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AU9781098A - Inhibitors of prenyl-protein transferase - Google Patents

Inhibitors of prenyl-protein transferase Download PDF

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Publication number
AU9781098A
AU9781098A AU97810/98A AU9781098A AU9781098A AU 9781098 A AU9781098 A AU 9781098A AU 97810/98 A AU97810/98 A AU 97810/98A AU 9781098 A AU9781098 A AU 9781098A AU 9781098 A AU9781098 A AU 9781098A
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substituted
alkyl
unsubstituted
aryl
hydrogen
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S. Jane Desolms
William C. Lumma
Anthony W. Shaw
John T. Sisko
Thomas J. Tucker
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Merck and Co Inc
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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Description

WO 99/18096 PCT/US98/20525 TITLE OF THE INVENTION INHIBITORS OF PRENYL-PROTEIN TRANSFERASE BACKGROUND OF THE INVENTION 5 The Ras proteins (Ha-Ras, 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. 10 Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTP bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and 15 D.M. Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively 20 transmit a growth stimulatory signal. Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus 25 contains a sequence motif termed a "CAAX" or "Cys-Aaal-Aaa 2 -Xaa" box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)). Depend ing on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein 30 transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386 (1992); W.R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237 (1992)). The Ras protein is one of several proteins that are known to undergo post-translational farnesyla -1- WO 99/18096 PCT/US98/20525 tion. 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 5 also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above. Inhibition of farnesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify 10 other aspects of their transformed phenotype. It has also been demon strated 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 15 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). 20 Indirect inhibition of famrnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck & Co., Rahway, NJ) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including 25 farnesyl pyrophosphate. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famrnesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci 30 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 required dose of a general inhibitor -2- WO 99/18096 PCT/US98/20525 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 5 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 containing molecules that 10 are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141,851, University 15 of Texas; N.E. Kohl et 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 20 inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable. Recently, certain tricyclic compounds which optionally incorporate a piperidine moiety have been disclosed to be inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516). Imidazole 25 containing compounds which are claimed to be inhibitors of farnesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 Al). WO 95/09001 discloses imidazolyl containing compounds that are inhibitors of farnesyl protein transferase. It has recently been reported that farnesyl-protein 30 transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7-112930). It is, therefore, an object of this invention to develop -3- WO 99/18096 PCT/US98/20525 low molecular weight compounds that will inhibit a prenyl-protein transferase and thus, the post-translational prenylation 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 this invention. SUMMARY OF THE INVENTION The present invention comprises bicyclic compounds which inhibit a prenyl-protein transferase. Further contained in 10 this invention are chemotherapeutic compositions containing these prenyl transferase inhibitors and methods for their production. The compounds of this invention are illustrated by the formula A:
R
6 a-e
R
3
A
3 Y
(R
8 )r (R 9 )q Q V - A' A2(2)A CR12) n W - (CR 2 2 )p - X-(CR22)p R
SR
4 15 A DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention are useful in the inhibition of prenyl-protein transferases and the prenylation of the oncogene 20 protein Ras. In a first embodiment of this invention, the inhibitors of prenyl-protein transferase are illustrated by the formula A: -4- WO 99/18096 PCT/US98/20525
R
6 a-e
R
3
A
3 Y
(R
8 )r
(R
9 )q Q V - A'(CR2)nA2(CR'2) n - W - (CR 2 2 )p - (CR22)p R 5 t R 4 A wherein: 5 Q is a 6-membered heterocyclic ring which comprises a nitrogen atom and 0-2 additional nitrogen atoms and having the remaining atoms being carbon atoms, and which also optionally comprises a carbonyl, thiocarbonyl, -C(=NR1 3
)
or sulfonyl moiety adjacent to a nitrogen atom, provided 10 that Q is not piperazine, piperazinone, diketopiperazine, piperidine, piperidinone, diketopiperidine or triketopiperidine; Y is a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 15 3 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein Y is attached to A 3 through a carbon atom; R1 and R 2 are independently selected from: 20 a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-, R 1 1 S(O)m-, R10C(0)NR 10 -, Rl 1 C(0)0-, (R 10 )2NC(0)-, R 10 2N-C(NR10)-, CN, NO2, R10OC(O)-, N3, -N(R 10 )2, or R 11
OC(O)NR
10 -, 25 c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected -5- WO 99/18096 PCT/US98/20525 from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
10 0-, R 1 S(O)m-, R 10
C(O)NR
1 0-, (R 10 )2NC(O)-,
R
10 2N-C(NRO10)-, CN, RO10C(O)-, N3, -N(R 10 )2, and 5 R 1 1 0oC(O)-NR10-;
R
3 , R 4 and R 5 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or 10 substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, R 11S(O)m-, R10C(O)NR10-, (R 10 )2NC(O)-, R 11C(O)O-,
R
10 2N-C(NR 1 0)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 1 1
OC(O)NR
10 -, 15 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, 20 R 12 0-, R 1 1 S(O)m-, R 10
C(O)NR
10 -, (R 10 )2NC(O)-,
R
10 2N-C(NRO10)-, CN, R 10 C(O)-, N3, -N(R 1 0 )2, and
R
1 1OC(O)-NR10-;
R
6 a, R6b, R 6 C, R6d and R 6 e are independently selected from: 25 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-,
R
1 1 S(O)m-, R 10 C(O)NR10-, (R10)2NC(O)-, R11C(O)O-, 30 R 10 2N-C(NR10)-, CN, NO2, R10C(O)-, (R 10 )2NS(O)2-,
R
1 1 S(O)mNR 10 -, N3, -N(R 10 )2, or R 1 1
OC(O)NR
10 -, c) unsubstituted C1-C6 alkyl, -6- WO 99/18096 PCT/US98/20525 d) substituted C1-C6 alkyl wherein the substituent on the substituted C 1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 5 R 12 0-, R 1 1 S(O)m-, R 10
C(O)NR
10 -, (R10)2NC(O)-,
(R
1 0)2NS(O)2-, R 1 1 S(O)mNR 10 -, R 10 2N-C(NR 1 0)-, CN, R10C(O)-, N3, -N(R 10 )2, and R 1 1
OC(O)-NR
10 -; or any two of R 6 a, R6b, R 6 C, R6d and R 6 e on adjacent carbon atoms are 10 combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
R
7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or 15 substituted with: a) C1-4 alkoxy, b) aryl or heterocycle, c) " R 0 O d) SO 2
R
11 e) N(R 10 )2 or 20 f) CI1-4 perfluoroalkyl; R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, 25 C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-, RO10C(O)NR10-, (R 10 )2NC(O)-, (R 10 )2NS(O)2-,
R
1 1 S(O)mNR 10 -, R 10 2N-C(NR 10 )-, CN, NO2, R 10 C(O)-, N3, -N(R 10 )2, or R 11 OC(0)NR 10 -, and -7- WO 99/18096 PCT/US98/20525 c) C 1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-,
R
1 1 S(O)m-, R10C(O)NH-, (R 10 )2NC(O)-, (R 10 )2NS(O)2-, 5 R 1 1 S(O)mNR 10 -, R 10 2N-C(NR 10 )-, CN, R10C(O)-, N3,
-N(R
10 )2, or R10OC(O)NH-; R9 is independently selected from: a) hydrogen, 10 b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R1 0 0-, R 1 1 S(O)m-, R10C(O)NR10-, (R 10 )2NC(O)-,
R
10 2N-C(NR10)-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, or
R
1 1
OC(O)NR
10 -, and c) C 1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, 15 F, Cl, Br, R 10 0-, R 1 1 S(O)m-, R 10 C(O)NR10-,
(R
10 )2NC(O)-, R 10 2N-C(NR10)-, CN, RO10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-;
R
10 is independently selected from hydrogen, C 1 -C6 alkyl, benzyl, 20 2,2,2-trifluoroethyl and aryl;
R
1 1 is independently selected from C1-C6 alkyl and aryl;
R
12 is independently selected from hydrogen, C 1-C6 alkyl, C1 -C6 25 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; 30 R 13 is selected from hydrogen, C1-C6 alkyl, cyano, C1-C6 alkylsulfonyl and C 1-C6 acyl;
A
1 and A 2 are independently selected from: a bond, -CH=CH-, -8- WO 99/18096 PCT/US98/20525 -C-C-, -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R 10 )-, -S(O)2N(R 10 )-, -N(RO10)S(O)2-, or S(O)m;
A
3 is selected from: -CH2-, -CH 2
CH
2 -, -C--C-, O, -N(R10)-, S(O)m, 5 -C(O)NRO 10 -, -NRO10C(0)-, - CH2C(O)NRO10-, - CH2NR10C(O)-,
-C(O)NR
10 CH2-, -NR 10 C(0)CH2-, -CH20-, -CH2N(R 10 )_, -CH2S(0)m-, -OCH2-, -N(R 10 )CH2- and -S(0)mCH2-; V is selected from: 10 a) hydrogen, b) heterocycle, c) aryl, d) C 1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and 15 e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; 20 X is a bond, -CH=CH-, O, -C(=0)-, -C(O)NR 7 -, -NR 7 C(O)-, -C(0)O-, -OC(0)-, -C(O)NR 7 C(O)-, -NR 7 -, -S(O)2N(R 10 )-, -N(R 10 )S(O)2- or-S(=O)m-; 25 mis 0, 1 or2; n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; qis 0, 1, 2 or3; r is 0 to 5, provided that r is 0 when V is hydrogen; and 30 t is 0 or 1; or a pharmaceutically acceptable salt thereof. -9- WO 99/18096 PCT/US98/20525 In a preferred embodiment of this invention, the inhibitors of prenyl-protein transferase are illustrated by the formula A:
R
6 a-e
R
3
A
3 Y
(R
8 )r R 9 Q V - A 1
'(CR
1
'
2 )nA 2
(CR
1 2
)
n - W - (CR 2 2 )p - X -(CR 2 2 )p R t R 4 A 5 wherein: Q is a 6-membered heterocyclic ring which comprises a nitrogen atom and 0-2 additional nitrogen atoms and having 10 the remaining atoms being carbon atoms, and which also optionally comprises a carbonyl, thiocarbonyl, -C(=NR1 3
)
or sulfonyl moiety adjacent to a nitrogen atom, provided that Q is not piperazine, piperazinone, diketopiperazine, piperidine, piperidinone, diketopiperidine or 15 triketopiperidine; Y is a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein Y is attached to A 3 through a 20 carbon atom; R1 and R 2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, - 10 - WO 99/18096 PCT/US98/20525 C2-C6 alkynyl, R 10 0-, R 1 1 S(O)m-, R 10 C(O)NR10-,
R
1 1C(O)O-, (R 10 )2NC(O)-, R 10 2N-C(NR10)-, CN, NO2, R10OC(O)-, N3, -N(R 10 )2, or R 1 OC(O)NR10-, c) unsubstituted or substituted C 1-C6 alkyl wherein the 5 substituent on the substituted C 1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
10 0-, R 1 1 S(O)m-, R 10
C(O)NR
10 -, (R 10 )2NC(O)-,
R
10 2N-C(NRO10)-, CN, R10C(O)-, N3, -N(R 10 )2, and 10 R11OC(O)-NR10-;
R
3 , R 4 and R 5 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or 15 substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-,
R
1 1 S(O)m-, R10C(O)NR 10 -, (R 10 )2NC(O)-, R 1 1 C(O)O-,
R
10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R110C(O)NR10-, 20 c) unsubstituted C1-C6 alkyl, d) substituted C 1-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, 25 R 12 0-, R 1 1 S(O)m-, R 10
C(O)NR
10 -, (R 10 )2NC(O)-,
R
10 2N-C(NR10)-, CN, RO10C(O)-, N3, -N(R 10 )2, and
R
1 1OC(O)-NR10-;
R
6 a, R6b, R 6 C, R6d and R 6 e are independently selected from: 30 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, CI1-C6 perfluoroalkyl, R 12 0-, - 11 - WO 99/18096 PCT/US98/20525
R
1 1 S(O)m-, R 10 C(O)NR10-, (R 10 )2NC(O)-, R 1 1 C(O)O-,
R
10 2N-C(NR 10 )-, CN, NO2, RO10C(O)-, (R 10 )2NS(O)2-,
R
1 1 S(O)mNR 10 -, N3, -N(R 10 )2, or R11 OC(O)NR10-, c) unsubstituted C 1-C6 alkyl, 5 d) substituted C1 -C6 alkyl wherein the substituent on the substituted C 1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
12 0-, R 1 1 S(O)m-, R 10
C(O)NR
10 -, (R 10 )2NC(O)-, 10 (R 10 )2NS(O)2-, R 1 1 S(O)mNR 10 -, R 10 2N-C(NR 10 )-, CN, RO10C(O)-, N3, -N(R 10 )2, and R 1 1 0C(O)-NR 10 -; or any two of R 6 a, R6b, R 6 C, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, 15 -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
R
7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: 20 a) C1-4 alkoxy, b) aryl or heterocycle, c) ""R 0 d) - SO 2 R11 e) N(R 1 0 )2 or f) C1-4 perfluoroalkyl; 25
R
8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 30 perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-, - 12 - WO 99/18096 PCT/US98/20525 R10OC(O)NR 10 -, (R 10 )2NC(O)-, (R 10 )2NS(O)2-,
R
1 1 S(O)mNR 10 -, R 10 2N-C(NR 10 )-, CN, NO2, R 10 C(O)-, N3, -N(R 10 )2, or R 1 1
OC(O)NR
10 -, and c) Ci1-C6 alkyl unsubstituted or substituted by aryl, 5 cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-,
R
1 1 S(O)m-, R10C(O)NH-, (R 10 )2NC(O)-, (R10)2NS(O)2-,
R
1 1 S(O)mNR 10 -, R 10 2N-C(NR 1 0)-, CN, R 10 C(O)-, N3, -N(R10)2, or R10OC(O)NH-; 10
R
9 is independently selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br,
R
10 0-, R 11S(O)m-, R 10 C(O)NR10-, (R10)2NC(O)-, 15 R 10 2N-C(NRO10)-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, or
R
1 1
OC(O)NRO
10 -, and c) Ci1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-, R 10
C(O)NR
10 _,
(R
10 )2NC(O)-, R 10 2N-C(NR10)-, CN, RO10C(O)-, N3, 20 -N(R 10 )2, or R11OC(O)NR10-;
R
10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; 25 R 1 1 is independently selected from C1 -C6 alkyl and aryl;
R
12 is independently selected from hydrogen, C 1-C6 alkyl, C 1-C6 aralkyl, C 1-C6 substituted aralkyl, C1 -C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, 30 heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; - 13 - WO 99/18096 PCT/US98/20525
R
13 is selected from hydrogen, C1-C6 alkyl, cyano, C1-C6 alkylsulfonyl and C1-C6 acyl;
A
1 and A 2 are independently selected from: a bond, -CH=CH-, 5 -CEC-, -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R10)-, -S(O)2N(R 10 )-, -N(R 10 )S(O)2-, or S(O)m;
A
3 is selected from: -CH2-, O, -N(R10)-, S(O)m, -C(O)NR 10 -, -NR10C(O)-, - CH2C(O)NR 1 0-, - CH2NR10C(O)- , -C(O)NR 10 CH2-, 10 -NR 10 C(O)CH2-, -CH20-, -CH2N(R 10 )-, CH2S(0)m-, -OCH2-,
-N(R
10 )CH2- and -S(0)mCH2-; V is selected from: a) hydrogen, 15 b) heterocycle, c) aryl, d) C1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, 20 provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; 25 X is a bond, -CH=CH-, O, -C(=0)-, -C(0)NR 7 -, -NR 7 C(O)-, -C(0)O-, -OC(0)-, -C(O)NR 7 C(O)-, -NR 7 -, -S(0)2N(R 10 )-, -N(R 10 )S(0)2- or -S(=O)m-; m is 0, 1 or 2; 30 n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; qis 0, 1, 2 or3; r is 0 to 5, provided that r is 0 when V is hydrogen; and - 14 - WO 99/18096 PCT/US98/20525 t is 0 or 1; or a pharmaceutically acceptable salt thereof. Another preferred embodiment of the compounds of this 5 invention is illustrated by the following formula A: R6a-e
R
3
A
3 Y (R )r Q 2 R -(R V - A 1
(CR
1 2 )nA 2
(CR
1 2 )n - W - (CR 2 2 )p - X -(CR22p R t R 4 A wherein: Q is a 6-membered heterocyclic ring which comprises a 10 nitrogen atom and 0-2 additional nitrogen atoms and having the remaining atoms being carbon atoms, and which also optionally comprises a carbonyl, thiocarbonyl, -C(=NR1 3
)
or sulfonyl moiety adjacent to a nitrogen atom, provided that Q is not piperazine, piperazinone, diketopiperazine, 15 piperidine, piperidinone, diketopiperidine or triketopiperidine; Y is selected from: phenyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thiazolyl, isothiazolyl, tetrahydrofuryl, piperdinyl, 20 thiazolidinyl, piperazinyl and tetrahydrothienyl; R1 is independently selected from: hydrogen, C3-CO10 cycloalkyl, R 10 0-,
-N(R
10 )2, F or C1-C6 alkyl; 25 - 15 - WO 99/18096 PCT/US98/20525
R
2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 10 0-, -N(R 10 )2, F or C2-C6 alkenyl, 5 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, R 10 0- and -N(R 10 )2; 10 R 3 , R 4 and R 5 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, 15 R 12 0-, R 1 1 S(O)m-, R10C(O)NR 10 -, (R 10 )2NC(O)-,
R
10 2N-C(NR 1 0)-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, or R 1 1 0C(O)NR 10 -, c) unsubstituted C1-C6 alkyl; d) substituted C1-C6 alkyl wherein the substituent on the 20 substituted C 1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
12 0-, R 1 1 S(O)m-, R 10 C(O)NR10-, (R 10 )2NC(O)-,
R
10 2N-C(NR10)-, CN, R 10 C(O)-, N3, -N(R 10 )2, and 25 R 1 1
OC(O)-NR
10 -;
R
6 a, R6b, R 6 c, R6d and R 6 e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or 30 substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R
12 0-, R 1 1 S(O)m-, R10C(O)NR1 0 -, (R 10 )2NC(O)-, - 16 - WO 99/18096 PCT/US98/20525
(R
1 0)2NS(O)2-, R 1 1 S(O)mNR 10 -, R 10 2N-C(NR 10 )-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, or R 1 lOC(O)NR10-, c) unsubstituted C1-C6 alkyl; d) substituted C1-C6 alkyl wherein the substituent on the 5 substituted CI1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
12 0-, R 1 1 S(O)m-, R 10
C(O)NR
10 -, (R 10 )2NC(O)-,
(R
10 )2NC(O)-, (R 10 )2NS(O)2-, R 11 S(O)mNR 10 -, 10 R 10 2N-C(NR10)-, CN, RO10C(O)-, N3, -N(R 10 )2, and
R
1 1
OC(O)-NRO
10 -; or any two of R 6 a, R6b, R 6 C, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, 15 -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
R
7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: 20 a) C1-4 alkoxy, b) aryl or heterocycle, c) "" R 0 d) - SO 2
R
1 e) N(R 10 )2 or f) C1-4 perfluoroalkyl; 25 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 30 perfluoroalkyl, F, Cl, R 10 0-, R 10
C(O)NR
10 -, - 17 - WO 99/18096 PCT/US98/20525
(R
10 )2NC(O)-, CN, NO2, (R 10 )2N-C(NRO10)-, RO10C(O)-,
(R
10 )2NS(O)2-, R 1 1 S(O)mNR 10 -, -N(R10)2, or
R
1 1
OC(O)NR
10 -, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, 5 R 10 0-, R10C(O)NR10-, (R 10 )2N-C(NR10)-, RO10C(O)-, -N(R10)2, or R11 OC(O)NR10-;
R
9 is selected from: a) hydrogen, 10 b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 10 0-, R 1 1 S(O)m-, R10C(O)NR10-, (R 10 )2NC(O)-, CN, NO2, (R 10 )2N-C(NR10)-, RO10C(O)-, -N(R 10 )2, or
R
1 1OC(O)NRO10-, and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 15 perfluoroalkyl, F, Cl, R 10 0-, R 1 1 S(O)m-, R 10 C(O)NR10-, (R1 0 )2NC(O)-, CN, (R'10)2N-C(NR 10 )-, R 10C(O)-, -N(R10)2, or R 1 1
OC(O)NR
10 -;
R
10 is independently selected from hydrogen, C1 -C6 alkyl, benzyl, 20 2,2,2-trifluoroethyl and aryl;
R
1 1 is independently selected from C1-C6 alkyl and aryl;
R
12 is independently selected from hydrogen, C 1-C6 alkyl, C1-C6 25 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; 30 A 1 and A 2 are independently selected from: a bond, -CH=CH-, -C--C-, -C(O)-, -C(O)NRO 10 -, O, -N(RO10)-, or S(O)m;
A
3 is selected from: -CH2-, O, -N(RO10)-, S(O)m, -C(0)NR 10 -, - 18 - WO 99/18096 PCT/US98/20525 -NR 10OC(O)-, -CH2C(O)NR 10 -, -CH2NR 10C(O)-, -C(O)NR 10CH2-,
-NR
10 C(O)CH2-, -CH20-, -CH2N(R 10 )-, -CH2S(O)m-, -OCH2-,
-N(R
10 )CH2- and -S(O)mCH2-; 5 V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, oxazolyl, indolyl, quinolinyl, 10 isoquinolinyl, triazolyl and thienyl, c) aryl, d) C 1-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 15 provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, oxazolyl, indolyl, 20 quinolinyl, triazolyl or isoquinolinyl; X is a bond, O, -C(=0)-, -CH=CH-, -C(O)NR 7 -, -NR 7 C(0)-, -NR 7 -, -S(O)2N(R 10 )-, -N(R10)S(O)2- or -S(=O)m-; 25 mis 0, 1 or2; n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; qis 0, 1, 2 or3; r is 0 to 5, provided that r is 0 when V is hydrogen; and 30 t is 0 or 1; or a pharmaceutically acceptable salt thereof. A preferred embodiment of the compounds of this invention are illustrated by the formula B: - 19 - WO 99/18096 PCT/US98/20525 R6a-e
(R
8 )r R9a R3 A 3 V- A'(CR 2 )nA2(CR 2 N N B (CR 2 2 )P-X R 5
R
4 wherein: Q is a 6-membered heterocyclic ring which comprises a 5 nitrogen atom and 0-2 additional nitrogen atoms and having the remaining atoms being carbon atoms, and which also optionally comprises a carbonyl, thiocarbonyl, -C(=NR1 3
)
or sulfonyl moiety adjacent to a nitrogen atom, provided that Q is not piperazine, piperazinone, diketopiperazine, 10 piperidine, piperidinone, diketopiperidine or triketopiperidine; Y is selected from: phenyl, cyclohexyl and pyridyl; 15 R1 is selected from: hydrogen, C3-C10 cycloalkyl, R 10 0-, -N(R 10 )2, F or C1-C6 alkyl;
R
2 is independently selected from: a) hydrogen, 20 b) aryl, heterocycle, C3-C10 cycloalkyl, R 10 0-, -N(R 10 )2, F or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C 1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 25 cycloalkyl, C2-C6 alkenyl, R 10 0- and -N(R 10 )2;
R
3 and R 4 are independently selected from: - 20 - WO 99/18096 PCT/US98/20525 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, 5 R 12 0-, R 1 1 S(O)m-, R 10
C(O)NR
10 -, (R 10 )2NC(O)-,
R
10 2N-C(NR10)-, CN, NO2, R 10 C(O)-, N3, -N(R 10 )2, or R 1 1OC(O)NR10-, c) unsubstituted C 1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the 10 substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
12 0-, R 1 1 S(O)m-, R 10
C(O)NR
10 -, (R 10 )2NC(O)-,
R
10 2N-C(NRO10)-, CN, R 10 C(O)-, N3, -N(R 10 )2, and 15 R 1 1 0C(O)-NR10-;
R
6 a, R6b, R 6 c, R6d and R 6 e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or 20 substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-,
R
1 1 S(O)m-, R 10
C(O)NR
10 -, (R 10 )2NC(O)-,
(R
10 )2NS(O)2-, R11S(O)mNR 10 -, R 10 2N-C(NR 10 )-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, or R 1 lOC(O)NR10-, 25 c) unsubstituted C1-C6 alkyl, d) substituted C 1-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, R 12 0-, 30 R 1 1S(O)m-, R 10
C(O)NR
10 -, (R 10 )2NC(O)-,
(R
10 )2NS(O)2-, R 1 1 S(O)mNR 10 -, R 10 2N-C(NR 10 )-, CN, RlOC(O)-, N3, -N(R 10 )2, and R11 OC(O)-NRO10-; or - 21 - WO 99/18096 PCT/US98/20525 any two of R6a, R6b, R 6 C, 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-; 5 R 8 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, R 10 0-, R10C(O)NR10-, 10 (R10)2NC(O)-, (R 10 )2NS(O)2-, R 1 1 S(O)mNR 10 -, CN, NO2, (R 10 )2N-C(NR10)-, R10C(O)-, -N(RO10)2, or
R
1 1
OC(O)NRO
10 -, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 0-,
R
1 0C(O)NR10-, (R 10 )2N-C(NR10)-, (R 10 )2NS(O)2-, 15 R1 1 S(O)mNR 10 -, R 1 0C(O)-, -N(R 10 )2, or
R
1 1 0C(O)NR10-; R9a and R9b are independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen; 20
R
10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R
11 is independently selected from C 1-C6 alkyl and aryl; 25
R
12 is independently selected from hydrogen, C1-C6 alkyl, C1 -C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C 1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Ci1-C6 perfluoroalkyl, 30 2-aminoethyl and 2,2,2-trifluoroethyl;
A
1 and A 2 are independently selected from: a bond, -CH=CH-, -C-C-, -C(O)-, -C(O)NRO 10 -, O, -N(R10)-, or S(O)m; - 22 - WO 99/18096 PCT/US98/20525
A
3 is selected from: -CH2-, O, -N(RO10)-, - C(O)NR10-,
-C(O)NR
10 CH2-, -CH2C(O)NR10-, -CH20-, -OCH2- or S(O)m; 5 V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, pyridonyl, 2 oxopiperidinyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, 10 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 15 provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; X is a bond, -CH=CH-, -C(O)NR 10 -, -NRO10C(0)-, -NR 1 0-, O or -C(=O)-; 20 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; 25 or a pharmaceutically acceptable salt thereof. Another preferred embodiment of the compounds of this invention are illustrated by the formula C: - 23 - WO 99/18096 PCT/US98/20525
R
6 a-e (R )r
R
3
A
3 Y (I r N R 9 a V -A' (CR 2 )nA2(CR' 2 )n Q R9b (CR 2 2 )- *5 C R 5
R
4 wherein: Q is a 6-membered heterocyclic ring which comprises a 5 nitrogen atom and 0-2 additional nitrogen atoms and having the remaining atoms being carbon atoms, and which also optionally comprises a carbonyl, thiocarbonyl, -C(=NR1 3
)
or sulfonyl moiety adjacent to a nitrogen atom, provided that Q is not piperazine, piperazinone, diketopiperazine, 10 piperidine, piperidinone, diketopiperidine or triketopiperidine; Y is selected from: phenyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thiazolyl, isothiazolyl, tetrahydrofuryl, piperdinyl, thiazolidinyl, 15 piperazinyl and tetrahydrothiophenyl; R1 is selected from: hydrogen, C3-C10 cycloalkyl, R 10 0-, -N(R 10 )2, F or C1-C6 alkyl; 20 R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 10 0-, -N(R 10 )2, F or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the 25 substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-CO10 cycloalkyl, C2-C6 alkenyl, R 10 0- and -N(R 10 )2; - 24 - WO 99/18096 PCT/US98/20525
R
3 and R 4 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or 5 substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R
12 0-, R 1 1 S(O)m-, R10C(O)NR 10 -, CN(R10)2NC(O)-,
R
10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 1 1 0C(O)NR 10 -, 10 c) unsubstituted C 1-C6 alkyl, d) substituted C 1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-CO10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 15 R 12 0-, R 1 1 S(O)m-, R 10
C(O)NR
10 -, (R 10 )2NC(O)-,
R
10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R 10 )2, and
R
1 1 OC(O)-NR10-;
R
6 a, R6b, R 6 C, R6d and R 6 e are independently selected from: 20 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, RlS(O)m-, R 10 C(O)NR10-, (R 10 )2NC(O)-, 25 R 1 1 S(O)2NR 10 -, (R 10 )2NS(O)2-, R 10 2N-C(NR10)-, CN, NO2, RO10C(O)-, N3, -N(R 10 )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 30 substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, - 25 - WO 99/18096 PCT/US98/20525
R
12 0-, R 1 1 S(O)m-, R 10
C(O)NR
10 -, (R 10 )2NC(O)-, Rl'S(O)2NR 10 -, (R 10 )2NS(O)2-, R 10 2N-C(NRO10)-, CN,
R
1 0C(O)-, N3, -N(R 10 )2, and R11OC(O)-NR10-; or 5 any two of R 6 a, R6b, R 6 C, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
R
8 is independently selected from: 10 a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 10 0-, RO10C(O)NR10-,
(R
10 )2NC(O)-, R 1 1 S(O)2NR 10 -, (R 10 )2NS(O)2-, CN, 15 NO2, (R 10 )2N-C(NR10)-, RO10C(0)-, -N(R 10 )2, or
R
1 1OC(0)NRO10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl,
R
10 0-, R 10 C(O)NR10-, (R 10 )2NC(0)-, R 1 1 S(O)2NR 10 _-, (R10)2NS(0)2-, (R1 0 )2N-C(NR 1 0)-, R 10OC(O)-, 20 -N(R 10 )2, or R11OC(0)NR10-;
R
9 a and R9b are independently hydrogen, C 1-C6 alkyl, trifluoromethyl and halogen; 25 R 10 is independently selected from hydrogen, C 1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R
1 1 is independently selected from C1 -C6 alkyl and aryl; 30 R 12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, CI1-C6 substituted aralkyl, CI1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, - 26 - WO 99/18096 PCT/US98/20525 2-aminoethyl and 2,2,2-trifluoroethyl;
A
1 and A 2 are independently selected from: a bond, -CH=CH-, -C-C-, -C(O)-, -C(O)NR 10 -, O, -N(RO10)-, or S(O)m; 5
A
3 is selected from: -CH2-, O, -N(RO10)- or S(O)m; V is selected from: a) hydrogen, 10 b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, 15 d) C 1-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 A 1 is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; 20 X is a bond, -CH=CH-, -C(O)NRO10-, -NR10C(0)-, -NRO10-, O or -C(=O)-; m is 0, 1 or 2; 25 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 or O; and r is 0 to 5, provided that r is 0 when V is hydrogen; 30 or a pharmaceutically acceptable salt thereof. In a more preferred embodiment of this invention, the inhibitors of prenyl-protein transferase are illustrated by the formula D: - 27 - WO 99/18096 PCT/US98/20525 R . 6a-e R9a f - \. R A 3 4 ,f A'C' N N f-f
A
1
(CR
1 2)n Q S/ R 9 b (CR 2 2 )p
-
X R 5
(R
8 )r D wherein: Q is selected from - - -\N - Nj 0 0
N
-I N{- - and 11"0 NH 5 0 from 0-1 of f(s) are independently N, and the remaining fs are independently CH; R1 is selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl; 10
R
2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 10 0-, -N(R 10 )2, F or C2-C6 alkenyl, 15 c) CI1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, R100-, or -N(R10)2; - 28 - WO 99/18096 PCT/US98/20525
R
3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, 5 C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, RlS(O)m-, R 10
C(O)NR
10 -, (R 10 )2NC(O)-, R 10 2N C(NRO10)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or
R
1 1 0C(O)NR 10 -, c) unsubstituted Ci1-C6 alkyl, 10 d) substituted Ci1-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,
R
12 0-, R 1 1 S(O)m-, R 10
C(O)NR
10 -, (R10)2NC(O)-, 15 R 10 2N-C(NRO10)-, CN, R10C(O)-, N3, -N(R 10 )2, and
R
1 1
OC(O)-NR
10 -;
R
4 is selected from H, halogen, C1 -C6 alkyl and CF3; 20 R 6 a, R6b, R6C, R6d and R 6 e 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, 25 R 12 0-, R 11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R
10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 1 1 0C(O)NR 10 -, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the 30 substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, - 29 - WO 99/18096 PCT/US98/20525
R
12 0-, R11S(O)m-, R10C(O)NR 10 -, (R10)2NC(O)-,
R
10 2N-C(NR10)-, CN, RO10C(O)-, N3, -N(R 10 )2, and
R
1 1
OC(O)-NR
10 -; or 5 any two of R 6 a , R6b, R 6 c, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
R
8 is independently selected from: 10 a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C 1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 10 0-, R10C(O)NR10-, (R1 0 )2NC(O)-, CN, NO2, (R1 0 )2N-C(NR 10 )., 15 R10C(O)-, -N(R 10 )2, or R 1 1 OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 0-,
R
1 0OC(O)NR10-, (R10)2NC(O)-, (R1 0 )2N-C(NR 1 0)-, R10OC(O)-, -N(R 10 )2, or R11OC(O)NRO-10; 20 R 9 a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl;
R
10 is independently selected from hydrogen, C 1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; 25 R 1 1 is independently selected from C1-C6 alkyl and aryl;
R
12 is independently selected from hydrogen, C1 -C6 alkyl, C1 -C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, CI1-C6 substituted heteroaralkyl, aryl, substituted aryl, 30 heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A
1 is selected from: a bond, -C(O)-, O, -N(RO10)-, or S(O)m; - 30 - WO 99/18096 PCT/US98/20525
A
3 is selected from: -CH2-, O, -N(R 10 )- or S(O)m; X is a bond, -CH=CH-, -C(O)NRO 10 -, -NR 10 C(O)-, -NR 1 0-, O or 5 -C(=O)-, n is 0 or 1; provided that n is not 0 if A 1 is a bond, O, -N(RO10)- or S(O)m; m is 0, 1 or 2; 10 pis 0, 1, 2, 3 or 4; and r is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. In another more preferred embodiment of this invention, 15 the inhibitors of prenyl-protein transferase are illustrated by the formula E: ff
R
6a -e 3
A
3 -- ,f N R 9 a R A f A'(CR'2)n N - R 9 b (CR 2 2 )p-X R 5
R
4 1 E
(R
8 )r E wherein: 20 Q is selected from - 31 - WO 99/18096 PCT/US98/20525 NN 00 -- -and Il/O NH O 0 from 0-1 of f(s) are independently N, and the remaining fs are independently CH; 5 R1 is selected from: hydrogen, C3-C10 cycloalkyl, R 10 0-, -N(R 10 )2, F or C1-C6 alkyl;
R
2 is independently selected from: a) hydrogen, 10 b) aryl, heterocycle, C3-C10 cycloalkyl, R 10 0-, -N(R 10 )2, F or C2-C6 alkenyl, c) C 1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R100-, or -N(R10)2; 15
R
3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 20 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R1 2 0-, R 1 1 S(O)m-, R10C(O)NR 1 0-, (R10)2NC(O)-,
R
10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 1 1
OC(O)NR
10 -, c) unsubstituted C1-C6 alkyl, - 32 - WO 99/18096 PCT/US98/20525 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, 5 R 12 0-, R 1 1 S(O)m-, R 10 C(O)NR10-, (R 1 0)2NC(O)-,
R
10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R 10 )2, and R11OC(O)-NR10-;
R
4 is selected from H, halogen, C1-C6 alkyl and CF3; 10
R
6 a, R6b, R 6 C, R6d and R 6 e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 15 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R
12 0-, R 1 1 S(O)m-, R10C(O)NR 10 -, (R 10 )2NC(O)-,
R
10 2N-C(NR10)-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, or R11 OC(O)NR10-, c) unsubstituted C1-C6 alkyl, 20 d) substituted C 1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-CO10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
12 0-, R 1 1 S(O)m-, R10C(O)NR 10 -, (R 1 0)2NC(O)-, 25 R 10 2N-C(NR10)-, CN, RO10C(O)-, N3, -N(RO10)2, and
R
1 1
OC(O)-NR
10 -; or any two of R 6 a, R6b, R 6 c, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, 30 -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; R8 is independently selected from: a) hydrogen, - 33 - WO 99/18096 PCT/US98/20525 b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 10 0-, R10C(O)NR 10 -,
(R
10 )2NC(O)-, CN, NO2, (R 10 )2N-C(NR10)-, RO10C(O)-, 5 -N(R 10 )2, or R 1 1
OC(O)NR
10 -, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 0-, R 10OC(O)NR10-, (R10)2NC(O)-, (R10)2N-C(NR 10 )_,
R
1 0C(O)-, -N(R 10 )2, or R 1 1
OC(O)NRO-
10 ; 10 R 9 a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl;
R
10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; 15 R 1 1 is independently selected from C1 -C6 alkyl and aryl;
R
12 is independently selected from hydrogen, C1-C6 alkyl, C1 -C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C 1-C6 substituted heteroaralkyl, aryl, substituted aryl, 20 heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A
1 is selected from: a bond, -C(O)-, O, -N(RO10)-, or S(O)m; 25 A 3 is selected from: -CH2-, O, -N(R10)- or S(O)m; X is a bond, -CH=CH-, -C(0)NRO10-, -NRO10C(0)-, -NR 1 0-, O or -C(=O)-; 30 n is 0 or 1; mis 0, 1 or 2; p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O; and - 34 - WO 99/18096 PCT/US98/20525 r is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. In a further embodiment of this invention, the inhibitors of 5 prenyl-protein transferase are illustrated by the formula F: f=f R9a 3 A 3 -N R N 6a-e CR12N R 9 b 6 ae 2 R 4 (CR 2)p-X
R
8
R
8 F wherein: from 0-1 of f(s) are independently N, and the remaining fs are 10 independently CH; R1 is selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl;
R
2 is independently selected from: 15 a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 10 0-, -N(R 10 )2 or F, c) C 1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, R 10 0-, or -N(R10)2; 20
R
3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CO10 cycloalkyl, C2-C6 25 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R
12 0-, R 1 1 S(O)m-, R 10
C(O)NR
10 -, (R 10 )2NC(O)-, - 35 - WO 99/18096 PCT/US98/20525
R
10 2N-C(NRO10)-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, or R 1 1 0C(O)NR 10 - ', c) unsubstituted C 1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the 5 substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
12 0-, R 1 1 S(O)m-, R10C(O)NR 10 -, (R 1 0)2NC(O)-,
R
10 2N-C(NR 1 0)-, CN, R10C(O)-, N3, -N(R 10 )2, and 10 R 1 1
OC(O)-NR
10 -;
R
4 is selected from H, halogen, CH3 and CF3;
R
6 a, R6b, R 6 C, R6d and R 6 e are independently selected from: 15 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R
12 0-, R 1 1 S(O)m-, R10C(O)NR 10 -, (R10)2NC(O)-, 20 R 10 2N-C(NR 1 0)-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, or R 1 1
OC(O)NR
10 -, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C 1-C6 alkyl is selected from unsubstituted or 25 substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
12 0-, R 1 1 S(O)m-, R10C(O)NR1 0 -, (R 10 )2NC(O)-,
R
10 2N-C(NRO10)-, CN, RO10C(O)-, N3, -N(R 10 )2, and
R
1 1
OC(O)-NRO
10 -; or 30 any two of R 6 a, R6b, R 6 c, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; - 36 - WO 99/18096 PCT/US98/20525
R
8 is independently selected from: -CN, Cl, -NO2, C1-C6 alkoxy, and 2,2,2-trifluoroethoxy; 5 R 9 a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl;
R
10 is independently selected from hydrogen, Cl1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; 10 R 1 1 is independently selected from C1-C6 alkyl and aryl;
R
12 is independently selected from hydrogen, C1-C6 alkyl, C 1-C6 aralkyl, C1 -C6 substituted aralkyl, C1 -C6 heteroaralkyl, C 1-C6 substituted heteroaralkyl, aryl, substituted aryl, 15 heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A
3 is selected from: -CH2-, O, -N(RO10)- or S(O)m; 20 X is a bond, -CH=CH-, -C(O)NRO 10 -, -NR10C(0)-, -NR 10 -, O or -C(=O)-; m is 0, 1 or 2; and pis 0, 1, 2, 3 or4; 25 or a pharmaceutically acceptable salt thereof. In a further embodiment of this invention, the inhibitors of prenyl-protein transferase are illustrated by the formula G: - 37 - WO 99/18096 PCT/US98/20525 f-f AR 3 3 \ R4 R9 R R 6 a-e S R4
R
8 R 9 b -- NR4 R /\
A
1
'(CR
1 2
)
n 2 R 2 G wherein: from 0-1 of f(s) are independently N, and the remaining fs are 5 independently CH; R1 is selected from: hydrogen, C3-C10 cycloalkyl, R 10 0-, -N(R 10 )2, F or C1-C6 alkyl; 10 R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle or C3-C10 cycloalkyl, c) C 1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R 10 0-, 15 or -N(R10)2;
R
3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or 20 substituted heterocycle, C3-CO10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R
12 0-, R11S(O)m-, R 10
C(O)NR
10 -, (R 10 )2NC(O)-,
R
10 2N-C(NR 10 )-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, or R 11OC(O)NR10-, 25 c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted Ci1-C6 alkyl is selected from unsubstituted or - 38 - WO 99/18096 PCT/US98/20525 substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
12 0-, R1 1 S(O)m-, R 10
C(O)NR
10 -, (R10)2NC(O)-,
R
10 2N-C(NRO10)-, CN, R10C(O)-, N3, -N(R 10 )2, and 5 R11OC(O)-NR10-;
R
4 is selected from H, halogen, CH3 and CF3;
R
6 a, R6b, R6C, R6d and R6e are independently selected from: 10 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R1 2 0-, R 1 1 S(O)m-, R10C(O)NR 10 -, (R 10 )2NC(O)-, 15 R 10 2N-C(NR 1 0)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 1 1
OC(O)NR
10 -, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or 20 substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
12 0-, R11S(O)m-, R 10
C(O)NR
10 -, (R 10 )2NC(O)-,
R
10 2N-C(NR10)-, CN, RO10C(O)-, N3, -N(R 10 )2, and
R
1 1
OC(O)-NRO
10 -; or 25 any two of R6a, R6b, R 6 C, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; 30 R 8 is independently selected from: -CN, Cl, -NO2, C1-C6 alkoxy, and 2,2,2-trifluoroethoxy; R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl; - 39 - WO 99/18096 PCT/US98/20525
R
10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R
1 1 is independently selected from C1-C6 alkyl and aryl; 5
R
12 is independently selected from hydrogen, C 1-C6 alkyl, C 1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C 1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 10 2-aminoethyl and 2,2,2-trifluoroethyl;
A
1 is selected from: a bond, -C(O)-, O, -N(RO10)-, or S(O)m;
A
3 is selected from: -CH2-, O, -N(R10)- or S(O)m; 15 m is 0, 1 or 2; and n is 0 or 1; or a pharmaceutically acceptable salt thereof. 20 Specific examples of the compounds of the invention are: 5-(4'-Cyanobenzyl)- 1- [2-(3' '-methylphenylthio)pyrid-5-ylmethyl) imidazole 25 5-(4'-Cyanobenzyl)- 1-[2-(3' '-methylphenylphenoxy) pyrid-5 ylmethyl)imidazole 5-(4'-Cyanobenzyl)- 1-[2-(3' '-chlorophenylthio) pyrid-5-ylmethyl)] imidazole 30 5-(4'-Cyanobenzyl)- 1- [2-(cyclohexylthio)pyrid-5-ylmethyl]imidazole 5-(4'-Cyanobenzyl)-1-[2-(3"-methylphenylthio)pyrid-4-ylmethyl)] imidazole 35 - 40 - WO 99/18096 PCT/US98/20525 5-(4'-Cyanobenzyl)- 1- [2-(cyclohexylamino)pyrid-5-ylmethyl)]imidazole 5-(4'-Cyanobenzyl) 1-[2-(3"-chlorophenylthio)pyrid-5-ylmethyl] imidazole -S- oxide 5 2-[N-( 1 -(4'-Cyanobenzyl)- 1H-imidazol-5-ylethyl)carbamoyl] -6-(3 trifluoromethylphenoxy)pyridine 3-[N-( 1 -(4'-Cyanobenzyl)- 1H-imidazol-5-ylethyl)carbamoyl] -6-(3 10 trifluoromethylphenoxy)pyridine 3-[N-( 1 -(4'-Cyanobenzyl)- 1H-imidazol-5-ylethyl)carbamoyl] -5-(3 trifluoromethylphenoxy)pyridine 15 3-[N-(1-(4'-Cyanobenzyl)- 1H-imidazol-5-ylethyl)carbamoyl] -5-(3 trifluoromethylbenzyloxy)pyridine 5-chloro- 1-(3-chlorobenzyl)-2-oxo- 1,2-dihydro-pyridine-3-carboxylic acid { 2- [3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl }-amide 20 1-(3-Chlorobenzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid { 2 [3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl }-amide 1-(3-Trifluoromethylbenzyl)-2-oxo- 1,2-dihydro-pyridine-5-carboxylic 25 acid { 2- [3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl I -amide 1-(3-Chlorobenzyl)-2-oxo-1,2-dihydro-pyridine-5-carboxylic acid { 2 [3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl }I -amide 30 5-Chloro- 1-(3-chlorobenzyl)-2-oxo- 1,2-dihydro-pyridine-5-carboxylic acid { 2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl } -amide 6-[N-(3-Chlorobenzyl) carbamoyl]- 4-ethoxy-pyridine-2-carboxylic acid { 2- [3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl } -amide - 41 - WO 99/18096 PCT/US98/20525 6-[N-(3-Chlorophenyl) carbamoyl]- 4-ethoxy-pyridine-2-carboxylic acid { 2- [3- (4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl } -amide 5 4-(3-Chlorobenzyloxy)- 6-methoxycarbonyl- pyridine-2-carboxylic acid { 2- [3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl } -amide 4-(5- { [6-(3-chloro-phenoxy)-pyridin-2-ylamino]-methyl } -imidazol- 1 ylmethyl)-benzonitrile 10 4-(5- { [6-(phenylethynyl)-pyridin-2-ylamino]-methyl } -imidazol- 1 ylmethyl)-benzonitrile 4-(5- { [6-(1,2,3,4-tetrahydronaphth-6-yloxy)-pyridin-2-ylamino] 15 methyl } -imidazol- 1-ylmethyl)-benzonitrile and 4-(5- { [6-(2-phenylethyl)-pyridin-2-ylamino]-methyl }-imidazol- 1 ylmethyl)-benzonitrile 20 or the pharmaceutically acceptable salts thereof. Particular examples of the compounds of the instant invention are: 5-(4'-Cyanobenzyl)- 1-[2-(3' '-chlorophenylthio) pyrid-5-ylmethyl)] 25 imidazole NC Cl NN S 5-(4'-Cyanobenzyl)-1-[2-(3' '-methylphenylphenoxy) pyrid-5 ylmethyl)imidazole - 42 - WO 99/18096 PCT/US98/20525 NC
CH
3 NN O 5-chloro- 1-(3-chlorobenzyl)-2-oxo- 1,2-dihydro-pyridine-3-carboxylic acid { 2- [3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl } -amide NC 0 N/N H (N N I ND O C CI 5 4-(3-Chlorobenzyloxy)- 6-methoxycarbonyl- pyridine-2-carboxylic acid { 2- [3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl } -amide NCH 0 Cl H N N N OCH 3 N 0 0 or the pharmaceutically acceptable salts thereof. The compounds of the present invention may have 10 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 1 , R 2 etc.) occurs more than one time in any constituent, its definition on each occurence is independent at every 15 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 - 43 - WO 99/18096 PCT/US98/20525 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 5 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 10 bonds. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like. "Alkynyl" groups include those groups having the specified 15 number of carbon atoms and having one triple bond. Examples of 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. 20 As used herein, "carbocyclic ring" is intended to mean any stable monocyclic carbon ring of the designated ring atoms, which can either be aromatic or non-aromatic. As used herein, "aryl," and the aryl portion of aroyl and aralkyl, is intended to mean any stable monocyclic or bicyclic carbon 25 ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. The term heterocycle or heterocyclic, as used herein, 30 represents a stable 5- to 7-membered monocyclic or stable 8- to 11-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 - 44 - WO 99/18096 PCT/US98/20525 cyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, 5 benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, 10 isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, 15 tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl. As used herein, "heteroaryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, 20 wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S. Examples of such heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, 25 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, 30 pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, and thienyl. As used herein in the definition of R 3 , R 4 , R 5 and R6a-e, the term "the substituted group" is intended to mean a substituted C1-8 - 45 - WO 99/18096 PCT/US98/20525 alkyl, substituted C2-8 alkenyl, substituted C2-8 alkynyl, substituted aryl or substituted heterocycle from which the substituent(s) R 3 , R 4 , R 5 and R6a-e are selected. As used herein in the definition of R 7 , the substituted C1-8 5 alkyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted hetero arylsulfonyl and substituted heterocycle include moieties containing from 1 to 3 substituents in addition to the point of attachment to the rest of the compound. 10 Lines drawn into the ring systems from substituents (such as from R 3 , R 4 , Q etc.) means that the indicated bond may be attached to any of the substitutable ring carbon or nitrogen atoms. The substituent illustrated by the structure 15 represents a 6-membered heterocyclic ring which comprises a nitrogen atom and 0-2 additional heteroatoms selected from N, S and O, and which optionally comprises a carbonyl, thiocarbonyl, -C(=NR1 3 )- or sulfonyl moiety adjacent to the nitrogen atom and includes the following ring systems: - 46 - WO 99/18096 PCT/US98/20525 -NN NN J o HO N-K O NR 13
NR
13 O O H -SN -S N - SNj O O O O N 0 0 0 0 -~ ,N-- -~ N - - N-j- - Nj N-SS S \\ \\O S O O O Preferably, the structure 5 is selected from: - 47 - WO 99/18096 PCT/US98/20525 N N Nr -N Q N{ } O NR3 NR 13
R
13 Most preferably, Q is .N 5 It is understood that such rings may be substituted by R 3 , R 4 and/or R 5 as defined hereinabove. The substituent illustrated by the structure represents a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3 10 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein Y is attached to A 3 through a carbon atom and includes the following ring systems: - 48 - WO 99/18096 PCT/US98/20525 H HI SS 0 H H 0N N N N N S /> N NHH, H \NH Preferably Y is the moiety designated by the following structure f f// f- f f 5 which represents an aromatic 6-membered ring and includes the following ring systems: - 49 - WO 99/18096 PCT/US98/20525 NNN O ... N 'N N 0 N N N"N HN ) NH wherein it is understood that one of the ring carbon atoms is substituted with A 3 . Preferably, the Y is selected from phenyl and pyridyl. The moiety described as 5
R
6 a-e 5 where any two of R 6 a, R6b, R6c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH-, -(CH2)4- and -(CH2)4- includes, but is not limited to, the following structures: 10 - 50 - WO 99/18096 PCT/US98/20525 A.¢ N0 N I xCOw It is understood that such fused ring moieties may be further substituted by the remaining R 6 a, R6b, R 6 C, R6d and/or R 6 e as defined 5 hereinabove. Preferably, R1 and R 2 are independently selected from: hydrogen, R 1 1 C(O)O-, -N(R 10 )2, R10C(O)NRO10-, R 10 0- or unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1 -C6 alkyl is selected from unsubstituted or substituted 10 phenyl, -N(R 10 )2, R100- and RO10C(O)NR 10 -. Preferably, R 3 is selected from: a) hydrogen, b) C3-C10 cycloalkyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, CN, NO2, RO10C(O)- or-N(R10)2, 15 c) unsubstituted C 1-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, 20 R 12 0-, R 11 S(O)m-, R 10
C(O)NR
10 -, (R 10 )2NC(O)-,
R
10 2N-C(NRO10)-, CN, R10C(O)-, N3, -N(R 10 )2, and
R
1 10 iC(O)-NR10_. Preferably, R 4 is selected from: hydrogen, halogen, trifluoromethyl, trifluoromethoxy and C1-C6 alkyl. 25 Preferably, R 5 is hydrogen. Preferably, R6a, R6b, R 6 c, R6d and R 6 e are independently selected from: - 51 - WO 99/18096 PCT/US98/20525 a) hydrogen, b) C3-C10 cycloalkyl, halogen, C1-C6 perfluoroalkyl, R 12 0-,
R
1 1 S(O)m-, CN, NO2, RO10C(O)- or -N(R 10 )2, c) unsubstituted C 1-C6 alkyl; and 5 d) substituted C 1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, C3-CO10 cycloalkyl, R 12 0-, R 1 1 S(O)m-,
R
1 0C(O)- or -N(R 10 )2. Preferably, R8 is independently selected from: 10 a) hydrogen, and b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 perfluoroalkyl, C1-C6 alkoxy, C 1-C6 perfluoroalkoxy, 2,2,2-trifluoroethoxy, -CH2NHC(O)CH3, -NHC(O)CH3 or CN. 15 Preferably, R 9 is hydrogen, halogen or methyl. Preferably, R 10 is selected from H, C1-C6 alkyl and benzyl. Preferably, A 1 and A 2 are independently selected from: a bond, -C(O)NR10-, -NR10C(O)-, O, -N(RO10)-, -S(O)2N(R 10 )- and 20 -N(R 10 )S(O)2-. Preferably, A 3 is selected from-CH2-, O, -N(R10)-,
-C(O)NR
1 0-, -C(O)NR10CH2-, - CH2C(0)NR 1 0-, -CH20-, -OCH2 or S(O)m. Most preferably, A 3 is selected from: -C(O)NR 10 -, -C(0)NR10CH2-, -OCH2-, O or S(O)m. 25 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 preferably, W is selected from imidazolyl and pyridyl. 30 Preferably, n and r are independently 0, 1, or 2. Preferably s is 0. Preferably t is 1. Preferably, the moiety - 52 - WO 99/18096 PCT/US98/20525
(R
8 )r
(
9 ) (RR )) V - A 1
'(CR
1 2 )nA 2
(CR
1 2
)
n - W - (CR 2 2 )p - X -(CR22)p is selected from: R9a
R
9 b -N N N R __ 9 b /N R9 a (R 8) C H and (R 8 )r -C H It is intended that the definition of any substituent or 5 variable (e.g., R1, R2, R 9 , n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, -N(R10)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art 10 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 15 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, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, 20 lactic, malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like. - 53 - WO 99/18096 PCT/US98/20525 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 5 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 suitable solvent or various combinations of solvents. Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the 10 Schemes 1-19, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Substituents R 3 , R 6 and R 8 , as shown in the Schemes, represent the substituents R 3 , R 4 , R 5 , R 6 a, R6b, R 6 c, R6d, R 6 e 15 and R 8 ; although only one such R 3 , R 6 or R 8 is present in the intermediates and products of the schemes, it is understood that the reactions shown are also applicable when such aryl or heterocyclic moieties contain multiple substituents. These reactions may be employed in a linear sequence 20 to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Schemes. The reactions described in the Schemes are illustrative only and are not meant to be limiting. Other reactions useful in the preparation of heteroaryl moieties are 25 described in "Comprehensive Organic Chemistry, Volume 4: Heterocyclic Compounds" ed. P.G. Sammes, Oxford (1979) and references therein. Synopsis of Schemes 1-19: 30 The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures. Schemes 1-9 illustrate synthesis of the instant bicyclic compounds which incorporate a preferred benzylimidazolyl sidechain. Thus, in Scheme 1, for example, a bicyclic intermediate - 54 - WO 99/18096 PCT/US98/20525 that is not commercially available may be synthesized by methods known in the art. Thus, a suitably substituted halogenated picoline 1 may be converted to the dibromo intermediate 2. The dibromide 2 may be coupled to a suitably substituted benzylimidazolyl 3 to 5 provide, after deprotection, the intermediate 4. This intermediate 4 may then be coupled under vigorous conditions to a carbocyclic/ heterocyclic ring having a nucleophilic heteroatom to provide a compound of the instant invention 5. Scheme 2 illustrates an analogous synthesis of an 10 isomeric intermediate 8 starting from a suitably substituted picoline 6. Synthesis of the instant compounds wherein ring Q is a pyridinone moiety is illustrated in Scheme 3. Thus, a suitably substituted pyridinonyl alcohol 10 may be synthesized starting from 15 the corresponding isonicotinate 9 according to procedures described by Boekelhiede and Lehn (J. Org. Chem., 26:428-430 (1961)). The alcohol is then protected and alkylated with a suitably substituted benzyl halide, to provide the intermediate bicyclic alcohol. The intermediate alcohol 3 may converted to the corresponding bromide 20 11. The bromide 11 may be coupled to a suitably substituted benzylimidazolyl 3 to provide, after deprotection, the instant compound 12. Scheme 4 illustrates synthesis of an instant compound wherein a non-hydrogen R9b is incorporated in the instant 25 compound. Thus, a readily available 4-substituted imidazole 13 may be selectively iodinated to provide the 5-iodoimidazole. That imidazole may then be protected and coupled to a suitably substituted benzyl moiety to provide intermediate 14. Intermediate 14 can then undergo the alkylation reactions that were described 30 hereinabove. Scheme 5 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the biscyclic portion of the instant compounds via an alkyl amino, sulfonamide - 55 - WO 99/18096 PCT/US98/20525 or amide linker. Thus, the 4-aminoalkylimidazole 15, wherein the primary amine is protected as the phthalimide, is selectively alkylated then deprotected to provide the amine 16. The amine 16 may then react under conditions well known in the art with various activated 5 arylheteroaryl moieties to provide the instant compounds shown. Compounds of the instant invention wherein the Al(CR12)nA 2 (CR12)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 6. The suitably substituted phenol 17 may be reacted with methyl 10 N-(cyano)methanimidate to provide the 4-phenoxyimidazole 18. After selective protection of one of the imidazolyl nitrogens, the intermediate 19 can undergo alkylation reactions as described for the benzylimidazoles hereinabove. Compounds of the instant invention wherein the 15 A 1 (CR12)nA 2
(CR
1 2)n linker is a substituted methylene may be synthesized by the methods shown in Scheme 7. Thus, the N-protected imidazolyl iodide 20 is reacted, under Grignard conditions with a suitably protected benzaldehyde to provide the alcohol 21. Acylation, followed by the alkylation and nucleophilic 20 displacement procedures illustrated in the Schemes above (in particular, Scheme 1) provides the instant compound 22. If other
R
1 substituents are desired, the acetyl moiety can be manipulated as illustrated in the Scheme. Scheme 8 illustrates incorporation of an acetyl moiety 25 as the (CR 2 2)pX(CR 2 2)p linker of the instant compounds. Thus, the suitably substituted acetyl pyridine 23 is brominated to provide intermediate 24. Reaction with the imidazolyl reagent 5 provides, after deprotection and further functionalization, the instant compound 25. 30 Scheme 9 illustrates a synthetic route to the instant compounds wherein the heterocyclic-linker-cyclic moiety is first formed and then couple to the preferred imidazolyl moiety. - 56 - WO 99/18096 PCT/US98/20525 SCHEME 1 R CH 3 NBS Br ________Br Br N benzoyl peroxide Br N 1 2 Tr ZnBr N N R8 N NiCI 2 (PPh 3
)
2 DMF/reflux NI
R
8 3 Tr
R
3 N N N 550C, CH 3 OH R R 3 R \ Br / 4
R
8 - 57 - WO 99/18096 PCT/US98/20525 SCHEME 1 (continued) R6 N NBrI A
H-A
3 z"/ f NN base/solvent / 4 sealed tube
R
8
H-A
3 = OH, SH,
NH
2
R
3
R
6 NN A / 5
R
8
A
3 = O, NH, S - 58 - WO 99/18096 PCT/US98/20525 SCHEME 2
CH
3 1) HBr
CH
3
\R
3 2) Br 2 R
H
2 N N 3) NaNO 2 Br N 6 4) NaOH Br
R
3 NBS benzoyl peroxide Br N 7 Tr N /DMF/reflux
R
8 3 Tr
R
3 N N 1+I N Br 8 R88 59 - WO 99/18096 PCT/US98/20525 SCHEME 3 COOMe COOMe ri 30% H202 I 3 30% H 2 0 2 3 Ac 2 0 / 1600C R3 R N HOAc/A N+ 9 O OH COOMe R LiBH4 / THF TBDMSCI
R
3 I' R 3, N 0 N O imidazole /DMF H H 10 Br OTBDMS -N I R6 R3 O N 0 H OTBDMS - 60 - WO 99/18096 PCT/US98/20525 SCHEME 3 (continued) TBAF R 3 R _"~N 6 CBr 4 /Ph 3 P N R6 THF \ O CH 2 '2 O S11 OH Br Tr N l N
/CH
3 CN/reflux
R
8 3 Tr R N N 6N N55oC, CH 3 OH
R
8
R
3 N N 6 /7 - 1 2
R
8 - 61 - WO 99/18096 PCT/US98/20525 SCHEME 4 H H
R
9 b j Nal, NaHCO 3 ,1 2
R
9 b Nf Tr~l, NEtS NN 13I T N N R____ _ Nb R 9 b \NiCI 2 (PPh 3
)
2 N~ ZnBr Tr N Br,"I
R
9 b N 2 / \ CH 3 CN/reflux 8/ ii. MeOH, reflux 14 R3 Br N R~b -62 - WO 99/18096 PCT/US98/20525 SCHEME 5 0
R
8 - L. \ O 'j . R'Br O N O 55oC,CH 3 ,CN , N N ii. EtOH,80oC, NH 2
NH
2 15 O N N
NH
2
R
8 ,. 1 16 N acylation, sulfonylation / O N N.. . N 0 or alkylation RNNR6 N /N O SO
R
8 H R 6 R
R
a N R 3 N N 0' ; Y R 8 N H R6
R
3 - 63 -63 - WO 99/18096 PCT/US98/20525 SCHEME 6 OH i, Na, MeOH NC ii. 1200C 17 H 3 C-O - N H Tk NN N TrCI, NEt 3 ,N NC O NC 19 Tr
R
3 Br i. CH 3 CN/reflux N+ N ii. MeOH reflux NCO Br 2 NC 19 N R3 Br
NC
O - 64 - WO 99/18096 PCT/US98/20525 SCHEME 7 ,Tr Tr "N N EtMgBr N O OH 20 R8
R
8 21
R
3 Tr R3 . Br N 1. N Ac 2 0,py N Br 2 / \- O- c CH 3 CN/reflux // OAc / 2. MeOH
R
8 Nz R3 Br H-A3. R I\~ R6_ OAc R N3
NA
3
-
R6
N
a
R
8 LiOH ' OAc 22 - 65 - WO 99/18096 PCT/US98/20525 SCHEME 7 (continued) R 3 3 N A
-
R6 S OH S 2
R
8 N
A
3
/NH
3 , MeOH Cl
R
8
R
3
A
3 N NIAN R6
NH
2
R
8 +
R
3
A
3 N A3 -R
R
8 - 66 - WO 99/18096 PCT/US98/20525 SCHEME 8
R
3
R
3 N Br 2
/CHCI
3 -N
H
3 C Br Br Br O 23 O 24 Tr N R 8
R
3
R
3 R 8 5 / N Br
CH
3 CN/reflux Nj 0 2) reflux/MeOH R 8
R
3 -4 6 -N H-A 3 / R / N A - R 6 R N N J 0 25 - 67 - WO 99/18096 PCT/US98/20525 SCHEME 9
R
6
R
3
R
3
R
6 Br
-H-A
3 Br N Br base/solvent N A sealed tube
H-A
3 = OH, SH, NH 2 1. nBu-Li, -780 OH R 3 R6 THE
(CH
2 )n N + 2. (CH 2 )nCHO N A 3 N II N Tr Tr
R
3
R
6 1. catalytic (CH hydrogenation On(CH 2 ) I N Tr - 68 - WO 99/18096 PCT/US98/20525 SCHEME 9 (continued)
R
3
R
6 R3/6 1) Ar CH 2 X, CH 3 CN
(CH
2 )n N "" f 2) CF 3
CO
2 H, 0H 2 01 2 N A (C 2 Hs) 3 SiH N Tr
R
3
R
6 Ar-- (CH 2 )nA3 N ,N 5 Schemes 10-18 illustrate reactions wherein the moiety (R )q Ir
(R
9 )q V - A 1
(CR
1
'
2 )nA 2
(CR)
n W - (CR' 2 )p-X. t incorporated in the compounds of the instant invention is represented by other than the substituted imidazole-containing group illustrated 10 in the previous Schemes. Thus, the intermediates whose synthesis are illustrated in the above Schemes, and other pyridinonecarbocyclic and pyridinone-heterocyclic intermediates obtained commercially or readily synthesized, can be coupled with a variety of aldehydes. The 15 aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses, 1988, 67, 69-75, from the appropriate amino - 69 - WO 99/18096 PCT/US98/20525 acid. Thus, as shown in Scheme 10, a suitably substituted bromopyridine is lithiated and is reacted with an aldehyde to provide the C-alkylated instant compound 27. Compound 27 can be deoxygenated by methods known in the art, such as a catalytic 5 hydrogention, then deprotected with trifluoroacetic acid in methylene chloride to give the final compound 28. The compound 28 may be isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine 28 can further be selectively protected to obtain 29, which can 10 subsequently be reductively alkylated with a second aldehyde to obtain compound 30. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole 31 can be accomplished by literature procedures. If the bromopyridine reagent is reacted with an aldehyde 15 which also has a protected hydroxyl group, such as 32 in Scheme 11, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 11, 12). 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 alkyl 20 lithium reagents, to obtain secondary alcohols such as 34. In addition, the fully deprotected amino alcohol 35 can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as 36 (Scheme 12), or tertiary amines. 25 The Boc protected amino alcohol 33 can also be utilized to synthesize 2-aziridinylmethylarylheteroaryl such as 37 (Scheme 13). Treating 33 with 1,1'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine 37. The aziridine is reacted with a nucleophile, such as a 30 thiol, in the presence of base to yield the ring-opened product 38. In addition, the arylpyridinone reagent can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as 40, as shown in Scheme 14. When R' is an aryl group, 40 - 70 - WO 99/18096 PCT/US98/20525 can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce 41. Alternatively, the amine protecting group in 40 can be removed, and O-alkylated phenolic amines such as 42 produced. 5 Schemes 15-18 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. 10 Scheme 19 illustrates preparation of substituted aldehydes which incorporate the benzylimidazolyl sidechain. As set forth in Scheme 19, these aldehydes can be reductively aminated with various amines to give the instant compounds. - 71 - WO 99/18096 PCT/US98/20525 SCHEME 10 R3 1. nBu-Li, 780C Br N
A
3 2. Boc NH Boc NH CHO 26 1. catalytic OH R 3 hydrogenation O 2. CF 3
CO
2 H Boc NH A
CH
2 C1 2 NHBoc 27 R 3 / A 3
-
BOC
2 0
NH
2 N
CH
2
C
2
NH
2 28 - 72 - WO 99/18096 PCT/US98/20525 SCHEME 10 (continued) R3 CHO BocNH
A
3 N
NH
2 NaBH(OAc) 3 29 Et 3 N, CICH 2
CH
2 CI R3 BocNH / A 3
CF
3
CO
2 H, CH 2
CI
2 ; N - NH NaHCO 3 / \/ 30 R3
NH
2
/A
3 NC - NH AgCN & R3 Q N N N 31 - 73 - WO 99/18096 PCT/US98/20525 SCHEME 11 R3 1. nBu-Li, 780C Br A3 BnO BocNH CHO 32 HO BnO A 3 20% Pd(OH) 2
H
2 N
CH
3 OH NHBoc
CH
3
CO
2 H R3 HO A 3 CICOCOCI N DMSO CH 2
CI
2 NHBoc 33 (0 2
H
5
)
3 N
R
3 R 0 k/ -A O~ A 3H OA H' NH-o N R'MgX HO N H NHBoc , NHBoc 34 - 74 - WO 99/18096 PCT/US98/20525 SCHEME 12 R 3 HO / A N
CH
2 C1 2 NHBoc 33
R
3 H= R'CHO HO
/A
3 RCHO N NaBH(OAc) 3
NH
2 35 CICH 2
CH
2 CI
R
3 HO N A 3 NH
R'CH
2 36 - 75 - WO 99/18096 PCT/US98/20525 SCHEME 13 SH H HO A 3 02 N NaH, DMF OoC NHBoc R3 - - R"SH / A 3
(C
2
H
5
)
3 N N N CH 3 0H H 37
R
3 R"S-/ A3 N
NH
2 38 38- 76 - 76 - WO 99/18096 PCT/US98/20525 SCHEME 14 HO HO 1) Boc20, K 2
CO
3
THF-H
2 0 2) CH2N2, EtOAc
H
2 N C0 2 H 2) H 2 2 , EtOAc BocNH CO 2
CH
3 HO LiAIH 4
R"'CH
2 X THF 0S 2 C00 3 0-20 0 C BocNH
CH
2 OH DMF
R"'CH
2 0 R"'CH 2 0 R"HO pyridine SO DMSO (C2Ha)3N BocNH CH 2 OH 20C BocNH CHO 20O 5 - 77 - WO 99/18096 PCT/US98/20525 SCHEME 14 (continued)
R'CH
2 0 R3 Li A 3 + L N BocNH CHO - 26 39 1. Et20 R"'notaryl Et 2 0 2.20% Pd(OH) 2 , H 2
CH
3 OH, CH 3
CO
2 H
R
3 3. HCI, EtOAc \/OH - A
R'"CH
2 0 \ N NHBoc 40 2. 20% Pd(OH) 2 , H 2 3
CH
3 0H, CH 3 C0 2 H R 2) HCI, EtOAc A 3C
R"'CH
2 0 N NH
R
3 42 HO N N 41 NH 2 - 78 - WO 99/18096 PCT/US98/20525 SCHEME 15
CH
3 1) HNO 2 ,Br 2 / C0 2
CH
3 2) KMnO 4
H
2 N N 3) MeOH, H Br N
R
8 I MgCI R 8
SCO
2
CH
3 ZnCI 2 ,NiCI 2 (Ph 3
P)
2
R
8 NaBH 4 (excess)
CH
2 0H NY
R
8
SO
3 Py, Et 3 N CHO DMSO N - 79 - WO 99/18096 PCT/US98/20525 SCHEME 16 1. EtO(CO)CI R 8 2. R Br C0 2 0H 3 Zn, CuN 00 2
CH
3 Zn, CuCN N 3. S, xylene, heat N
R
8 R 8 NaBH 4
SO
3 Py, Et 3 N (excess) CH 2 OH DMSO CHO N N
R
8 R8 Br, CO2CH3 MgCl ZnCl 2, NC2(Ph3P) 2 N
R
8
R
8 NaBH4 S03"Py, Et3N 511 CH2OH CHO (excess) DMSO N N -80 - WO 99/18096 PCT/US98/20525 SCHEME 17 CO2CH 3 Br 1. LDA, 002 Br N 2. MeOH, H + N
R
8
R
8 IMgCI CO2CH 3 ZnCI 2 , NiCI 2 (Ph 3
P)
2 N
R
8 NaBH 4 (excess) CH 2 OH SO 3 Py, Et 3 N DMSO N
R
8 CHO N - 81 - WO 99/18096 PCT/US98/20525 SCHEME 18 CO2CH 3 1. LDA, C0 2 Br N Br N 2. (CHa) 3 SiCHN 2 Ra Br R ' N, CO2CH 3 Zn, NiCI 2 (Ph 3
P)
2 N 0 2 0H 3 R" excess NaBH 4
SO
3 Py, Et 3 N N CH 2 OH DMSO N CHO - 82 - WO 99/18096 PCT/US98/20525 SCHEME 19 N CH 2 0H DMF N CH20 H Et3 N (C 6
H
5
)
3 CCI HI Tr X o d 1) 1 pyridine (/N\ / R8 N acetic anhydride I EtOAc, 600C Tr 2) MeOH, 600C N LiOH N CH20H OO, R 000 / N HX
THF/H
2 0 R8 N Et3N N CHO
SO
3 -pyridine complex R N DMSO
R
8 NN 1) HN R N N H titanium isopropoxide R8N THF 2) NaCNBH 4 , ethanol - 83 - WO 99/18096 PCT/US98/20525 In a preferred embodiment of the instant invention the compounds of the invention are selective inhibitors of farnesyl-protein transferase. A compound is considered a selective inhibitor of farnesyl 5 protein transferase, for example, when its in vitro farnesyl-protein transferase inhibitory activity, as assessed by the assay described in Example 17, is at least 100 times greater than the in vitro activity of the same compound against geranylgeranyl-protein transferase-type I in the assay described in Example 19. Preferably, a selective compound 10 exhibits at least 1000 times greater activity against one of the enzymatic activities when comparing geranylgeranyl-protein transferase-type I inhibition and farnesyl-protein transferase inhibition. In another preferred embodiment of the instant invention the compounds of the invention are dual inhibitors of farnesyl-protein 15 transferase and geranylgeranyl-protein transferase type I. Such a dual inhibitor will exhibit certain characteristics when assessed in in vitro assays, which are dependent on the type of assay employed. In a SEAP assay, such as described in Examples 21, it is preferred that the dual inhibitor compound has an in vitro inhibitory 20 activity (IC50) that is less than about 12gM against K4B-Ras dependent activation of MAP kinases in cells. More preferably, the dual inhibitor compound has an in vitro inhibitory activity (IC50) against K4B-Ras dependent activation of MAP kinases in cells which is more than about 5 times lower than the inhibitory activity (IC50) against Myr-Ras 25 dependent activation of MAP kinases in cells. Also more preferably, in a SEAP assay, the dual inhibitor compound has an inhibitory activity (IC50) that is less than about 10 nM against H-Ras dependent activation of MAP kinases in cells. In a GGTase plus anion assay, such as described in Example 30 19, it is preferred that the dual inhibitor compound has an in vitro inhibitory activity (IC50) that is less than about 5 gM against transfer of a geranylgeranyl residue to a protein or peptide substrate comprising a CAAXG motif by geranylgeranyl-protein transferase type I in the presence of a modulating anion. More preferably, the dual inhibitor - 84 - WO 99/18096 PCT/US98/20525 compound has an in vitro inhibitory activity (IC50) that is less than about 1 gM against transfer of a geranylgeranyl residue to a protein or peptide substrate comprising a CAAXG motif by geranylgeranyl-protein transferase type I in the presence of a modulating anion. Preferably, the 5 dual inhibitor compound has an in vitro inhibitory activity (IC50) in the in vitro assay as described in Example 17 that is less than about 1 RM against transfer of a farnesyl residue to a protein or peptide substrate, comprising a CAAXF motif, by famrnesyl-protein transferase. More preferably, the dual inhibitor compound has an in vitro inhibitory 10 activity (IC50) that is less than about 100nM against transfer of a farnesyl residue to a protein or peptide substrate, comprising a CAAXF motif, by farnesyl-protein transferase. Also preferably, the dual inhibitor compound has an in vitro inhibitory activity (IC50) in the in vitro assay as described in Example 20, that is less than about 100 nM 15 against the anchorage independent growth of H-ras-transformed mammalian fibroblasts. The protein or peptide substrate utilized in the instant assay may incorporate any CAAX motif that is geranylgeranylated by GGTase-I. The term "CAAX
G
" will refer to such motifs that 20 may be geranylgeranylated by GGTase-I. It is understood that some of the "CAAX
G
" containing protein or peptide substrates may also be farnesylated by famrnesyl-protein transferase. In particular such
"CAAX
G
" motifs include (the corresponding human protein is in parentheses): CVIM (K4B-Ras) (SEQ.ID.NO.: 1), CVLL (mutated H 25 Ras) (SEQ.ID.NO.: 2), CVVM (N-Ras) (SEQ.ID.NO.: 3), CIIM (K4A Ras) (SEQ.ID.NO.: 4), CLLL (Rap-IA) (SEQ.ID.NO.: 5), CQLL (Rap IB) (SEQ.ID.NO.: 6), CSIM (SEQ.ID.NO.: 7), CAIM (SEQ.ID.NO.: 8), CKVL (SEQ.ID.NO.: 9) and CLIM (PFX) (SEQ.ID.NO.: 10). Preferably, the CAAX motif is CVIM. 30 As used herein, the term "CAAX
F
,
' is used to designate a protein or peptide substrate that incorporates four amino acid C-terminus motif that is farnesylated by farnesyl-protein transferase. It is understood that certain of the "CAAX
F
" containing protein or peptide substrates may also be geranylgeranylated by GGTase-I. In particular - 85 - WO 99/18096 PCT/US98/20525 such "CAAX
F
" motifs include (the corresponding human protein is in parentheses): CVLS (H-ras) (SEQ.ID.NO.: 11), CVIM (K4B-Ras) (SEQ.ID.NO.: 1) and CVVM (N-Ras) (SEQ.ID.NO.: 3). The instant compounds are useful as pharmaceutical agents 5 for mammals, 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. 10 Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity (i.e., neurofibromin (NF-1), neu, src, abl, Ick, fyn) or by other mechanisms. The compounds of the instant invention inhibit prenyl protein transferase and the prenylation of the oncogene protein Ras. 15 The instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55: 4575-4580 (1995)). Such anti-angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of vision deficit related to retinal vascularization. 20 The compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished 25 by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment. For example, a component of NF-1 is a benign proliferative disorder. The instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis 30 delta and related viruses (J.S. Glenn et al. Science, 256:1331-1333 (1992). The compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary - 86 - WO 99/18096 PCT/US98/20525 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. 5 American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)). The instant compounds may also be useful for the treatment of fungal infections. The instant compounds may also be useful as inhibitors of 10 proliferation of vascular smooth muscle cells and therefore useful in the prevention and therapy of arteriosclerosis and diabetic vascular pathologies. The compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in 15 combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of 20 administration. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or 25 elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide 30 pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium - 87 - WO 99/18096 PCT/US98/20525 phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl pyrrolidone or acacia, and lubricating agents, for example, magnesium 5 stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a water soluble taste masking material such as hydroxypropylmethyl 10 cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate buryrate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or 15 kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous 20 suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an 25 alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or 30 condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one - 88 - WO 99/18096 PCT/US98/20525 or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, 5 sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of 10 an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting 15 agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. 20 The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean 25 lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring agents, preservatives and antioxidants. 30 Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant. - 89 - WO 99/18096 PCT/US98/20525 The pharmaceutical compositions may be in the form of a sterile injectable aqueous solutions. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. 5 The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase. For example, the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to 10 form a microemulation. The injectable solutions or microemulsions may be introduced into a patient's blood-stream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating 15 concentration of the instant compound. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump. The pharmaceutical compositions may be in the form of a 20 sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or 25 suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find 30 use in the preparation of injectables. Compounds of Formula A may also be administered in the form of a suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non irritating excipient which is solid at ordinary temperatures but liquid at - 90 - WO 99/18096 PCT/US98/20525 the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. 5 For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula A are employed. (For purposes of this application, topical application shall include mouth washes and gargles.) The compounds for the present invention can be 10 administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather 15 than intermittent throughout the dosage regimen. 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, from combination of the specific ingredients in the specified amounts. 20 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, sex and response of the individual patient, as well as the severity of the patient's symptoms. 25 In one exemplary application, a suitable amount of compound is administered 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 of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight 30 per day. 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 - 91 - WO 99/18096 PCT/US98/20525 being treated. For example, the compounds of the instant invention may also be co-administered with other well known cancer therapeutic agents that are selected for their particular usefulness against the condition that is being treated. Included in such 5 combinations of therapeutic agents are combinations of the instant farnesyl-protein transferase inhibitors and an antineoplastic agent. It is also understood that such a combination of antineoplastic agent and inhibitor of farnesyl-protein transferase may be used in conjunction with other methods of treating cancer and/or tumors, including 10 radiation therapy and surgery. Examples of an antineoplastic agent include, in general, microtubule-stabilizing agents ( such as paclitaxel (also known as Taxol®), docetaxel (also known as Taxotere®), epothilone A, epothilone B, desoxyepothilone A, desoxyepothilone B or their 15 derivatives); microtubule-disruptor agents; alkylating agents, anti metabolites; epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes; biological response modifiers and growth inhibitors; hormonal/anti-hormonal therapeutic agents and 20 haematopoietic growth factors. Example classes of antineoplastic agents include, for example, the anthracycline family of drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, the taxanes, the epothilones, discodermolide, the pteridine family of drugs, diynenes 25 and the podophyllotoxins. Particularly useful members of those classes include, for example, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo-phyllotoxin 30 derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like. Other useful antineoplastic agents include estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine, thiotepa, - 92 - WO 99/18096 PCT/US98/20525 cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins. The preferred class of antineoplastic agents is the 5 taxanes and the preferred antineoplastic agent is paclitaxel. Radiation therapy, including x-rays or gamma rays which are delivered from either an externally applied beam or by implantation of tiny radioactive sources, may also be used in combination with the instant inhibitor of farnesyl-protein transferase alone to treat cancer. 10 Additionally, compounds of the instant invention may also be useful as radiation sensitizers, as described in WO 97/38697, published on October 23, 1997, and herein incorporated by reference. The instant compounds may also be useful in combination with other inhibitors of parts of the signaling pathway that links cell 15 surface growth factor receptors to nuclear signals initiating cellular proliferation. Thus, the instant compounds may be utilized in combination with farnesyl pyrophosphate competitive inhibitors of the activity of farnesyl-protein transferase or in combination with a compound which has Raf antagonist activity. The instant compounds 20 may also be co-administered with compounds that are selective inhibitors of geranylgeranyl protein transferase or farnesyl-protein transferase. In particular, the compounds disclosed in the following patents and publications may be useful as farnesyl pyrophosphate 25 competitive inhibitor component of the instant composition: U.S. Ser. Nos. 08/254,228 and 08/435,047. Those patents and publications are incorporated herein by reference. In practicing methods of this invention, which comprise administering, simultaneously or sequentially or in any order, two or 30 more of a protein substrate-competitive inhibitor and a farnesyl pyrophosphate-competitive inhibitor, such administration can be orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration. It is preferred that such administration be orally. It is more preferred that such - 93 - WO 99/18096 PCT/US98/20525 administration be orally and simultaneously. When the protein substrate-competitive inhibitor and farnesyl pyrophosphate-competitive inhibitor are administered sequentially, the administration of each can be by the same method or by different methods. 5 The instant compounds may also be useful in combination with an integrin antagonist for the treatment of cancer, as described in U.S. Ser. No. 09/055,487, filed April 6, 1998, which is incorporated herein by reference. As used herein the term an integrin antagonist refers to 10 compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to an integrin(s) that is involved in the regulation of angiogenisis, or in the growth and invasiveness of tumor cells. In particular, the term refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the 15 av33 integrin, which selectively antagonize, inhibit or counteract binding of a physiological ligand to the axvP5 integrin, which antagonize, inhibit or counteract binding of a physiological ligand to both the xav33 integrin and the xv35 integrin, or which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed 20 on capillary endothelial cells. The term also refers to antagonists of the avP6, av38, alpl, u201, a5pl, a6P1 and u634 integrins. The term also refers to antagonists of any combination of av33, av5, avP6, avP8, alpl, u2pl3, a5131p, a613 and a6P4 integrins. The instant compounds may also be useful with other agents that inhibit angiogenisis 25 and thereby inhibit the growth and invasiveness of tumor cells, including, but not limited to angiostatin and endostatin. Similarly, the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF-1, restenosis, polycystic kidney disease, infections 30 of hepatitis delta and related viruses and fungal infections. If formulated as a fixed dose, such combination products employ the combinations of this invention within the dosage range described below and the other pharmaceutically active agent(s) within - 94 - WO 99/18096 PCT/US98/20525 its approved dosage range. Combinations of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a multiple combination formulation is inappropriate. 5 The compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and quantity of farnesyl-protein transferase (FPTase) in a composition. Thus the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate 10 of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to allow the FPTase to farnesylate the substrate, the chemical content 15 of the assay mixtures may be determined by well known immuno logical, radiochemical or chromatographic techniques. Because the compounds of the instant invention are 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 20 presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested. It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying 25 tissue samples which contain farnesyl-protein transferase and quantitat ing the enzyme. Thus, potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract containing an unknown amount of farnesyl 30 protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate are incubated for an 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 - 95 - WO 99/18096 PCT/US98/20525 that has a Ki substantially smaller than the concentration of enzyme in the assay vessel) required to inhibit the enzymatic activity of the sample by 50% is approximately equal to half of the concentration of the enzyme in that particular sample. 5 EXAMPLES Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species 10 and conditions are intended to be further illustrative of the invention and not limitative of the reasonable scope thereof. EXAMPLE 1 15 5-(4'-Cyanobenzyl)-1-[2-(3"-methylphenylthio)pyrid-5-ylmethyl) imidazole Step 1: 1-Trityl-4-(4-cyanobenzyl)imidazole To an oven dried 500 ml flask was added Zn (92mmol, 20 5.96g) and then 45 mL of distilled THF via syringe. To this well stirred mixture was added 1,2-dibromoethane ( 9.2 mmol, 1.72g) via pipet. This mixture was stirred at ambient temperature for 3 hr and then a solution of p-cyanobenzylbromide (59.5 mmol, 11.68g) in THF (50mL) was added via addition funnel over 20 minutes. The resulting mixture 25 was stirred at ambient temperature for 6 hr. Then a mixture of 1-trityl-4-iodoimidazole (45.8mmol, 20g) and bis-triphenylphosphine dichloronickel (4.6 mmol, 3.0g) was added. This was stirred at ambient temperature for 36 hr. A saturated ammonium chloride solution (125mL) was added. Stirring was continued for 3 hr and then 1L 30 of chloroform was added to this mixture. The chloroform layer was drawn off, washed with dilute sodium bicarbonate then saturated sodium chloride. Dried with sodium sulfate and evaporated to a thick oil. Purified on a silica gel column eluted with chloroform to provide the - 96 - WO 99/18096 PCT/US98/20525 title compound. H-NMR (CDC1 3 ): 4.0ppm (s, 2H); 7.1-7.6ppm (20H); 6.6ppm(s, 1H). Step 2: 2-bromo-5-bromomethyl pyridine 5 To a flask was charged 2-bromo-5-methylpyridine (34.9mmol, 6.0g), N-bromosuccinimide (38.4 mmol, 6.83g), benzoyl peroxide (3.49mmol, 0.85g) and carbon tetrachloride (60mL). This solution was refluxed for 6 hr, cooled to ambient temperature and purified on a silica gel column. Eluted with ethyl acetate: hexane (1:9) 10 to provide the title compound. FAB MS: calc: 250.9 found: 251.9. 1 H-NMR (CDC1 3 ): 4.4ppm (s, 2H); 7.5ppm (d, 1H); 7.6ppm (d, 1H); 8.4ppm (s, 1H). Steop 3: 5-(4-Cyanobenzyl)- 1-(2-bromopyrid-5-ylmethyl)imidazole 15 To a flask was charged 1-trityl -4-p-cyanobenzyl imidazole (2.77mmol, 1.18g) from Step 1 and 2-bromo-5-bromomethyl pyridine (2.77mmol, 0.67g) from Step 2 in DMF (10mL) and the mixture heated at 100oC for 6 hr. The DMF was then removed in vacuo and the residue was triturated with ethyl ether. The ethyl ether was then decanted off 20 and replaced with methanol (20mL).This solution was then refluxed for 4 hr, cooled to ambient temperature and purified on a C 18 preperative hplc column to provide the title compound. High resolution FAB-MS: calc; 353.040183 found; 353.040183. 1 H-NMR (CD 3 OD): 4.2ppm (s, 2H); 5.4ppm (s, 2H); 7.2 and 7.6ppm (d, 2H); 8.1ppm (s, 1H); 9.1ppm 25 (s, 1H). Step 4: 5-(4'-cyanobenzyl)-1-[2-(3'"'methylphenylthio)pyrid-5 ylmethyl)imidazole The compound from Step 3 (0.28 mmol, 0.164g), 3-methyl 30 thiophenol (0.85 mmol, 0.106g) and triethylamine (3.59mmol, 0.36g) were placed in an N 2 purged sealed tube. This was heated at 105oC for 15 hr. The residue was dissolved in methanol and purified on a C 18 preperative hplc column. Lyophilized from dioxane/HCI to provide - 97 - WO 99/18096 PCT/US98/20525 the title compound. FAB-MS: calc: 396.4 found: 397.2 1 H-NMR
(CD
3 OD): 2.4ppm (s, 3H); 4.2ppm (s, 2H); 5.4ppm (s, 2H); 7.2-7.6ppm (10H); 8.1ppm (s, 1H); 9.1ppm (s, 1H). 5 EXAMPLE 2 5-(4'-Cyanobenzyl)-1-[2-(3"-methylphenylphenoxy)-pyrid-5 ylmethyl)imidazole 10 The compound from Example 1 Step 3 (0.1 1g 0.20mmol), m-cresol (0.064g, 0.59mmol) and sodium hydride (60% dispersion in oil, 4.0 equiv, 0.032g) were suspended in DMF (0.5mL) in an N 2 purged sealed tube and heated at 110oC for 24hr. The residue was dissolved in methanol and purified on a C 18 preperative hplc column. 15 Lyophilized from dioxane/HCI to provide the title compound. FAB-MS: calc: 380.4 found: 381.0. 2 1 H-NMR (CD 3 OD): 2.4ppm (s, 3H); 4.2ppm (s, 2H); 5.4ppm (s, 2H); 6.8-7.6ppm (11H); 7.9 ppm (s, 1H); 9.1ppm (s,1H). 20 EXAMPLE 3 5-(4'-Cyanobenzyl)- 1-[2-(3' '-chlorophenylthio) pyrid-5-ylmethyl)] imidazole The compound from Example 1 Step 3 (0.26 mmol, 25 0.090g), 3-chloro phenol (0.76 mmol, 0.11 g) and triethylamine (0.726g) were placed in an N 2 purged sealed tube. This was heated at 105 0 C for 4 hr. The residue was dissolved in methanol and purified on a C 18 preperative hplc column. Lyophilized from dioxane/HCI to Provide the title compound. FAB-MS: calc: 416.9 found:417.1. 2 30 H-NMR (CD 3 OD): 4.2ppm (s, 2H); 5.4ppm (s, 2H); 6.9ppm (d, 1H); 7.2-7.6ppm (m, O10H); 8.1ppm (s, 1H); 9.1ppm (s, 1H). - 98 - WO 99/18096 PCT/US98/20525 EXAMPLE 4 5-(4'-cyanobenzyl)- 1- [2-(cyclohexylthio)pyrid-5-ylmethyl]imidazole The compound from Example 1, Step 3 (0.16g 0.45mmol), 5 cyclohexyl mercaptan (0.16g, 1.35.mmol) and sodium hydride (60% dispersion in oil, 4.0 equiv, 0.032g) were suspended in DMF (0.5mL) in an N 2 purged sealed tube and heated at 110oC for 4hr. The residue was dissolved in methanol and purified on a C 18 preperative hplc column. Lyophilized from dioxane/HCI to provide the title compound. FAB-MS: 10 calc: 389 found: 389. 1 H-NMR (CD 3 OD): 1.4-2.1ppm (10H); 3.8ppm (1H); 4.2ppm (2H); 5.45ppm (2H); 7.2-7.6ppm (7H); 8.2ppm (1H); 9. lppm (1H). EXAMPLE 5 15 5-(4'-Cyanobenzyl)- 1- [2-(3"-methylphenylthio)pyrid-4-ylmethyl)] imidazole Stel 1: 2-Bromo-4-bromomethyl pyridine Following the procedure of Adams et.al. (J. Am. Chem. 20 Soc., 76, 3168 (1954)) 2-bromo-4-methylpyridine was obtained from 2-amino-4-methylpyridine. H-NMR (CDCl 3 ): 2.3ppm (s, 3H); 7.05ppm (d, 1H); 7.3ppm (s, 1H); 8.2ppm (s, 1H). Step 2: 5-(4'-Cyanobenzyl)- 1-(2-bromo-4-pyridylmethyl)imidazole 25 Following the procedure in Example 1, Step 2 the product was obtained from 2-bromo-4-methylpyridine. FAB-MS: calc: 249 found: 250. 1 H-NMR (CDCl 3 ): 4.4ppm (s, 2H); 7.2ppm (d, 1H); 7.5ppm (s, 1H); 8.4ppm (d, 1H). 30 Step 3: 5-(4'-cyanobenzyl)- 1- [2-bromopyrid-4-ylmethyl)]imidazole Following the procedure in Example 1, Step 3 1-trityl-4 p-cyanobenzyl imidazole and 2-bromo-4-bromomethyl pyridine were reacted to give the product as a free base solid after washing the preparative hplc purified material with Na 2
CO
3 . FAB-MS: calc: 353 - 99 - WO 99/18096 PCT/US98/20525 found:353. 1 H-NMR (CDCl 3 ): 3.8ppm (s, 2H); 4.9ppm (s, 2H); 6.8ppm (d, 1H); 6.9-7.6 (7H); 8.3ppm (d, 1H). Step 4: 5-(4'-cyanobenzyl)- 1- [2-(3' ' methylphenylthio)4 5 pyridylmethyl)limidazole Following the procedure in Example 1, Step 4, 5-(4' cyanophenyl)-1-[2-bromopyrid-4-ylmethyl)]imidazole and 3-methyl thiophenol were reacted and the product was obtained. FAB-MS: calc: 396.5 found: 397.1. 1 H-NMR (CD 3 OD): 2.4ppm (s, 3H); 4.05ppm(s, 10 2H); 5.5ppm (s, 2H); 6.3ppm (s, 1H); 7.0ppm (d,1H); 7.2-7.6ppm (9H); 8.35ppm (d, 1H); 9.02ppm (s, 1H). EXAMPLE 6 15 5-(4'-Cyanobenzyl)- 1- [2-(cyclohexylamino)pyrid-5-ylmethyl)]imidazole hydrochloride Stel 1: 2- cyclohexylamino-5-pyridine carboxylic acid 2-Chloro-5-pyridinecarboxylicacid ethylester ( g,,5.0 20 mMol) was treated with 10 mMol cyclohexylamine and the mixture heated for 6 hours at 1000 in a sealed tube. Preparative HPLC of the crude product gave the title compound along with equal amounts of the N-cyclohexylamide of the starting ester. 25 Step 2: (2- cyclohexylamino-5-pyridyl)methanol The product from Step 1 was reduced with 3 equivalents of LiAlH 4 in THF for 4 hours at room temperature. Lithium salts were precipitatedwith water and aqueous NaOH. The THF layer was filtered through FILTER -AID and the filtrate conc in vac to give 2 30 cyclohexylamino-5-pyridine methanol. Step 3: 5-(4'-cyanobenzyl)- 1- [2-(cyclohexylamino)pyrid-5-yl methyl)]imidazole hydrochloride The product from Step 2 was treated with 1.1 equivalent of triphenylphosphine in refluxing CBr. The crude 2-cyclohexylamino-5 - 100 - WO 99/18096 PCT/US98/20525 pyridylmethyl bromide was purified by silica gel chromatography and reacted with 1-trityl-4-(4-cyanobenzyl)imidazole from Example 1, Step 1 for 12 hours at 60' in dry acetonitrile. The mixture was concentrated and the residue boiled 12 hours in methanol The methanol was 5 concentrated andthe residue purified by preparative HPLC to give the trifluoroacetic salt of the title compound, This was converted to the HCI salt by lyophilization: from dioxane containing 1 equivalent of HC1. EXAMPLE 7 10 5-(4'-Cyanobenzyl) 1- [2-(3"-chlorophenylthio)pyrid-5-ylmethyl] imidazole -S-oxide hydrochloride. The product of Example 1 was oxidized with 1.1 equivalent of 3-chloroperbenzoic acid in THF at -60' to room temperature. 15 Preparative HPLC followed by lyophilization from dioxane HC1 gave pure title compound. EXAMPLE 8 20 Preparation of 2-[N-(1-(4'-Cyanobenzyl)- 1H-imidazol-5 ylethyl)carbamovll -6-(3-trifluoromethylphenoxy)pyridine Step A: 4-Cyanobenzyl histamine NF'-Pivaloyloxymethyl-NU-phthaloylhistamine (4.55 g, 25 12.8 mmol) prepared as previously described (J. C. Emmett, F. H. Holloway, and J. L. Turner, J. Chem. Soc., Perkin Trans. 1, 1341, (1979)) and -Bromo-p-tolunitrile (3.77 g, 19.2 mmol) were dissolved in acetonitrile (70 mL) and heated at 550C for 4 h, cooled to room temperature, and filtered to remove the white solid. The acetonitrile 30 (30 mL) was concentrated to 1/2 its volume under reduced pressure and the solution was heated at 55 0 C overnight. The solution was cooled and filtered to give a white solid. The solids were combined, dried, and used without further purification. 1-Pivaloyloxymethyl-3-(4-cyanobenzyl)-4-(2 35 phthalimidoethyl) imidazolium bromide (1.00 g, 1.81 mmol) was - 101 - WO 99/18096 PCT/US98/20525 dissolved in ethanol (50 mL), treated with hydrazine (0.287 mL, 9.06 mmol), and heated at reflux for 16 h. Dimethyl phthalate (2.22 mL, 13.57 mmol) was added and reflux was continued for 6 h. The reaction mixture was cooled in an ice-H20 bath, the solid precipitate filtered off, 5 the filtrate concentrated to dryness, and the residue chromatographed (SiO2, CH2Cl2(NH4OH): 3 -8% CH3OH) to give the title compound. 1 H NMR (CD3OD) 8 7.76 (s, 1H), 7.74 (d, 2H, J = 8 Hz), 7.27 (d, 2H, J = 8 Hz), 6.88 (s, 1H), 5.35 (s, 2H), 2.76 (t, 2H, J = 6 Hz), 2.60 (t, 2 H, J = 6 Hz). 10 Step B: 2-[N-(1-(4'-Cyanobenzyl)-1H-imidazol-5 ylethyl)carbamoyl] -6-(3-trifluoromethylphenoxy)pyridine 6-(3-Trifluoromethylphenoxy)pyridine-2-carboxylic acid (0.05 g, 0.146 mmol) was dissolved in DMF (2 mL) and treated 15 with EDC (0.0338 g, 0.176 mmol), HOBT (0.0238 g, 0.176 mmol), 4-cyanobenzyl histamine (0.0399 g, 0.176 mmol) and N methylmorpholine (0.048 mL, 0.438 mmol) and stirred at ambient temperature for 18 hr. Purification of the crude reaction by preparative RP HPLC on a Vydac column gave the title compound. 20 Anal. calcd for C26H20N502F 3 * 1.35 CF 3
CO
2 H *0.5 H20: C, 52.67; H, 3.44; N, 10.70; Found: C, 52.67; H, 3.42; N, 10.76. FAB MS 492 (M+1). 25 Using the procedure described above, but substituting the requisite acids in Step B, the following compounds were prepared: 3-[N-( 1 -(4'-Cyanobenzyl)- 1H-imidazol-5-ylethyl)carbamoyl] -6-(3 trifluoromethylphenoxy)pyridine Anal. calcd for C26H20N502F 3 * 0.3 H20: 30 C, 62.84; H, 4.18; N, 14.10; Found: C, 62.80; H, 4.09; N, 13.97. FAB MS 492 (M+1). - 102 - WO 99/18096 PCT/US98/20525 3-[N-( 1 -(4'-Cyanobenzyl)- 1H-imidazol-5-ylethyl)carbamoyl] -5-(3 trifluoromethylphenoxy)pyridine Anal. calcd for C26H20N502F 3 * 0.15 CH2Cl2: C, 62.29; H, 4.06; N, 13.89; 5 Found: C, 62.68; H, 4.44; N, 13.51. FAB MS 492 (M+1). 3-[N-(1-(4'-Cyanobenzyl)- 1H-imidazol-5-ylethyl)carbamoyl] -5-(3 trifluoromethylbenzyloxy)pyridine 10 Anal. called for C27H22N502F 3 * 0.20 H20: C, 63.69; H, 4.44; N, 13.76; Found: C, 63.70; H, 4.48; N, 13.67. FAB MS 506 (M+1). 15 EXAMPLE 9 Preparation of 5-chloro- 1-(3-chlorobenzyl)-2-oxo-1,2-dihydro pyridine-3-carboxylic acid { 2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl] ethyl } -amide 20 5-Chloro- 1-(3-chlorobenzyl)-2-oxo- 1,2-dihydro-pyridine 3-carboxylic acid (0.10 g, 0.335 mmol) was dissolved in DMF (10 mL) and treated with EDC (0.077 g, 0.402 mmol), HOBT (0.054 g, 0.402 mmol), 4-cyanobenzyl histamine (0.079 g, 0.352 mmol) and NMM (0.11 mL, 1.00 mmol) and stirred at ambient temperature for 18 hr. 25 The reaction mixture was concentrated to remove the DMF, then partitioned between EtOAc and aq saturated NaHCO 3 solution, the organic layer separated, washed with brine and dried (MgSO 4 ). The title compound was obtained upon purification by RP HPLC on a PrepPak column eluting with an acetonitrile/H20/TFA gradient followed 30 by neutralization with NaHCO 3 and extraction. Anal. calcd for C26H21N502C12 * 0.20 H20: C, 61.23; H, 4.23; N, 13.73; Found: C, 61.19; H, 4.20; N, 13.59. FAB MS 506 (M+1). - 103 - WO 99/18096 PCT/US98/20525 Using the procedure described above, but substituting the requisite acids, the following compounds were prepared: 1-(3-Chlorobenzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 5 { 2- [3-(4-cyanobenzyl)-3H-imidazol-4-yl] -ethyl } -amide Anal. calcd for C26H22N502C1 * 0.45 H20: C, 65.05; H, 4.81; N, 14.59; Found: C, 65.12; H, 4.84; N, 14.35. FAB MS 472 (M+1). 10 1 -(3-Trifluoromethylbenzyl)-2-oxo- 1,2-dihydro-pyridine-5-carboxylic acid { 2- [3-(4-cyanobenzyl)-3H-imidazol-4-yl]l-ethyl } -amide Anal. calcd for C27H22N502F3 * 0.40 H20: C, 63.25; H, 4.48; N, 13.66; 15 Found: C, 63.30; H, 4.26; N, 13.32. FAB MS 506 (M+1). 1-(3-Chlorobenzyl)-2-oxo-1,2-dihydro-pyridine-5-carboxylic acid { 2 [3-(4-cyanobenzyl)-3H-imidazol-4-yl] -ethyl I -amide 20 Anal. calcd for C26H22N502C1 * 0.30H20: C, 65.41; H, 4.77; N, 14.67; Found: C, 65.42; H, 4.64; N, 14.42. FAB MS 472 (M+1). 25 5-Chloro- 1-(3-chlorobenzyl)-2-oxo- 1,2-dihydro-pyridine-5-carboxylic acid { 2- [3-(4-cyanobenzyl)-3H-imidazol-4-yll -ethyl I -amide Anal. calcd for C26H21N502C12* 0.75 H20: C, 60.06; H, 4.36; N, 13.47; Found: C, 60.08; H, 4.11; N, 13.32. 30 FAB MS 506 (M+1). - 104 - WO 99/18096 PCT/US98/20525 EXAMPLE 10 Preparation of 6-[N-(3-Chlorobenzyl) carbamoyl]- 4-ethoxy-pyridine-2 carboxylic acid { 2- [3-(4-cyanobenzyl)-3H-imidazol-4-yl]l-ethyl }-amide 5 Step A: Diethyl 4-hydroxy-2,6-pyridine dicarboxylate Chelidamic acid (15.1 g, 0.825 mol), abs EtOH (48 mL) and coned H 2
SO
4 (0.9 mL) were combined and heated at reflux for 8 hr. The reaction mixture was concentrated to remove the EtOH, and 10 partitioned between EtOAc and H 2 0. After numerous extractions, concentration of the organic layer, the title compound was obtained after RP HPLC. Step B: Mono methyl ester of 4-ethoxy-2,6-pyridine dicarboxylate 15 The diethyl ester ( 0.300 g, 1.12 mmol) was dissolved in THF (4 mL) and treated with LiOH (0.052 g, 1.23 mmol) in
H
2 0/CH30H (24 mL) and stirred overnight at ambient temperature. The title compound was obtained after preparative RP HPLC. FAB MS 226 (M+1). 20 Step C: 4-Ethoxy-6-methoxycarbonyl-pyridine-2-carboxylic acid { 2- [3-(4-cyanobenzyl)-3H-imidazol-4-yll -ethyl } -amide The mono methyl ester of 4-ethoxy-2,6-pyridine dicarboxylate (0.098 g, 0.435 mmol) was dissolved in DMF ( 1 mL) 25 and treated with EDC (0.108 g, 0.503 mmol), HOBT (0.062 g, 0.456 mmol), 4-cyanobenzylhistamine (0.098 g, 0.435 mmol) and the pH adjusted to 7.5 with NMM. After stirring overnight at ambient temperature, the reaction mixture was concentrated to remove the DMF, then chromatographed on RP HPLC to give the title compound as the 30 TFA salt. FAB MS 434 (M+1). - 105 - WO 99/18096 PCT/US98/20525 Step D: 4-Ethoxy-6-carboxyl-pyridine-2-carboxylic acid {2-[3-(4 cyanobenzyl)-3H-imidazol-4-yl]l-ethyl I -amide 4-Ethoxy-6-methoxycarbonyl-pyridine-2-carboxylic acid { 2- [3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl } -amide (0.249 g, 0.376 5 mmol) was dissolved in THF ( 2 mL) and treated with LiOH (0.052 g, 1.24 mmol) in CH 3 OH (4 mL)- H 2 0 (2 mL) with stirring at ambient temperature for 5 hr. The reaction mixture was concentrated to dryness and used in the next step. 10 Step E: 6-[N-(3-Chlorobenzyl) carbamoyl]- 4-ethoxy-pyridine-2 carboxylic acid { 2- [3-(4-cyanobenzyl)-3H-imidazol-4-yl] ethyl }-amide 4-Ethoxy-6-carboxyl-pyridine-2-carboxylic acid { 2-[3-(4 cyanobenzyl)-3H-imidazol-4-yl]-ethyl }-amide (0.120 g, 0.185 mmol) 15 was dissolved in DMF (2mL) and treated with EDC (0.043 g, 0.222 mmol), HOBT (0.024 g, 0.176 mmol), 3-chlorobenzylamine (0.113 mL, 0.925 mmol) and the pH adjusted to 7.5 with NMM. After stirring overnight at ambient temperature, the reaction mixture was concentrated to remove the DMF, the residue partitioned between 20 EtOAc and aq saturated NaHCO 3 solution, the organic layer separated, washed with brine and dried (MgSO 4 ). Filtration and concentration gave the crude product which was chromatographed on RP HPLC to give the title compound as the TFA salt. Anal. calcd for C29H27N603C1 2.5 CF 3
CO
2 H * 1.15 H20: 25 C, 48.11; H, 3.78; N, 9.90; Found: C, 48.10; H, 3.79; N, 9.69. FAB MS 543 (M+1). - 106 - WO 99/18096 PCT/US98/20525 EXAMPLE 11 Preparation of 6-[N-(3-Chlorophenyl) carbamoyl]- 4-ethoxy-pyridine 2-carboxylic acid { 2- [3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl } 5 amide 4-Ethoxy-6-carboxyl-pyridine-2-carboxylic acid { 2-[3-(4 cyanobenzyl)-3H-imidazol-4-yl]-ethyl }-amide (0.124 g, 0.191 mmol) was dissolved in DMF (2 mL), treated with Bop reagent (0.093 g, 0.210 10 mmol) and NMM (0.083 mL, 0.764 mmol) and stirred overnight at ambient temperature. The solvent was removed in vacuo and the residue partitioned between EtOAc and aq saturated NaHCO 3 solution. The organic layer was separated, washed with brine and dried (MgSO 4 ). Filtration and concentration gave the title compound after 15 chromatography (CH 2 Cl 2 with 1% CH30H then 4.5% CH 3 OH/0.5%
NH
4 OH). Anal. calcd for C28H25N603C1 *0.70 CF 3
CO
2 H * 1.15 H20: C, 56.09; H, 4.48; N, 13.35; Found: C, 56.10; H, 4.52; N, 13.31. 20 FAB MS 529 (M+1). EXAMPLE 12 Preparation of 4-(3-Chlorobenzyloxy)- 6-methoxycarbonyl- pyridine-2 25 carboxylic acid { 2- r3-(4-cyanobenzyl)-3H-imidazol-4-yll -ethyl I -amide Step A: 4-(3-Chlorobenzyloxy)- pyridine-2,6- dicarboxylic acid Chelidamic acid (10.0 g, 0.055 mol) was dissolved in
CH
3 OH (300 mL), treated with concd H2SO 4 (1.8 mL) and heated at 30 reflux for 6 hr, then cooled and concentrated to give an amber oil. Step B: Dimethyl 4-(3-Chlorobenzyloxy) - pyridine-2,6 dicarboxylate 4-(3-Chlorobenzyloxy)- pyridine-2,6- dicarboxylic acid 35 (2.00 g, 9.47 mmol) was dissolved in DMF (19 mL) and treated with - 107 - WO 99/18096 PCT/US98/20525
K
2 C0 3 (3.93 g, 28.4 mmol) and 3-chlorobenzylbromide (1.24 mL, 9.47 mmol). After stirring overnight at ambient temperature, the solvent was removed in vacuo and the residue partitioned between EtOAc and aq saturated NaHCO 3 solution. The organic layer was separated, washed 5 with brine and dried (Na 2
SO
4 ). Filtration and concentration gave the title compound. Step C: Mono methyl ester of 4-(3-Chlorobenzyloxy)- pyridine 2,6- dicarboxylic acid 10 The dimethyl ester ( 3.18 g, 9.46 mmol) was dissolved in THF (10 mL) and treated with LiOH (0.4372 g, 10.41 mmol) in H 2 0/CH30H: 1/3 (200 mL) and stirred overnight at ambient temperature. The title compound was obtained after preparative RP HPLC. 15 Step D: 4-(3-Chlorobenzyloxy)- 6-methoxycarbonyl- pyridine-2 carboxylic acid { 2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl] ethyl } -amide The mono methyl ester of 4-(3-chlorobenzyloxy)- pyridine 20 2,6-_dicarboxylic acid (0.236 g, 0.622 mmol) was dissolved in DMF (2mL) and treated with EDC (0.125 g, 0.653 mmol), HOBT (0.080 g, 0.59 mmol), 4-cyanobenzylhistamine (0.141 g, 0.622 mmol) and the pH adjusted to 7.5 with NMM. After stirring overnight at ambient temperature, the reaction mixture was concentrated to remove the DMF, 25 the residue partitioned between EtOAc and aq saturated NaHCO 3 solution, the organic layer separated, washed with brine and dried (MgSO4). Filtration and concentration gave the crude product which was chromatographed on RP HPLC to give the title compound which was isolated as the HCI salt. 30 Anal. calcd for C28H24N504C1 * HCI * 0.55 H20: C, 58.35; H, 4.56; N, 12.15; Found: C, 58.33; H, 4.73; N, 11.87. FAB MS 530 (M+1). 35 - 108 - WO 99/18096 PCT/US98/20525 EXAMPLE 13 Preparation of 4-(5- { [6-(3-chloro-phenoxy)-pyridin-2-ylamino] methyl I -imidazol- 1 -ylmethyl)-benzonitrile 5 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 10 temperature was added triethylamine (90.6 mL, 650 mmol). A white solid precipitated from the solution. Chlorotriphenylmethane (76.1 g, 273 mmol) 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 15 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: 1-Triphenylmethyl-4-(acetoxymethyl)-imidazole 20 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 48 hours during which it became homogeneous. The solution was poured into 2 L of EtOAc, washed with water (3 x 1 L), 5% aq. HCI 25 soln. (2 x 1 L), sat. aq. NaHCO3, and brine, then dried (Na2SO4), filtered, 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. 30 Step C: 1-(4-Cyanobenzyl)-5-(acetoxymethyl)-imidazole hydrobromide A solution of the product from Step B (85.8 g, 225 mmol) and x-bromo-p-tolunitrile (50.1 g, 232 mmol) in 500 mL of 35 EtOAc was stirred at 60'C for 20 hours, during which a pale yellow - 109 - WO 99/18096 PCT/US98/20525 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 60oC for two hours, cooled to room temperature, and filtered again. 5 The filtrate was concentrated in vacuo to a volume 100 mL, reheated at 60oC for another 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 500 mL of methanol, and warmed to 60oC. After two hours, the solution was reconcentrated 10 in vacuo to provide a white solid which was triturated with hexane to remove soluble materials. Removal of residual solvents in vacuo provided the titled product hydrobromide as a white solid which was used in the next step without further purification. 15 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 0 C was added lithium hydroxide monohydrate (18.9 g, 450 mmol). After one hour, the 20 reaction was concentrated in vacuo, diluted with EtOAc (3 L), and washed with water, sat. aq. NaHCO3 and brine. The solution was then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product as a pale yellow fluffy solid which was sufficiently pure for use in the next step without further purification. 25 Step E: 1-(4-Cyanobenzyl)-5-imidazolecarboxaldehyde To a solution of the alcohol from Step D (21.5 g, 101 mmol) in 500 mL of DMSO at room temperature was added 30 triethylamine (56 mL, 402 mmol), then SO3-pyridine complex (40.5 g, 254 mmol). After 45 minutes, the reaction was poured into 2.5 L of EtOAc, washed with water (4 x 1 L) and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the aldehyde as a white - 110 - WO 99/18096 PCT/US98/20525 powder which was sufficiently pure for use in the next step without further purification. Step _F: 2-Amino-6-(3-chlorophenoxy)-pyridine 5 A mixture of 2-acetylamino-6-bromopyridine (200 mg, 0.93 mmol), 3-chlorophenol (240 mg, 1.86 mmol), CsCO 3 (606 mg, 1.86 mmol), copper (II) triflate benzene complex (10 mg, 0.02 mmol), 1-naphthoic acid (321 mg, 1.86 mmol), ethyl acetate (5 mg, 10 00.5 mmol), and freshly activated powdered 4-angstrom mol. sieves (250 mg) in 2 mL dry toluene was heated with stirring at 110 0 C in a sealed tube for 72 hours. The mixture was cooled and filtered through a Celite pad, and the filtrate concentrated in vacuo. The crude oil was redissolved in ethyl acetate and was washed twice with 15 20% aq. NaOH solution. The organic layer was dried over anhydrous MgSO 4 and was filtered and concentrated to give a yellow oil. The oil was purified by gravity column chromatography over silica gel with 4:1 hexanes/ethyl acetate. Suspected product fractions were combined and concentrated in vacuo to give the product as a 20 yellow oil. The oil was dissolved in 2 mL of 10% aq. sulfuric acid, and the solution heated at 100 0 C for 18 hours. The reaction was cooled and basified to pH 11 with concentrated NH 4 OH solution, and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4, 25 filtered and concentrated to give the title product as an oil. 400 Mhz
H
1 NMR (CDCl 3 ): 4.44(br s, 2H), 6.15(d, 1H), 6.21(d, 1H), 7.02(d, 1H), 7.11(m, 2H), 7.28(m, 1H), 7.42(t, 1H). Step G: 1-(4-Cyanobenzyl)imidazole-5-[6-(3 30 chlorophenoxy)pyridin-2-yl]lmethanamide A mixture of 1-(4-cyanobenzyl)imidazole-5 carboxaldehyde (79 mg, 0.37 mmol) from Step E, 2-amino-6-(3 chlorophenoxy)-pyridine (81 mg, 0.37 mmol) from Step F, and titanium 35 isopropoxidc (131 mg, 0.46 mmol) in 0.50 mL of anhydrous THF was stirred vigorously at room temperature in an argon atmosphere for 1 - 111 - WO 99/18096 PCT/US98/20525 hour. The reaction was diluted with 0.50 mL of anhydrous ethanol and was treated with sodium cyanoborohydride (23 mg, 0.37 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo, and the residue partitioned between 5 ethyl acetate and water. The aqueous layer was reextracted twice with ethyl acetate, and combined extracts washed with brine and dried over anhydrous MgSO4. Filtration and concentration provided the product as a yellow oil. The crude product was purified by reverse phase preparatory LC to give the pure desired product as a tacky white 10 amorphous powder after lyophilization from water. 400 Mhz H NMR (CDCl 3 ): 4.37(s, 2H), 5.31(s, 2H), 6.18(d, 1H), 6.25(d, 1H), 6.94(d, 1H), 7.09(s, 1H), 7.18(d, 2H), 7.19(d, 1H), 7.21(s, 1H), 7.30(m, 1H), 7.42(t, 1H), 7.64(d, 2H), 8.46(s, 1H). High res. FAB MS: theo. = 416.1273, obs. = 416.1286. Elemental analysis for C 23
HI
8
N
5 0C1l 15 0.60 water * 1.15TFA: C(54.47 calc., 54.44 obs.); H (3.68 calc., 3.72 obs.); N(12.56 calc., 1.54 obs.). EXAMPLE 14 20 Preparation of 4-(5-{ [6-(phenylethynyl)-pyridin-2-ylamino]-methyl } imidazol- 1-ylmethyl)-benzonitrile Step A: 2-Amino-6- (1-phenylethyn-2-yl)pyridine 25 A solution of 2-amino-6-bromopyridine (200 mg, 1.16 mmol), 1-phenylacetylene (142 mg, 1.39 mmol), bis (triphenylphosphine) palladium (II) chloride (14 mg, 0.02 mmol), and Cul (2 mg, 0.01 mmol) in 2 mL triethylamine was stirred at 60 0 C in a sealed tube for 18 hours. The reaction was cooled and concentrated in 30 vacuo to a dark oil. The oil was purified by gravity column chromatography over silica gel with 2% methanol/chloroform to give the desired product as a brown oil. 400 Mhz H NMR (CDCl 3 ): 4.57(br s, 2H), 6.49(d, 1H), 6.93(d, 1H), 7.38(m, 3H), 7.41(t, 1H), 7.58(d, 1H). 35 Step B: 1-(4-Cyanobenzyl)imidazole-5-[6-(1-phenylethyn-2 yl)pyridin-2-yllmethanamine Via a procedure identical to that described above in 40 Example 13, Step G, from 100 mg (0.47 mmol) of aldehyde (from - 112 - WO 99/18096 PCT/US98/20525 Example 13, Step E) and 92 mg (0.47 mmol) of 2-amino-6-(1 phenylethyn-2-yl)pyridine (from Step A) the desired product was obtained as an amorphous tacky light yellow powder. 400 Mhz H NMR (CDCl 3 ): 4.50(s, 2H), 5.61(s, 2H), 6.71(d, 1H), 6.89(d, 1H), 5 7.23(d, 2H), 7.38-7.48(complex, 4H), 7.62(d, 2H), 7.65-7.73(complex, 4H), 7.78(t, 1H), 8.58(s, 1H), 10.90(br s, 1H). High res. FAB MS: theo = 390.3713, obs. = 390.1728. Elemental analysis for C 25
H
19
N
5 * 1.00 water * 2.5TFA: C(calc. 43.36, obs. 43.63); H(calc. 3.42, obs. 3.61); N(calc. 10.11, obs. 9.85). 10 EXAMPLE 15 Preparation of 4-(5- { [6-(1,2,3,4-tetrahydronaphth-6-yloxy)-pyridin-2 ylaminol-methyl } -imidazol- 1 -ylmethyl)-benzonitrile 15 Step A: 2-Amino-6-(1,2.3,4-tetrahydronaphthyloxy-6-yl)pyridine Via an identical procedure to that described in Example 13, Step F, from 200 mg (0.93 mmol) of 2-acetylamino-6-bromopyridine 20 and 276 mg (1.86 mmol) of 6-hydroxy-(1,2,3,4-tetrah dro)naphthylene was obtained the title compound as an oil. 400 Mhz H NMR (CDC13): 1.79(d, 4H), 2.77(d, 4H), 6.56(d, 1H), 6.81(d, 1H), 7.04(d, 1H), 7.65(t, 1H), 7.84(d, 1H), 8.12(s, 1H). 25 Step B: 1-(4-Cyanobenzyl)imidazole-5-[6-(1,2,3,4 tetrahydronaphthyloxy-6-yl)pyridin-2-yl] methanamine Via a procedure identical to that described in Example 13, Step G from 132 mg (0.62 mmol) of aldehyde (from Example 13, Step 30 E) and 148 mg (0.62 mmol) of 2-amino-6-(1,2,3,4 tetrahydronaphthyloxy-6-yl)pyridine (from Step A) was obtained the desired product as a clear oil. 400 Mhz H NMR (CDCl 3 ): 1.81(m, 4H), 2.77(m, 4H), 4.43(s, 2H), 5.53(s, 2H), 6.03(d, 1H), 6.18(m, 1H), 6.85(s, 1H), 7.14(d, 1H), 7.25(d, 2H), 7.46(s, 1H), 7.56(t, 1H), 7.66(d, 35 2H), 8.61(s, 1H). High res. FAB MS: theo. = 436.2132, obs. = 436.2143. 40 - 113 - WO 99/18096 PCT/US98/20525 EXAMPLE 16 Preparation of 4-(5- { [6-(2-phenylethyl)-pyridin-2-ylamino]-methyl } imidazol- 1-ylmethyl)-benzonitrile 5 A solution of 1-(4-cyanobenzyl)imidazole-5-[6-(1 phenylethyn-2-yl)-2-pyridyl]methanamine * 2.5TFA (85 mg, 0.13 mmol) from Example 14, Step B in 10 mL of absolute EtOH over 10% Pd on C catalyst (20 mg) was hydrogenated for 18 hours at atmospheric 10 pressure (balloon). The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give an oil. The crude oil was purified via reversed phase preparatory LC to give the desired product as an oil/foam. 400 Mhz H NMR (CDCl 3 ): 2.98(dd, 2H), 3.02(dd, 2H), 4.38(d, 2H), 5.49(d, 2H), 6.59(d, 2H), 7.16-7.37(complex, 7H), 15 7.62(complex, 3H), 7.76(t, 1H), 8.52(s, 1H). FAB MS: M+ = 390. EXAMPLE 17 In vitro inhibition of ras farnesyl transferase 20 Assays of farnesyl-protein transferase. Partially purified bovine FPTase and Ras peptides (Ras-CVLS (SEQ.ID.NO.: 11), Ras CVIM (SEQ.ID.NO.: 1) and Ras-CAIL (SEQ.ID.NO.: 12)) were prepared as described by Schaber et al., J. Biol. Chem. 265:14701 14704 (1990), Pompliano, et al., Biochemistry 31:3800 (1992) and 25 Gibbs et al., PNAS U.S.A. 86:6630-6634 (1989), respectively. Bovine FPTase was assayed in a volume of 100 gl containing 100 mM N-(2 hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgC12, 5 mM dithiothreitol (DTT), 100 mM [ 3 H]-farnesyl diphosphate ([ 3 H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM 30 Ras-CVLS and 10 gg/ml FPTase at 31 C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol. Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB 0 plate counter. The assay was linear with respect to both substrates, 35 FPTase levels and time; less than 10% of the [ 3 H]-FPP was utilized during the reaction period. Purified compounds were dissolved in - 114 - WO 99/18096 PCT/US98/20525 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 5 compound. Human FPTase was prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10 RM ZnCl 2 and 100 nM Ras-CVIM were 10 added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 Rl of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme. The compounds of the instant invention described in the above Examples 1-16 were tested for inhibitory activity against human 15 FPTase by the assay described above and were found to have IC50 of <50 gM. EXAMPLE 18 20 In vivo ras farnesylation assay The cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21. The assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75% 25 confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 37 0 C, the cells are labelled in 3 ml methionine-free DMEM supple meted with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[ 3 5 S]methionine (1000 Cilmmol). After an additional 20 hours, the 30 cells are lysed in 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgC12/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45 min. Aliquots of lysates containing equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (lysis - 115 - WO 99/18096 PCT/US98/20525 buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et al., J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at 4oC, 200 ml of a 25% suspension of protein A-Sepharose coated with rabbit anti rat IgG 5 is added for 45 min. The immunoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1% Triton X 100.0.5% deoxycholate/0.1%/SDS/0.1 M NaCl) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and 10 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. EXAMPLE 19 15 Modified in vitro GGTase inhibition asssay The modified geranylgeranyl-protein transferase inhibition assay is carried out at room temperature. A typical reaction contains (in a final volume of 50 gL): [ 3 H]geranylgeranyl diphosphate, biotinylated 20 Ras peptide, 50 mM HEPES, pH 7.5, a modulating anion (for example 10 mM glycerophosphate or 5mM ATP), 5 mM MgC1 2 , 10 gM ZnC1 2 , 0.1% PEG (15-20,000), 2 mM dithiothreitol, and geranylgeranyl protein transferase type I(GGTase). The GGTase-type I enzyme employed in the assay is prepared as described in U.S. Pat. No. 25 5,470,832, incorporated by reference. The Ras peptide is derived from the K4B-Ras protein and has the following sequence: biotinyl GKKKKKKSKTKCVIM (single amino acid code) (SEQ.ID.NO.: 13). Reactions are initiated by the addition of GGTase and stopped at timed intervals (typically 15 min) by the addition of 200 gL of a 3 mg/mL 30 suspension of streptavidin SPA beads (Scintillation Proximity Assay beads, Amersham) in 0.2 M sodium phosphate, pH 4, containing 50 mM EDTA, and 0.5% BSA. The quenched reactions are allowed to stand for 2 hours before analysis on a Packard TopCount scintillation counter. - 116 - WO 99/18096 PCT/US98/20525 For inhibition studies, assays are run as described above, except inhibitors are prepared as concentrated solutions in 100% dimethyl sulfoxide and then diluted 25-fold into the enzyme assay mixture. IC 50 values are determined with Ras peptide near KM 5 concentrations. Enzyme and nonsaturating substrate conditions for inhibitor IC 5 0 determinations are as follows: 75 pM GGTase-I, 1.6 RM Ras peptide, 100 nM geranylgeranyl diphosphate. EXAMPLE 20 10 Cell-based in vitro growth inhibition assay To determine the biological consequences of FPTase inhibition, the effect of the compounds of the instant invention on the anchorage-independent growth of Ratl cells transformed with either a 15 v-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Raf and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation. Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 10 4 cells per plate (35 mm in diameter) in 20 a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layers contain 0.1% methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay). The 25 cells are fed 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. 30 - 117 - WO 99/18096 PCT/US98/20525 EXAMPLE 21 Construction of SEAP reporter plasmid pDSE100 The SEAP reporter plasmid, pDSE100 was 5 constructed by ligating a restriction fragment containing the SEAP coding sequence into the plasmid pCMV-RE-AKI. The SEAP gene is derived from the plasmid pSEAP2-Basic (Clontech, Palo Alto, CA). The plasmid pCMV-RE-AKI was constructed by Deborah Jones (Merck) and contains 5 sequential copies of the 'dyad symmetry response 10 element' cloned upstream of a 'CAT-TATA' sequence derived from the cytomegalovirus immediate early promoter. The plasmid also contains a bovine growth hormone poly-A sequence. The plasmid, pDSE100 was constructed as follows. A restriction fragment encoding the SEAP coding sequence was cut out 15 of the plasmid pSEAP2-Basic using the restriction enzymes EcoR1 and HpaI. The ends of the linear DNA fragments were filled in with the Klenow fragment of E. coli DNA Polymerase I. The 'blunt ended' DNA containing the SEAP gene was isolated by electrophoresing the digest in an agarose gel and cutting out the 1694 base pair fragment. The vector 20 plasmid pCMV-RE-AKI was linearized with the restriction enzyme Bgl II and the ends filled in with Klenow DNA Polymerase I. The SEAP DNA fragment was blunt end ligated into the pCMV-RE-AKI vector and the ligation products were transformed into DH5-alpha E. coli cells (Gibco-BRL). Transformants were screened for the proper insert and 25 then mapped for restriction fragment orientation. Properly oriented recombinant constructs were sequenced across the cloning junctions to verify the correct sequence. The resulting plasmid contains the SEAP coding sequence downstream of the DSE and CAT-TATA promoter elements and upstream of the BGH poly-A sequence. 30 Cloning of a Myristylated viral-H-ras expression plasmid A DNA fragment containing viral-H-ras can be PCRed from plasmid "H-I" (Ellis R. et al. J. Virol. 36, 408, 1980) using the following oligos. - 118 - WO 99/18096 PCT/US98/20525 Sense strand: 5'TCTCCTCGAGGCCACCATGGGGAGTAGCAAGAGCAAGCCTAA GGACCCCAGCCAGCGCCGGATGACAGAATACAAGCTTGTGGTG 5 G 3'. (SEQ.ID.NO.: 14) Antisense: 5'CACATCTAGATCAGGACAGCACAGACTTGCAGC 3'. (SEQ.ID.NO.: 15) 10 A sequence encoding the first 15 aminoacids of the v-src gene, containing a myristylation site, is incorporated into the sense strand oligo. The sense strand oligo also optimizes the 'Kozak' translation initiation sequence immediately 5' to the ATG start site.To prevent 15 prenylation at the viral-ras C-terminus, cysteine 186 would be mutated to a serine by substituting a G residue for a C residue in the C-terminal antisense oligo. The PCR primer oligos introduce an XhoI site at the 5' end and a XbaI site at the 3'end. The XhoI-XbaI fragment can be ligated into the mammalian expression plasmid pCI (Promega) cut with XhoI 20 and XbaI. This results in a plasmid in which the recombinant myr viral-H-ras gene is constitutively transcribed from the CMV promoter of the pCI vector. 25 Cloning of a viral-H-ras-CVLL expression plasmid A viral-H-ras clone with a C-terminal sequence encoding the amino acids CVLL can be cloned from the plasmid "H-1" (Ellis R. et al. J. Virol. 36, 408, 1980) by PCR using the following oligos. 30 Sense strand: 5'TCTCCTCGAGGCCACCATGACAGAATACAAGCTTGTGGTGG 3' (SEQ.ID.NO.: 16) - 119 - WO 99/18096 PCT/US98/20525 Antisense strand: 5'CACTCTAGACTGGTGTCAGAGCAGCACACACTTGCAGC-3' (SEQ.ID.NO.: 17) 5 The sense strand oligo optimizes the 'Kozak' sequence and adds an XhoI site. The antisense strand mutates serine 189 to leucine and adds an XbaI site. The PCR fragment can be trimmed with XhoI and XbaI and ligated into the XhoI-XbaI cut vector pCI (Promega). This results in a plasmid in which the mutated viral-H-ras-CVLL gene is constitutively 10 transcribed from the CMV promoter of the pCI vector. Cloning of c-H-ras-Leu61 expression plasmid The human c-H-ras gene can be PCRed from a human cerebral cortex 15 cDNA library (Clontech) using the following oligonucleotide primers. Sense strand: 5'-GAGAGAATTCGCCACCATGACGGAATATAAGCTGGTGG-3' (SEQ.ID.NO.: 18) 20 Antisense strand: 5'-GAGAGTCGACGCGTCAGGAGAGCACACACTTGC-3' (SEQ.ID.NO.: 19) 25 The primers will amplify a c-H-ras encoding DNA fragment with the primers contributing an optimized 'Kozak' translation start sequence, an EcoRI site at the N-terminus and a Sal I stite at the C-terminal end. After trimming the ends of the PCR product with EcoRI and Sal I, the c-H-ras fragment can be ligated ligated into an EcoRI -Sal I cut 30 mutagenesis vector pAlter-1 (Promega). Mutation of glutamine-61 to a leucine can be accomplished using the manufacturer's protocols and the following oligonucleotide: 5'-CCGCCGGCCTGGAGGAGTACAG-3' (SEQ.ID.NO.: 20) - 120 - WO 99/18096 PCT/US98/20525 After selection and sequencing for the correct nucleotide substitution, the mutated c-H-ras-Leu61 can be excised from the pAlter-1 vector, using EcoRI and Sal I, and be directly ligated into the vector pCI 5 (Promega) which has been digested with EcoRI and Sal I. The new recombinant plasmid will constitutively transcribe c-H-ras-Leu61 from the CMV promoter of the pCI vector. Cloning of a c-N-ras-Val-12 expression plasmid 10 The human c-N-ras gene can be PCRed from a human cerebral cortex cDNA library (Clontech) using the following oligonucleotide primers. Sense strand: 15 5'-GAGAGAATTCGCCACCATGACTGAGTACAAACTGGTGG-3' (SEQ.ID.NO.: 21) Antisense strand: 5'-GAGAGTCGACTTGTTACATCACCACACATGGC-3' 20 (SEQ.ID.NO.: 22) The primers will amplify a c-N-ras encoding DNA fragment with the primers contributing an optimized 'Kozak' translation start sequence, an EcoRI site at the N-terminus and a Sal I stite at the C-terminal end. 25 After trimming the ends of the PCR product with EcoRI and Sal I, the c-N-ras fragment can be ligated into an EcoRI -Sal I cut mutagenesis vector pAlter-1 (Promega). Mutation of glycine-12 to a valine can be accomplished using the manufacturer's protocols and the following oligonucleotide: 30 5'-GTTGGAGCAGTTGGTGTTGGG-3' (SEQ.ID.NO.: 23) After selection and sequencing for the correct nucleotide substitution, the mutated c-N-ras-Val-12 can be excised from the pAlter-1 vector, - 121 - WO 99/18096 PCT/US98/20525 using EcoRI and Sal I, and be directly ligated into the vector pCI (Promega) which has been digested with EcoRI and Sal I. The new recombinant plasmid will constitutively transcribe c-N-ras-Val-12 from the CMV promoter of the pCI vector. 5 Cloning of a c-K-ras-Val-12 expression plasmid The human c-K-ras gene can be PCRed from a human cerebral cortex cDNA library (Clontech) using the following oligonucleotide primers. 10 Sense strand: 5'-GAGAGGTACCGCCACCATGACTGAATATAAACTTGTGG-3' (SEQ.ID.NO.: 24) 15 Antisense strand: 5'-CTCTGTCGACGTATTTACATAATTACACACTTTGTC-3' (SEQ.ID.NO.: 25) The primers will amplify a c-K-ras encoding DNA fragment with the 20 primers contributing an optimized 'Kozak' translation start sequence, a KpnI site at the N-terminus and a Sal I stite at the C-terminal end. After trimming the ends of the PCR product with Kpn I and Sal I, the c-K-ras fragment can be ligated into a KpnI -Sal I cut mutagenesis vector pAlter-1 (Promega). Mutation of cysteine-12 to a valine can be 25 accomplished using the manufacturer's protocols and the following oligonucleotide: 5'-GTAGTTGGAGCTGTTGGCGTAGGC-3' (SEQ.ID.NO.: 26) 30 After selection and sequencing for the correct nucleotide substitution, the mutated c-K-ras-Val-12 can be excised from the pAlter-1 vector, using KpnI and Sal I, and be directly ligated into the vector pCI (Promega) which has been digested with KpnI and Sal I. The new - 122 - WO 99/18096 PCT/US98/20525 recombinant plasmid will constitutively transcribe c-K-ras-Val-12 from the CMV promoter of the pCI vector. SEAP assay 5 Human C33A cells (human epitheial carcenoma - ATTC collection) are seeded in 10cm tissue culture plates in DMEM + 10% fetal calf serum + 1X Pen/Strep + lX glutamine + IX NEAA. Cells are grown at 37 0 C in a 5% CO2 atmosphere until they reach 50 -80% of conflunecy. 10 The transient transfection is performed by the CaPO4 method (Sambrook et al., 1989). Thus, expression plasmids for H-ras, N-ras, K-ras, Myr-ras or H-ras-CVLL are co-precipitated with the DSE-SEAP reporter construct. For 10cm plates 600 1 of CaCl 2 -DNA solution is added dropwise while vortexing to 600ptl of 2X HBS buffer 15 to give 1.2ml of precipitate solution (see recipes below). This is allowed to sit at room temperature for 20 to 30 minutes. While the precipitate is forming, the media on the C33A cells is replaced with DMEM (minus phenol red; Gibco cat. # 31053-028)+ 0.5% charcoal stripped calf serum + 1X (Pen/Strep, Glutamine and nonessential 20 aminoacids). The CaPO4-DNA precipitate is added dropwise to the cells and the plate rocked gently to distribute. DNA uptake is allowed to proceed for 5-6 hrs at 370C under a 5% CO2 atmosphere. Following the DNA incubation period, the cells are washed with PBS and trypsinized with lml of 0.05% trypsin. The 1 ml of 25 trypsinized cells is diluted into 10ml of phenol red free DMEM + 0.2% charcoal stripped calf serum + 1X (Pen/Strep, Glutamine and NEAA ). Transfected cells are plated in a 96 well microtiter plate (100gl/well) to which drug, diluted in media, has already been added in a volume of 100l. The final volume per well is 200 1 with each drug concentration 30 repeated in triplicate over a range of half-log steps. Incubation of cells and drugs is for 36 hrs at 370 under CO2. At the end of the incubation period, cells are examined microscopically for evidence of cell distress. Next, 100tl of media containing the secreted alkaline phosphatase is removed from each well - 123 - WO 99/18096 PCT/US98/20525 and transferred to a microtube array for heat treatment at 65 0 C for 1 hr to inactivate endogenous alkaline phosphatases (but not the heat stable secreted phosphatase). The heat treated media is assayed for alkaline phosphatase 5 by a luminescence assay using the luminescence reagent CSPD® (Tropix, Bedford, Mass.). A volume of 50 gl media is combinRased with 200 gl of CSPD cocktail and incubated for 60 minutes at room temperature. Luminesence is monitored using an ML2200 microplate luminometer (Dynatech). Luminescence reflects the level of activation 10 of the fos reporter construct stimulated by the transiently expressed protein. DNA-CaPO 4 precipitate for 10cm. plate of cells 15 Ras expression plasmid (lgg/pgl) 1Opl DSE-SEAP Plasmid (lgg/gl) 2gl Sheared Calf Thymus DNA (lgg/tl) 81gl 2M CaC12 7441 dH 2 0 506gl 20 2X HBS Buffer 280mM NaCl 10mM KCl 25 1.5mM Na 2
HPO
4 2H 2 0 12mM dextrose 50mM HEPES Final pH = 7.05 30 Luminesence Buffer (26ml) Assay Buffer 20ml Emerald ReagentTM (Tropix) 2.5ml 100mM homoarginine 2.5ml - 124 - WO 99/18096 PCT/US98/20525 CSPD Reagent® (Tropix) 1.0ml Assay Buffer 5 Add 0.05M Na 2
CO
3 to 0.05M NaHCO 3 to obtain pH 9.5. Make ImM in MgCl 2 EXAMPLE 22 10 In vivo growth inhibition assay To determine the biological consequences of FPTase inhibition, the effect of the compounds of the instant invention on the anchorage-independent growth of Rat1 cells transformed with either a v-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Raf 15 and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation. Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 104 cells per plate (35 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's 20 medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layers contain 0.1% methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay). The cells are fed twice weekly with 0.5 ml of medium A containing 0.1% 25 methanol or the concentration of the instant compound. Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made. - 125 -

Claims (31)

1. A compound of the formula A: R6a-e R 3 A 3 Y (R 8 )r Q V - A'(CR 1 2 )nA 2 (CR 1 2 )n - - (CR 2 2 )p - X-(CR 2 2 )p R R 4 5 A wherein: Q is a 6-membered heterocyclic ring which comprises a 10 nitrogen atom and 0-2 additional nitrogen atoms and having the remaining atoms being carbon atoms, and which also optionally comprises a carbonyl, thiocarbonyl, -C(=NR1 3 ) or sulfonyl moiety adjacent to a nitrogen atom, provided that Q is not piperazine, piperazinone, diketopiperazine, 15 piperidine, piperidinone, diketopiperidine or triketopiperidine; Y is a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from 20 N, S and O, and wherein Y is attached to A 3 through a carbon atom; R1 and R 2 are independently selected from: a) hydrogen, 25 b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, - 126 - WO 99/18096 PCT/US98/20525 C2-C6 alkynyl, R 10 0- , R 1 1 S(O)m-, R 10 C(O)NR 10 -, R 1 1 C(O)O-, (R 10 )2NC(O)-, R 10 2N-C(NR10)-, CN, NO2, R 1 0C(O)-, N3, -N(R 10 )2, or R11OC(O)NR10-, c) unsubstituted or substituted C 1-C6 alkyl wherein the 5 substituent on the substituted C 1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R1 0 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NRO10)-, CN, R10C(O)-, N3, -N(R 10 )2, and 10 R11OC(O)-NR10-; R 3 , R 4 and R 5 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or 15 substituted heterocycle, C3-CO10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, R11S(O)m-, R10C(O)NR 10 -, (R10)2NC(O)-, R 11C(O)O-, R 10 2N-C(NR10)-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, or R 1 1 0C(O)NR 1 0-, 20 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, 25 R 12 0-, R 1 1 S(O)m-, R10C(O)NR 10 -, (R10)2NC(O)-, R 10 2N-C(NRO10)-, CN, R10C(O)-, N3, -N(R 10 )2, and R 1 1 OC(O)-NR 10 -; R 6 a, R6b, R 6 C, R6d and R 6 e are independently selected from: 30 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, - 127 - WO 99/18096 PCT/US98/20525 R 1 1 S(O)m-, R10C(O)NR10-, (R 1 0)2NC(O)-, R 11 C(O)O-, R 10 2N-C(NR10)-, CN, NO2, R10OC(O)-, (R10)2NS(O)2-, R 1 1 S(O)mNR 10 -, N3, -N(R 10 )2, or RllOC(O)NR 10 -, c) unsubstituted C1-C6 alkyl, 5 d) substituted C 1-C6 alkyl wherein the substituent on the substituted C 1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-, R 1 1 S(O)m-, R10C(O)NR10-, (R 10 )2NC(O)-, 10 (R 10 )2NS(O)2-, R 11 S(O)mNR 10 -, R 10 2N-C(NR 10 )-, CN, RO10C(O)-, N3, -N(R 10 )2, and R 1 1 OC(O)-NR 10 -; or any two of R 6 a, R6b, R 6 C, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, 15 -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; R 7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: 20 a) C1-4 alkoxy, b) aryl or heterocycle, c) R 0 d) - S0 2 R e) N(R 1 0 )2 or f) C1-4 perfluoroalkyl; 25 R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C3-CO10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 30 perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-, - 128 - WO 99/18096 PCT/US98/20525 R10OC(O)NR10-, (R 10 )2NC(0)-, (R 10 )2NS(0)2-, RlS(0)mNR10-, R 10 2N-C(NR 10 )-, CN, NO2, R10C(0)-, N3, -N(R 10 )2, or R 1 1 OC(0)NRO 10 -, and c) C1-C6 alkyl unsubstituted or substituted by aryl, 5 cyanophenyl, heterocycle, C3-CO10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-, R 10 C(O)NH-, (R10)2NC(0)-, (R10)2NS(0)2-, R 1 1 S(O)mNR 10 -, R 10 2N-C(NR 10 )-, CN, R 10 C(O)-, N3, -N(R10)2, or R10OC(0)NH-; 10 R 9 is independently selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(0)m-, R 10 C(0)NR1 0 -, (R 10 )2NC(0)-, 15 R 10 2N-C(NRO10)-, CN, NO2, R10C(0)-, N3, -N(R 10 )2, or R 1 1OC(0)NRO10-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(0)m-, R10C(0)NR 10 -, (R 10 )2NC(0)-, R 10 2N-C(NR 10 )-, CN, R10C(0)-, N3, 20 -N(R 10 )2, or R 1 1 OC(0)NR 10 -; R 10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; 25 R 1 1 is independently selected from C1-C6 alkyl and aryl; R 12 is independently selected from hydrogen, C 1-C6 alkyl, C 1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, 30 heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl; - 129 - WO 99/18096 PCT/US98/20525 R 13 is selected from hydrogen, C1-C6 alkyl, cyano, C1-C6 alkylsulfonyl and C 1-C6 acyl; A 1 and A 2 are independently selected from: a bond, -CH=CH-, 5 -C-C-, -C(O)-, -C(O)NRO10-, -NR10C(O)-, O, -N(R10)-, -S(0)2N(R 10 )-, -N(R 10 )S(O)2-, or S(O)m; A 3 is selected from: -CH2-, -CH 2 CH 2 -, -C-C-, O, -N(R 10 )-, S(O)m, -C(O)NR10-, -NR 10 C(O)-, - CH2C(O)NR 10 -, - CH2NR 10 C(0)-, 10 -C(O)NR10CH2-, -NR10C(O)CH2-, -CH20-, -CH2N(R 10 )-, -CH2S(O)m-, -OCH2-, -N(R 10 )CH2- and -S(0)mCH2-; V is selected from: a) hydrogen, 15 b) heterocycle, c) aryl, d) C 1-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, 20 provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; 25 X is a bond, -CH=CH-, O, -C(=0)-, -C(O)NR 7 -, -NR 7 C(0)-, -C(0)O-, -OC(0)-, -C(O)NR 7 C(O)-, -NR 7 -, -S(0)2N(R 10 )-, -N(R 10 )S(0)2- or -S(=O)m-; m is 0, 1 or 2; 30 n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; qis 0, 1, 2 or3; r is 0 to 5, provided that r is 0 when V is hydrogen; and - 130 - WO 99/18096 PCT/US98/20525 t is 0 or 1; or a pharmaceutically acceptable salt thereof. 2. The compound according to Claim 1 having the formula A, wherein: 5 Q is a 6-membered heterocyclic ring which comprises a nitrogen atom and 0-2 additional nitrogen atoms and having the remaining atoms being carbon atoms, and which also optionally comprises a carbonyl, thiocarbonyl, -C(=NR1 3 ) 10 or sulfonyl moiety adjacent to a nitrogen atom, provided that Q is not piperazine, piperazinone, diketopiperazine, piperidine, piperidinone, diketopiperidine or triketopiperidine; 15 Y is a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein Y is attached to A 3 through a carbon atom; 20 R1 and R 2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 0-, R 1 1 S(O)m-, R10C(O)NR 10 -, R 1 1 C(O)O-, (R 10 )2NC(O)-, R 10 2N-C(NR10)-, CN, NO2, 25 RO10C(0)-, N3, -N(R 10 )2, or R11 OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C 1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 30 R 10 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NR 10 )-, CN, RO10C(0)-, N3, -N(R 10 )2, and R 1 1O C(0)-NR 10 -; R
3 , R 4 and R 5 are independently selected from: - 131 - WO 99/18096 PCT/US98/20525 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, 5 R 11 S(O)m-, R 10 C(O)NR 10 -, (R10)2NC(O)-, R 1 1 C(O)O-, R 10 2N-C(NR 1 0)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 1 1 0 O C(O)NR 10 -, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the 10 substituted C 1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, (R 1 0)2NC(O)-, R 10 2N-C(NR10)-, CN, RO10C(O)-, N3, -N(R 10 )2, and 15 R 11 OC(O)-NR 10 -; R 6 a, R6b, R 6 C, R6d and R 6 e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or 20 substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, R 1 1 S(O)m-, R10C(O)NR 10 -, (R10)2NC(O)-, R 1 1 C(O)O-, R 10 2N-C(NR 1 0)-, CN, NO2, RO10C(O)-, (R 10 )2NS(O)2-, R 1 1 S(O)mNR 10 -, N3, -N(R 10 )2, or R11OC(O)NR10-, 25 c) unsubstituted C 1-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-CO10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 30 R1 2 0-, R 1 1 S(O)m-, R10C(O)NR 10 -, (R 10 )2NC(O)-, (R 10 )2NS(O)2-, R 1 1 S(O)mNR10-, R 10 2N-C(NR 10 )-, CN, RO10C(O)-, N3, -N(R 10 )2, and R11oC(O)-NRO10-; or - 132 - WO 99/18096 PCT/US98/20525 any two of R 6 a, R6b, R 6 C, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; 5 R 7 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) " R l 0 10 d) -S0 2 R 11 e) N(R 1 0 )2 or f) C1-4 perfluoroalkyl; R 8 is independently selected from: 15 a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-, R 1 0C(O)NR10-, (R 10 )2NC(O)-, (R 10 )2NS(O)2-, 20 R 1 1 S(O)mNR 10 -, R 10 2N-C(NR 10 )-, CN, NO2, R 1 0C(O)-, N3, -N(R 10 )2, or R 1 1 0C(O)NRO 10 -, 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, R 10 0-, 25 R 1 1 S(O)m-, R 10 C(O)NH-, (R 10 )2NC(O)-, (R 10 )2NS(O)2-, R 1 1 S(O)mNR10-, R 10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, or R 10 0C(O)NH-; R9 is independently selected from: 30 a) hydrogen, - 133 - WO 99/18096 PCT/US98/20525 b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-, R 10 C(O)NR10-, (R 10 )2NC(O)-, R 10 2N-C(NRO10)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R11 OC(O)NR10-, and 5 c) C 1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 0-, R 1 1 S(O)m-, R10C(O)NR10-, (R 10 )2NC(O)-, R 10 2N-C(NR10)-, CN, RO10C(O)-, N3, -N(R 10 )2, or R11 OC(O)NR10-; 10 R 10 is independently selected from hydrogen, C1 -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R 11 is independently selected from C 1-C6 alkyl and aryl; 15 R1 2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C 1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; 20 R 13 is selected from hydrogen, C1-C6 alkyl, cyano, C1-C6 alkylsulfonyl and C1-C6 acyl; A 1 and A 2 are independently selected from: a bond, -CH=CH-, -C--C-, 25 -C(O)-, -C(O)NR10-, -NR10C(O)-, O, -N(R 10 )-, -S(O)2N(R 10 )-, -N(R 10 )S(0)2-, or S(O)m; A 3 is selected from: -CH2-, O, -N(R 10 )-, S(O)m, -C(0)NR10-, -NR10C(O)-, - CH2C(O)NR10-, - CH2NR10C(O)-, 30 -C(O)NR10CH2-, -NR 10 C(0)CH2-, -CH20-, -CH2N(R 10 )-, -CH2S(O)m-, -OCH2-, -N(R 10 )CH2- and -S(0)mCH2-; V is selected from: - 134 - WO 99/18096 PCT/US98/20525 a) hydrogen, b) heterocycle, c) aryl, d) C1 -C20 alkyl wherein from 0 to 4 carbon atoms are 5 replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; 10 W is a heterocycle; X is a bond, -CH=CH-, O, -C(=0)-, -C(0)NR 7 -, -NR 7 C(0)-, -C(0)O-, -OC(0)-, -C(0)NR 7 C(0)-, -NR 7 -, -S(0)2N(R 10 )-, -N(R10)S(0)2- or -S(=O)m-; 15 m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; qis 0, 1, 2 or3; 20 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. 25 3. The compound according to Claim 1 having the formula A, wherein: Q is a 6-membered heterocyclic ring which comprises a nitrogen atom and 0-2 additional nitrogen atoms and having 30 the remaining atoms being carbon atoms, and which also optionally comprises a carbonyl, thiocarbonyl, -C(=NR1 3 ) or sulfonyl moiety adjacent to a nitrogen atom, provided that Q is not piperazine, piperazinone, diketopiperazine, - 135 - WO 99/18096 PCT/US98/20525 piperidine, piperidinone, diketopiperidine or triketopiperidine; Y is selected from: phenyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, 5 furyl, thiazolyl, isothiazolyl, tetrahydrofuryl, piperdinyl, thiazolidinyl, piperazinyl and tetrahydrothienyl; R1 is independently selected from: hydrogen, C3-CO10 cycloalkyl, 10 R 10 0-, -N(R 10 )2, F or C1-C6 alkyl; R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 10 0-, -N(R 10 )2, 15 F or C2-C6 alkenyl, c) unsubstituted or substituted CI1-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, R 10 0- and -N(R 10 )2; 20 R 3 , R 4 and R 5 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 25 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R1 2 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NRO10)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 11OC(O)NR10-, c) unsubstituted C1-C6 alkyl; 30 d) substituted C1-C6 alkyl wherein the substituent on the substituted Cl1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-CO10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, - 136 - WO 99/18096 PCT/US98/20525 R 12 0-, R 1 1 S(0)m-, R10C(0)NR 10 -, (R 10 )2NC(0)-, R 10 2N-C(NR10)-, CN, R10C(0)-, N3, -N(R 10 )2, and R 1 1O C(O)-NR 10 -; 5 R 6 a, R6b, R 6 C, R6d and R 6 e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CO10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, 10 R 11 S(O)m-, R10C(0)NR10-, (R 1 0)2NC(O)-, (R 10 )2NS(O)2-, R 1 1 S(O)mNR 10 -, R 10 2N-C(NR 10 )-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or RllOC(O)NR10-, c) unsubstituted C1-C6 alkyl; d) substituted C1-C6 alkyl wherein the substituent on the 15 substituted CI1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-, R 1 1 S(0)m-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, (R 10 )2NC(O)-, (R 10 )2NS(0)2-, R 1 1 S(0)mNR 10 - , 20 R 10 2N-C(NR 10 )-, CN, RO10C(0)-, N3, -N(R 10 )2, and R1 1 OC(0)-NRO 10 -; or any two of R6a, R6b, R 6 C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, 25 -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; R 7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: 30 a) C1-4 alkoxy, b) aryl or heterocycle, - 137 - WO 99/18096 PCT/US98/20525 c) "" R O 0 d) - SO 2 R l l e) N(R 10 )2 or f) C1-4 perfluoroalkyl; 5 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, R 10 0-, RO10C(O)NR10-, 10 (R 10 )2NC(O)-, CN, NO2, (R 10 )2N-C(NR10)-, RO10C(O)-, (R 10 )2NS(O)2-, R11S(O)mNR 10 -, -N(R 10 )2, or R 1 1 OC(O)NR 10 -, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 0-, R10C(O)NR10-, (R 10 )2N-C(NR10)-, 15 RO10C(O)-, -N(R 10 )2, or R 1 lOC(O)NR 10 -; R 9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, 20 Cl, R1 0 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, (R10)2NC(O)-, CN, NO2, (R 10 )2N-C(NR10)-, RO10C(O)-, -N(R 10 )2, or R 1 1 OC(O)NR 10 -, and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, R1 0 0-, R 1 1 S(O)m-, 25 R10C(O)NR10-, (R 10 )2NC(O)-, CN, (R 10 )2N-C(NR 1 0)-, R10OC(O)-, -N(R 10 )2, or R11 OC(O)NR 10 -; R 10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; 30 - 138 - WO 99/18096 PCT/US98/20525 R 1 1 is independently selected from C1-C6 alkyl and aryl; R 12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, 5 C 1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; A 1 and A 2 are independently selected from: a bond, -CH=CH-, -C-C-, 10 -C(O)-, -C(O)NRO 10 -, O, -N(R10)-, or S(O)m; A 3 is selected from: -CH2-, O, -N(R 10 )-, S(O)m, -C(O)NR 10 -, -NR 10OC(O)-, -CH2C(O)NR 10 -, -CH2NR 10OC(O)-, -C(0)NR 10CH2-, -NR10C(O)CH2-, -CH20-, -CH2N(R 10 )-, -CH2S(0)m-, -OCH2-, 15 N(R 10 )CH2- and -S(0)mCH2-; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, 20 imidazolinyl, pyridinyl, thiazolyl, pyridonyl, 2 oxopiperidinyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C 1-C20 alkyl wherein from 0 to 4 carbon atoms are 25 replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; 30 W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, oxazolyl, indolyl, quinolinyl, triazolyl or isoquinolinyl; - 139 - WO 99/18096 PCT/US98/20525 X is a bond, O, -C(=0)-, -CH=CH-, -C(O)NR 7 -, -NR 7 C(O)-, -NR 7 -, -S(0)2N(RO10)-, -N(R10)S(O)2- or-S(=O)m m is 0, 1 or 2; 5 n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; qis 0, 1, 2 or3; r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1; 10 or a pharmaceutically acceptable salt thereof.
4. The compound according to Claim 1 having the formula B: R 6 a-e (R 8 )r R9a R 3 A 3 -0 V - A'(CR 1 ' 2 )nA 2 (CR 1 2 R N N B (CR 2)-X R 5 15 R 4 wherein: Q is a 6-membered heterocyclic ring which comprises a nitrogen atom and 0-2 additional nitrogen atoms and having 20 the remaining atoms being carbon atoms, and which also optionally comprises a carbonyl, thiocarbonyl, -C(=NR1 3 ) or sulfonyl moiety adjacent to a nitrogen atom, provided that Q is not piperazine, piperazinone, diketopiperazine, piperidine, piperidinone, diketopiperidine or 25 triketopiperidine; Y is selected from: phenyl, cyclohexyl and pyridyl; - 140 - WO 99/18096 PCT/US98/20525 R1 is selected from: hydrogen, C3-C10 cycloalkyl, R 10 0-, -N(R 10 )2, F or C1-C6 alkyl; 5 R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 10 0-, -N(R 10 )2, F or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the 10 substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R 10 0- and -N(R 10 )2; R 3 and R 4 are independently selected from: 15 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Ci1-C6 perfluoroalkyl, R 12 0-, R 1 1S(O)m-, R10C(O)NR 10 -, (R 10 )2NC(O)-, 20 R 10 2N-C(NR 10 )-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, or R 1 1 OC(O)NR 10 -, c) unsubstituted C1-C6 alkyl, d) substituted C 1-C6 alkyl wherein the substituent on the substituted C 1-C6 alkyl is selected from unsubstituted or 25 substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NR 1 0)-, CN, RO10C(O)-, N3, -N(R 10 )2, and R 1 1 OC(O)-NR10-; 30 R 6 a, R6b, R6c, R6d and R 6 e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CO10 cycloalkyl, C2-C6 alkenyl, - 141 - WO 99/18096 PCT/US98/20525 C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, R 1 1 S(O)m-, R10C(O)NR 10 -, (R 10 )2NC(O)-, (R 10 )2NS(O)2-, R 1 1 S(O)mNR 10 -, R 10 2N-C(NR10)-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, or R 1 1 OC(O)NR 10 -, 5 c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C 1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 10 R 12 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, (R 10 )2NS(O)2-, R 1 1 S(O)mNR 10 -, R 10 2N-C(NR 10 )-, CN, R 10 C(O)-, N3, -N(R 10 )2, and R 1 1 0C(O)-NR 10 -; or any two of R 6 a, R6b, R 6 C, R6d and R 6 e on adjacent carbon atoms are 15 combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; R 8 is independently selected from: a) hydrogen, 20 b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 10 0-, R10C(O)NR10-, (R 10 )2NC(O)-, (R 10 )2NS(O)2-, R 1 1 S(O)mNR 10 -, CN, NO2, (R 10 )2N-C(NR10)-, RO10C(O)-, -N(R 10 )2, or 25 R 1 1 OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 0-, R10C(O)NR10-, (R 10 )2N-C(NR 10 )-, (R 10 )2NS(O)2-, R 1 1 S(O)mNR10-, RO10C(O)-, -N(R 10 )2, or R 1 1 OC(O)NR10-; 30 R 9 a and R9b are independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen; - 142 - WO 99/18096 PCT/US98/20525 R 10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R 1 1 is independently selected from C1-C6 alkyl and aryl; 5 R 12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C 1-C6 heteroaralkyl, C 1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Ci1-C6 perfluoroalkyl, 10 2-aminoethyl and 2,2,2-trifluoroethyl; A 1 and A 2 are independently selected from: a bond, -CH=CH-, -C=C-, -C(O)-, -C(O)NR10-, O, -N(RO10)-, or S(O)m; 15 A 3 is selected from: -CH2-, O, -N(RO10)-, - C(O)NR 10 -, -C(O)NR10CH2-, -CH2C(O)NR10-, -CH20-, -OCH2- or S(O)m; V is selected from: 20 a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, 25 c) aryl, d) Cl1-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 A 1 is S(O)m and V is not hydrogen 30 if A 1 is a bond, n is 0 and A 2 is S(O)m; X is a bond, -CH=CH-, -C(0)NR10-, -NR 10 C(0)-, -NR 10 -, O or -C(=O)-; - 143 - WO 99/18096 PCT/US98/20525 m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; pis 0, 1, 2, 3 or 4; and 5 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 1 having the 10 formula C: R6a-e (R 8 )r R 3 A3 " V - A1(CR1 2 )nA2(CR 2 ) ' R 9a C R 9 b (CR 2 2 )-" R 5 R 4 wherein: Q is a 6-membered heterocyclic ring which comprises a 15 nitrogen atom and 0-2 additional nitrogen atoms and having the remaining atoms being carbon atoms, and which also optionally comprises a carbonyl, thiocarbonyl, -C(=NR13). or sulfonyl moiety adjacent to a nitrogen atom, provided that Q is not piperazine, piperazinone, diketopiperazine, 20 piperidine, piperidinone, diketopiperidine or triketopiperidine; Y is selected from: phenyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thiazolyl, isothiazolyl, tetrahydrofuryl, piperdinyl, thiazolidinyl, 25 piperazinyl and tetrahydrothiophenyl; - 144 - WO 99/18096 PCT/US98/20525 R1 is selected from: hydrogen, C3-C10 cycloalkyl, R 10 0-, -N(R 10 )2, F or C1-C6 alkyl; R 2 is independently selected from: 5 a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 10 0-, -N(R 10 )2, F or C2-C6 alkenyl, c) unsubstituted or substituted Ci1-C6 alkyl wherein the substituent on the substituted C 1-C6 alkyl is selected from 10 unsubstituted or substituted aryl, heterocycle, C3-CO10 cycloalkyl, C2-C6 alkenyl, R 10 0- and -N(RO10)2; R 3 and R 4 are independently selected from: a) hydrogen, 15 b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R120-, R1 1 S(O)m-, RO10C(O)NR10-, CN(R 10 )2NC(O)-, R102N-C(NR10)-, CN, NO2, RO10C(O) - , N3, -N(RO10)2, 20 or R110C(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted Ci1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, 25 C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-, R11S(O)m-, RO10C(O)NR 10 - , (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O) - , N3, -N(RO10)2, and R 1 1 iOC(O )- NR 10 - ; 30 R 6 a, R6b, R 6 c, R6d and R 6 e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CO10 cycloalkyl, C2-C6 alkenyl, - 145 - WO 99/18096 PCT/US98/20525 C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, R 11S(O)m-, R10C(O)NR10-, (R 10 )2NC(O)-, R 1 1 S(O)2NR 10 -, (R 10 )2NS(O)2-, R 10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 1 1 OC(O)NR 10 -, 5 c) unsubstituted C1-C6 alkyl, d) substituted C 1-C6 alkyl wherein the substituent on the substituted C 1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 10 R 12 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 1 1 S(O)2NR 10 -, (R 10 )2NS(O)2-, R 10 2N-C(NR 1 0)-, CN, R 10 C(O)-, N3, -N(R 10 )2, and R 1 1 0C(O)-NR 10 -; or any two of R 6 a, R6b, R 6 C, R6d and R 6 e on adjacent carbon atoms are 15 combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; R 8 is independently selected from: a) hydrogen, 20 b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 10 0-, RO10C(O)NR10-, (R 10 )2NC(O)-, R11S(O)2NR 10 -, (R 10 )2NS(O)2-, CN, NO2, (R 10 )2N-C(NR 1 0)-, R10C(O)-, -N(R 10 )2, or 25 R 1 1 0C(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 0-, R10OC(O)NRO10-, (R 10 )2NC(O)-, R 11 S(O)2NR 10 -, (R 10 )2NS(0)2-, (R 10 )2N-C(NR 1 0)-, R10C(O)-, -N(R10)2, or R 1 1 OC(O)NR 10 -; 30 R9a and R9b are independently hydrogen, C 1-C6 alkyl, trifluoromethyl and halogen; - 146 - WO 99/18096 PCT/US98/20525 R 10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R 1 1 is independently selected from C 1-C6 alkyl and aryl; 5 R 12 is independently selected from hydrogen, C 1-C6 alkyl, C 1-C6 aralkyl, C1 -C6 substituted aralkyl, C1 -C6 heteroaralkyl, C 1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 10 2-aminoethyl and 2,2,2-trifluoroethyl; A 1 and A 2 are independently selected from: a bond, -CH=CH-, -C-C-, -C(O)-, -C(O)NRO 10 -, O, -N(RO10)-, or S(O)m; 15 A 3 is selected from: -CH2-, O, -N(R10)- or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, 20 imidazolinyl, pyridinyl, thiazolyl, pyridonyl, 2 oxopiperidinyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C 1-C20 alkyl wherein from 0 to 4 carbon atoms are 25 replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O)m; 30 X is a bond, -CH=CH-, -C(0)NRO 10 -, -NRO10C(0)-, -NR 10 -, O or -C(=O)-; m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; - 147 - WO 99/18096 PCT/US98/20525 p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or 0; and r is 0 to 5, provided that r is 0 when V is hydrogen; 5 or a pharmaceutically acceptable salt thereof.
6. The compound according to Claim 4 having the formula D: R6a-e R9a f \1 R3 A34 -/ N f-f A 1 (CR 2)n N Q \ / R 9 b (CR 2 )p-X R 5 (R 8 )r D 10 wherein: Q is selected from N 00 SNN ||"O NH O 0 from 0-1 of f(s) are independently N, and the remaining fs are 15 independently CH; R1 is selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl; - 148 - WO 99/18096 PCT/US98/20525 R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 10 0-, -N(R 10 )2, F or C2-C6 alkenyl, 5 c) Ci1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R 10 0-, or -N(R10)2; R 3 is selected from: 10 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R120-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)- , 15 R 10 2N-C(NRO10)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 11 OC(O)NR 10 -, c) unsubstituted C1-C6 alkyl, d) substituted CI1-C6 alkyl wherein the substituent on the substituted CI -C6 alkyl is selected from unsubstituted or 20 substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-, R11S(O)m-, R10C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NR10)-, CN, RO10C(O)-, N3, -N(R 10 )2, and R 1 1 0C(O)-NR10-; 25 R 4 is selected from H, halogen, C1 -C6 alkyl and CF3; R6a, R6b, R6c, R6d and R6e are independently selected from: a) hydrogen, 30 b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, - 149 - WO 99/18096 PCT/US98/20525 R 10 2N-C(NRO10)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 1 1 OC(O)NR 10 -, c) unsubstituted C1-C6 alkyl, d) substituted C 1-C6 alkyl wherein the substituent on the 5 substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-, R 11S(O)m-, R10C(O)NR10-, (R 10 )2NC(O)-, R 10 2N-C(NR 1 0)-, CN, RO10C(O)-, N3, -N(R 10 )2, and 10 R 1 1 OC(O)-NRO 10 -; or any two of R 6 a, R6b, R 6 C, 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-; 15 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 20 perfluoroalkyl, F, Cl, R 10 0-, RO10C(O)NR10-, (R 10)2NC(O)-, CN, NO2, (R 10)2N-C(NR 1 0)_, R 1 0C(O)-, -N(RO10)2, or R 1 1OC(O)NRO10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 0-, R10C(O)NRO10-, (R 10 )2NC(O)-, (R 10 )2N-C(NR 1 0)-, 25 R10C(O)-, -N(R 10 )2, or R 1 1OC(O)NR10-; R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl; R10 is independently selected from hydrogen, C 1-C6 alkyl, benzyl, 30 2,2,2-trifluoroethyl and aryl; R 1 1 is independently selected from C1-C6 alkyl and aryl; - 150 - WO 99/18096 PCT/US98/20525 R 12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C 1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 5 2-aminoethyl and 2,2,2-trifluoroethyl; A 1 is selected from: a bond, -C(O)-, O, -N(RO10)-, or S(O)m; A 3 is selected from: -CH2-, O, -N(RO10)- or S(O)m; 10 X is a bond, -CH=CH-, -C(O)NRO 10 -, -NR 10 C(O)-, -NR 10 -, O or -C(=O)-, n is 0 or 1; provided that n is not 0 if A 1 is a bond, O, 15 -N(R10) - or S(O)m; mis 0, 1 or 2; p is 0, 1, 2, 3 or 4; and r is 0, 1 or 2; 20 or a pharmaceutically acceptable salt thereof.
7. The compound according to Claim 5 having the formula E: f- f., R 6a -e R9a R A 3 A'(CRi2)n - R 9 b (CR 2 2 )p-X R 4 \ / R 4 1
8 E (R 8 )r E 25 wherein: - 151 - WO 99/18096 PCT/US98/20525 Q is selected from NN 0 0 N S\,N{- - and 110 NH 0 from 0-1 of f(s) are independently N, and the remaining fs are independently CH; 5 R1 is selected from: hydrogen, C3-C10 cycloalkyl, R 10 0-, -N(R 10 )2, For C1-C6 alkyl; R 2 is independently selected from: 10 a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 10 0-, -N(R 10 )2, F or C2-C6 alkenyl, c) C 1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-CO10 cycloalkyl, C2-C6 alkenyl, R 10 0-, or 15 -N(R10)2; R 3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or 20 substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, R 1 1 S(O)m-, R 10 C(0)NR 10 -, (R 10 )2NC(0)-, R 10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R11 OC(O)NR10-, - 152 - WO 99/18096 PCT/US98/20525 c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted CI1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, 5 C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-, R 1 1 S(O)m-, R10C(O)NR 10 -, (R10)2NC(O)-, R 10 2N-C(NR10)-, CN, RO10C(O)-, N3, -N(R 10 )2, and R 1 1 OC(O)-NR 10 -; 10 R 4 is selected from H, halogen, C1-C6 alkyl and CF3; R 6 a, R6b, R 6 C, R6d and R 6 e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or 15 substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NRO10)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 1 1 OC(O)NRIO-, 20 c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted Ci1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 25 R 12 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NR10)-, CN, RO10C(O)-, N3, -N(R 10 )2, and R 1 1 0oC(O)-NR10-; or any two of R 6 a, R6b, R 6 c, R6d and R 6 e on adjacent carbon atoms are 30 combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; R8 is independently selected from: a) hydrogen, - 153 - WO 99/18096 PCT/US98/20525 b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R100-, R10C(O)NR10-, (R 10 )2NC(O)-, CN, NO2, (R 10 )2N-C(NR10)-, RO10C(O)-, 5 -N(R 10 )2, or R11 OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 0-, R10C(O)NR10-, (R10)2NC(O)-, (R10)2N-C(NR10)_, R10OC(O)-, -N(R 10 )2, or R 1 1OC(O)NR10-; 10 R 9 a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl; R 10 is independently selected from hydrogen, C1 -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; 15 R 1 1 is independently selected from C1-C6 alkyl and aryl; R 12 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, 20 heteroaryl, substituted heteraryl, CI1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; A 1 is selected from: a bond, -C(O)-, O, -N(RO10)-, or S(O)m; 25 A 3 is selected from: -CH2-, O, -N(RO10)- or S(O)m; X is a bond, -CH=CH-, -C(0)NR 10 -, -NR 10 C(O)-, -NR 10 -, O or -C(=O)-; 30 nis 0 or 1; m is 0, 1 or 2; p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O; and - 154 - WO 99/18096 PCT/US98/20525 r is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 5 8. The compound according to Claim 6 having the formula F: f=f 3 A 3 N R N R9a R3A R 6 a-e CR2 N R 9b R4 (CR 2 2 )p X R 8 R 8 F wherein: 10 from 0-1 of f(s) are independently N, and the remaining fs are independently CH; R1 is selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl; 15 R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 10 0-, -N(R 10 )2 or F, c) Ci1-C6 alkyl unsubstituted or substituted by aryl, 20 heterocycle, C3-C10 cycloalkyl, R 10 0-, or -N(R10)2; R 3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or 25 substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, R 1 1 S(O)m-, R 10 C(O)NR10-, (R 10 )2NC(O)-, - 155 - WO 99/18096 PCT/US98/20525 R 10 2N-C(NRO10)-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, or R 1 1 0C(O)NR 10 -, c) unsubstituted C1-C6 alkyl, d) substituted C 1-C6 alkyl wherein the substituent on the 5 substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-, R 1 1 S(O)m-, R10C(O)NR10-, (R 10 )2NC(O)-, R 10 2N-C(NR10)-, CN, RO10C(O)-, N3, -N(R 10 )2, and 10 R 1 1 0C(O)-NR10-; R 4 is selected from H, halogen, CH3 and CF3; R6a, R6b, R 6 C, R6d and R 6 e are independently selected from: 15 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, R 1 S(O)m-, R 10 C(O)NR10-, (R10)2NC(O)-, 20 R 10 2N-C(NRO10)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 1 1 OC(O)NR 10 -, c) unsubstituted C1-C6 alkyl, d) substituted C 1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or 25 substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NR 10 )-, CN, R10C(O)-, N3, -N(R 10 )2, and R 1 1 OC(O)-NRO 10 -; or 30 any two of R 6 a, R6b, R 6 c, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-, - 156 - WO 99/18096 PCT/US98/20525 R8 is independently selected from: -CN, Cl, -NO2, C1-C6 alkoxy, and 2,2,2-trifluoroethoxy; 5 R 9 a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl; R 1 0 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; 10 R 1 1 is independently selected from C1 -C6 alkyl and aryl; R 12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C 1-C6 substituted heteroaralkyl, aryl, substituted aryl, 15 heteroaryl, substituted heteraryl, C 1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; A 3 is selected from: -CH2-, O, -N(R 10 )- or S(O)m; 20 X is a bond, -CH=CH-, -C(O)NRO 10 -, -NR10C(O)-, -NR 10 -, O or -C(=O)-; m is 0, 1 or 2; and pis 0, 1, 2, 3 or4; 25 or a pharmaceutically acceptable salt thereof.
9. The compound according to Claim 7 having the formula G: - 157 - WO 99/18096 PCT/US98/20525 f=f N A N~~Ra - 6 a-e R /R R 8 R 9 b B A1(CR 2 )n 2R 2 G wherein: from 0-1 of f(s) are independently N, and the remaining fs are 5 independently CH; R1 is selected from: hydrogen, C3-C10 cycloalkyl, R 10 0-, -N(R 10 )2, F or C1-C6 alkyl; 10 R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle or C3-C10 cycloalkyl, c) CI1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R 10 0-, or 15 -N(R10)2; R 3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or 20 substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NRO10)-, CN, NO2, RO10C(O)-, N3, -N(R 10 )2, or R11OC(O)NR10-, 25 c) unsubstituted C1-C6 alkyl, d) substituted C 1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or - 158 - WO 99/18096 PCT/US98/20525 substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NR10)-, CN, RO10C(O)-, N3, -N(R 10 )2, and 5 R 1 1 0C(O)-NR10-; R 4 is selected from H, halogen, CH3 and CF3; R 6 a, R6b, R 6 c, R6d and R 6 e are independently selected from: 10 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, R 1 1 S(O)m-, R 10 C(O)NR 10 -, (R10)2NC(O)-, 15 R 10 2N-C(NR 1 0)-, CN, NO2, R10C(O)-, N3, -N(R 10 )2, or R 1 1 OC(O)NR 10 -, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or 20 substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-, R 1 1S(O)m-, R 10 C(O)NR 10 -, (R 10 )2NC(O)-, R 10 2N-C(NRO10)-, CN, R10C(O)-, N3, -N(R 10 )2, and R 1 1 OC(O)-NR 10 -; or 25 any two of R 6 a, R6b, R 6 C, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; 30 R8 is independently selected from: -CN, Cl, -NO2, C1-C6 alkoxy, and 2,2,2-trifluoroethoxy; R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl; - 159 - WO 99/18096 PCT/US98/20525 R 10 is independently selected from hydrogen, C 1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R 1 1 is independently selected from C1 -C6 alkyl and aryl; 5 R 12 is independently selected from hydrogen, C 1-C6 alkyl, C 1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C 1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 10 2-aminoethyl and 2,2,2-trifluoroethyl; A 1 is selected from: a bond, -C(O)-, O, -N(R 10 )-, or S(O)m; A 3 is selected from: -CH2-, O, -N(RO10)- or S(O)m; 15 m is 0, 1 or 2; and n is 0 or 1; or a pharmaceutically acceptable salt thereof. 20
10. A compound which inhibits farnesyl-protein transferase which is selected from: 5-(4'-Cyanobenzyl)-1-[2-(3"-methylphenylthio)pyrid-5-ylmethyl) 25 imidazole; 5-(4'-Cyanobenzyl)-1-[2-(3"-methylphenylphenoxy)pyrid-5 ylmethyl)imidazole; 30 5-(4'-Cyanobenzyl)-1-[2-(3"-chlorophenylthio) pyrid-5-ylmethyl)] imidazole; 5-(4'-Cyanobenzyl)- 1- [2-(cyclohexylthio)pyrid-5-ylmethyl]imidazole; - 160 - WO 99/18096 PCT/US98/20525 5-(4'-Cyanobenzyl)- 1-[2-(3"-methylphenylthio)pyrid-4-ylmethyl)] imidazole; 5-(4'-Cyanobenzyl)- 1- [2-(cyclohexylamino)pyrid-5 5 ylmethyl)]imidazole; 5-(4'-Cyanobenzyl) 1- [2-(3' '-chlorophenylthio)pyrid-5-ylmethyl] imidazole -S-oxide; 10 2-[N-(1-(4'-Cyanobenzyl)- 1H-imidazol-5-ylethyl)carbamoyl] -6-(3 trifluoromethylphenoxy)pyridine; 3-[N-( 1 -(4'-Cyanobenzyl)- 1H-imidazol-5-ylethyl)carbamoyl] -6-(3 trifluoromethylphenoxy)pyridine; 15 3-[N-( 1 -(4'-Cyanobenzyl)- 1H-imidazol-5-ylethyl)carbamoyl] -5-(3 trifluoromethylphenoxy)pyridine; 3-[N-(1-(4'-Cyanobenzyl)- 1H-imidazol-5-ylethyl)carbamoyl] -5-(3 20 trifluoromethylbenzyloxy)pyridine; 5-chloro- 1- (3-chlorobenzyl)-2-oxo- 1,2-dihydro-pyridine-3-carboxylic acid { 2- [3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl } -amide; 25 1-(3-Chlorobenzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid { 2 [3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl}-amide; 1-(3-Trifluoromethylbenzyl)-2-oxo- 1,2-dihydro-pyridine-5-carboxylic acid { 2- [3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl I -amide; 30 1-(3-Chlorobenzyl)-2-oxo-1,2-dihydro-pyridine-5-carboxylic acid { 2 [3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl } -amide; 5-Chloro- 1-(3-chlorobenzyl)-2-oxo- 1,2-dihydro-pyridine-5-carboxylic 35 acid { 2- [3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl } -amide; - 161 - WO 99/18096 PCT/US98/20525 6-[N-(3-Chlorobenzyl) carbamoyl]- 4-ethoxy-pyridine-2-carboxylic acid { 2- [3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl } -amide; 5 6-[N-(3-Chlorophenyl) carbamoyl]- 4-ethoxy-pyridine-2-carboxylic acid { 2- [3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl } -amide; 4-(3-Chlorobenzyloxy)- 6-methoxycarbonyl- pyridine-2-carboxylic acid { 2- [3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl } -amide; 10 4-(5- { [6-(3-chloro-phenoxy)-pyridin-2-ylamino]-methyl } -imidazol- 1 ylmethyl)-benzonitrile; 4-(5- { [6-(phenylethynyl)-pyridin-2-ylamino]-methyl I -imidazol- 1 15 ylmethyl)-benzonitrile; 4-(5- { [6-(1,2,3,4-tetrahydronaphth-6-yloxy)-pyridin-2-ylamino] methyl } -imidazol-1-ylmethyl)-benzonitrile; and 20 4-(5- { [6-(2-phenylethyl)-pyridin-2-ylamino]-methyl }-imidazol- 1 ylmethyl)-benzonitrile or pharmaceutically acceptable salts thereof. 25
11. The compound according to Claim 10 which is: 5-(4'-Cyanobenzyl)- 1-[2-(3' '-chlorophenylthio) pyrid-5-ylmethyl)] imidazole NC CI NCN Cl 30 N S - 162 - WO 99/18096 PCT/US98/20525 or a pharmaceutically acceptable salt thereof.
12. The compound according to Claim 10 which is: 5 5-(4'-Cyanobenzyl)- 1-[2-(3' '-methylphenylphenoxy) pyrid-5 ylmethyl)imidazole NC OH 3 NN or a pharmaceutically acceptable salt thereof. 10
13. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 1.
14. A pharmaceutical composition comprising a 15 pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 4.
15. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective 20 amount of a compound of Claim 5.
16. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 10. 25
17. 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 13. - 163 - WO 99/18096 PCT/US98/20525
18. 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 14. 5
19. 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 15.
20. A method for inhibiting farnesyl-protein transferase 10 which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 16.
21. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective 15 amount of a composition of Claim 13.
22. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 14. 20
23. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 15. 25
24. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 16.
25. A method for treating neurofibromin benign 30 proliferative disorder which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 13. - 164 - WO 99/18096 PCT/US98/20525
26. 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 13. 5
27. 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 13.
28. A method for preventing restenosis which comprises 10 administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 13.
29. A method for treating polycystic kidney disease which comprises administering to a mammal in need thereof a 15 therapeutically effective amount of a composition of Claim 13.
30. A pharmaceutical composition made by combining the compound of Claim 1 and a pharmaceutically acceptable carrier. 20
31. A process for making a pharmaceutical composition comprising combining a compound of Claim 1 and a pharmaceutically acceptable carrier. - 165 -
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