Urea derivatives as FLT-3 modulators

• US 20050267182A1
• Filed: 11/15/2004
• Published: 12/01/2005
• Est. Priority Date: 11/13/2003
• Status: Abandoned Application

• Current Assignee: Ambit Biosciences Corporation (Daiichi Sankyo Company Limited)
• Original Assignee: Ambit Biosciences Corporation (Daiichi Sankyo Company Limited)
• Inventors: Patel, Hitesh K., Lockhart, David J., Lai, Andiliy G., Milanov, Zdravko V., Mehta, Shamal A., Grotzfeld, Robert M.
• Application Number:
  US10/989,717
• Publication Number:
  US 20050267182A1
• Time in Patent Office: Days
• US Class Current: 514/378
• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/08 Bronchodilators
• 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 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/40 Acylated on said nitrogen atom
• CPC Class Codes: C07D 261/08 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 261/14 Nitrogen atoms
• CPC Class Codes: C07D 261/18 Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
• CPC Class Codes: C07D 277/46 by carboxylic acids, or sulfur or nitrogen analogues thereof
• CPC Class Codes: C07D 277/82 Nitrogen atoms
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 471/06 : Peri-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides methods and compositions for treating conditions mediated FLT-3. The invention also provides methods of using the compounds and/or compositions in the treatment of a variety of diseases and unwanted conditions in subjects.

Claims

1. A method for modulating FLT-3 kinase, said method comprising administering an effective amount of a FLT-3 modulating compound corresponding to Formula (IA):

wherein;

M is substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl;

N is a substituted or unsubstituted aryl, or substituted or unsubstituted hetroaryl; and

K is

Y is O or S;

each R_k is independently H, halogen, substituted or unsubstituted alkyl, —

OH, substituted or unsubstituted alkoxy, —

OC(O)R₂, —

NO₂, —

N(R₂)₂, —

SR₂, —

C(O)R₂, —

C(O)₂R₂, —

C(O)N(R₂)₂, or —

N(R₂)C(O)R₂,

each R₂ is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

or wherein two R₂ groups are linked together by an optionally substituted alkylene; and

each n is independently 0, 1, 2, 3 or 4;

or an active metabolite, or a pharmaceutically acceptable prodrug, isomer, pharmaceutically acceptable salt or solvate thereof.

2. The method of claim 1, wherein said compound corresponds to Formula (IB):

wherein;

each Z is independently C, CR₃, N, NR₃, O, or S, provided that no more than two Z'"'"'s are heteroatoms and wherein no two adjacent Z'"'"'s are O or S,

where R₃ is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; and

each R₁ is independently H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —

OR_c —

OH, —

OC(O)R_c, —

NO₂, —

N(R_c)₂, —

SR_c, S(O)_jR_c where j is 1 or 2, —

NR_cC(O)R_c, —

C(O)N(R_c)₂, C(O)₂R_c, or —

C(O)R_c;

or two adjacent R₁'"'"'s, are taken together to form a substituted or unsubstituted aryl or heteroaryl, where

each R_c is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

3. The method of claim 2, wherein said compound corresponds to Formula (I):

4. The method of claim 3, wherein said compound corresponds to Formula (II):

5. The method of claim 4, wherein said compound corresponds to Formula (III):

wherein Z₁ is CR₃ or N; and

Z₂ is O or S.

6. The method of claim 5, wherein said compound is selected from the group consisting of:

7. The method of claim 5, wherein said compound corresponds to Formula (IV):

wherein;

each R₁ is independently H, halogen, substituted or unsubstituted alkyl, —

O(substituted or unsubstituted alkyl), —

O(substituted or unsubstituted alkenyl), —

NR_cC(O)O(substituted or unsubstituted alkyl), —

NR_cC(O)(substituted or unsubstituted alkyl), —

NR_cC(O)(substituted or unsubstituted alkenyl), —

C(O)NR_c(substituted or unsubstituted alkyl), —

C(O)NR_c(substituted or unsubstituted alkenyl), —

NO₂, —

S(═

O)R_c, —

SR_c, C(O)₂R_c, or —

C(O)R_c; and

each R₂ is independently H or substituted or unsubstituted alkyl.

8. The method of claim 5, wherein said compound corresponds to Formula (V):

9. The method of claim 8, wherein said compound is selected from the group consisting of:

11. The method of claim 1, wherein said compound corresponds to Formula (VI):

wherein;

each R₁ is independently H, halogen, substituted or unsubstituted alkyl, —

O(substituted or unsubstituted alkyl), —

O(substituted or unsubstituted alkenyl), —

NR_cC(O)O(substituted or unsubstituted alkyl), —

NR_cC(O) (substituted or unsubstituted alkyl), —

NR_cC(O)(substituted or unsubstituted alkenyl), —

C(O)NR_c(substituted or unsubstituted alkyl), —

C(O)NR_c(substituted or unsubstituted alkenyl), —

NO₂, —

S(═

O)R_c, —

SR_c, C(O)₂R_c, or —

C(O)R_c; and

each R₂ is independently H or substituted or unsubstituted alkyl.

14. The method of claim 5, wherein said compound corresponds to Formula (IX):

wherein;

L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene, —

C(O)NH—

, —

C(O)—

, —

NH—

, —

O—

, —

S—

, —

O(substituted or unsubstituted alkylene)-, —

N(substituted or unsubstituted alkylene)-, —

C(O)NH(substituted or unsubstituted alkylene)-, —

C(O)NH(substituted or unsubstituted alkenylene)- —

NHC(O)(substituted or unsubstituted alkylene)-, —

NHC(O)(substituted or unsubstituted alkenylene)-, —

C(O)(substituted or unsubstituted alkenylene)-, and —

NHC(O)(substituted or unsubstituted alkylene)S(substituted or unsubstituted alkylene)C(O)NH—

; and

T is a mono-, bi, -or tricyclic, substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl.

15. The method of claim 14, wherein said compound is selected from the group consisting of:

16. The method of claim 14, wherein T of said compound corresponds to Formula (X):

wherein A is a substituted or unsubstituted five or six-membered heterocyclyl, aryl, or heteroaryl; and

B is a substituted or unsubstituted five or six-membered heterocyclene, arylene, or heteroarylene, wherein A and B together form a fused two ring moiety.

17. The method of claim 16, wherein said compound corresponds to Formula (XI):

18. The method of claim 17, wherein L of said compound is a covalent bond, —

C(O)NH(substituted or unsubstituted alkylene)-, —

NHC(O)—

, —

NHC(O)(substituted or unsubstituted alkylene)-, —

NH—

, or —

O(substituted or unsubstituted alkylene)-.

19. The method of claim 18, wherein said compound corresponds to Formula (XII):

20. The method of claim 19, wherein B of said compound is a substituted or unsubstituted five-membered arylene or heteroarylene.

21. The method of claim 20, wherein said compound is:

22. The method of claim 20, wherein B is substituted or unsubstituted thiophenylene.

23. The method of claim 22, wherein said compound is selected from the group consisting of:

24. The method of claim 20, wherein B is substituted or unsubstituted imidazolylene.

25. The method of claim 24, wherein said compound is selected from the group consisting of:

26. The method of claim 20, wherein B is substituted or unsubstituted pyrrolylene.

27. The method of claim 26, wherein said compound is selected from the group consisting of:

28. The method of claim 19, wherein B of said compound is a substituted or unsubstituted 6-membered arylene or heteroarylene.

29. The method of claim 28, wherein B is substituted or unsubstituted phenylene.

30. The method of claim 29, wherein said compound is selected from the group consisting of:

31. The method of claim 28, wherein B is substituted or unsubstituted pyridinylene, pyrimidinylene, or pyridazine.

32. The method of claim 31, wherein said compound is selected from the group consisting of:

33. The method of claim 18, wherein said compound corresponds to Formula (XIII):

34. The method of claim 33, wherein B of said compound is a substituted or unsubstituted six-membered heteroarylene.

35. The method of claim 34, wherein said six-membered heteroarylene is substituted or unsubstituted pyrimidinylene.

36. The method of claim 35, wherein said compound is selected from the group consisting of:

37. The method of claim 18, wherein L of said compound —

OCH₂—

.

38. The method of claim 37, wherein said compound is selected from the group consisting of:

39. The method of claim 14, wherein L of said compound is —

C(O)NH.

40. The method of claim 39, wherein said compound is selected from the group consisting of:

41. The method of claim 14, wherein said compound is selected from the group consisting of:

42. The method of claim 5, wherein said compound corresponds to Formula (XIV):

wherein;

L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene, —

C(O)NH—

, —

C(O)—

, —

NH—

, —

O—

, —

S—

, —

O(substituted or unsubstituted alkylene)-, —

N(substituted or unsubstituted alkylene)-, —

C(O)NH(substituted or unsubstituted alkylene)-, —

C(O)NH(substituted or unsubstituted alkenylene)- —

NHC(O)(substituted or unsubstituted alkylene)-, —

NHC(O)(substituted or unsubstituted alkenylene)-, —

C(O)(substituted or unsubstituted alkenylene)-, and —

NHC(O)(substituted or unsubstituted alkylene)S(substituted or unsubstituted alkylene)C(O)NH—

; and

each of X₁-X₅ is independently C, CR, N, NR, S, or O, wherein no more than three of X₁-X₅ is a heteroatom, and no two adjacent ring atoms are O or S;

where

each R is independently H, halogen, substituted or unsubstituted alkyl, —

OH, substituted or unsubstituted alkoxy, —

OC(O)R_d, —

NO₂, —

N(R_d)₂, —

SR_d, —

S(O)_jR_d where j is 1 or 2, —

NR_d C(O)R_d, —

C(O)₂R_d, —

C(O)N(R_d)₂ or —

C(O)R_d, or two adjacent R'"'"'s are taken together to form a substituted or unsubstituted aryl or hetroaryl, where

each R_d is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

43. The method of claim 42, wherein said compound corresponds to Formula (XV):

44. The method of claim 43, wherein L of said compound is a covalent bond, —

C(O)NH—

, or —

O(substituted or unsubstituted alkylene)-.

45. The method of claim 44, wherein

of said compound is selected from the group consisting of:

46. The method of claim 45, wherein said compound is selected from the group consisting of:

47. The method of claim 5, wherein said compound corresponds to Formula (XVI):

wherein;

L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene, —

C(O)NH—

, —

C(O)—

, —

NH—

, —

O—

, —

S—

, —

O(substituted or unsubstituted alkylene)-, —

N(substituted or unsubstituted alkylene)-, —

C(O)NH(substituted or unsubstituted alkylene)-, —

C(O)NH(substituted or unsubstituted alkenylene)- —

NHC(O)(substituted or unsubstituted alkylene)-, —

NHC(O)(substituted or unsubstituted alkenylene)-, —

C(O)(substituted or unsubstituted alkenylene)-, and —

NHC(O)(substituted or unsubstituted alkylene)S(substituted or unsubstituted alkylene)C(O)NH—

; and

each of X₁-X₅ is independently C, CR, N—

O, or N, wherein no more than two of X₁-X₅ is N, where

each R is independently H, halogen, substituted or unsubstituted alkyl, —

OH, substituted or unsubstituted alkoxy, —

OC(O)R_d, —

NO₂, —

N(R_d)₂, —

SR_d, —

S(O)_jR_d where j is 1 or 2, —

NR_dC(O)R_d, —

C(O)₂R_d, —

C(O)N(R_d)₂ or —

C(O)R_d, or two adjacent R'"'"'s are taken together to form a substituted or unsubstituted aryl or hetroaryl, where

each R_d is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

48. The method of claim 47, wherein said compound corresponds to Formula (XVII):

49. The method of claim 48, wherein said compound is:

50. The method of claim 48, wherein said compound corresponds to Formula (XVIII):

51. The method of claim 50, wherein said compound is selected from the group consisting of:

52. The method of claim 48, wherein said compound corresponds to Formula (XXI):

53. The method of claim 52, wherein said compound is selected from the group consisting of:

54. The method of claim 48, wherein said compound corresponds to Formula (XXII):

wherein L is —

O (substituted or unsubstituted alkylene)- or —

C(O)(substituted or unsubstituted alkenylene)-.

55. The method of claim 54, wherein said compound is selected from the group consisting of:

56. The method of claim 48, wherein said compound corresponds to Formula (XXIII):

57. The method of claim 56, wherein said compound is selected from the group consisting of:

58. The method of claim 56, wherein said compound is selected from the group consisting of:

59. The method of claim 58, wherein said compound is selected from the group consisting of:

60. The method of claim 48, wherein said compound corresponds to Formula (XXV):

61. The method of claim 60, wherein L of said compound is —

O(substituted or unsubstituted alkylene)- or —

O(substituted or unsubstituted alkenylene)-.

62. The method of claim 48, wherein said compound is selected from the group consisting of:

63. The method of claim 60, wherein L of said compound is —

NHC(O)—

.

64. The method of claim 63, wherein said compound is selected from the group consisting of:

65. The method of claim 60, wherein L of said compound is a covalent bond, substituted or unsubstituted alkylene, —

NHC(O)(substituted or unsubstituted alkylene)-, —

NHC(O)(substituted or unsubstituted alkenylene)-, —

NH(alkylene)-, —

NHC(O)CH₂SCH₂C(O)NH—

, and —

NHC(O)(substituted alkylene)S—

.

66. The method of claim 65, wherein said compound is selected from the group consisting of:

70. The method of claim 5, wherein said compound corresponds to Formula (XVIII):

wherein;

each of L and L₁ is independently a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene, —

C(O)NH—

, —

C(O)—

, —

NH—

, —

O—

, —

S—

, —

O(substituted or unsubstituted alkylene)-, —

N(substituted or unsubstituted alkylene)-, —

C(O)NH(substituted or unsubstituted alkylene), —

C(O)NH(substituted or unsubstituted alkenylene)- —

NHC(O)(substituted or unsubstituted alkylene)-, —

NHC(O)(substituted or unsubstituted alkenylene)-, —

C(O)(substituted or unsubstituted alkenylene)-, and —

NHC(O)(substituted or unsubstituted alkylene)S(substituted or unsubstituted alkylene)C(O)NH—

;

U is a substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and

V is a substituted or unsubstituted cycloalkylene, heterocyclene, arylene, or heteroarylene.

71. The method of claim 70, wherein said compound corresponds to Formula (XIX):

72. The method of claim 71, wherein said compound corresponds to Formula (XX):

73. The method of claim 72, wherein said compound is selected from the group consisting of:

74. The method of claim 71, wherein said compound corresponds to Formula (XXXI):

wherein;

each of X₁-X₅ is independently C, CR, N, NR, S, or O, wherein no more than three of X₁-X₅ is a heteroatom, and no two adjacent ring atoms are O or S; and

each R is independently H, halogen, substituted or unsubstituted alkyl, —

OH, substituted or unsubstituted alkoxy, —

OC(O)R_d, —

NO₂, —

N(R_d)₂, —

SR_d, —

S(O)_jR_d where j is 1 or 2, —

NR_d C(O)R_d, —

C(O)₂R_d, —

C(O)N(R_d)₂ or —

C(O)R_d, or two adjacent R'"'"'s are taken together to form a substituted or unsubstituted aryl or hetroaryl, where

each R_d is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

78. The method of claim 71, wherein said compound is selected from the group consisting of:

79. The method of claim 4, wherein said compound corresponds to Formula (XXIII):

wherein;

Z₃ is NR₈, O, or S;

Z₄ is N or CR₈; and

R₈ is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl.

80. The method of claim 79, wherein said compound corresponds to Formula (XXIV):

81. The method of claim 80, wherein said compound is selected from the group consisting of:

82. The method of claim 80, wherein said compound corresponds to Formula (XXV)

wherein:

L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene, —

C(O)NH—

, —

C(O)—

, —

NH—

, —

O—

, —

S—

, —

O(substituted or unsubstituted alkylene)-, —

N(substituted or unsubstituted alkylene)-, —

C(O)NH(substituted or unsubstituted alkylene)-, —

C(O)NH(substituted or unsubstituted alkenylene)- —

NHC(O)(substituted or unsubstituted alkylene)-, —

NHC(O)(substituted or unsubstituted alkenylene)-, —

C(O)(substituted or unsubstituted alkenylene)-, and —

NHC(O)(substituted or unsubstituted alkylene)S(substituted or unsubstituted alkylene)C(O)NH—

; and

T is a substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

83. The method of claim 82, wherein said compound is selected from the group consisting of:

84. The method of claim 1, wherein said compound corresponds to Formula (A):

wherein;

each Z is independently C, CR₃, N. NR₃, O, or S, provided that no more than two Z'"'"'s are heteroatoms where

R₃ is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl.

each R₂ is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

or wherein two R₂ groups are linked together by an optionally substituted alkylene; and

each R₁ is independently H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —

OR_c —

OH, —

OC(O)R_c, —

NO₂, —

N(R_c)₂, —

SR_c, S(O)_jR_c where j is 1 or 2, —

NR_cC(O)R_c, —

C(O)N(R_c)₂, C(O)₂R_c, or —

C(O)R_c;

or two adjacent R₁ '"'"'s, are taken together to form a substituted or unsubstituted aryl or heteroaryl, where

each R_c is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

85. The method of claim 84, wherein said compound corresponds to Formula (B):

86. The method of claim 85, wherein said compound is selected from the group consisting of:

87. The method of claim 1, wherein said compound is selected from the group consisting of:

10. The method of claim 10, wherein said compound corresponds to Formula (VII):

wherein Z₁ is O or S; and

Z₂ is CR₃ or N.

12. The method of claim 10, wherein said compound corresponds to Formula (VIII):

13. The method of claim 12, wherein said compound is selected from the group consisting of:

67. The method of claim 10, wherein said compound corresponds to Formula (XXVI):

wherein;

L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene, —

C(O)NH—

, —

C(O)—

, —

NH—

, —

O—

, —

S—

, —

O(substituted or unsubstituted alkylene)-, —

N(substituted or unsubstituted alkylene)-, —

C(O)NH(substituted or unsubstituted alkylene)-, —

C(O)NH(substituted or unsubstituted alkenylene)- —

NHC(O)(substituted or unsubstituted alkylene)-, —

NHC(O)(substituted or unsubstituted alkenylene)-, —

C(O)(substituted or unsubstituted alkenylene)-, and —

NHC(O)(substituted or unsubstituted alkylene)S(substituted or unsubstituted alkylene)C(O)NH—

; and

each of X₁-X₅ is independently C, CR, or N, wherein no more than two of X, —

X₅ is N, where

each R is independently H, halogen, substituted or unsubstituted alkyl, —

OH, substituted or unsubstituted alkoxy, —

OC(O)R_d, —

NO₂, —

N(R_d)₂, —

SR_d, —

S(O)_jR_d where j is 1 or 2, —

NR_d C(O)R_d, —

C(O)₂R_d, —

C(O)N(R_d)₂ or —

C(O)R_d, or two adjacent R'"'"'s are taken together to form a substituted or unsubstituted aryl or hetroaryl, where

each R_d is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

Z₁ is O or S; and

Z₂ is CR₃ or N.

68. The method of claim 67, wherein said compound corresponds to Formula (XXVII):

69. The method of claim 68, wherein said compound is selected from the group consisting of;

76. The method of claim 75, wherein U is a substituted or unsubstituted five-membered heteroaryl, substituted or unsubstituted phenyl, or substituted or unsubstituted six-membered heteroaryl.

77. The method of claim 76, wherein said compound is selected from the group consisting of:

88. A method for treating a disease mediated by FLT-3 kinase, said method comprising administering a therapeutically effective amount of a compound corresponding to Formula (IA):

wherein;

M is substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl;

N is a substituted or unsubstituted aryl, or substituted or unsubstituted hetroaryl; and

K is

Y is O or S;

each R_k is independently H, halogen, substituted or unsubstituted alkyl, —

OH, substituted or unsubstituted alkoxy, —

OC(O)R₂, —

NO₂, —

N(R₂)₂, —

SR₂, —

C(O)R₂, —

C(O)₂R₂, —

C(O)N(R₂)₂, or —

N(R₂)C(O)R₂,

each R₂ is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

or wherein two R₂ groups are linked together by an optionally substituted alkylene; and

each n is independently 0, 1, 2, 3 or 4;

or an active metabolite, or a pharmaceutically acceptable prodrug, isomer, pharmaceutically acceptable salt or solvate thereof.