Novel thioredoxin interacting protein (TXNIP) inhibitor

Abstract

Through flux screening, synthesis and structure-function relationship research, a series of novel inhibitors of TXNIP are developed, and the inhibitors have the structure as shown in the general formula I, including preparation and application of the inhibitors. As a key regulatory protein in an oxidative stress effect pathway, TXNIP has become an important target protein for evaluating curative effects of drugs for diseases such as diabetes and complications thereof, atherosclerosis, hepatocyte ischemia / reperfusion injury and the like. Therefore, by inhibiting the expression of the TXNIP, the TXNIP can be used for treating glucagon level related diseases, such as diabetes, diabetic retinopathy and related diseases; the inhibition of TXNIP can also be used for treating hyperlipidemia or fatty liver related diseases; inhibition of TXNIP can reduce inflammatory reactions related to NLRP3 and inhibit generation of inflammatory factors such as IL-1beta, and the TXNIP can be used for treating immune system related diseases, such as inflammatory diseases such as chronic kidney diseases and neurodegenerative diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention develops a novel class of TXNIP inhibitors having the structure shown in General Formula I. Compounds of this class contain a disubstituted heterocyclic structure, can inhibit the transcription of TXNIP, and can be used to treat diseases caused by up-regulation of TXNIP; at the same time, they can inhibit inflammation-related diseases by inhibiting the production of IL-1beta. It belongs to the field of pharmaceutical technology. Background Art

[0002] Pancreatic beta-cell dysfunction and death play a central role in the occurrence and development of diabetes, which can be caused by a variety of stress factors, including glucotoxicity, glucolipotoxicity, and cytokine toxicity (Endocrinology (2002), 143: 339 - 342; Diabetologia (2001), 44: 2115 - 2133). Long-term exposure to glucotoxicity induced by high concentrations of glucose promotes apoptosis, which is related to elevated glucagon levels, further causing a series of vicious cycles and promoting the occurrence and development of diabetes, cardiovascular diseases, and inflammation-related diseases. Studies have shown that thioredoxin-interacting protein (TXNIP), a ubiquitously expressed cellular redox regulator (J. Biol. Chem (1999), 274: 21645 - 21650). Glucose mediates TXNIP transcription through carbohydrate response element-binding protein (ChREBP); the upregulation of TXNIP in turn causes the upregulation of Caspase-3, resulting in apoptosis. Therefore, TXNIP is a key mediator of glucose toxicity-induced beta-cell apoptosis (Diabetes (2008) 7: 938 - 944). Further studies have shown that in pancreatic beta-cells of diabetic patients, glucose promotes the upregulation of TXNIP gene transcription (Endocrinology (2005), 146: 2397 - 2405), further causing beta-cell death through the mitochondrial apoptosis pathway (Diabetes (2010), 59: 440 - 447). In addition, the upregulation of TXNIP levels induces the expression of miR-204, knocking down the insulin transcription factor MafA, thereby inhibiting insulin production (Nature medicine (2013), 19: 1141 - 1146). Experiments on TXNIP gene knockdown mice have shown that TXNIP deficiency increases beta-cell numbers without developing type 1 and type 2 diabetes (FASEB J (2008), 22: 3581 - 3594). At the same time, TXNIP gene knockout reduces hepatic gluconeogenesis, resulting in benefits in terms of renal, retinal, and cardiovascular protection. Although inhibiting TXNIP has good application prospects, there is currently a lack of inhibitors targeting TXNIP. Only the Anath Shalev group reported quinazoline TXNIP inhibitors, namely SRI-37330 (Cell Metabolism (2020), 32: 353 - 365). Given the broad application prospects of TXNIP inhibitors, there is an urgent need to develop new inhibitors.

[0003] The NLRP3 inflammasome plays a major role in regulating innate immunity. Dysregulation of inflammasome activity is associated with various inflammatory diseases. NLRP3 interacts with thioredoxin (TRX)-interacting protein (TXNIP), a protein associated with insulin resistance. Inflammasome activators such as uric acid crystals induce the dissociation of TXNIP from thioredoxin in a reactive oxygen species (ROS)-sensitive manner and enable its binding to NLRP3 (Nature Immunology (2010), 11, 136–140). Therefore, inhibiting TXNIP can be applied in the field of treating autoimmune diseases. Summary of the Invention

[0004] The present invention has developed a novel class of TXNIP inhibitors having the structure shown in General Formula I. Wherein R 1 may be alkyl, cycloalkyl, alkenyl, phenyl, deuterated phenyl, aromatic ring, heteroaromatic ring, substituted aromatic ring, substituted heteroaromatic ring; R 2 is hydrogen, halogen, alkyl, ether, amide; R 3 is alkyl, cycloalkyl, alkenyl, aromatic ring, substituted aromatic ring, heteroaromatic ring; U is a carbon atom, a nitrogen atom; V is a chemical bond, an oxygen atom, a sulfur atom, a nitrogen atom; W is a carbon atom, a nitrogen atom; X is an oxygen atom, a sulfur atom, a nitrogen atom.

[0005] In a preferred technical solution of the present invention, the compound of Formula I is selected from the following

[0006] The present invention also provides a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt, and a composition comprising at least one pharmaceutically acceptable carrier or diluent.

[0007] The TXNIP inhibitor of the present invention is used for preventing or treating diabetes and glucose-induced inflammatory responses such as liver-related and cardiovascular-related diseases.

[0008] The diseases or disorders improved by inhibiting the TXNIP function as described above are preferably diabetes, hepatitis-related diseases, cardiovascular diseases, and diabetic retinopathy. Specific implementation mode:

[0009] For a clearer understanding of the technical features, objectives, and beneficial effects of the present invention, the technical solutions of the present invention will now be described in the form of the following specific examples, which are further detailed descriptions of the above content of the present invention. However, this should not be construed as a limitation on the scope of implementation of the present invention. All technologies implemented based on the above content of the present invention fall within the scope of the present invention.

[0010] In the following examples, the experimental methods are conventional methods unless otherwise specified; the reagents and materials can be obtained from commercial sources unless otherwise specified.

[0011] In the experimental methods described in the following examples, the solvents and drugs used are all of analytical purity or chemical purity; anhydrous solvents are treated according to standard methods; the column chromatography and silica gel plates are of conventional models. Unless otherwise specified, anhydrous sodium sulfate is used as the desiccant for the organic phase obtained by extraction. LC-MS uses an Agilent 1260 high-performance liquid-ion trap mass spectrometer (ESI source), a diode array detector (DAD), with detection wavelengths of 210 nm and 254 nm. The system model is a conventional method unless otherwise specified; the reagents and materials can be obtained from commercial sources unless otherwise specified. Synthesis of representative compounds

[0012] Route A: Synthesis of compound A1 Reaction conditions: a) int-1 (1.0 equiv), int-6 (1.5 equiv), sodium hydroxide (solid powder, 1.5 equiv), dimethyl sulfoxide (0.4 M), room temperature, 6 hours; b) 2-methylaminothiophene (1.0 equiv), chloroacetyl chloride (1.2 equiv), potassium carbonate (1.5 equiv), acetonitrile (0.6 M), 0 °C - room temperature, overnight; c) int-3 (0.3 M), V(TFA) / V(DCM) = 0.7, 0 °C – room temperature, 6 hours; d) int-4 (1.0 equiv), int-5 (2.5 equiv), potassium carbonate (1.5 equiv), acetonitrile (0.2 M), reflux, overnight.

[0013] Synthesis of compound int-1: Methyl 4-hydroxybenzoate (20.0 mmol, 3.043 g) was dissolved in anhydrous tetrahydrofuran. Under cooling, sodium hydride (60%, 1.5 equiv, 1.20 g) was added portionwise. After stirring at 0 °C for 30 minutes, MOMCl (1.2 equiv, 1.9 mL) was added dropwise, and then the mixture was warmed to room temperature and stirred overnight. After the reaction was completed, the reaction was quenched with saturated ammonium chloride, and then extracted with ethyl acetate (5 × 10.0 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the colorless oily compound int-1 (3.775 g, 96%). R f R = 0.42 (petroleum ether:EtOAc = 20:1). ESI-MS m / z: 197.1 [M+H] +

[0014] Synthesis of compound int-2: Hydroxylamine hydrochloride (2.0 equiv, 1.390 g) was dissolved in methanol (20 mL). Sodium bicarbonate (2.0 equiv, 1.680 g) was added at room temperature, and then the mixture was stirred for 30 minutes. p-Methoxybenzonitrile (10.00 mmol, 1.331 g) was added, and then the mixture was refluxed overnight. After the reaction was completed, the reaction mixture was concentrated in vacuo to obtain the crude product int-2, which was directly used in the next step. ESI-MS m / z: 167.3 [M+H] +

[0014] Synthesis of compound int-3: int-1 (1.5 equiv, 19.33 mmol, 3.793 g) and int-2 (12.89 mmol, 2.142 g) were dissolved in dimethyl sulfoxide (32 mL). Sodium hydroxide powder (1.5 equiv, 1.184 g) was added, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction was quenched by adding a large amount of ice water, and then the solid product was precipitated, filtered by suction, and dried to obtain the white solid int-3 (3.876 g, 71%). R f R = 0.55 (petroleum ether:EtOAc = 5:1). ESI-MS m / z: 313.2 [M+H] +

[0015] Synthesis of compound Int-4: Compound int-3 (8.24 mmol, 2.573 g) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (TFA, 21 mL) was added dropwise thereto at 0 °C. After the reaction was completed, toluene was added to remove TFA and dichloromethane, and then the mixture was washed with saturated sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Then the crude product was washed with petroleum ether and dried to obtain solid compound int-4 (2.157 g, 98%). R f = 0.14 (petroleum ether:EtOAc = 5:1). ESI-MS m / z: 291.1 [M+Na] +

[0016] Synthesis of compound int-5: Compound 2-thiophene benzylamine (20.00 mmol, 2.1 mL) was dissolved in anhydrous acetonitrile, and solid potassium carbonate (1.5 equiv, 1.146 g) and chloroacetyl chloride (1.2 equiv, 1.9 mL) were added thereto in sequence at 0 °C. Then the reaction system was warmed to room temperature and stirred overnight. After the reaction was completed, acetonitrile was removed under reduced pressure, and then water and ethyl acetate were added. The organic phase was washed with saturated sodium bicarbonate and saturated brine respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain solid compound int-5 (2.782 g, 74%). R f = 0.41 (petroleum ether:EtOAc = 3:1). ESI-MS m / z: 190.2 [M+H] +

[0017] Synthesis of Example A1: Compound int-5 (0.12 mmol, 32 mg) was dissolved in anhydrous acetonitrile, and solid potassium carbonate (1.5 equiv, 25 mg) and compound int-4 (2.5 equiv, 57 mg) were added thereto in sequence at room temperature. Then the mixture was refluxed overnight. After the reaction was completed, acetonitrile was removed by concentration under reduced pressure. The crude product was dissolved in ethyl acetate and washed successively with water, saturated ammonium chloride, and brine; the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain white solid compound A1 (33 mg, 63%). R f = 0.31 (petroleum ether:EtOAc = 2:1).

[0018] Route B: Synthesis of Example A23 Reaction conditions: a) Methyl p-aminobenzoate (1.0 equiv), int-6 (1.5 equiv), sodium hydroxide (s) (powder, 1.5 equiv), dimethyl sulfoxide (0.4 M), 60 °C, overnight; b) int-7 (1.0 equiv), 2-furanmethanol (1.2 equiv), acetic acid (4.0 equiv), sodium triacetoxyborohydride (2.0 equiv), 1,2-dichloroethane (0.1 M), room temperature, overnight.

[0019] Synthesis of compound int-6: Hydroxylamine hydrochloride (2.0 equiv, 2.780 g) was dissolved in methanol (30 mL), solid sodium bicarbonate (2.2 equiv, 3.530 g) was added, and the mixture was stirred at room temperature for 30 minutes. Then benzonitrile (20.00 mmol, 2.1 mL) was added, and the mixture was refluxed overnight. After the reaction was completed, the reaction solution was concentrated and directly used for the next step. ESI-MS m / z: 137.2 [M+H] +

[0020] Synthesis of compound int-7: Methyl 4-aminobenzoate (19.73 mmol, 2.982 g) and compound int-6 (1.5 equiv, 4.028 g) were dissolved in dimethyl sulfoxide (50 mL), solid sodium hydroxide (1.5 equiv, 1.184 g) was added at room temperature, and then the mixture was stirred at 60 °C overnight. After the reaction was completed, cold water (100 mL) was added to quench the reaction, and the target compound int-7 (3.649 g, 78%) precipitated as a solid. R f = 0.44 (petroleum ether:EtOAc = 2:1). ESI-MS m / z: 238.1 [M+H] +

[0021] Synthesis of Example A23: Compound int-7 (1.00 mmol, 237 mg) was dissolved in 1,2-dichloroethane (10 mL), and then furfural (1.2 equiv, 99 μL) and acetic acid (4.0 equiv, 229 μL) were added successively. After stirring at room temperature for 4 h, NaBH(OAc)3 (2.0 equiv, 424 mg) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with dichloromethane, and the organic phase was washed successively with saturated ammonium chloride and brine. The organic phases were combined, dried, and concentrated. The crude product was purified by column chromatography to give compound A23 (197 mg, 62%). R f = 0.17 (petroleum ether:EtOAc = 10:1).

[0022] Route B: Synthesis of compound A26: Compound A23 was dissolved in anhydrous DMF (0.5 mL), and NaH (60%, dispersion in mineral oil, 2.1 equiv, 61 mg) was added portionwise at 0 °C. After 30 min, methyl iodide (1.5 equiv, 70 μL) was added, and then the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was quenched with saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried, filtered, and concentrated. The crude product was purified by column chromatography to give A26 (202 mg, 84%). R f = 0.42 (petroleum ether:EtOAc = 7:1).

[0023] Route B: Synthesis of Example A27: Compound int-7 (1.0 mmol, 237 mg) was dissolved in dry tetrahydrofuran (10 mL), and NaH (60%, dispersion in mineral oil, 1.5 equiv, 60 mg) was added at 0 °C. After 30 min, 2-furoyl chloride was added, and the mixture was slowly warmed to room temperature and stirred overnight. After completion of the reaction, the reaction was quenched with saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried, filtered, and concentrated. The crude product was purified by column chromatography to give A27 (245 mg, 74%). R f = 0.22 (petroleum ether:EtOAc = 3:1).

[0024] Route C: Synthesis of Example A66 Reaction conditions: a) Methyl 4-aminobenzoate (1.0 equiv), tert-butyl trichloroacetimidate (2.5 equiv), copper(II) trifluoromethanesulfonate (5% mmol), nitromethane (0.25 M), under argon atmosphere, at 60 °C, overnight; b) int-8 (1.0 equiv), int-6 (1.5 equiv), sodium hydroxide (s) (powder, 1.5 equiv), dimethyl sulfoxide (0.5 M), at room temperature, overnight.

[0025] Synthesis of compound int-8: Methyl 4-aminobenzoate (2 mmol, 303 mg) was dissolved in dry nitromethane (8 mL). Trichloroacetonitrile (2.5 equiv, 894 μL) was added at room temperature, and a catalytic amount of Cu(OTf)2 (5% mmol, 36 mg) was added. After addition, the mixture was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate, quenched with saturated ammonium chloride, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to give int-8 (345 mg, 83%). R f = 0.62 (petroleum ether:EtOAc = 10:1). ESI-MS m / z: 208.4 [M+H] +

[0026] Synthesis of Example A66: Compound int-9 (1.5 equiv, 462 mg) and int-8 (2 mmol, 415 mg) were dissolved in DMSO (4 mL). Solid NaOH (1.5 equiv, 120 mg) was added portionwise, and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction was quenched with ice water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to give A66 (375 mg, 61%). R f = 0.51 (petroleum ether:EtOAc = 10:1).

[0027] Route D: Synthesis of Example A92: Reaction conditions: int-4 (1.0 equiv), furfuryl alcohol (1.0 equiv), triphenylphosphine (1.5 equiv), diethyl azodicarboxylate (1.5 equiv), tetrahydrofuran (0.25 M), 0 °C - room temperature, overnight. A round-bottom flask containing int-4 (1 mmol, 268 mg), triphenylphosphine (1.5 equiv, 86 mg), and a magnetic stir bar was sealed and evacuated and filled with nitrogen three times to make the system an atmosphere of nitrogen. Then, the solvent tetrahydrofuran (4 mL) was added to this system. Then it was placed in an ice bath. After the system temperature dropped to 0 °C, furfuryl alcohol (1.0 equiv, 160 μL) and diethyl azodicarboxylate (1.5 equiv, 236 μL) were slowly added dropwise in sequence. After the sample addition was completed, the ice bath was removed and the reaction system was stirred at room temperature overnight. After the reaction was completed, water (4 mL) was added to the system, and then extraction was carried out with ethyl acetate (3×4 mL). The obtained organic phases were combined and dried over anhydrous sodium sulfate. Finally, it was filtered, concentrated, and separated and purified by a chromatographic column to finally obtain the target product A92 (219 mg, 69%). R f = 0.51 (petroleum ether:EtOAc = 10:1).

[0028] Route E: Synthesis of compound A107: Reaction conditions: a) int-10 (1.0 equiv), reduced iron powder (5.0 equiv), ammonium chloride (s, 5.0 equiv), ethanol:water (V:V = 1:1, 0.1 M), (0.25 M), 100 °C, 17 h; b) int-11 (1.0 equiv), HATU (1.3 equiv), N,N-diisopropylethylamine (1.6 equiv), D-biotin (1.0 equiv), DMF (0.3 M), room temperature, 17 h; c) int-12 (1.0 equiv), int-6 (1.5 equiv), sodium hydroxide (s, 1.5 equiv), dimethyl sulfoxide (0.5 M), room temperature, overnight.

[0029] Compound int-10 can be prepared by Route C. Among them, R f = 0.67 (petroleum ether:EtOAc = 7:1). ESI-MS m / z: 253.2 [M+H] + .

[0030] a): At room temperature, int-10 (4.7 mmol, 1.200 g), reduced iron powder (5.0 equiv, 1.330 g), and ammonium chloride (s, 5.0 equiv, 1.270 g) were added to a pressure-resistant reaction tube, and then the mixed solvent ethanol: water (V:V = 1:1, 50 mL) was added. Then the reaction was carried out at 100 °C for 17 hours. After the reaction was completed, suction filtration was carried out to remove the solids in the reaction system. The filtrate was extracted, dried, and concentrated, and then separated and purified using a chromatography column to finally obtain the intermediate compound int-11 (891 mg, 85%). R f = 0.41 (petroleum ether:EtOAc = 3:1). ESI-MS m / z: 223.1 [M+H] + .

[0031] b): At room temperature, int-11 (0.5 mmol, 154 mg), HATU (1.3 equiv, 247 mg), N,N-diisopropylethylamine (1.6 equiv, 142 μL), and D-biotin (1.0 equiv, 125 mg) were successively added to a reaction tube, and then the solvent DMF (1.7 mL) was added immediately. Then the reaction was stirred at room temperature for 24 hours. After the reaction was completed, the reaction system was diluted with water (20 mL), and then extracted with ethyl acetate (3 * 10 mL). The obtained organic phases were combined, dried, filtered, and then separated by column chromatography to finally obtain the intermediate compound int-12 (202 mg, 96%). R f = 0.37 (DCM:MeOH = 15:1). ESI-MS m / z: 535.4 [M+H] + .

[0032] c): The intermediate compound int-12 was reacted with int-6 under the relevant reaction conditions shown in Route B to finally obtain the target compound A107 with a yield of 69%.

[0033] Synthesis methods of A1 - A110 in the examples, as well as structural analysis and spectral data of the obtained compounds

[0034] In this example, the A series of compounds prepared, namely A01 to A110, were tested for their activity in inhibiting TXNIP transcription.

[0035] Specific cell culture conditions: All cells were cultured in a humidified atmosphere of 37 °C and 5% CO2. All cell experiments were carried out under high glucose conditions (25 mM), including the culture of INS-1 cells, aTC1-6α cells and isolated mouse islet cells. These cells were initially cultured in RPMI 1640 medium containing 5 mM glucose for 6 hours. Subsequently, the medium was changed to RPMI 1640 (Gibco) containing 25 mM glucose and cultured for 24 hours. During this period, different concentrations of SKL-1223 were added, and DMSO was used as the corresponding solvent control. Rat INS-1 cells were cultured in RPMI 1640 medium (HyClone) containing 11.1 mM glucose, supplemented with 10% fetal bovine serum (Gibco) and 1% penicillin-streptomycin (Gibco). aTC1-6α cells (CRL-2934) were purchased from ATCC and cultured in Dulbecco's Modified Eagle Medium (Gibco), which was supplemented with 10% fetal bovine serum, 1% penicillin-streptomycin, 11.1 mM glucose, 1 mM sodium pyruvate, 100 μg / ml gentamicin and 15 mM HEPES.

[0036] Specific method for screening the inhibition of TXNIP transcription: To screen for compounds that inhibit the activity of the human TXNIP promoter, we cloned a region approximately 1518 bp upstream of the ATG start codon of the human TXNIP promoter into the pGL4.17 vector (Promega). After successful sequencing, we obtained a luciferase reporter gene vector containing the TXNIP promoter. Rat INS-1 cells were cultured and, when confluent, seeded into 24-well plates with medium containing 5.5 mmol / L glucose. When the cell density reached 60-70%, the TXNIP promoter luciferase reporter gene and TK plasmid were transfected into rat INS-1 cells using Lipofectamine TM 2000 transfection reagent at a dose of 300 ng of TXNIP promoter plasmid and 100 ng of TK plasmid per well. After 8 hours of transfection, the medium was changed to medium containing 25 mmol / L glucose, and the corresponding compounds were added, with DMSO as a control. After 24 hours, we used a luciferase detection system (Promega) to perform the detection according to its protocol. The TXNIP inhibitory activities of A01 to A110 were tested by this method.

[0037] Activity list of compounds A1–A110 -: Inhibition rate < 10% at 20 μM +: Inhibition rate 10% - 50% at 20 μM ++: Inhibition rate 50% - 80% at 20 μM +++: Inhibition rate > 50% at 5 μM ++++: Inhibition rate > 50% at 1 μM Description of the drawings

[0038] Figure 1 The A23 inhibits TXNIP expression in a dose-dependent manner.

[0039] Figure 2 The pharmacokinetics of A23

[0040] Figure 3 The A23 inhibits the production of TXNIP protein in a dose-dependent manner.

[0041] Figure 4 The A23 prevents STZ-induced type I diabetes.

[0042] Figure 5 The A23 treats STZ-induced type I diabetes.

[0043] Figure 6 The A23 inhibits the development of diabetes in db / db mice.

[0044] Figure 7 TXNIP inhibitors can inhibit the generation of IL-1beta.

[0045] Figure 8 A series of TXNIP inhibitors can inhibit the protein of IL-1beta generation under various stimulants.

[0046] Figure 9 A series of TXNIP inhibitors can inhibit the cytokine of IL-1beta generation under various stimulants.

Claims

1. A novel thioredoxin-interacting protein (TXNIP) inhibitor, a compound represented by general formula I, and its pharmaceutically acceptable salts, isotopes and isomers, having the structure shown in general formula I: The technical route is as follows: Wherein R 1 may be alkyl, cycloalkyl, alkenyl, phenyl, deuterated phenyl, aromatic ring, heteroaromatic ring, substituted aromatic ring, substituted heteroaromatic ring; R 2 is hydrogen, halogen, alkyl, ether, amide; R 3 is alkyl, cycloalkyl, alkenyl, aromatic ring, substituted aromatic ring, heteroaromatic ring; U is a carbon atom, a nitrogen atom; V is a chemical bond, an oxygen atom, a sulfur atom, a nitrogen atom; W is a carbon atom, a nitrogen atom; X is an oxygen atom, a sulfur atom, a nitrogen atom; Y is a nitrogen atom, a carbon atom.

2. The compound of general formula I according to claim 1, characterized in that R 1 may be alkyl, cycloalkyl, alkenyl, aromatic ring, substituted aromatic ring, heteroaromatic ring, including: but not limited to the above substituents.

3. The compound of general formula I according to claim 1, characterized in that R 2 is hydrogen, halogen, alkyl, ether, amide, nitro, including: wherein R4 may be an alkyl group, an aryl group, R5 may be an alkyl group, an aryl group, a cycloalkyl group and a substituted alkyl group, but not limited to the above substituents.

4. The compound of general formula I according to claim 1, characterized in that R 3 is alkyl, cycloalkyl, alkenyl, phenyl, deuterated phenyl, aromatic ring, heteroaromatic ring, substituted aromatic ring, substituted heteroaromatic ring, including:

5. The compound of general formula I according to claim 1, characterized in that U is a carbon atom, a nitrogen atom; V is a chemical bond, an oxygen atom, a sulfur atom, a nitrogen atom; W is a carbon atom, a nitrogen atom; X is an oxygen atom, a sulfur atom, a nitrogen atom.

6. The compound of general formula I according to claims 1-5, including 7. A pharmaceutical composition, which comprises the compound of general formula I according to any one of claims 1-6, or its pharmaceutically acceptable salt, and a composition composed of at least one pharmaceutically acceptable carrier or diluent.

8. Use of the compound of general formula I according to any one of claims 1-7, or its pharmaceutically acceptable salt, or the composition according to claim 7 in the preparation of the following drugs, which are used for preventing or treating diseases or disorders improved by inhibiting TXNIP gene transcription or activity, including inflammatory diseases such as diabetes, diabetic retinopathy, colonic ulcer, neurodegenerative diseases, etc.

9. Use of the compound of general formula I according to any one of claims 1-7, or its pharmaceutically acceptable salt, or the composition according to claim 7 in the preparation of the following drugs, which are used for preventing or treating diseases or disorders mediated by inhibiting IL-1beta or NLRP3, including inflammatory diseases such as diabetes, diabetic retinopathy, colonic ulcer, neurodegenerative diseases, etc.

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