CA2216654A1 - Inhibitors of farnesyl-protein transferase - Google Patents

Abstract

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

Description

CA 022166~4 1997-09-26 W O 96131~2~ PCT~US96/039'74 TITLE OF THE INVENTION
INHIBITORS OF FARNESYL-PROTEIN TRANSE~ERASE

R~LATED APPLIC~TION
The present patent application is a continuation-in-part application of copending application Serial No. 08/412,626, filed Malrch 29, 1995.

BACKGROUND OF THE INVENTION
The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of a ~i~n~lling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions likl~ a G-regulatory protein. In the inactive state, Ras is bound to GDP. Upon growth factor receptor activation Ras is inclllced to exchange GDP for GTP and undergoes a conformational change. The GTP-bound form of Ras propagates the growth stimulatory signal until the signal is termin~ted by the intrin~;c GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M. Willumsen, Ann. ~ev. Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-Aaal-Aaa2-Xaa"
box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino ~ acid) ~Willumsen et al., Nature 310:583-586 (1984)). Depending on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which CA 022166~4 1997-09-26 W O96/31525 PCTrUS96/03974 catalyze the aIkylation of the cysteine residue of the CAAX motif with a Cls or C20 isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem.
61:355-386 (1992); W.R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237 (1992)). The Ras protein is one of several proteins that are known to 5 undergo post-translational farnesylation. Other farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal m~ting factors, the nuclear l~min~, and the gamma subunit of tr~n~ cin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also 10 suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.
Inhibition of farnesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been 15 demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the Ras 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-~Lol~ill transferase blocks the growth of ras-20 dependent tumors in nude mice (N.E. Kohl et al., Proc. Natl. Acad. SciU.S.A., 91:9141-9145 (1994) and induces regression of m~mm~ry and salivary carcinomas in ras transgenic mice (N.E. Kohl et al., Nature Medicine, 1:792-797 (1995).
Indirect inhibition of farnesyl-protein transferase in vivo has 25 been demonstrated with lovastatin (Merck & Co., Rahway, NJ) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Farnesyl-protein transferase utilizes farnesyl 30 pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990);
Schaber etal., J. Biol. Chem., 265:14701-14704 (1990); Schaferetal., Science, 249:1133-1139 (1990); Manne etal., Proc. Natl. Acad. Sci USA, 87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesis CA 022166~4 1997-09-26 W O96/31525 PCTrUS96/039'74 by inhibiting HMG-CoA reductase blocks Ras membrane loc~li7~tion in cultured cells. However, direct inhibition of farnesyl-protein transferase ~ would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene 5 biosynthesis.
Inhibitors of farnesyl-protein transferase (E~PTase) have been described in two general classes. The first are analogs of farnesyl diphosphate (FPP), while the second class of inhibitors is related to the protein substrates (e.g., Ras) for the enzyme. The peptide derived 10 inhibitors that have been described are generally cysteine cont~inin~
molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNA,S, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase 15 enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141,851, University of Texas; N.E. Kohl et al., Science, 260: 1934- 1937 (1993)l;
Graham, et al., J. Med. Chem., 37, 725 (1994)). In general, deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound. However, the thiol group 20 potentially places limit~tions on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharrnacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable.
It has recently been reported that farnesyl-protein transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells 25 and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7-112930).
It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516).
30 ~mic1~7.ole-cont~ining inhibitors of farnesyl protein transferase have also been dLisclosed (WO 95/09001 and EP 0 675 112 Al).
It is, therefore, an object of this invention to develop tetrapeptide-based compounds that do not have a thiol moiety, and that will inhibit farnesyl-protein transferase and thus, the post-translational CA 022166~4 1997-09-26 W O96/31S25 PCTrUS96/03974 farnesylation of proteins. It is a further object of this invention to develop chemotherapeutic compositions cont~inin~ the compounds of this invention and methods for producing the compounds of this invention.

S SUMMARY OF THE INVENTION

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

W O96)31525 PCTrUS96/03974 S
The compounds of this invention are illustrated by the formulae:

V-A1(cR1R2)nA2(cR1-2)n-(w (CR1b2)p~N~;~OH

V - A1 (CR1 82)nA2(CRl ~Z)n ~W - (CR1b2)p\l~N ~oR12 HOCH2(CH~)q V - A1 (CR1 ~2)nA2(CR 1a2)n \W - (CR1 b2) ~f N i ~ J

V-A1(CR1e'2)nA2(CR1~2)n~W~-(CR1b2)p~N,~ /~r \;

CA 022166~4 1997-09-26 W O96/3152S PCT~US96/03974 ~ETAILED l~ SCRIPTION OF THE INVENTION
The compounds of this invention inhibit the farnesyl-protein transferase. In a first embodiment of this invention, the farnesyl-protein transferase inhibitors are illustrated by the formula I:
S

V - A (C R1r2)nA~(c R1a2)n-(w )-(G R1b2)p wherem:
Rla and Rlb are independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloaL~yl, aL~enyl, alkynyl, R100-, RllS(O)m-, R10C(O)NRl0-~ CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or Rl lOC(o)NR10 c) C l-C6 aL~yl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, aL~enyl, alkynyl, R100-, Rl lS(O)m-, R10C(O)NRl0-~ CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or Rl loC(O) NRlO;

20 R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C l-C20 aL~cyl, C2-C20 aL~enyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R10)2, N02, R100-, Rl lS(O)m-, RlOC(O)NR10-, CA 022166~4 1997-09-26 W 09613152~ PCTAUS96103974 - CN, (R10)2N-C(NR10)-, RlOC(O)-, RlOoc(o)-~ N3, -N(R10)2, Rl 10C(O)NR10- and Cl-C20 alkyl, and ~ dL) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-S Clo cycloaL~yl; or R2 and R3 are combined to form - (CH2)S -; or R2 or R3 are combined with R6 to form a ring such that ~ N R7a ~k~7~

R4a, R4b, R7a and R7b are independently selected from:
a) hydrogen, b) Cl-C6 aL~yl unsubstituted or substituted by alkenyl, RlQO-, Rl lS(O)m-, RlOC(O)NR10-, CN, N3, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, Rl lS(O)m-, RlOC(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or Rl 1OC(O)NR10-, and d) Cl-C6 aL~yl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-Clo cycloalkyl;
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, CA 022166~4 1997-09-26 W O96/31S25 PCTrUS96/03974 c) substituted or unsubstituted C l-C20 aLl~yl, C2-C20 aL~enyl, C3-Clo cycloaL~yl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, (R1o)2Nc(o)-~ N02, R100-, Rl lS(o)m RlOc(o)NRlo-~ CN, (Rlo)2N-c(NRlo)-~ RlOc(o) R1OOC(O)-, N3, -N(R10)2, Rl lOC(O)NR10- and C 1 -C20 aL~cyl, d) C l-C6 aL~yl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C1o cycloalkyl; or R5a and RSb are combined to form - (CH2)S - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;
R6 is independently selected from hydrogen or Cl-C6 aL~yl;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloaL~yl, aL~enyl, alkynyl, perfluoroaL~yl, F, Cl, Br, R100-, Rl lS(O)m-, RlOC(O)NR10-, CN, NO2, R102N-C(NR10)-, RlOC(O)-~
R1OOC(O)-, N3, -N(R10)2, or Rl lOC(O)NR10-, and c) Cl-C6 aL~yl unsubstituted or substitllte~l by aryl, heterocycle, cycloaL~yl, aL~enyl, aL~ynyl, perfluoroaL~yl, F, Cl, Br, R1OO-, Rl lS(O)m-, RlOC(O)NH-, CN, H2N-C(NH)-, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or RlOOC(O)NH-;

30 R9 is selected from:
a) hydrogen, b) aL~enyl, aL~ynyl, perfluoroaL~yl, F, Cl, Br, R100-, R1 1S(O)m-, R1OC(O)NR10-, CN, NO2, (R10)2N-C-CA 022166~4 1997-09-26 (NR10), R10C(o), R10Oc(o)-~ N3, -N(R10)2, or RllOC(O)NR10-, and ~ c) Cl-C6 aL~yl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R1OO-, R1 1S(O)m-, R1OC(O)NR10-, CN, (R10)2N-c(NRlo)-~ Rloc(o)-~ R10Oc(o)-~ N3, -N(R10)2, or Rl 1OC(O)NR10;

R10 is independently selected from hydrogen, Cl-C6 aL~yl, benzyl and aryl;
R11 is independently selected from Cl-C6 aL~yl and aryl;

A1 and A2 are independently selected from: a bond, -CH=CH-, -ec-, -C(O)-, -C(O)NR 10 , -NR 1 ~C(O)-, O, -N(R 10) , -S(O)2N(R10)-, -N(R1O)S(O)2-, or S(O)m;

Q is a substituted or unsubstituted nitrogen-cont~ining C6-Cg bicyclic ring system, wherein the non-nitrogen cont~inin~; ring is selected from an aromatic ring and a heterocycle;
V is selected from:
a) hydrogen, b) heterocycle, c) aryl, d) Cl-C20 aLkyl wherein from 0 to 4 carbon atoms are replac.ed with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;

W is a heterocycle;
.

X, Y and Z are independently H2 or O;

CA 022166~4 1997-09-26 W O96/31525 PCTrUS96/03974 m is 0, 1 or 2; .
nis 0,1,2,30r4;
pis 0,1,2,30r4;
r is O to 5, provided that r is O when V is hydrogen;
sis 40r5;
t is 3, 4 or 5; and uis Oor l;
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:

A1(CR1~ ) A2(CR1H2)n-(W) (CR1b2)p~N,; i~ ;oR~2 wherein:~5 Rla and Rlb are independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, aLkenyl, alkynyl, R100-, Rl lS(o)m, RlOc(o)NRlo-~ CN, N02, (Rlo)2N-c(NRlo)-~ Rloc(o)-~ RlOoc(o)-~ N3, -N(R10)2, or Rl lOC(O)NR10 c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, ~l~o, Rl lS(O)m-, RlOC(O)NR10-, CN, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or Rl loC(O)-NR10-;

R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, W O96/31S25 PCTrUS96/03974 b~ an oxidized form of a side chain of a naturally occurring amino acid which is:
~ i) methionine sulfoxide, or ii) me~ior~ine sulfone, and c) substit-lttq.-1 or unsubstituted Cl-C20 alkyl, C2-C20 alkenyl, C3-Clo cycloaLkyl, aryl or heterocyclic group, wherein ~e substituent is selected from F, Cl, Br, N(R10)2, N02, R100-, Rl 1 S(O)m-, RlOC(O)NRl~-, CN, (R10)2N-C(NR10)-, R1OC(O)-, R1OOC(O)-, ]~3, -N(R10)2, Rl 1OC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloaLkyl; or 15 R2 and lR3 are combined to form - (CH2)S -; or R2 or R3 are combined with R6 to forrn a ring such that R6 ~
~N~;, is ~N (CjH2)t;
R2 R3 R7a ~ R7b R4a, R4b, R7a and R7b are independently selected from:
a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R1OO-, R11S(O)m, R1OC(O)NR10-~ CN, N3, (R10)2N-C(NR10)-, R1OC(O)-, R1OOC(O)-, -N(R10)2, or Rl 1OC(O)NR10-, c~ aryl, heterocycle, cycloalkyl, alkenyl, R1OO-, R1 1S(O)m-, R1OC(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R1OC(O)-, R1OOC(O)-, N3, -N(R10)2, or Rl 1OC(O)NR10-, and CA 022l66~4 l997-09-26 W O96/31525 PCTrUS96/03974 d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-Clo cycloalkyl;

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 C l-C20 alkyl, C2-C20 alkenyl, C3-Clo cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, (RlO)2NC(o)-, N02, R100-, Rl lS(o)m R10C(O)NRl0-~ CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, Rl lOC(O)NR10- and Cl-C20 alkyl, d) C l -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl; or RSa and Rsb are combined to form - (CH2)S - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and-N(COR10);
R6 is independently selected from hydrogen or Cl-C6 alkyl;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroaLkyl, F, Cl, Br, R10O-~ Rl lS(o)m R10C(O)NRl0-~ CN, NO2, R102N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or Rl lOC(O)NR10-, and CA 022166~4 1997-09-26 W O96/31525 PCTfiUS961039'74 c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, ~ Cl, Br, R100-, Rl lS(O)m-, RlOC(O)NH-, CN, H2N-C(NH)-, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or S RlOOC(O)NH-;

R9 is selected from:
a) hydrogen, b) alkenyl, alkynyl, perfluoroaL~yl, F, Cl, Br, R100-, Rl lS(O)m-, RlOC(O)NR10-, CN, NO2, (R10)2N-C-(NR10) RlOC(O)-~ RlOOC(O)-~ N3, -N(R10)2, or Rl lOC(O)NR10-, and c) Cl-C6 aLkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(O)m-, RlOC(O)NR10-, CN, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or Rl lOC(O)NR10;

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

R12 is a) substituted or unsubstituted Cl-Cg aLkyl, substituted or unsubstituted C5-Cg cycloalkyl, or substituted or unsubstituted cyclic amine, wherein the substituted alkyl, cycloalkyl or cyclic amine is substituted with 1 or 2 substituents independently selected from:
1) Cl-C6 alkyl, 2) aryl, 3) heterocycle, 4) -N(Rl 1)2, S) -OR10, or b) CA 022166~4 1997-09-26 W O96/31S25 PCTrUS96/03974 R13 o 1 J~
~, O R14 R13 is independently selected from hydrogen and Cl-C6 aL~yl;

S R14 is independently selected from Cl-c6 aL~yl;

Al and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(0)-, -C(O)NR 10 , -NR 1 ~C(0)-, 0, -N(R 10) -S(0)2N(R10)-, -N(R10)S(0)2-, or S(O)m;
Q is a substituted or unsubstituted nitrogen-cont~inin~: C6-Cg bicyclicring system, wherein the non-nitrogen cont7~inin~ ring is selected from an aromatic ring and a heterocycle;

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

25 W is a heterocycle;

X, Y and Z are independently H2 or 0;

mis 0,1 or2;
30 nis 0,1,2,30r4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5, provided that r is 0 when V is hydrogen;

CA 022166~4 1997-09-26 W O 96/31525 PCT~US96/039'74 sis 40rS;
tis 3,40rS;and ~ uis Oorl;
or the ph~ ceutically acceptable salts thereof.
,5 In a third embodiment of this invention, the inhibitors of farnesyl transferase are illustrated by the formula III:

HOCH2(CH2~q V - A1(CR1a2)nA2(CR1a2)n ~W)- (CR1b2)p~N~'~

111 R4a R

wherein:
R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloaLkyl, aLkenyl, aLkynyl, R100-, lS R1 1S(O)m-, R1OC(O)NR10-, CN, N02, (R10)2N-C(NR10)-, R1OC(O)-, R1OOC(O)-, N3, -N(R10)2, or Rl lOC(o)NR10 c) C l-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloaLkyl, aLkenyl, alkynyl, R100-, R1 1S(O)m-, R1OC(O)NR10-, CN, (R10)2N-C(NR10)-, R1OC(O)-, R1OOC(O)-, N3, -N(R10)2, or Rl loC(O)-R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or CA 022166~4 1997-09-26 W O96/31525 PCT~US96/03974 ii) methionine sulfone, and c) substituted or unsubstituted Cl-C20 alkyl, C2-C20 alkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, RlOO-, Rl 1 S(O)m-~ RlOc(o)NRlo-~
CN, (R10)2N-C(NR10)-, RlOc(o)-~ RlOOC(O)-, N3, -N(R10)2, Rl lOC(O)NR10- and Cl-C20 alkyl, and d) Cl-C6 aLkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl; or R2 and R3 are combined to form - (CH2)S -; or R2 or R3 are combined with R6 to form a ring such that R6 ~
~ N~ R7a ~HRZ)b R4a, R4b, R7a and R7b are independently selected from:
a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by alkenyl, RlOO-, Rl lS(O)m-, RlOC(O)NR10-, CN, N3, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, Rl lS(O)m-, RlOC(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, N3, -N(Rlo)2 or Rl lOC(O)NR10-, and d) C l-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-Clo cycloalkyl;
R6 is independently selected from hydrogen or Cl-C6 alkyl;

CA 022166~4 1997-09-26 W 096/31525 PCTAUS96/039'74 R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, aL~enyl, aL~ynyl, S perfluoroaL~yl, F, Cl, Br, R100-, Rl lS(O)m-, RlOC(O)NR10-, CN, NO2, R102N-C(NR10)-, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or Rl lOC(O)NR10-, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloaL~yl, aL~enyl, aL~ynyl, perfluoroaL~yl, F, Cl, Br, RlOO-, Rl lS(O)m-, RlOC(O)NH-, CN, H2N-C(NH)-, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or RlOOC(O)NH-;

R9 is selected from:
a) hydrogen, b) aL~enyl, aL~ynyl, perfluoroaL~yl, F, Cl, Br, R100-, RllS(O)m-, RlOC(O)NR10-, CN, NO2, (R10)2N-C-(NR10), RlOC(O)-~ RlOOC(O)-~ N3, -N(R10)2, or Rl loc(o)NRlo-~ and c) Cl-C6 aL~yl unsubstituted or substituted by perlluoroal~yl, F, Cl, Br, RlOO-, RllS(O)m-, RlOC(O)NR10-, CN, (R10)2N-C(NR10)-, RlOC(O)-~ RlOOC(O)-, N3, -N(Rl~)2, or Rl lOC(O)NR10;

25 R10 is independently selected from hydrogen, Cl-C6 aL~yl, benzyl and aryl;

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

30 Al and A2 are independently selectedfrom: abond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR 10 , -NR 1 ~C(O)-, O, -N(R 10) , > -S(O)2N(R10)-, -N(RlO)S(O)2-~ or S(O)m;

CA 022l66~4 l997-09-26 W O96/31525 PCTrUS96/03974 Q is a substituted or unsubstituted nitrogen-cont~inin~ C6-Cg bicyclic ring system, wherein the non-nitrogen cont~ining ring is selected from an aromatic ring and a heterocycle;

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

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

m is 0, 1 or 2;
n is 0,1, 2, 3 0r 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1 or 2;
r is O to 5, provided that r is O when V is hydrogen;
sis 40rS;
tis 3,40rS;and uis Oor l;
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:

CA 022166~4 1997-09-26 W O96/31525 PCTrUS96/03974 V - A1 (CR1 a2)nA2(CR1 R2)n ~W)- (CR~b2)p~N~\ ~ N~

IV R4a~ R4b wherein:
Rla and Rlb are independently selected from:
a) hydrogen, S b) aryl, heterocycle, cycloalkyl, aLkenyl, alkynyl, R100-, RllS(O),m-, RlOC(O)NR10-, CN, N02, (R10)2N-C(NR10)-~ RlOC(O)-~ RlOOC(O)-~ N3, -N(R10)2, or RllOC(O)NR10 c) Cl-C6 aLkyl unsubsti~lte~l or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RlOO-, RllS(O)m-, RlOC(O)NR10-, CN, (R10)2N-C(NR10)-, RlOC(O)-~ RlOOC(O)-, N3, -N(R10)2, or Rl loC(O)-NR10;

15 R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl-C20 alkyl, C2-C20 aLkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, . N(R10)2, N02, R100-, Rl lS(O)m-, RlOC(O)NR10-, CN, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-., N3, -N(R10)2, Rl 10C(O)NR10- and Cl-C20 aL~yl, and d) Cl-C6 aLkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl; or CA 022166~4 1997-09-26 W O96/3152~ PCTrUS96/03974 R2 and R3 are combined to form - (CH2)S -; or R2 or R3 are combined with R6 to form a ring such that R6 r~
~-,N2~ R7a ~HR2)t R4a, R4b, R7a and R7b are independently selected from:
a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by alkenyl, R l~o, R1 lS(O)m-, RlOC(O)NR10-, CN, N3, (R10)2N-C(NR10)-, R1OC(O)-, R1OOC(O)-, -N(R10)2, or R1 1OC(O)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, R1OO-, R1 1S(O)m-, R1OC(O)NR10-, CN, NO2, (R10)2N-lS C(NR10)-, R1OC(O)-, R1OOC(O)-, N3, -N(R10)2, or R1 lOC(O)NR10-, and d) C 1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-Clo cycloalkyl;
R6 is independently selected from hydrogen or Cl-C6 alkyl;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R1OO-, Rl 1 S(O)m R1OC(O)NR10-~ CN, NO2, R102N-C(NR10)-, R1OC(O)-~
RlOOC(O)-, N3, -N(Rlo)2~ or Rl lOC(O)NR10-, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, aLkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RllS(O)m-, RlOC(O)NH-, CN, H2N-CA 022166~4 1997-09-26 W O 96/31525 PCT~US96/039'14 C(NH)-, R1OC(O)-, R1OOC(O)-, N3, -N(R10)2, or RlOOC(O)NH-;

R9 is selected from:
S a) hydrogen, b) alkenyl, aL~ynyl, perfluoroaL~yl, F, Cl, Br, R100-, R1 1S(O)m-, R1OC(O)NR10-, CN, NO2, (Rlo)2N
(NR10)-, R1OC(O)-, R1OOC(O)-, N3, -N(R10)2, or R1 1OC(O)NR10-, and c) Cl-C6 alkyl unsubstituted or substituted by perfluoroaL~yl, F, Cl, Br, R1OO-, R11S(O)m-, R1OC(O)NR10-, CN, (R10)2N-C(NR10)-, R1OC(O)-, R1OOC(O)-, N3, -N(R10)2, or Rl 1OC(O)NR10;
~5 R10 is independently selected from hydrogen, Cl-C6 aL~yl, benzyl and aryl;

R11 is independently selected from Cl-C6 aLkyl and aryl;
~0 A1 and A2 areindependently selectedfrom: abond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR 10 , -NR 1 ~C(O)-, O, -N(R 10) -S(O)2N(R10)-, -N(R1O)S(O)2-~ or S(O)m;

Q is a substituted or unsubstituted nitrogen-cont~ining C6-Cg bicyclic 25 ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle;

V is selected from:
a) hydrogen, b) heterocycle, c) aryl, d) Cl-C20 aL~yl wherein from 0 to 4 carbon atoms are repLlced with a a heteroatom selected from O, S, and N, and e) C2-C20 aL~enyl, W O96/31525 PCTrUS96/03974 provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is O and A2 is S(O)m;

W is a heterocycle;

X, Y and Z are independently H2 or 0;

m is 0, 1 or 2;
nis 0, 1,2,30r4;
pis 0,1,2,30r4;
q is 0, 1 or 2;
r is O to 5, provided that r is O when V is hydrogen;
sis 40rS;
tis 3,40r5;arld lS uis Oorl;
or the pharmaceutically acceptable salts thereof.

In a more preferred embodiment of this invention, the Ras 20 farnesyl transferase inhibitors are illustrated by the Formula I:

V A1(CR1~2)nA2(CH1A2)n-(W (CH1b2)p~N~OH

wherein:

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

Rlb is independently selected from:
a) hydrogen, CA 022166~4 1997-09-26 W O9613152S PCTAUS96/039'74 b) aryl, heterocycle, cycloalkyl, RlOO-, -N(R10)2 or alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, aL~enyl, R100-, or-N(R10)2;

5 R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino aci'd which is:
i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-Clo alkyl, C2-Clo alkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, RlOO-, Rl lS(O)m-, RlOC(O)NR10-, CN, (RlO)2N C(NR10), RlOC(O)-~ RlOOC(O)-~ N3, -N(R10)2, Rl lOC(O)NR10- and Cl-C20 alkyl, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl; or R2 and R3 are combined to form - (CH2)S -; or R2 or R3 are combined with R6 to form a ring such that R6 ~
~7,,N~, is ~ (~H2)t;
R2 R3 R7a ~ R7b R4a and R7a are independently selected from:
a) hydrogen, b) C l-C6 alkyl unsubstituted or substituted by alkenyl, R 1 0O-, Rl lS(O)m, RlOC(O)NR10-~ CN, N3, (RlO)2N-c(NRlo) RlOC(O)-, RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10-, CA 022166~4 1997-09-26 W O96/3152S PCTrUS96/03974 c) aryl, heterocycle, cycloaLkyl, alkenyl, R100-, Rl lS(O)m-, RlOC(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, N3, -N(Rl0)2, or Rl lOC(O)NR10-, and d) C 1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-Clo cycloaLkyl;

R4b and R7b are hydrogen;
R5a is selected from:
a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glllt~mine, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl-Clo alkyl, C2-Clo alkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R100-, Rl 1 S(O)m-, RlOC(O)NR10-, (R10)2NC(o)-~ CN, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, Rl lOC(O)NR10- and Cl-C20 alkyl, and d) C l-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl;

RSb is selected from:
a) hydrogen, and b) Cl-C3 alkyl;

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

W O96/31~25 PCT~US96tO397 R8 is independently selected from:
a) hydrogen, b) Cl-C6 aLkyl, C2-C6 alkenyl, C2-C6 aL~cynyl, Cl-C6 perfluoroaLkyl, F, Cl, R100-, RlOC(O)NR10-, CN, N02, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10-, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroaLkyl, R100-., RlOC(o)NR10, (Rlo)2N-c(NRlo)-~ RlO
RlOOC(O)-, -N(RlO)2~ or Rl lOC(O)NR10-;
R9 is selected from:
a) hydrogen, b) C2-C6 aLkenyl, C2-C6 aLkynyl, C l-C6 perfluoroalkyl, F, Cl, RlOO-, RllS(O)m-, RlOC(O)NR10-~ CN, NO2, (R10)2~-lS C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10-, and c) Cl-C6 aLkyl unsubstituted or substituted by Cl-C6 perfluoroaLkyl, F, Cl, R100-, Rl lS(O)m-, RlOC(o)NRl'3-, CN, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10;

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

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

Q is selected from:

~r -~-N~, ~--N~ and ~;

CA 022166~4 1997-09-26 W O96/31525 PCTrUS96103974 Al and A2 are independently selected from: a bond, -CH=CH-, -C-C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;

5 V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C l-C20 alkyl wherein from O to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) C2-C20 aL~enyl, and provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if 15 Al is a bond, n is O and A2 is S(O)m;

W is a heterocycle selected from pyrrolidinyl, imic1~olyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;
X, Y and Z are independently H2 or 0;

m is 0, 1 or 2;
nis 0, 1,2,30r4;
pis 0,1,2,30r4;
r is O to 5, provided that r is O when V is hydrogen;
t is 3, 4 or 5; and uis Oor l;

30 or the pharmaceutically acceptable salts thereof.

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

CA 022166~4 1997-09-26 W O96131S2~ PCTfUS96/03974 V-A1(CR1a2)nA2(CR1az)n (W (CR1b2)p~N~ ~oR12 wherem:

Rla is independently selected from: hydrogen or Cl-C6 alkyl;
s Rlb is independently selected from:
a~ hydrogen, b) aryl, heterocycle, cycloalkyl, RlOO-, -N(R10)2 or alkenyl, c) Cl-C6 aLkyl unsubstituted or substituted by aryl, heterocycle, cycloaL~yl, alkenyl, R100-, or-N(R10)2;

R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-Clo alkyl, C2-Clo alkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, RlOO-, Rl lS(O)m-, RlOC(O)NR10-, CN, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, Rl lOC(O)NR10- and Cl-C20 alkyl, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl; or R2 and R3 are combined to form - (CH2)S -; or CA 022166~4 1997-09-26 W O96/31525 PCT~US96/03974 R2 or R3 are combined with R6 to form a ring such that R6 ~

~2 ~ R7a ~ R7b R4a and R7a are independently selected from:
a) hydrogen, b) C l-C6 alkyl unsubstituted or substituted by alkenyl, R l Oo, Rl lS(O)m, RlOC(O)NR10-, CN, N3, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, Rl lS(O)m-, RlOC(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or Rl lOC(O)NR10-, and d) Cl-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-Clo cycloaLkyl;

R4b and R7b are hydrogen;
R5a is selected from:
a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glut~mine, 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 Cl-Clo alkyl, C2-Clo alkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R100-, Rl lS(O)m-, RlOC(O)NR10-, CA 022166~4 1997-09-26 W O96/31525 PCTrUS96/03974 ~ (RlO)2Nc(o)-~ CN, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, Rl lOC(O)NR10- and - Cl-C20 aLkyl, and d) Cl-C6 aL~yl substituted with an unsubstituted or S substituted group selected from aryl, heterocycle and C3-Clo cycloaL~yl;

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

R6 is independently selected from hydrogen or Cl-C6 aL~yl;

R8 is independently selected from:
a) hydrogen, b) Cl-C6 alkyl, C2-c6 alkenyl, C2-C6 alkynyl, Cl-c6 perfluoroaLkyl, F, Cl, R100-, RlOC(O)NR10-, CN, N02, (R10)2N-C(NR10)-, RlOc(o)-~ RlOoc(o)-~ -N(R10)2, or RllOC(O)NR10-, and c) Cl-C6 aL~yl substituted by Cl-C6 perfluoroalkyl, R100-, RlOC(O)NR10-, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10-;

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 aL~ynyl, Cl-C6 perfluoroaL~yl, F, Cl, RlOO-, Rl lS(O)m-, RlOC(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or RllOC(O)NR10-, and ~ 30 c) Cl-C6 alkyl unsubstituted or substituted by Cl-C6 perfluoroaLkyl, F, Cl, R100-, Rl lS(O)m-, RlOC(O)NRl()-, CN, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10;

W O96/31S25 PCTrUS96103974 R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl;

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

R12 is a) substituted or unsubstituted Cl-Cg alkyl, substituted or unsubstituted C5-Cg cycloaLkyl, or substituted or unsubstituted cyclic amine, wherein the substituted aLkyl, cycloaLkyl or cyclic amine is substituted with 1 or 2 substituents independently selected from:
1) Cl-C6 alkyl, 2) aryl, 3) heterocycle, 4) -N(Rll)2, 5) -OR10, or b) ~, O Rl4 20 R13 is independently selected from hydrogen and Cl-C6 aLkyl;

R14 is independently selected from Cl-C6 aLkyl;

Q is selected from:

-~-N~ ~;--N~1 and ~;

CA 022166~4 1997-09-26 A1 and A2 are independently selectedfrom: abond, -CH=CH-, -C~C-, -C(0)-, -C(O)NR10-, 0, -N(R10)-, or S(O)m;

V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyL, isoquinolinyl, and thienyl, c) aryl, d) Cl-C20 aL~yl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) C2-C20 aL~enyl, and provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(O)m;
W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;
20 X, Y and Z are independently H2 or 0;

m is 0, 1 or 2;
nis 0,1,2,30r4;
pis 0, 1,2,30r4;
r is 0 to S, provided that r is 0 when V is hydrogen;
tis 3,40r5;and u is 0 or 1;

or the pharmaceutically acceptable salts thereof.~0 In a third more preferred embodiment of this invention, the inhibitors of farnesyl transferase are illustrated by the forrnula III:

CA 022166~4 1997-09-26 W O96/31525 PCT~US96/03974 HOCH2(CH2)q V - A1 (CR1~2)nA2(CR1a2) -(WJ~ (CR1b ) N~ ~ OH

wherein:

S Rla is independently selected from: hydrogen or Cl-C6 aL~yl;

R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloaLkyl, R100-, -N(R10)2 or aLkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloaLkyl, aLkenyl, R100-, or-N(R10)2;

R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-Clo aL~yl, C2-Clo alkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, R10O-, Rl lS(O)m-, R10C(O)NRl0-~ CN, (R10)2N-C(NR10)-, Rl0c(o)-~ R10OC(O)-, N3, -N(R10)2, Rl lOC(O)NR10- and Cl-C20 alkyl, and d) C 1 -C6 aL~yl substituted with an unsubstituted or substituted group selected frorn aryl, heterocycle and C3-C1o cycloalkyl; or CA 022166~4 1997-09-26 R2 and R3 are combined to form - (CH2)S -; or ~ R2 or R3 are combined with R6 to form a ring such that R , ~

~ ; N~ R7~a~R7b;

R4a and R7a are independently selected from:
a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by alkenyl, RlOO-, Rl lS(O)m-, RlOC(O)NR10-, CN, N3, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, Rl lS(O)m-, RlOC(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or Rl lOC(O)NR10-, and d) Cl-C6 aLkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-Clo cycloalkyl;

20 R4b and R7b are hydrogen;

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

R8 is independently selected from:
a) hydrogen, b) Cl-C6 alkyl, C2-C6 alkenyl, C2-c6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, RlOO-, RlOC(O)NR10-, CN, NO2, (R10)2N C(NR10), RlOC(O)-~ RlOOC(O)-~ -N(RlO)2~ or RllOC(O)NR10-, and CA 022166~4 1997-09-26 W O96/31525 PCTrUS96/03974 c) Cl-C6 alkyl substituted by Cl-C6 perfluoroaL~yl, R100-, RlOC(O)NR10, (R10)2N-C(NR10), RlOC(O)-~
RlOOC(O)-, -N(Rlo)2~ or Rl 1 OC(O)NR10-;

S R9 is selected from:
a) hydrogen, b) C2-C6 aLkenyl, C2-c6 alkynyl, C l-C6 perfluoroalkyl, F, Cl, RlOO-, Rl 1 S(O)m-~ RlOC(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or RllOC(O)NR10-, and c) Cl-C6 alkyl unsubstituted or substituted by Cl-C6 perfluoroalkyl, F, Cl, RlOO-, Rl lS(O)m-, RlOC(O)NR10-, CN, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl;

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

~ ;~ \~ and ~;

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

V is selected from:
a) hydrogen, CA 022l66~4 l997-09-26 W O96/31525 PCTrUS96/039'74 - b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinoliny]., isoquinolinyl, and thienyl, c) aryl, d) Cl-C20 aL~yl wherein from O to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and e) C2-C20 aL~enyl, and provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is O and A2 is S(O)m;

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

15 X, Y and ~ are independently H2 or 0;

m is 0, 1 or 2;
nis 0, 1,2,30r4;
pis 0, 1,2,30r4;
qis 0,lor2;
r is O to 5, provided that r is O when V is hydrogen;
t is 3, 4 or 5; and uis Oorl;

25 or the ph~ ceutically acceptable salts thereof.

In a fourth more preferred embodiment of this invention.~ the prodrugs of the preferred compounds of Formula m are illustrated by the Formula IV:

CA 022166~4 1997-09-26 W O96/31S2S PCTrUS96/03974 V - A1 (CR1~2)nA Z(cR1az)n ~r~ (CR1bz)p wherem:

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

Rlb is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloaL~yl, R100-, -N(R10)2 or aL~enyl, c) Cl-C6 aLkyl unsub~tit~lte-l or substituted by aryl, heterocycle, cycloaLkyl, aL~enyl, R100-, or-N(R10)2;

R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-Clo aLkyl, C2-Clo aLkenyl, C3-Clo cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, RlOO, Rl lS(o)m, RlOc(o)NRlo-~ CN, (R 1 0)2N-C(NR 10) , R 1 ~C(O)-, R 1 ~OC(O)-, N3, -N(R10)2, Rl lOC(O)NR10- and Cl-C20 aLkyl, and d) C 1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloaLkyl; or R2 and R3 are combined to form - (CH2)S -; or CA 022166~4 1997-09-26 W O96131525 PCT~US96/03974 R2 or R3 are combined with R6 to form a ring such that ~;N~, R7a~R7)b;

R4a and R7a are independently selected from:
a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by alkenyl, RlOC)-, Rl lS(O)m-, RlOC(O)NR10-, CN, N3, (R10)2N-C(NRl~)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10-, c) aryl, heterocycle, cycloalkyl, aLkenyl, R100-, Rl lS(O)m-, RlOC(O)NR10-, CN, NO2, (R10)2N-C(NR10)-~ RlOC(O)-, RlOOC(O)-~ N3, -N(R10)2, or Rl lOC(O)NR10-, and dL) Cl-C6 aL~yl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-Clo cycloaL~yl;

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

R8 is independently selected from:
a) hydrogen, b) Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, RlOO-, RlOC(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, RlOC(O)-~ RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10-, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, RlOO-, RlOC(O)NR10-, (R10)2N-C(NR10)-, RlOC(O)-~
RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10-;

CA 022166~4 1997-09-26 W O96/31S25 PCTrUS96/03974 R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-c6 aLkynyl, C l-C6 perfluoroalkyl, F, Cl, R100-, Rl lS(O)m-, RlOC(O)NR10-, CN, N02, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10-, and c) Cl-C6 alkyl unsubstituted or substituted by Cl-C6 perfluoroalkyl, F, Cl, R100-, Rl lS(O)m-, RlOc(o)NRlo-~
CN, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10;

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

Q is selected from:

~ N~ N~ and ,~:

Al and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;
V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, CA 022166~4 1997-09-26 W O 96131525 PCTrUS96/03974 c) aryl, d) Cl-C20 aL~yl wherein from O to 4 carbon atoms are replaced ~ with a a heteroatom selected from 0, S, and N, and e) C2-C20 aL~enyl, and 5 provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is O and A2 is S(O)m;

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

m is 0, 1 or 2;
nis 0,1,2,30r4;
pis 0, 1,2,30r4;
qis 0,1 or2;
r is O to 5, provided that r is O when V is hydrogen;
t is 3, 4 or 5; and uis Oor l;
or the pharmaceutically acceptable salts thereof.

The preferred compounds of this invention are as follows:
N-[(lH-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]- 1 ,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester N-[(lH-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-1,2,3,4-30 tetrahydro-3(S)-isoquinolinecarbonyl-methionine N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]- 1 ,2,3,4-tetrahydro -3(S)-isoquinolinecarbonyl-methionine methyl ester 35 N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]- 1 ,2,3,4-tetrahydro-3(S)-isoquinolinP,c~rbonyl-methionine CA 022166~4 1997-09-26 W 096131525 PCTrUS96/03974 N-[(lH-imidazol-4-ylpropionyl)-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tekahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester 5 N-[(lH-imidazol-4-ylpropionyl)-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine N-[( 1 -(4-cyanobenzyl)- lH-imidazol-5-yl)acetyl]-2(S)-amino-3(S)-methylpentyl]-1,2,34-tekahydro-3(S)-isoquinolinecarbonyl methionine 10 methyl ester N-[(1-(4-cyanobenzyl)-lH-imidazol-5-yl)acetyl]-2(S)-amino-3(S)-methylpentyl]-1,2,34-tekahydro-3(S)-isoquinolinecarbonyl methionine 15 N-[N-(4-cyanobenzyl)-L-pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tekahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester N-[N-(4-cyanobenzyl)-L-pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1 ,2,3,4-tekahydro-3(S)-isoquinolinecarbonyl-methionine or the pharmaceutically acceptable salts or optical isomer thereof.

Specific examples of compounds of the invention are:
N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tekahydro-3(S)-isoquinolinecarbonyl-methionine O~N N~

W O 96/31525 PCTrUS9610397 N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]- 1 ,2,3,~tetrahydro-~ 3(S)-isoquinolinecarbonyl-methionine methyl ester O
~N~H ~ N ~ 3 ~~ ~

5 or the ph~rm~ceutically acceptable salts or optical isomer thereof.

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

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

CA 022166~4 1997-09-26 W O 96/31525 PCTrUS96/03974 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 15 isomers, being included in the present invention.
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-20 aromatic cyclic hydrocarbon groups having the specified number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
"Alkenyl" groups include those groups having the specified number of carbon atoms and having one or several double bonds.
25 Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, l-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like.
As used herein, "aryl" is intended to include any stable 30 monocyclic, bicyclic or tricyclic carbon ring(s) of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like.

CA 022166~4 1997-09-26 W O96/31525 PCTrUS96/0397'1 The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic or stable 11-15 membered tricyclic heterocycle ring which is either saturated or un~ rated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydro-benzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide, pyridonyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolinyl N-oxide, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.
As used herein, the terms "substituted aryl", "substituted heterocycle" and "substituted cycloaL~yl" 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( C6 aL~yl)2, NO2, CN, (cl-c6 alkyl)O-, -OH, (cl-c6 alkyl)s(o)m-~ ~Cl-C6 aL~yl)C(O)NH-, H2N-C(NH)-, (cl-c6 alkyl)C(O)-, (C1-C6 aL~yl)OC(O)-, N3,(Cl-C6 aL~yl)OC(O)NH- and Cl-C20 alkyl.

CA 022166~4 1997-09-26 W O96/31525 PCTrUS96103974 The following structure:

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

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

When R5a and R5b are combined to form - (CH2)S -, cyclic moieties as described hereinabove for R3 and R4 are formed. In addition, 20 such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-cont~ining cyclic moieties include, but are not limited to:

W O96/31525 PCTrUS96/0397~1 7~J ~o~ SJ

O o H O N~

As used herein, the phrase "nitrogen cont~inin~: C6-Cg S bicyclic ring system wherein the non-nitrogen cont~ining ring is selecl:ed from an aromatic ring and a heterocycle" which defines moiety "Q" of the instant invention includes but is not limited to the following ring systems:

~A,~r --N;~ -55sS-~

~ N~

It is well understood by persons of ordinary skill in the art that the "side chain" of the naturally occurring amino acid glycine is a hydrogen moiety.
The pharmaceutically acceptable salts of the compounds of 15 this invention include the conventional non-toxic salts of the compounds CA 022166~4 1997-09-26 W O96/31525 PCTrUS96103974 of this invention as formed, e.g., from noh-toxic inorganic 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 5 organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, ~ malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenyl-acetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, ffimaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
It is intended that the definition of any substituent or variable (e.g., R10, Z, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, -N(R10)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to 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.
Preferably, R1a and R1b are independently selected from:
hydrogen, -N(R8)2, R8C(O)NR8- or Cl-C6 aL~yl unsubstituted or substituted by -N(R8)2~ R8O- or R8C(O)NR8-.
Preferably, R2 is the sidechain of glycine (hydrogen).
Preferably, R3 is selected from:
a) a side chain of a naturally occurring arnino acid, b) substituted or unsubstituted C l-C20 aLkyl, wherein the substituent is selected from F, Cl, Br, N(R10)2, N02, R100-, Rl lS(O)m-, RlOC(O)NR10-, CN, (R10)2N C(NR10), R1OC(O)-~ R1OOC(O)-, N3, -N(R10)2, R1 1OC(O)NR10- and Cl-C20 alkyl, and c) C 1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-Clo cycloalkyl; or R3 is combined with R6 to form pyrrolidinyl ring.
Preferably, R4a, R4b, R7a and R7b are independently selected from: hydrogen, Cl-C6 alkyl, aryl and benzyl.

CA 022166~4 1997-09-26 W O96/31525 PCTrUS96103974 Preferably, R5a and R5b are independently selected from:
a s;de chain of a naturally occurring amino acid, methionine sulfoxide, methionine sulfone and unsubstituted or substituted Cl-C6 aL~yl .
Preferably, R6 is: hydrogen or is combined with R3 to form pyrrolidinyl ring.
Preferably, R8 is selected from: hydrogen, perfluoroaLkyl, F, Cl, Br, R10O-, Rlls(o)m-~ CN, NO2, R102N-C(NR10)-, Rl0c(o) RlOOC~O)-, N3, -N(R10)2, or Rl lOC(O)NR10- and Cl-C6 aL~yl.
Preferably, R9 is hydrogen.
Preferably, R10 is selected from H, Cl-C6 aLkyl and benzyl.
Preferably, R12 is selected from Cl-C6 alkyl and benzyl.
Preferably, Al and A2 are independently selected from: a bond, -C(O)NR 10 , -NR 1 ~C(O)-, O, -N(R 10) , -S (O)2N(R 10) and-N(R10)S(0)2-.
Preferably, Q is a tetrahydroisoquinolinyl moiety.
Preferably, V is selected from hydrogen, heterocycle and aryl.
Preferably, n, p and r are independently 0, 1, or 2.
Preferably t is 3.
The ph~r~n~reutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety conventional chemical methods. GeneraLlly, the salts are prepared by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired 25 salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
The compounds of the invention can be synthesized from their constituent amino acids by conventional peptide synthesis techniques, and the additional methods described below. Standard 30 methods of peptide synthesis are disclosed, for example, in the following works: Schroeder et al., "The Peptides", Vol. I, Academic Press 1965, or Bo(l~n.s7ky 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, CA 022166~4 1997-09-26 W O96/31S25 PCT~US96/03974 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 5 the Examples that follow are:

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

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

CA 022166~4 1997-09-26 W O96/31525 PCT~US96/0397'1 Reaction A Amide bond formation and protecting group cleavage using standard solution or solid phase methodologies.

l~eaction 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 Deprotection of the reduced peptide subunit 10 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.
Reaction Schemes A-E illustrate bond-forming and peptide modifying reactions incorporating acyclic peptide units. It is well understood that such reactions are equally useful when the - NHC(RA) -moiety of the reagents and compounds illustrated is replaced with the 20 following moiety:
~\ ~C
(CH2)t ~ R7b R7a These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments 25 which are subsequently joined by the reactions described in the Reaction Schemes.

W O96/31525 PCTrUS96103974 REACTION SCHEME A

Reaction A. Coupling of residues to forrn an amide bond >~oJ~ N I OH + ,~

R4a EDC, HOBT H ~ CO2R
or HOOBT >1'~'~' N Jl~ <
Et3N, DMF ~ RA ~R4b TFA . H2N

RA ( ~ R4b R4a W O96/31525 PCTrUS96/03974 REACTION SCHEME B

~eaction B. Preparation of reduced peptide subunits by reductive aLkylation ~ ~ H~ ~_R4b NaCNBH3 >,0~ N ~U~~

~R4b R4a REACTION SCHEME C

Reaction C. Deprotection of reduced peptide subunits TFA or O RA ~ Q \
~ R4b HCI
R4a H2N ~ CO2R

RA ( Q~_ R4a ~ / R4b W O96/31525 PCTrUS96103974 REACTION SCHEME D

Rçaction D. Couplin~ of residues to form an amide bond EDC, HOBT
>~ ~ C~:l H ¦ or HOOBT

R4b R4a O ,~ ~ O
,~R4b O

~H O

~R4b R4a W O 96/31S25 PCT~US96103974 RE~CTI()N SC~Fl\~E E

Reaction E. Preparation of reduced dipeptides from peptides H '~ CO2R BH3 THF

O RA ~Q ~
~R4b R4a >~0~N ~
O RA ~- R4b R4a where RA is R2, R3, RSa or R5b as previously defined; R4a and R4b are as previously defined; and R is an a~lo~,iate protecting group for the carboxylic acid.

Reaction Schemes F - M illustrate reactions wherein the non-sulfhydryl-cont~ining moiety at the N-terminus of the compounds of the instant invention is attached to an acyclic peptide unit which may be further elaborated to provide the instant compounds. It is well understood that such reactions are equally useful when the - NHC(RA) - moiety of 15 the reagents and compounds illustrated is replaced with the following moiety:

(~ (CjH2)t ~ R7b R7a CA 022166~4 1997-09-26 W O 96/31525 PCT~US96103974 These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the reactions described in Reaction Schemes A- E.
The intermediates whose synthesis are illustrated in Reaction Schemes A and C can be reductively aLkylated with a variety of aldehydes, such as I, as shown in Reaction Scheme F. The aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses~ 1988, 67, 69-75, from the aL~Lo~Liate amino acid (Reaction Scheme F). The reductive aLkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloroethane, methanol or dimethylformamide. The product II can be deprotected to give the ~mal compounds m with trifluoroacetic acid in methylene chloride. The final product m is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product ~ mine III can further be selectively protected to obtain IV, which can subsequently be reductively alkylated with a second aldehyde to obtain V. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole VII can be accomplished by literature procedures.
Alternatively, the protected dipeptidyl analog intermediate can be reductively alkylated with other aldehydes such as l-trityl-4-carboxaldehyde or l-trityl-4-imidazolylacetaldehyde, to give products such as vm (Reaction Scheme G). The trityl protecting group can be removed from vm to give IX, or alternatively, vm can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole X. Alternatively, the dipeptidyl analog intermediate can be acylated or sulfonylated by standard techniques.
The imidazole acetic acid XI can be converted to the acetate XIII by standard procedures, and XIII can be first reacted with an aLkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XIV. Hydrolysis and reaction with the protected dipeptidyl analog intermediate in the CA 022166~4 1997-09-26 W O96131525 PCTrUS96/0397'1 presence of condensing reagents such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) leads to acylated products such as XV.
If the protected dipeptidyl analog intermediate is reductively aLkylated with an aldehyde which also has a protected hydroxyl group, 5 such as XVI in Reaction Scheme I, the protecting groups can be subsequently removed to llnm~k the hydroxyl group (Reaction Schemes I, J). The alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as 10 X~. In addition, the fully deprotected amino alcohol XXI can be reductively aL~ylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXII (Reaction Scheme K), or tertiary amines.
The Boc protected amino alcohol XVIII can also be lltili7e~1 15 to synthesize 2-aziridinylmethylpiperazines such as xxlll (Reaction Scheme L). Treating XVIII with l,l'-sulfonyldiimidazole and sodiurn hydride in a solvent such as dimethylformamide led to the formation of aziridine xx 111 . The ~7irirline reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product 20 XXIV.
In addition, the protected dipeptidyl analog interrnediate can be reacted with aldehydes derived from amino acids such as O-aL~ylated tyrosines, according to standard procedures, to obtain compounds such as XXX, as shown in Reaction Scheme M. When R' is an aryl group, XXX
25 can first be hydrogenated to lmma~k the phenol, and the amine group deprotected with acid to produce XXX~ Alternatively, the amine protecting group in XXX can be removed, and O-aL~ylated phenolic amines such as x x x 11 produced.
Similar procedures as are illustrated in Reaction Schemes F-30 M may be employed using other peptidyl analog intermediates such asthose whose synthesis is illustrated in Reaction Schemes B - E.
Reaction Schemes N-R illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic CA 022l6654 l997-09-26 W O96/31525 PCTrUS96/03974 strategies for preparing aLkanols that incorporate other heterocyclic moieties for variable W are also well known in the art.

W O96/31S2S PCTrUS96/0397 REACTION SCHEME F

Boc NH~ I

H2 J~ ~02R Boc NH CHO
R ~J Q ~ NaBH(OAc)3 ~ R4b Et3N, CICH2CH2CI
R4a NHBoc ~_H Y CO2R CF3C02H
Boc NH ~ CH2CI2 RA ~Q \

R4a ~ R4b ~ H Y CO2R Boc20 NH2 N~
RA ~J O CH2CI2 R4a~ R4b N~BH(OA ~3 R4b Et3N, CICH

W O96/31525 PCT~US96103974 RE~CTION SCHEME F (continued) ?-NH CF3CO2H, CH2CI2;

~ H 11 CO2R
BocNH \ N ~ < NaHCO3 RA ~Q \
/~ R4a>~ R4b ~, NH
NH2 ~J'~ < ~NC
RA ~J Q ~ AgCN
Vl )~ R4b R4a <
~ -A
N~N~ >C ~R4b R4a ~ Vll W

W O96/31525 PCTrUS96/03974 _ 59 _ REACTION SC~:~Fl\IE G
H2N ~ COzR NaBH(oAc)3 -A ~--< Et3N, CICH2CH2CI

R4a~ R4b ~ (CHz)ncHo NTr H ) NJI~ CO2R

~NI~C R4a~R4b Tr 1 ) Ar CH2X, CH3CN
Vlll 2) CF3CO2H, CH2GI2 CF3CO2H, CH2CI2 (c2H5)3siH
((~2H5)3siH

H )~N~ <02R
~C ~~ R4b A (CH2)A~ b PCTrUS96/03974 REACTION SCHEME H

CH30H ~ ~
H HCI H HCI
Xl Xll (C H ) CB N CH2C02CH31) ArCH2X CH3CN

6 5 3 r ~ reflux (C2Hs)3N ,N 2) CH30H, reflux DMF Tr Xlll Ar~\N-~cH2co2cH3 2.5N HCl 55~C

XIV

Ar~\ CH2CO2H

W O96/31525 PCT~US96/03974 REACTION SCHEME I
Ar~\N~5CH2CO2H ~2R

R4a R4b EDC HCI
HOBt DMF

~N ~ N~2R

R4b XV R4a/ ~~

W 096/31525 PCTtUS96tO3974 REACTION SCHEME J
NaBH(OAc)3 CO2R Et3N, CICH2CH2CI
H2N ~Jl~ l - ~ \ BnO
RA ~ Q ~ ~
R4a>~ R4bBocNH CHO
XVI

NHBoc y BnO ~ H ~ C 02R 20 % Pd(O H)2 H2 RA ~ Q ~C H3C 02H
Xvll 4 ~ R4b R a NHBoc /~ N ~ CO2R CICOCOCI
HO H~\ ~ ~ DMSO CH2CI2 RA ~ Q ~ (C2H5)3N
XVI 11 R4a ~ R4b W O96/31525 PCTrUS96/0397"

REACTION SCHEME J (CONTINUED) H NHBoc y O~H ~ < (C2Hs)~O
R ~ Q ~ 2. TFA, CH2C12 ~R4b XIX R4a R' NH2 HO~ HN~JI~ <
RA ~ Q
XX >~ R4b R4a W O96/3152S PCT~US9610397 REACTION SCHEME K

NHBoc y CF3CO2H

HO/~--H < CH2Ci2 RA //~Q \
XVIII ~ R4b R4a NH2 y R'CHO

HO/~--H <02R CICH 2CH2CI

XXI R4a ~ R4b R'CH2~
NH y HO/~NJ~ CO2R

RA ~Q \
R4a~ R4b W O96/31525 PCT~US96/039'14 REACTION SCHEME L

NHBoc y H H
HO~--N~JI~ CO2R ~\N N

XVIII R4b NaH, DMF 0~C
R a <~H \J~' < (c2Hs)3N ~, XXIII ~ R4b CH30H
R4a NH2 y R'S/~H \.J~ CO2R

RA ~Q ~
XXIV ~ R4b R4a W O96131525 PCTrUS96/03974 REACTION SCHEME M

HO~ 1) Boc20, K2C~3 HO~

~/ THF-H20 J~ 2) CH2N2, EtOAc ,1~
H2N CO2H BocNH CO2CH3 XXV XXVI

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

R'CH20 R'CH20 pyridine SO3 DMSO
BocNH CH2OH 20~C BocNH CHO
XXVIII XXIX

W O96/31525 PCT~US96/03974 REACTION SCHEME M (continued) R'CH~ HzN

+ RA ~ Q ~
BocNH CHO R4a>~ R4b XXIX NaBH(OAc)3 NHBoc R'CH20~

HC~\ EtOAc 1 ) 20% Pd(OH)2 CH30H, CH3C02H / ~
2) HCI, EtOAc / NH2 ~ CO2R

/ R'C H2O ~ ~ ~4b XXXI I R4a R4a R4b W O96/31S25 PCTrUS96/03974 REACTION SCHEME N

CH3 1) HNO2,Br2 C02CH3 ~ 2) KMnO
H2N N~ 3) MeOH,H+ Br~'N~

~\~\ MgCI R6 ~ ~,C02CH3 ZnCI2, NiCI2(Ph3P)2 N

NaBH4 (excess) ~CH20H

DMSO ~CHO

W O96131525 PCTrUS96/039'74 REACTION SCHEME P

~C02CH3 ~\ MgCI ~"CO~CH

Zn, CuCN

NaBH4 ~j~ S03Py, Et3N ~
(excess) ~,CH20H DMS0 ~f CH0 Br~,CO2CH3 ~\ MgCI ¢~

N ZnC12, NiC12(Ph3P)2 ~CO2C~l3 NaBH4 T S03Py, Et3N ~' ~ CH20H ~ ~CH0 (excess) N DMS0 N

W O 96/31525 PCTrUS96/03974 REACTION SCHEME Q

co2CH3 Br~[~31. LDA, CO2 Br~

N2. MeOH, H+ N

R6 MgCI ~ CO2CH3 ZnCI2, NiC12(Ph3P)2 N

NaBH4 (excess) \~ CH20H SO3Py, Et3N
~ JJ DMSO
N

CHO

REACTION SCHEME R

co2CH3 ~3~ 1. LDA, CO2 ~Br 2. (CH3)3sicHN2 R6 ~\ Br R6 ~

N~CO2CH3 Zn, NiC12(Ph3P)2 l~l 6 ~
excess NaBH4 ~1~ SO3 Py, Et3N
N~CH20H OMSO

R6 I~ q N ~CHO

CA 022166~4 1997-09-26 W O96/31525 PCT~US96/03974 The instant compounds are useful as pharmaceutical agents for m~mm~l~, especially for humans. These compounds may be ~tlmini~tered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this 5 invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors. Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras formation (i.e., neurofibromin (NF-l), neu, scr, abl, lck, fyn) or by other mech~ni~m~.
The compounds of the instant invention inhibit farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
The instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575-4580 (1995)). Such anti-angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascul~ri7~tion.
The compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the ~-lmini~tration of an effective amount of the compounds of the invention to a m~mm~l in need of such treatment. For example, a component of NF- 1 is a benign proliferative disorder.
The instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256:1331-1333 (1992).
The compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transl~lmin~l coronary angioplasty by inhibiting neointim~l formation (C. Indolfi et al. Nature medici~e, 1:541-545(1995).
The instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al.

CA 022166~4 1997-09-26 W O96131525 PCTrUS96103974 American Journal of Pathology, 142:1051-1060 (1993) andB. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)).
The compounds of this invention may be ~lministered to m~mm~s, preferably hllm~n~, either alone or, preferably, in combination 5 with ph~ eutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a ph~ ceutical composition, according to standard pharmaceutical practice. The compounds can be ~lmini~tered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of 10 ~lminictration.
For oral use of a chemotherapeutic compound according to this invention, the selected compound may be ~rlmini.ctered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are 15 commonly used include lactose and corn starch, and lubricating agents~
such as magnesium stearate, are commonly added. For oral ~(lmini.stration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If 20 desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render 25 the preparation isotonic.
The present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the ~1ministration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or 30 diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may be introduced into a patient's intramuscular blood-stream by local bolus injection.

CA 022166~4 1997-09-26 W O96/31525 PCTrUS96/03974 When a compound according to this invention is ~t1mini~tered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual 5 patient, as well as the severity of the patient's symptoms.
In one exemplary application, a suitable amount of compound is ~tlmini.~tered to a m~mm~l undergoing treatment for cancer.
A-1mini~tration occurs in an amount between about 0.1 mg/kg of body weight to about 20 mg/kg of body weight per day, preferably of between 10 0.5 mg/kg of body weight to about 10 mg/kg of body weight per day.
The compounds of the instant invention are also useful as a component in an assay to rapidly 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 15 contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to allow the FPTase to 20 farnesylate the substrate, the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the 25 compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying 30 tissue samples which contain farnesyl-protein transferase and quantitating the enzyme. Thus, potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract containing an unknown amount of farnesyl-protein CA 022166~4 1997-09-26 W O96/31525 PCTrUS96/03974 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~lo~liate period of time iin 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~nti~lly smaller than the concentration of enzyme in the assay vessel) required to inhibit the enzymatic activity of the sarnple by 50% is approximately equal to half of the concentration of the enzyme in that particular sample.

EXAMPLES

Fx~mples 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 and not limit~tive of the reasonable scope thereof.
The standard workup referred to in the examples refers to solvent extraction and washing the organic solution with 10% citric acid, lO~o sodium bicarbonate and brine as ~lopliate. Solutions were dried over sodium sulfate and evaporated in vacuo on a rotary evaporator.

E~AMPLE 1 Preparation of N-[(lH-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]- 1,2,3 ,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester and N-[(lH-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]- 1 ,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine trifluoroacetate Step A: N-(t-Butoxycarbonyl)-isoleucinal ~ This compound was synthesized by applying the procedure of Goel, Krolls, Stier, and Kesten [Organic Syntheses, 67, 69 (1988)] to N-(t-butoxycarbonyl-isoleucine. The compound was obtained as a colorless oil, which was used without purification.

CA 022166~4 1997-09-26 W O96/31S25 PCT~US96/03974 Step B: N-[(2S)-(t-Butyloxycarbonylamino)-3(S)-methylpentyl)-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxylic acid benzyl ester.
N-(t-Butyloxycarbonyl)-isoleucinal (1.5 g, 0.0070 mol) and 1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxylic acid benzyl ester (2.23 g, 0.0084 mol) were dissolved in MeOH (30 mL) at ambient tempelalule under nitrogen and treated with 3A molecular sieves (3 g) and sodium cyanoborohydride (0.66 g, 0.0105 mol) with stirring. After 18 h the 10 mixture was filtered, concentrated, and the residue was partitioned between EtOAc (50 mL) and satd aq NaHCO3 solution (50 mL). The basic layer was washed with EtOAc (3 x 30 mL), the organics combined, washed with brine, and dried (Na2so4). Filtration and concentration to dryness gave the title compound as a colorless oil after chromatography (SiO2, hexane: EtOAc, 6:1). lH NMR (CDC13) ~i 7.02-7.35 (m, 9H), 5.11 (s, 2H), 4.6-4.78 (m, lH), 3.98 (s, 2H), 3.84 (t, lH, J=5 Hz), 3.64-3.75 (m, lH), 3.05-3.27 (m, 2H), 2.84 (dd, lH, J=5, 13 Hz), 2.59 (dd, lH, J=5, 13 Hz), 1.70-1.82 (m, lH), 1.40 (s, 9H), 1.26-1.37 (m, lH), 0.97-1.13(m, lH),0.92(d,3H,J=7Hz),0.86(t,3H,J=7Hz).
Step C: N-[(2S)-(t-Butyloxycarbonylamino)-3(S)-methylpentyl)-1.2 3~4-tetrahydro-3(S)-isoquinolinecarboxylic acid N-[(2S)-(t-Butyloxycarbonylamino)-3(S)-methylpentyl)-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxylic acid benzyl ester (1.5 g, 0.0032 mol) was dissolved in methanol (50 mL) - EtOAc (50 mL), treated with 10% palladium on carbon (0.15 g) and hydrogenated under a balloon of hydrogen for 4 h. Filtration and concentration to dryness gave the title compound as a white solid which was used without further purification.

Step D: N-[2(S)-(t-Butyloxycarbonylamino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester N-[(2S)-(t-Butyloxycarbonylamino)-3(S)-methylpentyl)-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxylic acid (0.67 g, 0.00178 mol) CA 022166~4 1997-09-26 W O96131S25 PCT~US96/03974 was dissolved in DMF (10 mL) with stirring at ambient temperature and treated with EDC (0.376 g, 0.00196 mol), HOBT (0.265 g, 0.00196 molL), - and methionine methyl ester hydrochloride (0.427 g, 0.00214 mol). The pH was adjusted to 7 with Et3N (0.546 mL, 0.00392 mol) and stirring 5 was continued for 18 h. The reaction mixture was concentrated, then partitioned between EtOAc (50 mL) - H2O (50 mL). The aq layer was washed with EtOAc (2 x 30 mL), the organics combined, washed with aq satd NaHCO3 solution, brine, and dried (Na2SO4). Filtration and concentration gave the title compound after chromatography (sio2~
10 CH2C12: MeOH, 99.5:0.5). lH NMR (CD30D) o7.05-7.2 (m, 4H), 4.43-4.52 (m, lH), 3.98 (d, lH, J=13 Hz), 3.68-3.82 (m, 2H), 4.87 (s, 3H), 3.55 (t, lH, J=6 Hz), 2.96-3.14 (m, 2H), 2.84 (dd, lH, J= 5, 13 Hz,~, 2.70 (dd, lH, J= 5,13 Hz), 1.88-2.14 (m, 2H), 1.95 (s, 3H), 1.32-1.57(m, 2H), 1.41 (s, 9H), 1.06-1.25 (m, lH), 0.84-0.96 (m, 6H).
Step E: N-[2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester HCl gas was bubbled into a solution of N-[2(S)-(t-butyloxycarbonylamino-3(S)-methylpentyl]- 1,2,3,4-tetrahydro-3(S)-20 isoquinolinecarbonyl-methionine methyl ester (0.37 g, 0.71 mmol) in EtOAc (25 mL) with stirring at -20~C over 0.5 h. The solution was purged with argon for 0.5 h, then concentrated to give the title compound as a white solid which was used without further purification.

25 Step F: N-[(lH-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]- l ,2,3,4-tetrahydro-3 (S)-isoquinolinecarbonyl-methionine methyl ester trifluoroacetate lH-Imidazol-4-ylacetic acid (0.18 g, 1.11 mmol) was dissolved in DMF (10 mL) and treated with EDC (0.213 g, 1.11 mmol), 30 HOBT (0.15 g, 1.11 mmol), and N-[2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester (0.275 g, 0.556 mmol) with stirring at ambient temperature. Et3N (0.618 rnL, 4.44 mol) was added to bring the pH of the solution to 8, and stirrir.~g was continued for 16 h. The reaction mixture was concentrated to CA 022166~4 1997-09-26 W O~6131525 PCTrUS96/03974 remove the DMF, and the residue was partitioned between EtOAc (20 mL) and H20 (30 mL). The aqueous layer was washed with EtOAc (3 x 20 mL), the organics combined, washed with brine and dried (Na2so4).
Filtration and concentration to dryness gave the title compound after 5 preparative reverse phase chromatography (CH3CN: H2O gradient). lH
NMR (CD30D) ~ 8.48 (s, lH), 7.07 (s, lH), 6.92-7.04 (m, 4H), 4.29 (d, lH, J= 14 Hz), 4.0-4.15 (m, 3H), 3.85-3.9 (m, lH), 3.45 (ABq, 2H), 3.35 (s, 3H), 2.9 - 3.2 (m, 4H), 2.05-2.2 (m, 2H), 1.72 (s, 3H), 1.55-1.7 (m, 2H), 1.2-1.35 (m, lH), 1.1 - 1.20 (m, lH), 0.8-0.9 (m, lH), 0.55 - 0.6 (m, 6H). FAB MS 530 (M + 1).

Step G: N-[(lH-imidazol-4-ylacetyl)-2(S)-amino-3(S)-methylpentyl]- 1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine trifluoroacetate N-[( lH-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]- l ,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester (0.037 g, 0.049 mmol) was dissolved in CH30H (2 mL) in an ice-H2O bath and treated with ln NaOH (0.195 mL, 0.195 mmol) with stirring. After 3 h the reaction mixture was neutralized with lN HCl 20 (0.195 mL, 0.195 mmol), then chromatographed on a preparative VYDAC reverse phase column, eluting with 0.1% TFA, H2O: 0.1%
TFA, CH3CN 95:5 to 5:95 gradient to give the title compound. lH
NMR (CD30D) ~ 8.81 (s, lH), 7.42 (s, lH), 7.2-7.4 (m, 4H), 4.52 (d, lH, J= 14 Hz), 4.25-4.45 (m, 3H), 4.15-4.25 (m, lH), 3.80 (ABq, 2H), 3.25 -3.5 (m, 2H), 2.3-2.5 (m, 2H), 2.05 (s, 3H), 2.03 - 2.15 (m, lH), 1.9-2.0 (m, lH), 1.57 - 1.7 (m, lH), 1.42-1.55 (m, lH), 1.1 - 1.23 (m, lH), 0.9-1.0 (m, 6H). FAB MS 516 (M + 1).

Using the methods outlined above, the following compounds are 30 prepared:

N-[(lH-imidazol-4-ylpropionyl)-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester CA 022166~4 1997-09-26 W O 96131S25 PCTrUS96/03~74 ~ N- [(1 H-imidazol-4-ylpropionyl)-2(S)-amino-3 (S)-methylpentyl]- 1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine Preparation of N-[(1-(4-Cyanobenzyl)-lH-imidazol-5-yl)acetyl]-2(S)-amino-3(S)-methylpentyl]- 1,2,34-tetrahydro-3(S)-isoquinolinecarbonyl methionine methyl ester and N-[(1-(4-Cyanobenzyl)-lH-irnidazol-S-yl)acetyl]-2(S)-amino-3(S)-methylpentyll - 1.2.34-tetrahydro-3 (S)-isoquinolinecarbonyl methionine Step A: lH-Imidazole-4- acetic acid methyl ester hydrochloride A solution of lH-imidazole-4-acetic acid hydrochloride (4.00g, 24.6 mmol) in methanol (100 ml) was saturated with gaseous hydrogen chloride. The resulting solution was allowed to stand at room temperature (RT) for 18hr. The solvent was evaporated in vacuo to afford the title compound as a white solid.
lH NMR(CDC13, 400 MHz) â 8.85(1H, s),7.45(1H, s), 3.89(2H, s) and 3.75(3H, s) ppm.
Step B: l-(Triphenylmethyl)-lH-imidazol-4-ylacetic acid methyl ester To a solution of lH-imidazole-4- acetic acid methyl ester hydrochloride (24.85g, 0.141mol) in dimethyl formamide (DMF) (l lSml) was added triethylamine (57.2 ml, 0.412mol) and triphenylmethyl bromide(55.3g, 0.171mol) and the suspension was stirred for 24hr. After this time, the reaction mixture was diluted with ethyl acetate (EtOAc) (1 1) and water (350 ml). The organic phase was washed with sat. aq. NaHCO3 (350 ml), dried (Na2SO4) and evaporated in - 30 vacuo. The residue was purified by flash chromatography (SiO2, O-lOO~o ethyl acetate in hexanes; gradient elution) to provide the title compoundL
as a white solid.
lH NMR (CDC13, 400 MHz) o7.35(1H, s), 7.31(9H, m), 7.22(6H, m), 6.76(1H, s), 3.68(3H, s) and 3.60(2H, s) ppm.

CA 022l66~4 l997-09-26 W O96t31525 PCTrUS96/03974 ~tep C: [1-(4-Cyanobenzyl)-lH-imidazol-5-yl]acetic acid methyl ester To a solution of l-(triphenylmethyl)-lH-imidazol-4-ylacetic acid methyl ester (8.00g, 20.9mmol) in acetonitrile (70 ml) was added bromo-p-toluonitrile (4.10g, 20.92 mmol) and heated at 55~C for 3 hr.
After this time, the reaction was cooled to room tempelalule and ~e resulting imidazolium salt (white precipitate) was collected by filtration.
The filtrate was heated at 55~C for 18hr. The reaction mixture was cooled to room temperature and evaporated in vacuo. To the residue was added EtOAc (70 ml) and the resulting white precipitate collected by filtration. The precipitated imidazolium salts were combined, suspended in methanol (100 ml) and heated to reflux for 30min. After this time, the solvent was removed in vacuo, the resulting residue was suspended in EtOAc (75ml) and the solid isolated by filtration and washed (EtOAc).
The solid was treated with sat aq NaHCO3 (300ml) and CH2Cl2 (300ml) and stirred at room temperature for 2 hr. The organic layer was separated, dried (MgSO4) and evaporated in vacuo to afford the title compound as a white solid:
1HNMR(CDC13, 400 MHz) â 7.65(1H, d, J=8Hz), 7.53(1H, s), 7.15(1H, d, J=8Hz), 7.04(1H, s), 5.24(2H, s), 3.62(3H, s) and 3.45(2H, s) ppm.

Step D: rl-(4-Cyanobenzyl)-lH-imidazol-5-yl~acetic acid A solution of [1-(4-cyanobenzyl)-lH-imidazol-5-yl]acetic acid methyl ester (4.44g, 17.4mmol ) in THF (lOOml) and 1 M lithium hydroxide (17.4 ml, 17.4 mmol) was stirred at RT for 18 hr. 1 M HCl (17.4 ml) was added and the THF was removed by evaporation in vacuo.
The aqueous solution was lyophilized to afford the title compound con~ining lithium chloride as a white solid.
lH NMR(CD30D, 400 MHz) o 8.22(1H, s), 7.74(1H, d, J=8.4Hz), 7.36(1H, d, J=8.4Hz), 7.15(1H, s), 5.43(2H, s) and 3.49(2H, s) ppm.

CA 022166~4 1997-09-26 W O96131S25 PCT~US96103974 Step E: N-[( 1 -(4-Cyanobenzyl)- l H-imidazol-5-yl)acetyl]-2(S)-amino-3(S)-methylpentyl]- 1 ,2,34-tetrahydro-3(S)-isoquinolinecarbonyl methionine methyl ester Using the method described in Example 1, Step F, but S substituting [1-(4-cyanobenzyl)-lH-imidazol-5-yl]acetic acid for lH-imidazol-4-ylacetic acid, the title compound is obtained.

Step F: N-[( 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl)acetyl]-2(S)-arnino-3(S)-methylpentyl]- 1 ,2,34-tetrahydro-3(S)-isoquinolinecarbonyl methionine Using the method described in Example 1, Step G, the title compound is obtained.

Preparation of N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1.2.3.4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine trifluoroacetate Step A: N-[L-Pyroglutamyl-2(S)-~mino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester trifluoroacetate Following the methods described in Example 1, but using L-pyroglutamic acid in place of lH-imidazol-4-yl acetic acid, the title compound was prepared. Anal. calcd for C27H40N4O5S ~ 1.5 CF3CO2H: C, 51.20; H, 5.94; N, 7.96; Found: C, 51.01; H, 6.00; N, 8.23.

Step B: N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine trifluoroacetate The title compound was prepared following the method dscribed in Example 1, Step G. FAB MS 519 (M + 1).

CA 022166~4 1997-09-26 W O96/31525 PCT~US96103974 Preparation of N-[N-(4-Cyanobenzyl)-L-Pyroglutamyl-2(S)-amino-3(S)-methylpentylJ- 1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine 5 methyl ester and N-[N-(4-Cyanobenzyl)-L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1.2.3~4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine Step A: L-Pyroglutamic acid methyl ester L-Pyroglutamic acid (15.17 g, 0.1175 mol) was dissolved in CH30H (100 mL), cooled to 0~C. under Ar and treated dropwise with thionyl chloride (18.9 mL, 0.259 mol) with stirring. The bath was removed and stirring was continued at ambient tempelalule for 3.5 h.
Water (150 mL) and solid NaHCO3 (60 g) were added, the CH30H was 15 removed on a rotary evaporator, and ~e residue extracted with CH2C12 (3 x 150 mT ~). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to dryness to give the title compound.

20 Step B: N-(4-Cyanobenzyl)-L-pvroglutamic acid methyl ester L-Pyroglutamic acid methyl ester (1.36 g, 0.0095 mol) was dissolved in dry THF (20 mL) under Ar, treated with NaH (60% oil dispersion) (0.58 g, 0.0145 mol) with stirring for 5 min, then the mixture was cooled to 0~C. p-Cyanobenzylbromide (1.78 g, 0.0091 mol) was 25 added, and the mixture left to slowly warm to ambient temperature. After 48 h the reaction mixture was partitioned between EtOAc and satd NaHCO3 solution, the aqueous layer separated and washed with CH2C12, the organics combined, washed with brine and dried (MgSO4). Filtration and concentration to dryness followed by trituration with ether gave the 30 white solid product. lH NMR(CDC13, 400 MHz) o 7.62(2H, d, J=8 Hz), 7.33(2H,d,J=8Hz),4.98(1H,d,J=15.4Hz),4.13(1H,d,J=15.4Hz), 3.99(1H, dd, J=3, 9 Hz) and 2.5-2.6 (lH, m), 2.4-2.5 (lH, m), 2.2-2.45 (lH,m),2.1-2.2(1H,m)ppm.

CA 022166~4 1997-09-26 Step C: N-(4-Cyanobenzyl)-L-pyroglutamic acid N-(4-Cyanobenzyl)-L-pyroglutamic acid methyl ester (0.875 g, 0.0034 mol) was dissolved in THF:H2O (3:1) (12 mL) and treated with LiOH (0.294 g, 0.007 mol) with stirring at ambient temperature. After S stirring for 3 h, the solution was neutralized with 1 N HCl, and concentrated to dryness to give the title compound and 2.1 eq of LiCl which was used without further puri~lcation.

Step D: N-[N-(4-Cyanobenzyl)-L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester Using the method described in Fx~mple 1, Step F, but substitlltin~ N-(4-Cyanobenzyl)-L-pyroglutamic acid for lH-imidazol-4-ylacetic acid, the title compound is obtained.
Step E: N-[N-(4-Cyanobenzyl)-L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]- l ,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine Using the method described in Example 1, Step G, the title compound is obtained.

In vitro inhibition of ras farnesyl transferase Assays offarnesyl-protein transferase. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and RAS-CAIL) were prepared as described by Schaber et al., J. Biol. Chem.
265: 14701-14704 (1990), Pompliano, et al., Biochemishy 31:3800 (1992) and Gibbs et al., PNAS U.S.A. 86:6630-6634 (1989), respectively.
- 30 Bovine FPTase was assayed in a volume of 100 ,ul cont~inin~ 100 mM N-(2-hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH
7.4, 5 mM MgC12, 5 mM dithiothreitol (DTT), 100 mM [3H]-farnesyl diphosphate ([3H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM
Ras-CVLS and 10 ~Lg/ml FPTase at 31~C for 60 min. Reactions were CA 022166~4 1997-09-26 W O96/31525 PCTrUS96/03974 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, S FPTase levels and time; less than 10% of the [3H]-FPP was utilized during the reaction period. Purified compounds were dissolved in 100%
dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay.
Percentage inhibition is measured by the amount of incorporation of radioactivity in the presence of the test compound when compared to the 10 amount of incorporation in the absence of the test compound.
Human FPTase was prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1 % (w/v) polyethylene glycol 20,000, 10 ,u M ZnCl2 and 100 nM Ras-CVIM were added to ~e 15 reaction mixture. Reactions were performed for 30 min., stopped with 100 ~Ll of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
The compounds of the in~t~nt invention described in Examples 1, Step G, and Example 3, Step B, were tested for inhibitory 20 activity ~ in~t human FPTase by the assay described above and were found to have ICso of < 10 ,uM.

25 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%
30 confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1 %). After 4 hours at 37~C, 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 CA 022166~4 1997-09-26 W O96131525 PCT~US96/03974 cells are lysed in 1 ml lysis buffer (l~o NP40/20 mM HEPES, pH 7.5/5 mM Mg~12/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/mLl 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 immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et al., J. Virol. 43:294-304, (1982)).
Following a 2 hour antibody incubation at 4~C, 200 ml of a 25%
suspension of protein A-Sepharose coated with rabbit anti rat IgG is added for 45 min. The immllnoprecipitates are washed four times with IP
buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1% Triton X-100Ø5%
deoxycholate/0. 1 %/SDS/0. 1 M NaCl) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to farnesylated and nonfarnesylated ras proteins are compared to deterrnine the percent inhibition of farnesyl transfer to protein.

In vivo ~rowth inhibition assay To determine the biological consequences of FPTase inhibition, the effect of the compounds of the instant invention on the anchorage-independent growth of Ratl cells transformed with either a v-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Raf and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation.
Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded a~ a density of 1 x 104 cells per plate (35 mm in diameter) in a ~ 30 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layers contain 0.1% methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay). The cells are f~d W O96/31525 PCTrUS96/03974 twice weekly with 0.5 ml of medium A cont~ining 0.1% methanol or the concentration of the instant compound. Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made.

Claims (25)

WHAT IS CLAIMED IS:

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

wherein:
R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-;
R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl; or R2 and R3 are combined to form -(CH2)S-; or R2 or R3 are combined with R6 to form a ring such that is ;

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

R5a and R5b are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:

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

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

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, R102N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R1OC(O)NH-, CN, H2NC(NH)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R10OC(O)NH-;

R9 is selected from:
a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, -S(O)2N(R10)-, -N(R10)S(O)2-, or S(O)m;

Q is a substituted or unsubstituted nitrogen-containing C6-C9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle;

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

W is a heterocycle;

X, Y and Z are independently H2 or O;

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

2. A prodrug of the compound according to Claim 1 illustrated by the formula II:

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

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

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

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

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

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, R102N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, CN, H2NC(NH)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R10OC(O)NH-;

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

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

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

R14 is independently selected from C1-C6 alkyl;

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

Q is a substituted or unsubstituted nitrogen-containing C6-C9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle;

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

W is a heterocycle;

X, Y and Z are independently H2 or O;

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

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

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

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

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

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

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, R102N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, CN, H2NC(NH)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R10OC(O)NH-;

R9 is selected from:
a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C-(NR10), R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R110C(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, -S(O)2N(R10)-, -N(R10)S(O)2-, or S(O)m;

Q is a substituted or unsubstituted nitrogen-containing C6-C9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle;

V is selected from:
a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;
W is a heterocycle;
X, Y and Z are independently H2 or O;

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

4. A prodrug of the compound according to Claim 3 illustrated by the formula IV:

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

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

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

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

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

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

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

Q is a substituted or unsubstituted nitrogen-containing C6-C9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle;

V is selected from:
a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;
W is a heterocycle;
X, Y and Z are independently H2 or O;

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

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

wherein:

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

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

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

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

R4b and R7b are hydrogen;

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

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

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

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

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

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

and ;

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

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

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

X, Y and Z are independently H2 or O;

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

or a pharmaceutically acceptable salt thereof.

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

wherein:

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

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

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

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

R4b and R7b are hydrogen;

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

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

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

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

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;

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

R13 is independently selected from hydrogen and C1-C6 alkyl;
R14 is independently selected from C1-C6 alkyl;
Q is selected from:

and A1 and A2 are independently selected from: a bond, -CH=CH-, -C=C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;
V is selected from:
a) hydrogen, b) hetero cycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from O to 4 carbon atoms are replaced with a a hetero atom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is O and A2 is S(O)m;
W is a hetero cycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;
X, Y and Z are independently H2 or O;
m is 0, 1 or 2;
n is 0, 1,2,3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5, provided that r is 0 when V is hydrogen;
t is 3,4 or 5; and u is . 0 or 1;

or the pharmaceutically acceptable salts thereof.

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

wherein:

R1a is independently selected from: hydrogen or C1-C6 alkyl;
R1b is independently selected from:
a) hydrogen, b) aryl, hetero cycle, cycloalkyl, R10O-, -N(R10)2 or alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, hetero cycle, cycloalkyl, alkenyl, R10O-, or-N(R10)2;
R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, R11OC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, hetero cycle and C3-C10 cycloalkyl; or R2 and R3 are combined to form - (CH2)S -; or R2 or R3 are combined with R6 to form a ring such that is R4a and R7a are independently selected from:
a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R10O-, R11S(O)m, R10C(O)NR10-, CN, N3, (R10)2N-C(NR10)-,R10C(O)-, R10OC(O)-, -N(R10)2, or R1 10C(O)NR10-,c) aryl, hetero cycle, cycloalkyl, alkenyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, N02, (R10)2N-C(NR10)-, R10C(o)-, R10OC(o)-, N3, -N(R10)2, or R1 10C(O)NR10-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- C10 cycloalkyl;
R4b and R7b are hydrogen;
R6 is independently selected from hydrogen or C1-C6 alkyl;
R8 is independently selected from:
a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R110C(O)NR10-;
R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 aklyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
Q is selected from:

and ;

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

V is selected from:
a) hydrogen, b) hetero cycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a hetero atom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is O and A2 is S(O)m;
W is a hetero cycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;
X, Y and Z are independently H2 or O;
m is 0, 1 or 2;
n is 0,1,2,3 or 4;
p is 0, 1,2,3 or 4;
q is 0,1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
t is 3,4 or 5;and u is 0 or l;
or a pharmaceutically acceptable salt thereof.

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

wherein:

R1a is independently selected from: hydrogen or C1-C6 alkyl;
R1b is independently selected from:
a) hydrogen, b) aryl, hetero cycle, cycloalkyl, R10O-, -N(R10)2 or alkenyl., c) C1-C6 alkyl unsubstituted or substituted by aryl, hetero cycle, cycloalkyl, alkenyl, R10O-, or-N(R10)2;
R2 and R3 are independently selected from:
a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is:
i) methionine sulfoxide, or ii) methionine cellophane, c) substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R10O-, R11S(O)m-, R10C(o)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, R10OC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, hetero cycle and C3-C10 cycloalkyl; or R2 and R3 are combined to form - (CH2)s -; or R2 or R3 are combined with R6 to form a ring such that is ;

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

R4b and R7b are hydrogen;
R6 is independently selected from hydrogen or C1-C6 alkyl;
R8 is independently selected from:
a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10), R10C(O)-, R10OC(O)-,-N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-;

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R11S(O)m, R10C(O)NR10-, CN, N02, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, -N(R10)2, or R11OC(O)NR10;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and.
aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
Q is selected from:

and A1 and A2 are independently selected from: a bond, -CH=CH-, -C=C-, -C(O)-, -C(O)NR10-, O ,-N(R10)-, or S(O)m;
V is selected from:
a) hydrogen, b) hetero cycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from O to 4 carbon atoms are replaced with a a hetero atom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is O and A2 is S(O)m;
W is a hetero cycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;
X, Y and Z are independently H2 or O;
m is 0,1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1,2,3 or 4;
q is 0,1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
t is 3,4 or 5; and u is 0 or l;
or a pharmaceutically acceptable salt thereof.

9. A compound which inhibits farnesyl-protein transfers which is:
N-[(1H-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester N-[( 1H-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]- 1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]- 1 ,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine N-[(lH-imidazol-4-ylpropionyl)-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester N-[(lH-imidazol-4-ylpropionyl)-2(S)-amino-3(S)-methylpentyl]- 1 ,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine N-[(1-(4-cyanoben_yl)-lH-imidazol-5-yl)acetyl]-2(S)-amino-3(S)-methylpentyl]-1,2,34-tetrahydro-3(S)-isoquinolinecarbonyl methionine methyl ester N-[( 1-(4-cyanobenzyl)- lH-imidazol-5-yl)acetyl]-2(S)-amino-3(S)-methylpentyl]-1,2,34-tetrahydro-3(S)-isoquinolinecarbonyl methionine N-[N-(4-cyanoben_yl)-L-pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester or N-[N-(4-cyanobenzyl)-L-pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1 ,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine or a pharmaceutically acceptable salt or optical isomer thereof.

10. The compound according to Claim 9 which inhibits farnesyl-protein transfers which is:
N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine or a pharmaceutically acceptable salt or optical isomer thereof.

11. The compound according to Claim 9 which inhibits farnesyl-protein transfers which is:
N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]- 1 ,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester or a pharmaceutically acceptable salt or optical isomer thereof.

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

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

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

15. 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 12.

16. 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 13.

17. 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.

18. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12.

19. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 13.

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

21. A method for treating neurofibromin benign proliferative disorder which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12.

22. A method for treating blindness related to retinal vascularization which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12.

23. A method for treating infections from hepatitis delta and related viruses which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12.

24. A method for preventing restenosis which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12.

25. A method for treating polycystic kidney disease which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12.