WO2020177587A1 - 治疗脂肪性肝病和/或脂肪性肝炎的方法 - Google Patents

治疗脂肪性肝病和/或脂肪性肝炎的方法 Download PDF

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WO2020177587A1
WO2020177587A1 PCT/CN2020/076723 CN2020076723W WO2020177587A1 WO 2020177587 A1 WO2020177587 A1 WO 2020177587A1 CN 2020076723 W CN2020076723 W CN 2020076723W WO 2020177587 A1 WO2020177587 A1 WO 2020177587A1
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days
ring
group
compound
alkylene
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English (en)
French (fr)
Chinese (zh)
Inventor
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
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Beijing Tide Pharmaceutical Co Ltd
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Beijing Tide Pharmaceutical Co Ltd
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Priority to IL285989A priority Critical patent/IL285989B2/en
Priority to EP20765982.2A priority patent/EP3932404A4/en
Priority to KR1020217031621A priority patent/KR102906316B1/ko
Priority to US17/435,061 priority patent/US12485108B2/en
Priority to AU2020230574A priority patent/AU2020230574B2/en
Priority to CA3132228A priority patent/CA3132228A1/en
Priority to JP2021551785A priority patent/JP7565292B2/ja
Priority to CN202080017129.7A priority patent/CN113490493B/zh
Priority to BR112021017354A priority patent/BR112021017354A2/pt
Publication of WO2020177587A1 publication Critical patent/WO2020177587A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of biomedicine, and specifically relates to a method for preventing, alleviating and/or treating fatty liver disease and/or steatohepatitis, which comprises administering an effective amount of a compound of formula (I) or its pharmacy to an individual in need thereof
  • a method for preventing, alleviating and/or treating fatty liver disease and/or steatohepatitis which comprises administering an effective amount of a compound of formula (I) or its pharmacy to an individual in need thereof.
  • Fatty liver disease is a general term for a class of diseases in which fat is deposited in liver cells to cause liver disease, which includes alcoholic fatty liver disease and non-alcoholic fatty liver disease (NAFLD).
  • liver disease includes alcoholic fatty liver disease and non-alcoholic fatty liver disease (NAFLD).
  • Alcoholic fatty liver disease is a liver disease caused by long-term heavy drinking.
  • the clinical symptoms are non-specific. It may be asymptomatic, or have right upper abdominal distension and pain, loss of appetite, fatigue, weight loss, etc.
  • Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are common liver diseases. Histopathologically, these conditions are similar to alcoholic liver disease, but they appear in people who rarely or do not drink alcohol. Pathological changes in the liver include, but are not limited to, fat accumulation in hepatocytes, signs of hepatocyte degeneration, inflammatory cell infiltration, hepatocyte nodule formation, cirrhosis and hepatocellular carcinoma. To date, there is no specific therapy for these conditions. Therefore, there is a need to provide methods for treating these conditions.
  • the present invention provides a method for preventing, alleviating and/or treating fatty liver disease and/or steatohepatitis, which comprises administering to an individual in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable compound thereof Accepted salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs:
  • Ring D does not exist or is selected from a saturated or partially unsaturated C 3-10 hydrocarbon ring, a saturated or partially unsaturated 3-10 membered heterocyclic ring, a C 6-10 aromatic ring and a 5-14 membered heteroaromatic ring.
  • Ring E is selected from
  • R 1 and R 10 is a C 1-6 alkyl group and the other is H or a C 3-10 cycloalkyl group, at least one of X and Y is a direct bond and ring C is not a 5-membered heteroaromatic ring ;
  • R 1 and R 10 are both H, ring A contains at least 1 nitrogen atom and is not a 5- or 6-membered ring;
  • R 1 and R 10 is H and The other is When, ring C is not a 5-membered heteroaromatic ring; and when one of R 1 and R 10 is H and the other is H or acetyl, ring D does not exist;
  • R 5 and R 6 are independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
  • m is independently 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;
  • g is an integer of 0, 1, 2, 3 or 4;
  • the fatty liver disease is preferably alcoholic fatty liver disease (AFLD) or non-alcoholic fatty liver disease (NAFLD), and the fatty liver disease is preferably alcoholic steatohepatitis (ASH) or non-alcoholic steatohepatitis ( NASH).
  • AFLD alcoholic fatty liver disease
  • NAFLD non-alcoholic fatty liver disease
  • ASH alcoholic steatohepatitis
  • NASH non-alcoholic steatohepatitis
  • the present invention provides the compound of the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound , Metabolites or prodrugs in the preparation of drugs for the prevention, alleviation and/or treatment of fatty liver disease and/or steatohepatitis, wherein the fatty liver disease is preferably alcoholic fatty liver disease (AFLD) or non- Alcoholic fatty liver disease (NAFLD), the steatohepatitis is preferably alcoholic steatohepatitis (ASH) or non-alcoholic steatohepatitis (NASH).
  • AFLD alcoholic fatty liver disease
  • NAFLD non- Alcoholic fatty liver disease
  • the steatohepatitis is preferably alcoholic steatohepatitis (ASH) or non-alcoholic steatohepatitis (NASH).
  • the present invention provides the compound of the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound , Metabolites or prodrugs, which are used to prevent, alleviate and/or treat fatty liver disease and/or steatohepatitis, wherein the fatty liver disease is preferably alcoholic fatty liver disease (AFLD) or non-alcoholic fatty liver disease (NAFLD), the steatohepatitis is preferably alcoholic steatohepatitis (ASH) or non-alcoholic steatohepatitis (NASH).
  • AFLD alcoholic fatty liver disease
  • NAFLD non-alcoholic fatty liver disease
  • ASH alcoholic steatohepatitis
  • NASH non-alcoholic steatohepatitis
  • Figure 1 shows the body weight (Figure 1A) and body weight changes (Figure 1B) of the animals during the experiment.
  • Figure 2 shows the average body weight of each group of animals at the end of the administration (Figure 2A) and liver weight/body weight percentage ( Figure 2B).
  • Figure 3 shows the inhibition rate of fatty degeneration injury of the liver tissue (Figure 3A), the inhibition rate of collagen accumulation ( Figure 3B), and the inhibition rate of ballooning (Figure 3C) after the administration.
  • Figure 4A shows the Sirius Red staining (100 ⁇ ) image of liver tissue in Example 2, where A is the normal group, B is the model group, C is the compound C-100 mg/kg administration group, and D is the telmisartan administration group .
  • FIG. 4B shows the collagen accumulation of liver tissue in Example 2.
  • Figure 5A shows the serum cholesterol level in the mouse model of Example 2.
  • Figure 5B shows the serum low-density lipoprotein level in the mouse model of Example 2.
  • Figure 6A shows the percentage of endothelial cells in the liver tissue of Example 2.
  • Figure 6B shows the percentage of macrophages in the liver tissue of Example 2.
  • Figure 7A shows the Sirius Red staining (200 ⁇ ) image of liver tissue in Example 3, where A is the normal group, B is the model group, C is the compound C-100 mg/kg administration group, and D is the telmisartan administration group .
  • FIG. 7B shows the collagen accumulation of liver tissue in Example 3.
  • Figure 8A shows the serum cholesterol levels in the mouse model of Example 3.
  • Figure 8B shows the serum low-density lipoprotein levels in the mouse model of Example 3.
  • Figure 9A shows the Sirius red staining (100 ⁇ ) image of liver tissue in Example 4, where A is the normal group, B is the model group, C is the compound C-300mg/kg administration group, and D is the compound C-100mg/kg administration group.
  • E is the Telmisartan administration group.
  • FIG. 9B shows the collagen accumulation of liver tissue in Example 4.
  • Figure 10A shows the H&E stained image of the liver tissue in Example 5.
  • A is the normal control group, in which the liver tissue structure is complete and the cells are arranged regularly;
  • B is the model group, in which the liver tissue has obvious hepatocyte steatosis, which is transparent vacuole. There are ballooning and inflammatory cell infiltration foci;
  • C is the OCA-30mg/kg administration group;
  • D is the compound C-50mg/kg administration group;
  • E is the compound C-100mg/kg administration group.
  • FIG. 10B shows the NAS score of liver tissue in Example 5.
  • alkylene means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, Propylene or butylene.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
  • the alkyl group has 1 to 12, for example 1 to 6 carbon atoms.
  • C 1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl Group, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents
  • halogen substitution in this case, the group is called "haloalkyl" (for example, CH 2 F, CHF 2 , CF 3 , CCl 3 , C 2 F 5 , C 2 Cl 5
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sec-butyl or tert-butyl).
  • alkenyl means a linear or branched monovalent hydrocarbon group that contains one double bond and has 2-6 carbon atoms (“C 2-6 alkenyl”).
  • the alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2 -Hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
  • the compound of the present invention contains an alkenylene group, the compound may exist in the form of pure E (ent ought), pure Z (zusammen) or any mixture thereof.
  • alkynyl means a monovalent hydrocarbon group containing one or more triple bonds, which preferably has 2, 3, 4, 5, or 6 carbon atoms, such as ethynyl or propynyl.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , Cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl Or bicyclo[5.2.0]nonyl, decalinyl, etc.)), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , Cyclooctyl, cyclon
  • the cycloalkyl group has 3 to 15 carbon atoms.
  • C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclic ring) of 3 to 6 ring carbon atoms Hexyl), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, such as methyl substituted cyclopropyl.
  • cycloalkylene As used herein, the terms “cycloalkylene”, “cycloalkyl” and “hydrocarbon ring” refer to having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbons Saturated (ie, “cycloalkylene” and “cycloalkyl”) or unsaturated (ie, having one or more double bonds and/or triple bonds in the ring) monocyclic or polycyclic hydrocarbon ring of atoms, which Including but not limited to (ylidene) cyclopropyl (ring), (ylidene) cyclobutyl (ring), (ylidene) cyclopentyl (ring), (ylidene) cyclohexyl (ring), (ylidene) cycloheptyl ( (Cyclo), (ylidene)cyclooctyl (ring), (ylidene)cyclononyl (ring), (ylidene)cyclohexenyl (ring
  • heterocyclyl refers to having, for example, 3-10 (suitably 3-8, more suitably 3-6) Ring atoms, at least one of which is a heteroatom selected from N, O, and S, and the remaining ring atoms are saturated (ie, heterocycloalkyl) or partially unsaturated (ie, have one or more in the ring Double bond and/or triple bond) cyclic group.
  • 3-10 membered (ylidene) heterocycle (yl) has 2-9 (such as 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and is independently selected from N
  • One or more (for example, 1, 2, 3, or 4) heteroatoms of, O, and S are saturated or partially unsaturated (ylidene) heterocycles (groups).
  • heterocyclylene and heterocyclic examples include, but are not limited to: (ethylene) oxirane, (ethylene) aziridinyl, (azetidinyl), (ethylene) oxygen Oxetanyl (oxetanyl), (ylidene)tetrahydrofuranyl, (ylidene)dioxolinyl (dioxolinyl), (ylidene)pyrrolidinyl, (ylidene)pyrrolidonyl, (ylidene)imidazolidinyl, (ylidene) ) Pyrazolidinyl, (ylidene) pyrrolinyl, (ylidene) tetrahydropyranyl, (ylidene) piperidinyl, (ylidene) morpholinyl, (ylidene) dithialyl (dithianyl), (ylidene) Thiomorpholinyl, (ylidene)piperazinyl, or (tri
  • the group also encompasses bicyclic ring systems, including spirocyclic, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-nitrogen Heterobicyclo[2.2.2]octane etc.).
  • the heterocyclylene and heterocyclic (radical) groups may be optionally substituted with one or more (for example, 1, 2, 3, or 4) suitable substituents.
  • (arylene) and “aromatic ring” refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ -electron system.
  • C 6-10 (arylene)” and “C 6-10 aromatic ring” mean aromatic groups containing 6 to 10 carbon atoms, such as (phenylene) (Benzene ring) or ()naphthylene (naphthalene ring) (Arylene) and aromatic ring are optionally substituted by 1 or more (such as 1 to 3) suitable substituents (e.g. halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.) .
  • (arylene) heteroaryl and “heteroaromatic ring” refer to monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and it contains at least one heteroatom which may be the same or different (the heteroatom is for example oxygen, nitrogen Or sulfur), and, in addition, may be benzo-fused in each case.
  • (ylidene)heteroaryl or “heteroaryl ring” is selected from (ylidene)thienyl, (ylidene)furanyl, (ylidene)pyrrolyl, (ylidene)oxazolyl, (ylidene)thiazolyl, (Sub)imidazolyl, (sub)pyrazolyl, (sub)isoxazolyl, (sub)isothiazolyl, (sub)oxadiazolyl, (sub)triazolyl, (sub)thiadiazolyl Etc., and their benzo derivatives; or (ylidene) pyridinyl, (ylidene) pyridazinyl, (ylidene) pyrimidinyl, (ylidene) pyrazinyl, (ylidene) triazinyl, etc., and their benzo derivative.
  • aralkyl preferably denotes an aryl or heteroaryl substituted alkyl group, wherein the aryl, heteroaryl and alkyl are as defined herein.
  • the aryl group may have 6-14 carbon atoms
  • the heteroaryl group may have 5-14 ring atoms
  • the alkyl group may have 1-6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • halo or halogen group is defined to include F, Cl, Br, or I.
  • substituted means that one or more (eg, one, two, three, or four) hydrogens on the specified atom are replaced by a selection from the indicated group, provided that no more than the specified atom is present In the case of normal valence and the substitution forms a stable compound. Combinations of substituents and/or variables are only allowed when such combinations form stable compounds.
  • substituent can be (1) unsubstituted or (2) substituted. If the carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogens present) may be independently and/or together independently Optional substitution of selected substituents. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be independently selected optionally Substituent replacement.
  • each substituent is selected independently of the other. Therefore, each substituent may be the same or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5, or 10 under reasonable conditions.
  • the point of attachment of a substituent can be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotope-labeled compounds, which are the same as the compounds of the present invention, except that one or more atoms have the same atomic number but the atomic mass or mass number is different from the predominant atomic mass in nature. Or atomic substitution of mass number.
  • isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (such as deuterium ( 2 H), tritium ( 3 H)); isotopes of carbon (such as 11 C, 13 C, and 14 C) ; Isotopes of chlorine (such as 36 Cl); isotopes of fluorine (such as 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (such as 13 N and 15 N); isotopes of oxygen (such as 15 O , 17 O and 18 O); phosphorus isotopes (such as 32 P); and sulfur isotopes (such as 35 S).
  • isotopes of hydrogen such as deuterium ( 2 H), tritium ( 3 H)
  • isotopes of carbon such as 11 C, 13 C, and 14 C
  • Isotopes of chlorine such as 36 Cl
  • isotopes of fluorine
  • Certain isotope-labeled compounds of the invention can be used in drug and/or substrate tissue distribution studies (such as analysis).
  • the radioisotopes tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect.
  • Substitution with positron emission isotopes (such as 11 C, 18 F, 15 O, and 13 N) can be used to test substrate receptor occupancy in positron emission tomography (PET) studies.
  • the isotopically-labeled compounds of the present invention can be prepared by methods similar to those described in the attached routes and/or examples and preparations by using appropriate isotopically-labeled reagents instead of previously used non-labeled reagents.
  • the pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be replaced by an isotope, for example, D 2 O, acetone-d 6 or DMSO-d 6 .
  • stereoisomer means an isomer due to at least one asymmetric center. In compounds with one or more (for example, one, two, three, or four) asymmetric centers, it can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual The diastereomers. Certain individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention may exist in mixtures of two or more structurally different forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait.
  • Solid lines can be used in this article , Solid wedge Virtual wedge Depicts the chemical bonds of the compounds of the invention.
  • the use of a solid line to depict the bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.) are included.
  • the use of real or imaginary wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, use real and imaginary wedges to define relative stereochemistry, rather than absolute stereochemistry.
  • the compounds of the present invention are intended to be stereoisomers (which include cis and trans isomers, optical isomers (such as R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformational isomers, atropisomers and mixtures thereof) exist in the form of.
  • the compounds of the present invention can exhibit more than one type of isomerism, and are composed of mixtures thereof (for example, racemic mixtures and diastereomeric pairs).
  • the present invention covers all possible crystalline forms or polymorphs of the compounds of the present invention, which can be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the present invention may exist in free form for treatment, or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs, which can be administered to patients in need thereof. After medication, the compound of the present invention or its metabolites or residues can be directly or indirectly provided. Therefore, when “the compound of the present invention” is referred to herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate , Citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate Salt, sea benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleic acid Salt, malonate, methanesulfonate, methyl sulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmi
  • Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salt, arginine salt, benzathine penicillin salt, calcium salt, choline salt, diethylamine salt, diethanolamine salt, glycinate, lysine salt, magnesium salt, meglumine salt, ethanolamine salt, Potassium, sodium, tromethamine and zinc salts.
  • ester means an ester derived from each of the compounds of the general formula in this application, which includes physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the present invention Compound).
  • the compound of the present invention may itself be an ester.
  • the compound of the present invention may exist in the form of a solvate (preferably a hydrate), wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly, for example, water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, particularly, for example, water, methanol or ethanol.
  • the amount of polar solvent, especially water can be present in a stoichiometric or non-stoichiometric ratio.
  • N-oxides can be formed.
  • Nitrogen-containing heterocycle Those skilled in the art will also recognize that tertiary amines can form N-oxides.
  • metabolites of the compounds of the present invention that is, substances formed in the body when the compounds of the present invention are administered. Such products can be produced by, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by contacting the compound of the present invention with a mammal for a time sufficient to produce its metabolites.
  • the present invention further includes within its scope the prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have less pharmacological activity or no pharmacological activity when administered to or on the body It can be converted into the compound of the present invention having the desired activity by, for example, hydrolytic cleavage.
  • prodrugs will be functional group derivatives of the compound, which are easily converted into the desired therapeutically active compound in vivo.
  • prodrugs please refer to "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • prodrugs of the present invention can be used, for example, by using certain parts known to those skilled in the art as “pro-moiety (for example, “Design of Prodrugs", described in H. Bundgaard (Elsevier, 1985))" It is prepared by substituting appropriate functional groups present in the compounds of the present invention.
  • the present invention also encompasses compounds of the present invention containing protecting groups.
  • protecting groups In any process of preparing the compounds of the present invention, protection of sensitive groups or reactive groups on any relevant molecule may be necessary and/or desirable, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, such as those described in T.W. Greene & P.G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, and these references are incorporated herein by reference. Using methods known in the art, the protecting group can be removed at an appropriate subsequent stage.
  • Non-alcoholic steatohepatitis is a liver disease that is not related to alcohol consumption and is characterized by fatty changes in liver cells accompanied by inflammation in the lobules.
  • NASH is similar to alcoholic liver disease, but it occurs in people who hardly or do not drink alcohol.
  • the main characteristics of NASH are fat in the liver and inflammation and damage. Most people with NASH feel good and don't realize they have liver problems. Nonetheless, NASH can be severe and can lead to cirrhosis, where the liver is permanently damaged and scarred and can no longer function normally.
  • Non-alcoholic fatty liver disease is a fatty liver disease commonly seen in individuals with chronic liver disease. Excess liver fat can cause liver complications. Although not related to alcohol, these conditions may be related to obesity, diet, and other health-related issues.
  • Enzyme, fat, or fatty liver index reduction is an indicator to improve or correct the condition.
  • an "effective amount” refers to an amount sufficient to achieve the desired therapeutic effect under the conditions of administration, for example, the amount is sufficient to lower fasting blood glucose (FPG), reduce body weight, lower blood lipids such as cholesterol and triglycerides (TG), lower liver enzymes, Increase high-density lipoprotein cholesterol (HDL-C) levels and lower blood pressure.
  • FPG fasting blood glucose
  • TG cholesterol and triglycerides
  • HDL-C high-density lipoprotein cholesterol
  • an "effective amount” of a compound of formula (I) administered to a patient who exhibits, suffers from, or is susceptible to fatty liver disease and/or steatohepatitis (such as NASH or NAFLD) is an amount that results in Pathological symptoms, disease progression, and related physiological conditions improve or induce resistance to the aforementioned diseases.
  • prevention refers to pre-administering drugs to avoid or prevent the appearance of one or more symptoms of a disease or disorder.
  • prevention is not an absolute term.
  • prophylactic administration of drugs to substantially reduce the likelihood or severity of the disorder or the symptoms of the disorder is the intended meaning in the present disclosure.
  • Prevention is divided into primary prevention (to prevent the development of the disease) and secondary prevention (therefore the disease has developed and the patient is protected to prevent the progress of the process).
  • treating means reversing, alleviating, or inhibiting the disease or condition to which such term is applied or the progression of one or more symptoms of such a condition or condition, or Preventing such a disorder or condition or one or more symptoms of such a disorder or condition.
  • the treatment results in an improvement in at least one measurable fatty liver disease and/or steatohepatitis (e.g. NAFLD and/or NASH) physical symptoms, such as weight loss, weakness or fatigue.
  • the treatment results in improvement of at least one clinical parameter or performance of fatty liver disease and/or steatohepatitis (e.g.
  • NAFLD and/or NASH e.g., abnormal liver fat accumulation, abnormal levels of liver enzymes, fat Degeneration (e.g., evaluated by the percentage of fatty liver cells or graded by image analysis), collagen accumulation (e.g., evaluated by the percentage of positive liver tissue staining with Sirius red, which indicates collagen), or ballooning (e.g., swollen liver cells) Percentage evaluation).
  • fat Degeneration e.g., evaluated by the percentage of fatty liver cells or graded by image analysis
  • collagen accumulation e.g., evaluated by the percentage of positive liver tissue staining with Sirius red, which indicates collagen
  • ballooning e.g., swollen liver cells
  • a measurable symptom or set of symptoms e.g., fatigue, weight loss, or weakness
  • stabilizing, for example, a measurable parameter such as abnormal fat accumulation in the liver, liver enzymes
  • a measurable parameter such as abnormal fat accumulation in the liver, liver enzymes
  • the treatment leads to fatty liver disease and/or steatohepatitis (such as NAFLD and/or NASH) The reduction, inhibition or slowing down of progress.
  • the treatment can also lead to avoiding the causes and/or effects or clinical manifestations of fatty liver disease and/or steatohepatitis (such as NAFLD and/or NASH) before the disease or condition is fully manifested, or caused by fat
  • fatty liver disease and/or steatohepatitis such as NAFLD and/or NASH
  • the treatment results in an increase in the survival rate or survival time of patients with fatty liver disease and/or steatohepatitis (eg, NAFLD and/or NASH).
  • treatment results in patients with fatty liver disease and/or steatohepatitis (e.g. (NAFLD and/or NASH)) less likely to require liver transplantation.
  • treatment results in elimination of fatty liver disease. The need for liver transplantation for patients with liver disease and/or steatohepatitis (such as NAFLD and/or NASH).
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from diseases such as the diseases described herein.
  • “non-human animals” include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs). , Cats, cows, pigs, etc.).
  • the present invention provides a method for preventing, alleviating and/or treating fatty liver disease and/or steatohepatitis, which comprises administering to an individual in need thereof an effective amount of a compound of formula (I) or its pharmaceutically Acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs:
  • Ring D does not exist or is selected from a saturated or partially unsaturated C 3-10 hydrocarbon ring, a saturated or partially unsaturated 3-10 membered heterocyclic ring, a C 6-10 aromatic ring and a 5-14 membered heteroaromatic ring.
  • Ring E is selected from
  • R 5 and R 6 are independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
  • m is independently 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;
  • g is an integer of 0, 1, 2, 3 or 4;
  • the fatty liver disease is preferably alcoholic fatty liver disease (AFLD) or non-alcoholic fatty liver disease (NAFLD), and the fatty liver disease is preferably alcoholic steatohepatitis (ASH) or non-alcoholic steatohepatitis ( NASH).
  • AFLD alcoholic fatty liver disease
  • NAFLD non-alcoholic fatty liver disease
  • ASH alcoholic steatohepatitis
  • NASH non-alcoholic steatohepatitis
  • the above group is connected to X through one of the two positions marked by # or ##, and the other position is connected to R 1 ,
  • j 0, 1, 2, 3 or 4;
  • halogen for example, F, Cl or Br
  • methyl for example, ethyl
  • propyl for example, n-propyl or isopropyl
  • Vinyl cyclopropyl, cyclobutyl,
  • the above group is connected to X through one of the two positions marked with # or ##, and the other position is connected to R 1 , provided that the atom connected to X is not a nitrogen atom.
  • k 0, 1, 2, 3 or 4;
  • ring E is Preferably
  • each occurrence of R 3 and R 4 is independently selected from H, F, Cl, Br, I, -OH, methyl, ethyl, propyl, methoxy, -NH 2 , -N(CH 3 ) 2 , -O-ethylene-N(CH 3 ) 2 .
  • ring E is
  • R 1a and R 1b are each independently selected from H, methyl, -CF 3 , ethyl, -CH 2 CF 3 , -CH 2 CH 2 CF 3 , -CH(CH 3 )CF 3. N-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -ethylene-O-methyl, -CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH 2 OH,
  • R 1a and R 1b together with the atoms to which they are connected form the following groups: (E.g ),
  • the compound has a structure of any of the following formulas:
  • the compound has a structure of formula (XVII) or formula (XVII'):
  • R is selected from H and C 1-6 alkyl
  • Ring D is a saturated or partially unsaturated 3-10 membered heterocyclic ring, a C 6-10 aryl group or a 5-10 membered heteroaromatic ring, preferably Benzene ring, N-methylpyrrole ring, furan ring or thiophene ring;
  • R 2 is selected from H and C 1-6 alkyl
  • R 3 , R 4 , R 7 , R 7'and R 8 are each independently selected from H, halogen, -NH 2 , -OH, C 1-6 alkyl and -OR 5 at each occurrence;
  • alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaromatic and aralkyl groups are each optionally selected from halogen, C 1 -6 alkyl and -OR 5 substituents;
  • R 5 and R 6 are independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
  • m is independently an integer of 0, 1, 2 or 3;
  • n is an integer of 0, 1, or 2.
  • R 5 and R 6 are each independently selected from H, methyl and ethyl at each occurrence.
  • R 3 , R 4 , R 7 , R 7 ' and R 8 are each independently selected from H, F, Cl, Br, -NH 2 , -OH, methyl, Trifluoromethyl, -CH 2 -Ph, methoxy, ethoxy and -CH 2 OCH 3 .
  • the present invention covers embodiments obtained by arbitrarily combining the respective embodiments.
  • the compound has the following structure:
  • the compound is prepared according to the method disclosed in WO 2019/001572 A1 (which is incorporated herein by reference).
  • the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound is in an amount of about 0.005 mg/day to about 5000 mg/day, for example, 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 compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvent compound, N-oxide, or isotope-labeled compound , Metabolites or prodrugs are administered in an amount of about 1 ng/kg to about 200 mg/kg, about 1 ⁇ g/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg of body weight per day, for example, per unit dose of about 1 ⁇ g/kg, about 10 ⁇ g/kg, about 25 ⁇ g/kg, about 50 ⁇ g/kg, about 75 ⁇ g/kg, about 100 ⁇ g/kg, about 125 ⁇ g/kg, about 150 ⁇ g/kg, about 175 ⁇ g/kg, about 200 ⁇ g/kg, about 225 ⁇ g/kg, about 250 ⁇ g/kg, about 275 ⁇ g/kg, about 300 ⁇ g/kg, about 325 ⁇ g/kg, about 350 ⁇ g/kg, about 375 ⁇ g/kg, about 400 ⁇ g/kg, about 425 ⁇ g/kg, about 425
  • the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound The daily dose of metabolites or prodrugs is given at one time or in two, three or four doses.
  • the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, Metabolites or prodrugs are 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 compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound One or more (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) courses of metabolites or prodrugs, wherein each course lasts 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; and the interval between every two courses of treatment is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three
  • the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, Metabolites or prodrugs are administered by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including drip) or transdermal; or by oral, buccal, transnasal, transmucosal, topical, or The form of ophthalmic preparations or administration by inhalation.
  • the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, Metabolites or prodrugs are selected from tablets, capsules, lozenges, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions In the form of drugs, injectable solutions, elixirs and syrups.
  • the prevention or treatment includes reducing steatosis, reducing collagen accumulation, and/or reducing ballooning.
  • the method further comprises administering one or more other therapeutic agents.
  • the compound C used in the examples is compound 331, which is prepared according to the method disclosed in WO 2019/001572 A1.
  • mice Purchase pregnant rats from Shanghai Lingchang Laboratory Animal Co., Ltd. Thirty two-day-old male newborn mice were selected for the experiment. Each mouse was injected with 200 ⁇ g of streptozotocin (STZ, purchased from Sigma). From the age of 4 weeks, the fat was induced by feeding high-fat food for 2 weeks. Hepatitis model. At the same time, another 10 mice were selected and fed with a normal diet without STZ injection as the normal group. After 2 weeks of high-fat diet, the mice were divided into 3 groups according to their body weight and fasting blood glucose level: model group, compound C administration group and telmisartan administration group (telmisartan purchased from TOKYO CHEMICAL) , And started the administration, once a day orally for 21 consecutive days.
  • STZ streptozotocin
  • the recorded animal groups are shown in Table 1.
  • the weight of the mice was recorded every day (see Figure 1A and Figure 1B), and the weight of the mice after fasting was recorded after the last dose (see Table 2 and Figure 2A and Figure 2B).
  • the animals were euthanized, the liver tissues were weighed, and histological scores (blind assessment) for ballooning, steatosis, and collagen accumulation were performed.
  • the histological changes were evaluated by H&E staining, oil red O staining, and Sirius red staining of liver tissue.
  • H&E staining was used to evaluate hepatocyte ballooning
  • oil red O was used to reflect liver steatosis
  • Sirius red staining was used to evaluate collagen.
  • the related scores are shown in Figure 3A, Figure 3B and Figure 3C, and the inhibition rate of various histological changes is shown in Table 3.
  • Scoring principle steatosis score is 0-3 points, lesion area ⁇ 5% is rated as 0 point, lesion area is 5-33% as 1 point, lesion area is 33-66% as 2 points, and lesion area>66 % Is rated as 3 points; hepatocyte ballooning score is 0-2 points, no ballooning is rated as 0 points, a small amount of ballooning is rated as 1 point, most cells or obvious ballooning is rated as 2 points; collagen accumulation The score is 0-4 points, and the scoring principle refers to the principle reported in Brunt EM, et al. Hepatology. 2011.
  • Inhibition rate of steatosis injury 100% ⁇ (average score of model group-average score of administration group) / (average score of model group-score of normal group)
  • Inhibition rate of hepatocyte ballooning injury 100% ⁇ (average score of model group-average score of administration group) / (average score of model group-score of normal group)
  • Inhibition rate of collagen accumulation in liver tissue 100% ⁇ (average score of model group-average score of administration group) / (average score of model group-score of normal group)
  • compound C shows good tolerance and obvious therapeutic effect in the mouse model induced by STZ combined with high fat.
  • Compound C mainly improves liver tissue steatosis, ballooning and collagen accumulation in three aspects. Play a therapeutic role.
  • mice aged 8-10 weeks were given a Western diet (high fat + high cholesterol feed, purchased from Beijing Huafukang Biotechnology Co., Ltd.) and a high-sugar solution (23.1 g/LD-fructose and 18.9g/L D-glucose) feeding combined with intraperitoneal injection of carbon tetrachloride to induce steatohepatitis model.
  • a Western diet high fat + high cholesterol feed, purchased from Beijing Huafukang Biotechnology Co., Ltd.
  • a high-sugar solution (23.1 g/LD-fructose and 18.9g/L D-glucose) feeding
  • intraperitoneal injection of carbon tetrachloride was intraperitoneally injected, once a week, 12 times.
  • mice On the 28th day, the animals were divided into groups (8 animals in each group): model group (given vehicle, consisting of PEG400, Tween-80 and deionized water), compound C administration group (100mg/kg) and Telmisa Tan administration group (10mg/kg).
  • the vehicle, compound C, and telmisartan were all administered orally, starting on the 28th day, once a day, 21 days as a course of treatment, and 3 courses of treatment, with an interval of 1 week between each course.
  • a normal control group was set up, in which mice were fed with normal feed and normal drinking water.
  • peripheral blood sampling and serum separation Two hours after the last administration, the animals were subjected to peripheral blood sampling and serum separation. The animals were euthanized and liver tissues were taken. Serum is mainly used to detect cholesterol and low-density lipoprotein content. Liver tissue was stained with Sirius Red to evaluate collagen accumulation, and the ratio of endothelial cells and macrophages was detected by flow cytometry to reflect
  • the mouse liver tissue endothelial cells in the model group decreased, while the level of macrophages increased.
  • compound C increased the proportion of mouse liver tissue endothelial cells (p ⁇ 0.01), and also reduced the proportion of macrophages to a certain extent.
  • compound C had stronger effects on endothelial cells than telmisartan, and the downregulation effects on macrophages were similar.
  • mice 8-10 week old mice (purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.) were fed with a Western diet (high fat + high cholesterol feed, purchased from Beijing Huafukang Biotechnology Co., Ltd.) combined with intraperitoneal injection of tetrachloride Carbonization-induced steatohepatitis model.
  • the experimental animals were randomly divided into 3 groups (8 animals in each group) according to their body weight: the model group (given the vehicle, consisting of PEG400, Tween-80 and deionized water), the compound C-administration group (100mg/kg) and the alternative Misartan administration group (10mg/kg).
  • Each group was intraperitoneally injected with 0.05 ml of 20% CCl 4 on the fifth day (D5) after the start of Western diet feeding, once a week, 12 times.
  • the vehicle, compound C, and telmisartan were all administered orally, once a day, 21 days as a course of treatment, and 3 courses of treatment, with an interval of 1 week between each course.
  • a normal control group was set up, in which mice were fed with normal feed and normal drinking water. Two hours after the last administration, the animals were subjected to peripheral blood sampling and serum separation. The animals were euthanized and liver tissues were taken. Serum is mainly used to detect cholesterol and low-density lipoprotein content. Liver tissue was stained with Sirius Red to evaluate collagen accumulation.
  • mice The 8-10 week old mice (purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.) were randomly divided into 4 groups (8 animals in each group) according to their body weight: model group (given vehicle, 0.5% CMC-Na), compound C -300mg/kg administration group, compound C-100mg/kg administration group, telmisartan administration group (10mg/kg), and start intraperitoneal injection of 0.05ml of 40% CCl 4 twice a week for 6 consecutive week. Gavage started on the 15th day, once a day for 28 consecutive days. At the same time, a normal control group was set up, in which mice were fed with normal feed and normal drinking water. The animals were euthanized 2 hours after the last administration, and liver tissues were taken for Sirius red staining to evaluate collagen accumulation.
  • model group given vehicle, 0.5% CMC-Na
  • compound C -300mg/kg administration group compound C-100mg/kg administration group
  • telmisartan administration group 10mg
  • the pregnant SD rats were purchased from Shanghai Jihui Company, and the newborn rats obtained therefrom were used in this study. Forty male newborn rats were selected and injected with N-diethylnitrosamine (DEN, purchased from Sigma) 2 weeks after birth. After feeding the newborn rats with mother mouse milk for 2 weeks, they were randomly divided into 4 groups (10 in each group) according to the animal weight: model group (0.5% CMC-Na), compound C-50mg/kg administration group, compound C-100mg/kg administration group, obeticholic acid (OCA, purchased from Wuhan WuXi AppTec, 30mg/kg) administration group, and adopt Western diet (high fat + high cholesterol feed, purchased from Nantong Trofi Feed Technology Co., Ltd., Su Shizheng (2014) 06092) diet for 8 weeks.
  • model group (0.5% CMC-Na
  • OCA obeticholic acid
  • OCA purchased from Wuhan WuXi AppTec
  • the animals were euthanized 2 hours after the last administration, liver tissue was taken, and the liver tissue was fixed and embedded, and stained with H&E (see Figure 10A for stained images) for NAS score.
  • H&E see Figure 10A for stained images
  • the NAS score is the sum of the liver steatosis score, the inflammatory cell infiltration score, and the hepatocyte ballooning score.
  • the NAS score of the model group was significantly higher than that of the normal group, reaching 6 points, and the liver tissue NAS score of the animal in the compound C treatment group was significantly reduced to about 4.2 (see Figure 10B)

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