the following: a) C1-4alkoxy, b) NR 6 R 7 C) C3-6cycloalkyl, d) -NR 6 C(O)R 7 e) HO, f) -S(O)mR 6 a, g) halogen, or h) perfluoroalkyl; m isO0, 1 or 2; n isO, 1, 2, 3or 4; p isO0, 1, 2, 3or 4; qis 1 or 2; r is 0to provided that r is 0 when V is hydrogen; s is 0 or 1; t is 1; and u is 4 or 5; provided that the substituent (R8)r-VA(CRa 2 )nA2(CRla2)n- is H; or a pharmaceutically acceptable salt thereofwhen used in inhibiting farnesyl-protein transferase.

34. The use of a compound of the formula A: C04212 \j~iaIN-Z in Ian 1p R3 R wherein: Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, O3-locycloalkyl, C2-6alkenyl, C2.6alkynyl, R'0O-, R 1 1 RioC(O)NR10-, CN(R 1 0 2 NC0O)-, R 1 2N-C(NRIO)-, ON, NO 2 R 1 0 N 3 -N(R10) 2 or RllOC(O)NR0-, c) unsubstituted or substituted C1l6alkyl wherein the substituent on the substituted C1l6alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3.iocycloalkyl, C2-6alkenyI, C2-6alkynyl, R 1 0 R' 1 RloC(O)NR10-, (R 1 0 2 R1o 2 ON, R1OC(O)-, N 3 -N(Rl0) 2 and RllOC(O)-NR0-; R 2 and R 3 are independently selected from: H; unsubstituted or substituted C1-8alkyl, unsubstituted or substituted C2.8alkenyl, unsubstituted or substituted C2-8alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted YNR6R 7 "YOR 6 heterocycle, 0 or 0 wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) Ci-4alkyl, b) (CH 2 )pOR 6 C) (CH 2 )pNR 6 R 7 d) halogen, e) ON, f) aryl or heteroaryl, g) perfluoro~l~alkyl, h) SR6a, S(O)R 6 a, SO2R 6 a, 2) C3- ta a a. 0* 0 to.. *J a 0W* a a a. j 4 a a *a -N YR7 0 -N NR7R 7 a 0 6cycloalkyl, 3) OR 6 4) SR 6 a, -0 YNR 6 R7 ON 0 S(O)R 6 a, or SO 2 R 6 a, 5) -NR 6 R 7 6) -0O OR 6 3' 0 ~10) 0 .JR 6 R7 -S 2 -NR 6 R 7 Ill) -R6 OR 6 too,, *of. a '0 a *.0 -NSO-R 6 a 11 1,13) ,14) 0 15) N 3 16) F, or 17) perfluoroC,4alkyl; or R 2 and R 3 are attached to the same C atom and are combined to form -(OH 2 wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(CORO)-; R 4 is selected from H and OH 3 and any two of R 2 R 3 and R 4 are optionally attached to the same carbon atom; R 6 R7 and R7a are independently selected from: H; C1-4alkyl, O3-6cycloa lkyl, heterocycle, aryl, aroyl, heteroaroyl, 20 arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C1-4alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) 0 f -S0 2 R 11 or g) N(R1O) 2 or R 6 and R 7 may be joined in a ring; R 7 and Rla may be joined in a ring; R 6 a is selected from: Ol4alkyl, O3-6cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) Oi-4alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) f) -S0 2 R 11 or g) N(RO) 2 R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, 03. C04212 iccycloalkyl, C2-6alkenyl, C2-6alkynyl, perfluoroalkyl, F, CI, Br, R 1 0 R 1 1 RlOC(O)NRO-, (R' 0 2 R1O2N-(NRi0)-, CN, NO 2 N 3 -N(RiO) 2 or RilOC(O)NRO-, and c) Cl-6alkyl -unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-locycloalkyl, C2.6alkenyl, C2-6alkynyl, perfluoroalkyl, F, Cl, Br, Rl00-, R 1 1 R 1 0 C(O)NH-, (R 1 O) 2 RlO2N-(NRI0)-, ON, RIOC(O)-, N 3 -N(RO) 2 or RiOOC(O)NH-; R 9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, CI, Br, R 1 0 R 11 RlOC(O)NR1O-, (RI 0 2 RiO 2 ON, NO 2 R 1 0 N 3 -N(RO) 2 or RllOC(O)NR'o-, and c) CI-6alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 1 0 0-, R 1 R 1 O0(O)N R1 0 (R 1 O) 2 R 1 0 2 N-(N RIO)-, ON, R1OC(O)-, N 3 -N(RlO) 2 or R 1 OC(O)NRO-; RIO is independently selected from hydrogen, C1-6alkyl, benzyl and aryl; R 1 1 is independently selected io from C1-6alkyl and aryl; A' and A 2 are independently selected from: a bond, -CH=CH-, C(O)NRO-, -NRiOC(O)-, 0, -S(O) 2 -N(RiO)S(O) 2 or S(O)m; G is H 2 V is selected from: a) hydrogen, b) heterocycle, c) aryl; d) Ol-2oalkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from 0, S, and N, and e) C2.2oalkenyl, provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A' is a bond, n is 0 and A 2 is S(O)m; W is imidazolyl; X is -H 2 or Z is unsubstituted Cl-6alkyl, substituted C1-6alkyl, unsubstituted C3-6cycloalkyl or substituted C3-6cycloalkyl, wherein the substituted Ci.6alkyl and substituted C3-6cycloalkyl is substituted with one or two of the following: a) Ci~alkoxy, b) NR 6 R7, C) C3-6cycloalkyl, d) -NR 6 C(O)R7, e) HO, f) -S(O)mR~a, g) SO.halogen, or h) perfluoroalkyl; m isO0, 1 or 2; n is 0, 1,2, 3 or 4; p is0, 1, 2, 3 or 4; q is 1 or 2; r is 0to .:.provided that r isO0 when V is hydrogen; s is 0 or 1; t is 1; and u is 4 or 5; provided that the substituent (R 8 )r-V-Al(CRia2)nA 2 (CRIa2)n- is H; or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for inhibiting farnesyl-protein transferase. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of the formula: (R9)q 550 R 1 A 2 Ria W Rib X R 2 G S V tN t N-Z n 1 nlaP R R 3 wherein: Ria and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3ilocycloalkyl, *C2-6alkenyl, C2-6alkynyl, R 1 0 R 11 RiOC(O)NRiO, CN(Rlo)2NC(O)-, R 1 0 2N-(NR 1 0 ON, NO 2 R1OC(O)-, N 3 -N(RO) 2 or RiiOC(O)NRO-, c) unsubstituted or substituted Oi-6alkyl wherein the :30 substituent on the substituted C1-6alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3.iocycloalkyl, O2e6alkenyl, O2-6alkynyl, R 10 R 11 Ri 0 O(O)NRO-, (Ri 0 2 R1 0 2 N-(NRIO)-, ON, RIOO(O)-, N 3 -N(R'C) 2 and R'iOC(O)-NRO-; R 2 and R 3 are independently selected from: H; unsubstituted or substituted Oi-8alkyl, unsubstituted or substituted O2-8alkenyl, unsubstituted or substituted C2-8alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C04212 'Y NR6R 7 OR 6 0or 0 ,wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) Ci~alkyl, b) (CH 2 )pOR6, c) (0H2)pNR6R7, d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoroC 1 4 alkyl, h) SR 6 a, S(O)R 6 a, SO 2 R6a, 2) C3-6cycloalkyl, 3) OR 6 4) R 6 R -N ,,R7 -NyNR7R 7 a -OyNR 6 R7 SR6a, S(O)R 6 a, or SO 2 R~a, 5) -NR 6 R7, 6) 0 7) 8) 0 9) -0 OR 6 NR 6 R7 R 6 NY R 6 00-S0 2 -NR 6 R 7 -N-S0 2 -R 6 a ,4 OR 6 0 ,15) N 3 16) F, or 17) perfluoroCl4alkyl; or R 2 and R 3 are attached to the same C atom and are combined to form -(0H2)u- wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(COR0)-; R 4 is selected from H and OH 3 and any two of R 2 R 3 and R4 are optionally attached to the same carbon atom; R 6 RI and R7a are independently selected from: H; C1-4alkyl, C3-6cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, 00. unsubstituted or substituted with: a) C14alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) 0 000 f) -S02R 11 or g) N(RlO) 2 or R 6 and R 7 may be joined in a ring; R 7 and R~a may be joined in a ring; Rea is **selected from: C- 4 alkyl, C3-6cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) Ol4alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) f) SOOR', or g) N(RO) 2 R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-iocycloalkyl, C2-6alkenyl, O2-6alkynyl, perfluoroalkyl, F, Cl, Br, R 10 R 11 R 10 0(O)NRl 0 (R 1 O) 2 NC(O)- Rlo 2 N-(NR10), CN, NO 2 RIOC(O), N 3 N(RlO) 2 or RllOO(O)NR0-, and c) C1-6alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3i1ocycloalkyl, C2-6alkenyl, O2-6alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R 11 S(O)m-, RI 0 0(O)NH-, (R 1 0 2 R 1 0 2 N-(NR10)-, ON, RlOO(O)-, N 3 -N(RO) 2 or R 10 00(O)NH-; R 9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R' 0 R 11 S(O)m, R 10 C(O)NR1 0 (Rlo) 2 RlO 2 N.(NR10)-, ON, NO 2 RlOO(O)-, N 3 -N(Rlo) 2 or RilOC(O)NRO-, and c) Cl-6alkyl unsubstituted or substituted by pertluoroalkyl, F, Cl, Br, R 10 R 11 R 10 C(O)NR1 0 (Rlo) 2 N0(O)-, 2 N(NR10)-, CN, RlOC(O)-, N 3 -N(RO) 2 or R"lOC(O)NRO-; R 1 0 is independently selected from hydrogen, C1l6alkyl, benzyl and aryl; R 1 1 is independently selected from C1l6alkyl and aryl; A' and A 2 are independently selected from: a bond, -OH=CH-, -C(O)NR0-, -NRiOC(O)-, 0, S(O) 2 N(RlO)-, -N(R1O)S(O) 2 or S(O)m; G is H2 or 0; 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 C04212 -bond, n is 0 and A 2 is W is a heterocycle; X is or Z is unsubstituted C1l6alkyl, substituted C 1 6alkyl, unsubstituted C3-6cycloalkyl or substituted C3.6cycloalkyl, wherein the substituted C6alkyl and substituted C3.6cycloalkyl is substituted with one or two of the following: a) C1-4alkoxy, b) NR6R7, C) C3-6cycloalkyl, d) -NR 6 C(O)R7, e) HO, I) -S(O)mR6a, g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; nis0, 1, 2 3or4; pis 0, 1, 2, 3or4; qisl1 or 2 ris 0to 5,provided that riso0when Vis hydrogen; s is 0 or 1; t is 0 or 1; and u is 4 or 5; provided that if t is 1, then the substituent (R 8 )r-V- Ai(CRla 2 )nA2(ORla 2 is H; or a pharmaceutically acceptable salt thereof.

36. A compound of the formula: (R9)q A, Ri A 2 RIa W 7tRib X R 2 G V 0P N t N-Z Ri1 Rla Rib n n P R3 R 4 lo wherein: Ria and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-locycloalkyl, C2-6alkenyl, C2-6alkynyl, R 1 0 R' S(O)m, RlOC(O)NR10-, CN(R 10 2 R1O2N-(NR10)-, ON, NO 2 RIOC(O)-, N 3 -N(Ri0) 2 or RllOC(O)NR0-, c) unsubstituted or substituted C1l6alkyl wherein the substituent on the substituted C1-6alkyl is selected from unsubstituted or substituted aryl, heterocyclic, e**C3-iocycloalkyl, C2-6alkenyl, C2-6alkynyl, R 1 0 R 11 S(O)mn-, RlOC(O)NR10-, (Rlo) 2 R 1 0 2 N-(NR 1 0 ON, RlOC(O)-, N 3 -N(R10) 2 and RllOC(O)-NR0-; R 2 and R 3 are independently selected from: H; :unsubstituted or substituted C1l8alkyl, unsubstituted or substituted C2-8alkenyl, unsubstituted or :.~substituted C2-8alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, *NR6R 7 OR 6 0. 0 **or ,wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or suJbstituted with: a) C1-4alkyl, b) (CH 2 )pOR 6 C) (CH 2 )pNR 6 R 7 d) halogen, 2o e) ON, f) aryl or heteroaryl, g) perfluoroCi-4 alkyl, h) SR 6 a, S(O)R 6 a, SO 2 R 6 a, 2) C3-6CYCloalkyl, 3) OR 6 4) R6 R6 ,R 7 -NyNR7R 7 a -OYNR 6 R7 SR~a, S(O)R~a, or SO 2 R 6 a, 5) -NR 6 R7, 6) 0 0 0 9) -0 OR 6 NR 6 R 7 IR 6 011)) -S 2 -NR 6 R 7 12) -N-S0 2 -R6a 13) 0 14) cc OR 6 15) N 3 16) F, or 17) perfluoroCl-4alkyl; 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, S(O)m, and -N(CORO)-; R 4 is selected from H and OH 3 and any two of R 2 R 3 and R 4 are optionally attached to the same carbon atom; R 6 R 7 and R7a are independently selected from: H; Ol-4alkyl, O3-6Cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, C04212 unsubstituted or substituted with: a) Ci-4alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) 0 I) -SO 2 Rl1, or g) N(RO) 2 or R 6 and R 7 may be joined in a ring; R 7 and R 7 a may be joined in a ring; R 6 a is selected from: C14alkyl, C3-6cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) Gl4alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) 0 f) -SO 2 R 1 1, or g) N(R1O) 2 R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3.locycloalkyl, C2-6alkenyl, C2-6alkynyI, pertluoroalkyl, F, Cl, Br, R100-, R 1 1 RiOC(O)NRO-, (Rlo) 2 R1O2N-(NR10)-, ON, NO 2 Rl 0 N 3 N(RlO) 2 or RllOC(O)NR0-, and C) Cl-6alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-locycloalkyl, C2-6alkenyl, C2-6alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R 11 S(O)m-, R 10 0(O)NH-, (R' 0 2 R1O2N-(NR10)-, ON, RlOC(O)-, N 3 -N(R10) 2 or R 10 0C(O)NH-; R 9 is selected lo from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R 1 1 RlOC(O)NR'O-, (Rlo) 2 R1O 2 N-(NR10)-, CN, NO 2 RlOC(O)-, N 3 -N(RO) 2 or RllOC(O)NR0-, and c) C1-6alky unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RI 0 R 11 RlOC(O)NR'o-, (R 10 2 NC(O)-, RlO 2 N-(NRIO)-, ON, R 1 0 N 3 -N(R10) 2 or RllOC(O)NR0-; R 1 0 is independently selected from hydrogen, C1l6alkyl, benzyl and aryl; R 1 1 is independently selected from Cl-6alkyl and aryl; A' and A 2 are 15i independently selected from: a bond, -CH=CH-, -C(O)NRO-, -NRl0C(O)-, 0, -N(R 1 0 2 N(RlO)-, -N(Rlo)S(O) 2 or S(O)m; G is H2 or 0; V is selected fro m: a) hydrogen, b) heterocycle, c) aryl, d) Cli2oalkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from 0, S, and N, and e) C2-2oalkenyl, provided that V is not hydrogen if A' is S(O)m and V is not hydrogen if A' is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X is or Z is unsubstituted Ci-6alkyl, 209 substituted C1-6alkyl, unsubstituted C3-6cycloalkyI or substituted C3-6cycloalkyl, wherein the substituted Cl-6alkyl and substituted C3-6cycloalkyI is substituted with one or two of the following: a) Ci~alkoxy, b) NR 6 R 7 c) C3-6cycloalkyI, d) -NR 6 C(O)R7, e) HO, f) -S(O)mR 6 a, g) halogen, or h) perfluoroalkyl; mn is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; q is 1 or 2; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 0 or 1; t is 0 or 1; and u is 4 or 5; provided that if t is 1, then the substituent (R 8 )r-V- Al(CRa 2 )nA 2 (CRla 2 is H; or a pharmaceutically acceptable salt thereofwhen used in inhibiting farnesyl-protein transferase. *bee *37. The use of a compound of the formula: OCOC~g(R9)q I G A, A R 1 A 2 Rla W7 Rib X R 2 G #0 0 4'-N1 N-Z 1 n Rla n Rib 00 C R 3 R 4 wherein: Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C2-6alkenyl, C2-6alkynyl, R 1 0 R 1 1 RlOC(O)NR10-, CN(Rlo) 2 R1 0 2 N-(NRl 0 ON, NO 2 RlOC(0)-, N 3 -N(R1O) 2 or RllOC(O)NR0-, c) unsubstituted or substituted C1-6alkyl wherein the substituent on the substituted C1-6alkyl is selected from unsubstituted or substituted aryl, heterocyclic, 0~ ~A C04212 -C3.iocycloalkyl, C2-6alkenyl, C2-6alkynyl, R' 0 R 11 RlOC(O)NR'o-, (R 10 2 R 10 2 N-(NR 1 ON, R 10 N 3 -N(RO) 2 and RllOC(O)-NR0-; R 2 and R 3 are independently selected from: H; unsubstituted or substituted Cis8alkyl, unsubstituted or substituted C2.8alkenyl, unsubstituted or substituted C2-8alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, YNR6R 7 "YOR 6 0or 0 wherein the substituted group is substituted with one or more of: 1) aryl or hieterocycle, unsubstituted or substituted with: a) Ci4alkyl, b) (CH 2 )pOR 6 C) (CH 2 )pNR6R7, d) halogen, e) ON, f) aryl or heteroaryl, g) perfluoroC14 alkyl, h) SR 6 a, S(O)R 6 a, SO 2 R 6 a, 2) C3-6cycloalkyl, 3) OR 6 4) -N YR7 0 -N NR7R 7 a 0 -0O NR 6 R7 0 SR6a, S(O)R 6 a, or SO 2 R6a, 5) -NR 6 R 7 6) -0 OR 6 Y NR 6 R7 0 1W 0 -N-S 02- R 6 a 0 Z) 14) -S0 2 -NR 6 R 7 I) ,12) IuI I 13) p. o 00 4400 0 004 0 a a. 4 0 0S 0 Ot. 4 OS *0 4 44 0040 0S 00 0 *4&0 4 0

4044. S *~4d S a OS 44 S S 4. 4 44 I. 4* 'YOR 6 0 ,15) N 3 16) F, or 17) perfluoroCl-4alkyl; or R 2 and R 3 are attached to the same C atom and are combined to form -(0H2)u- wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(CORO)-; R 4 is selected from H and OH 3 and any two of R 2 R 3 and R 4 are optionally attached to the same carbon atom; R 6 R 7 and R7a are independently selected from: H; Ol-4alkyl, C3-6CYCloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Ol-4alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) 0 f) -S0 2 R 11 or g) N(RO) 2 or R 6 and RI may be joined in a ring; R 7 and R 7 a may be joined in a ring; R 6 a is selected from: Oi-4alkyl, 03-6cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) Oi-4alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) 0 f) -S0 2 R 11 or g) N(RO) 2 R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, O3-locycloalkyl, O2-6alkenyl, O2-6alkynyl, perfluoroalkyl, 20 F, Cl, Br, R 1 0 R 11 R 10 0(O)NR 1 0 (R 1 0 2 R1O 2 N-(NR10)-, ON, NO 2 R100(0)., N 3 N(RlO) 2 or RllOO(O)NRO., and C) Ol-6alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3.iocycloalkyl, O2-6alkenyl, O2-6alkynyl, perfluoroalkyl, F, Cl, Br, R10- R 1 1 S(O)m-, R 10 0(O)NH-, (R 1 0 2 R 1 0 2 N-(NR10)-, ON, RIOC(O)-, N 3 -N(RO) 2 or RlOOO(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, 01, Br, R100-, R 11 R' 0 O(O)NR 10 (R 1 0 2 R 1 0 2N-(NRIO)-, ON, NO 2 R1OO(O)-, N 3 -N(RO) 2 or R 11 00(O)NR 10 and c) Oi-6alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 1 0 R 11 RiOC(O)NR1O-, (R 10 2 N0(O)-, R1O2N-(NR10)-, ON, Rl0C(O)-, N 3 -N(R10) 2 or RllOC(O)NR0-; RIO is independently selected from hydrogen, Ol-6alkyl, benzyl and aryl; R" is independently selected from Cl-6alkyl and aryl; A' and A 2 are C04212 independently selected from: a bond, -CH=CH-, -C(O)NRo-, -NRioC(O)-, O, -N(Rio), S(0) 2 N(R1o)-, -N(RIO)S(0) 2 Or S(O)m; G is H 2 or O; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) Cl-2oalkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-2oalkenyl, provided that V is not hydrogen if A' is S(O)m and V is not hydrogen if A' is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X is or Z is unsubstituted C1.6alkyl, substituted C16alkyl, unsubstituted C3-6cycloalkyl or substituted C3-6cycloalkyl, wherein the substituted C1-6alkyl and substituted C36cycloalkyl is substituted with one or two of the following: a) C14alkoxy, b) NR 6 R7, c) C3-6CyCloalkyl, d) -NR 6 C(O)R7, e) HO, f) -S(O)mR6a, g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; q is 1 or 2; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 0 or 1; t is 0 or 1; and u is 4 or 5; provided that if t is 1, then the substituent (R 8 Al(CRla2)A2(CR1a 2 is H; or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for inhibiting farnesyl-protein transferase, 38. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of the formula A: (R9)q IG A R 1 A2 Ra W Rib X R2 .rV N Sn n t N Z *P RR 1 Rn RR4b R 4 wherein: Ria and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-1ocycloalkyl, C2-6alkenyl, C2-6alkynyl, R 10 0oO-, R11S(O)m-, RlOC(O)NR10-, CN(R 1 0 2 R 1 0 2N-(NR 1 0 CN, NO 2 RloC(O)-, N 3 -N(R10) 2 or Rl1OC(O)NRO-, c) unsubstituted or substituted Cl.6alkyl wherein the substituent on the substituted C1.6alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-locycloalkyl, C2.6alkenyl, C2-6alkynyl, R 10 R 11 R 1 oC(O)NR 10 (R 1 0 2 R1 0 2 N-(NRI 0 CN, R 1 N 3 -N(R10) 2 and R 11 0C(O)-NRio-; R 2 and R 3 are independently selected from: H; A unsubstituted or substituted C1-alkyl, unsubstituted or substituted C28alkenyl, unsubstituted or substituted C2-8alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, **B NR6R 7 OR 6 Sr 25 O wherein the substituted group is substituted with one or more of: 1) aryl 0" or heterocycle, unsubstituted or substituted with: a) C1-4alkyl, b) (CH 2 )pOR 6 c) (CH 2 )pNR6R 7 d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoroCl-4alkyl, h) SR 6 a, S(O)R 6 a, SO 2 R 6 a, 2) C3-6CYClOalkyl, 3) OR 6 4) R6 R6 -N R 7 -N NR7R 7 a -0 NR 6 R 7 SR 6 a, S(O)R 6 a, Or SO 2 R 6 a, 5) -NR6R7, 6) o 7) o o 9) -0 OR NR 6 R7 R 6 R6 -S0 2 -NRR 7 -N-S0 2 -R6a, 12) 13) 14) C04212 OR 6 0Y 0 15) N 3 16) F, or 17) perfluoroCI- 4 alkyl; or R 2 and R 3 are'attached to the same C atom and are combined to form wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, and -N(COR10)-; 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; R 6 R 7 and R7a are independently selected from: H; Cl-4alkyl, C3-6Cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C14alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) 0 f) -SO 2 R1 I, or g) N(R1O) 2 or R 6 and R 7 may be joined in a ring; R 7 and R 7 a may be joined in a ring; R 6 a is selected from: Ci-4alkyl, C3-6cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) Ci~alkoxy, 0- 1 b) aryl or heterocycle, c) halogen, d) HO, e) 0 f) -SO 2 R1l, or g) N(R1O) 2 R 8 is independently io selected from: a) hydrogen, b) aryl, heterocycle, C3-iocycloalkyl, C2-6alkenyl, C2-6alkynyl, perfluoroalkyl, F, Cl, Br, R 1 00Q R 11 RlOC(O)NR10-, (Rlo) 2 R1O2N-(NR10)-, CN, NO 2 R 1 0 N 3 2 or R 11 0C(O)NRO-, and c) Cl-6alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-iocycloalkyl, C2-6alkenyl, C2-6alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R"lS(O)m-, R 10 C(O)NH, (R u)2iNC(U)-, R1O2N-(NR10)-, ON, t-vuu(u)-, N3, -IN(R10)2, or R'O(ON- R 9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R 11 RlOC(O)NR'O-, 1 0 2 R1O 2 N-(NRl0)-, ON, NO 2 RlOC(O)-, N 3 -N(RO) 2 or R 11 00(O)NRIO-,and c) Cl-6alkyl *unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 1 0 R 11 RlOC(O)NR10-, (Rlo) 2 NC(O)-, RlN-(NR1O)-, ON, RlOC(O)-, N 3 -N(R1O) 2 or RllOC(O)NR0-; R 1 0 is independently selected from hydrogen, Cl-6alkyl, benzyl and aryl; R 1 1 is independently selected from Oi-6alkyl and aryl; A' and A 2 are independently selected from: a bond, -CH=OH-, -C(O)NR0-, -NRlOC(O)-, 0, -N(R 1 S(O) 2 N(RlO)-, -N(R 10 )S(O) 2 or S(O)m; G is H- 2 V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1l2oalkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from 0, S, and and e) C2-2o alkenyl, provided that V is not hydrogen if A' is S(O)m and V is not hydrogen if A' is a bond, n is 0 and A 2 is S(O)m; W is imidazolyl; X is -OH 2 or Z is unsubstituted Ci- 6alkyl, substituted Cl-6alkyl, unsubstituted C3.6cycloalkyl or substituted C3-6cycloalkyl, wherein the substituted C1l6alkyl and substituted C3-6cycloalkyl is substituted with one or two of the following: a) Ci. 4alkoxy, b) NR 6 FR7, C) C3-6cycloalkyl, d) -NR 6 C(O)R7, e) HO, f) -S(O)mR6a, g) halogen, or h) perfluoroalkyl; m isO0, 1 or 2; n isO0, 1, 2, 3 or4; pis 0, 1,2, 3 or4; q is 1 or 2; r is 0to 5, provided that r :is 0 when V is hydrogen; s is 0 or 1; t is 1; and u is 4 or 5; provided that the substituent (R 8 )r-V- *30 Al(CRla2)nA2(CRla2)n- is H; or a pharmaceutically acceptable salt thereof. 39. A compound of the formula A: C04212 wherein: Ria and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-locycloalkyl, C2-6alkenyl, C2-6alkynyl, R 1 0 R 1 1 RlOC(O)NR'O-, CN(R' 0 2 R1o 2 CN, NO 2 RIOC(O)-, N 3 -N(R10) 2 or RllOC(O)NR0-, c) unsubstituted or substituted C1l6alkyl wherein the substituent on the substituted Ol-6alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-locycloalkyl, C2-6alkenyl, C2-6alkynyl, R 1 0 R 1 1 RlOC(O)NR10-, (Rlo) 2 R 1 0 2 N-(N R 1 0 CN, Rl 0 N 3 -N(R10) 2 and RllOC(O)-NR0-; R 2 and R 3 are independently selected from: H; unsubstituted or substituted Cl-8alkyl, unsubstituted or substituted C2-8alkenyl, unsubstituted or substituted C2-8alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, 'Y NR 6 R 7 OR 6 0 or 0 whe in the czihztifiifz r~Jn +c A 0O 0 S 0S 0@0e S *5 S 0 OSS 0 S S 0sS 0 S. S 0O *5 up a o a u vve wit, in orure OT: I) aryl or heterocycle, unsubstituted or substituted with: a) C1-4alkyl, b) (CH 2 )pOR6, C) (CH 2 )pNR6R7, d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoroCl~alkyl, h) SR~a, S(O)R6a, SO 2 R 6 a, 2) C3-6cycloalkyl, 3) OR 6 4) -N YR7 -N YNR7R 7 a -0 YNR 6 R7 ,qP6a q(l)iP6a nr QC),6a 1,1067 0 0Cn -0 OR 6 Y NR 6 R7 0 0 1) 11 -S0 2 -NR 6 R 7 ,12) -N-S0 2 -R6a 13) 0 ,14) fOR 6 0 115) N 3 16) F, or 17) perfluoro~il4alkyl; or R 2 and R 3 are attached to the same C atom and *5 S. S are combined to form -(CH2)u- wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(CORO)-; 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; R 6 R 7 and R7a are independently selected from: H; C14alkyl, C3-6cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, R 1 unsubstituted or substituted with: a) Ci-4alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) 0 f) -SO 2 R11, or g) N(RO) 2 or R 6 and R 7 may be joined in a ring; R 7 and Rla may be joined in a ring; R 6 a is selected from: Cl-4alkyl, C3-6cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) Cl-4alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) 0 f) -S0 2 R 11 or g) N(RO) 2 R 8 is independently -~-..selected from: a) hydrogen, b) aryl, heterocycle, C3l1ocycloalkyl, C2-6alkenyl, C2-6alkynyl, perfluoroalkyl, C042 12 F, CI, Br, R 1 0 R 11 RoOC(O)NR0-, (R 10 2 R1o 2 N-(NRlo)-, ON, NO 2 Rl 0 N 3 N(RiO) 2 or RllOC(O)NR0-, and c) C1-6alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-locycloalkyl, 02.6alkenyl, O2-6alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R 11 S(O)m-, R' 0 C(O)NH, (Rlo) 2 RiO2N-(NR10)-, ON, RlOO(O)-, N 3 -N(RIO) 2 or R'OOC(O)NH-; R 9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R 11 RoOC(O)NR0-, (Rlo) 2 RlO 2 N-4NRIO)-, ON, NO 2 Rl 0 N 3 -N(R10) 2 or RllOC(O)NR10-,and c) Ois6alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 R 11 RlOC(O)NR'O-, (R 10 2 N0(O)-, RlO2N-(NR10)-, ON, RlOC(O)-, N 3 -N(Rl0) 2 or RllOO(O)NR0-; R 1 0 is independently selected from hydrogen, Ol-6alkyl, benzyl and aryl; R" is independently selected from Ol-6alkyl and aryl; A' and A 2 are lo independently selected from: a bond, -OH=OH-, -O(O)NR0-, -NR0OC(O)-, 0, -N(Rl0)-, S(O) 2 N(Rl0)-, -N(R10)S(O) 2 or S(O)m; G is H- 2 V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) Ol-2oalkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from 0, S, and N, and e) 02-20 alkenyl, provided that V is not hydrogen if A' is S(O)m and V is not hydrogen if A' is a bond, n is 0 and A 2 is S(O)m; W is imidazolyl; X is -OH 2 or Z is unsubstituted 0i- 6alkyl, substituted O1-6alkyl, unsubstituted O3-6cycloalkyl or substituted O3-6cycloalkyl, wherein the substituted Ol-6alkyl and substituted O3-6cycloalkyl is substituted with one or two of the following: a) Oi- 4alkoxy, b) NR 6 R 7 C) O3-6cycloalkyl, d) -NR 6 O(O)R 7 e) HO, f) -S(O)mR6a, g) halogen, or h) pertluoroalkyl; m is 0, 1 or 2; n isO0, 1, 2, 3 or 4; p isO0, 1, 2, 3 or 4; q is 1 or 2; r is 0to 5, provided that r is 0 when V is hydrogen; s is 0 or 1; t is 1; and u is 4 or 5; provided that the substituent (R8)r-V- Al(ORa2)nA 2 (OR1a2)n- is H; or a pharmaceutically acceptable salt thereof when used in treating cancer. *40. The use of a compound of the formula A: S(R9)q A, R 1 A2 Ria W t Rib X R 2 G f nat bP N q R R1 PN-Z wherein: Ria and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, O3-locycloalkyl, O2-6alkenyl, O2s6alkynyl, R 1 0 R 11 RoOC(O)NR10-, ON(RI0) 2 R1 0 2 N-(NRIO)-, ON, NO 2 6:25 RlOC(O).., N 3 -N(RO) 2 or RllOO(O)NR0-, c) unsubstituted or substituted CI-6alkyl wherein the substituent on the substituted Ou-6alkyl is selected from unsubstituted or substituted aryl, heterocyclic, 03ilocycloalkyl, O2-6alkenyl, 02-6alkynyl, R 10 R 11 R100(O)NR10L, (R 10 2 R 10 2 N, RlOO(O)-, N 3 -N(R10) 2 and R 11 00(O)-NRO-; R 2 and R 3 are independently selected from: H; see. *unsubstituted or substituted Ou-8alkyl, unsubstituted or substituted C2-8alkenyl, unsubstituted or 30 substituted O2-8alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, Y NR6R 7 "Y OR 6 0 or 0 wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) Ou-4alkyl, b) (0H2)pOR 6 C) (OH 2 )pNR 6 R 7 d) halogen, e) ON, f) aryl or heteroaryl, g) perfluoro~i-4alkyl, h) SR 6 a, S(O)R 6 a, SO 2 R 6 a, 2) O3-6CYCloalkyl, 3) OR 6 4) C04212 -N YR7 0 -N NR7R 7 a 0 -0O NR 6 R7 SR 6 a, S(O)R 6 a, or SO 2 R 6 a, 5) -NR 6 R 7 6) -0O OR 6 "YNR 6 R 7 0 if) 0 4 I I 1 -S0 2 -NR 6 R 7 1 2 -N-S0 2 -R6a ,13) 0 ,14) "YOR 6 N 3 16) F, or 17) perfluoroC1i 4 alkyl; or R 2 and R 3 are attached to the same 0 atom and are combined to form -(CH 2 wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(COR10)-; R 4 is selected from H and OH 3 and any two of R 2 R 3 and R 4 are optionally attached to the same carbon atom; R 6 R7 and R7a are independently selected from: H; Oi-4alkyl, O3-6cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Oi4alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) 0 I) -SQ 2 R11, or g) N (R'0) 2 or R 6 and R 7 may be joined in a ring; R7 and R 7 a may be joined in a ring; R 6 a is lo selected from: C1-4alkyl, O3-6cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) Ci-4alkoxy, 0* S 00 OSOC S "Y R11 b) aryl or heterocycle, c) halogen, d) HO, e) 0 f) -SO 2 R11, or g) N(RO) 2 R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-iocycloalkyl, C2-6alkenyl, O2-6alkynyl, perfluoroalkyl, F, Cl, Br, R 10 R 11 R' 0 0(O)NRl 0 (R' 0 2 R1o 2 N.(NRIO)-, CN, NO 2 Rl 0 N 3 S N(RlO) 2 or RllOC(O)NR0-, and c) Ol-6alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-locycloalkyl, O2-6alkenyl, O2-6alkynyl, pertluoroalkyl, F, Cl, Br, R1 0 R 11 S(O)m-, RIOC(O)NH, (Rlo) 2 RlO 2 N-(NR10)-, ON, Rl0C(O)-, N 3 -N(R10) 2 or R 10 00(O)NH-; R 9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R100-, R 11 R 10 0(O)NR 1 0 :(R 10 2 Rlo 2 N-(NR10)-, ON, NO 2 P100(O)., N 3 -N(RO) 2 or P 11 00(O)NR 1 O-,and c) Ol-6alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R100-, R' 1 P 10 0(O)NR 10 (Rlo) 2 N0(O)-, RlO 2 N-4NRO), ON, RlOO(O)-, N 3 -N(RO) 2 or RllOC(O)NR0-; R1 is independently selected from hydrogen, Cl-6alkyl, benzyl and aryl; R 1 1 is independently selected from Ol.6alkyl and aryl; A' and A 2 are independently selected from: a bond, -OH=OH-, -O(O)NRiO-, -NR 1 0 0, -N(R 0 S(O) 2 -N(R 0 )S(O) 2 or S(O)m; G is H- 2 V is selected from: a) hydrogen, b) heterocycle, c) ary, S d) C1l2oalkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from 0, S, and 25 N, and e) 02-2o alkenyl, provided that V is not hydrogen if A' is S(O)m and V is not hydrogen if A' is a bond, n is 0 and A 2 is S(O)m; W is imidazolyl; X is -OH 2 or Z is unsubstituted Ci- 6alkyl, substituted 01-6alkyl, unsubstituted O3-6CYCloalkyl or substituted O3-6CYCloalkyl, wherein the substituted Ci-6alkyl and substituted O3-6cycloalkyl is substituted with one or two of the following: a) C1. 4alkoxy, b) NP 6 R7, C) O3-6CYCloalkyl, d) -NR6O(O)R7, e) HO, f) -S(O)mR6a, g) halogen, or h) miso0, 1 or 2; n is0, 1, 2, 3or4; pis 0, 1, 2, 3or4; qisl1 or 2; r is 0,to 5, provided that r C0421 2 I 123 is 0 when V is hydrogen; s is 0 or 1; t is 1; and u is 4 or 5; provided that the substituent (R 8 )r-V- Ai(CRia2)nA2(CR1a2)n- is H; or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer. 41. A method for treating cancer which comprises administering to a mammal in need thereof s a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of the formula: Al, 0 S *0 S. 0 00 0 0 0* 0 0* S. 0 0* OS A 0 0 0 S wherein: Ria and R1b are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-locycloalkyl, C2-6alkenyl, C2-6alkynyl, R 1 0 0oO-, R 1 1 RIOC(O)NR 1 CN(R 1 0 2 R 10 2 N-(NR 0 CN, NO 2 RIOC(O)-, N 3 -N(R10) 2 Or RlOC(O)NRIO-, c) unsubstituted or substituted CI6 alkyl wherein the substituent on the substituted C.6alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-locycloalkyl, C2-6alkenyl, C2-6alkynyl, Ro 1 0 RuS(O)m-, RioC(O)NRO-, (R 10 2 R 1 0 2 N-(NRio)-, CN, RlOC(O)-, N 3 -N(R1O) 2 and RlOC(O)-NR1O-; R 2 and R 3 are independently selected from: H; unsubstituted or substituted Cl18alkyl, unsubstituted or substituted C2-8alkenyl, unsubstituted or substituted C2-8alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, NR6R 7 OR 6 0 or wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C1-4alkyl, b) (CH 2 )pOR6, c) (CH 2 )pNR6R7, d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoroC1-4alkyl, h) SR 6 a, S(O)R6a, SO 2 R 6 a, 2) C3-6cycloalkyl, 3) OR 6 4) R6 R6 -N R7 -N NR7R 7 a -0 NR 6 R7 RP6a (l)R6a or SORea KIDR6D7 0 0 0 A 1 I- I )I -0 OR 6 NR 6 R7 0 O [U) I I -S 2 -NR 6 R 7 1) 12) I N-S02-R~a R6 0 13) 14) OR 6 0 15) N 3 16) F, or 17) perfluoroC1-4alkyl; 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, S(0)m, and -N(CORo)-; 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; R 6 R 7 and R7a are independently selected from: H; C1-4alkyl, C36cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C1-4alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) 0 C04212 -S0 2 R 11 or g) N(R1O) 2 or R 6 and R 7 may be joined in a ring; R 7 and R 7 a may be joined in a ring; R 6 a is selected from: C14alkyl, C3ecycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) CI-4alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) 0 f) -S0 2 R 11 or g) N(R1O) 2 R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-iocycloalkyl, C2-6alkenyl, C2-6alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R 1 1 RlOC(O)NR10-, (R 10 2 RlO2N-(NR10)-, ON, NO 2 R' 0 N 3 N(R 10 2 or RilOC(O)NR0-, and C) C1l6alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, 03.iocycloalkyl, C2-6alkenyl, C2-6alkynyl, pertluoroalkyl, F, Cl, Br, R 1 0 R 11 S(O)m.. R 1 0 0(O)NH, (Rlo) 2 RlO 2 N-(NR1O)-, ON, RlOC(O)-, N 3 -N(R10) 2 or R 10 0C(O)NH-; R 9 is selected from: a) hydrogen, b) alkenyl, alkynyl, pertluoroalkyl, F, Cl, Br, R 1 0 R' 1 S(O)m, RlOC(O)NR'O-, lo (R 10 2 RlO2N-(NR10)-, ON, NO 2 RlOC(O)-, N 3 -N(RO) 2 or R 11 00(O)NR 1 O-,and c) Cl-6alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 1 0 R 1 1 S(O)m- RoOC(O)NR'o-, (Rlo) 2 NC(O)-, RlO 2 N-(NRl0)-, ON, RlOO(O)-, N 3 -N(RO) 2 or RllOO(O)NRO.; R 1 0 is independently selected from hydrogen, Ol-6alkyl, benzyl and aryl; R 1 1 is independently selected from Ol-6alkyl and aryl; A' and A 2 are independently selected from: a bond, -OH=OH-, -O(O)NRO-, 0, S(0) 2 N(Rl0)-, -N(Rl0)S(O) 2 or S(O)m; G is H 2 or 0; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) Ol-2oalkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from 0, S, and N, and e) O2-2oalkenyl, provided that V is not hydrogen if A' is S(O)m and V is not hydrogen if A' is a &mo bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X is or Z is unsubstituted Ol-6alkyl, 20we substituted OI-6alkyl, unsubstituted O3-6cycloalkyl or substituted O3-6cycloalkyl, wherein the substituted 0& O 2 16alkyl and substituted O3-6cycloalkyl is substituted with one or two of the following: a) C14alkoxy, b) W* 4 NR 6 R 7 C) O3-6cycloalkyl, d) -NR 6 O(O)R7, e) HO, f) -S(O)mR 6 a, g) halogen, or h) perfluoroalkyl; m is 0, 1 or2; nis 0, 1,2, 3or4; pis 0, 1, 2, 3or4; qis 1 or 2; ris 0to 5,provided that ris 0when Vis hydrogen; s is 0 or 1; t is 0 or 1; and u is 4 or 5; provided that if t is 1, then the substituent (R 8 )r-V- Al(ORla2)nA 2 (ORla2)n- is H; or a pharmaceutically acceptable salt thereof. 42. A compound of the formula: I '4 (R9)q Al RI A 2 Ria WJ Rib X R V N wherein: Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, O3.10cycloalkyl, C2-6alkenyl, O2-6alkynyl, R 1 0 R 11 RlOO(O)NR10-, ON(RO) 2 R 10 2 N-(NR 10 ON, NO 2 0RO(O)-, N 3 -N(RO) 2 or R 11 00(O)NRO-, c) unsubstituted or substituted C1-6 alkyl wherein the substituent on the substituted Ol-6alkyl is selected from unsubstituted or substituted aryl, heterocyclic, Oa-iocycloalkyl, C2-6alkenyl, O2-6alkynyl, R 1 0 R 1 1 RO(O)N Rl 0 (Rlo) 2 R 1 0 2 N-(NR1 0 ON, R 1 N 3 -N(RlO) 2 and RllOO(O)-NRO-; R 2 and R 3 are independently selected from: H; unsubstituted or substituted Oie8alkyl, unsubstituted or substituted O2-8alkenyl, unsubstituted or substituted O2-8alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C04212 'Y NR6R 7 n~ "YOR 6 or Q wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C1-4alkyl, b) (0H2)pOR6, c) (CH2)pNR 6 R7, d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoroCl-4alkyl, h) SR 6 a, S(O)R 6 a, SO 2 R 6 a, 2) C3-6cycloalkyl, 3) OR 6 4) R 6 R -NyR 7 -NyNR7R7a -OyNR 6 R7 SR6a S((y)R6a rnrq P(6a rl -KIP6Q7 P 0 0 0 1 J IIi I U -OyOR 6 YNR 6 R7 0fl 0 -N-S 2 -R6a 0 -S 2 -NR 6 R 7 I) 12) I I I 13) 14) 00 00 0 00 05'50'~ 0000 0* 0 000 0 4, 0 0 .00 0 05 0 0 00 I 00 'a 00 000 *0 0 ~000 0 6000 0 *E 0040 0 00 0 0 00 0 0 00 0 00 Y OR 6 0 ,15) N 3 16) F, or 17) perfluoroC,- 4 alkyl; or R 2 and FR 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, S(O)m, and -N(COO); R 4 is selected from H and CH 3 and any two of FR 2 R 3 and FR 4 are optionally attached to the same carbon atom; R 6 R 7 and R7a are independently selected lo from: H; C1-4alkyl, C3-6cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, rR 1 1 unsubstituted or substituted with: a) C,-4alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) 0 f) -SO 2 or g) N(R'O) 2 or FR 6 and R 7 may be joined in a ring; R 7 and FR~a may be joined in a ring; FR 6 a is selected from: CI-4alkyl, C3-6cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) C1-4alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) f) -SO 2 or g) N(R'O) 2 FR 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-locycloalkyl, C2-6alkenyl, C2-6alkynyl, perfluoroalkyl, F, Cl, Br, R1 0 R"IS(O)m, Rl 0 C(O)NR' 0 (Rlo) 2 R1 0 2 N-(NR1 0 CN, NO 2 Rl 0 N 3 N(RlO) 2 or R"OC(O)NRO-, and c) C1l6alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-locycloalkyl, C2-6alkenyl, C2-6alkynyl, perfluoroalkyl, F, Cl, Br, R1 0 R"S(O)m-, R'OC(O)NH, (Rlo) 2 R1O 2 CN, RlOC(O)-, N 3 -N(R10) 2 or R'OOC(O)NH-; R 9 is selected 20 from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R100-, R"S(O)m, R'OC(O)NRIO-, (Rlo) 2 RlO 2 N-(NR10)-, ON, NO 2 RIOC(O)-, N 3 -N(R'O) 2 or R"OC(O)NR'O-,and c) C1l6alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R1 0 R'OC(O)NR' 0 (R' 0 2 NC(O)-, R1 0 2 N-(NFR1 0 ON, R1 0 N 3 -N(R10) 2 or R"OC(O)NRO-; RH 0 is independently selected from hydrogen, C1-6alkyl, benzyl and aryl; R" is independently selected from C1.6alkyl and aryl; A' and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NFR' 0 0, -N(Rl 0 S(O)2N(R 10 -N(R' 0 )S(O) 2 or S(O)m; G is H 2 or 0; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1.2oalkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from 0, S, and N, and e) C2-2oalkenyl, provided that V is not hydrogen if A' is S(O)m and V is not hydrogen if A' is a C04212 bond, n is 0 and A 2 is S(O)M; W is a heterocycle; X is or Z is unsubstituted C1-6alkyl, substituted Cl-6alkyl, unsubstituted C3-6cycloalkyl or substituted C3-6cycloalkyl, wherein the substituted Cl-6alkyl and substituted C3-6cycloalkyl is substituted with one or two of the following: a) C1-4alkoxy, b) NR 6 R 7 C) C3-6Cycloalkyl, d) -NR 6 C(O)R7, e) HO, f) -S(O)mR6a, g) halogen, or h) perfluoroalkyl; m is 0, 1 or 2; nis 0, 1,2, 3or 4; pis 0, 1, 2, 3or 4; qis1 or 2 ris 0to, provided that riso0when Vis hydrogen; s is 0 or 1; t is 0 or 1; and u is 4 or 5; provided that if t is 1, then the substituent (R 8 )r- Al(CRla2)nA2(CRla2)n- is H; or a pharmaceutically acceptable salt thereof when used in treating cancer. 43. The use of a compound of the formula: (R9)q A, R 1 A 2 Ria W Rib X R 2 G- V NX R1 nJ R'at Rl P N-Z nl Ria Rib S lo wherein: Ria and R1b are independently selected from: a) hydrogen, b) aryl, heterocycle, C3.iocycloalkyl, C2-6alkenyl, C2s6alkynyl, R 10 R 1 S(O)m- RlOC(O)NRO-, CN(Rlo) 2 R 1 0 2N-(NR10)-, CN, NO 2 R 1 0 N 3 -N(RO) 2 or RllOC(O)NR0-, c) unsubstituted or substituted C 16 alkyl wherein the substituent on the substituted Cl-6alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3ilocycloalkyl, C2s6alkenyl, C2-6alkynyl, R' 0 R 11 R 1 0 C(O)N R 1 0 (Rlo) 2 R1o 2 15 CN, RIOC(O)-, N 3 -N(RO) 2 and RllOC(O)-NR0-; R 2 and R 3 are independently selected from: H; unsubstituted or substituted Ci-8alkyl, unsubstituted or substituted C2-8alkenyl, unsubstituted or substituted C2-8alkynyl, unsubstituted or substituted aryl, u nsubstituted or substituted heterocycle, NR 6 R 7 OR 6 "Y 'Y0 0 or 0 ,wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C1-4alkyl, b) (CH 2 )pOR6, C) (CH 2 )pNR 6 R7, d) halogen, 20 e) CN, f) aryl or heteroaryl, g) perfluoroCl-4alkyl, h) SR 6 a, S(O)R 6 a, SO 2 R 6 a, 2) C3-6CYCloalkyl, 3) OR 6 4) -NyR 7 -NYNR7R 7 a -0 NR 6 R7 QQ~6a Q/C0\D&a ~DRa KI0607 0 0 7 0 nk) 0@ 0 0@ @000 @000 S. S S S 5@ S S eS 0 SO *0 S. S 0 55 0.55 S S. S S 0550.. 5 S. Os S 0 55 S 0. 05 -0 OR 6 'Y NR 6 R7 0 0 -S0 2 -NR 6 R 7 I) 12) -N-S0 2 -R 6 a ,13) 0 14) I uI I I 'YOR 6 C'N 15) N 3 16) F, or 17) perfluoroC, 1 4 alkyl; 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, S(O)m, and -N(CORO)-; 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; R 6 R 7 and R7a are independently selected from: H; C1-4alkyl, C3-6cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, C04212 unsubstituted or substituted with: a) C14alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) 0YR1 f)~SOR~i org) (R1O 2 r R an R 7 may be joined in a ring; R7 and R7a may be joined in a ring; R 6 a is selected from. C14alkyl, C3-6cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) Cl-4alkoxy, 0Y R1 b) aryi or heterocycle, c) halogen, d) HO, e) 0 f) -SO 2 or g) N(R1O) 2 R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, 03.iocycloalkyl, C2-6alkenyl, C2-6alkynyl, perfluoroalkyl, F, Cl, Br, R1 0 RloC(O)NR10-, (R' 0 2 RlO2N-(NR10)-, ON, NO 2 RloO(O)-, N 3 N(R1O) 2 or RllOC(O)NR10-, and c) C1i6alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-locycloalkyl, C2-6alkenyl, C2-6alkynyl, perfluoroalkyl, F, Cl, Br, R1 0 R"1S(O)m,-, R1 0 C(O)NH, (R1 0 2 RlO2N-(NR10)-, CN, R1OC(O)-, N 3 -N(R10) 2 or R'OOC(O)NH-; R 9 is selected lo from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, CI, Br, Rl00-, R 11 S(O)rn, RlOC(O)NR0-, (R 1 0 2 R1O 2 N-(NR10)-, ON, NO 2 R1OC(O)-, N 3 -N(R10) 2 or RliOC(O)NR'o-,and c) C1-6alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R1 0 RlOC(O)NR'O-, (R' 0 2 NC(O)-, RlO 2 N-(NR10)-, ON, R1 0 N 3 -N(RO) 2 or R 11 0C0)NR'0-; R1 0 is independently selected from hydrogen, CI-6alkyl, benzyl and aryl; R" is independently selected from Cl-6alkyl and aryl; A' and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR0-, 0, S S(O) 2 N(RIO)-, -N(R' 0 )S(O) 2 or G is H2 or 0; V is selected from: a) hydrogen, b) heterocycle, c) :0 aryl, d) C1l2oalkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from 0, S, ::.and N, and e) C2-2oalkenyl, provided that V is not hydrogen if A' is S(O)m and V is not hydrogen if A' is a 0S bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X is or Z is unsubstituted Cl-6alkyl, substituted Cl-6alkyl, u nsubstituted C3-6cycloalkyl or substituted C3-6cycloalkyl, wherein the substituted Ci-6alkyl and substituted C3-6cycloalkyl is substituted with one or two of the following: a) C14alkoxy, b) NR 6 R7, C) C3-6cyclOalkyl, d) -NR 6 C(O)R7, e) HO, f) -S(O)mR 6 a, g) halogen, or h) perfluoroalkyl; mn is 0, 1 or2; nisO, 1, 2 3or4; pis0, 1, 2 3or4; qis 1 or 2 ris 0to 5,provided that riso0when Vis hydrogen; s is 0 or 1; t is 0 or 1; and u is 4 or 5; provided that if t is 1, then the substituent (R8)r-V- Al(CRa2),A2(CR1a2),- is H; or a pharmaceutically acceptable salt thereof for the manufacture of a *~ee medicament for treating cancer. Dated 21 October 1998 MERCK CO., INC. 30 S.U O &F R U O C04212