Aromatic heterocyclic derivative with S1P receptor regulation activity and preparation method and application thereof

Abstract

The invention relates to the technical field of medicinal chemistry, in particular to an aromatic heterocyclic derivative with S1P receptor regulation activity and a preparation method and application thereof. In a specific embodiment, the aromatic heterocyclic derivative is a compound shown in a general formula (I) or a geometric isomer, an enantiomer, a diastereoisomer or a pharmaceutically acceptable salt thereof. In another specific embodiment, the use is as a therapeutic agent, in particular as an S1P1 receptor agonist. General formula (I)

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry. Specifically, it relates to aromatic heterocyclic derivatives as S1P receptor modulators, their preparation methods, and their applications as therapeutic agents, particularly S1P1 receptor agonists. Background Technology

[0002] Sphingosine-1-phosphate (S1P) is a key bioactive lipid mediator that participates in and regulates a wide range of important physiological and pathological processes, including cell proliferation, migration, survival, and immune inflammatory responses, by activating S1P receptors (S1PR1-S1PR5) in the G protein-coupled receptor (GPCR) family. Among these, the S1P1 receptor subtype plays a central role in immune regulation, mediating the migration of lymphocytes from secondary lymphoid organs to the circulatory system (blood and lymph).

[0003] Based on this well-defined mechanism, S1P receptor modulators (especially functional modulators) have become an important class of drugs for treating autoimmune diseases. These drugs bind to the S1P1 receptor on the surface of lymphocytes, inducing internalization and functional downregulation of the receptor, thereby effectively retaining lymphocytes in lymphoid tissues, blocking their recruitment pathways to sites of inflammation, and ultimately suppressing the autoimmune response. Currently, several S1P receptor agonists have been approved for marketing, with indications in the field of autoimmune diseases such as multiple sclerosis.

[0004] In addition to its confirmed immunomodulatory function, a growing body of preclinical and clinical research reveals that the S1P1 receptor signaling pathway also plays a crucial role in disease progression, including tumorigenesis, angiogenesis, atherosclerosis, and thrombosis. Therefore, targeting the S1P receptor not only provides a mature treatment strategy for autoimmune diseases but also demonstrates significant therapeutic potential in oncology and cardiovascular diseases. Given the well-defined mechanism and broad therapeutic prospects of the S1P receptor signaling pathway, the development of novel, highly effective, and safe drugs targeting the S1P receptor is of great scientific and market value in meeting clinical needs. Summary of the Invention

[0005] The purpose of this invention is to provide aromatic heterocyclic derivatives as S1P receptor modulators, methods for their preparation, and their applications as therapeutic agents, particularly S1P1 receptor agonists.

[0006] In a first aspect, the present invention provides an aromatic heterocyclic derivative having S1P receptor regulatory activity, said derivative being a compound of general formula (I) or its geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, as follows: General Formula (I) Where X is selected from C or N; R1 and R2 may be the same or different, and are independently selected from hydrogen, halogen, cyano, amino, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, phenyl, or substituted or unsubstituted 5-7 heteroaryl; R3 is selected independently , , , or Where L is selected from carbonyl, methylene or sulfonyl, n is selected from integers from 0 to 3, and R is selected from carboxyl, hydroxyl, amino or formamide; A is selected from a benzene ring or a 5-9 membered aromatic heterocycle, wherein the heteroatom in the aromatic heterocycle is selected from N, O or S; C is selected from substituted or unsubstituted saturated five-membered heterocycles or five-membered aromatic heterocycles, wherein the heteroatom in the five-membered heterocycle or the five-membered aromatic heterocycle is selected from N, O or S; B is selected from substituted or unsubstituted five-membered aromatic heterocycles, wherein the heteroatom in the five-membered aromatic heterocycle is selected from N, O or S; Alternatively, when C is selected from substituted or unsubstituted saturated five-membered heterocycles, B is selected from... or ; Preferably, structural unit Selected from: ; B is selected from: ; R1 and R2 may be the same or different, and are independently selected from hydrogen, halogen, cyano, amino, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, phenyl, or substituted or unsubstituted 5-7 heteroaryl; R3 is selected independently , , , or Where L is selected from carbonyl, methylene or sulfonyl, n is selected from integers from 0 to 3, and R is selected from carboxyl, hydroxyl, amino or formamide; More preferably, A is a phenyl group, structural unit B is selected from: ; R1 and R2 may be the same or different, and are independently selected from hydrogen, halogen, cyano, amino, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, phenyl, or substituted or unsubstituted 5-7 heteroaryl; R3 is selected independently , , , or Where L is selected from carbonyl, methylene or sulfonyl, n is selected from integers from 0 to 3, and R is selected from carboxyl, hydroxyl, amino or formamide; More preferably, the derivative is: 4-(5-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)propionic acid 4-(5-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)butyric acid 2-(5-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)ethane-1-ol 3-(5-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)propane-1,2-diol 3-(5-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)cyclopentane-1-carboxylic acid 4-(5-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)cyclohexane-1-carboxylic acid 4-(5-(1-(4-isopropylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)butyric acid 5-(5-(1-(3-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)butyric acid 5-(5-(1-(3-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)valeric acid 4-(5-(1-(4-(pyrrolidone-1-yl)phenyl)-1 H-1,2,3-triazol-4-yl)isoindolin-2-yl)butyric acid 5-(5-(1-(4-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)valeric acid 3-(5-(4-(4-propylphenyl)-1 H -1,2,3-triazol-1-yl)isoindolin-2-yl)propionic acid 3-(5-(4-(4-propylphenyl)-1 H -1,2,3-triazol-1-yl)isoindolin-2-yl)butyric acid 3-(5-(4-(4-isopropylphenyl)-1 H -1,2,3-triazol-1-yl)isoindolin-2-yl)propionic acid 3-(5-(4-(4-isopropylphenyl)-1 H -1,2,3-triazol-1-yl)isoindolin-2-yl)butyric acid 3-(5-(4-(4-tert-butylphenyl)-1 H -1,2,3-triazol-1-yl)isoindolin-2-yl)propionic acid 5-(5-(4-(4-tert-butylphenyl)-1 H -1,2,3-triazol-1-yl)isoindolin-2-yl)valeric acid 4-(5-(5-(4-isobutylphenyl)thiazolyl)isoindoline-2-yl)butyric acid 5-(5-(5-(4-isobutylphenyl)thiazolyl)isoindoline-2-yl)valeric acid 5-(5-(5-(4-ethylphenyl)thiazo-2-yl)isoindoline-2-yl)butyric acid 5-(5-(5-(4-ethylphenyl)thiazo-2-yl)isoindoline-2-yl)valeric acid 3-(5-(5-(3,4-dimethylphenyl)thiazolyl)isoindoline-2-yl)butyric acid 4-(6-(1-(4-propylphenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid 4-(6-(1-(4-tert-butylphenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid 4-(6-(1-(4-isopropoxyphenyl)-1 H -1,2,3-triazol-4-yl)-1H -Indazole-1-yl)butyric acid 4-(6-(1-(4-isopropylphenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid 4-(6-(1-(4-ethoxyphenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid 4-(6-(1-(3-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)-1H-indazol-1-yl)butyric acid 4-(6-(1-(4-morpholinylphenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid 4-(6-(1-(4-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid 4-(6-(1-(4-(4-propylpiperazin-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid 4-(6-(1-(4-cyclohexylphenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid 4-(6-(1-(4-propylphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(4-tert-butylphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(4-isopropoxyphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(4-isopropylphenyl)-1 H-1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(4-ethoxyphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(3-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(4-morpholinophenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(4-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(4-(4-propylpiperazin-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(4-cyclohexylphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(4-cyclopentylphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid.

[0007] In a second aspect, the present invention provides a pharmaceutical composition having S1P receptor regulatory activity, the pharmaceutical composition comprising the derivative described in the first aspect above, and a pharmaceutically acceptable carrier.

[0008] In a preferred embodiment, the pharmaceutical composition is a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, or powders.

[0009] In a third aspect, the present invention provides the use of the derivatives described in the first aspect or the pharmaceutical compositions described in the second aspect in the preparation of medicaments for treating or preventing S1P receptor-mediated diseases or for modulating S1P receptors.

[0010] In a preferred embodiment, the regulation of the S1P receptor is the activation of the S1P receptor.

[0011] In a preferred embodiment, the S1P receptor is the S1P1 receptor.

[0012] In a preferred embodiment, the S1P receptor-mediated disease is an autoimmune disease.

[0013] The autoimmune diseases mentioned are selected from: multiple sclerosis, myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, or Crohn's disease.

[0014] In the definitions of compounds of general formula (I) given above, the terms used in the compilation are generally defined as follows: In the general formula, "alkyl" refers to a saturated branched or straight-chain alkyl group with a carbon chain length of 1-10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, or tert-butyl. Alkyl groups can be substituted with one or more substituents, such as halogens or haloalkyl groups. Examples include trichloromethyl and trifluoromethyl.

[0015] In the general formula, "cycloalkyl" refers to a cyclic alkyl group with 3-8 carbon atoms, such as cyclobutyl, cyclopentyl or cyclohexyl. The alkyl group can be substituted by one or more substituents, such as cycloalkyl groups substituted by N, O or S, tetrahydrofuranyl, piperidinyl, piperazineyl, pyrroleyl, morpholinyl.

[0016] In the general formula, "alkoxy" refers to 1-10 straight-chain or branched alkyl groups. The hydrogen atom of the hydroxyl group can be replaced by these straight-chain or branched alkyl groups, such as methoxy, ethyloxy, propyloxy, isopropyloxy, etc.; the alkoxy group can also be replaced by one or more substituents, such as halogens or haloalkyl groups. In the general formula, "heteroaryl" refers to a group containing 5-7 ring atoms, with 6, 10, or 14 electrons shared in the ring system. The ring atoms are 1-3 atoms selected from C, N, O, and S. Examples include phenyl, piperidinyl, pyrrolyl, thiophene, furanyl, pyranyl, pyrroloyl, imidazolyl, pyrazolyl, pyridinyl, and pyrimidinyl. The heteroaryl group may optionally be substituted by 1-5 (e.g., 1, 2, 3, 4, or 5) substituents selected from: halogen, C1-C4 aldehyde, C1-C6 straight-chain or branched alkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, etc.

[0017] In the general formula, "halogen" refers to fluorine, chlorine, bromine or iodine.

[0018] The preparation method of the derivative shown in general formula (I) is as follows: When B is selected Structural unit Selected from The derivative structure shown in general formula (I) is as described in general formula 5 or general formula 10, specifically: Starting with 5-bromoisoindoline-2-tert-butyl carbonate 1, an alkynyl structure was introduced via a Sonogashira coupling reaction with trimethylsilylacetylene. The trimethylsilyl group was then removed using tetrabutylammonium fluoride to obtain alkynyl intermediate 2. Intermediate 2 was then reacted with para-substituted azidebenzene (prepared from different substituted bromobenzenes via a sodium azide reaction) in a click chemistry reaction to obtain the key triazole intermediate 3. Intermediate 3 underwent a tert-butyloxycarbonyl protecting group removal in an acidic system to obtain amino intermediate 4. Intermediate 4 was derivatized using two strategies to obtain the target compound 5: first, reductive amination with chain / cyclic carboxylic esters with different aldehyde / ketone groups; second, alkylation with chain / cyclic carboxylic esters with different halogen substitutions, followed by ester removal under alkaline conditions to obtain the target compound.

[0019] Furthermore, starting with compound 5-bromoisoindoline-2-tert-butyl carbonate 1, a coupling reaction is carried out with trimethylsilylacetylene under the catalysis of dichlorobis(triphenylphosphine)palladium, cuprous iodide, and triethylamine to obtain the corresponding intermediate. This reaction is carried out at 60-100°C, preferably 80°C; the solvent used can be DMF, 1,4-dioxane, or DMSO, preferably DMF. The obtained intermediate is deprotected at room temperature under the action of tetrabutylammonium fluoride to obtain compound 2. The solvent for this step can be tetrahydrofuran, methanol, ethanol, acetonitrile, or ethyl acetate, preferably methanol. Separately, bromobenzenes with different substitutions are reacted with sodium azide in DMSO at high temperature (80-110°C, preferably 95°C) under the catalysis of cuprous iodide, sodium ascorbate, and N,N'-dimethylethylenediamine to prepare the corresponding substituted azide benzenes; subsequently, compound 2 is added to the reaction system, and by click chemistry, it is converted into the key intermediate 3. Intermediate 3 undergoes acidolysis at 20-30°C to remove the Boc protecting group, yielding compound 4. Suitable acids include hydrochloric acid and trifluoroacetic acid, with hydrochloric acid being preferred; reaction solvents can be ethyl acetate or dichloromethane, with ethyl acetate being preferred. Compound 4 can be further derivatized via two pathways: one is a reductive amination reaction in methanol with acetic acid as a catalyst and sodium cyanoborohydride as a reducing agent, at room temperature, yielding the corresponding intermediate; the other is a nucleophilic substitution reaction with different halogenated reagents under alkaline conditions. Suitable bases include triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, or sodium bicarbonate, with potassium carbonate or triethylamine being preferred; reaction solvents can be acetonitrile, DMF, tetrahydrofuran, or acetone, with DMF being preferred; the reaction temperature is 50-100°C, preferably 80°C. Finally, the intermediate obtained above is hydrolyzed under alkaline conditions to remove the ester group. The available bases include sodium hydroxide, potassium hydroxide, or lithium hydroxide, with sodium hydroxide being preferred; the reaction solvent is a methanol / water mixture, and the reaction temperature is 20-50°C, preferably 40°C, to obtain the target product.

[0020] Starting with substituted bromobenzene 6, an alkynyl structure was introduced via a Sonogashira coupling reaction with trimethylsilylacetylene. The trimethylsilyl group was then removed using tetrabutylammonium fluoride to yield alkynyl intermediate 7. Intermediate 7 was then reacted with azidebenzene (prepared from 5-bromoisoindoline-2-tert-butyl carbonate 1 via a sodium azide reaction) in a click chemistry reaction to obtain the key triazole intermediate 8. Intermediate 8 underwent a tert-butyloxycarbonyl protecting group removal in an acidic system to yield an amino intermediate 9. Intermediate 9 was derivatized using two strategies to obtain the target compound 10: first, reductive amination with chain / cyclic carboxylic acid esters with different aldehyde / ketone groups; second, alkylation with chain / cyclic carboxylic acid esters with different halogen substitutions, followed by ester removal under alkaline conditions to obtain the target compound.

[0021] Furthermore, starting with substituted bromobenzene 6, a coupling reaction is carried out with trimethylsilylacetylene under the catalysis of dichlorobis(triphenylphosphine)palladium, cuprous iodide, and triethylamine to obtain the corresponding intermediate. This reaction is carried out at 60-100°C, preferably 80°C; the solvent used can be DMF, 1,4-dioxane, or DMSO, preferably DMF. The obtained intermediate is deprotected with a silicon protecting group at room temperature under the action of tetrabutylammonium fluoride to obtain compound 7. The solvent for this step can be tetrahydrofuran, methanol, ethanol, acetonitrile, or ethyl acetate, preferably methanol. Separately, starting material 5-bromoisoindoline-2-tert-butyl carbonate 1 is reacted with sodium azide in DMSO at high temperature (80-110°C, preferably 95°C) under the catalysis of cuprous iodide, sodium ascorbate, and N,N'-dimethylethylenediamine to prepare the corresponding azidebenzene; subsequently, compound 7 is added to the reaction system, and a click cycloaddition reaction yields the key intermediate 8. Intermediate 8 is acid-degraded at 30°C to remove the Boc protecting group, yielding compound 9. Suitable acids include hydrochloric acid and trifluoroacetic acid, with hydrochloric acid being preferred; reaction solvents include ethyl acetate and dichloromethane, with ethyl acetate being preferred. Compound 9 can be further derivatized via two pathways: one is a reductive amination reaction in methanol with acetic acid as a catalyst and sodium cyanoborohydride as a reducing agent, at room temperature, yielding the corresponding intermediate; the other is a nucleophilic substitution reaction with different halogenated reagents under alkaline conditions. Suitable bases include triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, or sodium bicarbonate, with potassium carbonate or triethylamine being preferred; reaction solvents include acetonitrile, DMF, tetrahydrofuran, or acetone, with DMF being preferred; the reaction temperature is 50-100°C, preferably 80°C. Finally, the intermediate obtained above is hydrolyzed under alkaline conditions to remove the ester group. The available bases include sodium hydroxide, potassium hydroxide, or lithium hydroxide, with sodium hydroxide being preferred; the reaction solvent is a methanol / water mixture, and the reaction temperature is 20-50°C, preferably 40°C, to obtain the target product.

[0022] When B is selected Structural unit Selected from The derivative structure shown in general formula (I) is as described in general formula 24, specifically: Starting with 5-bromoisoindoline-2-tert-butyl carbonate 1, a cyanolation reaction was carried out with zinc cyanide under tetraphenylphosphine palladium catalysis to obtain a cyano-substituted compound 20. Subsequently, compound 20 was oxidized with hydrogen peroxide to convert into a compound 21 containing an amide structure. Compound 21 underwent a thiolation reaction under Lawson's reagent to generate a thioamide derivative 22. 22 was further cyclized with different haloacylbenzenes to construct a key intermediate. This key intermediate was deprotected under acidic conditions with a tert-butyloxycarbonyl protecting group to obtain an amino intermediate 23. Intermediate 23 can be further derivatized into the target compound 24 through two derivatization strategies: Strategy 1, structural modification by reductive amination with chain or cyclic carboxylic esters substituted with different aldehyde or ketone groups; Strategy 2, alkylation with chain or cyclic carboxylic esters substituted with different halogens. Finally, the products obtained by both strategies were hydrolyzed under alkaline conditions to remove the ester group, yielding the target compound 24.

[0023] Furthermore, starting with compound 5-bromoisoindoline-2-tert-butyl carbonate 1, a cyanation reaction is carried out with zinc cyanide under tetraphenylphosphine palladium catalysis to obtain intermediate 20. This reaction is conducted at 80-120°C, preferably 90°C, using DMF as the solvent. Intermediate 20 is then oxidized at room temperature with 30% hydrogen peroxide to obtain amide intermediate 21, using DMSO as the solvent. Subsequently, 21 is thiolated with Lawson's reagent to obtain intermediate 22, at a temperature of 50-80°C, preferably 55°C, using tetrahydrofuran as the solvent. Then, different haloacrylbenzenes are cyclized with intermediate 22 to obtain a key intermediate, at a temperature of 70-90°C, preferably 80°C, using ethanol as the solvent. The intermediate is then acid-cleaved at room temperature to remove the Boc protecting group, yielding compound 22. Suitable acids include hydrochloric acid and trifluoroacetic acid, with hydrochloric acid being preferred; the reaction solvent can be ethyl acetate or dichloromethane, with ethyl acetate being preferred. Compound 22 can be further derived via two pathways: First, a reductive amination reaction is carried out in methanol with a chain / cyclic carboxylic acid ester substituted with different aldehyde or ketone groups, catalyzed by acetic acid and using sodium cyanoborohydride as a reducing agent, to obtain the corresponding intermediate. Second, a nucleophilic substitution reaction is carried out with different halogenating agents under basic conditions. Suitable bases include triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, or sodium bicarbonate, preferably potassium carbonate or triethylamine; the reaction solvent can be acetonitrile, DMF, tetrahydrofuran, or acetone, preferably DMF; the reaction temperature is 50-100°C, preferably 80°C. Finally, the intermediate obtained above is hydrolyzed under basic conditions to remove the ester group. Suitable bases include sodium hydroxide, potassium hydroxide, or lithium hydroxide, preferably sodium hydroxide; the reaction solvent is a methanol / water mixture, and the reaction temperature is 20-50°C, preferably 40°C, to obtain the target product.

[0024] When B is selected Structural unit Selected from or The derivative structure shown in general formula (I) is as shown in general formula 14 or general formula 17, specifically: Starting with 6-bromo-1H-indazole 11, alkylation of chain carboxylic acid esters with different halogen substitutions yields compounds 12 or 15. Compounds 12 or 15 are then coupled with trimethylsilylacetylene via a Sonogashira coupling reaction to introduce an alkynyl structure. Subsequently, the trimethylsilylate group is removed using tetrabutylammonium fluoride to obtain alkynyl intermediates 13 or 16. Intermediate 13 or 16 is then reacted with para-substituted azidebenzene (prepared from bromobenzenes with different substitutions via sodium azide) in a click chemistry reaction to obtain a key triazole intermediate. Finally, the ester group is removed under alkaline conditions to obtain the target compound.

[0025] Furthermore, starting with compound 6-bromo-1H-indazole 11, compounds 12 or 15 are obtained through nucleophilic substitution reactions with different halogenating agents under basic conditions. Suitable bases include sodium hydride, cesium carbonate, potassium carbonate, sodium carbonate, or sodium bicarbonate, with sodium hydride being preferred; the reaction solvent can be acetonitrile, DMF, tetrahydrofuran, or acetone, with DMF being preferred; the reaction temperature is 0-100°C, preferably 0°C. Compound 12 or 15 undergoes a coupling reaction with trimethylsilylacetylene under the catalysis of dichlorobis(triphenylphosphine)palladium, cuprous iodide, and triethylamine to obtain the corresponding intermediates. This reaction is carried out at 60-100°C, preferably 80°C; the solvent used can be DMF, 1,4-dioxane, or DMSO, with DMF being preferred. The obtained intermediate is deprotected from the trimethylsilyl protecting group at room temperature under the action of tetrabutylammonium fluoride to give compound 13 or 16. The solvent for this step can be tetrahydrofuran, methanol, ethanol, acetonitrile, or ethyl acetate, preferably methanol. Separately, bromobenzenes with different para-substituted forms are reacted with sodium azide in dimethyl sulfoxide at high temperature (80–110°C, preferably 95°C) and catalyzed by cuprous iodide, sodium ascorbate, and N,N'-dimethylethylenediamine to prepare the corresponding substituted azidebenzenes. Compound 13 or 16 is then added to the reaction system, and a click cycloaddition reaction yields the key intermediate. Finally, the obtained intermediate is hydrolyzed under alkaline conditions to remove the ester group. Suitable bases include sodium hydroxide, potassium hydroxide, or lithium hydroxide, preferably sodium hydroxide; the reaction solvent is a methanol / water mixture, and the reaction temperature is 20–50°C, preferably 40°C, to obtain the target product. Detailed Implementation

[0026] The examples are intended to illustrate, and not limit, the scope of the invention. The proton NMR spectra of the compounds were determined using a Bruker ARX-400; all reagents used were of analytical or chemically pure grade.

[0027] The specific implementation structure is as follows: The preparation route of Example 1 is shown below: The specific synthesis steps are as follows: Synthesis of Compound 2 Compound 1 (5 g), trimethylsilylacetylene (4.76 mL), triethylamine (11.48 mL), cuprous iodide (0.64 g), and dichlorobis(triphenylphosphine)palladium (0.59 g) were dissolved in DMF (30 mL). Under nitrogen protection, the reaction mixture was heated to 80 °C and stirred for 8 hours. After the reaction was complete as monitored by TLC, the reaction solution was cooled to room temperature, poured into water (300 mL), stirred for 10 minutes, and then extracted with ethyl acetate. The combined organic phases were concentrated under reduced pressure, dried under vacuum, and dissolved directly in anhydrous methanol (10 mL) without purification. Tetrabutylammonium fluoride (10 mL) in 1 M tetrahydrofuran solution was added. The reaction was stirred at room temperature for 1.5 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography to give a yellow oily compound 5 (2.96 g), with a yield of 81.76%.

[0028] Synthesis of Compound 3 p-Isopropylbromobenzene (0.5 mg), sodium azide (0.31 mg), cuprous iodide (0.05 g), and sodium ascorbate (0.05 g) were dissolved in a mixed solvent of DMSO and water (DMSO / H2O = 9 / 1, 10 mL). The reaction system was heated to 95 °C and stirred for 5 hours. After the reaction was confirmed to be complete by TLC, anhydrous copper sulfate (0.59 g), sodium ascorbate (1.40 g), and water (5 mL) were added directly to the reaction solution without separating the intermediates. Then, compound 5 was added, and the reaction was continued at 95 °C for 0.5 hours. After the reaction was confirmed to be complete by TLC, the reaction mixture was cooled to room temperature, and the precipitated brownish-yellow solid was collected by filtration. The crude product was purified by column chromatography to obtain a yellow solid product, compound 3 (0.97 g), with a yield of 86.67%.

[0029] Synthesis of Compound 4 Compound 3 (2 g) was dissolved in ethyl acetate (5 mL), followed by the addition of hydrochloric acid-ethyl acetate solution (5 mL). The reaction mixture was stirred at room temperature for 12 hours, and TLC monitoring showed that the reaction was complete. The resulting dark brown solid, compound 4 (1.86 g), was collected by direct filtration, with a yield of 93.00%.

[0030] 4-(5-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)propionic acid Compound 4 (200 mg) was dissolved in DMF (5 mL). Triethylamine (328.48 μL) and methyl 4-bromobutyrate (86.84 mg) were then added to the reaction solution. After confirming the reaction was complete by TLC, the reaction solution was cooled to room temperature and poured into water (50 mL). The mixture was stirred for 10 minutes and then extracted with ethyl acetate. The extract was concentrated under reduced pressure to remove the organic solvent. A 1 / 1 ratio of 2M sodium hydroxide aqueous solution and methanol was added. After confirming the reaction was complete by TLC, the reaction solution was concentrated under reduced pressure to remove methanol. Hydrochloric acid aqueous solution was added to adjust the pH to 2-3. The mixture was filtered to obtain a white product 5 (100 mg), with a yield of 41.12%. 1 H NMR (400 MHz, DMSO-) d 6) δ 9.22 (s, 1H), 7.88 – 7.83 (m, 2H), 7.83 – 7.75 (m, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 7.8 Hz, 1H), 3.93 (d, J = 13.6 Hz, 4H), 2.95 (t, J = 7.1 Hz, 2H), 2.56 (s, 2H), 1.99 (dt, J = 14.3, 7.3 Hz, 1H), 1.89(dq, J = 13.5, 6.7 Hz, 2H), 0.91 (s, 3H), 0.89 (s, 3H). Calcd. for C 23 H 25 N4O2 - [MH] - 389.2056; found.389.1956. Example 2 4-(5-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)butyric acid Following the method of Example 1, a white solid was obtained with a yield of 36.25%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.22 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.81 (s, 1H), 7.78 (d, J= 7.8 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 7.8 Hz, 1H), 3.91 (d, J = 13.6 Hz, 4H), 2.71 (t, J = 7.0 Hz, 2H), 2.55 (d, J = 7.1 Hz, 2H), 2.32 (t, J = 7.2 Hz, 2H), 1.90 (dt, J = 13.4, 6.8 Hz, 1H), 1.76 (p, J = 7.2 Hz, 2H), 0.90 (d, J = 6.6 Hz, 6H). Calcd. for C 24 H 27 N4O2 - [MH] - 403.2212; found.403.2155. Example 3 2-(5-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)ethane-1-ol Following the method of Example 1, a white solid was obtained with a yield of 53.62%. 1 H NMR (400 MHz, DMSO- d 6) δ9.22 (s, 1H), 7.87 – 7.83 (m, 2H), 7.81 (s, 1H), 7.78 (dd, J = 7.7, 1.6 Hz,1H), 7.43 – 7.39 (m, 2H), 7.35 (d, J = 7.8 Hz, 1H), 4.56 (s, 1H), 3.95 (d, J =13.0 Hz, 4H), 3.59 (q, J = 6.5, 6.0 Hz, 2H), 2.80 (t, J = 6.2 Hz, 2H), 2.55 (d, J = 7.1 Hz, 2H), 1.93 – 1.85 (m, 1H), 0.90 (d, J= 6.6 Hz, 6H). Calcd. for C 22 H 27 N4O2Na + [M+Na] + 385.2107; found.385.1936. Example 4 3-(5-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)propane-1,2-diol Following the method of Example 1, a white solid was obtained with a yield of 21.25%. 1 H NMR (400 MHz, DMSO- d 6) δ9.22 (s, 1H), 7.87 – 7.83 (m, 2H), 7.81 (s, 1H), 7.78 (dd, J = 7.7, 1.5 Hz,1H), 7.43 – 7.40 (m, 2H), 7.35 (d, J = 7.8 Hz, 1H), 4.57 (s, 1H), 3.96 (d, J =12.6 Hz, 4H), 3.67 (t, J = 6.0 Hz, 1H), 3.39 (t, J = 5.9 Hz, 2H), 2.83 (dd, J =12.2, 4.9 Hz, 1H), 2.65 (dd, J = 12.3, 7.0 Hz, 1H), 2.55 (d, J = 7.2 Hz, 2H),2.04 – 1.94 (m, 1H), 1.93 – 1.86 (m, 1H), 0.90 (d, J = 6.6 Hz, 6H). Calcd. for C 23 H 28 N4O2Na + [M+Na] + 415.2212; found.415.2143. Example 5 3-(5-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)cyclopentane-1-carboxylic acid After obtaining compound 4 according to the method in Example 1, compound 4 (150 mg) was dissolved in 1,2-dichloromethane (5 mL). Then, methyl 3-oxocyclopentacarboxylate (94.49 mg), acetic acid (232.15 mg), and sodium triacetoxyborohydride (149.42 mg) were added to the reaction solution. After confirming the reaction was complete by TLC, the reaction solution was cooled to room temperature, poured into water (50 mL), and stirred for 10 minutes. The solution was then extracted with ethyl acetate. The extract was concentrated under reduced pressure to remove the organic solvent. A 1 / 1 ratio of 2M sodium hydroxide aqueous solution and methanol was added. After confirming the reaction was complete by TLC, the reaction solution was concentrated under reduced pressure to remove methanol. Hydrochloric acid aqueous solution was added to adjust the pH to 2-3. The product was obtained by filtration, yielding an off-white product with a yield of 30.12%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.21 (s, 1H), 7.88 – 7.74 (m, 4H), 7.41 (d, J = 8.0 Hz, 2H), 7.35(d, J = 7.8 Hz, 1H), 3.89 (d, J = 12.9 Hz, 4H), 3.05 – 2.97 (m, 1H), 2.87 (s,1H), 2.55 (d, J = 7.2 Hz, 2H), 2.01 – 1.96 (m, 2H), 1.88 (s, 2H), 1.76 (s,1H), 1.60 (s, 1H), 1.46 (s, 1H), 0.90 (d, J = 6.5 Hz, 6H). Calcd. for C 26 H 29 N4O2 - [MH] - 429.2369; found.429.2312. Example 6 4-(5-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)cyclohexane-1-carboxylic acid Following the method of Example 5, a white solid was obtained with a yield of 31.66%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.21 (s, 1H), 7.85 (d, J= 8.1 Hz, 2H), 7.80 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 7.8 Hz, 1H), 3.87 (d, J = 13.5 Hz, 4H), 2.67 (d, J = 6.4 Hz, 2H), 2.55 (d, J = 7.1 Hz, 2H), 2.26 (d, J = 7.2 Hz, 2H),2.01 – 1.95 (m, 1H), 1.89 (d, J = 6.7 Hz, 1H), 1.57 (dd, J = 15.2, 8.7 Hz, 4H), 1.46 (d, J = 8.4 Hz, 1H), 0.90 (d, J = 6.6 Hz, 6H). Calcd. for C 27 H 31 N4O2 - [MH] - 443.2525; found.443.2488. Example 7 4-(5-(1-(4-isopropylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)butyric acid Referring to the method of Example 1, p-isobutylbromobenzene in step b was replaced by p-propylbromobenzene in proportion to obtain Example 7, a white solid with a yield of 38.53%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.36 (s, 1H), 9.31 (s, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.95 (dd, J = 8.2, 2.1 Hz, 1H), 7.90 – 7.84 (m,2H), 7.64 (d, J= 8.3 Hz, 1H), 7.41 – 7.35 (m, 2H), 4.87 (s, 2H), 4.59 (s,2H), 3.43 – 3.39 (m, 2H), 2.94 (p, J = 6.9 Hz, 1H), 2.42 (t, J = 7.3 Hz, 2H), 2.01 (p, J = 7.5 Hz, 2H), 1.25 (s, 3H), 1.23 (s, 3H). Calcd. for C 23 H 25 N4O2 - [MH] - 389.2056; found.389.1971.

[0031] Example 8 5-(5-(1-(3-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)butyric acid Referring to the method of Example 1, replacing p-isobutylbromobenzene in step b with 1-(3-bromophenyl)pyrrole in proportion yielded Example 8, a white solid with a yield of 33.41%. 1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H),9.35 (s, 1H), 7.98 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz,1H), 7.36 (t, J = 8.1 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 2.4 Hz,1H), 6.65 (dd, J = 8.3, 2.3 Hz, 1H), 4.68 (s, 4H), 3.38 (t, J = 7.9 Hz, 6H), 2.41 (t, J = 7.3 Hz, 2H), 2.06 – 1.96 (m, 6H). Calcd. for C24H26N5O2- [MH]-416.2165; found.416.2079. Example 9 5-(5-(1-(3-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)valeric acid Referring to the method of Example 1, the p-isobutylbromobenzene in step b was replaced by 1-(3-bromophenyl)pyrrole in proportion to obtain Example 9, a white solid with a yield of 37.42%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.22 (s, 1H), 7.83– 7.76 (m, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.9 Hz, 1H), 7.02 (s,1H), 6.66 – 6.62 (m, 1H), 3.88 (d, J = 13.9 Hz, 4H), 2.69 (t, J = 6.6 Hz, 2H), 2.27 (t, J = 7.0 Hz, 2H), 1.99 (q, J = 3.3 Hz, 5H), 1.91 (s, 2H), 1.66 – 1.47(m, 5H). Calcd. for C 25 H 28 N5O2 - [MH] - 430.2321; found.430.2249. Example 10 4-(5-(1-(4-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)butyric acid Following the method of Example 1, replacing p-isobutylbromobenzene in step b with 1-(4-bromophenyl)pyrrolidine in proportion yielded Example 10, a white solid with a yield of 44.31%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.08 (s, 1H), 9.15 (s, 1H), 7.99 – 7.88 (m, 2H), 7.70 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 7.9Hz, 1H), 6.70 (d, J = 8.6 Hz, 2H), 4.89 – 4.73 (m, 2H), 4.59 – 4.43 (m, 2H), 3.29 (d,J = 6.4 Hz, 4H), 2.31 (t, J = 7.3 Hz, 2H), 2.03 – 1.95 (m, 4H), 1.80(p, J = 8.0 Hz, 2H), 1.59 (p, J = 7.5 Hz, 2H). Calcd. for C 24 H 26 N5O2 - [MH] - 416.2165; found.416.2097. Example 11 5-(5-(1-(4-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)valeric acid Following the method of Example 1, replacing p-isobutylbromobenzene in step b with 1-(4-bromophenyl)pyrrolidine in proportion yielded Example 11, a white solid with a yield of 49.21%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.05 (s, 1H), 7.83 – 7.74 (m, 2H), 7.70 – 7.65 (m, 2H), 7.32 (d, J = 7.7 Hz, 1H), 6.69 (d, J = 8.9 Hz, 2H), 3.87 (d, J = 12.4 Hz, 4H), 2.66 (d, J = 14.5 Hz, 2H), 2.09 (d, J = 7.3 Hz, 2H), 2.02 – 1.97 (m, 4H), 1.72 (s, 6H). Calcd. for C 25 H 28 N5O2 - [MH] - 430.2321; found.430.2235. The preparation route of Example 12 is shown below: Synthesis of Compound 7 Compound 6 (1.4 g), trimethylsilylacetylene (1.99 mL), triethylamine (4.81 mL), cuprous iodide (0.27 g), and dichlorobis(triphenylphosphine)palladium (0.25 g) were dissolved in DMF (15 mL). Under nitrogen protection, the reaction mixture was heated to 80 °C and stirred for 8 hours. After the reaction was complete as monitored by TLC, the reaction solution was cooled to room temperature, poured into water (200 mL), stirred for 10 minutes, and then extracted with ethyl acetate. The combined organic phases were concentrated under reduced pressure, dried under vacuum, and dissolved directly in anhydrous methanol (5 mL) without purification. Tetrabutylammonium fluoride (TBAF, 5 mL) in 1 M tetrahydrofuran solution was added. The reaction was stirred at room temperature for 1.5 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography to give a yellow oily compound 5 (1.02 g), with a yield of 84.76%.

[0032] Synthesis of Compound 8 5-Bromoisoindoline-2-tert-butyl carbonate (1.00 g), sodium azide (0.44 g), cuprous iodide (0.06 g), and sodium ascorbate (0.07 g) were dissolved in a mixed solvent of DMSO and water (DMSO / H2O = 9 / 1, 10 mL). The reaction system was heated to 95 °C and stirred for 5 hours. After the reaction was confirmed to be complete by TLC, anhydrous copper sulfate (0.59 g), sodium ascorbate (1.40 g), and water (5 mL) were added directly to the reaction solution without separating the intermediates. Then, compound 7 (0.50 g) was added, and the reaction was continued at 95 °C for 0.5 hours. After the reaction was confirmed to be complete by TLC, the reaction mixture was cooled to room temperature, and the precipitated brownish-yellow solid was collected by filtration. The crude product was purified by column chromatography to obtain a yellow solid product, compound 8 (0.87 g), with a yield of 85.01%.

[0033] Synthesis of Compound 9 Compound 3 (2.00 g) was dissolved in ethyl acetate (5 mL), followed by the addition of hydrochloric acid-ethyl acetate solution (5 mL). The reaction mixture was stirred at room temperature for 12 hours, and TLC monitoring showed that the reaction was complete. The resulting dark brown solid, compound 4 (1.86 g), was collected by direct filtration, with a yield of 93.00%.

[0034] 3-(5-(4-(4-propylphenyl)-1 H -1,2,3-triazol-1-yl)isoindolin-2-yl)propionic acid Compound 9 (200 mg) was dissolved in DMF (5 mL). Triethylamine (328.48 μL) and methyl 4-bromobutyrate (86.84 mg) were then added to the reaction solution. After confirming the reaction was complete by TLC, the reaction solution was cooled to room temperature and poured into water (50 mL). The mixture was stirred for 10 minutes and then extracted with ethyl acetate. The extract was concentrated under reduced pressure to remove the organic solvent. A 1 / 1 ratio of 2M sodium hydroxide aqueous solution and methanol was added. After confirming the reaction was complete by TLC, the reaction solution was concentrated under reduced pressure to remove methanol. Hydrochloric acid aqueous solution was added to adjust the pH to 2-3. The product was filtered to obtain an off-white product with a yield of 56.32%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.29 (s, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.95 (dd, J = 8.2, 2.1 Hz, 1H), 7.85(d, J = 7.9 Hz, 2H), 7.65 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 4.75(s, 4H), 3.65 (d, J = 7.7 Hz, 2H), 2.92 (t, J = 7.6 Hz, 2H), 2.60 (t, J = 7.6Hz, 2H), 1.63 (h, J = 7.4 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H). Calcd. for C 22 H 23 N4O2 - [MH] - 375.1899; found.375.1824. Example 13 3-(5-(4-(4-propylphenyl)-1 H -1,2,3-triazol-1-yl)isoindolin-2-yl)butyric acid Following the method of Example 12, a white solid was obtained with a yield of 58.25%. 1 H NMR (400 MHz, DMSO- d 6) δ12.10 (s, 1H), 9.30 (s, 1H), 8.03 (d, J= 2.0 Hz, 1H), 7.95 (dd, J = 8.2, 2.0Hz, 1H), 7.86 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 7.9Hz, 2H), 4.87 (td, J = 14.0, 5.1 Hz, 2H), 4.57 (td, J = 14.9, 6.0 Hz, 2H), 2.60(t, J = 7.6 Hz, 2H), 2.31 (t, J = 7.3 Hz, 2H), 1.87 – 1.74 (m, 2H), 1.62 (m,4H), 0.92 (t, J = 7.3 Hz, 3H). Calcd. for C 23 H 25 N4O2 - [MH] - 389.2056; found.389.1982. Example 14 3-(5-(4-(4-isopropylphenyl)-1 H -1,2,3-triazol-1-yl)isoindolin-2-yl)propionic acid Referring to the method of Example 12, p-propylbromobenzene in step a was replaced by p-isopropylbromobenzene in proportion to obtain Example 14, a white solid with a yield of 53.37%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.64 (s, 1H), 9.32 (s, 1H), 8.03 (d, J = 2.1 Hz, 1H), 7.96 (dd, J = 8.2, 2.0 Hz, 1H), 7.89 – 7.84(m, 2H), 7.65 (d, J = 8.3 Hz, 1H), 7.42 – 7.35 (m, 2H), 4.74 (s, 4H), 3.63 (t, J = 7.8 Hz, 2H), 2.94 (p, J= 6.4 Hz, 3H), 1.25 (s, 3H), 1.23 (s, 3H). Calcd.for C 22 H 23 N4O2 - [MH] - 375.1899; found.375.1823. Example 15 3-(5-(4-(4-isopropylphenyl)-1 H -1,2,3-triazol-1-yl)isoindolin-2-yl)butyric acid Referring to the method of Example 12, p-propylbromobenzene in step a was replaced by p-isopropylbromobenzene in proportion to obtain Example 15, a white solid with a yield of 54.66%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.36 (s, 1H), 9.31 (s, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.95 (dd, J = 8.2, 2.1 Hz, 1H), 7.90 – 7.84(m, 2H), 7.64 (d, J = 8.3 Hz, 1H), 7.41 – 7.35 (m, 2H), 4.87 (s, 2H), 4.59 (s,2H), 3.43 – 3.39 (m, 2H), 2.94 (p, J = 6.9 Hz, 1H), 2.42 (t, J = 7.3 Hz, 2H), 2.01 (p, J = 7.5 Hz, 2H), 1.25 (s, 3H), 1.23 (s, 3H). Calcd. for C 23 H 25 N4O2 - [MH] - 389.2056; found.389.1981. Example 16 3-(5-(4-(4-tert-butylphenyl)-1 H -1,2,3-triazol-1-yl)isoindolin-2-yl)propionic acid Referring to the method of Example 12, p-propylbromobenzene in step a was replaced by p-tert-butylbromobenzene in proportion to obtain Example 16, a white solid with a yield of 48.71%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.49 (s, 1H), 9.31 (s, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.96 (dd, J = 8.2, 2.1 Hz, 1H), 7.89 – 7.84(m, 2H), 7.65 (d, J = 8.3 Hz, 1H), 7.56 – 7.50 (m, 2H), 4.74 (s, 4H), 3.63 (t, J = 7.7 Hz, 2H), 2.92 (t, J = 7.7 Hz, 2H), 1.32 (s, 9H). Calcd. for C 23 H 25 N4O2 - [MH] - 389.2056; found. 389.1982. Example 17 5-(5-(4-(4-tert-butylphenyl)-1 H -1,2,3-triazol-1-yl)isoindolin-2-yl)valeric acid Referring to the method of Example 12, p-propylbromobenzene in step a was replaced by p-tert-butylbromobenzene in proportion to obtain Example 17, a white solid with a yield of 51.63%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.25 (s, 1H), 7.90 –7.85 (m, 2H), 7.83 (d, J = 2.0 Hz, 1H), 7.77 (dd, J = 8.0, 2.1 Hz, 1H), 7.53 –7.49 (m, 2H), 7.46 (d, J = 8.1 Hz, 1H), 3.90 (d, J = 13.7 Hz, 4H), 2.66 (s,2H), 2.02 (d, J= 7.3 Hz, 2H), 1.71 (s, 2H), 1.32 (s, 9H). Calcd. forC 24 H 27 N4O2 - [MH] - 403.2212; found.403.2137. The preparation route of Example 18 is shown below: Synthesis of Compound 20 Compound 1 (5.00 g), zinc cyanide (2.95 g), and tetraphenylphosphine palladium (0.97 g) were dissolved in DMF (15 mL). Under nitrogen protection, the reaction mixture was heated to 95 °C and stirred for 8 hours. After the reaction was complete as monitored by TLC, the reaction solution was cooled to room temperature, poured into water (200 mL), and stirred for 10 minutes, followed by extraction with ethyl acetate. The reaction solution was concentrated under reduced pressure to remove the solvent, and the crude product was purified by column chromatography to give a white solid, compound 20 (3.52 g), in 86.06% yield.

[0035] Synthesis of Compound 21 Compound 20 (5.00 g) was dissolved in DMSO (5 mL), followed by the sequential addition of 30% H₂O₂ (2.79 mL) and potassium carbonate (2.83 g). The reaction was carried out at room temperature for 1 hour. After the reaction was completed by TLC monitoring, the reaction solution was cooled to room temperature, poured into water (200 mL), and stirred for 10 minutes, followed by extraction with ethyl acetate. The reaction solution was concentrated under reduced pressure to remove the solvent, giving a white product 21 (5.26 g) in 98.00% yield.

[0036] Synthesis of Compound 22 Compound 21 (1.00 g) was dissolved in tetrahydrofuran (5 mL), Lawson's reagent (0.77 g) was added, and the mixture was heated to 55 °C and reacted for 5 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure to remove the solvent and obtain a crude product. The crude product was then slurried with ethyl acetate and filtered to obtain product 22 (0.64 g), with a yield of 60.95%.

[0037] Synthesis of Compound 23 Compound 22 (500 mg) and p-isopropylphenylacetyl bromide (458.29 mg) were dissolved in ethanol and reacted at reflux for 2 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure to remove the solvent. Hydrochloric acid-ethyl acetate was added directly without treatment, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the solid product was directly filtered, reconstituted with water, and the pH was adjusted to 10-12. Then, it was extracted with ethyl acetate. The reaction solution was concentrated under reduced pressure to remove the solvent, giving an off-white solid (386.52 mg), with a yield of 64.41%.

[0038] 4-(5-(5-(4-isobutylphenyl)thiazolyl)isoindoline-2-yl)butyric acid Compound 23 (320.00 mg) was dissolved in DMF (5 mL). Triethylamine (390.00 μL) and methyl 4-bromobutyrate (133.80 mg) were then added to the reaction solution. After confirming the reaction was complete by TLC, the reaction solution was cooled to room temperature and poured into water (50 mL). The mixture was stirred for 10 minutes and then extracted with ethyl acetate. The extract was concentrated under reduced pressure to remove the organic solvent. A 1 / 1 ratio of 2M sodium hydroxide aqueous solution and methanol was added. After confirming the reaction was complete by TLC, the reaction solution was concentrated under reduced pressure to remove methanol. Hydrochloric acid aqueous solution was added to adjust the pH to 2-3. The product was filtered to obtain an off-white product with a yield of 51.32%. 1 H NMR (400MHz, DMSO- d 6) δ 11.81 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 8.03 (d, J = 8.0Hz, 1H), 7.97 (s, 1H), 7.95 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.26 (s, 1H), 4.88 (td, J = 14.1, 5.5 Hz, 2H), 4.59 – 4.53 (m, 2H), 3.39 (d, J = 4.4 Hz, 2H), 2.40 (d, J = 7.2 Hz, 2H), 2.06 – 1.92 (m, 3H), 1.87 (dq, J =13.5, 6.7 Hz, 2H), 0.90 (s, 3H), 0.88 (s, 3H). Calcd. for C 25 H 27 N2O2S - [MH]- 419.1817; found.419.1710. Example 19 5-(5-(5-(4-isobutylphenyl)thiazolyl)isoindoline-2-yl)valeric acid Following the method of Example 18, a white solid was obtained with a yield of 61.34%. 1 H NMR (400 MHz, DMSO- d 6) δ11.52 (s, 1H), 8.15 (d, J = 12.0 Hz, 1H), 8.10 – 8.01 (m, 2H), 7.96 (d, J = 8.0Hz, 2H), 7.57 (t, J = 9.9 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 4.87 (td, J = 14.4,5.1 Hz, 2H), 4.61 – 4.48 (m, 2H), 2.54 (s, 4H), 2.32 (t, J = 7.2 Hz, 2H), 1.88(dt, J = 13.5, 6.7 Hz, 1H), 1.78 (s, 2H), 1.61 (q, J = 7.4 Hz, 2H), 0.91 (dd, J = 12.1, 6.6 Hz, 6H). Calcd. for C 26 H 29 N2O2S - [MH] - 433.2028; found.433.1882. Example 20 5-(5-(5-(4-ethylphenyl)thiazo-2-yl)isoindoline-2-yl)butyric acid Referring to the method of Example 18, p-isopropylphenylacetyl bromide in step i was replaced by p-ethylphenylacetyl bromide in proportion to obtain Example 20, a white solid with a yield of 52.41%. 1 H NMR (400 MHz, DMSO- d 6) δ 8.06 (s, 1H), 7.96 (d, J= 8.0 Hz, 2H), 7.90 (s, 1H), 7.87 (dd, J = 7.8, 1.6 Hz, 1H), 7.38(d, J = 7.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 3.93 (d, J = 13.7 Hz, 4H), 2.72(t, J = 7.1 Hz, 2H), 2.65 (q, J = 7.6 Hz, 2H), 2.32 (t, J = 7.2 Hz, 2H), 1.76(p, J = 7.2 Hz, 2H), 1.23 (d, J = 7.5 Hz, 3H). Calcd. for C 23 H 23 N2O2S - [MH] - 391.1558; found.391.391 Example 21 5-(5-(5-(4-ethylphenyl)thiazo-2-yl)isoindoline-2-yl)valeric acid Following the method of Example 20, a white solid was obtained with a yield of 56.08%. 1 H NMR (400 MHz, DMSO- d 6) δ12.00 (s, 1H), 8.11 (s, 1H), 8.02 (s, 1H), 7.97 (d, J = 7.8 Hz, 3H), 7.49 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 7.8 Hz, 2H), 4.42 (d, J = 11.3 Hz, 4H), 3.14 (s,2H), 2.66 (q, J = 7.5 Hz, 2H), 2.30 (t, J = 7.3 Hz, 2H), 1.79 – 1.66 (m, 2H), 1.59 (p, J = 7.4 Hz, 2H), 1.23 (d, J= 6.8 Hz, 3H). Calcd. for C 24 H 25 N2O2S - [MH] - 405.1715; found.405.1537. Example 22 3-(5-(5-(3,4-dimethylphenyl)thiazolyl)isoindoline-2-yl)butyric acid Referring to the method of Example 18, the p-isopropylphenylacetyl bromide in step i was replaced by 2-bromo-3',4'-dimethylbenzene in proportion to obtain Example 22, an off-white solid with a yield of 52.21%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.06 (s, 1H), 8.09 (d, J = 8.1 Hz, 2H), 8.02 (dd, J = 7.9, 1.7 Hz, 1H), 7.85 (d, J =1.9 Hz, 1H), 7.77 (dd, J = 7.8, 1.9 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.24(d, J = 7.9 Hz, 1H), 4.86 (s, 2H), 4.57 (s, 2H), 3.40 (t, J = 8.1 Hz, 2H), 2.41(t, J = 7.3 Hz, 2H), 2.31 (s, 3H), 2.27 (s, 3H), 2.00 (p, J = 7.5 Hz, 2H). Calcd. for C 23 H 23 N2O2S - [MH] - 391.1558; found.391.1404. The preparation route of Example 23 is shown below: 4-(6-(1-(4-propylphenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid Synthesis of Compound 12 Compound 11 (10.00 g) was dissolved in DMF (20 mL), and sodium hydride (2.44 g) was added in portions at low temperature. After reacting for half an hour, methyl 4-bromobutyrate (9.32 g) was slowly added. After the reaction was completed by TLC monitoring, the reaction solution was cooled to room temperature, poured into water (200 mL), and stirred for 10 minutes, followed by extraction with ethyl acetate. The reaction solution was concentrated under reduced pressure to remove the solvent, and the crude product was purified by column chromatography to give compound 12 (9.68 g) as a white solid, with a yield of 64.06%.

[0039] Synthesis of compounds 13 and 14 The reaction steps are the same as steps a and b above.

[0040] Synthesis of Compound 15 Compound 14 was dissolved in a 1:1 mixture of 2M sodium hydroxide aqueous solution and methanol. The reaction was confirmed to be complete by TLC monitoring. The reaction solution was concentrated under reduced pressure to remove methanol. Hydrochloric acid aqueous solution was added to adjust the pH to 2-3. The product was obtained by filtration and was off-white with a yield of 51.32%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.16 (s, 1H), 9.33 (s, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 7.88 (d, J = 8.0 Hz, 3H), 7.74 (d, J = 8.4 Hz, 1H), 7.47 (d, J =7.9 Hz, 2H), 4.51 (d, J = 7.9 Hz, 2H), 2.66 (t, J = 7.5 Hz, 2H), 2.29 (s, 2H), 2.11 (s, 2H), 1.66 (h, J = 7.4 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H). Calcd. for C 22 H 22 N5O2 - [MH] - 388.1852; found.388.1692. Example 24 4-(6-(1-(4-tert-butylphenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 59.16%. 1 H NMR (400 MHz, DMSO- d 6) δ9.35 (s, 1H), 8.22 (s, 1H), 8.09 (s, 1H), 7.92 – 7.85 (m, 3H), 7.75 (d, J =8.4 Hz, 1H), 7.65 (d, J = 7.1 Hz, 2H), 4.48 (s, 2H), 2.09 (s, 2H), 1.35 (s,9H). Calcd. for C 23 H 24 N5O2 - [MH] - 402.2008; found.402.1865. Example 25 4-(6-(1-(4-isopropoxyphenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 56.08%. 1 H NMR (400 MHz, DMSO- d 6) δ9.31 (s, 1H), 8.21 (s, 1H), 8.05 (s, 1H), 7.98 – 7.79 (m, 3H), 7.73 (d, J =8.4 Hz, 1H), 7.15 (d, J = 6.9 Hz, 2H), 4.71 (p, J = 6.0 Hz, 1H), 4.45 (s, 2H), 2.25 – 1.78 (m, 4H), 1.31 (d, J = 5.9 Hz, 6H). Calcd. for C 22 H 22 N5O3 - [MH] - 404.1801; found.404.1665. Example 26 4-(6-(1-(4-isopropylphenyl)-1 H-1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 61.38%. 1 H NMR (400 MHz, DMSO- d 6) δ12.16 (s, 1H), 9.33 (s, 1H), 8.23 ​​(s, 1H), 8.11 (s, 1H), 7.89 (dd, J = 8.5, 2.3 Hz, 3H), 7.74 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 4.51 (t, J =6.8 Hz, 2H), 3.01 (p, J = 6.9 Hz, 1H), 2.27 (t, J = 7.1 Hz, 2H), 2.11 (p, J =6.9 Hz, 2H), 1.27 (d, J = 6.9 Hz, 6H). Calcd. for C 22 H 22 N5O2 - [MH] - 388.1852; found.388.1728. Example 27 4-(6-(1-(4-ethoxyphenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 65.03%. 1 H NMR (400 MHz, DMSO- d 6) δ12.16 (s, 1H), 9.33 (s, 1H), 8.23 ​​(s, 1H), 8.11 (s, 1H), 7.89 (dd, J = 8.5, 2.3 Hz, 3H), 7.74 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 4.51 (t,J =6.8 Hz, 2H), 3.01 (p, J = 6.9 Hz, 1H), 2.27 (t, J = 7.1 Hz, 2H), 2.11 (p, J =6.9 Hz, 2H), 1.27 (d, J = 6.9 Hz, 6H). Calcd. for C 21 H 20 N5O3 - [MH] - 390.1644.1961; found.390.1527. Example 28 4-(6-(1-(3-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 63.47%. 1 H NMR (400 MHz, DMSO- d 6) δ9.36 (s, 1H), 8.41 (s, 1H), 8.19 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.37 (t, J = 8.1 Hz, 1H), 7.15 (dd, J = 7.7, 1.9 Hz, 1H), 7.06(d, J = 2.3 Hz, 1H), 6.65 (dd, J = 8.3, 2.3 Hz, 1H), 4.47 (t, J = 6.5 Hz, 2H),3.39 (s, 4H), 2.23 – 2.18 (m, 2H), 2.16 – 2.11 (m, 2H), 2.04 – 1.97 (m, 4H).Calcd. for C 23 H 23 N6O2 - [MH] - 415.1961; found.415.1850. Example 29 4-(6-(1-(4-morpholinylphenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 59.29%. 1 H NMR (400 MHz, DMSO- d 6) δ12.22 (s, 1H), 9.24 (s, 1H), 8.21 (s, 1H), 8.10 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 8.2 Hz,2H), 4.50 (s, 2H), 3.78 (t, J = 4.6 Hz, 4H), 3.22 (t, J = 4.9 Hz, 4H), 2.47 –2.19 (m, 2H), 2.11 (s, 2H). Calcd. for C 23 H 23 N6O3 - [MH] - 431.1910; found. 431.1797. Example 30 4-(6-(1-(4-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 53.49%. 1 H NMR (400 MHz, DMSO- d 6) δ12.22 (s, 1H), 9.24 (s, 1H), 8.21 (s, 1H), 8.10 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.73 (d, J= 8.4 Hz, 1H), 7.17 (d, J = 8.2 Hz,2H), 4.50 (s, 2H), 3.78 (t, J = 4.6 Hz, 4H), 3.22 (t, J = 4.9 Hz, 4H), 2.47 –2.19 (m, 2H), 2.11 (s, 2H). Calcd. for C 23 H 23 N6O2 - [MH] - 415.1961; found.415.1880. Example 31 4-(6-(1-(4-(4-propylpiperazin-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 57.34%. 1 H NMR (400 MHz, DMSO- d 6) δ12.22 (s, 1H), 9.24 (s, 1H), 8.21 (s, 1H), 8.10 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 8.2 Hz,2H), 4.50 (s, 2H), 3.78 (t, J = 4.6 Hz, 4H), 3.22 (t, J = 4.9 Hz, 4H), 2.47 –2.19 (m, 2H), 2.11 (s, 2H). Calcd. for C 26 H 30 N7O2 - [MH] - 472.2539; found.472.2470. Example 32 4-(6-(1-(4-cyclohexylphenyl)-1 H -1,2,3-triazol-4-yl)-1H -Indazole-1-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 56.39%. 1 H NMR (400 MHz, DMSO- d 6) δ12.22 (s, 1H), 9.24 (s, 1H), 8.21 (s, 1H), 8.10 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 8.2 Hz,2H), 4.50 (s, 2H), 3.78 (t, J = 4.6 Hz, 4H), 3.22 (t, J = 4.9 Hz, 4H), 2.47 –2.19 (m, 2H), 2.11 (s, 2H). Calcd. for C 25 H 26 N5O2 - [MH] - 428.2165; found.428.2087 Example 33 4-(6-(1-(4-propylphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 63.33%. 1 H NMR (400 MHz, DMSO- d 6) δ12.13 (s, 1H), 9.30 (s, 1H), 8.41 (s, 1H), 8.18 (s, 1H), 7.89 – 7.85 (m, 2H),7.83 (d, J = 8.7 Hz, 1H), 7.67 (dd, J = 8.6, 1.3 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 4.48 (t, J= 6.7 Hz, 2H), 2.66 (t, J = 7.6 Hz, 2H), 2.25 (d, J = 6.5 Hz, 2H), 2.17 (p, J = 7.7, 7.0 Hz, 2H), 1.66 (dt, J = 14.9, 7.4 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H). Calcd. for C 22 H 22 N5O2 - [MH] - 388.1852; found.388.1779. Example 34 4-(6-(1-(4-tert-butylphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 64.35%. 1 H NMR (400 MHz, DMSO- d 6) δ9.30 (s, 1H), 8.40 (s, 1H), 8.19 (s, 1H), 7.88 (t, J = 7.2 Hz, 3H), 7.82 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 8.2 Hz, 2H), 4.48 (d, J = 5.7 Hz, 2H), 2.19 – 2.12(m, 4H), 1.35 (s, 9H). Calcd. for C 23 H 24 N5O2 - [MH] - 402.2008; found. 402.1939. Example 35 4-(6-(1-(4-isopropoxyphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 69.75%. 1 H NMR (400 MHz, DMSO- d 6) δ9.22 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 7.83 (t, J = 9.7 Hz, 3H), 7.68 –7.63 (m, 1H), 7.20 – 7.13 (m, 2H), 4.72 (p, J = 6.0 Hz, 1H), 4.47 (s, 2H), 2.21 (d, J = 31.6 Hz, 4H), 1.32 (d, J = 6.0 Hz, 6H). Calcd. for C 22 H 22 N5O3 - [MH] - 404.1801; found. 404.1726. Example 36 4-(6-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 67.51%. 1 H NMR (400 MHz, DMSO- d 6) δ12.17 (s, 1H), 9.29 (s, 1H), 8.41 (s, 1H), 8.18 (s, 1H), 7.85 (q, J = 8.6, 8.2Hz, 3H), 7.66 (t, J = 6.3 Hz, 1H), 7.42 (d, J = 7.6 Hz, 2H), 4.47 (q, J = 6.5, 6.1 Hz, 2H), 2.55 (d, J = 7.2 Hz, 2H), 2.24 (q, J = 7.0, 6.3 Hz, 2H), 2.16 (q, J = 6.8 Hz, 2H), 1.89 (dq, J= 13.0, 6.5 Hz, 1H), 0.90 (d, J = 6.7 Hz, 6H). Calcd. for C 23 H 24 N5O2 - [MH] - 402.2008; found.402.1935. Example 37 4-(6-(1-(4-isopropylphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 63.67%. 1 H NMR (400 MHz, DMSO- d 6) δ12.17 (s, 1H), 9.28 (s, 1H), 8.40 (s, 1H), 8.18 (s, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.82 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 4.48 (t, J = 6.7 Hz, 2H), 3.00 (hept, J = 6.9 Hz, 1H), 2.25 (t, J = 7.3 Hz, 2H), 2.16 (p, J = 7.7, 7.1 Hz, 2H), 1.26 (d, J = 6.9 Hz, 6H). Calcd. for C 22 H 22 N5O2 - [MH] - 388.1852; found.388.1776. Example 38 4-(6-(1-(4-ethoxyphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 66.91%. 1 H NMR (400 MHz, DMSO- d 6) δ9.29 (s, 1H), 8.42 (s, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.84 (dd, J = 22.7, 8.7Hz, 3H), 7.66 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 9.0 Hz, 2H), 4.48 (t, J = 7.0Hz, 2H), 4.13 (q, J = 7.0 Hz, 2H), 2.33 (d, J = 3.5 Hz, 2H), 2.02 (d, J = 7.4Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H). Calcd. for C 21 H 20 N5O3 - [MH] - 390.1644.1961;found.390.1570. Example 39 4-(6-(1-(3-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 57.96%. 1 H NMR (400 MHz, DMSO- d 6) δ12.13 (s, 1H), 9.33 (s, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.14 (d, J = 7.9 Hz,1H), 7.05 (s, 1H), 6.66 (d, J= 8.4 Hz, 1H), 4.51 (t, J = 6.9 Hz, 2H), 2.26 (t, J = 7.3 Hz, 2H), 2.11 (q, J = 7.1 Hz, 2H), 2.04 – 1.91 (m, 4H). Calcd. forC 23 H 23 N6O2 - [MH] - 415.1961; found.415.1887. Example 40 4-(6-(1-(4-morpholinophenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 67.63%. NMR (400 MHz, DMSO- d 6) δ12.14 (s, 1H), 9.20 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 7.80 (t, J = 9.3 Hz, 3H), 7.66 (d, J = 8.7 Hz, 1H), 7.16 (d, J = 8.7 Hz, 2H), 4.48 (t, J = 6.7 Hz, 2H), 3.77 (t, J = 4.8 Hz, 4H), 3.22 (t, J = 4.8 Hz, 4H), 2.25 (t, J = 7.3 Hz, 2H), 2.16 (p, J = 7.4, 7.0 Hz, 2H). Calcd. for C 23 H 23 N6O3 - [MH] - 431.1910; found. 431.1838. Example 41 4-(6-(1-(4-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 54.78%. 1 H NMR (400 MHz, DMSO- d 6) δ12.16 (s, 1H), 9.11 (s, 1H), 8.39 (s, 1H), 8.16 (d, J = 1.3 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.76 – 7.68 (m, 2H), 7.66 (dd, J = 8.7, 1.4 Hz, 1H), 6.76 –6.67 (m, 2H), 4.47 (t, J = 6.8 Hz, 2H), 3.30 (t, J = 6.6 Hz, 4H), 2.25 (dd, J =7.8, 5.6 Hz, 2H), 2.20 – 2.11 (m, 2H), 2.04 – 1.93 (m, 4H). Calcd. forC 23 H 23 N6O2 - [MH] - 415.1961; found.415.1880. Example 42 4-(6-(1-(4-(4-propylpiperazin-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 53.51%. 1 H NMR (400 MHz, DMSO- d 6) δ11.07 (s, 1H), 9.25 (s, 1H), 8.41 (s, 1H), 8.17 (s, 1H), 7.84 (d, J = 8.5 Hz, 3H), 7.67 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 8.7 Hz, 2H), 4.48 (t, J = 6.7 Hz, 2H), 3.95 (d, J= 13.1 Hz, 2H), 3.57 (d, J = 11.8 Hz, 2H), 3.26 (s, 2H), 3.19 –3.12 (m, 2H), 3.11 – 3.05 (m, 2H), 2.25 (t, J = 7.2 Hz, 2H), 2.16 (p, J = 7.0Hz, 2H), 1.83 – 1.74 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). Calcd. for C 26 H 30 N7O2 - [MH] - 472.2539; found.472.2463. Example 43 4-(6-(1-(4-cyclohexylphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 52.75%. 1 H NMR (400 MHz, DMSO- d 6) δ12.21 (s, 1H), 9.37 (s, 1H), 8.42 (s, 1H), 8.19 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.6 Hz, 1H), 7.67 (t, J = 7.3 Hz, 3H), 6.31 (d, J = 4.9 Hz, 1H), 4.48 (t, J = 6.7 Hz, 2H), 2.43 (s, 2H), 2.29 – 2.07 (m, 6H), 1.83 – 1.69(m, 2H), 1.63 (t, J = 5.9 Hz, 2H), 1.23 (s, 2H). Calcd. for C 25 H 26 N5O2 - [MH] - 428.2165; found.428.2159. Example 44 4-(6-(1-(4-cyclopentylphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid Following the method of Example 23, a white solid was obtained with a yield of 53.98%. 1 H NMR (400 MHz, DMSO- d 6) δ9.37 (s, 1H), 8.43 (s, 1H), 8.20 (d, J = 1.2 Hz, 1H), 7.96 – 7.92 (m, 2H), 7.84 (d, J = 8.7 Hz, 1H), 7.71 (dd, J = 8.9, 2.0 Hz, 3H), 6.44 (p, J = 2.3 Hz, 1H), 4.49 (t, J = 6.8 Hz, 2H), 2.72 (ddd, J = 8.0, 6.0, 2.2 Hz, 2H), 2.57 –2.51 (m, 4H), 2.28 – 2.24 (m, 2H), 2.21 – 2.14 (m, 2H), 2.00 (p, J = 7.6 Hz, 2H). Calcd. for C 24 H 24 N5O2 - [MH] - 414.2008; found.414.1934. Example 45: Bioactivity test of some products of the present invention Experimental materials: Flp-In-CHO-S1P1, fetal bovine serum (AUS GeneX), penicillin-streptomycin solution (Cisbio), hygromycin B Gold (Invivogen), cAMP kit (Perkin Elmer), 7.5% bovine serum albumin stabilizer (Perkin Elmer), IBMX (Sigma), HEPES (Gibco), 384-well culture plate (Perkin Elmer), 384-Well Low Dead Volume Microplate (LABCYTE).

[0041] Experimental methods: The Flp-In-CHO-S1P1 cell line was used. F12K culture medium supplemented with 10% fetal bovine serum, 1× penicillin-streptomycin solution, and 800 μg / mL HB reagent was used as the complete medium. 1×HBSS containing 20 mM HEPES, 0.1% BSA, and 500 μM IBMX was used as the detection buffer. The target compound was serially diluted 4-fold with DMSO (starting concentration 1 μM). 100 nL of each solution was added to a 384-well plate using an Echo pipetting system, followed by 15 μL of working buffer containing 8000 target cells. The plate was incubated at 37°C for 10 minutes, then 5 μL of 4×forskolin (final concentration 4 μM) was added, and incubation continued at 37°C for 30 minutes. Then, 5 μL of diluted Eu-cAMP tracer (1:50) and 5 μL of diluted Ulight-anti-cAMP reagent (1:150) were added sequentially. After incubation at room temperature for 1 hour, the cells were read from the plate using an Envision 2105 microplate reader at 665 nm. The signals were detected at wavelengths of 615 nm and 615 nm, and the EC values ​​of the compounds were calculated using Graphpad Prism software. 50 .

[0042] Test results: Table 1. Agonism of compounds on S1P receptor-mediated cAMP inhibition (100 nM) Table 2. Activation of S1P receptor-mediated cAMP inhibition by compounds Discussion: Through extensive and in-depth research, the inventors designed and synthesized a series of previously unreported S1P receptor agonist small molecules. Cellular activity tests of the obtained compounds revealed a number of compounds capable of effectively activating the S1P1 receptor. This lays the foundation for the treatment of S1P receptor-mediated diseases, particularly autoimmune diseases.

Claims

1. An aromatic heterocyclic derivative with S1P receptor regulatory activity, characterized in that: The derivative is a compound of general formula (I) or its geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, as shown in the following compound formula (I): General Formula (I) Where X is selected from C or N; R1 and R2 may be the same or different, and are independently selected from hydrogen, halogen, cyano, amino, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, phenyl, or substituted or unsubstituted 5-7 heteroaryl; R3 is selected independently , , , or Where L is selected from carbonyl, methylene or sulfonyl, n is selected from integers from 0 to 3, and R is selected from carboxyl, hydroxyl, amino or formamide; A is selected from a benzene ring or a 5-9 membered aromatic heterocycle, wherein the heteroatom in the aromatic heterocycle is selected from N, O or S; C is selected from substituted or unsubstituted saturated five-membered heterocycles or five-membered aromatic heterocycles, wherein the heteroatom in the five-membered heterocycle or the five-membered aromatic heterocycle is selected from N, O or S; B is selected from substituted or unsubstituted five-membered aromatic heterocycles, wherein the heteroatom in the five-membered aromatic heterocycle is selected from N, O or S; Alternatively, when C is selected from substituted or unsubstituted saturated five-membered heterocycles, B is selected from... or .

2. The aromatic heterocyclic derivative with S1P receptor regulatory activity according to claim 1, characterized in that: The derivatives shown are compounds of general formula (II) or their geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs. The compounds of general formula (II) are as follows: General Formula (II) R1 and R2 may be the same or different, and are independently selected from hydrogen, halogen, cyano, amino, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, phenyl, or substituted or unsubstituted 5-7 heteroaryl; R3 is selected independently , , , or Where L is selected from carbonyl, methylene or sulfonyl, n is selected from integers from 0 to 3, and R is selected from carboxyl, hydroxyl, amino or formamide; A is selected from benzene rings or 5-9 membered aromatic heterocycles, wherein the heteroatom in the aromatic heterocycle is selected from N, O or S; B is selected from substituted or unsubstituted five-membered aromatic heterocycles. or The heteroatom in the five-membered aromatic heterocycle is selected from N, O or S; Y is independently selected from CH2 or CO; Z is independently selected from CH2 or CO.

3. The aromatic heterocyclic derivative with S1P receptor regulatory activity according to claim 1, characterized in that: The derivative is a compound of general formula (III) or its geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, as shown in the following compounds of general formula (III): General Formula (III) R1 and R2 may be the same or different, and are independently selected from hydrogen, halogen, cyano, amino, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, phenyl, or substituted or unsubstituted 5-7 heteroaryl; R3 is selected independently or Where L is selected from methylene, n is selected from an integer from 1 to 2, and R is selected from carboxyl, hydroxyl, amino, or formamide; A is selected from a benzene ring or a 5-9 membered aromatic heterocycle, wherein the heteroatom in the heteroaryl group is selected from N, O or S; B is selected from substituted or unsubstituted five-membered heteroaryl groups, wherein the heteroatom in the five-membered heteroaryl ring is selected from N, O or S; X is selected from C or N; Y is selected from C, N, O, or S.

4. The aromatic heterocyclic derivative having S1P receptor regulatory activity according to any one of claims 1 to 3, characterized in that: The derivative is a compound of formula II-1, II-2, II-3, III-1 or III-2, or its geometric isomers, enantiomers, diastereomers, pharmaceutically acceptable salts, hydrates, solvates or prodrugs: R1 and R2 may be the same or different, and are independently selected from hydrogen, halogen, cyano, amino, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, phenyl, or substituted or unsubstituted 5-7 heteroaryl; R3 is selected independently , , , or Where L is selected from carbonyl, methylene or sulfonyl, n is selected from integers from 0 to 3, and R is selected from carboxyl, hydroxyl, amino or formamide.

5. The aromatic heterocyclic derivative with S1P receptor regulatory activity according to claim 1, characterized in that: The derivative is: 4-(5-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)propionic acid 4-(5-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)butyric acid 2-(5-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)ethane-1-ol 3-(5-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)propane-1,2-diol 3-(5-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)cyclopentane-1-carboxylic acid 4-(5-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)cyclohexane-1-carboxylic acid 4-(5-(1-(4-isopropylphenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)butyric acid 5-(5-(1-(3-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)butyric acid 5-(5-(1-(3-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)valeric acid 4-(5-(1-(4-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)butyric acid 5-(5-(1-(4-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)isoindolin-2-yl)valeric acid 3-(5-(4-(4-propylphenyl)-1 H -1,2,3-triazol-1-yl)isoindolin-2-yl)propionic acid 3-(5-(4-(4-propylphenyl)-1 H -1,2,3-triazol-1-yl)isoindolin-2-yl)butyric acid 3-(5-(4-(4-isopropylphenyl)-1 H -1,2,3-triazol-1-yl)isoindolin-2-yl)propionic acid 3-(5-(4-(4-isopropylphenyl)-1 H -1,2,3-triazol-1-yl)isoindolin-2-yl)butyric acid 3-(5-(4-(4-tert-butylphenyl)-1 H -1,2,3-triazol-1-yl)isoindolin-2-yl)propionic acid 5-(5-(4-(4-tert-butylphenyl)-1 H -1,2,3-triazol-1-yl)isoindolin-2-yl)valeric acid 4-(5-(5-(4-isobutylphenyl)thiazolyl)isoindoline-2-yl)butyric acid 5-(5-(5-(4-isobutylphenyl)thiazolyl)isoindoline-2-yl)valeric acid 5-(5-(5-(4-ethylphenyl)thiazo-2-yl)isoindoline-2-yl)butyric acid 5-(5-(5-(4-ethylphenyl)thiazo-2-yl)isoindoline-2-yl)valeric acid 3-(5-(5-(3,4-dimethylphenyl)thiazolyl)isoindoline-2-yl)butyric acid 4-(6-(1-(4-propylphenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid 4-(6-(1-(4-tert-butylphenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid 4-(6-(1-(4-isopropoxyphenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid 4-(6-(1-(4-isopropylphenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid 4-(6-(1-(4-ethoxyphenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid 4-(6-(1-(3-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)-1H-indazol-1-yl)butyric acid 4-(6-(1-(4-morpholinylphenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid 4-(6-(1-(4-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid 4-(6-(1-(4-(4-propylpiperazin-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid 4-(6-(1-(4-cyclohexylphenyl)-1 H -1,2,3-triazol-4-yl)-1 H -Indazole-1-yl)butyric acid 4-(6-(1-(4-propylphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(4-tert-butylphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(4-isopropoxyphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(4-isobutylphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(4-isopropylphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(4-ethoxyphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(3-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(4-morpholinophenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(4-(pyrrolidone-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(4-(4-propylpiperazin-1-yl)phenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(4-cyclohexylphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid 4-(6-(1-(4-cyclopentylphenyl)-1 H -1,2,3-triazol-4-yl)-2 H -Indazole-2-yl)butyric acid.

6. A pharmaceutical composition having S1P receptor modulatory activity, characterized in that: The pharmaceutical composition comprises a derivative as described in any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

7. The use of the derivative of any one of claims 1 to 5 or the pharmaceutical composition of claim 6 in the preparation of an S1P receptor modulator, characterized in that: Preferably, the S1P receptor modulator is an S1P1 receptor agonist.

8. The use of the derivative of any one of claims 1 to 5 or the pharmaceutical composition of claim 6 in the preparation of a medicament for the prevention or treatment of diseases related to S1P receptor activity.

9. The application according to claim 8, characterized in that: The disease in question is an autoimmune disease.

10. The application according to claim 9, characterized in that: The autoimmune diseases mentioned are multiple sclerosis, myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, or Crohn's disease.

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