阅读说明：本技术 治疗脂肪性肝病和/或脂肪性肝炎的方法 (Methods of treating fatty liver disease and/or steatohepatitis ) 是由 姜媛媛 仲伟婷 赵焰平 王红军 赵静 李晶 刘伟娜 周丽莹 刘亚男 于 2020-02-26 设计创作，主要内容包括：本发明属于生物医药领域,并具体涉及预防、缓解和/或治疗脂肪性肝病和/或脂肪性肝炎的方法,其包括向需要其的个体给药有效量的式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药。()

A method of preventing, ameliorating and/or treating fatty liver disease and/or steatohepatitis comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof:

wherein:

x and Y are each independently selected from a direct bond, C (═ O), O, S (═ O)_iAnd NR;

r is selected from H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, saturated or partially unsaturated C_3-10Cycloalkyl, saturated or partially unsaturated 3-to 10-membered heterocyclyl, C_6-10Aryl, 5-14 membered heteroaryl and C_6-12Aralkyl, up to 2 ring members of said cycloalkyl and heterocyclyl are C (═ O);

ring A and ring B are each independently selected from saturated or partially unsaturated C_3-10Hydrocarbon ring, saturated or partially unsaturated 3-to 10-membered heterocyclic ring, C_6-10An aromatic ring and a 5-14 membered heteroaromatic ring, up to 2 ring members of said hydrocarbon ring and heterocyclic ring being C (═ O), with the proviso that when ring B is a heterocyclic ring containing a nitrogen atom, ring B is not attached to X through said nitrogen atom;

ring C is selected from saturated or partially unsaturated C_3-10Hydrocarbon ring, saturated or partially unsaturated 3-to 10-membered heterocyclic ring, C_6-10Aromatic rings and 5-14 membered heteroaromatic rings, up to 2 ring members of the hydrocarbon rings and heterocyclic rings being C (═ O);

ring D is absent or selected from saturated or partially unsaturated C_3-10Hydrocarbon rings, saturated or partially unsaturated3-to 10-membered heterocycle, C_6-10Aromatic rings and 5-14 membered heteroaromatic rings, up to 2 ring members of the hydrocarbon rings and heterocyclic rings being C (═ O);

ring E is selected from

Ring F is selected from saturated or partially unsaturated C_3-10Hydrocarbon ring, saturated or partially unsaturated 3-to 10-membered heterocyclic ring, C_6-10Aromatic rings and 5-14 membered heteroaromatic rings, up to 2 ring members of the hydrocarbon rings and heterocyclic rings being C (═ O);

R ¹selected from H, -NH₂、C _1-6Alkyl radical, C_6-10Aryl, 5-to 14-membered heteroaryl, N-methyltetrahydropyrrolyl, N-methylpiperidinyl, N-isopropylidene,Acetyl group, acetyl group,-C(＝O)-(C _1-6Alkylene radical)_n-CF ₃、-C(＝O)-(C _1-6Alkylene radical)_n-CN, -C (═ O) - (saturated or partially unsaturated C)_3-10Cycloalkyl), -NHC (═ O) - (saturated or partially unsaturated C)_3-10Cycloalkyl), -C (═ O) - (saturated or partially unsaturated 3-to 10-membered heterocyclyl), -C (═ O) -C_1-6Alkylene- (saturated or partially unsaturated 3-to 10-membered heterocyclyl), -C (═ O) - (5-to 14-membered heteroaryl), -C (═ O) -C_1-6alkylene-NH (C)_1-6Alkyl), -C (═ O) -C_1-6alkylene-N (C)_1-6Alkyl radical)₂N-methylpiperazine substituted acetyl, -S (═ O)₂R ^1a、-P(＝O)R ^1aR ^1b、 Provided that when R is¹And R¹⁰One of them is C_1-6Alkyl and the other is H or C_3-10(ii) when cycloalkyl, at least one of X and Y is a direct bond and ring C is not a 5-membered heteroaromatic ring; when R is¹And R¹⁰One of which is H and the other isWhen ring C is not a 5 membered heteroaromatic ring; when R is¹And R¹⁰Ring a contains at least 1 nitrogen atom and is not a 5 or 6 membered ring when both are H; when R is¹And R¹⁰One of which is H and the other isWhen ring C is not a 5 membered heteroaromatic ring; and when R is¹And R¹⁰Ring D is absent when one is H and the other is H or acetyl;

R ^1aand R^1bEach independently selected from H, halogen, amino, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, 3-to 10-membered heterocyclic group, C_6-10Aryl, 5-14 membered heteroaryl, C_6-12Aralkyl, -C (═ O) R⁵、-OC(＝O)R ⁵、-C(＝O)OR ⁵、-OR ⁵、-SR ⁵、-S(＝O)R ⁵、-S(＝O) ₂R ⁵、-S(＝O) ₂NR ⁵R ⁶、-NR ⁵R ⁶、-C(＝O)NR ⁵R ⁶、-NR ⁵-C(＝O)R ⁶、-NR ⁵-C(＝O)OR ⁶、-NR ⁵-S(＝O) ₂-R ⁶、-NR ⁵-C(＝O)-NR ⁵R ⁶、-C _1-6alkylene-NR⁵R ⁶、-C _1-6alkylene-OR⁵and-O-C_1-6alkylene-NR⁵R ⁶Provided that when R is^1aAnd R^1bWhen one is n-propyl, the other is not H; or R^1aAnd R^1bTogether with the atoms to which they are attached form a 3-12 membered heterocyclic or heteroaromatic ring;

R ²、R ³、R ⁴、R ⁷、R ⁸、R ⁹and R¹⁰Each occurrence is independently selected from H, halogen, amino, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, 3-to 10-membered heterocyclic group, C_6-10Aryl, 5-14 membered heteroaryl, C_6-12Aralkyl, -C (═ O) R⁵、-OC(＝O)R ⁵、-C(＝O)OR ⁵、-OR ⁵、-SR ⁵、-S(＝O)R ⁵、-S(＝O) ₂R ⁵、-S(＝O) ₂NR ⁵R ⁶、-NR ⁵R ⁶、-C(＝O)NR ⁵R ⁶、-NR ⁵-C(＝O)R ⁶、-NR ⁵-C(＝O)OR ⁶、-NR ⁵-S(＝O) ₂-R ⁶、-NR ⁵-C(＝O)-NR ⁵R ⁶、-C _1-6alkylene-NR⁵R ⁶、-C _1-6alkylene-O (P ═ O) (OH)₂and-O-C_1-6alkylene-NR⁵R ⁶；

The above alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, hydrocarbon ring, heterocyclyl, heterocycle, aryl, heteroaryl ring, and aralkyl group, at each occurrence, are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxy, oxo, amino, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, 3-to 10-membered heterocyclic group, C_6-10Aryl, 5-14 membered heteroaryl, C_6-12Aralkyl, ═ N-OR⁵、-C(＝NH)NH ₂、-C(＝O)R ⁵、-OC(＝O)R ⁵、-C(＝O)OR ⁵、-OR ⁵、-SR ⁵、-S(＝O)R ⁵、-S(＝O) ₂R ⁵、-S(＝O) ₂NR ⁵R ⁶、-NR ⁵R ⁶、-C(＝O)NR ⁵R ⁶、-NR ⁵-C(＝O)R ⁶、-NR ⁵-C(＝O)OR ⁶、-NR ⁵-S(＝O) ₂-R ⁶、-NR ⁵-C(＝O)-NR ⁵R ⁶、-C _1-6alkylene-NR⁵R ⁶and-O-C_1-6alkylene-NR⁵R ⁶Said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are further optionally substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxy, oxo, amino, cyano, nitro, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 10-membered heterocyclic group, C_6-10Aryl, 5-14 membered heteroaryl and C_6-12Aralkyl radical；

R ⁵And R⁶Each occurrence is independently selected from H, C_1-6Alkyl radical, C_3-10Cycloalkyl, 3-to 10-membered heterocyclic group, C_6-10Aryl, 5-14 membered heteroaryl and C_6-12Aralkyl group;

m is independently at each occurrence an integer of 0, 1, 2 or 3;

n is an integer of 0, 1 or 2;

i is an integer of 0, 1 or 2; and is

g is an integer of 0, 1, 2, 3 or 4;

wherein the fatty liver disease is preferably Alcoholic Fatty Liver Disease (AFLD) or non-alcoholic fatty liver disease (NAFLD), and the steatohepatitis is preferably Alcoholic Steatohepatitis (ASH) or non-alcoholic steatohepatitis (NASH).

The method of claim 1, wherein the compound has the structure of any of the following formulae:

wherein:

z is selected from O, S (═ O)_iAnd NR;

R ¹¹is H, halogen, amino, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, 3-to 10-membered heterocyclic group, C_6-10Aryl, 5-14 membered heteroaryl, C_6-12Aralkyl, -C (═ O) R⁵、-OC(＝O)R ⁵、-C(＝O)OR ⁵、-OR ⁵、-SR ⁵、-S(＝O)R ⁵、-S(＝O) ₂R ⁵、-S(＝O) ₂NR ⁵R ⁶、-NR ⁵R ⁶、-C(＝O)NR ⁵R ⁶、-NR ⁵-C(＝O)R ⁶、-NR ⁵-C(＝O)OR ⁶、-NR ⁵-S(＝O) ₂-R ⁶、-NR ⁵-C(＝O)-NR ⁵R ⁶、-C _1-6alkylene-NR⁵R ⁶or-O-C_1-6alkylene-NR⁵R ⁶；

The remaining groups are as defined in claim 1.

The method of claim 1 or 2, wherein the compound has the structure:

the method of any one of claims 1-3, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof is administered in an amount of from about 0.005 mg/day to about 5000 mg/day, for example, in an amount of about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500 or 5000 mg/day.

The method of any one of claims 1-3, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof is administered in an amount of from about 1ng/kg to about 200mg/kg, from about 1 μ g/kg to about 100mg/kg, or from about 1mg/kg to about 50mg/kg body weight per day, e.g., in an amount of about 1 μ g/kg, about 10 μ g/kg, about 25 μ g/kg, about 50 μ g/kg, about 75 μ g/kg, about 100 μ g/kg, about 125 μ g/kg, about 150 μ g/kg, about 175 μ g/kg, about 200 μ g/kg, about 225 μ g/kg, about 250 μ g/kg, per unit dose, About 275. mu.g/kg, about 300. mu.g/kg, about 325. mu.g/kg, about 350. mu.g/kg, about 375. mu.g/kg, about 400. mu.g/kg, about 425. mu.g/kg, about 450. mu.g/kg, about 475. mu.g/kg, about 500. mu.g/kg, about 525. mu.g/kg, about 550. mu.g/kg, about 575. mu.g/kg, about 600. mu.g/kg, about 625. mu.g/kg, about 650. mu.g/kg, about 675. mu.g/kg, about 700. mu.g/kg, about 725. mu.g/kg, about 750. mu.g/kg, about 775. mu.g/kg, about 800. mu.g/kg, about 825. mu.g/kg, about 850. mu.g/kg, about 875. mu.g/kg, about 900. mu.g/kg, about 925. mu.g/kg, about 950. mu.g/kg, about 975. mu.g/kg, About 1mg/kg, about 5mg/kg, about 10mg/kg, about 15mg/kg, about 20mg/kg, about 25mg/kg, about 30mg/kg, about 35mg/kg, about 40mg/kg, about 45mg/kg, about 50mg/kg, about 60mg/kg, about 70mg/kg, about 80mg/kg, about 90mg/kg, about 100mg/kg, about 125mg/kg, about 150mg/kg, about 175mg/kg, about 200mg/kg or about 300mg/kg of body weight.

The method of any one of claims 1-5, wherein the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof is administered once or in two, three or four divided doses.

The method of any one of claims 1-6, wherein the compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, is administered continuously for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days.

The method of any one of claims 1-7, wherein the compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, is administered for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) courses of treatment, wherein each course of treatment lasts at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days; and the interval between every two treatment courses is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three weeks or four weeks.

The method of any one of claims 1-8, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof is administered by injection (such as intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

The method of any one of claims 1-9, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, is administered in a dosage form selected from the group consisting of tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs and syrups.

The method of any one of claims 1-10, wherein the preventing or treating comprises reducing steatosis, collagen accumulation, and/or ballooning.

The method of any one of claims 1-11, further comprising administering one or more additional therapeutic agents.