CA2216707A1 - Inhibitors of farnesyl-protein transferase - Google Patents

Abstract

The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.

Description

W 096/30343 PCTrUS96/04019 TITLE OF THE INVENTION
,, INHIBITORS OF FARNESYL-PROTEIN TRANSE~ERASE

RELATED APPLICATION
The present patent application is a continuation-in-part application of copending application Serial No. 08/470,690, filed June 6, 1995, which is a continuation-in-part application of copending application Serial No. 08/412,829, filed March 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 ~i~n~l.s initi~ting cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP. Upon 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 stimlll~tQry signal until the signal is termin~te-l by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M.
Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many human cancers, including colorectal ca~cinoma, 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-tr~n~l~tional modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-tenninll~
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 W 096/30343 PCTrUS96104019 enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation 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, 5 Ann. Rev. Genetics 30:209-237 (1992)). The Ras protein is one of several proteins that are known to undergo post-tr~n~l~tional farnesylation. Other farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear l~mins, andthe ~ mm~ subunit of transducin. 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 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 15 block the glo~vlh of Ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been 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., 20 Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of ras-dependent tumors in nude mice (N.E. Kohl et al., Proc. Natl. Acad. Sci U.S.A., 91:9141-9145 (1994) and induces regression of m~mm~ry and salivary carcinomas in ras transgenic mice (N.E. Kohl et al., Nature 25 Medicine, 1:792-797 (1995).
Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck & Co., Rahway, NJ) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the 30 rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Farnesyl-protein transferase lltili7es farnesyl 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 et al., J. Biol. Chem., 265: 14701-14704 (1990); Schafer et al., - W 096/30343 PCTrUS96/04019 Science, 249:1133-1139 (1990); Marlne et al., Proc. Natl. Acad. Sci USA, 87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane loc~li7.~tion in cultured cells. However, direct inhibition of farnesyl-5 protein transferase would be more specific and attended by fewer sideeffects than would occur with the required dose of a general inhibitor of isoprene biosynthesis.
Inhibitors of farnesyl-protein transferase (FPTase) have been described in two general classes. The first are analogs of farnesyl 10 diphosphate (FPP), while the second class of inhibitors is related to the protein substrates (e.g., Ras) for the enzyme. The peptide derived inhibitors that have been described are generally cysteine 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., 15 PNAS, 88:732-736 (1991)). Such inhibitors may inhibit ~loteh prenylation while serving as alternate substrates for the farnesyl-L,lolt;i transferase enzyme, or may be purely competitive inhibitors (U.S.
Patent 5,141,851, University of Texas; N.E. Kohl e~ al., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
20 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 potentially places limit~tions on the therapeutic application of FPTase-inhibitors with respect to ph~rm~rokinetics, ph~rm~codynamics and toxicity. Therefore, a 25 functional replacement for the thiol is desirable.
It has recently been reported that farnesyl-protein transferase inhibitors are inhibitors of ~proliferation of vascular smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7-30 112930).
It has recently been disclosed that certain tricycliccompounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516).

W 096/30343 PCTrUS96/04019 Tmicl~7.ole-cont~inin~ inhibitors of farnesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 A1).
It is, therefore, an object of this invention to develop peptidomimetic compounds that do not have a thiol moiety, and that will 5 inhibit farnesyl-protein transferase and thus, the post-tr~n.cl~tional farnesylation of proteins. It is a further object of this invention to develop chemotherapeutic compositions COI~ lg the compounds of this invention and methods for producing the compounds of this invention.
SUMMARY OF THE INVENTION
The present invention comprises peptidomimetic piperazine-co-~t~ compounds which inhibit the farnesyl-~loteill transferase. The in~t~nt compounds lack a thiol moiety and thus offer 15 unique advantages in terms of improved ph~ cokinetic behavior in ~nim~l~, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Purther contained in this invention are chemotherapeutic compositions cont~ininp these farnesyl transferase 20 inhibitors and methods for their production.

The compounds of this invention are illustrated by the formulae A, B and C:

W 096/30343 PCTrUS96/04019 V-A1(CR1a2)nA2(cR1a2)n~ (cR1b2)p\ ~N\ /N~

( l ~8)r ~R9)\ R\~
V - A1(CR1a2)nA2(CR1a2)n -\W/- (CR1b2)p~ ~N N--Z

( lR8)r ~R9~; R2 R3 V ~ A1(CRla2)nA2(CR1a2)n ~W~!- (CR1b2)p~N\ /N Z

W 096/30343 PCTrUS96/04019 DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are useful in the inhibition of farnesyl-protein transferase and the farnesylation of the oncogene protein Ras. In a first embodiment of this invention, the inhibitors of 5 farnesyl-protein transferase are illustrated by the formula A:

(R8)r ~9~ R j R3 V ~ Al(CRla2)nA2(CRla2)n ~W~!- (CRlb2)p~ ~N~ /N~

.
whereln:
R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, R100-, Rl lS(O)m-, RlOC(O)NR10-, (R10)2N-c(o)-~ CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or Rl 1OC(O)NR10-, c) unsubstituted or substituted Cl-C6 aLkyl wherein the sub~LiLulellt on the substituted Cl-C6 aLkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 aLkynyl, R100-, Rl lS(o)m, R10c(o)NRlo-~ (R10)2N-c(o)-~ CN, (Rlo)2N-c(NRlo)-~ Rloc(o)-~ R10Oc(o)-~ N3, -N(R10)2, and Rl 1OC(O)-NR10-;

R2 and R3 are independently selected from: H; unsubstituted or substituted C1 8 aLkyl, unsubstituted or substituted C2 8 aLkenyl, 25 unsubstituted or substituted C2 g alkynyl, unsubstituted or substituted aryl, ~NR6R7 or ~oR6 unsubstituted or substituted heterocycle, ~ ~

W 096/30343 PCTrUS96/04019 wherein the substituted group is substituted with one or more of:
,, 1) aryl or heterocycle, unsubstituted or substituted with:
a) Cl 4 aLkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, e) CN, 2) C3-6 cycloaLkyl, 3) oR6, 4) SR6a, s(o)R6a~ So2R6a, 5) --NR6R7 ~6 6) --N~ R7 o 8) - O ~ N R6R7 o 9) --o~OR6 10) NR6R7 ..
11 ) --SO2--NR6R7 12) --N--SO2--R6a W 096/30343 PCTrUS96/04019 13) ~ R6 14) ~ o R6 15) N3, or 16) F; or R2 and R3 are attached to the same C atom and are combined to form 5 - (CH2)U - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R4 and R5 are independently selected from H and CH3;

and any two of R2, R3, R4 and RS are optionally attached to the same carbon atom;

R6, R7 and R7a are independently selected from: H; Cl 4 aL~yl, C3-6 cycloaL~yl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, lS heteroarylsulfonyl, unsubstituted or substituted with:
a) Cl 4 aLkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) ~R
O "
f) SO2R , or g) N(R10)2; or R6 and R7 may be joined in a ring;

R7 and R7a may be joined in a ring;

R6a is selected from: Cl 4 aL~yl, C3-6 cycloaL~yl, heterocycle, aryl, unsubstituted or substituted with:
S a) Cl 4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) ~R11 fl --SO2R 1 , or g) N(R10)2;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RllS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-7 RlO2N-c(NRlo)-7 CN, NO2, RlOC(O)-, RlOOC(O)-, N3, -N(Rl0)2, or RllOC(O)NR10-, and c) Cl-C6 aLkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RllS(O)m-, RlOC(O)NH-, (RlO)2NC(O)-, R102N-C(NR10)-, CN, RlOC(O)-, RlOOC(O)-, N3, -N(Rl0)2, or RlOOC(O)NH-;
R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R100-, RllS(O)m-, RlOC(O)NR10-, (RlO)2NC(O)-, RlO2N-c(NRlo)-7 CN, NO2, RlOC(O)-, RlOOC(O)-, N3, -N(Rl0)2, or Rl lOC(O)NR10-, and W 096/30343 PCTrUS96/04019 c) Cl-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, RllS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~ R102N-C(NR10)-, CN, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or Rl loC(ojNR10-;

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

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

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

25 W is a heterocycle;

X is -cH2-~ -C(=O)-, or -S(=O)m-;

Y is unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or more of:
1) Cl 4 alkyl, unsubstituted or substituted with:
a) Cl 4 alkoxy, W O 96/30343 PCTnUS96/04019 b) NR6R7, c) C3-6 cycloaLkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR6a, or g) -c(o)NR6R7~
2) aryl or heterocycle, 3) halogen, 4) oR6~
5) NR6R7, 6) CN, 7) N02, 8) CF3;

9) -S(O)mR6a 10) -C(o)NR6R7, or 11) C3-C6 cycloaLkyl;

m is 0, 1 or 2;
nis 0, 1, 2, 3 or4;
pis 0, 1, 2, 3 or4;
q is 1 or 2;
r is O to 5, provided that r is O when V is hydrogen;
s is O or 1 ;
tis Oorl;and uis 4 or 5;
or the plh~ reutically acceptable salts thereof.
.
In a second embodiment of this invention, the inhibitors of 30 farnesyl-protein transferase are illustrated by the formula B:

=

W O 96/30343 PCTrUS96/04019 (18)r ~ 9)~ R j ~

V ~ A1(CRla2)nA2(CR1a2)n tW~- (CRlb2)p~ ~N~ ~N--Z

B
.

wherem:

Rla and Rlb are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-clo cycloaL~yl, C2-c6 alkenyl, C2-C6 alkynyl, RlOO-, RllS(O)m-, RlOC(O)NR10-, CN(RlO)2Nc(o)-~ R102N-C(NR10)-, CN, NO2, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or Rl 10C(O)NR10 c) unsubstituted or substituted Cl-C6 alkyl wherein the sub~liLulellt on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-Clo cycloaL~yl, C2-C6 alkenyl, C2-C6 aLkynyl, R100-, RllS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~ R102N-C(NR10)-, CN, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, and Rl lOC(o)-NR10;

R2 and R3 are independently selected from: H; unsubstituted or substituted C1 8 alkyl, unsubstituted or substituted C2 8 alkenyl, unsubstituted or substituted C2 8 aL~ynyl, unsubstituted or substituted aryl, ~NR6R7 or ~l~~R6 unsubstituted or substitutedheterocycle, ~ O
wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) Cl 4 alkyl, b) (CH2)pOR6, W 096/30343 PCTrUS96/04019 c) (CH2)pNR6R7, r d) halogen, e) CN, 2) C3-6 cycloaLkyl, 3) 0 R6, 4) SR6a,S(o)R6a, S 02R6a 5) - NR6R~
6) n6 o --N~ NR7R7a 8) --~ NR6R7 O
o 10) ~ N R6R7 1 1 ) --S02--NR6R7 F~6 r 12) --N SO2--R

W 096/30343 PCTrUS96/04019 13) ~ R6 o 15) N3, or 16) F; or R2 and R3 are attached to the same C atom and are combined to form - (CH2)u - wherein one of the carbon atoms is optionally replaced by a S moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R4 is selected from H and CH3;

and any two of R2, R3 and R4 are optionally attached to the same carbon atom;

R6, R7 and R7a are independently selected from: H; Cl 4 alkyl, C3-6 cycloaL~yl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) Cl 4 aL~oxy, b) aryl or heterocycle, c) halogen, d) HO, e) ~Rl1 f) --SO2Rl 1 , or g) N(Rlo)2; or R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

W 096/30343 PCTrUS96104019 R6a is selected from: Cl 4 aL~yl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) Cl 4 alkoxy, S b) aryl or heterocycle, c~ halogen, d) HO, e) ~R
o f) --SO2R1 1 , or g) N(R10)2;
R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-clo cycloaL~yl, C2-c6 alkenyl, C2-C6 aL~ynyl, perfluoroaL~yl, F, Cl, Br, R100-, RllS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~ R102N-C(NR10)-, CN, NO2, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or RllOC(O)NR10-, and c) Cl-C6 aL~yl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 aL~ynyl, perfluoroaL~yl, F, Cl, Br, R100-, RllS(O)m-, RlOC(O)NH-, (RlO)2Nc(o)-~ R102N-C(NR10)-, CN, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or RlOOC(O)NH-;

R9 is selected from:
a) hydrogen, b) aL~enyl, aL~ynyl, perfluoroalkyl, F, Cl, Br, R100-, RllS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~ R102N-C(NR10)-, CN, NO2, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or Rl 1 OC(O)NR10-, and c) Cl-C6 aL~yl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, RllS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~ R102N-C(NR10)-, CN, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or Rl lOC(O)NR10-;
s R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl;

Rl 1 is independently selected from Cl-C6 aL~yl and aryl;
Al and A2 are independently selectedfrom: abond, -CH=CH-, -C--C-, -C(O)-, -C(O)NR10-,-NRlOC(O)-, O, -N(R10)-, -S(O)2N(R10)-, -N(RlO)S(O)2-~ or S(O)m;

15 G is H2 or O;

V is selected from:
a) hydrogen, b) heterocycle, c) aryl, d) Cl-C20 aL~yl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 aL~enyl, 25 provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(O)m;

W is a heterocycle;

30 X is -cH2-~ -C(=O)-, or -S(=O)m-;

Z is a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, W 096t30343 PCT~US96/04019 heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
1) Cl 4 aL~yl, unsubstituted or substituted with:
a) Cl 4 aL~oxy, S b) NR6R7 c) C3-6 cycloaL~yl, d) aryl or heterocycle, e) HO, f) -S(O)mR6a, or g) -c(o)NR6R7~
2) aryl or heterocycle, 3) halogen, 4) oR6, S) NR6R7, 6) CN, 7) NO2, 8) CF3;
9) -S(O)mR6a 10) -C(o)NR6R7, or 11) C3-C6 cycloaL~yl;

mis 0,lor2;
nis 0, 1, 2, 3 or4;
pis 0, 1, 2, 3 or4;
q is 1 or 2;
r is 0 to S, provided that r is 0 when V is hydrogen;
s is 0 or 1 ;
t is 0 or 1 ; and u is 4 or S;
or the pharmaceutically acceptable salts thereof.

In a third embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula C:

W 096/30343 PCTrUS96/04019 (R~)r ~1~ R~ R3 V - A (CR a2)nA2(CR1a2)n - (CR1b2)p\ ,N /N--Z
/~G
C R
.

wherem:

R1a and Rlb are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, R1OO-, R11S(O)m-, R1OC(O)NR10-, (R10)2Nc(o)-7 RlO2N-c(NRlo)-7 CN, NO2, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or R1 1OC(O)NR10-, c) unsubstituted or substituted Cl-C6 alkyl wherein the sub~liLulellt on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, RllS(O)m-, RlOC(O)NR10-, (RlO)2NC(O)-, R102N-C(NR10)-, CN, RlOC(O)-, R1OOC(O)-, N3, -N(R10)2, and Rl 1Oc(o)-NRlo;

R2 and R3 are independently selected from: H; unsubstituted or substituted C1 8 alkyl, unsubstituted or substituted C2 8 alkenyl, unsubstituted or substituted C2 g alkynyl, unsubstituted or substituted aryl, ~NR6R7 or ~oR6 unsubstituted or substituted heterocycle, ~ O
wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1 4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, W O 96130343 PCT~US96/04019 e) CN, 2) C3-6 cycloaLkyl, 3) oR6, 4) SR6a, s(o)R6a~ So2R6a, 5) --NR6R7 6) --N~ R7 o 8) - O ~ N R6R7 o 10) 'f NR6R7 1 1 ) --S02--NR6R7 12) --N--S02--R6a W 096~0343 PCTrUS96/04019 13) ~ R6 , , o 15) N3, or 16) F; or R2 and R3 are attached to the same C atom and are combined to form - (CH2)U - wherein one of the carbon atoms is optionally replaced by a 5 moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R4 is selected from H and CH3;

and any two of R2, R3 and R4 are optionally ~tt~c.hed to the same carbon atom;

R6, R7 and R7a are independently selected from: H; Cl 4 alkyl, C3-6 cycloaLkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstihlte~l or substituted with:
a) Cl-4 aLkoxy, b) aryl or heterocycle, c) halogen, d) HO, O
f) --SO2R1 1 , or g) N(R10)2; or R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

CA 022l6707 l997-09-29 W 096/30343 ' PCTnUS96/04019 R6a is selected from: Cl 4 aL~yl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) Cl 4 alkoxy, S b) aryl or heterocycle, c) halogen, d) HO, e) ~ R11 f) --SO2R1 1 , or g) N(R10)2;
R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RllS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~ R102N-C(NR10)-, CN, NO2, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or RllOC(O)NR10-, and c) Cl-C6 aLkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RllS(O)m-,RlOC(O)NH-,(RlO)2Nc(o)-~R102N-C(NR10)-, CN, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or RlOOC(O)NH-;

~ 25 R9 is seleeted from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R100-, RllS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~
R102N-C(NR10)-, CN, NO2, RlOC(O)-, RlOOC(O)-, N3, -N(R10)2, or Rl lOC(O)NR10-, and CA 022l6707 l997-09-29 W 096/30343 PCTrUS96/04019 c) Cl-C6 aL~yl unsubstituted or substituted by perfluoroaL~yl, F, Cl, Br, R1OO-, R11S(O)m-, R1OC(O)NR10-, (R10)2Nc(o)-~ R102N-C(NR10)-, CN, R1OC(O)-, R1OOC(O)-, N3, -N(R10)2, or R1 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-, -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;

15 G is O;

V is selected from:
a) hydrogen, b) heterocycle, c) aryl, d) Cl-C20 aL~yl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 aL~enyl, 25 provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(O)m;

W is a heterocycle;

30 X is -CH2-, -C(=O)-, or -S(=O)m-;

Z is a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, wherein the substituted group is ,~ substituted with one or more of the following:
1) Cl 4 alkyl, unsubstituted or substituted with:
a) Cl 4 alkoxy, S b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) H0, f) -S(O)mR6a, or g) -C(o)NR6R7, 2) aryl or heterocycle, 3) halogen, 4) oR6~
S) NR6R7, lS 6) CN, 7) N02, 8) CF3;
g) -S(o)mR6a~
10) -C(o)NR6R7, or 11) C3-C6 cycloalkyl;

m is 0, 1 or 2;
nis 0, 1, 2, 3 or4;
p is 0, 1, 2, 3 or 4;
q is 1 or 2;
r is 0 to S, provided that r is 0 when V is hydrogen;
sis l;
t is 0 or 1; and uis 40rS;
or the ph~ ceutically acceptable salts thereof.

A preferred embodiment of the compounds of this invention is illustrated by the following formula:

W 096130343 PCTrUS96/04019 V - A (CR 2)nA2(CR 1a2)n -(W)- (CR1 b2)p~X~N\ ~f N~

A

whereln:

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

Rlb is independently selected from:
a) hydrogen, b) aryl, heterocycle, cycloaLkyl, R100-, -N(R10)2 or C2-C6 aLkenyl, c) unsubstituted or substituted Cl-C6 aLkyl wherein the substitutent on the substituted Cl-C6 aLkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, RlOO- and N(R10)2;

R3, R4 and R5 are independently selected from H and CH3;
~ NR6R7 R2 is H; O or Cl 5 aLkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1 ) aryl, 2) heterocycle, 3) oR6, 4) SR6a, SO2R6a, or 5) ~ NR6R7 o and any two of R2, R3, R4, and R5 are optionally attached to the same carbon atom;

W 096/30343 PCTrUS96/04019 R6, R7 and R7a are independently selected from:
H; Cl 4 aL~yl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with:
a) Cl 4 aL~oxy, S b) halogen, or c) aryl or heterocycle;

R6a is selected from:
Cl 4 aL~yl or C3-6 cycloaL~yl, unsubstituted or substituted with:
a) C 1-4 aL~oxy, b) halogen, or c) aryl or heterocycle;

15 R8 is independently selected from:
a) hydrogen, b) Cl-c6 aL~yl, C2-c6 aL~enyl, C2-c6 alkynyl, Cl-C6 perfluoroaL~yl, 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 perfluoroaL~yl, R100-, RlOC(o)NR10, (Rlo)2N-c(NRlo)-~ RlO
RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10-;

25 R9 is selected from:
a) hydrogen, b) C2-C6 aL~enyl, C2-C6 aL~ynyl, Cl-C6 perfluoroalkyl, F, Cl, RlOO, Rl lS(o)m, Rloc(o)NRlo-~ CN, NO2, (R10)2N-C(NR10)-, RlOC(O)-, RlOOC(O)- -N(R10)2 or Rl 1 OC(O)NR10-, and c) Cl-C6 alkyl unsubstituted or substituted by Cl-C6 perfluoroaL~yl, F, Cl, R100-, RllS(O)m-, RlOC(O)NR10-, CN, (Rlo)2N-c(NRlo)-~ RlOC(O)-, RlOOC(O)-, -N(R10)2, or Rl lOC(O)NR10-;

=

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

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

Al and A2 are independently selected from: a bond, -CH=CH-, -~C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;
~0 V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) Cl-C20 aL~yl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 aL~enyl, and 20 provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(O)m;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or 25 isoquinolinyl;

X is -CH2- or -C(=O)-;

Y is mono- or bicyclic aryl, or mono- or bicyclic heterocycle, unsubstituted or substituted with one or more of:
a) Cl 4 aLkyl, b) Cl 4 alkoxy, c) halogen, or d) NR6R7;

CA 022l6707 l997-09-29 W 096/30343 PCTrUS96/04019 m is 0, 1 or 2;
nis 0, 1, 2, 3 or4;
pis 0, 1, 2, 3 or4;
r is O to 5, provided that r is O when V is hydrogen;
s is O or l; and - tis Oor l;

or the phalmaceutically acceptable salts thereof.
In a second preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula B:

( I 8)r ~R9~ R2,~
V - A1 (CR1 a2)nA2(CR 1 a2)n -\W~!- (CR1 b2)p\ ~ N~ JN--Z

B
wherein:

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

20 Rlb is independently selected from:
a) hydrogen, - b) aryl, heterocycle, cycloalkyl, R100-, -N(R10)2 or C2-C6 alkenyl, c) unsubstituted or substituted Cl-C6 alkyl wherein the sub~Lilu~ellt on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R100- and N(R10)2;

W 096/30343 PCTrUS96/04019 R3 and R4 are independently selected from H and CH3;
~ NR6R7 R2 is H; O or Cl 5 aLkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl, S 2) heterocycle, 3) oR6, 4) SR6a, SO2R6a, or 5) NR6R7 ~ ;
and any two of R2, R3, R4, and RS are optionally attached to the same carbon atom;

R6, R7 and R7a are independently selected from:
H; Cl 4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with:
lS a) Cl 4 alkoxy, b) halogen, or c) aryl or heterocycle;

R6a is selected from:
Cl 4 aLkyl or C3-6 cycloalkyl, unsubstituted or substituted with:
a) Cl-4 aL~oxy, b) halogen, or c) aryl or heterocycle;
R8 is independently selected from:
a) hydrogen, b) Cl-C6 alkyl, C2-C6 aL~enyl, 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 RllOC(O)NR10-, and W 096/30343 PCTnUS96/04019 -c) Cl-C6 aL~yl substituted by Cl-C6 perfluoroalkyl, R100-, RlOC(o)NR10, (Rlo)2N-c(NRlo)-~ RlO
RlOOC(O)-, -N(R10)2, or RllOC(O)NR10-;

5 R9 is selected from:
a) hydrogen, b) C2-C6 aL~enyl, C2-C6 aL~ynyl, Cl-C6 perfluoroaL~yl, F, Cl, RlOO-, RllS(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 aL~yl unsubstituted or substituted by Cl-C6 perfluoroalkyl, F, Cl, R100-, RllS(O)m-, RlOC(O)NR10-, CN, (RlO)2N-c(NRlo)-~ RlOC(O)-~ RlOOC(O)-~
-N(R10)2, or Rl lOC(O)NR10-;
R10 is independently selected from hydrogen, Cl-C6 aL~yl, benzyl and aryl;

Rll is independently selected from Cl-C6 alkyl and aryl;
Al and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;

V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d,) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 aL~enyl, and W 096/30343 PCTrUS96/04019 provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(O)m;

G is H2 or O;
s W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;

10 X is -CH2- or -C(=O)-;

Z is mono- or bicyclic aryl, mono- or bicyclic heteroaryl, mono- or bicyclic arylmethyl, mono- or bicyclic heteroarylmethyl, mono- or bicyclic arylsulfonyl, mono- or bicyclic heteroarylsulfonyl, unsubstituted or substituted with one or two of the following:
1) Cl 4 alkyl, unsubstituted or substituted with:
a) Cl 4 aLkoxy, b) NR6R7, c) C3-6 cycloaL~yl, d) aryl or heterocycle, e) HO, f) -S(O)mR6, or g) -c(o)NR6R7~
2) aryl or heterocycle, 3) halogen, 4) oR6, S) NR6R7, 6) CN, 7) NO2, 8) CF3;
9) -S(O)mR6, 10) -C(o)NR6R7, or 11) C3-C6cycloaLkyl;

W O9~1~0~ PCTrUS96/04019 m is 0, 1 or 2;
nis 0, 1, 2, 3 or4;
pis 0, 1, 2, 3 or4;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 0 or 1;
t is 0 or 1; and u is 4 or 5;

10 provided that when G is H2 and W is imicl~7.olyl, then the substitutent (R8)r- V - Al(CRla2)nA2(CRla2)n - is not H and provided that when X is -C(=O)-, or -S(=O)m-~ then t is 1 and the sub~Lilu~ellt (R8)r- V - Al(CRla2)nA2(CRla2)n - is not H;
or the ph~rm~eutically acceptable salts thereof.

The preferred compounds of this invention are as follows:

20 2(S)-Butyl-1-(2,3-~ minoprop-1-yl)-4-(1-naphthoyl)-plperazme 1-(3-Annino-2-(2-naphthylmethylamino)prop- 1-yl)-2(S)-butyl-4-(1-naphthoyl)piperazine 2(S)-Butyl-1-{5-[1-(2-naphthylmethyl)]-4,5-dihydroimidazol }methyl-4-( 1 -naphthoyl)piperazine 1-[5-(1-Benzylimidazol)methyl]-2(S)-butyl-4-(1-naphthoyl)piperazine 1-{5-[1-(4-Nitrobenzyl)imidazolyl]methyl}-2(S)-butyl-4-(1-naphthoyl)piperazine 1 -(3-Acetamidomethylthio-2(R)-aminoprop- l-yl)-2(S)-butyl-4-(1-35 naphthoyl)piperazine ~ =

2(S)-Butyl- 1-[2-(1-imidazolyl)ethyl]sulfonyl-4-(1-naphthoyl)piperazine 2(R)-Butyl- 1 -imidazolyl-4-methyl-4-( 1 -naphthoyl)piperazine 2(S)-Butyl-4-( 1 -naphthoyl)- 1 -(3-pyridylmethyl)piperazine 1-2(S)-butyl-(2(R)-(4-nitrobenzyl)amino-3-hydroxypropyl)-4-(1-naphthoyl)piperazine 1-(2(R)-Amino-3-hydroxyheptadecyl)-2(S)-butyl-4-(1-naphthoyl)piperazine 2(S)-Benzyl- 1 -imidazolyl-4-methyl-4-( 1 -naphthoyl)piperazine 1-(2(R)-Amino-3-(3-benzylthio)propyl)-2(S)-butyl-4-(1-naphthoyl)-piperazine 1 -(2(R)-Amino-3-[3-(4-nitrobenzylthio)propyl]))-2(S)-butyl-4-( 1-20 naphthoyl)piperazine 2(S)-Butyl-1-[(4-imidazolyl)ethyl]-4-(1-naphthoyl)piperazine 2(S)-Butyl-1-[(4-imi(1~7.olyl)methyl]-4-(l-naphthoyl)piperazine 2(S)-Butyl-l-[(l-naphth-2-ylmethyl)-lH-imi(1~7ol-5-yl)acetyl]-4-(l-naphthoyl)piperazine 2(S)-Butyl- 1- [( 1 -naphth-2-ylmethyl)- 1 H-imidazol-5-yl)ethyl]-4-( 1-30 naphthoyl)piperazine 1 -(2(R)-Amino-3-hydroypropyl)-2(S)-butyl-4-( 1-naphthoyl)piperazine 1-(2(R)-Amino-4-hydroxybutyl)-2(S)-butyl-4-(1-naphthoyl)piperazine W 096/30343 PCTrUS96/04019 1-(2-Amino-3-(2-benzyloxyphenyl)propyl)-2(S)-butyl-4-(1-- naphthoyl)piperazine 1-(2-Amino-3-(2-hydroxyphenyl)propyl)-2(S)-butyl-4-(1-5 naphthoyl)piperazine 1- [3-(4-imidazolyl)propyl] -2(S)-butyl-4-( 1-naphthoyl)piperazine 10 2(S)-n-Butyl-4-(l-naphthoyl)-l-[l-(l-naphthylmethyl)imi-1~7.ol-5-ylmethyl] -piperazine 2(S)-n-Butyl-4-(1-naphthoyl)- 1-[1 -(2-naphthylmethyl)imicl~701-5-ylmethyl] -piperazine 2(S)-n-Butyl-1-[1-(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine 2(S)-n-Butyl-1-[1-(4-methoxybenzyl)imidazol-5-ylmethyl]-4-(1-20 naphthoyl)piperazine 2(S)-n-Butyl-1-[1-(3-methyl-2-butenyl)imicl~7.ol-5-ylmethyl]-4-(l-naphthoyl)piperazine 25 2(S)-n-Butyl-1-[1-(4-fluorobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine 2(S)-n-Butyl-1-[1-(4-chlorobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine 1-[1 -(4-Bromobenzyl)imidazol-5-ylmethyl]-2(S)-n-butyl-4-( 1-naphthoyl)piperazine 1-[1-(4-Bromobenzyl)imidazol-5-ylmethyl]-2(S)-n-butyl-4-(1-35 naphthoyl)piperazine .

W O 96130343 PCTrUS96/04019 2(S)-n-Butyl-4-(1-naphthoyl)-1-[1 -(4-trifluoromethylbenzyl)imidazol-5-ylmethyl] -piperazine 2(S)-n-Butyl- 1- [ 1 -(4-methylbenzyl)imidazol-5-ylmethyl] -4-(1-5 naphthoyl)-piperazine 2(S)-n-Butyl-1-[1-(3-methylbenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)-piperazine 1-[l-(4-phenylbenzyl)imic1~7ol-5-ylmethyl]-2(s)-n-butyl-4-( naphthoyl) -piperazine 2(S)-n-Butyl-4-(1-naphthoyl)-1-[1-(2-phenylethyl)irnidazol-5-ylmethyl]-piperazine 2(S)-n-Butyl-4-(l-naphthoyl)-1-[1-(4-trifluoromethoxy)-imic1~7.ol-5-ylmethyl]piperazine 1-{ [1-(4-cyanobenzyl)-lH-imicl~7.ol-5-yl]acetyl }-2(S)-n-20 butyl-4-(1-naphthoyl)piperazine 5(S)-n-Butyl- 1 -(2,3-dimethylphenyl)-4-(4-imidazolylmethyl)-piperazin-2-one 5(S)-n-Butyl-4-[1-(4-cyanobenzyl)imidazol-5-ylmethyl]-1-(2,3-dimethylphenyl)piperazin-2-one 4-[1 -(4-Cyanobenzyl)imidazol-5-ylmethyl]- 1 -(2,3-dimethylphenyl)-5(S)-(2-methoxyethyl)piperazin-2-one (S)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(methanesulfonyl)ethyl] -2-piperazinone (S)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)ethyl]-2-piperazinone (S)- 1-(3-Chlorophenyl)-4-[ 1 -(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl] -2-piperazinone (S)- 1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imicl~7.olylmethyl]-5-5 [N-ethyl-2-acetamido]-2-piperazinone (+)-5-(X-Butynyl)- 1 -(3-chlorophenyl)-4-[1 -(4-cyanobenzyl)-5-imidazolylmethyl] -2-piperazinone 10 1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imicl~7.olylmethyl]-2-piperazinone 5(S)-Butyl-4-[1-(4-cyanobenzyl-2-methyl)-5-imidazolylmethyl]-1-(2,3-dimethylphenyl) -piperazin-2-one 4-[1-(2-(4-Cyanophenyl)-2-propyl)-5-imi~1~7.olylmethyl]- 1-(3-chlorophenyl)-5(S)-(2-methylsulfonylethyl)piperazin-2-one 5(S)-n-Butyl-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-1-(2-20 methylphenyl)piperazin-2-one 4-[1-(4-Cyanobenzyl)-5-imidazolylmethyl]-5(S)-(2-fluoroethyl)-1-(3-chlorophenyl)piperazin-2-one 25 4-[3-(4-Cyanobenzyl)pyridin-4-yl]-1-(3-chlorophenyl)-5(S)-(2-methylsulfonylethyl)-piperazin-2-one 4-[5-(4 -Cyanobenzyl)- 1 -imidazolylethyl]- 1 -(3-chlorophenyl)piperazin-2-one.
or the ph~ eutically acceptable salts thereof.

Specific examples of the compounds of the invention are:

1-{5-[1-(4-Nitrobenzyl)imidazolyl]methyl}-2(S)-butyl-4-(1-naphthoyl)piperazine PCTrUS96/04019 <'N~

1-[5-(1-Benzylimidazol)methyl]-2(S)-butyl-4-(1-naphthoyl)piperazine ~0 S N~
1-(2(R)-Amino-3-(3-benzylthio)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine 1-(2(R)-Amino-3-[3-(4-nitrobenzylthio)propyl])-2(S)-butyl-4-(1-naphthoyl)piperazine - CA 022l6707 l997-09-29 W 096t30343 PCTrUS96/04019 02N ~S ,N~NJ~

2(S)-n-Butyl-1-[1-(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine O

N~

2(S)-n-Butyl-1-[1-(4-cyanobenzyl)imil1~7.ol-5-ylmethyl]-4-(2,3-dimethylphenyl)piperazin-5-one ~ H3C CH3 NC~ ~N~N~

W 096/30343 PCTrUS96/04019 2(S)-n-Butyl- 1- [ 1 -(4-chlorobenzyl)imidazol-5-ylmethyl]-4-( 1-naphthoyl)~i~erazine Nf 1-{ [1-(4-Cyanobenzyl)-lH-imidazol-5-yl]acetyl}-2(S)-n-butyl-4-(1-naphthoyl)piperazine ~\N~

1-[ 1 -(4-Cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3-dimethylphenyl)-2(S)-(2-methoxyethyl)piperazin-5-one CA 022l6707 l997-09-29 W 096130343 PCTrUS96/04019 ,CH3 O~

NC ~ ~N~N~

5(S)-n-Butyl-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-1-(2-methylphenyl)piperazin-2-one NC

N~

(S)-1-(3-Chlorophenyl)-4-tl-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-10 (methanesulfonyl)ethyl]-2-piperazinone o2 NC ~

W 096130343 PCTrUS96/04019 (S)- 1 -(3-Chlorophenyl)-4-[ 1 -(4-cyanobenzyl)-5-imicl~7.olylmethyl]-5-[2-(ethanesulfonyl)ethyl] -2-piperazinone ,CH2CH3 o2 NC ~N~N--<' O

(S)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imicl~zolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone <CH3 NC~ ~N N~

N

1 -(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imicl~zolyl-methyl]-2-piperazinone NC ~

N

W 096/30343 PCTrUS96/04019 or the ph~ r.eutically acceptable salts thereof.
The compounds of the present invention may have asymmetric centers and occur as racemates, racemic rnixtures, and as 5 individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. When any variable (e.g. aryl, heterocycle, Rl, R2 etc.) occurs more than one time in any constituent, its definition on'each occurence is independent at every other occurence. Also, combinations of substituents/or variables are 10 permis~ible only if such combinations result in stable compounds.
As used herein, "aL~yl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "aL~oxy" represents an alkyl group of indicated number of carbon atoms ~tt~rhed through an oxygen 15 bridge. "Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.
As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Fx~mples of such aryl elements 20 include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
The term heterocycle or heterocyclic, as used herein, represents a stable S- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or 25 Im.~tllrated, 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 30 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, dihydrobenzothienyl, dihydrobenzothiopyranyl, W 096/30343 PCTrUS96/04019 dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, S 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.
As used herein, "heteroaryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S. Examples of such heterocyclic elements include, but are not limited to, ben7imidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, 2~ thienothienyl, and thienyl.
As used herein in the definition of R2 and R3, the term "the substituted group" intended to mean a substituted Cl ~ alkyl, substituted C2 ~ alkenyl, substituted C2 ~, alkynyl, .substituted aryl or substituted heterocycle from which the substitutent(s) R2 and R3 are selected.
As used herein in the definition of R6, R7 and R7a, the substituted Cl ~ alkyl, substituted C3-6 alkenyl, substituted aroyl, sub.stituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroarylsulfonyl and substituted heterocycle include W 096/30343 PCTrUS96/04019 moieties cont~ining from 1 to 3 substitutents in addition to the point of attachment to the rest of the compound.
As used herein, the term "substituted aryl"is intended to include the aryl group which is substituted with 1 or 2 substitutents S selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(cl-c6 aLkyl)2, NO2, CN, (cl-c6 alkyl)O-, -OH, (Cl-C6 alkyl)s(o)m-~ (cl-c~6 alkyl)C(O)NH-, H2N-c(NHk (Cl-C6 aLkyl)C(O)-, (Cl-C6 alkyl)OC(O)-, N3,(C1-C6 aLkyl)OC(O)NH- and Cl-C20 aLkyl.
When R2 and R3 are combined to form - (CH2)U -, cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to:

In addition, such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-cont~ining cyclic moietie~s include, but are not limited to:

OJ ~S~

~"~ ~ ~ ~ ~10 Lines drawn into the ring systems from substituents (such as from R2, R3, R4 etc.) indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.

W 096/30343 PCTrUS96/04019 Preferably, R1a and Rlb are independently selected from:
hydrogen, -N(R 1~)2, RlOC(O)NR 10 or unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted phenyl, -N(R10)2, R100- and 5 R 1 OC(O)NR 10 Preferably, R2 is selected from: H, ~NR6R7 ~oR6 ~ ~ and an unsubstituted or substituted group, the group selected from Cl ~S aL~yl, C2 ~ aL~enyl and C2 ~s alkynyl;
wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C 1-4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, 2) C3-6 cycloalkyl, 3) oR6, 4) SR6a, s(o)R6a~ So2R6a, 5) --N R6R7 I

6) --N~ R7 o --N~ N R7R7a -CA 022l6707 l997-09-29 W O 96/30343 PCTrUS96/04019 8) --O~ NR6R7 O

9) --o~OR6 10) ~NR6R7 11) - S02- NR6R7 12) N SO2 R

o 1 4) oR6 ~r 15) N3, or 16) F.

Preferably, R3 is selected from: hydrogen and Cl-C6 aIkyl.
Preferably, R4 and R5 are hydrogen.
Preferably, R6, R7 and R7a is selected from: hydrogen, - unsubstituted or substituted Cl-C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloaLkyl.
- 10 Preferably, R6a is unsubstituted or substituted Cl-C6 aLkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl.
Preferably, R9 is hydrogen or methyl. Most preferably, Ra is hydrogen.

W 096t30343 PCTrUS96/04019 Preferably, R10 is selected from H, Cl-C6 alkyl and benzyl.
Preferably, A 1 and A2 are independently selected from: a bond, -C(O)NR 10, -NR I ~C(O)-, O, -N(R 10), -S(O)2N(R 10)- and-N(R l ~)S(O)2 .
Preferably, V is selected from hydrogen, heterocycle and ' aryl. More preferably, V is phenyl.
Preferably, Y is selected from unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted pyridyl, unsubstituted or substituted furanyl and unsubstituted or substituted thienyl. More preferably, Y is unsubstituted or substituted phenyl.
Preferably, Z is selected from unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted pyridyl, unsubstituted or substituted furanyl and unsubstituted or substituted thienyl. More preferably, Z is unsubstituted or substituted phenyl.
Preferably, W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl.
Preferably, n and r are independently 0, l, or 2.
Preferably p is 1, 2 or 3.
Preferably s is 0.
Preferably t is 1.
Preferably, in compounds of the formula B, when G is H2 and W is imidazolyl, then the substitutent (R~)r- V -A l (CR 1 a2)nA2(CR l a2)n - is not H.
Preferably, in compounds of the formula B, when X is -C(=O)-, or -S(=O)m-, then t is 1 and the substitutent (R~)r- V -A 1 (CR 1 a2)nA2(CR 1 a2)n - is not H;

It is intended that the definition of any substituent or variable (e.g., Rla, R9, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, -N(R10)2 represents -NHH, -NHCH3, -NHC2Hs, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the ~rt to provide compounds that are chemically stable and that can be readily S .synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.
The ph~ ceutically acceptable salts of the compounds of this i~vention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic 10 acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, 15 phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
The phz~ eeutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention 20 which contain a basic moiety by conventional chemical methods.
Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amoumts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1-22, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., a,s may be known in the literature or exemplified in the experimental procedure~. Substituents R, Ra and Rb, 30 as shown in the Schemes, represent the substituents R2, R3, R4, and R5;
however their point of attachment to the ring is illustrative only and i~s not meant to be limiting.
These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to =

W 096/30343 PCT~US96/04019 - 4~ -synthesize fragments which are subsequently joined by the alkylation reactions described in the Schemes.

Synop.sis of Schemes 1-22:
The requisite interrnediates are in some cases commercially available, or can be prepared according to literature procedures, for the most part. In Scheme 1, for example, the synthesis of 2-alkyl substituted piperazines is outlined, and is essentially that described by J.
S. Kiely and S. R. Priebe in Or~anic Preparation,s and Proceedings Int., 1990, 22, 761-76~. Boc-protected amino acids I, available commercially or by procedures known to those skilled in the art, can be coupled to N-benzyl amino acid esters using a variety of dehydrating agents such as DCC (dicyclohexycarbodiimide) or EDC-HCl (l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such as methylene chloride, chloroform, dichloroethane, or in dimethylformamide. The product II is then deprotected with acid, for example hydrogen chloride in chloroform or ethyl acetate, or trifluoroacetic acid in methylene chloride, and cyclized under weakly basic conditions to give the diketopiperazine III. Reduction of III with lithium aluminum hydride in re~uxing ether gives the piperazine IV, which is protected as the Boc derivative V. The N-benzyl group can be cleaved under standard conditions of hydrogenation, e.g., 10%
palladium on carbon at 60 psi hydrogen on a Parr apparatus for 24-48 h. The product VI can be treated with an acid chloride, or a carboxylic acid under standard dehydrating conditions to furnish the carboxamides VII; a final acid deprotection as previously described gives the intermediate VIII (Scheme 2). The intermediate VIII can be reductively alkylated with a variety of aldehydes, such as IX. The aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Or~anic Syntheses. 1988, 67, 69-75, from the appropriate amino acid (Scheme 3). 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 -W O 96/30343 PCT~US96/04019 -~ or dimethylformamide. The product X can be deprotected to give the final compounds XI with trifluoroacetic acid in methylene chloride.
The final product XI is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The S product ~ mine XI can further be selectively protected to obtain XII, which can ~ubsequently be reductively alkylated with a second aldehyde to obtain XIII. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XV can be accomplished by literature procedures.
Alternatively, the protected piperazine intermediate VII can be reductively alkylated with other aldehydes such as l-trityl-4-imidazolyl-carboxaldehyde or l-trityl-4-imidazolylacetaldehyde, to give products such as XVI (Scheme 4). The trityl protecting group can be removed from XVI to give XVII, or alternatively, XVI can first be 15 treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole XVIII. Alternatively, the intermediate VIII can be acylated or sulfonylated by standard techniques. The imidazole acetic acid XIX can be converted to the acetate XXI by standard procedures, and XXI can be first reacted with an alkyl halide, then treated with 20 refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XXII. Hydrolysis and reaction with piperazine VIII in the presence of condensing reagents such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) leads to acylated products such as XXIV.
If the piperazine VIII is reductively alkylated with an 25 aldehyde which also has a protected hydroxyl group, such as XXV in Scheme 6, the protecting groups can be subsequently removed to unmaslc the hydroxyl group (Schemes 6, 7). The alcohol can be oxidized under standard conditions to e.~. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard 30 reagents, to obtain secondary alcohols such as XXIX. In addition, the fully deprotected amino alcohol XXX can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXXI (Scheme 7), or tertiary amines.

W 096/30343 PCTrUS96/04019 The Boc protected amino alcohol XXVII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXXII
(Scheme 8). Treating XXVII with l,l'-sulfonyl~liimi(1~7ole and sodium hydride in a solvent such as dimethyl~ormamide led to the formation of S ~iricline XXXII. The aziridine reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product XXXIII.
In addition, the piperazine VIII can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, 10 according to standard procedures, to obtain compounds such as XXXIX.
When R' is an aryl group, XXXIX can first be hydrogenated to llnm~k the phenol, and the amine group deprotected with acid to produce XL.
~ltern~tively, the amine protectin~ group in XXXIX can be removed, and O-alkylated phenolic amines such as XLI produced.
Depending on the identity of the amino acid I, various side chains can be incorporated into the piperazine. For example when I is the Boc-protected ~-benzyl ester of aspartic acid, the intermediate diketopiperazine XLII where n=l and R=benzyl is obtained, as shown in Scheme 10. Subsequent lithium aluminum hydride reduction reduces the ester to the alcohol XLIII, which can then be reacted with a variety of alkylating agents such as an aLkyl iodide, under basic conditions, for example, sodium hydride in dimethylformamide or tetrahydrofuran.
The resulting ether XLIV can then be carried on to final products as described in Schemes 3-9.
N-Aryl piperazines can be prepared as described in Scheme 11. An aryl amine XLV is reacted with bis -chloroethyl amine hydrochloride (XLVI) in refluxing n -butanol to furnish compounds XLVII. The resulting piperazines XLVII can then be carried on to ~mal products as described in Schemes 3-9.
Piperazin-5-ones can be prepared as shown in Scheme 12.
Reductive ~min~tion of Boc-protected amino aldehydes XLIX
(prepared from I as described previously) gives rise to compound L.
This is then reacted with bromoacetyl bromide under Schotten-B~llm~nn conditions; ring closure is effected with a base such as sodium hydride ..
in a polar aprotic solvent such as dimethylform~micle to give LI. The carbamate protecting group is removed under acidic conditions such as trifluoroacetic acid in methylene chloride, or hydrogen chloride gas in methanol or ethyl acetate, and the resulting piperazine can then be 5 carried on to final products as described in Schemes 3-9.
The isomeric piperazin-3-ones can be prepared as described in Schelme 13. The imine formed from arylcarboxamides LII and 2-aminoglycinal diethyl acetal (LIII) can be reduced under a variety of conditions, including sodium triacetoxyborohydride in dichloroethane, 10 to give the amine LIV. Amino acids I can be coupled to amines LIV
under st~nc~rd conditions, and the resulting amide LV when treated with aqueous acid in tetrahydrofuran can cyclize to the lln~ lrated LVI. Catalytic hydrogenation under standard conditions gives the requisite intçrmediate LVII, which is elaborated to final products as 15 described in Schemes 3-9.
Access to alternatively substituted piperazines is described in Scheme 14. Following deprotection with trifluoroacetic acid, the N-benzyl piperazine V can be acylated with an aryl carboxylic acid. The resulting N-benzyl aryl carbox~ e LIX can be hydrogenated in the 20 presence of a catalyst to give the piperazine carbox~mi~le LX which can then be carried on to final products as described in Schemes 3-9.
Reaction Scheme 15 provides an illustrative example the synthesis of compounds of the instant invention wherein the substituents R2 and R3 are combined to form - (CH2)U -. For example, 1-25 aminocyclohexane-l-carboxylic acid LXI can be converted to the spiropiperazine LXVI essentially according to the procedures outlined in Schemes 1 and 2. The piperazine interrnediate LXIX can be deprotected as before, and carried on to final products as described in Schemes 3-9. It is understood that reagents utilized to provide the 30 substituent Y which is 2-(naphthyl) and the imidazolylalkyl substituent may be readily replaced by other reagents well known in the art and readily available to provide other N-substituents on the piperazine.
The aldehyde XLIX from Scheme 12 can also be reductively aLkylated with an aniline as shown in Scheme 16. The W 096t30343 PCTrUS96/04019 product LXXI can be converted to a piperazinone by acylation with '~
chloroacetyl chloride to give LXXII, followed by base-intlllce-1 cyclization to LXXIII. Deprotection, followed by reductive alkylation with a protected imicl~7.ole carboxaldehyde leads to LXXV, which can S be aLkylation with an arylmethylh~licle to give the imit1~7olium salt LXXVI. Final removal of protecting groups by either solvolysis with a lower alkyl alcohol, such as methanol, or treatment with triethylsilane in methylene chloride in the presence of trifluoroacetic acid gives the final product LXXVII.
Scheme 17 illustrates the use of an optionally substituted homoserine lactone LXXIX to prepare a Boc-protected piperazinone LXXXII. Intermediate LXXXII may be deprotected and reductively aLkylated or acylated as illustrated in the previous Schemes.
~ltern~tively, the hydroxyl moiety of intermediate LXXXII may be 15 mesylated and displaced by a suitable nucleophile, such as the sodium salt of ethane thiol, to provide an intermediate LXXXIII. Tntermediate LXXXII may also be oxidized to provide the carboxylic acid on intermediate LXXXIV, which can be lltili7e-1 form an ester or amide moiety.
Amino acids of the general formula LXXXVI which have a sidechain not found in natural amino acids may be prepared by the reactions illustrated in Scheme 18 starting with the readily prepared imine LXXXV.
Schemes 19-22 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 strategies for preparing alkanols that incorporate other heterocyclic moieties for variable W are also well known in the art.

W 096/30343 PCTrUS96/04019 O Ra Rb ~OJ~ N ~OH PhCH2NHCHCO2C2H5 H o DCC, CH2CI2 O N ~N~,COzc2Hs H I ~ Rb Ra 1) HCI, CH2CI2 R)~o LAH ~ HN N
~ HN N \ THF, reflux \
2) N~HCO3 O Rb ~ \Rb 111 lV

Ra Ra Boc20 0,\ ) \ 10% Pd/C ~~ ) V ;~ Vl PCTrUS96/04019 a EDC-HCI, HOBT
R ~ ~ DMF
BocN NH
Y, Rb ~CO2H

) ~ ~ HCI, EtOAc Y O
Rb Vll Vlll W O 96/30343 PCT~US96/04019 Boc NHl IX
Ra~ ~ ~ Boc NH CHO
HCI N N NaBH(OAc)3 YRb Et3N, CICH2CH2CI
Vlll Ra Q; 3 CF3CO2H
Boc NH~NyN~ CH2C12 NHBoc R

Ra ~ Boc20 NH~ N N CH2C12 NH2 Rb Xl Ra ~Q3 ~CHO

BocNH~ NyN NaBH(OAc)3 NH2 Rb Et3N, CICH2CH2CI
Xll W 096130343 PCTrUS96/04019 SCHEME 3 (continllerl) BocNH~N N~ CF3CO2H, CH2CI2;
y O NaHCO3 =\ NH R~b ~/ Xlll NH~ N N $~ ~ NC

NH R AgCN
~ XIV

Ra ~ NyN
N~N~ R
~3 XV
--W 096/30343 PCTrUS96/04019 a /= NaBH(OAc)3 R~ Et3N, CICH2CH2CI
HCI ~ NyN~ (CH2)nCHO
Rb o N

Vlll Tr RN~ ~3 (CH2)n+1 y o N~ Rb N, XVI
Tr 1 ) Ar CH2X, CH3CN
CF3CO2H, CH2CI2 (c2H5)3siH

Ra N~3 9~H2)n+1 y O
N;~ Rb H XVII

.
Ra~

Ar (/CH2)n+1 y o N~ Rb N~ XVIII

W 096/30343 PCTrUS96/04019 SCHEME S

N~ 2 02H CH N~CH2C02CH3 H HCI H HCI
XIX XX
CH2C02CH3 1) ArCH2X CH3CN
(C6H5)3CBr ~ reflux (C2H )3FN Tr 2) CH30H, reflux XXI

Ar~\N~cH2c02cH3 2.5N HCla N 55~C
XXII

Ar~\ CH2C02H
N~
N

XXIII

W 096130343 PCTrUS96/04019 - 59 _ SCHEME 5 (continued) .

Ar~\N~cH2c02H Ra ~3 + HCI H N~N

XXIII ~ . Rb Vlll EDC- HCI
HOBt DMF

~ HCI

~3~N ~N~3 N Rb XXIV

W 096/30343 PCTrUS96/04019 NaBH(OAc)3 ~ Et3N, CICH2CH2CI
HCI N N~ ~=' BnO~
y 0 Rb BocNH CHO
Vlll XXV

BnO ~NyN~ zoyO Pd(OH)2 H2 NHBoc Rb CH3CO2H
XXVI

HO N N ~ CICOCOCI

NHBoc Rb (C2Hs)3N
XXVII

W 096/30343 PCTrUS96/04019 SCHEME 6 (CONTINUED) - R~ ~ ~ 1. R'MgX
0~N N ~ \=/ (C2H5)20 HNHBoc Rb CH2Cl2 XXVIII

Ra ~ 9 HO~N N
R' NH2 Rb XXIX

W O 96/30343 PCTrUS96/04019 Ra /~
~ ~ CF3CO2H
HO~ NyN~ CH2CI2 NHBoc Rb XXVII

Ra /~
~ ~ R'CHO
HO,~N N~ NaBH(OAc)3 ~ b ~ CIC H2C H2CI

XXX

HO ~N <N~
NH Rb R'CH2 XXXI

W 096130343 PCTrUS96/04019 F~a ~3 8 HO ~N N
y o NaH, DMF0~C
NHBoc Rb XXVII

R~ ~ ~ R'SH

<~ y o CH30H
H Rb XXXII

Ra R'S ~N N~
NH2 Rb XXXIII

W 096/30343 PCTrUS96/04019 HO~ 1) Boc20, K2C~3 HO~

~ THF-H20 J~ 2) CH2N2, EtOAc J~
H2NCO2H BocNH CO2CH3 XXXIV
XXXV

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

XXXVI

R'CH ~ pyrldine SO

BocNH CH2OH 20~C BocNH CHO
XXXVII XXXVIII

W O 96/30343 PCTrUS96/04019 SCHEME 9 (continued) R'CH~3 + HCI N N~
BocNH CHO \~Rb XXXVIII Vlll NaBH(OAc)3 R'CH20~ ~\
NHBoc Rb XXXIX \ HCI
ETOAc 1 ) 20% Pd(OH)2 CH30H, CH3CO2H /
2) HCI, EtOAc / R'CH20~ y HO~; \N~ XLI
NH2 Rb XL

CO2R ' n( S~~ 1) LAH, Et20 HN N 2) Boc20 0~ ~
XLII

HO
R61 . n ( < ) O n( S~, aH, DMF ~N~\N~

XLIV
XLIII

W O 96130343 PCTrUS96/04019 Rb ArNH2 + Cl~)2NH ~ HCI
XLV Ra XLVI

Ra Rb n- butanol ArN NH ~ HCI
reflux >~
Ra Rb XLVII

W 096130343 PCTrUS96/04019 OH CH3NHOCH3 ~ HCI
O N ~EDC . HCI, HOBT
~ DMF, Et3N, pH 7 O Ra >~oJ~ N ~ N(CH3)0CH3 LAH, Et20 XLVIII

>~ ~ Ra ArCH2NH2 O N ~ NaBH(OAc)3 XLIX pH 6 1, C 1) BrCH2COBr H 2) NaH, THF, DMF

W 096/30343 PCTrUS96/04019 SCHEME 12 (CONT'D) r Ra o ) ~ 1) TFA, CH2CI2 _~ ~N N~
o Ra~

HN N~
~~ Ar W O 96t30343 PC~rrUS96/04019 S C ~I]~n~ 13 NaBH(OAc)3 ArCHO +NH2CH2CH(Oc2H5)2 Lll Llll ~ Ra Ar CH2NHCH2CH(Oc2Hs)2 >~o~ N~
LIV EDC. HCI, HOBT
DMF, Et3N, pH 7 O Ra ~Ar 6N HCI
>~0~ N~N~CH(OC2Hs)2 THF

LV

Ra O H2 1 0%Pd/C
N~=~N~ CH30H
t~ Ar LVI
Ra o ~N N~
~0 \~ Ar LVII

CA 022l6707 l997-09-29 W 096130343 PCTrUS96/04019 .
Rb GF CO H CH Cl /~ ArCO2H
V 1) 3 2 ~ 2 2 rN NH
2) NaHCO3 /=~, RaY EDC HCI
HOBT, DMF
LVIII

Rb Rb N N~ 10% Pd/C , HN N~

LIX Ar H2 CH3oH RLY Ar ~ W 096130343 PCTAUS96/04019 r ul PhcH2NHcH2co2c2H5 ~ DCC, CH2C12 BocNH C02H
LXI
a) TFA, CH2CI2 BocNH~N~C02c2Hs b) NaHCO3 ~ LXII

H N~N~,C02C2H5 CHC13 LXIII
~/<~
0~ ~ LiAlH4 HN \N~

LXIV ~ LXV

Boc20 BocN~ N H2 Pd/C
CH2CI2 ~ CH30H "

LXVI

CA 022l6707 l997-09-29 W 096/30343 PCTrUS96/04019 SCHEME 15 (continued) COCI
~\ ~
BocN~NH NaHCO3 EtOAc LXVII
~u~
~ \ a) TFA, CH2C12 BocN N~ /=\ b) NaBH(OAc)3 ~ ~C(=O)H
LXVIII ,N
~ CPh3 ~ u~ .

~N ~~ TFA CH2CI2 (c2H5)3siH
N, CPh3LXIX

/ \ ,0 ~ H 2 TFA
~- LXX

W 096/30343 PCTrUS96/04019 SC~nE~nE 16 R R H
BocNH CHO ArNH2 ~ BocNH~N~Ar NaBH(OAc)3 XLIX LXXI

CI~J~cI BocNH N-Ar EtOAc / H20 ~
NaHCO3 Cl O
LXXII

BocN N-Ar HCI
DMF ~ EtOAc o LXXIII

W 096/30343 PCTrUS96/04019 SCHEME 16 (continued) CHO

~\ ' N N--Ar HCIHN~N--Ar C(Ph)3 N~ \~O
O NaBH(OAc)3 N
LXXIV pH 5-6 (Ph)3C

LXXV

R
~, Ar~ ~N N--Ar ArCH2X N~ ~~
CH3CN ~ O
,N ~
(Ph)3c X

LXXVI

MeOH ~
or Ar~ ~ N N--Ar TFA, CH2CI ~N~ ~
(C2H5)3SiH
LXXVII

W 096/30343 PCTrUS96/04019 ~o 1. Boc20, i-Pr2EtN \-\0 H2N O 2. DIBAL BocHN~

LXXIX OH
~ sub ArNH2 /~ N
NaBH(OAc)3 ' BocNH Ar HO sub O ~/
C~ CI BocNH N-Ar EtOAc / H20 /~
NaHCO3 Cl O
LXXXI

HO sub ,'1~
Cs2CO3 ~
BocN N-Ar DMF \~
o LXXXII

W 096/30343 PCT~US96/04019 SCHEME 17 (continued) HO /sub BocN~N--Ar ~ 1. (COCI)2, Et3N
1. MsCI, iPr2NEt LXXXII \
2. NaCI02, t-BuOH
2. NaSEt,~ ~ 2-Me-2-butene EtS /sub HO /sub BocN N--Ar BocN~N--Ar O O
LXXXIII LXXXIV

W 096/30343 PCT/u~-5lQ~ol9 1. KOtBu, THF R2 r CO2Et R2x ~ CO2Et r N ~ H2N
Ph 2. 5% aqueous HCI HCI
LXXXV

1. Boc20, NaHCO3 R2 ~ CO2H
BocHN
2. LiAlH4, Et20 LXXXVI

W 096/30343 PCTrUS96/04019 CH3 1 ) HNo2~Br2 CO2CH3 ~ 2) KMnO
H2N N 3) MeOH,H+ Br~N~

~\~\ MgCI R6 ~ ~,CO2CH3 zncl2~Nicl2(ph3p)2 N

NaBH4 (excess) ~CH20H

DMSO ~CHO

W 096130343 PCTrUS96/04019 1. EtO(CO)CI R6 Br 2 R6 MgCI [~
~C02CH3 Zn CuCN ~CO2CH3 N 3. S, xylene, heat N

NaBH4 ~j~ SO3Py, Et3N ~
(excess) ~CH20H DMSO ,~CHO

Br~ ~c02cH3 [~\MgCI ¢~j ~,CO2CH3 N ZnC12, NiC12(Ph3P)2 N~

NaBH4 ¦ S03Py, Et3N
~CH20H ~ ~CHO
(excess) N DMSO N ~I

W O 96/30343 PCT~US96/04019 co2CH3 Br~ 1. LDA, C02 Br~

N 2. MeOH, H~ N

ZnCI2, Nici2(ph3p)2 N

NaE3H4(excess) ¢~OH SO3Py, Et3N
DMSO

CHO

W 096/30343 PCTrUS96/04019 cO2CH3 r 1. LDA, CO2 [~Br 2. (CH3)3SiCHN2 R6 ~\ Br R6 ~q Zn, NiCI2(Ph3P)2 N~CO2CH3 R6 1~
excess NaBH4 1~ SO3 Py, Et3N
~CH20H DMSO

R6 ~

N ~,CHO

W 096/30343 PCTrUS96/04019 J' The instant compounds are useful as ph~rm~reutical agents for m~mm~l.c, especially for hllm~n~. These compounds may be ~t1mini~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 activity (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 vasc~ ri7~tion.
The compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and m~li n~nt wherein Ras ~loteills 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 ~1mini~tration of an effective amount of the compounds of the inventiom to a m~mm~l in need of such tre~tment For example, a component of NF-l is a benign proliferative disorder.
The instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256:1331-1333 (1992).
The compounds of the instant invention are also useful in the prevention of restenosis after percutaneous translumin~l coronary angioplasty by inhibiting neointim~l formation (C. Indolfi et al. Nature medicine, 1:541-545(1995).
The instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al.

American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)). ..
The instant compounds may also be useful for the treatment of fungal infections.
The compounds of this invention may be ~lmini.~tered to m~mm~l~, preferably hnm~n~, either alone or, preferably, in combination with ph~nn~ceutically acceptable ca~Tiers or diluents, optionally with known adjuvants, such as alum, in a ph~rTn~ceutical composition, according to standard ph~rtn~eutical practice. The compounds can be ~-lmini~tered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of ~-lmini~tration.
For oral use of a chemotherapeutic compound according to this invention, the selected compound may be ~tlmini~tered~ for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly ~-lclecl For oral ~1mini.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 desired, certain sweetening and/or flavoring agents may be ~ e~l For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic.
The compounds of the instant invention may also be co-~tlmini.~tered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
For example, the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents. Simil~rly, the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF-l, restinosis, polycystic kidney W O 96/30343 PCTrUS96/04019 o ~ disease, infections of hepatitis delta and related viruses and fungal infections.
If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range 5 described below and the other ph~rm~ceutically active agent(s) within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known ph~rm~ceutically acceptable agent(s) when a combination formulation is inaL~ iate.
The present invention also encompasses a ph~ reutical 10 composition useful in the treatment of cancer, comprising the ~lmini.~tration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and ph~rm~colo-15 gically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. Thesolutions may be introduced into a patient's blood-stream by local bolus injection.
When a compound according to this invention is ~tlmini.~tered into a human subject, the daily dosage will normally be 20 determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's sy~ toms.
In one exemplary application, a suitable amount of compound is ~1mini~tered to a m~mm~l undergoing treatment for 25 cancer. ~Clmini.~tration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
The compounds of the instant invention are also useful 30 as a component in an assay to rapidly determine the presence and quantity of farnesyl-protein transferase (FPTase) in a composition.
Thus the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine W 096/30343 PCTrUS96/04019 terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention. After the assay mi~ules are incubated for an sufficient period of time, well known in the art, to allow the FPTase to farnesylate the substrate, the chemical content of 5 the assay mixhlres may be deter~nined by well known immunological, radiochemical or chromatographic techniques.
Because the compounds of the instant invention are selective inhibitors of FPTase, absence or qll~ntit~tive reduction of the amount of substrate in the assay mixture without the compound of the instant 10 invention relative to the presence of the unchanged substrate in the assay cont~inin~ 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 15 tissue s~mples which contain farnesyl-protein transferase and q~l~ntit~tin~ the enzyme. Thus, potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract cont~inin~ an unknown amount 20 of farnesyl-protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate are incubated for an a~pro~liate period of time in the presence of varying concentrations of a compound of the instant invention. The concentration of a sufficiently potent 25 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 sample by 50% is approximately equal to half of the concentration of the enzyme in that particular sample.

EXAMPLES

Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species CA 022l6707 l997-09-29 W 096/30343 PCTrUS96/04019 and conditions are intended to be further illustrative of the invention and not limit~tive of the reasonable scope thereof. Purification by HPLC was accomplished with a 40 X 100 mm Waters PrepPak(~
reverse phase HPLC column (Delta-PakTM C18 15 ,um, 100 A).
5 Gradient elution employed 0.1% trifluoroacetic acid in water (Solvent A) and 0.1~o trifluoroacetic acid in acetonitrile (Solvent B). Chloride salts were obtained by passing an aqueous solution of the trifluoroacetic acid salt through a Biorad A~@~ 3X4 ion exchange resin column (100-200 mesh, C1-form). Purification by HPLC was utilized for each of the 10 Fx~mples 1-23, 27, 48 and 49 as set forth below.

2(S)-Butyl- 1 -(2,3-~ minoprop- 1 -yl)-4-(1 -naphthoyl)piperazine 15 trihydrochloride Step A: 1-Benzyl-3(S)-n -butylpiperazine-2~5-dione The title compound was prepared according to the procedure described by John S. Kiely and Stephen R. Priebe in Organic 20 Preparations and Procedures Int.. 22 (6), 761-768 (1990). Thus dicyclohexylcarbodiimide (9.33 g, 45.2 mmol) in methylene chloride (0.5 M) was added to methylene chloride (250 mL). This solution was cooled to 0 C under nitrogen and Boc-L-norleucine (10.5 g, 45.2 mmol) was added. The resulting slurry was stirred for 5 min, and then ethyl N-benzylglycinate (8.72 g, 45.2 mmol) was added. The reaction was stirred for 2 h at 0 C, then at 20 C overnight. The precipitate was removed by filtration, and hydrogen chloride gas bubbled through the methylene chloride solution for 2-4 h, until the reaction was shown to be complete by tlc. The solvent was removed in vacuo~ and the residue partitioned between ethyl acetate (150 mL) and saturated sodium " bicarbonate solution (42 mL). The organic phase was washed with saturated sodium chloride, dryed over magnesium sulfate, filtered and evaporated. The crude diketopiperazine was triturated with hexane to give the title compound as a white powder. 1HNMR (300 MHz, CDCl3) W 096t30343 PCTrUS96/04019 o 7.24-7.40 (5H, m), 6.22 (lH, br s), 4.07 (lH, dt, J=3, 6 Hz), 3.87 (lH, d, J=17 Hz), 3.80 (lH, d, J=17 Hz), 1.88 (2H, m), 1.35 (4H, m), 0.91 (3H, t, J=7 Hz).

Step B: 4-Benzyl-l-tert -butoxycarbonyl-2(S)-n -buLyl~i~elazine The product from Step A (4.95 g, 0.019 mol) was dissolved in THF (200 mL) and cooled under nitrogen to 0 C with mechanical stirrin3~. Lithium al~lminllm hydride (2.60 g, 0.0685 mol) was added slowly. The reaction was refluxed for 18 h, cooled to 0 C, and quenched by the sequential slow addition o~ 5 rnL H20, 5 mL 10%
sodium hydroxide solution and 5 mL H2O. The reaction was stirred for 30 min and filtered. The solvent was removed in vacuo, the crude product taken up in methylene chloride and dried over magnesium sulfate. The drying agent was removed by filtration, and the filtrate treated with di-tert -butyl dicarbonate ((4.35 g, 0.020 mol). After 2 h at 20 C, saturated sodium bicarbonate was added. The layers were separated, and the organic phase washed with saturated sodium chloride solution, then dried over magnesium sulfate. Filtration and evaporation gave the crude product which was purified by column chromatography on silica gel, eluting with 5% ethyl acetate in hexane. The title compound was obtained as a foam. lHNMR (300 MHz, DMSO-d6) 7.25 (5H, m), 3.90 (lH, br s,), 3.73 (lH, d, J=13 Hz), 3.51 (lH, d, J=13 Hz), 3.34 (lH, d, J=13 Hz), 2.93 (lH, m), 2.75 (lH, d, J=ll Hz), 2.62 (lH, d, J=ll Hz), 1.90 (2H, m), 1.60 (2H, m), 1.38 (9H,s), 1.26 (2H, m), 1.04 (2H, m), 0.84 (3H, t, J=7 Hz).

Step C: l-tert -Butoxycarbonyl-2(S)-n -butylpiperazine The product from Step B (3.75 g, 11.3 mmol) was dissolved in methanol (75 mL) in a Parr bottle, and the vessel purged with argon. To this was added 10 % palladium on carbon (0.80 g) and the reaction hydrogenated under 60 psi hydrogen for 24 h. The catalyst O
was removed by filtration through Celite, and the filtrate evaporated in vacuo to give the title compound as an oil. lHNMR (300 MHz, CDC13) W 096/30343 PCTrUS96/04019 t!
o 4.08 (lH, br s), 3.90 (lH, d, J=12 Hz), 2.5-3.8 (6H, m), 1.80 (lH, m), 1.60 (lH, m), 1.46 (9H, s), 1.30 (4H, m),0.90 (3H, t, J=7 Hz).

Step D: l-tert -Butoxycarbonyl-2(S)-n -butyl-4-(1-naphthoyl)-piperazine l-tert-butoxycarbonyl-2(S)-n -butylpiperazine (0.325 g, 1.34 mrnol), l-hydroxybenzotriazole (HOBT) (0.203 g, 1.34 mmol) and l-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (EDC -HCl) (0.254 g, 1.34 mmol) were added to dry, degassed 10 dimethylform~mi~le (7 mL). The pH of the reaction was adjusted to 7 with triethyl~mine, and the reaction stirred for 2 h. The dimethylform~mide (DMF) was distilled in vacuo. and the residue partitioned between ethyl ~cet~te and water. The organic phase was washed with 2% aqueous potassium hydrogen sulfate, saturated sodium 15 bicarbonate solution, saturated sodium chloride solution, and dried over m~gnesium sulfate. The title compound was obtained as a thick oil.

Step E: 2(S)-n -Butyl-4-(1-naphthoyl)piperazine hydrochloride The product from Step D was dissolved in ethyl ~cet~te, 20 cooled to -40~C under nitrogen, and the solution saturated with HCl(g).
The solution was warmed to 0~C for 30 min, and then purged with nitrogen. The solvent was removed in vacuo. The product was evaporated from ethyl acetate three times. The title compound was obtained as a white solid.
Step F: 2.3-(bis-tert-Butoxycarbonylamino)propanoic acid Diaminopropanoic acid monohydrochloride (2.86 g, 0.0204 mol) was suspended in 1:1 water-dioxane (100 mL) cont~ining triethyl~mine (5.97 mL, 0.0204 mol). BOC-ON (11.0 g, 0.0448 mol) 30 was added along with additional triethylamine to adjust the pH to 9.5.
The reaction was stirred under nitrogen overnight at 20~C. The clear solution was diluted with water and extracted with diethyl ether (5 x 100 mL). The aqueous solution was adjusted to pH 1 with cold 5%
aqueous hydrochloric acid and extracted with ethyl acetate. The organic W 096/30343 PCTrUS96/04019 layer was washed with water, saturated sodium chloride, then dried over m~gnesium sulfate. The resulting foam (5.46 g) was cryst~lli7e-1 from ethyl acetate to give the title compound as a white solid.

5 Step G: N-Methoxy-N-methyl-2,3-(bis-tert-butoxycarbonyl-amino)proprionamide 2,3-bis-(ter~-Butoxycarbonylamino)propanoic acid (1.80 g, 5.92 mmol) in dimethylfonn~mide (25 mL) was stirred overnight with N-methoxy-N-methylamine hydrochloride (0.635 g, 6.51 mmol), EDC
10 HCl (1.24 g, 6.51 mmol), N-hydroxybenzotriazole (0.80 g, 5.92 mmol) and triethylamine (0.825 mL, 5.92 mmol). The dimethylform~mi~1e was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was washed with 10% hydrochloric acid, s~Lulat~;d sodium bicarbonate solution, saturated brine, and dried over 15 m~gnesium sulfate. The crude product was chromatographed on silica gel with 30% ethyl acetate in hexane. The title compound was obtained as a foam. lHNMR (CDC13, 300 MHz) d 5.51 (lH, br d), 4.87 (lH, br s), 4.72 (lH, br s), 3.77 (3H, s), 3.50 (lH, m), 3.40 (lH, dt, J=12, 6 Hz), 3.20 (3H, s), 1.44 (9H, s), 1.42 (9H, s).
Step H: 2~3-(bis-tert-Butoxycarbonylamino)propanal Lithium aluminum hydride (0.384 g, 10.14 mmol) was suspended in diethyl ether (20 mL) and cooled to -45~C under nitrogen.
N-Methoxy-N-methyl-2,3-(bis-tert-butoxycarbonylamino)-25 proprionamide (2.07 g, 5.96 mrnol) in 1:1 ether-tetrahydrofuran (60 mL) was added at such a rate so as to keep the reaction temperature less than -35~C. The reaction was allowed to warm to 5~C, then cooled to -45~C and quenched with a solution of potassium hydrogen sulfate (3.08 g, 22.6 mmol) in water (20 mL). The reaction was stirred at 20~C lh, 30 then ~lltered through celite. The organic phase was washed with 10%
citric acid and saturated brine, then dried over magnesium sulfate. The title compound was obtained as a foam. NMR (CDC13, 300 MHz) d 9.61 (lH,s),5.60(1H,brs),4.88(1H,brs),4.24(1H,brd,J=6Hz), 3.68 (lH, m), 3.50 (lH, m), 1.40 (9H, s), 1.39 (9H, s).

Step I: 1-[(2,3-bis-tert-Butoxycarbonylamino)prop-l-yl]-2(S)-butvl-4-(1-naphthoyl)piperazine A solution of 3(S)-butyl-l-(l-naphthoyl)piperazine (1.83 g, 6.20 mmol) (free base of the product from Step E), acetic acid (0.17 mL, 2.9 mmol) in dichloroethane (20 mL) was adjusted to pH 5.5 with triethyl~nnine. Sodium triacetoxyborohydride (1.87 g, 8.79 mmol) and crushed molecular sieves (1 g) were added, and the reaction cooled to 0~C under nitrogen. A solution of 2,3-(bis-tert-butoxycarbonyl-amino)propanal (1.69 g, 5.86 mmol) in dichloroethane (10 mL) was added dropwise, and the reaction stirred at 20~C overnight The reaction was cooled to 0~C, quenched with saturated sodium bicarbonate and stirred for lh. The layers were separated and the organic layer washed with saturated brine, then dried over m~n~sium sulfate. The crude product was chromatographed on silica gel with 40-50% ethyl acetate in hexane, and the title compound was isolated as a foam (Rf 0.30, 50% ethyl acetate in hexane).

Step J: 1 (2,3 Diaminoprop-l-yl)-2(S)-butyl-4-(1-naphthoyl)piperazine trihydrochloride Trifluoroacetic acid (25 mL) was added to a solution of 1-[(2,3-bis-tert-butoxycarbonylamino)prop- 1 -yl]-2(S)-butyl-4-( 1-naphthoyl)piperazine (2.13 g, 3.75 mmol) in dichloromethane (75 mL).
After 25 min at 20~C, the solvent was evaporated and the residue partitioned between chlorform and 20% aqueous sodium hydroxide.
The organic layer was washed with saturated brine and dried over m~gnesium sulfate. The free base of the title compound was obtained as a yellow gum (1.72 g). A portion of this material (52 mg) was pllrifie-1 by preparative HPLC using a 100 mm Waters PrepPak@~ reverse phase column (DeltaPakTM Clg, 50 mM, 100 A), and pure product isolated by gradient elution using 100% 0.1% trifluoroacetic acid in water (Solvent A) to 50% Solvent A and 50% 0.1% trifluoracetic acid in acetonitrile (Solvent B). The pure fractions were combined and the solvent evaporated, and the crude product dissolved in water and passed CA 022l6707 l997-09-29 W 096/30343 PCTrUS96/04019 - 92 - t through an ion exchange column (Biorad AG(~) 3X4 ion exchange resin, chloride form). A~ter lyophili7~tion, the title compound was obtained as a white solid. Anal. Calc. for C22H32N4O ~ 4.45 HCl C, 49.78; H, 6.92; N, 10.56. Found: C, 49.75, H, 6.72; N, 10.36.

1-(3-Amino-2-(2-naphthylmethylamino)prop-1-yl)-2(S)-butyl-4-(1-naphthoyl)piperazine trihydrochloride Step A: 1-[(2-Amino-3-tert-butoxycarbonylaminoprop-1-yl]-2(S)-butyl-4-(1 -naphthoyl)piperazine Di-tert-butyl dicarbonate (0.282 g, 1.29 mmol) was added to a solution of 4-(2,3-~ minoprop-1-yl)-2(S)-butyl-1-(1-naphthoyl)piperazine (0.476 g, 1.29 mmol) in dichloromethane (10 mL). The reaction was stirred a total of 2h at 20~C, then quenched and extracted with water. The organic phase was washed with sa~ul~ted brine and dried over magnesium sulfate. The crude product was chromatographed on silica gel with 5% methanol in chloroform followed by 5% (9:1 methanol-ammonium hydroxide) in chloroform.
The title compound was isolated as the major product. FAB ms (m+1) 469.

Step B: 1-(3-tert-Butoxycarbonylamino-2-(2-naphthylmethylamino)prop- 1 -yl)-2(S)-butyl-4-(1 -naphthoyl)piperazine The title compound was prepared according to the procedure described in Fx~mple 1, Step D except using 1-[(2-amino-3-tert-butoxycarbonylaminoprop- 1 -yl] -2(S)-butyl-4-(1 -naphthoyl)piperazine (0.287 g, 0.613 mmol), naphthalene-2-carboxaldehyde (0.95 g, 0.613 mmol), sodium triacetoxyborohydride (0.194 g, 0.919 mmol), in dichloroethane (15 mL) at pH 6. The crude product was chromatographed on silica gel with 5% methanol in W O 96/30343 PCTrUS96/04019 chloroform (Rf 0.30), and the title compound isolated as a foam. FAB
ms (m+l) 609.

Step C: 1-(3-Amino-2-(2-naphthylmethylamino)prop-1-yl)-2(S)-butvl-4-(1-naphthovl)piperazine trihvdrochloride A solution of 1-(3-tert-butoxycarbonylamino-2-(2-naphthylmethylamino)prop-l-yl)-2(S)-butyl-4-(1-naphthoyl)piperazine (0.313 g, 0.514 mmol) in methylene chloride (10 mL) was deprotected with trifluoroacetic acid (5 mL) and converted to the free base (255 mg) according to the procedure described in F,x~mple 1, Step E.
Purification of 40 mg by preparative HPLC used gradient elution with solvents A and B (from Fx~mple 1; 95% to 5% solvent A). Ion exchange and lyophili7~tion as described fi~ hed the title compound as a white solid. FAB ms (m+l) 509. Anal. Calc. for C33H40N4O 0.05 H2O 4.45 HCl: C, 59.00; H, 6.68; N, 8.34. Found: C, 59.00; H, 6.51;
N, 8.44.

2(S)-Butyl-1-{5-[1-(2-naphthylmethyl)]-4,5-dihydroimidazol}methyl-4-(l-naphthoyl)piperazine ditrifluoroacetate 1 -(3-Amino-2-(2-naphthylmethylamino)prop- 1 -yl)-2(S)-butyl-4-(1-naphthoyl)piperazine (0.105 g, 0.207 mmol), tert-butylisocyanate (1.5 mL) and silver cyanide (0.023 g, 0.207 mmol) were h~,~te,-l in a sealed tube under nitrogen at 90~C overni~ht The volatiles were removed in vacuo, and the residue chromatographed on silica gel with 5-10% methanol in chloroform to give the free base (73 ,., mg). This was purified by preparative HPLC as described in Example 1 by gradient elution with solvents A and B (from Example 1; 95% to 5%
solvent A ). Lyophili7~tion furnished the title compound as a white solid. FAB ms (m+l) 519. Anal. Calc. for C34H38N4O ~ 0.85 H2O
3.75 TFA: C, 51.84; H, 4.55; N, 5.83. Found: C, 51.83; H, 4.56; N, 6.32.

- W 096/30343 PCTrUS96/04019 1-[5-(1-Benzylimi~l~7.ol)methyl]-2(S)-butyl-4-(1-naphthoyl)piperazine dihydrochloride Benzyl bromide (0.012 mL, 0.103 mmol) was added to a solution of 2(S)-butyl-1-[5-(3-triphenylmethylimidazol)]methyl-4-(1-naphthoyl)piperazine (63 mg, 0.103 mmol) in acetonitrile (0.5 mT ) at 20~C under nitrogen. The rèaction was stirred overni~ht concentrated in vacuo, and taken up in dichlormethane (2 mL) cont~inin~?
triethylsilane (0.100 mL). Trifluoroacetic acid was added and the reaction stirred for lh at 20~C. The solvent was evaporated and the residue purified by HPLC (95% to 5% solvent A). Pure fractions were combined and converted to the HCl salt as described in Fx~mrle 1, Step E. After lyophili7~tion, the title compound was isolated as a white solid. FAB ms (m+1) 467. Anal. Calc. for C30H34N4O ~ 0.05 H20 -3.70 HCl: C, 59.81; H, 6.32; N, 9.30. Found: C, 59.78; H, 6.33; N, 9.30.

1 - { 5-[1 -(4-nitrobenzyl)]imidazolylmethyl }-2(S)-butyl-4-(1 -naphthoyl)piperazine ditrilluoroacetate The title compound was prepared according to the procedure described in Example 4, except using p-nitrobenzylbromide (0.043 g, 0.199 mmol) and 2(S)-butyl-1-[5-(3-triphenylmethylimidazol)]methyl-4-(1-naphthoyl)piperazine (123 mg, 0.199 mmol) in acetonitrile (2 mL). The crude product was treated with triethylsilane (0.127 mL, 0.80 mmol) and trifluoroacetic acid (2 mL) in dichloroethane (4 mL). Preparative HPLC (95-5% solvent A) provided the title compound as a white solid. FAB ms (m+1) 512. "
Anal. Calc. for C30H33N5O3 2 CF2CO2H 0.03 H2O: C, 41.42; H, 3.98; N, 10.18. Found: C, 41.43; H, 3.96; N, 10.51.

W O 96/30343 PCT~US96/0~019 1 -(3-Acetamidomethylthio-2(R)-aminoprop- 1 -yl)-2(S)-butyl-4-(1 -naphthoyl)piperazine ditrifluoroacetate 1-(3-Acetamidomethylthio-2(R)-aminoprop-1-yl)-2(S)-butyl-4-(1-naphthoyl)piperazine dihydrochloride and N-hydroxymethyl~cet~mide (0.010 g, 0.105 mmol) (prepared as described in M. Bodansky, A. Bodansky, "The Practice of Peptide Synthesis", Springer-Verlag, 1984, p.82) were dissolved in trifluoroacetic acid for 0.5h. The solvent was removed in vacuo and the residue purified by preparative HPLC (85-60% solvent A). After lyophili7~tion, the title compound was isolated as a solid. FAB ms (m+1) 457. Anal. Calc. for C25H36N4O2 S ~-2 CF2CO2H ~ 1.9 H2O . C, 44.38 H, 5.12; N, 6.64.
Found: C, 44.35; H, 5.11, N, 6.97.

2(S)-Butyl-1-[2-(1-imidazolyl)ethyl]sulfonyl-4-(1-naphthoyl)piperazine ditrifluoroacetate Step A: 2(S)-Butyl-4-(1 -naphthoyl)- 1 -vinylsulfonylpiperazine Chloroethylsulfonylchloride (0.038 mL, 0.314 mmol) was added to a solution of 3(S)-butyl-1-(1-naphthoyl)piperazine (0.095 g, 0.285 mmol) and diisopropylethyl~mine (0.119 mT~, 0.685 mmol) in dichloromethane (3 mL). The reaction was stirred overnight under nitrogen, quenched with saturated sodium bicarbonate and extracted into ethyl acetate. After drying with magnesium sulfate, the title compound was isolated.

Step B: 2(S)-Butyl-1-[2-(1-imidazolyl)ethyl]sulfonyl-4-(1-naphthoyl)piperazine ditrifluoroacetate Imidazole (0.043 g, 0.627 mmol) was added to sodium hydride (60% dispersion in oil, 0.024 g, 0.598 mmol) suspended in dimethylform~mide (2 mL). The reaction was cooled to 0~C under CA 022l6707 l997-09-29 W 096/30343 PCTrUS96/04019 nitrogen, and 2(S)-butyl-4-(1 -naphthoyl)- 1 -vinylsulfonylpiperazine (0.011 g, 0.29 mmol) in dimethylform~micle (5 mL) was ~cldecl The reaction was stirred at 20~C overnight. The dimethylforrn~ e was removed in vacuo and the residue dissolved in ethyl acetate. This was S extracted with saturated sodium bicarbonate solution, satu.ated brine and dried over m~gnesium sulfate. The crude product was first purified by silica gel chromatography using 8% methanol in chloroform, then by preparative HPLC (80 to 40% solvent A). The trifluoroacetate salt was dissolved in water and partitioned between saturated sodium bicarbonate 10 and ethyl acetate. The organic phase was washed with saturated brine and dried over m~gnesium sulfate. The title compound was obtained as a foam. FAB ms (m+1) 455. Anal. Calc. for C25H36N4O2 S ~0-8 H20 . C, 61.46; H, 6.79; N, 11.95. Found: C, 61.44; H, 6.97; N, 10.72.

2(R)-Butyl- 1 -imidazolyl-4-methyl-4-(1 -naphthoyl)piperazine Step A: 2(R)-Butyl-4-(1-naphthoyl)-1-[4-(1-triphenylmethylimidazolyllmethyl-piperazine 3(R)-Butyl-l-(1-naphthoyl)piperazine (0.202 g, 0.607 mmol) (prepared as described for the (S) enantiomer in Example 1) was reacted with 1-triphenylmethylimidazole-4-carboxaldehye (0.226 g, 0.667 mmol), sodium triacetoxyborohydride (0.321 g, 1.52 mmol), in dichloroethane (7 mL) in the presence of crushed molecular sieves. The pH was adjusted to 5-6 with triethylamine/acetic acid. The reaction was stirred overnight, then quenched with saturated sodium bicarbonate.
The organic layer was washed with saturated brine, and dried over m~gnesium sulfate. The crude product was purified by chromatography on silica gel with 30% ethyl acetate in hexane followed by 5% methanol in chloroform, to obtain the title compound.

Step B: 2(R)-Butyl-1-imidazolyl-4-methyl-4-(1-naphthoyl)piperazine ditrifluoroacetate CA 022l6707 l997-09-29 W O9~/~03~ PCTrUS96/04019 ~, Triethylsilane (1.0 mL, 11.80 mmol) was added to a solution of 2(R)-butyl-4-(1-naphthoyl)-1-[4-(1-triphenylmethyl-imitl~zolyl]methyl-piperazine (0.381 g, 0.616 mmol) in dichloro-methane, followed by trifluoroacetic acid (8 mL). After lh, the 5 solvents were evaporated and the residue partitioned between water and hexaIle. The aqueous phase was injected directly onto a preparative HPLC column (100-40% solvent A) and the title compound isolated after lyophili7~tion. FAB ms'(m+l) 377. Anal. Calc. for C25H36N4O2 ~ 2.35 CF3co2H ~0.32 H2O . C, 48.93; H, 4.52; N, 7.98.
Found: C, 48.93; H, 4.55; N, 8.26.

2(S)-Butyl-4-(1 -naphthoyl)- 1 -(3-pyridylmethyl)piperazine dihydrochloride 3 (S)-Butyl- 1 -(1 -naphthoyl)piperazine hydrochloride (0.200 g, 0.601 mmol) was reacted with pyridine-3-carboxaldehyde (0.062 mL, 0.661 mmol), sodium triacetoxyborohydride (0.321 g, 1.52 mmol), in dichloroethane (7 mL) at pH 5-6 in the presence of crushed molecular sieves as described in F.x~mple 8, Step A. The crude product was puri~led by silica gel chromatography with 30% acetone in hexane, followed by preparative HPLC (80-75% solvent A). After ion exchange, the title compound was isolated. FAB ms (m+l) 388. Anal.
Calc. for C25H29N3O ~ 2.3 HCl ~0.95 H2O . C, 61.49; H, 6.85; N, 8.60. Found: C, 61.49; H, 7.01; N, 8.76.

1 -2(S)-Butyl-(2(R)-(4-nitrobenzyl)amino-3-hydroxypropyl)-4-(1-30 naphthoyl)piperazine dihydrochloride 1 -(2(R)-amino-3-hydroxypropyl)-2(S)-butyl-4-(1 -naphthoyl)piperazine (120 mg, 0.326 mmol) was converted to the title compound according to the procedure described in Example 8, Step A
using 4-nitrobenzaldehyde (0.493 g, 0.327 mmol), sodium W 096/30343 PCT~US96/04019 triacetoxyborohydride (0.173 g, 0.817 mmol), in dichloroethane. The crude product was purified by preparative HPLC (100-75% solvent A), and after ion exchange to the HCl salt and lyophili7z~tion, the title compound was obtained. FAB ms (m+l) 505. Anal. Calc. for 5 C25H29N3O ~ 3.6 HCl -0.10 H2O . C, 54.69; H, 6.30; N, 8.80. Found:
C, 54.66; H, 5.85; N, 8.31.

1-(2(R)-Amino-3-hydroxyheptadecyl)-2(S)-butyl-4-(1-naphthoyl)piperazine di~ luoroacetate Step A: 1-(2(R)-t-Butyoxycarbonylamino-2-formylethyl)-2(S)-butyl-4-(1-naphthoyl)piperazine A solution of oxalyl chloride (1.36 mL, 14.9 mmol) in dichloromethane (35 mL) was cooled to -65~C under nitrogen, and dimethylsulfoxide (2.30 mL, 32.4 mmol) in methylene chloride (7 mL) added, and the reaction stirred 2 min. A solution of 1-(2(R)-amino-3-hydroxypropyl)-2(S)-butyl-4-(1-naphthoyl)piperazine (3.19 g, 6.79 mmol) was added to this solution at -10~C and the reaction stirred at this temperature for 15 min. The reaction was cooled to -55~C and triethylamine (4.76 mL, 34 mmol) ~ 1e-1 The reaction was stirred for 5 min then warmed to room temperature. Additional methylene chloride is added and the reaction is extracted with water. The organic phase was washed with 2% potassium hydrogen sulfate, water, dilute sodium bicarbonate solution, and saturated brine. After drying with magnesium sulfate, the title compound was obtained.

Step B: 1-(2(R)-Amino-3-hydroxyheptadecyl)-2(S)-butyl-4-(l-naphthoyl)piperazine ditrifluoroacetate A solution of 0.25 g, 0.53 mmol)l-(2(R)-t-butoxycarbonylamino-2-formylethyl)-2(S)-butyl-4-(1 -naphthoyl)piperazine in dry tetrahydrofuran (5 rnL) was cooled to 0~C
under nitrogen in a flame-dried three necked flask. A solution of CA 022l6707 l997-09-29 W 096/30343 PCTIU~ 1C19 _ 99 _ heptadecy1m~gnesium chloride (1.01 mL of a lM solution in ether, 1.01 mmol) ~as added via syringe, and the reaction allowed to warm to room temperature. The reaction was quenched with saLulated sodium bicarbonate solution, and then extracted with ethyl acetate. After 5 drying over magnesium sulfate, the crude product was chromatographed on silica gel with 25% ethyl acetate in hexane followed by 5% methanol in chloroform. The puri~led product was dissolved in methylene chloride (7 rnL) and treated with trifluoroacetic acid (3.5 mL). After 45 min, the solvents were removed in vacuo and 10 the residue purified by preparative HPLC (95-40% solvent A). Two isomers were separated. After lyophili7~tion, the title compound was isolated as diastereomer A (retention time 8.405 min, gradient 100-50%
solvent A overlS min), FAB ms (m+l) 566, Anal. Calc. for C36H59N302 ~ 2.35 CF3C02H ~ 0.35 H20. C, 58.19; H, 7.44; N, 15 5.00. Found: C, 58.21; H, 7.46; N, 5.36. After lyophili7~tion, the title compound was also isolated as diastereomer B (retention time 9.269 min, gradient 100-50% solvent A overl5 min), FAB ms (m+l) 566, Anal. Calc. for C36H59N302 ~ 2.35 CF3C02H ~ 0.05 H20. C, 58.56;
H, 7.42; N, 5.03. Found: C, 58.53; H, 7.41; N, 5.17.

2(S)-Benzyl-l-imidazolyl-4-methyl-4-(1-naphthoyl)piperazine 25 Step A: 1~(3S)-Dibenzylpiperazine-2.5-dione The title compound was prepared according to the procedure described in Example 1, Step A, except using Boc-L-phenyl~l~nine (12.8 g, 48.2 mmol), ethyl N-benzylglycinate (9.32 g, 48.2 mmol) and dicyclohexylcarbodiimide (96.5 mL 0.5 M in 30 dichloromethane, 48.2 mmol). The crude diketopiperazine was triturated with hexane to give the title compound as a white powder.
lHNMR (300 MHz, CD30D) o 7.0-7.4 (lOH, m), 4.61 (lH, d, J=16 Hz), 4.37 (lH, t, J=5 Hz), 4.24 (lH, d, J=16 Hz), 3.42 (lH, d, J=18 Hz), CA 022l6707 l997-09-29 3.28 (lH, dd, J=4, 16 Hz), 2.96 (lH, dd, J=6, 16 Hz), 2.55 (lH, d, J=18 Hz).

Step B: l-tert-Butoxycarbonyl-2(S)-~(S)~4-dibenzylpiperazine The title compound was prepared according to the procedure described in Example 1, Step B, except using 1,3(S)-dibenzylpiperazine-2,5-dione (5.01 g, 17.1 mmol) and lithium alllmimlm hydride (2.33 g, 61.4 mmol), followed by di-tert -butyl dicarbonate (4.02 g, 18.4 mmol). The crude product was purified by column chromatography on silica gel, eluting with 7.5% ethyl acetate in hexane. The title compound was obtained as a white solid. lHNMR
(300 MHz, CD30D) ~ 7.2-7.4 (5H, m), 7.0-7.2 (5H, m), 4.15 (lH, m), 3.90 (lH, d, J=15 Hz), 3.60 (lH, d, J=15 Hz), 3.15 (lH, m), 2.95 (3H, m), 2.7 (lH, d, J=13 Hz), 2.02 (lH, dt, J=6, 13 Hz), 1.95 (lH, br d), 1.35 (9H, s).

Step C: 2(S)-Benzyl-l-tert -butoxycarbonylpiperazine The title compound was prepared according to the procedure described in Fx~mple 1, Step C, except using l-tert -20 butoxycarbonyl-2(S),4-dibenzylpiperazine (4.78 g, 11.3 mmol) and 10% palladium on carbon (1.04 g). The title compound was obtained as an oil. lHNMR (300 MHz, CD30D) o 7.25 (SH, m), 4.35 (lH, m), 4.00 (lH, d, J=12 Hz), 2.7-3.3 (7H, m), 1.25 (9H, s).

25 Step D: 2(S)-Benzyl-l-tert-butoxycarbonyl-4-(1-naphthoyl)piperazine The title compound was prepared according to ~e procedure described for Example 1, Step A except using 2(S)-benzyl-l-tert-butoxycarbonylpiperazine (0.292 g, 1.06 mmol), 2,3-dimethyl-30 benzoic acid (0.159 g, 1.06 mmol), HOBT (0.157 g, 1.02 mmol),EDC-HCl (0.213 g, 1.11 mmol) and triethylamine to adjust the pH to 7.
The title compound was obtained as a thick oil. lHNMR (DMSO-d6, 300 MHz) o 7.15 (2H, m), 6.06 (lH,m), 4.42 (lH,m), 3.6-4.2 (2H, m), W O 96/30343 PCTrUS96/04019 - 2.7-3.24 (4H, m), 2.24 (3H, s), 2.03-2.20 (3H, 4s), 1.10-1.6 (lSH, m), 0.72-1.00 (3H, m).

Step E: 2(S)-Benzyl-4-(1-naphthoyl)-1-[4-(1-triphenylmethylimidazolyllmethyl-piperazine 3(S)-Benzyl-l-(l-naphthoyl)piperazine (0.173 g, 0.472 mmol) was reacted with l-triphenylmethylimitl~701e-4-carboxaldehyde (0.160 g, 0.472 rnmol), sodium triacetoxyborohydride (0.300 g, 1.42 mmol), in dichloroethane (7 mL) in the presence of crushed molecular sieves as described in Example 8, Step A. The title compound was obtained as an oil.

Step F: 2(S)-Benzyl-l-imidazolyl-4-methyl-4-(1-naphthoyl)piperazine ditrifluoroacetate Triethylsilane (0.300 mL, 1.89 mmol) was added to a solution of 2(S)-benzyl-4-(1-naphthoyl)-1-[4-(1-triphenylmethylimi~ olyl]methyl-piperazine (0.310 g, 0.472 mmol) in dichloromethane (5 mL), followed by trifluoroacetic acid (5 mL).
After lh, the solvents were evaporated and the residue partitioned between water and hexane. The aqueous phase was injected directly onto a preparative HPLC column (85-45% solvent A) and the title compound isolated after lyophili7~tion. FAB ms (m+l) 411. Anal.
Calc. for C26H26N4O2 ~ 2.75 CF3CO2H ~0.05 H2O. C, 52.11, H, 4.14;
N, 7.72. Found: C, 52.10, H, 4.03, N, 8.16.

1-(2(R)-Amino-3-(3-benzylthio)propyl)-2(S)-butyl-4-(1-naphthoyl)-piperazine ditrifluoroacetate Step A: l-[(l-Aziridinyl)methyl]-2(S)-butyl-4-(1-naphthoyl)-piperazine A solution of 1-(2(R)-butoxycarbonylamino-3-hydroxypropyl)-2(S)-butyl-4-(1-naphthoyl)piperazine (1.67 g, 3.56 W 096/30343 PCTrUS96/04019 mmol) in dimethylform~rnide (10 mL) was cooled to 0~C under nitrogen. Sodium hydride (0.427 g, 10.6 mmol, 60% dispersion in oil) was ~(l(le~l, followed by l,l'-sulfonyldiimidazole (0.704 g, 3.56 mol).
The reaction was warmed to 20~C for lh, cooled to 0~C and quenched 5 with water. Dimethylform~mide was distilled in vacuo. and the residue partitioned between ethyl acetate and water. The organic phase was washed with saturated brine and dried over magnesium sulfate. The crude product was chromatographed on silica gel with 70% ethyl acetate in hexane, followed by 5~o methanol in chloroform. The title 10 compound was obtained as the major product, FAB ms (m+l) 352. A
lesser amount of l-[(l-butoxycarbonylaziridinyl)methyl]-2(S)-butyl-4-(l-naphthoyl)piperazine was also isolated.

Step B: 1-(2(R)-Amino-3-(3-benzylthio)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine ditrifluoroacetate l-[(l-Aziridinyl)methyl]-2(S)-butyl-4-(1-naphthoyl)piperazine (0.050 g, 0.142 mmol) was refluxed for 18h with benzyl mercaptan (0.100 mL, 0.852 mmol) and triethylamine (0.200 mL) in methanol (4 mL). The crude product was first chromatographed on silica gel with 3% methanol in chloroform, and then purified by preparative HPLC (85% to 10% solvent A). The title compound was obtained after lyophili7~tion. FAB ms (m+l) 476.
Anal. Calc. for C29H37N3OS ~ 2.6 CF3CO2H ~0.3 H2O. C, 52.83; H, 5.21; N, 5.40. Found: C, 52.78; H, 5.17; N, 5.66.

1 -(2(R)-Amino-3-[3-(4-nitrobenzylthio)propyl]))-2(S)-butyl-4-(1 -naphthoyl)piperazine ditrifluoroacetate A solution ofl-[(l-butoxycarbonylaziridinyl)methyl]-2(S)-butyl-4-(1-naphthoyl)piperazine (0.050 g, 0.111 mmol) in methanol (4 mL) was reluxed with p-nitrobenzylthioacetate (0.070 g, 0.333 mmol) and triethylamine (0.200 mL) for 2h. The crude product was chromatographed on silica gel with 3~o methanol in chloroform. The CA 022l6707 l997-09-29 W ~96130343 PCTrUS96/04019 ., purified product was treated with 33% trifluoroacetic acid in methylene chloride for 20 min. The solvents were evaporated and the product puri~led by preparative HPLC (85%-10~o solvent A). The title compound was obtained after lyophili7~tion. FAB ms (m+l) 529.
Anal. Calc. for C29H36N4O3 ~ 2 CF3CO2H ~0.08 H2O. C, 51.94; H, 5.23; N, 7.34. Found. C, 51.87; H, 5.06; N, 7.47.

2(S)-Butyl-1-[(4-imidazolyl)ethyl]-4-(1-naphthoyl)piperazine dihydrochloride Step A: N-Methyl-N-methoxy-2-(1 -triphenylmethyl- 1 H-imidazol-4-yl)acetamide To a solution of 4-imill~7oleacetic acid (1.04g, 6.40 mmol) and triphenylmethyl bromide (2.48 g, 7.68 mmol) in dimethylform~micle (40 ml) was added triethyl~mine (4.46 ml, 32 mmol) and the suspension allowed to stir for 18 hours at room temperature. After this time, the mixture was treated with 3-hydroxy-1,2,3-benzotriazin-4(3)-one (HOOBT) (1.31g, 8 mmol), N, O-dimethylhydroxyamine hydrochloride (1.56g, 16 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.53 g, 8 mmol) and stirred for 24 hours at room temperature. After this time, sat. aq. sodium bicarbonate (50 ml) and water (50 ml) were added and the mixtllre was extracted with ethyl acetate ( 2 x 100 ml ).
The combined extracts were washed with sat. aq. NaHCO3 (100 ml) and then brime (50 ml) and the solvent evaporated in vacuo. The residue was suspended in ether (20 ml) and the white solid filtered to give the title compound as a white solid.
1NMR(CD3OD, 300 MHz) ~ 7.37(10H, m), 7.16(6H, m), 6.84(1H, s), 3.73(2H, s), 3.68(3H, s) and 3.18(3H, s)ppm.

W 096/30343 PCTrUS96/04019 Step B: 2-(1-triphenylmethyl-lH-imidazol-4-yl)acetaldehyde To a solution of the product from Step A (300 mg, 0.73 mmol) in freshly distilled THF (15 ml) cooled to -40~C over dry ice/acetone was added lithium aluminum hydride (33.2 mg, 0.874 5 mmol). The resulting suspension was allowed to warm to +5~C and then m~int~in~.d at 0~C for 30 min. After this time, the reaction mixture was recooled to -40~C and quenched sequentially with water (33 ,ul), 1.0N NaOH (33 ,ul) and water (100 ,ul). The resulting suspension was stirred for 30 min, filtered and the solvent removed in vacuo. The 10 residue was dissolved in methylene chloride (5 ml) and washed with 10% aq. citric acid (5 ml) and then water (Sml). The organic layer was dried(MgSO4) and the solvent evaporated in vacuo to give the title compound.
lHNMR (CDCl3, 300 MHz) ~ 9.79(1H, t, J=3Hz), 7.44(1H, s), 7.4-15 7.1(15H, m), 6.76(1H, s) and 3.63(2H, d, J=3Hz)ppm.

Step C: 2(S)-Butyl-1-[(4-imi~1~7olyl)ethyl]-4-(1-naphthoyl)piperazine di~ luoroacetate To a solution of the product from Step B (89 mg, 0.263 20 mmol) and 3(S)-butyl-1-naphthoylpiperazine hydrochloride (62.6 mg, 0.188 mmol) in 1,2-dichloroethane (4 ml) was added 3A molecular sieves (400 mg) and sodium triacetoxyborohydride (200 mg, 0.94 mmol). This mixture was stirred at room temperature for 4 days. After this time, filtered the mixture through sintered glass. The filtrate was 25 diluted with methylene chloride (50 ml) and washed with water (25 ml).
The solvent was evaporated in vacuo and the residue was purified by flash chromatography eluting with 2-5% methanol/methylene chloride to provide the trityl protected title compound as an oil. This oil was dissolved in methylene chloride (2 ml) and trifluoroacetic acid (1 ml) 30 and treated with triethylsilane (2 drops) to give a colorless solution.
This solution was stirred at room temperature for 3 hours and then the solvent was evaporated in vacuo. The resulting residue was dissolved in water (20 ml) and washed with hexanes (20 ml). The aqueous layer was lyophilized to give the title compound.

W 096/30343 PCTrUS96/04019 ., lHNMR (CD30D, 300 MHz) o 8.83(1H, s), 8.08-7.75(3H, m), 7.67-7.49(4H, m), 7.45(1H, s), 4.5-3.8(2H, m), 3.65-2.95(9H, m), 2.0-- 1.3(4H, m) and 2.2-0.2(5H, m)ppm.
Anal. calc'd for C24H30N4O 3.45 TFA 0.75H20: C, 46.54; H, 4.42; N, 7.03. Found: C, 46.54; H, 4.41; N, 7.35.
FAB H~MS exact mass calc'd for C23H31N40 391.249787 (MH+), found 391.249028 2(S)-Butyl-1-[(4-imidazolyl)methyl]-4-(1-naphthoyl)piperazine dil~ uoroacetate To a solution of the product from Step C (102 mg, 0.30 mmol) and 3(S)-butyl-l-naphthoylpiperazine hydrochloride (62.6 mg, 15 0.188 mmol) in 1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride (200 mg, 0.94 mmol) and triethyl~minP to pH =
5.5 and stirred at room temp. for 18 hours. After this time, the mixtllre was filtered. The filtrate was concentrated in vacuo and dissolved in ethyl acetate (25 ml) and washed with sat. aq. NaEICO3 (10 20 ml) and then brine (10 ml). The solvent was evaporated in vacuo and the residue was purified by ilash chromatography eluting with 3-8%
methanol/methylene chloride to provide the trityl protected title compound. This oil was dissolved in methylene chloride (4 ml) and trifluoroacetic acid (2 ml) and treated with triethylsilane until the 25 yellow color disappeared to give a colorless solution. Stirring continued at room temp. for 10 min. and the solvent evaporated in vacuo. The resulting white solid was partially dissolved in water (7 ml) and filtered. The filtrate was purified by Prep HPLC using a Nova Prep 5000 Semi Preparative HPLC system and a Waters PrepPak 30 cartridge (47 X 300mm, C18, 15 ,um, lOOA) eluting with 5 - 95%
acetonitrile/water ( 0.1% TFA) at 100 ml/min ( Chromatography A ) to give the title compound after lyophili7~tion lHNMR (DMSO-d6, 400 MHz, 150~C) o 8.53(1H, s), 7.94(2H, m), 7.79(1H, m), 7.53(3H, m), 7.41(1H, m), 7.40(1H, s), 4.12(1H, d, W 096/30343 - PCTrUS96/04019 ,.
J=4.8Hz), 3.95(1H, d, J=4.8Hz), 3.70(1H, s), 3.63(1H, s), 3.48(1H, s), 3.40(1H, s), 3.01(1H, s), 2.82(1H, s), 2.74(1H, s), 1.70(1H, m), 1.49(1H, m). 1.18(2H, s), 1.08(2H, s) and 0.77(3H, t, J=5.5Hz)ppm.
Anal. calc'd for C23H2gN4o 2 TFA 0.70H20: C, 52.55; H, 5.13; N, 9.08. Found: C, 52.54; H, 5.11; N, 9.35.
FAB MS mass calc'd for C23H30N4o 377 (MH+), found 377.

2(S)-Butyl-l-[(l-naphth-2-ylmethyl)-lH-imiclz~7.ol-5-yl)acetyl]-4-(l-naphthoyl~piperazine dihydrochloride Step A: Preparation of lH-Tmicl~7ole-4- acetic acid methyl ester hydrochloride To a solution of lH-imidazole-4-acetic acid hydrochloride (4.00g, 24.6 mmol) in methanol (100 ml) was bubbled hydrogen chloride gas until satu~ted. This solution was allowed to stand for 18h at room temperature and the solvent evaporated in vacuo to give the title compound as a white solid.
lH NMR(CDC13, 400 MHz) ~ 8.85(1H, s),7.45(1H, s), 3.89(2H, s) and 3.75(3H, s) ppm.

Step B: Preparation of l-(Triphenylmethyl)-lH-imi~1~7ol-4-ylacetic acid methyl ester To a suspension of the product from Step A (7.48g, 42.4 mmol) in methylene chloride (200ml) was added triethyl~tnine (17.7 ml, 127 mmol) and triphenylmethyl bromide(l6.4g, 50.8 mmol) and stirred for 72h. After this time, the reaction mixture was washed with sat. aq. NaHCO3 (100 ml) and water ( 100 ml). The organic layer was evaporated in vacuo and the residue was purified by flash chromatography( 30-100% ethyl acetate in hexanes gradient elution) to provide the title compound as a white solid. lH NMR(CDC13, 400 MHz) ~ 7.35(1H, s), 7.31(9H, m), 7.22(6H, m), 6.76(1H, s), 3.68(3H, s) and 3.60(2H, s) ppm.

W 096/30343 PCTrUS96/04019 ;

Step C: Preparation of 2- [1-(Naphth-2-ylmethyl)-lH-imidazol-S-yl)lacetic acid methyl ester To a solution of the product of Step B (4.36g, 11.4 mmol) S in acetonitrile (70 ml) was added 2-(bromomethyl)naphthalene and heated to 55~C for 4h. After this time, the reaction was cooled to room temperature and the resulting white precipitate was collected by filtration. The filtrate was concentrated to 30 ml and heated to 55~C for 18h. After this time, the reaction was cooled to room teperature and 10 filtered the resulting white precipitate collected by filtration. The ltrate was concellLl~ted to 10 ml volume and heated to 55~C for lh.
After this time, the reaction was again cooled to room tempel~lur~ and diluted with ethyl acetate (25 ml). The resulting preci~ te was collecte~ by filtration and combined with the previous 2 precipitates in 15 methanol (100 ml) and heated to reflux for 30m. After this time, the solvent was removed in vacuo and the resulting residue was partioned between methylene chloride(200 ml) and sodium bicarbonate (100 ml).
The organic layer was evaporated in vacuo to dryness and the residue was puri~led by flash chromatography (0-6% methanol/methylene 20 chloride gradient) to provide the title compound as an off white solid:
lHNMR (CDC13, 400 MHz) ~ 7.82(2H, m), 7.75(1H, m), 7.70(1H, s), 7.49(3H, m), 7.20(1H, d, J=8.4Hz), 7.06(1H, s), 5.32(2H, s), 3.57(3H, s) and 3.49(2H, s) ppm.

25 Step D: Preparation of 2-[1-(Naphth-2-ylmethyl)-lH-imidazol-5-yllacetic acid hydrochloride 2-[1-(Naphth-2-ylmethyl)-lH-imidazol-5-yl]acetic acid methyl ester (0.92g, 3.28mmol ) was dissolved in 2.5N hydrochloric acid ( 50ml ) and heated to 55~C for 3h. After this time, the solution 30 was concentrated to dryness in vacuo to give the title compound as a white solid.
lHNMR (CD30D, 400 MHz) ~ 8.92(1H, s),7.94(1H, d, J=8.6Hz), 7.88(2H, m), 7.83(1H, s), 7.54(3H, m), 7.43(1H, d, J=14Hz), 5.60(2H, s) amd 3.82(2H, s) ppm.

W 096/30343 PCTrUS96/04019 Step E: Preparation of 2(S)-Butyl-l-[(l-(naphth-2-ylmethyl)-lH-imidazol-5-yl)acetyl]-4-(1 -naphthoyl)piperazine dihydrochloride To a solution of the product from Step D (100 mg, 0.330mmol), 3(S)-butyl-l-naphthoylpiperazine hydrochloride (100 mg, 0.300 mmol) and 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (HOOBT) (54 mg, 0.33mmol) in dimethylform~mide (2 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) 10 (63mg, 0.33 mmol) and triethylamine (161ul, 1.16mmol) and ~e resulting suspension stirred for 18 hours. After this time, sat. aq.
NaHCO3 (7 ml) was added and the resulting precipitate filtered. The solid was redissolved in methylene chloride and washed with water (25 ml) and brine (20 ml). The solvent was evaporated in vacuo and the 15 residue puri~led by Preparative HPLC (Chromatography A ) to give after lyophilli7~tion the title compound.
lHNMR (CDC13, 400 MHz) o 8.98(1H, m), 8.03-7.27(15H, m), 5.69-5.50(2H, m), 4.79-4.34(2H, m), 4.15-2.50(7H, m), 1.8-0.2(9H, m)ppm.
Anal. calc'd for C35H35N402 HCl 0.65H20: C, 67.30; H, 6.16; N, 20 8.97. Found: C, 67.25; H, 6.16; N, 9.15.
FAB HRMS exact mass calc'd for C35H36N4O2 545.291652 (MH~), found 545.292050.

2(S)-Butyl-l-[(l-naphth-2-ylmethyl)-lH-imidazol-5-yl)ethyl]-4-(1-naphthoyl)piperazine ditrifluoroacetate Step A: Preparation of N-Methyl-N-methoxy-2-[1-(naphth-2-ylmethyl)-lH-imidazol-5-yl)lacetamide To a solution of 2-[1-(naphth-2-ylmethyl)-lH-imidazol-5-yl]acetic acid hydrochloride (0.819 mg, 2.70 mmol) in dimethylform~rnide (15 ml) was added sequentially N, O-dimethylhydroxylamine hydrochloride (293 mg, 3.0 mmol ), 3-W 096/30343 PCTrUS96/04019 hydroxy-1,2,3-benzotriazin-4(3H)-one (HOOBT) (489 mg, 3.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (575 mg, 3.0 mmol) and triethylamine (1.67 ml, 12.0 mmol). This mixture was stirred at room temperature for 18h. After this time, sat.
aq. NaHCO3 (30ml) and water (30ml) were added and the mixture was extracted with methylene chloride ( 2 x 50rnl ). The combined organic extracts were washed with brine (50 ml) and the solvent evaporated in vacuo. The residue was purified by flash chromatography eluting with 2-4% methanol/methylene chloride gradient to provide the title compound as an oil.
lHNMR (CDC13, 400 MHz) o 7.80(2H, m), 7.74(1H, m), 7.56(1H, s), 7.47(3H, m), 7.22(1H, d, J=8.6Hz), 6.97(1H, s), 5.37(2H, s), 3.58(2H, s), 3.51(3H, s) and 3.12(3H, s)ppm.

Step B: Preparation of 2-[1-(Naphth-2-ylmethyl)(lH-imi~ ol-5-yl)lacetaldehyde To a suspension of lithillm ~ hydride (40.8mg, 1.07mmol) in tetrahydrofuran (Sml) cooled to -45~C over a dry ice/acetone bath was added a solution of the product from Step A (243 mg, 0.895 mmol) in tetrahydrofuran (S ml) via canula at such a rate to m~int~in tempel~lure the temperaLulc; at <-35~C. After the addition was complete, the solution was allowed to warm to +5~C and then recooled to -35~C. To this solution was added a solution of potassium bisulfate (272 mg) in water (1 ml). This mix1~1re was stirred for 30 min at room temperature and filtered through celite. The celite pad was washed with ethyl acetate (25 ml). The combined filtrates were washed with sat.
sodium bicarbonate (10 ml) and then water (lOml). The organic layer was dried over m~p~nesium sulfate, filtered and evaporated to give the title compound as a clear oil.
lHNMR (CDC13, 400 MHz) ~ 9.50(1H, t, 2Hz), 7.85-7.70(3H, m), 7.64(1H, s), 7.53-7.40(3H, m), 7.16(1H, d, J=12Hz), 7.06(1H, s), 5.20(2H, s) and 3.53(2H, m)ppm.

W 096130343 PCT/U~5~10JA19 Step C: Preparation of 2(S)-Butyl-l-[(l-naphth-2-ylmethyl)-lH-imidazol-5-yl)ethyl]-4-(1-naphthoyl)piperazine ditrifluoroacetate To a solution of the product from Step B (58.4 mg, 0.232 5 mmol) and 3(S)-butyl-l-naphthoylpiperazine hydrochloride (96.5 mg, 0.279 mmol) in 1,2-dichloroethane (lOml) and dimethylform~mide (Sml) was added 3A molecular sieves (250mg) and sodium triacetoxyborohydride (236.5 mg, 1.12 mmol). This mixture was stirred at room temperature for 18 h. After this time, the mixture was 10 filtered . The filtrate was diluted with methylene chloride (lOOml) and washed with sat sodium bicarbonate (SOml). The organic layer was dried(MgS04), filtered and evaporated in vacuo. The residue was purified first by flash chromatography eluting with 2-5~o methanol /
methylene chloride and then by Prep HPLC (Chromatography A) to 15 provide the title compound.
lH NMR(CD30D, 400 MHz) ~i 9.04(1H, s), 8.17-7.30(15H, m), 5.65(2H, s), 4.6-2.2(11H, m) and 1.6-0.2(9H, m)ppm.
FAB HRMS exact mass calc'd for C35H39N40 531.312387 (MH+), found 531.313011.

1 -(2(R)-Amino-3-hydroypropyl)-2(S)-butyl-4-(1 -naphthoyl)piperazine bis trifluoracetate salt Step A: N-Boc-O-Benzylserine-(N'-Methoxy) methyl amide N-Boc-O-Benzylserine (Bachem; 5.0g, 16.9 mmol) and HOBT (2.29g, 16.9 mmol) were dissolved in dry DMF (100 mL) under argon. To this solution was added N,O-dimethylhydroxyl amine 30 hydrochloride (1.98 g, 20.3 mmol) and then, at 0~C, EDC
hydrochloride (3.56 g, 18.6 mmol). 4-Methylmorpholine was added to bring the pH to ~7 (4.5 mL) and the mixture was stirred at room temperature for 3h. The solution was diluted with EtoAc and poured into 0.5N HCl. After extraction with EtoAc (twice), the organic layers W O 96130343 PCTrUS96/04019 were washed with water then brine, dried (MgSO4) and evaporated in vacuo to give a pale yellow oil. Column chromatograph (silica gel;
hexanel/EtoAc 2:1) gave the title compound as an oil Rf (silica;
hexare/EtoAc 1:1) = 0.45.

Step B: N-Boc-O-Benzyl-serine aldehyde The amide from Step A (5.7 g, 16.9 mmol) in dry ether (20 mL) was added L~)~wise to a suspension of LAH (0.705 g, 18.5 mmol) in 80 mL of ether at -50~C. After the addition was complete, the solution was stirred at 0~C for 45 min. then cooled back to -50~C and a solution of KHSO4 (4 g in 11 mL H2O) was added slowly. This mixhlre was then stirred at room temperature for 1 h, filtered through celite, washed successively wit~h 10% citric acid solution, sa~ ted NaHCO3 solution and brine, dried (MgSO4) and evaporated to give an oil which was used as such in the next step. Rf (silica; hexane/EtoAc 2:1) = 0.58.

Step C: 1-(2(R)-N-Boc-Amino-3-benzyloxy propyl)-2(S)-butyl-4-(l-naphythoyl) piperazine A solution of the piperazine hydrochloride from Example 1, Step E (1.7 g, 574 mmol) in CH2C12 (25 mL) was adjusted to pH 6 using Et3N then freshly ground and activated 4 A sieves were added followed by sodium triacetoxyborohydride (4.85 g, 22.9 mmol). The aldehyde from Step B (2.08g, 747 mmol) dissolved in 20 mT . CH2C12 was added dro~wise at 0~C over 20 rnin. then the mixture was sitrred at room temperature for 16 h. After this time, the mixture was filtered through celite, diluted with EtoAc and washed successively with H2O, KHSO4, solution, NaHCO3 solution and then brine. The dried (MgSO4) solution was evaporated in vacuo to give a pale yellow oil ~, 30 which was subjected to column chromatography (silica gel;
hexane/EtOAc 1:1) to give the title compound as a foam. Rf (silica;
hexane/EtoAc 2:1) = 0.15.

Step D: 1-(2(R)-N-Boc-Amino-3-hydroxy propyl)-2-(S)-butyl-4-(l-naphythoyl) piperazine The benzyl ether from Step C (700 mg, 1.25 mmol) was dissolved in 20 mL MeOH with 150 ,~LL of acetic acid and then 20%
5 Pd(OH)2 on carbon (500 mg) was added and the mixture hydrogenated at 50 psi for 16 hr. After filtration through celite, the solvent was removed and the residue was chromatographed on silica gel (EtoAc/hex~ne 1:1 then 5% hIeOH/EtoAc) to give the title compound as an oil.
Step E: 1-(2(R)-Amino-3-hydroxy propyl)-2(S)-butyl-4-(1-naphythoyl)piperazine bis trifluoroacetate salt A solution of the N-Boc amine from Step D (140 mg) in 10 mT~ EtoAc was treated with HCl (gas) until saturated. After 5 min, the 15 solution was purged with argon then the solvent was removed to give a solid which was pllrifi~tl by preparative HPLC (C-18 column;
H2O/CH3CN with 0.1% TGA; gradient). The aqueous solution was frozen and lyophilized to give the title compound as a hygroscopic powder. FAB mass spectrum m/z = 370 (M+l).
Analysis calculated for C22H32N3O2-2.35 TFA
C, 50.31; H, 5.27; N, 6.59 Found: C, 50.28; H, 5.49; N, 6.70 1-(2(R)-Amino-4-hydroxybutyl)-2(S)-butyl-4-(1-naphthoyl)piperazine bishydrochloride salt Following the procedure of Example 19, Steps A to E but using N-Boc-O-benzyl homoserine (Bachem) as starting material, the 30 title compound was obtained as the bis hydrochloride salt. FAB Mass spectrum, m/z = 384 (M+l).
Analysis calculated for C23H33N3O2-1.5 HCl C, 54.04; H, 7.20; N, 8.22 Found: C, 53.95; H, 7.23; N, 8.50 W 096/30343 PCTrUS96/04019 ..
1-(2-Amino-3-(2-benzyloxyphenyl)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine bistrifluoroacetate salt s Step A: D.L-N-Boc-ortho-tyrosine methyl ester The title compound was prepared as a crystalline solid from D,L-orthotyrosine (Sigma) in two steps ((Boc)20/K2C03 in THF/H20 followed by diazomethane in EtOAc).
Step B: 3-(2-Hydroxyphenyl)-2-(N-Boc-Amino)propanol To a solution of the ester from Step A (1.34 g, 4.54 mmol) in THF (20 mL) at 0~C was added LAH (400 mg, 10.5 mmol) in portions. After 4 hs at room temperatrue, 0.4 mL H2O was added 15 d,o~wise followed by 0.4 mL lN NaOH and then 1.2 mL H20. The slurry was stirred for 1 h, filtered through celite rin~inp with THF and the solvent was removed chromatography of the residue (silica gel;
hexane/EtoAc 1:1) gave the title compound as a solid. Rf (silica;
hexane/EtoAc 1:1) = 0.45.
Step C: 3-(2-Benzyloxyphenvl)-2-(N-Boc-amino)propanol A mixture of the alcohol from Step B (280 mg, 1.05 mmol) benzyl bromide (150 ,uL, 1.26 mmol) and CS2CO3 (513 mg, 1.57 mmol) in DMF (10 mL) was stirred at room tempe-atul~ under argon 25 for 16 h. The mixtllre was poured into H2O, extracted twice with EtOAc, washed with water then brine, dried (MgSO4) and evaporated to give an oil. Purification by chromatography (silica gel;
hexane/EtoAc 2: 1) gave the title compound as an oil. Rf (silica;
hexane/EtoAc 2:1) = 0.36.
Step D: 3-(2-Benzyloxyphenyl)-2-(N-Boc-amino)propanol To a solution of the alcohol from Step C (280 mg, 0.78 mmol) in 3 mL DMSO, 3 mL CH2C12 and 0.55 mL Et3N at room temperature under argon was added pyridine SO3 complex (500 mg, W 096/30343 PCTrUS96/04019 3.14 mmol) and the mixture stirred for lh. The solution was poured into saturated NaHCO3 solution, extracted twice with EtoAc, washed with water then brine, dried (MgSO4) and concentrated in vacuo. The title compound was thus obtained as an oil and was used as such in the following step. Rf (silica; hexane/EtoAc 4:1) = 0.41.

Step E: 1-(2-N-Boc-Amino-3-(2-benzyloxyphenyl)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine The aldehyde from Step D and the piperazine hydrochloride from Example 1, Step E were coupled via reductive aL~yltion using the procedure described for Example 19, Step C.
Purification by column chromatgraphy (silica gel; hexane/EtoAc 3:2) gave the title compound as a 1:1 mixture of diastereomers. Rf (silica;
hexane/EtOAc 1:1) = 0.51 and 0.45.
Step F: 1-(2-Amino-3-(2-benzyloxyphenyl)propyl)-2(S)-butyl-4-(l-naphthoyl)piperazine bis trifluoroacetate salt A solution of the N-Boc amine from Step E (70 mg) in EtOAc (15 mL) was treated with HCl (g) until saturated. After 15 min., the solution was purged with argon and then the solvent removed to yield a solid. Purification by preparative HPLC (C-18 column, H2O/CH3CN with 0.1% TFA; gradient) afforded (after lyophili~tion) the title compound as a powder. FAB mass spectrum, m/z = 536 (M+ 1).
Analysis calculated for C~35H41N302-2.2 TFA-0.35 H20 C, 59.68; H, 5.58; N, 5.30 Found: C, 59.70; H, 5.60; N, 5.56 W 096130343 PCTrUS96/04019 ..
1 -(2-AmLino-3 -(2-hydroxyphenyl)propyl)-2(S)-butyl-4-(1 -naphthoyl)piperazine bis trifluoroacetate salt~ diastereomer A
s Step A: 1-(2-N-Boc-Amino-3-(2-hydroxyphenyl)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine A mix~lre of 1-~2-N-Boc-Amino-3-(2-benzyloxy-phenyl)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine (from Fx~mple 19, Step E; 290 mg, 0.5 mmol), acetic acid (60 ,UL, 1.0 mmol) and 20%
Pd(OH)2 on carbon (100 mg) in MeOH (20 mL) was hydrogenated at 67 psi for 5 h. The solution was filtered through celite and the solvent evaporated to give an oil which showed 2 well resolved spots on silica tlc. Column chromatography (silica gel; hexane:EtoAc 1:1) gave:
a) diastereomer A of the title compound RF (silica;
hexane/EtoAc 1:1) = 0.49.
b) diastereomer B of the title compound RF (silica;
hexane/EtoAc 1:1) = 0.35.

Step B: 1-(2-Amino-3-(2-hydroxyphenyl)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine bis trifluoroacetate salt, diastereomer A
The N-Boc amine, diastereomer A from Step A, was deprotected using HCl (gas) in EtoAc. Removal of the solvent followed 25 by preparative HPLC (C-18 column; H2O/CH3CN with 0.1% TFA;
gradient) gave (after lyophili~tion) the title compound as a powder.
FAB mass spectrum, m/z = 446 (M+l).
Analysis calculated for C2gH35N3O2-2 TFA
C, 57.05; H, 5.54; N, 6.24 30 Found: C, 57.08; H, 5.64; N, 6.32 1-[3-(4-imidazolyl)propyl]-2(S)-butyl-4-(1-naphthoyl)piperazine bis 35 trifluoroacetate salt W O9''3031~ PCTrUS96/04019 Step A: Ethyl 3-(4-imidazolyl)propionate The title compound was prepared from urocanic acid (Aldrich) in 2 steps using standard chemical procedures (esterification using HCl in EtOH followed by hydrogenation with 10% Pd-C in EtOH).
lH NMR (CDC13): o 1.23 (3H, t), 2.65 (2H, t), 2.94 (2H, t), 4.15 (2H, q), 6.81 (lH, S), 7.56 (lH, s).

Step B: 3-(4-imidazolyl) propanol To a solution of the ester from Step A (120 g, 71.4 mmol) in dry THF (230 mL) at 0~C was added LAH (2.99 g, 78.6 mmol) portionwise over 30 min. The mixtllre was stirred for 2 h at room temperatrue then cooled back to 0~C and H2O (4.2 mT~) was added (care!) ~l~wise. This was followed by the dro~wise addition of 10.6 mE of lN NaOH then the resulting slurry was stirred at room temperature for 1 h. After filtration through celite w~hing with EtOAc, the solvent was removed to give the title compound as a clear oil (8.16 g).
lH NMR (CD30D): ~ 1.84 (2H, pentet), 2.68 (2H, t), 3.58 (2H, t), 6.88 (lH, s), 7.80 (lH, s).

Step C: 3-(4-N-BOC-imidazolyl)propanol The imidazole from Step B (166 mg, 1.32 mmol), (BOC)2o (302 mg, 1.38 mmol) and K2CO3 (190 mg, 1.38 mmol) were stirred in THF (10 mL) for 2 h. After filtration, the solvent was removed in vacuo to give the desired compound as an oil. Rf (silica; 5%
MeOH/CHCl3) = 0.17. This was used as such in the next step.

Step D: 1-[3-(4-imidazolyl)propyl]-2(S)-butyl-4-(1-naphthoyl)-piperazine bis trifluoroacetate salt The alcohol from Step C (~1.32 mmol) was dissolved in 4 mL DMSO, 4 mL CH2cl2 and 0.92 mL Et3N and then pyridine SO3 complex (600 mg, 5.28 mmol) was added in portions. After 3 h, the CA 022l6707 l997-09-29 W 096/30343 PCTrUS96/04019 -mixture was poured into EtOAc, extracted with saturated NaHCO3 solution then brine, dried and evaporated to afford the corresponding - aldehyde which was used without further purification.
This aldehyde was coupled with the piperazine from 5 Fx~ le 1, Step E by reductive alkylation following the procedure described for F.x~mrle 19, Step C and the product was obtained by column chromatography (silica gel; 5% MeOH/CHCl3). This product was dissolved in 10 mL EtOAc saturated with HCl (gas). The solvent was removed and the residue purified by preparative HPLC (C-18;
10 H2O/CH3CN with 0.1% TFA; gradient). Lyophili7~tion of the frozen aqueous solution gave the title compound as a hygroscopic powder.
FAB mass spectrum, m/z = 405 (M+l).
Analysis calculated for C25H32N40-2.35 TFA 0.4 H2O
C, 52.48; H, 5.21; N, 8.24 15 Found: C, 52.45; H, 5.22; N, 8.27 2(S)-n-Butyl-4-(1 -naphthoyl)- 1 -[1 -(1 -naphthylmethyl)imidazol-5-20 ylmethyll-piperazine ditrifluoroacetic acid salt The title compound was prepared from 2(S)-n-butyl-1-[5-(3-triphenylmethylimidazolyl)methyl]-4-(1 -naphthoyl)piperazine (0.124 g, 0.200 mmol) and l-bromomethylnaphthalene (0.046 g, 0.21 mmol) according to the procedure described in Example 4. The title 25 compound was obtained after purification by reverse phase preparative HPLC (gradient elution with 30%-75% acetonitrile/0.1% TFA; 70%-25% 0.1% aqueous TFA over 50 min.) and lyophili7~tion. FAB ms (m+l) 517. Anal. Calc. for C34H36N4O ~ 0.05 H2O ~ 2.0 TFA: C, 60.55; H, 5.22; N, 7.43. Found: C, 60.48; H, 5.12; N, 7.42.

., CA 022l6707 l997-09-29 r W 096/30343 PCTrUS96/04019 2(S)-n-Butyl-4-(1-naphthoyl)-1-[1-(2-naphthylmethyl)imidazol-5-ylmethyll-piperazine ditrifluoroacetic acid salt The title compound was prepared from 2(S)-n-butyl-1-[5-(3-triphenylmethylimill~7.olyl)methyl]-4-( l -naphthoyl)piperazine (0.124 g, 0.200 mmol) and 2-bromomethylnaphthalene (0.046 g, 0.21 mmol) according to the procedure described in Fx~mI)le 4. The title compound was obtained after purification by reverse phase preparative HPLC (gradient elution with 30%-75% acetonitrile/0.1% TFA; 70%-25% 0.1% aqueous TFA over 50 min.) and lyophili7~tion. FAB ms (m+l) 517. Anal. Calc. for C34H36N4O ~ 1.7 H2O ~ 2.0 TFA: C, 58.87; H, 5.38; N, 7.23. Found: C, 58.90; H, 4.93; N, 7.13.

2(S)-n-Butyl-1-[1-(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine dihilluoroacetic acid salt The title compound was prepared from 2(S)-n-butyl-1-[5-(3-triphenylmethylimidazolyl)methyl]-4-(1-naphthoyl)piperazine (0.124 g, 0.200 mmol) and 4-cyanobenzylbromide (0.041 g, 0.21 mmol) according to the procedure described in Example 4. The title compound was obtained after purification by reverse phase preparative HPLC (gradient elution with 25%-65% acetonitrile/0.1% TFA; 75%-35% 0.1% aqueous TFA over 50 rnin.) and lyophili~tion. FAB ms (m+l) 492. Anal. Calc. for C31H33N5O ~ 0.35 H20 2.0 TFA: C, 57.91; H, 4.96; N, 9.65. Found: C, 57.93; H, 4.91; N, 9.55.

2(S)-n-Butyl- 1 -[1 -(4-methoxybenzyl)imidazol-5-ylmethyl]-4-(1 -naphthoyl)piperazine ditrifluoroacetic acid salt The title compound was prepared from 2(S)-n-butyl-1-[5-(3-triphenylmethylimidazolyl)methyl]-4-(1 -naphthoyl)piperazine (0.124 W 096/3034~ PCTAUS96/04019 -g, 0.200 mmol) and 4-methyoxybenzylchloride (0.041 mL, 0.21 mmol) according to the procedure described in Example 4, with the addition of potassium iodide (100 mg) to the reaction mixtnre. The title compound was obtained after purification by reverse phase ~lepal~tive HPLC
5 (gradient elution with 25%-65% acetonitrile/0.1% TFA; 75%-35%
0.1% aqueous TFA over 50 min.) and lyophili7~tion. FAB ms (m+1) 497. Anal. Calc. for C31H36N402 ~ 1.7 H20 ~ 2.0 TFA: C, 53.40; H, 5.30; N, 7.12. Found: C, 53.37; H, 4.78; N, 7.00.

2(S)-n-Butyl-1-[1-(3-methyl-2-butenyl)imi~1~7ol-5-ylmethyl]-4-(1-naphthoyl)piperazine dillinuoroacetic acid salt The title compound was prepared from 2(S)-n-butyl-1-[5-15 (3-triphenylmethylimi~l~7Olyl)methyl]-4-(l-n~phtlloyl)piperazine (0.124 g, 0.200 mmol) and 4-bromo-2-methyl-2-butene (0.024 mT~, 0.21 mmol) a.ccording to the procedure described in Example 4. The title compound was obtained after purification by reverse phase preparative HPLC (gradient elution with 5%-95% acetonitrile/0.1% TFA, 95%-5%
20 0.1% aqueous TFA over 50 min.) and lyophili7~tiom. FAB ms (m+1) 445. Anal. Calc. for C2gH36N4O ~ 1.8 H2O ~ 2.0 TFA: C, 54.51; H, 5.95; N, 7.95. Found: C, 54.54; H, 5.39; N, 7.73.

2(S)-n-Butyl-1-[1-(4-fluorobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine ditrifluoroacetic acid salt The title compound was prepared from 2(S)-n-butyl-1-[5-(3-triphenylmethylimidazolyl)methyl]-4-(1-naphthoyl)piperazine (0.124 30 g, 0.200 mmol) and 4-fluorobenzylbromide (0.026 mL, 0.21 mmol) according to the procedure described in Example 4. The title compound was obtained after purification by reverse phase preparative HPLC (gradient elution with 25%-65% acetonitrile/0.1% TFA; 75%-35% 0.1% aqueous TFA over 50 min.) and lyophili7~tion. FAB ms W O 96/30343 PCTrUS96/04019 (m+l) 485. Anal. Calc. for C30H33FN4o ~ 3.0 H2O ~ 2.0 TFA: C, 53.26, H, 5.39; N, 7.31. Found: C, 53.21; H, 4.56; N, 7.08.

s 2(S)-n-Butyl-1-[1-(4-chlorobenzyl)imi-1~7.ol-5-ylmethyl]-4-(l-naphthoyl)piperazine ditrifluoroacetic acid salt The title compound was prepared from 2(S)-n-butyl-1-[5-(3-triphenylmethylimidazolyl)methyl] -4-(1 -naphthoyl)piperazine (0.124 g, 0.200 mmol) and 4-chlorobenzylchloride (0.034 mg, 0.21 mmol) according to the procedure described in Fx~mple 4, with the addition of sodium iodide (100 mg) to the reaction mixtllre. The title compound was obtained after purification by reverse phase preparative HPLC
(gradient elution with 25%-65% acetonitrile/0.1% TFA; 75%-35%
0.1% aqueous TFA over 50 min.) and lyophili7~tion. FAB ms (m+l) 501. Anal. Calc. for C30H33ClN4O ~ 4.8 H2O ~ 2.0 TFA: C, 50.07; H, 5.51; N, 6.87. Found: C, 50.10; H, 4.25; N, 6.48.

1 - [1 -(4-Bromobenzyl)imidazol-5-ylmethyl] -2(S)-n-butyl-4-(1 -naphthoyl)piperazine ditrifluoroacetic acid salt The title compound was prepared from 2(S)-n-butyl-1-[5-(3-triphenylmethylimidazolyl)methyl]-4-(1 -naphthoyl)piperazine (0.124 g, 0.200 mmol) and 4-bromobenzylbromide (0.053 mg, 0.21 mrnol) according to the procedure described in Example 4, with the addition of sodium iodide (100 mg) to the reaction mixture. The title compound was obtained after purification by reverse phase preparative HPLC
(gradient elution with 30%-65% acetonitrile/0.1% TFA; 70%-35%
0.1% aqueous TFA over 50 min.) and lyophili7~tion. FAB ms (m+l) 545. Anal. Calc. for C30H33BrN4O ~ 1.7 H2O ~ 2.0 TFA: C, 50.78; H, 4.81; N, 6.97. Found: C, 50.81; H, 4.39; N, 6.88.

W 096/30343 PCTrUS96/04019 -2(S)-n-Butyl-4-(1-naphthoyl)-1-[1-(4-trifluoromethylbenzyl)imidazol-5-ylmethyll-piperazine dillinuoroacetic acid salt The title compound was prepared from 2(S)-n-butyl-l-[S-(3-triphenylmethylimi~ olyl)methyl]-4-(1-naphthoyl)pipera_ine (0.124 g, 0.200 mmol) and 4-trifluoromethylbenzylbromide (0.053 mg, 0.21 mmol) according to the procedure described in Fx~mple 4. The title compound was obtained after purification by reverse phase preparative HPLC (gradient elution with 30%-65% acetonillilelo.l% TFA; 70%-35% 0.1% aqueous TFA over 50 min.) and lyophili~tion. FAB ms (m+l) 535. Anal. Calc. for C30H33BrN4O ~ 2.0 TFA: C, 55.12; H, 4.63; N, 7.35. Found: C, 57.46; H, 4.98; N, 7.84.

2(S)-n-Butyl-1-[1-(4-methylbenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)-piperazine ditrifluoroacetic acid salt The title compound was prepared from 2(S)-n-butyl-1-[5-(3-triphenylmethylimirl~7.olyl)methyl]-4-(l-naphthoyl)piperazine (0.124 g, 0.200 mmol) and 4-methylbenzylbromide (0.029 mL, 0.21 mmol) according to the procedure described in Fx~mple 4, with the addition of sodium iodide (100 mg) to the reaction mixture. The title compound was obtained after purification by reverse phase preparative HPLC
(gradient elution with 30%-65% acetonitrile/0.1% TFA; 70%-35%
0.1% aqueous TFA over 50 min.) and lyophili7~tion. FAB ms (m+l) 481. Anal. Calc. for C31H36N4O ~ 2.6 H2O ~ 2.0 TFA: C, 55.64; H, 5.76; N, 7.42. Found: C, 55.61,- H, 5.09; N, 7.43.
.
-W 096t30343 PCTrUS96/04019 2(S)-n-Butyl-1-[1-(3-methylbenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)-piperazine ditrifluoroacetic acid salt The title compound was prepared from 2(S)-n-butyl-1-[5-(3-triphenylmethylimidazolyl)methyl]-4-(1-naphthoyl)piperazine (0.124 g, 0.200 mmol) and 3-methylbenzylbromide (0.029 mL, 0.21 mmol) according to the procedure described in Example 4. The title compound was obtained after purification by reverse phase preparative HPLC (gradient elution with 25%-65% acetonitrile/0.1% TFA; 75%-35% 0.1% aqueous TFA over 50 min.) and lyophili7~tion. FAB ms (m+l) 481. Anal. Calc. for C31H36N4O ~ 2.0 TFA: C, 67.26; H, 6.92;
N, 10.12. Found: C, 69.60; H, 6.98; N, 10.51.

1-[1-(4-Phenylbenzyl)imicl~7.ol-5-ylmethyl]-2(S)-n-butyl-4-(l-naphthoyl)-piperazine ditrifluoroacetic acid salt The title compound was prepared from 2(S)-n-butyl-1-[5-(3-triphenylmethylimidazolyl)methyl]-4-(1-naphthoyl)piperazine (0.124 g, 0.200 mmol) and 4-phenylbenzylbromide (0.029 mL, 0.21 mmol) according to the procedure described in F.x~mple 4. The title compound was obtained after purification by reverse phase preparative HPLC (gradient elution with 30%-65% acetonitrile/0.1% TFA; 70%-35% 0.1% aqueous TFA over 50 min.) and lyophili7~tion. FAB ms (m+l) 543. Anal. Calc. for C36H3gN4o ~ 4.95 H2O ~ 2.0 TFA: C, 55.87; H, 5.85; N, 6.52. Found: C, 55.55; H, 4.58; N, 6.23.

2(S)-n-Butyl-4-(1-naphthoyl)-1-[1-(2-phenylethyl)imidazol-5-ylmethyl]-piperazine ditrifluoroacetic acid salt The title compound was prepared from 2(S)-n-butyl-l-[S-(3-triphenylmethylimidazolyl)methyl]-4-(1 -naphthoyl)piperazine (0.124 W 096/30343 PCTrUS96/04019 -g, 0.200 mmol) and 2-phenylethylbromide (0.029 mL, 0.21 mmol) according to the procedure described in Example 4, except with the addition of sodium iodide (120 mg) and refluxing for 12 h. The title compound was obtained after purification by reverse phase preparative 5 HPLC (gradient elution with 30%-65% acetonitrile/0.1% TFA; 70%-35% 0.1% aqueous TFA over 50 min.) and lyophili7~tion. FAB ms (m+l) 481. Anal. Calc. for C36H3gN4O ~ 4.20 H2O ~ 2.0 TFA: C, 53.60; H, 5.96; N, 7.14. Found: C, 53.54; H, 4.86; N, 6.86.

2(S)-n-Butyl-4-(l-naphthoyl)-1-[1-(4-trifluoromethoxy)imitl~7.ol-5-ylmethyllpiperazine ditrifluoroacetic acid salt The title compound was prepared from 2(S)-n-butyl-1-[5-(3-triphenylmethylimi~ olyl)methyl]-4-(1-naphthoyl)piperazine (0.124 g, 0.200 mmol) and 4-trifluoromethoxybenzylbromide (0.032 mT~, 0.21 mmol) according to the procedure described in F.x~mple 4, except with the addition of sodium iodide (120 mg) and refluxing for 12 h. The title compound was obtained after puri~lcation by reverse phase preparative HPLC (gradient elution with 35%-70% acetonitrile/0.1%
TFA; 65%-30% 0.1% aqueous TFA over 50 min.) and lyophili7~tion.
FAB ms (m+l) 551. Anal. Calc. for C31H33F3N4O2 ~ 4.00 H2O ~ 2.0 TFA: C, 49.42; H, 5.09; N, 6.59. Found: C, 48.95; H, 4.06; N, 6.26.

Preparation of 1 - { [1 -(4-cyanobenzyl)- lH-imidazol-5-yl] acetyl }-2(S)-n-butyl-4-(1-naphthoyl)piperazine trifluoroacetate 30 Step A: Preparation of 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 W 096/30343 PCT~US96/04019 temperature (RT) for 18hr. The solvent was evaporated in vacuo to afford the title compound as a white solid.
lH NMR(CDCl3, 400 MHz) o 8.85(1H, s), 7.45(1H, s), 3.89(2H, s) and 3.75(3H, s) ppm.
s Step B: Preparation of l-(Triphenylmethyl)-lH-imidazol-4-ylacetic acid methyl ester.
To a solution of the product from Step A (24.85g, 0.141mol) in dimethyl form~micle (DMF) (115m1) was added triethylamine (57.2 ml, 0.412mol) and triphenylmethyl bromide(SS.3g, 0.171mol) and the suspension was stirred for 24hr. After this time, the reaction mixtllre was diluted with ethyl acetate (EtOAc) (1 L) and water (350 ml). The organic phase was washed with sat. aq. NaHCO3 (350 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (SiO2, 0-100% ethyl acetate in hexanes; gradient elution) to provide the title compound as a white solid.
lH NMR (CDC13, 400 MHz) o 7.35(1H, s), 7.31(9H, m), 7.22(6H, m), 6.76(1H, s), 3.68(3H, s) and 3.60(2H, s) ppm.
Step C: Preparation of [1-(4-cyanobenzyl)-lH-imi~1~7ol-5-yl]acetic acid methyl ester.
To a solution of the product from Step B (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 temperature and the 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 re~ux 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 W 096/3034~ PCT~US96/04019 -solid was treated with sat aq NaHCO3 (300ml) and CH2C12 (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) ~ 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: Preparation of [I-(4-cyanobenzyl)-lH-imi-1~7ol-S-yl]acetic acid A solution of [1-(4-cyanobenzyl)-lH-imic1~ol-5-yl]acetic acid methyl ester (4.44g, 17.4mmol ) in THF (100ml) and 1 M lithium hydoxide (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 lyophilised to afford the title compound cont~ining lithium chloride as a white solid.
lH NMR(CD30D, 400 MHz) ~i 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.

Step E: Preparation of 1-{ [1-(4-cyanobenzyl)-lH-imidazol-5-yl]acetyl}-2(S)-n-butyl-4-(1-naphthoyl)piperazine trifluoroacetate To a solution of the acid from step D (100 mg, 0.35 mmol), the amine hydrochloride salt from example step (117 mg, 0.35mmol), HOOBT (58 mg, 0.35 mmol), and triethyl~mine (0.123ml, 0.88 mmol) in DMF (2ml) was added EDC (75 mg, 0.38mmol). The reaction was stirred at room tempelalule for 16hrs, diluted with EtOAc and the organic layer washed with sat. aq NaHCO3, brine, dried - (Na2S043~ and evaporated in vacuo. The residue was purified by .!4, preparative HPLC (C-18; 95:5 to 5:95 water:CH3CN cont~ining 0.1%
. 30 trifluoroacetic acid; gradient elution). Lyophilisation of the collected fractions afforded the title compound as a white solid.
lH NMR(CD30D, 400 MHz) o 9.00-8.90(1H, m), 8.05-7.94(2H,m), 7.94-7.40(10H,m), 5.60-5.40(2H,m), 5.00-2.80(9H,m), 1.90-1.15(4H,m) and 1.05-0.40(5H, m)ppm.

W 096/30343 PCTrUS96/04019 Anal. calc'd for C32H33N5O2 1.40 TFA; 0.55H20: C, 60.65; H, 5.19;
N, 10.16. Found: C, 60.66; H, 5.17; N, 10.06.

s 5(S)-n-Butyl- 1 -(2,3-dimethylphenyl)-4-(4-imidazolylmethyl)piperazin-2-one ditrifluoroacetic acid salt Step A: N-Methoxy-N-methyl 2(S)-(tert-butoxycarbonylamino)-hexanamide 2(S)-(tert-Butoxycarbonylamino)hexanoic acid (24.6 g, 0.106 mol), N,O-dimethylhydroxylamine hydrochloride (15.5 g, 0.15 mol), EDC hydrochloride ( 22.3 g, 0.117 mol) and HOBT (14.3 g, 0.106 mol) were stirred in dry, de~a~se-l DMF (300 mL) at 20~C under 15 nitrogen. N-Methylmorpholine was added to obtain pH 7. The reaction was stirred overni~ht, the DMF distilled under high vacuum, and the residue partitioned between ethyl acetate and 2% potassium hydrogen sulfate. The organic phase was washed with saturated sodium bicarbonate, water, and saturated brine, and dried with magnesium 20 sulfate. The solvent was removed in vacuo to give the title compound.

Step B: 2(S)-(tert-Butoxycarbonylamino)hexanal A mechanically stirred suspension of lithium alnminllm hydride (5.00 g, 0.131 mol) in ether (250 mL) was cooled to -45~C
25 under nitrogen. A solution of the product from Step A (28.3 g, 0.103 mol) in ether (125 mL) was added, maintaining the tempelalu~e below -35~C. When the addition was complete, the reaction was warmed to 5~C, then recooled to -45~C. A solution of potassium hydrogen sulfate (27.3 g, 0.200 mol) in water was slowly added, m~int~ining the 30 temperature below -5~C. After quenching, the reaction was stirred at room temperature for lh. The mixture was filtered through Celite, the ether evaporated, and the remainder partitioned between ethyl acetate and 2% potassium hydrogen sulfate. After wa~hin~; with saturated W 096/30343 PCTrUS96104019 brine, dLrying over m~gnesium sulfate and solvent removal, the title compound was obtained.
-Step C: N-(2,3-Dimethylphenyl)-2(S)-(tert-butoxycarbonylamino)-hex~n~mine 2,3-Dimethyl~niline (8.32 mL, 68.3 mmol) was dissolved in dichloroethane under nitrogen. Acetic acid was added to obtain pH 5, and sodium triacetoxyborohydride (17.2 g, 80.8 mmol) and crushed molecular sieves (4 g) were added. A solution of the product from Step B (13.3 g, 62.1 mmol) in dichloroethane (80 mL) was added slowly dropwise at 20~C. The reaction was stirred overni~ht, then quenched with saturated sodium bicarbonate solution. The aqueous layer was removed, the organic phase washed with sa~ulated brine and dried over magnesium sulfate. Cryst~lli7~tion from hexane gave the title compound.

Step D: 4-tert-Butoxycarbonyl-5(S)-n-butyl-1-(2,3-dimethylphenyl)piperazin-2-one A solution of the product from Step C (8.50 g, 26.5 mmol) in ethyl acetate (250 mL) was vigorously stirred at 0~C with saturated sodium bicarbonate (150 mL). Chloroacetyl chloride (2.33 mL, 29.1 mmol) was added, and the reaction stirred at ) 0~C for lh. The layers were separated, and the ethyl acetate phase was washed with saturated brine, and dried over magnesium sulfate. The crude product was dissolved in DMF (300 mL) and cooled to 0~C under nitrogen. Sodium hydride (1.79 g, 60% dispersion in oil, 44.9 mmol) was added portionwise to m~int~in moderate hydrogen evolution. After 30 min, an additional amount of sodium hydride was added (0.8 g). The reaction was stirred another 30 min, then quenched with saturated " 30 ammonium chloride. The DMF was distilled zn vacuo, and the residue t partitioned between ethyl acetate and water. The organic phase was washed with water, saturated brine, and dried over magnesium sulfate.
The crude product was chromatographed on silica gel with 20-30%
ethyl acetate in hexane to obtain the title compound.

W 096/30343 PCTrUS96/04019 Step E: 5(S)-n-Butyl-1-(2,3-dimethylphenyl)-4-[4-(1-triphenylmethylimidazolyl)methyllpiperazin-2-one A solution of the product from Step D (0.570 g, 1.58 5 mmol) in ethyl acetate (50 mL) was cooled to -15~C under nitrogen.
HCl gas was bubbled through for 15 min, and the reaction solution warmed to 0~C for 2h. The solvent was removed in vacuo, and the resulting solid was dissolved in dichloroethane (20 mL). Sodium triacetoxyborohydride (0.502 g, 2.37 mmol) and 1-triphenylmethyl-4-10 imida_olyl carboxaldehyde (0.534 g, 1.58 mmol) was added. Thereaction was stirred overnight at 20~C then poured into saturated sodium bicarbonate solution. The organic phase was washed with saturated brine and dried over magnesium sulfate. Silica gel chromatography using 4% methanol in dichloromethane as eluant 15 yielded the title compound.

Step F: 5(S)-n-Butyl-1-(2,3-dimethylphenyl)-4-(4-imidazolylmethyl)piperazin-2-one dill;rluoroacetic acid salt To a solution of the compound from Step E (0.233 g, 0.40 20 mmol) in dichloromethane (6 mL) was added triethylsilane (0.254 mL) and trifluoroacetic acid (2 mL) were added, and the reaction stirred at 20~C for 2h. The volatiles were removed in vacuo, and the residue partitioned between hexane and water-methanol. The aqueous phase was injected onto a preparative HPLC column and purified with a mixed 25 gradient of 15%-60% acetonitrile/0.1% TFA; 85%-40% 0.1% aqueous TFA over 50 min. The title compound was isolated after lyophili7~tion.
FAB ms (m+l) 341. Anal. Calc. for C20H2gN4O 2.0 TFA: C, 50.80;
H, 5.15; N, 9.87. Found: C, 51.31; H, 5.41; N, 10.11.

W 096130343 PCTrUS96/04019 5(S)-n-Butyl-4-[1-(4-cyanobenzyl)imi~1~7Ol-5-ylmethyl]-1-(2,3-dimethylphenyl)piperazin-2-one ditrifluoroacetic acid salt 4-Cyanobenzylbromide (0.043 g, 0.22 mmol) was added at 20~C to a solution of 5(S)-n-butyl-1-(2,3-dimethylphenyl)-4-[4-(1-triphenylmethylimidazolyl)methyl]piperazin-2-one (0.120 g, 0.21 mmol) :~rom Example 39, Step E, in acetonitrile (10 mL). After 48 h, the solvent was removed in vacuo, and the crude product dissolved in dichloromethane (6 mL). Triethylsilane (0.13 mr ) and trifluoroacetic acid (2 mL) were ~ e~1, and the reaction stirred at 20~C for 2h. The volatiles were removed in vacuo, and the residue partitioned between hexane and water-methanol. The aqueous phase was injected onto a reverse phase preparative HPLC column and pllrifiP~l with a mixed gradient of 30%-60% acetol~iLIile/0.1% TFA; 70%-40% 0.1% aqueous TFA over 50 min. The title compound was isolated after lyophili7~tion from water-acetonitrile solution. FAB ms (m+l) 456. Anal. Calc. for C28H33N50 ~ 0.7 H2O ~ 2.0 TFA: C, 55.28; H, 5.13; N, 10.07. Found:
C, 55.27; H, 5.20; N, 10.41.

4-[1-(4-Cyanobenzyl)imicl~7Ol-5-ylmethyl]-1-(2,3-dimethylphenyl)-5(S)-(2-methoxyethyl)piperazin-2-one diLIilluoroacetic acid salt Step A: N-Methoxy-N-methyl 4-benzyloxy-2(S)-(tert-butoxycarbonylamino)bllt~n~mide 4-Benzyloxy-2(S)-(tert-butoxycarbonylamino)butanoic acid (1.00 g, 3.23 mmol) was converted to the title compound following the procedure described in Example 39, Step A, using EDC ~ HCl (0.680 g, 3.55 mmol). HOBT (0.436 g, 3.23 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.473 g, 4.85 mmol) in DMF
(50 mL) at pH 7. After workup, the title compound was obtained as a clear gum.

W 096/30343 PCTrUS96/04019 Step B: 4-(1-Benzyloxyethyl)-2(S)-(tert-butoxycarbonylamino) butanal The title compound was obtained by lithium ~ mimlm 5 hydride reduction of the product of Step A using the procedure described in Example 39, Step B.

Step C: N-(2,3-Dimethylphenyl)-4-(2-benzyloxyethyl)-2-(S)-(tert-butoxycarbonylamino)bllt~n~rnine The title compound was prepared from the product of Step C according to the procedure described in Example 39, Step B, using 2,3-dimethyl~niline (0.505 mL, 4.14 mmol), sodium triacetoxyborohydride (1.20 g, 5.65 mmol) and crushed molecular sieves (1 g) at pH 5 in dichloroethane (20 mL). The title compound was 15 obtained after purification on silica gel, eluting with 15% ethyl acetate in hexane.

Step D: 5(S)-(2-Benzyloxyethyl)-4-tert-butoxycarbonyl-1-(2,3-dimethylphenyl)piperazin-2-one The title compound was prepared from the product of Step C according to the procedure described in Example 39, Step D, using chloroacetyl chloride (0.21 mL, 2.57 mmol) in 60 mL 1:1 ethyl acetate:saturated sodium bicarbonate, followed by reaction of the crude product with sodium hydride (0.373 g, 60% dispersion in oil, 9.32 25 mmol) in D~F (30 mL). After workup, the crude product was chromatographed on silica gel with 30% ethyl acetate in hexane to obtain the title compound.

Step E: 4-tert-Butoxycarbonyl-1-(2,3-dimethylphenyl)-5(S)-(2-hydroxyethyl)piperazin-2-one The product from Step D was dissolved in methanol (40 mL) and 10% Pd/C was added (0.160 g). The reaction was shaken under 60 psi hydrogen overnight. The catalyst was removed by filtration, and the solvent evaporated to give the title compound.

CA 022l6707 l997-09-29 W 096/30343 PCTrUS96/04019 - Step F: 4-tert-Butoxycarbonyl-1-(2,3-dimethylphenyl)-5(S)-(2-methoxyethyl)piperazin-2-one The product from Step E (0.241 g, 0.688 mmol) was dissolved in DMF (10 mL) cont~ining methyl iodide (0.21 mT, 3.44 mmol) and the stirred solution cooled to 0~C under nitrogen. Sodium hydride (0.070 g, 60% dispersion in oil, 1.72 mmol) was added and the reaction stirred for lh. The reaction was quenched with water, and the DMF removed under vacuum. The residue was partitioned between ethyl acetate and water, and the organic phase washed with saturated brine and dried over m~gnesium sulfate. The crude product was chromatographed on silica gel with 40% ethyl :~cet~te in hexane to give the title compound.

Step G: 1-(2,3-Dimethylphenyl)-5(S)-(2-methoxyethyl)-4-[4-(1-triphenylmethylimidazolyl)methyllpiperazin-2-one The product from Step F (0.113 g, 0.312 mmol) was converted to the title compound according to the procedure described in Example 39, Step E, except using 30% trifluoroacetic acid in dichloromethane (10 mL) for 1 h for the initial deprotection. The volatiles were removed in vacuo, and the residue dissolved in dichloroethane. Triethyl~mine was added to obtain pH 5. Sodium triacetoxyborohydride (0.100 g, 0.468 mmol) and l-triphenylmethyl-4-imidazolylcarboxaldehyde (0.1164 g, 0.343 mmol) was ~ le~l. The reaction was stirred overnight at 20~C then poured into saturated sodium bicarbonate solution. The organic phase was washed with saturated brine and dried over magnesium sulfate. Silica gel chromatography using 5% methanol in chloroform as eluant yielded the title compound.

W 096130343 PCTrUS96/04019 Step H: 4-[1 -(4-Cyanobenzyl)imidazol-S-ylmethyl]- 1 -(2,3-dimethylphenyl)-5(S)-(2-methoxyethyl)piperazin-2-one ditrifluoroacetic acid salt The product from Step G (0.182 g, 0.312 mmol) was S converted to the title compound according to the procedure described in Fx~mple 40, using 4-cyanobenzylbromide (0.061 g, 0.312 mmol) in acelo~ e (10 mT.), followed by reaction of the crude imi(l~7olium salt with triethylsilane (0.13 mL) and trifluoroacetic acid (2 mL) in dichloromethane (6 mT ). Purification was accompli.~hed by reverse phase preparative HPLC with a mixed gradient of 0%-70%
acetonitrile/0.1% TFA, 100%-30% 0.1% aqueous TFA over 60 rnin.
The title compound was isolated after lyophili7~tion from water. FAB
ms (m+l) 458. Anal. Calc. for C27H3lNso2 ~ 0.35 H20 ~ 2.0 TFA: C, 53.81, H, 4.91; N, 10.21. Found: C, 53.83, H, 4.95; N, 10.29.

Preparation of (S)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imitl~7olylmethyl]-5-[2-(methanesulfonyl)ethyl]-2-piperazinone dihydrochloride Step A: Preparation of l-triphenylmethyl-4-(hydroxymethyl)-imidazole To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260 mmol) in 250 mL of dry DMF at room temperature was added triethylamine (90.6 mL, 650 mmol). A white solid precipitated from the solution. Chlorotriphenylmethane (76.1 g, 273 mmol) in S00 mL of DMF was added dropwise. The reaction mixture was stirred for 20 hours, poured over ice, filtered, and washed with ice water. The resulting product was slurried with cold dioxane, filtered, and dried in vacuo to provide the titled product as a white solid which was sufficiently pure for use in the next step.

CA 022l6707 l997-09-29 W 096130343 PCTrUS96/04019 c StepB: Preparation of 1-triphenylmethyl-4-(acetoxymethyl)-., imidazole Alcohol from Step A (260 mmol, prepared above) was suspendLed in 500 mL of pyridine. Acetic anhydride (74 mL, 780 5 mmol) was added dl~wise, and the reaction was stirred for 48 hours during which it became homogeneous. The solution was poured into 2 L of EtOAc, washed with water (3 x 1 L), 5% aq. HCl soln. (2 x 1 L), sat. aq. NaHCO3, and brine, then dried (Na2S04), filtered, and concentrated in vacuo to provide the crude product. The acetate was 10 isolated as a white powder which was sufficiently pure for use in the next reaction.

Step C: Preparation of 1-(4-cyanobenzyl)-5-(acetoxymethyl)-imitl~701e hydrobromide A solution of the product from Step B (85.8 g, 225 mmol) and a-bromo-p-tolunitrile (50.1 g, 232 mmol) in 500 mL of EtOAc was stirred at 60 ~C for 20 hours, during which a pale yellow precipitate formed. The reaction was cooled to room temperature and filtered to provide the solid imi~l~7.olium bromide salt. The filtrate was 20 concelltlated in vacuo to a volume 200 mL, reheated at 60 ~C for two hours, cooled to room tempe~ ;, and filtered again. The filtrate was concentrated in vacuo to a volume 100 mL, reheated at 60 ~C for another two hours, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was 25 combined, dissolved in 500 mL of methanol, and warmed to 60 ~C.
After two hours, the solution was reconcentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble materials. Removal of residual solvents in vacuo provided the titled product hydrobromide as a white solid which was used in the next step 30 without further purification.

CA 022l6707 l997-09-29 W 096/30343 PCTrUS96/04019 Step D: Preparation of 1-(4-cyanobenzyl)-5-(hydroxymethyl)-imidazole To a solution of the acetate from Step C (50.4 g, 150 mmol) in 1.5 L of 3:1 THF/water at 0 ~C was added lithium hydroxide monohydrate (18.9 g, 450 mmol). After one hour, the reaction was concentrated in vacuo, diluted with EtOAc (3 L), and washed with water, sat. aq. NaHCO3 and brine. The solution was then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product as a pale yellow fluffy solid which was suf~lciently pure for use in the next step without further purification.

Step E: Preparation of 1-(4-cyanobenzyl)-5-imidazolecarboxaldehyde To a solution of the alcohol from Step D (21.5 g, 101 mmol) in 500 mL of DMSO at room temper~lule was added triethylamine (56 mL, 402 mmol), then SO3-pyridine complex (40.5 g, 254 mmol). After 45 minutes, the reaction was poured into 2.5 L of EtOAc, washed with water (4 x 1 L) and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the aldehyde as a white powder which was sufficiently pure for use in a subsequent step (Step L) without further purification.

Step F: Preparation of (S)-2-(tert-butoxycarbonylamino)-N-methoxy-N-methyl-4-(methylthio)bllt~n~mide L-N-Boc-methionine (30.0 g, 0.120 mol), N,O-dimethylhydroxylamine hydrochloride (14.1 g, 0.144 mol), EDC
hydrochloride (27.7 g, 0.144 mol) and HOBT (19.5 g, 0.144 mol) were stirred in dry DMF (300 mL) at 20~C under nitrogen. More N,O-dimethylhydroxylamine hydrochloride (2.3 g, 23 mmol) was added to obtain pH 7-8. The reaction was stirred overnight, the DMF distilled to half the original volume under high vacuum, and the residue partitioned between ethyl acetate and sat. NaHCO3 soln. The organic phase was washed with saturated sodium bicarbonate, water, 10% citric acid, and W 096130343 PCTrUS96/04019 brine, and dried with sodium sulfate. The solvent was removed in vacuo to give the title compound.

Step G: Preparation of (S)-2-(tert-butoxycarbonylamino)-4-(methylthio)butanal A suspension of lithium alllminllm hydride (5.02 g, 0.132 mol) in ether (500 mL) was stirred at room tempe~atul~ for one hour.
The solution was cooled to -50 ~C under nitrogen, and a solution of the product from Step F (39.8 g, ca. 0.120 mol) in ether (200 mL) was added over 30 rnin, m~int~ining the temperature below -40 ~C. When the addition was complete, the reaction was warmed to 5~C, then recooled to -45~C. Analysis by tlc revealed incomplete reaction. The solution was rewarmed to 5 ~C, stirred for 30 ~ lules~ then cooled to -50 ~C. A solution of potassium hydrogen sulfate (72 g, 0.529 mol) in 200 mL water was slowly ~ltle~l, m~i"l~i"i"g the tempel~lule below -20 ~C. The mixture was warmed to 5 ~C, ~lltered through Celite, and concentrated in vacuo to provide the title aldehyde.

Step H: Preparation of (S)-2-(tert-butoxycarbonylamino)-N-(3-chlorophenyl)-4-(methylthio)bllt~n~mine To a solution of 3-chloroaniline (10.3 mL, 97.4 mmol), the product from Step G (23.9 g, 97.4 mmol), and acetic acid (27.8 mT., 487 mmol) in dichloroethane (250 mL) under nitrogen was added sodium triacetoxyborohydride (41.3 g, 195 mmol). The reaction was stirred overni~;ht then quenched with saturated sodium bicarbonate solution. The solution was diluted with CHC13, and the organic phase was washed with water, 10% citric acid and brine. The solution was dried over sodium sulfate and concentrated in vacuo to provide the crude product (34.8 g) which was chromatographed on silica gel with 20% ethyl acetate in hexane to obtain the title compound.

W O 96130343 PCT/U~3./~1019 Step I: Preparation of (S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-S-r2-(methylthio)ethvllpiperazin-2-one A solution of the product from Step H (22.0 g, 63.8 mmol) in ethyl acetate (150 InT ) was vigorously stirred at 0~C with saturated sodium bicarbonate (150 ml). Chloroacetyl chloride (5.6 ml, 70.2 mmol) was added dl~wise, and the reaction stirred at 0~C for 2h. The layers were separated, and the ethyl ~cet~t.o phase was washed with 10%
citric acid and saturated brine, and dried over sodium sulfate. After concentration in vacuo, the resulting crude product (27.6 g) was dissolved in DMF (300 mL) and cooled to 0~C under argon. Cesium carbonate (63.9 g, 196 mmol) was added, and the reaction was stirred for two days, allowing it to warm to room tempelalule. Another portion of cesium carbonate (10 g, 30 mmol) was added, and the reaction was stirred for 16 hours. The DMF was distilled in vacuo, and the residue partitioned between ethyl acetate and water. The organic phase was washed with saturated brine, and dried over sodium sulfate.
The crude product was chromatographed on silica gel with 20-25%
ethyl acetate in hexane to obtain the title compound.

Step J: Preparation of (S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-S-r2-(methanesulfonyl)ethyllpiperazin-2-one A solution of the product from Step I (14.2 g, 37 mmol) in methanol (300 mL) was cooled to 0 ~C, and a solution of magnesium monoperoxyphth~l~te (54.9 g, 111 mmol) in 210 mL MeOH was added over 20 minlltes. The ice bath was removed, and the solution was allowed to warm to room temperature. After 45 minlltes, the reaction was concentrated in vacuo to half the ori~:in~l volume, then quenched by the addition of 2N Na2s2o3 soln. The solution was poured into EtOAc and sat NaHCO3 solution, and the organic layer was washed with brine, dried (Na2so4)~ filtered, and concentrated in vacuo to provide the .t crude sulfone. This material was chromatographed on silica gel with 60-100% ethyl acetate in hexane to obtain the titled compound.

W 096/30343 PCTrUS96/04019 Step K: Preparation of (S)-1-(3-chlorophenyl)-5-[2-(methanesulfonvl)ethyllpi~el azin-2-one Through a solution of Boc-protected piperazinone from Step J (1.39 g, 3.33 mmol) in 30 mL of EtOAc at O ~C was bubbled 5 anhydrous HCl gas. The saturated solution was stirred for 35 minlltes7 then conce~ ated in vacuo to provide the hydrochloride salt as a white powder. This material was suspended in EtOAc and treated with dilute aqueous NaHC03 solution. The aqueous phase was extracted with EtOAc, and the combined organic mixtllre was washed with brine, dried 10 (Na2S~4), filtered, and concentrated in vacuo. The resulting amine was reconcentrated from toluene to provide the titled material suitable for use in the next step.

Step L: Preparation of (S)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(methanesulfonyl)-ethyll-2-piperazinone dihydrochloride To a solution of the amine from Step K (898 mg, 2.83 mmol) and imicl~701e carboxaldehyde from Step E (897 mg, 4.25 mmol) in 15 mT~ of 1,2-dichloroethane was added sodium 20 triacetoxyborohydride (1.21 g, 5.7 mmol). The reaction was stirred for 23 hours, then quenched at O ~C with sat. NaHC03 solution. The solution was poured into CHC13, and the aqueous layer was back-extracted with CHCl3. The combined organics were washed with brine, dried (Na2S04), filtered, and concentrated in vacuo. The resulting 25 product was purified by silica gel chromatography (95:5:0.5-90:10:0 EtOAc:MeOH:NH4Cl), and the resultant product was taken up in EtOAc/methanol and treated with 2.1 equivalents of 1 M HCl/ether solution. After concentrated in vacuo, the product dihydrochloride was isolated as a white powder.

W 096/30343 . PCTrUS96/04019 Preparation of (S )- 1 -(3 -chlorophenyl)-4- [1 -(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)ethyl]-2-piperazinone 5 dihydrochloride Step A: Preparation of (S)-N-(tert-butoxycarbonyl)homoserine lactone To a solution of (S)-homoserine lactone hydrochloride 10 (11.0 g, 79.9 mmol) and di-tert-butylpyrocarbonate (19.2 g, 88.0 mmol) in 160 mL of dichloromethane at 0 ~C was added diisopropylethylamine (13.9 mL, 79.9 mmol) over 3 min. The solution was allowed to warm to room temp~ lulc;. After 3 hours, another portion of di-tert-butylpyrocarbonate (1.75 g, 8.0 rnmol) and 15 diisopropylethylamine (0.70 mL, 4.0 mmol) were added, and the mixture was stirred for an additional 2.5 hours. The solution was washed with 10% citric acid, sat. NaHCO3, and brine, dried (Na2S04), filtered, and concentrated in vacuo. The resulting material was purified by silica gel chromatography (50% EtOAc/hexane) to provide pure 20 titled compound.

Step B: Preparation of (S)-N-(ter~-butoxycarbonyl)homoserine lactol To a solution of the lactone from Step A (7.0 g, 35 mmol) 25 in 175 mL of THF at -78 ~C was added diisobutylaluminum hydride (72.0 mL, lM in THF, 72 mmol) dropwise, while m~int~inin~ the reaction temperature below -72 ~C. After 3 hours, another portion of diisobutylaluminum hydride (10.0 mL, 10 mmol) was ~ le~l, followed by another after 1 hour (20.0 mL, 20 mmol). After an additional hour, 30 the reaction was quenched with EtOAc at -78 ~C, followed by sat. Na-K-tartrate soln., then warmed to room temperature. The solution was poured into EtOAc, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting material was purified by silica gel chromatography (50% EtOAc/hexane) to give the titled lactol.

Step C: Preparation of (S)-3-(tert-butoxycarbonylamino)-N-(3-chlorophenyl)-4-hydroxy- 1 -bllt~n~mine To a solution of lactol from Step B (4.49 g, 22.2 m~ol) S and 3-chloro~niline (2.58 mL. 24.4 mmol) in 50 mL of dichloromethane at room temperaLule was added acetic acid (1.27 ml.
22.2 m~nol). After 10 min~ sodium triacetoxyborohydride (6.59 g, 31.1 mmol) was ~ e-l7 and the solution was stirred for 1.5 hours. The reaction was quenched with sat. aq. NaHCO3, ~lillltecl with CH2C12, and 10 the layers were separated. The organic material was dried (Na2SO4), filtered, and concentrated in vacuo to provide a solid which was purified by silica gel chromatography (EtOAc/hexane) to give the titled amine.
~5 Step D: Preparation of (S)-N-[2-(tert-butoxycarbonylamino)-4-hydroxybutyll -2-chloro-N-(3-chlorophenyl)acetamide The ~niline derivative from Step C (5.29 g, 16.9 m~ol) was dissolved in 60 mL of EtOAc and 60 ml of sat. NaHCO3 soln., then cooled to 0 ~C. With vigorous stirring~ chloroacetyl chloride (1.48 20 mT . 18.5 mmol) was added d~ wise. After 2 hours, the reaction was diluted with water and EtOAc, and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled chloroacet~micle, which was used without further purification.
~5 Step E: Preparation of (S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-(2-hydroxyethyl)piperazin-2-one To a solution of the chloroacetamide from Step D (6.32 g, 16.1 mmol) in 80 mL of DMF at 0 ~C was added cesium carbonate (15.8 g, 48.3 mmol). The solution was stirred until tlc analysis 30 indicated con~uln~ion of the starting material (ca. 5 hours). The solution was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. This material was purified by silica gel chromatography W O 96130343 PCTrUS96/04019 (99:1:0-95:5:0.15 CHC13:MeOH:NH40H) to yield the product cont~ining a minor amount of DMF i~ ulily.

Step F: Preparation of (S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-[2-(methanesulfonyloxy)ethyl]piperazin-2-one To a solution of the alcohol from Step E (3.58 g, 10.1 mmol) in 50 mL of dichlororhethane at 0 ~C was added diisopropylethylamine (3.5 mL, 20.2 mmol), followed by methanesulfonyl chloride (0.936 mL, 12.1 mmol). The solution was stirred for 45 minutes, then quenched with 10% citric acid. The solution was washed with brine, dried (Na2S04), filtered, and concentrated in vacuo to provide the crude product which was used in the next step without further purification.
Step G: Preparation of (S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-S-r2-(ethylthio)ethyllpiperazin-2-one To a solution of the mesylate from Step F (3.6 g, 8.3 mmol) in 100 mL of DMF at 0 ~C was added sodium ethanethiolate (1.4 g, 16.6 mmol). After 2 hours, the reaction was poured into EtOAc, washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product which was used in the next step without further purification.

StepH: Preparation of (S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-r2-(ethanesulfonyl)ethyl~piperazin-2-one To solution of the product from Step G (3.12 g, 7.82 mmol) in methanol (50 mL) was added a solution of magnesium monoperoxyphth~l~te (11.6 g, 23.5 mmol) in 50 mT. MeOH at room t temperature. After 45 min~ltes, the reaction was quenched by the addition of 2N Na2S203 soln. The solution was poured into EtOAc and sat NaHCO3 solution, and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the CA 022l6707 l997-09-29 W096/30343 PCTrUS96/04019 ~ crude sulfone. This m~teri~l was chromatographed on silica gel wi~
2% methanol in chloroform to obtain the titled compound.

Step I: Preparation of (S)-1-(3-chlorophenyl)-5-[2-(ethanesulfonyl)ethyllpiperazin-2-one Through a solution of the Boc-protected piperazinone from Step H (1.75 g, 4.06 mmol) in 20 mL of EtOAc at 0 ~C was bubbled anhydrous HCl gas. The saturated solution was stirred for 30 minllte.s, then concentrated in vacuo to provide the hydrochloride of title compound as a white powder. This m~teri~l was suspended in EtOAc and treated with dilute aqueous NaHCO3 solution. The aqueous phase was extracted with EtOAc, and the combined orgallic mixtllre was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo.
The resulting titled amine was reconcentrated from toluene to provide the title compound suitable for use in the next step.

Step J: Preparation of (S)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imi~1~7olylmethyl]-5-[2-(ethanesulfonyl)ethyll-2-piperazinone dihydrochloride To a solution of the amine from Step I (480 mg, 1.45 mmol), imicl~7ole carboxaldehyde from Step E of Fx~mple 42 (460 mg, 2.2 mmol), and acetic acid (0.415 rnL, 7.25 mmol) in 10 mL of 1,2-dichloroethane was added sodium triacetoxyborohydride (615 mg, 2.9 mmol). The reaction was stirred for 18 hours, then quenched at 0 ~C
with sat. NaHCO3 solution. The solution was poured into CH2C12, and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was purified by silica gel chromatography (2-5% MeOH:CHC13), to give the desired product and less polar boron complex. The latter compound was taken up in dichloromethane (1 mL) and benzene (5 mL), treated with n-propylamine (1 mL) for 18 hours, and concentrated in vacuo. The residue was purified by silica gel chromatography (2-5%
MeOH:CHC13), combined with the former batch, taken up in EtOAc/methanol, and treated with 2.1 equivalents of 1 M HCl/ether =

W 096/30343 PCTrUS96/04019 solution. After concentrated in vacuo, the product dihydrochloride was isolated as a white powder.

s Preparation of (S)- 1 -(3-chlorophenyl)-4- [1 -(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone dihydrochloride ~0 Step A: Preparation of (S)-2-(tert-butoxycarbonylamino)-N-(3-chlorophenyl)-3- r(triphenylmethyl)thiol- 1 -prop~n~mine To a solution of 3-chloro~niline (0.709 mT . 6.70 mrnol) in 30 mT of dichloromethane at room tempel~ure was added 1.2 g of crushed 4A molecular sieves. Sodium triacetoxyborohydride (3.55 g, 15 16.7 mmol) was ~-lcle~l, followed by dlu~wise addition of N-methylmorpholine to achieve a pH of 6.5. L-S-Trityl-N-Boc-cysteinal (3.15 g, 7.04 mmol) (prepared according to S.L. Graham et al. J. Med.
Chem., (1994) Vol. 37, 725-732) was added, and the solution was stirred for 48 hours. The reaction was quenched with sat. aq. NaHCO3, 20 diluted with EtOAc, and the layers were separated. The organic material was washed with brine, dried (Na2SO4), filtered, and concellllated in vacuo to provide an oil which was purified by silica gel chromatography (15% EtOAc/hexane) to give the title amine.

~5 Step B: Preparation of (S)-N-t2-(tert-butoxycarbonylamino)-3-((triphenylmethyl)thio)propyl] -2-chloro-N-(3-chlorophenyl)acetamide The aniline derivative from Step A (2.77 g, 4.95 mmol) was dissolved in 73 mL of EtOAc and 73 mL of sat. NaHCO3 soln., 30 then cooled to 0 ~C. With vigorous stirring, chloroacetyl chloride (0.533 mL. 6.69 mmol) was added dropwise. After 3 hours, the reaction was diluted with water and EtOAc, and the organic layer was washed with brine, dried (Na2so4)~ filtered, and concentrated in vacuo W 096130~43 PCT/U~''01~19 .

to provide crude titled chloroacetamide which was used without further purification.

Step C: Preparation of (S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-[S-(triphenylmethyl)thiomethyl]piperazin-2-one To a solution of chloroacetamide from Step B (3.29 g crude, theoretically 4.95 mmol) in 53 mL of DMF at 0 ~C was added cesium carbonate (4.84 g, 14.85 mmol). The solution was stirred for 48 hours, allowing it to warm to room temperature. The solution was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product as an oil. This m~t~ was purified by silica gel chromatography (20%
EtOAc/hexane) to yield the product as a white solid.
Step D: Preparation of (S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-(thiomethyl)piperazin-2-one A solution of piperazinone from Step C (625 mg, 1.04 mmol) in degassed EtOAc (38 mL) and EtOH (12 mL) was warmed to 30 ~C. A solution of AgNO3 (177 mg, 1.04 mmol) and pyridine (0.084 mL, 1.04 mmol) in 8 mL of EtOH was added, and the solution was heated to reflux. After 45 minutes, the reaction was concentrated in vacuo, then redissolved in 26 mL of degassed EtOAc. Through this solution was bubbled H2S gas for 2.5 minutes, then activated charcoal was added after 4 minutes. The material was filtered through celite and rinsed with degassed EtO~c, concentrated in vacuo, then reconcentrated from degassed CH2C12 to provide the crude product which was used without further purification.

Step E: Preparation of (S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-S-r(ethylthio)methyllpiperazin-2-one A solution of the thiol from Step D (ca. 1.04 mmol) in 3 mL of THF was added via cannula to a suspension of NaH (51.4 mg, 60% disp. in mineral oil, 1.28 mmol) in 2 mL THF at 0 ~C. After 10 W O 96/30343 PCTrUS96/04019 minutes, iodoethane was added (0.079 mL, 0.988 mmol), and the solution was stirred for 1.5 hours. The reaction was poured into EtOAc, washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. This material 5 was purified by silica gel chromatography (l~o MeOH/CH2C12) to yield the titled product.

Step F: Preparation of (S)-4-(tert-butoxycarbonyl)- 1-(3-chlorophenyl)-S-r(ethanesulfonyl)methyllpiperazin-2-one To a solution of the sulfide from Step E (217 mg, 0.563 mmol) in 3 mL of MeOH at 0 ~C was added a solution of m~nesium monoperoxyphth~l~te (835 mg, 1.69 mmol) in 2 rnL MeOH. The reaction was stirred overnight, allowing it to warm to room temperature. The solution was cooled to 0 ~C, quenched by the addition 15 of 4 mL 2N Na2S2O3 soln., then concentrated in vacuo. The residue was partitioned between EtOAc and sat NaHCO3 solution, and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude sulfone as a white waxy solid.
Step G: Preparation of (S)- 1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyll-2-piperazinone dihvdrochloride To a solution of the Boc-protected piperazinone from Step F (224 mg, 0.538 mmol) in 5 mL of dichloromethane at 0 ~C was added 2.5 mL of trifluoroacetic acid (TFA). After 45 minutes, the reaction was concentrated in vacuo, then azeotroped with benzene to remove the excess TFA. The residue was taken up in 4 mL of 1,2-dichloroethane and cooled to 0 ~C. To this solution was added 4A powdered molecular .
sieves (340 mg), followed by sodium triacetoxyborohydride (285 mg, 1.34 mmol) and several drops of triethylamine to achieve pH = 6. The imidazole carboxaldehyde from Step E of Example 42 (125 mg, 0.592 mmol) was added, and the reaction was stirred at 0 ~C. After 2 days, the reaction was poured into EtOAc, washed with dilute aq. NaHCO3, CA 022l6707 l997-09-29 W O 96130343 ~CTrUS96/04019 and brine, dried (Na2so4)~ filtered, and concentrated in vacuo. The - crude product was taken up in methanol and injected onto a preparative HPLC column and purified with a mixed gradient of 15%-50%
acetonitrile/0.1% TFA; 85%-50% 0.1% aqueous TFA over 60 min~tes.
After concentration in vacuo, the resultant product was parti~ioned betweell dichloromethane and aq. NaHCO3 soln., and the aqueous phase was extracted with CH2cl2~ The organic solution was washed with brine, dried (Na2SO4), filtered, and concentrated to dryness to provide the product free base, which was taken up in CH2C12 and treated with 2.1 equivalents of 1 M HCl/ether solution. After concentrated in vacuo, the product dihydrochloride was isolated as a white powder.

Preparation of (S)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imid~7.olylmethyl]-5-[N-ethyl-2-acetamido]-2-piperazinone dihydrochloride Step A: Preparation of (S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-r2-(oxo)ethyllpipe.~zin-2-one To a solution of oxalyl chloride (0.608 mL, 6.97 mmol) in dichloromethane (40 mL) at -78 ~C was added DMSO (0.990 mL, 13.9 mmol) over 2-3 minlltes. The solution was stirred for 10 minutes, then a solution of the alcohol from Step E of Example 43 (2.06 g, 5.81 mmol) in 10 mL of dichloromethane was added over 5 minlltes, keeping the reaction temperature below -70 ~C. The reaction was stirred for 10 minutes, then triethylamine (2.43 mL) was ~lderl, and the reaction was stirred at -78 ~C for 5 minutes, then allowed to warm to room temperature. After 45 minutes, the solution was poured into dichloromethane, and washed with sat. NH4Cl soln., 10% citric acid soln., water, and brine. The solution was dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled aldehyde.

, W 096/30343 PCTrUS96/04019 Step B: Preparation of (S)-4-(tert-butoxycarbonyl)-5-(carboxymethyl)- 1 -(3-chlorophenyl)piperazin-2-one To a solution of the aldehyde from Step A (1.52 g, 4.31 mmol) in 2-methyl-2-propanol (50 mL) and 2-methyl-2-butene (10 mL) 5 at room temperature was added a solution of sodium chlorite (585 mg, 5.17 mmol) and sodium dihydrogenphosphate (595 mg, 4.31 mmol) in 10 mL of water. The reaction turned yellow, then slowly faded to light pink over 45 minutes. The solution was poured into EtOAc, and washed with sat. sodium bisulfite soln. The aqueous layer was acidified 10 to pH 3 with 2.75 M KHSO4 soln., and extracted several times with EtOAc. The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled carboxylic acid.

Step C: Preparation of (S)-4-(tert-butoxycarbonyl)-5-[N-ethyl-2-acetamidol-1-(3-chlorophenyl)piperazin-2-one The product from Step B (200 mg, 0.56 mmol), ethyl~rninç
hydrochloride (114 mg, 1.4 mmol), EDC hydrochloride (140 mg, 0.73 mmol) and HOBT hydrate (113 m g, 0.84 mmol) were stirred in dry DMF (3 mL) at 0~C under nitrogen. After one hour, the solution was 20 warmed to room temperature, and stirred overnight. The DMF was removed in vacuo, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with 10% citric acid, saturated sodium bicarbonate, water, and brine, and dried with sodium sulfate. The solvent was removed in vacuo to give the title compound.
Step D: Preparation of (S)- 1 -(3-chlorophenyl)-4-[ 1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[N-ethyl-2-acetamido]-2-piperazinone dihydrochloride The titled product was prepared from the product of Step C
(184 mg, 0.47 mmol) in analogy to Example 42, Steps K and L. The J
product was isolated as a white solid.

W O 96130343 PCTnUS96/04019 -Preparation of (+)-5-(2-butynyl)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyll-2-piperazinone dihydrochloride s Step A: Preparation of l-(methanesulfonyl)-2-butyne To a solution of 2-butynol (10.0 mL, 134 rnmol) in 200 mL of dichloromethane at 0 ~C was added methanesulfonyl chloride (23.4 g, 134 mmol), followed by dropwise addition of 10 diisopropylethylamine (30 mL, 174 mmol). After 1.5 hours, the solution was poured into 0.5 N KHSO4 soln, and the organic layer was washed with brine. The solution was dried over Na2SO4, filtered, and concentrated in vacuo to provide the titled product.

15 Step B: Preparation of (+)-ethyl 2-[(phenylmethyl)imino]-4-hexynoate To a solution of glycine ethyl ester hydrochloride (10.11 g, 72.4 mmol) in 200 mL of dichloromethane was added ben7~ ehyde (7.36 mL, 72.4 mmol), triethylamine (20.0 mL, 143 mmol), and 20 magnesium sulfate (6g). The solution was stirred at room temperature for 16 hours, filtered through a glass frit, and concentrated in vacuo.
The residue was partitioned between ether and water, and the organic layer was washed with brine. The solution was dried over Na2SO4, filtered, and concentrated in vacuo to provide a pale yellow oil. A
25 portion of this oil (9.90 g, 51.8 mmol) was dissolved in 200 mL of THF
and cooled to -78 ~C under nitrogen atmosphere. A solution of potassium tert-butoxide in THF (51.8 mL of 1 M, 51.8 mmol) was added dropwise to produce a bright red solution. After 20 minutes, a solution of the mesylate from Step A (8.05 g, 54,4 mmol) in 20 mL of 30 THF was added dropwise via c~nmll~, and the solution was allowed to warm to room temperature. After 2 hours, the reaction was poured into EtOAc and washed with sat. NaHCO3 soln. and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product.

W O 96/30343 PCTrUS96/04019 Step C: Preparation of (+)-ethyl 2-~(tert-butoxycarbonyl)amino]-4-hexvnoate A solution of the product from Step B (ca. 51.8 mmol) was5 stirred at room temperature in 5% aqueous HCl solution (100 mL).
After 12 hours, the solution was concentrated in vacuo to give an orange oil. This product was taken up in 50 mL of THF and sat.
NaHCO3 soln. was added (50 mL), followed by di-tert-butylpyrocarbonate (11.3 g, 51.8 mmol) at room temperature. After 6 10 hours, the reaction was poured into EtOAc and washed with sat.
NaHCO3 soln. and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product.

Step D: Preparation of (+)-2-[(tert-butoxycarbonyl)amino]-4-hexynoic acid To a solution of the product from Step C (ca. 51.8 mmol)in THF (100 mL) and water (20 mL) was added at 0 ~C a solution of lithium hydroxide monohydrate (6.5 g, 155 mmol). The solution was stirred for 1 hour at 0 ~C, then warmed to room temperature. After 48 20 hours, the solution was concentrated in vacuo. The aqueous mixture was extracted with EtOAc, acidified at 0 ~C with 10% aq. HCl soln., then extracted with three portions of dichloromethane. The combined dichloromethane extracts were dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product as an orange oil.
Step E: Preparation of (+)-2-(tert-butoxycarbonylamino)-N-methoxy-N-methyl-4-hexynamide The product from Step D (10.58 g, 46.6 mmol), N,O-dimethylhydroxylamine hydrochloride (9.09 g, 93.2 mrnol), HOBT
30 hydrate (9.44 g, 69.9 mmol) and triethylamine (13.0 mL, 93.2 mmol) were stirred in dry DMF (150 mL) at 0~C under nitrogen. EDC
hydrochloride (11.5 g, 60.6 mmol) was added, and the reaction was stirred for 3 hours. The solution was partitioned between 2:1 ethyl acetate:hexane and water, washed with water, 10% aq. HCl, sat.

CA 022l6707 l997-09-29 W 096/30343 PCT~US96/04019 ..
NaHCO3 soln and brine, then dried with sodium sulfate. The solvent - was removed in vacuo to give the title compound as an orange oil Step F: Preparation of (+)-2-(tert-butoxycarbonylamino)-4-hexynal A suspension of lithium aluminum hydride (1.56 g, 41.1 mmol) in ether (150 mL) was stirred at room temperature for 30 minutes. The solution was cooled to -55 ~C under nitrogen, and a solution of the product from Step E (11.10 g, 41.1 mmol) in ether (150 mL) was added over 15 min, m~int~inin~; the temp~ ure below -50 ~C.
When the addition was complete, the reaction was warmed to 5 ~C, then recooled to -40 ~C. A solution of potassium hydrogen sulfate (21.8 g) in 25 mL water was slowly added, m~int~inin~ the tempelalule below -35 ~C. The mixture was warmed to room temperature and stirred for one hour, filtered through Celite, and concentrated in vacuo to provide the title aldehyde.

Step G: Preparation of (+)-2-(tert-butoxycarbonylamino)-N-(3-chlorophenyl)-4-butyn~mine To a 0 ~C solution of 3-chloro~niline (4.33 mL, 40.9 mmol), the product from Step F (ca. 41 mmol), and crushed 4 A
molecular sieves (10 g) in dichloroethane (100 mL) under nitrogen was added sodium triacetoxyborohydride (12.9 g, 61.5 mmol). The reaction was stirred for one hour, then warmed to room tempel~alule. After 3 hours, the solution was poured into EtOAc and washed with water, sat.
NaHCO3 soln. and brine. The solution was dried over sodium sulfate and concentrated in vacuo to provide the crude product.

Step H: Preparation of (+)-N-[2-(tert-butoxycarbonylamino)-4-hexynyll-2-chloro-N-(3-chlorophenyl)acetamide . 30 A solution of the product from Step G (1.68 g, 5.22 mmol) and triethylamine (1.20 mL, 8.61 mmol) in 15 mL of CH2C12 was cooled to 0 ~C. Chloroacetyl chloride (0.457 mT, 5.74 mmol) was added dropwise, and the reaction was m~int~ined at 0 ~C with stirring.
After 30 minutes, another portion of chloroacetyl chloride (0.20 mL) W 096t30343 PCTAUS96/04019 and triethylamine (0.5 mL) was added dropwise. After 30 min, the reaction was poured into EtOAc and washed with 10% aq. HCl, sat. aq.
NaHCO3 soln., and brine. The solution was dried (Na2SO4), filtered, and concentrated in vacuo to provide a brown oil This material was purified by silica gel chromatography (20-35% EtOAc/hexane) to yield the titled product.

Step I: Preparation of (+)-4-(tert-butoxycarbonyl)-5-(2-butynyl)-1 -(3 -chlorophenyl)-2-piperazinone To a solution of the chloroacetamide from Step H (1.68 g, 4.23 mmol) in 15 mL of dry DMF at 0 ~C was added CS2CO3 (3.08 g, 9.48 mmol). The solution was stirred for 30 minlltes, then allowed to warm to room temperature. After 14 hours, the reaction was poured into 50% EtOAc/hexane, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. This m~teri~l was purified by silica gel chromatography (20-40%
EtOAc/hexane) to yield the titled product.

Step J: Preparation of (+)-5-(2-butynyl)- 1 -(3-chlorophenyl)-4-[1 -(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone dihydrochloride To a solution of the Boc-protected piperazinone from Step I (1.03 g, 2.85 mmol) in 7 mL of dichloromethane at 0 ~C was added 4 mL of trifluoroacetic acid (TFA). After 4 hours, the reaction was warmed to room temperature, and stirred an additional 6 hours. The solution was concentrated in vacuo, then azeotroped with benzene to remove the excess TFA. A portion of the residue (255 mg, 0.678 mmol) was taken up in 6 mL of 1,2-dichloroethane and cooled to 0 ~C.
To this solution was added 4A powdered molecular sieves (600 mg), followed by sodium triacetoxyborohydride (214 mg, 1.02 mmol). The imidazole carboxaldehyde from Step E of Example 42 (186 mg, 0.881 mmol) was added, and the reaction was stirred at 0 ~C. After 24 hours, the reaction was poured into EtOAc, washed with dilute aq. NaHCO3, and brine, dried (Na2so4)~ filtered, and concentrated in vacuo. This W 096/303~3 PCTrUS96/04019 material was purified by silica gel chromatography (2-5%
MeOH:CH2Cl2) to yield a white foam which was taken up in CH2C12 and treated with 2.1 equivalents of 1 M HCl/ether solution. After concentrated in vacuo, the product dihydrochloride was isolated as a white powder.

Preparation of 1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)imidazolyl-methyll-2-piperazinone dihydrochloride Step A: Preparation of N-(3-chlorophenyl)ethylene~ mine hydrochloride To a solution of 3-chloroaniline (30.0 mL, 284 mmol) in 500 mL of dichloromethane at 0 ~C was added dlo~wise a solution of 4 N HCl in 1,4-dioxane (80 mL, 320 mmol HCl). The solution was warmed to room tempeldlul~, then concentrated to dryness in vacuo to provide a white powder. A mixture of this powder with 2-oxazolidinone (24.6 g, 282 mmol) was heated under nitrogen atmosphere at 160 ~C for 10 hours, during which the solids melted, and gas evolution was observed. The reaction was allowed to cool, forming the crude ~ mine hydrochloride salt as a pale brown solid.

Step B: Preparation of N-(tert-butoxycarbonyl)-N'-(3-chlorophenvl)ethylenediamine The amine hydrochloride from Step A (ca. 282 mmol, crude material prepared above) was taken up in 500 mL of THF and 500 mL of sat. aq. NaHCO3 soln., cooled to 0 ~C, and di-tert-butylpyrocarbonate (61.6 g, 282 mmol) was added. After 30 h, the reaction was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled carbamate as a brown oil which was used in the next step without further purification.

W 096t30343 PCT/US9"~19 Step C: Preparation of N-[2-(tert-butoxycarbamoyl)ethyl]-N-(3-chlorophenyl)-2-chloroacetamide A solution of the product from Step B (77 g, ca. 282 mmol) and triethylamine (67 mL, 480 mmol) in 500 mL of CH2C12 was 5 cooled to 0 ~C. Chloroacetyl chloride (25.5 mT, 320 mmol) was added dropwise, and the reaction was m~int~ined at 0 ~C with stirring. After 3 h, another portion of chloroacetyl chloride (3.0 mL) was added dl~wise. After 30 min, the reaction was poured into EtOAc (2 L) and washed with water, sat. aq. NH4Cl soln, sat. aq. NaHCO3 soln., and 10 brine. The solution was dried (Na2SO4), filtered, and concentrated in vacuo to provide the chloroacetamide as a brown oil which was used in the next step without further purification.

Step D: Preparation of 4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-2-piperazinone To a solution of the chloroacetamide from Step C (ca. 282 mmol) in 700 mL of dry DMF was added K2CO3 (88 g, 0.64 mol).
The solution was heated in an oil bath at 70-75 ~C for 20 hours, cooled to room temperature, and concentrated in vacuo to remove ca. 500 mL
of DMF. The rem~ininp material was poured into 33~o EtOAc/hexane, washed with water and brine, dried (Na2SO4), ~lltered, and concentrated in vacuo to provide the product as a brown oil. This m~teri~l was puri~led by silica gel chromatography (25-50%
EtOAc/hexane) to yield pure product, along with a sample of product (ca. 65% pure by HPLC) cont~ining a less polar impurity.

Step E: Preparation of 1-(3-chlorophenyl)-2-piperazinone Through a solution of Boc-protected piperazinone from f Step D (17.19 g, 55.4 mmol) in 500 mL of EtOAc at -78 ~C was bubbled anhydrous HCl gas. The saturated solution was warmed to 0 ~C, and stirred for 12 hours. Nitrogen gas was bubbled through the reaction to remove excess HCl, and the mixture was warmed to room temperature. The solution was concentrated in vacuo to provide the hydrochloride as a white powder. This material was taken up in 300 W 096/30343 PCTrUS96/04019 - mL of CH2C12 and treated with dilute aqueous NaHCO3 solution. The aqueous phase was extracted with CH2C12 (8 x 300 m~ ) until tlc analysis indicated complete extraction. The combined organic mixture was dried (Na2SO4), filtered, and concentrated in vacuo to provide the S titled free amine as a pale brown oil.

Step F: Preparation of 1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyll-2-piperazinone dihydrochloride To a solution of the amine from Step E (55.4 mmol, 10 prepared above) in 200 mL of 1,2-dichloroethane at 0 ~C was added 4A
powdered molecular sieves (10 g), followed by sodium triacetoxyborohydride (17.7 g, 83.3 mmol). The imidazole carboxaldehyde from Step E of Example 42 (11.9 g, 56.4 mmol) was added, and the reaction was stirred at 0 ~C. After 26 hours, the reaction 15 was poured into EtOAc, washed with dilute aq. NaHCO3, and the aqueous layer was back-extracted with EtOAc. The combined orgar~ics were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was taken up in 500 mL of 5:1 benzene:CH2C12, and propyl~mine (20 mL) was added. The mixture 20 was stirred for 12 hours, then concentrated in vacuo to afford a pale yellow foam. This material was purified by silica gel chromatography (2-7% MeOH/CH2C12), and the resultant white foam was taken up in CH2C12 and treated with 2.1 equivalents of 1 M HCVether solution.
After concentrated in vacuo, the product dihydrochloride was isolated 25 as a white powder.

5(S)-Butyl-4-[ 1 -(4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]- 1-(2,3-30 dimethylphenyl)-piperazin-2-one dihydrochloride WO 9, /3~3A~ PCTAUS96/04019 Step A: 4-Bromo-2-methylimidazole-5-carboxaldehyde 4-Bromo-5-hydroxymethyl-2-methylimidazole was prepared according to the procedure described by S. P. Watson, Synthetic Communications, 22, 2971-2977 (1992). A solution of 4-S bromo-5-hydroxymethyl-2-methylimidazole (4.18 g, 21.9 mmol) was refluxed with m~ng~nese dioxide (16.1 g) in 1:1 methylene chloride:dioxane (200 mL) for 16 h. The cooled reaction was filtered through celite and concentrated to yield the title compound as a pale yellow solid. lH NMR (CDCl3, 300 MHz) ~ 9.57 (lH, s), 2.52 (3H, s).
Step B: 4-Bromo-1-(4-cyanobenzyl)-2-methylimidazole-5-carboxaldehyde 4-Cyanobenzylbromide (1.05 g, 5.39 mmol) was added to a solution of 4-bromo-2-methylimidazole-5-carboxaldehyde (1.02 g, 5.39 mmol) in dimethylacet~ e (15 mL). The solution was cooled to -10~C and powdered potassium carbonate (0.745 g, 5.39 mmol) ~ltle-l The reaction was stirred at -10~C for 2 h, and a further 4 h at 20~C.
The reaction was diluted with water and extracted with ethyl acetate.
The organic phase was washed with water, saturated brine, and dried over m~gnesium sulfate. Solvent evaporation yielded a white solid. IH
NMR (CDCl3, 400 MHz) o 9.68 (lH, s), 7.64 (2H, d, J=7 Hz), 7.15 (2H, d, J=7Hz) 5.59 (2H, s), 2.40 (3H, s).

Step C: 1-(4-Cyanobenzyl)-2-methylimidazole-5-carboxaldehyde A solution of 4-bromo-1-(4-cyanobenzyl)-2-methylimidazole-5-carboxaldehyde (1.33 g, 4.37 mmol) and imidazole (0.600 g, 8.74 mmol) in 1:1 ethyl acetate-alcohol (150 mL) was stirred with 10% palladium on carbon (0.020 g) under 1 atm hydrogen. After 2 h, the reaction was filtered through celite and concentated to give the title compound as a white solid. IH NMR (DMSO-d6 400 MHz) ~ 9.62 (1 H, s), 7.90 (lH, s), 7.81 (2H, d, J=8 Hz), 7.20 (2H, d, J=8 Hz), 5.64 (2H, s), 2.33 (3H, s).
-W 096/30343 PCTrUS96/04019 e ~ 155 -Step D: 5(S)-Butyl-4-[1-(4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]- 1 -(2,3-dimethylphenyl)piperazin-2-one dihydrochloride Sodium triacetoxyborohydride (0.265 g, 1.25 mmol) was 5 added to a solution of 1-(4-cyanobenzyl)-2-methylimidazole-5-carboxaldehyde (0.190 g, 0.843 mmol), 5(S)-butyl-1-(2,3-dimethylphenyl)piperazin-2-one hydrochloride (0.250 g, 0.843 mmol), N-methylmorpholine (0.093 mL, 0.843 mmol) in dichloroethane (10 m~ ), according to the procedure described in Example 39, Step E. The 10 title compound was purified by preparative HPLC using a gradient of 70 to 45% Solvent A. The free base was isolated and converted to dihydrochloride salt. The title compound was obtained as a white solid.
FAB ms: 470 (M+l). Anal. Calc for C2gH3sN5O ~ 2 HCl - 1.45 H2O, C, 61.25; H, 7.07; N,12.32. Found: C, 61.56; H, 6.99; N, 11.32.

4- [1 -(2-(4-Cyanophenyl)-2-propyl)-5-imidazolylmethyl] - 1 -(3-chlorophenyl)-5(S)-(2-methylsulfonylethyl)piperazin-2-one 20 dihydrochloride Step A: 4-(tert-Butyldimethylsilyloxymethyl)-l-triphenylmethylimidazole tert-Butyldimethylsilylchloride (2.83 g, 18.76 mmol) was 25 added to a suspension of 4-hydroxymethyl-1-triphenylmethylimidazole (5.80 g, 17.05 mmol) in DMF (200 mL) containing imidazole (3.48 g, 51.1 mmol). After 15 min, a clear colorless solution was obtained which was stirred at room temperature. When reaction was complete, the DMF was removed in vacuo and the residue patitioned between ethyl 30 acetate and water. The organic phase was washed with water, saturated brine, and dried over magnesium sulfate. The title compound was obtained as a clear gum.

W O 96/30343 PCTrUS96/04019 Step B: S-tert-Butyldimethylsilyloxymethyl-1-(4-cyanobenzyl)imidazole A solution of 4-(tert-butyldimethylsilyloxymethyl)-1-triphenylmethylimidazole (4.66 g, 10.26 mmol) and 1-bromomethyl-4-cyanobenzene (2.01 g, 10.26 mmol) in acetonitrile (50 mL) was rei~luxed 4 h. The reaction was cooled, acetonitrile removed in vacuo, and the residue dissolved in methanol (30 mL). This solution was refluxed for 2h, cooled and methanol evaporated. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The crude product was chromatographed on silica with 3% methanol in chloroform. The title compound was obtained as a white solid.

Step C: S-tert-Butoxydimethylsilyloxymethyl-1-[2-(4-cyanophenyl)-2-propyl)limidazole A solution of 5-tert-butyldimethylsilyloxymethyl-1-(4-cyanobenzyl)imidazole (1.005 g, 3.07 mmol) in THF (25 mL) under nitrogen was cooled to -78~C. A solution of lithium hexamethylfli~ 7.ide (4.61 mL, 1 M in THF) was added and the reaction stirred at -78~C for 1 h, then warmed to -60~C over 30 min. The reaction was cooled to -78~C, methyl iodide added (0.287 mL, 4.61 mmol), and stirring continued at -78~C for an additional 2 h, before w~rmin~ to 0~C over 2 h. After 30 min, the reaction was cooled to -78~C, and lithium hexamethyl~ 7ide (4.61 mL, 1 M in THF) ~ 1e~1 After 1 h, methyl iodide was added (0.287 mL, 4.61 mmol) and the reaction allowed to warm to room temperature overnight. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase washed with saturated brine. The crude product was chromatographed on silica gel with 6:4 ethyl acetate: methylene chloride. The title compound was obtained as a golden oil. lH NMR
(CDCl3, 400 MHz) o 7.78 (lH, s), 7.61 (2H, d, J=8Hz), 7.15 (2H, d, J=8Hz), 7.02, (lH, s), 4.00 (2H, s), 1.99 (6H, s), 0.79 (9H, s), -0.74 (6H, s).

CA 022l6707 l997-09-29 W 096/30343 PCTrUS96/04019 Step D: 1-[2-(4-Cyanophenyl)-2-propyl)]-5-hydroxymethyl-imidazole Tetra-N-butylammonium fluoride (2.99 mL, lM in THF) was added to a solution of 5-tert-butoxydimethylsilyloxymethyl-1-[2-(4-S cyanophenyl)-2-propyl)]imidazole (0.750 g, 2.72 mmol) in THF (10 mL). After 2 h at room temperature, the reaction was poured into ethyl acetate and extracted with saturated sodium bicarbonate solution. The organic phase was extracted with saturated brine, and dried over m~n~,sium sulfate. The crude product was chromatographed on silica 10 gel with 3% methanol in ethyl acetate. The title compound was obtained as a semi-solid. lH NMR (CDCl3, 400 MHz) ~ 7.77 (lH, s), 7.62 (2H, d, J=8Hz), 7.19 (2H, d, J=8Hz), 7.02, (lH, s), 4.01 (2H, s), 2.57 (lH, br s), 2.01 (6H, s).

Step E: 1-[2-(4-Cyanophenyl)-2-propyl)]imidazole-5-carboxaldehyde A solution of 1-[2-(4-cyanophenyl)-2-propyl)]-5-hydroxymethylimidazole (0.450 g, 1.87 mmol) was refluxed in dioxane 20 (20 mL) with m~ng~nese dioxide (1.62 g, 18.7 mmol) for Sh. The reaction was cooled, filtered through celite and concellLIated. The crude product was purified by chromatography on silica gel; the title compound was isolated as a semi-solid. lH NMR (CDCl3, 400 MHz) o 9.37 (lH, s), 8.11 (lH, s), 7.92 (lH, s), 7.58 (2H, d, J=8Hz), 7.15 (2H, d, J=8Hz), 2.01 (6H, s).

Step F: 4-[1-(2-(4-Cyanophenyl)-2-propyl)-5-imi(1~7.olylmethyl]-l-(3-chlorophenyl)-5(S)-(2-methylsulfonylethyl)piperazin-2-one dihydrochloride ,s The title compound was prepared according to the procedure described in Example 39, Step E, except using 1-(3-chlorophenyl)-5(S)-(2-methylsulfonylethyl)piperazin-2-one hydrochloride (0.297 g, 0.84 mmol), 1-[2-(4-cyanophenyl)-2-propyl)]imidazole-5-carboxaldehyde (0.200 g, 0.84 mmol), N-~CA 02216707 1997-09-29 W 096~0343 PCTrUS96/04019 methylmorpholine (0.092 mL, 0.84 mmol) and sodium triacetoxyborohydride (0.267 g, 1.26 mmol). The crude product was purified by preparative HPLC with an 80 to 58% Solvent A gradient.
The pure fractions were combined and converted to the hydrochloride 5 salt, yielding the title compound. FAB ms: 540 (M+l). Anal. Calc for C27H30ClNsO3S ~ 2 HCl ~ 3 H2O, C, 48.62; H, 5.74; N,10.50. Found: C, 48.62; H, 5.73; N, 9.89.

5(S)-n-Butyl-4-~1 -(4-cyanobenzyl)-5-imidazolylmethyl]-1 -(2-methylphenyl)piperazin-2-one dihydrochloride ~tep A: N-(2-Methylphenyl)-2(S)-(tert-butoxycarbonylamino)-hex~n~mine The title compound was prepared according to the procedure described in Example 39, Step C, except using o-tol~ line (0.32 mL, 3.00 mmol), 2(S)-(tert-butoxycarbonylamino)hexanal (0.538, 2.50 mmol), sodium triacetoxyborohydride (0.795 g, 3.75 mmol) in dichloroethane (10 mT.) The crude product was purified by column chromatography to yield the title compound.

Step B: 4-tert-Butoxycarbonyl-5(S)-n-butyl-1-(2-methylphenyl)piperazin-2-one The title compound was prepared essentially according to the procedure described in Example 39, Step D, except using N-(2-methylphenyl)-2(S)-(tert-butoxycarbonylamino)hex~n~mine (0.506 g, 1.65 mmol), chloroacetyl chloride (0.158 mL, 1.98 mmol) in ethyl acetate-saturated sodium bicarbonate at 0~C. The crude product thus obtained was dissolved in DMF (15 mL), cooled to 0~C under nitrogen, and treated with cesium carbonate (1.61 g, 4.95 mmol). The reaction was stirred at 0~C for 2h, and at room temperature for 2h. The reaction was quenched with saturated ammonium chloride, and W O 96/30343 PCTrUS96/04019 extracted with ethyl acetate. The extracts were dried and evaporated to give the title compound.

Step C: 5(S)-n-Butyl-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]- 1 -(2-methylphenyl)piperazin-2-one dihydrochloride The product from Step B (0.534 g, 1.50 mmol) was deprotected with trifluoroacetic acid (4 mL) in methylene chloride (10 mL). The title compound was prepared according to the procedure described in Example 39, Step E, except using 5(S)-n-butyl-1-(2-methylphenyl)piperazin-2-one ditrifluoroacetic acid salt, 1-(4-cyanobenzylirnidazole)-5-carboxaldehyde (0.317 g, 1.50 mmol), and sodium triacetoxyborohydride (0.477 g, 2.25 mmol) in dichloroethane (15 mL). The crude product was injected onto a preparative HPLC
column and purified with a mixed gradient of acetonitrile/0.1% TFA
and 0.1% aqueous TFA. The pure fractions were combined and converted to the HCl salt. The title compound was obtained as a white solid. FAB ms (m+l) 442. Anal. Calc. for C27H31N5O ~ 2.5 HCl -2.05 H;2O: C, 56.95; H, 6.66; N, 12.30. Found: C, 56.93; H, 5.75; N, 1 1.55.

4-[1-(4-Cyanobenzyl)-5-imidazolylmethyl]-5(S)-(2-fluoroethyl)-1-(3-chlorophenyl)piperazin-2-one dihydrochloride Step A: 4-tert-Butoxycarbonyl-1-(3-chlorophenyl)-5(S)-(2-fluoroethyl)-piperazin-2-one .~ 30 4-tert-Butoxycarbonyl-1-(3-chlorophenyl)-5(S)-(2-methylsulfonyloxyethyl)- piperazin-2-one (0.433 g, 1.00 mmol) and tert-butylammonium fluoride (3.0 mL, lM in THF) were stirred at room temperature in acetonitrile (5 mL) for 72 h. The reaction was quenched with saturated sodium bicarbonate and extracted with ethyl W 096t30343 PCTrUS96/04019 acetate. The organic e~tracts were dried, concentrated and purified by column chromatography using 20% ethyl acetate in hexane. The title compound was obtained as a thick oil.

Step B: 4-[1-(4-Cyanobenzyl)-5-imidazolylmethyl]-5(S)-(2-fluoroethyl)- 1 -(3-chlorophenyl)piperazin-2-one dihydrochloride 4-tert-Butoxycarbonyl- 1 -(3-chlorophenyl)-5(S)-(2-10 fluoroethyl)-piperazin-2-one (0.191 g, 0.54 mmol) was deprotected with trifluoroacetic acid (4 mL) in methylene chloride (10 mL). The title compound was prepared according to the procedure described in Example 39, Step E, except using 1-(3-chlorophenyl)-5(S)-(2-fluoroethyl)piperazin-2-one ditrifluoroacetic acid salt, 1-(4-15 cyanobenzylimidazole)-5-carboxaldehyde (0.114 g, 0.54 rnmol), and sodium triacetoxyborohydride (0.172 g, 2.25 mmol) in dichloroethane (5 mL). The crude product was injected onto a preparative HPLC
column and purified with a mixed gradient of acetonitrile/0.1% TFA
and O. l~o aqueous TFA. The pure fractions were combined and 20 converted to the HCl salt. The tide compound was obtained as a white solid. FAB ms (m+l) 452. Anal. Calc. for C24H23ClFN50 ~ 2. HCl 1.7 H2O: C, 51.90; H, 5.15; N, 12.61. Found: C, 52.22; H, 5.10; N, 12.22.

4-[3-(4-Cyanobenzyl)pyridin-4-yl]- 1-(3-chlorophenyl)-5(S)-(2-methylsulfonylethyl) -piperazin-2-one ~0 Step A: 3-(4-Cyanobenzyl)pyridin-4-carboxylic acid methyl ester A solution of 4-cyanobenzyl bromide (625 mg, 3.27 mmol) in dry THF (4mL) was added slowly over ~3 min. to a suspension of activated Zn (dust; 250 mg) in dry THF (2 mL) at Oo under an argon atmosphere.

W O 96/30343 PC~rrUS96/04019 - The ice-bath was removed and the slurry was stirred at room temperatul~ for a further 30 min. Then 3-bromopyridin-4-carboxylic acid methyl ester (540 mg. 2.5 mmol) followed by dichlorobis(triphenylphosphine)nickel (II) (50 mg). The resultant re~ h-brown mixture was stirred for 3h at ~40-450c. The mixture was cooled and distributed between EtOAc (100 ml) and 5% aqueous citric acid (50 mL). The organic layer was washed with H20 (2X50 mL), dried with Na2SO4. After evaporation of the solvent the residue was purified on silica gel, eluting with 35% EtOAc in hexane to give 420 mg as a clear gum. FAB ms (M+l) 253.

Step B: 3-(4-Cyanobenzyl)-4-(hydroxymethyl)pyridine The title compound was obtained by sodium borohydride (300 m~) reduction of the ester from Step A (415 mg) in methanol (5 mL) at room tempel~lure. After stirring for 4 h the solution was evaporated and the product was purified on silica gel, eluting with 2%
methanol in chloroform to give the title compound. FAB ms (M+l) 225.

Step C: 3-(4-Cyanobenzyl)-4-pyridinal The title compound was obtained by activated manganese dioxide (l.Og) oxidation of the alcohol from Step B (240 mg, 1.07 mmol) in dioxane (10 mL) at reflux for 30 min. Filtration and evaporation of the solvent provided title compound, mp 80-830C.

Step D: 4-[3-(4-Cyanobenzyl)pyridine-4-yl]-1-(3-chlorophenyl)-5(S)-(2-methylsulfonylethyl)-piperazin-2-one.
This compound was prepared essentially by the same methods as described in Example 39, Step E, except that the imidazolyl t carboxaldehyde was replaced by an equal amount of product from Step C (vide supra) and the piperazinone was replaced by an equal amount of 1-(3-chlorophenyl)-5(S)-(2-methylsulfonylethyl)-piperazin-2-one, there was obtained the title compound. FAB ms 523. Anal. Calc. for W 096/30343 PCTrUS96104019 C27H27ClN403S-0.15 CHCl3:C, 60.28; H, 5.06; N, 10.36 Found: C, 60.37; H, 5.03; N, 10.64.

4-[5-(4-Cyanobenzyl)- 1 -imidazolylethyl] - 1 -(3-chlorophenyl)piperazin-2-one.

Step A: l-Trityl-4-(4-cyanobenzyl)-imidazole.
To a suspension of activated zinc dust (3.57g, 54.98mmol) in THF (50ml)was added dibromoethane (0.315ml, 3.60mmol) and the reaction stirred under argon at 20~C. The suspension was cooled to 0~C
and o~-bromo-p-tolunitrile (9.33g, 47.6mmol) in THF (lOOml) was added d~c~wise over a period of 10 min. The reaction was then allowed to stir at 20~C for 6hr and bis(triphenylphosphine)Nickel II chloride (2.4g, 3.64mmol) and 5-iodotrityl imidazole (15.95g, 36.6mmol) was added in one portion.The resulting mixt~lre was stirred 16hr at 20~C
and then quenched by addition of saturated NH4Cl solution (lOOml) and the mixture stirred for 2 hours. Saturated NaHC03 solution was added to give a pH of 8 and the solution was extracted with EtOAc ( 2x250ml), dried MgS04 and the solvent evaporated in vacuo. The residue was chromatographed (sio2~ 0-20% EtOAc/CH2C12 to afford the title compound as a white solid.
1H NMR o CDCl3 (7.54 (2H,d, J=7.9Hz), 7.38(1H,s), 7.36-7.29 (llH,m), 7.15-7.09(6H,m), 6.58(1H,s), and 3.93(2H,s)ppm.

Step B: l-Methyl acetyl-5-(4-cyanobenzyl)-imidazole.
To a solution of 1-trityl-4-(4-cyanobenzyl)-imidazole (3.01 g, 6.91 mmol) in acetonitrile (SOml) was added methyl bromoacetate (0.687ml, 7.26mmol) and the mixture heated at 55~C for 16 hours, and f then the solvent was evaporated in vacuo. The solids were triturated with EtOAc, collected by filtration and dissolved in methanol (60ml).
This suspension was heated at refux for 20min, cooled and evaporated W 096/30343 PCTrUS96/04019 to dryness. The residue was triturated with EtOAc and the title compound was obtained as a white solid by filtration 1H NMR o CDCl3 (7.61 (2H,d, J=7.9Hz), 7.53(1H,s), 7.27(2H,d,J=7.9Hz), 6.89(1H,s), 4.47(2H,s), 3.98(2H,s) and 5 3.66(3H,s)ppm.

Step C: 1-Hydroxyethyl-5-(4-cyanobenzyl)-imi(l~zole.
A solution of 1-methyl acetyl-5-(4-cyanobenzyl)-imicl~7ole (0.113 g, 0.472 mmol) in methanol (2ml) at 0~C was treated with 10 sodium borohydride (80.7mg, 2.1mmol). After 1 hour the reaction was quenched by addition of saturated NH4Cl solution (2ml). Saturated NaHCO3 was added and the mixture extracted with ethyl acetate (3x25ml1), dried MgSO4 and evaporated in vacuo. The title compound was isolated by chromatography (SiO2, 10%MeOH in CH2Cl2) as a 15 white solid. 1H NMR o CDCl3(7.61 (2H,d, J=7.9Hz), 7.55(1H,s), 7.27(2H,d,J=7.9Hz), 6.83(1H,s), 4.05(2H,s), 3.87(2H,t, J=5.lHz) and 3.74(2H,t, J=5.1Hz)ppm.

20 StepD: 2-(-5-(4-Cyanobenzyl)-imidazolvl)ethyl methanesulfonate A solution of 1-hydroxyethyl-5-(4-cyanobenzyl)-imidazole (0.532 g, 2.34 mmol) in methylene chloride (70ml) at 0~C was treated with Hunigs base (0.489ml, 2.81mmol) and methane sulfonyl chloride (0.219ml, 2.81mmol). After 2 hour the reaction was quenched by 25 addition of saturated NaHCO3 solution (SOml) and the mixture extracted with methylene chloride (50ml), dried MgSO4 and the solvent evaporated in vacuo. The title compound was used without ru~ u purification. 1H NMR ~ CDCl3(7.62 (2H,d, J=7.9Hz), 7.54(1H,s), 7.29(2H,d,J=7.9Hz), 6.87(1H,s), 4.25(2H,t), 4.10-4.00(4H,m), 30 3.74(2H,t, J=5.lHz) and 2.90(3H,s)ppm.

-Step E: 4-[5-(4-Cyanobenzyl)- 1 -imidazolylethyl]- 1-(3-chlorophenyl)piperazin-2-one.

A solution of 2-(-5-(4-cyanobenzyl)-imidazolyl)ethyl methanesulfonate (24 mg, 0.079 mmol) in DMF (0.2ml) was added to 3-(chlorophenyl)piperazin-2-one( 17.7mg, 0.084mmol), sodium iodide (50mg, 0.336mmol) and Hunigs base (0,0146ml, 0.084mmol). The 5 mixt~lre was stirred at 55~C for 12 hours, and the solvent evaporated in vacuo. The residue was purified by preparative tlc eluting with 10%
saturated ammonia/acetonitrile to afford the title compound.
1H NMR o CDC13(7.61 (2H,d, J=8.4Hz), 7.56(1H,s), 7.35-7.20 (7H,m), 7.16(1H,d, J=8Hz), 6.85(1H,s), 4.03(2H,s),, 3.83(2H,t, J=6.5Hz), 10 3.61(2H,t, J=5.4Hz), 3.27(2H,s), 2.68(2H,t, J=5.4Hz) and 2.57(2H,t, J=6.5Hz)ppm.

15 In vitro inhibition of ras farnesyl transferase Assays of farnesyl-protein transferase. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) were prepared as described by Schaber et aL, J. Biol. Chem. 265: 14701-14704 (1990), Pompliano, et al., Biochemistry 31:3800 (1992) and 20 Gibbs et al., PNAS U.S.A. 86:6630-6634 (1989), respectively. Bovine FPTase was assayed in a volume of 100 ,ul cont~ining 100 mM N-(2-hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM [3H]-farnesyl diphosphate ([3H]-FPP; 740 CBq/mmol, New Fn.~l~n~l Nuclear), 650 25 nM Ras-CVLS and 10 llg/ml FPTase at 31 ~C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol. Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in ..
an LKB ~-plate counter. The assay was linear with respect to both 30 substrates, FPTase levels and time; less than 10% of the [3H]-FPP was tili7e~1 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 W O 96/30343 PCTrUS96/04019 when compared to the amount of incorporation in the absence of the test - compoundL.
Human FPTase was prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity was 5 assayed as described above with the exception that 0.1 % (w/v) polyethylene glycol 20,000, 10 ,llM ZnCl2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 ,ul of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
The compounds of the instant invention described in the above Examples and in the Tables hereinafter were tested for inhibitory activity against hllm~n FPTase by the assay descril~ed above and were found to have IC50 of < 50 ,uM.

In vivo ras farnesylation assay The cell line used in this assay is a v-ras line derived from either ~atl or NIH3T3 cells, which expressed viral Ha-ras p21. The assay is performed essentially as described in DeClue, J.E. et aL, Cancer Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75%
confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 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 cells are lysed in 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM M~C12/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipainl0.5 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 W 096/30343 PCTIU'~ Ol9 25% suspension of protein A-Sepharose coated with rabbit anti rat IgG
is added for 45 min. The immunoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1% Triton X-100Ø5% deoxycholate/0.1%/SDS/0.1 M NaCl) boiled in SDS-PAGE
sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Fnlightening, dried and autoradiographed. The intensities of the bands corresponding to farnesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein.

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 in.c~nt compounds for Ras-induced cell transformation.
Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 104 cells per plate (35 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layers contain 0.1% methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay). The cells are fed twice weekly with 0.5 ml of medium A cont~ining 0.1%
methanol or the concentration of the instant compound.
Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made.

W 096130343 PCTrUS96/04019 Tables 1-18 show other compounds of the instant invention that were prepared by the procedures described in Examples 1-53.
5 These compounds are meant to be illustrative and are not meant to be limiting. In Table 2, the stereochemistry of the arnino-cont~inin~
carbon atom is as indicated (R or S) or, if unknown, the two separated stereoisomers are delineated by an "A" or "B" de~i~n~tion.

W 096/30343 PCTrUS96/04019 Tablel ~ O
R-S ~ N N

NH2 ~J

R FAB ms(m+1) Formula 526 C,56.16;H,5.40;N,7.22.
C,56.12;H,5.37;N,7.39.

C30H39N3O2S2-55 TFA0.55 H2O
CH3O ~ CH2 506 C,53.19;H,5.46;N,5.36.
C,53.17;H,5.46;N,5.60.

C29H36N3OS2-25 TFA0.35 H2O
F ~ CH2 494 C,53.19;H,5.18;N,5.55.
C,53.16;H,5.18;N,5.68.

CH2CH2 490 C,55.64;H,5.88;N,5.73.
C,55.57;H,5.81;N,5.83.

~ C29H35F2N3OS2-4 TFA0.6 H2O
</ \~ CH2 512 C,50.99;H,4.89;N,5.28.
~ C,50.98;H,4.86;N,5.56.
F

W 096/30343 PCTrUS96/04019 ;

Table 2 r y u~

FAB mass amine spectrum stereo. X Y (M+l) Analysis (calcd.. found) A n-Bu 2-O(CH2)13CH3 642.5 C42H63N3O2-2.55HCl C, 68.46; H, 8.97; N, 5.70.
C, 68.40; H, 8.70; N, 5.61.
l S B n-Bu 2-0(CH2) 13CH3 642.6 C42H63N302-2.65HCl C, 68.63; H, 8.99; N, 5.72.
C, 68.66; H, 8.90; N, 5.70.

A n-Bu 2-O(CH2)11CH3 614.4 C40H59N302-2.8HCl C, 67.09; H, 8.70; N, 5.87.
C, 67.03; H, 8.66; N, 5.76.

B n-Bu 2-O(CH2)11CH3 614.4 C40H59N3o2-2~8sHcl-o~osH2o C, 66.84; H, 8.69; N, 5.85.
C, 67.20; H, 8.70; N, 5.45.

W 096/30343 PCTrUS96/04019 FAB mass amine spectrum stereo. X Y (M~l) Analysis (calcd.~ found) S A n-Bu 2-O(CH2)9CH3 586.5 C3gH5sN3O2-3HCl-0.25hexane C, 66.18; H, 8.65; N, 5.86.
C, 66.14; H, 8.44; N, 5.50.

B n-Bu 2-O(CH2)9CH3 586.5 C3gH55N302-3HCl-0.15hexane C, 65.97; H, 8.55; N, 5.93.
C, 66.04; H, 8.41; N, 5.57.

A n-Bu 2-o(cH2)7cH3 558 C36H5lN3o2-2.lsHcl-o.6sH2 C, 66.73; H, 8.47; N, 6.49.
C, 66.74; H, 8.46; N, 6.52.

B n-Bu 2-o(cH2)7cH3 558 C36H5lN3o2-2.l5Hcl-o.65H2o C, 66.82; H, 8.42; N, 6.49.
C, 66.85; H, 8.43; N, 6.52.
A n-Bu 2-o(cH2)3ph 564 C37H45N302-2HC1-1.05H20 C, 67.78; H, 7.55; N, 6.41.
C, 67.78; H, 7.52; N, 6.26.
B n-Bu 2-O(CH2)3Ph 564 C37H45N3o2-2Hcl-l.o5H2o C, 67.78; H, 7.55; N, 6.41.
C, 67.78; H, 7.44; N, 6.33.

A n-Bu 3-OCH2Ph 536 C3sH41N3O2-3.55HCl C, 63.19; H, 6.75; N, 6.32.
C, 63.12; H, 6.61; N, 6.47.

B n-Bu 3-OCH2Ph 536 C3sH41N302-3.55HCl-0.4H20 C, 62.52; H, 6.80; N, 6.25.
C, 62.14; H, 6.69; N, 6.65.

W 096/30343 PCTrUS96/04019 r FAB mass amine spectrum stereo. X Y (M+l) Analysis (calcd.~ found) s A n-Bu 3-O(CH2)13CH3 642 C42H63N302-2.4HCl C, 69.15; H, 9.04; N, 5.76.
C, 69.08; H, 9.08; N, 5.73.

B n-Bu 3-o(cH2)l3cH3 642.5 C42H63N3o2-2.3sHcl-o.25H2o C, 69.15; H, 9.04; N, 5.76.
C, 69.08; H, 9.08; N, 5.73.

R n-Bu 4-O(CH2)13CH3 642 C42H63N302-2.2HCl-lH20 C, 68.14; H, 9.15; N, 5.68.
C, 68.13; H, 9.03; N, 5.68.

S n-Bu 4-O(CH2)13CH3 642 C42H63N302-2.8HCl C, 67.79; H, 8.91; N, 5.65.
C, 67.77; H, 9.80; N, 5.64.

S nL-Bu 4-OCH2Ph 536 C35H41N302-2.15HCl-lH20 C, 66.49; H, 7.20; N, 6.65.
C, 66.48; H, 7.15; N, 6.62.
R/S H 2-o(cH2)l3cH3 586 C38HssN3o2-l.sHcl-o.3H2o C, 66.88; H, 8.58; N, 6.16.
C, 66.82; H, 8.64; N, 6.15.

W O 96/30343 PC~rrUS96/04019 Table 3 Me~

NC ~ ~N N~
s FAB mass spectrum Y (M+l) Analysis (calcd.~ found) 3-SO2Me 506 C27H31N5O3S-3.0 HCl-0.10 H2O
C, 52.61; H, 5.59; N, 11.36.
C, 52.63; H, 5.41; N, 10.72.
3-OCF3 512.23 C27H2gN5O2F3-2.30 HCl-0.50 H2O
C, 53.66; H, 5.22; N, 11.59.
C, 53.73; H, 5.23; N, 10.86.

W 096/30343 PCTrUS96/04019 r 173 -~ Table 4 X ~_~ Y
NC~N~ \~

N
FAB mass S spec~um X Y (M+l) Analysis (calcd.~ found) CH2OCH2Ph CF3 574 C32H30Nso2F3-l.4oHcl-o.3oH2o C,61.02; H,5.12; N,11.12.
C,61.01; H,5.10; N,10.78.

CH2SO2E~ CF3 560 C27H28Nso3F3s ~3.20HCl-O. lOH20 C,47.86; H,4.67; N,10.34.
C,47.89; H,4.49; N,9.92.
CH2SO2Ph CF3 608 C3lH2gNsO3F3S-2.10HCl C,54.42; H,4.43; N,10.24.
C,54.43; H,4.42; N,9.98.
CH2SOzMe Cl 512 C25H26N5O3ClS
~2.0HCl-0.25CHC13-0.25H20 C,48.97; H,4.68; N,11.31.
C,48.95; H,4.64; N,11.51.

W 096~0343 PCTAUS96/04019 Table 4 (continued) NC~ ~\

FAB mass spectrum X Y (M+1) Analysis (calcd.. found) CH2SO2Et Cl 526 C26H2gN503ClS-2HCl-0.25CHCl3 C, 50.14; H, 4.85; N, 11.14.
C, 50.20; H, 4.91; N, 10.93.

CONHMe CF3 511 C26H25N6O2F3-1.90HCl-1.70H20 C, 51.20; H, 5.01; N, 13.78.
C, 51.17; H, 4.99; N, 13.36.

CONHEt CF3 525 C27H27N6O2F3-1.60HCl-0.10H20 C, 55.54; H, 4.97; N, 14.39.
C, 55.57; H, 4.87; N, 15.28.

CH2SO2Ph Cl 574 C30H28N5o3cls-2Hcl-o.3oH2o C, 55.23; H, 4.73; N, 10.73.
C, 55.25; H, 4.57; N, 10.61.

W 096/30343 PCTrUS96/04019 Table 4 (continued) -NC~3~N~ \~

FAB mass S spectrum X Y (M+l) Analysis (calcd.. found) CONHMe Cl 477 C25H25N602Cl-2HCl ~0. lOSCHC13-0.85H20 C, 52.24; H, 5.03; N, 14.56.
C, 52.21; H, 5.07; N, 14.98.

CONHEt Cl 491 C26H27N6O2Cl-2HCl-0.25CHC13 C, 53.10; H, 4.97; N, 14.15 C, 53.32; H, 5.21; N, 13.77.

CONHc-Pr Cl 503 C27H27N6O2Cl-2HCl-0.40CHC13 C, 52.77; H, 4.75; N, 13.47.
C, 53.01; H, 4.99; N, 13.32.

CONHc-Pr CF3 537 C28H27N6O2F3 ~2.45HCl-0.55dioxane C, 53.81; H, 5.06; N, 12.47.
C, 53.76; H, 5.09; N, 12.44.

W 096/30343 PCTrUS96/04019 Table 4 (continued) NC~ ~N~N~

FAB mass spectrum X Y (M+l) Analysis (calcd.~ found) NHCOMe Cl 477 C25H25N6O2Cl ~2HCl-0.60CHC13-2-0H20 C, 46.76; H, 4.84; N, 12.78.
C, 46.79; H, 4.46; N, 12.37.

CONMe2 CF3 525 C27H27N6O2F3-2.0HCl-0.10H2O
C, 54.12; H, 4.91; N, 14.02.
C, 54.10; H, 4.96; N, 13.79.

SO2Et Cl 512 C25H26N5O3ClS-2.0HCl-0.10H20 C, 51.18; H, 4.84; N, 11.94.
C, 51.24; H, 5.19; N, 11.10.

CH2SMe Cl 480 C25H26N5OClS
~0. lSCHC13-0.05H20 C, 52.83; H, 4.98; N, 12.25.
C, 52.82; H, 5.36; N, 11.85.

W 096/30343 PCTnUS96/04019 - Table 4 (continued) b NC~ ~N N~

FAB mass S spectrum X Y (M+l) Analysis (calcd.. found) (+) C=CMe Cl 458 C26H24N5OCl-2.0HCl-l.OOH20 C, 56.89; H, 5.14; N, 12.76.
C, 56.99; H, 5.20; N, 12.42.

.

W 096/30343 PCT/U~ l9 Table S

NC~, 5X--N~N~

FAB mass spectrum X Y (M+l) Analysis (calcd.. found) CH2CH2 H 386 C23H23N5O-1.40HCl-0.40H20 C, 62.29; H, 5.73; N, 15.79.
C, 26.26; H, 5.71; N, 15.43.

CH2CO H 400 C23H21N5O2-2.6HCl-1.70H2O
C, 52.71; H, S.l9; N, 13.36.
C, 52.82; H, 5.21; N, 13.04.

CH2 H 372 C22H21Nso-2.oHcl.2.6oH2o C, 53.80; H, 5.79; N, 14.26.
C, 52.86; H, 5.98; N, 13.92.

CH2 3-C1 406 C22H20N5ocl-2.5oHcl-o.9oH2o C, 51.48; H, 4.77; N, 13.65.
C, 51.55; H, 4.75; N, 13.34.

CA 022l6707 l997-09-29 W 09.'3~3 PCTrUS96/04019 Table 5 (continued) NC~ X--N N~

FAB mass spectrum X Y (M+1) Analysis (calcd.~ found) NHSO~ H C2lH2oN6o3s-l~oHcl-2.6oH2o C, 48.53; H, 5.08; N, 16.17 C, 48.60; H, 5.19; N, 15.80.

CH2CH2CO 3-C1 448 C24H22N5O2Cl-l.OHCl-l.lOH2O
C, 57.17; H, 5.04; N, 13.89.
C, 57.22; H, 4.94; N, 13.47.

CH2 2,3-C12 440 C22HlgN5OC12-2.0HCl-0.60H20 C, 50.42; H, 4.27; N, 13.36.
C, 50.51; H, 4.56; N, 12.18.

CH2 2-Br 450 C22H20NsoBr-2.oHcl-o.3oH2o C, 49.98; H, 4.31; N, 13.25.
C, 49.94; H, 4.47; N, 12.53.

W O 96130343 PCTrUS96/04019 Table S (continued) NC ~ ,~3X--N~N~

FAB mass S spectrum X Y (M+l) Analysis (calcd.~ found) CH2 3-CF3 440 C23H20N50~3-l.70HC1-0.40H20 C, 54.40; H, 4.47; N, 13.79.
C, 54.45; H, 4.49; N, 13.82.

CH2 4-Cl C22H2oN5ocl-l.soHcl-o.8oH2o C, 55.71; H, 4.91; N, 14.77.
C, 55.81; H, 4.94; N, 14.11.

CH2CO 3-Cl C23H20Nso2cl-l.4oHcl-l.loH2o C, 54.73; H, 4.71; N, 13.87.
C, 54.80; H, 4.73; N, 13.46.

CH2 3-F C22H20N5oF-2Hcl ~0.35CHC13-0.95H20 C, 51.50; H, 4.69; N, 13.44.
C, 51.56; H, 4.73; N, 13.30.

CA 022l6707 l997-09-29 W 096/30343 PCTrUS96/04019 Table 5 (continued) t NC ~ X--N N~

N
FAB mass S spectrum X Y (M+l) Analysis (calcd.~ found) CH2 3-Br C22H20NsoBr-l.4oHcl-l.3oH2o C, 50.35; H, 4.61; N, 13.34.
C, 50.36; H, 4.63; N, 12.84.

W 096/30343 PCTrUS96/04019 Table 6 MeO2S

X~ N~z N N~

S FAB mass spectrum X Y Z (M+l) Analysis (calcd.~ found) 4-CN CH2 S-CH2CH2CO 554 C27H2gN5O4ClS- 1.30HCl- 1.20H20 C, 52.05; H, 5.13; N, 11.24.
C, 52.09; H, 5.15; N, lO.9S.

3-CN CH2 S-CH2 512 C25H26N5O3ClS-2.0HCl-O. lOCHC13-0.60H20 C, 49.61; H, 4.86; N, 11.52.
C, 49.63; H, S.01; N, 11.14.

2-CN CH2 S-CH2 512 C25H26N5O3ClS-2HCl-0.35H2O

C, 50.79; H, 4.89; N, 11.84. 4 C, 50.82; H, 5.29; N, 11.90.

4-CN CH2 4-CH2CH2CO 554 C27H2gN5O4ClS
~2.oHcl-o.socHcl3-o.6oH2o C, 47.36; H, 4.58; N, 10.04.
C, 47.35; H, 4.60; N, 9.66.

W 096130343 PCTnUS96/04019 Table 6 (continued) ~.
MeO2S

~N ~

S FAB mass spectrum X Y Z (M+l) Analysis (calcd.. found) 4-CN ~CH2)2 4-CH2CH2CO C2gH30N5O4ClS
~1 .OHCl-0.40CHC13-0.95H20 C, 50.96; H, 5.01; N, 10.46.
C, 50.91; H, 5.02; N, 10.13.

Table 7 Y~ Cl Xl'/. ,~ ~

FAB mass spectrum X Y (M+1) Analysis (calcd.~ found) 4-Me CH2CH2SO2Me 526 C26H2gN5O3ClS
~2HCl-0.35CHC13-0.85H20 C, 48.24; H, 4.92; N, 10.67.
C, 48.25; H, 4.93; N, 10.36.

4-Me H 420 C23H22NsOCl-2.0Hcl.o.goH2o C, 54.27; H, 5.11; N, 13.76.
C, 54.21; H, 5.37; N, 12.97.

2-Me H 420 C23H22N5OCl-3.20HCl-O.10H20 C, 51.31; H, 4.76; N, 13.01.
C, 51.30; H, 4.74; N, 12.87.

W ~ 96130343 PCTAUS96~040I9 n-C4H~

NC ~ ~O

Fo~nula FAB ms Y (m+l) Analysis C~c Found 3-CF3 496 C27H2gF3N5O 2HCl 1.55 H2C
C,54.36; H,5.59; N,11.74 C,54.40; H,5.29; N,11.26 3-CH3 442 C27H3lNsO 2 HCl C,63.01;H,6.47;N,13.61 C,63.45; H,6.71; N,13.53 2,3-(CH2)4 482 C30H3sNsO 5.2 HCl 0.1 H2C
C,53.66; H,6.06; N,10.43 C,53.62; H,5.30; N,9.35 3-OCH3 458 C27H3lNs~2 2 HCl t C, 61.13; H,6.27; N,13.20 C,62.43; H,6.53; N,13.24 ;

W 096/30343 PCTrUS96/04019 TABLE 8 (continued) n-C4Hg ~ ~,y ~r NC ~~ ~N N~

Formula y FAB ms Analysis Found 3-Cl 463C26H28ClNsO 2HCl 0.75 H2C
C, 56.94; H, 5.79; N, 12.77 C, 56.92; H, 5.59; N, 12.30 2-CH3 3-Cl 477C27H30ClNsO2 2HCl 3.1 H2O
C, 53.62; H, 6.37; N, 11.58 C, 53.44; H, 5.37; N, 10.76 H 428C26H29NsO 3.9 HCl 2 H2O
C,51.63;H,6.51;N, 11.58 C, 51.59; H, 5.10; N, 10.35 W O 96l30343 PCTAUS96/040~g TABLE 8 (continued) ..

n-C4Hg NC ~~ ~\ ~Y

Formula Y (m+l) Analysis Found 3-F 446C26H2sFN50 2 HCl 2.55 H2C
C, 55.87; H, 6.22; N, 12.53 C, 55.83; H, 5.84; N, 11.71 W 096/30343 PCTrUS96/04019 NC~ ~N N~

Formula FAB ms R (m+1) Analysis C~c Found CH2CH2OCH2CF3 566 C27H2sF6NsO2 2 HCl 0.67 H2O
C,49.85; H,4.39; N,10.77 C,49.86; H,4.26; N,10.33 OCH2CH2 524 C28H28F3NsO2 2 HCl C,56.38; H,5.07; N,11.74 C,56.21;H,5.27;N,11.46 CH2CH2N3 509 C2sH23F3NgO2 2 HCl 2.35 H2O
C,48.14; H,4.80; N,17.96 C,48.79; H,4.38; N,16.99 CH2CH2NHCOCH3 525 C27H27F3N6O2 2 HCl 0.7 H2O
C,53.16; H,5.02; N,13.78 C,53.30; H,5.07; N,13.39 CH2CH2NHCOC2Hs 539 C2gH2gF3N6O2 2 HCl 3.66 H2O
C,52.43; H,5.39; N,13.10 C,52.44; H,5.20; N,12.48 W 096130343 PCT/U~ I9 TABLE 9 (continued) ~.
F~ ~ CF3 NC ~\

Formula FAB ms R (m+l)Analysis Calc Found CH2CH2SO2CH(CH3)2 574C2gH3oF3NsO3S 2HCl 1.35 H2C
C, 50.13; H, 5.21; N, 10.44 C, 50.10; H, 4.88; N, 10.08 CH2CH2SCH(CH3)2 542 C2sH3oF3Nsos 2 HCl 0.75 H2O
C, 53.55; H, 5.38; N, ll.Sl C, 53.57; H, 5.33; N, 11.04 CH2CH2S(O)CH(CH3)2 558 C2sH3oF3Nso2s 2 HCl 0-7 H2O
C, 52.29; H, 5.23; N, 10.89 C, 52.27; H, 5.08; N, 10.35 W 096130343 PCTrUS96/04019 n~C4Hs CH3 CH3 ~\ )=~ ' R--N N~

R FAB ms Formula (m+l)Analysis Calc Found 02N~N/~ 462C26H3lNsO3 2 CF2CO2H 2.8 H2C
C, 48.69; H, 5.26; N, 9.46 C,48.70;H,4.42;N,9.12 NC ~ CH3 470 0 6 Cs Hs 2 HCl 0.3 CH2C12 C, 63.76; H, 7.48; N, 11.30 CH2 C, 64.77; H, 7.07; N, 11.26 431 C27H34N4O 2 HCl C,64.41;H,7.21;N, 11.13 C, 66.35; H, 7.28; N, 11.25 ~CH2 C28H36N4O 2 HCl 1-3 H20 C, 62.17; H, 7.56; N, 10.36 NC~ C, 62.15; H, 7.09; N, 9.83 N CH2 470 C29H3sNsO 2HCl 3.05 H20 C, 58.30; H, 7.27; N, 11.72 N C, 58.30; H, 6.28; N, 10.90 ~¢~\N~ 548, SS0 C2gH34BrNsO 2 HCl 0.1 H2O
NC ~'N~ Br C, 55.89; H, 5.85; N, 11.24 C, SS.91; H, 5.96; N, 10.73 W O 96/30343 PCT~U~ J019 ., ~ Y
~ ~<
R - N N~

Fonnu1a R Y (m+1) ~nalysis FC~Cd Cl 511 C26H27ClN4O3s N 2 HCl 2.85 H2O
C,49.16;H,5.51;N,8.82 C,49.17; H,4.74; N,8.87 ~ F 496 C2sH26FNso3s NC N 2 HCl 1.65 H2O
C,50.20; H,5.27; N,11.71 C,50.19; H,4.90; N,11.44 ~N--~CH2 Cl 527 C26H28ClNsO3S
NC ~J ~ ~ 2 HCl 0.55 H20 N C,51.29;H,5.15;N,11.50 C,51.32; H,5.39; N,11.31 r P
r~ ~
HN N- C --<\ />-- CN Cl 530 C26H32ClNsO3S
H2 ~ Y 3 HCl 0.6 HCl C,48.02; H,5.61; N,10.77 C,48.30; H,5.91; N,9.78 W 096t30343 PCTrUS96/04019 \ Cl R--N N~
o Fonnula FAB ms R (m+1) An~ysis C~c CH3 Found ~ CH2 C26H30ClN504S
H2N~ N~ 545 2 HCl 0.75 H2O
~ C,49.53; H,5.36; N,11.11 C,49.56; H,5.58; N,10.65 552 C2gH2sClNsO3S

N C, 53.90; H, S.01; N,11.22 C,54.06; H,5.78; N,10.67 396 Cl7H20clN4O3s N C,42.41 ; H,4.90; N,11.64 CH2 C, 42.98; H,5.49; N,11.06 L

HN N-C~CN 544 C26H30clNsO4s --/ O 2 HCl 0.75 H20 C,49.51;H,5.36;N,11.11 C,49.74; H,5.66; N,10.11 W O 96130343 PCTrUS96/04019 TABLE 12 (continued) R--N N~

Fonnula FAB ms R (m+l)~nalysis Calc Found N~
~CH2 < 524 C27H27ClN4O3S 0.55 CHCl3 P~
C,58.67; H,4.92; N,10.03 CN C, 58.71; H,4.94; N,9.95 ~,,CH2 ~, 1 523 C28H28ClN3O3S 0.1 CHCl 0.2 CH30H
C,62.89; H,5.39; N,7.78 CN C, 62.87; H,5.37; N,7.84 CA 022l6707 l997-09-29 W 096/30343 PCTrUS96/04019 ~ Cl ~ ~<
R--N N~
o Fonn~a R (m+l) Analysis FC~cd ~ 563 C3~H3lClN403S
Ph N 2 HCl 1.8 H2O
C,53.90; H,5.52; N,8.38 C,53.90; H,5.38; N,7.82 ~ 540 C27H30clNso3s NC ~ 2HCl 1.35 H2O
C,50.88; H,5.49; N,10.99 C,51.37;H,5.51;N,10.20 ~CH2 512 C25H26ClNsO3s NC 2 HCl 0.3 H2O
C,50.86; H,4.88; N,11.86 CH2 C,51.06; H,5.33; N,10.87 HN NH 415 C28H27ClN4O3s C,36.25;H,6.42;N,9.39 CH2 C,38.12;H,5.91;N,7.41 HN N - S ~ CN 580 C25H30clNsoss2 2 HCl 0.85 H2O
C,44.93; H,5.08; N,10.48 C,44.96; H,5.08; N,9.96 W 096t30343 PCTnUS96104019 "

.. R2 Cl R1_N N~

~ Formula FAB ms Rl R2 (m+l)Analysis Calc Found N~ ~CH H 355ClgHl9clN4O
2 HCl 0.5 H2O
C,52.25; H,5.08; N,12.83 CH2 C,52.31; H,5.14; N,12.23 N~ CH2CH2F 452C24H23ClFNso ~= N 2 HCl 1.70 H20 ~ C,51.90; H,5.15; N,12.61 NC/-- C, 52.22; H,5.10; N,12.22 ~ ~ O C24H22ClNsO2 1 HCl HN~ H 4480.30 CHCl3 0-85 H20 C,54.50; H,4.71; N,13.08 C,54.51; H,4.69; N,12.87 ,~
~, ~
NC

W 096/30343 PCTrUS96/04019 R--N N~ ' Formula R Y FAB ms Analysis Calc (m+l) Found N~ 2,3-(CH2)4 426 C26H27Ns~
/=<-- \=N 2 HCl ~ 0.15 H20 ~ C, 62.31; H, 5.89; N, 13.97 NC C,62.38;H,6.18;N, 13.27 --N~ 2-CH3, 3-C1 420 C23H~ClN5o \=N 2 HCl 1.0 H20 ~ C, 54.08; H, 5.13; N, 13.71 NC C, 54.57; H, 5.77; N, 12.92 0~
3-C1 420 C22HlsClNsO2 N> 2 HCl 0.5 H20 <\ /~ C, 56.78; H, 4.33; N, 15.05 ~ C, 56.79; H, 4.69; N, 13.47 NC

n-C4H~

Formula R FAB ms Analysis Calc Found ,~ , CH2CH2 NC J~ 506 C32H3sNsO 3-2 CF3CO2H

C, 54.14; H, 5.75; N, 9.15 C, 54.15; H, 5.74; N, 9.18 ~CH2 ~,N~ N 484 C29H33NsO2 4 HCl 3 H20 C, 51.03; H, 6.35; N, 10.26 C, 51.02; H, 5.66; N, 9.67 NC

506 C32H35N5O 2 HCl 1-7 H2C
N
C, 63.09; H, 6.68; N, 10.26 C,51.02;H,5.66;N,9.67 W 096/30343 PCT~US96104019 Table 17 /--\ /=\ r R--N N~

Formula FAB ms R (m+l) Analysis Found 347 C21H22N4O 0.2 CHCl3 <~ 0.4 CH30H
C, 67.71; H, 6.26; N, 14.62 C, 67.71; H, 6.26; N, 14.53 ~CH2 N~
,~, 358 C23H23N3O 0.55 CHCl3 C, 66.85; H, 5.61; N, 9.93 C, 66.87; H, 5.70; N, 10.03 WO g''303~1~ PCI~US96/040~9 Table 18 ., FAB mass spectrum (M+l) Analysis (calcd.~ found) Me Me Me ~_3 C29H33N502- 1.OHCl-0.25cHcl3-o-7oH2o C, 62.45; H, 6.39; N, 12.45.
C, 62.45; H, 6.46; N, 12.37.

H~ N~

406 C22H20Nsocl-2.6oHcl C, 53.97; H, 4.78; N, 14.30 C, 53.97; H, 5.21; N, 13.10.

MeO25 ~ ~Cl NC ~ ~N N
.. N
526 C26H2gN503ClS-2.0HCl- 1.20H20 C, 50.32; H, 5.26; N, 11.28 C, 50.31; H, 5.31; N, 10.72.

Table 18 (continued) FAB mass spectrum (M+l) Analysis (calcd..... found) N~ \J ~

420 C23H22N50Cl-2-OHCl-2- 1~H2O
C, 52.06; H, 5.36; N, 13.20 C, 51.99; H, 5.36; N, 12.57.

Claims (42)

WHAT IS CLAIMED IS:

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

wherein:
R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R1S(O)m-, R10C(O)NR10-, (R10)2N-C(O)-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2N-C(O)-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

R2 and R3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, or , wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:

a) C1-4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, e) CN, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6a, S(O)R6a, SO2R6a, 5) -NR6R7, 6) , 7) , 8) , 9) , 10) , 11) ~SO2~NR6R7 12) , 13) , 14) , 15) N3, or 16) F; or R2 and R3 are attached to the same C atom and are combined to form - (CH2)U - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R4 and R5 are independently selected from H and CH3;

and any two of R2, R3, R4 and R5 are optionally attached to the same carbon atom;

R6, R7 and R7a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) ~SO2R11 , or g) N(R10)2; or R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) ~SO2R11 , or g) N(R10)2;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R10OC(O)NH-;

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, -R102N-C(NR10)-, CN, NO2, R1OC(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-, (R10)2NC(O)-, R102N-C(NR10)-, CN, 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;

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 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 is -CH2-, -C(=O)-, or -S(=O)m-;

Y is unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or more of:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR6a, or g) -C(O)NR6R7, 2) aryl or heterocycle, 3) halogen, 4) OR6, 5) NR6R7, 6) CN, 7) NO2, 8) CF3;
9) -S(O)mR6a, 10) -C(O)NR6R7, or 11) C3-C6 cycloalkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 0 or 1 ;
t is 0 or 1; and u is 4 or 5;
or an optical isomer or pharmaceutically acceptable salt thereof.

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

wherein:

R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, R10OC(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

R2 and R3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, or , wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, e) CN, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6a, S(O)R6a, SO2R6a, 5) ~NR6R7 , 6) , 7) , 8) , 9) , 10) , 11) ~SO2~NR6R7 , 12) , 13) , 14) , 15) N3, or 16) F; or R2 and R3 are attached to the same C atom and are combined to form -(CH2)u- wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R4 is selected from H and CH3;

and any two of R2, R3 and R4 are optionally attached to the same carbon atom;

R6, R7 and R7a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) ~SO2R11 , or g) N(R10)2; or R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) -SO2R11 , or g) N(R10)2;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroaLkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-,R10C(O)NH-,(R10)2NC(O)-, R102N-C(NR10)-, CN, 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-, (R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, 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-, (R10)2NC(O)-, R102N-C(NR10)-, CN, 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;
G is H2 or O;

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, provident 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 is -CH2-, -C(=O)-, or -S(=O)m-;

Z is a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR6a, or g) -C(O)NR6R7, 2) aryl or heterocycle, 3) halogen, 4) OR6, 5) NR6R7, 6) CN, 7) NO2, 8) CF3;
9) -S(O)mR6a, 10) -C(O)NR6R7, or 11) C3-C6 cycloalkyl;

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

provided that when G is H2 and W is imidazolyl, then the substitutent (R8)r- V - A1(CR1a2)n A2(CR1a2)n - is not H and provided that when X is -C(=O)-, or -S(=O)m-, then t is 1 and the substitutent (R8)r- V - A1(CR1a2)nA2(CR1a2)n - is not H;

or an optical isomer or pharmaceutically acceptable salt thereof.

3. A compound which inhibits farnesyl-protein transferase of the formula C:

wherein:

R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, R10OC(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

R2 and R3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, or , wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, e) CN, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6a, S(O)R6a, SO2R6a, 5) ~NR6R7 , 6) , 7) , .

8) , 9) , 10) , 11) ~SO2~NR6R7 , 12) , 13) , 14) , 15) N3, or 16) F; or R2 and R3 are attached to the same C atom and are combined to form -(CH2)u- wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R4 is selected from H and CH3;

and any two of R2, R3 and R4 are optionally attached to the same carbon atom;

R6, R7 and R7a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) ~SO2R11 , or g) N(R10)2; or R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) ~SO2R11 , or g) N(R10)2;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R10OC(O)NH-;

R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by perfluorolkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, 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;
G is O;

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 is -CH2-, -C(=O)-, or -S(=O)m-;

Z is a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR6a, or g) -C(O)NR6R7, 2) aryl or heterocycle, 3) halogen, 4) OR6, 5) NR6R7, 6) CN, 7) NO2, 8) CF3;
9) -S(O)mR6a, 10) -C(O)NR6R7, or 11) C3-C6 cycloalkyl;

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

4. The compound according to Claim 1 of the formula A:
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 C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R10O- and -N(R10)2;

R3, R4 and R5 are independently selected from H and CH3;

R2 is H; ; or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl, 2) heterocycle, 3) OR6, 4) SR6a, SO2R6a, or 5) ;

and any two of R2, R3, R4, and R5 are optionally attached to the same carbon atom;
R6, R7 and R7a are independently selected from:
H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with:
a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle;
R6a is selected from:
C14 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle;

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;

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 O and A2 is S(O)m;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;
X is -CH2- or -C(=O)-;

Y is mono- or bicyclic aryl, or mono- or bicyclic heterocycle, unsubstituted or substituted with one or more of:
a) C1-4 alkyl, b) C1-4 alkoxy, c) halogen, or d) NR6R7;

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 0 or 1; and t is 0 or 1;
or an optical isomer or pharmaceutically acceptable salt thereof.

5. The compound according to Claim 2 of the formula B:

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 C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R10O- and N(R10)2;

R3 and R4 are independently selected from H and CH3;

R2 is H; ; or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl, 2) heterocycle, 3) OR6, 4) SR6a, SO2R6a, or 5) ;

and any two of R2, R3, R4, and R5 are optionally attached to the same carbon atom;

R6, R7 and R7a are independently selected from:
H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with:
a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle;
R6a is selected from:
C1-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) halogen, or c) aryl or heterocycle;

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;

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;

G is H2 or O;

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

X is -CH2- or -C(=O)-;

Z is mono- or bicyclic aryl, mono- or bicyclic heteroaryl, mono- or bicyclic arylmethyl, mono- or bicyclic heteroarylmethyl, mono- or bicyclic arylsulfonyl, mono- or bicyclic heteroarylsulfonyl, unsubstituted or substituted with one or two of the following:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR6, or g) -C(O)NR6R7 2) aryl or heterocycle, 3) halogen, 4) OR6, S) NR6R7, 6) CN, 7) NO2, 8) CF3;
9) -S(O)m R6, 10) -C(O)NR6R7, or 11) C3-C6 cycloalkyl;

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

provided that when G is H2 and W is imidazolyl, then the substitutent (R8)r- V - A1(CR1a2)n A2(CR1a2)n - is not H and provided that when X is -C(=O)-, or -S(=O)m-, then t is 1 and the substitutent (R8)r- V - A1(CR1a2)n A2(CR1a2)n - is not H;

or pharmaceutically acceptable salt thereof.

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

2(S)-Butyl-1-(2,3-diaminoprop-1-yl)-4-(1-naphthoyl)-piperazine 1-(3-Amino-2-(2-naphthylmethylamino)prop-1-yl)-2(S)-butyl-4-(1-naphthoyl)piperazine 2(S)-Butyl-1-{5-[1-(2-naphthylmethyl)]-4,5-dihydroimidazol}methyl-4-(1-naphthoyl)piperazine 1-[5-(1-Benzylimidazol)methyl]-2(S)-butyl-4-(1-naphthoyl)piperazine 1-{5-[1-(4-Nitrobenzyl)imidazolyl]methyl}-2(S)-butyl-4-(1-naphthoyl)piperazine 1-(3-Acetamidomethylthio-2(R)-aminoprop-1-yl)-2(S)-butyl-4-(1-naphthoyl)piperazine 2(S)-Butyl-1-[2-(1-imidazolyl)ethyl]sulfonyl-4-(1-naphthoyl)piperazine 2(R)-Butyl-1-imidazolyl-4-methyl-4-(1-naphthoyl)piperazine 2(S)-Butyl-4-(1-naphthoyl)-1-(3-pyridylmethyl)piperazine 1-2(S)-Butyl-(2(R)-(4-nitrobenzyl)amino-3-hydroxypropyl)-4-(1-naphthoyl)piperazine 1-(2(R)-Amino-3-hydroxyheptadecyl)-2(S)-butyl-4-(1-naphthoyl)piperazine 2(S)-Benzyl-1-imidazolyl-4-methyl-4-(1-naphthoyl)piperazine 1-(2(R)-Amino-3-(3-benzylthio)propyl)-2(S)-butyl-4-(1-naphthoyl)-piperazine 1-(2(R)-Amino-3-[3-(4-nitrobenzylthio)propyl]))-2(S)-butyl-4-(1-naphthoyl)piperazine 2(S)-Butyl-1-[(4-imidazolyl)ethyl]-4-(1-naphthoyl)piperazine 2(S)-Butyl-1-[(4-imidazolyl)methyl]-4-(1-naphthoyl)piperazine 2(S)-Butyl-1-[(1-naphth-2-ylmethyl)-1H-imidazol-5-yl)acetyl]-4-(1-naphthoyl)piperazine 2(S)-Butyl-1-[(1-naphth-2-ylmethyl)-1H-imidazol-5-yl)ethyl]-4-(1-naphthoyl)piperazine 1-(2(R)-Amino-3-hydroypropyl)-2(S)-butyl-4-(1-naphthoyl)piperazine 1-(2(R)-Amino-4-hydroxybutyl)-2(S)-butyl-4-(1-naphthoyl)piperazine 1-(2-Amino-3-(2-benzyloxyphenyl)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine 1-(2-Amino-3-(2-hydroxyphenyl)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine 1-[3-(4-Imidazolyl)propyl]-2(S)-butyl-4-(1-naphthoyl)piperazine 2(S)-n-Butyl-4-(1-naphthoyl)-1-[1-(1-naphthylmethyl)imidazol-5-ylmethyl]-piperazine 2(S)-n-Butyl-4-(1-naphthoyl)-1-[1-(2-naphthylmethyl)imidazol-5-ylmethyl]-piperazine 2(S)-n-Butyl-1-[1-(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine 2(S)-n-Butyl-1-[1-(4-methoxybenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine 2(S)-n-Butyl-1-[1-(3-methyl-2-butenyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine 2(S)-n-Butyl-1-[1-(4-fluorobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine 2(S)-n-Butyl-1-[1-(4-chlorobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine 1-[1-(4-Bromobenzyl)imidazol-5-ylmethyl]-2(S)-n-butyl-4-(1-naphthoyl)piperazine 1-[1-(4-Bromobenzyl)imidazol-5-ylmethyl]-2(S)-n-butyl-4-(1-naphthoyl)piperazine 2(S)-n-Butyl-4-(1-naphthoyl)-1-[1-(4-trifluoromethylbenzyl)imidazol-5-ylmethyl]-piperazine 2(S)-n-Butyl-1-[1-(4-methylbenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)-piperazine 2(S)-n-Butyl-1-[1-(3-methylbenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)-piperazine 1-[1-(4-Phenylbenzyl)imidazol-5-ylmethyl]-2(S)-n-butyl-4-(1-naphthoyl)-piperazine 2(S)-n-Butyl-4-(1-naphthoyl)-1-[1-(2-phenylethyl)imidazol-5-ylmethyl]-piperazine 2(S)-n-Butyl-4-(1-naphthoyl)-1-[1-(4-trifluoromethoxy)-imidazol-5-ylmethyl]piperazine 1-{[1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetyl}-2(S)-n-butyl-4-(1-naphthoyl)piperazine 5(S)-n-Butyl-1-(2,3-dimethylphenyl)-4-(4-imidazolylmethyl)-piperazin-2-one 5(S)-n-Butyl-4-[1-(4-cyanobenzyl)imidazol-5-ylmethyl]-1-(2,3-dimethylphenyl)piperazin-2-one 4-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-1-(2,3-dimethylphenyl)-5(S)-(2-methoxyethyl)piperazin-2-one (S)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(methanesulfonyl)ethyl]-2-piperazinone (S)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)ethyl]-2-piperazinone (S)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone (S)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[N-ethyl-2-acetamido]-2-piperazinone (~)-5-(2-Butynyl)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone 1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone S(S)-Butyl-4-[1-(4-cyanobenzyl-2-methyl)-5-imidazolylmethyl]-1-(2,3-dimethylphenyl)-piperazin-2-one 4-[1-(2-(4-Cyanophenyl)-2-propyl)-5-imidazolylmethyl]-1-(3-chlorophenyl)-5(S)-(2-methylsulfonylethyl)piperazin-2-one 5(S)-n-Butyl-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-1-(2-methylphenyl)piperazin-2-one 4-[1-(4-Cyanobenzyl)-5-imidazolylmethyl]-5(S)-(2-fluoroethyl)-1-(3-chlorophenyl)piperazin-2-one 4-[3-(4-Cyanobenzyl)pyridin-4-yl]-1-(3-chlorophenyl)-5(S)-(2-methylsulfonylethyl)-piperazin-2-one 4-[5-(4-Cyanobenzyl)-1-imidazolylethyl]-1-(3-chlorophenyl)piperazin-2-one.
or a pharmaceutically acceptable salt or optical isomer thereof.

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

Table 1 Table 2 stereo. X Y
R n-Bu 2-O(CH2)13CH3 S n-Bu 2-O(CH2)13CH3 R n-Bu 2-O(CH2)11CH3 S n-Bu 2-O(CH2)11CH3 R n-Bu 2-O(CH2)9CH3 S n-Bu 2-O(CH2)9CH3 R n-Bu 2-O(CH2)7CH3 S n-Bu 2-O(cH2)7cH3 R n-Bu 2-O(CH2)3Ph S n-Bu 2-O(CH2)3Ph R n-Bu 3-OCH2Ph Table 2 (continued) stereo. X Y
S n-Bu 3-OCH2Ph R n-Bu 3-O(CH2)13CH3 S n-Bu 3-O(CH2)13CH3 R n-Bu 4-O(CH2)13CH3 S n-Bu 4-O(CH2)13CH3 S n-Bu 4-OCH2Ph R/S H 2-O(CH2)13CH3 Table 3 3-SO2Me Table 4 X Y
CH2OCH2Ph CF
CH2SO2Et CF
CH2SO2Ph CF3 CH2SO2Me Cl CH2SO2Et Cl CONHMe CF3 CONHEt CF3 CH2SO2Ph Cl CONHMe Cl CONHEt Cl CONHc-Pr Cl CONHc-Pr CF3 Table 4 (continued) X Y

NHCOMe Cl CONMe2 CF3 SO2Et Cl CH2SMe Cl (~) C~CMe Cl Table 5 X Y

CH2 3-Cl CH2CH2CO 3-Cl CH2 2,3-Cl2 CH2 2-Br CH2 4-Cl CH2CO 3-Cl CH2 3-Br Table 6 X Y Z

4-CN (CH2)2 4-CH2CH2CO

Table 7 X Y
4-Me CH2CH2SO2Me 4-Me H
2-Me H

2,3-(CH2)4 3-Cl 2-CH3, 3-Cl H

CH2CH2SO2CH(CH3)2 CH2CH2SCH(CH3)2 CH2CH2S(O)CH(CH3)2 TABLE 12 (continued) Table 17 R
Table 18 or or a pharmaceutically acceptable salt or optical isomer thereof.

8. The compound according to Claim 6 which is:

1- {5-[1-(4-nitrobenzyl)]imidazolylmethyl}-2(S)-butyl-4-(1-naphthoyl)piperazine , or a pharmaceutically acceptable salt thereof.

9. The compound according to Claim 6 which is:
1-[5-(1-Benzylimidazol)methyl]-2(S)-butyl-4-(1-naphthoyl)piperazine , or a pharmaceutically acceptable salt or optical isomer thereof.

10. The compound according to Claim 6 which is:

1-(2(R)-Amino-3-(3-benzylthio)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine , or a pharmaceutically acceptable salt or optical isomer thereof.

11. The compound according to Claim 6 which is:

1-(2(R)-Amino-3-[3-(4-nitrobenzylthio)propyl])-2(S)-butyl-4-(1-naphthoyl)piperazine , or a pharmaceutically acceptable salt or optical isomer thereof.

12. The compound according to Claim 6 which is:

2(S)-n-Butyl- 1-[1 -(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine , or a pharmaceutically acceptable salt or optical isomer thereof.

13. The compound according to Claim 6 which is:

2(S)-n-Butyl-1-[1-(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3-dimethylphenyl)piperazin-5-one , or a pharmaceutically acceptable salt or optical isomer thereof.

14. The compound according to Claim 6 which is:

2(S)-n-Butyl-1-[1-(4-chlorobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine , or a pharmaceutically acceptable salt or optical isomer thereof.

15. The compound according to Claim 6 which is:

1- {[1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetyl}-2(S)-n-butyl-4-(1-naphthoyl)piperazine , or a pharmaceutically acceptable salt or optical isomer thereof.

16. The compound according to Claim 6 which is:

1-[1-(4-Cyanobenzyl)irnidazol-5-ylmethyl]-4-(2,3-dimethylphenyl)-2(S)-(2-methoxyethyl)piperazin-5-one , or a pharmaceutically acceptable salt or optical isomer thereof.

17. The compound according to Claim 6 which is:

5(S)-n-Butyl-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-1-(2-methylphenyl)piperazin-2-one , or a pharmaceutically acceptable salt or optical isomer thereof.

18. The compound according to Claim 6 which is:

(S)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(methanesulfonyl)ethyl]-2-piperazinone , or a pharmaceutically acceptable salt or optical isomer thereof.

19. The compound according to Claim 6 which is:

(S)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)ethyl]-2-piperazinone , or a pharmaceutically acceptable salt or optical isomer thereof.

20. The compound according to Claim 6 which is:

(S)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone , or a pharmaceutically acceptable salt or optical isomer thereof.

21. The compound according to Claim 6 which is:

1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolyl-methyl]-2-piperazinone , or a pharmaceutically acceptable salt or optical isomer thereof.

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

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

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

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

26. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 22.

27. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 23.

28. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 24.

29. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 25.

30. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of the formula B:

wherein:

R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, R10OC(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

R2 and R3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, or , wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl, b) (CH2)p OR6, c) (CH2)p NR6R7, d) halogen, e) CN, 2) C3-6 cycloaLkyl, 3) OR6, 4) SR6a, S(O)R6a, SO2R6a, 5) ~NR6R7 , , , , , , 11) ~SO2~NR6R7 , , , , 15) N3, or 16) F; or R2 and R3 are attached to the same C atom and are combined to form - (CH2)u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R4 is selected from H and CH3;

and any two of R2, R3 and R4 are optionally attached to the same carbon atom;

R6, R7 and R7a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) ~SO2R11 , or g) N(R10)2; or R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, f) ~SO2R11 , or g) N(R10)2;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, 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-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, 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-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, 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;
G is H2;

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 Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(O)m;

W is imidazolyl;

X is -CH2-, -C(=O)-, or -S(=O)m-;

Z is a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)m R6a, or g) -C(O)NR6R7, 2) aryl or heterocycle, 3) halogen, 4) OR6, 5) NR6R7, 6) CN, 7) NO2, 8) CF3;
9) -S(O)m R6a 10) -C(O)NR6R7, or 11) C3-C6 cycloalkyl;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or4;
q is 1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 0 or 1 ;
t is 1; and u is 4 or 5;

provided that the substitutent (R8)r- V - Al(CR1a2)n A2(CR1a2)n - is H;
or a pharmaceutically acceptable salt thereof.

31. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective arnount of a pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of the formula:

wherein:

R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, R10OC(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

R2 and R3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, or , wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl, b) (CH2)p OR6, c) (CH2)p NR6R7, d) halogen, e) CN, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6a, S(O)R6a, SO2R6a, 5) ~NR6R7, , , , , , 11) ~SO2~NR6R7 , , , , 15) N3, or 16) F; or R2 and R3 are attached to the same C atom and are combined to form - (CH2)u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R4 is selected from H and CH3;

and any two of R2, R3 and R4 are optionally attached to the same carbon atom;

R6, R7 and R7a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, , f) ~SO2R11 , or g) N(R10)2; or R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, , f) ~SO2R11 , or g) N(R10)2;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R1OC(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, 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-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, 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-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, 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;
G is H2 or O;

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 is -C(=O)- or-S(=O)m-;

Z is a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)m R6a, or g) -C(O)NR6R7, 2) aryl or heterocycle, 3) halogen, 4) OR6, 5) NR6R7, 6) CN, 7) NO2, 8) CF3;
9) -S(O)m R6a, 10) -C(O)NR6R7, or 11) C3-C6 cycloalkyl;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or4;
p is 0, 1, 2, 3 or 4;
q is 1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 0 or 1;
t is 0 or 1; and u is 4 or 5;

provided that if t is 1, then the substitutent (R8)r- V - A1(CR1a2)n A2(CR1a2)n - is H;
or a pharmaceutically acceptable salt thereof.

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

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

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

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

36. 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 23.

37. 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 23.

38. 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 23.

39. A method for preventing restenosis which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 23.

40. 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 23.

41. A method for treating or preventing a disease selected from cancer, neurofibromin benign proliferative disorder, blindness related to retinal vascularization, infections from hepatitis delta and related viruses, restenosis and polycystic kidney disease, which comprises administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of the formula B:

wherein:

R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-, C(NR10)-, CN, R10C(O)-, R10OC(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

R2 and R3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, or , wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, e) CN, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6a, S(O)R6a, SO2R6a, 5) ~NR6R7 , , , , , , 11) ~SO2~NR6R7 , , , , 15) N3, or 16) F; or R2 and R3 are attached to the same C atom and are combined to form -(CH2)u- wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R4 is selected from H and CH3;

and any two of R2, R3 and R4 are optionally attached to the same carbon atom;

R6, R7 and R7a are independently selected from: H, C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, , f) ~SO2R11 , or g) N(R10)2; or R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, , f) ~SO2R11 , or g) N(R10)2;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, (R10)2NC(O)-, R10 2NC(NR10)-, CN, 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-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, 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-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, 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;
G is H2;

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 imidazolyl;

X is -CH2-, -C(=O)-, or -S(=O)m-;

Z is a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR6a, or g) -C(O)NR6R7, 2) aryl or heterocycle, 3) halogen, 4) OR6, 5) NR6R7, 6) CN, 7) NO2, 8) CF3;
9) -S(O)mR6a, 10) -C(O)NR6R7, or 11) C3-C6 cycloalkyl;

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

provided that the substitutent (R8)r- V - A1(CR1a2)nA2(CR1a2)n - is H;
or a pharmaceutically acceptable salt thereof.

42. A method for treating or preventing a disease selected from cancer, neurofibromin benign proliferative disorder, blindness related to retinal vascularization, infections from hepatitis delta and related viruses, restenosis and polycystic kidney disease, which comprises administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of the formula:

wherein:

R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2NC(NR10)-, CN, R10C(O)-, R10OC(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

R2 and R3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, or , wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, e) CN, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6a, S(O)R6a, SO2R6a, 5) ~NR6R7 , , , , , , 11) ~SO2~NR6R7 , , , , 15) N3, or 16) F; or R2 and R3 are attached to the same C atom and are combined to form -(CH2)u- wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R4 is selected from H and CH3;

and any two of R2, R3 and R4 are optionally attached to the same carbon atom;

R6, R7 and R7a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, , f) ~SO2R11 , or g) N(R10)2; or R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, , f) ~SO2R , or g) N(R10)2;

R8 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, (R10)2NC(O)-, R10 2NC(NR10)-, CN, 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-, (R10)2NC(O)-, R10 2NC(NR10)-, CN, NO2, 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-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, 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: abond, -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;
G is H2 or O;

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 is --C(=O)- or -S(=O)m-;

Z is a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
1) C1-4 alkyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, f) -S(O)mR6a, or g) -C(O)NR6R7, 2) aryl or heterocycle, 3) halogen, 4) OR6, 5) NR6R7, 6) CN, 7) NO2, 8) CF3;
9) -S(O)mR6a, 10) -C(O)NR6R7, or 11) C3-C6 cycloalkyl;

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

provided that if t is 1, then the substitutent (R8)r- V - A1(CR1a2)n A2(CR1a2)n - is H;
or a pharmaceutically acceptable salt thereof.