Hclpp agonist compounds and uses thereof

Abstract

The application discloses a kind of HClpP agonist compound and its purposes, specifically, the application discloses a kind of compound shown in formula I, or its pharmaceutically acceptable salt, solvate, hydrate, isomer, wherein, each group is as defined above.The compound of the application has good safety and tolerability, and can be used to agonize HClpP, treat diseases or conditions mediated by HClpP.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a class of HClpP agonist compounds and their uses. Background Technology

[0002] Human caseinolytic protease P (HClpP) is an ATP-dependent serine protease located in the mitochondrial matrix, playing a crucial role in maintaining mitochondrial protein homeostasis and regulating cellular metabolism. HClpP maintains mitochondrial functional stability by participating in the degradation of damaged proteins and participates in the regulation of cellular stress and inflammatory responses. Studies have shown that mitochondrial dysfunction is closely related to various autoimmune diseases and chronic inflammatory diseases, leading to abnormal activation of immune responses by affecting reactive oxygen species levels and inflammatory signaling pathways. As an important component of the mitochondrial protein quality control system, HClpP has potential applications in regulating mitochondrial function and immune inflammatory responses. Previous studies have explored HClpP agonists in the field of oncology, but its application in inflammatory and metabolic diseases remains limited. Inflammatory bowel disease, MASH, and other diseases are considered to be closely related to mitochondrial dysfunction, and regulating HClpP activity holds promise for improving these pathological processes.

[0003] However, agonists targeting HClpP are still relatively scarce, and many suffer from insufficient selectivity or safety issues. Therefore, developing a novel class of HClpP agonists and using them to treat HClpP-mediated diseases is of significant research importance and promising application prospects. Summary of the Invention

[0004] One object of the present invention is to provide a class of novel compounds of Formula I as HClpP agonists.

[0005] Another object of the present invention is to provide the use of a compound of Formula I in the treatment of HClpP-mediated diseases or conditions.

[0006] In a first aspect of the invention, a compound of formula I is provided, or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof. in, R1 is selected from the following group: halogen, cyano, C1-C4 haloalkyl; X is either N or CH; Y is either N or CH; In this case, one of X and Y is N, and N is connected to Z; Z is selected from the following group: -CH2-, -C(=O)-, -C(=O)NH-, -C(=O)(CH2) n -、-C(=O)NH-(CH2) n -; n is 1, 2, 3, 4, 5 or 6; A is selected from the following group of substituted or unsubstituted groups: H, C6-C10 aryl, 5-10 membered heterocyclic group; The substitution refers to the substitution of one or more hydrogen atoms on a group by a group selected from the group consisting of: halogen, cyano, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C2-C4 alkenyl, and C2-C4 alkynyl.

[0007] In another preferred embodiment, R1 is located in the opposite or intermediate position.

[0008] In another preferred embodiment, Z is selected from the group consisting of: -CH2-, -C(=O)-, -C(=O)NH-, -C(=O)CH2-, -C(=O)NH-CH2-.

[0009] In another preferred embodiment, only one of X and Y is X; more preferably, X is N and Y is CH. X is connected to -ZA.

[0010] In another preferred embodiment, the compound has the structure shown in Formula IA or Formula IB: Wherein, each group is as defined in the first aspect of the present invention.

[0011] In another preferred embodiment, A is selected from the following group of substituted or unsubstituted groups: phenyl, naphthyl, benzo5-6 membered heterocycles (preferably 1,4-benzodioxane, 1,3-benzodioxanepentenyl).

[0012] In another preferred embodiment, -ZA is selected from the following group of substituted or unsubstituted groups: benzyl, phenyl, -C(=O)-benzyl, -C(=O)NH-benzyl, -C(=O)NH-phenyl, -C(=O)NH-1,4-benzodioxane, -C(=O)NH-1,3-benzodioxanepentenyl, -C(=O)NH-naphthyl.

[0013] In another preferred embodiment, the compound has a structure represented by formula II-A or II-B: Wherein, each group is as described in the first aspect of the present invention.

[0014] In another preferred embodiment, the compound has a structure represented by formula II-C or II-D: Wherein, each group is as described in the first aspect of the present invention.

[0015] In another preferred embodiment, the compound has the structure shown in Formula III-A or Formula III-B: Wherein, at least one of X and Y is N, and -C(=O)-NH-A is connected to N, and each group is as described in the first aspect of the present invention.

[0016] In another preferred embodiment, the compound is selected from the group consisting of: .

[0017] In a second aspect of the invention, a pharmaceutical composition is provided, comprising: the compound described in the first aspect of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, isomer thereof, and a pharmaceutically acceptable carrier.

[0018] In a third aspect of the invention, there is provided a use of the compound described in the first aspect of the invention for preparing a medicament, said medicament being used for (a) as a ClpP agonist; and (b) for the prevention and / or treatment of diseases or conditions mediated by HsClpP.

[0019] In another preferred embodiment, the disease or condition mediated by HsClpP is selected from the group consisting of: autoimmune diseases, inflammatory diseases, metabolic diseases, diseases associated with inflammation or metabolic abnormalities, tumors, or combinations thereof; preferably inflammatory diseases or metabolic diseases.

[0020] In another preferred embodiment, the disease or condition mediated by HsClpP is selected from the group consisting of inflammatory bowel disease, hepatitis (preferably metabolic-associated steatohepatitis), or a combination thereof.

[0021] In another preferred embodiment, the autoimmune disease is selected from the group consisting of: inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, ankylosing spondylitis, type 1 diabetes, autoimmune hepatitis, autoimmune thyroid diseases (including Hashimoto's thyroiditis and Graves' disease), Sjögren's syndrome, systemic sclerosis, and Behçet's disease.

[0022] In another preferred embodiment, the inflammatory disease is selected from the group consisting of: acute or chronic colitis, gastritis, hepatitis, pancreatitis, pneumonia, acute lung injury, asthma, chronic obstructive pulmonary disease (COPD), inflammatory skin diseases (including atopic dermatitis), arthritis, and sepsis-related inflammatory reactions.

[0023] In another preferred embodiment, the metabolic disease is selected from the group consisting of: obesity, insulin resistance, type 2 diabetes, metabolic syndrome, metabolic fatty liver disease (MAFLD), metabolic steatohepatitis (MASH), hyperlipidemia, atherosclerosis, and chronic inflammatory diseases associated with metabolic disorders.

[0024] In another preferred embodiment, the disease associated with inflammation or metabolic abnormalities is selected from the group consisting of heart failure, kidney injury, aging, or a combination thereof.

[0025] In another preferred embodiment, the tumor is selected from the group consisting of: central nervous system tumors, brain tumors, peripheral nervous system tumors, pheochromocytomas, paragangliomas, neuroendocrine tumors, liver cancer, lung cancer, gastric cancer, colon cancer, colorectal cancer, rectal cancer, pancreatic cancer, breast cancer, prostate cancer, endometrial cancer, hematologic malignancies, lymphatic system tumors, or combinations thereof.

[0026] A fourth aspect of the present invention provides a method for stimulating HsClpP, comprising: Contacting the compound of formula I as described in the first aspect, or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof, with the target thereby activating HsClpP.

[0027] In another preferred embodiment, the method is performed in vitro.

[0028] In another preferred embodiment, the method is non-therapeutic.

[0029] In another preferred embodiment, the object is a cell or protein expressing HsClpP.

[0030] A fifth aspect of the present invention provides a method for treating diseases or conditions mediated by HsClpP, comprising: To treat a disease or condition mediated by HsClpP by contacting a compound of Formula I as described in the first aspect, or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof, with a target.

[0031] 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

[0032] Figure 1 The effects of compound A11 on colonic histopathology in a DSS-induced mouse model of inflammatory bowel disease (IBD) are shown. The top left corner represents the normal control group, the top right corner represents the model group and the positive control group, and the bottom row, from left to right, represents the low-dose, medium-dose, and high-dose treatment groups. Figure 2 The study showed the effects of compound A11 on changes in body weight and disease activity index (DAI) scores in DSS-induced IBD model mice. Figure 3 The results of H&E staining of liver tissue in a mouse MASH model induced by a high-fat diet are shown, with the left side representing the drug-treated group and the right side representing the model group. Figure 4 The image shows the Oil Red O staining results of the liver in a mouse MASH model induced by a high-fat diet, with the left side representing the treated group and the right side representing the model group. Figure 5 The results of H&E staining of brown adipose tissue in a mouse MASH model induced by a high-fat diet using compound A12 are shown. The left side represents the drug-treated group, and the right side represents the model group. Detailed Implementation

[0033] Through extensive and in-depth research, the inventors have, for the first time, provided a compound of novel formula I, which can be used as an agonist of the casein lyase HsClpP and also for the treatment of diseases or conditions mediated by HsClpP. Based on this, the inventors have completed this invention.

[0034] the term In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0035] The term "alkyl" refers to a straight-chain or branched alkane group or a cyclic hydrocarbon group (including hydrocarbon groups connected to other parts via a carbon atom on a ring or a non-cyclic atom), preferably a straight-chain or branched alkane group, containing 1-6 carbon atoms, more preferably 1-4 carbon atoms (C1-C4). Typical "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, etc. , pentyl, isopentyl, hexyl, etc. In this invention, alkyl also includes substituted alkyl groups. "Substituted alkyl" means that one or more positions in an alkyl group are substituted, particularly 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl3), nitrile, nitro, oxygen (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl.

[0036] In this article, chemical structures are written from left to right (e.g., (CR) Le R Lf (-O) Unless otherwise explicitly defined, this includes the right-to-left form, i.e. (CR) Le R Lf -O can be (CR)Le R Lf )-O or O-(CR Le R Lf ).

[0037] In this invention, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing one or more double bonds and typically having a length of 2 to 10 carbon atoms. Alkenyl groups are preferably C2-C6 alkenyl groups, more preferably C2-C4 alkenyl groups. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc. In this invention, alkenyl groups include substituted alkenyl groups. In this invention, alkenyl groups also include substituted alkenyl groups, and the substituents can be halogenated, hydroxylated, cyano, nitro, etc.

[0038] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing one or more triple bonds and typically having a length of 2 to 10 carbon atoms. The alkynyl group is preferably C2-C6 alkynyl, more preferably C2-C4 alkynyl. The alkynyl group includes, but is not limited to, ethynyl, propynyl, or similar groups. In this invention, the alkynyl group also includes substituted alkynyl groups, which can be halogenated, hydroxyl, cyano, nitro, etc.

[0039] In this invention, the term "heterocyclic group" refers to a fully saturated (i.e., heterocyclic alkyl) or partially unsaturated cyclic group (including, but not limited to, 3-7 membered monocyclic rings and 4-7 membered monocyclic rings), wherein at least one heteroatom is present in a ring with at least one carbon atom. The term "4-7 membered heterocyclic group" refers to a heterocyclic group containing 4, 5, 6, or 7 ring atoms. "Heterocyclic group" has the same meaning as "saturated or partially unsaturated heterocyclic group". "Heterocyclic group" is preferably a 4-7 membered heterocyclic group, more preferably a 4-6 membered heterocyclic group, and even more preferably a 5-7 membered heterocyclic group. Each heterocyclic group containing a heteroatom may have 1, 2, or 3 heteroatoms, each independently selected from nitrogen, oxygen, or sulfur atoms, wherein the nitrogen or sulfur atom may be oxidized or quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom residue of a ring or ring system molecule, preferably to an N or C atom of a ring or ring system molecule. Typical monocyclic heterocycles include, but are not limited to, nitrogen-containing heterocyclic butyl, pyrrolyl, oxoheterocyclic butyl, pyrazolinyl, imidazolinyl, imidazolinyl, oxazolinyl, isoxazolinyl, thiazolinyl, isothiazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylyl, hexahydroacoxaneyl, 4-piperidinoneyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxaneyl, and tetrahydro-1,1-dioxothiophene, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring; the heterocyclic group can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuteralkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylic acid ester groups.

[0040] In this invention, the term "aryl" refers to an aromatic cyclic hydrocarbon group having 1-2 rings, particularly monocyclic and bicyclic groups. Specifically, "C6-C..." 10 "Aryl" refers to an aromatic cyclic hydrocarbon compound group containing 6, 7, 8, 9, or 10 carbon atoms. C6 aryl is preferred. Aryl groups include phenyl and naphthyl. "Substituted aryl" means that one or more positions of the aryl group are substituted, especially 1-3 substituents, which can be substituted at any position.

[0041] In this invention, the term "alkoxy" refers to a straight-chain or branched alkoxy group, including alkyl-O- and alkyl-O-alkyl groups. "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, including C1-C6 alkyl-O- and -C1-C4 alkyl-O-C1-C4 alkyl groups, and non-limitingly includes methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups. C1-C6 alkoxy is preferred; C1-C4 alkoxy is more preferred.

[0042] In this invention, the term "halogen" or "halogen" refers to chlorine, bromine, fluorine, and iodine.

[0043] In this invention, the term "halogenated" refers to being replaced by a halogen.

[0044] In this invention, the term "hydroxyl group" refers to a group with the structure OH.

[0045] In this invention, the term "nitro" refers to a group containing the structure NO2.

[0046] In this invention, the term "cyano" refers to a group containing the structure CN.

[0047] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are stable or chemically feasible combinations. Such substituents include, but are not limited to, halogens, hydroxyl groups, cyano groups, carboxyl groups (-COOH), C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, and C1-C6 ureyl groups, etc.

[0048] Unless otherwise stated, it is assumed that any heteroatom in a suboptimal valence state has enough hydrogen atoms to compensate for its valence state.

[0049] When the substituent is a non-terminal substituent, it is a subunit of the corresponding group. For example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclic corresponds to heterocyclic, alkoxy corresponds to alkoxy, etc.

[0050] In this invention, "multiple" refers to 2, 3, 4, and 5.

[0051] In this invention, the term 1-6 refers to 1, 2, 3, 4, 5, or 6. Other similar terms have similar meanings.

[0052] compound As used herein, “compound of the present invention” means a compound of formula I, or formulas IA to IB, or formulas II-A to II-D, and also includes pharmaceutically acceptable salts, solvates, hydrates, enantiomers, diastereomers, racemates, deuterium isotope variants, and prodrugs.

[0053] Unless otherwise specified, the structural formulas described in this invention are intended to include all stereoisomers (such as cis-trans isomers, enantiomers, diastereomers, and conformational isomers): R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, cis-trans isomers of cycloalkanes, etc. Therefore, any single stereochemical isomer of the compounds of this invention, or a mixture of its enantiomers, diastereomers, or conformational isomers, is within the scope of this invention.

[0054] The compounds of this invention may contain cis-trans isomers, one or more chiral carbon atoms, and thus can produce cis-trans isomers, chiral isomers, enantiomers, diastereomers, and other combinations of stereoisomers. Cis-trans isomerism refers to the diastereomeric phenomenon in which different functional groups in a compound molecule are arranged differently in space due to a restrictive factor that allows for free rotation. This restrictive factor is generally caused by non-rotating functional groups in the structure of organic compounds, such as C=C double bonds, C=N double bonds, C=S double bonds, N=N double bonds, heterocycles, or cycloalkanes. Organic molecules containing such isomers, such as alkenes, azo compounds, and cycloalkanes, are considered cis-trans isomers. Cis refers to the same ligands being in adjacent positions, generally denoted by "cis" or "cis-"; trans refers to the same ligands being in diagonal positions, generally denoted by "trans" or "trans-". Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. This invention aims to include all possible isomers, their racemic and optically pure forms. The compounds of this invention can be prepared using racemic, cis-trans, chiral, diastereomer, or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0055] Conventional techniques for preparing / separating individual optical isomers (i.e., cis-trans isomers and chiral isomers) include chiral synthesis from suitable cis-trans precursors or optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography.

[0056] To design the synthesis of a specific stereoisomer of the compound of this invention, it can be prepared asymmetrically or derivatized with a chiral auxiliary. The resulting stereo mixture is then separated, and the chiral auxiliary is removed to obtain pure cis-trans monomers, chiral monomers, or mixed stereoisomers. If the molecule contains a cis-trans isomer center, it can be purified by column chromatography (normal-phase silica gel column or reverse-phase high-performance liquid chromatography) to obtain pure cis or trans products. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomeric salt, which is then separated by conventional methods such as separation crystallization or chromatography to obtain pure enantiomers.

[0057] This invention also includes isotopically labeled compounds (i.e., isotopic derivatives), equivalent to the original compounds disclosed herein. However, it is common practice for one or more atoms to be substituted with atoms of different atomic weights or mass numbers. Examples of isotopes in the isotopic derivatives of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2H, 3H, 13C, 11C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Isotopic derivatives of the compounds of this invention are all within the scope of protection of this invention. In this document, 3H-labeled and 14C-labeled compounds are useful in tissue distribution experiments of drugs and substrates. Tritium (i.e., 3H) and carbon-14 (i.e., 14C)-labeled compounds are relatively easy to prepare and detect, and are the preferred isotopes. Furthermore, heavier isotope substitutions, such as deuterium (2H), are preferred in certain cases due to their excellent metabolic stability, which offers advantages in some therapies, such as increasing half-life or reducing dosage in vivo. Isotope-labeled compounds can be prepared using general methods by replacing non-isotopic reagents with readily available isotope-labeling reagents, according to the schemes disclosed in the examples.

[0058] As used herein, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0059] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionates, hexanoates, octanoates, decanoates, undecenoates, glycolates, gluconates, lactates, sebates, adipates, glutarate, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbic acid salts, salicylates, 4-aminosalicylic acid salts, and naphthalene disulfonates. These salts can be prepared using methods known in this field.

[0060] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

[0061] Metabolites of the compound represented by formula (I) and its pharmaceutically acceptable salts, as well as prodrugs that can be converted in vivo into the compound represented by formula (I) and its pharmaceutically acceptable salts, are also included within the scope of protection of this invention.

[0062] As used herein, the term "solvent compound" refers to a complex of a compound of formula (I) coordinated with a solvent molecule in a specific ratio.

[0063] As used herein, the term "hydrate" refers to a complex of a compound of formula (I) coordinated with water molecules in a specific ratio.

[0064] Preparation method The preparation method of the compound of Formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations can be easily performed by those skilled in the art.

[0065] Typically, the preparation process of the compounds of the present invention is as follows, wherein the raw materials and reagents used can be purchased commercially unless otherwise specified.

[0066] Typically, in the preparation process, each reaction is carried out under inert gas protection, in a suitable solvent, at 0 to 150°C, and the reaction time is usually 2 to 48 hours.

[0067] Unless otherwise specified, all of the above starting materials can be purchased commercially or synthesized according to the reported literature.

[0068] Specifically, the representative synthetic route of the compound represented by Formula I of the present invention is shown below: (a) Compound 1A-1C is thiolated to give intermediates 2A-2B; (b) Intermediate 2A-2B is cyclized to give intermediate 3A-3B; (c) Intermediate 3A-3B is hydrolyzed to obtain intermediate 4A-4B; (d) Intermediate 4A-4B is subjected to a Weinreb amidation reaction to obtain intermediate 5A-5B; (e) Intermediate 5A-5B reacts with an organometallic reagent via Weinreb amide to generate intermediate 6A, 6B-1-6B-3, 6C; (f) Intermediates 6A, 6B-1-6B-3, and 6C were respectively subjected to Boc removal reactions to obtain intermediates 7A, 7B-1-7B-3, and 7C. (g) Intermediates 7A, 7B-1, 7B-3, and 7C were obtained as final products via substitution or nucleophilic addition reactions, respectively.

[0069] Pharmaceutical Compositions and Administration 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, 5-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0070] "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.

[0071] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule.

[0072] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0073] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0074] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0075] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0076] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0077] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0078] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0079] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0080] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0081] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0082] 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 5–1000 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.

[0083] Compared with the prior art, the main advantages of the present invention include: 1) The compound described in this invention showed significant metabolic improvement in a high-fat diet-induced obese mouse model and could effectively improve adipose tissue abnormalities.

[0084] (2) The compound described in this invention can significantly improve hepatic steatosis and lipid deposition, and significantly reduce the accumulation of lipid droplets in hepatocytes at the histological level, and has a significant therapeutic effect on metabolic-associated steatohepatitis (MASH).

[0085] (3) The compound described in this invention can regulate the function of adipose tissue, improve the hypertrophy of white adipose tissue and promote the functional recovery of brown adipose tissue, suggesting that it has the function of regulating energy metabolism.

[0086] (4) The compounds described in this invention also showed good efficacy in inflammation-related disease models, effectively alleviating inflammatory responses and having potential immunomodulatory effects.

[0087] (5) The compounds described in this invention have both metabolic regulation and anti-inflammatory mechanisms, which are different from existing drugs with a single mechanism of action and have a wider range of application prospects.

[0088] 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 as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0089] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0090] Example 1: Preparation of intermediate 2A N-tert-Butoxycarbonyl-L-proline amide (2 g, 10 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL) at room temperature to obtain a clear solution. Lawesson's reagent (2 g, 6 mmol) was added in portions to the solution with stirring, and the reaction was continued at room temperature for 8 hours. After the reaction was complete, the solvent was removed under reduced pressure. The system was extracted three times with dichloromethane and water, and the organic phases were combined. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Recrystallization from ethanol gave a white solid (2 g, 86% yield). The obtained intermediate did not require further purification and could be used directly in the next reaction.

[0091] Example 2: Preparation of intermediate 2B The preparation method of intermediate 2B was the same as in Example 1, except that the starting material used was N-tert-butoxycarbonyl-D-prolylamide (or the corresponding enantiomer), instead of N-tert-butoxycarbonyl-L-prolylamide in Example 1. The reaction and post-treatment were carried out under the same reaction conditions to obtain intermediate 2B, a yellow solid (yield 78%).

[0092] Example 3: Preparation of intermediate 2C The preparation method of intermediate 2C was basically the same as in Example 1, except that (R)-3-carbamoylpyrrolidine-1-carboxylic acid tert-butyl ester was used as the starting material, instead of N-tert-butoxycarbonyl-L-proline amide in Example 1. Apart from the above differences, the other reaction conditions, operating steps, and post-treatment processes were the same, thus obtaining intermediate 2C, a yellow solid (yield 58%).

[0093] Example 4: Preparation of intermediate 3A At room temperature, intermediate 2A (2.0 g, 8.6 mmol) and potassium bicarbonate (6.9 g, 68.8 mmol) were added to DME and stirred for 10 minutes to form a suspension. Ethyl bromide pyruvate (5.0 g, 26 mmol) was then added dropwise to the reaction mixture, and the mixture was stirred at room temperature for another 30 minutes after the addition was complete. The reaction mixture was cooled to 0 °C, and then trifluoroacetic anhydride (7.3 g, 34.4 mmol) and 2,6-dimethylpyridine (8.0 g, 74 mmol) were added dropwise sequentially. After the addition was complete, the mixture was stirred at 0 °C for another 30 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was partition extracted with dichloromethane and 1 N hydrochloric acid to separate the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography to give intermediate 3A as a yellow solid (64% yield).

[0094] Example 5: Preparation of intermediate 3B The preparation method of intermediate 3B was the same as in Example 4, except that intermediate 2B was used instead of intermediate 2A in Example 4. The reaction and post-processing were carried out under the same reaction conditions to obtain intermediate 3B, a yellow solid (70% yield).

[0095] Example 6: Preparation of intermediate 3C The preparation method of intermediate 3C was the same as in Example 4, except that intermediate 2C was used instead of intermediate 2A in Example 4. The reaction and post-processing were carried out under the same reaction conditions to obtain intermediate 3C, a colorless solid (yield 55%).

[0096] Example 7: Preparation of Intermediate 4A Intermediate 3A (1.8 g, 5.5 mmol) and lithium hydroxide (396 mg, 15 mmol) were dissolved in a tetrahydrofuran / water mixture at room temperature, and the mixture was stirred for 6 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was diluted with an appropriate amount of water. The pH of the system was then adjusted to approximately 6 with 1 N hydrochloric acid, and a solid precipitated. The precipitate was collected by filtration to give compound 4A as a yellow solid (73% yield). The obtained compound did not require further purification and could be used directly in the next reaction.

[0097] Example 8: Preparation of intermediate 4B The preparation method of intermediate 4B was the same as in Example 7, except that intermediate 3B was used instead of intermediate 3A in Example 4. The reaction and post-processing were carried out under the same reaction conditions to obtain intermediate 4B, a pale yellow solid (yield 67%).

[0098] Example 9: Preparation of intermediate 4C The preparation method of intermediate 4C was the same as in Example 7, except that intermediate 3C was used instead of intermediate 3A in Example 4. The reaction and post-processing were carried out under the same reaction conditions to obtain intermediate 4B, a pale yellow solid (yield 60%).

[0099] Example 10: Preparation of Intermediate 5A Intermediate 4A (1.2 g, 4 mmol) and N,O-dimethylhydroxylamine hydrochloride (585 mg, 6 mmol) were dissolved in anhydrous dichloromethane at room temperature. Under stirring, N,N-diisopropylethylamine (12 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (920 mg, 4.8 mmol) were added sequentially, and the reaction was stirred at room temperature for 16 hours. After the reaction was complete, water was added to quench the reaction mixture, and the organic and aqueous phases were separated. The aqueous phase was extracted three times with dichloromethane, and the organic phases were combined. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain intermediate 5A as a colorless oil (yield 85%).

[0100] Example 11: Preparation of intermediate 5B The preparation method of intermediate 5B was the same as in Example 10, except that intermediate 4B was used instead of intermediate 4A in Example 10. The reaction and post-processing were carried out under the same reaction conditions to obtain intermediate 5B, a pale yellow solid (yield 78%).

[0101] Example 12: Preparation of intermediate 5C The preparation method of intermediate 5C was the same as in Example 10, except that intermediate 4C was used instead of intermediate 4A in Example 10. The reaction and post-processing were carried out under the same reaction conditions to obtain intermediate 5C, a pale yellow solid (yield 70%).

[0102] Example 13: Preparation of Intermediate 6A At -20 °C, a solution of 6.9 mmol of 4-fluorophenyl magnesium bromide was added dropwise to a solution of intermediate 5A (1.3 g, 3.8 mmol) dissolved in tetrahydrofuran. After the addition was complete, the reaction mixture was allowed to warm naturally to room temperature over 1 hour and stirred for another 5 hours at room temperature. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of ammonium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the target compound as a colorless oil (yield 83%).

[0103] Example 14: Preparation of intermediate 6B-1 The preparation method of intermediate 6B-1 was the same as in Example 13, except that intermediate 5B was used instead of intermediate 5A in Example 13. The reaction and post-processing were carried out under the same reaction conditions to obtain intermediate 6B-1, a pale yellow solid (yield 77%).

[0104] Example 15: Preparation of intermediate 6B-2 The preparation method of intermediate 6B-2 was the same as in Example 14, except that 4-chlorophenyl magnesium bromide was used instead of intermediate 4-fluorophenyl magnesium bromide in Example 14. The reaction and post-processing were carried out under the same reaction conditions to obtain intermediate 6B-2, a pale yellow solid (yield 66%).

[0105] Example 16: Preparation of intermediate 6B-3 The preparation method of intermediate 6B-3 was the same as in Example 14, except that 3-fluorophenyl magnesium bromide was used instead of intermediate 4-fluorophenyl magnesium bromide in Example 14. The reaction and post-processing were carried out under the same reaction conditions to obtain intermediate 6B-3, a pale yellow solid (yield 60%).

[0106] Example 17: Preparation of intermediate 6C The preparation method of intermediate 6C was the same as in Example 13, except that intermediate 5C was used instead of intermediate 5A in Example 13. The reaction and post-processing were carried out under the same reaction conditions to obtain intermediate 6C, a pale yellow solid (yield 55%).

[0107] Example 18: Preparation of Intermediate 7A Compound 6A (1.2 g, 3.2 mmol) was dissolved in dichloromethane (10 mL) at room temperature, followed by the addition of trifluoroacetic acid. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the solvent was evaporated under reduced pressure to give a yellow solid. The residue was adjusted to neutral by adding a saturated aqueous sodium bicarbonate solution, and then extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to remove the solvent, yielding intermediate 7A as a yellow solid (85% yield). The obtained product did not require further purification and could be used directly in the next reaction.

[0108] Example 19: Preparation of intermediate 7B-1 The preparation method of intermediate 7B-1 was the same as in Example 18, except that intermediate 6B-1 was used instead of intermediate 6A in Example 18. The reaction and post-processing were carried out under the same reaction conditions to obtain intermediate 7B-1, a pale yellow solid (60% yield).

[0109] Example 20: Preparation of intermediate 7B-2 The preparation method of intermediate 7B-2 was the same as in Example 18, except that intermediate 6B-2 was used instead of intermediate 6A in Example 18. The reaction and post-processing were carried out under the same reaction conditions to obtain intermediate 7B-2, a pale yellow solid (yield 65%).

[0110] Example 21: Preparation of intermediate 7B-3 The preparation method of intermediate 7B-3 was the same as in Example 18, except that intermediate 6B-3 was used instead of intermediate 6A in Example 18. The reaction and post-processing were carried out under the same reaction conditions to obtain intermediate 7B-3, a pale yellow solid (yield 62%).

[0111] Example 22: Preparation of intermediate 7C The preparation method of intermediate 7C was the same as in Example 18, except that intermediate 6C was used instead of intermediate 6A in Example 18. The reaction and post-processing were carried out under the same reaction conditions to obtain intermediate 7C, a pale yellow solid (yield 60%).

[0112] Example 23: Preparation of final product A1 Intermediate 7A (100 mg, 0.36 mmol), cesium carbonate (234 mg, 0.72 mmol), and benzyl bromide (307 mg, 1.8 mmol) were added to acetonitrile at room temperature and the mixture was stirred for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The resulting residue was dispersed in a mixture of dichloromethane and saturated sodium bicarbonate aqueous solution, and the organic phase was separated after separation of the layers. The aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound A1 as a white solid (70% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.30 - 8.21 (m, 2H), 8.14 (s, 1H), 7.42 - 7.35 (m, 2H), 7.35- 7.29 (m, 2H), 7.29 - 7.23 (m, 1H), 7.17 (t, J = 8.6 Hz, 2H), 4.20 - 4.12(m, 1H), 4.07 (d, J = 13.1 Hz, 1H), 3.49 (d, J = 13.1 Hz, 1H), 3.13 (t, J =6.7 Hz, 1H), 2.47 - 2.34 (m, 2H), 2.04 - 1.78 (m, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 185.78, 179.44, 165.65 (d, J = 254.4 Hz), 154.42, 138.86,133.77 (d, J = 3.1 Hz), 133.23 (d, J = 9.2 Hz), 128.90, 128.68, 128.38,127.22, 115.43 (d, J = 21.8 Hz), 65.72, 59.10, 53.68, 34.47, 23.55. HRMS(ESI) [[ID= : calculated for C 21 H 19 FN2OS [M+H] + : 367.1269; found: 367.1278. The preparation methods for final products A2-A4 were carried out according to Example 23, using intermediate 7A as the starting material, and the reaction and post-processing were performed under the same reaction conditions to obtain final products A2-A4. The preparation methods for final products A5-A8 were the same as described above, except that intermediate 7B-1 was used instead of intermediate 7A in Example 23, and the reaction and post-processing were performed under the same reaction conditions to obtain final products A5-A8.

[0113] Compound A2 11H NMR (400 MHz, Chloroform-d) δ 8.29 - 8.18 (m, 2H), 8.10 (s, 1H), 7.58 (d, J J = 7.6 Hz, 1H), 7.33 (d, J J = 7.8 Hz, 1H), 7.28 - 7.22 (m, 1H), 7.21 - 7.12 (m, 3H), 4.33 - 4.17 (m, 1H), 3.93 (q, J J = 14.4 Hz, 2H), 3.31 - 3.18 (m, 1H), 2.56 - 2.35 (m, 2H), 2.07 - 1.80 (m, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 185.69 (d, J J = 1.6 Hz), 179.00, 165.60 (d, J J = 254.5 Hz), 154.27, 136.29, 133.77, 133.68 (d, J J = 3.0 Hz), 133.20 (d, J J = 9.3 Hz), 130.36,​​​​​​​​​​​​​​​​​​= 13.4 Hz, 1H), 3.46 (d, J = 13.4 Hz, 1H), 3.21 - 3.04(m, 1H), 2.52 - 2.27 (m, 2H), 2.03 - 1.80 (m, 3H).<\(0000023\)>C NMR (101 MHz,Chloroform-d) δ 185.70, 178.89, 165.61 (d, J = 254.4 Hz), 154.33, 140.95,134.21, %133.65 (d, J = 3.0 Hz), 133.15 (d, J = 9.2 Hz), 129.60, 128.85,128.58, 127.34, 126.69, 115.39 (d, J = 21.8 Hz), 65.73, 58.49, 53.69, 34.40,23.48. HRMS (ESI) ​ : calculated for C 21 H 18 ClFN2OS [M+H] + : 401.0884; found:401.0894. Compound A4 1 H NMR (400 MHz, Chloroform-d) δ 8.32 - 8.\\(20\) (m, 2H), 8.14 (s, 1H),7.30 (s, 4H), 7.17 (t, J = 8.6 Hz, 2H), 4.15 (s, 1H), 4.01 (d,{0}] J [[ID=3{1}]] = 13.3 Hz,1H), 3.46 (d,[[ID=3{2}]] J [[ID=3{3}]] = 13.3 Hz, 1H), 3.10 (s, 1H), 2.55 - 2.27 (m, 2H), 2.05 -1.70 (m, 3H).[[ID=3{4}]] 13 [[ID=3{5}]]C NMR (101 MHz, Chloroform-d) δ 185.69, 179.02, 165.61 (d,[[ID=3{6}]] J [[ID=3{7}]] =254.4 Hz), 154.37, 13\\(7.33\), 133.67 (d,[[ID=3{8}]] J Note: There are some tags like 13 etc. which seem to be in a non-standard format in the original. I've tried to keep them as close as possible while translating. Also, the text seems to have some inconsistent formatting which might be due to the source being in a non - standard format. If there are any specific requirements regarding these tags, it would be helpful to have more context.= 3.0 Hz), 133.15 (d, J = 9.1 Hz),132.86, 129.91, 128.82, 128.47, 115.40 (d, J = 21.7 Hz), 65.69, 58.32, 53.61,34.39, 23.48. HRMS (ESI) ​ : calculated for C 21 H 18 ClFN2OS [M+H] + : 401.0884;found: 401.0895. Compound A5 1 H NMR (400 MHz, Chloroform-d) δ 8.30 - 8.20 (m, 2H), 8.14 (s, 1H),7.41 - 7.36 (m, 2H), 7.33 (t, J = 7.4 Hz, 2H), 7.29 - 7.24 (m, 1H), 7.17 (t, J = 8.6 Hz, 2H), 4.19 - 4.12 (m, 1H), 4.07 (d, 1H), 3.49 (d, J = 13.1 Hz,1H), 3.19 - 3.09 (m, 1H), 2.48 - 2.35 (m, 2H), 2.00 - 1.78 (m, 3H). 13 C NMR(101 MHz, Chloroform-d) δ 185.73, 179.40, 165.61 (d, J = 254.7 Hz), 154.38,138.82, 133.73 (d, J = 2.9 Hz), 133.20 (d, J = 8.8 Hz), 128.87, 128.64,128.35, 127.19, 115.39 (d, J = 21.8 Hz), 65.68, 59.07, 53.65, 34.43, 23.52.HRMS (ESI) ​ : calculated for C21 H 19 FN2OS [M+H] + : 367.1269; found: 367.1278. Compound A6 1 H NMR (400 MHz, Chloroform-d) δ 8.20 - 8.10 (m, 2H), 8.00 (s, 1H), 7.53 - 7.44 (m, 1H), 7.25 - 7.18 (m, 1H), 7.18 - 7.10 (m, 1H), 7.08 - 6.96(m, 3H), 4.21 - 4.06 (m, 1H), 3.92 - 3.70 (m, 2H), 3.21 - 3.05 (m, 1H), 2.47- 2.23 (m, 2H), 1.95 - 1.71 (m, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 185.66,178.98, 165.59 (d, J = 254.6 Hz), 154.27, 136.29, 133.76, 133.68 (d, J = 3.1Hz), 133.20 (d, J = 9.3 Hz), 130.36, 129.38, 128.82, 128.23, 126.77, 115.36(d, J = 21.7 Hz), 65.93, 55.79, 54.03, 34.45, 23.68. HRMS (ESI) ​ :calculated for C 21 H 18 ClFN2OS [M+H] + : 401.0884; found: 401.0892. Compound A7 1 H NMR (400 MHz, Chloroform-d) δ 8.23 ​​- 8.11 (m, 2H), 8.06 (s, 1H),7.29 (s, 1H), 7.20 - 7.11 (m, 3H), 7.07 (t,J = 8.7 Hz, 2H), 4.12 - 4.00 (m,1H), 3.93 (d, J = 13.3 Hz, 1H), 3.37 (d, J = 13.4 Hz, 1H), 3.12 - 2.94 (m,1H), 2.44 - 2.20 (m, 2H), 1.94 - 1.65 (m, 3H). 13 C NMR (101 MHz, Chloroform-d)δ 184.66, 177.81, 164.58 (d, J = 254.6 Hz), 1…​​​​​​​​​​​​​​​​​​​​​​​​​​​​C NMR (101 MHz, Chloroform-d) δ 185.69,179.03, 165.61 (d, J = 254.6 Hz), 154.38, 137.35, 133.67 (d, J = 3.1 Hz), 133.16 (d, J = 9.1 Hz), 132.85, 129.90, 128.80, 128.47, 115.39 (d, J = 21.8Hz), 65.70, 58.33, 53.62, 34.40, 23.49. HRMS (ESI) ​ : calculated forC 21 H 18 ClFN2OS [M+H] + : 401.0884; found: 401.0895. Example 24: Preparation of final product A9 Intermediate 7B-1 (100 mg, 0.36 mmol) was dissolved in dichloromethane (5 mL) at room temperature, and triethylamine (45 mg, 0.43 mmol) was added and stirred until homogeneous. Then, phenylacetyl chloride (55 mg, 0.36 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane and washed successively with 1M hydrochloric acid and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound A5 as a white solid (70% yield). 1 H NMR (400 MHz, Chloroform-d) δ 8.21 - 8.13 (m, 2H), 8.04 - 8.01 (m, 1H), 7.20 (s, 4H), 7.10- 6.99 (m, 3H), 5.48 - 5.42 (m, 1H), 3.64 (s, 2H), 3.55 - 3.42 (m, 2H), 2.37- 2.25 (m, 1H), 2.21 - 2.11 (m, 1H), 2.06 - 1.94 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 184.27, 171.47, 169.32, 164.54 (d,J = 254.6 Hz), 152.68,133.06, 132.30 (d, J = 9.3 Hz), 128.03, 127.66, 127.56, 127.44, 125.97,114.22 (d, J = 21.9 Hz), 57.61, 46.48, 41.11, 30.64, 23.45. HRMS (ESI) ​ :calculated for C 22 H 19 FN2O2S [M+H] + : 395.1229; found: 395.1232. Example 25: Preparation of final product A10 Intermediate 7A (100 mg, 0.36 mmol) was dissolved in dichloromethane at room temperature, and triethylamine (73 mg, 0.72 mmol) was added, followed by stirring until homogeneous. The reaction mixture was then cooled to 0 °C, and benzyl isocyanate (67 mg, 0.5 mmol) was added dropwise. After the addition was complete, the mixture was warmed back to room temperature and the reaction was continued with stirring for 8 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane and washed successively with 2 N sodium hydroxide solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound A10 as a yellow solid (60 mg, 41% yield). 1 H NMR (400 MHz, Chloroform-d) δ 8.22 - 8.08 (m, 2H), 8.00 (s, 1H), 7.22- 7.09 (m, 5H), 7.06 - 6.94 (m, 2H), 5.27 (t, J = 5.2 Hz, 1H), 5.21 - 5.07(m, 1H), 4.30 (d, J = 4.6 Hz, 2H), 3.59 - 3.43 (m, 1H), 3.40 - 3.27 (m, 1H), 2.33 - 2.13 (m, 2H), 2.05 - 1.85 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ185.64, 178.50, 165.62 (d, J= 254.6 Hz), 154.33, 140.50, 133.58 (d, J = 3.0Hz), 133.12 (d, J = 9.2 Hz), 132.92, 131.96, 130.92, 129.20, 128.87, 115.42(d, J = 21.7 Hz), 65.84, 58.24, 53.70, 34.37, 23.50. HRMS (ESI) ​ :calculated for C 22 H 20 FN3O2S [M+H] + : 410.1335; found: 410.1342. The preparation methods of the final products A11-A18 and A32-A40 were carried out in accordance with Example 25, except that intermediate 7B-1 was used instead of intermediate 7A in Example 25, and the reaction and post-processing were carried out under the same reaction conditions to obtain the final products A11-A18 and A32-A40.

[0114] The preparation method of the final products A19-A23 is the same as that described above, except that intermediate 7B-2 is used instead of intermediate 7A in Example 25, and the reaction and post-processing are carried out under the same reaction conditions to obtain the final products A19-A23.

[0115] The preparation method of the final products A24-A27 is the same as that described above, except that intermediate 7B-3 is used instead of intermediate 7A in Example 25, and the reaction and post-processing are carried out under the same reaction conditions to obtain the final products A24-A27.

[0116] The preparation method of the final products A28-A31 is the same as that described above, except that intermediate 7C is used instead of intermediate 7A in Example 23, and the reaction and post-processing are carried out under the same reaction conditions to obtain the final products A28-A31.

[0117] Compound A11 1 H NMR (400 MHz, Chloroform-d) δ 8.21 - 8.09 (m, 2H), 8.01 (s, 1H), 7.23 - 7.11 (m, 5H), 7.02 (t, J = 8.7 Hz, 2H), 5.28 (t, J= 5.2 Hz, 1H), 5.16(t, J = 5.9 Hz, 1H), 4.31 (d, J = 5.7 Hz, 2H), 3.54 - 3.45 (m, 1H), 3.41 - 3.30 (m, 1H), 2.30 - 2.17 (m, 2H), 2.02 - 1.92 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 185.38, 175.01, 165.64 (d, [[ID=?]] J = 254.8 Hz), 156.75, 154.13, 139.26, 133.45 (d, J = 3.0 Hz), 133.26 (d, J = 9.2 Hz), 128.61, 128.47, 127.59, 127.35, 115.34 (d, J = 2 / 7 Hz), 59.03, 46.53, 44.71, 33.12, 24.19. HRMS (ESI) ​ : calculated for C 22 H 20 FN3O2S [M + H] + : 410.1335; found: 410.1339. Compound A12 1 H NMR (400 MHz, Chloroform-d) δ 8.23 - 8.14 (m,??), 8.07 (s, 1H), 7.29 - 7.22 (m, 1H), 7.18 - 7.12 (m, 1H), 7.07 (t, J = 8.7 Hz, 2H), 7.02 - 6.97 (m, 1H), 6.96 - 6.89 (m, 1H), 5.33 - 5.25 (m, 1H), 4.94 (s, 1H), 4.40(d, J = 5.7 Hz, 2H), 3.59 - 3.49 (m, 1H), 3.41 (q, J It seems there is an unclear value "2 / 7 Hz" in the provided text which might be a mistake. Please double-check the original content for accuracy.= 8.5 Hz, 1H), 2.33 - 2.24 (m, 2H), 2.06 - 1.99 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 184.30, 174.00, 164.56 (d, J = 254.7 Hz), 159.82 (d, J = 245.6 Hz), 155.72, 153.01, 132.39 (d, J = 3.0 Hz), 132.20 (d, J = 9.2 Hz), 128.89, 128.85, 127.92 (d, J = 8.2 Hz), 127.45, 123.16 (d, J = 3.5 Hz), 114.27 (d, J = 21.7 Hz), 114.15(d, J = 21.4 Hz), 57.97, 45.41, 37.54, 31.99, 23.08. HRMS (ESI) ​ : calculated for C 22 H 19 F2N3O2S [M+H] + : 428.1238; found: 428.1247. Compound A13 1 H NMR (400 MHz, Chloroform-d) δ 8.19 - 8.11 (m, 2H), 8.06 (s, 1H), 7.18 - 7.10 (m, 1H), 7.09 - 7.00 (m, 2H), 6.93 (d, J = 7.6 Hz, 1H), 6.88 - 6.79 (m, 2H), 5.36 - 5.25 (m, 1H), 5.17 - 5.08 (m, 1H), 4.33 (d, J = 5.8 Hz, 2H), 3.59 - 3.49 (m, 1H), 3.47 - 3.35 (m, 1H), 2.33 - 2.23 (m, 2H), 2.08 - 1.95 (m, 2H).13 13C NMR (101 MHz, Chloroform-d) δ 184.32, 173.78, 164.61 (d, J J = 254.9 Hz), 161.93 (d, J J = 246.0 Hz), 155.65, 153.07, 140.99 (d, J J = 7.0 Hz),132.39 (d, J J = 3.0 Hz), 132.17 (d, J J = 9.2 Hz), 129.05 (d, J J = 8.2 Hz),127.45, 121.91 (d, J J = 2.9 Hz), 114.32 (d, J J = 21.8 Hz), 113.19 (d, J J = 21.6Hz), 113.09 (d, J J = 21.1 Hz). HRMS (ESI) ​ : calculated for C 22 H 19 F2N3O2S [M+H] + : 428.1245; found: 428.1248. Compound A14 1 1H NMR (400 MHz, Chloroform-d) δ 8.28 – 8.19 (m, 2H), 8.14 (s, 1H),7.24 - 7.16 (m, 2H), 7.13 (t, J J = 8.6 Hz, 2H), 7.00 - 6.88 (m, 2H), 5.37 (t, J J = 5.1 Hz, 1H), 5.20 - 5.02 (m, 1H), 4.37 (d, J J = 5.5 Hz, 2H), 3.65 - 3.56(m, 1H), 3.55 - 3.42 (m, 1H), 2.46 - 2.24 (m, 2H), 2.19 - 2.02 (m, 2H). 13CNMR (101 MHz, DMSO-d6) δ 185.25, 176.81, 165.33 (d, J J = 251.8 Hz), 161.47 (d, J J = 241.6 Hz), 157.08, 153.50, 134.02 (d, J J = 2.9 Hz), 133.58 (d, J J = 9.4Hz), 130.06, 129.41, 129.28 (d, J J = 8.2 Hz), 115.91 (d, J J = 21.8 Hz), 115.24(d, J J = 21.1 Hz), 59.04, 46.69, 43.05, 32.82, 24.20. HRMS (ESI) ​ : calculated for C 22 [[ID=​​​​​​​​​​​​​​​​​​​​= 9.1 Hz), 131.99, 127.87, 127.65, 127.43, 114.34 (d, J = 21.8 Hz), 57.96,45.53, 42.94, 32.11, 23.14. HRMS (ESI) ​ : calculated for C 22 H 19 ClFN3O2S [M+H] + : 444.0949; found: 444.0956. Compound A16 1 H NMR (400 MHz, Chloroform-d) δ 8.28 - 8.20 (m, 2H), 8.16 (s, 1H),7.45 - 7.35 (m, 2H), 7.18 - 7.08 (m, 4H), 5.41 - 5.33 (m, 1H), 4.37 (s, 2H),3.65 - 3.56 (m, 1H), 3.51 (q, J = 8.4 Hz, 1H), 2.45 - 2.31 (m, 2H), 2.21 -2.02 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 184.30, 173.73, 164.63 (d, J =255.0 Hz), 155.65, 153.05, 137.35, 132.36 (d, J = 3.0 Hz), 132.18 (d, J = 9.3Hz), 130.62, 128.24, 127.44, 120.10, 114.35 (d, J = 21.8 Hz), 57.95, 45.54,43.00, 32.12, 23.13. HRMS (ESI) ​ : calculated for C 22 H 19 BrFN3O2S [M+H] + :488.0455; found: 488.0459. Compound A17 1 1H NMR (400 MHz, Chloroform-d) δ 8.30 - 8.21 (m, 2H), 8.15 (s, 1H), 7.37 - 7.29 (m, 1H), 7.15 (t, J J = 8.7 Hz, 2H), 6.83 - 6.72 (m, 2H), 5.41 - 5.30 (m, 1H), 4.42 (s, 2H), 3.65 - 3.56 (m, 1H), 3.49 (q, J J = 8.4 Hz, 1H), 2.44 - 2.33 (m, 2H),​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ 1 1H NMR (400 MHz, Chloroform-d) δ 8.23 - 8.14 (m, 2H), 8.07 (s, 1H), 7.47 (d, J J = 8.0 Hz, 2H), 7.27 (d, J J = 7.9 Hz, 2H), 7.06 (t, J J = 8.6 Hz, 2H), 5.36 - 5.25 (m, 2H), 4.44 - 4.33 (m, 2H), 3.62 - 3.50 (m, 1H), 3.48 - 3.37 (m, 1H), 2.39 - 2.24 (m, 2H), 2.12 - 1.92 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 185.35, 174.61, 165.74 (d, J J = 255.1 Hz), 156.78, 154.15, 145.15, 133.44 (d, J J = 3.1 Hz), 133.25 (d, J J = 9.2 Hz), 132.41, 128.03, 118.88, 115.48 (d, J J = 21.7 Hz), 111.00, 59.06, 46.72, 44.25, 33.21, 24.24. HRMS (ESI) ​ : calculated for C 23 H 19 FN4O2S [M+H] + : 435.1288; found: 435.1294. Compound A19 1 1H NMR (400 MHz, Chloroform-d) δ 8.12 - 7.96 (m, 3H), 7.36 - 7.30 (m, 2H), 7.22 - 7.10 (m, 5H), 5.29 (t, J J = 5.2 Hz, 1H), 5.07 (t, J J = 5.7 Hz, 1H), 4.32 (d, J= 5.7 Hz, 2H), 3.55 - 3.44 (m, 1H), 3.42 - 3.29 (m, 1H), 2.33 - 2.19 (m, 2H), 2.05 - 1.92 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 185.69, 175.10, 156.77, 153.95, 139.29, 139.27, 135.48, 131.97, 128.70, 128.62, 128.52, 127.57, 127.33, 59.02, 46.51, 44.69, 33.07, 24.20. HRMS (ESI) ​ : calculated for C 22 H 20 ClN3O2S [M+H] + : 425.1044; found: 426.1047. Compound A20 1 H NMR (400 MHz, Chloroform-d) δ 8.28 (s, 1H), 8.15 - 8.08 (m, 2H), 7.51 - 7.44 (m, 2H), 7.35 - 7.29 (m, 1H), 7.11 - 6.95 (m, 3H), 5.38 - 5.31 (m, 1H), 4.42 (d, J = 2.6 Hz, 2H), 4.36 (s, 1H), 3.74 - 3.61 (m, 1H), 3.47 (q, J = 8.6 Hz, 1H), 2.45 – 2.28 (m, 1H), 2.30 - 2.15 (m, 1H), 2.12 - 1.95 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 185.70, 174.94, 160.98 (d, J = 245.7 Hz), 156.68, 153.93, 139.32, 135.46, 131.96, 130.12 (d, J = 4.4 Hz), 129.10 (d, J= 8.2 Hz), 128.71, 128.52, 126.14 (d, J = 14.5 Hz), 124.26 (d, J = 3.5 Hz), 115.27 (d, J = 21.4 Hz), 58.99, 46.48, 38.79, 33.08, 24.14. HRMS(ESI) ​ : calculated for C 22 H 19 ClFN3O2S [M+H] + : 444.0951; found: 444.0957. Compound A21 1 H NMR (400 MHz, Chloroform-d) δ 8.28 (s, 1H), 8.21 - 7.97 (m, 2H),7.58 - 7.41 (m, 2H), 7.35 - 7.16 (m, 2H), 7.09 - 6.87 (m, 2H), 5.45 - 5.25(m, 1H), 4.43 - 4.22 (m, 2H), 3.73 - 3.60 (m, 1H), 3.46 (q, J = 8.6 Hz, 1H),2.44 - 2.29 (m, 1H), 2.27 - 2.18 (m, 1H), 2.13 - 2.01 (m, 2H). 13 C NMR (101MHz, Chloroform-d) δ 185.75, 174.99, 162.10 (d, J = 245.4 Hz), 156.80,153.97, 139.44, 135.49, 135.12 (d, J = 3.2 Hz), 131.98, 129.27 (d, J = 8.1Hz), 128.76, 128.61, 115.46 (d, J = 21.4 Hz), 59.04, 46.60, 44.01, 33.16,24.23. HRMS (ESI) ​ : calculated for C 22 H19 ClFN3O2S [M+H] + : 444.0951; found: 444.0956. Compound A22 1 H NMR (400 MHz, Chloroform-d) δ 8.22 - 8.10 (m, 3H), 7.44 (d, J J = 8.1 Hz, 2H), 7.26 - 7.23 (m, 2H), 7.18 (d, J J = 8.1 Hz, 2H), 5.37 (s, 1H), 4.98 (s, 1H), 4.39 (s, 2H), 3.60 (s, 1H), 3.51 (d, J J = 8.4 Hz, 1H), 2.38 (s, 2H), 2.11 (s, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 185.62, 174.88, 156.71, 153.94, 139.35, 137.92, 135.44, 133.00, 131.92, 128.89, 128.68, 128.65, 128.54, 58.98, 46.54, 43.96, 33.08, 24.19. HRMS (ESI) ​ : calculated for C 22 H 19 Cl2N3O2S [M+H] + : 459.0659; found: 460.0662. Compound A23 1 H NMR (400 MHz, Chloroform-d) δ 8.15 - 8.06 (m, 3H), 7.51 (d, J J = 8.0 Hz, 2H), 7.44 - 7.39 (m, 2H), 7.33 (d, J J = 8.0 Hz, 2H), 5.45 (t, J J = 5.9 Hz, 1H), 5.37 (t, J= 5.2 Hz, 1H), 4.43 (d, J = 5.9 Hz, 2H), 3.65 - 3.56 (m,1H), 3.53 - 3.42 (m, 1H), 2.50 - 2.23 (m, 2H), 2.12 - 2.04 (m, 2H). 13 C NMR(101 MHz, Chloroform-d) δ 185.64, 174.83, 156.77, 153.93, 143.57, 139.38,135.42, 131.88, 129.40 (q, J = 32.3 Hz), 128.54, 127.58, 125.46 (q, J = 3.7Hz), 124.13 (q, J = 271.1 Hz) 59.00, 46.56, 44.09, 33.06, 24.16. HRMS (ESI) ​ : calculated for C 23 H 19 ClF3N3O2S [M+H] + : 494.0928; found: 494.0930. Compound A24 1 H NMR (400 MHz, Chloroform-d) δ 8.04 (s, 1H), 7.92 - 7.76 (m, 2H),7.40 - 7.30 (m, 1H), 7.26 - 7.15 (m, 2H), 7.13 - 7.04 (m, 1H), 6.99 - 6.82(m, 2H), 5.35 - 5.22 (m, 1H), 5.19 - 5.04 (m, 1H), 4.39 - 4.31 (m, 2H), 3.59- 3.45 (m, 1H), 3.43 – 3.30 (m, 1H), 2.35 - 2.17 (m, 2H), 2.11 - 1.86 (m,2H). 13 C NMR (101 MHz, Chloroform-d) δ 185.56, 175.10, 162.43 (d, J = 246.9Hz), 161.00 (d,J = 245.8 Hz), 156.73, 153.80, 139.18 (d, J = 6.6 Hz), 130.03(d, J = 20.3 Hz), 129.97 (d, J = 23.4 Hz), 129.10 (d, J = 7.6 Hz), 126.29 (d, J = 2.9 Hz), 126.15, 124.28 (d, J = 3.6 Hz), 124.19 (d, J = 3.6 Hz), 119.87(d, J = 21.4 Hz), 117.33 (d, J = 22.9 Hz), 115.29 (d, J = 21.3 Hz), 59.03,46.52, 38.79, 33.09, 24.20. HRMS (ESI) ​ : calculated for C 22 H 19 F2N3O₂S [M+H] + :428.124¹; found: 428.1247. Compound A25 1 ¹H NMR (400 MHz, Chloroform-d) δ 8.11 - 8.03 (m, 1H), 7.93 - 7.77 (m,2H), 7.42 - 7.31 (m, 1H), 7.25 - 7.20 (m, 3H), 7.17 - 7.13 (m,³H), 5.34 -5.20 (m, 1H), 4.94 - 4.73 (m, 1H), 4.38 - 4.26 (m, 2H), 3.55 - 3.45 (m, 1H),3.44 - 3.28 (m, 1H), 2.37 - 2.18 (m, 2H), 2.11 - 1.92 (m, 2H). 13 ¹³C NMR (101MHz, Chloroform-d) δ 185.53, 175.13, 162.42 (d, J Note: In the translation, "¹H NMR" and "¹³C NMR" are marked as such to indicate that they are hydrogen-1 nuclear magnetic resonance and carbon-13 nuclear magnetic resonance respectively, which are specific terms in the field of chemistry. Also, "d" in the chemical shift values represents a doublet, which is a common notation in NMR spectroscopy. The "m" represents a multiplet which indicates a complex splitting pattern. These notations are kept as they are to maintain the accuracy of the chemical information. And the "Hz" stands for Hertz, which is the unit of frequency used to describe the NMR signals. The chemical formula "C H F₂N₃O₂S" is translated as it is because it is a chemical formula and needs to be accurately represented. The "[M+H]" notation is related to the mass spectrometry calculation and is also kept as it is. The values in the chemical shift tables are translated as they are to convey the specific NMR data.= 247.0 Hz), 158.69, 156.83, 153.77, 139.16 (d, J = 6.8 Hz), 129.90 (d, J = 7.6 Hz), 129.08, 128.64, 128.49, 127.55, 126.27 (d, J = 3.1 Hz), 119.88 (d, J = 21.4 Hz), 117.33 (d, J = 22.9 Hz), 59.02, 46.52, 44.68, 33.06, 24.20. HRMS (ESI) ​ : calculated for C 22 H 20 FN3O2S [M+H] + : 410.1337; found: 410.1341. Compound A261] 1 H NMR (400 MHz, Chloroform-d) δ 8.11 (s, 1H), 7.95 - 7.81 (m, 2H), 7.42 - 7.33 (m, 1H), 7.25 - 7.19 (m, 2H), 7.17 - 7.12 (m, 2H), 6.94 - 6.85 (m, 2H), 5.31 (t, J = 5.1 Hz, 1H), 4.32 (s, 2H), 3.56 – 3.49 (m, 1H), 3.47 - 3.36 (m, 1H), 2.37 - 2.28 (m, 2H), 2.12 - 1.98 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 184.41 (d, J = 2.3 Hz), 174.10, 161.33 (d, J = 247.1 Hz), 160.94 (d, J = 245.2 Hz), 155.72, 152.69, 138.05 (d, J = 6.7 Hz), 134.16 (d, J= 3.1 Hz), 128.85 (d, J = 7.6 Hz), 128.12 (d, J = 8.1 Hz), 127.96, 125.16(d, J = 3.0 Hz), 118.82 (d, J = 21.3 Hz), 116.22 (d, J = 23.0 Hz), 114.28 (d, J = 21.4 Hz), 57.94, 45.46, 42.84, 31.99, 23.13. HRMS (ESI) ​ : calculated for C 22 H 19 F2N3O2S [M+H] + : 428.1240; found: 428.1245. Compound A27 1 H NMR (400 MHz, Chloroform-d) δ 8.03 (s, 1H), 7.87 - 7.73 (m, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.36 - 7.29 (m, 1H), 7.23 - 7.13 (m, 3H), 5.42 (t, J = 5.7 Hz, 1H), 5.26 (t, J = 5.1 Hz, 1H), 4.32 (d,​​​​​​​​​​​= 32.3 Hz), 127.53, 126.14 (d, J = 2.9 Hz), 125.43 (q, J = 3.6Hz), 124.13 (q, J = 270.1 Hz), 119.90 (d, J = 21.4 Hz), 117.23 (d, J = 23.0Hz), 58.98, 46.54, 44.06, 33.04, 24.13. HRMS (ESI) ​ : calculated forC 23 H 19 F4N3O2S [M+H] + : 478.1214; found: 478.1219. Compound A28 1 H NMR (400 MHz, Chloroform-d) δ 8.27 - 8.16 (m, 2H), 8.08 (s, 1H),7.35 - 7.24 (m, 1H), 7.18 - 7.12 (m, 1H), 7.10 - 7.03 (m, 2H), 7.03 - 6.98(m, 1H), 6.97 - 6.89 (m, 1H), 4.72 (t, J = 6.0 Hz, 1H), 4.40 (d, J = 5.7 Hz,2H), 3.89 - 3.72 (m, 2H), 3.68 - 3.59 (m, 1H), 3.57 - 3.49 (m, 1H), 3.45 -3.36 (m, 1H), 2.45 - 2.33 (m, 1H), 2.30 - 2.15 (m, 1H). 13 C NMR (101 MHz,Chloroform-d) δ 184.06, 169.81, 164.68 (d, J = 255.0 Hz), 160.05 (d, J =245.5 Hz), 155.31, 153.05, 132.31 (d, J = 9.2 Hz), 129.36 (d, J = 4.4 Hz),128.07 (d,J = 8.2 Hz), 126.98, 123.26 (d, J = 3.4 Hz), 123.15 (d, J = 3.6 Hz), 114.37 (d, J = 21.8 Hz), 114.25 (d, J = 21.2 Hz), 114.07 (d, J = 21.4 Hz), 50.30, 43.91, 41.31, 37.71, 31.50. HRMS (ESI) ​ : calculated for C 22 H 19 F2N3O2S [M + H] + : 428.1241; found: 428.1247. Compound A29 1 H NMR (400 MHz, Chloroform - d) δ 8.42 - 8.27 (m, 2H), 8.17 (s, 1H), 7.39 - 7.19 (m, 1H), 7.15 (t, J = 8.6 Hz, 2H), 7.08 (d, J = 7.7 Hz, 1H), 7.04 - 7.00 (m, 1H), 6.97 - 6.90 (m, 1H), 4.76 (t, J = 5.7 Hz, 1H), 4.44 (d, J = 5.7 Hz, 2H), 4.04 - 3.85 (m, 2H), 3.80 - 3.70 (m, 1H), 3.69 - 3.61 (m, 1H), 3.59 - 3.44 (m, 1H), 2.54 - 2.45 (m, 1H), 2.42 - 2.28 (m, 1H). 13 C NMR (101 MHz, Chloroform - d) δ 184.07, 169.80, 164.68 (d, J = 255.1 Hz), 161.96 (d, J = 246.2 Hz), 155.32, 153.06, 141.24 (d,J = 6.9 Hz), 132.31 (d, J = 9.2 Hz),132.29 (d, J = 3.7 Hz), 129.06 (d, J = 8.3 Hz), 126.99, 122.08 (d, J = 2.9Hz), 114.38 (d, J = 21.8 Hz), 113.38 (d, J = 21.6 Hz), 113.10 (d, J = 21.2Hz), 50.35, 43.96, 43.12, 41.32, 31.52. HRMS (ESI) ​ : calculated forC 22 H 19 F2N3O2S [M+H] + : 428.1241; found: 428.1248. Compound A30 1 H NMR (400 MHz, Chloroform-d) δ 8.26 - 8.16 (m, 2H), 8.08 (s, 1H),7.24 - 7.14 (m, 2H), 7.06 (t, J = 8.7 Hz, 2H), 6.93 - 6.87 (m, 2H), 4.70 (t, J = 5.8 Hz, 1H), 4.31 (d, J = 5.7 Hz, 2H), 3.88 - 3.75 (m, 2H), 3.70 - 3.62(m, 1H), 3.58 - 3.50 (m, 1H), 3.45 – 3.36 (m, 1H), 2.47 - 2.34 (m, 1H), 2.30– 2.19 (m, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 184.08, 169.83, 164.68 (d, J = 255.2 Hz), 161.03 (d, J= 245.5 Hz), 155.38, 153.02, 134.31 (d, J = 3.1Hz), 132.29 (d, J = 9.2 Hz), 132.28 (d, J = 2.9 Hz), 128.33 (d, J = 8.0 Hz),127.01, 114.38 (d, J = 21.7 Hz), 114.36 (d, J = 21.3 Hz), 50.32, 43.94,42.95, 41.30, 31.50. HRMS (ESI) ​ : calculated for C 22 H 19 F2N3O2S [M+H] + :428.1241; found: 428.1249. Compound A31 1 H NMR (400 MHz, Chloroform-d) δ 8.25 - 8.14 (m, 2H), 8.04 (s, 1H),7.20 - 7.11 (m, 4H), 7.09 - 6.97 (m, 2H), 4.98 - 4.82 (m, 1H), 4.29 (d, J =5.9 Hz, 2H), 3.87 - 3.73 (m, 2H), 3.68 - 3.59 (m, 1H), 3.58 - 3.49 (m, 1H),3.44 - 3.35 (m, 1H), 2.45 - 2.33 (m, 1H), 2.31 - 2.16 (m, 1H). 13 C NMR (101MHz, Chloroform-d) δ 184.07, 169.83, 164.66 (d, J = 255.2 Hz), 155.40,152.99, 137.18, 132.29 (d, J = 8.5 Hz), 132.26 (d, J = 2.9 Hz), 131.91,128.00, 127.61, 127.03, 114.38 (d,J = 21.9 Hz), 50.32, 43.95, 42.93, 41.29, 31.49. HRMS (ESI) ​ : calculated for C 22 H 19 ClFN3O2S [M+H] + : 444.0954; found: 444.0958. Compound A32 1 H NMR (^{400} MHz, Chloroform-d) δ 8.27 - 8.20 (m, 2H), 8.15 (s, 1H), 7.25 - 7.17 (m, 2H), 7.12 (t, J = 8.7 Hz, 2H), 6.93 (s, 1H), 6.83 - 6.71 (m, 2H), 5.47 - 5.36 (m, 1H), 3.75 (s, 3H), 3.70 - 3.55 (m, 2H), 2.47 - 2.35 (m, 2H), 2.23 – 2.07 (m, 2H). 13 C NMR (^{101} MHz, Chloroform-d) δ 185.47,^{174.23},^{165.66} (d, J = 254.9 Hz), 155.89, 154.77, 154.02, 133.45 (d, J = 3.0 Hz), 133.19 (d, J = 9.3 Hz), 131.72, 128.45, 122.00, 115.43 (d, J = 21.8 Hz), 114.08, 58.85, 55.50, 46.79, 33.02, 24.31. HRMS (ESI) ​ : calculated for C 22 H 20 FN3O3S [M+H] + : 426.^{(}_1286; found: 426.1293. Compound A33 1 Note: There seems to be a formatting issue in the original text where some chemical shift values are not properly separated (e.g., "174.23,165.66" should probably be separated more clearly). Also, the "426.^{(}_1286" in the English translation might be a typo in the original input which should be corrected for a more accurate representation. I've translated it as best as possible with the given text.1H NMR (400 MHz, Chloroform-d) δ 8.24 - 8.17 (m, 2H), 8.13 (s, 1H),7.16 - 7.05 (m, 4H), 6.80 (d, J J = 8.0 Hz, 1H), 6.58 - 6.52 (m, 1H), 5.51 -5.37 (m, 1H), 3.72 (s, 3H), 3.69 (s, 2H), 2.48 - 2.33 (m, 2H), 2.22 - 2.05(m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 185.51, 173.96, 165.71 (d, J J =255.0 Hz), 160.15, 154.52, 153.99, 140.22, 139.92, 133.37 (d, J J = 3.0 Hz),133.14 (d, J J = 9.3 Hz), 129.54, 129.48, 128.52, 115.49 (d, J J = 21.8 Hz),111.98, 58.84, 55.23, 46.86, 33.06, 24.25. HRMS (ESI) ​ : calculated forC 22 H 20 FN3O3S [M+H] + : 426.1286; found: 426.1289. Compound A34 1 1H NMR (400 MHz, Chloroform-d) δ 8.24 - 8.12 (m, 3H), 7.43 (s, 4H),7.13 (t, J J = 8.5 Hz, 2H), 5.46 - 5.38 (m, 1H), 3.78 - 3.71 (m, 1H), 3.71 -3.62 (m, 2H), 2.54 - 2.38 (m, 2H), 2.26 - 2.10 (m, 2H). 1313C NMR (101 MHz, Chloroform-d) δ 185.43, 173.41, 165.73 (d, J J = 255.3 Hz), 153.96, 142.15, 133.40 (d, J J = 3.1 Hz), 133.05 (d, J J = 9.1 Hz), 128.38, 126.05 (q, J J = 3.7Hz), 124.65 (q, J J = 32.7 Hz), 124.26 (q, J J = 271.3 Hz), 118.83, 115.55 (d, J J = 21.8 Hz), 58.60, 46.96, 32.97, 24.26. HRMS (ESI) ​ : calculated for C 22 H 17 F4N3O2S [M+H] + : 463.1059; found: 464.1063. Compound A35 1 1H NMR (400 MHz, Chloroform-d) δ 8.25 - 8.16 (m, 2H), 8.15 (s, 1H), 7.68 (s, 1H), 7.45 (d, J J = 8.1 Hz, 1H), 7.34 - 7.18 (m, 2H), 7.11 (t, J J = 8.​​​​​​​= 9.3 Hz), 131.12 (q, J = 32.3 Hz), 129.26, 128.37, 123.95 (q, J =271.1 Hz), 122.62, 119.55 (q, J = 4.5 Hz), 116.25 (q, J = 4.4 Hz), 115.51 (d, J = 21.7 Hz), 58.72, 46.91, 32.97, 24.25. HRMS (ESI) ​ : calculated forC 22 H 17 F4N3O2S [M+H] + : 464.1059; found: 464.1062. Compound A36 1 H NMR (400 MHz, Chloroform-d) δ 8.23 - 8.18 (m, 2H), 8.17 (s, 1H),7.32 (d, J = 8.5 Hz, 2H), 7.13 (t, J = 8.6 Hz, 2H), 7.06 (d, J = 8.6 Hz, 2H),5.49 - 5.36 (m, 1H), 3.78 - 3.73 (m, 1H), 3.71 - 3.60 (m, 2H), 2.52 - 2.40(m, 2H), 2.26 - 2.06 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 185.43,173.61, 165.71 (d, J = 255.2 Hz), 153.98, 144.45 (q, J = 2.1 Hz), 137.60,133.41 (d, J = 3.1 Hz), 133.09 (d, J = 9.2 Hz), 128.39, 121.63, 120.59,120.51 (q, J = 256.6 Hz), 115.51 (d,J = 21.8 Hz), 58.66, 46.91, 32.99, 24.27. HRMS (ESI) ​ : calculated for C 22 H 17 F4N3O3S [M+H] + : 480.1009; found: 480.1011. Compound A37 1 H NMR (400 MHz, Chloroform-d) δ 8.28 - 8.18 (m, 2H), 8.17 (s, 1H), 7.13 (t, J = 8.6 Hz, 2H), 7.02 (d, J = 2.0 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.61 - 6.53 (m, 1H), 5.90 (s, 2H), 5.49 - 5.33 (m, 1H), 3.73 - 3.54 (m, 2H), 2.53 - 2.36 (m, 2H), 2.28 - 2.08 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 185.47, 173.96, 165.69 (d, J = 255.0 Hz), 154.61, 154.04, 147.77, 143.67, 133.44 (d, J = 3.0 Hz), 133.15 (d, J = 9.2 Hz), 132.92, 128.40, 115.47 (d, J = 21.8 Hz), 113.02, 107.90, 103.12, 101.14, 58.77, 46.82, 33.02, 24.31. HRMS(ESI) ​ : calculated for C 22 H 18 FN3O4S [M+H] + : 440.1082; found: 440.1085. Compound A38 1 1H NMR (400 MHz, Chloroform-d) δ 8.27 - 8.19 (m, 2H), 8.16 (s, 1H), 7.12 (t, J J = 8.7 Hz, 2H), 6.94 - 6.90 (m, 1H), 6.74 - 6.69 (m, 2H), 5.48 - 5.37 (m, 1H), 4.19 (s, 4H), 3.76 - 3.52 (m, 2H), 2.51 - 2.34 (m, 2H), 2.24 – 2.07 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 185.48, 174.12, 165.68 (d, J J = 254.7 Hz), 154.58, 154.04, 143.43, 139.80, 133.43 (d, J J = 2.9 Hz), 133.18 (d, J J = 9.2 Hz), 132.37, 12,8.42, 117.00, 115.44 (d, J J = 21.8 Hz), 113.73, 109.92, 64.41, 58.81, 46.78, 32.99, 24.31. HRMS (ESI) ​ : calculated for C 23 H 20 FN3O4S [M + H] + : 454.1241; found: 454.1244. Compound A39 1 1H NMR (400 MHz, DMSO-d6) δ 8.^9 (d, J J = 2.8 Hz, 1H), 8.49 (d, J= 2.7Hz, 1H), 8.29 - 8.20 (m, 2H), 8.09 (s, 1H), 7.86 - 7.77 (m, 2H), 7.76 - 7.71(m, 1H), 7.70 - 7.62 (m, 1H), 7.45 - 7.33 (m, 4H), 5.45 (d, J = 7.9 Hz, 1H),3.88 - 3.75 (m, 1H), 3.70 - 3.53 (m, 1H), 2.46 - 2.31 (m, 1H), 2.21 (s, 1H),2.06 (s, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 185.41, 173.89, 165.71 (d, J =255.1 Hz), 154.44, 154.08, 136.29, 133.99, 133.45 (d, J = 2.9 Hz), 133.20 (d, J = 9.2 Hz), 130.10, 128.55, 128.44, 127.50, 127.40, 126.35, 124.50, 120.12,115.68, 115.50 (d, J = 21.8 Hz), 58.83, 46.89, 33.05,​​​​​​​​​​​​​​​​​​​​​​=8.2 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.37 (d, J = 7.8 Hz, 1H), 7.19 (s, 1H),7.00 (t, J = 8.7 Hz, 2H), 5.60 - 5.50 (m, 1H), 3.91 - 3.72 (m, 2H), 2.63 -2.42 (m, 2H), 2.35 - 2.13 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 185.40,174.25, 165.57 (d, J = 255.0 Hz), 155.04, 154.04, 134.13, 133.48, 133.35 (d, J = 3.0 Hz), 133.14 (d, J = 9.2 Hz), 128.61, 128.57, 127.78, 125.99, 125.81,125.76, 125.07, 121.05, 120.81, 115.32 (d, J = 21.8 Hz), 59.04, 46.90, 33.11,24.24. HRMS (ESI) ​ : calculated for C 25 H 20 FN3O2S [M+H] + : 446.1341; found:446.1343. Test Example 1: Compound Enzyme Activity Assay This experiment evaluated the regulatory activity of compounds on HClpP by investigating their effects on the hydrolytic substrates of HClpP protein.

[0118] The test system volume was 100 μL, with a final HsClpP protein concentration of 0.5 μM and a substrate concentration of 200 μM. The preferred compound stock solution was diluted to a concentration of 1 μM. The small molecule and HClpP protein solution were first added to a flat-bottomed black 96-well plate, with three replicates per group. After incubation at room temperature for 10 min, the substrate was added, and the fluorescence intensity in the wells was immediately detected using a fluorescence microplate reader. Readings were taken every 5 min, with shaking for 5 s before each reading, for a total of 30 min. DMSO was used instead of the small molecule in the negative control group. The fold change in the DMSO group at different concentrations was recorded as an evaluation index of hydrolytic activity. Graphpad Prism was used to plot the obtained fold changes and calculate the activating fold.

[0119] The results are shown in Table 1. At a single concentration of 1 μM, most of the invented compounds showed certain regulatory performance against HClpP.

[0120] Table 1 Test Example 2: Acute Toxicity Experiment in Mice Healthy ICR mice (weighing 18–22 g), half male and half female, were selected and acclimatized for 3 days before being used in the experiment. The experimental animals were randomly divided into a control group and a treatment group, with 6–10 mice in each group. The treatment groups were administered compound A11 of this invention via gavage at doses of 50 mg / kg, 100 mg / kg, and 200 mg / kg, respectively, while the control group received an equal volume of the solvent. The mice were observed for 14 consecutive days after administration, recording their behavior, activity levels, diet, and weight changes, and observing for any signs of poisoning or death. Weight was measured periodically during the observation period. At the end of the experiment, the animals were euthanized, and the major organs (including the heart, liver, spleen, lungs, and kidneys) were visually examined.

[0121] Experimental results showed that within the above-mentioned dosage range, the mice in the treatment group did not exhibit significant abnormal behavior or death, their body weight changed normally, and no significant abnormalities were observed in the major organs. These results suggest that compound A11 of the present invention has good safety and tolerability within the stated dosage range.

[0122] Test Example 3: Evaluation of the therapeutic effect of compound A11 on DSS-induced inflammatory bowel disease in mice Six- to eight-week-old C57BL / 6 mice (weighing 18–22 g) were selected and acclimatized for 3 days before being used in the experiment. The animals were randomly divided into a normal control group, a model group, and a treatment group, with 6–10 mice in each group. Except for the normal control group, the mice in the other groups received drinking water containing 3% (w / v) dextran sulfate sodium (DSS) for 7 consecutive days to establish an inflammatory bowel disease model. From the start of modeling, the treatment group was simultaneously administered compound A12 of this invention via gavage at a dose of 10–50 mg / kg once daily; the normal control group and the model group received an equal volume of the solvent. During the experiment, daily changes in mouse weight, fecal characteristics, and the presence or absence of fecal hematochezia were recorded, and the Disease Activity Index (DAI) was calculated based on relevant indicators. After the experiment, the mice were sacrificed, the colon was harvested for measurement, and histopathological observation was performed.

[0123] like ​ As shown, the experimental results indicate that, compared with the model group, the mice in the drug-treated group experienced a reduction in body weight loss, a decrease in DAI scores, a certain improvement in colon length shortening, and a reduction in tissue inflammation. These results suggest that compound A11 of this invention has a certain ameliorative effect on DSS-induced inflammatory bowel disease in mice.

[0124] Test Example 4: Evaluation of the effect of compound A12 on a high-fat diet-induced MASH model in mice SPF-grade C57BL / 6J mice, weighing 40–42 g, were housed under constant temperature and humidity conditions with free access to food and water. A metabolic-associated steatohepatitis (MASH) model was induced by feeding a high-fat diet. After modeling, mice were randomly divided into a model group and a treatment group, with 6–10 mice in each group. A normal control group fed a standard diet was also included. The treatment group was administered compound A12 of this invention by gavage at a dose of 10–50 mg / kg once daily for 4 weeks. The model group and the normal control group received an equal volume of the solvent. During the treatment period, changes in mouse weight and food intake were recorded regularly. After the treatment, the animals were sacrificed, and liver, brown adipose tissue, and white adipose tissue were collected for histological analysis using standard methods, including hematoxylin-eosin (H&E) staining and Oil Red O staining, to evaluate histopathological changes and lipid deposition.

[0125] like ​ As shown, the experimental results indicate that, compared with the model control group, administration of compound A12 reduced the degree of steatosis in the liver of mice and decreased lipid deposition; at the same time, the morphology of brown adipose tissue and white adipose tissue was improved.

[0126] 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. A compound of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof. in, R1 is selected from the following group: halogen, cyano, C1-C4 haloalkyl; X is either N or CH; Y is either N or CH; In this case, one of X and Y is N, and N is connected to Z; Z is selected from the following group: -CH2-, -C(=O)-, -C(=O)NH-, -C(=O)(CH2) n -、-C(=O)NH-(CH2) n -; n is 1, 2, 3, 4, 5 or 6; A is selected from the following group of substituted or unsubstituted groups: H, C6-C10 aryl, 5-10 membered heterocyclic group; The substitution refers to the substitution of one or more hydrogen atoms on a group by a group selected from the group consisting of: halogen, cyano, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C2-C4 alkenyl, and C2-C4 alkynyl.

2. The compound according to claim 1, characterized in that, The compound has the structure shown in formula IA or formula IB: Wherein, each group is as defined in claim 1.

3. The compound according to claim 1, characterized in that, A is selected from the following group, whether substituted or unsubstituted: phenyl, naphthyl, benzo5-6 membered heterocycle (preferably 1,4-benzodioxane, 1,3-benzodioxanepentenyl).

4. The compound according to claim 1, characterized in that, -ZA is selected from the following group of substituted or unsubstituted groups: benzyl, phenyl, -C(=O)-benzyl, -C(=O)NH-benzyl, -C(=O)NH-phenyl, -C(=O)NH-1,4-benzodioxane, -C(=O)NH-1,3-benzodioxanepentenyl, -C(=O)NH-naphthyl.

5. The compound according to claim 1, characterized in that, The compound has a structure as shown in formula II-A or II-B: Wherein, each group is as described in claim 1.

6. The compound according to claim 1, characterized in that, The compounds are selected from the following group: 。 7. A pharmaceutical composition, characterized in that, include: The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, and pharmaceutically acceptable carrier thereof.

8. Use of the compound according to claim 1, characterized in that, Used to prepare a drug for (a) as a ClpP agonist; (b) to prevent and / or treat diseases or conditions mediated by HsClpP.

9. The use as described in claim 8, characterized in that, The diseases or conditions mediated by HsClpP are selected from the group consisting of: autoimmune diseases, inflammatory diseases, metabolic diseases, diseases associated with inflammation or metabolic abnormalities, tumors, or combinations thereof; preferably inflammatory diseases or metabolic diseases.

10. The use as described in claim 8, characterized in that, The tumors mentioned are selected from the following group: central nervous system tumors, brain tumors, peripheral nervous system tumors, pheochromocytoma, paraganglioma, neuroendocrine tumors, liver cancer, lung cancer, stomach cancer, colon cancer, colorectal cancer, rectal cancer, pancreatic cancer, breast cancer, prostate cancer, endometrial cancer, hematologic malignancies, lymphatic system tumors, or combinations thereof.

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