Heterocyclic compounds, pharmaceutical compositions and uses thereof

Abstract

The application discloses a heterocyclic compound, a pharmaceutical composition and application thereof, relates to the field of medicinal chemistry, and particularly relates to a heterocyclic compound as shown in the formula, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate or a polymorph thereof, a pharmaceutical composition containing the same, and the use of the heterocyclic compound as a TRPM3 antagonist and the use of the heterocyclic compound in the preparation of a drug for preventing or treating a TRPM3-mediated disease. The compound of the application exhibits excellent inhibitory activity on a TRPM3 channel, and can be used for preventing or treating a TRPM3-mediated disease, in particular a pain-related disease, such as an inflammatory pain, a neuropathic pain, a migraine, an epilepsy and an inflammatory hypersensitivity reaction disease.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to heterocyclic compounds, their stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or polymorphs, pharmaceutical compositions and their applications. Background Technology

[0002] Human genetic evidence provides “natural experimentation” support for TRPM3 as a target. In recent years, multiple studies have found that gain-of-function (GOF) mutations in TRPM3 are closely associated with various human genetic diseases characterized by abnormal pain, such as developmental and epileptic encephalopathy (DEE). The vast majority of pathogenic GOF mutations are concentrated in the transmembrane core region that regulates channel opening and closing. These mutations make the channel more prone to opening in the resting state, causing persistent calcium channel blockers (CMBs). 2+ Influx and abnormal neuronal firing perfectly replicate the pathological features of NPP at the molecular level. This series of genetic findings demonstrates that overactivation of TRPM3 channels is the direct cause of pathological pain; therefore, inhibiting its function through small molecules is logically the most direct and reasonable treatment strategy. The TRP superfamily consists of proteins with six transmembrane domains (6TM), which assemble in the form of homotetramers or heterotetramers to form cation-permeable ion channels. TRP channel dysfunction is directly involved in the etiology of various hereditary and acquired diseases. In fact, loss-of-function and gain-of-function mutations in TRP channel genes have been identified as direct causes of hereditary diseases, including shortness of breath, hypomagnesemia with secondary hypocalcemia, polycystic kidney disease, mucopolysaccharidosis type IV, and familial focal segmental glomerulosclerosis. Furthermore, TRP channel function / dysfunction has been directly associated with a wide range of pathological symptoms, including chronic pain, hypertension, cancer, and neurodegenerative diseases. TRPM3 inhibitors have demonstrated significant efficacy in various pain models, including inflammatory pain, neuropathic pain, and migraine. Studies have shown that the TRPM3 inhibitor primidone effectively reduces thermal hyperalgesia, mechanohypia, and cold hyperalgesia by blocking calcium ion influx in peripheral DRG neurons. For example, knocking out TRPM3 or using the TRPM3 antagonist isosakuranetin effectively reduces oxaliplatin-induced acute peripheral neuropathy. Furthermore, in migraine models, TRPM3 inhibitors reduce neurogenic inflammation and pain sensitization by inhibiting CGRP release in trigeminal ganglion neurons. A significant medical need remains for new, alternative, and / or better treatments for TRPM3-mediated conditions, more specifically for pain such as inflammatory pain. There is an urgent need for therapeutics with good efficacy, low or no side effects, and / or good or better pharmacokinetic or pharmacokinetic properties for a particular type of pain. Summary of the Invention

[0003] Objective of the Invention: The objective of this invention is to provide a class of heterocyclic compounds, pharmaceutical compositions, and their applications, which are TRPM3 antagonists and can be used as modulators of TRPM3-mediated diseases. The compounds provided by this invention exhibit good TRPM3 inhibitory activity and are expected to be used in the preparation of drugs for the prevention or treatment of TRPM3-mediated diseases. This invention provides a heterocyclic compound, its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or polymorphs.

[0004] The technical solution of this application is as follows: a heterocyclic compound of formula (I), its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or polymorphs, with the following structural formula: Formula (I), in, R 1 This represents -F, -Cl, -Br, -I, -CN, and -R. W -OR W -OC (=O)R W -NR W R X -NR W C(=O)R X -SR W -S (=O)R W -S(=O)2R W -C (=O)R W -C (=O) OR W or -C (=O)NR W R X ; Q indicates -NR 3 R 4 ; X1, X2, X3, X4, and X5 are represented independently of each other -NR 3 R 4 C or O; R 3 Indicates -OH or -R Y1 ; R 4 Indicates -R Y2 or -S(=O)2R Y3 ; Or R 3 and R 4 Together they form 4, 5, 6, 7 or 8-membered heterocycles containing 1 to 3 heteroatoms selected from N, O and S, which are saturated or unsaturated, unsubstituted or monosubstituted or polysubstituted; T represents -O-, -NR W -, -S-, and U represents -(CR) 5 R 5' )n-; or T represents -(CR 5 R 5' )n-, and U represents -O-; n is an integer selected from 1, 2, 3, 4 or 5; R 5 and R 5' Represented independently of each other -R Y4 ; R 6 Independently represent -F, -Cl, -Br, -I, -CN, -NO2, -SF5, -R W -OR W -OC (=O)R W NR W R X -NR W C(=O)R X -SR W -S (=O)R W -S(=O)2R W -C (=O)R W -C (=O) OR W or -C (=O)NR W R X ; R 7 and R 8 Linked to form unsaturated aromatic rings or independently represented as -F, -Cl, -Br, -I, -CN, -NO2, -SF5, -R W -OR W -OC (=O)R W NR W R X -NR W C(=O)R X -SR W -S (=O)R W -S(=O)2R W -C (=O)R W -C (=O) OR W or -C (=O)NR W R X ; W indicates 3-14 membered cycloalkyl, which is saturated or non-aromatic unsaturated; unsubstituted, monosubstituted or polysubstituted; or -C1-C6-alkyl, -C2-C6-alkenyl, -C2-C6-ynyl; which in each case is unsubstituted, monosubstituted or polysubstituted. in R W and R X -H is independently represented in each case; -C1-C6-alkyl, which is saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted; -C1-C6-heteroalkyl, which is saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted. 3-14 membered cycloalkyl groups, which are saturated or non-aromatic unsaturated, unsubstituted, monosubstituted or polysubstituted; wherein said 3-14 membered cycloalkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, which in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted; or 3-14-membered heterocyclic alkyl groups, which are saturated or non-aromatic unsaturated, unsubstituted, monosubstituted or polysubstituted; wherein the 3-14-membered heterocyclic alkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, which in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted. R Y1 R Y2 R Y3 and R Y4 -H is independently represented in each case; -C1-C6-alkyl, which is saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted; -C1-C6-heteroalkyl, which is saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted; 3-14 membered cycloalkyl, which is saturated or non-aromatic unsaturated, unsubstituted, monosubstituted or polysubstituted; wherein the 3-14 membered cycloalkyl is optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, which in each case is saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted; 3-14-membered heterocyclic alkyl groups, which are saturated or non-aromatic unsaturated, unsubstituted, monosubstituted or polysubstituted; wherein the 3-14-membered heterocyclic alkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, which in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted. 6-14 aryl groups, which are unsubstituted, monosubstituted, or polysubstituted; wherein the 6-14 aryl groups are optionally linked by a C1-C6-alkylene- or -C1-C6-heteroalkylene-, which in each case are saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted; or 5-14-membered heteroaryl groups, which are unsubstituted, monosubstituted, or polysubstituted; wherein the 5-14-membered heteroaryl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, which in each case are saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted.

[0005] Preferred, Selected from: One of them.

[0006] Preferably, T, U, and W are selected from: One of them.

[0007] Preferably, Q is selected from: One of them.

[0008] Preferably, the compound is selected from any of the following specific compounds or pharmaceutically acceptable salts thereof: ; ; ; .

[0009] Preferably, the compound has a structure as shown in formula (II) or formula (III): Equation (II), in, R 9 and R 10 Linked to form unsaturated aromatic rings or independently represented as -F, -Cl, -Br, -I, -CN, -NO2, -SF5, -R W -OR W -OC (=O)R W NR W R X -NR W C(=O)R X -SR W -S (=O)R W -S(=O)2R W -C (=O)R W -C (=O) OR W or -C (=O)NR W R X ; R 11 This indicates -F, -Cl, -Br, -I, -CN, -NO2, -SF5, -R W -OR W -OC (=O)RW NR W R X -NR W C(=O)R X -SR W -S (=O)R W -S(=O)2R W -C (=O)R W -C (=O) OR W or -C (=O)NR W R X ; R 12 or R 13 With R 7 Linked to form saturated or unsaturated rings, or independently represented as -F, -Cl, -Br, -I, -CN, -NO2, -SF5, -R W -OR W -OC (=O)R W NR W R X -NR W C(=O)R X -SR W -S (=O)R W -S(=O)2R W -C (=O)R W -C (=O) OR W or -C (=O)NR W R X ; Formula (III) in, T represents -O-, -NR W -, -S- or does not exist, and U represents - (CR 5 R 5' n- or does not exist; R 14 Indicates -CN, -R W -OR W -OC (=O)R W NR W R X -NR W C(=O)R X -SR W -S (=O)R W -S(=O)2R W -C (=O)R W -C (=O) OR W or -C (=O)NR W RX .

[0010] A pharmaceutical composition comprising any of the heterocyclic compounds described above, their stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or polymorphs, and at least one pharmaceutically acceptable carrier, diluent or excipient.

[0011] The use of any of the heterocyclic compounds described above, their stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or polymorphs, or the pharmaceutical compositions described above, as a TRPM3 antagonist.

[0012] The use of any of the heterocyclic compounds described above, their stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or polymorphs, or the pharmaceutical compositions described above, in the preparation of medicaments for the prevention or treatment of TRPM3-mediated diseases.

[0013] Preferably, the TRPM3-mediated condition is a pain-related disease, such as inflammatory pain, neuropathic pain, migraine, epilepsy, and inflammatory hypersensitivity syndrome.

[0014] Explanation of principle: This application provides a heterocyclic compound, its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or polymorphs, which connect an amide / heterocyclic structure, a fused heterocyclic core, and a hydrophobic group W through a linker arm -TU-, forming a specific spatial configuration and electronic distribution. The compound of this application can bind with high affinity to specific allosteric regulatory sites of the TRPM3 channel protein, thereby effectively stabilizing the closed state of the channel, inhibiting calcium ion influx, and thus blocking the transmission of downstream pain signals.

[0015] Compared with the prior art, this application has the following advantages: 1. Excellent TRPM3 inhibitory activity: In vitro fluorescence assay results show that most of the representative compounds of this invention have sub-micromolar to nanomolar inhibitory activities on human and mouse TRPM3 channels. 50 The value is in Grade A, significantly superior to or equivalent to known TRPM3 inhibitors in the prior art; 2. Potentially high selectivity: The structural optimization of this invention is expected to improve the selectivity of the TRPM3 channel relative to other members of the TRP family (such as TRPV1, TRPA1, etc.), thereby reducing potential off-target side effects; 3. Good drug-like potential: The compounds of the present invention have controllable physicochemical properties and are expected to have good solubility, permeability and metabolic stability, showing potential to become oral drugs. Detailed Implementation

[0016] The invention is described in detail below with reference to embodiments, but this does not imply any adverse limitation of the present disclosure. The present disclosure has been described in detail, including specific embodiments thereof. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope thereof. All reagents used in this disclosure are commercially available and can be used without further purification.

[0017] Unless otherwise stated, the proportions of mixed solvents are volume ratios. For example, "petroleum ether / ethyl acetate = 60 / 1" means that the volume ratio of petroleum ether to ethyl acetate is 60:1.

[0018] Compounds are named manually or using ChemDraw® software; commercially available compounds are named using the supplier catalog name.

[0019] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts were measured in units of 10⁻⁶ (ppm). Solvents used for NMR measurements included deuterated dimethyl sulfoxide, deuterated chloroform, and deuterated methanol, with tetramethylsilane (TMS) as the internal standard. 50 "Half-inhibitory concentration" refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0020] The following abbreviations are used in this disclosure: NaH represents sodium hydride; RT represents retention time; and TLC represents thin-layer chromatography.

[0021] Example 1, N -(2) S 3 R The synthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methyl-5-((5-methyl-3-phenylisoxazol-4-yl)methoxy)benzofuran-3-carboxamide (Cpd001) is described below via the following reaction route: ; Reagents and conditions : (a) ZnCl2, Toluene, reflux, 12h; (b) CDI, THF, rt, then NaBH4, THF: H2O=2:1, 0℃→rt; (c) SOCl2, DCM, rt; (d) K2CO3, DMF, 60℃, 12h; (e) NaOH, H2O:THF=1:2, 60℃, 6h; (f) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0022] Step a, Synthesis of intermediates 1-2 of ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate: p-Benzoquinone (10 g, 92.51 mmol) was added to a 250 mL flask and dissolved in toluene (60 mL). Zinc chloride (15.13 g, 111.01 mmol) and ethyl acetoacetate (12.04 g, 92.51 mmol) were added with stirring. The mixture was heated to 70 °C, and after 15 minutes, to 140 °C. The reaction mixture was stirred under reflux for 12 hours. After the reaction was complete as monitored by TLC, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (3 × 60 mL). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 3 / 1) to give intermediate 1-2 (3.6 g, 18% yield) as a pale yellow solid.

[0023] LC-MS (ESI): m / z=221.08 [M+H] + compound N -(2) S 3 R Synthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methyl-5-((5-methyl-3-phenylisoxazol-4-yl)methoxy)benzofuran-3-carboxamide (Cpd001): Step b, Synthesis of (5-methyl-3-phenylisoxazole-4-yl)methanol: Compounds 1-3 (550 mg, 2.71 mmol) were added to a 50 mL flask and dissolved in 15 mL of THF. CDI (482.79 mg, 2.98 mmol) was added in two portions over 5 minutes, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then added to a mixture of NaBH4 (409.6 mg, 10.83 mmol) in 8 mL of THF and 4 mL of water at 0 °C, and stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give intermediate 1-4 (440 mg, 86%) as a pale yellow solid.

[0024] LC-MS (ESI): m / z=190.09 [M+H] + Step c, Synthesis of 4-(chloromethyl)-5-methyl-3-phenylisoxazole: Compounds 1-4 (440 mg, 2.33 mmol) were added to a 50 mL flask, dissolved in 15 mL of DCM, and then thionyl chloride (1.11 g, 9.3 mmol) was added dropwise with stirring at room temperature for 6 hours. After the reaction was complete as monitored by TLC, the system was concentrated under reduced pressure to obtain the crude product. Water (30 mL) was added to the crude product, and the mixture was extracted with DCM (3 × 30 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated. Without column chromatography purification, intermediate 1-5 (468 mg, 97% yield) was obtained as a yellow liquid.

[0025] LC-MS (ESI): m / z=208.05 [M+H] + Step d, synthesis of ethyl 2-methyl-5-((5-methyl-3-phenylisoxazol-4-yl)methoxy)benzofuran-3-carboxylic acid: Intermediate 1-2 (300 mg, 1.36 mmol), intermediate 1-5 (311.17 mg, 1.50 mmol), K2CO3 (376.54 mg, 2.72 mmol), and DMF (15 mL) were added to a 50 mL flask and stirred at 60 °C for 12 h. After the reaction was complete as monitored by TLC, water (60 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 × 90 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to obtain intermediate 1-6 (512 mg, 96% yield) as a pale yellow solid.

[0026] LC-MS (ESI): m / z=392.15 [M+H] + Step e, Synthesis of 2-methyl-5-((5-methyl-3-phenylisoxazol-4-yl)methoxy)benzofuran-3-carboxylic acid: Intermediate 1-6 (512 mg, 1.31 mmol) was added to a 50 mL flask, followed by 10 mL of THF, and stirred until fully dissolved. NaOH solid (209.27 mg, 5.23 mmol) was dissolved in 5 mL of water. The prepared sodium hydroxide aqueous solution was added dropwise to the reaction system, and the mixture was heated to 60 °C and stirred for 6 hours. After the reaction was complete as monitored by TLC, the solvent was removed by concentration under reduced pressure. Water (10 mL) was then added to the system, and the mixture was extracted with ethyl acetate (3 × 30 mL). The aqueous phase was adjusted to pH 4, at which point a white solid precipitated from the water. The precipitate was filtered, collected, and dried under an infrared lamp. No column chromatography purification was required to obtain intermediate 1-7 (470 mg, 99% yield), a white solid.

[0027] LC-MS (ESI): m / z=362.10 [MH] - Step f, N -(2) S 3 R Synthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methyl-5-((5-methyl-3-phenylisoxazol-4-yl)methoxy)benzofuran-3-carboxamide (Cpd001): Add intermediate 1-7 (100 mg, 0.275 mmol), DIPEA (71.14 mg, 0.550 mmol), HATU (136.03 mg, 0.358 mmol), and DMF (5 mL) to a 50 mL orb-shaped flask. Add (2 mL) of the solution while stirring at room temperature. S 3 R 2-Amino-3-hydroxybutyramide hydrochloride (170.18 mg, 1.10 mmol) was reacted at room temperature for 3 hours. After the reaction was complete as monitored by TLC, water (50 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 × 80 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give Cpd001 (94 mg, yield 74%) as a white solid.

[0028] LC-MS (ESI): m / z=464.18 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ7.77-7.68 (m, 2H), 7.54-7.37 (m, 7H), 7.16 (s, 1H), 6.97 (dd, J = 8.9, 2.6Hz, 1H), 5.05 (d, J =5.6Hz, 1H), 4.99 (s, 2H), 4.36 (dd, J = 8.7, 3.5Hz, 1H), 4.17-4.07 (m, 1H), 2.66 (s, 3H), 2.52 (s, 3H), 1.13 (d, J =6.3Hz, 3H).

[0029] Example 2, N -(( 2R , 3R )-1-amino-3-hydroxy-1-oxo-2-butyl)-2-methyl-5-(2-methylbenzo[ dThe synthesis of [1,3]dioxane-2-yl)benzofuran-3-carboxamide is described by the following reaction route: ; Reagents and conditions : (a) DABCO, CH3CN, 70℃, 2h; (b) Pd (dppf) Cl2, Et3N, CH3CN, 80℃, 24h; (c) P-Toluenesulfonic acid, Toluene, reflux; (d) NaOH, H2O: THF=1:2, 60℃, 6h; (e) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0030] The synthesis of intermediate 2-3: ethyl 5-acetyl-2-methylbenzofuran-3-carboxylic acid ester is carried out in the following steps: Step a, ethyl ( E Synthesis of 3-(4-acetyl-2-iodophenoxy)-but-2-enoate: Add DABCO (107 mg, 0.954 mmol) and 4-hydroxy-3-iodophenyl ethyl ketone (300 mg, 1.14 mmol) to a 100 mL flask. Under nitrogen protection, add 16 mL of anhydrous acetonitrile to completely dissolve the substances. Then heat the flask to 70 °C and add ethylbutyrate-2-acetylacetate (106 mg, 0.954 mmol). Stir at 70 °C for 2 h. After the reaction is complete as monitored by TLC, add 12 mL of methyl tert-butyl ether to dilute the system. Cool to 0 °C and add 11 mL of 1 M hydrochloric acid dropwise below 20 °C. Observe that the system separates into layers. Take the upper organic phase, wash once with 7 mL of 1 M NaOH, and then wash with pure water until neutral. Concentrate the organic phase under reduced pressure. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to give intermediate 2-2 (289 mg, yield 81%), which is a colorless liquid.

[0031] Step b, synthesis of ethyl 5-acetyl-2-methylbenzofuran-3-carboxylic acid ester: Intermediate 2-2 (319 mg, 0.852 mmol), Pd(dppf)Cl2 (62 mg, 0.085 mmol), and Et3N (172 mg, 1.71 mmol) were added to a 50 mL dry, sealed tube, followed by 5 mL of anhydrous acetonitrile. The mixture was stirred and heated to 82 °C under nitrogen protection for 24 h. After the reaction was completed by TLC, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether) to obtain intermediate 2-3 (142 mg, yield 68%), which was a viscous, colorless liquid.

[0032] compound N -(( 2R , 3R)-1-amino-3-hydroxy-1-oxo-2-butyl)-2-methyl-5-(2-methylbenzo[ d Synthesis of [1,3]dioxane-2-yl)benzofuran-3-carboxamide (Cpd002): Step c, ethyl 2-methyl-5-(2-methylbenzo[ d Synthesis of [1,3]dioxane-2-yl)benzofuran-3-carboxylic acid ester: Intermediate 2-3 (166 mg, 0.674 mmol), catechol (74 mg, 0.674 mmol), and p-toluenesulfonic acid (5.8 mg, 0.033 mmol) were added to a 100 mL round-bottom flask. The mixture was refluxed under nitrogen protection for 2 hours. Water produced during the reaction was separated using a water separator, and the mixture was cooled to room temperature. After the reaction was completed as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether) to give intermediate 2-4 (112 mg, 49% yield) as a white solid.

[0033] Step d, 2-methyl-5-(2-methylbenzo[ d Synthesis of [1,3]dioxane-2-yl)benzofuran-3-carboxylic acid: Intermediate 2-4 (30 mg, 0.088 mmol) was added to a 50 mL flask, followed by 10 mL of THF, and stirred until fully dissolved. NaOH solid (14 mg, 0.354 mmol) was dissolved in 5 mL of water. The prepared sodium hydroxide aqueous solution was added dropwise to the reaction system. The mixture was heated to 60 °C and stirred for 2 hours. After the reaction was complete as monitored by TLC, the THF was removed by concentration under reduced pressure. Water (10 mL) was then added to the system, and the mixture was extracted with ethyl acetate (3 × 10 mL). The aqueous phase was adjusted to pH 4. A white solid precipitated from the water. The precipitate was filtered, collected, and dried under an infrared lamp. No column chromatography purification was required to obtain intermediate 2-5 (27 mg, 99% yield), a white solid.

[0034] Step e, N -(( 2R , 3R )-1-amino-3-hydroxy-1-oxo-2-butyl)-2-methyl-5-(2-methylbenzo[ d Synthesis of [1,3]dioxane-2-yl)benzofuran-3-carboxamide (Cpd002): Add intermediate 2-5 (21 mg, 0.067 mmol), DIPEA (21 mg, 0.169 mmol), HATU (33 mg, 0.087 mmol), and DMF (5 mL) to a 50 mL orb-shaped flask. Add (2...) while stirring at room temperature.S 3 R 2-Amino-3-hydroxybutyramide hydrochloride (12 mg, 0.081 mmol) was reacted at room temperature for 12 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give Cpd002 (12 mg, yield 44%) as a white solid.

[0035] 1 H NMR (300 MHz, DMSO) δ 8.04 (d, J =1.8Hz, 1H), 7.63 (d, J = 8.7Hz, 1H), 7.59-7.50 (m, 2H), 7.48-7.43 (m, 1H), 7.18 (s, 1H), 6.98-6.88 (m, 2H), 6.81 (dd, J =5.7, 3.4Hz, 2H), 5.10 (d, J =5.3Hz, 1H), 4.36 (dd, J = 8.7, 3.4Hz, 1H), 4.21-4.07 (m, 1H), 2.68 (s, 3H), 2.02 (s, 3H), 1.16 (d, J =6.2Hz, 3H).

[0036] Example 3, N -(( 2S , 3R The synthesis of 1-amino-3-hydroxy-1-oxo-2-butyl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)-1H-indole-3-carboxamide (Cpd003) is described below via the following reaction route: ; Reagents and conditions : (a) NaBH4, MeOH, 0℃→rt, 2h; (b) SOCl2, DCM, 0℃→rt, 5h; (c) K2CO3, DMF, 75℃, 12h; (d) LiOH·H2O, H2O: EtOH=1:1, 80℃, 24h; (e) HATU, DIPEA, DMF, 70℃, 3h.

[0037] Synthesis of intermediate 3-3: 5-chloromethyl-4-methylthiazole: Step a, Synthesis of (4-methylthiazolyl)methanol: Compound 3-1 (50 mg, 0.393 mmol) was added to a 50 mL orb-shaped flask and dissolved in 5 mL of methanol. NaBH4 (15 mg, 0.401 mmol) was dissolved in 5 mL of methanol and added dropwise to the reaction mixture at 0 °C over 5 minutes. The mixture was stirred at room temperature for 2 h. After the reaction was complete as monitored by TLC, the reaction mixture was concentrated under reduced pressure. The crude product was dissolved in ethyl acetate and washed 2-3 times with water. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. No further purification was required to give intermediate 3-2 (50 mg, 99% yield) as a white solid.

[0038] Step b, synthesis of 5-chloromethyl-4-methylthiazole: Intermediate 3-2 (50 mg, 0.387 mmol) was added to a 50 mL orbicular flask and dissolved in 6 mL of DCM. Thionyl chloride (55 mg, 0.464 mmol) dissolved in 6 mL of DCM was added dropwise at 0 °C, and the reaction was continued for 5 hours. After the reaction was complete as monitored by TLC, the crude product was dissolved in ethyl acetate and washed 2-3 times with water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. No further purification was required to obtain intermediate 3-3 (57 mg, 99% yield), a brown solid.

[0039] compound N -(( 2S , 3R Synthesis of 1-amino-3-hydroxy-1-oxo-2-butyl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)-1H-indole-3-carboxamide (Cpd003): Step c, synthesis of ethyl-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)-1H-indole-3-carboxylic acid ester: Intermediate 3-3 (258 mg, 1.75 mmol), compound 3-4 (300 mg, 1.46 mmol), K₂CO₃ (404 mg, 2.92 mmol), and DMF (15 mL) were added to a 50 mL flask and stirred at 75 °C for 6 hours. After the reaction was complete as monitored by TLC, water (60 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 × 60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give intermediate 3-5 (278 mg, 60% yield) as a white solid.

[0040] Step d, synthesis of 2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)-1H-indole-3-carboxylic acid: Intermediate 3-5 (30 mg, 0.090 mmol) and EtOH (5 mL) were added to a 50 mL flask and stirred until fully dissolved. LiOH·H2O (114 mg, 2.72 mmol) and water (5 mL) were added, and the mixture was heated to 80 °C and reacted for 24 hours. After the reaction was completed by TLC monitoring, the solvent in the system was removed by concentration under reduced pressure. Water (10 mL) was then added to the system, and the mixture was extracted with ethyl acetate (3 × 10 mL). The aqueous phase was adjusted to pH 4, at which point a white solid precipitated from the water. The precipitate was filtered, collected, and dried with an infrared lamp. Intermediate 3-6 (27 mg, 99% yield) was obtained as a white solid without the need for column chromatography purification.

[0041] Step e, N -(( 2S , 3R Synthesis of 1-amino-3-hydroxy-1-oxo-2-butyl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)-1H-indole-3-carboxamide: Add intermediate 3-6 (20 mg, 0.063 mmol), DIPEA (20 mg, 0.158 mmol), HATU (31 mg, 0.082 mmol), and DMF (5 mL) to a 50 mL orb-shaped flask. Add (2...) while stirring at room temperature. S 3 R 2-Amino-3-hydroxybutyramide hydrochloride (11 mg, 0.075 mmol) was reacted at room temperature for 12 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 2) to give Cpd003 (12 mg, yield 30%) as a white solid.

[0042] 1 H NMR (300 MHz, DMSO) δ 11.46 (s, 1H), 8.97 (s, 1H), 7.56 (d, J =2.3Hz, 1H), 7.43 (s, 1H), 7.26 (d, J = 8.7Hz, 1H), 7.14 (s, 1H), 6.91 (d, J = 8.7Hz, 1H), 6.82 (dd, J = 8.7, 2.3Hz, 1H), 5.27 (s, 2H), 5.10 (d, J =5.1Hz, 1H), 4.38 (dd, J= 8.7, 3.0Hz, 1H), 4.19-4.07 (s, 1H), 2.60 (s, 3H), 2.41 (s, 3H), 1.14 (d, J =6.3Hz, 3H).

[0043] Example 4, N -(( 2R , 3R )-1-amino-3-hydroxy-1-oxo-2-butyl)-1,2-dimethyl-5-((4-methylthiazolyl-5-yl)methoxy)-1 H The synthesis of indole-3-carboxamide (Cpd004) follows the reaction route described below: ; Reagents and conditions : (a) CH3I, NaH, DMF, 0℃→rt, 2h; (b) KOH, H2O:EtOH=1:1, 80℃, 24h; (e) HATU, DIPEA, DMF, 70℃, 3h.

[0044] Step a, ethyl-1,2-dimethyl-5-((4-methylthiazolyl)methoxy)-1 H Synthesis of -indole-3-carboxylic acid esters: Intermediate 3-5 (45 mg, 0.136 mmol) and 5 mL of anhydrous DMF were added to a 50 mL flask. While stirring at 0 °C, NaH (60%) (8 mg, 0.204 mmol) was added. After 30 min, 5 mL of DMF solution containing 23 mg, 0.163 mmol of iodomethane was added to the flask. The mixture was heated to room temperature and the reaction was continued for 1.5 h. After the reaction was complete as monitored by TLC, saturated sodium thiosulfate solution was added to quench the reaction. 30 mL of water was added, and the mixture was extracted three times with EA (3 × 20 mL). The organic phases were combined, washed 2-3 times with saturated brine, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to obtain intermediate 4-1 (23 mg, 50% yield), a yellow solid.

[0045] Step b, 1,2-Dimethyl-5-((4-methylthiazolyl)methoxy)-1 H Synthesis of -indole-3-carboxylic acid: Intermediate 4-1 (53 mg, 0.153 mmol) was added to a 50 mL flask, followed by 10 mL of ethanol and stirring until fully dissolved. Solid KOH (172 mg, 3.08 mmol) was dissolved in 10 mL of water. A potassium hydroxide aqueous solution was added dropwise to the reaction system, and the mixture was heated to 80 °C and reacted for 24 hours. After the reaction was complete as monitored by TLC, the solvent was removed by concentration under reduced pressure. Water (10 mL) was then added to the system, and the mixture was extracted with ethyl acetate (3 × 10 mL). The aqueous phase was adjusted to pH 4, at which point a white solid precipitated from the water. The precipitate was filtered, collected, and dried under an infrared lamp. Intermediate 4-2 (48 mg, 99% yield), a yellow solid, was obtained without column chromatography purification.

[0046] Step c, N -(( 2R , 3R )-1-amino-3-hydroxy-1-oxo-2-butyl)-1,2-dimethyl-5-((4-methylthiazolyl-5-yl)methoxy)-1 H Synthesis of indole-3-carboxamide: Add intermediate 4-2 (34 mg, 0.107 mmol), DIPEA (35 mg, 0.268 mmol), HATU (53 mg, 0.139 mmol), and DMF (5 mL) to a 50 mL orb-shaped flask. Add (2...) while stirring at room temperature. S 3 R 2-Amino-3-hydroxybutyramide hydrochloride (20 mg, 0.129 mmol) was reacted at room temperature for 12 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give Cpd004 (15 mg, yield 34%) as a yellow solid.

[0047] 1 H NMR (400 MHz, DMSO) δ 8.97 (s, 1H), 7.59 (d, J =2.4Hz, 1H), 7.51-7.36 (m, 2H), 7.15 (s, 1H), 7.01 (d, J = 8.8Hz, 1H), 6.89 (dd, J = 8.8, 2.4Hz, 1H), 5.29 (s, 2H), 5.10 (d, J =5.1Hz, 1H), 4.40 (dd, J= 8.7, 3.1Hz, 1H), 4.21-4.09 (s, 1H), 3.68 (s, 3H), 2.63 (s, 3H), 2.40 (s, 3H), 1.23 (s, 1H), 1.14 (d, J =6.3Hz, 3H).

[0048] Example 5, N -(2) S 3 R The synthesis of 1-amino-3-hydroxy-1-oxobutan-2-yl)-2-methyl-5-((3-oxo-1,3-dihydroisobenzofuran-5-yl)methoxy)benzofuran-3-carboxamide (Cpd005) is described below via the following reaction route: ; Reagents and conditions : (a) NBS, AIBN, CHCl3, 70℃, 3h; (b) K2CO3, DMF, 75℃, 6h; (c) NaOH, H2O: THF=1:2, 60℃, 6h; (d) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0049] Step a, 6-(bromomethyl)isobenzofuran-1 (3 H )-Ketone synthesis: Compound 5-1 (690 mg, 4.66 mmol), NBS (911.78 mg, 5.12 mmol), and AIBN (76.48 mg, 0.47 mmol) were added to a 50 mL double-necked flask, dissolved in 10 mL of CHCl3, and stirred at 70 °C for 3 hours under nitrogen. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to give intermediate 5-2 (180 mg, yield 17%) as a pale yellow solid.

[0050] LC-MS (ESI): m / z=226.96 [M+H] + Compound 5; N -(2) S 3 R Synthesis of 1-amino-3-hydroxy-1-oxobut-2-yl)-2-methyl-5-((5-methyl-3-phenylisoxazol-4-yl)methoxy)benzofuran-3-carboxamide: The method is the same as in Example 1, except that intermediates 1-5 in step d are replaced with intermediates 5-2, and Cpd005 is prepared by steps d, e and f.

[0051] LC-MS (ESI): m / z=439.15 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ7.95-7.84 (m, 2H), 7.70 (d, J =7.8Hz, 1H), 7.55-7.35 (m, 4H), 7.18 (s, 1H), 7.02 (dd, J = 8.9, 2.6Hz, 1H), 5.42 (s, 2H), 5.27 (s, 2H), 5.11 (d, J =5.5Hz, 1H), 4.37 (dd, J = 8.9, 3.4Hz, 1H), 4.20-4.07 (m, 1H), 2.64 (s, 3H), 1.13 (d, J =6.3Hz, 3H).

[0052] Example 6, 5-(adamantane-1-ylmethoxy)- N -(2) S 3 R The synthesis of 1-amino-3-hydroxy-1-oxobut-2-yl)-2-methylbenzofuran-3-carboxamide (Cpd006) is described below via the following reaction route: ; Reagents and conditions : (a) TsCl, Pyridine, rt, 12h; (b) K2CO3, DMF, 150℃, 6h; (c) NaOH, H2O:THF=1:2, 60℃, 6h; (d) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0053] Step a, Synthesis of adamantane-1-ylmethyl-p-toluenesulfonate: Compound 6-1 (1 g, 6.01 mmol) and TsCl (1.72 g, 9.02 mmol) were added to a 50 mL flask, and 3 mL of Pyridine was added to dissolve them. The mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give intermediate 6-2 (1.91 g, 99% yield) as a white solid.

[0054] LC-MS (ESI): m / z=321.14 [M+H] + Compound 6,5-(adamantane-1-ylmethoxy)- N -(2)S 3 R Synthesis of 1-amino-3-hydroxy-1-oxobut-2-yl)-2-methylbenzofuran-3-carboxamide: The method is the same as in Example 1, except that intermediates 1-5 in step d are replaced with intermediates 6-2, the temperature is raised to 150°C, and Cpd006 is prepared by steps d, e and f.

[0055] LC-MS (ESI): m / z=441.24 [M+H] + 1 H NMR (400 MHz, DMSO-) d 6) δ7.45 (d, J = 8.7Hz, 2H), 7.38 (d, J = 8.9Hz, 1H), 7.31 (d, J =2.6Hz, 1H), 7.18 (s, 1H), 6.89 (dd, J = 8.9, 2.6Hz, 1H), 5.07 (d, J =5.6Hz, 1H), 4.36 (dd, J = 8.7, 3.3Hz, 1H), 4.18-4.08 (m, 1H), 3.56 (s, 2H), 2.64 (s, 3H), 1.98 (s, 3H), 1.78-1.58 (m, 12H), 1.23 (s, 1H), 1.14 (d, J =6.3Hz, 3H).

[0056] Example 7, 5-acetyl- N -(2) S 3 R The synthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methylbenzofuran-3-carboxamide (Cpd007) is described below via the following reaction route: ; Reagents and conditions : (a) NaOH, H2O:THF=1:2, 60℃, 6h; (b) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0057] The method of Example 1 is used, except that intermediates 1-6 in step e are replaced with intermediates 2-3, and Cpd007 is prepared by steps e and f.

[0058] LC-MS (ESI): m / z=319.13 [M+H] + 1 H NMR (400 MHz, DMSO-) d 6) δ 8.45 (d, J =1.8Hz, 1H), 7.94 (dd, J = 8.7, 1.8Hz, 1H), 7.70 (d, J = 8.7Hz, 1H), 7.65 (d, J = 8.7Hz, 1H), 7.48 (s, 1H), 7.20 (s, 1H), 5.09 (d, J =5.7Hz, 1H), 4.39 (dd, J = 8.8, 3.6Hz, 1H), 4.20-4.08 (m, 1H), 2.70 (s, 3H), 2.63 (s, 3H), 1.16 (d, J =6.3Hz, 3H).

[0059] Example 8, N -(2) S 3 R The synthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methyl-5-((2-methylallyl)oxy)benzofuran-3-carboxamide (Cpd008) is described below via the following reaction route: ; Reagents and conditions : (a) K2CO3, DMF, 75℃, 6h; (b) NaOH, H2O:THF=1:2, 60℃, 6h; (c) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0060] Following the method of Example 1, except that intermediates 1-5 in step d are replaced with 3-bromo-2-methylprop-1-ene, and Cpd008 is prepared by steps d, e and f.

[0061] LC-MS (ESI): m / z=347.16 [M+H] + 1 H NMR (400 MHz, DMSO-) d 6) δ7.48 (d, J = 8.9Hz, 2H), 7.41-7.33 (m, 2H), 7.20 (s, 1H), 6.94 (dd, J = 8.9, 2.6Hz, 1H), 5.10 (d, J=5.9Hz, 2H), 4.96 (s, 1H), 4.50 (s, 2H), 4.38 (dd, J = 8.7, 3.3Hz, 1H), 4.21-4.09 (m, 1H), 2.65 (s, 3H), 1.78 (s, 3H), 1.14 (d, J =6.1Hz, 3H).

[0062] Example 9, N -(2) S 3 R The synthesis of 1-amino-3-hydroxy-1-oxobutan-2-yl)-5-(but-2-yn-1-yloxy)-2-methylbenzofuran-3-carboxamide (Cpd009) is described below: ; Reagents and conditions : (a) K2CO3, DMF, 75℃, 6h; (b) NaOH, H2O:THF=1:2, 60℃, 6h; (c) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0063] Following the method of Example 1, except that intermediates 1-5 in step f are replaced with 1-bromo-2-butyne, and Cpd009 is prepared by steps d, e and f.

[0064] LC-MS (ESI): m / z=345.15 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ7.50 (d, J = 8.9Hz, 1H), 7.45 (s, 1H), 7.40-7.32 (m, 2H), 7.17 (s, 1H), 6.95 (dd, J = 8.9, 2.6Hz, 1H), 5.08 (d, J =5.6Hz, 1H), 4.75 (q, J =2.3Hz, 2H), 4.36 (dd, J = 8.8, 3.4Hz, 1H), 4.21-4.07 (m, 1H), 2.65 (s, 3H), 1.82 (t, J =2.3Hz, 3H), 1.15 (d, J =6.3Hz, 3H).

[0065] Example 10, N -((4-(dimethylamino)tetrahydro-2-) HThe synthesis of (-pyran-4-yl)methyl)-2-methyl-5-((4-methylthiazolyl)methoxy)benzofuran-3-carboxamide (Cpd010) is described below via the following reaction route: ; Reagents and conditions : (a) K2CO3, DMF, 75℃, 6h; (b) NaOH, H2O:THF=1:2, 60℃, 6h; (c) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0066] Referring to the method of Example 1, the difference is that intermediates 1-5 in step d are replaced with intermediates 3-3, and (2) in step f are replaced with intermediates 3-3. S 3 R Replace 2-amino-3-hydroxybutyramide hydrochloride with 4-(aminomethyl)- N , N -dimethyltetrahydro-2 H -Pyran-4-amine dihydrochloride was prepared by steps d, e and f to obtain Cpd010.

[0067] LC-MS (ESI): m / z=444.20 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) 1H NMR (300 MHz, DMSO) δ 8.99 (s, 1H), 7.77 (t, J =6.3Hz, 1H), 7.49 (d, J = 8.9Hz, 1H), 7.31 (d, J =2.6Hz, 1H), 6.98 (dd, J = 8.9, 2.6Hz, 1H), 5.31 (s, 2H), 3.75-3.47 (m, 6H), 2.61 (s, 3H), 2.41 (s, 3H), 2.32 (s, 6H), 1.73 (m, 2H), 1.61-1.45 (m, 2H).

[0068] Example 11, N -(2) S 3 R )-1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methyl-6-((4-methylthiazolyl-5-yl)methoxy)imidazo[1,2- a The synthesis of pyridine-3-carboxamide (Cpd011) follows the reaction route described below: ; Reagents and conditions : (a) EtOH, reflux, 12h; (b) K2CO3, DMF, 75℃, 6h; (c) NaOH, H2O:THF=1:2, 60℃, 2h; (d) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0069] Intermediate 11-4: 2-Methyl-6-((4-methylthiazolyl-5-yl)methoxy)-imidazolium[1,2-] a Synthesis of pyridine-3-carboxylic acid: Step a, ethyl 6-hydroxy-2-methylimidazo[1,2- a Synthesis of pyridine-3-carboxylic acid esters: Compound 11-1 (950 mg, 7.59 mmol) and ethyl 2-chloroacetoacetate (1.25 g, 7.59 mmol) were added to a 50 mL flask, dissolved in 20 mL of ethanol, and the mixture was heated under reflux for 12 h. The reaction was monitored by TLC. After the reaction was complete, the system was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give compound 11-2 (923 mg, 49%) as a brown solid.

[0070] LC-MS (ESI): m / z=221.09 [M+H] + Step b, ethyl-2-methyl-6-((4-methylthiazolyl-5-yl)methoxy)-imidazolium[1,2- a Synthesis of pyridine-3-carboxylic acid esters: Intermediate 3-3 (258 mg, 1.75 mmol), intermediate 11-2 (300 mg, 1.46 mmol), K2CO3 (404 mg, 2.92 mmol), and DMF (15 mL) were added to a 50 mL flask and stirred at 75 °C for 6 hours. After the reaction was complete as monitored by TLC, water (60 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 × 60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to obtain intermediate 11-3 (278 mg, 60% yield), which was a brown solid.

[0071] Step c, 2-methyl-6-((4-methylthiazolyl-5-yl)methoxy)-imidazolium[1,2- a Synthesis of pyridine-3-carboxylic acid: Intermediate 11-3 (434 mg, 1.31 mmol) was added to a 50 mL flask, followed by 10 mL of THF, and stirred until fully dissolved. NaOH solid (209.27 mg, 5.23 mmol) was dissolved in 5 mL of water. The prepared sodium hydroxide aqueous solution was added dropwise to the reaction system, and the mixture was heated to 60 °C and stirred for 2 hours. After the reaction was complete as monitored by TLC, the solvent was removed by concentration under reduced pressure. Water (10 mL) was then added to the system, and the mixture was extracted with ethyl acetate (3 × 30 mL). The aqueous phase was adjusted to pH 4. A brown solid precipitated from the water. The precipitate was filtered, collected, and dried under an infrared lamp. No column chromatography purification was required to obtain intermediate 11-4 (397 mg, 99% yield), a brown solid.

[0072] Compound 11: N -(2) S 3 R )-1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methyl-6-((4-methylthiazolyl-5-yl)methoxy)imidazo[1,2- a Synthesis of pyridine-3-carboxamide (Cpd011): Add intermediate 11-4 (19 mg, 0.063 mmol), DIPEA (20 mg, 0.158 mmol), HATU (30 mg, 0.082 mmol), and DMF (5 mL) to a 50 mL orb-shaped flask. Add (2...) while stirring at room temperature. S 3 R 2-Amino-3-hydroxybutyramide hydrochloride (11 mg, 0.075 mmol) was reacted at room temperature for 12 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 2) to give Cpd011 (12 mg, yield 48%) as a pale yellow solid.

[0073] LC-MS (ESI): m / z=404.14 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ 9.00 (s, 1H), 8.98 (d, J =1.7Hz, 1H), 7.55 (d, J =9.6Hz, 1H), 7.49 (s, 1H), 7.29 (dd, J = 9.6, 2.4Hz, 1H), 7.25-7.17 (m, 2H), 5.33 (s, 2H), 5.15 (s, 1H), 4.35 (dd,J = 8.6, 3.1Hz, 1H), 4.17 (m, 1H), 2.64 (s, 3H), 2.43 (s, 3H), 1.14 (d, J =6.3Hz, 3H).

[0074] Example 12, ( S )- N -(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-6-((4-methylthiazo-5-yl)methoxy)imidazo[1,2-] a The synthesis of pyridine-3-carboxamide (Cpd012) follows the reaction route described below: ; Reagents and conditions : DIPEA, HATU, DMF, 0℃→rt, 12h.

[0075] Referring to the method of Example 11, the only difference is that in step d, (2) S 3 R Replace 2-amino-3-hydroxybutyramide hydrochloride with L Cpd012 was prepared from 1-serineamide hydrochloride.

[0076] LC-MS (ESI): m / z=390.12 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ 9.00 (s, 1H), 8.93 (d, J =2.5Hz, 1H), 7.62-7.49 (m, 2H), 7.45 (d, J =7.8Hz, 1H), 7.27 (dd, J = 9.6, 2.5Hz, 1H), 7.21 (s, 1H), 5.37 (s, 2H), 5.08 (t, J =4.8Hz, 1H), 4.52-4.42 (m, 1H), 3.76 (m, 2H), 2.61 (s, 3H), 2.42 (s, 3H).

[0077] Example 13, N -(4-(hydroxymethyl)tetrahydro-2- H -pyran-4-yl)-2-methyl-6-((4-methylthiazo-5-yl)methoxy)imidazo[1,2-] a The synthesis of pyridine-3-carboxamide (Cpd013) follows the reaction route described below: ; Reagents and conditions : DIPEA, HATU, DMF, 0℃→rt, 12h.

[0078] Referring to the method of Example 11, the only difference is that in step d, (2) S 3 R Replace 2-amino-3-hydroxybutyramide hydrochloride with (4-amino-tetrahydro-2-amino-3-hydroxybutyramide hydrochloride). H- Cpd013 was prepared by pyran-4-yl)methanol.

[0079] LC-MS (ESI): m / z=417.16 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ 9.00 (s, 1H), 8.60 (d, J =3.3Hz, 1H), 7.54-7.46 (m, 1H), 7.28-7.19 (m, 2H), 5.32 (s, 2H), 4.93 (t, J =5.8Hz, 1H), 3.76-3.55 (m, 6H), 2.58 (s, 3H), 2.43 (s, 3H), 2.24-2.11 (m, 2H), 1.72-1.58 (m, 2H).

[0080] Example 14, N -(( 2R , 3R )-1-amino-3-hydroxy-1-oxo-2-butyl)-2-methyl-5-((2-methylbenzo[ d The synthesis of [1,3]dioxane-2-yl)methoxy)benzofuran-3-carboxamide (Cpd014) is described below via the following reaction route: ; Reagents and conditions : DIPEA, HATU, DMF, 0℃→rt, 12h.

[0081] Referring to the method of Example 2, the only difference is that in step e, (2) S 3 R Replace 2-amino-3-hydroxybutyramide hydrochloride with (4-amino-tetrahydro-2-amino-3-hydroxybutyramide hydrochloride). H- Cpd014 was prepared by pyran-4-yl)methanol.

[0082] LC-MS (ESI): m / z=424.18 [M+H] + 1H NMR (300 MHz, DMSO-) d 6) δ7.92(d,J =1.8Hz, 1H), 7.65-7.46 (m, 3H), 6.97-6.76 (m, 4H), 4.97-4.84 (m, 1H), 3.79- 3.60 (m, 6H), 2.61 (s, 3H), 2.23-2.10 (m, 2H), 2.01 (s, 3H), 1.73-1.53 ​​(m, 2H).

[0083] Example 15, N -(( 2S , 3R The synthesis of 1-amino-3-hydroxy-1-oxo-2-butyl)-2-methyl-5-(prop-2-yn-1-oxy)-benzofuran-3-carboxamide (Cpd015) is described below: ; Reagents and conditions : (a) K2CO3, DMF, 75℃, 6h; (b) NaOH, H2O:THF=1:2, 60℃, 6h; (c) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0084] Following the method of Example 1, the only difference is that intermediates 1-5 in step d are replaced with 3-bromopropyne, and Cpd015 is prepared by steps d, e and f.

[0085] 1 H NMR (300 MHz, DMSO) δ7.51 (d, J = 8.9Hz, 1H), 7.45 (s, 1H), 7.42-7.34 (m, 2H), 7.17 (s, 1H), 6.98 (dd, J = 8.9, 2.6Hz, 1H), 5.07 (d, J =5.6Hz, 1H), 4.81 (d, J =2.4Hz, 2H), 4.36 (dd, J = 8.8, 3.4Hz, 1H), 4.19-4.08 (m, 1H), 3.54 (t, J =2.3Hz, 1H), 2.65 (s, 3H), 1.14 (d, J =6.3Hz, 3H).

[0086] Example 16, N -(( 2S , 3R )-1-amino-3-hydroxy-1-oxo-2-butyl)-5-(2,4-dimethylbenzo[d The synthesis of [1,3]dioxane-2-yl)-2-methylbenzofuran-3-carboxamide (Cpd016) is described below via the following reaction route: ; Reagents and conditions : (a) P-Toluenesulfonic acid, Toluene, reflux; (b) NaOH, H2O: THF=1:2, 60℃, 6h; (c) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0087] Following the method of Example 2, the only difference is that catechol in step c is replaced with 3-methylbenzene-1,2-diol, and Cpd016 is prepared by steps c, d, and e.

[0088] LC-MS (ESI): m / z=425.17 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ 8.04 (s, 1H), 7.63 (d, J = 8.6Hz, 1H), 7.53 (dd, J =8.6, 2.1Hz, 2H), 7.44 (s, 1H), 7.17 (s, 1H), 6.82-6.59 (m, 3H), 5.21-4.89 (dd, J =5.7, 2.3Hz, 1H), 4.37 (dd, J = 8.8, 3.8Hz, 1H), 4.18-4.07 (m, 1H), 2.67 (s, 3H), 2.19 (s, 3H), 2.02 (s, 3H), 1.15 (d, J =6.3Hz, 3H).

[0089] Example 17, N -(( 2S , 3R )-1-amino-3-hydroxy-1-oxo-2-butyl)-5-(2,5-dimethylbenzo[ d The synthesis of [1,3]dioxane-2-yl)-2-methylbenzofuran-3-carboxamide (Cpd017) is described below via the following reaction route: ; Reagents and conditions : (a) P-Toluenesulfonic acid, Toluene, reflux; (b) NaOH, H2O: THF=1:2, 60℃, 6h; (c) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0090] Following the method of Example 2, the only difference is that catechol in step c is replaced with 4-methylbenzene-1,2-diol, and Cpd017 is prepared by steps c, d, and e.

[0091] LC-MS (ESI): m / z=425.17 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ 8.02 (d, J =1.9Hz, 1H), 7.62 (d, J = 8.7Hz, 1H), 7.51 (dt, J = 8.7, 1.9Hz, 2H), 7.45 (s, 1H), 7.17 (s, 1H), 6.84-6.71 (m, 2H), 6.59 (d, J =7.8Hz, 1H), 5.09 (d, J =5.7Hz, 1H), 4.35 (dd, J = 8.7, 3.6Hz, 1H), 4.21-4.07 (m, 1H), 2.67 (s, 3H), 2.19 (s, 3H), 2.00 (s, 3H), 1.23 (s, 1H), 1.15 (d, J =6.3Hz, 3H).

[0092] Example 18, N -(( 2S , 3R )-1-amino-3-hydroxy-1-oxo-2-butyl)-5-(4-chloro-2-methylbenzo[ d The synthesis of [1,3]dioxane-2-yl)-2-methylbenzofuran-3-carboxamide (Cpd018) is described below via the following reaction route: ; Reagents and conditions : (a) P-Toluenesulfonic acid, Toluene, reflux; (b) NaOH, H2O: THF=1:2, 60℃, 6h; (c) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0093] Following the method of Example 2, the only difference is that catechol in step c is replaced with 3-chlorobenzene-1,2-diol, and Cpd018 is prepared by steps c, d, and e.

[0094] LC-MS (ESI): m / z=445.12 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ 8.04 (s, 1H), 7.66 (d, J = 8.6Hz, 1H), 7.66-7.53 (m, 2H), 7.44 (s, 1H), 7.18 (s, 1H), 7.02-6.78 (m, 3H), 5.06 (d, J =6.8Hz, 1H), 4.36 (dd, J =8.8, 3.5Hz, 1H), 4.20-4.09 (m, 1H), 2.68 (s, 3H), 2.09 (s, 3H), 1.15 (t, J =6.6Hz, 3H).

[0095] Example 19, N -(( 2S , 3R )-1-amino-3-hydroxy-1-oxobutyryl)-6-((4-methylthiazolyl-5-yl)methoxy)-1 H The synthesis of indole-1-carboxamide (Cpd019) follows the reaction route described below: ; Reagents and conditions : (a) NaH, DMF, rt; (b) HCl, Dioxane, rt; (c) CDI, DMAP, MeCN, rt.

[0096] Step a, tert-butyl 6-((4-methylthiazolyl-5-yl)methoxy)-1 H Synthesis of -indole-1-carboxylic acid esters: Compound 19-1 (950 mg, 4.07 mmol) was added to a 50 mL flask and dissolved in DMF (10 mL). NaH (136.8 mg, 5.70 mmol) was added dropwise at room temperature, and stirring was continued for 2 hours. Intermediate 3-3 (841.7 mg, 5.70 mmol) was added at room temperature, and stirring was continued for 2 hours. After the reaction was complete as monitored by TLC, water (50 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 × 60 mL). The organic phases were combined, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain intermediate 19-2 (1.035 g, 74% yield), a pale yellow solid.

[0097] LC-MS (ESI): m / z=345.13 [M+H] + Step b, 5-(((1) H Synthesis of -indol-6-yl)oxy)methyl)-4-methylthiazole: Intermediate 19-2 (1.035 g, 3.00 mmol) was added to a 50 mL flask, and a 4 mol / L HCl solution of dioxane (22 mL) was added at 0 °C. The mixture was stirred at room temperature for 8 hours. After the reaction was completed by TLC, water (50 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 × 60 mL). The organic phases were combined, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain intermediate 19-3 (253 mg, yield 34%) as a pale yellow solid.

[0098] LC-MS (ESI): m / z=245.07 [M+H] + Step c, N -(2) S 3 R )-1-amino-3-hydroxy-1-oxobutane-2-yl)-6-((4-methylthiazolyl-5-yl)methoxy)-1 H Synthesis of -indole-1-carboxamide: Add intermediate 19-3 (90 mg, 0.37 mmol) to a 50 mL double-necked flask. N,N '-Carbonyldiimidazole (95.57 mg, 0.59 mmol), 4-dimethylaminopyridine (2.25 mg, 0.02 mmol), and anhydrous acetonitrile (5 mL) were added under a nitrogen atmosphere, and the mixture was stirred at 90°C for 3 hours. After cooling to room temperature, 2... S 3 R2-Amino-3-hydroxybutyramide hydrochloride (113.90 mg, 0.74 mmol) N,N - Diisopropylethylamine (95.22 mg, 0.74 mmol) was added and stirred at 90 °C for 3 hours. After the reaction was complete as monitored by TLC, water (10 mL) was added to the system and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 10 / 1) to give Cpd019 (15 mg, yield 11%) as a white solid.

[0099] LC-MS (ESI): m / z=389.13 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ 8.97 (s, 1H), 7.90 (d, J =3.5Hz, 2H), 7.74-7.45 (m, 3H), 7.20 (s, 1H), 6.90 (dd, J = 8.6, 2.5Hz, 1H), 6.62 (d, J =3.5Hz, 1H), 5.31 (s, 2H), 4.96 (d, J =6.4Hz, 1H), 4.23 (dd, J = 8.5, 4.5Hz, 1H), 4.14-4.06 (m, 1 H), 2.43 (s, 3H), 1.16 (d, J =6.4Hz, 3H).

[0100] Example 20, N -(( 2S , 3R The synthesis of 1-amino-3-hydroxy-1-oxo-2-butyl)-2-methyl-5-(prop-2-yn-1-oxy)-benzofuran-3-carboxamide (Cpd020) is described below: ; Reagents and conditions : (a) K2CO3, DMF, 75℃, 6h; (b) NaOH, H2O:THF=1:2, 60℃, 6h; (c) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0101] Following the method of Example 1, except that intermediates 1-5 in step d are replaced with 1-bromo-3-methyl-2-butene, and Cpd020 is prepared by steps d, e and f.

[0102] LC-MS (ESI): m / z=361.17 [M+H] + 1 H NMR (300 MHz, DMSO) δ7.53-7.43 (m, 2H), 7.41-7.29 (m, 2H), 7.18 (s, 1H), 6.90 (dd, J = 8.9, 2.6Hz, 1H), 5.47 (t, J =6.7Hz, 1H), 5.10 (d, J =5.7Hz, 1H), 4.54 (d, J =6.7Hz, 2H), 4.37 (dd, J = 8.8, 3.4Hz, 1H), 4.22-4.05 (m, 1H), 2.64 (s, 3H), 1.72 (d, J =10.4Hz, 6H), 1.14 (d, J =6.3Hz, 3H).

[0103] Example 21, N -(( 2S , 3R The synthesis of 1-amino-3-hydroxy-1-oxo-2-but-2-yl)-2-methyl-5-((2,3-dimethylbut-2-en-1-yl)oxy)-benzofuran-3-carboxamide (Cpd021) is described below via the following reaction route: ; Reagents and conditions : (a) HBr, DCM, 0℃, 12h; (b) K2CO3, DMF, 75℃, 6h; (c) NaOH, H2O:THF=1:2, 60℃, 6h; (d) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0104] Step a, Synthesis of 1-bromo-2,3-dimethyl-2-butene: Compound 21-1 (500.0 mg, 6.1 mmol) and anhydrous dichloromethane (10 mL) were added to a 50 mL flask. 48% hydrobromic acid solution (1.0 mL, 6.1 mmol) was added dropwise under ice-water bath conditions. The mixture was heated to room temperature and stirred for 12 h. After the reaction was complete as monitored by TLC, the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to give intermediate 21-2 (575.8 mg, yield 58.1%).

[0105] LC-MS (ESI): m / z=163.00 [M+H] + Compound 21: N -(( 2S , 3R Synthesis of 1-amino-3-hydroxy-1-oxo-2-but-2-yl)-2-methyl-5-((2,3-dimethylbut-2-en-1-yl)oxy)-benzofuran-3-carboxamide (Cpd021): The method is the same as in Example 1, except that intermediates 1-5 in step d are replaced with intermediates 21-2, and Cpd021 is prepared by steps d, e and f.

[0106] LC-MS (ESI): m / z=375.18 [M+H] + 1 H NMR (300 MHz, DMSO) δ7.54-6.89 (m, 6H), 5.09 (d, J =5.7Hz, 1H), 4.53 (s, 2H), 4.39 (d, J =4.7Hz, 1H), 4.26-4.06 (m, 1H), 2.66 (s, 3H), 1.75 (s, 9H), 1.16 (d, J =6.4Hz, 3H).

[0107] Example 22, N -(( 2S , 3R The synthesis of 1-amino-3-hydroxy-1-oxo-2-butyl)-5-((1,1-difluoroallyl)oxy)-2-methylbenzofuran-3-carboxamide (Cpd022) is described below via the following reaction route: ; Reagents and conditions: (a) K2CO3, DMF, 60℃; (b) NaOH, H2O:THF=1:2, 60℃, 6h; (c) DIPEA, HATU, DMF, 0℃→rt.

[0108] Following the method of Example 1, except that intermediates 1-5 in step d are replaced with 3-bromo-3,3-difluoro-1-propene, and Cpd022 is prepared by steps d, e and f.

[0109] LC-MS (ESI): m / z=369.12 [M+H] + 1 H NMR (300 MHz, DMSO-) d6) δ7.68-7.58 (m, 2H), 7.51-7.43 (m, 2H), 7.22-7.13 (m, 2H), 6.35-6.16 (m, 1H), 5.98-5.67 (m, 2H), 5.06 (d, J =5.6Hz, 1H), 4.36 (dd, J = 8.8, 3.5Hz, 1H), 4.18-4.08 (m, 1H), 2.68 (s, 3H), 1.13 (d, J = 6.3Hz, 3H).

[0110] Example 23, N -(( 2S , 3R The synthesis of 1-amino-3-hydroxy-1-oxo-2-butyl)-2-methyl-5-(but-3-en-2-oxy)-benzofuran-3-carboxamide (Cpd023) is described below: ; Reagents and conditions : (a) DIAD, PPh3, DMF, 0℃→rt; (b) NaOH, H2O:THF=1:2, 60℃, 6h; (c) HATU, DIPEA, DMF, rt, 12h.

[0111] Step a, Synthesis of ethyl 5-(3-buten-2-yloxy)-2-methylbenzofuran-3-carboxylate: Under an argon atmosphere, intermediate 1-2 (50 mg, 0.23 mmol), 3-buten-2-ol (16.37 mg, 0.23 mmol), triphenylphosphine (71.46 mg, 0.27 mmol), and DMF (5 mL) were added to a 50 mL flask and stirred at room temperature. DIAD (55.09 mg, 0.27 mmol) was added dropwise to the reaction system, and stirring was continued for 3 hours. After the reaction was complete as monitored by TLC, water (20 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with saturated brine (10 mL), concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to give intermediate 23-1 (26 mg, 42%) as a yellow solid.

[0112] LC-MS (ESI): m / z=275.13 [M+H] + Compound 023: N -(( 2S , 3RSynthesis of 1-amino-3-hydroxy-1-oxo-2-butyl)-2-methyl-5-(but-3-en-2-oxy)-benzofuran-3-carboxamide (Cpd023): The implementation method of steps e and f in Example 1 is the same, except that intermediates 1-6 are replaced with intermediates 23-1 to prepare Cpd023.

[0113] LC-MS (ESI): m / z=347.16 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ7.64-7.09 (m, 5H), 6.90 (d, J =11.6Hz, 1H), 6.01-5.78 (m, 1H), 5.32 (d, J =16.0Hz, 1H), 5.22-5.02 (m, 2H), 4.92 (t, J =6.6Hz, 1H), 4.43-4.30 (m, 1H), 4.24-4.06 (m, 1H), 2.64 (s, 3H), 1.38 (d, J =6.3Hz, 3H), 1.13 (d, J =6.3Hz, 3H).

[0114] Example 24, N -(( 2S , 3R The synthesis of 1-amino-3-hydroxy-1-oxo-2-butyl)-5-((3-fluoro-bicyclo[1.1.1]pentan-1-yl)methoxy)-2-methyl-benzofuran-3-carboxamide (Cpd024) is described below via the following reaction route: ; Reagents and conditions : (a) LiAlH4, THF, rt; (b) TsCl, Pyridine, rt; (c) K2CO3, DMF, 150℃, 12h; (d) NaOH, H2O:THF=1:2, 60℃, 6h; (e) HATU, DIPEA, DMF, rt, 12h.

[0115] Step a, Synthesis of (3-fluorobicyclo[1.1.1]pentan-1-yl)methanol: Compound 24-1 (130 mg, 1.00 mmol) was added to a 50 mL flask and dissolved in anhydrous THF (10 mL). Lithium aluminum hydride (75.84 mg, 2.00 mmol) was added dropwise at 0 °C, and the mixture was heated to room temperature and stirred for 2 hours. After the reaction was complete as monitored by TLC, 0.1 mL of water, followed by 0.1 mL of 15% NaOH aqueous solution, and then 0.3 mL of water were added dropwise. The mixture was heated to room temperature and stirred for 10 minutes. Anhydrous sodium sulfate was added to remove water, and the mixture was filtered. The filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure without column chromatography to obtain intermediate 24-2 (83 mg, 72% yield), a colorless liquid.

[0116] LC-MS (ESI): m / z=117.07 [M+H] + Step b, Synthesis of (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl 4-methylbenzenesulfonate: Intermediate 24-2 (83 mg, 0.71 mmol) was added to a 50 mL orbicular flask and dissolved in pyridine (3 mL). At room temperature, p-toluenesulfonyl chloride (245.25 mg, 1.29 mmol) was added to the system, and the mixture was purged with nitrogen three times. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After the reaction was complete, 1 mol / L hydrochloric acid aqueous solution was added to the system to adjust the pH to 5–7, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined and concentrated under reduced pressure. No column chromatography was required to obtain intermediate 24-3 (62 mg, 32%) as a white solid.

[0117] LC-MS (ESI): m / z=271.08 [M+H] + Compound 24: N -(( 2S , 3R Synthesis of 1-amino-3-hydroxy-1-oxo-2-butyl)-5-((3-fluoro-bicyclo[1.1.1]pentan-1-yl)methoxy)-2-methyl-benzofuran-3-carboxamide (Cpd024): Referring to the implementation method of steps b, c and d in Example 6, the difference is that intermediate 6-2 is replaced with intermediate 23-3, and Cpd024 is prepared by steps b, c and d.

[0118] LC-MS (ESI): m / z=391.17 [M+H] + 1 H NMR (300 MHz, DMSO-) d6) δ7.53-7.43 (m, 2H), 7.35 (s, 2H), 7.19 (s, 1H), 6.92 (dd, J = 8.6, 2.4Hz, 1H), 5.07 (d, J =4.8Hz, 1H), 4.38 (dd, J = 8.6, 3.6Hz, 1H), 4.29 (s, 2H), 4.20-4.07 (s, 1H), 2.64 (s, 3H), 2.08 (s, 6H), 1.13 (d, J =6.6Hz, 3H).

[0119] Example 25, N -(( 2S , 3R The synthesis of (Cpd025)-1-amino-3-hydroxy-1-oxo-2-butyl)-7-((4-methylthiazolyl-5-yl)methoxy)-2-naphthamide (Cpd025) is described below: ; Reagents and conditions: (a) K2CO3, DMF, rt; (b) NaOH, H2O: THF=1:2, 60℃; (c) DIPEA, HATU, DMF, 0℃→rt.

[0120] Step a, synthesis of methyl-7-((4-methylthiazolyl-5-yl)methoxy)-2-naphthyl ester: The method of step c in Example 3 is followed, except that intermediate 3-4 is replaced with compound 25-1 and reacted at room temperature to prepare intermediate 25-2.

[0121] LC-MS (ESI): m / z=314.08[M+H] + Compound 25: N -(( 2S , 3R Synthesis of (Cpd025)-1-amino-3-hydroxy-1-oxo-2-butyl)-7-((4-methylthiazolyl-5-yl)methoxy)-2-naphthamide: The method is the same as in Example 1, except that intermediates 1-6 in step e are replaced with intermediates 25-2, and Cpd027 is obtained after steps e and f.

[0122] LC-MS (ESI): m / z=400.13 [M+H] + 1 H NMR (300 MHz, DMSO-) d6) δ 9.01 (s, 1H), 8.41 (s, 1H), 8.02 (d, J = 8.6Hz, 1H), 7.94 (t, J = 8.0Hz, 2H), 7.83 (d, J = 8.6Hz, 1H), 7.63 (s, 1H), 7.45 (s, 1H), 7.31 (dd, J =8.9, 2.7Hz, 1H), 7.15 (s, 1H), 5.45 (s, 2H), 4.97 (d, J =6.5Hz, 1H), 4.40 (dd, J = 8.6, 4.1Hz, 1H), 4.20-4.07 (m, 1H), 2.46 (s, 3H), 1.14 (d, J =6.2Hz, 3H).

[0123] Example 26, N -(( 2S , 3R The synthesis of (Cpd026)-1-amino-3-hydroxy-1-oxo-2-butyl)-7-((4-methylthiazolyl-5-yl)methoxy)-1-naphthamide (Cpd026) is described below: ; Reagents and conditions : (a) K2CO3, DMF, 120℃; (b) NaOH, H2O:EtOH=1:1, 80℃; (c) HATU, DIPEA, DMF, rt.

[0124] Step a, Synthesis of 7-((4-methylthiazolyl-5-yl)methoxy)-1-naphthonitrile: The method of step c in Example 3 is followed, except that intermediate 3-4 is replaced with compound 26-1 and the temperature is raised to 120°C to prepare intermediate 26-2.

[0125] Step b, synthesis of 7-((4-methylthiazol-5-yl)methoxy)-1-naphtholic acid: Intermediate 26-2 (100 mg, 0.36 mmol) was added to a 50 mL flask and dissolved in ethanol (5 mL). A 5 mol / L NaOH aqueous solution (5 mL) was added while stirring at room temperature, and the mixture was heated to 100 °C and stirred for 2 hours. After the reaction was complete as monitored by TLC, the ethanol was removed by concentration under reduced pressure. Water (10 mL) was then added to the system, and the mixture was extracted with ethyl acetate (3 × 10 mL). The aqueous phase was adjusted to pH 4, at which point a white solid precipitated from the water. The precipitate was filtered, collected, and dried under an infrared lamp. No column chromatography was required to obtain intermediate 26-3 (90 mg, 84% yield), a white solid.

[0126] LC-MS (ESI): m / z=300.07 [M+H] + Step c, N -(( 2S , 3R Synthesis of (Cpd026)-1-amino-3-hydroxy-1-oxo-2-butyl)-7-((4-methylthiazolyl-5-yl)methoxy)-1-naphthamide: The method of implementing step f of Example 1 is the same, except that intermediates 1-7 are replaced with intermediates 26-3 to prepare Cpd026.

[0127] LC-MS (ESI): m / z=400.13 [M+H] + 1 H NMR (400 MHz, DMSO-) d 6) δ 8.99 (s, 1H), 8.32-7.00 (m, 9H), 5.41 (s, 2H), 4.88 (s, 1H), 4.61-4.35 (m, 1H), 4.24-3.99 (m, 1H), 2.43 (s, 3H), 1.17 (d, 3H).

[0128] Example 27, N -(( 2S , 3R The synthesis of 1-amino-3-hydroxy-1-oxo-2-butyl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide (Cpd027) is described below via the following reaction route: ; Reagents and conditions : (a) CuI, THF, 100℃, 30h; (b) H2, Pd / C, MeOH, rt, 12h; (c) Toluene, reflux, 12h, then NaBH4, MeOH, rt; (d) NaOH, H2O: THF=1:2, 60℃; (e) DIPEA, HATU, DMF, 0℃→rt.

[0129] Synthesis of intermediate 27-4: Ethyl-2-methyl-5-((4-methylthiazolyl-5-yl)methylamino)-benzofuran-3-carboxylic acid ester: Step a, Synthesis of ethyl-2-methyl-5-nitro-benzofuran-3-carboxylic acid ester: Compound 27-1 (200 mg, 0.609 mmol), ethyl acetoacetate (158 mg, 1.22 mmol), potassium carbonate (252 mg, 1.83 mmol), and cuprous iodide (11 mg, 0.060 mmol) were added to a 100 mL three-necked flask. Under nitrogen protection, 30 mL of anhydrous THF was added, and the reaction was carried out at 100 °C for 30 h. After the reaction was completed by TLC, the reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 2 / 1) to give intermediate 27-2 (102 mg, yield 67%) as a yellow solid.

[0130] Step b, synthesis of ethyl-5-amino-2-methyl-benzofuran-3-carboxylic acid ester: Intermediate 27-2 (61 mg, 0.244 mmol) and Pd / C (10%) (100 mg, 0.084 mmol) were added to a 50 mL flask and dissolved in 10 mL of methanol. The mixture was reacted under H2 (1 atm) for 12 h. After the reaction was completed by TLC, the reaction solution was filtered through diatomaceous earth. The residue was washed 2-3 times with methanol, and the filtrate was collected and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain intermediate 27-3 (35 mg, yield 66%) as a pale yellow solid.

[0131] Step c, synthesis of ethyl-2-methyl-5-((4-methylthiazolyl-5-yl)methylamino)-benzofuran-3-carboxylic acid ester: Intermediate 27-3 (35 mg, 0.159 mmol) and 5-methylthiazol-4-carboxaldehyde (24 mg, 0.191 mmol) were added to a 50 mL flask, followed by 10 mL of toluene. The mixture was refluxed for 12 h. After TLC monitoring showed complete consumption of intermediate 27-3, the reaction mixture was concentrated to dryness under reduced pressure. 10 mL of methanol was added to dissolve the intermediate, and sodium borohydride (9.66 mg, 0.255 mmol) was dissolved in 5 mL of methanol. This solution was added dropwise to the reaction mixture over an ice-water bath, completing the addition over 5 min. Stirring was continued for 1 h. After TLC monitoring showed complete reaction, the reaction mixture was concentrated to dryness under reduced pressure. 20 mL of water and 20 mL of ethyl acetate were added for extraction three times. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 3 / 1) to obtain intermediate 27-4 (52 mg, 99% yield) as a white solid.

[0132] Compound 27: N -(( 2S , 3R Synthesis of 1-amino-3-hydroxy-1-oxo-2-butyl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide (Cpd027): The method is the same as in Example 1, except that intermediates 1-6 in step e are replaced with intermediates 27-4, and Cpd027 is obtained after steps e and f.

[0133] 1 H NMR (400 MHz, DMSO) δ 8.81 (s, 1H), 7.49-7.40 (m, 1H), 7.30 (dd, J = 8.8, 3.7Hz, 2H), 7.20-7.11 (m, 1H), 7.00 (d, J =2.3Hz, 1H), 6.65 (dd, J = 8.8, 2.3Hz, 1H), 6.13 (t, J =6.0Hz, 1H), 5.11 (s, 1H), 4.41 (d, J =6.0Hz, 2H), 4.36 (dd, J = 8.6, 3.4Hz, 1H), 4.19-4.09 (m, 1H), 2.61 (s, 3H), 2.41 (s, 3H), 1.12 (d, J =6.3Hz, 3H).

[0134] Example 28, N -(( 2S , 3RThe synthesis of 1-amino-3-hydroxy-1-oxo-2-butyl)-2-methyl-5-(methyl((4-methylthiazo-5-yl)methyl)amino)-benzofuran-3-carboxamide (Cpd028) is described below: ; Reagents and conditions : (a) CH2O, EtOH, NaCNBH3, reflux, 12h; (e) NaOH, H2O: THF=1:2, 60℃, 6h; (f) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0135] Step a, Synthesis of ethyl-2-methyl-5-(methyl((4-methylthiazolyl)methyl)amino)-benzofuran-3-carboxylic acid ester: Intermediate 27-4 (60 mg, 0.189 mmol), paraformaldehyde (11 mg, 0.379 mmol), and sodium cyanoborohydride (30 mg, 0.474 mmol) were added to a 50 mL flask. 10 mL of ethanol was added, and the mixture was refluxed for 12 h. After complete reaction by TLC, the reaction mixture was concentrated to dryness under reduced pressure. The mixture was extracted three times with 20 mL of water and 20 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to give intermediate 28-1 (61 mg, 99% yield) as a white solid.

[0136] Compound 28: N -(( 2S , 3R Synthesis of 1-amino-3-hydroxy-1-oxo-2-butyl)-2-methyl-5-(methyl((4-methylthiazolyl-5-yl)methyl)amino)-benzofuran-3-carboxamide (Cpd028): The method is the same as in Example 1, except that intermediates 1-6 in step e are replaced with intermediate 28-1, and Cpd028 is obtained after steps e and f.

[0137] 1 H NMR (300 MHz, DMSO) δ 8.76 (s, 1H), 7.45 (s, 1H), 7.41 (d, J = 9.0Hz, 1H), 7.32 (d, J = 9.0Hz, 1H), 7.21 (d, J =2.5Hz, 1H), 7.18 (s, 1H), 6.91 (dd, J = 9.0, 2.5Hz, 1H), 5.07 (d,J =5.6Hz, 1H), 4.71 (s, 2H), 4.35 (dd, J = 8.8, 3.2Hz, 1H), 4.18-4.07 (m, 1H), 2.86 (s, 3H), 2.62 (s, 3H), 2.40 (s, 3H), 1.11 (d, J =6.3Hz, 3H).

[0138] Example 29, N -(( 2S , 3R The synthesis of 1-amino-3-hydroxy-1-oxo-2-butyl)-2-methyl-5-((4-phenylthiazolyl-5-yl)methoxy)-benzofuran-3-carboxamide (Cpd029) is described below via the following reaction route: ; Reagents and conditions : (a) Pd (dppf) Cl2, Na2CO3, 80℃, 3h; (b) POBr3, DCM, 0℃→rt; (c) NaOH, CH3CN, rt, 4h; (d) NaOH, H2O: EtOH=1:1, 60℃; (e) HATU, DIPEA, DMF, rt.

[0139] Step a, Synthesis of (4-phenylthiazolyl)methanol: Compound 29-1 (500 mg, 2.58 mmol), phenylboronic acid (345.6 mg, 2.83 mmol), sodium carbonate (505.77 mg, 5.15 mmol), and anhydrous dioxane (15 mL) were added to a 100 mL flask. The mixture was purged with nitrogen three times, heated to 100 °C, and stirred for 3 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give intermediate 29-2 (427 mg, yield 87%) as a yellow solid.

[0140] LC-MS (ESI): m / z=192.05 [M+H] + Step b, synthesis of 5-(bromomethyl)-4-phenylthiazole: Intermediate 29-2 (100 mg, 0.52 mmol) was added to a 100 mL orb-shaped flask and dissolved in anhydrous DCM (5 mL). Phosphorus tribromooxygenate (194.87 mg, 0.68 mmol) was added dropwise to the reaction mixture at 0 °C, and the mixture was heated to room temperature and stirred for 1 hour. After the reaction was complete as monitored by TLC, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to give intermediate 29-3 (103 mg, 78% yield) as a pale yellow solid.

[0141] LC-MS (ESI): m / z=253.96 [M+H] + Step c, synthesis of ethyl-2-methyl-5-((4-phenylthiazolyl-5-yl)methoxy)-benzofuran-3-carboxylic acid ester: Intermediate 1-2 (100 mg, 0.454 mmol), 20 mL of acetonitrile, and NaOH (19 mg, 0.477 mmol) were added to a 50 mL flask. The mixture was stirred at 0 °C for 30 min, and the reaction solution changed from a clear, transparent solution to a white emulsion. At this point, intermediate 29-3 (138 mg, 0.544 mmol) was added, and stirring continued for 3.5 hours. After the reaction was completed as monitored by TLC, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to obtain intermediate 29-4 (150 mg, yield 84%) as a pale yellow solid.

[0142] Step d, synthesis of 2-methyl-5-((4-phenylthiazolyl-5-yl)methoxy)-benzofuran-3-carboxylic acid: Intermediate 29-4 (161 mg, 0.410 mmol) was added to a 50 mL flask, followed by 10 mL of ethanol and stirring until fully dissolved. NaOH solid (65 mg, 1.640 mmol) was dissolved in 10 mL of water. The prepared sodium hydroxide aqueous solution was added dropwise to the reaction system. The mixture was heated to 60 °C and stirred for 6 hours. After the reaction was complete as monitored by TLC, the solvent was removed by concentration under reduced pressure. Water (10 mL) was then added to the system, and the mixture was extracted with ethyl acetate (3 × 30 mL). The aqueous phase was adjusted to pH 4. A white solid precipitated from the water. The precipitate was filtered, collected, and dried under an infrared lamp. Intermediate 29-5 (149 mg, 99% yield) was obtained as a white solid without the need for column chromatography purification.

[0143] Step e, N -(( 2S , 3RSynthesis of 1-amino-3-hydroxy-1-oxo-2-butyl)-2-methyl-5-((4-phenylthiazolyl-5-yl)methoxy)-benzofuran-3-carboxamide (Cpd029): The method of Example 1 is used, except that intermediates 1-7 in step f are replaced with intermediates 29-5, and Cpd028 is obtained after the preparation.

[0144] LC-MS (ESI): m / z=466.14 [M+H] + 1 H NMR (400 MHz, DMSO-) d 6) δ 9.19 (s, 1H), 7.72 (d, J =7.6Hz, 2H), 7.62-7.28 (m, 7H), 7.17 (s, 1H), 7.01 (dd, J = 8.7, 3.6Hz, 1H), 5.40 (s, 2H), 5.07 (s, 1H), 4.48-4.26 (m, 1H), 4.20-4.04 (m, 1H), 2.65 (s, 3H), 1.13 (d, J =6.3Hz, 3H).

[0145] Example 30, N -(( 2S , 3R )-1-amino-3-hydroxy-1-oxo-2-butyl)-5-((4-methylthiazolyl-5-yl)methoxy)-benzo[ d The synthesis of isoxazol-3-carboxamide follows the reaction route described below: ; Reagents and conditions: (a) NaNO2, HNO3, 0℃; (b) ethanol, sulfuric acid, reflux, 2h; (c) K2CO3, DMF, 60℃; (d) EtONa, EtOH, 60℃; (e) NaH, Diglyme, 120℃, 5h; (f) NaOH, H2O, 60℃; (g) DIPEA, HATU, DMF, 0℃→rt.

[0146] Step 1, Synthesis of 2-(5-hydroxy-2-nitrophenyl)acetic acid: Compound 30-1 (500 mg, 3.29 mmol) was added to a 100 mL round-bottom flask and dissolved in a prepared 40% NaNO2 aqueous solution (446.9 mg, 5.26 mmol). The solution was then added dropwise with stirring in an ice bath, followed by stirring, and the reaction was allowed to proceed for 20 minutes. The mixture was then allowed to cool to room temperature and react for another 3 hours. After the reaction was complete as monitored by TLC, water (50 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 × 80 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1, 0.1% HAc) to give intermediate 30-2 (283 mg, 44% yield) as a yellow solid.

[0147] LC-MS (ESI): m / z=198.03 [M+H] + Step 2, Synthesis of ethyl 2-(5-hydroxy-2-nitrophenyl)acetic acid ester: Intermediate 30-2 (283 mg, 1.44 mmol) was added to a 100 mL round-bottom flask and dissolved in anhydrous ethanol (10 mL). Concentrated sulfuric acid (65 μL) was added, and the mixture was reacted at 85 °C for 3 hours. After the reaction was complete as monitored by TLC, water (50 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 × 80 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give intermediate 30-3 (254 mg, 79% yield) as a yellow solid.

[0148] LC-MS (ESI): m / z=226.06 [M+H] + Step 3, Synthesis of ethyl 2-(5-((4-methylthiazolyl-5-yl)methoxy)-2-nitrophenyl)acetate: Intermediate 30-3 (200 mg, 0.89 mmol), intermediate 1-2 (262.2 mg, 1.78 mmol), K2CO3 (245.5 mg, 1.78 mmol), and DMF (6 mL) were added to a 50 mL flask and stirred at 60 °C for 6 hours. After the reaction was complete as monitored by TLC, water (30 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 × 40 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give intermediate 30-4 (137 mg, yield 46%) as a pale yellow solid.

[0149] LC-MS (ESI): m / z=337.08 [M+H] + Step 4, ethyl ( Z Synthesis of 2-(hydroxyimino)-2-(5-((4-methylthiazolyl-5-yl)methoxy)-2-nitrophenyl)acetate: Intermediate 30-4 (50 mg, 0.15 mmol) was added to a 50 mL orb-shaped flask and dissolved in anhydrous ethanol (5 mL). Then, under stirring at room temperature, 2 mL of an ethanol solution of tert-butyl nitrite (53 μL, 0.46 mmol) and sodium ethoxide (12 mg, 0.18 mmol) was added, and the mixture was stirred at 60 °C for 6 hours. After the reaction was complete as monitored by TLC, water (20 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 × 30 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to obtain intermediate 30-5 (29 mg, 53% yield) as a yellow solid.

[0150] LC-MS (ESI): m / z=366.07 [M+H] + Step 5, ethyl 5-((4-methylthiazolyl-5-yl)methoxy)benzo[ d Synthesis of isoxazole-3-carboxylic acid ester: Sodium hydride (3.24 mg, 0.13 mmol) was added to a 50 mL double-necked flask and dissolved in diethylene glycol dimethyl ether (2 mL). The system was evacuated three times with N2. Under vigorous stirring, a solution of intermediate 30-5 (29 mg, 0.08 mmol) in diethylene glycol dimethyl ether (1.5 mL) was added, and the mixture was stirred at 120 °C for 5 hours. After the reaction was complete as monitored by TLC, water (10 mL) was added to adjust the pH to 5, followed by extraction with ethyl acetate (3 × 20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 8 / 1) to obtain intermediate 30-6 (9 mg, yield 36%) as a white solid.

[0151] LC-MS (ESI): m / z=319.07[M+H] + Step 6, 5-((4-methylthiazolyl-5-yl)methoxy)benzo[ d Synthesis of isoxazole-3-carboxylic acid: Intermediate 30-6 (9 mg, 0.03 mmol) was added to a 50 mL flask, followed by ethanol (2 mL) and stirring until fully dissolved. NaOH solid (40 mg, 1 mmol) was dissolved in water (1 mL), and the prepared sodium hydroxide aqueous solution was added dropwise to the reaction system. The mixture was heated to 60 °C and stirred for 2 hours. After the reaction was complete as monitored by TLC, the ethanol was removed by concentration under reduced pressure. Water (10 mL) was then added to the system, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phase was discarded, and the aqueous phase was retained and the pH was adjusted to 4. A white solid precipitated from the water. The system was filtered, the filtrate was collected, and dried under an infrared lamp. No column chromatography purification was required to obtain intermediate 30-7 (6 mg, 73% yield), a white solid.

[0152] LC-MS (ESI): m / z=291.04 [M+H] + Step 7, N -(2) S 3 R )-1-amino-3-hydroxy-1-oxobutane-2-yl)-5-((4-methylthiazolyl-5-yl)methoxy)benzo[ d Synthesis of isoxazol-3-carboxamide: Add intermediate 30-7 (6 mg, 0.02 mmol), DIPEA (21 mg, 29 μL, 0.16 mmol), HATU (10 mg, 0.03 mmol), and DMF (3 mL) to a 50 mL flask. Add (2...) while stirring at room temperature. S 3 R 2-Amino-3-hydroxybutyramide hydrochloride (13 mg, 0.08 mmol) was added, and the reaction was continued for 3 hours. After the reaction was completed by TLC monitoring, water (10 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give Cpd030 (4 mg, yield 49%) as a white solid.

[0153] LC-MS (ESI): m / z=391.10 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ 9.00 (s, 1H), 8.16 (d, J = 8.7Hz, 1H), 7.83 (d, J =9.5Hz, 1H), 7.62 (d, J=2.6Hz, 1H), 7.56 (s, 1H), 7.40 (dd, J = 9.5, 2.6Hz, 1H), 7.22 (s, 1H), 5.40 (s, 2H), 5.14 (d, J =6.1Hz, 1H), 4.36 (dd, J = 8.7, 3.8Hz, 1H), 4.22-4.10 (m, 1H), 2.45 (s, 3H), 1.14 (d, J =6.3Hz, 3H).

[0154] Example 31, N -(( 2S , 3R )-1-amino-3-hydroxy-1-oxo-2-butyl)-5-(4-fluoro-2-methylbenzo[ d The synthesis of [1,3]dioxane-2-yl)-2-methyl-benzofuran-3-carboxamide (Cpd031) is described below via the following reaction route: ; Reagents and conditions : (a) LiAlH4, THF, rt; (b) TsCl, NaH, THF, rt; (c) K2CO3, DMF, 150℃; (d) NaOH, H2O: THF=1:2, 60℃; (e) HATU, DIPEA, DMF, rt.

[0155] Step a, Synthesis of 2-fluoro-2-en-1-propanol: Compound 31-1 (104 mg, 1.00 mmol) was added to a 50 mL flask and dissolved in anhydrous THF (10 mL). Lithium aluminum hydride (75.84 mg, 2.00 mmol) was added dropwise at 0 °C, and the mixture was heated to room temperature and stirred for 2 hours. After the reaction was complete as monitored by TLC, 0.1 mL of water, followed by 0.1 mL of 15% NaOH aqueous solution, and then 0.3 mL of water were added dropwise to the system. The mixture was then heated to room temperature and stirred for 10 minutes. Anhydrous sodium sulfate was added to the system to remove water. The mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure without column chromatography to obtain intermediate 31-2 (66 mg, 86% yield), a colorless liquid.

[0156] Step b, synthesis of 2-fluoroallyl-4-methylbenzenesulfonate: Intermediate 31-2 (560 mg, 7.36 mmol) was added to a 50 mL orb-shaped flask and dissolved in anhydrous dichloromethane (12 mL). Sodium hydride (211.99 mg, 60%, 8.83 mmol) was added dropwise at 0 °C, and the mixture was heated to room temperature and stirred for 2 hours. p-Toluenesulfonyl chloride (1.68 g, 8.83 mmol) was added to the system at room temperature, and stirring was continued for 2 hours. After complete TLC monitoring, 1 mol / L hydrochloric acid aqueous solution was added to the system to adjust the pH to 5–7, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to obtain intermediate 31-3 (637 mg, 38% yield), a colorless liquid.

[0157] LC-MS (ESI): m / z=231.05 [M+H] + Compound 31: N -(( 2S , 3R )-1-amino-3-hydroxy-1-oxo-2-butyl)-5-(4-fluoro-2-methylbenzo[ d Synthesis of [1,3]dioxane-2-yl)-2-methyl-benzofuran-3-carboxamide (Cpd031): Referring to the implementation method of steps b, c and d in Example 6, the difference is that intermediate 6-2 is replaced with intermediate 31-3, and Cpd031 is obtained by steps b, c and d.

[0158] LC-MS (ESI): m / z=351.14 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ7.64-7.28 (m, 4H), 7.20 (s, 1H), 6.99 (d, J = 9.0Hz, 1H), 5.10 (d, J =3.4Hz, 1H), 4.96 (d, J =17.0Hz, 1H), 4.87 (d, J =13.5Hz, 1H), 4.70 (d, J =15.1Hz, 2H), 4.38 (d, J = 8.9Hz, 1H), 4.22-4.08 (m, 1H), 2.65 (s, 3H), 1.14 (d, J =4.3Hz, 3H).

[0159] Example 32, N -(( 2S , 3R )-1-amino-3-hydroxy-1-oxobutane-2-yl)-5-((( E The synthesis of 2,3-difluoroallyl)oxy)-2-methylbenzofuran-3-carboxamide (Cpd032) is described below via the following reaction route: ; Reagents and conditions : (a) LiAlH4, THF, rt; (b) TsCl, NaH, THF, rt; (c) K2CO3, DMF, 150℃; (d) NaOH, H2O: THF=1:2, 60℃; (e) HATU, DIPEA, DMF, rt.

[0160] The method of Example 31 is used, except that intermediate 31-1 in step a is replaced with intermediate 31-2 to prepare Cpd032.

[0161] LC-MS (ESI): m / z=369.13 [M+H] + 1 H NMR (400 MHz, DMSO-) d 6) δ7.55-7.47 (m, 2H), 7.44-7.37 (m, 2H), 7.35-7.14 (m, 2H), 6.98 (dd, J = 8.9, 2.7Hz, 1H), 5.09 (s, 1H), 4.71 (dd, J =21.8, 4.4Hz, 2H), 4.38 (dd, J = 8.8, 3.4Hz, 1H), 4.18-4.10 (m, 1H), 2.65 (s, 3H), 1.14 (d, J =6.4Hz, 3H).

[0162] Example 33, N -(( 2S , 3R The synthesis of 1-amino-3-hydroxy-1-oxobutan-2-yl)-5-(cyclopent-1-en-1-ylmethoxy)-2-methylbenzofuran-3-carboxamide (Cpd033) is described below: ; Reagents and conditions : (a) DIBAL-H, DCM, 0℃; (b) DIAD, PPh3, DMF, 0℃→rt; (c) NaOH, H2O: THF=1:2, 60℃; (d) HATU, DIPEA, DMF, rt.

[0163] Step a, Synthesis of cyclopenten-1-yl-1-methanol: Add diisobutylaluminum hydride (1.5 M in toluene, 5.83 mmol) to a 50 mL flask, dilute with anhydrous dichloromethane (3 mL), and add compound 33-1 (320 mg, 2.54 mmol) dropwise at 0 °C, stirring for 2 hours. After the reaction is complete as monitored by TLC, add 2 mL of methanol dropwise to the system at 0 °C, followed by 2 mL of 15% NaOH aqueous solution, and continue stirring at room temperature for 5 minutes. Remove methanol from the system by vacuum concentration, add water (10 mL) to the system, and extract with dichloromethane (3 × 20 mL). Combine the organic phases, concentrate under reduced pressure, and obtain intermediate 33-2 (192 mg, 77% yield) as a colorless liquid without column chromatography purification.

[0164] Compound 33: N -(( 2S , 3R Synthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-5-(cyclopent-1-en-1-ylmethoxy)-2-methylbenzofuran-3-carboxamide: The method of Example 23 is followed, except that 3-buten-2-ol in step a is replaced with intermediate 33-2, and Cpd033 is prepared by steps a, b and c.

[0165] LC-MS (ESI): m / z=373.18 [M+H] + 1 H NMR (400 MHz, DMSO-) d 6) δ7.51-7.44 (m, 2H), 7.39-7.32 (m, 2H), 7.19 (s, 1H), 6.92 (dd, J = 8.9, 2.6Hz, 1H), 5.75 (s, 1H), 5.09 (d, J =5.6Hz, 1H), 4.63 (s, 2H), 4.37 (dd, J = 8.9, 3.4Hz, 1H), 4.21-4.08 (m, J =6.1, 3.4Hz, 1H), 2.64 (s, 3H), 2.39-2.27 (m, 4H), 1.86 (p,J =7.4Hz, 2H), 1.14 (d, J =6.4Hz, 3H).

[0166] Example 34, 5-((1,2,5-thiadiazol-3-yl)methoxy)- N -(2) S 3 R The synthesis of 1-amino-3-hydroxy-1-oxobutyryl)-2-methylbenzofuran-3-carboxamide is described below: ; Reagents and conditions : (a) (i) (COCl)2, DCM, DMF, rt; (ii) EtOH, rt; (iii) NaBH4, EtOH, 0℃→30℃, 12h; (b) SOCl2, DCM, 0℃ →rt, 5h; (c) K2CO3, DMF, 75℃, 12h; (d) NaOH, H2O:THF=1:2, 60℃, 6h; (e) HATU, DIPEA, DMF, 70℃, 3h.

[0167] Step a, Synthesis of (1,2,5-thiadiazol-3-yl)methanol: Compound 34-1 (100 mg, 0.769 mmol) was added to a 50 mL flask and dissolved in anhydrous dichloromethane (5 mL). Oxaloyl chloride (195.08 mg, 1.54 mmol) and 1 drop of DMF were added dropwise to the reaction mixture with stirring at room temperature. The reaction mixture produced bubbles and gradually became translucent over one hour. After one hour, the reaction mixture was concentrated under vacuum to give a brown, oily acyl chloride. The acyl chloride was dissolved in ethanol (8 mL) and stirred at room temperature for 1 hour to give an ethanol solution of ethyl ester. An ethanol solution (3 mL) of sodium borohydride (58.15 mg, 1.54 mmol) was added directly to the reaction system with stirring at 0 °C. After 5 minutes, the temperature was raised to 30 °C, and the reaction mixture was stirred for 12 hours. After the reaction was complete as monitored by TLC, the reaction mixture was concentrated to dryness under reduced pressure without further purification to give intermediate 34-2 (78 mg, 87% yield), a pale yellow oil.

[0168] LC-MS (ESI): m / z=117.00 [M+H] + Step b, Synthesis of 3-(chloromethyl)-1,2,5-thiadiazole: Following the method described in step b of Example 3, except that compound 3-2 is replaced with compound 34-2, and the reaction is carried out at room temperature to prepare intermediate 34-3.

[0169] LC-MS (ESI): m / z=134.97 [M+H] + Step c, Synthesis of ethyl 5-((1,2,5-thiadiazol-3-yl)methoxy)-2-methylbenzofuran-3-carboxylate: The method of step d in Example 1 is followed, except that intermediate 1-5 is replaced with intermediate 34-3 and reacted at 60°C to prepare intermediate 34-4.

[0170] LC-MS (ESI): m / z=319.07 [M+H] + Compound 34: 5-((1,2,5-thiadiazol-3-yl)methoxy)- N -(2) S 3 R Synthesis of 1-amino-3-hydroxy-1-oxobutyryl)-2-methylbenzofuran-3-carboxamide (Cpd034): The method is the same as in Example 1, except that intermediates 1-6 in step e are replaced with intermediates 34-4, and Cpd034 is obtained after steps e and f.

[0171] LC-MS (ESI): m / z=391.10 [M+H] + 1 H NMR (400 MHz, DMSO) δ 8.99 (s, 1H), 7.61-6.99 (m, 6H), 5.47 (s, 2H), 5.10 (s, 1H), 4.37 (d, J =5.4Hz, 1H), 4.23-4.04 (m, 1H), 2.65 (s, 3H), 1.14 (d, J =6.5Hz, 3H).

[0172] Example 35, 3-(((2) S 3 R The synthesis of 1-amino-3-hydroxy-1-oxo-2-butyl)carbamoyl)-2-methylbenzofuran-5-yl 1,2,5-thiazolyl-3-carboxylic acid ester (Cpd035) is described below via the following reaction route: ; Reagents and conditions : (a) Oxalyl chloride, DCM, DMF, 0℃→rt, 3h; (b) DIPEA, DCM, 0℃, 3h; (c) NaOH, H2O:MeOH:THF=1:2:2, 60℃; (d) DIPEA, HATU, DMAc, 0℃→rt.

[0173] Step a, Synthesis of 1,2,5-thiazol-3-carbonyl chloride: Compound 35-1 (100 mg, 0.768 mmol) was added to a 50 mL flask and dissolved in 10 mL of anhydrous dichloromethane. One drop of DMF was added dropwise, followed by the addition of 146 mg, 1.15 mmol of oxaloyl chloride dissolved in 5 mL of anhydrous dichloromethane at 0 °C. The mixture was then heated to room temperature and stirred for 3 hours. After the reaction was completed by TLC, the reaction solution was concentrated to dryness under reduced pressure. No further purification was required to give intermediate 35-2 (114 mg, 99% yield) as a yellow-green solid.

[0174] Step b, Synthesis of 3-(ethoxycarbonyl)-2-methylbenzofuran-5-yl 1,2,5-thiadiazole-3-carboxylic acid ester: Intermediate 1-2 (122 mg, 0.639 mmol) was added to a 50 mL orb-shaped flask, and DIPEA (95 mg, 0.831 mmol) was dissolved in anhydrous dichloromethane (12 mL). Intermediate 35-2 (114 mg, 0.767 mmol) dissolved in dichloromethane (5 mL) was added dropwise to the system at 0 °C. The mixture was then heated to room temperature and stirred for 3 hours. After complete TLC monitoring, the pH was adjusted to 7–9 with 1 mol / L sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined and concentrated to dryness under reduced pressure. No further purification was required to obtain intermediate 35-3 (190 mg, 98% yield) as a white solid.

[0175] Compound 35: 3-(((2) S 3 R Synthesis of 1-amino-3-hydroxy-1-oxo-2-butyl)carbamoyl)-2-methylbenzofuran-5-yl 1,2,5-thiazol-3-carboxylic acid ester: Referring to the implementation method of steps c and d in Example 6, the difference is that intermediate 6-3 is replaced with intermediate 35-3, and Cpd035 is obtained by steps c and d.

[0176] 1 H NMR (300 MHz, DMSO-) d 6) δ7.46 (s, 1H), 7.35 (d, J = 8.8Hz, 1H), 7.27 (d, J =8.8Hz, 1H), 7.17 (s, 1H), 7.14 (d, J =2.5Hz, 1H), 6.74 (dd, J = 8.6, 2.5Hz, 1H), 4.36 (dd,J = 8.6, 3.4Hz, 1H), 4.14 (dd, J =6.3, 3.4Hz, 1H), 2.62 (s, 3H), 1.14 (d, J =6.3Hz, 3H).

[0177] Example 36, N -(2) S 3 R The synthesis of 1-amino-3-hydroxy-1-oxo-2-butyl)-5-(4-oxytrypanan)-2-methylbenzofuran-3-carboxamide (Cpd036) is described below via the following reaction route: ; Reagents and conditions : (a) PBr3, DCM, Pyridine, 0℃→rt, 6h; (b) K2CO3, DMF, 60℃; (c) NaOH, H2O:MeOH:THF=1:2:2, 60℃; (d) DIPEA, HATU, DMAc, 0℃→rt.

[0178] Step a, Synthesis of 4-bromotryptane: Under nitrogen protection, PBr3 (90 mg, 0.332 mmol) dissolved in CHCl3 (5 mL) was added dropwise to a 25 mL two-necked flask containing compound 36-1 (100 mg, 0.665 mmol), pyridine (79 mg, 0.999 mmol), and CHCl3 (5 mL). The reaction was carried out at 0 °C for 6 hours. After the reaction was completed as monitored by TLC, dichloromethane (10 mL) was added, and the mixture was washed 2-3 times with water. The organic phase was concentrated to dryness without further purification to give intermediate 36-2 (140 mg, 99% yield), which was a yellow oily liquid.

[0179] Compound 36: N -(2) S 3 R Synthesis of 1-amino-3-hydroxy-1-oxo-2-butyl)-5-(4-oxytrypanan)-2-methylbenzofuran-3-carboxamide (Cpd036): The method is the same as in Example 1, except that intermediates 1-5 in step d are replaced with intermediates 36-2, and Cpd036 is prepared by steps d, e and f.

[0180] 1 H NMR (300 MHz, DMSO-) d 6) δ7.61-7.40 (m, 4H), 7.37-7.14 (m, 3H), 7.05 (dd, J=8.8, 2.5Hz, 1H), 6.96-6.79 (m, 2H), 5.46 (t, J =3.7Hz, 1H), 5.11 (t, J =5.6Hz, 1H), 4.53-4.01 (m, 4H), 2.66 (s, 3H), 2.27-2.09 (m, 2H), 1.15 (d, J =6.2Hz, 3H).

[0181] Example 37, N -(2) S 3 R The synthesis of 3-hydroxy-1-(hydroxyamino)-1-oxo-2-butyl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide (Cpd037) is described below: ; Reagents and conditions : (a) K2CO3, DMF, 60℃; (b) NaOH, H2O:MeOH:THF=1:2:2, 60℃; (c) DIPEA, HATU, DMAc, 0℃→rt (d) NH2OH·HCl, KOH, MeOH, rt.

[0182] Step a, ethyl(2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)benzofuran-3-carbonyl)- L Synthesis of threonine esters: Add intermediate 10⁻² (290 mg, 0.956 mmol), DIPEA (309 mg, 2.39 mmol), HATU (399 mg, 1.05 mmol), and DMF (15 mL) to a 50 mL orb-shaped flask, and add the solution while stirring at room temperature. L -Threonine ethyl ester hydrochloride (210 mg, 1.15 mmol) was reacted for another 3 hours. After the reaction was complete as monitored by TLC, water (50 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 × 80 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give intermediate 37-1 (247 mg, yield 80.4%) as a white to slightly yellow solid.

[0183] Compound 37: N-((2) S 3 RSynthesis of 3-hydroxy-1-(hydroxyamino)-1-oxo-2-butyl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide (Cpd037): Intermediate 37-1 (50 mg, 0.115 mmol), hydroxylamine hydrochloride (241 mg, 3.47 mmol), KOH (201 mg, 3.58 mmol), and methanol (20 mL) were added to a 50 mL flask and reacted at room temperature for 18 h. After the reaction was completed by TLC, the reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 2) to give Cpd037 (24 mg, 50% yield) as a white solid.

[0184] 1 H NMR (300 MHz, DMSO-) d 6) δ 8.99 (s, 1H), 7.69-7.33 (m, 3H), 6.99 (d, J = 8.9Hz, 1H), 5.31 (s, 3H), 4.45-4.15 (m, 1H), 4.15-3.94 (m, 1H), 2.64 (s, 3H), 2.42 (s, 3H), 1.18-1.04 (m, 3H).

[0185] Example 38, N -(2) S 3 R )-1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)naphtho[1,2- b The synthesis of furan-3-carboxamide follows the reaction route described below: ; Reagents and conditions : (a) ZnCl2, Toluene, reflux, 12h; (b) K2CO3, DMF, 75℃, 6h; (c) NaOH, H2O:THF=1:2, 60℃, 6h; (d) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0186] Step a, 5-hydroxy-2-methylnaphtho[1,2- b Synthesis of ethyl furan-3-carboxylate: The method of step a in Example 1 was followed, except that compound 1-1 was replaced with compound 38-1, the temperature was raised to 70°C, and after 15 minutes the temperature was raised to 140°C to prepare intermediate 38-2.

[0187] LC-MS (ESI): m / z=271.09 [M+H] + Step b, 2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)naphtho[1,2- b Synthesis of ethyl furan-3-carboxylate: The method of step c in Example 3 is followed, except that intermediate 3-4 is replaced with intermediate 38-2 and reacted at 60°C to prepare intermediate 38-3.

[0188] LC-MS (ESI): m / z=382.10 [M+H] + Compound 38: N -(2) S 3 R )-1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)naphtho[1,2- b Synthesis of furan-3-carboxamide (Cpd038): The method is the same as in Example 1, except that intermediates 1-6 in step e are replaced with intermediates 38-3, and Cpd038 is obtained after steps e and f.

[0189] LC-MS (ESI): m / z=454.14 [M+H] + 1 H NMR (300 MHz, DMSO) δ 9.03 (s, 1H), 8.17 (dd, J = 8.4, 3.5Hz, 2H), 7.68 (ddd, J = 8.4, 7.0, 1.2Hz, 1H), 7.61-7.50 (m, 4H), 7.23 (s, 1H), 5.51 (s, 2H), 5.13 (d, J =5.7Hz, 1H), 4.43 (dd, J = 8.9, 3.6Hz, 1H), 4.23-4.11 (m, 1H), 2.77 (s, 3H), 2.47 (s, 3H), 1.19 (d, J =6.3Hz, 3H).

[0190] Example 39, N -(2) S 3 R )-1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methyl-6-((4-methylthiazolyl-5-yl)methoxy)-4-oxo-4 HThe synthesis of benzopyran-3-carboxamide follows the reaction route described below: ; Reagents and conditions: (a) K2CO3, DMF, 75℃, 6h; (b) NaOH, H2O:THF=1:2, 60℃, 6h; (c) SOCl2, DMF, 75℃; (d) NaH, Toluene, 120℃; (e) NaOH, H2O, EtOH, 60℃; (f) DIPEA, HATU, DMF, 0℃→rt.

[0191] Step a, Synthesis of methyl 2-fluoro-5-((4-methylthiazolyl-5-yl)methoxy)benzoate: The method of step c in Example 3 is followed, except that intermediate 3-4 is replaced with compound 39-1 and reacted at 60°C to prepare intermediate 39-2.

[0192] LC-MS (ESI): m / z=282.05 [M+H] + Step b, synthesis of 2-fluoro-5-((4-methylthiazol-5-yl)methoxy)benzoic acid: The method of step e in Example 1 is followed, except that intermediates 1-6 in step e are replaced with intermediate 39-2, and the reaction is carried out at 60°C to prepare intermediate 39-3.

[0193] LC-MS (ESI): m / z=267.04 [M+H] + Step c, Synthesis of 2-fluoro-5-((4-methylthiazolyl-5-yl)methoxy)benzoyl chloride: Intermediate 39-3 (60 mg, 0.224 mmol) was added to a 50 mL orb-shaped flask and dissolved in SOCl2 (5 mL). One drop of DMF was added dropwise to the reaction mixture while stirring at 0°C. After 10 minutes, the temperature was raised to 80°C. The reaction mixture was stirred under reflux for 2 hours until complete, and then concentrated to dryness under reduced pressure. No further purification was required to obtain intermediate 39-4 (64 mg, 99% yield), a pale yellow solid.

[0194] LC-MS (ESI): m / z=286.00 [M+H] + Step d, 2-methyl-6-((4-methylthiazo-5-yl)methoxy)-4-oxo-4 H Synthesis of ethyl benzopyran-3-carboxylate: Ethyl acetoacetate (105.63 mg, 0.812 mmol) and toluene (5 mL) were added to a 50 mL double-necked flask, followed by sodium hydride (19.48 mg, 0.812 mmol). The system was subjected to nitrogen evacuation three times and stirred at room temperature. After 1 hour, a toluene solution of intermediate 39-4 (29 mg, 0.08 mmol) was added dropwise at 0 °C with vigorous stirring. The mixture was stirred at 120 °C for 5 hours. After the reaction was complete as monitored by TLC, water (30 mL) was added to adjust the pH to 5. The mixture was then extracted with ethyl acetate (3 × 40 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 2 / 1) to obtain intermediate 39-5 (34 mg, yield 16%) as a white solid.

[0195] LC-MS (ESI): m / z=360.08 [M+H] + Compound 39: N -(2) S 3 R )-1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methyl-6-((4-methylthiazolyl-5-yl)methoxy)-4-oxo-4 H Synthesis of benzopyran-3-carboxamide (Cpd039): The method is the same as in Example 1, except that intermediates 1-6 in step e are replaced with intermediates 39-5, and Cpd039 is obtained after steps e and f.

[0196] LC-MS (ESI): m / z=432.12 [M+H] + 1 H NMR (400 MHz, DMSO-) d 6) δ14.03 (s, 1H), 8.99 (s, 1H), 7.68 (s, 1H), 7.54 (d, J =3.0Hz, 1H), 7.47 (s, 1H), 7.28 (dd, J = 8.9, 3.0Hz, 1H), 7.22 (d, J = 8.9Hz, 1H), 5.46 (d, J =4.6Hz, 1H), 5.36 (s, 2H), 4.44 (dd, J = 8.1, 4.8Hz, 1H), 4.15-4.07 (m, 1H), 2.60 (s, 3H), 2.43 (s, 3H), 1.17 (d, J=6.3Hz, 3H).

[0197] Example 40, N -(2) S 3 R )-1-amino-3-hydroxy-1-oxobutane-2-yl)-6-((4-methylthiazolyl-5-yl)methoxy)-2-oxo-2 H The synthesis of benzopyran-3-carboxamide follows the reaction route described below: ; Reagents and conditions: (a) Pd (dppf) Cl2, KOAc, Dioxane, 85℃, 12h; (b) H2O2, THF, H2O, 0℃→30℃; (c) K2CO3, DMF, 60℃, 6h; (c) NaOH, H2O:EtOH=1:1, 60℃, 6h; (d) DIPEA, HATU, DMAc, 0℃→rt, 12h.

[0198] Step a, 2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-2 H Synthesis of ethyl benzopyran-3-carboxylate: Compound 40-1 (400 mg, 1.35 mmol), pinacol diborate (1.03 g, 4.04 mmol), potassium acetate (330.33 mg, 3.37 mmol), and Pd(dppf)Cl2 (49.26 mg, 0.067 mmol) were added to a 100 mL three-necked flask. Anhydrous dioxane (8 mL) was added to dissolve the compound. The system was subjected to nitrogen evacuation three times and stirred at 80 °C for 12 hours. After the reaction was complete as monitored by TLC, water (30 mL) was added to adjust the pH to 5. The mixture was then extracted with ethyl acetate (3 × 60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to give intermediate 40-2 (414 mg, 89% yield) as a white solid.

[0199] LC-MS (ESI): m / z=345.14 [M+H] + Step b, 6-hydroxy-2-oxo-2 H Synthesis of ethyl benzopyran-3-carboxylate: Intermediate 40-2 (414 mg, 1.2 mmol) was added to a 50 mL orb-shaped flask and dissolved in THF (4 mL) and H2O (4 mL). Glacial acetic acid (264.96 mg, 6.01 mmol) and hydrogen peroxide (409.15 mg, 12.03 mmol) were added dropwise to the reaction mixture under stirring at 0 °C. After 10 minutes, the mixture was heated to 30 °C and stirred for 3 hours. After the reaction was complete as monitored by TLC, water (30 mL) was added to the system and the pH was adjusted to 7. The mixture was then extracted with ethyl acetate (3 × 60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. No further purification was required to obtain intermediate 40-3 (275 mg, 98% yield) as a white solid.

[0200] LC-MS (ESI): m / z=235.05 [M+H] + Step c, 6-(4-methylthiazolyl-5-yl)methoxy-2-oxo-2 H Synthesis of ethyl benzopyran-3-carboxylate: The method of step c in Example 3 is followed, except that intermediate 3-4 is replaced with compound 40-3, and the reaction is carried out at 60°C to prepare intermediate 40-4.

[0201] LC-MS (ESI): m / z=346.07 [M+H] + Compound 40: N -(2) S 3 R )-1-amino-3-hydroxy-1-oxobutane-2-yl)-6-((4-methylthiazolyl-5-yl)methoxy)-2-oxo-2 H Synthesis of benzopyran-3-carboxamide (Cpd040): The method is the same as in Example 1, except that intermediates 1-6 in step e are replaced with intermediates 40-4, and Cpd040 is obtained after steps e and f.

[0202] LC-MS (ESI): m / z=418.10 [M+H] + 1 H NMR (300 MHz, DMSO) δ 9.19 (d, J = 8.2Hz, 1H), 9.01 (s, 1H), 8.84 (s, 1H), 7.69 (d, J =3.0Hz, 1H), 7.53-7.39 (m, 3H), 7.17 (s, 1H), 5.37 (s, 2H), 5.15 (d, J=4.3Hz, 1H), 4.28 (dd, J = 8.2, 2.9Hz, 1H), 4.24-4.14 (m, 1H), 2.43 (s, 3H), 1.08 (d, J =6.4Hz, 3H).

[0203] Example 41, N -(( 2S , 3R )-1-amino-3-hydroxy-1-oxobutyryl)-6-((4-methylthiazolyl-5-yl)methoxy)-1 H The synthesis of indole-1-carboxamide (Cpd041) follows the reaction route described below: ; Reagents and conditions : (a) DIBAL-H, DCM, 0℃; (b) DIAD, PPh3, DMF, 0℃→rt; (c) NaOH, H2O: THF=1:2, 60℃; (d) HATU, DIPEA, DMF, rt.

[0204] The method of Example 33 is used, except that intermediate 33-1 in step a is replaced with intermediate 41-1, and Cpd041 is prepared by steps b, c and d.

[0205] LC-MS (ESI): m / z=367.11 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ7.55-7.31 (m, 4H), 7.18 (s, 1H), 6.94 (dd, J = 9.0, 2.7Hz, 1H), 6.57 (d, J =7.2Hz, 1H), 6.30-6.09 (m, 1H), 5.08 (s, 1H), 4.76 (d, J =6.1Hz, 2H), 4.37 (dd, J = 8.8, 3.6Hz, 1H), 4.20-4.03 (m, 1H), 2.65 (s, 3H), 1.14 (d, J =6.3Hz, 3H).

[0206] Example 42, N -(2) S 3 RThe synthesis of 1-hydrazino-3-hydroxy-1-oxo-2-butyl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide (Cpd042) is described below: ; Reagents and conditions : NH2NH2·H2O, EtOH, 60℃.

[0207] Intermediate 37-1 (100 mg, 0.231 mmol), hydrazine hydrate (54 mg, 85%, 0.924 mmol), and ethanol (20 mL) were added to a 50 mL flask and reacted at 60 °C for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 2) to give Cpd042 (80 mg, yield 83%) as a white solid.

[0208] 1 H NMR (300 MHz, DMSO) δ 9.21 (s, 1H), 8.99 (s, 1H), 7.51 (d, J = 8.8Hz, 2H), 7.41 (d, J =2.6Hz, 1H), 7.00 (dd, J = 8.8, 2.6Hz, 1H), 5.32 (s, 2H), 5.08 (d, J =5.4Hz, 1H), 4.52-4.20 (m, 3H), 4.25-3.95 (m, 2H), 2.65 (s, 3H), 2.42 (s, 3H), 1.14 (d, J =6.3Hz, 3H).

[0209] Example 43, N -(2) S 3 R The synthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-6-((4-methylthiazolyl-5-yl)methoxy)-2-oxo-2H-benzopyran-4-carboxamide (Cpd043) is described below: ; Reagents and conditions:(a) Ph3P, DCM, 0℃→40℃ ; (b) Pd (dppf) Cl2, KOAc, Dioxane, 85℃, 12h; (c) H2O2, THF, H2O, 0℃→30℃; (d) K2CO3, DMF, 75℃, 6h; (e) NaOH, H2O:THF=1:2, 60℃, 6h; (f) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0210] Step a, Synthesis of methyl 6-bromo-2-oxo-2H-benzopyran-4-carboxylic acid: Compound 43-1 (122 mg, 0.70 mmol) and triphenylphosphine (185 mg, 0.70 mmol) were added to a 50 mL single-necked flask and dissolved in DCM (5 mL). The system was then stirred at 0 °C, and dimethyl 2-butynedioic acid (100 mg, 0.70 mmol) was added dropwise to the reaction flask. After stirring at 0 °C for 10 minutes, the mixture was refluxed at 40 °C for 8 hours. After the reaction was complete as monitored by TLC, water (30 mL) was added to the system, followed by extraction with DCM (3 × 60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 20 / 1) to obtain intermediate 43-2 (89 mg, yield 54%), a colorless oil.

[0211] LC-MS (ESI): m / z=282.95 [M+H] + Compound 43: N -(2) S 3 R Synthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-6-((4-methylthiazolyl-5-yl)methoxy)-2-oxo-2H-benzopyran-4-carboxamide (Cpd043): The method of Example 40 is followed, except that compound 40-1 in step a is replaced with intermediate 43-2, and Cpd043 is prepared by steps a, b, c, d and e.

[0212] LC-MS (ESI): m / z=418.10 [M+H] + 1 H NMR (400 MHz, DMSO) δ 8.99 (s, 1H), 8.69 (d, J = 8.5Hz, 1H), 7.54-7.31 (m, 4H), 7.21 (s, 1H), 6.67 (s, 1H), 5.42-5.25 (m, 2H), 4.94 (d, J=6.0Hz, 1H), 4.34 (dd, J =8.7, 4.6Hz, 1H), 4.13-4.02 (m, 1H), 2.41 (s, 3H), 1.14 (d, J =6.4Hz, 3H).

[0213] Example 44, N -(2) S 3 R The synthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-5-((4,5-dihydrofuran-3-yl)methoxy)-2-methylbenzofuran-3-carboxamide (Cpd044) is described below via the following reaction route: ; Reagents and conditions: (a) LiAlH4, THF, 0℃; (b) DIAD, Ph3P, DMF, 0℃→rt; (c) NaOH, H2O, EtOH, 60℃; (d) DIPEA, HATU, DMF, rt.

[0214] Step a, Synthesis of (4,5-dihydrofuran-3-yl)methanol: Compound 44-1 (200 mg, 1.75 mmol) was added to a 50 mL flask, followed by 5 mL of anhydrous tetrahydrofuran. Lithium aluminum hydride (120 mg, 3.16 mmol) was added dropwise at 0 °C, and the mixture was stirred for 4 hours. After the reaction was complete as monitored by TLC, 0.1 mL of water, followed by 0.1 mL of 15% NaOH aqueous solution, and then 0.3 mL of water were added dropwise to the system at 0 °C. The mixture was then heated to room temperature and stirred for 10 minutes. Anhydrous sodium sulfate was added to the system to remove water. The mixture was filtered, the organic phases were combined, and the solution was concentrated under reduced pressure without column chromatography purification to obtain intermediate 44-2 (82 mg, 47%), a colorless oil.

[0215] LC-MS (ESI): m / z=101.05 [M+H] + Compound 44: N -(2) S 3 R Synthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-5-((4,5-dihydrofuran-3-yl)methoxy)-2-methylbenzofuran-3-carboxamide (Cpd044): Following the method of Example 23, except that 3-buten-2-ol in step a is replaced with intermediate 44-2, Cpd044 is prepared by steps a, b and c.

[0216] LC-MS (ESI): m / z=375.15 [M+H] + 1 H NMR (400 MHz, DMSO) δ7.55-7.42 (m, 3H), 7.39 (d, J = 8.9Hz, 1H), 7.17 (d, J =3.4Hz, 1H), 7.02 (dd, J = 8.9, 2.6Hz, 1H), 5.98 (s, 1H), 5.36 (s, 1H), 5.29 (s, 1H), 5.06 (dd, J =5.7, 3.3Hz, 1H), 4.40-4.31 (m, 1H), 4.17-4.08 (m, 1H), 4.08-3.96 (m, 2H), 2.76-2.57 (m, 5H), 1.14 (dd, J =6.4, 2.5 Hz, 3H).

[0217] Example 45, ( R The synthesis of 1-(2-methyl-5-((2-methylallyl)oxy)benzofuran-3-carbonyl)piperidine-2-carboxamide (Cpd045) is described below: ; Reagents and conditions : (a) K2CO3, DMF, 75℃, 6h; (b) NaOH, H2O:THF=1:2, 60℃, 6h; (c) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0218] Referring to the method of Example 8, the only difference is that in step c, (2) S 3 R Replace )-2-amino-3-hydroxybutyramide hydrochloride with ( S Cpd045 was prepared by steps a, b, and c from piperidine-2-carboxamide.

[0219] LC-MS (ESI): m / z=357.17 [M+H] + 1 H NMR (300 MHz, DMSO) δ 7.58-6.81 (m, 5H), 5.23-4.19 (m, 5H), 3.29 (s, 2H), 2.42 (s, 3H), 2.17 (s, 1H), 1.78 (s, 3H), 1.72-0.76 (m, 6H).

[0220] Example 46, (S The synthesis of 1-(2-methyl-5-((2-methylallyl)oxy)benzofuran-3-carbonyl)azacyclobutane-2-carboxamide (Cpd046) is described below via the following reaction route: ; Reagents and conditions : (a) K2CO3, DMF, 75℃, 6h; (b) NaOH, H2O:THF=1:2, 60℃, 6h; (c) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0221] Referring to the method of Example 8, the only difference is that in step c, (2) S 3 R Replace )-2-amino-3-hydroxybutyramide hydrochloride with ( S Cpd046 was prepared by steps a, b, and c from 2-azacyclobutane-2-carboxamide hydrochloride.

[0222] LC-MS (ESI): m / z=329.14 [M+H] + 1 H NMR (300 MHz, DMSO) δ7.59-6.78 (m, 5H), 5.10 (s, 1H), 4.97 (s, 1H), 4.73 (dd, J = 9.7, 5.4Hz, 1H), 4.49 (s, 2H), 4.10 (s, 1H), 3.82 (d, J =6.1Hz, 1H), 2.51-1.87 (m, 5H), 1.79 (s, 3H).

[0223] Example 47, N The synthesis of 1-(1-carbamoylcyclopropyl)-2-methyl-5-((2-methylallyl)oxy)benzofuran-3-carboxamide (Cpd047) is described below via the following reaction route: ; Reagents and conditions : (a) K2CO3, DMF, 75℃, 6h; (b) NaOH, H2O:THF=1:2, 60℃, 6h; (c) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0224] Referring to the method of Example 8, the only difference is that in step c, (2) S 3 R Cpd047 was prepared by replacing 1-aminocyclopropane-1-carboxamide hydrochloride with 2-amino-3-hydroxybutyramide hydrochloride via steps a, b, and c.

[0225] LC-MS (ESI): m / z=329.14 [M+H] + 1 H NMR (300 MHz, DMSO) δ 8.31 (s, 1H), 7.69-6.71 (m, 5H), 5.09 (s, 1H), 4.97 (s, 1H), 4.50 (s, 2H), 2.60 (s, 3H), 1.79 (s, 3H), 1.35 (s, 2H), 1.02 (s, 2H).

[0226] Example 48, ( Z )- N The synthesis of -(1-cyano-1-propen-1-yl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide (Cpd048) is described below: ; Reagents and conditions : (a) DIPEA, HATU, DMF, 0℃→rt, 12h; (b) Et3N, TFAA, DCM, 0℃→rt.

[0227] Step a, N -(2) S 3 R Synthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide: Referring to the method of Example 37, the only difference is that in step a... L -Threonine ethyl ester hydrochloride is replaced with (2) S 3 R 2-Amino-3-hydroxybutyramide hydrochloride was reacted at room temperature to prepare intermediate 48-1.

[0228] LC-MS (ESI): m / z=404.12 [M+H] + Compound 48: ( Z )- N Synthesis of -(1-cyano-1-propen-1-yl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide (Cpd048): Compound 48-1 (197 mg, 0.49 mmol) was added to a 50 mL flask, followed by anhydrous DCM (5 mL) and triethylamine (395 mg, 3.91 mmol). Trifluoroacetic anhydride (410 mg, 1.95 mmol) was added dropwise at 0 °C. After stirring for 1 hour, the mixture was allowed to react at room temperature for 8 hours. Once the reaction was complete as monitored by TLC, water (30 mL) was added to the system, followed by extraction with DCM (3 × 60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give Cpd048 (93 mg, 52% yield) as a white solid.

[0229] LC-MS (ESI): m / z=368.10 [M+H] + 1 H NMR (300 MHz, DMSO) δ 9.89 (s, 1H), 9.00 (s, 1H), 7.52 (s, 1H), 7.33 (s, 1H), 7.00 (s, 1H), 6.54 ( s, 1H), 5.34 (s, 2H), 2.63 (s, 3H), 2.43 (s, 3H), 1.98 (s, 2H), 1.85 (s, 1H).

[0230] Example 49, N -(2) S 3 R The synthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methyl-5-((4-(pyridin-4-yl)thiazo-5-yl)methoxy)benzofuran-3-carboxamide (Cpd049) is described below via the following reaction route: ; Reagents and conditions : (a) Imidazole, TIPSCl, DCM, 0℃→rt; (b) Pd(dppf)Cl2, Na2CO3, 90℃, 3h; (c) TBAF, THF, rt; (d) SOCl2 , DCM, rt; (e) K2CO3, DMF, 75℃, 6h; (f) NaOH, H2O:THF=1:2, 60℃, 6h; (g) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0231] Step a, Synthesis of 4-bromo-5-(((triisopropylsilyl)oxy)methyl)thiazole: Compound 49-1 (30 mg, 0.15 mmol), imidazole (31.58 mg, 0.46 mmol), and DCM (3 mL) were added to a 50 mL round-bottom flask. TIPSCl (35.77 mg, 0.19 mmol) was added dropwise with stirring at 0 °C. After stirring for 10 minutes, the mixture was allowed to react at room temperature for 2 hours. After the reaction was complete as monitored by TLC, water (30 mL) was added to the system, followed by extraction with DCM (3 × 60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give intermediate 49-2 (55 mg, 100% yield), a colorless oil.

[0232] LC-MS (ESI): m / z=350.05 [M+H] + Step b, synthesis of 4-(pyridin-4-yl)-5-(((triisopropylsilyl)oxy)methyl)thiazole: Compound 49-2 (55 mg, 0.16 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridine (37 mg, 0.18 mmol), sodium carbonate (33 mg, 0.32 mmol), Pd(dppf)Cl2 (5.88 mg, 0.008 mmol), and anhydrous dioxane (15 mL) were added to a 100 mL flask. The mixture was purged with nitrogen three times, heated to 100 °C, and stirred for 3 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give intermediate 49-3 (47 mg, 86% yield) as a white solid.

[0233] LC-MS (ESI): m / z=349.17 [M+H] + Step c, Synthesis of (4-(pyridin-4-yl)thiazolyl)methanol: Intermediate 49-3 (12 mg, 0.034 mmol) was added to a 50 mL orbicular flask and dissolved in 3 mL of THF. A THF solution of TBAF (4.5 mg, 0.017 mmol) was added to the reaction mixture under stirring at room temperature, and the reaction was continued for 30 minutes. After the reaction was complete as monitored by TLC, the reaction mixture was concentrated under reduced pressure, and water (30 mL) was added to the system. The mixture was then extracted with ethyl acetate (3 × 60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. No further purification was required to obtain intermediate 49-4 (6.6 mg, 100% yield) as a white solid.

[0234] LC-MS (ESI): m / z=193.04 [M+H] + Step d, synthesis of 5-(chloromethyl)-4-(pyridin-4-yl)thiazole: Following the method of Example 1, the only difference is that intermediate 1-4 in step c is replaced with intermediate 49-4, and the reaction is carried out at room temperature to prepare intermediate 49-5.

[0235] LC-MS (ESI): m / z=211.00 [M+H] + Compound 49: N -(2) S 3 R Synthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methyl-5-((4-(pyridin-4-yl)thiazo-5-yl)methoxy)benzofuran-3-carboxamide (Cpd049): The method is the same as in Example 1, except that intermediates 1-5 in step d are replaced with intermediates 49-5, and Cpd049 is prepared by steps d, e and f.

[0236] LC-MS (ESI): m / z=467.13 [M+H] + 1 H NMR (300 MHz, DMSO) δ 9.24 (s, 1H), 8.70 (s, 2H), 7.73 (s, 2H), 7.61-7.38 (m, 4H), 7.26-6.97 (m, 2H), 5.52 (s, 2H), 5.06 (d, J =5.9Hz, 1H), 4.38 (d, J = 9.2Hz, 1H), 4.26-4.02 (m, 1H), 2.66 (s, 3H), 1.14 (d, J =6.2Hz, 3H).

[0237] Example 50, N -(2) S 3 R The synthesis of 1-amino-3-hydroxy-1-oxobutan-2-yl)-2-methyl-5-((4,5,6,7-tetrahydrobenzofuran-4-yl)oxy)benzofuran-3-carboxamide (Cpd050) is described below via the following reaction route: ; Reagents and conditions : (a) NaBH4, MeOH, rt; (b) TBUP, TMAD, THF, rt; (c) NaOH, H2O:THF=1:2, 60℃, 6h; (d) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0238] Synthesis of step a, 4,5,6,7-tetrahydrobenzofuran-4-ol: Following the method of Example 3, except that compound 3-1 in step a is replaced with compound 50-1, and the reaction is carried out at room temperature to prepare intermediate 50-2.

[0239] LC-MS (ESI): m / z=139.07 [M+H] + Step b, synthesis of ethyl 2-methyl-5-((4,5,6,7-tetrahydrobenzofuran-4-yl)oxy)benzofuran-3-carboxylate: To a 50 mL two-necked flask, add intermediate 1-2 (138.67 mg, 0.63 mmol), intermediate 50-2 (87 mg, 0.63 mmol), and THF (5 mL). The system was then subjected to nitrogen evacuation three times. Next, add dropwise 2 mL of THF solution containing tributylphosphine (247 mg, 1.22 mmol) and 3 mL of THF solution containing TMAD (254 mg, 1.47 mmol) to the reaction system, and continue stirring at room temperature for 3 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to obtain intermediate 50-3 (187 mg, 88% yield) as a white solid.

[0240] LC-MS (ESI): m / z=341.13 [M+H] + Compound 50: N -(2) S 3 R Synthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methyl-5-((4,5,6,7-tetrahydrobenzofuran-4-yl)oxy)benzofuran-3-carboxamide (Cpd050): The method is the same as in Example 1, except that intermediates 1-6 in step e are replaced with intermediates 50-3, and Cpd050 is prepared by steps e and f.

[0241] LC-MS (ESI): m / z=413.16 [M+H] + 1H NMR (300 MHz, DMSO) δ7.53-7.36 (m, 5H), 7.18 (s, 1H), 6.98 (d, J = 9.0Hz, 1H), 6.49-6.28 (m, 1H), 5.39 (s, 1H), 5.09 (t, J =5.1Hz, 1H), 4.36 (d, J =7.3Hz, 1H), 4.22-4.03 (m, 1H), 2.75-2.56 (m, 5H), 2.07-1.75 (m, 4H), 1.13 (d, J =6.4Hz, 3H).

[0242] Example 51, N The synthesis of 3,3-difluorobut-2-yl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide (Cpd051) is described below via the following reaction route: ; Reagents and conditions : (a) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0243] Referring to the method of Example 48, the only difference is that in step a, (2) S 3 R Cpd051 was prepared by replacing 2-amino-3-hydroxybutyramide hydrochloride with 3,3-difluoro-2-butamine hydrochloride and reacting at room temperature.

[0244] LC-MS (ESI): m / z=395.12 [M+H] + 1 H NMR (300 MHz, DMSO) δ 8.98 (s, 1H), 8.28 (d, J = 9.1Hz, 1H), 7.48 (d, J =8.9Hz, 1H), 7.20 (d, J =2.6Hz, 1H), 6.97 (dd, J = 8.9, 2.6Hz, 1H), 5.31 (s, 2H), 4.62-4.42 (m, 1H), 2.56 (s, 3H), 2.41 (s, 3H), 1.67 (t, J =19.2Hz, 3H), 1.26 (d, J =7.1Hz, 3H).

[0245] Example 52, N -((S The synthesis of 1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-((4,5,6,7-tetrahydrobenzofuran-4-yl)oxy)benzofuran-3-carboxamide (Cpd052) is described below via the following reaction route: ; Reagents and conditions : (a) NaBH4, MeOH, rt; (b) TBUP, TMAD, THF, rt; (c) NaOH, H2O:THF=1:2, 60℃, 6h; (d) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0246] Referring to the method of Example 50, the only difference is that in step d, (2) S 3 R Replace )-2-amino-3-hydroxybutyramide hydrochloride with ( S Cpd052 was prepared by reacting 2-amino-3-hydroxypropionamide hydrochloride at room temperature.

[0247] LC-MS (ESI): m / z=399.15 [M+H] + 1 H NMR (400 MHz, DMSO-) d 6) δ7.62 (d, J = 8.1Hz, 1H), 7.52-7.41 (m, 4H), 7.18 (s, 1H), 6.97 (dd, J = 8.8, 2.6Hz, 1H), 6.38 (s, 1H), 5.39 (s, 1H), 5.01 (t, J =5.7Hz, 1H), 4.53-4.42 (m, 1H), 3.75 (t, J =6.2Hz, 2H), 2.64 (s, 5H), 2.04-1.77 (m, 4H).

[0248] Example 53, N -(( S The synthesis of 1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-((4,5,6,7-tetrahydrobenzofuran-4-yl)oxy)benzofuran-3-carboxamide (Cpd052) is described below via the following reaction route: ; Reagents and conditions : (a) BH3·THF, THF, 80℃; (b) DIPEA, HATU, DMF, 0℃→rt, 12h, (c) HCl / dioxane, Dioxane, rt.

[0249] Step a, Synthesis of tert-butyl 3-amino-3-(hydroxymethyl)piperidine-1-carboxylic acid: Intermediate 53-1 (100 mg, 0.409 mmol) was added to a 50 mL orb-shaped flask and dissolved in 5 mL of THF. 1.64 mL of 1 mol / L BH3·THF solution was added to the reaction mixture while stirring at room temperature, and the mixture was heated to 80 °C and reacted for 4 hours. After the reaction was complete as monitored by TLC, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain intermediate 53-2 (89 mg, 94% yield), a colorless liquid.

[0250] LC-MS (ESI): m / z=231.17 [M+H] + Step b, synthesis of tert-butyl-3-(hydroxymethyl)-3-(2-methyl-5-((4,5,6,7-tetrahydrobenzofuran-4-yl)oxy)benzofuran-3-carboxamide)piperidine-1-carboxylic acid ester: Referring to the method of Example 50, the only difference is that in step d, (2) S 3 R Intermediate 53-3 was prepared by replacing 2-amino-3-hydroxybutyramide hydrochloride with intermediate 53-2 and reacting at room temperature.

[0251] LC-MS (ESI): m / z=525.25 [M+H] + Step c, N Synthesis of -(3-(hydroxymethyl)piperidin-3-yl)-2-methyl-5-((4,5,6,7-tetrahydrobenzofuran-4-yl)oxy)benzofuran-3-carboxamide: Intermediate 53-3 (33 mg, 0.063 mmol) and dioxane (4 mL) were added to a 50 mL round-bottom flask. While stirring at 0 °C, 4 equivalents of HCl / dioxane solution (2 mL) were added to the reaction system. After stirring for 10 minutes, the mixture was allowed to react at room temperature for 2 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 1 / 1) to obtain Cpd053 (11 mg, yield 41%) as a white solid.

[0252] LC-MS (ESI): m / z=425.20 [M+H]+ 1 H NMR (400 MHz, DMSO-) d 6) δ7.81 (s, 1H), 7.56-7.44 (m, 2H), 7.36 (d, J =2.1Hz, 1H), 6.98 (dd, J = 8.8, 2.8Hz, 1H), 6.53 (dd, J =2.0, 0.7Hz, 1H), 5.24 (ddt, J =4.7, 4.0, 0.7Hz, 1H), 4.91 (t, J =5.3Hz, 1H), 3.81 (dd, J =12.3, 5.4Hz, 1H), 3.69-3.61 (m, 1H), 3.50 (dd, J =12.3, 5.3Hz, 1H), 3.24-3.16 (m, 1H), 2.98-2.72 (m, 4H), 2.45 (s, 2H), 2.21-1.80 (m, 4H), 1.72-1.46 (m, 3H).

[0253] Example 54: ( S The synthesis of 1-(2-methyl-5-((2-methylallyl)oxy)benzofuran-3-carbonyl)pyrrolidine-2-carboxamide (Cpd054) is described below: ; Reagents and conditions : (a) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0254] Referring to the method of Example 8, the only difference is that in step c, (2) S 3 R Replace )-2-amino-3-hydroxybutyramide hydrochloride with ( S Cpd054 was prepared by step c using pyrrolidine-2-carboxamide.

[0255] LC-MS (ESI): m / z=343.17 [M+H] + 1 H NMR (300 MHz, DMSO-) d6) δ7.55-6.73 (m, 5H), 5.08 (s, 1H), 4.95 (s, 1H), 4.47 (s, 3H), 3.76-3.37 (m , 2H), 2.48-2.31 (m, 3H), 2.29-2.14 (m, 1H), 1.94-1.79 (m, 3H), 1.77 (s, 3H).

[0256] Example 55, ( S The synthesis of 4,4-difluoro-1-(2-methyl-5-((2-methylallyl)oxy)benzofuran-3-carbonyl)pyrrolidine-2-carboxamide (Cpd055) is described below via the following reaction route: ; Reagents and conditions : (a) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0257] Referring to the method of Example 8, the only difference is that in step c, (2) S 3 R Replace )-2-amino-3-hydroxybutyramide hydrochloride with ( S Cpd055 was prepared by step c of 4,4-difluoropyrrolidine-2-carboxamide hydrochloride.

[0258] LC-MS (ESI): m / z=379.15 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ7.73-6.84 (m, 5H), 5.08 (s, 1H), 4.95 (s, 1H), 4.48 (s, 3H), 3.90 (d, J =17.2Hz, 2H), 3.08-2.74 (m, 2H), 2.46-2.29 (m, 3H), 1.78 (s, 3H).

[0259] Example 56, (2) S 4 R The synthesis of 4-hydroxy-1-(2-methyl-5-((2-methylallyl)oxy)benzofuran-3-carbonyl)pyrrolidine-2-carboxamide (Cpd056) is described below via the following reaction route: ; Reagents and conditions : (a) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0260] Referring to the method of Example 8, the only difference is that in step c, (2) S 3 RReplace 2-amino-3-hydroxybutyramide hydrochloride with (2) S 4 R Cpd056 was prepared by step c from 4-hydroxypyrrolidine-2-carboxamide hydrochloride.

[0261] LC-MS (ESI): m / z=358.15 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ7.57-6.71 (m, 5H), 5.20-4.98 (m, 2H), 4.95 (s, 1H), 4.65-4.18 (m, 4H), 3.64-3.50 (m, 1H), 3.21 (d, J =10.8Hz, 1H), 2.48-2.30 (m, 3H), 2.27-2.09 (m, 1H), 1.92 (t, J = 8.9Hz, 1H), 1.78 (s, 3H).

[0262] Example 57, (2) S 3 S The synthesis of 3-hydroxy-1-(2-methyl-5-((2-methylallyl)oxy)benzofuran-3-carbonyl)pyrrolidine-2-carboxamide (Cpd057) is described below via the following reaction route: ; Reagents and conditions : (a) SOCl2, MeOH, reflux; (b) NH3·H2O, 0℃→rt; (c) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0263] Step a, methyl (2 S 3 S Synthesis of 3-hydroxypyrrolidine-2-carboxylic acid ester: Compound 57-1 (250 mg, 1.91 mmol) was added to a 50 mL round-bottom flask, dissolved in 20 mL MeOH, and thionyl chloride (453.59 mg, 3.81 mmol) was added dropwise at 0 °C. The mixture was then heated to 80 °C and stirred for 3 hours. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure without column chromatography purification to give intermediate 57-2 (267 mg, 96% yield) as a pale yellow solid.

[0264] LC-MS (ESI): m / z=146.08 [M+H] + Step b, (2) S 3 SSynthesis of 3-hydroxypyrrolidine-2-carboxamide: Compound 57-2 (266 mg, 1.83 mmol) was added to a 50 mL round-bottom flask, dissolved in 6 mL of ammonia, and stirred at room temperature for 4 hours. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure without column chromatography purification to give intermediate 57-3 (206 mg, 86% yield), a pale yellow solid.

[0265] LC-MS (ESI): m / z=131.08 [M+H] + Compound 57: (2 S 3 S Synthesis of 3-hydroxy-1-(2-methyl-5-((2-methylallyl)oxy)benzofuran-3-carbonyl)pyrrolidine-2-carboxamide (Cpd057): Referring to the method of Example 8, the only difference is that in step c, (2) S 3 R Cpd057 was prepared by replacing 2-amino-3-hydroxybutyramide hydrochloride with intermediate 57-3 and then proceeding to step c.

[0266] LC-MS (ESI): m / z=358.15 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ7.61-7.29 (m, 2H), 7.14-6.83 (m, 3H), 5.44-5.35 (m, 1H), 5.07 (s, 1H), 4.95 (s, 1H), 4.4 9-4.40 (m, 2H), 4.35-4.03 (m, 2H), 3.84-3.40 (m, 2H), 2.48-2.34 (m, 3H), 2.10-1.67 (m, 5H).

[0267] Example 58, N The synthesis of 3-(3-(hydroxymethyl)piperidin-3-yl)-2-methyl-5-((2-methylallyl)oxy)benzofuran-3-carboxamide (Cpd058) is described below: ; Reagents and conditions : (a) DIPEA, HATU, DMF, 0℃→rt, 12h, (b) HCl / dioxane, Dioxane, rt.

[0268] The method of Example 53 is used, except that intermediate 50-4 in step b is replaced with intermediate 8-2, and Cpd058 is prepared by steps b and c.

[0269] LC-MS (ESI): m / z=359.20 [M+H] + 1 H NMR (400 MHz, DMSO-) d 6) δ7.45 (d, J = 8.9Hz, 1H), 7.36 (d, J =2.6Hz, 1H), 7.05 (s, 1H), 6.92 (dd, J = 8.9, 2.6Hz, 1H), 5.09 (s, 1H), 4.96 (s, 1H), 4.53-4.43 (m, 2H), 3.81-3.51 (m, 3H), 3.21-2.85 (m, 2H), 2.62 (s, 3H), 2.60-2.51 (m, 2H), 2.31-2.21 (m, 1H), 1.79 (s, 3H), 1.64-1.21 (m, 4H).

[0270] Example 59, ( S )- N The synthesis of -(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-5-((2-methylallyl)oxy)benzofuran-3-carboxamide (Cpd058) is described below: ; Reagents and conditions : (a) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0271] Referring to the method of Example 8, the only difference is that in step c, (2) S 3 R Replace 2-amino-3-hydroxybutyramide hydrochloride with L - Serine amide hydrochloride was prepared by step c to obtain Cpd059.

[0272] LC-MS (ESI): m / z=333.15 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ7.69-7.13 (m, 5H), 6.93 (d, J= 8.5Hz, 1H), 5.16-4.89 (m, 3H), 4.50 (s, 3H), 3.74 (s, 2H), 2.63 (s, 3H), 1.78 (s, 3H).

[0273] Example 60, N -(2) S 3 R The synthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-5-((2,5-dihydrofuran-3-yl)methoxy)-2-methylbenzofuran-3-carboxamide (Cpd060) is described below via the following reaction route: ; Reagents and conditions : (a) SOCl2, MeOH, reflux; (b) DIBAL-H, DCM, 0℃→rt; (c) K2CO3, DMF, 75℃, 6h; (d) NaOH, H2O:THF=1:2, 60℃, 6h; (e) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0274] Step a, Synthesis of methyl 2,5-dihydrofuran-3-carboxylic acid: The method of step a in Example 57 is followed, except that intermediate 57-1 is replaced with compound 60-1 to prepare intermediate 60-2.

[0275] LC-MS (ESI): m / z=129.06 [M+H] + Step b, synthesis of (2,5-dihydrofuran-3-yl)methanol: The method of step a in Example 33 is followed, except that intermediate 33-1 is replaced with compound 60-2 to prepare intermediate 60-3.

[0276] LC-MS (ESI): m / z=101.06 [M+H] + Compound 60: N -(2) S 3 R Synthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-5-((2,5-dihydrofuran-3-yl)methoxy)-2-methylbenzofuran-3-carboxamide (Cpd060): The method of Example 23 is followed, except that but-3-en-2-ol in step a is replaced with intermediate 60-3, and Cpd060 is prepared by steps a, b and c.

[0277] LC-MS (ESI): m / z=375.16 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ7.55-7.29 (m, 4H), 7.19 (s, 1H), 6.94 (dd, J = 8.7, 2.6Hz, 1H), 6.01 (s, 1H), 5.09 (s, 1H), 4.75 (s, 2H), 4.56 (s, 4H), 4.37 (dd, J = 8.7, 3.5Hz, 1H), 4.19-4.06 (m, 1H), 2.64 (s, 3H), 1.14 (d, J =6.3Hz, 3H).

[0278] Example 61, N -(2) S 3 R )-1-amino-3-hydroxy-1-oxobutane-2-yl)-5-(4-fluoro-2-methylbenzo[ d The synthesis of [1,3]dioxolane-2-yl)-2-methylbenzofuran-3-carboxamide (Cpd061) is described below via the following reaction route: ; Reagents and conditions : (a) P-Toluenesulfonic acid, Toluene, reflux; (b) NaOH, H2O: THF=1:2, 60℃, 6h; (c) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0279] Following the method of Example 2, the only difference is that catechol in step c is replaced with 3-fluorobenzene-1,2-diol, and Cpd061 is prepared by steps c, d, and e.

[0280] LC-MS (ESI): m / z=429.15 [M+H] + 1 H NMR (400 MHz, DMSO-) d 6) δ 8.04 (s, 1H), 7.65 (d, J = 8.7Hz, 1H), 7.58-7.51 (m, 2H), 7.45 (s, 1H), 7.18 (s, 1H), 6.93-6.74 (m, 3H), 5.07 (s, 1H), 4.36 (dd, J= 8.7, 3.5Hz, 1H), 4.21-4.07 (m, 1H), 2.68 (s, 3H), 2.09 (s, 3H), 1.19-1.12 (m, 3H).

[0281] Example 62, N -(( S )-1-amino-3-hydroxy-1-oxopropane-2-yl)-5-(4-fluoro-2-methylbenzo[ d The synthesis of [1,3]dioxolane-2-yl)-2-methylbenzofuran-3-carboxamide (Cpd062) is described below via the following reaction route: ; Reagents and conditions : (a) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0282] Referring to the method of Example 61, the only difference is that in step c, (2) S 3 R Replace 2-amino-3-hydroxybutyramide hydrochloride with L - Serine amide hydrochloride was prepared by step c to obtain Cpd062.

[0283] LC-MS (ESI): m / z=415.13 [M+H] + 1 H NMR (400 MHz, DMSO-) d 6) δ 8.02 (d, J =2.0Hz, 1H), 7.79 (d, J =7.9Hz, 1H), 7.63 (d, J = 8.7Hz, 1H), 7.54 (dd, J = 8.7, 2.0Hz, 1H), 7.48 (s, 1H), 7.18 (s, 1H), 6.89-6.78 (m, 3H), 5.00 (s, 1H), 4.52-4.44 (m, 1H), 3.75 (t, J =5.3Hz, 2H), 2.67 (s, 3H), 2.08 (s, 3H).

[0284] Example 63, 5-(4-fluoro-2-methylbenzo[ d [1,3]dioxolane-2-yl)- N The synthesis of 3-(3-(hydroxymethyl)piperidin-3-yl)-2-methylbenzofuran-3-carboxamide (Cpd063) is described below via the following reaction route: ; Reagents and conditions : (a) DIPEA, HATU, DMF, 0℃→rt, 12h, (b) HCl / dioxane, Dioxane, rt.

[0285] Following the method of Example 53, except that intermediate 50-4 in step b is replaced with intermediate 60-2, Cpd063 is obtained through steps b and c. δ7.45 (d, J = 8.9Hz, 1H), 7.36 (d, J =2.6Hz, 1H), 7.05 (s, 1H), 6.92 (dd, J = 8.9, 2.6 Hz, 1H).

[0286] LC-MS (ESI): m / z=441.18 [M+H] + 1 H NMR (400 MHz, DMSO-) d 6), δ 8.03 (d, J =2.1Hz, 1H), 7.77 (d, J =7.8Hz, 1H), 7.63 (d, J = 8.7Hz, 1H), 7.54 (dd, J = 8.7, 2.1Hz, 1H), 6.90-6.78 (m, 3H), 3.83-3.52 (m, 3H), 3.21-2.85 (m, 2H), 2.62 (s, 3H), 2.63-2.52 (m, 2H), 2.30-2.21 (m, 1H), 2.18 (s, 3H), 1.64-1.21 (m, 4H).

[0287] Example 64, ( S )- N The synthesis of -(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-((4-(pyridin-2-yl)thiazolyl)methoxy)benzofuran-3-carboxamide (Cpd064) is described below: ; Reagents and conditions : (a) Pd(PPh3)4, Dioxane, 110℃, 6h; (b) LiAlH4, THF, 0℃→rt, 3h; (c) TMAD, PPh3, DMF, 0℃→rt; (d) NaOH, H2O: THF=1:2, 60℃, 6h; (e) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0288] Step a, Synthesis of ethyl 4-(pyridin-2-yl)thiazolyl-5-carboxylate: Compound 64-1 (500 mg, 2.12 mmol), 2-(tributyltinyl)pyridine (857.7 mg, 6.33 mmol), tetrakis(triphenylphosphine)palladium (244.7 mg, 0.21 mmol), and anhydrous dioxane (15 mL) were added to a 100 mL flask. The mixture was purged with nitrogen three times, heated to 110 °C, and stirred for 6 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give intermediate 64-2 (352 mg, 71% yield), a yellow liquid.

[0289] LC-MS (ESI): m / z=235.05 [M+H] + Step b, synthesis of (4-(pyridin-2-yl)thiazolyl-5-yl)methanol: The method of step a in Example 31 is followed, except that intermediate 31-1 is replaced with compound 64-2 to prepare intermediate 64-3.

[0290] LC-MS (ESI): m / z=193.04 [M+H] + Compound 64: ( S )- N Synthesis of -(1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-5-((4-(pyridin-2-yl)thiazolyl)methoxy)benzofuran-3-carboxamide (Cpd064): Referring to the method of Example 50, the only difference is that intermediate 50-2 in step b is replaced with intermediate 64-3, and (2) in step d is replaced with intermediate 64-3. S 3 R Replace 2-amino-3-hydroxybutyramide hydrochloride with L - Serine amide hydrochloride was prepared by steps b, c, and d to obtain Cpd064.

[0291] LC-MS (ESI): m / z=453.13 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ 9.16 (s, 1H), 8.71 (d, J =6.7Hz, 1H), 8.21-8.13 (m, 1H), 7.94 (td, J=7.7, 1.8Hz, 1H), 7.69 (d, J = 8.0Hz, 1H), 7.52-7.34 (m, 4H), 7.19 (s, 1H), 7.00 (dd, J = 8.9, 2.6Hz, 1H), 5.91 (s, 2H), 5.05 (s, 1H), 4.53-4.43 (m, 1H), 3.74 (s, 2H), 2.64 (s, 3H).

[0292] Example 65, N -(2) S 3 R The synthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methyl-4-((4-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide (Cpd065) is described below via the following reaction route: ; Reagents and conditions : (a) [RhCp×Cl2]2, AgNTf2, DCE, 50℃; (b) K2CO3, DMF, 75℃, 6h; (c) NaOH, H2O:THF=1:2, 60℃, 6h; (d) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0293] Step a, Synthesis of ethyl 4-hydroxy-2-methylbenzofuran-3-carboxylate: Compound 65-1 (200 mg, 1.45 mmol), ethyl diazoacetoacetate (271.3 mg, 1.74 mmol), silver bis(trifluoromethanesulfonyl)imide (112.4 mg, 0.29 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (22.4 mg, 0.036 mmol), and 10 mL of DCE were added to a 50 mL flask. The mixture was heated to 50 °C and stirred for 12 hours. After the reaction was completed by TLC, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 1 to 10 / 1) to give intermediate 65-2 (188 mg, yield 59%) as a pale yellow solid.

[0294] LC-MS (ESI): m / z=221.23 [M+H] + Compound 65: N -(2) S 3 RSynthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methyl-4-((4-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide (Cpd065): The method of Example 3 is used, except that intermediate 3-4 in the steps is replaced with intermediate 65-2, and Cpd065 is prepared by steps c, d and f.

[0295] LC-MS (ESI): m / z=404.13 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ 9.02 (d, J =7.8Hz, 1H), 8.89 (s, 1H), 7.37-7.06 (m, 4H), 6.87 (d, J =7.5Hz, 1H), 5.68 (s, 2H), 5.06 (d, J =4.6Hz, 1H), 4.45-4.34 (m, 1H), 4.17-4.05 (m, 1H), 2.68 (s, 3H), 2.46 (s, 3H), 1.10 (d, J =6.3Hz, 3H).

[0296] Example 66, 2-Methyl-5-((4-methylthiazolyl-5-yl)methoxy)- N The synthesis of (2,2,2-trifluoroethyl)benzofuran-3-carboxamide (Cpd066) follows the reaction route described below: ; Reagents and conditions : (a) DIPEA, HATU, DMF, 0℃→rt, 12h.

[0297] Referring to the method of Example 48, the only difference is that in step a, (2) S 3 R Cpd066 was prepared by replacing 2,2,2-trifluoroethylamine hydrochloride with 2,2,2-amino-3-hydroxybutyramide hydrochloride at room temperature.

[0298] LC-MS (ESI): m / z=385.08 [M+H] + 1 H NMR (300 MHz, DMSO) δ 8.98 (s, 1H), 8.28 (d, J = 9.1Hz, 1H), 7.48 (d, J=8.9Hz, 1H), 7.20 (d, J =2.6Hz, 1H), 6.97 (dd, J = 8.9, 2.6Hz, 1H), 5.31 (s, 2H), 3.48 (s, 2H), 2.56 (s, 3H), 2.41 (s, 3H).

[0299] Example 67, N -(2) S 3 R The synthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide (Cpd067) is described below via the following reaction route: ; Reagents and conditions : (a) SOCl2, EtOH, reflux, 12h; (b) m -CPBA, CHCl3, rt, 12h; (c) DMAP, acetic anhydride, DBU, DCM, rt overnight; (d) Pd (dppf) Cl2, (Bpin) 2, AcOK, Dioxane, 80℃, 12h; (e) H2O2, AcOH, THF:H2O=1:1, rt; (f) K2CO3, DMF, 60℃; (g) NaOH, EtOH:H2O =1:1; (h) DIPEA, HATU, DMAc, 0℃→rt.

[0300] Step a, Synthesis of ethyl 2-(5-bromopyridin-3-yl)acetic acid ester: Compound 67-1 (1 g, 4.63 mmol), thionyl chloride (825 mg, 6.94 mmol), and ethanol (40 mL) were added to a 100 mL flask and refluxed for 12 h. After the reaction was completed by TLC, the reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to give intermediate 67-2 (1 g, 91% yield) as a white solid.

[0301] Step b, synthesis of 3-bromo-5-(ethoxyacetyl)pyridine-1-oxide: Add intermediate 67-2 (100 mg, 0.409 mmol) and chloroform (5 mL) to a 50 mL orb-shaped flask. At room temperature, add dropwise the solution dissolved in chloroform. m-CPBA (106 mg, 0.614 mmol) was stirred at room temperature for 12 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give intermediate 67-3 (85 mg, yield 81%) as a yellow solid.

[0302] Step c, ethyl 5-bromo-2-methylfuran [2,3- b Synthesis of pyridine-3-carboxylic acid esters: Add intermediate 67-3 (115 mg, 0.442 mmol), DBU (80 mg, 0.53 mmol), and DMAP (108 mg, 0.884 mmol) to a 50 mL orb-shaped flask. Add dropwise the solution dissolved in chloroform to the reaction mixture at room temperature. m -CPBA (106 mg, 0.614 mmol) was stirred at room temperature for 12 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give intermediate 67-4 (85 mg, yield 81%) as a yellow solid.

[0303] Compound 67: N -(2) S 3 R )-1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)furan[2,3- b Synthesis of pyridine-3-carboxamide: The method of implementing steps a, b, c, d, and e of Example 40 is the same, except that compound 40-1 is replaced with intermediate 67-4 to prepare Cpd067.

[0304] LC-MS (ESI): m / z=405.11 [M+H] + 1 H NMR (400 MHz, DMSO-) d 6) δ 9.01 (s, 1H), 8.06 (d, J =2.9Hz, 1H), 7.85 (d, J =2.9Hz, 1H), 7.57 (d, J = 8.8Hz, 1H), 7.46 (s, 1H), 7.19 (s, 1H), 5.42 (s, 2H), 5.08 (s, 1H), 4.36 (dd, J = 8.8, 3.9Hz, 1H), 4.12 (dd, J=6.5, 3.9Hz, 1H), 2.69 (s, 3H), 2.42 (s, 3H), 1.14 (d, J =6.5Hz, 3H).

[0305] Example 68, N -(2) S 3 R The synthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide (Cpd068) is described below via the following reaction route: ; Reagents and conditions : (a) Pd(PPh3)2Cl2, CuI, PPh3, Et3N, 80℃, 12h; (b) KOH, MeOH:DCM=1:2, 1.5h; (c) Tf2O, Pyridine, DCM, rt; (d) Pd(PPh3)2Cl2, CuI, PPh3, Et3N, 80℃; (e) NaOH, EtOH:H2O =1:1; (f) DIPEA, HATU, DMAc, 0℃→rt.

[0306] Step a, Synthesis of 2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)pyridine: Compound 68-1 (100 mg, 0.442 mmol), trimethylsilylacetylene (152 mg, 1.55 mmol), bis(triphenylphosphine)palladium dichloride (31 mg, 0.044 mmol), cuprous iodide (16 mg, 0.088 mmol), triphenylphosphine (116 mg, 0.442 mmol), and triethylamine (5 mL) were added to a 25 mL dry Schlenk reaction tube. The reaction was carried out at 80 °C for 12 h under nitrogen protection. After the reaction was completed by TLC, the reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether (100%)) to give intermediate 68-2 (64 mg, yield 59%), which was a colorless and transparent liquid.

[0307] Step b, Synthesis of 3-ethynyl-2-trifluoromethylpyridine: Intermediate 68-2 (64 mg, 0.263 mmol), KOH (29 mg, 0.526 mmol), methanol (2 mL), and dichloromethane (4 mL) were added to a 50 mL flask and reacted at room temperature for 1.5 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether (100%)) to obtain intermediate 68-3 (23 mg, yield 51%), which was a colorless and transparent liquid.

[0308] Step c, synthesis of ethyl 2-methyl-5-(((trifluoromethyl)sulfonyl)oxy)benzofuran-3-carboxylic acid ester: Intermediate 1-2 (100 mg, 0.454 mmol), pyridine (43 mg, 0.544 mmol), and anhydrous dichloromethane (10 mL) were added to a 50 mL flask. While stirring, trifluoromethanesulfonic anhydride (134 mg, 0.476 mmol) dissolved in dichloromethane (3 mL) was added dropwise. The reaction was carried out at room temperature for 3 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to give intermediate 68-4 (103 mg, yield 64%) as a white solid.

[0309] Step d, synthesis of ethyl 2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)ethynyl)benzofuran-3-carboxylic acid ester: Intermediate 68-3 (97 mg, 0.276 mmol), intermediate 68-4 (71 mg, 0.414 mmol), bis(triphenylphosphine) palladium dichloride (19 mg, 0.027 mmol), cuprous iodide (10 mg, 0.055 mmol), triphenylphosphine (72 mg, 0.276 mmol), and triethylamine (10 mL) were added to a 50 mL dry Schlenk reaction tube. The reaction was carried out at 80 °C for 12 h under nitrogen protection. After the reaction was completed by TLC, the reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to give intermediate 68-5 (71 mg, 69% yield) as a white solid.

[0310] Compound 68: N -(( 2S , 3R Synthesis of 1-amino-3-hydroxy-1-oxobut-2-yl)-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)ethynyl)benzofuran-3-carboxamide: The method of implementing steps e and f in Example 1 is the same, except that intermediates 1-6 are replaced with intermediates 68-5 to prepare Cpd068.

[0311] LC-MS (ESI): m / z=446.13 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ 8.73 (dd, J =4.8, 1.5Hz, 1H), 8.31 (dd,J = 8.3, 1.6Hz, 1H), 8.01 (d, J =1.6Hz, 1H), 7.80 (dd, J = 8.3, 4.8Hz, 1H), 7.75-7.62 (m, 2H), 7.53 (dd, J = 8.8, 1.7Hz, 1H), 7.48 (s, 1H), 7.23-7.15 (m, 1H), 5.08 (s, 1H), 4.36 (dd, J = 8.8, 3.7Hz, 1H), 4.12 (dd, J =6.5, 3.7Hz, 1H), 2.42 (s, 3H), 1.14 (d, J =6.5Hz, 3H).

[0312] Example 69, N -(2) S 3 R The synthesis of 1-amino-3-hydroxy-1-oxobutane-2-yl)-2-methyl-5-((4-methylthiazolyl-5-yl)methoxy)benzofuran-3-carboxamide (Cpd068) is described below via the following reaction route: ; Reagents and conditions : (a) SEMCl, DMF, NaH, rt; (b) Pd (dppf) Cl2, (Bpin) 2, AcOK, Dioxane, 80℃, 12h; (c) H2O2, AcOH, THF:H 2O=1:1, rt; (d) K2CO3, DMF, 60℃, 12h; (e) TFA: DCM=1 / 4, rt, 12h; (f) Et3N, THF, rt; (g) Et3N, THF, rt.

[0313] Step a, 5-bromo-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[ d Oxazole-2 (3) H Synthesis of ketones: DMF (30 mL) and NaH (373 mg, 60%, 9.35 mmol) were added to a 100 mL flask and stirred at room temperature for 5 min. Compound 69-1 (1 g, 4.67 mmol) was added to the reaction mixture, and stirring was continued for another 5 min. SEMCl (1.05 g, 6.31 mmol) was then added dropwise to the reaction mixture, and the reaction was carried out at room temperature for 12 h. After the reaction was completed by TLC, 100 mL of ethyl acetate was added to the reaction mixture, and the mixture was added to 100 mL of ice water. After separation, the organic phase was washed 2-3 times with saturated brine, and the organic phase was concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to obtain intermediate 69-2 (1.05 g, yield 65%) as a pink solid.

[0314] Step b, ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[ d Oxazole-2 (3) H Synthesis of ketones: The difference between step a and step a in Example 40 is that compound 40-1 is replaced with intermediate 69-2 to prepare intermediate 69-3.

[0315] Step c, 5-hydroxy-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[ d Oxazole-2 (3) H Synthesis of ketones: The difference in step b of Example 40 is that intermediate 40-2 is replaced with intermediate 69-3 to prepare intermediate 69-4.

[0316] Step d, 5-((4-methylthiazolyl-5-yl)methoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[ d Oxazole-2 (3) H Synthesis of ketones: The difference in step c of Example 3 is that intermediate 3-4 is replaced with intermediate 69-4 to prepare intermediate 69-5.

[0317] Step e, 5-((4-methylthiazolyl-5-yl)methoxy)benzo[ d Oxazole-2 (3) H Synthesis of ketones: Intermediate 69-5 (70 mg, 0.177 mmol) and 4 mL of dichloromethane were added to a 50 mL flask. 1 mL of trifluoroacetic acid was added dropwise to the reaction mixture, and the reaction was carried out at room temperature for 12 h. After the reaction was completed by TLC monitoring, the reaction mixture was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give intermediate 69-6 (42 mg, 90% yield) as a white solid.

[0318] Step f, 4-nitrophenyl 5-((4-methylthiazolyl-5-yl)methoxy)-2-oxobenzo[ d Oxazole-3 (2) H Synthesis of α-carboxylic acid esters: Intermediate 69-6 (80 mg, 0.305 mmol), triethylamine (61 mg, 0.610 mmol), and anhydrous THF (5 mL) were added to a 50 mL two-necked flask. Under nitrogen protection, p-nitrophenyl chloroformate (73 mg, 0.366 mmol) dissolved in THF was added dropwise to the reaction solution, and the reaction was carried out at room temperature for 12 h. After the formation of the target product was monitored by TLC, the reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain intermediate 69-7 (33 mg, yield 25%) as a white solid.

[0319] Step g, S - N -(1-amino-3-hydroxy-1-oxopropane-2-yl)-5-((4-methylthiazolyl-5-yl)methoxy)-2-oxobenzo[ d Oxazole-3 (2) H Synthesis of α-carboxamides: Intermediate 69-7 (33 mg, 0.077 mmol) and anhydrous THF (5 mL) were added to a 50 mL two-necked flask. Under nitrogen protection, compound 69-8 (21 mg, 0.154 mmol) and triethylamine (31 mg, 0.308 mmol) dissolved in THF were added dropwise to the reaction solution. The reaction was carried out at room temperature for 12 h. After the formation of the target product was monitored by TLC, the reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 2) to give Cpd069 (7 mg, yield 23%) as a white solid.

[0320] LC-MS (ESI): m / z=392.08 [M+H] + 1 H NMR (300 MHz, DMSO-) d 6) δ 8.97 (s, 1H), 7.90 (d,J =3.5Hz, 2H), 7.74-7.45 (m, 2H), 6.90 (dd, J = 8.6, 2.5Hz, 1H), 6.62 (d, J =3.5Hz, 1H), 5.31 (s, 2H), 4.96 (d, J =6.4Hz, 1H), 4.25–4.20 (m, 2H), 4.14-4.06 (m, 1 H), 2.43 (s, 3H).

[0321] Biological activity assay: To monitor the inhibitory effect of the compound on the TRPM3 ion channel, a cell line overexpressing hTRPM3 (hTRPM3 HEK293) was used. Stimulation / opening of the TRPM3 channel by a TRPM3 agonist (1 μM CIM0216) resulted in an increase in intracellular calcium levels.

[0322] Cells were stained with 4 μM Fluo-4 AM calcium ion indicator; the TRPM3 channel was activated with 1 μM TRPM3 agonist CIM0216, and 30 μM Primidone was set as a reference inhibitor and a corresponding control group; fluorescence intensity changes were recorded using a high-throughput fluorescence imaging system (FLIPR), and the sensitivity and stability of the screening system were ensured by optimizing the agonist concentration, reaction time and signal-to-noise ratio.

[0323] hTRPM3 HEK293 cells were seeded at 2 weeks per well into 96-well black-walled, light-transmitting cell culture plates. After 6 hours of adhesion, 4 μM Fluo-4AM dye was prepared and incubated at 37°C in the dark for 40 minutes. The specific steps were as follows: The original culture medium was aspirated, and 60 μL of Locke's 4 μM Fluo-4 / AM fluorescent dye (in mM: 8.6 HEPES, 5.6 KCl, 154 NaCl, 5.6 Glucose, 1.0 MgCl2, 2.3 CaCl2, 0.0001 glycine, pH 7.4) was added. The plate was incubated in the dark for 60 minutes. After incubation, the cells were rinsed 5 times with pre-warmed Locke's buffer at 37°C, resulting in a final liquid volume of 150 μL per well. After rinsing, the cell culture plate was placed in a FLIPRTETRA® instrument and allowed to stabilize for 5 minutes. The stock solution of the compound was diluted 8-fold with Locke's buffer. 60 μL of solvent control or compound solution was added to the corresponding well in a 96-well V-plate (drug plate) beforehand. After reading the baseline for 100 s, 25 μL of solvent control or compound solution was added using the FLIPR auto-dispensing arm, and readings were continued for 500 s. Then, 25 μL of solvent control or 1 μM CIM0216 solution was added using the FLIPR auto-dispensing arm, and readings were continued for another 500 s. Experimental data are expressed as F / F0, where F represents the fluorescence signal at different time points, and F0 represents the average fluorescence signal of the initial 10 points.

[0324] The activities of the example compounds tested are depicted in the table below. Activity ranges A, B, and C refer to the IC50 values ​​determined in Fluo-4 AM assays. 50 Values ​​are as follows: "A": IC 50 <1 μM; “B”: 1 μM ≤ IC 50 ≤20 μM, and “C”: IC 50 >20 μM.

[0325] Table 1-1 IC 50 Test data ; Table 1-2 IC 50 Test data .

[0326] The present invention and its embodiments have been described above illustratively, and this description is not restrictive; the actual structure is not limited thereto. Therefore, if those skilled in the art are inspired by this description and design similar structures and embodiments without departing from the spirit of the invention, such designs should fall within the protection scope of the present invention.

Claims

1. A heterocyclic compound of formula (I), its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or polymorphs, characterized in that, The structural formula is: Equation (I), in, R 1 represents -F, -Cl, -Br, -I, -CN, -R W , -OR W , -OC(=O)R W , -NR W R X , -NR W C(=O)R X , -SR W , -S(=O)R W , -S(=O)₂R W , -C(=O)R W , -C(=O)OR W or -C(=O)NR W R X ; Q indicates -NR 3 R 4 ; X1, X2, X3, X4, and X5 are represented independently of each other -NR 3 R 4 C or O; R 3 Indicates -OH or -R Y1 ; R 4 Indicates -R Y2 or -S(=O)2R Y3 ; Or R 3 and R 4 Together they form 4, 5, 6, 7 or 8-membered heterocycles containing 1 to 3 heteroatoms selected from N, O and S, which are saturated or unsaturated, unsubstituted or monosubstituted or polysubstituted; T represents -O-, -NR W -, -S-, and U represents -(CR) 5 R 5' )n-; or T represents -(CR 5 R 5' )n-, and U represents -O-; n is an integer selected from 1, 2, 3, 4 or 5; R 5 and R 5' Represented independently of each other -R Y4 ; R 6 Independently represent -F, -Cl, -Br, -I, -CN, -NO2, -SF5, -R W -OR W -OC (=O)R W NR W R X -NR W C(=O)R X -SR W -S (=O)R W -S(=O)2R W -C (=O)R W -C (=O) OR W or -C (=O)NR W R X ; R 7 and R 8 Linked to form unsaturated aromatic rings or independently represented as -F, -Cl, -Br, -I, -CN, -NO2, -SF5, -R W -OR W -OC (=O)R W NR W R X -NR W C(=O)R X -SR W -S (=O)R W -S(=O)2R W -C (=O)R W -C (=O) OR W or -C (=O)NR W R X ; W indicates 3-14 membered cycloalkyl, which is saturated or non-aromatic unsaturated; unsubstituted, monosubstituted or polysubstituted; or -C1-C6-alkyl, -C2-C6-alkenyl, -C2-C6-ynyl; which in each case is unsubstituted, monosubstituted or polysubstituted. in R W and R X -H is independently represented in each case; -C1-C6-alkyl, which is saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted; -C1-C6-heteroalkyl, which is saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted. 3-14 membered cycloalkyl groups, which are saturated or non-aromatic unsaturated, unsubstituted, monosubstituted or polysubstituted; wherein said 3-14 membered cycloalkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, which in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted; or 3-14-membered heterocyclic alkyl groups, which are saturated or non-aromatic unsaturated, unsubstituted, monosubstituted or polysubstituted; wherein the 3-14-membered heterocyclic alkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, which in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted. R Y1 R Y2 R Y3 and R Y4 -H is independently represented in each case; -C1-C6-alkyl, which is saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted; -C1-C6-heteroalkyl, which is saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted; 3-14 membered cycloalkyl, which is saturated or non-aromatic unsaturated, unsubstituted, monosubstituted or polysubstituted; wherein the 3-14 membered cycloalkyl is optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, which in each case is saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted; 3-14-membered heterocyclic alkyl groups, which are saturated or non-aromatic unsaturated, unsubstituted, monosubstituted or polysubstituted; wherein the 3-14-membered heterocyclic alkyl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, which in each case are saturated or unsaturated, unsubstituted, monosubstituted or polysubstituted. 6-14 aryl groups, which are unsubstituted, monosubstituted, or polysubstituted; wherein the 6-14 aryl groups are optionally linked by a C1-C6-alkylene- or -C1-C6-heteroalkylene-, which in each case are saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted; or 5-14-membered heteroaryl groups, which are unsubstituted, monosubstituted, or polysubstituted; wherein the 5-14-membered heteroaryl groups are optionally linked by -C1-C6-alkylene- or -C1-C6-heteroalkylene-, which in each case are saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted.

2. The heterocyclic compound, its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or polymorphs according to claim 1, characterized in that, Selected from: One of them.

3. The heterocyclic compound, its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or polymorphs according to claim 1, characterized in that, T, U, and W are selected from: One of them.

4. The heterocyclic compound, its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or polymorphs according to claim 1, characterized in that, Q is selected from: One of them.

5. The heterocyclic compound, its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or polymorphs according to claim 1, characterized in that, The compound is selected from any of the following specific compounds or their pharmaceutically acceptable salts: ； ； ； 。 6. The heterocyclic compound, its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or polymorphs according to claim 1, characterized in that, The compound has a structure as shown in formula (II) or formula (III): Equation (II), where, R 9 and R 10 Linked to form unsaturated aromatic rings or independently represented as -F, -Cl, -Br, -I, -CN, -NO2, -SF5, -R W -OR W -OC (=O)R W NR W R X -NR W C(=O)R X -SR W -S (=O)R W -S(=O)2R W -C (=O)R W -C (=O) OR W or -C (=O)NR W R X ; R 11 represents -F, -Cl, -Br, -I, -CN, -NO2, -SF5, -R W , -OR W , -OC(=O)R W , NR W R X , -NR W C(=O)R X , -SR W , -S(=O)R W , -S(=O)2R W , -C(=O)R W , -C(=O)OR W or -C(=O)NR W R X ; R 12 or R 13 With R 7 Linked to form saturated or unsaturated rings, or independently represented as -F, -Cl, -Br, -I, -CN, -NO2, -SF5, -R W -OR W -OC (=O)R W NR W R X -NR W C(=O)R X -SR W -S (=O)R W -S(=O)2R W -C (=O)R W -C (=O) OR W or -C (=O)NR W R X ; Formula (III) in, T represents -O-, -NR W -, -S- or does not exist, and U represents - (CR 5 R 5' n- or does not exist; R 14 represents -CN, -R W , -OR W , -OC(=O)R W , NR W R X , -NR W C(=O)R X , -SR W , -S(=O)R W , -S(=O)₂R W , -C(=O)R W , -C(=O)OR W or -C(=O)NR W R X .

7. A pharmaceutical composition, characterized in that: It comprises the heterocyclic compound of any one of claims 1-6, its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or polymorphs, and at least one pharmaceutically acceptable carrier, diluent or excipient.

8. The use of a heterocyclic compound, its stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or polymorph as claimed in any one of claims 1-6, or a pharmaceutical composition according to claim 7, as a TRPM3 antagonist.

9. The use of a heterocyclic compound, stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or polymorph of any one of claims 1-6, or a pharmaceutical composition according to claim 7, in the preparation of a medicament for the prevention or treatment of TRPM3-mediated diseases.

10. The application according to claim 9, characterized in that: The TRPM3-mediated conditions are pain-related diseases, such as inflammatory pain, neuropathic pain, migraine, epilepsy, and inflammatory hypersensitivity disorders.

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