Application of a class of benzopyrimidine sulfide compounds as small molecule inhibitors of STING protein

Abstract

The present invention discloses the use of a class of benzopyrimidine sulfide compounds as small molecule inhibitors of the STING protein, relating to the technical field of inhibitors. The present invention finds that these compounds are effective in inhibiting activation of the STING signaling pathway and have high STING protein inhibitory activity, and can be used in the preparation of small molecule inhibitors of the STING protein.

Description

Technical Field

[0001] The present invention relates to the technical field of inhibitors, and in particular to the use of a class of benzopyrimidine thioether compounds as small molecule inhibitors of STING protein. Background Art

[0002] The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway is a crucial component of the innate immune system. It activates a robust immune response by nonspecifically recognizing DNA, thereby inducing the expression of IFN-β and other proinflammatory cytokines to combat pathogen invasion and inhibit tumor growth. The cGAS-STING pathway can detect foreign DNA in many organisms. It also integrates DNA sensors with innate immune defenses, playing a crucial role in host immune protection. Current research indicates that the cGAS-STING pathway is involved in IFN-β expression and correlates with the uptake of tumor-derived DNA by dendritic cells (DCs). Furthermore, activation of the STING pathway in tumor cells can induce the secretion of the chemokines CCL5 (CC motif chemokine ligand 5) and CXCL10 (CX-C motif chemokine ligand 10), promoting the recruitment and activation of natural killer (NK) and T cells in tumors.

[0003] Transient inflammatory signaling is crucial for the body's defense against pathogen invasion. However, persistent, chronic inflammatory signaling can lead to STING-related autoimmune and inflammatory diseases. Small molecule STING inhibitors may offer a promising therapeutic approach for these diseases. Compared to the use of established STING agonists as anti-tumor immunotherapy, research into STING inhibitors is still in its early stages. Reported STING inhibitors to date have demonstrated limitations, including low potency and poor drug-like properties. Furthermore, no STING small molecule inhibitors have entered clinical development. Patients with chronic inflammatory and autoimmune diseases often require long-term medication, making the safety and potential side effects of STING inhibitors crucial. Therefore, developing STING small molecule inhibitors with novel backbones, high potency, drug-like properties, and minimal toxicity is crucial for advancing the treatment of autoimmune and inflammatory diseases. Summary of the Invention

[0004] The purpose of the present invention is to provide a benzopyrimidine sulfide compound as a small molecule inhibitor of STING protein to solve the problems existing in the above-mentioned prior art.

[0005] To achieve the above object, the present invention provides the following solutions:

[0006] The present invention provides a use of a benzopyrimidine sulfide compound in the preparation of a drug for inhibiting activation of the STING signaling pathway. The compound has a structure shown in Formula I, Formula II, or Formula III:

[0007]

[0008] Wherein, R1 is selected from any one of the following:

[0009]

[0010] L1 is selected from any one of the following: H, -CH3, -CH2CH3;

[0011] R2 is selected from any one of the following:

[0012]

[0013] R3 is selected from any of the following:

[0014]

[0015] The present invention also provides a use of a benzopyrimidine sulfide compound in the preparation of a drug for treating or preventing STING-mediated diseases, wherein the compound has a structure shown in Formula I, Formula II, or Formula III:

[0016]

[0017] Wherein, R1 is selected from any one of the following:

[0018]

[0019] L1 is selected from any one of the following: H, -CH3, -CH2CH3;

[0020] R2 is selected from any one of the following:

[0021]

[0022] R3 is selected from any of the following:

[0023]

[0024] Furthermore, the disease is an autoimmune disease or an inflammatory disease.

[0025] Furthermore, the disease includes STING-associated vasculopathy, Parkinson's disease, systemic lupus erythematosus or non-alcoholic fatty liver disease.

[0026] The present invention also provides a pharmaceutical composition for preventing or treating STING-mediated diseases, comprising a benzopyrimidine sulfide compound having a structure represented by Formula I, Formula II, or Formula III as an active ingredient:

[0027]

[0028] Wherein, R1 is selected from any one of the following:

[0029]

[0030] L1 is selected from any one of the following: H, -CH3, -CH2CH3;

[0031] R2 is selected from any one of the following:

[0032]

[0033] R3 is selected from any of the following:

[0034]

[0035] The preparation route of the compound of formula I is as follows:

[0036]

[0037]

[0038] The preparation route of the compound of formula II is as follows:

[0039] The preparation route of the compound of formula III is as follows:

[0040]

[0041] The present invention discloses the following technical effects:

[0042] The present invention provides a new application of a compound as a small molecule inhibitor of the STING protein. The compound has a good effect in inhibiting the activation of the STING signaling pathway, has high STING protein inhibitory activity, and can be used in the preparation of small molecule inhibitors of the STING protein. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0044] Figure 1 The inhibitory activity of compounds A1-A43 prepared in the examples of the present invention on STING protein;

[0045] Figure 2 The inhibitory activity of compounds D1-D12 prepared in the examples of the present invention on STING protein;

[0046] Figure 3 The inhibitory activity of compounds AB1-AB4 prepared in the examples of the present invention on the STING protein. DETAILED DESCRIPTION

[0047] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0048] It should be understood that the terms described herein are intended only to describe particular embodiments and are not intended to limit the present invention. In addition, for numerical ranges herein, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. The intermediate value within any stated value or stated range, and each smaller range between any other stated value or intermediate value within the stated range, is also encompassed within the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded within the scope.

[0049] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of any conflict with any incorporated document, the contents of this specification shall prevail.

[0050] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from the description of the invention. The description and examples are intended to be illustrative only.

[0051] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0052] Example 1. Preparation of Compound A1. The specific steps of the preparation process are as follows:

[0053] Step I: First, weigh 0.8 g (20 mmol, 1 eq) of sodium hydroxide into a 100 mL eggplant-shaped flask and dissolve it in 15 mL of water. Then, add 2.72 g (20 mmol, 1 eq) of benzoylhydrazide (1) and 2.78 g (10 mmol, 0.5 eq) of S-methylisothiourea sulfate (2) to the system. Then, add 20 mL of water. Stir at room temperature for 72 h, then heat at 50°C for 3 h. After cooling, filter, and wash with ice water to obtain a purple solid 3 without further treatment. The yield does not need to be calculated in this step, and the reaction can be directly carried out in the next step.

[0054] Step II: The purple solid 3 obtained in the previous step was transferred to a 100 mL eggplant-shaped flask. 30 mL of water was added as the solvent and the reaction was refluxed at 100°C for 2 h (the solution became clear and transparent). Needle-shaped white crystals precipitated upon cooling. These were filtered, washed with ice water, and dried to afford crystals 4 (2.3 g, 72% yield).

[0055] Step III: Weigh 0.64 g (4 mmol, 1 eq) of amino-5-phenyl-1,2,4-triazole (4) into a reaction flask, then add 1.04 g (8 mmol, 2 eq) of ethyl acetoacetate (5) to the system. Then, add 15 mL of acetic acid solvent and reflux at 120°C for 6 h. During the reaction, the solution changes from clear to white solid precipitation. After the reaction is completed, the solution is cooled, filtered, and washed with ethyl acetate (EA). Without further treatment, a white solid 6 (0.5 g, 55% yield) is obtained.

[0056] Step IV: 0.5 g (2.2 mmol, 1 eq) of the white solid 6 obtained in the previous step was added to a reaction flask. 1.5 mL of phosphorus oxychloride (POC) was added dropwise, acting as both the oxidant and the reaction solvent. The reaction was refluxed at 100°C for 2 h. The reaction was complete by TLC. The solution in the reaction system turned brown-black and was cooled. 4 M sodium hydroxide solution was then slowly added dropwise in an ice-water bath to adjust the pH to approximately 10. The pH was checked using pH paper to determine the end of the addition. A large amount of solid precipitated in the reaction system and was filtered. The residue and filtrate were collected. The filtrate was extracted with water and dichloromethane (DCM). The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure for disposal. The residue was evaporated under reduced pressure with anhydrous methanol and the sample was purified by column chromatography (PE / EA = 5:1) along with the filtrate to be processed, yielding 7 as a white solid (0.21 g, 39% yield).

[0057] Step VIII: 0.5 g (4 mmol, 1 eq) of 2-aminobenzenethiol (8) was weighed into a dry Schlenk flask. The atmosphere was evacuated and replaced with nitrogen three times, followed by the addition of 15 mL of dry tetrahydrofuran (THF). Under an ice-water bath, 1.01 g (10 mmol, 2.5 eq) of triethylamine was injected via syringe. Benzoyl chloride (9e) (1.36 g (8 mmol, 2 eq)) was then slowly injected via syringe. A vigorous reaction was observed, with the formation of a white solid. The reaction was stirred at room temperature for 6 h. TLC confirmed the completion of the reaction. A large amount of water was added to the reaction system, and the mixture was extracted with ethyl acetate (EA). The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography and mass spectrometry (PE / EA = 6:1) to afford compound 10e (1.13 g, 72% yield).

[0058] Step IX: Compound 10 (1.1 g, 2.8 mmol, 1 eq) was weighed into a reaction flask, followed by potassium hydroxide (0.63 g, 11.2 mmol, 4 eq). 30 mL of anhydrous methanol (MeOH) was added as the reaction solvent. The mixture was stirred at room temperature for 12 h. The reaction was completed by TLC. Hydrochloric acid was slowly added dropwise to the reaction system to adjust the pH to neutral. The pH was checked with pH paper. The mixture was then extracted with water and dichloromethane (DCM). The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography-mass spectrometry (PE / EA = 7:1) to afford 11e (0.49 g, 68% yield) as a white solid.

[0059] Step X: Weigh 0.73 g (0.3 mmol, 1 eq) of compound 11e into a reaction flask, then add 0.1 g (0.75 mmol, 2.5 eq) of potassium carbonate and 15 mL of acetone. Stir at 25°C for 30 min. Then, add 0.93 g (0.36 mmol, 1.2 eq) of compound 7. The reaction was allowed to react at 25°C for 15 h. TLC confirmed the reaction was complete. After completion, 0.1 M HCl solution was added to quench the reaction, followed by extraction with water and dichloromethane (DCM). The organic phase was separated, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified by column chromatography-mass spectrometry (PE / EA = 3:1) to afford 15 mg of the final product, A1, as a white solid in a 7.5% yield.

[0060] 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),9.18(d,J=7.2Hz,1H),8.70-8.65(m,1H),8.15-8.11(m,2H),8.04(dd,J=7.8,1.9Hz,1H),7.78(dd,J=7.7, 1.6Hz,1H),7.69(ddd,J=8.7,7.4,1.6Hz,1H),7.53-7.49(m,4H),7.33(t d,J=7.5,1.4Hz,1H),7.17-7.13(m,2H),7.11-7.07(m,1H),3.86(s,3H).

[0061] Example 2. Preparation of Compound A2. The preparation steps differ from those of A1 in that in step VIII, 4-methylbenzoyl chloride is used as the starting material to prepare derivative 10a, and the corresponding derivative 11a is reacted with compound 18 to obtain white solid A2 in a yield of 5.5%.

[0062] 1 H NMR (600MHz, DMSO-d6) δ10.13(s,1H),9.12(d,J=7.2Hz,1H),8.16-8.13(m,2H),7.80-7.78(m,3H),7.76(d,J=7.9Hz,1H), 7.65(s,1H),7.52(dd,J=5.3,2.0Hz,3H),7.45(d,J=7.5Hz,1H),7.28(d,J=7.9Hz,2H),6.97(d,J=7.2Hz,1H),2.33(s,3H).

[0063] Example 3. Preparation of Compound A3. The preparation steps differ from those of A1 in that in step VIII, 2-methylbenzoyl chloride is used as the starting material to prepare derivative 10a, and the corresponding derivative 11a is reacted with compound 7 to obtain white solid A3 in a yield of 6.5%.

[0064] 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),8.22(dd,J=6.7,2.9Hz,2H),7.89(dd,J=7.8,1.4Hz,1H),7.83(d,J=8.0Hz,1H),7.76(t,J=7.7Hz, 1H),7.56(dd,J=5.2,1.9Hz,3H),7.52(t,J=7.7Hz,1H),7.30(t,J=7.1Hz,2H),7.22-7.13(m,2H),6.20(s,1H),2.43(s,3H),2.22(s,3H).

[0065] Example 4. Preparation of Compound A4. The preparation steps differ from those of A1 in that in step VIII, 4-methylbenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain A4 as a white solid in a yield of 6.8%.

[0066] 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),8.22(dd,J=6.7,2.9Hz,2H),7.90(dd,J=7.8,1.4Hz,1H),7.83(d,J=8.0Hz,1H),7.77(d,J=7.6Hz, 1H),7.57(dd,J=5.2,1.9Hz,3H),7.53(d,J=7.9Hz,1H),7.31(t,J=7.1Hz,2H),7.23-7.14(m,2H),6.21(s,1H),2.44(s,3H),2.23(s,3H).

[0067] Example 5. Preparation of Compound A5. The preparation steps of A1 are different in that: in step VIII, 4-chlorobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain white solid A5 in a yield of 7.8%.

[0068] 1 H NMR(400MHz,Chloroform-d)δ8.92(s,1H),8.48(dd,J=8.3,1.3Hz,1H),7.71-7.65(m,2H),7.57 -7.50(m,1H),7.47-7.39(m,3H),7.29(ddd,J=8.7,7.4,1.6Hz,1H),6.93(td,J=7.6,1.4Hz,1H).

[0069] Example 6. Preparation of Compound A6. The preparation steps differ from those of A1 in that in step VIII, 3-methoxybenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain A6 as a white solid in a yield of 6.5%.

[0070] 1H NMR(600MHz,DMSO-d6)δ10.38(s,1H),8.21-8.18(m,2H),7.91(dd,J=7.7,1.4Hz,1H),7.79-7.75(m,2H),7.57 -7.51(m,4H),7.44-7.41(m,1H),7.38-7.34(m,2H),7.11-7.09(m,1H),6.24(s,1H),3.72(s,3H),2.43(s,3H).

[0071] Example 7. Preparation of Compound A7. The preparation steps of A1 are different in that: in step VIII, benzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain white solid A7 in a yield of 6.6%.

[0072] 1 H NMR(600MHz, DMSO-d6)δ10.49(s,1H),8.22(dt,J=6.6,2.7Hz,2H),7.91-7.86(m,2H),7.78(t,J=7.7 Hz,1H),7.58-7.51(m,4H),7.44-7.39(m,3H),7.34(td,J=7.2,1.7Hz,1H),6.15(s,1H),2.42(s,3H).

[0073] Example 8. Preparation of Compound A8. The preparation steps differ from those of A1 in that in step VIII, 3-fluorobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain white solid A8 in a yield of 6.9%.

[0074] 1 H NMR (400MHz, DMSO-d6) δ10.49(s,1H),8.22-8.18(m,2H),7.91(dd,J=7.6,1.2Hz,1H),7.78-7.75(m,2H),7.71(dt,J=7.7,1 .3Hz,1H),7.64(dt,J=9.9,2.1Hz,1H),7.58-7.54(m,4H),7.53-7.48(m,1H),7.43-7.37(m,1H),6.24(s,1H),2.43(s,3H).

[0075] Example 9. Preparation of Compound A9. The preparation steps differ from those of A1 in that in step VIII, 2-chlorobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain A9 as a white solid in a yield of 7.2%.

[0076] 1 H NMR(600MHz, DMSO-d6)δ10.50(s,1H),8.23(dt,J=6.6,2.7Hz,2H),7.92-7.87(m,2H),7.79(t,J=7.7 Hz,1H),7.59-7.53(m,4H),7.45-7.40(m,3H),7.35(td,J=7.2,1.7Hz,1H),6.16(s,1H),2.43(s,3H).

[0077] Example 10. Preparation of Compound A10. The preparation steps differ from those of A1 in that in step VIII, 2-fluorobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain white solid A10 in a yield of 7.1%.

[0078] 1 H NMR (400MHz, DMSO-d6) δ10.29(d,J=2.4Hz,1H),8.22(dd,J=6.0,2.5Hz,2H),7.96(d,J=8.1Hz,1H),7.89(d,J=7.8Hz,1H),7.76(t,J =7.7Hz,1H),7.61(t,J=7.4Hz,1H),7.56(dd,J=4.1,2.6Hz,3H),7.50(t,J=7.8Hz,2H),7.28-7.19(m,2H),6.20(s,1H),2.42(s,3H).

[0079] Example 11. Preparation of Compound A11. The preparation steps differ from those of A1 in that in step VIII, 4-fluorobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain white solid A11 in a yield of 6.9%.

[0080] 1 H NMR (400MHz, DMSO-d6) δ10.42 (s, 1H), 8.21-8.16 (m, 2H), 7.98-7.87 (m, 3H), 7.75 (d, J = 6.0Hz, 2H), 7.54 (t, J = 3.4Hz, 4H), 7.29 (t, J = 8.6Hz, 2H), 6.23 (d, J = 1.3Hz, 1H), 2.43 (d, J = 1.3Hz, 3H).

[0081] Example 12. Preparation of Compound A12. The preparation steps differ from those of A1 in that in step VIII, 3-chlorobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain white solid A12 in a yield of 6.3%.

[0082] 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.20(dd,J=6.6,3.0Hz,2H),7.91(d,J=7.8Hz,1H),7.86-7.78(m,2H),7.7 6(d,J=4.4Hz,2H),7.61(d,J=7.8Hz,1H),7.55(q,J=4.3Hz,4H),7.49(t,J=7.9Hz,1H),6.24(s,1H),2.43(s,3H).

[0083] Example 13. Preparation of Compound A13. The preparation steps differ from those of A1 in that in step VIII, 4-bromobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain A13 as a white solid in a yield of 6.5%.

[0084] 1 H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.22-8.16(m,2H),7.92-7.87(m,1H),7.83-7.78(m ,2H),7.77-7.73(m,2H),7.70-7.64(m,2H),7.58-7.45(m,5H),6.22(s,1H),2.42(s,3H).

[0085] Example 14. Preparation of Compound A14. The preparation steps differ from those of A1 in that in step VIII, 4-methoxybenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain A14 as a white solid in a yield of 7.5%.

[0086] 1 H NMR (400MHz, DMSO-d6) δ10.25(s,1H),8.19(dd,J=6.6,2.9Hz,2H),7.87(dd,J=10.0,7.7Hz,3H),7.78-7.70(m,2 H),7.55(dd,J=5.1,1.8Hz,3H),7.50(d,J=1.9Hz,1H),7.00-6.94(m,2H),6.22(s,1H),3.76(s,3H),2.42(s,3H).

[0087] Example 15. Preparation of Compound A15. The preparation steps differ from those of A1 in that in step VIII, 2-bromobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain white solid A15 in a yield of 7.1%.

[0088] 1 H NMR(400MHz,DMSO-d6)δ10.50(s,1H),8.26-8.21(m,2H),7.93-7.84(m,2H),7.79(s, 1H),7.57(ddt,J=10.1,7.6,4.5Hz,5H),7.41-7.29(m,3H),6.16(s,1H),2.43(s,3H).

[0089] Example 16. Preparation of Compound A16. The preparation steps differ from those of A1 in that in step VIII, 3-bromobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain white solid A16 in a yield of 7.3%.

[0090] 1 H NMR (400MHz, DMSO-d6) δ10.25(s,1H),8.20(dd,J=6.6,2.9Hz,2H),7.87(dd,J=10.0,7.7Hz,3H),7.79-7.71(m, 2H),7.58-7.53(m,3H),7.50(td,J=7.4,1.9Hz,1H),7.01-6.95(m,2H),6.23(s,1H),3.77(s,3H),2.43(s,3H).

[0091] Example 17. Preparation of Compound A17. The preparation steps differ from those of A1 in that in step VIII, furoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain white solid A17 in a yield of 7.4%.

[0092] 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),8.21(dd,J=5.8,2.7Hz,2H),7.87(d,J=8.1Hz,2H),7.81(d,J=8.0Hz,1H),7.73(t,J=7.7Hz,1H),7.55 (dd,J=4.6,2.5Hz,3H),7.50(t,J=7.6Hz,1H),7.28-7.24(m,1H),6.64(dt,J=3.4,1.6Hz,1H),6.21(d,J=1.5Hz,1H),2.42(d,J=1.5Hz,3H).

[0093] Example 18. Preparation of Compound A18. The preparation steps differ from those of A1 in that in step VIII, the 10a derivative is prepared using thiophenecarbonyl chloride as the starting material, and the 11a derivative is then reacted with compound 7 to obtain white solid A18 in a yield of 7.8%.

[0094] 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.22-8.18(m,2H),7.91-7.87(m,1H),7.85(dd,J=3.9,1.2Hz,1H),7.82(dd ,J=5.0,1.1Hz,1H),7.76-7.72(m,2H),7.56-7.50(m,4H),7.12(dd,J=5.0,3.8Hz,1H),6.22(s,1H),2.42(s,3H).

[0095] Example 19. Preparation of Compound A19. The preparation steps differ from those of A1 in that in step VIII, 4-trifluoromethylbenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain white solid A19 in a yield of 7.5%.

[0096] 1 H NMR (600MHz, DMSO-d6) δ10.64(s,1H),8.19-8.16(m,2H),8.04(d,J=8.2Hz,2H),7.91(dd,J=7.7,1 .4Hz,1H),7.83(d,J=8.2Hz,2H),7.79-7.74(m,2H),7.56-7.52(m,4H),6.23(s,1H),2.43(s,3H).

[0097] Example 20. Preparation of Compound A20. The preparation steps differ from those of A1 in that, in step III, amino-5-phenyl-1,2,4-triazole (4) reacts with ethyl propionyl acetate (12) to produce compound 13. Subsequent steps are the same as in A1. In step VIII, 4-methylbenzoyl chloride is used as the starting material to produce derivative 10a. This derivative 11a is then reacted with compound 14 to produce A20 as a white solid in a 7.4% yield.

[0098] 1H NMR (400MHz, DMSO-d6) δ10.28(s,1H),8.23-8.17(m,2H),7.89(d,J=7.8Hz,1H),7.76(dd,J=13.6,7.8Hz,4H),7.55(t,J=3.5Hz,3H ),7.49(d,J=8.0Hz,1H),7.23(d,J=7.8Hz,2H),6.22(d,J=1.4Hz,1H),2.72-2.66(m,2H),2.30(s,3H),1.13(dd,J=8.1,6.8Hz,3H).

[0099] Example 21. Preparation of compound A21. The difference from the preparation of A20 is that in step VIII, 2-methoxybenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 14 to obtain white solid A21 in a yield of 6.7%.

[0100] 1 H NMR (400MHz, DMSO-d6) δ10.71 (s, 1H), 8.58 (d, J = 8.3Hz, 1H), 8.28-8.24 (m, 2H ),7.98(d,J=7.8Hz,1H),7.89(d,J=7.7Hz,1H),7.77(t,J=7.9Hz,1H),7.61-7. 57(m,3H),7.48(t,J=7.9Hz,1H),7.41(t,J=7.6Hz,1H),7.07(dd,J=13.1,7.9H z,2H),6.18(s,1H),3.64(s,3H),2.67(d,J=7.5Hz,2H),1.06(t,J=7.5Hz,3H).

[0101] Example 22. Preparation of Compound A22. The difference from the preparation of A20 is that in step VIII, 4-bromobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 14 to obtain white solid A22 in a yield of 6.5%.

[0102] 1 H NMR(400MHz, DMSO-d6)δ10.47(s,1H),8.19(dd,J=6.6,3.0Hz,2H),7.92-7.88(m,1H),7.81-7.74(m ,4H),7.68-7.64(m,2H),7.57-7.52(m,4H),6.22(s,1H),2.72-2.66(m,2H),1.14(t,J=7.5Hz,3H).

[0103] Example 23. Preparation of compound A23. The difference from the preparation of A20 is that in step VIII, 4-fluorobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 14 to obtain white solid A23 in a yield of 6.9%.

[0104] 1 H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.22-8.17(m,2H),7.96-7.88(m,3H),7.78-7.72(m,2H), 7.58-7.51(m,4H),7.29(t,J=8.9Hz,2H),6.22(s,1H),2.71-2.66(m,2H),1.14(t,J=7.5Hz,3H).

[0105] Example 24. Preparation of compound A24. The difference from the preparation of A20 is that in step VIII, 4-methoxybenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 14 to obtain white solid A24 in a yield of 7.9%.

[0106] 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),8.22-8.17(m,2H),7.90-7.82(m,3H),7.79-7.68(m,2H),7.55(dd,J=5.0,2.0Hz,3H ),7.49(td,J=7.4,1.7Hz,1H),6.99-6.94(m,2H),6.21(s,1H),3.76(s,3H),2.68(d,J=7.5Hz,2H),1.13(t,J=7.5Hz,3H).

[0107] Example 25. Preparation of Compound A25. The difference from the preparation of A20 is that in step VIII, 2-fluorobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 14 to obtain white solid A25 in 8.1% yield.

[0108] 1H NMR (400MHz, DMSO-d6) δ10.31(d,J=2.5Hz,1H),8.26-8.21(m,2H),7.98(d,J=7.9Hz,1H),7.91(dd,J=7.8,1.5Hz,1H),7.77(td,J=7.8 ,1.6Hz,1H),7.63-7.56(m,4H),7.51(tt,J=7.9,2.4Hz,2H),7.28-7.19(m,2H),6.21(s,1H),2.73-2.67(m,2H),1.13(t,J=7.5Hz,3H).

[0109] Example 26. Preparation of Compound A26. The difference from the preparation of A20 is that in step VIII, 2-bromobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 14 to obtain white solid A26 in 8.3% yield.

[0110] 1 H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.25-8.21(m,2H),7.92-7.86(m,2H),7.79(t,J=7.7Hz,1 H),7.60-7.51(m,5H),7.39-7.30(m,3H),6.14(s,1H),2.72-2.66(m,2H),1.14(t,J=7.5Hz,3H).

[0111] Example 27. Preparation of Compound A27. The difference from the preparation of A20 is that in step VIII, 4-trifluoromethylbenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 14 to obtain white solid A27 in 8.0% yield.

[0112] 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.22-8.17(m,2H),8.04(d,J=8.1Hz,2H),7.92(dd,J=7.7,1.3Hz,1H),7.84(d, J=8.2Hz,2H),7.80-7.74(m,2H),7.56(dd,J=7.2,2.8Hz,4H),6.24(s,1H),2.72-2.66(m,2H),1.15(t,J=7.5Hz,3H).

[0113] Example 28. Preparation of Compound A28. The difference from the preparation of A20 is that in step VIII, 2-methylbenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 14 to obtain white solid A28 in a yield of 7.0%.

[0114] 1 H NMR(600MHz,DMSO-d6)δ10.32(s,1H),8.24-8.21(m,2H),7.90(dd,J=7.8,1.5Hz, 1H),7.83(dd,J=8.1,1.4Hz,1H),7.77(td,J=7.8,1.5Hz,1H),7.59-7.55(m,3H),7 .52(td,J=7.6,1.5Hz,1H),7.31-7.27(m,2H),7.20(d,J=7.5Hz,1H),7.16(t,J=7 .5Hz,1H),6.19(s,1H),2.70(q,J=7.5Hz,2H),2.19(s,3H),1.14(t,J=7.5Hz,3H).

[0115] Example 29. Preparation of Compound A29. The difference from the preparation of A20 is that in step VIII, 3-methylbenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 14 to obtain white solid A29 in a yield of 7.6%.

[0116] 1 H NMR (600MHz, DMSO-d6) δ10.33(s,1H),8.22-8.18(m,2H),7.90(dd,J=7.9,1.5Hz,1H),7.78-7.73(m,2H),7.61(dd,J=5.3,3.7Hz,1H),7. 57-7.54(m,4H),7.51(td,J=7.4,1.8Hz,1H),7.34-7.29(m,2H),6.22(s,1H),2.68(q,J=7.5Hz,2H),2.25(s,3H),1.13(t,J=7.5Hz,3H).

[0117] Example 30. Preparation of compound A30. The difference from the preparation of A20 is that in step VIII, 3-bromobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 14 to obtain white solid A30 in a yield of 7.2%.

[0118] 1H NMR (600MHz, DMSO-d6) δ10.53(s,1H),8.21-8.17(m,2H),7.95(t,J=1.9Hz,1H),7.91(dd,J=7.7,1.1Hz,1H),7.82(dt,J=7.8,1. 3Hz,1H),7.77-7.72(m,3H),7.57-7.51(m,4H),7.41(t,J=7.9Hz,1H),6.22(s,1H),2.68(d,J=7.6Hz,2H),1.13(t,J=7.5Hz,3H).

[0119] Example 31. Preparation of compound A31. The difference from the preparation of A20 is that in step VIII, 3-methoxybenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 14 to obtain white solid A31 in a yield of 6.8%.

[0120] 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.19(dd,J=6.6,3.1Hz,2H),7.91(dd,J=7.7,1.3Hz,1H),7.80-7.72(m,2H),7.58-7.49(m,4H),7.41(dt, J=7.7,1.3Hz,1H),7.37-7.30(m,2H),7.09(ddd,J=8.1,2.7,1.1Hz,1H),6.22(s,1H),3.71(s,3H),2.69(d,J=7.5Hz,2H),1.14(t,J=7.5Hz,3H).

[0121] Example 32. Preparation of compound A32. The difference from the preparation of A20 is that in step VIII, 3-fluorobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 14 to obtain white solid A32 in a yield of 6.4%.

[0122] 1H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.19(dd,J=6.6,3.1Hz,2H),7.90(dd,J=7.7,1.3Hz,1H),7.75(qd,J=8.1,1.8Hz,2H),7.58-7.49(m,4H),7.40 (dt,J=7.7,1.3Hz,1H),7.37-7.29(m,2H),7.08(ddd,J=8.1,2.7,1.1Hz,1 H), 6.22 (s, 1H), 3.70 (s, 3H), 2.68 (d, J = 7.5Hz, 2H), 1.13 (t, J = 7.5Hz, 3H).

[0123] Example 33. Preparation of compound A33. The difference from the preparation of A20 is that in step VIII, 4-chlorobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 14 to obtain white solid A33 in a yield of 6.6%.

[0124] 1 H NMR (400MHz, DMSO-d6) δ10.49 (s, 1H), 8.21-8.17 (m, 2H), 7.90 (dd, J = 7.6, 1.3Hz, 1H), 7.88-7.85 (m, 2H), 7.77 -7.74(m,2H),7.57-7.53(m,5H),7.52(d,J=2.1Hz,1H),6.22(s,1H),2.70-2.66(m,2H),1.14(t,J=7.5Hz,3H).

[0125] Example 34. Preparation of compound A34. The difference from the preparation of A20 is that in step VIII, furoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 14 to obtain white solid A34 in 8.6% yield.

[0126] 1 H NMR(600MHz,DMSO-d6)δ10.26(s,1H),8.23-8.20(m,2H),7.90-7.85(m,2H), 7.81(dd,J=8.2,1.4Hz,1H),7.74(dd,J=7.6,1.5Hz,1H),7.56(dd,J=5.3,2. 0Hz, 3H), 7.51 (dd, J=7.7, 1.4Hz, 1H), 7.25 (dd, J=3.6, 0.8Hz, 1H), 6.63 (dd, J=3.5,1.8Hz,1H),6.20(s,1H),2.69(q,J=7.5Hz,2H),1.13(t,J=7.5Hz,3H).

[0127] Example 35. Preparation of compound A35. The difference from the preparation of A20 is that in step VIII, the 10a derivative is prepared using thiophenecarbonyl chloride as the starting material, and the 11a derivative is then reacted with compound 14 to obtain white solid A35 in 8.8% yield.

[0128] 1 H NMR (600MHz, DMSO-d6) δ10.35(d,J=3.9Hz,1H),8.20-8.17(m,1H),8.09-8.06(m,1H),7.90-7.87(m,1H),7.74(dt,J=6.5,1.5Hz,2H),7.62(d d,J=7.0,2.0Hz,1H),7.58(d,J=4.1Hz,1H),7.55-7.50(m,2H),7.36-7.31(m,3H),6.21(d,J=14.7Hz,1H),2.41(d,J=6.1Hz,3H),2.38(s,2H).

[0129] Example 36. Preparation of compound A36. The preparation steps differ from those of A1 in that in step VIII, 2,6-difluorobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain white solid A36 in a yield of 9.4%.

[0130] 1 H NMR (400MHz, DMSO-d6) δ10.78 (s, 1H), 8.29-8.19 (m, 2H), 7.90 (td, J = 8.1, 1.4Hz, 2H), 7.84-7.7 5(m,1H),7.60-7.52(m,4H),7.51-7.43(m,1H),7.11(t,J=8.1Hz,2H),6.15(s,1H),2.41(s,3H).

[0131] Example 37. Preparation of compound A37. The preparation steps are different from those of A1 in that in step VIII, 3,5-difluorobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain white solid A37 in a yield of 9.1%.

[0132] 1H NMR (400MHz, DMSO-d6) δ10.55(s,1H),8.21-8.17(m,2H),7.93-7.89(m,1H),7.75(dd,J=6. 3,1.7Hz,2H),7.55(dp,J=7.8,2.7Hz,6H),7.48(d,J=2.4Hz,1H),6.23(s,1H),2.43(s,3H).

[0133] Example 38. Preparation of compound A38. The preparation steps are different from those of A1 in that in step VIII, 4,5-difluorobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain white solid A38 in a yield of 9.4%.

[0134] 1 H NMR (400MHz, Chloroform-d) δ10.79 (s, 1H), 8.77-8.67 (m, 2H), 8.58 (ddd, J = 23.4, 7.2, 1.7Hz, 2H), 8. 39(s,1H),8.20-8.09(m,2H),8.06(s,1H),8.02(s,1H),7.84-7.73(m,2H),5.63(s,2H),3.10(s,3H).

[0135] Example 39. Preparation of compound A39. The preparation steps differ from those of A1 in that in step VIII, 4,5-dichlorobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain white solid A39 in a yield of 9.2%.

[0136] 1 H NMR (600MHz, DMSO-d6) δ10.58(s,1H),8.20-8.17(m,2H),8.03(d,J=2.1Hz,1H),7.91(dd,J=7.6,1.3Hz,1 H),7.81(dd,J=8.4,2.1Hz,1H),7.76-7.73(m,3H),7.55(dd,J=5.2,1.9Hz,4H),6.23(s,1H),2.42(s,3H).

[0137] Example 40. Preparation of compound A40. The preparation steps are different from those of A1 in that in step VIII, 5,6-dichlorobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain white solid A40 in a yield of 8.2%.

[0138] 1H NMR (400MHz, DMSO-d6) δ10.57(s,1H),8.26-8.19(m,2H),7.90(dd,J=7.8,1.7Hz,2H),7.79(t,J=7.7 Hz,1H),7.68(dd,J=7.3,2.3Hz,1H),7.59-7.52(m,4H),7.41-7.35(m,2H),6.16(s,1H),2.43(s,3H).

[0139] Example 41. Preparation of compound A41. The preparation steps differ from those of A1 in that in step VIII, 3,5-dichlorobenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain white solid A41 in a yield of 8.6%.

[0140] 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.22-8.16(m,2H),7.94-7.89(m,1H),7.80(q,J=1.6 Hz,3H),7.75(dd,J=6.8,1.7Hz,2H),7.55(qd,J=4.3,2.7Hz,4H),6.23(s,1H),2.42(s,3H).

[0141] Example 42. Preparation of compound A42. The difference from the preparation of A20 is that in step VIII, 2,6-difluorobenzoyl chloride is used as the raw material to prepare the 10a derivative, which is then reacted with compound 14 to obtain white solid A42 with a yield of 7.5%.

[0142] 1 H NMR (600MHz, DMSO-d6) δ10.79(s,1H),8.25-8.21(m,2H),7.90(ddd,J=13.3,7.9,1.5Hz,2H),7.79(td,J=7.8,1.6Hz,1H),7.59- 7.52(m,4H),7.47(ddd,J=8.6,6.7,1.9Hz,1H),7.10(t,J=8.1Hz,2H),6.14(s,1H),2.68(d,J=7.6Hz,2H),1.12(t,J=7.5Hz,3H).

[0143] Example 43. Preparation of compound A43. The preparation steps differ from those of A1 in that in step VIII, 4-p-ethoxybenzoyl chloride is used as the starting material to prepare derivative 10a, which is then reacted with compound 7 to obtain white solid A43 in a yield of 8.4%.

[0144] 1 H NMR(600MHz,DMSO-d6)δ10.23(s,1H),8.22-8.16(m,2H),7.87(dd,J=7.8,1 .5Hz,1H),7.85-7.82(m,2H),7.77-7.75(m,1H),7.73(dd,J=7.2,1.5Hz,1H ),7.55(dd,J=5.1,2.0Hz,3H),7.50(dd,J=7.5,1.7Hz,1H),6.97-6.93(m,2 H), 6.22 (s, 1H), 4.03 (d, J = 7.0Hz, 2H), 2.42 (s, 3H), 1.30 (t, J = 7.0Hz, 3H).

[0145] Example 44. Preparation of compound D1. The synthetic route is the same as the preparation route of the compound of formula II. Compound 23b is obtained by reacting 19a as the starting material through four steps, and then reacted with 26 to obtain the final product D1 with a yield of 4.8%.

[0146] 1 H NMR(600MHz,DMSO-d6)δ10.24(s,1H),8.10-8.06(m,2H),7.88-7.83(m,3H),7.76-7.71(m,2H),7.49(d, J=1.7Hz,1H),7.36-7.33(m,2H),6.98-6.95(m,2H),6.20(s,1H),3.76(s,3H),2.41(s,3H),2.38(s,3H).

[0147] Example 45. Preparation of compound D2. The synthetic route is the same as the preparation route of the compound of formula II. Compound 23b is obtained by reacting 19b in 4 steps, and then reacting with 26 to obtain the final product D2 with a yield of 4.5%.

[0148] 1 H NMR(600MHz,DMSO-d6)δ10.24(s,1H),8.22-8.16(m,2H),7.88-7.83(m,3H),7.76-7.71(m,2H), 7.63-7.59(m,2H),7.51-7.47(m,1H),6.99-6.94(m,2H),6.23(s,1H),3.76(s,3H),2.42(s,3H).

[0149] Example 46. Preparation of compound AD3. The synthetic route is the same as that of the compound of formula II. Compound 23c is obtained from 19c through four steps of reaction, and then reacted with 26 to obtain the final product D3 with a yield of 4.7%.

[0150] 1 H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.27-8.19(m,2H),7.89-7.82(m,3H),7.78-7.70(m,2H),7.49(dd d,J=7.9,7.0,1.9Hz,1H),7.41-7.34(m,2H),7.02-6.94(m,2H),6.23(s,1H),3.77(s,3H),2.42(s,3H).

[0151] Example 47. Preparation of compound D4. The synthetic route is the same as the preparation route of the compound of formula II. Compound 23d is obtained by reacting 19d as the starting material through four steps, and then reacted with 26 to obtain the final product D4 with a yield of 5.4%.

[0152] 1 H NMR(400MHz, DMSO-d6)δ10.23(s,1H),8.16(td,J=7.7,1.8Hz,1H),7.90-7.82(m,3H),7.78-7.69(m,2H),7.62-7.56(m ,1H),7.49(ddd,J=8.8,7.0,1.9Hz,1H),7.43-7.36(m,2H),7.00-6.94(m,2H),6.23(s,1H),3.77(s,3H),2.43(s,3H).

[0153] Example 48. Preparation of compound D5. The synthetic route is the same as the preparation route of the compound of formula II. Compound 23e is obtained by reacting 19e as the starting material through four steps, and then reacted with 26 to obtain the final product D5 with a yield of 5.9%.

[0154] 1 H NMR(400MHz, DMSO-d6)δ10.23(s,1H),8.04(dt,J=7.8,1.2Hz,1H),7.90-7.83(m,4H),7.78-7.70(m,2H),7.61(td,J=8.1,5 .9Hz,1H),7.50(ddd,J=7.8,6.9,2.0Hz,1H),7.43-7.37(m,1H),7.01-6.94(m,2H),6.26(s,1H),3.77(s,3H),2.43(s,3H).

[0155] Example 49. Preparation of compound D6. The synthetic route is the same as the preparation route of the compound of formula II. Compound 23f is obtained by reacting 19f in 4 steps, and then reacting with 26 to obtain the final product D6 with a yield of 4.9%.

[0156] 1 H NMR (600MHz, DMSO-d6) δ10.23(s,1H),8.15-8.09(m,2H),7.89-7.83(m,3H),7.78-7.70(m,2H),7.49(td,J= 7.5,1.6Hz,1H),7.11-7.07(m,2H),7.00-6.95(m,2H),6.18(s,1H),3.83(s,3H),3.77(s,3H),2.40(s,3H).

[0157] Example 50. Preparation of compound D7. The synthetic route is the same as the preparation route of the compound of formula II. 19g is used as the raw material and compound 23g is obtained through 4 steps of reaction. It is then reacted with 26 to obtain the final product D7 with a yield of 4.5%.

[0158] 1 H NMR (600MHz, DMSO-d6) δ10.26(s,1H),7.88(dd,J=7.7,1.5Hz,1H),7.87-7.81(m,3H),7.77-7.71(m,2H),7.50(tdd,J=7.5,4.1,1.8Hz ,2H),7.19(dd,J=8.5,1.0Hz,1H),7.08(td,J=7.5,1.0Hz,1H),7.00-6.95(m,2H),6.20(s,1H),3.82(s,3H),3.77(s,3H),2.41(s,3H).

[0159] Example 51. Preparation of compound D8. The synthetic route is the same as the preparation route of the compound of formula II. Compound 23h is obtained by reacting 19h as the starting material through 4 steps, and then reacted with 26 to obtain the final product D8 with a yield of 4.5%.

[0160] 1H NMR (400MHz, DMSO-d6) δ10.22(s,1H),8.28(t,J=1.8Hz,1H),8.18(dt,J=7.8,1.2Hz,1H),7.89-7.82(m ,3H),7.78-7.70(m,3H),7.54-7.48(m,2H),7.00-6.94(m,2H),6.26(s,1H),3.77(s,3H),2.43(s,3H).

[0161] Example 52. Preparation of compound D9. The synthetic route is the same as the preparation route of the compound of formula II. Compound 23i is obtained by reacting 19i as the starting material through four steps, and then reacted with 26 to obtain the final product D9 with a yield of 4.5%.

[0162] 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),7.96(dd,J=7.5,2.0Hz,1H),7.88(dd,J=7.8,1.4Hz,1H),7.86-7.81(m,2H),7.78-7.71(m, 2H),7.64(dd,J=7.8,1.5Hz,1H),7.58-7.53(m,1H),7.53-7.47(m,2H),7.00-6.95(m,2H),6.28(s,1H),3.78(s,3H),2.44(s,3H).

[0163] Example 53. Preparation of compound D10. The synthetic route is the same as the preparation route of the compound of formula II. Compound 23j is obtained by reacting 19j as the starting material through 4 steps, and then reacted with 26 to obtain the final product D10 with a yield of 5.1%.

[0164] 1 H NMR (400MHz, CDCl3) δ8.80(s,1H),8.72(dd,J=8.4,1.3Hz,1H),8.38(d,J=1.9Hz,1H),8.26(dt,J=7.0,1.7Hz,1H),7.75-7.72(m,2H ),7.71-7.68(m,2H),7.48-7.42(m,2H),7.31(td,J=7.6,1.4Hz,1H),6.86(d,J=8.9Hz,2H),6.17(s,1H),3.78(s,3H),2.51(s,3H).

[0165] Example 54. Preparation of compound D11. The synthetic route is the same as the preparation route of the compound of formula II. Compound 23k is obtained by reacting 19k as the starting material through four steps, and then reacted with 26 to obtain the final product D11 with a yield of 5.3%.

[0166] 1 H NMR(400MHz, DMSO-d6)δ10.22(s,1H),7.93(dd,J=1.8,0.8Hz,1H),7.88-7.82(m,3H),7.78-7.70(m,2H),7.53-7.46(m, 1H),7.23(dd,J=3.4,0.8Hz,1H),7.02-6.94(m,2H),6.71(dd,J=3.4,1.8Hz,1H),6.21(s,1H),3.77(s,3H),2.41(s,3H).

[0167] Example 55. Preparation of compound D12. The synthetic route is the same as the preparation route of the compound of formula II. Compound 231 is obtained by reacting 191 in 4 steps, and then reacted with 26 to obtain the final product D12 with a yield of 6.2%.

[0168] 1 H NMR (600MHz, DMSO-d6) δ10.31(s,1H),8.09-8.06(m,2H),7.87(dd,J=7.8,1.5Hz,1H),7.77-7.71(m,4H),7.50(td,J=7 .5,1.7Hz,1H),7.35(dd,J=8.3,2.2Hz,2H),7.24(d,J=8.1Hz,2H),6.19(s,1H),2.41(s,3H),2.38(s,3H),2.30(s,3H).

[0169] Example 56. Preparation of Compound AB1. The synthetic route is the same as that of the compound of formula III, wherein the synthetic steps of compound 7 are the same as those of A1. The final reaction step is the same as A1, where 2-naphthalenethiol (29) reacts with compound 7 to obtain orange solid AB1 with a yield of 34%.

[0170] 1H NMR(600MHz,Chloroform-d)δ8.43-8.40(m,2H),8.30(d,J=1.8Hz,1H),8.04(d,J=8.6Hz,1H),8.00-7. 97(m,1H),7.95(dd,J=8.0,1.3Hz,1H),7.70-7.63(m,3H),7.53-7.49(m,3H),6.09(s,1H),2.45(s,3H).

[0171] Example 57. Preparation of Compound AB2. The synthetic route is the same as that for the compound of formula III, wherein the synthetic steps of compound 7 are the same as those of A1. The final reaction step is the same as A1, where benzothiazole-2-thiol (30) reacts with compound 7 to obtain solid product AB2 in a yield of 38%.

[0172] 1 H NMR (400MHz, DMSO-d6) δ8.27-8.23(m,1H),8.21-8.15(m,3H),7.67-7.58(m,2H),7.58-7.53(m,3H),7.24(s,1H),2.57(s,3H).

[0173] Example 58. Preparation of Compound AB3. The synthetic route is the same as that for the compound of formula III, wherein the synthetic steps for compound 7 are the same as those for A1. The final reaction step is the same as that for A1, where 1-phenyl-5-mercaptotetrazole (31) reacts with compound 7 to obtain solid product AB3 in a yield of 31%.

[0174] 1 H NMR (400MHz, DMSO-d6) δ8.10 (ddd, J=6.1, 2.4, 1.5Hz, 2H), 7.83-7.77 (m, 2H), 7.62(tt,J=4.2,2.9Hz,3H),7.54(h,J=2.8Hz,3H),7.12(s,1H),2.55(s,3H).

[0175] Example 59. Preparation of compound AB4. The synthetic route is the same as that of the compound of formula III, wherein the synthetic steps of compound 7 are the same as those of A1, and AB4 is a white solid with a yield of 21%.

[0176] 1 H NMR (600MHz, DMSO-d6) δ8.16-8.13(m,2H),8.11-8.08(m,2H),7.72-7.69(m,1H),7.68-7.64(m,2H),7.54-7.48(m,3H),7.38(s,1H),2.58(s,3H).

[0177] The compound structures are shown in Tables 1 to 3.

[0178] Table 1 Structure of compounds of formula I

[0179]

[0180]

[0181]

[0182] Table 2 Structure of compound of formula II

[0183]

[0184]

[0185] Table 3 Structure of compound of formula III

[0186]

[0187] Effect verification example

[0188] Luciferase reporter gene assay system. 190 μL of THP-1-luc cells in good condition were plated at 5×10 5 THP-1-luc cells were plated evenly at a density of 10 μg / well in a 96-well plate and subjected to various treatments: an activation control group treated with c-di-GMP (final c-di-GMP concentration of 10 μg / mL); an experimental group treated with c-di-GMP and a test compound (final c-di-GMP concentration of 10 μg / mL and test compound concentration of 5 μM); and a blank control group treated without c-di-GMP or a test compound. Each group contained an equal amount of DMSO (solvent) to a final concentration of 0.1 vol.%. The cells were then incubated at 37°C, 5% CO₂ for 48 hours. 10 μL of supernatant was then removed from each well and applied to the opaque white plate of a 96-well plate for luciferase activity analysis. The microplate reader was programmed as follows: 50 μL injection per well, 4-second start time, and 0.1-second read time. The IC50 value was measured, and the concentration gradient of the compound was 20.0 μM, 10.0 μM, 5.0 μM, 2.5 μM, 1.25 μM, 0.625 μM, and 0.3125 μM. The inhibition rate was measured and the IC50 was calculated.

[0189] The inhibitory activity data of each compound on STING protein in THP1-Dual cells are shown in Table 4 and Figure 1-Figure 3 .

[0190] Table 4 IC50 of some compounds

[0191]

[0192]

[0193] Among the 59 compounds prepared in the examples of the present invention, A8, A9, A10, A11, A12, A14, A16, A24, A32, A34, and D1 have good inhibitory activity on the activation of STING protein (Table 4), among which A24 has the best activity.

[0194] The embodiments described above are merely descriptions of preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Without departing from the spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should fall within the scope of protection determined by the claims of the present invention.

Claims

1. A use of a benzopyrimidine sulfide compound in the preparation of a drug for inhibiting activation of the STING signaling pathway, characterized in that: The compound has a structure shown in Formula I, Formula II or Formula III: Formula I; Formula II; Formula III; Wherein, R1 is selected from any one of the following: ； L1 is selected from any one of the following: H, -CH3, -CH2CH3; R2 is selected from any one of the following: ； R3 is selected from any of the following: 。 2. Use of a benzopyrimidine sulfide compound in the preparation of a drug for treating or preventing STING-mediated diseases, characterized in that: The compound has a structure shown in Formula I, Formula II or Formula III: Formula I; Formula II; Formula III; Wherein, R1 is selected from any one of the following: ； L1 is selected from any one of the following: H, -CH3, -CH2CH3; R2 is selected from any one of the following: ； R3 is selected from any of the following: 。 3. The use according to claim 2, characterized in that The disease is an autoimmune disease or an inflammatory disease.

4. The use according to claim 3, characterized in that Such diseases include STING-associated vasculopathy, Parkinson's disease, systemic lupus erythematosus, or non-alcoholic fatty liver disease.

5. A pharmaceutical composition for preventing or treating a STING-mediated disease, characterized in that: A benzopyrimidine sulfide compound containing a structure represented by formula I, formula II or formula III as an active ingredient: Formula I; Formula II; Formula III; Wherein, R1 is selected from any one of the following: ； L1 is selected from any one of the following: H, -CH3, -CH2CH3; R2 is selected from any one of the following: ； R3 is selected from any of the following: 。

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