CA2249599A1 - Inhibitors of farnesyl-protein transferase - Google Patents

Abstract

The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.

Description

CA 02249~99 1998-09-22 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 receptor~s 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 GTP-bound form of Ras propagates the growth stimulatory signal until the signal is termin~ted by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and l~S D.M. Willumsen, Ann. Rev. Biochem. 62:gSl-~91 (1993)). Mutated ras genes (Ha-7 as, 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 con.stitutively 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-Aaal-Aaa2-Xaa"
box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (19~S4)). Depending on the specific .se4uence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or ~eranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a Cls or C2() isoprenoid, respectively. (S. Clarke., Ann. Rev. Bi~chem. 61:355-3~6 (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 CA 02249F,99 1998-09-22 farnesylation. Other farnesylated proteins include the Ras-related GTP-binding proteins ,such a~s Rho, fungal mating factors, the nuclear lamin.s, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 141~2 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.
Inhibition of farnesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify other aspects of their trans~ormed phenotype. It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the Ra~s oncoprotein intracellularly (N.E. Kohl et al., Science, 260:1934-1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of ras-dependent tumors in nude mice (N.E. Kohl et al., P) oc. Natl. Acad. Sci U.S.A., 91:9141-9145 (1994) and induces regression of m~mm~ry and salivary carcinomas in ras transgenic mice (N.E. Kohl et al., Nature Medicine, 1 :792-797 (1995).
Indirect inhibition of farnesyl-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 (19~9)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al., Cell, 62:81-g~ (1990);
Schaber etal.. J. Biol. Chem., 265:14701-14704 (1990); Schafer etal., Science, 249: 1133- 1139 (1990); Manne et al., Proc. Natl. Acacl. Sci 30 USA, 87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthe.sis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cell~. However, direct inhibition of farnesyl-protein transferase would be more specific and attended by fewer side CA 02249~99 1998-09-22 W O 97/36593 PCTrUS97/05144 effects 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 farnesyl 5 diphosphate (FPP), while the second class of inhibitor.s is related to the protein substrates (e.g., Ras) for the enzyme. The peptide derived inhibitors that have been described are generally cysteine cont~ining molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ihid; Reiss et. al., i1~id; Reiss e~ al., 0 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,g51, University of Texas; N.E. Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
15 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 pharrnacokinetics, pharmacodynamics and toxicity. Therefore, a 20 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 H7-25 112930).
It has recently been disclosed that certain tricycliccompounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516).
Imidazole-containin~ inhibitors of farnesyl protein transferase have also 30 been disclosed (WO 95/09001 and EP 0 675 112 A1).
It is, therefore, an object of this invention to develop peptidomimetic compounds that do not have a thiol moiety, and that will inhibit farnesyl-protein transferase and thus, the po~st-translational farnesylation of proteins. It is a further object of this invention to CA 02249~99 1998-09-22 WO 97/36593 PCTrUS97/05144 develop chemotherapeutic compositions containing the compounds of this invention and methods for producing the compounds of this invention.

The present invention comprises peptidomimetic piperazine- or piperazinone-containing compounds which inhibit the farnesyl-protein transferase. The instant compounds lack a thiol moiety and thus offer unique advantages in terms of improved pharmacokinetic 10 behavior in animals, prevention of thiol-dependent chemical reaction.s, such as rapid autoxidation and disulfide formation with endogenou~
thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions cont~ining these farnesyl transferase inhibitors and methods for their production.
The compounds of this invention are illustrated by the formulae A and B:
( IR8)r IR9)~\ R2 ~
V - A1(CR1a2)nA2(CR1a2)n -\W~- (CR1b2)P~ ~N N Z

(IR8)r !R9~ R2 R3 V A1 (C R 1 a2)nA2(C R 1 a2)n ~Wl - (C R 2)p\ ,N~--Z

CA 02249~99 1998-09-22 W O 97/36~93 PCTrUS97/05144 DETAILED DESCRIPTION OF THE ~VENTION
The compounds of this invention are useful in the inhibition of farnesyl-protein transferase and the farnesylation of the oncogene protein Ras. In a first embodiment of this invention, the inhibitors of 5 farnesyl-protein transferase are illustrated by the formula A:

~7 '~ R\~
V - A1(CR1a2)nA2(CR1a2)n -\W~- (CR1b2)p\ /N N--Z

R~ R4 wherem:

Rla and Rlb are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, R 1 0O-, R 1 1 S(O)m ~ R 1 0C(o)NR 10, CN(R 1 0)2NC(o)-, R 1 02N-C(NR 1 0)-, CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 , c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, Rl lS(O)m-, R10C(o)NR10-, (R10)2NC(o)-~ R102N-C(NR10)-, CN, R10C(o)-, N3, -N(R10)2, and Rl loc(O)-NRlO;

R2 and R3 are independently ,selected from: H; unsubstituted or substituted Cl ~ alkyl, unsubstituted or substituted C2 ~ alkenyl, W O 97/36593 PCTrUS97/05144 unsubstituted or substituted C2 8 alkynyl, unsubstituted or substituted aryl, ~NR6R7 or ~oR6 unsubstituted or substituted heterocycle, ~ ~
wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
S a) C1 4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-Cl 4 alkyl, h) SR6a, s(o)R6a~ So2R6a 2) C3 6 cycloalkyl, 3) oR6, 1~ 4) SR6a, S(O)R6a~ or S02R6a 5) --N R6R7 o --N~ N R7R7a WO 97/36~93 PCT/US97/05144 8) --~~ NR6R7 9) --o~OR6 10) ~ NR6R7 o 1 1 ) --SO2--N R6R7 ~6 12) --N--SO2--R6a o o 1 5) N3, 16) F, or 17) perfluoro-C1 4-alkyl; or S R2 and R3 are attached to the same C atom and are combined to form -(CH2)U - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

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

WO 97/36593 PCT/US97/0~144 R6, R7 and R7a are independently selected from: H; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) Cl 4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, o f) --S02R , or g) N(R 1 0)2; or R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

15 R6a is selected from: Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, o f) --S02R1 1 , or g) N(R 1~)2;

R~ is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C1o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl 1 S(O)m 7 CA 02249~99 1998-09-22 W O 97/36593 PCTrUS97/05144 R 1 0C(O)NR 10, (R 1 0)2NC(O)-, R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 , and c) C 1 -C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, Rl lS(O)m-, RlOC(O)NH-, (R10)2NC(o)-, R102N-C(NR 1 0)-, CN, R 1 ~C(O)-, N3, -N(R 1 0)2, or R 1 0OC(O)NH-;

10 R9 is selected from:
a) hydrogen, b) alkenyl, alkynyl, per~luoroalkyl, F, Cl, Br, R100-, R 1 1 S(O)m-~ R 1 0C(o)NR 10, (R 1 0)2NC(o)-, R 1 02N-C(NR 1 0)-, CN, NO2, R 1 ~C(O)-, N3, -N(R 1 0)2, or R l l OC(O)NR 1 0-, and c) Cl-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, Rl lS(O)m-, R10C(o)NR10-, (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R10)2, or Rl lOC(O)NR10-;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl;

Rl 1 is independently selected from C1-C6 alkyl and aryl;
Al and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR 10, -NR 1 ~C(O)-, O, -N(R 10), -S(O)2N(R10)-, -N(R10)S(o)2-~ or S(O)m;

30 G is H2 or O;

V is selected from:
a) hydrogen, b) heterocycle, CA 02249~99 1998-09-22 W O 97/36593 PCTrUS97/0~144 c) aryl, d) C1-C20 alkyl wherein from O 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 A1 isabond, Il iS 0 andA2isS(O)m;

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

Z is unsubstituted Cl-C6 alkyl, .substituted Cl-C6 alkyl, unsub,stituted C3-C6 cycloalkyl or sub,stituted C3-C6 cycloalkyl,wherein the substituted Cl-C6 alkyl and substituted C3-C6 cycloalkyl is substituted with one or two of the following:
a) C 1 -4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) -NR6C(o)R7, e) HO, f) -s(o)mR
g) halogen, or h) perfluoroalkyl;

mis 0, 1 or2;
nis 0, 1, 2, 3 or4;
pis 0, 1, 2, 3 or4;
qis 1 or 2;
r is O to 5, provided that r is O when V is hydrogen;
sis O or l;
tis Oorl;and u is 4 or 5;

CA 02249~99 1998-09-22 W O 97/36593 PCTrUS97/05144 or the phalmaceutically acceptable salts thereof.

In a second embodiment of this invention, the inhibitors of 5 farnesyl-protein transferase are illustrated by the forrnula B:

(R8)r ~9~ R~ ~ R3 V ~ Al(CR1a2)nA2(CR1a2)n -\W~!- (CR1b2)p~ ,N /N--Z
/~G

wherein:

Rla and Rlb are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, R 1 0O-, R 1 1 S(O)m ~ R 1 0C(o)NR 10, (R 1 0)2NC(o)-, R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 , c) unsubstituted or substituted Cl-C6 alkyl wherein the substitutent on the substituted Cl-C6 alkyl is .selected from unsubstituted or substituted aryl, heterocyclic, C3-Cln cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R 1 I S(O)m-, R 1 0C(o)NR 10, (R 1 0)2NC(o)-, R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1 ~)2, and R 1 1 OC(O)-NRlO;

R2 and R3 are independently selected from: H; unsubstituted or substituted Cl ~ alkyl, unsubstituted or sub.stituted C2 ~ alkenyl, 25 unsubstituted or substituted C2 X alkynyl, unsubstituted or substituted aryl, ~NR6R7 or ~oR6 unsubstituted or substituted heterocycle. ~ ~

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)pOR6, c) (CH2)pNR6R7, d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C1 4 alkyl, h) SR6a, s(o)R6a? So2R6a 2) C3-6 cycloalkyl, 3) oR6, 4) SR6a, s(o)R6a~ or So2R6a 5) --NR~R7 --N~ N R7R7a WO 97136593 PCT/US97/0~144 8) --~~ NR6R7 9) --O oR6 10) ~ NR6R7 1 1 ) --SO2--N R6R7 ~6 12) --N--SO2--R6a o o 1 5) N3~
16) F, or 17) perfluoro-C1 4-alkyl; or R2 and R3 are attached to the same C atom and are combined to form -(CH2)U - wherein one of the carbon atom,s is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

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

CA 02249~99 1998-09-22 W O 9~136593 PCTrUS97tO5144 R6, R7 and R7a are independently selected from: H; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) Cl 4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) ~I~R

f) --SO2R , or g) N(Rl0)2; or R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

15 R6a is selected from: Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, o f) --SO2R1 ' , or g) N(R 1~)2;

R~ is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, perfluoroalkyl~ F, Cl, Br, Rloo-~ Rl lS(o)m-,, .

CA 02249~99 1998-09-22 W O 97/36593 PCTrUS97/05144 R 1 0C(o)NR 10, (Rl0)2Nc(o)-~Rl 02N-C(NR 10)-, CN, NO2, R 1 ~C(O)-, N3,-N(R 1~)2, or R 1 1 OC(O)NR 10-, and c) Cl-C6 alkyl unsub~tituted or substituted by aryl, cyanophenyl, heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, Rl lS(O)m-, RlOC(O)NH-, (R10)2NC(o)-, R102N-C(NR10)-,CN,R10C(O)-, N3,-N(R10)2, or R10OC(O)NH-;

R9is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, Rl0o-~Rlls(o)m-~Rl 0C(o)NR I ~-, (R 1 0)2NC(O)-, R102N-c(NRlo)-~cN~No2~Rloc(o)-~ N3,-N(Rl0)2~or RllOC(O)NR10-, and c) Cl-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, Rl lS(O)m-, R10C(o)NR10-, (Rl0)2Nc(o)-~Rlo2N-c(NRlo)-~cN~Rloc(o)-~ N3, -N(R10)2, or R 1 1 OC(O)NR 10;
R10 i~ independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl;

Rl 1 is independently selected from Cl-C6 alkyl and aryl;
Al and A2 are independently selected from: a bond, -CH-CH-, -C_C-, -C(O)-, -C(O)NR 10 , -NR 1 ~C(O)-, O, -N(R 10) , -S(O)2N(R 10), -N(R 1 ~)S(O)2-, or S(O)m;

30 G is O;

V is selected from:
a) hydrogen, b ) heterocycle, CA 02249~99 1998-09-22 W O 97/36S93 PCTrUS97/05144 c) aryl, d) Cl-C20 alkyl wherein from O to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and S e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is O and A2 is S(O)m;

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

Z is un.substituted Cl-C6 alkyl, substituted Cl-C6 alkyl, unsubstituted C3-C6 cycloalkyl or substituted C3-C6 lS cycloalkyl,wherein the ~substituted Cl-C6 alkyl and substituted C3-C6 cycloalkyl is substituted with one or two of the following:
a) C 1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) -NR6C(o)R7, e) HO, f) -S(O)mR6a, g) halogen, or h) perfluoroalkyl;

mis 0, l or2;
nis 0, l, 2, 3 or4;
pis 0, 1, 2, 3 or4;
q is l or 2;
r IS 0 to S, provided that r i,s O when V i,s hydrogen;
~ls l;
tis Oor l; and uis 40rS;

CA 02249~99 1998-09-22 W O 97136593 PCTrUS97/05144 or the pharmaceutically acceptable salts thereof.

In a preferred embodiment of this invention, the inhibitors S of farnesyl-protein transferase are illustrated by the formula A:
(l 8)r ! ~ R2~
V ~ A1(CR1a2)nA2(CR1a2)n -\W~!- (CRlb2)p~ /N~ JN--Z

wherein:

10 Rla is independently selected from: hydrogen or C1-C6 alkyl;

Rlb is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, R lOo, -N(R 1~)2 or C2-C6 1 5 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted Cl-C6 alkyl is selected from unlsubstituted or sub,stituted aryl, heterocycle, ~cycloalkyl, alkenyl, RlOO- and -N(R10)2;

R3 and R4 are independently selected from H and CH3;
~,~NR6R7 R2 is H; O or C1 5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl, 2;S 2) heterocycle, 3 ) oR6, 4) SR6a, SO2R6a, or CA 02249~99 1998-09-22 W O 97/36593 PCTrUS97/05144 5) ~f NR6R7 o and any two of R2, R3, R4, and RS are optionally attached to the same carbon atom;

S R6, R7 and R7a are independently selected from:
H: Cl 4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with:
a) C l 4 alkoxy, b) halogen, or c) aryl or heterocycle;

R6a is selected from:
Cl 4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with:
a) Cl 4 alkoxy, b) halogen, or c) aryl or heterocycle;

Rfs is independently selected from:
a) hydrogen, b) Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R10O-, R10C(o)NR10-, CN, NO2, (R 1 0)2N-C(NR 10) , R 1 ~C(O)-, -N(R 1~)2, or Rl lOC(O)NR10-, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R10O-, Rloc(o)NRlo-~ (Rlo)2N-c(NRlo)-~ Rl0 -N(R 1~)2, OI R 1 1 OC(O)NR 10;

R9 is selected from:
a) hydrogen, b) C~-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl. R10O-, Rl lS(O)m-, R10C(o)NR10-, CN, NO2, CA 02249~99 1998-09-22 (R10)2N-C(NR10)-,R10C(O)-,-N(R10)2,or RllOC(O)NR10-, and c) Cl-C6 alkyl unsubstituted or substituted by Cl-C6 pe~uoroalkyl, F, Cl, Rl0o-~Rlls(o)m-~Rloc(o)NR
CN,(R10)2N-C(NR10)-,Rl0C(o)-~-N(R 1~)2, or RllOC(O)NR10-;

R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl;
Rll i.s independently selected from Cl-C6 alkyl and aryl;

Al and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;
V is selected from:
a) hydrogen, b) heterocycle ~selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, i,soquinolinyl. and thienyl, c) aryl, d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and 25 e) C2-C20 alkenyl, and provided that V i~ not hydrogen if Al is S(O)m and V is not hydrogen if Al isabond,n isOandA2isS(O)m;

G is H2 or O;
W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl. indolyl, quinolinyl, or isoquinolinyl;

CA 02249~99 1998-09-22 W O 97/36593 PCT~US97/05144 X is -CH2- or -C(=O)-;

Z is unsubstituted Cl-C6 alkyl, substituted Cl-C6 alkyl, unsubstituted C3-C6 cycloalkyl or sub.stituted C3-C6 cycloalkyl,wherein the substituted Cl-C6 alkyl and substituted C3-C6 cycloalkyl is substituted with one or two of the following:
a) C 1 -4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) -NR6C(o)R7, e) HO, f) -S(o)mR6a~
g) halogen, or h) perfluoroalkyl;

mis 0, 1 or2;
nis 0, 1, 2, 3 or4;
pi.s 0, 1, 2, 3 or4;
r is O to ;~, provided that r is O when V is hydrogen;
s is O or 1 ;
tis Oorl;and uis 40r5;

25 provided that when G is H2 and W is imidazolyl, then the substitutent (R~)r- V - A 1 (CR 1 a2)nA2(CR 1 a2)n - is not H and provided that when X is -C(=O)-, or -S(=O)m-, then t is 1 and the substitutent (RP~)r- V - Al(CRla2)nA2(CRla2)n - is not H;
or the pharmaceutically acceptable salt.s thereof.

A preferred embodiment of the compounds of this invention are illu.~itrated by the formula C:

CA 02249~99 1998-09-22 W O 97136593 PCTr~S9710~144 (R8)r R9a V - A1(CR1a2)nA2(CR1a2)n N ~J N N-Z
(C R 1 b2)p X/

wherein:
R1a is selected from: hydrogen or Cl-C6 alkyl;
s R1b is independently ~selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, R l OO-, -N(R 1 0)2 or C2-C6 alkenyl, c) Cl-C6 alkyl unsub.stituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, or -N(R10)2;

R3 is selected from H and CH3;
~NR6R7 R2 is selected from H; O orCl S alkyl, unbranched or 15branched, unsubstituted or substituted with one or more of:
1) aryl, 2) heterocycle, 3) oR6, 4) SR6a, S02R7a, or 5) ~ N R6R7 O
and R2 and R3 are optionally attached to the same carbon atom;

R6 and R7 are independently selected from:
H; Cl 4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, 25unsubstituted or sub.stituted with:
a) C l 4 alkoxy, CA 02249~99 1998-09-22 W O 9713G593 PCTrUS97/05144 b) halogen, or c) aryl or heterocycle;

R6a is selected from:
Cl 4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1 4 alkoxy, b) halogen, or c) aryl or heterocycle;
R~ i.s independently selected from:
a) hydrogen, b) Cl-C6 alkyl, C2-C6 alkenyl, C2-c6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R 1 0O-, R 1 0C(o)NR 1 0-, CN, NO2, (R 1 0)2N C(NR 10), R 1 ~C(O)-, -N(R 1 ~)2, or R 1 1 OC(O)NR 10, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R10O-, Rloc(o)NRlo-~ (R10)2N C(NR10) RlO
-N(R 1~)2, or R 1 1 OC(O)NR 10;
R9a is hydrogen or methyl;

R10 is independently selected from hydrogen, Cl-c6 alkyl, benzyl and aryl;
Rl 1 is independently selected from Cl-C6 alkyl and aryl;

Al and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;
V is selected from:
a) hydrogen, CA 02249~99 1998-09-22 b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(O)m and V is not hydrogen 10 if Al i.sabond,n isOandA2isS(O)m;
X is -CH2- or-C(=O)-;

Z is unsubstituted Cl-C6 alkyl, substituted Cl-C6 alkyl, unsubstituted C3-C6 cycloalkyl or substituted C3-C6 cycloalkyl,wherein the substituted Cl-C6 alkyl and ~ubstituted C3-C6 cycloalkyl is .substituted with one or two of the following:
a) C1 4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) -NR6C(o)R7, e) HO, f) -s(o)mR
g) halogen, or h) perfluoroalkyl;

mis 0, 1 or2;
nis 0, 1, 2, 3 or4;
pis 0, 1, 2, 3 or4; and r is 0 to 5, provided that r is 0 when V is hydrogen;
or the pharmaceutically acceptable salts thereof.

CA 02249C,99 1998-09-22 In a more preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the forrnula D:
H

~N ~
/ N N - Z
<¦~ (CR 2)p X /2\ 3 wherein:

Rlb is independently .selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, R l OO-, -N(R 1 0)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, or-N(R10)2;

15 R3 is selected from H and CH3;
,,~ NR6R7 Il ;
R2 is selected from H; o or Cl 5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1 ) aryl, 2) heterocycle, 3) oR6, 4) SR6a, S02R7a, or 5) ~f NR6R7 and R2 and R3 are optionally attached to the same carbon atom;

25 R6 and R7 are independently selected from:

CA 02249~99 1998-09-22 W O 97136593 PCTrUS97/05144 H; Cl 4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsub,stituted or substituted with:
a) Cl 4 alkoxy, b) halogen, or c) aryl or heterocycle;

R6a is selected from:
C 1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with:
a) Cl 4 alkoxy, b) halogen, or c) aryl or heterocycle;

R~ is independently selected from:
a) hydrogen, b) Cl-c6 alkyl, C2-c6 alkenyl, C2-c6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R10O-, R10C(o)NR10-, CN, NO2, (R 1 0)2N-C(NR 10) , R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) Cl-C6 alkyl ,substituted by Cl-C6 perfluoroalkyl, R10O-, R 1 0C(o)NR 10, (R 1 0)2N-C(NR 10) R 1 ~C(O) -N(R 1~)2, or R 1 1 OC(O)NR 10;

R10 i~s independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl;

Rl 1 i~s independently selected from Cl-C6 alkyl and aryl;

X is -CH2- or-C(=O)-;
Z is unsubstituted Cl-C6 alkyl, substituted Cl-C6 alkyl, unsubstituted C3-C6 cycloalkyl or substituted C3-C6 cycloalkyl,wherein the substituted Cl-c6 alkyl and W O 97136593 PCTrUS97/05144 substituted C3-C6 cycloalkyl is substituted with one or two of the following:
a) C 1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) -NR6C(o)R7, e) HO, f) -S(O)mR6a, g) halogen, or h) perfluoroalkyl;

m is 0, 1 or 2; and pis 0, 1, 2, 3 or4;
15 or the pharmaceutically acceptable salts thereof.

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

H

N~,~y ' /~~
(CR1b2)p X ~/-\J

NC E
wherein:

Rlb is independently selected from:
a) hydrogen, b) aryl. heterocycle, cycloalkyl, RlOO-, -N(R10)2 or C2-C6 alkenyl, CA 02249~99 1998-09-22 c) Cl-C6 alkyl unsub.stituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R100-, or -N(R10)2;

R2 and R3 are independently selected from: hydrogen or Cl-C6 alkyl;
s R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;

Rl 1 is independently selected from Cl-C6 alkyl and aryl;
X i.'i -CH2- or -C(=O)-;

Z is unsubstituted Cl-C6 alkyl, substituted Cl-C6 alkyl, unsubstituted C3-C6 cycloalkyl or substituted C3-C6 cycloalkyl,wherein the substituted Cl-C6 alkyl and substituted C3-C6 cycloalkyl is substituted with one or two of the following:
a) CI 4 alkoxy, b) NR6R7, C) C3-6 cycloalkyl, d) -NR6C(o)R7, e) HO, f) -s(o)mR
g) halogen, or 2~ h) perfluoroalkyl;

m is 0, 1 or 2; and pis 0, 1, 2, 3 or4;

30 or the pharmaceutically acceptable salts thereof.

The preferred compounds of this invention are as follows:

CA 02249~99 1998-09-22 W O 97/36593 PCTrUS97/05144 - 2~ -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-[ 1-(3 ,3 ,3-S trifluoropropyl)]-piperazin-5-one dihydrochloride 2(S)-n-Butyl- 1-[1 -(4-cyanobenzyl)-5-imidazolylmethyl]-4-(cyclopropylmethyl)piperazin-5-one dihydrochloride and 2(S)-n-Butyl- 1 -[3-(4-cyanobenzyl)pyridin-4-yl]-4-(2,2,2-trifluoroethyl)piperazin-5-one dihydrochloride 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-(2,2,2-trifluoroethyl)piperazin-5-one dihydrochloride NCi ~ N N-CH2CF~

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 25 individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. When any variable (e.g. aryl, heterocycle, Rl, R2 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 30 permissible only if such combinations result in stable compounds.

CA 02249~99 1998-09-22 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 S 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 10 include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
The term heterocycle or heterocyclic, as used herein, repre.sents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or 15 unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the 20 creation of ~ .stable structure. Examples of .~uch heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, 25 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, 30 pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.

CA 02249~99 1998-09-22 W O 97/36593 PCT~US97tO~144 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 ~S consisting of N, O, 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 R2 and R3, the term "the substituted group" intended to mean a substituted Cl ~ alkyl, substituted C2 ~ alkenyl, substituted C2 X alkynyl, substituted aryl or substituted heterocycle from which the sub~stitutent(s) R2 and R3 are selected.
As u,sed herein in the definition of R6, R6a, R7 and R7a, the substituted Cl ~ 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 R2 and R3 are combined to form - (CH2)U -, cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to:

~ ~J

W O 97/36593 PCTrUS97/05144 In addition, such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include, but are not limited to:

~ ~J ~OJ ~S J

~ H O NJ

Lines drawn into the ring ~systems from substituents (such as from R2, R3, R4 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(R 1 0)2, R l OC(O)NR 1 0- or unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsub.stituted or substituted phenyl, -N(R10)2, R100- and R 1 ~C(O)NR 10 Preferably, R2 is selected from: H, ~NR6R7 ~oR6 ~ ~ and an unsubstituted or substituted group, the group selected from Cl ~ alkyl, C2 ~ alkenyl and C2 ~, alkynyl;
wherein the substituted group is substituted with one or more of:
I) aryl or heterocycle, unsubstituted or substituted with:
a) C 1-4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, 2) C3-6 cycloalkyl, 3) oR6, 6~93 PCTrUS97/05144 4) SR6a,S(o)R6a~s 02R6a 5) - N R6R7 F~6 6) --N~ R7 7) --N~ NR7R7a 8) --O~ NR6R7 9) --o~OR6 10) ~ NR6R7 1 1 ) --S02--NR6R7 ~6 12) --N-SO2--R

CA 02249~99 1998-09-22 o 1 4) oR6 ~r 15) N3, or 16) F

Preferably, R3 is selected from: hydrogen and Cl-C6 alkyl.
Preferably, R4 and RS are hydrogen.
S Preferably, R6, R7 and R7a is selected from: hydrogen, unsubstituted or substituted Cl-C6 alkyl, unsubstituted or substituted aryl and unsubstituted or sub.stituted cycloalkyl.
Preferably, R6a is unsubstituted or substituted Cl-C6 alkyl, unsubstituted or sub.stituted aryl and unsubstituted or substituted l 0 cycloalkyl.
Preferably, R9 is hydrogen or methyl. Most preferably, Ra is hydrogen.
Preferably, RlO is .selected from H, Cl-C6 alkyl and benzyl.
Preferably, Al and A2 are independently selected from:
bond, -C(O)NR l O, -NR l ~C(O)-, O, -N(R l O)-, -S(O)2N(R l O)- and-N(R l ~)S (O)2- -Preferably, V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.
Preferably, Z is unsubstituted or substituted C l -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 l, 2 or 3.
Preferably ~ is 0.
Preferably t is l.

CA 02249~99 1998-09-22 W O 97136593 PCTrUSg7/05144 It is intended that the definition of any substituent or variable (e.g., R1a, R9, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, S -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 10 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, e.g., from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those 15 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, 20 fumaric, toluenesulfonic, methanesulfonic, ethane di,sulfonic, 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.
25 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 ~ suitable solvent or various combinations of solvents.
Reactions used to generate the compounds of this invention 30 are prepared by employing reactions as shown in the Schemes 1-21, in addition to other standard manipulations such a~s ester hydroly.sis, 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 Scheme~;, represent the substituents R2, R3, R4, and R5;

CA 02249~99 l998-09-22 W O 97/36593 PCT~US97/05144 however their point of attachment to the ring is illustrative only and is not meant to be limiting. Substituent Z', 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.
S The~se reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragment,s which are subsequently joined by the alkylation reactions described in the Schemes.

Synopsis of Schemes 1-21:
The re4uisite intermediates are in some case~i commercially available, or can be prepared according to literature procedures, for the most part. In Scheme 1, for example, the synthesis of 2-aL~yl substituted piperazines is outlined, and is essentially that described by J.
1~ S. Kiely and S. R. Priebe in Or~anic Preparations and Proceedin~s Int.
1990, 22, 761-76~. Boc-protected amino acids I, available comrnercially 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-HCl (l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such as methylene chloride, chloroform, dichloroethane, or in dimethylforrnamide. 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 condition,s of hydrogenation, e.g., 10%
palladium on carbon at 60 psi hydrogen on a Parr apparatus for 24-48 h. The product VI can be 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 2). The interrnediate VII1 can it.self be reductively alkylated with a variety of aldehydes, such as IX. The aldehydes can be prepared CA 02249~99 1998-09-22 W O 97/36593 PCTrUS97/05144 by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Svntheses, 1988, 67, 69-75, from the appropriate amino acid (Scheme 3). The reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium 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 i.s isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among other.s. 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-imidazolyl-carboxaldehyde or l-trityl-4-imidazolylacetaldehyde, to give products such as XVI (Scheme 4). The trityl protecting group can be removed from XVl to give XVII, or alternatively, XVT 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 condensin~ reagents such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) leads to acylated products such as XXIV.
If the piperazine VIIl is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such a.s XXV in Scheme 6, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 6, 7). The alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then CA 02249~99 1998-09-22 W 097/36593 PCTrUS97/05144 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 7), or tertiary amines.
The Boc protected amino alcohol XXVII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as xxxn (Scheme ~). Treating XXVII with 1,1'-sulfonyldiimidazole and sodium hydride in a solvent such a~s dimethylformamide led to the formation of aziridine XXXII. The aziridine reacted in the presence of a nucleophile, such a~s a thiol, in the presence of base to yield the protected ring-opened product XXXIII.
In addition, the piperazine VIIl 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 fir~st 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 1, various side chains can be incorporated into the piperazine. For example when I is the Boc-protected ~-benzyl ester of aspartic acid, the intermediate diketopiperazine XLII (where n=l 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 XLrV 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.

CA 02249~99 1998-09-22 Piperazin-5-ones can be prepared as shown in Scheme 12.
Reductive ~min~tion 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 S 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 10 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 2-aminoglycinal diethyl acetal (LIII) can be reduced under a variety of conditions, including sodium triacetoxyborohydride in dichloroethane, 15 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 requi.site intermediate LVII, which is elaborated to final products as 20 described in Schemes 3-9.
Reaction Scheme 14 provides an illustrative example the synthesis of compounds of the instant invention wherein the substituents R2 and R3 are combined to form - (CH2)U -. For example, 1-aminocyclohexane-l-carboxylic acid LVIII can be converted to the 25 spiropiperazine LXVI essentially according to the procedures outlined in Scheme,s 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 30 well known in the art and readily available to provide other N-substituents on the piperazine.
The aldehyde XLIX from Scheme 12 can also be reductively alkylated with an alkyl amine as shown in Scheme 15. The product LXVIII can be converted to a piperazinone by acylation with CA 02249~99 1998-09-22 W O 97/36593 PCTrUS97/05144 chloroacetyl chloride to give LXIX, followed by base-induced cyclization to LXX. Deprotection, followed by reductive alkylation with a protected imidazole carboxaldehyde leads to LXXII, which can be alkylation with an arylmethylhalide to give the imidazolium salt 5 LXXIII. Final removal of protecting groups by either solvolysi,s with a lower alkyl alcohol, such as methanol, or treatment with triethylsilane in methylene chloride in the presence of trifluoroacetic acid givels the final product LXXTV.
Scheme 16 illu,strates the use of an optionally substituted 10 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 Isuitable nucleophile, such as the sodium 15 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 20 sidechain not found in natural amino acid.s may be prepared by the reactions illustrated in Scheme 17 Istarting with the readily prepared imine LXXXII.
Schemes 1~-21 illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the 25 variable W is present as a pyridyl moiety. Similar synthetic strategie~s for preparing alkanols that incorporate other heterocyclic moietie~s for variable W are allso well known in the art.

O Ra Rb >~0 N~ PhcH2NHcHco2c2Hs H o DCC, CH2Ci2 O Ra ~3 >~oJI' N~N~,CO2C2H5 H ~ Rb Ra 1) HCI, C H2CI2 R)~o LAH ~ HN N
~ HN N~ THF, reflux \ ( 2) NaHCO3 0 Rb ~ R

a Ra Boc2OrO~ \ 10% Pd/C ~~ )~
-~o < ~H2 CH~OH ~o V Vl NaBH(OAc)3 Ra~ ~ CICH2CH2CI
BocN NH Z'-ICl-H

Rb O
Ra )~ HCI, EtOAc BocN~N-CH2Z
Rb Vll HCI N ~N- CH2Z
Rb Vlll WO 97/36593 PCTrUS97/05144 Boc NH ~ IX
Ra Boc NH CHO
HCI N N- CH2Z' ~( NaBH (OAc)3 Rb Et3N, CIC
Vlll Boc NH ~ NyN-CH2Z' NHBoc Rb X
Ra Boc20 NH2 r N N- CH2Z
b C H2Cl2 Xl Ra~ ~ ~CHO
BocNH r N N-CH2Z' < bNaBH (OAc)3 NH2 R Et3N, CIC
Xll SCHEME 3 (continued) BocNH N N-CH2z~ CF3C~2H, CH2CI2;
~r y NaHco3 /=~ NH Rb ~/ Xlll Ra ) ~ ~NC
NH2 r N N-CH2Z' AgCN
=~ NH Rb ~/ XIV

Ra~ ~

~N N-CH2Z
b N~N~ R
~ XV
W

CA 02249599 l998-09-22 WO 97t36593 PCT/US97/0~144 SCHEl\/IE 4 a NaBH(OAC)3 R~ ~Et3N, CICH2CH2CI
HCI N N--CH2Z~ (CH2)ncHo Rb ~N5 Vlll Tr R,~ ~

(CH2)n ~ N ~N-CH2Z
N~ Rb Nl XVI
Tr 1 ) Ar C H2X, C H3CN
2) CF3CO2H, CH2CI~
CF3CO2H, CH2CI2 (C2H5)3siH
Ra (,5~H2)n+1N (N~CH2Z
Ntr Rb N
H XVII
Ra Ar (/CH2)n 1 N ~N-CH2z N~ Rb N XVIII

SCHEME ~

N~ 2CO2H C N.~CH2C02CH3 NH HCI NH . HCI
XIX XX
CH2C02CH3 1 ) ArCH2X CH3CN
(C6H5)3CBr ~ reflux (C2Hs)3N N 2) CH30H, reflux DMF Tr XXI

Ar~\N ;~CH2C02CH3 2.5N HCl N'~ 55~C
XXII

Af\N~CH2co2H

N
XXIII

W O 97/36593 PCTrUS97/05144 SCHEME 5 (continued) Ar~\N~CH2C02H R~ ~
N + HCI H NyN~CH2Z' XXIII Rb Vlll EDC HCI
HOBt DMF

Ar~ Ra~ ~
N~N N-CH2Z

XXIV
-~ BocNH CHO
HCI N N- CH2Z' \~ NaBH(OAc)3 Rb Et3N, CICH2CH2CI
Vlll Ra BnO N N-CH2Z' 20% Pd(OH)2 H2 \~ ~ CH30H
NHBoc ~ RbCH3CO2H
XXVI
Ra ~\ CICOCOCI
HO ~ N ~N- CH2Z' DMSO CH2C12 NHBoc Rb (C2Hs)3N
XXVII

WO 97136593 PCTrUS97/05144 - 4~ -SCHEME 6 (CONTINUED) Ra~ 1. R'MgX
09~ N~N - C H2Z
H NHBoc Rb CH2C12 XXVIII

HO~N <N-CH2Z
R' N H2 Rb XXIX

) \ CF3CO2H
HO ~N N-CH2Z
y --( CH2CI2 NHBoc Rb XXVII
Ra ~ R'CHO
HO ~N N-CH2Z~
y ~ NaBH(OAc)3 NH2 Rb CICH2CH2CI
XXX
Ra HOy~N ~N - CH2Z' NH Rb R'CH2 XXXI

W O 97/36593 PCTrUS9710S144 SCHEME

R a~ ~ ~ N~ S

H O ~ N ~ N- CH2Z ~2 NHBoc Rb NaH, DMF0~C
XXVI I

N N- CH2Z' R'SH
--( (C2H5)3N
N Rb CH30H
Boc XXXI I

) ~ TFA
R'S ~ N (N- CH2Z' N HBoc Rb XXXIII
Ra R'S ~N ~N- CH2Z
NH2 Rb CA 02249599 l998-09-22 HO~ 1) Boc20, K2C~3 HO,~3 ~/ THF-H20 , ~

H2N CO2H 2) CH2N2~ Et~AC gocNHJ\co2cH3 XXXIV XXXV

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

XXXVI

R'CH2O~ pyridine SO3 ) ~ 3 ~ DMSO
BocNH CH20H (C2H5)3N BocNH ~CHO
XXXVII XXXVIII

W O 97/36593 PCT~US97/05144 SCl IEME 9 (continued) R'C H ~ R a~ ~

+ HCI N ~N- CH2Z' BocNH CHO Rb XXXVIII Vlll NaB H (OAc)3 ~ Ra~ ~
R'C H20 N N - C H2Z' NHBoc Rb XXXIX \ HCI
ETOAc 1 ) 20% Pd(OH)2 CH30H, CH3CO2H /

2) HCI, EtOAc / ~ ~
R'CH20 ~ N N--CH2Z' N H2 Rb ~ Ra XLI

HO ~N N-CH2Z~
NH2 Rb n( ~~ 1) LAH, Et20 HN N 2) Boc20 0~ ~
XLII

HO~ R6l n( ~'~
O n( 5~ NaH DMF ~N N~

XLIV
XLIII

W O 97/36593 PCTrUS97/05144 Rb Z-NH2 + CI~J\ )2NH HCI
XLV Ra XLVI

Ra Rb n - butanol ~( Z-N NH HCI
reflux >~
Ra Rb XLVII

. .

W O 97/36S93 PCTrUS97/05144 55 _ O Ra CH3NHOCH3 HCI
>~O N~ EDC . HCI, HOBT
H o DMF, Et3N, pH 7 I

~O~N~N(CH3)0CH3 LAH, Et20 H O
XLVIII

>~O N~ Z-NH2 XLIX pH 6 O Ra 1) BrCH2COBr >~OJ~N~NH-Z EtOAc, H20, NaHC,03 H 2) NaH, THF, DMF
L

W O 97/36593 PCTrUS97/05144 SCHEME 12 (CONT'D) 1) TFA, CH2CI2 ~N N--Z
~0 ~
o Ll Ra ~.~
HN N-Z
o PCTrUS97/05144 NaBH(OAc)3 Z'-CHO + NH2cH2cH(oc2H5)2 Zl-cH2NHcH2cH(oc2H5~2 I H~
LIV EDC. HCI, HOBT
DMF, Et3N, pH 7 O Ra ~Z 6N HCI
>~OJ~ N ~N~,CH(Oc2H5)2 THF
H o LV

Ra o CH30H

~0 ~ Z' LVI
R a o ~0 --/ Z' LVII

- 5~ -r ul PhCH2NHCH2c02c2H5 ~ DCC, CH2CI2 BocNH C02H
LVIII
a) TFA, C H2CI2 BocNH~f N~Co2c2Hs b) NaHCO3 ~0 H2N~ N~Co2c2Hs (C H3)3AI
~u)~o HN N~ LiAlH4 HN N
o~J ~3 TH F ~/

LXI 1 \ LXII

Boc20 BocN N H2 Pd/C
CH2CI2 ~ CH30H

LXIII

SCHEME 14 (continued) 4~\ NaBH(OAc)3 ~ u~ CICH2CH2 BocN NH Z'- ICl - H
LXIV O
~, ~ u ~ a) TFA, CH2CI2 BocN~N- CH2Z b) NaBH(OAc)3 N~
LXV N
CPh3 ~N N-CH2Z' (C2H5)3siH
~N, CPh3 LXVI
~\
rN N- CH2Z' N ~

LXVI I

W O 97/36593 PCTrUS97/05144 R R H
BocNHlCHO NaBH(OAc)3 BocNH~N~

XLIX LXVIII

O R
Cl ~J~c I BocN H N--Z
EtOAc / H20 ~
NaHCO ~ Cl O
LXIX

NaH ) \ HCI
BocN N--Z
DMF \~ EtOAc o LXX

W O 97/36593 PCTrUS97/05144 SCHEME 15 (continued) CHO
N~3 R

HCI HN~N-Z ( )3 , N~ ~~
ONaBH(OAc)3 N
LXXI pH 5-6 (Ph)3C

LXXII

Ar~ N N-Z
ArCH2X N~ ~~
CH3CN ~ ~ O
,N ~3 ~3 (Ph)3C X

LXXIII

MeOH ~
or Ar~ rN N-Z
TFA, CH2CI ~ O
(c2H5)3siH N
LXXIV

W O 97/36S93 PCTrUS97/05144 sub\~o 1. Boc20, i-Pr2EtN ~0 H2N~ 2. DIBAL BocHN
HCI
LXXV OH
~/sub Z-NH2 ' BocNH~/N'Z
NaBH(OAc)3 HO sub O ~/~
CI~J~cl BocNH N- Z
EtOAc / H20 ~
NaHCO3 Cl O
LXXVII

HO sub ~I~
2 , BocN N - Z
DMF ~~
o LXXVIII
-WO 97/36~93 SCHEME 16 (continued) HO /sub BocN N--Z

~ 1. (COCI)2, Et3N
DMSO
1. MsCI, iPr2NE~ \ 2. NaCI02,t-BuOH
2-Me-2-butene 2. NaSEt,~ ~ NaH2PO4 HO sub EtS sub O/rl~
BocN N--Z
BocN N--Z ~
O O
LXXX
LXXIX

W O 97/36593 PCTrUS97/05144 1. KOtBu, THF R2 r CO2Et R2x ~ CO2Et rN ~ H2N
Ph 2. 5%aqueous HCI HCI
LXXXI

1. Boc20, NaHCO3 R2 ~ CO2H
BocHN
2. LiAlH4, Et20 LXXXII

REACTION SCHEME l ~

CH3 1) HNo27Br2 ~CO2CH3 ~ 2) KMnO
H2N N3) MeOH,H+ Br~N~

ZnC, N C ,~Ph,P)2CO2CH3 NaBH4 (excess) ~CH20H

DM50 ~J~CHO

RE~ACTION SCHEME 19 1. EtO(CO)CI R6 Br ~/\
Zn, CuCN ~CO2CH3 N 3. S, xylene, heat N

NaBH4 ~ SO3Py, Et3N ~
(excess) ~,CH20H DMSO ~CHO

Br~,CO2CH3 ~/\MgCI
N ~CO2CH3 ZnCI2, NiC12(Ph3P)2 N

NaBH4 I SO3Py, Et3N
~ CH20H ~ ~CHO
(excess) N DMSO N

W O 97/36S93 PCTrUS97/05144 Br~ 1. LDA, CO2 Br~

N2. MeOH, H+ N

R6 MgCI 1~ C~2CH3 ZnCI2, Nicl2(ph3p)2 N

~R6 NaBH4 (excess) ~ CH20H SO3 Py, Et3N
~ JJ DMSO
N

¢~ CHO

[~ 1. LDA, CO2 ~N,CBHr3 2. (CH3)3SiCHN2 R6 3/\Br R6 3~

Zn, NiCI2(Ph3P)y N~Co2cH3 R6 ~
excess NaBH4 1~1~ SO3 Py, Et3N
N~CH20H DMSO

R6. ~

N ~,CHO

CA 02249~99 1998-09-22 W O 97/36593 PCTrUS97/05144 The instant compounds are useful as pharmaceutical agents for m~mmals, especially for humans. These compounds may be ~llministered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compound~ of this S 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 (i.e., neurofibromin (NF-l), neu, scr, abl, lck, fyn) or by other mechanisms.
The compounds of the instant invention inhibit farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
The instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cance~ Research, 55:4575-45~0 (199~)). 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 (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accompli!ihed by the administration of an effective amount of the compounds of the invention to a m~mm;~l in need of such treatment. For example, a component of NF-l 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 (J.S. Glenn et al. Science, 256:1331-1333 ( I 992).
The compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. 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 (D.L. Schaffner et al.

CA 02249~99 1998-09-22 W O 97/36593 PCTrUS97/05144 American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Jol/rllal, 2:A3160 (198~)).
The instant compounds may also be useful for the treatment of fungal infections.
The compounds of this invention may be admini.stered to m~mm~ls, 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 a~ministration.
For oral use of a chemotherapeutic compound according to this invention, the selected compound may be ~ministered, for example, in the form of tablets or capsules, or as an a4ueous 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 ~lministration 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 emul,sifying 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 in.stant invention may also be co-~flministered with other well known therapeutic agents that are selected 30 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-l, restinosis, polycystic kidney .. . . .

CA 02249~99 1998-09-22 W O 97/36593 PCTrUS97J05144 disease, infection.s 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 S 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 al~so encompasses a pharmaceutical 10 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 ac3ueous solutions comprising compounds of this invention and pharmacolo-15 gically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. Thesolutions may be introduced into a patient's blood-stream by local bolus injection.
When a compound according to this invention is a~1mini~tered into a human subject, the daily dosage will normally be 20 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 ~dministered to a m~mm~l undergoing treatment for 25 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 30 as a component in an assay to rapidly determine the presence and 4uantity of farnesyl-protein transferase (FPTase) in a composition.
Thus the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine CA 02249~99 1998-09-22 W 097/36593 PCTrUS97/05144 terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to allow the FPTase to farnesylate the substrate, the chemical content of 5 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, ab.sence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant 10 invention relative to the pre~ience of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be te.sted.
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 15 tissue samples which contain farnesyl-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 20 of farnesyl-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 25 inhibitor (i.e., 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 in~ention. Particular materials employed, species CA 02249~99 1998-09-22 WO 97/36593 PCTIUS97tO5144 and conditions are intended to be further illustrative of the invention and not limitative of the reasonable .scope thereof.

2(S)-n-Butyl- 1 -[1 -(4-cyanobenzyl)-5-imidazolylmethyl 1-4-(2,2,2-trifluoroethyl)piperazin-5-one dihydrochloride NC ' ' ~ CH2CF3 L-7~6,017 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~C under nitrogen.
N-Methylmorpholine was added to obtain pH 7. The reaction was 20 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 ma nesium ~sulfate. The solvent was removed in vacuo to give the title compound.
Step B: 2(S)-(tert-Butoxycarbonylamino)hexanal A mechanically stirred suspension of lithium aluminum hydride (~S.00 g, 0.131 mol) in ether (250 mL) was cooled to -45~C
under nitrogen. A solution of the product from Step A (2~.3 g, 0.103 30 mol) in ether (125 mL) was added, maintainin~ the temperature below CA 02249~99 1998-09-22 W O 97136593 PCTrUS97/05144 -35~C. When the addition was complete, the reaction was warmed to 5~C, then recooled to -45~C. A solution of potassium hydrogen sulfate (27.3 g, 0.200 mol) in water was slowly added, maintaining the temperature below -5~C. After quenching, the reaction was stirred at room temperature for lh. 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)-(tert-butoxycarbonylamino)-hexanamine 2,2,2-Trifluoroethylamine hydrochloride (0.407 g, 3.0 mmol) wa.s dissolved in dichloroethane under nitrogen. N-Methyl 15 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 (~0 mL) was added slowly dropwi.se at 20~C. The reaction was stirred overnight, then quenched with saturated sodium 20 bicarbonate solution. The aqueou.s 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: l-tert-Butoxycarbonyl-2(S)-n-butyl-4-(2,2,2-trifluoroethyl)piperazin-5-one A solution of the product from Step C (0.590 g, 1.9~
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.
30 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.
C~esium 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 CA 02249~99 1998-09-22 was 4uenched with ~mminium 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: l -Triphenylmethyl-4-(hydroxymethyl)imidazole To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260 mmol) in 250 mL of dry DMF at room temperature was added triethylamine (90.6 mL, 650 mmol). A white 10 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 15 which was sufficiently pure for use in the next step.

Step F: I -Triphenylmethyl-4-(acetoxymethyl)-imidazole Alcohol from Step E (260 mmol, prepared above) was suspended in 500 mL of pyridine. Acetic anhydride (74 mL, 780 20 mmol) was added dropwise, and the reaction was stirred for 4~s hours during which it became homogeneous. The solution was poured into 2 L of EtOAc, washed with water (3 x 1 L), 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 25 isolated as a white powder which wa.s ~ufficiently pure for use in the next reaction.

Step G: 1-(4-Cyanobenzyl)-5-(acetoxymethyl)-imidazole hydrobromide A solution of the product from Step F (85.~ g, 225 mmol) and ~-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 CA 02249~99 1998-09-22 W O 97/36593 PCTrUS97/05144 concentrated 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 5 vacuo to provide a pale yellow solid. All of the solid material wa.s combined, dissolved in 500 mL of methanol, and warmed to 60 ~C.
After two hours, the solution was reconcentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble materials. Removal of residual solvents in vacuo provided the titled 10 product hydrobromide as a white solid which was used in the next step without further purification.

Step H: 1-(4-Cyanobenzyl)-5-(hydroxymethyl)-imidazole To a solution of the acetate from Step G (50.4 g, 150 15 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 L), and washed with water, sat. aq. NaHCO3 and brine. The solution was then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude 20 product as a pale yellow fluffy solid which was sufficiently pure for use in the next step without further purification.

Step I: 1 -(4-Cyanobenzyl~-5-imidazolecarboxaldehyde To a solution of the alcohol from Step H (21.5 g, 101 25 mmol) in 500 mL of DMSO at room temperature was added triethylamine (56 mL, 402 mmol), then SO3-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 a~i a white 30 powder which was sufficiently pure for use in the next step without further purification.

Step J: 2(S)-n-Butyl-1-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-4-(2,2.2-trifluoroethyl)-piperazin-5-one dihydrochloride CA 02249~99 1998-09-22 A solution of the product from Step D (0.57~s g, 1.71 mmol) wa,~ stirred in 30% trifluoroacetic acid in methylene chloride for 1 h. The volatile~ were removed in vacuo, and the residue dissolved in dichloroethane (5 mL). The pH wa~ adjusted to 5-6 with N-5 methylmorpholine. Sodium triacetoxyborohydride (0.544 g, 2.57mmol) and l-(4-cyanobenzyl)imidazolyl-5-carboxaldehyde from Step I
(0.361 g, 1.71 mmol) was added. The reaction was stirred overnight at 20~C then poured into saturated sodium bicarbonate ~solution. The organic phase wa~ washed with saturated brine and dried over 10 magne.~ium sulfate. The crude product was purified by preparative HPLC on a 40 X 100 mm Waters PrepPak(~) rever~e phase HPLC
column (Delta-PakTM Cl~ 15 lum, 100 A) using a gradient elution of 25% (0.1% TFA in acetonitrile), 75% (0.1% TFA in water) progressing to 45% (0.1% TFA in acetonitrile), 55% (0.1% TFA in water) over 50 15 min. Pure fraction~s were c-ombined, concentrated, and the re~iidue partitioned between ethyl acetate and saturated ~;odium bicarbonate ~olution. The organic layer was dried over magnesium sulfate. The purified product was converted to the hydrochloride salt with HCI in dichloromethane. The title compound was obtained as a white solid.
20 FAB ms (m+1) 434. Anal. Calc. for C22H26F3N5O 2.0 HCI: C, 52.1~; H? 5.57; N, 13.g3. Found: C, 52.41; H, 5.60; N, 13.65.

25 2(S)-n-Butyl- 1 -[1 -(4-cyanobenzyl)-5-imidazolylmethyl]-4-L 1 -(3,3,3-trifluoropropyl)l-piperazin-5-one dihvdrochloride ~=~ N~
N

CA 02249~99 1998-09-22 W O 97/36593 PCTrUS97/OS144 - 7~ -Step A: N- 1-(3 ,3 ,3 -Trifluoropropyl)-2(S)-(te7 t-butoxycarbonylamino)-hex~n~mine The title compound is prepared according to the procedure de.scribed in Example 1, Step C, except using 1-(3,3,3-5 trifluoropropyl)amine hydrochloride in place of 2,2,2-trifluoroethylamine hydrochloride.

Step B: 1 -te) t-Butoxycarbonyl-2(S)-n-butyl-4-L 1-(3,3,3-trifluoropropyl)lpiperazin-5 -one The title compound is prepared according to the procedure described in Example 1, Step D, except using N-1-(3,3,3-trifluoropropyl)-2(S)-~te7 t-butoxycarbonylamino)hexanamine in place of N-(2,2,2,-trifluoroethyl)-2(S)-(tert-butoxycarbonylamino)hexanamine.
Step C: 2(S)-n-Butyl-1-[1-(4-cyanobenzyl)-5-imidazolylrnethyl]-4-~1-(3,3~3-trifluoropropyl)lpiperazin-5-one dihydrochloride The title compound is prepared according to the procedure described in Example 1, Step J, except using l-~ert-butoxycarbonyl-20 2(S)-n-butyl-4-[1-(3,3,3-trifluoropropyl)~piperazin-5-one in place of 1-tert-butoxycarbonyl-2(S)-n-butyl-4-(2,2,2-trifluoroethyl)piperazin-5-one. The purified product is converted to the hydrochloride salt with HCl in dichloromethane.

2(S)-n-Butyl-1-[ 1 -(4-cyanobenzyl)-5-imidazolylmethyl]-4-(cvclopropylmethyl)piperazin-5-one dihydrochloride ..... ~

NC ------<~ --~--- ( --- N N-J

N

CA 02249~99 1998-09-22 W O97/36593 PCT~US97/05144 Step A: N-(Cyclopropylmethyl)-2(S)-(Iert-butoxycarbonylamino)-hexanamme The title compound is prepared according to the procedure 5 described in Example 1, Step C, except using cyclopropylmethylamine hydrochloride in place of 2,2,2-trifluoroethylamine hydrochloride.

Step B: l-tert-Butoxycarbonyl-2(S)-n-butyl-4-(cyclopropylmethyl)piperazin-5 -one The title compound is prepared according to the procedure described in Example 1, Step D, except using N-(cyclopropylmethyl)-2(S)-(tert-butoxycarbonylamino)hexanamine in place of N-(2,2,2,-trifluoroethyl)-2(S)-(tert-butoxycarbonylamino)hexanamine.
~5 Step C: 2(S)-n-Butyl-1-[ 1-(4-cyanobenzyl)-5-imidazolylmethyl]-4-(cyclopropylmethyl)piperazin-5-one dihydrochloride The title compound is prepared according to the procedure described in Example 1, Step J, except using l-tert-butoxycarbonyl-2(S)-n-butyl-4-(cyclopropylmethyl)piperazin-5-one in place of l-tert-20 butoxycarbonyl-2(S)-n-butyl-4-(2,2,2-trifluoroethyl)piperazin-5-one to obtain the title compound. The purified product is converted to the dihydrochloride salt with HCI in dichloromethane.

EXAMPL~ 4 2(S)-n-Butyl- 1 -[3-(4-cyanobenzyl)pyridin-4-yll-4-(2,2,2-trifluoroethvl)piperazin-5-one dihydrochloride NC ~ ~ N~ N- CH2CF3 N~

CA 02249~99 1998-09-22 W O 97/36593 PCTrUS97/05144 Step A: 3-(4-Cyanobenzyl)pyridin-4-carboxylic 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 5 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-4-carboxylic acid methyl ester (0.540 g. 2.5 mmol) followed by dichlorobis(triphenylphosphine)nickel (II) (50 mg). The resultant 10 reddish-brown mixture was stirred for 3 h at ~40-45~C. The mixture was cooled and di~stributed between ethyl acetate (100 ml) and 5%
aqueous citric acid (50 mL). The organic layer was washed with water (2X50 mL), dried with Na2SO4. After evaporation of the solvent the residue was purified on silica gel, eluting with 35% ethyl acetate in 15 hexane to give 0.420 g as a~clear gum. FAB ms (M+l) 253.

Step B: 3-(4-Cyanobenzvl)-4-(hydroxymethyl)pyridine The title compound was obtained by sodium borohydride (300 mg) reduction of the ester from Step A (0.415 g) in methanol (5 20 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+l ) 225.

25 Step C: 3-(4-Cyanobenzyl)-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 (lO mL) at reflux for 30 min. Filtration and evaporation of the solvent provided title compound, mp ~0-~3~C.
Step D: 3(S)-n-Butyl-1-[3-(4-cyanobenzyl)pyridin-~-yl]-4-(2,2,2-trifluoroethyl)piperazin-~S-one dihvdrochloride The title compound is prepared according to the procedure described in Example 1 Step J, except using 3-(4-cyanobenzyl)-4-CA 02249~99 1998-09-22 W O 97/36593 PCTrUS97/05144 pyridinal from Step C in place of 1-(4-cyanobenzyl)imidazolyl-5-carboxaldehyde. The purified product is converted to the dihydrochloride salt with HCl in dichloromethane.

In vitro inhibition of ras farnesyl transferase Assays of fa) nesyl-protein ~ ansfe7 ase. Partially purified bovine FPTa.se and Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) 10 were prepared as described by Schaber et ah, J. Biol. Chem. 265:14701-14704 (1990), Pompliano, et ah, Biochemistry 31:3~00 (1992) and Gibbs et ah, PNAS U.S.A. ~6:6630-6634 (1989), respectively. Bovine FPTase was assayed in a volume of 100 ~I containing 100 mM N-(2-hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 15 5 mM MgC12, 5 mM dithiothreitol (DTT), 100 mM [3H]-farnesyl diphosphate ([3H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM
Ras-CVLS and 10 ~g/ml FPTase at 31~C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol.
Precipitate.s were collected onto filter-mat,s using a TomTec Mach II cell 20 harvestor, washed with 100% ethanol, dried and counted in an LKB ,B-plate counter. The assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the [3H]-FPP was utilized during the reaction period. Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the 25 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 ah, 30 Biochemistry 32:5167-5176 (1993). Human FPTase activity was as.sayed a.s de.scribed above with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10 ~M ZnCI2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., CA 02249~99 1998-09-22 W O 97/36593 PCT~US97/05144 stopped with 100 ~l of 30% (v/v) 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 5 activity against human FPTase by the assay described above and were found to have IC50 of c50 ~M.

0 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 ah, Cancer Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75%
15 confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 37~C, the cells are labelled in 3 ml methionine-free DMEM supple-meted with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[35S]methionine (1000 Ci/mmol). After an additional 20 hours, the 20 cells are lysed in 1 ml lysis buffer (1% NP40t20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 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 25 buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et al., J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at 4~C, 200 ml of a 25% suspension of protein A-Sepharose coated with rabbit anti rat IgG
is added for 45 min. The immunoprecipitates are washed four times 30 with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1% Triton X-100Ø5% deoxycholate/0.1%/SDS/0.1 M NaCl) 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 CA 02249~99 1998-09-22 W O 97/36~93 PCTrUS97/05144 - ~3 -farne,sylated and nonfarne~sylated ras proteins are compared to determine the percent inhibition of farne~syl transfer to protein.

In vivo ~rowth 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 tran~sformed with either a V-1aS, v-raf; or V-m05 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 tran,sformation.
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 15 a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layers contain 0.1% methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay). The 20 cells are fed twice weekly with 0.5 ml of medium A cont:~ining 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 (29)

WHAT IS CLAIMED IS:

1. A compound which inhibits farnesyl-protein transferase of the formula A:

wherein:

R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

R2 and R3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsublstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, or , wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl, b) (CH2)p OR6, c) (CH2)p NR6R7, d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C1-4 alkyl, h) SR6a, S(O)R6a, SO2R6a 2) C3-6 cycloalkyl, 3) OR6, 4) SR6a, S(O)R6a, or SO2R6a 5) ~NR6R7, 6) , 7) , 8) , 9) , 10) , 11) ~SO2~NR6R7, 12) , 13) , 14) , 15) N3, 16) F, or 17) perfluoro-C1-4-alkyl; or R2 and R3 are attached to the same C atom and are combined to form -(CH2)u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;
R4 is selected from H and CH3;

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

R6, R7 and R7a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) ~SO2R11 , or g) N(R10)2; or R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or,substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) ~SO2R11 , or g) N(R10)2;

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

R9 is selected from:
a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, -S(O)2N(R10)-, -N(R10)S(O)2-, or S(O)m;
G is H2 or O;
V is selected from:
a) hydrogen, b) heterocycle.

c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;

W is a heterocycle;

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

Z is unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C3-C6 cycloalkyl or substituted C3-C6 cycloalkyl,wherein the sub.stituted C1-C6 alkyl and substituted C3-C6 cycloalkyl is substituted with one or two of the following:
a) C1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) -NR6C(O)R7, e) HO, f) -S(O)mR6a g) halogen, or h) perfluoroalkyl;

m is 0, 1 or2;
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 when G is H2 and W is imidazolyl, then the substitutent (R8)r-V-A1(CR1a2)n A2(CR1a2)n- is not H and provided that when X is -C(=O)-, or -S(=O)m-, then t is 1 and the substitutent (R8)r-V-A1(CR1a2)n A2(CR1a2)n - is not H;
or a pharmaceutically acceptable salt thereof.

2. A compound which inhibits farnesyl-protein transferase of the formula B:

wherein:

R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted or substituted C1-c6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-c6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10), CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

R2 and R3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, or , wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C1-4 alkyl, h) SR6a, S(O)R6a, SO2R6a, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6a, S(O)R6a, or SO2R6a, 5) -NR6R7, 6) , 7) , 8) , 9) , 10) , 11) ~SO2~NR6R7 , 12) , 13) , 14) , 15) N3, 16) F, or 17) perfluoro-C1-4-alkyl; or R2 and R3 are attached to the same C atom and are combined to form -(CH2)u- wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;
R4 is selected from H and CH3;

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

R6, R7 and R7a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, un.substituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) ~SO2R11 , or g) N(R10)2; or R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) -SO2R11 , or g) N(R10)2;

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

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, -S(O)2N(R10)-, -N(R10)S(O)2-, or S(O)m;
G is O;

V is selected from:
a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;
W is a heterocycle;
X is -CH2-, -C(=O)-, or -S(=O)m-;

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) NR6R7, c) C3-6 cycloalkyl, d) -NR6C(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 1;
t is 0 or 1; and u is 4 or 5;

or a pharmaceutically acceptable salt thereof.

3. The compound according to Claim 1 of the formula A:

wherein:

R1a is independently selected from: hydrogen or C1-C6 alkyl;

R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, R10O, -N(R10)2 or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R10O- and N(R10)2;

R3 and R4 are independently selected from H and CH3;

R2 is H; or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl, 2) heterocycle, 3) OR6, 4) SR6a, SO2R6a, or and any two of R2, R3, R4, and R5 are optionally attached to the same carbon atom;
R6, R7 and R7a are independently selected from:
H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with:
a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle;
R6a is selected from:
C1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle;

R8 is independently selected from:
a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10), R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R10C(O)NR10, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-;

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10), R10C(O)-, -N(R10)2, or R11OC(O)NR10, and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, 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) 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 A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;

G is H2 or O;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl. pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;

X is -CH2- or -C(=O)-;

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) NR6R7, c) C3-6 cycloalkyl, d) -NR6C(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;
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 when G is H2 and W is imidazolyl, then the substitutent (R8)r- V - A1(CR1a2)nA2(CR1a2)n - is not H and provided that when X is -C(=O)-, or -S(=O)m-, then t is 1 and the substitutent (R8)r- V - A1(CR1a2)nA2(CR1a2)n - is not H;
or a pharmaceutically acceptable salt thereof.

4. The compound according to Claim 1 of the formula C:

wherein:

R1a is selected from: hydrogen or C1-C6 alkyl;

R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, R10O-, -N(R10)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10O-, or -N(R10)2;

R3 is selected from H and CH3;

R2 is selected from H; or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl, 2) heterocycle, 3) OR6, 4) SR6a, SO2R7a, or 5) and R2 and R3 are optionally attached to the same carbon atom;

R6 and R7 are independently selected from:
H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with:
a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle;
R6a is selected from:
C1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle;

R8 is independently selected from:
a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-;

R9a is hydrogen or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, 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) 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 A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;
X is -CH2- or -C(=O)-;

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) NR6R7, c) C3-6 cycloalkyl, d) -NR6C(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; and r is 0 to 5, provided that r is 0 when V is hydrogen;

provided that when X is -C(=O)-, or -S(=O)m-, then t is 1 and the substitutent (R8)r- V - A1(CR1a2)nA2(CR1a2)n - is not H;

or a pharmaceutically acceptable salt thereof.

5. The compound according to Claim 1 of the formula D:

wherein:

R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, R10O-, -N(R10)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10O-, or -N(R10)2;

R3 is selected from H and CH3;

R2 is selected from H; or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl, 2) heterocycle, 3) OR6, 4) SR6a, SO2R7a, or 5) and R2 and R3 are optionally attached to the same carbon atom;

R6 and R7 are independently selected from:
H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with:
a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle;
R6a is selected from:
C1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle;

R8 is independently selected from:
a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10), R10C(O)-, -N(R10)2, or R11OC(O)NR10, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R10C(O)NR10, (R10)2N-C(NR10), R10C(O)-, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
X is -CH2- or -C(=O)-:

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) NR6R7, c) C3-6 cycloalkyl, d) -NR6C(O)R7, e) HO, f) -S(O)mR6a, g) halogen, or h) perfluoroalkyl;

m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof.

6. The compound according to Claim 1 of the formula E:

wherein:

R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, R10O, -N(R10)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10O-, or -N(R10)2;
R2 and R3 are independently selected from: hydrogen or C1-C6 alkyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
X is -CH2- or -C(=O)-;

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) NR6R7, c) C3-6 cycloalkyl, d) -NR6C(O)R7, e) HO, f) -S(O)mR6a, g) halogen, or h) perfluoroalkyl;

m is 0, 1 or 2; and p is 0, 1, 2, 3 or 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-[1-(3,3,3-trifluoropropyl)]-piperazin-5-one dihydrochloride 2(S)-n-Butyl-1-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-4-(cyclopropylmethyl)piperazin-5-one dihydrochloride and 2(S)-n-Butyl-1-[3-(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 or a pharmaceutically acceptable salt or optical isomer thereof.

9. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 1.

10. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 2.

11. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 3.

12. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 7.

13. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 9.

14. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 10.

15. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 11.

16. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12.

17. 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 A:

wherein:

R1a and R1b are independently selected from:
a) hydrogen, b) aryl. heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

R2 and R3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, or unsubstituted or substituted heterocycle, wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl, b) (CH2)p OR6, c) (CH2)p NR6R7, d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C1-4 alkyl, h) SR6a, S(O)R6a, SO2R6a, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6a, S(O)R6a, or SO2R6a, 5) ~N R6R7 , 6) , 7) , 8) , 9) , 10) , 11) ~SO2~NR6R7 , 12) , 13) , 14) , 15) N3, 16) F, or 17) perfluoro-C1-4-alkyl; or R2 and R3 are attached to the same C atom and are combined to form -(CH2)u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R4 is selected from H and CH3;

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

R6, R7 and R7a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) f) ~SO2R11 , or g) N(R10)2; or R6 and R7 may be joined in a ring;

R7 and R7a may be joined in a ring;

R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) -SO2R11 , or g) N(R10)2;

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

R9 is selected from:
a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, N3,-N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10) , CN, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, C(O)- -C(O)NR10, -NR10C(O)-, O, -N(R10), -S(O)2N(R10)-, -N(R10)S(O)2-, or S(O)m;
G is H2;

V is selected from:
a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;

W is imidazolyl;

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

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) NR6R7, c) C3-6 cycloalkyl, d) -NR6C(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 substitutent (R8)r- V - A1(CR1a2)nA2(CR1a2)n - is H;
or a pharmaceutically acceptable salt thereof.

18. 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:

wherein:

R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10;

R2 and R3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, or unsubstituted or substituted heterocycle, wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl, b) (CH2)p OR6, c) (CH2)p NR6R7, d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C1-4 alkyl, h) SR6a, S(O)R6a, SO2R6a, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6a, S(O)R6a, or SO2R6a 5) ~NR6R7 , 6) , 7) , 8) , 9) , 10) , 11) ~SO2~NR6R7 , 12) , 13) , 14) , 15) N3, 16) F, or 17) perfluoro-C1-4-alkyl; or R2 and R3 are attached to the same C atom and are combined to form -(CH2)u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R4 is selected from H and CH3;

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

R6, R7 and R7a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or.substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) ~SO2R11 , or g) N(R10)2; or R6 and R7 may be joined in a ring;

R7 and R7a may be joined in a ring;

R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) ~SO2R11 , or g) N(R10)2;

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

R9 is selected from:
a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10, -NR10C(O)-, O, -N(R10)-, -S(O)2N(R10)-, -N(R10)S(O)2-, or S(O)m;
G is H2 or O;

V is selected from:
a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;

W is a heterocycle;

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

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) NR6R7, c) C3-6 cycloalkyl, d) -NR6C(O)R7, e) HO, f) -S(O)mR
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 substitutent (R8)r- V - A1(CR1a2)nA2(CR1a2)n - is H;
or a pharmaceutically acceptable salt thereof.

19. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 9.

20. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 10.

21. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 11.

22. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12.

23. 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:

wherein:

R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R1OC(O)-, N3, -N(R10)2, and R11OC(O)-NR10;

R2 and R3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, or unsubstituted or substituted heterocycle, wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl, b) (CH2)p OR6, c) (CH2)p NR6R7, d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C1-4 alkyl, h) SR6a, S(O)R6a, SO2R6a, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6a, S(O)R6a, or SO2R6a, 5) ~NR6R7 , 6) , 7) , 8) , 9) , 10) , 11) ~SO2~NR6R7 , 12) , 13) , 14) , 15) N3, 16) F, or 17) perfluoro-C1-4-alkyl; or R2 and R3 are attached to the same C atom and are combined to form -(CH2)u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R4 is selected from H and CH3;

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

R6, R7 and R7a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) ~SO2R11 , or g) N(R10)2; or R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) ~SO2R11 , or g) N(R10)2;

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

R9 is selected from:
a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, -S(O)2N(R10)-, -N(R10)S(O)2-, or S(O)m;
G is H2;

V is selected from:
a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;
W is imidazolyl;
X is -CH2-, -C(=O)-, or -S(=O)m-;

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) NR6R7, c) C3-6 cycloalkyl, d) -NR6C(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 substitutent (R8)r- V - A1(CR1a2)nA2(CR1a2)n - is H;
or a pharmaceutically acceptable salt thereof.

24. 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:

wherein:

R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

R2 and R3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, or , wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C1-4 alkyl, h) SR6a, S(O)R6a, SO2R6a, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6a, S(O)R6a, or SO2R6a, 5) ~R6R7 , 6) , 7) , 8) , 9) , 10) , 11) ~SO2-NR6R7 , 12) , 13) , 14) , 15) N3, 16) F, or 17) perfluoro-C1-4-alkyl; or R2 and R3 are attached to the same C atom and are combined to form -(CH2)u- wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(CORl0)-;

R4 is selected from H and CH3;

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

R6, R7 and R7a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroaryl,sulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) ~SO2R11 , or g) N(R10)2; or R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) ~SO2R11 , or g) N(R10)2;

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

R9 is selected from:
a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently .selected from C1-C6 alkyl and aryl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, -S(O)2N(R10)-, -N(R10)S(o)2-, or S(O)m;
G is H2 or O;

V is selected from:
a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;
W is a heterocycle;
X is --C(=O)-, or -S(=O)m-;

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) NR6R7, c) C3-6 cycloalkyl, d) -NR6C(O)R7, e) HO, f) -S(O)m R6a, 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 substitutent (R8)r- V - A1(CR1a2)n A2(CR1a2)n - is H;

or a pharmaceutically acceptable salt thereof.

25. A method for treating neurofibromin benign proliferative disorder which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 9.

26. A method for treating blindness related to retinal vascularization which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 9.

27. 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 composition of Claim 9.

28. A method for preventing restenosis which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 9.

29. A method for treating polycystic kidney disease which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 9.