CA2249605A1 - Inhibitors of farnesyl-protein transferase - Google Patents

Abstract

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

Description

CA 0224960~ 1998-09-23 WO 97/36890 PCT/US97tO5309 TITLE OF THE INVENTION
lNHIBITORS OF FARNESYL-PROTEIN TRANSFERASE

BACKGROUND OF THE INVENTION
The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP.
Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTP-bound form of Ras propagates the growth sttm~ tory signal until the signal is termin~ed 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 mem~rane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminu.s 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 310:583-5~6 (1984)). Depend-ing on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a Cl~ or C20 isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-3~6 (1992); W.R. Schafer and J. Rine, AnM. Rev. Genetics 30:209-237 (1992)). The Ras protein is one CA 0224960~ 1998-09-23 W 097/36890 PCTrUS97/05309 of several proteins that are known to undergo post-translational farnesylation. Other farnesylated proteins include the Ras-related GTP-binding proteins such a.s Rho, fungal mating factors, the nuclear lamin~, and the gamma subunit of transducin. James, et al., J. Biol. Chenl. 2fj9, 5 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. ~ames, 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 10 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 20 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 (19f~9)). These drugs inhibit HMG-CoA reductase, the 25 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-g8 (1990);
Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., 30 Science, 249:1133-1139 (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 localization in cultured cells. However, direct inhibition of farnesyl-CA 0224960~ 1998-09-23 W 097/36890 PCT~US97/05309 protein transferase would be more specific and attended by fewer side effect.s than would occur with the required dose of a general inhibitor of i.soprene bio,synthesis.
Inhibitor.s of farnesyl-protein transferase (FPTase) have been described in four general classes (S. Graham, Expe) t Opinion The~. Patents, (1995) 5:1269-12X5). The fir,st are analogs of farne,syl diphosphate (FPP), while a second class of inhibitors is related to the protein substrates (e.g., Ras) for the enzyme. Bisubstrate inhibitor.s and inhibitors of farnesyl-protein transferase that are non-competitive with the substrates have also been described. The peptide derived inhibitor.s 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; Rei.ss et. al., ihid; Reiss et al., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141,851, University of Texas; N.E. Kohl et al., Science, 2~0:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)). In general, deletion of the thiol from a CAAX
derivative has been shown to dramatically reduce the inhibitory potency of the compound. However, the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity.
Therefore, a functional replacement for the thiol is desirable.
lt has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516). Imidazole-containing inhibitor~s of farnesyl protein transfera,se have also been disclosed (WO 95/09001 and EP0 675 112 A1).
It has recently been reported that farnesyl-protein transferase inhibitors are inhibitons of proliferation of vascular smooth muscle cells and are therefore u,seful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood CA 0224960~ 1998-09-23 W 097/36890 PCT~US97/05309 vessels (JP H7- 1 12930).
It is, therefore, an object of this invention to develop low molecular weight compounds that will inhibit farnesyl-protein transferase and thus, the post-translational farnesylation of proteins.
S It is a further object of thi.s invention to develop chemotherapeutic compositions containing the compounds of this invention and methods for producing the compounds of this invention.

SUMMARY O~ THE INVENTION
The present invention comprises peptidomimetic biheteroaryl-cont~ining compounds which inhibit the farnesyl-protein transferase. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.
The compounds of this invention are illustrated by the formula A:
,9 9~

V ~ A1(CR12)nA2(CR12)n ~ ~ (CR22)p - X -(CR22 1 R5 DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are useful in the inhibition 20 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:

CA 0224960~ 1998-09-23 W 097/36890 PCTrUS97105309 9_9 V - A1 (C R 1 2)nA2(C R 1 2)n ~;W~ (C R22)p - X -(C R22 ¦ R 5 wherein:

from 1-2 of f(s) are independently N or N->O, and the rem~ining fs S are independently CH;

from 1-3 of g(s) are independently N or N->O, and the rem~ining g's are independently CR6;

10 R1 and R2 are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R1 0O, R 11 S(O)m-~ R10C(O)NR 10, R1 lC(o)O-, (R10)2Nc(o)-~ R102N-C(NR10)-, CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10, c) unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-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-, R10C(O)NRl0-~ (R10)2Nc(o)-~
R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and Kl IOC(O)-NR10-;

R3, R4 and RS are independently selected from:
a) hydrogen, CA 0224960~ 1998-09-23 W O 97/36890 PCTrUS97/05309 b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, R I l S(O)m-~ R 10C(o)NR 10, (R l 0)2NC(O)-, R l l C(O)O-, R 1 02N-C(NR 10), CN, NO2, R I ~C(O)-, N3, -N(R 1~)2, or R l l OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~
R102N-C(NR10)-, CN, R10c(o)-~ N3, -N(Rl0)2, and Rlloc(o) NRlO;
each R6 is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, Rl2O-, Rl lS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~ RllC(O)O-, Rl02N-C(NRl0)-, CN, NO2, R10C(o)-, N3, -N(Rl0)2, or R l 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, Rl lS(O)m-, R10C(O)NR10-, (R10)2NC(o)-, Rl02N-C(NRl0)-, CN, Rl0C(O)-, N3, -N(Rl0)2, and R l l OC(O)-NR 10; or CA 0224960~ 1998-09-23 any two of R6 on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

S provided that when R3, R4, R5 or R6 is unsubstituted orsub,stituted heterocycle, attachment of R3, R4, R5, or R6 to the 6-membered heteroaryl ring, is through a substitutable heterocycle ring carbon;

10 R7 is selected from: H; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) "R1' O

f) --So2R
g) N(R 1~)2 or h) C 1-4 perfluoroalkyl;
R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R l Oo, R 1 1 S(O)m ~ R 1 OC(O)NR 10, (R 1 0)2NC(O)-, R 1 02N-C(NR 1 0)-, CN, NO2, R l ~C(O)-~ N3, -N(R 1 0)2, or Rl loc(o)NRlo-~ and c) Cl-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R100-, Rl lS(O)m-, RlOC(O)NH-, (RlO)2Nc(o) CA 0224960~ 1998-09-23 W O 97136890 PCT~US97/05309 R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 0OC(O)NH-;
provided that when R~ is heterocycle, attachment of R~ to V is through a ~substitutable ring carbon;
s R9 is independently selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, Br, Rl lo-, Rl lS(O)m-, R10c(o)NRlo-~
(R 1 0)2NC(O)-, R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) C 1 -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, Rl 1S(O)m-, R10C(O)NRl0-~
(R 1 0)2NC(O)-, R 102N-C(NR 10), CN, R 10C(O)-, N3, -N(R10)2, or R1 lOC(O)NR10-;

R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;

Rl 1 is independently selected from Cl-C6 alkyl and aryl;

R12 is independently selected from hydrogen, Cl-c6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted araLkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;

Al and A2 are independently selected from: a bond, -C~=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-, or S(O)m;

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 heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, 5 provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if A 1 i~s a bond, n is 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to Al is through a substitutable ring carbon;

10 W is a heterocycle;

X is a bond, -CH=CH-, O, -C(=O)-, -C(o)NR7-, -NR7C(o)-, -C(O)O-, -OC(O)-, -C(o)NR7C(o)-, -NR7-, -S(O)2N(R 10), -N(R 1 ~)S(O)2- or -S(=O)m-;
mis 0, 1 or2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
q is 0, 1, 2 or 3;
20 r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1;

or the pharmaceutically acceptable salts thereof.
A preferred embodiment of the compounds of this 25 invention is illustrated by the following formula A:
"9 9~

V A1 (C R 1 2)nAZ(C R 1 Z)n \W¦ - (C R2z)p - X -(CRZz)p~ R s CA 0224960~ 1998-09-23 WO 97/36890 PCTrUS97/05309 wherein:

from 1-2 of f(s) are independently N or N-~O, and the remaining f's are independently CH;
s from 1-3 of g(s) are independently N or N->O, and the rem~ining g's are independently CR6;

R1 is independently selected from: hydrogen, C3-Clo cycloalkyl, 10 R1OO-, -N(R10)2, F or Cl-C6 alkyl;

R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C l o cycloalkyl, R l OO-, -N(R 1 0)2, F
or C2-C6 alkenyl, c) unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, R I OO- and -N(R 1 0)2;

R3, R4 and R5 are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (R10)2NC(o)-, R 102N-C(NR 10), CN, NO2, R 10c(O)-, N3, -N(R10)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl;
d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, CA 0224960~ 1998-09-23 W 097/36890 PCTrUS97/0~309 R 1 20, R 1 1 S(O)m-~ R 1 0C(O)NR 10, (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10;

5 each R6 is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (R10)2NC(o)-, R 1 02N-C(NR 10), CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(o)NR10 c) unsubstituted Cl-C6 alkyl;
d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~
R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10; or any two of R6 on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;~5 provided that when R3, R4, R5 or R6 is unsubstituted or substi~uted heterocycle, attachment of R3, R4, R5, or R6 to the 6-membered heteroaryl ring, is through a substitutable heterocycle ring carbon;
R7 is selected from: H; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1 4 alkoxy, CA 0224960~ 1998-09-23 b) aryl or heterocycle, c) halogen, d) HO, o f) --SO2R
S g) N(Rlo)2 or h) C 1-4 perfluoroalkyl;

R~s is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-c6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F~ Cl, R10O-, R10C(O)NRl0-~ CN, NO2, (R10)2N-C(NR 10), R10C(O)-, -N(R10)2, or Rl lOC(O)NR10-, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;

20 R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R11O-, R11S(O)m-, R10C(O)NR10-, (Rl0)2Nc(o) CN, NO2, (R 1 0)2N-C(NR 10), R 1 ~C(O)-, -N(R 1~)2, or R1 loc(o)NR 10, and c) C 1 -C6 alkyl unsubstituted or substituted by C 1 -C6 perfluoroalkyl, F, Cl, R 1 0O-, R l l S(O)m-, R 1 0C(o)NR 1 0-, (R 1 0)2NC(O)-, CN, (R 1 0)2N-C(NR 10), R 1 ~C(O)-, -N(R10)2, or R1 1OC(O)NR10-;

CA 0224960~ 1998-09-23 W 097/36890 PCTrUS97/05309 R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;

R l l is independently selected from Cl -C6 alkyl and aryl;

Rl2 is independently selected from hydrogen, Cl-c6 alkyl, C1-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;

A1 and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NRl0-, O, -N(Rl0)-, or S(O)m;

15 V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) Cl-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, and provided that V is not hydrogen if Al is S(O)m and V is not hydrogen 25 if Al is a bond, n is 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R~ and to Al is through a substitutable ring carbon;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, 30 pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or isoquinolinyl;

X is a bond, O, -C(=O)-, -CH=CH-, -C(o)NR7-, -NR7C(o)-, -NR7-, -S(O)2N(R l O)-, -N(R lo)s(o)2- or -S(=O)m-;

.

W 097/36890 PCTrUS97/05309 mis 0, l or2;
n is independently 0, l, 2, 3 or 4;
p is independently 0, l, 2, 3 or 4;
S q is 0, l, 2 or 3;
r is 0 to ~, provided that r is 0 when V is hydrogen; and t is 0 or l ;

or the pharmaceutically acceptable salts thereof.
A preferred embodiment of the compounds of this invention are illustrated by the formula B:

V A1(CR12)nA2(CR 2~Nj,~J
B (CR 2)p X R

wherem:

lS from 1-2 of f(s) are independently N or N->O, and the rem~ining f's are independently CH;

from 1-3 of g(s) are independently N or N->O, and the rem~ining g's are independently CR6;
Rl is independently selected from: hydrogen, C3-Clo cycloalkyl, R l OO-, -N(R 1 0)2, F or C ~ -C6 alkyl;

R2 is independently selected from:
a) hydrogen, b~ aryl, heterocycle, C3-Clo cycloalkyl, RlOO-~ -N(Rl0)2, F
or C2-C6 alkenyl, CA 0224960~ 1998-09-23 c) unsubstituted or substituted C I -C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-CIo cycloalkyl, C2-C6 alkenyl, R100- and -N(R10)2;

R3 and R4 are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (R10)2NC(o)-, R102N-C(NR10)-, CN, N02, RlOC(0)-~ N3, -N(R10)2, or Rl l OC(o)NR10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R 1 1 S(O)m ~ R 1 OC(O)NR 10 (R 1 0)2NC(o)-R102N-C(NR10)-, CN, RlOc(o)-~ N3, -N(R10)2, and R 1 1 0C(0)-NR 10;

each R6 is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (R10)2NC(o)-, R102N-C(NR10)-, CN, N02, RlOc(o)-~ N3, -N(R10)2, or R 1 1 0C(0)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or CA 0224960~ 1998-09-23 W 097/36890 PCTrUS97/05309 sub.stituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R 1 1 S(O)m-~ R I OC(O)NR 10 , (R 1 0)2NC(O)-, R102N-C(NR10)-, CN, RlOC(O)-, N3, -N(R10)2, and R 1 1 OC(O)-NR 10; or any two of R6 on adjacent carbon atoms are combined to form a diradical .selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;~0 provided that when R3, R4 or R6 is unsubstituted or substituted heterocycle, attachment of R3, R4 or R6 to the 6-membered heteroaryl ring, is through a substitutable heterocycle ring carbon;~5 R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R100-, RlOc(o)NRlo-~ CN, N02, (R10)2N-C(NR10)-, R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R100-, RlOC(O)NR10-, (R10)2N-C(NR10)-, RlOC(O)-, -N(R10)2, or Rl 1OC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;

R9a and R9b are independently hydrogen, Cl-C6 alkyl, trifluoromethyl and halogen;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;

K11 is independently selected *om C1-C6 alkyl and aryl;

CA 0224960~ 1998-09-23 W 097/36890 PCT~US97/05309 R12 is independently selected from hydrogen, Cl-c6 alkyl, Cl-c6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;

Al and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR 1 0-, O, -N(R 10)-, or S(O)m;
V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, 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, and 20 provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R~ and to Al is through a substitutable ring carbon;

25 X is a bond, -CH=CH-, -C(O~NR10-, -NRlOC(O)-, -NR10-, O or -C(=O)-;

mis 0, 1 or2;
n is independently 0, 1, 2, 3 or 4;
30 pis 0, 1, 2, 3 or4; and r is 0 to 5, provided that r is 0 when V is hydrogen;
or the pharmaceutically acceptable salts thereof.

CA 0224960~ 1998-09-23 W O 97/36890 PCTrUS97/05309 Another preferred embodiment of the compounds of this invention are illustrated by the formula C:

V A (CR 2)nA (CR 2)n~/N
C R9b (CR22)p X R
wherem:

from 1-2 of f(s) are independently N or N->O, and the rem~ining fs are independently CH;

from 1-3 of g(s) are independently N or N->O, and the rem~ining g's 10 are independently CR6;

Rl is independently selected from: hydrogen, C3-Clo cycloalkyl, RlOO-, -N(R10)2, F or Cl-C6 alkyl;

15 R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C l o cycloalkyl, R l OO-, -N(R 1 0)2, F
or C2-C6 alkenyl, c) unsubstituted or sublstituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, RlOO- and -N(R10)2;

R3 and R4 are independently selected from:
2~ a) hydrogen, b) unsubstituted or sub,stituted aryl, un~sub,stituted or substituted heterocycle, C3-clo cycloalkyl, C2-C6 CA 0224960~ 1998-09-23 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, RIOC(O)NR10-, CN(R10)2NC(o)-, R102N-C(NR10)-, CN, NO2, R10C(o)-, N3, -N(R10)2, or R I 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-CIo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (R10)2NC(o)-, R102N-C(NR10)-, CN, R10C(o)-, N3, -N(R10)2, and R 1 1 OC(O)-NR 10;

each R6 is independently selected from:
I S a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, CN(R10)2NC(o)-, R102N-C(NR10)-, CN, NO2, R10C(o)-, N3, -N(R10)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) su~stituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl i.s selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, Rl lS(O)m-, RlOC(o)NRlo- (R10)2NC(o) R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R 1 1 OC(O)-NR 10; or any two of R6 on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CEI-CH2-, -(CH2)4- and -(CH2)3-;

.

CA 0224960~ 1998-09-23 provided that when R3, R4 or R6 is unsubstituted or substituted heterocycle, attachment of R3, R4 or R6 to the 6-membered heteroaryl ring, i~s through a .substitutable heterocycle ring carbon;
s R~ is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-c6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R 1 0O-, R 1 0C(O)NR 10 , CN, NO2, (R 1 0)2N-C(NR 10) , R 10c(O)-, -N(R 1 0)2, or R l 1 OC(O)NR 10, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R10O-, RlOC(O)NR10-, (R10)2N-C(NR10)-, RlOC(O)-, -N(R10)2, or Rl lOC(O)NR10-;
provided that when R8 is heterocycle, attachment of RX to V is through a substitutable ring carbon;

R9a and R9b are independently hydrogen, Cl-C6 alkyl, trifluoromethyl and halogen;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;

R11 is independently selected from Cl-C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-c6 alkyl, Cl-c6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;

Al and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(O~-, -C(O)NR 1 0-, O, -N(R 1 0)-, or S(O)m;

CA 0224960~ 1998-09-23 W 097136890 PCTrUS97/05309 V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, S quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) Cl-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, and 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;
provided that when V is heterocycle, attachrnent of V to R~S and to Al is through a substitutable ring carbon;

X is a bond, -CH=CH-, -C(O)NR 10, -NR 1 ~C(O)-, -NR 10, O or -C(=O)-;

mis 0, 1 or2;
n is independently 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O;
and r is 0 to 5, provided that r is 0 when V is hydrogen;

or the pharmaceutically acceptable salts thereof.
In a more preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula D:

g_ 9 Dga g Al(CR12)n~N I \~ R~ 9 Rsb (CR22)p X R4 CA 0224960~ 1998-09-23 W O 97t36890 PCTrUS97/0~309 wherein:

from 1-2 of f(s) are independently N or N->O, and the remaining f's are independently CH;

*om 1-3 of g(s) are independently N or N->O, and the rem~ining g's are independently CR6;

R l is independently selected from: hydrogen, C3-Clo cycloalkyl or Cl -C6 alkyl;

R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloalkyl, RlOO-, -N(R10)2, F
or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-CIo cycloalkyl, C2-C6 alkenyl, R1OO-, or -N(R 1 ~)2;

20 R3 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NRlO-, (R10)2NC(o)-~
R 1 02N-C(NR 10), CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, CA 0224960~ 1998-09-23 R 1 20, R 1 1 S(O)m-~ R 1 OC(O)NR 10-, (R 1 0)2NC(O)-, R102N-C(NR10)-, CN, RlOC(O)-, N3, -N(R10)2, and R 1 1 OC(O)-NR 10;
5 R4 is selected from H, halogen, Cl-C6 alkyl and CF3;

each R6 is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 20, R 1 1 S(O)m-, R 1 OC(O)NR 10-, (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, N02, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10-, c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, Rl lS(O)m-, RlOC(O)NRlO-, (R10)2Nc(o)-~
R 1 02N-C(NR 10)-, CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10-; or any two of R6 on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R3 or R6 is unsubstituted or substituted heterocycle, attachment of R3 or R6 to the 6-membered heteroaryl ring, is through a substitutable heterocycle ring carbon;

R~ is independently selected from:
a) hydrogen, CA 0224960~ 1998-09-23 W O 97136890 PCT~US97/05309 b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R 1 0O-, R 1 0C(O)NR 10, CN, NO2, (R 1 0)2N-C(NR 10), R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R10O-, RlOC(O)NR10, (Rlo)2N-c(NRlo)- RlO
-N(R 1~)2, or R 1 1 OC(O)NR 10;
provided that when R8 is heterocycle, attachment of Rg to V is through a substitutable ring carbon;
R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl;

R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;

Rl 1 is independently selected from Cl-C6 alkyl and aryl;

R12 is independently selected from hydrogen, Cl-c6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;

25 Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;

X is a bond, -CH=CH-, -C(O)N~10-, -NR10C(O)-, -NR10-, O or -C(=O)-;

n is 0 or 1; provided that n is not 0 if Al is a bond, O~
-N(R10)- or S(O)m;
m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4;

or the pharmaceutically acceptable salt~s thereof.
In another more preferred embodiment of this invention, the inhibitor~s of farne~syl-protein transfera,se are illustrated by the formula E:

g_ 9 ~N~R9a R3 ~-- 9 (CR12)n ,,~N (CR2 ) ~f R4 E

wherein:

from 1-2 of f(s) are independently N or N->O, and the rem~ining i~s are independently CH;
from 1-3 of g(s) are independently N or N->O, and the rem~ining g's are independently CR6;

Rl is independently selected from: hydrogen, C3-Clo cycloalkyl, R1OO-, -N(R10)2, F or Cl-C6 alkyl;

R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloalkyl, RlOO-, -N(R10)2, F
or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, RlOO-, or -N(R 1 ~)2;

R3 is selected from:
a) hydrogen, CA 0224960~ 1998-09-23 WO 97/36890 PCTrUS97/05309 b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 1 20, R 1 1 S(O)m ~ R 1 0C(O)NR 10 , (R 1 0)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(o)-, N3, -N(R10)2, or R 1 1 OC(O)NR 10, c) unsubstituted Cl-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R 1 1 S(O)m-~ R 1 0C(o)NR 10 , (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10;
R4 is selected from H, halogen, C1-C6 alkyl and CF3;

each R6 is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 1 20, R 1 1 S(O)m-~ R 1 0C(o)NR 10 , (R 1 0)2NC(o)-R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R 1 1 OC(O)NR 10 c) unsubstituted C 1 -C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (R10)2NC(o)-, R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10; or CA 0224960~ 1998-09-23 W O 97/36890 PCTrUS97/05309 any two of R6 on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3 or R6 is unsubstituted or substituted heterocycle, attachment of R3 or R6 to the 6-membered heteroaryl ring, is through a substitutable heterocycle ring carbon;

R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-c6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C~-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R10O-, RlOC(O)NR10-, (R10)2N-C(NR10)-, RlOC(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;
R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl;

R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;

Rl 1 is independently selected from Cl-C6 alkyl and aryl;

R12 is independently selected from hydrogen, Cl-c6 alkyl, Cl-c6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;

.. .. .. .. .

CA 0224960~ 1998-09-23 W O 97/36890 PCT~US97105309 - 2~ -X is a bond, -CH=CH-, -C(O)NR10-, -NRlOC(O)-, -NR10-, O or -C(=O)-;

n is 0 or 1 ;
S m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O;

or the pharmaceutically acceptable salts thereof.
In a further embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula F:

CRl ~ 9b NC F

wherem:

from 1-2 of f(s) are independently N or N->O, and the rem~ining fs are independently CH;

from 1-3 of g(s) are independently N or N->O, and the rem~ining g's are independently CR6;

R1 is independently selected from: hydrogen, C3-CIo cycloalkyl or Cl-C6 alkyl;

R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C I o cycloalkyl, R I OO-~ -N(R 1 0)2 or F, CA 0224960~ 1998-09-23 WO 97t36890 PCT/US97/05309 c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl, RlOO-, or-N(R10)2;

R3 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~
R 1 02N-C(NR 1 0)-, CN, NO2, R l OC(O)-, N3, -N(R 1 0)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, RllS(O)m-, RIoc(o)NRlo-~ (R10)2NC(O)-, R102N-C(NR10)-, CN, RlOC(O)-, N3, -N(R10)2, and R11OC(O) NR10;
R4 is selected from H, halogen, CH3 and CF3;

each R6 is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~
R102N-C(NR10)-, CN, NO2, R10c(o)-~ N3, -N(R10)2, or R 1 1 OC(O)NR 10 c) unsubstituted C I -C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or CA 0224960~ 1998-09-23 W 097/36890 PCTrUS97/05309 substituted aryl, unsub~stituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R 1 1 S(O)m-, R 1 OC(O)NR 10 , (R 1 0)2NC(o)-, R102N-C(NR10)-, CN, RlOC(O)-, N3, -N(R10)2, and R 1 1 OC(O)-NR 10-; or any two of R6 on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;~0 provided that when R3 or R6 is unsubstituted or substituted heterocycle, attach~nent of R3 or R6 to the 6-membered heteroaryl ring, is through a substitutable heterocycle ring carbon;
R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl;

R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
Rl 1 is independently selected from Cl-C6 alkyl and aryl;

R12 is independently selected from hydrogen, Cl-c6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
X is a bond, -CH=CH-, -C(O)NR 10-, -NR 1 ~C(O)-, -NR 10-, O or -C(=O)-;

mis 0, 1 or2; and pis 0, 1, 2, 3 or4;

CA 0224960~ 1998-09-23 W O 97/36890 PCT~US97/05309 or the pharmaceutically acceptable ,salt,s thereof.
In a further embodiment of this invention, the inhibitors of farnesyl-protein tran~sferase are illustrated by the formula G:
9~,9'9 NC ~

G
wherein:

from 1-2 of f(s) are independently N or N->O, and the remaining f's are independently CH;
from 1-3 of g(s) are independently N or N->O, and the rem~ining g's are independently CR6;

Rl is independently selected from: hydrogen, C3-C1o cycloalkyl, 15 R l OO-, -N(R 1 0)2, F or C l -C6 alkyl;

R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle or C3-CIo cycloalkyl c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, RlOO-, or -N(R I ~)2;

R3 is selected from:
a) hydrogen, CA 0224960~ 1998-09-23 W 097/36890 PCTrUS97/05309 b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120, Rl lS(o)m, RlOc(o)NRlo-~ (R10)2NC(o)-, R 1 02N-C(NR 10), CN, NO2, R I ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R 1 1 S(O)m-~ R 1 0C(O)NR 1 0 , (R 1 0)2NC(o)-, R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10;
R4 is selected from H, halogen, CH3 and CF3;

each R6 is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~
R102N-C(NR10)-, CN, NO2, R1OC(O)-, N3, -N(R10)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or ~substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R 1 1 S(O)m-~ R 1 0C(o)NR 10, (R 1 0)2NC(O)-, Rl02N-C(NRl0)-, CN, R10C(O)-, N3, -N(R10)2~ and R 1 1 OC(O)-NR 10; or CA 0224960~ 1998-09-23 W 097/36890 rCTrUS97/05309 any two of R6 on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(cH2)3-;

S provided that when R3 or R6 is unsubstituted or ~substituted heterocycle, attachment of R3 or R6 to the 6-membered heteroaryl ring, is through a substitutable heterocycle ring carbon;

R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl;

R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
Rl 1 is independently selected from Cl-C6 alkyl and aryl;

R12 is independently selected from hydrogen, Cl-c6 alkyl, C1-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;

Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;
m is 0, 1 or 2; and n is 0 or I ;

or the pharmaceutically acceptable salts thereof.
Specific examples of the compounds of the invention are:

1 -(2-[Pyrid-2-yl]pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole . . ~ . .

CA 0224960~ 1998-09-23 W 097/36890 PCT~US97/05309 NC ~
~l ~ N ~
N

N- ~ 1 -(4-Cyanobenzyl)- l H-imidazol-5-yl)methyl } -5-(pyrid-2-yl)-2-amino-pyrimidine NC ~ N

~'~ N 1' or the pharmaceutically acceptable salts thereof.
The compounds of the present invention may have 10 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 15 other occurence. Also, combination.s of substituents/or variables are permissible only if such combinations result in stable compounds.
As used herein, "alkyl" and the alkyl portion of aralkyl and similar terms, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of 20 carbon atoms; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
As used herein, "cycloalkyl" is intended to include non-aromatic cyclic hydrocarbon groups having the specified number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, 25 cyclobutyl, cyclopentyl, cyclohexyl and the like.

CA 0224960~ 1998-09-23 W O 97/36890 PCT~US97/05309 "Alkenyl" groups include tho~se groups having the specified number of carbon atom,s and having one or several double bond.s. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, S cyclopentenyl, cyclohexenyl, l-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farne.syl, geranyl, geranylgeranyl and the like.
"Alkynyl" groups include those groups having the specified number of carbon atoms and having one triple bonds. Examples of alkynyl groups include acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl 10 and the like.
"Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.
As used herein, "aryl," and the aryl portion of aroyl and aralkyl, is intended to mean any stable monocyclic or bicyclic carbon 15 ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
The term heterocycle or heterocyclic, as used herein, 20 represents a stable 5- to 7-membered monocyclic or stable ~- to 1 l-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms .selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined 25 heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which result~s in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, 30 benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, CA 0224960~ 1998-09-23 W 097/36890 PCT~US97/05309 naphthyridinyl, 2-oxopyrrolidinyl,, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, 5 thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.
As used herein, "heteroaryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 member,s in each ring, wherein at least one ring is aromatic and wherein from one to four 10 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, 15 dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, 20 tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, and thienyl.
As used herein in the definition of R7, the substituted C1 8 alkyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted 25 heteroarylsulfonyl and substituted heterocycle include moieties containing from l to 3 substituent s in addition to the point of attachment to the rest of the compound.
As used herein, when no specific substituents are set forth, the terms "substituted aryl", "substituted heterocycle" and "substituted 30 cycloalkyl" are intended to include the cyclic group which is substituted on a substitutable ring car~on atom with l or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Cl-C6 alkyl)2, NO2, CN, (cl-c6 alkyl)O-, -OH, (Cl-C6 alkyl)s(o)m-~ (Cl-C6 alkyl)C(O)NH-, H2N-c(NH)-~ (Cl-C6 alkyl)C(O)-, (Cl-C6 alkyl)OC(O)-, N3,(CI-C6 alkyl)OC(O)NH-, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, i.sothiazolyl and Cl-C20 alkyl.
Lines drawn into the ring systems from substituents (such S as from R3, R4 etc.) means that the indicated bond may be attached to any of the substitutable ring carbon atoms.
The moiety designated by the following structure f"f ~,),~f' represents an aromatic 6-membered heterocyclic ring and includes the 10 following ring systems:
o ,~,~ N ~, N~ N ,~,~ N ~ O

The moiety designated by the following structure "f_ f ~,,~f/f represents an aromatic 6-membered heterocyclic ring and includes the 15 following ring sy,stems:

W097t36890 PCTrUS97/05309 N~ N ~ N ~'' ,\~N ~,J N~N ,~J~N

N~N ~N~N HN NH N~
,~0 -~? ,~ N~o wherein it is understood that one of the ring carbon atoms is substituted with 9_9 ~,~9' S Preferably, the aromatic 6-membered heterocyclic ring is a pyridyl ring.
The moiety designated by the following structure 9_9 ~,,,~9' represents an aromatic 6-membered heterocyclic ring and includes the 10 following ring systems:

R6 R6 ,~
N~R6 R6~N R6 R6~ ~ 1 J~ R ~ R6 ~'~ R6 '~ N R6 R6 R6 ,~
N~R6 R6~R6 R6~rR6 HN NH

N~N R6 N~N HN~NH O~N~R6 -~.J~ R6 -~ R6 ~o ~ R6 wherein R6 is as defined hereinabove.
The moiety described as g_g ~,~g' S where any two of R6 on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH-, -(CH2)4-and -(CH2)4- includes, but is not limited to the following ~structures:

.. ... . ..

W097/36890 PCTrUS97/05309 ~r ~r ~ N/~ N~
N,~ ~ N~
~r ~r ¢ ~ ,¢N~

~0 N~3 ~r N~
~r .

It is understood that such fused ring moieties may be further substituted by the rem~ining R6s as defined hereinabove.
Preferably, the "terminal" aromatic 6-membered S heterocyclic ring is a pyridyl ring.
Preferably, Rl and R2 are independently selected from:
hydrogen, Rl 1C(O)O-, -N(R1~)2, R1 OC(O)NR10, R 10o- or unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted 10 phenyl, -N(R10)2, R100- and RlOC(O)NR10-.
Preferably, R3 is selected from:
a) hydrogen, b) C3-Clo cycloalkyl, halogen, Cl-C6 perfluoroalkyl, R120-, CN, N02, R 1 ~C(O)- or -N(R 1 ~)2, c) unsubstituted Cl-C6 alkyl, CA 0224960~ 1998-09-23 d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is ,selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R 1 I S(O)m-~ R 1 OC(O)NR 10 , (R 1 0)2NC(0)-, R 1 02N-C(NR 10) , CN, R 1 ~C(0)-, N3, -N(R 1~)2, and R110C(O) NR10 Preferably, R4 is selected from: hydro~en, halogen, 10 trifluoromethyl, trifluoromethoxy and Cl-C6 alkyl.
Preferably, R5 is hydrogen.
Preferably, R6 is independently selected from:
a) hydrogen, b) C3-Clo cycloalkyl, halogen, Cl-C6 perfluoroalkyl, R120-, R 1 1 S(O)m ~ CN, N02, R 1 ~C(0)- or -N(R 1 ~)2, c) unsubstituted Cl-C6 alkyl;
d) substituted C1-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl i~s selected from unsubstituted or substituted aryl, C3-Clo cycloalkyl, R120-, Rl lS(O)m-, R l OC(0)- or -N(R 1 0)2; or any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(cH2)4- and-(CH2)3-.
Preferably, R~ is independently selected from:
a) hydrogen, and b) aryl, substituted aryl, heterocycle, substituted heterocycle, Cl-C6 perfluoroalkyl or CN.
Preferably, R9 is hydrogen, halogen, CF3 or methyl.
Preferably, R10 is selected from H, Cl-C6 alkyl and benzyl.
Preferably, Al and A2 are independently selected from:
a bond, -C(O)NR10-, -NR1OC(0)-, 0, -N(R10)-, -S(0)2N(R10)- and-N(R 1 ~)S(0)2 CA 0224960~ 1998-09-23 W 097/36890 PCTrUS97/05309 Preferably, V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.
Preferably, W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More S preferably, W is selected from imidazolyl and pyridyl.
Preferably, n and r are independently 0, 1, or 2.
Preferably s is 0.
Preferably t is 1.
Preferably from 1-2 of f(s) are independently N, and the 10 rem~ining fs are independently CH.
Preferably from 1-3 of g(s) are independently N, and the remainirlg g's are independently CR6.
Preferably, the moiety (F18)r ~g~

V Al(CRl2)nA2(CR12)ntWl - (CR 2)p - X -(CR 2)p 15 is selected from:
R9a R9b N \~N

R9b and ~f ~CH~9a NC NC
It is intended that the definition of any substituent or variable (e.g., Rl, R2, R9, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule.
20 Thus, -N(R10)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be W 097/36890 PCTrUS97/05309 readily synthesized by techniques known in the art, a.s 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 5 of this invention as formed, e.g., from non-toxic inorganic or organic acid,s. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such a,s acetic, propionic, succinic, glycolic, stearic, 10 lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
The pharmaceutically acceptable salts of the compounds 15 of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or 20 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 1-12, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature 25 or exemplified in the experimental procedures. Substituents R3, R6 and R8, as shown in the Schemes, represent the substituents R3, R4, R5, R6 and R8; although only one such R3, R6 or R8 is present in the intermediates and products of the schemes, it is understood that the reactions shown are also applicable when such aryl or heteroaryl 30 moieties contain multiple substituents.
These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Schemes. The reactions described in the ... .. .......

CA 0224960~ 1998-09-23 Scheme.s are illustrative only and are not meant to be limiting. Other reactions useful in the preparation of heteroaryl moietie,s are described in "Comprehensive Organic Chemistry, Volume 4: Heterocyclic Compounds" ed. P.G. Sammes, Oxford (1979) and references therein.
5 Aryl-aryl coupling is generally de,scribed in "Comprehensive Organic Functional Group Transformations," Katritsky et al. eds., pp 472-473, Pergamon Press (1995).

Synopsis of Schemes 1-12:
The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures, for the most part. Schemes 1-12 illustrate synthesis of the instant biheteroaryl compound which incorporate a preferred benzylimidazolyl sidechain.
Thus, in Scheme 1, for example, a biheteroaryl intermediate that is not 15 commercially available may be synthesized by methods known in the art. Thus, a suitably substituted pyridyl boronic acid I may be reacted under Suzuki coupling conditions (Pllre Appl. Chem., 63:419 (1991)) with a suitably substituted halogenated nicotinic acid, such as 4-bromo-nicotinic acid, to provide the biheteroaryl carboxylic acid II. The acid 20 may be reduced and the triflate of the intermediate alcohol III may be formed in situ and coupled to a suitably substituted benzylimidazolyl IV
to provide, after deprotection, the instant compound V.
Schemes 2-4 illustrate other methods of synthesizing the key alcohol intermediates, which can then be processed as described in 25 Scheme 1. Thus, Scheme 2 illustrates the analogous series of bihetero-aryl alcohol forming reactions starting with the methyl nicotinate boronic acid and the "terminal" heteroaryl moiety employed in the Suzuki coupling as the halogenated reactant. Such a coupling reaction is also compatible when one of the reactants incorporates a suitably 30 protected hydroxyl functionality as illustrated in Scheme 3.
Negishi chemistry (Org. Synth., 66:67 (l9~s)) may also be employed to form the biheteroaryl component of the instant compounds, as shown in Scheme 4. Thus, a suitably substituted zinc bromide adduct may be coupled to a suitably substituted heteroaryl CA 0224960~ 1998-09-23 W 097/36890 PCT~US97/05309 halide in the presence of nickel (Il) to provide the biheteroaryl VII.
The heteroaryl halide and the zinc bromide adduct may be selected based on the availability of the starting reagents.
Scheme 5 illustrates the preparation of the pyridylmethanol 5 interrnediate starting with the 3-methyl pyridine.
As illustrated in Scheme 6, the se4uence of coupling reactions may be modified such that the heteroaryl-heteroaryl bond is formed last. Thus, a suitably substituted imidazole may first be alkylated with a suitably substituted benzyl halide to provide 10 intermediate VIII. Intermediate VIII can then undergo Suzuki type coupling to a suitably substituted pyridyl boronic acid.
Scheme 7 illustrates synthesi.s of an instant compound wherein a non-hydrogen R9b is incorporated in the instant compound.
Thus, a readily available 4-substituted imidazole IX may be selectively 15 iodinated to provide the 5-iodoimidazole X. That imidazole may then be protected and coupled to a suitably substituted benzyl moiety to provide intermediate XI. Intermediate XI can then undergo the alkylation reactions that were described hereinabove.
Scheme fs illustrates synthesis of instant compounds that 20 incorporate a preferred imidazolyl moiety connected to the biaryl via an alkyl amino, sulfonamide or amide linker. Thus, the 4-aminoalkyl-imidazole XII, wherein the primary amine is protected as the phthalimide, is selectively alkylated then deprotected to provide the amine XIII. The amine XIII may then react under conditions well 25 known in the art with various activated biheteroaryl moieties to provide the instant compounds shown.
Compounds of the instant invention wherein the A l (CR l 2)nA2(CR l 2)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 9.
30 The suitably substituted phenol XIV may be reacted with methyl N-(cyano)meth~nimidate to provide the 4-phenoxyimidazole XV.
After selective protection of one of the imidazolyl nitrogens, the intermediate XVI can undergo alkylation reactions as described for the benzylimidazoles hereinabove.

.~ . .

CA 0224960~ 1998-09-23 W O 97/36890 PCTrUS97/05309 Scheme 10 illustrates an analogous series of reactions wherein the (CR22)pX(CR22)p linker of the instant compounds is oxygen. Thus, a suitably substituted halopyridinol, such as 3-chloro-2-pyridinol, is reacted with methyl N-(cyano)methanimidate to provide 5 intermediate XVI. lntermediate XVI is then protected and, if desired to form a compound of a preferred embodiment, alkylated with a suitably protected benzyl. The intermediate XVII can then be coupled to a heteroaryl moiety by Suzuki chemistry to provide the instant compound.
Compounds of the instant invention wherein the 10 A 1 (CR 1 2)nA2(CR 1 2)n linker is a substituted methylene may be synthesized by the methods shown in Scheme 11. Thus, the N-protected imidazolyl iodide XVIII is reacted, under Grignard conditions with a suitably protected benzaldehyde to provide the alcohol XIX. Acylation, followed by the alkylation procedure illustrated in the Schemes above 15 (in particular, Scheme 1) provides the instant compound XX. If other R1 substituent s are desired, the acetyl moiety can be manipulated as illustrated in the Scheme.
Scheme 12 illustrates the use of halogenated 2-amino-pyrimidine in the preapration of compounds of the instant invention.

N Br (HO)2B N

o R2 pd(pph3)4 N~ LiAlH4 HO~'\ 2 O 11 ~ R6 . . . . ~. .

W 097/36890 PCTrUS97/05309 - 4~ -SCHEME I (continued) Tr T~
N C ,( Ph~)2 ~il R6 f~ ~ N~ (CF3S02)20,;780C ~
H~ ~\R2 NEtiPr2 -78~C-20~C

~_~,N~,~R2 55~C H30H

~q J~,~

/~ V

r~N 6 ~,N~ B(OH)2 ,J~ R
MeO ,~\
~ \ 2 Pd(PPh3)4 ~N R6 ~N~ LiAlH4 MeO~
o R2 N~N R6 HoJ~,\

...... . .... ..

W 097/36890 PCTrUS97/05309 SC~nE~DE 3 N~B(OH)2 J~--, R6 R3SiO,~,\ r R2 Pd(PPh3)4 ~N~,I R6 N~ Bu4NF
R3SiO~J~,\
R~N~

HO~,\

N~ (HO) BJ~N\J?

R2 Pd(PPh3)4 ~ R6 N~N~ Bu4NF
R3SiOJ~'\R2 1~ R6 N~N
HO J~\J~

11/ BrZn/~
R3SiOJ~
\R2 NiCI2(PPh3)2 ~;N~ Bu4NF
R3SiO ~'\ 2 ~ R6 HOJ~,\

O N ~f~; O
~,Znl ~,NH

R3SiO ~\R2 NiCI2(PPh3)2 H

0~ N~pO
~N~NH Bu4NF
R3SiO~,~R2 H
Oq~N~O
,~N~I~ N H
~~~\~ 2 -W 097/36890 PCTrUS97/05309 (H~)2B ~ 4 R2 Pd(Pph3)4 N~ R6 LiAlH4 HO2C ~\R2 N~ ? R
HoJ~,\

W 097/36890 PCTrUS97/05309 Tr~

<~N j; MeOH
reflux /~d ~ J~ Pd(PP

R8 Vlll 1~ R6 ~Nq ~N
~_ N ~,\, N
~/ R2 R8/~

W 097/36890 PCTnJS97/05309 H H
Rgb~ Nal, NaHCO3,!~ Rsb~ TrCI, NEt~

IX X

Rsb~_ ~IC~I~h~2 ~N

Tr ~ R6 R9b~--~N OTf~\R2 ~/ i. -78~C-20~C
/~J ii. MeOH, reflux Xl \ ~, SCHEME ~

0~
<O Rs~~Br <N~l 1~l 55~C,CH3CN
N~ N~3i. EtOH,80~C. NH2NH2 o Xll N
<' '11 R8 ~/
~d Xlll acylation, sulfonylation </ 31 ~ R2 or alkylation R~ N ~/~

R~/ H ~R6 _~N31\--NH ~ ~ 9 .. . .

W 097/36890 PCTrUS97/05309 ~,--OH i~ Na, MeOH
NC ~/ ii. 1 20~C
XIV H3C~o N--\~N

H Tr~
N N
~N Trcl~ NEt3 r ~ N
~0 _~0 NC ~/ NC \~1 XV XVI

T~ 78~C-20~C

<~N + ~N ii. MeOH reflux ~~ OTf NC ~\~

XVI

~ ~R6 ~0 NC ~\~

W O 97/36890 PCT~US97/05309 N

~ N\~_ OH i, Na, MeOH <~N
Cl--~\J ii. 120~C ~N\~_o R2 H3C~o Cl \J

N~ R2 XVI

~/~
Tr~ J~l TrCI, NEt3 ~N OTf -78~C-20~C
~ \~~~ ii. MeOH reflux Cl ~\J

R2 R8 ~B(OH)2 N ~ J~ ~N
Cl~ \~O DMF, Pd(PPh3)4 \=IJ K3PO4, 80~C

N

R 6~ lR~ ~

W 097/36890 PCT~US97105309 - 5~ -Tr <N~
N~ EtMgBr ~N

<~ N ~ ~OH

9~g'9 Ac20, PY N~ R2~9'9 ~OA (CF3SO2)20,-78~C
R8/ NEtiPr2,CH2Cl2 9~ ~R6 g LiOH

~OAc R2 9 ~ R6 N [~,~' '9 R8/~J OH

CA 0224960', 1998-09-23 SCHEME 11 (continued) 9~9'9 '~N'~\~ NH3, MeOH

/J Cl g~ ~ R6 ~3--N,J~

~J NH2 9~ 9 R6 --NJ~
~ R2 8 / ~ OMe WO 97/368gO rCTlUSg7105309 N~ (HO)2B/~N~
H2N~N

<N3~,CI

R-N~\ 6 ~N~ N

CA 0224960~ 1998-09-23 W O 97/36890 PCTrUS97/05309 The instant compounds are u,seful a,~i pharmaceutical agents for m~mm~ls, e~pecially for humans. The,se compounds may be administered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compound.s of thi,'i 5 invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors.
Such tumors may arise by mutation~s in the r as genes themselves, mutations in the proteins that can regulate Ras activity (i.e., neurofibromin (NF-l), neu, scr, abl, lck, fyn) or by other mechanisms.
The compounds of the instant invention inhibit farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
The instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. 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 ~lmini~tration of an effective amount of the compounds of the invention to a m~mmal in need of such treatment. For example, a component of NF- I 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 ( 1 992).
The compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Natu1 e medicine, 1:541-545(1995).
The instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al.

CA 0224960~ 1998-09-23 W 097/36890 PCT~US97/05309 American Journal of Path~logy, 142:1051-1060 (1993) and B. Cowley, Jr. et al .FASEB Journal, 2:A3160 ( l 9~S~)).
The instant compounds may also be useful for the treatment of fungal infections.
The compounds of this invention may be administered to m~mmals, 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 10 compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
For oral use of a chemotherapeutic compound according to this invention, the selected compound may be administered, for 15 example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral ~ministration in capsule form, useful diluents include lactose and dried 20 corn starch. When aqueous suspension,s 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 25 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-a~lministered with other well known therapeutic agents that are 30 selected for their particular usefulness against the condition that is being treated. For example, the instant compounds may be u~seful 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 CA 0224960~ 1998-09-23 W 097/36890 PCTrUS97/0~309 kidney 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 pharmaceutical 10 composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the compound~
of this invention, with or without pharrnaceutically 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 nJection.
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, a~s well as the severity of the patient's symptoms.
In one exemplary application, a suitable amount of compound is administered 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/lcg of body weight to about 40 mg/kg of body weight per day.
The compounds of the instant invention are also useful a.s a component in an assay to rapidly determine the presence and CA 0224960~ 1998-09-23 W 097/36890 PCTrUS97/05309 quantity of farnesyl-protein transferase (FPTase) in a composition.
Thus the compo~sition 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 sub.strate, the chemical content of the assay mixtures may be determined 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 cont~ining 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 20 and quantitating the enzyme. Thus, potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract containing an unknown amount of 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 tirne 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 subst~ntially smaller than the concen-30 tration of enzyme in the assay vessel) required to inhibit the enzymaticactivity of the sample by 50% is approximately equal to half of the concentration of the enzyme in that particular sample.

CA 0224960~ 1998-09-23 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.

1 -(2-1 Pyrid-2-yllpyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole.

Step A: 2-Trifluoromethanesulfonyloxy-5-pyridine carboxylic acid To a solution of 2-hydroxy 5-pyridine carboxylic acid (lg5 mg, 1.33 mmol) and diisopropylethylamine (0.464 mL, 2.66 15 mmol) in dichloromethane (7 mL) at -7~~C is added trifluoromethane-sulfonic anhydride (0.224 mL, 1.33 mmol) and the mixture stirred at -78~C for I hour and then at ambient temperature for I hour. The reaction is diluted with water and extracted with CH2C12, and the organic extract is dried, (MgSO4) and the solvent is evaporated in 20 vacuo. The residue is purified by chromatography to afford the title compound.

Step B: 2-(Pyrid-2-yl)-5-pyridine carboxylic acid A mixture of 2-trifluoromethanesulfonyloxy-5-pyridine-25 carboxylic acid (0.442 g, 1.72 mmol), 2-pyridylboronic acid (1.57 g, 12.79 mmol), barium hydroxide (0.813 mg, 2.5~s mrnol), DME (~ mL) and water (1.5 mL) is purged with dry argon. Tetrakis(triphenyl-phosphine) palladium(0) (99.0 mg, 0.0~S6 mmol) is added, and the resultant solution is stirred at ~0~C for 4 hours. The solvents are 30 evaporated in vacuo, and the residue is partitioned between EtOAc and water. The aqueous extract is separated, and extracted with EtOAc.
The organic extracts are combined, washed with sat. aq. NaHCO3 and 5% aq. Na2S2O3, dried, (Na2SO4) and the solvent is evaporated in CA 0224960~ 1998-09-23 W 097/36890 PCTrUS97/05309 vacuo. The residue is purified by chromatography to afford the title compound.

Step C: 2-(Pyrid-2-yl)-5-hydroxymethyl-pyridine To a solution of 2-(pyrid-2-yl)-5-pyridine carboxylic acid (0.320 g, 1.60 mmol) in THF (5 mL) at 0~C is added 1.0 M lithium aluminum hydride in diethyl ether (1.60 mL, 1.60 mmol) over 10 minutes. The reaction is allowed to stir at ambient temperature for 3 hours, cooled to 0~C, and water (0.10 mL), 4 N aq. NaOH (0.10 mL), 10 and water (0.30 mL) are added sequentially. The reaction is filtered through a pad of Celite and the filtrate is evaporated in vacuo. The residue is purified by chromatography to afford the title compound.

Step D: 1 -(2-(Pyrid-2-yl) pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole To a solution of 2-(pyrid-2-yl)-5-hydroxymethyl-pyridine (269 mg, 1.33 mmol) and diisopropylethylamine (0.464 mL, 2.66 mmol) in dichloromethane (7 mL) at -7g~C is added trifluoromethane-sulfonic anhydride (0.224 mL, 1.33 mmol) and the mixture stirred at 20 -7g~C for 1 hour. To this mixture is added a solution of l-trityl-4-(4-cyanobenzyl)-imidazole (566mg, 1.33 mmol) in dichloromethane (5 mL). The mixture is allowed to warm to ambient temperature and stirred for 2 hours. The solvent is evaporated in vacuo. The residue is dissolved in methanol (50 mL), heated at reflux for 1 hour, and 25 the solvent is evaporated in vacuo. The residue is partitioned between dichloromethane and sat. a4. NaHCO3 solution. The organic layer is dried, (Na2SO4) and the solvent evaporated in vacuo. The residue is chromatographed to afford the title compound.

N- { 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl)methyl } -5-(pyrid-2-yl)-2-amino-pyrimidine CA 0224960~ 1998-09-23 W O97/36890 PCT~US97/05309 Step A: 5-(Pyrid-2-yl)-2-aminopyrimidine A mixture of 2-amino-5-bromopyrimidine (0.299 g, 1.72 mmol), 2-pyridylboronic acid (1.57 g, 12.79 mmol), barium hydroxide (0.813 mg, 2.5~ mmol), DME (~ mL) and water (1.5 mL) 5 is purged with dry argon. Tetrakis(triphenylphosphine) palladium(0) (99.0 mg, 0.0~6 mmol) is added, and the resultant solution is stirred at fs0~C for 4 hours. The solvents are evaporated in vacuo, and the residue is partitioned between EtOAc and water. The aqueous extract is separated, and extracted with EtOAc. The organic extracts are 10 combined, washed with sat. aq. NaHCO3 and 5% aq Na2s2o3 dried, (Na2so4) and the solvent is evaporated in vacuo. The residue is purified by chromatography to afford the title compound.

Step B: l-Triphenylmethyl-4-(hydroxymethyl)imidazol To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260 mmol) in dry DMF (250 mL) at room temperature was added triethylamine (90.6 mL, 650 mmol). A white solid precipitated from the solution. Chlorotriphenylmethane (76.1 g, 273 mmol) in DMF (500 mL) was added dropwise. The reaction 20 mixture was stirred for 20 hours, poured over ice, filtered, and washed with ice water. The resulting product was slurried with cold dioxane, filtered, and dried in vacuo to provide the titled product as a white solid which was sufficiently pure for use in the next step.

25 Step C: I-Triphenylmethyl-4-(acetoxymethyl)-imidazole The alcohol from Step B (260 mmol, prepared above) wa.s suspended in pyridine (500 mL). Acetic anhydride (74 mL, 7~0 mmol) was added dropwise, and the reaction was stirred for 4~ hours during which it became homogeneous. The solution was poured into EtOAc, 30 washed sequentially with water, 5% aq. HCI solution, sat. aq. NaHCO3, solution, and brine. The organic extracts were dried, (Na2SO4), and concentrated in vacuo to provide the product as a white powder, which was sufficiently pure for use in the next reaction.

.. . .

CA 0224960~ 1998-09-23 WO 97/36890 PCTrUS97/05309 Step D: 1 -(4-Cyanobenzyl)-S-(acetoxymethyl)-imidazole hydrobromide A solution of the product from Step C (85.8 g, 225 mmol) and 4-cyanobenzyl bromide (50.1 g, 232 mmol) in EtOAc (SOO mL) was stirred at 60~C for 20 hours, during which a pale yellow precipitate formed. The reaction was cooled to room temperature and filtered to provide the solid imidazolium bromide salt. The filtrate was concentrated in vacuo to a volume (200 mL), heated at 60~C for 2 hours, cooled to room temperature, and filtered. The filtrate was concentrated in vacuo to a volume (100 mL), heated at 60~C for 2 hours, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in methanol (SOO mL), and warmed to 60~C. After 2 hours, the solution was concentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble by products. Removal of residual solvents in vacuo provided the titled product as a white solid which was used in the next step without further purification.

Step E: I -(4-Cyanobenzyl)-S-(hydroxymethyl)-imidazole To a solution of the acetate from Step D (50.4 g, lSO
mmol) in 3:1 THF/water (l.S L) at 0~C was added lithium hydroxide monohydrate (18.9 g, 450 mmol). After 1 hour, the reaction was concentrated in vacuo, diluted with EtOAc (3 L), and washed with water, sat. aq. NaHC03 and brine. The solution was then dried (Na2S04), filtered, and concentrated in vacuo to provide the crude product as a pale yellow fluffy solid which was sufficiently pure for use in the next step without further purification.

Step ~ (4-Cyanobenzyl)-S-(chloromethyl)-imidazol A solution of 1-(4-cyanobenzyl)-S-(hydroxymethyl)-imidazole (l.OOg, 4.70 mmol), in thionyl chloride (S mL), was stirred at 70~C for 16 hours. The solvent was evaporated in vacuo and the resulting solid suspended in CH2C12, collected by filtration and dried CA 0224960~ 1998-09-23 in vacuo. The material was sufficiently pure for use in the next step without further purification.
lH NMR (CD30D 400MHz) ~ 9.06 (lH, s), 7.~s3(2H, d, J=8.0Hz), 7.77(1H, s), 7.55(2H, d, J=~s.OHz), 5.67(2H, s) and 4.78(2H, ~s) ppm.
s Step G: N- ~ 1 -(4-Cyanobenzyl)- 1 H-imidazol-S-yl)methyl } -5-(pyrid-2-yl)-2-amino pyrimidine To a solution of the chloride from step F (SOOmg, 1.65 mmol) in DMF (10 mL) at 0~C is added sequentially, the amine from step A (284mg, 1.65 mmol) and sodium hydride (145mg, 60%
dispersion in mineral oil, 3.62 mmol). Stirring is continued at 0~C
for 1 hour and then at room temperature for 16 hours. The reaction is quenched with water (50 mL), and extracted with CH2C12. The organic extracts are dried, (MgS04), and the solvent is evaporated in vacuo.
The residue is purified by chromatography to afford the title compound In vitro inhibition of ra.s farnesyl transferase Assays offarnesyl-protein transferase. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) were prepared as described by Schaber et al., J. Biol. Chem. 265: 14701 -14704 (1990), Pompliano, etal., Biochemistry 31:3800 (1992) and Gibbs et al., PNAS U.S.A. 86:6630-6634 (1989), respectively. Bovine FPTase was assayed in a volume of 100 ,ul containing 100 mM N-(2-hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH
7.4, 5 mM MgC12, 5 mM dithiothreitol (DTT), 100 mM [3H]-farnesyl diphosphate ([3H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM ~as-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; les~s than 10% of the [3H~-FPP was .. . . .. . . ..... ...

CA 0224960~ 1998-09-23 W 097/36890 PCTrUS97/05309 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 incorpora-tion of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound.
Human FPTase was prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity wa.s assayed as described above with the exception that 0.1 % (w/v) polyethylene glycol 20~000, 10 ~lM ZnC12 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 ~1 of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
The compounds of the instant invention are tested for inhibitory activity against human FPTase by the assay described above.

In vivo ras farnesylation assay The cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21.
The assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51 :712-717, (1991). Cells in 10 cm dishes at 50-75%
confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1 %). After 4 hours at 37~C, the cells are labelled in 3 ml methionine-free DMEM supple-meted with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[35S]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are Iysed in 1 ml Iysis buffer (1 % NP40/20 mM HEPES, pH 7.5/5 mM MgC12/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the Iy,sates cleared by centrifugation at 100,000 x g for 45 min. Aliquots of Iysates containing equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (Iysis buffer lacking DTT) and immunoprecipitated with the ras-specific CA 0224960~ 1998-09-23 W 097/36890 PCTrUS97/05309 monoclonal antibody Y13-259 (Furth, M.E. et al., J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at 4~C, 200 ml of a 25% suspension of protein A-Sepharose coated with rabbit anti rat IgG
is added for 45 min. The immunoprecipitates are washed four time~
5 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 reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to lO farnesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein.

15 In viv~ growth inhibition assay To deterrnine the biological consequences of FPTase inhibition, the effect of the compounds of the instant invention on the anchorage-independent growth of Ratl cells transformed with either a v-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Raf 20 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 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 25 medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layers contain 0.1% methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay).
The cells are fed twice weekly with 0.5 ml of medium A containing 30 0.1 % methanol or the concentration of the instant compound. Photo-micrographs are taken 16 days after the cultures are seeded and comparisons are made.

.. . ..

Claims (28)

WHAT IS CLAIMED IS:

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

wherein:

from 1-2 of f(s) are independently N or N->O, and the remaining f's are independently CH;

from 1-3 of g(s) are independently N or N->O, and the remaining's are independently CR6;

R1 and R2 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-, R11C(O)O-, (R10)2NC(O)-, R102N-C(NR10), CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent 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-;

R3, R4 and R5 are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)- R11C(O)O-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

each R6 is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R11C(O)O-, R10 2N-C(NR10)-, CN, NO2. R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6 on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R3, R4, R5 or R6 is unsubstituted or substituted heterocycle, attachment of R3, R4, R5, or R6 to the 6-membered heteroaryl ring, is through a substitutable heterocycle ring carbon;

R7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, , f) -SO2R11 , g) N(R10)2 or h) C1-4 perfluoroalkyl;

R8 is independently selected from:
a) hydrogen, b) aryl, substituted 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-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;

R9 is independently selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Br, R11O-, 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, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
Al and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, -S(O)2N(R10) , -N(R10)S(O)2-, or S(O)m;

V is selected from:
a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a 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 O and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to A1 is through a substitutable ring carbon;

W is a heterocycle;

X is a bond, -CH=CH-, O, -C(=O)-, -C(O)NR7-, -NR7C(O)-, -C(O)O-, -OC(O)-, -C(O)NR7C(O)-, -NR7-, -S(O)2N(R10)-, -N(R10)S(O)2- or -S(=O)m-;

m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
q is 0, 1, 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1;
or a pharmaceutically acceptable salt thereof.

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

wherein:

from 1-2 of f(s) are independently N or N->O, and the remaining f's are independently CH;

from 1-3 of g(s) are independently N or N->O, and the remaining g's are independently CR6;

R1 is independently selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F or C1-C6 alkyl;

R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O- and -N(R10)2;

R3, R4 and R5 are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, 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-, c) unsubstituted C1-C6 alkyl;
d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

each R6 is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, 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-, c) unsubstituted C1-C6 alkyl;
d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Cl0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6 on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R3, R4, R5 or R6 is unsubstituted or substituted heterocycle, attachment of R3, R4, R5, or R6 to the 6-membered heteroaryl ring, is through a substitutable heterocycle ring carbon;

R7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, , f) ~SO2R11 , g) N(R10)2 or h) C1-4 perfluoroalkyl;

R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, 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-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R11O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, 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-, (R10)2NC(O)-, CN, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;

V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, 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, 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;

provided that when V is heterocycle, attachment of V to R8 and to A1 is through a substitutable ring carbon;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or isoquinolinyl;

X is a bond, O, -C(=O)-, -CH=CH-, -C(O)NR7-, -NR7C(O)-, -NR7-, -S(O)2N(R10)-, -N(R10)S(O)2- or -S(=O)m-;

m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
q is 0, 1, 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1;
or a pharmaceutically acceptable salt thereof.

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

wherein:

from 1-2 of f(s) are independently N or N->0, and the remaining f's are independently CH;

from 1-3 of g(s) are independently N or N->0, and the remaining g's are independently CR6;

R1 is independently selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F or C1-C6 alkyl;

R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O- and -N(R10)2;

R3 and R4 are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, 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-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

each R6 is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, 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-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6 on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R3, R4 or R6 is unsubstituted or substituted heterocycle, attachment of R3, R4 or R6 to the 6-membered heteroaryl ring, is through a substitutable heterocycle ring carbon;

R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, 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-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;

R9a and R9b are independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;

V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, 4uinolinyl, isoquinolinyl, triazolyl and thienyl, 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, 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;
provided that when V is heterocycle, attachment of V to RX and to A1 is through a substitutable ring carbon;

X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR10-, O or -C(=O)-;

m is 0, 1 or 2;
n is independently 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.

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

wherein:

from 1-2 of f(s) are independently N or N->O, and the remaining f's are independently CH;

from 1-3 of g(s) are independently N or N->O, and the remaining g's are independently CR6;

R1 is independently selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F or C1-C6 alkyl;

R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle. C3-C10 cycloalkyl, C2-C6 alkenyl, R10O- and -N(R10)2;

R3 and R4 are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O, 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-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

each R6 is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12)-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-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2. and R11OC(O)-NR10-; or any two of R6 on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R3, R4 or R6 is unsubstituted or substituted heterocycle, attachment of R3, R4 or R6 to the 6-membered heteroaryl ring, is through a substitutable heterocycle ring carbon;

R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, 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-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;

R9a and R9b are independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;

V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, 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, 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;
provided that when V is heterocycle, attachment of V to R8 and to A1 is through a substitutable ring carbon;

X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR10-, O or -C(=O)-;

m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O;
and r is 0 to 5, provided that r is 0 when V is hydrogen;
or a pharmaceutically acceptable salt thereof.

5. The compound according to Claim 3 of the formula D:

wherein:

from 1-2 of f(s) are independently N or N->O, and the remaining f's are independently CH;

from 1-3 of g(s) are independently N or N->O, and the remaining g's are independently CR6;

R1 is independently selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl;

R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O-, or -N(R10)2;

R3 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, 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-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is elected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;
R4 is selected from H, halogen, C1-C6 alkyl and CF3;

each R6 is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, 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-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10), CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6 on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R3 or R6 is unsubstituted or substituted heterocycle, attachment of R3 or R6 to the 6-membered heteroaryl ring, is through a substitutable heterocycle ring carbon;

R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, 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-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;

R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A1 is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR10-, O or -C(=O)-;

n is 0 or 1; provided that n is not 0 if A1 is a bond, O, -N(R10)- or S(O)m;
m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof.

6. The compound according to Claim 4 of the formula E:

wherein:

from 1-2 of f(s) are independently N or N->O, and the remaining f's are independently CH;

from 1-3 of g(s) are independently N or N->O, and the remaining g's are independently CR6;

R1 is independently selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F or C1-C6 alkyl;

R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O-, or -N(R10)2;

R3 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O, 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-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O, R11S(O)m-, R1OC(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;
R4 is selected from H, halogen, C1-C6 alkyl and CF3;
each R6 is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, 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-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10; or any two of R6 on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R3 or R6 is unsubstituted or substituted heterocycle, attachment of R3 or R6 to the 6-membered heteroaryl ring, is through a substitutable heterocycle ring carbon;

R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, 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-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;

R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;

R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
X is a bond, -CH=CH-, -C(O)NR10-, -NR1OC(O)-, -NR10-, O or -C(=O)-;

n is 0 or 1;
m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O;
or a pharmaceutically acceptable salt thereof.

7. The compound according to Claim 5 of the formula F:

wherein:

from 1-2 of f(s) are independently N or N->O, and the remaining f's are independently CH;

from 1-3 of g(s) are independently N or N->O, and the remaining g's are independently CR6;

R1 i.s independently selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl;

R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2 or F, c) C1-C6 alkyl unsubstituted or sublstituted by aryl, heterocycle, C3-C10 cycloalkyl, R10O-, or -N(R10)2;

R3 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsub.stituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, 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-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

R4 i,s selected from H, halogen, CH3 and CF3;

each R6 is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, 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-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6 on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R3 or R6 is unsubstituted or substituted heterocycle, attachment of R3 or R6 to the 6-membered heteroaryl ring, is through a substitutable heterocycle ring carbon;

R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;

X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR10-, O or -C(=O)-;

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

8. The compound according to Claim 6 of the formula G:

wherein:

from 1-2 of f(s) are independently N or N->O, and the remaining f's are independently CH;

from 1-3 of g(s) are independently N or N->O, and the remaining g's are independently CR6;

R1 is independently selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F or C1-C6 alkyl;

R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle or C3-C10 cycloalkyl c) C1-C6 alkyl un,substituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O-, or -N(R10)2;

R3 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O, 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-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;
R4 is selected from H, halogen, CH3 and CF3;

each R6 is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsub,stituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, 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-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6 on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and-(CH2)3-;

provided that when R3 or R6 is unsubstituted or substituted heterocycle, attachment of R3 or R6 to the 6-membered heteroaryl ring, is through a substitutable heterocycle ring carbon;

R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A1 is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;

m is 0, 1 or 2; and n is 0 or 1;

or the pharmaceutically acceptable salts thereof.

9. A compound which inhibits famesyl-protein transferase which is:

1-(2-[Pyrid-2-yl]pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole N-{1-(4-Cyanobenzyl)-1H-imidazol-5-yl)methyl}-5-(pyrid-2-yl)-2-amino-pyrimidine or a pharmaceutically acceptable salt thereof.

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

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

12. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 4.

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

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

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

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

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

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

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 neurofibromin benign proliferative disorder which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 10.

23. 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 10.

24. 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 10.

25. A method for preventing restenosis which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 10.

26. 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 10.

27. A pharmaceutical composition made by combining the compound of Claim 1 and a pharmaceutically acceptable carrier.

28. A process for making a pharmaceutical composition comprising combining a compound of Claim 1 and a pharmaceutically acceptable carrier.