COMPOSITIONS AND METHODS TO TREAT NON-ALCOHOLIC FATTY LIVER DISEASES (NAFLD)

1 . A method of treating non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof comprising administering to the subject

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, wherein the amounts of (a) and (b) together are effective in treating NAFLD.

2 . A method of treating a subject, the method comprising:

selecting a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, to the selected subject,

wherein the amounts of (a) and (b) together are effective in treating NAFLD.

3 . A method of treating a subject, the method comprising:

identifying a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, to the selected subject,

wherein the amounts of (a) and (b) together are effective in treating NAFLD.

4 . A method of treating non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof comprising administering to the subject

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) a therapeutically effective amount of an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.

5 . A method of treating a subject, the method comprising:

selecting a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) a therapeutically effective amount of an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, to the selected subject.

6 . A method of treating fibrosis in a subject in need thereof comprising administering to the subject

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, wherein the amounts of (a) and (b) together are effective in treating fibrosis.

7 . A method of treating fibrosis in a subject in need thereof comprising administering to the subject

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) a therapeutically effective amount of an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof.

8 . The method of claims 6 or 7 , wherein the fibrosis is cirrhosis.

9 . The method of any one of claims 6 to 8 , wherein the fibrosis is associated with NAFLD.

10 . The method of any one of claims 6 to 9 , wherein the fibrosis is caused by NAFLD.

11 . The method of any one of claims 1 to 10 , wherein the NAFLD is NASH.

12 . The method of any one of claims 1 to 11 , wherein the SGLT-2 inhibitor is selected from the group consisting of: empagliflozin, canagliflozin, dapagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, serfliflozin etabonate, sotagliflozin, tofogliflozin, or a combination of two or more thereof.

13 . The method of any one of claims 1 to 12 , wherein the SGLT-2 inhibitor is empagliflozin or dapagliflozin propylene glycol hydrate.

14 . The method of any one of claims 1 to 13 , wherein (a) and (b) are administered concurrently.

15 . The method of any one of claims 1 to 14 , wherein (a) and (b) are administered sequentially in either order.

16 . The method of any one of claims 1 to 15 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose from about 1 to about 350 mg.

17 . The method of any one of claims 1 to 16 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose from about 85 to about 325 mg.

18 . The method of any one of claims 1 to 17 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose from about 5 to about 15 mg.

19 . The method of any one of claims 1 to 18 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 10 mg.

20 . The method of any one of claims 1 to 19 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 8 mg.

21 . The method of any one of claims 1 to 20 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 5 mg.

22 . The method of any one of claims 1 to 21 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject twice a day, daily, every other day, three times a week, twice a week, weekly, every other week, twice a month, or monthly.

23 . The method of any one of claims 1 to 22 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject daily.

24 . The method of any one of claims 1 to 23 , wherein the method further comprises administering (c) a GLP-1 receptor agonist.

25 . The method of claim 24 , wherein the GLP-1 receptor agonist is selected from the group consisting of: liraglutide, dulaglutide, exenatide, taspoglutide, lixisenatide, albiglutide, semaglutide, GLP-1, or a combination of two or more thereof.

26 . The method of claim 24 or 25 , wherein the GLP-1 receptor agonist is liraglutide.

27 . A method of treating non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof comprising administering to the subject

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, wherein the amounts of (a) and (b) together are effective in treating NAFLD.

28 . A method of treating a subject, the method comprising:

selecting a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, to the selected subject

wherein the amounts of (a) and (b) together are effective in treating NAFLD.

29 . A method of treating a subject, the method comprising:

identifying a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, to the selected subject

wherein the amounts of (a) and (b) together are effective in treating NAFLD.

30 . A method of treating non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof comprising administering to the subject

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) a therapeutically effective amount of a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof.

31 . A method of treating a subject, the method comprising:

selecting a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) a therapeutically effective amount of a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, to the selected subject.

32 . A method of treating fibrosis in a subject in need thereof comprising administering to the subject

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, wherein the amounts of (a) and (b) together are effective in treating fibrosis.

33 . A method of treating fibrosis in a subject in need thereof comprising administering to the subject

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) a therapeutically effective amount of a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof.

34 . The method of claims 32 or 33 , wherein the fibrosis is cirrhosis.

35 . The method of any one of claims 32 to 34 , wherein the fibrosis is associated with NAFLD.

36 . The method of any one of claims 32 to 35 , wherein the fibrosis is caused by NAFLD.

37 . The method of any one of claims 27 to 36 , wherein the NAFLD is NASH.

38 . The method of any one of claims 27 to 37 , wherein the GLP-1 receptor agonist is selected from the group consisting of: liraglutide, dulaglutide, exenatide, taspoglutide, lixisenatide, albiglutide, semaglutide, GLP-1, or a combination of two or more thereof.

39 . The method of any one of claims 27 to 38 , wherein the GLP-1 receptor agonist is liraglutide.

40 . The method of any one of claims 27 to 39 , wherein (a) and (b) are administered concurrently.

41 . The method of any one of claims 27 to 40 , wherein (a) and (b) are administered sequentially in either order.

42 . The method of any one of claims 27 to 41 , wherein the GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose from about 0.1 to about 10 mg.

43 . The method of any one of claims 27 to 42 , wherein the GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose from about 0.1 to about 5 mg.

44 . The method of any one of claims 27 to 43 , wherein the GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 1.0 mg.

45 . The method of any one of claims 27 to 43 , wherein the GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 1.5 mg.

46 . The method of any one of claims 27 to 43 , wherein the GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 1.8 mg.

47 . The method of any one of claims 27 to 46 , wherein the GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject twice a day, daily, every other day, three times a week, twice a week, weekly, every other week, twice a month, or monthly.

48 . The method of any one of claims 27 to 47 , wherein the GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject daily.

49 . The method of any one of claims 27 to 47 , wherein the GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject weekly.

50 . The method of any one of claims 27 to 49 , wherein the method further comprises administering (c) a SGLT-2 inhibitor.

51 . The method of claim 50 , wherein the SGLT-2 inhibitor is selected from the group consisting of: empagliflozin, canagliflozin, dapagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, serfliflozin etabonate, sotagliflozin, tofogliflozin, or a combination of two or more thereof.

52 . The method of claim 50 or 51 , wherein the SGLT-2 inhibitor is empagliflozin.

53 . The method of claim 50 or 51 , wherein the SGLT-2 inhibitor is dapagliflozin propylene glycol hydrate.

54 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 53 , wherein the treatment of NAFLD comprises a reduction in hepatic steatosis.

55 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 54 , wherein the treatment of NAFLD comprises a reduction in hepatic inflammation.

56 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 55 , wherein the NAFLD activity score (NAS) following administration is 7 or less.

57 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 56 , wherein the NAS is 5 or less.

58 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 57 , wherein the NAS is 3 or less.

59 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 58 , wherein the treatment of the NAFLD comprises treatment of liver fibrosis.

60 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 59 , wherein the treatment of the NAFLD comprises treatment of liver cirrhosis.

61 . The method of any one of claims 6 to 11 , 32 - 37 , and 58 to 60 , wherein the treatment of fibrosis comprises a decrease in the stage of fibrosis, a lack of progression of the fibrosis, or a slowing in the progression of the fibrosis.

62 . The method of any one of claims 6 to 11 , 32 - 37 , and 58 to 61 , wherein the treatment of fibrosis comprises a decrease in the stage of fibrosis.

63 . The method of any one of claims 6 to 11 , 32 - 37 , and 58 to 62 , wherein the decrease in the stage of fibrosis is from stage 4 to stage 3, from stage 4 to stage 2, from stage 4 to stage 1, from stage 4 to stage 0, from stage 3 to stage 2, from stage 3 to stage 1, from stage 3 to stage 0, from stage 2 to stage 1, from stage 2 to stage 0, or from stage 1 to stage 0.

64 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 63 , wherein the adiponectin level in the subject is increased by at least about 30%, at least about 68%, at least about 175%, or at least about 200%.

65 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 64 , wherein the level of one or more biomarkers indicative of one or more of liver damage, inflammation, fibrosis, and/or cirrhosis is decreased.

66 . The method of claim 65 , wherein the increase is by at least about 175%.

67 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 66 , wherein the treatment of NAFLD decreases the level of serum bile acids in the subject.

68 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 67 , wherein the treatment of NAFLD comprises treatment of pruritus.

69 . The method of any one of 1 to 5 , 11 to 31 , and 38 to 68 , wherein the subject has liver fibrosis associated with the NAFLD.

70 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 69 , wherein the subject has hepatic cirrhosis associated with the NAFLD.

71 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 70 , wherein the subject has liver fibrosis as a comorbidity.

72 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 71 , wherein the subject has hepatic cirrhosis as a comorbidity.

73 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 72 , wherein the subject has liver fibrosis caused by the NAFLD.

74 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 73 , wherein the subject has hepatic cirrhosis caused by the NAFLD.

75 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 74 , wherein the NAFLD is simple nonalcoholic fatty liver (NAFL).

76 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 75 , wherein the NAFLD is NAFL with attendant liver fibrosis.

77 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 76 , wherein the NAFLD is NAFL with attendant liver cirrhosis.

78 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 77 , wherein the treatment of NAFL decreases the level of serum bile acids in the subject.

79 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 78 , wherein the treatment of NAFL comprises treatment of pruritus.

80 . The method of any one of claims 1 to 5 , 11 to 31 , and 38 to 79 , wherein the NAFLD is nonalcoholic steatohepatitis (NASH).

81 . The method of any one of claims 1 to 5 , 11 to 31 , 38 to 74 and 80 , wherein the NAFLD is NASH with attendant liver fibrosis.

82 . The method of any one of claims 1 to 5 , 11 to 31 , 38 to 74 , 79 , and 81 , wherein the NAFLD is NASH with attendant liver cirrhosis.

83 . The method of any one of claims 1 to 5 , 11 to 31 , 38 to 74 , and 79 to 81 , wherein the treatment of NASH decreases the level of serum bile acids in the subject.

84 . The method of any one of claims 1 to 5 , 11 to 31 , 38 to 74 , and 79 to 83 , wherein the treatment of NASH comprises treatment of pruritus.

85 . A method of treating non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof comprising administering to the subject

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof,

(c) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, and

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (b), (c), and (d) together are effective in treating NAFLD.

86 . A method of treating a subject, the method comprising:

selecting a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof,

(c) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, and

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (b), (c), and (d) together are effective in treating NAFLD.

87 . A method of treating a subject, the method comprising:

identifying a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof,

(c) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, and

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (b), (c), and (d) together are effective in treating NAFLD.

88 . A method of treating non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof comprising administering to the subject

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof,

(c) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, and

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (b), (c), and (d) together are effective in treating NAFLD.

89 . A method of treating a subject, the method comprising:

selecting a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof,

(c) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, and

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (b), (c), and (d) together are effective in treating NAFLD.

90 . A method of treating fibrosis in a subject in need thereof comprising administering to the subject

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof,

(c) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, and

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (b), (c), and (d) together are effective in treating fibrosis.

91 . A method of treating fibrosis in a subject in need thereof comprising administering to the subject

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof,

(c) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, and

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (b), (c), and (d) together are effective in treating fibrosis.

92 . A method of treating non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof comprising administering to the subject

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof,

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (b), and (d) together are effective in treating NAFLD.

93 . A method of treating a subject, the method comprising:

selecting a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof,

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (b), and (d) together are effective in treating NAFLD.

94 . A method of treating a subject, the method comprising:

identifying a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof,

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (b), and (d) together are effective in treating NAFLD.

95 . A method of treating non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof comprising administering to the subject

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof,

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (b), and (d) together are effective in treating NAFLD.

96 . A method of treating a subject, the method comprising:

selecting a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof,

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (b), and (d) together are effective in treating NAFLD.

97 . A method of treating fibrosis in a subject in need thereof comprising administering to the subject

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof,

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (b), and (d) together are effective in treating fibrosis.

98 . A method of treating fibrosis in a subject in need thereof comprising administering to the subject

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof,

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (b), and (d) together are effective in treating fibrosis.

99 . A method of treating non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof comprising administering to the subject

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(c) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, and

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (c), and (d) together are effective in treating NAFLD.

100 . A method of treating a subject, the method comprising:

selecting a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(c) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, and

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (c), and (d) together are effective in treating NAFLD.

101 . A method of treating a subject, the method comprising:

identifying a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(c) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, and

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (c), and (d) together are effective in treating NAFLD.

102 . A method of treating non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof comprising administering to the subject

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(c) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, and

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (c), and (d) together are effective in treating NAFLD.

103 . A method of treating a subject, the method comprising:

selecting a subject having non-alcoholic fatty liver disease (NAFLD); and

administering

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(c) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, and

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (c), and (d) together are effective in treating NAFLD.

104 . A method of treating fibrosis in a subject in need thereof comprising administering to the subject

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(c) GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, and

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (c), and (d) together are effective in treating fibrosis.

105 . A method of treating fibrosis in a subject in need thereof comprising administering to the subject

(a) a therapeutically effective amount of the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(c) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, and

(d) metformin, or a pharmaceutically acceptable salt thereof;

wherein the amounts of (a), (c), and (d) together are effective in treating fibrosis.

106 . The method of claims 90 , 91 , 97 , 98 , 104 , or 105 , wherein the fibrosis is cirrhosis.

107 . The method of any one of claims 90 , 91 , 97 , 98 , 104 , or 105 - 106 , wherein the fibrosis is associated with NAFLD.

108 . The method of any one of claims 90 , 91 , 97 , 98 , 104 , or 105 - 107 , wherein the fibrosis is caused by NAFLD.

109 . The method of any one of claims 85 - 89 , 92 - 96 , or 99 - 103 wherein the NAFLD is NASH.

110 . The method of any one of claims 85 - 98 , wherein the SGLT-2 inhibitor is selected from the group consisting of: empagliflozin, canagliflozin, dapagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, serfliflozin etabonate, sotagliflozin, tofogliflozin, or a combination of two or more thereof.

111 . The method of any one of claims 85 - 98 or 110 , wherein the SGLT-2 inhibitor is empagliflozin.

112 . The method of any one of claims 85 - 98 or 110 - 111 , wherein the SGLT-2 inhibitor is dapagliflozin propylene glycol hydrate.

113 . The method of any one of claims 85 - 98 or 110 - 112 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose from about 1 to about 350 mg.

114 . The method of any one of claims 85 - 98 or 110 - 113 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose from about 85 to about 325 mg.

115 . The method of any one of claims 85 - 98 or 110 - 114 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose from about 5 to about 15 mg.

116 . method of any one of claims 85 - 98 or 110 - 115 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 10 mg.

117 . The method of any one of claims 85 - 98 or 110 - 116 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 8 mg.

118 . The method of any one of claims 85 - 98 or 110 - 117 , wherein the SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 5 mg.

119 . The method of any one of claims 85 - 91 or 99 - 105 , wherein the GLP-1 receptor agonist is selected from the group consisting of: liraglutide, dulaglutide, exenatide, taspoglutide, lixisenatide, albiglutide, semaglutide, GLP-1, or a combination of two or more thereof.

120 . The method of any one of claims 85 - 91 , 99 - 105 or 119 , wherein the GLP-1 receptor agonist is liraglutide.

121 . The method of any one of claims 85 - 91 , 99 - 105 or 119 - 120 , wherein the GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose from about 0.1 to about 10 mg.

122 . The method of any one of claims 85 - 91 , 99 - 105 or 119 - 121 , wherein the GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose from about 0.1 to about 5 mg.

123 . method of any one of claims 85 - 91 , 99 - 105 or 119 - 123 , wherein the GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 1.0 mg.

124 . The method of any one of claims 85 - 91 , 99 - 105 or 119 - 123 , wherein the GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 1.5 mg.

125 . The method of any one of claims 85 - 91 , 99 - 105 or 119 - 123 , wherein the GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 1.8 mg.

126 . The method of any one of claims 85 - 125 , wherein the metformin, or a pharmaceutically acceptable salt thereof, is administered at a dose of from about 250 to about 2,500 mg.

127 . The method of any one of claims 85 - 126 , wherein the metformin, or a pharmaceutically acceptable salt thereof, is administered at a dose of from about 500 to about 2,000 mg.

128 . The method of any one of claims 85 - 127 , wherein the metformin, or a pharmaceutically acceptable salt thereof, is administered at a dose of from about 750 to about 1,500 mg.

129 . The method of any one of claims 85 - 128 , wherein the metformin, or a pharmaceutically acceptable salt thereof, is administered at a dose of from about 1,000 to about 1,250 mg.

130 . The method of any one of claims 85 - 91 or 110 - 129 , wherein (a), (b), (c), and (d) are administered concurrently.

131 . The method of any one of claims 85 - 91 or 110 - 129 , wherein (a), (b), (c), and (d) are administered sequentially in any order.

132 . The method of any one of claims 92 - 98 or 110 - 129 , wherein (a), (b), and (d) are administered concurrently.

133 . The method of any one of claims 92 - 98 or 110 - 129 , wherein (a), (b), and (d) are administered sequentially in any order.

134 . The method of any one of claims 99 - 105 or 110 - 129 , wherein (a), (c), and (d) are administered concurrently.

135 . The method of any one of claims 99 - 105 or 110 - 129 , wherein (a), (c), and (d) are administered sequentially in any order.

136 . The method of any one of claims 1 to 135 , wherein the compound of Formula (I), a pharmaceutically acceptable salt or solvate thereof, is administered prophylactically.

137 . The method of any one of claims 1 to 136 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose from about 0.1 to about 15 mg.

138 . The method of any one of claims 1 to 137 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose from about 1 to about 10 mg.

139 . The method of any one of claims 1 to 138 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose from about 2 to about 6 mg.

140 . The method of any one of claims 1 to 139 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose from about 0.5 to about 3 mg.

141 . The method of any one of claims 1 to 140 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 3 mg.

142 . The method of any one of claims 1 to 141 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 2 mg.

143 . The method of any one of claims 1 to 142 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 1 mg.

144 . The method of any one of claims 1 to 143 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject twice a day, daily, every other day, three times a week, twice a week, weekly, every other week, twice a month, or monthly.

145 . The method of any one of claims 1 to 144 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject daily.

146 . The method of any one of claims 1 to 145 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject daily and the dose of the compound of Formula (I) is about 3 mg.

147 . The method of any one of claims 1 to 146 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose from about 0.1 to about 10.0 mg per day.

148 . The method of any one of claims 1 to 147 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose from about 0.1 to about 3 mg per day.

149 . The method of any one of claims 1 to 148 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 0.5 milligram per day.

150 . The method of any one of claims 1 to 148 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 1 milligram per day.

151 . The method of any one of claims 1 to 148 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 2 mg per day.

152 . The method of any one of claims 1 to 151 , wherein the compound of Formula (I) is in the form of a besylate salt.

153 . The method of any one of claims 1 to 152 , wherein the method further comprises performing a liver biopsy to determine the NAFLD activity score of the biopsy sample obtained from the subject.

154 . A method of treating non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof consisting essentially of administering to the subject

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, wherein the amounts of (a) and (b) together are effective in treating NAFLD.

155 . A method of treating non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof consisting essentially of administering to the subject

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof,

wherein the amounts of (a) and (b) together are effective in treating NAFLD.

156 . A method of treating non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof consisting essentially of administering to the subject

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof,

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt, salt or solvate thereof, and

(c) an GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof,

wherein the amounts of (a), (b), and (c) together are effective in treating NAFLD.

157 . A method of treating non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof consisting essentially of administering to the subject

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof,

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof,

(c) an GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, and

(d) metformin, or a pharmaceutically acceptable salt thereof,

wherein the amounts of (a), (b), (c), and (d) together are effective in treating NAFLD.

158 . A pharmaceutical composition comprising

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof,

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and

one or more pharmaceutical excipients, wherein the amounts of (a) and (b) together are effective in treating NAFLD.

159 . The pharmaceutical composition of claim 158 , wherein the composition further comprises metformin, or a pharmaceutically acceptable salt thereof.

160 . A pharmaceutical composition comprising

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof,

(b) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutical excipients,

wherein the amounts of (a) and (b) together are effective in treating NAFLD.

161 . The pharmaceutical composition of claim 160 , wherein the composition further comprises metformin, or a pharmaceutically acceptable salt thereof.

162 . A pharmaceutical composition comprising

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof,

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof,

(c) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, and

one or more pharmaceutical excipients, wherein the amounts of (a) and (b) together are effective in treating NAFLD.

163 . The pharmaceutical composition of claim 162 , wherein the composition further comprises metformin, or a pharmaceutically acceptable salt thereof.

164 . A pharmaceutical combination comprising

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) an SGLT-2 inhibitor, or a pharmaceutically acceptable salt or solvate thereof,

for concurrent or sequential administration for use in the treatment of non-alcoholic fatty liver disease (NAFLD).

165 . The pharmaceutical combination of claim 164 , wherein the composition further comprises metformin, or a pharmaceutically acceptable salt thereof.

166 . A pharmaceutical combination comprising

(a) the compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof, and

(b) a GLP-1 receptor agonist, or a pharmaceutically acceptable salt or solvate thereof,

for concurrent or sequential administration for use in the treatment of non-alcoholic fatty liver disease (NAFLD).

167 . The pharmaceutical combination of claim 166 , wherein the composition further comprises metformin, or a pharmaceutically acceptable salt thereof.

168 . A pharmaceutical combination of any one of claims 164 - 167 , further comprising at least one pharmaceutically acceptable carrier.