CA2413426A1 - Methods and compositions utilizing quinazolinones - Google Patents

Methods and compositions utilizing quinazolinones Download PDF

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CA2413426A1
CA2413426A1 CA002413426A CA2413426A CA2413426A1 CA 2413426 A1 CA2413426 A1 CA 2413426A1 CA 002413426 A CA002413426 A CA 002413426A CA 2413426 A CA2413426 A CA 2413426A CA 2413426 A1 CA2413426 A1 CA 2413426A1
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substituted
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chosen
hydrogen
aryl
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CA2413426C (en
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Jeffrey T. Finer
Gustav Bergnes
Bainian Feng
Whitney W. Smith
John C. Chabala
David J. Morgans, Jr.
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Cytokinetics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3

Abstract

Quinazolinones of formulae (a, b, c and d) are disclosed. They are useful fo r treating cellular proliferative diseases and disorders associated with KSP kinesin activity.

Claims (64)

1. A method of treating cellular proliferative diseases comprising administering a compound chosen from the group consisting of:

wherein:
R1 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;
R2 and R2' are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; or R2 and R2' taken together form a 3- to 7-membered ring;
R3 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, oxaalkyl, oxaalkylaryl, substituted oxaalkylaryl, oxaalkylheteroaryl, substituted oxaalkylheteroaryl, R15O- and R15-NH-;

R3' is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R15-NH-;
R3" is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;
R4 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R16-alkylene-;
R5, R6, R7 and R8 are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, cyano, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;
R15 is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; and R16 is chosen from alkoxy, amino, alkylamino, dialkylamino, N-heterocyclyl and substituted N-heterocyclyl, or a pharmaceutically acceptable salt thereof.
2. A method of treating a disorder associated with KSP kinesin activity comprising administering a compound chosen from the group consisting of:

wherein:
R1 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;
R2 and R2' are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; or R2 and R2' taken together form a 3- to 7-membered ring;
R3 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, oxaalkyl, oxaalkylaryl, substituted oxaalkylaryl, oxaalkylheteroaryl, substituted oxaalkylheteroaryl, R15O-and R15-NH-;
R3' is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl and R15-NH-;
R3" is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;
R4 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R16-alkylene-;
R5, R6, R7 and R8 are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, cyano, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;
R15 is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; and R16 is chosen from alkoxy, amino, alkylamino, dialkylamino, N-heterocyclyl and substituted N-heterocyclyl, or a pharmaceutically acceptable salt thereof.
3. A method of inhibiting KSP kinesin comprising contacting KSP
kinesin with a compound chosen from the group consisting of:

wherein:
R1 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;
R2 and R2' are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; or R2 and R2' taken together form a 3- to 7-membered ring;
R3 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, oxaalkyl, oxaalkylaryl, substituted oxaalkylaryl, oxaalkylheteroaryl, substituted oxaalkylheteroaryl, R15O-and R15-NH-;
R3' is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl and R15-NH-;
R3" is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;
R4 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R16-alkylene-;
R5, R6, R7 and R8 are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, cyano, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;
R15 is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; and R16 is chosen from alkoxy, amino, alkylamino, dialkylamino, N-heterocyclyl and substituted N-heterocyclyl, or a pharmaceutically acceptable salt thereof.
4. A method according to claim 1, 2 or 3 wherein:
R1 is chosen from hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl and substituted alkylheteroaryl;
R2 is chosen from hydrogen, alkyl and substituted alkyl;
R2' is hydrogen;
R3 is chosen from alkyl, substituted alkyl, alkylaryl, heteroaryl, aryl, substituted aryl, substituted hereroaryl, substituted oxaalkylaryl R15O- and R15-NH-;
R4 is chosen from alkyl, aryl, alkylaryl, alkylheteroaryl, substituted alkyl, substituted aryl, and R16-alkylene-;
R5 is hydrogen;
R6, R7 and R8 are independently chosen from hydrogen, halogen, methyl, cyano and trifluoromethyl;
R15 is chosen from alkyl, aryl and substituted aryl;
R16 is chosen from alkoxy, amino, alkylamino, dialkylamino and N-heterocyclyl.
5. A method according to claim 1, 2 or 3 wherein: R2 is chosen from hydrogen, alkyl and substituted alkyl; R2' is hydrogen; and the stereogenic center to which R2 and R2' are attached is of the R configuration.
6. A method according to claim 1, 2 or 3 comprising administering a compound of the formula:

or a pharmaceutically acceptable salt thereof.
7. A method according to claim 6 wherein R1 is chosen from hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, alkylaryl and substituted alkylaryl.
8. A method according to claim 7 wherein R1 is chosen from hydrogen, ethyl, propyl, methoxyethyl, naphthyl, phenyl, bromophenyl, chlorophenyl, methoxyphenyl, ethoxyphenyl, tolyl, dimethylphenyl, chorofluorophenyl, methylchlorophenyl, ethylphenyl, phenethyl, benzyl, chlorobenzyl, methylbenzyl, methoxybenzyl, tetrahydrofuranylmethyl and (ethoxycarbonyl)ethyl.
9. A method according to claim 6 wherein R2 is chosen from hydrogen, lower alkyl and substituted lower alkyl; R2' is hydrogen; and the stereogenic center to which R2 and R2' are attached is of the R configuration.
10. A method according to claim 9 wherein R2 is chosen from hydrogen, methyl, ethyl, propyl, methylthioethyl, aminobutyl, (CBZ)aminobutyl, cyclohexylmethyl, benzyloxymethyl, methylsulfinylethyl, methylsulfinylmethyl, hydroxymethyl, benzyl and indolylmethyl.
11. A method according to claim 6 wherein R3 is chosen from C1-C13 alkyl; substituted lower alkyl; aryl, substituted aryl, alkylaryl, alkylheteroaryl, oxaalkylaryl, oxaalkylheteroaryl, substituted alkylaryl, substituted alkylheteroaryl, substituted oxaalkylaryl, and substituted oxaalkylheteroarlyl.
12. A method according to claim 11 wherein R3 is chosen from ethyl, propyl, chloropropyl, butoxy, heptyl, butyl, octyl, tridecanyl, (ethoxycarbonyl)ethyl, dimethylaminoethyl, dimethylaminomethyl, phenyl, naphthyl, halophenyl, dihalophenyl, cyanophenyl, halo(trifluoromethyl)phenyl, chlorophenoxymethyl, methoxyphenyl, carboxyphenyl, ethylphenyl, tolyl, biphenylyl, methylenedioxyphenyl, methylsulfonylphenyl, methoxychlorophenyl, chloronaphthyl, methylhalophenyl, trifluoromethylphenyl, butylphenyl, pentylphenyl, methylnitrophenyl, phenoxymethyl, dimethoxyphenyl, phenylvinyl, nitrochlorophenyl, nitrophenyl, dinitrophenyl, bis(trifluoromethyl)phenyl, benzyloxymethyl, benzyl, furanyl, benzofuranyl, pyridinyl, indolyl, methylpyridinyl, quinolinyl, picolinyl, pyrazolyl, and imidazolyl.
13. A method according to claim 6 wherein R3 is R15-NH- and R15 is chosen from lower alkyl; cyclohexyl; phenyl; and phenyl substituted with halo, lower alkyl, loweralkoxy, or lower alkylthio.
14. A method according to claim 13 wherein R15 is chosen from isopropyl, butyl, cyclohexyl, phenyl, bromophenyl, dichlorophenyl, methoxyphenyl, ethylphenyl, tolyl, trifluoromethylphenyl and methylthiophenyl.
15. A method according to claim 6 wherein R4 is chosen from lower alkyl, substituted lower alkyl, cyclohexyl; phenyl substituted with hydroxy, lower alkoxy or lower alkyl; benzyl; heteroarylmethyl; heteroarylethyl; heteroarylpropyl and alkylene-, wherein R16 is amino, lower alkylamino, di(lower alkyl)amino, lower alkoxy, or N-heterocyclyl.
16. A method according to claim 15 wherein R4 is chosen from methyl, ethyl, propyl, butyl, cyclohexyl, carboxyethyl, carboxymethyl, methoxyethyl, hydroxyethyl, hydroxypropyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, diethylaminopropyl, aminopropyl, methylaminopropyl, 2,2-dimethyl-3-(dimethylamino)propyl, 1-cyclohexyl-4-(diethylamino)butyl, aminoethyl, aminobutyl, aminopentyl, aminohexyl, aminoethoxyethyl, isopropylaminopropyl, diisopropylaminoethyl, 1-methyl-4-(diethylamino)butyl, (t-Boc)aminopropyl, hydroxyphenyl, benzyl, methoxyphenyl, methylmethoxyphenyl, dimethylphenyl, tolyl, ethylphenyl, (oxopyrrolidinyl)propyl, (methoxycarbonyl)ethyl, benzylpiperidinyl, pyridinylethyl, pyridinylmethyl, morpholinylethyl, morpholinylpropyl, piperidinyl, azetidinylmethyl, azetidinylpropyl, pyrrolidinylethyl, pyrrolidinylpropyl, piperidinylmethyl, piperidinylethyl, imidazolylpropyl, imidazolylethyl, (ethylpyrrolidinyl)methyl, (methylpyrrolidinyl)ethyl, (methylpiperidinyl)propyl, (methylpiperazinyl)propyl, furanylmethyl and indolylethyl.
17. A method according to claim 6 wherein R1 is chosen from lower alkyl, benzyl, substituted benzyl and substituted phenyl;
R2 is chosen from hydrogen, alkyl, substituted lower alkyl and benzyl;
R2' is hydrogen;
R3 is chosen from substituted phenyl and naphthyl;
R4 is chosen from substituted alkyl and R16-alkylene-;
R5 is hydrogen or halo R6 is hydrogen, methyl or halo;
R7 is hydrogen, halo, lower alkyl, substituted lower alkyl, lower alkoxy or cyano;
R8 is hydrogen or halo; and R16 is chosen from di(lower alkylamino), (lower alkyl)amino, amino, N-heterocyclyl and substituted N-heterocyclyl.
18. A method according to claim 1, 2 or 3 wherein R1 is benzyl or halobenzyl;
R2 is chosen from ethyl and propyl;
R2' is hydrogen;
R3 is substituted phenyl;
R3' is substituted phenyl;
R3" is substituted phenyl;
R4 is -(CH2)m OH or -(CH2)p-R16 wherein m is 2 or 3 and p is 1-3;
R5 is hydrogen;
R6 is hydrogen;
R7 is halo;
R8 is hydrogen; and R16 is chosen from amino, propylamino, and azetidinyl.
19. A method according to claim 18 wherein the stereogenic center to which R2 and R2' are attached is of the R configuration.
20. A method according to claim 1, 2 or 3 comprising administering a compound of formula:

or a pharmaceutically acceptable salt thereof.
21. A method according to claim 20 wherein:
R1 is chosen from hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl, naphthyl and substituted phenyl;
R2 is chosen from hydrogen, lower alkyl and substituted lower alkyl and R2' is hydrogen;
R3' is chosen from C1-C13 alkyl; phenyl; naphthyl; phenyl substituted with halo, lower alkyl, lower alkoxy, nitro, methylenedioxy, or trifluoromethyl; biphenylyl, benzyl and heteroaryl; and R4 is chosen from lower alkyl, substituted lower alkyl, cyclohexyl; phenyl substituted with hydroxy, lower alkoxy or lower alkyl; benzyl; heteroarylmethyl;
heteroarylethyl; heteroarylpropyl and R16-alkylene, wherein R16 is amino, (lower alkyl)amino, di(lower alkyl)amino, lower alkoxy, or N-heterocyclyl.
22. A method according to claim 20 wherein R1 is chosen from lower alkyl, benzyl, substituted benzyl and substituted phenyl;
R2 is hydrogen or lower alkyl;
R2' is hydrogen;
R3' is chosen from substituted phenyl and naphthyl;
R4 is R16-alkylene-, hydroxy lower alkyl or carboxy lower alkyl;
R6 and R7 are chosen from hydrogen and halo;

R5 and R8 are hydrogen;

R16 is chosen from di(lower alkylamino), (lower alkyl)amino, amino, piperidinyl, azetidinyl pyrrolidinyl and morpholinyl.
23. A method according to claim 1, 2 or 3 comprising administering a compound of formula:

or a pharmaceutically acceptable salt thereof.
24. A method according to claim 23 wherein:
R1 is chosen from hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl, naphthyl and substituted phenyl;

R2 is chosen from hydrogen, lower alkyl and substituted lower alkyl and R2' is hydrogen; and R4 is chosen from lower alkyl, cyclohexyl; phenyl substituted with hydroxy, lower alkoxy or lower allcyl; benzyl; heteroarylmethyl; heteroarylethyl;
heteroarylpropyl and R16-alkylene, wherein R16 is di(lower alkyl)amino, alkylamino, amino, lower allcoxy, or N-heterocyclyl.
25. A method according to claim 23 wherein R1 is chosen from lower alkyl, benzyl, substituted benzyl and substituted phenyl;
R2 is hydrogen or lower alkyl;
R2' is hydrogen;
R4 is R16-alkylene-;
R6 and R7 are chosen from hydrogen and halo;

R5 and R8 are hydrogen; and R16 is chosen from di(lower alkylamino), (lower alkyl)amino, amino, pyrrolidinyl, piperidinyl, imidazolyl and morpholinyl.
26. A method according to claim 1, 2 or 3 comprising administering a compound of formula:

27. A method according to claim 26 wherein:

R1 is chosen from hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl, naphthyl and substituted phenyl;
R2 is chosen from hydrogen, lower alkyl and substituted lower alkyl and R2' is hydrogen;
R3" is chosen from C1-C13 alkyl; substituted lower alkyl; phenyl; naphthyl;
phenyl substituted with halo, lower alkyl, lower alkoxy, nitro, methylenedioxy, or trifluoromethyl; biphenylyl; benzyl and heterocyclyl; and R4 is chosen from lower alkyl, substituted lower alkyl; cyclohexyl; phenyl substituted with hydroxy, lower alkoxy or lower alkyl; benzyl; substituted benzyl;
heterocyclyl; heteroarylmethyl; heteroarylethyl; heteroarylpropyl and R16-alkylene, wherein R16 is di(lower alkyl)amino, (lower alkyl)amino, amino, lower alkoxy, or N-heterocyclyl.
28. A method according to claim 27 wherein R1 is chosen from lower alkyl, benzyl, substituted benzyl and substituted phenyl;

R2 is hydrogen or lower alkyl;

R2' is hydrogen;

R3" is chosen from substituted phenyl, heterocyclyl and naphthyl;
R4 is chosen from subtituted benzyl, heterocyclyl substituted lower alkyl and alkylene-;

R6 and R7 are chosen from hydrogen and halo;
R5 and R8 are hydrogen;
R16 is chosen from di(lower alkylamino), (lower alkyl)amino, amino, pyrrolidinyl, azetidinyl piperidinyl, imidazolyl and morpholinyl.
29. A method according to claim 28 wherein R1 is benzyl;
R2 is ethyl;
R2' is hydrogen;
R3" is chosen from halophenyl, polyhalophenyl, tolyl, dimethylphenyl, methoxyphenyl, dimethoxyphenyl, cyanophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, bis(trifluoromethyl)phenyl, carboxyphenyl, t-butylphenyl, methoxycarbonylphenyl, piperidinyl and naphthyl;
R4 is chosen from substituted benzyl, piperidinyl, hydroxy (lower alkyl) and Rlb-allcylene-;

R6 and R7 are chosen from hydrogen and halo;
R5 and R8 are hydrogen;
R16 is chosen from dimethylamino, amino, pyrrolidinyl and piperidinyl.
30. A method according to claim 1 or 2 wherein said disease or disorder is chosen from the group consisting of cancer, hyperplasia, restenosis, and cardiac hypertrophy.
31. A compound chosen from the group consisting of:

wherein:
R1 is chosen from hydrogen, alkyl, alkylaryl, alkylheteroaryl, substituted alkyl, substituted alkylaryl, and substituted alkylheteroaryl;

R2 and R2' are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted allcylaryl, substituted heteroaryl, and substituted alkylheteroaryl; or R2 and R2' taken together form a 3- to 7-membered ring;

R3 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, allcylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, oxaalkyl, oxaalkylaryl, substituted oxaalkylaryl, oxaalkylheteroaryl, substituted oxaalkylheteroaryl, R15O- and R15-NH-;

R3" is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;

R4 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R16-alkylene-;

R5, R6, R7 and R8 are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, cyano, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;

R15 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; and R16 is chosen from alkoxy, amino, alkylamino, dialkylamino, N-heterocyclyl and substituted N-heterocyclyl, or a pharmaceutically acceptable salt thereof, with the proviso that when R3 is R15-NH-, both of R2 and R4 must be other than hydrogen.
32. A compound chosen from the group consisting of:
wherein:
R1 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;

R2 and R2' are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; or R2 and R2' taken together form a 3- to 7-membered ring;

R3' is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl and R15-NH-;

R4 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R16-alkylene-;

R5, R6, R7 and R8 are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, cyano, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;

R15 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; and R16 is chosen from alkoxy, amino, alkylamino, dialkylamino, N-heterocyclyl and substituted N-heterocyclyl, or a pharmaceutically acceptable salt thereof.
33. A compound or salt according to claim 31 or 32 wherein:
R1 is chosen from hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, alkylheteroaryl and substituted alkylaryl;

R2 is chosen from hydrogen, alkyl and substituted alkyl; R2' is hydrogen; and the stereogenic center to which R2 and R2' are attached is of the R configuration.

R3 is chosen from alkyl, aryl, alkylaryl, heteroaryl, substituted aryl, substituted alkyl, substituted heteroaryl, oxaalkylaryl, substituted oxaalkylaryl, R15O- and R15-NH-;

R4 is chosen from alkyl, aryl, alkylaryl, alkylheteroaryl, substituted alkyl, substituted aryl, and R16-alkylene-;

R5 is hydrogen;

R6, R7 and R8 are independently chosen from hydrogen, halogen, methyl and trifluoromethyl;

R15 is chosen from alkyl, aryl and substituted aryl; and R16 is chosen from alkoxy, amino, alkylamino, dialkylamino and N-heterocyclyl.
34. A compound according to claim 31 of formula:

or a pharmaceutically acceptable salt thereof.
35. A compound or salt according to claim 34 wherein R1 is chosen from hydrogen, lower alkyl, substituted lower alkyl, alkylaryl or substituted alkylaryl.
36. A compound or salt according to claim 35 wherein R1 is chosen from hydrogen, ethyl, propyl, methoxyethyl, phenethyl, benzyl, chlorobenzyl, methylbenzyl, methoxybenzyl, tetrahydrofuranylmethyl and (ethoxycarbonyl)ethyl.
37. A compound or salt according to claim 34 wherein R2 is chosen from hydrogen, lower alkyl and substituted lower alkyl; R2' is hydrogen.; and the stereogenic center to which R2 and R2' are attached is of the R configuration.
38. A compound or salt according to claim 37 wherein R2 is chosen from ethyl, i-propyl, c-propyl or t-butyl.
39. A compound or salt according to claim 34 or 37 wherein R3 is chosen from aryl, substituted aryl, alkylaryl, alkylheteroaryl, oxaalkylaryl, oxaalkylheteroaryl, substituted alkylaryl, substituted alkylheteroaryl, substituted oxaalkylaryl or substituted oxaalkylheteroaryl.
40. A compound or salt according to claim 39 wherein R3 is chosen from phenyl, substituted phenyl, benzyl, substituted benzyl, phenylvinyl, substituted phenylvinyl, phenoxy lower alkyl and substituted phenoxy lower alkyl, furanyl, benzofuranyl, pyridinyl, indolyl, methylpyridinyl, quinolinyl, picolinyl, pyrazolyl, and imidazolyl.
41. A compound or salt according to claim 40 wherein R3 is chosen from halophenyl, dihalophenyl, cyanophenyl, halo(trifluoromethyl)phenyl, chlorophenoxymethyl, methoxyphenyl, carboxyphenyl, methylphenyl, ethylphenyl, tolyl, biphenylyl, methylenedioxyphenyl, methylsulfonylphenyl, methoxychlorophenyl, methylhalophenyl, trifluoromethylphenyl, butylphenyl, pentylphenyl, methylnitrophenyl, dimethoxyphenyl, phenylvinyl, nitrochlorophenyl, nitrophenyl, dinitrophenyl, bis(trifluoromethyl)phenyl,
42. A compound or salt according to claim 37 wherein R3 is R15-NH-where R15 is chosen from isopropyl, butyl, cyclohexyl, phenyl, bromophenyl, dichlorophenyl, methoxyphenyl, ethylphenyl, tolyl, trifluoromethylphenyl and.
methylthiophenyl.
43. A compound or salt according to claim 34, 37 or 39 wherein R4 is chosen from lower alkyl, substituted lower alkyl, and R16-alkylene-, wherein R16 is amino, lower alkylamino, di(lower alkyl)amino, lower alkoxy, or N-heterocyclyl.
44. A compound or salt according to claim 34, 37 or 39 wherein R5, R6, R7 and R8 are chosen from hydrogen, halo, lower alkyl, substituted lower alkyl, lower alkoxy and cyano.
45. A compound or salt according to claim 44 wherein R5, R6 and R8 are hydrogen.
46. A compound or salt according to claim 45 wherein R7 is halo.
47. A compound or salt according to claim 34 wherein:
R1 is chosen from alkylaryl or substituted alkylaryl;

R2 is lower alkyl; R2' is hydrogen; and the stereogenic center to which R2 and R2' are attached is of the R configuration;

R3 is substituted aryl;
R4 is substituted alkyl;
R5 is hydrogen;
R6 is hydrogen;
R7 is halo or cyano; and R8 is hydrogen.
48. The compound or salt according to claim 47 wherein:
R1 is benzyl or substituted benzyl;
R2 is i-propyl;
R3 is methyl- and/or halo-substituted phenyl;
R4 is 3-amino-n-propyl;
R5 is hydrogen;
R6 is hydrogen;
R7 is chloro or cyano; and R8 is hydrogen.
49. The compound or salt according to claim 47 wherein:
R1 is benzyl;
R2 is i-propyl;
R3 is p-fluorophenyl;
R4 is 3-amino-n-propyl;
R5 is hydrogen;
R6 is hydrogen;
R7 is fluoro; and R8 is hydrogen.
50. The compound or salt according to claim 47 wherein:
R1 is benzyl;
R2 is i-propyl;
R3 is p-fluorophenyl;
R4 is 3-amino-n-propyl;
R5 is hydrogen;
R6 is hydrogen;
R7 is chloro; and R8 is hydrogen.
51. The compound or salt according to claim 47 wherein:
R1 is benzyl;
R2 is i-propyl;
R3 is 3-fluoro-4-methylphenyl;
R4 is 3-amino-n-propyl;
R5 is hydrogen;
R6 is hydrogen;
R7 is chloro; and R8 is hydrogen.
52. The compound or salt according to claim 47 wherein:
R1 is benzyl;
R2 is i-propyl;
R3 is p-methylphenyl;
R4 is 3-amino-n-propyl;
R5 is hydrogen;
R6 is hydrogen;
R7 is chloro; and R8 is hydrogen.
53. The compound or salt according to claim 47 wherein:
R1 is benzyl;
R2 is i-propyl;
R3 is p-methylphenyl;
R4 is 3-amino-n-propyl;
R5 is hydrogen;
R6 is hydrogen;
R7 is cyano; and R8 is hydrogen.
54. A compound according to claim 32 of formula:
or a pharmaceutically acceptable salt thereof.
55. A compound according to claim 54 wherein:
R1 is chosen from hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl, naphthyl and substituted phenyl;
R2 is chosen from hydrogen, lower alkyl and substituted lower alkyl and R2' is hydrogen;
R3' is chosen from C1-C13 alkyl; phenyl; naphthyl; phenyl substituted with halo, lower alkyl, lower alkoxy, nitro, methylenedioxy, or trifluoromethyl; biphenylyl, benzyl and heteroaryl; and R4 is chosen from lower alkyl, substituted lower alkyl, cyclohexyl; phenyl substituted with hydroxy, lower alkoxy or lower alkyl; benzyl; heteroarylmethyl;
heteroarylethyl; heteroarylpropyl and R16-alkylene, wherein R16 is amino, (lower alkyl)amino, di(lower alkyl)amino, lower alkoxy, or N-heterocyclyl.
56. A compound according to claim 55 wherein:
R1 is chosen from lower alkyl, benzyl, substituted benzyl and substituted phenyl;
R2 is hydrogen or lower alkyl;
R2' is hydrogen;
R3 is chosen from substituted phenyl and naphthyl;
R4 is R16-alkylene-, hydroxy(lower alkyl) or carboxy (lower alkyl);
R7 is hydrogen, fluoro, chloro or methyl;
R5, R6 and R8 are hydrogen;
R16 is chosen from di(lower alkyl)amino, (lower alkyl)amino, amino, pyrrolidinyl and piperidinyl.
57. A compound according to claim 32 of formula:
or a pharmaceutically acceptable salt thereof.
58. A compound or salt according to claim 57 wherein:
R1 is chosen from hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl, naphthyl and substituted phenyl;
R2 is chosen from hydrogen, lower alkyl and substituted lower alkyl and R2' is hydrogen; and R4 is chosen from lower alkyl, cyclohexyl; phenyl substituted with hydroxy, lower alkoxy or lower alkyl; benzyl; heteroarylmethyl; heteroarylethyl;
heteroarylpropyl and R16-alkylene, wherein R16 is di(lower alkyl)amino, (lower alkyl)amino, amino, lower alkoxy, or N-heterocyclyl.
59. A compound or salt according to claim 58 wherein:
R1 is chosen from lower alkyl, benzyl, substituted benzyl and substituted phenyl;
R2 is hydrogen or lower alkyl;
R2' is hydrogen;
R4 is R16-alkylene-;
R7 is hydrogen, fluoro, chloro or methyl;
R5, R6 and R8 are hydrogen;
R16 is chosen from di(lower alkylamino), (lower alkyl)amino, amino, pyrrolidinyl, piperidinyl, imidazolyl and morpholinyl.
60. A compound according to claim 31 of formula:
or a pharmaceutically acceptable salt thereof.
61. A compound or salt according to claim 60 wherein:
R1 is chosen from hydrogen, lower alkyl, substituted lower alkyl, alkylaryl or substituted alkylaryl;
R2 is chosen from hydrogen, lower allcyl and substituted lower alkyl; R2' is hydrogen;
and the stereogenic center to which R2 and R2' are attached is of the R
configuration;
R3'' is chosen from aryl, substituted aryl, alkylaryl, alkylheteroaryl, oxaalkylaryl, oxaalkylheteroaryl, substituted alkylaryl, substituted alkylheteroaryl, substituted oxaalkylaryl or substituted oxaalkylheteroaryl; and R4 is chosen from lower alkyl, substituted lower alkyl, and R16-alkylene, wherein R16 is di(lower alkyl)amino, (lower alkyl)amino, amino, lower alkoxy, or N-heterocyclyl.
62. A compound according to claim 31 wherein said compound is of a formula as defined in Figure 3.
63. A method of screening for KSP kinesin modulators comprising:
(a) combining a kinesin, a candidate bioactive agent and a compound chosen from the group consisting of:
wherein:
R1 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;
R2 and R2' are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; or R2 and R2' taken together form a 3- to 7-membered ring;
R3 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, oxaalkyl, oxaalkylaryl, substituted oxaalkylaryl, oxaalkylheteroaryl, substituted oxaalkylheteroaryl, R15O- and R15-NH-;
R3' is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl and R15-NH-;
R3'' is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;
R4 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R16-alkylene-;
R5, R6, R7 and R8 are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, cyano, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;
R15 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; and R16 is chosen from alkoxy, amino, alkylamino, dialkylamino, N-heterocyclyl and substituted N-heterocyclyl; and (b) determining the effect of said candidate bioactive agent on the activity of said kinesin.
64. A method of screening for compounds that bind to KSP kinesin comprising:
(a) combining a kinesin, a candidate bioactive agent and a labeled compound chosen from the group consisting of:
wherein:
R1 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;
R2 and R2' are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; or R2 and R2' taken together form a 3- to 7-membered ring;
R3 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, oxaalkyl, oxaalkylaryl, substituted oxaalkylaryl, oxaalkylheteroaryl, substituted oxaalkylheteroaryl, R15O- and R15-NH-;

R3' is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl and R15-NH-;
R3'' is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;
R4 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R16-alkylene-;
R5, R6, R7 and R8 are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, cyano, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;
R15 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; and R16 is chosen from alkoxy, amino, alkylamino, dialkylamino, N-heterocyclyl and substituted N-heterocyclyl; and (b) determining the binding of said candidate bioactive agent to said kinesin.
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