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CA2250231A1 - Inhibitors of farnesyl-protein transferase - Google Patents

Inhibitors of farnesyl-protein transferase Download PDF

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Publication number
CA2250231A1
CA2250231A1 CA002250231A CA2250231A CA2250231A1 CA 2250231 A1 CA2250231 A1 CA 2250231A1 CA 002250231 A CA002250231 A CA 002250231A CA 2250231 A CA2250231 A CA 2250231A CA 2250231 A1 CA2250231 A1 CA 2250231A1
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substituted
alkyl
unsubstituted
cyanobenzyl
imidazole
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CA002250231A
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Inventor
Robert P. Gomez
Kelly M. Solinsky
Gerald E. Stokker
Neville J. Anthony
Wasyl Halczenko
John H. Hutchinson
Theresa M. Williams
Steven D. Young
John S. Wai
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Merck and Co Inc
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Priority claimed from GBGB9613462.2A external-priority patent/GB9613462D0/en
Priority claimed from GBGB9617257.2A external-priority patent/GB9617257D0/en
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Publication of CA2250231A1 publication Critical patent/CA2250231A1/en
Abandoned legal-status Critical Current

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Abstract

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

Description

CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 TITLE OF THE INVENTION
~HIBITORS OF FARNESYL-PROTEIN TRANSFERASE
"
BACKGROUND OF THE INVENTION
The Ras proteins (Ha-Ra.s, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP.
Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoe,s a conformational change. The GTP-bound form of Ras propagates the growth stimulatory signal until the signal is termin~ted by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M. Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). Mutated ra~ genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terrninus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-Aaa1-Aaa2-Xaa"
box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:5R3-586 (1984)). Depend-ing on the specific sequence, this motif .serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a Cls or C20 isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386 (1992); W.R. Schafer and J. Rine, An7l. Rev. Genetics 30:209-237 (1992)). The Ras protein is one of several proteins that are known to undergo post-translational farnesyl-CA 022~0231 1998-09-28 ation. Other farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesyl-ated proteins of unknown structure and function in addition to those listed above.
Inhibition of farnesyl-protein transferase has been shown to block the growth of Ras-tran,sformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the Ras oncoprotein intracellularly (N.E. Kohl et al., Science, 260:1934-1937 (1993~ and G.L. James et al., Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of ras-dependent tumors in nude mice (N.E. Kohl et al., Proc. Natl. Acad.
Sci U.S.A., 91:9141-9145 (1994) and induces regression of 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 includ-ing farnesyl pyrophosphate. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al., Cell, 62:P~ l -88 (1990); Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad.
Sci USA, 87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. However, direct inhibition of farnesyl-protein transferase would be more specific and attended by fewer side effects than would occur with the reguired do.se of a general inhibitor CA 022~0231 1998-09-28 of isoprene biosynthesis.
Inhibitors of farnesyl-protein transferase (FPTase) have been described in four general classes (S. Graham, Expert Opinion Ther. Patents, (1995) 5:1269-1285). The first are analogs of farnesyl diphosphate (FPP), while a second class of inhibitors is related to the protein substrates (e.g., Ras) for the enzyme. Bisubstrate inhibitors and inhibitors of farnesyl-protein transferase that are non-competitive with the substrates have also been described. The peptide derived inhibitors that have been described are generally cysteine cont~ining molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ibid; Reiss et. al., i~id; Reiss et al., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141,851, University of Texas; N.E. Kohl e~ al., Science, 260: 1934- 1937 (1993); Graham, et al., J. Med .
Chem., 37, 725 (1994)). In general, deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound. However, the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity.
Therefore, a functional replacement for the thiol is desirable.
It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516).
Imidazole-containing inhibitors of farnesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 Al).
It has recently been reported that farnesyl-protein transferase inhibitors are inhibitors of proliferation of vascular ~ 30 smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels - (JP H7-112930).
It is, therefore, an object of this invention to develop CA 022~0231 1998-09-28 W O 97136875 PCTrUS97/05383 low molecular weight compounds that will inhibit farnesyl-protein transferase and thus, the post-translational farnesylation of proteins.
It is a further object of this invention to develop chemotherapeutic compositions containing the compounds of this invention and methods 5 for producing the compounds of thi,s invention.

SUMMARY OF THE INVENTION
The present invention comprises novel biaryl-containing compounds which inhibit the farnesyl-protein transferase. Further 10 contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.

The compounds of this invention are illustrated by the 15 formula A:
R6a-e ~\~
(R8)r /(~ ~ R2~RJ5 V - A1(CR1a2)nA2(CR1a2)n tW~ - (CR1b2)p - X -(CR1b2)p R4 DET ~ 'LED DESCRIPTION OF THE INVENTION

The compounds of this invention are useful in the inhibition of farnesyl-protein transferase and the farnesylation of the oncogene protein Ras. In a first embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula A:

._ CA 022~0231 1998-09-28 ' R 6a-e ~\~

(R8)r /(~ ~\ R2~

V - A1(CR1a2)nA2(CR1a2)n~Wl - (CR1b2)p - X -(CR1b2)p R4 wherein:

Rla and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R1 lS(O)m-, R10C(O)NRl0-~
R 1 1 C(O)O-, (R 1 0)2NC(O)-, R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R100-, Rl lS(O)m, RlOC(O)NR10-, (RlO)2Nc(o)-~
R102N-C(NR10)-, CN, R10C(o)-, N3, -N(R10)2, and RllOC(O) NR10;

R2, R3, R4 and R5 are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C1o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R12O-, R 1 1 S(O)m-~ R 1 0C(o)NR 10, (R 1 0)2NC(O)- R 1 1 C(O)O-R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 CA 022~0231 1998-09-28 c) unsubstituted C1 -C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R 1 1 S(O)m-~ R 1 OC(O)NR 10, (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and RllOC(o) NR10;

10 R6a, R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o) R1 lC(o)o R 1 02N-C(NR 10) , CN, N02, R 1 ~C(O)-, N3, -N(R 1~)2, or Rl lOC(O)NR10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, RllS(O)m-, RllS(O)mNR10-, (R10)2NS(o)m-, R 1 3C(o)NR 10, (R 1 0)2NC(O)-, R 1 02N-C(NR 1 0), CN, R 10C(o)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 1 0-;

any two of R6a R6b, R6C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;~0 provided that when R2, R3, R4, R5, R6a~ R6b, R6C, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R2 R3, R4, R5, R6a~ R6b, R6C~ R6d or R6e to the phenyl ring is through a substitutable heterocycle ring carbon;

CA 022~0231 1998-09-28 WO 97/3687~ PCT/US97/05383 R7 i.s selected from: H; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, - aroyl, heteroaroyl, aryl.sulfonyl, heteroarylsulfonyl, un~ubstituted or substituted with:
S a) Cl 4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) o f) --SO2R
g) N(R10)2 or h) C 1-4 perfluoroalkyl;

R~ is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycleC3-C10 cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R1OO-, Rl IS(O)m-, R1OC(O)NR10-, (R10)2NC(o)-~ R102N-C(NR10)-, CN, NO2, RlOC(O)-, N3, -N(R10)2, or Rl IOC(O)NRlO-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R l Oo, R 1 I S(O)m-~ R 1 OC(O)NH-, (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 OOC(O)NH-;
provided that when R~ is heterocycle, attachment of R~ to V is through a substitutable ring carbon;

R9 is independently selected from:
a) hydrogen, b) C2-c6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, halogen Rl lo-, Rl lS(O)m-, R10C(o)NR10-, (R 1 0)2NC(O)-, R 1 02N C(NR 10) , CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) Cl-c6 alkyl unsubstituted or substituted by Cl-C6 perfluoroalkyl, F, Cl, Br, R10O-~ Rl lS(o)m R 1 0C(o)NR 10 , (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 ;

10 R10 is independently selected from hydrogen, Cl-C6 alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;

R l 1 is independently selected from Cl -C6 alkyl and aryl;
lS R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
R13 is independently selected from hydrogen, Cl-C6 alkyl, 2,2,2-trifluoroethyl, -CH2N(R10)2, benzyl and aryl;

Al and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR 10, -NR 1 ~C(O)-, O, -N(R 10) , -S(O)2N(R10)-, -N(R10)S(0)2- or S(O)m;

V is selected from:
a) hydrogen, b) heterocycle, c) aryl, d) Cl-c2o alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and , CA 022~0231 1998-09-28 e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is O and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to Al is S through a substitutable ring carbon;

W is a heterocycle;

X is a bond, -CH=CH-, O, -C(=O)-, -C(o)NR7-, -NR7C(o)-, -C(O)O-, -OC(O)-, -C(o)NR7C(o)-, -S(0)2N(R10)-, -N(RlO)s(o)2 or -S(=O)m-;

m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
15 p is independently 0, 1, 2, 3 or 4;
q is 0, 1, 2 or 3;
r is O to 5, provided that r is O when V is hydrogen; and tis Oor l;

20 or the pharmaceutically acceptable salts thereof.
A preferred embodiment of the compounds of this invention is illustrated by the following formula:
p6a-e V-A1(CR1a2)nA2(cR1a2)n~w ~-(CR1b2)p-X-(CR~ 2 wherein:

CA 022~0231 1998-09-28 Rla is independently selected from: hydrogen, C3-Clo cycloalkyl, R10O-, -N(R10)2, F or Cl-C6 alkyl;

5 Rlb is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3 -C l o cycloalkyl, R 1 0O-, -N(R 1 0)2, F
or C2-C6 alkenyl, c) unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, R10O- and -N(R10)2;

R2, R3, R4 and RS are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, K120, RllS(O)m, RlOC(O)NR10-, (RlO)2Nc(o)-~
R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R~0)2, or R 1 1 OC(O)NR 10-, c) unsubstituted C 1 -C6 alkyl;
d) substituted C1-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, Rl lS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o) R 1 02N-C(NR 10), C~, R 1 ~C(O)-, N3, -N(R 1~)2, and R 1 1OC(O) NR10;
R6a R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, -b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-c6 CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o) - R102N-C(NR10)-, CN, NO2, R10C(o)-, N3, -N(R10)2, or R 1 1 OC(O)NR 10, c) unsubstituted Cl-C6 alkyl;
d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or sub~stituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, Rl lS(O)m-, Rl lS(O)mNR10-, (R10)2NS(o)m-, R 1 3C(o)NR 10, (R 1 0)2NC(o)-, R 1 02N-C(NR 10) , CN, R10C(o)-, N3, -N(R10)2, and Rl lOC(O)-NR10-;

any two Of R6a, R6b, R6C, R6d and R6e on adjacent carbon atom.s are lS combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R2, R3, R4, R5, R6a~ R6b, R6C, R6d or R6e is unsubstituted or sub,stituted heterocycle, attachment of R2 R3, R4, R5, R6a~ R6b, R6C, R6d or R6e to the phenyl ring is through a .substitutable heterocycle ring carbon;

R7 is selected from: H; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, o f) --SO2R
g) N(R 1~)2 or CA 022~0231 1998-09-28 h) Cl 4 perfluoroalkyl;

R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6 alkenyl, C2-c6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R 1 0O, R 1 0C(O)NR 10, CN, NO2, (R 1 0)2N-C(NR 10), R 10c(O)-, -N(R 1 ~)2, or R 1 1 OC(O)NR 10, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R 10C(o)NR 10, (R 10)2N-C(NR 10), R 10c(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;

15 R9 is independently selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 1 l o, K1 lS(O)m-, R 10C(o)NR 10 (R10)2NC(o) CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R 1 1 OC(O)NR 10, and c) C1-C6 alkyl unsubstituted or substituted by Cl-C6 perfluoroalkyl, F, Cl, R10O-, R11S(O)m-, R10C(O)NR10-, (Rl0)2Nc(o)-~ CN, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or Rl 1OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;

R11 is independently selected from Cl-C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-c6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, CA 022~0231 1998-09-28 2-aminoethyl and 2,2,2-trifluoroethyl;
R13 is independently selected from hydrogen, Cl-C6 alkyl, 2,2,2-trifluoroethyl, -CH2N(R10)2, benzyl and aryl;

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

V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 aL~enyl, and provided that V is not hydrogen if Al is S(O)m and V is not hydrogen 20 if Al is a bond, n is 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to Al is through a substitutable ring carbon;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, 25 pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or isoquinolinyl;

X is a bond, O, -C(=O)-, -CH=CH-, -C(o)NR7-, -NR7C(o)-, -S(0)2N(R10)-, -N(R10)S(0)2- or-S(=O)m-;

mis 0, 1 or2;
n is independently 0, 1, 2, 3 or 4;
qis 0, 1, 2 or 3;
p is independently 0, 1, 2, 3 or 4;

CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97105383 r is O to 5, provided that r is O when V is hydrogen; and tis Oor 1;

or the pharmaceutically acceptable ~salts thereof.
A preferred embodiment of the compounds of this invention are illustrated by the formula B:
F 6a-e (R8)r R9a R2 ~g V - A1(CR1a2)nA2(cR1a2)n N~ \J X~R3 (CR1b ~
wherein:

10 Rla is independently selected from: hydrogen, C3-Clo cycloalkyl, R l Oo, -N(R 1~)2, F or C 1 -C6 alkyl;

Rlb is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C l o cycloalkyl, R 1 00-, -N(R 1 0)2, F
or C2-C6 alkenyl, c) unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R100- and -N(R10)2;

R2 and R3 are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-c6 CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 20, R I 1 S(O)m-~ R 1 OC(O)NR 10, (R 1 0)2NC(o)-, - R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 C) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20 R 1 1 S(O)m ~ R 1 OC(O)NR 10 , (R 1 0)2NC(O)-, R102N-C(NR10)-, CN, RlOC(O)-, N3, -N(R10)2, and RllOc(o) NRlO;

R6a R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 2O R 1 1 S(O)m-~ R 1 OC(O)NR 10, (R 1 0)2NC(O)-, R102N-C(NR10)-, CN, NO2, RlOC(O)-, N3, -N(R10)2, or R 1 1 OC(O)NR 10 c) un,substituted C~-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, Rl lS(O)m-, Rl lS(O)mNR10-, (R10)2NS(o)m-, R13C(o)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, RlOC(O)-, N3, -N(R10)2, and Rl lOC(O)-NR10-;
any two Of R6a, R6b, R6C, R6d and R6e on adjacent carbon atoms are - combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

CA 022~0231 1998-09-28 W O 97/3687~ PCTrUS97/05383 provided that when R2, R3, R6a~ R6b, R6C, R6d or R6e is unsubstituted or substituted heterocycle, attachrnent of R2, R3 R6a, R6b, R6C, R6d or R6e to the phenyl ring is through a substitutable heterocycle ring carbon;
s R~ independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-c6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R 1 0C(O)NR 10, (R1 0)2N-C(NR 1 0)-, R 1 ~C(O)-, -N(R10)2, or R1 1OC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;

R9a and R9b are independently hydrogen, Cl-C6 alkyl, trifluoromethyl and halogen;
R10 is independently selected from hydrogen, Cl-C6 alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;

Rl 1 is independently selected from Cl-C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-c6 alkyl, Cl-c6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;

R13 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2-trifluoroethyl, -CH2N(R10)2, benzyl and aryl;

CA 022~0231 1998-09-28 A l and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR10-, -NRlOC(O)-, O, -N(R10)- or S(O)m;

5 V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 aL~enyl, and provided that V is not hydrogen if Al is S(O)m and V is not hydrogen 15 if Al is a bond, n is 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to Al is through a substitutable ring carbon;

X is a bond, -CH=CH-, -C(O)NR10-, -NRlOC(O)-, O or -C(=O)-;

mis 0, 1 or2;
n is independently 0, 1, 2, 3 or 4;
pis 0, 1, 2, 3 or4; and 25 r is 0 to 5, provided that r is 0 when V is hydrogen;

or the pharmaceutically acceptable salts thereof.
Another preferred embodiment of the compounds of this invention are illustrated by the formula C:

CA 022~0231 1998-09-28 W O 97J36875 PCTrUS97/OS383 ] ~

F 6a-e (R8)r R2 ~/
N~ R9a \~/~
V - A1a(cR12)nA2(cR 2)~N ~ R3 C R9b (CR1b2~/

wherein:

Rla is independently selected from: hydrogen, C3-Clo cycloalkyl, 5 R100-, -N(Rl0)2, F or Cl-C6 alkyl;

Rlb is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C l o cycloalkyl, R 1 00-, -N(R 1 0)2, F
or C2-C6 alkenyl, c) unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, R 1 00- and -N(R 1 0)2;
R2 and R3 are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 20 R 1 1 S(O)m ~ R 1 OC(O)NR 10, CN(R 1 0)2NC(O)-, R102N-C(NR10)-, CN, N02, RlOC(O)-, N3, -N(R10)2, or R 1 1 OC(O)NR 10, c) unsubstituted C I -C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl i.s selected from unsubstituted or CA 022~0231 1998-09-28 W O 97/3687~ PCTrUS97/05383 - substituted aryl, unsubstituted or substituted heterocyclic,C3-C1o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120, Rl lS(O)m, RlOC(O)NR10-, (RlO)2Nc(o)-~
R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R 1 1 OC(O)-NR 10;

R6a, R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, CN(R10)2NC(o)-, R 1 02N-C(NR 1 0)-, CN, NO2, R 10c(O)-, N3, -N(R 1 ~)2, or R 1 1 OC(O)NR 10 c) unsubstituted C1-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, Rl lS(O)m-, Rl lS(O)mNR10-, (Rl0)2Ns(o)m R 1 3C(o)NR 10, (R 1 0)2NC(o)-, R 1 02N-C(NR 10) , CN, R 10c(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10;

any two of R6a R6b, R6C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R2, R3, R6a~ R6b, R6C, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R2, R3 R6a, R6b, R6C, R6d or R6e to the phenyl ring is through a substitutable heterocycle ring carbon;

R8 is independently selected from:
a) hydrogen, CA 022~0231 1998-09-28 b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, Rl0o~Rloc(o)NRlo~cN~No2~(Rlo)2N-c(NRlo) R10C(o)-~-N(Rlo)2, or RllOC(o)NRl0-, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, RlOO-, R10C(o)NRlo-~(Rlo)2N-c(NRlo)-~Rloc(o) -N(R 1~)2, or RllOC(o)NR10-;
provided that when R8 is heterocycle, attachment of R~ to V is through a substitutable ring carbon;
R9a and R9b are independently hydrogen, Cl-C6 alkyl, trifluoromethyl and halogen;

R10 is independently selected from hydrogen, Cl-C6 alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;

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

R12 is independently selected from hydrogen, C1-C6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, hetéroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;

25 R13 is independently selected from hydrogen, Cl-C6 alkyl, 2,2,2-trifluoroethyl, -CH2N(R10)2, benzyl and aryl;

A1 and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;
V is selected from:
a) hydrogen, CA 022~0231 1998-09-28 WO 97/36875 PCT/US97tO5383 b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, S d) C l-c2o alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(O)m;
10 provided that when V is heterocycle, attachment of V to R8 and to Al is through a substitutable ring carbon;
X is a bond, -CH=CH-, -C(O)NR10-~ NRlOC(O), O or -C(=O)-;

mis 0, 1 or2;
n is independently 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond, -NRlOC(O)-, -NR10- or O; and 20 r is 0 to 5, provided that r is 0 when V is hydrogen;

or the pharmaceutically acceptable salts thereof.
In a more preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula 25 D:
6a-e 1 b )--X~

wherein:

CA 022~0231 1998-09-28 Rla is independently selected from: hydrogen, C3-CIo cycloalkyl or Cl-C6 alkyl;

5 R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloalkyl, RlOO-, -N(R10)2, F
or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl~ C2-C6 alkenyl, RIOO-, or -N(R 1 ~)2;

R2 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (R10)2NC(o)-, R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 c) unsubstituted C1-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120, RllS(o)m, RlOC(O)NR10-, (R10)2NC(o)-, R102N-C(NR10)-, CN, RlOC(O)-, N3, -N(R10)2, and RllOC(O) NR10;

30 R3 is selected from ~, halogen, Cl-C6 alkyl and CF3;

R6a R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, CA 022~0231 1998-09-28 WO 97t36875 PCT/US97/05383 b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 120, R 1 l S(O)m-~ R 1 OC(O)NR l 0, (R l 0)2NC(O)-, R l O2N-c(NR l o)-~ CN, N02, R l OC(O)-, N3, -N(R 1 0)2, or R l l OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-c6 alkyl wherein the substituent on the ,substituted Cl-c6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rl 20, R l 1 S(O)m-, Rl Oc(o)NRlo-~ (R10)2NC(o)-, RlO2N-c(NRlo)-~ CN, RlOC(O)-, N3, -N(Rl0)2, and R 1 1 OC(O)-NR l O;~5 any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon atoms are combined to forrn a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R2, R6a, R6b, R6C, R6d or R6e i~;
unsubstituted or substituted heterocycle, attachment of R2, R6a R6b, R6C, R6d or R6e to the phenyl ring is through a substitutable heterocycle ring carbon;

R~ is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-c6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R l Oo R l OC(O)NR l O, CN, N02, (R l 0)2N-C(NR 1 0), R l ~C(O)-, -N(R 1~)2, or R l l OC(O)NR l O, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, RlOO-, R l OC(O)NR l O, (R 1 0)2N-C(NR 1 0) , R I ~C(O)-, -N(R 1~)2, or R l l OC(O)NR l O; or CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;
~9a and R9b are independently hydrogen, halogen, CF3 or methyl;

R10 is independently selected from hydrogen, Cl-C6 alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;

Rl 1 is independently selected from Cl-C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;

X is a bond, -CH=CH-, -C(O)NR10-, -NRlOC(O)-, O or -C(=O)-;

n is 0 or 1; provided that n is not 0 if Al is a bond, O, -N(R10)-, or S(O)m;
mis 0,lor2;and pis 0, 1, 2, 3 or4;

or the pharmaceutically acceptable salts thereof.
In another more preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the 30 formula E:

CA 022~0231 1998-09-28 ~; R 6a-e Al(CF~1a ) ~ ~

wherein:

Rla is independently selected from: hydrogen, R100-, -N(R10)2, F, 5 C3-Clo cycloalkyl or Cl-C6 alkyl;

Rlb is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloalkyl, R100-, -N(R10)2, F
or C2-C6 alkenyl, c) C 1 -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R100-, or -N(R 1 ~)2;

15 R2 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 120, R 1 1 S(O)m-~ R 1 OC(0)NR 10 , (R 1 0)2NC(0)-, R 1 02N-C(NR 10) , CN, N02, R 1 ~C(0)-, N3, -N(R 1~)2, or R 1 1 0C(0)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, un.substituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 R 120, R 11 S(O)m-, R 10C(O)NR 10 , (R 10)2NC(O)-, R 102N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1 ~)2, and R l l OC(O)-NR 10;
5 R3 is .selected from H, halogen, Cl-C6 alkyl and CF3;

R6a, R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C l o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 120, R 11 S(O)m-, R 10C(O)NR 10-, (R 10)2NC(o)-, R 102N-C(NR 10) , CN, N02, R 10C(o)-, N3, -N(R 1 ~)2, or Rl lOC(O)NR10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (R10)2NC(o)-~
R 102N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1 ~)2, and R 11 OC(O)-NR 10; or any two of R6a, R6b, R6C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R2, R6a~ R6b~ R6C, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R2, R6a, R6b, R6C, R6d or R6e to the phenyl ring is through a substitutable heterocycle ring carbon;

R8 is independently selected from:
a) hydrogen, CA 022~0231 1998-09-28 b) aryl, substituted aryl, heterocycle, substituted heterocycle, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, RlOO-, RlOC(O)NR10-, CN, NO2, (R 10)2N C(NR10), R 10c(O)-~ -N(R10)2, or Rl loc(o)NRlo-~ and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, RlOO-, RlOC(o)NRlo-~ (Rlo)2N-c(NRlo)-~ RlOC(O)-, -N(R10)2, or Rl lOC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;

R9a and R9b are independently hydrogen, halogen, CF3 or methyl;

R10 is independently selected from hydrogen, Cl-C6 alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;

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

R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;

X is a bond, -CH=CH-, -C(O)NR10-, -NRlOC(O)-, O or -C(=O)-;

n is 0 or 1;
m is 0, 1 or 2; and - 30 p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O;
or the pharmaceutically acceptable salts thereof.

CA 022~0231 1998-09-28 - 2~ -In a further embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the fo~nula F:

,~ R6a-e n9a -~

~ ~ ~3 (CR1b2)p X

NC F
wherein:
s Rla is independently selected from: hydrogen, C3-Clo cycloalkyl or Cl-C6 alkyl;

R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C l o cycloalkyl, R l OO-, -N(R 1 0)2 or F, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C l o cycloalkyl, R 1 0O-, or -N(R 1 0)2;
R2 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 2O , R 1 1 S(O)m-~ R 1 OC(O)NR 10, (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or , CA 022~0231 1998-09-28 W O 97136875 PCTrUS97/0~383 substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 120, Rlls(o)m-~Rloc(o)NRlO,(Rl 0)2NC(o)-, R102N-c(NRlo)-~cN~Rloc(o)-~ N3,-N(R10)2, and S Rlloc(o)-NRlo-;

R3is selected from H, halogen, CH3 and CF3;

R6a, R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120, RllS(O)m, RlOC(O)NR10-, (RlO)2Nc(o)-~
R102N-C(NRl0)-,cN,No2~ R10C(O)-, N3,-N(R10)2, or RllOC(O)NR10-c) unsubstituted C 1 -C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120, Rl lS(o)m, RlOC(O)NR10-, (R10)2NC(o)-, R102N-c(NRlo)-~cN~Rloc(o)-~ N3,-N(R 1~)2, and RllOC(o)-NR10-; or any two of R6a R6b, R6C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R2, R6a, R6b~ R6C, R6d or R6e is unsub,stituted or substituted heterocycle, attachment of R2, R6a R6b, R6C, R6d or R6e to the phenyl ring is through a substitutable heterocycle ring carbon;

CA 022~0231 1998-09-28 W O 97136875 PCTrUS97/05383 R9~ and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl;
s R11 is independently selected from Cl-c6 alkyl and aryl;

R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;

X is a bond, -CH=CH-, -C(O)NR10-, -NR1OC(O)-, O or -C(=O)-;

m is 0, 1 or 2; and pis 0, 1, 2, 3 or4;

20 or the pharmaceutically acceptable salts thereof.
In a further embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula G:

NC ~ ~ ~ ~ R6a~

wherein:

CA 022~0231 1998-09-28 WO 97/36875 PCTtUS97/05383 - Rla is independently selected from: hydrogen, RlOO-, -N(R10)2, F, C3-Clo cycloalkyl or Cl-C6 alkyl;

Rlb is independently selected from:
a) hydrogen, b) aryl, heterocycle or C3-CIo cycloalkyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R100-, or -N(R 1 ~)2;
R2 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~
R102N-C(NR10)-, CN, NO2, RlOC(O)-, N3, -N(R10)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~
R102N-C(NR10)-, CN, R1OC(O)-, N3, -N(R10)2, and RllOC(O) NR10;

R3 is selected from H, halogen, CH3 and CF3;

30 R6a, R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 CA 022~0231 1998-09-28 W 097/36875 PCTrUS97/05383 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (R10)2NC(o)-, R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 S c) unsubstituted Cl-C6 alkyl, d) substituted Cl-c6 a}kyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R 1 1 S(O)m ~ R 1 0C(O)NR 10, (R 1 0)2NC(o)-R 1 02N-C(NR 10), CN, R I ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10-; or any two Of R6a, R6b, R6C, R6d and R6e on adjacent carbon atoms are combined to forrn a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R2, R6a, R6b, R6C, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R2, R6a, R6b, R6C, R6d or R6e to the phenyl ring is through a substitutable heterocycle ring carbon;

R9a and R9b are independently hydrogen, halogen, CF3 or methyl;

R10 is independently selected from hydrogen, Cl-C6 alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;

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

R12 is independently selected from hydrogen, Cl-c6 alkyl, Cl-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, CA 022~0231 1998-09-28 2-aminoethyl and 2,2,2-trifluoroethyl;

- Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;

S m is 0, 1 or 2; and n is 0 or 1 ;

or the pharmaceutically acceptable salts thereof.
The preferred compounds of this invention are as follows:
1 -(4-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1 -(4-Cyanobenzyl)-5-(4'-phenylbenzamido)ethyl-imidazole 1 -(2'-Trifluoromethyl-4-biphenylmethyl)-5 -(4-cyanobenzyl)imidazole 20 1-(4-Biphenylethyl)-5-(4-cyanobenzyl)imidazole 1 -(2'-Bromo-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1 -(2'-Trifluoromethoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) - 30 imidazole 1-(4-(3',5'-dichloro)-biphenylmethyl)-5-(4-cyanobenzyl) imidazole CA 022~0231 1998-09-28 1-(2'-Methoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 5 1 -(2'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(3-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1 -(4-(3 ' ,5'-Bis-trifluoromethyl)-biphenylmethyl)-5 -(4-cyanobenzyl) 1 5 imidazole 1 -(2'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)-4-methylimidazole 1 -(4-Biphenylmethyl)-5 -(4-cyanophenyloxy)-imidazole 5-(4-Cyanophenyloxy)- 1 -(2'-methyl-4-biphenylmethyl)-imidazole 5-(4-Biphenyloxy)- 1 -(4-cyanobenzyl)-imidazole 30 5-(2'-Methyl-4-biphenoxy)- 1 -(4-cyanobenzyl)-imidazole 5-(4-(3',5'-dichloro)biphenylmethyl)- 1 -(4-cyanobenzyl)imidazole CA 022~0231 1998-09-28 W 097/3687S PCTrUS97/05383 1 -(4-biphenylmethyl)-5-( 1 -(R,S)-acetoxy- 1-(4-cyanophenyl)methylimidazole 1 -(4-Biphenylmethyl)-5-( 1 -(R,S)-hydroxy- 1 -(4-cyanophenyl) methylimidazole 10 1 -(4-Biphenylmethyl)-5-( 1 -(R,S)-amino- 1 -(4-cyanophenyl) methylimidazole 1 -(4-biphenylmethyl)-5-( 1 -(R,S)-methoxy- 1 -(4-cyanophenyl)-1 5 methylimidazole 1 -(4-Cyanobenzyl)-5-( 1 -hydroxy- 1 -(4-biphenyl)-methyl) imidazole 1-(4-Cyanobenzyl)-5-(1-oxo-1-(4-biphenyl)-methyl) imidazole 1 -(4-Cyanobenzyl)-5-( 1 -hydroxy- 1 -(3-fluoro-4-biphenyl)-methyl)-imidazole 1 -(4-Cyanobenzyl)-5-( 1 -hydroxy- 1 -(3-biphenyl)methyl-imidazole 30 5-(2-[1,1'-Biphenyl]vinylene)-1-(4-cyanobenzyl)imidazole 1 -(4-Biphenylmethyl)-5-(4-bromophenyloxy)-imidazole 1-(3'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole CA 022~0231 1998-09-28 W O 97/36875 PCTrUSg7/05383 1-(4'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(3 '-Trifluoromethyl-4-biphenylmethyl)-5 -(4-cyanobenzyl) imidazole 1-(4'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(3'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(4'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 20 1-(2' 3 ' -Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'4'-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'5'-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1 -(3 ' -Trifluoromethoxy-4-biphenylmethyl)-S -(4-cyanobenzyl) 30 imidazole 1-(2'-Fluoro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazo}e CA 022~0231 1998-09-28 W O 97136875 PCTnUS97/05383 1 -(4-(2 ' -Trifluoromethylphenyl)-2-Chlorophenylmethyl )-5 -(4-cyanobenzyl) imidazole 1- { 1 -(4-(2'-trifluoromethylphenyl)phenyl)ethyl ~ -5-(4-cyanobenzyl) imidazole 1 -(2'-Trifluoromethyl-4-biphenylpropyl)-5 -(4-cyanobenzyl) 1 0 imidazole 1 -(2'-N-t-Butoxycarbonylamino-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1 -(2'-Aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1 -(2'-Acetylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) irnidazole 1 -(2'-Methylsulfonylaminomethyl-4-biphenylmethyl)-5 -(4-cyanobenzyl) imidazole 1 -(2'-Ethylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) 25 imidazole 1 -(2'-Phenylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'-Glycinylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1 -(2'-Methyl-4-biphenylmethyl)-2-chloro-5-(4-cyanobenzyl) imidazole CA 022~0231 1998-09-28 W O 97136875 PCTrUS97/05383 - 3~ -1-(2'-Methyl-4-biphenylmethyl)- 4-chloro 5-(4-cyanobenzyl) imidazole 1 -(3 '-Chloro-2-methyl -4-biphenylmethyl) -4-(4-5 cyanobenzyl)imidazole 1-(3 '-Chloro-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1 -(3 '-Trifluoromethyl-2-methyl -4-biphenylmethyl)-4-(4-cyanobenzyl) imidazole 1-(3'-Trifluoromethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1 -(3 '-Methoxy-2-methyl -4-biphenylmethyl)-5 -(4-20 cyanobenzyl)imidazole 1 -(2'-Chloro-4'-fluoro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1 -(2'-Ethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 30 1-(2'-(2-Propyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1 -(2'-(2-Methyl-2-propyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole CA 022~0231 1998-09-28 W 097/36875 PCTrUS97/05383 - 1 -(2'-Ethyl-4-biphenylmethyl)-5-(4-( 1 H-tetrazol-5-yl))benzyl)imidazole s 1-[ 1 -(4-Cyanobenzyl)imidazol-5-ylmethoxy]-4-(2'-methylphenyl)-2-(3-N-phthalimido- 1 -propyl)benzene 1 -(3 ' ,5 ' -Ditrifluoromethyl -2-methyl -4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(3',5'-Chloro-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1 -(3 ',5 ' -Dimethyl -2-methyl-4-biphenylmethyl)-5 -(4-20 cyanobenzyl)imidazole 1 -(3-(N-Boc-aminomethyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)-imidazole 1 -(3-Aminomethyl-4-biphenylmethyl)-5 -(4-cyanobenzyl)imidazole 30 1-(4-Cyanobenzyl)-2-methyl-5-(2'-methylbiphenyl-4-yloxy)imidazole CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 5-(4-Cyanobenzyl)- 1 -(3-cyano-2'-trifluoromethylbiphenyl-4-ylmethyl)-imidazole S 2-Amino-5-(biphenyl-4-ylmethyl)- l -(4-cyanobenzyl)imidazole 2-Amino- l -(biphenyl-4-ylmethyl)-5-(4-cyanobenzyl)imidazole l -(3-Butylbiphenyl -4-ylmethyl)-5-(4-cyanobenzyl)-imidazole 1-(3 -Propylbiphenyl -4-ylmethyl)-5-(4-cyanobenzyl)-imidazole 1 -(4-Biphenylmethyl)-4-(4-cyanobenzyl-2-methylimidazole 20 1-(4-Cyanobenzyl)-5-[(3-fluoro-4-biphenyl)methyl]imidazole I -(4-Cyanobenzyl)-5- [ l -(4-biphenyl)- l -hydroxy]ethyl-2-methylimidazole 1 -(4-Cyanobenzyl)-5 -(4-biphenylmethyl)-2-methylimidazole 1 -(4-Cyanobenzyl)-5-[ 1 -(4-biphenyl)]ethyl-2-methyl imidazole 1-(4-Cyanobenzyl-5-[ l -(4-biphenyl)]vinylidene-2-methylimidazole and 1 -(4-Cyanobenzyl)-5-[2-(4-biphenyl)]vinylene-2-methylimidazole or the pharmaceutically acceptable salts or optical isomers thereof.
Specific examples of the compounds of the invention are:

I -(4-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole NC
~"-~N~

1-(2'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole NC~

~N~

1-(2'-Methoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole NC~

~\N ''¢5~ 0CH3 1-(4-(3',5'-dichloro)-biphenylmethyl)-5-(4-cyanobenzyl) irnidazole NC _~

N~ "CI

S Cl 5-(2'-Methyl-4-biphenoxy)- 1 -(4-cyanobenzyl)-imidazole ~i ~~1~ H3 1 -(4-Cyanobenzyl)-S-( 1 -hydroxy- 1 -(3-fluoro-4-biphenyl)-methyl)-1 0 imidazole W O 97/36875 PCTrUS97/05383 NC ~ j OH

N~ ~

1-(4'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole NC_O~

'~CI

1-(2',5'-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole NC~
~, N ~¢~

Cl 1 -(3 '-Methoxy-2-methyl-4-biphenylmethyl )-5 -(4-1 0 cyanobenzyl)imidazole CA 022~0231 1998-09-28 W O 97/36875 PCT~US97/05383 NC~, ~,~
..~. , .~

~N~ CH3 N -=J ~ ,OC H

or the pharmaceutically acceptable salts thereof.
The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. When any variable (e.g. aryl, heterocycle, R~a, Rlb etc.) occurs more than one time in any constituent, its definition on each occurence is independent at every other occurence. Also, combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
As used herein, "alkyl" and the alkyl portion of aralkyl and similar terms, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
As used herein, "cycloalkyl" is intended to include non-aromatic cyclic hydrocarbon groups having the specified number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
"Alkenyl" groups include those groups having the specified number of carbon atoms and having one or several double bonds.
Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, l-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like.
"Alkynyl" groups include those groups having the specified number of carbon atoms and having one triple bonds. Examples of CA 022~0231 1998-09-28 W 097/36875 PCTrUS97/05383 alkynyl groups include acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.
"Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.
As used herein, "aryl," and the aryl portion of aralkyl and aroyl, is intended to mean any ,stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic.
Examples of such aryl elements include phenyl, naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
The term heterocycle or heterocyclic, as used herein, represents a stable S- to 7-membered monocyclic or stable 8- to 1 l-membered bicyclic 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 hetero-cyclic rings is fu.sed to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a .stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, i,sochromanyl, isoindolinyl, i.soquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, phthalimid-l-yl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl ~sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.
A~s used herein, "heteroaryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four CA 022~0231 1998-09-28 W O 97/36875 PCT~US97/05383 carbon atoms are replaced by heteroatom.s selected 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, 5 benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, 10 pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, and thienyl.
As used herein in the definition of R7, the substituted C1 8 alkyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl, 15 substituted heteroaroyl, substituted arylsulfonyl, substituted heteroaryl-sulfonyl and substituted heterocycle include moieties containing from 1 to 3 substituents in addition to the point of attachment to the rest of the compound.
As used herein, when no specific substituents are set forth, 20 the terms "substituted aryl", "substituted heterocycle" and "substituted cycloalkyl" are intended to include the cyclic group which is substituted on a substitutable ring carbon atom with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(cl-c6 alkyl)2, NO2, CN, (cl-c6 alkyl)O-, -OH, (Cl-C6 25 alkyl)S(O)m-, (Cl-C6 alkyl)C(O)NH-, H2N-C(NH)-, (Cl-C6 alkyl)C(O)-, (Cl-C6 alkyl)OC(O)-, N3,(Cl-C6 alkyl)OC(O)NH-, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl and Cl-C20 alkyl.
Lines drawn into the ring systems from substituents (such 30 a~s from R2, R3, R4 etc.) indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.
The substituent illustrated by the structure W O 97136875 PCT~US97/05383 ~,,Q R6a-e is a simplified representation of a phenyl ring having five (5) substituents (hydrogens and/or non-hydrogen.s) and may also be represented by the structure R6b R6a~ R6c ~R6d 5 R6e The moiety described as f 3,, R6a-e where any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon atoms are combined to folm a diradical selected from -CH=CH-CH=CH, 10 -CH=CH-CH-, -(CH2)4- and -(CH2)4- includes the following structures:

~Ar ~r It is understood that such fused ring moieties may be further substituted by the remaining R6a, R6b, R6C~ R6d and/or R6e as defined 1 5 hereinabove.

CA 022~0231 1998-09-28 W O 97/36875 PCT~US97105383 Preferably, Rla and Rlb are independently selected from:
hydrogen, R 1 1 C(0)0-, -N(R 1 ~)2, R 1 OC(O)NR 10, R loo or unsub~stituted or substituted Cl-c6 alkyl wherein the substituent on the substituted Cl-c6 alkyl is selected from unsubstituted or substituted 5 phenyl, -N(R10)2, R100- and RlOC(O)NR10-.
Preferably, R2 is selected from:
a) hydrogen, b) C3-clo cycloalkyl, halogen, Cl-C6 perfluoroalkyl, R120-, CN, N02, R 1 ~C(0)- or -N(R 1~)2 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-c6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120, RllS(o)m, RlOC(O)NR10-, (R10)2NC(0)-, R102N-C(NR10)-, CN, R1OC(0)-, N3, -N(R10)2, and R 1 1 OC(0)-NR 10 Preferably, R3 is selected from: hydrogen, halogen, trifluoromethyl, trifluoromethoxy and C1-C6 alkyl.
Preferably, R4 and R5 are hydrogen.
Preferably R6a, R6b, R6C~ R6d and R6e are independently selected from:
a) hydrogen, b) C3-Clo cycloalkyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, CN, N02, R1OC(0)- or -N(R10)2, c) unsubstituted Cl-C6 alkyl;
d) substituted Cl-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, C3-c l o cycloalkyl, R 1 20, R l l S(O)m-, R 10C(o)- or -N(R10)2; or any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon atoms are combined to form a diradical Iselected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-.

CA 022~0231 1998-09-28 W O 97/36875 PCT~US97/05383 Preferably, R8 is independently selected from:
a) hydrogen, and b) aryl, substituted aryl, heterocycle, substituted heterocycle, Cl-C6 perfluoroalkyl or CN.
Preferably, R9 is hydrogen, halogen, CF3 or methyl.
Preferably, R10 is selected from H, Cl-C6 alkyl and benzyl.
Preferably, Al and A2 are independently selected from:
a bond, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, -S(0)2N(R10)- and 10 -N(Rl ~)S(0)2-.
Preferably, V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.
Preferably, W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More 15 preferably, W is selected from imidazolyl and pyridyl.
Preferably, X is a bond, -NRlOC(O)-, O or -C(=O)-.
Most preferably, X is a bond.
Preferably, n and r are independently 0, 1, or 2.
Preferably s is 0.
Preferably t is 1.
Preferably, the moiety ~7 )q V~A1(CR1a2~nA2(CR1a2)n~W~!-(CR1b2)p-X-(CR1b2tp~-is selected from:
R9a R9b >= N \~N
,=~N,~ R9b ~N~--R9a ~ CH2~ CH2--~.

NC NC

CA 022~0231 1998-09-28 W 097/36875 PCTrUS97/05383 It is intended that the definition of any substituent or variable (e.g., Rla, R9, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, -N(R~0)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood 5 that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.
The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, 15 sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, 20 isethionic, trifluoroacetic and the like.
The pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared either by ion exchange 25 chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a ~uitable solvent or various combinations of solvents.
Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1-22, 30 in addition to other standard manipulations such a.s ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Substituents R2, R6 and R~, as shown in the Schemes, represent the substituents R2, R3, R4, RS, R6a R6b, R6C, R6d and R8; although only one such R2, R6 or R8 is CA 022~0231 1998-09-28 WO 97/36875 PCTtUS97/05383 present in the intermediates and products of the schemes, it i,s understood that the reaction,s shown are also applicable when such aryl or heteroaryl moieties contain multiple substituents.
These reactions may be employed in a linear sequence S to provide the compounds of the invention or they may be u~sed to synthesize fragments which are subsequently joined by the alkyla-tion reactions described in the Schemes. Aryl-aryl coupling is generally described in "Comprehensive Organic Functional Group Transformations," Katrit,sky et al. eds., pp 472-473, Pergamon Press (1995).

Synopsis of Schemes 1-22:
The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures, for the most part. Schemes 1- 13 illustrate synthesis of the instant biaryl compound which incorporate a preferred benzylimidazolyl sidechain.
Thus, in Scheme 1, for example, a biaryl intermediate that i.s not commercially available may be synthesized by methods known in the art. Thus, a suitably substituted phenyl boronic acid I may be reacted under Suzuki coupling conditions (Pure Appl. Chem., 63:419 (1991)) with a suitably substituted halogenated benzoic acid, such as 4-bromobenzoic acid, to provide the biaryl carboxylic acid II. The acid may be reduced and the triflate of the intermediate alcohol III may be formed in situ and coupled to a suitably substituted benzylimidazolyl IV to provide, after deprotection, the instant compound V.
Schemes 2-5 illustrate other methods of synthesizing the key alcohol intermediates, which can then be proces.sed a.s described in Scheme 1. Thus, Scheme 2 illustrates the analogou.s series of biaryl alcohol forming reactions starting with the halogenated biarylaldehyde.
Scheme 3 illustrates the reaction wherein the "terminal"
phenyl moiety is employed in the Suzuki coupling as the halogenated reactant. Such a coupling reaction i.s also compatible when one of the reactants incorporates a suitably protected hydroxyl functionality as illustrated in Scheme 4.

CA 022~0231 1998-09-28 W O 97/36875 PCT~US97/05383 Negishi chemistry (Or,~,J. Synth., 66:67 (1988)) may also be employed to form the biaryl component of the instant compounds, as shown in Scheme 5. Thus, a suitably substituted zinc bromide adduct may be coupled to a suitably substituted aryl halide in the presence of S nickel (II) to provide the biheteroaryl VII. The aryl halide and the zinc bromide adduct may be selected based on the availability of the starting reagents.
Scheme 6 illustrates the preparation of a suitably substituted biphenylmethyl bromide which could also be utilized in the reaction 10 with the protected imidazole as described in Scheme 1.
Preparation of biaryl intermediates having a suitably substituted alkyl moiety on the carbon adjacent to the eventual point of attachrnent to the rest of the instant compounds is illustrated in Scheme 6a. Thus a suitably substituted biaryl carboxylic acid is first converted 15 to the amide and then the phenyl lithium is prepared and reacted in situ with a suitably substituted alkanal to provide the hydroxyalkane side-chain. The amide is then converted sequentially to the hydroxymethyl-biaryl IIIa or bromomethylbiaryl intermediates which may then be utilized in reactions that have been previously described or will be 20 described below.
As illustrated in Scheme 7, the sequence of coupling reactions may be modified such that the biphenyl bond is formed last. Thus, a suitably substituted imidazole may first be alkylated with a suitably substituted benzyl halide to provide intermediate VIII.
25 Intermediate VIII can then undergo Suzuki type coupling to a suitably substituted phenyl boronic acid.
Scheme 8 illustrates synthesis of an instant compound wherein a non-hydrogen R9b is incorporated in the instant compound.
Thus, a readily available 4-substituted imidazole IX may be selectively 30 iodinated to provide the 5-iodoimidazole X. That imidazole may then be protected and coupled to a suitably substituted benzyl moiety to provide intermediate XI. Intermediate XI can then undergo the alkylation reactions that were described hereinabove.
Scheme 9 illustrates synthesis of instant compounds CA 022~0231 1998-09-28 that incorporate a preferred imidazolyl moiety connected to the biaryl via an alkyl amino, sulfonamide or amide linker. Thus, the 4-aminoalkylimidazole XII, wherein the primary amine i~s protected as the phth~limide, is selectively alkylated then deprotected to provide S the amine XIII. The amine XIII may then react under conditions well known in the art with various activated biaryl moieties to provide the instant compounds shown.
Compounds of the instant invention wherein the A I (CR 1 a2)nA2(C3~ 1 a2)n linker is oxygen may be synthesized by methods known in the art, for example a.s shown in Scheme 10.
The suitably substituted phenol XIV may be reacted with methyl N-(cyano)meth~nimidate to provide the 4-phenoxyimidazole XV.
After selective protection of one of the imidazolyl nitrogens, the intermediate XVI can undergo alkylation reactions as described for the benzylimidazoles hereinabove.
Scheme 11 illu,strates an analogous series of reactions wherein the (cR~b2)px(cRlb2)p linker of the instant compounds is oxygen. Thus, a suitably substituted haloaryl alcohol, such as, is reacted with methyl N-(cyano)methanimidate to provide intermediate XVI. Intermediate XVI is then protected and, if desired to form a compound of a preferred embodiment, alkylated with a suitably protected benzyl. The intermediate XVII can then be coupled to a second aryl moiety by Suzuki chemistry to provide the instant compound.
Compounds of the instant invention wherein the A 1 (CR 1 a2)nA2(CR 1 a2)n linker is a substituted methylene may be synthesized by the methods shown in Scheme 12. Thus, the N-protected imidazolyl iodide XVIII is reacted, under Grignard conditions with a suitably protected benzaldehyde to provide the alcohol XIX. Acylation, followed by the alkylation procedure illustrated in the Schemes above (in particular, Scheme 1) provides the instant compound XX. If other Rl substituents are desired, the acetyl moiety can be manipulated a.s illustrated in the Scheme.

W O 97/36875 PCTrUS97/05383 Grignard chemistry may also be employed to form a substituted alkyl linker between the biaryl and the preferred W
(imidazolyl) as shown in Scheme 13. Similar substituent manipulation as shown in Scheme 12 may be performed on the fully functionalized 5 compound which incorporates an Rlb hydroxyl moiety.

Br(HO)2B
~1 I
o R2Pd(PPh3)4 i~ LiAI H4 H~~\J 2 R

HOJ~ R6 W O 97136875 PCTrUS97/0~383 ~5 SCHEME 1 (continued) Tr Tr NiCl2(Pl~hl)2 ~,N

~ (CF3SO2)20,-78 C
HO R2 NEtiPr2 -78~C-20~C

--R ~

~--N,~\~2 /,~ V

~' Pd(PPh3)4 ~R2 1~1 R6 HO J~,\ 2 R

Br~
MeO
l R2 Pd(PPh3)4 1~--R6 ~ LiAlH4 MeO~\R2 o HO~

.

R3SiO~J~' Br R2 Pd(PPh3)4 ~--R6 f~ Bu4NF
R3SiO ~'\R2 ~3 R6 R3SiOJ~ (HO)2B
R2 Pd(PPh3)4 ~, R6 ~J Bu4NF
R3SiO ~'\R2 ~- R6 ~y~
H~~,~,~R2 SCHEME S

J~ BrZn/~
R3SiO
R2 NiCI2(PPh3)2 ~ Bu4NF
R3SiO~,~

HO~ --R6 ,~ Br R3SiO
R2 NiCi2(Pph3)2 1~3 R6 ~ Bu4NF
R3SiO~ ~,\

~ ~ 6 - ~S9 -~ NBS, AIBN
H3C ~R2 CCI4 ~ R6 Br S RZ

WO 9713687S PCTtUS97/05383 SCHEME 6a COOH CONHBut J~ 1 ) (COC1)2 / CH2CI2 1 2) tert-butylamlne/ Et3N ~

R6 [~--R6 lla ButNHOC OH
I~R
1. n-BuLi / THF ~ H2 / Pd-C
EtOH / RT
2. RC HO ~ R6 ButNHOC CICH2CH200C

¢~f HOCH2CH20H ~f R
~ 1 2N HCI / reflux ~

[~ R6 ~--R6 OH Br LiBH4 ~ Ph3P / CBr4 ~R
THF ~--R6 CH2CI2 [ ~

WO 97/36875 PCT/US97/0~383 T~
N~ Br N j; MeOH
~J reflux ~ J~'2 Pd(PPh,~, R8 Vlll f~, R6 ~J R2 SCHEME ~i H H
~,~ Nal, NaHCO3, !2 Rsb~
I

IX X

ZnBr ~N

Tr OTf ~/ i. -78 C-20 C
/~1 ii. MeOH, reflux Xl N~ ~~ - R6 . .

0~
~ R8 ~, i. ~/ Br <N~ O 55~C,CH3CN
N N~ ii. EtOH,80~C, NH2NH2 0~

Xll N
</~

R ~/
~, Xlll acylation, sulfonylation</N3'~ ~ R2 or alkylation R~ H ~

<' 31 ~ ~" "~ R2 R6 W~ N ~ ~ ~
N~ R6 Ra~

OH i, Na, MeOH
NC ~J ii. 1 20~C
XIV H3C~o ~'N~N

H Tr~
N N
~N TrCI, NEt3 ~ ~N
~0 ~0 NC~J NC~/
XV XVI

,~ R
Tr\N~ R2 ~ i. -78~C-20~C

~N + ~/ii. MeOH reflux ~ OTf NC~/

XVI
<~ ~R6 ~0 NC~I

N

~,_OH i, Na, MeOH ~ N
Br~~ \J ii. 120~C q~~_o R2 H3C~o Br--~\J
N~ R2 XVI

Tr~ ~,~
TrCI, NEt3 ~N OTf -78oC-20~C
~~ ii. MeOH reflux Br ~\J

R2 R8 ~B(OH)2 ~_N /~I R6 ~

Br~O DMF, Pd(PPh3)4 K3PO4, 80~C

N~ ¢~

Tr~ <N~
~N~ EtMgBr ~N

~O ~OH

Tr~ ~ J3 R6 Ac20, PY ~_N H~J~\
~ (CF3S02)20,-78"C
/,~ OAc NEtiPr2,CH2cl2 ~ R6 ~OAc R2 ~OCI2 SCHEME 12 (continued) ~ R6 <~NJ~/ NH3, MeOH

/J Cl ~q q~ R2 ~J NH2 R8 ~ R6 ~/ OMe < 3~1 BrMg J

CA 022~0231 1998-09-28 - 6~ -Schemes l6-20 illustrate reactions wherein the moiety (R8), /(~9~

V - A1(CR1a2) A2(CR1a ) tW (CR1b ) X

incorporated in the compounds of the instant invention is represented by other than a substituted imidazo~e-cont~ining group.
Thus, the intermediates whose synthesis are illustrated in Schemes hereinabove and other biheteroaryl intermediates obtained commercially or readily .synthesized, can be coupled with a variety of aldehydes. The aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in l0 Or~anic Syntheses. 1988, 67, 69-75, from the appropriate amino acid (Scheme 14). Grignard chemistry may be utilized, as shown in Scheme 14, to incorporate the biaryl moiety. Thus, a suitably sub.stituted biaryl Grignard reagent is reacted with an aldehyde to provide the C-alkylated instant compound XXI. Compound XXI can be deoxygenated by 15 methods known in the art, such as a catalytic hydrogention, then deprotected with trifluoroacetic acid in methylene chloride to give the final compound XXII. The final product XXII may be isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine XXII can further 20 be selectively protected to obtain XXIII, which can subsequently be reductively alkylated with a second aldehyde to obtain XXIV. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XXV can be accomplished by literature procedures.
If the biaryl subunit reagent is reacted with an aldehyde 25 which also has a protected hydroxyl group, such as XXVI in Scheme l5, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 15, 16). The alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, CA 022~0231 1998-09-28 W O 97/36875 PCT~US97/05383 to obtain secondary alcohols such a.s XXX. In addition, ~he fully deprotected amino alcohol XXXI can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXXII (Scheme 16), or tertiary amines.
The Boc protected amino alcohol XXVIII can also be utilized to synthesize 2-aziridinylmethylbiaryl such as XXXIII
(Scheme 17). Treating XXVIII with 1,1'-sulfonyldiimidazole and Isodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXXIII . The aziridine is reacted with a 10 nucleophile, such as a thiol, in the presence of base to yield the ring-opened product XXXIV .
In addition, the biaryl subunit reagent can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XL, 15 as shown in Scheme 18. When R' is an aryl group, XL can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XLI. Alternatively, the amine protecting group in XL can be removed, and O-alkylated phenolic amines such as XLII
produced.
Schemes 19-22 illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic strategies for preparing alkanols that incorporate other heterocyclic moieties for variable W are also well known in the art.

W O 97136875 PCTrUS97/05383 R5 Boc N H

3 Boc NH CHO

BrMg R2 R 1. catalytic hydro~enation Boc NH~J 2. CF3CO2H

NHBoc NH2~ Boc20 R2~R6 ~CHO

BocN H
NaBH(OAc)3 NH2 Et3N, CICH2CH2CI
XXIII

SCHEME 14 (continued) BocNH~ CF3CO2H, CH2CI2, =~ NH NaHCO3 XXIV

NH2~ ~ NC

NH AgCN
~ R6 N~,N~

¢~ XXV
~3 SCHEME l~S

Et20 BrMg BnO 1 BocNH CHO
XXVi BnO HO ~-¦=\ ~ R6 20% Pd(OH)2 H2 N HBoc HO ¦-~ /==\~ R6ClcOcOcl , ~ ~d DMSO CH2CI2 NHBoc (C2Hs)3N
XXVII

W O 97/36875 PCT~US97/05383 SCHEME 15 (continued) H~ R'MgX

N H Boc XXIX

HO~ R6 NHBoc XXX

R6 CF3co2H
HO~ ~ CH2CI2 NHBoc XXVIII

,=1=, ,=', R6 R'CHO
HO~) NaBH(OAc)3 XXXI

HO~ R6 NH
R'CH2 XXXII

.

CA 022',0231 1998-09-28 W O 97/36875 PCTrUS97/05383 H H
R2 N=\ / N

H0 =F~6 ~N~S,N~
NaH, DMF 0~C
NHBoc XXVIII

,=¦=, ,=, R"SH

< (~ CH30H
NH

XXXIII

R"S~ R6 XXXIV

SCHEME IX

HO~ 1) Boc20, K2C~3 HO,~

~/ TH F- H20 ~ 2) CH2N2, EtOAc ~1~
H2N CO2H BocNH CO2CH3 XXXV XXXVI

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

XXXVII

R"'CH20 R"'CH20 ~ DMSO
BocNH CH2OH (C2H5)3N B NH CHO
XXXVIII

SCHEME 1~ (continued) R"'CH~ ~ + BrMg~R6 BocNH CH0 IXL ~~\ R"' not aryl 1. Et20 Et20 2. 20% Pd(oH)2~ H2 \
CH30H, CH3C02H
3. HCI, EtOAc R"'CH20 ~
NHBoc 1) 20% Pd(oH)2~ H2 CH30H, CH3CO2H / /~ R2 2) HCI, EtOAc / R"'CH20~R6 XLII

HO <

XLI

W O 97/36875 PCT~US97105383 - 7~ -CH3 1) HNO2,Br2 ~CO2CH3 J~ 2) KMnO4 , l' H2N N 3) MeOH, H+ Br N

ZnC~ C~(Ph3P)~ Co2cH3 NaBH4 (excess) ~"~CH20H

DMSO ~3"C HO

W O 97/3687~ PCTrUS97/0~383 1. EtO(CO)CI R6 2 R~ ~3.CO2CH3 N 3. S, xylene, heat N

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

Br~,CO2CH3 ~\ 9 N ~COzCH3 ZnCI2, NiC12(Ph3P)2 N

NaBH4 ~ SO3Py, Et3N ~CHO
(excess) N DMSO bN ~

- gO -Br~ 1. LDA, CO2 Br~

N 2. MeOH, H+ N

¢~

ZnCI2, Nicl2(ph3p)2 N
~/1 NaBH4 (excess) ~ CH20H SO3 Py, Et3N

~ JJ DMSO
N

~R6 ~30 W O 97/36875 PCTrUS97/05383 1. LDA, CO2 ~Br N Br 2. (CH3)3SiCHN2 ~N

R6 ~\Br R6 ~

Zn, NiCI2(Ph3P)2 N~CO2CH3 R6 1~
excess NaBH4 1~1~ SO3 Py, Et3N
~,CH20H DMSO

R6 ~'~

N~3,C HO

The instant compounds are u.seful as pharmaceutical agents for m~mm~ls, especially for humans. These compounds may be administered to patients for use in the treatment of cancer.
Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors. Such tumor.s may arise by mutations in the ras gene~s themselves, mutation,s in the proteins that can regulate CA 022~0231 1998-09-28 W O 97/36875 PCT~US97/05383 Ras activity (i.e., neurofibromin (NF-l), neu, scr, abl, lck, fyn) or by other mechanisms.
The compounds of the instant invention inhibit farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
5 The instant compound~s may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575-4580 (1995)). Such anti-angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization.
The compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras protein.s are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a m~mm~l in need of such treatment. For example, a component of NF-l is a benign proliferative disorder.
The instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256:1331-1333 (1992).
Thé compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1:541-545(1995).
The instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al.
American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al .FASEB Journal, 2:A3160 ( l 9~S~)).
The instant compounds may also be useful for the treatment of fungal infections.
The compounds of this invention may be administered to m~mm~ls, preferably humans, either alone or, preferably, in combina-CA 022~0231 1998-09-28 - ~3 -tion with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such als alum, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be ~(lministered orally or parenterally, including the intravenous, 5 intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of ~lministration.
For oral use of a chemotherapeutic compound according to this invention, the selected compound may be :~(lministered, for example, in the form of tablets or capsules, or as an aqueous solution 10 or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral ~(lrnini~tration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the 15 active ingredient is combined with emulsifying and suspending agents.
If desired, certain sweetening and/or flavoring agents may be added.
For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For 20 intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic.
The compounds of the instant invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is 25 being treated. For example, the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents. Similarly, the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF-l, restinosis, polycystic kidney disease, infections of hepatitis delta and related viruses and 30 fungal infections.
If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of the instant invention may CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97tO~383 - ~4 -alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
The present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the 5 ~f~mini~tration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacolo-gically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. The 10 solutions may be introduced into a patient's blood-stream by local bolus injection.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, 15 from combination of the specific ingredients in the specified amounts.
When a compound according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual 20 patient, as well as the severity of the patient's symptoms.
In one exemplary application, a suitable amount of compound is ~clministered to a mammal undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably 25 of between 0.5 mg/l~g of body weight to about 40 mg/kg of body weight per day.
The compounds of the instant invention are also u.seful as a component in an assay to rapidly determine the presence and quantity of farnesyl-protein transferase (FPTase) in a compo.sition.
30 Thus the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate and, in one of the mixtures, CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 - ~5 -a compound of the instant invention. After the assay mixture~s are incubated for an sufficient period of time, well known in the art, to allow the FPTase to farnesylate the substrate, the chemical content of the assay mixture~s may be determined by well known 5 immunological, radiochemical or chromatographic techniques.
Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the 10 assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain farnesyl-protein transfera.se and quantitat-15 ing the enzyme. Thus, potent inhibitor compounds of the instantinvention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of .samples composed of aliquots of a tissue extract containing an unknown amount of farnesyl-protein transferase, an excess amount of a known substrate of FPTase 20 (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention. The concentration of a sufficiently potent inhibitor (i.e., one that has a Ki substantially smaller than the concentration of enzyme in 25 the assay vessel) required to inhibit the enzymatic activity of the sample by 50% is approximately equal to half of the concentration of the enzyme in that particular sample.

EXAMPLES
Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species and conditions are intended to be further illustrative of the invention and not limitative of the reasonable scope thereof.

.

CA 022~0231 1998-09-28 1-(4-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt Step A: 1 -Trityl-4-(4-cyanobenzyl)-imidazole To a suspension of activated zinc du.st (3.57g, 54.98 mmol) in THF (50 mL) was added dibromoethane (0.315 mL, 3.60 mmol) and the reaction stirred under argon for 45 minutes, at 20~C.
10 The suspension was cooled to 0~C and a-bromo-p-tolunitrile (9.33g, 47.6 mmol) in THF (100 mL) was added dropwise over a period of 10 minutes. The reaction wa.s then allowed to stir at 20~C for 6 hours and bis(triphenylphosphine)Nickel II chloride (2.40g, 3.64 mmol) and 4-iodo-1-tritylimidazole (15.95g, 36.6 mmol, S. V. Ley, et al., 15 J. Org. Chem. 56, 5739 (1991)) were added in one portion.The resulting mixture was stirred 16 hours at 20~C and then quenched by addition of saturated NH4CI solution (100 mL) and the mixture stirred for 2 hours. Saturated aq. NaHCO3 solution was added to give a pH
of 8 and the solution was extracted with EtOAc (2 x 250 mL), dried 20 (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 0-20% EtOAc inCH2C12) to afford the title compound as a white solid.
lH NMR (CDC13, 400Mz) â (7.54 (2H, d, J=7.9Hz), 7.38(1H, s), 7.36-7.29 (1 IH, m), 7.15-7.09(6H, m), 6.58(1H, s) and 3.93(2H, s) 25 ppm.

Step B: 1-(4-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydochloride salt To l-trityl-4-(4-Cyanobenzyl)-imidazole (608mg, 1.43 30 mmol) in acetonitrile (2 mL) was added 4-chloromethylbiphenyl (290mg, 1.43 mmol) and the mixture heated at 55~C for 16 hours. The residue was dissolved in methanol (30 ml) and heated at reflux for 20 minutes, cooled and evaporated to dryness. The residue was partitioned between sat. aq. NaHCO3 solution and CH2cl2. The organic layer was CA 022~0231 1998-09-28 W O 97/3687~ PCTAUS97/05383 dried, (MgS04) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 5% MeOH in CH2C12) to afford the imidazole which wa.s converted to the HCl salt by treatment with one equivalent of HCl in aqueous acetonitrile. Evaporation of solvent in vacuo afforded the title compound as a white powder.
Anal. Calcd for C24HlgN3-1.00 HCI:
C, 74.70; H, 5.22; N, 10.89.
Found: C, 74.70; H, 5.31; N, 10.77.
FAB MS 350 (MH+) lH NMR CD30D ~ 9.03(1H, s), 7.65-7.50(5H, m), 7.44(2H, t, J=7.5Hz), 7.39(1H, s), 7.35(1H, t, J=7.3Hz), 7.26(2H, d, J=8.1Hz), 7.20(2H, d, J=8.1Hz), 5.42(2H, s) and 4.17(2H, s) ppm.

1-(2-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt To l-trityl-4-(4-cyanobenzyl)-imidazole (250 mg, 0.588 mmol) in acetonitrile (1 mL) was added 2(bromomethyl)biphenyl (0.108 mL, 0.591 mmol) and the mixture heated at 55~C for 16 hours.
The solvent was evaporated in vacuo. The residue was dissolved in methanol (10 mL) and heated at reflux for 30 minutes, cooled and the solvent evaporated in vacuo. The residue was partitioned between sat. aq. NaHC03 solution and CH2C12. The organic layer was dried, (NaS04) and the solvent evaporated in vacuo. The residue was chromatographed (silica gel, 3%MeOH in CH2C12) to afford the imidazole, which was converted to the HCI salt by treatment with one equivalent of HCI in aqueous acetonitrile. Evaporation of solvent in vacuo afforded the title compound as a white solid.
Anal. Calcd. for C24H 1 gN3- 1.OOHCI:
C, 74.70; H, 5.22; N, 10.89.
Found: C, 74.60; H, 5.26; N, 10.97.
FAB MS 350 (MH+) CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 lH NMR (CD30D, 400MHz) ~ 8.39(1H, s), 7.59(2H, d, J=8.4Hz), 7.48(1H, t, J=6.5Hz), 7.46-7.36(3H, m), 7.30(1H, d, J=6.6Hz), 7.2~-7.1~(3H, m), 7.13(2H, d, J=8.1Hz), 5.31(2H, s) and 3.7~(2H, s) ppm.

1-(3-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole trifluoroacetate salt Step A: 3-(Bromomethyl)biphenyl To a solution of 3-phenyltoluene (1.80 mL, 10.9 mmol) in carbon tetrachloride (50 mL) was added N-bromosuccinimide (2.124 g, 11.93 mmol) and the mixture heated to 70~C. AIBN (50 mg, 0.30 mmol) was added and the mixture refluxed for 30 mins. Additional AIBN was added (50 mg, 0.30 mmol) and the mixture refluxed for 16 hours. The reaction was cooled, filtered, and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 5% EtOAc in hexanes) to afford the title compound as a white solid.

Step B: 1 -(3-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole trifluoroacetate salt To 1 -trityl-4-(4-cyanobenzyl)-imidazole (251 mg, 0.590 mmol) in acetonitrile (1 mL) was added 3-(bromomethyl)biphenyl (145 mg, 0.5~¢7 mmol) and the mixture heated at 55~C for 16 hours.
The residue was dissolved in methanol (10 mL) and heated at reflux for 30 minutes, cooled and evaporated to dryness. The residue was partitioned between sat. aq. NaHCO3 solution and CH2C12. The organic layer was dried, (NaSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 2-5% MeOH in CH2C12) and further purified by preparative HPLC, (gradient elution, 95 :5 to 5:95%
water:acetonitrile containing 0.1% trifluoroacetic acid) to afford the title compound.
Anal. Calcd. for C24HlgN3 1.10 C2Ho2F3-o.6s H2O:
C, 64.6~; H, 4.43; N, ~.64.
Found: C, 64.68; H, 4.43; N, g.50.

CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 ~9 FAB MS 350 (MH+) lH NMR (CD30D, 400MHz) ~ 9.05(1H, d, J=1.6Hz), ), 7.58(1H, d, J=7.6Hz), 7.55-7.48(4H, m), 7.48-7.32(5H, m), 7.29(1H, s), 7.24(2H, d, g.1Hz), 7.13(1H, dd, J=7.7 and 0.8Hz), 5.46(2H, s) and 4.20(2H, s) ppm.

1 -(4-Cyanobenzyl)-5 -(4'-phenylbenzamido)ethyl-imidazole Step A: 1 -(4-Cyanobenzyl)-5-aminoethylimidazole NG-Pivaloyloxymethyl-Na-phthaloylhistaminel (4.55 g, 12.~ mmol) and a-bromo-p-tolunitrile (3.77 g, 19.2 mmol) were dissolved in acetonitrile (70 mL) and heated at 55 C for 4 hours, cooled to room temperature, filtered and the imidazolium salt retained as a white solid . The filtrate wa~ evaporated in vacuo to a volume of 30 mL and heated at 55 C for 16 hours. The solution was cooled and the white solid collected by filtration. The solids were combined, and dissolved in ethanol (50 mL). Hydrazine (0.2~7 mL, 9.06 mmol) was added and the mixture heated at reflux for 16 hours. Dimethyl phthalate (2.22 mL, 13.57 mmol) was added and reflux was continued for 6 hours. The reaction mixture was cooled to 0~C, the solid was removed by filtration, concentrated to dryness, and the residue chromatographed (Siilica gel, 3% CH2C12 then ~%NH40H in CH30H) to afford the title compound.
lH NMR (CD30D, 400MHz) ~ 7.76 (lH, s), 7.74 (2H, d, J = ~ Hz, ), 7.27 ( 2H, d, J = 8 Hz), 6.~ ( lH, s), 5.35 (2H, s), 2.76 (2H, t, J = 6 Hz) and 2.60(2H, t, J = 6 Hz) ppm.
1. C. Emmett, F. H. Holloway, and J. L. Turner, J. Chem. S~
- 30 Perkin Trans. I, 1341, (1979)) Step B: 1-(4-Cyanobenzyl)-5-(4'-phenylbenzamido)ethyl-imidazole To a solution of 1-(4-cyanobenzyl)-5-aminoethylimidazole (107 mg, 0.35~ mmol), 4-phenylbenzoic acid (70.9 mg, 0.35~ mmol), CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 3-hydroxy-1,2,3-benzotriazin-4(3H)-one, (72.6 mg, 0.445 mmol) and triethylamine (0.215 mL, 1.54 mmol) in DMF (4.0 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, EDC, (~3.3mg, 0.435 mmol) and the mixture stirred for 16 hours at ambient 5 temperature. The reaction was partitioned between sat. aq. NaHCO3 solution and EtOAc. The organic layer wa~s dried, (Na2SO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 5% MeOH in CH2cl2) to afford the imidazole which was converted to the HCl salt by treatment with one equivalent of HCI in aqueous 10 acetonitrile. Evaporation of the solvent in vacuo afforded the title compound as a white solid.
Anal. Calcd. for C26H22N40-1.00 HC1 0.95 H2O:
C, 67.8~s; H, 5.46; N, 12.1~.
Found: C, 67.83; H, 5.47; N, 11.97.
15 FAB MS 407 (MH+) lH NMR (CD30D, 400MHz) â 9.00(1H, s), ), ~.67(1H, m), 7.90-7.60(8H, m),7.58-7.30(6H, m), 5.65(2H, s), 3.65(2H, t, J=5.4Hz) and 2.95(2H, t, J=6.4Hz) ppm.

1 -(2'-Trifluoromethyl-4-biphenylmethyl)-5 -(4-cyanobenzyl)imidazole hydrochloride salt StepA: 4-(2-trifluoromethylphenyl)benzoic acid To a solution of 4-carboxybenzeneboronic acid (1.21~ g, 7.340 mmol) and Na2CO3 (2.40 g, 22.6 rnmol) in water (75 mL) was added p-dioxane (75 mL). This mixture was treated sequentially with 2-iodobenzotrifluoride (1.05 mE, 7.4~s mmol) and palladium (II) acetate (151 mg, 0.673 mmol) and allowed to stir at ambient temperature for 16 hours. The solvent was evaporated in vacuo. To the residue was added EtOAc (400 mL) and water (300 mE). The aqueous layer was acidified to pH 1 with 1.0 N aq. HCl and the layers separated. The aqueous layer was extracted with EtOAc (2 x 200 mL). The organic .. ..

CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 extracts were combined, washed with brine (200 mL), 5% aq. Na2s2o3 (200 mL), saturated NaCI (200 mL), dried (Na2so4)~ and the solvent evaporated in vacuo to afford the title compound as a yellow solid.
lH NMR (CDC13, 400MHz) d ~.14(2H, d, J=P~.lHz), ), 7.77(1H, d, S J=7.9Hz), 7.60(1H, t, J=7.5Hz), 7.52(1H, t, J=7.3Hz), 7.44(2H, d, J=8.1Hz) and 7.33(1H, d, J=7.5Hz) ppm.

Step B: 4-(2'-trifluoromethylphenyl)benzvlalcohol To a solution of 4-(2'-trifluoromethylphenyl)benzoic acid 10 (1.525 g, 5.728 mmol) in THF (25 mL) at 0~C was added 1.0 M lithium aluminum hydride in tetrahydrofuran (12.0 mL, 12.0 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 3 hours, cooled to 0~C, and quenched by dropwise addition of water (0.5 mL), 4 N aq. NaOH (0.5 mL), and water (1.5 mL). The reaction was 15 filtered through a pad of Celite and the filtrate evaporated in vacuo.
The residue was chromatographed (Silica gel, 20% EtOAc in hexanes) to afford the title compound.
lH NMR (CDC13, 400MHz) ~ 7.74(1H, d, J=7.7Hz), ), 7.55(1H, d, J=7.4Hz), 7.47(1H, t, J=7.4Hz), 7.41(2H, d, J=7.9Hz), 7.36-7.30(3H, m) 20 and 4.7~(2H, s) ppm.

Step C: 1-(2'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt To a solution of 4-(2'-trifluoromethylphenyl) benzylalcohol 25 (362 mg, 1.44 mmol) and diisopropylethylamine (0.260 mL, 1.49 mmol) in dichloromethane (6.0 mL) at -7~~C was added trifluoro-methanesulfonic anhydride (0.250 mL, 1.49 mmol) and the mixture stirred at -7~~C for 1 hour. To thi~s mixture was added a solution of l-trityl-4-(4-cyanobenzyl)-imidazole (613 mg, 1.44 mmol) in 30 dichloromethane (6.0 mL). The mixture was allowed to warm to ambient temperature and stirred for 2 hours. The solvent was evaporated in vacuo. The residue was dissolved in methanol (15 mL), heated at reflux for 1 hour, and the solvent evaporated in vacuo. The residue was partitioned between CH2C12 and sat. aq. NaHCO3 solution.

CA 022~0231 1998-09-28 The organic layer was dried, (Na2S04) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 0-2% MeOH in CH2C12) and further purified by preparative HPLC, (gradient elution, 95 :5 to 5:95% water:acetonitrile containing 0.1% trifluoroacetic acid) 5 to afford the trifluoroacetic acid salt. The salt was partitioned between EtOAc and sat. aq. NaHCO3 solution, the organic layer dried, (Na2SO4) and the solvent evaporated in vacuo to afford the imidazole.
The amine was converted to the HCl salt by treatment with 1.0 equivalent of HCl in aqueous acetonitrile. Evaporation of the solvent in 10 vacuo afforded the title compound as a white solid.
Anal. Calcd. for C2sHlgN3F3-l.oo HCl 0.85 H2O:
C, 64.00; H, 4.45; N, 8.96.
Found: C, 64.05; H, 4.24; N, 8.80.
FAB MS 418 (MH+) 1 H NMR (CD30D, 400MHz) ~ 9.10(1 H, s), ), 7.78(1 H, d, J=7.~Hz), 7.70-7.62(3H, m), 7.56(1H, t, J=7.5Hz), 7.43(1H, s), 7.38-7.24(5H, m), 7.19(2H, d, 8.1Hz)), 5.48(2H, s) and 4.18(2H, s) ppm.

1-(4-Biphenylethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt Step A: 4-Biphenylethanol The 4-biphenylethanol was prepared using the protocol 25 described in example 5, step B and 4-biphenylacetic acid.
1H NMR (CDC13, 400MHz) ~ .60-7.55(4H, m), 7.43(2H, t, J=7.8Hz), 7.37-7.28(3H, m), 3.91(2H, q, J=6.4Hz), 2.92(2H, t, J=6.6Hz), 1.40(1H, t, J=5.8Hz) ppm.

30 Step B: 1-(4-Biphenylethyl)-5-(4-cyanobenzyl)imidazole hydrochloride ~salt The title compound was prepared using the protocol described in example 5, step C and 4-biphenylethanol Anal. Calcd. for C25H21N3- 1.00 HCI 0.30 H2O:

CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 C, 74.0~; H, 5.62; N, 10.37.
Found: C, 74.40; H, 5.52; N, 9.9P~.
FAB MS 364 (MH+) lH NMR (CDC13, 400MHz) ~ P~.7~(1H, d, J=1.6Hz), 7.70(2H, d, 5 J=8.2Hz), 7.62-7.54(4H, m), 7.4g-7.30(5H, m), 7.20-7.12(3H, m), 4.43(2H, t, J=6.9Hz), 4.04(2H, s), and 3.10(2H, t, J=6.8Hz) ppm.

10 1 -(2'-Bromo-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride ~salt Step A: 4-(2'-Bromophenyl)benzaldehyde To a solution of 4-formylbenzeneboronic acid (1.19 g, 15 7.96 mmol) and Na2CO3 (1.6g g, 15.8 mmol) in water (60 mL) was added p-dioxane (60 mL). This mixture was treated sequentially with 2-bromo iodobenzene (2.25g, 7.95 mmol) and palladium (II) acetate (159 mg, 0.70P mmol) and allowed to stir at ambient temperature for 16 hours. The solvent was evaporated in vacuo. To the residue wa~s 20 added EtOAc (400 rnL) and water (300 mL). The aqueous layer was extracted with EtOAc (2 x 200 mL). The organic extracts were combined, washed with brine (200 mL), 5% aq. Na2S2O3 (200 mL), brinel (200 mL), dried, (Na2so4) and the solvent evaporated in vacuo to afford the title compound which was used in the next step without 25 furthur purification.

Step B: 4-(2'-Bromophenyl)benzyl alcohol To a solution of 4-(2'-bromophenyl)benzaldehyde 1.55g, 7.95 mmol) in ethanol (15 mL) at 0~C was added sodium 30 borohydride (2.22g, 5~.7 mmol) and the reation stirred for 1 hour.
The reaction was quenched with saturated aq. NH4Cl and extracted into diethyl ether. The organic extracts were washed with brine, dried, (Na2S04) and evaporated in vacuo. The residue was purified CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97105383 by chromatography (Silica gel, 25% EtOAc in hexanes) to afford the title compound as a colourless oil.
lH NMR (CDC13, 400MHz) ~ 7.66(1H, dd, J=~.l and l.lHz), 7.45-7.30(6H, m), 7.23(1H, m) and 4.66(2H, s) ppm.

Step C: 1-(2'-Bromo-4-biphenylmethyl)-5-(4-cyanobenzyl)-imidazole hydrochloride salt The title compound was prepared using the protocol described in example 5, step C and 4-(2'-bromophenyl) benzyl alcohol.
Anal. Calcd. for C24Hl 8N3Br 1.00 HC1 1.46 H2O:
C, 58.70; H, 4.50; N, 8.56.
Found: C, 5P~.66; H, 4.10; N, 8.27.
FAB MS 430(MH+) lH NMR (CD30D 400MHz) ~ 9.11(1H, s), 7.68(1H, d, J=8.1Hz), 7.62(2H, d, J=~.3Hz), 7.50-7.16(10H, m), 5.48(2H, s) and 4.20(2H, s) ppm.

EXAMPLE 8s 1-(2'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hYdrochloride salt Thé title compound was prepared using the protocol described in example 5, steps A-C using 2-iodotoluene.
Anal. Calcd. for C25H21N3-1.00 HC1 0.65 H2O:
C, 73.13; H, 5.47; N, 10.23.
Found: C, 73.16; H, 5.70; N, 10.20.
1H NMR (CD30D 400MHz) ~ 9.06(1H, d, J=1.6Hz), 7.62(2H, d, J=8.4Hz), 7.42(1H, s), 7.35-7.10(10H, m), 5.44(2H, s), 4.21(2H, s) and 2.20(3H, s) ppm.

CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 1 -(2'-Trifluoromethoxy-4-biphenylmethyl)-5 -(4-cyanobenzyl) imidazole hydrochloride salt The title compound was prepared using the protocol described in example 5, steps A-C using 2-trifluoromethoxy-iodobenzene.
lH NMR (CD30D 400MHz) ~ 9.08(1H, d, J=1.6Hz), 7.61(2H, d, J=8.4Hz), 7.52-7.38(7H, m), 7.29(2H, d, J=~.lHz), 7.23(2H, d, 10 J=8.1Hz), 5.47(2H, s) and 4.17(2H, s) ppm.

1-(4-(3',5'-dichloro)-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 15 hydrochloride salt The title compound was prepared using the protocol described in example 5, steps A-C using 3,5-dichloroiodobenzene.
Anal. Calcd. for C24Hl7N3cl2-l.oo HC1 0.35 H2O:
C, 62.52; H, 4.09; N, 9.11.
20 Found: C, 62.57; H, 3.88; N, 9.04.
FAB MS 418(MH+) lH NMR (CD30D 400MHz) ~ 9.0~(1H, s), 7.57(6H, m), 7.44(2H, d, J=4.2Hz), 7.32-7.20(4H, m), 5.46(2H, s) and 4.17(2H, s) ppm.

1-(2'-Methoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride salt The title compound was prepared using the protocol 30 described in example 5, steps A-C using 2-methoxyiodobenzene.
Anal. Calcd. for C25H21N30-1.00 HCI:
C, 72.19 H, 5.33; N, 9.79.
Found: C, 72.12; H, 5.31; N, 10.10.
lH NMR (CD30D, 400MHz) ~ 9.05(1H, d, J=1.3Hz), 7.60(2H, CA 022~0231 1998-09-28 W O 97136875 PCTrUS97/05383 d, J=7.2Hz), 7.44(2H, d, J=8.2Hz), 7.41 (1 H, s), 7.3~-7.20(4H, m), 7.16(2H, d, J=8.1Hz), 7.07(1H, d, J=X.OHz), 7.01(1H, t, J=7.5Hz), 5.42(2H, ,s), 4.19(2H, s) and 3.80(3H, s) ppm.

1-(2'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride ~salt The title compound was prepared using the protocol 10 described in example 5, steps A-C using 2-chloro iodobenzene.
Anal. Calcd. for C24H 18N3 1 -oo HCI- 0.20H20:
C, 68.00 H, 4.61; N, 9.91.
Found: C, 68.00; H, 4.77; N, 9.56.
lH NMR (CD30D, 400MHz) o 9.09(1H, d, J=1.3Hz), 7.61(2H, d, 15 J=7.2Hz), 7.55-7.25(9H, m), 7.20(2H, d, J=8.1Hz), 5.47(2H, s) and 4.21(2H, s) ppm.

20 1 -(2-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hydrobromide salt Step A: 2-Chloro-4-phenyl toluene A mixture of 2-chloro-4-iodotoluene(2.94 g, 11.63 mmol), 25 phenyl boronic acid (1.56 g, 12.79 mmol), barium hydroxide (5.50 g, 17.44 mrnol), DME (3 mL) and water (15 mL) was purged with dry argon. Tetrakis(triphenyl-phosphine)palladium(0) (672 mg, 0.58 mmol) was added, and the resultant solution was stirred at 80~C for 4 hours. The solvents were evaporated in vacuo, and the residue 30 partitioned between EtOAc and water and acidified with lM a4. HCI.
The aqueous extract was separated, and extracted with EtOAc. The organic extracts were combined, washed with NaHCO3 and 5% a4.
Na2S2O3, dried, (Na2SO4) filtered and the solvent evaporated in .

CA 022~0231 1998-09-28 W O 97/36875 PCT~US97/~5383 vacuo. The residue was purified by chromatography (Silica gel, 10%
EtOAc in hexanes) to afford the title compound.
1 H NMR (CDC13 400MHz) ~ 7.62-7.54 (3H, m), 7.4X-7.25(5H, m) and 2.43(3H, s) ppm.
s Step B: 1-(Bromomethyl)-2-chloro-4-biphenyl To a solution of 2-chloro-4-phenyl toluene (911 mg, 4.50 mmol) in carbon tetrachloride (l~S mL) was added N-bromosuccinimide (~00 mg, 4.50 mmol) and the mixture heated to 70~C. AIBN (16.4 mg, 0.10 mmol) was added and the mixture refluxed for 2 hours. The reaction was cooled, filtered, and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 15% CH2C12 in hexanes) to afford the title compound as a white solid.
lH NMR (CDC13, 400MHz) â 7.62(1H, d, J=1.7Hz), 7.60-7.34(7H, m) and 4.65(2H, s) ppm.

Step C: 1-(2-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl)-imidazole hydrobromide salt.
A suspension of l-(bromomethyl)-2-chloro-4-biphenyl (SOOmg, 1.78 mmol), 1-trityl-4-(4-cyanobenzyl)-imidazole (756mg, 1.78 mmol) in acetonitrile (5 mL) was stirred at 55~C for 16 hours. The solvent was evaporated in vacuo and the residue dissolved in methanol and stirred at reflux for 1 hour. The solvent was evaporated in vacuo.
The residue suspended in EtOAc (10 mL) and the product isolated as a white solid by filtration. The solids were washed with EtOAc (5 mL) and diethylether (10 mL) and dried in vacuo.
Anal. Calcd. for C24Hl~N3Cl-1.00 HBr- 0.30H20 C, 61.31 H, 4.20 N, ~.94.
Found: C, 61.61; H, 4.23; N, ~.55.
lH NMR (CD30D, 400MHz) ~ X.99(lH, d, J=1.4Hz), 7.65(1H, d, J=2.3Hz), 7.62-7.54(4H, m), 7.54-7.43(4H, m), 7.40(1H, m), 7.29(2H, d, J=g.4Hz), 7.11(1H, d, J=7.~Hz), 5.52(2H, s) and 4.24(2H, s) ppm.

CA 022~0231 1998-09-28 - 9~S -1-(3-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride salt The title compound was prepared ulsing the protocol described in example 13, steps A-C using 3-chloro-4-iodotoluene.
The imidazole was isolated by chromatography (Silica gel, 2-3% MeOH
in CH2C12), and converted to the HCI salt by treatment with HCI gas in EtOAc and evaporation of the solvent in vacuo.
Anal. Calcd. for C24H l 8CIN3 - l .oo HCI- 0.30H20:
C, 67.71 H, 4.64; N, 9.~7.
Found: C, 67.75; H, 4.69; ~, 9.73.
lH NMR (CD30D, 400MHz) ~ 9.19(1H, s), 7.58(2H, d, J=~.OHz), 7.55-7.30(6H, m), 7.30-7.00(5H, m), 5.45(2H, s) and 4.23(2H, s) ppm.

I -(4-(3 ' ,5 '-Bis-trifluoromethyl)-biphenylmethyl)-5 -(4-cyanobenzyl) imidazole hydrochloride salt Step A: Methyl 4-(3'~5'-Bis-trifluoromethvlphenyl)benzoate To a solution of 3',5'-Bis-trifluoromethylbenzeneboronic acid (0.430 g, 1.57 mmol) and barium hydroxide octahydrate (0.675 g, 2.14 mmol) in water (1.5 mL) was added DME (8 mL). This mixture was treated sequentially with methyl-4-iodobenzoate (0.375g, 1.43 mmol) and tetrakis triphenylphosphine palladium (0) (83 mg, 0.07 mmol) and heated at ~0~C for 5 hours. The reaction cooled, acidified to pH 1 with aq. HCl and extracted with EtOAc (2 x 50 mL) The combined organic extracts were washed with sat. aq. NaHCO3, brine, 30 dried, (Na2so4) and the solvent evaporated in vacuo. The residue was dissolved in methanol (50 mL), saturated with gas~seous HCI and stirred for 16 hours at ambient temperature. The solvent was evaporated in vacuo to afford the title compound as a solid.

CA 022~0231 1998-09-28 99 _ lH NMR (CDC13, 400MHz) â ~S.17(2H, d, ~=8.4 Hz), ~.04(2H, s), 7.91(1H, s), 7.68(2H, d, J=8.4Hz) and 3.97(3H, s) ppm.

Step B: 1-(4-(3',5'-Bis-trifluoromethyl)-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hydroch~oride salt The title compound was prepared using the protocoldescribed in example 5, steps B-C using methyl-{4-(3',5'-bi.s-trifluoromethylphenyl)benzoate .
Anal. Calcd. for C26Hl7N3F6-l.~o HCI
C, 60.69; H, 3.49, N, 8.17.
Found: C, 60.69; H, 3.35; N, 7.92.
FAB MS 486(MH+) IH NMR (CD30D ,400MHz) ~ 9.70(1H, d, J=1.4Hz),8.16(2H, s), 7.98(1H, s), 7.68(2H, d, J=g.4Hz), 7.57(2H, d, J=~.4Hz), 7.43(1H, s), 15 7.27(4H, m), 5.47(2H, s) and 4.17(2H, s) ppm.

1 -(2'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)-4-20 methylimidazole hydrochloride salt Step A: 4-Iodo-5-methylimidazole To a solution of 4-methyl imidazole(8.20g, 100 mmol) and sodium carbonate (21.2g, 200 mmol) in water (650 mL) was added 25 a solution of sodium iodide (26.5g, lgO mmol) and iodine (25.4g, 100 mmol) in water (350 mL) over 90 minutes at room temperature. The reaction was .stirred a furthur 30 minutes and filtered. The resulting white solid was washed with water and dried in vacuo at 50~C.
lH NMR (CD30D 400MHz) d 7.57 (lH, s) 4.~6(1H, brs) and 2.20(3H, 30 s) ppm.

Step B: l-Trityl-4-iodo-5-methylimidazole To a cold (0~C) solution of 4-iodo-5-methylimidazole (5.0g, 24.0 mmol) and triethylamine (5.0 mL, 36.0 mmol) in CH2C12 CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 (100 mL) and 1,4-dioxane (50 mL) was added trityl chloride (~s.0g, 29.0 mmol). The re.sultant mixture was stirred for 2 hours and quenched with ice and extracted with diethyl ether. The organic extracts were washed with sat. aq. NaHCO3, dried (K2CO3) and the solvent evaporated in vacuo. The product mixture was concentrated onto silica gel and chromatographed (Silica gel, 30-50% EtOAc in hexanes) to afford the title compound as a pale yellow powder.
lH NMR (CDC13, 400MHz) ~ 7.43(1H, s), 7.35-7.30 (9H, m), 7.2~S-7.10 (6H, m) and 2.27(3H, s) ppm.
Step C: 1 -Trityl-4-(4-cyanobenzyl)5-methylimidazole To a suspension of activated zinc dust (0.262g, 3.99 mmol) in THF (1 mL) was added dibromoethane (0.035 mL, 0.039 mmol) and the reaction stirred under argon at 20~C for 45 minutes. The suspension 15 was cooled to 0~C and a-bromo-p-tolunitrile (0.51g, 2.60 mmol) in THF
(3 mL) was added dropwise over a period of 10 minutes. The reaction was then allowed to stir at 20~C for 45 minutes and bis(triphenyl-phosphine)Nickel II chloride (0.130g, 0.399 mmol) and 5-iodo-1-trityl imidazole (15.9Sg, 36.6mmol) were added in one portion.The resulting 20 mixture was stirred 3 hours at 20~C and then quenched by addition of saturated NH3 solution (2 mL) and the mixture stirred for 3 hours, extracted with EtOAc (2 x 25 mL), dried (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 20% EtOAc in CH2C12 to afford the title compound as a white solid.
25 lH NMR (CD30D, 400MHz) ~ 7.62 (2H, d, J=8.3Hz), 7.40-7.34(9H, m), 7.31(2H, d, J=8.3Hz), 7.26(1H, s), 7.1~s-7.10(6H, m), 3.93(2H, s), and 1.41 (3H, s) ppm.

Step D: 1 -(2'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)-4-methylimidazole hydrochloride salt The title compound was prepared using the protocol described in example 5, step C using l-trityl-4-(4-cyanobenzyl)-5 -methylimidazole . .
Anal. Calcd. for C26H20N3F3- 1.00 HCI

CA 022~0231 1998-09-28 C, 66.74 H, 4.52; N, 8.98.
Found: C, 66.42; H, 4.42; N, 8.86.
lH NMR (CD30D 400MHz) ~ 8.98(1H, s), 7.77(1H, d, J=7.8Hz), 7.66(1H, t, J=7.5Hz), 7.62-7.50(3H, m), 7.35-7.00( 7H, m), 5.37(2H, s), 5 4.20(2H, s) and 2.34(3H, s) ppm.

1 -(4-Biphenylmethyl)-5 -(4-cyanophenyloxy)-imidazole Step A: 5-(4-Cyanophenyloxy)imidazole Sodium metal (1.10 g, 47.8 mmol) was dissolved in anhydrou,s methanol and 4-cyanophenol (5.70 g, 47.8 mmol) was added. The resultant ,solution was concentrated and dried under 15 vacuum overnight. A mixture of this sodium salt and 4-cyanophenol (25 g, mp 110-113~C) was heated to 125- 130~C and neat methyl N-(cyanomethyl)meth~nimidate (5.0 g, 51 mmol; Hosmane, R. S. et al, J. Org. Chem., 1212, 1984) was added dropwise over a period of 10 minutes under a slow stream of dry argon. The resultant mixture 20 was stirred at 120~C for 2 hours, cooled, and the reaction product partitioned between methylene chloride (500 mL) and aqueous sodium hydroxide (lM, 500 mL). The aqueou.s layer was separated and extracted with methylene chloride (3 x 100 mL). The organic extracts were combined, wa.shed with brine (100 mL), dried (K2CO3), and the 25 solvent evaporated in vacuo. The residue was purified by chroma-tography (Silica gel, 3:7 acetone in CHC13) to afford the title compound as a white powder.
1 H NMR (DMSO-d6 400MHz) ~ 7.79 (2H, d, J = 9.0 Hz), 7.54 ( lH, s), 7.11 (2H, d, J = 9.0 Hz) and 6.96 (lH, ~i) ppm.
Step B: 4-(4-Cyanophenyloxy)-l-trityl-imidazole To a cold (0~C) ,~olution of 4-(4-cyanophenyloxy)-imidazole (155 mg, 0.84 mmol) and triethylamine (0.129 mL, 0.92 mmol) in DMF (I mL) was added trityl chloride (245 mg, 0.88 mmol).

CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 The resultant mixture wa~s stirred at ambient temperature for 5 days.
The product mixture was concentrated onto silica gel, chromatographed (Silica gel, 1:9 acetone in CHC13) to afford the title compound as a white powder.
lH NMR (CDC13 400MHz) ~ 7.57 (2H, d, J = 9.0 Hz), 7.38 (lH, s), 7.35-7.09 (16H, m), 7.0~ (2H, d, J = 9.0 Hz) and 6.54(1H, s) ppm.

Step C: 1-(4-Biphenylmethyl)-5-(4-cyanophenyloxy)-imidazole The title compound was prepared using the protocol 10 described in example 5, step C using 4-biphenyl methanol and substituting 4-(4-cyanobenzyl)-1-trityl-imidazole with 4-(4-cyanophenyloxy)-l-trityl-imidazole. The title compound was purified by chromatography (Silica gel 3:7 acetone in CHC13) and obtained as a white solid.
15 Anal. Calcd for C23H17N3O-0~35 H2O:
C, 77.23; H, 4.99; N, 11.75.
Found: C, 77.30; H, 4.95; N, 11.5~.
lH NMR (CDC13, 400MHz) ~ 7.80-7.35 (10 H, m), 7.16 (2H, d, J = 8.1 Hz), 7.01(2H, d, J = 8.8 Hz), 6.74 (lH, s) and 4.98 (2H, s) ppm.
Using the same procedure but substituting 4-(2-trifluoromethylphenyl)-benzylalcohol for biphenylmethanol in Step C the following compound was prepared:

25 1-(4-(2-trifluoromethylphenyl)phenyl methyl)-5-(4-cyanophenyloxy)-imidazole Anal. Calcd for C24H16N3OF3-0.3 H2O:
C, 67.86; H, 3.94; N, 9.89.
Found: C, 67.~5; H, 3.84; N, 9.73.
Using the same procedure but substituting 4-bromophenol for 4-cyanophenol in Step A the following compound was prepared:

CA 022~0231 1998-09-28 1 -(4-Biphenylmethyl)-5 -(4-bromophenyloxy)-imidazole Anal. Calcd for C22Hl7BrN2o: C, 65.20; H, 4.23; N, 6.91.
Found: C, 65.26; H, 4.33; N, 6.80.

EXAMPLE l~s 5-(4-Cyanophenyloxy)-1 -(2'-methyl-4-biphenylmethyl)-imidazole hydrochloride salt The title compound was prepared using the protocol 10 described in example 17, step C, substituting 4-biphenylmethanol with 2'-methyl-4-biphenylmethanol. The hydrochloride salt was obtained by treatment of a solution of the imidazole in acetonitrile with aq. HCl and evaporation of the solvents in vacuo.
Anal. Calcd for C23H17N3O-0.5~ H20-1.45 HCl:
C, 67.23; H, 5.08; N, 9.~0.
Found: C, 67.30; H, 5.08; N, 9.74.
lH NMR CDC13 ~ 7.56 (2H, d, J = 6.9 Hz), 7.46 (lH, s), 7.26-7.10 (8H, m), 7.02 (2H, d, J = g.~ Hz), 6.75 (lH, s), 4.99 (2H, s) and 2.19 (3H, s) ppm.

5-(4-Biphenyloxy)-1-(4-cyanobenzyl)-imidazole trifluoroacetate ~salt 25 Step A: 4-(4-Bromophenyloxy)irnidazole The title compound was prepared as white solid using the protocol described in example 17 - step A, substituting 4-cyanophenol with 4-bromophenol, and performing the reaction at 100-110~C.
1H NMR (DMSO-d6 400MHz) ~ 7.49(1H, s), 7.48(2H, d, J = 9.0 Hz), 30 6.93(2H, d, J = 9.0 Hz) and 6.~s5(1H, s) ppm.

CA 022~0231 1998-09-28 W 097/36875 PCTrUS97/05383 Step B: 4-(4-Bromophenyloxy)-l-trityl-imidazole The title compound was prepared as white solid using the protocol described in example 17 - step B, using 4-(4-bromophenyloxy) imidazole.

Step C: 5-(4-Bromophenyloxy)-1-(4-cyanobenzyl)-imidazole The title compound was prepared as a white solid using the protocol described in example 5, step C using 4-cyanobenzyl alcohol and 4-(4-bromophenyloxy)-1-trityl-imidazole. The title compound was 10 purified by chromatography (Silica gel 3:7 acetone in CHC13).
lH NMR (CDC13 400MHz) ~ 7.61(2H, d, J = 8.1 Hz), 7.3P~(2H, d, J = 9.0 Hz), 7.37(1H, s), 7.21(2H, d, J = 9.0 Hz), 6.63(1H, s) and 5.03(2H, s) ppm.

15 Step D: 5-(4-Biphenyloxy)-1-(4-cyanobenzyl)-imidazole trifluoroacetate salt A mixture of 5-(4-bromophenyloxy)-1-(4-cyanobenzyl)-imidazole (100 mg, 0.28 mmol), phenyl boronic acid (69 mg, 0.56 mmol), K3PO4 (240 mg, 1.13 mmol), and DMF (5 mL) was purged 20 with dry argon for a period of 15 minutes. Tetraki.s(triphenyl-phosphine)palladium(0) (33 mg, 0.028 mmol) was added, and the resultant solution was stirred at 80 ~C for 1 ~ hours. The solvents were evaporated in vacuo, and the residue partitioned between CH2C12 and water. The aqueous extract was separated, and extracted with CH2C12.
25 The organic extracts were combined, dried (Na2SO4, filtered and evaporated in vacuo. The residue was purified by chromatography (Silica gel, eluting with 3:7 acetone in CHC13, and the trifluoroacate salt obtained by treatment of a solution of the imidazole in acetonitrile with aqueous TFA and evaporation of the solvent.s in vacuo.
30 Anal. Calcd for C23H 17N30- 1 25 TFA:
C, 62.01; H, 3.72; N, 8.51.
Found: C, 61.99; H, 3.69; N, 8.13.

CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 lH NMR (CDC13, 400MHz) o 7.60(2H, d, J = ~.3 Hz), 7.54-7.32(g H, m), 7.23(2H, d, J = 8.5 Hz), 7.00(2H, d, J = 8.8 Hz), 6.72(1H, Is) and 5.06 (2H, s) ppm.

5-(2'-Methyl-4-biphenoxy)- 1 -(4-cyanobenzyl)-imidazole trifluoroacetate salt The title compound was prepared as a white solid using the 10 protocol described in example 19- step D, substituting phenyl boronic acid with o-tolylboronic acid, and stirring the reaction mixture at 100~C for 24 hours.
Anal. Calcd for C24Hl9N3o-l~3o TFA-0.75 H2O:
C, 60.72; H, 3.98; N, 7.99.
15 Found: C, 60.77; H, 4.00; N, 7.76.
1H NMR (CDC13 400MHz) ~ 7.61(2H, d, J = 8.5 Hz), 7.41(1H, s), 7.27-7.18(8 H, m), 6.98(2H, d, J = ~.g Hz),6.70 (lH, s), 5.08(2H, s) and 2.25(3H, s) ppm.

5-(4-(3',5'-dichloro)biphenylmethyl)- 1 -(4-cyanobenzyl)imidazole hydrochloride salt 25 Step A: 4-(3',5'-Dichlorophenyl) benzyl alcohol The title compound was prepared using the protocol described in example 5, steps A-B using 3,5-dichloroiodobenzene.
lH NMR (CDC13, 400MHz) o 7.54(2H, dt, J=8.20 and 2.0Hz), 7.4g-7.43(4H, m), 7.33(1H, t, J=2.0Hz), 4.76(2H, d, J=5.9Hz) and 1.6~(1H, - 30 t, J=5.9Hz) ppm.

Step B: 4-(3'~5'-Dichlorophenyl) benzyl bromide To a solution of triphenylphospine (636mg, 2.42 mmol) and carbon tetrabromide (g30mg, 2.50 mmol) in diethyl ether (S mL) CA 022~0231 1998-09-28 was added a solution of 4-(3',5'-bis- chlorophenyl) benzyl alcohol (50mg, 1.98 mmol) in CH2cl2 (12 mL). The reaction was stirred at ambient temperature for 16 hours, silica gel was than added and the solvent evaporated in vacuo. The product was isolated by chroma-5 tography (Silica gel, 10-30% EtOAc in hexanes) and obtained as a white solid.
lH NMR (CDC13, 400MHz) ~ 7.54-7.46(4H, m), 7.46-7.43(2H, m), 7.35(1H, m) and 4.54(2H, s) ppm.

10 Step C: l-Trityl-4-(4-(3'~5'-dichloro)-biphenylmethyl- imidazole To a suspension of activated zinc dust (0.0~S0g, 1.22 mmol) in THF (0.25 mL) was added dibromoethane (0.011 mL, 0.122 mmol) and the reaction stirred under argon at 20~C for 45 minutes. 4-(3',5'-Dichlorophenyl) benzyl bromide (0.250g, 0.791 mmol) in THF (1 mL) 15 was added dropwise over a period of 10 minutes. The reaction was then allowed to stir at 20~C for 45 minutes and bis(triphenylphosphine) Nickel II chloride (0..04g, 0.031 mmol) and 4-iodo-1-trityl-imidazole (15.95g, 36.6mmol) were added in one portion. The resulting mixture was stirred 16 hours at 20~C and then quenched by addition of sat. ac}.
20 NH4CI solution (2 mL) and the mixture stirred for 3 hours, extracted with EtOAc (2 x 25 mL), dried (MgSO4) and the ~solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 30-50% EtOAc in CH2C12) to afford the title compound as a white solid.
lH NMR (CDC13, 400MHz) ~ 7.50-7.28 (lSH, m), 7.1~-7.10(6H, m), 25 6.59(1H, s) and 3.93(2H, s) ppm.

Step D: 5-(4-(3',5'-Dichloro)-biphenylmethyl)-1-(4-cyanobenzyl) imidazole hydrochloride salt A suspension of 4-cyanobenzyl bromide (l9.lmg, 0.097 30 mmol) and the trityl derivative from step C (52.5mg, 0.096 mmol) in acetonitrile (0.4 mL) was stirred at 55~C for 16 hours. The solvent was evaporated in vacuo and the residue dissolved in methanol (4 mL) and stirred at reflux for 1 hour. The solvent was evaporated in vacuo and . ~

CA 022~0231 1998-09-28 partitioned between EtOAc and sat. aq. NaHCO3, the organic layer was dried, (Na2SO4) and evaporated in vacuo. The residue was chroma-tograped (Silica gel, 2% MeOH in CH2C12), to afford the imidazole, which was dissolved in acetonitrile and converted to the HCI salt by 5 addition of 1 equivalent of lM HCl. Evaporation of the solvent in vacuo a~forded the title compound as a white solid.
IH NMR (CD30D 400MHz) ~ 8.97~1H, s), 7.63(2H, d, J=8.2Hz), 7.53(2H, s), 7.48(2H, d, J=8.2Hz), 7.42(2H, s), 7.21(2H, d, J=8.0Hz), 7.1 ~S(2H, d, J=~.2Hz), 5.49(2H, s) and 4.07(2H, s) ppm.

1 -(4-biphenylmethyl)-5-(1 -(R,S)-acetoxy- 1 -(4-cyanophenyl)methylimidazole hydrochloride salt Step A: 1 -Trityl-4-(1 -(R,S)-hydroxy- 1 -(4-cyanophenyl) methylimidazole To a solution of l-trityl-4-iodoimidazolel (lOg, 23 mmol) in CH2C12 (93 mL) at room temperature was added ethyl magnesium 20 bromide (8.4 mL of a 3M solution in diethyl ether) and the reaction stirred for 2 hours. 4-Cyanobenzaldehyde (3.36g, 25.21 mmol) was added and the reaction stirred a furthur 16 hours. The reaction was quenched with sat. aq. NH4CI and stirred until homogeneous. The pH
was adjusted to 8.5 with sat. aq. NaHCO3 and extracted with CH2C12.
25 The combined organic extracts were washed with brine, dried (MgSO4) and the solvent evaporated in vacuo. The resulting white solid was suspended in EtOAc (200 mL) and collected by filtration.
lH NMR (CDC13, 400MHz) o 7.60(2H, d, J=8.2Hz), 7.52(2H, d, J=8.2Hz), 7.41(1H, d, J=1.4Hz), 7.38-7.20(9H, m), 7.15-7.02(6H, m), 30 6.62(1 H, s), 5.79(1 H, d, J=4.6Hz), and 3.11 (1 H, d, J=4.6Hz) ppm.
lJournal of Organic Chemist~y 56, 5739, 1991 CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 Step B: 1 -Trityl-4-(1 -(R,S)-acetoxy- 1 -(4-cyanophenyl) methylimidazole A .solution of 1 -trityl-4-(1 -(R,S)-hydroxy- 1 -(4-cyanophenyl)methylimidazole (2.00g, 4.53 mmol), pyridine (1.10 5 mL) and acetic anhydride (0.641 mL) in DMF (20 mL) at room temperature was stirred for 16 hours. The reaction was 4uenched with sat. aq. NaHCO3 (50 mL) and water (50 mL), extracted with ethyl acetate dried, (MgSO4) and the solvent evaporated in vacuo.
The resulting solids were washed with diethylether to provide the 10 title compound as an off white solid.
lH NMR (CDC13, 400MHz) â 7.62(2H, d, J=8.4Hz), 7.53(2H, d, J=8.2Hz), 7.39(1H, d, J=1.3Hz), 7.38-7.28(9H, m), 7.15-7.02(6H, m), 6.78(2H, s) and 2.12(3H, s) ppm.

15 Step C: 1-(4-Biphenylmethyl)-5-(1-(R,S)-acetoxy-1-(4-cyanophenyl)methylimidazole hydrochloride salt The title compound was prepared using the protocol described in example 5, step C using l-trityl-4-(1-(R,S)-acetoxy-1-(4-cyanophenyl)methylimidazole and 4-biphenylmethanol.
20 Anal. Calcd. for C26H21N3O2-1.00 HC1-0.55H20 C, 68.81 H, 5.13 N, 9.26.
Found: C, 68.98; H, 5.22; N, 8.87.
FAB MS 408(MH+) 1H NMR (CD30D 400MHz) ~ 9.09(1H, s), 7.70(2H, d, J=8.4Hz), 25 7.61(4H, t, J=8.2Hz), 7.45(1H, s), 7.45( 4H, t, J=8.2Hz), 7.36(1H, t, J=7.3Hz), 7.23(2H, d, J=8.3Hz), 7.05(1H, s), 5.54(2H, d, J=2.2Hz) andl.96(3H, s) ppm.

1 -(4-Biphenylmethyl)-5-(1 -(R,S)-hydroxy- I -(4-cyanophenyl) methylimidazole hydrochloride salt To a solution of 1-(4-biphenylmethyl)-5-(1-(R,S)-acetoxy-1-(4-cyanophenyl)methylimidazole, from example 22, (389mg 0.955 CA 022~0231 1998-09-28 W O 97/36875 PCTnUS97/05383 mmol) in THF (5 mL) at 0~C was added lithium hydroxide (0.192 mL), 0.192 mmol)and the reaction stirred at room temperature for 3 hours.
EtOAc (75 mL) and water (25 mL) were added and the organic layer separated, dried (MgSO4) and the solvent evaporated in vacuo. The residue was purified by chromatography (Silica gel, 5% MeOH in CH2C12) and converted to the HCI salt by treatment with HCI in EtOAc and evaporation of the solvent in vacuo.
Anal. Calcd. for C24HlgN30-0.70 HCI
C, 73.73 H, 5.0~ N, 10.75.
Found: C, 73.76; H, 5.17; N, 10.5~s.
1H NMR (CD30D, 400MHz) ~ 8.57(1H, s),7.67(2H, d, J=8.4Hz), 7.63-7.56(4H, m), 7.51 (2H, d, J=~.OHz), 7.44( 2H, t, J=7.4Hz), 7.35(1H, t, J=7.5Hz), 7.23(2H, d, J=g.2Hz), 7.05(1H, s), 5.94(1H, s), 5.50(1H, d, J=15.4Hz) and 5.45(1H, d, J=15.4Hz) ppm.

1 -(4-Biphenylmethyl)-5-(1 -(R,S)-amino- 1 -(4-cyanophenyl) methvlimidazole hydrochloride salt A solution of 1 -(4-biphenylmethyl)-5-(1 -(R,S)-hydroxy-1-(4-cyanophenyl)methylimidazole (49.0mg, 0.122 mmol) in thionyl chloride (5 mL) at room temperature wa~s stirred for 45 minutes. The solvent was evaporated in vacuo and the residue was treated with 4M
NH3 in MeOH and the solution stirred for 1 hour and the solvents evaporated in vacuo.The residue was purified by chromatography (Silica gel, 2-5% NH40H in acetonitrile) and converted to the HCI salt by treatment with HCI in acetonitrile and evaporation of the solvent in vacuo.
Anal. Calcd. for C24H20N4 2.35HCI
C, 64.04H, 5.00 N, 12.45.
Found: C, 64.13; H, 4.9~; N, 12.43.
1 H NMR (CD30D 400MHz) ~ 9.20(1 H, s), 7.93(1 H, s), 7.64(2H, d, J=~s.4Hz), 7.54(2H, d, J=7.3Hz), 7.4~-7.40(4H, m), 7.36(3H, m), CA 022~0231 1998-09-28 W O 97/36875 PCTAUS97tO5383 7.09(2H, d, J=8.2Hz), 5.98(1H, s), 5.54(1H, d, J=14.9Hz) and 5.45(1H, d, J=14.9Hz) ppm.

1 -(4-biphenylmethyl)-5-(1 -(R,S)-methoxy- 1 -(4-cyanophenyl)-methylimidazole The title compound was obtained as a minor component by the protocol described in example 24.
lH NMR (CD30D 400MHz) â 7.76(2H, d, J=8.2Hz), 7.75(1H, s), 7.64(2H, d, J=7.6Hz), 7.58(2H, d, J-8.2Hz), 7.50-7.40(4H, m), 7.36(1H, t, J=7.5Hz), 7.13(2H, d, J=7.9Hz), 6.56(1H, s), 5.47(1H, s), 5.25(1H, d, J=15.4Hz), 5.20(1H, d, J=15.4Hz) and 3.17(3H, s) ppm.

1-(4-Cyanobenzyl)-5-(1-hydroxy-1-~4-biphenyl)-methyl imidazole Step A: 1-Triphenylmethyl-4-(hydroxymethyl)imidazole To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260 mmol) in 250 mL of dry DMF at room temperature was added triethylamine (90.6 mL, 650 mmol), a white solid precipitated from the solution. Chlorotriphenylmethane (76.1 g, 273 mmol) in DMF (500 mL ) was added dropwise. The reaction mixture was stirred for 20 hours, poured over ice, filtered, and washed with ice water. The resulting product was slurried with cold dioxane, filtered, and dried in vacuo to provide the titled product as a white solid which was sufficiently pure for use in the next .step.

Step B: l-Triphenylmethyl-4-(acetoxymethyl)imidazole Alcohol from Step A (260 mmol, prepared above) was suspended in 500 mL of pyridine. Acetic anhydride (74 mL, 780 mmol) was added dropwise, and the reaction was stirred for 4~ hours during which it became homogeneous. The solution was poured into ~--CA 022~0231 1998-09-28 WO 97136875 PCTIU~;97/05383 2 L of EtOAc, washed with water (3 x I L), 5% aq. HCI (2 x 1 L), sat.
aq. NaHCO3, and brine, and then dried, (Na2SO4) and concentrated in - vacuo to provide the crude product. The acetate was isolated as a white powder which was sufficiently pure for use in the next reaction.

Step C: 1 -(4-Cyanobenzyl)-5-(acetoxymethyl)imidazole hydrobromide A solution of the product from Step B (85.~S g, 225 mmol) and a-bromo-p-tolunitrile (50.1 g, 232 mmol) in EtOAc (500 mL ) was stirred at 60~C for 20 hours, during which a pale yellow precipitate formed. The reaction was cooled to room temperature and filtered to provide the solid imidazolium bromide salt. The filtrate was concen-trated in vacuo to a volume 200 mL, heated at 60~C for two hours, cooled to room temperature, and filtered. The filtrate was concentrated in vacuo to a volume 100 mL, then heated at 60~C for two hours, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in methanol (500 mL), and warmed to 60 ~C. After two hours, the solution was concentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble materials. Evaporation of residual solvent in vacuo provided the titled product hydrobromide as a white solid which was used in the next step without further purification.

Step D: 1-(4-Cyanobenzyl)-5-(hydroxymethyl)imidazole To a solution of the acetate from Step C (50.4 g, 150 mmol) in 1.5 L of 3:1 THF/water at 0~C was added lithium hydroxide monohydrate (18.9 g, 450 mmol). After one hour, the reaction was concentrated in vacuo, diluted with ~tOAc (3 L), and washed with water, sat. aq. Na~CO3 and brine. The solution was then dried, (Na2SO4) filtered, and concentrated in vacuo to provide the crude product as a pale yellow fluffy solid which was sufficiently pure for use in the next step without further purification.

CA 022~0231 1998-09-28 Step E: 1-(4-Cyanobenzyl)-5-imidazole carboxaldehyde To a solution of the alcohol from Step D (21.5 g, 101 mmol) in DMSO (500 mL) at room temperature was added triethyl-amine (56 mL, 402 mmol), then SO3-pyridine complex (40.5 g, 254 5 mmol). After 45 minutes, the reaction was poured into 2.5 L of EtOAc, washed with water (4 x 1 L) and brine, dried, (Na2SO4), and concentrated in vacuo to provide the aldehyde as a white powder which was sufficiently pure for use in the next step without further purification.
Step F: 1 -(4-Cyanobenzyl)-S-( 1 -hydroxy- 1 -(4-biphenyl)-methyl imidazole A Grignard reagent, freshly prepared from 4-bromo-biphenyl (116 mg, 0.500 mmol) and magnesium turnings (18 mg, 0.73 15 mmol) in dry THF (0.50 mL) was added to a dry Argon-purged 3mL
flask cont~ining the 1-(4-cyanobenzyl)-5-imidazole carboxaldehyde (105 mg, 0.50 mmol) in dry THF (0.2 mL) with vigorous stirring at room temperature. After 1 hour the reaction was quenched with sat. aq.
NH4CI (5 mL) and distributed between EtOAc (50 mL) and H2O (50 20 mL). The organic phase was evaporated in vacuo and the residue chromatographed (Silica gel, 5% MeOH in CHCI3) to afford the title compound.
Anal. Calcd for C24H19N3O-0.10 CHC13-0.10 CH30H:
C, 76.37 H, 5.16; N, 11.04.
25 Found: C, 76.13; H, 5.10; N, 10.76.
FAB MS 366 (MH+) 30 1-(4-Cyanobenzyl)-S~ oxo-1-(4-biphenyl)-methyl imidazole The alcohol from example 26 (105 mg, 0.228 mmol) in dioxane (3 mL) and activated manganese dioxide (300 mg) and CA 022~0231 1998-09-28 W O 97t36875 PCT~US97/05383 the mixture was stirred at reflux for 2 hour~. The mixture was filtered and the clear filtrate was evaporated and the residue chromatographed (Silica gel, 3%MeOH in CHCI3) to afford the title compound.
Anal. Calcd for C24Hl7N3o-o.35 CHC13:
C, 72.17; H, 4.32; N, 10.37.
Found: C, 71.87; H, 4.45; N, 10.29.

EXAMPLE 2~

1 -(4-Cy~nobenzyl)-5-( 1 -hydroxy- 1 -(3-fluoro-4-biphenyl)-methyl imidazole A Grignard reagent, freshly prepared from 4-bromo-2-fluorobiphenyl] (251 mg, 1 mmol) and magnesium turnings (36 mg, 1.45 mmol) in dry THF (1 mL) was added to a dry argon-purged 5mL
flaskcont~iningl-(4-cyanobenzyl)-5-imidazolecarboxaldehyde (212 mg, 1 mmol) in dry THF (0.40 mL) with vigorous stirring at room temperature. After 1 hour the reaction was quenched with sat. aq.
NH4Cl (10 mL) and distributed between EtOAc (100 mL) and H2O
(50 mL). The organic phase was evaporated and the residue was chromatographed (Silica gel, 5% MeOH in CHC13) to afford the title compound.
Anal. Calcd for C24H18N3OF-0.05 CHC13:
C, 74.18; H, 4.67; N, 10.79.
Found: C, 74.13; H, 4.97; N, 10.48.
FAB MS 3~s4(MH+) lH NMR (CDC13, 400MHz) â 5.25( 2H, d, J=3.6Hz), 5.7~ (lH7 s), 6.~s4 (lH, s), 7.04-7.13 (4H, m), 7.30-7.39(2H, m) and 7.45-7.55 (7H, m) ppm-1 -(4-Cyanobenzyl)-5-( 1 -hydroxy- I -(3-biphenyl)methyl-imidazole A Grignard reagent, freshly prepared from 3-biphenyl-CA 022~0231 1998-09-28 bromide (116 mg, 0.50 mmol) and magnesium turnings (18 mg, 0.73 mmol) in dry THF (0.5 mL) was added to a dry Argon-purged 3 mL
flask containing 1 -(4-cyanobenzyl)-5-imidazole carboxaldehyde (105 mg, 0.50 mmol) in dry THF (0.20 mL) with vigorous stirring at room 5 temperature. After 1 hour the reaction was quenched with sat. NH4CI
(5 mL) and distributed between EtOAc (50 mL) and H2O (50 mL).
The organic phase was evaporated and the residue chromatographed (Silica gel, 5% MeOH in CHC13) to afford the title compound.
Anal. Calcd for C24HlgN3O-0.10 CHC13:-0.15CH30H:
C, 75.34 H, 5.10; N, 10.87.
Found: C, 75.25 H, 5.13; N, 10.48.
FAB MS 366 (MH+) lH NMR (CDC13, 400MHz) ~ 5.23 (2H, d,J=3.6 Hz), 5.78 (lH, s), 6.81(1H, s), 7.02(2H, d, J=3.6Hz), 7.26 (2H, d, J=3.6Hz) 7.32-7.37(3H, m) and 7.39-7.52 (7H, m) ppm.

5-(2-~ 1,1 '-Biphenyl]vinylene)- 1 -(4-cyanobenzyl)imidazole trifluoroacetic acid salt A mixture of 4-biphenyl bromide (260 mg, 1.1 mmol), 5-vinyl-1-(4-cyanobenzyl)imidiazole (24~ mg, 1 mmol), palladium (II) acetate (10 mg), tri-o-tolylphosphine (30 mg), triethylamine (500 mL) in DMF (1 mL) was heated at 95 C for 20 hours. The dark solution was cooled and chromatographed (Silica gel, 1% MeOH in CHC13) to yield crude product which was furthur purified by preparative HPLC, (gradient elution, 95 :5 to 5:95% water:acetonitrile containing 0.1%
trifluoroacetic acid) to afford the title compound as a white solid.
Anal. Calcd. for C24HlgN3-1.40 C2HO2F3:
C, 64.07; H, 3.95; N, 8.06.
Found: C, 64.05; H, 3.99; N, 7.6g.
FAB MS 362 (MH+).

CA 022~0231 1998-09-28 W O 97/3687~ PCTrUS97/05383 1 - [N-( 1 -(4-cyanobenzyl)-5-imidazolylmethyl)amino] -3-methoxy-4-phenylbenzene Step 1: Preparation of l-triphenylmethyl-4-(hydroxymethvl)-imidazole To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35 g) in 250 mL of dry DMF at room temperature was added triethylamine (90.6 mL). A white solid precipitated from the solution. Chlorotriphenylmethane (76.1 g) in 500 mL of DMF was added dropwise. The reaction mixture was stirred for 20 hours, poured over ice, filtered, and washed with ice water. The resulting product was slurried with cold dioxane, filtered, and dried in vac~o to provide the titled product as a white solid which was sufficiently pure for use in the next step.
Step 2: Preparation of l-triphenylmethyl-4-(acetoxymethyl)-imidazole The product from Step 1 was suspended in 500 mL of pyridine. Acetic anhydride (74 mL) was added dropwise, and the reaction was stirred for 4~ hours during which it became homogeneous.
The solution was poured into 2 L of EtOAc, washed with water (3 x 1 L), 5% aq. HCl soln. (2 x 1 L), sat. aq. NaHCO3, and brine, then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. The titled acetate product was isolated as a white powder (85.8 g) which was sufficiently pure for use in the next step.
Step 3: Preparation of 1 -(4-cyanobenzyl)-5-(acetoxymethyl)imidazole hydrobromide A solution of the product from Step 2 (~5.~ g) and oc-bromo-p-tolunitrile (50.1 g) in 500 mL of EtOAc was stirred at - 30 60~C for 20 hours, during which a pale yellow precipitate formed.
The reaction was cooled to room temperature and filtered to provide the solid imidazolium bromide salt. The filtrate was concentrated in vacuo to a volume 200 mL, reheated at 60~C for two hours, cooled to room temperature, and filtered again. The filtrate was concentrated CA 022~0231 1998-09-28 - l 1 6 -in vacuo to a volume 100 mL, reheated at 60~C for another two hour~, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in 500 mL of methanol, and warmed to 60~C. After two hours, the 5 solution was reconcentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble materials. Removal of residual solvents in vacuo provided the titled product hydrobromide as a white solid (50.4 g, 89% purity by HPLC) which was used in the next step without further purification.
Step 4: Preparation of l -(4-cvanobenzyl)-5-(hydroxymethyl)-imidazole To a solution of the acetate from Step 3 (50.4 g) in 1.5 L of 3:1 THF/water at 0 ~C was added lithium hydroxide monohydrate (18.9 g). After one hour, the reaction was concentrated in vacuo, diluted with 15 EtOAc (3 L), and washed with water, sat. aq. NaHCO3 and brine. The solution was then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product (26.2 g) as a pale yellow fluffy solid which was sufficiently pure for use in the next step without further purification.
Step 5: Preparation of 1-(4-cyanobenzyl)-5-imidazole-carboxaldehyde To a solution of the alcohol from Step 4 (21.5 g) in 500 mL of DMSO at room temperature was added triethylamine (56 mL), then SO3-pyridine complex (40.5 g). After 45 minutes, the reaction was 25 poured into 2.5 L of EtOAc, washed with water (4 x l L) and brine, dried (Na2SO4), filtered, and concentrated in vac~o to provide the titled aldehyde (18.7 g) as a white powder which was sufficiently pure for use in the next step without further purification.

CA 022~0231 1998-09-28 Step 6: Preparation of 1 -I N-( l -(4-cyanobenzyl)-5 -imidazolylmethyl)aminol -3-methoxy-4-phenylbenzene To a solution of l-amino-3-methoxy-4-phenylbenzene in 1,2-dichloroethane at 0 ~C was added 4A powdered molecular sieves and sodium triacetoxyborohydride. 1-(4-Cyanobenzyl)-5-imidazole-carboxaldehyde was added, followed by 5 drops of acetic acid. The cooling bath was removed after 5 hours, and the reaction was stirred for another 15 hours. The reaction was poured into ethyl acetate and water. The organic layer was extracted with sat. aq. NaHCO3 solution and brine, then dried (Na2SO4) and concentrated in vc~cu(~ to provide the product.
Analysis calculated for C2~H22N4O:
C, 73,3~s; H, 6.07; N, 12.53;
Found: C, 73.36; H, 6.00; N, 12.49.

1-(3'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride salt The title compound was prepared using the protocol described in Example 5, ~teps A-C using 3-iodotoluene.
Anal. Calcd. for C2sH2lN3 1.00 HC1-0.45 H20:
C, 73.75; H, 5.64; N, 10.32.
Found: C, 73.69; H, 5.40; N, 10.39.
FABMS 364 (MH+) 1-(4'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride salt The title compound was prepared using the protocol described in ~xample 5, steps A-C using 4-iodotoluene.

CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 Anal. Calcd. for C2sH2lN~ l.OO HCI O.I0 H20:
C, 74.75; H, ;S.57; N, 10.46.
Found: C, 74.79; H, 5.37; N, 10.09.
FABMS 364 (MH+) s 1 -(3 '-Trifluoromethyl-4-biphenylmethyl)-5 -(4-cyanobenzyl) imidazole hydrochloride salt The title compound was prepared using the protocol described in Exarnple 5, steps A-C using 3-trifluoromethyl iodobenzene.
FABMS 418 (MH+) 1 -(4'-Trifluoromethyl-4-biphenylmethyl)-5 -(4-cyanobenzyl) imidazole hydrochloride salt The title compound was prepared using the protocol described in Exan~ple 5, steps A-C using 4-trifluoromethyl iodobenzene.
Anal. Calcd. for C2sHIsN3F3 0.95 HC1 1.15 H20:
C, 58.97; H, 4.40; N, 8.25.
Found: C, 58.92; H, 4.40; N, ~.43.
FABMS 41 ~ (MH+) 1-(3'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride salt The title compound was prepared using the protocol described in Example 5, steps A-C using 3-chloroiodobenzene.
Anal. Calcd. for C2sH21N~ l.00 HCI 0.20 H20:

CA 022~0231 1998-09-28 C, 68.00; H, 4.61; N, 9.91.
Found:C, 67.95; H, 4.57; N, 10.30 FABMS 3~4 (MH+) 1-(4'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride salt The title compound was prepared using the protocol described in Example 5, steps A-C using 4-chloroiodobenzene.
Anal. Calcd. for C2sH2lN~ l.00 HCI 0.90 H20:
C, 66.03; H, 4.PsO; N, 9.63.
Found: C, 66.09; H, 4.75; N, 9.4 FABMS 384 (MH+) 1-(2'3'-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride salt The title compound was prepared using the protocol described in Example 5, steps A-C using 2,3-dichloroiodobenzene.
FABMS 418 (MH+) 1-(2'4'-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride salt The title compound was prepared using the protocol described in Example 5, steps A-C using 2,4-dichloroiodobenzene.
Anal. Calcd. for C24~I17N~,CI2-1.00 HCl 0.30 H20:
C, 62.64; H, 4.07; N, 9.13.
Found: C, 62.64; H, 4.23; N, g.~6 FABMS 41~ (MH+) W O 97/36875 PCTrUS97105383 1-(2'5'-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride salt The title compound was prepared using the protocol described in Example 5, steps A-C using 2,5-dichloroiodobenzene.
Anal. Calcd. for C24HI7N3Ck 1.20 HC1-0.35 H20:
C, 61.55; H, 4.07; N, 2~.97 Found: C, 61.53; H, 4.08; N, 9.03 FABMS 418 (MH+) 1 -(3 ' -Trifluoromethoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hydrobromide salt The title compound was prepared using the protocol 15 described in Example 13, steps A-C using 3-trifluoro iodobenzene.
Anal. Calcd. for C25H,8N3OF3 1.00 HCl:
C, 63.91; H, 4.08; N, 8.94 Found: C, 63.77; H, 3.97; N, 8.60 FAB HRMS exact mass calcd for C25HI8N3OF3 434.147543 (MH+);
20 found 434.148022.

1-(2'-Fluoro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 25 hvdrobromide salt The title compound was prepared using the protocol described in Example 13, steps A-C using 2-fluoro iodobenzene.

CA 022~0231 1998-09-28 Anal. Calcd. for C24HIsN~F-1.20 HBr0.15 H20:
C, 63.91; H, 4.31; N, 9.32 - Found: C, 64.04; H, 4.12; N, X.92 FABMS 36f~ (MH+) s 1 -(4-(2 ' -Trifluoromethylphenyl)-2-Chlorophenylmethyl)-5 -(4-cyanobenzvl) imidazole hydrochloride salt The title compound was prepared using the protocol described in Example 13, steps A-C using 2-chloro-4-iodotoluene and 2-trifluoromethylbenzene boronic acid.
Anal. Calcd. for C2sHI7N3F3Cl 1.00 HCI 0.15 EtOAc:
C, 61.31; H, 3.86; N, 8.38 Found: C, 61.33; H, 3.7~; N, 8.15 FABMS 452 (MH+) 1 - { 1 -(4-(2'-trifluoromethylphenyl)phenyl)ethyl } -5 -(4-cyanobenzyl) imidazole hydrochloride salt Step A: 4-(2'-trifluoromethylphenyl)benzaldehyde To a solution of 4-formylbenzeneboronic acid (4.00 g, 26.7 mmol) and Na2CO3 (5.66 g, 53.4 mmol) in water (240 mL) was added p-dioxane (240 mL). This mixture wa,s treated sequentially with 2-iodobenzotrifluoride (3.74 mL, 26.7 mmol) and palladium (II) acetate (540 mg, 2.40 mmol) and allowed to stir at ambient temperature for 24 hours. The solvent was evaporated in vacuo. To the residue was added EtOAc (400 mL) and water (300 mL). The aqueous layer was acidified to pH 2 with 1.0 N aq. HCl and the layers separated. The aqueous layer was extracted with EtOAc (2 x 200 mL). The organic extracts were combined, washed with brine (200 mL), 5% aq. Na2S2O3 (200 mL), saturated NaCI

CA 022~0231 1998-09-28 W O 97136875 PCTrUS97/0~383 (200 mL), dried (Na2S04), and the solvent evaporated in vacuo and the residue chromatographed (Silica gel, 20-50% CH2CI2 in hexanes) to afford the title compound.
1H NMR (CDC13, 400MHz) o 10.09(1H, s), 7.93(2H, d, J=8.0Hz), 5 7.78(1H, d, J=8.2Hz), 7.60(1H, t, J=7.5Hz), 7.55-7.45(3H, m) and 7.33(1H, d, J=P~.OHz) ppm.

Step B: 1-(4-(2'-trifluoromethylphenyl)phenvl)ethanol To a solution of 4-(2-trifluoromethylphenyl)-10 benzaldehyde (1.00 g, 0.40 mmol) in Et2O (20 mL) at -70~C
was added methyl lithium (2.85mL of a 1.4 M in Et2O 0.40 mmol) over 10 minutes. The reaction was allowed to warm to ambient temperature and stirred for 1 hour. The reaction was quenched by dropwise addition of sat. aq. NH40H and extracted with Et2O The 15 organic layer was washed with brine and dried(MgSO4), and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 20-50% CH2Cl2 in hexanes) to afford the title compound.
1H NMR (CDC13, 400MHz) ~ 7.75(1H, d, J=7.7Hz), ), 7.55(1H, t, J=7.4Hz), 7.47(1H, t, J=7.4Hz), 7.41(2H, d, J=7.9Hz), 7.36-7.28(3H, 20 m)and4.98(1H,m)ppm.

Step C~ 1 -(4-(2'-trifluoromethylphenyl)phenyl)ethyl ~ -5-(4-cyanobenzyl)imidazole hydrochloride salt The title compound was prepared using the protocol 25 described in Example 5, step C using the alcohol from step B.
Anal. Calcd. for C26H20N3F3-1.00 HCl 0.1 EtOAc:
C, 66.52; H, 4.61; N, 8.81.
Found: C, 66.74; H, 4.52; N, 8.98.

1 -(2'-Trifluoromethyl-4-biphenylpropyl)-5-(4-cyanobenzyl) imidazole CA 022~0231 1998-09-28 W O 97136875 PCT~US97/05383 Step A: E-Ethyl -3-(4-(2'-trifluoromethylphenyl)phenyl)prop-2-enoate - To a solution of 4-(2'-trifluoromethylphenyl) benzaldehyde (l.OOg, 3.996 mmol, prepared using the protocol 5 described in Example 44, step A) in CH2CI2 (8.0 mL) was added (carbethoxymethylene) triphenylphosphorane (1.46g, 4.196 mmol)and the reaction was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo and the residue chromatographed (Silica gel, 2.5% EtOAc in hexanes) to afford 10 the title compound.
1H NMR (CD30D 400MHz) o 7.90-7.50(6H,m), ), 7.40 7.35(3H,m), 6.60(1H,d, J=16.1Hz), 4.27(2H, q, J=7.1Hz), 1.34(3H, t, J=7.1 Hz),)ppm.

15 Step B: Ethyl-3-(4-(2'-trifluoromethylphenyl)phenyl)-propionoate A solution of E-Ethyl -3-(4-(2'-trifluoromethylphenyl) phenyl)prop-2-enoate (0.444g, 1.3g~ mmol) and 10% palladium on carbon (0.044g) in EtOH (13.~s8 mL) was hydrogenated in a parr 20 apparatus. The catalyst was removed by filtration through celite and thetitle compound obtained by solvent evaporation in vacuo.
1 H NMR (CD30D 400MHz) ~ 7.73(1 H, d, J=7.7Hz), 7.5~S(1 H, t, J=7.7Hz), 7.48(1H, t, J=7.7Hz), 7.29(1H, d, J=7.7Hz), 7.24 (2H, d, J=~.2Hz), 7.19(2H, d, J=~.2Hz), 4.10(2H, q, J=7.1Hz), 2.96(2H, 25 t, J=7.7Hz), 2.65(2H, t, J=7.5Hz) and 1.20(2H, qn, J=7.5Hz) ppm.

Step C: 1-(2'-Trifluoromethyl-4-biphenylpropyl)-5-(4-cyanobenzyl) imidazole The title compound was prepared using the protocol 30 described in Example 5, steps B-C using the product from step B.
1H NMR (CD30D 400MHz) ~ 7.75(1H, d, J=7.7Hz), 7.70-7.60(3H, m), 7.52(1H, t, J=7.5Hz), 7.33(1H, d, J=7.9Hz), 7.21 CA 022~0231 1998-09-28 W 097/36875 PCTrUS97/05383 (lH, d, J=7.6Hz), 7.13 (2H, d, J=~s.l Hz), 6.78$(1H, s), 4.03(2H, q, J=7.1Hz), 3.86 (2H, t, J=7.5Hz), 2.60(2H, t, J=7.5Hz) and 1.92(2H, qn, J=7.5Hz) ppm.

EXAMPL~ 46 1 -(2'-N-t-Butoxycarbonylamino-4-biphenylmethyl)-5 -(4-cyanobenzyl) imidazole Step A: 4-(2'-Cyanophenyl)benzoic acid methyl ester.
To a solution of 2-bromobenzonitrile (l.OOg, 5.494 mmol), in THF (16.5 mL) at -100~C was added t-butyl lithium (6.46mL, of a 1.7M solution in pentane, 10.98 mmol. After 5 minutes zinc chloride(5.494 m~, of a lM solution in THF, 5.494 mmol) was added. The reaction was stirred for 10 minutes at -78~C and then allowed to warm to 0~C and stirred for 1 hour.
This solution was added via cannula to a solution of methyl-4-iodobenzoate (1.44g, 5.494 mmol) and bis(triphenylphosphine) Nickel II chloride (0.359g, 0.549 mmol) in THF (12 mL). The reaction stirred for 1 hour at 0~C and then at ambient temperature for a furthur 16 hours. Saturated ammonium hydroxide solution (5 mL) was added and the mixture stirred until homogenous, extracted with EtOAc and the organic extracts washed with saturated brine, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed (Silica gel, 50% CH2CI2 to 50% EtOAc in hexanes) to afford the title compound.
lH NMR (CD30D, 400MHz) ~ 8.15(2H, d, J=8.7Hz), ),7.87(1H, d, J=7.7Hz), 7.77(1H, t, J=7.5Hz), ), 7.69(2H, d, J=8.7Hz), 7.65-7.55(2H, m), and 3.95(3H, s) ppm.

CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 Step B: 4-(2'-Aminomethylphenyl)hydroxymethylbenzene To a solution of 4-(2'-cyanophenyl)benzoic acid methyl ester (0.428g, 1.804 mmol) in tetrahydrofuran (14.3 mL) at 0~C was added 1.0 M lithium aluminum hydride in tetrahydrofuran 5 (3.61 mL, 3.61 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 3 hours, then warmed to 45~C for 3 hours, cooled and quenched by dropwise addition of saturated Na2SO4 (0.46 mL). The reaction was diluted with diethylether, Na2SO4 was added, the mixture filtered through a pad of Celite 10 and the filtrate evaporated in vacuo to afford the title compound.
1H NMR (CD30D, 400MHz) ~ 7.47(1H, d, J=7.5Hz), 7.42(2H, d, J=8.4Hz), 7.40-7.15 (4H,m), 4.66(2H,s) and 3.73(2H,s) ppm.

Step C: 4-(2'-t-Butoxycarbonylaminomethylphenyl) hvdroxymethylbenzene To a solution of 4-(2'-aminomethylphenyl) hydroxy-methylbenzene (0.374g, 1.754 mmol) and triethylamine (0.269mL, 1.929 mmol) in DMF (8.0 mL) at 0~C was added t-butylcarbonate (0.383g, 1.754 mmol) in DMF (2.0 mL) over 10 minutes. The reaction was allowed to stir at ambient temperature for 16 hours.
The reaction was diluted with EtOAc, washed with 10% aq. citric acid, and then sat. aq. NaHCO3 and dried(Na2SO4). The solvent was evaporated in vacuo and the residue chromatographed (Silica gel, EtOAc) to afford the title compound.
1H NMR (CD30D, 400MHz) ~ 7.50-7.15(8H, m), 4.66(2H,s), 4.15(2H,s) and 1.43(9H,s) ppm Step D: 1 -(2'-N-t-Butoxycarbonylaminomethyl-4-biphenylmethyl)-;~-(4-cyanobenzyl~ imidazole The title compound wa~s prepared using the protocol described in Example 5, step C using the product from step C.
FAB HRMS exact mass calcd for C~oH30N4 ~2 479.244702 (MH+);
found 479.244189.
Anal. Calcd. for C~oH30N4 O, ~0.10 H2O:

CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 C, 75.29; H, 6.32; N, 11.71.
Found: C, 75.20; H, 5.g7; N, 11.27.

5 1 -(2'-Aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride salt A solution of 1-(2'-N-t-Butoxycarbonylaminomethyl-4-biphenylmethyl) -5-(4-cyanobenzyl) imidazole (43.7mg, 0.094 mmol) in EtOAc (lOmL) was saturated with HCI gas. After 10 10 minutes the solvent was evaporated in vacuo to afford the title compound as a white solid.
FAB HRMS exact mass calcd for C2sH22N4 379.192272 (MH+);
found 379.192525.
Anal. Calcd. for C2sH22N4-0.75 HCl:
C, 62.71; H, 5.21; N, 11.70.
Found: C, 62.71; H, 5.14; N, 11.32.

EXAMPLE 4~s 1 -(2'-Acetylaminomethyl-4-biphenylmethyl)-5 -(4-cyanobenzyl) 20 imidazole To a solution of 1-(2'-aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hyrochloride (0.107g, 0.237 mrnol) and triethylamine (0.033mL, 0.237 mmol) in CH2CI2 (4.7 mL) at 0~C
was added acetic anhydride (0.383g, 1.754 mrnol). The reaction was 25 allowed to stir at arnbient temperature for 16 hours. The reaction was diluted with CH2CI2, washed sat. aq. Na2CO3 and dried (Na2SO4). The solvent was evaporated in vacuo and the residue chromatographed (Silica gel, 3% MeOH in CH2CI2 ) to afford the free base which was converted to the HCl salt..
30 FAB HRMS exact mass calcd for C2sH22N4O 421.202837 (MH+);
found 421.203621.
Anal. Calcd. for C2sH22N4O 1.60 HCI:
C, 67.72; H, 5.39; N, 11.70.
Found: C, 67.58; H, 5.21; N, 11.77.

CA 022~0231 1998-09-28 W O 97/36875 PCT~US97/05383 1 -(2'-Methylsulfonylaminomethyl-4-biphenylmethyl)-5-(4-5 cvanobenzyl) imidazole hydrochloride The title compound was prepared using the protocol described in Example 48, using methanesulfonyl chloride.
FAB HRMS exact mass calcd for C26H24N402S 457.169823 (MH+);
found 457.170937.
10 Anal. Calcd. for C26H24N402S 1.70 HCl 0.20 EtOAc:
C, 60.03; H, 5.13; N, 10.45.
Found: C, 59.99; H, 4.93; N, 10.15.

1 -(2'-Ethylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride To a solution of 1-(2'-aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hyrochloride (O.lOOg, 0.222 mmol) 20 acetaldehyde (0.024mL, 0.444 mmol) and 4A molecular sieves (300mg) in MeOH (0.44 mL) at room temperature was added triethylamine to a pH of 7. Sodium cyanoborohydride (0.028g, 0.444 mmol) was added and the reaction was stirred for 16 hours.. The reaction was filtered through celite and the filtrate evaporated in 25 vacuo. The residue was partitioned between CH2CI2, and sat. aq.
Na2CO3 and the organic layer separated and dried (Na2SO4). The solvent was evaporated in vacuo and the residue chromatographed (Silica gel, 3% NH40H in Acetonitrile) to afford the free base which was converted to the HCI salt..
30 FAB HRMS exact mass calcd for C27H2hN~ 407.223572 (MH+);
found 421.223572.

W 097/36875 PCT~US97/05383 - 12~s -1 -(2'-Phenylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride To a slurry of 1-(2'-aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hyrochloride (0.097g, 0.216 mmol) 5 triphenyl bismuth (0.166g, 0.377 mmol) and copperII acetate (0.059g, 0.323 mmol) in CH2Cl2 (0.43 mL) at room temperature was added triethylamine (0.045mL, 0.323 mmol) and the reaction was stirred for 16 hours.. Silica gel was added and the solvent evaporated in vacuo.The solid was applied to a column and 10 chromatographed (Silica gel, 2% MeOH in CH2Cl2) to afford the free base which was converted to the HCl salt..
FAB HRMS exact mass calcd for C31H26N4 454.215747 (MH+);
found 454212863.

1 -(2'-Glycinylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride To a slurry of 1-(2'-aminomethyl-4-biphenylmethyl)-20 5-(4-cyanobenzyl) imidazole hyrochloride (0.lOOg, 0.222 mmol) N-Boc glycine (0.039g, 0.222 mmol), triethylamine (0.093mL, 0.666 mmol) and HOBT (0.030g, 0.222 mmol) in CH2CI2 (2.2 mL) at room temperature was added EDC (0.042g, 0.222 mmol) and the reaction was stirred for 16 hours.. The reaction was diluted with 25 CH2CI2 and washed with NaHCO3 and the organic extracts dried (Na2SO4) and evaporated in vacuo. The residue was chroma-tographed (Silica gel, 2.5-5% MeOH in CH2Cl2) to afford the N-Boc glycinyl derivative. This material was dissolved in EtOAc (3mL) and saturated with HCI gas. The reaction was stirred for 40 minutes at 30 0~C and the solvent evaporated to afford the title compound as a white solid FABMS 436(MH+) C27H2sNsO
Anal. Calcd. for C27H2sNsO 1.55 HCI 2.70 H2O:
C, 60.06; H, 5.96; N, 12.97.

CA 022~0231 1998-09-28 - Found: C, 60.04; H, 5.96; N, 12.93.

1-(2'-Methyl-4-biphenylmethyl)-2-chloro-5-(4-cyanobenzyl) imidazole and 1-(2'-Methyl-4-biphenylmethyl)- 4-chloro 5-(4-cyanobenzyl) imidazole A solution of 1-(4-(4'-Methylbiphenylmethyl)-5-(4-cyanobenzyl)imidazole (120mg, 0.330 mmol) in CH2CI2 was treated with NCS (44mg, 0.330 mmol) and the reaction stirred for 16 hours at room temperature. The solvent was evaporated in vacuo and the residue chromatographed (Silica gel, 2% MeOH in CH2CI2) to afford a mixture of regioisomers. These were separated by preparative HPLC to afford the title compounds.
1 -(2'-Methyl-4-biphenylmethyl)-2-chloro-5-(4-cyanobenzyl) imidazole lH NMR (CD30D, 400MHz) ~ 7.54(1H, d, J=~s.2Hz), 7.27(2H, d, J=8.4Hz), 7.25-7.10 (7H, m), 6.93(2H, d, J=8.4Hz), 6.85(1H, s), 5.21(2H, s), 4.05(2H, s) and 2.20(3H, s)ppm.
20 1-(2'-Methyl-4-biphenylmethyl)-4-chloro 5-(4-cyanobenzyl) imidazole 1 H NMR (CD30D, 400MHz) ~ 7.79(1 H, s), 7.50(1 H, d, J=X.2Hz), 7.25-7.02 (9H, m), 7.00(2H, d, ~=8.4Hz), 5.15(2H, s), 4.05(2H, s) and 2.16(3H, s)ppm.

1 -(3'-Chloro-2-methyl-4-biphenylmethyl)-4-(4-cyanobenzyl)-imidazole hydrochloride salt Step A: Preparation of 4-trifluoromethylsulfonylyoxy-3-methylbenzaldehyde To a solution of 4-hydroxy-3-methylbenzaldehyde (Aldrich; (1 g; 7.34 mmol) in 20 mL of CH2CI2 at room temper-CA 022~0231 1998-09-28 W O 97136875 PCTrUS97/05383 ature was added triethylamine (1.13 mL, ~.0~ mmol), then triflic anhydride (1.36 mL, ~.0~ mmol). After 2 h, the reaction was poured into CH2CI2, washed with saturated NaHCO3, then brine, dried, filtered, and concentrated in vac~o to provide the crude 5 aldehyde. Column chromatography (silica gel; hexane:EtOAc 4:1) af~orded the title compound as an oil.

Step B: Preparation of (3'-chlorophenyl)-3-methylbenzaldehyde Following the procedure described for Example 13, ~step 10 A, but using the product from step A above and 3-chlorobenzene-boronic acid às starting materials the title product was obtained.

Step C: Preparation of (3'-chlorophenyl)-3-methylbenzylalcohol Following the procedure described for Example 7, step 15 B, but using the product from step B above as starting material, the title product wa~s obtained.

CA 022~0231 1998-09-28 W O 97/3687S PCT~US97/05383 Step D: Preparation of 1 -(3'-chloro-2-methyl-4-biphenylmethyl)-4-(4-cyanobenzyl)imidazole hydrochloride ,salt Using the alcohol from step C and following the procedure described for Example 5, step C with a subsequent purification by silica gel chromatography (EtOAc then 2% MeOH in CHCl3). The first eluted material afforded the title compound after treatment with HCI and Et2O.
Analysis calculated for C2sH2oN3cl-2.7Hcl-o.3Et2o:
C, 60.67; H, 4.99; N, 8.10;
Found: C, 60.67; H, 4.62; N, 7.95.

1 -(3'-Chloro-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt Following the precedure of l~xample 53, step D, but collecting the later eluting material the title compound was obtained.
Analysis calculated for C2~H2oN3cl-l.7Hcl-o.2Et2o:
C, 65.27; H, 5.03; N, 8.85;
Found: C, 65.36; H, 5.03; N, 8.86.

1-(3'-Trifluoromethyl-2-methyl-4-biphenylmethyl)-4-(4-cyanobenzyl) imidazole hydrochloride salt Following the procedure described for Example 53, steps B-C but using 3-trifluoromethylbenzeneboronic acid as starting materials, the title compound was obtained. It was isolated by silica gel chromatography (EtOAc then 2% MeOH in CHCl3) collecting the first eluted material and then subsequent treatment with HCI and Et2O.
Analysis calculated for C26H2nN3F3- 1.4HCl-0.35EtOAc:
C, 64.10; H, 4.75; N, ~.lX;

CA 022~0231 1998-09-28 Found: C, 64.14; H, 4.50; N, ~.10.

1-(3'-Trifluoromethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzvl)imidazole trifluoroacetic acid .salt Following the procedure described for Example 53, steps B-C but using 3-trifluoromethylbenzeneboronic acid as starting materials, the title compound was obtained. It was isolated by silica gel chromatography (EtOAc then 2% MeOH in CHCl3) collecting the second eluted material and then subsequent preparative HPLC
purification.
Analysis calculated for C26H20N3F3- 1 .35T~A-0.4H20:
C, 58.17; H, 3.77; N, 7.09;
Found: C, 5g.17; H, 3.7~; N, 7.19.

1-(3 '-Methoxy-2-methyl-4-biphenylmethyl)-5 -(4-cyanobenzyl)imidazole hydrochloride salt Step A: Preparation of 2-bromo-5-hydroxymethyltoluene To a solution of 4-bromo-3-methylbenzoic acid (Aldrich; (3 g, 14 mmol) in 75 mL of THF at 0~C was added BH3.THF complex (lM in TH~; 15 mL, 15 mmol). After stirring for 3 h at room temperature, 10 mL lN NaOH was added slowly.
The solution was poured into water and extracted with CHCl3, washed with water then brine, dried and evaporated. Column chromatography of the product (silica gel; EtOAc) afforded the title compound as a solid.

Step B: Preparation of 4-(3'-methoxyphenyl)-3-methyl-benzylalcohol CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 Following the procedure described for Example 13, step A, but using the product from step A above and 3-methoxybenzene-boronic acid as starting materials the title product was obtained.

5 Step C: Preparation of 1-(3'-methoxy-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt Following the procedure described for Example 5, step C, but using the product from step B above as starting material, the 10 title product was obtained.
Analysi,s calculated for C26H23N3O-1.2HCl:
C, 71.41; H, 5.5~; N, 9.61;
Found: C, 71.34; H, 5.45; N, 9.83.

EXAMPLE 5~s 1 -(2'-Chloro-4 ' -fluoro-4-biphenylmethyl)-5 -(4-cyanobenzyl)imidazole hydrochloride salt ~0 Step A: Preparation of l-chloro-5-fluoro-2-trifluoromethyl-sulfonylyoxybenzene Following the procedure described for Example A, step A, but using 2-chloro-4-fluorophenol as starting materials the title product was obtained.
Step B: Preparation of 1-(2'-Chloro-4'-fluoro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride ~salt Following the procedure described for Example 5, steps A-C, but using the product from step A above as starting material, 30 the title product was obtained.
Analysis calculated for C24HI7N3OClF-l.lHCl:
C, 65.22; H, 4.13; N, 9.51;
Found: C, 65.33; H, 4.27; N, 9.24.

CA 022~0231 1998-09-28 W O 97/36875 PCT~US97/05383 1 -(2'-Ethyl -4-biphenylmethyl)-5 -(4-cyanobenzyl)imidazole trifluoroacetic acid salt Following the procedure described for Example S, step~s A-C, but using l-iodo-2-ethylbenzene as starting material, the title product was obtained.
Analysis calculated for C26H23N3-1.35TFA-1.4H2O:
C, 61.93; H, 4.92; N, 7.55;
Found: C, 61.96; H, 5.12; N, 7.16.

1 -(2'-(2-Propyl)-4-biphenylmethyl)-5 -(4-cyanobenzyl)imidazole trifluoroacetic acid salt Following the procedure described for Example 5, steps A-C, but using l-iodo-2-(2-propyl)benzene as starting material, the title product was obtained.
Analysis calculated for C27H2~N3-1.5TFA-0.75H20:
C, 62.55; H, 4.90; N, 7.29;
Found: C, 62.56; H, 4.95; N, 6.98.

1-(2'-(2-Methyl-2-propyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt Step A: Preparation of 2-(2-methyl-2-propyl)- 1 -trifluoromethyl-sulfonylyoxybenzene Following the procedure described for Example 53, step A, but using 2-(2-methyl-2-propyl)phenol as starting materials the title product was obtained.

CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 Step B: Preparation of 1-(2'-(2-methyl-2-propyl)-4-biphenyl-methyl)-5-(4-cyanobenzyl)imidazole hydrochloride ~salt Following the procedure described for Example 5, steps A-C, but using the product from step A above a.s starting material, S the title product was obtained.
Analysis calculated for C2gH27N3-1.75HCl:
C, 71.64; H, 6.17; N, 8.95;
Found: C, 71.71; H, 5.93; N, ~.56.

1 -(2'-Ethyl-4-biphenylmethyl)-5-(4-(lH-tetrazol-S-yl))benzyl)imidazole trifluoroacetic acid salt 1 -(2'-Ethyl-4-biphenylmethyl)-S -(4-cyanobenzyl) lS imidazole (from Example S9; 150 mg, 0.4 mmol) was dissolved in toluene (10 mL) and treated with trimethylsilylazide (0.15 mL, 1.08 mmol) and dibutyltin oxide (110 mg, 0.44 mmol). The mixture was heated at 100~C for 16 h, cooled and the solvent removed in vacuo.
Chromatography of the residue (silica gel; EtOH: NH40H: H2O
20 20:1:1) gave an oil which was further purified by preparative HPLC
to give the title compound.
FAB mass spectrum (M+H) = 421.08 Analysis calculated for C26H24N6- 1.35TFA-0.15H2O:
C, 59.72; H, 4.48; N, 14.56;
Found: C, 59.71; H, 4.42; N, 14.54.

CA 022~0231 1998-09-28 W O 9713687~ PCT~USg7/05383 1-[ 1 -(4-Cyanobenzyl)imidazol-5-ylmethoxy]-4-(2'-methylphenyl)-2-(3-N-phthalimido-l-propyl)benzene trifluoroacetic acid salt s Step A: Preparation of 4-(2'-methylphenyl)phenol Following the procedure described for Example 5, step A, but 4-bromophenol 2-methylbenzeneboronic acid as starting materials the title product was obtained Step B: Preparation of l-allyloxy-4-(2'-methylphenyl)benzene The phenol from step A (1.72 g, 9.35 mmol), Cs2CO3 (3.6 g, 10.5 mmol) and allylbromide (0.9 mL, 10.3 mmol) in DMF
(47 nmL) were stirred at room temperature for 4~S h. The mixture was poured into water and extracted with EtOAc, washed with water (3x), brine, dried and evaporated to give the title compound as an oll.

Step C: Preparation of 2-allyl-4-(2-methylphenyl)phenol To a stirred solution of BCI3 (lM in p-xylene; 6.7 mL, 6.7 mmol) in chlorobenzene at -15~C was added the allyl ether from step B (1.4~ g, 6.6 mmol) in 5 mL of chlorobenzene. After lh at -15~C, the mixture was poured into ice/MeOH, extracted with Et2O
(3x), washed with saturated NaHCO3, water then brine. The dried solution was evaporated to give the title compound as an oil.

Step D: Preparation of 2-allyl- 1 -benzyloxy-4-(2-methylphenyl)benzene Following the procedure of step B but using benzyl bromide, the phenol from step C was converted into the title compound Step E: Preparation of l-benzyloxy-2-(3-hydroxypropyl)-4-(2'-methylphenyl)benzene CA 022~0231 1998-09-28 To a stirred solution of the allyl derivative from step D, (3.2 g, 10.2 mmol) in THF (40 mL) at 0~C was added 9-BBN (0.5 M
- in THF; 30.6 mL, 15 mmol) and the mixture stirred for 4 h. The solution was treated with 30%H2O2/lN NaOH and after 15 minutes, 5 poured into water. and extracted with EtOAc (2x). The organic layers were washed with water, brine, dried and evaporated to give an oil. Chromatography on silica gel (hexane/EtOAc 4:1) afforded the title compound as an oil.

10 Step F: Preparation of l-benzyloxy-2-(3-N-phth~limido-l-propyl)-4-(2 ' -methylphenyl)benzene To a stirred solution of the alcohol from step E, (1.5 g, 4.52 mmol) and triphenylphosphine (1.7~S g, 5.65 rnmol) in THF (30 mL) at room temperature was added dropwise a solution of DEAD (0.9 15 mL, 5.65 mmol) and phthalimide (731 mg, 5 mmol) in THF (5 mL).
After stirring for 16 h, the mixture was concentrated in vacuo and the residue taken up in EtOAc. The solution was washed with 10~o citric acid solution, .saturated NaHCO3, water then brine, dried and evaporated to give an oil. Column chromatography (silica gel; hexane:EtOAc 9:1) 20 afforded the title compound a.s an oil.

Step G: Preparation of 2-(3-N-phthalimido-1 -propyl)-4-(2'-methylphenyl)phenol To a degassed solution of the benzylether from step F, 25 (1.5 g, 3.3 mmol) in EtOH (30 mL) and EtOAc (5 mE) was added 300 ,uL of HOAc and 10% palladium hydroxide on carbon (150 mg) and this was then placed on ~ Parr hydrogenation apparatus at 50 psi of hydrogen. After shaking for 24 h, the mixture was filtered through celite, the solvent removed and the residue chromatographed 30 (silica gel; hexane:EtOAc 3:1) to give the title compound as an oil.

Step H: Preparation of 1 -(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride A ~suspension of 1-(4-cyanobenzyl)-~S-hydroxy-CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97tO5383 - 13g -methylimidazole (Example 26, .step D; 3.1 g, 14.5 mmol) in thionyl chloride (20 mL) was heated at 60~C for 1 ~ h. The excess thionyl chloride was removed in vacuo and the residue was azeotroped with CHCl3 (3x) to give the title compound.

Step I: Preparation of 1 -[1 -(4-cyanobenzyl)imidazol-5-ylmethoxy]-4-(2'-methylphenyl)-2-(3-N-phthalimido- 1 -propyl)benzene trifluoroacetic acid salt Following the procedure described for step B, but 10 using the phenol from step G and 5-chloromethyl-1-(4-cyanobenzyl) imidazole hydrochloride from step H as starting materials, the title compound was obtained.
FAB mass spectrum (M+H) = 567.10.
Analysis calculated for C36H30N403-1.5TFA-1.OH20:
C, 61.9~S; H, 4.47; N, 7.41;
Found: C, 61.91; H, 4.46; N, 7.31.

20 1-(3',5'-Ditrifluoromethyl-2-methyl-4-biphenylmethyl)-5-(4-cvanobenzyl)imidazole hydrochloride salt Following the procedure described for Example 5, steps A-C, but using 4-bromo-3-methylbenzoic acid and 3,5-ditrifluoro-methylbenzeneboronic acid as starting materials, the title product 25 was obtained.
Analysis calculated for C27HIgN3-l.OHCl-0.25H20:
C, 60.00; H, 3.~s2; N, 7.7~;
Found: C, 59.91; H, 3.74; N, 7.75.

CA 022~0231 1998-09-28 1 -(3 ',5 ' -Chloro-2-methyl -4-biphenylmethyl )-5 -(4-cyanobenzyl)imidazole hydrochloride salt S Following the procedure described for Example S, step.s A-C, but using 4-bromo-3-methylbenzoic acid and 3,5-dichloro-benzeneboronic acid as starting materials, the title product was obtained.
Analysis calculated for C2~HIgN3 C12-1.0HCI-l.SH20:
C, 60.56; H, 4.68; N, 8.47;
Found: C, 60.40; H, 4.~3; N, 8.23.

l S 1 -(3 ',5 ' -Dimethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt Following the procedure described for Example 5, steps A-C, but using 4-bromo-3-methylbenzoic acid and 3,5-dimethylbenzeneboronic acid as starting materials, the title product was obtained.
Analysis calculated for C27H2~N3- 1.OHCI:
C, 75.77; H, 6.12; N, 9.~2;
Found: C, 75.66; H, 6.10; N, 9.71.

1 -(3-(N-Boc-aminomethyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)-imidazole CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 Step A: Preparation of 4-hvdroxymethyl-biphenyl-3-carbaldehyde To a solution of 4-biphenylmethanol (0.368 g, 2 rnrnol) in ether (25 mL) and TMEDA (1.21 mL, ~ mmol) at 0~C wa~s added n-butyllithium (2.5N hexanes; 3.2 mL, ~S mmol). The solution was S then heated at reflux for lh, cooled to -60~C and CuCN (0.2 g, 2.2 mmol) added. After 30 minutes, the solution was cooled to -7~s~C
and N-formylpiperidine (1.11 mL, 10 mmol) was then added drop-wise and stirring was continued for 1 h. The mixture was then warmed to -10~C, quenched with saturated NH4Cl, extracted with 10 ether washed withbrine, dried and the solvent removed in vacuo.
Chromatography of the residue (silica gel; hexane:EtOAc 4:1) afforded the title compound as a colorless oil.

Step B: Preparation of 4-hydroxymethyl-biphenyl-3-carbaldehyde O-methyl-oxime A solution of the aldehyde from step A (0.13 g, 0.61 mmol), methoxylamine hydrochloride (61 mg, 0.735 mmol) and pyridine (2 mL) in EtOH (10 mL) was heated at reflux for 16 h.
Further portions of methoxylamine hydrochloride (61 mg, 0.735 20 mmol) and pyridine (2 mL) were added and heating was continued for 24 h. The solution was cooled, diluted with EtOAc, extracted with water (2x) then brine, dried and concentrated to give the title compound as an oil. This was used as such in the next step.

25 Step C: Preparation of 3-aminomethyl-biphenyl-4-methanol To a solution of the oxime from step B (0.51 g, 2.1 mrnol) in THF (15 mL) at 0~C was added BH3.THF (lM in hexane;
~i mL, ~ mmol) and the resulting solution was stirred at room temperature for 16 h then heated to reflux for 24 h. The solution 30 was cooled to 0~C and lN NaO~I (10 mL) was added slowly. After 1 h, the mixture was diluted with water, extracted withEtOAc (3x), washed with brine, dried and evaporated to give the title compound as an oil. This was used as such in the next step.

CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 Step D: Preparation of 3-N-Boc-aminomethyl-biphenyl-4-methanol To a solution of the amine from step C (0.39 g, 1.8 mmol) and Et3N (0.255 mL, 1.8 mmol) in DMF (10 mL) wa.s added Boc-anhydride (0.4 g, l.P~ rnmol) and the mixture was stirred for 16 S h. The solution was diluted with water, extracted with EtOAc (3x) and the combined organic layers were then extracted with saturated NaHCO3 then brine, dried and evaporated. Chromatography of the residue (silica gel; hexane:EtOAc 3:1) afforded the title compound as a solid.
Step F: Preparation of 3-(N-Boc-aminomethyl)-4-biphenylmethyl bromide A solution of the alcohol from step D (0.157 g, 0.5 mmol), triphenylphosphine (0.191 g, 0.75 mmol) and CBr4 (0.249 g, 15 0.75 mmol) in THF (15 mL) was stirred at room temperature for 16 h. The solvent was removed in vacuo and EtOAc was added to the residue. Filtration removed the insoluble material and the EtOAc solution was washed with water then brine, dried and evaporated.
Purification of the residue on silica gel, eluting with hexane:EtOAc 20 12:1, afforded the title compound.

Step G: Preparation 1 -(3-(N-Boc-aminomethyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole Following the procedure of Example 1, step B but using 25 the bromide from step G as starting material, the title compound was obtained as a ~solid.
Fab mass spectrum (M+H) = 479.12 Analysis calculated for C30H30N4O2-0.05CHCI3:
C, 74.41; H, 5.67; N, 11.38;
Found: C, 74.48; H, 6.25; N, 11.56.

CA 022~0231 1998-09-28 W O 97/36875 rCTAJS97/OS383 EXAMPLE 6P~

1 -(3-Aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole dihvdrochloride salt 1-(3-(N-Boc-aminomethyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole from Example 67 was dissolved in EtOAc 0~C and treated with HCI gas. The solvent was removed to give the title compound.
Fab mass spectrum (M+H) = 379.16 1 -(4-Cyanobenzyl)-2-methyl-S -(2'-methylbiphenyl -4-yloxy)imidazole trifluoroacetate salt Step A: Methyl N-(cyanomethyl~eth~nimidate Finely grounded aminoacetonitrile hydrochloride (21 g) was stirred in a solution of chloroform (200 mL) saturated with ammonia gas for 10-lS minutes. The slurry was filtered through a plug of Celite. The filtrate was concentrated, and the residue distilled (36-40~C, 0.1 mmHg) to provide aminoacetonitrile as clear, colorless oil. Aminoacetonitrile (14 g) was added at a rate of 1 mL/min to a boiling mixture of trimethyl orthoacetate (200 mL), concentrated sulfuric acid (5 drops), and anhydrou.s sodium sulfate (20 g), with removal of distillate. The resultant mixture was heated for additional 30 minutes, filtered through Celite, and concentrated.
The residue was distilled (50-60~C, 0.1 mmHg) to provide methyl N-(cyanomethyl)ethanimidate as clear, colorless oil. The ethanimidate was stored under dry argon at -10~C.
1 H NMR (CDC13 300MHz) ~ 4.1 1 (2H, s), 3.66 (3H, s), 1.97 (3H, s) ppm.

Step B: 5-(4-Bromophenyloxy)-2-methylimidazole CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 Using procedure described for the preparation of 5-(4-cyanophenyloxy)imidazole in Example 17, Step A, but substituting 4-bromophenol for 4-cyanophenol, methyl N-(cyanomethyl) eth~nimidate for methyl N-(cyanomethyl)meth~nimidate, and after 5 heating the resultant mixture at 100 ~C for 4 hours, 5-(4-bromo-phenyloxy)-2-methylimidazole was prepared:
1H NMR (DMso-d6 300MHz) o 7.45 (2H, d, J = ~.8 Hz), 6.93 (2H, d, J = 8.8 Hz), 6.91 (lH, ,s) and 2.22 (3H, s) ppm.
~0 Step C: 5-(4-Bromophenyloxy)-1-(4-cyanobenzyl)-2-methylimidazole To a cold (-78~C) solution of 5-(4-bromophenyloxy)-2-methylimidazole (2.06 g, 8.14 mmol) in THF (30 mL), a solution of MeLi in diethyl ether (1.4 M, 8.96 mmol) was added. The resultant 15 mixture was stirred at -78~C for 1 hour, and a solution of 4-cyano-benzyl bromide (1.68 g, 8.55 mInol) in THF (3 mL) was added.
The mixture wa,s allowed to warm up to room temperature, ~stirred overnight, and concentrated under vacuum. The residue was partitioned between water and a 9: 1 mixture of methylene chloride 20 and methanol. The organic extract was washed with brine, dried (anhydrou.s sodium sulfate), filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a mixture of chloroform and acetone (8:2 v/v).
Two alkylation products were isolated. 1 H NMR NOE experiments 25 indicated that the major product to be 5-(4-bromophenyloxy)-3-(4-cyanobenzyl)-2-methylimidazole, and the minor product to be desired 5-(4-bromophenyl-oxy)-1-(4-cyanobenzyl)-2-methylimidazole .
1 H NMR (minor isomer; CDC13 300MHz) ~ 7.62 (2H, d, J = 8.8 30 Hz), 7.39 (2H, d, J = 9.0 Hz), 7.16 (2~I, d, J = 8.8 Hz), 6.89 (2H, d, J = 9.0 Hz), 6.54 (lH, s), 4.98 (2H, s), and 2.30 (3H, s) ppm.

Step D: 1-(4-Cyanobenzyl)-2-methyl-5-(2'-methylbiphenyl-4-yloxv)-imidazole trifluoroacetate salt CA 022~0231 1998-09-28 The title compound wa.s prepared as a white solid using the protocol described in Example 19 - Step D, substituting 5-(4-bromo-phenyloxy)-1-(4-cyanobenzyl)imidazole with ~S-(4-bromophenyl-oxy)-1-(4-cyanobenzyl)-2-methylimidazole, phenyl 5 boronic acid with o-tolylboronic acid, and stirring the reaction mixture at 100 ~C for 1~ hours.
Anal. Calcd for C2sH2lN3o-l.lo TFA-0.95 H20:
C, 62.59; H, 4.63; N, 8.05.
Found: C, 62.61; H, 4.66; N, 7.75.
lH NMR (CDC13 300MH~) ~ 6.68 (lH, s), 5.04 (2H, s), 2.31 (3H, s), and 2.23 (3H, s) ppm.

5-(4-Cyanobenzyl)- 1 -(3-cyano-2' -trifluoromethylbiphenyl-4-ylmethyl)-imidazole hydrochloride salt Step A: 3-Cyano-4-methyl-2'-trifluoromethylbiphenyl The title compound was prepared as a white solid using the protocol described in Example 19 - Step D, substituting 5-(4-bromophenyloxy)-1-(4-cyanobenzyl)imidazole with 2-methyl-5-iodobenzonitrile, phenyl boronic acid with o-trifluoromethylboronic acid, and stirring the reaction mixture at 100~C for 1~ hours.
lH NMR (CDC13 300MHz) ~ 7.X - 7.2 (7H, m) and 2.61 (3H, s) ppm.

Step B: 4-Bromomethyl-3-cyano-2'-trifluoromethylbiphenyl A mixture of 3-cyano-4-methyl-2'-trifluoromethyl-biphenyl (420 mg, 1.61 mmol), N-bromosuccinimide (2~6 mg, 1.61 mmol), AIBN (10 mg), and carbon tetrachloride (20 mL) was refluxed for 1 hour. The resultant mixture was concentrated, and the residue subjected to column chromatography on silica gel eluting with a mixture of ethyl acetate in hexane (7.5 to 92.5 v/v).

CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 Collection and concentration of appropriate fraction~s provided the title compound.
lH NMR (CDC13 300MHz) ~ 7.8 - 7.2 (7H, m) and 4.69 (2H, s) ppm.
s Step C: 5-(4-Cyanobenzyl)-1-(3-cyano-2'-trifluoromethylbiphenyl-4-ylmethyl)-imidazole hydrochloride salt The title compound wa,s prepared as a white solid 10 using the protocol described in Example 1 - Step B, substituting 4-chloromethyl-biphenyl with 4-bromomethyl-3-cyano-2'-trifluoromethylbiphenyl.
Anal. Calcd for C26Hl7N4 F3-1.50 HC1-1.45 H2O:
C, 59.68; H, 4.12; N, 10.71.
lS Found: C, 59.74; H, 4.12; N, 10.53.

2-Amino-S-(biphenyl-4-ylmethyl)- 1 -(4-cyanobenzyl)imidazole Step A: N-Methoxy-N-methyl 2-(N-tert-butyloxycarbonylamino)-2-(biphenyl-4-ylmethyl)acetamide To a cold (0~C) solution of N-Boc 4-biphenylalanine 25 (2.5 g, 7.33 mmol) and N-methylmorpholine (0.96 mL, 8.79 mrnol) in ethyl acetate (20 mL), isobutyl chloroformate (1.04 mL, 8.06 mmol) was added. The resultant mixture was stirred at 0~C for 30 min. N,N-Dimethyl-hydroxyamine hydrochloride (0.86 g, 8.79 mmol) and N-methyl-morpholine (0.96 mL, 8.79 mmol) was added, 30 and the re.sultant mixture was stirred at room temp. overnight. The product mixture was diluted with ethyl acetate (100 mL). The organic extract was washed with brine, dried over anhydrous magnesium ,sulfate, filtered, and concentrated. The residue was subjected to column chromatography on silica gel eluting with 40%

CA 022~0231 1998-09-28 W O 97/36875 PCT~US97/05383 ethyl acetate in hexane. Coliection and concentration of appropriate fractions provided the title compound as white solid.
lH NMR (CDC13 300MHz) ~ 7.6 - 7.2 (9H, m), 5.2 (lH, br s), 5.0 (lH, br s), 3.69 (3H, s), 3.19 (3H, s), 3.0 (2H, m), and 1.39 (9H, s).

Step B: N-Methoxy-N-methyl 2-[(N-tert-butyloxycarbonyl)-(N-4-bromobenzyl)aminol -2-(biphenyl-4-ylmethyl)acetamide To a cold (-78~C) solution of N-methoxy-N-methyl 2-(N-tert-butyloxycarbonylamino)-2-(biphenyl -4-ylmethyl)acetamide (2.25 g, 5.86 mmol) in THF (60 mL), a solution of sodium bis(trimethylsilyl)amide in THF (1 M, 6.44 mL, 6.44 mmol) was added. The resulting mixture was stirred at -7~~C for 1 hour. A
solution of 4-bromobenzyl bromide (1.61 g) in THF (5 mL) was added, and the resultant mixture was allowed to warm up to room temp, and stirred overnight. The product mixture was diluted with diethyl ether. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum.
The residue was subjected to column chromatography on silica gel eluting with 20% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.

Step C: 2-Amino-5-(biphenyl-4-ylmethyl)-1-(4-bromobenzyl)-imidazole To a cold (-40~C) slurry of LiAlH4 in anhydrous diethyl ether (50 mL), a solution of N-Methoxy-N-methyl 2-L(N-tert-butyloxy-carbonyl)-(N-4-bromobenzyl)amino} -2-(biphenyl-4-ylmethyl)acetamide (2.11 g, 3.82 mmol) in THF (10 mL) was added.
The resultant mixture was stirred at -40 ~C for 10 min. and allowed to warm up to 0~C. The mixture was then cooled back to -40~C, and quenched with aqueous KHSO4 solution with temperature of the mixture maintained below -30 ~C. The resultant mixture was diluted with diethyl ether and stirred at room temp for 30 min.

CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 The ethereal solution was isolated, washed with brine, dried over anhydrous magnesium .sulfate, filtered, and concentrated under vacuum to provide a foamy product.
Without further purification, 0.6 g of the aldehyde obtained from the above procedure was dissolved in dichloromethane (10 mL) and treated with trifluoroacetic acid (2 mL) at room temperature for 15 min. The resulting mixture was concentrated under vacuum. The residue was dissolved in a mixture of absolute ethanol and dichloromethane (~ mL, 5:1 v/v; pH adjusted to about 4 -5 with addition of diisopropylethylamine), treated with cyanamide (0.16 g, 3.69 mmol), and heated under reflux for 3 h. The resultant mixture was concentrated, and the residue subjected to column chromatography on silica gel eluting with a 1:1 mixture of 5%
methanol in chloroform and chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provided the title aminoimidazole as white solid.
lH NMR (CDC13 300MHz) ~ 7.6-7.1(1 lH, m), 6.79 (2H, d, J = 8.5 Hz), 6.59 (lH, s), 4.73 (2H, s), 3.81 (2H, s), and 3.72 (2H, br s) ppm.
FAB MS 418/420 (MH+) Step D: 2-Amino-5-(biphenyl-4-ylmethyl)-1-(4-cyanobenzyl)imidazole A mixture of 2-amino-5-(biphenyl-4-ylmethyl)-1-(4-bromo-benzyl)imidazole (114 mg, 0.27 mmol), anhydrous zinc cyanide (19 mg, 0.16 mmol), and anhydrous dimethylformamide (2 mL) was purged with argon for 20 minutes. Tetrakis(triphenyl-phosphine)palladium(0) (32 mg, 0.02~ mmol) was added, and the resultant solution was stirred under argon at ~0 ~C for 36 hours.
The product mixture was concentrated under vacuum, and the residue subjected to column chromatography on silica gel eluting with a 1:1 mixture of 10% methanol in chloroforrn and chloroforrn saturated with ammonia gas. Collection and concentration of CA 022~0231 1998-09-28 - 14~s -appropriate fractions provided the title aminoimidazole as white solid.
Anal. Calcd for C24H20N4-o.lo CHC13:
C, 76.91; H, 5.3P~; N, 14.89.
5 Found: C, 77.04; H, 5.47; N, 14.78.

2-Amino- 1 -(biphenyl-4-ylmethyl)-5-(4-cyanobenzyl)imidazole 10 trifluoroacetate salt Step A: N-Methoxy-N-methyl 2-(N-tert-butyloxycarbonylamino)-2-(4-bromobenzyl)acetamide The title compound was prepared as a white solid using 15 the protocol described in Example 71 - Step A, substituting N-Boc 4-biphenyl-alanine with N-Boc 4-bromophenylalanine.
1H NMR (CDC13 300MHz) ~ 7.39 (2H, J 8.5 Hz, d), 7.04 (2H, J 8.5 Hz, d), 5.2 (lH, br s), 4.9 (lH, br s), 3.69 (3H, s), 3.17 (3H, s), 2.9 (2H, m), and 1.39 (9H, s).
Step B: N-Methoxy-N-methyl 2-[(N-tert-butyloxycarbonyl)-(N-biphenyl-4-ylmethyl)aminol -2-(4-bromobenzyl)acetamide The title compound was prepared as a white solid using the protocol described in Example 71 - Step B, substituting 25 N-methoxy-N-methyl 2-(N-tert-butyloxycarbonylamino)-2-(biphenyl-4-ylmethyl)-acetamide with N-Methoxy-N-methyl 2-(N-tert-butyloxycarbonylamino)-2-(4-bromobenzyl)acetamide, and 4-bromobenzyl bromide with biphenyl-4-ylmethyl iodide.

Step C: 2-Amino-l-(biphenyl-4-ylmethyl)-5-(4-bromobenzyl)-imidazole The title compound was prepared as a white solid using the protocol described in Example 71 - Step C, substituting CA 022~0231 1998-09-28 W O 97136875 PCTrUS97/05383 N-Methoxy-N-methyl 2-[(N-tert-butyloxy-carbonyl)-(N-4-bromobenzyl)amino]-2-(biphenyl-4-ylmethyl)acetamide with N-Methoxy-N-methyl 2-[(N-tert-butyloxycarbonyl)-(N-biphenyl-4-ylmethyl)amino~-2-(4-bromobenzyl)-acetamide.
lH NMR (CDC13 300MHz) ~ 7.6-7.3 (8 H, m), 7.04 - 6.97 (4 H, m), 6.53 (lH, s), 4.7~s (2H, s), 3.83 (2H, br s), and 3.76 (2H, s) ppm.
FAB MS 418/420 (MH+) Step D: 2-Amino-l-(biphenyl-4-ylmethyl)-5-(4-cyanobenzyl)-imidazole trifluoroacetate salt The title compound was prepared as a white solid using the protocol described in Example 71 - Step D, substituting 2-Amino-5-(biphenyl-4-ylmethyl)- 1 -(4-bromobenzyl)imidazole with 2-amino- 1 -(biphenyl-4-ylmethyl)-5-(4-bromobenzyl)imidazole.
Anal. Calcd for C24H20N4-l.2s TFA:
C, 62.78; H, 4.22; N, 11.05.
Found: C, 62.93; H, 4.04; N, 10.68.

1 -(3-Butylbiphenyl -4-ylmethyl)-5-(4-cyanobenzyl)-imidazole hydrochloride Step A: (N-tert-butyl)-4-biphenylcarboxamide To a lL round bottomed flask with a stirring bar and a drying tube was added 4-biphenylbenzoic acid (35.14g, 177.26 mmol), CH2Cl2 (500 mL) and oxalyl chloride (17.18 mL, 196,96 mmol). To thi~s well stirred mixture was added 10 drops of DMF.
This mixture was stirred at ambient temperature for Sh. The solvent and excess oxalyl chloride were removed in vacuo and the solid acid chloride was redissolved in fresh CH Cl2 (500 mL). This solution was cooled to 0~C and te)-t-butylamine (23.28 mL, 221.58 mmol), CA 022~0231 1998-09-28 W 097/36875 PCTrUS97/05383 Et3N (30.~8 mL, 221.5~ mmol) and 4-DMAP (0.20g) were added sequentially. The cooling bath was allowed to expire and the mixture was stirred at ambient temperature for l~Sh. The reaction mixture was diluted with an equal volume of CHCI3 and this solution 5 was washed successively with lN HCl, NaHCO3 solution and brine.
Drying (MgSO4), filtration and removal of the solvent in vacuo gave an off white solid. This material was triturated with Et2O (100 mL) and collected on a frit and dried in vacuo to afford the title compound.
10 ~H NMR (CDCl3) ~ 1.49 (9H,s), 5.9~ (lH, br s), 7.3~ (lH, m), 7.45 (2H, t, j=6 Hz), 7.62 (4H, m), 7.80 (2H, d, j=7 Hz).

Step B: (N-tert-butyl)-3-(1-hydroxybutylyl)-4-biphenylcarboxamide To three necked, 500 mL, oven dried round bottomed flask with a stirring bar, argon inlet, low temperature thermometer and a septum was added (N-tert-butyl)-4-biphenylcarboxamide (5.00g, 19.66 mmol) and dry THF (200 mL). This solution was cooled to -78~C and n-butyllithium (16.12 mL of a 2.5M solution 20 in hexane, 40.30 mmol) was added with a syringe at dropwise so that the temperature did not exceed -65~C. The cooling bath was replaced with an ice-H2O bath and the reaction was allowed to warm to 0~C and stir 45 min. The solution was recooled to -7P~~C and butyraldehyde (1.~0 mL, 20.00 mmol) was added with a syringe.
25 This mixture was warmed to 5~C during which time the mixture became homogenous. The mixture was poured into 10% aqueous citric acid and extracted with EtOAc. The organic fraction was washed with aqueous NaHCO3 solution and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave a colorless foam.
30 This material was chromatographed on silica gel using 15% EtOAc in hexane as eluant to afford the title compound.
'H NMR (CDCI ,) ~ 0.95 (3H, t, j=7.5 Hz), 1.36 (lH, m), 1.49 (9H, ,s), 1.50 (lH, m), 1.79 (lH, m), 1.95 (lH, m), 4.5~¢ (lH, m), 4.75 (lH, 4, j=7 Hz), 6.00 (lH, br s), 7.3~ (lH, m), 7.47 (4H, m), 7.59 35 (3H, m).

CA 022~0231 1998-09-28 W O 97/36875 PCT~US97/05383 Step C: (N-tert-butyl)-3-butyl-4-biphenylcarboxamide - To 500 mL Parr flask was added (N-tert-butyl)-3-(1-hydroxybutyl)-4-biphenylcarboxamide (3.50 g, 10.75 mmol), abs EtOH (125 mL) and 10% palladium on carbon (3.50g). This mixture was hyrogenolyzed at 60 psig and ambient temperature for 48h. The catalyst was removed by filtration on a celite pad anfd the solvent was removed in vacuo. This material wa~s chromatographed on silica gel using 10% EtOAc in hexane a~ eluant to afford the title compound as a white crystalline solid.
1H NMR (CDCI3) ~ 0.94 (3H7 t, j=7.5 Hz), 1.39 (2H, m), 1.48 (9H, s), 1.63 (2H, m), 2.83 (2H, m), 5.60 (lH, br s), 7.38 (lH, m), 7.47 (4H, m), 7.59 (3H, m).

Step D: 2-Chloroethyl 3-butyl-4-phenylbenzoate To a 200 mL round bottomed flask with a strirring bar and a reflux condenser was added (N-tert-butyl)-3-butyl-4-biphenylcarboxamide (3.17g, 10.24 mmol), ethylene glycol (25 mL) and 12N HCl (25 mL). This mixture was heated at reflux 72h. The cooled mixture was extracted with EtOAc and the EtOAc extracts were combined, washed with H20 (3X) and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on silica gel using 30% EtOAc in hexane as eluantto afford the title compound as an oil.
lH NMR (CDCl3) â 0.95 (3H, T, J= 6.4 Hz), 1.41 (2H, m), 1.65 (2H, m), 3.04 (2H, dd, j= 5.6, 1.0 Hz), 3.82 (2H, t, j=5.6 Hz), 4.58 (2H, t, j= 5.6), 7.38 (lH, m), 7.47 (3H, m), 7.62 (2H, m), 8.02 (lH, d, j=8.9 Hz).

CA 022~0231 1998-09-28 W O 97136875 PCT~US97/05383 Step E: 2-ButyJ-4-phenylbenzenemethanol To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 2-chloroethyl 3-butyl-4-phenylbenzoate (570 mg, 1.80 mmol), THF (9 mL) and LiBH4 (9 mL of a 2M
5 solution in THF, 18 mmol). This mixture was heated at reflux for 18h. The cooled reaction mixture was treated with lN HCl and extracted with EtOAc. The combined EtOAc extracts were washed with H2O and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. Ths material was chromatographed on 10 silica gel using 20% EtOAc in hexane as eluant to afford the title compound as a crystalline solid.
1H NMR (CDCl3) o 0.97 (3H, t, j= 7.3), 1.41 (2H, m), 1.59 (2H, m), 2.76 (2H, dd, j= 5.6, 1.0 Hz), 4.77 (2H, s), 7.35 (lH, m), 7.44 (SH, m), 7.58 (2H, m).
Step F: 2-Butyl-4-phenylbenzenemethyl bromide To a 200 mL round bottomed flask with a stirring bar and an argon inlet was added NBS (675 mg, 3.8 mmol) in 25 ml CH2C12. This solution was cooled to 0~C and was added 20 methylsulfide (.33 ml, 4.55 mmol). The resulting suspension was cooled to -20~C and was added and solution of 2-butyl-4-phenylbenzenemethanol ( 608 mg, 2.53 mmol) in 15 ml CH2C12.
The reaction mixture was stirred at 0~C for 3 h. Poured the solution mixture in 200ml ice. separated the layers, CH2C12 layer was washed 25 with H20 and brine, dried (MgSO4), filtration and remeved solvent in vacuo to afford the title product a,s an oil.
~H NMR (CDCl3) ~ 0.98 (t, 3H), 1.45 (m, 2H), 1.69 (m, 2H), 2.79 (m, 2H), 4.6 (s, 2H), 7.36 (m, IH), 7.43 (m, 4H), 7.5~ (d, J=7.32, 2H).

CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 Step G: 1-(3-Butylbiphenyl-4-ylmethyl)-5-(4-cyanobenzyl)-imidazole hydrochloride To a 50 mL round bottomed flask with a .stirring bar and an argon inlet was added 2-Butyl-4-phenylbenzenemethyl bromide (750 mg, 1.70 mmol), and 1-trityl-4-(4-cyanobenzyl) imidazole (638 mg, 1.5mmol) in CH3CN (12 mL). The mixture was re~luxed for 24 hours. The solvent was evaporated in vacuo. The residue was dissolved in methanol (10 mL), heated at reflux for 4 hour, removal of solvent in vacuo. The residue was partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic layer was dried, (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 3% 2-propanol in CHC13).
The amine was converted to the HCl salt by treatment with 4.0M
HCI in 1,4 dioxane. Triturated with EtOAc to afford a white solid.
1H NMR (DMSO-d6, 400MHz) ~ 0.90(t, 3H), 1.28(m, 2H), 1.45(m, 2H), 2.42(m, 2H), 4.09(s, 2H), 5.14(s, 2H), 6.94(d, J=X.06Hz, IH), 7.26(m, lH), 7.40-7.49(m, 7H), 7.56(d, J=6.96Hz, 2H), 7.6~(d, J=7.87Hz, 2H), 8.38(br, s lH).

1 -(3 -Propylbiphenyl-4-ylmethyl)-5 -(4-cyanobenzyl)-imidazole hydrochloride Title compound was prepared using the procedure described in Example 73 substituting propionaldehyde for butyraldehyde in step B.
1 H NMR (DMSO-d6, 400MHz) o 0.91 (t, 3H), 1.46- 1.51 (m, 2H), 2.5(m, 2H), 4.16(s, 2H), 5.44(s, 3H), 6.69(d, J=7.6Hz, lH), 7.31-7.39(m, 4H), 7.44-7.4~(m, 3H), 7.59-7.63(m, 3H), 7.69(d, J=~s.OSHz, 2H), 9.05(br, s lH).

CA 022~0231 1998-09-28 1 -(4-Cyanobenzyl)-5-[(3-fluoro-4-biphenyl)methyl]imidazole trifluoroacetate salt Step A: 1-(4-Cyanobenzyl)-S-[l-chloro-(3-fluoro-4-S biphenyl)methyllimidazole The alcohol from Example 28 (380 mg. lmmol) was dissolved in thionyl chloride (500 !11) and the solution was stirred at room temperature for 4 hours and then evaporated solution in vacuo to afford title compound.
Step B: 1-(4-Cyanobenzyl)-5-[(3-fluoro-4-biphenyl)methyllimidazole trifluoroacetate salt The chloride from step A was hydrogenolyzed in absolute ethanol (10 mL) over 10% Pd/C (SOmg) in a Parr apparatus lS at 40 psi (initial) for 6 days. The catalyst was filtered off, washed well with EtOH and the solvent was evaporated. The residue was chromatographed (silica gel, 2-5% MeoH-CHC13) and further purified by preparative HPLC. (gradient elution, 95:5 to 5:95%
H20-CH3CN containing 0.1% TFA) to afford the title compound as a very hygroscopic white solid.
FAB MS 368.13 (MH+) Hl NMR (CD30D, 400 MHz) ~ 4.10 (2H,s) 5.54 (2H,s), 6.~8 (H,dd, J=11.6 and 1.6 Hz), 6.97 (H,dd, J=11.6 and 1.6 Hz), 7.23 (2H,d, J=~.8 HZ), 7.30 (H,t, J=8Hz), 7.30-7.49 (SH,m), 7.52 (H, brs), 7.64 (2H,dd, J=6.4 and 1.6 Hz), 9.07 (H, brs)ppm.

1-(4-Biphenylmethyl)-4-(4-cyanobenzyl-2-methylimidazole trifluoroacetate salt CA 022~0231 1998-09-28 W O 97t36875 PCTrUS97/05383 Step A: l-Trityl-4-(4-cyanobenzyl)-2-methylimidazole The title compound was prepared using the protocol described in Example 16, Step C using l-trityl-4-iodo-2-methylimidazole.
FAB MS 440.27 (MH+) Hl NMR (CDC13, 400 Mhz) ~ 1.61 (3H,s), 3.87 (2H,s), 6.45 (H,s), 7.09-7.15 (SH,m), 7.3-7.36 (12H,m), 7.54 (2H,d, J=8 Hz) ppm.

Step B: 1-(4-Biphenylmethyl)-4-(4-cyanobenzyl-2-methylimidazole trifluoroacetate salt The title compound wa~ prepared using the protocol described in Example 2 using the product from Step A above but purified as in Example 3, Step B to give the product as a very hygroscopic white solid.
FAB MS 364.09 (MH+) Hl NMR (CD30D, 500 MHz) ~ 2.62 (3H,s), 4.12 (2H,s), 5.36 (2H,s), 7.33 (H,s), 7.35-7.55 (13 H,m) ppm.

1 -(4-Cyanobenzyl)-5-[1 -(4-biphenyl)- 1 -hydroxy]ethyl-2-methylimidazole 25 Step A: l-Trityl-4-[1-(4-biphenyl)-1-hydroxy]ethyl-2-methylimidazole A l.OM solution of EtMgBr in THF (4 mL, 4 mmol) was added to a solution of l-trityl-4-iodo-2-methylimidazole (1.8 g, 4 mmol) in dry CH2CI2 (8mL) at room temperature. After 1 hour a 30 solution of 4-acetylbiphenyl (780 mg, 4mmol) in dry CH2C12 (4mL) was added and stirring at room temperture was continued for 16 hours. The reaction mixture was quenched with sat. NH4CI and then the product was extracted into CHC13, dried and the solvent was evaporated. The residue was chromatographed (silica gel 0.5-10%

CA 022~0231 1998-09-28 W O 97136875 PCTrUS97/OS383 MeOH-CHC13) and further purified by cry~stallization from CHC13-hexane to afford title compound, mp 231-232~C.
FAB MS 521.25 (MH+) Hl NMR (CDC13, 400 MHz) o 1.60 (3H,s), 1.76 (3H,s), 6.65 (H,s), 5 7.13-7.18 (6H,m), 7.30-7.36 (lOH, m), 7.42 (2H, t, J=7.2 Hz), 7.51 (4H,s), 7.57 (2H,dd, J=8.4 and 1.2 Hz) ppm.

Step B 1 -(4-Cyanobenzyl)-5-[ 1 -(4-biphenyl)- 1 -hydroxy]ethyl-2-methylimidazole The title compound was prepared using the protocol described in Example 5, Step C using the product from Step A
above and the corresponding amount of 4-cyanobenzyl alcohol.
The residue was chromatographed (silica gel, 1.2-5.0%
MeOH-CHC13) to yield the title compound.
FAB MS 394.16 (MH+) H1 NMR (CDC13, 500 MHz) o 1.95 (3H,s), 2.18 (3H,2), 4.98 (H,d, J=17.6 Hz) 5.22 (H,d, J=17.6 Hz), 6.72 (2H, d, J=8.4 Hz), 7.16 (H,s), 7.28-7.37 (5H,m), 7.39 (2H,d, J=8.4 Hz), 7.42-7.47 (4H,m) ppm.

1 -(4-Cyanobenzyl)-5 -(4-biphenylmethyl)-2-methylimidazole trifluoroacetate salt Step A: l-Trityl-4-(4-biphenylmethyl)-2-meth~Jlimidazole The title compound was prepared using the protocol described in Example 1, Step A except using the corresponding amounts of 4-chloromethylbiphenyl and 1-trityl-4-iodo-2-methylimidazole.
FAB MS 491 .3 1 (MH+) H 1 NMR (CDCL3, 400 MHz) o 1.63 (3H,s), 3.88 (2H,s), 6.47 (H,s), 7.12-7.16 (6H, m), 7.29-7.34 (12H,m), 7.41 (2H,t, J=7.6 Hz), 7.49 (2H,d, J=7.6Hz) 7.56 (2H, dd, J=8.X and 0.8 Hz) ppm.

CA 022~0231 1998-09-28 W 097/36875 PCT~US97/05383 - Step B: 1-4-Cyanobenzyl)-5-(4-biphenylmethyl)-2-methylimidazole trifluoroacetate salt The title compound was prepared using the protocol described in Example 5, Step C using the product from Step A above and the corresponding amount of 4-cyanobenzyl alcohol but purified as in Example 3, Step B.
Anal. Calc'd for C2sH21N3-0.70 H20-0.40 TFA:
C, 62.32; H, 4.48; N, 7.84.
Found: C, 62.36; H, 4.42; N, 7.87 FAB MS 364.09 (MH+) H 1 NMR (CD30D, 500 MHz) â 2.58 (3H,s), 4.05 (2H,s), 5.49 (2H,s), 7.06 (2H, d, J=8.8Hz), 7.18 (2H, d J=8.8Hz), 7.33 (H,m), 7.39 (H,s), 7.42 (2H,m), 7.43 (2H,m), 7.51 (2H,m), 7.60 (2H,d, J=8.8.Hz) ppm.

1-(4-Cyanobenzyl)-5-11-(4-biphenyl)lethyl-2-methyl imidazole The alcohol from Example 77 (1~1 mg, 460 mmol) dissolved in CH2C12 (~mL) and this solution was added to a mixture of trimethylsilyl chloride (770 mL, 6mmol) and NaI (900 mg, 6 mmol). The dark mixture was stirred at room temperature for 20 hours.The reaction mixture was distributed between H20 (100 mL) and CHC13 (50 mL). The organic layer was washed with saturated Na2S2O3 and water. The solvent was evaporated and the residue was chromatographed (silica gel, 2.5-5% CH30H-CHC13) to afford the title compound.
Anal. Calc'd for C26H23N3-0.15 CHC13;
C, 79.43; H, 5.90; N, 10.63.
Found: C, 79.21; H, 5.74; N, 10.06.

CA 022~0231 1998-09-28 W O 97/36875 rcTrusg7/0~383 - 15~ -FAB MS 378.13 (MH+) H1 NMR (CDC13, 400 MHz) ~ 1.59 (3H, d, J=7.2 Hz), 2.27 (3H,s), 3.74 (H,q, J=7.2 Hz). 4.76 (H,d, J=18 Hz), 4.93 (H,d, J=l~ HZ, 6.~3 (2H,d, J=8.4Hz), 7.05-7.09 (3H, m), 7.32-7.36 (H,m) 7.38-7.46 5 (4H,m) 7.48-7.53 (4H,m) ppm.

1-(4-Cyanobenzyl-5-11-(4-biphenyl)lvinylidene-2-methylimidazole The alcohol from Example 77 (59 mg, 150 ~mol) was stirred in TFA (1 mL) at 55 C for 20 hours. The clear solution was then cooled and distributed between EtOAc and sat. NaHCO3. The organic layer was separated, dried and the solvent was evaporated.
15 The residue was chromatographed (silica gel. 2.5% CH30H-CHC13) to afford the title compound.
Anal. Calc'd for C26H21N3-0.05 CHC13-0.25 CH30H;
C, 81.10; H, 5.71; N. 10.79 Found: C, 81.43; H, 6.0~S; N, 10.59.
20 FAB MS 376.43 (MH+) H 1 ~MR (CDC13, 400 MHz) ~ 2.34 (3H,s), 4.83 (2H,s), 5.32 (H,d, J=1.2 Hz), 5.56 (H,d, =1.2 Hz), 6.90 (2H, d, J=~S.4 Hz), 7.10 (H,s), 7.26-7.29 (2H,m) 7.34-7.39 (H,m), 7.43-7.59 (8H,m) ppm.

EXAMPLE ~l 1 -(4-Cyanobenzyl)-5-[2-(4-biphenyl)]vinylene-2-methylimidazole trifluoroacetate salt Step A: l -Tritvl-4-~(2-(4-biphenyl)lvinylene-2-methyl imidazole The title compound was prepared using the protocol described in Example 30 using 1-trityl-4-iodo-2-methylimidazole.
The dark solution was cooled and chromatographed (silica gel, CA 022~0231 1998-09-28 0.5% MeOH-CHC13) and rechromatographed (silica gel, 20%
EtOAc-hexane) to give product as a 3: 1 mixture of the desired 1,2 vinylene and 1,1 vinylidene as evidenced by NMR.
FAB MS 503.39 (MH+) s Step B: 1-(4-Cyanobenzyl)-5-[2-(4-biphenyl)]vinylene-2-me~yimidazole trifluoroacetate salt The title compound was prepared using the protocol described in Example 5, Step C using the corresponding amounts of the product from Step A above and 4-cyanobenzyl alcohol.
Anal. Calc'd for C26H21N3-1.25 TFA-0.60 H2O:
C, 64.73; H, 4.47; N, 7.95 Found: C, 64.71; H, 4.47; N. 7.82 FAB MS 376.0~ (MH+) Hl NMR (CD30D, 500 Hz) â 2.67 (3H,s), 5.70 (2H,s), 6.9~ (H,d, J=16.7 Hz), 7.29 (H,d, J=16.7 Hz), 7.34 (H,m), 7.39-7.46 (4H,m) 7.57 (2H,d, J=7.5 Hz), 7.61-7.64 (4H,m) 7.79 (2H, d, J=9Hz), 7.86 (H,s) ppm.

ln vitro inhibition of ras farnesvl transferase Assays offarnesyl-protein transferase. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM
25 and Ras-CAIL) were prepared as described by Schaber et al., J. Biol.
Chem. 265:14701-14704 (1990), Pompliano, et ah, Biochemistry 31:3800 (1992) and Gibb~s et al., PNAS U.S.A. ~s6:6630-6634 (1989), respectively. Bovine FPTase was assayed in a volume of 100 ~1 cont~ining 100 mM N-(2-hydroxy ethyl) piperazine-N'-(2-ethane 30 sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM [3H]-farnesyl diphosphate ([3H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 ~g/ml FPTase at 31 ~C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol. Precipitates were collected onto CA 022~0231 1998-09-28 W O 97/36875 PCT~US97/OS383 filter-mats using a TomTec Mach Il cell harvestor, wa,shed with 100%
ethanol, dried and counted in an LKB ~-plate counter. The assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the [3H]-FPP was utilized during the reaction period. Purified 5 compounds were dis~solved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay. Percentage inhibition is measured by the amount of incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound.
Human FPTase was prepared a,s described by Omer et ah, Biochemistrv 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10 ,UM ZnCl2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 ~l of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
The compounds of the instant invention described in the above Example 1-31 were tested for inhibitory activity against human FPTase by the assay de,scribed above and were found to have IC50 of <50 ~M.

EXAMPLE ~3 In vivo ras farnesylation assay The cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21.
The assay is performed essentially as described in DeClue, J.E. et ah, Cancer Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75%
confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 37~C, the cells are labelled in 3 ml methionine-free DMEM supple-meted with 10% regular DMEM, 2% fetal bovine serum and 400 CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/0~383 mCi~35S]methionine (1000 Ci/mmol). After an additional 20 hour~, the cells are Iysed in 1 ml Iysis buffer (1 % NP40/20 mM HEPES, pH 7.5/5 mM MgC12/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the Iysates cleared by centrifugation at 100,000 x g for 45 min. Aliquots of Iysates cont~ining equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (Iysis buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et ah, J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at 4~C, 200 ml of a 25% suspension of protein A-Sepharose coated with rabbit anti rat IgG
is added for 45 min. The immunoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/l % Triton X-100Ø5% deoxycholate/0.1%/SDS/0.1 M NaCI) boiled in SDS-PAGE
sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to farnesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein.

In vivo ~rowth inhibition assay To deterrnine the biological consequences of FPTase inhibition, the effect of the compounds of the instant invention on the 25 anchorage-independent growth of Ratl cells transformed with either a v-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Raf and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation.
Rat 1 cells transformed with either v-ras, v-raf, or v-mos 30 are seeded at a density of 1 x 104 cells per plate (35 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's , CA 022~0231 1998-09-28 W O 97/36875 PCTrUS97/05383 medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layers contain 0.1% methanol or an appro-priate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay). The cells are fed 5 twice weekly with 0.5 ml of medium A containing 0.1% methanol or the concentration of the instant compound. Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made.

Claims (36)

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

wherein:

R1a and R1b are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-, R11C(O)O-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

R2, R3, R4 and R5 are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R11C(O)O-, R10 2N-C(NR10), CN, NO2, R1OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O, R11S(O)m-, R1OC(O)NR10, (R10)2NC(O)-, R10 2N-C(NR10), CN, R10C(0)-, N3, -N(R10)2, and R11OC(O)NR10-;

R6a, R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R11C(O)O-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O, R11S(O)m-, R11S(O)m NR10-, (R10)2NS(O)m-, R13C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R2, R3, R4, R5, R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R2, R3, R4, R5, R6a, R6b, R6C, R6d or R6e to the phenyl ring is through a substitutable heterocycle ring carbon;

R7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) ~SO2R11, g) N(R10)2 or h) C1-4 perfluoroalkyl;

R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, periluoroalkyl, F, Cl, Br, R10O-, R11S(o)m-, R10C(O)NR10, (R10)2NC(O)-, R102N-C(NR10), CN, No2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10o-, R11S(O)m-, R10C(O)NH-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, or R10OC(O)NH-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;

R9 is independently selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, halogen, R11O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3,-N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
R13 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2-trifluoroethyl, -CH2N(R10)2, benzyl and aryl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10 , -NR10C(O)-, O, -N(R10)-, -S(O)2N(R10)-, -N(R10)S(O)2- or S(O)m;

V is selected from:
a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a 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;
provided that when V is heterocycle, attachment of V to R8 and to A1 is through a substitutable ring carbon;

W is a heterocycle;
X is a bond, -CH=CH-, O, -C(=O)-, -C(O)NR7-, -NR7C(O)-, -C(O)O-, -OC(O)-, -C(O)NR7C(O)-, -S(O)2N(R10)-, -N(R10)S(O)2-or -S(=O)m-;

m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
q is 0, 1, 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1;
or a pharmaceutically acceptable salt thereof.
2. The compound according to Claim 1 of the formula A:

wherein:

R1a is independently selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F or C1-C6 alkyl;

R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O- and -N(R10)2;

R2, R3, R4 and R5 are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O , R11S(O)m-, R10C(O)NR10, (R10)2NC(O)-, R10 2N-C(NR10), CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl;

d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O, R11S(O)m-, R10C(O)NR10, (R10)2NC(O)-, R10 2N-C(NR10), CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

R6a, R6b, R6c, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl;
d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R11S(O)m NR10-, (RlO)2NS(O)m-, R13C(O)NR10, (R10)2NC(O)-, R10 2N-C(NR10), CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

any two of R6a R6b, R6C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R2, R3, R4, R5, R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R2 R3, R4, R5, R6a, R6b, R6C, R6d or R6e to the phenyl ring is through a substitutable heterocycle ring carbon;

R7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, aryl,sulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) ~SO2R11, g) N(R10)2 or h) C1-4 perfluoroalkyl;
R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;

R9 is independently selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R11o, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, CN, NO2, (R10)2N-C(NR10), R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or,substituted by C1-C6 perfluoroalkyl, F, Cl, R10O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, CN, (R10)2N -C(NR10), R10C(O)-, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
R13 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2-trifluoroethyl, -CH2N(R10)2, benzyl and aryl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;

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

provided that when V is heterocycle, attachment of V to R8 and to A1 is through a substitutable ring carbon;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or isoquinolinyl;

X is a bond, O, -C(=O)-, -CH=CH-, -C(O)NR7-, -NR7C(O)-, -S(O)2N(R10)-, -N(R10)S(O)2- or -S(=O)m-;

m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
q is 0, 1, 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1 ;
or a pharmaceutically acceptable salt thereof.
3. The compound according to Claim 1 of the formula B:

wherein:

R1a is independently selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F or C1-C6 alkyl;

R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O- and -N(R10)2;

R2 and R3 are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

R6a, R6b, R6c, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the sub.stituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R11S(O)mNR10-, (R10)2NS(O)m-, R13C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

any two of R6a, R6b, R6C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R2, R3, R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R2, R3, R6a, R6b, R6c, R6d or R6e to the phenyl ring is through a substitutable heterocycle ring carbon;

R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2NC(NR10), R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R10C(O)NR10, (R10~N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(~NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;

R9a and R9b are independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen;

R10 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
R13 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2-trifluoroethyl, -CH2N(R10)2, benzyl and aryl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, or S(O)m;

V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, 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;
provided that when V is heterocycle, attachment of V to R8 and to A1 is through a substitutable ring carbon;

X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, O or -C(=O)-;

m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4; and r is 0 to 5, provided that r is 0 when V is hydrogen;
or a pharmaceutically acceptable salt thereof.
4. The compound according to Claim 1 of the formula C:

wherein:

R1a is independently selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F or C1-C6 alkyl;

R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O- and -N(R10)2;

R2 and R3 are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O, R11S(O)m-, R10C(O)NR10, CN(R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

R6a R6b, R6c, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-, R10 2N-C(NR10), CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R11S(O)m NR10-, (R10)2NS(o)m-, R13C(O)NR10, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R2, R3, R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R2, R3, R6a, R6b, R6c, R6d or R6e to the phenyl ring is through a substitutable heterocycle ring carbon;

R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is through a Isubstitutable ring carbon;

R9a and R9b are independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen;
R10 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
R13 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2-trifluoroethyl, -CH2N(R10)2, benzyl and aryl;

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

V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, 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;
provided that when V is heterocycle, attachment of V to R8 and to A1 is through a substitutable ring carbon;

X is a bond, -CH=CH-, -C(O)NR10-, -NR1OC(O)-, O or -C(=O)-;

m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond, -NR10C(O)-, -NR10- or O; and r is 0 to 5, provided that r is 0 when V is hydrogen;

or a pharmaceutically acceptable salt thereof.
5. The compound according to Claim 3 of the formula D:

wherein:

R1a is independently selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl;

R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O-, or -N(R10)2;

R2 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O, R11S(O)m-, R1OC(O)NR10, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O, R11S(O)m-, R1OC(O)NR10, (R10)2NCO)-, R10 2N-C(NR10), CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

R3 is selected from H, halogen, C1-C6 alkyl and CF3;

R6a R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O, R11S(o)m, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O, R11S(O)m-, R10C(O)NR10, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R110C(O)-NR10;
any two of R6a R6b, R6c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R2, R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R2, R6a R6b, R6c, R6d or R6e to the phenyl ring is through a substitutable heterocycle ring carbon;
R8 is independently selected from:

a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, N02, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and C) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-, N(R10)2, or R11OC(O)NR10-; or provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;

R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A1 is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, O or -C(=O)-;

n is 0 or 1; provided that n is not 0 if A1 is a bond, O, -N(R10)-, or S(O)m;
m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4;
or the pharmaceutically acceptable salts thereof.
6. The compound according to Claim 4 of the formula E:

wherein:

R1a is independently selected from: hydrogen, R10O-, -N(R10)2, F, C3-C10 cycloalkyl or C1-C6 alkyl;

R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O-, or -N(R10)2;

R2 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

R3 is selected from H, halogen, C1-C6 alkyl and CF3;

R6a, R6b, R6c, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10 c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R2, R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R2, R6a, R6b, R6c, R6d or R6e to the phenyl ring is through a substitutable heterocycle ring carbon;

R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;

R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, O or -C(=O)-;

n is 0 or 1 ;
m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O;
or the pharmaceutically acceptable salts thereof.
7. The compound according to Claim 5 of the formula F:

wherein:
R1a is independently selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl;

R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2 or F, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, R10O-, or -N(R10)2;

R2 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)NR10-;

R3 is selected from H, halogen, CH3 and CF3;

R6a, R6b, R6c, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or provided that when R2, R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R2, R6a, R6b, R6c, R6d or R6e to the phenyl ring is through a substitutable heterocycle ring carbon;

R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, O or -C(=O)-;

m is 0, 1 or 2;and p is 0, 1, 2, 3 or 4;

or the pharmaceutically acceptable salts thereof.
8. The compound according to Claim 6 of the formula G:

wherein:

R1a is independently selected from: hydrogen, R10O-, -N(R10)2, F, C3-C10 cycloalkyl or C1-C6 alkyl;

R1b is independently selected from:
a) hydrogen, b) aryl, heterocycle or C3-C10 cycloalkyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O-, or -N(R10)2;

R2 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;

R3 is selected from H, halogen, CH3 and CF3;

R6a, R6b, R6c, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

provided that when R2, R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R2, R6a, R6b, R6c, R6d or R6e to the phenyl ring is through a substitutable heterocycle ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;

R10 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A1 is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;

m is 0, 1 or 2; and n is 0 or 1;
or the pharmaceutically acceptable salts thereof.
9. A compound which inhibits farnesyl-protein transferase which is:

1-(4-Cyanobenzyl)-5-(4'-phenylbenzamido)ethyl-imidazole 1-(2'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(4-Biphenylethyl)-5-(4-cyanobenzyl)imidazole 1-(2'-Bromo-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'-Trifluoromethoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(4-(3',5'-dichloro)-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'-Methoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(3-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(4-(3',5'-Bis-trifluoromethyl)-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)-4-methylimidazole 1-(4-Biphenylmethyl)-5-(4-cyanophenyloxy)-imidazole 5-(4-Cyanophenyloxy)-1-(2'-methyl-4-biphenylmethyl)-imidazole 5-(4-Biphenyloxy)-1-(4-cyanobenzyl)-imidazole 5-(2'-Methyl-4-biphenoxy)-1-(4-cyanobenzyl)-imidazole 5-(4-(3',5'-dichloro)biphenylmethyl)-1-(4-cyanobenzyl)imidazole 1-(4-biphenylmethyl)-5-(1-(R,S)-acetoxy-1-(4-cyanophenyl)methylimidazole 1-(4-Biphenylmethyl)-5-(1-(R,S)-hydroxy-1-(4-cyanophenyl) methylimidazole 1-(4-Biphenylmethyl)-5-(1-(R,S)-amino-1-(4-cyanophenyl) methylimidazole 1-(4-biphenylmethyl)-5-(1-(R,S)-methoxy-1-(4-cyanophenyl)-methylimidazole 1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(3-fluoro-4-biphenyl)-methyl)-imidazole 1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(3-biphenyl)methyl-imidazole 5-(2-[1,1'-Biphenyl]vinylene)-1-(4-cyanobenzyl)imidazole 1-(4-Biphenylmethyl)-5-(4-bromophenyloxy)-imidazole 1-(3'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(4'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(3'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(4'-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(3'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(4'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'3'-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'4'-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'5'-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(3'-Trifluoromethoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'-Fluoro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(4-(2'-Trifluoromethylphenyl)-2-Chlorophenylmethyl)-5-(4-cyanobenzyl) imidazole 1-{1-(4-(2'-trifluoromethylphenyl)phenyl)ethyl}-5-(4-cyanobenzyl) imidazole 1-(2'-Trifluoromethyl-4-biphenylpropyl)-5-(4-cyanobenzyl) imidazole 1-(2'-N-t-Butoxycarbonylamino-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'-Aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'-Acetylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'-Methylsulfonylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'-Ethylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'-Phenylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'-Glycinylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole 1-(2'-Methyl-4-biphenylmethyl)-2-chloro-5-(4-cyanobenzyl) imidazole 1-(2'-Methyl-4-biphenylmethyl)-4-chloro 5-(4-cyanobenzyl) imidazole 1-(3'-Chloro-2-methyl-4-biphenylmethyl)-4-(4-cyanobenzyl)imidazole 1-(3'-Chloro-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(3'-Trifluoromethyl-2-methyl-4-biphenylmethyl)-4-(4-cyanobenzyl) imidazole 1-(3'-Trifluoromethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(3'-Methoxy-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2'-Chloro-4'-fluoro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2'-Ethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2'-(2-Propyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2'-(2-Methyl-2-propyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2'-Ethyl-4-biphenylmethyl)-5-(4-(1H-tetrazol-5-yl)) benzyl)imidazole 1-[1-(4-Cyanobenzyl)imidazol-5-ylmethoxy]-4-(2'-methylphenyl)-2-(3-N-phthalimido-1-propyl)benzene 1-(3',5'-Ditrifluoromethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(3',5'-Chloro-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(3',5'-Dimethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(3-(N-Boc-aminomethyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)-imidazole 1-(3-Aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(4-Cyanobenzyl)-2-methyl-5-(2'-methylbiphenyl-4-yloxy)imidazole 5-(4-Cyanobenzyl)-1-(3-cyano-2'-trifluoromethylbiphenyl-4-ylmethyl)-imidazole 2-Amino-5-(biphenyl-4-ylmethyl)-1-(4-cyanobenzyl)imidazole 2-Amino-1-(biphenyl-4-ylmethyl)-5-(4-cyanobenzyl)imidazole 1-(3-Butylbiphenyl-4-ylmethyl)-5-(4-cyanobenzyl)-imidazole 1-(3-Propylbiphenyl-4-ylmethyl)-5-(4-cyanobenzyl)-imidazole 1-(4-Biphenylmethyl)-4-(4-cyanobenzyl-2-methylimidazole 1-(4-Cyanobenzyl)-5-[(3-fluoro-4-biphenyl)methyl]imidazole 1-(4-Cyanobenzyl)-5-[1-(4-biphenyl)-1-hydroxy]ethyl-2-methylimidazole 1-(4-Cyanobenzyl)-5-(4-biphenylmethyl)-2-methylimidazole 1-(4-Cyanobenzyl)-5-[1-(4-biphenyl)]ethyl-2-methyl imidazole 1-(4-Cyanobenzyl-5-[1-(4-biphenyl)]vinylidene-2-methylimidazole or 1-(4-Cyanobenzyl)-5-[2-(4-biphenyl)]vinylene-2-methylimidazole or a pharmaceutically acceptable salt or optical isomer thereof.
10. The compound according to Claim 9 which is:

1-(2'-Methoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole or a pharmaceutically acceptable salt or optical isomer thereof.
11. The compound according to Claim 9 which is:

1-(2'-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole or a pharmaceutically acceptable salt or optical isomer thereof.
12. The compound according to Claim 9 which is:

1-(4-(3',5'-dichloro)-biphenylmethyl)-5-(4-cyanobenzyl) imidazole or a pharmaceutically acceptable salt or optical isomer thereof.
13. The compound according to Claim 9 which is:

1-(4'-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole or a pharmaceutically acceptable salt or optical isomer thereof.
14. The compound according to Claim 9 which is:

5-(2'-Methyl-4-biphenoxy)-1-(4-cyanobenzyl)-imidazole or a pharmaceutically acceptable salt or optical isomer thereof.
15. The compound according to Claim 9 which is:

1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(3-fluoro-4-biphenyl)-methyl)-imidazole or a pharmaceutically acceptable salt or optical isomer thereof.
16. The compound according to Claim 9 which is:

1-(2',5'-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole or a pharmaceutically acceptable salt or optical isomer thereof.
17. The compound according to Claim 9 which is:

1-(3'-Methoxy-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole or a pharmaceutically acceptable salt or optical isomer thereof.
18. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 1.
19. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 3.
20. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 4.
21. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 9.
22. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 18.
23. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 19.
24. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 20.
25. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 21.
26. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 18.
27. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 19.
28. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 20.
29. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 21.
30. A method for treating neurofibromin benign proliferative disorder which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 18.
31. A method for treating blindness related to retinal vascularization which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 18.
32. A method for treating infections from hepatitis delta and related viruses which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 18.
33. A method for preventing restenosis which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 18.
34. A method for treating polycystic kidney disease which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 18.
35. A pharmaceutical composition made by combining the compound of Claim 1 and a pharmaceutically acceptable carrier.
36. A process for making a pharmaceutical composition comprising combining a compound of Claim 1 and a pharmaceutically acceptable carrier.
CA002250231A 1996-04-03 1997-04-01 Inhibitors of farnesyl-protein transferase Abandoned CA2250231A1 (en)

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