Compounds as S1P receptor modulators and their applications

Abstract

This invention discloses compounds of Formula I or pharmaceutically acceptable salts thereof. Compounds of Formula I exhibit excellent S1PR1 receptor modulatory activity and high selectivity, thereby effectively avoiding potential cardiovascular toxicity while exerting immunomodulatory effects. The compounds and pharmaceutical compositions of this invention lay a solid chemical and biological foundation for the development of next-generation drugs targeting autoimmune diseases and specific malignant tumors, demonstrating promising clinical application prospects, social benefits, and potential industrialization value.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry. Specifically, this invention relates to compounds that act as S1P receptor modulators, their synthetic methods, and their applications in the preparation of drugs for the prevention or treatment of diseases such as tumors and immune disorders. Background Technology

[0002] Sphingosine-1-phosphate receptors (S1PRs) belong to the G protein-coupled receptor (GPCR) family and include five subtypes: S1P1-5. Among them, the S1P1 receptor is mainly expressed on lymphocytes and vascular endothelial cells and is a key switch regulating the transport of lymphocytes from secondary lymphoid organs into the blood and lymphatic circulation. By regulating the S1P1 receptor (such as inducing receptor endocytosis and degradation), pathogenic lymphocytes can be effectively isolated in lymph nodes, thereby blocking their infiltration into the central nervous system or damaged peripheral organs.

[0003] Currently, S1P1 receptor modulators have become important targets for the treatment of autoimmune diseases such as multiple sclerosis and ulcerative colitis. Although drugs such as fingolimod, siponimod, and ozanimod have been approved for marketing, safety challenges remain in clinical application. For example, non-selective agonists may cause cardiotoxicity such as S1P3-mediated bradycardia and atrioventricular block. Therefore, developing next-generation S1P1 receptor modulators with higher subtype selectivity, better pharmacokinetic properties, and a wider safety window remains a hot topic and a challenge in current drug research. Summary of the Invention

[0004] The purpose of this invention is to provide an S1P1 receptor modulator with higher subtype selectivity, better pharmacokinetic properties and a wider safety window.

[0005] Another object of the present invention is to provide a pharmaceutical composition comprising the above-described compounds.

[0006] Another object of the present invention is to provide the use of the above-mentioned compounds in the preparation of medicaments for treating S1P-related diseases or modulating S1P receptors.

[0007] In a first aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof: I In the formula, X is selected from NR4, S or O, wherein R4 is selected from H or optionally substituted C1-C6 alkyl; R1 is selected from the following group: optional substituted C6-C 18Aryl, optional substituted C7-C 18 Aryl groups; n is any integer selected from 1 to 4; R2 is a substituent containing at least one carboxyl group (-COOH) with the structure -L-R3, wherein: the linking group L is selected from -NH-, -CH2- or -C(=O)NR5R6, R5 and R6 are independently selected from absent, H, optional substituted C1-C6 alkyl groups, or R5 and R6 together with the N atom attached to them form an optional substituted 5 or 6-membered cyclic group; R3 is selected from: optionally substituted C0-C6 alkylene carboxylic acid groups, or optionally substituted 4-6 membered heterocyclic groups containing one or two heteroatoms independently selected from N, O or S, and the heterocyclic group has at least one carboxyl group.

[0008] In a specific implementation, n is an integer of 1 or 2; R1 is selected from: optionally substituted phenyl, optionally substituted naphthyl, optionally substituted biphenyl; R2 is selected from: -(CH2) m -NH-(CH2) p -COOH, where m is 0, 1 or 2, and p is 2, 3, 4 or 5; -(CH2) o -Het-COOH, where o is 1 or 2, and Het is selected from optionally substituted pyrrolidinyl or azacyclobutane; -CONH-L'-COOH, where L' is selected from optionally substituted C1-C3 alkylene groups.

[0009] In a preferred embodiment, the optional substitution refers to substitution by one or more substituents selected from the following: halogen, hydroxyl, nitro, C1-C3 alkyl, C1-C3 alkoxy, amino (-NH2), oxo (=O), C5-C8 aryl (preferably phenyl), benzyl.

[0010] In a specific implementation, X is selected from S; n is an integer of 1 or 2; R1 is selected from: optionally substituted naphthyl, optionally substituted biphenyl; R2 is -(CH2) o -Het-COOH, where o is 1 or 2, and Het is selected from optionally substituted pyrrolidinyl or azacyclobutane.

[0011] In a specific embodiment, the compound is selected from the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , .

[0012] In a specific embodiment, the compound is selected from the following compounds: or ; Preferred .

[0013] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound described in the first aspect or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0014] 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, and powders.

[0015] In a third aspect, the present invention provides the use of the compounds described in the first aspect or pharmaceutically acceptable salts thereof in the preparation of S1PR1, S1PR4, and S1PR5 receptor modulators.

[0016] In a specific implementation, the S1PR1, S1PR4, and S1PR5 receptor modulators are highly selective S1P1 receptor modulators.

[0017] In a specific implementation, the highly selective S1P1 receptor modulator is a drug for treating or preventing S1P receptor-mediated diseases.

[0018] In a specific implementation, the S1P receptor-mediated disease is cancer or an autoimmune disease.

[0019] In a preferred embodiment, the cancer is selected from the group consisting of: esophageal cancer, renal cell carcinoma, pancreatic cancer, colon cancer, breast cancer, lung cancer, prostate cancer, ovarian cancer, endometrial cancer, head and neck squamous cell carcinoma, acute myeloid leukemia, and solid tumors. The autoimmune diseases mentioned are selected from the following group: multiple sclerosis, myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, and Crohn's disease.

[0020] In a fourth aspect, the present invention provides a method for treating or preventing S1P-mediated diseases, the method comprising the step of administering a therapeutically or preventively effective amount of the compound of the first aspect or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the second aspect, to a subject in need of such treatment.

[0021] In a preferred embodiment, the cancer is selected from the group consisting of: esophageal cancer, renal cell carcinoma, pancreatic cancer, colon cancer, breast cancer, lung cancer, prostate cancer, ovarian cancer, endometrial cancer, head and neck squamous cell carcinoma, acute myeloid leukemia, and solid tumors. The autoimmune diseases mentioned are selected from the following group: multiple sclerosis, myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, and Crohn's disease.

[0022] In a preferred embodiment, the object is a mammal, preferably a human.

[0023] 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. Detailed Implementation

[0024] Through extensive and in-depth research, the inventors unexpectedly discovered a batch of compounds with novel structures that can regulate S1P receptor activity and affect the EC2 receptor agonist activity of S1P receptors. 50 The values ​​reached the nM level. Furthermore, some compounds of this invention exhibited good selectivity among S1P receptor subtypes. Based on these findings, this invention was completed.

[0025] Terminology Definition The definitions of some functional groups involved in this article are as follows: In this article, "C6-C" 18 "Aryl" refers to an aromatic ring system consisting of a monocyclic, bicyclic, or fused polycyclic aromatic ring with 6 to 18 carbon atoms. Examples include, but are not limited to: phenyl, naphthyl (including 1-naphthyl and 2-naphthyl), anthracene, phenanthrene, and biphenyls formed by direct covalent bonding (such as [1,1'-biphenyl]-4-yl).

[0026] In this article, "C7-C" 18 "Aryl group" refers to an alkyl group substituted with the above-mentioned aryl group, with a total number of carbon atoms of 7-18. Examples include, but are not limited to: benzyl, phenethyl (such as 2-phenethyl), phenylpropyl, naphthylmethyl, etc.

[0027] In this document, "4-6 membered saturated nitrogen-containing heterocyclic group" refers to a non-aromatic saturated ring system containing 4 to 6 ring atoms, with at least one nitrogen atom among the ring atoms. In addition to the nitrogen atom, this ring system may optionally contain 1-2 heteroatoms selected from O, S, or N. Examples include, but are not limited to, aziridine, pyrrolidinyl, piperidinyl, piperazine, morpholinyl, etc.; more preferably, aziridine and pyrrolidinyl are used. This heterocyclic group may optionally be further substituted by 1-5 substituents selected from the following: oxo (=O), amino, and carboxyl substituents.

[0028] In this paper, "linker L" refers to the bridging divalent group located between the parent nucleus and the terminal functional fragment R3. In this invention, linker L is selected from: imino (-NH-), methylene (-CH2-), or amide (-C(O)NH-). When L is selected from an amide group, the amide bond is preferably with the carbonyl (C=O) end connected to the 2-position of the parent nucleus, and the imino (NH) end connected to R3.

[0029] In this article, "optionally substituted" means that one or more hydrogen atoms in the modified substituent may be optionally substituted by 1 to 5 (e.g., 1, 2, 3, 4 or 5) substituents selected from the following: halogen, C1-C6 straight or branched alkyl (e.g., methyl, ethyl, isopropyl), C1-C6 straight or branched alkoxy, cyano, nitro, amino, hydroxy, hydroxymethyl, halogen-substituted alkyl (e.g., trifluoromethyl), carboxyl, aryl (e.g., phenyl), or aralkyl (e.g., benzyl), etc.

[0030] In this article, "C1-C6 alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group having 1-6 carbon atoms. Examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0031] In this article, L' is selected from ethylene or propylene oxide substituted with amino groups.

[0032] The compounds of the present invention The inventors synthesized candidate compounds with S1P receptor regulatory activity. The structures of the obtained candidate compounds were optimized, and a series of previously unreported compounds were designed and synthesized, and their structures were characterized.

[0033] Specifically, the compounds of the present invention are compounds of Formula I or pharmaceutically acceptable salts thereof: I In the formula, X, R1, and R2 are as described above.

[0034] The compounds of this invention can serve as highly selective S1P1 receptor modulators, enabling precise intervention in lymphocyte efflux and immune responses by regulating, activating, or functionally antagonizing S1P1 receptor-mediated signaling pathways.

[0035] In specific embodiments, the diseases include, but are not limited to, autoimmune diseases, chronic inflammatory diseases, and malignant tumors. Regarding immune regulation, because the compounds of this invention can effectively induce S1P1 receptor endocytosis, thereby isolating pathogenic lymphocytes in secondary lymphoid organs, they can be used to prepare drugs for treating multiple sclerosis, myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and inflammatory bowel diseases (such as ulcerative colitis and Crohn's disease). Regarding antitumor activity, the compounds of this invention, by intervening in S1PR1-mediated tumor microenvironment regulation, can be used to prepare drugs for treating various malignant tumors, including lung cancer, breast cancer, colorectal cancer, renal cell carcinoma, pancreatic cancer, prostate cancer, and acute myeloid leukemia.

[0036] Based on the compounds of the present invention, the present invention provides a pharmaceutical composition containing a therapeutically effective amount of the compounds of the present invention or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or excipient.

[0037] Examples of pharmaceutically acceptable salts of the compounds of the present invention include, but are not limited to, inorganic and organic acid salts, such as hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, and oxalate; and inorganic and organic base salts formed with bases such as sodium hydroxyl, tris(hydroxymethyl)aminomethane (TRIS, aminobutanetriol), and N-methylglucosamine.

[0038] The pharmaceutical compositions of the present invention can be formulated into dosage forms suitable for various routes of administration, including but not limited to those formulated for parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial, nasal, or topical administration for the treatment of tumors and other diseases. A dosage is an amount of medicine that effectively improves or eliminates one or more symptoms. For the treatment of a specific disease, an effective amount is an amount sufficient to improve or, in some way, alleviate the symptoms associated with the disease. Such a dosage may be administered as a single dose or may be administered according to an effective treatment regimen. A dosage may cure the disease, but administration is usually intended to improve the symptoms of the disease. Repeated administration is generally required to achieve the desired symptom improvement. The dosage of the medicine will be determined based on the patient's age, health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.

[0039] The pharmaceutical formulations of this invention can be administered to any mammal, provided they can obtain the therapeutic effects of the compounds of this invention. Humans are the most important of these mammals.

[0040] The compounds or pharmaceutical compositions thereof of the present invention can be used to treat various S1P-mediated diseases. In specific embodiments, the S1P receptor-mediated diseases are cancers and autoimmune diseases, including but not limited to esophageal cancer, renal cell carcinoma, pancreatic cancer, colon cancer, breast cancer, lung cancer, prostate cancer, ovarian cancer, endometrial cancer, head and neck squamous cell carcinoma, acute myeloid leukemia, and solid tumors. The autoimmune diseases include, but are not limited to, multiple sclerosis, myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, and Crohn's disease.

[0041] The pharmaceutical formulations of the present invention can be manufactured using known methods. For example, they can be manufactured by conventional mixing, granulation, tableting, dissolving, or freeze-drying processes. When manufacturing oral formulations, solid excipients and active compounds can be combined, and the mixture can be selectively ground. If desired or necessary, appropriate excipients can be added, and the granular mixture can be processed to obtain tablets or tablet cores.

[0042] Suitable excipients, especially fillers, include sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, such as tricalcium phosphate or dicalcium phosphate; and binders, such as starch pastes, including corn starch, wheat starch, rice starch, potato starch, gelatin, astragalus gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone. If necessary, disintegrants, such as the starches mentioned above, as well as carboxymethyl starch, croscarmellose, agar, or alginate or its salts, such as sodium alginate, can be added. Adjuvants, especially flow conditioners and lubricants, include silica, talc, stearates such as calcium magnesium stearate, stearic acid, or polyethylene glycol. If necessary, a suitable coating that resists gastric juices can be provided to the tablet core. For this purpose, a concentrated sugar solution can be applied. This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, varnish solutions, and suitable organic solvents or solvent mixtures. To prepare a coating resistant to gastric juice, a suitable cellulose solution, such as cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate, can be used. Dyes or pigments can be added to the coating of the tablet or lozenge core, for example, to identify or characterize combinations of active ingredient dosages.

[0043] Based on the above-described compounds and pharmaceutical compositions, the present invention further provides a method for treating S1P-mediated diseases, the method comprising administering to a desired subject the compounds or pharmaceutical compositions of the present invention.

[0044] Administration methods include, but are not limited to, various administration methods known in the art, which may be determined based on the patient's actual condition. These methods include, but are not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial, nasal, or external routes of administration.

[0045] This invention also includes the use of the compounds of this invention in the preparation of medicaments for the prevention or treatment of S1P-mediated diseases or for activating S1PR1 activity.

[0046] Advantages of this invention: 1. This invention provides a class of S1PR receptor modulators with a novel skeletal structure. Through specific substitutions at positions 4-7 of the parent benzene nucleus and the introduction of a carboxyl fragment at position 2, precise adaptation of the molecule to the S1PR1 receptor binding pocket is achieved.

[0047] 2. The compounds provided by this invention exhibit excellent S1PR1 receptor regulatory activity. Experimental data show that some preferred compounds can significantly induce S1PR1 receptor endocytosis at nanomolar (nM) concentrations. More importantly, the compounds of this invention have high selectivity for S1PR1 and significantly reduce the impact on subtypes such as S1PR3, thereby effectively avoiding potential cardiovascular toxicity while exerting immunomodulatory effects.

[0048] 3. The compounds and pharmaceutical compositions provided by this invention lay a solid chemical and biological foundation for the development of a new generation of drugs targeting autoimmune diseases (such as multiple sclerosis and ulcerative colitis) and specific malignant tumors, demonstrating good clinical application prospects, social benefits and potential industrialization value.

[0049] The technical solution of the present invention is further described below with reference to specific implementation examples. However, the following implementation examples do not constitute a limitation on the present invention. All application methods based on the principles and technical means of the present invention are within the scope of the present invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0050] Materials and Methods The synthesis of the compounds of the present invention is as follows: Example 1. 3-(4-([1,1'-biphenyl]-4-yl)-1 H Synthetic route of (-indole-2-carboxamido)-2-aminopropionic acid (compound 1) 4-([1,1'-biphenyl]-4-yl)-1 H Synthesis of -indole-2-carboxylic acid In a 100 mL double-necked flask, [1,1'-biphenyl]-4-ylboronic acid (1.08 mmol, 214 mg), 4-bromoindole-2-carboxylic acid (0.83 mmol, 200 mg), DPPF palladium dichloride (0.06 mmol, 49 mg), and sodium carbonate (2.05 mmol, 221 mg) were added sequentially. A mixture of DMF and water (4:1) was used as the solvent. The mixture was purged with nitrogen three times and reacted at 102 °C for 2 h. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was extracted three times with ethyl acetate and water. The organic phase was concentrated and separated by column chromatography to obtain the corresponding intermediate 4-([1,1'-biphenyl]-4-yl)-1 H Synthesis of 1-indole-2-carboxylic acid (white solid, 176 mg, 67%).

[0051] 3-(4-([1,1'-biphenyl]-4-yl)-1 H Synthesis of methyl indole-2-carboxamido)-2-(((benzyloxy)carbonyl)amino)propionate Add 4-([1,1'-biphenyl]-4-yl)-1 to a 100 mL single-necked flask H -Indole-2-carboxylic acid (0.19 mmol, 60 mg) was dissolved in anhydrous DCM. After stirring in an ice bath for 10 minutes, SOCl2 (0.23 mmol, 0.03 mL) was slowly added dropwise. The reaction was carried out in an ice bath for 10 minutes, and then at room temperature for 2 hours. After the reaction was completed, the intermediate was concentrated and dissolved in DCM. Methyl 3-amino-2-(((benzyloxy)carbonyl)amino)propionate hydrochloride (0.14 mmol, 83 mg) and DIPEA (1.15 mmol, 0.2 mL) were added in an ice bath. The reaction was carried out in an ice bath for 2 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the organic phase was concentrated and separated by column chromatography to obtain the corresponding intermediate 3-(4-([1,1'-biphenyl]-4-yl)-1 H Methyl indole-2-carbamate)-2-(((benzyloxy)carbonyl)amino)propionate (yellow solid, 66 mg, 63%).

[0052] 1 H NMR (500 MHz, Chloroform- d ) δ 10.45 (s, 1H), 7.85 – 7.62 (m, 7H), 7.52 (dt, J = 22.3, 7.0 Hz, 4H), 7.45 – 7.38 (m, 2H), 7.30 (d, J = 7.0 Hz, 1H), 7.27 (d,J = 2.1 Hz, 2H), 6.40 (d, J = 7.8 Hz, 1H), 5.09 (s, 2H), 4.66(q, J = 6.8 Hz, 1H), 4.06 – 3.82 (m, 2H), 3.74 (s, 3H). 3-(4-([1,1'-biphenyl]-4-yl)-1 H Synthesis of -indole-2-carboxamido)-2-(((benzyloxy)carbonyl)amino)propionic acid Add 3-(4-([1,1'-biphenyl]-4-yl)-1 to a 100 mL single-necked flask H Methyl indole-2-carbamate)-2-(((benzyloxy)carbonyl)amino)propionate (0.12 mmol, 66 mg) was dissolved in methanol, and sodium hydroxide (0.72 mmol, 29 mg) was added. The mixture was reacted overnight at room temperature. After the reaction was completed, the solution was concentrated and separated by column chromatography to obtain the corresponding intermediate 3-(4-([1,1'-biphenyl]-4-yl)-1 H -Indole-2-carbamate)-2-(((benzyloxy)carbonyl)amino)propionic acid (pale yellow solid, 50 mg, 78%).

[0053] 3-(4-([1,1'-biphenyl]-4-yl)-1 H Synthesis of (-indole-2-carboxamido)-2-aminopropionic acid Add 3-(4-([1,1'-biphenyl]-4-yl)-1 to a 100 mL single-necked flask H 0.09 mmol, 50 mg of indole-2-carbamate)-2-(((benzyloxy)carbonyl)amino)propionic acid was dissolved in THF:H2O = 1:1, 10 mg of palladium on carbon was added, and the mixture was purged with hydrogen three times. The reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the solution was concentrated and separated by column chromatography to obtain 3-(4-([1,1'-biphenyl]-4-yl)-1 H (-indole-2-carbamoyl)-2-aminopropionic acid (gray solid, 28 mg, 75%).

[0054] 1 H NMR (500 MHz, DMSO- d 6) δ 12.12 (s, 1H), 8.76 (s, 1H), 7.82 – 7.66 (m, 7H), 7.46 (d, J= 7.6 Hz, 3H), 7.40 – 7.30 (m, 2H), 7.26 (t, J = 7.7 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 3.78 (s, 1H), 3.49 (d, J = 11.7 Hz, 2H). 13 CNMR (126 MHz, DMSO) δ 183.7, 161.9, 140.2, 140.0, 139.3, 139.2, 137.6, 134.3,133.4, 133.0, 129.5, 129.3, 127.9, 127.4, 127.0, 125.6, 124.0, 119.6, 64.3,43.8. LC-MS (ESI): m / z: 398.20 [MH] - . 1-(4-(2-benzylphenyl)-1 H Synthetic route of (indole-2-carbonyl)pyrrolidine-3-carboxylic acid (compound 2) 4-(2-Benzylphenyl)-1 H Synthesis of -indole-2-carboxylic acid In a 250 mL double-necked flask, (2-benzylphenyl)boric acid (4.59 mmol, 973 mg), 4-bromoindole-2-carboxylic acid (4.6 mmol, 1104 mg), DPPF palladium dichloride (0.36 mmol, 269 mg), and sodium carbonate (11.5 mmol, 1216 mg) were added sequentially. A mixture of DMF and water (4:1) was used as the solvent. The mixture was purged with nitrogen three times and reacted at 102 °C for 2 h. The reaction progress was monitored by TLC. After the reaction was complete, EA and H2O were added for extraction three times. The organic phase was concentrated and separated by column chromatography to obtain the corresponding intermediate 4-(2-benzylphenyl)-1. H -Indole-2-carboxylic acid (yellow solid, 640 mg, 41%).

[0055] 1-(4-(2-benzylphenyl)-1 H Synthesis of methyl indole-2-carbonyl)pyrrolidine-3-carboxylic acid Add 4-(2-benzylphenyl)-1 to a 100 mL single-necked flask H-Indole-2-carboxylic acid (0.33 mmol, 110 mg) was dissolved in anhydrous DCM. After stirring in an ice bath for 10 minutes, SOCl2 (1 mmol, 0.1 mL) was slowly added dropwise. The reaction was carried out in an ice bath for 10 minutes, and then at room temperature for 2 hours. After the reaction was completed, the intermediate was concentrated and dissolved in DCM. Pyrrolidine-3-carboxylic acid methyl ester hydrochloride (0.50 mmol, 84 mg) and DIPEA (2.0 mmol, 0.36 mL) were added in an ice bath. The reaction was carried out in an ice bath for 2 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the organic phase was concentrated and separated by column chromatography to obtain the corresponding intermediate 1-(4-(2-benzylphenyl)-1 H Methyl 3-indole-2-carbonyl)pyrrolidine-3-carboxylic acid (yellow solid, 140 mg, 95%).

[0056] LC-MS (ESI): m / z: 439.20 [M+H] + . 1-(4-(2-benzylphenyl)-1 H Synthesis of (indole-2-carbonyl)pyrrolidine-3-carboxylic acid Add 1-(4-(2-benzylphenyl)-1- into a 100 mL single-necked flask H Methyl 1-(4-(2-benzylphenyl)-1H-indole-2-carbonyl)pyrrolidine-3-carboxylic acid (0.33 mmol, 140 mg) was dissolved in methanol, and sodium hydroxide (1.60 mmol, 64 mg) was added. The mixture was reacted overnight at room temperature. After the reaction was completed, the mixture was concentrated and separated by column chromatography to obtain the final product 1-(4-(2-benzylphenyl)-1H-indole-2-carbonyl)pyrrolidine-3-carboxylic acid (white solid, 25 mg, 18%).

[0057] 1 H NMR (500 MHz, Chloroform- d ) δ 7.36 (d, J = 8.3 Hz, 1H), 7.30 –7.17 (m, 5H), 7.01 (dd, J = 18.7, 7.2 Hz, 3H), 6.86 (d, J = 7.0 Hz, 1H), 6.80(d, J = 7.3 Hz, 2H), 6.40 (d, J = 19.3 Hz, 1H), 3.87 (s, 1H), 3.81 – 3.46 (m,3H), 3.06 (dt, J= 36.0, 7.0 Hz, 1H), 2.92 (s, 2H), 2.30 – 2.02 (m, 2H). 13 CNMR (126 MHz, CDCl3) δ 185.8, 165.1, 141.3, 140.2, 139.1, 135.5, 130.3,130.2, 129.8, 128.8, 128.0, 127.6, 126.0, 125.6, 124.5, 121.3, 121.3, 110.8,105.4, 105.3, 50.2, 47.7, 46.7, 39.1, 29.7. LC-MS (ESI): m / z: 425.15 [M+H] + . 3-(4-(2-benzylphenyl)-1 H Synthetic route of (indole-2-carbamoyl)propionic acid (compound 3) 4-(2-Benzylphenyl)-1 H Synthesis of -indole-2-carboxylic acid In a 250 mL double-necked flask, (2-benzylphenyl)boric acid (4.59 mmol, 973 mg), 4-bromoindole-2-carboxylic acid (4.6 mmol, 1104 mg), DPPF palladium dichloride (0.36 mmol, 269 mg), and sodium carbonate (11.5 mmol, 1216 mg) were added sequentially. A mixture of DMF and water (4:1) was used as the solvent. The mixture was purged with nitrogen three times and reacted at 102 °C for 2 h. The reaction progress was monitored by TLC. After the reaction was complete, EA and H2O were added for extraction three times. The organic phase was concentrated and separated by column chromatography to obtain the corresponding intermediate 4-(2-benzylphenyl)-1. H -Indole-2-carboxylic acid (yellow solid, 640 mg, 41%).

[0058] 3-(4-(2-benzylphenyl)-1 H Synthesis of methyl indole-2-carboxamido)propionate Add 4-(2-benzylphenyl)-1 to a 100 mL single-necked flask H-Indole-2-carboxylic acid (0.36 mmol, 120 mg) was dissolved in anhydrous DCM. After stirring in an ice bath for 10 minutes, SOCl2 (1 mmol, 0.1 mL) was slowly added dropwise. The reaction was carried out in an ice bath for 10 minutes, and then at room temperature for 2 hours. After the reaction was completed, the intermediate was concentrated and dissolved in DCM. Methyl 3-aminopropionate hydrochloride (0.54 mmol, 75 mg) and DIPEA (2.2 mmol, 0.4 mL) were added in an ice bath. The reaction was carried out in an ice bath for 2 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the organic phase was concentrated and separated by column chromatography to obtain the corresponding intermediate methyl 3-(4-(2-benzylphenyl)-1H-indole-2-carboxamido)propionate (yellow solid, 110 mg, 73%).

[0059] LC-MS (ESI): m / z: 411.20 [MH] - . 1 H NMR (500 MHz, Chloroform- d ) δ 9.65(s, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.36 – 7.27 (m, 5H), 7.13 (t, J = 7.3 Hz, 2H), 7.07 (t, J = 7.2 Hz, 1H), 6.96 (d, J = 7.1 Hz, 1H), 6.91 – 6.85 (m, 2H), 6.64 (t, J = 6.3 Hz, 1H), 6.45 (d, J = 2.2 Hz, 1H), 3.86 (d, J = 2.5 Hz, 2H),3.76 (s, 2H), 3.71 (s, 3H), 2.66 (t, J = 6.0 Hz, 2H). 3-(4-(2-benzylphenyl)-1 H Synthesis of -indole-2-carboxamido)propionic acid Add 3-(4-(2-benzylphenyl)-1- into a 100 mL single-necked flask HMethyl indole-2-carbamate (0.27 mmol, 110 mg) was dissolved in methanol, and sodium hydroxide (1.33 mmol, 53 mg) was added. The mixture was reacted overnight at room temperature. After the reaction was completed, the solution was concentrated and separated by column chromatography to obtain the final product 3-(4-(2-benzylphenyl)-1 H (indole-2-carbamoyl)propionic acid (white solid, 40 mg, 38%).

[0060] 1 H NMR (500 MHz, Chloroform- d ) δ 7.40 (d, J = 8.2 Hz, 1H), 7.31 –7.22 (m, 5H), 7.09 (t, J = 7.3 Hz, 2H), 7.03 (t, J = 7.2 Hz, 1H), 6.91 (d, J = 7.1 Hz, 1H), 6.84 (d, J = 7.5 Hz, 2H), 6.53 (s, 1H), 3.84 – 3.78 (m, 2H), 3.62 (t, J = 6.3 Hz, 2H), 2.59 (t, J = 6.1 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ174.8, 162.2, 141.4, 140.2, 139.2, 136.4, 135.3, 130.3, 130.2, 130.0, 128.8,128.0, 127.5, 127.4, 125.9, 125.6, 124.2, 121.1, 110.9, 102.7, 39.1, 35.0,33.8. LC-MS (ESI): m / z: 397.20 [MH] - . Synthetic route of 4-(((5-(naphth-2-yl)benzofuran-2-yl)methyl)amino)butyric acid (compound 4) Synthesis of 5-(naphthyl-2-yl)benzofuran-2-carboxaldehyde In a 50 mL two-necked flask, the following starting materials were added: 5-bromobenzofuran-2-carboxaldehyde (100 mg, 0.45 mmol), 2-naphthylboronic acid (92 mg, 0.54 mmol), sodium carbonate (112.5 mg, 1.125 mmol), and dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium (32.9 mg, 0.045 mmol). Under nitrogen protection, 5 mL of solvent (DMF:H2O = 4:1) was added, and the temperature was raised to 110 °C. The reaction was monitored by TLC. The reaction was stirred for 2 h, and after complete reaction, water was added to quench the reaction. The organic phase was extracted by filtration. The organic phase was purified by column chromatography after rotary evaporation. The intermediate 5-(naphthyl-2-yl)benzofuran-2-carboxaldehyde (51 mg, yield 41.7%) was obtained.

[0061] 1 H NMR (500 MHz, CDCl3) δ 9.92 (s, 1H), 8.07 – 8.04 (m, 2H), 7.96 –7.87 (m, 4H), 7.76 (dd, J = 8.5, 1.8 Hz, 1H), 7.72 (dt, J = 8.7, 0.9 Hz, 1H), 7.64 (d, J = 1.1 Hz, 1H), 7.56 – 7.49 (m, 2H). Synthesis of 4-(((5-(naphth-2-yl)benzofuran-2-yl)methyl)amino)butyric acid In a 50 mL single-necked flask, 50 mg (50 mg, 0.184 mmol) of intermediate 5-(naphthyl-2-yl)benzofuran-2-carboxaldehyde and 57 mg (57 mg, 0.552 mmol) of 4-aminobutyric acid were added to dissolve them in a suitable amount of methanol and 1 drop of glacial acetic acid. After stirring at room temperature for 15 min, sodium cyanoborohydride (11.6 mg, 0.184 mmol) was added, and the reaction progress was monitored by TLC. After the reaction was complete, the mixture was extracted three times with ethyl acetate and water. The combined organic phases were rotary evaporated and purified by column chromatography to obtain 4-(((5-(naphthyl-2-yl)benzofuran-2-yl)methyl)amino)butyric acid (white powder, 20 mg, yield 30.2%).

[0062] 1 H NMR (500 MHz, DMSO- d 6) δ 8.22 (d, J= 2.1 Hz, 1H), 8.07 – 7.82 (m,5H), 7.73 – 7.59 (m, 2H), 7.57 – 7.47 (m, 2H), 6.81 (s, 1H), 3.88 (s, 2H), 2.60 (t, J = 6.9 Hz, 2H), 2.27 (t, J = 7.2 Hz, 2H), 1.67 (p, J = 7.1 Hz, 2H). 13 C NMR (126 MHz, DMSO- d 6) δ 158.99, 154.39, 138.52, 135.57, 133.87, 132.45,129.53, 128.85, 128.56, 127.94, 126.83, 126.37, 126.03, 125.71, 123.61,119.66, 111.72, 104.20, 48.39, 46.08, 32.67, 25.07. LC-MS / ESI [M + H] + 360.10 Synthetic route of 4-(((5-(p-tolyl)benzofuran-2-yl)methyl)amino)butyric acid (compound 5) Synthesis of 5-(p-Tolyl)benzofuran-2-carboxaldehyde In a 50 mL two-necked flask, the following starting materials were added: 5-bromobenzofuran-2-carboxaldehyde (100 mg, 0.45 mmol), 4-tolueneboronic acid (73 mg, 0.54 mmol), sodium carbonate (112.5 mg, 1.125 mmol), and dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium (32.9 mg, 0.045 mmol). Under nitrogen protection, 5 mL of solvent (DMF:H₂O = 4:1) was added, and the temperature was raised to 110 °C. The reaction was monitored by TLC. The reaction was stirred for 2 h, and after complete reaction, water was added to quench the reaction. The organic phase was extracted by filtration. The organic phase was purified by column chromatography after rotary evaporation. The intermediate 5-(p-tolyl)benzofuran-2-carboxaldehyde (75 mg, yield 70.6%) was obtained.

[0063] Synthesis of 4-(((5-(p-Tolyl)benzofuran-2-yl)methyl)amino)butyric acid In a 50 mL single-necked flask, intermediates 5-(p-tolyl)benzofuran-2-carboxaldehyde (70 mg, 0.297 mmol) and 4-aminobutyric acid (91.7 mg, 0.889 mmol) were added, dissolved in a suitable amount of methanol, and 1 drop of glacial acetic acid was added. After stirring at room temperature for 15 min, sodium cyanoborohydride (18.7 mg, 0.297 mmol) was added, and the reaction progress was monitored by TLC. After the reaction was complete, the mixture was extracted three times with ethyl acetate and water, and the combined organic phases were rotary evaporated. The resulting product was purified by column chromatography to obtain 4-(((5-(p-tolyl)benzofuran-2-yl)methyl)amino)butyric acid (white powder, 45 mg, yield 46.9%).

[0064] 1 H NMR (600 MHz, DMSO- d 6) δ 7.79 (s, 1H), 7.52 (dd, J = 38.1, 7.3 Hz, 4H), 7.26 (d, J = 7.5 Hz, 2H), 6.75 (s, 1H), 3.85 (s, 2H), 2.57 (t, J = 6.2Hz, 2H), 2.45 – 2.12 (m, 5H), 1.76 – 1.53 (m, 2H). 13 C NMR (151 MHz, DMSO- d 6)δ 175.40, 158.83, 154.14, 138.31, 136.58, 135.72, 129.94, 129.39, 127.21,123.10, 118.99, 111.54, 104.12, 48.50, 46.09, 33.05, 25.25, 21.10. LC-MS / ESI[M + H] + 324.20 2-Amino-3-(5-phenyl-1-amino) H Synthetic route of (indole-2-carbamoyl)propionic acid (compound 6) Referring to the synthetic route and method of compound 1 in Example 1, only phenylboronic acid was used instead of [1,1'-biphenyl]-4-ylboronic acid as the starting material, and it was Suzuki coupled with 4-bromoindole-2-carboxylic acid. Subsequently, through amidation, ester hydrolysis and deprotection steps, the target compound 6 (white solid) was obtained.

[0065] 1 H NMR (500 MHz, DMSO-d 6) δ 11.84 (s, 1H), 8.91 (s, 1H), 7.89 (s, 1H), 7.67 (d, J = 7.6 Hz, 2H), 7.56 – 7.48 (m, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.30(t, J = 7.4 Hz, 1H), 7.22 (s, 1H), 3.89 – 3.75 (m, 1H), 3.65 (d, J = 20.2 Hz, 2H). 13 C NMR (126 MHz, DMSO) δ 162.1, 152.1, 145.0, 141.8, 136.6, 132.7,129.3, 128.1, 127.2, 126.9, 123.4, 119.9, 113.3, 104.2, 62.5, 55.4. LC-MS(ESI): m / z: 322.10 [MH] - . ( S )-1-((5-([1,1'-biphenyl]-4-yl)benzo[ b Synthetic route of thiophene-2-yl)methyl)pyrrolidine-3-carboxylic acid (compound 7) 5-([1,1'-biphenyl]-4-yl)benzo[ b Synthesis of thiophene-2-carboxaldehyde Add 5-bromobenzo[] to a 10 ml Shrek tube b Thiophene-2-carboxaldehyde (200 mg, 0.83 mmol), [1,1'-biphenyl]-4-ylboronic acid (247 mg, 1.24 mmol), DPPF palladium dichloride (61 mg, 0.08 mmol), sodium carbonate (220 mg, 2.08 mmol), under nitrogen protection, 4 ml of solvent (DMF:H2O = 4:1) was injected, and the reaction was carried out at 102 °C. The reaction progress was monitored by TLC. After the reaction was complete, the product was extracted three times with ethyl acetate and water, the organic phases were combined, anhydrous sodium sulfate was added to remove water, and the product was concentrated. The product was separated by column chromatography (PE:EA = 3:1) to give 5-([1,1'-biphenyl]-4-yl)benzo[ b Thiophene-2-carboxaldehyde (yellow solid, 118 mg, yield 45.2%).

[0066] 1 H NMR (400 MHz, Chloroform- d ) δ 10.14 (s, 1H), 8.18 (d, J = 1.7 Hz,1H), 8.09 (s, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.81 (dd, J = 8.5, 1.8 Hz, 1H),7.73 (s, 4H), 7.68 – 7.64 (m, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.41 – 7.35 (m,1H). ( S )-1-((5-([1,1'-biphenyl]-4-yl)benzo[ b Synthesis of thiophene-2-yl)methyl)pyrrolidine-3-carboxylic acid Add 5-([1,1'-biphenyl]-4-yl)benzo[ b Thiophene-2-carboxaldehyde (100 mg, 0.32 mmol) and ( S 44 mg of pyrrolidine-3-carboxylic acid (0.38 mmol) was injected into 6 mL of a mixed solvent (DCM:MeOH = 3:1). After stirring at room temperature for 15 min, a small amount of glacial acetic acid was added dropwise to adjust the pH of the system to 4-6. Then, sodium cyanoborohydride (30 mg, 0.48 mmol) was added, and the reaction was continued to be stirred at room temperature for 12 h, with the reaction progress monitored by TLC. After the reaction was complete, most of the solvent was removed by rotary evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain ( S )-1-((5-([1,1'-biphenyl]-4-yl)benzo[ b Thiophene-2-yl)methyl)pyrrolidine-3-carboxylic acid (white powder, 66 mg, yield 50.4%).

[0067] 1 H NMR (400 MHz, DMSO- d 6) δ 8.10 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H),7.87 – 7.58 (m, 7H), 7.49 (t, J= 7.5 Hz, 2H), 7.43 – 7.30 (m, 2H), 3.91 (t, J = 9.2 Hz, 2H), 2.96 (q, J = 8.0 Hz, 1H), 2.82 (t, J = 8.9 Hz, 1H), 2.72 (t, J = 8.0 Hz, 1H), 2.66 – 2.56 (m, 2H), 1.99 (q, J = 7.5 Hz, 2H). 13 C NMR (151MHz, DMSO- d 6) δ 175.78, 145.33, 140.13, 139.65, 139.38, 138.95, 138.53,129.02, 127.53, 127.37, 127.23, 126.58, 122.90, 122.85, 121.77, 121.09,56.18, 54.27, 53.26, 41.57, 27.22. LC-MS (ESI): m / z: 414.10 [M+H] + . ( S )-1-((5-Benzylbenzo[ b Synthetic route of thiophene-2-yl)methyl)pyrrolidine-3-carboxylic acid (compound 8) Following the synthetic route and method of compound 7 in Example 1, but using 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborane instead of [1,1'-biphenyl]-4-ylboronic acid as the starting material, the target compound 9 was obtained through similar steps.

[0068] 1 H NMR (400 MHz, DMSO- d 6) δ 7.77 (d, J = 8.2 Hz, 1H), 7.59 (d, J = 1.6Hz, 1H), 7.33 – 7.22 (m, 4H), 7.22 – 7.11 (m, 3H), 4.02 (s, 2H), 3.89 – 3.78(m, 2H), 2.94 (p, J = 7.8 Hz, 1H), 2.78 (t, J= 8.8 Hz, 1H), 2.68 (dd, J =9.2, 6.5 Hz, 1H), 2.64 – 2.52 (m, 2H), 1.96 (q, J = 7.3 Hz, 2H). 13 C NMR (151MHz, DMSO) δ 175.78, 144.69, 141.58, 139.66, 137.46, 136.99, 128.69, 128.42,125.95, 125.20, 122.98, 122.29, 121.35, 56.14, 54.27, 53.20, 41.55, 41.00,27.19.LC-MS (ESI): m / z: 352.10 [M+H] + . Synthetic route of 4-(((6-(naphth-2-yl)benzofuran-2-yl)methyl)amino)butyric acid (compound 9) Synthesis of 6-bromobenzofuran-2-carboxylic acid Ethyl 6-bromobenzofuran-2-carboxylic acid (1.35 g, 5.0 mmol) was added to a 50 mL single-necked flask and dissolved in 4 times the volume of methanol solution. Sodium hydroxide solution was slowly added dropwise to initiate the reaction at 60 °C. The reaction was monitored by TLC, and after completion, the product was purified by column chromatography to obtain the intermediate 6-bromobenzofuran-2-carboxylic acid (974 mg, yield 81.2%).

[0069] 1 H NMR (500 MHz, CD3OD) δ 7.82 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.57(s, 1H), 7.47 (dd, J = 8.4, 1.7 Hz, 1H). Synthesis of (6-bromobenzofuran-2-yl)methanol The intermediate 6-bromobenzofuran-2-carboxylic acid (970 mg, 4.04 mmol) was added to a 50 mL single-necked flask, dissolved in THF, and then borane-tetrahydrofuran solution was added. The reaction was allowed to proceed for 1 h until it was complete. The reaction was quenched with water, washed with sodium hydroxide solution, and the organic phase was extracted. The organic phase was purified by column chromatography to obtain the intermediate (6-bromobenzofuran-2-yl)methanol (347 mg, yield 38.1%).

[0070] 1 H NMR (500 MHz, CDCl3) δ 7.63 (s, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.35 (dd, J = 8.3, 1.6 Hz, 1H), 6.64 (s, 1H), 4.76 (d, J = 5.9 Hz, 2H), 1.92 (t, J = 6.2 Hz, 1H). Synthesis of 6-bromobenzofuran-2-carboxaldehyde In a 50 mL single-necked flask, the intermediate (6-bromobenzofuran-2-yl)methanol (318 mg, 1.40 mmol) was added, followed by the addition of 10 mL DMSO and stirring to dissolve. IBX (471 mg, 1.68 mmol) was then added, and the mixture was stirred at 25 °C. The reaction was monitored by TLC. After 70 min, the reaction was complete, quenched, and filtered. The extracted organic phase was evaporated to dryness and purified by column chromatography (PE:EA = 3:1) to obtain 6-bromobenzofuran-2-carboxaldehyde (290 mg, 91.9% yield).

[0071] Synthesis of 6-(naphthyl-2-yl)benzofuran-2-carboxaldehyde In a 50 mL two-necked flask, the intermediate 6-bromobenzofuran-2-carboxaldehyde (158 mg, 0.71 mmol), 2-naphthoboric acid (146 mg, 0.85 mmol), sodium carbonate (176 mg, 1.76 mmol), and dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium (51.9 mg, 0.07 mmol) were added. Under nitrogen protection, 5 mL of solvent (DMF:H2O = 4:1) was injected, and the temperature was raised to 110 °C. The reaction was monitored by TLC. The reaction was stirred for 2 h, and after complete reaction, water was added to quench the reaction. The organic phase was extracted by filtration. The organic phase was purified by column chromatography after rotary evaporation. The intermediate 6-(naphthyl-2-yl)benzofuran-2-carboxaldehyde (58 mg, yield 30.0%) was obtained.

[0072] Synthesis of 4-(((6-(naphth-2-yl)benzofuran-2-yl)methyl)amino)butyric acid In a 50 mL single-necked flask, 6-(naphth-2-yl)benzofuran-2-carboxaldehyde (55 mg, 0.20 mmol) and 4-aminobutyric acid (62.5 mg, 0.60 mmol) were added, dissolved in a suitable amount of methanol, and 1 drop of glacial acetic acid was added. After stirring at room temperature for 15 min, sodium cyanoborohydride (12.6 mg, 0.20 mmol) was added, and the reaction progress was monitored by TLC. After the reaction was complete, the mixture was extracted three times with ethyl acetate and water, and the combined organic phases were rotary evaporated. The organic phases were purified by column chromatography to obtain 4-(((6-(naphth-2-yl)benzofuran-2-yl)methyl)amino)butyric acid (white powder, 31 mg, yield 43.2%).

[0073] 1 H NMR (600 MHz, DMSO- d 6) δ 8.27 (s, 1H), 8.13 – 7.82 (m, 5H), 7.70 (s, 2H), 7.59 – 7.46 (m, 2H), 6.79 (s, 1H), 3.90 (s, 2H), 2.62 (t, J = 6.8Hz, 2H), 2.36 – 2.20 (m, 2H), 1.79 – 1.55 (m, 2H). 13 C NMR (151 MHz, DMSO- d 6)δ 175.10, 158.76, 155.51, 138.14, 136.54, 133.86, 132.59, 128.90, 128.64,128.22, 127.95, 126.86, 126.49, 125.87, 125.78, 122.57, 121.56, 109.70,104.01, 48.35, 46.04, 32.62, 24.97. LC-MS / ESI [M + H] + 360.10 Synthetic route of 4-(((6-(p-tolyl)benzofuran-2-yl)methyl)amino)butyric acid (compound 10) Synthesis of 6-(p-Tolyl)benzofuran-2-carboxaldehyde In a 50 mL two-necked flask, the intermediate 6-bromobenzofuran-2-carboxaldehyde (100 mg, 0.45 mmol), 4-tolueneboronic acid (73 mg, 0.54 mmol), sodium carbonate (112.5 mg, 1.125 mmol), and dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium (32.9 mg, 0.045 mmol) were added. Under nitrogen protection, 5 mL of solvent (DMF:H₂O = 4:1) was injected, and the temperature was raised to 110 °C. The reaction was monitored by TLC. The reaction was stirred for 2 h, and after complete reaction, water was added to quench the reaction. The organic phase was extracted by filtration. The organic phase was purified by column chromatography after rotary evaporation. The intermediate 6-(p-tolyl)benzofuran-2-carboxaldehyde (70 mg, yield 65.9%) was obtained.

[0074] 1 H NMR (500 MHz, CD3OD) δ 9.86 (s, 1H), 8.02 (dd, J = 2.0, 0.9 Hz, 1H), 7.84 (d, J = 0.9 Hz, 1H), 7.82 (dd, J = 8.7, 2.0 Hz, 1H), 7.69 (dt, J =8.7, 0.9 Hz, 1H), 7.56 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 2.40 (s, 3H). Synthesis of 4-(((6-(p-Tolyl)benzofuran-2-yl)methyl)amino)butyric acid In a 50 mL single-necked flask, intermediates 6-(p-tolyl)benzofuran-2-carboxaldehyde (35 mg, 0.148 mmol) and 4-aminobutyric acid (46 mg, 0.445 mmol) were added, dissolved in a suitable amount of methanol, and 1 drop of glacial acetic acid was added. After stirring at room temperature for 15 min, sodium cyanoborohydride (9.3 mg, 0.148 mmol) was added, and the reaction progress was monitored by TLC. After the reaction was complete, the mixture was extracted three times with ethyl acetate and water, and the combined organic phases were rotary evaporated. The organic phases were purified by column chromatography to obtain 4-(((6-(p-tolyl)benzofuran-2-yl)methyl)amino)butyric acid (white powder, 32 mg, yield 66.9%).

[0075] 1 H NMR (500 MHz, DMSO- d 6) δ 7.76 (s, 1H), 7.61 (dd,J = 13.7, 8.1 Hz, 3H), 7.50 (dd, J = 8.1, 1.4 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 6.77 (s, 1H), 3.91 (s, 2H), 2.63 (t, J = 6.8 Hz, 2H), 2.34 (s, 3H), 2.25 (t, J = 7.1 Hz, 2H), 1.67 (p, J = 7.0 Hz, 2H). 13 C NMR (126 MHz, DMSO- d 6) δ 157.35, 155.02,137.44, 136.53, 136.41, 129.57, 127.29, 126.74, 121.67, 121.05, 108.65,103.86, 48.63, 47.93, 45.36, 32.72, 20.68. LC-MS / ESI [M + H] + 324.15 2-Amino-3-(6-phenyl-1-amino) H Synthetic route of -indole-2-carbamate)propionic acid (compound 11) Referring to the synthetic route and method of compound 1 in Example 1, phenylboronic acid and 6-bromo-1 H 6-phenyl-1-indole-2-carboxylic acid was prepared by Suzuki coupling reaction using indole-2-carboxylic acid as the starting material. H The target compound 12 (white solid) was obtained by amidation condensation, alkaline hydrolysis and hydrogenation deprotection steps following the intermediate of indole-2-carboxylic acid.

[0076] 1 H NMR (500 MHz, DMSO- d 6) δ 11.84 (s, 1H), 8.91 (s, 1H), 7.89 (s, 1H), 7.67 (d, J = 7.6 Hz, 2H), 7.56 – 7.48 (m, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.30(t, J= 7.4 Hz, 1H), 7.22 (s, 1H), 3.89 – 3.75 (m, 1H), 3.65 (d, J = 20.2 Hz, 2H). 13 C NMR (126 MHz, DMSO) δ 162.1, 152.1, 145.0, 141.8, 136.6, 132.7, 129.3,128.1, 127.2, 126.9, 123.4, 119.9, 113.3, 104.2, 62.5, 55.4. LC-MS / ESI [M +H] + 324.10 4-(((6-(naphth-2-yl)benzo[ b Synthetic route of thiophene-2-yl)methyl)amino)butyric acid (compound 12) 6-Bromobenzo[ b Synthesis of thiophene-2-carboxaldehyde Add (6-bromobenzo[] to a 100 ml single-necked flask b Thiophene-2-yl)methanol (1.00 g, 4.11 mmol, 500 mg) was dissolved in DMSO with stirring. IBX (11.52 g, 20.57 mmol) was added, and the mixture was stirred. The reaction was monitored by TLC. After 40 min, the reaction was complete. The mixture was extracted three times with ethyl acetate and water. The organic phases were combined, and anhydrous sodium sulfate was added to remove water. The mixture was then concentrated by rotary evaporation. The product was separated by column chromatography (PE:EA = 10:1) to give 6-bromobenzo[ b Thiophene-2-carboxaldehyde (yellow powder, 200 mg, yield 20.2%).

[0077] 1 H NMR (400 MHz, DMSO- d 6) δ 10.15 (s, 1H), 8.45 (d, J = 1.5 Hz, 1H),8.42 (s, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.67 (dd, J = 8.6, 1.8 Hz, 1H). 6-(naphthyl-2-yl)benzo[ b Synthesis of thiophene-2-carboxaldehyde Add 6-bromobenzo[] to a 50 ml Shrek tube b Thiophene-2-carboxaldehyde (100 mg, 0.47 mmol), 2-naphthylboronic acid (80 mg, 0.47 mmol), DPPF palladium dichloride (28 mg, 0.038 mmol), and anhydrous sodium carbonate (124 mg, 1.18 mmol) were added under nitrogen protection. 5 ml of solvent (DMF:H2O = 4:1) was injected, and the reaction was carried out at 102 °C. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was extracted three times with ethyl acetate and water. The organic phases were combined, and anhydrous sodium sulfate was added to remove water. The mixture was then concentrated by rotary evaporation, and the product was separated by column chromatography (PE:EA = 20:1) to give 6-(naphthyl-2-yl)benzo[ b Thiophene-2-carboxaldehyde (pale yellow powder, 136 mg, yield 100.3%).

[0078] 1 H NMR (400 MHz, DMSO- d 6) δ 10.17 (s, 1H), 8.64 – 8.58 (m, 1H), 8.48(d, J = 0.8 Hz, 1H), 8.44 – 8.38 (m, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.10 –7.92 (m, 5H), 7.63 – 7.52 (m, 2H). 4-(((6-(naphth-2-yl)benzo[ b Synthesis of thiophene-2-ylmethylaminobutyric acid Add 6-(naphth-2-yl)benzo[] to a 100 mL single-necked flask b Thiophene-2-carboxaldehyde (136 mg, 0.47 mmol) and 4-aminobutyric acid (73 mg, 0.71 mmol) were injected into 5 ml of solvent (DCM:MeOH = 3:1). After reacting for 15 min, the pH was adjusted to approximately 4-6, and sodium cyanoborohydride (30 mg, 0.47 mmol) was added. The reaction was carried out at room temperature for 12 h, and the reaction progress was monitored by TLC. After the reaction was complete, the mixture was extracted three times with ethyl acetate and water. The organic phases were combined, and anhydrous sodium sulfate was added to remove water. The mixture was then concentrated by rotary evaporation, and the product was separated by column chromatography (DCM:MeOH = 10:1) to obtain 4-(((6-(naphthyl-2-yl)benzo[ b Thiophene-2-yl)methyl)amino)butyric acid (yellow powder, 80 mg, yield 45.3%).

[0079] 1H NMR (600 MHz, DMSO- d 6) δ 8.38 (s, 1H), 8.31 (s, 1H), 8.02 (t, J =7.9 Hz, 2H), 7.97 – 7.92 (m, 2H), 7.87 (d, J = 8.2 Hz, 1H), 7.81 (dd, J =8.2, 1.7 Hz, 1H), 7.57 – 7.50 (m, 2H), 7.34 (s, 1H), 4.04 (s, 2H), 2.62 (t, J = 6.9 Hz, 2H), 2.30 (t, J = 7.3 Hz, 2H), 1.69 (p, J = 7.1 Hz, 2H). 13 C NMR (151 MHz, DMSO-) d 6) δ 148.11, 139.96, 139.07, 137.51, 133.45, 132.16, 128.48,128.19, 127.52, 126.44, 126.06, 125.31, 123.44, 120.29, 48.74, 48.42, 34.60,23.94. LC-MS (ESI): m / z: 376.20 [M+H] + . 4-(((6-(6-phenylnaphth-2-yl)benzo[ b Synthetic route of thiophene-2-yl)methyl)amino)butyric acid (compound 13) 6-(6-phenylnaphth-2-yl)benzo[ b Synthesis of thiophene-2-carboxaldehyde Add 6-bromobenzo[] to a 50 ml Shrek tube. bThiophene-2-carboxaldehyde (400 mg, 0.83 mmol), 6-phenyl-2-naphthylboronic acid (412 mg, 1.66 mmol), DPPF palladium dichloride (97 mg, 0.13 mmol), and anhydrous sodium carbonate (440 mg, 4.15 mmol) were added under nitrogen protection. The mixture was injected with 6 ml of solvent (DMF:H2O = 4:1) and reacted at 102 °C. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was extracted three times with ethyl acetate and water. The organic phases were combined, and anhydrous sodium sulfate was added to remove water. The mixture was then concentrated by rotary evaporation, and the product was separated by column chromatography (PE:EA = 40:1) to give 6-(6-phenylnaphth-2-yl)benzo[ b Thiophene-2-carboxaldehyde (pale yellow powder, 268 mg, yield 44.3%).

[0080] 1 H NMR (400 MHz, Chloroform- d ) δ 10.14 (s, 1H), 8.28 – 8.24 (m, 1H), 8.16 (d, J = 1.8 Hz, 1H), 8.12 – 7.97 (m, 5H), 7.89 – 7.79 (m, 3H), 7.78 –7.72 (m, 2H), 7.51 (t, J = 7.7 Hz, 2H), 7.44 – 7.37 (m, 1H). 4-(((6-(6-phenylnaphth-2-yl)benzo[ b Synthesis of thiophene-2-ylmethylaminobutyric acid Add 6-(6-phenylnaphth-2-yl)benzo[] to a 100 mL single-necked flask b Thiophene-2-carboxaldehyde (63 mg, 0.17 mmol) and 4-aminobutyric acid (17 mg, 0.16 mmol) were added to 5 ml of solvent (DCM:MeOH = 3:1). After reacting for 15 min, the pH was adjusted to approximately 4-6, and sodium cyanoborohydride (11 mg, 0.17 mmol) was added. The reaction was carried out at room temperature for 12 h, and the reaction progress was monitored by TLC. After the reaction was complete, the product was extracted three times with ethyl acetate and water. The organic phases were combined, and anhydrous sodium sulfate was added to remove water. The product was then concentrated by rotary evaporation and separated by column chromatography (DCM:MeOH = 10:1) to obtain 4-(((6-(6-phenylnaphth-2-yl)benzo[ b Thiophene-2-yl)methyl)amino)butyric acid (yellow powder, 20 mg, yield 26.1%).

[0081] 1H NMR (400 MHz, DMSO- d 6) δ 8.39 (s, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 8.10 (d, J = 8.5 Hz, 2H), 7.98 (d, J = 8.6 Hz, 1H), 7.92 – 7.83 (m, 5H), 7.53(t, J = 7.5 Hz, 3H), 7.44 – 7.41 (m, 1H), 7.32 (s, 1H), 4.02 (s, 2H), 2.60(t, J = 6.8 Hz, 2H), 2.24 (t, 2H), 1.68 (p, J = 14.2, 7.1 Hz, 2H). 4-(((6-phenylbenzo[ b Synthetic route of thiophene-2-yl)methyl)amino)butyric acid (compound 14) (6-bromobenzo[ b Synthesis of thiophene-2-yl)methanol Add 6-bromobenzo[] to a 250 mL two-necked flask b Methyl thiophene-2-carboxylate (2.00 g, 7.38 mmol) was purged with nitrogen to remove air, and 55 ml of anhydrous tetrahydrofuran solution was injected. 1 M DIBAL-H (22 ml, 22.13 mmol) was slowly added dropwise at -40°C. After 2 h of reaction, methanol was slowly added at 0°C to quench the reaction, resulting in a large amount of white solid. A suitable amount of dilute hydrochloric acid was added to dissolve the solid. The solid was extracted with ethyl acetate and water, and the organic phases were combined. Anhydrous sodium sulfate was added to remove water, and the mixture was concentrated by rotary evaporation. The product was separated by column chromatography (PE:EA = 3:1). (6-Bromobenzo[…] b Thiophene-2-yl)methanol (white powder, 1.86 g, yield 103.7%).

[0082] 1 H NMR (400 MHz, Chloroform- d ) δ 7.95 (d, J = 1.7 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.44 (dd, J= 8.5, 1.8 Hz, 1H), 7.17 (s, 1H), 4.92 (s, 2H). 6-Bromobenzo[ b Synthesis of thiophene-2-carboxaldehyde Add (6-bromobenzo[] to a 250 mL single-necked flask b Thiophene-2-yl)methanol (1.87 g, 7.68 mmol) was added to 45 mL of dichloromethane with stirring. Desmartin reagent (4.88 g, 11.51 mmol) was slowly added, and the reaction was monitored by TLC. After the reaction was complete, an appropriate amount of sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate and water. The organic phases were combined, and after removing water with anhydrous sodium sulfate, the mixture was concentrated by rotary evaporation. The product was separated by column chromatography (PE:EA = 3:1). 6-Bromobenzo[ b Thiophene-2-carboxaldehyde (white powder, 1.22 g, yield 65.9%).

[0083] 1 H NMR (400 MHz, Chloroform- d ) δ 10.10 (s, 1H), 8.06 (d, J = 1.9 Hz,1H), 7.99 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.55 (dd, J = 8.6, 1.7 Hz, 1H). 6-Phenylaceto[ b Synthesis of thiophene-2-carboxaldehyde Add 6-bromobenzo[] to a 50 ml Shrek tube. b Thiophene-2-carboxaldehyde (300 mg, 1.24 mmol), phenylboronic acid (182 mg, 1.49 mmol), DPPF palladium dichloride (73 mg, 0.10 mmol), sodium carbonate (329 mg, 3.10 mmol), under nitrogen protection, 6 ml of solvent (DMF:H2O=4:1) was injected, and the reaction was carried out at 102 °C. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was extracted three times with ethyl acetate and water. The organic phases were combined, and anhydrous sodium sulfate was added to remove water. The mixture was then concentrated by rotary evaporation, and the product was separated by column chromatography (PE:EA=3:1) to give 6-phenylbenzo[ b Thiophene-2-carboxaldehyde (pale yellow powder, 300 mg, yield 101.6%).

[0084] 1H NMR (400 MHz, DMSO- d 6) δ 10.15 (s, 1H), 8.45 (s, 1H), 8.44 (d, J =1.8 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.89 – 7.76 (m, 3H), 7.57 – 7.48 (m,2H), 7.47 – 7.40 (m, 1H). LC-MS: m / z: 239.10 [M+H] + . 4-(((6-phenylbenzo[ b Synthesis of thiophene-2-ylmethylaminobutyric acid Add 6-phenylbenzo[] to a 50 mL single-necked flask b Thiophene-2-carboxaldehyde (300 mg, 1.26 mmol) and 4-aminobutyric acid (195 mg, 1.89 mmol) were injected into 6 ml of solvent (DCM:MeOH = 3:1). After reacting for 15 min, the pH was adjusted to approximately 4-6, and sodium cyanoborohydride (119 mg, 1.89 mmol) was added. The reaction was carried out at room temperature for 12 h, and the reaction progress was monitored by TLC. After the reaction was complete, the product was extracted three times with dichloromethane and water. The organic phases were combined, and anhydrous sodium sulfate was added to remove water. The product was then concentrated by rotary evaporation and separated by column chromatography (DCM:MeOH = 10:1) to obtain 4-(((6-phenylbenzo[ b Thiophene-2-yl)methyl)amino)butyric acid (white powder, 221 mg, yield 51.4%).

[0085] 1 H NMR (400 MHz, DMSO- d 6) δ 8.21 (d, J = 1.6 Hz, 1H), 7.82 (d, J = 8.3Hz, 1H), 7.75 (s, 1H), 7.73 (s, 1H), 7.64 (dd, J = 8.3, 1.7 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.31 (s, 1H), 4.02 (s, 2H), 2.60(t, J= 6.8 Hz, 2H), 2.29 (t, J = 7.3 Hz, 2H), 1.68 (p, J = 7.1 Hz, 2H). 13 CNMR (151 MHz, DMSO- d 6) δ 174.98, 140.62, 140.43, 139.30, 136.44, 129.45,127.75, 127.33, 123.93, 123.81, 120.81, 48.32, 48.12, 32.36, 24.79. LC-MS(ESI): m / z: 326.20 [M+H] + . ( S )-1-((6-(naphth-2-yl)benzo[ b Synthetic route of thiophene-2-yl)methyl)pyrrolidine-3-carboxylic acid (compound 15) 6-(naphthyl-2-yl)benzo[ b Synthesis of thiophene-2-carboxaldehyde Add 6-bromobenzo[] to a 50 ml Shrek tube b Thiophene-2-carboxaldehyde (200 mg, 0.83 mmol), 2-naphthylboronic acid (143 mg, 0.83 mmol), DPPF palladium dichloride (49 mg, 0.066 mmol), and anhydrous sodium carbonate (220 mg, 2.08 mmol) were added under nitrogen protection. The mixture was injected with 6 ml of solvent (DMF:H2O = 4:1) and reacted at 102 °C. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was extracted three times with ethyl acetate and water. The organic phases were combined, and anhydrous sodium sulfate was added to remove water. The mixture was then concentrated by rotary evaporation, and the product was separated by column chromatography (PE:EA = 10:1) to give 6-(naphthyl-2-yl)benzo[ b Thiophene-2-carboxaldehyde (pale yellow powder, 220 mg, yield 91.9%).

[0086] 1 H NMR (400 MHz, DMSO- d 6) δ 10.17 (s, 1H), 8.64 – 8.58 (m, 1H), 8.48(d, J = 0.8 Hz, 1H), 8.44 – 8.38 (m, 1H), 8.25 (d, J= 8.4 Hz, 1H), 8.10 –7.92 (m, 5H), 7.63 – 7.52 (m, 2H). ( S )-1-((6-(naphth-2-yl)benzo[ b Synthesis of thiophene-2-yl)methyl)pyrrolidine-3-carboxylic acid Add 6-(naphth-2-yl)benzo[] to a 100 mL single-necked flask b Thiophene-2-carboxaldehyde (314 mg, 1.09 mmol), ( S )-pyrrolidine-3-carboxylic acid (119 mg, 1.04 mmol) was injected into 5 ml of solvent (DCM:MeOH = 3:1). After reacting for 15 min, the pH was adjusted to approximately 4-6, and sodium cyanoborohydride (68 mg, 1.09 mmol) was added. The reaction was carried out at room temperature for 12 h, and the reaction progress was monitored by TLC. After the reaction was complete, the product was extracted three times with ethyl acetate and water. The organic phases were combined, and anhydrous sodium sulfate was added to remove water. The product was then concentrated by rotary evaporation and separated by column chromatography (DCM:MeOH = 10:1) to obtain ( S )-1-((6-(naphth-2-yl)benzo[ b Thiophene-2-yl)methyl)pyrrolidine-3-carboxylic acid (yellow powder, 105 mg, yield 24.9%).

[0087] 1 H NMR (600 MHz, DMSO- d 6) δ 8.37 (d, J = 1.7 Hz, 1H), 8.31 (d, J = 1.8Hz, 1H), 8.02 (t, J = 8.0 Hz, 2H), 7.97 – 7.92 (m, 2H), 7.88 (d, J = 8.3 Hz, 1H), 7.82 (dd, J = 8.3, 1.7 Hz, 1H), 7.59 – 7.49 (m, 2H), 7.34 (s, 1H), 3.92(q, 2H), 3.02 – 2.93 (m, 1H), 2.83 (t, J = 8.8 Hz, 1H), 2.73 (dd, J = 9.4,6.4 Hz, 1H), 2.67 – 2.55 (m, 2H), 2.04 – 1.95 (m, 2H).13 C NMR (151 MHz, DMSO- d 6) δ 176.22, 140.73, 139.20, 137.93, 132.65, 128.95, 128.66, 127.98, 126.91,126.55, 125.82, 125.78, 124.12, 124.06, 121.71, 121.11, 56.64, 54.81, 53.75,42.01, 27.69. LC-MS: m / z: 388.10 [M+H] + . ( S )-1-((6-(6-phenylnaphth-2-yl)benzo[ b Synthetic route of thiophene-2-yl)methyl)pyrrolidine-3-carboxylic acid (compound 16) 6-(6-phenylnaphth-2-yl)benzo[ b Synthesis of thiophene-2-carboxaldehyde Add 6-bromobenzo[] to a 50 ml Shrek tube b Thiophene-2-carboxaldehyde (400 mg, 0.83 mmol), 6-phenyl-2-naphthylboronic acid (412 mg, 1.66 mmol), DPPF palladium dichloride (97 mg, 0.13 mmol), and anhydrous sodium carbonate (440 mg, 4.15 mmol) were added under nitrogen protection. The mixture was injected with 6 ml of solvent (DMF:H2O = 4:1) and reacted at 102 °C. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was extracted three times with ethyl acetate and water. The organic phases were combined, and anhydrous sodium sulfate was added to remove water. The mixture was then concentrated by rotary evaporation, and the product was separated by column chromatography (PE:EA = 40:1) to give 6-(6-phenylnaphth-2-yl)benzo[ b Thiophene-2-carboxaldehyde (pale yellow powder, 268 mg, yield 44.3%).

[0088] 1 H NMR (400 MHz, Chloroform- d ) δ 10.14 (s, 1H), 8.28 – 8.24 (m, 1H), 8.16 (d, J = 1.8 Hz, 1H), 8.12 – 7.97 (m, 5H), 7.89 – 7.79 (m, 3H), 7.78 –7.72 (m, 2H), 7.51 (t, J= 7.7 Hz, 2H), 7.44 – 7.37 (m, 1H). ( S )-1-((6-(6-phenylnaphth-2-yl)benzo[ b Synthesis of thiophene-2-yl)methyl)pyrrolidine-3-carboxylic acid Add 6-(6-phenylnaphth-2-yl)benzo[] to a 100 mL single-necked flask b Thiophene-2-carboxaldehyde (120 mg, 0.33 mmol), ( S 3-pyrrolidine-3-carboxylic acid (36 mg, 0.31 mmol) was injected into 5 ml of solvent (DCM:MeOH = 3:1). After reacting for 15 min, the pH was adjusted to approximately 4-6, and sodium cyanoborohydride (21 mg, 0.33 mmol) was added. The reaction was carried out at room temperature for 12 h, and the reaction progress was monitored by TLC. After the reaction was complete, the product was extracted three times with ethyl acetate and water. The organic phases were combined, and anhydrous sodium sulfate was added to remove water. The product was then concentrated by rotary evaporation and separated by column chromatography (DCM:MeOH = 10:1) to obtain ( S )-1-((6-(6-phenylnaphth-2-yl)benzo[ b Thiophene-2-yl)methyl)pyrrolidine-3-carboxylic acid (yellow powder, 30 mg, yield 19.6%).

[0089] 1 H NMR (600 MHz, DMSO- d 6) δ 8.26 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 1.9Hz, 1H), 8.13 (d, J = 1.8 Hz, 1H), 7.97 (dd, J = 8.7, 2.3 Hz, 2H), 7.85 (dd, J = 8.5, 1.9 Hz, 1H), 7.78 – 7.74 (m, 2H), 7.74 – 7.66 (m, 3H), 7.40 (t, J =7.7 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.21 (s, 1H), 3.77 (q, 2H), 2.83 (p, J = 7.9 Hz, 1H), 2.70 (t, J= 8.9 Hz, 1H), 2.60 (dd, J = 9.4, 6.4 Hz, 1H), 2.56– 2.39 (m, 2H), 1.86 (q, J = 7.3 Hz, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ 145.81,140.75, 140.39, 139.24, 138.03, 132.99, 129.55, 127.43, 126.03, 125.52,125.45, 124.14, 124.01, 121.70, 121.07, 56.74, 54.85, 53.80, 40.51. ( S )-1-((6-([1,1'-biphenyl]-4-yl)benzo[ b Synthetic route of thiophene-2-yl)methyl)pyrrolidine-3-carboxylic acid (compound 17) Referring to the synthetic route and method of compound 16 in Example 1, [1,1'-biphenyl]-4-ylboronic acid was used instead of 6-phenyl-2-naphthoboronic acid as the starting material, and 6-bromobenzyl... b Thiophene-2-carboxaldehyde was coupled via a Suzuki reaction to yield 6-([1,1'-biphenyl]-4-yl)benzo[ b Thiophene-2-carboxaldehyde intermediate, subsequently with (S) The target compound 18 (white solid) was prepared by reductive amination of pyrrolidine-3-carboxylic acid.

[0090] 1 H NMR (500 MHz, DMSO- d 6) δ 8.27 (d, J = 1.4 Hz, 1H), 7.85 (d, J = 8.5Hz, 3H), 7.78 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 7.7 Hz, 2H), 7.72 – 7.69 (m,1H), 7.49 (t, J = 7.6 Hz, 2H), 7.39 (t, J= 7.4 Hz, 1H), 7.31 (s, 1H), 3.98 –3.81 (m, 2H), 3.02 – 2.90 (m, 1H), 2.83 (t, J = 8.8 Hz, 1H), 2.73 (dd, J =9.3, 6.4 Hz, 1H), 2.67 – 2.55 (m, 2H), 1.99 (q, J = 7.3 Hz, 2H). 13 C NMR (126MHz, DMSO- d 6) δ 176.35, 145.65, 140.68, 140.07, 139.42, 139.17, 135.93,129.46, 127.98, 127.81, 127.66, 127.02, 124.06, 123.66, 121.65, 120.66,56.70, 54.80, 53.75, 42.16, 27.73. LC-MS (ESI): m / z: 414.20 [M+H] + . ( S )-1-((6-benzylbenzo[ b Synthetic route of thiophene-2-yl)methyl)pyrrolidine-3-carboxylic acid (compound 18) Referring to the synthetic route and method of compound 16 in Example 1, 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborane was used instead of 6-phenyl-2-naphthoboric acid as the starting material, and 6-bromobenzo[ b Thiophene-2-carboxaldehyde was coupled via a Suzuki reaction to produce 6-benzylbenzo[ b ]Thiophene-2-carboxaldehyde intermediate, subsequently with ( S The target compound 19 (white solid) was prepared by reductive amination of 3-pyrrolidine-3-carboxylic acid.

[0091] 1 H NMR (500 MHz, DMSO- d 6) δ 7.73 (s, 1H), 7.65 (d, J= 8.1 Hz, 1H),7.31 – 7.24 (m, 4H), 7.23 – 7.16 (m, 3H), 4.03 (s, 2H), 3.88 – 3.79 (m, 2H),2.98 – 2.88 (m, 1H), 2.79 (t, J = 8.8 Hz, 1H), 2.69 – 2.65 (m, 1H), 2.62 –2.57 (m, 1H), 2.57 – 2.52 (m, 1H), 1.96 (q, J = 7.2 Hz, 2H). 13 C NMR (126 MHz, DMSO- d 6) δ 176.26, 144.15, 141.91, 140.02, 137.97, 129.16, 128.90, 126.43,125.94, 123.57, 122.43, 121.64, 56.66, 54.73, 53.68, 42.12, 41.55, 27.70. LC-MS (ESI): m / z: 352.20 [M+H] + . 4-(((7-(6-phenylnaphth-2-yl)benzo[ b Synthetic route of thiophene-2-yl)methyl)amino)butyric acid (compound 19) 7-Bromobenzo[ b Synthesis of thiophene-2-carboxaldehyde Add (7-bromobenzo[] to a 100 ml single-necked flask b Thiophene-2-yl)methanol (4.11 mmol, 500 mg) was dissolved in an appropriate amount of DMSO with stirring. IBX (8.22 mmol, 2.30 g) was added, and the reaction was stirred. The reaction progress was monitored by TLC. After 40 min, the reaction was complete. The mixture was extracted three times with ethyl acetate and water. The combined organic phases were rotary evaporated, and the product was separated by column chromatography (PE:EA = 10:1) to give 7-bromobenzo[ b Thiophene-2-carboxaldehyde (white solid, 503 mg, unresolved, directly added to the next reaction step).

[0092] 7-(6-phenylnaphth-2-yl)benzo[ b Synthesis of thiophene-2-carboxaldehyde Add 7-bromobenzo[] to a 50 ml Shrek tube b Thiophene-2-carboxaldehyde (0.83 mmol, 200 mg), 2-phenyl-6-naphthylboronic acid (0.83 mmol, 206 mg), DPPF palladium dichloride (0.066 mmol, 48 mg), sodium carbonate (2.08 mmol, 2.20 mg), under nitrogen protection, 5 ml of solvent (DMF:H2O=4:1) was injected, and the reaction was carried out at 102 °C. The reaction progress was monitored by TLC. After the reaction was complete, the product was extracted three times with ethyl acetate and water, the organic phases were combined and rotary evaporated, and the product was separated by column chromatography (PE:EA=40:1) to give 7-(6-phenylnaphth-2-yl)benzo[ b Thiophene-2-carboxaldehyde (pale yellow powder, 280 mg, yield 92.6%).

[0093] 4-(((7-(6-phenylnaphth-2-yl)benzo[ b Synthesis of thiophene-2-ylmethylaminobutyric acid Add 7-(6-phenylnaphth-2-yl)benzo[] to a 100 mL single-necked flask b Thiophene-2-carboxaldehyde (0.59 mmol, 214 mg) and 4-aminobutyric acid (0.89 mmol, 91 mg) were injected into 8 ml of solvent (DCM:MeOH = 3:1). After reacting for 15 min, the pH was adjusted to approximately 4-6, and sodium cyanoborohydride (0.59 mmol, 37 mg) was added. The reaction was carried out at room temperature for 12 h, and the reaction progress was monitored by TLC. After the reaction was complete, the product was extracted three times with ethyl acetate and water, and the combined organic phases were rotary evaporated. The product was separated by column chromatography (DCM:MeOH = 10:1) to obtain 4-(((7-(6-phenylnaphthyl-2-yl)benzo[ b Thiophene-2-yl)methyl)amino)butyric acid (white powder, 172 mg, yield 64.6%).

[0094] 1 H NMR (600 MHz, DMSO- d 6) δ 8.31 (d, J = 16.4 Hz, 2H), 8.17 (d, J =8.5 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.93 (dd, J = 8.5, 1.9 Hz, 1H), 7.91 –7.85 (m, 3H), 7.80 (dd, J= 7.2, 1.7 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.53– 7.48 (m, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.40 (s, 1H), 4.00 (s, 2H), 2.56(t, J = 6.9 Hz, 2H), 2.17 (t, J = 7.3 Hz, 2H), 1.63 (p, J = 7.1 Hz, 2H). 13 CNMR (151 MHz, DMSO- d 6) δ 141.09, 140.32, 138.45, 138.24, 138.13, 132.77,129.57, 129.43, 129.40, 128.19, 127.50, 126.99, 126.83, 126.23, 48.65. LC-MS(ESI): m / z: 452.20 [M+H] + . ( S )-1-((7-(naphth-2-yl)benzo[ b Synthetic route of thiophene-2-yl)methyl)pyrrolidine-3-carboxylic acid (compound 20) 7-(naphthyl-2-yl)benzo[ b Synthesis of thiophene-2-carboxaldehyde Add 7-bromobenzo[] to a 50 ml Shrek tube. b Thiophene-2-carboxaldehyde (1.24 mmol, 300 mg), 2-naphthylboronic acid (1.24 mmol, 213 mg), DPPF palladium dichloride (0.10 mmol, 73 mg), and sodium carbonate (3.10 mmol, 329 mg) were added under nitrogen protection. 10 ml of solvent (DMF:H2O = 4:1) was injected, and the reaction was carried out at 102 °C. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was extracted three times with ethyl acetate and water. The combined organic phases were rotary evaporated, and the product was separated by column chromatography (PE:EA = 40:1) to give 7-(naphthyl-2-yl)benzo[ b Thiophene-2-carboxaldehyde (pale yellow solid, 317 mg, yield 88.7%).

[0095] ( S)-1-((7-(naphth-2-yl)benzo[ b Synthesis of thiophene-2-yl)methyl)pyrrolidine-3-carboxylic acid Add 7-(naphth-2-yl)benzo[] to a 100 mL single-necked flask b Thiophene-2-carboxaldehyde (0.52 mmol, 150 mg), ( S )-pyrrolidine-3-carboxylic acid (0.78 mmol, 90 mg) was injected into 8 ml of solvent (DCM:MeOH = 3:1). After reacting for 15 min, the pH was adjusted to approximately 4-6, and sodium cyanoborohydride (0.52 mmol, 33 mg) was added. The reaction was carried out at room temperature for 12 h, and the reaction progress was monitored by TLC. After the reaction was complete, the product was extracted three times with ethyl acetate and water, and the combined organic phases were rotary evaporated. The product was separated by column chromatography (DCM:MeOH = 10:1) to obtain ( S )-1-((7-(naphth-2-yl)benzo[ b Thiophene-2-yl)methyl)pyrrolidine-3-carboxylic acid (white powder, 104 mg, yield 51.6%).

[0096] 1 H NMR (600 MHz, DMSO- d 6) δ 8.25 (d, J = 1.9 Hz, 1H), 8.08 (d, J = 8.4Hz, 1H), 8.06 – 7.97 (m, 2H), 7.88 – 7.79 (m, 2H), 7.62 – 7.56 (m, 2H), 7.54– 7.47 (m, 2H), 7.40 (s, 1H), 2.92 (p, J = 7.9 Hz, 1H), 2.81 (t, J = 8.9 Hz,1H), 2.71 – 2.65 (m, 1H), 2.61 (q, J = 7.4 Hz, 1H), 2.56 – 2.52 (m, 1H), 1.94(q, J = 7.3 Hz, 2H). 13 C NMR (151 MHz, DMSO- d6) δ 176.26, 145.18, 140.81,138.54, 137.93, 136.11, 133.53, 132.96, 129.01, 128.68, 128.11, 127.10,126.99, 126.53, 125.66, 124.63, 123.13, 122.49, 56.74, 54.68, 53.73, 27.70.LC-MS (ESI): m / z: 388.20 [M+H] + . ( R )-1-((7-(naphth-2-yl)benzo[ b Synthetic route of thiophene-2-yl)methyl)pyrrolidine-3-carboxylic acid (compound 21) Referring to the synthetic route and method of compound 20 in Example 1, 7-bromobenzo[ b The Suzuki coupling reaction of thiophene-2-carboxaldehyde and 2-naphthylboronic acid yields 7-(naphth-2-yl)benzo[ b Thiophene-2-carboxaldehyde intermediate, subsequently... (R) -Pyrrolidine-3-carboxylic acid substitution (S) The target compound 22 (white solid) was prepared by reductive amination of pyrrolidine-3-carboxylic acid.

[0097] 1 H NMR (600 MHz, DMSO- d 6) δ 8.25 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H),8.05 – 7.97 (m, 2H), 7.88 – 7.78 (m, 2H), 7.62 – 7.56 (m, 2H), 7.55 – 7.46(m, 2H), 7.40 (s, 1H), 3.88 (s, 2H), 2.90 (p, J = 7.7 Hz, 1H), 2.81 (t, J =8.8 Hz, 1H), 2.68 – 2.64 (m, 1H), 2.61 (q, J = 7.3 Hz, 1H), 1.97 – 1.87 (m,3H). 13 C NMR (151 MHz, DMSO- d6) δ 176.43, 145.22, 138.53, 136.10, 132.96,129.01, 128.68, 128.11, 127.10, 126.99, 126.53, 125.65, 124.62, 123.12,122.47, 56.87, 54.73, 53.78, 42.33, 27.79. LC-MS (ESI): m / z: 388.20 [M+H] + . 3-(((7-(6-phenylnaphth-2-yl)benzo[ b Synthetic route of thiophene-2-yl)methyl)amino)cyclobutane-1-carboxylic acid (compound 22) Referring to the synthetic route and method of compound 20 in Example 1, 7-bromobenzo[ b The Suzuki coupling reaction of thiophene-2-carboxaldehyde and 6-phenyl-2-naphthylboronic acid yields 7-(6-phenylnaphth-2-yl)benzo[ b The thiophene-2-carboxaldehyde intermediate was subsequently replaced by 3-aminocyclobutane-1-carboxylic acid. S The target compound 23 (yellow powder) was prepared by reductive amination of 3-pyrrolidine-3-carboxylic acid.

[0098] 1 H NMR (400 MHz, DMSO- d 6) δ 8.30 (d, J = 14.0 Hz, 2H), 8.14 (dd, J =17.1, 8.5 Hz, 2H), 7.93 (d, J = 8.9 Hz, 1H), 7.90 – 7.83 (m, 3H), 7.80 (d, J = 6.6 Hz, 1H), 7.63 – 7.30 (m, 6H), 3.92 (s, 2H), 3.61 – 3.42 (m, 1H), 3.20 –3.05 (m, 1H), 1.96 – 1.81 (m, 2H), 1.73 – 1.55 (m, 2H). Synthetic route of 4-(((7-(naphth-2-yl)benzofuran-2-yl)methyl)amino)butyric acid (compound 23) Synthesis of ethyl 7-bromobenzofuran-2-carboxylate Add 1 g (4.97 mmol) of 3-bromo-2-hydroxybenzaldehyde to a 100 mL single-necked flask, and then add 15 mL of [unclear text - possibly a typo, should be "1 g, 4.97 mmol"]. N - N Dimethylformamide (DMF) was dissolved under stirring, and sodium carbonate (2 g, 14.47 mmol) was added. The mixture was heated to 90 °C and stirred for more than 20 h. The reaction progress was monitored by TLC. After the reaction was complete, the product was extracted three times with ethyl acetate and water. The combined organic phases were rotary evaporated, and the product was separated by column chromatography (PE:EA = 10:1) to obtain ethyl 7-bromobenzofuran-2-carboxylate (550 mg, yield 41.9%).

[0099] 1 H NMR (500 MHz, CD3OD) δ 7.71 (dd, J = 7.9, 1.1 Hz, 1H), 7.68 – 7.62(m, 2H), 7.23 (t, J = 7.8 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1Hz, 3H). Synthesis of (7-bromobenzofuran-2-yl)methanol Ethyl 7-bromobenzofuran-2-carboxylic acid (550 mg, 2.05 mmol) was added to a 100 mL single-necked flask, followed by the addition of 20 mL of tetrahydrofuran (THF) with stirring to dissolve. Ultradry 1.0 M lithium aluminum hydride solution (2.05 mmol) was slowly added dropwise under ice bath conditions, and the reaction was stirred for 40 min. The reaction progress was monitored using thin-layer chromatography (TLC). After the reaction was complete, sodium carbonate solution was added to quench the reaction, and the organic phase was evaporated by rotary evaporation after filtration. The solution was purified by column chromatography to give (7-bromobenzofuran-2-yl)methanol (300 mg, yield 64.8%).

[0100] Following the synthetic method of compound 9, (7-bromobenzofuran-2-yl)methanol was oxidized by IBX to obtain 7-bromobenzofuran-2-carboxaldehyde, which was then subjected to a Suzuki coupling reaction with 2-naphthoboric acid to obtain the intermediate 7-(naphtho-2-yl)benzofuran-2-carboxaldehyde. Finally, it was subjected to a reductive amination reaction with 4-aminobutyric acid to obtain the target compound 24 (white powder).

[0101] 1H NMR (500 MHz, CD3OD) δ 8.36 (s, 1H), 7.98 (s, 3H), 7.90 (d, J = 7.3Hz, 1H), 7.65 (d, J = 5.5 Hz, 2H), 7.52 (d, J = 5.6 Hz, 2H), 7.43 – 7.36 (m,1H), 7.11 (s, 1H), 4.41 (s, 2H), 3.12 (d, J = 6.0 Hz, 2H), 2.38 (d, J = 6.0Hz, 2H), 1.93 – 1.85 (m, 2H). 13 C NMR (126 MHz, CD3OD) δ 152.79, 148.66,133.63, 133.43, 132.96, 128.68, 128.01, 127.89, 127.33, 127.26, 126.19,126.00, 125.48, 124.94, 123.82, 120.63, 108.66, 43.16, 34.17, 21.85. LC-MS / ESI [M - H] - 360.10 4-(((7-(naphthyl-2-yl)-1 H Synthetic route of -indol-2-yl)methyl)amino)butyric acid (compound 24) Referring to the synthetic method of compound 23, 7-bromo-1 H Starting with ethyl indole-2-carboxylate, reduction with lithium aluminum hydride yields (7-bromo-1-carboxylate). H -Indole-2-yl)methanol, which is then oxidized by IBX to give 7-bromo-1 H -Indole-2-carboxaldehyde, followed by a Suzuki coupling reaction with 2-naphthoboric acid, yields 7-(naphtho-2-yl)-1 H The intermediate 2-indole-2-carboxaldehyde was finally reacted with 4-aminobutyric acid via a reducing amination reaction to obtain the target compound 25 (pale yellow powder).

[0102] 1 H NMR (600 MHz, DMSO- d 6) δ 10.82 (s, 1H), 8.18 (d, J = 1.8 Hz, 1H), 8.07 (d,J = 8.4 Hz, 1H), 8.05 – 8.02 (m, 1H), 8.00 – 7.98 (m, 1H), 7.78 (dd, J = 8.4, 1.8 Hz, 1H), 7.59 – 7.54 (m, 2H), 7.51 (d, J = 7.3 Hz, 1H), 7.19(dd, J = 7.3, 1.1 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 6.45 (d, J = 1.7 Hz,1H), 3.90 (s, 2H), 2.59 (d, J = 6.5 Hz, 2H), 2.26 (t, J = 6.9 Hz, 2H), 1.64(p, J = 6.7 Hz, 2H). LC-MS / ESI [M + H] + 359.15 ( S )-1-((7-(naphthyl-2-yl)-1 H Synthetic route of -indol-2-yl)methyl)pyrrolidine-3-carboxylic acid (compound 25) Referring to the synthetic method of compound 24, 7-bromo-1 H Starting with ethyl indole-2-carboxylate, reduction with lithium aluminum hydride yields (7-bromo-1-carboxylate). H -Indole-2-yl)methanol, which is then oxidized by IBX to give 7-bromo-1 H -Indole-2-carboxaldehyde, followed by a Suzuki coupling reaction with 2-naphthoboronic acid, yields 7-(naphtho-2-yl)-1-indo-carboxaldehyde. H -Indole-2-carboxaldehyde intermediate, finally with ( S The target compound 26 (white powder) was prepared by reductive amination of pyrrolidine-3-carboxylic acid.

[0103] 1 H NMR (600 MHz, DMSO- d 6) δ 10.70 (s, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.85 – 7.77 (m, 2H), 7.59 (dd,J = 8.4, 1.8 Hz, 1H), 7.37 (tt, J = 7.0, 5.2 Hz, 2H), 7.33 (d, J = 7.8 Hz, 1H), 6.99 (dd, J =7.2, 1.1 Hz, 1H), 6.93 (t, J = 7.5 Hz, 1H), 6.22 (s, 1H), 3.55 (q, J = 13.6Hz, 3H), 2.57 (q, J = 5.9 Hz, 2H), 2.48 – 2.37 (m, 2H), 2.31 – 2.27 (m, 1H), 1.74 (tt, J = 7.9, 3.9 Hz, 1H), 1.67 (p, J = 7.0 Hz, 1H). 13 C NMR (151 MHz, DMSO- d 6) δ 138.44, 136.78, 133.90, 133.69, 132.63, 129.43, 128.83, 128.74,127.93, 127.42, 126.63, 126.44, 125.34, 121.70, 119.88, 119.60, 101.44,57.37, 53.91, 52.19, 43.49, 28.17. LC-MS / ESI [M + H] + 371.15 Example 2. Bioactivity Test 1. Experimental Principle: A Tango-CHO stable expression cell line targeting the S1PR1 and S1PR3 receptors was constructed. Upon receptor activation by the compound, the β-arrestin-TEV fusion protein was recruited and cleaved a specific C-terminal sequence of the receptor, releasing transcription factors into the nucleus and initiating luciferase reporter gene expression. The degree of receptor activation was quantified by detecting chemiluminescence intensity (RLU) using the Bright-Glo™ system.

[0104] 2. Experimental Procedure Cell seeding: Cells were seeded into 384-well plates (5000 cells / well) using a Multidrop separator and incubated at 37°C for 18 hours.

[0105] Serial dilution and drug administration: The test compound was serially diluted 4-fold (10 concentration points) using the Bravo platform; 50 nL of the compound was transferred to a cell plate (DMSO final concentration 0.1%) using the Mosquito system and incubated for 20 h.

[0106] Signal detection: Add 5 μL of Bright-Glo™ working solution to each well, vortex and incubate for 15 min, and then read the RLU value using an EnVision microplate reader.

[0107] 3. Data Analysis and Activity Determination: GraphPad Prism was used to fit dose-response curves and calculate EC50. 50 value.

[0108] 4. Test results of compounds on S1PR1 and S1PR3: Grade A: EC 50 < 100 nM Grade B: 100 nM < EC 50 < 1000 nM Grade C: EC 50 > 1000 nM discuss: Through extensive and in-depth research, the inventors designed and synthesized a series of previously unreported small-molecule compounds that act as S1P receptor modulators. Cellular-level activity tests were conducted on these compounds, revealing that they can activate S1PR1, while exhibiting almost no activity against the S1PR3 receptor, which is associated with side effects. This lays the foundation for the treatment of S1P-mediated cancers and autoimmune diseases.

[0109] 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. The compound represented by Formula I or a pharmaceutically acceptable salt thereof: I In the formula, X is selected from NR4, S or O, wherein R4 is selected from H or optionally substituted C1-C6 alkyl; R1 is selected from the following group: optional substituted C6-C 18 Aryl, optional substituted C7-C 18 Aryl alkyl groups; n is any integer selected from 1 to 4; R2 is a substituent containing at least one carboxyl group (-COOH), with the structure -L-R3, wherein: The linking group L is selected from: -NH-, -CH2- or -C(=O)NR5R6, where R5 and R6 are independently selected from absent, H, optional substituted C1-C6 alkyl groups, or R5 and R6 together with the N atom attached to them form an optional substituted 5 or 6-membered cyclic group. R3 is selected from: optionally substituted C0-C6 alkylene carboxylic acid groups, or optionally substituted 4-6 membered heterocyclic groups containing one or two heteroatoms independently selected from N, O or S, and the heterocyclic group has at least one carboxyl group.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, n is an integer of 1 or 2; R1 is selected from: optionally substituted phenyl, optionally substituted naphthyl, optionally substituted biphenyl; R2 is selected from: -(CH2) m -NH-(CH2) p -COOH, where m is 0, 1 or 2, and p is 2, 3, 4 or 5; -(CH2) o -Het-COOH, where o is 1 or 2, and Het is selected from optionally substituted pyrrolidinyl or azacyclobutane; -CONH-L'-COOH, where L' is selected from optionally substituted C1-C3 alkylene groups.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, X is selected from S; n is an integer of 1 or 2; R1 is selected from: optionally substituted naphthyl, optionally substituted biphenyl; R2 is -(CH2) o -Het-COOH, where o is 1 or 2, and Het is selected from optionally substituted pyrrolidinyl or azacyclobutane.

4. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-3, characterized in that, The compound is selected from the following: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from the following: or ; Preferred .

6. A pharmaceutical composition comprising the compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

7. Use of the compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof in the preparation of S1PR1, S1PR4, and S1PR5 receptor modulators.

8. The use as described in claim 7, characterized in that, The S1PR1, S1PR4, and S1PR5 receptor modulators are highly selective S1P1 receptor modulators.

9. The use as described in claim 8, characterized in that, The highly selective S1P1 receptor modulator is a drug for treating or preventing S1P receptor-mediated diseases.

10. The use as described in claim 9, characterized in that, The diseases mediated by the S1P receptor are cancer or autoimmune diseases.

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