CA2216532A1 - Inhibitors of farnesyl-protein transferase - Google Patents

Abstract

The present invention comprises analogs of the CA1A2X motif of the protein Ras that is modified by farnesylation in vivo. These CA1A2X analogs inhibit the farnesyl-protein transferase and the farnesylation of certain proteins. Furthermore, these CA1A2X analogs differ from those previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. The compounds of the instant invention also incorporate a cyclic amine moiety in the A2 position of the motif. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.

Description

CA 02216~32 1997-09-26 W O 96/34010 PCTrUS96/03975 TITLE OF THE INVENTION
INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE

RELATED APPLICATION
The present patent application is a continuation-in-part application of copending application Serial No. 08/412,828, filed March 29, 1995.

BACKGROUND OF THE INVENTION
The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of a si~n~llinp pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochernical studies of Ras action indicate that Ras functions like a G-regulatory ~r~teill. In the inactive state, Ras is bound to GDP. Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTP-bound form of Ras propagates the growth stim~ tory signal until the signal is termin~te-l by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound forrn (D.R. Lowy and D.M. Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many hllm~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 transrnit a growth stimlll~tory signal.
Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-Aaal-Aaa2-Xaa"
box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino ~ acid) (Willumsen et al.. Nature 310:583-586 (1984)). Depending on the specific sequence, this motif ser~ es as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeran~ l-protein transferase, ~~ hich CA 02216~32 1997-09-26 W O96/34010 PCTrUS96/0397 catalyze the aL~ylation of the cysteine residue of ~e CAAX motif with a C1s or C20 isoprenoid, respec*ively. (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 5 undergo post-tr~n~l~tional farnesyla*ion. Other farnesylated ~ teills include the Ras-related GTP-binding ~ teil~s such as Rho, fungal m~*n~
factors, the nuclear l~min~, and the ~s~mm~ subunit of transducin. James, et al., J. BioL Chem. 269, 14182 (1994) have iden*fied a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also 10 suggested that there are farnesylated proteins of unknown structure and function in addi*ion to those listed above.
Inhibi*on of farnesyl-~r~teill transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been 15 demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the Ras onc~ t~in intracellularly (N.E. Kohl et al., Science, 260:1934-1937 (1993) and G.L. James et al., Science, 260: 1937- 1942 (1993). Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of ras-20 dependent tumors in nude mice (N.E. Kohl et al., Proc. Natl. Acad. SciU.S.A., 91:9141-9145 (1994) and induces regression of m~mm~ry and salivary carcinomas in ras transgenic mice (N.E. Kohl et al., Nature Medicine, 1:792-797 (1995).
Indirect inhibition of farnesyl-protein transferase in vivo has 25 been demonstrated with lovastatin (Merck & Co., Rahway, NJ) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Farnesyl-protein transferase utilizes farnesyl 30 pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl, roup (Réiss et al.. Cell, 62:81-88 (1990);
Schaber et al., J. Biol. Chem. . 265: l 4701 - l 4704 (1990); Schafer et al., Science, 249: l 133-1139 (1990); Manne et al.. Proc. Natl. Acad. Sci USA, 87:7541-7545 (1990)) Inhibition of famesyl pyrophosphate biosynthesis CA 02216~32 1997-09-26 W O96/34010 PCTnUS96/0397 by inhibiting HMG-CoA reductase blc~cks Ras membrane loc~li7~tion in cultured cells. However, direct inhibition of farnesyl-protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene 5 biosynthesis.
Tnhibitors of farnesyl-protein transferase (FPTase) have been described in two general classes. The first are analogs of farnesyl diphosphate (FPP), while the second class of inhibitors is related to the protein substrates (e.g., Ras) for the enzyme. The peptide derived 10 inhibitors that have been described are generally cysteine con~inin~
molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit ~l~)t~ prenylation while serving as alternate substrates for the farnesyl-proteill transferase 15 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)). 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 20 potentially places limit~tions on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, ph~ codynamics and toxicity. Therefore, a 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 25 and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7-112930).
It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516).
30 Imidazole-cont~ining inhibitors of farnesyl protein transferase have also been disclosed (WO 95/09OO l 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-translational CA 02216~32 1997-09-26 W O96134010 ' PCTrUS9610397 farnesylation of proteins. It is a further object of this invention to develop chemotherapeutic compositions cont~inin~ the compounds of this invention and methods for producing the compounds of this invention.

S SUMMARY OF THE INVENTION
The present invention comprises analogs of the CAlA2X
motif of the protein Ras that is modified by farnesylation in vivo. These CAlA2X analogs inhibit the farnesylprotein transferase. Furthermore, these CAlA2X analogs differ from those previously described as 10 inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved ph~rm~t~okinetic behavior in ~nim~l.c, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and re~ re~ systemic toxicity. The 15 compounds of the instant invention also incorporate a cyclic amine moiety in the A2 position of the motif. Further cont~in~.-l in this invention are chemotherapeutic compositions cont~ining these farnesyl transferase inhibitors and methods for their production.

W O 96/34010 PCTrUS96/0397 l~e compounds of this invention are illustrated by the forrn~

V- A1(CR1a2)nA2(CR1~2)n ~- (CR1b2)p~N~OH

R4a R4b V A1 (CR1 a2)nA2(CR 1a2)n ~W)- (CR1b2)p~

R4a R4b HOCH2(CH2)q V-A1(cR1~2)nA2(cR182)n-(w (CR1b2)p~N~

V - A1 (CR1 a2)nA2(cR 1 a2)n (W)- (CRl bz)p~f N ~H~

X R4b IV R4a/
DETAILED D~;S(~RIPTION OF THE INVENTION
S The compounds of this invention inhibit the farnesyl-protein transferase. In a first embodiment of this invention, the farnesyl-protein transferase inhibitors are illustrated by the forrnula I:

CA 022l6~32 l997-09-26 W O 96/34010 PCTrUS96/0397 (R~), ( ), R6 Y ~, V-A (CR1a2),~AZ(CR1a2)n (CR1b2)p~fN~R4bo wherem:
Rla and Rlb are independently selected from:
a) hydrogen, S b) aryl, heterocycle, cycloaLkyl, aL~enyl, aL~cynyl, R100-, Rl lS(O)m-, RlOC(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, RlOC(O)-, RlOoc(o)-~ N3, -N(R10)2, or Rl lOC(o)NRlO
c) Cl-C6 aL~yl unsubstituted or substituted by aryl, heterocyclic, cycloaLkyl, aL~enyl, alkynyl, R100-, RllS(O)m-, RlOC(O)NR10-, CN, (R10)2N-C(NR10)-, RlOc(o)-~ RlOoc(o)-7 N3, -N(R10)2, or Rl loC(O) NRlO;

15 R2 and R3 are independently selected from:
a) a side chain of a naturally occurring arnino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C 1 -C20 alkyl, C2-C20 alkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R10)2, N02, R100-, Rl lS(O)m-, RlOC(O)NR10-, CN, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, Rl lOC(O)NR10- and Cl-C20 alkyl, and W O 96/34010 PCTrUS96/0397 d) Cl-C6 alkyl substituted with an unsubstituted or substituted group s~ cte-l from aryl, heterocycle and C3-Clo cycloalkyl; or S R2 and R3 are combined to forrn - (CH2)S -; or R2 or R3 are combined with R6 to forrn a ring such that R6 ~
~;N2~' R7a~H2), - R4a, R4b, R7a and R7b are independently selected from:
a) hydrogen, b) Cl-C6 alkyl unsubsti~lte~l or subctitlltç-l by alkenyl, R100-, RllS(O)m-, RlOC(O)NR10-, CN, N3, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10-, c) aryl, heterocycle, cycloaLkyl, alkenyl, R100-, Rl lS(O)m-, RlOC(O)NR10-, CN, NO2, (R10)2N-C(NRlo)-~ RlOc(o)-~ Rlooc(o)-~ N3, -N(R10)2, or Rl lOC(O)NR10-, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and - C3-Clo cycloalkyl;

R5a and Rsb are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C 1 -C20 alkyl, C2-c2o alkenyl, C3-C l o cycloalkyl, aryl or heterocycle group, CA 02216~32 1997-09-26 W O96/34010 PCTrUS96/03975 wherein the substituent is selected from F, Cl, Br, (RlO)2Nc(o)-~ N02, R10O-, RllS(o)m R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, Rl 1OC(O)NR10- and S Cl-C20 aL~yl, d) Cl-C6 aLkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloallyl; or 10 RSa and R5b are combined to form - (CH2)S - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R6 is independently selected from hydrogen or C l-C6 aLkyl;
R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, aL~cenyl, aLkynyl, perfluoroalkyl, F, Cl, Br, R100-, Rl lS(O)m-, R10c(o)NRlo-~ CN, NO2, R102N-C(NR10)-, R10C(O)-, R10oc(o)-~ N3, -N(R10)2, or R1 1OC(O)NR10-, and c) C 1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloaL~yl, alkenyl, aLkynyl, perfluoroaL~yl, F, Cl, Br, R10O-, Rl lS(O)m-, R10C(O)NH-, CN, H2N-C(NH)-, R10C(O)-, Rl0oc(o)-~ N3, -N(R10)2, or RlOOC(O)NH-;

R9 is selected from:
a) hydrogen, 30 b) alkenyl, alkynyl, perfluoroaLkyl, F. Cl, Br, R100-, Rl l~S(O)m-, RlOC(O)NR10-, CN. N02, (R10)2N-C-(NR 10), R 1 ~C(O)-, R 1 ~OC(O)-. N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 and CA 02216~32 1997-09-26 W O96/34010 PCTrUS96103975 c) Cl-C6 aL~yl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R100-, Rl lS(O)m-, RlOC(O)NR10-, CN, (Rlo)2N-c(NRlo)-7 Rloc(o)-7 RlOoc(o)-7 N3, -N(R10)2, or Rl lOC(O)NR10;
s R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl;

Rl 1 is independently selected from Cl-C6 aL~yl and aryl;
Al and A2 are independently selected from: a bond, -CH=CH-, -C--C-, -C(0)-, -C(O)NR 10 , -NR 1 ~C(0)-, 0, -N(R 10) , -S(0)2N(R10)-, -N(RlO)s(o)2-7 or S(O)m;

15 Q is a substituted or unsubstituted nitrogen-cont~ining C4-Cg mono or bicyclic ring system, wherein the non-nitrogen cont~ining ring may be a C5-C7 saturated ring;

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 0, S, and N, and e) C2-C20 aLkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(O)m;

W is a heterocycle;
X, Y and Z are independently H2 or 0;
., m is 0 1 or ';
nis 0, 1. '.30r4;

CA 02216~32 1997-09-26 W O96/34010 PCTrUS96/0397 pis 0, 1,2, 3 or4;
r is 0 to S, provided that r is 0 when V is hydrogen;
sis 40rS;
t is 3, 4 or S; and S u is 0 or 1;
or the ph~ ceutically acceptable salts thereof.

In a second embodiment of this invention the prodrugs of compounds of formula I are illustrated by the formula II:

V - A (cR1a2)nA2(cR1~2)n -(W)- (CR1b2)p~ J ~ ~ J

R4a wherein:
R1a and Rlb are independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R100-, lS R1 lS(O)m, RlOC(O)NR10-~ CN, N02, (R10)2N-C(NR10)-, R1OC(0)-~ RlOoc(o)-~ N3, -N(R10)2, or Rl 1OC(O)NR10 c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R100-, RllS(O)m-, RlOC(O)NR10-, CN, (R10)2N-C(NR10)-, RlOC(0)-, RlOOC(0)-, N3, -N(Rl0)2, or Rl loC(0) NRlO;

R2 and R3 are independently selected from:
a) a side chain of a naturally occurrin~ amino acid, b) an oxidized form of a side chain of a naturally occurrin~
amino acid which is:
i) methionine sulfoxide~ or ii) methionine sulfone. and CA 02216~32 1997-09-26 W O96/34010 PCTrUS96/03975 c) substituted or unsubstituted Cl-C20 aL~yl, C2-C20 aL~enyl, C3-Clo cycloaL~yl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R10)2, N02, R100-, Rl lS(O)m-, RlOC(O)NR10-, S CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, Rl 10C(O)NR10- and Cl-C20 aL~yl, and d) Cl-C6 aL~yl substitllte~1 with an unsubstituted or sub~titlltç-1 group selected from aryl, heterocycle and C3-Clo cycloaL~yl; or R2 and R3 are combined to form - (CH2)S -; or R2 or R3 are combined with R6 to form a ring such that R6 R7a ~R7b R4a, R4b, R7a and R7b are independently selected from:
a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by aL~enyl, R100-,R1 1S(O)m-, R10C(O)NRl0-~ CN, N3, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or Rl lOC(O)NR10-, c) aryl, heterocycle, cycloaLkyl, alkenyl, R100-, Rl1S(O)m-, R10C(O)NRl0-~ CN, NO2, (R10)2N-C(NRlo)-~ R10C(o), R10oc(o)-~ N3, -N(R10)2, or R 1 1 OC(O)NR 10 , and d) C 1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C l o cycloalkyl;
c~
30 RSa and R5b are independently selected from:
a) a side chain of a naturallv occurring amino acid~

CA 022l6~32 l997-09-26 W O 96/34010 PCTrUS96/0397 b) an oxitli~ecl form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, S c) substituted or unsubstituted Cl-C20 aIkyl, C2-C20 alkenyl, C3-Clo cycloaL~yl, aryl or heterocycle group, wherein ~e substituent is selected from F, Cl, Br, (RlO)2Nc(o)-~ N02, R10O-, Rl lS(o)m RlOC(O)NR10, CN, (R10)2N-c(NRlo)-~ RlOC(O)-~
RlOOC(O)-, N3, -N(R10)2, RllOC(O)NR10- and Cl-C20 alkyl, d) Cl-C6 aL~yl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloaIkyl; or RSa and Rsb are combined to form - (CH2)S - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;
R6 is independently selected from hydrogen or Cl-C6 aLkyl;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroaIkyl, F, Cl, Br, RlOO-, Rl lS(O)m-, R 1 OC(O)NR 10 , CN, NO2, R 1 02N-C(NR 10) , Rl ~C(O)-, RlOOC(O)-, N3, -N(R10)2, or R1 lOC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl. alkynyl, perfluoroalkyl, F, 3Q Cl, Br, R100-, Rl lS(O)m-, RlOC(O)NH-, CN, H2N-C(NH)-, R1OC(O)-, RlOOC(O)-. N3, -N(Rl0)2, or R 1 OOC(O)NH-;

R9 is selected from:

CA 02216~32 1997-09-26 W O96/34010 PCTrUS96/03975 a) hydrogen, b) aLkenyl, alkynyl, perfluoroaL~yl, F, Cl, Br, R100-, Rl1S(O)m-, RlOC(O)NR10-, CN, NO2, (R10)2N-C-(NR10)-, R10c(o)-~ R10oc(o)-~ N3, -N(R10)2, or S RllOC(O)NR10-, and c) Cl-C6 aL~yl unsubstituted or substituted by perfluoroaL~yl, F, Cl, Br, R1OO-, R11S(O)m-, RlOC(O)NR10-, CN, (R10)2N-C(NR10)-, RlOC(O)-~ RlOOC(O)-, N3, -N(R10)2, or Rl 1OC(O)NR10;
R10 is independently selected from hydrogen, Cl-C6 aL~yl, benzyl and aryl;

R11 is independently selected from Cl-C6 aLkyl and aryl;
R12 is a) substituted or unsubstitllteA Cl-Cg aL~yl, substituted or unsubstituted C5-Cg cycloaL~yl, or substituted or unsubstituted cyclic amine, wherein the substituted aLkyl, cycloaLkyl or cyclic amine is substituted with 1 or 2 substituents independently selected from:
1 ) C 1 -C6 alkyl, 2) aryl, 3) heterocycle, 4) -N(R 1 1)2, 5) -OR10, or b) R13 o 0~ R14 30 R13 is independently selected from hydrogen and Cl-C6 alkyl;

R14 is independently selected from Cl-C6 ~l};yl;

CA 02216~32 1997-09-26 W O 96/34010 PCTrUS96/0397 Al and A2 are independently selected from: a bond, -CH=CH-, -C-C-, -C(O)-, -C(O)NR 1 0, -NR 1 ~C(O)- , O, -N(R 1 0), -S(0)2N(R10)-, -N(RlO)s(o)2-~ or S(O)m;

S Q is a substihlte-l or unsubstituted nitrogen-cont~ining C4-Cg mono or bicyclic ring ~y~ , wherein the non-nitrogen cont~inin~ ring may be a C5-C7 saturated ring;

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

W is a heterocycle;
X, Y and Z are independently H2 or 0;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or4;
pis 0,1,2,30r4;
r is O to 5, provided that r is O when V is hydrogen;
sis 40rS;
tis 3,40rS;and uis Oorl;
30 or the pharrnaceutically acceptable salts thereof.

In a third embodiment of this in- ention, the inhibitors of farnesyl transferase are illustrated by the forrnula III:

W O96/34010 PCTrUS96/03975 HOCH2(CH2)q V-A (CR 2)nA2(CR1a2)n-(W) (CR1bz)p~

wherein:
Rla and R1b are independently selected from:
S a) hydrogen, b) aryl, heterocycle, cycloaLkyl, aLkenyl, aLkynyl, R100-, Rl 1S(O)m-, RlOc(o)NRlo-~ CN, NO2, (R10)2N-C(NR10)-, RlOC(O)-, R1OOC(O)-, N3, -N(R10)2, or RllOC(O)NR10 c) Cl-C6 alkyl unsubstituted or substitllte-l by aryl, heterocyclic, cycloaLkyl, aLkenyl, alkynyl, R100-, R1 lS(O)m-, R1OC(O)NR10-, CN, (R10)2N-C(NR10)-, R1OC(O)-, R10oc(o)-~ N3, -N(R10)2, or Rl loC(O)-NR10;

R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C 1 -C20 alkyl, C2-C20 aLkenyl, C3-C1o cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RlO)2~ NO2, RlOO-, Rl lS(O)m, RlOC(O)NR10-CN, (R 1 0)2N-C(NR 10), R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R10)2, Rl lOC(O)NR10- and Cl-C20 alk~l, and CA 02216~32 1997-09-26 W O96134010 PCTrUS96/0397 d) Cl-C6 aL~yl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl; or 5 R2 and R3 are combined to form - (CH2)S -; or R2 or R3 are combined with R6 to form a ring such ~at R6 ~

~-,N2~ R7a ~HR2)b R4a, R4b, R7a and R7b are independently selected from:
a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by aL~enyl, R100-, Rl lS(O)m-, R10C(O)NRl0-~ CN, N3, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or Rl lOC(O)NR10-, c) aryl, heterocycle, cycloaL~yl, aL~enyl, R100-, R1 1S(O)m-, R10C(O)NRl0-~ GN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or Rl lOC(O)NR10-, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-Clo cycloaLkyl;

R6 is independently selected from hydrogen or Cl-C6 aLkyl;
R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, a~enyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-. Rl lS(O)m-, R 1 0C(O)NR 1 0-, CN. NO2, R 10 N-C(NR 10)-, Rl ~C(O)-~
R 1 ~OC(O)-. N3, -N(R 1 ~)2. or R l l OC(O)NR 10-. and CA 02216~32 1997-09-26 W O 96/34010 PCTrUS96/0397 c) Cl-C6 aL~yl unsubstituted or substituted by aryl, heterocycle, cycloaL~yl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(O)m-, RlOC(O)NH-, CN, H2N-C(NH)-, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or RlOOC(O)NH-;

R9 is selected from:
a) hydrogen, b) alkenyl, aL~ynyl, per~1uoroaL~yl, F, Cl, Br, R100-, RllS(O)m-, RlOC(O)NR10-, CN, NO2, (R10)2N-C-(NR10)-, RlOC(O)-, RlOoc(o)-~ N3, -N(R10)2, or RllOC(O)NR10-, and c) Cl-C6 aL~yl unsubstituted or substit-lte-l by perfluoroallyl, F, Cl, Br, RlOO-, RllS(O)m-, RlOc(o)NRlo-~ CN, (R10)2N-C(NR10)-, RlOC(O)-, RlOoc(o)-~ N3, -N(R10)2, or Rl lOC(O)NR10;

R10 is independently selected from hydrogen, Cl-C6 aL~yl, benzyl and aryl;
Rl 1 is independently selected from Cl-C6 aL~yl and aryl; -Al and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR 10 , -NR 1 ~C(O)-, O, -N(R 10) , -S(O)2N(R10)-, -N(RlO)S(O)2-, or S(O)m;

Q is a substituted or unsubstituted nitrogen-cont~ining C4-Cg mono or bicyclic ring system, wherein the non-nitrogen cont~inin~: ring may be a Cs-C7 saturated ring;
r 30 V is selected from:
a) hydrogen, b) heterocycle, c) aryl W O 96/34010 PCTrUS96/03975 d) Cl-C20 aLkyl wherein from O to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if 5 Al is a bond, n is O and A2 is S(O)m;

W is a heterocycle;

X, Y and Z are independently H2 or 0;
mis 0,1 or2;
nis 0, 1,2,30r4;
pis 0, 1,2,30r4;
qis 0,1 or2;
lS r is O to S, provided that r is O when V is hydrogen;
sis 40r5;
tis 3,40rS;and uis Oor l;

20 or the ph~ çeutically acceptable salts thereof.

In a fourth embodiment of this invention the prodrugs of compounds of formula III are illustrated by the formula IV:
V Al(CR1a2)nA2(CR1a2 n ~w - (CR1b )p~ à

25 wherein:
Rla and Rlb are independently selected from:
a) hydrogen, CA 02216~32 1997-09-26 W O 96t34010 PCTnUS96tO397 b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R100-, R11S(o)m, Rloc(o)NRlo-~ CN, NO2, (R10)2~-C(NR10)-, RlOC(O)-, RlOOC(O)-, N3, -N(Rl0)2, or RllOC(O)NR10 Sc) Cl-C6 alkyl unsubstitllte-l or substitllterl by aryl, heterocyclic, cycloaL~yl, aL~enyl, alkynyl, R100-, R11S(O)m-, R1OC(O)NR10-, CN, (R10)2N-C(NR10)-, R1OC(O)-, R1OOC(O)-, N3, -N(R10)2, or Rl loC(O)-NR10, R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxi~li7e-1 form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C1o cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, RlOO-, R11S(O)m-, R1OC(O)NR10-, CN, (R10)2N-C(NR10)-, R1OC(O)-, R1OOC(O)-, N3, -N(R10)2, R1 1OC(O)NR10- and C1-C20 alkyl, and d) C 1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1o cycloalkyl; or R2 and R3 are combined to form - (CH2)S -; or R2 or R3 are combined with R6 to form a rin~ such that R6 r~
;N~ is ~ (~H2)~ ;
R2 R7a R7b CA 022l6~32 l997-09-26 W O96/34010 PCTrUS96/03975 R4a, R4b, R7a and R7b are independently selected from:
a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by aL~cenyl, R100-, S RllS(O)m-, RlOC(O)NR10-, CN, N3, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or Rl lOC(O)NR10-, c) aryl, heterocycle, cycloaL~yl, aL~enyl, R100-, Rl1S(O)m-, R10C(O)NRl0-~ CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or Rl lOC(O)NR10-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-Clo cycloalkyl;

15 R6 is independently selected from hydrogen or Cl-C6 alkyl;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, aLkynyl, perfluoroalkyl, F, Cl, Br, R10O-, Rl lS(O)m-, Rl0c(o)NRlo-~ CN, NO2, R102N-C(NR10)-, R10C(O)-~
R10OC(O)-, N3, -N(R10)2, or R1 1OC(O)NR10-, and c) C l-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloaLkyl, alkenyl, aL~ynyl, perfluoroalkyl, F, Cl, Br, R10O-, R1 1S(O)m-, R10C(O)NH-, CN,H2N-C(NH)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or RlOOC(O)NH-;

R9is selected from:
a) hydrogen, b) aL~cenyl, aL~cynyl, perfluoroaL~cyl, F, Cl, Br, R100-, Rl ls(o)m-~ RlOC(O)NR10-, CN. N02, (R10)2N-C-(NR10), Rl0C(o), R10OC(O)-~ N3, -N(R10)2. or R I 1 OC(O)NR 10-. and CA 02216~32 1997-09-26 W O96/34010 PCTrUS96/0397 c) Cl-C6 alkyl unsubstituted or substituted by perfluoroaL~yl, F, Cl, Br, RlOO-, Rl 1S(O)m-, RlOC(O)NR10-, CN, (Rlo)2N-c(NRlo)-~ Rloc(o)-~ R10Oc(o)-~ N3, -N(R10)2, or Rl lOC(O)NR10;
s R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl;

R11 is independently selected from Cl-C6 aL~yl and aryl;
A1 and A2 are independently selected from: a bond, -CE~=CH-, -C_C-, -C(O)-, -C(O)NR 10 , -NR 1 ~C(O)-, O, -N(R 10 -S(O)2N(R10)-, -N(RlO)S(O)2-, or S(O)m;

15 Q is a substi1~lte-1 or unsubstihlte~l nitrogen-cont~ining C4-Cg mono or bicyclic ring system, wherein the non-nitrogen cont~inin~ ring may be a C5-C7 saturated ring;

V is selected from:
a) hydrogen, b) heterocycle, 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 aL~enyl, provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;

W is a heterocycle;
X, Y and Z are independently H2 or O;

y m is 0~ l or'';
n is 0. 1, ', 3 or4:

W O 96/34010 PCTrUS9610397 pis 0,1,2,30r4;
qis 0,lor2;
r is 0 to S, provided that r is 0 when V is hydrogen;
sis 40rS;
S tis 3,40rS;and u is 0 or 1;
or the ph~ eutically acceptable salts thereof.

In a more preferred embodiment of this invention, the Ras farnesyl transferase inhibitors are illustrated by the Formula I:

V-A1(CR1a2)nAZ(cR1l2)n-(w) (CR1b2)p~N? ~

wherein:
Rla is independently selected from: hydrogen or Cl-C6 aLkyl;

R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, R100-, -N(R10)2 or alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, or-N(R10)2;

R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide. or ii) methionine sulfone~

CA 022l6~32 l997-09-26 W O 96/34010 PCTnUS96/03975 c) substihlte~l or unsubstituted Cl-Clo aL~yl, C2-Clo aL~enyl, C3-Clo cycloaL~yl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-c(NRlo)-~ R10C(O)-~ R10OC(O)-~ N3, -N(R10)2, Rl lOC(O)NR10- and Cl-C20 aL~yl, and d) Cl-C6 aL~yl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloaL~yl, or R2 and R3 are combined to form - (CH2)S -; or R2 or R3 are combined with R6 to form a ring such that ~,; N~, R7a ~R7b R4a and R7a are independently selected from:
a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by alkenyl, R100-, R11S(O)m-, R10C(O)NRl0-~ CN, N3, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R1 lOC(O)NR10-, c) aryl, heterocycle, cycloaLkyl, alkenyl, R100-, R1 lS(O)m-, R10C(O)NRl0-~ CN, NO2, (R10)2N-C(NR10), RlOC(O)-~ RlOOC(O)-, N3,-N(R10)2, or R 1 1 OC(O)NR 10, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C l o cycloalkyl;
~0 R4b and R7b are hydrogen;

CA 02216~32 1997-09-26 W O96/34010 PCTrUS96/0397S

RSa is selected from:
a) a side chain of a naturally occurring ~mino acid, wherein the aII~ino acid is selected from methionine and glllt~mine, b) an oxidized form of a side chain of a naturally occurring S amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, and c) substihlte~l or unsubstituted Cl-Clo aL~yl, C2-Clo aL~enyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R100-, RllS(O)m-, RlOC(O)NR10-, (R10)2Nc(o)-~ CN, (R10)2N-C(NR10)-, RlOC(O)-, R10OC(O)-, N3, -N(R10)2, R11OC(O)NR10- and Cl-C20 alkyl, and 15 d) Cl-C6 aL~yl substihlte~l with an unsubstituted or sub~titllte.-1 group selected from aryl, heterocycle and C3-Clo cycloaLkyl;
RSb is selected from:
a) hydrogen, and b) Cl-C3 alkyl;

R6 is independently selected from hydrogen or C 1-C6 alkyl;

2~ R8 is independently selected from:
a) hydrogen, b) Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroaLkyl, F, Cl, R100-, RlOC(O)NR10-, CN, N02, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-~ -N(R10)2, or R 1 1 OC(O)NR 10 , and c) C l ~C6 alkyl substituted by C l -C6 perfluoroaLkyl, R l ~O-~
R10C(O)NR10-, (R10)2N-C(NR10)-, RlOC(O)-, R10OC(O)-, -N(R10)2, or Rl lOC(03NR10-;

CA 02216~32 1997-09-26 R9 is selected from:
a) hydrogen, b) C2-C6 aL~enyl, C2-C6 alkynyl, C l-C6 perfluoroaL~yl, F, Cl, R1OO-, Rl 1S(O)m-, R1OC(O)NR10-, CN, NO2, (R10)2N-S C(NR10)-, R1OC(O)-, R1OOC(O)-, -N(R10)2, or R1 1OC(O)NR10-, and c) Cl-C6 aLkyl unsubstitllte~l or substituted by Cl-C6 perfluoroaLkyl, F, Cl, R100-, Rl lS(O)m-, RlOC(O)NR10-, CN, (R10)2N-C(NR10)-, R10c(o)-~ R10oc(o)-~ -N(R10)2, or R1 1OC(O)NR10;

R10 is independently selected from hydrogen, Cl-C6 aLkyl, benzyl and aryl;

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

Q is selected from:

,~
~~N~ N~ and -~- N~

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;

25 V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, W O96/34010 PCTrUS96/03975 d) Cl-C20 alkyl wherein from O to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) C2-C20 aLkenyl, and provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if 5 A1 is a bond, n is O and A2 is S(O)m;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;
X, Y and Z are independently H2 or 0;

mis 0,1 or2;
nis 0,1,2,30r4;
pis 0,1,2,30r4;
r is O to 5, provided that r is O when V is hydrogen;
tis 3,40r5;and uis Oor l;

20 or the pharmaceutically acceptable salts thereof.

In a second more preferred embodiment of this invention, the prodrugs of the preferred compounds of Formula I are illustrated by the Formula II:

V ~ A1(CR1a2)nA2(CRla2)n (W)- (CR1b2)p~oRl2 X R4b 11 R4a wherein:
Rla is independently selected from: hvdro~en or Cl-C6 alkyl;

CA 02216~32 1997-09-26 W O96134010 PCTrUS96/03975 R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloaL~yl, R100-, -N(R10)2 or aL~enyl, S c) Cl-C6 aL~yl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, aL~enyl, R100-, or-N(R10)2;

R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-Clo alkyl, C2-Clo alkenyl, C3-Clo cycloaLkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, R1OO-, R11S(O)m-, R10c(o)NRlo-~ CN, (R10)2N-C(NR10)-, R10c(o)-~ R10oc(o)-~ N3, -N(R10)2, Rl lOC(O)NR10- and Cl-C20 aLkyl, and d) Cl-C6 aLkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloaLkyl; or R2 and R3 are combined to form - (CH2)s -; or R2 or R3 are combined with R6 to form a ring such that R6 ~
R7a ~HR2)b 30 R4a and R7a are independently selected from:
a) hvdrogen, CA 02216~32 1997-09-26 W O 96/34010 PCTrUS96/03975 b) Cl-C6 aL~yl unsubstituted or substituted by alkenyl, R100-, Rl lS(O)m-, R1OC(O)NR10-, CN, N3, (R10)2N-C(NR10)-, R1OC(O)-, R1OOC(O)-, -N(R10)2, or R1 1OC(O)NR10-, c) aryl, heterocycle, cycloaL~yl, aL~enyl, R100-, R1 1S(O)m-, R1OC(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R1OC(O)-, R1OOC(O)-, N3, -N(R10)2, orR11OC(O)NR10-, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-Clo cycloaL~yl;

R4b and R7b are hydrogen;

RSa is selected from:
a) a side chain of a naturally occl-rnn~ amino acid, wherein the amino acid is selected from methionine and gl~
b) an o~itli7e~1 form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl-Clo aL~yl, C2-Clo alkenyl, C3-Clo cycloaL~yl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02,R100-,RllS(O)m-,RlOC(O)NR10-, (R10)2Nc(o)-~ CN, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, Rl lOC(O)NR10- and Cl-C20 aL~yl, and d) Cl-C6 aL~cyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl;

R~b is selected from:
a) hydro~en. and b) C1-C~ al~yl;

- ==
CA 02216~32 1997-09-26 W O96/34010 PCTrUS96/0397 ., R6 is independently selected from hydrogen or Cl-C6 aL~yl;

R8 is independently selected from:
5a) hydrogen, b) Cl-c6 aL~yl, C2-c6 aL~enyl, C2-c6 alkynyl, Cl-c6 perfluoroalkyl, F, Cl, R100-, RlOC(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or R11OC(O)NR10-, and 10c) Cl-C6 aL~yl substituted by Cl-C6 perfluoroaL~yl, R100-, RlOC(O)NR10-, (RlO)2N-C(NR10)-, RlOC(O)-, R1OOC(O)-, -N(R10)2, or Rl 1OC(O)NR10-;

R9 is selected from:
15a) hydrogen, b) C2-C6 aL~enyl, C2-C6 aL~ynyl, C l-C6 perfluoroaL~yl, F, Cl, RlOO-, Rl 1S(O)m-, R1OC(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, RlOC(O)-, R1OOC(O)-, -N(R10)2, or R1 lOC(O)NR10-, and 20c) Cl-C6 aL~yl unsubstituted or substituted by Cl-C6 perfluoroaL~yl, F, Cl, R100-, Rl lS(O)m-, RlOC(O)NR10-, CN, (R10)2N-C(NR10)-, RlOc(o)-~ RlOoc(o)-~ -N(R10)2, or Rl lOC(O)NR10;
25 R10 is independently selected from hydrogen, Cl-C6 aLkyl, benzyl and aryl;

R l 1 is independently selected from C l -C6 aLkyl and aryl;

30 R 1 2 is a) substituted or unsubstitutéd C I -C8 aL~cyl or substituted or unsubstituted C5-Cg cycloalkyl. wherein the substituent on the aLkyl or cycloalkvl is selected from:
1 ) aryl, -W O96/34010 PCTrUS96/0397 2) heterocycle, 3) -N(R1 1)2, 4) -OR10, or b) ~,loJ~ Rl4 R13 is independently selected from hydrogen and Cl-C6 allyl;

R14 is independently selected from Cl-C6 alkyl;
Q is selected from:

~ ~\

N~> and -~- N 2~>

Al and A2 are independently selected from: a bond, -CH=CH-, -~C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;

V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) Cl-C20 aL~cyl 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 hydro~en if Al is S(O)m and V is not hydro~en if A1 is a bond, n is 0 and A2 is S(O)m;

CA 022l6532 l997-09-26 W O96/34010 PCTrUS96/0397 W is a heterocycle selected from pyrrolidinyl, imi~ 7.olyl, pyridinyl, thiaaolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;
X, Y and Z are independently H2 or 0;

m is 0, 1 or 2;
nis 0, 1,2,30r4;
pis 0,1,2,30r4;
r is O to 5, provided that r is O when V is hydrogen;
tis 3,40rS;and uis Oor l;

15 or the ph~ ceutically acceptable salts thereof.

In a third more preferred embotliment of this invention, the inhibitors of farnesyl transferase are illustrated by the formula m HOCH2(CH2)q V ~ A1(CR1a2)nA2(CR1~z)n (W)~ (CR1bZ)p~N~OH

Il 4a R
wherein:
Rla is independently selected from: hydro~en or Cl-C6 aL~cyl;
Rlb is independently selected from:
a) hydro~en, b) aryl. heterocycle. cycloalkyl. R l Oo, -N(R l ~)~ or alkenyl.

CA 022l6~32 l997-09-26 W O96/34010 PCTrUS96/03975 c) Cl-C6 aL~cyl unsubstituted or substituted by aryl, heterocycle, cycloaL~yl, alkenyl, R100-, or-N(R10)2;

R2 and R3 are independendy selected from:
a) a side chain of a naturally occurring ~mino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) me~ionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-Clo aL~yl, C2-Clo alkenyl, C3-Clo cycloaL~yl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R100-, Rl lS(O)m-, RlOC(O)NR10-, CN, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, Rl lOC(O)NR10- and Cl-C20 alkyl, and d) C l-C6 aLkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloaLkyl; or 20 R2 and R3 are combined to forrn - (CH2)S -; or R2 or R3 are combined with R6 to form a ring such that R6 ~
~N~, is ~ (CH2)t;

R2 R3 R7a ~ R7b R4a and R7a are independently selected from:
a) hydrogen, b) C l-C6 alkyl unsubstituted or substituted by alkenyl, R l Oo, R 1 1 S(O)m-~ R 1 OC(O)NR 10, CN. N3, (R 1 0)2N-C(NR 10), RlOC(O)-, RlOoc(o)-~ -N(R10)~. or Rl lOC(O)NR10-, CA 02216~32 1997-09-26 W O 96/34010 PCTrUS9610397 c) aryl, heterocycle, cycloaL~yl, alkenyl, R100-, Rl lS(O)m-, RlOC(O)NR10-, CN, N02, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or Rl lOC(O)NR10-, and S d) Cl-c6 aL~yl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-Clo cycloaL~yl;

R4b and R7b are hydrogen;
R6 is independently selected from hydrogen or C l-C6 alkyl;

R8 is independently selected from:
a) hydrogen, 15 b) Cl-C6 aL~yl, C2-c6 alkenyl, C2-c6 alkynyl, Cl-c6 perfluoroaIkyl, F, Cl, R10O-, R10C(O)NRl0-~ CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, Rl0oc(o)-~ -N(R10)2, or Rl lOC(O)NR10-, and c) Cl-C6 aL~yl substit~lteA by Cl-C6 perfluoroalkyl, R100-, Rl0c(o)NRlo, (Rlo)2N-c(NRlo)-~ Rl0C(o), Rl0oc(o)-~ -N(R10)2, or Rl lOC(O)NR10-;

R9 is selected from:
a) hydrogen, 25 b) C2-C6 alkenyl, C2-C6 alkynyl, C l-C6 perfluoroalkyl, F, Cl, R10O-, Rl lS(O)m, Rl0c(o)NRlo-~ CN, NO2, (R10)2N-C(NR 10) , R 1 ~C(O)-, R 1 ~OC(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10 , and c) Cl-C6 alkyl unsubstituted or substituted by Cl-C6 perfluoroalkyl, F, Cl, R10O-, Rl lS(O)m-. R10C(O)NR10-, CN, (Rl0)2N-c(NRlo)-~ Rl0C(O)-, RlOOC(O)-, -N(Rl0)2 or R l l OC(O)NR 10 ;

R10 is independently selected from hydro~en. Cl-C6 alkyl, benzyl and CA 02216~32 1997-09-26 W O96/34010 PCTrUS96/03975 aryl;

Rl 1 is independently selected from Cl -C6 aL~yl and aryl;

5 Q is selected from:

s~-N~ N~ and -~-N =>

~0 Al and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;

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

25 W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl. quinolinyl, or isoquinolinyl;
X, Y and Z are independently H2 or O;
m is 0, 1 or'';

W O 96134010 PCTrUS96/03975 nis 0, 1,2,30r4;
pis 0,1,2,30r4;
q is 0, l or 2;
r is O to 5, provided that r is O when V is hydrogen;
t is 3, 4 or 5; and uis Oorl;
or the ph~ eutically acceptable salts ~ereof.

In a fourth more ~lefcl,ed embodiment of this invention, the prodrugs of the preferred compounds of Follllula III are illustrated by the Formula IV:

V A1 (CR182)nA2(CR 1 ~2)n 4~~ (CR1 b2)p~N~

IV R4a R

wherein:

Rla is independently selected from: hydrogen or Cl-C6 aLkyl;

Rlb is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, R100-, -N(R10)2 or alkenyl, c) C 1 -C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloaLkyl, alkenyl, R100-, or-N(R10)2;

- S R2 and R3 are independently selected from:
a) a side chain of a naturally occurrinC amino acid, b) an oxidized form of a side chain of a naturally occurrin~
amino acid which is:

CA 02216~32 1997-09-26 W O 96/34010 PCTrUS96/0397 i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstit~lte~l Cl-Clo alkyl, C2-Clo alkenyl, C3-C1o cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (Rlo)2N-c(NRlo)-~ Rloc(o)-~ R10Oc(o)-~ N3, -N(R10)2, Rl 10C(O)NR10- and Cl-C20 alkyl, and d) Cl-C6 alkyl substituted with an unsul~s~i~uled or substituted group selected from aryl, heterocycle and C3-C1o cycloalkyl; or R2 and R3 are combined to form - (CH2)S -; or 15 R2 or R3 are combined with R6 to form a ring such that R6 ~_~
~;N~; is ~ H2)t;
R2 -R3 R7a ~ R7b R4a and R7a are independently selected from:
a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by alkenyl, R100-, R11S(O)m-, R10C(O)NRl0-~ CN, N3, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R1 lOC(O)NR10-, c) aryl, heterocycle, cycloalkyl, aLkenyl, R100-, Rl lS(O)m-, R10C(O)NRl0-~ CN. NO2, (R10)2N-C(NR10)-~ Rl0c(o), R10OC(O)-~ N3, -N(R10)2, or R 1 1 OC(O)NR 10, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted ~roup selected from arvl. heterocyclic and C3-Clo cycloalkyl;

CA 02216~32 1997-09-26 W O~6134010 PCTrUS96/03975 R4b and R7b are hydrogen;

R6 iS independently selected from hydrogen or Cl-C6 alkyl;

5 R8 is independently selected from:
a) hydrogen, b) Cl-c6 alkyl, C2-c6 aL~enyl, C2-c6 aL~ynyl, Cl-C6 perfluoroaLkyl, F, Cl, R100-, RlOC(O)NR10-, CN, N02, (R10)2N-C(NR10)-, RlOc(o)-7 R10oc(o)-7 -N(R10)2, or R11OC(O)NR10-, and c) Cl-C6 aL~yl substituted by Cl-C6 perfluoroaL~yl, R100-, RlOC(O)NR10-, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10-;

15 R9 is selected from:
a) hydrogen, b) C2-C6 aL~enyl, C2-C6 aL~ynyl, C l-C6 perfluoroaL~cyl, F, Cl, RlOO-, R11S(O)m-, RlOc(o)NRlo-~ CN, NO2, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or RllOC(O)NR10-, and c) Cl-C6 aL~cyl unsubstituted or substituted by Cl-C6 perfluoroaL~yl, F, Cl, R100-, Rl lS(O)m-, RlOC(O)NR10-, CN, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10;
R10 is independently selected from hydrogen, Cl-C6 aL~yl, benzyl and aryl;
Rl 1 is independently selected from Cl-C6 aL~yl and aryl;
Q is selected from:

CA 02216~32 1997-09-26 W O96/34010 PCTrUS96/0397S

~ N~ -~ N~ and -~- N~>

A1 and A2 are independently selected from: a bond, -CH=CH-, -C_C-, S -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;

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

W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, 20 thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;

X, Y and Z are independently H2 or 0;

mis 0, 1 or2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or4;
q is 0, 1 or 2;
r is O to 5, provided that r is O when ~' is hydrogen;
tis 3,40r5:and uis Oor l;

CA 02216~32 1997-09-26 W O96/34010 PCTrUS96/03975 or the ph~ ceutically acceptable salts thereof.
The ~refell~d compounds of this invention are as follows:
s N-[1-(lH-Tmicl~7.ol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-prolyl-methionine methyl ester N-[1-(lH-Tmi~1~7.ol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-10 prolyl-methionine N-[l-tl-(4-Cyanobenzyl)-lH-imidazol-S-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine isopropyl ester 15 N-[1-[1-(4-Cyanobenzyl)-lH-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine sulfone isopropyl ester N-[1-[1-(4-Cyanobenzyl)-lH-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine sulfoxide N-[1-[1-(4-Cyanobenzyl)-lH-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine sulfoxide isopropyl ester N-[ 1- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-ylacetyl]pyrrolidin-2(S)-25 ylmethyl]-3(S)-ethyl-prolyl-methionine sulfone N- [ 1-[1 -(4-Cyanobenzyl)- 1 H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester N-[1-[1-(4-Cyanobenzyl)-lH-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[ l -(1 H-Imidazol-4-ylacetyl)-pyrrolidin-2(S )-ylmethyl]-3 (S )-ethyl-prolyl-methionine methyl ester N-[ l-(lH-Imidazol-4-ylacetyl)-pyrrolidin-r'(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine CA 022l6~32 l997-09-26 W O96/34010 PCTrUS96/0397 N-[1-Glycyl-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester 5 N-[1-Glycyl-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[ 1 -(3-[lH-Tmi~1~7.ol-4-yl]propionyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester 10 N-[1-(3-[lH-Imidazol-4-yl]propionyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[1-[3-(1-(4-Cyanobenzyl)- lH-imidazol-5-yl)propionyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester N-[1-[3-(1-(4-Cyanobenzyl)-lH-imidazol-5-yl)propionyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[2(S)-(lH-Tmi-1~7.ol-4-ylacetyl-amino)-3(S)-methylpentyl]-prolyl-20 methionine methyl ester N-[2(S)-(lH-Imidazol-4-ylacetyl-amino)-3(S)-methylpentyl]-prolyl-methionine 25 N-[1-(lH-Imidazol-4-ylacetyl)-pyrrolidin-2(S-)ylmethyl]-prolyl-methionine methyl ester N-~ 1-(1 H-Imidazol-4-ylacetyl)-pyrrolidin-2(S-)ylmethyl] -prolyl-methionine N-[ 1-[1 -(4-Cyanobenzyl)- lH-imidazol-5-ylacetyl~pyrrolidin-2(S)-ylmethyl]-prolyl-methionine methyl ester N-[ 1-[1 -(4-Cyanobenzyl)- 1 H-imidazol-5-ylacetyl]pyrrolidin-2(S)-35 ylmethyl]-prolyl-methionine N- [ l -( l H-Imidazol-4-ylacetyl )-3 ( S )-ethylpyrrol idin-2(S )-ylmethyl ]- 3 ( S ) ethyl-prolyl-methionine methvl ester CA 02216~32 1997-09-26 W O 96/34010 PCTfUS9610397 ., .
N-[1-(lH-Imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine 5 N-[1-[1-(4-Cyanobenzyl)-lH-imidazol-5-ylacetyl]-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester N-[1-[1-(4-Cyanobenzyl)-lH-imicl~7.ol-5-ylacetyl]-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[1-[1-(4-Cyanobenzyl)-lH-imidazol-5-ylacetyl]-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine isopropyl ester N-[1-(3-[lH-Imidazol-4-yl]propionyl)-3(S)-ethylpyrrolidin-2(S)-15 ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester N-[1-(3-[lH-Imidazol-4-yl]propionyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine 20 N-[1-Glycyl-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester N-[ 1 -Glycyl-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[1-[1-(4-Nitrobenzyl)-lH-imidazol-4-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[ 1-[1 -(4-Nitrobenzyl)- 1 H-imidazol-5-ylacetyl] pyrrolidin-2(S)-30 ylmethyl]-3(S)-ethyl-prolyl-methionine N-[ 1-(1-(1 -Farnesyl)- 1 H-imidazol-5-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl methionine CA 02216~32 1997-09-26 W O96134010 PCTrUS96/0397 N-[l-(l-(1-Geranyl)-lH-imida_ol-5-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[1-[1-(4-Methoxyben_yl)-lH-imida_ol-5-ylacetyl]pyrrolidin-2(S)-5 ylmethyl]-3(S)-ethyl-prolyl-methionine N-[1-[1-(2-Naphthylmethyl)-lH-imi~1~7.ol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine and 10 N-[l-(lH-Tmi~l~7.ol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-(~-acetylamino)~l~nine or the ph~rm~eeutically acceptable salts thereof.

Specific examples of compounds of the invention are:
N-[l-(lH-Imida_ol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine O

HN~ H ' N ~OH

N-[ 1-(1 H-Imidazol-4-ylacetyl)-pyrrolidin-2(S )-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester W O96/34010 PCTrUS96/0397 H~ H OCH3 N-[1-(3-[lH-~mi~l~7.ol-4-yl]propionyl)-pyrrolidin-2(S)-ylme~yl]-3(S)-ethyl-prolyl-methionine O
H ~ ~ ~OH

N-t 1-(3-~ lH-Imidazol-4-yl]propionyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester O
~ H ~ N ~OCH3 N~ N~N~

.
N- [ 1-(3-[ l H-Imidazol-4-yl]propionyl )-3 (S )-ethylpyrrolidin-2(S )-ylmethyl]-3(S)-ethyl-prolyl-methionine W O 96/34010 PC~rrUS96/03975 <N ~ ~ ~

N-tl-(3-[lH-~mi-1~7.ol-4-yl]propionyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester O
~ H \~N~fOCH3 <N~ ~\

N-~2(S)-(lH-Imida_ol-4-ylacetyl-amino)-3(S)-methylpentyl]-prolyl-methionine methyl ester ~SCH3 O
H ~ N--~OCH3 HN/~N O
\=N O

N-[2(S)-( 1 H-Imida_ol-4-ylacetyl-amino)-3(S )-methylpentyl]-prolyl-methionine W O96134010 PCTrUS96/0397 H ~ N OH
HN/~ I - ~
\= N O ~ -N- [ 1- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine NC

r~ 1~
~, N-[1-[1-(4-Cyanobenzyl)-lH-imidazol-S-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester NC

N ~ H ~ NH ~OCH3 \~N~N

W O96/34010 PCTrUS96/0397 N-[1-[1-(4-Cyanobenzyl)-lH-imi-l~7.ol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine isopropyl ester NC
Q~ ~ CH3 r~ H ~ N ~ ~

5 or the ph~n~eutically acceptable salts thereof.

In the present invention, the amino acids which are disclosed are identified both by conventional 3 letter and single letter abbreviations as indicated below:

Alanine Ala A
Arginine Arg R
Asparagine Asn N
Aspartic acid Asp D
Asparagine or Aspartic acid Asx B
Cysteine Cys C
Glutamine Gln Q
Glutamic acid Glu E
Ghlt~mine or Glutamic acid Glx Z
Glycine Gly G
Histidine His H
Isoleucine Ile Leucine Leu L

CA 02216~32 1997-09-26 W O 96/34010 PCTrUS96/0397 Lysine Lys K
Methionine Met M
Phenyl~l~nint- Phe F
Proline Pro P
Serine Ser S
Threonine Thr T
Tryptophan Trp W
Tyrosine Tyr Y
Valine Val V

The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical 15 isomers, being included in the present invention.
As used herein, "aL~yl" is int~qnc1e~1 to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
As used herein, "cycloaLkyl" is intended to include non-20 aromatic cyclic hydrocarbon groups having the specified number of carbon atoms. Examples of cycloaLkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
"Alkenyl" groups include those groups having the specified number of carbon atoms and having one or several double bonds.
25 Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, l-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like.
As used herein, "aryl" is intended to include any stable 30 monocyclic, bicyclic or tricyclic carbon ring(s) of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of aryl groups include phenyl, naphthyl, anthracenyl, biphen~ l~ tetrahydronaphthyl, indanyl, phenanthrenyl and the like.

CA 02216~32 1997-09-26 W O 96/34010 PCTrUS9610397 The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic or stable 11-15 membered tricyclic heterocycle ring which is either saturated or lm~ ated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limite~l to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydro-benzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imi-l~701inyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide, pyridonyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolinyl N-oxide, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.
As used herein, the terms "substituted aryl", "substituted heterocycle" and "substituted cycloalkyl" are intended to include the cyclic group which is substituted with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Cl-C6 alkyl)2, N02, 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 ,(C 1 -C6 alkyl)OC(O)NH- and C 1 -C20 alkyl.

W O 96134010 PCTrUS96/0397 The following structure:

,N~
( ~H2)t represents a cyclic amine moiety having 5 or 6 members in the ring, such 5 a cyclic amine which may be optionally fused to a phenyl or cyclohexyl ring. Examples of such a cyclic amine moiety include, but are not limite-l to, the following specific structures:

It is also understood that substitution on the cyclic amine moiety by R8a and R8b may be on different carbon atoms or on the same carbon atom.
When R3 and R4 are combined to form - (CH2)S -, cyclic moieties are formed. Examples of such cyclic moieties include, but are 15 not limited to:

When Rsa and R5b are combined to form - (CH2)S -, cyclic moieties as described hereinabove for R3 and R4 are formed. In addition, 20 such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include. but are not limited to:

W O96134010 PCTrUS96/03975 ~0~ SJ ' '~ ~0 ~S NJ
~ CORl~

As used herein, the phrase "nitrogen co,.t~i..inp C4-Cg mono S or bicyclic ring system wherein the non-nitrogen cont~inin.~ ring may be a C5-C7 saturated ring" which defines moiety "Q" of the instant invention includes but is not limited to the following ring systems:

~- N~ N~

N~>
~, The pharmaceuticallv acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed. e.~.. from non-toxic inor~anic or or~anic CA 02216~32 1997-09-26 W O 96!34010 PCTrUS96/03975 acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, slllf~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, phenyl-acetic, glllt~mic, benzoic, salicylic, slllf~nilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesuLfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
It is inte.ncled that the definition of any substituent or variable (e.g., R10, Z, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, -N(R10)2 represents -NHH, -NHCH3, -NHC2Hs, etc. It is understood that substituents and substitution p~ .rn~ on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in ~e art as well as those methods set forth below.
Preferably, R1a and R1b are independently selected from:
hydrogen, -N(R8)2, R8C(O)NR8- or Cl-C6 alkyl unsub~ti~lte~l or substituted by -N(R8)2, R8O- or R8C(O)NR8-.
Preferably, R2 is the sidechain of glycine (hydrogen).
Preferably, R3 is selected from:
a) a side chain of a naturally occurring amino acid, b) substituted or unsubstituted C1-C20 alkyl, wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, RlOO-, R1 lS(O)m-, R1OC(O)NR10-, CN, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, Rl lOC(O)NR10- and Cl-C20 alkyl, and c) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-- 30 Clo cycloalkyl; or R3 is combined~with R6 to form pyrrolidinyl ring.
Preferably, R4a, R4b~ R7a and R7b are independently selected from: hydro~en, Cl-C6 alkyl. aryl and benzyl.
Preferably, R5~ and RSb are independentlv selected from:

CA 02216~32 1997-09-26 W O96/34010 PCTrUS96/03975 a side chain of a naturally occurring amino acid, methionine sulfoxide, methionine sulfone and unsubstituted or substituted C l-C6 alkyl .
Preferably, R6 is: hydrogen or is combined with R3 to forIn pyrrolidinyl ring.
Preferably, R8 is selected from: hydrogen, per~luoroaL~yl, F, Cl, Br, R100-, RllS(O)m-, CN, NO2, Rlo2N-c(NRlo)-~ RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or Rl lOC(O)NR10- and Cl-C6 aL~yl.
Preferably, R9 is hyd~ogen.
Preferably, R10 is selected from H, Cl-C6 alkyl and benzyl.
Preferably, R12 is selected from Cl-C6 alkyl and benzyl.
Preferably, Al and A2 are independently selected from: a bond, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, -S(O)2N(R10)- and-N(R10)S(0)2-.
Preferably, Q is a pyrrolidinyl ring.
Preferably, V is selected from hydrogen, heterocycle and aryl.
Preferably, n, p and r are independently 0, 1, or 2.
Preferably t is 3.
The pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety conventional chemical methods. Generally, the salts are prepared by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
The compounds of the invention can be synthesized from their constituent amino acids by conventional peptide synthesis techniques, and the additional methods described below. Standard methods of peptide synthesis are disclosed, for example, in the following works: Schroeder et al., "The Peplides", Vol. I~ Academic Press 1965, or Bo~l~n~7ky et al~, "Peptide Svnthesis", Interscience Publishers, 1966, or McOmie (ed.) "Protective Groups in Organic Chemistr~ ", Plenum Press, 1973, or Barany et al., "The Peptides: Anal~sis. S~nthesis, Biolog~" 2, Chapter 1, Academic Press, 1980 or Stewart et al., "Solid Phase Peptide W O 96/34010 PCTrUS96/03975 Synthesis", Second Edition, Pierce Chernical Company, 1984. The te~cllin~.~ of these works are hereby incorporated by reference.
J Abbreviations used in the description of the chemistry and in the Examples that follow are:

Ac2O Acetic anhydride;
Boc t-Butoxycarbonyl;
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene;
DMAP 4-Dimethylaminopyridine;
DME 1,2-Dimethoxyethane;
DMF Dimethylform~mi~le;
EDC 1-(3-dimethylaminopropyl)-3-ethyl-carbo~liimicl.-hydrochloride;
HOBT l-Hydroxybenzotriazole hydrate;
Et3N Triethyl~rninP;
EtOAc Ethyl ~et~t~;
FAB Fast atom bombar~lm~.nt;
HOOBT 3-Hydroxy- 1 ,2,2-benzotriazin-4(3H)-one;
HPLC High-performance liquid chromatography;
MCPBA m-Chloroperoxybenzoic acid;
MsCl Methanesulfonyl chloride;
NaHMDS Sodium bis(trimethylsilyl)amide;
Py Pyridine;
TFA Trifluoroacetic acid;
THF Tetrahydrofuran.

Compounds of this invention are prepared by employing the reactions shown in the following Reaction Schemes A-J, in addition to other standard manipulations such as ester hydrolysis, cleavage of 30 protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Some key bond-forming and peptide modifying reactions are:

CA 02216~32 1997-09-26 W O96/34010 PCTrUS96/0397 Reaction A Amide bond formation and protecting group cleavage using ~t~n~l~rd solution or solid phase methodologies.

Reaction B Preparation of a reduced peptide subunit by reductive S aL~ylation of an amine by an aldehyde using sodium cyanoborohydride or other reducing agents.

Reaction C Deprotection of the rerlllce-l peptide subunit Reaction D Peptide bond formation and protecting group cleavage using standard solution or solid phase methodologies.

Reaction E ~ al~tion of a re~l~lce~l subunit by borane reduction of the amide moiety.
Reaction Schemes A-E illustrate bond-forming and peptide modifying reactions incorporating acyclic peptide units. It is well understood that such reactions are equally useful when the - NHC(RA) -moiety of the reagents and compounds illustrated is replaced with the following moiety:

(~H2)t ~R7b R7a These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments 2~ which are subsequently joined by the reactions described in the Reaction Schemes.

W O96/34010 PCTrUS96/03975 REACTION SCHEME A

Reaction A. Coupling of residues to form an amide bond >~O~N I OH + ~R4b EDC, HOBT H ~ CO2R
or HOOBT >~O~NJI~ <
Et3N, DMF ( l R4a />~/~ R4b TFA H N~J~ CO2R

~ R4b R4a W O96134010 PCTrUS96/0397 REACTION SCHEME B

Reaction B. Preparation of reduced peptide subunits by reductive aLkylation >~oJ~N~H +

R4a NaCNBH3 >~0~ N ~ <02R

~R4b R4a REACTION SCHEME C

Reaction C. Deprotection of reduced peptide subunits >~ ~ ~~,~~~ TFA or O RA ~ Q
~ R4b HCI
R4a ~ CO2R

RA ~Q ~
~R4b R4a/

CA 022l6532 l997-09-26 W O96/34010 PCTrUS96/0397 REACTION SCHEME D

Reaction D. Coupling of residues to form an amide bond EDC, HOBT

>~oJI, < + H2N
fl ~) o Et3N, DMF

R4a~ R4b O ~ O

R4a R4b H _~--H o R4a ~ R4b W O96/34010 PCTrUS96/0397 REACTION SCHEME E

Reaction E. Plc;pal~tion of reduced dipeptides from peptides O RA ~Q ~
>~ R4b R a >~ O ~ Q
4a ~ R4b R
s where RA is R2, R3, RSa or Rsb as previously defined; R4a and R4b are as previously defined; and R is an a~lo~fiate protecting group for the carboxylic acid.

Reaction Schemes F - M illustrate reactions wherein the non-sulfhydryl-cont~ining moiety at the N-terminus of the compounds of the instant invention is attached to an acyclic peptide unit which may be further elaborated to provide the instant compounds. It is well understood that such reactions are equally useful when the - NHC(RA) - moiety of 1~ the reagents and compounds illustrated is replaced with the following moiety:

(Cj H2)t >~ R7b R7a CA 02216~32 1997-09-26 W O96/34010 PCTnUS96/0397 _ 59 _ These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the reactions described in Reaction Schemes A - E.
S The intermediates whose synthesis are illustrated in Reaction Schemes A and C can be reductively aL~ylated with a variety of aldehydes, such as I, as shown in Reaction Scheme F. The aldehydes can be prepared by t~n~l~rd procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses. 1988, 67, 69-75, from the a~rol~liate amino acid (Reaction Scheme F). The reductive aL~ylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloroethane, meth~nol or dimethylform~mide. The product II can be deprotected to give the final compounds m with trifluoroacetic acid in methylene chloride. The final product m is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product ~ minlo m can further be selectively protected to obtain IV, which can subsequently be reductively aL~ylated with a second aldehyde to obtain V. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole VII can be accomplished by literature procedures.
Alternatively, the protected dipeptidyl analog intermediate can be reductively aIkylated with other aldehydes such as 1-trityl-4-carboxaldehyde or l-trityl-4-imidazolylacetaldehyde, to give products 2~ such as vm (Reaction Scheme G). The trityl protecting group can be removed from VIII to give IX, or alternatively, VIII can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole X. Alternatively, the dipeptidyl analog interrnediate can be acylated or sulfonylated by standard techniques.
The imidazole acetic acid XI can be converted to the acetate XIII by standard procedures, and XIII can be first reacted with an alkyl halide, then treated with refluxine methanol to provide the reoiospecifically alkylated imidazole acetic acid ester XI~7. Hydrolysis and reaction with the protected dipeptidyl analocr intermediate in the CA 022l6~32 l997-09-26 W 096/34010 PCTrUS96tO397 presence of condensing reagents such as 1-(3-dimethyl~minopropyl)-3-ethylcarbo-liimi~le (EDC) leads to acylated products such as XV.
If the protected dipeptidyl analog intermediate is reductively aL~ylated with an aldehyde which also has a protected hydroxyl group, S such as XVI in Reaction Scheme I, the protçctin~: groups can be subsequently removed to llnm~k the hydroxyl group (Reaction Schemes I, J). The alcohol can be oxicli7~1 under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as 10 XX. In addition, the fully deprotected amino alcohol XXI can be reductively aL~ylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXII (Reaction Scheme K), or tertiary ~mines.
The Boc protected amino alcohol XVIII can also be lltili7e-1 15 to synthesi_e 2-a_iridinylmethylpipera_ines such as xxlll (Reaction Scheme L). Treating XVIII with l,1'-sulfonyl-liimi-1~7.ole and sodium hydride in a solvent such as dimethylform~mide led to the formation of z~7~ inf~ X X l l l . The aziridine reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product 20 XXIV.
In addition, the protected dipeptidyl analog intermediate can be reacted with aldehydes derived from amino acids such as O-aL~cylated tyrosines, according to standard procedures, to obtain compounds such as XXX, as shown in Reaction Scheme M. When R' is an aryl group, XXX
25 can first be hydrogenated to llnm~.~k the phenol, and the amine group deprotected with acid to produce XXXI. Alternatively, the amine protecting group in XXX can be removed, and O-aL~ylated phenolic amines such as XXXll produced.
Similar procedures as are illustrated in Reaction Schemes F-30 M may be employed using other peptidyl analog intermediates such asthose whose synthesis is illustrated in Reaction Schemes B - E.

W O96/34010 PCTrUS9610397 Reaction Schemes N-R illustrate syntheses of suitably substihltç~l aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic strategies for preparing aLkanols that incorporate other heterocyclic S moieties for variable W are also well known in the art.

CA 022l6532 l997-09-26 REACTION SCHEME F

Boc NH ~ I
2 J~\ CO2R Boc NH CHO

R (~J Q ~ NaBH(OAc)3 ~ R4b Et3N, CICH2CH2CI
R4a NHBoc Boc NH/~2R CF3CO2H

R4a R4b NH/~HN~JI~ CO2R Boc20 RA ~ Q ~ CH2CI2 R4a~ R4b BocNH/~N~ ~ CHO
,~ NaBH(OAc)3 Et3N, CICH2CH2CI
IV ~ R4b R4a W O96/34010 PCTrUS96/0397 REACTION SCHEME F (conhnued) /=\
~3, NH CF3CO2H, CH2C12;
BocNH/~ _<02R NaHCO3 RA ~ Q ~
/= R4a>~ R4b NH

NH/~N~JI~ < ~NC
RA ~ R4b AgCN

Vl R4a ~N~ <
RA ~Q ~
~1 R4a R4b Vll W

W O96/34010 PCTnUS96/0397 REACTION SCHEME G

H2N ~ CO2R NaBH(OAc)3 RA 1/~ Q Et3N, CICH2CH2CI

R4a ~ R4b ~(CH2)nCHO

Tr H2)n+1 \,~
~C RA ~_ R4b D4a Tr ' ' 1 ) Ar CH2X, CH3CN
Vlll 2) CF3C02H, CH2C12 H CH Cl (C2H5)3siH
CF3C ~2 ~ 2 2 (c2H5)3siH

(CH2)n+1 N RA ~--R4b A (CH2)~ ~ 4b W O~6/34010 PCTrUS96/Q397a REACTION SCHEME H

~N~ CH30H ~N~

Xl Xll N CH2C02CH31 ) ArCH2X CH3CN
(c6H5)3cBr ~ reflux (C2DH )3FN NTr 2) CH30H, reflux Xlll Ar~\N~cH2c02cH3 2.5N HClaq, 55~C

XIV

Ar~\N j~CH2C~2H

N

W O96/34010 PCTrUS96/03975 REACTION SCHEME I

,~5 H2N ~JJ~

RA ~ Q
>~ R4b R4a EDC- HCI
HOBt DMF

Ar~~~2R
XV R4a R4b W O96/34010 PCTnUS96/03975 REACTION SCHEME J
NaBH(OAc)3 H2N ~ ~02R BnO 1 ,~ R4b BocNH CHO
R4a XVI

NHBoc ~N~L~ CO2R 20% Pd(OH)2 H2 BnO H - J~~< CH30H
R ~ Q ~ CH3C02H
\/ ~ R4b XVII R4a~

NHBoc HO H~ ~ DMSO CH2C12 -A ~ (C2H5)3N
XVIII R4a W O96/34010 PCTrUS96103975 REACTION SCHEME J (CONTINUED) H NHBoc y O~HN~ < (c2H5)2o R ~ Q ~ 2. TFA, CH2C12 ~ R4b XIX R4a R' NH2 HOX--HN~JI~ <
RA 1/~ Q
XX >~ R4b R4a W O96/34010 PCTrUS96103975 REACTION SCHEME K

NHBoc y CF3C02H

HO~--H ~02R CH2CI2 RA ~Q ~
XVIII ~ R4b R4a NH2 y R'CHO
HO/~H CO2R NaBH(OAc)3 RA (PI Q ) CICH2CH2CI
~ ~' ~4b XXI R4a~

R'CH2 NH y HO/~H .J~ <02R
RA ~Q ~
XXII >~ R4b R4a W O96/34010 PCTrUS96/03975 REACTION SCHEME L

NHBoc y H H
HO/~--N~ll <02R ~\N N

XVIII ~ R4b NaH, DMF 0~C

N y H ~ ~OzR (C2Hs)3N

NH2 y R'S/~H \JI ~02R
RA ~Q ~
R4a R4b W O96134010 PCTrUS96/0397 REACTION SCHEME M

HO~ 1) Boc2O, K2CO3 HO~

~ THF-H20 .~/
J~ 2) CH2N2, EtOAc ~1~
H2NC02H BocNH CO2CH3 XXV XXVI

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

R'CH20 R'CH20 ~ pyndine so3"~

BocNH CH2OH 20~C BocNH CHO
XXVIII XXIX

W O9~!34010 PCTrUS96/0397 REACTION SCHEME M (continued) R'CH20~ ~ ~ C02R

+ RA ~ Q ~
BocNH CHO >~ R4b R a XXIX NaBH(OAc)3 NHBoc R'CH20~ ~2R

R4a R4b HC~ EtOAC
1) 20% Pd(OH)2 CH30H, CH3CO2H /

2) HCI, EtOAc / ~ y CO2R

XXXI I ~"

XXXI ~ 4b R4a W O 96/34010 PCTrUS96/03975 REACTION SCHEME N

CH3 1) HN~2~Br2 ,~CO2CH3 1' ~ 2) KMnO4 . 1' JJ
H2N N 3) MeOH,H+ Br N

~MgCI R~l C02CH3 Zncl2~Nicl2(ph3p)2 NaBH4 (excess) ~CH20H

S03 Py, Et3N ~CHO

PCTrUS96/03975 REACTION SCHEME P

R6 [~i~
[~CO2CH3 ~ MgCI ~CO2CH3 N Zn, CuCN R6 NaBH4 [~j~ SO3Py, Et3N [~
(excess) [~,CH20H DMSO ~CHO

Br CO2CH3 ~\ MgCI

~ ZnC12, Nicl2(ph3p)2 ~CO2CH3 NaBH4 ~ SO3 Py, Et3N CHO
(excess) N DMSO N

W O 96/34010 PCTrUS96/0397 REACTION SCHEME Q

co2CH3 Br~1. LDA, CO2 Br~

N 2. MeOH, H+ N

ZnCI2, NiCI2(Ph3P)2 N

~/'1 NaBH4 (excess) \~2OH SO3 Py, Et3N
~ ,~ DMSo N

CHO

W O96/34010 PCTrUS96/0397 REACTION SCHEME R

co2CH3 ~3~ 1. LDA, C02 ~Br 2. (CH3)3SiCHN2 R6 ~\ Br R6 3~

~1~ co2CH3 Zn, NiC12(Ph3P)2 N~

R6 ~
excess NaBH4 ~ S03Py, Et3N
N~CH20H DMSO

R6 ~

N~,CHO

CA 02216~32 1997-09-26 W O 96/34010 PCTrUS96/0397 The instant compounds are useful as pharmaceutical agents for m~mm~l~, especially for hllm~n~. These compounds may be ~lmini~tered to p~ti~nt~ for use in the treatment of cancer. Fx~mples of the type of cancer which may be treated with the compounds of this S invention include, but are not limitetl to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid lellk~omi~ and neurological tumors. Such tumors may arise by mutations in the ras genes themselves, mllt~tions in the ~lott;ills that can regulate Ras formation (i.e., neurofibromin (NF-l), neu, scr, abl, lck, fyn) or by other mech~nicmc.
The compounds of the instant invention inhibit farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
The instant compounds may also inhibit tumor angiogenesis, thereby affecting the ~,lOWlll of tumors (J. Rak et al. Cancer Research, 55:4575-4580 (1995)). Such anti-angiogenesis properties of the in~t~nt compounds may also be useful in the tre~tm~nt of certain forms of blindness related to retinal vasclll~ri7~tion.
The compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the ~-lmini~tration of an effective amount of the compounds of the invention to a m~mm~l in need of such treatment. For example, a component of NF-l is a benign proliferative disorder.
The instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256:1331-1333 (1992).
The compounds of the instant invention are also useful in the prevention of restenosis after percutaneous translllmin~l coronary 3Q angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1:541-545(1995).
The instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al.

CA 02216~32 1997-09-26 W O 96134010 PCTrUS96/03975 American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)).
The compounds of this invention may be ~1mini.ctered to m~mm~l~, preferably hllm~n~, either alone or, preferably, in combination S with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a ph~rm~relltical composition, according to standard ph~rm~eutical practice. The compounds can be ~1mini.~tered orally or parenterally, including the intravenous, intramuscular, i~ ilolleal, subcutaneous, rectal and topical routes of 10 ~lmini.~tration.
For oral use of a chemotherapeutic compound according to this invention, the selected compound may be ~rlmini~tered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are 15 commonly used include lactose and corn starch, and lubricating agents, such as m~nesium stearate, are commonly added. For oral ~tlmini~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. If 20 desired, certain sweetening and/or flavoring agents may be ~ 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 concentration of solutes should be controlled in order to render 25 the preparation isotonic.
The present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the ~rlminictration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or 30 diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharrnacologically acceptable carriers, e.g., saline, at a pH level, e.~., 7.4. The solutions may be introduced into a patient's intramuscular blood-stream by local bolus injection.

CA 02216~32 1997-09-26 W O 96/34010 PCTrUS96/0397 Y When a compound according to this invention is ~lmini~tered into a hllm~n subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's S~ tOlllS.
In one exemplary application, a suitable amount of compound is ~rlmini~tered to a m~mm~l undergoing tre~tm~nt for cancer.
~clmini.ctration occurs in an amount between about 0.1 mgfkg of body weight to about 20 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 10 mg/kg of body weight per day.
The compounds of the instant invention are also useful as a component in an assay to rapidly ~leterminp the presence and quantity of fa~nesyl-protein transferase (E~PTase) in a composition.
Thus the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of l;PTase (for example a tetrapeptide having a cysteine at the ~mine tel...;..l.s) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to allow the FPTase to farnesylate the substrate, the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective inhibitors of ~Tase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in ~ 30 identifying tissue samples which contain farnesyl-protein transferase and quantitating the enzyme. Thus, potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract containing an unknown amount of farnesyl-CA 02216~32 1997-09-26 W O 96/34010 PCTrUS96/0397 protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminll~) and farnesyl pyrophosphate are incubated for an ayylopliate period of time in the presence of varying concentrations of a compound of the instant 5 invention. The concentration of a sufficiently potent inhibitor (i.e., one that has a Ki substantially smaller than the concentration of enzyrne in the assay vessel) required to inhibit the enzymatic activity of the sample by 50% is approximately equal to half of the concentration of the enzyme in that particular sample.
EXAMPLES

Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species 15 and conditions are intended to be further illustrative of the invention and not limit~tive of the reasonable scope thereof.
The standard workup referred to in the examples refers to solvent extraction and washing the organic solution with 10% citric acid, lO~o sodium bicarbonate and brine as appropriate. Solutions were dried 20 over sodium sulfate and evaporated in vacuo on a rotary evaporator.

CA 02216~32 1997-09-26 Preparationof N-[l-(lH-Tmicl~7ol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-prolyl-methionine methyl ester and S N-[l-(lH-Tmi~l~7ol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-prolyl-methionine trifluoroacetate Step A: P~ al~lionofDiethyl l-acetyl-5-hydroxy-3-ethylpyrrolidine-2.2-dicarboxylate Sodium (4.02 g, 0.175 mol) was dissolved in a stirred solution of diethyl acetamidomalonate (235.4 g, 1.19 mol) in abs EtOH
(1.4 L) at ambient te~ el~ule under argon. The reaction mixture was cooled to 0~C, and trans-2-pentenal (100 g, 1.08 mol) was added d~ wise m~int~inin~ the reaction tempel~Lule at <5~C. After the addition, the reaction was allowed to warm to room telll~el~Lule, stirred for 4 h, then quenched with acetic acid (28 mL). The solution was concentrated in vacuo, and the residue dissolved in EtOAc (1.5 L), washed with 10% NaHCO3 solution (2 x 300 mL), brine, and dried (MgSO4). The solution was filtered and concentrated to 700 rnL, then heated to reflux and treated with hexane (1 L). On cooling, the title compound precipitated and was collected, mp 106 - 109~C. lH NMR
(CD30D) ~ 5.65 (d, lH, J= 5 Hz), 4.1 - 4.25 (m, 4H), 2.7-2.8 (m, lH), 2.21 (s, 3H), 2.10 (dd, lH, J = 6, 13, Hz),1.86- 1.97 (m, 2H), 1.27 (t, 3H, J= 7 Hz), 1.23 (t, 3H, J= 7 Hz), 1.1- 1.25 (m, lH), 0.97 (t, 3H, J= 7 Hz).

~tep B: Preparation of Diethyl l-acetyl-3-ethylpyrrolidine-2,2-dicarboxvlate To a solution of diethyl l-acetyl-5-hydroxy-3-- 30 ethylpyrrolidine-2,2-dicarboxylate (287 g, 0.95 mol) and triethylsilane (228 mL, 1.43 mol) in CH2Cl2 (3 L) under argon was added trifluoroacetic acid (735 mL, 9.53 mol) dropwise with stirring while maintainin~ the internal temperature at 25 ~C b~ means of an ice bath.
After stirring for 3 h at 23~C, the solution was concentrated in vacuo. ~
the residue diluted with CH2CI~ (1.5 L). then treated ~ith H2O (l L) and CA 02216~32 1997-09-26 W O96134010 PCTrUS96/0397 solid Na2CO3 with vigorous stirring until the solution was basic. The organic layer was separated, dried (Na2SO4), filtered, then concentrated to give the title compound as a yellow oil which was used without further puri~lcation.
s Step C: P~ al~lion of 3-Ethylproline hydrochloride (Cis:Trans Mixture) Diethyl l-Acetyl-3-ethylpyrrolidine-2,2-dicarboxylate (373 g, 0.95 mol) was suspended in 6N HCl (2 L) and HOAc (500 mL) and heated at reflux for 20 h. The reaction mixture was cooled, washed with EtOAc (lL), then concentrated in vacuo to give an oil which crystallized upon l~ilul~tion with ether to give the title compound. lH NMR (D20) o 4.23(d, lH,J=8Hz),3.84(d, lH,J=8Hz),3.15-3.4(m,4H),2.33-2.44 (m, lH), 2.19-2.4 (m, lH), 2.02- 2.15 (m, 2H), 1.53- 1.72 (m, 3H), 1.23-1.43 (m, 2H), 1.0- 1.15 (m, lH), 0.75 - 0.83 (m, 6H).

Step D: Plc~ tion of N-[(tert-Butyloxy)carbonyl]-cis:trans-3-ethylproline methyl ester 3-Ethylproline hydrochloride (Cis:Trans Mixture) (20 g, 0.11 mol) was dissolved in CH30H (200 mL), and the solution was saturated with HCl gas, then stirred at 23~C for 24 h. Argon was bubbled through the solution to remove excess HCl. The solution was treated with NaHCO3 (>84 g) to a pH of 8, then di-tert-butyl dicarbonate (25.1 g, 0.115 mol) dissolved in CH30H (20 mL) was added slowly. After stirring for 18 h at 23~C, the mixture was filtered, the filtrate concentrated, and the residue triturated with EtOAc, filtered again, and concentrated to give the title compound as an oil.

Step E: Preparation of N-[(tert-Butyloxy)carbonyl]-trans-3-ethylproline and N-[(tert-Butyloxy)carbonyl]-cis-3-ethylproline methyl ester N-[(tert-Butyloxy)carbonyl]-cis.Irans-3-ethylproline methyl ester ('~9.1 g, 0.113 mol) was dissolved in CH~OH (114 mL) with cooling to 0~C, then treated with 1 N NaOH (114 mL). After stirring for '~0 h at CA 02216~32 1997-09-26 W O 96/34010 PCTrUS96/0397 23~C, the solution was conce~ ted to remove the CH30H and then extracted with EtOAc (3 x). The organic layers were combined, dried (MgSO4), filtered, and conc~ ated to give 12.8 g of N-[(tert-Butyloxy)carbonyl]-cis-3-ethylproline methyl ester as an oil. The 5 aqueous layer was acidified with solid citric acid and extracted with EtOAc (2 x), the organic layers combined, dried (MgSO4), filtered, and concentrated to give N-[(tert-Butyloxy)carbonyl]-trans-3-ethylproline as an oil. lH NMR (CD30D) o 3.86 and 3.78 (2 d, lH, J = 6 Hz), 3.33 -3.58 (m, 2H), 2.01 - 2.22 (m, 2H), 1.5 - 1.74 (m, 2H), 1.33 - 1.5 (m, lH), 1.45 and 1.42 (2 s, 9H), 0.98 (t, 3H, J= 8 Hz).

Step F: Preparation of 3(S)-Ethvl-2(S)-proline hydrochloride N-[(tert-Butyloxy)carbonyl]-trans-3-ethylproline (15.5 g, 0.064 mol), S-a-methylbenzyl~mine (9.03 mL, 0.070 mol), HOBT (10.73 15 g, 0.70 mol), and N-methylmorpholine (8 mL, 0.076 mol) were dissolved in CH2C12 (150 mL) with sitrring in an ice-H2O bath, treated with EDC
(13.4 g, 0.070 mol) stirred at 23~C for 48 h. The reaction mixture was partitioned between EtOAc and 10% citric acid solution, the organic layer washed with satd NaHCO3 solution, brine and dried (MgSO4), filtered, 20 and concentrated to give an oil. This oil was dissolved in a minimum amount of ether (10 mL) to crystallize the desired S,S,S diastereomer (4.2 g), mp 118-121~C. A solution of this product in 8N HCl (87 mL) and glacial acetic acid (22 mL) was heated at reflux overnight. The solution was concentrated on a rotary evaporator, and the residue taken up in H20 25 and extracted with ether. The aqueous layer was concentrated to dryness to give a 1: 1 mixture of 3(S)-ethyl-2(S)-proline hydrochloride and a-methylbenzylamine.
3(S)-Ethyl-2(S)-proline containing a-methylbenzylamine (2.0 g, 0.0128 mol) was dissolved in dioxane (10 mL) and H2O (10 mL) 30 with stirring and cooling to 0~C. N,N-diisopropylethylamine (2.2 mL, 0.0128 mol) and di-tert-butyl-dicarbonate (2.79 g, 0.0128 mol) were added and stirring was continued at '3~C for 48 h. The reaction mixture was partitioned between EtOAc (60 mL) and H~O (30 mL), the organic layer washed with 0.5N NaOH (2 x 40 mL). the aqueous layers CA 02216~32 1997-09-26 W O 96/34010 PCTrUS96/03975 combined and washed with EtOAc ( 30 mL) and this layer back-extracted with 0.5 N NaOH (30 mL). The aqueous layers were combined and carefully acidified at 0~C with lN HCl to pH 3. This mixhlre was extracted with EtOAc (3 x 40 mL), the organics combined, dried S (MgSO4), filtered and conc~ ted to give N-[(tert-Butyloxy)carbonyl-3(S)-ethyl-2(S)-proline as a colorless oil. N-t(tert-Butyloxy)carbonyl-3(S)-ethyl-2(S)-proline was dissolved in EtOAc (50 mL) and the solution was saturated with HCl gas with cooling in an ice-H2O bath. The solution was stoppered and stirred at 0~C. for 3 hr. Argon was bubbled through the solution to remove excess HCl, and the solution was concentrated to dryness to give 3(S)-ethyl-2(S)-proline hydrochloride.
Step G: N-r(tert-Butyloxy)carbonyll-3(S)-ethyl-2(S)-prolinol 3(S)-Ethyl-2(S)-proline hydrochloride cont~inin~ a-methylbenzyl~mine (2.0 g, 0.0128 mol) was dissolved in dioxane (10 mL) and H2O (10 mL) with stirring and cooling to 0~C. N,N-diisopropylethyl~min~ (2.2 mL, 0.0128 mol) and di-tert-butyl-dicarbonate (2.79 g, 0.0128 mol) were added and stirring was continued at 23~C for 48 h. The reaction rnixture was partitioned between EtOAc (60 mL) and H20 (30 mL), the organic layer washed with 0.5N NaOH (2 x 40 mL), the aqueous layers combined and washed with EtOAc ( 30 mL) and this layer back-extracted with 0.5 N NaOH (30 mL). The aqueous layers were combined and carefully acidified at 0~C with lN HCl to pH
2. T-his mixture was extracted with EtOAc (3 x 40 mL), the organics combined, dried (MgSO4), filtered and concentrated to give N-[(tert-Butyloxy)carbonyl--3(S)-ethyl-2(S)-proline as a colorless oil which was used without punfication.

N-~(lert-Butyloxy)carbonyl]-3(S)-ethyl-2(S)-proline (1.6 g, 6.58 mmol) was dissolved in dry THF (10 mL) and treated with borane (lM in THF~
12.5 mL, 12.5 mmol) with stirring at 0 ~C for ~ h, then 23~C for l h. The solution was cooled to 0~C, treated with H2O (20 mL). and extracted with EtOAc (2 x 30 mL). The organics were u ashed u ith brine, satd NaHCO3. H2O dried (MgSO4). filtered and concentrated to give a 3~ viscous oil. The oil uas dissolved in CH~CI~. filtered throu~h dr~ SiO~.

CA 02216~32 1997-09-26 W O 96/34010 PCTnUS96/0397 and the filtrate concentrated to give the title compound as an oil. 1H
NMR (CDC13) ~ 4.97 (d, lH, J= 7 Hz), 3.71 (t, lH, J = 8 Hz), 3.51-3.62 (m, 3H), 3.18 - 3.26 (m, lH), 1.9 - 2.0 (m, lH), 1.53-1.7 (m, 2H), 1.47 (s, 9H), 1.26 - 1.43 (m, 2H), 0.95 (t, 3H, J = 7 Hz).
s Step H: N-r(tert-Butvloxv)carbonyll-3(S)-ethyl-2(S)-prolinal N-[(ter~-Butyloxy)carbonyl-3(S)-ethyl-2(S)-prolinol (0.638 g, 2.78 mmol) and Et3N (1.4 mT ., 9.74 mmol) were dissolved in dry CH2Cl2 (10 mL) with stirring and cooling to -10~C and treated dropwise with a solution of S03.pyr (1.33 g, 8.35 mmol) in dry DMSO (5 mL) keeping the reaction mixture temperature at < 0~C. The mixture was stirred at 0~C. for 20 min then at 5~C for 20 min, and at 15~C for 1 h, then poured into ice-cold 0.5 N HCl and the layers separated. The aqueous layer was extracted with CH2C12 (3 x 20 mL), organics combined, washed with H2O, aq satd NaHCO3 solution, brine, and dried (Na2SO4).
Filtration and concentration to dryness gave the title compound which was used without purification.

Step I: N-t(tert-Butyloxy)carbonyl-3(S)-ethylpyrrolidin-2(S)-ylmethyll-proline methyl ester N-[(tert-Butyloxy)carbonyl]-3(S)-ethyl-2(S)-prolinal (0.315 g, 0.0014 mol) and proline methyl ester hydrochloride (0.233 g, 0.0014 mol) were dissolved in MeOH (5 mL) at ambient temperature under argon with cooling in an ice-H2O bath, and treated with sodium cyanoborohydride (0.131 g, 0.002 mol) with stirring. After 18 h the mixture was poured into 5% NaHCO3 solution (20 mL), the CH30H
removved and the aq layer washed with EtOAc (3 x 30 mL), the organics combined, washed with brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound as a colorless oil after chromatography (sio2~ hexane: EtOAc, 6:1). lH NMR (CDCl3) ~ 3.70 (s, 3H), 3.1 - 3.7'(m, SH), 2.2 - 2.65 (m, 4H), 1.7 - 2.15 (m, 5H), 1.5 -1.65 (m, lH), 1.46 (s, 9H) 1.2 - 1.5 (m, 2H), 0.93 (t, 3H, J = 7 Hz).

CA 02216~32 1997-09-26 W O96134010 PCTrUS9610397S

Step J: N-[(tert-Butyloxy)carbonyl-3(S)-ethylpyrrolidin-2(S)-ylmethyll -proline N-[(tert-Butyloxy)carbonyl-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-proline methyl ester 0.081 g, 0.238 mmol) was dissolved in CH30H (2 mT .), cooled to 0~C and treated with lN NaOH solution (0.952 mL, 0.952 mmol). After stirrin~ at 23~C for 3h, the solution was neutralized with lN HCl (0.952 mL, 0.952 mmol), concentrated to remove the CH30H, then lyophilized and the residue used as is.

Step K: N-[(tert-Butyloxy)carbonyl-3(S)-ethylpyrrolidin-2(S)-ylmethyll-prolyl-methionine methyl ester N-[(tert-Butyloxy)carbonyl-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-proline (0.238 mrnol), HOBT (0.048 g, 0.262 mmol), EDC
(0.068 g, 0.0357 mmol), and methionine methyl ester hydrochloride (0.048 g, 0.238 mmol) were dissolved in CH2CL2 (10 mL) and stirred at 23~C for 18 h. EtOAc (100 mL) was ~lrl~rl, and the mixture washed with satd NaHCO3 solution, H20, bnne, and dried (MgSO4). Filtration and concentration to dryness gave 0.085 g of title compound. lH NMR
(CD30D) ~i (major rotamer) 4.63 (t, lH, J = 7 Hz), 3.73 (s, 3H), 3.55 -3.7 (m, lH), 3.0-3.5 (m, 4H), 2.3 - 2.7 (m, 5H?, 1.9 - 2.2 (m, 3H), 2.08 (s, 3H), 1.6 - 1.9 (m, 4H), 1.46 (s, 9H), 1.3 - 1.45 (m, 2H), 0.92 - 1.02 (m, 3H).

Step L: N-[3(S)-Ethylpyrrolidin-2(S)-ylmethyl]-prolyl-methionine methyl ester hydrochloride HCl gas was bubbled into a solution of N-[(tert-butyloxy)carbonyl-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-prolyl methioninine methyl ester (0.085 g, 0.18 mmol) in EtOAc (5 mL) with stirring and cooling in an ice-H20 bath until saturation. The solution was stoppered and stirred at 0~C for 2 h, then purged with Ar and concentrated to give the title compound as a yellow foam.

Step M: N-[ l -( lH-Imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyll-prc-lyl-methionine methyl ester CA 02216~32 1997-09-26 W O 96134010 PCTrUS96/03975 N-[3(S)-Ethylpyrrolidin-2(S)-ylmethyl]-prolyl methionine methyl ester hydrochloride (0.075 g, 0.169 mmol), lH-imida_ol-4-ylacetic acid (0.052 g, 0.253 mmol), HOBT (0.34 g, 0.253 mmol), EDC
(0.49 g, 0.253 mmol) and Et3N ( 0.176 mL, 1.27 mmol) were dissolved in DMF (4 mL) and stirred at 23~C for 18 h. The solvent was removed in vacuo, EtOAc (60 mL) was ~.1.1~,.17 and the solution was washed seqllPnti~lly with satd NaHCO3 solution, H2O, brine, and dried (MgSO4). Filtration and concentration to dryness gave dle title compound after chromatography (SiO2, 5 - 10% CH30H/CH2C12). lH
NMR (CD30D) o (major rotamer) 7.62 (s, lH), 6.93 (s, lH), 4.6 - 4.67 (m, lH), 4.1-4.16 (m, lH), 3.74 (s, 3H), 3.65 (s, 2H), 3.5 - 3.68 (m, 2H), 3.2 - 3.25 (m, lH), 3.04 - 3.1 (m, lH), 2.44 - 2.7 (m, 5H), 2.05 - 2.26 (m, 4H), 2.08 (s, 3H), 1.68 - 1.87 (m, 4H), 1.26 - 1.5 (m, 3H), 0.99 (t, 3H, J =
7 H_). FAB MS 480 (M + 1).
Step N: N-tl-(lH-Tmicl~7ol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)- ylmethyll-prolyl-methionine trifluoroacetate N-[l-(lH-Imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-prolyl-methionine methyl ester (0.020 g, 0.042 mmol) was dissolved in CH30H (2 mL) at O~C and treated with lN NaOH solution (0.167 mL, 0.167 mmol) with stirring. After S h at 23~C lN HCl (0.167 mL, 0.167 mmol) was added and the mixture was purified by preparative RP HPLC on a Vydac column eluting with 0.1% TFA/CH3CN: 0.1%
TFA/ H20 gradient to give the title compound.
lH NMR (CD30D) ~ 8.88 (d, lH, J = lHz)), 7.43 (d, lH, J = lHz), 4.53 - 4.58 (m, lH), 4.25-4.31 (m, lH), 3.96 (ABq, 2H), 3.7 - 3.85 (m, 3H), 3.58-3.66(m, lH),3.50(dd, lH,J=3, 14Hz),3.39(dd, lH,J=3, 14 Hz), 3.23 - 3.42 (m, lH), 2.45 - 2.67 (m, 3H), 2.12 - 2.28 (m, 4H), 2.08 (s, 3H), 1.98 - 2.05 (m, 3H), 1.54- 1.68 (m, 2H), 1.26 - 1.4 (m, lH), 1.03 (t, 3H, J = 7 Hz). FAB MS 466 (M + 1).

CA 02216~32 1997-09-26 W O 96/34010 PCTrUS96/0397 r~ lion of N-[1-[1-(4-Cyanobenzyl)-lH-imitl~7.ol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine isopropyl ester Step A: N-[(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-proline 3(S)-Ethyl-2(S)-proline hydrochloride (from Example 1, Step F) (2.33 g, 0.013 mol) was dissolved in CH30H (20 mL), treated with 3A molecular sieves (2 g) and KOAc (1.27 g, 0.013 mol) to adjust the pH of the reaction mixture to 4.5-5, then N-[(tert-Butyloxy)carbonyl-prolinal (Pettit et al., J. Org. Chem. (1994) S9, [21]
6287-95) (3.36 g, 0.017 mol) was ~tlde~l, and the mixture was stirred for 16 hrs at room temperature. The reaction mixture was filtered, quenched with aq satd NaHCO3 (5 mL) and concentrated to dryness. The residue was extracted with CHC13. The extract was dried (MgSO4), filtered, and conce~ t~d to give the title compound and inorganic salts.

Step B: N-[(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine isopropyl ester N-t(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-proline (2.4 g, 0.008 mol), methionine isopropyl ester hydrochloride (2.21 g, 0.0097 mol), HOBT (1.49 g, 0.0097 mol) and EDC (1.86 g, 0.0097 mol) were dissolved in DMF (15 mL) at room temperature and treated with N-methylmorpholine (3 mL, 0.024 mol). The reaction mixture was stirred overnight at room temperature, then concentrated and partitioned between EtOAc and H2O. The organic layer was washed with aq satd NaHCO3 solution, brine, and dried (MgSO4). The crude product was chromatographed on a flash silica gel column eluting with hexane: EtOAc, 7:3 to give N-(t-butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine isopropyl ester.

CA 02216~32 1997-09- 26 W O 96/34010 PCTnUS96/03975 Step C: N-(Pyrrolidin-2(S)-ylmethyl)-3(S)-ethyl-prolyl methionine isopropyl ester hydrochloride N-[(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine isopropyl ester (1.38 g, 0.0028 mol) was dissolved in EtOAc (40 mL), cooled to -20~C, saturated with HCl gas, and stirred at 0~C. for 1.25 hr, and room tempe~alul~ for 0.25 hr.
Concentration to dryness gave the title compound.

Step D: lH-Imidazole-4- acetic acid methyl ester hydrochloride A solution of lH-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 (RT) for 18hr. The solvent was evaporated in vacuo to afford the title compound as a white solid.
lH NMR(CDC13, 400 MHz) o 8.85(1H, s),7.45(1H, s), 3.89(2H, s) and 3.75(3H, s) ppm.

Step E: l-(Triphenylmethyl)-lH-imidazol-4-ylacetic acid methyl ester To a solution of lH-Imidazole-4- acetic acid methyl ester hydrochloride (24.85g, 0.141mol) in dimethyl formamide (DMF) (115ml) was added triethylamine (57.2 ml, 0.412mol) and tribenzyl bromide(55.3g, 0.171mol) and the suspension was stirred for 24hr. After this time, the reaction mixture was diluted with ethyl acetate (EtOAc) (1 1) and water (350 ml). The organic phase was washed with sat. aq.
NaHCO3 (350 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (sio2~ 0-100% ethyl acetate in hexanes; gradient elution) to provide the title compound as a white solid.
1 H NMR (CDC13, 400 MHz) o 7.35(1 H, s), 7.31 (9H, m), 7.22(6H, m), 6.76(1H, s), 3.68(3H, s) and 3.60('H, s) ppm.

Step F: [1-(4-Cyanobenzyl)-lH-imidazol-:--yl]acetic acid methyl ester CA 02216~32 1997-09-26 W O96/34010 PCTrUS96/0397 To a solution of l-(Triphenylmethyl)-lH-imidazol-4-ylacetic acid methyl ester (8.00g, 20.9mmol) in acetonitrile (70 ml) was added bromo-p-toluonitrile (4.10g, 20.92 mmol) and heated at 55~C for 3 hr. After this time, the reaction was cooled to room tempel~lul~ and the S resulting imicl~7olium salt (white precipitate) was collected by filtration.
The filtrate was heated at 55~C for 18hr. The reaction mixt~lre was cooled to room tempel~lul~ and evaporated in vacuo. To the residue was added EtOAc (70 ml) and the resulting white preci~ te collected by filtration. The precipitated imicl~7.olium salts were combined, suspended 10 in methanol (100 ml) and heated to reflux for 30min. After this time, the solvent was removed in vacuo, the resulting residue was suspended in EtOAc (75ml) and the solid isolated by filtration and washed (EtOAc).
The solid was treated with sat aq NaHCO3 (300ml) and CH2C12 (300ml) and stirred at room temp~l~lul~ for 2 hr. The organic layer was 15 separated, dried (MgSO4) and evaporated in vacuo to afford the title compound as a white solid:
lHNMR(CDCl3, 400 MHz) o7.65(1H, d, J=8Hz), 7.53(1H, s), 7.15(1H, d, J=8Hz), 7.04(1H, s), 5.24(2H, s), 3.62(3H, s) and 3.45(2H, s) ppm.
~0 Step G: rl-(4-Cyanobenzyl)-lH-imidazol-5-yllacetic acid A solution of [1-(4-cyanobenzyl)-lH-imid~7ol-5-yl]acetic acid methyl ester (4.44g, 17.4mmol ) in THF (lOOml) and 1 M lithium hydroxide (17.4 ml, 17.4 mmol) was stirred at RT for 18 hr. 1 M HCl (17.4 ml) was added and the THF was removed by evaporation in vacuo.
25 The aqueous solution was lyophili7e-1 to afford the title compound containing lithium chloride as a white solid.
lH NMR(CD30D, 400 MHz) o 8.22(1H, s), 7.74(1H, d, J=8.4Hz), 7.36(1H, d, J=8.4Hz), 7.15(1H, s), 5.43(2H, s) and 3.49(2H, s) ppm.
~0 Step H: N-[1-[1-(4-Cyanobenzyl)-lH-imidazol-5-ylacetyl]-pyr~olidin-2(S )-ylmethyl] -3 (S )-ethyl-prolyl-methionine isopropyl ester [1-(4-Cyanobenzyl)-lH-imidazol-5-yl]acetic acid ~ LiCl (0.416 c. 1.47 mmol). N-(pyrrolidin-2(S)-ylmethyl)-3(S)-ethyl-prolyl-CA 02216~32 1997-09-26 W O 96/34010 PCTrUS96/03975 methionine isopropyl ester hydrochloride (Step I) ( 0.63 g, 1.33 rnmol), HOOBT (0.239 g, 1.47 mmol), and EDC (0.281 g, 1.47 rnmol) were dissolved in degassed DMF (20 mL) with stirnng at room tempelalul~, N-methylmorpholine (0.8 mL, 5.32 rnmol) was added to achieve a pH of 5 7, and stilTing was continued overni~ht The reaction mix~lre was concentrated to remove most of the DMF, and the residue was partitioned between EtOAc and aq satd NaHCO3 solution. The aq layer was washed with EtOAc, the organics combined, washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title 10 compound after chromatography on silica gel eluting with CH2C12:CH30H, 95:5.
Anal. calcd for C33H46N6O4S ~ 0.7 H2O: C, 62.38; H, 7.52; N, 13.23;
found: C, 62.40; H, 7.17; N, 13.11.
FAB MS 623 (M+1) Following the procedures outlined above, but substit~ltin~ methionine sulfone isopropyl ester for methionine isopropyl ester, the following compound was prepared:
N-tl-~1-(4-Cyanobenzyl)-lH-irnidazol-S-ylacetyl]pyrrolidin-2(S)-20 ylmethyll-3(S)-ethyl-prolyl-methionine sulfone isopropyl ester Anal. calcd for C33H46N6O6S ~ 0.9 H2O: C, 59.07; H, 7.18; N, 12.52, found: C, 58.99; H, 6.87; N, 12.86.
FAB MS 655 (M+1) Preparation of N-[ l -[1 -(4-Cyanobenzyl)- 1 H-imidazol-5-ylacetyl] pyrrolidin-2(S )-ylmethyl] -3 (S )-ethyl-prolyl-methionine sulfoxide To a solution of N-[1-[1-(4-Cyanobenzyl)-lH-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine (0.15 g, 0.186 mM) in 3 mL of MeOH:H ~O 1: 1 was added sodium periodate (0 048 c~ 0.~23 mM). The mixture was stirred for 1 h. diluted with 3 mL

CA 022l6~32 l997-09-26 W O 96/34010 PCTrUS96/0397 of H2O and purified by prep HPLC (Delta-pak, C-18). The pure fractions were pooled and lyophilli7e~1 to yield the title compound.
Anal. calcd for C30H40N6oss ~ 4.2 CF3C02H ~ 0.5 H20:
C, 42.52; H, 4.20; N, 7.75;
found: C, 42.51; H, 4.21; N, 8.11.
FAB MS 597 (M+l) Following the procedure above the following compound was prepared:
N-[1-[1-(4-Cyanobenzyl)-lH-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyll-3(S)-ethyl-prolyl-methionine sulfoxide isopropvl ester Anal. calcd for C33H46N605S ~ 1.0 H2O:
C, 60.34; H, 7.37; N, 12.80;
found: C, 60.32; H, 7.19; N, 12.42.

Pl~al~ion of N-[1-[1-(4-Cyanobenzyl)-lH-imi~1~7ol 5 ylacetyl~pyrrolidin-2(S)-ylmethyll-3(S)-ethyl-prolyl-methionine sulfone 20 To a solution of N-[1-[1-(4-Cyanobenzyl)-lH-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine (0.15 g, 0.186 mM) in 5 mL of MeOH:H2O 1:1 was added Oxone (1.1 g, 0.372 mM). After stirring for 0.5 h, the mixture was partially evaporated and diluted with 5 mL of H2O and purified by prep HPLC (Vydac, C-18).
25 The pure fractions were pooled and lyophilized to yield the title compound.
Anal. calcd for C30H4oN6o6s ~ 3.2 CF3C02H ~ 1.2 H20:
C, 43.75; H, 4.60; N, 8.41;
found: C, 43.75; H, 4.59; N, 8.45.
30 FAB MS 613 (M+l) CA 02216~32 1997-09-26 W O 96/34010 PCTrUS96/03975 E~AMPLE 5 Preparation of N-[1-[1-(4-Cyanobenzyl)-lH-imi~1~7.ol 5 ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl 5 esterand N-[1-[1-(4-Cyanobenzyl)-lH-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyll-3(S)-ethyl-prolyl-methionine Step A: N- [ 1- [ 1 -(4-Cyanobenzyl)- 1 H-iII~idazol-5-ylacetyl]-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methvl ester Following the procedures described for Fx~mrle 2, but substihltin~ methionine methyl ester hydrochloride for methionine isopropyl ester hydrochloride in Step B, the title compound was prepared.
Anal. calcd for C31H42N6O4S ~ 3.7 CF3C02H ~ 0.3 H20:
C, 45.13; H, 4.57; N, 8.22;
found: C, 45.10; H, 4.53; N, 8.39.

Step B: N-[l-tl-(4-Cyanobenzyl)-lH-imidazol-5-l)acetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine trifluoroacetate N- [ 1- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester (0.016 g, 0.02 mmol) was dissolved in CH30H (1 mL) and H2O (1 mL) at ambient temperature and treated with 1 N NaOH (0.3 mL, 0.3 mmol) with stirring. After 1 hr the reaction mixture was neutralized with lN HCl (0.3 mL) and purified on a VYDAC preparative RP HPLC
column and lyophilized to give the title compound.
Anal. calcd for C30H40N604S ~ 3.9 CF3C02H ~ 0.6 H20:
C, 43.81; H, 4.39; N, 8.11;
found: C, 43.79; H, 4.39; N, 8.27.

Followin~ the procedures outlined in Examples 2 and 3, but substituting the appropriate carboxylic acid in Example 2. Step H; the followin~
compounds were prepared:

CA 02216~32 1997-09-26 W O 96/34010 PCTrUS96/03975 N-rl-(lH-Imidazol-4-ylacetyl)-pyrrolidin-2(S-)vlmethyll-3(S)-ethyl-prolyl-methionine methyl ester lH NMR (CD30D) o 8.88 (s, lH), 7.43 (s, lH), 4.64 - 4.71 (m, lH), 4.19-4.27 (m, lH), 3.94 (s, 2H), 3.75 - 3.88 (m, 2H), 3.74 (s, 3H), 3.57 -3.61 (m, 2H), 3.34 - 3.5 (m, 3H), 3.15 - 3.25 (m, lH), 2.45 - 2.67 (m, 2H), 1.98 - 2.37 (m, 6H), 2.08 (s, 3H), 1.83 - 1.98 (m, 3H), 1.4 - 1.56 (m, lH), 1.01 (t, 3H, J = 7 Hz).
Anal. calcd for C23H37N504S ~ 2.8 CF3C02H ~ 1.3 H20:
C, 41.88; H, 4.96; N, 8.54;
Found: C, 41.85; H, 4.95; N, 8.54.
FAB MS 480 (M + 1).

N-rl-(lH-Imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyll-3(S)-ethyl-prolyl-methionine lH NMR (CD30D) ~ 8.87 (s, lH), 7.43 (s, lH), 4.61 - 4.71 (m, lH), 4.2-4.3 (m, lH), 3.94 (brs, 2H), 3.75 - 3.88 (m, 2H), 3.6 - 3.73 (m, lH), 3.16 - 3.48 (m, SH), 2.5 - 2.7 (m, 2H), 2.0 - 2.38 (m, 6H), 2.10 (s, 3H), 1.83 - 1.98 (m, 3H), 1.4- 1.55 (m, lH), 1.01 (t, 3H, J = 7 Hz).
Anal. calcd for C22H35N504S ~ 2.8 CF3C02H:
C, 42.24; H, 4.85; N, 8.92;
Found: C, 42.18; H, 4.86; N, 8.95.
FAB MS 466 (M + 1).

N-r 1 -Glycyl-pyrrolidin-2(S)-ylmethyll-3(S)-ethyl-prolyl-methionine methyl ester FAB MS 429 (M + 1).

N-r l -Glycyl-pyrrolidin-2(S)-ylmethyl~-3(S)-ethyl-prolyl-methionine Anal. calcd for ClgH34N404S ~ 3.0 CF3C02H ~ 0.5 H20:
C, 39.72; H, 5.00; N, 7.3 ';
Found: C. 39.21; H. 5.02: N, 7.68.
FAB MS 415 (M + l ).

CA 02216~32 1997-09-26 W O96/34010 PCTrUS9610397 N-rl-(3-rlH-Imidazol-4-yllpropionyl)-pyrrolidin-2(S-)vlmethyll-3(S)-ethyl-prolyl-methionine methyl ester Anal. calcd for C24H3gN5O4S ~ 0.75 H20:
C, 56.84; H, 8.05; N, 13.81, Found: C, 56.79; H, 7.95; N, 13.90.
FAB MS 494 (M + 1).

N-rl -(3-rlH-Imidazol-4-yllpropionyl)-pvrrolidin-2(S-)ylmethyll-3(S)-ethyl-prolvl-methionine FAB MS 480(M+ 1).

N-rl-r3-(1-(4-Cyanobenzyl)-lH-imidazol-S-vl)propionyllpyrrolidin-2(S)-vlmethyll-3(S)-e~yl-prolyl-methionine methyl ester Anal. calcd for C32H44N604S ~ 2.0 HCl ~ 0.4 H20:
C, 55.79; H, 6.85; N, 12.20;
Found: C, 55.86; H, 6.85; N, 11.95.
FAB MS 609 (M + 1).

N-r 1 -r3-(1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl)propionyllpyrrolidin-2(S)-20 ylmethyll-3(S)-ethyl-prolyl-methionine Anal. calcd for C31H42N604S ~ 2.9 CF3C02H ~ 0.8 H20:
C, 47.03; H, 4.99; N, 8.94;
Found: C, 47.05; H, 4.96; N, 9.31.
FAB MS 595 (M + 1).

Preparation of N-[2(S)-(lH-Imidazol-4-ylacetyl-amino)-3(S)-methylpentyl]-prolyl-methionine methyl ester and N-[2(S)-(lH-30 Imidazol-4-ylacetyl-amino)-3(S)-methylpentvll-prolvl-methionine Step A: N-~2(S)-( l H-Imidazol-4-ylacetyl-amino)-3(S)-methylpentyll-prolyl-methionine methyl ester CA 02216~32 1997-09-26 W O96/34010 PCTrUS96/0397 Following the methods outlined in Example 1, but sub~ N-(t-Butyloxycarbonyl)-isoleucinal for N-t(t-Butyloxy)carbonyl]-3(S)-ethyl-2(S)-prolinal in Step I, the title compound was prepared.
5 Anal. calcd for C22H37N504S ~ 0.5 H20: C, 55.43; H, 8.04; N, 14.69;
Found: C, 55.75; H, 7.82; N, 14.36.
FAB MS 468 (M + 1).

Step B: N-[2(S)-(lH-Imidazol-4-ylacetyl-amino)-3(S)-methvlpentyll-prolyl-methionine The title compound was prepared following the method dscribed in Example 1, Step N.
Anal. calcd for C21H35N504S ~ 2.5 CF3C02H:
C, 42.27; H, 5.12; N, 9.48;
Found: C,41.91;H,5.17;N,9.51.
FAB MS 454 (M + 1).

Preparationof N-[l-(lH-Imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-prolyl-methionine methyl ester and N-[l-(lH-Imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyll -prolyl-methionine Step A: N-[l-(lH-Imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-prolyl-methionine methyl ester Following the methods outlined in Example 1, but substituting N-(t-Butyloxycarbonyl)-prolinal for N-[(t-Butyloxy)carbonyl]-3(S)-ethyl-2(S)-prolinal in Step I, the title compound was prepared.
Anal. calcd for C21H33N504S ~ l.9 CF3C02H ~ 2 HCl:
C, 39.80; H, 5.00; N, 9.36;
Found: C. 39.82; H, 5.01; N, 9.33.
FAB MS 452 (M + l).

CA 02216~32 1997-09-26 W O 96/34010 PCTnUS96/0397 Step B: N-[1-(lH-Tmi~1~7O1-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-prolyl-methionine The title compound was prepared following the method dscribed in Example 1, Step N.
Anal. calcd for C20H31N504S ~ 2.6 CF3C02H ~ 1.1 HCl:
C,40.15,H,4.79;N,9.29;
Found: C, 40.15; H, 4.85; N, 9.02.
FAB MS 438 (M + 1).

10 Following the procedures outlined in Examples 1, 2, and 7, the following compounds were prepared:

N-[1-[1-(4-Cyanoberlzyl)-lH-imidazol-S-ylacetyl]pyrrolidin-2(S)-ylmethyll-prolyl-methionine methyl ester Anal. calcd for C29H3gN6O4S ~ 1.2 H20: C, 59.20; H, 6.92; N, 14.28;
Found: C,59.25;H,6.81;N, 14.14.
FAB MS 567 (M+ 1).

N-[ l -[1 -(4-Cyanobenzyl)- lH-imidazol-5-ylacetyl]pyrrolidin-2(S)-20 ylmethvll-prolyl-methionine Anal. calcd for C28H36N6O4S ~ 3.4 CF3C02H ~ 1.0 H20:
C, 43.61; H, 4.35; N, 8.77;
Found: C, 43.59; H, 4.35; N, 8.91.
FAB MS 553 (M + 1).

Using the procedures described in Example l, but substituting 3(S)-Ethyl-2(S)-proline hydrochloride for proline methyl ester in Step I, the - 30 following compounds were prepared:
N-[1 -( lH-Imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester Anal. calcd for Cr~5H4lNsO4S ~ 0.5 H2O: C. 50.93: H, 7.52; N l 1.88;
Found: C. 50.. 90; H. 7.38; 1~,'. l l.87.

CA 02216~32 1997-09-26 W O 96/34010 PCT~US96/03975 N-[1-(lH-Imidazol-4-ylacety1)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine trifluoroacetate Anal. calcd for C24H39N504S ~ 2.95 CF3C~2H:
C, 43.27; H, 5.09; N, 8.44;
Found: C,43.17;H,5.16;N,8.54.

N-[1-[1-(4-Cyanobenzyl)-lH-imicl~7.ol-5-ylacetyl]-3(S)-ethylpyrrolidin-2(S)-ylmethyll-3(S)-ethyl-prolyl-methionine methyl ester Anal. calcd for C33H46N6O4S: C, 63.63; H, 7.45; N, 13.50;
Found: C, 63.53; H, 7.36; N, 13.39.

N-[1-[1-(4-Cyanobenzyl)-lH-imidazol-5-ylacetyl]-3(S)-ethylpyrrolidin-2(S)-ylmethyll-3(S)-ethyl-prolyl-methionine trifluoroacetate Anal. calcd for C32H44N6O4S ~ 3.2 CF3C02H ~ 0.6 H20:
C, 46.85; H, 4.96; N, 8.54;
Found: C, 46.86; H, 4.96; N, 8.78.

N-[1 -[1 -(4-Cyanobenzyl)- lH-imidazol-5-ylacetyl]-3(S)-ethylpyrrolidin-2(S)-ylmethyll-3(S)-ethyl-prolyl-methionine isopropyl ester Anal. calcd for C35H50N6o4s ~ 0.25 H2O: C, 64.14; H, 7.77; N, 12.82;
Found: C, 64.16; H, 7.73; N, 12.82.

N-[1-(3-[lH-IIr~idazol-4-yl]propionyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyll-3(S)-ethyl-prolyl-methionine methyl ester FAB MS 522 (M + 1).

N-[1-(3-[lH-Imidazol-4-yl]propionyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyll-3(S)-ethyl-prolyl-methionine trifluoroacetate FAB MS 508 (M + 1).

N-[ l -Glycyl-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methvl ester CA 02216~32 1997-09-26 W O 96134010 PCTrUS96/0397 _ 99 _ N-[ l -Glycyl-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine trifluoro~et~te s Preparation of N-~1-(1-(4-Nitrobenzyl)-lH-imidazol4-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine bis trifluoroacetate and N-[1-(1-(4-Nitrobenzyl)-lH-imi(1~7ol-5-ylacetyl]
pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine bis trifluoroacetate.

Step A: 1-(4-Nitrobenzyl)-lH-imidazol-4-ylacetic acid methyl ester and 1-(4-Nitrobenzyl)-lH-imic1~7ol-5-ylacetic acid methyl ester (3: 1 rnixture) To a solution of sodium hydride (60% in mineral oil, 99 mg, 2.5 mmol) in dimethylform~mide (2 ml) cooled to 0~C was ~ cl via c~nn~ , a solution of lH-imidazole-4-acetic acid methyl ester hydrochloride (200 mg, 1.13 mmol) in dimethylform~n~ide (3 ml). This suspension was allowed to stir at 0~C for 15 min. To this suspension was added 4-nitrobenzyl bromide (244 mg, 1.13 mmol) and stirred at room temperature for 2 h. After this time, the mixture was quenched with sat.
aq. sodium bicarbonate (15 ml) and water (20 ml) and extracted with methylene chloride (2 x 50 ml). The combined organic extracts were washed with brine (20 rnl), dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography using acetonitrile as eluent to give the title compounds as a yellow oil.
1H NMR (CDC13, 400 MHz) o 8.20 (2H, d, J=8.5 Hz), 7.49 (lH, s), 7.27 (2H, d, J=8.5 Hz), 7.03 (0.25H, s), 6.87 (0.75H, s), 5.28 (O.SH, s), 5.18 (1.5H, s), 3.70 (2.25H, s), 3.65 (l.SH, s), 3.61 (0.75H, s) and 3.44 (O.SH, - 30 s) ppm.

Step B: 1-(4-Nitrobenzyl)-1H-imidazol-~-ylacetic acid hydrochloride and 1 -(4-Nitrobenzyl)- 1 H-imidazol-5-ylacetic acid (3: I mixture) CA 02216~32 1997-09-26 W O96/34010 PCTrUS96/03975 To a solution of a mixture of 1-(4-Nitrobenzyl)-lH-imi~l~7.ol-4-ylacetic acid methyl ester and 1-(4-Nitrobenzyl)-lH-imidazol-5-ylacetic acid methyl ester (3:1mixture, 216 mg, 0.785 mmol) in methanol (3 ml) and tetrahydrofuran (3 ml) under argon was added 1.0 5 M sodium hydroxide (1.18 ml, 1.18 mmol) and stirred for 18 h. After this time, 1.0 N hydrochloric acid (2.36 ml, 2.36 mmol) was added and the .~ixL..~ evaporated in vacuo to give the title compounds.
lH NMR (CDC13, 400 MHz) o 9.04 (0.75H, s), 8.83 (0.25H, s), 8.28 (2H, d, J=8.8 Hz), 7.61 (2H, d, J=8.8 Hz), 7.54 (0.75H, s), 7.43 (0.25H, 10 s), 5.61 (0.SH, s), 5.58 (l.SH, s), 3.84 (0.SH, s) and 3.82 (l.SH, s) ppm.

Step C: N-[1-(1-(4-Nitrobenzyl)-lH-imidazol-4-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester bis trifluoroacetate and N-[1-(1-(4-Nitrobenzyl)-lH-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl methionine methyl ester bis trifluoro~et~te To a solution of 1-(4-nitrobenzyl)-lH-imidazol-4-ylacetic acid hydrochloride and 1-(4-nitrobenzyl)-lH-imidazol-5-ylacetic acid hydrochloride (3:1 mixtllre, 0.392 mmol), N-[pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl methionine methyl ester hydrochloride (0.392 mmol), prepared as described in Example 1, Steps A-L (but lltili7ing the substitutions described in Example 2, Step A), and 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (HOOBT, 0.39 mmol) in methylene chloride (10 ml) are added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 0.392 mmol) and triethyl~mine (1.57 mmol) and the mixture is stirred overnight at room temperature. After this time, sat. aq.
sodium bicarbonate (10 ml) is added and the mixture is extracted with methylene chloride. The combined extracts are washed with sat. aq.
sodium bicarbonate (10 ml) and the solvent evaporated in vacuo. The regioisomers are separated by preparative HPLC using a Nova Prep 5000 Semi preparative HPLC system and a Waters PrepPak cartridge (47X300mm, C18, l5,um, 100 A) eluting with 5-95% acetonitrile/water s (0.1% TFA) at 100 ml/min (chromatography method A) to give the title compounds after lyophilization.

CA 02216~32 1997-09-26 W O 96/34010 PCTrUS96/0397S

..
Step D: N-[1-(1-(4-Nitrobenzyl)-lH-imi~1~7ol-4-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine bis trifluoroacetate To a solution of N-[1-(1-(4-nitrobenzyl)-lH-imidazol4-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl methioninemethyl ester bis trifluoroacetate (0.023 mmol) in methanol (1 ml ) at room tempel~ul~ is added l.ON lithillm hydroxide (135 ~Ll, 0.135 mmol). This solution is stirred for 4 h and treated with trifluoroacetic acid (100 ~Ll).
10 This mixture is pllrifi~.rl by preparative HPLC using chromatography method A to give the title compound.

Step E: N-[1-(1-(4-Nitrobenzyl)-lH-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine bis trifluoroacetate Toasolutionof N-[1-(1-(4-nitrobenzyl)-lH-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl methioninemethyl ester bis trifluoroacetate (0.031 mmol) in methanol (1 ml ) is added l.ON
20 lithium hydroxide (187 ~Ll, 0.187 mmol ). This solution is stirred for 4 h and treated with trifluoroacetic acid (100 ,ul). This mixture is purified by preparative HPLC using chromatography method A to give the title compound.

Preparation of N-[ 1-(1-(1 -Farnesyl)- 1 H-imidazol-5-ylacetyl)-pyrrolidin-2(S)-ylmethyll-3(S)-ethyl-prolyl methionine bis trifluoroacetate - 30 Step A: 1-(1-Farnesvl)-lH-imidazol-5-ylacetic acid methyl ester To a solution of l-(tribenzyl)-lH-imidazol~-ylacetic acid methyl ester (200 mg, 0.523 mmol) in acetonitrile (5 ml) was added trans, trans-farnesyl bromide (156 ~I, 0.575 mmol) and heated at 55~C for 16 h.
After this time. the reaction was heated at 80~C for 3 h and then the CA 02216~32 1997-09-26 W O96134010 PCTrUS96/03975 reaction mixture was evaporated in vacuo. The residue was dissolved in me~anol (5 ml ) and heated to reflux for 30 min and dlen evaporated in vacuo. The residue was purified by flash chromatography (2-4%
me~anolJmethylene chloride gradient elution) to provide the title 5 compound.
lH NMR (CDC13, 400 MHz) ~i 7.50 (lH, s), 6.92 (lH, s), 5.24 (lH, t, J=5.9 Hz), 5.09 (2H, m), 4.49 (2H, d, J=6.9 Hz), 3.69 (3H, s), 3.60 (2H, s), 1.91-2.15 (8H, m), 1.72 (3H, s), 1.65 (3H, s), 1.59 (3H, s) and 1.57 (3H, s) ppm.
Step B: N-t 1 -(1 -(1 -Farnesyl)- 1 H-imidazol-5-ylacetyl)pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl methioninemethylester bis trifluoroacetate Following the procedure described in Example 9, Steps C-D, but using l-farnesyl-lH-imic1~7ol-5-ylacetic acid me~yl ester described in Step A in place of 1-(4-nitrobenzyl)-lH-imic1~7ol-5-ylacetic acid me~yl ester provides the title compound.

Step C: N-~l-(l-(l-Farnesyl)-lH-imicl~701-5-ylacetyl)pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl methionine bis trifluoroacetate Following the procedure described in Example 1, Step N, but using the methyl ester prepared as described in Step B provides the title compound.

Preparation of N-[ l -(1 -(1 -Geranyl)- 1 H-imidazol-5-ylacetyl)-pyrrolidin-2(S)-ylmethyll-3(S)-ethyl-prolyl-methionine bis trifluoroacetate Step A: N-~ 1 -(1 -(1 -Geranyl)- 1 H-imidazol-5-ylacetyl)pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester bis .
trifluoroacetate CA 02216~32 1997-09-26 W O96/34010 PCTrUS96/0397 Following the procedure described in Example 10, Steps A-B, but using trans-geranyl bromide in place of farnesyl bromide provides the title compound.

S Step B: N-[1-(1-(1-Geranyl)-lH-imi~1~7.ol-5-ylacetyl)pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine bis trifluoroacetate Following the procedure described in Example 1, Step N, but using the methyl ester prepared as described in Step A provides the title compound.

P,~alation of N-[1-(1-(4-Methoxybenzyl)-lH-imidazol-5-ylacetyl)pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine bis trifluoroacetate Step A: N-[1-(1-(4-Methoxybenzyl)-lH-imidazol-5-yl)acetyl)pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester bis trifluoroacetate Following the procedure described in Example 9, Steps B-D, but using 4-methoxybenzyl chloride in place of 4-nitrobenzylbromide provides the title compound.

Step B: N-[ 1-(1 -(4-Methoxybenzyl)- 1 H-imidazol-5-ylacetyl)pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine bis trifluoroacetate Following the procedure described in Example 1, Step N, but substituting the methyl ester from Step A provides the title compound.

CA 02216~32 1997-09-26 W O96/34010 PCTrUS96/03975 Preparation of N-[1-(1-(2-Naphthylmethyl)-lH-irnidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine bis 5 trifluoroacetate Step A: N-[1-(1-(2-Naph~ylmethyl)-lH-imi~1~7O1-5-ylacetyl]3(S)-ethylpyrrolidin-2(S)-ylmethyl]-prolyl-methionine methyl ester bis trifluoroacetate Following the procedure described in Example 9, Steps B-D, but using 2-(bromomethyl)naphthylene in place of 4-nitrobenzylbromide provided the title compound.

Step B: N-[1-(1-(2-Naphthylmethyl)-lH-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine bis trifluoroacetate Following the procedure described in Example 1, Step N, but using the methyl ester prepared as described in Step A provided the title compound.

Preparation of N-[ l -(1 H-Irnidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl] -3(S)-ethyl-prolyl-(~-acetylamino)alanine trifluoroacetate Step A: Methyl 2(S)-benzyloxycarbonylamino-3-amino propionate A solution of 2(S)-benzyloxycarbonylamino-3-aminopropionic acid (2.4 g) in methanol at 0~ C was saturated with HCl gas. After stirring for 2 h at 20~ C the solution was evaporated to obtain the title compound. 1HNMR (300 MHz, CD30D ) o 7.35 (5H, m), 5.13 (2H, s), 4.50 (lH, m), 3.77 (3H, s), 3.45 (lH, m), 3.22 (lH, m).

Step B: Methyl 2(S)-benzyloxycarbonylamino-3-acetylamino-propionate CA 02216~32 1997-09-26 W O96134010 . PCTrUS96/0397 To a solution of methyl 2(S)-benzyloxycarbonyl~mino-3-amino propionate (2.5 g) in methylene chloride was added pyridine (20 mL) and acetic anhydride (5 mL). After ~tirrin~ for 2 h the solution was conce~ ted in vacuo. The residue was partitioned between ethyl ~ et~te and water. The ethyl acetate layer was extracted w/ 50 mL each of 2%
potassium hydrogen slllf~te, saturated sodium bicarbonate, saturated sodium chloride, dried over m~gnesium sulfate and concel~ ted in vacuo. Upon evaporation pyridine hydrochloride precipitated and was removed by filtration. The filtrate was evaporated to obtain the title compound. 1HNMR (300 MHz, CDC13 ) ~ 7.28 (5H, s), 6.14 (lH, s), 5.97 (lH, d), 5.10 (2H, s), 4.41 (lH, m), 3.78 (3H, s), 1.93 (3H, s).

Step C: Methyl 2(S)-amino-3-acetylaminopropionate To a solution of methyl 2(S)-benzyloxycarbonylamino-3-acetylamino-propionate (2.2 g ) in ethanolic HCl was added 10% Pd/C ( 0.3 g) under nitrogen atmosphere. Hydrogen was applied to the mixt lre at 60 psi for 16 h. The mixture was filtered and concellLI~t~d in vacuo.
The residue was ~ ul~ted with diethyl ether to obtain the product.
lHNMR (300 MHz, CD30D) ~ 4.20 (lH, m), 3.88 (3H, s), 3.82 (lH, m), 3.60 (lH, m), 1.99 (3H, s).

Step D: N-t 1 -(1 H-Imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-(,3-acetylamino)alanine methyl ester trifluoroacetate Following the procedures outlined in Examples 1 and 2, but substituting the methyl 2(S)-amino-3-acetylaminopropionate of Step C
for methionine methyl ester hydrochloride in Example 1, Step K, the title compound is prepared.

- 30 Step E: N-[l-(lH-Imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethvl-prolyl-(~-acetylamino)alanine trifluoroacetate The title compound is prepared following the method described in Example 1, Step N.

CA 02216~32 1997-09-26 In vitro inhibition of ras farnesyl transferase Assays offarnesyl-protein transferase. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and RAS-CAIL) were ~lG~aled as described by Schaber et al., J. Biol. Chem.
265: 14701-14704 (1990), Pompliano, et al., Biochemistry 31:3800 (1992) and Gibbs et al., PNAS U.S.A. 86:6630-6634 (1989), respectively.
Bovine FpTase was assayed in a volume of 100,ul cont~inin~ 100 mM N-(2-hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH
7.4, 5 mM MgC12, 5 mM dithiothreitol (DTT), 100 mM [3H]-farnesyl diphosphate ([3H]-FPP; 740 CBq/mmol, New Fn~l~ncl Nuclear), 650 nM
Ras-CVLS and 10 ~g/ml FPTase at 31~C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol.
Preci~i~ates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB ~-plate counter. The assay was linear with respect to both substrates, FpTase levels and time; less than 10% of the [3H]-FPP was lltili7ell during the reaction period. Purified compounds were dissolved in 100%
dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay.
Percentage inhibition is measured by the arnount of incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound.
Human FPTase was prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1 % (w/v) polyethylene glycol 20,000, 10 ~lM ZnCl2 and 100 nM Ras-CVIM were added to the reaction rnixture. Reactions were performed for 30 min., stopped with 100 ~l of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
The compounds of the instant invention were tested for inhibitory activity a~ainst human FPTase by the assay described above and were found to have IC50 of < l 0 ~LM.

CA 02216~32 1997-09-26 W O 96!34010 PCTrUS96/03975 In vivo ras farnesylation assav The cell line used in this assay is a v-ras line derived from S either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21. The assay is ~lrol,lled essentially as described in DeClue, J.E. et al., Cancer Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75%
confluency are treated with the test compound (final concentration of solvent, methanol or ~lim~.thyl sulfoxide, is 0.1 %). After 4 hours at 37~C, 10 the cells are labelled in 3 ml methionine-free DMEM supple-meted with 10% regular DMEM, 2% fetal bovine serum and 400 mCit35S]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgC12/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml 5 ~ntip~in/O.S mM 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 buffer lacking DTT) and immllnoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et al., J. Virol. 43:294-304, (1982)).
20 Following a 2 hour antibody incubation at 4~C, 200 ml of a 25%
suspension of protein A-Sepharose coated with rabbit anti rat IgG is added for 45 min. The 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-PAGE sample 25 buffer and loaded on 13% acryl~micle gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to farnesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein.

CA 02216~32 1997-09-26 W O96/34010 PCTrUS96/0397 In vivo ~rowth inhibition assay To dete~ le the biological consequences of FPTase 5 inhibition, the effect of the compounds of the in~t~nt invention on the anchorage-independent growth of Ratl cells transformed with either a v-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Raf and v-Mos maybe included in the analysis to evaluate the specificity of in~t~nt compounds for Ras-in-lllce~l 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 diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layers contain 0.1% methanol or an 15 a~ro~liate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay). The cells are fed twice weeldy with 0.5 ml of medium A cont~inin~ 0.1% methanol or the concentration of the instant compound. Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made.

Claims (30)

WHAT IS CLAIMED IS:

1. A compound which inhibits farnesyl-protein transferase having the Formula I:

I

wherein:
R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)-NR10-;

R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl. Br, N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or R2 and R3 are combined to form -(CH2)s-; or R2 or R3 are combined with R6 to form a ring such that is ;

R4a, R4b, R7a and R7b are independently selected from:
a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, N3, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl;

R5a and R5b are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, (R10)2NC(O)-, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN,(R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl, d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or R5a and R5b are combined to form -(CH2)s- wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R6 is independently selected from hydrogen or C1-C6 alkyl;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, R102N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, CN, H2N-C(NH)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R10OC(O)NH-;

R9 is selected from:
a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C-(NR10)-, R10C(O)-, R10OC(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-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;

A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, -S(O)2N(R10)-, -N(R10)S(O)2-, or S(O)m;

Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be a C5-C7 saturated ring;

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

W is a heterocycle;

X, Y and Z are independently H2 or O;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 4 or 5;
t is 3, 4 or 5; and u is 0 or 1;

or a pharmaceutically acceptable salt thereof.

2. A prodrug of a compound which inhibits farnesyl-protein transferase, the prodrug which is illustrated by the formula II:

II

wherein:
R1a and Rlb are independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)-NR10;

R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid.

b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or R2 and R3 are combined to form -(CH2)s-; or R2 or R3 are combined with R6 to form a ring such that is ;

R4a, R4b, R7a and R7b are independently selected from:
a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, N3, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl;

R5a and R5b are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, (R10)2NC(O)-, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl, d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or R5a and R5b are combined to form -(CH2)s- wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)- ;
R6 is independently selected from hydrogen or C1-C6 alkyl;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, R102N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, CN, H2N-C(NH)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R10OC(O)NH-;

R9 is selected from:
a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C-(NR10), R10C(O)-, R10OC(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-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;

R12 is a) substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C5-C8 cycloalkyl, or substituted or unsubstituted cyclic amine, wherein the substituted alkyl, cycloalkyl or cyclic amine is substituted with 1 or 2 substituents independently selected from:
1) C1-C6 alkyl, 2) aryl, 3) heterocycle, 4) -N(R11)2.
5) -OR10, or b) ;

R13 is independently selected from hydrogen and C1-C6 alkyl;

R14 is independently selected from C1-C6 alkyl;

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;

Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be a C5-C7 saturated ring;

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

W is a heterocycle;

X, Y and Z are independently H2 or O;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5, provided that r is 0 when V is hydrogen;

s is 4 or 5;
t is 3, 4 or 5; and u is 0 or 1;
or a pharmaceutically acceptable salt thereof.

3. A compound which inhibits farnesyl-protein transferase having the Formula III:

wherein:
R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)-NR10;

R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or R2 and R3 are combined to form -(CH2)s-; or R2 or R3 are combined with R6 to form a ring such that is ;

R4a, R4b, R7a and R7b are independently selected from:
a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, N3, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl;
R6 is independently selected from hydrogen or C1-C6 alkyl;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, R102N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, CN, H2N-C(NH)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R10OC(O)NH-;

R9 is selected from:
a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C-(NR10), R10C(O)-, R10OC(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-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;

R11 is independently selected from C1-C6 alkyl and aryl;

A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, -S(O)2N(R10)-, -N(R10)S(O)2-, or S(O)m;

Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be a C5-C7 saturated ring;

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 O and A2 is S(O)m;

W is a heterocycle;

X, Y and Z are independently H2 or O;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 4 or 5;
t is 3, 4 or 5; and u is 0 or 1;

or a pharmaceutically acceptable salt thereof.

4. A prodrug of a compound which inhibits farnesyl-protein transferase, the prodrug which is illustrated by the formula IV:

IV

wherein:
R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)-NR10;

R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted ~-substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or R2 and R3 are combined to form -(CH2)s-; or R2 or R3 are combined with R6 to form a ring such that is ;

R4a, R4b, R7a and R7b are independently selected from:
a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, N3, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl;

R6 is independently selected from hydrogen or C1-C6 alkyl;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, R102N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, CN, H2N-C(NH)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R10OC(O)NH-;

R9 is selected from:
a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C-(NR10), R10C(O)-, R10OC(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-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;

R11 is independently selected from C1-C6 alkyl and aryl;

A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, -S(O)2N(R10)-, -N(R10)S(O)2-, or S(O)m;

Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be a C5-C7 saturated ring;

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

W is a heterocycle;

X, Y and Z are independently H2 or O;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 4 or 5;
t is 3, 4 or 5; and u is 0 or 1;

or a pharmaceutically acceptable salt thereof.

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

I

wherein:

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

R1b is independently selected from:

a) hydrogen, b) aryl, heterocycle, cycloalkyl, R10O-, -N(R10)2 or alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R10O-, or -N(R10)2;

R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or R2 and R3 are combined to form -(CH2)s-; or R2 or R3 are combined with R6 to form a ring such that is ;

R4a and R7a are independently selected from:
a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, N3, (R10)2N-C(NR10)-, R10C(O)- R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl;

R4b and R7b are hydrogen;

R5a is selected from:
a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glutamine, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, R10O-, R11S(O)m, R10C(O)NR10-, (R10)2NC(O)-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl;

R5b is selected from:
a) hydrogen, and b) C1-C3 alkyl;

R6 is independently selected from hydrogen or C1-C6 alkyl;

R8 is independently selected from:
a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(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)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-;

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-;

R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;

R11 is independently selected from C1-C6 alkyl and aryl;

Q is selected from:

and ;

A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;

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

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

X, Y and Z are independently H2 or O;

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;
t is 3, 4 or 5; and u is 0 or 1;

or a pharmaceutically acceptable salt thereof.

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

II

wherein:

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

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

R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or R2 and R3 are combined to form -(CH2)s-; or R2 or R3 are combined with R6 to form a ring such that is ;

R4a and R7a are independently selected from:
a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, N3, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl;

R4b and R7b are hydrogen;

R5a is selected from:
a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glutamine, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl;

R5b is selected from:
a) hydrogen, and b) C1-C3 alkyl;

R6 is independently selected from hydrogen or C1-C6 alkyl;

R8 is independently selected from:
a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(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)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-;

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-;

R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;

R11 is independently selected from C1-C6 alkyl and aryl;

R12 is a) substituted or unsubstituted C1-C8 alkyl or substituted or unsubstituted C5-C8 cycloalkyl, wherein the substituent on the alkyl or cycloalkyl is selected from:
1) aryl, 2) heterocycle, 3) -N(R11)2, 4) -OR10, or b) ;

R13 is independently selected from hydrogen and C1-C6 alkyl;

R14 is independently selected from C1-C6 alkyl;

Q is selected from:

and A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;

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

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

X, Y and Z are independently H2 or O;

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;
t is 3, 4 or 5; and u is 0 or 1;

or the pharmaceutically acceptable salts thereof.

7. The compound according to Claim 3 of the formula III:

III

wherein:

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

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

R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or R2 and R3 are combined to form -(CH2)s-; or R2 or R3 are combined with R6 to form a ring such that is ;

R4a and R7a are independently selected from:
a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, N3, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- C10 cycloalkyl;

R4b and R7b are hydrogen;

R6 is independently selected from hydrogen or C1-C6 alkyl;

R8 is independently selected from:
a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(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)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-;

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R11S(O)m, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;

R11 is independently selected from C1-C6 alkyl and aryl;

Q is selected from:

and ;

A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;

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

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

X, Y and Z are independently H2 or O;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
t is 3, 4 or 5; and u is 0 or 1;

or a pharmaceutically acceptable salt thereof.

8. The compound according to Claim 4 of the formula Formula IV:

IV

wherein:

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

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

R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or R2 and R3 are combined to form -(CH2)s-; or R2 or R3 are combined with R6 to form a ring such that is ;

R4a and R7a are independently selected from:
a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, N3, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl;

R4b and R7b are hydrogen;

R6 is independently selected from hydrogen or C1-C6 alkyl;

R8 is independently selected from:
a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(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)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-;

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10;

R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;

R11 is independently selected from C1-C6 alkyl and aryl;

Q is selected from:

and A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;

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

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

X, Y and Z are independently H2 or O;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
t is 3, 4 or 5; and u is 0 or 1;

or a pharmaceutically acceptable salt thereof.

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

N-[1-(1H-Imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-prolyl-methionine methyl ester N-[1-(1H-Imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-prolyl-methionine N-[1-[1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine isopropyl ester N-[1-[1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine sulfone isopropyl ester N-[1-[1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine sulfoxide N-[1-[1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine sulfoxide isopropyl ester N-[1-[1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine sulfone N-[1-[1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester N-[1-[1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[1-(1H-Imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester N-[1-(1H-Imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[1-Glycyl-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester N-[1-Glycyl-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[1-(3-[1H-Imidazol-4-yl]propionyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester N-[1-(3-[1H-Imidazol-4-yl]propionyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[1-[3-(1-(4-Cyanobenzyl)-1H-imidazol-5-yl)propionyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester N-[1-[3-(1-(4-Cyanobenzyl)-1H-imidazol-5-yl)propionyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[2(S)-(1H-Imidazol-4-ylacetyl-amino)-3(S)-methylpentyl]-prolyl-methionine methyl ester N-[2(S)-(1H-Imidazol-4-ylacetyl-amino)-3(S)-methylpentyl]-prolyl-methionine N-[1-(1H-Imidazol-4-ylacetyl)-pyrrolidin-2(S-)ylmethyl]-prolyl-methionine methyl ester N-[1-(1H-Imidazol-4-ylacetyl)-pyrrolidin-2(S-)ylmethyl]-prolyl-methionine N-[1-[1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-prolyl-methionine methyl ester N-[1-[1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-prolyl-methionine N-[1-(1H-Imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester N-[1-(1H-Imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[1-[1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl]-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester N-[1-[1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl]-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[1-[1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl]-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine isopropyl ester N-[1-(3-[1H-Imidazol-4-yl]propionyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester N-[1-(3-[1H-Imidazol-4-yl]propionyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[1-Glycyl-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester N-[1-Glycyl-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[1-[1-(4-Nitrobenzyl)-1H-imidazol-4-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[1-[1-(4-Nitrobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[1-(1-(1-Farnesyl)-1H-imidazol-5-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl methionine N-[1-(1-(1-Geranyl)-1H-imidazol-5-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[1-[1-(4-Methoxybenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine N-[1-[1-(2-Naphthylmethyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine or N-[1-(1H-Imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-(.beta.-acetylamino)alanine or a pharmaceutically acceptable salt thereof.

10. The compound according to Claim 9 which inhibits farnesyl-protein transferase which is:
N-[1-(1H-Imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester ;

or a pharmaceutically acceptable salt thereof.

11. The compound according to Claim 9 which inhibits farnesyl-protein transferase which is:

N-[(1H-Imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-prolyl-methionine methyl ester ;

or a pharmaceutically acceptable salt thereof.

12. The compound according to Claim 9 which inhibits farnesyl-protein transferase which is:

N-[1-(3-[1H-Imidazol-4-yl]propionyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester ;

or a pharmaceutically acceptable salt thereof.

13. The compound according to Claim 9 which inhibits farnesyl-protein transferase which is:
N-[1-(3-[1H-Imidazol-4-yl]propionyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester ;

or a pharmaceutically acceptable salt thereof.

14. The compound according to Claim 9 which inhibits farnesyl-protein transferase which is:

N-[1-[1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine ;

or a pharmaceutically acceptable salt thereof.

15. The compound according to Claim 9 which inhibits farnesyl-protein transferase which is:

N-[1-[1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester ;

or a pharmaceutically acceptable salt thereof.

16. The compound according to Claim 9 which inhibits farnesyl-protein transferase which is:

N-[1-[1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine isopropyl ester ;

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

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

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

20. A method for inhibiting farnesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 17.

21. A method for inhibiting farnesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 18.

22. A method for inhibiting farnesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 19.

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

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

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

26. 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 17.

27. 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 17.

28. 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 17.

29. A method for preventing restenosis which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 17.

30. 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 17.