CA2250204A1 - 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 022~0204 1998-09-24 TITLE OF THE INVENTION
INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE

BACKGROUND OF THE INVENTION
The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ra~) are part of a ~ignalling 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, Ra,s is bound to G~P.
Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTP-bound form of Ra~s propagates the growth stimulatory signal until the signal i~ terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M. Willumsen, Ann. Rev. Bi~chem. ~2:X51-~91 (1993)). Mutated ras genes (Ha-~ as, Ki4a-7 as, Ki4b-ras and N-ra~) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of the~se genes are defective in their GTPase activity and con~stitutively transmit a growth stimulatory ~signal.
Ras must be localized to the pla~;ma membrane for both normal and oncogenic functions. At least 3 post-translational modification.s are involved with Ras membrane localization, and all 3 modification~ occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-Aaal-Aaa2-Xaa"
box (Cys is cy~teine? Aaa is an aliphatic amino acid, the Xaa i~s any amino acid) (Willumsen et al., Natu~-e 310:5~3-5~6 (19~4)). Depend-ing on the ~pecific ~sequence, this motif serves as a ~iignal se~uence for the enzyme~i f~rnesyl-protein transferase or geranylgeranyl-protein transferase~ which catalyze the alkylation of the cysteine residue of the CAAX motif with a Cl~ or C2() i~oprenoid, re~ipectively. (S. Clarke., Ann. Rel~. Bioehenl. ~1:355-3~6 (1992); W.R. Schafer and J. Rine, Ann. Rel!. Genelie~ 30:209-237 (1992)). The Ra~ protein i.~ one of ~ieveral protein~ that are known to undergo po~t-translational W O 97/36585 PCT~US97/06259 farnesylation. Other farnesylated proteins include the Ra.s-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. Jarnes, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also sugge.sted that there are farnesylated proteins of unknown structure and function in addition to those listed above.
Inhibition of farnesyl-protein transferase ha.s been .shown to block the growth of Ras-transforrned cell.s in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of farnesyl-protein tran.sferase .selectively block the processing of the Ras oncoprotein intracellularly (N.E. Kohl et al., S~ience, 2~0:1934-1937 (1993) and G.L. James et al., S~ienc~e, 2~0:1937-1942 (1993). Recently, it ha.s been shown that an inhibitor of farnesyl-protein transfera.se blocks the growth of ras-dependent tumors in nude mice (N.E. Kohl et al., p~AO(~. Natl. Ac~ad.
Sci U.S.A ., 91 :9141 -9145 (1994) and induces regression of mammary and salivary carcinomas in ras transgenic mice (N.E. Kohl et al., Nature Medicine, 1:792-797 (1995).
Indirect inhibition of farnesyl-protein transfera.se i~Z ViV(~
has been demonstrated with lovastatin (Merck & Co., Rahway, NJ) and compactin (Hancock et al., ihid; Casey et al., ihid; Schafer et C~
S~ience 245:379 (19~9)). These drug.s inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoid.s including farnesyl pyrophosphate. Farnesyl-protein tranlsferase utilize.s farne~syl pyrophosphate to covalently modify the Cys thiol group of the Ra.s CAAX box with a farnesyl group (Rei.ss et al., Cell, f)2:Xl -~ (1990);
Schaber etal., J. Bi~l. Chen1., 2~5:14701-14704 (1990); Schafer etal., Scie~lce, 249:1133-1139 (1990); Manne et al., Pr0c. Natl. Acad. Sci USA. 87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase block.s R~.s membrane localization in cultured cell.s. However, direct inhibition of farne.syl-protein transfera.se would be more specific and attended by fewer .side effects than would occur with the re4uired dose of a general inhibitor CA 022~0204 1998-09-24 W O 97/36585 PCTrUS97106259 of isoprene biosynthesis.
Inhibitors of farnesyl-protein transferase (FPTase) have been described in four general classes (S. Graham, Expe7t Opinion Ther. Patents, (1995) 5:1269-1285). The first are analogs of farne.syl 5 diphosphate (FPP), while a second clas.s 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 inhibitors that have been described are generally cysteine containing molecules 10 that are related to the CAAX motif that is the signal for protein prenyl-ation. (Schaber et ~11., ihid; Reiss et. al., il~id; Reiss ef f~l., PNAS, f~8:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein trans-ferase enzyme, or may be purely competitive inhibitors (U.S. Patent 15 5,141,~51, Univer.sity of Texas; N.E. Kohl et al., S~ien~, 260:1934-1937 (1993); Graham, et al., J. Med. Chen1., 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 place.s limitations 20 on the therapeutic application of FPTase inhibitors with respect to pharrnacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol i~s desirable.
It has recently been disclo.sed that certain tricyclic compounds which optionally incorporate a piperidine moiety are 25 inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516).
Imidazole-containing inhibitors of farnesyl protein transferase have also been disclo.sed (WO 95/09001 and EP 0 675 112 Al).
It has recently been reported that farnesyl-protein transferase inhibitor.s are inhibitor.s of proliferation of vasculal- smooth 30 muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7-112930).
It is, therefore, an object of this invention to develop W O 97/36585 PCTrUS97/06259 low molecular weight compounds that will inhibit farnesyl-protein transferase and thus, the post-translational farnesylation of proteins.
It is a further object of this invention to develop chemotherapeutic compositions containing the compounds of this invention and methods 5 for producing the compounds of this invention.

SUMMARY OF THE INVENTION
The present invention comprises biheteroaryl-containing compound~s which inhibit the farnesyl-protein transferase. Further 10 contained in this invention are chemotherapeutic compo~ition,s containing these farnesyl transferase inhibitors and methods for their production, The compounds of this invention are illustrated by the formula A:
R6a-d (Fl8)r /(~9~ b~a~e' V - A1 (CR12)nA2(CR 12)n ~W~l - (CR22)p - X -(CR22~ R5 A

W O 97/36585 PCT~US97/06259 DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are useful in the inhibition of farne~yl-protein transferase and the farnesylation of the oncogene protein Ras. In a first embodiment of this invention, the inhibitors of 5 farnesyl-protein transferase are illustrated by the formula A:
R6a-d ( l 8)r ~R9~\ bà~e' V - A (CR 2)nA (CR 2)ntW~ (CR22)p - X -(CR22~ R5 wherem:

a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the rem~ining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
15 a' is N or C;

from 0-4 of b', c'. d' and e' are independently N. NH, O and S, and the remaining b', c', d' and e' atoms are independently CH, provided that if a' i,s C, then at least one of b', c', d' or e' i~ independently N, NH, O or 20 S;
~ - Rl ~nd R2 are independently selected from:
a) hydrogen, b) aryl. heterocycle, C3-CIo cycloalkvl. C2-C6 alkenyl, CA 022~0204 1998-09-24 C2-C6 alkynyl, R~0O-, Rl 1S(O)m-, Rl lC(o)O-, R 1 0C(O)NR 10, (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R I 1 OC(O)NR 10 c) unsubstituted or substituted Cl-C6 alkyl wherein the S substituent on the ~substituted Cl-c6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R100-, RllS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o) R 1 02N-C(NR 10), CN, R I ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10;

R3, R4 and R5 are independently selected from:
a) hydrogen, b) unsub~stituted or sub~stituted aryl, unsubstituted or ~sub,stituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 ~Ikynyl, halogen, Cl-C6 perfluoroalkyl, R120, Rl lS(o)m, Rloc(o)NRlo-~ Rl lc(o)o-, (R 1 0)2NC(o)-, R 1 02N-C(NR 10), CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)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, C~-CIo 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 I ~C(O)-, N3, -N(R 1~)2, and R l 10C(O)-NR10-;

R6a, R6b R6C and R6d are independently selected from:
a) hydrogen, b) un.substituted or substituted aryl, unsubstituted or ~sub~stituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-c6 alkynyl, halogen, Cl-c6 perfluoroalkyl, R 1 20, R I 1 S(O)m ~ R 1 0C(O)NR 10, R 1 I C(O)O-, CA 022~0204 1998-09-24 W 097/36585 PCTrUS97/06259 (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, NO2, R 1 ~C(O)-, N3, -N(R10)2, or Rl IOC(O)NRl0-, c) un,substituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the S ~ub~itituted Cl-C6 alkyl is ~elected from unsubstituted orsubstituted aryl, unsub~tituted or ~ubstituted heterocyclic, C3-C1o 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 1 0 R 1 1 OC(O) NR 10 ;

R7 i,s selected from: H; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, un~iubstituted or substituted with:
a) C1 4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) ~ R

f) --SO2R
g) N(R10)2 or h) C 1-4 perfluoroalkyl;

R~ is independently selected from:
a) hydrogen, b) aryl, sub.stituted aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, Rl lS(O)m-, R10C(o)NR10-, (R10)2NC(o)-~
R102N-C(NR10)-, CN, NO2, R10C(o)-, N3, -N(R10)2, or R 1 1 OC(O)NR 10, and WO g7/36585 PCTtUS97/062!j9 c) Cl-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0O-, R 1 1 S(O)m ~ R 1 0C(O)NH-, (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, R I ~C(O)-, N3, -N(R 1~)2, or R 1 0OC(O)NH-;
provided that when R~ is heterocycle, attachment of R8 to V is through a substitutable ring carbon;

10 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)NRl0-~
(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) Cl-C6 alkyl unsub.stituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, Rl lS(O)m-, R10C(O)NR10-, (R 1 0)2NC(O)-, R 1 02N-C(NR 10) , CN, R 1 ~C(O)-, N3, -N(R 1~)2, or R I 1 OC(O)NR 10-;
R10 i.s independently selected from hydrogen, C]-C6 alkyl, 2,2,2-trifluoroethyl, benzyl 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 sub~stituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2 2-trifluoroethyl;

A 1 and A2 are independently selected from: a bond, -CH=CH-, -C-C-, -C(O)-, -C(O)NR 10, -NR I ~C(O)-, O, -N(R 10) , -S(O)2N(R 10), -N(R I ~)S(O)2-, or S(O)m;

W O 97/36585 PCTrUS97/06259 - V i~ selected from:
a) hydrogen, b) heterocycle, S c) aryl, d) Cl-C20 alkyl wherein from 0 to 4 carbon atom,s are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, 10 provided that V is not hydrogen if Al i~i S(O)m and V i~s not hydrogen if Al i~ a bond, n is 0 and A2 ;~s S(O)nl; and provided that when V i~ heterocycle, attachment of V to R~ and to Al i~
through a ~substitutable ring carbon;

1~ W is a heterocycle;

X i.s 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(RIo)s(o)2- or -S(=O)m-, provided that if a i.s N, then X i,s not O, -C(o)NR7-, -C(O)O-, -C(o)NR7C(o)-, -S(0)2N(R10)- or-NR7-;

mis 0, 1 or2;
n i,~ independently 0, 1, 2, 3 or 4;
2~ p i!i independently 0, 1, 2, 3 or 4;
q i~ 0, 1, 2 or 3;
r i!i 0 to ~. provided that r i~ 0 when V i~i hydro~en; and t i~ 0 or 1;

30 or the pharmaceutically acceptable ~alt~ thereof.
A preferred embodiment of the compound~; of this invention is illu~strated by the following formula A:

W O 97/36585 ~CTrUS97/06259 R6a-d (I )r ~RW~
V - A (CR 2)nA (CR 2)n - (CR22)p - X -(CR22~ R5 wherein:
a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and the rem~ining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;

a' is N or C;

from 0-4 of b', c', d' and e' are independently N, NH, O and S, and the remaining b', c'. d' and e' atoms are independently CH, provided that if a' is C, then at least one of b', c', d' or e' i.s independently N, NH, O or S;

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

R2 is independently selected from:
a) hydro~en, b) aryl. heterocycle, C3 -C I o cycloalkyl. R l OO-, -N(R 1 ~)2 F Ol C~-C6 alkenyl, c) un.~iubstituted or substituted Cl-C6 alky] wherein the sub~tituent on the ~ubstituted Cl-C6 alkyl is ~;elected from CA 022~0204 1998-09-24 W O 97/36585 PCTrUS97/062~9 unsubstituted or sub.stituted aryl, heterocycle, C3-Clo Gycloalkyl, C2-C6 alkenyl, RlOO- and -N(R10)2;

R3~ R4 and R5 are independently selected from:
5 a) hydrogen, b) unsubstituted or substituted aryl, un~substituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen~ Cl-c6 perfluoroalkyl, R 1 20, R 1 1 S (~)m-, R 1 OC(O)NR 10 , (R 1 0)2NC(O)-, R1o2N-c(NRlo)-~ CN, NO2, RIOC(o)-~ N3~ -N(R10)2, or R I 1 OC(O)NR 10 c) unsub,stituted Cl-C6 alkyl;
d) .substituted Cl-C6 alkyl wherein the sub.stituent on the sub~stituted 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(o)-, R102N-C(NR10)-, CN, RlOC(O)-, N3, -N(R10)2, and R 1 1 OC(O)-NR 10;
R6a, R6b, R6c ~nd R6d are independently .selected *om:
a) hydrogen, b) unsub.stituted 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, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 c) un.sub,stituted Cl-C6 alkyl;
30 d) .substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl i~s selected from unsub.stituted 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 ~

W O 97/36585 PCT~US97/06259 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;

R7 is selected from: H; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, 5 aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsublstituted or ~ubstituted with:
a) Cl 4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, o f) --SO2R
g) N(R 1~)2 or h) C 1_4 perfluoroalkyl;

R2 is independently selected from:
a) hydrogen, b) aryl, _stituted 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 .~ubstituted by Cl-C6 perfluoroalkyl, R10O-, R 1 0C(O)NR 1 0-, (R 1 0)2N-C(NR 1 0)-, R 1 ~C(O)-, -N(R 1~)2, or R I I OC(O)NR 10-;
provided that when R~ heterocycle, attachment of R~ to V i~
through a ~substitutable ring carbon;

R9 is ~elected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F~
Cl, Rl lo-, Rl lS(O)m-, R10C(O)NR10-, (Rl0)2Nc(o) CA 022~0204 1998-09-24 W O 97/36585 PCTrUS97/06259 CN, NO2, (R 1 0)2N-C(NR 10), R 1 ~C(O)-, -N(R 1 ~)2 or Rl lOC(O)NR10-, and c) Cl-C6 alkyl unsubstituted or substituted by Cl-C6 perfluoroalkyl, F, Cl, R 1 0O-, R 1 1 S(O)m-~ R 1 0C(O)NR 10, S (R 1 0)2NC(o)-, CN, (R 1 0)2N-C(NR 10), R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10;

R10 is independently selected from hydrogen, Cl-C6 alkyl~ 2,2,2-trifluoroethyl. benzyl and aryl;
Rl I is independently l~ielected from Cl-C6 alkyl and aryl;

R12 j~ independently selected from hydrogen, Cl-C6 alkyl, Cl-C6 aralkyl, Cl-C6 .substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 sub~tituted heteroaralkyl, aryl, ~ubstituted aryl, heteroaryl, sub~tituted heteroaryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;

A ~ 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, V is ~ielected from:
a) hydrogen, b) heterocycle l~elected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, i.soquinolinyl, triazolyl and thienyl, c) aryl, d) Cl-C20 alkyl wherein from 0 to 4 carbon atom,s are replaced with a a heteroatom .~elected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al i~ S(O)m and V i~ not hydrogen if Al i.~i a bond, n i~ 0 and A2 i,~; S(O)m;

WO 97136585 PCT~US97/062S9 provided that when V i.s heterocycle, attachment of V to R~ and to Al i~s through a substitutable ring carbon;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, 5 pyridinyl, thiazolyl, oxazolyl, indolyl, ~luinolinyl, triazolyl or isoquinolinyl;

X i.s a bond, 0, -C~=0)-, -CH=CH-, -C(o)NR7-, -NR7C(o)-, -NR7-~
-S(0)2N(R10)-, -N(R10)s(o)2- or-S(-O)m-; provided I0 that if a is N, then X i.s not 0~ -C(o)NR7-~-s(o)2N(Rlo) or -NR7;

mis 0, 1 or2;
n is independently 0, 1, 2, 3 or 4;
15 p is independently 0, 1, 2, 3 or 4;
clis 0,1,20r3;
r i.s 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1 ;

20 or the pharmaceutically acceptable salts thereof.
A preferred embodiment of the compounds of thi~
invention are illustrated by the formula B:
R6a-d ( lR8)r R9~ R à~

V ~ Al(CR12)nA2(CR12)~N,~ \~ à~R4 R (C R22)F X

wherein:
a i.s N or C;

CA 022~0204 1998-09-24 from 0-4 of b, c, d and e are independently N, NH, O and S, and the ~ rem~ining b. c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e i.s independently N, NH, O or S;

S a' is N or C:

from 0-4 of b', c', d' and e' are independently N, NH, O and S, and the remaining b~ c', d' and e' atoms are independently CH, provided that if ~' is C, then at lea.st one of b'. c'~ d' or e' is independently N. NH, O or 10 S;

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

15 R2 is independently .~elected from:
a) hydrogen, b) aryl~ heterocycle, C3-C I o cycloalkyl, R I OO-, -N(R 1 0)2, F or C2-C6 alkenyl, c) unsubstituted or substituted Cl-C6 alkyl wherein the ~ubstituent on the substituted Cl-C6 alkyl is ~selected from un~ubstituted or sub.stituted aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, RIOO- and -N(R10)2;

R3 and R4 ~re independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or ~ub.stituted heterocycle, C3-clo cycloalkyl, C2-C6 ~Ikenyl, C2-C6 alkynyl~ halogen, Cl-C6 perfluoroalkyl, R120-, RllS(O)m-, RIOC(O)NR10-, (R10)2NC(o)-, R10~N-C(NRlO)-, CN, NO2, RIOC(o)-~ N3, -N(R10)2, or R l l OC(O)NR l o-c) un,sub~stituted Cl-C6 alkyl, d) ~ubstituted Cl-c6 alkyl wherein the ~ub,stituent on the ~ub.stituted Cl-c6 alkyl i,~ .selected from un,sub.stituted or W 097/36585 PCT~US97/06259 ~substituted aryl, unsubstituted or ,substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R I I S(O)m-, R 1 0C(O)NR 10, (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R1 1OC(O) NR10;

R6a, R6b, R6C and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsub~tituted or sub~stituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C:2-C6 alkynyl halogen, Cl-C6 perfluoroalkyl, R 1 20, R I 1 S(O)m-~ R 1 0C(O)NR 10, (R 1 0)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) un.substituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the sub~stituted Cl-C6 alkyl is selected from unsub~tituted or substituted aryl, unsub,stituted or substituted heterocyclic, C3-CIo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R I I S(O)m-, R 1 0C(O)NR 1 0-, (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, R I ~C(O)-, N3, -N(R 1 ~)2, and R11OC(O) NR10;

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 ~O-, R 1 0C(O)NR 10 CN. NO2, (R 1 0)2N-C(NR 10), R I ~C(O)-, -N(R 1~)2, or R I 1 OC(O)NR 10, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R10O-, R 1 0C(O)NR 10, (R 1 0)2N-C(NR 10), R 1 ~C(O)-, -N(R10)2, or Rl IOC(O)NRl0-;
provided that when R~ i.s heterocycle, attachment of RX to V i.s through a sub~stitutable ring carbon;

CA 022~0204 1998-09-24 W O 97/3658S PCT~US97/06259 R9a and R9b are independently hydrogen, C I -C6 alkyl, trifluoromethyl and halogen;

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

R l I is independently selected from Cl -C6 alkyl and aryl;
~0 R12 is independently ~selected from hydrogen, Cl-C6 alkyl, Cl-C6 aralkyl, Cl-c6 ~sub~tituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 ,sub~tituted heteroaralkyl, aryl, ~ub~tituted aryl, heteroaryl, ~sub.stituted heteroaryl, 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)NR10-, O, -N(R10)-, or S(O)m;

V is .selected from:
a) hydrogen, b) heterocycle ,~elected 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 atom~ are replaced with a a heteroatom ~elected from O, S, and N, and e) C2-C20 alkenyl~ and provided that V i.~ not hydrogen if A~ S(O)m and V i~ not hydl-ogen 30 if A1 i~ a bond, n i~ 0 and A2 i~ S(O)m;
provided that when V i~ heterocycle, att~chment of V to Rg and to A
through a ,~ub.stitutable ring carbon;

W O 97/36585 PCTAUS97tO6259 X is a bond, -CH=CH-, -C(O)NR 10, -NR 1 ~C(03-, -NR 10, 0 or -C(=O)-;
provided that if a is N, then X is not -C(O)NR10-, -NR10-, or 0;

5 mi.s 0, 1 or2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4; and r is 0 to 5, provided that r i.s 0 when V is hydrogen;

10 or the pharmaceutically acceptable ~alt,s thereof.
Another preferred embodiment of the compound.s of thi.s invention are illu,strated by the forrnula C:
6a-d (R8)r R3 1 V- Al(cRl2)nA2(cR12)n~/~ à~e' C R9b (CR22)F)(/
.

wherem:
a i,s N or C;

from 0-4 of b, c, d and e are independently N, NH, 0 and S, and the rem~ining b, c, d and e atoms are independently CH, provided that if a 20 is C, then at least one of b, c. d or e i~s independently N, NH, 0 or S;
a' is N or C;

from 0-4 of b', c'. d' ~nd e' are independently N, NH, 0 and S, and the 25 remaining b'. c', d' and e' atoms are independently CH, provided that if ar i,s C, then at lea,st one of b', c', d' or e' i.s independently N, NH, 0 or S;

CA 022~0204 1998-09-24 W O 97136585 PCTrUS97/06259 R1 is independently selected from: hydrogen, C3-clo cycloalkyl, R10O-, -N(R10)2, F or C1-C6 alkyl;

5 R2 i~s independently ~elected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloalkyl, RIOO-~ -N(R10)2, F or C2-C6 alkenyl, c) unsubstituted or ~ubstituted Cl-C6 alkyl wherein the ~ub~tituent on the substituted Cl-C6 alkyl i.~ selected from unsubstituted or substituted aryh heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, R100- ;md -N(R10)2;

R3 and R4 are independently ~ielected from:
a) hydrogen, b) unsubstituted or substituted aryl, un~ub~tituted 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, CN(R I 0)2NC(O)-, R 1 02N-C(NR 1 0)-, CN, NO2, R l OC(O)-, N3 ? -N(R I o)27 or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) ~ubstituted Cl-C6 alkyl wherein the ~substituent on the ~ubstituted Cl-C6 alkyl i~ elected from un~sub~tituted or .substituted aryl, unsubstituted or substituted heterocyclic, C~-CIo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R I 1 S(O)m ~ R 1 OC(O)NR 10, (R 1 0)2NC(O)-, R102N-C(NR10)-, CN, RlOC(O)- N~, -N(R10)2~ and RllOc(o)NRlo;
R6a R6b R6C and R6d are independently ,~elected from:
a) hydrogen, b) un_stituted or ~iub~tituted aryl. un~iub.stituted or .~ub.~tituted heterocycle. C3-Clo cycloalkyl, C2-C6 W O 97/36585 PCT~US97/06259 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 20 , R 1 I S(O)m-~ R 1 0C(O)NR 1 0-, CN(R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, NO2, R 1 ~C(O)-, N3, -N(R 1 ~)2, or R 1 1 OC(O)NR 10 c) un.substituted Cl-C6 alkyl, d) .substituted Cl-C6 alkyl wherein the ~substituent on the substituted Cl-C6 alkyl is .~ielected from unsubstituted or .substituted aryl, un~ubstituted 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 1 O-? (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, R l Oc(O)-? N3, -N(R 1 ~)2, and RllOc(o) NRlO;

R~ 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 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10 ~ and c) Cl-C6 alkyl sub,~tituted by Cl-C6 perfluoroalkyl, R 1 0O R 1 0C(O)NR 10 , (R 1 0)2N-C(NR 10) , R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10;
provided that when Rg is heterocycle, attachrnent of R~ to V is through a sub,stitutable ring carbon;
R9a and R9b are independently hydrogen, Cl-C6 alkyl, trifluoromethyl and halogen;

R10 i~ independently selected from hydrogen, Cl-C6 alkyl, 2,2,2-trifluoroethyl, benzyi and aryl;

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

CA 022~0204 1998-09-24 R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-c6 aralkyl, Cl-C6 sub,stituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, sub~stituted heteroaryl, 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 I 0)-, or S(O)m;

10 V i~ selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, Lluinolinyl, i,soquinolinyl, triazolyl and thienyl, c) aryl, d) Cl-C20 alkyl wherein from 0 to 4 carbon atom.~ are replaced with a a heteroatom ~ielected from O, S, and N, and e) C2-C20 alkenyl, and 20 provided that V i~ not hydrogen if Al is S(O)m and V is not hydrogen if Al i~ a bond, n i~ 0 and A2 is S(O)m;
provided that when V i~ heterocycle, attachment of V to RX and to A
through a .substitutable ring carbon;

2~ X i.~ a bond, -CH=CH-, -C(O)NR 10, -NR 1 ~C(O)-, -NR 10-, O or -C(=O)-;
provided that if a i~ N, then X i.s not -C(O)NR10-, -NR10- or O;

mis 0, 1 or2;
ni~; 0, 1, 2, 3 or4;
p i.~i 0~ 1, 2, 3 or 4, provided that p i~ not 0 if X i~ a bond, -NR 10 or O; and r i~ 0 to ~, provided that r i~ 0 when V i~i hydrogen;

or the phalmaceutically acceptable .salts thereof.
In a more preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula D:
6a-d (CR12)l~--N ~ ~J

9b (C R2 ) X

wherein:
a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and the rem~ining b, c, d and e atoms are independently CH, provided that if a i,s C, then at least one of b, c, d or e is independently N, NH, O or S;

a' is N orC;
from 0-4 of b', c', d' and e' are independently N, NH, O and S, and the remaining b', c', d' and e' atoms are independently CH, provided that if a' is C, then at least one of b', c', d' or e' is independently N, NH, O or S;
Rl is independently selected from: hydrogen, C3-Clo cycloalkyl Cl-C6 alkyl;

R2 i,s independently .selected from:
a) hydrogen.
b) aryl. heterocycle, C3-CIo cycloalkyl, RlOO-, -N(R10)2, CA 022~0204 1998-09-24 W O 97/36585 PCTrUS97/06259 F or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C1o cycloalkyl, C2-C6 alkenyl, R100-, or -N(R 1 ~)2;

R3 i~s ~selected from:
a) hydrogen, b) unsubstituted or substituted aryl, un~substituted or substituted heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 20, R 1 I S(O)m-, R I OC(O)NR 1 0-, (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, N02, R I ~C(O)-, N3, -N(R 1~)2, or R I 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) ~ub~stituted Cl-C6 alkyl wherein the ~ubstituent on the substituted Cl-C6 alkyl i~; selected from unsubstituted or substituted aryl, un~substituted or sub,stituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (R10)2NC(o)-, R102N-C(NR10)-, CN, RlOC(O)-, N3, -N(R10)2, and R 1 1 OC(O)-NR 10;

R4 is selected from H, halogen, C1-C6 alkyl and CF3;

25 R6a, R6b, R6C and R6d 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, Rl~O-, Rl lS(O)m-, RlOC(O)NR10-, (R10)2Nc(o)-~
R10~N-C(NRlO)-, CN, N02, RIOC(O)-~ N3. -N(R10)2, or R 1 1 OC(O)NR 10, c) un.sub~stituted Cl-C6 alkyl, W O 97t36585 PCT~US97/06259 d) sublstituted Cl-C6 alkyl wherein the substituent on the substituted C~-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)-, R 1 02N-C(NR 1 0)-, CN, R l OC(O)-, N3, -N(R 1 0)2, and Rl IOC(O)-NRlO;

RX i~s independently ,selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6 allcenyl, C2-C6 alkynyl, C~-C6 perfluoroalkyl, F, Cl, R l 0O, R 1 OC(O)NR 10, CN, N02, (R 1 0)2N-C(NR 1 0), 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-, R 1 OC(O)NR 1~-, (R 1 0)2N-C(NR 10), R 1 ~C(O)-, -N(R10)2, or Rl lOC(O)NR10-;
provided that when R8 is heterocycle, attachment of R~ to V is through a substitutable ring carbon;
R9a and R9b are independently hydrogen~ halogen, CF3 or methyl;

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

Rl'~ i.s independently selected from hydrogen, Cl-c6 alkyl, Cl-c6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 ,sublstituted heteroaralkyl, aryl, substituted aryl, heteroaryl, .sub,stituted heteroaryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluo1oethyl;

Al i.s Iselected from: a bond, -C(O)-, 0~ -N(R10)-, or S(O)m;

W 097/36585 PCT~US97/06259 X is a bond, -CH=CH-, -C(O)NR10-, -NRlOC(O)-, -NR10-, O or -C(=O)-, provided that if a i~s N, then X is not -C(O)NR10-, -NR10-or O;

n is 0 or 1; provided that n is not 0 if A l is a bond, O, -N(R10)-, or S(O)m;
m is 0, 1 or 2; and pis 0, 1, 2, 3 or4;
or the pharmaceutically acceptable salt,s thereof.
In another more preferred embodiment of this invention, the inhibitors of farne~yl-protein transferase are illustrated by the formula E:
R6a-d R

2)n ~;/ \ à~R4 9b (CR22)p X

~¦~ E

wherein:
a i.s N or C;

20 from 0-4 of b~ c, d and e are independently N, NH, O and S, and the rem~ining b, c, d and e atoms are independently CH, provided that if a i,s C. then at lea~st one of b, c, d or e i.s independently N, NH, O or S;

a' i!i N or C;

W O 97/36585 PCT~US97/06259 from 0-4 of b', c', d' and e' are independently N, NH, O and ~, and the remaining b', c', d' and e' atoms are independent]y CH, provided that if a' is C, then at least one of b', c', d' or e' i,s independently N, NH, O or S;

Rl is independently .selected from: hydrogen, R10O-, -N(R10)2, F, C3-C l o cycloalkyl or C l -C6 alkyl;

R2 is independent]y selected from:
a) hydrogen, b) aryl, heterocycle, C3-C I o cycloalkyl. R 1 ~O-~ -N(R 1 ~)2 F or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted Ol substituted by aryl, heterocycle, C3-CIo cycloalkyl, C2-C6 alkenyl, R10O-, or 1 :S -N(R 1 ~)2;

R3 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or .~ubstituted heterocycle, C3-CIo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C~ perfluoroalkyl, 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, 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 ~;ubstituent on the .substituted Cl-C6 alkyl i,s ,selected from unsub.stituted or sub,stituted aryl, un,sub~stituted or ~substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R I I S(~)m-, R 1 0C(O)NR 1{~ , (R 1 0)2NC(O)-, R102N-c(NRlo)-~ CN, R10C(O)-~ N3, -N(RIo)2~ and R I 1 OC(O)-NR 10;

R4 is ,~ielected from H~ halogen, Cl-C6 alkyl and CF3;

CA 022~0204 1998-09-24 W 097136585 PCT~US97/06259 R6a R6b, R6C and R6d 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, R 1 20, R 1 1 S(O)m-, R 1 OC(O)NR 10, (R 1 0)2NC(O)-, R102N-C(NR10)-. CN, N02, RlOC(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 sub.stituent on the substituted Cl-C6 alkyl is selected from un_stituted 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, RlOC(O)-, N3, -N(R10)2, and R 1 1 OC(O) NR 10;

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, R100-, RlOC(O)NR1O-, CN, N02, (R10)2N-c(NRlo) 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 lOC(O)NR10-;
provided that when R~ is heterocycle, attachment of R~s to V is through a substitutable ring carbon~
R9~ and R9b ~re independently hydrogen, halo~en. CF;3 or methyl;

R10 is independently selected from hydrogen. Cl-c6 alkyl? 2,2,2-trifluoroethyl, benzyl and aryl;

W O 97/36585 PCTnUS97/06259 - 2~ -Rl 1 i.s independently selected from Cl-C6 alkyl and aryl;

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

10 X is a bond. -CH=CH-, -(~(O)NR 10, -NR 1 ~C(O)-, -NR 10, o or -C(=O)-;
provided that if a is N, then X is not -C(O)NR10-, -NR~ ~- or O;

nis Oor 1;
m is 0. 1 or 2; and p is 0, 1, 2, 3 or 4, provided that p is not O if X is a bond, -NR10- or 0;

or the pharmaceutically acceptable salts thereof.
In a further embodiment of this invention, the inhibitors of farne~syl-protein tran.sfera~se are illustrated by the formula F:
R6a-d R9a~ R3 l~it/
CR12--N\~ R9b (CR22)p X

NC F
- wherein:

a is N or C;

CA 022~0204 1998-09-24 W 097/36585 PCTrUS97/06259 from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e i,s independently N, NH, O or S;
5 a' is N or C;

from 0-4 of b', c', d' and e' are independently N, NH, O and S, and the remaining b', c', d' and e' atom~s are independently CH, provided that if a' is C, then at least one of b', c', d' or e' is independently N, NH, O or 10 S;

Rl is independently ~elected from: hydrogen, C3-Clo cycloalkyl or Cl-C6 alkyl;

1~ R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C I o cycloalkyl, R 1 0O-, -N(R I o)2 or F, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C~o cycloalkyl, R10O-, 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, halo~en, Cl-C6 perfluoroalkyl, R120-,RllS(O)m-,RIOC(O)NR10-,(R10)2NC(o)-, R10~N-C(NR10)-, CN, NO2, R10C(o)-, N3, -N(R10)2 or R I I 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 un_stituted or sub,stituted aryl, unsubstituted or sub,stituted heterocyclic, C~-CIo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, WO 97/36585 PCT/US97tO6259 R120, Rl lS(o)m, Rloc(o)NRlo-7 (R10)2NC(o)-, R102N-C(NR10)-, CN, RlOC(0)-, N3, -N(R10)2, and RllOC(O) NR10;

S R4 is .selected from H, halogen, CH3 and CF3;

R6a, R6b, R6C and R6d are independently .selected from:
a) hydrogen, b) un.substituted or.substituted aryl? un,substituted or Isubstituted heterocycle, C3-Clo cycloalkyl~ C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, 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, N02, R 1 ~C(0)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 c) un,substituted Cl-C6 alkyl, d) ,substituted Cl-c6 alkyl wherein the Isubstituent on the ,sub,stituted Cl-C6 alkyl i,s selected from un.substituted or sub.stituted aryl, unsubstituted or sub,stituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R 1 I S(O)m-~ R 1 OC(O)NR 1 0-, (R 1 0)2NC(0)-, RlO2N-c(NRlo)-7 CN, RIOC(o)-~ N3, -N(RIo)2~ and R 1 1 0C(O)-NR 10;

R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently ~elected from hydrogen, Cl-C6 alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;

R 1 1 is independently ~selected from Cl -C6 alkyl and aryl:
R12 i~ independently ~ielected from hydrogen, Cl-C6 alL~yl, Cl-C6 aralkyl, Cl-c6 .sub,stituted aralkyl, Cl-C6 heteroaralkyl.
Cl-C6 substituted heteroaralkyl, aryl, .substituted aryl, heteroaryl, sub.stituted heteroaryl, Cl-c6 perfluoroalkyl?

W O 97/36585 PCT~US97/06259 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)-;
5 provided that if a i~ N, then X is not -C(O)NR10-, -NR10- or O;

m i~ 0. 1 or 2; and pi~ 0. 1, '', 3 or4;

10 or the pharmaceutically acceptable salts thereof.
In a further embodiment of thi.s invention, the inhibitor.~ of farne~yl-protein tran,~ifera~e are illustrated by the formula G:
R6a-d R à~' 9b~ R4e NC~--A (CR 2)n R

wherein:
a i,s C;

from 0-4 of b~ c, d and e are independently N, NH, O and S, and the rem~ining b, c~ d and e atom~s are independently CH, provided that if a 20 i,~ C, then at lea~t one of b, c, d or e i,s independently N, NH, O or S;
a' is N or C;

from 0-4 of b'~ c', d' and e' are independently N, NH, O and S, and the 25 remaining b'~ c'~ d' and e' atoms are independently CH, provided that if W O 97/36585 PCT~US97/06259 a' is C, then at lea~t one of b', c', d' or e' i.s independently N, NH, O or S;

K l is independently selected from: hydrogen, R1 00-, -N(R10)2, F, C3-CIo cycloalkyl or Cl-C6 alkyl;

R2 i,s independently ~elected from:
a) hydrogen, b) aryl, heterocycle or C3-CIo cycloalkyl, c) C]-C6 alkyl un,~ubstituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R100-, or -N(R I ~)2;

R3 i~ ~elected 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-, RllS(O)m, RlOC(o)NRlo- (R10)2NC(o) R 1 02N-C(NR 10), CN, N02, R 1 ~C(O)-, N3, -N(R 1~)2, or Rl 10c(o)NRlo c) un~ubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the Isubstituted C1-C6 alkyl is ~selected from unsubstituted or substituted aryl, unsub~tituted or Isubstituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R 1 I S(O 3m-~ R 1 OC(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 i~ ~ielected from H, halogen, CH3 and CF~;

R6a R6b R6c and R6d are independently !;elected from:
a) hydrogen, W O 97/3658~ PCT~US97/0625g b) unsubstituted or substituted aryl, unsubstituted or ~ub~stituted heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 2O, 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 OC(O)-, N3, -N(R 1 0)2, or R 1 1 OC(O)NR 10 c) un,substituted C1-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl i.s selected from unsubstituted or ~sub~stituted aryl, unsubstituted or ,sub,stituted heterocyclic, C~-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(O)-, R 1 02N-C(NR 1 0)-, CN, R l OC(O)-, N3, -N(R 1 0)2, and R l l OC(O) NR 10;

R9~ and R9b are independently hydrogen, halogen, CF3 or methyl;

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

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

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

30 AI is selected from: a bond, -C(O)-, O. -N(R10)-, or S(O)m;

m i~ 0, 1 or 2; and n is 0 or I ;

W O 97136585 PCTrUS97/06259 or the pharmaceutically acceptable salts thereof.
Specific examples of the compounds of the invention are:

I -(5-(Thien-2'-yl)thien-2-ylmethyl)-5 -(4-cyanobenzyl)imidazole NC~,~
ii ~ N~

I -(4-Cyanobenzyl)-~-(5-( 1 -methylpyrrol-2-yl)-thiazol-2-ylmethyl~imidazole NC ~,fi~, H3C~
~N~"~ 5>~

10 or the pharmaceutically acceptable Isaltls thereof.
The compounds of the pre~sent invention may have asymmetric centers and occur a.s racemates, racemic mixtures, and a.
individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. Also, combinations 15 of substituents/or variable.s are permissible only if such combinations result in stable compounds.
A.s u~ed herein, "alkyl" and the alkyl portion of aralkyl and similar term.<;~ i.s intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the .specified number of 20 carbon atom.s; "alkoxy" represent.s an ;llkyl group of indicated number of carbon atoms attached through an oxygen bridge.
A.s u.sed herein, "cycloalkyl" is intended to include non-aromatic cyclic hydrocarbon group~ having the specified number of CA 022~0204 1998-09-24 W O 97/36585 PCTrUS97/062S9 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
"Alkenyl" group~ include those groups having the specified number of carbon atoms and having one or several double bonds.
5 Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, l-propenyl, 2-butenyl, 2-methyl-2-butenyl, i.soprenyl, farne~yl, geranyl, geranylgeranyl and the like.
"Alkynyl" groups include tho,se group.s having the specified 10 number of carbon atoms and having one triple bond.s. Examples of alkynyl groups include acetylene. 2-butynyl, 2-pentynyl. 3-pentynyl and the like.
"Halogen" or "halo" a.s u.sed herein means fluoro, chloro, bromo and iodo.
A.s used herein, "aryl," and the aryl portion of aralkyl, i~ intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic.
Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or 20 acenaphthyl.
The term heterocycle or heterocyclic~ a~ ulsed herein, repre,sents 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 25 four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic ring~s i~ fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which re~ult~; in the creation of a stable structure. Example~ of ~uch heterocyclic element~i 30 include, but are not limited to, azepinyl, benzimidazolyl, benzil~oxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyh benzofuryl, benzothiazolyl. benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl ~ulfone, furyl, imidazolidinyl~ imidazolinyl, CA 022~0204 1998-09-24 W O 97/36S8S PCT~US97/06259 imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopyrrolidinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, S pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, cluinazolinyl, quinolinyl, 4uinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydro~uinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl~ thiazolinyl, thienofuryl, thienothienyl, and thienyl.
As ulsed herein, "heteroaryl" i,s intended to mean any .stable lO monocyclic or bicyclic carbon ring of up to 7 members in each ring.
wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S. Example,s of .such heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, 15 benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, 20 oxadia~olyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl quinazolinyl, quinolinyl, 4uinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl~ triazolyl and thienyl.
As used herein in the definition of R3, R4, R5 and R6a-d, 25 the term "the sub,stituted group" i,s intended to mean a substituted Cl g alkyl, substituted C2 ~ alkenyl, substituted C2 X alkynyl, substituted aryl or .substituted heterocycle from which the ,sub~stituent(s) R3, R4, RS and R6a-e are selected.
As used herein in the definition of R7, the substituted C
30 alkyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroaryl-sulfonyl and substituted heterocycle include moieties containing from l to 3 ,substituellt.s in addition to the point of attachment to the rest of the compound.

W O 97/3658~ PCTAJS97/06259 As used herein, when no specific substituent,s are set forth, the terms "substituted aryl", "substituted heterocycle" and "substituted cycloalkyl" are intended to include the cyclic group which i~ substituted on a substitutable ring carbon atom with 1 or 2 substitutents ,selected 5 from the group which include.s 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,(Cl-C6 alkyl)OC(O)NH-, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, 10 furyl, isothiazolyl and Cl-C20 alkyl.
The moieties designated by the following structures bà~)/d b'~, repre,sent aromatic 5-membered heterocyclic ring~s and includes the following ring system.s:

~N ~ N N~N N--N~N

N~ N~\ N~ N--~
N ' N ' N 11 N
N~/ N~/ N-N~ N--N

[C~ N ~ ¢~ N~

~ N_ N> N~ S,> 'N ~

N~ ~ N - N/> N~O>

Preferably the aromatic :~-membered heterocyclic ring is selected from:

W 097/36585 PCT~US971062S9 - 3?s -~N

N~

~ ~> N~>

It i.s under.stood that .such ring sy.stem,s may be independently selected and that bl~),d and b ~, 5 may be the same or different in the instant compound~.
Lines drawn into the rin~ systems from sub~stituents (,such as ~rom R3, R4 etc.) means that the indicated bond may be attached to any of the sub,stitutable ring carbon or nitrogen atoms.
Preferably, Rl and R2 are independently selected from:
10 hydrogen, R 1 1 C(0)0-, -N(R 1 ~)2, R I OC(O)NR 10, R l ~O or unsubstituted or substituted Cl-C6 alkyl wherein the sub~stituent on the substituted Cl-C6 alkyl is selected from un~ubstituted or,substituted phenyl, -N(R 1 ~)2, R l ~O and R 1 OC(O)NR 10 .
Preferably, R3 is selected from:
a) hydrogen, b) C~-C I o cycloalkyl, halogen, C l -C6 perfluoroalkyl, R 1 20, CN, N02, R l OC(0)- or -N(R 1 0)2, c) un~ub.stituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the ~ub.~titutent on the 2Q ~iub,stituted Cl-C6 ~Ikyl i~s selected from unsub.stituted or Isub~stituted aryl, un.substituted or .substituted heterocyclic, C~-CIo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, CA 022=,0204 1998-09-24 W O 97/36585 PCTrUS97/06259 R120-, Rl lS(O)m-, RlOC(O)NR10-, (R10)2NC(o)-, - R102N-C(NR10)-, CN, RlOC(0)-, N3, -N(R10)2, and R 1 1 OC(0)-NR 10 Preferably, R4 is selected from: hydrogen, halogen, 5 trifluoromethyl, trifluoromethoxy and Cl-C6 alkyl.
Preferably, R5 is hydrogen.
Preferably R6a, R6b, R6C and R6d are independently selected from:
a) hydrogen, b) C3-CIo cycloalkyl, halogen, C~-c6 perfluoroalkyl, R120-, R l l S(O)m-, CN, N02, R I ~C(0)- or -N(R l O)2, c) unsub~tituted Cl-C6 alkyl;
d) .~iubstituted Cl-c6 alkyl wherein the sub~titutent on the substituted Cl-C6 alkyl is selected from unsub.stituted or substituted aryl, C3-Clo cycloalkyl, R120, Rl lS(O)m-, R 1 ~C(0)- or -N(R 1~)2.
Preferably, R~ is independently selected from:
a) hydrogen, and b) aryl, substituted aryl, heterocycle, substituted heterocycle, C 1 -C6 perfluoroalkyl or CN.
Preferably, R9 i~, hydrogen, halogen, CF3 or methyl.
Preferably, R10 is selected from H, Cl-C6 alkyl and benzyl.
Preferably, Al and A2 are independently selected from:
25 a bond, -C(O)NR 10, -NR 1 ~C(0)-, 0, -N(R 10), -S(0)2N(R 10) and -N(R 1 ~)S(0)2-.
Preferably, V i~ selected from hydrogen, heterocycle and aryl. More preferably, V i~ phenyl.
Preferably, W is selected from imidazolinyl, imidazolyl, 30 oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W i~ .~,elected from imidazolyl and pyridyl.
Preferably, n and r are independently 0, 1, or 2.
Preferably s i~, 0.
Preferably t i~i 1.

W 097/36S85 PCTnUS97/06259 It is intended that the definition of any sub~tituent or variable (e.g., R1, R2, R9, n, etc.) at a particular location in a molecule be independent of it,s definitions elsewhere in that molecule. Thus, -N(R10)2 represents -NHH, -NHCH3, -NHC2H5, etc. lt is understood 5 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 synthe-sized by technique,s known in the art, as well as those methods set forth below. from readily available starting materials.
The pharmaceutically acceptable salt~ of the compounds of this invention include the conventional non-toxic salts of the compounds of thi.s invention as fonned, e.g., from noll-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochlolic, hydrobromic, 15 sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, ,sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, 20 isethionic, trifluoroacetic and the like.
The pharmaceutically acceptable .~;alt,~i of the compounds of this invention can be .synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared either by ion exchange 25 chroma-tography or by reacting the fiee base with stoichiometric amounts or with an exces,s of the desired ~salt-forming inorganic or organic acid in a suitable solvent or various combination.s of solvents.
Reactions used to generate the compounds of this invention are prepared by employing reactions a.s shown in the Schemes 1-24, 30 in addition to other ,standard manipulations such as e,ster hydrolysis, cleavage of protecting groups, etc., a~s may be known in the literature or exemplified in the experimental procedures. Substituents R3, R6 and RX. as ~shown in the Schemes, repre,sent the sub.stituent.s R3, R4, R5, R6a R6b. R6C, R6d ~nd R~; although only one such R6 or RX i.s present CA 022~0204 1998-09-24 W 097/36585 PCT~US97/06259 in the intermediates and products of the schemes, it i~ understood that the reactions .shown are also applicable when such aryl or heteroaryl moietie~i contain multiple substituents.
These reactions may be employed in a linear sec~uence to provide the compounds of the invention or they may be used to synthesize fragment,s which are ~subsequently joined by the alkylation reaction,s de,scribed in the Scheme~i. Other reactions useful in the preparation of heteroaryl moieties are described in "Comprehensive Organic Chemi~try, Volume 4: Heterocyclic Compounds" ed. P.G.
Samme~i, Oxford (1979) and references therein. Aryl-aryl coupling i~s generally de.scribed in "Comprehensive Organic Functional Group Transformations," Katritsky et al. ed,s., pp 472-473, Pergamon Pre,ss (1995).

Synop~i,s of Scheme.s 1-24:
The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures, for the most part. Scheme~ 1- 14 illustrate synthesis of the instant diheteroaryl compound which incorporate a preferred benzylimidazolyl sidechain.
Thus, in Scheme 1, for example, the comInercially available dithienyl-carboxylic acid I may be reduced. The triflate of the interrnediate alcohol II may be formed in situ and coupled to a ~uitably sub,stituted benzylimidazolyl III to provide, after deprotection, the in~tant compound IV.
Those biheteroaryl intermediates that are not commercially ;~vailable may be synthesized by methods known in the art a~s well as tho~e reaction,s illu~strated in Schemes 2-6. Thus, a~ illustrated in Scheme 2 a thienyl boronic acid V may be reacted under Suzuki coupling condition.~ (Pur~ Appl. Chem., 63:4l9 (1991)) with a liuitably ~ub~tituted halogenated heteroaryl moiety, ~such a.s 2-bromo, to provide the biheteroaryl carboxylic acid VI, which can then be processed a~
de~cribed in Scheme 1. Scheme 3 illu~trate~ the analogou~s serie.s of reaction.~; .starting with the halogenated heteroarylaldehyde.

WO 97/36585 PCT~S97/062S9 Scheme 4 illustrates the reaction wherein the "telTninal"
heteroaryl moiety is employed in the Suzuki coupling a,s the halogenated reactant. Such a coupling reaction is also compatible when one of the reactants incorporates a suitably protected hydroxyl functionality a~
5 illustrated in Scheme 5.
Negishi chemi~stry (07g. Synth., 66:67 (1988)) may also be employed to form the biheteroaryl component of the instant compounds, as shown in Scheme 6. Thus, a zinc bromide adduct, .such as 3-thieny]
zinc bromide, may be coupled to a suitably ~ub,stituted heteroaryl halide 10 in the pre,sence of nickel (Il) to provide the biheteroaryl VII. The heteroaryl halide and the zinc bromide adduct may be selected ba.sed on the availability of the ,starting reagents.
As illu~trated in Scheme 7, the ,~e4uence of coupling reactions may be modified .such that the heteroaryl-heteroaryl bond 1~ is formed la~t. Thus, a suitably substituted imidazole may first be alkylated with a heteroarylmethyl halide to provide intermediate VIII.
Intermediate VIII can then undergo Suzuki type coupling to a ~suitably substituted heteroaryl boronic acid.
Scheme g illustrate.s the ~synthesis of a thiazole containing 20 instant compound from the acyclic precursor.~. Similar strategies may be utilized to prepare other bisheteroatom moietie,~.
Scheme 9 illustrates synthe~i,s of an instant compound wherein a non-hydrogen R9b i.~ incorporated in the instant compound.
Thus, a readily available 4-substituted imidazole IX may be selectively 25 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 de.scribed hereinabove.
Scheme 10 illustrate.s .synthe.si.s of in.stant compounds 30 that incorporate a preferred imidazolyl moiety connected to the biheteroaryl via an alkyl amino, .sulfonamide or amide linker. Thu.~, the 4-aminoalkylimidazole XII, wherein the primary amine is protected als the i-lhthalimide, i.s ~selectively alkylated then deprotected to provide the amine XIII. The amine XIII may then react under condition~ well CA 022~0204 1998-09-24 WO 97136585 PCT/[JS97/06259 known in the art with various activated biheteroaryl moieties to provide the instant compounds shown.
Compounds of the instant invention wherein the A 1 (CR 1 2)nA2(CR 1 2)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 11.
The suitably substituted phenol XIV may be reacted with methyl N-(cyano)methanimidate 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 benzylimidazole~s hereinabove.
Scheme 12 illustrates an analogous .series of reactions wherein the (CR22)pX(CR22)p linker of the instant compounds i.s oxygen. Thus, a suitably ,substituted haloheteroaryl alcohol, such as, is reacted with methyl N-(cyano)methanimidate to provide intermediate XVI. lntermediate XVI is then protected and, if de.~ired to forrn a compound of a preferred embodiment, alkylated with a ,suitably protected benzyl. The intermediate XVII can then be coupled to a second heteroaryl moiety by Suzuki chemistry to provide the instant compound.
Compounds of the instant invention wherein the A 1 (CR 1 2)nA2(CR 1 2)n linker is a substituted methylene may be synthesized by the method,s ~;hown in Scheme 13. Thus, the N-protected imidazolyl iodide XVIII i~s reacted, under Grignard condition~ with a suitably protected benzaldehyde to provide the alcohol XIX. Acylation, followed by the alkylation procedure illustrated in the Scheme,s above (in particular, Scheme 1 ) provides the instant compound XX. If other R 1 ~sub~stituents are desired, the acetyl moiety can be manipulated as illustrated in the Scheme.
Addition of various nucleophile,s to an imidazolyl aldehyde may also be employed to form a sub,stituted alkyl linker between the bihetero~ryl moiety and the prel'erred W (imidazolyl) as shown in Scheme 14. Thus a bishalogenated five membered heteroaryl, such a~
2,4-dibromothiophene. may undergo metal halogen exchange followed by reaction with a suitably substituted imidazolyl aldehyde and W O 97/36585 PCT~US97/06259 acteylation to form a regioisomeric mixture of the acetyl intermediates.
The halogenated regioisomeric mixture may be chromatographically separated at this stage, if convenient. Suzuki coupling with a suitably substituted 5-membered heteroaryl boronic acid affords the instant 5 acetoxy compound, which can be treated with lithium hydroxide to remove the acetyl group. Then, similar substituent manipulation a,s ,shown in Scheme 13 may be performed on a fully functionalized compound which incorporate.s an R2 hydroxyl moiety.

~OH rOH
,~ LiAlH

Tr Tr~
N~ NiCI2(PPh3)2, <~N

/~~ ~J

OH
S--~ (CF3SO2)20,-78~C
NEtiPr2-78~G 20~C

Il T~

<\_N'~ 5~ r ~J 55~C, C H30H

-~

IV

PCT~US97/06259 (HO)2B~

HO ~ Br ~r Pd(PPh3)4 HO ~ '~) 4 O Vl HO~ ¢~

(HO)2B
Pd(PPh3)4 ,¢~ NaBH4 d A ~ S
HO ~

W O 97/36585 PCTrUS97/06259 Br MeO~ ~ ~(OH)2 Pd(PPh3)4 MeO ~ LiAlH~
o HO~ '~

SCHEME ;~

P3SiO ~/~B(OH)2 Pd(PPh3)4 R3SiO ~ ~ Bu 4N F

HO~

W 097/36585 PCT~US97/06259 SCHEME 5 (continued) R3SiO~_~ (HOkB /¢~
Pd(P Ph3~4 R3SiO ~ J~'r~ Bu4NF

HO ~¢~

W O 97/36585 PCT~US97/06259 BrZn~
R3SiO~,~Br NiCI2(PPh3)2 R3SiOJt~ 4 HO~,¢~r~

R3SiO~ ~ Br~
NiCI2(PPh3)2 R3SiO ~ Bu4N F

HO~

PCTtUS97tO6259 ~J~Br li. MeOH
~J reflux <~_N~ ~r~Br (H~) ~J Pd(PPh3)4 R8 Vlll <~N

W O 97/36585 PCTrUS97/06259 SCHEME ~s R8 ~ NH3/EtOH/RT

~ y'COOCH3 N

R8 ~ Lawesson' s Reagent N 1,4-dioxane ~ ~CONH2 80~C
N~

8 1~1 R

~CSNH2 N
-CA 02250204 lg9X-09-24 W O 97t36S8S PCTrUS971062S9 SCHEME ~s (continued) Me Me Py.HBr.Br O O

N~

<N3~\~JN, Me H H
R9b~? Nal, NaHCO3,!2 Rgb~ TrCI, NEt~

IX X

9b~ ~I C ,lPPh3l2 ~ ~N

b,,~/, R6 Tr b~a~ e' ~/ i. -78~C-20~C
R8/~J ii. MeOH, reflux Xl R9b b~

~ N

- ~4 -0~

~~Br <\ ~ ~ 55~C,CH~CN
N N~i. EtOH,80~C, NH2NH2 Xll N
<~ ~I

R8 ~/
~, Xlll acylation, sulfonylation <i 3~
or alkylatiorl R8 ~J ~ R6 </ ~ O~ "~

~/ e~o~P~ R6 </ 11 - R6 ~ N~,,~R6 OH i. Na, MeOH
NC~/ ii. 120~C
XIV H3C o N--\~N

H Tr N N
~ TrCI, NEt3, ~N

NC ~ NC
XV XVI

Tr~N~ b~a~ 78~C-20~C

NC~ OTf ii. MeOH reflux XVI

~_N ~ a~e, d ~0 NC ~' W O 97/36585 PCT~US97/06259 H

~\~OH i, Na, MeOH ~_ ~S ii 1 20~C ,~ O

Br N--~N XVI

Tr, N~
TrCI, NEt3, R2 <\_N OTf 78~C-20~C
B ~5 ii. MeOH reflux R8 ~B(~H)2 R2 ~N , ¢~ A~\JR6 ~\3 0 DMF, Pd(PPh~)4 )~S K3PO4, 80~C
Br XVI I

2 ~ q J ~
~\~0 ~-S
A~\jJ

W O 97/36585 PCTrUS97106259 Tr~ ~N~
~N~ EtMgBr ~N
~N ~ ~('OH

Ac O py ~N ~ ~z OAc (C F3SO2)20, -78~C
R8/ NEtiPr2,CH2cl2 b,r~,, R 6 ~ bl~a LiOH
~ <
~/ OAc W O 97/36585 PCT~US97/062S9 - 5~ -SCHEME 13 (continued) b,~/, R 6 N ~ b~ a ~ e ' ~ ~ Cl R8 l R6 b~

<~N~, a(~ R~

~,J NH2 N~ abl,~d/'R6 b~

OMe 59 _ SC~IEME 14 Br BuLi Br Br ~ Br ;
N

1. </ 11 (i~ OAc 2. AcCI

~ R6 a'_ e~'' (HO)2B LiOH

Pd(PPh3)4 ~J R6 W O 97/36585 PCT~US97/06259 Schemes 15-24 illustrate reaction,s wherein the moiety (l 8)r /'T9~
V ~ A1(CRl2~nA2(CR12)n~;~W,~ ~ (CR22)p-X

incorporated in the compounds of the in.stant invention i.s repre,sented by other than ~ Isubstituted imidazole-containing group.
Thu.s, the intermediates who.se synthesis are illu.strated in Scheme~s hereinabove and other biheteroalyl intermediate.s obtained commercially or readily synthesized, can be coupled with a variety of aldehyde.s. The aldehydes can be prepared by .~itandard procedures? .such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in 10 Or~anic Synthelses, 19X8, ~7, 69-75, from the appropriate amino acid (Scheme 15). Metal halogen exchange chemistry (Scheme 14) may be employed when manipulating the aldehydes. Alternatively, Grignard chemistry may be utilized, as shown in Scheme 15. Thu.s, Suzul~i coupling provides, for example, the pyrrole containing biheteroaryl 15 XXI. Reaction of the intermediate XXI with a Grignard reagent provides the N-pyrrylmagnesium derivative XXIa, which i~s then reacted with an aldehyde to provide the C-alkylated instant compound XXII. The product XXII can be deoxygenated by methods known in the art, such as a catalytic hydrogention, then deprotected with 20 trifluoroacetic acid in methylene chloride to give the final compound XXlla. The final product XXII may be isolated in the salt forrn, for example. as a trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine XXII can further be selectively protected to obtain XXIII, which can subse4uently be reductively alkylated with 25 second aldehyde to obtain XXIV. Removal of the protecting group, and conversion to cyclized product.s such a,s the dihydroimidazole XXV can - be accomplished by literature procedures.
Scheme 16 illustrates the u.se of in .situ forrnation of a lithium anion of a ,suitably ,sub~stituted N-alkyl pyrrole to provide the 30 C-alkylated compound of the instant invention.

CA 022~0204 1998-09-24 W O 97/36585 PCTrUS97/06259 If the biheteroaryl ,subunit is reductively alkylated with an aldehyde which al~so has a protected hydroxyl group, ~uch a,~ XXVI in Reaction Scheme 17, the protecting groups can be subsequently removed to unmask the hydroxyl group (Reaction Schemes 17, l~). The alcohol 5 can be oxidized under standard condition,s to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohol,s such als XXX. In addition, the fully deprotected amino alcohol XXXI can be reductively alkylated (under condition,s de~scribed previously) with a variety of 10 aldehyde~ to obtain ~secondary amine~ uch a~ XXXII (Reaction Scheme I X), or tertiary amine~;.
The Boc protected amino alcohol XXVIII can al,so be utilized to ,synthesize 2-aziridinylmethylbiheteroaryl ~uch a~s XXXIII
(Reaction Scheme l9). Treating XXVIII with l,l'-sulfonyldiimidazole 1 ~S and ,sodium hydride in a ,solvent ~iuch a,s dimethylformamide led to the formation of aziridine XXXIII . The aziridine i~s reacted with a nucleophile, ,such a~s a thiol, in the pre~ience of ba~se to yield the ring-opened product XXXIV .
In addition, the biheteroaryl ,subunit can be reacted with 20 aldehyde~s derived from amino acid~s ,such as O-alkylated tyro.sine~, according to ~standard procedure~ to obtain compound~ ~uch a.~ XL, as .shown in Reaction Scheme 20. When R' i~ an aryl group, XL can fir~;t be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XLI. Alternatively, the amine protecting ~roup in 25 XL can be removed, and O-alkylated phenolic amines such as XLII
produced.
Scheme~ 21-24 illustrate .synthe,ses of ,suitably .substituted aldehyde~i u~seful in the synthe.se~s of the in.stant compounds wherein the variable W i,s pre~ent as a pyridyl moiety. Similar .synthetic strategie~
30 for preparing alkanols that incorporate other heterocyclic moietie~ for variable W are al~o well known in the art.

PCT~US97/06259 ~3 + ,b~ R

b~ EtMgBr a e H XXI

b~R

B M~ XXla SCHEME 15 (continued) R6 Boc N H
ab~ e~d~ Boc NH CHO

~;~ Et20 BrMg b~ 1. catalytic a~ d~ hydrogenation HO h~ 2. CF3CO2H
Boc NH~ ) 'N CH2CI2 NHBoc 6 XXII ab'~e,,d/'R Boc20 NH2~_~ CH2CI

XXlla b~
a,~Jd' ~,CHO

BocN H <~
\ < H NaBH(OAc)3 NH2 Et3N, CICH2CH2CI
XXIII

W O 97/36585 PCTfUS97/06259 SCHEME 15 (continued) ~;

BocNH~ C~3CO2H, = NH NaHCO3 ~;~ XXIV R6 b~

NH2 ~ ~ NC

~= NH AgCN

b~R

N
/ H
N~N~

XXV
~3 W 097/36585 PCTrUS97/06259 ~3 (HO) B/a e alkyl Boc NH~
~R6 BuLi Boc NH CHO
a TMEDA Et20 alkyl b~
a~ d Boc NH ) ~
~ I
alkyl NHBoc - 66 ~

~2 Et~<) BocNH CHO
XXVI

BnO~ b~ a'(~ 20% Pd(oH)2 H2 NHBoc HO ~ ~ R6 e R2 DMSO CH2C12 NHBoc (C2Hs~3N

XXVI I

SCHEME 17 (CONTINUED~
OH~ ~ b'$~ R6 NHBoc XXIX

HO '~ a;(~
R')~ e R2 NHBoc XXX

PCT~US97/06259 - 6~ -HO b b~ R6 e 2 C H2C12 NHBoc XXVIII

HO ~ b b~,R6 R2 NaBH(OAc)3 XXXI

~- a~

NH
R'CH2 XXXII

6 N =~ / N

H0 a~ 2 \f R2NaH, DMF0~C
NHBoc XXVIII

b~ b~R R~SH

<,~ a~d e' CH30H
H

XXXIII

b,~ R6 ,~_ a~, d' R"S ~ a~<d e \~

XXXIV

W 097/36585 PCTtUS97tO6259 Hl~ 1 ) Boc20, K2CO3 )~

H2NCO2H2) CH2N2, EtOAc XXXV XXXVI

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

XXXVII

R"'CH20~ R"'CH20 DMSON
BocNH CH2OH 20~C BocNH CHO
XXXVI I I IXL

WO 97t36585 PCT/US97/06259 SCHEME 20 (continued) R"'CH~3 g ~2 BocN H C HO

~~~~ R"' is not aryl 1. Et20 Et20 2. 20% Pd(OH)2, H2 CH30H, CH3CO2H
3. HCI, EtOAc \
~ ,b~ a'~(~

R"'CH20 R2 NHBoc 1) 20% Pd(~H)2~ H2 CHq,OH,CH3CO2H/

S~ a~

~H R2 XLI I

XLI
-W O 97/36585 PCT~US97/06259 ,~ CH3 1) HNo2~Br2 ~CO2CH3 ~I 2) KMnO4 , ~
H2N N 3) MeOH,H+ Br N

~\MgCI R~ CO CH

NaBH4 (excess) SO Py Et3N ~ 3 CHO

W O 97/36S85 PCT~US97/06259 1. EtO(CO)CI R6 Zn C~C~
N 3. S, xylene, heat N

NaBH4 ~ SO3Py, Et3N ~
(excess) ~; 3"CH20H DMSO ~CHO

Br~"CO2CH3 [~\ 9 ¢~

NZnCI2, NiC12(Ph3P)2 l~Co2cH3 ' NaBH4 I SO3 Py, Et3N
~CH20H ~ ~CHO

(excess) N DMSO N

W O 97/36585 PCT~US97/06259 Br~ 1. LDA, CO2 Br~

N2. MeOH. H+ N

~\ MgCI ~ co2CH3 ZnCI2, NiC12(Ph3P)2 N

NaBH4 ~excess) ~32~H SO3 Py, Et3N

DMSO
N

CHO
~3 W O 97/36S85 PCTrUS97/06259 [~ 1. LDA, CO2 ~N,CBHr3 2. (CH3)3SiCHN2 R6 ~\ Br R6 ~

Zn, NiCI2(Ph3P)2 N~CO2CH3 R6 ~q excess NaBH4 l~ SO3Py, Et3N
N~CH20H DMSO

R6 1~

N ~,CHO

The in~tant compounds are u.seful als pharmaceutical a 5 gent.s for m~mnl:~l.s, especially for humans. These compounds may be administel-ed to patient.~ for u~e in the treatment of cancer. Example.~i of the type of cancel which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma~ exocrine W O 97/36585 PCT~US97/06259 pancreatic carcinoma, myeloid leukemia,s and neurological tumors.
Such tumors may arise by mutations in the ras genes them.selves, mutations in the proteins that can regulate Ras activity (i.e., neurofibromin (NF-I), neu, scr, abl, Ick, fyn) or by other mechanisms.
The compounds of the instant invention in~ibit farnesyl-protein transferase and the farne,sylation of the oncogene protein Ras.
The instant compound,s may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Can~er Research, 55:4575-45X0 (1995)). Such anti-angiogenesils properties of the 10 in.stant compounds may also be u~seful in the treatment of certain forms of blindne~ss related to retinal va.scularization.
The compounds of thi~s invention ale also useful for inhibiting other proliferative disea~ies, both benign and malignant, wherein Ra~i proteins are aberrantly activated a,s a result of oncogenic 15 mutation in other genes (i.e., the Ras gene itself i~s not activ~ted by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a m~mm~l in need of ,such treatment. For example, a component of NF-I is a benign proliferative disorder.
The instant compound,s may also be u,seful in the treatment of certain ~iral infections, in particular in the treatment of hepatitis delta and related viru~e~ (J.S. Glenn et al. S~ n~c, 256:1331-1333 ( I 992).
The compound,s of the instant invention are al,so u,seful in 25 the prevention of re,steno~is after percutaneous transluminal coronary angioplalsty by inhibiting neointimal forrnation (C. Indolfi et al. Natu~
medic~ e~ 1:541-545(1995).
The instant compounds may also l~e useful in the tre~tment and prevention of polycy,stic kidney disease (L L. Schaffner et al.
30 Ame)i~an Jourllal (~f Path~logy, 142:1051-1060 (1993) ~nd B. Cowley, Jr. et al.~AS~B J~ ,rnal, 2:A3160 (19~
The instant compound~s m~y ~]so be useful for the treatment of fungal infection.~.
The compound,s of thi,s invention may be adminis~ered CA 022~0204 1998-09-24 W O 97/36585 PCTrUS97/062~9 to m~mmals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluent~, optionally with known adjuvant~s, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice. The 5 compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneou.s, rectal and topical routes of administration.
For oral use of a chemotherapeutic compound according to this invention, the selected compound may be administered, for 10 example, in the form of tablet.~ or capsule.~, or as an aqueous solution or suspension. ln the case of tablet~i for oral use~ carriers which are commonly u.sed include lactose and corn starch, and lubricating agent~.
such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents include lactose and dried 15 corn ~starch. When aqueous suspen~sions are re(luired for oral use, the active ingredient is combined with emul,sifying and suspending agents.
If desired, certain sweetening and/or flavoring agents may be added.
For intramuscular, intraperitoneal, subcutaneous and intravenou~ use, sterile solutions of the active ingredient are usually prepared, and the 20 pH of the solution~s should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes ~hould be controlled in order to render the preparation i~otonic.
The compounds of the instant invention may also be co-~lministered with other well known therapeutic agents that are 25 selected for their particular usefulness again,st the condition that is being treated. For example, the instant compounds may be useful in combination with known anti-cancer and cytotoxic agent~i. Similarly~
the instant compounds may be u.seful in combination with agents that are effective in the treatment and prevention of NF-l, restinosis, 30 polycystic kidney disease, infections of hepatitis delta and related viruses and fungal infections.
If formulated as a fixed dose, such combination product~
employ the compound~ of thi.'i invention within the do~sage ran~e de.~cribed below and the other pharm~ceutically active a~ent(.~) within W 097/36585 PCT~US97/06259 its approved dosage range. Compound~s 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 encompa,sses a pharmaceutical 5 composition useful in the treatment of cancer, comprising the arlministration of a therapeutically effective amount of the compounds of thi~ invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueou.s ~solutions comprising compoundls of this invention and pharmacolo-10 ~ically acceptable carrier~s, e.g.t saline, at a pH level, e.g.. 7.4. The~olutions may be introduced into a patient'~ blood-stream by local bolu,~
injection.
A~ used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specific 15 amounts, as well a.s any product which result~i, directly or indirectly, from combination of the specific ingredients in the .specified amounts.
When a compound according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing phy.~ician with the dosa~,e generally 20 varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
In one exemplary application, a suitable amount of compound is administered to a m~mm~l undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg 25 of body weight to about 60 mg/kg of body weight per day, preferably of between 0.~ mg/kg of body weight to about 40 mg~g of body weight per day.
The compounds of the instant invention are al.~o useful as a component in an a~s~iay to rapidly determine the presence and 30 quantity of farnesyl-protein tran.sferase (FPTa.se) in a composition.
Thus the composition to be te~;ted may be divided and the two portions contacted with mixture.s which compri.se a known sub.strate of FPTase (for example a tetrapeptide having a cy.steine at the amine terminus) and farnesyl pyropho.sphate and, in one of the mixture.s, CA 022~0204 1998-09-24 W O 97/36585 PCTrUS97/06259 a compound of the instant invention. After the as.say mixtures are incubated for an ,sufficient period of time, well known in the art, to allow the FPTa.se to farnesylate the substrate, the chemical content of the assay mixtures may be determined by well known immuno-5 logical, radiochemical orchromatographic technique~s. Becausethe compound.s of the in.stant invention are selective inhibitors of FPTa,se, ab.sence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged .substrate in the assay 10 containing the instant compound is indicative of the presence of FPTa.se 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 u.seful in identifying tissue samples which contain farnesyl-protein transferase and quantitat-15 ing the enzyme. Thus, potent inhibitor compound.s of the in.stantinvention may be used in an active ~site titration assay to determine the quantity of enzyme in the sample. A serie,s of samples composed of aliquots of a tissue extract containing an unknown amount of farnesyl-protein transferase, an exces.s amount of a known _strate of FPTase 20 (for example a tetrapeptide having a cysteine at the amine terminu.s) and farnesyl pyropho,sphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention. The concentration of a .~ufficiently potent inhibitor (i.e., one that has a Ki substantially smaller than the concentration of enzyme in 25 the assay vessel) required to inhibit the enzymatic activity of the sample by 50% is approximately e~lual to half of the concentration of the enzyme in that particular .sample.

EXAMPLES
Example.~ provided are intended to assist in a further under.standing of the invention. Particular material~ employed, specie.s and condition~s are intended to be further illu.strative of the invention and not limitative of the reasonable scope thereof.

W O 97/36585 PCT~US97/06259 - ~0 -EXAMPLE I

I -(5-(Thien-2'-yl)thien-2-ylmethyl)-5 -(4-cyanobenzyl)imidazole 5 trifluoroacetic acid salt Step A: l-Trity]-4-(4-cyanobenzyl)-imidazole To a suspension of activated zinc dust (3.57g, 54.9~ mmol) in THF (50 mL) was added dibromoethane (0.315 mL, 10 3.60 mmol) and the reaction stirred under argon for 45 minute,s, at 20~C. The su~pension wa.s cooled to 0~C and a-bromo-p-tolunitrile (9.33g, 47.6 mmol) in TH~ (100 mL) wa~ added dropwi~e over a period of 10 minutes. The reaction wa~ then allowed to xtir at 20~C
for 6 hour~ and bis(triphenylphosphine)Nickel II chloride (2.40g, 15 3.64 mmol) and 4-iodotritylimidazole (15.9Sg, 36.6 mmol) were added in one portion. The resulting mixture wa~i stirred 16 hours at 20~C and then quenched by addition of saturated NH4CI .solution (100 mL) and the mixture stirred for 2 hour.s. Saturated aq.
NaHCO3 solution was added to give a pH of 8 and the solution was 20 extracted with EtOAc (2 x 250 mL), dried (MgSO4) and the solvent evaporated in vacuo. The residue wa.s chromatographed (Silica ge], 0-20% EtOAc incH2cl2) to afford the title compound a~i a white solid.
IH NMR (CDC13, 400Mz) ~ (7.54 (2H, d, J=7.9Hz), 7.3X(lH, s), 25 7.36-7.29 (1 IH. m), 7.I5-7.09(6H, m), 6.5~(1H, ~) and 3.93(2H, ,s) ppm.

Step B: S-'Thien-2-yl)-thiophene-2-carboxaldehyde To a ~olution of thien-2-ylboronic acid (0.939 g, 30 7.34 mmol) and Na2CO3 (2.40 g, 22.6 mmol) in water (75 mL) i.~ added p-dioxane (75 mL). Thi.~ mixture i~ treated ,~equentially with 5-carboxy-2-thiophenecarboxaldehyde (1.43g, 7.4~ mmol) and palladium (Il) acetate (151 mg, 0.673 mmo]) and allowed to CA 022~0204 1998-09-24 W O 97136585 PCTrUS97/06259 stir at ambient temperature for 16 hour~s. The ~solvent i~i evaporated in vacuo. To the residue i.s added EtOAc (400 mL) and water (300 mL). The aqueous layer is acidified to pH I with 1.0 N a~l. HCl.
The aqueous layer is extracted with EtOAc (2 x 200 mL). The organic extracts are combined, washing with brine (200 mL), 5~O aq.
Na2S~O3 (200 mL), sat. aq. NaCI (200 mL), drying (Na2SO4), and the solvent evaporation in vacuo affords the title compound.

Step C: S-(Thien-2-vl)-2-hydroxymethylthiophene To a solution of ~-(thien-2'-yl)-thiophen-2-ylcarboxaldehyde (1.11 g, 5.73 mmol) in THF (25 mL) at 0~C i.s added 1.0 M lithium aluminum hydride in tetrahydrofuran (12.0 mL, 12.0 mmol) over 10 minutes. The reaction i~ allowed to ~;tir at ambient temperature for 3 hours. The reaction i~ cooled to 0~C, and 1~ water (0.5 mL), 4 N aq. NaOH (0.5 mL), and water (1.5 mL) are added sequentially. The reaction i.s filtered through a pad of Celite and the filtrate is evaporated in vacuo. The residue ils chromatographed to afford the title compound.

20 Step D: 1-(5-(Thien-2-yl)thien-2-ylmethyl)-5-(4-cyanobenzyl)imidazole trifluoroacetic acid salt To a solution of 5-(thien-2'-yl)-2-hydroxymethyl thiophene (2~s3 mg, 1.44 mmol) and diisopropylethylamine (0.260 mL, 1.49 mmol) in dichloromethane (6.0 mL) at -7g~C is added 2~ trifluoromethanesulfonic anhydride (0.250 mL, 1.49 mmol) and the mi~ture stirred at -7~i~C for I hour. To this mixture i!i added a .solution of l-trityl-4-(4-cyanobenzyl)imidazole (613 m~ . 1.44 mmol) in dichloromethane (6.0 mL). The mixture is allowed to warm to ambient temperature and stirred ~or 2 hours. The solvent i~
30 evaporated in vacuo. The residue i,~ di~s.~olved in methanol (15 mL), heated at reflux for I hour~ and the solvent i~i evaporated in vacuo.
The residue i~i partitioned between C~12C12 and ~sat. aq. NaHCO3 ~olution. The organic layer i.s dried, (Na2S04) and the solvent i,~;
evaporated in vacuo. The residue i~i purified by preparative HPLC, W 097/36585 PCTrUS97/06259 - ~2 -(gradient elution, 95 :5 to 5:95% water:acetonitrile containing 0.1%
trifluoroacetic acid) to afford the title compound a.s a trifluoroacetic acid salt.

I -(4-Cyanobenzyl)-5-(5-( 1 -methylpyrrol-2-yl)-thiazol-2-ylmethyl)imidazole Step A: IH-Imidazole-4-acetic acid methyl ester hydrochloride A solution of 1 H-imidazole-4-acetic acid hydrochloride (4.00g, 24.6 mmol) in methanol (100 ml) was saturated with gaseous hydrogen chloride. The resulting solution was allowed to stand at room temperature for lX hours. The solvent was evaporated in vacuo to afford the title compound as a white solid.
lH NMR (CDC13, 400MHz) ~ 5(lH, s), 7.45(1H, ~;), 3.~9(2H, s) and 3.75(3H, s) ppm.

Step B: I-(Triphenylmethyl)-lH-imidazol-4-ylacetic acid methyl ester To ~ solution of the product from S~ep A (24.~5 g, 0.141 mol) in DMF (115 mL) wals added triethylamine (57.2 mL, 0.412 mol) and triphenylmethyl bromide (55.3 g, 0.171 mol) and the suspension was stirred for 24 hours. After this time, the reaction mixture wa,s diluted with EtOAc and water. The organic phase wa~
washed with sat. aq. NaHCO3 dried, (Na2SO4) and the solvent evaporated in vacuo. The residue wa~ purified by chromatography (Silica gel, 0-100% EtOAc in hexanes) to provide the title compound a~ a white solid.
I H NMR (CDC13, 400MHz) ~ 7.35(1 H, ~i), 7 .3 1 (9H, m), 7 .22(6H, m), 6.76(1H, ~), 3.6~(3H, s) and 3.60(2H, ~) ppm.

CA 022~0204 1998-09-24 W O 97136585 PCTrUS97/06259 - ~3 -Step C: [1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl]acetic acid methyl ester To a solution of the product from Step B (8.00g, 20.9 mmol) in acetonitrile (70 mL) was added 4-cyanobenzyl bromide 5 (4.10g, 20.92 mmol) and heated at 55~C for 3 hour.s. The reaction was cooled to room temperature and the resulting imidazolium salt was collected by filtration. The filtrate was heated àt 55~C for lX
hours. The reaction mixture was cooled to room temperature and evaporated in vacuo. To the residue was added EtOAc (70 mL) and 10 the relsulting precipitate collected by filtration. The precipitated imidazolium .salt~ were combined, suspended in methanol (100 mL) and heated to reflux for 30 minute.s. After thi.s time, the solvent was removed in vacuo. The resulting residue was suspended in EtOAc (75 mL) and the solid i.solated by filtration and washed with EtOAc.
15 The solid was treated with sat. aq. NaHCO3 solution (300 mL) and CH2C12 (300 mL) and .stirred at room temperature for 2 hours. The organic layer was separated, dried, (MgSO4) and evaporated in vacuo to afford the title compound as a white .solid lHNMR (CDC13, 400MHz) ~ 7.65(1H, d, J=~Hz), 7.53(1H, s), 7.15(1H, d, J=~Hz), 7.04(1H, s), 5.24(2H, s), 3.62(3H, s) and 3.45(2H, s) ppm.

Step D: 4-[5-(Aminocarbonylmethyl)imidazol- I -ylmethyllbenzonitrile To a 100 mL gla.~s pres~sure vessel with a stirring bar was addedl-(4-Cyanobenzyl)-lH-imidazol-5-yl]acetic acid methyl ester (6.00g, 23.5 mmol) and absolute ethanol (50 mL). Thi,s well stirred solution was cooled to -7~~C and 50 mL of anhydrous ammonia was condensed in. The vessel was sealed and the mixture warmed to ambient temperature. This solution wa.s .stirred 24 hours at ambient temperature. The exces.~ ammonia wa.s allowed to evaporate and the ethanol wa~s removed in vacuo. The solid residue was triturated with EtOAc and collected on a frit. This material wa~
dried in vacuo to give the title compound as a white ~iolid.

CA 02250204 lg9X-09-24 W O 97/36585 PCTrUS97/062S9 - ~4 -lH NMR (DMSO-d6, 400MHz) ~ 3.25(s, 2H), 5.32(s, 2H), 6.~(s, lH), 6.96(s,1H), 7.24(d, j-8Hz,2H), 7.42(s,1H), 7.6~(s,1H), 7.~3(d, j=8Hz, 2H).

5 Step E: 1-(4-Cyanobenzyl)-5-(aminothiocarbonyl)methyl-lH-imidazole To a 50 mL round bottomed flask with a stirring bar, reflux condenser and an argon inlet was added 4-15-(aminocarbonyl-methyl)imidazol-l-ylmethyl]benzonitrile (0.36g, 1.49 mmol), 10 Lawes,son's reagent ~0.73g, 1 .X mrnol) and 1 ,4-dioxane ( 10 mL).
This well stirred mixture wa~s heated at X0~C for 24 hours. The cooled reaction mixture was concentrated in vacuo and the residue wa.s chromatographed (silica gel, 10% 2-propanol in ammonia saturated CHC13). The title compound was obtained as a yellow, 1~ crystalline solid.
lH NMR (DMSO-d6, 400MHz) ~ 3.66(s, 2H), ;S.41(s, 2H), 6.~5(s, lH), 7.24(d. j-~Hz,2H), 7.70(s,1H), 7.~2(d, j=8Hz, 2H), 9.21(s, lH), 9.56(.s, lH).
~0 Step F: 1-(4-Cyanobenzyl)-5-~5-(1-methylpyrrol-2-yl)-thiazol-2-ylmethyllimidazole To a 25 ml round bottomed flask with a stirring bar reflux condenser and an argon inlet is added 1-(4-cyanobenzyl)-5-(aminothiocarbonyl)methyl-lH-imidazole (0.12g, 0.468 mmol), dry 25 THF (10 mL). and N-methyl-a-bromoacetylpyrrole (0.098g, 0.491 mmol). This mixture i.s heated at 50~C for 7 hours. The cooled reaction mixture is diluted with EtOAc and washed suces.sively with aq. NaHCO3 ~ water, and brine. The organic extract is dried, -(MgSO4) and the solvent is evapor~ted in vacuo. The residue is 30 purified by chromatography to afford the title compound.

- ~5 -In vitrf) inhibition of ras farne,syl transferase Assay~ of fa) nesy~-prc)tein tran~fèrclse. Partially purified S bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) were prepared a~ described by Schaber et al., J. Biol . Chem. 26~: 14701 -14704 (1990), Pompliano,_ah, Biochemi,stry 31:3~00 (1992) and Gibbs et ah, PNAS U.S.A. ~s6:6630-6634 (19~9), respectively. Bovine FPTase wa,s assayed in a volume of 100 ~I containing 100 mM N-(2-10 hydroxy ethyl) piperazine-N'-(2-ethane ~sulfonic acid) (HEPE~), 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 Ras-CVLS and 10 ~g/ml FPTa,se at 31 ~C for 60 min. Reaction.s were initiated with FPTase and stopped with I ml of 1.0 M HCL in 15 ethanol. Precipitate,s 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 re,spect to both substrates, FPTase levels and time; less than 10% of the [3H]-FPP was utilized during the reaction period. Purified compounds were dissolved 20 in 100% dimethyl ,sulfoxide (DMSO) and were diluted 20-fold into the assay. Percenta~e inhibition i,s measured by the amount of incorpora-tion of radioactivity in the pre,sence of the test compound when compared to the amount of incorporation in the absence of the test compound.
Human FPTase was prepared a,s described by Omer et ah, Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed a,s described above with the exception that 0.1 % (w/v) polyethylene glycol 20,000, 10 ~lM ZnCl~ and 100 nM Ra,s-CVIM were added to the reaction mixture. Reaction.s 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 as~ay de.scribed above.

W 097/36585 PCT~US97/06259 - ~6 -In vivo ras farne.sylation assay The cell line used in this assay is a v-ras line derived 5 from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21.
The assay i~ performed e.ssentially as described in DeClue, J.E. et ah, Cancer Re~search 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 hourls at 10 37~C, the cells are labelled in 3 ml methionine-free DMEM supple-meted with 10% regular DMEM, 2% fetal bovine Iserum and 400 mCi[35S]methionine (1000 Ci/mmol). After an addition~l 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 15 antipain/0.5 mM PMSF) and the lysate~s cleared by centrifugation at 100,000 x g for 45 min. Aliquot.s of Iysates containing equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (lysi,s buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et al., J. Virol. 43:294-304, 20 (19~2)). Following a 2 hour antibody incubation at 4~C, 200 ml of a 25% .suspension of protein A-Sepharo~;e coated with rabbit anti rat IgG
is added for 45 min. The immunoprecipitates are washed four time~
with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/I % Triton X-100Ø5% deoxycholate/0.1%/SDS/0.1 M NaCI) boiled in SDS-PAGE
25 sample buffer and loaded on 13% acrylamide gel~. When the dye front reached the bottom, the gel i.s fixed~ soaked in Enlightening, dried and autoradiographed. The intensitie.s of the bands corresponding to farne.sylated and nonfarnesylated ras protein,s are compared to determine the percent inhibition of farne.syl transfer to protein.

-CA 022~0204 1998-09-24 W O 97/36585 PCT~US97/06259 - ~7 -EXAMPLE S

In viv(~ .rowth inhibition assay To determine the biological consequences of FPTase 5 inhibition, the effect of the compounds of the instant invention on the anchorage-independent growth of Ratl cell,s tran,sformed with either a v-7~as, v-ra~; or v-mos oncogene is te.sted. Cells transformed by v-Raf and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation.
Rat I cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 104 cells per plate (~5 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle'~
medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layer.s contain 0.1% methanol or an 15 appropriate concentration of the in~stant compound (dissolved in methanol at 1000 time.s the final concentration u~sed in the assay).
The cell~s are fed twice weekly with 0.5 ml of medium A containing 0.1% methanol or the concentration of the in,stant compound.
Photomicrographs are taken 16 days after the cultures are seeded 20 and comparison~s are made.

Claims (28)

WHAT IS CLAIMED IS:

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

wherein:
a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
a' is N or C;

from 0-4 of b', c', d' and e' are independently N, NH, O and S, and the remaining b', c', d' and e' atoms are independently CH, provided that if a' is C, then at least one of b', c', d' or e' is independently N, NH, O or S;

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

R6a, R6b, R6c and R6d 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-, R11C(O)O-, (R10)2NC(O)-, R102N-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-;

R7 is elected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) ~SO2R11, 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)-, R102N-C(NR10), CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, or R10OC(O)NH-;
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)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1 -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2-trifluoroethyl, benzyl 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 heteroaryl, 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-, -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 a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;
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-, provided that if a is N, then X is not O, -C(O)NR7-, -C(O)O-, -C(O)NR7C(O)-, -S(O)2N(R10)- or -NR7-;

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:
a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
a' is N or C;

from 0-4 of b', c', d' and e' are independently N, NH, O and S, and the remaining b', c', d' and e' atoms are independently CH, provided that if a' is C, then at least one of b', c', d' or e' is independently N, NH, O or S;

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)-, R102N-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-;

R6a, R6b, R6c and R6d 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)-, R102N-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-;

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, e) , 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 R11 OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, R10O-, R11 S(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, 2,2,2-trifluoroethyl, benzyl 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 heteroaryl, 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 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-; provided that if a is N, then X is not O, -C(O)NR7-, -S(O)2N(R10)-or -NR7-;

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:

a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
a' is N or C;

from 0-4 of b', c', d' and e' are independently N, NH, O and S, and the remaining b', c', d' and e' atoms are independently CH, provided that if a' is C, then at least one of b', c', d' or e' is independently N, NH, O or S;

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)-, R102N-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-;

R6a, R6b, R6c and R6d 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)-, R102N-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-;

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-, R10OC(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-, R10OC(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, 2,2,2-trifluoroethyl, benzyl 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 heteroaryl, 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 a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A1 S(O)m amd 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)-;
provided that if a is N, then X is not -C(O)NR10-, -NR10-, or O;

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

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

wherein:
a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
a' is N or C:

from 0-4 of b', c', d' and e' are independently N, NH, O and S, and the remaining b', c', d' and e' atoms are independently CH, provided that if a' is C, then at least one of b', c', d' or e' is independently N, NH, O or S;

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, C2-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-;

R6a, R6b, R6c and R6d 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-;

R8 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, 2,2,2-trifluoroethyl benzyl 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 heteroaryl, 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 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)-;
provided that if a is N, then X is not -C(O)NR10-, -NR10- or O;

m is 0, 1 or 2;
n is 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, -NR10- 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:
a is N or C:

from 0-4 of b, c, d and e are independently N. NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
a' is N or C:

from 0-4 of b', c', d' and e' are independently N, NH, O and S, and the remaining b', c', d' and e' atoms are independently CH, provided that if a' is C, then at least one of b', c', d' or e' is independently N, NH, O or S;

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 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, C1-C6 alkyl and CF3;

R6a, R6b, R6c and R6d 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-;

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, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2-trifluoroethyl, benzyl 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 heteroaryl, 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)-, provided that if a is N, then X is not -C(O)NR10-, -NR10- or 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:
a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
a' is N or C;

from 0-4 of b', c', d' and e' are independently N, NH, O and S, and the remaining b', c', d and e' atoms are independently CH, provided that if a' is C, then at least one of b', c', d' or e' is independently N, NH, O or S;
R1 is independently selected from: hydrogen, R10O-, -N(R10)2, F, 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 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, C1-C6 alkyl and CF3;

R6a, R6b, R6c and R6d 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-;

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 heterocycle, attachment of R8 to V is through a substitutable ring carbon;

R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2-trifluoroethyl, benzyl 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 heteroaryl, 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)-;
provided that if a is N, then X is not -C(O)NR10-, -NR10- or 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, -NR10- or O;
or a pharmaceutically acceptable salt thereof.

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

wherein:

a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
a' is N or C;

from 0-4 of b', c', d' and e' are independently N, NH, O and S, and the remaining b', c', d' and e' atoms are independently CH, provided that if a' is C, then at least one of b', c', d' or e' is independently N, NH, O or S;
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 or F, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, 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-, R1OC(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;

R6a, R6b, R6c and R6d 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-;

R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2-trifluoroethyl, benzyl 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 heteroaryl, 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)-;
provided that if a is N, then X is not -C(O)NR10-, -NR10- or 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:
a is C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
a' is N or C;

from 0-4 of b', c', d' and e' are independently N, NH, O and S, and the remaining b', c', d' and e' atoms are independently CH, provided that if a' is C, then at least one of b', c', d' or e' is independently N, NH, O or S;
R1 is independently selected from: hydrogen, R10O-, -N(R10)2, F, C3-C10 cycloalkyl or C1-C6 alkyl;

R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle or C3-C10 cycloalkyl, 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-, 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;

R6a, R6b, R6c and R6d 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-;

R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2-trifluoroethyl, benzyl 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 heteroaryl, 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 farnesyl-protein transferase which is:

1-(5-(Thien-2'-yl)thien-2-ylmethyl)-5-(4-cyanobenzyl)imidazole 1-(4-Cyanobenzyl)-5-(5-(1-methylpyrrol-2-yl)-thiazol-2-ylmethyl)imidazole 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.