Substituted indazoles as glucokinase activators

• US 8,008,332 B2
• Filed: 05/25/2007
• Issued: 08/30/2011
• Est. Priority Date: 05/31/2006
• Status: Expired due to Fees

• Current Assignee: Takeda San Diego, Inc. (Takeda Pharmaceutical Company Limited)
• Original Assignee: Takeda San Diego, Inc. (Takeda Pharmaceutical Company Limited)
• Inventors: Skene, Robert J., Gwaltney, Stephen L., Feng, Jun, Hosfield, David J., Tang, Mingnam, Stafford, Jeffrey A., Cao, Sheldon X.
• Primary Examiner(s): Moore; Susanna
• Application Number:
  US11/754,205
• Publication Number:
  US 20070281942A1
• Time in Patent Office: 1,558 Days
• Field of Search: 548/361.1, 514/406
• US Class Current: 514/371
• 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, ester, tautomer, enantiomer, or pharmaceutically acceptable salt according to claim 1 having the formula:

3. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt according to claim 1 having the formula:

4. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt according to claim 1 having the formula:

5. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt according to claim 1 having the formula:

6. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt according to claim 1 having the formula:

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

2-(3-amino-2H-methyl-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)pentanamide; and

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

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

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

11. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1, wherein p is selected from the group consisting of 1, 2 and 3.

12. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1, wherein p is 1.

13. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1, wherein R₃′

is hydrogen 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_8-12)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.

14. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1, wherein Q is C(═

O).

15. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1, wherein Q is C(═

S).

16. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1, wherein Q is C(═

NR₆).

17. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1, wherein Q is SO.

18. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1, wherein Q is SO₂.

19. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 4, wherein n is 0.

20. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 4, wherein n is 1.

21. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 4, wherein n is 2.

22. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1, wherein R₁ is a substituted or unsubstituted hetero(C_3-12)cycloalkyl.

23. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1, wherein R₁ is a substituted or unsubstituted heteroaryl.

24. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1, wherein R₁ is selected from the group consisting of furanyl, thiophenyl, 2H-pyrrolyl, 1,3-dioxanyl, oxazolyl, thiazolyl, 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.

25. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt 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.

26. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1, wherein R₁ is a substituted or unsubstituted thiazolyl.

27. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1, wherein R₁ is a substituted or unsubstituted pyridinyl.

28. The, ester, tautomer, enantiomer, or pharmaceutically acceptable salt compound of claim 1, wherein R₃′

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

29. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1, wherein R₃′

is hydrogen.

30. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1, wherein R₃ is selected from the group consisting of (C_1-10)alkyl, hetero(C_1-10)alkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl(C_1-5)alkyl, aryl(C_1-5)alkyl, and heteroaryl(C_1-5)alkyl, each substituted or unsubstituted.

31. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1, 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.

32. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1, wherein R₃ is selected from the group consisting of isobutyl and cyclohexylmethyl, each substituted or unsubstituted.

33. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt 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.

34. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt 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.

35. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt 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.

36. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt 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.

37. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt 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.

38. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1, wherein at least one R₅ is hydrogen.

39. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1, wherein at least one R₅ is halo.

40. The compound, ester, tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1, wherein at least one R₆ is selected from the group consisting of hydrogen, (C_1-10)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, (C_4-12)aryl, hetero(C_1-10)aryl, aryl(C_1-10)alkyl, heteroaryl(C_1-5)alkyl, (C_9-12)bicycloaryl, hetero(C_8-12)bicycloaryl, each substituted or unsubstituted.

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

42. The pharmaceutical composition according to claim 41, wherein the composition is a solid formulation adapted for oral administration.

43. The pharmaceutical composition according to claim 41, wherein the composition is a liquid formulation adapted for oral administration.

44. The pharmaceutical composition according to claim 41, wherein the composition is a tablet.

45. The pharmaceutical composition according to claim 41, wherein the composition is a liquid formulation adapted for parenteral administration.

46. 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.

47. The compound of claim 1, wherein R₁ is a substituted or unsubstituted pyrazinyl.

48. The compound of claim 1, wherein R₁ is a substituted or unsubstituted pyrazolyl.

49. The compound of claim 1, wherein R₃ is a substituted or unsubstituted hetero(C_3-12)cycloalkyl(C_1-5)alkyl.

10. The compound according to claim wherein the compound comprises a single stereoisomer.