Aldehyde dehydrogenase 2 (ALDH2) agonists, methods of making and uses thereof

Abstract

The application discloses a class of acetaldehyde dehydrogenase 2 (ALDH2) agonists, and a preparation method and application thereof. Specifically, the application provides a compound or stereoisomers, optical isomers, non-racemic or racemic thereof, or a pharmaceutically acceptable salt thereof, or a solvate or N-oxide thereof, or a pharmaceutical composition comprising the same, and the use of the compound in (i) preparing an acetaldehyde dehydrogenase 2 (ALDH2) agonist and / or (ii) preparing a drug for treating or preventing alcohol-related diseases and / or diseases capable of being treated or prevented by promoting the metabolism of acetaldehyde or other aldehydes; wherein the compound is shown as formula A.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a class of acetaldehyde dehydrogenase 2 (ALDH2) agonists, their preparation methods, and their uses for hangover relief and liver protection. Background Technology

[0002] Alcoholic beverages, containing ethanol (i.e., alcohol), are widely consumed globally. It is noteworthy that even small amounts of alcohol consumption pose health risks, and alcohol abuse has become a major global public health issue threatening public health and quality of life.

[0003] The liver, as the core organ of alcohol metabolism, is also the primary target organ for its toxic effects. Nearly 90% of ingested alcohol is absorbed through the gastrointestinal tract and accumulates in the liver, where it is converted to acetaldehyde by alcohol dehydrogenase (ADH), then to acetic acid by aldehyde dehydrogenase 2 (ALDH2), and finally broken down into carbon dioxide and water, or participates in some biosynthetic processes. In addition, alcohol can also be metabolized via alternative pathways such as cytochrome P450 enzymes (CYP2E1) and catalase. The CYP2E1 pathway is particularly crucial—this process is accompanied by the generation of large amounts of reactive oxygen species (ROS). These free radicals can attack polyunsaturated fatty acids in cell membranes, inducing a lipid peroxidation cascade reaction, leading to the excessive accumulation of highly electrophilic reactive aldehydes such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). These toxic aldehydes can form adducts with proteins, DNA, and lipid molecules, causing persistent damage to hepatocytes. As a key rate-limiting enzyme in alcohol metabolism, ALDH2 not only removes acetaldehyde but also efficiently metabolizes reactive aldehydes such as 4-HNE and MDA, converting them into non-toxic carboxylic acids, thereby playing a protective role in the liver. Enhancing the activity of this enzyme is expected to fundamentally accelerate the clearance of toxic aldehydes and alleviate the harmful effects of alcohol on the body.

[0004] Short-term heavy drinking can trigger acute alcohol poisoning (AAI), while long-term continuous intake can induce the development of chronic alcoholic liver disease (ALD). The pathological process typically begins with simple fatty liver, gradually evolving into alcoholic hepatitis, liver fibrosis, and even cirrhosis; this series of pathological changes is collectively referred to as alcoholic disease. However, this field currently lacks specific therapeutic targets, and clinical interventions are mostly limited to symptomatic treatment. For example, anti-inflammatory and antioxidant drugs such as thioproline, glutathione, and silymarin are used to intervene in ALD, or hepatoprotective agents are combined with adjuvant drugs such as wakefulness promoters and sedatives in AAI treatment. While these approaches can alleviate clinical symptoms to some extent, they are insufficient to fundamentally eliminate toxic substances. With increasing public health awareness, scientific drinking has gradually become a social focus, and the huge market demand has spurred a large number of functional foods and health products marketed as "hangover relief and liver protection." However, most of these products have unclear mechanisms of action and lack systematic pharmacodynamic validation.

[0005] Against this backdrop, we aim to develop a class of hangover-relieving and liver-protecting drugs with clear targets, good safety profiles, and well-defined pharmacological effects to meet the clinical needs for the prevention and treatment of alcoholic diseases.

[0006] In summary, there is an urgent need in the field for a drug compound with ALDH2 agonist activity. Summary of the Invention

[0007] This invention provides a class of novel small molecule compounds with ALDH2 agonist activity and hepatoprotective effects, or pharmaceutically acceptable salts, stereoisomers, and optical isomers thereof. In a first aspect of the invention, a compound or a stereoisomer, optical isomer, non-racemic or racemic mixture thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or an N-oxide thereof, or a pharmaceutical composition comprising one or more of the compound or a stereoisomer, optical isomer, non-racemic or racemic mixture thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or an N-oxide thereof, is provided for use in (i) the preparation of an acetaldehyde dehydrogenase 2 (ALDH2) agonist and / or (ii) the preparation of a medicament for the treatment or prevention of alcohol-related diseases and / or diseases that can be treated or prevented by promoting the metabolism of acetaldehyde or other aldehydes; in, The compound is shown in Formula A: in, W is selected from the group consisting of: unsubstituted or substituted C1-C6 alkylene, substituted or unsubstituted C3-C6 cycloalkylene, substituted or unsubstituted C3-C6 cycloalkylene, substituted or unsubstituted -C1-C2 alkylene-C3-C6 cycloalkylene-C1-C2 alkylene-, and substituted or unsubstituted -C1-C2 alkylene-4 to 6-membered heterocyclic alkylene-C1-C2 alkylene-; X is O, N(R) N ) or S; R 1 and R 2 Each is independently selected from the group consisting of: H, D, halogen, hydroxyl, amino, cyano, nitroso, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and substituted or unsubstituted C1-C6 alkoxy. Ring A is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R 3Represents one or more (e.g., 1, 2, 3, or 4) monovalent or divalent groups, each independently selected from the group consisting of: H, D, halogen, hydroxyl, amino, cyano, nitroso, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkylene, substituted or unsubstituted 3- to 6-membered heteroalkylene, and R. 3a ; R 3a -R 4 -CO-X 1 -R 5 ; R 4 Selected from the following group: none (not present), substituted or unsubstituted C1-C5 alkylene, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkyne, and substituted or unsubstituted C3-C6 cycloalkylene; R 5 Selected from the following group: H, D, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C3-C6 cycloalkyl; X 1 For O, N(R) N (or does not exist;) R N Selected from the following group: H, D, C1-C6 alkyl; Unless otherwise specified, substitution refers to the substitution of a group by one or more R groups. S replace; Each R S Each of the following groups is independently selected from the group consisting of: D, halogen, hydroxyl, amino, cyano, nitroso, nitro, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclic alkyl, phenyl, 5- to 6-membered heteroaryl, -C1-C4 alkylene-C3-C6 cycloalkyl, -C1-C4 alkylene-4- to 6-membered heterocyclic alkyl, -C1-C4 alkylene-phenyl, and -C1-C4 alkylene-5- to 6-membered heteroaryl; and wherein the alkylene, alkyl, alkoxy, cycloalkyl, heterocyclic alkyl, phenyl, and 5- to 6-membered heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of: D, halogen, hydroxyl, amino, cyano, nitroso, nitro, C1-C6 alkyl, and C1-C6 alkoxy.

[0008] In another preferred embodiment, the alcohol-related disease is selected from the group consisting of acute alcohol poisoning (AAI), alcoholic liver disease (ALD), or a combination thereof.

[0009] In another preferred embodiment, the disease that can be treated or prevented by promoting the metabolism of acetaldehyde or other aldehydes is selected from the group consisting of: heart failure, myocardial ischemia / reperfusion injury, diabetic cardiomyopathy, obesity, type 2 diabetes, non-alcoholic fatty liver disease, alcohol use disorder, or a combination thereof.

[0010] In another preferred embodiment, the dosage form of the drug or drug composition is an oral preparation, a parenteral preparation, or a topical preparation.

[0011] In another preferred embodiment, the dosage form of the drug or drug composition is selected from the group consisting of: tablets, capsules, powders, granules, lozenges, solutions, and gels.

[0012] In another preferred embodiment, the pharmaceutical composition further comprises pharmaceutically acceptable excipients.

[0013] In another preferred embodiment, the pharmaceutically acceptable excipient is any one or a combination of at least two of the following: excipients, diluents, carriers, flavoring agents, binders, or fillers.

[0014] In another preferred embodiment, W is selected from the group consisting of: no, substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C3-C6 cycloalkylene; more preferably, W is selected from the group consisting of: no, C1-C6 alkylene, cyclohexylene.

[0015] In another preferred embodiment, W is an unsubstituted or substituted C1-C6 alkylene group; more preferably, W is an unsubstituted or C1-C6 alkylene group.

[0016] In another preferred embodiment, W is ; where the subscript n is selected from the following group: integers from 0 to 6.

[0017] In another preferred embodiment, the compound is as shown in Formula I; Among them, R 1 R 2 R 3 X and ring A are defined as in equation A; the subscript n is selected from the following group: integers from 0 to 6.

[0018] In another preferred embodiment, n is 4, 5, or 6.

[0019] In another preferred embodiment, X is O or N(R) N Preferably, X is O or NH.

[0020] In another preferred example, X is 0.

[0021] In another preferred embodiment, R 1Selected from the group consisting of: H, D, substituted or unsubstituted C1-C6 alkyl groups, and substituted or unsubstituted C2-C6 alkynyl groups; preferably, R 1 Selected from the group consisting of: H, D, C1-C6 alkyl, and C2-C6 alkynyl; more preferably, R 1 Selected from the following group: H, D, methyl, ethyl, and .

[0022] In another preferred embodiment, R 1 Selected from the group consisting of: H, D, and substituted or unsubstituted C1-C6 alkyl groups; preferably, R 1 Selected from the group consisting of H, D, and C1-C6 alkyl groups; more preferably, R 1 Selected from the following group: H, D, methyl, and ethyl.

[0023] In another preferred embodiment, R 2 Selected from the group consisting of: H, D, halogens, amino, cyano, and substituted or unsubstituted C1-C6 alkyl groups; preferably, R 2 Selected from the group consisting of: H, D, halogens, amino groups, and C1-C6 alkyl groups; more preferably, R 2 Selected from the following group: H, D, fluorine, chlorine, bromine, amino, methyl, ethyl, and propyl.

[0024] In another preferred embodiment, R 2 Selected from the group consisting of: H, D, halogens, and substituted or unsubstituted C1-C6 alkyl groups; preferably, R 2 Selected from the group consisting of: H, D, halogens, and C1-C6 alkyl groups; more preferably, R 2 Selected from the group consisting of: H, D, fluorine, chlorine, bromine, methyl, ethyl, and propyl; preferably, R 2 Selected from the following group: H, D, fluorine, methyl, and ethyl.

[0025] In another preferred embodiment, ring A is aryl or heteroaryl; more preferably, ring A is C6-C. 12 Aryl or 5 to 12 heteroaryl groups.

[0026] In another preferred embodiment, the aryl group in ring A is phenyl, biphenyl, or naphthyl.

[0027] In another preferred embodiment, the heteroaryl group in ring A is selected from the group consisting of: furanyl, thiophene, pyrrole, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, benzofuranyl, benzothiophene, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, inazolyl, benzothiazolyl, quinazolinyl, phthalazinyl, purinyl, benzo[1,3]dioxane, and benzo[1,4]dioxane.

[0028] In another preferred embodiment, ring A is phenyl, naphthyl, or pyridyl; more preferably, ring A is phenyl.

[0029] In another preferred embodiment, when R 3 When representing a divalent group (such as a substituted or unsubstituted C2-C5 alkylene, or a substituted or unsubstituted 3- to 5-membered heteroalkylene), the divalent group is attached to an adjacent atom of ring A to form a substituted or unsubstituted C4-C7 cycloalkane or a substituted or unsubstituted 4- to 7-membered heteroalkylene that is fused with ring A.

[0030] In another preferred embodiment, R 3 When representing 1, 2, or 3 monovalent groups, at least one monovalent group is R. 3a .

[0031] In another preferred embodiment, R 3 When representing 1, 2, or 3 monovalent groups, one monovalent group is R. 3a The remaining monovalent groups are R 3b And R 3b Each is independently selected from the following group: H, D, halogen, hydroxyl, amino, cyano, nitroso, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy.

[0032] In another preferred embodiment, R 3b Each is independently selected from the group consisting of: H, D, halogen, hydroxyl, amino, cyano, nitroso, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; preferably, R 3b Selected from the following groups: H, D, halogen, hydroxyl, amino, cyano, nitroso, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy.

[0033] In another preferred embodiment, R 3b Selected from the group consisting of: H, D, halogen, hydroxyl, amino, cyano, nitroso, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; preferably, R 3b Selected from the following groups: H, D, halogen, hydroxyl, amino, cyano, nitroso, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy.

[0034] In another preferred embodiment, R 3b Each is independently selected from the group consisting of: H, D, halogens, and substituted or unsubstituted C1-C6 alkyl groups; preferably, R 3b Each is independently selected from the following groups: H, D, and halogens; more preferably, R 3b Each of them is independently selected from the following groups: H, D, and fluorine.

[0035] In another preferred example, X 1 For O or N(R) N ); Preferably, it is X 1 It can be O or NH.

[0036] In another preferred example, X 1 It is O.

[0037] In another preferred embodiment, R 4 Selected from the group consisting of unsubstituted, substituted, or unresubstituted C2-C6 alkenyl groups; preferably, R 4 Selected from the following group: None, -CH=C(CN)-.

[0038] In another preferred embodiment, R 4 It is none.

[0039] In another preferred embodiment, R 5 Selected from the group consisting of: H, D, and substituted or unsubstituted C1-C6 alkyl groups; preferably, R 5 Selected from the group consisting of H, D, and C1-C6 alkyl groups; more preferably, R 5 Selected from the following group: H, D, methyl, ethyl, and propyl.

[0040] In another preferred embodiment, R 5 It is a substituted or unsubstituted C1-C6 alkyl group; preferably, R 5 It is a C1-C6 alkyl group; more preferably, R 5 Selected from the group consisting of methyl, ethyl, and propyl.

[0041] In another preferred embodiment, for or Where the subscript m is 0, 1, 2 or 3, R 3a -R 4 -CO-X 1 -R 5 , and R 3b Each is independently selected from the group consisting of: H, D, halogen, hydroxyl, amino, cyano, nitroso, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; R 4 X 1 and R 5 As defined in claim 1.

[0042] In another preferred embodiment, for .

[0043] In another preferred embodiment, the pharmaceutically acceptable salt is an acid addition salt of a guanidine compound.

[0044] In another preferred embodiment, the acid in the acid addition salt is an inorganic acid or an organic acid.

[0045] In another preferred embodiment, the inorganic acid is selected from any one or a combination of at least two of hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, bromic acid, or iodic acid.

[0046] In another preferred embodiment, the organic acid is selected from any one or a combination of at least two of the following: trifluoroacetic acid, acetic acid, methanesulfonic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, p-toluenesulfonic acid, benzoic acid, benzenesulfonic acid, lactic acid, glutamic acid, or mandelic acid, preferably trifluoroacetic acid and methanesulfonic acid.

[0047] In another preferred embodiment, the solvate comprises: hydrate and / or alcohol.

[0048] In another preferred embodiment, the compound is selected from the group consisting of: .

[0049] In a second aspect of the invention, a compound or a stereoisomer, optical isomer, non-racemate or racemate thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or an N-oxide thereof is provided, wherein the compound is shown in Formula A: Among them, R 1 R 2 R 3 W, X and ring A are defined as in the first aspect.

[0050] In another preferred embodiment, the compound is shown in Formula I; Among them, R 1 R 2 R 3 X, ring A, and subscript n are defined as in the first aspect.

[0051] In another preferred embodiment, the compound is selected from the group consisting of: .

[0052] In a third aspect of the invention, a pharmaceutical composition is provided comprising: (i) one or more compounds or stereoisomers, optical isomers, non-racemic or racemic derivatives thereof, pharmaceutically acceptable salts thereof, solvates thereof, or N-oxides thereof; wherein the compounds are as defined in the first aspect.

[0053] In another preferred embodiment, the pharmaceutical composition further comprises (ii) pharmaceutically acceptable excipients.

[0054] In another preferred embodiment, the pharmaceutically acceptable excipient is any one or a combination of at least two of the following: excipients, diluents, carriers, flavoring agents, binders, or fillers.

[0055] In another preferred embodiment, the dosage form of the pharmaceutical composition is an oral preparation, a parenteral preparation, or a topical preparation.

[0056] In another preferred embodiment, the dosage form of the pharmaceutical composition is selected from the group consisting of: tablets, capsules, powders, granules, lozenges, solutions, and gels.

[0057] In another preferred embodiment, the pharmaceutical composition is (i) used as a preparation of an acetaldehyde dehydrogenase 2 (ALDH2) agonist and / or (ii) used to treat or prevent alcohol-related diseases and / or diseases that can be treated or prevented by promoting the metabolism of acetaldehyde or other aldehydes.

[0058] In a fourth aspect of the invention, a method for preparing a compound as described in the second aspect, or a stereoisomer, optical isomer, non-racemate, or racemate thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an N-oxide thereof, is provided, the method comprising the steps shown in the following flowchart: In each formula, R 1 R 2 R 3X, ring A and subscript n are as defined in the first aspect, and R is a protecting group of amino group (preferably Boc (tert-butoxycarbonyl)).

[0059] In another preferred embodiment, the preparation method includes the steps of: (1) reacting compound Ia with the corresponding alcohol Ib via a Mitsunobu reaction to obtain compound Ic; (2) reacting Ic with amino acid Id under alkaline conditions. N - Alkylation reaction to obtain guanidine acid Ie; (3) Ie undergoes ester condensation / amide condensation with the corresponding phenol / amine / thiophenol If to obtain compound Ig; and (4) Finally, Ig is deprotected to obtain compound I.

[0060] In another preferred embodiment, step 1 is carried out in the presence of triphenylphosphine and diisopropyl azodicarboxylate (DIAD); and / or, step 2 is carried out in the presence of a base (preferably triethylamine (TEA)); and / or the solvent for step 2 is preferably acetonitrile or methanol; and / or the reaction temperature for step 2 is preferably room temperature; and / or, step 3 is carried out in the presence of a condensing agent (preferably...). N , N , N' , N' -Tetramethylchloromethylammonium hexafluorophosphate (TCFH) and base (preferred) N The reaction is carried out in the presence of N-methylimidazolium (NMI), and / or the solvent for step 3 is preferably acetonitrile, and / or the reaction temperature for step 3 is preferably room temperature; and / or step 4 is carried out in the presence of an acid (preferably trifluoroacetic acid (TFA)), and / or the solvent for step 4 is preferably dichloromethane, and / or the reaction temperature for step 5 is preferably room temperature.

[0061] In a fifth aspect of the invention, a method for activating acetaldehyde dehydrogenase 2 (ALDH2) enzyme is provided, comprising the steps of: administering to a desired object a safe and effective amount of one or more compounds or their stereoisomers, optical isomers, non-racemic or racemic mixtures, or pharmaceutically acceptable salts thereof, or their solvates or N-oxides thereof; wherein the compounds are as defined in the first aspect.

[0062] In a sixth aspect of the invention, a method for promoting the metabolism of acetaldehyde or other aldehydes is provided, comprising the steps of: administering to a desired object a safe and effective amount of one or more compounds or stereoisomers, optical isomers, non-racemic or racemic compounds thereof, or pharmaceutically acceptable salts thereof, or solvates thereof or N-oxides thereof; wherein the compounds are as defined in the first aspect.

[0063] In a seventh aspect of the invention, a method for treating or preventing alcohol-related diseases and / or diseases that can be treated or prevented by promoting the metabolism of acetaldehyde or other aldehydes is provided, comprising the steps of: administering to a desired subject a safe and effective amount of one or more compounds or stereoisomers, optical isomers, non-racemic or racemic compounds thereof, or pharmaceutically acceptable salts thereof, or solvates thereof or N-oxides thereof; wherein the compounds are as defined in the first aspect.

[0064] In an eighth aspect of the invention, a method for activating aldehyde dehydrogenase 2 (ALDH2) enzyme is provided, comprising the steps of contacting the object with one or more compounds or their stereoisomers, optical isomers, non-racemic or racemic mixtures, pharmaceutically acceptable salts thereof, solvates thereof, or N-oxides thereof, thereby activating aldehyde dehydrogenase 2 (ALDH2) enzyme; wherein the compounds are as defined in the first aspect.

[0065] In another preferred embodiment, the object is a protein or a cell.

[0066] In another preferred embodiment, the method is non-therapeutic in vitro.

[0067] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0068] Figure 1 The results show the effect of the test compound on ethanol-induced liver injury at the cellular level.

[0069] Figure 2 The results show the effect of the test compound on ethanol-induced liver injury at the cellular level.

[0070] Figure 3 The results show the effect of the test compound on ROS in ethanol-induced liver injury at the cellular level.

[0071] Figure 4 The results show the stability of the test compound in artificial gastrointestinal fluid.

[0072] Figure 5 The results of liver microsomal stability of the test compound (22) are shown. Detailed Implementation

[0073] Through long-term and in-depth research, the inventors unexpectedly discovered compounds with ALDH2 agonist activity. These compounds not only possess excellent ALDH2 agonist activity but also exhibit excellent stability and demonstrate protective effects against alcohol-induced damage. Based on this, the inventors completed this invention.

[0074] the term Unless otherwise specified, the terms or abbreviations herein have the conventional meanings as understood by those skilled in the art.

[0075] As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). The term "halogenated" means that one or more hydrogen atoms in a group are replaced by the aforementioned halogen atoms.

[0076] As used herein, single bonds indicated by dashed lines or bonds marked with wavy or dashed lines indicate the connection position of the group to other parts.

[0077] As used in this article, C a-b Or C a -C b (where a and b are distinct natural numbers and a < b) indicates that the group contains any number of carbons within the range a to b (including a, b, or any integer number between a and b), for example, C 1-6 C1-C6 indicates that the group contains 1, 2, 3, 4, 5, or 6 carbon atoms. When the subscript 'a' is 0, it means there are no carbon atoms. For example, C0-C6 alkylene represents no (non-existent) or C1-C6 alkylene.

[0078] As used herein, the term "alkyl," either on its own or as part of another substituent, refers to a straight-chain or branched hydrocarbon group having a specified number of carbon atoms (i.e., C64-C ... 1-6 Alkyl groups are alkyl groups containing 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, tert-butyl, isobutyl, sec-butyl), pentyl (e.g., n-pentyl, n-hexyl, n-heptyl, n-octyl), etc.

[0079] Unless otherwise stated, the term "heteroalkyl" on its own or in combination with other terms refers to a stable group formed by replacing one or more carbon atoms (such as O, N, and S) in an alkyl group as defined above, wherein the specified number of atoms refers to the number of carbon atoms before the C is replaced; for example, a 3- to 5-membered heteroalkyl group refers to a group containing 3 to 5 carbon atoms and a heteroatom. The heteroatoms O, N, and S can be located at any internal position within the heteroalkyl group. Examples include -CH2-CH2-O-CH3.

[0080] As used herein, the term "alkenyl," either alone or as part of another substituent, refers to an unsaturated alkyl group having one or more (preferably one) double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl group having one or more (preferably one) triple bonds. Generally, alkenyl groups have 2-6 carbon atoms, i.e., C2-C6 alkenyl groups, and alkynyl groups have 2-6 carbon atoms, i.e., C2-C6 alkynyl groups. Examples of such unsaturated alkyl groups include: vinyl, 2-propenyl, crotonyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologues and isomers.

[0081] As used herein, the term "cycloalkyl" refers to a ring having a specified number of ring atoms (e.g., C10, C20, C30, C40, C50, C60, C7 ... 3-6 A cycloalkyl ring is a hydrocarbon ring that is fully saturated or has no more than one double bond between the ring apexes, preferably a fully saturated ring. “Cycloalkyl” can be a monocyclic ring (such as cyclopropyl, cyclobutyl, cyclohexyl, etc.) or a bicyclic or polycyclic hydrocarbon ring, such as bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, etc.

[0082] As used herein, the term "heterocyclic alkyl," sometimes also referred to herein as "heterocyclic group," refers to a cycloalkyl group containing one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Heterocyclic alkyl groups can be monocyclic, bicyclic, or polycyclic systems. Generally, heterocyclic groups typically comprise 4 to 12 ring atoms (i.e., 4 to 12-membered heterocyclic alkyl groups), preferably comprising 5 to 7 ring atoms (i.e., 5 to 7-membered heterocyclic groups) and containing 1, 2, 3, or 4 heterocyclic atoms.

[0083] As used herein, the terms “alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “cycloalkylene,” and “heterocycloalkylene,” etc., either alone or as part of another substituent, refer to a divalent group derived from the corresponding group (such as alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl) as defined above. Examples of alkylene include methylene (-CH2-), examples of heteroalkylene include -O-CH2-O-, and examples of alkenylene include -CH=CH-, etc.

[0084] As used herein, the term "alkoxy" is used in its conventional sense to refer to those alkyl groups that are attached to the rest of the molecule by an oxygen atom.

[0085] Unless otherwise stated, the term "aryl" refers to a polyunsaturated (usually aromatic) hydrocarbon group, which can be monocyclic or fused together or covalently linked polycyclic (up to three rings). Generally, aryl groups have 6-12 ring atoms. The term "heteroaryl" refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Generally, heteroaryl groups have 5-12 ring atoms, i.e., 5-12-membered heteroaryl groups, preferably 5-6 ring atoms, i.e., 5-6-membered heteroaryl groups, and contain 1, 2, 3, or 4 heteroatoms (such as nitrogen). Heteroaryl groups can be attached to the rest of the molecule via heteroatoms (such as N). Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, etc.

[0086] Unless otherwise defined, the terms above will include both substituted and unsubstituted forms of the specified group. Preferred substituents for each type of group are provided below. For brevity, the terms aryl and heteroaryl will refer to the substituted or unsubstituted forms provided below. In this document, unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on a group are substituted by a substituent selected from the group consisting of: D, halogens, unsubstituted or halogenated or deuterated C1-C6 alkyl groups.

[0087] As used in this article, the term “heteroatoms” is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0088] For the compounds provided herein, a bond from a substituent (typically an R group) to the center of an aromatic ring (e.g., benzene, naphthalene, pyridine, etc.) will be understood as a bond that provides a connection at any available vertex of the aromatic ring. In some embodiments, this description also includes connections on rings fused to the aromatic ring.

[0089] As used herein, the terms “containing,” “comprising,” or “including” indicate that various ingredients may be used together in mixtures or compositions of the present invention. Therefore, the terms “consistent with…” and “composed of…” are included in the term “containing.”

[0090] As used herein, the term "pharmaceutically acceptable" means a substance suitable for human and / or animal use without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), i.e., a reasonable benefit / risk ratio.

[0091] As used herein, the term "therapeutic effective dose" refers to any amount of a drug as described below, which, when used alone or in combination with another therapeutic agent, promotes disease regression, manifested as a reduction in the severity of disease symptoms, an increase in the frequency and duration of symptom-free periods, or prevention of impairment or disability caused by the disease. The "therapeutic effective dose" of the drug of this invention also includes a "preventive effective dose," which is any amount of a drug as described below, which, when administered alone or in combination with another therapeutic agent to a subject at risk of developing the disease or suffering from a relapse of the disease, inhibits the occurrence or recurrence of the disease.

[0092] Unless otherwise specified, all compounds mentioned in this invention are intended to include all possible optical isomers, such as compounds with a single chirality, or mixtures of various chiral compounds (i.e., racemates). In all compounds of this invention, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0093] ALDH2 agonists, their applications, and preparation methods As used herein, the terms “compound of the invention,” “derivative of the invention,” “acetaldehyde dehydrogenase 2 agonist,” or “ALDH2 agonist” are used interchangeably to refer to the compounds described in the first aspect of the invention (e.g., compounds represented as of Formula A or Formula I). ​​The term also includes various crystalline forms of the compounds, pharmaceutically acceptable salts, various solvates (e.g., hydrates), and various isomers.

[0094] In one aspect, a compound of formula A or formula I, or a stereoisomer, optical isomer, or pharmaceutically acceptable salt thereof, or a composition containing the thereof, is provided: Among them, R 1 R 2 R 3 W, subscript n, A, and X are as defined above.

[0095] In other implementations, in Formula I, The subscript n is selected from the following group: integers from 0 to 6; and / or X is O, N, or S; and / or A is aryl or heteroaryl; and / or Each R 1 R 2 R 3Each is independently selected from the following group: H, D, halogen, hydroxyl, amino, cyano, nitroso, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted R. 4 -CO-X 1 -R 5 Any one or at least two combinations of R, where R 4 R 5 Each is independently selected from the following group: H, D, substituted or unsubstituted C1-C6 alkyl and substituted or unsubstituted C3-C6 cycloalkyl, where X1 is O, N or absent.

[0096] Optionally, the compound, or its stereoisomers, optical isomers, pharmaceutically acceptable salts, or combinations thereof, have ALDH2 agonist activity.

[0097] Optionally, in the structure shown in Equation I, R 1 R 2 R 3 This only illustrates that there are multiple substituents on the relevant group, and does not mean that there is exactly only one substituent. It can be two, three, four, or five, as mentioned above with R. 1 R 2 R 3 Each group can be any one or a combination of at least two of the stated groups, meaning that the combination of at least two groups can be more than the four groups represented in the expression. For example, when A is a five-membered aryl group, the number of substituents on it can be four or less than four. If A is a six-membered aryl group, the number of substituents on it can be four, less than four, or five.

[0098] Optionally, aryl refers to a monocyclic, bicyclic, or tricyclic carbocyclic aromatic group, and includes groups containing two monocyclic carbocyclic aromatic groups directly linked by covalent bonds. Heteroaryl refers to a monocyclic, bicyclic, or tricyclic aromatic group containing one or more heteroatoms selected from S, N, or O, and includes groups containing two such monocyclic rings or one such monocyclic ring and a monocyclic aryl ring directly linked by covalent bonds; Optionally, the substituted or unsubstituted C1-C6 alkyl group is a substituted or unsubstituted C1, C2, C3, C4, C5 or C6 alkyl group, specifically, it can be methyl, ethyl, trifluoromethyl, 1,1,1-trifluoroethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, n-pentyl, isopentyl, neopentyl or n-hexyl, etc. Optionally, the substituted or unsubstituted C1-C6 alkoxy group can be a substituted or unsubstituted C1, C2, C3, C4, C5 or C6 alkoxy group, specifically, it can be methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, etc. Optionally, the aryl group is phenyl, biphenyl, or naphthyl; Optionally, the heteroaryl group is furanyl, thiophene, pyrrole, thiazolyl, imidazole, oxazolyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, benzofuranyl, benzothiophene, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, inzolyl, benzothiazolyl, quinazolinyl, phthalazinyl, purine, benzo[1,3]dioxane, benzo[1,4]dioxane; Optionally, A is phenyl, naphthyl, or pyridyl, preferably phenyl; Optionally, the pharmaceutically acceptable salt is an acid addition salt of a guanidine compound; Optionally, the acid in the acid addition salt is an inorganic acid or an organic acid; Optionally, the inorganic acid is selected from any one or a combination of at least two of hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, bromic acid, or iodic acid; Preferably, the organic acid is selected from any one or a combination of at least two of the following: trifluoroacetic acid, acetic acid, methanesulfonic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, p-toluenesulfonic acid, benzoic acid, benzenesulfonic acid, lactic acid, glutamic acid, or mandelic acid, with trifluoroacetic acid and methanesulfonic acid being the most preferred.

[0099] In some specific implementation schemes, R 1 R 2 R 3 R 3a R 3b X, ring A, W, subscript n, R 4 R 5 X 1 and R S Each is a corresponding group in the specific compound prepared in the examples (such as a compound having the structure shown in formulas (1) to (30)).

[0100] Optionally, the compound, or its stereoisomer, optical isomer, pharmaceutically acceptable salt, or composition thereof, is characterized by having any one or a combination of at least two of the compounds having the structures shown in formulas (1) to (30): .

[0101] Optionally, the compound of the present invention, or its stereoisomer, optical isomer, pharmaceutically acceptable salt, or composition thereof, is characterized in that the preparation method of the compound can be represented by the following general formula: (1) Where n, A, X, R 1 R 2 R 3 As defined in claim 1, R is a protecting group of an amino group, preferably a Boc (tert-butyloxycarbonyl) group; Optionally, compound Ia reacts with the corresponding alcohol Ib via a Mitsunobu reaction to yield compound Ic; Ic then reacts with amino acid Id under alkaline conditions. N - Alkylation reaction yields guanidinoic acid Ie; Ie undergoes ester condensation / amide condensation with the corresponding phenol / amine / thiophenol If to yield compound Ig; finally, Ig is deprotected to yield compound I.

[0102] Optionally, in step 1, triphenylphosphine and diisopropyl azodicarboxylate (DIAD) are used; in step 2, the base is preferably triethylamine (TEA), the solvent is preferably acetonitrile or methanol, and the reaction temperature is preferably room temperature; in step 3, the condensing agent is preferably... N , N , N' , N' -Tetramethylchloromethylammonium hexafluorophosphate (TCFH), base preferred N -Methylimidazole (NMI), preferably acetonitrile as the solvent, and preferably room temperature as the reaction temperature; the acid in step 4 is preferably trifluoroacetic acid (TFA), preferably dichloromethane as the solvent, and preferably room temperature as the reaction temperature.

[0103] Based on the teachings of the above preparation method, those skilled in the art can obtain all the compounds contained in Formula I without creative effort; On the other hand, the present invention provides compounds as described above, or stereoisomers, optical isomers thereof, or pharmaceutically acceptable salts thereof, or solvates of compositions thereof; On the other hand, the present invention provides the compounds described above, or their stereoisomers, optical isomers, or pharmaceutically acceptable salts thereof, or hydrates and / or alcoholic compounds of the same thereof; On the other hand, the present invention provides the compounds described above, or their stereoisomers, optical isomers, pharmaceutically acceptable salts, or N-oxides of compositions thereof.

[0104] Pharmaceutical Compositions and Administration Because the compounds of this invention possess excellent aldehyde dehydrogenase 2 (ALDH2) agonist activity, the compounds of this invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of this invention as the main active ingredient can be used to treat, prevent, or alleviate various alcohol-related or alcohol-induced diseases, or to treat, prevent, or alleviate diseases that can be treated or prevented by promoting the metabolism of acetaldehyde or other aldehydes. According to the prior art, the compounds of this invention can be used to treat the following diseases: acute alcohol poisoning (AAI), alcoholic liver disease (ALD), heart failure, myocardial ischemia / reperfusion injury, diabetic cardiomyopathy, obesity, type 2 diabetes, non-alcoholic fatty liver disease, alcohol use disorder, etc.

[0105] On the other hand, the present invention provides a pharmaceutical composition, characterized in that the composition comprises: a class of compounds as described above and their optical isomers, non-racemic, racemic, or pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier; Optionally, the pharmaceutical composition further comprises pharmaceutically acceptable excipients; Optionally, the pharmaceutically acceptable excipient is any one or a combination of at least two of the following: excipients, diluents, carriers, flavoring agents, binders, or fillers; Optionally, the dosage form of the pharmaceutical composition is an oral preparation, a parenteral preparation, or a topical preparation; Optionally, the dosage form of the pharmaceutical composition is tablets, capsules, powders, granules, lozenges, solutions, or gels; The uses include: (i) Used to activate aldehyde dehydrogenase 2 (ALDH2); (ii) Medicines and / or preparations for the treatment of acute alcohol poisoning (AAI) and alcoholic liver disease (ALD) or related diseases; (iii) Used in the preparation of drugs and / or formulations for the treatment of other related diseases by promoting the metabolism of acetaldehyde and other aldehydes.

[0106] The present invention provides the use of the compound as described above, or its stereoisomers, optical isomers, or pharmaceutically acceptable salts thereof, or combinations thereof, characterized in that the disease is selected from the group consisting of: heart failure, myocardial ischemia / reperfusion injury, diabetic cardiomyopathy, obesity, type 2 diabetes, non-alcoholic fatty liver disease, alcohol use disorder, or combinations thereof.

[0107] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-500 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0108] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0109] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0110] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 20–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0111] The main advantages of this invention include: (a) The compounds of the present invention (especially the preferred compounds of the present invention) exhibit good or even excellent agonistic activity in in vitro enzyme activity experiments (see Test Example 1 of this application).

[0112] (b) The preferred compounds of the present invention have shown excellent effects in reducing alcohol-induced liver injury in in vitro cellular experiments (see Test Examples 2-4 of this application).

[0113] (c) The preferred compounds of the present invention exhibit excellent stability (see Test Examples 5-6 of this application).

[0114] The compounds of the present invention (especially the preferred compounds of the present invention) can activate the ALDH2 protein, thereby accelerating the rate of ethanol / acetaldehyde metabolism, reducing the rate of intoxication, prolonging the latency period of intoxication, shortening the duration of intoxication, and improving intoxication behavior. They also exhibit hepatoprotective activities such as improving alcoholic liver damage, reducing lipid droplet accumulation, slowing fibrosis, reducing blood lipid levels, and reducing inflammatory factors and ROS levels, showing potential application value in the treatment of acute alcohol poisoning (AAI) and alcoholic liver disease (ALD).

[0115] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0116] Example 1: Preparation of 6-(2,3-bis(tert-butoxycarbonyl)guanidinyl)hexanoic acid (intermediate 1) Dissolve 255 mg of 6-aminohexanoic acid in 10 mL of an acetonitrile / water mixture (MeCN:H2O = 10:1), cool to 0-5 °C in an ice bath, add 2 mL of triethylamine with stirring, and then add... N , N' -di-tert-butoxycarbonyl-1 H 500 mg of pyrazole-1-formamidin was added, and the ice bath was removed. The reaction mixture was allowed to return to room temperature and stirred for 6 h. After the reaction was complete, acetonitrile was removed from the system under reduced pressure. The residue was extracted twice with ethyl acetate / 1 M KHSO4 aqueous solution, washed twice with saturated NaCl, and finally dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a white solid, which could be used for the next reaction without further treatment. Yield: 95%. 1 H NMR (400 MHz, chloroform-) d ) d 3.57 (s, 2H), 2.39 (t, J = 7.3 Hz, 2H), 1.74–1.65 (m, 4H), 1.51 (s, 18H), 1.45 (d, J = 7.8 Hz, 2H). Example 2: Preparation of ethyl 4-hydroxy-3,5-dimethylbenzoate (intermediate 2) 1 g of 4-hydroxy-3,5-dimethylbenzoic acid was dissolved in 10 mL of ethanol, and a catalytic amount of concentrated sulfuric acid was added dropwise. After the addition was complete, the reaction mixture was heated to 78 °C and stirred overnight for 12 h. After the reaction was complete, the ethanol in the system was removed by vacuum distillation. The residue was extracted twice with ethyl acetate / saturated NaHCO3 aqueous solution, washed twice with saturated NaCl, and finally dried with anhydrous sodium sulfate. The solvent was removed by vacuum distillation to obtain a pale yellow solid, which could be used for the next reaction without further treatment. Yield: 99%. 1 H NMR (400 MHz, chloroform-) d ) d 7.70 (s, 2H), 5.03 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H),2.28 (s, 6H), 1.38 (t, J = 7.1 Hz, 3H). Example 3: Preparation of 4-((6-guanidinohexanoyl)oxy)-3,5-dimethylbenzoate ethyl trifluoroacetate (Formula (1)) Dissolve 100 mg of 6-(2,3-bis(tert-butoxycarbonyl)guanidinyl)hexanoic acid and ethyl 4-hydroxy-3,5-dimethylbenzoate (52 mg) in 10 mL of ultra-dry acetonitrile and stir. Add N After adding methylimidazole (NMI, 44 μL), add it all at once. N , N , N' , N' Tetramethylchloromethanesulfonium hexafluorophosphate (TCFH, 83 mg) was stirred for 2 h. After the reaction was complete, the solvent was directly removed under reduced pressure. The remaining solid was crudely purified by silica gel column chromatography and dissolved in dichloromethane (5 mL). The solution was cooled to 0-5 °C in an ice bath, and trifluoroacetic acid (2.5 mL) was added dropwise while stirring for 2 h. After the reaction was complete, the solvent was directly removed under reduced pressure. The remaining solid was slurried with dichloromethane / n-hexane to give a white solid, yield: 73%. 1 H NMR (400 MHz, DMSO- d 6 ) d 7.73 (s, 2H), 7.65–7.56 (m, 1H), 7.16 (s, 4H), 4.30 (q, J = 7.1 Hz, 2H), 3.12 (q, J = 6.5 Hz, 2H), 2.70 (t, J= 7.3 Hz, 2H), 2.14 (s, 6H), 1.70 (p, J = 7.4 Hz, 2H), 1.52 (dq, J = 12.2,6.1, 5.1 Hz, 2H), 1.41 (td, J = 8.5, 4.3 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). HRMS (ESI) m / z calculated value C 18 H 27 N3O4, [M + H]+ 350.2080, Measured value: 350.2084. Examples 4-15: Preparation of compounds of formulas (2)-(13) The preparation method in this embodiment is similar to that in Example 3, except that the raw materials with different groups are selected according to the different reaction products (the synthesis of intermediate T2 is as described in Example 2). The rest of the reaction process and the control of the reaction conditions are the same as in Example 3. The compounds of formula (2)-(13) were successfully prepared. The specific reaction formula can be represented by the following route 1: Example 4: Preparation of ethyl 4-((6-guanidinohexanoyl)oxy)-3-methylbenzoate trifluoroacetate (Formula (2)) Route 1 - R a =-CH3,-R b =-H, X=O, Y=C, Z=C; white solid, yield: 81%. 1 H NMR (400 MHz, DMSO- d 6 ) d 7.91 (d, J = 2.2 Hz, 1H), 7.83 (dd, J = 8.4, 2.2 Hz, 1H), 7.46 (t, J = 5.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 5H), 4.31 (q, J = 7.1 Hz, 2H), 3.12 (q, J = 6.7 Hz, 2H), 2.67 (t, J = 7.3 Hz, 2H), 2.18 (s, 3H), 1.69 (p,J = 7.4 Hz, 2H), 1.52 (p, J = 7.0 Hz, 2H), 1.40 (td, J = 8.3, 4.0 Hz, 2H), 1.32 (t, J =7.1 Hz, 3H). HRMS (ESI) m / z calculated value C 17 H 25 N3O4, [M + H] + 336.1923, Measured value: 336.1925. Example 5: Preparation of ethyl 4-((6-guanidinohexanoyl)oxy)-3-methoxybenzoate trifluoroacetate (Formula (3)) Route 1 - R a =-OCH3,-R b =-H, X=O, Y=C, Z=C; white solid, yield: 71%. 1 H NMR (400 MHz, DMSO- d 6 ) d 7.76 (t, J = 5.5 Hz, 1H), 7.60 (d, J = 7.0 Hz, 2H), 7.24 (d, J =8.2 Hz, 5H), 4.33 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 3.12 (q, J = 6.5 Hz, 2H), 2.61 (t, J = 7.3 Hz, 2H), 1.67 (p, J = 7.4 Hz, 2H), 1.52 (p, J = 7.1 Hz, 2H), 1.36 (dt, J = 27.0, 7.1 Hz, 5H). HRMS (ESI) m / z calculated value C 17 H 25 N3O5, [M + H] + 352.1872, Measured value: 352.1871. Example 6: Preparation of ethyl 4-((6-guanidinohexanoyl)oxy)-3-hydroxybenzoate trifluoroacetate (formula (4)) Route 1 - R a =-OH, -R b =-H, X=O, Y=C, Z=C; white solid, yield: 77%. 1 H NMR (400 MHz, DMSO- d 6 ) d 10.71 (s, 1H), 7.72 (dd, J = 8.5, 2.2 Hz, 1H), 7.64–7.48 (m, 2H), 7.07 (dd, J = 42.9, 8.4 Hz, 5H), 4.33–4.20 (m, 2H), 3.11 (q, J = 6.6 Hz, 2H), 2.60 (t, J = 7.4 Hz, 2H), 1.66 (p, J = 7.4 Hz, 2H), 1.52 (p, J = 7.2 Hz, 2H), 1.40 (qd, J = 7.6, 6.9, 4.2 Hz, 2H), 1.33–1.26 (m, 3H). HRMS (ESI) m / z calculated value C 16 H 23 N3O5, [M + H] + 338.1716, Measured value: 338.1714. Example 7: Preparation of 6-((6-guanidinohexanoyl)oxy)nicotinic acid ethyl ester trifluoroacetate (Formula (5)) Route 1 - R a Does not exist, -R b =-H, X=O, Y=N, Z=C; reddish-brown oil, yield: 58%. 1 H NMR (400 MHz, DMSO- d 6 ) d 7.64 (t, J = 5.6 Hz, 1H), 7.09 (s, 4H), 4.05 (q, J = 7.1 Hz, 6H), 3.08 (q, J = 6.6 Hz, 2H), 2.28 (t, J = 7.4 Hz, 2H), 1.50 (dp,J = 28.7, 7.4Hz, 4H), 1.28 (qd, J = 10.0, 9.1, 6.0 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H). HRMS(ESI) m / z calculated value C 15 H 22 N4O4, [M + H] + 323.1719, Measured value: 323.1720. Example 7: Preparation of ethyl 5-((6-guanidinohexanoyl)oxy)pyridinecarboxylate trifluoroacetate (Formula (6)) Route 1 - R a =-H,-R b =-H, X=O, Y=C, Z=N; reddish-brown oil, yield: 66%. 1 H NMR (400 MHz, DMSO- d 6 ) d 8.56 (d, J = 2.6 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.82 (dd, J =8.5, 2.6 Hz, 1H), 7.46 (d, J = 5.1 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.12(q, J = 6.6 Hz, 2H), 2.69 (d, J = 7.4 Hz, 2H), 1.67 (q, J = 7.4 Hz, 2H), 1.51(q, J = 7.2 Hz, 2H), 1.45–1.25 (m, 5H). HRMS (ESI) m / z calculated value C 15 H 22 N4O4, [M + H] + 323.1719, Measured value: 323.1718. Example 8: Preparation of ethyl 3,5-difluoro-4-((6-guanidinohexanoyl)oxy)benzoate trifluoroacetate (formula (7)) Route 1 - Ra =-F,-R b =-F, X=O, Y=C, Z=C; white solid, yield: 95%. 1 H NMR (400 MHz, DMSO- d 6 ) d 7.84–7.77 (m, 2H), 7.55 (t, J = 5.6 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.11 (q, J = 6.6 Hz, 2H), 2.78 (t, J = 7.2 Hz, 2H), 1.69 (p, J = 7.4 Hz, 2H), 1.51 (q, J = 7.3 Hz, 2H), 1.44–1.36 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H). HRMS (ESI) m / z calculated value C 16 H 21 F2N3O4, [M + H] + 358.1573, Measured value: 358.1577. Example 9: Preparation of ethyl 3-fluoro-4-((6-guanidinohexanoyl)oxy)benzoate trifluoroacetate (Formula (8)) Route 1 - R a =-F,-R b =-H, X=O, Y=C, Z=C; white solid, yield: 91%. 1 H NMR (400 MHz, DMSO- d 6 ) d 7.86 (ddd, J = 9.8, 5.7, 2.1 Hz, 2H), 7.60–6.88 (m, 6H), 4.33 (q, J = 7.1 Hz, 2H), 3.11 (q, J = 6.6 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 1.69 (q, J = 7.6 Hz, 2H), 1.51 (q, J= 7.2 Hz, 2H), 1.44–1.29 (m, 5H). HRMS (ESI) m / z calculated value C 16 H 22 FN3O4, [M + H] + 340.1667, Measured value: 340.1674. Example 10: Preparation of ethyl 3-chloro-4-((6-guanidinohexanoyl)oxy)benzoate trifluoroacetate (formula (9)) Route 1 - R a =-Cl,-R b =-H, X=O, Y=C, Z=C; white solid, yield: 94%. 1 H NMR (400 MHz, DMSO- d 6 ) d 8.07 (d, J = 2.0 Hz, 1H), 7.98 (dd, J = 8.4, 2.1 Hz, 1H), 7.66 (d, J = 5.9 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.25 (s, 4H), 4.34 (q, J = 7.1 Hz, 2H), 3.12 (q, J = 6.6 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 1.70 (p, J = 7.4 Hz, 2H), 1.53 (p, J = 7.0 Hz, 2H), 1.41 (td, J = 8.4, 4.2 Hz, 2H), 1.33 (t, J =7.1 Hz, 3H). HRMS (ESI) m / z calculated value C 16 H 22 ClN3O4, [M + H] + 356.1377, Measured value: 356.1380. Example 11: Preparation of ethyl 3,5-dichloro-4-((6-guanidinohexanoyl)oxy)benzoate trifluoroacetate (Formula (10)) Route 1 - Ra =-Cl,-R b =-Cl, X=O, Y=C, Z=C; white solid, yield: 95%. 1 H NMR (400 MHz, DMSO- d 6 ) d 8.07 (s, 2H), 7.52 (s, 1H), 6.99 (s, 4H), 4.35 (q, J = 7.1 Hz, 2H), 3.11 (q, J = 6.5 Hz, 2H), 2.78 (t, J = 7.2 Hz, 2H), 1.73 (p, J = 7.3 Hz, 2H), 1.52 (q, J = 7.3 Hz, 2H), 1.42 (ddt, J = 15.2, 9.6, 5.6 Hz, 2H), 1.33(t, J = 7.1 Hz, 3H). HRMS (ESI) m / z calculated value C 16 H 21 Cl2N3O4, [M + H] + 390.0987, Measured value: 390.0991. Example 12: Preparation of ethyl 3-cyano-4-((6-guanidinohexanoyl)oxy)benzoate trifluoroacetate (Formula (11)) Route 1 - R a =-CN,-R b =-H, X=O, Y=C, Z=C; brown solid, yield: 42%. 1 H NMR (400 MHz, DMSO- d 6 ) d 8.45 (d, J = 2.2 Hz, 1H), 8.32 (dd, J = 8.6, 2.1 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.47 (t, J = 5.7 Hz, 1H), 7.18 (s, 4H), 4.35 (q, J = 7.1 Hz, 2H), 3.11 (q,J = 6.6 Hz, 2H), 2.73 (t, J = 7.3 Hz, 2H), 1.72 (p, J = 7.4 Hz, 2H), 1.52 (q, J = 7.3 Hz, 2H), 1.42 (q, J = 8.3 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). HRMS (ESI) m / z calculated value C 17 H 22 N4O4, [M + H] + 347.1719, Measured value: 347.1718. Example 13: Preparation of ethyl 4-((6-guanidinohexanoyl)oxy)-3-(trifluoromethyl)benzoate trifluoroacetate (Formula (12)) Route 1 - R a =-CF3, -R b =-H, X=O, Y=C, Z=C; grayish-green solid, yield: 37%. 1 H NMR (400MHz, DMSO- d 6 ) d 8.32 (dd, J = 8.5, 2.1 Hz, 1H), 8.23 ​​(d, J = 2.1 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.15 (s, 4H), 4.37 (q, J = 7.1 Hz, 2H), 3.11 (q, J = 6.6 Hz, 2H), 2.68 (t, J = 7.3 Hz, 2H), 1.68 (p, J = 7.5 Hz, 2H), 1.52 (p, J = 7.2 Hz, 2H), 1.36 (dt, J = 14.2, 7.1 Hz, 5H). HRMS (ESI) m / z calculated value C 17 H 22 F3N3O4, [M + H] +390.1640, Measured value: 390.1643. Example 14: Preparation of ethyl 4-((6-guanidinohexanoyl)thio)benzoate trifluoroacetate (Formula (13)) Route 1 - R a =-H,-R b =-H, X=S, Y=C, Z=C; Brown oil, yield: 44%. 1 H NMR (400 MHz, DMSO- d 6 ) d 8.05–7.98 (m, 2H), 7.62–7.51 (m, 3H), 7.18 (s, 4H), 4.34 (q, J =7.1 Hz, 2H), 3.09 (q, J = 6.7 Hz, 2H), 2.77 (t, J = 7.3 Hz, 2H), 1.63 (q, J =7.5 Hz, 2H), 1.48 (p, J = 7.2 Hz, 2H), 1.33 (t, J = 7.1 Hz, 5H). HRMS (ESI) m / z calculated value C 16 H 23 N3O3S, [M + H] + 338.1538, Measured value: 338.1536. Examples 16-17: Preparation of compounds of formulas (14)-(15) The preparation method in this embodiment is similar to that in Example 3, except that the raw materials with different groups are selected according to the different reaction products. The rest of the reaction process and the control of the reaction conditions are the same as in Example 3. The compound of formula (14)-(15) was successfully prepared. The specific reaction formula can be represented by the following route 2: Example 16: Preparation of ethyl 6-((6-guanidinohexanoyl)oxy)-2-naphthoic acid trifluoroacetate (Formula (14)) Route 2 - R c = Grayish-white solid, yield: 93%. 1 H NMR (400 MHz, DMSO- d6 ) d 8.67 (s, 1H), 8.22 (d, J = 8.9 Hz, 1H), 8.03 (s, 2H), 7.77 (s, 1H), 7.56 (s, 1H), 7.47–6.77 (m, 5H), 4.39 (q, J = 7.1 Hz, 2H), 3.13 (q, J = 6.5Hz, 2H), 2.68 (t, J = 7.2 Hz, 2H), 1.70 (q, J = 7.7 Hz, 2H), 1.53 (q, J = 7.4Hz, 2H), 1.40 (dt, J = 14.2, 7.3 Hz, 5H). HRMS (ESI) m / z calculated value C 20 H 25 N3O4, [M +H] + 372.1923, Measured value: 372.1926. Example 17: Benzo[ d Preparation of [1,3]dioxolane-5-yl-6-guanidinium hexanoate trifluoroacetate (Formula (15)) Route 2 - R c = Reddish-brown solid, yield: 66%. 1 H NMR (400 MHz, DMSO- d 6 ) d 7.48 (t, J = 5.8 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 2.3 Hz, 1H), 6.54 (dd, J = 8.4, 2.3 Hz, 1H), 6.05 (s, 2H), 3.11 (q, J = 6.8 Hz, 2H), 2.55(d, J = 7.3 Hz, 2H), 1.64 (p, J = 7.4 Hz, 2H), 1.50 (p, J= 7.0 Hz, 2H), 1.36(tt, J = 9.6, 5.8 Hz, 2H). HRMS (ESI) m / z calculated value C 14 H 19 N3O4, [M + H] + 294.1454, Measured value: 294.1457. Example 18: 4-(( N 6 Preparation of ethyl carbamoyl iminolysyl)oxy)benzoate trifluoroacetate (formula (16)) The preparation method in this embodiment is similar to that in Example 3, except that the raw materials with different groups are selected according to the different reaction products. The 6-aminohexanoic acid in Example 1 is replaced with 6-amino-2-((tert-butoxycarbonyl)amino)hexanoic acid, resulting in intermediate 3. The remaining reaction process and reaction conditions were controlled in the same way as in Example 3, and the compound of formula (16) was successfully prepared as a white solid with a yield of 70%. 1 H NMR (400 MHz, DMSO- d 6 ) d 8.68 (s, 3H), 8.08 (d, J = 8.5 Hz, 2H), 7.81 (d, J = 5.3 Hz, 1H), 7.55–6.89(m, 6H), 4.35 (dq, J = 14.2, 7.1, 6.7 Hz, 3H), 3.14 (d, J = 6.2 Hz, 2H),2.07–1.89 (m, 2H), 1.61–1.42 (m, 4H), 1.33 (t, J = 7.1 Hz, 3H). HRMS (ESI) m / z calculated value C 16 H 24 N4O4, [M + H] + 337.1876, Measured value: 337.1880. Example 19: Preparation of ethyl 2-cyano-3-(4-hydroxyphenyl)acrylate (intermediate 4) 100 mg of 4-hydroxybenzaldehyde and 73 μL of cyanoacetate were dissolved in 5 mL of anhydrous ethanol. 135 μL of tetrahydropyrrole (THP) was added, and the reaction mixture was heated to 80 °C and stirred for 1 h. After the reaction was complete, the ethanol was removed from the system under reduced pressure, and the remaining solid was purified by silica gel column chromatography to obtain a yellow solid with a yield of 94%. 1 H NMR (400 MHz, chloroform-) d ) d 8.18 (s, 1H), 8.00–7.93 (m, 2H), 6.98–6.92 (m, 2H), 5.86 (s, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). Examples 20-23: Preparation of compounds of formulas (17)-(20) (1) In this embodiment, the preparation method of the intermediate is similar to that of Example 19, except that the raw materials with different groups are selected according to the different reaction products. The rest of the reaction process and the control of the reaction conditions are the same as in Example 19. Compounds of intermediate 5-7 were successfully prepared. The specific reaction formula can be represented by the following route 3: (2) The preparation method in this embodiment is similar to that in Example 3, except that the raw materials with different groups are selected according to the different reaction products. The rest of the reaction process and the control of the reaction conditions are the same as in Example 3. The compounds of formula (17)-(20) were successfully prepared. The specific reaction formula can be represented by the following route 4: Example 20: Preparation of trifluoroacetate of 2-cyano-3-(4-((6-guanidinohexanoyl)oxy)phenyl)acrylate (Formula (17)) Route 3 or 4 - R d =-OH, -R e =H, X=O, intermediate 5= Grayish-white solid, yield: 45%. 1 H NMR (400 MHz, DMSO- d 6 ) d 8.36 (s, 1H), 8.13–8.08 (m, 2H), 7.53 (t, J=5.7 Hz, 1H), 7.38–7.34 (m, 2H), 3.15–3.10 (m, 3H), 2.64 (t, J = 7.3 Hz, 2H), 1.67 (p, J = 7.4 Hz, 3H), 1.52 (t, J = 7.6 Hz, 3H), 1.40 (dt, J = 11.5, 4.9Hz, 3H). HRMS (ESI) m / z calculated value C 17 H 20 N4O4, [M + H] + 345.1563, Measured value: 345.1565. Example 21: Preparation of trifluoroacetate of 2-cyano-3-(4-(6-guanidinohexamido)phenyl)acrylate (Formula (18)) Route 3 or 4 - R d =-NH2,-R e =H, X=N, intermediate 7= Brown solid, yield: 51%. 1 H NMR (400 MHz, DMSO- d 6 ) d 10.38 (s, 1H), 8.23 ​​(s, 1H), 8.07–7.97 (m,2H), 7.82–7.76 (m, 2H), 7.49 (t, J = 5.7 Hz, 1H), 3.13–3.07 (m, 2H), 2.38 (t, J = 7.3 Hz, 2H), 1.62 (p, J = 7.4 Hz, 2H), 1.50 (p, J = 7.9, 7.3 Hz, 2H), 1.33 (ddt, J = 9.4, 7.2, 4.3 Hz, 2H). HRMS (ESI) m / z calculated value C 17 H 21 N5O3, [M + H] + 344.1722, Measured value: 344.1726. Example 22: Preparation of 4-(2-cyano-3-ethoxy-3-oxoprop-1-en-1-yl)phenyl-6-guanidinohexanoate trifluoroacetate (formula (19)) Route 3 or 4 - R d =-OH, -R e =-CH2CH3, X=O, intermediate 4= Grayish-white solid, yield: 70%. 1 H NMR (400 MHz, DMSO- d 6 ) d 8.43 (s, 1H), 8.16–8.10 (m, 2H), 7.53 (t, J = 5.7 Hz, 1H), 7.39–7.35 (m, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.12 (q, J =6.7 Hz, 2H), 2.64 (t, J = 7.3 Hz, 2H), 1.67 (p, J = 7.5 Hz, 2H), 1.56–1.48(m, 2H), 1.43–1.36 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H). HRMS (ESI) m / z calculated value C 19 H 24 N4O4, [M + H] + 373.1876, Measured value: 373.1879. Example 23: Preparation of ethyl 2-cyano-3-(4-(6-guanidinohexamido)phenyl)acrylate trifluoroacetate (Formula (20)) Route 3 or 4 - R d =-NH2,-R e =-CH2CH3, X=N, intermediate 6= Light green solid, yield: 82%. 1 H NMR (400 MHz, DMSO- d 6 ) d 10.40 (s, 1H), 8.28 (s, 1H), 8.05 (d, J = 9.0 Hz, 2H), 7.80 (d,J = 8.9 Hz, 2H), 7.47 (t, J = 5.6 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.12–3.07 (m, 2H), 2.38 (t, J = 7.4 Hz, 2H), 1.62 (t, J =7.7 Hz, 2H), 1.49 (t, J = 7.4 Hz, 3H), 1.30 (t, J = 7.1 Hz, 6H). HRMS (ESI) m / z calculated value C 19 H 25 N5O3, [M + H] + 372.2035, Measured value: 372.2038. Example 24: Preparation of ethyl 4-(ethylcarbamoyl)phenylacetate (intermediate 8) Dissolve 4-acetoxybenzoic acid (500 mg) and ethylamine hydrochloride (230 mg) in 20 mL of ultra-dry dichloromethane and stir. Add 2-(7-azabenzotriazole)- N , N , N' , N' Tetramethylurea hexafluorophosphate (HATU, 1583 mg) was stirred for 30 min, followed by the addition of triethylamine (1.158 mL) and stirring overnight for 12 h. After the reaction was complete, the solvent was removed directly under reduced pressure, and the remaining solid was purified by silica gel column chromatography to obtain a white solid with a yield of 91%. 1 H NMR (400 MHz, DMSO- d 6 ) d 8.47(t, J = 5.5 Hz, 1H), 7.92–7.84 (m, 2H), 7.25–7.18 (m, 2H), 3.28 (td, J = 7.2,5.5 Hz, 2H), 2.29 (s, 3H), 1.12 (t, J = 7.2 Hz, 3H). Example 25: N Preparation of ethyl-4-hydroxybenzamide (intermediate 9) Ethyl 4-(ethylcarbamoyl)phenylacetate (550 mg) was dissolved in ethanol (10 mL) and stirred. Sodium hydroxide (213 mg) was dissolved in water (2 mL). The resulting solution was added to the reaction system and stirred for 6 h. After the reaction was complete, the ethanol in the system was removed by vacuum distillation. The residue was extracted twice with ethyl acetate / 1M KHSO4 aqueous solution, washed twice with saturated NaCl, and finally dried over anhydrous sodium sulfate. The solvent was removed by vacuum distillation to obtain a white solid, which could be used for the next reaction without further treatment. Yield: 99%. 1 H NMR (400 MHz, chloroform-) d ) d 7.73–7.59 (m, 2H), 6.94–6.81 (m, 2H), 6.09 (s,1H), 3.49 (qd, J = 7.2, 5.5 Hz, 2H), 1.25 (t, J = 7.3 Hz, 3H). Example 26: Preparation of 4-(ethylcarbamoyl)phenyl 6-guanidinyl hexanoate trifluoroacetate (formula (21)) The preparation method in this embodiment is similar to that in Example 3, except that the raw materials with different groups are selected according to the different reaction products. The rest of the reaction process and the control of the reaction conditions are the same as in Example 3. The product is a grayish-white solid with a yield of 90%. 1 H NMR (400 MHz, DMSO- d 6 ) d 8.50 (t, J = 5.5 Hz, 1H), 7.95–7.85 (m, 2H), 7.69 (t, J = 5.4 Hz, 1H), 7.53–6.90 (m, 6H), 3.29 (qd, J = 7.2, 5.4 Hz, 2H), 3.12 (q, J = 6.7 Hz, 2H), 2.62 (t, J = 7.3 Hz, 2H), 1.67 (p, J = 7.4 Hz, 2H), 1.53 (p, J = 7.2 Hz, 2H), 1.39 (dtt, J = 10.6, 7.1, 4.3 Hz, 2H), 1.12 (t, J=7.2 Hz, 3H). HRMS (ESI) m / z calculated value C 16 H 24 N4O3, [M + H] + 321.1926, Measured value: 321.1933. Example 27: Preparation of 3-methylazacycloheptan-2-one (intermediate 10) Azacycloheptan-2-one (1 g) was dissolved in ultradry tetrahydrofuran (40 mL), and the reaction system was cooled to -5 °C. Then, n-butyllithium (2.4 M in hexane, 9.21 mL) was added dropwise, and the reaction system was stirred at -5 °C for approximately 2 h. Subsequently, iodomethane (600 μL) was dissolved in ultradry tetrahydrofuran (2 mL) and added dropwise to the reaction system. The mixture was stirred at -5 °C for 3 h, then heated to room temperature for 30 min. After the reaction was complete, the mixture was quenched with saturated NH4Cl solution. Tetrahydrofuran and hexane were removed from the system by vacuum distillation. The residue was extracted twice with ethyl acetate / saturated NH4Cl solution, washed twice with saturated NaCl, and finally dried over anhydrous sodium sulfate. The remaining solid was purified by silica gel column chromatography to obtain a white solid with a yield of 77%. 1 H NMR (400MHz, chloroform-) d ) d 6.30 (s, 1H), 3.35–3.16 (m, 2H), 2.64–2.53 (m, 1H), 2.06–1.94(m, 1H), 1.80 (dt, J = 13.5, 4.5 Hz, 1H), 1.71–1.58 (m, 2H), 1.54–1.41 (m,2H), 1.15 (d, J = 6.9 Hz, 3H). Example 28: Preparation of 6-amino-2-methylhexanoate (intermediate 11) 400 mg of 3-methylazacycloheptan-2-one was dissolved in 5 mL of 37% concentrated hydrochloric acid. The reaction system was heated to 100 °C and stirred overnight for 12 h. After the reaction was complete, the 37% concentrated hydrochloric acid was removed from the system under reduced pressure. The residue was ultrasonically washed twice with dichloromethane, filtered, and dried under an infrared lamp to obtain a white solid. No further treatment was required for the next reaction. Yield: 99%. 1 H NMR (400 MHz, DMSO- d 6 ) d 12.09 (s, 1H), 7.93 (s, 3H), 2.74 (q, J = 6.8Hz, 2H), 2.34–2.28 (m, 1H), 1.60–1.25 (m, 6H), 1.05 (d, J = 6.9 Hz, 3H). Examples 29-30: Preparation of compounds of formulas (22)-(23) The preparation method in this embodiment is similar to that in Example 3, except that raw materials with different functional groups are selected according to the different reaction products. The 6-aminohexanoic acid in Example 1 is replaced with 6-amino-2-methylhexanoate and 6-amino-2-ethylhexanoate (synthesized according to Examples 27-28), yielding intermediate 12. and intermediate 13 The remaining reaction processes and reaction conditions were controlled in the same manner as in Example 3, and compounds of formulas (22)-(23) were successfully prepared: Example 29: Preparation of ethyl 4-((6-guanidino-2-methylhexanoyl)oxy)benzoate trifluoroacetate (Formula (22)) The raw material is intermediate 12, a white solid, with a yield of 88%. 1 H NMR (400 MHz, DMSO- d 6 ) d 8.09–7.95 (m, 2H), 7.67 (t, J = 5.7 Hz, 1H), 7.27 (d, J = 8.4 Hz, 6H), 4.32 (q, J = 7.1Hz, 2H), 3.13 (q, J = 6.5 Hz, 2H), 2.74 (h, J = 7.0 Hz, 1H), 1.72 (dt, J =14.9, 7.5 Hz, 1H), 1.54 (dp, J = 21.5, 7.3 Hz, 3H), 1.45–1.36 (m, 2H), 1.33(t, J = 7.1 Hz, 3H), 1.24 (d, J = 6.9 Hz, 3H). HRMS (ESI) m / z calculated value C 17 H25 N3O4, [M + H] + 336.1918, Measured value: 336.1924. Example 30: Preparation of ethyl 4-((2-ethyl-6-guanidinylhexanoyl)oxy)benzoate trifluoroacetate (Formula (23)) The raw material is intermediate 13, a white solid, with a yield of 89%. 1 H NMR (400 MHz, DMSO- d 6 ) d 8.11–7.94 (m, 2H), 7.62 (t, J = 5.7 Hz, 1H), 7.52–6.68 (m, 6H), 4.33 (q, J = 7.1 Hz, 2H), 3.13 (q, J = 6.6 Hz, 2H), 2.57 (dq, J = 11.4, 4.2, 2.9 Hz, 1H), 1.75–1.57 (m, 4H), 1.57–1.46 (m, 2H), 1.39 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.1Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H). HRMS (ESI) m / z calculated value C 18 H 27 N3O4, [M + H] + 350.2080, Measured value: 350.2082. Example 31: Preparation of ethyl 4-((2-chloro-6-guanidinylhexanoyl)oxy)benzoate trifluoroacetate (Formula (24)) The preparation method in this embodiment is similar to that in Example 3, except that the raw materials with different groups are selected according to the different reaction products. The 6-aminohexanoic acid in Example 1 is replaced with 6-amino-2-chlorohexanoate (synthesized according to Example 28, the raw material is commercially available 3-bromoazacycloheptane-2-one), to obtain intermediate 14. The remaining reaction process and reaction conditions were controlled in the same way as in Example 3, and the compound of formula (24) was successfully prepared as a white solid with a yield of 66%. 1 H NMR (400 MHz, DMSO-d 6 ) d 8.11–8.01 (m, 2H), 7.50 (s, 1H), 7.38–7.30 (m, 2H), 5.00 (dd, J = 8.0, 5.2 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.14(d, J = 6.1 Hz, 2H), 2.02 (d, J = 8.7 Hz, 2H), 1.60–1.45 (m, 4H), 1.33 (t, J = 7.1 Hz, 3H). HRMS (ESI) m / z calculated value C 16 H 22 ClN3O4, [M + H] + 356.1372, Measured value: 356.1376. Example 32: Preparation of ethyl 4-(2-(4-guanidinocyclohexyl)acetoxy)benzoate trifluoroacetate (Formula (25)) The preparation method in this embodiment is similar to that in Example 3, except that the raw materials with different functional groups are selected according to the different reaction products. The 6-aminohexanoic acid in Example 1 is replaced with commercially available 2-(4-aminocyclohexyl)acetic acid hydrochloride, yielding intermediate 15. The remaining reaction process and reaction conditions were controlled in the same way as in Example 3, and the compound of formula (25) was successfully prepared as a grayish-white solid with a yield of 81%. 1 H NMR (400 MHz, DMSO- d 6 ) d 8.07–7.97 (m, 2H), 7.47 (d, J = 8.3 Hz, 1H), 7.31–7.25 (m, 2H), 7.00 (s, 4H), 4.32 (q, J = 7.1 Hz, 2H), 2.53 (d, J = 6.6 Hz, 2H), 1.86 (d, J = 33.4 Hz, 5H), 1.36–1.16 (m, 7H). HRMS (ESI) m / z calculated value C 18 H 25 N3O4, [M + H]+ 348.1923, Measured value: 348.1928. Example 33: ( R Preparation of methyl 6-(((benzyloxycarbonyl)amino)-2-hydroxyhexanoate (intermediate 16) Will N 6 -((benzyloxy)carbonyl)- D Lysine (1 g) was dissolved in a 60 mL mixture of water and acetic acid (H₂O:AcOH = 1:1). The reaction system was cooled to 0 °C and stirred. Then, NaNO₂ (1.231 g) was dissolved in 2.5 mL of water and added dropwise to the reaction system. After the addition was complete, the reaction was continued at 0 °C for 1 h, followed by a 3 h reaction at room temperature. After the reaction was complete, the reaction solution was diluted with ethyl acetate until it separated into layers. The reaction solution was extracted five times, and the aqueous phase was back-extracted once. The organic phase was then washed twice with saturated NaCl. Finally, the solution was dried over anhydrous sodium sulfate and evaporated to remove as much acetic acid as possible. Subsequently, the resulting oily substance was dissolved in a 60 mL mixture of methanol and water (MeOH:H₂O = 1:1), and the pH was adjusted to 8-9 with potassium carbonate. The mixture was stirred overnight for 12 h to remove acetic acid. O -Acetyl. After the reaction was complete, methanol was removed from the system under reduced pressure, and the pH was adjusted to 1-2 with 1 M hydrochloric acid. The mixture was extracted twice with ethyl acetate, back-extracted from the aqueous phase once, washed twice with saturated NaCl, and finally dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a pink color. α Crude hydroxy acid was dissolved in methanol (20 mL), and thionyl chloride (259 μL) was added dropwise at 0 °C. The reaction system was then heated to 80 °C and stirred for 3 h. After the reaction was complete, the methanol in the system was removed by vacuum distillation, and the residue was directly purified by silica gel column chromatography to obtain a colorless oil with a yield of 43%. 1 H NMR (400 MHz, DMSO- d 6 ) d 7.40–7.28 (m, 5H), 7.24 (t, J = 5.7 Hz, 1H), 5.34 (d, J = 6.0 Hz, 1H), 5.00 (s, 2H), 4.00 (dt, J = 7.7, 5.1 Hz, 1H),3.62 (s, 3H), 2.97 (q, J = 6.5 Hz, 2H), 1.55 (ddd, J= 28.9, 13.2, 7.2 Hz,2H), 1.38 (dt, J = 9.5, 6.4 Hz, 2H), 1.31 (q, J = 7.2 Hz, 2H). Example 34: ( S Preparation of methyl 6-(2,3-bis(tert-butoxycarbonyl)guanidinyl)-2-fluorohexanoate (intermediate 17) Will( R Methyl 6-(((benzyloxycarbonyl)amino)-2-hydroxyhexanoate was dissolved in methanol. Under Pd / C and hydrogen conditions, Cbz protection was removed (excess trifluoroacetic acid was added dropwise to ensure salt formation). After reacting for 2 h, the mixture was directly filtered and evaporated to dryness to obtain a colorless oil. The obtained product was converted to guanidine according to Example 1. 200 mg of the product was dissolved in ultra-dry dichloromethane under nitrogen protection. Sulfur trifluoride (bis(2-methoxyethyl)amine) (BAST, 0.5 mL) was added dropwise at 0 °C. After stirring overnight for 12 h, saturated NaHCO3 solution was slowly added dropwise under ice bath to quench the reaction until no bubbles were produced. The product was extracted twice with dichloromethane, washed twice with saturated NaCl, and finally dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography to obtain a colorless oil with a yield of 23%. 1 H NMR (400 MHz, chloroform-) d ) d 11.54 (s, 1H), 4.93 (ddd, J = 49.1, 7.2, 4.6 Hz, 1H), 3.80 (s, 3H), 3.70 (d, J = 21.3 Hz, 2H), 2.03–1.87 (m, 2H), 1.68 (d, J = 6.6 Hz, 22H). Example 35: Preparation of 6-(2,3-bis(tert-butoxycarbonyl)guanidinyl)-2-fluorohexanoic acid (intermediate 18) Will( SMethyl 6-(2,3-bis(tert-butyloxycarbonyl)guanidinyl)-2-fluorohexanoate (80 mg) was dissolved in methanol (5 mL) and stirred. Then, lithium hydroxide (10 mg) was dissolved in water (1 mL), and the resulting solution was added to the reaction system, which was stirred for 30 min. After the reaction was complete, the methanol was removed from the system under reduced pressure. The mixture was extracted twice with ethyl acetate / 1M KHSO4 aqueous solution, washed twice with saturated NaCl, and finally dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a white solid, which could be used for the next reaction without further treatment. Yield: 97%. 1 H NMR (400 MHz, DMSO- d 6 ) d 13.16 (s, 1H), 11.50 (s, 1H), 8.32 (s, 1H), 5.00 (ddd, J = 49.0, 7.5, 4.2 Hz, 1H), 4.03 (q, J = 7.1 Hz, 2H), 3.29 (q, J = 6.7 Hz, 2H), 1.93–1.73 (m, 2H), 1.68–1.24 (m, 20H). Example 36: Preparation of ethyl 4-((2-fluoro-6-guanidinylhexanoyl)oxy)benzoate trifluoroacetate (Formula (26)) The preparation method in this embodiment is similar to that in Example 3, except that the raw materials with different groups are selected according to the different reaction products. The rest of the reaction process and the control of the reaction conditions are the same as in Example 3. White solid, yield: 35%. 1 H NMR (400 MHz, DMSO- d 6 ) d 8.13–7.99 (m, 2H), 7.62 (t, J = 5.7 Hz, 1H),7.40–6.84 (m, 6H), 5.48 (ddd, J = 47.8, 6.8, 4.5 Hz, 1H), 4.33 (q, J = 7.1Hz, 2H), 3.15 (q, J = 6.3 Hz, 2H), 2.02 (td, J = 15.9, 14.3, 6.9 Hz, 2H),1.53 (dq, J= 23.9, 7.0 Hz, 4H), 1.33 (t, J = 7.1 Hz, 3H). HRMS (ESI) m / z calculated value C 16 H 22 FN3O4, [M + H] + 340.1667, Measured value: 340.1675. Example 37: N -methyl- N' , N'' -di-tert-butoxycarbonyl-1 H Preparation of pyrazole-1-formamidine (intermediate 19) Will N , N' -di-tert-butoxycarbonyl-1 H 1-Pyrazole-1-formamidinium (500 mg) and triphenylphosphine (634 mg) were dissolved in 15 mL of ultra-dry tetrahydrofuran and stirred. Methanol (85 μL) was added, the reaction system was protected under nitrogen, and the temperature was lowered to 0 °C. Then, diisopropyl azodicarboxylate (DIAD, 476 μL) was added dropwise. The ice bath was removed, and the reaction was carried out at room temperature for 2 h. After the reaction was complete, the solvent was directly evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give a colorless oil, yield: 86%. 1 H NMR (400 MHz, DMSO- d 6 ) d 8.25 (s, 1H), 7.86 (d, J = 1.6 Hz, 1H), 6.60 (dd, J = 2.8, 1.6 Hz, 1H), 3.11(s, 3H), 1.44 (s, 9H), 1.23 (s, 9H). Examples 38-41: Preparation of compounds of formulas (27)-(30) The preparation method in this embodiment is similar to that in Example 3, except that the raw materials with different groups are selected according to the different reaction products (the synthesis of intermediate T7 is referred to Example 37). The rest of the reaction process and the control of the reaction conditions are the same as in Example 3. The compounds of formula (27)-(30) were successfully prepared. The specific reaction formula can be represented by the following route 5: Example 38: Preparation of ethyl 4-((6-(3-methylguanidino)hexanoyl)oxy)benzoate trifluoroacetate (Formula (27)) Route 5 - R f =-CH3; white solid, yield: 70%. 1 H NMR (400 MHz, DMSO- d 6 ) d 8.06–7.97 (m, 2H), 7.43 (t, J = 5.7 Hz, 1H), 7.33 (d, J = 20.8 Hz, 3H), 7.29–7.25(m, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.12 (q, J = 6.6 Hz, 2H), 2.73 (d, J = 4.8Hz, 3H), 2.63 (t, J = 7.3 Hz, 2H), 1.67 (p, J = 7.4 Hz, 2H), 1.52 (p, J = 7.3Hz, 2H), 1.39 (td, J = 8.6, 4.3 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). HRMS (ESI) m / z calculated value C 17 H 25 N3O4, [M + H] + 336.1918, Measured value: 336.1926. Example 39: Preparation of ethyl 4-((6-(3-ethylguanidinyl)hexanoyl)oxy)benzoate trifluoroacetate (Formula (28)) Route 5 - R f =-CH2CH3; white solid, yield: 65%. 1 H NMR (400 MHz, DMSO- d 6 ) d 8.07–7.97 (m, 2H), 7.48–7.21 (m, 6H), 4.32 (q, J = 7.1 Hz, 2H), 3.19–3.12 (m, 4H), 2.63 (t, J = 7.3 Hz, 2H), 1.67 (p, J= 7.5 Hz, 2H), 1.52 (q, J = 7.2 Hz, 2H),1.37–1.30 (m, 5H), 1.09 (t, J = 7.2 Hz, 3H). HRMS (ESI) m / z calculated value C 18 H 27 N3O4, [M+ H] + 350.2080, Measured value: 350.2083. Example 40: Preparation of ethyl 4-((6-(3-(prop-2-yn-1-yl)guanidinyl)hexanoyloxy)benzoate trifluoroacetate (Formula (29)) Route 5 - R f =-CH2C≡CH (The starting alcohol was commercially available 3-(trimethylsilyl)prop-2-yn-1-ol, which was then deprotected by tetrabutylammonium fluoride (TBAF); white solid, yield: 73%. 1 H NMR (600 MHz, DMSO- d 6 ) d 8.08–7.92 (m, 3H), 7.84 (t, J = 5.2 Hz, 1H), 7.64 (s, 2H), 7.28 (d, J = 8.7 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 4.04 (dd, J = 6.1, 2.5 Hz, 2H), 3.35 (d, J =2.4 Hz, 2H), 3.15 (d, J = 6.6 Hz, 1H), 2.63 (t, J = 7.3 Hz, 2H), 1.67 (p, J =7.5 Hz, 2H), 1.54 (p, J = 7.3 Hz, 2H), 1.40 (td, J = 8.5, 3.9 Hz, 2H), 1.32(t, J = 7.1 Hz, 3H). HRMS (ESI) m / z calculated value C 19 H 25 N3O4, [M + H] +360.1918, Measured value: 360.1924. Example 41: Preparation of ethyl 4-((6-(3-(but-3-yn-1-yl)guanidinyl)hexanoyloxy)benzoate trifluoroacetate (formula (30)) Route 5 - R f =-CH2CH2C≡CH; white solid, yield: 75%. 1 H NMR (600 MHz, DMSO- d 6 ) d 8.04–7.99 (m, 2H), 7.85–7.76 (m, 1H), 7.74 (t, J = 6.0 Hz, 1H), 7.56 (s, 2H),7.31–7.26 (m, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.31 (q, J = 6.6 Hz, 2H), 3.15(q, J = 6.6 Hz, 2H), 2.92 (t, J = 2.6 Hz, 1H), 2.63 (t, J = 7.4 Hz, 2H), 2.40(td, J = 7.0, 2.6 Hz, 2H), 1.67 (p, J = 7.5 Hz, 2H), 1.54 (p, J = 7.3 Hz,2H), 1.43–1.36 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H). HRMS (ESI) m / z calculated value C 20 H 27 N3O4, [M + H] + 374.2074, Measured value: 374.2078. Bioactivity Test Example 1 The effect of test compounds exhibiting agonistic activity on ALDH2 activity was initially screened, and three concentrations were set to investigate the agonistic fold of the compounds.

[0117] The effect of the test compound on ALDH2 activity was investigated using the following method: The test compound was dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 mmol / L stock solution. Tris buffer (50 mmol / L, pH = 8.0), 50 mmol / L NAD solution, and either ALDH2*2 protein or ALDH2*1 protein were added to a 96-well plate and mixed well. The stock solution of the test compound was diluted according to the target concentration and added to the 96-well plate (final concentrations of 2, 10, and 50 μmol / L). The samples were incubated at 37 °C for 30 min. After incubation, 40 mmol / L acetaldehyde solution was added, bringing the total sample volume to 200 μL. The 96-well plate was then quickly placed in a microplate reader for time-kinetic scanning, and the reading at 340 nm was recorded.

[0118] The experimental results are as follows: The test results of ALDH2*1 are shown in Table 1: Table 1. Structure of the derivatives of this invention and their in vitro ALDH2*1 agonist activity. The test results for ALDH2*2 are shown in Table 2: Table 2. Structure of the derivatives of the present invention and their in vitro ALDH2*2 agonist activity. Based on the results in Tables 1 and 2, most of the compounds in this series (especially the preferred compounds) exhibit good or even excellent agonistic activity against ALDH2. Among them, the preferred compounds are selected as formulas (7), (8), (14), (22), (26), and (27), which correspond to the numbers JX41028, JX41049, JX41027, JX41024, JX41037, and JX41040 in bioactivity tests 2-6 and their accompanying figures, respectively.

[0119] Bioactivity Test Example 2 The effects of the test compounds on ethanol-induced liver injury at the cellular level were investigated.

[0120] (1) The experimental scheme is as follows: The experimental groups are divided into alcohol group, positive control group (Alda-1, 10 μM and gabexate mesylate, 50 μM) and test compound group.

[0121] HepG2 cells were cultured normally for 12 h. The positive control and test compound stock solutions were diluted with culture medium to the target concentration (final concentration varies from 1-10 μmol / L), and the corresponding test solution was added to each well. After incubation with cells for 6 h, an alcohol model was established by adding 350 mM ethanol solution to the culture medium and incubating for 16 h. After modeling, the supernatant was discarded, and cell viability was detected using the CellCounting Kit-8 (CCK8) method. Data were summarized, bar charts were generated using GraphPad, and significance differences (t-test) were calculated.

[0122] (2) Experimental results: such as Figure 1 As shown, most of the preferred compounds exhibit the ability to improve cell survival rate.

[0123] Bioactivity test example 3 The effects of the test compounds on ethanol-induced liver injury at the cellular level were investigated.

[0124] (1) The experimental scheme is as follows: The experimental groups are divided into alcohol group, positive control group (Alda-1, 10 μM and gabexate mesylate, 50 μM) and test compound group.

[0125] HepG2 cells were cultured normally for 12 h. The stock solutions of the positive control and test compounds were diluted with culture medium to the target concentration (final concentration varies from 1-10 μmol / L), and the corresponding test solution was added to each well. After incubation with cells for 6 h, an alcohol model was established by adding 350 mM ethanol solution to the culture medium and incubating for 16 h. After modeling, the supernatant was discarded, and the kit was used to detect aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the cell lysate. Data were summarized, bar charts were generated using GraphPad, and significance differences were calculated (t-test).

[0126] (2) Experimental results: such as Figure 2 As shown, most of the preferred compounds exhibit the ability to reduce AST and ALT levels.

[0127] Bioactivity test example 4 The effects of the test compounds on the ROS levels of ethanol-induced liver injury were investigated at the cellular level.

[0128] (1) The experimental scheme is as follows: The experimental groups are divided into alcohol group, (Alda-1, 10 μM and gabexate mesylate, 50 μM) and test compound group.

[0129] HepG2 cells were cultured normally for 12 h. The positive control and test compound stock solutions were diluted with culture medium to the target concentration (final concentration varies from 1-10 μmol / L), and the corresponding test solution was added to each well. After incubation with cells for 6 h, an alcohol model was established by incubating the culture medium with a predetermined concentration of 350 mM ethanol for 16 h. After modeling, the cells were washed three times with PBS, incubated with the DHE probe at 37 °C in the dark for 30 min, washed twice with PBS, and the fluorescence value of each well was read. The data were summarized, a bar chart was plotted using GraphPad, and the significance of differences (t-test) was calculated.

[0130] (2) Experimental results: such as Figure 3 As shown, most of the preferred compounds exhibit the ability to reduce ROS levels.

[0131] Bioactivity test example 5 The stability of the test compound in artificial gastrointestinal fluid was investigated.

[0132] (1) The experimental scheme is as follows: The compounds tested are gabexate mesylate and preferred compounds.

[0133] Preheat the simulated gastric fluid (containing enzymes) and simulated intestinal fluid (containing enzymes) to 37 °C. Take an appropriate amount (900 μL) of each preheated simulated solution and place it in a preheated EP tube. Add 100 μL of the compound stock solution to each tube (the initial concentration is usually 10 mg / mL, which can be adjusted according to the solubility of the compound and the detection sensitivity). Vortex mix immediately for 5-10 seconds. This time point is recorded as 0 hours. Simultaneously, immediately remove 100 μL of sample from the 0-hour tube and add it to an EP tube containing 300 μL of pre-cooled quenching solvent. Vortex mix and store on ice or at 4 °C for analysis to capture the initial state. Quickly return the remaining sample tubes to a 37 °C constant temperature water bath shaker and incubate with gentle shaking at an appropriate speed. At two precise time points, namely 5, 10, 15, 30, 60 minutes and 0.5, 1, 2, 3, 6 hours, remove 100 μL of sample from each incubation tube and immediately add it to the quenching solvent as described in step 3 to terminate the reaction. Vortex mix and store on ice or at 4 °C.

[0134] Quenched samples at all time points (including 0 hours) were filtered at 4 °C using a 0.22 μm filter membrane. The treated samples were immediately analyzed by HPLC, and the changes in the main peak area were compared with those of gabexate mesylate to observe whether the hydrolysis rate of gabexate was faster or slower.

[0135] (2) Experimental results: such as Figure 4 As shown, the preferred compound formula (22) exhibits superior stability of artificial gastrointestinal fluid compared to gabexate mesylate.

[0136] Bioactivity test example 6 The stability of the liver microsomes of the test compound (22) was investigated.

[0137] (1) The experimental design is as follows: • Multiple species (SD rats, humans) • 1 test concentration (1 μM), 1 replicate, 100 μL incubation system • Incubation times: 0, 5, 15, 30, 45, and 60 minutes (2) Experimental results: such as Figure 5 As shown, the preferred compound (22) exhibits superior liver microsomal stability compared to gabexate mesylate.

[0138] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. Use of a compound or a stereoisomer, optical isomer, non-racemic or racemic mixture thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or an N-oxide thereof, or a pharmaceutical composition comprising one or more of the compound or a stereoisomer, optical isomer, non-racemic or racemic mixture thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or an N-oxide thereof in (i) the preparation of an acetaldehyde dehydrogenase 2 (ALDH2) agonist and / or (ii) the preparation of a medicament for the treatment or prevention of alcohol-related diseases and / or diseases that can be treated or prevented by promoting the metabolism of acetaldehyde or other aldehydes; in, The compound is shown in Formula A: in, W is selected from the group consisting of: unsubstituted or substituted C1-C6 alkylene, substituted or unsubstituted C3-C6 cycloalkylene, substituted or unsubstituted C3-C6 cycloalkylene, substituted or unsubstituted -C1-C2 alkylene-C3-C6 cycloalkylene-C1-C2 alkylene-, and substituted or unsubstituted -C1-C2 alkylene-4 to 6-membered heterocyclic alkylene-C1-C2 alkylene-; X is O, N(R) N ) or S; R 1 and R 2 Each is independently selected from the group consisting of: H, D, halogen, hydroxyl, amino, cyano, nitroso, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and substituted or unsubstituted C1-C6 alkoxy. Ring A is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R 3 Represents one or more (e.g., 1, 2, 3, or 4) monovalent or divalent groups, each independently selected from the group consisting of: H, D, halogen, hydroxyl, amino, cyano, nitroso, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkylene, substituted or unsubstituted 3- to 6-membered heteroalkylene, and R. 3a ; R 3a for R 4 -CO-X 1 -R 5 ; R 4 Selected from the following group: none (not present), substituted or unsubstituted C1-C5 alkylene, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkyne, and substituted or unsubstituted C3-C6 cycloalkylene; R 5 Selected from the following group: H, D, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C3-C6 cycloalkyl; X 1 For O, N(R) N (or does not exist;) R N Selected from the following group: H, D, C1-C6 alkyl; Unless otherwise specified, substitution refers to the substitution of a group by one or more R groups. S replace; Each R S Each of the following groups is independently selected from the group consisting of: D, halogen, hydroxyl, amino, cyano, nitroso, nitro, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclic alkyl, phenyl, 5- to 6-membered heteroaryl, -C1-C4 alkylene-C3-C6 cycloalkyl, -C1-C4 alkylene-4- to 6-membered heterocyclic alkyl, -C1-C4 alkylene-phenyl, and -C1-C4 alkylene-5- to 6-membered heteroaryl; and wherein the alkylene, alkyl, alkoxy, cycloalkyl, heterocyclic alkyl, phenyl, and 5- to 6-membered heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of: D, halogen, hydroxyl, amino, cyano, nitroso, nitro, C1-C6 alkyl, and C1-C6 alkoxy.

2. The use as described in claim 1, characterized in that, The alcohol-related diseases are selected from the group consisting of: acute alcohol poisoning (AAI), alcoholic liver disease (ALD), or a combination thereof; and / or The diseases that can be treated or prevented by promoting the metabolism of acetaldehyde or other aldehydes are selected from the group consisting of: heart failure, myocardial ischemia / reperfusion injury, diabetic cardiomyopathy, obesity, type 2 diabetes, non-alcoholic fatty liver disease, alcohol use disorder, or combinations thereof.

3. The use as described in claim 1, characterized in that, The compound is shown in Formula I; Among them, R 1 R 2 R 3 X and ring A are defined as in equation A; the subscript n is selected from the following group: integers from 0 to 6 (preferably, n is 4, 5 or 6).

4. The use as described in claim 1, characterized in that, The compound has one or more of the following characteristics: (a) X is O or N(R) N Preferably, X is O or NH; even more preferably, X is O. (b)R 1 Selected from the group consisting of: H, D, substituted or unsubstituted C1-C6 alkyl groups, and substituted or unsubstituted C2-C6 alkynyl groups; preferably, R 1 Selected from the group consisting of H, D, C1-C6 alkyl, and C2-C6 alkynyl; preferably, R 1 Selected from the following group: H, D, methyl, ethyl, and Preferably, R 1 Selected from the group consisting of: H, D, and substituted or unsubstituted C1-C6 alkyl groups; preferably, R 1 Selected from the group consisting of H, D, and C1-C6 alkyl groups; more preferably, R 1 Selected from the following group: H, D, methyl, and ethyl; (c)R 2 Selected from the group consisting of: H, D, halogens, amino, cyano, and substituted or unsubstituted C1-C6 alkyl groups; preferably, R 2 Selected from the group consisting of: H, D, halogens, amino groups, and C1-C6 alkyl groups; preferably, R 2 Selected from the group consisting of: H, D, fluorine, chlorine, bromine, amino, methyl, ethyl, and propyl; preferably, R 2 Selected from the group consisting of: H, D, halogens, and substituted or unsubstituted C1-C6 alkyl groups; preferably, R 2 Selected from the group consisting of: H, D, halogens, and C1-C6 alkyl groups; more preferably, R 2 Selected from the group consisting of: H, D, fluorine, chlorine, bromine, methyl, ethyl, and propyl; preferably, R 2 Selected from the following group: H, D, fluorine, methyl, and ethyl; (d) Ring A is C6-C 12 Aryl or 5 to 12-membered heteroaryl; preferably, in ring A, the aryl group is phenyl, biphenyl, or naphthyl, and / or the heteroaryl group is selected from the group consisting of: furanyl, thiophene, pyrrolyl, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, benzofuranyl, benzothiophene, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, inzolyl, benzothiazolyl, quinazolinyl, phthalazinyl, purine, benzo[1,3]dioxane, benzo[1,4]dioxane; more preferably, ring A is phenyl, naphthyl, or pyridinyl; most preferably, ring A is phenyl; (e)X 1 For O or N(R) N ); Preferably, it is X 1 For O or NH; more preferably, X 1 It is O; (f)R 4 Selected from the group consisting of unsubstituted, substituted, or unresubstituted C2-C6 alkenyl groups; preferably, R 4 Selected from the following group: none, -CH=C(CN)-; more preferably, R 4 For nothing; and (g)R 5 Selected from the group consisting of: H, D, and substituted or unsubstituted C1-C6 alkyl groups; preferably, R 5 Selected from the group consisting of H, D, and C1-C6 alkyl groups; preferably, R 5 Selected from the group consisting of: H, D, methyl, ethyl, and propyl; preferably, R 5 It is a substituted or unsubstituted C1-C6 alkyl group; preferably, R 5 It is a C1-C6 alkyl group; more preferably, R 5 Selected from the group consisting of methyl, ethyl, and propyl.

5. The use as described in claim 1, characterized in that, for or ; Where the subscript m is 0, 1, 2 or 3, R 3a -R 4 -CO-X 1 -R 5 , and R 3b Each is independently selected from the group consisting of: H, D, halogen, hydroxyl, amino, cyano, nitroso, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; R 4 X 1 and R 5 As defined in claim 1.

6. The use as described in claim 1, characterized in that, The compounds are selected from the group consisting of: 。 7. A compound or its stereoisomers, optical isomers, racemic or non-racemic salts, pharmaceutically acceptable salts, solvates, or N-oxides thereof, characterized in that, The compound is shown in Formula A: Among them, R 1 R 2 R 3 W, X and ring A are as defined in any one of claims 1 to 5.

8. The use of the compound as claimed in claim 7, or its stereoisomers, optical isomers, non-racemic or racemic derivatives, or pharmaceutically acceptable salts thereof, or its solvates or N-oxides as claimed in claim 1, characterized in that, The compounds are selected from the group consisting of: 。 9. A pharmaceutical composition, characterized in that, It comprises: (i) one or more compounds or their stereoisomers, optical isomers, non-racemic or racemic derivatives, pharmaceutically acceptable salts thereof, or their solvates or N-oxides; wherein the compounds are as defined in any one of claims 1 to 6.

10. A method for preparing a compound or its stereoisomers, optical isomers, non-racemic or racemic derivatives, or pharmaceutically acceptable salts, solvates, or N-oxides thereof, characterized in that, The preparation method includes the steps shown in the following flowchart: In each formula, R 1 R 2 R 3 X, ring A and subscript n are defined as in claim 2, and R is a protecting group of amino group (preferably Boc (tert-butoxycarbonyl)).

Images