GLUCOKINASE ACTIVATORS

• US 20070281942A1
• Filed: 05/25/2007
• Published: 12/06/2007
• Est. Priority Date: 05/31/2006
• Status: Active Grant

• Current Assignee: Takeda San Diego, Inc. (Takeda Pharmaceutical Company Limited)
• Original Assignee: Takeda San Diego, Inc. (Takeda Pharmaceutical Company Limited)
• Inventors: Feng, Jun, Tang, Mingnam, Gwaltney, Stephen, Cao, Sheldon, Stafford, Jeffrey, Skene, Robert, Hosfield, David
• Granted Patent: US 8,008,332 B2
• Time in Patent Office: Days
• US Class Current: 514/249
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• 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: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Compounds are provided for use with hexokinases that comprise: wherein the variables are as defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds; methods and intermediates useful for making the compounds; and methods of using said compounds.

Claims

1. A compound of the formula:

2. The compound according to claim 1 having the formula:

3. The compound according to claim 1 having the formula:

4. The compound according to claim 1 having the formula:

5. The compound according to claim 1 having the formula:

6. The compound according to claim 1 having the formula:

7. The compound according to claim 1 having the formula:

8. The compound according to claim 1 having the formula:

9. The compound according to claim 1 having the formula:

10. The compound according to claim 1 having the formula:

11. The compound according to claim 1 having the formula:

12. The compound according to claim 1 having the formula:

13. The compound according to claim 1 having the formula:

14. The compound according to claim 1 having the formula:

15. The compound according to claim 1 having the formula:

16. The compound according to claim 1 having the formula:

17. The compound according to claim 1 having the formula:

18. The compound according to claim 1 having the formula:

19. The compound according to claim 1 having the formula:

20. The compound according to claim 1 having the formula:

21. The compound according to claim 1 having the formula:

22. The compound according to claim 1 having the formula:

23. The compound according to claim 1 having the formula:

24. The compound according to claim 1 having the formula:

25. The compound according to claim 1 having the formula:

26. The compound according to claim 1 having the formula:

27. The compound according to claim 1 having the formula:

28. The compound according to claim 1 having the formula:

29. The compound according to claim 1 having the formula:

30. The compound according to claim 1 having the formula:

31. The compound according to claim 1 having the formula:

32. The compound according to claim 1 having the formula:

33. The compound according to claim 1 having the formula:

34. The compound according to claim 1 comprising:

2-(2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;

2-(5-fluoro-2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;

4-methyl-2-(6-nitro-2H-indazol-2-yl)-N-(thiazol-2-yl)pentanamide;

4-methyl-2-(6-(methylsulfonyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)pentanamide;

2-(5-methoxy-2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;

2-(5-hydroxy-2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;

4-methyl-2-(3-methyl-2H-indazol-2-yl)-N-(thiazol-2-yl)pentanamide;

2-(5-fluoro-3-methyl-2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;

3-cyclohexyl-2-(1-iminoisoindolin-2-yl)-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-1-iminoisoindolin-2-yl)-N-(thiazol-2-yl)propanamide;

2-(1,3-dioxoisoindolin-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;

2-(1,3-dioxoisoindolin-2-yl)-4-methyl-N-(pyridin-2-yl)pentanamide;

2-(3-amino-2H-indazol-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

2-(3-amino-5-fluoro-2H-indazol-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

2-(3-amino-5-(methylsulfonyl)-2H-indazol-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

2-(3-amino-5-(N-methylsulfamoyl)-2H-indazol-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

2-(3-amino-2H-pyrazolo[4,3-b]pyridin-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

2-(3-amino-2H-pyrazolo[4,3-c]pyridin-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

2-(3-amino-2H-pyrazolo[3,4-c]pyridin-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

2-(3-amino-2H-pyrazolo[3,4-b]pyridin-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

2-(3-amino-2H-pyrazolo[4,3-b]pyrazin-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

2-(3-amino-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

2-(3-amino-2H-pyrazolo[4,3-d]pyrimidin-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

2-(3-amino-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

2-(3-amino-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

2-(3-amino-5-(methylsulfonyl)-2H-indazol-2-yl)-3-cyclohexyl-N-(pyridin-2-yl)propanamide;

3-cyclohexyl-2-(1-imino-6-(methylsulfonyl)isoindolin-2-yl)-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(1-imino-6-(N-methylsulfamoyl)isoindolin-2-yl)-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(7-imino-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N-(thiazol-2-yl)propanamide; and

3-cyclohexyl-2-(3-imino-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)-N-(thiazol-2-yl)propanamide.

35. The compound according to claim 1, wherein the compound is in the form of a pharmaceutically acceptable salt.

36. The compound according to claim 1, wherein the compound is present in a mixture of stereoisomers.

37. The compound according to claim 1, wherein the compound comprises a single stereoisomer.

44. The compound of claim 1, wherein L is

45. The compound of claim 44, wherein p is selected from the group consisting of 1, 2 and 3.

46. The compound of claim 44, wherein p is 1.

47. The compound of claim 1, wherein L is CHR₃ and R₃ is selected from the group consisting of hydrogen, carbonyl, sulfonyl, sulfinyl, (C_1-10)alkyl, halo(C_1-10)alkyl, carbonyl(C_1-3)alkyl, thiocarbonyl(C_1-3)alkyl, sulfonyl(C_1-3)alkyl, sulfinyl(C_1-3)alkyl, amino (C_1-10)alkyl, imino(C_1-3)alkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl(C_1-5)alkyl, aryl(C_1-10)alkyl, heteroaryl(C_1-5)alkyl, (C_9-12)bicycloaryl(C_1-5)alkyl, hetero(C_8-2)bicycloaryl(C_1-5)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, (C_9-12)bicycloalkyl, hetero(C_3-12)bicycloalkyl, aryl, heteroaryl, (C_9-12)bicycloaryl and hetero(C_4-12)bicycloaryl, each substituted or unsubstituted.

48. The compound of claim 1, wherein Q is C(═

O).

49. The compound of claim 1, wherein Q is C(═

S).

50. The compound of claim 1, wherein Q is C(═

NR₆).

51. The compound of claim 1, wherein Q is SO.

52. The compound of claim 1, wherein Q is SO₂.

53. The compound of claim 1, wherein U is selected from the group consisting of N, CH₂ and CO.

54. The compound of claim 1, wherein V is selected from the group consisting of N and CH.

55. The compound of claim 1, wherein W is selected from the group consisting of N, CH, C(NO₂) and C(SO₂CH₃).

56. The compound of claim 1, wherein X is selected from the group consisting of N, NH, CH, CF, C(OCH₃), C(OH), C(SO₂CH₃) and C(SO₂NHCH₃).

57. The compound of claim 1, wherein Y is selected from the group consisting of N, CH and CO.

58. The compound of claim 1, wherein Z is selected from the group consisting of C(CH₃), C(NH₂), C(═

NH) and CO.

59. The compound of claim 20, wherein k is 0.

60. The compound of claim 20, wherein k is 1.

61. The compound of claim 10, wherein l is 0.

62. The compound of claim 10, wherein l is 1.

63. The compound of claim 6, wherein m is 0.

64. The compound of claim 6, wherein m is 1.

65. The compound of claim 5, wherein n is 0.

66. The compound of claim 5, wherein n is 1.

67. The compound of claim 5, wherein n is 2.

68. The compound of claim 1, wherein R₁ is a or unsubstituted hetero(C_3-12)cycloalkyl.

69. The compound of claim 1, wherein R₁ is a substituted or unsubstituted heteroaryl.

70. The compound of claim 1, wherein R₁ is selected from the group consisting of furanyl, thiophenyl, 2H-pyrrolyl, 1,3-dioxoianyl, oxazolyl, thiazolyl, imidazolyl, 2-imidazolinyl, pyrazolyl, 2-pyrazolinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, pyridinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, 3-H-indolyl, benzo[b]furanyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, quinuclidinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl, each substituted or unsubstituted.

71. The compound of claim 1, wherein R₁ is selected from the group consisting of oxazolyl, thiazolyl, imidazolyl, 2-imidazolinyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl, each substituted or unsubstituted.

72. The compound of claim 1, wherein R₁ is a substituted or unsubstituted thiazolyl.

73. The compound of claim 1, wherein R₁ is a substituted or unsubstituted pyridinyl.

74. The compound of claim 1, wherein R₂ is hydrogen.

75. The compound of claim 2, wherein R₃′

is selected from the group consisting of hydrogen, halo, and substituted or unsubstituted (C_1-3)alkyl.

76. The compound of claim 2, wherein R₃′

is hydrogen.

77. The compound of claim 2, wherein R₃ is selected from the group consisting of (C_1-10)alkyl, hetero(C_1-10)alkyl, cycloalkyl(C_1-5)alkyl, heterocycloalkyl(C_1-5)alkyl, aryl(C_1-5)alkyl, and heteroaryl(C_1-5)alkyl, each substituted or unsubstituted.

78. The compound of claim 2, wherein R₃ is selected from the group consisting of isobutyl, methoxybutyl, methoxypentyl, cyclohexylmethyl, cyclopentylmethyl, cyclopropylmethyl, benzyl, imidazolylmethyl, pyridinylmethyl, pyrrolidinylmethyl, and piperidinylmethyl, each substituted or unsubstituted.

79. The compound of claim 2, wherein R₃ is selected from the group consisting of isobutyl and cyclohexylmethyl, each substituted or unsubstituted.

80. The compound of claim 1, wherein at least one R₄ is selected from the group consisting of hydrogen, halo, hydroxy, amino, nitro, (C_1-3)alkoxy, (C_1-3)alkylsulfonyl, aminosulfonyl and (C_1-10)alkyl, each substituted or unsubstituted.

81. The compound of claim 1, wherein at least one R₄ is selected from the group consisting of amino and (C_1-10)alkyl, each substituted or unsubstituted.

82. The compound of claim 1, wherein at least one R₄ is selected from the group consisting of hydrogen, halogen and (C_1-3)alkylsulfonyl, each substituted or unsubstituted.

83. The compound of claim 1, wherein at least one R₄ is selected from the group consisting of H, F, CH₃, NH₂, SO₂CH₃, SO₂NHCH₃, NO₂, OCH₃ and OH, each substituted or unsubstituted.

84. The compound of claim 1, wherein at least one R₅ is selected from the group consisting of hydrogen, halogen and (C_1-3)alkylsulfonyl, each substituted or unsubstituted.

85. The compound of claim 1, wherein at least one R₅ is hydrogen.

86. The compound of claim 1, wherein at least one R₅ is halo.

87. The compound of claim 1, wherein at least one R₆ is selected from the group consisting of hydrogen, (C_1-10)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C_1-10)alkyl, heteroaryl(C_1-10)alkyl, (C_9-12)bicycloaryl, hetero(C_8-12)bicycloaryl, each substituted or unsubstituted.

88. A pharmaceutical composition comprising as an active ingredient a compound according to claim 1.

89. The pharmaceutical composition according to claim 88, wherein the composition is a solid formulation adapted for oral administration.

90. The pharmaceutical composition according to claim 88, wherein the composition is a liquid formulation adapted for oral administration.

91. The pharmaceutical composition according to claim 88, wherein the composition is a tablet.

92. The pharmaceutical composition according to claim 88, wherein the composition is a liquid formulation adapted for parenteral administration.

93. A pharmaceutical composition comprising a compound according to claim 1, wherein the composition is adapted for administration by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, and intrathecally.

94. A kit comprising:

a compound according to claim 1;

and

instructions which comprise one or more forms of information selected from the group consisting of indicating a disease state for which the compound is to be administered, storage information for the compound, dosing information and instructions regarding how to administer the compound.

95. The kit according to claim 94, wherein the kit comprises the compound in a multiple dose form.

96. An article of manufacture comprising:

a compound according to claim 1;

and

packaging materials.

97. The article of manufacture according to claim 96, wherein the packaging material comprises a container for housing the compound.

98. The article of manufacture according to claim 97, wherein the container comprises a label indicating one or more members of the group consisting of a disease state for which the compound is to be administered, storage information, dosing information and/or instructions regarding how to administer the compound.

99. The article of manufacture according to claim 96, wherein the article of manufacture comprises the compound in a multiple dose form.

100. A therapeutic method comprising administering a compound according to claim 1 to a subject.

101. A method of activating glucokinase comprising contacting glucokinase with a compound according to claim 1.

102. A method of activating glucokinase comprising causing a compound according to claim 1 to be present in a subject in order to activate glucokinase in vivo.

103. A method of activating glucokinase comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound activates glucokinase in vivo, the second compound being a compound according to claim 1.

104. A method of treating a disease state for which increasing glucokinase activity ameliorates the pathology and/or symptomology of the disease state, the method comprising causing a compound according to claim 1 to be present in a subject in a therapeutically effective amount for the disease state.

105. A method of treating a disease state for which increasing glucokinase activity ameliorates the pathology and/or symptomology of the disease state, the method comprising administering a compound according to claim 1 to a subject, wherein the compound is present in the subject in a therapeutically effective amount for the disease state.

106. A method of treating a disease state for which increasing glucokinase activity ameliorates the pathology and/or symptomology of the disease state, the method comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound activates glucokinase in vivo, the second compound being a compound according to claim 1.

107. The method according to claim 104, wherein the disease state is selected from the group consisting of hyperglycemia, diabetes, dyslipidaemia, obesity, insulin resistance, metabolic syndrome X, impaired glucose tolerance, polycystic ovary syndrome and cardiovascular disease.

38. A process comprising:

reacting a compound having the formula

with a compound having the formula

under conditions that form a first reaction product having the formula

reacting the first reaction product with a compound having the formula

NHR₁R₂

under conditions that form a second reaction product having the formula

wherein

p is selected from the group consisting of 1, 2, 3, 4, 5 and 6;

Q is selected from the group consisting of C(═

O), C(═

S), C(═

NR₆), SO and SO₂;

V, W, X and Y are each independently selected from the group consisting of CR₄R₅, NR₆, C(═

O), C(═

S) and C(═

NR₆);

R₁ is selected from the group consisting of hetero(C_3-12)cycloalkyl, hetero(C_3-12)bicycloalkyl, heteroaryl, and hetero(C_4-12)bicycloaryl, each substituted or unsubstituted;

R₂ is selected from the group consisting of hydrogen and a substituent convertible to hydrogen in vivo;

R₃ and R₃′

are each independently selected from the group consisting of hydrogen, carbonyl, sulfonyl, sulfinyl, (C_1-10)alkyl, halo(C_1-10)alkyl, carbonyl(C_1-3)alkyl, thiocarbonyl(C_1-3)alkyl, sulfonyl(C_1-3)alkyl, sulfinyl(C_1-3)alkyl, amino (C_1-10)alkyl, imino(C_1-3)alkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl(C_1-5)alkyl, aryl(C_1-10)alkyl, heteroaryl(C_1-5)alkyl, (C_9-12)bicycloaryl(C_1-5)alkyl, hetero(C_8-2)bicycloaryl(C_1-5)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, (C_9-12)bicycloalkyl, hetero(C_3-12)bicycloalkyl, aryl, heteroaryl, (C_9-12)bicycloaryl and hetero(C_4-12)bicycloaryl, each substituted or unsubstituted, or R₃ and R₃′

are taken together to form a ring;

each R₄ and R₅ is independently selected from the group consisting of hydrogen, halo, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C_1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C_1-10)alkyl, halo(C_1-10)alkyl, carbonyl(C_1-3)alkyl, thiocarbonyl(C_1-3)alkyl, sulfonyl(C_1-3)alkyl, sulfinyl(C_1-3)alkyl, amino(C_1-10)alkyl, imino(C_1-3)alkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl(C_1-5)alkyl, aryl(C_1-10)alkyl, heteroaryl(C_1-5)alkyl, (C_9-12)bicycloaryl(C_1-5)alkyl, hetero(C_8-12)bicycloaryl(C_1-5)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, (C_9-12)bicycloalkyl, hetero(C_3-12)bicycloalkyl, aryl, heteroaryl, (C_9-12)bicycloaryl and hetero(C_4-12)bicycloaryl, each substituted or unsubstituted, or any two R₄ and R₅ are taken together to form a ring, with the proviso that R₅ is absent when the atom to which it is bound forms part of a double bond;

each R₆ is independently selected from the group consisting of hydrogen, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, oxycarbonyl, amino, (C_1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C_1-10)alkyl, halo(C_1-10)alkyl, carbonyl(C_1-3)alkyl, thiocarbonyl(C_1-3)alkyl, sulfonyl(C_1-3)alkyl, sulfinyl(C_1-3)alkyl, amino(C_1-10)alkyl, imino(C_1-3)alkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl(C_1-5)alkyl, aryl(C_1-10)alkyl, heteroaryl(C_1-5)alkyl, (C_9-12)bicycloaryl(C_1-5)alkyl, hetero(C_8-2)bicycloaryl(C_1-5)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, (C_9-12)bicycloalkyl, hetero(C_3-12)bicycloalkyl, (C_4-12)aryl, hetero(C_1-10)aryl, (C_9-12)bicycloaryl and hetero(C_4-12)bicycloaryl, each substituted or unsubstituted, or R₄ or R₅ and R₆ are taken together to form a ring, with the proviso that R₆ is absent when the atom to which it is bound forms part of a double bond; and

LG₁ and LG₂ are each independently a leaving group.

39. A process comprising:

reacting a compound having the formula

with a compound having the formula

NHR₁R₂

under conditions that form a first reaction product having the formula

reacting the first reaction product with a compound having the formula

under conditions that form a second reaction product comprising of formula

wherein

p is selected from the group consisting of 1, 2, 3, 4, 5 and 6;

Q is selected from the group consisting of C(═

O), C(═

S), C(═

NR₆), SO and SO₂;

V, W, X and Y are each independently selected from the group consisting of CR₄R₅, NR₆, C(═

O), C(═

S) and C(═

NR₆);

R₁ is selected from the group consisting of hetero(C_3-12)cycloalkyl, hetero(C_3-12)bicycloalkyl, heteroaryl, and hetero(C_4-12)bicycloaryl, each substituted or unsubstituted;

R₂ is selected from the group consisting of hydrogen and a substituent convertible to hydrogen in vivo;

R₃ and R₃′

are each independently selected from the group consisting of hydrogen, carbonyl, sulfonyl, sulfinyl, (C_1-10)alkyl, halo(C_1-10)alkyl, carbonyl(C_1-3)alkyl, thiocarbonyl(C_1-3)alkyl, sulfonyl(C_1-3)alkyl, sulfinyl(C_1-3)alkyl, amino (C_1-10)alkyl, imino(C_1-3)alkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl(C_1-5)alkyl, aryl(C_1-10)alkyl, heteroaryl(C_1-5)alkyl, (C_9-12)bicycloaryl(C_1-5)alkyl, hetero(C_8-2)bicycloaryl(C_1-5)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, (C_9-12)bicycloalkyl, hetero(C_3-12)bicycloalkyl, aryl, heteroaryl, (C_9-12)bicycloaryl and hetero(C_4-12)bicycloaryl, each substituted or unsubstituted, or R₃ and R₃′

are taken together to form a ring;

each R₄ and R₅ is independently selected from the group consisting of hydrogen, halo, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C_1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C_1-10)alkyl, halo(C_1-10)alkyl, carbonyl(C_1-3)alkyl, thiocarbonyl(C_1-3)alkyl, sulfonyl(C_1-3)alkyl, sulfinyl(C_1-3)alkyl, amino(C_1-10)alkyl, imino(C_1-3)alkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl(C_1-5)alkyl, aryl(C_1-10)alkyl, heteroaryl(C_1-5)alkyl, (C_9-12)bicycloaryl(C_1-5)alkyl, hetero(C_8-2)bicycloaryl(C_1-5)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, (C_9-12)bicycloalkyl, hetero(C_3-12)bicycloalkyl, aryl, heteroaryl, (C_9-12)bicycloaryl and hetero(C_4-12)bicycloaryl, each substituted or unsubstituted, or any two R₄ and R₅ are taken together to form a ring, with the proviso that R₅ is absent when the atom to which it is bound forms part of a double bond;

each R₆ is independently selected from the group consisting of hydrogen, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, oxycarbonyl, amino, (C_1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C_1-10)alkyl, halo(C_1-10)alkyl, carbonyl(C_1-3)alkyl, thiocarbonyl(C_1-3)alkyl, sulfonyl(C_1-3)alkyl, sulfinyl(C_1-3)alkyl, amino(C_1-10)alkyl, imino(C_1-3)alkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl(C_1-5)alkyl, aryl(C_1-10)alkyl, heteroaryl(C_1-5)alkyl, (C_9-12)bicycloaryl(C_1-5)alkyl, hetero(C_8-12)bicycloaryl(C_1-5)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, (C_9-12)bicycloalkyl, hetero(C_3-12)bicycloalkyl, (C_4-12)aryl, hetero(C_1-10)aryl, (C_9-12)bicycloaryl and hetero(C_4-12)bicycloaryl, each substituted or unsubstituted, or R₄ or R₅ and R₆ are taken together to form a ring, with the proviso that R₆ is absent when the atom to which it is bound forms part of a double bond;

PG is a protecting group; and

LG₂ and LG₃ are each independently a leaving group.

40. A process comprising:

reacting a compound having the formula

with a compound having the formula

under conditions that form a first reaction product having the formula

reacting the first reaction product with a compound having the formula

NHR₁R₂

under conditions that form a second reaction product comprising of formula

wherein

p is selected from the group consisting of 1, 2, 3, 4, 5 and 6;

Q is selected from the group consisting of C(═

O), C(═

S), C(═

NR₆), SO and SO₂;

V, W, X and Y are each independently selected from the group consisting of CR₄R₅, NR₆, C(═

O), C(═

S) and C(═

NR₆);

R₁ is selected from the group consisting of hetero(C_3-12)cycloalkyl, hetero(C_3-12)bicycloalkyl, heteroaryl, and hetero(C_4-12)bicycloaryl, each substituted or unsubstituted;

R₂ is selected from the group consisting of hydrogen and a substituent convertible to hydrogen in vivo;

R₃ and R₃′

are each independently selected from the group consisting of hydrogen, carbonyl, sulfonyl, sulfinyl, (C_1-10)alkyl, halo(C_1-10)alkyl, carbonyl(C_1-3)alkyl, thiocarbonyl(C_1-3)alkyl, sulfonyl(C_1-3)alkyl, sulfinyl(C_1-3)alkyl, amino (C_1-10)alkyl, imino(C_1-3)alkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl(C_1-5)alkyl, aryl(C_1-10)alkyl, heteroaryl(C_1-5)alkyl, (C_9-12)bicycloaryl(C_1-5)alkyl, hetero(C_8-2)bicycloaryl(C_1-5)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, (C_9-12)bicycloalkyl, hetero(C_3-12)bicycloalkyl, aryl, heteroaryl, (C_9-12)bicycloaryl and hetero(C_4-12)bicycloaryl, each substituted or unsubstituted, or R₃ and R₃′

are taken together to form a ring;

each R₄ and R₅ is independently selected from the group consisting of hydrogen, halo, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C_1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C_1-10)alkyl, halo(C_1-10)alkyl, carbonyl(C_1-3)alkyl, thiocarbonyl(C_1-3)alkyl, sulfonyl(C_1-3)alkyl, sulfinyl(C_1-3)alkyl, amino(C_1-10)alkyl, imino(C_1-3)alkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl(C_1-5)alkyl, aryl(C_1-10)alkyl, heteroaryl(C_1-5)alkyl, (C_9-12)bicycloaryl(C_1-5)alkyl, hetero(C_8-12)bicycloaryl(C_1-5)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, (C_9-12)bicycloalkyl, hetero(C_3-12)bicycloalkyl, aryl, heteroaryl, (C_9-12)bicycloaryl and hetero(C_4-12)bicycloaryl, each substituted or unsubstituted, or any two R₄ and R₅ are taken together to form a ring, with the proviso that R₅ is absent when the atom to which it is bound forms part of a double bond;

each R₆ is independently selected from the group consisting of hydrogen, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, oxycarbonyl, amino, (C_1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C_1-10)alkyl, halo(C_1-10)alkyl, carbonyl(C_1-3)alkyl, thiocarbonyl(C_1-3)alkyl, sulfonyl(C_1-3)alkyl, sulfinyl(C_1-3)alkyl, amino(C_1-10)alkyl, imino(C_1-3)alkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl(C_1-5)alkyl, aryl(C_1-10)alkyl, heteroaryl(C_1-5)alkyl, (C_9-12)bicycloaryl(C_1-5)alkyl, hetero(C_8-2)bicycloaryl(C_1-5)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, (C_9-12)bicycloalkyl, hetero(C_3-12)bicycloalkyl, (C_4-12)aryl, hetero(C_1-10)aryl, (C_9-12)bicycloaryl and hetero(C_4-12)bicycloaryl, each substituted or unsubstituted, or R₄ or R₅ and R₆ are taken together to form a ring, with the proviso that R₆ is absent when the atom to which it is bound forms part of a double bond; and

LG₂ is a leaving group.

41. A compound having the formula

42. A compound having the formula

43. A compound having the formula