CA2201346A1 - Inhibitors of farnesyl-protein transferase - Google Patents

Abstract

The present invention comprises analogs of the CAAX motif of the protein Ras that is modified by farnesylation in vivo. These CAAX analogs inhibit the farnesylation of Ras. Furthermore, these CAAX analogs differ from those previously described as inhibitors of Ras farnesyl 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 thioldependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.

Description

W096/09836 22 ~ ~ 3 4 6 PCT/US95/12319 TITLE OF THE INVENTION
INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE

BACKGROUND OF THE INVENTION
The Ras gene is found activated in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein, since Ras must be localized in the plasma membrane and must bind with GTP in order to transfonn cells (Gibbs, J. et al., Microbiol. Rev. 53:171-286 (1989). Forms of Ras in cancer cells have mutations that distinguish the protein from Ras in normal cells.
At least 3 post-translational modifications are involved with Ras membrane loc~li7~tion, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-Aaa1-Aaa2-Xaa" box (Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:~83-~86 (1984)). Other proteins having this motif include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin.
Farnesylation of Ras by the isoprenoid farnesyl pyrophosphate (FPP) occurs in vivo on Cys to form a thioether linkage (Hancock et al., Cell 57:1 167 (1989), Casey et al., Proc. Natl. Acad.
Sci. USA 86:8323 (1989)). In addition, Ha-Ras and N-Ras are palmitoylated via formation of a thioester on a Cys residue near a C-terminal Cys farnesyl acceptor (Gutierrez et al., EMBO J. 8:1093-1098 (1989), Hancock ef al., Cell 57:1167-1177 (1989)). Ki-Ras lacks the palmitate acceptor Cys. The last 3 amino acids at the Ras C-terminAl end are removed proteolytically, and methyl esterification occurs at the new C-telminus (Hancock et al., ibid). Fungal mating J factor and m~mm~ n nuclear lamins undergo identical modification steps (Anderegg et al., J. Biol. Chem. 263:18236 (1988), Farnsworth et al., J. Biol. Chenl. 264:20422 (1989)).

W096/09836 22 ~ ~ 3 ~ 6 P~usgs/l23l9 Inhibition of Ras farnesylation in vivo has been demonstrated with lovastatin (Merck & Co., Rahway, NJ) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids and the farnesyl pyrophosphate precursor. It has been shown that a farnesyl-protein transferase using farnesyl pyrophosphate as a precursor is responsible for Ras farnesylation. (Reiss et al., Cell, 62:81-88 (1990);
Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., 0 Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA, 87:7541 -7545 (1990)).
Inhibition of farnesyl-protein transferase and, thereby, of farnesylation of the Ras protein, blocks the ability of Ras to transform normal cells to cancer cells. The compounds of the invention inhibit Ras farnesylation and, thereby, generate soluble Ras which, as indicated infra, can act as a dominant negative inhibitor of Ras function. While soluble Ras in cancer cells can become a domin~nt negative inhibitor, soluble Ras in normal cells would not be an inhibitor.
A cytosol-localized (no Cys-Aaal-Aaa2-Xaa box membrane domain present) and activated (impaired GTPase activity, staying bound to GTP) form of Ras acts as a domin~nt negative Ras inhibitor of membrane-bound Ras function (Gibbs et al., Proc. Natl.
Acad. Sci. USA 86:6630-6634(1989)). Cytosollocalized forms of Ras with normal GTPase activity do not act as inhibitors. Gibbs et al., ibid, showed this effect in Xenopus oocytes and in m~mm~ n cells.
A~lmini~tration of compounds of the invention to block Ras farnesylation not only decreases the amount of Ras in the membrane but also generates a cytosolic pool of Ras. In tumor cells having activated Ras, the cytosolic pool acts as another antagonist of membrane-bound Ras function. In normal cells having normal Ras, the cytosolic pool of Ras does not act as an antagonist. In the absence of complete inhibition of farnesylation, other farnesylated proteins are able to continue with their ~unctions.

W096/09836 2~ ~ ~ 3 ~ 6 PCT/US95/12319 Farnesyl-protein transferase activity may be reduced or completely inhibited by adjusting the compound dose. Reduction of farnesyl-protein transferase enzyme activity by adjusting the compound dose would be useful for avoiding possible undesirable 5 side effects resulting from interference with other metabolic processes which utilize the enzyme.
These compounds and their analogs are inhibitors of farnesyl-protein transferase. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of 0 the Ras CAAX box with a farnesyl group. Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in vivo and inhibits Ras function.
Inhibition of farnesyl-protein transferase is more specific and is attended by fewer side effects than is the case for a general inhibitor 15 of isoprene biosynthesis.
Previously, it has been demonstrated that tetrapeptides cont~ining cysteine as an amino terminal residue with the CAAX
sequence inhibit Ras farnesylation (Schaber et al., ibid, Reiss et. al., ibid; Reiss et al., PNAS, 88:732-736 (1991)). Such inhibitors may 20 inhibit while serving as alternate substrates for the Ras farnesyl-transferase enzyme, or may be purely competitive inhibitors (U.S.
Patent 5,141,85 l, University of Texas).
It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively bloc~ the processing of Ras 25 oncoprotein intracellularly (N.E. Kohl et al., Science, 260:1934-1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993).
Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of ras-dependent tumors in nude mice (N.E. Kohl et al., Proc. Natl. Acad. Sci U.S.A., 91 :9141 -9145 30 (1994)-Inhibitors of Ras 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 substrate for the enzyme, Ras. Almost all of the W096/09836 22 0 ~ 3 4 6 PCTJUS95~12319 peptide derived inhibitors that have been described are cysteine cont~ining molecules that are related to the CAAX motif that is the signal for protein prenylation. The exception to this generalization is a class of natural products known as the pepticinn;~min~ (Omura, et al., J. Antibiotics 46:222 (1993). In general, deletion of the thiol from a CAAX derivative dramatically reduces the inhibitory potency of these compounds. However, the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to ph~ cokinetics, ph~rm~codynamics and toxicity.
Therefore, a functional replacement for the thiol is desirable. With the exception of the pepticinn~mins, non-thiol FPTase inhibitors that are competitive with the Ras substrate have not been described and are the subject of this invention.
It is, therefore, an object of this invention to develop tetrapeptide-based compounds which do not have a thiol moiety, and which will inhibit farnesyl transferase and the post-translational function~li7~tion of the oncogene Ras protein. It is a further object of this invention to develop chemotherapeutic compositions cont~ining the compounds af this invention and methods for producing the compounds of this invention.

SUMMARY OF THE INVENTION
The present invention comprises analogs of the CAAX
motif of the protein Ras that is modified by farnesylation in vivo.
2s These CAAX analogs inhibit the farnesylation of Ras. Furthermore, the.se CAAX analogues differ from those previously described as inhibitors of Ras farnesyl transfera,se in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in ~nim~ls, prevention of thiol-3 o dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. ~
Further contained in this invention are chemotherapeutic compositions cont~ining these farnesyl transferase inhibitors and methods for their production.

W096/09836 ~2 ~ PCT/US95/12319 The compounds of ~is invention are illustrated by the formulae:

V (CR1a ) -W (CR1b ) (CR1bR9)J~N~x~ ~N~

(R8)t ZR2aR21~ Z R5a p5b V (CR1a2) - W- (CR1b2)p(CR1bR9)r R12 ~ HN

Il R3 R4 HOCH2(/CH2)q V - (CR1a2)n - W- (cR1b2)p(cR1bR9)rJ~N1~2~x~ ~N

and 25 (R8)t z R2a~R2b z f~q v - (CR1a2)n - w - (cR1b2)p(cR1bR9)r/l~N~x~ ~ N~O

IV

W096/09836 ~ 0 1 ~ 4 6 PCT/US95/12319 DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention inhibit the farnesylation of Ras. In a first embodiment of this invention, the Ras farnesyl transferase inhibitors are illustrated by the formula I:

(R8)t Z ~z R ~R
R1a2) - W - (CR1b2)p(CR1bR9), NR12 ~ H~

wherein:
Rla is selected from:
a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, (R10)2N-C(NR10)-, R10C(O)-, or R10OC(O)-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R10O-, R 1 l S(O)m, R 10c(o)NR l 0-~ CN, (R1 0)2N-C(NR l 0)-, R10C(O)-, R10OC(O)-, N3, -N(Rl0)2, or Rl 1Oc(o)NRlo;

Rlb is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, (R10)2N-C(NR10)-, R10C(O)-, or R10OC(O)-, and c) Cl-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, R10O-, Rl lS(O)m-, R10C(O)NR10-, CN, (R10)2N C(NR10), R10C(O)-~ R10OC(O)-~ N3, -N(R10)2, or R 1 1 oc(o)NRlo;
provided that Rlb is not RlOC(O)NR10- when Rla is alkenyl, V is hydrogen and X-Y is -C(o)NR7a-;

W096t09836 ~2 ~ 13 ~ 6 PcTluS95/12319 R2a and R2b 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-C20 alkyl, C2-C20 alkenyl, C3-C1o cycloalkyl, aryl or heterocyclic group, o wherein the substituent is selected from F, Cl, Br, NO2, R1OO-, R1 1S(O)m-, R1OC(O)NR10-, CN, (R10)2N C(NR10), R1OC(O)-, R1OOC(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-C1o cycloalkyl; or R2a and R2b are combined to form - (CH2)s -;

R3 and R4 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 -C20 alkyl, C2-c2o alkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2 R1OO, Rl 1S(o)m, R10c(o)NRlo-~ CN, (R10)2N-C(NR 10), R1OC(O)-, R1OOC(O)-, N3, -N(R10)2, R1 1OC(O)NR10- and Cl-c2o alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1o cycloalkyl;

W096/09836 2a ~13 4 6 PCI'tUS95/12319 R3 and R4 are combined to form - (CH2)s -, RSa and RSb independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized forrn of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, o c) substituted or unsubstituted Cl-c2o alkyl, C2-c2o aLkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, RlOO-, Rl 1S(O)m-, R1OC(O)NR10-, CN, (R10)2N-C(NR10)-, R1OC(O)-, R1OOC(O)-, N3, -N(R10)2, Rl lOC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo 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(COR 1 O)-;

W0 96/09836 ~ 6 PCT/US95/12319 X-Y is ~7a a) ~ssS~N~5s R7b b) \sss~N~ss c) ~ O~

(, )m d) ~5ss~S~ss H

e) ~SSs~ , or H

f) -CH2-CH2-;

R7a is selected from a) hydrogen, 2s b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) Cl -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloaLkyl;

R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, W096/09836 22 0 1 ~ 4 S PCT/US95/12319 c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloaLkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, o heterocyclic and cycloaIkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R100-, Rl lS(O)m-, R1OC(O)NR10-, CN, NO2, R102N-C(NR10)-, R1OC(O)-, R1OOC(O)-, N3, -N(R10)2, or R1 loc(o)NRlo-~ and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R1OO-, R1 1S(O)m-, R1OC(O)NH-, CN, H2N-C(NH)-, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or R 1 1 OC(O)NH-;
0 R9 is selected from:
hydrogen, C 1 -C6 alkyl, R 1OO-, R l l S(O)m-, R1OC(O)NR10-, CN, NO2, N3, -N(R10)2, and Rl lOC(O)NR10;

~2 V ~ 3 ~ 6 provided that R9 is not RlOC(O)NR10- when Rla is aL~enyl, V
is hydrogen and X-Y is -C(o)NR7a-;

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

R1 l is independently selected from C1-C6 alkyl and aryl;

0 Rl2 is hydrogen or Cl-C6 alkyl;

V is selected from:
a) aryl;
b) heterocycle; or c) hydrogen;

W is -S(O)m-, -O-, -NHC(O)-, -C(O)NH-, -NHS02-, -S02NH-, -N(R7a)- or -N[C(o)R7a]-;

20 Z is independently H2 or O;

misO, l or2;
n is O, 1, 2, 3 or 4, provided that n ~ O when V is hydrogen and W is -S(O)m-;
25 p is 0, l, 2, 3 or 4, provided that p ~ 0 when R9 is not hydrogen or Cl-C6 lower alkyl;
r is O or l ;
s is 4 or 5; and t is 0, l or 2, provided that t = O when V is hydrogen;
or the pharmaceutically acceptable salts thereof.

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

W096/09836 22 0 ~ 3 4 6 PCT/US95/12319 (R8)t Z R2a R2b z R5a R~b (CR1a2) - W - (CR1b2)p(CR1bR ), R12 ~ ~ ` 6 wherem:
R1a is selected from:
o a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, (R10)2N-C(NR10)-, RlOC(O)-, or R1OOC(O)-, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R100-, R1 1S(O)m, R1OC(O)NR10-~ CN, (R10)2N-C(NR10)-R1OC(O)-, R1OOC(O)-, N3, -N(R10)2, or Rl lOC(O)NR10;

Rlb is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, (R1 0)2N-C(NR10)-, R 1 C(O)-, or R 1 OC(O)-, and c) Cl -C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, RlOO-, Rl lS(O)m-, RlOC(O)NR10-, CN, (R10)2N-C(NR10)-, R1OC(O)-, RlOOC(O)-, N3, -N(R10)2, or Rl lOC(O)NR10-;
provided that R1b is not R1OC(O)NR10- when Rla is alkenyl, V is hydrogen and X-Y is -C(o)NR7a-;

R2a and R2b are independently selected from:
a) a side chain of a naturally occu~ing amino acid, W096109836 ~2 ~ ~ ~ 4 6 PCT/US95/12319 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 -c20 alkyl, C2-c20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, C1, Br, NO2, R1OO-, Rl 1S(O)m-, RlOC(O)NR10-, CN, (R10)2N-C(NR10)-, R1OC(O)-, R1OOC(O)-, N3, o -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl,and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloaL~yl; or R2a and R2b are combined to form - (CH2)s -;

R3 and R4 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-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, RlOO, 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) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl; or R3 and R4 are combined to form - (CH2)s -;

W096/09836 22 n 13 4 6 PCTIUS95/12319 RSa and RSb 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 -c2o alkyl, C2-C20 alkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2 R10O-, R1 lS(O)m, R10C(O)NR10-~ CN, (Rl0)2N-c(NRlo)-~ R10C(O)-~ R10OC(O)-~ N3, -N(R10)2, RllOC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1Q cycloalkyl; or 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)-;

20 R6 is a) substituted or unsubstituted C1 -C~ alkyl, wherein the substituent on the alkyl is selected from:
1) aryl,

2) heterocycle,

3) -N(R1 1)2,

4) -OR 10, or b) ~loJI~ R13 3 4 ~ `

X-Y is R7a a) ~SSs~Nsss O

R7b b) \5sS~ N~ss c) ~ O~

(I )m d) ~5ss~S~ss e) ~5SS~ , or f) -CH2-CH2-;

R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;

R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, W 0 96/09836 22 0 ~ ~ 4 PC~rAUS95/12319 c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f~ a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloaL~yl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl-C6 aL~yl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;

R~S is independently selected from:
a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, Rl lS(O)m-, R 1 0C(O)NR 10 , CN, NO2, R 1 02N-C(NR 10 R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R 1 1 OC(O)NR 10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyL alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, Rl lS(O)m-, R10C(O)NH-, CN, H2N-C(NH)-, RlOC(O)-, RlOOC(O~-, N3, -N(R10)2, or R 1 1 OC(O)NH-;
0 R9 is selected from:
hydrogen, C1-C6 alkyl, R10O-, Rl lS(O)m-, R10C(O)NR10-, CN, NO2, N3, -N(R10)2, and R 1 1 OC(O)NR 10 ;

W096/09836 ~2 fl ~ 3 4 6 PCI/US95/12319 provided that R9 is not RlOC(O)NR10- when Rla is aLkenyl, V
is hydrogen and X-Y is -C(o)NR7a-;

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

5 and aryl;

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

o R12 is independently selected from hydrogen and Cl-C6 alkyl;

R13 is Cl -C6 alkyl;

V is selected from:
a) aryl;
b) heterocycle; or c) hydrogen, W is -S(O)m-, -O-, -NHC(O)-, -C(O)NH-, -NHS02-, -S02NH-, -N(R7a)- or-N[C(O)R7a];

Z is independently H2 or 0;

m is O, 1 or 2;
25 n is 0, 1, 2, 3 or 4, provided that n ~ O when V is hydrogen and W is -S(O)m-;
p is 0, 1, 2, 3 or 4, provided that p ~ O when R9 is not hydrogen or C 1 -C6 lower alkyl;
r is O or l ;
30 sis40r5;and `J t is 0, 1 or 2, provided that t = O when V is hydrogen;
or the pharmaceutically acceptable salts thereof.

W096/09836 2~ ~ ~ 3 ~ 6 PCT/US95/12319 ~

In a third embodiment of this invention, the inhibitors of farnesyl transferase are illustrated by the formula m HOCH2(CH2)q a ) - W - (CRlb2)p(CR1bR )r NR12 ~ H

wherein:
Rla is selected from:
a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, (R10)2N-C(NR10)-, RlOC(O)-, or RlOOC(O)-, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R100-, R1 lS(O)m-~ RlOC(O)NR10-~ CN, (Rl0)2N-C(NR10)-, R1OC(O)-, RlOOC(O)-, N3, -N(R10~2, or Rl lOC(O)NR10;

Rlb is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, cycloalkyl, alkenyl, 2 s alkynyl, (R l 0)2N-C(NR 1 0)-, R l OC(O)-, or R l OC(O)-, and c) Cl-C6 alkyl unsubstituted or .substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, RlOO-, Rl lS(O)m-, RlOC(O)NRl0-, CN, (R10)2N-C(NRlO)-~ R1OC(O)-, RlOOC(O)-, N3, -N(R l )2, or R l l OC(O)NR l 0 ;
provided that Rlb is not Rl OC(O)NR10- when Rla is alkenyl, V is hydrogen and X-Y is -C(o)NR7a-;

W0 96/09836 ~ ti PCT/US95112319 - 19- .
R2a and R2b 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-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, 0 NO2 R100-, Rl lS(O)m, R10C(O)NR10-~ CN, (R10)2N C(NR10), R10C(O)-~ R100C(o)-, N3, -N(R10)2, Rl loC(O)NR10- and C1-C20 alkyl, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl; or R2a and R2b are combined to form - (CH2)s -;

R3 and R4 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-c2o alkyl, C2-c20 alkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, R100-, Rl lS(O)m-, R10C(O)NR10-, CN, (R10)2N C(NR10), Rloc(o)-~ R10oc(o)-~ N3, 3 o -N(R 1)2, R 1 1 OC(O)NR 10 and C 1 -C20 alkyl, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl; or W0 96/09836 2 ~ 6 PCI/US95/12319 R3 and R4 are combined to form - (CH2)s -;

X-Y is R7a a) ~sss~N~ss o R7b b)\5sS~ N~ss c) ~ O~

1 5 ()m d) ~SsS~s~Ss e) ~555~5sS , or H

f) -C H2-C H2-R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and 3 o e) C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;

~ 2 Q ~

6 PCT/US95/12319 R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl-C6 aIkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-~ Rl lS(o)m-Rl0C(o)NRl0-, CN, NO2, Rl02N-C(NR10)-, R10C(O)-, Rl0OC(O)-, N3, -N(Rl0)2, or R l l OC(O)NR l 0-, and c) Cl -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, Rl0O-, Rlls(o)m-~ Rl0C(O)NH-, CN, H2N-C(NH)-, Rl0C(O)-, Rl0OC(O)-, N3, -N(Rl0)2, or 3 R l l OC(O)NH-;

W 0 96/09836 ~ ~ a ~ ~ 4 6 PC~rnuS95/12319 R9 is selected from:
hydrogen, C1-C6 alkyl, R100-, Rl 1S(O)m-, R1OC(O)NR10-, CN, N02, N3, -N(R10)2, and R1 1 OC(O)NR1 -;
provided that R9 is not RlOC(O)NR10- when Rla is alkenyl, V
is hydrogen and X-Y is -C(o)NR7a-;

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

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

R12 is hydrogen or Cl-C6 alkyl;

V is selected from:
a) aryl;
b) heterocycle; or c) hydrogen;
W is -S(O)m-, -O-, -NHC(O)-, -C(O)NH-, -NHS02-, -S02NH-, -N(R7a)- or-N[C(O)R7a]-;

Z is independently H2 or 0;
misO, 1 or2;
n is 0, 1, 2, 3 or 4, provided that n ~ O when V is hydrogen and W is -S(O)m-;
p is 0, 1, 2, 3 or 4, provided that p ~ O when R9 is not hydrogen or 3 o C1-C6 lower alkyl;
qisO, 1 or2;
risOor l;
sis40r5;and t is 0, 1 or 2, provided that t = O when V is hydrogen;

W0 96t09836 ~ 6 PCT/US95/12319 or the ph~ ceutically acceptable salts thereof.

In a fourth embodiment of this invention the prodrugs of 5 compounds of formula III are illustrated by the formula IV:

(I 8)t J~ ~" Z

V - (CR 2)n - W - (CR1b2)p(CR1bR9) N X'Y~ H O

IV

wherein:
R l a is selected from:
a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, (R10)2N-C(NR10)-, R1OC(O)-, or R1OOC(O)-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R1OO-, Rl lS(o)m, RlOC(o)NRlo-~ CN, (R10)2N-C(NR10)-, R 1 C(O)-, R 1 OC(O)-, N3, -N(R 1 )2, or R 1 1 OC(O)NR 10 ;

R1b is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, (R10)2N-C(NR10)-, R1OC(O)-, or R1OOC(O)-, and c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, RlOO-, R1 1S(O)m-, R1OC(O)NR10-, CN, (RlO)2N C(NR10), R1OC(O)-, RlOOC(O)-~ N3, -N(R 1)2, or R 1 1 OC(O)NR10-;

W096/09836 ~a~ll34~i PCT/US95/12319 provided that Rlb is not RlOC(O)NR10- when Rla is aLkenyl, V is hydrogen and X-Y is -C(o)NR7a-;

R2a and R2b 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-c2o alkyl, C2-C20 alkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, R10O-, Rl 1S(O)m-, R10C(O)NRl0-~ CN, (R10)2N C(NR10), Rloc(o)-~ R10oc(o)-~ N3, -N(R 1 0)2, R 1 1 OC(O)NR 1 0- 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 R2a and R2b are combined to form - (CH2)s -;

R3 and R4 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 -C20 alkyl, C2-C20 alkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, 3 wherein the substituent is selected from F, Cl, Br, NO2, R10O-, Rl lS(O)m-, R10C(O)NR10-~ CN, (R 1 0)2N-C(NR 10) , R 1 C(O)-, R 1 OC(O)-, N3, -N(R1)2, R11OC(O)NR10 and Cl-C20 alkyl, and ~ W096/09836 ~2 ~ ~ ~ 4 ~ PCT/US95/12319 d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl;or R3 and R4 are combined to form - (CH2)s -;

X-Y is R7a a) ~S5s NSsS

R7b b) \sSs~N~ss c) ~, (I )m d) ~Sss~S~ss e) ~sss~ , or H
f) -C H2-C H2-R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloaLkyl, and W096/09836 ~ 4 6 PCT/US95/12319 e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;

R7b iS selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, o e) C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl-C6 aLkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO, RllS(o)m R 10C(O)NR 10, CN, NO2, R 102N-C(NR10)-, R1OC(O)-, R1OOC(O)-, N3, -N(R10)2, or R1 lOC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R100-, Rl lS(O)m-, RlOC(O)NH-, CN, H2N-~ W091~ 1i`36 ~111346 PC~US95/1~319 C(NH)-, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or Rl lOC(O)NH-;
~, R9 is selected from:
hydrogen, C1 -C6 alkyl, R100-, R1 1S(O)m-, R1OC(O)NR10-, CN, N02, N3, -N(R10)2, and Rl lOC(O)NR10;
provided that R9 is not R1OC(O)NR10- when R1a is alkenyl, V
is hydrogen and X-Y is -C(o)NR7a-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;

5 Rl 1 is independently selected from C1-C6 alkyl and aryl;

R12 is hydrogen or C1-C6 alkyl;

V is selected from:
a) aryl;
b) heterocycle; or c) hydrogen;

W is -S(O)m-, -O-, -NHC(O)-, -C(O)NH-, -NHso2 -S02NH-, -N(R7a)- or-N~C(O)R7a]-;

Z is independently H2 or 0;

m is 0, 1 or2;
3 n is 0, 1, 2, 3 or 4, provided that n ~ O when V is hydrogen and W is -S(O)m-;
p is 0, 1, 2, 3 or 4, provided that p ~ O when R9 is not hydrogen or Cl-C6 lower alkyl;
qisO, 1 or2;

~ n ~ 3 ~ 6 r is O or 1 ;
s is 4 or 5, and t is 0, 1 or 2, provided that t = O when V is hydrogen;

5 or the pharmaceutically acceptable salts thereof.

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

10 (R8)t z R ~R z R ~R
(CRla2) -W-(CR1b2)p(CR1 R )r NRl2 ~N~ OH

I

wherein:
R 1 a is selected from:
a) hydrogen, and b) Cl-C6 alkyl;

Rlb iS independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl or cycloalkyl, and c) Cl -C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, Rl- or-N(R10)2;

R2a is selected from:
a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, 3 leucine, isoleucine and valine;
b) substituted or unsubstituted Cl -Clo alkyl, C2-C10 alkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R100-, Rl 1S(O)m-, R1OC(O)NR10-~ CN, ~2 ~ 6 (R10)2N-C(NR10)-, R1OC(O)-, R1OOC(O)-, N3, -N(R10)2, RllOC(O)NR10- and Cl-C20 alkyl, and c) C 1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl; and R2b is selected from hydrogen and Cl-C6 aLkyl; or R2a and R2b are combined to form - (CH2)s -;

R3 and R4 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 -Clo alkyl, C2-C10 aL~enyl, C3-C1o cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, RlOO-, R1 1S(O)m-, R1OC(O)NR10-, CN, (R10)2N C(NR10), RlOc(o)-~ RlOOC(O)-, N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl, and d) Cl-C6 aLkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1o cycloalkyl;

R5a is selected from:
a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glllt~mine, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, W096109836 ~!~ fl 11 3 4 6 PCI/US95/12319 c) substituted or unsubstituted Cl-clo alkyl, C2-C10 alkenyl, C3-C1o cycloalkyl, 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)-, R1OC(O)-, R1OOC(O)-, N3, -N(R10)2, RllOC(O)NR10- and Cl-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl;

RSb is selected from:
a) hydrogen, and b) Cl-C3 alkyl, or 5 X-Y is R7a a) ~ N5ss o R7b b) \sSs~N~sss c)~ ~O~ss d) ~5sS ~55S~ , or H
e) -CH2-CH2-;

W096/09836 ~2 ~ ~ ~ 4 ~ PCT/US95/12319 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) Cl-C6 aLkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
wherein heterocycle is selected from pyrrolidinyl, o imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;

R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or 3 0 an unsubstituted or substituted group selected from aryl, - heterocyclic and cycloalkyl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-W096/09836 2~ ~ 11 3 4 6 PCI/US95/12319 oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;

R8 is independently selected from:
a) hydrogen, b) Cl-C6 alkyl, C2-C6 alkenyl, C2-c6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R1OO-, R1OC(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or R l lOC(O)NR1 0-, and o c) Cl-C6 alkyl substituted by Cl-C6 perfluoroaLkyl, R100-, RlOC(O)NR10-~ (R10)2N-c(NRlo)-~ RlOC(O)-, R1OOC(O)-, -N(R10)2, or Rl lOC(O)NR10-;

R9 is selected from:
hydrogen, Cl-C6 lower alkyl, R100-, and -N(R10)2;

R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl;
K11 is independently selected from C1-C6 alkyl and aryl;

R12 iS hydrogen or Cl-C6 aLkyl;

25 V is selected from:
a) aryl;
b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; and c) hydrogen;

W is -S(O)m-, -O-, -NHC(O)-, -C(O)NH-, -NHS02-, -S02NH-, -N(R7a)- or-N~C(O)R7a]-;

WO 9G~r~3~ ~ 2 ~ ~ 3 4 ~ P~ 5S/12319 Z is independently H2 or 0;

misO, 1 or2;
n is 0, 1, 2, 3 or 4, provided that n ~ O when V is hydrogen and W is -S(O)m-;
p is 0, 1, 2, 3 or 4, provided that p ~ O when R9 is not hydrogen or C1-C6 lower aL~yl;
r is O or l ;
sis40r5;and 10 t is O or 1, provided that t = O when V is hydrogen;
or the pharmaceutically acceptable salts thereof.

In a second more preferred embodiment of the invention, 15 the prodrugs of the Ras farnesyl transferase inhibitors of the formula I
are illustrated by the formula I:I:

(R8)t z R2a R2b z R5a R5b (CR1a2) -W-(CR1b2)p(CR1bR ), R12 ~H

Il R3 R
wherein:
Rla is selected from:
a) hydrogen, and b) Cl-C6 alkyl;

Rlb is independently selected from:
a) hydrogen, 3 b) unsubstituted or substituted aryl or cycloalkyl, and c) Cl -C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, R100- or -N(R10)2;

wog~Y~ 3 4 6 PCT/US95/12319 ~

R2a is selected from:
a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine;
b) substituted or unsubstituted Cl-clo alkyl, C2-C10 alkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, R1OO-, Rl 1S(O)m-, R1OC(O)NR10-, CN, (R10)2N C(NR10), R1OC(O)-, R1OOC(O)-~ N3, o -N(R10)2, Rl lOC(O)N~10- and Cl-C20 alkyl, and c) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1o cycloalkyl; and 15 R2b is selected from hydrogen and C1-C6 alkyl; or R2a and R2b are combined to form - (CH2)s -;

R3 and R4 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-C10 alkenyl, C3-C1o cycloalkyl, aryl or heterocycle group, wherein the sub.stituent is selected from F, Cl, Br, NO2 RlOO, Rl lS(o)m, R10c(o)NRlo-~ CN, (R10)2N C(NR10), R10c(o)-~ R1OOC(O)-, N3, -N(R10)2, R1 lOC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloaLkyl;

WO 96/09836 ~ 2 ~ ~ 3 ~ ~ PCTIUS95/12319 R5a is selected from:
a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and gl~ le~
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-Clo alkyl, C2-C10 alkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2 R10O-, R1 1S(O)m, R10C(O)NR10-~ CN, (R10)2N C(NR10), R10C(O)-, R10OC(O)-~ N3, -N(R10)2, R1 1OC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1o cycloalkyl;

R5b is selected from:
a) hydrogen, and b) C1 -C3 alkyl; or R6 is a) substituted of unsubstituted Cl-c8 alkyl, wherein the substituent on the alkyl is selected from:
l)aryl, 2) heterocycle, 3) -N(R1 1)2, 4) -OR 10, or b) ~a ~ 7 3 4 6 X-Y is R7a a) ~sss~N~g R7b b) \SsS~ N~SsS

c) ~ O~s~

d) ~~
H

e) -CH2-CH2-;

R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsub,stituted or substituted cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;

R7b is selected from a) hydrogen, -W096/09836 ~ ~ 9 ~ ~ 6 PCT/US95/12319 b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloaLkyl, f~ a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C 1 -C6 alkyl substituted with hydrogen or o an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;

R8 is independently selected from:
a) hydrogen, b) Cl-C6 alkyl, C2-c6 alkenyl, C2-c6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R100-, RlOC(O)NR10-, CN, N02, (RlO)2N C(NR10), RlOC(O)-~ RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10-, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R100-, RlOC(O)NR10-~ (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or R1 1OC(O)NR10-;

R9 is selected from:
hydrogen, C1-C6 lower alkyl, R100-, and -N(R10)2;

W 0 96/09836 22 Q ~ 3 ~ 6 PC~r~US95/12319 R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;

5 R11 is independently selected from Cl-C6 alkyl and aryl;

R12 is independently selected from hydrogen and Cl-C6 alkyl;

R 1 3 is C l -C6 alkyl;

V is selected from:
a) aryl;
b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; and c) hydrogen;

W is -S(O)m-, -O-, -NHC(O)-, -C(O)NH-, -NHSO2-, -S0~2NH-, -N(R7a)- or-N[C(O)R7a]-;
Z is independently H2 or O;

misO, 1 or2;
n is 0, 1, 2, 3 or 4, provided that n ~ 0 when V is hydrogen and W is -S(O)m-;
p is 0, 1, 2, 3 or 4, provided that p ~ 0 when R9 is not hydrogen or C 1 -C6 lower alkyl;
r is 0 or 1 ;
s is 4 or 5; and 3 t is 0 or 1, provided that t = 0 when V is hydrogen;
or the pharmaceutically acceptable salts thereof.

~ Q q 3~6 WO 96/09836 L_ PCTlUS9~i/12319 In a third more preferred embodiment of the invention, the Ras farnesyl transferase inhibitors are illustrated by the formula III:
HOCH2(CH2)q V - (CR1 a2)n - W - (CR1 b2)p(CR1 bR9),/l~N~X' ~ NH

wherein:
Rla is selected from:
a) hydrogen, and b) C1-C6 alkyl;

R1b are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl or cycloalkyl, and c) C 1 -C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, RlOO- or -N(R10)2;

R2a is selected from:
a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine;
b) substituted or unsubstituted Cl-clo alkyl, C2-C10 alkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, RlOO-, R1 1S(O)m-, Rloc(o)NRlo- CN
(R10)2N-C(NR10)-, R1OC(O)-, R1OOC(O)-, N3, -N(RlO)æ Rl 1OC(O)NR10- and Cl-C20 alkyl, and WO 96109836 2 2 a ~ ~ 4 6 PCT/US95/12319 c) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1o cycloalkyl; and 5 R2b is selected from hydrogen and C1-C6 alkyl; or R2a and R2b are combined to form - (CH2)s -;

R3 and R4 are independently selected from:
o 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-C1o cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R1OO-, Rl 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 d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1o cycloalkyl;

WO 96/09836 2 ~ PCT/US95/12319 X-Y is - R7a a) ~ Nsss R7b b) \sSS~ N~ss c) ~ O~

d H

e) -CH2-CH2-;

R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;

R7b is selected from a) hydrogen, 22 0 ~ 3 4 6 ~

b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) Cl -C6 aLkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloaL~yl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl -C6 alkyl substituted with hydrogen or an-u-nsubstituted or substituted group selected from aryl, heterocyclic and cycloaLkyl, wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;

R~ is independently ~selected from:
a) hydrogen, b) Cl-C6 alkyl, C2-c6 alkenyl, C2-c6 alkynyl, Cl-C6 2 5 perfluoroalkyl, F, Cl, R l Oo , R l OC(O)NR 1 0-, CN, NO2, (R 1 0)2N-C(NR 10) , R 1 C(O)-, R 1 OC(O)-, -N(R 1 )2, or Rl lOC(O)NR10-, and c) Cl-C6 alkyl ,substituted by Cl-C6 perfluoroalkyl, R l Oo , R 1 OC(O)NR 10, (R 1 0)2N-C(NR 1 0), R 1 C(O)-, 3 o R 10oC(O~-, -N(R 1)2, or R 1 lOC(O)NR10-;

R9 is selected from:
hydrogen, Cl -C6 lower alkyl, RlOO-, and -N(R10)2;

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

5 R l 1 is independently selected from C1 -C6 alkyl and aryl;

R l 2 is hydrogen or Cl -C6 alkyl;

V is selected from:
o a) aryl;
b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; and c) hydrogen;
W is -S(O)m-, -O-, -NHC(O)-, -C(O)NH-, -NHS02-, -S02NH-, -N(R7a)- or-N[C(O)R7a]-;

Z is independently H2 or 0;
misO, 1 or2;
n is 0, 1, 2, 3 or 4, provided that n ~ O when V is hydrogen and W is -S(O)m-;
p is 0, 1, 2, 3 or 4, provided that p ~ O when R9 is not hydrogen or Cl -C6 lower aL~yl;
qisO, 1 or2;
r is O or 1 ;
s is 4 or S; and t is O or 1, provided that t = O when V is hydrogen;
- or the pharmaceutically acceptable salts thereof.

W096t09836 ~!~ Q ~ 3 ~ 6 PCT/US95/12319 In a fourth more preferred embodiment of the invention, the prodrugs of the Ras farnesyl transferase inhibitors of the formula m are illustrated by the formula IV:

(R8)t z R~R2~ z I q V - (CR 2)n - W- (CRlb2)p(CR1bR9) N X ~N O
R~ R4 IV
wherein:
Rla is selected from:
a) hydrogen, and b) C1-C6 alkyl;

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

R2a is selected from:
a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine;
b) substituted or unsubstituted Cl-clo alkyl, C2-C10 alkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, RlOO-, Rl lS(O)m-, RlOC(O)NR10-, CN, (R10)2N C(NR10), RlOc(o)-~ RlOOC(O)-, N3, -N(R10)2, Rl lOC(O)NR10- ~nd Cl-C20 alkyl, and WO 96/09836 ~ 3 ~ PCT/US95112319 c) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycioaLkyi; and 5 R2b is selected from hydrogen and Cl-C6 alkyl; or R2a and R2b are combined to form - (CH2)s -;

R3 and R4 are independently selected from:
o 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-Clo alkyl, C2-C10 alkenyl, C3-C1o cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R1OO-, Rl 1S(O)m-, RlOC(O)NR10-, CN, (R10)2N C(NR10), RlOC(O)-~ R1OOC(O)-, N3, -N(R10)2, Rl 1OC(O)NR10- and C1-C20 alkyl, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1o cycloalkyl;

W096/09836 ~aQ~'3~6 PCI~/US95112319 1-X-Y is R7a a) ~Sssb,N~s5s R7b b) \sSS~ N~SsS

c) ~ O~

lS d) 55S~Sss~ ~ or e) -CH2-CH2-;

R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and 2s e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, R7b is selected from a) hydrogen, W0 96,0g836 ~ 6 PCI/US95/12319 b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloaL~yl, e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;

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), RlOC(O)-~ RlOOC(O)-, -N(RlO)2 or R 1 1 OC(O)NR 10, and c) Cl-C6 alkyl substituted by Cl-C6 per~uoroalkyl, R10O-, RlOC(O)NR10-~ (R10)2N-C(NR10)-, RlOC(O)-, R10OC(O)-, -N(R10)2, or R1 1OC(O)NR10-;

R9 is selected from:
hydrogen, Cl -C6 lower alkyl, R100-, and -N(R10)2;

22~346 ` ~

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

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

R12 is hydrogen or Cl-C6 aL~yl;

V is selected from:
o a) aryl;
b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; and c) hydrogen;

W is -S(O)m-, -O-, -NHC(O)-, -C(O)NH-, -NHS02-, -S02NH-, -N(R7a)- or-N~C(O)R7a]-;

Z is independently H2 or 0;
m is 0, 1 or2;
n is 0, 1, 2, 3 or 4, provided that n ~ O when V is hydrogen and W is -S(O)m-;
p is 0, 1, 2, 3 or 4, provided that p ~ O when R9 is not hydrogen or C1-C6 lower alkyl;
qisO, 1 or2;
risOor 1;
s is 4 or 5; and t is O or 1, provided that t= O when V is hydrogen;
or the pharmaceutically acceptable salts thereof.

The preferred compounds of this invention are as follows:

WO ~ 36 PCTIUS95/12319 N- { 2(S)-[(4-Nitrobenzylthio)acetamido] -3 (S)-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine methyl ester s N- { 2(S)-[(4-Nitrobenzylthio)acetamido]-3(S)-methylpentyl } -N-(1-naphthylmethyl) -glycyl-methionine N- { 2(S)-[(Benzylthio)acetamido] -3(S)-methylpentyl } -N-(1-naphthylmethyl) -glycyl-methionine N-{2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(Phenylthio)acetamido]-3(S)-methylpentyl } -N-(1-s naphthylmethyl)-glycyl-methionine N- { 2(S)-[(Phenylthio)acetamido]-3(S)-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine methyl ester 20 N- { 2(S)-[(3-Nitrobenzylthio)acetamido]-3(S)-methylpentyl } -N-(1-naphthylmethyl) -glycyl-methionine N- { 2(S)-[(3-Nitrobenzylthio)acetamido]-3(S)-methylpentyl } -N-(1-naphthyimethyl)-glycyI-methionlne methyl ester N- { 2(S)-[(2-Nitrobenzylthio)acetamido]-3(S)-methylpentyl ) -N-(1-naphthylmethyl)-glycyl-methionine N- { 2(S)-[(2-Nitrobenzylthio)acetamido] -3 (S)-methylpentyl } -N-(1-30 naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(4-Cyanobenzylthio)acetamido]-3 (S)-methylpentyl } -N-( 1-naphthylmethyl) -glycyl-methionine ~a~346 ~, N- ~ 2(S)-[(4-Cyanobenzylthio)acetamido]-3(S)-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(4-Trifluoromethylbenzylthio)acetamido]-3(S)-methyl-5 pentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[(4-Trifluoromethylbenzylthio)acetamido]-3(S)-methyl-pentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester o N- { 2(S)-[(4-Methoxybenzylthio)acetamido]-3(S)-methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[(4-Methoxybenzylthio)acetamido]-3(S)-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(4-Methylsulfonylbenzylthio)acetamido]-3(S)-methyl-pentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[(4-Methylsulfonylbenzylthio)acetamido]-3(S)-methyl-20 pentyl)-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(4-Phenylbenzylthio)acetamido] -3(S)-methylpentyl } -N-( 1-naphthylmethyl) -glycyl-methionine 25 N- ~ 2(S)-[(4-Phenylbenzylthio)acetamido]-3(S)-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(4-(1 -H-Tetrazol-5-yl)benzylthio)acetamido]-3(S)-methyl-pentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[(4-( 1 -H-Tetrazol-5-yl)benzylthio)acetamido]-3(S)-methyl-pentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(4-Methylbenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N- { 2(S)-[(4-Methylbenzylthio)acetamido] -3(S)-methylpentyl } -N-( 1-5 naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(8-Chloronaphth-1 -ylthio)acetamido]-3(S)-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine o N-{2(S)-[(8-Chloronaphth-l-ylthio)acetamido]-3(S)-methylpentyl}-N-(l-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[((2-Methylindol-3-yl)thio)acetamido]-4-methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[((2-Methylindol-3-yl)thio)acetamido]-4-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(4-Pyridylthio)acetamido]-3(S)-methylpentyl } -N-(1-2 0 naphthylmethyl)-glycyl-methionine N- { 2(S)-[(4-Pyridylthio)acetamido]-3(S)-methylpentyl } -N-(l -naphthylmethyl)-glycyl-methlonine methyl ester 2 S N- { 2(S)-[(4-Picolinylthio)acetamido] -3 (S)-methylpentyl } -N-( 1-naphthylmethyl)-glycyl-methionine N- { 2(S)-[(4-Picolinylthio)acetamido] -3 (S)-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[3 -(Benzylthio)propionamido] -3 (S)-methylpentyl } -N-( 1 -naphthylmethyl) -glycyl-methionine WO 96/09836 2 2 Q lT 3 4 6 PCT/US95/12319 N- { 2(S)-[(Benzyloxy)acetamido]-3(S)-methylpentyl } -N-(1-naphthylmethyl) -glycyl-methionine N- { 2(S)-[(Benzyloxy)acetamido] -3(S)-methylpentyl } -N-(1-5 naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(N'-Benzylglycyl)amino]-3(S)-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine 10 N- { 2(S)-[(N'-Benzylglycyl)amino]-3(S)-methylpentyl } -N-( 1-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(N'-Acetyl-N~-benzylglycyl)amino]-3(S)-methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[(N'-Acetyl-N'-benzylglycyl)amino]-3(S)-methylpentyl } -N-(l-naphthylmethyl)-glycyl-methionine methyl ester N- ~ 2(S)-r(N'-Benzyl-N'-t-butoxycarbonylglycyl)amino]-3(S)-2 o methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[(N'-Benzyl-N'-t-butoxycarbonylglycyl)arnino]-3(S)-methyl-pentyl}-N-(I-naphthylmethyl)-glycyl-methionine methyl ester 25 N- { 2(S)-[(Benzylthio-S-oxide)acetamido]-3(S)-methylpentyl } -N-(I -naphthylrnethyl) -glycyl-methionine N- { 2(S)-[(Benzylthio-S-oxide)acetamido] -3(S)-methylpentyl } -N-(I -naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(Benzylthio-S,S-dioxide)acetamido]-3(S)-methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[(Benzylthio-S,S-dioxide)acetamido]-3(S)-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl } -N-(1-5 naphthylmethyl)-glycyl-methionine sulfone N- { 2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine sulfone methyl ester 0 N- { 2(S)-[(N'-4-Nitrobenzoylglycyl)amino]-3(S)-methylpentyl } -N-(1-naphthylmethyl) -glycyl-methionine N-{2(S)-[(N'-4-Nitrobenzoylglycyl)amino]-3(S)-methylpentyl}-N-(1 -naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(N'-Methyl-N'-4-nitrobenzoylglycyl)amino]-4-methyl-pentyl } -N-(1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[(N'-Methyl-N'-4-nitrobenzoylglycyl)amino]-4-methyl-2 o pentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine methyl ester N- ~ 2(S)-[(S-Benzyl-L-cysteinyl]-3(S)-methylpentyl } -N-(1-naphthylmethyl) -glycyl -methionine 2s N- { 2(S)-[S-Benzyl-L-cysteinyl]-3(S)-methylpentyl }-N-(1 -naphthyl-methyl)-glycyl-methionine methyl ester N- { 2(S)-[S-Benzyl-D-cysteinyl]-3(S)-methylpentyl } -N-(1 -naphthyl-methyl)-glycyl-methionine - N- { 2(S)-[S-Benzyl-D-cysteinyl]-3 (S)-methylpentyl } -N-( 1 -naphthyl-methyl)-glycyl-methionine methyl ester 3 -Benzylthiopropionyl-valyl-isoleucyl-methionine W 0 96/09836 22 0 1 3 4 ~ PC~rnUS95/12319 N-[2(S)-(2(S),3-Diaminopropionyl)amino-3(S)-methylpentyl] -N-(1 -naphthylmethyl)glycyl-methionine N-[2(S)-(2(S),3-Diaminopropionyl)amino-3(S)-methylpentyl]-N-(l -5 naphthylmethyl)glycyl-methionine methyl ester N-[2(S)-(3-Aminopropionyl)amino-3(S)-methylpentyl]-N-(1 -naphthylmethyl)glycyl-methionine o N-[2(S)-(3-Aminopropionyl)amino-3 (S)-methylpentyl] -N-( 1 -naphthylmethyl)glycyl-methionine methyl ester N-(2(S)-L-Glllt~minylamino-3(S)-methylpentyl)-N-(l -naphthyl-methyl)glycyl-methionine N-(2(S)-L-Glutaminylamino-3(S)-methylpentyl)-N-( 1 -naphthyl-methyl)glycyl-methionine methyl ester N-[2(S)-( 1,1 -Dimethylethoxycarbonylamino)-3S)-methylpentyl] -N-2 o ( 1 -naphthylmethyl)glycyl-methionine N-~2(S)-( 1,1 -Dimethylethoxycarbonylamino)-3S)-methylpentyl]-N-(l-naphthylmethyl)glycyl-methionine methylester 25 N-[2(S)-(l,l-Dimethylethoxycarbonylamino)-3(S)-methylpentyl]-N-benzylglycyl-methionine N-[2(S)-( 1,1 -Dimethylethoxycarbonylamino)-3(S)-methylpentyl] -N-benzylglycyl-methionine methyl ester N- ~ [ 1 -(4-Nitrobenzylthio)acetylamino]cyclopent-l -ylmethyl } -N-(l -naphthylmethyl)-glycyl-methionine N- { [ 1 -(4-Nitrobenzylthio)acetylamino]cyclopent- 1 -ylmethyl } -N-( 1-naphthylmethyl)-glycyl-methionine methyl ester W096/09836 ~ n ~ PCT/US95/12319`

N- { 2(S)-[2-(4-Nitrophenyl)ethylcarbamoylamino] -4-methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine 5 N- { 2(S)-[2-(4-Nitrophenyl)ethylcarbamoylamino]-4-methylpentyl } -N-(l-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(3(S)-tetrahydrofuryloxy)carbonylamino]-3(S)-methylpentyl } -N-(l -naphthylmethyl)-glycyl-methionine N- { 2(S)-[(3(S)-tetrahydrofuryloxy)carbonylamino]-3(S)-methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(cis-4-benzyloxytetrahydrofur-3-yloxy)carbonylamino] -3(S)-methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[(cis-4-benzyloxytetrahydrofur-3-yloxy)carbonylamino]-3 (S)-methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(N'-Methyl-N'-4-nitrophenylacetylglycyl)amino]-4-methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[(N'-Methyl-N'-4-nitrophenylacetylglycyl)amino]-4-2 5 methylpentyl } -N-~ 1 -naphthylmethyl)-glycyl-methionine methyl ester or the pharmaceutically acceptable salts thereof.

The most preferred compounds of the invention are:
N- { 2(S)-[(4-Methoxybenzylthio)acetamido]-3(~)-methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine W096/09836 2~ 4 Ç PCI/US95/12319 o ~ ~ N N~ NJ~oH

H3C~ o~ O /\ ~ SCH3 N- ~ 2(S)-[(4-Methoxybenzylthio)acetamido]-3(S)-methylpentyl } -N-o (1-naphthylmethyl)-glycyl-methionine methyl ester H H
~N--N~NJ~oCH3 H3C oJ\~ /`1 ~3 SCH3 N-{2(S)-[(4-Cyanobenzylthio)acetamido]-3(S)-methylpentyl~-N-(1-naphthylmethyl) -glycyl-methionine ~S~N N~ NJI~OH

- ~3 SCH3 N- { 2(S)-[(4-Cyanobenzylthio)acetamido] -3 (S)-methylpentyl ~ -N-( 1 -naphthylmethyl)-glycyl-methionine methyl ester H H
~S~N N~NJ~OCH3 ~ /`1 ~3 SCH3 ~2 013 4 6 N-(2(S)-L-Glllt~minylamino-3(S)-methylpentyl)-N-(1 -naphthyl-methyl)glycyl-methionine H2N~, H H
H2N~N N~N~oH

'`I ~3 SCH3 N-(2(S)-L-Glutaminylamino-3(S)-methylpentyl)-N-(1 -naphthyl-methyl)glycyl-methionine methyl ester H H
H2N ~ N N~ NJ~ OCH3 O /~ ~3 SCH3 N- { 2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl } -N-(1-25 naphthylmethyl)-glycyl-methionine sulfone H H
~S~ N~, ~

N- { 2(S)-~(Benzylthio)acetamido]-3(S)-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine sulfone methyl ester 2ao~i346 3--s~ --N~

or the pharmaceutically acceptable salts thereof.

~2 0 ~ 3 4 6 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
Asparticacid Asp D
Asparagine or Aspartic acid Asx B
Cysteine Cys C
Glllt~mine Gln Q
Glutamic acid Glu E
Glutamine or Glutamic acid Glx Z
Glycine Gly G
Histidine His H
Isoleucine Ile Leucine Leu L
Lysine Lys K
Methionine Met M
Phenyl~l~nine Phe F
Proline Pro P
Serine Ser S
Threonine Thr T
Tryptophan Trp W
Tyrosine Tyr Y
Valine Val V
s The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.

W0 96/09836 2 ~ 6 PCT/US95112319 As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
As used herein, "cycloaL~yl" is intended to include non-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 o bonds. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, l-propenyl, 2-butenyl, 2-methyl-2-butenyl, farnesyl, geranyl, geranylgeranyl and the like.
As used herein, "aryl" is intended to include any stable 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, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like.
When R2a and R2b and R3 and R4 are combined to form - (cH2)s -, cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to:

When R5a and R5b are combined to form - (CH2)s -, cyclic moieties as described hereinabove for R2a and R'~b and R3 and t 30 R4 are formed. ln addition, such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-cont~ining cyclic moieties include, but are not limited to:

- = ~

W096/09836 ~ ~) 'I 3 4 6 PCTtUS95/12319 oJ ~5J

o O O H O N

The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-5 membered bicyclic or stable 11-15 membered tricyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a 20 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 limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, 25 benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydro-benzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, 3~ 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, W096/09836 Zan134~ PCT/US95tl2319 tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.
As used herein, the terms "substituted aryl", "substituted 5 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, NH2, N(C1-C6 alkyl)2, NO2, CF3, (cl-c6 alkyl)O-, -OH, (C1-C6 alkyl)S(O)m-, (Cl-C6 alkyl)C(O)NH-, CN, H2N-C(NH)-, (Cl-C6 alkyl)C(O)-, (Cl-C6 alkyl)OC(O)-, N3~(Cl-C6 alkyl)OC(O)NH- and Cl-C20 aL~cyl.
The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic 15 or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, 20 pamoic, maleic, hydroxymaleic, phenyl-acetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
It is intended that the definition of any substituent or 25 variable (e.g., Rl, Z, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, -N(R 1 )2 represents -NHH, -NHCH3, -NHc2H5~ etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to 30 provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth below.
The pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this W0961~9836 ~2 0 1 3 ~S 6 PCI/US95/12319 invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared 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 5 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 10 following works: Schroeder et al., "The Peptides", Vol. I, Academic Press 1965, or Bod~n.s7.ky et al., "Peptide Synthesis", Interscience Publishers, 1966, or McOmie (ed.) "P7 0tective Groups in Organic Che,~,lis.t7y", Plenurrl Press, 1973, or B~ally et al., "The Pepiides:
Analysis, Synthesis, Biology" 2, Chapter 1, Academic Press, 1980, or Stewart et al., "Solid Phase Peptide Synthesis", Second Edition, Pierce Chemical Company, 1984. The teachings of these works are hereby incorporated by reference.
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 Dimethylformamide;
EDC 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide-hydrochloride;
HOBT l-Hydroxybenzotriazole hydrate;
3 o Et3N Triethylamine;
EtOAc Ethyl acetate;
FAB Fa.st atom bombardment;
HOOBT 3-Hydroxy- 1 ,2,2-benzotriazin-4(3H)-one;
HPLC High-performance liquid chromatography;

W096/09836 ~ ; 4 ~ ~Cr/US95/12319 MCPBA m-Chloroperoxybenzoic acid;
MsCl Methanesulfonyl chloride;
NaHMDS Sodium bis(trimethylsilyl)amide;
Py Pyridine;
TFA Trifluoroaceticacid;
THF Tetrahydrofuran.

Compounds of this invention are prepared by employing the reactions shown in the following Reaction Schemes A-J, in o addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Some key bond-forming and peptide modifying reactions are:
Reaction A. Amide bond formation and protecting group cleavage using standard solution or solid phase methodologies.
Reaction B. Preparation of a reduced peptide subunit by reductive alkylation of an amine by an aldehyde using sodium cyanoborohydride or other reducing agents.
Reaction C. Alkylation of a reduced peptide subunit with an alkyl or aralkyl halide or, alternatively, reductive alkylation of a reduced peptide subunit with an aldehyde using sodium cyanoborohydride or other reducing agents.
Reaction D. Peptide bond formation and protecting group cleavage using standard solution or solid phase methodologies.
Reaction E. Preparation of a reduced subunit by borane reduction of the amide moiety.
These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Reaction Schemes.

W096/09836 ~2 ~ 1 3 4 6 PCT/US95/12319 REACTION SCHEME A

Reac~ion A. Coupiing of residues to form an amide bond A RB
OH + H2N '~f o or HOOBT >loJ~ N J~OR

Et3N, DMFr RB

TFA H N$NJ~oR
O RB

REACTION SCHEME B

Reaction B. Preparation of reduced peptide subunits by reductive alkylation >~OJ~ N ~H + ~OR

R

22 0 ~ ~ 4 ~ ~

REACTION SCHEME C

Reaction C. Alkylation/reductive alkylation of reduced peptide subunit~

~O~N~NJ~oR R XL, base RB 1l RCCH, NaCNBH3 RA R7b H OR
RB

W096t09836 2~ 0 ~ 3 4 6 PCT/US95/12319 REACTION SCHEME D

Reaction D. Coupling of residues to form an amide bond RA EDC, HOBT
O I ~ or HOOBT

>~oJ~N~oH + H2N~ Et3N, DMF

>~ J~ 7 NJ~HCl or TFA

~A

H2N ~ J~o O -~,J

REACTION SCHEME E

Reaction E. Preparation of reduced dipeptides from peptides 2s >`O H~ J~OR

>loJ~N~NJl~oR
H RB

W 0 96/09836 2~ ~ 7 3 4 6 PC~r~US95/12319 where RA and RB are R2a, R2b, R3, R4, R5a or R5b as previously defined; XL is a leaving group, e.g., Br-, I- or MsO-; and RC is defined such that R7b is generated by the reductive alkylation process.
Certain compounds of this invention wherein X-Y is an ethenylene or ethylene unit are prepared by employing the reaction sequences shown in Reaction Schemes F and G. Reaction Scheme F
outlines the preparation of the alkene isosteres lltili7ing standard manipulations such as Weinreb amide formation, Grignard reaction, acetylation, ozonolysis, Wittig reaction, ester hydrolysis, peptide o coupling reaction, mesylation, cleavage of peptide protecting groups, reductive alkylation, etc., as may be known in the literature or exemplified in the Experimental Procedure. The key reactions are:
stereoselective reduction of the Boc-amino-enone to the corresponding syn amino-alcohol (Scheme F, Step B, Part 1), and stereospecific boron triflouride or zinc chloride activated organo-magnesio, organo-lithio, or organo-zinc copper(l) cyanide SN2' displacement reaction (Scheme F, Step G). Through the use of optically pure N-Boc amino acids as starting material and these two key reactions, the stereo-chemistry of the final products is well 20 defined. In Step H of Scheme F, Rx, which represents the amino terminus side chain substituent of the instant invention, is incorporated using coupling reaction A and RXCOOH; the alkylation reaction C using RXCHO and a reducing agent; or alkylation reaction C using RxcH2xL.
2s The alkane analogs are prepared in a similar manner by including an additional catalytic hydrogenation step a,s outlined in Reaction Scheme G.

2~ 4 6 pCTrus95/12319 REACTION SCHEME F
- 1. ClCO2i-Bu o BocNHJJ`OH MeONHMe BocNH
R2a2. I R2a BrMg Step A

1. NaBH4 OAc ~ BocN H ~J~
2. Ac20, Py R2a Step B

1. O3, Me2S OAc 2. Ph3P=CHCO2Me BocNH ~CO2Me Step C R2a W096/098362~7 ~ 7 3 4 6 PCT/US95/12319 ~

REACTION SCHEME F (CONT'D) Step D
1. LiOH OH H MsCI, py 2 EPDC, HOBT BocNH~ JlW~ Step F

amino acid (ester) W"
W'=OMe,W"=SMe W' -W"=O
OMs O
BocNH~ R3MgCuCNClBF3 R2a O ~ Step G
W"
1. HCI
R3 o 2. NaCNBH3 H ll RXCHO
BocNH ~ N ~~W' R2a O ~ Step H
W"

R CH2N ~ ~ J~W' R2a O W"

wherein Rx is:

R8 V - (CR12)n ~ W ~ (CR12)p(CRlR9)r-W096/09836 2~n~4~ PCT/US95112319 REACTION SCHEME F (CONT'D) NaOH

RXC H2N ~~ ~OH
2 ~W"

or 1. HCI Alternate 1l Step H
2. RxcOH
EDC, HOBT

~f ~NJ~W~
O R2a o W"
NaOH

2 5 RX N ~ OH

O R2a 0 ~'\W"

W096/09836 22 ~ ~ 3 4 6 PCT/US95112319 REACTION SCHEME G
0 1. ClCO2i-Bu o BocNH J~OH . BocNH

R2aBrMg ~ R2a 1. NaBH4 OAc 1. 03, Me2S
BocNH~
2. Ac20, py R2a 2. Ph~P=CHCO2Me OAc O
BocNH~cO Me + H2N~ 2 EDC, HOBT

OH H

R2a o - ~ MsCI, py WO 96/09836 ~ PCT/US95112319 REACTION SCHEME G (CONT'D) OMs O
H ll BocNH~N
R2a O
1. R3 MgCuCNCl-BF3 2. H2, 5% Pd/C
Step K

BocNH~ ,o R2a o -~
1. HCI

2. NaCNBH3, RXCHO

RXCH2NH~ o R2a o -~

NaOH

RXCH2NH ~ OH
R2a O OH

2~ ~3~B
WO 9~ ?~ PCT/US9~/12319 REACTION SCHEME G (CONT'D) or O
Il 1. HCI 2. RXCOH
EDC, HOBT

O R''CNH~~
R2a o NaOH

RXCNH~ ~ J~ OH
R2a O OH

The oxa isostere compounds of this invention are prepared according to the route outlined in Scheme H. An 25 aminoalcohol 1 is acylated with alpha-chloroacetyl chloride in the presence of trialkylamines to yield amide 2. Subsequent reaction of 2 with a deprotonation reagent (e.g., sodium hydride or potassium t-butoxide) in an ethereal solvent such as THF provides morpholinone 3. The N-Boc derivative 4 is then obtained by the treatment of ~ with 30 BOC anhydride and DMAP (4-dimethylaminopyridine) in methylene chloride. Alkylation of 4 with R3XL, where XL is a leaving group such as Br-, I- or Cl- in THF/DME (1,2-dimethoxyethane) in the presence of a suitable base, preferably NaHMDS [sodium bis(trimethylsilyl)amide], affords 5, which is retreated with NaHMDS
followed by either protonation or the addition of an alkyl halide R4X

W096/09836 ~n~46 PCT/US9S/12319 to give 6a or 6b, respectively. Alternatively, 6a can be prepared from 4 via an aldol condensation approach. Namely, deprotonation of 4 with NaHMDS followed by the addition of a carbonyl compound RYRZCO gives the adduct 7. Dehydration of 7 can be effected by 5 mesylation and subsequent elimin~ion catalyzed by DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or the direct treatment of 7 with phosphorus oxychloride in pyridine to give olefin 8. Then, catalytic hydrogenation of ~ yields 6a. Direct hydrolysis of 6 with lithium hydrogen peroxide in aqueous THF will produce acid 9b. Sometimes, 10 it is more efficient to carry out this conversion via a 2-step sequence, namely, hydrolysis of 6 in hydrochloric acid to afford 9a, which is then derivatized with BOC-ON or BOC anhydride to give 9b. The peptide coupli~g of aGid 9b with çither an alpha-arl~inolacto~e (e.g., homoserine lactone, etc.) or the ester of an amino acid is carried out under the conditions exemplified in the previously described references to yield derivative 10. Treatment of 10 with gaseous hydrogen chloride gives 11, which undergoes reductive alkylation in the presence of an aldehyde RXCHO (12) and a reducing agent (e.g., sodium cyanoboro-hydride); or acylation in the presence of RXCOOH
20 (13) and a peptide coupling reagent affording the products 14a and _.
Hydrolysis of compounds 14 to the corresponding hydroxy acids and acids, respectively, is accomplished by standard methods such as treatment with NaOH in alcoholic or aqueous milieux followed by careful acidifcation with dilute HCl.

W096109836 ~2 0 1 3 4 ~ PCTIUS95/12319 ~CHEME H
HO) Cl~ Cl~ HO) base H2N R2a o Cl O~ N ~R2a ~N~"'R2a ~~

BOC

4 Base o~N~ R2a Base ~kN~ R2a R3X I R4X or BOC H+ BOC
Base 5 6 RYRZCO

HO~o~ -H20 ~o H2, Pd/C

O IN ~ R2a O N "' R2a BOC BOC

7 8 2~ ~ ~ 3 4 ~

SCHEME H (CONT'D) LiOOH; ,~R4 oraq. HCI, RW-NH o CO2H
then BOC20 R2a a Rw = H
b, Rw = BOC

EDC IR~R4 9 + H-A ~ BOCNH ~A
R2a o HCI R3~R4 HCI NH2 o~A
R2a o W096/09836 2~ 4 6 PCI/US95112319 SCHEME H (CONT'D) RXCHO, NaCNBH3 ~ R
12 'RXCH2NH O A

11 R2a 0 14a RXCOOH, EDC, HOBT

13 ll R3~R4 RXCNH O A
R2a o 14b A

O or NH J~OR6 ~J R5a q The thia, oxothia and dioxothia isostere compounds of this invention are prepared in accordance to the route depicted in Scheme I. Aminoalcohol 1 is derivatized with BOC2O to give 15.
Mesylation of 15 followed by reaction with methyl alpha-mercaptoacetate in the presence of cesium carbonate gives sulfide 16.
Removal of the BOC group in 16 with TFA followed by neutralization with di-isopropylethylamine leads to lactam 17. N-BOC derivative lf~
30 iS obtained via the reaction of 17 with BOC anhydride in THF
catalyzed by DMAP. Sequential alkylation of 1 g with the alkyl halides R3X and R4X in THF/DME using NaHDMS as the deprotonation reagent produces 19. Hydrolysis of 19 in hydro-chloride to yield 20a, which is derivatized with Boc anhydride to yield 20b. The coupling of 20b with an alpha-aminolactone (e.g., W096/09836 ~2 a ~ ~ 4 ~ PCTIUS95/12319 homoserine lactone, etc.) or the ester of an amino acid is carried out under conventional conditions as exemplified in the previously described references to afford 21. Sulfide 21 is readily oxidized to sulfone 22 by the use of MCPBA (m-chloroperoxybenzoic acid). The 5 N-BOC group of either 21 or 22 is readily removed by treatment with gaseous hydrogen chloride. The resultant amine hydrochloride 23 undergoes reductive alkylation in the presence of an aldehyde RXCHO
(12) and a reducing agent (e.g., sodium cyanoborohydride); or acylation in the presence of RXCOOH (13) and a peptide coupling 10 reagent to afford the products 24 and 25.

WO 96/09836 ~ PCT/US95tl2319 2U~3~ .

SCHEME I
HO HO
~ ~ 1) MsCI
H2N 'R2a BOC20 HN "' 2 2) Cs2CO3 S

CH302CHN~"'R2a 1)TFA ~ ~ BOC20 1 2)(i-Pr)2- N "'R2a BOC NEt H

)"' R2a Base r ~ 2a BOC Base BOC

~ ~ S CO2H H-A,EDC BOCNH S ~ A
25 Rw R2a HOBT R2a O

a,RW=H ~ BOC20 NH ~ or NH ~ 6 30 b,RW=BOC ~ R5a q ~ W096t09836 22 ~ ~ ~ 4 6 PCI~/US95112319 SCHEME I (CONrr'D) BOCNH s(o)?~A HCI
R2a O

m=0, 20 ) MCPBA
m=2, 22 R3 R4 R ~R

-- , 23 NaCNBH3 24 m = 0 or 2 RXCOOH
EDC, HOBT

1l R3 R4 R CNH S(O)?~A
R2a o W0 96/09836 2 ~ 6 PCT/US95/12319 The compounds of this invention inhibit Ras famesyl transferase which catalyzes the first step in the post-translational processing of Ras and the biosynthesis of functional Ras protein.
These compounds are useful as ph~rm~ceutical agents for m~mm~
5 especially for hllm~n~. These compounds may be ~lmini~tered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias.
The compounds of this invention may be ~lmini~tered to m~mm~l~, preferably hllm~n~, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a ph~ eutical composition, according to standard pharmaceutical practice. The compounds can be ~lministered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of ~lmini~tration.
For oral use of a chemotherapeutic compound according to this invention, the selected compound may be a~lministered, for 20 example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral ~clmini~tration in capsule form, useful diluents include lactose and 25 dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active 3 o ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic.

W096/09836 2~ Q ~ 3 ~ 6 PCT/US95/12319 The present invention also encompasses a ph~rm~ceuticalcomposition useful in the treatment of cancer, comprising the ~lmini~tration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers 5 or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may be introduced into a patient's intramuscular blood-stream by local bolus injection.
When a compound according to this invention is a-lmini~tered into a human 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 symptoms.
In one exemplary application, a suitable amount of compound is ~lministered to a m~mm~l undergoing treatment for cancer. A~lmini~tration occurs in an amount between about 0.1 mg/kg 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 lO mg/kg of body 20 weight per day.
The compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and quantity of farnesyl-protein transferase (FPTase) in a composition.
Thus the composition to be tested may be divided and the two 25 portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to 3 o 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 FPTase, absence or quantitative reduction of the amount of substrate in the WO ~ 836 PCT/US95/12319 assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay con~ining the instant compound is indicative of the presence of FPTase in the composition to be tested.
It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain farnesyl-protein transferase and quantit~tin~ the enzyme. Thus, potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of 10 enzyme in the sample. A series of samples composed of aliquots of a tissue extract containing an unknown amount of farnesyl-protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention. The concentration of a sufficiently potent inhibitor (i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel) required to inhibit the enzymatic activity of the sample by 50% is approximately equal to half of the concentration of the enzyme in 20 that particular sample.

EXAMPLES

Examples provided are intended to assist in a further 25 understanding of the invention. Particular materials employed, species and conditions are intended to be further illustrative of the invention and not limitative 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 30 acid, l 0% sodium bicarbonate and brine as appropriate. Solutions were dried over sodium sulfate and evaporated in vacuo on a rotary evaporator.

W0 96/09836 ~ 6 PCT/US95tl2319 Preparation of N- { 2(S)-[(4-Nitrobenzylthio)acetamido] -3-methylpentyl } -N-(l-Naphthvlmethyl)-~lycyl-methionine methyl ester Step A: Preparation of N-(2(S)-t-butoxycarbonylamino)-3-methylpentvl)~lvcine methyl ester Glycine methyl ester hydrochloride (23.1 g, 0.1 8mol) was dissolved in methanol (700 mL) and treated with N-t-butoxycarbonyl-isoleucinal (40 g, 0.18 mol) with stirring at 0C.
Sodium cyanoborohydride (17.3 g, 0.28 mol) was added, and the pH
of the mixture was adjusted to 7 with HOAc . After stirring for 3 h, aqueous saturated NaHCO3 (50 mL) was added to the mixture which was then concentrated to 250 mL. The solution was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with aqueous saturated NaHCO3 solution, brine, and dried (MgSO4).
Filtration and concentration provided the title compound after purification by chromatography (sio27 EtOAc: hexane, 1:3). 1H
NMR (CDC13); ~ 4.69 (m, lH), 3.72 (s, 3H), 3.48-3.62 (m, lH), 3.42 (ABq, 2H), 2.65 (d, 2H, J=6Hz), 1.4-1.6 (m, 2H), 1.48 (s, 9H), 1.04-1.2 (m, lH), 0.85-0.95 (m, 6H).

Step B: Preparation of N-~2(S)-t-Butoxycarbonylamino)-3-methylpentyll-N-(l-naphthylmethyl) Iycine methyl ester N-~2(S)-t-Butoxycarbonylamino)-3-methylpentyl]glycine methyl ester (2.00 g, 6.97 mmol) was dissolved in 1,2-dichloroethane (56 ml) and 3A molecular sieves were added followed by 1-naphthaldehyde (1.~9 ml, 13.9 mmol) and sodium triacetoxy-borohydride (6.65 g, 31.4 mmol). The mixture was stirred at ambient temperature for 16 h, and filtered through glass fiber paper and concentrated. The residue was partitioned between EtOAc and sat.
NaHCO3 (100 ml/25 ml). The aqueous layer was washed with EtOAc (3x50 ml). The organic layers were combined, dried with Na2SO4, filtered, and concentrated to give crude product which was purified by W0 96/09836 ~ PCT/US95/12319 chromatography (silica gel 1 :6 to 1 :3 ethyl acetate in hexane) to provide the title compound. lH NMR (CD30D); ~ 8.44-8.38 (d, lH, J=6Hz), 7.88-7.77 (m, 2H), 7.55-7.35 (m, 4H), 6.34-6.27 (m, lH), 4.25 (ABq, 2H), 3.66 (s, 3H), 3.40-3.23 (m, lH), 2.95-2.85 (dd, lH, J=6, 15Hz), 2.68-2.57 (dd, lH, J=6, 15Hz), 1.57-1.46 (m, lH), 1.43 (s, 9H), 1.34-1.18 (m, 2H), 1.06-0.85 (m, lH), 0.85-0.71 (m, 6H).

Step C: Preparation of N-[2(S)-t-Butoxycarbonylamino)-3-methylpentyll-N-( l -naphthylmethyl) lycine N-[2(S)-t-Butoxycarbonylamino)-3-methylpentyl]-N-(1-naphthylmethyl)glycine methyl ester (2.61 g, 6.10 mmol) was dissolved in MeOH (50 ml) and lN NaOH (24.4 ml, 24.4 mmol) was added. The mixture was stirred at ambient temperature for 4 h and concentrated. The resulting residue was dissolved in H2O (25 ml) and neutralized with lN HCl (24.4 ml). The aqueous layer was washed with EtOAc (3x50 ml). The organic layers were combined, dried with Na2SO4, filtered, and concentrated to provide the title compound. 1H
NMR (CD3OD)2 ~ g.4~-8.39 (d, lH, J=6Hz), 8.03-7.91 (t, 2H, J=6Hz), 7.75-7.48 (m, 4H), 5.00-4.93 (d, lH, J=12Hz), 4.78-4.66 (d, lH, J=12Hz), 3.80-3.5~ (m, 3H), 3.49-3.40 (dd, lH, J=3, 12Hz), 3.09-2.98 (dd, lH, J=3, 12Hz), 1.42 (,s, 9H), 1.37-1.28 (m, 2H), 1.80-1.00 (m, lH), 0.94-0.78 (m, 6H).

Step D: Preparation of N-[2(S)-t-Butoxycarbonylamino)-3-methylpentyl]-N-( l -naphthylmethyl)glycine-methionine methyl elster N-~2(S)-t-Butoxycarbonylamino)-3-methylpentyl]-N-(l -naphthylmethyl)glycine (2.29 g, 5.53 mmol), dissolved in DMF (20 mL), was treated with HOBT (0.822 g, 6.08 mmol), EDC (1.17 g, 6.08 mmol), and methionine methyl ester hydrochloride (1.21 g, 6.08 mmol). The pH was adjusted to 7.5 with Et3N (1.7 mL, 12 mmol) and the mix~ure was stirred at ambient temperature for 24 h. The mixture was concentrated, and the residue was partitioned between EtOAc (50 mL) and saturated NaHCO3 solution (25 mL). The W096/09836 ~ 2 n ~ PCT/US9S/12319 aqueous layer was extracted with EtOAc (lx30 mL). The organic layers were combined, washed with brine (lx25 mL), dried (Na2S04), filtered, and concentrated to give crude product which was purified by chromatography (silica gel eluting with 1 :3 to 1 :2 ethyl acetate in hexane) to provide the title compound. 1H NMR (CD30D); ~ 8.36-

8.29 (d, lH, J=6Hz), 7.93-7.86 (d, lH, J=6Hz), 7.85-7.80 (d, lH, J=6Hz), 7.61-7.39 (m, 4H), 6.60-6.52 (m, lH), 4.32-4.06 (m, 2H), 3.90-3.69 (m, lH), 3.65 (s, 3H), 3.27-3.14 (m, 2H), 2.93-2.70 (m, 2H), 2.19-1.78 (m, 6H), 1.63-1.30 (m, 13H), 1.19-1.05 (m, lH), 0.95-0.81 0 (m, 6H).

Step E: Preparation of N-~2(S)-amino-3-methylpentyl)-N-(1-naphthylmethyl)-glycyl-methionine methyl ester hydrochloride N-[2(S)-(t-Butoxycarbonylamino)-3-methylpentyl]-N-(1-naphthylmethyl)-glycyl-methionine methyl ester (2.82 g, 5.04 mmol) was dissolved in EtOAc (50 mL) and cooled to -25C. HCI was bubbled through the mixture until TLC (95:5 CH2C12:MeOH) indicated complete reaction. Nitrogen was bubbled through the 20 mixture to remove excess HCI and the mixture was then concentrated to provide the title compound. lH NMR (CD30D); ~ 8.34-8.28 (d, lH, J=6Hz), 8.00-7.92 (d, 2H, J=6Hz), 7.83-7.71 (m, lH), 7.68-7.49 (m, 3H), 4.76-4.55 (m, 4H), 3.~4-3.75 (m, 2H), 3.71 (s, 3H), 3.59-3.70 (m~ lH), 3.21-3.00 (m, 2H), 2.57-2.38 (m, 3H), 2.17-2.04 (m, 4H), 25 1.97-1.81 (m, lH), 1.63-1.50 (m, lH), 1.39-1.20 (m, lH), 1.19 1.00 (m, lH), 0.95-0.79 (m, 6H).

Step F: Preparation of (4-nitrobenzylthio)acetic acid 4-Nitrobenzyl chloride (2.5 g, 15 mmol) was added to a 30 solution of mercaptoacetic acid (80% in H2O, 1 mL, ~ 12 mmol) in aqueous sodium hydroxide (2.75 N, 10 mL) and THF (10 mL) with stirring at 50C. After 1 hour, the reaction was cooled to ambient temperature, diluted with water (30 mL) and extracted with Et2O to remove excess halide. The aqueous layer was distributed between W0 96/09836 a ~ 6 PCT/US95/12319 EtOAc and 5% citric acid and the organic extract then washed with H20, dried (MgSO4) and evaporated to give the title compolmd as a pale yellow solid, m.p. 101-104C [lit. m.p. 114C]. 1H NMR
(CDCl3); ~ 3.10 (s, 2H), 3.94 (s, 2H), 5.37 (d, 2H, J = 8.7 Hz), 8.21 5 (d, 2H, J = 8.7 Hz).

Step G: Prepara~ion of N-{2~S)-[(4-Nitrobenzyl~io)acetamido]-3(S)-methylpentyl } -N-(l -naphthylmethyl)-glycyl-methionine methyl ester (4-Nitrobenzylthio)acetic acid (68 mg, 300 !lmol), dissolved in DMF (4 rnL), was treated with HOBT (51 mg, 300 ~mol), EDC (65 mg, 300 !lmol), and N-r2(S)-amino-3-methylpentyl)-N-( l -naphthylmethyl)-glycyl-methionine methyl ester hydrochloride (133 mg, 250 !lmol). The pH was adjusted to 7.5 with Et3N (110 ,uL, 250 ~lmol) and the mixture was stirred at ambient temperature for 16 h. The mixture was concentrated and the residue was partitioned between EtOAc (100 mL) and H20 (100 mL). The organic layer was washed with H2O (2x50 mL), dried (MgSO4), filtered, and concentrated to give a crude product which was purified by chromatography (silica gel, eluting with 1 :1 to 1 :2 hexane: EtOAc) to provide the title compound. lH NMR (CDCl3); ~ 0.89 (t, 3H, J = 7.5 Hz), 0.91 (d, 3H, J = 6.9 Hz), 1.02-1.19 (m, lH), 1.37-1.6 (m, 2H), 1.67-1.79 (m, lH), 1.85-1.98 (m, lH), 1.95 (s, 3H), 2.0-2.1 (m, 3H), 2.74 (dd, lH, J = 3, 12 Hz), 2.86-3.01 (m, 3H), 3.21 (d, lH, J = 14 Hz), 3.29 (d, lH, 14 Hz), 3.69 (s, 3H), 3.74 (d, lH, J = 12 Hz), 3.8 (d, lH,J=12Hz),3.83-3.94(m,1H),4.05(d,1H,J=9Hz),4.18(d,1H, J = 9 Hz), 4.41-4.49 (m, lH), 6.7 (d, lH, J = 8 Hz), 7.39-7.53 (m, 7H), 7.~s-7.9 (m, 2H), 8.14-8.22 (m, 2H).
Anal. Calcd for C34H44N4O6S2-0.15 EtOAc C, 60.92; H, 6.68; N, 8.21 C, 60.64; H, 6.65, N, 8.23 W096/09836 2 ~ e PCT/US95/12319 1. .

N- { 2(S)-[(4-Nitrobenzylthio)acetamido]-3(S)-methylpentyl } -N-(l -naphthylmethyl)-glycvl-methionine N- { 2(S)-[(4-Nitrobenzylthio)acetamido]-3(S)-methylpentyl)-N-(1-naphthylmethyl)-glycyl-methionine methyl ester (from Example 1; 100 mg, 150 !lmol) was dissolved in MeOH (1 mL) and 1.0N NaOH (300 ~L, 300,umol) was added. The mixture was stirred at 45C under argon for 45 minutes then the solution was 0 partitioned between EtOAc (100 mL) and 5% citric acid (50 mL).
The organic layer was washed with H2O (2x50 mL), dried (MgSO4), filtered and evaporated to give the title compound. lH NMR; o 0.84 (t, 3H, J = 7.5 Hz), 0.8$8 (d, 3H, J = 7 Hz), 0.91-1.0 (m, lH), 1.0-1.2 (m, lH), 1.2-2.1 (m, 5H), 1.90 (s, 3H), 2.8-2.86 (m, 2H), 3.0-3.3 (m, 15 4H), 3.90 (s, 2H), 3.91-4.22 (m, 4H), 7.37-7.56 (m, 6H), 7.78-7.88 (m, 2H), 8.15 (d, 2H, J = 8Hz), 8.27 (d, lH, J = 8.3 Hz).
Anal. Calcd for C33H42N406S2-0.25 CHCl3-1.0 CH30H
C, 57.39; H, 6.50; N, 7.82 C, 57.71; H, 6.42; N, 7.46 The following acids were prepared according to the procedure described for Example 1, Step F or were obtained 25 commercially:

(Benzylthio)acetic acid (3-Nitrobenzylthio)acetic acid (2-Nitrobenzylthio)acetic acid (4-Cyanobenzylthio)acetic acid (4-Trifluoromethylbenzylthio)acetic acid (4-Methoxybenzylthio)acetic acid (4-Methylsulfonylbenzylthio)acetic acid (4-Phenylbenzylthio)acetic acid W096/09836 22 ~ ~ 3 ~ ~ PCTIUS95/12319 (4-Methylbenzylthio)acetic acid (8-Chloronaphth-l-ylthio)acetic acid (2-Methylindol-3-ylthio)acetic acid 3-(Benzylthio)propionic acid (4-Picolinylthio)acetic acid (4-Pyridylthio)acetic acid The following compounds were prepared using the procedure described for Example 1, Step G, but substituting the appropriate acid from Example 3 for (4-nitrobenzylthio)acetic acid, and, in some cases, subsli~ulillg N-t-butoxycarbonylleucinal for N-t-butoxycarbonyl-isoleucinal in Step A in the preparation of the intermediate.

N- { 2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl } -N-(1 -naphthylmethvl)-~lycyl-methionine methyl ester FAB mass spectrum m/z = 624 (M+1).
Anal. Calcd for C34H45N304S2-0.30 TFA-0-95 H2O
C, 55.70; H, 6.16; N, 5.32 C,55.72;H,6.17;N,5.30 N- { 2(S)-[(3-Nitrobenzylthio)acetamido]-3(S)-methylpentyl } -N-(1 -naphthylmethyl)- lycyl-methionine methyl ester Anal. Calcd for C34H44N4O6S2-0.2 EtOAc C, 60.88; H, 6.70, N, 8.16 C, 60.52; H, 6.63; N, 8.31 N- { 2(S)-[(2-Nitrobenzylthio)acetamido]-3(S)-methylpentyl } -N-(1 -naphthylmethyl)- Iycyl-methionine methyl ester W096/09836 ~2n~46 PCTIUS95/12319 Anal. Calcd for C34H44N4O6S2-0.2 EtOAc C,60.88;H,6.70;N,8.16 C, 60.44; H, 6.67; N, 8.19 5 N-{2(S)-[(4-Cyanobenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthvlmethyl)-glycvl-methionine methvl ester Anal. Calcd for C35H44N404S2-0.5 EtOAc C, 64.13; H, 6.98; N, 8.09 C, 63.85; H, 6.91; N, 8.17 N- ~ 2(S)-~(4-Trifluoromethylbenzylthio)acetamido]-3(S)-methylpentyl } -N-(l-naphthylmethyl)-glycyl-methionine methyl ester Anal. Calcd for C35H44F3N3O4S2-0.4 EtOAc-1.0 H2O
C, 58.99; H, 6.66; N, 5.64 C,58.97;H,6.37;N,5.61 N- { 2(S)-[(4-Methoxybenzylthio)acetamido]-3(S)-methylpentyl } -N-(1 -naphthylmethyl)-glycvl-methionine methyl ester Anal. Calcd for C35H47N305S2-0.6 EtOAc 0.35 H2O
C, 62.99; H, 7.42; N, 5.89 C, 62.64; H, 7.17; N, 6.29 N- { 2(S)-~(4-Methylsulfonylbenzylthio)acetamido]-3(S)-methylpentyl } -N-(l-naphthylmethyl)- Iycyl-methionine methyl e.ster Anal. Calcd for C35H47N306S3 C, 59.~s9; H, 6.75; N, 5.99 C, 60.14; H, 6.90; N, 5.96 N- { 2(S)-[(4-Phenylbenzylthio)acetamido] -3(S)-methylpentyl } -N-(1 -naphthylmethyl)-glvcvl-methionine methyl ester W 0 96/09836 ~ PC~rrUS95/12319 FAB mass spectrum m/z = 700 (M+1).

N- { 2(S)-[(4-Methylbenzylthio)acetamido]-3(S)-methylpentyl } -N-( l -naphthylmethyl)-glycyl-methionine methyl ester s FAB mass spectrum m/z = 638 (M+1).

N- { 2(S)-[(8-Chloronaphth- 1 -ylthio)acetamido] -3(S)-methylpentyl } -N-(l-naphthylmethyl)-glvcyl-methionine methyl ester Anal. Calcd for C37H44ClN3O4S2-0.5 EtOAc C, 63.43; H, 6.55; N, 5.69 C,63.33;H,6.35;N,6.07 N- ~ 2(S)-[((2-Methylindol-3-yl)thio)acetamido]-4-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine methyl ester Anal. Calcd for C36H46N404S2-0.35 EtOAc C, 64.74; H, 7.09; N, 8.08 C, 64.73; H, 6.93; N, 8.32 N- { 2(S)-[(4-Pyridylthio)acetamido]-3(S)-methylpentyl } -N-(1 -naphthylmethvl)- lycvl-methioninemethyl e.ster 25 Anal. Calcd for C32H42N4O4S2-2.0 TFA-0.75 H2O
C, 50.72; H, 5.3~s; N, 6.57 C, 50.~4; H, 5.2~s; N, 6.56 N- ~ 2(S)-[(4-Picolinylthio)acetamidol-3(S)-methylpentyl } -N-(l -30 naphthvlmethyl)-~lvcvl-methionine methvl e,ster Anal. Calcd for C33H44N404S2-2.0 TFA-0.75 H20 C, 51.29; H, 5.53; N, 6.47 C, 51.27; H, 5.35; N, 6.70 I W096t09836 22 a ~ ~ 4 ~ PCT/US95/12319 , N- { 2(S)-[3-(Benzylthio)propionamido] -3 (S)-methylpentyl } -N-(1 -naphthylmethvl)-glycvl-methionine methvl ester lH NMR (CDCl3); o 0.~4 (t, 3H), 0.88 (d, 3H), 1.08 (m, lH), 1.40 (m, 2H~, 1.66-2.0 (m,7H), 2.33 (m, 2H), 2.7 (m, 3H), 2.99 (dd, lH), 3.21 (s, 2H), 3.68 (s, 3H), 3.7 (m, 3H), 4.4 (m, lH), 6.33 (d, lH), 7.2-7.4 (m, 10H), 7.7-7.9 (m, 4H), 8.19 (m, lH).

N- { 2(S)-[(Phenylthio)acetamido]-3(S)-methylpentyl } -N-(l -naphthylmethyl)-~lyGyl-m.ethionine m.ethyl ~st~r To solution of N-(2(S)-amino-3(S)-methylpentyl)-N-(1-naphthylmethyl)-glycyl-methionine methyl ester hydrochloride (125 mg, 0.23 mmol) and Et3N (65.5 ,uL, 0.47 mmol) in THF (2.5 mL) at room temperature was added bromo acetylbromide (24 ~L, 0.28 mmol). After 10 minutes, thiophenol (29 ,uL, 0.28 mmol) and Et3N
(49 IlL, 0.35 mmol) were added and the mixture was stirred for 4 20 hours. The solution was poured into saturated aqueous NaHCO3, extracted with EtOAc (x3), washed with brine, dried (MgSO4) and evaporated. Purification of the residue by column chromatography (silica gel; hexane/EtOAc 3:2) gave the title compound as an oil.

25 FAB mass spectrum m/z = 610 (M+l).
Anal. Calcd for C33H43N304S2 0.5 TFA-1.15 H2O
C, 53.94; H, 5.88; N, 5.24 C, 53.93; H, 5.91; N, 5.11 N- { 2(S)-[(4-(1 -H-Tetrazol-5-yl)benzylthio)acetamido] -3(S)-methylpentyl ~ -N-( l -naphthylmethyl)-glycyl-methionine methvl ester W 0 96/09836 ~7 ~ ~ ~ 3 ~ ~ PC~rrUS95/12319 ~

Step A: Preparation of ~4-(lH-tetrazol-5-yl)benzylthiolacetic acid (4-Cyanobenzylthio)acetic acid (from Fx~mple 3; 207 mg, 1 mmol) was added to a stirred solution of trimethylsilylazide (400 ,uL, 3 mmol) and dibutyltin oxide (25 mg, 100 !lmol) in toluene (0.5 mL) at 110C. After 6 hours, the reaction was quenched with MeOH (1 mL) and evaporated. The residue was purified by flash chromatography (silica gel, 1000:100:3 to 10Q0:100:13 CHC13/MeOH/HOAc) to give the title compound. Rf (silica;
1000:100:6 CHC13/MeOH/HOAc) = 0.2 compared to the nitrile 10 starting material of Rf = 0.67. lH NMR (d6 DMSO), ~ 3.15 (s, 2H), 3.88(s,2H),7.51 (d,2H,J=8.1 Hz),7.99(d,2H,J=8.1 Hz). FAB
mass spectrum m/z = 251 (M+1).

Step B: N- ~ 2(S)-[~4-(1 -H-Tetrazol-5-yl)benzylthio)acetamido]-3(S)-methylpentyl } -N-(1 -naphthylmethyl)-glycyl-methionine methyl e~ter Following the procedure described for Example 1, Step G, [4-(lH-tetrazol-5-yl)benzylthio]acetic acid was coupled with N-(2(S)-amino-3(S)-methylpentyl)-N-( l -naphthylmethyl)-glycyl-20 methionine methyl ester hydrochloride to give the title compound.

Anal. Calcd for C35H45N7O4S2-0.8 TFA
C, 51.67; H, 5.26; N, 10.93 C, 51.66; H, 5.26; N, 10.84 2s N- (2(S)-[(Benzyloxy)acetamido]-3(S)-methylpentyl } -N-(l -naphthylmethvl)-glycyl-methionine methyl e~ter The title compound was prepared from N-[2(S)-amino-3-methylpentyl)-N-( l -naphthylmethyl)-glycyl-methionine methyl ester hydrochloride (Example 1, Step E) and benzyloxyacetyl chloride (Aldrich) under standard conditions.
FAB mass spectrum m/z = 608 (M+l).

~ ~2 ~ ~ 3 4 6 N- { 2(S)-~(N'-Benzyl-N'-t-butoxycarbonylglycyl)amino]-3(S)-methylpentyl ~-N-(l -naphthylmethyl)-glvcyl-methionine methyl ester Step A: Preparation of N-benzyl-N-t-butoxycarbonylglycine N-Benzylglycine ethyl ester hydrochloride was converted to N-benzyl-N-t-butoxycarbonylglycine ethyl ester using di-t-butyl o dicarbonate under standard conditions. The ethyl ester was saponified using sodium hydroxide in methanol to give the title compound.

Step B: Preparation of N-{ 2(S)-[(N'-benzyl-N'-t-butoxycarbonylglycyl)amino]-3(S)-methylpentyl }-N-(1 -naphthylmethyl)-~lycvl-methionine methvl ester The glycine derivative prepared in Step A was converted to the title compound using the method of Example 1, Step G.

Anal. Calcd for C39H54N4O6S-0.5 H20 C, 65.42; H, 7.74; N, 7.83 C,65.31;H,7.33;N,8.01 N- { 2(S)-[(N'-Benzylglycyl)amino]-3(S)-methylpentyl } -N-(1-naphthvlmethyl)-~lvcyl-methionine methyl ester The t-butoxycarbonyl group of N-{2(S)-[(N'-benzyl-N'-t-butoxycarbonylglycyl)amino] -3 (S)-methylpentyl } -N-( 1 -naphthyl-methyl)-glycyl-methionine methyl ester, Example 8, was cleaved 3 0 using the method of Example 1, Step E to provide the title compound.

Anal. Calcd for C34H46N4O4S-2.0 HC1-0.75 H2O
C, 58.90; H, 7.20; N, 8.08 C, 59.07; H, 6.88; N, 7.87 W096/09836 22 ~ ~ ~ 4 ~ P~l/U~g51l23l9 N- { 2(S)-[(N'-Acetyl-N'-benzylglycyl)amino]-3(S)-methylpentyl } -N-(1-naphthylmethyl)-~lvcyl-methionine methvl ester A solution of N- { 2(S)-[(N'-benzylglycyl)amino]-3(S)-methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine methyl ester from Example 9 (200 mg, 0.3 mmol) was dissolved in CH2C12 (4 mL). Acetic anhydride (0.1 1 mL) and N,N-diisopropylethylamine (0.31 mL) were added and the mixture was stirred for 48 hours. The o mixture was concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried and evaporated to give a residue which was purified by silica gel chromatography (1-3% MeOH in CH2C12) to give the title compound.

Anal. Calcd for C36H4~N405S-0.5 H20 C,65.72,H,7.51;N,8.52 C, 65.87, H, 7.23, N, 8.69 N- { 2(S)-[(Benzylthio-S-oxide)acetamido]-3(S)-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine methyl ester Step A: Preparation of (benzvlthio)acetic acid S-oxide Benzylthioacetic acid was converted to the known title compound (Lindstrom and Mark, US Patent 4,637,833) by oxidation with sodium periodate in methanol.

Step B: N- { 2(S)-~(Benzylthio-S-oxide)acetamido]-3(S)-3 0 methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine methvl ester The sulfoxide derivative from Step A was converted to the title compound using the method of Example 1, Step G.

FAB mass spectrum m/z = 640 (M+l).

2a~34~ `

N- { 2(S)-[(Benzylthio-S,S-dioxide)acetamido]-3(S)-methylpentyl } -N-5 ( l -naphthylmethyl)-~lycyl-methionine methvl ester Step A: Preparation of (benzylthio)acetic acid S,S-dioxide Benzylthioacetic acid was converted to the known title compound (Lindstrom and Mark, US Patent 4,637,833) by oxidation with Oxone in methanol.

Step B: N- { 2(S)-[(Benzylthio-S,S-dioxide)acetamido]-3(S)-methylpentyl }-N-(1-naphthylrnethyl)-glycyl-methionine methyl ester The sulfone derivative from Step A was converted to the title compound using the method of Example 1, Step G.

FAB mass spectrum m/z = 656 (M+l).

N- ~ 2(S)-[(Benzylthio)acetamido] -3(S)-methylpentyl } -N-(1-naphthylmethyl)-~lycyl-methionine .sulfone methyl ester Using the method of Example 1, but substituting 25 methionine sulfone and benzylthioacetic acid as appropriate, the title compound was prepared.
FAB mass spectrum m/z = 6~6 (M+l).

N- { 2(S)-[(N'-4-Nitrobenzoylglycyl)amino]-3(S)-methylpentyl } -N-(1-naphthylmethyl)- Iycyl-methionine methyl ester Following the procedure described for Example 1, Step G, but substituting (4-nitrobenzylthio)acetic acid with N-(4-nitrobenzoyl)glycine (Aldrich) the title compound was obtained.

W096/09836 2~ ~ ~ 3 4 6 PCI/US95/12319 Anal. Calcd for C34H43N507S-0.8 H2O
C, 60.03; H, 6.61; N, 10.30 C, 59.99; H, 6.32; N, 10.28 N- ~ 2(S)-[(N'-Methyl-N'-4-nitrobenzoylglycyl)amino]-4-methyl-pentyl ~-N-(1-naphthylmethyl)-glycyl-methionine methyl ester 0 Following the procedure described for Example 1, but substituting (4-nitrobenzylthio)acetic acid with N-(4-nitrobenzoyl)sarcosine (A. Morgan et al, J. Med. Chem., 34:2126 (1991)) and N-t-butoxycarbonylleucinal for N-t-butoxycarbonylisoleucinal the title compound was obtained.
Anal. Calcd for C35H45N507S-0.35 EtOAc C,61.51;H,6.78;N,9.86 C, 61.13; H, 6.69; N, 10.11 N- ~ 2(S)-[S-Benzyl-L-cysteinyl]-3(S)-methylpentyl } -N-(1 -naphthylmethyl)-~lycvl-methionine methvl ester S-Benzyl-N-t-butoxycarbonyl-L-cysteine (Bachem) was 2s coupled with N-[2(S)-amino-3-methylpentyl)-N-(1-naphthylmethyl)-glycyl-methionine methyl ester hydrochloride according to the procedure described for Example 1, Step G. The product thus obtained was deprotected using TFA in CH2C12 to give the title compound.
FAB mass spectrum m/z = 653 (M+1).
Anal. Calcd for C35H4~N404S2-2.~ TFA-0.1 H2O
C, 50.07; H, 5.28; N, 5.75 C, 50.07; H, 5.32; N, 5.9 a2 0 ~ 3~ 6 _ 99 _ .

N- { 2(S)-[S-benzyl-D-cysteinyl]-3(S)-methylpentyl } -N-(1-5 naphthylmethyl)- lycyl-methionine methyl ester S-Benzyl-N-t-butoxycarbonyl-D-cysteine (Bachem) was coupled with N-[2(S)-amino-3-me~ylpentyl)-N-(1-naph~ylmethyl)-glycyl-methionine methyl ester hydrochloride according to the procedure described for Example 1, Step G. The product thus obtained was deprotected using TFA in CH2Cl2 to give the title compound.

FAB mass spectrum m/z = 653 (M+l).
Anal. Calcd for C35H48N404S2-2.3 TFA-0-5 H2O
C, 51.47; H, 5.60; N, 6.06 C, 51.49; H, 5.57; N, 6.33 EXAMPLE 1~

The following compounds were prepared from the corresponding esters (Examples 3-17) using the procedure described for Example 2.

N- ( 2(S)-[(Benzylthio)acetamido] -3(S)-methylpentyl } -N-( 1-naphthylmethyl)-glycyl-rnethionine FAB mass spectrum m/z = 610 (M+1).
Anal. Calcd for C33H43N304S2-0.05 TFA- 1.05 H2O
C, 56.32; H, 6.22; N, 5.61 C, 56.32; H, 5.99; N, 6.01 N- { 2(S)-[(Phenylthio)acetamido]-3(S)-methylpentyl } -N-(1-naphthylmethyl)- lycyl-methionine FAB mass spectrum m/z = 596 (M+1).

W096/09836 ~a Q ~ 3 ~ ~ PcTluS95/12319`

Anal. Calcd for C32H41N3O4S2-0.25 TFA-0.75 H20 C, 55.11; H, 5.87; N, 5.59 C, 55.14; H, 5.86; N, 5.46 N- { 2(S)-[(3-Nitrobenzylthio)acetamido] -3(S)-methylpentyl } -N-(1 -naphthylmethyl)-~lycvl-methionine Anal. Calcd for C33H42N4O6S2-1.2 H2O-0.5 EtOAc C, 58.34; H, 6.77; N, 7.78 C, 58.34; H, 6.54; N, 7.51 N- { 2(S)-[(2-Nitrobenzylthio)acetamido]-3(S)-methylpentyl } -N-(1 -naphthylmethyl)-glvcvl-methionine Anal. Calcd for C33H42N4O6S2-1.2 H2O-0.5 EtOAc C, 58.34; H, 6.77; N, 7.78 C,58.34;H,6.51;N,7.63 N- { 2(S)-[(4-Cyanobenzylthio)acetamido]-3(S)-methylpentyl } -N-(1 -naphthylmethyl)-glycyl-methionine Anal. Calcd for C34H42N4O4S2-0.3 CHCl3 C, 61.42; H, 6.36; N, 8.35 C,61.73;H,6.31;N,8.41 N- { 2(S)-[(4-Trifluoromethylbenzylthio)acetamido]-3(S)-methylpentyl ~ -N-( l -naphthylmethyl)-~lycyl-methionine Anal. Calcd for C34H42F3N3O4S2-0.5 EtOAc C, 59.89; H, 6.42; N, 5.82 C, 59.60; H, 6.25; N, 5.82 N- { 2(S)-[(4-Methoxybenzylthio)acetamido]-3(S)-methylpentyl } -N-( l -naphthvlmethyl)- lycyl-methionine W096/09836 ` a~n~34~ PCT/US9S/12319 Anal. Calcd for C34H45N305S2-0.5 EtOAc C,63.22;H,7.22,N,6.14 C, 63.22; H, 7.03; N, 6.19 5 N- { 2(S)-[(4-Methylsulfonylbenzylthio)acetamido]-3(S)-methvlpentyl ~ -N-( l -naphthylmethyl)-glycyl-methionine Anal. Calcd for C34H45N306S3-0.3 H2O
C, 58.~9; H, 6.63; N, 6.06 C, 58.85; H, 6.64; N, 6.00 N- ~ 2(S)-[(4-Phenylbenzylthio)acetamido] -3(S)-methylpentyl } -N-(1 -naphthylmethyl)-glycyl-methionine Anal. Calcd for C3gH47N3O4S2-0.5 TFA-0.5 H2O
C, 58.25; H, 5.76; N, 4.85 C, 58.26; H, 5.67; N, 4.87 N- (2(S)-[(4-Methylbenzylthio)acetamido]-3(S)-methylpentyl } -N-(1 -naphthylmethyl)- lvcyl-methionine Anal. Calcd for C34H4sN3O4S2-0.25 H20 C, 64.98; H, 7.30; N, 6.69 C, 64.95; H, 7.17; N, 6.66 N- ~ 2(S)-[(~s-Chloronaphth- 1 -ylthio)acetamido]-3(S)-methylpentyl } -N-( l -naphthylmethyl)-glvcyl-methionine Anal. Calcd for C36H42ClN3O4S2-1.0 EtOAc 1.0 H2O
C, 61.08; H, 6.66; N, 5.34 C, 61.09; H, 6.94; N, 5.38 N- { 2(S)-[((2-Methylindol-3-yl)thio)acetamido]-4-methylpentyl } -N-(I-naphthylmethyl)- Iycvl-methionine W096/09836 2~ 0 1 3 4 6 PCT/US95112319 Anal. Calcd for C35H44N404S2-0.5 EtOAc-0.5 H2O
C, 63.30; H, 7.04; N, 7.98 C,63.17;H,6.77;N,7.98 5 N- { 2(S)-[(4-Pyridylthio)acetamido]-3(S)-methylpentyl } -N-(l -naphthylmethyl)-glycyl-methionine FAB mass spectrum m/z = 579 (M+1).

10 N- { 2(S)-[(4-Picolinylthio)acetamido] -3 (S)-methylpentyl } -N-( l -naphthylmethyl)- Iycvl-methionine Anal. Calcd for C32H42N404S2-2.0 TFA-1.7 H2O
C, 49.72; H, 5.49; N, 6.44 C, 49.51; H, 5.10; N, 6.57 N- { 2(S)-[3-(Benzylthio)propionamido]-3 (S)-methylpentyl } -N-( l -naphthylmethyl)-~lycyl-methionine 20 FAB mass spectrum m/z = 624 (M+l).
Anal. Calcd for C34H4sN3O4S2-1.0TFA
C, 58.60; H, 6.28; N, 5.69 C, 58.63; H, 6.29; N, 5.92 25 N- { 2(S)-~(Benzyloxy)acetamido]-3(S)-methylpentyl } -N-(1 -naphthylmethyl)-~lvcyl-methionine FAB mass spectrum m/z = 594 (M+1).

30 N- { 2(S)-[(N'-Benzylglycyl)amino] -3(S)-methylpentyl } -N-(1 -naphthylmethvl~- Iycyl-methionine Anal. Calcd for C33H44N404S-2.0 TFA-1.0 H2O
C, 52.97; H, 5.77; N, 6.68 C, 52.91; H, 5.61; N, 6.63 W096/09836 ~ 4 6 PCI/US95/12319 ., .

N- { 2(S)-[(N'-Acetyl-N'-benzylglycyl)amino]-3(S)-methylpentyl } -N-( l -naphthylmethyl)-~lycyl-methionine Anal. Calcd for C35H46N405S-1.0 TFA-0.75 H2O
C, 58.29; H, 6.41; N, 7.35 C,58.13;H,6.19;N,7.68 N- { 2(S)-[(Benzylthio-S-oxide)acetamido]-3(S)-methylpentyl } -N-(1-o naphthylmethvl)-glvcvl-methionine FAB mass spectrum m/z = 626 (M+1).

N- { 2(S)-[(Benzylthio-S,S-dioxide)acetamido]-3(S)-methylpentyl } -N-( 1 -naphthylmethyl)- lycyl-methionine FAB mass spectr~m m/z = 642 (M+1).

N- { 2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl } -N-(1-naphthylmethyl)- lycyl-methionine ~ulfone The 1 H-NMR wa~ consistent with the titled structure.

N- { 2(S)-[(N'-4-Nitrobenzoylglycyl)amino]-3(S)-methylpentyl } -N-(1-naphthylmethyl)-~lycyl-methionine Anal. Calcd for C33H41N507S-0.5 H2O
C, 59.9g; H, 6.41; N, 10.60 C, 59.~4; H, 6.31; N, 10.22 N- { 2(S)-[(N'-Methyl-N'-4-nitrobenzoylglycyl)amino]-4-methylpentyl ~ -N-( I -naphthylmethyl)-glycyl-methionine Anal. Calcd for C34H43N507S 0.6 EtOAc-0.5 H2O

W096t09836 22 ~ ~ ~ 4 6 PCItUS95/12319 ~

.
C, 60.08; H, 6.76; N, 9.62 C,60.06;H,6.45;N,9.60 N- { 2(S)-[(S-Benzyl-L-cysteinyl] -3 (S)-methylpentyl } -N-(1 -naphthvlmethyl)- lycyl-methionine FAB mass spectrum m/z = 639 (M+1).
Anal. Calcd for C34H46N4O4S2-2.4 TFA-0-7 H20 C, 50.37; H, 5.43; N, 6.06 o C, 50.34; H, 5.39; N, ~.14 N-~2(S)-[S-Benzyl-D-cysteinyl]-3(S)-methylpentyl}-N-(1 -naphthylmethyl)-~lycyl-methionine FAB mass spectrum m/z = 639 (M+1).
Anal. Calcd for C34H46N4O4S2-2.9 TFA-0.5 H2O
C, 48.85; H, 5.14; N, 5.73 C, 48.82; H, 5.12; N, 5.84 3-Benzylthiopropionyl-valyl-isoleucyl-methionine This compound wa.s synthesized using standard techniques of solution phase peptide synthesis starting from methionine methyl ester 25 and other commercially available materials.
Anal. Calcd for C26H4 l N3O5S2 C, 57.86; H, 7.66; N, 7.79 C, 57.54; H, 7.58; N, 7.81 N- ~ 2(S)-[(4-(1 -H-Tetrazol-5-yl)benzylthio)acetamido]-3(S)-methylpentyl~-N-(I-naphthvlmethyl)- Iycyl-methionine sodium salt W096/09836 ~a~346 PCT/US95/12319 The sodium salt of N-{2(S)-[(4-(1-H-tetrazol-5-yl)-benzylthio)acetamido]-3(S)-methylpentyl } -N-(1 -naphthylmethyl)-glycyl-methionine was prepared from the corresponding methyl ester (2.1 mg) in 200 ~L of MeOH treated with 150 ,uL of 0.1N NaOH and the solution diluted to 1 mL for assay.

N- { 2(S)-[(N'-Benzyl-N'-t-butoxycarbonylglycyl)amino]-3(S)-methylpentyl~-N-(l-naphthylmethyl)-glycvl-methionine sodium salt The sodium salt of N-{2(S)-[(N'-benzyl-N'-t-butoxy-carbonylglycyl)amino]-3(S)-methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine was prepared in situ by hydrolysis of the corresponding methyl ester (2.2 mg) in 0.3 mL of MeOH with 6.2 ~L
of lN NaOH to give a 10 mM solution for assay.

N- { [ 1 -(4-Nitrobenzylthio)acetylamino]cyclopent- 1 -ylmethyl } -N-(1-naphthylmethyl)-glycyl-methionine methvl ester Step A: Preparation of 1-tert-(butyloxy)carbonylaminocyclopentane-1 -carboxaldehyde The title compound was prepared by a Swern oxidation (3 equivalents of pyridine-sulfurtrioxide complex and excess triethyl arnine in DMSO/CH2C12) of BOC protected 1-amino-1-hydroxymethyl-cyclopentane (Aldrich).

Step B: Preparation of N-{ [1-(4-Nitrobenzylthio)acetylamino]-cyclopent- 1 -ylmethyl } -N-( 1 -naphthylmethyl)-glycyl-methionine methyl ester Following the procedure described in Example 1, but substituting the 1-tert-(butyloxy)carbonylaminocyclopentane-1-carboxaldehyde from Step A for N-t-butoxycarbonylisoleucinal provided the title compound.

W0 96/09836 ~2 2 01~ 4 6 PCT/US95/12319 C34H42N406S2 FAB mass spectrum, m/e 667 (M+1).

5 N- { [ 1 -(4-Nitrobenzylthio)acetylamino]cyclopent- 1 -ylmethyl } -N-( 1-naphthylmethvl)-glycyl-methionine Following the procedure described in Example 2, but substituting the ester from Example 22 provided the title compound.
C33H40N4o6s2 FAB mass spectrum, m/e 653 (M+1).

N- { 2(S)-r2-(4-Nitrophenyl)ethylcarbamoylamino]-4-methylpentyl } -N-(l-naphthylmethvl)-glycyl-methionine methyl e~ster 2-(4-Nitrophenyl)ethylamine (0.5 mmol) and p-nitrophenylchloroformate (0.5 mmol) were allowed to react in the presence of triethylamine ( 1 mmol) in 5 ml of DMF to provide 2-(4-nitrophenyl)ethyl isocyanate. Without isolation, the isocyanate was mixed with N-(2(S)-amino-4-methylpentyl)-N-(1-naphthylmethyl)-20 glycyl-methionine methyl ester dihydrochloride (0.4 mmol) and triethylamine (1 mmol) in 4 mL of DMF to provide the title compound.
C34H45N5O6S-0.15 hexane Anal. Calcd for C26H4lN3oss2 C, 63.05; H, 7.14; N, 10.54 C, 63.10; H, 7.Q9; N, 10.16 N- { 2(S)-[2-(4-Nitrophenyl)ethylcarbamoylamino]-4-methylpentyl } -N-3 o ( I -naphthylmethyl)- Iycyl-methionine Following the procedure described in Example 2, but substituting the ester from Example 24 provided the title compound.
C33H43NsO6S EtOAc -W096/09836 ~ 3 ~ 6 PCT/US95112319 C, 61.22; H, 7.08; N, 9.65 C, 61.32; H, 6.72; N, 9.73 ~.

N- { 2(S)-[(3(S)-tetrahydrofuryloxy)carbonylamino]-3(S)-methylpentyl}-N-(l-naphthylmethyl)-~lycvl-methionine methyl ester The succinimidyl carbonate of 3(S)-hydroxytetrahydrofuran, was prepared as described by Ghosh, et al., (J. Med. Chem. 1993, o 36:292). The carbonate (46 mg, 0.20 mmol) and N-(2(S)-amino-3(S)-methylpentyl)-N-(l-naphthylmethyl)-glycyl-methionine methyl ester dihydrochloride (106 mg, 0.20 mmol) were dissolved in 3 mL of methylene chloride and 56 ,uL (0.40 mmol) of triethylamine was added.
After stirring overnight the mixture was diluted with ethyl acetate and washed successively with 10% citric acid, 10% sodium bicarbonate and brine. After drying, the solvent was evaporated and the residue was chromatographed on silica (1.5% methanol in methylene chloride) to provide N-{2(S)-[(3(S)-tetrahydrofuryloxy)-carbonylamino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester.

N- ~ 2(S)-[(3(S)-tetrahydrofuryloxy)carbonylamino~-3(S)-methylpentyl } -N-( l -naphthylmethyl)-~lycyl-methionine Following the procedure described in Example 2, but substituting the ester from Example 26 provided the title compound.
C29H4 1 N306S-CF3C02H-2. 1 H20 C, 52.32; H, 6.54; N, 5.91 C,51.85;H,6.01;N,6.34 N- { 2(S)-[(cis-4-benzyloxytetrahydrofur-3-yloxy)carbonylamino]-3(S)-methylpentyl ~ -N-t 1 -naphthylmethvl)-~lycyl-methionine methyl ester W096109836 ~2 ~ 1 3 4 6 PCT/US95/12319 Following the procedure described in Example 26, but substituting the succinimidyl carbonate of racemic cis-4-benzyloxy-3-hydroxytetrahydrofuran (prepared as described by Vacca, et al., (Can.
Pat. 2,084,800, June 17, 1993)) provided a 1:1 mixture of diastereomers 5 of N- { 2(S)-[(cis-4-benzyloxytetrahydrofur-3-yloxy)carbonylamino]-3(S)-methylpentyl } -N-( l -naphthylmethyl)-glycyl-methionine methyl ester which were inseparable by HPLC chromatography.

N- { 2(S)-[(cis-4-benzyloxytetrahydrofur-3-yloxy)carbonylamino]-3(S)-methylpentyl ~ -N-( l -naphthylmethyl)-glycyl-methionine Following the procedure described in Example 2, but substituting the ester from Example 28 provided the title compound as a mixture of diastereomers that were separated by reverse phase HPLC
chromatography .
Isomers A and B, C36H47N3O7S gave FAB MS m/e = 666 (M+l).

N- { 2(S)-(t-butoxycarbonylamino)-3(S)-methylpentyl } -N-(1 -naphthylmethyl)-glycvl -methionine Using the procedure described in Example 2, N-[2(S)-(t-butoxycarbonylamino)-3(S)-methylpentyl]-N-(1 -naphthylmethyl)-glycyl-25 methionine methyl ester (prepared in Example 1, Step B, was convertedto the title compound.
C29H43N3O5S-Q.4 H20 C, 62.99; H, 7.98; N, 7.60 C, 62.98; H, 7.83; N, 7.62 W096109836 ~2 ~ PCT/US95/12319 In vitro inhibition of ras farnesyl tran.sferase Assays offarnesyl-protein transferase. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and RAS-CAIL) were prepared as described by Schaber et al., J. Biol. Chem. 265:14701-14704 (1990), Pompliano, et al., Biochemistry 31:3800 (1992) and Gibbs et al., PNAS
U.S~. 86:6630-6634 (1989). Bovine FPTase was assayed in a volume of o 100 ~l containing 100 mM N-(2-hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM [3H]-farnesyl diphosphate ([3H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 ,ug/ml FPTase at 31 C
for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol. Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB ,~-plate counter. The assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the [3H]-FPP was utilized during the reaction period. Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay. Percentage inhibition is measured by the amount of incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound.
Human FPTase was prepared as described by Omer et 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 mixture. Reactions were performed for 30 min., stopped with 100 ,ul of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
The compounds of the instant invention were tested for inhibitory activity against human FPTase by the assay described above and were found to have ICso of < 10 ~M.

-W096/09836 ~2 0 13 4 6 PCT/US95/12319 In vivo ras farnesvlation assay The cell line used in this assay is a v-ras line derived from 5 either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21. The assay is perfo~ned 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 (~1nal concentration of solvent, methanol or dirnethyl sulfoxide, is 0.1%). After 4 hours at 37C, o the cells are labelled in 3 ml methionine-free DMEM supple-meted with 10% regular DMEM, ~% fetal bovine serum and 400 mCil35S]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 antipain/0.5 mM PMS~) 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 immunoprecipitated 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 4C, 200 ml of a 25%
suspension of protein A-Sepharose coated with rabbit anti rat IgG is added for 45 min. The immunoprecipitates are washed four 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% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to farnesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein.

>
-W096/09836 ~ Q ~ ~ ~ 6 PCT/US95/12319 In vivo growth inhibition assay To determine the biological consequences of FPTase inhibition, the effect of the compounds of the instant invention on the anchorage-independent growth of Ratl cells transformed with either a v-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Raf and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation.
o 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 appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay). The cells are fed twice weekly with 0.5 ml of medium A cont~ining 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 (32)

WHAT IS CLAIMED IS:

1. A compound which inhibits Ras farnesyl-transferase having the formula I:

I

wherein:
R1a is selected from:
a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, (R10)2N-C(NR10)-, R10C(O)-, or R10OC(O)-, and 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;
R1b is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, (R10)2N-C(NR10)-, R10C(O)-, or R10OC(O)-, and c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, 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-;
provided that R1b is not R10C(O)NR10- when R1a is alkenyl, V is hydrogen and X-Y is -C(O)NR7a-;

R2a and R2b 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 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 R2a and R2b are combined to form - (CH2)s -;
R3 and R4 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 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 R3 and R4 are combined to form - (CH2)s -, R5a and R5b 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 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 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)-;

X-Y is a) , b) , C) , d) , e) , or f) -CH2-CH2- ;

R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
R8 is independently selected from:
a) hydrogen, b) aryl, heterocyclic, 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, heterocyclic, 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 R11OC(O)NH-;
R9 is selected from:
hydrogen, C1-C6 alkyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, N3, -N(R10)2, and R11OC(O)NR10;

provided that R9 is not R10C(O)NR10- when R1a is alkenyl, V
is hydrogen and X-Y is -C(O)NR7a-;

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

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

R12 is hydrogen or C1-C6 alkyl;
V is selected from:
a) aryl;
b) heterocycle; or c) hydrogen;

W is -S(O)m-,-O-,-NHC(O)-,-C(O)NH-,-NHSO2-, -SO2NH-, -N(R7a)- or-N[C(O)R7a]-;
Z is independently H2 or O;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4, provided that n ? 0 when V is hydrogen and W is -S(O)m-;
p is 0, 1, 2, 3 or 4, provided that p ? 0 when R9 is not hydrogen or C1-C6 lower alkyl;
r is 0 or 1 ;
s is 4 or 5; and t is 0, 1 or 2, provided that t = 0 when V is hydrogen;
or a pharmaceutically acceptable salt thereof.

2. A prodrug of a compound of Claim 1 having the formula II:

II

wherein:
R1a is selected from:
a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, (R10)2N-C(NR10)-, R10C(O)-, or R10OC(O)-, and 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-;
R1b is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, (R10)2N-C(NR10), R10C(O)-, or R10OC(O)-, and c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, 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-;
provided that R1b is not R10C(O)NR 10- when R1a is alkenyl, V is hydrogen and X-Y is -C(O)NR7a-;
R2a and R2b 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 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 R2a and R2b are combined to form - (CH2)s -;
R3 and R4 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 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 R3 and R4 are combined to form - (CH2)s -;

R5a and R5b 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 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 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 a) substituted or unsubstituted C1-C8 alkyl, wherein the substituent on the alkyl is selected from:
1) aryl, 2) heterocycle, 3) -N(R11)2, 4) -OR10, or b) ;

X-Y is a) , b) , c) , d) , e) , or f) -CH2-CH2-;

R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
R8 is independently selected from:
a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10O, R11S(O)m-, R10C(O)NR10-, CN, NO2, R102N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR 10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, 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 R11OC(O)NH-;
R9 is selected from:
hydrogen, C1-C6 alkyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, N3, -N(R10)2, and R11OC(O)NR10-;

provided that R9 is not R10C(O)NR10- when R1a is alkenyl, V
is hydrogen and X-Y is -C(O)NR7a-;

R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl, R11 is independently selected from C1-C6 alkyl and aryl;

R12 is independently selected from hydrogen and C1-C6 alkyl;

R13 is C1-C6 alkyl, V is selected from:
a) aryl;
b) heterocycle; or c) hydrogen;

W is -S(O)m-, -O-, -NHC(O)-, -C(O)NH-, -NHSO2-, -SO2NH-, -N(R7a)- or-N[C(O)R7a]-;
Z is independently H2 or O;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4, provided that n ? 0 when V is hydrogen and W is -S(O)m-;
p is 0, 1, 2, 3 or 4, provided that p ? 0 when R9 is not hydrogen or C1-C6 lower alkyl;
r is 0 or 1;
s is 4 or 5; and t is 0, 1 or 2, provided that t = 0 when V is hydrogen;
or a pharmaceutically acceptable salt thereof.

3. A compound which inhibits Ras farnesyl-transferase having the formula III:

III

wherein:
R1a is selected from:
a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, (R10)2N-C(NR10)-, R10C(O)-, or R10OC(O)-, and 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-;
R1b is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, (R10)2N-C(NR10)-, R10C(O)-, or R10OC(O)-, and c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, NR10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-;
provided that R1b is not R10C(O)NR10- when R1a is alkenyl, V is hydrogen and X-Y is -C(O)NR7a-;

R2a and R2b 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 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 R2a and R2b are combined to form - (CH2)s -;
R3 and R4 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 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 R3 and R4 are combined to form - (CH2)s -, X-Y is a) , b) , c) , d) , e) , or f) -CH2-CH2- ;

R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
R8 is independently selected from:
a) hydrogen, b) aryl, heterocyclic, 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, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R11S(O)m-, R10C(O)NH-, CN, H2N-C(NH)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NH-, R9 is selected from:
hydrogen, C1-C6 alkyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, N3, -N(R10)2, and R11OC(O)NR10-;

provided that R9 is not R10C(O)NR10- when R1a is alkenyl, V
is hydrogen and X-Y is -C(O)NR7a-;

R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is hydrogen or C1-C6 alkyl;
V is selected from:
a) aryl;
b) heterocycle; or c) hydrogen;

W is -S(O)m-, -O-, -NHC(O)-, -C(O)NH-, -NHSO2-, -SO2NH-, -N(R7a)- or -N[C(O)R7a]-;
Z is independently H2 or O;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4, provided that n ? 0 when V is hydrogen and W is -S(O)m-;
p is 0, 1, 2, 3 or 4, provided that p ? 0 when R9 is not hydrogen or C1-C6 lower alkyl;
is 0, 1 or 2;
r is 0 or 1 ;
s is 4 or 5; and t is 0, 1 or 2, provided that t = 0 when V is hydrogen;
or a pharmaceutically acceptable salt thereof.

4. A prodrug of a compound of Claim 3 of the formula IV:

IV

wherein:
R1a is selected from:
a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, (R10)2N-C(NR10)-, R10C(O)-, or R10OC(O)-, and 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-;
R1b is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, (R10)2N-C(NR10)-, R10C(O)-, orR10OC(O)-, and c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, 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-;
provided that R1b is not R10C(O)NR10- when R1a is alkenyl, V is hydrogen and X-Y is -C(O)NR7a-;

R2a and R2b 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, 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 R2a and R2b are combined to form - (CH2)s -;
R3 and R4 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, 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 R3 and R4 are combined to form - (CH2)s -;

X-Y is a) , b) , c) , d) , e) , or f) -CH2-CH2- ;

R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;

R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
R8 is independently selected from:
a) hydrogen, b) aryl, heterocyclic, 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)NR 10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, 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 R11OC(O)NH-;
R9 is selected from:

hydrogen, C1-C6 alkyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, N3, -N(R10)2, and R11OC(O)NR10-;
provided that R9 is not R10C(O)NR10- when R1a is alkenyl, V
is hydrogen and X-Y is -C(O)NR7a-;

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

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

R12 is hydrogen or C1-C6 alkyl;
V is selected from:
a) aryl;
b) heterocycle; or c) hydrogen;

W is -S(O)m-, -O-, -NHC(O)-, -C(O)NH-, -NHSO2-, -SO2NH-, -N(R7a)- or-N[C(O)R7a]-;
Z is independently H2 or O;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4, provided that n ? 0 when V is hydrogen and W is -S(O)m-;
p is 0, 1, 2, 3 or 4, provided that p ? 0 when R9 is not hydrogen or C1-C6 lower alkyl;
is 0, 1 or 2;
r is 0 or 1 ;
s is 4 or 5; and t is 0, 1 or 2, provided that t = 0 when V is hydrogen;

or a pharmaceutically acceptable salt thereof.

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

I

wherein:
R1a is selected from:
a) hydrogen, and b) C1-C6 alkyl;
R1b is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl or cycloalkyl, and c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, R10O- or -N(R10)2;
R2a is selected from:
a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine;
b) 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 c) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; and R2b is selected from hydrogen and C1-C6 alkyl; or R2a and R2b are combined to form - (CH2)s -;
R3 and R4 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 heterocycle 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;
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-, 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; or X-Y is a) , , b) C) , d) , or e) -CH2-CH2-;

R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or.substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
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 perfluoroalyl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-;
R9 is selected from:
hydrogen, C1-C6 lower alkyl, R10O-, and -N(R10)2;

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

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

R12 is hydrogen or C1-C6 alkyl;
V is selected from:
a) aryl;
b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; and c) hydrogen;

W is -S(O)m-, -O-, -NHC(O)-, -C(O)NH-, -NHSO2-, -SO2NH-, -N(R7a)- or -N[C(O)R7a]-;
Z is independently H2 or O;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4, provided that n ? O when V is hydrogen and W is -S(O)m-;
p is 0, 1, 2, 3 or 4, provided that p ? 0 when R9 is not hydrogen or C1-C6 lower alkyl;
r is 0 or 1;
s is 4 or 5;and t is 0 or 1, provided that t = 0 when V is hydrogen;
or a pharmaceutically acceptable salt thereof.

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

II

wherein:
R1a is selected from:
a) hydrogen, and b) C1-C6 alkyl;
R1b is independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl or cycloalkyl, and c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, R10O- or -N(R10)2;
R2a is selected from:
a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine;

b) 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)NR 10- and C1-C20 alkyl, and c) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; and R2b is selected from hydrogen and C1-C6 alkyl; or R2a and R2b are combined to form - (CH2)s -;
R3 and R4 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 heterocycle 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)-, R10C(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;
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-, CN, (R 10)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; or R6 is a) substituted or unsubstituted C1-C8 alkyl, wherein the substituent on the alkyl is selected from:
1) aryl, 2) heterocycle, 3) -N(R11)2, 4) -OR 10, or b) ;

X-Y is a) , b) , C) , d) , or e) -CH2-CH2-;

R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
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:
hydrogen, C1-C6 lower alkyl, R10O-, and -N(R10)2;

R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl, R11 is independently selected from C1-C6 alkyl and aryl, R12 is independently selected from hydrogen and C1-C6 alkyl;
R13 is C1-C6 alkyl;
V is selected from:
a) aryl;
b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; and c) hydrogen;

W is -S(O)m-, -O-, -NHC(O)-, -C(O)NH-, -NHSO2-, -SO2NH-, -N(R7a)- or -N[C(O)R7a]-;
Z is independently H2 or O;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4, provided that n ? 0 when V is hydrogen and W is -S(O)m-;
p is 0, 1, 2, 3 or 4, provided that p ? 0 when R9 is not hydrogen or C1-C6 lower alkyl;
r is 0 or 1;
s is 4 or 5; and t is 0 or 1, provided that t = 0 when V is hydrogen;
or a pharmaceutically acceptable salt thereof.

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

III
wherein:
R1a is selected from:
a) hydrogen, and b) C1-C6 alkyl;
R1b are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl or cycloalkyl, and c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, R10O or -N(R10)2;
R2a is selected from:
a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine;
b) 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 c) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloaIkyl; and R2b is selected from hydrogen and C1-C6 alkyl; or R2a and R2b are combined to form - (CH2)s -;
R3 and R4 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 heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, 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;

X-Y is a) , b) , c) , d) , or e) -CH2-CH2-;

R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
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:
hydrogen, C1-C6 lower alkyl, R10O-, and -N(R10)2;

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

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

R12 is hydrogen or C1-C6 alkyl;
V is selected from:
a) aryl;
b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; and c) hydrogen;

W is -S(O)m-, -O-, -NHC(O)-, -C(O)NH-, -NHSO2-, -SO2NH-, -N(R7a)- or -N[C(O)R7a]-;
Z is independently H2 or O;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4, provided that n ? 0 when V is hydrogen and W is -S(O)m-;
p is 0, 1, 2, 3 or 4, provided that p ? 0 when R9 is not hydrogen or C1-C6 lower alkyl;
q is 0, 1 or 2;
r is 0 or 1 ;
s is 4 or 5; and t is 0 or 1, provided that t = 0 when V is hydrogen;

or a pharmaceutically acceptable salt thereof.

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

IV
wherein:
R1a is selected from:
a) hydrogen, and b) C1-C6 alkyl;
R1b are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl or cycloalkyl, and c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, R10O or -N(R10)2;
R2a is selected from:
a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine;
b) 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 c) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; and R2b is selected from hydrogen and C1-C6 alkyl; or Ra and Rb are combined to form -(CH2)s-;
R3 and R4 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 heterocycle 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;

X-Y is a) , b) , c) , d) , or e) -CH2-CH2-;

R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
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:
hydrogen, C1-C6 lower alkyl, R10O-, and -N(R10)2;

R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is hydrogen or C1-C6 alkyl;
V is selected from:
a) aryl;
b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; and c) hydrogen;

W is -S(O)m-, -O-, -NHC(O)-, -C(O)NH-, -NHSO2-, -SO2NH-, -N(R7a)- or -N[C(O)R7a]-;
Z is independently H2 or O;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4, provided that n ? 0 when V is hydrogen and W is -S(O)m-;
p is 0, 1, 2, 3 or 4, provided that p ? 0 when R9 is not hydrogen or C1-C6 lower alkyl;
q is 0, 1 or 2;
r is 0 or 1 ;
s is 4 or 5; and t is 0 or 1, provided that t = 0 when V is hydrogen;
or a pharmaceutically acceptable salt thereof.

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

N-{2(S)-[(4-Nitrobenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(4-Nitrobenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(Phenylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(Phenylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(3-Nitrobenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(3-Nitrobenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(2-Nitrobenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(2-Nitrobenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(4-Cyanobenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(4-Cyanobenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(4-Trifluoromethylbenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(4-Trifluoromethylbenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(4-Methoxybenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(4-Methoxybenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(4-Methylsulfonylbenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(4-Methylsulfonylbenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(4-Phenylbenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(4-Phenylbenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(4-(1-H-Tetrazol-5-yl)benzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(4-(1-H-Tetrazol-5-yl)benzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(4-Methylbenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(4-Methylbenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(8-Chloronaphth-1-ylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(8-Chloronaphth-1-ylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[((2-Methylindol-3-yl)thio)acetamido]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[((2-Methylindol-3-yl)thio)acetamido]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(4-Pyridylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(4-Pyridylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(4-Picolinylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(4-Picolinylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[3-(Benzylthio)propionamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(Benzyloxy)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(Benzyloxy)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(N'-Benzylglycyl)amino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(N'-Benzylglycyl)amino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(N'-Acetyl-N'-benzylglycyl)amino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(N'-Acetyl-N'-benzylglycyl)amino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(N'-Benzyl-N'-t-butoxycarbonylglycyl)amino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(N'-Benzyl-N'-t-butoxycarbonylglycyl)amino]-3(S)-methyl-pentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(Benzylthio-S-oxide)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(Benzylthio-S-oxide)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(Benzylthio-S,S-dioxide)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(Benzylthio-S,S-dioxide)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine sulfone N-{2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine sulfone methyl ester N-{2(S)-[(N'-4-Nitrobenzoylglycyl)amino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(N'-4-Nitrobenzoylglycyl)amino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(N'-Methyl-N'-4-nitrobenzoylglycyl)amino]-4-methyl-pentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(N'-Methyl-N'-4-nitrobenzoylglycyl)amino]-4-methyl-pentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(S-Benzyl-L-cysteinyl]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[S-Benzyl-L-cysteinyl]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[S-Benzyl-D-cysteinyl]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[S-Benzyl-D-cysteinyl]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester 3-Benzylthiopropionyl-valyl-isoleucyl-methionine N-[2(S)-(2(S),3-Diaminopropionyl)amino-3(S)-methylpentyl]-N-(1-naphthylmethyl)glycyl-methionine N-[2(S)-(2(S),3-Diaminopropionyl)amino-3(S)-methylpentyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester N-[2(S)-(3-Aminopropionyl)amino-3(S)-methylpentyl]-N-(1-naphthylmethyl)glycyl-methionine N-[2(S)-(3-Aminopropionyl)amino-3(S)-methylpentyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester N-(2(S)-L-Glutaminylamino-3(S)-methylpentyl)-N-(1-naphthyl-methyl)glycyl-methionine N-(2(S)-L-Glutaminylamino-3(S)-methylpentyl)-N-(1-naphthyl-methyl)glycyl-methionine methyl ester N-[2(S)-(1,1-Dimethylethoxycarbonylamino)-3S)-methylpentyl]-N-(1-naphthylmethyl)glycyl-methionine N-[2(S)-(1,1-Dimethylethoxycarbonylamino)-3S)-methylpentyl]-N-(1-naphthylmethyl)glycyl-methionine methyl ester N-[2(S)-(1,1-Dimethylethoxycarbonylamino)-3(S)-methylpentyl]-N-benzylglycyl-methionine N-[2(S)-(1,1-Dimethylethoxycarbonylamino)-3(S)-methylpentyl]-N-benzylglycyl-methionine methyl ester N-{[1-(4-Nitrobenzylthio)acetylamino]cyclopent-1-ylmethyl}-N-(1-naphthylrnethyl)-glycyl-methionine N-{[1-(4-Nitrobenzylthio)acetylamino]cyclopent-1-ylmethyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[2-(4-Nitrophenyl)ethylcarbamoylamino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[2-(4-Nitrophenyl)ethylcarbamoylamino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(3(S)-tetrahydrofuryloxy)carbonylamino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(3(S)-tetrahydrofuryloxy)carbonylamino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(cis-4-benzyloxytetrahydrofur-3-yloxy)carbonylamino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine, N-{2(S)-[(cis-4-benzyloxytetrahydrofur-3-yloxy)carbonylamino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(N'-Methyl-N'-4-nitrophenylacetylglycyl)amino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine or N-{2(S)-[(N'-Methyl-N'-4-nitrophenylacetylglycyl)amino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester or a pharmaceutically acceptable salt thereof.

10. A compound which inhibits farnesyl-protein transferase which is:
N-{2(S)-[(4-Methoxybenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine ;

or the pharmaceutically acceptable salts thereof.

11. A compound which inhibits farnesyl-protein transferase which is:
N-{2(S)-[(4-Methoxybenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester ;

or a pharmaceutically acceptable salt thereof.

12. A compound which inhibits farnesyl-protein transferase which is:
N-{2(S)-[(4-Cyanobenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine ;

or a pharmaceutically acceptable salt thereof.

13. A compound which inhibits farnesyl-protein transferase which is:
N-{2(S)-[(4-Cyanobenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester ;

or a pharmaceutically acceptable salt thereof.

14. A compound which inhibits farnesyl-protein transferase which is:
N-(2(S)-L-Glutaminylamino-3(S)-methylpentyl)-N-(1-naphthyl-methyl)glycyl-methionine ;

or a pharmaceutically acceptable salt thereof.

15. A compound which inhibits farnesyl-protein transferase which is:
N-(2(S)-L-Glutaminylamino-3(S)-methylpentyl)-N-(1-naphthyl-methyl)glycyl-methionine methyl ester ;

or a pharmaceutically acceptable salt thereof.

16. A compound which inhibits farnesyl-protein transferase which is:
N-(2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine sulfone ;

or a pharmaceutically acceptable salt thereof.

17. A compound which inhibits farnesyl-protein transferase which is:
N-{2(S)-[(Benzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine sulfone methyl ester ;

or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

23. 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.

24. 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.

25. 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 20.

26. 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 21.

27. 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 22.

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

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

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

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

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