Methods and compositions utilizing quinazolinones

• US 20040023996A1
• Filed: 08/15/2003
• Published: 02/05/2004
• Est. Priority Date: 06/21/2000
• Status: Abandoned Application

• Current Assignee: Cytokinetics, Inc.
• Original Assignee: Cytokinetics, Inc.
• Inventors: Morgans, David J. Jr., Finer, Jeffrey T., Feng, Bainian, Chabala, John C., Smith, Whitney W., Bergnes, Gustave
• Application Number:
  US10/312,323
• Publication Number:
  US 20040023996A1
• Time in Patent Office: Days
• US Class Current: 514/266.3
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 239/90 with acyclic radicals attached in position 2 or 3
• CPC Class Codes: C07D 239/91 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 for treating cellular proliferative diseases and disorders associated with KSP kinesin activity.

Claims

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

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:

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 R₁₆-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;

R_3′

is substituted phenyl;

R_3″

is substituted phenyl;

R₄ is —

(CH₂)_mOH 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 R_2′

are attached is of the R configuration.

20. A method according to claim 1, 2 or 3 comprising administering a compound of formula:

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;

R_3′

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;

R_3′

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:

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 alkyl;

benzyl;

heteroarylmethyl;

heteroarylethyl;

heteroarylpropyl and R₁₆-alkylene, wherein R₁₆ is di(lower alkyl)amino, alkylamino, amino, lower alkoxy, 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;

R_3″

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;

R_3″

is chosen from substituted phenyl, heterocyclyl and naphthyl;

R₄ is chosen from subtituted benzyl, heterocyclyl substituted lower alkyl and R₁₆-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;

R_3″

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 R₁₆-alkylene-;

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.

2. A method of treating a disorder associated with KSP kinesin activity comprising administering a compound chosen from the group consisting of:

3. A method of inhibiting KSP kinesin comprising contacting KSP kinesin with a compound chosen from the group consisting of:

31. A compound chosen from the group consisting of:

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:

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.

60. A compound according to claim 31 of formula:

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 alkyl and substituted lower alkyl;

R₂′

is hydrogen; and

the stereogenic center to which R₂ and R₂′

are attached is of the R configuration;

R_3″

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 FIG. 3.

32. A compound chosen from the group consisting of:

54. A compound according to claim 32 of formula:

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:

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.

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—

;

R_3′

is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl and R₁₅—

NH—

;

R_3″

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—

;

R_3″

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.