Indazole derivatives as JNK inhibitors and compositions and methods related thereto

• US 20020103229A1
• Filed: 07/23/2001
• Published: 08/01/2002
• Est. Priority Date: 07/31/2000
• Status: Active Grant

• Current Assignee: Signal Pharmaceuticals, LLC (Bristol-Myers Squibb Company)
• Original Assignee: Signal Pharmaceuticals, LLC (Bristol-Myers Squibb Company)
• Inventors: Sapienza, John, Bhagwat, Shripad S., Buhr, Chris A., Chao, Qi, Sahasrabudhe, Kiran, Satoh, Yoshitaka, Sakata, Steven T., Albers, Ronald, Plantevin, Veronique, Ferri, Rachel
• Granted Patent: US 6,897,231 B2
• Time in Patent Office: Days
• US Class Current: 514/338
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/08 Antiseborrheics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/08 Mydriatics or cycloplegics
• CPC Class Codes: A61P 27/16 Otologicals
• 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 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• 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 231/56 : Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• 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

Abstract

Compounds having activity as selective inhibitors of JNK are disclosed. The compounds of this invention are indazole derivatives having the following structure:

wherein R₁, R₂ and A are as defined herein. Such compounds have utility in the treatment of a wide range of conditions that are responsive to JNK inhibition. Thus, methods of treating such conditions are also disclosed, as are pharmaceutical compositions containing one or more compounds of the above compounds.

Claims

22. A method for treating a condition responsive to JNK inhibition, comprising dministering to a patient in need thereof an effective amount of a compound having the structure:

23. The method of claim 22 wherein:

R₂ is —

R₄, —

(CH₂)_bC(═

O)R₅, —

(CH₂)_bC(═

O)OR₅, —

(CH₂)_bC(═

O)NR₅R₆, —

(CH₂)_bC(═

O)NR₅(CH₂)_cC(═

O)R₆, —

(CH₂)_bNR₅C(═

O)R₆, —

(CH₂)_bNR₅C(═

O)NR₆R₇, —

(CH₂)_bNR₅R₆, —

(CH₂)_bOR₅, —

(CH₂)_bSO_dR₅ or —

(CH₂)_bSo₂NR₅R₆.

24. The method of claim 22 wherein the condition is cancer.

25. The method of claim 22 wherein the condition is rheumatoid arthritis;

heumatoid spondylitis;

osteoarthritis;

gout;

asthma, bronchitis;

allergic rhinitis;

chronic obstructive ulmonary disease;

cystic fibrosis;

inflammatory bowel disease;

irritable bowel syndrome;

mucous olitis;

ulcerative colitis;

Crohn'"'"'s disease;

Huntington'"'"'s disease;

gastritis;

esophagitis;

hepatitis;

ancreatitis;

nephritis;

multiple sclerosis;

endotoxin shock;

lupus erythematosus;

Type II diabetes;

soriasis;

burn caused by exposure to fire, chemicals or radiation;

eczema;

dermatitis;

skin graft;

schemia;

ischemic conditions associated with surgery or traumatic injury;

cachexia or angiogenic nd proliferative diseases.

26. The method of claim 22 wherein the condition is atherosclerosis, restenosis ollowing angioplasty, left ventricular hypertrophy, or myocardial infarction.

27. The method of claim 22 wherein the condition is stroke or ischemic amages of heart, lung, gut, kidney, liver, pancreas, spleen or brain.

28. The method of claim 22 wherein the condition is acute or chronic organ ransplant rejection, preservation of the organ for transplantation, graft versus host disease or ultiple organ failure.

29. The method of claim 22 wherein the condition is epilepsy, Alzheimer'"'"'s disease, or Parkinson'"'"'s disease.

30. The method of claim 22 wherein the condition is an immunological response to bacterial or viral infection.

31. The method of claim 22 wherein the condition is solid tumor or cancers of a variety of tissues such as colon, rectum, prostate, liver, lung, bronchus, pancreas, brain, head, neck, stomach, skin, kidney, cervix, blood, larynx, esophagus, mouth, pharynx, urinary bladder, ovary or uterine.

32. The method of claim 22 wherein A is a direct bond.

33. The method of claim 22 wherein A is —

(CH₂)_a—

.

34. The method of claim 22 wherein A is —

(CH₂)_bCH═

CH(CH₂)_c—

.

35. The method of claim 22 wherein A is —

(CH₂)_bC═

C(CH₂)_c—

.

36. The method of claim 22 wherein RI is aryl optionally substituted with one to four substituents independently selected from R₃.

37. The method of claim 22 wherein R₁ is heteroaryl optionally substituted with one to four substituents independently selected from R₃.

38. The method of claim 22 wherein R₁ is heterocycle fused to phenyl optionally substituted with one to four substituents independently selected from R₃.

39. The method of claim 22 wherein R₂ is —

(CH₂)_bC(═

O)R₅.

40. The method of claim 22 wherein R₂ is —

(CH₂)_bC(═

O)NR₅R₆.

41. The method of claim 22 wherein R₂ is —

(CH₂)NR₅C(═

O)R₆.

42. The method of claim 22 wherein R₂ is —

(CH₂)_bNR₅R₆.

43. The method of claim 22 wherein R₂ is R₄.

44. The method of claim 43 wherein R₄ is substituted alkyl.

45. The method of claim 43 wherein R₄ is substituted arylalkyl.

46. The method of claim 43 wherein R₄ is substituted heterocycle.

47. The method of claim 43 wherein R₄ is 3-triazolyl, optionally substituted at its 5-position with:

(a) a C₁-C₄ straight or branched chain alkyl group optionally substituted with a hydroxyl, methylamino, dimethylamino or I-pyrrolidinyl group;

or

(b) a 2-pyrrolidinyl group.

48. The method of claim 43 wherein R₄ is tetrazole.

49. The method of claim 43 wherein R₄ is imidazole.

75. The method of claim 22, wherein -A—

R, is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, —

NR₈C(═

O)R₉, —

C(═

O)NR₈R₉, and —

O(CH₂)_bNR₈R₉, wherein b is 2 or 3.

76. The method of claim 22, wherein R₂ is —

(CH₂)_bC(═

O)NR₅R₆, —

(CH₂)_bNR₅C(═

O)R₆, 3-triazolyl or 5-tetrazolyl, wherein b is 0.

77. The method of claim 22, wherein R₂ is 3-triazolyl or 5-tetrazolyl.

78. The method of claim 22, wherein:

(a) -A-R₁ is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, —

NR₈C(═

O)R₉, —

C(═

O)NR₈R₉, and —

O(CH₂)_bNR₈R₉, wherein b is 2 or 3; and

(b) R₂ is —

(CH₂)_bC(═

O)NR₅R₆, —

(CH₂)_bNR₅C(═

O)R₆, 3-triazolyl or 5-tetrazolyl, wherein b is 0.

79. The method of claim 22, wherein

(a) -A-R₁ is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, —

NR₈C(═

O)R₉, —

C(═

O)NR₈R₉, and —

O(CH₂)_bNR₈R₉, wherein b is 2 or 3; and

(b) R₂ is 3-triazolyl or 5-tetrazolyl.

86. The method of claim 47 wherein R₄ is methyl, n-propyl, isopropyl, 1-hydroxyethyl, 3-hydroxypropyl, methylaminomethyl, dimethylaminomethyl, 1-(dimethylamino)ethyl, 1-pyrrolidinylmethyl or 2-pyrrolidinyl.

50. A method for treating or preventing rheumatoid arthritis;

rheumatoid spondylitis;

osteoarthritis;

gout;

asthma, bronchitis;

allergic rhinitis;

chronic obstructive pulmonary disease;

cystic fibrosis;

inflammatory bowel disease;

irritable bowel syndrome;

mucous colitis;

ulcerative colitis;

Crohn'"'"'s disease;

Huntington'"'"'s disease;

gastritis;

esophagitis;

hepatitis;

pancreatitis;

nephritis;

multiple sclerosis;

lupus erythematosus;

Type II diabetes;

atherosclerosis;

restenosis following angioplasty;

left ventricular hypertrophy;

myocardial infarction;

stroke;

ischemic damages of heart, lung, gut, kidney, liver, pancreas, spleen and brain;

acute or chronic organ transplant rejection;

preservation of an organ for transplantation;

graft versus host disease;

endotoxin shock;

multiple organ failure;

psoriasis;

burn caused by exposure to fire, chemicals, or radiation;

eczema;

dermatitis;

skin graft;

ischemia;

ischemic conditions associated with surgery or traumatic injury;

epilepsy;

Alzheimer'"'"'s disease;

Parkinson'"'"'s disease;

immunological response to bacterial or viral infection;

cachexia;

angiogenic and proliferative dieseases;

solid tumor; and

cancers of a variety of tissues such as colon, rectum, prostate, liver, lung, bronchus, pancreas, brain, head, neck, stomach, skin, kidney, cervix, blood, larynx, esophagus, mouth, pharynx, urinary bladder, ovary, or uterine comprising administering to a patient in need of such treatment or prevention an effective amount of a compound having the structure;

1. A compound having the structure:

2. The compound of claim 1 wherein:

R₂ is —

R₄, —

(CH₂)_bC(═

O)R₅, —

(CH₂)_bC(═

O)OR₅, —

(CH₂)_bC(═

O)NR₅R₆, —

(CH₂)_bC(═

O)NR₅(CH₂)_cC(═

O)R₆, —

(CH₂)_bNR₅C(═

O)R₆, —

(CH₂)_bNR₅C(═

O)NR₆R₇, —

(CH₂)_bNR₅R₆, —

(CH₂)_bOR₅, —

(CH₂)_bSO_dR₅ or —

(CH₂)_bSO₂NR₅R₆.

3. The compound of claim 1 wherein A is a direct bond.

4. The compound of claim 1 wherein A is —

(CH₂)_a—

.

5. The compound of claim 1 wherein A is —

(CH₂)_bCH═

CH(CH₂)_c—

.

6. The compound of claim 1 wherein A is —

(CH₂)_bC≡

C(CH₂)_c—

.

7. The compound of claim 1 wherein R₁ is aryl optionally substituted with one to four substituents independently selected from R₃.

8. The compound of claim 1 wherein R₁ is heteroaryl optionally substituted with one to four substituents independently selected from R₃.

9. The compound of claim 1 wherein R₁ is heterocycle fused to phenyl optionally substituted with one to four substituents independently selected from R₃.

10. The compound of claim 1 wherein R₂ is —

(CH₂)_bC(═

O)R₅.

11. The compound of claim 1 wherein R₂ is —

(CH₂)_bC(═

O)NR₅R₆.

12. The compound of claim 1 wherein R₂ is —

(CH2)_bNR₅C(═

O)R₆.

13. The compound of claim 1 wherein R₂ is —

(CH₂)_bNR₅R₆.

14. The compound of claim 1 wherein R₂is R₄.

15. The compound of claim 14 wherein R₄ is substituted alkyl.

16. The compound of claim 14 wherein R₄ is substituted arylalkyl.

17. The compound of claim 14 wherein R₄ is substituted heterocycle.

18. The compound of claim 14 wherein R₄ is 3-triazolyl, optionally substituted at its 5-position with:

(a) a C₁-C₄ straight or branched chain alkyl group optionally substituted with a hydroxyl, methylamino, dimethylamino or 1-pyrrolidinyl group;

or

(b) a 2-pyrrolidinyl group.

19. The compound of claim 14 wherein R₄ is tetrazole.

20. The compound of claim 14 wherein R₄ is imidazole.

21. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

51. The method of claim 50 wherein:

R₂ is —

R₄, —

(CH₂)_bC(═

O)R₅, —

(CH₂)_bC(═

O)OR₅, —

(CH₂)_bC(═

O)NR₅R₆, —

(CH₂)_bC(═

O)NR₅(CH₂)_cC(═

O)R₆, —

(CH₂)_bNR₅C(═

O)R₆, —

(CH₂)_bNR₅C(═

O)NR₆R₇, —

(CH₂)_bNR₅R₆, —

(CH₂)_bOR₅, —

(CH₂)_bSO_dR₅ or —

(CH₂)_bSO₂NR₅R₆.

52. The method of claim 50 wherein A is a direct bond.

53. The method of claim 50 wherein A is —

(CH₂)_a—

.

54. The method of claim 50 wherein A is —

(CH₂)_bCH═

CH(CH₂)_c—

.

55. The method of claim 50 wherein A is —

(CH₂)_bC≡

C(CH₂)_c—

.

56. The method of claim 50 wherein RI is aryl optionally substituted with one to four substituents independently selected from R₃.

57. The method of claim 50 wherein R₁ is heteroaryl optionally substituted with one to four substituents independently selected from R₃.

58. The method of claim 50 wherein R₁ is heterocycle fused to phenyl optionally substituted with one to four substituents independently selected from R₃.

59. The method of claim 50 wherein R₂ is —

(CH₂)_bC(═

O)R₅.

60. The method of claim 50 wherein R₂ is —

(CH₂)_bC(═

O)NR₅R₆.

61. The method of claim 50 wherein R₂ is —

(CH₂)NR₅C(═

O)R₆.

63. The method of claim 50 wherein R₂ is R₄.

64. The method of claim 63 wherein R₄ is substituted alkyl.

65. The method of claim 63 wherein R₄ is substituted arylalkyl.

66. The method of claim 63 wherein R₄ is substituted heterocycle.

67. The method of claim 63 wherein R₄ is 3-triazolyl, optionally substituted at its 5-position with:

(a) a C₁-C₄ straight or branched chain alkyl group optionally substituted with a hydroxyl, methylamino, dimethylamino or I-pyrrolidinyl group;

or

(b) a 2-pyrrolidinyl group.

68. The method of claim 63 wherein R₄ is tetrazole.

69. The method of claim 63 wherein R₄ is imidazole.

70. The compound of claim 1, wherein -A-R₁ is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, —

NR₈C(═

O)R₉, —

C(═

O)NR₈R₉, and —

O(CH₂)_bNR₈R₉, wherein b is 2 or 3.

71. The compound of claim 1, wherein R₂ is —

(CH₂)_bC(═

O)NR₅R₆, —

(CH₂)_bNR₅C(═

O)R₆, 3-triazolyl or 5-tetrazolyl, wherein b is 0.

72. The compound of claim 1, wherein R₂ is 3-triazolyl or 5-tetrazolyl.

73. The compound of claim 1, wherein:

(a) -A-R₁ is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, —

NR₈C(═

O)R₉, —

C(═

O)NR₈R₉, and —

O(CH₂)_bNR₈R₉, wherein b is 2 or 3; and

(b) R₂ is —

(CH₂)_bC(═

O)NR₅R₆, —

(CH₂)_bNR₅C(═

O)R₆, 3-triazolyl or 5-tetrazolyl, wherein b is 0.

74. The compound of claim 1, wherein

(a) -A—

R, is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, —

NR₈C(═

O)R₉, —

C(═

O)NR₈R₉ and —

O(CH₂)_bNR₈R₉, wherein b is 2 or 3; and

(b) R₂ is 3-triazolyl or 5-tetrazolyl.

80. The method of claim 50, wherein -A-R₁ is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, —

NR₈C(═

O)R₉, —

C(═

O)NR₈R₉, and —

O(CH₂)_bNR₈R₉, wherein b is 2 or 3.

81. The method of claim 50, wherein R₂ is —

(CH₂)_bC(═

O)NR₅R₆, —

(CH₂)_bNR₅C(═

O)R₆, 3-triazolyl or 5-tetrazolyl, wherein b is 0.

82. The method of claim 50, wherein R₂ is 3-triazolyl or 5-tetrazolyl.

83. The method of claim 50, wherein:

(a) -A-R₁ is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, —

NR₈C(═

O)R₉, —

C(═

O)NR₈R₉, and —

O(CH₂)_bNR₈R₉, wherein b is 2 or 3; and

(b) R₂ is —

(CH₂)_bC(═

O)NR₅R₆, —

(CH₂)_bNR₅C(═

O)R₆, 3-triazolyl or 5-tetrazolyl, wherein b is 0.

84. The method of claim 50, wherein:

(a) -A-R₁ is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, —

NR₈C(═

O)R₉, —

C(═

O)NR₈R₉, and —

O(CH₂)_bNR₈R₉, wherein b is 2 or 3; and

(b) R₂ is 3-triazolyl or 5-tetrazolyl.

85. The compound of claim 18 wherein R₄ is methyl, n-propyl, isopropyl, 1-hydroxyethyl, 3-hydroxypropyl, methylaminomethyl, dimethylanminomethyl, 1-(dimethylamino)ethyl, 1-pyrrolidinylmethyl or 2-pyrrolidinyl.

87. The method of claim 67 wherein R₄ is methyl, n-propyl, isopropyl, 1-hydroxyethyl, 3-hydroxypropyl, methylaminomethyl, dimethylaminomethyl, 1-(dimethylamino)ethyl, 1-pyrrolidinylmethyl or 2-pyrrolidinyl.

61-1. The method of claim 50 wherein R₂ is —

(CH₂)_bNR₅R₆.