Application of phenylalanine derivative in liver, lung and kidney diseases

Abstract

The invention relates to application of phenylalanine derivatives in liver, lung and kidney diseases. Specifically, the invention provides application of a compound as shown in a formula I or a stereoisomer, a hydrate, a solvate, an isotope label, a prodrug or a pharmaceutically acceptable salt thereof in preparation of drugs, wherein the drugs are used for preventing, treating, treating or relieving non-alcoholic fatty liver disease, steatohepatitis, hepatic fibrosis, cirrhosis, pulmonary fibrosis or renal fibrosis. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to the use of phenylalanine derivatives in treating liver, lung and kidney diseases. Background Art

[0002] The main functions of the liver are to metabolize nutrients, detoxify and remove harmful substances, regulate blood, etc. It is the main metabolic organ in the body. Non-alcoholic fatty liver disease (NAFLD) refers to a chronic metabolic disease of the liver caused by excessive accumulation of lipids in liver cells without a history of excessive drinking and no clear cause. NAFLD has become the number one chronic liver disease in my country. The disease can further develop into hepatic fatty degeneration, non-alcoholic fatty hepatitis, liver fibrosis, cirrhosis and even hepatocellular carcinoma, and its prevalence is increasing year by year. At present, there is no specific drug approved for clinical treatment of NAFLD.

[0003] Liver fibrosis is a type of injury-repair reaction caused by chronic liver damage. It is a pathological process that can gradually develop into cirrhosis, liver cancer, liver failure and even death. Its main pathological feature is the abnormal proliferation of extracellular matrix after liver damage. After liver damage, hepatocytes secrete proinflammatory cytokines, which activate hepatic stellate cells (HSCs) in a quiescent state and promote the transformation of HSCs into myofibroblasts; the activated HSCs gradually undergo morphological changes and lose the ability to store lipid droplets, producing a large amount of ECM components mainly composed of collagen and proinflammatory mediators, which are deposited in the liver tissue, inducing liver cell necrosis and apoptosis, and ultimately leading to the destruction of liver structure and the formation of liver fibrosis. Transforming growth factor-β1 (TGF-β1) plays a key regulatory role in promoting liver fibrosis. TGF-β1 can activate downstream signal regulatory factors Smad2 and Smad3, thereby regulating collagen metabolism and promoting liver fibrosis. TGF-β1 / Smad signaling disorder is a key factor in the imbalance between ECM synthesis and degradation. Inhibiting the TGF-β1 / Smad pathway can effectively improve liver fibrosis.

[0004] Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease of unknown cause. Patients with pulmonary fibrosis have excessive proliferation of pulmonary fibroblasts and excessive deposition of extracellular matrix (ECM). The main characteristics are pulmonary interstitial scar formation and irreversible decline in lung function. The risk factors for IPF are smoking, air pollution such as toxic and harmful gases, viral infection and occupational exposure. The pathogenesis of IPF is complex. The transformation of pulmonary fibroblast phenotype to myofibroblast is one of its key pathogenesis. Continuous epithelial cell damage can cause abnormal activation of epithelial cells and secrete a large amount of transforming growth factor-β (TGF-β). It can lead to the formation of pulmonary fibroblast lesions and the massive production and deposition of extracellular matrix (ECM), causing abnormal damage and repair of lung tissue and the formation of fibrous scars.

[0005] Therefore, the development of drugs for the treatment of non-alcoholic fatty liver disease, steatohepatitis, liver fibrosis, cirrhosis, pulmonary fibrosis or renal fibrosis is of great clinical significance. Summary of the invention

[0006] In order to solve the above technical problems, the present invention provides phenylalanine derivatives, which have the use of preventing, treating, curing or alleviating liver and lung diseases, especially the use of preventing, treating, curing or alleviating non-alcoholic fatty liver, steatohepatitis, liver fibrosis, liver cirrhosis, pulmonary fibrosis or renal fibrosis. Specifically, the present invention verifies the inhibitory effect of the phenylalanine compound on TGF-β-induced rat hepatic stellate cells, the inhibitory effect on liver fibrosis of bile duct ligated mice, the inhibitory effect on TGF-β-induced human embryonic lung fibroblasts and the inhibitory effect on TGF-β-induced human renal cortical proximal tubule epithelial cells, and proves that it has the use of preventing, treating, curing or alleviating non-alcoholic fatty liver, steatohepatitis, liver fibrosis, liver cirrhosis, pulmonary fibrosis or renal fibrosis.

[0007] In one aspect, the present invention provides a use of a compound of formula I or its stereoisomers, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof in the preparation of a medicament, wherein the medicament is used to prevent, treat, cure or alleviate non-alcoholic fatty liver disease, steatohepatitis, liver fibrosis, cirrhosis, pulmonary fibrosis or renal fibrosis;

[0008]

[0009] in:

[0010] R 1 , R 2 , R3 , R 4 , R 5 Each is independently selected from H, D, halogen, -CN, -NO2, -OH, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkoxy, C 6-14 Aryl, C 6-14 Aryloxy, R a C(=O)O- and R a S(=O)2O-,R a Selected from C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl and C 6-14 Aryl, wherein the C 6-14 Aryl and C 6-14 The aryloxy groups are each independently optionally unsubstituted or substituted with 1-3 substituents selected from H, D, halogen, -OH; optionally, R 1 , R 2 Together with the atoms to which they are attached, or R 2 , R 3 Together with the atoms to which they are attached, they form C 6-14 Aryl; preferably, R 1 , R 2 , R 3 , R 4 , R 5 Each is independently selected from H, D, halogen, -CN, -NO2, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryloxy, R a C(=O)O- and R a S(=O)2O-,R a Preferred from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and C 6-10 Aryl, wherein the C 6-10 Aryl and C 6-10 The aryloxy groups are each independently optionally unsubstituted or substituted with 1-3 substituents selected from H, D, halogen, -OH; optionally, R 1 , R 2 Together with the atoms to which they are attached, or R 2 , R 3 Together with the atoms to which they are attached, they form C 6-10 Aryl;

[0011] R6 Selected from H, D, C 1-10 Alkyl and C 3-10 Cycloalkyl; preferably, R 6 Selected from H, D, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0012] R 7 Selected from H, D and -OR b ; where R b Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-; preferably, R 7 Selected from H, D and -OR b ; where R b Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(═O)-;

[0013] R 8 , R 9 Each independently selected from H, -NHR c 、-OR d , C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-OC(=O)-, C 3-10 Cycloalkyl-OC(=O)-, C 6-14 Aryl-OC(=O)-, C 6-14 Aryl-C 1-4 Alkyl-OC(=O)-, C 1-10 Alkyl-S(=O)2-, C 1-10 Haloalkyl-S(=O)2-, C 3-10 Cycloalkyl-S(=O)2-, C 6-14 Aryl-S(=O)2-, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-; wherein R c Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-OC(=O)-, C 3-10Cycloalkyl-OC(=O)-, C 6-14 Aryl-OC(=O)-, C 6-14 Aryl-C 1-4 Alkyl-OC(=O)-, C 1-10 Alkyl-S(=O)2-, C 1-10 Haloalkyl-S(=O)2-, C 3-10 Cycloalkyl-S(=O)2-, C 6-14 Aryl-S(=O)2-, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-, R d Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-; preferably, R 8 , R 9 Each independently selected from H, -NHR c 、-OR d , C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-OC(=O)-, C 3-6 Cycloalkyl-OC(=O)-, C 6-10 Aryl-OC(=O)-, C 6-10 Aryl-C 1-4 Alkyl-OC(=O)-, C 1-6 Alkyl-S(=O)2-, C 1-6 Haloalkyl-S(=O)2-, C 3-6 Cycloalkyl-S(=O)2-, C 6-10 Aryl-S(=O)2-, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(=O)-; wherein R c Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-OC(=O)-, C 3-6 Cycloalkyl-OC(=O)-, C 6-10 Aryl-OC(=O)-, C 6-10 Aryl-C 1-2 Alkyl-OC(=O)-, C 1-6 Alkyl-S(=O)2-, C1-6 Haloalkyl-S(=O)2-, C 3-6 Cycloalkyl-S(=O)2-, C 6-10 Aryl-S(=O)2-, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(=O)-, R d Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(═O)-;

[0014] X is the formula:

[0015]

[0016] Among them, R 10 Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl and C 6-14 Aryl; R 11 , R 12 Each independently selected from H, -OH, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 6-14 Aryl and C 6-14 Aryl C 1-10 Alkyl; or R 11 , R 12 Together with the atoms to which they are attached, they form a 3-8 membered heterocyclic group; preferably, R 10 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 6-10 Aryl; R 11 , R 12 Each independently selected from H, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl and C 6-10 Aryl C 1-6 Alkyl; or R 11 , R 12 Together with the atoms to which they are attached, they form a 3-6 membered heterocyclic group.

[0017] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5Each is independently selected from H, D, F, Cl, Br, I, -CN, -NO2, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, phenyl, naphthyl, phenanthrenyl, phenoxy, naphthyloxy, phenanthrenoxy, CH3C(=O)O-, CH3CH2C(=O)O-, CH3CH2CH2C(=O)O-, (CH3)2CHC(=O)O-, (CH3)3C(=O)O-, cyclopropyl-C(=O)O-, cyclobutyl-C(=O)O-, cyclopentyl-C(=O)O-, cyclohexyl-C(=O)O-, phenyl-C(=O)O-, CH3S(=O)2O-, CF3S(=O)2O-, cyclohexyl-S(=O)2O-, phenyl-S(=O)2O-, quinolyl-S(=O)2O-, isoquinolyl-S(=O)2O-, p-CH3-phenyl-S(=O)2O-; wherein the C 6-14 Aryl, C 6-14 The aryloxy groups are each independently optionally unsubstituted or substituted with 1-3 substituents selected from H, D, F, Cl, Br, I, -OH; optionally, R 1 , R 2 Together with the atoms to which they are attached, or R 2 , R 3 Together with the atoms to which they are attached they form a phenyl or naphthyl group.

[0018] In some embodiments, R 6 is selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0019] In some embodiments, R 7 Selected from H, D, OR b ; where R b Selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, CH3C(=O)-, CH3CH2C(=O)-, CH3CH2CH2C(=O)-, (CH3)2CHC(=O)-, (CH3)3CC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, phenyl-C(=O)-.

[0020] In some embodiments, R 8 , R 9 Each independently selected from H, -NHRc 、-OR d , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 9-fluorenylmethoxycarbonyl, CH3-OC(=O)-, CH3CH2-OC(=O)-, CH3CH2CH2-OC(=O)-, (CH3)2CH-OC(=O)-, (CH3)3C-OC(=O)-, cyclopropyl-OC(=O)-, cyclobutyl-OC(=O)-, cyclopentyl-OC(=O)-, cyclohexyl-OC(=O)-, phenyl-CH2-OC(=O)-, phenyl-CH 2CH2-OC(=O)-, phenyl-OC(=O)-, CH3C(=O)-, CH3CH2C(=O)-, CH3CH2CH2C(=O)-, (CH3)2CHC(=O)-, (CH3)3CC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, phenyl-C(=O)-, CH3S(=O)2-, CF3S(=O)2-, cyclohexyl-S(=O)2O-, phenyl-S(=O)2-, p-CH3-phenyl-S(=O)2-; wherein R c is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 9-fluorenylmethoxycarbonyl, CH3-OC(=O)-, CH3CH2-OC(=O)-, CH3CH2CH2-OC(=O)-, (CH3)2CH-OC(=O)-, (CH3)3C-OC(=O)-, cyclopropyl-OC(=O)-, cyclobutyl-OC(=O)-, cyclopentyl-OC(=O)-, cyclohexyl-OC(=O)-, phenyl-CH2-OC(=O)-, phenyl -CH2CH2-OC(=O)-, phenyl-OC(=O)-, CH3C(=O)-, CH3CH2C(=O)-, CH3CH2CH2C(=O)-, (CH3)2CHC(=O)-, (CH3)3CC(=O)-, cyclopropyl-C(=O)-, cyclobutylC(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, phenyl-C(=O)-, CH3S(=O)2-, CF3S(=O)2-, cyclohexyl-S(=O)2O-, phenyl-S(=O)2-, p-CH3-phenyl-S(=O)2-, R dSelected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, CH3C(=O)-, CH3CH2C(=O)-, CH3CH2CH2C(=O)-, (CH3)2CHC(=O)-, (CH3)3CC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, phenyl-C(=O)-.

[0021] In some embodiments, R 10 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, benzyl and phenyl;

[0022] R 11 , R 12 are each independently selected from H, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, benzyl and phenyl, or R 11 , R 12 Together with the atoms to which they are attached they form a pyrrolidinyl, piperidinyl or piperazinyl.

[0023] In some embodiments, Formula I has one of the following structures:

[0024]

[0025] In some embodiments, Formula I has one of the following structures:

[0026]

[0027] On the other hand, the present invention provides the use of compound (S)-4-(2-(N-methylisoquinoline-5-sulfonamido)-3-oxo-3-(4-phenylpiperazin-1-yl)propyl)phenylisoquinoline-5-sulfonate or its stereoisomers, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof in the preparation of a medicament, wherein the medicament is used to prevent, treat, cure or alleviate non-alcoholic fatty liver disease, steatohepatitis, liver fibrosis, cirrhosis, pulmonary fibrosis or renal fibrosis;

[0028]

[0029] In some embodiments, the medicament is used to combat liver fibrosis or lung fibrosis.

[0030] Terminology

[0031] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0032] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in a single embodiment, may also be provided separately or in any suitable sub-combination.

[0033] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0034] Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0035] Unless otherwise specified or there is a clear conflict in context, the articles "a", "an", and "the" as used herein are intended to include "at least one" or "one or more". Therefore, these articles as used herein refer to articles that refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in the implementation of the described embodiment.

[0036] The term "subject" refers to an animal. Typically, the animal is a mammal. Subjects, for example, also refer to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0037] The term "patient" refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0038] The term "comprising" is an open expression, namely including the contents specified in the present invention but not excluding other contents.

[0039] When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0040] The term "enantiomers" refers to two non-superimposable isomers of a compound that are mirror images of each other.

[0041] The term "diastereoisomer" refers to stereoisomers that have two or more chiral neutrals and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, for example HPLC.

[0042] The terms "racemate," "racemate" or "racemic mixture" refer to an equimolar mixture of two enantiomers devoid of optical activity.

[0043] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (protontautomers) (also known as prototropic tautomers) include mutual conversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include mutual conversions by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4 (1H)-one tautomers. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0044] The term "stereoisomers" refers to compounds that have identical chemical constitution, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like.

[0045] The stereochemical definitions and rules used in the present invention generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light caused by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are right-handed. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or a racemate and this may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0046] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.

[0047] Depending on the choice of starting materials and process, the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, such as a racemate and a diastereomeric mixture (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0048] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0049] Any racemate of the final product or intermediate obtained can be separated into optical antipodes by known methods by methods familiar to those skilled in the art, such as by separation of the diastereoisomeric salts obtained thereof. The racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0050] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammals treated therewith. Preferably, the "pharmaceutically acceptable" of the present invention refers to those approved by federal regulatory agencies or national governments or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeias for use in animals, particularly humans.

[0051] The term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable salts include salts formed by compounds with acids, including but not limited to inorganic acid salts (such as hydrochlorides, hydrobromides, phosphates, sulfates, nitrates, perchlorates) and organic acid salts (such as acetates, glycolates, oxalates, maleates, tartrates, citrates, succinates, fumarates, mandelates, sulfosalicylate), or other methods described in books and literature, such as ion exchange methods, to obtain these salts. More pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts also include salts of compounds formed with bases, including, but not limited to, inorganic base salts (such as alkali metal salts, alkaline earth metal salts, ammonium salts and N+(C 1-4 The present invention also contemplates quaternary ammonium salts formed by compounds of any N-containing group. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates. Organic base salts (e.g., primary, secondary and tertiary amine salts, substituted amine salts (including naturally occurring substituted amines, cyclic amines, basic ion exchange resins) salts), certain organic amine salts include, for example, isopropylamine salts, benzathine salts, choline salts, diethanolamine salts, diethylamine salts, lysine salts, meglumine salts, piperazine salts and tromethamine salts.

[0052] Pharmaceutically acceptable acid addition salts can be formed by the compounds of the present invention and inorganic or organic acid, and pharmaceutically acceptable base addition salts can be formed by the compounds of the present invention and inorganic or organic base. Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds, alkaline or acidic moieties. Generally speaking, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg or K), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are usually carried out in water or an organic solvent or a mixture of the two. Generally, in appropriate cases, it is necessary to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Additional lists of suitable salts can be found in, for example, "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahland Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0053] The term "solvate" refers to an association formed by one or more solvent molecules and the compound of the present invention. The solvent can be water, acetic acid, ether, isopropyl ether, petroleum ether, ethyl formate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, methyl tert-butyl ether (MTBE), n-heptane, a mixed solvent of ethanol and water in a volume ratio of 10:90 to 90:10, acetone, methyl isobutyl ketone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, ethylene glycol, n-butanol, tert-butanol , sec-butyl alcohol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, n-hexane, cyclohexane, n-heptane, a mixed solvent of n-heptane and ethyl acetate in a volume ratio of 1:5 to 5:1, isopropanol, methanol, butanone, l-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, n-propanol, isopropanol, 2-acetone, 4-methyl-2-pentanone, pyridine, tetrahydrofuran, methyl ethyl ketone, toluene, xylene, isopropylbenzene or a mixture thereof, etc.

[0054] The term "hydrate" refers to an association of one or more water molecules with a compound of the present invention.

[0055] In addition, the compounds disclosed in the present invention, including their salts, can also be obtained in the form of their hydrates or in the form of containing their solvents (such as ethanol, DMSO, etc.) for their crystallization. The compounds disclosed in the present invention can form solvates with pharmaceutically acceptable solvents (including water) inherently or by design; therefore, the present invention is intended to include both solvated and unsolvated forms.

[0056] The term "isotopically labeled compound" means that a compound of the present invention is labeled with an isotope. It is identical to those compounds described herein except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Exemplary isotopes that may also be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 Oh, 17 Oh, 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0057] Compounds of the present invention containing the aforementioned isotopic labels and / or other isotopic labels of other atoms and pharmaceutically acceptable salts of the compounds are all within the scope of the present invention. Isotope-labeled compounds of the present invention, such as radioisotope-labeled compounds, such as 3 H and 14 C incorporation into the compounds of the present invention can be used for drug and / or substrate tissue distribution analysis. Due to the ease of preparation and detection, tritiated, i.e., 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred. In addition, isotopes with larger mass numbers, such as deuterium, 2 H substitution may offer some therapeutic advantage of greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances.

[0058] In addition, heavier isotopes, especially deuterium (i.e. 2The substitution of H or D) can provide certain therapeutic advantages, which are brought about by higher metabolic stability. For example, the half-life in vivo is increased or the dosage requirement is reduced or the therapeutic index is improved. It should be understood that deuterium in the present invention is regarded as a substituent of the compound of formula I. The concentration of such heavier isotopes, especially deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" used in the present invention refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. Where a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates according to the invention include those wherein the solvent of crystallization may be isotopically substituted, for example D2O, acetone-d6, DMSO-d6.

[0059] The term "prodrug" as used in the present invention refers to a compound that is converted in vivo into a compound of Formula I. Such conversion is affected by the hydrolysis of the prodrug in the blood or by the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compounds of the present invention may be esters. In the prior invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, please refer to the following documents: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium Series; Roche et al., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270, and Hecker et al., Prodrugs of Phosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328-2345.

[0060] Unless explicitly stated otherwise, the descriptions used in the present invention such as "each...is independently" and "...are each independently" and "...are independently" are interchangeable and should be understood in a broad sense, which may mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0061] The terms "optional", "optionally" or "arbitrarily", "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted with..." means that the substitution may or may not occur.

[0062] When the term "each independently" is used in combination with "arbitrarily", for example, "each independently arbitrarily replaced by..." means that the specific options are replaced by... or not by... without affecting each other.

[0063] The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0064] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl as disclosed independently.

[0065] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is linked.

[0066] The term "heteroatom" refers to O, S, N, P and Si, including any oxidation state of S, N and P; primary, secondary, tertiary amines and quaternary ammonium salts; or the hydrogen on the nitrogen atom in the heterocyclic ring is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NRT (such as NRT in N-substituted pyrrolidinyl, RT is a substituent on N). In the compounds involved in the present invention, when containing multiple heteroatoms, the compounds composed thereof conform to the covalent rules and composition rules of organic compounds, that is, the compounds containing multiple heteroatoms should exclude compounds that do not conform to the covalent rules and composition rules of organic compounds.

[0067] The term "heterocyclyl" or "heterocycle" means a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system containing carbon atoms and heteroatoms. The heteroatoms have the meanings as described herein. Saturated or partially unsaturated heterocyclyls may be fully saturated or contain one or more degrees of unsaturation, but none of the aromatic rings may be present. In one embodiment, the heterocyclyl group is a 3-8 membered ring, such as a 3-8 membered saturated or partially unsaturated heterocyclyl (2-7 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give groups such as SO, SO2, PO, PO2), which may be represented as a 3-8 membered heterocyclyl. In one embodiment, the heterocyclyl is a 3-6 membered heterocyclyl. In one embodiment, the heterocyclyl is a 5-6 membered heterocyclyl. In one embodiment, the saturated or partially unsaturated heterocyclic group is selected from the group consisting of a saturated monocyclic heterocyclic group, a saturated bicyclic heterocyclic group, a saturated tricyclic heterocyclic group, a partially unsaturated monocyclic heterocyclic group, a partially unsaturated bicyclic heterocyclic group, and a partially unsaturated tricyclic heterocyclic group. Bicyclic heterocyclic groups refer to heterocyclic groups of bicyclic ring systems. Monocyclic heterocyclic groups refer to heterocyclic groups of monocyclic ring systems. 5-6 membered heterocyclic groups refer to heterocyclic groups with 5-6 ring atoms. 4-7 membered heterocyclic groups refer to heterocyclic groups with 4-7 ring atoms. 3-6 membered heterocyclic groups refer to heterocyclic groups with 3-6 ring atoms.

[0068] The term "cycloalkyl" refers to a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system containing carbon atoms. Saturated or partially unsaturated cycloalkyl groups may be fully saturated or contain one or more degrees of unsaturation, but may not have an aromatic ring. In one embodiment, the cycloalkyl group contains 3 to 10 carbon atoms, such as C 3-10 Saturated or partially unsaturated cycloalkyl, represented by C 3-10 In some embodiments, the cycloalkyl group is C 3-8 In some embodiments, the cycloalkyl group is C 3-6 Cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and the like. In one embodiment, the saturated or partially unsaturated cycloalkyl is selected from: saturated monocyclic cycloalkyl, saturated bicyclic cycloalkyl, saturated tricyclic cycloalkyl, partially unsaturated monocyclic cycloalkyl, partially unsaturated bicyclic cycloalkyl, partially unsaturated tricyclic cycloalkyl. 4-7 Cycloalkyl refers to a cycloalkyl group having 4 to 7 ring atoms. 3-6 Cycloalkyl refers to a cycloalkyl group having 3 to 6 ring atoms.

[0069] The term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic, bicyclic and tricyclic aromatic system containing heteroatoms. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". The heteroatoms have the definition described in the present invention. In some embodiments, the heteroaryl group is a heteroaryl group composed of 5-10 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a 5-10-membered heteroaryl group; the heteroaryl group is a heteroaryl group composed of 5-8 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a 5-8-membered heteroaryl group; in some embodiments, the heteroaryl group is a heteroaryl group composed of 5-7 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a 5-7-membered heteroaryl group. ; In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-6 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-6 membered heteroaryl group; In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-membered heteroaryl group; In some embodiments, the heteroaryl group is a heteroaryl group consisting of 6 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 6-membered heteroaryl group.

[0070] The term "aryl" or "aromatic ring" refers to a monocyclic, bicyclic, or tricyclic aromatic carbon ring system. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic ring". 6-14 membered aryl refers to an aromatic group containing 6-14 ring carbon atoms, also represented by C 6-14Aryl. 6-10 membered aryl refers to an aromatic group containing 6-10 ring carbon atoms, also represented by C 6-10 Aryl. Examples include, but are not limited to, phenyl, naphthyl, and the like.

[0071] The term "hydrogen" means 1 H.

[0072] Deuterium means 2 H.

[0073] The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0074] The term "amino" refers to -NH2.

[0075] The term "hydroxy" refers to -OH.

[0076] The term "cyano" refers to -CN.

[0077] The term "nitro" refers to -NO2.

[0078] The term "carboxyl" refers to HO(C=O)-.

[0079] The term "O=" refers to oxo, that is, when the substituent is O=", O is connected to the substituted group through a double bond.

[0080] The term "alkyl" or "alkyl group" refers to a saturated straight or branched hydrocarbon group containing carbon atoms. In one embodiment, the alkyl group contains 1 to 10 carbon atoms, i.e., C 1-10 In one embodiment, the alkyl group contains 1-8 carbon atoms, i.e., C 1-8 In one embodiment, the alkyl group contains 1-6 carbon atoms, i.e., C 1-6 In another embodiment, the alkyl group contains 1-4 carbon atoms, i.e., C 1-4 Alkyl; In another embodiment, the alkyl group contains 1-3 carbon atoms, i.e., C 1-3 Alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0081] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as defined herein. In one embodiment, the alkoxy group contains 1 to 10 carbon atoms, i.e., C 1-10 In one embodiment, the alkoxy group contains 1-8 carbon atoms, i.e., C 1-8 In one embodiment, the alkoxy group contains 1-6 carbon atoms, i.e., C 1-6In another embodiment, the alkoxy group contains 1-4 carbon atoms, i.e., C 1-4 In another embodiment, the alkoxy group contains 1-3 carbon atoms, i.e., C 1-3 Alkoxy.

[0082] The term "alkylamino" means an alkyl group attached to the rest of the molecule via a nitrogen atom, wherein the alkyl group has the meaning as defined herein. In one embodiment, the alkylamino group contains 1 to 10 carbon atoms, i.e., C 1-10 In one embodiment, the alkylamino group contains 1-8 carbon atoms, i.e., C 1-8 In one embodiment, the alkylamino group contains 1 to 6 carbon atoms, i.e., C 1-6 In another embodiment, the alkylamino group contains 1-4 carbon atoms, i.e., C 1-4 In another embodiment, the alkylamino group contains 1-3 carbon atoms, i.e., C 1-3 Alkylamino.

[0083] The term "comprising" is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended, and does not exclude additional, unrecited elements or ingredients from the drug (or, in the case of a method, a step). The phrase "consisting of excludes any element, step, or ingredient not specified in the drug (or, in the case of a method, a step). The phrase "consisting essentially of refers to the specified materials and those materials that do not materially affect the basic and novel characteristics of the drug (or, in the case of a method, a step).

[0084] The term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is a substituent described above, or a substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position, i.e., each substitution is independent of each other. It will be appreciated by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.

[0085] The compound of the present invention can be combined with a pharmaceutically acceptable carrier to form a pharmaceutical preparation for preventing, treating, curing or alleviating non-alcoholic fatty liver, steatohepatitis, liver fibrosis, liver cirrhosis or pulmonary fibrosis.

[0086] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance that can be used to prepare or use a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd ed., Pharmaceutical Press, 2013, pp. 1049-1070).

[0087] The compounds of the invention are formulated for non-parenteral administration, such as nasal, oral, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ophthalmic, or especially for oral administration, for example in the form of oral solid dosage forms, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard and soft capsules or hydroxypropylmethylcellulose (HPMC) capsules (suitably coated), orally disintegrating tablets, oral solutions, lipid emulsions or suspensions, or for parenteral administration, such as intravenous, intramuscular or subcutaneous, intrathecal, intradermal or epidural administration to mammals, especially humans, for example in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles. These compositions may contain the active ingredient alone, or preferably, together with a pharmaceutically acceptable carrier.

[0088] The compounds of the present invention or their pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or organic excipients for the production of oral solid dosage forms, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules or HPMC capsules or orally disintegrating tablets. Fillers such as lactose, cellulose, mannitol, sorbitol, calcium phosphate, starch or its derivatives, binders such as cellulose, starch, polyvinyl pyrrolidone or its derivatives, glidants such as talc, stearic acid or its salts, flow agents such as fumed silicon dioxide, can be used as such excipients for the preparation and manufacture of oral solid dosage forms, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules or HPMC capsules or orally disintegrating tablets. Suitable excipients for soft capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols, etc.

[0089] Suitable excipients for the production of oral solutions, lipid emulsions or suspensions are, for example, water, alcohols, polyols, sucrose, invert sugar, glucose and the like.

[0090] Suitable excipients for parenteral formulations are, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants and the like.

[0091] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. The pharmaceutical preparations may also contain other therapeutically valuable substances.

[0092] The dosage can vary within wide limits and, of course, will be in accordance with individual requirements in each particular case. In general, in the case of oral administration, a daily dosage of about 1 to 1000 mg of a compound of formula I per person should be appropriate, although the above lower or upper limits may also be exceeded if necessary.

[0093] The compounds of the invention may also be used in combination with one or more other pharmacologically active compounds which are also effective against the same disease, preferably using a different mode of action, or which reduce or prevent possible undesirable side effects of the compounds. The combination partners may be administered simultaneously in such treatment, for example by incorporating them into a single pharmaceutical formulation, or sequentially by administering two or more different dosage forms, each containing one or more than one combination partner.

[0094] The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that will cause a biological or medical response in a subject (e.g., a reduction or inhibition of enzyme or protein activity, or improvement of symptoms, alleviation of symptoms, slowing or delaying disease progression, or prevention of disease, etc.). In a non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, is effective in at least partially preventing, treating, curing, or alleviating nonalcoholic fatty liver disease, steatohepatitis, liver fibrosis, cirrhosis, or pulmonary fibrosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0095] Figure 1 The western blot activity diagram at a concentration of 10 μM measured by the TGF-β-induced rat hepatic stellate cell CFSC activation experiment in Example 1; (A) is the results of compounds 11-a, 24, 6, 25, 23, 21-a, 7, 8, 10-a, and 13, and (B) is the results of compounds 20, 10-b, 22, 11-b, 21-b, 4-a, 4-b, 26, and 9.

[0096] Figure 2These are the results of visual inspection, HE (40×), Masson (100×), and Sirius Red (100×) staining of the livers of Sham, OJ, 4-a, 4-b, 6, 9, 20, 21-b, 22, and 26 groups of mice in the bile duct ligation mouse experiment in Example 2; (A) is the result for compounds 20, 22, 21-b, and 4-a, (B) is the result for compounds 4-b, 26, 9, and 6, and (C) is the result for each concentration of compound 22.

[0097] Figure 3 These are the results of visual inspection, HE (100×), Masson (100×), Sirius Red (100×), and Oil Red O (100×) staining of the livers of the blank, MCD, and MCD+22 groups of mice in the MCD mouse experiment in Example 3.

[0098] Figure 4 This is the western blot activity diagram at a concentration of 10 μM measured by the TGF-β-induced human embryonic lung fibroblast MRC-5 activation experiment in Example 4; (B) is the results of compounds 15, 22, 11-b, 4-a, 4-b, 26, 9, 21-b, 17, and 18.

[0099] Figure 5 This is the western blot activity diagram at a concentration of 10 μM measured by the TGF-β-induced human renal cortical proximal tubule epithelial cell HK-2 activation experiment in Example 5; the results of 12, 20, 10-b, 22, 21-b, 10, 11-a, 6, 25, and 23. Specific embodiments

[0100] In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0101] The reagents used in the present invention can all be purchased from the market.

[0102] Compounds 4-a, 4-b, 6, 10-b, 21-a, and 21-b were purchased from Shanghai Titan Technology Co., Ltd., and their ID names are: MFCD00002597, MFCD00063059, MFCD00063065, MFCD00063061, MFCD00065684, and MFCD08059708, respectively;

[0103] Compound 7 was purchased from Shanghai BiDe Pharmaceutical Technology Co., Ltd. with ID name: MFCD01318878.

[0104] Compound 9 was purchased from Shanghai E-En Chemical Technology Co., Ltd. with the ID name: MFCD00007123;

[0105] Compound 10-a was purchased from Anhui Zesheng Technology Co., Ltd. with ID name: MFCD00002598;

[0106] Compound 15 was purchased from Shanghai Taoshu Biotechnology Co., Ltd. with the ID name: MFCD00004272;

[0107] Compound 20 was purchased from Chengdu Caoyuankang Biotechnology Co., Ltd. with the ID name: MFCD00069231;

[0108] Compounds 22 and 23 were purchased from Shanghai Yuanye Biotechnology Co., Ltd. with ID names: MFCD00799030,

[0109] MFCD00038958;

[0110] Compound 24 was purchased from Shanghai MacLean Biochemical Technology Co., Ltd. with ID name: MFCD00871210.

[0111] Compound 25 was purchased from Shanghai Pulse Pharmaceutical Technology Co., Ltd. with the ID name: MFCD00865839.

[0112] Compound 26 was purchased from Beijing Jinming Biotechnology Co., Ltd. with ID name: MFCD00083180.

[0113]

[0114]

[0115] Example 1: Experiment on TGF-β-induced rat hepatic stellate cells

[0116] 1. Experimental purpose:

[0117] The inhibitory effect of the compounds of the present invention on TGF-β-induced rat hepatic stellate cells was determined.

[0118] 2. Experimental methods:

[0119] (1) TGF-β stimulates CFSC signal transduction and activation: Rat hepatic stellate cells (CFSCs) were cultured in RPMI-1640 medium containing 10% fetal bovine serum. After trypsin digestion and centrifugation, an appropriate amount of CFSC cells in logarithmic growth was resuspended in RPM-1640 medium containing serum. After being fully mixed with a pipette, the cells were inoculated into a 12-well plate and cultured in a cell culture incubator. When the cell density reached 60%, the cell culture medium was sucked out with a vacuum pump, and serum-free RPMI-1640 medium containing TGF-β (5 μg / L) and serum-free RPMI-1640 medium containing TGF-β (5 μg / L) and drugs (10 μM) were added for 24 hours.

[0120] (2) Extraction of total cell protein: After 24 hours, use a vacuum pump to suck out the cell culture medium, add pre-cooled 1×PBS along the wall of the well to wash twice, then add an appropriate amount of cell lysis buffer and lyse at 4°C for 10 minutes. Use a scraper to collect the cells and transfer them to a 1.5mL EP tube. Centrifuge at 4°C, 12,000rpm for 10 minutes, then carefully aspirate the upper protein lysate and transfer it to a new 1.5mL EP tube for protein quantification using the BCA method. After quantification, adjust the protein concentration of the same batch of samples to the same level, add 5×SDS gel protein loading buffer, mix thoroughly, and boil in a 100°C metal bath for 10 minutes to denature the protein. After boiling, centrifuge the protein sample for western blot detection.

[0121] (3) Polyacrylamide gel electrophoresis (SDS-PAGE): After cleaning and fixing the glass plate, prepare 10% separation gel and 5% concentration gel in a certain ratio. After the perfusion is completed, wait for solidification, wash and load the sample. After adding buffer to the tank, start electrophoresis. Stop when the sample runs to the bottom and perform the membrane transfer operation. Control the transfer time according to the required protein amount. Block the protein-containing PVDF membrane with 5% skim milk at room temperature for 1 hour, then wash with TBST and add the primary antibody, and incubate overnight at 4°C. Wash away the unbound primary antibody with TBST and then add the corresponding secondary antibody. Incubate on a shaker at room temperature for 1 hour. After the TBST washing is complete, add the color developing solution and develop with a Biorad chemiluminescent imager.

[0122] Experimental reagent information is shown in Table 1:

[0123] Table 1

[0124]

[0125] 3. Test results:

[0126] When the compound concentration was 10 μM, the test results were as follows Figure 1As shown in ((A) is the results for compounds 11-a, 24, 6, 25, 23, 21-a, 7, 8, 10-a, and 13; (B) is the results for compounds 20, 10-b, 22, 11-b, 21-b, 4-a, 4-b, 26, and 9); the results showed that compounds 4-a, 4-b, 6, 9, 10-a, 10-b, 26, 20, 21-a, 21-b, 22, 23, 24, and 25 exhibited certain TGF-β-induced inhibitory activity on rat hepatic stellate cells.

[0127] The experimental results show that the compound of the present invention has good anti-liver fibrosis activity.

[0128] Example 2: Mouse bile duct ligation experiment

[0129] 1. Experimental purpose:

[0130] The inhibitory effect of the compounds of the present invention on liver fibrosis in bile duct ligated mice was determined.

[0131] 2. Experimental methods:

[0132] (1) Mouse modeling: After 7-8 week C57 / BL6 mice were adaptively fed for one week, they were weighed and skinned, and then anesthetized with isoflurane inhalation. The mice were fixed on the operating table and disinfected with alcohol cotton balls. After disinfection, the mouse abdomen was opened layer by layer along the midline of the abdomen, and the mouse abdomen was fully exposed using an animal abdominal opener. The mouse liver lobe was gently spread apart with a cotton swab soaked in saline. After the mouse portal vein was fully exposed, the common bile duct was found at the beginning of the duodenum and separated. In the sham group, the mouse common bile duct was exposed after laparotomy without ligation. The mouse abdominal organs were returned to their original positions with a cotton swab soaked in saline, and then the abdomen was closed in layers with 4-0 sterile sutures. After the abdomen was closed, the mouse abdominal incision was disinfected. Because the body temperature of the mouse was low after anesthesia recovery, the postoperative mouse was placed on a heating pad to maintain the rectal temperature at 37±0.5℃ and wait for awakening. The mice after recovery were fed a normal diet. After bile duct ligation and laparotomy, the common bile duct of the mouse was exposed and two sutures were passed under the common bile duct and ligated separately. The abdomen was then closed in layers with 4-0 sterile sutures. The rest of the steps were the same as those in the sham operation group.

[0133] (2) Drug administration: The mice with successful modeling were randomly divided into an obstructive jaundice group (OJ) and a drug intervention group. The experiments were all administered by intragastric administration for 14 consecutive days. The daily intragastric dose of compounds 4-a, 4-b, 6, 9, 20, 21-b, 22, and 26 after surgery was 5 mg kg -1 (Dissolved in 0.5% CMCNa solution to prepare 5 mg mL -1 Solution), the daily oral dose of compound 22 after surgery was 1.25, 2.5, and 5 mg kg -1The sham group and the OJ group should be given the same amount of 0.5% CMCNa solution within the same time period.

[0134] (3) Experimental records: 14 days later, mice in each group were fasted but not watered for 12 hours after the last administration, and blood was collected from the eyeballs after weighing. The livers of mice were dissected and separated, and the appearance of the livers was observed and photographed; the same position of the left lobe of the liver was removed and fixed in 4% paraformaldehyde solution for histopathological experiments.

[0135] 3. Experimental results

[0136] Test results such as Figure 2 As shown in ((A) is the results of compounds 20, 22, 21-b, and 4-a, (B) is the results of compounds 4-b, 26, 9, and 6, and (C) is the results of various concentrations of compound 22): Compounds 4-a, 4-b, 6, 9, 20, 21-b, 22, and 26 can effectively and significantly improve the degree of liver fibrosis in bile duct ligated mice.

[0137] Example 3: Experiment on non-alcoholic steatohepatitis in mice induced by methionine-choline deficient diet

[0138] 1. Experimental purpose:

[0139] The improving effect of the compound of the present invention on non-alcoholic steatohepatitis mice induced by methionine-choline deficient diet (MCD) was determined.

[0140] 2. Experimental methods:

[0141] Fifteen male C57BL / 6 mice were randomly divided into blank group (n=5), MCD model group (n=5), and MCD+Compound 22 (5 mg / kg) group (n=5) according to body weight. After one week of adaptive feeding of mice, the blank group was given a normal diet, and the mice in the MCD model group and the MCD treatment group were fed with MCD feed transition: the first two days were fed with a mixed feed of MCD: normal feed = 1:2; on the third day, they were fed with a mixed feed of MCD: normal feed = 1:1 for two days; starting from the fifth day, they continued to be fed with a mixed feed of MCD: normal feed = 2:1 for two days. Starting from the seventh day, after three weeks of formal feeding with MCD feed, oral administration began, and the administration time was two weeks. The oral dose of Compound 22 was 5 mg·kg -1 (dissolved in 0.5% CMCNa solution); the blank group and MCD model group should be given the same amount of 0.5% CMCNa solution in the same time period.

[0142] After 14 days, mice in each group were fasted but not watered for 12 hours after the last administration, and blood was collected from the eyeballs after weighing. The livers of mice were dissected and separated, and the appearance of the livers was observed and photographed; the same position of the left lobe of the liver was removed and fixed in 4% paraformaldehyde solution for histopathological experiments.

[0143] 3. Experimental results

[0144] Test results such as Figure 3 The results for compound 22 are shown in FIG. 2 : Compound 22 can effectively and significantly improve the degree of liver fibrosis in MCD mice.

[0145] Example 4: Experiment on TGF-β-induced human embryonic lung fibroblasts

[0146] 1. Experimental purpose:

[0147] The inhibitory effect of the compounds of the present invention on TGF-β-induced human embryonic lung fibroblasts was determined.

[0148] 2. Experimental methods:

[0149] (1) TGF-β stimulates MRC-5 signal transduction and activation: Human embryonic lung fibroblasts MRC-5 were cultured in MEM medium containing 10% fetal bovine serum. MRC-5 cells in logarithmic growth phase were digested with trypsin and centrifuged, and then an appropriate amount was resuspended in MEM medium containing serum. After being fully mixed with a pipette, the cells were inoculated into a 12-well plate and cultured in a cell culture incubator. When the cell density reached 60%, the cell culture medium was sucked out with a vacuum pump, and MEM medium containing TGF-β (5 μg / L) and MEM medium containing TGF-β (5 μg / L) and drugs (10 μM) were added for 24 hours.

[0150] (2) Extraction of total cell protein: After 24 hours, use a vacuum pump to suck out the cell culture medium, add pre-cooled 1×PBS along the wall of the well to wash twice, then add an appropriate amount of cell lysis buffer and lyse at 4°C for 10 minutes. Use a scraper to collect the cells and transfer them to a 1.5mL EP tube. Centrifuge at 4°C, 12,000rpm for 10 minutes, then carefully aspirate the upper protein lysate and transfer it to a new 1.5mL EP tube for protein quantification using the BCA method. After quantification, adjust the protein concentration of the same batch of samples to the same level, add 5×SDS gel protein loading buffer, mix thoroughly, and boil in a 100°C metal bath for 10 minutes to denature the protein. After boiling, centrifuge the protein sample for western blot detection.

[0151] (3) Polyacrylamide gel electrophoresis (SDS-PAGE): After cleaning and fixing the glass plate, prepare 10% separation gel and 5% concentration gel in a certain ratio. After the perfusion is completed, wait for solidification, wash and load the sample. After adding buffer to the tank, start electrophoresis. Stop when the sample runs to the bottom and perform the membrane transfer operation. Control the transfer time according to the required protein amount. Block the protein-containing PVDF membrane with 5% skim milk at room temperature for 1 hour, then wash with TBST and add the primary antibody, and incubate overnight at 4°C. Wash away the unbound primary antibody with TBST and then add the corresponding secondary antibody. Incubate on a shaker at room temperature for 1 hour. After the TBST washing is complete, add the color developing solution and develop with a Biorad chemiluminescent imager.

[0152] Experimental reagent information is shown in Table 2:

[0153] Table 2

[0154]

[0155] 3. Test results:

[0156] When the compound concentration was 10 μM, the test results were as follows Figure 4 As shown ((A) is the results for compounds 3, 13, 10-a, 5, 12, 1, 2, 19, 20, and 10-b, (B) is the results for compounds 15, 22, 11-b, 4-a, 4-b, 26, 9, 21-b, 17, and 18): Compounds 2, 5, 10-a, 10-b, 12, 19, 20, 22, and 26 showed certain TGF-β-induced inhibitory activity on human embryonic lung fibroblasts.

[0157] It can be seen from the experimental results that the compound of the present invention has good anti-pulmonary fibrosis activity.

[0158] Example 5: Experiment on TGF-β-induced human renal cortical proximal tubule epithelial cells

[0159] 1. Experimental purpose:

[0160] The inhibitory effect of the compounds of the present invention on TGF-β-induced human renal cortical proximal tubule epithelial cells (HK-2) was determined.

[0161] 2. Experimental methods:

[0162] (1) TGF-β stimulates HK-2 signal transduction and activation: Human embryonic lung fibroblasts HK-2 were cultured in DMEM medium containing 10% fetal bovine serum. HK-2 cells in logarithmic growth phase were digested with trypsin and centrifuged, and then an appropriate amount was resuspended in DMEM medium containing serum. After being fully mixed with a pipette, the cells were inoculated into 12-well plates and cultured in a cell culture incubator. When the cell density reached 60%, the cell culture medium was sucked out with a vacuum pump, and DMEM medium containing TGF-β (5 μg / L) and DMEM medium containing TGF-β (5 μg / L) and drugs (10 μM) were added for 24 hours.

[0163] (2) Extraction of total cell protein: After 24 hours, use a vacuum pump to suck out the cell culture medium, add pre-cooled 1×PBS along the wall of the well to wash twice, then add an appropriate amount of cell lysis buffer and lyse at 4°C for 10 minutes. Use a scraper to collect the cells and transfer them to a 1.5mL EP tube. Centrifuge at 4°C, 12,000rpm for 10 minutes, then carefully aspirate the upper protein lysate and transfer it to a new 1.5mL EP tube for protein quantification using the BCA method. After quantification, adjust the protein concentration of the same batch of samples to the same level, add 5×SDS gel protein loading buffer, mix thoroughly, and boil in a 100°C metal bath for 10 minutes to denature the protein. After boiling, centrifuge the protein sample for western blot detection.

[0164] (3) Polyacrylamide gel electrophoresis (SDS-PAGE): After cleaning and fixing the glass plate, prepare 10% separation gel and 5% concentration gel in a certain ratio. After the perfusion is completed, wait for solidification, wash and load the sample. After adding buffer to the tank, start electrophoresis. Stop when the sample runs to the bottom and perform the membrane transfer operation. Control the transfer time according to the required protein amount. Block the protein-containing PVDF membrane with 5% skim milk at room temperature for 1 hour, then wash with TBST and add the primary antibody, and incubate overnight at 4°C. Wash away the unbound primary antibody with TBST and then add the corresponding secondary antibody. Incubate on a shaker at room temperature for 1 hour. After the TBST washing is complete, add the color developing solution and develop with a Biorad chemiluminescent imager.

[0165] Experimental reagent information is shown in Table 3:

[0166] Table 3

[0167]

[0168] 3. Test results:

[0169] When the compound concentration was 10 μM, the test results were as follows Figure 5As shown (the results of compounds 12, 20, 10-b, 22, 21-b, 10, 11-a, 6, 25, and 23): Compounds 12, 20, 10-b, 22, 21-b, 10, and 6 exhibited certain TGF-β-induced inhibitory activity on human embryonic lung fibroblasts.

[0170] The experimental results show that the compound of the present invention has good activity against renal fibrosis.

[0171] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0172] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. Use of a compound of formula I or its stereoisomers, hydrates, solvates, isotope-labeled substances, prodrugs thereof or pharmaceutically acceptable salts thereof in the preparation of a medicament, wherein the medicament is used to prevent, treat, cure or alleviate non-alcoholic fatty liver disease, steatohepatitis, liver fibrosis, cirrhosis, pulmonary fibrosis or renal fibrosis; in: R 1 , R 2 , R 3 , R 4 , R 5 Each is independently selected from H, D, halogen, -CN, -NO2, -OH, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkoxy, C 6-14 Aryl, C 6-14 Aryloxy, R a C(=O)O- and R a S(=O)2O-,R a Selected from C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl and C 6-14 Aryl, wherein the C 6-14 Aryl and C 6-14 The aryloxy groups are each independently optionally unsubstituted or substituted with 1-3 substituents selected from H, D, halogen, -OH; optionally, R 1 , R 2 Together with the atoms to which they are attached, or R 2 , R 3 Together with the atoms to which they are attached, they form C 6-14 Aryl; preferably, R 1 , R 2 , R 3 , R 4 , R 5 Each is independently selected from H, D, halogen, -CN, -NO2, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryloxy, R a C(=O)O- and R a S(=O)2O-,R a Preferred from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and C 6-10 Aryl, wherein the C 6-10 Aryl and C 6-10 The aryloxy groups are each independently optionally unsubstituted or substituted with 1-3 substituents selected from H, D, halogen, -OH; optionally, R 1 , R 2 Together with the atoms to which they are attached, or R 2 , R 3 Together with the atoms to which they are attached, they form C 6-10 Aryl; R 6 Selected from H, D, C 1-10 Alkyl and C 3-10 Cycloalkyl; preferably, R 6 Selected from H, D, C 1-6 Alkyl and C 3-6 Cycloalkyl; R 7 Selected from H, D and -OR b ; where R b Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-; preferably, R 7 Selected from H, D and -OR b ; where R b Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(═O)-; R 8 , R 9 Each independently selected from H, -NHR c 、-OR d , C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-OC(=O)-, C 3-10 Cycloalkyl-OC(=O)-, C 6-14 Aryl-OC(=O)-, C 6-14 Aryl-C 1-4 Alkyl-OC(=O)-, C 1-10 Alkyl-S(=O)2-, C 1-10 Haloalkyl-S(=O)2-, C 3-10 Cycloalkyl-S(=O)2-, C 6-14 Aryl-S(=O)2-, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-; wherein R c Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-OC(=O)-, C 3-10 Cycloalkyl-OC(=O)-, C 6-14 Aryl-OC(=O)-, C 6-14 Aryl-C 1-4 Alkyl-OC(=O)-, C 1-10 Alkyl-S(=O)2-, C 1-10 Haloalkyl-S(=O)2-, C 3-10 Cycloalkyl-S(=O)2-, C 6-14 Aryl-S(=O)2-, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-, R d Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 1-10 Alkyl-C(=O)-, C 3-10 Cycloalkyl-C(=O)- and C 6-14 Aryl-C(=O)-; preferably, R 8 , R 9 Each independently selected from H, -NHR c 、-OR d , C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-OC(=O)-, C 3-6 Cycloalkyl-OC(=O)-, C 6-10 Aryl-OC(=O)-, C 6-10 Aryl-C 1-4 Alkyl-OC(=O)-, C 1-6 Alkyl-S(=O)2-, C 1-6 Haloalkyl-S(=O)2-, C 3-6 Cycloalkyl-S(=O)2-, C 6-10 Aryl-S(=O)2-, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(=O)-; wherein R c Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-OC(=O)-, C 3-6 Cycloalkyl-OC(=O)-, C 6-10 Aryl-OC(=O)-, C 6-10 Aryl-C 1-2 Alkyl-OC(=O)-, C 1-6 Alkyl-S(=O)2-, C 1-6 Haloalkyl-S(=O)2-, C 3-6 Cycloalkyl-S(=O)2-, C 6-10 Aryl-S(=O)2-, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(=O)-, R d Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-C(=O)-, C 3-6 Cycloalkyl-C(=O)- and C 6-10 Aryl-C(═O)-; X is the formula: Among them, R 10 Selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl and C 6-14 Aryl; R 11 , R 12 Each independently selected from H, -OH, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 6-14 Aryl and C 6-14 Aryl C 1-10 Alkyl; or R 11 , R 12 Together with the atoms to which they are attached, they form a 3-8 membered heterocyclic group; preferably, R 10 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 6-10 Aryl; R 11 , R 12 Each independently selected from H, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl and C 6-10 Aryl C 1-6 Alkyl; or R 11 , R 12 Together with the atoms to which they are attached, they form a 3-6 membered heterocyclic group.

2. The use according to claim 1, characterized in that R 1 , R 2 , R 3 , R 4 , R 5 Each is independently selected from H, D, F, Cl, Br, I, -CN, -NO2, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, phenyl, naphthyl, phenanthrenyl, phenoxy, naphthyloxy, phenanthrenoxy, CH3C(=O)O-, CH3CH2C(=O)O-, CH3CH2CH2C(=O)O-, (CH3)2CHC(=O)O-, (CH3)3C(=O)O-, cyclopropyl-C(=O)O-, cyclobutyl-C(=O)O-, cyclopentyl-C(=O)O-, cyclohexyl-C(=O)O-, phenyl-C(=O)O-, CH3S(=O)2O-, CF3S(=O)2O-, cyclohexyl-S(=O)2O-, phenyl-S(=O)2O-, quinolyl-S(=O)2O-, isoquinolyl-S(=O)2O-, p-CH3-phenyl-S(=O)2O-; wherein the C 6-14 Aryl, C 6-14 The aryloxy groups are each independently optionally unsubstituted or substituted with 1-3 substituents selected from H, D, F, Cl, Br, I, -OH; optionally, R 1 , R 2 Together with the atoms to which they are attached, or R 2 , R 3 Together with the atoms to which they are attached they form a phenyl or naphthyl group.

3. The use according to claim 1, characterized in that R 6 is selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

4. The use according to claim 1, characterized in that R 7 Selected from H, D, OR b ; where R b Selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, CH3C(=O)-, CH3CH2C(=O)-, CH3CH2CH2C(=O)-, (CH3)2CHC(=O)-, (CH3)3CC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, phenyl-C(=O)-.

5. The use according to claim 1, characterized in that: R 8 , R 9 Each independently selected from H, -NHR c 、-OR d , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 9-fluorenylmethoxycarbonyl, CH3-OC(=O)-, CH3CH2-OC(=O)-, CH3CH2CH2-OC(=O)-, (CH3)2CH-OC(=O)-, (CH3)3C-OC(=O)-, cyclopropyl-OC(=O)-, cyclobutyl-OC(=O)-, cyclopentyl-OC(=O)-, cyclohexyl-OC(=O)-, phenyl-CH2-OC(=O)-, phenyl-CH 2CH2-OC(=O)-, phenyl-OC(=O)-, CH3C(=O)-, CH3CH2C(=O)-, CH3CH2CH2C(=O)-, (CH3)2CHC(=O)-, (CH3)3CC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, phenyl-C(=O)-, CH3S(=O)2-, CF3S(=O)2-, cyclohexyl-S(=O)2O-, phenyl-S(=O)2-, p-CH3-phenyl-S(=O)2-; wherein R c is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 9-fluorenylmethoxycarbonyl, CH3-OC(=O)-, CH3CH2-OC(=O)-, CH3CH2CH2-OC(=O)-, (CH3)2CH-OC(=O)-, (CH3)3C-OC(=O)-, cyclopropyl-OC(=O)-, cyclobutyl-OC(=O)-, cyclopentyl-OC(=O)-, cyclohexyl-OC(=O)-, phenyl-CH2-OC(=O)-, phenyl -CH2CH2-OC(=O)-, phenyl-OC(=O)-, CH3C(=O)-, CH3CH2C(=O)-, CH3CH2CH2C(=O)-, (CH3)2CHC(=O)-, (CH3)3CC(=O)-, cyclopropyl-C(=O)-, cyclobutylC(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, phenyl-C(=O)-, CH3S(=O)2-, CF3S(=O)2-, cyclohexyl-S(=O)2O-, phenyl-S(=O)2-, p-CH3-phenyl-S(=O)2-, R d Selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, CH3C(=O)-, CH3CH2C(=O)-, CH3CH2CH2C(=O)-, (CH3)2CHC(=O)-, (CH3)3CC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, phenyl-C(=O)-.

6. The use according to claim 1, characterized in that: R 10 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, benzyl and phenyl; R 11 , R 12 Each is independently selected from H, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, benzyl, phenyl, or R 11 , R 12 Together with the atoms to which they are attached they form a pyrrolidinyl, piperidinyl or piperazinyl.

7. The use according to claim 1, characterized in that Formula I has one of the following structures:

8. The use according to claim 1, characterized in that Formula I has one of the following structures:

9. Use of (S)-4-(2-(N-methylisoquinoline-5-sulfonamido)-3-oxo-3-(4-phenylpiperazin-1-yl)propyl)phenylisoquinoline-5-sulfonate or its stereoisomers, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof in the preparation of a medicament, wherein the medicament is used to prevent, treat, cure or alleviate non-alcoholic fatty liver disease, steatohepatitis, liver fibrosis, cirrhosis, pulmonary fibrosis or renal fibrosis; 10. The use according to claim 1 or 9, characterized in that: The medicine is used for preventing liver fibrosis or lung fibrosis.

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