CA2243507A1 - 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

TITLE OF THF INVENTION
INE~BITORS OF FARNESYL-PROTEIN TRANSFERASE

P~ACKGROUND OF THE INVENTION
The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of a ~ign~lling pathway that links cell ~ ce glo~ factor receptors to nuclear si n~l~ initi~ting cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP. Upon 10 growth factor receptor activation Ras is in(l-lce-l to exchange GDP for GTP and undergoes a conformational change. The GTP-bound form of Ras prop~g~tes the growth stin~ tory signal until the signal is termin~t~(l by the intrin~ic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M.
15 Willllm.~en, Ann. Rev. Biochem. 62:851-891 (1993)). Mutated ras genes ~Ia-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many hnm~n cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively tr~n~mit a grow~
20 stim~ tQry sign~l Ras must be loc~li7.e~1 to the plasma membrane for both normal and oncogenic functions. At least 3 post-tr~n~l~tional modifications are involved with Ras membrane loc~li7~tion, and all 3 modifications occur at the C-te, ...i....s of Ras. The Ras C-te~ s 25 contains a sequence motif termed a "CAAX" or "Cys-Aaal-Aaa2-Xaa"
box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)). Depending on the specific sequence, this motif serves as a signal se~uence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein 30 transferase, which catalyze the alkylation of the cy~,lei,le residue of the CAAX motif with a Cls or C20 isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386 (1992); W.R. Schafer and J. Rine, Ann.
Rev. Genetics 30:209-237 (1992)). The Ras protein is one of several proteins that are known to undergo post-tr~n~1~tional farnesylation.

WO 97/277S2 PCT/US!J7/OlS99 Other farnesylated ~roteills include the Ras-related GTP-binding ~te~lls such as Rho, fungal m~ting factors, ~e nuclear l~min~, and Ihe mm~ subunit of t~n~(lllcin. James, et al., J. Biol. Chem. 269, 141~2 (1994) have iclPntifi~ll a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated ~l~teills of unknown structure and function in addition to ~ose listed above.
Inhibition of farnesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify 10 o~er aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the proces~in~ of the Ras oncoprotein intracellularly (N.E. Kohl et al., Science, 260:1934-1937 (1993) and G.L. James et,al., Science, 260:1937-1942 (1993). Recently, it has been shown ~at an 15 inhibitor of farnesyl-protein transferase blocks the growth of ras-dependent tumors in nude mice (N.E. Kohl et al., Proc. Natl. Acad. Sci U.S.A., 91:9141-9145 (1994) and induces regression of m~rnm~ry and salivary carcinomas in ras transgenic mice (N.E. Kohl et al., Nature Medicine, 1:792-797 (1995).
Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck & Co., Rahway, NJ) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., - Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limitin~ enzyme for the production of polyisoprenoids in~ lin~
25 farnesyl pyrophosphate. Fa~nesyl-protein transferase lltili7es fa~nesyl pyrophosphate to covalently modify the Cys ~iol group of the Ras CAAX box wi~ a farnesyl group (Reiss et al., Cell, 62:81-88 (1990);
Schaber et al., J. Biol. Chem., 265: 14701-14704 (1990); Schafer et al., Science, 249: 1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci U~A, 87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA re~ ct~e blocks Ras membrane loc~li7~tion in cultured cells. However, direct inhibition of farnesyl ~ro~eil~ transferase would be more specific and attended by fewer sicle CA 02243~07 1998-07-1~
WO 97/27752 PCT/US97/OlS99 effects than would occur with the recluired dose of a general inhibitor of isoprene biosynthe~
Inhibitors of farnesyl-~lotei" transferase (FPTase) have been described in two general classes. The first are analogs of farnesyl 5 diphosphate (FPP), while the second class of inhibitors is related to the protein substrates (e.g., Ras) for the enzyme. The peptide derived inhibitors that have been described are generally cysteine co..l~
molecules that are related to the CAAX motif that is the signal for ~l~,tei" prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., lO PNAS, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as ~ltern~te substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S.
Patent 5,141,851, University of Texas; N.E. Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
15 In general, deletion of the thiol from a CAAX derivative has been shown to dramatically reduce ~e inhibitory potency of the compound.
However, the thiol group pot~rti~lly places limit~tions on the therapeutic application of FPTase inhibitors with respect to ph~rm~rokinetics, ph~rm~codynamics and toxicity. Therefore, a 20 functional replacement for the thiol is desirable.
It has recently been reported that farnesyl-protein transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and thereapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7-25 112930).
It has recently been disclosed that certain tricycliccompounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516).
Tmit1~7ole-co~tz~ inhibitors of farnesyl protein transferase have also 30 been disclosed (WO 95/09001 and EP 0 675 112 Al).
It is, therefore, an object of this invention to develop peptidomimetic compounds that do not have a thiol moiety, and that will inhibit farnesyl-protein transferase and thus, the post-tr~ncl~tional farnesylation of proteins. It is a further object of this invention to WO 97/27752 PCT/US97/OlS99 develop chemothel~eulic compositions co..l~i..i..~ the compounds oiF
this invention and methods for producing the compounds of this invention.

5 ~IJMM~RY OF T~E INVENTION
The present invention comprises small molecule peptidomim~tic urea-co..~ co~ oullds which inhibit the farnesyl-~ro~ill transferase. The instant compounds lack a thiol moiety and thus offer unique advantages in terms of improved ph~ rokinetic behavior 10 in ~nimP~l~, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reflllce-l ~y~lell~ic toxicity. Further contained in this invention are chemotherapeutiic compositions co--t~ these farnesyl transferase inhibitors and methods for their productiion.
The compounds of this invention are illustrated by the formula I:

V Al(CR1a2) A2(CR1a2)n (W~- (CRlb2)p NJ~N (CR 2) R5a R5b R4 DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are useful in the inhib:ition of farnesyl~ otei" transferase and ~e farnesylation of the oncogene protein Ras. In a first embodiiment of this invention, the inhibitors of 25 farnesyl-protein transferase are illustrated by the forrn~

V-A (CR 2)nA~(CR182)n!~W) (CRlb ) J~ /
R5a R5b R4 wherein:
Rla, Rlb and R2 are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloaLkyl, C2-C6 aLkenyl, C2-C6 alkynyl, R80-, R9s(o)m-~ R8C(O)NR8-, CN, N02, (R8)2N-C(NR8)-, R8C(O)-, R8OC(O)-, N3, -N(R8)2, or R9OC(o)NR8-c) Cl-C6 aL~yl unsubstihlte~l or substit ltç-l by aryl, heterocyclic, C3-Clo cycloaLkyl, C2-c6 aLkenyl, C2-c6 alkynyl, R80-, R9S(o)m-~ R8C(O)NR8-, CN, (R8)2N-C(NR8)-, R8C(O)-, R80C(O)-, N3, -N(R8)2, or R9OC(o)-NR8-;
R3 and R4 are independently selected from F, Cl, Br, N(R8)2, CF3, N02, (R8)o-, (R9)S(O)m-, (R8)C(O)NH-, H2 C(NH)-, (R8)C(O)-, (R8)OC(O)-, N3, CN, CF3(CH2)nO-, (R9)OC(O)NR8-, Cl-C20 alkyl, substitllte~l or unsubstit~lte-l aryl and substihlterl or unsubstituted heterocycle;

R5a and R5b are independently selected from:
a) hydrogen, b) unsubstit~lte~l or substitllte-l aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substitllte-l C3-Clo cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or a group selected from unsubstituted or substituted aryl, WO 97/277S2 PCT/US,97/OlS99 unsubstituted or substituted heterocyclic, unsubstituted or subst~ terl C3-Clo cycloaLkyl, N(R8)2, CF3, N02, (R8)o-, (R9)S(o)m-~ (R8)C(O)NH-, H2N-C(NH)-, (R8)C(O)-, (R8)0C(O)-, N3, CN (R9)OC(O)NR8-;

R6 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloaLkyl, C2-C6 alkenyl, C2-C6 aLkynyl, perfluoroaLkyl, F, Cl, Br, R80-, R9S(o)m R8C(O)NR8-, CN, N02, R82N-C(NR8)-, R8C(O)-, R8OC(O)-, N3, -N(R8)2, or R9OC(o)NR8-, and c) Cl-C6 aLkyl unsubstit-lte-l or substituted by aryl, heterocycle, C3-Clo cycloaLkyl, C2-c6 alkenyl, C2-C6 aLkynyl, per~uoroaLkyl, F, Cl, Br, R80-, R9S(o)m-~
R8C(O)NH-, CN, H2N-C(NH)-, R8C(O)-, R8OC(O)-, ]N3, -N(R8)2, or R8OC(O)NH-;

R7 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 aLkynyl, perfluoroalkyl, F, Cl, Br, R80-, R9S(o)m-~ R8C(O)NR8-, CN, N02, (R8)2N-C-(NR8)-, R8C(O)-, R8OC(O)-, N3, -N(R8)2, or R9OC(o)NR8-, and - c) Cl-C6 alkyl unsubsti1~-~e-l or substituted by perfluoroaD~yl, F, Cl, Br, R8O-, R9S(o)m-~ R8C(O)NR8-, CN, (R8)2N-C(NR8)-, R8C(O)-, R80C(O)-, N3, -N(R8)2, or R9OC(o)NR8-;
R8 is independently selected from hydrogen, Cl-C6 aLkyl, benzyl and aryl;
R9 is independently selected from Cl-C6 alkyl and aryl;

Al and A2 are independently selected from: a bond, -CH=CH-, -C~C-, WO 97/27752 PCT/US97/OlS99 -C(O)-, -C(O)NR8-, -NR8C(O)-, O, -N(R8)-, -S(0)2N(R8)-, -N(R8)S(0)2-, or S(O)m;

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

m is 0, 1 or 2;
nis 0, 1, 2, 3 or4;
pis 0, 1, 2, 3 or4;
r is 0 to S, provided that r is 0 when V is hydrogen; and t is 0 or 1;
or the ph~ relltically acceptable salts thereof.

A preferred embodim.~--nt of the c ompounds of t-his invention are illustrated by the formula Ia:

WO 97127752 PCT/U$97/OlS99 ( l 6)r R7a V ~ A1(CR1a2)nA2(CRla2)~N \~ F~3 1b2)p J~ (CR22) R5a R5b F~4 wherein:

5 Rla and R2 are independently selected from: hydrogen or Cl-C6 aLkyl;

Rlb is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloaLkyl, R80-, -N(R8)2 or C2-C6 10alkenyl, c) Cl-C6 aLkyl unsubstituted or substit~lte-l by aryl, heterocycle, cycloaLkyl, alkenyl, R80-, or-N(R8)2;

R3 and R4 are independently selected from F, Cl, Br, N(R8)2, CF3, N02, (R8)o-, (R9)S(o)m-~ (R8)C(O)NH-, H2N-C(NH)-, (R8)C(O)-, (R8)OC(O)-, N3, CN, (R9)OC(O)NR8-, Cl-C20 aLkyl, sub~tit lteA or unsubstil~lte~l aryl and substit!lte-l or unsubstitllte~l heterocycle;
RSa and Rsb ale independently selected from:
a) hydrogen, aIld b) Cl-C6 aLkyl substituted with hydrogen or a group selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, unsubstituted or substi1~lte~1 C3-Clo cycloalkyl, N(R8)2, CF3, NO2, (R~)O-, CA 02243~07 1998-07-1~
WO 97/277S2 PCT/US97/OlS99 (R9)s(o)m-~(R8)C(O)NH-,H2N-C(NH)-,(R8)C(O)-, (R8)OC(O)-, N3, CN (R9)OC(O)NR8-;

R6 is independently selected from:
a) hydrogen, b) Cl-c6 aL~yl, C2-c6 aL~enyl, C2-c6 aL~ynyl, Cl-c6 perfluoroalkyl, F, Cl, R80-, R8C(O)NR8-, CN, N02, (R8)2N-C(NR8)-, R8C(O)-, R8OC(O)-, -N(R8)2, or R9OC(o)NR8-, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R80-, R8C(O)NR8-, (R8)2N-C(NR8)-, R8C(O)-, R80C(O)-, -N(R8)2, or R9OC(o)NR8-;

R7a is hydrogen or methyl;
R8 is independently selected from hydrogen, Cl-C6 aL~yl, benzyl and aryl;

R9 is independently selected from Cl-C6 alkyl and aryl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR8-, O, -N(R8)-, or S(O)m;

V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) Cl-C20 aL~yl 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 WO 97/27752 PCT/US97/OlS99 provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;

mis 0, 1 or2;
S nis 0, 1, 2, 3 or4;
pis 0, 1, 2, 3 or4;
r is 0 to S, provided that r is 0 when V is hydrogen; and or the pharm~elltically acceptable salts thereof.
-- A second preferred embodiment of the compounds of this invention are illustrated by the formula Ib:

V - A~ (CR1~)nA ~(CR1~2)n ~- (CR1b2)p\ ~ (CR22~

Ib R5a RSb 15 wherein:
Rla and R2 are independently selected from: hydrogen or Cl-C6 alkyl;

Rlb is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, R80-, -N(R8)2 or C2-C6 aLkenyl, c) Cl-C6 alkyl unsubstihlteA or substituted by aryl, heterocycle, cycloaLkyl, aLkenyl, R80-, or -N(R8)2;
R3 and R4 are independently selected from F, Cl, Br, N(R8)2, CF3, N02, (R8)o-, (R9)S(o)m-~ (R8)C(O)NH-, H2N
C(NH)-, (R8)C(O)-, (R8)OC(O)-, N3, CN, (R9)OC(O)NR8-, Cl-C20 aL~cyl, substituted or WO 97127752 PCT/US97/OlS99 unsubstihltt-.-1 aryl and substituted or unsubstituted heterocycle;

R5a and R5b are independently selected from:
S a) hydrogen, and b) Cl-C6 alkyl substit~lte~l wi~ hydrogen or a group selected from unsubsti~lt~-l or substituted aryl, unsubstihlte~l or substituted heterocyclic, unsubstituted or substituted C3-Clo cycloaLkyl, N(R8)2, CF3, NO2, (R8)o-, (R9)S(o)m-~ (R8)C(O)NH-, H2N-C(NH)-, (R8)C(O)-, (R8)OC(O)-, N3, CN (R9)OC(O)NR8-;

R6 is independently selected from:
a) hydrogen, b) Cl-C6 aL~;yl, C2-c6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroaLkyl, P, Cl, R80-, R8C(O)NR8-, CN, NO2, (R8)2N-C(NR8)-, R8C(O)-, R8OC(O)-, -N(R8)2, or R9OC(o)NR8-, and c) Cl-C6 aLkyl substituted by Cl-C6 perfluoroaLkyl, R80-, R8C(O)NR8-, (R8)2N-C(NR8)-, R8C(O)-, R80C(O)-, -N(R8)2, or R9OC(o)NR8-;

R7 is selected from: hydrogen and Cl-C6 alkyl;
R8 is independently selected from hydrogen, Cl-C6 aLkyl, benzyl and aryl;

R9 is independently selected from Cl-C6 alkyl and aryl;

- 3() A1 and A2 are independently selected from: a bond, -CH=CH-, -C--C-, - -C(O)-, -C(O)NR8-, O, -N(R8)-, or S(O)m;

V is selected from:

a) hydrogen, b) heterocycle selected from pyrrolidinyl, imirl~7.olyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) Cl-C20 aLkyl wherein from 0 to 4 ca~bon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and 10 provided that V is not hydrogen if Al is S(O)m and V is not hydrog;en if Al is a bond, n is 0 and A2 is S(O)m;

W is a heterocycle selected from pyrrolidinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;
mis 0, 1 or2;
nis 0, 1, 2, 3 or4;
p is 0, 1, 2, 3 or 4;
r is 0 to ~, provided that r is 0 when V is hydrogen; and t is 1;

or the ph~ e~ltically acceptable salts thereof.

In a more preferred embodiment of ~his invention, the 2~ inhibitors of famesyl-protein transferase are illustrated by the formula Ic:

(CR1b2)p NJ~ (CRZ ) {~
R6 R5a R5b R4 lc WO 97/27752 ~CT/US97/01599 wherein:

Rlb is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, R80-, -N(R8)2 or C2-C6 alkenyl, c) Cl-C6 aLkyl unsul~ e-l or substihlte-l by aryl, heterocycle, cycloalkyl, alkenyl, R80-, or-N(R8)2;

10 R2 are independently selected from: hydrogen or Cl-C6 aLkyl;

R3 and R4 are independently selected from F, Cl, Br, N(R8)2, CF3, N02, (R8)o-, (R9)S(o)m-~ (R8)C(O)NH-, H2N-C(NH)-, (R8)C(O)-, (R8)OC(O)-, N3, CN, (R9)OC(O)NR8-, Cl-C20 alkyl, substih-tecl or unsub~ti~lte~l aryl and substit~lterl or unsubstituted heterocycle;

RSa and R5b are indepen~lP-rltly selected from:
a) hydrogen, and b) Cl-C6 aLkyl substihltt-.-l with hydrogen or a group selected from unsubstihlt. -1 or substihlt~-l aryl, unsubstituted or substituted heterocyclic, unsubstituted or substit~lt~l C3-Clo cycloaL~yl, N(R8)2~ CF3, NO2, (R8)o-, (R9)S(O)m-, (R8)C(O)NH-, H2N-C(NH)-, (R8)C(O)-, (R8)OC(O)-, N3, CN (R9)OC(O)NR8-;

R6 is independently selected from:
~ 30 a) hydrogen, b) Cl-C6 aLkyl, C2-c6 alkenyl, C2-C6 alkynyl, Cl-C6 ~ perfluoroaLkyl, F, Cl, R80-, R8C(O)NR8-, CN, N02, (R8)2N-C(NR8)-, R8C(O)-, R8OC(O)-, -N(R8)2, or R9OC(o)NR8-, and WO 97127752 PCT/US'97/OlS99 c) Cl-C6 aLkyl substihlte-l by Cl-C6 perfluoroaLkyl, R80-., R8C(O)NR8-, (R8)2N-c(NR8)-7 R8C(O)- R80C(O)--N(R8)2, or R9OC(o)NR8-;
~ R8 is independently selected from hydrogen, Cl-C6 aLkyl, benzyl an,d aryl;

R9 is independently selected from Cl-C6 aLkyl and aryl;

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

or the ph~ relltically acceptable salts thereof.

In a second more preferred embo~lim~--nt of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula Id:

NC (CR1b2)p NJ~N (CR22)~,{
Id 20 wherein:

Rlb is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloaLkyl, R80-, -N(R8)2 or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstitllte-1 or substituted by aryl, heterocycle, cycloaLkyl, alkenyl, R80-, or-N(R8)2;

WO 97127752 PCT/US97/OlS99 R2 are independently selected from: hydrogen or Cl-C6 aLkyl;

R3 and R4 are independently selected from F, Cl, Br, N(R8)2, CF3, NO2, (R8)o-, (R9)S(o)m-~ (R8)C(O)NH-, H2N-C(NH)-, (R8)C(O)-, (R8)OC(O)-, N3, CN, (R9)OC(O)NR8-, Cl-C20 aLkyl, sul~sliluled or unsubstituted aryl and substitllte-l or unsubstit~lte-l heterocycle;
RSa and RSb are independently selected from:
a) hydrogen, and b) Cl-C6 aLkyl substit~lt~.A with hydrogen or a group selected from unsubstituted or substit~lte-l aryl, unsubstitllte.-l or substihlte-l heterocyclic, unsubstituted or substihlt~1 C3-Clo cycloaLkyl, N(R8)2, CF3, N02, (R8)o-, (R9)S(O)m-, (R8)C(O)NH-, H2N-c(NH)-~ (R8)C(O)-, (R8)0C(O)-, N3, CN (R9)OC(O)NR8-;
R8 is independently sel~-cte-l from hydrogen, Cl-C6 aLkyl, benzyl and aryl;
R9 is independently selected from Cl-C6 alkyl and aryl;
mis 0,lor2;and pis 0, 1, 2, 3 or4;

or the pharmaceutically acceptable salts thereof.

Specific examples of the compounds of the invention are:

N-(3-chlorophenyl)-N'-[ 1 -(4-cyanobenzyl)-5-imidazolylmethyl]-N'-(n-pentyl)urea hydrochloride (1) CA 02243507 l998-07-l5 WO 97/27752 PCT/US97/OlS99 NC~< ~ ~

N-(3-chlorophenyl)-N-methyl-N'-[ 1 -(4-cyanobenzyl)-5-imicl~olyl-methyl]-N'-(n-pentyl)urea hydrochloride (8) s NC ~N ~ ~N ~ 3,CI

or the ph~ e~l~icaIly acceptable salts thereof.
The compounds of the present invention may have asymm~ ic centers and occur as r~em~tes, racemic mixtures, and as 10 individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. When any variable (e.g. aryl, heterocycle, Rla, R2 etc.) occurs more than one time in ~myconstituent, its definition on each occurence is independent at every other occurence. Also, combinations of substituents/or variables are 15 permissible only if such combinations result in stable compounds.
As used here~n, "alkyl" is intended to include both bran~ched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "alkoxy" represents an aLkyl gra,up of indicated number of carbon atoms attached through an oxygen CA 02243~07 1998-07-1~

bridge. "Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.
As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, 5 wherein at least one ring is aromatic. Fx~mples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acena~htllyl.
The term heterocycle or heterocyclic, as used hereirl, represents a stable S- to 7-membered monocyclic or stable 8- to 11-10 membered bicyclic heterocyclic ring which is either saturated ornn~hlrated, and which consists of carbon atoms and from one to four hetero~tom~ selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above--lefinP-l heterocyclic rings is fused to a berl7~ne ring. The heterocyclic ring may 15 be ~tt~chto~l at any heteroatom or carbon atom which results in the creation of a stable structure. Fx~mrles of such heterocyclic elements include, but are not 1imit~1 to, azepinyl, benzirnidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, 20 dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiop~ yl sulfone, furyl, imitl~7olidinyl, imicl~7olinyl, imicl~7.olyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, n~phthyridinyl, oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-25 oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyricl~7.inyl, pyrimi~linyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, 30 thienofuryl, thienothienyl, and thienyl.
As used herein, "heteroaryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S. Examples of such heterocyclic elements include, but are not limite-l to, ben7imi~ olyl, benzisoxazolyl, benzo~razanyl, benzopyranyl, benzo~iopyranyl, benzofuryl, benzothiazolyl, benzo~ienyl, benzoxazolyl, chromanyl, cinnolinyl, S dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imi~1~7.olyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, ox~ 7olyl, pyridyl, pyrazinyl, pyrazolyl, pyritl~7.inyl, pyrimidinyl, pyrrolyl, qllin~7olinyl, quinolinyl, quinoxalinyl, 10 tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, and thienyl.
Lines drawn into the ring systems from substituents (such as from R3, R4 etc.) indicate that ~e inr1ic~te~1 bond may be attachecl to aIly of the subs*hlt~hle ring carbon atoms.
Preferably, Rl a, Rlb and R2 are independently selected from: hydrogen, -N(R8)2, R8C(O)NR8- or Cl-C6 alkyl unsubsti~lte~l or substihlte-l by -N(R8)2, R80- or R8C(O)NR8-.
P~eft;l,lbly, R3 and R4 are independently selected from:
hydrogen, perfluoroaLkyl, F, Cl, Br, R80-, R9S(o)m-~ CN, N02, R82N-C(NR8)-, R8C(O)-, R80C(O)-, N3, -N(R8)2, or R9OC(o)NR8-and Cl-C6 alkyl.
Preferably, R5a and R5b are independently selected from hydrogen or Cl-C6 aLkyl subs*hlte-l with hydrogen, R9S(o)m-~ CF3-or an unsubstituted or substil~lte-l aryl group.
Preferably, R6 is selected from: hydrogen, perfluoroalkyl, F, Cl, Br, R8O-, R9S(O)m-, CN, NO2, R82N-C(NR8)-, R8C(O)-, R80C(O)-, N3, -N(R8)2, or R9OC(o)NR8- and Cl-C6 aLkyl.
Preferably, R7 is hydrogen or methyl. Most preferably, R7 is hydrogen.
Preferably, R8 is selected from H, Cl-C6 aL~cyl and benzyl.
Preferably, Al and A2 are independently selected from: a bond, -C(O)NR8-, -NR8C(O)-, O, -N(R8)-, -S(0)2N(R8)- and-N(R8)S(0)2-.

CA 02243~07 1998-07-1~
WO 97/277~2 PCT/US97/OlS99 Preferably, V is selected from hydrogen, heterocycle and aryl. Most ~Lefelably7 V is phenyl.
Preferably, Y is selected from phenyl, pyridyl, furyl and thienyl. Most preferably, Y is phenyl.
Preferably, n, p and r are independently 0, 1, or 2.
Preferably t is 1.
The ph~rm~elltic~lly acceptable salts of the compounds of this il~vt;l~lion include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic 10 acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, s-llf~mic, 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, 15 phenylacetic, gl~ .nic, benzoic, salicylic, slllfiqnilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, m~th~nlosulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
It is intended that the cle~lnition of any substituent or variable (e.g., R1a, Z, n, etc.) at a particular location in a molecule be 20 independent of its definitions elsewhere in that molecule. Thus, -N(R8)2 represents -NHH, -NHCH3, -NHC2Hs, etc. It is understood that substituents and substitution patterns on the compounds of the in~t~nt invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily 25 syntht-si7e-l by techniques known in the art, as well as those methods set forth below, from readily available starting materials.
The ph~ eutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods.
30 Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric - ~mounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.

WO 97/27752 PCT/US97/OlS99 Reactions used to generate ~he compounds of ~is invention are prepared by employing reactions as shown in Schemes 1-13, in addition to other standard manipulations such as ester hydrolysis, cleavage of protectin~ groups, etc., as may be known in the literature or S exemplified in the e~ nt~l procedures. Substituents R and RC'H2-, as shown in the Sch~ s, represent ~e substit lent.~ R8, R9 and others, - depe-n~ling on the compound of ~e in~t~nt invention that is being synthesi7.~-i. The variable p' represents p-l.
These reactions may be ernployed in a linear sequence to 10 provide the compounds of the invention or they may be used to synthe~i7e fragments which are subse~uently joined by the aLkylatiom reactions ~iescribed in the Sch~om~os.

Synopsis of Schemes 1-13:
The requisite intto.nnediates are in some cases commercially available, or can be ~ ed according to literature procedures, for ~e = most part. Schemes 1-3 illustrates the synthesis of one of the ~lc;fel~ed embodiments of the instant invention, wherein the variable W is present as a imi~1~7.olyl moiety that is substituted with a suitably substil~lte-l~0 benzyl group. Substituted protected irni~l~7.ole aLkanols II can be ed by methods known in the art, such as those described by F.
Schneic~er, Z. Physiol. Chem., 3:206-210 (1961) and C.P. Stewart, Biochem. Journal, 17:130-133(1923). Benzylation aIld deprotection of the imitl~7.ole aLkanol provides intPrmediate III which can be oxi~1i7~.-1 to 25 the corresponding aldehyde IV. Aldehyde IV can then be reductively coupled to a suitably suL.~ e~l arnine to provide interm~ e V.
Scheme 2 illustrates other methods of ~lGyaLillg amirle interme~ tes. Thus, the aLkanol II may be converted to the co~.G~onding amine VI via the azide. Alternatively, if the 30 a~p~ iately substi~lt~l protected amine, such as a protected hist~min~
VII, is available, that reagent may be ring aLkylated to provide the intermediate amine VIII.
Amines such as those illustrated in Schemes 1 and 2 may be reacted with a suitably substit~lte~l isocyanate IX to provide the instant CA 02243~07 1998-07-1~
WO 97/27752 PCT/US97/OlS99 compound X. Compound X can be selectively N-aL~ylated under standard conditions, such as those illustrated, to provide the in~t~nt compound XI.
Schemes 4-7 illustrate synth~ses of suitably substitllte-l alkanols useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic strategies for ~l~a~ g ~lk~nols that incorporate other heterocyclic moieties for variable W are also well known in the art.
The isocyanate IX can be reacted with a variety of other 10 amines, such as XII, as shown in Scheme 8. The product XIII can be deprotected to give the in~t~nt compound XIV. The compound XIV is isolated in the salt form, for e~mrle, as a trifluoro~ et~tto, hydrochloride or acetate salt, among others. Compound XIV can further be selectively protected to obtain XV which can subsequently be 15 reductively a1~ylated with a second aldehyde, such as XVI, to obt~in XVII. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XIX can be accomplished by literature procedures.
As shown in Scheme 9, a bis-protected aldehyde XX may be 20 reacted with a suitable (~ri n~rd reagent to provide the secondary alcohol XXI. Subsequent protection and reductive deprotection provides the primary alcohol XXII. This alcohol can then be converted to the col,e~onding amine by the techniques illustrated in Schemes 1-2 above. Amine XXIII may then be reacted with isocyanate IX to provide 25 the carbamate XXIV. Removal of the protecting groups then provides the instant compound XXV In addition, a fully deprotected amino alcohol XXVII can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary ~min~s, such as XXVIII (Scheme 10), or tertiary amines.
The Boc protected ~mino alcohol XXIX can also be lltili7.~.
to synthesize 2-~7.iri~1inylmethylureas such as XXX (Scheme 11).
Treating X~X with l,1'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylform~micl~ can lead to the formation of WO 97/27752 PCT/US97/OlS99 ~7.iri~1ine XXX. The ~7irirlinP. can be reacted witlh a nucleophile, SUC]l as a thiol, in the presence of base to yield ~he ring-opened product XXXI.
In addi~ion, the isocyanate IX can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to S st~nfl~rd procedures, to obtain cornpounds such as XXXVII, as shown in Scheme 12. When R' is an aryl group, XXXVII can first be hydrogenated to llnm~ek the phenol, and the amine group deprotected with acid to produce XXXVIII. Alternatively, the amine protecting group in XXXVII can be rernoved, and O-aLkylated phenolic ~lninP.s 10 such as IXL produced.
Schemes 13 illustrates an alternate ~ tion of ~e in~ nt compounds. As shown in Scheme 13, the isocyanate XL is formed first and is then treated with the suitably substihlte~l ~niline such as XLI to provide the in~t~nt compound X.

SC~F,~E 1 (CR1b2)p,-CH20H Prot1X Et3N Prot 'N~/~>
\~ N \~ N
H DMF lla (CR1b2)p.-CH20Ac R6~EtOAc AC20, Py ,~
Prot1~N N2. N-~le~-ut~

(&R1b2)p-cH2oAc,~ (CR1b2)p.-CH20H
HBr ~ N~/~ N~
N> LiOH >
b~ THF. H20 lll SCHEME 1 (co~ lued) (CRlb ) '-CHO

SO3 Py~ Et3N N~ R5aNH2 DMSO 6~ Na(AcO)3BH
R

lV
N~ (CRl b2)p,-CH2NHR5a \~N
;

(CR1b ) -OH (CR1b ) -N
\~N 1. MsCI, NEt3 \~N H2, Pd/C
~ 2. BU4N-N

R~ R~

(CR1b ) -NH2 ~N

R6/~
Vl N~ --NHProt2 R Prot1 ~;~NHProt2 H EtOAc ~>
Vll R6~ Br~

de~ ,te~,tion ~ NH2 Vlll WO 97/27752 PCT/US97/OlS99 SCHE~ E 3 N~(CR z)p-NH2 N~(CRtb2)p N~ ~R4 N NaH, DMF N

R6~ ' ~

lX

Rsb 3 \ ~
Rsb-x N~ (CR 2)p-N ~ ~)R4 1 e~uiv. NaH N
n-Bu4NI, DMF ~

Xl WO 97/27752 PCT/US97/Ol~i99 CH3 1) HNO2,Br2 ~CO2CH3 ~[~ 2) KMnO4 . ~
H2N N 3) MeOH,H+ Br N

~ MgCI R.~CO2CH3 zncl2~Nicl2(ph3p)2 N

NaBH4 (excess) ~CH20H

WO 97/27752 PCT/US97/OlS99 ~CO2CH3 ~\MgCi ~"CO2CH3 N Zn, CuC~I

NaBH4 (~sYcess) ~
~CH20H

~N~

Br~[~3,C~2CH3 ~\ MgCI

N ZnCI2, Nicl2(Ph3P)2 NaBH4 (excess) ~,CH20H

SCHEM~ 6 c02CH3 Br~3 1. LDA, CO2 Br~

N 2. MeOH, H+ N

~\ MgCI ~2CH3 ZnCI2, NiC12(Ph3P)2 N

NaBH4 (e~ .ess) ~ CH20H

co2CH3 1. LDA, CO2 ~Br 2. (CH3)3SiCHN2 R6 ~\ Br R6 ~

Zn, NiC12(Ph3P)z N~C02CH3 R6 ~q excess NaBH4 I~L~
N ~CH20H

SC~ME 8 Prot1 NH~ Xll OCN~ Pro* NHlCH2NH2 '' 4 NaH, DMF

O~N H
Protl NH~ le~rot~

NHProt2 Xlll R3 ~N Prot3X
NH~NH ~R4 ~,CHO
~N H ~ XVI
Prot3NH ,~ H 2~ NaBH(OAc)3 NH2 \=1=/ Et3N, CICH2CH2CI

CA 02243507 l998-07-l5 SCHEME 8 (continued) Prot3NH~ ~ ~N~ R4 deprotection o ~N H
NH~N ~ R4 ~ NC

~= NH 13 AgCN
XVIII R

~N H

N~,N~ ¦
~ XIX

CA 02243507 1998-07-1~
WO 97127752 PCT/US97/OlS99 ScHE~ g BnOl R'MgX BnO~

Prot1 NH CHO Protl NH ~OH
XX XXI R

BnO
Prot2X Prot1NH~OPrOt2 20% Pd(~H)2 H2 R' CH3C02H

HO NH2~

Prot1NH~OProt2 Prot1NH~OProt2 R' R' XXII XXIII

WO 97/27752 PCT/US97/OlS99 SCHEME 9 (conlin~le-l) OCN

R3 R4 ProY ~ N~
NaH, DMF R'~Y l Prot1 NH R3 XIV

deprotection ~~ R4 XXV

BnOl R5aNH2 BnO~

Prot1 NH CHO Na(AC0)3BH Prot1 NH NHR5a XX \ BnO
R5a = H
Prot1 NH ~OH

OCN ~
IX /~\~ 4 ~NH de~.n~te~lion . BnO
NaH, DMF NHProt1 1 ~NH R'CHO
HO ~NR5a ,~ R NaBH(OAc)3 NH2 \=1=/ CICH2CH2CI

XXVII

O~NH
HO~NR5a ~R4 NH
R'CH2 R3 XXVIII

SC~F,~ 1 1 ~N H
BnO ~ 20% Pd(OH)2 H2 NHBoc ¦ CH3CO2H
XVlla R3 H H
O~N H ~/ S
HO ~N Sa ~R4 NaH, DMF 0~C
NHBoc XXIX

~N H R'SH
<~ R5a ~R (C2Hs) Boc R3 XXX

O~N H ~S--N H
R'S~ R5a ~/R4 TFA R'S ~ RSa ~R4 NHBoc 1~ CH2CI2 NH

XXXI

WO 97/27752 PCT/US97/OlS99 SC:~HE~F 12 H,~ 1) Prot1X

2) CH2N2, EtOAc H2N CO2H Prot1 NH CO2CH3 XXXII XXXIII

HO~
LiAlH4 ~l~ R'CH2X
THF 1 Cs2CO3 0-20~C Prot1 NH CH2OH DMF

XXXIV

R'CH20~,~ 1. DMSO, Et3N R'CH20 ~ CICOCOCI f~
2. R5aNH2 Prot1NH CH2OH Na(AcO)3BH Prot NH CH2NHR5a XXXV XXXVI

CA 02243507 l998-07-l5 SCHEME 12 (contin R'CH2,~ OCN~

Prot1NH CH2NHR5a R3 lX
XXXVI
NaH, DMF

R'CH20~ ~N H
NHProt XXXVII
deprotect 1) 20% Pd(OH)2 CH30H, CH3C02H/
2) deprotect /

R'CH20 ~ ~N~

6~ ~N IXL R3 HO/~ Rsa ~R

XXXVIII

SC~Fl\~E 13 (CR1b ) -NH2 1~l (CR1b ) -NCO
N Cl3C-O-C-O-CCI3 ~N

R6~ R
Vl NaH
H2N'[~

N~(CR 2)p-NH ~o R

~R6 WO 97/27752 PCT/U~;97/OlS99 The inst~nt compounds are useful as pharmaceutical agents for m~rnm~l~, especially for hl~m~n.s. These compounds may be ~rlmini~tered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this S invention include, but are not limite~l to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors.
Such tumors may arise by mutations in the ras genes themselves, mutations in the ~l~t~hls that can regulate Ras formation (i.e., neurofibromen (NF-l), neu, scr, abl, lck, fyn) or by other mech~ni~m~.
Irhe compounds of the in~t~nt invention inhibit farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
The in~t~nt compounds rnay also inhibit turnor angiogenisis, thereby affecting the 2;1owlll of tumors (J. Rak et al. Cancer Research, 55:4575-4580 (1995)). Such anti-angiogenisis propeties of the in~t~nt compounds rnay also be useful in the tre~tn~nt of certain forms of blin-ln~ss related to retinal v~c~ ri7sltion.
The compounds of this invention are also useful for inhibiting other proliferative ~ e~es" both benign and malignant, wherein Ras ~-oteills are aberrantly activated as a result of oncogeni~c mutation in other genes (i.e., ~e Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomrli~h~cl by the ~tlmini~tration of an effective amount of the compounds of the invention to a m~mm~l in need of such tre~tmPn~ For example, a component of NF-l is a benign proliferative disorder.
The instant compounds may also be useful in the treatment of cel~Lill viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256:1331-1333 (1992).
The compounds of the in~t~nt invention are also useful in the prevention of restenosis after percutaneous translllmin~l coronary angioplasty by inhibiting neointim~l formation (C. Indolfi et al. Nature Medicine, 1:541-545(1995).
The instant compounds may also be useful in ~e treatment and prevention of polycystic kidney disease (D.L. Schaffner et al.

:

American Jou7nal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)).
The compounds of this invention may be ~timini~tered to m~mm~ , preferably hllm~n~, either alone or, ~,erelably, in S combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a ph~rm~elltical col,l~osition, according to st~n(l~rd rh~rm~eutical practice. The compounds can be ~-lmini~tered orally or pa~e;,,lerally~ including dle intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and 10 topical routes of ~tlmini~tration~
For oral use of a chemotherapeutic compound according to this invention, the selected compound may be ~imini.~tered, for tox~mple, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are 15 commonly used include lactose and corn starch, and lubricating agents, such as m~-Jn~sium stearate, are commonly ~cl(le-l For oral ~lmini~tration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents.
20 If desired, certain sweetening andlor flavoring agents may be ~.l.le.l For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH
of the solutions should be suitably adjusted and buffered. For intravenous use, the total conct;"L.~Lion of solutes should be controlled 25 in order to render the p~ lion isotonic.
The present invention also encomp~ses a ph~nn~eutical composition useful in the treatment of cancer, comprising the ~t1mini.ctration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers 30 or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and ph~ colo-gically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may be introduced into a patient's i~ c~ r blood-stream by local bolus injection.

WO 97127752 PCT/US97/OlS99 When a compound according to this invention is ~lmini~tered into a human subject, the daily dosage will normally be ~ie~e~ ..Pfl by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual 5 psltient as well as ~dhe severity of the pz~ nt~s ~y~ tOlLIS.
In one exemplary application, a suitable amount of compound is ~-lmini~tered to a m~rnm~l undergoing treatment for cancer. A~lrnini~tration occurs in an amount between about 0.1 mgA~g of body weight to about 60 mg/kg of body weight per day, preferably of 10 between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
The compounds of the in~t~nt invention are also useful as a component in an assay to rapidly ~lele~ e the presence and quantity of farnesyl~ teill transferase (FPTase) in a composition.
15 Thus the composition to be tested may be divided and the two portions cont~cte~l with mixtures which comprise a known substrate of FPI ase (for examLple a tetrapeptide having a cysteine at ~e amine te....i....~) and farnesyl pyrophosphate and? in one of the ..~ix~..,es, a co~ oulld of the in~t~nt invention. After the assay mixtures are 20 incllb~ for an suf~lcient period of time, well known in the art, to allow the FPTase to farnesylate ~e substrate, the chemical content of the assay n-ixtllres may be determined by well known immllnological, radiochemical or chromatographic techniques.
Because the compounds of ~e in~t~nt invention are selective 25 inhihitors of FPTase, absence or qll~ ;ve reduction of ~e amounit of substrate in ~e assay mix~lre wi~out the compound of the in~nl-invention relative to the presence of the unchanged substrate in the assay co..~;..i..~ ~e instant compound is in-lic~tive of the presence of FPTase in the composition to be tested.
It would be readily a~alel,t to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain farnesyl-protein transferase and ;n~ the enzyme. Thus, potent inhibitor compounds of the i..x~ t invention may be used in an active site titration assay to WO 97/27752 PCT/US97/OlS99 dete~ e the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract co~ i..i..g an unknown amount of farnesyl-protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine 5 te~ ) and farnesyl pyrophosphate are incubated for an a~ro~liate period of time in the presence of varying concentrations of a compound of the in~t~nt invention. The conce~ tion of a sufficiently potent inhibitor (i.e., one that has a Ki subst~nti~lly ~m~llP.r than the concentration of enzyme in the assay vessel) required to inhibit the 10 enzymatic activity of the sample by 50% is approximately equal to half of the concentration of the enzyme in that particular sample.

EXAl~IPLES
- Examples provided are intended to assist in a further underst~n~lin~ of the illvelltion. Particular m~teri~l~ employed, species and conditions are int~n~led to be further illustrative of the invention and not limit~tive of the reasonable scope thereof.

N-(3-chlorophenyl)-N'-[1-(4-cyanobenzyl)-5-imi~l7.701ylmethyl]-N'-(n-pentyl)urea hydrochloride (1) Step 1: Preparation of l-triphenylmethyl4-(hydroxymethyl~-imidazole (2) To a solution of 4-(hydroxymethyl)imi(1~7.ole hydrochloride (35 g) in 250 mL of dry DMF at room tempe~atuie was 30 added triethyl~min~. (90.6 mL). A white solid precipitated from the solution. Chlorotriphenylmethane (76.1 g) in 500 mL of DMF was added dlo~wise. The reaction mixture was stirred for 20 hours, poured over ice, ~lltered, and washed with ice water. The resulting product was WO 97/27752 PCT/US97/OlS99 slurried with cold dioxane, filtered, and dried in vacuo to provide 2' as a white solid which was sufficiently pure for use in the next step.

Step ? Preparation of l-triphenylrnethyl-4-(acetoxymethyl)-imidazole !3) Alcohol 2 (prepared above) was suspended in 500 mL of pyridine. Acetic anhydride (74 mL) was added &u~vise, and the reaction was stirred for 48 hours dunng which it bec~qmP homogenc ous.
The solution was poured into 2 L of EtOAc, washed with water (3 ~c 1 10 L), 5% aq. HCl soln. (2 x 1 L), sat. aq. NaHCO3, and brine, then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. The ~cet~te 3 was isûlated as a white powder (85.8 g) whi,ch was sufficiently pure for use in the next step.

15 Step 3: Preparation of 1-(4-cyanobenzyl)-5-(acetoxymethyl)imidazole hydrobromide (4) A solution of 3 (85.8 g) and a-bromo-p-tolunitrile (50.1 g) in 500 mT. of EtOAc was stilTed at 60 ~C for 20 hours, during which a pale yellow precipi~te formed. The reaction was cooled to room 20 t~ el~ture and filtered to provide the solid imicl~7olium bromide salt.
The filtrate was concentrated in vacuo to a volume 200 mL, reheated at 60 ~C for two hours, cooled to room temperature, and filtered again.
The f;ltrate was conce~ ated in vacuo to a volume 100 mL, re-h~-~t~rl at 60 ~C for another two hours, cooled to room tellyL,elature, and 25 conce~ l in vacuo to provide a pale yellow solid. All of the solid rnaterial was combined, dissolved in 500 rnL of methanol, and warmed to 60 ~C. After two hours, ~e solution was reconcentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble materials. Removal of residual solvents in vacuo provided the 30 titled product hydrobromide as a white solid (50.4 g, 89% purity by HPLC) which was used in the next step wi~out further pllrific~tion.

Step 4: Pl~alation of 1-(4-cyanobenzyl)-5-(hydroxymethyl)-;midazole (~) To a solution of the ~ret~te. 4 (50.4 g) in 1.5 L of 3:1 THF/water at 0 ~C was added lithium hydroxide monohydrate (18.9 g).
After one hour, the reaction was concentrated in vacuo, diluted with EtOAc (3 L), and washed with water, sat. aq. NaHCO3 and brine. The 5 solution was then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product (26.2 g) as a pale yellow fluffy solid which was sufficiently pure for use in the next step without further purification.
~0 StepS: Preparation of 1-(4-cyanobenzyl)-5-imitl~7ole-carboxaldehyde (6) To a solution of the alcohol 5 (21.5 g) in 500 mL of DMSO
at room tempt;l~Lule was added triethyl~mine (56 mL), then SO3-pyridine complex (40.5 g). After 45 min~ltes, the reaction was poured 15 into 2.5 L of EtOAc, washed with water (4 x 1 L) and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the aldehyde 6 (18.7 g) as a white powder which was sufficiently pure for use in the next step without further purification.
~0 Step6: Preparation of 1-(4-cyanobenzyl)-5-(n-pentylamino-methyl)imidazole (7) To a solution of the aldehyde 6 (132 mg) in 3 mL of 1,2-dichloroeth~n~ at 0 ~C was added 4A powdered molecular sieves (300 mg), n-pentyl~nine (0.217 mL), and sodium triacetoxyborohydride 25 (260 mg). After five days, the reaction was poured into EtOAc and washed with water, sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and conce,ltl~led in vacuo to provide the amine 7 as a brown oil which was used in the next step without further purification.

30 Step 7: Preparation of N-(3-chlorophenyl)-N'-[1-(4-cyanobenzyl)-5-imidazolylmethyll-N'-(n-pentyl)urea hydrochloride (1) To a solution of the amine 7 (prepared above) in 2 mL of dry DMF at 0 ~C was added NaH (37 mg, 60% dispersion in rnineral oil). The solution was warmed to room tempe~alul~ for 10 mimltes, WO 97127752 PCT/U597/OlS99 then recooled to 0 ~C. 3-Chlorophenylisocyanate (0.084 mL) was added ~ ise, and ~e cooling bath was removed. After three hours, the reaction was poured into EtOAc/hexane (2:1) and water, washed with sat. aq. NaHCO3 and bIine, dried (Na2SO4), filtered, and concentrated in S vacuo to provide the crude urea 1 as a yellow foam. Half of this m~t~ri~l was purified by silica gel chromatography (3-5%
MeOH/CH2Cl2), taken up in CH2Cl2 and treated with 1 M HCI/ether solution, and conce~ led in vacuo. The product hydrochloride 1 (7'5 mg) was isolated as a yellow solid.
FAB mass spectrum m/e 436 (M+l).
Analysis calc~ tt-~l for C24H26ClNsO ~ 1.00 HCl ~ 1.10 H20:
C, 58.56; H, 5.98; N, 14.23;
E~ound: C, 58.58; H, 6.14; N, 13.26.

N-(3-chlorophenyl)-N-methyl-N'-[ 1 -(4-cyanobenzyl)-S-imitl~olyl-methyll-N'-(n-pentyl)urea hydrochloride (8) To a solution of urea 1 (rem~ining half of crude producl:
~r~aled above) in 1 mL of dry DMF at 0 ~C was added NaH (14 mg, 60% dispersion in mineral oil). After 15 minllte~, iodomethane (0.029 mL) was added dlo~ise. The reaction was stirred at 0 ~C for four 25 hours, then poured into EtOAc/h~x~ne (2:1) and water, washed with sat.
aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide a puIple oil. This material was purified by silica gel ehromatography (2-5% MeOH/CH2Cl2), taken up in CH2Cl2 and treated wi~ 1 M HCl/ether solution, and concentrated in vacuo. I~e product 30 hydrochloride 8 (22 mg) was isolated as a yellow solid.

FAB mass spectrum m/e 450 (M+l).
Analysis calculated for C2sH28ClNsO ~ 1.20 HCl ~ 1.60 H20:
C, 57.46; H, 6.25; N, 13.40;

Found: C, 57.52; H, 6.27; N, 12.55.

5 In vitro inhibition of ras farnesyl transferase Assays of farnesyl-protein transferase. Partially pllrifiP~
bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) were ~lG~alGd as described by Schaber et al., J. Biol. Chem. 265:14701-14704 (1990), Pompliano, et al., Biochemistry 31:3800 (1992) and 10 Gibbs et al., PNAS U.S.A. 86:6630-6634 (1989), respectively. Bovine FPTase was assayed in a volume of 100 ,ul co~ i..g 100 mM N-(2-hydro~y ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, S mM MgC12, 5 mM dithiollllGilol (DTT), 100 rnM t3H]-farnesyl diphosphate ([3H]-FPP; 740 CBq/mmol, New F.ngl~n~l Nuclear), 650 nM
Ras-CVLS and 10 ,ug/ml FPTase at 31~C for 60 min. Reactions were initi~tell with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol.
Preci~ tes were collecte~l onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% eth~nol, dried and counted in an LKB ,B-plate counter. The assay was linear with respect to both substrates, 20 FPTase levels and time; less than 10% of the [3H]-FPP was lltili7~1 during the reaction period. Purified compounds were dissolved in 100% rlime~thyl sulfoxide (DMSO) and were diluted 20-fold into ~e assay. Percentage inhibition is mP.~ red by the amount of incorporation of radioactivity in the presence of ~e test compound 25 when compared to the amount of incorporation in the absence of the test compound.
Human FPTase was ~l~aled as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1 % (w/v) 30 polyethylene glycol 20,000, 10 ~LM ZnCl2 and 100 nM Ras-CVIM were added to the reaction mixhlre. Reactions were performed for 30 min,, stopped with 100 ,ul of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.

WO 97/27752 PCT/U~97/OlS99 The compounds of the in.~t~nt invention described in F~mples 1 and 2 were tested for inhibitory activity against hllms-n FPIase by the assay described above and were found to have IC50 of <
lO~

n vivo ras farnesylation assay The cell line used in this assay is a v-ras line derived from 10 either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21. The assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75%
conflllency are treated with ~e test compound (final concentration of solvent, meth~nol or dimethyl sulfoxide, is 0.1%). After 4 hours at 15 37~C, t~e cells are labelle~:l in 3 rnl methionine-free DMEM supple-meted with lO~o regular DMEM, 2% fetal bovine serum and 400 mCi[35S]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer (1% NP40/20 rnM HEPES, pH 7.:5/5 mM MgC12/lrnM Dl-r/10 mg/ml ~1olil,en/2 mg/ml leupeptin/2 mg/ml 20 ~ntip~in/0.5 rnM PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45 min. Aliquots of lysates cont~ining equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (lysis buf~er l~t~kin~ DIT) and immllnopreci~iLated with the ras-specific monoclonal antibody Y13-259 (Fur~, M.E. et al., J. Virol. 43:294-304, 25 (1982)). Following a 2 hour antibody incubation at 4~C, 200 ml of a 25% suspension of protein ~-Sepharose coated with rabbit aIlti rat IgG
is added for 45 min. The immllnoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1% Triton X-100Ø5% deoxycholate/0.1 %/SDS/0.1 M NaCl) boiled in SDS-PAGF
30 sample buffer a~d loaded on 13% acryl~rnicle gels. When the dye front re~.h~-~ the bottom, the gel is fixed, soaked in F.nlighterlinp, dried and : autoradiographed. The inten.~ities of the bands corresponding to farnesylated and nonfarnesylated ras proteins are compared to ~lete. ..~ the percent inhibition of farnesyl transfer to protein.

WO 97/27752 PCT/US97/OlS99 F.XAMpT F. S

In vivo ~rowth inhibition assay S To rl~termin~. the biological consequences of FPTase inhibition, the effect of the compounds of the in~t~nt invention on the anchorage-independent ~ wlll of Ratl cells transformed with either a v-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Raf and v-Mos maybe incl~l~le-l in the analysis to evaluate the specificity of 10 in~t~nt compounds for Ras-intlllsetl cell transformation.
Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 104 cells per plate (35 mm in ~ meter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's meAillm supplemlonte~1 with 10% fetal bovine serum) over a bottom 15 agarose layer (0.6%). Both layers co~ ill 0.1% methanol or an ~ iate concentration of the in~t~nt compound (dissolved in methanol at 1000 times the fimal conce~ tion used in the assay). The cells are fed twice weekly with 0.5 ml of m~ lnn A cont~ining 0.1%
m~-th~nol or the concentration of the instant compound.
20 Photomicrographs are taken 16 days after the cultures are seeded and co...~.~.;.cons are made.

Claims (23)

WHAT IS CLAIMED IS:

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

wherein:
R1a, R1b and R2 are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R8O-, R9S(O)m-, R8C(O)NR8-, CN, NO2, (R8)2N-C(NR8)-,R8C(O)-, R8OC(O)-, N3, -N(R8)2, or R9OC(O)NR8-;
c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R8O-, R9S(O)m-, R8C(O)NR8-, CN, (R8) 2N-C(NR8)-,R8C(O)-, R8OC(O)-, N3, -N(R8)2, or R9OC(O)-NR8-;
R3 and R4 are independendy selected from F, C1, Br, N(R8)2, CF3, NO2, (R8)O-, (R9)S(O)m-, (R8)C(O)NH-, H2N-C(NH)-, (R8)C(O)-, (R8)OC(O)-, N3, CN, CF3(CH2)nO-, (R9)OC(O)NR8-, C1-C20 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocycle;
R5a and R5b are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted C3-C10 cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or a group selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, unsubstituted or substituted C3-C10 cycloalkyl, N(R8)2, CF3, NO2, (R8)O-,(R9)S(O)m-, (R8)C(O)NH-, H2N-C(NH)-, (R8)C(O)-,(R8)OC(O)-, N3,CN(R9)OC(O)NR8-;

R6 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, C1, Br, R8O-, R9S(O)m, R8C(O)NR8-, CN, N02, R82N-C(NR8)-, R8C(O)-, R8OC(O)-, N3, -N(R8)2, or R9OC(O)NR8-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O-, R9S(O)m-, R8C(O)NH-, CN, H2N-C(NH)-, R8C(O)-, R8OC(O)-, N3, -N(R8)2, or R8OC(O)NH-;

R7 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O-, R9S(O)m-, R8C(O)NR8-, CN, NO2, (R8)2N-C-(NR8)-, R8C(O)-, R8OC(O)-, N3, -N(R8)2, or R9OC(O)NR8-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R8O-, R9S(O)m-, R8C(O)NR8-, CN, (R8) 2N-C(NR8)-, R8C(O)-, R8OC(O)-, N3, -N(R8)2, or R9OC(O)NR8-;
R8 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;

R9 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR8-, -NR8C(O)-, O, -N(R8)-, -S(O)2N(R8)-, -N(R8)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;
W is a heterocycle;
Y is aryl or heteroaryl;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or4;
p is 0, 1, 2, 3 or4;
r is 0 to 5, provided that r is O when V is hydrogen; and t is 0 or 1;
or an optical isomer or pharmaceutically acceptable salt thereof.

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

wherein:

R1a and R2 are independently selected from: hydrogen or C1-C6 alkyl;

R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, R8O-, -N(R8)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R8O-, or-N(R8)2;
R3 and R4 are independently selected from F, C1, Br, N(R8)2, CF3, NO2, (R8)O-, (R9)S(O)m-, (R8)C(O)NH-, H2N-C(NH)-, (R8)C(O)-, (R8)OC(O)-, N3, CN, (R9)OC(O)NR8-, C1-C20 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocycle;
R5a and R5b are independently selected from:
a) hydrogen, and b) C1-C6 alkyl substituted with hydrogen or a group selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, unsubstituted or substituted C3-C10 cycloalkyl, N(R8)2, CF3, NO2, (R8)O-, (R9)S(O)m-, (R8)C(O)NH-, H2N-C(NH)-, (R8)C(O)-, (R8)OC(O)-, N3, CN (R9)OC(O)NR8-;

R6 is independently selected from:
a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, C1, R8O-, R8C(O)NR8-, CN, NO2, (R8)2N-C(NR8)-, R8C(O)-, R8OC(O)-, -N(R8)2, or R9OC(O)NR8-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R8O-, R8C(O)NR8-, (R8)2N-C(NR8)-, R8C(O)-, R8OC(O)-, -N(R8)2, or R9OC(O)NR8-;

R7a is hydrogen or methyl;
R8 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R9 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR8-, O, -N(R8)-, or S(O)m;

V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;

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

3. A compound which inhibits farnesyl-protein transferase of the formula Ib:
wherein:
R1a and R2 are independently selected from: hydrogen or C1-C6 alkyl;
R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, R8O-, -N(R8)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R8O-, or-N(R8)2;

R3 and R4 are independently selected from F, Cl, Br, N(R8)2, CF3, NO2, (R8)O-, (R9)S(O)m-, (R8)C(O)NH-, H2N-C(NH)-, (R8)C(O)-, (R8)OC(O)-, N3, CN, (R9)OC(O)NR8-, C1-C20 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocycle;
R5a and R5b are independently selected from:
a) hydrogen, and b) C1-C6 alkyl substituted with hydrogen or a group selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, unsubstituted or substituted C3-C10 cycloalkyl, N(R8)2, CF3, NO2, (R8)O-, (R9)S(O)m-,(R8)C(O)NH-, H2N-C(NH)-,(R8)C(O)-, (R8)OC(O)-, N3, CN (R9)OC(O)NR8-;

R6 is independently selected from:
a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-c6 alkynyl, C1-C6 perfluoroalkyl, F, C1, R8O-, R8C(O)NR8-, CN, NO2, (R8)2N-C(NR8)-, R8C(O)-, R8OC(O)-, -N(R8)2, or R9OC(O)NR8-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R8O-, R8C(O)NR8-, (R8)2N-C(NR8)-, R8C(O)-, R8OC(O)-, -N(R8)2, or R9OC(O)NR8-;

R7 is selected from: hydrogen and C1-C6 alkyl;
R8 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R9 is independently selected from C1-C6 alkyl and alkyl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR8-, O, -N(R8)-, or S(O)m;
V is selected from:

a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is O and A2 is S(O)m;

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

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

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

wherein:

R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, R8O-, -N(R8)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R8O-, or-N(R8)2;

R2 are independently selected from: hydrogen or C1-C6 alkyl;
R3 and R4 are independently selected from F, C1, Br, N(R8)2, CF3, NO2, (R8)O-, (R9)S(O)m-, (R8)C(O)NH-, H2N-C(NH)-, (R8)C(O)-, (R8)OC(O)-, N3, CN, (R9)OC(O)NR8-, C1-C20 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocycle;
R5a and R5b are independently selected from:
a) hydrogen, and b) C1-C6 alkyl substituted with hydrogen or a group selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, unsubstituted or substituted C3-C10 cycloalkyl, N(R8)2, CF3, NO2, (R8)O-, (R9)S(O)m-, (R8)C(O)NH-, H2N-C(NH)-, (R8)C(O)-, (R8)OC(O)-, N3, CN (R9)OC(O)NR8-;

R6 is independently selected from:
a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, C1, R8O-, R8C(O)NR8-, CN, NO2, (R8)2N-C(NR8)-, R8C(O)-, R8OC(O)-, -N(R8)2, or R9OC(O)NR8-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R8O-, R8C(O)NR8-,(R8)2N-C(NR8)-,R8C(O)-, R8OC(O)-, -N(R8)2, or R9OC(O)NR8-;
R8 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R9 is independently selected from C1-C6 alkyl and aryl;

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

5. The compound according to Claim 4 of the formula Id:

wherein:

R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, R8O-, -N(R8)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R8O-, or-N(R8)2;

R2 are independently selected from: hydrogen or C1-C6 alkyl;
R3 and R4 are independently selected from F, C1, Br, N(R8)2, CF3, NO2, (R8)O-, (R9)S(O)m-, (R8)C(O)NH-, H2N-C(NH)-, (R8)C(O)-, (R8)OC(O)-, N3, CN, (R9)OC(O)NR8-, C1-C20 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocycle;
R5a and R5b are independently selected from:
a) hydrogen, and b) C1-C6 alkyl substituted with hydrogen or a group selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, unsubstituted or substituted C3-C10 cycloalkyl, N(R8)2, CF3, NO2, (R8)O-, (R9)S(O)m-, (R8)C(O)NH-, H2N-C(NH)-, (R8)C(O)-, (R8)OC(O)-, N3, CN (R9)OC(O)NR8-;
R8 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R9 is independently selected from C1-C6 alkyl and aryl;

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

6. A compound which inhibits farnesyl-protein transferase which is selected from:

N-(3-chlorophenyl)-N'-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-N' -(n-pentyl)urea hydrochloride (1) , N-(3-chlorophenyl)-N-methyl-N'-[1-(4-cyanobenzyl)--5-imidazolyl-methyl]-N'-(n-pentyl)urea hydrochloride (8) , or a pharmaceutically acceptable salt thereof.

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

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

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

10. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 6.

11. 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 7.

12. 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 8.

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

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

15. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 7.

16. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 8.

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

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 neurofibromen benign proliferative disorder which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 7.

20. 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 7.

21. 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 7.

22. A method for preventing restenosis which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 7.

23. 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 7.