Compounds, compositions and methods

• US 20050165089A1
• Filed: 10/05/2004
• Published: 07/28/2005
• Est. Priority Date: 10/06/2003
• Status: Abandoned Application

• Current Assignee: Cytokinetics, Inc.
• Original Assignee: Cytokinetics, Inc.
• Inventors: Dhanak, Dashyant, Bergnes, Gustave
• Application Number:
  US10/959,610
• Publication Number:
  US 20050165089A1
• Time in Patent Office: Days
• US Class Current: 514/456
• 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 37/04 Immunostimulants
• 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 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 491/052 the oxygen-containing ring being six-membered

Abstract

Compounds useful for treating cellular proliferative diseases and disorders by modulating the activity of KSP are disclosed.

Claims

1. A compound having the structure:

4. A compound according to claim 1, wherein one of T and T′

is optionally substituted alkylene, and the other is a covalent bond.

5. A compound according to claim 4, wherein one of T and T′

is optionally substituted methylene, and the other is a covalent bond.

6. A compound according to claim 1, wherein T and T′

are covalent bonds.

7. A compound according to claim 1, wherein one of W, X, Y, and Z is N, and the others are C.

8. A compound according to claim 1, wherein two of W, X, Y, and Z are N, and the others are C.

9. A compound according to claim 1, wherein the ring incorporating W, X, Y, and optionally Z is a pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl, furanyl, pyrrolyl, or thiophenyl ring, each of which is optionally substituted.

10. A compound according to claim 1 any of claims 19, wherein only one of R₂ or R_2′

is hydrogen.

11. A compound according to claim 1, wherein R₂ is optionally substituted C₁-C₄ alkyl and R₂ is hydrogen or optionally substituted C₁-C₄ alkyl.

12. A compound according to claim 11, wherein R_2′

is hydrogen and R₂ is optionally substituted C₁-C₄ alkyl.

13. A compound according to claim 12, wherein R_2′

is hydrogen and R₂ is ethyl or propyl.

14. A compound according to claim 13, wherein R₂ is i-propyl.

15. A compound according to claim 1, wherein R₁ is hydrogen, optionally substituted C₁-C₄ alkyl, optionally substituted phenyl-C₁-C₄-alkyl-, optionally substituted heteroaryl-C₁-C₄-alkyl-, optionally substituted naphthalenylmethyl, optionally substituted phenyl, or naphthyl.

16. A compound according to claim 15, wherein R₁ is optionally substituted phenyl-C₁-C₄-alkyl-, optionally substituted heteroaryl-C₁-C₄-alkyl-, optionally substituted naphthalenylmethyl-, optionally substituted phenyl, or napthyl.

17. A compound according to claim 16, wherein R₁ is naphthyl, phenyl, bromophenyl, chlorophenyl, methoxyphenyl, ethoxyphenyl, tolyl, dimethylphenyl, chorofluorophenyl, methylchlorophenyl, ethylphenyl, phenethyl, benzyl, chlorobenzyl, bromobenzyl, methylbenzyl, methoxybenzyl, cyanobenzyl, hydroxybenzyl, dichlorobenzyl, dimethoxybenzyl, or naphthalenylmethyl.

18. A compound according to claim 17, wherein R₁ is benzyl-, halobenzyl, methylbenzyl, hydroxybenzyl, cyanobenzyl-, methoxybenzyl-, or naphthalenylmethyl.

19. A compound according to claim 18, wherein R₁ is benzyl.

20. A compound according to claim 1, wherein R₄ taken together with R₂ form an optionally substituted 5- to 12-membered nitrogen-containing heterocycle, which optionally incorporates from one to two additional heteroatoms, selected from N, O, and S in the heterocycle ring.

21. A compound according to claim 1, wherein R₁₂ is chosen from optionally substituted C₁-C₁₃ alkyl;

optionally substituted aralkyl; and

optionally substituted heteroaralkyl.

22. A compound according to claim 21, wherein R₁₂ is benzyl or benzyl substituted with one or more of the following groups:

carboxy, alkoxycarbonyl, cyano, halo, C₁-C₄ alkyl-, C₁-C₄ alkoxy, nitro, methylenedioxy, and trifluoromethyl.

23. A compound according to claim 1, wherein R₁₂ is —

C(O)R₃ and R₃ is selected from optionally substituted C₁-C₈ alkyl-, optionally substituted aryl-C₁-C₄-alkyl-, optionally substituted heteroaryl-C₁-C₄-alkyl-, optionally substituted heteroaryl-, optionally substituted aryl-, R₁₅O—

, and R₁₇NH—

;

R₁₅ is chosen from optionally substituted C₁-C₈-alkyl and optionally substituted aryl; and

R₁₇ is chosen from hydrogen, optionally substituted C₁-C₈-alkyl, and optionally substituted aryl.

24. A compound according to claim 23, wherein R₃ is chosen from phenyl;

benzyl;

phenoxymethyl-;

halophenoxymethyl-;

phenylvinyl-;

heteroaryl-;

heteroaryl-substituted with C₁-C₄ alkyl or C₁-C₄ alkyl substituted with halo;

C₁-C₄ alkyl substituted with C₁-C₄ alkoxy-;

benzyloxymethyl-; and

phenyl substituted with one or more of the following substituents;

halo, C₁-C₄ alkyl, C₁-C₄ alkyl substituted with hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkyl substituted with C₁-C₄ alkoxy, nitro, formyl, carboxy, cyano, methylenedioxy, ethylenedioxy, acyl, —

N-acyl, and trifluoromethyl.

25. A compound according to claim 24, wherein R₃ is chosen from phenyl, halophenyl, dihalophenyl, cyanophenyl, halo(trifluoromethyl)phenyl, hydroxymethlylphenyl, methoxymethylphenyl, methoxyphenyl, ethoxyphenyl, carboxyphenyl, formylphenyl, ethylphenyl, tolyl, methylenedioxyphenyl, ethylenedixoyphenyl, methoxychlorophenyl, dihydro-benzodioxinyl, methylhalophenyl, trifluoromethylphenyl, furanyl, C₁-C₄ alkyl substituted furanyl, trifluoromethylfuranyl, C₁-C₄ alkyl substituted trifluoromethylfuranyl, benzofuranyl, thiophenyl, C₁-C₄ alkyl substituted thiophenyl, benzothiophenyl, benzothiadiazolyl, pyridinyl, indolyl, methylpyridinyl, trifluoromethylpyridinyl, pyrrolyl, quinolinyl, picolinyl, pyrazolyl, C₁-C₄ alkyl substituted pyrazolyl, N-methylpyrazolyl, C₁-C₄ alkyl substituted N-methylpyrazolyl, C₁-C₄ alkyl substituted pyrazinyl, C₁-C₄ alkyl substituted isoxazolyl, benzoisoxazolyl, morpholinomethyl, methylthiomethyl, methoxymethyl, N-methyl imidazolyl, and imidazolyl.

26. A compound according to claim 25, wherein R₃ is tolyl, halophenyl, methylhalophenyl, hydroxymethylphenyl, halo(trifluoromethyl)phenyl-, methylenedioxyphenyl, formylphenyl or cyanophenyl.

27. A compound according to claim 23, wherein R₃ is R₁₇NH—

; and

R₁₇ is chosen from hydrogen, C₁-C₄ alkyl, cyclohexyl, phenyl, and phenyl substituted with halo, C₁-C₄ alkyl, trifluoromethyl, C₁-C₄ alkoxy, or C₁-C₄ alkylthio.

28. A compound according to claim 23, wherein R₃ is R₁₅O—

; and

R₁₅ is chosen from optionally substituted C₁-C₈ alkyl and optionally substituted aryl.

29. A compound according to claim 1 wherein R₁₂ is —

SO₂R_3a and R_3a is chosen from C₁-C₁₃ alkyl;

phenyl;

naphthyl;

phenyl substituted with halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, cyano, nitro, methylenedioxy, or trifluoromethyl;

biphenylyl; and

heteroaryl.

30. A compound according to claim 1, wherein R₄ is chosen from hydrogen, optionally substituted C₁-C₁₃ alkyl, optionally substituted aryl, optionally substituted aryl-C₁-C₄-alkyl-, optionally substituted heterocyclyl, and optionally substituted heteroaryl-C₁-C₄-alkyl.

31. A compound according to claim 30, wherein R₄ is chosen from hydrogen;

C₁-C₄alkyl;

cyclohexyl;

phenyl substituted with hydroxyl, C₁-C₄ alkoxy, or C₁-C₄ alkyl;

benzyl; and

R₁₆-alkylene-, wherein R₁₆ is hydroxyl, carboxy, (C₁-C₄ alkoxy)carbonyl;

di(C₁-C₄ alkyl)amino-, (C₁-C₄ alkyl)amino-, amino, (C₁-C₄ alkoxy)carbonylamino-, C₁-C₄ alkoxy-, optionally substituted N-heterocyclyl-, or furanyl.

32. A compound according to claim 31, wherein R₄ is chosen from hydrogen, methyl, ethyl, propyl, butyl, cyclohexyl, carboxyethyl, carboxymethyl, methoxyethyl, hydroxyethyl, hydroxypropyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, diethylaminopropyl, aminopropyl, methylaminopropyl, 2,2-dimethyl-3-(dimethylamino)propyl, aminoethyl, aminobutyl, aminopentyl, aminohexyl, 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, azetidinylethyl, azetidinylpropyl, pyrrolidinylethyl, pyrrolidinylpropyl, piperidinylmethyl, piperidinylethyl, imidazolylpropyl, imidazolylethyl, (ethylpyrrolidinyl)methyl, (methylpyrrolidinyl)ethyl, (methylpiperidinyl)propyl, (methylpiperazinyl)propyl, furanylmethyl, and indolylethyl.

33. A compound according to claim 31, wherein R₄ is R₁₆-alkylene-, wherein R₁₆ is amino, C₁-C₄ alkylamino-, di(C₁-C₄ alkyl)amino-, C₁-C₄ alkoxy-, hydroxyl, or N-heterocyclyl.

34. A compound according to claim 33, wherein R₄ is aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, methylaminoethyl, methylaminopropyl, methylaminobutyl, methylaminopentyl, methylaminohexyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, dimethylaminopentyl, dimethylaminohexyl, ethylaminoethyl, ethylaminopropyl, ethylaminobutyl, ethylaminopentyl, ethylaminohexyl, diethylaminoethyl, diethylaminopropyl, diethylaminobutyyl, diethylaminopentyl, or diethylaminohexyl.

35. A compound according to claim 1, wherein R₁₂ and R₄ taken together with the nitrogen to which they are bound form an optionally substituted imidazolyl ring of the formula:

36. A compound according to claim 1, wherein R₁₂ and R₄ taken together with the nitrogen to which they are bound form an optionally substituted imidazolinyl ring of the formula:

37. A compound according to claim 1, wherein R₁₂ and R₄ form an optionally substituted diazepinone ring of the formula:

38. A compound according to claim 1, wherein R₁₂ and R₄ form an optionally substituted piperazine or diazepam of the formula:

39. A compound according to claim 1, wherein one of W, X, Y, and Z is N and the others are C;

R₁ is benzyl, halobenzyl, methylbenzyl, hydroxybenzyl, cyanobenzyl, methoxybenzyl, or naphthalenylmethyl-;

R₂ is optionally substituted C₁-C₄ alkyl;

R₂, is hydrogen;

R₅, R₆, R₇, and R₈ are independently chosen from hydrogen, amino, alkylamino, dialkylamino, hydroxyl, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, and cyano;

T and T′

are independently a covalent bond or optionally substituted lower alkylene; and

R₁₂ is —

C(O)R₃, wherein R₃ is tolyl, halophenyl, methylhalophenyl-, hydroxymethylphenyl, halo(trifluoromethyl)phenyl-, methylenedioxyphenyl-, formylphenyl, or cyanophenyl; and

R₄ is R₁₆-alkylene-, wherein R₁₆ is amino, C₁-C₄ alkylamino-, di(C₁-C₄ alkyl)amino-, C₁-C₄ alkoxy, hydroxyl, or N-heterocyclyl.

40. A compound according to claim 39, wherein R₂ is propyl.

41. A compound according to claim 1, wherein one of W, X, Y, and Z is N and the others are C;

R₁ is benzyl, halobenzyl, methylbenzyl, hydroxybenzyl, cyanobenzyl, methoxybenzyl, or naphthalenylmethyl-;

R₂ is optionally substituted C₁-C₄ alkyl;

R_2′

is hydrogen;

R₅, R₆, R₇, and R₈ are independently chosen from hydrogen, amino, alkylamino, dialkylamino, hydroxyl, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, and cyano;

T and T′

are independently a covalent bond or optionally substituted lower alkylene; and

R₄ taken together with R₁₂ form an optionally substituted imidazolinyl ring of the formula;

42. A compound according to claim 41, wherein R₂ is propyl.

43. A compound according to claim 1, wherein one of W, X, Y, and Z is N and the others are C;

R₁ is benzyl, halobenzyl, methylbenzyl, hydroxybenzyl, cyanobenzyl, methoxybenzyl, or naphthalenylmethyl-;

R₂ is optionally substituted C₁-C₄ alkyl;

R_2′

is hydrogen;

R₅, R₆, R₇, and R₈ are independently chosen from hydrogen, amino, alkylamino, dialkylamino, hydroxyl, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, and cyano;

T and T′

are independently a covalent bond or optionally substituted lower alkylene; and

R₄ taken together with R₁₂ form an optionally substituted imidazolyl ring of the formula;

44. A compound according to claim 43, wherein R₂ is propyl.

45. A compound according to claim 1, wherein one of W, X, Y, and Z is N and the others are C;

R₁ is benzyl, halobenzyl, methylbenzyl, hydroxybenzyl, cyanobenzyl, methoxybenzyl, or naphthalenylmethyl-;

R₂ is optionally substituted C₁-C₄ alkyl;

R₂, is hydrogen;

R₅, R₆, R₇, and R₈ are independently chosen from hydrogen, amino, alkylamino, dialkylamino, hydroxyl, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, and cyano;

T and T′

are independently a covalent bond or optionally substituted lower alkylene; and

R₄ taken together with R₁₂ form an optionally substituted imidazolidinyl ring.

46. A compound according to claim 45, wherein R₂ is propyl.

47. A compound according to claim 1, wherein one of W, X, Y, and Z is N and the others are C;

R₁ is benzyl, halobenzyl, methylbenzyl, hydroxybenzyl, cyanobenzyl, methoxybenzyl, or naphthalenylmethyl-;

R₂ is optionally substituted C₁-C₄ alkyl;

R₂ is hydrogen;

R₅, R₆, R₇, and R₈ are independently chosen from hydrogen, amino, alkylamino, dialkylamino, hydroxyl, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, and cyano;

T and T′

are independently a covalent bond or optionally substituted lower alkylene; and

R₄ taken together with R₁₂ form an optionally substituted piperazinyl ring.

48. A compound according to claim 47, wherein R₂ is propyl.

49. A compound according to claim 1, wherein one of W, X, Y, and Z is N and the others are C;

R₁ is benzyl, halobenzyl, methylbenzyl, hydroxybenzyl, cyanobenzyl, methoxybenzyl, or naphthalenylmethyl-;

R₂ is optionally substituted C₁-C₄ alkyl;

R_2′

is hydrogen;

R₅, R₆, R₇, and R₈ are independently chosen from hydrogen, amino, alkylamino, dialkylamino, hydroxyl, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, and cyano;

T and T′

are independently a covalent bond or optionally substituted lower alkylene; and

R₄ taken together with R₁₂ form an optionally substituted diazepinoyl ring.

50. A compound according to claim 49, wherein R₂ is propyl.

68. A compound according to claim 1, wherein R₂ and R_2′

are each attached to a stereogenic center having an R-configuration, or a pharmaceutically acceptable salt or solvate thereof.

69. A composition comprising a pharmaceutical excipient and a compound, salt, or solvate thereof of claim 1.

70. A composition according to claim 69, wherein said composition further comprises a chemotherapeutic agent other than a compound of Formula I, II, or III, or a pharmaceutical salt or solvate thereof.

71. A composition according to claim 70, wherein said composition further comprises a taxane.

72. A composition according to claim 70, wherein said composition further comprises a vinca alkaloid.

73. A composition according to claim 70, wherein said composition further comprises a topoisomerase I inhibitor.

74. A method of inhibiting KSP which comprises contacting said kinesin with an effective amount of a compound according to claim 1.

75. A method for the treatment of a cellular proliferative disease comprising administering to a subject in need thereof a compound according to claim 1.

76. A method according to claim 75 wherein said disease is selected from the group consisting of cancer, hyperplasias, restenosis, cardiac hypertrophy, immune disorders, and inflammation.

2. A compound having the structure:

51. A compound according to claim 2, wherein R₁ is benzyl, halobenzyl, methylbenzyl, hydroxybenzyl, methoxybenzyl-, cyanobenzyl, or naphthalenylmethyl-;

R₂ is optionally substituted C₁-C₄ alkyl;

R₂ is hydrogen;

R₅, R₆, R₇, and R₈ are independently chosen from hydrogen, amino, alkylamino, dialkylamino, hydroxyl, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, and cyano;

one of T and T′

is a covalent bond and the other is optionally substituted lower alkylene; and

R₁₂ is —

C(O)R₃, wherein R₃ is tolyl, halophenyl, methylhalophenyl-, hydroxymethylphenyl, halo(trifluoromethyl)phenyl-, methylenedioxyphenyl-, formylphenyl, or cyanophenyl; and

R₄ is R₁₆-alkylene-, wherein R₁₆ is amino, C₁-C₄ alkylamino-, di(C₁-C₄ alkyl)amino-, C₁-C₄ alkoxy, hydroxyl, or N-heterocyclyl.

52. A compound according to claim 51, wherein R₂ is propyl.

53. A compound according to claim 2, wherein R₁ is benzyl, halobenzyl, methylbenzyl, hydroxybenzyl, methoxybenzyl-, cyanobenzyl, or naphthalenylmethyl-;

R₂ is optionally substituted C₁-C₄ alkyl;

R_2′

is hydrogen;

R₅, R₆, R₇, and R₈ are independently chosen from hydrogen, amino, alkylamino, dialkylamino, hydroxyl, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, and cyano;

one of T and T′

is a covalent bond and the other is optionally substituted lower alkylene; and

R₄ taken together with R₁₂ form an optionally substituted imidazolinyl ring of the formula;

54. A compound according to claim 53, wherein R₂ is propyl.

55. A compound according to claim 2, wherein R₁ is benzyl, halobenzyl, methylbenzyl, hydroxybenzyl, methoxybenzyl-, cyanobenzyl, or naphthalenylmethyl-;

R₂ is optionally substituted C₁-C₄ alkyl;

R_2′

is hydrogen;

R₅, R₆, R₇, and R₈ are independently chosen from hydrogen, amino, alkylamino, dialkylamino, hydroxyl, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, and cyano;

one of T and T′

is a covalent bond and the other is optionally substituted lower alkylene; and

R₄ taken together with R₁₂ form an optionally substituted imidazolyl ring of the formula;

56. A compound according to claim 55, wherein R₂ is propyl.

57. A compound according to claim 2, wherein R₁ is benzyl, halobenzyl, methylbenzyl, hydroxybenzyl, methoxybenzyl-, cyanobenzyl, or naphthalenylmethyl-;

R₂ is optionally substituted C₁-C₄ alkyl;

R_2′

is hydrogen;

R₅, R₆, R₇, and R₈ are independently chosen from hydrogen, amino, alkylamino, dialkylamino, hydroxyl, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, and cyano;

one of T and T′

is a covalent bond and the other is optionally substituted lower alkylene; and

R₄ taken together with R₁₂ form an optionally substituted imidazolidinyl ring.

58. A compound according to claim 57, wherein R₂ is propyl.

59. A compound according to claim 2, wherein R₁ is benzyl, halobenzyl, methylbenzyl, hydroxybenzyl, methoxybenzyl-, cyanobenzyl, or naphthalenylmethyl-;

R₂ is optionally substituted C₁-C₄ alkyl;

R_2′

is hydrogen;

R₅, R₆, R₇, and R₈ are independently chosen from hydrogen, amino, alkylamino, dialkylamino, hydroxyl, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, and cyano;

one of T and T′

is a covalent bond and the other is optionally substituted lower alkylene; and

R₄ taken together with R₁₂ form an optionally substituted piperazinyl ring.

60. A compound according to claim 59, wherein R₂ is propyl.

61. A compound according to claim 2, wherein R₁ is benzyl, halobenzyl, methylbenzyl, hydroxybenzyl, methoxybenzyl-, cyanobenzyl, or naphthalenylmethyl-;

R₂ is optionally substituted C₁-C₄ alkyl;

R_2′

is hydrogen;

R₅, R₆, R₇, and R₈ are independently chosen from hydrogen, amino, alkylamino, dialkylamino, hydroxyl, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, and cyano;

one of T and T′

is a covalent bond and the other is optionally substituted lower alkylene; and

R₄ taken together with R₁₂ form an optionally substituted diazepinoyl ring.

62. A compound according to claim 61, wherein R₂ is propyl.

3. A compound having the structure:

63. A compound according to claim 3, wherein R₁ is benzyl, halobenzyl, methylbenzyl, hydroxybenzyl, methoxybenzyl, cyanobenzyl, or naphthalenylmethyl;

R₂ is optionally substituted C₁-C₄ alkyl;

R₂ is hydrogen;

R₅, R₆, R₇, and R₈ are independently chosen from hydrogen, amino, alkylamino, dialkylamino, hydroxyl, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, and cyano; and

R₄ taken together with R₁₂ form an optionally substituted piperazinyl ring.

64. A compound according to claim 63, wherein R₂ is propyl.

65. A compound according to claim 3, wherein R₁ is benzyl, halobenzyl, methylbenzyl, hydroxybenzyl, methoxybenzyl, cyanobenzyl, or naphthalenylmethyl;

R₂ is optionally substituted C₁-C₄ alkyl;

R_2′

is hydrogen;

R₅, R₆, R₇, and R₈ are independently chosen from hydrogen, amino, alkylamino, dialkylamino, hydroxyl, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, and cyano; and

R₄ taken together with R₁₂ form an optionally substituted diazepinoyl ring.

66. A compound according to claim 65, wherein R₂ is propyl.

67. A compound selected from

N-(3-aminopropyl)-N-{1-[7-chloro-4-oxo-3-(phenylmethyl)-4H-pyrano[2,3-b]pyridin-2-yl]-2-methylpropyl}-4-methylbenzamide;

2-{1-[2-(1,3-benzodioxol-5-yl)-4,5-dihydro-1H-imidazol-1-yl]-2-methylpropyl}-7-chloro-3-{[3-(methyloxy)phenyl]methyl}-4H-pyrano[2,3-b]pyridin-4-one;

4-{1-[7-Chloro-4-oxo-3-(phenylmethyl)-4H-chromen-2-yl]-2-methylpropyl} hexahydro-5H-1,4-diazepin-5-one; and

7-Chloro-2-[2-methyl-1-(7-oxohexahydro-1H-1,4-diazepin-1-yl)propyl]-3-(phenylmethyl)-4H-pyrano[2,3-b]pyridin-4-one.

77. (canceled)

78. (canceled)