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Title:
METHODS AND AGENTS FOR TREATING DISEASES
Document Type and Number:
WIPO Patent Application WO/2017/070536
Kind Code:
A1
Abstract:
Compounds having the general structure of Formula (I) and pharmaceutical compositions thereof are described for treating non-alcoholic steatohepatitis and other liver disease.

Inventors:
SMITH DAVID E (US)
PANICKER BIJOY (US)
Application Number:
PCT/US2016/058213
Publication Date:
April 27, 2017
Filing Date:
October 21, 2016
Export Citation:
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Assignee:
ANGION BIOMEDICA CORP (US)
International Classes:
A61K31/165; A61P1/16; A61P3/00; A61P13/12; C07C233/11
Other References:
WULFF H. ET AL.: "Therapeutic potential of KCa3.1 blockers: an overview of recent advances, and promising trends.", EXPERT REV CLIN PHARMACOL., vol. 3, no. 3, May 2010 (2010-05-01), pages 385, XP055376510, Retrieved from the Internet
Attorney, Agent or Firm:
YAMIN, Michael A. (US)
Download PDF:
Claims:
Claims:

1. A method for preventing or treating a disease or disorder selected from among nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, chronic viral hepatitis, alcoholic liver disease, drug induced hepatitis, hemochromatosis, primary biliary cirrhosis, primary sclerosing cholangitis, portal hypertension, Budd-Chiari syndrome, bile desaturation, Gaucher' s disease, Wilson's disease, al -antitrypsin deficiency, total parenteral nutrition (TPN) cholelithiasis, TPN-associated cholestasis, polycystic kidney disease, fibropolycystic liver disease, Caroli syndrome, hepatomegaly or sepsis, comprising administering to a subject in need thereof a compound or a pharmaceutical composition comprising a compound having a structure according to Formula (I):

wherein Q is selected from OH, CN, carboxyalkyl, -CR R2, -CO-NR R2 or, - NR^2, wherein R1 and R2 are independently selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, a cycloalkyl, a substituted cycloalkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O- alkyl, an alkyl-O-alkenyl, an acyl, an ether, an ester or a hydroxyl, or

R1 and R2 may combine to form a saturated or unsaturated heterocylic ring and optionally substituted with up to 3 additional heteroatoms selected from N, O, and S, which may be optionally substituted with a lower alkyl or amino group; and

R3, R4, and R5 are independently selected from hydrogen, alkyl, alkyl ester, CN, N3, F, CI, Br, I and CF3, wherein m, n and p are independently selected from 0, 1, 2, and 3, wherein at least one of m, n and p is not 0.

2. The method of claim 1 wherein the saturated or unsaturated heterocyclic ring pyrrolidine, piperidine, pyrazole, imidazole, oxazole, isoxazole, tetrazole, azepine, pyridine, pyrimidine or purine.

3. The method of claim 1 wherein the compound has a structure according to Formula (II):

wherein R3, R4, and R5 are independently selected from F, CI and CF3, wherein m, n and p are independently selected from 0, 1, 2, and 3, wherein at least one of m, n and p is not 0, and wherein R1 and R2 are independently selected from the group consisting of H, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, an ester or a hydroxyl.

4. The method of claim 3 wherein at least one of R1 and R2 is an alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl.

5. The method of claim 3 wherein R1 and R2 are each independently H or alkyl. 6. The method of claim 3 wherein R1 is H and R2 is alkyl.

7. The method of claim 3 wherein at least one of R1 and R2 is H.

8. The method of claim 3 wherein both of R1 and R2 are H.

9. The method of claim 3 wherein at least one of R3, R4, or R5 is CF3.

10. The method of claim 3 wherein m, n and p are independently selected from 0, 1 and 2, at least one of R3 is CF3, or at least one of R4 is CF3; or at least one of R5 is CF3.

11. The method of claim 3 wherein m, n and p are independently selected from 0, 1 and 2 wherein at least one of m, n and p is not 0, and R3, R4, and R5 are independently selected from F, CI and CF3.

12. The method of claim 3 wherein wherein m, n and p are independently selected from 0 and 1 wherein at least one of m, n and p is not 0, R4, and R5 are independently selected from F, CI and CF3.

13. The method of claim 3 wherein R1 and R2 are both H or not both H.

14. The method of claim 3 wherein at least one of R1 and R2 is substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O- alkenyl, an ether, an ester or a hydroxyl.

15. The method of claim 3 wherein R1 and R2 are each independently H or alkyl.

16. The method of claim 3 wherein R1 is H and R2 is alkyl.

17. The method of claim 3 wherein one of R1 and R2 is H.

18. The method of claim 3 wherein n and p are both 1, the fluoro substituents at ring 1 and at ring 2 are located at a position independently selected from ortho to the acetamide substituent, meta to the acetamide substituent and para to the acetamide substituent, and the substituent at ring 3 is at a position selected from ortho to the acetamide substituent and para to the acetamide substituent.

19. The method of claim 3 wherein when p is 0, and m is 1 and n is 1, the fluoro substituent at ring 1 is para to the acetamide substituent, and the substituent at ring 2 is located at a position selected from ortho to the acetamide substituent and para to the acetamide substituent.

20. The method of claim 3 wherein one or more of R1 and R2 may alternatively be selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, and ester, a halogen, a cyano, an azide, and a hydroxyl.

21. The method of claim 3 wherein R3, R4, and R5 may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, a C5 alkyl, a C6 alkyl, CN, N3, a Ci to C6 alkyl ester, F, CI, Br, or I.

22. The method of claim 3 wherein the compound has a structure according to Formula (III):

wherein R3, R4, and R5 are independently selected from F and CF3, wherein m, n and p are independently selected from 0, 1, 2, and 3, wherein at least one of m, n and p is not 0, and wherein R1 and R2 are independently selected from the group consisting of H, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, an ester or a hydroxyl.

23. The method of claim 22 wherein at least one of R1 and R2 is an alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl.

24. The method of claim 22 wherein R1 and R2 are each independently H or alkyl; or R1 is H and R2 is alkyl; or at least one of R1 and R2 is H; or both of R1 and R2 are H.

25. The method of claim 3 wherein compound has a structure according to Formula IV: wherein R3, R4, and R5 are independently selected from F and CF3, wherein n is 0, 1, 2, or 3, and wherein R1 and R2 are independently selected from the group consisting of H, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, an ester or a hydroxyl.

26. The method of claim 25 wherein R1 and R2 are each independently H or alkyl.

27. The method of claim 25 wherein R1 is H and R2 is alkyl. 28. The method of claim 25 wherein at least one of R1 and R2 is an alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl.

29. The method of claim 25 wherein at least one of R1 and R2 is H.

30. The method of claim 25 wherein both of R1 and R2 are H.

31. The method of claim 3 wherein the compound has a structure according to Formula V:

wherein R1 and R2 are independently selected from the group consisting of H, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, an ester or a hydroxyl.

32. The method of claim 31 wherein R1 and R2 are each independently H or alkyl. 33. The method of claim 31 wherein R1 is H and R2 is alkyl.

34. The method of claim 31 wherein at least one of R1 and R2 is an alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl.

35. The method of claim 31 wherein at least one of R1 and R2 is H.

36. The method of claim 31 wherein both of R1 and R2 are H. 37. The method of claim 3 wherein the compound has a structure according to Formula VI:

38. The method of claim 3 wherein the compound has a structure according to Formula (Ha):

wherein m, n and p are independently selected from 0 and 1 and at least one of m, n and p is 1.

39. The method of claim 38 wherein when m, n and p are all 1, the fluoro substituents at ring 1 and at ring 2 are located at a position independently selected from ortho to the acetamide substituent, meta to the acetamide substituent and para to the acetamide substituent, and the substituent at ring 3 is at a position selected from ortho to the acetamide substituent and para to the acetamide substituent.

40. The method of claim 38 wherein when p is 0, and m is 1 and n is 1, the fluoro substituent at ring 1 is para to the acetamide substituent, and the substituent at ring 2 is located at a position selected from ortho to the acetamide substituent and para to the acetamide substituent.

41. The method of claim 3 wherein the compound has a structure according to Formula (Ilia):

wherein m, n and p are independently selected from 0 and 1, and at least one of m, n and p is 1.

42. The method of claim 3 wherein the compound has a structure according to Formula IVa:

wherein n is either 0 or 1.

43. The method of claim 3 wherein the compound has a structure according to

Formula VI.

44. The method of claim 1 wherein the compound has a structure according

Formula VII:

wherein X is C or N;

R1 and R2 are selected from H, alkyl, cycloalkyl, aryl, acyl, amido, or R1 and R2 may combine to form a saturated or unsaturated heterocylic ring and optionally substituted with up to 3 additional heteroatoms selected from N, O, and S, which may be optionally substituted with a lower alkyl or amino group.

45. The method of claim 44 wherein the saturated or unsaturated heterocyclic ring is pyrrolidine, piperidine, pyrazole, thiazole, oxazole, isoxazole, tetrazole, azepine, pyridine, pyrimidine or purine. 46. The method of claim 44 wherein R1 and R2 are selected from H, acyl, amido, or R1 and R2 combine to form a saturated or unsaturated heterocyclic ring, optionally substituted with up to three heteroatoms selected from N, O, or S.

47. The method of claim 1 wherein the compound has a structure according to Formula (VIII):

74

75

76

49. A method for preventing or treating fibrosis, the method comprising

administering to a subject in need thereof a compound or pharmaceutical composition of a compound represented by Formula (II):

wherein R3, R4, and R5 are independently selected from F, CI and CF3, wherein m, n and p are independently selected from 0, 1, 2, and 3, wherein at least one of m, n and p is not 0, and wherein R1 and R2 are independently selected from the group consisting of H, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, an ester or a hydroxyl.

50. The method of claim 49 wherein at least one of R1 and R2 is an alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl.

51. The method of claim 49 wherein R1 and R2 are each independently H or alkyl.

52. The method of claim 49 wherein R1 is H and R2 is alkyl.

53. The method of claim 49 wherein at least one of R1 and R2 is H.

54. The method of claim 49 wherein both of R1 and R2 are H.

55. The method of claim 49 wherein at least one of R3, R4, or R5 is CF3.

56. The method of claim 49 wherein m, n and p are independently selected from 0, 1 and 2, at least one of R3 is CF3, or at least one of R4 is CF3; or at least one of R5 is CF3.

57. The method of claim 49 wherein m, n and p are independently selected from 0, 1 and 2 wherein at least one of m, n and p is not 0, and R3, R4, and R5 are independently selected from F, CI and CF3.

58. The method of claim 49 wherein m, n and p are independently selected from 0 and 1 wherein at least one of m, n and p is not 0, R4, and R5 are independently selected from F, CI and CF3.

59. The method of claim 49 wherein R1 and R2 are both H or not both H.

60. The method of claim 49 wherein at least one of R1 and R2 is substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O- alkenyl, an ether, an ester or a hydroxyl.

61. The method of claim 49 wherein R1 and R2 are each independently H or alkyl.

62. The method of claim 49 wherein R1 is H and R2 is alkyl.

63. The method of claim 49 wherein one of R1 and R2 is H. 64. The method of claim 49 wherein n and p are both 1, the fluoro substituents at ring 1 and at ring 2 are located at a position independently selected from ortho to the acetamide substituent, meta to the acetamide substituent and para to the acetamide substituent, and the substituent at ring 3 is at a position selected from ortho to the acetamide substituent and para to the acetamide substituent. 65. The method of claim 49 wherein when p is 0, and m is 1 and n is 1, the fluoro substituent at ring 1 is para to the acetamide substituent, and the substituent at ring 2 is located at a position selected from ortho to the acetamide substituent and para to the acetamide substituent.

66. The method of claim 49 wherein one or more of R1 and R2 may alternatively be selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, and ester, a halogen, a cyano, an azide, and a hydroxyl.

67. The method of claim 49 wherein R3, R4, and R5 may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, a C5 alkyl, a C6 alkyl, CN, N3, a Ci to C6 alkyl ester, F, CI, Br, or I.

68. The method of claim 49 wherein the compound has a structure according to Formula (III):

wherein R3, R4, and R5 are independently selected from F and CF3, wherein m, n and p are independently selected from 0, 1, 2, and 3, wherein at least one of m, n and p is not 0, and wherein R1 and R2 are independently selected from the group consisting of H, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, an ester or a hydroxyl.

69. The method of claim 68 wherein at least one of R1 and R2 is an alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl.

70. The method of claim 68 wherein R1 and R2 are each independently H or alkyl. In one embodiment, R1 is H and R2 is alkyl.

71. The method of claim 68 wherein at least one of R1 and R2 is H.

72. The method of claim 68 wherein both of R1 and R2 are H.

73. The method of claim 49 wherein compound has a structure according to Formula IV:

wherein R3, R4, and R5 are independently selected from F and CF3, wherein n is 0, 1, 2, or 3, and wherein R1 and R2 are independently selected from the group consisting of H, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, an ester or a hydroxyl.

74. The method of claim 73 wherein R1 and R2 are each independently H or alkyl.

75. The method of claim 73 wherein R1 is H and R2 is alkyl.

76. The method of claim 73 wherein at least one of R1 and R2 is an alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl.

77. The method of claim 73 wherein at least one of R1 and R2 is H.

78. The method of claim 73 wherein both of R1 and R2 are H.

79. The method of claim 49 wherein the compound has a structure according to Formula V: wherein R1 and R2 are independently selected from the group consisting of H, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, an ester or a hydroxyl.

80. The method of claim 79 wherein R1 and R2 are each independently H or alkyl.

81. The method of claim 79 wherein R1 is H and R2 is alkyl.

82. The method of claim 79 wherein at least one of R1 and R2 is an alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl.

83. The method of claim 79 wherein at least one of R1 and R2 is H.

84. The method of claim 79 wherein both of R1 and R2 are H.

85. The method of claim 49 wherein the compound has a structure according to Formula VI:

86. The method of claim 49 wherein the compound has a structure according to Formula (Ha): wherein m, n and p are independently selected from 0 and 1 and at least one of m, n and p is 1.

87. The method of claim 86 wherein when m, n and p are all 1, the fluoro substituents at ring 1 and at ring 2 are located at a position independently selected from ortho to the acetamide substituent, meta to the acetamide substituent and para to the acetamide substituent, and the substituent at ring 3 is at a position selected from ortho to the acetamide substituent and para to the acetamide substituent.

88. The method of claim 86 wherein when p is 0, and m is 1 and n is 1, the fluoro substituent at ring 1 is para to the acetamide substituent, and the substituent at ring 2 is located at a position selected from ortho to the acetamide substituent and para to the acetamide substituent.

89. The method of claim 49 wherein the compound has a structure according to Formula (Ilia):

wherein m, n and p are independently selected from 0 and 1, and at least one of m, n and p is 1.

90. The method of claim 49 wherein the compound has a structure according to Formula IVa: wherein n is either 0 or 1.

91. The method of claim 49 wherein the compound has a structure according to Formula VI.

92. The method of claim 49 wherein the compound has a structure selection from among:

84

93. The method of claim 49 wherein the fibrosis is liver, kidney, cardiac or skin fibrosis.

94. The method of claim 49 wherein the fibrosis is or is a sequela of liver fibrosis associated with hepatitis C, hepatitis B, delta hepatitis, chronic alcoholism, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, extrahepatic obstructions (stones in the bile duct), cholangiopathies (primary biliary cirrhosis and sclerosing cholangitis), autoimmune liver disease, and inherited metabolic disorders (Wilson's disease, hemochromatosis, and alpha-1 antitrypsin deficiency); damaged and/or ischemic organs, transplants or grafts; ischemia/reperfusion injury; stroke; cerebrovascular disease; myocardial ischemia; atherosclerosis; renal failure; renal fibrosis; treatment of wounds for acceleration of healing; vascularization of a damaged and/or ischemic organ, transplant or graft; amelioration of ischemia/reperfusion injury in the brain, heart, liver, kidney, and other tissues and organs; normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction; development or augmentation of collateral vessel development after vascular occlusion or to ischemic tissues or organs; fibrotic diseases; hepatic disease including fibrosis and cirrhosis; radiocontrast nephropathy; fibrosis secondary to renal obstruction; renal trauma and transplantation; renal failure secondary to chronic diabetes and/or hypertension; and/or diabetes mellitus.

95. A method for treating, stabilizing, preventing or reversing one or more disease- related 1 or symptom such as but not limited to: 1) increased liver weight as a percentage of body weight, 2) increased Oil Red O staining in the liver determined in solution, 3) increased Oil Red O staining in the liver determined quantitatively or semiquantitatively in tissue sections, 4) increased vesicular steatosis, 5) increased liver function test value including but not limited to ALT and AST, 6) increased non-alcoholic liver disease (NAFLD) activity score (NAS), 7) increased KCa3.1 expression, 8) increased liver triglycerides, 9) increased liver hydroxyproline, 10) increased liver collagen by histology, 11) increased liver triglycerides by antibody staining, 12) increased macrosteatosis and 13) increased liver alpha SMA content, comprising administering to a subject in need thereof a compound or a pharmaceutical composition comprising a compound having a structure according to Formula (I):

wherein Q is selected from OH, CN, carboxyalkyl, -CRZR2, -CO- RV or, - NR^R2, wherein R1 and R2 are independently selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, a cycloalkyl, a substituted cycloalkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O- alkyl, an alkyl-O-alkenyl, an acyl, an ether, an ester or a hydroxyl, or

R1 and R2 may combine to form a saturated or unsaturated heterocyclic ring and optionally substituted with up to 3 additional heteroatoms selected from N, O, and S, which may be optionally substituted with a lower alkyl or amino group; and

R3, R4, and R5 are independently selected from hydrogen, alkyl, alkyl ester, CN, N3, F, CI, Br, I and CF3, wherein m, n and pare independently selected from 0, 1, 2, and 3, wherein at least one of m, n and p is not 0.

96. A method for treating, stabilizing, preventing or reversing one or more disease- related abnormality or symptom such as but not limited to: 1) increased liver weight as a percentage of body weight, 2) increased Oil Red O staining in the liver determined in solution, 3) increased Oil Red O staining in the liver determined quantitatively or semiquantitatively in tissue sections, 4) increased vesicular steatosis, 5) increased liver function test value including but not limited to ALT and AST, 6) increased nonalcoholic liver disease (NAFLD) activity score (NAS), 7) increased increased KCa3.1 expression, 8) increased liver triglycerides, 9) increased liver hydroxyproline, 10) increased liver collagen by histology, 11) increased liver triglycerides by antibody staining, 12) increased macrosteatosis and 13) increased liver alpha SMA content, comprising administering to a subject in need thereof a compound or a pharmaceutical composition comprising a compound having a structure according to Formula (II):

wherein R3, R4, and R5 are independently selected from F, CI and CF3, wherein m, n and p are independently selected from 0, 1, 2, and 3, wherein at least one of m, n and p is not 0, and wherein R1 and R2 are independently selected from the group consisting of H, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, an ester or a hydroxyl.

Description:
METHODS AND AGENTS FOR TREATING DISEASES

BACKGROUND OF THE INVENTION

[001] Obesity, diabetes and metabolic syndrome drive non-alcoholic fatty liver disease (NAFLD), the accumulation of fat in hepatocytes not caused by excessive consumption of alcohol. Twenty-five percent of the adult US population is thought to suffer from NAFLD, which can progress to non-alcoholic steatohepatitis (NASH) or accumulation of fat within the liver accompanied by inflammation. Left untreated, NASH, which affects several million persons in the US alone, can progress to liver fibrosis, the precursor to cirrhosis and decompensated organ failure. The development of new therapies that prevent the transition from steatosis and inflammation to fibrosis would have substantial clinical value.

[002] It is toward prevention or treatment of liver injury or disease that the present invention is directed.

SUMMARY OF THE INVENTION

[003] In one embodiment, the present invention is directed to the treatment of nonalcoholic steatohepatitis (NASH). NASH is a form of non-alcoholic fatty liver disease (NAFLD). In one embodiment, compounds useful for the treatment of NASH or NAFLD are represented by the compound of formula (I):

wherein Q is selected from OH, CN, carboxyalkyl, -CR R 2 , -Co-Nit 1 !* 2 or, - NR R 2 , wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, a cycloalkyl, a substituted cycloalkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-

O-alkenyl, an acyl, an ether, an ester, a hydroxyl, and the like, or

R 1 and R 2 may combine to form a saturated or unsaturated heterocyclic ring and optionally substituted with up to 3 additional heteroatoms selected from N, O, and S, for example, pyrimidine, piperidine, pyrazole, imidazole, oxazole, isoxazole, tetrazole, azepine, pyridine, pyrimidine, purine etc., which may be optionally substituted with a lower alkyl or amino group;

R 3 , R 4 , and R 5 are independently selected from hydrogen, alkyl, alkyl ester, CN, N 3 , F, CI, Br, I and CF 3 , wherein m, n and p are independently selected from 0, 1, 2, and 3, wherein at least one of m, n and p is not 0.

[004] In another embodiment, embraced herein are pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable excipient, carrier or diluent, for the aforementioned uses.

[005] In another embodiment, the invention is directed to methods of preventing, treating or reversing various fibrotic conditions and diseases affecting certain organs, including but not limited to liver or hepatic fibrosis, kidney or renal fibrosis, heart or cardiac fibrosis and fibrotic disorders of the skin (dermal fibroses). Compounds useful for the aforementioned purposes are represented in Formula (II):

wherein R 3 , R 4 , and R 5 are independently selected from F, CI and CF 3 , wherein m, n and p are independently selected from 0, 1, 2, and 3, wherein at least one of m, n and p is not 0, and wherein R 1 and R 2 are independently selected from the group consisting of H, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, an ester, a hydroxyl, and the like.

[006] In one embodiment, at least one ofR^ and R 2 is an alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl.

[007] In some embodiments, R 1 and R 2 are each independently H or alkyl. In one embodiment, R 1 is H and R 2 is alkyl.

[008] In a particular embodiment at least one of R 1 and R 2 is H. In another particular embodiment, both of R 1 and R 2 are H.

[009] In another embodiment, embraced herein are pharmaceutical compositions comprising a compound of Formula (II) and a pharmaceutically acceptable excipient, carrier or diluent, for the aforementioned uses.

[0010] This application claims priority under 35 U.S.C. § 119(e) to U.S. provisional applications serial number 62/245,610, filed October 23, 2015; and serial number 62/256,576, filed November 17, 2015; the contents both of which are incorporated by reference herein in their entireties.

[0011] These and other aspects of the invention are described in additional detail below.

BRIEF DESCRIPTIONS OF THE FIGURES

[0012] Figure 1 shows the increased expression of KCa3.1 in diseased livers; Figure 2 shows the effects of senicapoc intervention in the TAA model; Figure 3 shows the effects of senicapoc intervention in the CDAHFD model; Figure 4 shows further effects of senicapoc intervention in the CDAHFD model; Figure 5 shows the effect of senicapoc co-treatment in the CDAHFD model; Figure 6 shows the effect of senicapoc co-treatment in the HFD model; and Figure 7 shows the effect of senicapoc on lipid-induced apoptosis in vitro. DEFINITIONS

[0013] Unless otherwise stated, the connections of compound name moieties are at the rightmost recited moiety. For example, hetarylthioCi- 4 alkyl has a heteroaryl group connected through a thio sulfur to a C 1-4 alkyl that connects to the chemical species bearing the substituent.

[0014] As used herein, for example, " Co- 4 alkyl" is used to mean an alkyl having 0-4 carbons— that is, 0, 1, 2, 3, or 4 carbons in a straight or branched configuration. An alkyl having no carbon is hydrogen when the alkyl is a terminal group. An alkyl having no carbon is a direct bond when the alkyl is a bridging (connecting) group.

[0015] In all embodiments of this invention, the term "alkyl" includes both branched and straight chain alkyl groups. Typical alkyl groups are methyl, ethyl, n-propyl, isopropyl (iPr), n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, isooctyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl, eicosyl and the like.

[0016] The term "halo" or "halogen" refers to fluoro, chloro, bromo or iodo.

[0017] The term "haloalkyl" refers to an alkyl group substituted with one or more halo groups, for example chl orom ethyl, 2-bromoethyl, 3-iodopropyl, trifluorom ethyl, perfluoropropyl, 8-chlorononyl and the like.

[0018] The term "cycloalkyl" refers to a cyclic saturated or unsaturated aliphatic ring structure, such as cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, 2-hydroxycyclopentyl, cyclohexyl, cyclohexenyl, 4-chlorocyclohexyl, cycloheptyl, cyclooctyl and the like. Each cycloalkyl may be optionally substituted with halogen, haloalkyl, N0 2 , CN, COOR 10 , CO R 10 R U , R 10 R U , OR 10 or lower alkyl, where R 10 and R 11 are independently hydrogen, haloalkyl or lower alkyl.

[0019] The term "monocyclic ring" refers to a cycloalkyl, aryl, heteroaryl or heterocyclyl group having a single ring.

[0020] The term "polycyclic ring" refers to a cycloalkyl, aryl, heteroaryl or heterocyclyl group having two or more rings. [0021] The term "alkylcarbonyloxyalkyl" refers to an ester moiety, for example acetoxymethyl, n-butyryloxyethyl and the like.

[0022] The term "alkynylcarbonyl" refers to an alkynylketo functionality, for example propynoyl and the like.

[0023] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, for example hydroxymethyl, 2,3-dihydroxybutyl and the like.

[0024] The term "alkylsulfonylalkyl" refers to an alkyl group substituted with an alkylsulfonyl moiety, for example mesylmethyl, isopropylsulfonylethyl and the like.

[0025] The term "alkylsulfonyl" refers to a sulfonyl moiety substituted with an alkyl group, for example mesyl, n-propyl sulfonyl and the like.

[0026] The term "acetylaminoalkyl" refers to an alkyl group substituted with an amide moiety, for example acetylaminomethyl and the like.

[0027] The term "acetylaminoalkenyl" refers to an alkenyl group substituted with an amide moiety, for example 2-(acetylamino)vinyl and the like.

[0028] The term "alkenyl" refers to an ethylenically unsaturated hydrocarbon group, straight or branched chain, having 1 or 2 ethylenic bonds, for example vinyl, allyl, 1-butenyl, 2-butenyl, isopropenyl, 2-pentenyl and the like.

[0029] The term "haloalkenyl" refers to an alkenyl group substituted with one or more halo groups.

[0030] The term "unsaturated ring" refers to a substituted or unsubstituted "cycloalkenyl" or a phenyl group.

[0031] The term "cycloalkenyl" refers to a cyclic aliphatic ring structure, optionally substituted with alkyl, hydroxy and halo, having 1 or 2 ethylenic bonds such as methylcyclopropenyl, trifluoromethylcyclopropenyl, cyclopentenyl, cyclohexenyl, 1,4-cyclohexadienyl and the like.

[0032] The term "alkynyl" refers to an unsaturated hydrocarbon group, straight or branched, having 1 or 2 acetylenic bonds, for example ethynyl, propargyl and the like. [0033] The term "haloalkynyl" refers to an alkynyl group substituted with one or more halo groups.

[0034] The term "alkylcarbonyl" refers to an alkylketo functionality, for example acetyl, n-butyryl and the like.

[0035] The term "alkenylcarbonyl" refers to an alkenylketo functionality, for example, propenoyl and the like.

[0036] The term "aryl" refers to phenyl or naphthyl which may be optionally substituted. Typical aryl groups include, but are not limited to, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 3-chlorophenyl, 3 -fluorophenyl, 3-nitrophenyl, 3-(trifluoromethyl)phenyl, 2-methoxyphenyl, 2-methylphenyl,

3- methyphenyl, 4-methylphenyl, 4-ethylphenyl, 2-methyl-3methoxyphenyl, 2,4-dibromophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 2,4,6-trichlorophenyl,

4- methoxyphenyl, naphthyl, 2-chloronaphthyl, 2,4-dimethoxyphenyl,

4- (trifluoromethyl)phenyl and 2-iodo-4-methylphenyl.

[0037] The term "heterocyclic unsaturated ring" refers to a substituted or unsubstituted "heteroaryl" or a heteroaliphatic ring structure having 1 or 2 ethylenic bonds such as dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydroimidazole and the like.

[0038] The terms "heteroaryl" or "hetaryl" refer to a substituted or unsubstituted 3-10 membered unsaturated ring containing one, two, three or four heteroatoms, preferably one or two heteroatoms independently selected from oxygen, nitrogen and sulfur or to a bicyclic unsaturated ring system containing up to 10 atoms including at least one heteroatom selected from oxygen, nitrogen and sulfur. Examples of heteroaryls include, but are not limited to, 2-pyridinyl (synonym: 2-pyridyl), 3-pyridinyl (synonym: 3-pyridyl) or 4-pyridinyl (synonym: 4-pyridyl), pyrazinyl, 2-, 4-, or

5- pyrimidinyl, pyridazinyl, triazolyl, tetrazolyl, imidazolyl, 2- or 3-thienyl, 2- or 3-furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, and benzothienyl. The heterocyclic ring may be optionally substituted with up to two substituents. Tetrazole is a synonym for tetrazolyl. [0039] The terms "aryl-alkyl" or "arylalkyl" are used to describe a group wherein the alkyl chain can be branched or straight chain with the aryl portion, as defined hereinbefore, forming a bridging portion of the aryl-alkyl moiety. Examples of aryl-alkyl groups include, but are not limited to, optionally substituted benzyl, phenethyl, phenpropyl and phenbutyl such as 4-chlorobenzyl, 2,4-dibromobenzyl,

2-methylbenzyl, 2-(3-fluorophenyl)ethyl, 2-(4-methylphenyl)ethyl,

2-(4-(trifluoromethyl)phenyl)ethyl, 2-(2-methoxyphenyl)ethyl,

2- (3-nitrophenyl)ethyl, 2-(2,4-dichlorophenyl)ethyl, 2-(3,5-dimethoxyphenyl)ethyl, 3 -phenylpropyl, 3 -(3 -chlorophenyl)propyl, 3 -(2-methylphenyl)propyl, 3-(4-methoxyphenyl)propyl, 3-(4-(trifluoromethyl)phenyl)propyl,

3- (2,4-dichlorophenyl)propyl, 4-phenylbutyl, 4-(4-chlorophenyl)butyl,

4- (2-methylphenyl)butyl, 4-(2,4-dichlorophenyl)butyl, 4-(2-methoxphenyl)butyl and 10-phenyldecyl.

[0040] The terms "aryl-cycloalkyl" or "arylcycloalkyl" are used to describe a group wherein the aryl group is attached to a cycloalkyl group, for example phenylcyclopentyl and the like.

[0041] The terms "aryl-alkenyl" or "arylalkenyl" are used to describe a group wherein the alkenyl chain can be branched or straight chain with the aryl portion, as defined hereinbefore, forming a bridging portion of the aralkenyl moiety, for example styryl (2-phenylvinyl), phenpropenyl and the like.

[0042] The terms "aryl-alkynyl" or "arylalkynyl" are used to describe a group wherein the alkynyl chain can be branched or straight chain with the aryl portion, as defined hereinbefore, forming a bridging portion of the aryl-alkynyl moiety, for example 3 -phenyl- 1-propynyl and the like. [0043] The terms "aryl-oxy" or "aryloxy" are used to describe a terminal aryl group attached to a bridging oxygen atom. Typical aryl-oxy groups include phenoxy, 3,4-dichlorophenoxy and the like.

[0044] The terms "aryl-oxyalkyl" or "aryloxyalkyl" are used to describe a group wherein an alkyl group is substituted with an aryl-oxy group, for example pentafluorophenoxymethyl and the like. [0045] The terms "hetaryl-oxy" or "heteroaryl-oxy" or "hetaryloxy" or " heteroaryl oxy" are used to describe a terminal hetaryl group attached to a bridging oxygen atom. Typical hetaryl-oxy groups include 4,6-dimethoxypyrimidin-2-yloxy and the like. [0046] The terms "hetarylalkyl" or "heteroarylalkyl" or "hetaryl-alkyl" or

"heteroaryl-alkyl" are used to describe a group wherein the alkyl chain can be branched or straight chain with the heteroaryl portion, as defined hereinbefore, forming a bridging portion of the heteroaralkyl moiety, for example 3-furylmethyl, thienyl, furfuryl and the like. [0047] The terms "hetarylalkenyl" or "heteroarylalkenyl" or " hetaryl -alkenyl" or

"heteroaryl-alkenyl" are used to describe a group wherein the alkenyl chain can be branched or straight chain with the heteroaryl portion, as defined hereinbefore, forming a bridging portion of the heteroaralkenyl moiety, for example 3 -(4-pyridyl)- 1 -propenyl . [0048] The terms "hetarylalkynyl" or "heteroaryl alky nyl" or "hetaryl-alkynyl" or

"heteroaryl-alkynyl" are used to describe a group wherein the alkynyl chain can be branched or straight chain with the heteroaryl portion, as defined hereinbefore, forming a bridging portion of the heteroaralkynyl moiety, for example 4-(2-thieny 1)- 1 -butynyl . [0049] The term "heterocyclyl" or "heterocyclic saturated ring" refers to a substituted or unsubstituted 3-10 membered saturated ring containing one, two or three heteroatoms, preferably one or two heteroatoms independently selected from oxygen, nitrogen and sulfur or to a bicyclic ring system containing up to 10 atoms including at least one heteroatom selected from oxygen, nitrogen and sulfur wherein the ring containing the heteroatom is saturated. Examples of heterocyclyl s include, but are not limited to, tetrahydrofuranyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, 4-pyranyl, tetrahydropyranyl, thiolanyl, morpholinyl, piperazinyl, dioxolanyl, dioxanyl, indolinyl and 5-methyl-6-chromanyl.

[0050] The term "monoheterocyclic" refers to a single heterocyclic ring structure, while "polyheterocyclic" refers to more than one ring fused together to form a heterocyclic structure. [0051] The terms "heterocyclylalkyl" or "heterocyclyl-alkyl" are used to describe a group wherein the alkyl chain can be branched or straight chain with the heterocyclyl portion, as defined hereinabove, forming a bridging portion of the heterocyclylalkyl moiety, for example 3-piperidinylmethyl and the like.

[0052] The terms "heterocyclylalkenyl" or "heterocyclyl-alkenyl" are used to describe a group wherein the alkenyl chain can be branched or straight chain with the heterocyclyl portion, as defined hereinbefore, forming a bridging portion of the heterocyclylalkenyl moiety, for example 2-morpholinyl-l-propenyl.

[0053] The terms "heterocyclylalkynyl" or "heterocyclyl-alkynyl" are used to describe a group wherein the alkynyl chain can be branched or straight chain with the heterocyclyl portion, as defined hereinbefore, forming a bridging portion of the heterocyclylalkynyl moiety, for example 2-pyrrolidinyl-l-butynyl.

[0054] The term "carboxylalkyl" includes both branched and straight chain alkyl groups as defined hereinbefore attached to a carboxyl (-COOH) group.

[0055] The term "carboxylalkenyl" includes both branched and straight chain alkenyl groups as defined hereinbefore attached to a carboxyl (-COOH) group.

[0056] The term "carboxylalkynyl" includes both branched and straight chain alkynyl groups as defined hereinbefore attached to a carboxyl (-COOH) group.

[0057] The term "carboxylcycloalkyl" refers to a carboxyl (-COOH) group attached to a cyclic aliphatic ring structure as defined hereinbefore.

[0058] The term "carboxylcycloalkenyl" refers to a carboxyl (-COOH) group attached to a cyclic aliphatic ring structure having 1 or 2 ethylenic bonds as defined hereinbefore.

[0059] The terms "cycloalkylalkyl" or "cycloalkyl-alkyl" refer to a cycloalkyl group as defined hereinbefore attached to an alkyl group, for example cyclopropylmethyl, cyclohexylethyl and the like.

[0060] The terms "cycloalkylalkenyl" or "cycloalkyl-alkenyl" refer to a cycloalkyl group as defined hereinbefore attached to an alkenyl group, for example cyclohexylvinyl, cycloheptylallyl and the like. [0061] The terms "cycloalkylalkynyl" or "cycloalkyl-alkynyl" refer to a cycloalkyl group as defined hereinbefore attached to an alkynyl group, for example cyclopropylpropargyl, 4-cyclopentyl-2-butynyl and the like.

[0062] The terms "cycloalkenylalkyl" or "cycloalkenyl-alkyl" refer to a cycloalkenyl group as defined hereinbefore attached to an alkyl group, for example 2(cyclopenten-l-yl)ethyl and the like.

[0063] The terms "cycloalkenylalkenyl" or "cycloalkenyl-alkenyl" refer to a cycloalkenyl group as defined hereinbefore attached to an alkenyl group, for example l-(cyclohexen-3-yl)allyl and the like.

[0064] The terms "cycloalkenylalkynyl" or "cycloalkenyl-alkynyl" refer to a cycloalkenyl group as defined hereinbefore attached to an alkynyl group, for example l-(cyclohexen-3-yl)propargyl and the like.

[0065] The term "carboxylcycloalkylalkyl" refers to a carboxyl (-COOH) group attached to the cycloalkyl ring portion of a cycloalkylalkyl group as defined hereinbefore.

[0066] The term "carboxylcycloalkylalkenyl" refers to a carboxyl (-COOH) group attached to the cycloalkyl ring portion of a cycloalkylalkenyl group as defined hereinbefore.

[0067] The term "carboxylcycloalkylalkynyl" refers to a carboxyl (-COOH) group attached to the cycloalkyl ring portion of a cycloalkylalkynyl group as defined hereinbefore.

[0068] The term "carboxylcycloalkenylalkyl" refers to a carboxyl (-COOH) group attached to the cycloalkenyl ring portion of a cycloalkenylalkyl group as defined hereinbefore.

[0069] The term "carboxylcycloalkenylalkenyl" refers to a carboxyl (-COOH) group attached to the cycloalkenyl ring portion of a cycloalkenylalkenyl group as defined hereinbefore. [0070] The term "carboxylcycloalkenylalkynyl" refers to a carboxyl (-COOH) group attached to the cycloalkenyl ring portion of a cycloalkenylalkynyl group as defined hereinbefore.

[0071] The term "alkoxy" includes both branched and straight chain terminal alkyl groups attached to a bridging oxygen atom. Typical alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy and the like.

[0072] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halo groups, for example chloromethoxy, trifluoromethoxy, difluoromethoxy, perfluoroisobutoxy and the like.

[0073] The term "alkoxy alkoxy alkyl" refers to an alkyl group substituted with an alkoxy moiety which is in turn substituted with a second alkoxy moiety, for example methoxymethoxymethyl, isopropoxymethoxy ethyl and the like.

[0074] The term "alkylthio" includes both branched and straight chain alkyl groups attached to a bridging sulfur atom, for example methylthio.

[0075] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halo groups, for example trifluoromethylthio.

[0076] The term "alkoxy alkyl" refers to an alkyl group substituted with an alkoxy group, for example isopropoxymethyl.

[0077] The term " alkoxy alkenyl" refers to an alkenyl group substituted with an alkoxy group, for example 3 -m ethoxy allyl.

[0078] The term " alkoxy alkynyl" refers to an alkynyl group substituted with an alkoxy group, for example 3-methoxypropargyl.

[0079] The term "alkoxycarbonylalkyl" refers to a straight chain or branched alkyl substituted with an alkoxycarbonyl, for example ethoxycarbonylmethyl, 2-(methoxycarbonyl)propyl and the like.

[0080] The term "alkoxycarbonylalkenyl" refers to a straight chain or branched alkenyl as defined hereinbefore substituted with an alkoxycarbonyl, for example 4-(ethoxycarbonyl)-2-butenyl and the like. [0081] The term "alkoxycarbonylalkynyl" refers to a straight chain or branched alkynyl as defined hereinbefore substituted with an alkoxycarbonyl, for example

4-(ethoxycarbonyl)-2-butynyl and the like.

[0082] The term "haloalkoxyalkyl" refers to a straight chain or branched alkyl as defined hereinbefore substituted with a haloalkoxy, for example 2-chloroethoxymethyl, trifluoromethoxymethyl and the like.

[0083] The term "haloalkoxyalkenyl" refers to a straight chain or branched alkenyl as defined hereinbefore substituted with a haloalkoxy, for example 4-(chloromethoxy)-2-butenyl and the like.

[0084] The term "haloalkoxyalkynyl" refers to a straight chain or branched alkynyl as defined hereinbefore substituted with a haloalkoxy, for example 4-(2-fluoroethoxy)-2-butynyl and the like.

[0085] The term "alkylthioalkyl" refers to a straight chain or branched alkyl as defined hereinbefore substituted with an alkylthio group, for example methylthiomethyl, 3-(isobutylthio)heptyl and the like.

[0086] The term "alkylthioalkenyl" refers to a straight chain or branched alkenyl as defined hereinbefore substituted with an alkylthio group, for example 4-(methylthio)-2-butenyl and the like.

[0087] The term "alkylthioalkynyl" refers to a straight chain or branched alkynyl as defined hereinbefore substituted with an alkylthio group, for example 4-(ethylthio)-2-butynyl and the like.

[0088] The term "haloalkylthioalkyl" refers to a straight chain or branched alkyl as defined hereinbefore substituted with an haloalkylthio group, for example 2-chloroethylthiomethyl, trifluoromethylthiomethyl and the like.

[0089] The term "haloalkylthioalkenyl" refers to a straight chain or branched alkenyl as defined hereinbefore substituted with an haloalkylthio group, for example 4-(chloromethylthio)-2-butenyl and the like.

[0090] The term "haloalkylthioalkynyl" refers to a straight chain or branched alkynyl as defined hereinbefore substituted [0091] The term "dialkoxyphosphorylalkyl" refers to two straight chain or branched alkoxy groups as defined hereinbefore attached to a pentavalent phosphorous atom, containing an oxo substituent, which is in turn attached to an alkyl, for example diethoxyphosphorylmethyl.

[0092] The term "oligomer" refers to a low-molecular weight polymer, whose number average molecular weight is typically less than about 5000 g/mol, and whose degree of polymerization (average number of monomer units per chain) is greater than one and typically equal to or less than about 50.

[0093] Compounds described herein may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. The above Formula (I) is shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included.

[0094] During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

[0095] The invention also encompasses a pharmaceutical composition that is comprised of a compound of Formula (I) in combination with a pharmaceutically acceptable carrier.

[0096] Such a composition is comprised of a pharmaceutically acceptable carrier, excipient or diluent, and a non-toxic therapeutically effective amount of a compound of Formula (I) as described above, or an E or Z isomer thereof, syn or anti isomer thereof, an optically pure isomer thereof, or a pharmaceutically acceptable salt thereof.

[0097] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium slats. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline,

Ν',Ν'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,

2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine,

N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylameine, trimethylamine, tripropylamine, komethamine and the like.

[0098] When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic, formic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. Particularly preferred are formic and hydrochloric acid. [0099] The pharmaceutical compositions of the present invention comprise a compound represented herein (or E or Z isomer thereof, syn or anti isomer thereof, an optically pure isomer thereof, or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[00100] The phrase, "pharmaceutically acceptable derivative", as used herein, denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof. Pharmaceutically acceptable derivatives thus include among others pro-drugs. A pro-drug is a derivative of a compound, usually with significantly reduced pharmacological activity, which contains an additional moiety, which is susceptible to removal in vivo yielding the parent molecule as the pharmacologically active species. An example of a pro-drug is an ester, which is cleaved in vivo to yield a compound of interest. Another example is an N-methyl derivative of a compound, which is susceptible to oxidative metabolism resulting in N-demethylation. Pro-drugs of a variety of compounds, and materials and methods for derivatizing the parent compounds to create the pro-drugs, are known and may be adapted to the present invention. Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in more detail herein below.

[00101] The term "tautomerization" refers to the phenomenon wherein a proton of one atom of a molecule shifts to another atom. See, Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pages 69-74 (1992). The term "tautomer" as used herein, refers to the compounds produced by the proton shift. Thus, the present invention encompasses the tautomeric moieties like pyrazoles, pyridones and enols, etc.

[00102] The term "geometrical isomers" refers to cis-trans isomerism, syn-anti or E/Z isomerism based on the Cahn-Ingold-Prelog system. See March's Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Sixth Edition, Wiley-Interscience, pages 182-195 (2007). The term "geometrical isomers" as used herein, refers to compounds having double bond with an E or Z configuration or cis-trans isomers of monocyclic or fused ring systems.

[00103] By the term "protecting group", as used herein, it is meant that a particular functional moiety, e.g., O, S, or N, is temporarily blocked so that a reaction can be carried out selectively at another reactive site in a multifunctional compound. In preferred embodiments, a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; the protecting group must be selectively removed in good yield by readily available, preferably nontoxic reagents that do not attack the other functional groups; the protecting group forms an easily separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group has a minimum of additional functionality to avoid further sites of reaction. As detailed herein, oxygen, sulfur, nitrogen and carbon protecting groups may be utilized. For example, in certain embodiments, as detailed herein, certain exemplary oxygen protecting groups are utilized. These oxygen protecting groups include, but are not limited to methyl ethers, substituted methyl ethers (e.g., MOM (methoxymethyl ether), MTM (methylthiomethyl ether), BOM (benzyloxymethyl ether), PMBM or MPM (p-methoxybenzyloxymethyl ether), to name a few), substituted ethyl ethers, substituted benzyl ethers, silyl ethers (e.g., TMS (trimethylsilyl ether), TES (triethylsilylether), TIPS (triisopropyl silyl ether), TBDMS (t-butyldimethylsilyl ether), tribenzyl silyl ether, TBDPS (t-butyldiphenyl silyl ether), to name a few), esters (e.g., formate, acetate, benzoate (Bz), trifluoroacetate, dichloroacetate, to name a few), carbonates, cyclic acetals and ketals. In certain other exemplary embodiments, nitrogen protecting groups are utilized. These nitrogen protecting groups include, but are not limited to, carbamates (including methyl, ethyl and substituted ethyl carbamates (e.g., Troc), to name a few) amides, cyclic imide derivatives, N-Alkyl and N-Aiyl amines, imine derivatives, and enamine derivatives, to name a few. Certain other exemplary protecting groups are detailed herein, however, it will be appreciated that the present invention is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can be readily identified using the above criteria and utilized in the present invention. Additionally, a variety of protecting groups are described in "Protective Groups in Organic Synthesis" Third Ed. Greene, T.W. and Wuts, P.G., Eds., John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.

[00104] As used herein, the term "isolated" when applied to the compounds of the present invention, refers to such compounds that are (i) separated from at least some components with which they are associated in nature or when they are made and/or

(ii) produced, prepared or manufactured by the hand of man.

[00105] As used herein the term "biological sample " includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from an animal (e.g., mammal) or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof; or purified versions thereof. For example, the term "biological sample" refers to any solid or fluid sample obtained from, excreted by or secreted by any living organism, including single-celled microorganisms (such as bacteria and yeasts) and multicellular organisms (such as plants and animals, for instance a vertebrate or a mammal, and in particular a healthy or apparently healthy human subject or a human patient affected by a condition or disease to be diagnosed or investigated). The biological sample can be in any form, including a solid material such as a tissue, cells, a cell pellet, a cell extract, cell homogenates, or cell fractions; or a biopsy, or a biological fluid. The biological fluid may be obtained from any site (e.g. blood, saliva (or a mouth wash containing buccal cells), tears, plasma, serum, urine, bile, seminal fluid, cerebrospinal fluid, amniotic fluid, peritoneal fluid, and pleural fluid, or cells therefrom, aqueous or vitreous humor, or any bodily secretion), a transudate, an exudate (e.g. fluid obtained from an abscess or any other site of infection or inflammation), or fluid obtained from a joint (e.g. a normal joint or a joint affected by disease such as rheumatoid arthritis, osteoarthritis, gout or septic arthritis). The biological sample can be obtained from any organ or tissue (including a biopsy or autopsy specimen) or may comprise cells (whether primary cells or cultured cells) or medium conditioned by any cell, tissue or organ. Biological samples may also include sections of tissues such as frozen sections taken for histological purposes. Biological samples also include mixtures of biological molecules including proteins, lipids, carbohydrates and nucleic acids generated by partial or complete fractionation of cell or tissue homogenates. Although the sample is preferably taken from a human subject, biological samples may be from any animal, plant, bacteria, virus, yeast, etc. The term animal, as used herein, refers to humans as well as non-human animals, at any stage of development, including, for example, mammals, birds, reptiles, amphibians, fish, worms and single cells. Cell cultures and live tissue samples are considered to be pluralities of animals. In certain exemplary embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig). An animal may be a transgenic animal or a human clone. If desired, the biological sample may be subjected to preliminary processing, including preliminary separation techniques.

DETAILED DESCRIPTION OF THE INVENTION

[00106] In one aspect, compounds of the present invention have been found useful for the prevention or treatment of a number of conditions and diseases related pathologies related to lipid metabolism and its effect on the liver and other organs.

[00107] In one aspect, the invention includes the use, wherein the disease is a liver disease selected from nonalcoholic steatohepatitis (also called NASH), nonalcoholic fatty liver disease (also called NAFLD), chronic viral hepatitis, alcoholic liver disease, drug induced hepatitis, hemochromatosis, primary biliary cirrhosis, primary sclerosing cholangitis, portal hypertension, Budd-Chiari syndrome, bile desaturation, Gaucher' s disease, Wilson's disease, al -antitrypsin deficiency, total parenteral nutrition (TPN) cholelithiasis, polycystic kidney disease, fibropolycystic liver disease, Caroli syndrome TPN-associated cholestasis, hepatomegaly and sepsis. The invention includes a method of treating or preventing a liver disease selected from nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, chronic viral hepatitis, alcoholic liver disease, drug induced hepatitis, hemochromatosis, primary biliary cirrhosis, primary sclerosing cholangitis, portal hypertension, Budd-Chiari syndrome, bile desaturation, Gaucher's disease, Wilson's disease, al -antitrypsin deficiency, total parenteral nutrition (TPN) cholelithiasis, TPN-associated cholestasis, polycystic kidney disease, fibropolycystic liver disease, Caroli syndrome, hepatomegaly and sepsis by administering to a subject in need thereof a compound of a pharmaceutical composition comprising a compound having a structure according to Formula (I):

wherein Q is selected from OH, CN, carboxyalkyl, -CR R 2 , -CO-NRV or, -

NR R 2 , wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, a cycloalkyl, a substituted cycloalkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl- O-alkenyl, an acyl, an ether, an ester, a hydroxyl, and the like, or

R 1 and R 2 may combine to form a saturated or unsaturated heterocylic ring and optionally substituted with up to 3 additional heteroatoms selected from N, O, and S, for example, pyrrolidine, piperidine, pyrazole, imidazole, oxazole, isoxazole, tetrazole, azepine, pyridine, pyrimidine, purine etc., which may be optionally substituted with a lower alkyl or amino group;

R 3 , R 4 , and R 5 are independently selected from hydrogen, alkyl, alkyl ester, CN, N 3 , F, CI, Br, I and CF 3 , wherein m, n and p are independently selected from 0, 1, 2, and 3, wherein at least one of m, n and p is not 0.

[00108] In its various aspects, the present invention utilizes a compound having a structure according to Formula (II):

wherein R 3 , R 4 , and R 5 are independently selected from F, CI and CF 3 , wherein m, n and p are independently selected from 0, 1, 2, and 3, wherein at least one of m, n and p is not 0, and wherein R 1 and R 2 are independently selected from the group consisting of H, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, an ester, a hydroxyl, and the like. [00109] In one embodiment, at least one of R 1 and R 2 is an alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl.

[00110] In some embodiments, R 1 and R 2 are each independently H or alkyl.

[00111] In one embodiment, R 1 is H and R 2 is alkyl.

[00112] In a particular embodiment at least one of R 1 and R 2 is H.

[00113] In another particular embodiment, both of R 1 and R 2 are H.

[00114] In another embodiment, at least one of R 3 , R 4 , or R 5 is CF . In another embodiment wherein m, n and p are independently selected from 0, 1 and 2, at least one of R 3 is CF 3 , or at least one of R 4 is CF 3; or at least one of R 5 is CF 3.

[00115] In another embodiment, wherein m, n and p are independently selected from 0, 1 and 2 wherein at least one of m, n and p is not 0, R 3 , R 4 , and R 5 are independently selected from F, CI and CF 3 .

[00116] In another embodiment, wherein m, n and p are independently selected from 0 and 1 wherein at least one of m, n and p is not 0, R 4 , and R 5 are independently selected from F, CI and CF 3 .

[00117] In another embodiment of the above, R 1 and R 2 are both H or not both H. In another embodiment at least one of R 1 and R 2 is substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, an ester, a hydroxyl.

[00118] In some embodiments, R 1 and R 2 are each independently H or alkyl.

[00119] In one embodiment, R 1 is H and R 2 is alkyl. In a further embodiment of the above one of R 1 and R 2 is H.

[00120] In one embodiment, when in, n and p are all 1, the fluoro substituents at ring 1 and at ring 2 are located at a position independently selected from ortho to the acetamide substituent, meta to the acetamide substituent and para to the acetamide substituent, and the substituent at ring 3 is at a position selected from ortho to the acetamide substituent and para to the acetamide substituent. [00121] In another exemplary embodiment, when p is 0, and m is 1 and n is 1, the fluoro substituent at ring 1 is para to the acetamide substituent, and the substituent at ring 2 is located at a position selected from ortho to the acetamide substituent and para to the acetamide substituent.

[00122] In yet other embodiments of the invention, one or more of R 1 and R 2 may independently be selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaiyl, a substituted heteroaiyl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O- alkenyl, an ether, and ester, a halogen, a cyano, an azide, a hydroxyl, and the like.

[00123] In particular embodiments, R 3 , R 4 , and R 5 may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, a C 5 alkyl, a C 6 alkyl, CN, N 3 , a Ci to C 6 alkyl ester, F, CI, Br, I, and the like.

[00124] In another embodiment, the compounds utilized in the present invention have a structure according to Formula (III):

wherein R 3 , R 4 , and R 5 are independently selected from F and CF 3 , wherein m, n and p are independently selected from 0, 1, 2, and 3, wherein at least one of m, n and p is not 0, and wherein R 1 and R 2 are independently selected from the group consisting of H, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaiyl, a substituted heteroaiyl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, an ester, a hydroxyl, and the like.

[00125] In one embodiment, at least one of R 1 and R 2 is an alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl. [00126] In some embodiments, R 1 and R 2 are each independently H or alkyl.

[00127] In one embodiment, R 1 is H and R 2 is alkyl.

[00128] In a particular embodiment at least one of R 1 and R 2 is H.

[00129] In another particular embodiment, both of R 1 and R 2 are H.

[00130] In another embodiment, the compounds of the invention for the intended uses have a structure according to Formula IV:

wherein R 3 , R 4 , and R 5 are independently selected from F and CF 3 , wherein n is 0, 1, 2, or 3, and wherein R 1 and R 2 are independently selected from the group consisting of H, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, an ester, a hydroxyl, and the like.

[00131] In some embodiments, R 1 and R 2 are each independently H or alkyl. [00132] In one embodiment, R 1 is H and R 2 is alkyl.

[00133] In one embodiment, at least one of R 1 and R 2 is an alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl.

[00134] In a particular embodiment at least one of R 1 and R 2 is H.

[00135] In another particular embodiment, both of R 1 and R 2 are H.

[00136] In another embodiment, the compounds of the invention for the intended uses have a structure according to Formula V: wherein R 1 and R 2 are independently selected from the group consisting of H, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, an ester, a hydroxyl, and the like.

[00137] In some embodiments, R 1 and R 2 are each independently H or alkyl. [00138] In one embodiment, R 1 is H and R 2 is alkyl.

[00139] In one embodiment, at least one of R 1 and R 2 is an alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl.

[00140] In a particular embodiment at least one of R 1 and R 2 is H.

[00141] In another particular embodiment, both of R 1 and R 2 are H.

[00142] In a particular embodiment, the compound to be utilized according to the invention has a structure according to Formula VI:

[00143] In additional embodiments, the present invention utilizes a compound having a structure according to Formula (Ha): wherein m, n and p are independently selected from 0 and 1 and at least one of m, n and p is 1.

[00144] In an exemplary embodiment of the same, when m, n and p are all 1, the fluoro substituents at ring 1 and at ring 2 are located at a position independently selected from ortho to the acetamide substituent, meta to the acetamide substituent and para to the acetamide substituent, and the substituent at ring 3 is at a position selected from ortho to the acetamide substituent and para to the acetamide substituent.

[00145] In another exemplary embodiment, when p is 0, and m is 1 and n is 1, the fluoro substituent at ring 1 is para to the acetamide substituent, and the substituent at ring 2 is located at a position selected from ortho to the acetamide substituent and para to the acetamide substituent.

[00146] In another exemplary embodiment, the compounds utilized in the present invention have a structure according to Formula (Ilia):

wherein m, n and p are independently selected from 0 and 1, and at least one of m, n and p is 1.

[00147] In another exemplary embodiment, the compounds of the invention for the intended uses have a structure according to Formula IVa: wherein n is either 0 or 1.

[00148] In a particular aspect, the invention provides a method of treating any one of the aforementioned conditions or diseases with a compound having a structure according to Formula VI.

[00149] In certain aspects, the invention provides formulations useful for the treatment encompassed herein comprise a compound according to Formula VI. As used herein, "2,2-bis(4-fluorophenyl)-2-phenylacetamide" and "senicapoc" all refer to a compound having the structure according to Formula VI.

[00150] In another embodiment, the compounds or compositions thereof useful in the practice of the invention have a structure according to Formula VII:

wherein X is C or N; R 1 and R 2 are independently selected from H, alkyl, cycloalkyl, aryl, acyl, amido, or R 1 and R 2 may combine to form a saturated or unsaturated heterocylic ring and optionally substituted with up to 3 additional heteroatoms selected from N, O, and S, for example, pyrrolidine, piperidine, pyrazole, thiazole, oxazole, isoxazole, tetrazole, azepine, pyridine, pyrimidine, purine, etc., which may be optionally substituted with a lower alkyl or amino group.

[00151] In the most preferred embodiment of this invention, R 1 and R 2 are independently selected from H, acyl, amido, and R 1 and R 2 combine to form a saturated or unsaturated heterocyclic ring, optionally substituted with up to three heteroatoms selected from N, O, or S, for example, pyrrolidine, piperidine, pyrazole, oxazole, isoxazole, tetrazole, azepine, etc., which may be optionally substituted with a lower alkyl or amino group.

[00152] In a particular aspect, the invention provides a method of treating a patient in need thereof with a compound having a structure according to Formula (VIII):

[00153] In certain aspects, the invention provides formulations useful for the treatment of the conditions and diseases heretofore mentioned comprise a compound according to Formula VII. As used herein, " l-((2-chlorophenyl)diphenylmethyl)-lH- pyrazole", "TRAM-34" all refer to a compound having the structure according to Formula VI.

[00154] The embodiments of the invention extend to the use of compounds that are structurally closely related to compounds of the invention, non-limiting examples of which are displayed in Table I below. Table I



45 46 47 [00155] In one aspect, the compound or composition of the invention is administered to the subject orally, parentally, intravenously, or topically. In one aspect, the subject is a human.

[00156] In another aspect, the present invention provides a method for the prevention or treatment of cholestatic liver disease. The method comprises administering a therapeutically effective amount of the compound of formulas (I- VIII) or compounds 1-48 in Table 1. The present invention also provides the use of the compound of formulas (I- VIII) or compounds 1-48 in Table 1 for the preparation of a medicament for the prevention or treatment of cholestatic liver diseases.

[00157] In another aspect, compounds described here are useful for the treatment or prevention of fibrosis of certain organs such as but not limited to liver, kidney, cardiac and skin fibrosis. Compounds of pharmaceutical compositions thereof useful for this purpose are represented by Formula (II): In its various aspects, the present invention utilizes a compound having a structure according to Formula (II):

wherein R3, R4, and R5 are independently selected from F, CI and CF3, wherein m, n and p are independently selected from 0, 1, 2, and 3, wherein at least one of m, n and p is not 0, and wherein Rl and R2 are independently selected from the group consisting of H, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, an ester, a hydroxyl, and the like.

[00158] In one embodiment, at least one of Rl and R2 is an alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl.

[00159] In some embodiments, Rl and R2 are each independently H or alkyl. [00160] In one embodiment, Rl is H and R2 is alkyl. In a particular embodiment at least one of Rl and R2 is H.

[00161] In another particular embodiment, both of Rl and R2 are H.

[00162] In another embodiment, at least one of R3, R4, or R5 is CF3.

[00163] In another embodiment wherein m, n and p are independently selected from 0, 1 and 2, at least one of R3 is CF3, or at least one of R4 is CF3, or at least one of R5 is CF3.

[00164] In another embodiment, wherein m, n and p are independently selected from 0, 1 and 2 wherein at least one of m, n and p is not 0, R3, R4, and R5 are independently selected from F, CI and CF 3 .

[00165] In another embodiment, wherein m, n and p are independently selected from 0 and 1 wherein at least one of m, n and p is not 0, R4, and R5 are independently selected from F, CI and CF3.

[00166] In another embodiment of the above, Rl and R2 are both H or not both H. In another embodiment at least one of Rl and R2 is substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, an ester, a hydroxyl. In some embodiments, Rl and R2 are each independently H or alkyl. In one embodiment, Rl is H and R2 is alkyl. In a further embodiment of the above one of Rl and R2 is H.

[00167] In one embodiment, when in, n and p are all 1, the fluoro substituents at ring 1 and at ring 2 are located at a position independently selected from ortho to the acetamide substituent, meta to the acetamide substituent and para to the acetamide substituent, and the substituent at ring 3 is at a position selected from ortho to the acetamide substituent and para to the acetamide substituent. In another exemplary embodiment, when p is 0, and m is 1 and n is 1, the fluoro substituent at ring 1 is para to the acetamide substituent, and the substituent at ring 2 is located at a position selected from ortho to the acetamide substituent and para to the acetamide substituent.

[00168] In yet other embodiments of the invention, one or more of Rl and R2 may alternatively be selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O- alkenyl, an ether, and ester, a halogen, a cyano, an azide, a hydroxyl, and the like.

[00169] In particular embodiments, R3, R4, and R5 may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, a C5 alkyl, a C6 alkyl, CN, N3, a Ci to C6 alkyl ester, F, CI, Br, I, and the like.

[00170] Fibrosis includes but is not limited to fibrosis of organs and sequelae of fibrosis, such as but not limited to liver fibrosis associated with hepatitis C, hepatitis B, delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, extrahepatic obstructions (stones in the bile duct), cholangiopathies (primary biliary cirrhosis and sclerosing cholangitis), autoimmune liver disease, and inherited metabolic disorders (Wilson's disease, hemochromatosis, and alpha- 1 antitrypsin deficiency); damaged and/or ischemic organs, transplants or grafts; ischemia/reperfusion injury; stroke; cerebrovascular disease; myocardial ischemia; atherosclerosis; renal failure; renal fibrosis; treatment of wounds for acceleration of healing; vascularization of a damaged and/or ischemic organ, transplant or graft; amelioration of ischemia/reperfusion injury in the brain, heart, liver, kidney, and other tissues and organs; normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction; development or augmentation of collateral vessel development after vascular occlusion or to ischemic tissues or organs; fibrotic diseases; hepatic disease including fibrosis and cirrhosis; radiocontrast nephropathy; fibrosis secondary to renal obstruction; renal trauma and transplantation; renal failure secondary to chronic diabetes and/or hypertension; and/or diabetes mellitus. In one embodiment, fibrosis excludes lung fibrosis, including idiopathic pulmonary fibrosis. In one embodiment, fibrosis excludes any lung related disease or lung sequela of lung fibrosis.

[00171] In another embodiment, the compounds utilized in the present invention for the treatment or prevention of fibrosis have a structure according to Formula (III): wherein R3, R4, and R5 are independently selected from F and CF3, wherein m, n and p are independently selected from 0, 1, 2, and 3, wherein at least one of m, n and p is not 0, and wherein Rl and R2 are independently selected from the group consisting of H, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, an ester, a hydroxyl, and the like.

[00172] In one embodiment, at least one of Rl and R2 is an alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl.

[00173] In some embodiments, Rl and R2 are each independently H or alkyl.

[00174] In one embodiment, Rl is H and R2 is alkyl.

[00175] In a particular embodiment at least one of Rl and R2 is H.

[00176] In another particular embodiment, both of Rl and R2 are H.

[00177] In another embodiment, the compounds of the invention for the treatment or prevention of fibrosis have a structure according to Formula IV:

wherein R3, R4, and R5 are independently selected from F and CF3, wherein n is 0, 1, 2, or 3, and wherein Rl and R2 are independently selected from the group consisting of H, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, an ester, a hydroxyl, and the like.

[00178] In some embodiments, Rl and R2 are each independently H or alkyl.

[00179] In one embodiment, Rl is H and R2 is alkyl.

[00180] In one embodiment, at least one of Rl and R2 is an alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl.

[00181] In a particular embodiment at least one of Rl and R2 is H.

[00182] In another particular embodiment, both of Rl and R2 are H.

[00183] In another embodiment, the compounds of the invention for the treatment or prevention of fibrosis have a structure according to Formula V:

wherein Rl and R2 are independently selected from the group consisting of H, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, an alkyl-O-alkyl, an alkyl-O-alkenyl, an ether, an ester, a hydroxyl, and the like.

[00184] In some embodiments, Rl and R2 are each independently H or alkyl. [00185] In one embodiment, Rl is H and R2 is alkyl. [00186] In one embodiment, at least one of Rl and R2 is an alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl.

[00187] In a particular embodiment at least one of Rl and R2 is H.

[00188] In another particular embodiment, both of Rl and R2 are H.

[00189] In a particular embodiment, the compound to be utilized for the treatment or prevention of fibrosis according to the invention has a structure according to Formula VI:

[00190] In additional embodiments, the present invention utilizes a compound for the treatment or prevention of fibrosis having a structure according to Formula (lla):

wherein m, n and p are independently selected from 0 and 1 and at least one of m, n and p is 1.

[00191] In an exemplary embodiment of the same, when m, n and p are all 1, the fluoro substituents at ring 1 and at ring 2 are located at a position independently selected from ortho to the acetamide substituent, meta to the acetamide substituent and para to the acetamide substituent, and the substituent at ring 3 is at a position selected from ortho to the acetamide substituent and para to the acetamide substituent. [00192] In another exemplary embodiment, when p is 0, and m is 1 and n is 1, the fluoro substituent at ring 1 is para to the acetamide substituent, and the substituent at ring 2 is located at a position selected from ortho to the acetamide substituent and para to the acetamide substituent.

[00193] In another exemplary embodiment, the compounds utilized for the treatment or prevention of fibrosis in the present invention have a structure according to Formula (Ilia):

wherein m, n and p are independently selected from 0 and 1, and at least one of m, n and p is 1.

[00194] In another exemplary embodiment, the compounds of the invention for the treatment or prevention of fibrosis have a structure according to Formula IVa:

wherein n is either 0 or 1.

[00195] In a particular aspect, the invention provides a method of treatment or prevention of fibrosis with a compound having a structure according to Formula VI.

[00197] In certain aspects, the invention provides formulations useful for the treatment or prevention of fibrosis comprising a compound according to Formula VI. As used herein, "2,2-bis(4-fluorophenyl)-2-phenylacetamide", "Senicapoc" all refer to a compound having the structure according to Formula VI.

[00198] Non-limiting examples of compounds for the aforementioned uses in fibrotic conditions and diseases are shown in Table II below.

Table II



[00199] In another aspect, the present invention provides a method for the prevention or treatment of fibrosis. The method comprises administering a therapeutically effective amount of the compound of formulas (II- VI) or compounds 1-30 in Table 2 above. The present invention also provides the use of the compound of formulas (I- VIII) or compounds 1-30 in Table 2 for the preparation of a medicament for the prevention or treatment of fibrosis.

[00200] In another embodiment, the present invention provides compounds useful for treating, stabilizing, preventing or reversing one or more disease-related abnormality or symptom such as but not limited to: 1) increased liver weight as a percentage of body weight, 2) increased Oil Red O staining in the liver determined in solution, 3) increased Oil Red O staining in the liver determined quantitatively or semi quantitatively in tissue sections, 4) increased vesicular steatosis, 5) increased liver function test value including but not limited to ALT and AST, 6) increased nonalcoholic liver disease (NAFLD) activity score (NAS), 7) increased KCa3.1 expression, 8) increased liver triglycerides, 9) increased liver hydroxyproline, 10) increased liver collagen by histology, 11) increased liver triglycerides by antibody staining, 12) increased macrosteatosis and 13) increased liver alpha SMA content. Any one or any combination of two or more of these measures may be affected adversely or abnormally in the diseases and conditions described herein, and administration of a compound herein described may stabilize or reverse the disease- related change in one or more abnormality or symptom. Any of the foregoing compounds are useful for these purposes.

[00201 ] It will be appreciated that each of the compounds described herein and each of the classes and subclasses of compounds described above may be substituted as described generally herein, or may be substituted according to any one or more of the subclasses described above and herein.

[00202] Some of the foregoing compounds can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., stereoisomers and/or diastereomers. Thus, inventive compounds and pharmaceutical compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers. In certain embodiments, the compounds of the invention are enantiopure compounds. In certain other embodiments, mixtures of stereoisomers or diastereomers are provided.

[00203] Furthermore, certain compounds, as described herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated. The invention additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of stereoisomers. In addition to the above-mentioned compounds per se, this invention also encompasses pharmaceutically acceptable derivatives of these compounds and compositions comprising one or more compounds of the invention and one or more pharmaceutically acceptable excipients or additives.

[00204] Compounds of the invention may be prepared by crystallization of compound herein under different conditions and may exist as one or a combination of polymorphs of compound herein forming part of this invention. For example, different polymorphs may be identified and/or prepared using different solvents, or different mixtures of solvents for recrystallization; by performing crystallizations at different temperatures; or by using various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe MR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffractogram and/or other techniques. Thus, the present invention encompasses inventive compounds, their derivatives, their tautomeric and geometrical isomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. Tautomeric forms of compounds of the present invention include, pyrazoles, pyridones and enols, etc., and geometrical isomers include E/Z isomers of compounds having double bonds and cis-trans isomers of monocyclic or fused ring systems, etc.,

Pharmaceutical Compositions

[00205] In practice, the compounds represented herein, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented herein, or a pharmaceutically acceptable salt thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation. [00206] Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt ofa formula herein. The compounds, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[00207] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[00208] In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.

[00209] A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient. [00210] For example, a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about lmg to about 2g of the active ingredient, typically 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or lOOOmg.

[00211] Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[00212] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[00213] Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formulas (I- VIII) of this invention, or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt% to about 10wt% of the compound, to produce a cream or ointment having a desired consistency.

[00214] Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.

[00215] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by Formulas (I- VIII), or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.

[00216] Generally, dosage levels on the order of from about O.Olmg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above indicated conditions, or alternatively about 0.5mg to about 7g per patient per day. For example, dermatological diseases and cancers may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.

[00217] It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

[00218] Accordingly, in another aspect of the present invention, pharmaceutical compositions are provided, which comprise any one or more of the compounds described herein (or a prodrug, pharmaceutically acceptable salt or other pharmaceutically acceptable derivative thereof), and optionally comprise a pharmaceutically acceptable carrier. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. Alternatively, a compound of this invention may be administered to a patient in need thereof in combination with the administration of one or more other therapeutic agents. For example, additional therapeutic agents for conjoint administration or inclusion in a pharmaceutical composition with a compound of this invention may be an approved agent to treat the same or related indication, or it may be any one of a number of agents undergoing approval in the Food and Drug Administration that ultimately obtain approval for the treatment of a disorder. It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or a pro-drug or other adduct or derivative of a compound of this invention which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

[00219] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art. For example, S.M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting a free base or free acid function with a suitable reagent, as described generally below. For example, a free base function can be reacted with a suitable acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, di gluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[00220] Additionally, as used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

[00221] Furthermore, the term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the issues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood, or N-demethylation of a compound of the invention where R 1 is methyl. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. By way of example, N-methylated pro-drugs of the compounds of the invention are embraced herein.

[00222] As described above, the pharmaceutical compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogenfree water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[00223] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut (peanut), corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[00224] In one embodiment, liquid compositions or liquid formulations comprising compounds of the invention are provided that have increased solubility as compared to compounds of the invention dissolved in aqueous buffer such as phosphate-buffered saline. In one embodiment, such liquid compositions with increased solubility are provided by a composition comprising polyethylene glycol, polysorbate or a combination thereof. In one embodiment, the polyethylene glycol is polyethylene glycol 300. In another embodiment the polysorbate is polysorbate 80. In another embodiment the polyethylene glycol is present at about 40% to about 60% (v/v). In another embodiment the polysorbate is present at about 5% to about 15% (v/v). In another embodiment the polyethylene glycol is present at about 50% (v/v). In another embodiment the polysorbate is present at about 10% (v/v). In one formulation, the polyethylene glycol is present at 50% (v/v) together with polysorbate 80 at 10%) (v/v). The balance of the solution can be a saline solution, a buffer or a buffered saline solution, such as phosphate-buffered saline. The pH of the solution can be from about pH 5 to about pH 9, and in other embodiments, about from pH 6 to about pH 8. In one embodiment the pH of the buffer is 7.4. In the foregoing embodiments, the compound of the invention is soluble at a concentration higher than in buffer alone, and can be present at about 0.8 to about 10 milligrams per milliliter of solution, or even higher. These formulations offer the preparation of convenient dosing solutions of practical volumes for single dose administration, by any route, in particular a parenteral route. In one embodiment, the route is intravenous, subcutaneous or intraperitoneal. Such compositions with a higher solubility permit achievement of more elevated blood concentrations that provide efficacy when the threshold Cmax (maximal blood concentration after administration) should be achieved for optimal efficacy.

[00225] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer' s solution, U. S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[00226] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00227] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension or crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

[00228] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. [00229] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[00230] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[00231] In other embodiments, solid dosage forms of compounds embodied herein are provided. In some embodiment, such solid dosage forms have improved oral bioavailability. In one embodiment, a formulation is prepared in a solid formulation comprising about 20% (w/w) compound of the invention, about 10-20%) (w/w) GLUCIRE® 44/14, about 10-20% (w/w) vitamin E succinate (TPS), 0 to about 60% polyethylene glycol 400, 0 to about 40% Lubrizol, 0 to about 15% Cremophor RH 40 (w/w), and about 1%> (w/w) BHT. Formulations containing Cremophor RH 20 are liquid at room temperature but waxy solids at 4 C. The foregoing examples of one or more agents to aid in preparing formulations of inventive compound are merely illustrative and non-limiting. [00232] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose and starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. [00233] In other embodiments solid dosage forms are provided. In certain embodiments, such solid dosage forms provide a higher than about a 20% oral bioavailability. As will be shown in the examples below, compounds of the invention can be co-precipitated with one or more agents such as mannitol, a combination of mannitol and lactobionic acid, a combination of mannitol and gluconic acid, a combination of mannitol and methanesulfonic acid, a combination of microcrystalline cellulose and oleic acid or a combination of pregelatinized starch and oleic acid. The foregoing examples of one or more agents to aid in preparing formulations of inventive compound are merely illustrative and non-limiting. Non-limiting examples of inventive compounds in such solid dosage forms include [00234] The present invention encompasses pharmaceutically acceptable topical formulations of inventive compounds. The term "pharmaceutically acceptable topical formulation", as used herein, means any formulation which is pharmaceutically acceptable for intradermal administration of a compound of the invention by application of the formulation to the epidermis. In certain embodiments of the invention, the topical formulation comprises a carrier system. Pharmaceutically effective carriers include, but are not limited to, solvents (e.g. , alcohols, poly alcohols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffered solutions (e.g., hypotonic or buffered saline) or any other carrier known in the art for topically administering pharmaceuticals. A more complete listing of art-known carriers is provided by reference texts that are standard in the art, for example, Remington's Pharmaceutical Sciences, 16th Edition, 1980 and

17th Edition, 1985, both published by Mack Publishing Company, Easton, Pa., the disclosures of which are incorporated herein by reference in their entireties. In certain other embodiments, the topical formulations of the invention may comprise excipients. Any pharmaceutically acceptable excipient known in the art may be used to prepare the inventive pharmaceutically acceptable topical formulations. Examples of excipients that can be included in the topical formulations of the invention include, but are not limited to, preservatives, antioxidants, moisturizers, emollients, buffering agents, solubilizing agents, other penetration agents, skin protectants, surfactants, and propellants, and/or additional therapeutic agents used in combination to the inventive compound. Suitable preservatives include, but are not limited to, alcohols, quaternary amines, organic acids, parabens, and phenols. Suitable antioxidants include, but are not limited to, ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents like

EDTA and citric acid. Suitable moisturizers include, but are not limited to, glycerine, sorbitol, polyethylene glycols, urea, and propylene glycol. Suitable buffering agents for use with the invention include, but are not limited to, citric, hydrochloric, and lactic acid buffers. Suitable solubilizing agents include, but are not limited to, quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates. Suitable skin protectants that can be used in the topical formulations of the invention include, but are not limited to, vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.

[00235] In certain embodiments, the pharmaceutically acceptable topical formulations of the invention comprise at least a compound of the invention and a penetration enhancing agent. The choice of topical formulation will depend or several factors, including the condition to be treated, the physicochemical characteristics of the inventive compound and other excipients present, their stability in the formulation, available manufacturing equipment, and costs constraints. As used herein the term " penetration enhancing agent " means an agent capable of transporting a pharmacologically active compound through the stratum corneum and into the epidermis or dermis, preferably, with little or no systemic absorption. A wide variety of compounds have been evaluated as to their effectiveness in enhancing the rate of penetration of drugs through the skin. See, for example, Percutaneous Penetration Enhancers, Maibach H. I. and Smith H. E. (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which surveys the use and testing of various skin penetration enhancers, and Buyuktimkin et al, Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh

T. K., Pfister W. R., Yum S. I. (Eds.), Interpharm Press Inc., Buffalo Grove, 111. (1997). In certain exemplary embodiments, penetration agents for use with the invention include, but are not limited to, triglycerides {e.g., soybean oil), aloe compositions (e.g., aloe-vera gel), ethyl alcohol, isopropyl alcohol, octolyphenylpoly ethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethylsulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate) and N-methyl pyrrolidone.

[00236] In certain embodiments, the compositions may be in the form of ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. In certain exemplary embodiments, formulations of the compositions according to the invention are creams, which may further contain saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmito-oleic acid, cetyl or oleyl alcohols, stearic acid being particularly preferred. Creams of the invention may also contain a non-ionic surfactant, for example, polyoxy-40-stearate. In certain embodiments, the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Formulations for intraocular administration are also included. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are made by dissolving or dispensing the compound in the proper medium. As discussed above, penetration enhancing agents can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[00237] It will also be appreciated that the compounds and pharmaceutical compositions of the present invention can be formulated and employed in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated with or administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another anti -inflammatory agent), or they may achieve different effects (e.g., control of any adverse effects). In non-limiting examples, one or more compounds of the invention may be formulated with at least one cytokine, growth factor or other biological, such as an interferon, e.g., alpha interferon, or with at least another small molecule compound. Non-limiting examples of pharmaceutical agents that may be combined therapeutically with compounds of the invention include: antivirals and antifibrotics such as interferon alpha, combination of interferon alpha and ribavirin, Lamivudine,

Adefovir dipivoxil and interferon gamma; anticoagulants such as heparin and warfarin; antiplatelets e.g., aspirin, ticlopidine and clopidogrel; other growth factors involved in regeneration, e.g., VEGF and FGF and mimetics of these growth factors; antiapoptotic agents; and motility and morphogenic agents.

[00238] In certain embodiments, the pharmaceutical compositions of the present invention further comprise one or more additional therapeutically active ingredients (e.g., anti-inflammatory and/or palliative). For purposes of the invention, the term "Palliative " refers to treatment that is focused on the relief of symptoms of a disease and/or side effects of a therapeutic regimen, but is not curative. For example, palliative treatment encompasses painkillers, antinausea medications and anti-sickness drugs.

Research Uses, Clinical Uses, Pharmaceutical Uses and Methods of Treatment

Pharmaceutical Uses and Methods of Treatment

[00239] In certain embodiments, the method involves the administration of a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to a human or animal) in need of it. Subjects for which the benefits of the compounds of the invention are intended for administration include, in addition to humans, livestock, domesticated, zoo and companion animals.

[00240] Furthermore, after formulation with an appropriate pharmaceutically acceptable carrier in a desired dosage, the pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, subcutaneously, intradermally, intra-ocularly, topically (as by powders, ointments, or drops), buccally, as an oral or nasal spray, or the like, depending on the severity of the disease or disorder being treated. In certain embodiments, the compounds of the invention may be administered at dosage levels of about 0.001 mg/kg to about 50 mg/kg, preferably from about 0. 1 mg/kg to about 10 mg/kg for parenteral administration, or preferably from about 1 mg/kg to about 50 mg/kg, more preferably from about 10 mg/kg to about 50 mg/kg for oral administration, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. It will also be appreciated that dosages smaller than 0.001 mg/kg or greater than 50 mg/kg (for example 50-100 mg/kg) can be administered to a subject. In certain embodiments, compounds are administered orally or parenterally.

[00241] A subject can be a human or non-human subject, the latter including domesticated animals including cats and dogs, livestock including sheep, cattle, horses, and the like.

TREATMENT KIT

In other embodiments, the present invention relates to a kit for conveniently and effectively carrying out the methods in accordance with the present invention. In general, the pharmaceutical pack or kit comprises one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Such kits are especially suited for the delivery of solid oral forms such as tablets or capsules. Such a kit preferably includes a number of unit dosages, and may also include a card having the dosages oriented in the order of their intended use. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

EQUIVALENTS

[00242] The representative examples that follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. It should further be appreciated that the contents of those cited references are incorporated herein by reference to help illustrate the state of the art.

[00243] The following examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and the equivalents thereof. EXEMPLIFICATION

[00244] The compounds of this invention and their preparation can be understood further by the examples that illustrate some of the processes by which these compounds are prepared or used. It will be appreciated, however, that these examples do not limit the invention. Variations of the invention, now known or further developed, are considered to fall within the scope of the present invention as described herein and as hereinafter claimed.

1) General Description of Synthetic Methods:

[00245] The practitioner has a well-established literature of small molecule chemistry to draw upon, in combination with the information contained herein, for guidance on synthetic strategies, protecting groups, and other materials and methods useful for the synthesis of the compounds of this invention.

[00246] The various references cited herein provide helpful background information on preparing compounds similar to the inventive compounds described herein or relevant intermediates, as well as information on formulation, uses, and administration of such compounds which may be of interest. [00247] Moreover, the practitioner is directed to the specific guidance and examples provided in this document relating to various exemplary compounds and intermediates thereof.

[00248] The compounds of this invention and their preparation can be understood further by the examples that illustrate some of the processes by which these compounds are prepared or used. It will be appreciated, however, that these examples do not limit the invention. Variations of the invention, now known or further developed, are considered to fall within the scope of the present invention as described herein and as hereinafter claimed.

[00249] According to the present invention, any available techniques can be used to make or prepare the inventive compounds or compositions including them. For example, a variety of solution phase synthetic methods such as those discussed in detail below may be used. Alternatively or additionally, the inventive compounds may be prepared using any of a variety of combinatorial techniques, parallel synthesis and/or solid phase synthetic methods known in the art.

[00250] It will be appreciated as described below, that a variety of inventive compounds can be synthesized according to the methods described herein. The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Company (Milwaukee, WI), Bachem (Torrance, CA), Sigma (St. Louis, MO), or are prepared by methods well known to a person of ordinary skill in the art following procedures described in such references as Fieser and Fieser 1991, "Reagents for Organic Synthesis", vols 1-17, John Wiley and Sons, New York, NY, 1991; Rodd 1989 "Chemistry of Carbon Compounds", vols. 1-5 and supps, Elsevier Science Publishers, 1989; "Organic Reactions", vols 1-40, John Wiley and Sons, New York, NY, 1991; March 2001, "Advanced Organic Chemistry", 5th ed. John Wiley and Sons, New York, NY; and Larock 1990, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 2 nd ed. VCH Publishers. These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to a person of ordinary skill in the art having regard to this disclosure. [00251 ] The starting materials, intermediates, and compounds of this invention may be isolated and purified using conventional techniques, including filtration, distillation, crystallization, chromatography, and the like. They may be characterized using conventional methods, including physical constants and spectral data. 2) General Reaction Procedures:

[00252] Unless mentioned specifically, reaction mixtures are stirred using a magnetically driven stirrer bar. An inert atmosphere refers to either dry argon or dry nitrogen. Reactions are monitored either by thin layer chromatography, by proton nuclear magnetic resonance ( MR) or by high-pressure liquid chromatography (HPLC), of a suitably worked up sample of the reaction mixture.

3) General Work Up Procedures:

[00253] Unless mentioned specifically, reaction mixtures are cooled to room temperature or below then quenched, when necessary, with either water or a saturated aqueous solution of ammonium chloride. Desired products are extracted by partitioning between water and a suitable water-immiscible solvent (e.g. ethyl acetate, dichloromethane, diethyl ether). The desired product containing extracts are washed appropriately with water followed by a saturated solution of brine. On occasions where the product containing extract is deemed to contain residual oxidants, the extract is washed with a 10% solution of sodium sulphite in saturated aqueous sodium bicarbonate solution, prior to the aforementioned washing procedure. On occasions where the product containing extract is deemed to contain residual acids, the extract is washed with saturated aqueous sodium bicarbonate solution, prior to the aforementioned washing procedure (except in those cases where the desired product itself had acidic character). On occasions where the product containing extract is deemed to contain residual bases, the extract is washed with 10% aqueous citric acid solution, prior to the aforementioned washing procedure (except in those cases where the desired product itself had basic character). Post washing, the desired product containing extracts are dried over anhydrous magnesium sulphate, and then filtered. The crude products are then isolated by removal of solvent(s) by rotary evaporation under reduced pressure, at an appropriate temperature (generally less than 45°C).

4) General Purification Procedures: [00254] Unless mentioned specifically, chromatographic purification refers to flash column chromatography on silica, using a single solvent or mixed solvent as eluent.

Suitably purified desired product containing elutes are combined and concentrated under reduced pressure at an appropriate temperature (generally less than 45°C) to constant mass.

5) Synthesis of Exemplary Compounds:

[00255] Unless otherwise indicated, starting materials are either commercially available or readily accessible through laboratory synthesis by anyone reasonably familiar with the art. Described generally below, are procedures and general guidance for the synthesis of compounds as described generally and in subclasses and species herein. In addition, synthetic guidance can be found in Kinoshita, M. et al. Bull. Chem. Soc. Jpn. 1987, 60, 2151-2162; Natchev, I. A. Tetrahedron 1988, 44, 151 1-1522; Almirante, N. et al. Tetrahedron Lett. 1998, 39, 3287; and Bellassoued and Majidi, J. Org. Chem. 1993, 58, 2517-2522; the entire contents of which are hereby incorporated by reference.

[00256] Moreover, guidance for the synthesis of the compounds embodied herein may be found in Bioorganic & Medicinal Chemistry 15 (2007) 3692-3702; ARKIVOC 2007 (xiii) 150-154; J. Med. Chem. 784, 1970; J. Org. Chem. 2008, 73, 538-549; Synth. Commun.Vol. 32, No. 22, pp. 3399-3405, 2002; J. Org. Chem. 2007, 72, 8543-8546; J. Org. Chem. 2001, 66, 7945-7950; J. Med. Chem. 2007, 50,

61 16-6125; J. Org. Chem. 1993,58, 7899-7902; Tetrahedron, Vol. 53, No. 33, pp. 1 1355-1 1368, 1997; Synthesis 2006, No. 6, 995-998; Tetrahedron Letters 39 (1998) 9347-9350; and Synthesis- 1986, 620.

[00257] This invention embraces any of the compounds and formulas described herein above, such as but not limited to those described in Formulas I through VIII,

Formula Ila, Formula Ilia, Formula IVa, compounds 1 -48 in Table I and compounds 1-30 in Table II.

Example 1. Materials and Methods

[00258] Lipid Uptake and Cell Death: HepG2 cells (ATCC) were maintained in DMEM/10% FCS supplemented with L-glutamine. For the experiment, cells were seeded onto a 96 well plate using 10K cells/well. Cells were allowed to attach overnight. On the day of the study, cells were incubated with DMEM/0.2%FCS/L- glutamine. Senicapoc (OX-CHEM Corp., CA) was added to final concentrations of 0, 0.1, 1.0 or 10 μΜ and incubated for 30 minutes following which palmitic acid (hexadecanoic acid; C16H32O2; Sigma) coupled to fatty acid-free BSA (Sigma) was added to a final concentration of 0, 75 or 150 μΜ (Shan X, Miao Y, Fan R, Song C,

Wu G, Wan Z, Zhu J, Sun G, Zha W, Mu X, Zhou G, Chen Y. Suppression of Grb2 expression improved hepatic steatosis, oxidative stress, and apoptosis induced by palmitic acid in vitro partly through insulin signaling alteration. In Vitro Cell Dev Biol Anim. 49:576-82, 2013.; Yao H-R, Liu J, Plumeri D, Cao Y-B, He T, Ling L, Li Y, Jiang Y-Y, Li J, Shang J. Lipotoxicity in HepG2 cells triggered by free fatty acids. Am J Transl Res 3 : 284-291, 201 1.). Cells were incubated overnight and apoptosis measured using the CaspaseGlo 3/7 reagent (Promega).

[00259] Animal Studies. All studies relating to animals were approved by our institutional animal use and care committee. Animals had access to drinking water ad libitum throughout the experimental protocols.

[00260] Hepatic KCa3.1 Channel Expression. Biliary Obstruction - Adult male Wistar rats (175-200 g; n=3) were submitted to biliary occlusion using a previously reported method (Kawazoe Y, Miyauchi M, Nagasaki A, Furusho H, Yanagisawa S, Chanbora C, Inubushi T, Hyogo H, Nakamoto T, Suzuki K, Moriwaki S, Tazuma S, Niida S, Takata T. Osteodystrophy in Cholestatic Liver Diseases Is Attenuated by

Anti-Y-Glutamyl Transpeptidase Antibody. PLoS One ep 29; 10:e0139620, 2015.). Briefly, after general anaesthesia (25 mg/kg ketamine / 5 mg/kg xylazine, ip), laparotomy was performed by using midline abdominal skin and muscle incisions. The common bile duct was exposed and ligated with 6-0 silk sutures, the abdominal wall sutured closed and the animal returned to its cage. Twenty-eight days after surgery, animals were anesthetized and the livers removed. Sham- operated rats (n=3) were used as control.

[00261 ] Thioacetamide (TAA) Administration - Adult male Wistar-Furth rats (225- 250 g) were administered TAA (150 mg/kg; n=3) twice a week for 8 weeks after which some animals were sacrificed and the livers removed. Sham (saline- administered; n=3) rats were used as control. [00262] Diet-induced Liver Disease - Adult male C57BL/6 mice (18-22 g) were randomized to standard laboratory rodent diet (5001 LabDiet, MO; sham group) or an L-amino acid diet with 60 kcal% fat with 0.1% methionine and no added choline (CDAHFD; Research Diets, NJ) (Matsumoto M, Hada N, Sakamaki Y, Uno A, Shiga T, Tanaka C, Ito T, Katsume A, Sudoh M. An improved mouse model that rapidly develops fibrosis in non-alcoholic steatohepatitis. Int J Exp Pathol. 2013 Apr;94(2):93-103) for 8 weeks after which animals (n=3/group) were sacrificed and livers retrieved for analysis.

Senicapoc Efficacy Studies [00263] Intervention with Senicapoc in TAA Model - Adult male Wistar-Furth rats

(225-250 g) were administered TAA (150 mg/kg, IP) or saline (0.5 mL, IP) twice a week for 8 weeks after which some animals (n=6/group) were sacrificed and the livers retrieved to confirm disease. TAA-administered animals were then randomized to vehicle (Cremaphor 10% and PEG400 10% in water; n=12) or Senicapoc (50 mg/kg, PO, BID; n=12) for 8 weeks. Animals were sacrificed 16 weeks into TAA administration following which livers were retrieved for analysis.

[00264] Intervention with Senicapoc in CDAHFD Model - Adult male C57BL/6 mice (18-22 g) were randomized to standard laboratory rodent diet (sham group) or CDAHFD. After 4 weeks on these diets, animals (n=6/group) were sacrificed and the livers retrieved for confirmation of disease. Animals on the special diet were randomized immediately to vehicle (n=12) or Senicapoc (10 mg/kg, PO, BID; n=12) for 4 weeks following which they were sacrificed and their livers harvested.

[00265] Pretreatment with Senicapoc in CDAHFD Model - Adult male C57BL/6 mice (18-22 g) were randomized to standard laboratory rodent diet (sham group; n=8) or CDAHFD (n=16) for 7 days after which animals were sacrificed and livers retrieved for analysis. Treatment with vehicle (n=8) or Seniapoc (10 mg/kg, PO, BID; n=8) was started on day 1 of CDAHFD and continued until sacrifice.

[00266] Pretreatment with Senicapoc in HFD Model - Adult male C57BL/6 mice were randomized to standard laboratory rodent diet or a high fat diet fat (HFD) containing 10% lard, 5% corn oil and 2% cholesterol (Research Diets, NJ). Animals on the special diet were randomized immediately to vehicle or Senicapoc (10 mg/kg, PO, BID). After 6 weeks on this diet, animals were sacrificed and livers retrieved for analysis.

[00267] KCaS.l Channel Expression: As described by Freise et al. (Freise C, Heldwein S, Erben U, Hoyer J, Kohler R, Johrens K, Patsenker E, Ruehl M, Seehofer D, Stickel F, Somasundaram R. K + -channel inhibition reduces portal perfusion pressure in fibrotic rats and fibrosis associated characteristics of hepatic stellate cells. Liver Int 35: 1244-52, 2015) KCa3.1 protein expression (normalized to GAPDH) was determined in liver homogenates using anti-Kc a 3.1 (12 hr incubation, K4, IKc a l, #APC-06, Alomone Labs) antibody, followed by incubation with anti-rabbit secondary antibody (Santa Cruz Biotechnology, Santa Cruz, CA, USA). The signal was detected by enhanced chemiluminescence (Amersham Pharmacia Biotech, Piscataway, NJ, USA) and densitometry was performed using Bioquant. Immunohistochemical staining of liver sections were performed with the same antibody as described previously (Freise et al., 2015, Ibid.).

[00268] Liver hydroxyproline - Liver tissues (~ 200 mg) were prepared and analyzed for hydroxyproline. The total hydroxyproline within each liver was determined by correcting for total liver wet mass.

[00269] Liver Fibrosis: Fibrosis was detected histologically by Masson's trichrome and picosirius red staining of collagen by using digital slide scanning and associated image analysis software as described previously (Ronis MJ, Hennings L, Stewart B, Basnakian AG, Apostolov EO, Albano E, Badger TM, Petersen DR. Effects of long- term ethanol administration in a rat total enteral nutrition model of alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 300:G109-19, 2011).

[00270] NAFLD Activity Score (NAS), Steatosis and Inflammation. An observed blinded to the treatment groups assigned NAS (0-8 scale), steatosis (0-3 scale) and inflammation (0-3 scale) values to H&E-stained liver sections as described previously (Ronis et al., Ibid.).

[00271] Liver Triglycerides - Triglyceride content in liver homogenates was measured using a commercial enzyme-linked immunosorbent assay kit (ELI Tech, Seoul, Korea). [00272] Liver Histopathology - For hematoxylin and eosin (H&E) staining, formalin-fixed liver was embedded into paraffin and cut into 4 μπι sections. For Oil Red-0 staining, liver tissue was dehydrated before embedded into OCT compound (Sakura, Tokyo, Japan), and cut into 4 μπι frozen sections. Commercially available kits (Beyotime, Shanghai, China) were used to stain sections. Analysis was performed by an observer blinded to the treatment groups. Lipid vacuoles in H&E sections and lipid content in Oil Red O sections were semi-quantified using Bioaquant.

[00273] Hepatic Inflammation (F4/80) and Lipid Peroxidation 4-hydroxynonenal (4-HNE)) - Five^m-thick paraffin sections of liver tissue were prepared from the center of each hepatic lobe. Sections were subsequently stained with antibodies against F4/80 (anti-F4/80; sc-59171, Santa Cruz, CA) and 4-HNE (anti-4HNE antibody; JaICA, Shizuoka, Japan). Staining was quantified (Bioquant) by an observer blinded to the treatment groups.

[00274] Data Analysis - Data are expressed as mean+SEM. Differences between groups were measured by one-way ANOVA with Tukey's posthoc test for multiple comparisons. P values less than 0.05 were considered significant.

Example 2. KCa3.1 Channel Expression in Liver Disease

[00275] Hepatic KCa3.1 expression was evaluated in 3 distinct rodent models of liver fibrosis. As seen in Figure 1, hepatic KCa3.1 expression was elevated in livers from animals submitted to biliary occlusion for 4 weeks (Figure 1 A), in livers from animals fed CDAHFD for 8 weeks (Figure IB) and in fibrotic livers from animals administered TAA for 8 weeks (Figures 1C and ID).

Example 3. Anti-fibrotic Effect of Senicapoc

[00276] Drug effects of senicapoc were evaluated in two etiologically distinct models of liver fibrosis. Rats administered TAA for 8 weeks exhibited significant increase in liver collagen (hydroxyproline, Figure 2A) at which time they were randomized to Senicapoc or vehicle. As seen in Figures 2A and B, treatment with Senicapoc with continued administration of TAA, blocked the increase in liver collagen from weeks 8 through 16. [00277] Animals fed CDAHFD for 4 weeks exhibited hepatomegaly evidenced by increased liver to body mass ratio (7.5±0.2% vs. 4.8±0.1%, standard diet; P<0.05). Furthermore, animals on this diet exhibited a NAS (0 to 8 scale) of 5.1±0.9 vs. 1±0.2, standard diet; P<0.05). Randomization of animals on CDAHFD to Senicapoc for 4 weeks was associated with a decrease in liver fibrosis as evidenced by hydroxproline (Figure 3 A) and Masson's tri chrome staining (Figure 3B). The effect of senicapoc on liver weights is shown in Figure 3C.

Example 4: Anti-Steatotic Effect of Senicapoc

[00278] NAS and steatosis (0 to 3 scale) were first compared in CDAHFD (8 weeks) animals randomized to vehicle or Senicapoc (weeks 4 through 8). Intervention with Senicapoc reduced both NAS (Figure 4A) and steatosis (Figure 4B). Next, the effect of Senicapoc was evaluated on liver triglycerides, the main form of fat stored in the liver. Intervention with Senicapoc reduced hepatic triglyceride content (Figure 4C) in the CDAHFD model.

[00279] Lipid accumulation occurring in NAFLD can trigger a cascade including hepatocyte apoptosis, hepatic inflammation and extracellular matrix deposition. The effect of Senicapoc on steatosis was further investigated in models of diet-induced liver disease. In animals fed CDAHFD for 7 days and concomitantly treated with Senicapoc, a reduction in NAS was observed in comparison to the CDAHFD+vehicle cohort (Figure 5 A). Again, Senicapoc reduced steatosis (Figure 5B). To further verify this effect of Senicapoc on hepatic lipid homeostasis, the lipid vacuole area in hepatic sections was analyzed by staining with H&E from vehicle and drug-treated animals. As seen in Figure 5C, treatment with Senicapoc was associated with decreased hepatic lipid vacuole area. Furthermore, Senicapoc reduced hepatic lipid peroxidation, a measure of macrophage oxidative burst and early inflammation as evidenced by 4-HNE staining (Figure 5D). Effect on liver weight is shown in Figure 5E.

[00280] To confirm that the anti-steatotic effect of Senicapoc was not unique to the CDAHFD model, the use of this drug was evaluated in the HFD model of NAFLD- NASH. As seen in Figure 6A, treatment with Senicapoc reduced NAS observed in this model of metabolic insult. Senicapoc reduced steatosis (Figure 6B) which was also evident in the extent of Oil Red O staining of the liver (Figure 6C). Since 6 weeks on this diet is sufficient to trigger an inflammatory response in the liver, the anti- steatotic effect of Senicapoc were evaluated to determine if these results translate to a reduction in hepatic inflammation. Senicapoc reduced inflammation (Figure 6D, 0- 3 scale) which was also evident by decreased hepatic F4/80 staining (Figure 6E), a marker of active macrophage population.

[00281] While lipid accumulation in hepatocytes is a critical event in the genesis and progression of fatty liver disease, hepatocytes overloaded with saturated free fatty acids such as palmitic acid undergo apoptosis. Cell death is therefore a surrogate marker of hepatocyte lipid accumulation. The anti-steatotic effect of Senicapoc translates to reduced apoptosis in eHpG2 cells challenged with increasing concentrations of palmitic acid. Senicapoc was without effect on cells alone (without palmitic acid; data not shown). As seen in Figure 7, at each concentration of palmitic acid tested, Senicapoc dose-dependently decreased HepG2 apoptosis.