HRP960143A2 - Inhibitors of farnesyl-protein transferase - Google Patents

Description

Related application

According to the International Patent Classification, this invention belongs to group C07D-223/10.

This patent application is a partial continuation of the application from the pending application Serial No. 08/470, 690, filed on June 6, 1995, which is a partial continuation of the application from the pending application Serial No. 08/412, 829, filed March 29, 1995.

Condition of the vehicle

Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras, and N-Ras) are part of a signaling pathway that couples cell surface growth factor receptors to nuclear signals that promote cell proliferation. Biological and biochemical studies of Ras action show that Ras functions as a G-regulatory protein. In the inactive state, Ras is bound to GDP. Upon activation of the growth factor receptor, Ras is induced to exchange GDP with GTP and undergo a structural change. The GTP-bound form of Ras transmits the growth stimulatory signal until the signal is terminated 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)). Mutating ras genes (Ha-Ras, Ki4a-Ras, Ki4b-Ras, and N-Ras) have been found in many human cancers, including colorectal cancer, exocrine pancreatic cancer, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit the stimulatory signal Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif called “CAAX” or “Cys-Aaal-Aaa2-Xaa” ram (Cys is cysteine, Aaa is an aliphatic amino acid, Xaa is any amino acid), (Willumsen et al., Nature 310: 583-586 (1984)). Depending on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyzes the alkylation of the cysteine residues of the CAAX motif with a C15 or C20 isoprenoid (S. Clarke, Ann. Rev. Biochem. 61:355- 386 (1992); W.R. Schafer and J. Rine. Ann. Rev. Genetics 30: 209-237 (1992)). The Ras protein is one of several proteins known to undergo post-translational farnesylation. Other farnesylated proteins include Ras-related GTP-binding proteins such as Rho, fungal mating factors, nuclear lamins (platelets), and transducin gamma subunits. James, et al., J. Biol. Chem. 269 14182 (1994) identified the peroxisome-associated protein Pxf, which is also farnesylated. James, et al., also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.

Inhibition of farnesyl-protein transferase was shown to block the growth of ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. Certain farnesyl-protein transferase inhibitors have also been demonstrated to selectively block the processing of Ras intracellular oncoproteins (N. E. Kohl et al., Science, 260: 1937-1942 (1993) and G. L. James et al., Science, 260:1937-1942 (1993) More recently, a farnesyl-protein transferase inhibitor has been shown to block the growth of Ras-dependent tumors in nude mice (N. E. Kohl et al., Proc. Natl. Acad. Sci. U. S. A. 91419145 (1994)) and to induce regression of mammary and salivary carcinomas in Ras transgenic mice (N.E. Kohl et al., Nature Medicine, 1:792-797 (1995).

Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck & Co., Rahway, NJ) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al.

Science, 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate-limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Farnesyl-protein transferase uses farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX framework with a farnesyl group (Reiss et al., Cell. 62: 81-88 (1990); Schafer et al., Science, 249:1133-1139 (1990) ); Manne et al., Proc. Natl. Acad. Sci USA, 87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. However, direct inhibition of farnesyl protein transferase will be more specific and accompanied by the required dose of side effects than occurs with the required dose of a general inhibitor of isoprene biosynthesis.

Farnesyl-protein transferase (FPTase) inhibitors are described in two general classes. The first are analogs of farnesyl diphosphate (FPP), while the second class of inhibitors refers to protein substrates (eg, Ras) for the enzyme. Peptide-derived inhibitors that have been described are mostly molecules containing a cysteine related to the CAAX motif that is a signal for protein prenylation (Schaber et al., ibid; Reiss et al., ibid; Reiss et al., PNAS, 88:732-736 ( 1991)). Such inhibitors may inhibit protein prenylation while serving as alternative substrates for the enzyme farnesyl-protein transferase, or may be potential inhibitors (U.S. Patent 5,141,851, University of Texas; N.E. kohl et al., Science, 260:1934-1937(1993); Graham , et al., J. Med. Chem., 37,725 (1994)). In general, it has been shown that omitting the thiol from the CAAX derivative compound dramatically reduces the inhibitory potency of the compound. However, the thiol group potentially places limitations on the therapeutic use of FPTase inhibitors in terms of pharmacokinetics, pharmacodynamics, and toxicity. Therefore, a functional replacement for the thiol is preferred.

More recently, it has been reported that farnesyl-protein transferase inhibitors are inhibitors of the proliferation of vascular smooth muscle cells, and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic vascular disorders (JP H7 112930).

More recently, it has been described that certain tricyclic compounds can be incorporated into the piperidine moiety of FPTase inhibitors (WO 95/10514, WO 95/10515 and WO 95/10516).

Also described are imidazole-containing farnesyl-protein transferase inhibitors (WO 95/09001 and EP 0 675 112 A1).

Therefore, the subject of this invention is the development of peptidomimetic compounds that do not have a thiol part, and which will inhibit farensyl-protein transferase, and thus, post-translational farnesylation of proteins. Furthermore, the subject of this invention is the development of chemotherapeutic compositions containing compounds according to this invention, and to develop procedures for obtaining compounds according to this invention.

Brief description of the invention

The present invention encompasses peptidomimetic compounds containing a piperazine that inhibits farnesyl-protein transferase. These compounds do not have a thiol moiety and thus offer advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further, this invention provides chemotherapeutic compositions containing farnesyl-protein transferase inhibitors and methods for their preparation.

The compounds according to this invention are represented by formulas A, B and C:

[image]

Detailed description of the invention

The compounds of this invention are useful in inhibiting farnesyl-protein transferase and farnesylation of the oncogenic Ras protein. In the first embodiment of this invention, farensyl-protein transferase inhibitors are represented by formula A:

[image]

where 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)2N-C(O)-, CN, NO2, (R10) 2N-C(NR10)-, R10 C(O)-, R10OC(O)-, N3 -N(R10)2, or R11OC(O)NR10-,

c) unsubstituted or substituted C1-C6 alkyl, where the substituent on substituted C1-C6 is selected from unsubstituted or substituted aryl, heterocycle,

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

R 2 and R 3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-C8 alkenyl, unsubstituted or substituted C2-C8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle,

where the substituted supine is substituted with one or more of:

[image]

[image]

R2 and R3 are attached to the same C atom and are joined to form - (CH2) - where one of the carbon atoms is replaced by a moiety selected from: O, S(O)m, -NC(O) -, and -N (COR10)-

R 4 and R 5 are independently selected from H and CH 3 ;

and any two of R 2 , R 3 , R 4 and R 5 which may be attached to the same carbon atom;

R 6 , R 7 and R 7a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:

[image]

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,

[image]

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 with aryl, cyanophenyl; C3-C10 heterocycle,

cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, (R10)2NC(O)-, R102 N-C(NR10 )-, CN, R10C(O)-, R10-OC(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 with perfluoroalkyl,

F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, R10OC( O)-, N 3 , -N(R 10 ) 2 , or

R11OC(O)NR10,-;

R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;

R 11 is independently selected from C 1 -C 6 alkyl and aryl;

A1 and A2 are independently selected from: bonds -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 chosen by:

a) hydrogen,

b) heterocycle,

c) aril,

d) C1-C20 alkyl where from 0 to 4 carbon atoms are replaced by 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) 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, where the substituted aryl or substituted heterocycle is substituted with one or more:

1) C1-4 alkyl, unsubstituted or substituted with:

a) 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 pharmaceutically acceptable salts thereof.

In another embodiment of the present invention, farnesyl-protein transferase inhibitors are represented by formula B:

[image]

where are they:

R1a and R1b 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)-, H3, -N(R10)2, or R11OC(O)NR10-,

c) unsubstituted or substituted C1-C6 alkyl, where the substituent on substituted C1-C6 alkyl is chosen from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11(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,

[image]

of an unsubstituted or substituted heterocycle where it is substituted with one or more of:

[image]

[image]

[image]

R2 and R3 are attached to the same C atom and joined to form -(CH2)u- where one of the carbon atoms can be replaced with a moiety selected from: O, S(O)m, -NC(O)-, and - N(COR10)-;

R 4 is selected from H and CH 3 ;

and any two of R 2 , R 3 and R 4 may be attached to the same carbon atom.

R 6 , R 7 and R 7a are independently selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:

[image]

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:

[image]

R8 is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F,Cl,R10O-R11S(O)m-, R10C(O)NR10-, (R10)2NC(O) -, R10OC(O)-, R102N-C(NR10)-CN,NO2, R10OC(O)NR10-; and

c) C1-C6 alkyl, unsubstituted or substituted with 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)-, N-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)2 NC(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 with perfluoroalkyl. F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR, (R10)2NC(O)-, R10 2N-C(NR)-, R10C(O)-, R10OC(O) -, N3, -N(R10)2, or R11OC(O)NR10-;

R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;

R 11 is independently selected from C 1 -C 6 alkyl and aryl;

A1 and A2 are independently selected from: bonds, -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 H 2 or O;

V is chosen by:

a) hydrogen,

b) heterocycle,

c) aril,

d) C1-C20 alkyl where from 0 to 4 carbon atoms are replaced by a heteroatom selected from O, S, and N, and

e) C1-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 an unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, where 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;

or pharmaceutically acceptable salts thereof.

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

[image]

where are they:

R1a and R1b 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, where the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 alkyl, cycloalkyl, C2-C6 alkyl, alkenyl, C2-C6 alkyl, alkynyl, R102N - C(NR10)-, CN, R10C(O)-, R10OC(O)-, -N(R10)2, and R11OC(O)-NR10-;

R 2 and R 3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-C8 alkynyl, unsubstituted or substituted aryl,

[image]

unsubstituted or substituted heterocycle,

where the substituted group is substituted with one or more of:

1) aryl or heterocycle, unsubstituted or substituted with:

e) CN,

[image]

a) C1-4 alkyl,

b) (CH2)pOR6,

c) (CH2)pNR6R7,

d) halogen,

[image]

R2 and R3 are attached to the same C atom and combine to form -(CH2)u- where one of the carbon atoms can be replaced by a moiety selected from: O, S(O)m, -NC(O) -, and -N(COR10)-;

R 4 is selected from H and CH 3 ;

and any two of R2, R3, R4 can be attached to the same carbon atom;

R 6 , R 7 and R 7a are independently selected from H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:

[image]

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:

[image]

R8 is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F,Cl,R10O-,R11S(O)m-, R10C(O)NR10-, (R10)2NC(O )-, R10OC(O)-, R102N-C(NR10)-CN,NO2,R10OC(O)NR10-; and

c) C1-C6 alkyl unsubstituted or substituted with aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, perfluoroalkyl, F, Cl, R10O-, R11S(O)m-R10C(O)NH-,-( R10)2NC(O)-,(R10)2N,C(NR10)-,CN,R10C(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 with 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 R11 OC(O)NR10-, N(R10)2, or

R11 OC(O)NR10-;

R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;

R 11 is independently selected from C 1 -C 6 alkyl and aryl;

A1 and A2 are independently selected from: bonds, -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) aril,

d) C1-C20 alkyl wherein about 0 to 4 carbon atoms are replaced by 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)-, -S(O)m-;

Z is an unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, where the substituted group is substituted with one or more of the following:

1) C1-4 alkyl, unsubstituted or substituted with:

a) C1-4Alkoxy,

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) C3-6 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=0 when V is hydrogen;

s is 1;

t is 0 or 1; and

u is 4 or 5;

or pharmaceutically acceptable salts thereof.

The primary embodiment of the compound according to this invention is shown by the following formula:

[image]

R1a was independently selected from

R1b was independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, R10O-, -N(R10)2 or C2-C6 alkenyl,

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

R 3 , R 4 and R 5 are independently selected from H and CH 3 ;

[image]

R2 is H, or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:

1) aril,

2) heterocycle,

3) OR6,

4) SR6a, SO2R6a, or

[image]

and any two of R 2 , R 3 , R 4 , and R 5 may be attached to the same carbon atom;

R6, 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) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F,Cl,R10O-,R11S(O)m-, R10C(O)NR10-, (R10)2NC(O )-, R10OC(O)-, R102N-C(NR10)-CN,NO2, R10OC(O)NR10-; and

c) C1-C6alkyl unsubstituted or substituted with aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, perfluoroalkyl, F, CI, R10O-,R11 S(O)m-R10C(O)NH-,-( R10)2NC(O)-, (R10)2N, C(NR10)-, CN, R10C(O)-, N3, -N(R10)2 or R10OC(O)NH-;

R9 is selected from:

a) hydrogen,

b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11 S(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 with perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10OC(O)NR10-, R10)2NC(O)-, R102N-C(NR10)- , CN, R10C(O)-, R10OC(O)-, N3, N(R10)2, or R11OC(O)NR10-, N(R10)2, or R11OC(O)NR10-;

R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;

R 11 is independently selected from C 1 -C 6 alkyl and aryl;

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

V is chosen by:

a) hydrogen,

b) a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl,

c) aril,

d) C1-C20 alkyl where from 0 to 4 carbon atoms are replaced by a heteroatom selected from O, S, and N, and

e) C2-C20 alkenyl, and provided that V is not hydrogen if A1 is S(O)m, and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;

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

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

Y is mono- or bi-cyclic aryl, or mono- or bi-cyclic heterocycle, unsubstituted or substituted with one or more of:

a) C1-4 alkyl,

b) C1-4Alkoxy,

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 pharmaceutically acceptable salts thereof.

In another preferred embodiment of the present invention, farensyl-protein transferase inhibitors are represented by formula B:

[image]

where is:

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

R1b was independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, R10O-, -N(R10)2 or C2-C6 alkenyl,

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

R 3 and R 4 are independently selected from H and CH 3 ;

[image]

R 2 is H;

or C1-5 alkyl, unbranched or branched unsubstituted or substituted with one or more of:

[image]

and any two of R 2 , R 3 , R 4 and R 5 may be 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) C1-4Alkoxy,

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) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O )-, R10OC(O)-, R102N-C(NR10)-CN, NO2, R10OC(O)NR10-; and

C) C1-C6 alkyl unsubstituted or substituted with aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, perfluoroalkyl, F, Cl, R10O-, R11S(O)m- R10C(O)NH-,-( R10)2NC(O)-,(R10)2N,C(NR10)-,CN,R10C(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 R11 OC(O)NR10-, i

c) C1-C6 alkyl unsubstituted or substituted with 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 R11 OC(O)NR10-, N(R10)2, or R11 OC(O)NR10-;

R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;

R 11 is independently selected from C 1 -C 6 alkyl and aryl;

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

V is chosen by:

a) hydrogen

b) a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinite, indolyl, quinolinyl, isoquinolinyl, and thienyl,

c) aril,

d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced by a heteroatom selected from O, S, and N, and

e) C2-C20 alkenyl, i

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 H 2 or O;

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

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

Z is mono- or bi-cyclic aryl, mono- or bi-cyclic heteroaryl, mono- or bi-cyclic arylmethyl, mono- or bi-cyclic heteroarylmethyl, mono- or bi-cyclic arylsulfonyl, mono- or bi-cyclic heteroarylsulfonyl, unsubstituted or substituted with one or two of the following:

1) C1-4 alkyl, unsubstituted or substituted with:

a) C1-4 Alkoxy,

b) R6R7,

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.

5) NR6R7,

6) CN,

7) NO2,

8) CF3,

9) -S(O)mR6,

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;

u is 4 or 5;

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;

u is 4 or 5;

provided that when G is H2 and W is imidazolyl, then the substituent (R8)r -V-A1 (CR1a2)n -is not H and

provided that when X is -C(=O)-, or -S(=O)m-, then t is 1 and the substituent (R8)r-V-A1 (CR 1a2)n A2 (CR 1a2)n - is not H ;

or pharmaceutically acceptable salts thereof.

The primary compounds of this invention are as follows:

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-dihydroimidazole} methyl-4-(1-naphthoyl)piperazine

1-/5-(1-benzylimidazole)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-hydropropyl)-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-(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

5(S)-butyl-4-(1-(4-cyanobenzyl-2-methyl)-5-imidazolylmethyl)-1-(2,3-dimethylphenyl)-piperazin-2-ene

4-/1-(2-(4-cyanophenyl)-2-propyl)-5-imidazolylmethyl/-1-(3-chlorophenyl)-5(S)-(2-methylsulfonylethyl)-piperazin-2-ene

5(S)-n-butyl-4-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-1-(2-methylphenyl)-piperazin-2-ene

4-/1-(4-cyanobenzyl)-5-imidazolylmethyl/-5(S)-(2-fluoroethyl)-1-(3-chlorophenyl)-piperazin-2-ene

4-/3-(4-cyanobenzyl)pyridin-4-ene/-1-(3-chlorophenyl)-5(S)-(2-methylsulfonethyl)-piperazin-2-ene

4-(5-(4-cyanobenzyl)-1-imidazolylethyl)-1-(3-chlorophenyl)-piperazin-2-ene

or pharmaceutically acceptable salts thereof.

Specific examples of strains according to the invention are:

1-{5/1-(4-nitrobenzyl)imidazolyl/methyl}-2(S)-butyl-4-(1-naphthoyl)-piperazine

[image]

1-/5-(1-benzylimidazole)methyl/-2(S)-butyl-4-(1-naphthoyl)-piperazine

[image]

1-(2(R)-amino-3-(3-benzylthio)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine

[image]

1-(2(R)-amino-3-(3-(4-nitrobenzylthio)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine

[image]

2 (S)-n-butyl-1-(1-(4-cyanobenzyl)imidazol-5-ylmethyl)-4-(1-naphthoyl)piperazine

[image]

2(S)-n-butyl-1-(1-(4-cyanobenzyl)imidazol-5-ylmethyl)-4-(2,3-dimethylphenyl)piperazin-5-one

[image]

2 (S)-n-butyl-1-(1-(4-chlorobenzyl)imidazol-5-ylmethyl)-4-(1-naphthoyl)piperazine

[image]

1-{/1-(4-cyanobenzyl)-1H-imidazol-5-yl/acetyl/}-2(S)-n-butyl-4-(1-naphthoyl)piperazine

[image]

1-(1-(4-cyanobenzyl)imidazol-5-ylmethyl)-4-(2,3-dimethylphenyl)-2(S)-(2-methoxyethyl)piperazin-5-one

[image]

5 (S)-n-butyl-4-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-1-(2-methylphenyl)piperazin-2-one

[image]

(S)-1-(3-chlorophenyl)-4-/1-(4-cyanobenzyl)-5-imidazolyl-methyl/-5-/2-(methanesulfonyl)ethyl/-2-piperazinone

[image]

(S)-1-(3-chlorophenyl)-4-(1-(4-cyanobenzyl)-5-imidazolylmethyl-5-(2-(ethanesulfonyl)ethyl)-2-piperazinone

[image]

(S)-1-(3-Chlorophenyl)-4-[1,(4-cyanobenzyl)-5-imidazolylmethyl]-5-(2-(ethanesulfonyl)methyl)-2-piperazinone

[image]

1-(3-chlorophenyl)-4-(1-(4-cyanobenzyl)-5-imidazolyl-methyl)-2-piperazinone

[image]

component, its definition at each occurrence is independent at every other occurrence. Also, combinations of substituents/or variable sizes are allowed only if such combinations give stable compounds.

As used herein, "alkyl" is intended to include branched or normal chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms; "Alkoxy" represents an alkyl group with the indicated number of carbon atoms attached via an oxygen bridge. "Halogen" or "halo" as used herein refers to fluorine, chlorine, bromine and iodine.

As used herein, “aryl” is intended to denote any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, where at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, diphenyl, phananthryl, anthryl or acenaphthyl.

The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bi-cyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and including any bicyclic group in which any of the above-defined heterocyclic rings are fused to a benzene ring. A heterocyclic ring can be attached to any heteroatom or carbon atom, which leads to the formation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzoimidazolyl, benzoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone.

As used herein "heteroaryl" is intended to denote any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, where at least one ring is aromatic and where from one to four carbon atoms are replaced with heteroatoms selected from from the group consisting of N, O, and S. Examples of such heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, quinolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl/pyrazinyl, pyrazolyl, pyradazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl , thienothienyl, and thienyl.

As used herein in the definition of R 2 and R 3 , the term “substituted group” is intended to denote a substituted C 1-8 alkyl, substituted C 2-8 alkenyl, substituted C 2-8 alkynyl, substituted aryl, or substituted heterocycle from which the substituents R 2 and R3 selected.

As used herein in the definition of R6, R7, and R7a, substituted C1-8 alkyl, substituted C3-6 alkenyl, substituted aroyl, substituted aryl, substituted heteroaryl, substituted arylsulfonyl, substituted heteroarylsulfonyl, and substituted heterocycle include moieties containing from 1 to 3 substituents next to the binding site for the rest of the compound.

As used herein, the term “substituted aryl” is intended to include an aryl group that is substituted with 1 or 2 substituents selected from the group including but not limited to F, Cl, Br, CFs, NH2, N (C1-C6 alkyl)2, NO2, CN, (C1-C6 alkyl) O-, -OH, (C1-C6 alkyl)S(O)m-, (C1-C6 alkyl)C(O)NH-, H2N-C( NH)-, (C1-C6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)-, N3, (C1-C6 alkyl)OC(O)NH-, and C1-C20 alkyl.

When R2 and R3 are combined to form -(CH2)u-, cyclic moieties are obtained. Examples of such cyclical parts include, but are not limited to:

[image]

In addition, such cyclic moieties can be incorporated with a heteroatom. Examples of such heteroatom-containing cyclic moieties include, but are not limited to:

[image]

Lines drawn in ring systems of substituents (such as those of R 2 , R 3 , R 4 , etc.) indicate that the depicted bond may be attached to any of the substitutable carbon atoms.

Preferably, R1a and R1b are independently selected from: hydrogen, -N(R10)2, R10C(O)NR10-or unsubstituted or substituted C1-C6 alkyl, where the substituent on the substituted C1-C6 is alkyl, where the substituent on the substituted C1 -C6 alkyl selected from unsubstituted or substituted phenyl, -N(R10)2, R10O-, and R10C(O)NR10-.

Preferably, R2 is selected from: H,

[image]

and unsubstituted or

substituted groups, and this group is selected from C1-8 alkyl, C2-8 alkenyl and C2-8 alkynyl; where the substituted group is s

one or more of:

[image]

[image]

Preferably, R 3 is selected from: hydrogen and C 1 -C 6 alkyl.

Primarily, R 4 and R 5 are hydrogen.

Preferably, R 6 , R 7 and R 7a are selected from: hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted aryl, and unsubstituted or substituted cycloalkyl.

Preferably, R6a is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted aryl, and unsubstituted or substituted cycloalkyl.

Preferably, R 9 is hydrogen or methyl. Most preferably, R6a is hydrogen.

Preferably R 10 is selected from H, C 1 -C 6 alkyl and benzyl. Primarily A1 and A2 are independently selected from: bonds, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, -S(O)2N(R10)- and N(R10) 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, unsubstituted or substituted thienyl. More preferably, Z is unsubstituted or substituted phenyl.

Primarily, n and r are independently 0, 1, or 2.

Primarily, p is 1, 2 or 3.

Primarily s is 0.

Primarily t is 1.

Primarily, in compounds of formula B, when X

-C(=O)-, or -S(=O)m-, then t =1 and the substituent (R8)r - V -A1(CR1a2)nA2(CR1a2)n - is not H;

The definition for any substituent or variable (eg, R1a, R9, n, etc.) at a particular position in a molecule is intended to be independent of its definition elsewhere in that molecule.

Thus, -N(R10)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that the substituents and substitution models on the compounds according to this invention can be chosen by a person skilled in the art in order to provide compounds that are chemically stable and which can be easily synthesized, by techniques known in the art, as well as by those procedures shown below, from readily available starting materials.

Pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention as formed, for example, from non-toxic inorganic or organic acids. For example, such common non-toxic salts include those derived from acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxymaleic, phenyl-acetic, glutamic, benzene, salicylic, sulfanilic, 2-acetoxy -benzene, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isoethionic, trifluoroacetic and similar acids.

Pharmaceutically acceptable salts of the compounds according to the present invention can be synthesized from the compounds according to the present invention which contain a base moiety, by conventional chemical methods the salts are obtained either by ion exchange chromatography or by reaction of the free base with stoichiometric amounts or with an excess of the desired inorganic or organic acid which forms salts in a suitable solvent or different combinations of solvents.

The reactions used to obtain the compounds of this invention, using reactions as shown in Schemes 1-22, in addition to other standard manipulations, such as hydrolysis of esters, cleavage of protecting groups, etc., as known from the literature or experimental procedures given by examples. Substituents R1, R1a and R1b, as shown in the schemes, represent substituents R2, R3, R4 and R5; however their location of attachment to the ring is merely illustrative and not intended to be restrictive.

These reactions can be used in a linear sequence to provide compounds. according to the present invention or can be used to synthesize moieties that are subsequently joined by the alkylation reactions described in the schemes.

Synopsis Scheme 1-22

The necessary intermediates are in some cases commercially available, or for the most part they can be obtained according to literature procedures. For example, in Scheme 1, the synthesis of 2-alkyl substituted piperazines is shown, and substantially described by J. S. Kiely and S. R. Priebe in Organic Preparations and Proceedings Int., 1990, 22, 761-768. Boc-protected amino acids 1, which are commercially available or by methods known to those skilled in the art, can be coupled with N-benzyl amino acid esters using various dehydrating agents, such as DCC (dicyclohexycarbodiimide) or EDC HCl (1-ethyl-3-(3 -dimethylaminopropyl carbodiimide chloride) in a solvent such as methylene chloride, chloroform, dichloroethane, or in dimethylformamide. The product II is then deprotected with an acid, for example, hydrogen chloride in chloroform or ethyl acetate, or trifluoroacetic acid in methylene chloride, and cyclization under under weakly basic conditions, giving diketopiperazine III. Reduction of III with lithium aluminum chloride in ether at reflux gives piperazine IV, which is protected as the Boe derivative V. The N-benzyl group can be cleaved off under standard hydrogenation conditions, e.g., 10% palladium on coal, at 60 psi of hydrogen on a Parr apparatus in 24-48 hours Product VI may be treated with acid chloride, or carbonic acid under standard under dehydration conditions, whereby carboxyamides VII are obtained; Final acid deprotection, as described earlier, affords intermediate VIII (Scheme 2). Intermediate VIII can be reductively alkylated with various aldehydes, such as IX. Aldehydes can be prepared by standard procedures, as described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses. 1988. 67, 69-75 from the appropriate amino acid (Scheme 3). Reductive alkylation can be carried out at pH 5-7 with various reducing agents, such as sodium triacetoxyborohydride or sodium cyanoboride in a solvent such as dichloroethane, methanol or dimethylformamide. Product X can be deprotected with trifluoroacetic acid in methylene chloride to give the final compounds XI. The final product XI is isolated in salt form, for example, as the trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine XI, which can subsequently be reductively alkylated with another aldehyde, whereby XIII is obtained. Removal of the protecting group, and conversion to cyclized products such as dihydroimidazole XV can be achieved by literature procedures.

Alternatively, the protected piperazine intermediate VII can be reductively alkylated with other aldehydes such as 1-trityl-4-imidazolyl-carboxyaldehyde or 1-trityl-4-imidazolylacetaldehyde to give products such as XVI to give XVII, or alternatively , XVI can be first treated with an alkyl halide and then subsequently deprotected, yielding the alkylated imidazole XVIII. Alternatively, intermediate VIII can be acylated or sulfonylated by standard techniques, Imidazole acetic acid XIX can be converted to acetate XXI by standard procedures, and XXI can be first reacted with an alkyl halide and then treated with methanol at reflux to afford a regiospecific 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 piperazine VIII is reductively alkylated with an aldehyde that also has a protected hydroxyl group, such as XXV in Scheme 6, the protecting groups can subsequently be removed to unmask the group (Schemes 6, 7). An alcohol can oxidize under standard conditions, for example, an aldehyde, which can then react with various organometallic reagents, such as Grignard reagents, to give secondary alcohols, such as XXIX. In addition, the fully deprotected amino alcohol XXX can be reductively alkylated (under the conditions described earlier) with various aldehydes to give secondary amines, such as XXXI (Scheme 7), or tertiary amines.

The Boc-protected amino alcohol XXVII can also be used to synthesize 2-azirylmethylpiperazines such as XXXII (Scheme 8). Treatment of XXVII with 1,1-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide leads to the formation of aziridine XXXII. Aziridine reacts in the presence of a nucleophile, such as a thiol, in the presence of a base to give the ring-opened product XXXIII.

In addition, piperazine VIII can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to give compounds such as XXXIX. When R' is an aryl group. XXXIX must first be hydrogenated to unmask the phenol, and deprotect the amino group with acid, yielding XL. Alternatively, the amine protecting group in XXXIX can be removed, yielding O-alkylated phenolic amines such as XLI.

Depending on the identity of the amino acid l, different side chains can be incorporated into the piperazine. For example, when 1 is a Boc-protected B-benzyl ester of aspartic acid, the intermediate diketopiperazine XLll is obtained where n=1 and R=benzyl, as shown in Scheme 10. Subsequent lithium aluminum hydride reduction reduces the ester to alcohol XLIII , which can then be reacted with various alkylating agents such as alkyl iodide, under basic conditions, for example, sodium hydride in dimethylformamide or tetrahydrofuran. The resulting ether XLIV can then be carried to the final products as described in Schemes 3-9.

N-Aryl piperazines can be described in Scheme 11. Aryl amine XLV is reacted with bis-chloroethyl amine hydrochloride (XLVI) in refluxing n-butanol to give compounds XLVII. The resulting piperazines XLVII can then be carried to the final products as described in Schemes 3-9.

Piperazin-5-ones can be prepared as shown in Scheme 12. Reductive amination of Boc-protected amino aidehides XLIX (obtained from l as described earlier) leads to compound L. This compound is then reacted with bromo-acetyl bromide under “ Schotten-Baumann" conditions; ring closure is achieved with a base such as sodium hydride in a polar aprotic solvent such as dimethylformamide, whereby s yields LI. The carbamate protecting group is removed under acidic conditions such as trifluoroacetic acid in methylene chloride, hydrogen chloride gas in methanol, or acetate, and the resulting piperazine can then be routed to the final products, as described in Schemes 3-9.

The isomeric piperazin-3-ones can be prepared as described in Scheme 13. The imine derived from arylcarboxamide LII and 2-aminoglycinal diethyl acetyl (LIII) can be reduced under various conditions, including sodium triacetoxyborohydride in dichloroethane, to give amine LIV . Amino acids l can be cyclized to unsaturated LVI with amines LIV under standard conditions, and the resulting amide LV, when treated with aqueous acid in tetrahydrofuran. Catalytic hydrogenation under standard conditions affords the required intermediate LVII, which is processed to the final products as described in Schemes 3-9.

The approach to alternatively substituted piperazines is described in Scheme 14. After deprotection with trifluoroacetic acid, N-benzyl piperazine V can be acylated with an aryl carboxylic acid. The resulting N-benzyl aryl carboxyamide LIX can be hydrogenated in the presence of a catalyst to give the piperazine carboxyamide LX which can then be progressed to the final products as described in Schemes 3-9.

Reaction Scheme 15 provides an illustrative example of the synthesis of compounds of this invention where the substituents R 2 and R 3 are combined to form -(CH 2 )-. For example, 1-aminocyclohexane-1-carboxylic acid LXI can be converted to spiropiperazine LXVI essentially according to the procedures outlined in Schemes 1 and 2. The piperazine intermediate LXX can be deprotected as described in Schemes 3-9. It is understood that the reagents used to provide the substituent Y which is a -2-(naphthyl) and imidazolylalkyl substituent can be easily exchanged with other reagents well known in the art and readily available, thereby creating other N-substituents on the piperazine.

Aldehyde XLIX of Scheme 12 can also be reductively alkylated with aniline as shown in Scheme 16.

Product LXXI can be converted to piperazinone by acylation with chloroacetic chloride to give LXXII, followed by base-induced cyclization to LXXIII. Deprotection followed by reductive alkylation with a protected imidazole carboxyaldehyde gives LXXV, which can be alkylated with an arylmethylhalide to give the imidazolium salt LXXVI. Final deprotection either by 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 products LXXVII.

Scheme 17 shows the possible use of the substituted homoserine lactone LXXIX to obtain the Boc-protected piperazinone LXXXII. Intermediate LXXXII can be deprotected and reductively alkylated as shown in the previous Schemes. Alternatively, the hydroxy moiety of intermediate LXXXII can be mesylated (by introducing methylsulfonyl groups) and replaced with a suitable nucleophile, such as the sodium salt of ethylmercaptan, to give intermediate LXXXIII. Intermediate LXXXII can also be oxidized to form a carboxylic acid on intermediate LXXXIV, which can be used to form an ester or amide moiety.

Amino acids of general formula LXXXVI having a side chain not found in natural amino acids can be prepared by the reactions shown in Scheme 18 starting with the readily available imine LXXXV.

Schemes 19-22 depict the syntheses of suitably substituted aldehydes useful in the syntheses of the compounds of this invention where a variable size of W is present as the pyridyl moiety. Similar synthetic strategies for obtaining alkanols incorporating other heterocyclic moieties for variable W size are also well known in the art.

SCHEME 1

[image]

SCHEME 2

[image]

SCHEME 3

[image]

SCHEME 3 (continued)

[image]

SCHEME 4

[image]

SCHEME 5

[image]

SCHEME 5 (continued)

[image]

SCHEME 6

[image]

SCHEME 6 (CONTINUED)

[image]

SCHEME 7

[image]

SCHEME 8

[image]

SCHEME 9

[image]

SCHEME 9 (continued)

[image]

SCHEME 10

[image]

SCHEME 11

[image]

SCHEME 12

[image]

SCHEME 12 (CONTINUED)

[image]

SCHEME 13

[image]

SCHEME 14

[image]

SCHEME 15

[image]

SCHEME 15 (continued)

[image]

SCHEME 16 [image]

SCHEME 16 (continued)

[image]

SCHEME 17

[image]

SCHEME 17 (continued)

[image]

SCHEME 18

[image]

REACTION SCHEME 19

[image]

REACTION SCHEME 20

[image]

REACTION SCHEME 21

[image]

REACTION SCHEME 22

[image]

These compounds, according to the present invention, are useful as pharmaceutical agents for mammals, especially humans. These compounds can be applied to patients in the treatment of cancer. Examples of cancer types that can be treated with compounds of the present invention include, but are not limited to, colorectal cancer, exocrine pancreatic cancer, myeloid leukemia, and neurological tumors. Such tumors can arise from mutations in the ras genes themselves, mutations in proteins that can regulate activity (ie, neurofibromin (NF-I), neu, scr., Ick, fyn) or other mechanisms.

The compounds of the present invention inhibit farnesyl-protein transferase and farnesylation of the oncogenic Ras protein. These compounds also inhibit tumor angiogenesis, thereby affecting tumor growth (J. Rak et al., Cancer Research, 55:4575-4580 (1995). Such anti-angiogenic properties of certain types of adhesives are associated with rectal vascularization.

The compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, where Ras proteins are abnormally activated as a result of oncogenic mutations in other genes (ie, the Ras gene itself is not activated by mutation to an oncogenic form) with inhibition that is accompanied by the administration of an effective amount of the compounds of the present invention to a mammal to which it is a benign proliferative disruptor.

These compounds may also be useful in the treatment of certain viral infections in the treatment of hepatitis delta and related viruses (J.S. Glenn et al., Science. 256:1331-1333 (1992).

The compounds of this invention are also useful in preventing restenosis (occurrence of stenosis) after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al., Nature medicine, 1:541-545 (1995).

The compounds of this invention may also be useful in the treatment and prevention of polycystic kidney diseases.

(D. L. Schaffner et al., American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr., et al., FASEB Journal, 2:A3 160 (1988)).

The compounds of the present invention may also be useful in the treatment of fungal infections.

The compounds of this invention can be administered to mammals, primarily humans, either alone or, above all, in admixture with pharmaceutically acceptable carriers or diluents, such as alums, in pharmaceutical compositions, according to standard pharmaceutical practice, which can be administered orally or parenterally. , including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

For oral use of a chemotherapeutic compound according to the present invention, the selected compound can be administered, 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 commonly used include lactose in corn starch, and lubricants such as magnesium stearate are usually added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active component is mixed with emulsion and suspending agents. If desired, certain sweeteners and/or spices may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active component are usually obtained, and the pH of the solution should be adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to make an isotonic preparation.

The compounds of the present invention may also be administered in conjunction with other well-known therapeutic agents selected for their particular utility against the disease being treated. For example, the compounds of the present invention may be useful in combination with known anti-cancer and cytotoxic agents. Similarly, the compounds of this invention may be useful in combination with agents effective in the treatment and prevention of NF-1, restinosis, polycystic kidney disease, hepatitis delta and related virus infections, and fungal infections.

If formulated as a fixed dose, such combination products utilize the compounds of this invention within the dosage limits described below and other pharmaceutically active agents within the validated dosage limits. The compounds of this invention may alternatively be used in sequence with a pharmaceutically known acceptable agent(s), when a combined formulation is not suitable.

The present invention also encompasses a pharmaceutical composition for use in the treatment of cancer, comprising the administration of an effective amount of the compounds of the present invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of the present invention include aqueous solutions comprising the compounds of the present invention and pharmacologically acceptable carriers, eg, saline at a pH level of, eg, 7.4. The solutions can be introduced into the patient's bloodstream by local bolus injection.

When the compounds of this invention are administered to a human subject, the daily dosage will normally be determined by the prescribing physician with dosages usually varying with respect to age and weight, and the response of each individual patient, as well as the severity of the patient's symptoms.

In one preferred application, a suitable amount of the compound is administered to a mammal undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg body weight to about 60 mg/kg body weight to about 40 mg/kg body weight per day.

The compounds of this invention are also useful as a component in any assay for the rapid determination of the presence, in any assay for the rapid determination of the presence and amount of farensyl-protein transferase (FPTase) in the composition. Accordingly, the composition to be tested can be divided into two portions which are contacted with mixtures containing a known FPTase substrate (for example, a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the present invention . As the assay mixtures are incubated for a sufficiently long period of time, well known in the art, to allow FPTase to be determined by well known immunological, radiochemical or chromatographic techniques. Since the compounds of this invention are selective FPTase inhibitors, the absence of a quantitative decrease in the amount of substrate in an assay mixture without a compound of this invention relative to the presence of unchanged substrate in an assay containing a compound of this invention is indicative of the presence of FPTase in the composition to be tested.

It will be readily apparent to those skilled in the art that such an assay as described above will be useful in identifying cell samples containing farnesyl-protein transferase and quantifying the enzyme. Accordingly, the potent inhibitory compounds of the present invention can be used in an active site titration assay to determine the amount of enzyme in a sample. A series of samples consisting of aliquots of cell extracts containing unknown amounts of farnesyl-protein transferase, excess amounts of a known FPTase substrate (eg, a tetrapeptide that is cysteine at the same amine terminus), and farnesyl pyrophosphate are incubated for a suitable period of time in the presence of of different concentrations of compounds according to this invention. The concentration of a strong enough inhibitor (ie, one that has a Ki significantly lower than the enzyme concentration in the assay vessel) required to inhibit the enzyme activity of a sample by 50% is approximately equal to half the enzyme concentration in the sample just determined.

Examples

The examples provided are intended for further understanding of the invention. Certain materials used, types and conditions are intended to be further illustrative and not limiting of the invention, within their reasonable scope. Purification by HPLC is achieved with a 40 X 100 mm Waters PrePak reverse phase HPLC column (Delta-Pak™ C18 15μm, 100 Å). Gradient elution used 0.1% trifluoroacetic acid in water (Solvent A) and 0.1% trifluoroacetic acid in acetonitrile (Solvent B). Chloride salts are obtained by passing an aqueous solution of the salt of trifluoroacetic acid through a Biorad AG 3 X 4 ion exchange resin in a column (100-200 mix, Cl-form). HPLC purification was used for each of Examples 1-23, 27, 48 and 49 as shown below.

Example 1

2 (S) Butyl-1-(2,3-diaminoprop-1-yn-4-(1-naphthoyl)piperazine trihydrochloride

Step A: 1-Benzyl-3(S)-n-butylpiperazine-2,5-dione

The title compound is prepared according to the procedure described by John S Kiely and Stephen R. Priebe in Organic 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, 45.2 mmol) was added. The resulting suspension was stirred for 5 minutes, and then ethyl N-benzyl glycinate (8.72 g, 45.2 mmol) was added. The reaction is stirred for 2 hours at 0°C and then at 20°C overnight. The precipitate is removed by filtration, hydrogen chloride gas is bubbled through the methylene chloride solution for 2-4 hours until tlc shows that the reaction is complete. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate (150 mL) and saturated aqueous sodium bicarbonate (42 mL). The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The crude diketopiperazine is treated with hexane to give the title compound as a white powder.

1HNMR (300 Mhz, CDCl3) δ 7.24-7.40 (5H, m), 6.22 (1H broad s), 4.07 (1H, dt, J=3, 6 Hz)=, 3.87 (1H, d, J=17 Hz) , 3.80 (1H, d, J=17 Hz), 1.88 (2H, m), 1.35 (4H, m), 0.91 (3H, t, J=7Hz).

Grade B: 4-Benzyl-1-tert-butoxycarbonyl-2(S)-n-butyl piperazine

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 stirring. Lithium aluminum hydride (2.60 g, 0.0685 mol) is slowly added. The reaction is refluxed for 18 hours, cooled to 0°C and stopped by the subsequent slow addition of 5 ml of H2O. The reaction was stirred for 30 minutes and filtered. The waste is removed under vacuum, the crude product is taken up in methylene chloride and dried over magnesium sulfate. The drying agent is removed by filtration and the filtrate is treated with di-tertbutyl dicarbonate ((4.35 g, 0.020 mol). After 2 hours at a temperature of 20°C, a saturated solution of sodium bicarbonate is added. The layers are separated, and the organic phase is washed with saturated sodium chloride solution and 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.

1H NMR (30.0 MHz, DMSO-d6) δ 7.25 (5H, m), 3.90 (1H, broad s), 3.73 (1H, d, J=13 Hz), 3.51 (1H, d, J=13 Hz), 3.34 (1H, d, J-13 Hz), 2.93 (1H, m), 2.75 (1H, d, J-11 Hz), 2.62 (1H, d, J=11 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: 1-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 flask, and the flask was purged with argon. To this is added 10% palladium on carbon (0.80 g) and the reaction is hydrogenated under 60 psi of hydrogen for 24 hours. The catalyst is removed by filtration through Celite, and the compound is evaporated in vacuo to give the title compound as an oil.

1HNMR (300 MHz, CDCl3 δ 4.08 (1H, broad s), 3.90 (1H, d, J=12 Hz), 2.5-3.8 (6H, m), 0.90(3H,t,J=7Hz).

Grade D: I-tert-Butoxycarbonyl-2(S)-n-butyl-4-(1-naphthoyl)-piperazine

1-tert-butoxycarbonyl-2(S)-n-butylpiperazine (0.325 g, 1.34 mmol), 1-hydroxybenzotriazole (HOBT) (0.203 g, 1.34 mmol) and 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (EDC·HCl) (0.254 g, 1.34 mmol) was added to dry, degassed dimethylformamide (7 mL). The pH of the reaction is adjusted to 7 with triethylamine, and the reaction is stirred for 2 hours. Dimethylformamide between ethyl acetate and water. The organic phase is washed with 2% aqueous potassium bisulfate solution, saturated sodium bicarbonate solution, saturated sodium chloride solution, and dried over magnesium sulfate. The title compound is obtained as a thick oil.

Grade E: 2(S)-n-Butyl-4-(1-naphthoyl)piperazine hydrochloride

The product from step D is dissolved in ethyl acetate, cooled to -40°C under nitrogen, and the solution saturated with HCl (gas). The solution is heated to 0°C for 30 minutes and purged with nitrogen. The solvent is removed in vacuo. The product is evaporated from ethyl acetate three times. The title compound is obtained as a white solid.

Grade F: 2,3-(bis-tert-Butoxycarbonylamino)propionic acid)

Diaminopropionic acid monohydrochloride (2.86 g, 0.0204 mol) was suspended in 1:1 water-dioxane (100 ml) containing triethylamine (5.97 ml, 0.0204 mol). BOC-ON (11.0 g, 0.0448 mol) is 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 layer is washed with water, saturated sodium chloride, then dried over magnesium sulfate. The resulting foam (5.46 g) was crystallized from ethyl acetate to give the title compound as a white solid.

Grade G: N-Methoxy-N-methyl-2,3-(bis-tert-butoxycarbonyl-amino)propionamide

2,3-(bis-tert-butoxycarbonylamino)propionic acid (1.80 g, 5.92 mmol) in dimethylformamide (25 mL) was stirred overnight with N-methoxy-N-methylamine hydrochloride (0.635 g, 6.51 mmol), EDC·HCl (1.24 g, 6.51 mmol) with N-hydroxybenzotriazole (0.80 g, 5.92 mmol) and riethylamine (0.825 n, 5.92 mmol). Dimethylformamide is removed in vacuo and the residue is washed with 10% hydrochloric acid, saturated sodium bicarbonate solution, saturated brine, and dried over magnesium sulfate. The crude product is chromatographed on silica gel with 30% ethyl acetate in hexane. The title compound is obtained as a foam.

1HNMR (CDCl3, 300 MHz) d 5.51 (1H, broad d), 4.87 (1H, broad s), 4.72 (1H, broad s), 3.77 (3H, s), 3.50 (1H, m), 3.40 ( 1H, 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. Add N-methoxy-N-methyl-2,3-(bis-tert-butoxycarbonylamino)-propionamide (2.07 g, 5.96 mmol) in 1:1 ether to tetrahydrofuran (60 ml) at such a rate that the reaction temperature is maintained below - 35°C. The reaction is allowed to warm to 5°C, then cooled to -45°C and quenched with a solution of potassium bisulfate (3.08 g, 22.6 mmol) in water (20 ml). The reaction was stirred at 20°C for 1 hour, then filtered through celite. The organic phase is washed with 10% citric acid and saturated saline, then dried over magnesium sulfate. The title compound is obtained as a foam.

NMR (CDCl3, 300 MHz)d 9.61 (1H, s), 5.60 (1H, broad s), 4.88 (1H, broad s), 4.24 (1H, broad d, J=6 Hz), 3.68 (1H, m), 3.50 (1H, m), 1.40 (9H, s), 1.39 (9H, s).

Stage I: 1-(2,3-bis-tert-Butoxycarbonylamino)prop-1-yl/2(S)-butyl-4-(naphthoyl)piperazine

A solution of 3(S)-butyl-1-(1-naphthoyl)piperazine (1.83 g, 6.20 mmol) the 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 triethylamine. Sodium triacetoxyborohydride (1.87 g, 8.79 mmol) and crushed molecular sieves (1 g) were added, and the reaction was cooled to 0°C under nitrogen. A solution of 2,3-(bis-tert-Butoxycarbonylamino)propanol (1.69 g, 5.86 mmol) in dichloroethane (10 ml) was added dropwise, and the reaction was stirred at 20°C overnight. The reaction is cooled to 0°C, quenched with saturated sodium bicarbonate and stirred for 1 hour. The layers are separated and the organic layer is washed with saturated saline, then dried over magnesium sulfate. The crude product was chromatographed on silica gel with 40-45% ethyl acetate in hexane, and the title compound was isolated as a foam (Rf 0.30, 50% ethyl acetate in hexane).

Grade J: 1-(2,3-Diaminoprop-1-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 minutes at a temperature of 20°C, the solvent was evaporated and the residue was partitioned between chloroform and 20% aqueous sodium hydroxide solution. The organic layer is washed with saturated saline solution and dried over magnesium sulfate. The free base of the title compound is obtained as a yellow gum (1.72 g). A portion of this material (52 mg) is purified by preparative HPLC using a 100 mm Waters PrePAk® reverse phase column (DeltaPak™ C18, 50 mM, 100 Å) and the pure product is isolated by gradient elution using 100% 0.1% trifluoroacetic acid in water ( Solvent A) up to 50%, 0.1% trifluoroacetic acid in acetonitrile (Solvent B). The pure fractions are combined and the solvent is evaporated, and the crude product is dissolved in water and produced through an ion exchange column (Biorad AG® ion exchange resin, chloride form). After lyophilization, the title compound is 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.

Example 2

1-(3-Amino-2-(2-naphthylethylamino)prop-1-yl)-2(S)-butyl-4-(1-naphthoyl)piperazine trihydrochloride

Grade 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-diaminoprop-1-yl)-2(S)-butyl-1-(1-naphthoyl)piperazine (0.476 g, 1.29 mmol) in dichloromethane (10 ml). The reaction was stirred for a total of 2 hours at a temperature of 20°C, then stopped and extracted with water. The organic phase is washed with saturated saline solution and dried over magnesium sulfate. The crude product is chromatographed on silica gel with 5% methanol in chloroform and then with 5% (9:1 methanol-ammonium hydroxide). The title compound is 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 is obtained according to the procedure described in Example 1, Step D except that 1-(2-amino-3-tert-butoxycarbonylaminoprop-1-yl)/-2(S)-butyl-4-(1-naphthoyl) is used )piperazine (0.95 g, 0.613 mmol) sodium triacetoxyborohydride (0.194 g, 0.919 mmol), in dichloroethane on silica gel (15 ml) at pH 6. Crude products on silica gel with 5% methanol in chloroform (Rf 0.30), and title the compound is isolated as foam. FAB ms (m+1) 609.

Grade C: 1-(3-Amino-2-(2-naphthylmethylamino)prop-1-yl)-2(S)-butyl-4-(1-naphthoyl)piperazine trihydrochloride

A solution of 1-(3-tert-butoxycarbonylamino-2-(2-naphthylmethylamino)prop-1-yl)-2(S)-butyl-4-(1-naphthoyl)piperazine (0.313 g, 0.514 mmol) in methylene chloride ( 10 ml) is deprotected with trifluoroacetic acid (5 ml) and converted to the free base (255 mg) according to the procedure described in Example 1, Step E. Purification of 40 mg by preparative HPLC used gradient elution with solvents A and B (from Example 1; 95% to 5% solvent A). ion exchange and lyophilization as described afforded the title compound as a white solid. FAB ms (m+1) 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.

Example 3

2(S)-Butyl-{5-(1-(2-naphthylmethyl)/-4,5-dihydroimidazol}methyl-4-(1-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-butyl isocyanate (1.5 ml ) and silver cyanide (0.023 g, 0.207 mmol) are heated in a heated test tube under nitrogen at 90°C overnight. The volatiles were removed in vacuo, and the residue was chromatographed on silica gel with 5-10% methanol in chloroform to give the free base (73 mg). It is 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). Lyophilization gave the title compound as a white solid: FAB ms (m+1) 519. Anal. Calc. for C34H38N4O 0.85 H2O 3.75 TFA: C, 51.84; H, 5.83. Found: C, 51.83; H, 4.56; N, 6.32.

Example 4

1-/5-(1-Benzylimidazol-9methyl/-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-triphenylmethylimidazole)/methyl-4-(1-naphthoyl)piperazine (63 mg, 0.103 mmol) in acetonitrile. (0.5 ml) at a temperature of 20°C under nitrogen. The reaction was stirred overnight, concentrated in vacuo, and taken up in dichloromethane (2 mL) containing triethylsilane (0.100 mL). Trifluoroacetic acid is added and the reaction is stirred for 1 hour at 20°C. The solvent is evaporated and the residue is purified by HPLC (95% to 5% solvent A). The pure fractions were combined and converted to the HCl salt as described in Example 1, Step E. After lyophilization, the title compound was isolated as a white solid. FAB ms (m+1) 467. Anal. Calculated for C30H34N4O 0.05 H2O 3.70 HCl: C, 59.81; H, 6.32; N, 9.30. Found. C, 59.78; H, 6.33; N, 9.30.

Example 5

1-[5-(1-(4-nitrobenzyl)imidazolylmethyl]-2(S)-butyl-4-(1-naphthoyl)piperazine ditrifluoroacetate

The title compound was obtained according to the procedure described in Example 4, except that p-nitrobenzyl bromide (0.043 g, 0.199 mmol) and 2(S)-butyl-1-(5-(3-triphenylmethylimidazole)/methyl-4-(1 -naphthoyl)piperazine (123 mg, 0.199 mmol) in acetonitrile (2 ml) in dichloroethane (4 ml). Preparative HPLC (95-5% solvent A) affords the title compound as a white solid. FAB ms (m+1) 512. Anal. Calculated for: C30H33N5O3 2CF2CO2H 0.03H2O: C, 41.42; H, 3.98; N, 10.18. Found: C, 41.43; H, 3.96; N, 10.51.

Example 6

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-hydroxymethylacetamide (0.010 g, 0.105 mmol) (obtained as is described in M. Bodansky, A. Bodansky, “The Practice of Peptide Synthesis”, Springer Verlag, 1984, p. 82) is dissolved in trifluoroacetic acid for 0.5 hours. The solvent is removed in vacuo and the residue is purified by preparative HPLC (85-60% solvent A). After lyophilization, the title compound is isolated as a white solid. FAB ms (m+1) 457. Anal. Calc. for C25H36N4O2S 2 CF2CO2H 1.9 H2O C, 44.38; H, 5.12; N, 6.64. Found: C,44.35; H,5.11; N, 6.97.

Example 7

Grade A: 2(S)-Butyl-1-(2-(1-imidazolyl)ethyl/sulfonyl-4-(1-naphthoyl)piperazine ditrifluoroacetate

Chloroethylsulfonyl chloride (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 diisopropylethylamine (0.119 ml, 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 is isolated.

Grade B: 2(S)-Butyl-1-(2-(1-imidazolyl)ethyl/sulfonyl-4-(1-naphthoyl)piperazine ditrifluoroacetate

Imidazolyl (0.043 g, 0.627 mmol) was added to sodium hydride (60%, dispersion in oil, 0.024 g, 0.598 mmol) suspended in dimethicone (2 mL). The reaction is cooled to 0°C under nitrogen, 2(S)-butyl-4-(1-naphthoyl)-1-vinylsulfonylpiperazine (0.011 g, 0.29 mmol) in dimethylformamide (5 ml) is added. The reaction was stirred at 20°C overnight. Dimethylformamide is removed in vacuo and the residue is dissolved in ethyl acetate. This is extracted with saturated sodium bicarbonate solution, saturated brine and dried over magnesium sulfate. The crude product is first purified by silica gel chromatography using 8% methanol in chloroform, then by preparative HPLC (80 to 40% solvent A). The trifluoroacetic acid salt is dissolved in water and partitioned between saturated sodium bicarbonate and ethyl acetate. The organic phase is washed with saturated saline and dried over magnesium sulfate. The title compound is obtained as a foam. FAB ms (m+1) 455. Anal. Calc. for C25H36N4O2S 0.8 H2O; C, 61.46; H, 6.79; N, 11.95. Found: C, 61.44; H, 6.97; N, 10.72.

Example 8

Grade A: 2(R)-Butyl-4-(1-naphthoyl)-1-(4-(1-triphenylmethylimidazolyl)/methyl-piperazine

3(R)-Butyl-1-(1-naphthoyl)piperazine (0.202 g, 0.607 mmol) (prepared as described for the (S) enetiomer in Example 1) was reacted with 1-triphenylmethylimidazole-4-carboxy-aldehyde (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 is adjusted to 5-6 with triethylamine/acetic acid, stirred overnight, then quenched with saturated sodium bicarbonate. The organic layer is washed with saturated brine, and dried over magnesium sulfate. The crude product is purified by chromatography on silica gel with 30% ethyl acetate in hexane and then with 5% methanol in chloroform to give the title compound.

Grade B: 2(R)-Butyl-1-imidazolyl-4-methyl-4-(1-naphthoyl)piperazine ditrifluoroacetate

Triethylsilane (1.0 ml, 11.80 mmol) was added to a solution of 2(R)-butyl-4-(1-naphthoyl)-1-(1-triphenylmethyl-imidazolyl/methyl-piperazine) (0.381 g, 0.616 mmol) in dichloromethane, followed by trifluoroacetic acid (8 ml). After 1 hour, the solvents were evaporated and the residue was partitioned between water and hexane. The aqueous phase was injected directly onto a preparative HPLC column (100-40% solvent A) and the title compound was isolated after lyophilization. FAB ms (m + 1) 377. Analysis-Calcd 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.

Example 9

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) is reacted with pyridine-3-carboxyaldehyde (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 pulverized as described in Example 8, Step A. The crude product is purified by silica gel chromatography with 30% acetone in hexane and then by preparative HPLC (80-75% solvent A ). After ion exchange, the title compound is isolated. FAB ms (m+1) 388. Analysis. Calculated for C25H29N3O2.3 HCl • 0.95 H2O. C, 61.49; H, 6.85; N, 8.60. Found: C, 61.49; H, 7.01; N, 8.76.

Example 10

1-2(S)Butyl-(2(R)-(4-nitrobenzamino-3-hydroxypropyl)-4-(1-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 triacetoxyborohydride (0.173 g, 0.817 mmol), in dichloroethane. The crude product is purified by preparative HPLC (100-75% solvent A), and after ion exchange to the HCl salt and lyophilization, the title compound is obtained. FAB ms (m+1) 505. Analysis Calculated for: 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

Example 11

1-(2(R)-Amino-3-hydroxyheptadecyl)-2(S)-butyl-4-(1-naphthoyl)piperazine ditrifluoroacetate

Grade A: 1-(2(R)-t-Butoxycarbonylamino-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) was added and the reaction was stirred for 2 minutes. . 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 is stirred for 5 minutes, then it is heated to room temperature. Additional methylene chloride is added and the reaction is extracted with water. The organic phase is washed with 2% potassium bisulfate solution, water diluted with sodium bicarbonate solution, and saturated saline solution. After drying with magnesium sulfate, the title compound is obtained.

Step B: 1-(2(R)-Amino-3-hydroxyheptadecyl)-2(S)-butyl-4-(1-naphthoyl)piperazine ditrifluoroacetate

A solution of 0.25 g, 0.53 mmol) (2(R)-t-butoxycarbonylamino-2-formylethyl)-2(S)-butyl-4-(1-naphthoyl)piperazine in dry tetrahydrofuran 0.25 g, 0.53 mmol), (2( R)-t-butoxycarbonylamino-2-formylethyl)-2(S)-butyl-4-(1-naphthoyl)piperazine in dry tetrahydrofuran (5 ml) was cooled to 0°C under nitrogen in a flame-dried three-necked flask. A solution of heptadecylmagnesium chloride (1.01 ml of 1 M dissolved in ether, 1.01 mmol) is added via a tube, and the reaction is allowed to warm to room temperature. The reaction is quenched with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. After drying over magnesium sulfate, the crude product is chromatographed on silica gel with 25% ethyl acetate in hexane and then with 5% methanol in chloroform. The purified product is dissolved in methylene chloride (7 ml) and treated with trifluoroacetic acid (3.5 ml). After 45 minutes, the solvents are removed in vacuo and the residue is purified by preparative HPLC (95-40% solvent A). Two isomers are separated. After lyophilization, the title compound is isolated as diastereoisomer A (retention time 8.405 minutes, gradient 100-50% solvent A over 15 minutes). FAB ms (m+ 1) 566, Anal. Calc. for C36H59N3O2 • 2.35 CF3CO2H • 0.35 H2O. C, 58.56; H, 7.42; N, 5.03. Found: C, 58.53; H, 7.41; N, 517.

Example 12

2(S)-Benzyl-1-imidazolyl-4-methyl-4-(1-naphthoyl)piperazine

Grade A: 1.(3(S)-Dibenzylpiperazin-2,5-dione

The title compound was obtained according to the procedure described in Example 1, Step A, except that Boc-L-phenylalanine (12.8 g, 48.2 mmol), ethyl diimide (96.5 ml of 0.5 M in dichloromethane, 48.2 mmol) was used. The crude diketopiperazine is treated with hexane to give the title compound as a white powder.

1HNMR (300 MHz, CD3OD) δ 7.0-7.4 (10 H, m), 4.61 (1 H, d, J=16 Hz), 4.37 (1H, t, J=5 Hz), 4.24 (1 H, d, J=16 Hz), 3.42 (1 H, d, J=18 Hz), 3.28 (1 H, dd, J=4, 16 Hz), 2.96 (1H,d=6, 16Hz), 2.55(1H,d ,J=18Hz).

Grade B: 1-tert-Butoxycarbonyl-2(S)-,4-dibenzyl piperazine

The title compound was obtained according to the procedure described in Example 1, Step B, except that 1,3(S)-dibenzylpiperazine-2,5-dione (5.01 g, 17.1 mmol) and lithium aluminum hydride (2.33 g, 61.4 mmol) were used. ) and then with di-tert-butyl dicarbonate (4.02 g, 18.4 mmol). The crude product is purified by chromatography on a silica gel column, eluting with 7.5% ethyl acetate in hexane. The title compound is obtained as a white solid.

1HNMR (300 MHz, CD3OD) d 7.2-7.4 (5H, m), 7.0-7.2 (5H, m), 4.15 (1H, m), 3.90 (1H, d, J=15 Hz), 3.60 (1H, d, J=15 Hz), 3.15 (1H, m), 2.95 (3H, m), 2.7 (1H, d, J=13 Hz), 2.02 (1H, dt, J=6, 13 Hz) , 1.9.5 (1H, wide d), 1.35 (9H, s).

Step C: 2(S)-Benzyl-1-tert-butoxycarbonylpiperazine

The title compound is obtained according to the procedure described in Example 1, Step C, except that 1-tert-butoxycarbonyl-2(S),4-dibenzylpiperazine (0.292 g, 1.06 mmol), 2,3-dimethylbenzene 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 is obtained as a thick oil.

1HNMR (300 MHz, CD3OD) δ 7.25 (5H, m), 4.35 (1H, m), 4.00 (1H, d, J=12 Hz), 2.7-3.3 (7H, m), 1.25 (9H, s).

Grade D: 2(S)-Benzyl-1-tert-butoxycarbonyl-4-(1-naphthoyl)piperazine

The title compound was obtained according to the procedure described in Example 1, Step A, except that 2(S)-benzyl-1-tert-butoxycarbonyl piperazine (0.292 g, 1.06 mmol), 2,3-dimethylbenzene 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 to pH 7. The title compound is obtained as a thick oil.

1HNMR (DMSO-d6, 300 MHz) δ 7.15 (2H, m), 6.06 (1H, m), 4.42 (1H, m), 3.6-4.2 (2H, m)) 2.7-3.24 ) 4H, m), 2.24 (3H, s), 2.03-2.20 (3H, 4s), 1.10-1.6 (15H, m), 0.72-1.00 (3H, m)

Grade E: 2(S)-Benzyl-4-(1-naphthoyl)-1-/4-(1-triphenylmethylimidazolyl/methyl-piperazine)

3(S)-Benzyl-1-(1-naphthoyl)piperazine (0.173 g, 0.472 mmol) is reacted with 1-triphenylmethylimidazole-4-carboxyaldehyde (0.173 g, 0.472 mmol), sodium triacetoxyborohydride (0.300 g, 0.472 mmol) in dichloroethane. (7 ml) in the presence of broken molecular sieves as described in Example 8, Step A. The title compound is obtained as an oil.

Grade F: 2(S)-Benazil-4-(1-naphthoyl)-1-(4-(1-triphenylmethylimidazolyl)/methyl piperazine

Triethylsilane (0.300 ml, 1.89 mmol) was added to a solution of 2(S)-benzyl-4-(1-naphthoyl)-1-(4-(1-triphenylmethylimidazolyl/methyl-piperazine) (0.310 g, 0.472 mmol) in dichloromethane ( 5 ml) and then trifluoroacetic acid (5 ml) is added. After 1 hour, the solvents are evaporated and the residue is partitioned between water and hexane. The aqueous phase is injected directly onto the preparative HPLC column (85-45% solvent A), and the title the compound is isolated after lyophilization. FAV ms (m+1) 411. Anal. Calculated 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.

Example 13

1-(2(R)-Amino-3-(3-benzylthio)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine ditrifluoroacetate

A solution of 1-(2(R)-butoxycarbonylamino-3-hydroxypropyl)-2(S)-butyl-4-(1-naphthoyl)piperazine (1.67 g, 3.56 mmol) in dimethylformamide (10 ml) was cooled to 0°C. under nitrogen. Sodium chloride (0.427 g, 10.6 mmol, 60% dispersion in oil) is added, and then 1,1-sulfoazole (0.704 g, 3.56 mmol) is added. The reaction is heated to 20°C for 1 hour, cooled to 0°C and quenched with water. The dimethylformamide is distilled off in vacuo and the residue partitioned between ethyl acetate and water. The organic phase is washed with saturated brine and dried over magnesium sulfate. The crude product is chromatographed on silica gel in chloroform. The title compound is obtained as major product, FAB ms (m+ 1) ms A minor amount of 1-(1-butoxycarbonylaziridinyl)methyl/-2(S)-butyl-4-(1-naphthoyl)piperazine was also isolated.

Step B: 1-(2(R)-Amino-3-(3-benzylthio)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine ditrifluoroacetate

1-(1-Aziridinyl)methyl/-2(S)-butyl-4-(1-naphthoyl)piperazine (0.050 g, 0.142 mmol) was refluxed for 18 hours with benzyl mercaptan (0.100 ml, 0.852 mmol) and triethylamine ( 0.200 ml) in methanol (4 ml). The crude product is first chromatographed on silica gel with 3% merethanol in chloroform, and then purified by preparative HPLC (85% to 10% solvent A). The title compound is obtained after lyophilization. FAB ms (m+1) 476. Analysis Calculated for C29H37OS • 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.

Example 14

1-(2(R)-Amino-3-(3-(4-nitrobenzylthio)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine ditrifluoroacetate

A solution of 1-(1-butoxycarbonylaziridinyl)methyl/-2(S)-butyl-4-(1-naphthoyl)piperazine (0.050 g, 0.111 mmol) in methanol (4 ml) was refluxed with p-nitrobenzylthioacetate (0.070 g, 0.333 mmol) and triethylamine (0.200 ml) for 2 hours. The crude product is chromatographed on silica gel with 3% methanol in chloroform.

The purified product is treated with 33% trifluoroacetic acid in methylene chloride for 20 minutes. The solvents are evaporated and the product is purified by preparative HPLC (85-10% solvent A). The title compound is obtained after lyophilization. FAB ms (m+1) 529. Analysis Calculated 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.

Example 15

2(S)-Butyl-1-(4-imidazolyl)ethyl/-4-(1-naphthoyl)piperazine dihydrochloride

Grade A: N-Methyl-N-methoxy-2-(1-triphenylmethyl)-1H-imidazol-4-yl)acetamide

Triethylamine (4.46 ml, 32 mmol) was added to a solution of 4-imidazolacetic acid (1.04 g, 6.40 mmol) and triphenylmethyl bromide (2.48 g, 7.68 mmol) in dimethylformamide (40 ml) and the suspension was left to stir for 18 hours at room temperature. After this time, the mixture is treated with 3-hydroxy-1,2,3-benzotriazin-4(3)-ene (HOOBT) (1.31 g, 8 mmol), N,O-dimethylhydroxyamine chloride (1.56 g, 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, a saturated aqueous solution of sodium bicarbonate (50 ml) and water (50 ml) are added, the mixture is extracted with ethyl acetate (2 x 100 ml). The combined extracts are washed with saturated aqueous NaHCO3 solution (100 ml) and then with brine (50 ml), and the solvent is evaporated in vacuo. The residue was suspended in ether (20 ml) and the white solid was filtered to give the title compound as a white solid.

1NMR (CD3OD, 300 MHz) δ 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 .

Step B: 2-(1-triphenylmethyl-1H-imidazol-4-yl)acetaldehyde

Lithium aluminum hydride (33.2 mg, 0.874 mmol) was added to a solution of the product from Step A (300 mg, 0.73 mmol) in distilled THF (15 ml) cooled to -40°C over dry ice/acetone. The resulting suspension is allowed to warm up to +5°C and then kept at 0°C for 30 minutes. After this time, the reaction mixture is again cooled to -40°C and quenched sequentially with water (33 μl), 1.0 N NaOH (33 μl) and water (100 μl). The resulting suspension is stirred for 30 minutes, filtered and the solvent is removed under vacuum. The residue is dissolved in methylene chloride (5 ml) and washed with 10% aqueous citric acid solution (5 ml) and then with water (5 ml). The organic layer is dried (MgSO4) and the solvent is evaporated in vacuo to give the title compound.

1HNMR (CDCl3, 300 MHz) δ 9.79 (1H, t, J=3Hz), 7.44 (1H, s), 7.4-7.1 (15H, m), 6.76 (1H, s) and 3.63 (2H, d, J= 3Hz)ppm.

Step C: 2(S)-Butyl-1-(4-imidazolyl)ethyl/-4-(1-naphthoyl)piperazine ditrifluoroacetate

To a solution of the product from Step B (89 mg, 0.263 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 is stirred at room temperature for 4 days. After this time, the mixture is filtered through sintered glass. The filtrate is 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 give the trityl protected title compound as an oil. This oil is dissolved in methylene chloride (2 ml) and trifluoroacetic acid (1 ml) and treated with triethylsilane (2 drops), whereby a colorless solution is obtained. This solution was stirred at room temperature for 3 hours and then dissolved in water (20 ml) and washed with hexanes (20 ml). The aqueous layer is lyophilized to give the title compound.

1HNMR (CD3OD, 300 MHz) δ 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. Calculated for C24H30N4O • 3.45 TFA • 0.75 (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. Calculated for C24H30N4O • 3.45 TFA • 0.75 H2O: C, 46.54; H, 4.42; N, 7.03.

Found: C, 46.54; H, 4.41; N, 7.35.

FAB HRMS exact mass calcd for C23H31N4O 391.249787 (MH+), found 391.249028.

Example 16

2(S)-Butyl-1-(4-imidazolyl)methyl/-4-(1-naphthoyl)piperazine difluoroacetate

To a solution of the product from Step C (102 mg, 0.31 mmol) and 3(S)-butyl-1-naphthoylpiperazine hydrochloride (62.6 mg, 0.188 mmol) in 1,2-dichloroethane (5 mL), sodium triacetoxyborohydride (200 mg) was added. , 0.94 mmol) and triethylamine to pH = 5.5 and stirred at room temperature for 18 hours. After this time, the mixture is filtered. The filtrate is concentrated in vacuo and dissolved in ethyl acetate (25 ml), and washed with saturated aqueous NaHCO3 solution (10 ml) and then with brine (10 ml). The solvent was evaporated in vacuo and the residue was purified by flash chromatography eluting with 3-8% methanol/methylene chloride to give the tritylpm-protected title compound. This oil is dissolved in methylene chloride (4 ml) and trifluoroacetic acid (2 ml) and treated with triethylsilane until the yellow color disappears, after which a colorless solution is obtained. Stirring is continued at room temperature for 10 minutes and the solvent is evaporated in vacuo. The resulting white solid is partially dissolved in water (7 ml) and filtered. The filtrate is purified by Prep HPLC using a "Nova Prep 5000 semi-preparative HPLC" system and a "Waters PrePak" insert (47 x 300 mm, C18, 15μm, 100 Å) eluting with 5-95% acetonitrile/water (0.1% TFA) at 100 ml/minute (Chromatography A), whereby the title compound is obtained after lyophilization.

1HNMR (DMSO-d6, 400 MHz, 150°C) d 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, J=4.8 Hz), 3.95 (1H, d, J=4.8 Hz), 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=5.5 Hz) ppm.

Example 17

2(S)-Butyl-1-(1-naphth-2-ylmethyl)-1H-imidazol-5-yl)acetyl/-4-(1-naphthoyl)piperazine dihydrochloride

Step A: Preparation of 1H-imidazole-4-acetic acid methyl ester hydrochloride

Hydrogen chloride gas is bubbled into a solution of 1H-imidazole-4-acetic acid hydrochloride (4.00 g, 24.6 mmol) in methanol (100 ml) until the solution is saturated. This solution was allowed to stand for 18 hours at room temperature and the solvent was evaporated in vacuo to give the title compound as a white solid.

1H NMR (CDCl3, 400 MHz) δ 8.85 (1H, s), 7.45 (1H, s), 3.89 (2H, s) and 3.75 (3H, s) ppm.

Step B: Preparation of 1-(triphenylmethyl)-1H-imidazol-4-ylacetic acid methyl ester

To a suspension of the product from Step A (7.48 g, 42.4 mmol) in methylene chloride (200 ml), triethylamine (17.7 ml, 127 mmol) and triphenylmethyl bromide (16.4 g, 50.8 mmol) were added and stirred for 72 hours. After this time, the reaction mixture is washed with saturated aqueous NaHCO3 solution (100 ml) and water (100 ml). The organic layer is evaporated in vacuo and the residue is purified by flash chromatography, (30-100% ethyl acetate in hexanes, gradient elution) , giving the title compound as a white solid.

1H NMR (CDCl3, 400 MHz) d 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 methyl ester of 2-(1-(naphthyl-2-ylmethyl)-1H-imidazol-yl)acetic acid

2-(bromomethyl)naphthalene was added to a solution of the product from Step B (4.36 g, 11.4 mmol) in acetonitrile (70 ml) and heated to 55°C for 4 hours. After this time, the reaction is cooled to room temperature and the resulting white precipitate is collected by filtration. The filtrate is concentrated to 30 ml and heated to 55°C for 1 hour. After this time, the reaction is again cooled to room temperature and diluted with ethyl acetate (25 ml). The resulting precipitate is collected by filtration and combined with the two earlier precipitates in methanol (100 ml) and heated to reflux for 30 minutes. After this time, the solvent is removed in vacuo and the resulting precipitate is partitioned between methylene chloride (200 ml) and sodium bicarbonate (100 ml). The organic layer was evaporated in vacuo to dryness and the residue was purified by flash chromatography (0-6% methanol/methylene chloride chloride gradient) to give the title compound as an off-white solid:

1HNMR (CDCl3, 400 MHz) d 7.82 (2H, m), 7.75 (1H, m), 7.70

(1H, s), 7.49 (3H, m), 7.20 (1H, d, J=8.4 Hz), 7.06 (1H, s),

5.32 (2H, s), 3.57 (3H, s) and 3.49 (2H, s) ppm.

Step D: Preparation of 2-(1-naphth-2-ylmethyl)-1H-imidazol-5-yl/acetic acid hydrochloride

2-(1-(Naphthyl-2-ylmethyl)-1H-imidazol-5-yl)acetic acid methyl ester (0.92 g, 3.28 mmol) was dissolved in 2.5 N hydrochloric acid (50 ml) and heated to 55°C, 3 hours. After this time, the solution was concentrated to dryness in vacuo to give the title compound as a white solid.

1HNMR (CD3OD, 400 MHz) d 8.92 (1H, s), 7.94 (1H, d, J=8.6 Hz), 7.88 (2H, m), 7.83 (1H, s), 7.54 (3H, m), 7.43 ( 1H, d, J=14 Hz), 5.60 (2H, s) and 3.82 (2H, s) ppm.

Step E: Preparation of 2(S)-butyl-1-(1-naphth-2-ylmethyl)-1H-imidazol-5-yl)acetyl/-4-(1-naphthoyl)piperazine dihydrochloride

To a solution of the product from Step D (100 mg, 0.330 mmol), 3(S)-butyl-1-naphthoylpiperazine hydrochloride (100 mg, 0.300 mmol) and 3-hydroxy-1,2,3-benzotriazine-4(3H)- it (HOOBT) 54 mg, 0.33 mmol) in dimethylformamide (2 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (63 mg, 0.33 mmol) and triethylamine (161 μl, 1.16 mmol) were added. and the resulting suspension is stirred for 18 hours. After this time, saturated aqueous NaHCO 3 (7 ml) was added and the resulting precipitate was filtered. The solid was redissolved in methylene chloride and washed with water (25 ml) and brine (20 ml). The solvent is evaporated in vacuo and the residue is purified by preparative HPLC (Chromatography A) to give the title compound.

1HNMR (CDCl3, 400 MHz) d 8.9.8 (1H, m), 8.03-7.27 (15H, m), 5.6.9-5.50 (2H, m), 4.79-4.34 (2H, m)), 4.15- 2.50 (7H, m), 1.8-0.2 (9H, m) ppm.

Analysis calculated for C35H35N4O2 HC1 0.65H2O: C, 67.30; H, 6.16; N, 8.97.

Found: C, 61.25; H, 6.16; N, 9.15.

FAB HRMS exact mass calculated for C35H35N4O2 HCl 0.65H2O: C, 67.30; H, 6.16; N, 8.97. Found: C, 67.25; H, 6.16; N, 9.15.

FAB HRMS exact mass calcd for C35H36N4O2 545.291652 (MH+), found 545.292050.

Example 18

2(S)-butyl-4-(1-naphth-2-ylmethyl) 1H-imidazol-5-yl)ethyl/-4-(1-naphthoyl)piperazine ditrifluoroacetate

Step A: Preparation of N-methyl-N-methoxy-2-(1-naphth-2-yl-methyl)-1H-imidazol-5-yl)acetamide

To a solution of 2-(1-naphthyl-2-ylmethyl-1H-imidazol-5-yl/acetic acid) hydrochloride (0.819 mg, 2.70 mmol) in dimethyl (15 ml), N,O-dimethylhydroxylamine hydrochloride ( 293 mg, 3.0 mmol), 3-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 is stirred at room temperature for 18 hours. After this time, saturated aqueous NaHCO 3 (30 ml) and water (30 ml) were added and the mixture was extracted with methylene chloride (x 50 ml). The combined organic extracts are washed with brine (50 ml) and the solvent is evaporated in vacuo. The residue was purified by flash chromatography eluting with a 2-4% methane/methylene chloride gradient to give the title compound as an oil.

1HNMR (CDCl3, 400 MHz) d 7.80 (2H, m), 7.74 (1H, m), 7.56 (1H, s), 7.47 (3H, m), 7.22 (1H, d, J=8.6 hz), 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)-(1H-imidazol)-5-yl)/acetaldehyde

To a suspension of aluminum hydride (40.8 mg, 1.07 mmol) in tetrahydrofuran (5 m) cooled to -45°C over dry ice/acetone, a solution of the product from Step A (243 mg, 0.895 mmol) in tetrahydrofuran (5 ml) was added through tube at such a rate as to maintain the temperature at <-35°C. As the addition is complete, the solution is allowed to warm to +5°C, and then cooled again to -35°C. A solution of potassium bisulfite (272 mg) in water (1 ml) is added to this solution. This mixture is stirred for 30 minutes at room temperature and filtered through celite. The celite filter is washed with ethyl acetate (25 ml). The combined filtrates are washed with saturated sodium bicarbonate solution (10 ml) and then with water (10 ml). The organic layer is dried over magnesium sulfate, filtered and evaporated to give the title compound as a clear oil.

1HNMR(CDCl3, 400 MHz) δ 9.04 (1H, s), 8.17-7.30 (15H, m), 7.85-7.70 (3H, m), 7.64 (1H, s), 7.53-7.40 (3H, m), 7.16 (1H, d, J=12 Hz), 7.06 (1H, s), 5.20. (2H, s) and 3.53 (2H, m) ppm.

Step C: Preparation of 2(S)-Butyl-1-(1-naphth-2-ylmethyl)-1H-imidazol-5-yl)ethyl/-4-(1-naphthoyl)piperazine ditrifluoroacetate

To a solution of the product from Step B (58.4 mg, 0.232 mmol) and 3(S)-butyl-1-naphthoylpiperazine hydrochloride (96.5 mg, 0.279 mmol) in 1,2-dichloroethane (10 ml) and dimethylformamide (5 ml) are added 3Å molecular sieves (250 mg) sodium triacetoxyborohydride (236.5 mg, 1.12 mmol). This mixture is stirred: at room temperature, for 18 hours. After this time, the mixture is filtered. The filtrate is diluted with methylene chloride (100 ml) and washed with saturated sodium bicarbonate solution (50 ml). The organic layer is dried (MgSO4), filtered and evaporated in vacuo. The residue is purified first by flash chromatography eluting with 2-5% methanol/methylene chloride and then by preparative HPLC (Chromatography A), whereby the title compound is obtained.

1H NMR (CD3OD, 40.0 MHz) d 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 calcd for C35H39N4O 531.312387 (MH+), found 531.313011.

Example 19

1(2(R)-Amino-3-hydroxypropyl)-2(S)-butyl-4-(1-naphthoyl)piperazine bis trifluoroacetate salt

Step A: N-Boc-O-Benzylserine-(N'-methoxy)methyl amide

N-Boc-Benzylserine (Bachem, 5.0 g, 16.9 mmol) and HOBT (2.29 g, 16.9 mmol) were dissolved in dry DMF (100 ml) under argon. To this solution was added N,O-dimethylhydroxyl amine chloride (1.98 g, 20.3 mmol) and then, at 0°C, EDC hydrochloride (3.56 g, 18.6 mmol). 4-Methylmorpholine is added to adjust the pH to ~7 (4.5 ml), the mixture is stirred at room temperature for 3 hours. The solution was diluted with EtOAc and poured into 0.5 N HCl. After extraction with EtOAc (twice), the organic layers were washed with water, then with brine, dried (MgSO4) and evaporated in vacuo to give a light yellow oil. Column chromatography (silica gel; hexane/EtOAc 2:1) gave the title compound as an oil Rf (silica; hexane/EtOAc 1:1) = 0.45.

Grade B: N-Boc-O-Benzyl-serine aldehyde

Amide from Step A (5.7 g, 16.9 mmol) in dry ether (20 ml) was added dropwise to a suspension of LAH (0.705 g, 18.5 mmol) in 80 ml of ether at a temperature of -50°C. When the addition is complete, the solution is stirred at 0°C for 45 minutes, then cooled again to -50°C and KHSO 4 solution (4 g in 11 ml H 2 O) is slowly added. This mixture is then stirred at room temperature for 1 hour, filtered through celite, washed successively with 10% citric acid solution, saturated NaHCO 3 solution and brine, dried (MgSO 4 ) and evaporated to give an oil which is used as such. in the next step Rf (silica; hexane/EtOAc 2:1) = 0.58.

Grade C: 1-(2(R)-N-Boc-Amino-3-benzyloxy propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine

A solution of piperazine hydrochloride from Example 1, Step E (1.7 g, 574 mmol) in CH2Cl2 (25 ml) was adjusted to pH 6 using Et3N, then freshly ground activated 4 A sieves were added to the solution, followed by sodium triacetoxyborohydride (4.85 g, 22.9 mmol). The aldehyde from Step B (2.08 g, 747 mmol) dissolved in 20 ml of CH2Cl2 was added dropwise at 0°C over 20 minutes, and then the mixture was stirred at room temperature for 16 hours. After this time, the mixture is filtered through celite, diluted with EtOAc and washed successively with, H2O, KHSO4 solution, NaHCO3 solution and then with brine. The dried (MgSO4) solution was evaporated in vacuo to give the title compound as a foam. Rf (silica; hexane/EtOAc 2:1) = 0.15.

Grade D: 1-(2(R)-N-Boc-Amino-3-hydroxy-propyl(2-(S)-butyl-4-(1-naphthoyl)piperazine)

The benzyl ether from Step C (700 mg, 1.25 mmol) was dissolved in 20 ml of MeOH with 150 μl of acetic acid and then 20% Pd(=H)2 on carbon (500 mg) was added and the mixture was hydrogenated at 50 psi for 16 h . After filtration through celite, the solvent was removed and the residue was chromatographed on silica gel (EtOAc/hexane 1:1 followed by 5% MeOH/EtOAc) to give the title compound as an oil.

Grade E: 1-(2(R)-Amino-3-hydroxy-propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine bis trifluoroacetate salt

A solution of N-Boc amine from Step D (140 mg) in 10 mL EtOAc was treated with HCl (gas) until saturated. After 5 minutes, the solution is purged with argon, then the solvents are removed, yielding a solid which is further purified by preparative HPLC (C-18 column; H2O/CH3CN with 0.1% TGA; gradient). The aqueous solution is frozen and lyophilized to give the title compound as a hygroscopic powder. FAB mass spectrum m/z = 370 (m+1). 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

Example 20

1-(2(R)-Amino-4-hydroxybutyl)-2(S)-butyl-4-(1-naphthoyl)piperazine bis hydrochloride salt

Following the procedure of Example 19, Steps A to E, but using N-Boc-O-benzyl homoserine (Bachem) as starting material, the title compound is obtained as the bis hydrochloride salt. FAB mass spectrum, m/z = (m+1).

Analysis calculated for C22H33N3O2 • 1.5 HCl

C, 54.04; H, 7.20; N, 8.22 Found C, 53.95; H, 7.23; N, 8.50.

Example 21

1-(2-Amino-3-(2-benzyloxyphenyl(propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine bis-trifluoroacetate salt

Grade A: D,L-N-Boc-orthotyrosine methyl ester

The title compound was obtained as a crystalline solid from D,L-orthotyrosine (Sigma) in two steps ((Boc)2O/K2CO3 in THF/H2O followed by diaisomethane 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 a temperature of 0°C was added LAH (400 mg, 10.5 mmol) in portions. After 4 hours at room temperature, 0.4 ml of H2O is added dropwise. The suspension was stirred for 1 hour, filtered through celite, washed with THF and the solvent was removed, the residue was chromatographed (silica gel; hexane/EtOAc 1:1) to give the title compound as a solid. Rf (silica; hexane/EtOAc 1:1) = 0.45.

Step C: 3-(2-Benzyloxyphenyl)-2-(N-Boc-amino)propanol

A mixture of alcohol from Stage B (280 mg, 1.05 mmol), benzyl bromide (150 μl, 1.26 mmol) and Cs2CO3 (513 mg, 1.57 mmol) in DMF (10 ml) was stirred at room temperature under argon for 16 h. The mixture was taken up in H2O, extracted twice with EtOAc, washed with water, then with 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 alcohol from Grade C (280 mg, 0.78 mmol) in 3 ml of DMSO, 3 ml of CH2Cl2 and 0.55 ml of Et3N at room temperature under argon, pyridine SO3 complex (500 mg, 3.14 mmol) was added and the mixture was stirred for 1 hour. The solution was poured into saturated NaHCO3 solution, extracted twice with EtOAc, washed with water, then with brine, dried (MgSO4) and concentrated in vacuo. The title compound is obtained as an oil and used as such in the next step. Rf (silica; hexane/EtOAc 4:1) = 0.41.

Grade 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 cleaved by reductive alkylation using the procedure described in Example 19, Step C. Purification by column chromatography (silica gel; hexane/EtOAc 3:2) afforded the title compound as 1:1 mixture of diastereoisomers. Rf (silica; hexane/EtOAc 1:1) = 0.51 and 0.45.

Grade F: 1-(2-Amino-3-(2-benzyloxypheninpropyl)-2(S)-butyl-4-(1-naphthoyl)piperazine bis trifluoroacetate salt

A solution of N-Boc amine from Step E (70 mg) in EtOAc (15 mL) was treated with HCl (gas) until saturated. After 15 minutes, the solution is purged with argon, then the solvent is removed to give a solid. Purification by preparative HPLC C-18 column, H2O/CH3CN with 0.1% TFA; gradient) gives (after lyophilization) the title compound as a powder. FAB mass spectrum, m/z = 536 (m+1).

Analysis calculated for C35H41N3O2 • 2.2 TFA • 2.2 TFA • 0.35 H2O C, 59.68; H, 5.58; N, 5.30

Found: C, 59.70; H, 5.60; N, 5.56

Example 22

1-(2-Amino-3-(2-hydroxyphenyl)propyl)-2(S)-butyl--4-(1-naphthoyl)piperazine bis trifluoroacetate salt, diastereoisomer A

Grade A: 1-(2-N-Boc-Amino-3-(2-hydroxyphenyl)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine

2-(2-N-Boc-amino-3-(2-benzyloxyphenyl)propyl-2(S)-butyl-4-(1-naphthoyl)piperazine mixture (from Example 19, Step E; 290 mg, 0.5 mmol) , acetic acid (60 μl, 1.0 mmol) and 20% Pd(OH) on charcoal (100 mg) in MeOH (20 ml) was hydrogenated at 67 psi for 5 h. The solution was filtered through celite and the solvent was evaporated, the silica column chromatography (silica gel; hexane:EtOAc 1:1) gives:

a) diastereoisomer A of the title compound Rf (silicon dioxide; hexane/EtOAc 1:1) = 0.49

b) diastereoisomer B of the title compound Rf (silicon dioxide; 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, diastereoisomer A

N-Boc-Amine, diastereoisomer A from Step A, is deprotected using HCl (gas) in EtOAc. Solvent removal followed by HPLC (C-18 column; H2O/CH3Cn with 0.1 TFA; gradient afforded (after lyophilization) the title compound as a powder. FAB mass spectrum, m/z = 446 (m+1).

Analysis calculated for C28H35N3O2 • 2 TFA C, 57.05; H, 5.54; N, 6.24

Found C, 57.08; H, 5.64; N, 6.32

Grade A: Ethyl 3-(4-imidazolyl)propionate

The title compound is obtained from urocanic acid.

Aldrich) in two steps using standard chemical procedures (esterification using HCl in EtOAc followed by hydrogenation with 10% Pd-C EtOH).

1H NMR (CDCl3): δ 1.23 (3H, t), 2.65 (2H, t), 2.94 (2H, t), 4.15 (2H, q), 6.81 (1H, S), 7.56 (1H, s).

Step B: 3-(4-imidazolyl)propanol

To a solution of Step A (120 g, 71.4 mmol) in dry THF (230 mL) at 0°C, LAH (2.99 g, 78.6 mmol) was added portionwise over 30 minutes. The mixture was stirred for 2 hours at room temperature, then cooled again to 0°C and H2O (4.2 ml) was added dropwise. After that, 10.6 ml of 1N NaOH is added dropwise, and then the resulting suspension is stirred at room temperature for 1 hour. After filtration through celite and washing with EtOAc, the solvent was removed to give the title compound as a clear oil (8.16 g).

1H NMR (CD3OD): δ 1.84 (2H pentet), 2.68 (2H, t), 3.58 (2H, t), 6.88 (1H, s), 7.80 (1H, s).

Step C: (4-N-Boc-imidazolyl)propanol

The imidazole from Step B (166 mg, 1.32 mmol), (Boc) 2 O (302 mg, 1.38 mmol) and K 2 CO 3 (190 mg, 1.38 mmol) were stirred in THF (10 mL) for 2 hours. After filtration, the solvent is removed in vacuo, yielding the desired compound as an oil. Rf (silica; 5%MeOH/CHCl3 = 0.17. It is used as such in the next step.

Grade D: 1-(3-(4-imidazolyl)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine bis trifluoroacetate salt

The alcohol from Stage C (~1.32 mmol) is dissolved in 4 ml of DMSO, 4 ml of CH2Cl2 and 0.92 ml of Et3N and then the pyridine SO3 complex (600 mg, 5.28 mmol) is added in portions.

After 3 hours, the mixture was poured into EtOAc, extracted with saturated solution, dried and evaporated to give the corresponding aldehyde which was used without further purification. The aldehyde is cleaved with the piperazine of Example 1, Step E by reductive alkylation according to the procedure described for Example 19, Step C and the product is obtained by column chromatography (silica gel; 5% MeOH/CHCl 3 ). This product was dissolved in 10 ml of EtOAc, saturated with HCl (gas). The solvent is removed and the residue is purified by preparative HPLC (C-18; H2O/CH3CN with 0.1% TFA; gradient). By lyophilization of the frozen aqueous solution, the title compound and a hygroscopic powder are obtained. FAB mass spectrum, m/z = 405 (m+1)

Analysis calculated for C25H32N4O • 2.35 TFA • 0.4 H2O

C, 52.48; H, 5.21; N, 8.24

Found: C, 52.45; H, 5.22; N, 8.27

Example 24

2(S)-n-Butyl-4-(1-naphthoyl)-1-(1-(1-naphthylmethyl)imidazol-5-ylmethyl/piperazine salt of ditrifluoroacetic acid

The title compound was obtained from 2(S)-n-butyl-1-(5-(3-triphenylmethylimidazolyl)methyl)-4-(1-naphthoyl)piperazine (0.124 g, 0.200 mmol) and 1-bromomethylnaphthalene (0.046 g, 0.21 mmol) according to the procedure described in Example 4. The title compound is obtained after purification by reverse-phase preparative HPLC (elution gradient 30%-75% acetonitrile/0.1% TFA; 70%-25% 0.1% aqueous TFA over 50 minutes) and lyophilization . FAB ms (m+1) 517.

Analysis calculated for C34H36N4O • 2.0 TFA

C, 60.55; H, 5.22; N, 7.43

Found: C, 60.48; H, 5.12; N, 7.42.

Example 25

2(S)-Butyl-4-(1-naphthoyl)-1-(1-(2-naphthylmethyl)imidazol-5-ylmethyl)-piperazine salt of ditrifluoroacetic acid

The title compound was obtained from 2(S)-n-butyl-1-(5-(3-triphenylmethylimidazolyl)methyl)-4-(1-naphthoyl)piperazine (0.124 g, 0.200 mmol) and 2-bromomethylnaphthalene (0.046 g, 0.21 mmol) and 2-bromomethylnaphthalene (0.046 g, 0.21 mmol) according to the procedure described in Example 4. The title compound is obtained after purification by reverse-phase preparative HPLC (gradient elution with 30%-75% acetonitrile/0.1% TFA; 70%-25 % 0.1 % aqueous TFA during 50 minutes) and lyophilization FAB ms (m+1) 517.

Analysis Calculated for C34H36N4O • 2.0 TFA

C, 58.87; H, 5.38; N, 7.23

Found: C, 58.90; H, 4.93; N 7.13.

Example 26

Ditrifluoroacetic acid 2(S)-n-butyl-1-(1-(4-cyanobenzyl)imidazol-5-ylmethyl)-4-(1-naphthoyl)piperazinol

The title compound is obtained from 2(S)-n-butyl-1-(5-(3-triphenylmethylimidazolyl)methyl)-4-(1-naphthoyl)piperazine (0.124 g, 0.200 mmol) 14-cyanobenzyl bromide (0.041 g, 0.21 mmol) according to the procedure described in Example 4. The title compound is obtained after purification by reverse-phase preparative HPLC (gradient elution with 25%-65% acetonitrile/0.1% TFA; 75%-35% 0.1% aqueous TFA during 50 minutes) and lyophilization FAB ms (m+1) 492.

Analysis calculated for C31H33N5O • 2.0 TFA:

C, 57.91; H, 4.96; N, 9.65

Found: C, 57.93; H, 4.91; N, 9.55.

Example 27

2(S)-n-butyl-1-(1-(4-methoxybenzyl)imidazol-5-ylmethyl)-4-(1-naphthoyl)piperazine salt of ditrifluoroacetic acid

The title compound is obtained from 2(S)-n-butyl-1-(5-(3-triphenylmethylimidazolyl)methyl)-4-(1-naphthoyl)piperazine (0.124 g, 0.200 mmol) and 4-methyloxybenzyl chloride (0.041 ml, 0.21 mmol) according to the procedure described in Example 4, with the addition of potassium iodide (100 g) to the reaction mixture. The title compound is 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 minutes) and lyophilization FAB ms (m+1) 497.

Analysis Calculated for C31H36N4O2 • 1.7 H2O • 2.0 TFA;

C, 53.40; H, 5.30; N, 7.12

Found: C, 53.37; H, 4.78; N, 7.00.

Example 28

2(S)-n-Butyl-1-(1-(3-methyl-2-butenyl)imidazol-5-ylmethyl)-4-n-naphthoyl)piperazine salt of ditrifluoroacetic acid

The title compound is obtained from 2(S)-n-butyl-1-(5-(3-triphenylmethylimidazolyl)methyl)-4-(1-naphthoyl)piperazine (0.124 g, 0.200 mmol) and 4-bromo-2-methyl -2-butene (0.024 ml, 0.21 mmol) according to the procedure described in Example 4. The title compound is obtained after purification by reverse-phase preparative HPLC (gradient elution with 5%-95% acetonitrile 0.1% TFA: 95%-5% 0.1% aqueous TFA in progress 50 minutes) and lyophilization FAB ms(m+1)445.

Analysis Calculated for C28H36N4O • 2.0 TFA:

C, 54.51; H, 5.95; N, 7.95

Found: C, 54.54; H, 5.39; N, 7.73

Example 29

2(S)-n-Butyl-1-(1-(4-fluorobenzyl)imidazol-5-ylmethyl)-4-(1-naphthoyl)piperazine salt of ditrifluoroacetic acid

The title compound is obtained from 2(S)-n-butyl-1-(5-(3-triphenylmethylimidazolyl)methyl)-4-(1-naphthoyl)piperazine (0.124 g, 0.200 mmol) and 4-fluorobenzyl bromide (0.024 ml, 0.21 mmol) according to the procedure described in Example 4. The title compound is 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 minutes) and lyophilization. FAB ms (m+1) 485.

Analysis Calculated for C30H33FN4O • 2.0 TFA:

Example 30

2(S)-n-Butyl-1-(1-(4-chlorobenzyl)imidazol-5-ylmethyl)-4-(1-naphthoyl)piperazine salt of ditrifluoroacetic acid

The title compound was obtained from 2(S)-n-butyl-1-(5-(3-triphenylmethylimidazolyl)methyl)-4-(1-naphthoyl)piperazine (0.124 g, 0.200 mmol) and 4-chlorobenzyl chloride (0.034 mg, 0.21 mmol) according to the procedure described in Example 4, with the addition of sodium iodide (100 mg) to the reaction mixture. The title compound is obtained after purification by reverse-phase preparative HPLC (gradient elution with 25%-65% acetinitrile/0.1% TFA; 75%-35% 0.1% aqueous TFA over 50 minutes) and lyophilization ms (m+1) 501.

Analysis Calculated for C30H33CIN4O • 2.0 TFA:

C, 50.07; H, 5.51; N, 6.87.

Found: C, 50.10; H, 4.25; N, 6.48.

Example 31

1-(1-(4-Bromobenzeneimidazol-5-ylmethyl)-2(S)-n-butyl-4-perazine salt of ditrifluoroacetic acid

The title compound salt is obtained from 2(S)-n-butyl-1-(5-(3-triphenylmethylimidazolyl)methyl)-4-(1-naphthoyl)piperazine (0.124 g, =200 mmol) and 4-bromobenzyl bromide (0.053 mg) , 0.21 mmol) according to the procedure described in Example 4 with the addition of sodium iodide (100 mg) to the reaction mixture. The title compound is obtained by purification by reverse-phase preparative HPLC (gradient elution with 30%-65% acetonitrile/0-1% TFA; 70%-35% 0.1% aqueous TFA over 50 minutes) and lyophilization. FAB ms (m+1) 545.

Analysis Calculated 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.

Example 32

2(S)-n-butyl-4-(1-naphthoyl)-1-(1-(4-trifluoromethylbenzyl)-imidazol-5-ylmethyl)-piperazine salt of ditrifluoroacetic acid

The title compound was obtained from 2(S)-n-butyl-1-(5-(3-triphenylmethylimidazolylmethyl)-4-(1-naphthoyl)piperazine (0.124 g, 0.200 mmol) and 4-trifluoromethylbenzyl bromide (0.053 mg, 0.21 mmol). ) according to the procedure described in Example 4. The title compound is obtained after purification by reverse-phase preparative HPLC (gradient elution with 30%-65% acetonitrile,/0.1% TFA; 70%-35% 0.1% aqueous TFA during 50 minutes) and lyophilization FABms(m+1)535.

Analysis Calculated for C30H33BrN4O • 2.0 TFA:

C, 55.12; H, 4.63; N, 7.35

Found: C, 57.46; H, 4.98; N, 7.84.

Example 33

2(S)-n-butyl-1-(1-(4-methylbenzyl)-imidazol-5-ylmethyl)-4-(1-naphthoyl)piperazine salt of ditrifluoroacetic acid

The title compound was obtained from 2(S)-n-butyl-1-(5-(3-triphenylmethylimidazolyl)methyl)-4-(1-naphthoyl)piperazine (0.124 g, 0.200 mmol) and 4-methylbenzyl bromide (0.029 ml, 0.21 mmol) according to the procedure described in Example 4, with the addition of sodium iodide (100 mg) to the reaction mixture. The title compound is obtained after purification by reverse-phase preparative HPLC (gradient elution with 30%-65% acetonitrile/0.1% TFA; 70%-, 35% 0.1% aqueous TFA during 50 minutes) and lyophilization. FAB ms (m+ 1) 481.

Analysis Calculated for C31H36N4O • 2.6 H2O • 2.0 TFA:

C, 67.26; H, 6.92; N, 10.12

Found: C, 69.60; H, 6.98; N, 10.51.

Example 34

2(S)-n-butyl-1-(1-(3-methylbenzyl)-imidazol-5-ylmethyl)-4-(1-naphthoyl)piperazine salt of ditrifluoroacetic acid

The title compound was obtained from 2(S)-n-butyl-1-(5-(3-triphenylmethylimidazolyl)methyl)-4-(1-naphthoyl)piperazine (0.124 g, 0.200 mmol) and 4-methylbenzyl bromide (0.029 ml, 0.21 mmol) according to the procedure described in Example 4, with the addition of sodium iodide (100 mg) to the reaction mixture. The title compound is 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 minutes) and lyophilization. FABms(m+1)481.

Analysis Calculated for C31H36N4O • 2.6 H2O • 2.0 TFA:

C, 67.26; H, 6.92; N, 10.12

Found: C, 69.60; H, 6.98; N, 10.51

Example 35

1-(1-(4-Phenylbenzyl)imidazol-5-ylmethyl)-2(S)-n-butyl-4-(1-naphthoyl)piperazine salt of ditrifluoroacetic acid

The title compound was obtained from 2(S)-n-butyl-1-(5-(3-triphenylmethylimidazolyl)methyl)-4-(1-naphthoyl)piperazine (0.124 g, 0.200 mmol) and 4-ethylbenzyl bromide (0.029 ml, 0.21 mmol) according to the procedure described in Example 4, with the addition of sodium iodide (100 mg) to the reaction mixture. The title compound is 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 minutes) and lyophilization. FABms(m+1)481.

Analysis Calculated for C36H38N4O • 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.

Example 36

2(S)-n-butyl-4-(1-naphthoyl)-1-(1-(2-phenyethyl)imidazol-5-ylmethyl)-piperazine salt of ditrifluoroacetic acid

The title compound was obtained from 2(S)-n-butyl-1-(5-(3-triphenylmethylimidazolyl)methyl)-4-(1-naphthoyl)piperazine (0.124 g, 0.200 mmol) and 4-phenylethyl bromide (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 hours. The title compound is 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 minutes) and lyophilization. FABms(m+1)481.

Analysis Calculated for C36H38N4O • 4.95 H2O • 2.0 TFA:

C, 53.60; H, 5.96; N, 7.14

Found: C, 53.54; H, 4.86; N, 6.86.

Example 37

2(S)-n-butyl-4-(1-naphthoyl)-1-(1-(4-trifluoromethoxy)imidazol-5-ylmethyl)-piperazine salt of ditrifluoroacetic acid

The title compound is obtained from 2(S)-n-butyl-1-(5-(3-triphenylmethylimidazolyl)methyl)-4-(1-naphthoyl)piperazine (0.124 g, 0.200 mmol) and 4-trifluoromethoxybenzyl bromide (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 hours. The title compound is obtained after purification by reverse-phase preparative HPLC (gradient elution with 35%-70% acetonitrile/0.1% TFA; 65%-30% 0.1% aqueous TFA over 50 minutes) and lyophilization. FAB ms (m+1) 551.

Analysis Calculated 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.

Example 38

Preparation of 1-[/1-(4-cyanobenzyl)-1H-imidazol-5-yl/acetyl]-2(S)-n-butyl-4-(1-naphthoyl)piperazine trifluoroacetate

Step A: Preparation of 1H-imidazole-4-acetic acid methyl ester rochloride

A solution of 1H-imidazole-4-acetic acid hydrochloride (4.00 g, 24.6 mmol) in methanol (100 ml) was saturated with hydrogen chloride gas. The obtained solution is left to stand at room temperature (st) for 1 hour.

The solution was evaporated in vacuo to give the title compound as a white solid.

1H NMR (CDCl 3 , 400 MHz) δ 8.85 (1H, s), 7.45 (1H, s), 3.89 (2H, s) and 3.75 (3H, s) ppm.

Step B: Preparation of 1-(triphenylmethyl)-1H-imidazole-4-acetic acid methyl ester

To a solution of the product from Step A (24.85 g, 0.141 mol) in dimethyl formamide (DMF) (155 ml) was added triethylamine (57.2 ml, 0.412 mol) and triphenylmethyl bromide (55.3-g, 0.171 mol) and the suspension was stirred for 24 hours. . After this time, the reaction mixture is diluted with ethyl acetate (EtOAc) (1 liter) and water (350 ml). The organic phase is washed with a saturated aqueous solution of NaGCO3 (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 give the title compound as a white solid.

1H NMR (CDCl3, 400 MHz) δ 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 methyl ester / 1-(4-cyanobenzyl)-1H-imidazol-5-yl/acetic acid

To a solution of the product from Step B (8.00 g, 20.9 mmol) in acetonitrile (70 ml), bromo-p-toluenenitrile (4.10 g, 20.92 mmol) was added and heated to 55°C for 3 hours. After this time, the reaction is cooled to room temperature and the resulting imidazolium salt (white precipitate) is collected by filtration. The filtrate is heated to 55°C for 18 hours. The reaction mixture was cooled to room temperature and evaporated in vacuo. ETOAc (70 ml) was added to the residue and the obtained product was concentrated by filtration. The precipitated imidazolium salts are combined, suspended in methanol (100 ml) and heated to reflux for 30 minutes. After this time, the solvent is removed in vacuo, the resulting residue is suspended in EtOAc (75 ml) and the solid is isolated by filtration and washed with (EtOAc).

The solid was treated with a saturated aqueous solution of NaHCO3 (300 ml) and CH2Cl2 (300 ml) and stirred at room temperature for 2 hours. The organic layer was separated, dried (MgSO4) and evaporated in vacuo to give the title compound as a white solid:

1H NMR (CDCl3, 400 MHz) δ 7.65 (1H, d, J=8 Hz), 7.53 (1H, s), 7.15 (1H, d, J=8 Hz), 7.04 (1H, s), 5.24 (2H , s), 3.62 (3H, s) and 3.45 (2H, s) ppm.

Step D: Preparation of /1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetic acid

A solution of methyl ester/1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetic acid (4.44 g, 17.4 mmol) in THF (100 ml) and 1M lithium hydroxide (17.4 ml, 17.4 mmol) was stirred at room temperature. temperature for 18 hours. 1M HCl (17.4 ml) was added and the THF was removed by evaporation in vacuo. The aqueous solution is lyophilized to give a compound containing lithium chloride as a white solid.

1H NMR (CD3OD, 400 MHz) δ 8.22 (1H, s), 7.74 (1H, d, J=8.4 Hz) 7.36 (1H, d, J=8.4 Hz), 7.15 (1H, s), 5.43 (2H, s) and 3.49 (2H, s) ppm.

Step E: Preparation of 1-[/1-(4-cyanobenzyl)-1H-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 of Example D (117 mg, 0.35 mmol), HOOBT (58 mg, 0.35 mmol) and triethylamine (0.123 ml, 0.88 mmol) in DMF (2 ml ), EDC (75 mg, 0.38 mmol) is added. The reaction is stirred at room temperature for 16 hours, diluted with EtOAc and the organic layer is separated with saturated aqueous NaHCO3 solution, brine, dried (Na2SO4) and evaporated in vacuo. The residue is purified by preparative HPLC (C-18, 95:5 to 5:95 water:CH3CN containing 0.1% trifluoroacetic acid; gradient elution). Lyophilization of the precipitated fractions afforded the title compound as a white solid.

1H NMR (CD3OD, 400 MHz) δ 9.00-8.9-0 (1H, m), 8.05-7.9.4 (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.

Analysis calculated for C32H33N5O2, 1. 40 TFA; 0.55 H2O:

C, 60.65; H, 5. 19; N, 10.16.

Found: C, 60.66; H, 5.17; N, 10.06

Example 39

5(S)-n-Butyl-1 (2,3-dimethylphenyl)-4-(4-imidazolylmethyl)piperazin-2-ene ditrifluoroacetic acid salt

Grade A: N-Methoxy-N-methyl-2(S)-(tert-butoxycarbonyl-amino)hexanamide

2(S)-(tert-Butoxycarbonylamino)caproic acid (24.6 g, 0.106 mol), N,O-dimethylhydroxylamine hydrochloride (15.5 g, 0.15 mol) EDC hydrochloride (22.3 g, 0.1 17 mmol) and HOBT (14.3 g, 0.106 moles) are stirred in dry degassed DMF (300 ml) at 20°C under nitrogen. N-methylmorpholine was added to give pH 7. The reaction was stirred overnight, the DMF was distilled off under high vacuum, and the residue was partitioned between ethyl acetate and 2% potassium bisulfate. The organic phase is washed with saturated sodium bicarbonate solution, water, and saturated brine, and dried with magnesium sulfate. The solvent is removed in vacuo to give the title compound.

Step B: 2(S)-(tert-Butoxycarbonylamino)hexanal

A mechanically stirred suspension of lithium aluminum hydride (5.00 g, 0.131 mol) in ether (250 ml) was cooled to -45°C under nitrogen. A solution of the product from Step A (28.3 g, 0.103 mol) in ether (125 ml) is added, maintaining the temperature below -35°C. When the addition is complete, the reaction is warmed to 5°C, then cooled again to -45°C. A solution of potassium bisulfate (27.3 g, 0.200 mol) in water is added slowly, keeping the temperature below -5°C. After stopping, the reaction is stirred at room temperature for 1 hour. The mixture is filtered through celite, the ether is evaporated and the residue is partitioned between ethyl acetate and 2% potassium bisulfate. After washing with saturated saline solution, drying over magnesium sulfate and removing solvents, the title compound is obtained.

Grade C: N-(2,3-Dimethylphenyl)-2(S)-(tert-butoxycarbonylamino)hexanamine

2,3-Dimethylaniline (8.32 mL, 68.3 mmol) was dissolved in dichloroethane under nitrogen. Add acetic acid to give a pH of 5, sodium triacetoxyborohydride (17.2 g, 80.8 mmol) and crushed molecular sieves (4 g). 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 is stirred overnight, quenched with saturated sodium bicarbonate solution. The aqueous layer is removed, and the organic layer is washed with saturated brine and dried over magnesium sulfate. Crystallization from hexane gives the title compound.

Grade D: 4-tert-Butoxycarbonyl-5(S)-n-butyl-1-(2,3-dimethylphenyl)piperazin-2-ene

A solution of the product from Step C (8.50 g, 26.5 mmol) in ethyl acetate (250 ml) is stirred vigorously at a temperature of 0°C with a saturated solution of sodium bicarbonate (150 ml). Chloroacetyl chloride (2.33 mL, 29.1 mmol) was added, and the reaction was stirred at 0°C for 1 hour. The layers are separated, the ethyl acetate phase is washed with saturated saline, 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) is added in portions to maintain moderate hydrogen evolution. After 30 minutes, an additional amount of sodium hydride (0.8 g) is added. The reaction is stirred for another 30 minutes, then quenched with saturated ammonium chloride solution. The DMF was distilled off in vacuo, and the residue was partitioned between ethyl acetate and water. The organic phase is 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 afford the title compound.

Grade E: 5(S)-n-Butyl-1-(2,3-dimethylphenyl)-4-(4-n-triphenylmethylimidazolyl)methyl-piperazin-2-ene

A solution of the product from Step D (0.570 g, 1.58 mmol) in ethyl acetate (50 ml) was cooled to -15°C under nitrogen. HCl gas is blown through this solution for 15 minutes, and the reaction solution is heated to 0°C for 2 hours. 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-imidazolyl carboxyaldehyde (0.534 g, 1.58 mmol) were added. The reaction was stirred overnight at 20°C, then poured into saturated sodium bicarbonate solution. The organic phase is washed with saturated saline and dried over magnesium sulfate. Silica gel chromatography using 4% methanol in dimethylchloromethane as eluent afforded the title compound.

Grade F: Ditrifluoroacetic acid 5(S)-n-butyl-1-(2,3-dimethylphenyl)-4-(4-imidazolylmethyl)-piperazin-2-ene salt

Triethylsilane (0.254 ml) and trifluoroacetic acid (2 ml) were added to a solution of the compound from Step E (0.233 g, 0.40 mmol) in dichloromethane (6 ml) and the reaction was stirred at 20°C for 2 hours. The volatiles were removed in vacuo, and the residue was partitioned between hexane and water-methanol. The aqueous phase is injected onto a preparative HPLC column and purified with a mixed gradient of 15%-60% acetonitrile/0.1% TFA; 85%-40% 0.1% aqueous TFA during 50 minutes. The title compound is isolated after lyophilization. FAB ms (m+1) 341.

Analysis calculated for C20H28N4O • 2.0 TFA: C, 50.80; H, 5.15;

Example 40

5(S)-n-Butyl-4-(1-(4-cyanobenzyl)imidazol-5-ylmethyl)-1-(2,3-dimethylphenyl)piperazin-2-ene 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) of piperazin-2-ene (0.120 g, 0.21 mmol) from Example 39, Step E, in acetonitrile (10 ml). After 48 hours, the solvent was removed in vacuo, and the crude product was dissolved in dichloromethane (6 mL). Triethylsilane (0.13 ml) and trifluoroacetic acid (2 ml) were added, and the reaction was stirred at 20°C for 2 hours. The volatiles were removed in vacuo, and the residue was partitioned between hexane and water-methanol. The aqueous phase is injected onto a reverse-phase preparative HPLC column and purified by a mixed gradient of 30%-60% acetonitrile/0.1% TFA; 70%-40% 0.1% aqueous TFA during 50 minutes. The title compound is isolated by lyophilization from a water solution (m+1)456.

Analysis calculated for C28H33N5O • 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.

Example 41

4-(1-(4-Cyanobenzyl)imidazol-5-ylmethyl)-1-(2,3-dimethylphenyl)-5(S)-(2-methoxyethyl)piperazin-2-ene ditrifluoroacetic acid salt

Grade A: N-Methoxy-N-methyl-4-benzyloxy-2(S)-(tert-butoxycarbonylamino)butanamide

4-Benzyloxy-2(S)-tert-butoxycarbonylamino)butyric acid (1.00 g, 3.23 mmol) was converted to the title compound by 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 processing, the title compound is obtained as a breathable rubber.

Grade B: 4-(1-Benzyloxyethyl)-2(S)-(tert-butoxycarbonylamino)-butanal

The title compound is obtained by reduction with lithium aluminum hydride of the product from Step A, using the procedure described in Example 39, Step B.

Grade C: N-(2,3-Dimethylphenyl)-4-(2-benzyloxyethyl)-2(S)-(tert-butoxycarbonylamino)-butanamine

The title compound was obtained from the product of Step C according to the procedure described in Example 39, Step B, using 2,3-dimethylaniline (0.505 ml, 4.14 mmol), sodium triacetoborohydride (1.20 g, 5.65 mmol) and crushed molecular sieves (1 g) at pH 5 in dichloroethane (20 ml). The title compound is obtained after purification on silica gel, eluting with 15% ethyl acetate in hexane.

Grade D: 5(S)-(2-Benzyloxyethyl)-4-tert-butoxycarbonyl-1-(2,3-dimethylphenyl)piperazin-2-ene

The title compound was obtained from the product of Column C according to the procedure described in Example 39, Step D, using chloroacetyl chloride (0.21 ml, 2.57 mmol) in 60 ml of 1:1 ethyl acetate:saturated sodium bicarbonate, followed by the reaction of crude sodium hydride (0.373 g, 60% dispersion in oil, 9.32 mmol) in DMF (30 ml). After workup, the crude product was chromatographed on silica gel with 30% methyl acetate in hexane to give the title compound.

Grade E: 4-tert-Butoxycarbonyl-1-(2,3-dimethylphenyl)-5(S)-(2-hydroxyethyl)piperazin-2-ene

The product from Step D is dissolved in methanol (40 ml) and 10% Pd/C (0.160 g) is added. The reaction is stirred under 60 Psi hydrogen overnight. The catalyst is removed by filtration, and the solvent is evaporated to give the title compound.

Grade F: 4-tert-Butoxycarbonyl-1-(2,3-dimethylphenyl)-5(S)-(2-hydroxyethyl)piperazin-2-ene

The product from Step E (0.241 g, 0.688 mmol) was dissolved in DMF (10 mL) containing methyl iodide (0.21 mL, 3.44 mmol) and the solution was stirred and cooled to 0°C under nitrogen. Sodium hydride (0.070 g, 60% dispersion in oil, 1.72 mmol) was added and the reaction was stirred for 1 hour. The reaction is quenched with water, and the DMF is removed under vacuum. The residue was partitioned between ethyl acetate and water, and the organic phase was washed with saturated brine and dried over magnesium sulfate. The crude product is chromatographed on silica gel with 40% ethyl acetate in hexane to give the title compound.

Grade G: 1-(2,3-dimethylphenyl)-5(S)-(2-methoxyethyl)-4-(1-triphenylmethylimidazolyl)methyl/piperazin-2-ene_

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 hour for initial deprotection. The volatiles are removed in vacuo, and the residue is dissolved in dichloroethane. Triethylamine was added to give pH 5. Sodium triacetoxyborohydride (0.100 g, 0.468 mmol) and 1-triphenylmethyl-4-imidazolyl-carboxyaldehyde (0.1164 g, 0.343 mmol) were added. The reaction was stirred overnight at 20°C and then poured into sodium bicarbonate solution. The organic phase is washed with saturated saline solution and dried over magnesium sulfate. Silica gel chromatography using 5% methanol in chloroform as eluent afforded the title compound.

Step H: Ditrifluoroacetic acid 4-(1-(4-Cyanobenzyl)imidazol-5-ylmethyl)-1-(2,3-dimethylphenyl)-5(S)-(2-methoxyethyl)piperazin-2-ene salt

The product from Step G (0.182 g, 0.312 mmol) was converted to the title compound according to the procedure described in Example 40, using 4-cyanobenzylbromide (0.061 g, 0.312 mmol) in acetonitrile (10 mL), followed by reaction of the crude imidazolium salt with triethylsilane ( 0.13 ml) and trifluoroacetic acid (2 ml) in dichloromethane (6 ml). Purification is achieved by reverse phase preparative HPLC with a mixed gradient of 0%-70% acetonitrile/0.1% TFA; 100%-30% 0.1% aqueous TFA during 60 minutes. The title compound is isolated from water after lyophilization. FAB ms (m+1) 458.

Analysis calculated for C27H31N5O2 • 2.0 TFA:

C, 53.81; H, 4.91; N, 10.21

Found: C, 53.83; H, 4.95; N, 10.29.

Example 42

Preparation of (S)-1-(3-Chlorophenyl)-4-/1-(4-cyanobenzyl)-5-imidazolylmethyl/-5-(2-methanesulfonyl)ethyl/-2-piperazinone dihydrochloride

Step A: Preparation of 1-triphenylmethyl-4-(hydroxymethyl)-imidazole

Triethylamine (90.6 ml, 650 mmol) was added to a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260 mmol) in 253 ml of dry DMF at room temperature. A white solid precipitated from the solution. Chlorotriphenylmethane (76.1 g, 273 mmol) in 500 ml DMF was added dropwise. The reaction mixture was stirred for 20 hours, poured over ice, filtered, and washed with ice water. The resulting product is suspended with cold dioxane, filtered and dried in vacuo to give the title compound as a white solid that is pure enough for use in the next step.

Step B: Preparation of 1-triphenylmethyl-4-(acetoxymethyl)-imidazole

Alcohol from Grade A (260 mmol), obtained above is suspended in 500 ml of pyridine. Acetic anhydride (74 ml, 780 mmol) was added dropwise, and the reaction was stirred for 48 hours, during which time it became homogeneous. The solution was taken up in 2 L of EtOAc, washed with water (3 x 1 L), 5% aqueous HCl (2 x 1 L), saturated aqueous NaHCO 3 , and brine, then dried (Na 2 SO 4 ), filtered, and concentrated in a vacuum, whereby the crude product is obtained. The acetate is isolated as a white powder that is pure enough to be used in the next reaction.

Step C: Preparation of 1-(4-cyanobenzyl)-5-(hydroxymethyl)imidazole

A solution of the product from Step B (85.8 g, 225 mmol) and α-bromo-p-toluenenitrile (50.1 g, 232 mmol) in 500 mL EtOAc was stirred at 60°C for 20 h, during which time a light yellow precipitate formed. The reaction is cooled to room temperature and filtered to give the solid imidazolium bromide salt. The filtrate is concentrated in vacuo to a volume of 200 ml, heated again at 60°C for two hours, cooled to room temperature, and filtered again. The filtrate was concentrated in vacuo to a volume of 100 ml, reheated to 60°C for another two hours, cooled to room temperature, and concentrated in vacuo to give a light yellow solid. The entire solid material is combined, dissolved in 500 ml of methanol and heated to 60°C. After two hours, the solution was concentrated again in vacuo to give a white solid which was eluted with hexane to remove soluble materials. Removal of the remaining solvents in vacuo gives the hydrobromide of the title product as a white solid which is used in the next step without further purification.

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 liters 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 aqueous NaHCO 3 and brine. The solution is then dried (Na2SO4), filtered, and concentrated in vacuo to give the crude product as a light yellow fine-grained substance, which is pure enough to be used in the next step without further purification.

Step E: Preparation of 1-(4-cyanobenzyl)-5-imidazole-carboxyaldehyde

Triethylamine (56 ml, 402 mmol), then SO3-pyridine complex (40.5 g, 254 mmol) is added to a solution of alcohol from Grade D (21.5 g, 101 mmol) in 500 ml of DMSO at room temperature. After 45 minutes, the reaction was poured into 2.5 liters of EtOAc, washed with water (4 x 1 liters) and brine, dried (NaSO4), filtered to give the aldehyde as a white powder that was pure enough to be used in the next step (Step L) without further purification.

Step F: Preparation of (S)-2-(tert-butoxycarbonylamino)-N-methoxy-N-methyl-4-(methylthio)butanamide

L-N-Boc-methionine (30.0 g, 0.120 mmol), N,O-dimethylhydroxylamine hydrochloride (14.1 g, 0.144 mmol), EDC hydrochloride (27.7 g, 0.144 mmol) and HOBT (19.5 g, 0.144 mmol) were mixed in dry DMF. (300 ml) at 20°C under nitrogen. More N,O-dimethylhydroxylamine hydrochloride (2.3 g, 23 mmol) was added to give pH 7-8. The reaction was stirred overnight, the DMF was distilled to half the original volume under high vacuum, and the residue was partitioned between ethyl acetate and saturated NaHCO 3 . The organic phase is washed with saturated sodium bicarbonate solution, water, 10% citric acid, and brine, and dried with sodium sulfate. The solvent is removed in vacuo to give the title compound.

Step G: Preparation of (S)-2-(tert-butoxycarbonylamino)-4-(methylthio)butanal

A suspension of lithium aluminum hydride (5.02 g, 0.132 mmol) in ether (500 ml) was stirred at room temperature 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 mmol) in ether (200 mL) was added over 30 minutes, maintaining the temperature below -40°C. When the addition is complete, the reaction is warmed to 5°C, then cooled again to -45°C. Analysis by thin-layer chromatography shows an incomplete reaction. The solution is reheated to 5°C, stirred for 30 minutes, and then cooled to -50°C. A solution of potassium bisulfate (72 g, 0.529 mmol) in 200 ml of water is added slowly, keeping the temperature below -20°C. The mixture is warmed to 5°C, filtered through Celite, and concentrated in vacuo to give the title compound.

Step H: Preparation of (S)-2-(tert-butoxycarbonylamino)-N-(3-chlorophenyl)-4-(methylthio)butanamine

To a solution of 3-chloroaniline (10.3 ml, 97.4 mmol), the product of Step G (23.9 g, 97.4 mmol), and acetic acid (27.8 ml, 487 mmol) in dichloroethane (250 ml) under nitrogen was added sodium triacetoxyborohydride (41.3 g, 195 mmol) The reaction was stirred overnight, then quenched with saturated sodium bicarbonate solution. The solution is diluted with CHCl3, and the organic phase is washed with water, 10% citric acid, and brine. The solution is dried over sodium sulfate and concentrated in vacuo to give a crude product (34.8 g) which is chromatographed on silica gel with 20% ethyl acetate in hexane to give the title compound.

Stage I: Preparation of (S)-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-(2-(methylthio)ethyl/piperazin-2-ene)

A solution of the product from Step H (22.0 g, 6.8 mmol) in ethyl acetate (150 ml) was stirred vigorously at 0°C with a saturated solution of sodium bicarbonate (150 ml). Chloroacetyl chloride (5.6 mL, 70.2 mmol) was added dropwise, and the reaction was stirred at 0°C for 2 hours. The layers are separated, and the ethyl acetate phase is washed with 10% citric acid and saturated solution, and dried over sodium sulfate. After concentration in vacuo, the obtained 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 temperature. Another portion of cesium carbonate (10 g, 30 mmol) was added, and the reaction was stirred for 16 hours. The DMF was distilled off in vacuo, and the residue was partitioned between ethyl acetate and dried over sodium sulfate. The crude product is chromatographed on silica gel with 20-25% ethyl acetate in hexane to give the title compound.

Step J: Preparation of (S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-(2-(methanesulfonyl)ethyl/piperazin-2-ene)

A solution of the product from Step 1 (14 g, 37 mmol) in methanol (300 ml) is cooled to 0°C, and a solution of magnesium monoperoxyphthalate (54.9 g, 111 mmol) in 210 ml of MeOH is added over 20 minutes. The ice bath is removed and the solution is allowed to warm to room temperature. After 45 minutes, the reaction is concentrated in vacuo to half the original volume, then stopped by the addition of 2N Na2HCO3 solution. The solution was poured into EtOAc, saturated NaHCO3 solution, and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the crude sulfone. This material was chromatographed on silica gel with 60%-100% ethyl acetate in hexane to give the title compound.

Step K: Preparation of (S)-1-(3-chlorophenyl)-5-(2-(methanesulfonyl)ethyl/piperazin-2-ene)

Anhydrous HCl gas was boiled through a solution of the Boc-protected piperazinone from Step J (1.39g, 3.33 mmol in 0 ml EtOAc at 0°C. The saturated solution was stirred for 35 min, then concentrated in vacuo to give the hydrochloride salt as a white powder. This material is suspended in EtOAc and treated with dilute aqueous NaHCO3. The aqueous phase is extracted with EtOAc, and the combined organic mixture is washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting amine is reconcentrated from of toluene to give the title compound for use in the next step.

Step L: Preparation of (S)-1-(3-chloroenyl)-4-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-5-(2-(methanesulfonyl)ethyl)-2-piperazinone dihydrochloride

To a solution of the amine from Step K (898 mg, 2.83 mmol) and the imidazole carboxyaldehyde from Step E (897 mg, 4.25 mmol) in 15 ml of 2-dichloroethane is added sodium triacetoxyborohydride (1.21 g, 5.7 mmol). The reaction was stirred for 23 hours, then quenched at 0° with saturated NaHCO3 solution. The solution is poured into CHCl3, and the aqueous layer is back-extracted with CHCl3. The combined organic layers are washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The obtained product is purified by silica gel chromatography (95:5:0.5-90:10:0 EtOAc:MeOH:NH4Cl), and the obtained product is taken up in EtOAc/methanol. Then with 2.1 equivalents of 1M HCl/ether solution after concentration in vacuo, the dihydrochloride of the product is isolated as a white powder.

Example 43

Preparation of (S)-1-(3-chlorophenyl)-4-/1-(4-cyanobenzyl)-5-imidazolylmethyl/-5-/2-(ethanesulfonyl)ethyl/-2-piperazinone

dihydrochloride

Step A: Preparation of (S)-N-(tert-butoxycarbonyl)homoserine lactone

To a solution of (S)-homoserine lactone hydrochloride (11.0 g, 79.9 mmol) and di-tert-butylpyrocarbonate (19.2 g, 88.0 mmol) in 160 ml of dichloromethane at 0°C, diisopropylethylamine (13.9 ml, 79.9 mmol) was added in in progress for 3 minutes. The solution is allowed to warm to room temperature. After 3 hours, another portion of di-tert-butylpyrocarbonate (1.75 g, 8.0 mmol) and diisopropylethylamine (0.70 ml, 4.0 mmol) are added, and the mixture is stirred for another 2.5 hours, the solution is washed with 10% citric acid, saturated NaHCO3 solution, and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The obtained material is purified by silica gel chromatography (50%EtOAc/hexane), whereby the pure title compound is obtained.

Step B: Preparation of (S)-N-(tert-butoxycarbonyl)homoserine lactol

Diisobutylaluminum hydride (72.0 ml, 1M in THF, 72 mmol) was added dropwise to a solution from Step A (7.0 g, 35 mmol) in 175 ml of THF at -78°C, while maintaining the reaction temperature below -72°C. After 3 hours, another portion of diisobutylaluminum hydride (10.0 ml, 10 mmol) is added, and then after another 1 hour (20.0 ml, 20 mmol). After another hour, the reaction was quenched with EtOAc at -78°C, then with saturated Na-K-tartaric solution, then warmed to room temperature. The solution was taken up in EtOAc, washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated in vacuo. The obtained material is purified by silica gel chromatography (50% EtOAc/hexane), whereby the title lactol is obtained.

Step C: Preparation of (S)-3-(tert-butoxycarbonylamino)-N-(3-chlorophenyl)-4-hydroxy-1-butanamine

To a solution of lactol from Step B (49 g, 22.2 mmol) of 13-chloroaniline (2.58 ml, 24.4 mmol) in 50 ml of dichloromethane at room temperature, acetic acid (1.27 ml, 22.2 mmol) is added. After 10 minutes, sodium triethoxyborohydride (6.59 g, 31.1 mmol) was added, and the solution was stirred for 1.5 hours. The reaction is quenched with saturated NaHCO3 solution, diluted with CH2Cl2, and the layers are separated. The organic material was dried (Na2SO4), filtered, and concentrated in vacuo to give a solid which was purified by silica gel chromatography (EtOAc/hexane) to give the title amine.

Step D: Preparation of (S)-N-(2-(tert-butoxycarbonylamino)-4-hydroxybutyl)-2-chloro-N-(3-chlorophenyl)acetamide

The aniline derivative from Step C (5.29 g, 16.9 mmol) was dissolved in 60 ml EtOAc and 60 ml saturated NaHCO3 solution, then cooled to 0°C. With vigorous stirring, chloroacetyl chloride (1.48 ml, 18.5 mmol) was added dropwise. After 2 hours, the reaction was diluted with EtOAc, and the organic layer was washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated in vacuo to give the title chloroacetamide, which was used without further purification.

Step E: Preparation of (S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-hydroxyethyl)piperazin-2-ene

To a solution of chloracetamide from Step D (6.32 g, 16.1 mmol) in 80 ml of DMF at 0°C, was added esium carbonate (15.8 g, 48.3 mmol). The solution is stirred until thin-layer chromatographic analysis d+ shows the consumption of the starting material (about 5 hours). The solution was taken up in EtOAc, washed with water and brine, dried (Na 2 SO 4 ), filtered, and concentrated in vacuo to give the crude product. This material is purified by silica gel chromatography (99.1:0-95:5:0.15

CHCl3:MeOH:NH4OH), giving a product containing a minor amount of DMF impurity.

Step F: Preparation of (S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-(2-(methanesulfonyloxy)ethyl-piperazin-2-ene)

To a solution of alcohol from Grade E (3.58 g, 10.1 mmol) in 50 ml of dichloromethane at 0°C, diisopropylethylamine (3.5 ml, 20.2 mmol) is added, followed by methanesulfonyl chloride (0.936 ml, 12.1 mmol). The solution is stirred for 45 minutes, then stopped with 10% citric acid. The solution is washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the crude product which is used in the next step without further purification.

Step G: Preparation of (S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-(2-(ethylthio)ethyl)piperazin-2-ene

To a solution of the mesylate from Step F (3.6 g, 8.3 mmol) in 100 ml of DMF at 0°C is added sodium ethynethiolate (1.4 g, 16.6 mmol). After 2 hours, the reaction was poured into EtOAc, washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the crude product which was used in the next step without further purification.

Step H: Preparation of (S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-(2-(ethanesulfonyl)ethyl/piperazin-2-ene)

To a solution of the product from Step G (3.12 g, 7.82 mmol) in methanol (50 ml) is added a solution of magnesium monoperoxyphthalate (11.6 g, 23.5 mmol) in 50 ml of MeOH at room temperature. After 45 minutes, the reaction is stopped by adding 2N Na2S2O3 solution. The solution is poured into EtOAc and saturated NaHCO3 solution, and the organic layer is dried with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the crude sulfone. This material was chromatographed on silica gel with 2% methanol in chloroform to afford the title compound.

Stage I: Preparation of (S)-1-(3-chlorophenyl)-5-(2-(ethanesulfonineethyl-piperazin-2-ene)

Anhydrous HCl gas was bubbled 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. The saturated solution was stirred for 30 min, then concentrated in vacuo to give the hydrochloride of the title compound as a white powder. This material was suspended in EtOAc and treated with dilute aqueous NaHCO3. The aqueous phase was extracted with EtOAc, and the combined organic mixture was washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated in vacuo to give the title compound suitable for use in the next step.

Step J: Preparation of (S)-1-(3-chlorophenyl)-4-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-5-(2-(ethanesulfonyl)-ethyl)-2-piperazinone dihydrochloride

To a solution of the amine from Step 1 (480 mg, 1.45 mmol), imidazole carboxyaldehyde from Step E from Example 42 (460 mg, 2.2 mmol), and acetic acid (0.415 ml, 7.25 mmol) in 10 ml of 1,2-dichloroethane, is added sodium triacetoxyborohydride (615 mg, 2.9 mmol). The reaction was stirred for 18 hours, then quenched at 0°C with saturated NaHCO3 solution. The solution was taken up in CH2Cl2, and the organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The obtained product is purified by silica gel chromatography (2-5% MeOH:CHCl3), whereby the desired product and the less polar boron complex are obtained. This 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:CHCl3), combined with the earlier crop, taken up in EtOAc/methanol, and treated with 2.1 equivalents of 1M HCl/ether solution.

After concentration in vacuo, the product dihydrochloride is isolated as a white powder.

Example 44

Preparation of (S)-1-(3-chlorophenyl)-4-/1-(4-cyanobenzyl)-5-imidazolylmethyl/-5-/2-(ethanesulfonyl)methyl/-2-piperazinone

dihydrocorride

Step A: Preparation of (S)-2-(tert-butoxycarbonylamino)-N-(3-chlorophenyl)-3-(triphenylmethyl)thio/-1-propanamine

To a solution of 3-chloroaniline (0.709 ml, 6.70 mmol) in 30 ml of dichloromethane at room temperature, 1.2 g of crushed 4A molecular sieves is added. Sodium triacetoborohydride (3.55 g, 16.7 mmol) was added, followed by dropwise addition of N-methylmorpholine to bring the pH to 6.5. L-S-Trityl-N-Boc-cysteinal (3.15 g, 7.04 mmol) (obtained according to S. L. Graham et al., J. Med. Chem., (1994) Vol. 37, 725-732) was added, and a solution is mixed for 48 hours. The reaction was quenched with saturated aqueous NaHCO 3 , diluted with EtOAc, and the layers separated. The organic material is washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give an oil which is purified by silica gel chromatography (15% EtOAc/hexane) to give the amine.

Step B: Preparation of (S)-N-(2-(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 EtOAc and 73 ml saturated NaHCO3 solution, 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 (Na 2 SO 4 ), filtered, and concentrated in vacuo to give the title chloroacetamide, which was used without further purification.

Step C: Preparation of (S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-/S-(triphenylmethyl)thiomethyl/piperazin-2-ene

To a solution of chloracetamide from Step B (3.29 g crude, theoretically 4.95 mmol) in 53 ml of DMF at 0°C, cesium carbonate (4.84 g, 14.85 mmol) is added. The solution is stirred for 48 hours and allowed to warm to room temperature. The solution was taken up in EtOAc, washed with water and brine, dried (Na 2 SO 4 ), filtered, and concentrated in vacuo to give the crude product as an oil. This material was purified by silica gel chromatography (20% EtOAc/hexane) to give the product as a white solid.

Step D: Preparation of (S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-(thiomethyl)piperazin-2-ene

A solution of piperazinone from Step C (625 mg, 1.04 mmol) in degassed EtOAc (38 mL) and EtOH (12 mL) was heated to 30°C. A solution of AgNO3 (177 mg, 1.04 mL) and pyridine (0.084 mL, 1.04 mmol) in 8 mL of EtOH was added, and the solution was heated to reflux. After 45 min, the reaction was concentrated in vacuo and redissolved in 26 ml of degassed EtOAc. H2S gas is blown through this solution for 2.5 minutes, then activated charcoal is added after 4 minutes. The material was filtered through celite and washed with degassed EtOAc, concentrated in vacuo, then re-concentrated from degassed CH2Cl2 to give the crude product which was used without further purification.

Step E: Preparation of (S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-(ethylthio)methyl/piperazin-2-ene

A solution of the thiol from Step D (about 1.04 mmol) in 3 ml of THF is added through a tube to a suspension of NaH (51.4 mg, 60% dispersion in mineral oil, 1.289 mmol) in 2 ml of THF at 0°C. After 10 minutes, ethyl iodide (0.079 ml, 0.988 mmol) was added, and the solution was stirred for 1.5 hours. The reaction was taken up in EtOAc, washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the crude product. This material is purified by silica gel chromatography (1% MeOH/CH2Cl2) to give the title product.

Step F: Preparation of (S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-(ethanesulfonyl)methyl/piperazin-2-ene

To a solution of the sulfide from Step E (217 mg, 0.563 mmol) in 3 ml MeOH at 0°C, a solution of magnesium monoperoxyphthalate (835 mg, 1.69 mmol) in 2 ml MeOH was added. The reaction is stirred overnight, allowed to warm to room temperature. The solution is cooled to 0°C, quenched by the addition of 4 ml of 2N Na2S2O3 solution, and then concentrated in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3, and the organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the crude sulfone as a white waxy solid.

Step G: Preparation of (S)-1-(3-chlorophenyl)-5-4-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-5-(2-(ethanesulfonyl)methyl)-2-piperazinone dihydrochloride

To a solution of the Boc-protected piperazinone from Step F (224 mg, 0.538 mmol) in 5 ml of dichloroethane at 0°C, 2.5 ml of trifluoroacetic acid (TFA) was added. After 45 minutes, the reaction is concentrated in vacuo, then azeotroped with benzene to remove excess TFA. The residue is taken up in 4 ml of 1,2-dichloroethane and cooled to 0°C. to this solution are added 4A molecular sieves (340 mg), followed by sodium triacetoxyborohydride (285 mg, 1.34 mmol) and a few drops of triethylamine to achieve pH = 6. Imidazole carboxyaldehyde from Step E of Example 42 (125 mg , 0.592 mmol) is added, and the reaction is stirred at 0°C. After two days, the reaction was taken up in EtOAc, washed with dilute aqueous NaHCO 3 , and brine, dried (Na 2 SO 4 ), filtered, and concentrated in vacuo. The crude product is 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 during 60 minutes. After concentration in vacuo, the product obtained is partitioned between chloromethane and aqueous NaHCO3, and the aqueous phase is extracted with CH2Cl2. The organic solution is washed with brine, dried (Na2SO4), filtered, and concentrated to dryness to give the product free base, which is taken up in CH2Cl2 and treated with 2 L equivalents of 1M HCl/ether solution. After concentration in vacuo, the product dihydrochloride is isolated as a white powder.

Example 45

Preparation of (S)-1-(3-chlorophenyl)-4-/1-(4-cyanobenzyl)-5-imidazolylmethyl/-5-/N-ethyl-2-acetamido/-2-piperazinone

dihydrochloride

Step A: Preparation of (S)-4-(tert-butoxycarbonyl)-5-(carboxymethyl)-1-(3-chlorophenyl)piperazin-2-ene

DMSO (0.990 ml, 13.9 mmol) was added to a solution of oxalyl chloride (0.608 ml, 6.97 mmol) in dichloromethane (40 ml) at -78°C over 2-3 minutes. The solution is stirred for 10 minutes, and then a solution of alcohol from Stage E from Example 43 (2.06 g, 5.81 mmol) in 10 ml of dichloromethane is added over the course of 5 minutes, maintaining the reaction temperature below -70°C. The reaction was stirred for 10 minutes, then triethylamine (2.43 ml) was added, 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 saturated saline. The solution is dried (Na2SO4), filtered, and concentrated in vacuo to give the title aldehyde.

Step B: Preparation of (S)-4-(tert-butoxycarbonyl)-5-(carboxymethyl)-1-(3-chlorophenyl)piperazin-2-ene

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) at room temperature, a solution of sodium chloride (585 mg, 5.17 mmol) and sodium dihydrogen phosphate (595 mg, 4.31 mmol) in 10 ml of water. the reaction turns yellow, then turns light pink over the course of 45 minutes. The solution was poured into EtOAc, and washed with saturated sodium bisulfite solution. The aqueous layer was acidified to pH 3 with 2.75 M KHSO4 solution, and extracted several times with EtOAc. The combined organic extracts are dried (Na2SO4), filtered, and concentrated in vacuo to give the title carboxylic acid.

Step C: Preparation of (S)-4-(tert-butoxycarbonyl)-5/N-ethyl-2-acetamido/-1-(3-chlorophenyl)piperazin-2-ene

The product from Step B (200 mg, 0.56 mmol), ethylamine hydrochloride (114 mg, 1.4 mmol), EDC hydrochloride (140 mg, 0.73 mmol) and HOBT hydrate (113 mg, 0.84 mmol) were stirred in dry DMF (3 mL) at 0°C under nitrogen. After one hour, the solution is 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 is washed with 10% citric acid, saturated sodium bicarbonate solution, brine, and dried with sodium sulfate. The solvent is 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 title product is obtained from the product of Step C (184 mg, 0.47 mmol) analogously to Example 42, Steps K and L. The product is isolated as a white solid.

Example 46

Preparation of (±)-5-(2-butynyl)-1-(3-chlorophenyl)-4-/1-(4-cyanobenzyl)5-imidazolylmethyl/-2-piperazine dihydrochloride

Step A: Preparation of 1-(methanesulfonyl)-2-butyne

Methanesulfonyl chloride (23.4 g, 134 mmol) was added to a solution of 2-butynol (10.0 ml, 134 mmol) in 200 ml of dichloromethane at 0°C, and then diisopropylethylamine (30 ml, 174 mmol) was added dropwise. After 1.5 hours, the solution was poured into 0.5 N KHSO 4 solution, and the organic layer was washed with brine. The solution is dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound.

Step B: Preparation of (±)-ethyl-2-(phenylmethyl)imino/-4-hexinoate

To a solution of glycine ethyl ester hydrochloride (10.11 g, 72.4 mmol) in 200 ml of dichloromethane, besenaldehyde (7.36 ml, 72.4 mmol), triethylamine (20.0 ml, 143 mmol), and magnesium sulfate (6 g) were added. The solution was stirred at room temperature for 16 hours, filtered through a glass tube, and concentrated in vacuo. The residue was partitioned between ether and water, and the organic layer was washed with brine. The solution is dried over Na2SO4, filtered, and concentrated in vacuo to give a light yellow oil. One part of this oil (9.90 g, 51.8 mmol) is 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 IM, 51.8 mmol) was added dropwise to give 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 THF was added dropwise through the tube, and the solution was warmed to room temperature. After 2 hours, the reaction was poured into EtOAc and washed with sat. NaHCO 3 , brine, dried Na 2 SO 4 , filtered, and concentrated in vacuo to give the title product.

Step C: Preparation of (±)-ethyl-2-(tert-butoxycarbonyl)amino/-4-hexinoate

A solution of the product from Step B (about 51.8 mmol) is stirred at room temperature in a 5% 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 a saturated solution of NaHCO3 (50 ml) was added followed by di-tert-butylpyrocarbonate (11.3 g, 51.8 mmol) at room temperature. After 6 h, the reaction was poured into EtOAc and washed with saturated NaHCO 3 and brine, dried (Na 2 SO 4 ), filtered, and concentrated in vacuo to give the title product.

Step D: Preparation of (±)-ethyl-2-(tert-butoxycarbonyl/amino-4-hexenoic acid)

To a solution of the product from Step C (about 51.8 mmol) in THF (100 ml) and water (20 ml), a solution of lithium hydroxide monohydrate (6.5 g, 155 mmol) was added at 0°C. The solution is stirred for 1 hour at 0°C and then warmed to room temperature. After 48 hours, the solution is concentrated in vacuo. The aqueous mixture is extracted with EtOAc, acidified at 0°C with 10% aqueous and 10% HCl solution, then extracted with three portions of dichloromethane. The combined dichloromethane extracts were dried (Na 2 SO 4 ), filtered, and concentrated in vacuo to give the title compound as an orange oil.

Step E: Preparation of (±)-2-(tert-butoxycarbonylamino)-N-methoxy-N-methyl-4-hexinamide

The product from Step D ((10.58 g, 46.6 mmol), N,O-dimethylhydroxylamine hydrochloride (9.09 g, 93.2 mmol), HOBT 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 h. The solution was partitioned between 2:1 ethyl acetate:hexane and water, washed with water, 10 % aqueous HCl, saturated NaHCO 3 , and brine, and then dried over sodium sulfate.The precipitate was removed in vacuo to give the title compound as an orange oil.

Step F: Preparation of (±)-2-(tert-butoxycarbonylamino)-4-hexanal

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 minutes, maintaining the temperature below -50°C. When the addition is complete, the reaction is warmed to 5°C, then cooled again to -40°C. A solution of potassium bisulfate (21.8 g) in 25 ml of water is slowly added, keeping the temperature below -35°C. The mixture is warmed to room temperature. It is stirred for one hour, filtered through celite, and concentrated in vacuo to give the title aldehyde.

Step G: Preparation of (±)-2-(tert-butoxycarbonylamino)-N-(3-chlorophenyl)-4-butynamine

To a 0°C solution of 3-chloroanilyl (4.33 mL, 40.9 mmol), the product from Step F (ca. 41 mmol), and crushed molecular sieves (10 g) in dichloroethane (100 mL) under nitrogen is added sodium triacetoxyborohydride (12.9 g, 61.5 mmol). The reaction is stirred for one hour, then warmed to room temperature. After 3 hours, the solution was poured into EtOAc and washed with water, saturated NaHCO 3 , and brine. The solution is dried over sodium sulfate and concentrated in vacuo to give the crude product.

Step H: Preparation of (±)-N-(2-(tert-butoxycarbonylamino)-4-hexynyl)-2-chloro-N-(3-chlorophenyl)acetamide

A solution of the product from Step G (1.68 g, 5.22 mmol) and triethylamine (81.20 ml, 8.61 mmol) in 15 ml of CH2Cl2 was cooled to 0°C. Chloroacetyl chloride (0.457 mL, 5.74 mmol) was added dropwise, and the reaction was maintained at 0°C with stirring. After 30 minutes, another portion of chloroacetyl chloride (0.20 ml) and triethylamine (0.5 ml) was added dropwise. After 30 min, the reaction was poured into EtOAc and washed with 10% aqueous HCl, saturated aqueous NaHCO 3 , and brine. The solution is dried (Na2SO4), filtered, and concentrated in vacuo to give a brown oil. This material is purified by silica gel chromatography (20-35% EtOAc-hexane) to give the title product.

Step 1: Preparation of (±)-4-(tert-butoxycarbonyl)-5-(2-butynyl)-1-(3-chlorophenyl)-2-piperazinone

Cs2CO3 (3.08 g, 9.48 mmol) was added to a solution of chloracetamide from Step H (1.68 g, 4.23 mmol) in 15 ml of dry DMF at 0°C. The solution is stirred for 30 minutes, then warmed to room temperature. After 14 h, the reaction was taken up in 50% EtOAc-hexane, washed with water and brine, dried (Na 2 SO 4 ), filtered, and concentrated in vacuo to give the title product.

Step J: Preparation of (±)-5-(2-butynyl)-1-(3-chlorophenyl)-4/1-(4-cyanobenzyl)-5-imidazolylmethyl/2-piperazinone

To a solution of Boc-protected piperazinone from Step 1 (1.03 g, 2.85 mmol) in 7 ml of dichloromethane at 0°C, 4 ml of trifluoroacetic acid (TFA) is added. It is stirred for 4 hours, the reaction is heated to room temperature, and it is stirred for another 6 hours. The solution is concentrated in vacuo, then azeotroped with benzene to remove 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. 4A dusted molecular sieves (600 mg) are added to this solution, followed by sodium triacetoxyborohydride (214 mg, 1.02 mmol). Imidazole carboxyaldehyde 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 aqueous NaHCO 3 , and brine, dried (Na 2 SO 4 ), filtered, and concentrated in vacuo.

This material is purified by silica gel chromatography (2-5% MeOH:CH2Cl2) to give a white foam which is taken up in CH2Cl2 and treated with 2.1 equivalents of 1M HCl-ether solution. After concentration in vacuo, the product dihydrochloride is isolated as a white powder.

Example 47

Preparation of 1-(3-chlorophenyl)-4-/1-(4-cyanobenzyl)imidazolylmethyl/-2-piperazinone dihydrochloride

Step A: Preparation of N-(3-chlorophenyl)ethylenediamine hydrochloride

A solution of 4 N HCl in 1,4-dioxane (80 ml, 320 mmol HCl) was added dropwise to a solution of 3-chloroaniline (30.0 ml, 284 mmol) in 500 ml of dichloromethane at 0°C. The solution was warmed to room temperature, then concentrated to dryness in vacuo to give a white powder. A mixture of this powder with 2-oxazolidine (24.6 g, 282 mmol) is heated under a nitrogen atmosphere at 160°C for 10 hours, during which time the solids melt and gas is formed. The reaction was allowed to cool, forming the crude diamine hydrochloride salt as a light dark solid.

Step B: Preparation of N-(tert-butoxycarbonyl)-N'-(3-chlorophenyl)ethylenediamine

The amine hydrochloride from Step A (about 282 mmol, crude material obtained above) is taken up in 500 ml of THF and 500 ml of saturated aqueous NaHCO3 solution, cooled to 0°C, and di-tert-butylpyrocarbonate (61.6 g, 282 mmol) is he adds. After 30 hours, the reaction was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the title carbamate as a dark oil which was used in the next step without further purification.

Step C: Preparation of N-2/tert-butoxycarbamoyl)ethyl/-N-(3-chlorophenyl)-2-chloroacetamide

A solution of the product from Step B (77 g, about 282 mmol) and triethylamine (67 ml, 480 mmol) in 500 ml of CH2Cl2 is cooled to 0°C. Chloroacetyl chloride (25.5 ml, 320 mmol) was added dropwise, and the reaction was maintained at 0°C with stirring. After 3 hours, another portion of chloroacetyl chloride (3.0 ml) is added dropwise. After 30 minutes, the reaction was poured into EtOAc (2 L) and washed with water, saturated aqueous NH 4 Cl, saturated aqueous NaHCO 3 , and brine. The solution is dried (Na2SO4), filtered, and concentrated in vacuo to give chloracetamide as a dark oil which is evaporated in the next step without further purification.

Step D: Preparation of 4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-2-piperazinone

K2CO3 (88 g, 0.64 mol) is added to a solution of chloracetamide from Step C (about 282 mmol) in 700 ml of dry DMF. The solution is heated in an oil bath at 70-75°C for 20 hours, cooled to room temperature, and concentrated in vacuo to remove about 500 ml of DMF. The remaining material was taken up in 33% EtOAc-hexane, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to give a dark oil. This material is purified by silica gel chromatography (25-50% EtOAc-hexane) to give pure product with a product pattern (ca. 65% pure by HPLC) containing a less polar impurity.

Step E: Preparation of 1-(3-chlorophenyl)-2-piperazinone

A solution of the Boc-protected piperazinone from Step D (17.19 g, 55.4 mmol) in 500 ml EtOAc at -78°C is bubbled with anhydrous HCl gas. The saturated solution is heated to 0°C and stirred for 12 hours. Nitrogen gas was blown through the reaction mixture to neutralize the excess HCl, and the mixture was warmed to room temperature. The solution was concentrated in vacuo to give the hydrochloride as a white powder. This material is taken up in 300 ml of CH2Cl2 and treated with dilute aqueous NaHCO3. The aqueous phase was extracted with CH 2 Cl 2 (8 x 300 ml) until TLC analysis indicated that the extraction was complete. The combined organic mixture is dried (Na 2 SO 4 ), filtered, and concentrated in vacuo to give the isolated free amine as a light dark oil.

Step F: Preparation of 1-(3-chlorophenyl)-4-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-2-piperazinone dihydrochloride

To a solution of the amine from Step E (55.4 mmol, obtained above) in 00 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 carboxyaldehyde from Step E of Example 42 (11.9 g, 56.4 mmol) was added, and the reaction was stirred at 0°C. After 26 h, the reaction was poured into EtOAc, washed with dilute aqueous NaHCO 3 , and the aqueous layer was re-extracted with EtOAc. The combined organic solutions are washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The product obtained is taken up in 500 ml of 5:1 benzene:CH 2 Cl 2 , and propylamine (20 ml) is added. The mixture was stirred for 12 hours, then concentrated in vacuo to give a light yellow foam. This material is purified by silica gel chromatography (2-7% MeOH:CH2Cl2), and the resulting white foam is taken up in CH2Cl2 and treated with 2.1 equivalents of 1M HCl-ether solution. After concentration in vacuo, the product dihydrochloride is isolated as a white powder.

Example 48

5(S)-Butyl-4-(1-(4-cyanobenzyl)-2-methyl-5-imidazolylmethyl)-1-(2,3-dimethylphenyl)piperazin-2-ene dihydrochloride

Grade A: 4-Bromo-2-methylimidazole-5-carboxyaldehyde

4-Bromo-5-hydroxymethyl-2-methylimidazole is prepared according to the procedure described by S. P. Watson, Synthetic Communications, 22, 2971-2977 (1992). A solution of 4-bromo-5-hydroxymethyl-2-methylimidazole (4.18 g, 21.9 mmol) was refluxed with manganese 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 give the title compound as a light yellow solid.

1H NMR (CDCl 3 , 300 MHz) d 9.57 (1H, s), 2.52 (3H, s).

Grade B: 4-Bromo-1-(4-cyanobenzene-2-methylimidazole-5-carboxyaldehyde)

4-Cyanobenzyl bromide (1.05 g, 5.39 mmol) was added to a solution of 4-bromo-2-methylimildazole-5-carboxyaldehyde (1.02 g, 5.39 mmol) in dimethylacetamide (15 mL). The solution is cooled to -10°C and powdered potassium carbonate (0.745 g, 5.9 mmol) is added. The reaction was stirred at -10°C for 2 hours, and for a further 4 hours at 20°C. The reaction is diluted with water and extracted with ethyl acetate. The organic phase is washed with water, a saturated solution, and dried over magnesium sulfate. Evaporation of the solvent gives a white solid.

1H NMR (CDCl3, 400 MHz) δ 9.68 (1H, s), 7.64 (2H, d, J=7 Hz) 7.15 (2H, d, J=7 Hz), 5.59(2H, s), 2.40 (3H, with).

Step C: 1-(4-cyanobenzyl)-2-methylimidazole-5-carboxyaldehyde

A solution of 4-bromo-1-(4-cyanobenzyl)-2-methylimidazole-5-carboxyaldehyde (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 a hydrogen atom. After 2 hours, the reaction was filtered through celite and concentrated to give the title compound as a white solid.

1H NMR (DMSO-d6, 400 MHz) δ 9.62 (1H, s), 7.90 (1H, s), 7.81 (2H, d, J=8 Hz), 7.20 (2H, d, J=8 Hz), 5.64 (2H, s), 2.33 (3H, s).

Grade D: 5(S)-Butyl-4-(1-(4-cyanobenzyl)-2-methyl-5-imidazolylmethyl)-1-(2,3-dimethylphenyl)piperazin-2-ene dihydrochloride

Sodium triacetoxyborohydride (0.265 g, 1.25 mmol) was added to a solution of 1-(4-cyanobenzyl)-2-methylimidazole-5-carboxyaldehyde (0.190 g, 0.843 mmol), 5(S)-butyl-1-(2,3- dimethylphenyl)piperazin-2-ene hydrochloride (0.2250 g, 0.843 mmol), N-methylmorpholine (0.093 ml, 0.843 mmol) in dichloroethane (10 ml), according to the procedure described in Example 39, Step E. The title compound is purified by preparative HPLC, using a gradient of 70 to 45% solvent A. The free base is isolated and converted to the dihydrochloride salt. The title compound is obtained as a white solid. FAB ms: 470(m+1). Analysis calculated for C29H35N5O • 1.45 H2O

C, 61.25; H, 7.07, N, 11.32

Found: C, 61.56; H, 6.99, N, 11.32.

Example 49

4-/1-(2-(4-Cyanophenyl)-2-propyl)-5-imidazolylmethyl/-1-(3-chlorophenyl)-5(S)-(2-methylsulfonylethyl)piperazin-2-ene

Stage A: 4-(tert-Butyldimethylsilioxymethyl)-1-triphenylmethylimidazole

Tert-Butyldimethylsilichloride (2.83 g, 18.76 mmol) was 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 minutes, a clear, colorless solution is obtained, which is stirred at room temperature. When the reaction is complete, the DMF is removed in vacuo and the residue is partitioned between ethyl acetate and ethyl acetate. The organic phase is washed with water, saturated saline solution, and dried over magnesium sulfate. The title compound is obtained as a clear rubber.

Grade B: 5-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 refluxed for 4 hours. The reaction is cooled, the acetonitrile is removed in vacuo, and the residue is dissolved in methanol (30 ml). This solution is refluxed for 2 hours, cooled and methanol is evaporated. The residue is partitioned between ethyl acetate and saturated sodium bicarbonate. The crude product is chromatographed on silica with 3% methanol in chloroform. The title compound is obtained as a white solid.

Grade C: 5-tert-Butoxydimethylsilyloxymethyl-1-(2-(4-cyanophenyl)-2-propyl)-imidazole

A solution of 5-tert-Butyldimethylsilioxymethyl-1-(4-cyanobenzyl)imidazole (1.005 g, 3.07 mmol) in THF (25 ml) was cooled to -78°C under nitrogen. A solution of lithium hexamethylsilazide (4.61 ml, 1M in THF) was added and the reaction was stirred at -78°C for 1 hour, then warmed to -60°C over 30 minutes. The reaction was cooled to -78°C, methyl iodide (0.287 ml, 4.61 mmol) was added and stirring was continued at -78°C and lithium hexamethyldisilazide (4.61 ml, 1M in THF) was added. After 1 hour, methyl iodide (0.287 mL, 4.61 mmol) was added and the reaction was allowed to warm to room temperature overnight. The reaction is quenched with water, extracted with ethyl acetate, and the organic phase is washed with saturated brine. The crude product is chromatographed on silica gel with 6:4 ethyl acetate/methylene chloride. The title compound is obtained as a golden oil.

1H NMR (CDCl3, 400 MHz) δ 7.78 (1H, s), 7.61 (2H, d, J=8 Hz), 7.15 (2H, d, J=8 Hz), 7.02 (1H, s), 4.00 (2H , s), 1.9.9 (6H, s), 0.79(9H, s), -0.74 (6H, s).

Grade D: 1-(2-(4-Cyanophenyl)-2-propyl)/-5-hydroxymethyl-imidazole

Tetra-N-butylammonium fluoride (2.99 mL, 1M in THF) was added to a solution of 5-tert-butoxydimethylsilyloxymethyl-1-(2-(4-cyanophenyl)-2-propyl)/imidazole (0.750 g, 2.72 mmol) in THF. (10 ml). After 2 hours at room temperature, the reaction was poured into ethyl acetate and extracted with saturated sodium bicarbonate solution. The organic phase is extracted with saturated brine and dried over magnesium sulfate. The crude product is chromatographed on silica gel with 3% methanol in ethyl acetate. The title compound is obtained as a semi-solid.

1H NMR (CDCl3, 400 MHz) δ 7.77 (1h, s), 7.62 (2H, d, J=8 Hz), 7.19 (2H, d, J=8 Hz), 7.02 (1H, s), 4.01 (2H , s), 2.57 (1H, wide s), 2.01 (6 H, s).

Grade E: 1-(2-(4-cyanophenyl)-2-propyl)/imidazole-5-carboxyaldehyde

A solution of 1-(2-(4-cyanophenyl)-2-propyl)/imidazole-5-hydroxymethylimidazole (0.450 g, 1.87 mmol) was refluxed in dioxane (20 ml) with manganese dioxide (1.62 g, 18.7 mmol) for 5 hours. the reaction is cooled, filtered through celite and concentrated. The crude product is purified by chromatography on silica gel; the title compound is isolated as a semi-solid.

1H NMR (CDCl3, 400 MHz) δ 9.37 (1H, s), 8.11 (1H, s), 7.92 (1H, s), 7.58 (2H, d, J=8 Hz), 7.15 (2H, d, J= 8 Hz), 2.01 (6H, s).

Grade F: 4-(1-(4-Cyanophenyl)-2-propyl)-5-imidazolylmethyl/-1-(3-chlorophenyl)-5(S)-(2-methylsulfonylethyl)piperazine-2-ene dihydrochloride

The title compound was obtained according to the procedure described in Example 39, Step E, except that 1-(3-chlorophenyl)-5(S)-(2-methylsulfonylethyl)piperazin-2-ene hydrochloride (0.297 g, 0.84 mmol) was used. 1-(2-(4-cyanophenyl)-2-propyl/imidazole-5-carboxyaldehyde (0.200 g, 0.84 mmol), 1-(2-(4-cyanophenyl)-2-propyl/imidazole-5-carboxyaldehyde (0.200 g, 0.84 mmol), N-methylmorpholine (0.092 ml, 0.84 mmol) and sodium triacetoxyborohydride (0.267 g, 1.26 mmol). The crude product is purified by preparative HPLC with an 80% to 58% solvent A gradient. The crude fractions were combined and converted to the hydrochloride salt, affording the title compound. FAB ms (m+1)540.

Analysis calculated for C27H30CIN5O3S • 2HCl • 3H2O,

C, 48.62; H, 5.74; N, 10.50

Found: C, 48.62; H, 5.73; N, 9.89.

Example 50

5(S)-n-Butyl-4-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-(2-methylphenyl)piperazine-2-ene dihydrochloride

Grade A: N-(2-Methylphenyl)-2(S)-(tert-butoxycarbonylamino)hexanamine

The title compound was prepared according to the procedure described in Example 39, Step C, except that O-toluidine (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 ml). The crude product is purified by flash chromatography to give the title compound.

Grade B: 4-tert-Butoxycarbonyl-5(S)-n-butyl-1-(2-methylphenyl)piperazin-2-ene

The title compound was obtained essentially according to the procedure described in Example 39, Step D, except that using N-(2-methylphenyl)-2(S)-(tert-butoxycarbonylamino)hexanamine (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 2 hours, and at room temperature for 2 hours. The reaction is quenched with saturated ammonium chloride, and extracted with ethyl acetate. The extracts are evaporated and dried to give the title compound.

Grade C: 5(S)-n-Butyl-4-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-1-(2-methylphenyl)piperazin-2-ene 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 that 5(S)-n-butyl-1-(2-methylphenyl)piperazin-2-ene salt of ditrifluoroacetic acid, 1-(4-cyanobenzylimidazole) was used. -5-carboxyaldehyde (0.317 g, 1.50 mmol), and sodium triacetoxyborohydride (0.477 g, 2.25 mmol) in dichloroethane (15 mL). The crude product is 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 are combined and converted into HCl salt. The title compound is obtained as a white solid. FAB ms (m+1) 442. Analysis calculated for C27H31N5O • 2.5 HCl • 2.05 H2O

C, 56.95; H, 6.66; N, 12.30

Found: C, 56.93; H, 5.75; N, 11.55.

Example 51

4-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-5(S)-(2-fluoroethyl)-1-(3-chlorophenyl)piperazin-2-ene dihydrochloride

Grade A: 4-tert-Butoxycarbonyl-1-(3-chlorophenyl)-5(S)-(2-fluoroethyl)piperazin-2-ene

4-tert-Butoxycarbonyl-1-(3-chlorophenyl)-5(S)-(2-methylsulfonyloxyethyl)piperazin-2-ene (0.433 g, 1.00 mmol) and tert-butylammonium fluoride (3.0 ml, 1M in THF) were mix at room temperature in acetonitrile (5 ml) for 72 hours. The reaction is quenched with saturated sodium bicarbonate and extracted with ethyl acetate.

The organic extracts are dried, concentrated and purified by column chromatography using 20% ethyl acetate in hexane. The title compound is obtained as a thick oil.

Grade B: 4-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-5(S)-(2-fluoroethyl)-1-(3-chlorophenyl)piperazin-2-ene dihydrochloride

4-tert-butoxycarbonyl-1-(3-chlorophenyl)-5(S)-(2-fluoroethyl)piperazin-2-ene (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 that 1-(3-chlorophenyl)-5(S)-(2-fluoroethyl)piperazin-2-ene salt of ditrifluoroacetic acid, 1-(4- cyanobenzylimidazole)-5-carboxyaldehyde (0.114 g, 0.54 mmol), and sodium triacetoxyborohydride (0.172 g, 2.25 mmol) in dichloroethane (5 mL). The crude product is injected onto a preparative HPLC column and purified with a mixed gradient of acetonitrile/0.1% TFA and 0.1% aqueous TFA. The crude fractions are combined and converted to the HCl salt. The title compound is obtained as a white solid. FAB ms (m+1) 452.

Analysis calculated for C24H23CIFN5O • 2 HCl • 1.07H2O

C, 51.90; H, 5.15; N, 12.61

Found: C, 52.22 H, 5.10; N, 12.22.

Example 52

4-/3-(4-Cyanobenzyl)pyridin-4-yl/-1-(3-chlorophenyl)-5(S)-(2-methylsulfonethyl)piperazin-2-ene

Grade A: 3-(4-Cyanobenzyl)pyridine-4-carboxylic acid methyl ester

A solution of 4-cyanobenzyl bromide (625 mg, .27 mmol) in dry THF (4 mL) was added slowly over 3 min to a suspension of activating Zn (dust; 250 mg) in dry THF (2 mL) at 0°C under argon atmosphere.

The ice bath is removed and the suspension is stirred at room temperature for another 30 minutes. Then 3-bromopyridine-4-carboxylic acid methyl ester (540 mg, 2.5 mmol) was added followed by dihydrochlorobis(triphenylphosphine)nickel (II) (50 mg). The obtained dark red mixture is stirred for 3 hours at about 40-45°C. The mixture was cooled and partitioned between EtOAc (100 mL) and 5% aqueous citric acid (50 mL). The organic layer is washed with H2O (2 x 50 ml), dried with Na2SO4. After evaporation of the solvent, the residue is purified on silica gel by elution with 35% EtOAc in hexane, whereby 420 mg of clear gum is obtained. FAB ms (m+1) 253.

Step B: 3-(4-Cyanobenzyl)-4-(hydroxymethyl)pyridine

The title compound is obtained by reducing the ester from Step A (415 mg) with sodium borohydride (300 mg) in methanol (5 ml) at room temperature. After stirring for 4 hours, 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+1) 225.

Step C: -(4-Cyanobenzyl)-4-pyridinal

The title compound is obtained by oxidation with active manganese dioxide (1.0 g) of alcohol from Step B (240 mg, 1.07 mmol) in dioxane (10 ml) at reflux for 30 minutes. Filtration and evaporation of the solvent provides the title compound, m.p. 80-83°C.

Grade D: -/3-(4-Cyanobenzyl)pyridin-4-yl/-1-(3-chlorophenyl)-5(S)-(2-methylsulfonylethyl)piperazin-2-ene

This compound is prepared by essentially the same procedures as described in Example 39, Step E, except that the imidazolyl carboxyaldehyde is replaced by an equal amount of the product from Step C (see above) and the piperazinone is replaced by an equal amount of 1-(3-chlorophenyl)-5(S )-(2-methylsulfonylethyl)piperazin-2-ene, the title compound FAB ms 523 is obtained. Analysis calculated for C27H27CIFN4O3S • 0.15 CHCl3

C, 60.28; H, 5.06; N, 10.36

Found: C, 60.37 H, 5.03; N, 10.64.

Example 53

4-/5-(4-Cyanobenizyl)-1-imidazolylethyl/-1-(3-chlorophenyl)piperazin-2-ene

Step A: 1-Trityl-4-(4-cyanobenzyl)imidazole

To a suspension of activated zinc dust (3.57 g, 54.98 mmol) in THF (50 ml) was added diboromethane (0.15 ml, 3.60 mmol) and the reaction was stirred under argon at 20°C. The suspension is cooled to 0°C and α-bromo-p-tolunitrile (9.33 g, 47.6 mmol) in THF (100 ml) is added dropwise over a period of 10 minutes. The reaction was stirred at 200C for 6 hours and bis(triphenylphosphine)nickel II chloride (2.4 g, 3.64 mmol) and 5-iodotrityl imidazole (15.95 g, 36.6 mmol) were added in one portion. The resulting mixture was stirred for 16 hours at 20°C and then stopped by the addition of a saturated solution of NH4Cl (100 ml) and the mixture was stirred for 2 hours. Saturated NaHCO 3 solution was added to give a pH of 8 and the solution was extracted with EtOAc (2 x 250 mL), dried over MgSO 4 and the solvent was evaporated in vacuo. The residue was chromatographed (SiO2, 0-20% EtOAc/CH2Cl2) to give the title compound as a white solid.

1H NMR δ CDCl3 (7.54 (2H, d, J=7.9 Hz) , 7.38 (1H, s), 7.36-7.29 (11H, m), 7.15-7.09 (6H, m), 6.58 (1H, s), and 3.93 (2H, s) ppm.

Step B: 1-Methyl acetyl-5-(cyanobenzyl)imidazole

To a solution of 1-trityl-4-(4-cyanobenzyl)imidazole (3.01 g, 6.91 mmol) in acetonitrile (50 ml), methyl bromoacetate (0.687 ml, 7.26 mmol) was added and the mixture was heated at 55°C for 16 hours. and then the solvent is evaporated in vacuo. The solids were triturated with EtOAc, collected by filtration and dissolved in methanol (60 mL). This suspension is heated at reflux for 20 minutes, cooled and evaporated to dryness. The residue was filtered with EtOAc and the title compound was obtained by filtration as a white solid.

1H NMR δ CDCl3 (7.61 (2H, d, J=7.9 Hz), 7.53 (1H, s), 7.27 (2H, d, J=7.9 Hz), 6.89 (1H, s), 4.47 (2H, s), 3.98 (2H, s) and 3.66 (3H, s) ppm.

Step C: -Hydroxyethyl-5-(4-cyanobenzyl)imidazole

A solution of 1-methyl acetyl-5-(4-cyanobenzyl)imidazole (0.113 g, 0.472 mmol) in methanol (2 ml) at 0°C was treated with sodium borohydride (80.7 mg, 2.1 mmol). After 1 hour, the reaction is stopped by the addition of saturated NH4Cl solution (2 ml). Saturated NaHCO3 solution was added and the mixture was extracted with ethyl acetate. The title compound was isolated by chromatography (SiO2, 10% MeOH in CH2Cl2) as a white solid.

1H NMR d CDCl3 (7.61 (2H, d, J=7.9 Hz), 7.55 (1H, s), 15.27 (2 H, d, J=7.9 Hz), 6.83 (1H, s), 4.05 (2H, s) , 3.87 (2H, t, J=5.1 Hz) and 3.74 (2H, t, J=5.1 Hz) ppm.

Step D: 2-(5-(4-Cyanobenzyl)imidazolyl)ethyl methanesulfonate

A solution of 1-hydroxyethyl-5-(4-cyanobenzyl)imidazole (0.532 g, 2.34 mmol) in methylene chloride (70 ml) at 0°C is treated with "Hunigs" base (0.489 ml, 2.81 mmol) and methanesulfonyl chloride (0.219 ml, 2.81 mmol). After 2 hours, the reaction is stopped by the addition of saturated NaHCO3 solution (50 ml) and the mixture is extracted with methylene chloride (50 ml), dried with MgSO4 and the solvent is evaporated in vacuo. The title compound is used without further ado

purification.

1H NMR δ CDCl3 (7.62 (2H, d, J=7.9 Hz), 7.54 (1H, s), 7.29 (2H, d, J=7.9 Hz), 6.87 (1H, s), 4.25 (2H, t), 4.10-4.00 (4H,

m), 3.74 (2H, t, J=5.1 Hz) and 2.90 (3H, s) ppm.

Grade E: 4-(5-(4-Cyanobenzyl)-1-imidazolylethyl)-1-(3-chlorophenyl)piperazin-2-ene

A solution of 2-(5-(4-cyanobenzyl)imidazolyl)ethylmethanesulfonate (24 mg, 0.079 mmol) in DMF (0.2 mL) was added to 3-(chlorophenyl)piperazin-2-ene (17.7 mg, 0.084 mmol), sodium iodide (50 mg, 0.336 mmol) and "Hunigs" base 80.0146 ml, 0.084 mmol). The mixture was stirred at 55°C for 12 hours, and the solvent was evaporated in vacuo. The residue is purified by preparative thin-layer chromatography eluting with 10% saturated ammonia/acetonitrile to give the title compound,

1H NMR δ DCl3 (7.61 (2H, d, J=8.4 Hz), 7.56 (1H, s), 7.35 7.20 (7H, m), 7.16 (1H, d, J=8 Hz), 6.85 (1H, s) , 4.03 (2H, s), 3.83 (2H, t, J=6.5 Hz), 3.61 (2H, t, J=5.4 Hz), 3.27 (2H, s), 2.68 (2H, t, J=5.4 Hz) and 2.57 (2H, t, J=6.5 Hz) ppm.

Example 54

In vitro inhibition of ras farnesyl transferase

Farnesyl-protein transferase analyses.

Partial purification of FPTase and Ras peptides (Ras-CVLS, Ras,-CVIM and Ras-CAIL) were obtained as described by Schaber et al., J. Biol. Chem. 265:14701-14704 (1990), Pompliano, et al., Biochemistry 31:3800 (1992) and Gibbs et al., PNAS S. A. D. 86:6630-6634 (1989). Bovine FPTase is assayed in a 100 µl volume containing mMN-(2-hydroxy ethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), pH 7.4, 5 mg MgCl2, 5 mM dithiothreitol (DTT), 100 mM/ 3H/-farnesyl diphosphate (/3H/-FPP; 740 CBq/mmol, New England Nuclear), 650 nMRas-CVLS and 10 μg/ml FPTase at 31°C, 60 minutes. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCl in ethanol. Pellets are collected on filter media using a TomTec II cell harvester, washed with 100% ethanol, dried and counted in an LKB β-plate counter. This analysis was linear, considering both substrates, FPTase level and time; less than 10%/3H/-FPP was used during the reaction period. Purified compounds are dissolved in 100% dimethyl sulfoxide (DMSO) and diluted 20-fold in analysis. Percent inhibition is measured by the amount of incorporation of radioactivity in the presence of the test compound compared to the amount of incorporation in the absence of the test compound.

Human FPTase is prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993) Human FPTase activity is assayed as described above with the exception that 0.1% (w/v) polyethylene glycol is added to the reaction mixture. 20,000, 10 μM ZnCl2 and 100 nM Ras-CVIM. Reactions are run for 30 minutes, stopped with 100 µl of 30% (v/v) trichloroacetic acid (TCA) in ethanol and treated as described above for the bovine enzyme.

The compounds of this invention described in the above Examples and Tables were subsequently tested for inhibitory activity against human FPTase by the assay described above and found to have an IC50 of ≤ 50 μM.

Example 55

Analysis of in vivo ras farnellization

The cell line used in this analysis is a v-ras line derived from either Ras or NIH3T3 cells, which express viral Ha-ras p21. The assay is performed as described in DeClue, J.E. et al., Cancer Research 51:712-717, (1991). Cells in 10 cm plates at 50-75% confluence are treated with the test compound (the final concentration of the solvent, methanol or dimethyl sulfoxide, is 0.1%. After 4 hours at 37°C, the cells are labeled in 3 ml of DMEM without methionine supplemented with 10% regular DMEM, 2% fetal bovine serum at 400 mCi/35S/methionine (1000 Ci/mmol). After another 20 hours, cells are lysed in 1 ml of lysis buffer (1% NP40/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the lysates are clarified by centrifugation at 100,000 x g for 45 min. Aliquots of the lysates, containing the same numbers of acid-precipitated counts, are brought up to 1 ml with IP buffer (a lysis buffer that does not contain DTT ) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M. E. et al., J. Virol 43:294-304. (1982) ). After 2 hours the antibody is incubated at 4°C, and 200 ml of 25% protein A-Sepharose suspension coated with rabbit anti-rat IgG for 45 minutes. The immunoplates are washed four times with IP buffer (20 nM HEPES , pH 7.5/1 mM EDTA/1% Triton X-100, 0.5% deoxycholate/0.1%/SDS/0.1 M MaCl), boiled in SDS PAGE sample buffer and loaded onto 13% acrylamide gels. When the color front reaches the bottom, the gel is fixed, soaked in "Enlinghtening", dried and autoradiographed. Band intensities corresponding to farnesylated and non-farnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to the protein.

Example 56

In vivo growth inhibition assay

To determine the biological consequences of FPTase inhibition, the effect of a compound of the present invention on the anchorage-independent growth of Rat1 cells, transformed with either the V-ras, v-raf, or v-mos oncogene, is tested. Cells transformed with v-raf and v-mos can be included in an assay to determine the specificity of a compound of the present invention 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 10 cells per plate (35 mm in radius) in a 0.3% agarose top layer in medium A (Dulbecco's modified Engle -'s medium supplemented with 10% fetal bovine serum) above the bottom of the agar layer (0.6%). Both layers contain 0.1% methanol or a suitable concentration of the compound according to this invention (dissolved in methanol at 1000 times the final concentration used in the analysis). The cells are fed twice a week with 0.5 ml of medium A containing 0.1% methanol or the concentration of the compound according to the invention. Photomicrograms are taken 16 days after sowing the cultures and then compared.

Example 57

Tables 1-18 show other compounds of the present invention which were obtained by the procedures described in Examples 1-53. These compounds are intended to be illustrative, and are not intended to be limiting. In Table 2, the stereochemistry of the carbon atom containing the amino group is shown (R or S), or if unknown, the two separate stereoisomers are described with an “A” or “B” designation.

TABLE 1

[image]

TABLE 2

[image]

[image]

[image]

[image]

TABLE 3

[image]

TABLE 4

[image]

TABLE 4 (continued)

[image]

Table 4 (continued)

[image]

TABLE 4 (continued)

[image]

TABLE 4 (continued)

[image]

TABLE 5

[image]

TABLE 5 (continued)

[image]

TABLE 5 (continued)

[image]

Table 5 (continued)

[image]

TABLE 6

[image]

TABLE 6 (continued)

[image]

TABLE 7

[image]

TABLE 8

[image]

TABLE 8 (continued)

[image]

Table 8 (continued)

[image]

TABLE 9

[image]

TABLE 9 (continued)

[image]

TABLE 9 (continued)

[image]

TABLE 11

[image]

TABLE 10

[image]

TABLE 12

[image]

TABLE 12 (continued)

[image]

TABLE 13

[image]

TABLE 14

[image]

TABLE 15

[image]

TABLE 16

[image]

TABLE 17

[image]

TABLE 18

[image]

TABLE 18 (continued)

[image]

Claims (42)

1. Compound, which inhibits farnesyl-protein transferase, formula A: [image] characterized in that: R1a and R1b are selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(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, where the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, 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-; R 2 and R 3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, [image] unsubstituted or substituted heterocycle, where it is substituted with one or more of: 1) aryl, heterocycle, unsubstituted or substituted with: a) C1-4 alkyl, b) (CH2)pOR6, c) (CH2)PNR6, d) halogen, e) CN, [image] [image] R2 and R3 are attached to the same C atom and are combined to form -(CH2)u - where one of the carbon atoms is selected from: O, S(O)m, -NC(O)-, and -N( COR10)-; R 4 and R 5 are independently selected from H and CH 3 ; and any two of R 2 , R 3 , R 4 and R 5 may be attached to the same carbon atom; R 6 , R 7 and R 7a 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, [image] 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 b) aryl or heterocycle, c) halogen d) HO, [image] 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 with aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl. C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R O-, R S(O)m-, R10C(O)NH-, (R10)2NC(O)-, R102N-, C(NR10)-, CN , R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or R 10 OC(O)NH-; R9 is selected from: a) hydrogen, b) R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, R10OC(O) -, N3, -N(R10)2, or R10OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted with 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-; R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl; R 11 is independently selected from C 1 -C 6 alkyl and aryl; A1 and A2 are independently selected from: connections. -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 elected by; a) hydrogen, b) heterocycle, c) aril, d) C1-C20 alkyl where from 0 to 4 carbon atoms are replaced by a heteroatom selected from O, S and N, and e) C2-C20 alkenyl, provided V is not hydrogen if A1 is S(O)m and V is not hydrogen if bond A1 is 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, where the substituted aryl or substituted heterocycle is substituted with one or more of: I) 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) NR6 R7, 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 with the proviso 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 a pharmaceutically acceptable salt thereof. 2. Compound, which inhibits farnesyl-protein transferase, formula B: [image] characterized in that R1a and R1b are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 to alkenyl, C2-C6 alkynyl, R10O-, R11-S(O)m-, R10 C(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, where the substituent on substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R100-, 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-; R 2 and R 3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-C8 alkynyl, unsubstituted or substituted aryl, [image] unsubstituted or substituted heterocycle, where 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, [image] [image] R2 and R3 are attached to the same C atom and united to form -(CH2)u - where one of the carbon atoms can be replaced with a part selected from: O, S(O)m, -NC(O)-, and -N(COR10)-; R 4 is selected from H and CH 3 ; and any two of R 2 , R 3 and R 4 may be 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, [image] 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, [image] 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 with 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, umt c) C1-C6 alkyl unsubstituted or substituted with 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-; R 10 is independently selected from C 1 -C 6 alkyl or aryl; A1 and A2 are independently selected from: 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 H 2 or O; V is chosen by: a) hydrogen, b) heterocycle, c) aril, d) C1-C20 alkyl where from 0 to 4 carbon atoms are replaced by 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; It is a heterocycle; X is -CH2-, -C(=O)-, or -S(=O)m-; Z is an unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, where the substituted group is oriented 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 substituent (R8)r - V - A1 (CR1a2)nA2 (CR1a2)n- is not H and provided that when X is -C(=O)-, or S (=O)m-, then t = 1 and the substituent (R8)r - V - A1 (CR1a2)n-is not H; or an optical isomer or a pharmaceutically acceptable salt thereof. 3. Compound, which inhibits farnesyl-protein transferase, formula C:" [image] indicated by the fact that they are: R1a and R1b independently selected from: a) hydrogen, b) aryl, heterocycle, umt 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, where the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted 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, R10C(O)-, R10OC(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; R 2 and R 3 are independently selected from: H, unsubstituted or substituted C 1-8 alkyl, unsubstituted or substituted C 2-8 alkenyl; unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, [image] unsubstituted or substituted heterocycle, where the substituted group 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, [image] [image] R2 and R3 are attached to the same C atom and combined to form -(CH2)u- where one of the carbon atoms can be replaced with a moiety selected from: O, S(O)m, -NC(O)-, and - N(COR10)-; R4 is selected from H and CH3: and any two of R 2 , R 3 and R 4 may be attached to the same carbon atom; R 6 , R 7 and R 7a 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, [image] 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, [image] f) -SO2R11, 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)NC (O)-, R102N-C(NR10), CN, NO2, R10C(O)-, R10OC(O)-, N3 -N(R10)2, or R11 OC(O)NR10 -, and c) C1-C6 alkyl unsubstituted or substituted with aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, (R10)2NC(O )-, R102N-C(NR10)-, CN, R10OC(O)NH-; R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11 S(O)m-R10C(O)NR10-, (R10)2NC(O)-, R102N-C( NR10)-,CN, NO2, R10C(O)-, R10OC(O)-, N3, N(R10)2, or R11 OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted with 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 R11 OC(O)NR10-N3, N(R10)2, or R11 OC(O)NR10-; R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl; R 11 is independently selected from C 1 -C 6 alkyl and aryl; A1 and A2 are independently selected from: bonds, -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 chosen by: a) hydrogen, b) heterocycle, c) aril, d) C1-C20 alkyl where from 0 to 4 carbon atoms are replaced by a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is O and A2 is S(O)m; W is a heterocycle; Z is an unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, where the 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 = 0 when V is hydrogen; s is 1; t is 0 or 1; and u is 4 or 5; or an optical isomer or a pharmaceutically acceptable salt thereof. 4. Compound according to claim 1, formula A: indicated by the fact that: [image] R1a is independently selected from: hydrogen or C1-C6 alkyl; R1b was independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R10O-, -N(R10)2 or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl, where the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R10O-,-N(R10)2; and R5 are independently selected from H and CH3, [image] R 2 is H; or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: [image] and any two of R 2 , R 3 , R 4 and R 5 may be 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) C 1-4 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, -N-C(NR10),R10C(O) -, R10OC(O)-, N3, N(R10)2, or R11 OC(O)NR10-; and c) C1-C6 alkyl unsubstituted or substituted with C1-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)C(O)-, R10C (O)-N(R10)2, or R11OC(O)NR10-; 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 R11 OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted with perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, R10)2 NC(O)-, R102N-C(NR10) -, CN, R10C(O)-, R10OC(O)-, N3, N(R10)2, or R11 OC(O)NR10-, N(R10)2, or R11 OC(O)NR10-; R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl; R 11 is independently selected from C 1 -C 6 alkyl and aryl; A1 and A2 are independently selected from: bonds, -CH=CH-, -C≡C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O )m; V is chosen by: a) hydrogen, b) a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxypiperadinyl, indolyl, quinolinyl, isoquinolinyl and thienyl, c) aril, d) C1-C20 alkyl wherein about 0 to 4 carbon atoms are replaced by 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 selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X is -CH2- or -C(=O)-; Y is mono- or bi-cyclic aryl, or mono- or bi-cyclic 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; q is 1 or 2; r is 0 to 5, provided that r = 0 when V is hydrogen; s is 1; t is 0 or 1; and or an optical isomer or a pharmaceutically acceptable salt thereof. 5. Compound according to claim 2 of formula B: [image] indicated by the fact that: R1a is independently selected from: hydrogen or C1-C6 alkyl; R1b was independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R10O-, -N(R10)2 or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl, where the substituent on the substituted C1-C6 alkyl is chosen from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R10O-,-N(R10)2; R3 and R4 are independently selected from H and CH3: [image] R 2 is H; or C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: [image] and any two of R 2 , R 3 , R 4 and R 5 may be 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, -N-C(NR10), R10C(O) -, R10OC(O)-, N3, N(R10)2, or R11 OC(O)NR10-; and c) C1-C6 alkyl substituted with C1-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)C(O)-, R10C(O )-, N(R10)2, or R11OC(O)NR10-; 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 R11 OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted with 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 R11 OC(O)NR10-, N(R10)2, or R11 OC(O)NR10-; R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl; R 11 is independently selected from C 1 -C 6 alkyl and aryl; A1 and A2 are independently selected from: bonds, -CH=CH-, -C≡C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O )m; V is chosen by: a) hydrogen, b) a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, trazolyl, pyridonyl, 2-oxypiperadinyl, indolyl, quinolinyl/isoquinolinyl and thienyl, c) aril, d) C1-C20 alkyl where from 0 to 4 carbon atoms are replaced by 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; G is H 2 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 bi-cyclic heteroaryl, mono- or bi-cyclic arylmethyl, mono- or bi-cyclic heteroarylmethyl, mono- or bi-cyclic arylsulfonyl, mono- or bi-cyclic heteroarylsulfonyl, unsubstituted or heteroarylsulfonyl, where the substituted group is oriented with one or more of the following: 1) C1-4 alkyl, unsubstituted or substituted with: a) C1-4Alkoxy, 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)mR6, 10) -C(O)NR6R7, or 11) C3-6 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 substituent (R8)r - V - A1 (CR1a2)nA2(CR1a2)n- is not H and Provided that when X is -C(=O)- or -S(=O)m, then t is 1 and the substituent (R8)r - V - A1 (CR1a2)nA2 (CR1a2)n - is not H 6. A compound that inhibits farnesyl-protein transferase, characterized in that 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-benzylimidazole)methyl/-2(S)-buty1-4-(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-hydropropyl)-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-(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 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 thereof. 7. A compound that inhibits farnesyl-protein transferase, characterized in that Table 1 [image] Table 2 [image] Table 2 (continued) [image] Table 3 [image] Table 4 [image] Table 4 (continued) [image] Table 5 [image] Table 6 [image] Table 7 [image] Table 8 [image] Table 9 [image] Table 10 [image] Table 11 [image] Table 12 [image] Table 12 (continued) [image] Table 13 [image] Table 14 [image] Table 15 [image] Table 16 [image] Table 17 [image] Table 18 [image] or a pharmaceutically acceptable salt or optical isomer thereof. 8. Compound according to claim 6, characterized in that: 1-[5-/1-(4-nitrobenzyl/imidazolylmethyl]-2(S)-butyl-4-(1-naphthoyl)piperazine [image] or a pharmaceutically acceptable salt thereof. 9. Compound according to claim 6, characterized in that: 1-[5-(1-benzylimidazole)methyl]-2(S)-butyl-4-(1-naphthoyl)piperazine [image] or a pharmaceutically acceptable salt or optical isomer thereof. 10. Compound according to claim 6, characterized in that: 1-(2(R)-Amino-3-(3-benzylthio)propyl)-2(S)-butyl-4-(1-naphthoyl) piperazine [image] or a pharmaceutically acceptable salt or optical isomer thereof. 11. Compound according to claim 6, characterized in that: 1 (2(R)-amino-3-(3-(4-nitrobenzylthio)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine [image] or a pharmaceutically acceptable salt or optical isomer thereof. 12. Compound according to claim 12, characterized in that: 2(S)-n-butyl-1-(1-(4-cyanobenzyl)imidazol-5-ylmethyl)-4-(1-naphthoyl)piperazine [image] or a pharmaceutically acceptable salt or optical isomer thereof. 13. Compound according to claim 6, characterized in that: 2(S)-n-butyl-1-(1-(4-cyanobenzyl)imidazol-5-ylmethyl)4(2,3-dimethylphenyl)piperazin-5-one [image] or a pharmaceutically acceptable salt or optical isomer thereof. 14. Compound according to claim 6, characterized in that: 2(S)-n-butyl-1-(1-(4-chlorobenzyl)imidazol-5-ylmethyl)-4-(1-naphthoyl)piperazine [image] 15. Compound according to claim 6, characterized in that: 1-[/1-(4-cyanobenzyl)-1H-imidazol-5-yl/acetyl]-2(S)-n-butyl-4-(1-naphthoyl)piperazine [image] or a pharmaceutically acceptable salt or optical isomer thereof. 16. Compound according to claim 6, characterized in that: 1-(1-(4-cyanobenzyl)imidazol-5-ylmethyl)-2(S)-4-(2,3-dimethylphenyl)-2(S)-(2-methoxyethyl)piperazin-5-one [image] or a pharmaceutically acceptable salt or optical isomer thereof. 17. Compound according to claim 6, characterized in that: 5(S)-n-butyl-4-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-1-(2-methylphenyl)piperazin-2-ene [image] 18. Compound according to claim 6, characterized in that: (S)-1-(3-chlorophenyl)-4-/1-(4-cyanobenzyl)-5-imidazolylmethyl/-5/2-(methanesulfonyl)ethyl/-2-piperazinone [image] or a pharmaceutically acceptable salt or optical isomer thereof. 19. Compound according to claim 6, characterized in that: (S)-1-(3-chlorophenyl)-4-(1-(4-cyanobenzyl)-5-imidazoylmethyl)-5-(2-(ethanesulfonyl)ethyl)-2-piperazinone [image] or a pharmaceutically acceptable salt or optical isomer thereof. 20. Compound according to claim 6, characterized in that: (S)-1-(3-chlorophenyl)-4-/1-(4-cyanobenzyl)-5-imidazolylmethyl/-5/2-(ethanesulfonyl)methyl/-2-piperazinone [image] or a pharmaceutically acceptable salt or optical isomer thereof. 21. Compound according to claim 6, characterized in that: 1-(3-chlorophenyl)-4-(1-(4-cyanobenzyl)-5-imidazolyl-methyl)-2-piperazinone [image] or a pharmaceutically acceptable salt or optical isomer thereof. 22. Pharmaceutical composition, characterized in that it contains a pharmaceutical carrier, and a therapeutically effective amount of the compound according to claim 1 dispersed therein. 23. Pharmaceutical composition, characterized in that it contains a pharmaceutical carrier, and a therapeutically effective amount of the compound according to claim 2 dispersed therein. 24. Pharmaceutical composition, characterized in that it contains a pharmaceutical carrier, and a therapeutically effective amount of the compound according to claim 3 dispersed therein. 25. Pharmaceutical composition, characterized in that it contains a pharmaceutical carrier, and a therapeutically effective amount of the compound according to claim 6 dispersed therein. 26. A method of inhibiting farnesyl-protein transferase, characterized in that it comprises an exemplary in mammals in need of a therapeutically effective amount of the composition according to claim 22. 27. A method of inhibiting farnesyl-protein transferase, characterized in that it comprises an exemplary in mammals in need of a therapeutically effective amount of the composition according to claim 23. 28. A method of inhibiting farnesyl-protein transferase, characterized in that it comprises an exemplary in mammals in need of a therapeutically effective amount of the composition according to claim 24. 29. A method of inhibiting farnesyl-protein transferase, characterized in that it comprises an exemplary in mammals in need of a therapeutically effective amount of the composition according to request 25. 30. A method of inhibiting farnesyl-protein transferase, indicated by the fact that it comprises the use in mammals in need of a therapeutically effective amount of a pharmaceutical composition containing a pharmaceutical carrier and a therapeutically effective amount of the compound of formula B dispersed therein: [image] where are they: R1a and R1b independently selected from: a) hydrogen, b) aryl, heteocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10Om-R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-, R102N-C (NR10)-, N, NO2, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11 OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl, where the substituent on substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O) m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, NC, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10 -, R 2 and R 3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-C8 alkenyl, unsubstituted or substituted C2-C8 alkynyl, unsubstituted or substituted aryl, [image] unsubstituted or substituted heterocycle, where 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, [image] [image] R2 and R3 are attached to the same C atom and combined to form - (CH2)u - where one of the carbon atoms can be replaced with a moiety selected from: O, S(O)m, -NC(O)-, and - N(COR10)-; R 4 is selected from H and CH 3 ; and any two of R 2 , R 3 and R 4 may be 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, [image] 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) C1-4Alkoxy, b) aryl or heterocycle, c) halogen d) HO, [image] 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, R10O-, R11 S(O)m-, R10C(O)-, R10OC(O)-, R 10 OC(O)NR 10 -; and c) C1-C6 alkyl unsubstituted or substituted with aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6alkenyl, perfluoroalkyl, F,Cl,R10O-, R10C(O)NR10-(R10)2N-C(NR10)C (O)-, R10C(O)-, N(R10)2, or R11 OC(O)NR10-; 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 R11 OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted with 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 R11 OC(O)NR10-, N(R10)2, or R11OC(O)NR10-; R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl; R 11 is independently selected from C 1 -C 6 alkyl and aryl; A1 and A2 are independently selected from: 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 H2O V is chosen by: a) hydrogen, b) heterocycle, c) aril, d) C1-C20 alkyl where from 0 to 4 carbon atoms are replaced by a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A1S(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)-, -S(O)m-; Z is an unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, where 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) C3-6 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 the substituent (R8)r-V - A1 (CR1a2)nA2(CR1a2)n is H; or pharmaceutically acceptable salts thereof. 31. The method of inhibiting farnesyl-protein transferase, indicated by the fact that it comprises the application to mammals in need of a therapeutically effective amount of a pharmaceutical composition containing a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of the formula: [image] where are they: R1a and R1b independently selected from: a) hydrogen, b) aryl, heteocycle, C3-C10cycloalkyl, C2-C6alkenyl, C2-C6 alkynyl, R10Om-R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-, R102N-C(NR10 )-, N, NO2, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11 OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl, where the substituent on substituted C1-C6 alkyl is chosen from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O) m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, NC, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10 -, R 2 and R 3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-C8 alkenyl, unsubstituted or substituted C2-C8 alkynyl, unsubstituted or substituted aryl, [image] unsubstituted or substituted heterocycle, where the substituted group is substituted with one or more of: 1) aryl iii heterocycle, unsubstituted or substituted with: a) C1-4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, e) CN, 2) C3-C6 cycloalkyl, 3) OR6, 4) SR6a, S(O)R6a, SO2R6a, 5) -NR6R7, [image] [image] R2 and R3 are attached to the same C atom and combined to form - (CH2)u - where one of the carbon atoms can be replaced with a moiety selected from: O, S(O)m, -NC(O)-, and, -N(COR10)-; R 4 is selected from H and CH 3 ; and any two of R 2 , R 3 and R 4 may be 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: [image] 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: [image] R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, R10O-, R11 S(O)m-, R10C(O)-, R10OC(O)-, R 10 OC(O)NR 10 -; and c) C1-C6 alkyl unsubstituted or substituted with aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, perfluoroalkyl, F,Cl,R10O-, R10C(O)NR10-(R10)2N-C(NR10) C(O)-, R10C(O)-, N(R10)2, or R11 OC(O)NR10-; 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 R11 OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted with 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 R11 OC(O)NR10-, N(R10)2, or R11 OC(O)NR10-; R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl; R 11 is independently selected from C 1 -C 6 alkyl and aryl; A1 and A2 are independently selected from: bonds, -CH=CH-, -C≡C-, -C(O)-, -C(O)NR10-, NR10C(O)-, O, -NCR10)-, -S(O)2NCR10)-, -N(R10)S(O)2, or S(O)m; G is H2O V is chosen by: a) hydrogen, b) heterocycle, c) aril, d) C1-C20 alkyl where from 0 to 4 carbon atoms are replaced by 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)-, -S(O)m-; Z is an unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, where the substituted group is substituted with one or more of the following: 1) C 1-4 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) C3-6 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 = 0 then the substituent is (R8)r- V - A1 (CR1a2)nA2(CR1a2)n H; or pharmaceutically acceptable salts thereof. 32. The method of treating cancer, characterized by the fact that it includes the use in mammals that need a therapeutically effective amount of the composition according to article 22. 33. The method of treating cancer, characterized by the fact that it includes application in mammals that need a therapeutically effective amount of the composition according to article 23. 34. The method of treating cancer, indicated by the fact that it includes the use in mammals that need a therapeutically effective amount of the composition according to article 24. 35. The method of treating cancer, indicated by the fact that it includes application in mammals that need a therapeutically effective amount of the composition according to article 25. 36. A method of treating a neurofibrin benign proliferative disorder, characterized by the fact that it comprises administration to mammals in need of a therapeutically effective amount of the composition according to item 23. 37. A method of treating glaucoma related to retinal vasculature, indicated by the fact that it includes application in mammals that require a therapeutically effective amount of the composition according to article 23. 38. A method of treating hepatitis delta and related viruses, indicated by the fact that it comprises administration to mammals in need of a therapeutically effective amount of the composition according to claim 23. 39. A method for preventing restenosis, characterized in that it comprises administration to mammals in need of a therapeutically effective amount of the composition according to claim 23. 40. A method of treating polycystic kidney disease, indicated by the fact that it comprises administration to mammals in need of a therapeutically effective amount of the composition according to claim 23. 41. A method of treatment and prevention of diseases selected from cancer, neurofibroma benign proliferative disorder, blindness related to retinal vascularization, infection with hepatitis delta and related viruses, restenosis and polycystic kidney diseases, characterized by the fact that it includes application in mammals that require a therapeutically effective amount of pharmaceutical a composition containing a pharmaceutical carrier, and a therapeutically effective amount of the compound of formula B dispersed therein: [image] where are they: R1a and R1b independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10Om-R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-, R102N-C (NR10)-, N, NO2, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11 OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl, where the substituent on substituted C1-C6 alkyl is chosen from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O) m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, NC, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10 -, R 2 and R 3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-C8 alkenyl, unsubstituted or substituted C2-C8 alkynyl, unsubstituted or substituted aryl, [image] unsubstituted or substituted heterocycle, where 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, [image] [image] R2 and R3 are attached to the same C atom and combined to form - (CH2)u - where one of the carbon atoms can be replaced with a moiety selected from: O, S(O)m, -NC(O)-, and - N(COR10)-; R 4 is selected from H and CH 3 ; and any two of R 2 , R 3 and R 4 may be 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: [image] 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: [image] R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F,Cl,R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O )-, R10OC(O)-, R102N-C(NR10)- CN, NO2, R10 OC(O)NR10-; and c) C1-C6 alkyl unsubstituted or substituted with aryl, cyanophenyl, heterocycle, C3-C10cycloalkyl, C2-C6 alkenyl, perfluoroalkyl, F,Cl,R10O-, R11S(O)m- R10C(O)NH-, -(R10 )2NC(O)-, (R10)2N, C(NR10)-, CN, R10C(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 with 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 R11 OC(O)NR10-, N(R10)2, or R11 OC(O)NR10-; R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl; R 11 is independently selected from C 1 -C 6 alkyl and aryl; A1 and A2 are independently selected from: bonds, -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 chosen by: a) hydrogen, b) heterocycle, c) aril, d) C1-C20 alkyl where from 0 to 4 carbon atoms are replaced by 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)-,-S(O)m-; Z is an unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, where the substituted group is substituted with one or more of the following: 1) C1-4 alkyl, unsubstituted or substituted with: a) C1-4Alkoxy, 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) C3-6 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 = 0 then the substituent is (R8)r- V - A1 (CR1a2)nA2(CR1a2)n H; or pharmaceutically acceptable salts thereof. 42. Method of treatment or prevention of cancer, neurofibromin benign proliferative disorder, blindness related to retinal vascularization, infection with hepatitis delta and related viruses, restenosis and polycystic kidney diseases, indicated by the fact that it includes application to mammals in need of a therapeutically effective amount of the composition containing a pharmaceutical carrier, and a therapeutically effective amount of a compound of the formula dispersed therein: [image] where are they: R1a and R1b independently selected from: a) hydrogen, b) aryl, heteocycle, C3-C10 cycloalkyl, C2-C6alkenyl, C2-C6 alkynyl, R10Om-R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-, R102N-C( NR10)-, N, NO2, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl, where the substituent on substituted C1-C6 alkyl is chosen from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O) m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, NC, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10 -, R 2 and R 3 are independently selected from: H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-C8 alkenyl, unsubstituted or substituted C2-C8 alkynyl, unsubstituted or substituted aryl, [image] unsubstituted or substituted heterocycle, where 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, [image] [image] R2 and R3 are attached to the same C atom and combined to form -(CH2)u - where one of the carbon atoms can be replaced with a moiety selected from: O, S(O)m, -NC(O)-, and - N(COR10)-; R 4 is selected from H and CH 3 ; and any two of R 2 , R 3 and R 4 may be attached to the same carbon atom; R6, R7 and R7a are independently selected from: H, C1-4 alkyl, C3-5 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: [image] 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, C3-5 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: [image] R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F,Cl,R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O )-, R10OC(O)-, R102N-C(NR10)-CN, NO2, R10OC(O)NR10-; and c) C1-C6 alkyl unsubstituted or substituted with aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, perfluoroalkyl, F,Cl,R10O-, R11S(O)m- R10C(O)NH-, -( R10)2NC(O)-, (R10)2N, C(NR10)-, CN, R10C(O)-, N3,-N(R10)2 or R10OC(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11 S(O)m- R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, R10OC(O)-, N3, N(R10)2, or R11 OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted with 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 R11 OC(O)NR10-, N(R10)2, or R11 OC(O)NR10-; R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl; R 11 is independently selected from C 1 -C 6 alkyl and aryl; A1 and A2 are independently selected from: 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 H 2 or O; V is chosen by: a) hydrogen, b) heterocycle, c) aril, d) C1-C20 alkyl where from 0 to 4 carbon atoms are replaced by 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)-,-S(O)m-; Z is an unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, where the substituted group is substituted with one or more of the following: 1) C1-4 alkyl, unsubstituted or substituted with: a) C 1-4 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) C3-6 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 = 0 then the substituent is (R8)r-V - A1 (CR1a2)nA2(CR1a2)n H; or pharmaceutically acceptable salts thereof.