CA2201351A1 - 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 analogues 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 thioldependant chemical reactions, such as rapid auto-oxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containg these farnesyl transferase inhibitors and methods for their production.

Description

--- 22~135~ `

TI~LE OF THE INVENTION
INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE

BACKGROUND OF THE INVENTION
The Ras gene is found activated in many hllm~n 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 transform cells (Gibbs, J. et al., Microbiol. Rel~. 53:171-286 (1989).
Forms of Ras in cancer cells have mllt~tions that distinguish the protein from Ras in normal cells.
At least 3 post-tr~n~l~tional modifications are involved with Ras membrane loc~li7~tion, and all 3 modifications occur at the C-telmillus of Ras. The Ras C-termiml~ 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 310:583-~86 (1984)). Other proteins having this motif include the Ras-related GTP-binding proteins such as Rho, fungal m~ting factors, the nuclear l~min~, and the g~mm~ 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: 1167 (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 et al., Cell 57: 1167-1177 (1989)). Ki-Ras lacks the p~lmit~te acceptor Cys. The last 3 amino acids at the Ras C-terminal end are removed proteolytically, and methyl esterification occurs at the new C-terminus (Hancock et al., ibif~. Fungal mating factor and m~mm~ n nuclear l~min.~ undergo identical modification steps (Anderegg et al., J.
Biol. Chem. 263:18236 (1988); Farnsworth et al., J. Biol. Chem.
264:20422 (1989)).

22~1351 2- ~
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 limitin~
5 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., 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 domin~nt 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-Aaa1-Aaa2-Xaa box membrane 20 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 25 effect in Xenopus oocytes and in m~mm~ n cells.
Allmini~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 30 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 functions.

WO 96/10011 PCTlUS9Stl2321 ~ 22013~

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 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 the Ras 0 CAAX box with a farnesyl group. Inhibition of farnesyl pyrophosphatebiosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane loc~li7~tion 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 of isoprene biosynthesis.
Previously, it has been demonstrated that tetrapeptides cont~inin3~ cysteine as an amino terrnin~l 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 inhibit while serving as alternate substrates for the Ras farnesyl-transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141,851, University of Texas).
It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of Ras oncoprotein intracellularly (N.E. Kohl et al., Science, 260:1934-1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993).
Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of ras-dependent tumors in nude mice (N.E. Kohl et al., Proc. Natl. Acad. Sci U.S A., 91 :9141 -9145 (1994) -30 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 isrelated to the protein substrate for the enzyme, Ras. Almost all of the peptide derived inhibitors that have been described are cysteine WO 96/10011 . PCT/US95112321 ,; ," ~ ,- .
22~1351 cont~inin~ 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~mins (Omura, et al., J. Antibiotics 46:222 (1993). In general, deletion of the thiol from a 5 CAAX derivative dramatically reduces the inhibitory potency of these compounds. However, the thiol group potentially places limit~tions on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, 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 15 which will inhibit farnesyl transferase and ~e post-translational function~ tion of the oncogene Ras protein. It is a further object of this invention to develop chemotherapeutic compositions collt~ illg the compounds of 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.
These CAAX analogs inhibit the farnesylation of Ras. Purthermore, 25 these CAAX analogues 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 ~nim~l~, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide 30 formation with endogenous thiols, and reduced systemic toxicity.
Further contained in this invention are chemotherapeutic compositions cont~inin~; these farnesyl transferase inhibitors and methods for their production.

2 2 0 I 351 PCT/US95112321 The compounds of this invention are illustrated by ~e fonn R8~ (CR 2)n(C3p(CR Z~R12 ~H~
R8b R

R8 (1l) ~ R~ ~l R~ 6 (CH2)qCH20H

R ~ (CR1z)n(C)p(CR12)J~N~z X ~ H

and (CR 2)n(C)p(CR 2)n ~H~o IV

WO 96110011 ~ PCT/US95/12321 - 2 2 0 1 3 5 1 } ~ ! I

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:

R8a ~1~ R~R2b Z R~ ~R5b R8b (CR12)nWp(CR 2)n R12 wherein:
R1 is hydrogen, Cl-C6 alkyl or aryl;

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) methioninesulfone, c) substituted or unsubstituted Cl-c2o aLkyl, C2-c2o alkenyl, C3-Clo cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R9O-, Rl0s(o)m-~ R9C(o)NR9-, CN, (R9)2N-C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2, Rl0OC(O)NR9- 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, WO 96/10011 PCI~/US95/12321 ~ 2 2 0 1 3 S I

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-C1o cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R9O-, R10s(o)m-~ R9C(o)NR9-, CN, (R9)2N-C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2 o RlOOC(O)NR9- and Cl-C20 alkyl, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1o cycloalkyl; or R3 and R4 are combined to form - (CH2)s -;

RSa and R5b are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-c2o alkyl, C2-c2o alkenyl? C3-Clo cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R9O-, R10s(o)m-~ R9C(o)NR9-, CN, (R9)2N-C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2, R1OOC(O)NR9- 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 -220~351`
, i .. ~ .

RSa and RSb are combined to form - (CH2)S - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR9)-;

5 X-Y is F~7a a) ~s~N~ss O
~7b T
b) \5sS ,N~

c) ~ ~O~

(I )m d) ~sSs - ~ssss H

e) ~~5~555~ , or f) -CH2-CH2-;

R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and

3 e) Cl -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;

R7b is selected from 220135~1 s _ 9 _ a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, o cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, lS cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;

R8a and R8b are independently selected from:
hydrogen, F, Cl, Br, NO2, R1 lo, RlOs(o)m-7 CN, R9C(o)NR9-, (R9)2N-C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2, R1OOC(O)NR9-, Cl-C20 alkyl, aryl, heterocycle or C 1 -C20 alkyl substituted with aryl or heterocycle;

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

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

R 1 1 is independently selected from hydrogen, Cl -C6 alkyl and aryl, provided Rl 1 is Cl-C6 alkyl when n is 0;

R12 is independently hydrogen or C1-C6 alkyl;

WO 96/10011 P~ 55/12321 22~13~1 -~) is aryl or 1,2,3,4-tetrahydronaphthyl;

Z is independently H2 or 0;

misO, 1 or2;
n is independently O to 4;
pisOor 1; and sis40r5;
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:
R8a O\ z R2a R2b z R5a R5b R8b~ (CR12), ~Cl(CR12)n NR12 X ~H~

wherem:
R1 is hydrogen, Cl-C6 alkyl or aryl;

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:
3 o i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C 1 -C20 alkyl, C2-C20 alkenyl, C3-Clo cycloalkyl, aryl or heterocycle group, WO 96/10011 . PCTIUS95/12321 220I 3~1 wherein the substituent is selected from F, Cl, Br, NO2, R9O-, RlOs(o)m-~ R9C(o)NR9-, CN, (R9)2N-C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2, RlOOC(O)NR9- and Cl-C20 alkyl, and d) Cl-C6 aLkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clocycloalkyl; 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) me~ionine sulfoxide, or ii) methionine sulfone, c) sul sliluled or unsubstituted Cl-C20 alkyl, C2-C20 alkenyl, C3-Clo cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R9O-, RlOs(o)m-~ R9C(o)NR9-, CN, (R9)2N-C(NR9)-,R9C(o)-, R9OC(o)-,N3,-N(R9)2, RlOOC(O)NR9- 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 -;

R5a and R5b are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, WO 96110011 . PCI/US95112321 22~135~ s ~

c) substituted or unsubstituted Cl-c2o alkyl, C2-c2o aLkenyl, C3-Clo cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R9O-, Rl0s(o)m-~ R9C(o)NR9-, CN, (R9)2N-C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2, R10oC(o)NR9- 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 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(COR9)-;

R6 is a) substituted or unsubstituted Cl -C8 alkyl, wherein the substituent on the alkyl is selected from:
1) aryl, 2) heterocycle, 3)-N(R10)2,

4) -OR9, or b) R12 o 1 J~
~, O R13.

WO 96/10011 2 2 0 1 3 5 1 - ` P~TIUS95112321 X-Y is ~7a a) ~S5s~Ns~ss o ~7b b) \5sS~ N~ss C) ~SSS~0~55 ( 1)m d) ~sss~S5ss H
e) ~SSS~ or H

f) -CH2-CH2-;
R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloaLkyl, and e) Cl -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloaLkyl;

3 R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, WO 96/1001 1 o 1 3 5 1 PCT/US~5/12321 f ~ "~

e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or o substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;

R8a and R8b are independently selected from:
hydrogen, F, Cl, Br, NO2, R1 lo-, R10s(o)m-~ CN, R9C(o)NR9-, (R9)2N-C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2, RlOOC(O)NR9-, Cl-C20 aLkyl, aryl, heterocycle or C 1 -C20 alkyl substituted with aryl or heterocycle;

R9 is independently selected from hydrogen, C1-C6 alkyl and aryl9 R10 is independently selected from C1-C6 alkyl and aryl;

R11 is independently selected from hydrogen, C1-C6 alkyl and aryl, provided R 1 1 is Cl-C6 alkyl when n is 0;

R12 is independently hydrogen or Cl-C6 aLkyl;
30 R13 is Cl-C6 alkyl;

is aryl or 1,2,3,4-tetrahydronaphthyl;

WO 96/10011 . PCI/US95112321 ': `j ~;, _ 220i351 Z is independently H2 or 0;

misO, 1 or2;
n is independently O to 4;
pisOorl; and sis40r5;
or the pharmaceutically acceptable salts thereof.

In a third embodiment of this invention, the inhibitors of farnesyl transferase are illustrated by the formula Irl:
(cH2)qcH2oH

3~ (CR12)n(C3p(CR1~)n R1z ~NH~OH

wherein:
Rl is hydrogen, Cl-C6 alkyl or aryl;

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 heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, R90-, RlOs(o)m-~ R9C(o)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, RlOOC(O)NR9- and Cl-C20 alkyl, and WO 96/10011 PCT/USg5112321 2201~5} ~

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 o 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 heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, R9O-, RlOs(o)m-~ R9C(o)NR9-, CN, (R9)2N-C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2 RlOOC(O)NR9- 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 -;

y 2201 ~Sl X-Y is ~7a a) ~sss~N~ss R7b b) \sss~N~Ss C)~0~5S

( 1)m d) ~5ss~S~ss H
e)~SSs~ , or fl-CH2-CH2-;
R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;

3 R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, WO 96/10011 2 2 0 1 3 ~ ~ PCTIUSS15/12321 e) C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloaLkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloaLkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;

R~a and R8b are independently selected from:
hydrogen, F, Cl, Br, N02, Rl 1o-, RlOS(O)m-, CN, R9C(o)NR9-, (R9)2N-C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2, RlOOC(O)NR9-, Cl-C20 aLkyl, aryl, heterocycle or C 1 -C20 aLkyl substituted with aryl or heterocycle, R9 is independently selected from hydrogen, Cl-C6 aLkyl and aryl;

R10 is independently selected from Cl-C6 alkyl and aryl;

R l 1 is independently selected from hydrogen, C 1 -C6 alkyl and aryl, provided R 1 1 is C 1 -C6 alkyl when n is 0;

R12 is independently hydrogen or Cl-C6 alkyl;
30 f~
( V ) ~~ is aryl or 1,2,3,4-tetrahydronaphthyl;

Z is independently H2 or O;

.r ~

t 220I35 1 misO, l or2;
n is independently O to 4;
p is O or 1;

5 qisO, 1 or2; and sis40rS;
or the pharmaceutically acceptable salts thereof.

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

R8a 1 (C) J~ ~i ,Y ~0 R8b (CR 2) (CR12)n N12 X R~N

IV

wherein:
Rl is hydrogen, Cl-C6 alkyl or aryl;

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, 3 0 c) substituted or unsubstituted C1 -c20 alkyl, C2-c2o alkenyl, C3-Clo cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, R90-, R10s(o)m-~ R9C(o)NR9-, CN, (R9)2N-WO 96/10011 .. PCTIUS95/12321 ~ 2 0 1~

C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2 R1OOC(O)NR9- and Cl-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, o 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 heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, R9O-, RlOS(O)m-, R9C(o)NR9-, CN, (R9)2N-C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2, RlOOC(O)NR9- and Cl-C20 alkyl, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1o cycloalkyl; or R3 and R4 are combined to form - (CH2)S -;

WO 96/10011 ~2 û 1 35 1 ` ,',, ~ PCTIUS95112321 X-Y is R7a a) ~s~ Nsss R7b b)~sSs~N5ss C)~SSS~0~5S

()m d) ~5ss~S~ss H
e)--sSS~ or H

f) -CH2-CH2-;
.

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

R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, WO 96tlOOll PCT/US95112321 22 0 1~5 ~

d) unsubstituted or substituted cycloaLkyl, e) C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyL
f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and o g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;

R~sa and R~b are independently selected from:
hydrogen, F, Cl, Br, NO2, R1 lo, RlOs(o)m-~ CN, R9C(o)NR9-, (R9)2N-C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2, R1OOC(O)NR9-, Cl-C20 alkyl, aryl, heterocycle or C1-C20 alkyl substituted with aryl or heterocycle;

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

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

R11 is independently selected from hydrogen, C1-C6 alkyl and aryl, provided Rl 1 is C1-C6 alkyl when n is 0, R12 is independently hydrogen or Cl-C6 aLkyl;

is aryl or 1,2,3,4-tetrahydronaphthyl;

WO 96/10011 2~ a r ' ~ . PCTIUS95112321 ~ .

Z is independently H2 or 0;

misO, l or2;
n is independently O to 4;
5 pisOorl;
q is 0, l or2; and sis40rS;
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:

R8a 1 ~1~ ~ ,y ~ OH
Rsb~3 (CR 2)n\cJp(cR 2)n NR12 X ~NH ~
I

wherein:
Rl is hydrogen, Cl-C6 aLkyl or aryl;

R2a is selected from:
a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from ~l~nint~., leucine, isoleucine and valine;
b) substituted or unsubstituted Cl-clo alkyl, C2-Clo alkenyl, C3-C1o cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R90-, R10s(o)m-~ R9C(o)NR9-, CN, (R9)2N-C(NR9)-, R9C(o)-, R9OC(O)-, N3, -N(R9)2, - R1OOC(O)NR9- and C1-C20 alkyl, and WO 96/10011 ~ ~ = PCTIUS95/12321 2201'351 ~, , .

c) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl; or 5 R2b is hydrogen or 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 Cl-Clo alkyl, C2-clo alkenyl, C3-C1o cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, R9O-, RlOS(O)m-, R9C(O)NR9-, CN, (R9)2 C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2, RlOOC(O)NR9- and Cl-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 gl~
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, Cl-c2o alkenyl, C3-C1o cycloalkyl, aryl or heterocycle group, Wo 96110011 , ' ~ - PCTIUS95112321 t ' ' . : ' , 22Ol 3~i 1 wherein the substituent is selected from F, Cl, Br, N02, R90-, RlOs(o)m-~ R9C(o)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2 RlOOC(O)NR9- and Cl-C20 alkyl, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl;

R5b is selected from:
o a) hydrogen, and b) Cl -C3 alkyl; or X-Y is R7a a) ~S5s~Nsss R7b b) \~

c) ~ O~

2 5 d) ~sss~s5s~ , or e) -CH2-CH2-;
0 R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and WO 96110011 2 2 Q 1 3 5 1 . PCTtUS95/12321 e) C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloaL~yl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;

R7b is selected from o a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloaL~yl, e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloaL~yl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloaL~yl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 aL~yl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
wherein heterocycle is selected from pyrrolidiIlyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;

R8a and R8b are independently selected from: -hydrogen, F, Cl, Br, NO2, R1 lo, RlOs(o)m-~ CN, R9C(o)NR9-, (R9)2N-C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2, RlOOC(O)NR9-, Cl-C20 alkyl, aryl, heterocycle or C l-C20 alkyl substituted with aryl or heterocycle;

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

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

R 11 is independently selected from hydrogen, Cl-C6 alkyl and aryl, o provided Rl 1 is C 1 -C6 alkyl when n is 0;
R12 is independently hydrogen or Cl-C6 aLkyl;
(~) is aryl or 1,2,3,4-tetrahydronaphthyl;

Z is independently H2 or 0;

misO, 1 or2;
20 n is independently O to 4;
pisOorl; and s is 4 or S;

or the ph~ ceutically acceptable salts thereof.

In a second more preferred embodiment of the invention, the prodrugs of the preferred compounds of the formula I are illustrated by the formula II:
3 0 R8a /o\ Z R2a R2bZ R5a R5b ~ (CR 2)n~C)p(CR12)n NR12 X ~H~
R8b Il = -- ~

WO 96/10011 PCT/USg5112321 22013~

wherein:
R1 is hydrogen, Cl-C6 aL~yl or aryl, R2a is selected from:
a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from ~l~nine, leucine, isoleucine and valine; and b) substituted or unsubstituted Cl-clo alkyl, C2-Clo alkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, 13r, o NO2, R9O-, R10s(o)m-~ R9C(o)NR9-~ CN, (R9)2N-C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2, RlOOC(O)NR9- and Cl-C20 aLkyl, and c) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1o cycloalkyl; and R2b is hydrogen or 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 2s amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-clo alkyl, C2-clo aL~enyl, C3-Clo cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, R9O-, RlOS(O)m-, R9C(o)NR9-, CN, (lR9)2N-C(NR9)-, R9C(O)-, R9OC(o)-, N3, -N(R9)2~ -RlOOC(O)NR9- and Cl-C20 alkyl, and WO 96/10011 . PCT/US95/12321 ~ 22013S~

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 gl~
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, Cl-C20 alkenyl, C3-C1o cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R9O-, R10s(o)m-~ R9C(o)NR9-, CN, (R9)2N-C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2 R10OC(O)NR9- and C1-C20 alkyl, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl;

R5b is selected from:
a) hydrogen, and b) Cl -C3 alkyl; or R6 is a) substituted or unsubstituted Cl-Cg alkyl, wherein the substituent on the alkyl is selected from:
1) aryl, 2) heterocycle, 3) -N(R10)2, 4) -OR9, or WO 96110011 ~ PCI'IUS95/12321 b) ~, O R13 X-Y is R7a a) R7b b) \sSS~NSsS

C)~0;~5S
H

d) ~~ , or e) -CH2-CH2-;

R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and 3 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 heterocycle, d) unsubstituted or substituted cycloaLkyl, e) Cl-C6 aL~yl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloaL~yl, f~ a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 aL~yl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and lS g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloaL~yl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;

R8a and R8b are independently selected from:
hydrogen, F, Cl, Br, N02, Rl lo, R10s(o)m-~ CN, R9C(o)NR9-, (R9)2N-C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2, R1OOC(O)NR9-, C1-C20 alkyl, aryl, heterocycle or C 1 -C20 alkyl substituted with aryl or 3 o heterocycle;
R9 is independently selected from hydrogen, C1-C6 alkyl and aryl;

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

WO 96/10011 PCT/USg5/12321 22~135 ~ ~ - 32 -R 1 1 is independently selected from hydrogen, C 1 -C6 alkyl and aryl, provided Rl 1 is C1-C6 alkyl when n is 0;

R12 is independently hydrogen or Cl-C6 aLkyl;

R13 is C1 -C6 alkyl;
~, is aryl or 1,2,3,4-tetrahydronaphthyl;
Z is independently H2 or 0;

misO, 1 or2;
15 n is independently O to 4;
pisOorl; and sis40rS;

or the pharmaceutically acceptable salts thereof.

In a third more preferred embodiment of the invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula II:

2s (cH2)qcH2oH

R8~(CR12)(C3(CR1z)J~NF~ NH~

Rl ishydrogen, Cl-C6 alkyl or aryl;

R2a is selected from:

, 220135~ .

a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from ~l~nine, 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, R9O-, RlOs(o)m-~ R9C(o)NR9-, CN, (R9)2N-C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2, RlOOC(O)NR9- and Cl-C20 aLkyl, and o c) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1o cycloalkyl; and R2b is hydrogen or 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 amlI10 aCld WhlCh lS:
i) methionine sulfoxide, or ii) methionine sulfone, c) substituted orunsub~liluled Cl-Clo alkyl, C2-clo alkenyl, C3-C1o cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R9O-, R10s(o)m-~ R9C(o)NR9-, CN, (R9)2N-C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2, R1OOC(O)NR9- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1o cycloalkyl;

WO 96/10011 I; PCT/US~5/12321 220135 f - 34 -X-Y is a) ~s~Nss R7b b) \ss5~N~ss C) ~SSS~0~5S
H

d) ~sss~ , or e) -CH2-CH2-;

R7a is selected from a) hydrogen, b) unsubstituted or sul.~Liluled aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C 1 -C6 aLkyl substituted with hydrogen or an unsubstituted or sulJsliluled group selected from aryl, heterocycle a~d 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 heterocycle, W096/10011 2201 3S~ PCTIUS95112321 . .
r ~ 35 ~
d) unsubstituted or substituted cycloalkyl, e) Cl-C6 aLkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 aIkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloaL~yl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;

R8a and R8b are independently selected from:
hydrogen, F, Cl, Br, NO2, Rl lo, RlOs(o)m-~ CN, R9C(o)NR9-, (R9)2N-C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2, RlOOC(O)NR9-, Cl-C20 alkyl, aryl, heterocycle or C l -C20 alkyl substituted with aryl or heterocycle;

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

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

R l l is independently selected from hydrogen, Cl -C6 alkyl and aryl, provided Rl l is Cl-C6 alkyl when n is 0;

R12 is independently hydrogen or Cl-C6 aLkyl;

WO 96110011 ~ == PCT/USg5/12321 22013~

(~ is aryl or 1,2,3,4-tetrahydronaphthyl;

5 Z iS independently H2 or 0;

misO, 1 or2;
n is independently O to 4;
pisOorl;
10 qisO,lor2;and s is 4 or 5;

or the pharmaceutically acceptable salts thereof.

In a fourth more preferred embodiment of the invention, the prodrugs of the preferred compounds of formula m are illustrated by the formula IV:

R~ (cR12)n(c3p(cR12)J~N12 )~' ~NH~

IV
wherein:
R1 is hydrogen, Cl-C6 alkyl or aryl;

R2a is selected from:
a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from ~l~nine, leucine, isoleucine and valine;
b) substituted or unsubstituted Cl-clo alkyl, C2-C10 alkenyl, C3-C1o cycloalkyl, aryl or heterocyclic group, I

' 220135 ~, wherein the substituent is selected from F, Cl, Br, NOæ R90-, R10s(o)m-~ R9C(o)NR9-, CN, (R9)2N-C(NR9)-, R9C(o)-, R9OC(O)-, N3, -N(R9)2, R1OOC(O)NR9- and C1-C20 alkyl, and C) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl; and R2b is hydrogen or Cl-C6 alkyl; or o 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 substituent is selected from F, Cl, Br, N02, R90-, R10s(o)m-~ R9C(o)NR9-, CN, (R9)2N-C(NR9)-, R9C(o)-, R9OC(O)-, N3, -N(R9)27 R1OOC(O)NR9- and C1-C20 alkyl, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1o cycloalkyl;

.

-WO 96110011 . ~ ~ ~ PCTIUS95/12321 .
22 0 135 r X-Y is R7a a) ~S5s~Nsss R7b b) \sSs~N~ss C) ~,o~55 H

d) ~sss~ , or H
e) -CH2-CH2-;

R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) Cl-C6 aLkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle 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 heterocycle, r d) unsubstituted or substituted cycloalkyl, e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and o g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloaL~yl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;

R8a and R8b are independently selected from:
hydrogen, F, Cl, Br, NO2, R11o, RlS(O)m-, CN, R9C(o)NR9-, (R9)2N-C(NR9)-, R9C(o)-, R9OC(o)-, N3, -N(R9)2, RlOOC(O)NR9-, Cl-C20 alkyl, aryl, heterocycle or Cl -C20 alkyl substituted with aryl or heterocycle;

R9 is independently selected from hydrogen, Cl-C6 aL~yl and aryl;

R10 is independently selected from Cl-C6 alkyl and aryl;

R 1 1 is independently selected from hydrogen, C 1 -C6 alkyl and aryl, - provided R 1 1 is C 1-C6 alkyl when n is 0;

R12 is independently hydrogen or Cl-C6 alkyl;

WO 96110011 . PCTlUSgS112321 . :~ ? :

is aryl or 1,2,3,4-tetrahydronaphthyl;
5 Z iS indepenclently ~I2 or 0;

misO, 1 or2;
n is independently O to 4;
p is O or l;
o q is 0, 1 or 2; and sis40r5;

or the ph~ ceutically acceptable salts thereof.
The following compounds illustrate the preferred compounds of this invention:
N- { 2(S)-[4-(4-nitrophenyl)butanoylamino]-3(S)-methylpentyl ) -N-( 1-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[5-phenylpentanoylamino]-3(S)-methylpentyl } -N-( 1-naphthylmethyl-glycyl-methionine methyl ester N- { 2(S)-[4-phenylbenzoylamino]-3(S)-methylpentyl } -N-(1-naphthylmethyl-glycyl-methionine methyl ester N- { 2(S)-~5-(2,4-dinitrophenyl)pentanoylamino]-3(S)-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[4-nitrobenzoylamino]-3(S)-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[3-(3-indolyl)propanoylamino }-3(S)-methylpentyl } -N-( l -naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[3-(1 -indolyl)propanoylamino } -3(S)-methylpentyl } -N-( l -naphthylmethyl)-glycyl-methionine methyl ester WO 96/10011 . PCI/US95/12321 ' Sl N- { 2(S)-[4-(4-methoxyphenyl)-4-oxobutanoylamino]-4-methylpentyl}-N-(1-naphthylmethyl-glycyl-methionine methyl ester N- { 2(S)- { 2-(1 ,2,3,4-tetrahydro)naphthoylamino } -4-methylpentyl } -N-5 (1-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[1-(1 ,2,3,4-tetrahydro)naphthoylamino]-4-methylpentyl } -N-(1-naphthylmethyl-glycyl-methionine methyl ester N- { 2(S)-[4-(4-hydroxyphenyl)butanoylamino]-4-methylpentyl } -N-( l -naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[4-(4-aminophenyl)butanoylamino]-4-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine methyl ester 15 N- { 2(S)-[2-benzylbenzoylamino]-4-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(2-benzoylphenyl)acetylamino]-4-methylpentyl } -N-(l -naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(2-benzylphenyl)acetylamino]-4-methylpentyl } -N-( l -naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(4-beniylphenyl)acetylamino]-4-methylpentyl } -N-(l -25 naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[(3-benzoylphenyl)acetylamino]-4-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine methyl ester N- { 2(S)-[4-(4-nitrophenyl)butanoylamino]-3(S)-methylpentyl } -N-( 1-naphthylmethyl)-glycyl-methionine .

WO 96/10011 ~ ~ PCTtUS95/12321 ,, " . , , ~ ~ --2201351~

N- { 2(S)-[5-phenylpentanoylamino]-3(S)-methylpentyl } -N-( 1-naphthylmethyl) -glycyl -methionine N- { 2(S)-[4-phenylbenzoylamino] -3 (S)-methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[5-(2,4-dinitrophenyl)pentanoylamino]-3(S)-methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[4-nitrobenzoylamino]-3(S)-methylpentyl } -N-(1-naphthylmethyl) -glycyl-methionine N- { 2(S)-[3-(3-indolyl)propanoylamino] -3(S)-methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[3-( 1 -indolyl)propanoylamino] -3 (S)-methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[4-(4-methoxyphenyl)-4-oxobutanoylamino]-4-methylpentyl } -N-(1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[2-(1 ,2,3,4-tetrahydro)naphthoylamino]-4-methylpentyl } -N-20 (l-naphthylmethyl)-glycyl-methionine N- { 2(S)-[ 1-(1 ,2,3,4-tetrahydro)naphthoylamino]-4-methylpentyl } -N-( 1 -naphthylmethyl)-glycyl-methionine N- { 2(S)-[4-(4-nitrophenyl)butanoylamino]-4-methylpentyl } -N-(l -25 naphthylmethyl)-glycyl-methionine N- { 2(S)-[4-(4-hydroxyphenyl)butanoylamino]-4-methylpentyl } -N-( 1-naphthylmethyl) -glycyl-methionine 3 N- { 2(S)-[(3-benzoylphenyl)acetylamino]-4-methylpentyl } -N-( 1-naphthylmethyl) -glycyl-methionine N- { 2(S)-[4-(4-aminophenyl)butanoylamino]-4-methylpentyl } -N-(1-naphthylmethyl) -glycyl-methionine WO 96/10011 Z201 3~1 PCT/US95/12321 r ~ ~ .
~ 43 ~

N- { 2(S)-[2-benzylbenzoylamino]-4-methylpentyl } -N-(1-naphthylrnethyl)-glycyl-methionine 5 N- { 2(S)-[(2-benzoylphenyl)acetylamino]-4-methylpentyl } -N-( 1-naphthylmethyl)-glycyl-methionine N- { 2(S)-[(2-benzylphenyl)acetylamino]-4-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine N- { 2(S)-[(4-benzylphenyl)acetylamino]-4-methylpentyl } -N-( 1-naphthylmethyl)-glycyl-methionine or the pharmaceutically acceptable salts thereof.

The most preferred compounds of the invention are:

N- { 2(S)-[4-(4-nitrophenyl)butanoylamino]-3(S)-methylpentyl } -N-( 1-naphthylmethyl) -glycyl -methionine 02N ~ ~ N J~OH

/~1 ~3 SCH3 N- { 2(S)-[4-(4-nitrophenyl)butanoylamino]-3(S)-methylpentyl } -N-( 1-30 naphthylrnethyl)-glycyl-methionine methylester .

~ .
2 2 0 1 3 5 i r I Jc-02N `G~ H ~J~

s /\ ~3 SCH3 N-{2(s)-[5-(2~4-dilliLlophenyl)pentanoylamino]-3(s)-methylpentyl}-N
( 1 -naphthylmethyl)-glycyl-methionine N--N~ Jl`OH

02N O - ~3 SCH3 N- { 2(S)-[~-(2,4-dilliLl o~henyl)pentanoylamino]-3(S)-methylpentyl } -N-(1 -n~rhthylmethyl)-glycyl-methionine methyl ester H H ll ~ ~ .--N~N~U`OCH3 2s 02N~ NO /~ ~3 SCH3 or the pharmaceutically acceptable salts thereof.

~ . 2~0f 3~1 In the present invention, the amino acids which are disclosed are identified both by conventional 3 letter and single letter abbreviations as indicated below:

.Al~nine Ala A
Arginine Arg R
Asparagine Asn N
Asparticacid Asp D
Asparagine or Aspartic acid Asx B
Cysteine Cys C
Glut~min~o. Gln Q
Glutamic acid Glu E
Glut~mine 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

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.

2~Q13S I - 46 -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, "cycloalkyl" is intended to include non-5 aromatic cyclic hydrocarbon groups having the specified number ofcarbon 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 15 monocyclic, bicyclic or tricyclic carbon ring(s) of up to 7 members in each ring, wherein at least one ring is aromatic. Fx~mples of aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phen~ l,rt;llyl and the like.
The term heterocycle or heterocyclic, as used herein, 20 represents a stable 5- to 7-membered monocyclic or stable ~- to 1 ] -membered bicyclic or stable 11-15 membered tricyclic heterocyclic ring which is either saturated or lm~lrated, 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 25 which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, 3 0 benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydro-benzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, WO 96/10011 PCrlUS95112321 ~ 2201351 =~
.... . ~ I ....~

isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide, pyridonyl, pyrazinyl, 5 pyrazolidinyl, pyrazolyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolinyl N-oxide, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.
As used herein, the terms "substituted aryl", "substituted heterocycle" and "substituted cycloalkyl" are intended to include the cyclic group which is substituted with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(cl-c6 alkyl)2, NO2, CN, (cl-c6 alkyl)O-, -OH, (Cl-C6 15 alkyl)S(O)m-, (cl-c6 alkyl)C(O)NH-, H2N-c(NH)-~ (C1 -C6 alkyl)C(O)-, (Cl-C6 alkyl)OC(O)-, N3,(Cl-C6 aLkyl)OC(O)NH- and Cl-C20 aLkyl.
When R2a and R2b and R3 and R4 are combined to form - (CH2)S -, cyclic moieties are formed. Examples of such cyclic 2o moieties include, but are not limited to:

25 ~ ~
When R5a and R5b are combined to form - (CH2)s -, cyclic moieties as described hereinabove for R2a and R2b and R3 and R4 are formed. In addition, such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-cont~inin~
30 cyclic moieties include, but are not limited to:

~X` ' ~' 2201351~

o~ s ;~

The ph~nn~ceutically acceptable salts of the compoLmds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inor3~anic 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, slllf~nilic, 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(Rl)2 represents -NHH, -NHCH3, -NHC2Hs, 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 3 o 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 ph~ ceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this ~ 2201351 .

.;

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 following works: Schroeder et al., "The Peptides", Vol. I, Ac~lemic Press 1965, or Bo(l~n~7ky et al., "Peptide Synthesis", Interscience Publishers, 1966, or McOmie (ed.) "Protective Groups in Organic Chemistry", Plenum Press, 1973, or Barany et al., "The Peptides:
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 Dimethylform~mide;
EDC 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide-hydrochloride;
HOBT 1-Hydroxybenzotriazole hydrate;
Et3N Triethylamine;
EtOAc Ethyl acetate;
FAB Fast atom bombardment;
HOOBT 3-Hydroxy- 1,2,2-benzotriazin-4(3h~)-one;
HPLC High-performance liquid chromatography;

.
2~0~3~1 50 MCPBA m-Chloroperoxybenzoic acid;
MsCI Methanesulfonyl chloride;
NaHMDS Sodium bis(trimethylsilyl)amide;
Py Pyridine;
TFA Trifluoroacetic acid;
THF Tetrahydrorur~.

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 experiment~l 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 20 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 3 0 reactions described in the Reaction Schemes.

, 22I~Sl ~, REACTION SCHEME A

Reaction A. Couplin~ of residues to form an amide bond >lo~ N ~OH + H2N
O , O

EDC, HOBT RA H
or HOOBT >~O~N~ J~OR
Et3N, DMF RB

HCI or R

REACTION SCHEME B

Reaction B. Preparation of reduced peptide subunits by reductive alkylation O RA RB

2s >~OJ~NH~f + H2NJ~

3 0 ~ >I`oJ~ N ~ N ~JI~OR
H RB

WO 96/10~11 PCI/USgS1123~1 REACTION SCHEME C

Reaction C. Alkylation/reductive alkvlation of reduced peptide subunits >lOJ~N N~JI~OR R XL, base RB 1l RCCH, NaCNBH3 RA R7b ~ H -~OR

RB

REACTION SCHEME D

Reaction D. Couplin~ of residues to form an amide bond EDC, HOBT
o RA I or HOOBT
>~OJ~N OH + H2N~ Et3N, DMF

~ O RA H O
H ~ J

H N I NJI~O
o -~,1 ' 22013Sl ~
r REACTION SCHEME E

Reaction E. Preparation of reduced dipeptides from peptides >~OJ~ N N J~OR 3 0 >~0~N ~OR

where RA and RB are R2a, R2b, R3, R4, RSa or RSb as previously 15 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
20 outlines the preparation of the alkene isosteres lltili7ing standard manipulations such as Weinreb amide formation, Grignard reaction, acetylation, ozonolysis, Wittig reaction, ester hydrolysis, peptide coupling reaction, mesylation, cleavage of peptide protecting groups, reductive alkylation, etc., as may be known in the literature or 25 exemplified in the Experiment~l 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-m~gnesio, organo-lithio, or organo-zinc copper(l) cyanide SN2' displacement reaction 3 o (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 defined. In Step H of Scheme F, the amino terminus substituent Rx is incorporated using coupling WO 96110011 = ~ PCT/US95112321 ,, .
2 2 0 1 3 5 1 r reaction A and RXCOOH; the alkylation reaction C using RXCHO and a reducing agent; or alkylation reaction C using RxcH2xL.
The alkane analogs are prepared in a similar m~nner by including an additional catalytic hydrogenation step as outlined in 5 Reaction Scheme G.

REACTION SCHEME F
1. ClCO2i-Bu o BocNHJ~OH MeONHMe BocNH~
R2a2. ¦ R2a BrMg Step A

1. NaBH4 OAc BocNH ~J~
2. Ac2O, Py R2a Step B

1. O3, Me2S OAc 2. Ph3P=CHCO2Me BocNH ~CO2Me Step C R2a WO 96/10011 . PCT/US95/12321 REACTION SCHEME F (CONT'D) Step D
1. LiOH OH H MsCI, py Step E ~ BocNH~ Jl Step F
2. EDC, HOBT R2a 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 I`W~
R2a O ~ Step H
W"

R CH2N~ W' 2s R2a O W
wherein: R8a ~1l~

Rx is ~~ (CR12)n~cJp(cR 2)n R8b , ? = ~

REACTION SCHEME F (CONT'D) NaOH

RXCH2N~ ~OH
R2a 0 W"
or 1. HCI Alternate O Step H
Il .
2. RxcOH
EDC, HOBT

Rx N~f~ W
R2a0 W"
NaOH

Rx N~ ~OH
O R2a 0 I

W096/10011 2~013~1 PCIJUS95/12321 . ~

REACTION SC~IEME G
0 1. ClCO2i-Bu O
BocNH~J~ MeONHMe BocNH~

R2a BrMg ~ R2a 1. NaBH4 OAc I 1.03, Me2S
BocNH~
2. Ac20, py R2a 2. Ph3P=CHCO2Me QAc BocNH ~CO2Me + H2N~"~ 1. LiOH
R2a 1 2. EDC, HOBT

OH ~ O
BocNH~ N~ 1~ r R2a 0 0 MsCI, py WO 96/10011 PCr/US95/12321 o ~ s ~ `
22û 135 1 - 58 -REACTION SCHEME G (CONT'D) 8Ms H
BocN H ~ N~l, R2a O
1. R3MgCuCNCl-BF3 2. H2, 5% Pd/C
Step K
BocNH ~ O

R2a o -~

l 5 1 . HCI

2. NaCNBH3, RXCHO

RXCH2NH~ ~, O

NaOH
R CH2NH~ OH

R2a o ~,OH

, 2Z013~1 .

59 _ REACTION SCHEME G (CONT'D) or O

1. HCI 2. RXCOH
EDC, HOBT

RXCNH~ NH~,I~
R2a o NaOH

l ~J~`OH

The oxa isostere compounds of this invention are prepared according to the route outlined in Scheme H. An 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 3 with BOC
anhydride and DMAP (4-dimethylaminopyridine) in methylene chloride. Alkylation of_ 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

WO 96110011 _ PCT/US~5/12321 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 mesylation 5 and subsequent elimin~tion catalyzed by DBU (1,~-diazabicyclo[5.4.0~undec-7-ene) or the direct treatment of 7 with phosphorus oxychloride in pyridine to give olefin ~. Then, catalytic hydrogenation of 8 yields 6a. Direct hydrolysis of 6 with lithillm hydrogen peroxide in aqueous THF will produce acid 9b. Sometimes, 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 coupling of acid 9b with either an alpha-aminolactone (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 aL~ylation 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 _.
It is understood that RXCHO and RXCOOH reagents are readily available commercially or may be readily prepared by techniqes well known in the art from commercially available starting materials.
Hydrolysis of compounds 14 to the corresponding hydroxy acids and 25 acids, respectively, is accomplished by standard methods such as treatment with NaOH in alcoholic or aqueous milieux followed by careful acidifcation with dilute HCl.

. 2~?013SI PCT/US95112321 ! ! ' SCHEME H
HO) C~\CI ~I~N)~ 2 ~ N~"' R2a ~~

BOC

R3~,o~ P4 Base ~ o~N R2a R4Xor Base 6 RYRZCO

HO~o~ -H20- RZ~o 2 o N "~ R2a N~ R2a BOC BOC

WO 96/10011 PCIIUS9~/12321 .
~20 13~ ~ ~

SCHEME H (CONT'D) LiOOH; ,~R4 oraq. HCI, RW-NH o CO2H
then BOC2O R2a a Rw=H
b, Rw = BOC

EDC R~3~R4 HOBT O I A
R2a O

HCI R3~R4 HCI NH2 o A
R2a o W096/10011 2~013Sl PCI/US95/12321 r ~ 63 ~ = ~ =~
-SCHEME H (CONT'D) RXCHO, NaCNBH3 ~3~R4 12 RXC H2N H o~A
R2a O

RXCOOH, EDC, HOBT
13 ~ R4 RXCNH o~A

R2a o 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.
25 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-isopropylethyl~mine leads to lactam 17. N-BOC derivative 1~5 - is obtained via the reaction of 17 with BOC anhydride in THF
30 catalyzed by DMAP. Sequential alkylation of 1~ 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., homoserine lactone, etc.) or the -Wt>96/10011 j 1, PCI/US95/12321 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 N-BOC group of either 21 or 22 is 5 readily removed by treatment with gaseous hydrogen chloride. The resultant amine hydrochloride 23 undergoes reductive aLkylation in the presence of an aldehyde R1CHO (12) and a reducing agent (e.g., sodium cyanoborohydride); or acylation in the presence of R lCOOH
(13) and a peptide coupling reagent to afford the products 24 and 25.

-- pcrlus9sll232l Wog6110~ll 2~ ~I 351 , , .

ScHE~/IE 1 HO HO~ Scl )~ BOC20 ~ 2a 2) Cs~C03 H2N R2a ¦ HSCH2C02CH3 BOC

S S Boc2o tjTF~
CH302C H~ "'R2a ~ ~ /",R2a 16 t7 s? ~ R3~) H o t8 R3 ~R ~, R3 ~R4 H-A. E~)C goC~lH S~
~H s~`CO2H HoBT R2a 0 ~H~J~ OR
a Rw=H ~ BoC20 -~J R5a b, RW=BOC q WO 96110011 . PCI/US95/12321 '~ ~ J l~ h 22013~1 - 66 -SCHEME I (CONT'D) BOCNH S(O)~A HCI
R2a o m=o, ~Q ~ MCPBA
m=2, 22 HCI-NH2 X~A R CH2NH S(O)m~

~ NaCNBH3 24 m = 0 or 2 RXCOOH
EDC, HOBT

x1I R ~R
R CNH S(O) ~A
R2a o W096/lnO11 22013Sl PCI`/US95/12321 '~:1; J' ~' The compounds of this invention inhibit Ras farnesyl 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~ ceutical agents for m~mm~ls, 5 especially for humans. These compounds may be ~lministered 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 ~(lministered to m~mm~ls, preferably hllm~ns, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a ph~rm~ceutical composition, according to standard ph~rm~ceutical practice. The compounds can be ~lministered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of ~lministration.
For oral use of a chemotherapeutic compound according to this invention, the selected compound may be ~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 m~nesium stearate, are commonly added. For oral ~lministration in capsule form, useful ~ çnts 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 ingredient are usually 30 prepared, and the pH of the solutions should be suitably adjusted and bur~el~d. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic.
The present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the WO 96110011 . PCI/US95112321 ~''`'',. ' _ 22~13~51 a~lmini~tration of a therapeuticaliy effective amount of the compounds of this invention, with or without ph~rm~ceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and ph~rm~cologically 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 ~lmini~tered into a hllm~n subject, the daily dosage will normally be dete,mi~led 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 ~llmini~tered to a m~mm~l undergoing treatment for cancer. A~lmini~tration occurs in an amount between about 0. l mg/kg of body weight to about 20 mg/kg of body weight per day, preferably of between 0.5 mg/l~g of body weight to about l 0 mg~g of body 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 portions contacted with l~ ur~s which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine ~ell"il,us) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to allow the FPTase to farnesylate the substrate, the chemical content of the assay mixtures may be determined by well known immllnological, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay llli~Lure without the compound of the instant invention relative to the presence of the unchanged substrate in the assay cont~ining the WO 96/10011 P~,liU~55/12321 . ~
-- ~2aI3~t 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 5 samples which contain farnesyl-~roteill transferase and qll~ntit~ting the enzyme. Thus, potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract cont~inin~ 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 a~pro~liate 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 subst~n~i~lly smaller than the concentration of enzyme in the assay vessel) required to inhibit the enzymatic activity of the sample by 50% is approxim~tely equal to half of the concentration of the enzyme in that particular sample.

EXAMPLES
Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species and conditions are intended to be further illustrative of the invention 25 and not limit~tive of the reasonable scope thereof.
The standard workup referred to in the examples refers to solvent extraction and w~hing the organic solution with 10% citric acid, l 0% sodium bicarbonate and brine as appropriate. Solutions were dried over sodium sulfate and evaporated in vacuo on a rotary evaporator.

EXAMPLE l Preparation of N- { 2(S)-[4-(4-nitrophenyl)butanoylamino] -3 (S)-methylpentyl~-N-(l-naphthylmethyl)-~lycYl-methionine methyl ester 220135~ -70 -Step A: Preparation of N-(2(S)-(t-butoxycarbonylamino)-3(S)-methylpentyl)glycine methyl ester.

Glycine methyl ester hydrochloride (4.41 g, 0.035 mol) was dissolved in 1,2-dichloroethane (~0 mL) and DMF (5 mL) and treated with 3A molecular sieves (10 g) and N-t-butoxycarbonyl-isoleucinal (6.3 g, 0.029 mol) with stirring at 0C. Sodium triacetoxyborohydride (9.27 g, 0.044 mol) was added, and the pH of the mi~ul~ was adjusted to 6 with triethyl~mine (3 mL, 0.022 mol).
After stirring for 18 h the mixture was filtered, concentrated to a small volume and 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 (Na2SO4). Filtration and concentration afforded a residue which was purified by flash chromatography (sio2~ EtOAc:hexane, 1 :3) to give the title compound.
lH NMR (CDC13) ~ 4.69 (lH, m), 3.72 (3H, s), 3.48-3.62 (lH, m), 3.42 (2H, ABq), 2.65 (2H, d, J=6 Hz), 1.4-1.6 (2H, m), 1.48 (9H, s), 20 1.04-1.2 (lH, m), 0.85-0.95 (6H, m) ppm.

Step B: Preparation of N-[2(S)-(t-Butoxycarbonylamino)-3(S)-methylpentyl]-N-(l-naphthylmethyl)glycine methyl ester N-[2(S)-(t-Butoxycarbonylamino)-3(S)-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 l-naphthaldehyde (1.89 ml, 13.9 mrnol) and sodium triacetoxyborohydride (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 extracted with EtOAc (3x50 ml). The organic layers were combined, dried (Na2S04), filtered, and concentrated to give 5.0 g of crude product WO 96/10011 ; PCT/US95/12321 22013Sl ~

. .

which was purified by chromatography (sio2~ 15-33% ethyl acetate /hexane) to give the title compound.
lH NMR (CD30D) ~ 8.44-8.38 (lH, d, J=6Hz), 7.88-7.77 (2H, m,), 7.55-7.35 (4H, m), 6.34-6.27 (lH, m), 4.25 (2H, ABq), 3.66 (3H, s), 3.40-3.23 (lH, m), 2.90 (lH, dd, J=6 and 15Hz), 2.63 (lH, dd, J=6 and 15Hz), 1.57-1.46 (lH, m), 1.43 (9H, s), 1.34-1.18 (2H, m), 1.06-0.85 (lH, m) and 0.85-0.71 (6H, m) ppm.

Step C Preparation of N-[2(S)-(t-Butoxycarbonylamino)-3(S)-0 methylpentyl]-N-( l -naphthylmethyl)glycine.
N-[2(S)-(t-Butoxycarbonylamino)-3(S)-methylpentyl]-N-(l-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 15 added. The mixture was stirred at ambient temperature for 4 h and concentrated. The resulting residue was dissolved in water (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 give the product. 1 H
20 NMR (CD3OD) ~ 8.43 (lH, d, J=6Hz), 7.97 (2H, t, J=6 Hz) 7.75-7.48 (4H, m), 4.96 (lH, d, J=12Hz), 4.72 (lH, d, J=12 Hz), 3.80-3.58 (3H, m), 3.49-3.40 (lH, dd" J=3 and 12 Hz), 3.03 (lH, dd, J=3 and 12 Hz), 1.42 (9H, s,), 1.37-1.28 (2H, m), 1.80-1.00 (lH, m), 0.94-0.78 (6H,m,)ppm.

Step D: Preparation of N-[2(S)-(t-Butoxycarbonylamino)-3(S)-methylpentyl]-N-( l -naphthylmethyl)glycine-methionine methyl ester.

N-[2(S)-(t-Butoxycarbonylamino)-3(S)-methylpentyl]-N-(l-naphthylmethyl)glycine (2.29g, 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) WO 96110011 ; PCI/US~5/12321 ., . ~ . ,~

22013S~ ~

and the mixture was stirred at ambient temperature for 24 h. The llliXIIIfe was concentrated, and the residue was partitioned between EtOAc (50 mL) and saturated NaHCO3 solution (25 mL). The aqueous layer was extracted with EtOAc (lx30 mL). The organic 5 layers were combined, washed with brine (lx25 mL), dried (Na2SO4), ltered, and concentrated to give 3.2 g of crude product which was puri~led by chromatography (silica gel eluting with 1 :3 to 1 :2 ethyl acetate in hexane) to give pure product. 1H NMR (CD30D) ~ 8.33 (lH, d, J=6 Hz), 7.90 (lH, d, J=6 Hz), 7.82 (lH, d, J=6 Hz), 7.61-7.39 (4H, m), 6.60-6.52 (lH, m), 4.32-4.06 (2H, m), 3.90-3.69 (lH, m), 3.65 (3H, s), 3.27-3.14 (2H, m), 2.93-2.70 (2H, m), 2.19-1.78 (6H, m), 1.63-1.30 (13H, m), 1.19-1.05 (lH, m), 0.95-0.81 (6H, m) ppm.

Step E: Preparation of N-(2(S)-amino-3(S)-methylpentyl)-N-(l-naphthylmethyl)-glycyl-methionine methyl ester hydrochloride.

N-[2(S)-(t-Butoxycarbonylamino)-3(S)-methylpentyl]-N-(l-naphthylmethyl)-glycyl-methionine methyl ester (2.82 g, 5.04 20 mmol) was dissolved in EtOAc (50 mL) and cooled to -25C. HCl was bubbled through the ~ ul~ until TLC (95:5 CH2Cl2:MeO]:~) indicated complete reaction. Nitrogen was bubbled through the mi~lu.e to remove excess HCl and the nli~Lul~ was then concentrated to give the title compound. lH NMR (CD30D) d 8.31 (lH, d, J-6 2s Hz), 7.96 (2H, d, J=6 Hz), 7.83-7.71 (lH, m), 7.68-7.49 (3H, m)~
4.76-4.55 (4H, m), 3.84-3.75 (2H, m), 3.71 (3H, s), 3.70-3.59 (llH, m), 3.21-3.00 (2H, m), 2.57-2.38 (3H, m), 2.17-2.04 (4H, m), 1.97-1.81 (lH, m), 1.63-1.50 (lH, m), 1.39-1.20 (lH, m), 1.19-1.00 (lH, m), 0.95-0.79 (6H, m) ppm.
0 Step F: N- { 2(S)-[4-(4-nitrophenyl)butanoylammo]-3(S)-methylpentyl } -N-(l -naphthylmethyl)-glycyl-methionine methyl ester ,. ~'20~

4-(4-Nitrophenyl)butyric acid (73 mg, 350 ~lmol), dissolved in DMF (5 ml) was treated with HOBT (60 mg, 350 ~mol), EDC (76 mg, 350,umol) and N-[2(S)-amino-3-methylpentyl)-N-(1-naphthylmethyl)-glycyl-methionine methyl ester hydrochloride (160 mg, 300 ~lmol). The pH was adjusted to ~7.5 with Et3N (170,ul, 385 ,umol) and the mixture was stirred at ambient temperature for 16h.
The mixture was concentrated and the residue was partitioned between EtOAc (100 ml) and H20 (10ûml). The organic layer was washed with H2O (2 X 50 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 give the title compound.

Step G: Preparation of N-{2(S)-[4-(4-nitrophenyl)butanoyl-amino]-3(S)-methylpentyl } -N-(1 -naphthylmethyl)-glycyl-methionine.

The methyl ester from Step F (87 mg, 130 ,umol) was dissolved in MeOH (1 ml) and 1.00N NaOH (300 ~l, 300 ,umol) was 20 added. The mixture was stirred at 45 C under argon for 45 mimltes, then the solution was partitioned between EtOAc (100 ml) and 5%
citric acid (50 ml). The organic layer was washed with H2O (2 X 50 ml), dried (MgSO4), filtered and evaporated to give the title compound.
Anal. Calcd for C34H44N406S: C, 64.13; H, 6.96; N, 8.80.
Found: C, 64.31; H, 7.07; N, 8.70.

The following compounds were prepared using the procedure described for Example 1, Step F, but substituting 4-(4-nitrophenyl)butyric acid with the ~royliate acid.

22~13~ 1 ~ 74 ~
N-{2(S)-[5-phenylpentanoylamino]-3(S)-methylpentyl}-N-(1 -naphthylmethyl-glycyl-methionine methyl ester N- { 2(S)-[4-phenylbenzoylamino]-3(S)-methylpentyl } -N-(1 -5 naphthylmethyl-glycyl-methionine methyl ester Anal. Calcd. for C3gH45N3O4S
C, 71.33: H, 7.09: N, 6.57 C.71.09:H,7.07:N,6.77 Fab mass spectrum m/z = 640 (M+1) N- ~ 2(S)-[5-(2,4-dinitrophenyl)pentanoylamino]-3(S)-methylpentyl ~ -N-(l-naphthylmethyl)-glycyl-methionine methyl ester Anal. Calcd. for C36H47N5OgS 1.7 CF3(~02H
C,52.36:H,5.43:N,7.75 C,52.38 :H,5.49 :N,7.80 Fab mass spectrum m/z = 710 (M+1) N- { 2(S)-[4-nitrobenzoylamino]-3(S)-methylpentyl } -N-(1 -naphthylmethyl)-glycyl-methionine methyl ester Anal. Calcd. for C32H40N4O6S 0.3 EtOAc C, 62.77: H, 6.73: N, 8.82 C,62.41 :H,6.51 :N,8.96 N- { 2(S)-[3-(3-indolyl)propanoylamino } -3(S)-methylpentyl } -N-(1 -2 naphthylmethyl)-glycyl-methionine methyl ester Anal. Calcd. for C36H46N404S 1.6 CF3C02H
C, 57.89: H, 5.90: N, 6.89 C, 57.94: H, 5.96: N, 6.83 N- { 2(S)-[3-(1 -indolyl)propanoylamino } -3(S)-methylpentyl } -N-( l -naphthylrnethyl)-glycyl-methionine methyl ester Anal. Calcd. for C36H46N4O4S 1.65 CF3CO2H
C, 57.63: H, 5.86: N, 6.84 C,57.73 :H,5.94 :N,6.82 The following compounds were prepared using the procedure described for Example 1, Step G but subs~ i"g the methyl 5 ester used therein with the corresponding methyl ester from Example 2.

N- { 2(S)-[5-phenylpentanoylamino]-3(S)-methylpentyl } -N-(l -naphthylmethyl)-glycyl-methionine o Anal. Calcd. for C35H47N304S 0.35 CHC13 C,65.56:H,7.37:N,6.49 C, 65.59: H, 7.37: N, 6.68 N- { 2(S)-[4-phenylbenzoylamino] -3 (S)-methylpentyl ) -N-( l -naphthylmethyl)-glycyl-methionine Anal. Calcd. for C37H43N304S 0.75 EtOAc C,69.43:H,7.14:N,6.07 C, 69.52: H, 7.05: N, 5.87 20 N- { 2(S)-[5-(2,4-dhlill ophenyl)pentanoylamino]-3(S)-methylpentyl } -N-( l -naphthylmethyl)-glycyl-methionine Anal. Calcd. for C35H45N508S 1.0 EtOAc C, 59.75: H, 6.81: N, 8.93 C, 59.97: H, 6.57: N, 8.59 N- { 2(S)-[4-nitrobenzoylamino]-3(S)-methylpentyl ) -N-(l -naphthylmethyl) -glycyl -methionine Anal. Calcd. for C31 H3gN406S 0.45 EtOAc C,62.10:H,6.61 :N,8.83 C,61.71:H,6.37:N,9.16 N- { 2(S)-[3-(3-indolyl)propanoylamino] -3(S)-methylpentyl } -N-(1 -naphthylmethyl) -glycyl-methionine Anal. Calcd. for C35H44N404S 0.4 EtOAc 0.75 H20 WO 96110011 i PCT/US95/12321 C, 66.04: H, 7.38: N, 8.42 C,66.03 :H,7.15 :N,8.41 N- { 2(S)-[3-(1 -indolyl)propanoylamino] -3(S)-methylpentyl } -N-( l -5 naphthylmethyl)-glycyl-methionine Anal. Calcd.. for C35H44N404S 0.8 EtOAc 0.85 H2O
C, 65.30: H, 7.47: N, 7.97 C, 65.26: H, 7.11: N, 7.97 Preparation of N- { 2(S)-[4-(4-methoxyphenyl)-4-oxobutanoylamino]-4-methylpentyl}-N-(1-naphthylmethyl-glycyl-methionine methyl ester Step A: Preparation of N-(2(S)-amino-4-methylpentyl)-N-(l-naphthylmethyl)-glycyl-methionine methyl ester hydrochloride.

Using the methods of Example 1, Steps A-E, sub~lilul~lg N-t-butoxycarbonyl-leucinal for the N-t-butoxycarbonyl-isoleucinal used therein, the title compound was obtained.

Step B: Preparation of N-{2(S)-[4-(4-methoxyphenyl)-4-oxobutanoylamino]-4-methylpentyl }-N-(1 -naphthylmethyl-glycyl-methionine methyl ester Using the method of Example 1, Step F and the appropriate carboxylic acid, the product of step A was converted to the title compound.
Anal. Calcd. for C36H47N3o6s 1.8 CF3CO2H 0.45 H2O: C, 55.10:H,5.80:N,4.87 Found: C, 55.10: H, 5.80: N, 4.96 Fab mass spectrurn m/z = 650 (M+1) WO 96/10011 ~ PCT/US95/12321 ~3$1 Using the method of Example 4, the following compounds were obtained.

N- { 2(S)- { 2-(1,2,3,4-tetrahydro)naphthoylamino } -4-methylpentyl } -N-(1-naphthylmethyl)-glycyl-methionine methyl ester Anal. Calcd. for C36H47N3O4S 0.25 EtOAc C, 69.45: H, 7.72: N, 6.57 C,69.24:H,7.65:N,6.64 Fab mass spectrum m/z = 618 (M+1) N- { 2(S)-[1,2,3,4-tetrahydro)naphthoylamino]-4-methylpentyl } -N-(1 -naphthylmethyl-glycyl-methionine methyl ester Anal. Calcd. for C36H47N3O4S 0.50 EtOAc C, 68.95: H, 7.77: N, 6.35 C,69.07:H,7.71 :N,6.37 Fab mass spectrum m/z = 618 (M+1) 20 N- { 2(S)-[4-(4-hydroxyphenyl)butanoylamino]-4-methylpentyl } -N-(1 -naphthylmethyl)-glycyl-methionine methyl ester Anal. Calcd for C35H47N305S 0.3 TFA 0.5 H2O: C, 57.17; H, 6.20; N, 5.26.
Found: C, 57.16; H, 6.17; N, 5.50.

N- { 2(S)-[4-(4-aminophenyl)butanoylamino]-4-methylpentyl } -N-(1 -naphthylmethyl)-glycyl-methionine methyl ester Anal. Calcd for C35H48N404S 2.25 TFA 0.25 H2O: C, 53.79; H, ~.80; N, 6.35.
30 Found: C, 53.70; H, 5.78; N, 6.56.

N- { 2(S)-[2-benzylbenzoylamino] -4-methylpentyl } -N-(1 -naphthylmethyl)-glycyl-methionine methyl ester FAB MS m/z = 655 (M+1).

~,;t`.~';';
; ~ -N- { 2(S)-[(2-benzoylphenyl)acetylamino]-4-methylpentyl } -N-(1 -naphthylmethyl)-glycyl-methionine methyl ester Anal. Calcd for C40H48N305S 0.5 EtOAc: C, 69.39; H, 7.21; N, 5.78. ==
Found: C, 69.15; H, 6.99; N, 5.95.

N- { 2(S)-[(2-benzylphenyl)acetylamino]-4-methylpentyl } -N-(l -naphthylmethyl)-glycyl-methionine methyl ester Anal. Calcd for C40H50N304S 0.5 EtOAc: C, 70.75; H, 7.63; N, 5.89.
Found: C, 70.87; H, 7.34; N, 6.21.

N- { 2(S)-[(4-benzylphenyl)acetylamino]-4-methylpentyl } -N-(1 -naphthylmethyl)-glycyl-methionine methylester Anal. Calcd for C40H50N304S 0.75 EtOAc: C, 70.26; H, 7.68; N, 5.72.
Found: C, 70.14; H, 7.28; N, 5.89.

N- { 2(S)-[(3-benzoylphenyl)acetylamino]-4-methylpentyl } -N-(1 naphthylmethyl)-glycyl-methionine methyl ester Anal. Calcd for C40H48N305S 0.3 EtOAc: C, 69.76; H, 7.16; N, 5.92.
Found: C, 69.76; H, 6.95; N, 6.07.

The following compounds were prepared using the procedure described for Example 1, Step G but sub~ u~ g the methyl ester used therein with the corresponding methyl ester from Examples 4 and 5.

WO 96/10011 PCI'tUS95/12321 ,~, ~ .
N- { 2(S)-[4-(4-methoxyphenyl)-4-oxobutanoylamino]-4-methylpentyl } -N-(l -naphthylmethyl)-glycyl-methionine This compound was prepared by in situ hydrolysis of the corresponding methyl ester.

N- { 2(S)-[2-(1,2,3,4-tetrahydro)naphthoylamino]-4-methylpentyl ~ -N-(1 -naphthylmethyl)-glycyl-methionine Anal. Calcd. for C35H45N304S 0.8 H20 C, 67.99: H, 7.60: N, 6.80 C, 67.99: H, 7.35: N; 6.73 N- { 2(S)-[1 -(1,2,3,4-tetrahydro)naphthoylamino]-4-methylpentyl } -N-(1 -naphthylmethyl)-glycyl-methionine Anal. Calcd. for C35H45N304S 0.8 H2O
C,67.99:H,7.60:N,6.80 C, 67.60: H, 7.32: N, 6.82 N- { 2(S)-[4-(4-nitrophenyl)butanoylamino] -4-methylpentyl ) -N-( l -naphthylmethyl)-glycyl-methionine Anal. Calcd for C34H44N4O6S 0.75 EtOAc 0.25 H2O: C, 62.82; H,

7.20; N, 7.92.
Found: C, 62.84; H, 7.03; N, 7.83.

N- { 2(S)-[4-(4-hydroxyphenyl)butanoylamino] -4-methylpentyl } -N-( l -naphthylmethyl)-glycyl-methionine Anal. Calcd for C34H45N305S 0.1 EtOAc 0.80 H2O: C, 65.47; H, 7.57; N, 6.66. Found: C, 65.46; H, 7.26; N, 6.66.

N- { 2(S)-[(3-benzoylphenyl)acetylamino]-4-methylpentyl } -N-(1 -naphthylmethyl)-glycyl-methionine Anal. Calcd for C39H46N305S 0.5 EtOAc 0.35 H2O: C, 68.46; H, 7.11; N, 5.84. Found: C, 68.47; H, 6.83; N, 5.81.
N- { 2(S)-[4-(4-aminophenyl)butanoylamino] -4-methylpentyl } -N-( l -naphthylmethyl)-glycyl-methionine WO 96/10011 . PCT/US95/12321 22~135L

This compound was prepared by in situ hydrolysis of the corresponclin~ methyl ester.
N- { 2(S)-[2-benzylbenzoylamino] 4-methylpentyl } -N-( l -naphthylmethyl)-glycyl-methionine Anal. Calcd for C38H46N304S 0.5 H2O: C, 70.23, H, 7.29; N, 6.47.

Found: C, 70.05; H, 7.02; N, 6.49.

N- { 2(S)-[(2-benzoylphenyl)acetylamino]-4-methylpentyl ) -N-(1 -0 naphthylmethyl)-glycyl-methionine Anal. Calcd for C39H46N305S 0.45 H20: C, 69.19; H, 6.98; ~, 6.21.
Found: C, 69.23; H, 6.73; N, 6.09.

N-{2(S)-[(2-benzylphenyl)acetylamino]-4-methylpentyl}-N-(l-naphthylmethyl) -glycyl -methionine 1 H NMR was consistent wi~ the named structure.

N- { 2(S)-[(4-benzylphenyl)acetylamino]-4-methylpentyl } -N-(1 -naphthylmethyl)-glycyl-me~ionine Anal. Calcd for C3gH4gN3O4S 0.1 EtOAc 0.35 H20: C, 70.62; H, 7.45; N, 6.27.
Found: C, 70.64; H, 7.25; N, 6.18.

2s EXAMPLE 32 In vitrD inhibition of ras farnesvl transferase 30 Assays offa~nesyl-protein transferase. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and RAS-CAl[L) were prepared as described by Schaber et al., J. Biol. Chem.
26~:14701-14704 (1990), Pompliano, et al., Biochemistry 31:3800 (1992) and Gibbs et al., PNAS U.S A. 86:6630-6634 (1989). Bovine . 22~13 "' ' FPTase was assayed in a volume of 100 ,ul cont~inin~; 100 mM N-(2-hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH
7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM [3H]-farnesyl diphosphate ([3H]-FPP; 740 CBq/mmol, New Fn~l~n(l 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 b-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 farnesyl in the presence of the test compound 15 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) 20 polyethylene glycol 20,000, 10 ,UM ZnC12 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 hllm~n FPTase by the assay described above and were found to have IC50 of < 10 ,uM.

WO 96/10011 PCr/US95/12321 220135~ - 82 -In vivo ras farnesylation assay The cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21. The assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51 :712-717, (1991). Cells in 10 cm dishes at 50-75%
confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1 %). After 4 hours at 37C, the cells are labelled in 3 ml methionine-free DMEM supple-meted with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[35S]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are 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 PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45 min. Aliquots of lysates cont~ining equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (lysis buffer lacking DTT) and immllnoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et al., J. Virol. 43:294-304, (19~2)).
Following a 2 hour antibody incubation at 4C, 200 ml of a 25%
suspension of ~r~ A-Sepharose coated with rabbit anti rat IgG is added for 45 min. The i"~ oprecipitates 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 buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Fnlightening, 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.

-WO 96110011 . PCT/US95/12321 22~135 1 - 83 -In vivo ~rowth inhibition assay To determine the biological consequences of FPTase 5 inhibition, the effect of the compounds of the instant invention on the anchorage-independent growth of Ratl 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.
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 a~ro~riate 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 were seeded and comparisons are made.

Claims (28)

WHAT IS CLAIMED IS:

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

I

wherein:
R1 is hydrogen, C1-C6 alkyl or aryl;
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 heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9- 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 heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9- 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 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9- 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(COR9)-;

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 heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;

R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
R8a and R8b are independently selected from:
hydrogen, F, Cl, Br, NO2, R11O-, R10S(O)m-, CN, R9C(O)NR9-, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9-, C1-C20 alkyl, aryl, heterocycle or C1-C20 alkyl substituted with aryl or heterocycle;
R9 is independently selected from hydrogen, C1-C6 alkyl and aryl;
R10 is independently selected from C1-C6 alkyl and aryl;
R11 is independently selected from hydrogen, C1-C6 alkyl and aryl, provided R11 is C1-C6 alkyl when n is 0;
R12 is independently hydrogen or C1-C6 alkyl;

is aryl or 1,2,3,4-tetrahydronaphthyl;
Z is independently H2 or O;

m is 0, 1 or 2;
n is independently 0 to 4;
p is 0 or 1; and s is 4 or 5;

or a pharmaceutically acceptable salt thereof.

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

II

wherein:
R1 is hydrogen, C1-C6 alkyl or aryl;
Ra and Rb are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9- 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 heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9- 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 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:

i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9- 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(COR9)-;
R6 is a) substituted or unsubstituted C1-C8 alkyl, wherein the substituent on the alkyl is selected from:
1) aryl, 2) heterocycle, 3) -N(R10)2, 4) -OR9, 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 heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
R8a and R8b are independently selected from:
hydrogen, F, Cl, Br, NO2, R11O-, R10S(O)m-, CN, R9C(O)NR9-, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9-, C1-C20 alkyl, aryl, heterocycle or C1-C20 alkyl substituted with aryl or heterocycle;
R9 is independently selected from hydrogen, C1-C6 alkyl and aryl;
R10 is independently selected from C1-C6 alkyl and aryl;
R11 is independently selected from hydrogen, C1-C6 alkyl and aryl, provided R11 is C1-C6 alkyl when n is 0;
R12 is independently hydrogen or C1-C6 alkyl;
R13 is C1-C6 alkyl;

is aryl or 1,2,3,4-tetrahydronaphthyl;

Z is independently H2 or O;

m is 0, 1 or 2;
n is independently 0 to 4;
p is 0 or 1; and s is 4 or 5;

or a pharmaceutically acceptable salt thereof.

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

III

wherein:
R1 is hydrogen, C1-C6 alkyl or aryl;
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 heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9- 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 heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9- 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 heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
R8a and R8b are independently selected from:
hydrogen, F, Cl, Br, NO2, R11O-, R10S(O)m-, CN, R9C(O)NR9-, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9-, C1-C20alkyl, aryl, heterocycle or C1-C20 alkyl substituted with aryl or heterocycle;

R9 is independently selected from hydrogen, C1-C6 alkyl and aryl;

R10 is independently selected from C1-C6 alkyl and aryl;
R11 is independently selected from hydrogen, C1-C6 alkyl and aryl, provided R11 is C1-C6 alkyl when n is 0;
R12 is independently hydrogen or C1-C6 alkyl;

is aryl or 1,2,3,4-tetrahydronaphthyl;

Z is independently H2 or O;

m is 0, 1 or 2;
n is independently 0 to 4;
p is 0 or 1;
q is 0, 1 or 2; and s is 4 or 5;

or a pharmaceutically acceptable salt thereof.

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

IV

wherein:
R1 is hydrogen, C1-C6 alkyl or aryl;
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 heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9- 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 heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9- 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 heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
R8a and R8b are independently selected from:
hydrogen, F, Cl, Br, NO2, R11O-, R10S(O)m-, CN, R9C(O)NR9-, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9-, C1-C20 alkyl, aryl, heterocycle or C1-C20 alkyl substituted with aryl or heterocycle;
R9 is independently selected from hydrogen, C1-C6 alkyl and aryl;
R10 is independently selected from C1-C6 alkyl and aryl;
R11 is independently selected from hydrogen, C1-C6 alkyl and aryl, provided R11 is C1-C6 alkyl when n is 0;
R12 is independently hydrogen or C1-C6 alkyl;

is aryl or 1,2,3,4-tetrahydronaphthyl;

Z is independently H2 or O;

m is 0, 1 or 2;
n is independently 0 to 4;
p is 0 or 1;
q is 0, 1 or 2; and s is 4 or 5;

or a pharmaceutically acceptable salt thereof.

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

?

wherein:
R1 is hydrogen, C1-C6 alkyl or aryl;
Ra 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; and 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, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9- 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 hydrogen or 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, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9- 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, c) substituted or unsubstituted C1-C10 alkyl, C1-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9- 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 heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle 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 heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
R8a and R8b are independently selected from:
hydrogen, F, Cl, Br, NO2, R11O-, R10S(O)m-, CN, R9C(O)NR9-, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9-, C1-C20 alkyl, aryl, heterocycle or C1-C20 alkyl substituted with aryl or heterocycle;

R9 is independently selected from hydrogen, C1-C6 alkyl and aryl;

R10 is independently selected from C1-C6 alkyl and aryl;
R11 is independently selected from hydrogen, C1-C6 alkyl and aryl, provided R11 is C1-C6 alkyl when n is 0;
R12 is independently hydrogen or C1-C6 alkyl;

is aryl or 1,2,3,4-tetrahydronaphthyl;

Z is independently H2 or O;

m is 0, 1 or 2;
n is independently 0 to 4;
p is 0 or 1; and s is 4 or 5;

or a pharmaceutically acceptable salt thereof.

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

II

wherein:
R1 is hydrogen, C1-C6 alkyl or aryl;
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, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9- 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 hydrogen or 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, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9- 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, c) substituted or unsubstituted C1-C10 alkyl, C1-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, NO2, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9- 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(R10)2, 4) -OR9, 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 heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle 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 heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
R8a and R8b are independently selected from:
hydrogen, F, Cl, Br, NO2, R11O-, R10S(O)m-, CN, R9C(O)NR9-, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9-, C1-C20 alkyl, aryl, heterocycle or C1-C20 alkyl substituted with aryl or heterocycle;
R9 is independently selected from hydrogen, C1-C6 alkyl and aryl;
R10 is independently selected from C1-C6 alkyl and aryl;

R11 is independently selected from hydrogen, C1-C6 alkyl and aryl, provided R11 is C1-C6 alkyl when n is 0;
R12 is independently hydrogen or C1-C6 alkyl;
R13 is C1-C6 alkyl;

is aryl or 1,2,3,4-tetrahydronaphthyl;

Z is independently H2 or O;

m is 0, 1 or 2;
n is independently 0 to 4;
p is 0 or 1; and s is 4 or 5;

or a pharmaceutically acceptable salt thereof.

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

III

R1 is hydrogen, C1-C6 alkyl or aryl;
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; and 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, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; and R2b is hydrogen or 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, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9- 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 heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle 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 heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
R8a and R8b are independently selected from:
hydrogen, F, Cl, Br, NO2, R11O-, R10S(O)m-, CN, R9C(O)NR9-, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9-, C1-C20 alkyl, aryl, heterocycle or C1-C20 alkyl substituted with aryl or heterocycle;
R9 is independently selected from hydrogen, C1-C6 alkyl and aryl;
R10 is independently selected from C1-C6 alkyl and aryl;
R11 is independently selected from hydrogen, C1-C6 alkyl and aryl, provided R11 is C1-C6 alkyl when n is 0;
R12 is independently hydrogen or C1-C6 alkyl;

is aryl or 1,2,3,4-tetrahydronaphthyl;

Z is independently H2 or O;

m is 0, 1 or 2;
n is independently 0 to 4;
p is 0 or 1;
q is 0, 1 or 2; and s is 4 or 5;

or a pharmaceutically acceptable salt thereof.

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

?V

wherein:
R1 is hydrogen, C1-C6 alkyl or aryl;
Ra 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, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9- 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 hydrogen or 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, R9O-, R10S(O)m-, R9C(O)NR9-, CN, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9- 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 heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle 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 heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;

R8a and R8b are independently selected from:
hydrogen, F, Cl, Br, NO2, R11O-, R10S(O)m-, CN, R9C(O)NR9-, (R9)2N-C(NR9)-, R9C(O)-, R9OC(O)-, N3, -N(R9)2, R10OC(O)NR9-, C1-C20 alkyl, aryl, heterocycle or C1-C20 alkyl substituted with aryl or heterocycle;
R9 is independently selected from hydrogen, C1-C6 alkyl and aryl;
R10 is independently selected from C1-C6 alkyl and aryl;
R11 is independently selected from hydrogen, C1-C6 alkyl and aryl, provided R11 is C1-C6 alkyl when n is 0;
R12 is independently hydrogen or C1-C6 alkyl;

is aryl or 1,2,3,4-tetrahydronaphthyl;

Z is independently H2 or O;

m is 0, 1 or 2;
n is independently 0 to 4;
p is 0 or 1;
q is 0, 1 or 2; and s is 4 or 5;

or a pharmaceutically acceptable salt thereof.

9. A compound which inhibits farnesyl-protein transferase which is:
N-{2(S)-[4-(4-nitrophenyl)butanoylamino]-3(S)-methylpentyl }-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[5-phenylpentanoylamino]-3(S)-methylpentyl}-N-(1-naphthylmethyl-glycyl-methionine methyl ester N-{2(S)-[4-phenylbenzoylamino]-3(S)-methylpentyl}-N-(1-naphthylmethyl-glycyl-methionine methyl ester N-{2(S)-[5-(2,4-dinitrophenyl)pentanoylamino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[4-nitrobenzoylamino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[3-(3-indolyl)propanoylamino}-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[3-(1-indolyl)propanoylamino}-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[4-(4-methoxyphenyl)-4-oxobutanoylamino]-4-methylpentyl}-N-(1-naphthylmethyl-glycyl-methionine methyl ester N-{2(S)-{2-(1,2,3,4-tetrahydro)naphthoylamino}-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[1-(1,2,3,4-tetrahydro)naphthoylamino]-4-methylpentyl}-N-(1-naphthylmethyl-glycyl-methionine methyl ester N-{2(S)-[4-(4-hydroxyphenyl)butanoylamino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[4-(4-aminophenyl)butanoylamino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[2-benzylbenzoylamino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(2-benzoylphenyl)acetylamino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(2-benzylphenyl)acetylamino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(4-benzylphenyl)acetylamino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[(3-benzoylphenyl)acetylamino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester N-{2(S)-[4-(4-nitrophenyl)butanoylamino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine.

N-{2(S)-[5-phenylpentanoylamino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[4-phenylbenzoylamino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[5-(2,4-dinitrophenyl)pentanoylamino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[4-nitrobenzoylamino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[3-(3-indolyl)propanoylamino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[3-(1-indolyl)propanoylamino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[4-(4-methoxyphenyl)-4-oxobutanoylamino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[2-(1,2,3,4-tetrahydro)naphthoylamino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[1-(1,2,3,4-tetrahydro)naphthoylamino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[4-(4-nitrophenyl)butanoylamino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[4-(4-hydroxyphenyl)butanoylamino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(3-benzoylphenyl)acetylamino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[4-(4-aminophenyl)butanoylamino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[2-benzylbenzoylamino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(2-benzoylphenyl)acetylamino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine N-{2(S)-[(2-benzylphenyl)acetylamino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine or N-{2(S)-[(4-benzylphenyl)acetylamino]-4-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine or a pharmaceutically acceptable salt thereof.

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

N-{2(S)-[4-(4-nitrophenyl)butanoylamino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine ;

or a pharmaceutically acceptable salt thereof.

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

N-{2(S)-[4-(4-nitrophenyl)butanoylamino]-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)-[5-(2,4-dinitrophenyl)pentanoylamino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine ;

or the pharmaceutically acceptable salt thereof.

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

N-{2(S)-[5-(2,4-dinitrophenyl)pentanoylamino]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester ;

or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

19. 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 14.

20. A method for inhibiting farnesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 15.

21. A method for inhibiting farnesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of Claim 16.

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

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 treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 14.

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

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

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

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.