WO2021073643A1 - Drug for treating non-alcoholic steatohepatitis - Google Patents

Abstract

The present application relates to the field of medicine, relates to drugs for treating non-alcoholic steatohepatitis, in particular, to linked cyclic compounds for treating non-alcoholic steatohepatitis, more in particular, to a compound as represented by formula (I) or the use of pharmaceutically-acceptable salts thereof in preparing a drug for treating non-alcoholic steatohepatitis.

Description

Drugs used to treat non-alcoholic steatohepatitis Technical field

This application belongs to the field of medicine, and relates to a class of drugs for the treatment of non-alcoholic steatohepatitis, specifically, to a class of bicyclic compounds for the treatment of non-alcoholic steatohepatitis.

Background technique

Non-alcoholic steatohepatitis (NASH), also known as metabolic steatohepatitis, refers to a clinical syndrome with pathological changes similar to alcoholic hepatitis found in people without a history of excessive drinking. The main features are Fatty degeneration of liver cells, ballooning and inflammation of liver lobules, etc., severe cases can progress to liver cirrhosis, and even liver cancer or liver failure.

The pathogenesis of non-alcoholic steatohepatitis is complex and is closely related to metabolic disorders such as obesity, type II diabetes, and dyslipidemia. Due to the complexity of the pathogenesis, the drugs currently under research mainly target a variety of possible different receptors or enzymes, such as PPARα/δ, FXR, CCR2/5, ASK1, and Caspase. Many drug molecules have entered the clinic. Such as selonsertib, resmetirom, elafibranor and cenicriviroc. However, there is no known correspondence between the inhibition, antagonism or agonism of these receptors or enzymes and the effective treatment of non-alcoholic steatohepatitis.

Caspase is a class of cysteine proteases, and many important proteins in cells are its substrates. The process of apoptotic cell death involves the absorption of fragments of cells decomposed by caspase enzymes by other cells, or they are eliminated by macrophages without causing inflammation.

Summary of the invention

In one aspect, the application provides a method for treating non-alcoholic steatohepatitis, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need of the treatment.

On the other hand, the application also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of non-alcoholic steatohepatitis.

On the other hand, this application also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of non-alcoholic steatohepatitis.

In another aspect, the application also provides a pharmaceutical composition for treating non-alcoholic steatohepatitis, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In the present application, the “treatment of non-alcoholic steatohepatitis” includes one or more histopathological characteristics of the patient, for example, in terms of portal inflammation, hepatosteatosis, and ballooning degeneration. (ballooning degeneration), and/or lobular inflammation (lobular inflammation) provide improvement or stop progression.

Compound of formula (I)

As used in this application, the compound of formula (I) described in this application or a pharmaceutically acceptable salt thereof is as follows:

among them,

Ring A is selected from a 5-membered heteroaryl group or a 6-membered heteroaryl group, the 5-membered heteroaryl group or 6-membered heteroaryl group is optionally substituted by R;

Ring B is selected from phenyl or C _3-6 cycloalkyl, said phenyl or C _3-6 cycloalkyl is optionally substituted by R;

R is selected from halogen, OH, NH ₂ , or C _1-3 alkyl optionally substituted with 1, 2 or 3 R ^1;

R ^{1 is} selected from F, Cl, Br, I, OH, NH ₂ , NH(CH ₃ ) or N(CH ₃ ) ₂ .

In some embodiments, the heteroatoms of ring A are independently selected from O, S, or N.

In some embodiments, the number of heteroatoms of ring A is selected from 1, 2, or 3.

In some embodiments, the ring A is selected from oxazolyl, isoxazolyl, imidazolyl, thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or pyridine. Azole.

In some embodiments, the ring A is selected from

In some embodiments, the ring B is selected from phenyl or cyclohexyl, and the phenyl or cyclohexyl is optionally substituted with R.

In some embodiments, the R is selected from F, Cl, Br, I, OH, NH ₂ , or Me or Et optionally substituted with 1, 2, or 3 R ^1. In some aspects of the present application, the above-mentioned R ^{1 is} selected from F, Cl or NH ₂ .

In some embodiments, the R is selected from F, Cl, Br, I, OH, NH 2, or optionally substituted with 1, 2 or 3 F, Me or Et.

In some embodiments, the R is selected from F, Cl, Br, I, OH, NH ₂ or CF ₃ .

In some embodiments, the ring B is selected from:

In some embodiments, the

Selected from

The ring B is optionally substituted by R.

In some embodiments, the

Selected from

In some embodiments, the

Selected from

In some embodiments, the

Selected from

In some embodiments, the compound of formula (I) of the present application is selected from the compound represented by formula (II),

Wherein, ring A and ring B are as defined above.

In some embodiments, the compound of formula (I) of the present application is selected from the following compounds:

Method of application

In one aspect, the application provides a method for treating non-alcoholic steatohepatitis, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need of the treatment.

The compound of formula (I) can be administered in its free base form, or in the form of its salts, hydrates and prodrugs, which are converted into the free base form of the compound of formula (I) in vivo. In some embodiments, the compound of formula (I) is in crystalline form.

The compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered by a variety of routes, including but not limited to oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, and intraperitoneal , Intramuscular, subcutaneous, or intravenous administration, preferably oral administration.

The amount of the compound of formula (I) or its pharmaceutically acceptable salt administered can be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 2 mg to 100 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 5 mg to 80 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 5 mg to 50 mg.

The compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered one or more times a day. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered three times a day. The compound of formula (I) or a pharmaceutically acceptable salt thereof can also be administered in a single dose or multiple doses.

The method of administration can be determined comprehensively according to the drug activity, side effects, patient tolerance, etc., and it is preferable to administer the compound of formula (I) or a pharmaceutically acceptable salt thereof in a continuous administration manner.

In some embodiments, the administration period of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 28 days.

In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient alone as the sole active ingredient.

On the other hand, the application also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of non-alcoholic steatohepatitis. Alternatively, the application also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of non-alcoholic steatohepatitis.

The compound of formula (I) can be administered in its free base form, or in the form of its salts, hydrates and prodrugs, which are converted into the free base form of the compound of formula (I) in vivo. In some embodiments, the compound of formula (I) is in crystalline form.

The compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered by a variety of routes, including but not limited to oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, and intraperitoneal , Intramuscular, subcutaneous, or intravenous administration, preferably oral administration.

The amount of the compound of formula (I) or its pharmaceutically acceptable salt administered can be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 2 mg to 100 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 5 mg to 80 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 5 mg to 50 mg.

The compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered one or more times a day. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered three times a day. The compound of formula (I) or a pharmaceutically acceptable salt thereof can also be administered in a single dose or multiple doses.

The method of administration can be determined comprehensively according to the drug activity, side effects, patient tolerance, etc., and it is preferable to administer the compound of formula (I) or a pharmaceutically acceptable salt thereof in a continuous administration manner.

In some embodiments, the administration period of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 28 days.

In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient alone as the sole active ingredient.

In another aspect, the application also provides a pharmaceutical composition for treating non-alcoholic steatohepatitis, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

The compound of formula (I) can be administered in its free base form, or in the form of its salts, hydrates and prodrugs, which are converted into the free base form of the compound of formula (I) in vivo. In some embodiments, the compound of formula (I) is in crystalline form.

The amount of the compound of formula (I) or its pharmaceutically acceptable salt administered can be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 2 mg to 100 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 5 mg to 80 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 5 mg to 50 mg.

In some embodiments of the application, the pharmaceutical composition is a preparation suitable for oral administration, including tablets, capsules, powders, granules, dripping pills, pastes, powders, etc., preferably tablets and capsules. The tablets may be ordinary tablets, dispersible tablets, effervescent tablets, sustained-release tablets, controlled-release tablets or enteric-coated tablets, and capsules may be ordinary capsules, sustained-release capsules, controlled-release capsules or enteric-coated capsules. The oral preparations can be prepared by conventional methods using pharmaceutically acceptable carriers known in the art. Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants and the like.

In some embodiments, the aforementioned pharmaceutical composition may be administered in a single dose or multiple doses.

In one embodiment, there is provided a pharmaceutical composition formulated in a single dose form for the treatment of non-alcoholic steatohepatitis. In one embodiment, the single dose form contains 2 mg to 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the single dose form contains 5 mg to 80 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the single dose form contains 5 mg to 50 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

The above-mentioned pharmaceutical composition can be administered one or more times a day. In some embodiments, the pharmaceutical composition described above is administered once a day. In some embodiments, the pharmaceutical composition described above is administered twice a day. In some embodiments, the pharmaceutical composition described above is administered three times a day.

The method of administration can be determined comprehensively according to drug activity, side effects, patient tolerance, etc., and it is preferable to administer the above-mentioned pharmaceutical composition in a continuous administration manner.

In some embodiments, the administration cycle of the above-mentioned pharmaceutical composition is 28 days.

Unless otherwise stated, the dosages and ranges provided in this application are based on the molecular weight of the free base form of the compound of formula (I).

In this application, the crystalline form of the compound of formula (I) includes, but is not limited to, crystal I, crystal II, crystal IV, crystal V, crystal VII, crystal VIII, and crystal IX of the compound of formula (I) disclosed in the international patent application WO2019174589. .

The in vivo pharmacodynamic study in the DIO/CCl mouse model of this application shows that the compound of formula (I) or its pharmaceutically acceptable salt of this application has a good therapeutic effect on non-alcoholic steatohepatitis, NAS score, balloon Metamorphosis and steatosis have been improved. The compound of formula (I) of the present application also improves blood biochemical indicators in liver injury.

definition

Unless otherwise stated, the following terms and phrases used in this application have the following meanings. A specific term or phrase should not be considered uncertain or unclear without a special definition, but should be understood according to the ordinary meaning in the art. When a trade name appears in this article, it is meant to refer to its corresponding commodity or its active ingredient.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reactions or other problems or complications of the disease are commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present application, which is prepared from a compound with specific substituents discovered in the present application and a relatively non-toxic acid or base. When the compound of the present application contains a relatively acidic functional group, the base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compound of the present application contains a relatively basic functional group, the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain specific compounds in this application contain basic and acidic functional groups, which can be converted into any base or acid addition salt.

Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.

The pharmaceutically acceptable salt of the present application can be synthesized from a parent compound containing an acidic functional group or a basic functional group by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or organic solvent or a mixture of both. Generally, the organic solvent is preferably a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.

In addition to salt forms, the compounds provided in this application also exist in prodrug forms. The prodrugs of the compounds described herein can easily undergo chemical changes under physiological conditions to convert the claimed compounds. In addition, prodrugs can be converted to the compounds of the present application through chemical or biochemical methods in the in vivo environment.

Certain compounds of this application may exist in unsolvated or solvated forms, including hydrated forms. Generally speaking, the solvated form is equivalent to the unsolvated form, and both are included in the scope of this application.

Certain compounds of this application may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included in the scope of the present application.

Unless otherwise specified, use wedge-shaped solid and dashed keys

Represents the absolute configuration of a three-dimensional center, using wavy lines

A solid or dashed key representing a wedge

When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, they include E and Z geometric isomers. Likewise, all tautomeric forms are included within the scope of this application.

The compounds of the present application may exist in specific geometric or stereoisomeric forms. This application contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of this application.

The optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of this application, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is removed to provide Pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), the molecule is formed with a suitable optically active acid or base to form a diastereomeric salt, and then the salt is obtained by the art The diastereoisomers are resolved by well-known conventional methods, and then the pure enantiomers are recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).

The compound of the present application may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( ³ H), iodine-125 ( ¹²⁵ I), or C-14 ( ¹⁴ C). All changes in the isotopic composition of the compounds of this application, whether radioactive or not, are included in the scope of this application.

The term "optional" or "optionally" refers to the event or condition described later that may but not necessarily occur, and the description includes a situation in which the event or condition occurs and a situation in which the event or condition does not occur .

The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of. When the substituent is a keto group (ie, =0), it means that two hydrogen atoms are replaced. Ketone substitution does not occur on aromatic groups. The term "optionally substituted" means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.

_{C mn} as used herein refers to having mn carbon atoms in this part. For example, "C _3-10 cycloalkyl" means that the cycloalkyl has 3-10 carbon atoms. The numerical range in this article refers to each integer in the given range. For example, "C _1-10 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 Carbon atoms, 9 carbon atoms, or 10 carbon atoms.

When any variable (such as R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group can optionally be substituted with up to two Rs, and R has independent options in each case. In addition, combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.

When a substituent is vacant, it means that the substituent is absent. For example, when X in A-X is vacant, it means that the structure is actually A.

When a substituent can be connected to more than one atom on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit

It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. When the listed substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom. For example, a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group. When the listed linking group does not indicate its linking direction, its linking direction is arbitrary, for example,

The middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right

It can also be formed by connecting ring A and ring B in the direction opposite to the reading order from left to right

Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.

Unless otherwise specified, the term "hetero" means a heteroatom or group of atoms (ie, groups of atoms containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and groups of atoms containing these heteroatoms, such as oxygen (O ), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, =O, =S, -C(= O) O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O) ₂ -, and optionally substituted -C(=O) N(H)-, -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- or -S(=O)N(H)-.

Unless otherwise specified, the term "heterocycle" or "heterocyclic group" means a stable monocyclic, bicyclic or tricyclic ring containing heteroatoms or heteroatoms, which may be saturated, partially unsaturated or unsaturated ( Aromatic), they contain carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles can be fused to a benzene ring to form a bicyclic ring. Nitrogen and sulfur heteroatoms can optionally be oxidized (ie NO and S(O) _p , p is 1 or 2). The nitrogen atom may be substituted or unsubstituted (ie N or NR, where R is H or other substituents already defined herein). The heterocyclic ring can be attached to any heteroatom or carbon atom pendant group to form a stable structure. If the resulting compound is stable, the heterocyclic ring described herein can be substituted at the carbon or nitrogen position. The nitrogen atom in the heterocyclic ring is optionally quaternized. A preferred solution is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred solution is that the total number of S and O atoms in the heterocycle does not exceed 1.

The term "aromatic heterocyclic group" or "heteroaryl" means a stable 5-, 6, 7-membered monocyclic or bicyclic or 7, 8, 9 or 10-membered bicyclic heterocyclic aromatic ring, which contains carbon atoms And 1, 2, 3, or 4 ring heteroatoms independently selected from N, O, and S. The nitrogen atom may be substituted or unsubstituted (ie N or NR, where R is H or other substituents already defined herein). Nitrogen and sulfur heteroatoms can optionally be oxidized (ie NO and S(O) _p , p is 1 or 2). It is worth noting that the total number of S and O atoms in the aromatic heterocycle does not exceed 1. Bridged rings are also included in the definition of heterocycles. A bridged ring is formed when one or more atoms (ie, C, O, N, or S) connect two non-adjacent carbon atoms or nitrogen atoms. Preferred bridged rings include, but are not limited to: one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In bridged rings, substituents on the ring can also appear on the bridge.

Unless otherwise specified, the term "hydrocarbyl" or its subordinate concepts (such as alkyl, alkenyl, alkynyl, aryl, etc.) by itself or as part of another substituent means a linear, branched or cyclic hydrocarbon The atomic group or a combination thereof can be fully saturated (e.g. alkyl), unitary or polyunsaturated (e.g. alkenyl, alkynyl, aryl), can be mono- or multi-substituted, and can be monovalent (e.g. methyl Group), divalent (such as methylene) or multivalent (such as methine), which can include divalent or multivalent atomic groups, with a specified number of carbon atoms (such as C ₁ -C ₁₂ representing 1 to 12 carbons, C _{1-12 is} selected from C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ and C ₁₂ ; C _{3-12 is} selected from C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ and C ₁₂ .). "Hydrocarbon group" includes but is not limited to aliphatic hydrocarbon groups and aromatic hydrocarbon groups. The aliphatic hydrocarbon groups include chain and cyclic hydrocarbon groups, specifically including but not limited to alkyl, alkenyl, and alkynyl groups. The aromatic hydrocarbon groups include but are not limited to 6-12 Elementary aromatic hydrocarbon groups, such as phenyl, naphthyl and the like. In some embodiments, the term "hydrocarbyl" refers to linear or branched atomic groups or combinations thereof, which can be fully saturated, unitary or polyunsaturated, and can include divalent and multivalent atomic groups. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, ring Propylmethyl, and homologs or isomers of atomic groups such as n-pentyl, n-hexyl, n-heptyl, and n-octyl. Unsaturated hydrocarbon groups have one or more double bonds or triple bonds, examples of which include but are not limited to vinyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2-(butadienyl) , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.

Unless otherwise specified, the term "alkyl" is used to denote a linear or branched saturated hydrocarbon group, which may be mono-substituted (such as -CH ₂ F) or multi-substituted (such as -CF ₃ ), and may be monovalent (such as Methyl), divalent (such as methylene) or multivalent (such as methine). Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl , T-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl) and the like.

Unless otherwise specified, the term "cycloalkyl" includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom is saturated, can be mono- or poly-substituted, and can be monovalent, divalent or multivalent. Examples of these cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2] dicyclooctyl, [4.4.0] dicyclodecyl, and the like.

Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.

The term "treatment" means administering the compound or formulation described in this application to prevent, ameliorate or eliminate a disease or one or more symptoms related to the disease, and includes:

(i) Preventing the occurrence of a disease or disease state in mammals, especially when such mammals are susceptible to the disease state, but have not been diagnosed as having the disease state;

(ii) Suppress the disease or disease state, that is, curb its development;

(iii) Alleviate the disease or disease state, even if the disease or disease state subsides.

For drugs or pharmacologically active agents, the term "effective amount" or "therapeutically effective amount" means non-toxic but capable of (i) treating or preventing a specific disease, condition or disorder, (ii) reducing, ameliorating or eliminating specific One or more symptoms of a disease, condition, or disorder, or (iii) the amount of the compound of the present application to prevent or delay the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.

The term "active ingredient" refers to a chemical entity that can effectively treat the target disorder, disease or condition.

The term "patient" refers to a mammal, preferably a human. In some embodiments, the patient is a patient who has failed or lacks standard treatment.

The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent replacement manners, preferred implementation manners include but are not limited to the embodiments of the present application.

The solvent used in this application is commercially available. This application uses the following abbreviations: eq stands for equivalent, equivalent; NMM stands for N-methylmorpholine; DMSO stands for dimethyl sulfoxide; HOBt stands for 1-hydroxybenzotriazole; EDCI stands for 1-ethyl-( 3-Dimethylaminopropyl) carbodiimide hydrochloride; TEMPO stands for tetramethylpiperidine nitroxide; T3P stands for propyl phosphoric anhydride; DIPEA stands for N,N-diisopropylethylamine.

The compound is artificially or

The software is named, and the commercially available compounds use the supplier catalog name.

For the sake of clarity, examples are further used to illustrate the application, but the examples do not limit the scope of the application.

In this article, unless otherwise stated, the term "comprises, includes and contains" or equivalents is an open-ended expression, meaning that in addition to the listed elements, components and steps, other unspecified elements, Components and steps.

For the purpose of description and disclosure, all patents, patent applications and other established publications are expressly incorporated herein by reference. These publications are only provided because their publication is earlier than the filing date of this application. All statements regarding the dates of these documents or the representation of the contents of these documents are based on the information available to the applicant and do not constitute any recognition of the correctness of the dates of these documents or the contents of these documents. Moreover, in any country, any reference to these publications in this article does not constitute an endorsement that the publication has become part of the common general knowledge in the field.

Detailed ways

Preparation Example 1: Preparation of Compound 1-a

Step 1: Synthesis of compound A-3

Compound A-1 (30.00g, 92.78mmol, 1.00eq) and 4-methylmorpholine (15.02g, 148.45mmol, 16.33mL, 1.60eq) were dissolved in tetrahydrofuran (468mL) at -10°C under nitrogen protection, Compound A-2 (19.01g, 139.17mmol, 18.28mL, 1.50eq) was slowly added dropwise, and the temperature was kept at -10°C and stirred for 40 minutes. The reaction mixture was filtered, and the filter cake was washed with tetrahydrofuran (200 mL). The combined filtrates were poured into a three-necked flask and kept the temperature at 0°C. CH ₂ N _2- ether solution (370 mL) was added to the flask under nitrogen protection. Stirring was continued at 0°C for 20 minutes and the temperature was raised to 20°C. Stir for another 2 hours. Then the reaction mixture was continuously cooled to 0°C and treated with HBr (30 mL, 35% acetic acid solution). The mixture was stirred at 0°C for 15 minutes, and the temperature was raised to 20°C to continue stirring for 45 minutes. After the completion of the reaction, the reaction mixture was extracted and separated with ethyl acetate (500 mL) and water (400 mL). The organic phase was continuously washed with water (400 mL), saturated sodium bicarbonate solution (400 mL) and saturated brine (400 mL). After drying over anhydrous sodium sulfate and concentrating to obtain a crude product, the crude product was purified by column chromatography to obtain compound A-3 (30.00 g, yield: 76%) as a colorless oil.

Step 2: Synthesis of compound A-5

Compound A-3 (25.00g, 62.46mmol, 1.00eq) and A-4 (12.45g, 74.95mmol, 1.20eq) were dissolved in DMF (350.00mL), KF (14.52g, 249.84mmol) was added under nitrogen protection , 5.85 mL, 4.00 eq), the reaction was stirred at 20°C for 15 hours. After the reaction was completed, 500 mL of ethyl acetate was added, and the mixture was washed with saturated sodium bicarbonate (350 mL), water (350 mL) and saturated brine (350 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate=1:0-3:1) to obtain compound A-5 (18.00 g, yield: 56%) .

Step 3: Synthesis of compound A-6

Compound A-5 (9.50g, 19.57mmol, 1.00eq) was added to a mixed solvent of methanol (30.00mL) and tetrahydrofuran (30.00mL), and sodium borohydride (2.96g, 78.28mmol) was added to it while maintaining the temperature at 0°C. , 4.00eq), after the addition, the reaction mixture was stirred at 25°C for 1 hour. After the reaction was completed, the reaction mixture was added to water (200 mL), and NH ₄ Cl (200 mL, aq, 10%) was added, and then extracted with ethyl acetate (500 mL*3). The combined organic phase was washed with water (500 mL), brine (500 mL), dried with anhydrous sodium sulfate, and filtered to obtain a colorless oily compound A-6 (9.00 g, crude product), which was used directly without purification. One step response.

Step 4: Synthesis of compound A-7

Compound A-6 (9.00 g, 18.46 mmol, 1.00 eq) was dissolved in methanol (500.00 mL), and Pd-C (10%, 2.5 g) was added thereto. The mixture was replaced with hydrogen 3 times and the pressure was maintained at 15 psi, and the temperature was maintained at 25°C and stirred for 4 hours. After the reaction was completed, it was filtered and concentrated to obtain compound A (6.10 g, crude product) as a yellow oil, which was directly used in the next reaction without purification.

Step 5: Synthesis of compound A-9

Compound A-7 (6.10g, 17.2mmol, 1.00eq) and compound A-8 (3.85g, 17.2mmol, 1.00eq) were dissolved in ethyl acetate solution (100mL), and T ₃ P (16.42g, 25.8mmol, 1.50eq, 50% ethyl acetate solution) and DIPEA (4.44g, 34.4mmol, 2.0eq), stirred at 25°C for 4 hours. Water (50 mL) was added to the reaction solution for quenching and liquid separation. The organic phase was washed once with saturated sodium bicarbonate (50 mL), water (50 mL), and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was separated by column chromatography (ethyl acetate: petroleum ether=1:20-1:2), the product compound A-9 (3.50g, yield: 36.5%); LCMS m/z=581.2[M+Na ] ⁺ .

Step 6: Synthesis of compound 1-a

Compound A-9 (3.30 g, 5.91 mmol, 1.00 eq) was dissolved in a mixed solvent of methanol (33.0 mL) and THF (33.0 mL), and Pd-C (10%, 330 mg) was added thereto. The mixture was replaced with hydrogen three times and the pressure was maintained at 15 psi, and the temperature was maintained at 25°C and stirred for 2 hours. After the reaction was completed, it was filtered and concentrated to obtain compound A (2.18 g, 4.50 mmol, yield: 76.2%) as a yellow oil, which was directly used in the next reaction without purification; LCMS m/z=425.2[M+H] ⁺ .

Preparation Example 2: Preparation of compound 1-e (refer to the preparation route of compound 1-a, using chiral enantiomer instead of compound A-1)

Example 1: (S)-3-((S)-2-(5-(2-chlorophenyl)isoxazole-3-carboxamido)propionamido)-4-oxo-5-( 2,3,5,6-Tetrafluorophenoxy)valeric acid (Compound 1)

Step 1: Synthesis of compound 1-c

Compound 1-b (100.00 mg, 447.21 μmol, 1.00 eq) was dissolved in dichloromethane (10.00 mL), and compound NMM (135.71 mg, 1.34 mmol, 147.51 μL, 3.00 eq) and HOBt (82.78 mg, 612.67) were added to it μmol, 1.37 eq), EDCI (117.45 mg, 612.67 μmol, 1.37 eq) and compound 1-a (189.79 mg, 447.21 μmol, 1.00 eq). The reaction solution was stirred at 25°C for 4 hours. After the reaction is complete, the reaction solution is directly concentrated to obtain a crude product, and the crude product is subjected to flash silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain a colorless oily compound 1-c. LCMS m/z=652.3 [M+Na] ⁺ .

Step 2: Synthesis of compound 1-d

Compound 1-c (220.00 mg, 349.22 μmol, 1.00 eq) was dissolved in dichloromethane (10.00 mL), and diacetoxy iodobenzene (435.31 mg, 1.35 mmol, 3.87 eq) and TEMPO (54.92 mg, 349.22μmol, 1.00eq). The reaction solution was stirred at 25°C for 15 hours. After the reaction was completed, dichloromethane (20 mL) was added to the reaction solution, and the solution was washed with water (20 mL), saturated sodium bicarbonate (20 mL) and brine (20 mL) successively. The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain a crude product. The crude product was subjected to flash silica gel column chromatography (petroleum ether: ethyl acetate = 7:3) to obtain compound 1-d as a pale yellow oil. LCMS m/z=650.1 [M+Na] ⁺ .

Step 3: Synthesis of compound 1

Compound 1-d (210.00 mg, 334.41 μmol, 1.00 eq) was dissolved in dichloromethane (4.00 mL), and trifluoroacetic acid (1.54 g, 13.51 mmol, 1.00 mL, 40.39 eq) was added thereto. The reaction solution was stirred at 25°C for 3 hours. After the reaction is complete, the reaction solution is concentrated to obtain a crude product. The crude product was purified by prep-HPLC (trifluoroacetic acid conditions) and lyophilized to obtain compound 1. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.47 (br s, 1H), 9.01 (br s, 1H), 8.67 (br s, 1H), 7.96 (dd, J = 2.26, 7.28 Hz, 1H) ,7.72(d,J=7.39Hz,1H),7.48-7.65(m,3H),7.38(s,1H),5.02-5.42(m,2H),4.62(d,J=6.02Hz,1H), 4.40-4.54(m,1H),2.73-2.85(m,1H),2.52-2.65(m,1H), 1.37(d,J=7.03Hz,3H); LCMS m/z=572.1[M+H] ⁺ .

Example 2-17: Referring to the synthetic route of Example 1, the compound of Example 2-17 was prepared by replacing compound 1-b with a different intermediate acid.

Example 18: Referring to the synthetic route of Example 1, the compound of Example 18 was prepared by using intermediate 1-e instead of compound 1-a.

The nuclear magnetic and mass spectrometry data of Examples 2-13 and 17-18 are as follows:

Experimental example 1: In vivo pharmacodynamic study

1. The purpose of the experiment

The purpose of this study is to study the improvement effect of the _{compound of the application on NASH in the DIO/CCl 4 mouse model.} The DIO+CCl ₄ mouse model used in this study is an animal model that simulates the progression of human non-alcoholic fatty liver disease to the NASH process. High-fat diet leads to accumulation and degeneration of fat in liver cells; CCl ₄ (intraperitoneal injection, every time Twice a week) to simulate the "second blow" of liver injury. This model is stable and reliable, and has a high similarity to the pathogenesis of human NASH. It has the main pathological characteristics of NASH, including steatosis, apoptosis, inflammation, etc., and also shows elevated plasma aminotransferase (ALT and AST) levels.

2. Experimental instruments and materials

2.1 Experimental instrument

Table 1

name	Manufacturer	model
Precision electronic balance	Sartorius	CPA225D
Animal balance	Changzhou Keyuan Instrument Co., Ltd.	JA20002
Low temperature centrifuge for internal use	Thermo	Fresco 17
happy	Hitachi	Hitachi 7180
Centrifuge for qPCR detection	Eppendorf	5418(0006833)
Thermal Cycle	Bio-Rad	T100
Real-Time PCR System	Applied Biosystems	ABI Prism 7900HT
Janus Liquid Robotic Handler	Perkin Elmer	AJM8M01
Spectrophotometer	Thermo Scientific	Nano Drop 2000
Tissue grinding machine	QIAGEN	tissue lyser II
Microplate reader	SpectraMax	340PC384
Centrifuge for liver TG and TC detection	Eppendorf	Centrifuge 5418
Water bath	Thermo Scientific	2842
Automatic tissue dehydrator	Leica	ASP300S
Paraffin embedding machine	Microm	EC350-1&EC350-2
Paraffin microtome	Microm	HM315R
Automatic dyeing machine	Leica	autostainer XL
microscope	Zeiss Optical Instruments	MIC01964
Slice scanner	Hamamatsu Nanozoomer	S210

2.2 Experimental materials

Table 2

name	Manufacturer
High fat feed	Research diet
Carbon tetrachloride	Jiangsu Qiangsheng Functional Chemical Co., Ltd.
olive oil	aladdin
Triglyceride determination kit for serum testing	DiaSys Diagnostic Systems GmbH
Total Cholesterol Determination Kit for Serum Testing	DiaSys Diagnostic Systems GmbH
Aspartate aminotransferase detection kit for serum detection	DiaSys Diagnostic Systems GmbH
Alanine aminotransferase detection kit for serum detection	DiaSys Diagnostic Systems GmbH
GLU test kit	DiaSys Diagnostic Systems GmbH
Absolute ethanol	Sinopharm reagent
Ethanol 95%	Sinopharm reagent

Xylene	Sinopharm reagent
Hematoxylin staining solution	Zhuhai Besso Biotechnology Co., Ltd.
Eosin Staining Solution	Zhuhai Besso Biotechnology Co., Ltd.

2.3 Experimental animals

29 male C57BL/6J mice (Nanjing University-Nanjing Institute of Biological Medicine, SPF level, laboratory animal quality certificate number: 201700329), when they arrive at the facility, they require diet-induced obesity (DIO). The weight of the rat is greater than 35g.

9 male C57BL/6J mice in the healthy control group (Nanjing University-Nanjing Institute of Biological Medicine, SPF level, laboratory animal quality certificate number: 201700329).

3. Experimental method

The model in this experiment includes two steps: high-fat feed and CCl ₄ induction. First, the mice are fed with high-fat feed to induce non-alcoholic fatty liver, and mice with a body weight of >35g are selected, and the high-fat feed is continued to be fed at the same time. , Intraperitoneal injection of 25% CCl ₄ , 0.5 mg/kg, twice a week for four weeks. The day when the administration of CCl ₄ was started was set as day 0, and on _{the day when the administration of CCl 4} was started, the intragastric administration was started at a volume of 5 mL/kg, twice a day for 4 weeks (28 days). The injection time of CCl ₄ should be at least 4 hours apart from the time point of the first administration of the day, and at least 2 hours apart from the time point of the second administration of the BID group. The experiment was divided into 5 groups, namely healthy control group, model group, and test compound group (Example 1, 0.6, 2 and 6 mg/kg). The healthy control group consisted of 9 normal mice. During the experiment, they were fed with ordinary diet without CCl ₄ injection; 29 obese mice were used in the model group and the test compound group, the model group was 8 mice, and the test compound group was 7 mice in each group, after grouping, CCl ₄ was injected intraperitoneally and different doses of drugs or solvents were given respectively. The grouping and dosage design are shown in Table 3 below.

Table 3. Animal grouping and dosing schedule

Note: In Example 1, the 0.6 mg/kg group was euthanized on Day 11 and Day 20 due to a large weight loss. The number of animals actually included in the statistics in this group was 5.

4. Liver NAS score

Liver tissues of each group of animals were collected and analyzed for NAS scores after HE staining.

4.1 Tissue extraction and dehydration

(1) Put the liver tissue specimens into disposable plastic embedding cassettes in order, and the embedding cassette number is the same as the tissue number.

(2) Put all tissues into a fully automatic vacuum tissue dehydrator for dehydration, the dehydration procedure is as follows:

A. 70% ethanol solution for 30 minutes

B. 80% ethanol solution for 30 minutes

C. 95% ethanol solution for 30 minutes

D. 95% ethanol solution for 30 minutes

E. Anhydrous ethanol I for 30 minutes

F. Anhydrous ethanol Ⅱ 30 minutes

G. Anhydrous ethanol Ⅲ 30 minutes

H. Xylene Ⅰ 30 minutes

I. Xylene Ⅱ 30 minutes

J. Xylene Ⅲ 30 minutes

K.60℃ paraffin wax I for 60 minutes

L. 60 ℃ paraffin wax Ⅱ 60 minutes

M.60℃ Paraffin Ⅲ 60 minutes

4.2 Tissue embedding and sectioning

(1) Embedding

A. Ensure that there is enough paraffin in the fully automatic embedding machine;

B. Turn on the light source of the paraffin embedding machine (Microm EC350-1&EC350-2), use heated tweezers to take out the tissue in the embedding box, select a suitable embedding base mold according to the size of the tissue, and inject molten 60℃ paraffin wax;

C. Move the embedding bottom mold filled with molten 60℃ paraffin wax from the hot stage of the embedding machine to the cold stage;

D. Quickly bury the tissue-cut bread into the bottom of the bottom mold;

E. Quickly press the cassette with the same tissue number on the bottom mold;

F. After the molten paraffin at 60°C has solidified, remove the tissue wax block from the embedding bottom mold;

G. Turn off the light source of the embedding machine and clean the working surface of the instrument.

(2) Slicing

A. Use a paraffin microtome to slice the tissue wax block, the thickness of the slice used for hematoxylin-eosin staining is 3um.

B. Glass slide: without special treatment;

C. Baking time and temperature: 60°C for one hour.

4.3 Hematoxylin-eosin staining

A. Xylene Ⅰ 10 minutes

B. Xylene Ⅱ 2.5 minutes

C. Xylene Ⅲ 3.5 minutes

D. Anhydrous ethanol I for 1.5 minutes

E. Anhydrous ethanol Ⅱ 2 minutes

F. 95% ethanol for 2 minutes

G. 75% ethanol for 2 minutes

H. Rinse under running water for 1 minute

I. Hematoxylin dye solution for 2.5 minutes

J. Rinse under running water for 5 minutes

K. 2.5% hydrochloric acid and ethanol for 3 seconds

L. Rinse under running water for 3 minutes

M. Back to blue (1% ammonia water) for 7 seconds

N. Rinse under running water for 5 minutes

O. Eosin solution staining for 30 seconds

P. Rinse under running water for 2 seconds

Q. 75% ethanol for 5 seconds

R. 95% ethanol for 1 minute

S. Anhydrous ethanol I for 1 minute

T. Anhydrous ethanol Ⅱ 2 minutes

U. Anhydrous ethanol Ⅲ 2 minutes

V. Xylene Ⅰ, Ⅱ, Ⅲ 5 minutes respectively

4.4 Evaluation method

In hematoxylin-eosin stained sections, the sections were evaluated according to the following scoring criteria, and the evaluation criteria are as follows.

Table 4. Non-alcoholic hepatic steatohepatitis (NASH) pathological scoring criteria

Description of lesion coefficient in evaluation criteria

a) Balloon degeneration of hepatocytes: vacuole-like pathological changes can be seen in the liver cells, the cell volume increases due to the vacuole-like degeneration, and the nucleus is centered.

b) Inflammatory cell infiltration: A large number of aggregated inflammatory cells can be seen around the portal area of the liver lobules, mainly neutrophils and macrophages.

c) Fatty degeneration of liver cells: Regular fatty vacuoles can be seen in liver cells, with different sizes, and liver cell nuclei are located at the edge.

5. Experimental results

Compared with the healthy control group, the inflammatory infiltration, steatosis and ballooning scores of the model group were significantly increased, and the NAS score was also significantly increased, indicating the success of the modeling. After continuous administration for 27 days, the compound of Example 1 showed a dose-dependent improvement in the NAS score at the three doses of 0.6, 2 and 6 mg/kg. Compared with the model group, the NAS score of the high-dose 6 mg/kg group was significantly reduced (p <0.01). The compound of Example 1 can improve ballooning and steatosis at a high dose of 6 mg/kg.

Table 6. NAS score

(Data are expressed as mean±SEM, n=5-9. ^# p＜0.05, ^## p＜0.01, ^### p＜0.001 compared with healthy control group; *p＜0.05, **p＜0.01, ** *p＜0.001 compared with the model group.)

It can be seen that the compound of the present application can show a good effect in treating non-alcoholic steatohepatitis in animals.

Experimental example 2 Detection of blood biochemical indexes in _{DIO/CCl 4 mouse model}

For the research purpose, experimental equipment and materials, and experimental methods of this experimental example, please refer to experimental example 1.

1. Detection of blood biochemical indicators

In this study, blood biochemical tests reflected liver damage ALT (alanine aminotransferase) and AST (aspartate aminotransferase), TG (triglycerides) and TC (total cholesterol), which reflect blood lipid levels, and GLU (blood sugar), a total of 5 indicators, respectively select the corresponding kits from Desai and Roche, and test them in accordance with the use and maintenance of the EQUIP-065 biochemical analyzer (Hitachi 7180) and standard operating procedures.

Table 7. Detection method

parameter	method
ALT	UV continuous monitoring method
AST	UV continuous monitoring method

parameter	method
TG	Glycerol-3-phosphate oxidase (GPO) enzyme colorimetric method
TC	Cholesterol oxidase-4 aminoantipyrine (CHOD-PAP) enzyme colorimetric method
GLU	Glucose oxidase-4 aminoantipyrine (GOD-PAP) enzyme colorimetric method

Remarks: All operations are strictly in accordance with the kit instructions.

2. Experimental results

Compared with the healthy control group, the levels of ALT, AST, TG, TC and GLU in the model group were significantly higher.

Compared with the model group, the compound of Example 1 can significantly reduce the levels of TG, GLU, ALT, AST and TC in the serum at 2 mg/kg. The specific results are shown in Table 8.

Table 8. Blood Biochemical Index

(The data are expressed as mean±SEM, n=5-9.)

The above results indicate that the compound of formula (I) of the present application or a pharmaceutically acceptable salt thereof can improve liver damage, thereby exhibiting effective effects in the treatment of non-alcoholic steatohepatitis.

The above are only the preferred embodiments of this application. It should be pointed out that for those of ordinary skill in the art, without departing from the method of this application, several improvements and supplements can be made, and these improvements and supplements should also be considered. The scope of protection of this application.

Claims (15)

1. A method for treating non-alcoholic steatohepatitis, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need of the treatment,

   

   among them,

   Ring A is selected from a 5-membered heteroaryl group or a 6-membered heteroaryl group, the 5-membered heteroaryl group or 6-membered heteroaryl group is optionally substituted by R;

   Ring B is selected from phenyl or C _3-6 cycloalkyl, said phenyl or C _3-6 cycloalkyl is optionally substituted by R;

   R is selected from halogen, OH, NH ₂ , or C _1-3 alkyl optionally substituted with 1, 2 or 3 R ^1;

   R ^{1 is} selected from F, Cl, Br, I, OH, NH ₂ , NH(CH ₃ ) or N(CH ₃ ) ₂ .
2. The method of claim 1, wherein the heteroatoms of ring A are independently selected from O, S, or N, and the number of heteroatoms of ring A is selected from 1, 2, or 3.
3. The method of claim 1, wherein ring A is selected from oxazolyl, isoxazolyl, imidazolyl, thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl Or pyrazolyl.
4. The method of claim 1, wherein ring A is selected from

   

   
5. The method of any one of claims 1 to 4, wherein ring B is selected from phenyl or cyclohexyl, and said phenyl or cyclohexyl is optionally substituted by R.
6. The method according to any one of claims 1 to 5, wherein R is selected from F, Cl, Br, I, OH, NH ₂ , or Me or Et optionally substituted by 1, 2 or 3 R ^{1, preferably} Ground, R ^{1 is} selected from F, Cl or NH ₂ .
7. The method of claim 6, wherein R is selected from F, Cl, Br, I, OH, NH ₂ or CF ₃ .
8. The method of any one of claims 1-7, wherein ring B is selected from

   

   
9. The method of any one of claims 1-7, wherein:

   

   Selected from

   

   

   

   The ring B is optionally substituted by R.
10. The method of any one of claims 1-7 and 9, wherein:

    

    Selected from

    

    

    
11. The method of any one of claims 1-7 and 9-10, wherein:

    

    Selected from

    

    
12. The method of any one of claims 1-7 and 9, wherein:

    

    Selected from

    

    
13. The method of any one of claims 1-12, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from:

    

    
14. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of non-alcoholic steatohepatitis,

    

    among them,

    Ring A is selected from a 5-membered heteroaryl group or a 6-membered heteroaryl group, the 5-membered heteroaryl group or 6-membered heteroaryl group is optionally substituted by R;

    Ring B is selected from phenyl or C _3-6 cycloalkyl, said phenyl or C _3-6 cycloalkyl is optionally substituted by R;

    R is selected from halogen, OH, NH ₂ , or C _1-3 alkyl optionally substituted with 1, 2 or 3 R ^1;

    R ^{1 is} selected from F, Cl, Br, I, OH, NH ₂ , NH(CH ₃ ) or N(CH ₃ ) ₂ .
15. A pharmaceutical composition for the treatment of non-alcoholic steatohepatitis, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient,

    

    among them,

    Ring A is selected from a 5-membered heteroaryl group or a 6-membered heteroaryl group, the 5-membered heteroaryl group or 6-membered heteroaryl group is optionally substituted by R;

    Ring B is selected from phenyl or C _3-6 cycloalkyl, said phenyl or C _3-6 cycloalkyl is optionally substituted by R;

    R is selected from halogen, OH, NH ₂ , or C _1-3 alkyl optionally substituted with 1, 2 or 3 R ^1;

    R ^{1 is} selected from F, Cl, Br, I, OH, NH ₂ , NH(CH ₃ ) or N(CH ₃ ) ₂ .