CA2249641A1

CA2249641A1 - Inhibitors of farnesyl-protein transferase

Info

Publication number: CA2249641A1
Application number: CA002249641A
Authority: CA
Inventors: Samuel L. Graham; John S. Wai; Theresa M. Williams
Original assignee: Individual
Current assignee: Merck and Co Inc
Priority date: 1996-04-03
Filing date: 1997-03-27
Publication date: 1997-10-09
Also published as: WO1997036605A1; AU2542597A; EP0897303A4; EP0897303A1; AU717190B2; JP2000508631A

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

, TITLE OF THE INVENTION
INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE

BACKGROUND OF THE INVENTION
S The Ras ~roteills (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP. Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change. The 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 D.M.
Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terrninus 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 (1984)). Depending on the specific sequence, this motif serves as a signal sequence for the enzymes farne.syl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C1s or C20 isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61 :355-3~s6 (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 farnesylation.

Other farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also 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 transformed phenotype. It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the Ras oncoprotein intracellularly (N.E. Kohl et al., Science, 260:1934-1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of ras-dependent tumors in nude mice (N.E. Kohl et al., Proc. Natl. Acad. Sci U.S.A., 91:9141-9145 (1994) and induces regression of 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 (1989)). 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, 62:81-88 (1990);
Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science, 249:1 133- 1139 (1990); Manne et al ., Proc. Natl. Acad . Sci USA, 87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane loc~li7~tion in cultured cells. However, direct inhibition of farnesyl-protein transferase would be more specific and attended by fewer side W 097/36605 PCTrUS97/04713 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 inhibitors is related to the protein substrates (e.g., Ras) for the enzyme. The peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ibid; Reiss et. al., i~id; Reiss et 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 5,141,851, 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 pharmacokinetics, 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-cont~ining inhibitors of farnesyl protein transferase have also 30 been disclosed (WO 95/09001 and EP 0 675 112 A l ).
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 post-translational farnesylation of proteins. It is a further object of this invention to W O 97/36605 PCT~US97/04713 develop chemotherapeutic compositions cont~ining the compounds of this invention and methods for producing the compounds of this invention.

The present invention comprises peptidomimetic piperidinone-cont~ining compounds which inhibit the farnesyl-protein transferase. The instant compounds lack a thiol moiety and thus offer unique advantages in terms of improved pharrnacokinetic behavior in 10 ~nim~l~, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions cont~inin~ these farnesyl transferase inhibitors and methods for their production.
The compounds of this invention are illustrated by the formulae A, B and C:

R8)r /(~ ~ ~ Y~ G
V - A1 (C R 1 a2)nA2(C R 1 a2)n ~W ~ - (C R 1 b2)p~X~N )~

(R8), ~9)\ G1 R4G2 V - A1(CR1a2)nA2(cR1a2)n ~W/- (CR1b2)p~ ~ ~N--Z

CA 0224964l l998-09-22 W O 97/36605 PCTnUS97/04713 ( I ), (~9) Gl R3 V - A1(CR1a2)nA2(CR1a2)n ~W~ - (CR1b2)p~ ~ /N--Z

R

DETAILED DESCRIPTION OF THE rNVENTION
The compounds of this invention are useful in the inhibition 5 of farnesyl-protein transferase and the farnesylation of the oncogene protein Ras. In a first embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula A:

( l 8)r (/R9~ R2 V - A1 (C R1 a2)nA2(CR 1 a2)n \W ~ (CR1 b2)p\~N ,~

A

wherein:
Rla and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R100-, Rl lS(O)m-, RlOC(O)NR10-, (R10)2N-C(O)-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) unsubstituted or substituted Cl-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C1o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R 1 1 S(O)m-~ R 1 0C(O)NR 10, (R 1 0)2N-C(O)-, CN, W O 97136605 PCT~US97tO4713 (R 1 0)2N-C(NR 10), R 1 ~C(O)-, N3, -N(R 1~)2, and K 1 1 OC(O) NR10;

R2 and R3 are independently selected from: H; unsubstituted or 5 substituted Cl p~ alkyl, unsubstituted or substituted C2 ~ alkenyl, unsubstituted or substitu~ed C2-8 alkynyl, unsubstituted or substituted aryl, ~NR6R7 and ~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) C14alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C 1 -4 alkyl, h) SR6a, s(o)R6a~ S02R6a, 2) C3-6 cycloalkyl, 3) oR6, 4) SR6a, S(o)R6a~ or So2R6a 5) --N R6 R7 6) ~6 --N~ NR7R7a o 8) --O~ NR6R7 o 9) O~OR
o 10) ~ NR6R7 11 ) --S02--N R6R7 ~6 12) --N--SO2--R

13) R6 ~r 1 4) oR6 1 5) N~, 16) F, or 17) perfluoro-C1 4-alkyl; or 5 R2 and R3 are attached to the same C atom and are combined to form -(CH2)U - wherein one of the carbon atoms is optionally replaced by a moiety selected *om: O, S(O)m, -NC(O)-, and -N(COR10)-;

R4 and R5 are independently selected from H and CH3;
and any two of R2, R3, R4 and R5 are optionally attached to the - same carbon atom;

R6, R7 and R7a are independently selected from: H; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl and heteroarylsulfonyl, unsubstituted or substituted with:
a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, nl1 e) o f) --SO2R1 ~ , or g) N(R 1~)2; or R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

R6a is selected from: Cl 4 alkyl, C3-6 cycloalkyl, heterocycle and aryl,~5 unsubstituted or substituted with:
a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) ~R'1 f) --SO2R1 ~ , or g) N(R 1~)2;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, R l 1 S(O)m R10C(O)NR10-, (Rl0)2Nc(o)-~ R102N-C(NR10)-, CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 1 0 , and c) Cl-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-Clo cycloalkyl, C2-C6 S alkenyl, C2-c6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, Rl lS(O)m-, RlOC(O)NH-, (RlO)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) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R100-, RllS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~
R102N-c(NRlo)-~ CN, NO2, R10C(O)-, N3, -N(R10)2, or Rl lOC(O)NR10-, 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(R 1~)2, or R 1 1 OC(O)NR 10-;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl;

Rl 1 is independently selected from Cl-C6 alkyl and aryl;
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(0)2- and S(O)m;

30 G 1 and G2 are independently oxygen or absent, provided that at least one of G 1 and G2 is oxygen;

G3 is oxygen or H2;

WO 97/36605 PCTtUS97/04713 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 heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al isabond,n isOandA2i~sS(O)m;
W is a heterocycle;

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

Y is unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or more of:
1 ) Cl 4 alkyl, unsubstituted or substituted with:
a) Cl 4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR6a, or g) -C(o)NR6R7, 2) aryl or heterocycle, 3 ) halogen, 4) oR6, 5) NR6R7, 6) CN, 7) NO2, 8) CF3;

9) -S(O)mR6a 10) -C(o)NR6R7, or 11) C3-C6 cycloalkyl;

mis 0, 1 or2;
S nis 0, 1, 2, 3 or4;
pis 0, 1, 2, 3 or4;
q is 1 or 2;
r is O to S, provided that r is O when V is hydrogen;
sis Oor 1;
tis Oorl;and uis 40rS;
or the pharmaceutically acceptable salts thereof.

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

/ \ R2 (R8)r ,(79, G~ 4,G2 V - A1(CR1az)nA2(CR1a2)n -\W/- (CR1b2)p\ ~ JN--Z

B

wherein:
R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, R100-, RllS(O)m-, RlOC(O)NR10-, CN(R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, N02, R 1 OC(O)-, N3, -N(R 1 0)2, or R l 1 OC(O)NR 1 0-, and - c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted Cl-C6 alkyl is selected from W O 97136605 PCT~US97tO4713 unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R1OO-, Rl lS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~ R102N-C(NR10), CN, R1OC(O)-, N3, -N(R10)2, and R llOC(O)-NRlO;

R2 and R3 are independently selected from: H; unsubstituted or substituted C1 8 alkyl, unsubstituted or substituted C2 8 alkenyl, unsubstituted or substituted C2 g alkynyl, unsubstituted or substituted aryl, ~NR6R7 and ~oR6 unsubstituted or substituted heterocycle, ~ O
wherein the substituted group i,s substituted with one or more of:
1 ) aryl or heterocycle, unsubstituted or substituted with:
a) Cl 4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, e) CN, f) aryl or heteroaryl, g) perfluoro-C 1-4 alkyl, h) SR6a, s(o)R6a~ So2R6a 2) C3-6 cycloalkyl, 3) oR6, 4) SR6a, S(O)R6a~ or S02R6a 6) --N~ R7 7) --N~ NR7R7a 8) --O~ NR6R7 9' --~b'0R6 10) ~ NR6R7 11 ) --S02--N R6R7 12) --N--SO2--R6a o o 1 5) N3, 16) F, or 17) perfluoro-C1 4-alkyl; or W O 97t36605 PCT~US97/04713 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)-;
s 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; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl and heteroarylsulfonyl, unsubstituted or substituted with:
a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) ~R
o f) --SO2R1 1 , or g) N(R 1~)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 and aryl,~5 unsubstituted or substituted with:
a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, W 0 97/36605 PCT~US97/04713 o f) --SO2R1 1 , or g) N(R10)2;

R8 is independently selected from:
S a) hydrogen, b) aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RllS(O)m-, Rl0c(o)NRlo-~(Rlo)2Nc(o)-~Rlo2N-c(NRlo)-~cN~
NO2,Rl0c(o)-~N3~-N(Rlo)2~ or RllOC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R100-, RllS(O)m-,R10C(O)NH-~(Rl0)2Nc(o)-~Rlo2N
C(NR10)-,CN,R10C(O)-, N3,-N(R 1~)2, or lS R10OC(O)NH-;

R9is selected from:
a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R100-, Rl lS(O)m-, RlOC(O)NR1O-, (RlO)2Nc(o)-t R102N-C(NRl0)-~cN~No2~Rloc(o)-~ N3,-N(R10)2,or RllOC(O)NR10-, and c) Cl-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(O)m-, RlOC(O)NR10-, (Rl0)2Nc(o)-~Rlo2N-c(NRlo)-~cN~Rloc(o)-~N
-N(R10)2, or Kl lOC(O)NR10-;

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

WO 97t36605 PCTIUS97/04713 ~1 and A2 are independently selected from: a bond, -CH=CH-, -C-C-, -C(O)-, -C(O)NR10-, -NR 10c(O)-, o, -N(R 10), -S(O)2N(R10)-, -N(RlO)S(O)2- and S(O)m;
s G 1 and G2 are independently oxygen or absent provided that at least one of Gl and G2 is oxygen;

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 A 1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(O)m;

W is a heterocycle;

X is a bond, -cH2-~ -C(=O)-, or -S(=O)m-;

Z is selected from:
1) a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
a) Cl 4 alkyl, unsubstituted or substituted with:
C 1-4 alkoxy, NR6R7, C3-6 cycloalkyl, aryl, heterocycle, HO, -S(O)mR6a, or -C(o)NR6R7, b) aryl or heterocycle, c) halogen, d) oR6~

W O 97/36605 PCTrUS97/04713 e) NR6R7, f) CN, g) N02, h) CF3;
i) -S(O)mR6a, j) -C(o)NR6R7, or k) C3-C6 cycloalkyl; and 2) 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) C 1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) -NR6C(o)R7, e) H0, f) -s(o)mR
g) halogen, or h) perfluoroalkyl;

mis 0, 1 or2;
n is 0, 1 , 2, 3 or 4;
pis 0, 1, 2, 3 or4;
qis 1 or 2;
r is 0 to S, provided that r is 0 when V is hydrogen;
s is 0 or 1;
t is 0 or 1; and uis 40rS;
or the pharmaceutically acceptable salts thereof.

ln a third embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula C:

W O 97/36605 PCT~US97/04713 ( l 8)r (R9;~ /
V - A1 (CR1a2)nA2(CR 1 a2)n ~W/ - (CR1 b2)p\ ,~' N--Z
G ~O

wherein:

Rla and Rlb are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, RlOO-, Rl lS(O)m-, RlOC(O)NR10-, (R10)2Nc(o)-~ R102N-C(NR10)-, CN, NO2, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or Rl lOC(O)NR10-, and 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-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R l Oo, RllS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~ R102N-C(NR 10), CN, R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10;

R2 and R3 are independently selected from: H; unsubstituted or substituted Cl g alkyl, unsubstituted or substituted C2 ~ alkenyl, unsubstituted or substituted C2 8 alkynyl, unsubstituted or substituted aryl, ~NR6R7 and ~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, PCTtUS97/04713 WO 97t36605 - e) CN, f) aryl or heteroaryl, g) perfluoro-C1 4 alkyl, h) SR6a, s(o)R6a~ So2R6a S 2) C3-6 cycloalkyl, 3) oR6, 4) SR6a, S(O)R6a~ or S02R6a 5) --NR6R7 F~6 6) o --N NR7R7a 8) ~

9) --o~OR6 10)~ NR6R7 11 )--SO2--N R6R7 ~6 - 10 12)N--SO2--R

W O 97/36605 PCTrUS97/04713 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 S 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 and heteroarylsulfonyl, unsubstituted or substituted with:
a) Cl 4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, o f) --SO2R1 1 , or g) N(Rl0)2; or R6 and R7 may be joined in a ring;

W O 97/36605 PCTrUS97/04713 R7 and R7a may be joined in a ring;
-R6a is selected from: Cl 4 alkyl, C3-6 cycloalkyl, heterocycle and aryl, unsubstituted or substituted with:
a) Cl 4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) "R1' o f) --SO2R , or g) N(R 1~)2;

R8 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-, Rl0c(o)NRlo-~(Rlo)2Nc(o)-~Rlo2N-c(NR I ~)-7 CN, NO2,Rl0c(o)-~N3~-N(Rlo)2~ or Rl lOC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R100-, RllS(O)m-,R10C(O)NH-~(Rl0)2Nc(o)-~Rlo2N

C(NR10)-,CN,R10C(O)-, N3,-N(R10)2, or R100C(O)NH-;

R9is selected from:

a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, Rl00,Rlls(o)m-~Rloc(o)NRlo-~(Rlo)2Nc(o)-~

R102N-c(NRlo)-~cN~No2~Rloc(o)-~ N3,-N(R10)2, or RllOC(O)NRl0-~ and CA 0224964l l998-09-22 W O 9713660~ PCT~US97/04713 c) Cl-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, Rl 1S(O)m-, R10C(O)NR10-, (R10)2Nc(o)-~ R 102N-C(NR 10), CN, R10C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10;
s R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl;

Rl 1 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)NR 10-, -NR 1 ~C(O)-, O, -N(R 10 -S(O)2N(R10)-, -N(Rlo)s(o)2- and S(O)m;

15 Gl and G2 are independently oxygen or absent, provided that if Gl is oxygen then G2 is absent and if s=0, G 1 is oxygen;

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

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

Z is selected from:

W 0 97/36605 PCTnJSg7/04713 1) a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
S a) Cl 4 alkyl, unsubstituted or substituted with:
Cl 4 alkoxy, NR6R7, C3-6 cycloalkyl, aryl, heterocycle, HO, -S(O)mR6a, or -C(o)NR6R7, b) aryl or heterocycle, c) halogen, d) OR6, e) NR6R7, f) CN, g) NO2, h) CF3;
i) -S(O)mR6a, j ) -C(o)NR6R7, or k) C3-C6 cycloalkyl; and 2) 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) 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;

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

CA 0224964l l998-09-22 W 097l36605 PCTnUS97/04713 q is 1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
SlS l;
t is 0 or 1; and uis 4 orS;
or the pharmaceutically acceptable salts thereof.

In a preferred embodiment of this invention, the inhibitors 10 of farnesyl-protein transferase are illustrated by the formula B:

( lR8)r /F~9~ G1 4 2 V ~ A1(CRla2)nA2(CRla2)n ~\W~~ (CRlb2) ~ ~ N--Z

B

wherem:

Rla is independently selected from: hydrogen and Cl-C6 alkyl;

R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, R l OO-, -N(R 1 0)2 or C2-C6 alkenyl, and c) unsubstituted or substituted Cl-C6 alkyl wherein the substitutent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R l OO- and -N(R 1 0)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) heterocycle, 3) oR6, 4) SR6a, SO2R6a, or 5) N R6R7 Il ;
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, aryl and heterocycle, unsubstituted or substituted with:
a) C 1 4 alkoxy, b) halogen, or c) aryl or heterocycle;

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

25 R8 is independently selected from:
a) hydrogen, b) C1-C6 alkyl, C2-c6 alkenyl, C2-c6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R100-, RlOC(O)NR10-, CN, N02, (R 1 0)2N-C(NR 10) , R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and W O 97/36605 PCT~US97/04713 c) Cl-C6 alkyl substituted by C1-C6 perfluoroalkyl, R1OO-, RlOC(o)NRlo-~ (R10)2N-C(NR10)-, RlOC(O)-, -N(R10)2, or Rl lOC(O)NR10-;

S R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, 1:;, Cl, R100-, R 1 1 S(O)m-, R 10C(O)NR 10, CN, N02, (R 1 0)2N C(NR 1 0) , R 1 ~C(O)-, -N(R 1 ~)2, or Rl1OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, RlOO-, R1 lS(O)m-, R1OC(O)NR10-, CN, (R 1 0)2N-C(NR 1 0)-, R 10C(o)-, -N(R 1 0)2, or R l l Oc(O)NR 10;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl;

Rl 1 is independently selected from Cl-C6 alkyl and aryl;
Al and A2 are independently selected from: a bond, -CH=CH-, -C-C-, -C(O)-, -C(O)NR10-, O, -N(R10)- and S(O)m;

V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indo}yl, quinolinyl, isoquino}inyl, and thienyl, c) aryl, d) C 1 -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 if Al isabond,n isOandA2isS(O)m;

Gl is absent;
G2is oxygen;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl and isoquinolinyl;
X is -CH2- or -C(=O)-;

Z is selected from:
1 ) a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group i~s substituted with one or more of the following:
a) Cl 4 alkyl, unsubstituted or substituted with:
Cl 4 alkoxy, NR6R7, C3-6 cycloalkyl, aryl, heterocycle, HO, -S(O)mR6a, or -C(o)NR6R7, b) aryl or heterocycle, c) halogen, d) oR6, e) NR6R7, f) CN, g) N02, h) CF3;
i) -S(O)mR6a j) -C(o)NR6R7, or k) C3-C6 cycloalkyl; and 2) 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 CA 0224964l l998-09-22 W O 97/36605 PCTrUS97/04713 C3-C6 cycloalkyl is substituted with one or two of the following:
a) C 1-4 alkoxy, b) NR6R7 S 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;
r is 0 to 5, provided that r is 0 when V is hydrogen;
sis 0 or 1;
t is 0 or 1; and u is 4 or 5;

20 or the pharmaceutically acceptable salts thereof.

A preferred embodiment of the compounds of this invention are illustrated by the formula D:

( IR8)r R9~
V - A1(CR1a2)nA2(CR1a2~N \J ~,\~N--Z

(CR1b ) X R/3-\/4 25 wherein:

Rla is selected from: hydrogen and C1-C6 alkyl;

R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 1 OO-, -N(R 1 o)2 or C2-C6 alkenyl, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R1OO-, or-N(R10)2;

R3 and R4 independently selected from H and CH3;

Il ;
R2 is selected from H; O and Cl 5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1 ) aryl, 2) heterocycle, 3) oR6, 4) SR6a, SO2R6a, or 5) ~ NR6R7 O
and R2, R3 and R4 are optionally attached to the same carbon atom;

R6 and R7 are independently selected from:
H; C1 4 alkyl, C3-6 cycloalkyl, aryl and heterocycle, unsubstituted or substituted with:
a) C 1 4 alkoxy, b) halogen, or c) aryl or heterocycle;
R6a is selected from:
Cl 4 alkyl and C3-6 cycloalkyl, unsubstituted or substituted with:
a) Cl 4 alkoxy, b) halogen, or c) aryl or heterocycle;

W O 97/3660S PCTnUS97/04713 R8 is independently selected from:
a) hydrogen, b) Cl-C6 alkyl, C2-c6 alkenyl, C2-c6 alkynyl, C1-C6 S perfluoroalkyl, F, Cl, R 1 0O-, R 1 0C(O)NR 1 0-, CN, NO2, (R10)2N C(~R10), R10C(O), -N(R10)2, or R 1 1 OC(O)NR 10, and c) C1-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(R10)2, or Rl lOC(O)NR10-;

R9a is hydrogen or methyl;

R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl and 1 5 aryl;

R l 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)- and 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) 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 if Al isabond,n is0andA2 isS(O)m;

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

Z is selected from:
1 ) a unsubstituted or substituted group selected from aryl, S heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
a) Cl 4 alkyl, unsubstituted or substituted with:
Cl 4 alkoxy, NR6R7, C3-6 cycloalkyl, aryl, heterocycle, HO, -S(O)mR6a, or-C(O)NR6R7, b) aryl or heterocycle, c) halogen, d) oR6, e) NR6R7, f) CN, g) NO2, h) CF3;
i) -S(O)mR6a, j) -C(o)NR6R7, or k) C3-C6cycloalkyl; and 2) 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) 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;

W O 97136605 PCT~US97/04713 m is 0, 1 or 2;
nis 0, 1, 2, 3 or4;
p is 0, 1, 2, 3 or 4; and r is 0 to 5, provided that r is 0 when V is hydrogen;
s or the pharmaceutically acceptable salts thereof.

In another preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula 10 E:

R2 o r \ \J ~N--Z
~;~ (CR 2)p X /3\ 4 wherein:

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

R3 and R4 independently selected from H and CH3;

~ NR6R7 R2 is selectedfrom H; O and Cl 5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1 ) aryl, 2) heterocycle, W O 97/36605 PCTrUS97/04713 3 ) oR6, 4) SR6a, SO2R6a, or 5) ~ NR6R7 o and R2, R3 and R4 are optionally attached to the same carbon S atom;

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

R6a is selected from:
Cl 4 alkyl and C3-6 cycloalkyl, unsubstituted or substituted with:
a) C l 4 alkoxy, b) halogen, or c) aryl or heterocycle;
R8 is 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 l 0)2N-C(NR 10) , R l ~C(O)-, -N(R 1~)2, or KllOC(O)NRl0-~ and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, Rl0O-, RlOC(o)NRlo-~ (Rlo)2N-c(NRlo)-~ RlOC(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl;

W 097/36605 PCTrUS97104713 Rl 1 is independently selected from Cl-C6 alkyl and aryl;

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

S Z is selected from:
1) a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
a) Cl 4 alkyl, unsubstituted or substituted with:
C1 4 alkoxy, NR6R7, C3-6 cycloalkyl, aryl, heterocycle, HO, -S(O)mR6a, or -C(o)NR6R7, b) aryl or heterocycle, c) halogen, l S d) OR6, e) NR6R7, f) CN, g) N02, h) CF3;
i) -S(O)mR6a, j) -C(o)NR6R7, or k) C3-C6 cycloalkyl; and 2) 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) 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;

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

In another preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula F:

(CR 2)p X /;\
NC F
wherein:

Rlb is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, R l OO-, -N(R l O)2 or C2-C6 alkenyl, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, Rl0O-, or -N(Rl0)2;

R3 and R4 independently selected from H and CH3;
~NR6R7 R2is selected from H; O and C1 5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1 ) aryl, 2) heterocycle, W 0 97/36605 ' rCTAUS97/04713 3) oR6, 4) SR6a, S02R6a, or 5) ~ N R6R7 o and R2, R3 and R4 are optionally attached to the same carbon S atom;

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

R6a is selected from:
lS Cl 4 alkyl and C3-6 cycloalkyl, unsubstituted or substituted with:
a) C l 4 alkoxy, b) halogen, or c) aryl or heterocycle;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl;

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

Z is selected from:
1) a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
a) Cl 4 alkyl, unsubstituted or substituted with:

Cl 4 alkoxy, NR6R7, C3-6 cycloalkyl, aryl, heterocycle, HO, -S(O)mR6a, or -C(o)NR6R7, b) aryl or heterocycle, c) halogen, d~ oR6, e) NR6R7, f) CN, g) NO2, h) CF3;
i) -S(O)mR6a, j) -C(o)NR6R7, or k) C3-C6 cycloalkyl; and 2) 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) 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;

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

30 or the pharmaceutically acceptable salts thereof.

Examples of the compounds of this invention are as follows:

W 097/36605 PCT~US97104713 4- [5 -(4-Cyanobenzyl)imidazol- 1 -ylmethyl] -1 -phenyl-2-piperidinone 4-[2- { 5-(4-Cyanobenzyl)imidazol- 1 -yl } ethyl]- 1 -phenyl-2-piperidinone 4-~2- { 1 -(4-Cyanobenzyl)-5-imidazolyl } ethyl 1-1 -phenyl-2-piperidinone (+)cis- 4-[2- { l -(4-Cyanobenzyl)-5-imidazolyl } ethyl]-3-methyl- l -phenyl -2 -piperidinone 0 (+)trans- 4-[2- { 1 -(4-Cyanobenzyl)-5-imidazolyl } ethyl]-3 -methyl- l -phenyl-2-piperidinone 4-[2- { 1 -(4-Cyanobenzyl)-5-imidazolyl } carbonyl]- l -phenyl-2-piperidinone and Ethyl 1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-oxo-4-(3-methylbenzyl)piperidine-4-carboxylate or a pharmaceutically acceptable salt or optical isomer thereof.
The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. When any variable (e.g. aryl, heterocycle, R1, 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 permissible only if such combinations result in stable compounds.
As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. "Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.

WO 97/3660~ PCTIUS97/04713 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 nng is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, 5 phenanthryl, anthryl or acenaphthyl.
The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four 10 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 creation of a stable structure. Examples of such heterocyclic elements 15 include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, 20 imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, 25 pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.
As used herein, "heteroaryl" is intended to mean any stable 30 monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, 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, 5 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 C1 8 alkyl, substituted C2 8 alkenyl, substituted C2 8 alkynyl, substituted aryl or substituted heterocycle from which the substitutent(s) R2 and R3 are selected.
As used herein in the definition of R6, R6a, R7 and R7a, the substituted C1 8 alkyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroarylsulfonyl and substituted heterocycle include moieties containing from 1 to 3 substitutents in addition to the point of attachment to the rest of the compound.
As used herein in the definition of R 1 a and Rlb, the term substituted aryl includes moieties cont~ining from 1 to 3 substitutents in addition to the point of attachment to the rest of the compound.
Preferably, such substitutents are selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2~ N(cl-c6 alkyl)2 NO2, CN, (C1-C6 alkyl)O-, -OH, (cl-c6 alkyl)s(o)m-~ (Cl-C6 alkyl)C(O)NH-, H2N-c(NH)-~ (cl-c6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)-, N3,(C1-C6 alkyl)OC(O)NH-, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl and Cl-C20 alkyl.
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:

'~.

In addition, such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-cont~ining cyclic moieties include, but are not limited to:

~J ~ ~OJ ~S J

~ H O NJ
~ CORl~
Lines drawn into the ring systems from substituent.s (such as from R2, R3, R4 etc.) mean that the indicated bond may be attached to any of the substitutable ring carbon atoms. It is understood that the 10 carbon containing the moiety -C(=O)-Y is substitutable with a second substituent R2, R3, R4 or R5.
When substituents G1 and/or G2 are "absent," the ring carbons to which Gl and/or G2 are attached are understood to be substituted with two hydrogen atoms and are considered substitutable 15 ring carbon atoms, and are therefore optionally substituted with a substituent selected from R2, R3, R4 and R5.
Preferably, Rla and Rlb are independently selected from:
hydrogen, -N(Rl0)2, RlOC(O)NRlO- or unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is 20 selected from unsubstituted or substituted phenyl, -N(R10)2, RlOO- and Rloc(o)NRlo-Preferably, R2 is selected from: H, ~NR6R7 ~oR6 Il ' ~I ' ~ ~ and an unsubstituted or substituted group, the group selected from C1 8 alkyl, C2 8 alkenyl and C2 8 alkynyl;
wherein the substituted group is substituted with one or more of:
S 1) 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, 4) SR6a, s(o)R6a~ So2R6a 5) --N R6R7 ~6 6) --N~ R7 o O

W O 97/36605 PCTnUS97/04713 8) --0~, NR6R7 9) --o~OR6 10) ~ NR6R7 1 1 ) --S02--NR6R7 ~6 12) --N--SO2--R6a 13) --~R6 14) ~~r OR6 15) N3, or 16) F.

Preferably, R3 is selected from: hydrogen and Cl-C6 alkyl.
Preferably, R4 is hydrogen.
Preferably, R6, R7 and R7a is selected from: hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl.
Preferably, R6a is unsubstituted or substituted Cl-C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl.
Preferably, R9 is hydrogen or methyl. Most preferably, Ra is hydrogen.

W O 97/36605 PCT~US97/04713 Preferably, R10 is selected from H, Cl-C6 alkyl and benzyl.
Preferably, A 1 and A2 are independently selected from: a bond, -C(O)NR 10 , -NR 1 ~C(0)-, 0, -N(R 10) , -S (0)2N(R 10) and-N(R 1 ~)S (~)2--Preferably, V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.
Preferably, Y is selected from unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or 10 substituted pyridyl, unsubstituted or substituted furanyl and unsubstituted or substituted thienyl. More preferably, Y is unsubstituted or substituted phenyl.
Preferably, Z is selected from unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or 15 substituted pyridyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted Cl-C6 aL~yl and unsubstituted or substituted C3-C6 cycloalkyl. More preferably, Z is unsubstituted or substituted phenyl.
Preferably, W is selected from imidazolinyl, imidazolyl, 20 oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl.
Preferably, in compounds of the formula A, Gl is oxygen and G2 is absent.
Preferably, in compounds of the formula B, G2 is oxygen 25 and Gl is absent.
Preferably, in compounds of the formula C, Gl is oxygen and G2 is absent.
Preferably, n and r are independently 0, 1, or 2.
Preferably p is 1, 2 or 3.
Preferably s is 0.
Preferably t is 1.
Preferably, the moiety WO 97/36605 PCTrUS97/04713 (R8)r ~9)\

V A1(cRla ) A2(CR1a ) ~W~- (CRlb ) _~_ is selected from:
R9a R9b ~R and /~N R

(R8),~-- (R )r~ CH2--~

It is intended that the definition of any substituent or variable (e.g., Rla, R9, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, -N(RlO)2 represents -NH2, -NHCH3, -NHC2H5, etc. It is understood 10 that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.
The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, 20 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, W 097t36605 PCTnUS97/04713 furnaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
The ph~ ceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention 5 which contain a basic moiety by conventional chemical methods.
Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1-14, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Substituents R and Ra, as 15 shown in the Schemes, represent the substituents R2, R3, R4, and R~;
however their point of attachment to the ring is illustrative only and is not meant to be limiting.
These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to 20 synthesize fragments which are subsequently joined by the alkylation reactions described in the Schemes.

Synopsis of Schemes 1-14:
The requisite intermediates are in some cases commercially 25 available, or can be prepared according to literature procedures, for the most part. A general synthesis of multiply substituted piperidinones is illustrated in Scheme 1. Thus, a suitably substituted bromoacetonitrile is treated with the sodium salt of diethylmalonate to provide the diester I.
Intermediate I is itself deprotonated and alkylated to provide the triester 30 II, which, upon catalytic hydrogenation spontaneously cyclizes to the lactam III. Acidic rearragngement provides the substituted piperidone IV.
As shown is Scheme 2, the piperidone nitrogen may be arylated by employing a triaryl bismuth - copper coupling. The CA 0224964l l998-09-22 W O 97/36605 PCTrUS97/04713 resulting diester Va can then be converted to the acid VIa and the aldehyde VIIa by procedures well known in the art. Scheme 3 illustrates the analogous preparation of the piperidone having an alkyl substitutent on the ring nitrogen.
The aldehyde intermediates VII can undergo a Wittig coupling with a protected imidazole to provide compound IX, which can then be catalytically reduced to the intermediate X (Scheme 4).
Intermediate X can be deprotected to provide the instant compound XI
or it can be further alkylated to eventually provide the instant compound XII.
Synthesis of compounds of the invention that have an alternate connectivity of the piperidinon-4-ylethyl to the preferred imidazolyl moiety is illustrated in Scheme 4a. The Scheme illustrates use of a suitably substituted protected piperidine XIII, which is either commercially avaiable or may be prepared by techniques known in the art, as the precursor to the 2-piperidinone XV. The nitrogen of inte~nediate XV may then be functionalized and the suitably substituted imidazolyl moiety incorporated via nucleophilic displacement.
Schemes 4b and 4c illustrate syntheses of suitably substituted homologous 4-hydroxymethyl 2-piperidinones, that may be utilized in the reactions illustrated in Scheme 4a, starting with commercially available materials.
Schemes 4d and 4e illustrate alternate syntheses of the homologous piperidinon-4-ylmethyl-1-imidazolyl compounds starting with the previously described intermediate IV.
The key intermediates whose syntheses are illustrated in Schemes 2, 3a, 3b and 3c may also be utilized in the subsequent reactions.
Scheme 5 illustrates the preparation of the instant compound wherein the linker between the piperidone and the heterocyclic substitutent is a carbonyl. Thus the protected imidazolyl Grignard XVI is reacted with the key intelmediate VII to provide the secondary alcohol, which can be oxidized and alkylated as illustrated above to provide the instant compound XVII. Scheme 6 illustrates the analogous synthesis of the instant compound XVIII wherein the heterocyclic moity is linked to the piperidone carbon by an acetyl linker.
The carboxylic acid VI can be converted to the phosphonium salt XIX which can then be coupled to a variety of aldehydes, such as XX, as shown in Scheme 7. The aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses, 1988, 67, 69-75), from the appropriate amino acid. The coupling reaction provides the unsaturated intermediate, which is catalytically reduced to the bisprotected ~ mine XXI. The product XXI can be deprotected to give the instant compound XXII with trifluoroacetic acid in methylene chloride. The final product XXII is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine XXII can further be selectively protected to obtain XXIII, which can subsequently be reductively alkylated with a second aldehyde to obtain XXIV. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XXV can be accomplished by literature procedures.
If the phosphonium XIX is coupled with with an aldehyde which also has a protected hydroxyl group, such as XXV1 in Scheme 8, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes ~, 9). The alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as XXIX. In addition, the fully deprotected amino alcohol XXX can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXXI (Scheme 9), or tertiary amines.
The Boc protected amino alcohol XXVII can also be utilized to synthesize 2-aziridinylmethylpiperidones such as XXXII
(Scheme 10). Treating XXVII with 1,l'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXXII. The aziridine reacted in the presence of W 097/36605 PCTrUS97/04713 a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product XXXIII.
In addition, as illustrated in Scheme l 1, the phosphonium XVIII can be reacted with aldehydes derived from amino acids such as 5 O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXXIII. When R' is an aryl group, catalytic hydrogenation of XXXIII also llnm~k~ the phenol, and the amine group is then deprotected with acid to produce XXXV. Alternatively, when R' is not an aryl group, XXXV is an O-alkylated phenolic amines.
Schemes 12-15 illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic strategies for preparing alkanols that incorporate other heterocyclic moieties for variable W are also well known in the art.

CA 0224964l l998-09-22 W O 97136605 PCTrUS97/04713 Br C2Hs~2C) RCN C2H502C~R
C2H502C NaH, THF, O ~C C2Hs~2C CN
I
Ra C2Hs~2C H
ClCHRaCO2C2H5 R 2 C2HsO2C ~ Pd / C
NaH,THF, 0~C C2H502C CN CH3CH20H

C2H502C R Ra R

C2H5O2C ( ' C2H5O2 C2H5O2C ~ C2H502C ,~ NH

R

CHCI3 C2H5O2C>~\NH
CH3CO2H C2H502C >~
Ra O
IV

C2H5O2C~\NH (Za')3Bi C2H502C ~CU(oAc)2 R

C2H5O2C ~\ 1 ) NaOH, H20 >~ N--zar C2HsO2C ~ 2) HCI, Ra o HO2C ~N - zar TMSCHN2 Ra O toluene / methanol Vl R

~\ DIBAL
CH ,02C~ N--zar Ra~ THF, -78~C
R

~, OHC~N--Za' Ra O
Vll W O 97/3660~, PCTnUS97/04713 R 1. NaH, DMF
C2H502C~\NH 2. ZalkX
C2H5O2C ~
R O

C2Hs~2CX~\ 1 ) NaOH, H20 C2HsO2C ~ 2) HCI, Ra O

HO2C ~\N--zalk TMSCHN2 )~ toluene / methanol Ra o DIBAL
C H3O2C ~ N--zalk >~ THF,-78~C
Ra O
R

~, OHC ~ N--zalk ~.
Ra O

R LiHMDS
)~ THF,-78~C
OHC ~ N--Z
Ra~o ~CH2P(O)(OC2H5)2 Vll N
Tr R

~ H2, Pd/C
T ,N~N- Z CH30H

R
~, ~N~_~ N--Z
Tr,N ~ Ra/~\o X

~N ~ ~N--Z

H~N~~ Ra O
Xl CA 0224964l l998-09-22 W O 97/36605 PCTrUS97/04713 SCHEME 4 (continued) 1 . ~ C H2Br ~N~ N--Z
Tr,N ~ Ra/~o 2. CH30H, reflux X

\~
~ R
>~
~N ~ ~N--Z
N ~ Ra 0 Xll SCHEME 4a ~ 1) Boc20, CH2CI2 HOCH2CH2~NH 2) Ac20, pyridine, CH2C12 Xlll Ru04, NalO4 AcO~/ EtOAc, H20 Ra TFA, CH2CI2 ~ N- Boc AcO ~
Ra o XIV

>--~ (Zar)3Bi ~ NH
AcOJ ~ Cu(OAc)2 Ra O CH2CI2 XV

SCHEME 4a (continued) 1) LiOH, THF, H20 N--zar Ra o 2) ¢~/R8 XVI
Tr,N
Tf20, iPr2NEt CH2CI2, -78~C-20~C

Ar R

_ zar N=/ Ra o Xll wo s7/366ns PCT/USg7/04713 SCHEME 4b ~{~NH TMSCI, Imidazole, CH2C12 HO

Boc20, DMAP
~ NH r TMSO ~~ CH2C12 LDA, RaX
~ N- Boc TMSO ~ THF

TFA, CH2C12 ~, N- Boc TMSO )~
Ra O

~ NH
HO )~
Ra O

W O 97/36605 PCTrUS97/04713 SCHEME 4c ~ PtO2 H2 H3C02C ~/ N HCI
\=/ C2H5~H

~ Et3N Boc20 H3CO2c ~ NH HCI

~ LiAlH4 H3CO2C ~N- Boc TH F

~CF3CO20 pyridine HOCH2~ N-Boc \ CH2CI2 WO 97/3660~ PCT/US97/04713 _ 59 _ SCHEME 4c (continued) Ru04, NalO4 CF3CO2CH2 ~ N-Boc / EtOAc, H20 ~ NH3, CH30H
CF3CO2CH2 ~N-Boc HOCH2~\N- Boc TMSCI Imidazole \~ CH2CI2 TMSOC H2 ~N- Boc W O 97/36605 PCTnUS97/04713 SCHEME 4d R 1. NaH, DMF
C2Hs~2C >~\NH 2 zalkx C2H502C ~
Ra o R IV
C2H502C ~\ Ik 1 ) LiCI, DMSO/H2O 1 80~C
C2H5O2C >~ 2) LiOH, H20 Ra o HO2C ~\N--zalk C2H50COCI; (C2H5)3N
~ THF, NaBH4 Ra o Vlb ~, HOCH2~ N--zalk ,~
Ra o W O 97/3660~ rcTnusg71o4713 SCHEME 4d (continued) 1) ,~R
ry Tr,N
R Tf20, iPr2NEt HOCH2 ~ N--Zalk CH2CI2,-78~C-20~C
Ra 0 2) CH30H, reflux NC ~ ~N--zalk ~N
N~ Ra 0 Vllb WO 97t36605 PCT/US97/04713 SCHEME 4e R

C2Hs~2C >~\NH (Z ) IBi C2H5O2C ~ Cu(OAc)2 Ra o CH2CI2 C2H5O2C >~\ 1 ) LiCI, DMSO/H2O 1 80~C
C2H5O2C )~ 2) LiOH, H20 Ra o R

H O2C ~ N _ zar _________________ Ra o Vla Ar~ ~\N- zar ¢ J Ra o xva WO 97/36605 PCTtUS97tO4713 SCHEME S

N~3 Ph3C

C2H5MgBr R MgBr R

OHC ~N--Z + ~ 78~C N

Vll XVI Ph3C

R \~
o ~ 1. ~CH2Br ( )3 , ~ ~ CH3CN

(CH3)2Co ,N 2) CH30H, 60~C
Ph3C

--N~

XVII

CH2CI CH2MgCI
N~

Ph3C Ph3C

CH2MgCI R
N~ ) \ CH2CI2 ~ N~ + OHC ~N--Z -78~C

Ph3C Ra o HO ~

N~O
Ph3C' SCHEME 6 (continued) R

O" ~

(CH3)2C0 ,~N- Z
Ph3C

1 ) NC ~ CH2Br CH3CN

2) CH30H, 60~C

NC~ R

Z
XVIII

W O 97136605 PCTrUS97/04713 S C~CE~E 7 R R
~ BH3 THF ~
H02C ~N--Z ~ HOH2C ~N--Z

Ra o Ra o Vl Ph3P R (C2HsO)3p IH2C~ N--Z
12, imidazole ~, toluene Ra 0 Boc NH XX
R
~ BocNH CH0 (C2Hso)2opH2c~ N--Z
~ LiHMDS, THF
Ra o XIX
R

Boc NH
~\N-Z H2, Pd/C
BocHN ~ CH30H
Ra o BocNH
~N-Z CF3C02H
BocHN )~ CH2CI2 Ra o XXI

SCHEME 7 (continued) NH2 R Boc20 ~N--Z C H2CI2 Ra o XXII

BocNH~N--Z CHO

NH2 Ra NaBH(OAc)3 ~ Et3N, CIC
XXIII

BocNH R
CF3CO2H, CH2CI2;
~N- Z NaHCO3 XXIV

WO 97/36605 ~CT/US97104713 SCHEME 7 (continued) NHl2 R ~NC
,~N--Z AgCN

~\--Ra~O

~ XXV

R

LiHMDS, THF
(C2H~o)2opH2c~N--Z BnOl XIX BocNH CHO
XXVI

BnO R
~N-Z 20% Pd(OH)2 H2 NHBoc )~ CH30H
Ra o CH3CO2H
XXVII
HO R
~N z CICOCOCI
N HBoc >~ (C2H5)3N

XXVIII

SCHEME 8 (continued) R 1. R'MgX

H ~N--Z 2 TFA, NHBoc a CH2C12 OH
R'/~N--Z
2 Ra O
XXIX

HO R
~N--Z CF3CO2H
NHBoc ~ CH2C12 Ra o XXVII

HO
~ R'CHO
NH2 )~ NaBH(OAc)3 Ra o CICH2CH2 XXX

HO
~\~N--Z

R CH2 Ra O
XXXI

W O 97t36605 PCTrUS97/04713 H0~ ~N~

NHBoc NaH, DMF 0~C

XXVII

~\N z R'SH
N ~ (C2Hs)3 H Ra o CH30H
XXXII

R'S R
~N--Z
NH2 ~
Ra o XXXIII

H;~ THF-H20 ,~3 H2N CO2H2) CH2N2, EtOAC

HO~
LiAlH4 ,J~ R'CH2X
THF 1 CS2C~3 0-20~C BocNH CH2OH DMF

R'CH ~ ~3 pyridine SO3 ~ ~

BocNHCH2OH 20~C BocNH CHO

W O 97/36605 PCT~US97/04713 SCHEME 11 (continued) R 'C H20~, R

r+ (C2Hso)2opH2c~ N--Z
BocNH CHO Ra~

XVIII

LiHMDS
THF

R'CH20~ R

~N--Z
NHBoc Ra o XXXIII

1 ) 20% Pd(OH)2 CH30H, CH3CO2H
2) HCI, EtOAc ~, R''O~I R

R;' = H, if R' isphenyl R" is R'CH2-XXXV

CH3 1) HNo2lBr2 ~CO2CH3 ~ 2) KMnO
H2N N 3) MeOH,H~ Br~N~

~J/\MgCI R~CO2CH3 Zncl2~Nicl2(ph3p)2 NaBH4 (excess) ~CH20H

DMSO ~ C HO

W O 97/36605 PCTrUS97/04713 1. EtO(CO)CI R6 Br [~
Zn, CuCN [~CO2CH3 N 3. S, xylene, heat NaBH4 ~j~ SO3Py, Et3N ~
(excess) ~,CH20H DMSO ~CHO

Br~CO2CH3 ~
N ~CO2CH3 ZnCI2, NiC12(Ph3P)2 N

NaBH4 ¦ SO3 Py, Et3N
~,CH20H ~ ~ CHO
(excess) N DMSO ~N ~I

PCTtUS97/04713 WO 97t36605 co2CH3 Br~31. LDA, CO2 Br~

N 2. MeOH. H+ N

R6 MgCI 1~1 CO2CH3 ZnCI2, NiC12(Ph3P)2 N) NaBH4(excess) ¢~ CH20H SO3-Py, Et3N
\~3 DMSO
N

CHO

CA 0224964l l998-09-22 W O 97/36605 PCTrUS97/04713 co2CH3 ~3~ 1. LDA, CO2 ~Br Br ~,N
2. (CH3)3sicHN2 R6 3/\ Br R6 ~
N ~CO2CH3 Zn, NiCI2(Ph3P) R6 ~
excess NaBH4 l~ SO3Py, Et3N
N~CH20H DMSO

R6 ~

N~l,CHO

W O 97/36605 PCTrUS97/04713 N ~CO2Et 1. H2, Pd/C

~) 0 2. (Boc)20 0~ rRI 2 Br ~ sub N~ CO2Et ~ NaH

0~ r~CO2Et 1. HCI, EtOAc ~0 ' ~
O ~\sub 2. iPr2NEt ~;;;f ,=, ,1~ CO2Et R8~\N~ \~ sub WO 97/3660S rCTrUS97/04713 The instant compounds are useful as pharmaceutical agents for m~mm~ , especially for hllm~n~. These compounds may be ~lmini~tered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this 5 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-1), 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. Cancer Research, 55:4575-4580 (1995)). Such anti-angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization.
The compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the ~mini~tration 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 (1992).
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.

American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)).
The instant compounds may also be useful for the treatment of fungal infections.
S The compounds of this invention may be ~llmini~tered to m~mm~l~, 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 ~lmini~tered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of ~lministration.
For oral use of a chemotherapeutic compound according to this invention, the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablet.s 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 emulsifying and suspending agents.
If desired, certain sweetening and/or flavoring agents may be added.
For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH
of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic.
The compounds of the instant invention may also be co-~lministered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
For example, the instant compounds may be useful in combination with - known anti-cancer and cytotoxic agents. Similarly, the instant compounds may be useful in combination with agents that are effective - in the treatment and prevention of NF-1, restinosis, polycystic kidney W O 97/36605 PCTrUS97/04713 disease, infections of hepatitis delta and related viruses and fungal infections.
If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range 5 described below and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
The present invention also encompasses a ph~ ceutical 10 composition useful in the treatment of cancer, comprising the ~rlmini~tration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and 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.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specific 20 amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
When a compound according to this invention is ~lministered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally 25 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 ~lministered to a m~mm~l undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg 30 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/l~g of body weight per day.
The compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and CA 0224964l l998-09-22 W 097/36605 PCTrUS97/04713 quantity 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 5 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 the assay mixtures may be deterrnined by well known 10 immunological, radiochemical or chromatographic techniques.
Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the 15 assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain farnesyl-protein transferase and 20 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 sample~s composed of aliquots of a tissue extract containing an unknown amount of farnesyl-protein transferase, an excess amount of a known substrate 25 of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention. The concentration of a sufficiently potent inhibitor (i.e., one that has a Ki substantially smaller than the 30 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.

W O 97/36605 PCT~US97/04713 EXAMPLES

Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species 5 and conditions are intended to be further illustrative of the invention and not limitative of the reasonable scope thereof.

10 4-[5-(4-Cyanobenzyl)imidazol-l-ylmethyl3-1-phenyl-2-piperidinone hydrochloride NC ~ )~
N~
N~J ~b"
o Step A: l-Phenyl-2-piperidinone-4,4-dicarboxylic acid diethyl ester 2-Piperidinone-4,4-dicarboxylic acid diethyl ester, 20 prepared as described in US 4,fS70,173, is dissolved in methylene chloride and treated with triphenylbismuth (1.5 equivalents), copper(II)acetate (1.5 equivalents) and triethylamine (1.5 equivalents) and stirred for 17 h at 20~C in dichloromethane (60 mL). The reaction mixture was adsorbed onto silica gel and chromatographed to provide 25 the title compound.

Step B: l-Phenyl-2-piperidinone-4-carboxylic acid ethyl ester The product from Step A (4.78 g, 14.98 mmol) was dissolved in DMSO (90 mL) containing water (0.27 mL, 14.98 mmol) 30 and lithium chloride (1.27 g, 29.96 mmol). The reaction was heated at CA 0224964l l998-09-22 180~C under argon for 3.5 h. The cooled reaction mixture was partitioned between ethyl acetate and water. Ther organic phase was washed with saturated brine, and dried over magnesium sulfate. The title compound was isolated as a white solid following chromatography 5 on silica gel with 50% ethyl acetate in hexane.

Step C: 1 -Phenyl-2-piperidinone-4-carboxylic acid The product from Step B (2.60 g, 10.52 mmol) was dissolved in THF (60 mL) and lithium hydroxide hydrate (2.15 g, 51 10 mmol) and water (10 mL) were added. The reaction was stirred for 4 h at room temperature, at which time 6N aqueous hydrogen chloride solution was added to adjust the pH to 1, and the product extracted with ethyl acetate. The organic phase was dried with magnesium sulfate, filtered and evaporated to reveal the title compound.
Step D: 4-Hydroxymethyl-l-phenyl-2-piperidinone The product from Step C (1.57 g, 7.16 mmol) was dissolved in THF (30 mL) and triethylamine (1.20 mL, ~.59 mmol) was added. The reaction was cooled to 0~C under argon, and ethyl 20 chloroformate added (O.g2 mL, ~.59 mmol). The reaction was stirred for 1 h at 0~C, and then sodium borohydride was added (0.~1 g, 21.5 mmol). After 3 h, the reaction was quenched by the addition of saturated sodium bicarbonate solution. The a4ueous phase was extracted with ethyl acetate. The organic phase was washed with 2% aqueous 25 potassium hydrogen sulfate and saturated brine. After drying over m~gnesium sulfate, the crude product was chromatographed on silica gel with 5% methanol in chloroform. The title compound was obtained as a white solid.

30 Step E: I-Trityl-4-(4-cyanobenzyl)-imidazole.
To a suspension of activated zinc dust (3.57 g, 54.9P~
mmol) in THF (50 mL) was added dibromoethane (0.315 mL, 3.60 mmol) and the reaction stirred under argon at 20~C. The suspension was cooled to 0~C and oc-bromo-p-toluinitrile (9.33 g, 47.6 mmol) in THF

(100 mL) was added dropwise over a period of 10 min. The reaction was then allowed to stir at 20~C for 6 h and bis(triphenylphosphine)Nickel II chloride (2.4 g, 3.64 mmol) and 4 -iodotrityl imidazole (15.95 g, 36.6 mmol) were added in one 5 portion.The resulting mixture was stirred 16 h at 20~C and then quenched by addition of saturated ammonium chloride solution (100 mL) and the mixture stirred for 2 h. Saturated sodium bicarbonate solution was added to give a pH of 8 and the solution was extracted with ethyl acetate ( 2 x 250 mL), dried with magnesium sulfate, and the 10 solvent evaporated in vacuo. The residue was chromatographed on silica gel with 0-20% ethyl acetate in methylene chloride to afford the title compound as a white solid.
~H NMR ~ CDC13 (7.54 (2H,d, J=7.9Hz), 7.38(1H,s), 7.36-7.29 (1 lH,m), 7.15-7.09(6H,m), 6.58(1H,s), and 3.93(2H,s)ppm.
Step F: 4-l 5-(4-Cyanobenzyl)imidazol- 1 -ylmethyl]- 1 -phenyl-2-piperidinone hydrochloride The product from Step D (0.205 g, 1.00 mmol) and the product from Step E (0.425 g, 1.00 mmol) were dissolved in methylene 20 chloride (2 mL) containing diisopropylethylamine (0.191 mL, 1.10 mmol) and cooled to -78~C under argon. Trifluoromethane sulfonic anhydride was added (0.173 mL, 1.03 mmol) and the reaction stirred at -78~C for 1 h, followed by warming to room temperature over 2 h.
The solvent was evaporated, and the residue dissolved in methanol.
25 After refluxing for 30 min, the methanol was evaporated, and the residue is partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase is washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The free base product was chromatographed on silica gel with 3% methanol in 30 methylene chloride follwed by 7% 9:1 methanol:ammonium hydroxide in methylene chloride. The title compound was obtained after conversion to the hydrochloride salt. FAB ms: 371 (M+1). Anal. Calc for C23H22N4O ~ HCI ~ H2O, C, 65.01; H, 5.93; N,13.19. Found: C, 64.77; H, 5.89; N, 13.11.

-5 4-[2- ~ 5-(4-Cyanobenzyl)imidazol- 1 -yl ) ethyl]- 1 -phenylpiperidin-2-one hydrochloride CN
~J
,~,J
N~
~, N~
O

Step A: l-tert-Butoxycarbonyl-4-hydroxyethylpiperidine 4-(2-Hydroxyethyl)piperidine (4.91 g, 38.06 mmol) was dissolved in methylene chloride (80 mL) and di-tert-butyl dicarbonate (8.71 g, 39.96 mmol) wa~s added. After stirring at room temperature 15 overnight, saturated sodium bicarbonate was added, and the layers separated. The organic phase was washed with 2% potassium hydrogen sulfate, saturated sodium carbonate and saturated brine, then dried over magnesium sulfate. The title compound was obtained as a yellow oil.

20 Step B: 4-(2-Acetoxyethyl)-l-tert-butoxycarbonylpiperidine The product from Step A (6.62 g, 28.90 mmol) was dissolved in methylene chloride (50 mL) cont~ining pyridine (5.8 mL, 72.27 mmol). The reaction was cooled to 0~C under argon, and acetic anhydride added (3.3 mL, 34.68 mmol). The reaction was stirred 25 overnight at room temperature. Saturated sodium bicarbonate solution was added, and the layers separated. The organic phase was washed with 10% aqueous hydrogen chloride, saturated sodium bicarbonate solution, and saturated brine. The organic phase was dried over magnesium sulfate. The title compound was obtained as an oil.

S Step C: 4-(2-Acetoxyethyl)-l-ter~-butoxycarbonylpiperidin-2-one The product from Step B (0.275 g, 1.01 mmol) was dissolved in ethyl acetate (S mL). A solution of sodium periodate in water (0.5 g in 5 mL) and ruthenium tetroxide (13 mg, 0.10 mmol) was added, and the heterogeneous reaction stirred vigorously overnight at 10 room temperature. An additional portion of sodium periodate in water was added (0.5 g in 5 mL) and the reaction stirred overnight. The reaction was quenched with 10% sodium thiosulfate, and filtered through celite. The phases were separated, and the organic phase dried over magnesium sulfate. Filtration and evaporation gave the title 15 compound.

Step D: 4-(2-Acetoxyethyl)piperidin-2-one The product from Step C is dissolved in 2:1 methylene 20 chloride and trifluoroacetic acid. The reaction is stirred for l h, and evaporated, giving the title compound.

Step E: 4-(2-Acetoxyethyl)-l-phenylpiperidin-2-one The product from Step D is dissolved in methylene chloride and treated with triphenylbismuth (1.5 equivalents), copper(II)acetate (1.5 equivalents) and triethylamine (1.5 equivalents) and stirred for 17 h at 20~C in dichloromethane (60 mL). The reaction mixture is adsorbed onto silica gel and chromatographed to provide the title compound.
Step F: 4-(2-Hydroxyethyl)-l-phenylpiperidin-2-one The product from Step E is hydrolyzed according to the procedure described in Example 1, Step C, giving the title compound.

W O 97/36605 PCT~US97/04713 Step G: 4-[2- ~ 5-(4-Cyanobenzyl)imidazol- 1 -yl ~ ethyl]-1-phenylpiperidin-2-one hydrochloride The product from Step F (1 eq) and the product from 5 Example 1, Step E (1 eq) were dissolved in methylene chloride containing diisopropylethylamine, cooled to -78~C under argon and treated with trifluoromethane sulfonic anhydride as described in Example 1, Step F. After methanolysis, the title compound was isolated by chromatography on silica gel.

4-[2- ( 1 -(4-Cyanobenzyl)-5-imidazolyl }ethyl]- 1 -phenyl-2-piperidinone hydrochloride NC~ ~ ~

~q, N ~ ~'q ~ ~

~0 Step A: 1 -Phenyl-2-piperidinone-4,4-dicarboxylic acid diethyl ester 2-Piperidinone-4,4-dicarboxylic acid diethyl ester, prepared as described in US 4,870,173, is dissolved in methylene chloride and treated with triphenylbismuth (1.5 equivalents), 25 copper(II)acetate (1.5 equivalents) and triethylamine (1.5 equivalents) and stirred for 17 h at 20~C in dichloromethane (60 mL). The reaction mixture is adsorbed onto silica gel and chromatographed to provide the title compound.

30 StepB: l-Phenyl-2-piperidinone-4~4-dicarboxvlic acid ,, .

The product from Step A is dissolved in methanol and 5%
a~ueous sodium hydroxide added. When the hydrolysis is complete, 6 N
aqueous hydrochloric acid is added to obtain pH 1, and the solution extracted with ethyl acetate. The organic phase is washed with saturated 5 brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound.

Step C: I -Phenyl-2-piperidinone-4-carboxylic acid The product from step B is dissolved in toluene and 10 refluxed for 6 h. The reaction is cooled and concentrated to provide the title compound.

Step D: l-Phenyl-2-piperidinone-4-carboxylic acid methyl ester The product from Step C is dissolved in 10 % methanol in 15 toluene, and trimethylsilyldiazomethane added. The reaction is quenched with acetic acid and concentrated. The residue is partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase is washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound.
Step E: 4-Formyl-l-phenyl-2-piperidinone The product from Step D is dissolved in THF and cooled to -78~C under nitrogen. A solution of diisobutylaluminum hydride ( 1 eq.) in toluene is added dropwise. After 30 min, the reaction is 25 quenched with saturated sodium potassium tartrate solution. The mixture is extracted with ethyl acetate, and the organic phase washed with saturated brine, and dried over MgSO4. Filtration and concentration provides the title compound 30 Step F: 4-Hydroxvmethyl-l-triphenylmethylimidazole To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260 mmol) in 250 mL of dry DMF at room temperature is added triethylamine (90.6 mL, 650 mmol). A white solid precipitated from the solution. Chlorotriphenylmethane (76.1 g, 273 mmol) in 500 mL of DMF is added dropwise. The reaction mixture is stirred for 20 hours, poured over ice, filtered, and washed with ice water. The resulting product is slurried with cold dioxane, filtered, and dried in vacuo to provide the titled product as a white solid which is sufficiently pure for use in the next step.

Step G: 4-Chloromethyl- 1 -triphenvlmethylimidazole The product from Step F is dissolved in chloroform and cooled to 0~C under nitrogen. Thionyl chloride (molar equivalent) is added slowly via syringe. The reaction is stirred for 30 min, and extracted with sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, filtered and concentrated to provide the title compound.

Step H: 4-Diethylphosphonomethyl-l-triphenylmethylimidazole The product from Step G is di,ssolved in acetonitrile and cooled to 0~C. Triethyl phosphite (1 equivalent) and sodium iodide (1 equivalent) were added, and the reaction stirred at room temperature overnight. The reaction is quenched with ammonium chloride, and extracted with ethyl acetate. The organic phase i.s dried over magnesium sulfate, filtered and concentrated to provide the title compound.

Step I: 4-12-{ 1-(Triphenylmethyl)-4-imidazolyllethenyl]-1-phenyl-2-piperidinone The product from Step H is dissolved in THF and cooled to -78~C under nitrogen. A solution of LDA in THF is added dropwise.
The reaction is stirred at -78~C for 1 h, then a solution of 4-formyl-1-phenyl-2-piperidinone from Step E is added, and the reaction warmed to room temperature overnight. The reaction is quenched with ammonium chloride solution, and extracted with ethyl acetate. The title compound is obtained after chromatography on silica gel Step J: 4-[2-~1-(Triphenylmethyl)-4-imidazolyl}ethyl]-1-phenyl-2-piperidinone The product from Step I is dissolved in methanol and hydrogenated at 60 psi hydrogen with 10% palladium on carbon. When reaction is complete, the catalyst is filtered and the title compound obtained after evaporation of solvent.

Step K: 4-[2- {1 -(4-Cyanobenzyl)-5-imidazolyl ) ethyl]- 1 -phenyl-2-piperidinone hydrochloride The product from Step J is dissolved in acetonitrile and reacted with 4-cyanobenzylbromide (1 equivalent) at room temperature overnight. The reaction is concentrated in vac~o, and the residue dissolved in methanol. The methanol solution is refluxed for 3 h and then concentrated. The residue is partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase is washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The title compound is obtained after purification by silica gel chromatography, and conversion to the hydrochloride salt.

(+)cis- and (+)trans- 4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl~ethyl]-3-methyl-l-phenyl-2-piperidinone hydrochloride W O 97/3~605 PCTnUS97/04713 N~

H~C~
o O '~

Step A: (+)cis- and (+)trans-3-Methyl-l-phenyl-4-~2-{ 1-triphenylmethyl)-4-imidazolyl ~ ethyll -2-piperidinone 4-[2- ( 1 -(Triphenylmethyl)-4-imidazolyl } ethyl3- 1 -phenyl-2-piperidinone in THF is added to a solution of I eq lithium hexamethyldisilylazide in THF at -7~i~C, under argon. The reaction is stirred for 30 min, and 1 eq methyl iodide is added. The reaction is warmed to room temperature, quenched with saturated ammonium sulfate solution, and extracted with ethyl acetate. The organic phase is washed with saturated brine and dried over magnesium sulfate. The crude products are purified by columnm chromatography and provide the title compounds.

Step B: (+)cis- and (+)trans-4-[2-~ 1-(4-Cyanobenzyl)-5-imidazolyl } ethyl] -3-methyl- 1 -phenyl-2-piperidinone hydrochloride The title compound is prepared according to the procedure described in Example 3, Step K, except using the product from Step A
in place of 4-[2-~1-(triphenylmethyl)-4-imidazolyl}ethyl]-1-phenyl-2-piperidinone. The title compound is obtained after purification by silica gel chromatography, and conversion to the hydrochloride salt.

W O 97/36605 PCT~US97/04713 4-[2- { l -(4-Cyanobenzyl)-5-imidazolyl l carbonyl]- 1 -phenyl-2-piperidinone hydrochloride s NC ~, ~, O

N--~N~
o Step A: N-Methyl N-methoxy l -phenyl-2-piperidinone-4-carboxamide 1-Phenyl-2-piperidinone-4-carboxylic acid is stirred with l eq N,O-dimethylhydroxylamine hydrochloride, l.l eq EDC ~ HCI, l eq hydroxybenzotriazole in DMF at pH 7 overnight. The reaction is poured into water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated, and provide.s the title compound.

Step B: l -Phenyl-4-[ l -triphenylmethyl-4-imidazolyl 3 carbonyl] -2-piperidinone hydrochloride l-Triphenylmethylimidazole-4-magnesium iodide in methylene chloride is prepared as described by R.M. Turner, S.D.
Lindell and S.V. Ley in J. Org. Chem., 1991, 56, 5739-5740, and is added to l eq of N-methyl N-methoxy l-phenyl-2-piperidinone-4-carboxamide in dichloromethane under argon at -7~~C. The reaction is warmed to room temperature and quenched with saturated ammoniurn chloride solution. The reaction is extracted with ethyl acetate and the organic phase dried over magnesium sulfate, filtered and concentrated, providing the title compound.

Step C: 4-[2- ~ 1 -(4-Cyanobenzyl)-5-imidazolyl } carbonyl]- 1 -phenyl-2-piperidinone hydrochloride The title compound is prepared according to the procedure described in Example 3, Step K, except using the product from Step B
5 in place of 4-[2-{1-(triphenylmethyl)-4-imidazolyl}ethyl]-1-phenyl-2-piperidinone. The title compound is obtained after purification by silica gel chromatography, and conversion to the hydrochloride salt.

Preparation of Ethyl 1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-oxo-4-(3-methylbenzyl)piperidine-4-carboxylate trifluoroacetate salt \ CO2Et N~ \~

Step A: Preparation of Ethyl N-tert-butoxycarbonyl-3-oxo-1 5 piperidine-4-carboxylate A mixture of ethyl N-benzyl-3-oxo-piperidine-4-carboxylate hydrochloride salt (3.5 g, 11.7 mmol; purified) and 10%
palladium on charcoal (0.35 g) in a mixture of ethanol (100 mL) and water (100 mL) was hydrogenated at room temp. at 60 psi overnight.
20 The resultant mixture was filtered through a plug of Celite, and the filtrate was concentrated under vacuum. The residue was dissolved in mixture of triethylamine (5 mL), dioxane (20 mL) and water (19 mL), and treated with di-tert-butyl dicarbonate (3.2 g). The reaction mixture was stirred at room temp. overnight. The product mixture was 25 concentrated and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 20% ethyl acetate in hexane.
30 Collection and concentration of appropriate fractions provided the title WO 97136605 PC~/US97/04713 compound as clear colorless oil, which was stored under argon at -10 C.
Step B: Preparation of Ethyl N-tert-butoxycarbonyl-3-oxo-4-(3-methylbenzyl)piperidine-4-carboxylate To a cold (0 ~C) slurry of sodium hydride (0.29 g, 12 mmol) in anhydrous dimethylformamide (50 mL), a ,solution of ethyl N-tert-butoxycarbonyl-3-oxo-piperidine-4-carboxylate (2.73 g, 10 mmol) in DMF (10 mL) was added. The mixture was stirred at 0 ~C for 30 min., and at room temp. for 30 min. The resultant solution was cooled back to 0 ~C and treated with 3-methylbenzyl bromide (1.63 mL, 12 mmol). The reaction mixture was stirred at room temp. overnight and concentrated under vacuum. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 17.5% ethyl acetate in hexane.
Collection and concentration of appropriate fractions provided the title compound.
Step C: Preparation of Ethyl 3-oxo-4-(3-methylbenzyl)piperidine-4-carboxylate hydrochloride salt To a cold (0 ~C) solution of ethyl N-tert-butoxycarbonyl-3-oxo-4-(3-methylbenzyl)piperidine-4-carboxylate (1.55 g, 4.13 mmol) in 25 ethyl acetate (75 mL), a stream of anhydrous hydrogen chloride gas was bubbled for 20 min. The resultant mixture was stirred at 0 ~C for 1 h, purged with argon for 10 min., and concentrated under vacuum to provide the title compound as white solid.

30 Step D: Preparation of Ethyl 1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl] -3-oxo-4-(3 -methylbenzyl)piperidine-4-carboxylate trifluoroacetate salt A solution of ethyl 3-oxo-4-(3-methylbenzyl)piperidine-4-carboxylate hydrochloride salt (4.13 mmol), 1-(4-cyanobenzyl)-5-35 chloromethylimidazole hydrochloride salt (1.1 1 g, 4.13 mmol), and CA 0224964l l998-09-22 W O 97/36605 PCTnUS97/04713 diisopropylethylamine (1.58 mL, 9.1 mmol) in anhydrous acetonitrile (l0 mL) was heated under reflux overnight. The resultant mixture was concentrated under vacuum, and the residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic S extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 1:1 mixture of chloroform and chlorofo~n saturated with ammonia gas. After collection and concentration of appropriate fractions, the residue further 10 purified by subjecting to high pressure liquid column chromatography on C-18 reverse phase stationary phase. Collection and Iyophilization of appropriate fractions provided the title compound as white solid.
Anal. Calcd for C2gH30N4O3-1.6 TFA ~0.1 H2O: C, 57.23; H, 4.90;
N, 8.56. Found: C, 57.21; H, 4.85; N, 8.53.

In vitro inhibition of ras farnesyl transferase Assays of farnesyl-protein transferase. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) were prepared as described by Schaber et al., J. Biol. Chem. 265: 14701 -14704 (1990), Pompliano, et al., Biochemistry 31:3~00 (1992) and Gibbs et ah, PNAS U.S.A. 86:6630-6634 (19P~9), respectively. Bovine FPTase was assayed in a volume of 100 ~1 cont~ining 100 mM N-(2-hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 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.
Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB ~-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 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, Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10 ~ ZnCl2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., 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 are tested for inhibitory activity against human FPTase by the assay described above. The compound of the instant invention described in Examples l and 6 were tested for inhibitory activity against human FPTase by the assay described above and were found to have ICso of <10 ,uM.

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%
confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1%). After 4 hour,s 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 cells are lysed in 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 m~ MgC12/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 WO 97/36605 PCTtUS97/04713 _ 99 _ of acid-precipitable counts are bought to 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Yl3-259 (Furth, M.E. et ah, J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at 4~C, 200 ml of a 5 25% suspension of protein A-Sepharose coated with rabbit anti rat IgG
is added for 45 min. The immunoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/l mM EDTA/l % 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 lO reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to farnesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein.

In vivo growth inhibition assay To determine the biological consequences of FPTase inhibition, the effect of the compounds of the instant invention on the 20 anchorage-independent growth of Ratl cells transformed with either a v-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Raf and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation.
Rat l cells transformed with either v-ras, v-raf, or v-mos 25 are seeded at a density of l x 104 cells per plate (35 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layers contain 0.1% methanol or an appropriate concentration of the instant compound (dissolved in 30 methanol at l O00 times the final concentration used in the assay). The cells are fed twice weekly with 0.5 ml of medium A containing 0.1%
methanol or the concentration of the instant compound.
Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made.

Claims

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, R100O-, R11S(O)m-, R10C(O)NR10-, (R10)2N-C(O)-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and 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)2N-C(O)-, CN, (R10)2N-C(NR10)-, 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, and , 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)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 and R5 are independently selected from H and CH3;

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

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

R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle and 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)-, 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 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)-, R10 2N-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)-, 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- and S(O)m;

G1 and G2 are independently oxygen or absent, provided that at least one of G1 and G2 is oxygen;

G3 is oxygen or 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 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 a bond, -CH2-, -C(=O)-, or -S(=O)m-;

Y is unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or more of:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR6a, or g) -C(O)NR6R7, 2) aryl or heterocycle, 3) halogen, 4) OR6, 5) NR6R7, 6) CN, 7) NO2, 8) CF3;
9) -S(O)mR6a, 10) -C(O)NR6R7, or 11) C3-C6 cycloalkyl;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or4;
p is 0, 1, 2, 3 or4;
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;
or an optical isomer or 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-, CN(R10)2NC(O)-, R10 2N-C(NR10)-, CN,NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and 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, unsubstituted or substituted heterocycle, and , 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 and 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 and 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)-, 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 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)-, R10 2N-C(NR10)-, 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, R 10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-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- and S(O)m;

G1 and G2 are independently oxygen or absent provided that at least oneof G1 and G2 is oxygen;

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 a bond, -CH2-, -C(=O)-, or -S(=O)m-;

Z is selected from:
1) a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
a) C1-4 alkyl, unsubstituted or substituted with:
C1-4 alkoxy, NR6R7, C3-6 cycloalkyl, aryl, heterocycle, HO, -S(O)m R6a, or -C(O)NR6R7, b) aryl or heterocycle, c) halogen, d) OR6, e) NR6R7, f) CN, g) NO2, h) CF3;
i) -S(O)m R6a, j) -C(O)NR6R7, or k) C3-C6 cycloalkyl; and 2) 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;
or a pharmaceutically acceptable salt thereof.

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

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)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and 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, R10OC(O)-, R10OC(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, and , 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 and 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 and 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)NRl0-, (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 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)-, R10 2N-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)-, 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)-, R10 2N-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- and S(O)m;

G1 and G2 are independently oxygen or absent, provided that if G1 is oxygen then G2 is absent and if s=0, G1 is oxygen;

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 isabond, n is O and A2 is S(O)m;

W is a heterocycle;

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

Z is selected from:

1) a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
a) C1-4 alkyl, unsubstituted or substituted with:
C1-4 alkoxy, NR6R7, C3-6 cycloalkyl, aryl, heterocycle, HO, -S(O)m R6a, or -C(O)NR6R7, b) aryl or heterocycle, c) halogen, d) OR6, e) NR6R7, f) CN, g) NO2, h) CF3;
i) -S(O)m R6a, j) -C(O)NR6R7, or k) C3-C6 cycloalkyl; and 2) 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 1;
t is 0 or 1; and u is 4 or 5;
or a pharmaceutically acceptable salt thereof.

4. The compound according to Claim 2 of the formula B:

wherein:
R1a is independently selected from: hydrogen and C1-C6 alkyl;
R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, R10O-, -N(R10)2 or C2-C6 alkenyl, and c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent 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 5) ;

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, aryl and heterocycle, unsubstituted or substituted with:
a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle;

R6a is selected from:
C1-4 alkyl and 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)- and 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;

G1 is absent;
G2 is oxygen;

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

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

Z is selected from:
1) a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
a) C1-4 alkyl, unsubstituted or substituted with:
C1-4 alkoxy, NR6R7, C3-6 cycloalkyl, aryl, heterocycle, HO, -S(O)m R6a, or -C(O)NR6R7, b) aryl or heterocycle, c) halogen, d) OR6, e) NR6R7, f) CN, g) NO2, h) CF3;
i) -S(O)m R6a, j) -C(O)NR6R7, or k) C3-C6 cycloalkyl; and 2) 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;
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;
or a pharmaceutically acceptable salt thereof.

5. The compound according to Claim 2 of the formula D:

wherein:

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

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

R3 and R4 independently selected from H and CH3;

R2 is selected from H; ; and C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1 ) aryl, 2) heterocycle, 3) OR6, 4) SR6a, SO2R6a, or 5) ;

and R2, R3 and R4 are optionally attached to the same carbon atom;
R6 and R7 are independently selected from:
H; C1-4 alkyl, C3-6 cycloalkyl, aryl and heterocycle, unsubstituted or substituted with:
a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle;

R6a is selected from:
C1-4 alkyl and 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)- and 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 selected from:
1) a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
a) C1-4 alkyl, unsubstituted or substituted with:
C1-4 alkoxy, NR6R7, C3-6 cycloalkyl, aryl, heterocycle, HO, -S(O)m R6a, or -C(O)NR6R7, b) aryl or heterocycle, c) halogen, d) OR6, e) NR6R7, f) CN, g) NO2, h) CF3;
i) -S(O)m R6a, j) -C(O)NR6R7, or k) C3-C6 cycloalkyl; and 2) 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; and r is 0 to 5, provided that r is 0 when V is hydrogen;
or a pharmaceutically acceptable salt thereof.

6. The compound according to Claim 2 of the formula E:

wherein:

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

R3 and R4 independently selected from H and CH3;

R2 is selected from H; ; and C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl, 2) heterocycle, 3) OR6, 4) SR6a, SO2R6a, or 5) ;

and R2, R3 and R4 are optionally attached to the same carbon atom;
R6 and R7 are independently selected from:
H; C1-4 alkyl, C3-6 cycloalkyl, aryl and heterocycle, unsubstituted or substituted with:
a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle;

R6a is selected from:
C1-4 alkyl and 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 selected from:
1) a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
a) C1-4 alkyl, unsubstituted or substituted with:
C1-4 alkoxy, NR6R7, C3-6 cycloalkyl, aryl, heterocycle, HO, -S(O)m R6a, or -C(O)NR6R7, b) aryl or heterocycle, c) halogen, d) OR6, e) NR6R7, f) CN, g) NO2, h) CF3;
i) -S(O)m R6a, j) -C(O)NR6R7, or k) C3-C6 cycloalkyl; and 2) 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; and p is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof.

7. The compound according to Claim 2 of the formula F:

wherein:

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

R3 and R4 independently selected from H and CH3;

R2 is selected from H; ; and C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl, 2) heterocycle, 3) OR6, 4) SR6a, SO2R6a, or 5) ;

and R2, R3 and R4 are optionally attached to the same carbon atom;
R6 and R7 are independently selected from:
H; C1-4 alkyl, C3-6 cycloalkyl, aryl and heterocycle, unsubstituted or substituted with:
a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle;

R6a is selected from:
C1-4 alkyl and C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle;
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 selected from:
1) a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
a) C1-4 alkyl, unsubstituted or substituted with:
C1-4 alkoxy, NR6R7, C3-6 cycloalkyl, aryl, heterocycle, HO, -S(O)m R6a, or -C(O)NR6R7, b) aryl or heterocycle, c) halogen, d) OR6, e) NR6R7, f) CN, g) NO2, h) CF3;
i) -S(O)m R6a, j) -C(O)NR6R7, or k) C3-C6 cycloalkyl; and 2) 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; and p is 0, 1, 2, 3 or 4;
or pharmaceutically acceptable salt thereof.

8. A compound which inhibits farnesyl-protein transferase which is:
4-[5-(4-Cyanobenzyl)imidazol-1-ylmethyl]-1-phenyl-2-piperidinone 4-[2-{5-(4-Cyanobenzyl)imidazol-1-yl}ethyl]-1-phenyl-2-piperidinone 4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}ethyl]-1-phenyl-2-piperidinone (~)cis-4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}ethyl]-3-methyl-1-phenyl-2-piperidinone (~)trans-4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}ethyl]-3-methyl-1-phenyl-2-piperidinone 4-[2-{1-(4-Cyanobenzyl)-5-imidazolyl}carbonyl]-1-phenyl-2-piperidinone or Ethyl 1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-oxo-4-(3-methylbenzyl)piperidine-4-carboxylate or a pharmaceutically acceptable salt or optical isomer thereof.

9. The compound according to Claim 8 which is:

4-[5-(4-Cyanobenzyl)imidazol-1-ylmethyl]-1-phenyl-2-piperidinone or a pharmaceutically acceptable salt or optical isomer thereof.

10. The compound according to Claim 8 which is:
4-[2-{5-(4-Cyanobenzyl)imidazol-1-yl}ethyl]-1-phenyl-2-piperidinone or a pharmaceutically acceptable salt or optical isomer thereof.

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

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

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

14. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 8.

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 composition of Claim 13.

18. 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 14.

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

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

21. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 13.

22. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 14.

23. 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 12.

24. 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 12.

25. 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 12.

26. A method for preventing restenosis which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12.

27. 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 12.

28. A pharmaceutical composition made by combining the compound of Claim 2 and a pharmaceutically acceptable carrier.

29. A process for making a pharmaceutical composition comprising combining a compound of Claim 2 and a pharmaceutically acceptable carrier.