(S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid (APL) for use in the treatment of non-alcoholic steatohepatitis (NASH), hepatitis, hepatocyte ballooning, hepatic fibrosis and steatosis.

Abstract

To provide compounds for use in the treatment of non-alcoholic steatohepatitis (NASH), hepatitis, hepatocyte ballooning, hepatic fibrosis, and steatosis. [Solution] Compound according to the following formula I: JPEG2026062985000093.jpg23141 Or a pharmaceutically acceptable substance thereof, specifically, for example, the following compounds or pharmaceutically acceptable salts thereof. JPEG2026062985000094.jpg1859 JPEG2026062985000095.jpg1869

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of U.S. Provisional Application No. 63 / 015,175 filed on 24 April 2020, which is incorporated in its entirety by reference.

[0002] The present invention relates to a method and composition for the treatment of non-alcoholic steatohepatitis (NASH). [Background technology]

[0003] Non-alcoholic steatohepatitis (NASH) is a non-benign disorder characterized by substantial health risks. Individuals diagnosed with NASH are at high risk of morbidity and death. More specifically, NASH is characterized by an increased risk of cardiovascular and liver-related deaths. NASH can lead to cirrhosis, which can result in fluid retention, muscle wasting, intestinal bleeding, and liver failure. Liver transplantation is the only treatment for advanced cirrhosis with liver failure, and NASH is currently the second leading reason for liver transplantation.

[0004] Therefore, therapeutic agents for the treatment of NASH are still needed. [Overview of the Initiative]

[0005] Novel methods for treating liver diseases and disorders, including non-alcoholic steatohepatitis (NASH), are described herein.

[0006] In one embodiment, the present invention is characterized by a method for treating non-alcoholic steatohepatitis (NASH), wherein the method involves administering an effective amount of a compound according to formula I to a subject in need of treatment. [ka] or administering a pharmaceutically acceptable salt thereof, in the formula, R 1 These are hydrogen, -(C1-C8) alkyl, -(C1-C8) alkenyl, -(C1-C8) alkynyl, unsubstituted or substituted - ara(C1-C6) alkyl, unsubstituted or substituted - heteroara(C1-C6) alkyl, and is selected from the group consisting of, wherein the substituents on the substituted ara(C1-C6) alkyl and substituted heteroara(C1-C6) alkyl are halogen, -CN, -NO2, -NH2, -NH(C1-C6) alkyl, -N[(C1-C6) alkyl)]2, -OH, halo(C1-C6) alkyl, -(C1-C6) alkoxy, halo(C1-C6) alkoxy, -SH, thio(C1-C6) alkyl, -SONH2, -SO2NH2, -SO-(C1-C6) alkyl, -SO2-(C1-C6) alkyl, -NHSO2(C1-C6) alkyl, and -NHSO2NH2; R 2 is hydrogen, -(C1-C8) alkyl, -(C1-C8) alkenyl, -(C1-C8) alkynyl, unsubstituted or substituted - ara(C1-C6) alkyl, unsubstituted or substituted - heteroara(C1-C6) alkyl, and is selected from the group consisting of, wherein the substituents on the substituted ara(C1-C6) alkyl and substituted heteroara(C1-C6) alkyl are halogen, -CN, -NO2, -NH2, -OH, halo(C1-C6) alkyl, -(C1-C6) alkoxy, halo(C1-C6) alkoxy, -SH, thio(C1-C6) alkyl, -SONH2, -SO2NH2, -SO-(C1-C6) alkyl, -SO2-(C1-C6) alkyl, -NHSO2(C1-C6) alkyl, and -NHSO2NH2; R 3 R 4 R 7 R 8 R 9 R 10 R 13 R, and 14 are independently selected from the group consisting of hydrogen and -(C1-C6) alkyl; R 5 and R 6Independently, hydrogen, -Selected from the group consisting of (C1-C6)alkyl and -OH, however R 5 and R 6 Both cannot be -OH; R 11 and R 12 Independently, hydrogen, -Selected from the group consisting of (C1-C6)alkyl and -OH, however R 11 and R 12 Both cannot be -OH; m is an integer between 1 and 4. n is an integer between 0 and 4. o is an integer between 0 and 4. p is an integer between 1 and 4. q is an integer between 0 and 4. r is an integer between 0 and 4.

[0007] In another embodiment, the present invention is characterized by a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of NASH in a subject.

[0008] In another embodiment, the present invention is characterized by a compound of formula I, or a pharmaceutically acceptable salt thereof, for the preparation of a drug for the treatment of NASH.

[0009] In several embodiments, the compound of formula I is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid, [ka] (1) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula (I) is (S)-2-amino-6-((3-aminopropyl)amino)hexanoate dihydrochloride, [ka] That is the case.

[0010] In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid, [ka] (2) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoate trihydrochloride, [ka] That is the case.

[0011] In several embodiments, the compound of formula I is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid, [ka] (3) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula I is (S)-2-amino-5-((5-aminopentyl)amino)pentanoate trihydrochloride, [ka] That is the case.

[0012] In multiple embodiments, R 1 and R 2 These are independently selected from the group consisting of hydrogen and -(C1-C8)alkyl groups.

[0013] In multiple embodiments, R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 Each of these is independently selected from hydrogen and -(C1-C8)alkyl groups.

[0014] In multiple embodiments, R 9 , R 10 , R 11 , R 12, R 13 , and R 14 Each of these is independently selected from hydrogen and -(C1-C8)alkyl groups.

[0015] In multiple embodiments, R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of them is independently selected from hydrogen and -(C1-C8)alkyl, R 9 , R 10 , R 11 , R 12 , R 13 and R 14 Each of these is independently selected from hydrogen and -(C1-C8)alkyl groups.

[0016] In several embodiments, or in the pharmaceutically acceptable salt thereof, the sum of m+n+o is in the range of 2 to 10, and the sum of p+q+r is in the range of 2 to 10.

[0017] In some embodiments, m is 3, p is 4, and each of n, o, q and r is zero. In some embodiments, R 3 , R 4 , R 9 , and R 10 R is independently selected from hydrogen and -(C1-C8)alkyl. In some embodiments, R 1 and R 2 R is independently selected from the group consisting of hydrogen and -(C1-C8)alkyl. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 9 , and R 10 It is hydrogen.

[0018] In several embodiments, m is 4, n is 2, o is zero, p is 3, q ​​is 1, and r is zero. In several embodiments, R 3 , R 4 , R 5 , R 6 , R9 , R 10 , R 11 , and R 12 are independently selected from hydrogen and -(C1-C8) alkyl. In multiple embodiments, R 1 and R 2 are independently selected from the group consisting of hydrogen and -(C1-C8) alkyl. In multiple embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , R 11 , and R 12 is hydrogen.

[0019] In multiple embodiments, m is 4, n is 1, o is zero, p is 3, q is 1, and r is zero. In multiple embodiments, R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , R 11 , and R 12 are independently selected from hydrogen and -(C1-C8) alkyl. In multiple embodiments, R 1 and R 2 are independently selected from the group consisting of hydrogen and -(C1-C8) alkyl. In multiple embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , R 11 , and R 12 is hydrogen.

[0020] In multiple embodiments, the subject is human.

[0021] In several embodiments, a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)), or any pharmaceutically acceptable salt thereof, is administered to a subject for at least about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks.

[0022] In some embodiments, a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)), or any pharmaceutically acceptable salt thereof, is administered to a subject for at least about 4–6, 4–8, 4–10, 4–12, 4–14, or 4–16 weeks.

[0023] In several embodiments, a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)), or any pharmaceutically acceptable salt thereof, is administered to the subject at a dose of approximately 2 to 1000, 10 to 1000, or 10 to 100 mg / kg per day.

[0024] In several embodiments, a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)), or any pharmaceutically acceptable salt thereof, is administered to a subject at a dose of approximately 10 mg / kg or more per day.

[0025] In several embodiments, a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)), or any pharmaceutically acceptable salt thereof, is administered to a subject at a dose of approximately 2 mg / kg or more per day.

[0026] In several embodiments, a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)), or any pharmaceutically acceptable salt thereof, is administered to a subject in a total daily dose of approximately 100 to 5000, 500 to 5000, or 600 to 3000 mg per day.

[0027] In some embodiments, a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)), or any pharmaceutically acceptable salt thereof, is administered orally to a subject.

[0028] In some embodiments, the subject has a NAFLD activity score (NAS) of 4 or more.

[0029] In some embodiments, the subject has a NAFLD activity score (NAS) of 5 or higher.

[0030] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or any pharmaceutically acceptable salt thereof results in a NAFLD activity score (NAS) of less than 4.

[0031] In some embodiments, the subject has non-cirrhotic NASH.

[0032] In some embodiments, the subject has cirrhosis and NASH.

[0033] In some embodiments, the subject has hepatitis. In some embodiments, hepatitis is inflammation of the lobules.

[0034] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or a pharmaceutically acceptable salt thereof results in a reduction of hepatitis.

[0035] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or a pharmaceutically acceptable salt thereof results in a hepatitis score of 0 or 1.

[0036] In several embodiments, the target liver is characterized by hepatocyte ballooning.

[0037] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or a pharmaceutically acceptable salt thereof results in a reduction of hepatocyte ballooning.

[0038] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or a pharmaceutically acceptable salt thereof results in a ballooning score of 0.

[0039] In several embodiments, the liver alanine aminotransferase (ALT) levels of the subjects increased.

[0040] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or a pharmaceutically acceptable salt thereof results in a decrease in hepatic alanine aminotransferase (ALT) levels.

[0041] In several embodiments, the liver aspartate aminotransferase (AST) levels of the subjects increased.

[0042] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or a pharmaceutically acceptable salt thereof results in a decrease in hepatic aspartate aminotransferase (AST) levels.

[0043] In some embodiments, the subject has liver fibrosis. In some embodiments, the subject has stage 2, stage 3, or stage 4 liver fibrosis. In some embodiments, the subject has liver cirrhosis.

[0044] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or a pharmaceutically acceptable salt thereof results in stabilization of liver fibrosis in the subject.

[0045] In multiple embodiments, administering a compound of Formula I (e.g., any one of compound (1), compound (2), and compound (3)), or a pharmaceutically acceptable salt thereof, results in reversal of liver fibrosis in a subject.

[0046] In multiple embodiments, the subject has a steatosis score of 1, 2, or 3.

[0047] In multiple embodiments, administering a compound of Formula I (e.g., any one of compound (1), compound (2), and compound (3)), or a pharmaceutically acceptable salt thereof, results in a decrease in liver hypertrophy in a subject.

[0048] In one aspect, the present invention features a method of reducing hepatitis, the method comprising administering to a subject in need thereof an effective amount of a compound according to Formula I,

Chemical Formula

[0049] In several embodiments, the compound of formula I is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid, [ka] (1) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula (I) is (S)-2-amino-6-((3-aminopropyl)amino)hexanoate dihydrochloride, [ka] That is the case.

[0050] In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid, [ka] (2) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoate trihydrochloride, [ka] That is the case.

[0051] In several embodiments, the compound of formula I is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid, [ka] (3) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula I is (S)-2-amino-5-((5-aminopentyl)amino)pentanoate trihydrochloride, [ka] That is the case.

[0052] In several embodiments, hepatitis is inflammation of the lobules.

[0053] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or a pharmaceutically acceptable salt thereof results in a hepatitis score of 0 or 1.

[0054] In several embodiments, the subject has non-alcoholic steatohepatitis (NASH).

[0055] In one embodiment, the present invention is characterized by a method for reducing hepatocyte ballooning, wherein an effective amount of a compound according to formula I is applied to a target that requires it. [ka] or administering a pharmaceutically acceptable salt thereof, in the formula, R 1 These are hydrogen, -(C1-C8) alkyl, -(C1-C8) alkenyl, -(C1-C8)alkynyl, unsubstituted or substituted -ara(C1-C6)alkyl, unsubstituted or substituted - Selected from the group consisting of heteroara(C1-C6)alkyl, where the substituents on the substituted ara(C1-C6)alkyl and substituted heteroara(C1-C6)alkyl are halogen, -CN, -NO2, -NH2, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl)]2, -OH, halo(C1-C6)alkyl, -(C1-C6)alkoxy, Halo(C1-C6)alkoxy, -SH, Thio(C1-C6)alkyl, -SONH2, -SO2NH2, Selected from the group consisting of -SO-(C1-C6)alkyl, -SO2-(C1-C6)alkyl, -NHSO2(C1-C6)alkyl, and -NHSO2NH2; R 2 These are hydrogen, -(C1-C8) alkyl, -(C1-C8) alkenyl, -(C1-C8)alkynyl, unsubstituted or substituted -ara(C1-C6)alkyl, unsubstituted or substituted - Selected from the group consisting of heteroara(C1-C6)alkyl, where the substituents on the substituted ara(C1-C6)alkyl and the substituted heteroara(C1-C6)alkyl are halogens, -CN, -NO2, -NH2, -OH, Halo(C1-C6)alkyl, -(C1-C6)alkoxy, Halo(C1-C6)alkoxy, -SH, Thio(C1-C6)alkyl, -SONH2, -SO2NH2, -SO-(C1-C6)alkyl, -SO2-(C1-C6)alkyl, Selected from the group consisting of -NHSO2(C1-C6)alkyl and -NHSO2NH2; R 3 , R 4 , R 7 , R 8 , R 9 , R 10 , R 13 , and R 14 These are independently selected from the group consisting of hydrogen and -(C1-C6)alkyl groups; R 5 and R 6 Independently, hydrogen, -Selected from the group consisting of (C1-C6)alkyl and -OH, however R 5 and R 6 Both cannot be -OH; R 11 and R 12 Independently, hydrogen, -Selected from the group consisting of (C1-C6)alkyl and -OH, however R 11 and R 12 Both cannot be -OH; m is an integer between 1 and 4. n is an integer between 0 and 4. o is an integer between 0 and 4. p is an integer between 1 and 4. q is an integer between 0 and 4. r is an integer between 0 and 4.

[0056] In several embodiments, the compound of formula I is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid, [ka] (1) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula (I) is (S)-2-amino-6-((3-aminopropyl)amino)hexanoate dihydrochloride, [ka] That is the case.

[0057] In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid, [ka] (2) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoate trihydrochloride, [ka] That is the case.

[0058] In several embodiments, the compound of formula I is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid, [ka] (3) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula I is (S)-2-amino-5-((5-aminopentyl)amino)pentanoate trihydrochloride, [ka] That is the case.

[0059] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or a pharmaceutically acceptable salt thereof results in a ballooning score of 0.

[0060] In several embodiments, the subject has non-alcoholic steatohepatitis (NASH).

[0061] In one embodiment, the present invention is characterized by a method for treating liver fibrosis, wherein the method involves administering an effective amount of a compound according to formula I to a subject in need of treatment. [ka] or administering a pharmaceutically acceptable salt thereof, in the formula, R 1 These are hydrogen, -(C1-C8) alkyl, -(C1-C8) alkenyl, -(C1-C8)alkynyl, unsubstituted or substituted -ara(C1-C6)alkyl, unsubstituted or substituted - Selected from the group consisting of heteroara(C1-C6)alkyl, where the substituents on the substituted ara(C1-C6)alkyl and substituted heteroara(C1-C6)alkyl are halogen, -CN, -NO2, -NH2, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl)]2, -OH, halo(C1-C6)alkyl, -(C1-C6)alkoxy, Halo(C1-C6)alkoxy, -SH, Thio(C1-C6)alkyl, -SONH2, -SO2NH2, Selected from the group consisting of -SO-(C1-C6)alkyl, -SO2-(C1-C6)alkyl, -NHSO2(C1-C6)alkyl, and -NHSO2NH2; R 2 These are hydrogen, -(C1-C8) alkyl, -(C1-C8) alkenyl, -(C1-C8)alkynyl, unsubstituted or substituted -ara(C1-C6)alkyl, unsubstituted or substituted - Selected from the group consisting of heteroara(C1-C6)alkyl, where the substituents on the substituted ara(C1-C6)alkyl and the substituted heteroara(C1-C6)alkyl are halogens, -CN, -NO2, -NH2, -OH, Halo(C1-C6)alkyl, -(C1-C6)alkoxy, Halo(C1-C6)alkoxy, -SH, Thio(C1-C6)alkyl, -SONH2, -SO2NH2, -SO-(C1-C6)alkyl, -SO2-(C1-C6)alkyl, Selected from the group consisting of -NHSO2(C1-C6)alkyl and -NHSO2NH2; R 3 , R 4 , R 7 , R 8 , R 9 , R 10 , R 13 , and R 14 These are independently selected from the group consisting of hydrogen and -(C1-C6)alkyl groups; R 5 and R 6 Independently, hydrogen, -Selected from the group consisting of (C1-C6)alkyl and -OH, however R 5 and R 6 Both cannot be -OH; R 11 and R 12 Independently, hydrogen, -Selected from the group consisting of (C1-C6)alkyl and -OH, however R 11 and R 12 Both cannot be -OH; m is an integer between 1 and 4. n is an integer between 0 and 4. o is an integer between 0 and 4. p is an integer between 1 and 4. q is an integer between 0 and 4. r is an integer between 0 and 4.

[0062] In several embodiments, the compound of formula I is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid, [ka] (1) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula (I) is (S)-2-amino-6-((3-aminopropyl)amino)hexanoate dihydrochloride, [ka] That is the case.

[0063] In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid, [ka] (2) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoate trihydrochloride, The filename is JPEG2026062985000026.jpg18107.

[0064] In several embodiments, the compound of formula I is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid, [ka] (3) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula I is (S)-2-amino-5-((5-aminopentyl)amino)pentanoate trihydrochloride, [ka] That is the case.

[0065] In some embodiments, the subject has stage 2, stage 3, or stage 4 liver fibrosis.

[0066] In some embodiments, the subject has cirrhosis of the liver.

[0067] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or a pharmaceutically acceptable salt thereof results in stabilization of liver fibrosis in the subject.

[0068] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or a pharmaceutically acceptable salt thereof results in a reversal of hepatic fibrosis in a subject.

[0069] In several embodiments, the subject has non-alcoholic steatohepatitis (NASH).

[0070] In one embodiment, the present invention is characterized by a method for treating lipopathy, wherein an effective amount of a compound according to formula I is administered to a subject requiring treatment. [ka] or administering a pharmaceutically acceptable salt thereof, in the formula, R 1 These are hydrogen, -(C1-C8) alkyl, -(C1-C8) alkenyl, -(C1-C8)alkynyl, unsubstituted or substituted -ara(C1-C6)alkyl, unsubstituted or substituted - Selected from the group consisting of heteroara(C1-C6)alkyl, where the substituents on the substituted ara(C1-C6)alkyl and substituted heteroara(C1-C6)alkyl are halogen, -CN, -NO2, -NH2, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl)]2, -OH, halo(C1-C6)alkyl, -(C1-C6)alkoxy, Halo(C1-C6)alkoxy, -SH, Thio(C1-C6)alkyl, -SONH2, -SO2NH2, Selected from the group consisting of -SO-(C1-C6)alkyl, -SO2-(C1-C6)alkyl, -NHSO2(C1-C6)alkyl, and -NHSO2NH2; R 2These are hydrogen, -(C1-C8) alkyl, -(C1-C8) alkenyl, -(C1-C8)alkynyl, unsubstituted or substituted -ara(C1-C6)alkyl, unsubstituted or substituted - Selected from the group consisting of heteroara(C1-C6)alkyl, where the substituents on the substituted ara(C1-C6)alkyl and the substituted heteroara(C1-C6)alkyl are halogens, -CN, -NO2, -NH2, -OH, Halo(C1-C6)alkyl, -(C1-C6)alkoxy, Halo(C1-C6)alkoxy, -SH, Thio(C1-C6)alkyl, -SONH2, -SO2NH2, -SO-(C1-C6)alkyl, -SO2-(C1-C6)alkyl, Selected from the group consisting of -NHSO2(C1-C6)alkyl and -NHSO2NH2; R 3 , R 4 , R 7 , R 8 , R 9 , R 10 , R 13 , and R 14 These are independently selected from the group consisting of hydrogen and -(C1-C6)alkyl groups; R 5 and R 6 Independently, hydrogen, -Selected from the group consisting of (C1-C6)alkyl and -OH, however R 5 and R 6 Both cannot be -OH; R 11 and R 12 Independently, hydrogen, -Selected from the group consisting of (C1-C6)alkyl and -OH, however R 11 and R 12 Both cannot be -OH; m is an integer between 1 and 4. n is an integer between 0 and 4. o is an integer between 0 and 4. p is an integer between 1 and 4. q is an integer between 0 and 4. r is an integer between 0 and 4.

[0071] In several embodiments, the compound of formula I is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid, [ka] (1) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula (I) is (S)-2-amino-6-((3-aminopropyl)amino)hexanoate dihydrochloride, [ka] That is the case.

[0072] In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid, [ka] (2) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoate trihydrochloride, [ka] That is the case.

[0073] In several embodiments, the compound of formula I is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid, [ka] (3) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula I is (S)-2-amino-5-((5-aminopentyl)amino)pentanoate trihydrochloride, [ka] That is the case.

[0074] In some embodiments, the subject has a steatosis score of 1, 2, or 3.

[0075] In several embodiments, administration of the compound of formula I or a pharmaceutically acceptable salt thereof results in a reduction of steatosis in subjects.

[0076] In several embodiments, the subject has non-alcoholic steatohepatitis (NASH).

[0077] With respect to the substances and methods of the compositions disclosed herein, as assumed in this disclosure, in one embodiment, an embodiment of the disclosure includes the components and / or processes disclosed herein. In another embodiment, an embodiment of the disclosure is essentially composed of the components and / or processes disclosed herein. In yet another embodiment, an embodiment of the disclosure consists of the components and / or processes disclosed herein. [Brief explanation of the drawing]

[0078] A patent or application file includes at least one drawing made in color. A copy of the patent or patent application publication including the color drawing will be provided by the Japan Patent Office upon request and payment of the required fees.

[0079] The accompanying drawings, provided for further understanding of this disclosure, incorporated herein and constituting a part thereof, illustrate exemplary embodiments of this disclosure and, together with the description, serve to illustrate the principles of this disclosure.

[0080] [Figure 1]Figure 1 shows data on the effect of APL on impaired glucose tolerance in a rat model of NASH. Figure 1 plots the area under the curve (AUC) of the glucose tolerance test (GTT) in Zucker lean (Fa / fa) and obese (fa / fa) rats treated twice daily for 78 days using either a vehicle (positive control) or APL (treatment). Two-way ANOVA and Bonferroni multiple comparison post-hoc tests were performed. Significant statistical differences were observed between the positive control group and the treatment group (**p<0.01).

[0081] [Figure 2] Figure 2, including Figures 2A and 2B, shows data on the effect of APL on glucose tolerance in a diet-induced mouse model of NASH. Figure 2A is a plot of glucose levels in C57BL / 6J mice, which were fed either a solid diet (CHOW) and vehicle (negative control), a high-fat / high-fructose diet (HFD) and vehicle (positive control), or HFD and APL (treatment) for 131 days. After fasting, the animals were orally administered glucose (2 mg / g body weight) and blood glucose levels were measured. Two-way ANOVA and Bonferroni multiple comparison post-hoc tests were performed. Significant statistical differences were observed between the positive control group and the treatment group at 15 minutes (****p<0.0001), 60 minutes (*p<0.05), and 120 minutes (***p<0.001). Significant statistical differences were observed between the negative and positive control groups at 0 and 30 minutes (*p<0.05), 45 minutes (**p<0.01), and 15, 30, 60, and 120 minutes (****p<0.0001). No significant differences were observed between the negative and treatment groups at any of these time points. Figure 2B is a plot of AUC glucose levels in C57BL / 6J mice given either CHOW or HFD. CHOW animals were treated twice daily for 120 days with either vehicle (negative control) or APL. HFD animals were treated with either vehicle (positive control), APL (treatment), or pioglitazone (Pio). Significant statistical differences were observed between the positive and treatment groups (**p<0.01).

[0082] [Figure 3] Figure 3 shows liver biopsies at 20x magnification from C57BL / 6J mice fed either CHOW and vehicle (negative control), HFD and vehicle (positive control), or HFD and APL (TB-019, treatment) for 131 days. Sections were stained with hematoxylin and eosin (H&E). Sections from the positive control group showed severe hepatocyte fat accumulation, inflammatory infiltration, and pathophysiological signs of steatohepatitis, as well as ballooning, particularly in zone 3 of the liver. In contrast, liver sections from the treated group showed minimal or no ballooning induced by HFD. Therefore, APL (TB-019) was effective in reducing diet-induced microscopic liver damage.

[0083] [Figure 4] Figure 4 shows liver biopsies of C57BL / 6J mice fed either CHOW and vehicle (negative control), HFD and vehicle (positive control), or HFD and APL (treatment) for 131 days, at 100x magnification.

[0084] [Figure 5]Figure 5, including Figures 5A to 5D, shows data on hepatic steatohepatia in a mouse model of NASH. C57BL / 6J mice were given either CHOW or HFD. Mice were treated with either vehicle or APL (pobid). The APL dose was 200 mg / kg / day, administered orally twice daily (bid). Animals were fed simultaneously with the APL-treated vehicle for 20 weeks. CHOW (vehicle): Mice given solid feed and administered vehicle (negative control); HFD (vehicle): Mice given HFD and administered vehicle (positive control); HFD (APL): Mice given HFD and administered APL (treatment). Figure 5A includes representative images of hematoxylin and eosin (H&E) stained liver tissue samples, and Figure 5B includes representative images of liver tissue samples immunostained with BODIPY and DAPI. Figures 5C and 5D show plots of the number of nuclear data (Figure 5C) and fat deposition data (Figure 5D). Measurements were performed in 20x magnification fields. More than 21 fields were analyzed from three different animals in each group: negative control (number of fields = 26), positive control (number of fields = 25), and treated (number of fields = 23). Fat deposition was calculated using indirect measurements with ImageJ (Schneider et al., 2012, Nature Methods 9(7):671-675) (threshold is shown in red). Fields containing large blood vessels were excluded from the count. Nuclear counts were evaluated using Harmony® 4.6 High-Content Imaging and Analysis Software of Operetta CLS® (PerkinElmer, Waltham, MA) and a PerkinElmer confocal microscope. One-way ANOVA and Tukey's multiple comparison post-hoc tests were performed in both experiments. A significant statistical decrease in hepatocyte count was observed in the positive control group (***p<0.001). There was no statistical difference between the negative control group and the treatment group. Furthermore, there was a significant statistical difference in fat deposition between the positive and negative controls (**p<0.01). No significant statistical difference in fat deposition was observed between the negative control group and the treatment group.

[0085] [Figure 6] Figure 6, including Figures 6A and 6B, shows data on the Non-Alcoholic Fatty Liver Disease Activity Score (NAS) in diet-induced obesity (a DIO mouse model of NASH). C57BL / 6J mice were fed either a solid diet (CHOW) or a high-fat / high-fructose diet (HFD). Mice were treated with pobidity using either vehicle or APL (200 mg / kg body weight) for 130 days. CHOW vehicle: Mice fed solid diet and administered vehicle (negative control); HFD vehicle: Mice fed HFD and administered vehicle (positive control); HFD APL: Mice fed HFD and administered APL (treatment). Figure 6A includes representative images of liver tissue samples stained with hematoxylin and eosin (H&E). Arrow 1: Macrodrip stiposis. Arrow 2: Microvesicle stiposis. Arrow 3: Hypertrophy. Arrow 4: Inflammatory lesion. Figure 6B shows the NAS component scores for steatosis (hepatic steatosis), inflammation, and hypertrophy in various treatment groups. Two-way ANOVA and Bonferroni multiple comparison post-hoc tests were performed. Significant statistical differences were observed between the positive control group and the treatment groups (***p<0.001).

[0086] [Figure 7]Figure 7, including Figures 7A and 7B, shows data on NAS in the DIO mouse model of NASH. C57BL / 6J mice were given either CHOW or HFD. Mice were treated with pobidity for 130 days using either vehicle or APL (TB-019; 200 mg / kg body weight). CHOW vehicle: Mice were given solid feed and administered vehicle (negative control); HFD vehicle: Mice were given HFD and administered vehicle (positive control); HFD APL: Mice were given HFD and administered APL (TB-019, treatment). Histopathological analysis of non-alcoholic steatohepatitis and NASH activity score (NAS) were performed. Figure 7A shows the mean total NAS score of the groups (negative control = 0.28 ± 0.46, positive control = 6 ± 1.76, treatment group = 1.2 ± 1.06). One-way ANOVA and Tukey's multiple comparison post-hoc test were performed. ANOVA analysis showed significant differences between groups (****p<0.0001). Post-hoc multiple comparison analysis (Tukey) also showed significant differences across all group pairs (negative control vs. positive control, ***q=23.38; negative control vs. treatment group, *q=3.55; and positive control vs. treatment group, ***q=18.5). Figure 7B shows data on pathological changes in the liver of the DIO mouse model of NASH, specifically (1) steatosis (st), (2) lobular inflammation (li), and (3) hepatic ballooning (hb). Two-way ANOVA RM and Bonferroni multiple comparison post-hoc tests were performed. Significant statistical differences were observed between the negative control group and the positive control group in all comparisons (****p<0.0001). Significant statistical differences were observed between the negative control group and the treatment group for lobular inflammation (****p<0.0001). In all comparisons, a significant statistical difference was observed between the treatment group and the positive control (****p<0.0001).

[0087] [Figure 8]Figure 8, including Figures 8A, 8B, and 8C, shows data on liver collagen fibers in a rat NASH model. Figure 8A is a representative image (40x magnification) of liver sections stained with hematoxylin and eosin from Zucker (Fa / fa) lean rats, Zucker fa / fa obese rats treated with vehicle, and Zucker (fa / fa) obese rats treated with vehicle and APL. Figure 8B is a representative image (100x magnification) of liver sections stained with Mason trichrome. Figure 8C is a magnified view of the area within the red frame in Figure 8B. The arrows point to collagen fibers in mesenchymal liver tissue from Zucker obese rats treated with vehicle.

[0088] [Figure 9] Figure 9, including Figures 9A, 9B, and 9C, shows data on hepatic 4-hydroxynonenal (4-HNE) in a rat NASH model. Figure 9A is a representative image of 4-HNE immunofluorescence liver sections from Zucker(Fa / fa) lean rats, Zucker(fa / fa) obese rats administered vehicle (negative control), and Zucker(fa / fa) obese rats administered vehicle (positive control) or APL (treatment). Confocal microscopy of liver tissue at 63x magnification. Figures 9B and 9C are plots of quantification of 4HNE / immunofluorescence intensity (4HNE intensity per tissue area μm2) and quantification of total tissue area, respectively. One-way ANOVA and Tukey's multiple comparison post-hoc tests were performed in both experiments. Significant statistical differences were observed between the control group and the APL-treated group (***p<0.001). No significant statistical difference was observed between the negative control group and the treatment group (Ns = non-statistical difference).

[0089] [Figure 10]FIG. 10, including FIGS. 10A and 10B, shows data regarding hepatic 4 - hydroxy - nonenal (4 - HNE) in the DIO mouse model of NASH. FIG. 10A is a representative image of 4 - HNE immunofluorescence liver sections from C57BL / 6 mice fed CHOW and treated with vehicle (negative control; left image), C57BL / 6 mice fed HFD and treated with either vehicle (positive control; middle image) or APL (TB - 019; treatment; right image). Confocal microscopy of liver tissue at magnifications of 20x and 63x. FIG. 10B is a plot of the quantification of 4HNE / immunofluorescence intensity (4HNE intensity per μm2 of tissue area). One - way ANOVA and Tukey's multiple comparison post - test were performed. A significant statistical difference was observed between the positive control group and the treatment group (***p < 0.001). No statistical difference was observed between the negative control group and the treatment group.

[0090] [Figure 11]FIG. 11, including FIGS. 11A, 11B, 11C, 11D, 11E, and 11F, shows data on surrogate serum biomarkers in the AMLN diet mouse model of NASH. C57BL / 6J mice were fed either a CHOW or a modified AMLN diet and then changed to a HFD after 20 weeks. At week 50, the mice were treated with vehicle or APL (p.o. b.i.d.). APL doses of 25, 50, or 100 mg / kg, orally administered twice daily (b.i.d.) (total dose 50, 100, or 200 mg / kg / day). After 16 weeks of treatment with vehicle or APL, samples were collected for analysis. Dunnett's multiple comparison test was performed. FIG. 11A shows serum alanine aminotransferase (ALT) levels. FIG. 11B shows serum aspartate aminotransferase (AST) levels. FIG. 11C shows serum alkaline phosphatase (ALP) levels. FIG. 11D shows serum triglyceride levels. FIG. 11E shows serum non-esterified fatty acid (NEFA) levels. FIG. 11F shows serum cholesterol levels. All of the illustrated results were obtained from mice administered 50 mg / kg / day of APL, and for cholesterol only, from mice administered 200 mg / kg / day of APL. A significant statistical difference was observed between the positive control group and the treatment groups (*p<0.02; **p = 0.002; ***p = 0.0008, and ****p<0.0001).

[0091] [Figure 12]Figure 12, including Figures 12A and 12B, shows data on NAS and fibrosis in an AMLN diet mouse model of NASH. C57BL / 6J mice were fed either a CHOW or modified AMLN diet, and after 20 weeks, the diet was changed to HFD. At 50 weeks, mice were treated with a vehicle or APL (pobid). APL doses were 25, 50, or 100 mg / kg, administered orally twice daily (bid) (po) (total dose 50, 100, or 200 mg / kg / day). After 16 weeks of treatment with vehicle or APL, biopsies were collected, stained with hematoxylin and eosin (H&E), and evaluated for steatosis, inflammation, and hepatocyte ballooning. Figure 12A shows the reduction in NAS in the treatment group compared to the positive control group. A significant statistical difference was observed between the positive control group and the treatment group (***p<0.001). Figure 12B shows the reduction in liver fibrosis in the treatment group compared to the positive control group. A significant statistical difference was observed between the positive control group and the treatment group (****p<0.0001).

[0092] definition Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this disclosure pertains.

[0093] Furthermore, it should be understood that the terms used herein are for the purpose of describing specific embodiments only and are not intended to be limiting.

[0094] The articles "a" and "an" are used in this disclosure to refer to one or more (i.e., at least one) grammatical objects of the articles. For example, "element" means one or more elements. Thus, the term "cell" includes, for example, multiple cells of the same type.

[0095] As used herein, the term “about” is intended to encompass variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from a specific value when referring to a measurable value such as quantity or duration, and such variations are appropriate for the implementation of the present invention.

[0096] The term "alkyl" means, unless otherwise specified, a linear or branched hydrocarbyl having a specified number of carbon atoms, either by itself or as part of another substituent (i.e., C1-C6 means one to six carbon atoms). Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. In several embodiments, alkyl is a (C1-C6) alkyl such as (C1-C3) alkyl (e.g., methyl and ethyl).

[0097] The term "alkenyl," used alone or in combination with other terms, means a linear or branched hydrocarbyl having the specified number of carbon atoms and containing one or more double bonds, unless otherwise specified. Examples include ethenyl (vinyl), propenyl (allyl), clotyl, isopentenyl, butadienyl, 1,3-pentadienyl, and 1,4-pentadienyl. The functional group representing an alkenyl is exemplified by -CH2-CH=CH2-.

[0098] When used alone or in conjunction with other terms, the term "alkynyl" means, unless otherwise specified, a linear or branched hydrocarbyl having the number of carbon atoms specified and containing one or more triple bonds.

[0099] The term “alkoxy,” used alone or in conjunction with other terms, means, unless otherwise specified, the alkyl group defined above, which is connected to the rest of the molecule via an oxygen atom, such as methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy), and their higher homologs and isomers. The alkyl portion of the alkoxy group may have a specified number of carbon atoms, as defined for the alkyl groups above. In some embodiments, the alkoxy group is a (C1-C6) alkoxy, such as a (C1-C3) alkoxy (e.g., methoxy and ethoxy).

[0100] As used herein, the terms "APL" and "TB-019" refer to the compound of formula I, which is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid (compound (1)), or a pharmaceutically acceptable salt thereof.

[0101] The term "aromatic" refers to a carbocyclic or heterocyclic ring that has aromatic properties (i.e., one or more polyunsaturated rings with (4n+2) delocalized π (pi) electrons, where n is an integer).

[0102] The term "aryl" refers to an aromatic hydrocarbon ring system containing at least one aromatic ring. The aromatic ring can optionally be fused to or otherwise added to other aromatic or non-aromatic hydrocarbon rings. Examples of aryl groups include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene, and biphenyl. Examples of aryl groups include phenyl and naphthyl.

[0103] The term "aralkyl group" refers to an alkyl group substituted with an aryl group.

[0104] As used herein, “effective dose” means a quantity of the compound that, when administered to a subject in need (e.g., a patient suffering from or at risk of developing a disease or condition such as NASH), provides a therapeutic benefit in alleviating one or more symptoms of the disease or condition (e.g., preventing, inhibiting, treating, or reducing the symptoms of a specific disorder or disease (e.g., NASH)). However, it is understood that the complete therapeutic effect does not necessarily occur with a single dose, but may occur after a series of doses. Therefore, the effective dose may be administered in one or more doses. In the context of therapeutic (including preventive) applications, the amount of the active agent administered to the subject will depend on the type and severity of the disease or condition, as well as the subject's characteristics such as overall health, age, sex, weight, and drug tolerance. It will also depend on the degree, severity, and type of the disease or condition. A person skilled in the art will be able to determine an appropriate dosage in accordance with these and other factors. Compounds of Formula I may also be administered in combination with one or more additional therapeutic compounds.

[0105] The terms “halo” or “halogen,” either by themselves or as part of another substituent, mean an atom of fluorine, chlorine, bromine, or iodine, unless otherwise noted. In some embodiments, halogens include fluorine, chlorine, or bromine. In some embodiments, halogens are fluorine or chlorine.

[0106] The term "heteroaralkyl group" refers to an alkyl group substituted with a heteroaryl group.

[0107] The terms “heterocyclic,” “heterocyclyl,” or “heterocyclic formula,” whether in themselves or as part of another substituent, mean, unless otherwise specified, an unsubstituted or substituted monocyclic or polycyclic heterocyclic system consisting of a carbon atom and at least one heteroatom selected from the group consisting of N, O, and S. Heterocyclic systems typically contain 5 to 10 ring atoms. Unless otherwise specified, heterocyclic systems may be added to another atom at any heteroatom or carbon atom of the heterocyclic system that results in structural isomers.

[0108] The term "heteroaryl" or "heteroaromatic" refers to a heterocyclic ring having aromatic characteristics.

[0109] Unless otherwise specified, the term "hydrocarbyl", whether by itself or as part of another substituent, means a straight-chain or branched-chain hydrocarbon having the specified number of carbon atoms (i.e., C1-C6 means 1 to 6 carbons). Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. In multiple embodiments, the hydrocarbyl is a (C1-C6) alkyl such as a (C1-C3) alkyl such as methyl and ethyl. The term "unsaturated hydrocarbyl" means a hydrocarbyl containing at least one double bond or triple bond.

[0110] The term "haloalkyl" means an alkyl group in which at least one hydrogen atom is replaced by a halogen atom. The term "perhaloalkyl" means a haloalkyl group in which all hydrogen atoms are replaced by halogen atoms. Perhaloalkyl includes perfluoroalkyl such as -(C1-C6) perfluoroalkyl (e.g., -(C1-C3) perfluoroalkyl group, e.g., -CF3).

[0111] The term "haloalkoxy" means an alkoxy group in which at least one hydrogen atom is replaced by a halogen atom. The term "perhaloalkoxy" means a haloalkoxy group in which all hydrogen atoms are replaced by halogen atoms. Perhaloalkoxy groups include perfluoroalkoxy such as -(C1-C6) perfluoroalkoxy (e.g., -(C1-C3) perfluoroalkoxy, e.g., -OCF3).

[0112] As used herein, “individual,” “patient,” or “subject” (as in the case of the subject of treatment) means both mammals and non-mammals. Mammals include, for example, humans; non-human primates, such as apes and monkeys; dogs; cats; cattle; horses; sheep; and goats. Non-mammals include, for example, fish and birds. In one embodiment, the individual is a human.

[0113] As used herein, the term “pharmaceutically acceptable” means a formulation of a compound that, when administered to a patient, does not significantly impair the biological activity, pharmacological activity, and / or other properties of the compound. In some embodiments, a pharmaceutically acceptable formulation does not cause significant irritation to the patient.

[0114] The term "substituted" means that an atom or group of atoms substitutes a hydrogen atom as a substituent attached to another group. For aryl and heteroaryl groups, the term "substituted" refers to any level of substitution, i.e., one, two, three, four, or five-substitution, where such substitution is permitted. Substituents are independently selected, and substitutions can be at any chemically accessible position. Examples of substituents include one of the following groups: halo, oxy, azide, nitro, cyano, alkyl, alkoxy, alkyl-thio, alkyl-thio-alkyl, alkoxyalkyl, alkylamino, trihalomethyl, hydroxyl, mercapto, hydroxyl, alkylsilyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, alkenyl, alkynyl, aryl, and amino groups. Substituents containing carbon chains may contain 1 to 6, 1 to 3, or 1 to 2 carbon atoms.

[0115] As used herein, the terms “treat” and “treatment” are interchangeable in relation to a disease or condition (e.g., NASH) and include taking measures to obtain beneficial or desirable clinical outcomes in individual cases or at risk of the disease or condition (e.g., NASH), and include preventing, maintaining, inhibiting, treating, or reducing the symptoms of the disease or condition. Accordingly, treatment of a patient may include preventing or delaying further disease progression (e.g., prevention or maintenance), preventing or reducing the severity of symptoms that are present or expected to develop, improving existing symptoms and preventing further symptoms, and / or prophylactic treatment of a person at risk of developing the condition (e.g., NASH) that results in a reduced probability of the person developing the condition.

[0116] Scope: Throughout this disclosure, various aspects of this disclosure may be presented in scope form. It should be understood that scope form is for convenience and brevity only and should not be interpreted as an inflexible limitation on the scope of this disclosure. Therefore, scope descriptions should be considered to specifically disclose not only all sub-scopes but also individual numerical values ​​within those scopes, as far as possible. For example, a scope description such as 1-6 should be considered to have specifically disclosed sub-scopes such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, as well as individual numerical values ​​within that scope, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the width of the scope. [Modes for carrying out the invention]

[0117] Embodiments of this disclosure are described below. However, it should be noted that this disclosure is not limited to these embodiments, but is intended to include variations and their equivalents that would be obvious to those skilled in the art.

[0118] Non-alcoholic fatty liver disease (NAFLD) generally encompasses a range of conditions in which excess fat accumulates in the liver, and which are not caused by excessive alcohol consumption. For example, simple fatty liver (non-alcoholic fatty liver or NAFL) is a condition in which there is fat in the liver with little or no hepatitis or cell damage. This condition usually does not progress to liver damage or other complications. However, non-alcoholic steatohepatitis (NASH) is a different condition in which, in addition to fatty liver, the subject has inflammation (hepatitis) and / or cell damage of the liver, and can lead to fibrosis (including cirrhosis) or liver cancer. Only a subset of subjects with NAFLD have NASH (about 20%), and about 3-12% of adults in the United States have NASH. However, NASH has been identified as the second most common cause of enrollment on liver transplant waiting lists and liver transplants. Therefore, the severity of outcomes in patients with NASH indicates an urgent need for effective treatment.

[0119] Currently, the treatment of NAFLD and NASH relies on dietary and other lifestyle modifications rather than drug therapy. In particular, there have been considerable challenges in developing effective treatments for NASH and related conditions or complications (e.g., fibrosis and cirrhosis).

[0120] Surprisingly, the compound of formula I was found to be effective in treating liver diseases and disorders, including non-alcoholic steatohepatitis (NASH), as well as conditions that may be associated with or independent of NASH, such as hepatic fibrosis (including cirrhosis), hepatic steatosis, hepatitis (e.g., lobular inflammation), and hepatocyte ballooning.

[0121] For example, compounds of formula I, or pharmaceutically acceptable salts thereof, have been found to be effective in treating non-alcoholic steatohepatitis (NASH), as demonstrated in rodent models of NASH recognized in the art. In particular, compounds of formula I have been found to improve diabetes-related impaired glucose tolerance (IGT), reduce hepatic fat deposition, attenuate hepatic steatosis, attenuate hepatic fibrosis, hepatitis, hepatomegaly, and treat NASH. Therefore, compounds of formula I, or any pharmaceutically acceptable salt thereof, may be useful in treating (e.g., preventing, inhibiting, reducing, or maintaining) any of these conditions, including those described herein.

[0122] For example, individuals suffering from or at risk of non-alcoholic steatohepatitis (NASH) or other liver conditions (including steatosis, hepatitis (e.g., lobular inflammation), hepatocyte ballooning, and / or fibrosis (e.g., cirrhosis)) may benefit from treatment involving the administration of a compound according to Formula I or a pharmaceutically acceptable salt thereof.

[0123] Compound of formula I The compounds used in the treatment of non-alcoholic steatohepatitis (NASH) are compounds that conform to formula I. [ka] (I) and its pharmaceutically acceptable salts, During the ceremony, R 1 These are hydrogen, -(C1-C8) alkyl, -(C1-C8) alkenyl, -(C1-C 8) Alkynyl, unsubstituted or substituted -ara(C1-C6)alkyl, unsubstituted or substituted - Selected from the group consisting of heteroara(C1-C6)alkyl, where the substituents on the substituted ara(C1-C6)alkyl and the substituted heteroara(C1-C6)alkyl are halogen, -CN, -NO2, -NH2, Selected from the group consisting of -NH(C1-C6)alkyl, -N[(C1-C6)alkyl)]2, -OH, halo(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkoxy, -SH, thio(C1-C6)alkyl, -SONH2, -SO2NH2, -SO-(C1-C6)alkyl, -SO2-(C1-C6)alkyl, -NHSO2(C1-C6)alkyl, and -NHSO2NH2; R 2 These are hydrogen, -(C1-C8) alkyl, -(C1-C8) alkenyl, -(C1-C8)alkynyl, unsubstituted or substituted -ara(C1-C6)alkyl, unsubstituted or substituted - Selected from the group consisting of heteroara(C1-C6)alkyl, where the substituents on the substituted ara(C1-C6)alkyl and the substituted heteroara(C1-C6)alkyl are selected from the group consisting of halogen, -CN, -NO2, -NH2, -OH, halo(C1-C6)alkyl, -(C1-C6)alkoxy, halo(C1-C6)alkoxy, -SH, thio(C1-C6)alkyl, -SONH2, -SO2NH2, -SO-(C1-C6)alkyl, -SO2-(C1-C6)alkyl, -NHSO2(C1-C6)alkyl, and -NHSO2NH2; R 3 , R 4 , R 7 , R 8 , R 9 , R 10 , R 13 , and R 14 These are independently selected from the group consisting of hydrogen and -(C1-C6)alkyl groups; R 5 and R 6 Independently, hydrogen, -Selected from the group consisting of (C1-C6)alkyl and -OH, however R 5 and R 6 Both cannot be -OH; R 11 and R 12 Independently, hydrogen, -Selected from the group consisting of (C1-C6)alkyl and -OH, however R 11 and R12 Both cannot be -OH; m is 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; o is 0, 1, 2, 3, or 4; p is 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4.

[0124] In multiple embodiments, R 1 and / or R 2 Halo(C1-C6)alkyl and / or halo(C1-C6)alkoxy containing are selected from perhalo(C1-C6)alkyl and perhalo(C1-C6).

[0125] In multiple embodiments, R 1 R is selected from hydrogen and -(C1-C8)alkyl. In some embodiments, R 2 R is selected from hydrogen or -(C1-C8)alkyl. In some embodiments, R 1 and R 2 R is independently selected from hydrogen and -(C1-C8)alkyl. In the embodiments described above, -(C1-C8)alkyl is -(C1-C6)alkyl, -(C1-C3)alkyl, or methyl or ethyl. In some embodiments, R 1 and R 2 It is hydrogen.

[0126] In multiple embodiments, R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 Each of these is independently selected from hydrogen and -(C1-C8)alkyl. -(C1-C8)alkyl is -(C1-C6)alkyl, -(C1-C3)alkyl, or methyl or ethyl. In some embodiments, R 3 , R 4 , R 5 , R 6 , R 7 , and R8 It is hydrogen.

[0127] In multiple embodiments, R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 Each of these is independently selected from hydrogen and -(C1-C8)alkyl. -(C1-C8)alkyl is -(C1-C6)alkyl, -(C1-C3)alkyl, or methyl or ethyl. In some embodiments, R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 It is hydrogen.

[0128] In multiple embodiments, R 3 ~R 14 Each of these is independently selected from hydrogen and -(C1-C8)alkyl according to the scheme described above. In some embodiments, R 3 ~R 14 It is hydrogen.

[0129] In several embodiments of the compound of formula I, the sum of m+n+o is in the range of 2 to 10, 9, 8, 7, 6, 5, 4, or 3; or in the range of 3 to 10, 9, 8, 7, 6, 5, or 4; or in the range of 4 to 10, 9, 8, 7, 6, or 5. In several embodiments, the sum of m+n+o is 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2.

[0130] In several embodiments of the compound of formula I, the sum of p+q+r is in the range of 1 to 10, 9, 8, 7, 6, 5, 4, 3, or 2; in the range of 2 to 10, 9, 8, 7, 6, 5, 4, or 3; in the range of 3 to 10, 9, 8, 7, 6, 5, or 4; or in the range of 4 to 10, 9, 8, 7, 6, or 5. In several embodiments, the sum of p+q+r is 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1.

[0131] In some of the embodiments described above that define the sum of m+n+o and / or the sum of p+q+r, R 3 ~R 14 Each of these is independently selected from hydrogen and -(C1-C8)alkyl. In some embodiments, R 3 ~R 14 It is hydrogen.

[0132] In several embodiments of the compound of formula I, m is 3; p is 4; and n, o, q, and r are each zero. In several embodiments, R 3 , R 4 , R 9 , and R 10 R is independently selected from hydrogen and -(C1-C8)alkyl. In some embodiments, R 3 , R 4 , R 9 , and R 10 R is independently hydrogen. In some embodiments, R 1 and R 2 R may be independently selected from hydrogen and -(C1-C8)alkyl. In some embodiments, R 1 and R 2 R may be hydrogen independently. In some embodiments, 1 , R 2 , R 3 , R 4 , R 9 , and R 10 is hydrogen. In several embodiments, the compound of formula I is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid (compound (1)), or a pharmaceutically acceptable salt thereof.

[0133] In several embodiments of the compound of formula I, m is 4; n is 1 or 2; p is 3; and o, q, and r are each zero. In several embodiments, R 3 , R 4 , R 9 , and R 10 R is independently selected from hydrogen and -(C1-C8)alkyl. In some embodiments, R 3 , R4 , R 9 , and R 10 R is independently hydrogen. In some embodiments, R 1 and R 2 R may be independently selected from hydrogen and -(C1-C8)alkyl. In some embodiments, R 1 and R 2 R may be independently selected from hydrogen. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 9 , and R 10 is hydrogen. In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid or a pharmaceutically acceptable salt thereof, or (S)-2-amino-5-((6-aminopentyl)amino)pentanoic acid or a pharmaceutically acceptable salt thereof.

[0134] In multiple embodiments, R 1 and R 2 Each of these is hydrogen. In some embodiments, R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 Each of these is hydrogen. In some embodiments, R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 Each of these is hydrogen. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14Each of these is hydrogen. In multiple embodiments, (m+n+o) is 3. In multiple embodiments, (m+n+o) is 4. In multiple embodiments, (m+n+o) is 5. In multiple embodiments, (m+n+o) is 6. In multiple embodiments, (p+q+r) is 3. In multiple embodiments, (p+q+r) is 4. In multiple embodiments, (p+q+r) is 5. In multiple embodiments, (p+q+r) is 6.

[0135] In several embodiments, pharmaceutically acceptable salts of the compound of formula I are used in the methods described herein. Exemplary pharmaceutically acceptable salts are described herein. In several embodiments, the pharmaceutically acceptable salt is a hydrochloride salt of the compound of formula I (e.g., monohydrochloride, dihydrochloride, or trihydrochloride of the compound of formula I).

[0136] In several embodiments, the compound of formula I is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid, [ka] (1) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula (I) is (S)-2-amino-6-((3-aminopropyl)amino)hexanoate dihydrochloride, [ka] That is the case.

[0137] In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid, [ka] (2) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoate trihydrochloride, [ka] That is the case.

[0138] In several embodiments, the compound of formula I is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid, [ka] (3) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula I is (S)-2-amino-5-((5-aminopentyl)amino)pentanoate trihydrochloride, [ka] That is the case.

[0139] Compound Synthesis Compounds of formula I may be prepared according to methods known in the art. Exemplary synthesis is described herein.

[0140] Compound (1) An exemplary method for preparing the dihydrochloride salt of compound (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid (compound (1), dihydrochloride salt), which is a compound of formula I, is as follows. Preparation of A.(S)-(2-oxoazepan-3-yl)carbamate tert-butyl: [ka]

[0141] Di-tert-butyl dicarbonate (733 μL, 3.189 mmol) was added to a suspension of L-(-)-α-amino-ε-caprolactam hydrochloride (500 mg, 3.037 mmol) and triethylamine (847 μL, 6.074 mmol) in anhydrous tetrahydrofuran (4 mL). The resulting suspension was stirred overnight at room temperature and concentrated. The white solid residue was separated between ethyl acetate and water. The aqueous layer was removed. The organic layer was washed twice with 1N hydrochloric acid aqueous solution, twice with saturated sodium bicarbonate aqueous solution, and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The pure title compound ((S)-(2-oxoazepan-3-yl)carbamate tert-butyl) was obtained as a white solid. 1 H NMR(400 MHz,CD3OD)δ 6.45(bd,J = 5.8 Hz,1H),4.18-4.30(m,1H),3.17-3.30(m,2H),1.70-2.03(m,4H),1.48-1.57(m,1H),1.45(s,9H),1.28-1.42(m,1H);MS(ESI):m / z 250.8(M+Na) + . Preparation of B.(S)-(1-(3-((tert-butoxycarbonyl)amino)propyl)-2-oxoazepan-3-yl)carbamate tert-butyl: [ka]

[0142] Bis(trimethylsilyl)amide (2.524 mmol; 1.0 M solution in 2.5 mL of tetrahydrofuran) was added to (S)-(2-oxoazepan-3-yl)carbamate tert-butyl (288 mg, 1.262 mmol) solution in anhydrous tetrahydrofuran (12 mL).

[0143] The resulting suspension was stirred at room temperature for 30 minutes. 3-(Boc-amino)propyl bromide (2.524 mmol; 470 μL) was added all at once, and the reaction mixture was stirred at room temperature for 28 hours.

[0144] The reaction mixture was concentrated in a rotary evaporator, and the residue was partitioned between ethyl acetate and water. The aqueous layer was removed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography on silica gel using a gradient solvent system of 0-100% ethyl acetate in hexane to obtain the title compound ((S)-(1-(3-((tert-butoxycarbonyl)amino)propyl)-2-oxoazepan-3-yl)carbamate tert-butyl as a colorless oil. 1 H NMR(400MHz,CDCl3)δ5.96(bd,J=5.0Hz,1H),5.32(bs,1H),4.36(m,1H),3.45-3.62(m,2H),3.33-3.41(m,1H),3.08-3.22(m,2H),2.97-3. 06(m,1H),2.02-2.09(m,1H),1.92-2.00(m,1H),1.76-1.87(m,2H),1.61-1.70(m,2H),1.40-1.50(m,19H),1.31-1.38(m,1H);MS(ESI):m / z 407.8(M+Na) + . Preparation of C.(S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid dihydrochloride (compound (1), dihydrochloride): [ka]

[0145] (S)-(1-(3-((tert-butoxycarbonyl)amino)propyl)-2-oxoazepan-3-yl)carbamate tert-butyl (100 mg, 0.2596 mmol) was dissolved in 12N hydrochloric acid aqueous solution (4 mL). The resulting solution was stirred at room temperature until all foaming subsided. The solution was transferred to a microwave reaction vial and heated at 160°C for 90 minutes. Upon concentration, the pure title compound ((S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid dihydrochloride) was obtained as a pale yellowish-brown solid. 1H NMR(400MHz,D2O)δ4.00(t,J=6.3Hz,1H),3.08-3.20(m,6H),1.90-2.15(m,4H),1.72-1.83(m,2H),1.43-1.62(m,2H);MS(ESI):m / z 203.9(M+H) + .

[0146] The solubility, liver microsomal stability, and solution stability of (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid ("APL") have been evaluated. See WO2018 / 049019 and U.S. Publication 2019 / 0192462.

[0147] Compound (2) An exemplary method for preparing compound (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid trihydrochloride (compound (2), trihydrochloride), which is the compound of formula I, is as follows. A. Preparation of tert-butyl (6-oxohexyl)carbamate: [ka]

[0148] Anhydrous dimethyl sulfoxide (83 μL) was added dropwise to a stirred solution of oxalyl chloride (50 μL) in anhydrous dichloromethane (2 mL) at -78°C. After stirring for 15 minutes, a solution of 6-(tert-butoxy-carbonylamino)-1-hexanol (115 mg, 0.53 mmol) in anhydrous dichloromethane (1 mL) was added dropwise. The resulting mixture was stirred at -78°C for 45 minutes. Triethylamine (368 μL) was added, and the reaction mixture was warmed to room temperature. This solution was concentrated using a rotary evaporator to obtain the title compound ((6-oxohexyl)carbamate tert-butyl) as an off-white solid (86 mg, yield 75%), which was used without further purification. Preparation of B.(S)-2-(((benzyloxy)carbonyl)amino)-5-((6-((tert-butoxycarbonyl)amino)hexyl)amino)-pentanoic acid [ka]

[0149] To a stirred suspension of 94 mg (0.352 mmol) of N-alpha-benzyloxycarbonyl-L-ornithine in 2 mL of anhydrous methanol containing 100 μL of acetic acid, a solution of tert-butyl (6-oxohexyl)carbamate (114 mg, 0.528 mmol) in 1.9 mL of anhydrous methanol was added. The resulting mixture was stirred at room temperature for 30 minutes. Then, sodium borohydride (66 mg, 1.057 mmol) was added, and the reaction was stirred overnight at room temperature. After concentration using a rotary evaporator, the residue was partitioned between ethyl acetate and 1 M potassium bisulfate aqueous solution. The aqueous layer was removed. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated using a rotary evaporator. The resulting residue was purified by reverse-phase chromatography (C18 column) using a gradient of 10-100% acetonitrile in water containing a 0.1% formic acid regulator. The title compound ((S)-2-(((benzyloxy)carbonyl)amino)-5-((6-((tert-butoxycarbonyl)amino)hexyl)amino)-pentanoic acid) (87 mg, yield 53%) was obtained as a pale yellow oil. 1 H NMR(400MHz,D2O)δ3.94(t,J=5.92Hz,0.5H),3.63(m,0.5H),2.99-3.13(m,6H),1.65-2.04(m,8H),1.43(m,4H);MS(ESI):m / z 466.2[(M+H) + ]. Preparation of C.(S)-2-amino-5-((6-aminohexyl)amino)pentanoate trihydrochloride [ka]

[0150] A solution of (S)-2-(((benzyloxy)carbonyl)amino-5-((6-((tert-butoxycarbonyl)amino)hexyl)amino)pentanoic acid (18 mg, 0.039 mmol) in a 6N hydrochloric acid aqueous solution (4 mL) was refluxed for two hours. This solution was concentrated using a rotary evaporator to obtain the title compound ((S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid trihydrochloride) (12 mg, yield 90%) as a pale yellow oil. 1 H NMR(400MHz,D2O)δ4.27(m,0.5H),3.95(m,0.5H),3.33-3.48(m,6H),2.00-2.37(m,8H),1.77(m,4H);MS(ESI):m / z 232.2[(M+H) + ].

[0151] Compound (3) An exemplary method for preparing compound (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid trihydrochloride (compound (3), trihydrochloride), which is the compound of formula I, is as follows. A. Preparation of tert-butyl (5-oxopentyl)carbamate [ka]

[0152] Anhydrous dimethyl sulfoxide (58 μL) was added dropwise to a stirred solution of oxalyl chloride (35 μL) in anhydrous dichloromethane (1.5 mL) at -78°C. After stirring for 15 minutes, a solution of 6-(tert-butoxy-carbonylamino)-1-pentanol (75 mg, 0.37 mmol) in anhydrous dichloromethane (0.75 mL) was added dropwise. The resulting mixture was stirred at -78°C for 45 minutes. Triethylamine (257 μL) was added, and the reaction mixture was warmed to room temperature. This solution was concentrated using a rotary evaporator to obtain the title compound ((5-oxopentyl)carbamate tert-butyl) as an off-white solid (52 mg, yield 70%), which was used without further purification. Preparation of B.(S)-2-(((benzyloxy)carbonyl)amino)-5-((5-((tert-butoxycarbonyl)amino)pentyl)amino)-pentanoic acid [ka]

[0153] To a stirred suspension of 35 mg (0.13 mmol) of N-alpha-benzyloxycarbonyl-L-ornithine in 1 mL of anhydrous methanol containing 38 μL of acetic acid, a solution of tert-butyl (5-oxopentyl)carbamate (40 mg, 0.20 mmol) in 1 mL of anhydrous methanol was added. The resulting mixture was stirred at room temperature for 30 minutes. Then, sodium borohydride (25 mg, 0.40 mmol) was added, and the reaction was stirred at room temperature overnight. After concentration using a rotary evaporator, the residue was partitioned between ethyl acetate and 1 M potassium bisulfate aqueous solution. The aqueous layer was removed. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated using a rotary evaporator. The resulting residue was purified by reverse-phase chromatography (C18 column) using a gradient of 10-100% acetonitrile in water containing a 0.1% formic acid regulator. The title compound ((S)-2-(((benzyloxy)carbonyl)amino)-5-((5-((tert-butoxycarbonyl)amino)pentyl)amino)-pentanoic acid) (34 mg, yield 58%) was obtained as a colorless oil. 1 H NMR(400MHz,CD3OD)δ7.26-7.38(m,5H),5.08(s,2H),4.03(m,1H),2.90-3. 07(m,6H),1.87(m,1H),1.65-1.79(m,5H),1.34-1.54(m,13H);MS(ESI):m / z 452.30[(M+H) + ]. Preparation of C.(S)-2-amino-5-((5-aminopentyl)amino)pentanoate trihydrochloride [ka]

[0154] A solution of (S)-2-(((benzyloxy)carbonyl)amino-5-((5-((tert-butoxycarbonyl)amino)pentyl)amino)pentanoic acid (20 mg, 0.044 mmol) in a 6N hydrochloric acid aqueous solution (4 mL) was refluxed for two hours. This solution was concentrated using a rotary evaporator to obtain the title compound ((S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid trihydrochloride) (12 mg, yield 88%) as a pale yellow oil. 1 H NMR(400MHz,CD3OD)δ4.06(t,J=5.36Hz,1H),3.06(m,4H),2.96(t,J=7.52Hz ,2H),1.88-2.10(m,4H),1.68-1.83(m,4H),1.47-1.55(m,2H);MS(ESI):m / z 218.2[(M+H) + ].

[0155] Those skilled in the art will understand that the processes described in Schemes 1-16 of WO 2018 / 049019 and U.S. Publication 2019 / 0192462 are not the sole means for synthesizing the compounds of Formula I, and that there is a repertoire of available synthetic organic reactions that can be employed in synthesizing the compounds of this disclosure. Those skilled in the art will know how to select and carry out appropriate synthetic routes. Suitable synthetic methods are described in Comprehensive Organic Synthesis, Ed. BMTrost and I. Fleming (Pergamon Press, 1991), Comprehensive Organic Functional Group Transformations, Ed. ARKatritzky, O. Meth-Cohn, and CWRees (Pergamon Press, 1996), and Comprehensive Organic Functional Group Transformations II, Ed. ARKatritzky and RJKTaylor (Editor) (Elsevier, 2 ndIt can be identified by referring to literature that includes reference sources such as Edition, 2004), Comprehensive Heterocyclic Chemistry, Ed. ARKatritzky and CWRees (Pergamon Press, 1984), and Comprehensive Heterocyclic Chemistry II, Ed. ARKatritzky, CWRees, and EFVScriven (Pergamon Press, 1996).

[0156] The compounds and intermediates of formula I can be isolated from their reaction mixture and purified by standard methods such as filtration, liquid-liquid extraction, solid-phase extraction, distillation, recrystallization, or chromatography.

[0157] When a compound of formula I contains one or more chiral centers, it will be understood that the compound may exist or be isolated as a pure enantiomer or diastereomer, or as a racemic mixture. Accordingly, the present disclosure includes any possible enantiomers, diastereomers, racemic mixtures, or mixtures thereof of the compounds of the present disclosure that are bioactive in the treatment of NASH.

[0158] A chiral center is generated at the α-carbon of the α-amino acid functional group of the compound of formula I. The compound of formula I is characterized by the (S) absolute configuration of the α-carbon of the α-amino acid functional group it contains, according to the Kahn-Ingold-Prelogue rule. [ka] As exemplified by compound (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid (compound (1)), which is a compound of formula I. [ka] (1) (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid

[0159] According to several embodiments, the compound of formula I is an isolated (S) optical isomer with respect to the stereochemistry around the α-carbon of the α-amino acid functional group contained therein. “Isolated optical isomer” means a compound that has been substantially purified from the corresponding optical isomer of the same formula. In several embodiments, the isolated isomer is at least about 80%, at least 85%, at least 90%, at least 95%, at least 98%, and at least about 99% pure by weight, with the remainder being the corresponding (R) enantiomer. In several embodiments, the isolated (S) enantiomer does not contain the corresponding (R) enantiomer except for a small amount of (R) enantiomer.

[0160] Pharmaceutically acceptable salts Compounds of formula I may take the form of salts when appropriately substituted with groups or atoms capable of forming salts. Such groups or atoms are known to those skilled in the art of organic chemistry. The term “salt” encompasses addition salts of free acids or free bases that are compounds of the present disclosure. The term “pharmaceutically acceptable salt” refers to a salt that has a toxicity profile within a range that provides usefulness in pharmaceutical applications. Pharmaceutically unacceptable salts may have properties such as high crystallinity, but may still be useful in the implementation of the present disclosure, for example, in the processes of synthesis, purification, or formulation of the compounds of the present invention.

[0161] Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids may be selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carbocyclic, and sulfonic acid groups, and examples include formic acid, acetic acid, pivalic acid, propionic acid, furic acid, mucoic acid, isethionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, and anthracite. Examples of acid addition salts include nilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, camphosulfonic acid, and galacturonic acid. Examples of pharmaceutically unacceptable acid addition salts include perchlorates and tetrafluoroborates.

[0162] In some embodiments, a suitable pharmaceutically acceptable salt is the hydrochloride salt of one of the compounds described herein (e.g., the hydrochloride salt of any one of compound (1), compound (2), and compound (3)). In some embodiments, the hydrochloride salt is a monochloride salt. In some embodiments, the hydrochloride salt is a dichloride salt. In some embodiments, the hydrochloride salt is a trichloride salt.

[0163] Suitable pharmaceutically acceptable base addition salts of the compounds of this disclosure include, for example, metal salts such as alkali metals, alkaline earth metals, and transition metals, such as calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts derived from basic amines such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, tromethamine, meglumine (N-methylglucamine), and procaine. Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanates.

[0164] All of these salts can be prepared by conventional means from the corresponding compounds of formula I, for example, by reacting the compound of formula I with a suitable acid or base. The salts may also be in crystalline form and can be prepared by crystallizing the salt from a suitable solvent. Those skilled in the art will know how to prepare and select the appropriate salt form, for example, as described in Handbook of Pharmaceutical Salts: Properties, Selection, and Use by PHStahl and CGWermuth (Wiley-VCH 2002).

[0165] Treatment method Non-alcoholic steatohepatitis (NASH) In one embodiment, the present invention is characterized by a method for treating non-alcoholic steatohepatitis (NASH), the method comprising administering an effective amount of the compound according to formula I, or a pharmaceutically acceptable salt thereof, to a subject in need. In another embodiment, the present invention is characterized by the compound according to formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of NASH in a subject. In yet another embodiment, the present invention is characterized by the compound according to formula I, or a pharmaceutically acceptable salt thereof, for the preparation of a drug for the treatment of NASH.

[0166] Non-alcoholic fatty liver disease (NAFLD), reflecting the obesity epidemic, has become one of the most prominent forms of chronic liver disease worldwide. Hepatic steatosis, or "fatty liver," is the accumulation of fat in the liver. Apart from NAFLD, non-alcoholic steatohepatitis (NASH) is a disorder characterized by substantial health risks. In addition to excess fat in the liver, NASH may be characterized by histological evidence of hepatitis and hepatocellular damage (ballooning), with or without fibrosis. Individuals diagnosed with NASH have a significantly increased risk of morbidity and death and require ongoing medication for the treatment of NASH.

[0167] More specifically, NASH can be characterized by an increased risk of cardiovascular and liver-related death. NASH can lead to cirrhosis, a condition in which the liver is permanently damaged and scarred. Cirrhosis results in fluid retention, muscle wasting, intestinal bleeding, and liver failure. Liver transplantation is the only treatment for advanced cirrhosis with liver failure. Transplants are increasingly performed in NASH patients. NASH is currently the second leading reason for liver transplantation, and it is very likely to become the leading reason in 10 years, as new antiviral drugs suppress hepatitis C, which is currently the leading cause of liver failure.

[0168] In several embodiments, NASH may be diagnosed by liver biopsy (e.g., histological evidence of steatosis, inflammation, and hepatocyte ballooning in the absence of other causes of liver disease or substantial alcohol consumption). For example, the NAFLD activity score (NAS) may be useful in identifying patients with NASH. See Kleiner et al, “Design and Validation of a Histological Scoring System for Nonalcoholic Fatty Liver Disease”, Hepatology, 41(6):1313-1321 (2005).

[0169] The NAS is the sum of separate scores for steatosis (0-3), hepatocyte ballooning (0-2), and lobular inflammation (0-3), with a maximum score of 8. The NAS score can be generated at the time of biopsy according to the criteria described above by Kleiner et al. See also Table 1. [Table 1]

[0170] In several embodiments, subjects are selected based on liver biopsies (e.g., liver biopsies used to determine the NAS score).

[0171] In multiple embodiments, subjects are selected based on NAS scores. In multiple embodiments, the presence of NASH is established by an NAS score of 4 or higher (i.e., an NAS score of 4 or higher). In multiple embodiments, the presence of NASH may be established by a liver biopsy revealing an NAS score of 5 or higher (i.e., an NAS score of 5 or higher).

[0172] In several embodiments, subjects are selected based on a NAS score determined before treatment.

[0173] In several embodiments, the presence of NASH is established by a pretreatment NAS score of 4 or higher (i.e., an NAS score of 4 or higher). In several embodiments, the presence of NASH may be established by a liver biopsy revealing a pretreatment NAS score of 5 or higher (i.e., an NAS score of 5 or higher).

[0174] In several embodiments, NASH may be characterized by a NAFLD activity score (NAS) of 5 or higher, where NAS is the sum of individual scores for steatosis (range: 0-3), hepatocyte ballooning (range: 0-2), and lobular inflammation (range: 0-3). See Kleiner et al. above. Steatosis is an abnormal retention of lipids in the liver. The steatosis score represents the percentage of hepatocytes containing lipid droplets (steatosis) as 0 (<5%), 1 (5-33%), 2 (33-66%), and 3 (>66%). Patients treated with NASH according to this disclosure may have an NAS steatosis score of 1, 2, or 3. Hepatocyte ballooning is a type of cell death visually characterized by hypertrophy and localization of the cell nucleus in or near the center of the cell. In several embodiments, hepatocyte ballooning is scored as 0 (none), 1 (few), or 2 (many cells with significant ballooning). In several embodiments, lobular inflammation is scored according to the number of inflammatory lesions: 0 (no lesions), 1 (less than 2 lesions / 200x field), and 2 (2 to 4 lesions / 200x field). In several embodiments, a subject has a lobular inflammation score of 0, 1, 2, or 3, and a ballooning score of 0, 1, or 2, provided that the sum of the lobular inflammation score and ballooning score is at least 2.

[0175] In several embodiments, the methods and uses described herein include improvement of the NAS score. In several embodiments, the improvement occurs without exacerbating fibrosis.

[0176] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or any pharmaceutically acceptable salt thereof results in a NAFLD activity score (NAS) of less than 4.

[0177] In several embodiments, the methods and uses described herein result in a reduction of at least one (≧1) in the NAS score of the subject.

[0178] In several embodiments, the methods and uses described herein result in a reduction of at least two (≧2) in the NAS score of the subject.

[0179] In several embodiments, the methods and uses described herein result in a reduction of at least three (≧3) in the NAS score of the subject.

[0180] In several embodiments, the methods and uses described herein result in a reduction of 1(1) to 3(3) in the liver steatosis score of the subject.

[0181] In several embodiments, the methods and uses described herein result in a one(1) or two(2) reduction in the hepatocyte ballooning score of the subject.

[0182] In several embodiments, the methods and uses described herein result in a reduction of 1(1) to 3(3) in the inflammation score of the lobular in question.

[0183] In some embodiments, the subject has a steatosis score of 1, 2, or 3.

[0184] In some embodiments, steatosis includes macrodriptric steatosis. In some embodiments, steatosis includes microfollicular steatosis. In some embodiments, steatosis includes macrodriptric and microfollicular steatosis.

[0185] In several embodiments, the methods and uses described herein result in the resolution of steatohepatitis without exacerbation of fibrosis in patients in need thereof. In several embodiments, the resolution includes the absence of hepatocyte ballooning (e.g., ballooning score 0), asymptosis or mild inflammation (e.g., ballooning score 0-1), and / or the presence or absence of steatosis (e.g., steatosis score 0-3).

[0186] In some embodiments, NASH is a fatty liver disease characterized by at least one of lobular inflammation and hepatocyte ballooning. In some embodiments, NASH occurs in the absence of other causes of liver disease and / or substantial alcohol consumption.

[0187] In some embodiments, the subject has hepatitis. In some embodiments, hepatitis is inflammation of the lobules.

[0188] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or a pharmaceutically acceptable salt thereof results in a reduction of hepatitis.

[0189] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or a pharmaceutically acceptable salt thereof results in a hepatitis score of 0 or 1 (e.g., as described herein).

[0190] In several embodiments, the target liver is characterized by hepatocyte ballooning.

[0191] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or a pharmaceutically acceptable salt thereof results in a reduction of hepatocyte ballooning.

[0192] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or a pharmaceutically acceptable salt thereof results in a ballooning score of 0.

[0193] In several embodiments, treatment is initiated independently of determining the NAS score.

[0194] In several embodiments, subjects are selected based on a surrogate marker in parallel with a histological assessment of the NAS score (e.g., a biomarker).

[0195] In several embodiments, the methods and uses described herein result in improvement at least at two points in NAS without exacerbation of fibrosis in patients requiring it.

[0196] In some embodiments, the subject has liver fibrosis.

[0197] In several embodiments, fibrosis is scored / staged on a scale of 0 to 4 (Table 2). [Table 2]

[0198] In some embodiments, the subject has non-cirrhotic NASH.

[0199] In some embodiments, the subject has cirrhosis and NASH.

[0200] In several embodiments, the subject has a fibrosis stage score of 0 to 3. In several embodiments, the subject has a fibrosis stage score of 0. In several embodiments, the subject has a fibrosis stage score of 1. In several embodiments, the subject has a fibrosis stage score of 2. In several embodiments, the subject has a fibrosis stage score of 3. In several embodiments, the subject has a fibrosis stage score of 4 (cirrhosis). In several embodiments, the patient after treatment may have a fibrosis stage score that is at least no worse than the baseline score before treatment, or may have a reduction of at least one level, or at least two or three levels, in the fibrosis stage score.

[0201] In several embodiments, the methods and uses described herein do not result in an increase in the liver fibrosis score of the subject (stabilization of the liver fibrosis of the subject).

[0202] In several embodiments, the methods and uses described herein result in a reduction of at least one (≧1) in the liver fibrosis score of the subject (reversal of liver fibrosis of the subject).

[0203] In several embodiments, hepatic fibrosis is characterized using an enhanced hepatic fibrosis test (ELF) score. In several embodiments, hepatic fibrosis is characterized by an ELF score less than 7.7. In several embodiments, hepatic fibrosis is characterized by an ELF score greater than or equal to 7.7 and less than 9.8. In several embodiments, hepatic fibrosis is characterized by an ELF score greater than 9.8.

[0204] In several embodiments, the methods and uses described herein result in maintenance (no exacerbation) of the fibrotic stage in patients who require it.

[0205] In several embodiments, the methods and uses described herein result in regression of fibrosis in patients who require it.

[0206] In several embodiments, the methods and uses described herein result in a reduction of hepatomegaly in the subject.

[0207] In several embodiments, the methods and uses described herein result in a decrease in liver collagen levels in the subject.

[0208] In several embodiments, the methods and uses described herein result in a decrease in alpha-smooth muscle actin (α-SMA) levels in the target liver tissue.

[0209] In several embodiments, the methods and uses described herein result in a reduction of hepatocyte apoptosis in the subject.

[0210] In several embodiments, the methods and uses described herein result in a decrease in hyaluronic acid levels in the subject.

[0211] In several embodiments, the methods and uses described herein result in a reduction in the tissue inhibitor (TIMP-1) levels of the metalloproteinase in question.

[0212] In several embodiments, the methods and uses described herein result in a reduction of the target procollagen III-terminal peptide (PIIINP) level.

[0213] In several embodiments, the methods and uses described herein result in a reduction of the soluble Fas ligand level of the subject.

[0214] In several embodiments, the methods and uses described herein result in a reduction of the leptin level in question.

[0215] In several embodiments, the methods and uses described herein result in a reduction of the target aspartate aminotransferase (AST) versus platelet index (APRI).

[0216] In several embodiments, the methods and uses described herein result in a reduction in the subject's fibrosis 4 (FIB-4) score.

[0217] In several embodiments, the methods and uses described herein result in a reduction of liver stiffness in the subject.

[0218] In several embodiments, the methods and uses described herein result in an increase in the adiponectin levels of the subject.

[0219] Serum markers and biomarkers In several embodiments, any of the methods and uses described herein result in changes in serum markers (e.g., serum markers for hepatic pathologies such as hepatic fibrosis or NASH) in patients who require them. Thus, in several embodiments, patients are selected based on specific expression levels of serum markers (including any of those described herein). For example, the methods described herein may be particularly beneficial to patients with specific (e.g., threshold) levels of serum markers (e.g., any of those described herein). Furthermore, the methods described herein can result in desirable changes in serum markers (e.g., modulating levels of any of the serum markers described herein). In several embodiments, the methods described herein can result in a decrease in elevated serum markers (e.g., any of those described herein).

[0220] For example, non-invasive measurement of fibrosis to monitor treatment effectiveness may be useful in avoiding the need for repeated liver biopsies (e.g., to identify patients who may benefit from the methods described herein, including patients with any of the liver pathologies described herein, such as NASH). In several embodiments, the serum marker is FIB-4. In several embodiments, the serum marker is APRI. The APRI and FIB-4 scores are calculated by the following published formula (Kim et al., Hepatology 2013, 57:1357), where "PLT count" is platelet count, "AST" is aspartate transaminase with an upper limit of 40 IU / mL, and "ALT" is alanine aminotransferase. APRI=([AST / normal upper limit] / PLT number[109 / L]) FIB-4 = (Age [years] × AST [IU / L]) / (PLT [10⁹ / L] × (ALT [IU / L]) 1 / 2).

[0221] Therefore, exemplary serum markers include enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or gamma-glutamyltransferase (GGT), or any combination thereof. In some embodiments, the patient has at least one elevated liver enzyme.

[0222] Other exemplary serum markers include total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, bilirubin, albumin, C-peptide, apolipoprotein A1, apolipoprotein B, leptin, adiponectin, free fatty acids, ghrelin, and tumor necrosis factor alpha (TNF-α).

[0223] In several embodiments, the liver alanine aminotransferase (ALT) levels of the subjects increased. In several embodiments, the method and use described herein result in a decrease in liver alanine aminotransferase (ALT) levels. In several embodiments, the subjects have ALT levels that fall within normal levels (e.g., about 10–40 IU / L). In several embodiments, the subjects have ALT levels greater than about 40 IU / L. In several embodiments, ALT does not exceed about 30 IU / L (e.g., in male patients). In several embodiments, ALT exceeds about 30 IU / L (e.g., in male patients). In several embodiments, ALT does not exceed about 19 IU / L (e.g., in female patients). In several embodiments, ALT exceeds about 19 IU / L (e.g., in female patients).

[0224] In several embodiments, the liver aspartate aminotransferase (AST) levels of the subjects increased. In several embodiments, the subjects had AST levels that fell within the normal range (e.g., about 10–35 IU / L). In several embodiments, the subjects had AST levels greater than about 30 IU / L. In several embodiments, the subjects had AST levels greater than about 35 IU / L. In several embodiments, the methods and uses described herein resulted in a decrease in liver aspartate aminotransferase (AST) levels.

[0225] In several embodiments, the ratio of aspartate aminotransferase (AST) to alanine aminotransferase (AST) is determined. In several embodiments, the patient has an AST / ALT ratio greater than 1. In several embodiments, the patient has an AST / ALT ratio less than 1.

[0226] In several embodiments, the methods and uses described herein result in a reduction of the aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio of the subject.

[0227] In several embodiments, the methods and uses described herein result in a change such that the ratio of the aspartate aminotransferase (AST) to alanine aminotransferase (ALT) in question approaches 1.

[0228] In several embodiments, the subject has elevated alkaline phosphatase (ALP) levels. In several embodiments, the subject has ALP levels that fall within the normal range (e.g., about 20–140 or about 37–116 IU / L). In several embodiments, the subject has ALP levels exceeding about 120 IU / L or about 140 IU / L. In several embodiments, the subject has ALP levels exceeding about 150 IU / L. In several embodiments, the method and use described herein results in a decrease in alkaline phosphatase (ALP) levels.

[0229] In several embodiments, the subject has elevated gamma-glutamyltransferase (GGT) levels. In several embodiments, the subject has GGT levels that fall within the normal range (e.g., about 5–30 IU / L or about 9–48 IU / L). In several embodiments, the subject has GGT. In several embodiments, the subject has elevated GGT levels of at least about 50 IU / L. The GGT levels are at most about 90 IU / L or about 100 IU / L. In several embodiments, the methods and uses described herein result in a reduction of GGT levels.

[0230] In several embodiments, the subject has an increase in triglyceride levels. In several embodiments, the method and use described herein results in a decrease in triglyceride levels.

[0231] In several embodiments, the subject has an increase in non-esterified fatty acid (NEFA) levels. In several embodiments, the method and use described herein results in a decrease in non-esterified fatty acid (NEFA) levels.

[0232] In some embodiments, the subject has elevated cholesterol levels. In some embodiments, the methods and uses described herein result in a decrease in cholesterol levels.

[0233] In several embodiments, the subjects have reduced HDL cholesterol levels.

[0234] hepatitis In one embodiment, the present invention is characterized by a method for treating (e.g., alleviating) hepatitis, the method comprising administering an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0235] In several embodiments, hepatitis is inflammation of the lobules.

[0236] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or a pharmaceutically acceptable salt thereof results in a hepatitis score of 0 or 1.

[0237] In several embodiments, the subject has non-alcoholic steatohepatitis (NASH).

[0238] In several embodiments, the compound of formula I is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid (compound (1)) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula (I) is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid dihydrochloride (compound (1), dihydrochloride).

[0239] In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid (compound (2)), or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid trihydrochloride (compound (2), trihydrochloride).

[0240] In several embodiments, the compound of formula I is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid (compound (3)), or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula I is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid trihydrochloride (compound (3), trihydrochloride).

[0241] Hepatocyte ballooning In one embodiment, the present invention is characterized by a method for treating (e.g., reducing) hepatocyte ballooning, the method comprising administering an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0242] Hepatocyte ballooning is a type of cell death visually characterized by the enlargement and localization of the cell nucleus in or near the center of the cell.

[0243] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or a pharmaceutically acceptable salt thereof results in a ballooning score of 0.

[0244] In several embodiments, the subject has non-alcoholic steatohepatitis (NASH).

[0245] In several embodiments, the compound of formula I is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid (compound (1)) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula (I) is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid dihydrochloride (compound (1), dihydrochloride).

[0246] In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid (compound (2)), or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid trihydrochloride (compound (2), trihydrochloride).

[0247] In several embodiments, the compound of formula I is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid (compound (3)), or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula I is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid trihydrochloride (compound (3), trihydrochloride).

[0248] Liver fibrosis (including cirrhosis) In one embodiment, the present invention is characterized by a method for treating hepatic fibrosis, the method comprising administering an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0249] In some embodiments, the subject has stage 2, stage 3, or stage 4 liver fibrosis.

[0250] In several embodiments, the subject has cirrhosis (stage 4 hepatic fibrosis).

[0251] In some embodiments, the subject has one or more fibrosis stage scores.

[0252] In some embodiments, the subjects have a fibrosis stage score of 0 to 3.

[0253] In multiple embodiments, the subject has a fibrosis stage score of 0. In multiple embodiments, the subject has a fibrosis stage score of 1. In multiple embodiments, the subject has a fibrosis stage score of 2. In multiple embodiments, the subject has a fibrosis stage score of 3. In multiple embodiments, the subject has a fibrosis stage score of 4 (cirrhosis).

[0254] In several embodiments, post-treatment patients may have a fibrosis stage score that is at least no worse than their baseline score before treatment, or they may have a reduction in their fibrosis stage score by at least one level, or at least two or three levels.

[0255] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or a pharmaceutically acceptable salt thereof results in stabilization of liver fibrosis in the subject.

[0256] In several embodiments, administration of a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)) or a pharmaceutically acceptable salt thereof results in a reversal of hepatic fibrosis in a subject.

[0257] In several embodiments, the subject has non-alcoholic steatohepatitis (NASH).

[0258] In several embodiments, the compound of formula I is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid (compound (1)) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula (I) is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid dihydrochloride (compound (1), dihydrochloride).

[0259] In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid (compound (2)), or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid trihydrochloride (compound (2), trihydrochloride).

[0260] In several embodiments, the compound of formula I is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid (compound (3)), or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula I is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid trihydrochloride (compound (3), trihydrochloride).

[0261] Steroid disease In one embodiment, the present invention is characterized by a method for treating lipopathy, the method comprising administering an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0262] In several embodiments, administration of the compound of formula I or a pharmaceutically acceptable salt thereof results in a reduction of steatosis in subjects.

[0263] In some embodiments, steatosis includes macrodriptric steatosis. In some embodiments, steatosis includes microfollicular steatosis. In some embodiments, steatosis includes macrodriptric and microfollicular steatosis.

[0264] In several embodiments, the subject has non-alcoholic steatohepatitis (NASH).

[0265] In several embodiments, the compound of formula I is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid (compound (1)) or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula (I) is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid dihydrochloride (compound (1), dihydrochloride).

[0266] In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid (compound (2)), or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula I is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid trihydrochloride (compound (2), trihydrochloride).

[0267] In several embodiments, the compound of formula I is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid (compound (3)), or a pharmaceutically acceptable salt thereof. In several embodiments, the compound of formula I is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid trihydrochloride (compound (3), trihydrochloride).

[0268] Comorbidities The methods described herein may be useful for treating subjects with comorbidities.

[0269] In several embodiments, the subject is prediabetic.

[0270] In some embodiments, the subject is diabetes. In some embodiments, the subject has type 2 diabetes.

[0271] In some embodiments, the subject is not diabetic. In some embodiments, the subject does not have type 2 diabetes.

[0272] In several embodiments, the subject is obese. In several embodiments, the subject is not obese. In several embodiments, the subject has a body mass index (BMI) greater than 30. In several embodiments, the subject has a BMI less than 30. In several embodiments, the subject has a BMI less than 25.

[0273] In multiple embodiments, the subject has dyslipidemia. In multiple embodiments, the subject does not have dyslipidemia.

[0274] In some embodiments, the subject has hypertension. In some embodiments, the subject does not have hypertension.

[0275] In several embodiments, the subject is insulin-resistant. In several embodiments, the subject is not insulin-resistant.

[0276] In some embodiments, the subject has cardiovascular disease. In some embodiments, the subject is at risk of cardiovascular disease. In some embodiments, the subject does not have cardiovascular disease.

[0277] Pharmaceutical composition In another embodiment, the present invention features a pharmaceutical composition comprising a compound according to formula I (e.g., any of compounds (1), (2), and (3)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. "pharmaceutically acceptable carrier" means any carrier, diluent, or excipient that is compatible with the other components of the formulation and is not harmful to the recipient.

[0278] In some embodiments of the methods and uses described herein, the compounds may be administered in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier.

[0279] The activator can be formulated into dosage forms according to standard practices in the pharmaceutical field. See Alphonso Gennaro, ed., Remington's Pharmaceutical Sciences, 18th Edition (1990), Mack Publishing Co., Easton, PA. Appropriate dosage forms may include, for example, tablets, capsules, solutions, parenteral solutions, lozenges, suppositories, or suspensions.

[0280] Compounds of formula I may be administered by simple methods. Suitable local routes include oral, rectal, inhalation (including nasal), topical (including buccal and sublingual), percutaneous, and vaginal, for example, via the epidermis. Compounds of formula I can also be administered parenterally (including subcutaneous, intravenous, intramuscular, intradermal, intra-arterial, subarachnoid, and epidural). It will be evident that the chosen route may vary, for example, depending on the recipient's condition.

[0281] For parenteral administration, the activator may be mixed with a suitable carrier or diluent such as water, oil (especially vegetable oil), ethanol, physiological saline solution, aqueous dextrose (glucose) and related sugar solution, glycerol, or glycol such as propylene glycol or polyethylene glycol. The parenteral administration solution may contain a water-soluble salt of the activator. Stabilizers, antioxidants, and preservatives may also be added. Suitable antioxidants include sulfites, ascorbic acid, citric acid and their salts, and sodium EDTA. Suitable preservatives include benzalkonium chloride, methylparaben or propylparaben, and chlorbutanol. The parenteral administration composition may take the form of an aqueous solution, a non-aqueous solution, a dispersion, a suspension, or an emulsion.

[0282] In some embodiments, a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)), or any pharmaceutically acceptable salt thereof, is administered orally to a subject.

[0283] For oral administration, the activator may be combined with one or more solid inert components for the preparation of tablets, capsules, pills, powders, granules, or other suitable oral dosage forms. For example, the activator may be combined with at least one excipient such as a filler, binder, humectant, disintegrant, dissolution retarder, absorption enhancer, wetting agent, absorbent, or lubricant. According to an embodiment of a single tablet, the activator may be combined with carboxymethylcellulose (CMC) calcium, magnesium stearate, mannitol, and starch, and then formed into a tablet by a conventional tablet-forming method.

[0284] Furthermore, the pharmaceutical compositions of this disclosure may be formulated to delay or control the release of the active ingredients contained therein using various proportions of hydroxypropylmethylcellulose, other polymer substrates, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes and / or microspheres to provide a desired release profile.

[0285] Generally, controlled-release formulations are pharmaceutical compositions that release the active ingredient at the required rate and maintain a constant pharmacological activity for a desired period. Such dosage forms provide a supply of the drug to the body over a predetermined period and therefore maintain drug levels within the therapeutic range for a longer period than conventional uncontrolled formulations.

[0286] U.S. Patent No. 5,674,533 discloses a controlled-release pharmaceutical composition in liquid dosage form for the administration of moguisteine, a potent peripheral cough suppressant. U.S. Patent No. 5,059,595 describes controlled release of an activator by the use of a gastric acid-resistant tablet in relation to the treatment of organic mental disorders. U.S. Patent No. 5,591,767 describes a liquid-stored transdermal patch for controlled release. U.S. Patent No. 5,120,548 discloses a controlled-release drug delivery device composed of a swellable polymer. U.S. Patent No. 5,073,543 describes a controlled-release formulation containing nutrients encapsulated in a ganglioside-liposome vehicle. U.S. Patent No. 5,639,476 discloses a stable solid controlled-release formulation having a coating derived from an aqueous dispersion of a hydrophobic acrylic polymer. Biodegradable microparticles are known to have applications in controlled-release formulations. U.S. Patent No. 5,733,566 describes the use of polymer microparticles that release an antiparasitic composition.

[0287] The controlled release of active ingredients can be stimulated by various inducers, such as pH, temperature, enzymes, water, or other physiological conditions or compounds. Various drug release mechanisms exist. For example, in one embodiment, a controlled release component may swell after administration to a patient, forming a porous opening large enough to release the active ingredient. In the context of this disclosure, the term “controlled release component” is defined herein as a compound, such as a polymer, polymer substrate, gel, permeable membrane, liposome, and / or microsphere, that facilitates the controlled release of an active ingredient in a pharmaceutical composition. In another embodiment, the controlled release component is biodegradable and is induced by exposure to an aqueous environment, pH, temperature, or enzymes in the body. In another embodiment, a sol-gel may be used, in which case the active ingredient is incorporated into a sol-gel substrate that is solid at room temperature. This substrate is implanted into a patient, for example, a mammal with a body temperature high enough to induce gel formation of the sol-gel substrate, thereby releasing the active ingredient into the patient.

[0288] The components used in the formulation of pharmaceutical compositions are of high purity and substantially free of potentially harmful contaminants (e.g., at least national food grade, generally at least analytical grade, and more typically at least pharmaceutical grade). Particularly with regard to human consumption, the compositions may be manufactured or formulated under Good Manufacturing Practice standards as defined by applicable regulations of the U.S. Food and Drug Administration. For example, a suitable formulation may be sterile and / or substantially isotonic and / or fully compliant with all U.S. Food and Drug Administration Good Manufacturing Practice standards.

[0289] Dosage and administration regimen The physician determines the most appropriate dosage of the active ingredient. The dosage varies depending on the form of administration and the specific compound selected. Furthermore, the dosage may vary depending on various factors, including, but not limited to, the patient being treated, the patient's age, the severity of the condition being treated, and the route of administration. Physicians generally prefer to start treatment with a much lower dose than the optimal dose of the compound and gradually increase the dose until the optimal effect is achieved under those circumstances. In many cases, it turns out that when a composition is administered orally, a larger amount of the active ingredient is needed to achieve the same effect as when administered parenterally in small doses. The compound is useful in the same way as comparable therapeutic agents, and the dosage levels are the same as those commonly used with other therapeutic agents.

[0290] For example, the daily dose is approximately 2 mg / kg / day to approximately 1000 mg / kg / day, approximately 10 mg / kg / day to approximately 1000 mg / kg / day, or approximately 10 mg / kg / day to approximately 100 mg / kg / day. In multiple embodiments, the daily dose is approximately 2 mg / kg / day to approximately 1000 mg / kg / day. In multiple embodiments, the daily dose is approximately 10 mg / kg / day to approximately 1000 mg / kg / day. In multiple embodiments, the daily dose is approximately 10 mg / kg / day to approximately 100 mg / kg / day.

[0291] In several embodiments, a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)), or any pharmaceutically acceptable salt thereof, is administered to a subject (e.g., a human) at a dose of approximately 2 to 1000, 10 to 1000, or 10 to 100 mg / kg per day. In several embodiments, the dose is approximately 10 to 1000 mg / kg / day. In several embodiments, the dose is approximately 10 to 1000 mg / kg / day.

[0292] In some embodiments, a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)), or any pharmaceutically acceptable salt thereof, is administered to a subject (e.g., a human) at a total daily dose of approximately 10 mg / kg or more per day. In some embodiments, a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)), or any pharmaceutically acceptable salt thereof, is administered to a subject (e.g., a human) at a total daily dose of approximately 2 mg / kg or more per day.

[0293] In several embodiments, a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)), or any pharmaceutically acceptable salt thereof, is administered to a subject (e.g., a human) in a total daily dose of approximately 100–5000, 500–5000, or 600–3000 mg per day. In several embodiments, the total daily dose is approximately 500–5000 mg / day. In several embodiments, the total daily dose is approximately 600–3000 mg / day.

[0294] Treatment may be carried out over a long period, either in a single continuous period or in separate periods, as needed. In some embodiments, the subject receives treatment.

[0295] In some embodiments, a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)), or any pharmaceutically acceptable salt thereof, is administered to a subject (e.g., a human) for at least about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 16 weeks.

[0296] In several embodiments, a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)), or any pharmaceutically acceptable salt thereof, is administered to a subject (e.g., a human) for at least 14 weeks.

[0297] In some embodiments, a compound of formula I (e.g., any one of compound (1), compound (2), and compound (3)), or any pharmaceutically acceptable salt thereof, is administered to a subject (e.g., a human) for at least about 4–6, 4–8, 4–10, 4–12, 4–14, or 4–16 weeks.

[0298] The practice of this disclosure is illustrated by the following non-limiting embodiments. [Examples]

[0299] In the following examples, all protocols were approved by the Animal Care Committee (IACUC). All measures were taken to ensure the welfare, safety, health, and comfort of the animals and to minimize stress and pain. Procedures such as autopsies were carried out using euthanasia protocols approved by the IACUC.

[0300] Example 1 - APL and glucose tolerance in a rodent model of NASH This experiment was designed to determine the effect of (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid (APL) on impaired glucose tolerance (IGT) in models of NASH recognized in the art. The following rodent models were used: Zucker fa / fa obese rats and Zucker Fa / fa lean rats, as well as C57BL / 6J mice. C57BL / 6J mice are a diet-induced obesity (DIO) model, and these mice are highly sensitive to obesity-inducing diets and are prone to developing diet-induced hepatic necrotizing inflammation and fibrosis. See, for example, Liang et al, 2014, PLoS One, 9(12):e115922; and London & George, 2007, Clinics in Liver Disease, 11(1):55-74.

[0301] Zucker fa / fa obese rats and Zucker fa / fa lean rats (7-week-old male animals obtained from Charles Rivers Laboratories in Wilmington, Massachusetts, USA) were housed in individual cages (one rat per cage to promote sedentary activity) and given free access to standard rodent solid feed (catalog number 5053, obtained from Labdiet in St. Louis, Missouri) and water (filtered and filled using a Hydrapak system) for 7 days prior to the start of the experiment. The Zucker fa / fa obese rats were randomly assigned to two groups: 1) vehicle pobid (oral administration, twice daily) for 78 days (n=7), and 2) 100 mg / kg (mg / kg) body weight APL (pobid) for 78 days (n=8). The Zucker fa / fa lean rats (n=4) were administered vehicle (pobid) for 78 days. Phosphate-buffered saline (PBS), the solution used to dissolve APL, was used as the vehicle solution. APL powder was dissolved in PBS at a concentration of 100 mg / mL under sterile conditions, and the volume was adjusted according to the body weight of each animal. The animals had free access to food and water, except during the glucose tolerance test (GTT) procedure.

[0302] C57BL / 6J mice (5-week-old male mice obtained from Jackson Laboratories in Bar Harbor, Maine, USA) were housed in cages (5 mice per cage) and given free access to standard rodent solid feed (catalog number 5053, obtained from Labdiet in St. Louis, Missouri) and water (filtered and filled using a Hydrapak system) for 5 days prior to the start of the experiment. The animals were then randomly assigned to five groups (n=5 in each group) and given different diets and treatments for 130 days as shown in Table A. Each treatment was administered orally twice daily. The APL dose administered to each animal was 200 milligrams per kilogram of body weight in two divided doses by forced oral administration, and the pioglitazone dose administered to each animal was 20 milligrams per kilogram of body weight in two divided doses by forced oral administration. "HFD" is a high-fat / high-fructose diet containing 58% fat, 25% carbohydrates, and 17% protein. HFD was obtained from Research Diets, Inc. "Solid feed" refers to standard rodent solid feed (catalog number 5053, obtained from Labdiet, St. Louis, Missouri). Animals were free-feeding except during the GTT experiment. [Table 3]

[0303] At the end of the experimental period (78 days for rats and 130 days for mice), the animals were subjected to a glucose tolerance test (GTT) as follows: The animals were fasted for 5 hours, their body weight was measured, and their tails were removed to measure their fasting blood glucose levels. Immediately afterward, glucose (2 mg / g body weight) was administered orally. Glucose levels were measured at 0, 15, 30, 45, 60, and 120 minutes after glucose administration. Glucose was measured using an Abbott AlphaTRAK 2 blood glucose meter.

[0304] The area under the curve (AUC) of glucose tolerance test data was calculated. These data are shown in Figures 1 and 2. Figure 1 shows the rat data. The AUC of the GTT was significantly higher in all obese rats treated with the vehicle compared to control rats. The AUC of the GTT in obese rats treated with APL was significantly lower than in obese rats treated with the vehicle (**p<0.01). In mice, the GTT was performed at the beginning of week 18 (130 days). Figure 2 shows the mouse data. Figure 2A shows the GTT data over time. Significant statistical differences were observed between the positive control group and the treatment group at 15 minutes (****p<0.0001), 60 minutes (*p<0.05), and 120 minutes (***p<0.001). Significant statistical differences were observed between the negative and positive control groups at 0 and 30 minutes (*p<0.05), 45 minutes (**p<0.01), and 15, 30, 60, and 120 minutes (****p<0.0001). There were no significant differences between the negative control group and the treatment group at any of these time points. Figure 2B shows the combined AUC data. Mice fed an HFD diet and treated with vehicle solution had significantly higher GTT AUCs (**p<0.01) compared to both control mice (fed solid feed and treated with vehicle solution) and mice fed HFD and treated with APL.

[0305] Impaired glucose tolerance (IGT) and diabetes mellitus are significant comorbidities of NASH. These data demonstrate that APL statistically significantly improves IGT in both rat and mouse NASH models.

[0306] Example 2 - APL and hepatic steatohepatia in a high-fat / high-fructose rodent NASH model Similar to Example 1, C57BL / 6 mice (the same mouse samples as in Example 1) were housed in cages (5 mice per cage) and given free access to standard rodent solid feed (catalog number 5053, obtained from Labdiet, St. Louis, Missouri) and water (filtered and filled using a Hydrapak system) for 5 days. C57BL / 6J mice were fed either CHOW or a high-fat / high-fructose diet (HFD) and treated with either vehicle or APL orally twice daily (bid) for 18 weeks. The APL dose was 200 mg / kg (mg / kg) per day, with 100 mg / kg (mg / kg) of APL body weight administered twice daily (pobid). The animals were given free access. The animals were humanely euthanized, and their livers were removed for histological analysis. Liver samples were fixed in formalin for 48 hours and then processed into FFPE blocks. Slides were stained with hematoxylin and eosin (H&E), immunostained with BODIPY and DAPI, and lipid deposition and nucleus count were quantified using a confocal microscope. See, for example, Rico et al, 2007, J Cell Physiol, 211(2):504-12, and Daemen et al, 2016, Mol Metab, 5(3)153-63. The data are shown in Figures 3, 4, and 5.

[0307] Figures 3 and 4 show liver samples stained with hematoxylin and eosin (H&E). Figure 3 shows liver samples at 20x magnification. The leftmost column shows liver samples from mice given CHOW (negative control), the middle column shows liver samples from mice given HFD with vehicle (positive control), and the rightmost column shows liver samples from mice given HFD and treated with APL (treated). Figure 4 shows similar liver sections at 100x magnification. The leftmost column shows livers from the negative control group, the middle column shows livers from the positive control group, and the rightmost column shows livers from the treated group.

[0308] Liver sections from animals treated with APL showed less severe hepatocyte fat accumulation, inflammatory infiltration, and hepatocyte ballooning. These data demonstrate that APL improves characteristic liver damage associated with NASH.

[0309] Figure 5A shows multiple images of hematoxylin and eosin (H&E) staining of liver sections from C57BL / 6J mice fed either a CHOW or high-fat / high-fructose diet (HFD) and treated twice daily with either vehicle or APL. The left image in Figure 5A shows the normal anatomical structure of the liver observed in mice fed a CHOW diet. The normal anatomical structure is completely altered by fat accumulation (large white spots), showing the characteristic changes observed in non-alcoholic steatohepatitis (NASH) in mice fed HFD and treated with vehicle solution (Figure 5A, center image). In contrast, as shown in the right image in Figure 5A, mice fed HFD and treated with APL retained the normal anatomical structure of the liver.

[0310] Figure 5B illustrates multiple images of immunofluorescence staining using BODIPY and DAPI on liver sections from the same mouse, and Figure 5C shows quantification of nuclei from immunofluorescence slides stained with DAPI. Nucleic acid count quantification was performed using Harmony® 4.6 High-Content Imaging and Analysis Software from Operetta CLS® (PerkinElmer, Waltham, Massachusetts). HFD-treated mice had a statistically significantly lower number of nuclei compared to CHOW-treated mice or HFD-treated mice treated with APL (***p<0.001). These data indicate that APL improves the hepatocyte death (i.e., ballooning) pathogenesis of NASH.

[0311] Figure 5D is a plot of fat deposition evaluated using a confocal microscope. Measurements were performed in a 20x magnification field. More than 21 fields were analyzed from three different animals in each group: Chow-vehicle (number of fields = 26), HFD-vehicle (number of fields = 25), and HFD-APL (number of fields = 23). Fat deposition was calculated using indirect measurements with ImageJ (Schneider et al., 2012, Nature Methods 9(7):671-675). Fat deposition increased threefold in HFD / vehicle-treated mice compared to CHOW control mice and HFD / APL-treated mice (***p<0.001). These data demonstrate that APL reduces hepatic fat deposition and mitigates hepatic steatohepatism, both of which are characteristic of NASH.

[0312] Hepatocyte ballooning and steatosis are pathological features of NASH and indicate liver damage associated with this condition. These data suggest that APL significantly reduces these features and is effective in treating NASH.

[0313] Example 3 - APL and Non-Alcoholic Fatty Liver Disease Activity Score (NAS) in a High-Fat / High-Fructose Rodent NASH Model C57BL / 6J mice were housed in cages (5 mice per cage) and given free access to standard rodent solid feed (catalog number 5053, obtained from Labdiet, St. Louis, Missouri) and water (filtered and filled using a Hydrapak system) for 5 days prior to the start of the experiment. The animals were then randomly assigned to three groups (n=5 in each group) and given different diets and treatments for 130 days as shown in Table B. Each treatment was administered orally twice daily. The dose of APL was 200 mg / kg body weight. "HFD" refers to the high-fat / high-fructose diet described in Example 1. "Chow" refers to standard rodent solid feed as described in Example 1. The animals were given free access to these. [Table 4]

[0314] At the end of the study period, the animals were humanely euthanized, and their livers were removed for histological analysis. Liver samples were fixed in formalin for 48 hours and then processed into FFPE blocks. Slides were stained with hematoxylin and eosin (H&E). Figure 6A shows multiple images of hematoxylin and eosin (H&E) stained liver sections. These data demonstrate that APL attenuates morphological changes in the liver pathology of NASH. The positive control group showed increased macrodriplish and microvesicular steatosis (arrows 1 and 2, respectively). Furthermore, the positive control group showed advanced hypertrophy (i.e., ballooning) and inflammatory lesions (arrows 3 and 4, respectively).

[0315] Liver samples were evaluated for hepatic steatosis (lipidemia), inflammation, and hypertrophy according to the NAS scoring system. The NAS scoring is shown in Figure 6B. Compared to CHOW / vehicle-treated mice, the NAS scores of mice increased for all pathological parameters, including macrodrip steatosis, microfollicular steatosis, hepatomegaly, and inflammatory lesions. In particular, APL treatment showed a statistically significant improvement in all parameters (***p<0.001). Therefore, APL attenuates hepatic steatosis, hepatic inflammation, and hypertrophy, which are the respective pathological conditions of liver injury and NASH.

[0316] Figure 7 shows additional NASH activity score (NAS) data in the DIO mouse model of NASH. Figure 7A shows the total NAS of mice given CHOW and administered vehicle, mice given HFD and administered vehicle, mice given HFD, and mice treated with APL (200 mg / kg / day, divided into two doses). These data demonstrate that treatment with APL significantly reduces NAS (****p<0.0001). Figure 7B shows the NAS component scores for steatosis, lobular inflammation, and hepatic ballooning. Again, these data demonstrate that treatment with APL significantly reduces each component of NAS, including steatosis, lobular inflammation, and hepatic ballooning (****p<0.0001). Therefore, APL is effective in treating NASH by attenuating each feature of NASH (hepatic steatosis, hepatic inflammation, and hypertrophy), reducing total NAS.

[0317] Example 4 - APL and hepatic fibrosis in a rodent NASH model Zucker(fa / fa) obese rats and Zucker(Fa / fa) lean rats (7-week-old male animals obtained from Charles Rivers Laboratories in Wilmington, Massachusetts, USA) were housed in individual cages (one rat per cage to promote sedentary activity) and given free access to standard rodent solid feed (catalog number 5053, obtained from Labdiet in St. Louis, Missouri) and water (filtered and filled using a Hydrapak system) for 7 days prior to the start of the experiment. Zucker(fa / fa) obese rats were randomly assigned to two groups: 1) vehicle pobid (oral administration, twice daily) for 78 days, and 2) 100 mg / kg (mg / kg) body weight APL (pobid) for 78 days. Zucker(Fa / fa) lean rats served as the control. The APL dose was 100 mg / kg / day. The animals were given free access. The animals were humanely euthanized, and their livers were removed for histological analysis. Liver samples were fixed in formalin for 48 hours and then processed into FFPE blocks. Slides were stained with hematoxylin, eosin (H&E), and Mason trichrome.

[0318] The data is shown in Figure 8. Figure 8A is one of several photographs of hematoxylin and eosin-stained liver sections from Zucker rats. The image on the left is the liver from a control Zucker (Fa / fa) lean rat, showing normal liver morphology. The image in the middle is the liver from a Zucker (fa / fa) obese rat treated with vehicle, and the image on the right is the liver from a Zucker (fa / fa) obese rat treated with APL. This image clearly shows the significant changes in liver tissue due to fat accumulation in Zucker (Fa / fa) obese rats treated with vehicle (center image). In contrast, Zucker (Fa / fa) obese rats treated with APL maintain normal liver morphology (right image).

[0319] Figure 8B shows a Mason trichrome-stained liver section from the same Zucker rat as in Figure 8A. Figure 8C is a magnified view of one region in Figure 8B. In the magnified view of a vehicle-treated Zucker (Fa / fa) obese rat (center image), multiple blue-stained collagen fibers are clearly visible, whereas in the APL-treated Zucker (Fa / fa) obese rat (right image), blue staining is minimal. Therefore, APL attenuates the increase in liver collagen fibers.

[0320] These data indicate that APL attenuates hepatic fibrosis, a characteristic feature of liver injury associated with advanced and / or severe NASH. Therefore, APL attenuates the development of hepatic fibrosis and is effective in treating NASH.

[0321] Example 5 - APL and hepatic protein carbonyl in a rodent (rat) NASH model Numerous oxidative stress and antioxidant biomarkers, including 4-hydroxynonenal (4-HNE), are being studied for possible use in assessing the pathological state and progression of NASH. See, for example, Ore et al., 2019, Medicina (Kaunas) 55(2):26. Oxidative stress can directly or indirectly induce irreversible damage to proteins by forming reactive carbonyl groups, primarily aldehydes and ketones. The most common reactive aldehyde in the process of indirect carbonylation is 4-HNE. APL has a high affinity for 4-HNE and can prevent the harmful effects of 4-HNE on proteins, making it effective in reducing insulin resistance. See WO2018 / 049019 and U.S. Patent Application Publication 2019 / 0192462.

[0322] Liver samples from Zucker rats in Example 4 were stained with an anti-4HNE antibody from Abcam (rob. ab46545) for immunofluorescence analysis of the presence of 4-HNE. The data are shown in Figure 9. Figure 9A shows representative images of 4-HNE immunofluorescence liver sections from lean Zucker (Fa / fa) rats, Zucker (fa / fa) obese rats administered with vehicle, and Zucker (fa / fa) obese rats administered with both vehicle and APL. Figure 9B is a plot of 4HNE immunofluorescence intensity per unit tissue area, and Figure 9C is a plot of total tissue area. These data show that APL statistically significantly reduces protein carbonyl in the liver of Zucker (Fa / fa) obese rats compared to Zucker (Fa / fa) obese rats administered with vehicle, while maintaining total liver tissue area (***p<0.001). Cytotoxic lipids produced by 4-HNE and other products are known to be elevated in human NASH livers compared to healthy livers. See, for example, Serviddio et al., Uncoupling protein-2 (UCP2) induces mitochondrial proton leak and increases susceptibility of non-alcoholic steatohepatitis (NASH) liver to ischaemia-reperfusion injury. Gut. 2008 Jul;57(7):957-65. doi:10.1136 / gut.2007.147496. Epub 2008 Feb 28. This data suggests that 4-HNE plays a significant role in the pathogenesis of NASH. Furthermore, these data demonstrate that treatment with APL significantly reduces the presence of 4-HNE (***p<0.001). As disclosed herein, this reduction in 4-HNE and the improvement of NASH features such as steatosis, lobular inflammation, hepatocyte ballooning, and fibrosis demonstrate that reducing 4-HNE is an important therapeutic approach to attenuating NASH.

[0323] Example 6 - APL and hepatic protein carbonyl in a rodent (mouse) NASH model As described in Example 1, liver samples were prepared from C57BL / 6J mice treated with vehicle after being fed solid feed, C57BL / 6J mice treated with vehicle after being fed HFD, and C57BL / 6J mice treated with APL after being fed HFD. These samples were stained with Abcam's anti-4HNE antibody (catalog number ab46545) for immunofluorescence analysis to check for the presence of 4-HNE. The dose, frequency, and duration of treatment of APL were as described in Example 1 (the dose of APL administered to each animal was 200 milligrams per kilogram of body weight, administered orally in two divided doses per day; the treatment period was 130 days; the animals were ad libitum). The data are shown in Figure 10. Figure 10A shows representative images of 4-HNE immunofluorescence liver sections from C57BL / 6J mice treated with vehicle after being fed solid diet, and C57BL / 6J mice treated with either vehicle or APL(TB-019) after being fed HFD, magnified 20x or 63x. Figure 10B is a plot of 4-HNE immunofluorescence intensity per unit tissue area. These data show that APL(TB-019) statistically significantly reduced protein carbonylation in the liver of HFD-fed C57BL / 6J mice compared to C57BL / 6J mice given vehicle after being fed HFD (***p<0.001). As disclosed herein, this reduction in protein carbonylation, and the improvement of NASH features such as steatosis, lobular inflammation, hepatocyte ballooning, and fibrosis, demonstrate that reduction of 4-HNE is an important therapeutic approach to attenuate NASH.

[0324] The pathophysiological mechanism of NASH involves an increase in free fatty acids in hepatocytes, which subsequently leads to an increase in lipotoxic lipids, including 4-hydroxynonenal (4-HNE). Without being bound by theory, the mechanism of APL's efficacy in treating NASH is thought to be based on APL's high affinity for 4-HNE, which reduces or prevents the harmful effects of 4-HNE on hepatocyte proteins, including carbonylation.

[0325] Example 7 - Serum biomarkers for APL and liver function in a diet-induced mouse model C57BL / 6 mice were housed in cages and given free access to standard rodent solid feed (catalog number 5053, obtained from Labdiet, St. Louis, Missouri) and water. C57BL / 6J mice were fed either CHOW (negative control) or an amylin liver NASH (AMLN) diet (58% high-fat, 25% carbohydrate, 2% cholesterol) for 20 weeks. After 20 weeks, animals fed the AMLN diet were switched to HFD. At 50 weeks, animals were treated twice daily (bid) with either vehicle (positive control) or APL (treatment). The APL dose was 50, 100, or 200 milligrams (mg / kg) per kilogram per day, administered in two doses (i.e., 25 mg / kg twice daily, 50 mg / kg twice daily, or 100 mg / kg twice daily). After 66 weeks, serum samples were collected and assayed for ALT, AST, APL, triglycerides, unesterified fatty acids, and cholesterol. All treatment groups received 50 mg / kg / day, except for the cholesterol test group which received 200 mg / kg / day. These results are summarized in Figure 11. Animals treated with APL showed significant reductions in ALT, AST, ALP, triglycerides, unesterified fatty acids, and cholesterol compared to the positive control group (*p<0.02; **p=0.002; ***p=0.0008, and ****p<0.0001). Results regarding the reduction of NAS and hepatic fibrosis are summarized in Figure 12. Animals treated with APL showed significant reductions in NAS (***p<0.001) and hepatic fibrosis (****p<0.0001). This data shows that APL attenuates NAS, serum liver function biomarkers, and fibrosis, and is therefore effective in treating NASH.

[0326] Each patent, patent application, GenBank record, and published disclosure cited herein is incorporated herein in its entirety by reference.

[0327] Although this embodiment has been described in detail with reference to the above-described examples, it will be understood that various modifications can be made without departing from the spirit of these embodiments and will be readily apparent to those skilled in the art. The appended claims are intended to be construed as including all such embodiments and variations thereof.

Claims

1. A method for treating non-alcoholic steatohepatitis (NASH), wherein the method involves administering a therapeutically effective amount of a compound according to formula I to a subject in need of the treatment. 【Chemistry 1】 (I) or administering a pharmaceutically acceptable salt thereof, in the formula, R 1 is hydrogen, -(C 1 -C 8 ) alkyl, -(C 1 -C 8 ) Alkenil, -(C 1 -C 8 ), alkynyl, unsubstituted or substituted - ara(C 1 -C 6 ), alkyl, unsubstituted or substituted - Heteroara (C 1 -C 6 ) Selected from the group consisting of alkyl, in the formula, the substituted ara (C 1 -C 6 ) alkyl and substituted heteroala (C 1 -C 6 ) The substituents on the alkyl group are halogen, -CN, -NO 2 , -NH 2 , -NH(C) 1 -C 6 ) alkyl, -N[(C 1 -C 6 )alkyl) 2 ,-OH, Halo (C 1 -C 6 ) alkyl, -(C 1 -C 6 ) Alkoxy, Halo (C 1 -C 6 ) Alkoxy, -SH, Thio(C 1 -C 6 ) alkyl, -SONH 2 , -SO 2 NH 2 , -SO- (C 1 -C 6 ) alkyl, -SO 2 - (C 1 -C 6 ) alkyl, - NHSO 2 (C 1 -C 6 ) alkyl and -NHSO 2 NH 2 Selected from the group consisting of; R 2 is hydrogen, -(C 1 -C 8 ) alkyl, -(C 1 -C 8 ) Alkenil, - (C 1 -C 8 ) Alkinyl, unsubstituted or substituted -ara (C 1 -C 6 ) alkyl, unsubstituted or substituted - Heteroara (C 1 -C 6 ) Selected from the group consisting of alkyl, in the formula, the substituted ara (C 1 -C 6 ) alkyl and substituted heteroala (C 1 -C 6 ) The substituents on the alkyl group are halogen, -CN, -NO 2 , -NH 2 ,-OH, Halo (C 1 -C 6 ) alkyl, -(C 1 -C 6 ) Alkoxy, Halo (C 1 -C 6 ) Alkoxy, -SH, Thio(C 1 -C 6 ) alkyl, -SONH 2 , -SO 2 NH 2 , -SO- (C 1 -C 6 ) alkyl, -SO 2 - (C 1 -C 6 ) alkyl, -NHSO 2 (C 1 -C 6 ) alkyl and -NHSO 2 NH 2 Selected from the group consisting of; R 3 、 R 4 、 R 7 、 R 8 、 R 9 、 R 10 、 R 13 、 and R 14 are independently selected from the group consisting of hydrogen and -(C 1 -C 6 ) alkyl; R 5 and R 6 Independently, hydrogen, -(C 1 -C 6 ) alkyl, and selected from the group consisting of -OH, provided that both R 5 and R 6 cannot be -OH; R 11 and R 12 Independently, hydrogen, - (C 1 -C 6 ) Selected from the group consisting of alkyl and -OH, however R 11 and R 12 Both cannot be -OH; m is 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; o is 0, 1, 2, 3, or 4; p is 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; A method in which r is 0, 1, 2, 3, or 4.

2. The aforementioned compound is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid, 【Chemistry 2】 （１）、 The method according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The method according to claim 2, wherein the compound is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid dihydrochloride. 【Transformation 3】

4. The aforementioned compound is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid, 【Chemistry 4】 （２）、 The method according to claim 1, or a pharmaceutically acceptable salt thereof.

5. The method according to claim 4, wherein the compound is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid trihydrochloride. 【Transformation 5】

6. The aforementioned compound is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid, 【Transformation 6】 （３）、 The method according to claim 1, or a pharmaceutically acceptable salt thereof.

7. The method according to claim 6, wherein the compound is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid trihydrochloride. 【Transformation 7】

8. The method according to any one of claims 1 to 7, wherein the subject is a human.

9. The method according to any one of claims 1 to 8, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to a subject for a period of at least about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks.

10. The method according to any one of claims 1 to 8, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to a subject for a period of at least about 4 to 6, 4 to 8, 4 to 10, 4 to 12, 4 to 14, or 4 to 16 weeks.

11. The method according to any one of claims 1 to 8, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to a subject at a dose of about 2 to 1,000, 10 to 1,000, or 10 to 100 mg / kg per day.

12. The method according to any one of claims 1 to 8, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of about 10 mg / kg or more per day.

13. The method according to any one of claims 1 to 8, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to a subject in a total daily dose of about 100 to 5000, 500 to 5000, or 600 to 3000 mg per day.

14. The method according to any one of claims 1 to 13, wherein the compound of formula I is administered orally to a subject.

15. The method according to any one of claims 1 to 14, wherein the subject has a NAFLD activity score (NAS) of ≥ 4.

16. The method according to any one of claims 1 to 14, wherein the subject has a NAFLD activity score (NAS) of ≥ 5.

17. The method according to any one of claims 1 to 16, wherein administration of the compound of formula I or a pharmaceutically acceptable salt thereof results in a NAFLD activity score (NAS) of <4.

18. The method according to any one of claims 1 to 17, wherein the subject has non-cirrhotic NASH.

19. The method according to any one of claims 1 to 17, wherein the subject has cirrhotic NASH.

20. The method according to any one of claims 1 to 17, wherein the subject has hepatitis.

21. The method according to claim 20, wherein the hepatitis is inflammation of the lobules.

22. The method according to claim 20 or 21, wherein administration of the compound of formula I (for example, any one of compound (1), compound (2), and compound (3)), or a pharmaceutically acceptable salt thereof, results in a reduction of hepatitis.

23. The method according to any one of claims 20 to 22, wherein administration of the compound of formula I or a pharmaceutically acceptable salt thereof results in a hepatitis score of 0 or 1.

24. The method according to any one of claims 1 to 23, wherein the liver of the subject is characterized by hepatocyte ballooning.

25. The method according to claim 24, wherein administration of the compound of formula I or a pharmaceutically acceptable salt thereof results in a reduction of hepatocyte ballooning.

26. The method according to claim 24 or 25, wherein administration of the compound of formula I or a pharmaceutically acceptable salt thereof results in a ballooning score of 0.

27. The method according to any one of claims 1 to 26, wherein the liver alanine aminotransferase (ALT) level of the subject increases.

28. The method according to claim 27, wherein administration of the compound of formula I or a pharmaceutically acceptable salt thereof results in a decrease in hepatic alanine aminotransferase (ALT) levels.

29. The method according to any one of claims 1 to 27, wherein the liver aspartate aminotransferase (AST) level of the subject increases.

30. The method according to claim 29, wherein administration of the compound of formula I or a pharmaceutically acceptable salt thereof results in a decrease in hepatic aspartate aminotransferase (AST) levels.

31. The method according to any one of claims 1 to 30, wherein the subject has liver fibrosis.

32. The method according to claim 31, wherein the subject has stage 2, stage 3, or stage 4 liver fibrosis.

33. The method according to claim 31 or 32, wherein administration of the compound of formula I or a pharmaceutically acceptable salt thereof results in stabilization of liver fibrosis in the subject.

34. The method according to claim 31 or 32, wherein administration of the compound of formula I or a pharmaceutically acceptable salt thereof results in a reversal of hepatic fibrosis in the subject.

35. The method according to any one of claims 1 to 34, wherein the subject has a steatosis score of 1, 2, or 3.

36. The method according to claim 35, wherein administration of the compound of formula I or a pharmaceutically acceptable salt thereof results in a reduction of steatosis in the subject.

37. The method according to any one of claims 1 to 36, wherein administration of the compound of formula I or a pharmaceutically acceptable salt thereof results in a reduction of hepatomegaly in the subject.

38. A method for reducing hepatitis, wherein the method involves administering a therapeutically effective amount of a compound according to formula I to a subject in need of it. 【Transformation 8】 (I) or administering a pharmaceutically acceptable salt thereof, in the formula, R 1 is hydrogen, -(C 1 -C 8 ) alkyl, -(C 1 -C 8 ) Alkenil, - (C 1 -C 8 ) Alkinyl, unsubstituted or substituted -ara (C 1 -C 6 ) alkyl, unsubstituted or substituted - Heteroara (C 1 -C 6 ) Selected from the group consisting of alkyl, in the formula, the substituted ara (C 1 -C 6 ) alkyl and substituted heteroala (C 1 -C 6 ) The substituents on the alkyl group are halogen, -CN, -NO 2 , -NH 2 , -NH(C) 1 -C 6 ) alkyl, -N[(C 1 -C 6 )alkyl) 2 ,-OH, Halo (C 1 -C 6 ) alkyl, -(C 1 -C 6 ) Alkoxy, Halo (C 1 -C 6 ) Alkoxy, -SH, Thio(C 1 -C 6 ) alkyl, -SONH 2 , -SO 2 NH 2 , -SO- (C 1 -C 6 ) alkyl, -SO 2 - (C 1 -C 6 ) alkyl, - NHSO 2 (C 1 -C 6 ) alkyl and -NHSO 2 NH 2 Selected from the group consisting of; R 2 is hydrogen, -(C 1 -C 8 ) alkyl, -(C 1 -C 8 ) Alkenil, - (C 1 -C 8 ) Alkinyl, unsubstituted or substituted -ara (C 1 -C 6 ) alkyl, unsubstituted or substituted - Heteroara (C 1 -C 6 ) Selected from the group consisting of alkyl, in the formula, the substituted ara (C 1 -C 6 ) alkyl and substituted heteroala (C 1 -C 6 ) The substituents on the alkyl group are halogen, -CN, -NO 2 , -NH 2 ,-OH, Halo (C 1 -C 6 ) alkyl, -(C 1 -C 6 ) Alkoxy, Halo (C 1 -C 6 ) Alkoxy, -SH, Thio(C 1 -C 6 ) alkyl, -SONH 2 , -SO 2 NH 2 , -SO- (C 1 -C 6 ) alkyl, -SO 2 - (C 1 -C 6 ) alkyl, -NHSO 2 (C 1 -C 6 ) alkyl and -NHSO 2 NH 2 Selected from the group consisting of; R 3 , R 4 , R 7 , R 8 , R 9 , R 10 , R 13 , and R 14 Independently, hydrogen and -(C) 1 -C 6 ) Selected from the group consisting of alkyl groups; R 5 and R 6 Independently, hydrogen, - (C 1 -C 6 ) Selected from the group consisting of alkyl and -OH, however R 5 and R 6 Both cannot be -OH; R 11 and R 12 Independently, hydrogen, - (C 1 -C 6 ) Selected from the group consisting of alkyl and -OH, however R 11 and R 12 Both cannot be -OH; m is 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; o is 0, 1, 2, 3, or 4; p is 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; A method in which r is 0, 1, 2, 3, or 4.

39. The aforementioned compound is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid, 【Chemistry 9】 （１）、 The method according to claim 38, or a pharmaceutically acceptable salt thereof.

40. The method according to claim 39, wherein the compound is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid dihydrochloride. 【Chemistry 10】

41. The aforementioned compound is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid, 【Chemistry 11】 （２）、 The method according to claim 38, or a pharmaceutically acceptable salt thereof.

42. The method according to claim 41, wherein the compound is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid trihydrochloride. 【Chemistry 12】

43. The aforementioned compound is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid, 【Chemistry 13】 （３）、 The method according to claim 38, or a pharmaceutically acceptable salt thereof.

44. The method according to claim 43, wherein the compound is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid trihydrochloride. 【Chemistry 14】

45. The method according to any one of claims 38 to 44, wherein hepatitis is inflammation of the lobules.

46. The method according to any one of claims 38 to 45, wherein administration of the compound of formula I or a pharmaceutically acceptable salt thereof results in a hepatitis score of 0 or 1.

47. A method for reducing hepatocyte ballooning, wherein the method involves administering a therapeutically effective amount of a compound according to formula I to a target requiring such reduction. 【Chemistry 15】 (I) or administering a pharmaceutically acceptable salt thereof, in the formula, R 1 is hydrogen, -(C 1 -C 8 ) alkyl, -(C 1 -C 8 ) Alkenil, - (C 1 -C 8 ) Alkinyl, unsubstituted or substituted -ara (C 1 -C 6 ) alkyl, unsubstituted or substituted - Heteroara (C 1 -C 6 ) Selected from the group consisting of alkyl, in the formula, the substituted ara (C 1 -C 6 ) alkyl and substituted heteroala (C 1 -C 6 ) The substituents on the alkyl group are halogen, -CN, -NO 2 , -NH 2 , -NH(C) 1 -C 6 ) alkyl, -N[(C 1 -C 6 )alkyl) 2 ,-OH, Halo (C 1 -C 6 ) alkyl, -(C 1 -C 6 ) Alkoxy, Halo (C 1 -C 6 ) Alkoxy, -SH, Thio(C 1 -C 6 ) alkyl, -SONH 2 , -SO 2 NH 2 , -SO- (C 1 -C 6 ) alkyl, -SO 2 - (C 1 -C 6 ) alkyl, - NHSO 2 (C 1 -C 6 ) alkyl and -NHSO 2 NH 2 Selected from the group consisting of; R 2 is hydrogen, -(C 1 -C 8 ) alkyl, -(C 1 -C 8 ) Alkenil, - (C 1 -C 8 ) Alkinyl, unsubstituted or substituted -ara (C 1 -C 6 ) alkyl, unsubstituted or substituted - Heteroara (C 1 -C 6 ) Selected from the group consisting of alkyl, in the formula, the substituted ara (C 1 -C 6 ) alkyl and substituted heteroala (C 1 -C 6 ) The substituents on the alkyl group are halogen, -CN, -NO 2 , -NH 2 ,-OH, Halo (C 1 -C 6 ) alkyl, -(C 1 -C 6 ) Alkoxy, Halo (C 1 -C 6 ) Alkoxy, -SH, Thio(C 1 -C 6 ) alkyl, -SONH 2 , -SO 2 NH 2 , -SO- (C 1 -C 6 ) alkyl, -SO 2 - (C 1 -C 6 ) alkyl, -NHSO 2 (C 1 -C 6 ) alkyl and -NHSO 2 NH 2 Selected from the group consisting of; R 3 , R 4 , R 7 , R 8 , R 9 , R 10 , R 13 , and R 14 Independently, hydrogen and -(C) 1 -C 6 ) Selected from the group consisting of alkyl groups; R 5 and R 6 Independently, hydrogen, - (C 1 -C 6 ) Selected from the group consisting of alkyl and -OH, however R 5 and R 6 Both cannot be -OH; R 11 and R 12 Independently, hydrogen, - (C 1 -C 6 ) Selected from the group consisting of alkyl and -OH, however R 11 and R 12 Both cannot be -OH; m is 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; o is 0, 1, 2, 3, or 4; p is 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; A method in which r is 0, 1, 2, 3, or 4.

48. The aforementioned compound is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid, 【Chemistry 16】 （１）、 The method according to claim 47, or a pharmaceutically acceptable salt thereof.

49. The method according to claim 48, wherein the compound is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid dihydrochloride. 【Chemistry 17】

50. The aforementioned compound is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid, [Chemistry 18] （２）、 The method according to claim 47, or a pharmaceutically acceptable salt thereof.

51. The method according to claim 50, wherein the compound is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid trihydrochloride. 【Chemistry 19】

52. The aforementioned compound is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid, 【Chemistry 20】 （３）、 The method according to claim 47, or a pharmaceutically acceptable salt thereof.

53. The method according to claim 52, wherein the compound is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid trihydrochloride. 【Chemistry 21】

54. The method according to any one of claims 47 to 53, wherein administration of the compound of formula I or a pharmaceutically acceptable salt thereof results in a ballooning score of 0.

55. A method for treating liver fibrosis, wherein the method involves administering a therapeutically effective amount of a compound according to formula I to a subject in need of the treatment. 【Chemistry 22】 (I) or administering a pharmaceutically acceptable salt thereof, in the formula, R 1 is hydrogen, -(C 1 -C 8 ) alkyl, -(C 1 -C 8 ) Alkenil, - (C 1 -C 8 ) Alkinyl, unsubstituted or substituted -ara (C 1 -C 6 ) alkyl, unsubstituted or substituted - Heteroara (C 1 -C 6 ) Selected from the group consisting of alkyl, in the formula, the substituted ara (C 1 -C 6 ) alkyl and substituted heteroala (C 1 -C 6 ) The substituents on the alkyl group are halogen, -CN, -NO 2 , -NH 2 , -NH(C) 1 -C 6 ) alkyl, -N[(C 1 -C 6 )alkyl) 2 ,-OH, Halo (C 1 -C 6 ) alkyl, -(C 1 -C 6 ) Alkoxy, Halo (C 1 -C 6 ) Alkoxy, -SH, Thio(C 1 -C 6 ) alkyl, -SONH 2 , -SO 2 NH 2 , -SO- (C 1 -C 6 ) alkyl, -SO 2 - (C 1 -C 6 ) alkyl, - NHSO 2 (C 1 -C 6 ) alkyl and -NHSO 2 NH 2 Selected from the group consisting of; R 2 is hydrogen, -(C 1 -C 8 ) alkyl, -(C 1 -C 8 ) Alkenil, - (C 1 -C 8 ) Alkinyl, unsubstituted or substituted -ara (C 1 -C 6 ) alkyl, unsubstituted or substituted - Heteroara (C 1 -C 6 ) Selected from the group consisting of alkyl, in the formula, the substituted ara (C 1 -C 6 ) alkyl and substituted heteroala (C 1 -C 6 ) The substituents on the alkyl group are halogen, -CN, -NO 2 , -NH 2 ,-OH, Halo (C 1 -C 6 ) alkyl, -(C 1 -C 6 ) Alkoxy, Halo (C 1 -C 6 ) Alkoxy, -SH, Thio(C 1 -C 6 ) alkyl, -SONH 2 , -SO 2 NH 2 , -SO- (C 1 -C 6 ) alkyl, -SO 2 - (C 1 -C 6 ) alkyl, -NHSO 2 (C 1 -C 6 ) alkyl and -NHSO 2 NH 2 Selected from the group consisting of; R 3 , R 4 , R 7 , R 8 , R 9 , R 10 , R 13 , and R 14 Independently, hydrogen and -(C) 1 -C 6 ) Selected from the group consisting of alkyl groups; R 5 and R 6 Independently, hydrogen, - (C 1 -C 6 ) Selected from the group consisting of alkyl and -OH, however R 5 and R 6 Both cannot be -OH; R 11 and R 12 Independently, hydrogen, - (C 1 -C 6 ) Selected from the group consisting of alkyl and -OH, however R 11 and R 12 Both cannot be -OH; m is 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; o is 0, 1, 2, 3, or 4; p is 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; A method in which r is 0, 1, 2, 3, or 4.

56. The aforementioned compound is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid, 【Chemistry 23】 （１）、 The method according to claim 55, or a pharmaceutically acceptable salt thereof.

57. The method according to claim 56, wherein the compound is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid dihydrochloride. 【Chemistry 24】

58. The aforementioned compound is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid, 【Chemistry 25】 （２）、 The method according to claim 57, or a pharmaceutically acceptable salt thereof.

59. The method according to claim 58, wherein the compound is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid trihydrochloride. 【Chemistry 26】

60. The aforementioned compound is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid, 【Chemistry 27】 （３）、 The method according to claim 55, or a pharmaceutically acceptable salt thereof.

61. The method according to claim 60, wherein the compound is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid trihydrochloride. 【Chemistry 28】

62. The method according to any one of claims 55 to 61, wherein the subject has stage 2, stage 3, or stage 4 liver fibrosis.

63. The method according to any one of claims 55 to 61, wherein the subject has liver cirrhosis.

64. The method according to any one of claims 55 to 63, wherein administration of the compound of formula I or a pharmaceutically acceptable salt thereof results in stabilization of liver fibrosis in the subject.

65. The method according to any one of claims 55 to 63, wherein administration of the compound of formula I or a pharmaceutically acceptable salt thereof results in a reversal of hepatic fibrosis in the subject.

66. A method for treating lipopathy, wherein the method involves administering a therapeutically effective amount of a compound according to formula I to a subject requiring the treatment. 【Chemistry 29】 (I) or administering a pharmaceutically acceptable salt thereof, in the formula, R 1 is hydrogen, -(C 1 -C 8 ) alkyl, -(C 1 -C 8 ) Alkenil, - (C 1 -C 8 ) Alkinyl, unsubstituted or substituted -ara (C 1 -C 6 ) alkyl, unsubstituted or substituted - Heteroara (C 1 -C 6 ) Selected from the group consisting of alkyl, in the formula, the substituted ara (C 1 -C 6 ) alkyl and substituted heteroala (C 1 -C 6 ) The substituents on the alkyl group are halogen, -CN, -NO 2 , -NH 2 , -NH(C) 1 -C 6 ) alkyl, -N[(C 1 -C 6 )alkyl) 2 ,-OH, Halo (C 1 -C 6 ) alkyl, -(C 1 -C 6 ) Alkoxy, Halo (C 1 -C 6 ) Alkoxy, -SH, Thio(C 1 -C 6 ) alkyl, -SONH 2 , -SO 2 NH 2 , -SO- (C 1 -C 6 ) alkyl, -SO 2 - (C 1 -C 6 ) alkyl, - NHSO 2 (C 1 -C 6 ) alkyl and -NHSO 2 NH 2 Selected from the group consisting of; R 2 is hydrogen, -(C 1 -C 8 ) alkyl, -(C 1 -C 8 ) Alkenil, - (C 1 -C 8 ) Alkinyl, unsubstituted or substituted -ara (C 1 -C 6 ) alkyl, unsubstituted or substituted - Heteroara (C 1 -C 6 ) Selected from the group consisting of alkyl, in the formula, the substituted ara (C 1 -C 6 ) alkyl and substituted heteroala (C 1 -C 6 ) The substituents on the alkyl group are halogen, -CN, -NO 2 , -NH 2 ,-OH, Halo (C 1 -C 6 ) alkyl, -(C 1 -C 6 ) Alkoxy, Halo (C 1 -C 6 ) Alkoxy, -SH, Thio(C 1 -C 6 ) alkyl, -SONH 2 , -SO 2 NH 2 , -SO- (C 1 -C 6 ) alkyl, -SO 2 - (C 1 -C 6 ) alkyl, -NHSO 2 (C 1 -C 6 ) alkyl and -NHSO 2 NH 2 Selected from the group consisting of; R 3 , R 4 , R 7 , R 8 , R 9 , R 10 , R 13 , and R 14 Independently, hydrogen and -(C) 1 -C 6 ) Selected from the group consisting of alkyl groups; R 5 and R 6 Independently, hydrogen, - (C 1 -C 6 ) Selected from the group consisting of alkyl and -OH, however R 5 and R 6 Both cannot be -OH; R 11 and R 12 Independently, hydrogen, - (C 1 -C 6 ) Selected from the group consisting of alkyl and -OH, however R 11 and R 12 Both cannot be -OH; m is 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; o is 0, 1, 2, 3, or 4; p is 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; A method in which r is 0, 1, 2, 3, or 4.

67. The aforementioned compound is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid, 【Transformation 30】 （１）、 The method according to claim 66, or a pharmaceutically acceptable salt thereof.

68. The method according to claim 67, wherein the compound is (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid dihydrochloride. 【Chemistry 31】

69. The aforementioned compound is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid, 【Chemistry 32】 （２）、 The method according to claim 66, or a pharmaceutically acceptable salt thereof.

70. The method according to claim 69, wherein the compound is (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid trihydrochloride. 【Transformation 33】

71. The aforementioned compound is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid, 【Transformation 34】 （３）、 The method according to claim 66, or a pharmaceutically acceptable salt thereof.

72. The method according to claim 71, wherein the compound is (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid trihydrochloride. 【Chemistry 35】

73. The method according to any one of claims 66 to 72, wherein the subject has a steatosis score of 1, 2, or 3.

74. The method according to any one of claims 66 to 73, wherein administration of the compound of formula I or a pharmaceutically acceptable salt thereof results in a reduction of steatosis in the subject.

75. The method according to any one of claims 38 to 74, wherein the subject has non-alcoholic steatohepatitis (NASH).

76. The method according to any one of claims 38 to 75, wherein the subject is a human.

77. The method according to any one of claims 38 to 76, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to a subject for a period of at least about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks.

78. The method according to any one of claims 38 to 76, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to a subject for a period of at least about 4 to 6, 4 to 8, 4 to 10, 4 to 12, 4 to 14, or 4 to 16 weeks.

79. The method according to any one of claims 38 to 76, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to a subject at a dose of about 2 to 1,000, 10 to 1,000, or 10 to 100 mg / kg per day.

80. The method according to any one of claims 38 to 76, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of about 10 mg / kg or more per day.

81. The method according to any one of claims 38 to 76, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to a subject in a total daily dose of about 100 to 5000, 500 to 5000, or 600 to 3000 mg per day.

82. The method according to any one of claims 38 to 81, wherein the compound of formula I is administered orally to a subject.

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