An arylsulfonyl-substituted thiazole amide compound, a preparation method and application thereof

Abstract

The application provides an arylsulfonyl-substituted thiazole amide compound and a preparation method and application thereof. The compound has an arylsulfonyl-substituted thiazole amide skeleton of 'left aryl-sulfonyl-thiazole core-right amide side chain', can exhibit good anti-HBV activity, has more prominent cell level anti-HBV activity, and exhibits more definite HBV capsid assembly regulation characteristics. The arylsulfonyl-substituted thiazole amide new skeleton adopted in the application has shown activity optimization potential superior to that of a known structure related to a comparison patent and more definite capsid regulation characteristics under existing experimental conditions, and has great application potential in the field of HBV capsid protein modulators.

Description

Technical Field

[0001] This invention belongs to the field of compound pharmaceuticals, specifically relating to an arylsulfonyl-substituted thiazolidinyl compound, its preparation method, and its application. Background Technology

[0002] Hepatitis B virus (HBV) infection is a serious public health problem worldwide. Current clinical treatments mainly include nucleoside (acid) analogs and interferon. While these can inhibit viral replication and slow disease progression to some extent, they still have significant limitations in reducing viral antigen levels, minimizing relapse after drug withdrawal, and achieving functional cure. Therefore, developing novel anti-HBV drugs with novel mechanisms of action remains of great importance. HBV core proteins play a crucial role in viral nucleocapsid assembly, pregenomic RNA (pgRNA) encapsulation, and viral replication, and have thus become one of the important targets for anti-HBV drug development in recent years.

[0003] HBV capsid assembly modulators (CAMs) represent an important new class of anti-HBV drug candidates. Existing research indicates that these compounds typically interfere with the normal assembly kinetics of the viral capsid by binding to the dimer-dimer interface pocket of the HBV core protein, thereby inhibiting pgRNA encapsulation, reverse transcription, and subsequent viral replication. Compared to traditional polymerase inhibitors, CAMs offer advantages in their different mechanisms of action, making them an important direction for achieving combination therapy and improving antiviral efficacy.

[0004] HBV capsid protein modulators, such as NZ-4, which contain thiazole structural units, have been reported to possess certain anti-HBV activity. Studies have shown that these compounds can inhibit HBV DNA replication by interfering with pgRNA encapsulation and inducing abnormal capsid formation. However, the overall antiviral activity of these compounds still needs further improvement, and their structure-activity relationship studies are not yet systematic and in-depth. Therefore, it is necessary to further optimize and modify the relevant backbones based on existing research in order to obtain novel HBV capsid protein modulators with higher activity and better selectivity. Summary of the Invention

[0005] To overcome the problems existing in the prior art, one objective of the present invention is to provide an arylsulfonyl-substituted thiazolamide compound. A second objective of the present invention is to provide a method for preparing the above-mentioned arylsulfonyl-substituted thiazolamide compound. A third objective of the present invention is to provide applications of the above-mentioned arylsulfonyl-substituted thiazolamide compound.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: The first aspect of this invention provides an arylsulfonyl-substituted thiazolamide compound, the structural formula of which is shown in Formula A: Formula A; Among them, the five-membered ring containing X1, X2 and X3 is a thiazole ring, and X1, X2 and X3 are independently selected from N, S or CR3 respectively; in the thiazole ring, the number of S atoms is 1, and the number of N atoms is 1 or 2; R1 is a substituted or unsubstituted C6-C60 aryl group or a substituted or unsubstituted C5-C60 heteroaryl group; R2 is a substituted or unsubstituted C1-C40 alkyl, a substituted or unsubstituted C1-C40 heteroalkyl, a substituted or unsubstituted C2-C40 alkenyl, a substituted or unsubstituted C2-C40 alkynyl, a substituted or unsubstituted C3-C40 cycloalkyl, a substituted or unsubstituted C3-C40 heterocycloalkyl, a substituted or unsubstituted C6-C60 aryl, a substituted or unsubstituted C5-C60 heteroaryl, a substituted or unsubstituted C1-C40 alkoxy, or a substituted or unsubstituted C6-C60 aryloxy. R3 is hydrogen, deuterium, halogen, cyano, nitro, substituted or unsubstituted C1-C40 alkyl, or substituted or unsubstituted C3-C40 heterocyclic alkyl. The substitutions of R1, R2, and R3 are independently deuterated, halogenated, cyano, isocyanate, phosphine, hydroxyl, or C1. C6 alkyl, C1-C6 alkoxy, C3 C16 cycloalkyl, C1 C6 alkyl-substituted amino group, C1 C6 hydrocarbon group substituted or unsubstituted C6 C30 aryl, halogen-substituted C6 C30 aryl, C1 C6 hydrocarbon group substituted or unsubstituted C3 At least one of the C30 heteroaryl groups is substituted, wherein the number of substitutions ranges from monosubstituted to the maximum number of substitutions.

[0007] Preferably, the structural formulas of the arylsulfonyl-substituted thiazolidinyl compounds are shown in Formulas I-IV: .

[0008] Preferably, R1 is a substituted or unsubstituted phenyl group or a substituted or unsubstituted C5-C10 heteroaryl group; The substitution of R1 is independently of halogenated C1. The substituted substance is at least one of C6 alkyl or C1-C6 alkoxy groups, wherein the number of substitutions ranges from monosubstituted to the maximum number of substitutions.

[0009] Preferably, R2 is a substituted or unsubstituted C1-C15 alkyl, a substituted or unsubstituted C2-C15 alkynyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C3-C8 heterocycloalkyl, or a substituted or unsubstituted C6-C10 aryl. The substitution of R2 is independently determined by halogen, hydroxyl group, or C1. C6 alkyl, cyano, halogen-substituted C6 C10 aryl, C3 At least one of the C8 cycloalkyl groups is substituted, wherein the number of substitutions ranges from monosubstituted to the maximum number of substitutions.

[0010] More preferably, R2 is a substituted or unsubstituted C1-C10 alkyl, a substituted or unsubstituted C2-C10 alkynyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C3-C6 heterocycloalkyl, a substituted or unsubstituted phenyl, The substitution of R2 is independently determined by halogen, hydroxyl group, or C1. C6 alkyl, cyano, halogen-substituted phenyl, C3 At least one of the C8 cycloalkyl groups is substituted, wherein the number of substitutions ranges from monosubstituted to the maximum number of substitutions.

[0011] Preferably, R3 is a C1-C6 alkyl or a C3-C10 heterocyclic alkyl.

[0012] More preferably, R3 is methyl, isopropyl, isobutyl, or morpholine.

[0013] A second aspect of this invention provides a method for preparing the arylsulfonyl-substituted thiazole amide compounds described in the first aspect, comprising the following steps: The arylsulfonyl-substituted thiazole compounds are prepared by reacting sulfonyl-substituted thiazole amide compounds with amine compounds; The structural formulas of the sulfonyl-substituted thiazole compounds and the amine compounds are shown in Formula 5 and Formula 6, respectively: Formula 5 Formula 6; The definitions of X1, X2, X3, R1, R2, and R3 are as described in the first aspect.

[0014] Preferably, the preparation method of the sulfonyl-substituted thiazole compound includes the following steps: Thiazole carboxylic acid esters undergo nucleophilic substitution reactions with substituted thiophenols to generate the corresponding thioether intermediates; these intermediates are then oxidized to obtain sulfone intermediates; subsequently, they are hydrolyzed to carboxylic acids to prepare the sulfonyl-substituted thiazole compounds. The structural formulas of the thiazole carboxylic acid esters, substituted thiophenols, thioether intermediates, and sulfone intermediates are shown in Formulas 1-4, respectively: Formula 1 Formula 2 Formula 3 Formula 4.

[0015] The third aspect of the present invention provides the use of the arylsulfonyl-substituted thiazolidinamide compounds described in the first aspect in the preparation of medicaments for the prevention or treatment of hepatitis B virus infection.

[0016] Preferably, the drug is a hepatitis B virus capsid assembly modulator.

[0017] Preferably, the medicament comprises an arylsulfonyl-substituted thiazolidinyl compound in combination with one or more other therapeutic agents. Examples include HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators such as Toll-like receptor (TLR) modulators, interferon α receptor ligands, hyaluronidase inhibitors, hepatitis B surface antigen (HBsAg) inhibitors, cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors, cyclic protein inhibitors, HBV viral entry inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductase inhibitors, and HBV... E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesol X receptor agonists, HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein regulators, retinoic acid-induced gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2,3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin α-1, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginase inhibitors, and other HBV drugs.

[0018] The beneficial effects of this invention are: This invention provides an arylsulfonyl-substituted thiazolamide compound. Based on the lead compound isothiofuridine (NZ-4), the skeleton is reconstructed, retaining the key activity-related feature of a "heterocyclic core-amide side chain," while introducing an arylsulfonyl linker to construct a novel arylsulfonyl-substituted thiazolamide skeleton with a "left-end aryl-sulfonyl-thiazolium core-right-end amide side chain." This structure differs from existing chiral aromatic heteroamine frameworks not only in the type of core skeleton but also in the linker mode, substitution site design, and subsequent optimization potential, representing a novel structural design approach.

[0019] From an antiviral application perspective, the compounds in this application exhibit good anti-HBV activity even at lower test concentrations. In the HepAD38 cell model, at 5 μM, XJM1018 inhibited HBV DNA replication by 77.16±0.31%, while WG1080 and WG3003 achieved inhibition rates of 84.86±0.08% and 82.69±0.21%, respectively, both significantly higher than the lead compound NZ-4's 35.30±0.10%. Simultaneously, the representative compounds significantly enhanced the capsid assembly band in a concentration-dependent manner. The capsid band of XJM1018 at 5 μM was also stronger than that of NZ-4 at the same concentration, suggesting that the compounds in this application not only possess more prominent cellular-level anti-HBV activity but also exhibit more defined HBV capsid assembly regulation characteristics. The novel arylsulfonyl-substituted thiazolamide backbone used in this application has shown superior activity optimization potential and more defined capsid regulation characteristics compared to known structures in the relevant comparative patents under existing experimental conditions. Detailed Implementation

[0020] The present invention will be further described in detail below through specific embodiments. Unless otherwise specified, the raw materials used in the following embodiments can be obtained from conventional commercial channels or prepared and isolated through simple synthesis; unless otherwise specified, the processes employed are conventional processes in the art.

[0021] Example 1 This embodiment provides an arylsulfonyl-substituted thiazolidinyl amide compound, specifically... N -(4-fluorophenyl)-2-[(4-fluorophenyl)sulfonyl]thiazole-4-carboxamide (XJM1018), the specific preparation equation and method are as follows:

[0022] Ethyl 2-chlorothiazol-4-carboxylic acid ester (9) (1.20 g, 5.08 mmol, 1.0 eq) was dissolved in anhydrous ethanol (70 mL). 4-fluorothiophenol (1.47 g, 10.16 mmol, 2.0 eq) was added at 0 °C, and the mixture was stirred for 30 min. Then, sodium ethoxide (0.76 g, 10.16 mmol, 2.0 eq) was added, and the mixture was stirred at room temperature for another 6 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with dichloromethane (2 x 200 mL). The combined organic phases were washed successively with water (2 x 100 mL) and saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography [petroleum ether / ethyl acetate = 10:1] to give 1.39 g of ethyl 2-[(4-fluorophenyl)thio]thiazole-4-carboxylic acid ester XJM1014, a white solid, in 97% yield. ¹H NMR (500 MHz, CDCl3) δ 7.98 (s, 1H), 7.71–7.55 (m, 2H), 7.16 (t) J = 8.5 Hz, 2H), 4.41 (q, J = 7.1 Hz, 2H), 1.40 (t, J =7.2 Hz, 3H). XJM1014 (1.20 g, 5.08 mmol, 1.0 eq) was dissolved in dichloromethane (25 mL), and m-chloroperoxybenzoic acid (mCPBA) (1.30 g, 10.16 mmol, 2.0 eq) was added at 0 °C, followed by stirring overnight at room temperature. After the reaction was complete, the reaction system was diluted with dichloromethane (300 mL), and then washed successively with Na2S2O3 aqueous solution (200 mL), NaHCO3 aqueous solution (200 mL), and saturated brine (30 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography [petroleum ether / ethyl acetate = 5:1] to give 1.30 g of ethyl 2-[(4-fluorophenyl)sulfonyl]thiazole-4-carboxylic acid ester XJM1015. ¹H NMR (500 MHz, CDCl3) δ 8.39 (s, 1H), 8.24 – 8.08 (m, 2H), 7.25 (d, J = 8.6 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H). XJM1015 (1.30 g, 4.10 mmol, 1.0 eq) was dissolved in a mixed solvent of methanol (20 mL) and tetrahydrofuran (5 mL), and NaOH (493 mg, 12.3 mmol, 3.0 eq) dissolved in water (5 mL) was added. The mixture was stirred at room temperature for 3 h. After removing most of the methanol under reduced pressure, the pH of the system was adjusted to 3-4 with a 2 mol / L HCl aqueous solution at 0 °C, resulting in the precipitation of a white precipitate. The precipitate was filtered and dried under vacuum to obtain 2-[(4-fluorophenyl)sulfonyl]thiazole-4-carboxylic acid XJM1017.

[0023] XJM1017 (100 mg, 0.34 mmol, 1.0 eq) and 4-fluoroaniline (41a) (50 mg, 0.45 mmol, 1.3 eq) were dissolved in dichloromethane (15 mL). HBTU (264 mg, 0.69 mmol, 2.0 eq) and DIPEA (90 mg, 0.69 mmol, 2.0 eq) were added sequentially at 0°C, followed by stirring overnight at room temperature. The reaction mixture was extracted with dichloromethane (2 x 50 mL), and the combined organic phases were washed sequentially with water (2 x 50 mL) and saturated brine (20 mL), and dried over anhydrous Na₂SO₄. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography [petroleum ether / ethyl acetate = 5:1] to give the target compound XJM1018 (124 mg, 84.5%). HPLC purity 98.2% ( t R = 7.4 min). ¹HNMR (500 MHz, CDCl3) δ 8.88 (s, 1H), 8.50 (s, 1H), 8.19 – 8.11 (m, 2H), 7.71– 7.55 (m, 2H), 7.34 – 7.25 (m, 2H), 7.07 (t, J = 8.6 Hz, 2H). 13 C NMR (151 MHz, CDCl3) 167.0, 166.7 (d, J = 258.2 Hz), 159.9 (d, J = 244.6 Hz), 157.4, 152.2,134.3 (d, J = 3.0 Hz), 133.1 (d, J = 3.0 Hz), 131.9 (d, J= 10.1 Hz, 2C), 130.3,122.1 (d, J = 7.8 Hz, 2C), 117.4 (d, J = 22.9 Hz, 2C), 116.0 (d, J = 22.7 Hz, 2C). Example 2 This embodiment provides an arylsulfonyl-substituted thiazolidinyl amide compound, specifically... N -(3,4-Difluorophenyl)-2-[(4-fluorophenyl)sulfonyl]thiazole-4-carboxamide (XJM1022), the specific preparation equation and method are as follows:

[0024] An amidation reaction was carried out using intermediate XJM1017 and 3,4-difluoroaniline as starting materials. After separation and purification, the target compound XJM1022 was obtained as a white solid with a yield of 80.7% (108 mg). HPLC purity: 97.1%. t R = 7.9 min). 1 HNMR (500 MHz, CDCl3) 1 H NMR (500 MHz, CDCl3) δ 8.89 (s, 1H), 8.51 (s, 1H), 8.19– 8.11 (m, 2H), 7.79 – 7.75 (m, 1H), 7.34 – 7.22 (m, 3H), 7.20 – 7.11 (m,1H). 13 C NMR (126 MHz, CDCl3) δ 167.1, 166.6 (d, J = 259.6 Hz), 157.3, 151.7,150.2 (dd, J = 241.9, 13.9 Hz), 147.5 (dd, J = 247.0, 12.6 Hz) 134.2, 133.5,131.8 (d, J = 9.9 Hz, 2C), 130.4, 117.6 – 117.4 (m, 2C), 117.2, 115.0 – 115.8(m), 109.9 (d, J = 21.9 Hz). Example 3 This embodiment provides an arylsulfonyl-substituted thiazolidinyl amide compound, specifically...N -(4-fluoro-3-methylphenyl)-2-[(4-fluorophenyl)sulfonyl]thiazole-4-carboxamide (XJM1023), the specific preparation equation and method are as follows:

[0025] An amidation reaction was carried out using intermediate XJM1017 and 4-fluoro-3-methylaniline as starting materials. After separation and purification, the target compound XJM1023 was obtained as a white solid, with a yield of 91.5% (114 mg). HPLC purity: 98.2%. t R = 8.3 min). 1 H NMR (500 MHz, CDCl3) δ 8.74 (s, 1H), 8.42 (d, J = 2.0 Hz, 1H), 8.09 – 8.06(m, 2H), 7.44 (dd, J = 6.8, 2.7 Hz, 1H), 7.36 – 7.33 (m, 1H), 7.24 – 7.18 (m,2H), 6.92 (t, J = 9.0 Hz, 1H), 2.22 (d, J = 2.1 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ166.9, 166.5 (d, J = 259.6 Hz), 158.4 (d, J = 244.4 Hz), 157.2, 152.2, 134.2,132.6 (d, J = 3.1 Hz), 131.8 (d, J = 9.9 Hz, 2C), 130.0, 125.6, 123.3 (d, J = 5.0Hz), 119.2 (d, J = 7.8 Hz), 117.3 (d, J = 22.9 Hz, 2C), 115.4 (d, J = 23.6 Hz), 14.7 (d, J = 3.3 Hz). Example 4 This embodiment provides an arylsulfonyl-substituted thiazolidinyl amide compound, specifically... N-(3-cyano-4-fluorophenyl)-2-[(4-fluorophenyl)sulfonyl]thiazole-4-carboxamide (XJM1020), the specific preparation equation and method are as follows:

[0026] An amidation reaction was carried out using intermediate XJM1017 and 5-amino-2-fluorobenzonitrile as starting materials. After separation and purification, the target compound XJM1020 was obtained as a white solid with a yield of 94.9% (157 mg). HPLC purity: 97.5% ( t R = 7.1min).¹H NMR (500 MHz, CDCl3) δ 8.54 (s, 1H), 8.11 – 8.07 (m, 3H), 7.88 – 7.86(m, 1H), 7.28 – 7.23 (m, 3H), 7.18 (t, J = 8.7 Hz, 1H). 13 C NMR (151 MHz, CDCl3)δ 167.5, 166.7 (d, J = 237 Hz), 160.0 (d, J = 258 Hz), 157.6, 151.3, 134.2,134.0, 132.0 (d, J = 9.8 Hz, 2C), 131.0, 126.6 (d, J = 7.8 Hz), 124.5, 117.5 (d, J = 22.9 Hz, 2C), 117.3 (d, J = 20.8 Hz), 113.6, 102.1 (d, J = 16.9 Hz). Example 5 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 2-[(4-fluorophenyl)sulfonyl]-N-(3,4,5-trifluorophenyl)thiazol-4-carboxamide (XJM1029), and its preparation equation and method are as follows:

[0027] The intermediate XJM1017 and 3,4,5-trifluoroaniline were used as starting materials for an amidation reaction. After separation and purification, the target compound XJM1029 was obtained as a white solid with a yield of 84.5% (120 mg). HPLC purity: 97.5% ( tR = 7.1 min). 1 H NMR (500 MHz, CDCl3)δ 9.20 (s, 1H), 8.47 (s, 1H), 8.08 – 8.05 (m, 2H), 7.42 – 7.35 (m, 2H), 7.24 – 7.19 (m, 2H). Example 6 This embodiment provides an arylsulfonyl-substituted thiazolidinyl amide compound, specifically... N -(3-fluorophenyl)-2-[(4-fluorophenyl)sulfonyl]thiazole-4-carboxamide (XJM1034), the specific preparation equation and method are as follows:

[0028] An amidation reaction was carried out using intermediate XJM1017 and 3-fluoroaniline as starting materials. After separation and purification, the target compound XJM1034 was obtained as a white solid, with a yield of 84.6% (83 mg). HPLC purity: 99.5%. t R = 9.0 min). ¹H NMR(500 MHz, CDCl3) δ 8.33 (s, 1H), 8.14 – 7.97 (m, 2H), 7.43 (s, 1H), 7.45 –7.30 (m, 3H) 7.28 – 7.16 (m, 2H), 6.98 – 6.85 (m, 1H). 13 C NMR (151 MHz, CDCl3)δ 167.0,166.5 (d, J = 259.7 Hz), 163.0 (d, J = 246.1 Hz), 157.3, 151.9, 138.4(d, J = 10.8 Hz), 134.2 (d, J = 3.1 Hz), 131.8 (d, J = 10.0 Hz, 2C), 130.4 –130.2 (m), 117.3 (d, J = 23.0 Hz, 2C), 115.4 (d, J = 3.1 Hz), 111.9, 107.7. Example 7 This embodiment provides an arylsulfonyl-substituted thiazolidinyl amide compound, specifically... N-(4-fluorobenzyl)-2-[(4-fluorophenyl)sulfonyl]thiazole-4-carboxamide (XJM1019), the specific preparation equation and method are as follows:

[0029] The intermediate XJM1017 and 4-fluorobenzylamine were used as starting materials for an amidation reaction. After separation and purification, the target compound XJM1019 was obtained as a white solid, with a yield of 90.5% (140 mg). ¹H NMR (500 MHz, CDCl3) δ 8.43 (s, 1H), 8.09 (dd, J = 8.8, 5.0 Hz, 2H), 7.47 (t, J = 5.8 Hz, 1H), 7.30 (dd, J =8.4, 5.3 Hz, 2H), 7.26 (d, J = 4.2 Hz, 1H), 7.02 (t, J = 8.6 Hz, 2H), 4.57 (d, J = 6.2 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 166.8,166.5 (d, J = 264.6 Hz), 162.3(d, J = 252.2 Hz), 159.5, 152.0, 134.3 (d, J = 3.2 Hz), 133.4 (d, J = 3.3 Hz), 131.8 (d, J = 9.9 Hz, 2C), 129.9 – 129.2 (m, 3C), 117.2 (d, J = 22.8 Hz, 2C), 115.6 (2C), 42.8. Example 8 This embodiment provides an arylsulfonyl-substituted thiazolidinyl amide compound, specifically... N- The preparation equation and method for (tert-butyl)-2-[(4-fluorophenyl)sulfonyl]thiazole-4-carboxamide (XJM1032) are as follows:

[0030] An amidation reaction was performed using intermediate XJM1017 and tert-butylamine as starting materials. After separation and purification, the target compound XJM1032 was obtained as a white solid, with a yield of 93.7% (110 mg). HPLC purity: 99.4%. t R = 7.2 min). ¹H NMR(500 MHz, CDCl3) δ 8.27(d, J = 1.9 Hz, 1H), 8.15 – 8.10 (m, 2H), 7.30 – 7.25(m, 2H), 6.98 (s, 1H), 1.44 (d, J = 2.0 Hz, 9H). 13 C NMR (126 MHz, CDCl3) δ166.2, 166.4 (d, J = 252.1), 158.8, 153.4, 134.4 (d, J = 3.2 Hz), 131.8 (d, J =10.0 Hz, 2C), 128.8, 117.1 (d, J = 22.7 Hz, 2C), 51.8, 28.7 (3C). Example 9 This embodiment provides an arylsulfonyl-substituted thiazolidinyl amide compound, specifically 2-[(4-fluorophenyl)sulfonyl]- N -(3-methyloxetanebut-3-yl)thiazol-4-carboxamide (XJM1024), the specific preparation equation and method are as follows:

[0031] An amidation reaction was carried out using intermediate XJM1017 and 3-methyloxetane-3-amine as starting materials. After separation and purification, the target compound XJM1024 was obtained as a white solid with a yield of 97.3% (123 mg). HPLC purity: 99.9% ( t R = 6.3min). ¹H NMR (500 MHz, CDCl3) δ 8.39 (s, 1H), 8.14 – 8.08 (m, 2H), 7.51 (s,1H), 7.29 (d, J =8.5 Hz, 2H), 4.85 (d, J = 6.4 Hz, 2H), 4.54 (d, J= 6.5 Hz, 2H), 1.72 (s, 3H).

[0032] Example 10 This embodiment provides an arylsulfonyl-substituted thiazolidinyl amide compound, specifically (R)-2-[(4-fluorophenyl)sulfonyl]- N -(1,1,1-trifluoroprop-2-yl)thiazolyl-4-carboxamide (XJM1026), the specific preparation equation and method are as follows:

[0033] An amidation reaction was carried out using intermediate XJM1017 and (R)-1,1,1-trifluoropropane-2-amine as starting materials. After separation and purification, the target compound XJM1026 was obtained as a white solid, with a yield of 64.5% (77 mg). HPLC purity: 99.9%. t R = 6.3min). 1 H NMR (500 MHz, CDCl3) δ 8.39 (s, 1H), 8.15 – 7.99 (m, 2H), 7.24 – 7.18(m, 2H), 7.10 (d, J = 9.8 Hz, 1H), 4.79 – 4.73 (m, 1H), 1.37 (d, J = 7.1 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 167.2, 166.6 (d, J = 281.0 Hz), 159.1, 151.0,134.1, 131.8 (d, J = 10.0 Hz, 2C), 130.5, 125.1 (d, J = 264.6 Hz), 117.3 (d, J =22.8 Hz, 2C), 46.6 (q, J = 32.1 Hz), 14.3. Example 11 This embodiment provides an arylsulfonyl-substituted thiazole amide compound, specifically 2-[(4-fluorophenyl)sulfonyl]-N-(4-hydroxycyclohexyl)thiazole-4-carboxamide (XJM1027), and its preparation equation and method are as follows:

[0034] An amidation reaction was performed using intermediate XJM1017 and (1S,4S)-4-aminocyclohexanol as starting materials. After separation and purification, the target compound XJM1027 was obtained as a white solid, with a yield of 93.4% (120 mg). HPLC purity: 99.9%. t R = 6.7min). ¹H NMR(500 MHz, CDCl3) δ 8.32 (s, 1H), 8.08 – 8.04 (m, 2H), 7.21 (d, J =9.2 Hz, 2H), 7.05 (d, J = 8.4 Hz, 1H), 3.97 – 3.86 (m, 2H), 1.73 – 1.66 (m, 8H).. 13 C NMR (126 MHz, CDCl3) δ 166.6, 166.5 (d, J = 252.0 Hz), 158.7, 152.5,134.3, 131.8 (d, J = 10.0 Hz), 129.2, 117.2 (d, J = 22.9 Hz), 65.8, 47.3, 31.3(2C), 27.0 (2C). Example 12 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 2-[(4-chlorophenyl)sulfonyl]-N-(4-fluorophenyl)thiazol-4-carboxamide (XJM1012), and its preparation equation and method are as follows:

[0035] The synthesis of XJM1008–XJM1011 is similar to that of XJM1014–XJM1017, yielding 2-((4-chlorophenyl)thio)thiazole-4-carboxylic acid ethyl ester XJM1008 (1.5 g, 98.6%) as a white solid by reacting 2-chlorothiazol-4-carboxylic acid ethyl ester with 4-chlorobenzylthiophenol. ¹H NMR (500 MHz, CDCl3) δ 7.95 (s, 1H), 7.59 – 7.46 (m, 2H), 7.41 – 7.30 (m, 2H), 4.34 (q, J =7.1 Hz, 2H), 1.32 (s, J =7.1 Hz, 3H).

[0036] Following the synthetic method for compound XJM1018, an amidation reaction was carried out using intermediate XJM1011 and 4-fluoroaniline as raw materials. After separation and purification, the target compound XJM1012 was obtained as a white solid with a yield of 94.5% (144 mg). 1 H NMR (500MHz, CDCl3) δ 8.80 (s, 1H), 8.44 (s, 1H), 8.07 – 7.89 (m, 2H), 7.54 – 7.49(m, 2H), 7.00 (t, J = 8.6 Hz, 2H), 6.77 (s, 1H), 6.60 – 6.47 (m, 1H).¹³C NMR(151 MHz, CDCl3) δ 166.8, 159.9 (d, J = 245 Hz), 157.4, 152.3, 142.1, 136.7,133.1 (d, J = 2.8 Hz), 130.4, 130.3 (d, J = 2.4 Hz, 2C), 122.1 (d, J = 8.1 Hz, 2C), 116.2 (d, J = 7.5 Hz, 2C), 116.0 (d, J = 22.6 Hz, 2C). Example 13 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 2-[(4-chlorophenyl)sulfonyl]-N-(3,4-difluorophenyl)thiazol-4-carboxamide (XJM1031), and its preparation equation and method are as follows:

[0037] An amidation reaction was carried out using intermediate XJM1011 and 3,4-difluoroaniline as raw materials. After separation and purification, the target compound XJM1031 was obtained as a white solid with a yield of 87.4%. HPLC purity was 95.9%. t R = 9.0 min). 1 H NMR (500 MHz, CDCl3) δ 8.90 (s, 1H), 8.52 (s, 1H), 8.06 (d, J = 8.5 Hz, 2H), 7.79 –7.75 (m, 1H), 7.60 (d, J= 8.5 Hz, 2H), 7.26 (s, 1H), 7.19 – 7.13 (m, 1H). 13 CNMR (151 MHz, CDCl3) δ 167.0, 157.4, 151.9, 150.3 (dd, J = 240.1 Hz,13.6 Hz),147.6 (dd, J = 247.6, 12.8 Hz) 142.2, 136.7, 133.5 (d, J = 7.2 Hz), 130.7, 130.3 (d, J = 2.1 Hz, 2C), 117.6 (d, J = 18.2 Hz, 2C), 116.1 - 115.7 (m, 2C), 110.1(d, J = 21.9 Hz). Example 14 This embodiment provides an arylsulfonyl-substituted thiazole amide compound, specifically 2-[(4-chlorophenyl)sulfonyl]-N-(3,4,5-trifluorophenyl)thiazole-4-carboxamide (WG1034), and its preparation equation and method are as follows:

[0038] An amidation reaction was carried out using intermediate XJM1011 and 3,4,5-trifluoroaniline as starting materials. After separation and purification, the target compound WG1034 was obtained as a white solid with a yield of 81.5% (67 mg). HPLC purity: 94.2%. t R = 14.2 min). 1 HNMR (500 MHz, CDCl3) δ 8.93 (s, 1H), 8.52 (s, 1H), 8.19 – 8.13 (m, 2H), 7.65– 7.59 (m, 1H), 7.32 – 7.31 (m, 2H), 6.90 – 6.82 (m, 1H). Example 15 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 2-[(4-chlorophenyl)sulfonyl]-N-(4-fluorobenzyl)thiazol-4-carboxamide (XJM1013), and its preparation equation and method are as follows:

[0039] The intermediate XJM1011 and 4-fluorobenzylamine were used as starting materials for an amidation reaction. After separation and purification, the target compound XJM1013 was obtained as a white solid with a yield of 81.3% (95 mg). HPLC purity: 99.9% ( t R = 7.8 min). 1 H NMR (500 MHz, CDCl3) δ 8.37 (s, 1H), 7.98 – 7.81 (m, 2H), 7.51 – 7.41 (m, 2H), 7.40 (t, J = 6.2 Hz, 1H), 7.26 – 7.19 (m, 2H), 6.95 (t, J = 8.6 Hz, 2H), 4.50(d, J = 6.2 Hz, 2H). ¹³C NMR (151 MHz, CDCl3) δ 166.5, 162.3 (d, J = 241.6 Hz),159.4, 152.1, 141.8, 136.7, 133.4 (d, J = 3.3 Hz), 130.2 (2C), 130.1 (2C), 129.8, 129.6 (d, J = 8.0 Hz, 2C), 115.6 (d, J = 21.6 Hz, 2C), 42.8 Example 16 This embodiment provides an arylsulfonyl-substituted thiazole amide compound, specifically 2-[(4-chlorophenyl)sulfonyl]-N-(2-cyclohexylethyl)thiazole-4-carboxamide (WG1033), and its preparation equation and method are as follows:

[0040] An amidation reaction was carried out using intermediate XJM1011 and 2-cyclohexylethylamine as starting materials. After separation and purification, the target compound WG1033 was obtained as a white solid with a yield of 84.5% (78 mg). HPLC purity: 99.90%. t R = 16.3 min). 1 HNMR (500 MHz, CDCl3) δ 8.39 (s, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.60 – 7.55 (m,2H), 7.10 (t,J = 6.1 Hz, 1H), 3.47 – 3.40 (m, 2H), 1.77 – 1.65 (m, 6H), 1.50(d, J = 7.5 Hz, 1H), 1.27 – 1.11 (m, 4H), 0.99 – 0.91 (m, 2H).¹³C NMR (151MHz, CDCl3) δ 166.3, 159.5, 152.7, 141.9, 136.9, 130.3 (2C), 130.2 (2C),129.3, 37.6, 37.1, 35.5, 33.2 (2C), 26.6, 26.3 (2C). Example 17 This embodiment provides an arylsulfonyl-substituted thiazole amide compound, specifically 2-[(4-chlorophenyl)sulfonyl]-N-[(1S,4S)-4-hydroxycyclohexyl]thiazole-4-carboxamide (WG1035), and its preparation equation and method are as follows:

[0041] An amidation reaction was performed using intermediate XJM1011 and (1S,4S)-4-aminocyclohexanol as starting materials. After separation and purification, the target compound WG1035 was obtained as a white solid, with a yield of 74.0% (64 mg). HPLC purity: 99.6%. t R = 7.4 min). 1 H NMR (500 MHz, CDCl3)δ 8.40 (s, 1H), 8.07 – 8.02 (m, 2H), 7.62 – 7.56 (m, 2H), 7.13 (d, J = 8.4 Hz, 1H), 4.02 – 3.97 (m, 2H), 1.80 – 1.77 (m, 3H), 1.76 – 1.67 (m, 5H). Example 18 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 2-[(4-chlorophenyl)sulfonyl]-N-(prop-2-yn-1-yl)thiazol-4-carboxamide (WG2005), and its preparation equation and method are as follows:

[0042] The intermediate XJM1011 and prop-2-yn-1-amine were used as raw materials for amidation reaction. After separation and purification, the target compound WG2005 was obtained as a white solid with a yield of 71.2% (35 mg). 1 H NMR (500 MHz, CDCl3) δ 8.42 (d, J =1.3 Hz, 1H), 8.05 – 8.00 (m, 2H), 7.60 – 7.54 (m, 2H), 7.35 – 7.29 (m, 1H), 4.21 (dd, J = 5.7, 2.5 Hz, 2H), 2.27 (t, J = 2.6 Hz, 1H). 13 C NMR (151 MHz, CDCl3) δ 166.79, 159.22, 151.70, 142.01, 136.76, 130.3 (d, J = 12.9 Hz),130.1, 78.86, 72.21, 29.32. Example 19 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically N-(4-fluorophenyl)-2-[(3-fluorophenyl)sulfonyl]thiazol-4-carboxamide (WG3110), and its preparation equation and method are as follows:

[0043] Using ethyl 2-chlorothiazol-4-carboxylic acid ester and 3-fluorobenzylthiophenol as raw materials, ethyl 2-[(3-fluorophenyl)thio]thiazol-4-carboxylic acid ester (XJM1025) is a white solid. ¹H NMR (500 MHz, CDCl3) δ 7.99 (d, J =5.0 Hz,1H), 7.40 – 7.06 (m, 4H), 4.35 (q, J =7.1 Hz, 2H), 1.33 (t, J =7.1 Hz, 3H).

[0044] XJM1025 (1.3 g, 5.4 mol) was dissolved in dichloromethane (50 mL), and m-chloroperoxybenzoic acid (3.65 g, 15.8 mol) was added at 0 °C. After the addition was complete, the reaction mixture was stirred overnight at room temperature. Subsequently, dichloromethane (150 mL) was added to dilute the reaction solution, and the mixture was washed successively with Na2S2O3 aqueous solution (30 mL) and saturated brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography [PE / EA = 5 / 1] to give ethyl 2-[(3-fluorophenyl)sulfonyl]thiazole-4-carboxylate XJM1028 (1.3 g, 92.8%).

[0045] XJM1028 (1.3 g, 3.82 mmol) was dissolved in methanol (20 mL) and THF (5 mL), and NaOH (746 mg, dissolved in 5 mL H2O) was added. The reaction mixture was stirred at room temperature for 3 h, and then most of the solvent was evaporated. The pH of the reaction mixture was adjusted to 3–4 at 0 °C with 2 M hydrochloric acid aqueous solution. The precipitated white precipitate was separated by suction filtration and dried under reduced pressure to give 2-[(3-fluorophenyl)sulfonyl]thiazole-4-carboxylic acid XJM1033 (1.2 g, 97.4%).

[0046] The intermediate XJM1033 and 4-fluoroaniline were used as raw materials for amidation reaction. After separation and purification, the target compound WG3110 was obtained as a white solid with a yield of 61.2% (55 mg). 1 H NMR (500 MHz, CDCl3) δ 8.89 (s, 1H),8.53 (s, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.85 – 7.82 (m, 1H), 7.66 – 7.64 (m,2H), 7.64 – 7.59 (m, 1H), 7.43 – 7.40 (m, 1H), 7.08 (t, J = 8.6 Hz, 2H). ¹³CNMR (151 MHz, CDCl3) δ 166.4, 162.7 (d, J = 242.0 Hz), 159.9 (d, J = 242.0 Hz),157.3, 152.3, 140.3 (d, J = 6.9 Hz), 133.1 (d, J = 2.8 Hz), 131.8 (d, J = 7.6Hz), 130.6, 124.7 (d, J= 3.4 Hz), 122.4 (d, J = 21.3 Hz), 122.1 (d, J = 7.9 Hz, 2C), 116.2 (d, J = 24.7 Hz), 116.0 (d, J = 22.6 Hz, 2C) Example 20 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 2-[(3-fluorophenyl)sulfonyl]-N-(prop-2-yn-1-yl)thiazol-4-carboxamide (WG2008), and its preparation equation and method are as follows:

[0047] Using intermediate XJM1033 and propargyl-1-amine as starting materials, the reaction was carried out in a POCl3 / pyridine system. After separation and purification, the target compound WG2008 was obtained as a white solid with a yield of 83.2% (47 mg). HPLC purity: 96.9% ( t R = 6.6min). 1 H NMR (500 MHz, CDCl3) δ 8.46 (s, 1H), 7.91 – 7.89 (m, 1H), 7.82 – 7.80 (m, 1H), 7.62 – 7.59 (m, 1H), 7.44 – 7.35 (m, 2H), 4.24 – 4.22 (m, 2H), 2.29(t, J = 2.6 Hz, 1H). 13 C NMR (151 MHz, CDCl3) δ 166.3, 162.6 (d, J = 256.7 Hz),159.1, 151.6, 140.2 (d, J = 6.7 Hz), 131.6 (d, J = 7.5 Hz), 130.1, 124.6 (d, J =3.5 Hz), 122.1 (d, J = 21.1 Hz), 116.0 (d, J = 24.8 Hz), 78.7, 72.0, 29.2. Example 21 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically N-(4-fluorobenzyl)-2-[(3-fluorophenyl)sulfonyl]thiazol-4-carboxamide (WG1065), and its preparation equation and method are as follows:

[0048] Using intermediate XJM1033 and 4-fluorobenzylamine as starting materials, the reaction was carried out in a POCl3 / pyridine system. After separation and purification, the target compound WG1065 was obtained as a white solid with a yield of 83.5% (117 mg). HPLC purity: 96.8% ( t R = 7.0min). 1 H NMR (500 MHz, CDCl3) δ 8.46 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 8.0, 2.3Hz, 1H), 7.79 – 7.76 (m, 1H), 7.60 – 7.56 (m, 1H), 7.53 (d, J = 6.3 Hz, 1H),7.40 – 7.37 (m, 1H), 7.33 – 7.27 (m, 2H), 7.05 – 7.01 (m, 2H), 4.58 (d, J =6.2 Hz, 2H). 13 C NMR (151 MHz, CDCl3) δ 166.3, 162.7 (d, J = 256.7 Hz), 162.3(d, J = 246.1 Hz), 159.6, 152.3, 140.4 (d, J = 6.8 Hz), 133.5 (d, J = 3.3 Hz), 131.7 (d, J = 7.7 Hz), 130.12, 129.80 (d, J = 8.2 Hz), 124.7 (d, J = 3.4 Hz), 122.3 (d, J = 21.0 Hz, 2C), 116.2 (d, J = 24.6 Hz), 115.8 (d, J = 21.5 Hz, 2C), 43.0. Example 22 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically N-(4-fluorophenyl)-2-[(2-fluorophenyl)sulfonyl]thiazol-4-carboxamide (WG3116), and its preparation equation and method are as follows:

[0049] 1 g (1.00 g, 4.42 mmol) of ethyl 2-bromothiazol-4-carboxylic acid ester was dissolved in anhydrous ethanol (100 mL), and 1.08 g (8.47 mmol) of 2-fluorothiophenol was added at 0 °C, followed by stirring for 30 min. Sodium ethoxide (0.57 g, 8.47 mmol) was then added, and the reaction was continued at room temperature with stirring for 6 h. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, the mixture was extracted with dichloromethane (2 × 200 mL), and the organic phases were combined and washed successively with water (2 × 100 mL) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give WG1001 (1.08 g, 90%) as a white solid. 1 H NMR (500 MHz, CDCl3) δ 8.01(d, J = 1.6 Hz, 1H), 7.69 – 7.64 (m, 1H), 7.53 – 7.49 (m, 1H), 7.26 – 7.22 (m,2H), 4.42 – 4.39 (m, 2H), 1.43 – 1.39 (m, 3H). WG1001 (1.08 g, 3.84 mmol) was dissolved in dichloromethane (25 mL), and m-chloroperoxybenzoic acid (m-CPBA, 2.6 g, 11.52 mmol) was added at 0 °C. After the addition was complete, the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with dichloromethane (150 mL), washed successively with sodium thiosulfate aqueous solution (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to obtain WG1002 (350 mg, 31%). WG1003 (550 mg, 1.75 mmol) was dissolved in a mixed solvent of methanol (4 mL) and tetrahydrofuran (1 mL), and sodium hydroxide (209 mg, dissolved in 2 mL of water) was added. The mixture was stirred at room temperature for 3 h. After the reaction was complete, most of the methanol was removed, and the pH of the reaction solution was adjusted to 3–4 at 0 °C using a 2 mol / L hydrochloric acid aqueous solution. The precipitated white precipitate was separated by suction filtration and dried under reduced pressure to obtain 2-[(2-fluorophenyl)sulfonyl]thiazole-4-carboxylic acid WG1004 (456 mg, 91%). 1 H NMR (500 MHz, MeOD) δ 8.2 (s, 1H), 7.7 (t, J = 7.7 Hz, 1H), 7.7 – 7.6(m, 1H), 7.3 (d, J = 8.1 Hz, 2H). An amidation reaction was carried out using intermediate WG1004 and 4-fluoroaniline as starting materials. After separation and purification, the target compound WG3116 was obtained as a white solid, with a yield of 51.7% (53 mg). HPLC purity: 97.6%. t R = 7.3 min). 1 H NMR (500MHz, CDCl3) δ 8.99 (s, 1H), 8.44 (s, 1H), 8.01 – 7.94 (m, 1H), 7.65 (dd, J =8.9, 4.8 Hz, 2H), 7.62 – 7.55 (m, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.21 (t, J =8.8 Hz, 1H), 7.06 (d, J = 8.7 Hz, 2H). ¹³C NMR (151 MHz, CDCl3) δ 174.9,159.8 (d, J = 241.6 Hz), 159.1 (d, J = 256.7 Hz), 157.9, 151.7, 134.7 (d, J = 7.8Hz), 133.4 (d, J = 2.9 Hz), 130.4 (d, J = 16.0 Hz), 128.5, 125.9, 125.9, 121.8(d, J= 8.0 Hz, 2C), 116.8 (d, J = 19.6 Hz), 116.0 (d, J = 22.7 Hz, 2C). Example 23 This embodiment provides an arylsulfonyl-substituted thiazole amide compound, specifically N-(3,4-difluorophenyl)-2-[(2-fluorophenyl)sulfonyl]thiazole-4-carboxamide (WG1005), and its preparation equation and method are as follows:

[0050] An amidation reaction was carried out using intermediate WG1004 and 3,4-difluoroaniline as starting materials. After separation and purification, the target compound WG1005 was obtained as a white solid, with a yield of 71.2% (53 mg). HPLC purity: 98.90% t R = 8.9 min). 1 H NMR(500 MHz, CDCl3) δ 9.05 (s, 1H), 8.70 (s, 1H), 8.35 – 8.28 (m, 1H), 7.91 –7.86 (m, 2H), 7.56 (t, J = 7.7 Hz, 1H), 7.39 – 7.35 (m, 2H), 7.28 – 7.22 (m,1H). ¹³C NMR (151 MHz, CDCl3) δ 166.4, 159.8(d, J = 259.7 Hz), 157.5, 151.5,150.3 (dd, J = 247.6, 13.6 Hz), 147.5 (dd, J = 246.1, 12.1 Hz), 137.9 (d, J =8.6 Hz), 133.6 (d, J = 8.8 Hz), 131.0 (d, J = 4.6 Hz), 129.0, 126.6 (d, J = 13.4Hz), 125.3 (d, J = 3.7 Hz), 117.9 (d, J = 20.6 Hz), 117.5 (d, J = 18.1 Hz), 115.9(t, J= 4.8 Hz), 110.0 (d, J = 21.9 Hz). Example 24 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 2-[(2-fluorophenyl)sulfonyl]-N-[(1S,4S)-4-hydroxycyclohexyl]thiazol-4-carboxamide (WG1006), and its preparation equation and method are as follows:

[0051] Using intermediate WG1004 and (1S,4S)-4-aminocyclohexanol as starting materials, a condensation reaction was carried out in an HBTU / DIPEA system. After separation and purification, the target compound WG1006 was obtained as a white solid, with a yield of 57.9% (60 mg). HPLC purity 99.90% t R = 6.4 min). 1 H NMR (500 MHz, CDCl3) δ 8.47 – 8.44 (m, 1H), 8.22 –8.15 (m, 1H), 7.77 – 7.69 (m, 1H), 7.45 – 7.41 (m, 1H), 7.27 – 7.20 (m, 1H),7.18 – 7.12 (m, 1H), 4.01 – 3.96 (m, 2H), 1.77 – 1.71 (m, 8H). 13 C NMR (151MHz, CDCl3) δ 165.9, 159.9 (d, J = 241.6 Hz), 158.9, 152.3, 137.7 (d, J = 8.6Hz), 131.1, 129.9, 126.7 (d, J = 13.3 Hz), 125.2 (d, J = 3.7 Hz), 117.8 (d, J =20.5 Hz), 65.9, 47.4, 31.4 (2C), 27.1 (2C). Example 25 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 2-[(3,4-difluorophenyl)sulfonyl]-N-(4-fluorophenyl)thiazol-4-carboxamide (XJM1039), and its preparation equation and method are as follows:

[0052] Ethyl 2-chlorothiazol-4-carboxylate (1.20 g, 5.08 mmol) was dissolved in anhydrous ethanol (70 mL), and 3,4-difluorothiophenol (1.47 g, 10.16 mmol) was added at 0 °C, followed by stirring for 30 min. Sodium tert-butoxide (0.76 g, 10.16 mmol) was then added, and the reaction mixture was brought to room temperature and stirred for 6 h. The reaction was monitored by TLC until completion. The reaction solution was extracted with dichloromethane (2 × 200 mL), and the organic phases were combined, washed successively with water (2 × 100 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate ratio of 10 / 1 to 5 / 1 as eluent to give a white solid ethyl 2-[(3,4-difluorophenyl)thio]thiazole-4-carboxylate (XJM1030) (1.60 g, yield 98.6%). 1 H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 7.55 – 7.47 (m,1H), 7.46 – 7.39 (m, 1H), 7.29 – 7.20 (m, 1H), 4.42 (q, J = 7.2 Hz, 2H), 1.40(t, J = 7.2 Hz, 3H). Compound XJM1030 (1.56 g, 5.40 mmol) was dissolved in dichloromethane (50 mL), and m-chloroperoxybenzoic acid (m-CPBA, 3.65 g, 15.80 mmol) was added at 0 °C. After the addition was complete, the reaction system was brought to room temperature and stirred overnight. After the reaction was complete, the reaction solution was diluted with dichloromethane (150 mL) and washed successively with sodium thiosulfate aqueous solution (30 mL) and saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate = 5 / 1 as eluent to give ethyl 2-[(3,4-difluorophenyl)sulfonyl]thiazole-4-carboxylate (XJM1031) (1.43 g, yield 82.8%). 1 H NMR (500 MHz, CDCl3) δ 8.36 (s, 1H), 7.94– 7.81 (m, 2H), 7.39 – 7.29 (m, 1H), 4.34 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1Hz, 3H). Compound XJM1031 (1.40 g, 3.82 mmol) was dissolved in a mixed solvent of methanol (20 mL) and tetrahydrofuran (5 mL), and an aqueous solution of sodium hydroxide (746 mg, dissolved in 5 mL) was added. The reaction mixture was stirred at room temperature for 3 h, and most of the methanol was removed under reduced pressure. Subsequently, the pH of the reaction mixture was adjusted to 3–4 with 2 M hydrochloric acid at 0 °C, resulting in the precipitation of a white precipitate. The precipitate was collected by filtration and dried under vacuum to give 1.35 g of 2-[(3,4-difluorophenyl)sulfonyl]thiazole-4-carboxylic acid (XJM1035), with a yield of 97.4%.

[0053] The intermediate XJM1035 and 4-fluoroaniline were used as raw materials for amidation reaction. After separation and purification, the target compound XJM1039 was obtained as a white solid with a yield of 81.2% (105 mg). 1 H NMR (500 MHz, CDCl3) δ 8.85 (s, 1H), 8.53 (s, 1H), 8.02 – 7.92 (m, 2H), 7.68 – 7.61 (m, 2H), 7.42 (td, J = 9.0, 7.1Hz, 1H), 7.07 (t, J = 8.6 Hz, 2H). ¹³C NMR (151 MHz, CDCl3) δ 166.3, 160.0 (d, J = 244.6 Hz), 157.3, 154.8 (dd, J = 261.2 Hz), 152.4, 150.7 (dd, J = 256.7 Hz), 135.0, 133.0 (d, J = 2.9 Hz), 130.6, 126.4 (dd, J = 8.0, 3.9 Hz), 122.1 (d, J =8.0 Hz, 2C), 119.2 (d, J = 18.6 Hz), 118.9 (d, J = 19.9 Hz), 116.0 (d, J = 22.7Hz, 2C). Example 26 This embodiment provides an arylsulfonyl-substituted thiazole amide compound, specifically N-(4-fluorophenyl)-2-[(4-methoxyphenyl)sulfonyl]thiazole-4-carboxamide (XJM1005), and its preparation equation and method are as follows:

[0054] Ethyl 2-chlorothiazol-4-carboxylic acid ester (1.1 g, 4.42 mmol, 1.0 equiv) was dissolved in anhydrous ethanol (70 mL), and 4-methoxythiophenol (1.08 g, 8.47 mmol, 1.9 equiv) was added at 0 °C, followed by stirring for 30 min. Sodium ethoxide (0.57 g, 8.47 mmol, 1.9 equiv) was then added, and the reaction mixture was stirred at room temperature (rt) for 6 h. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, the reaction mixture was extracted with dichloromethane (DCM, 2 × 200 mL). The combined organic phases were washed successively with water (2 × 100 mL) and saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE / EA = 10:1 → 5:1) to give a white solid XJM1001 (1.54 g, 98.4%).

[0055] XJM1001 (1.3 g, 4.4 mmol, 1.0 equiv) was dissolved in DCM (25 mL), and m-chloroperoxybenzoic acid (m-CPBA) (2.53 g, 11.1 mmol, 2.5 equiv) was added at 0 °C. The reaction mixture was stirred overnight at room temperature. It was then diluted with DCM (150 mL) and washed successively with Na₂S₂O₃ aqueous solution (30 mL) and saturated brine (30 mL). The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE / EA = 3:1) to give XJM1002 (1.3 g, 92.8%). 1 H NMR (500 MHz, CDCl3) δ 8.36 (s, 1H), 8.11–8.01 (m,2H), 7.11 – 7.00 (m, 2H), 4.39 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 1.37 (t, J =7.1 Hz, 3H).

[0056] XJM1002 (1.25 g, 3.82 mmol, 1.0 equiv) was dissolved in a mixed solvent of MeOH (20 mL) and THF (5 mL), and NaOH (746 mg, 18.6 mmol, 4.9 equiv) dissolved in H2O (5 mL) was added. The reaction mixture was stirred at room temperature for 3 h. Subsequently, most of the MeOH was removed under reduced pressure, and the pH of the system was adjusted to 3–4 with 2 M HCl aqueous solution at 0 °C. The precipitated white precipitate was collected by suction filtration and dried under vacuum to give XJM1003 (1.1 g, 96.4%). The intermediate XJM1003 and 4-fluoroaniline were used as starting materials for an amidation reaction. After separation and purification, the target compound XJM1005 was obtained as a white solid, with a yield of 49.2% (33 mg). HPLC purity: 99.9% ( t R = 8.9 min). 1 H NMR(500 MHz, CDCl3) δ 8.91 (s, 1H), 8.45 (s, 1H), 8.09 – 7.99 (m, 2H), 7.66 –7.61 (m, 2H), 7.08 – 7.06 (m, 2H), 7.06 – 7.04 (m, 2H), 3.89 (s, 3H). Example 27 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically N-(3-cyano-4-fluorophenyl)-2-[(4-methoxyphenyl)sulfonyl]thiazol-4-carboxamide (XJM1006), and its preparation equation and method are as follows:

[0057] Using intermediate XJM1003 and 5-amino-2-fluorobenzonitrile as starting materials, the reaction was carried out in a POCl3 / pyridine system. After separation and purification, the target compound XJM1006 was obtained as a white solid, with a yield of 49.3% (54 mg). HPLC purity: 93.33%. t R = 7.2 min). 1 H NMR (500 MHz, CDCl3) δ 9.06 (s, 1H), 8.49 (d, J = 1.4 Hz, 1H),8.10 – 8.07 (m, 1H), 8.03 (d, J= 1.5 Hz, 1H), 7.88 – 7.84 (m, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.10 – 7.04 (m, 2H), 3.90 (d, J = 1.4 Hz, 3H Example 28 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically N-(4-fluorobenzyl)-2-[(4-methoxyphenyl)sulfonyl]thiazol-4-carboxamide (XJM1004), and its preparation equation and method are as follows:

[0058] The intermediate XJM1003 and 4-fluorobenzylamine were used as starting materials for an amidation reaction. After separation and purification, the target compound XJM1004 was obtained as a white solid with a yield of 69.3% (74 mg). HPLC purity: 99.9% ( t R = 7.0 min). 1 H NMR (500 MHz, CDCl3) δ 8.31 (s, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.44 (t, J = 6.3 Hz,1H), 7.25 – 7.19 (m, 2H), 6.96 – 6.94 (m, 4H), 4.49 (d, J = 6.2 Hz, 2H), 3.80 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 167.8, 164.7, 163.9 (d, J = 241.6 Hz),159.6, 151.7, 133.46 (d, J = 3.1 Hz), 131.1 (2C), 129.6 (d, J = 8.0 Hz, 2C),129.4, 129.1, 115.6 (d, J = 21.3 Hz, 2C), 115.0 (2C), 55.8, 42.8. Example 29 This embodiment provides an arylsulfonyl-substituted thiazole amide compound, specifically N-(3,4-difluorophenyl)-2-[(4-fluorophenyl)sulfonyl]-5-methylthiazole-4-carboxamide (WG1070), and its preparation equation and method are as follows:

[0059] Ethyl 2-chloro-5-methylthiazolium-4-carboxylate (1 g, 4.86 mmol) was dissolved in anhydrous ethanol (150 mL), and 4-fluorothiophenol (1.24 g, 9.72 mmol) was added at 0 °C, followed by stirring for 30 min. Sodium ethoxide (0.9 g, 9.72 mmol) was then added, and the resulting mixture was stirred at room temperature for 6 h. The reaction progress was monitored by TLC until the reactants were completely reacted. The reaction solution was extracted with dichloromethane (2 × 200 mL), and the combined organic phases were washed successively with water (2 × 100 mL) and saturated brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography [PE / EA = 10 / 1] to give ethyl 2-[(4-fluorophenyl)thio]-5-methylthiazolium-4-carboxylate WG1067 (270 mg, 19%). ¹H NMR (500 MHz, CDCl3) δ 7.65(dd, J = 8.4, 5.2 Hz, 2H), 7.14 (t, J = 8.4 Hz, 2H), 4.41 (q, J = 7.2 Hz, 2H),2.63 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H). WG1067 (270 mg, 0.96 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (498.7 mg, 2.89 mmol) was added at 0 °C. After the addition was complete, the reaction mixture was stirred overnight at room temperature. Subsequently, dichloromethane (80 mL) was added to dilute the reaction solution, and the mixture was washed successively with Na2S2O3 aqueous solution (50 mL) and saturated brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography [PE / EA = 5 / 1] to give ethyl 2-[(4-fluorophenyl)sulfonyl]-5-methylthiazol-4-carboxylate WG1068 (310 mg, 96%).

[0060] WG1068 (300 mg, 0.91 mmol) was dissolved in methanol (5 mL), and NaOH (109.1 mg, 2.73 mmol, dissolved in 2 mL H2O) was added. The reaction mixture was stirred at room temperature for 2 h, and then most of the methanol was evaporated. The precipitated white precipitate was separated by suction filtration and dried under reduced pressure to give 2-[(4-fluorophenyl)sulfonyl]-5-methylthiazol-4-carboxylic acid WG1069 (200 mg, 72.9%) as a white solid.

[0061] WG1069 (50 mg, 0.16 mmol) and (4-fluorophenyl)methylamine (41.5 mg, 0.33 mmol) were dissolved in dichloromethane (15 mL), and HBTU (188.8 mg, 0.49 mmol) and DIPEA (64.3 mg, 0.49 mmol) were added at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction solution was extracted with dichloromethane (2 × 80 mL), and the combined organic phases were washed successively with water (2 × 50 mL) and saturated brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography [PE / EA = 3 / 1] to give N-(4-fluorobenzyl)-2-[(4-fluorophenyl)sulfonyl]-5-methylthiazol-4-carboxamide WG1071 (51 mg, 73%). HPLC purity 96.4% ( t R = 9.3 min). 1 H NMR (500 MHz, CDCl3) δ9.00 (s, 1H), 8.13 – 8.11 (m, 1H), 7.77 – 7.73 (m, 1H), 7.32 – 7.25 (m, 3H),7.24 – 7.19 (m, 1H), 7.19 – 7.10 (m, 1H), 2.93 (s, 3H). Example 30 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically N-(4-fluorobenzyl)-2-[(4-chlorophenyl)sulfonyl]-5-methylthiazol-4-carboxamide (WG1070), and its preparation equation and method are as follows:

[0062] Using intermediate WG1069 and 4-fluorobenzylamine as raw materials, the target compound WG1070 was obtained after subsequent amidation and oxidation reactions, followed by separation and purification. The compound was a white solid with a yield of 46.0% (34 mg). 1H NMR (500 MHz, CDCl3) δ 8.08 –8.05 (m, 2H), 7.58 (t, J = 6.4 Hz, 1H), 7.32 – 7.26 (m, 2H), 7.26 – 7.21 (m,2H), 7.05 – 7.00 (m, 2H), 4.53 (d, J = 6.2 Hz, 2H), 2.90 (s, 3H). Example 31 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 2-[(4-chlorophenyl)sulfonyl]-N-(4-fluorobenzyl)-5-methylthiazol-4-carboxamide (WG1077), and its preparation equation and method are as follows:

[0063] Ethyl 2-chloro-5-methylthiazolium-4-carboxylate (0.5 g, 2.43 mmol) was dissolved in anhydrous ethanol (50 mL), and 4-chlorothiophenol (1.05 g, 7.29 mmol) was added at 0 °C, followed by stirring for 30 min. Sodium ethoxide (0.4 g, 4.86 mmol) was then added, and the resulting mixture was stirred at room temperature for 6 h. The reaction progress was monitored by TLC until the reactants were completely reacted. The reaction solution was extracted with dichloromethane (2 × 200 mL), and the combined organic phases were washed successively with water (2 × 100 mL) and saturated brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography [PE / EA = 20 / 1] to give ethyl 2-[(4-chlorophenyl)thio]-5-methylthiazolium-4-carboxylate WG1072 (300 mg, 55%). ¹H NMR (500 MHz, CDCl3) δ 7.59 – 7.53 (m, 2H), 7.43 – 7.37 (m, 2H), 4.45 – 4.37 (m, 2H), 2.66 (s, 3H), 1.44 – 1.36 (m, 3H). WG1072 (300 mg, 0.95 mmol) was dissolved in methanol (5 mL), and NaOH (109.1 mg, 2.73 mmol, dissolved in 2 mL H2O) was added. The reaction mixture was stirred at room temperature for 2 h, and then most of the methanol was evaporated. The precipitated white precipitate was separated by suction filtration and dried under reduced pressure to give 2-[(4-chlorophenyl)thio]-5-methylthiazol-4-carboxylic acid WG1073 (153 mg, 56.2%) as a white solid.

[0064] WG1073 (50 mg, 0.16 mmol) and 4-fluorobenzylamine (43.8 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL), and HBTU (199 mg, 0.52 mmol) and DIPEA (67.8 mg, 0.52 mmol) were added at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction solution was extracted with dichloromethane (2 × 80 mL), and the combined organic phases were washed successively with water (2 × 50 mL) and saturated brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography [PE / EA = 3 / 1] to give N-(4-fluorobenzyl)-2-[(4-chlorophenyl)thio]-5-methylthiazol-4-carboxamide WG1074 (46 mg, 73%).

[0065] WG1074 (60 mg, 0.15 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (79.1 mg, 0.45 mmol) was added at 0 °C. After the addition was complete, the reaction mixture was stirred overnight at room temperature. Subsequently, dichloromethane (80 mL) was added to dilute the reaction solution, and the mixture was washed successively with Na2S2O3 aqueous solution (50 mL) and saturated brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography [PE / EA = 5 / 1] to give 2-[(4-chlorophenyl)sulfonyl]-N-(4-fluorobenzyl)-5-methylthiazol-4-carboxamide WG1077 (51 mg, 69%). 1 H NMR (500 MHz, CDCl3) δ8.00 – 7.94 (m, 2H), 7.60 – 7.54 (m, 2H), 7.53 (d, J = 2.0 Hz, 1H), 7.31 – 7.26(m, 2H), 7.02 (dd, J = 9.7, 7.7 Hz, 2H), 4.53 (d, J = 6.2 Hz, 2H), 2.91 (s, 3H).¹³C NMR (151 MHz, CDCl3) δ 162.4 (d, J = 246.1 Hz), 161.3, 161.0, 148.9,145.1, 141.7, 137.2, 133.8 (d, J = 3.4 Hz), 130.1 (d, J = 4.3 Hz, 2C), 129.7(d, J= 8.1 Hz, 2C), 115.7 (d, J = 21.4 Hz, 2C), 42.7, 13.5. Example 32 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 2-[(4-chlorophenyl)sulfonyl]-N-(3,4-difluorophenyl)-5-methylthiazol-4-carboxamide (WG1076), and its preparation equation and method are as follows:

[0066] Using intermediate WG1073 and 3,4-difluoroaniline as starting materials, the target compound WG1076 was obtained after subsequent amidation and oxidation reactions, followed by separation and purification. The compound was a white solid with a yield of 73.0% (54 mg). HPLC purity was 94.33% (tR = 11.3 min). 1 H NMR (500 MHz, CDCl3) δ 9.00 (s, 1H), 8.05 – 8.00 (m, 2H), 7.79 – 7.71(m, 1H), 7.61 – 7.51 (m, 2H), 7.25 – 7.10 (m, 2H), 2.93 (s, 3H). ¹³C NMR (151MHz, CDCl3) δ 161.3, 159.1,150.3 (dd, J = 248.4, 12.8 Hz), 150.0, 147.4 (dd, J =246.9, 12.8 Hz), 144.8, 141.9, 137.0, 133.7 (d, J = 25.4 Hz), 130.3 (t, J =10.9 Hz, 2C), 128.4, 117.5 (d, J = 18.3 Hz, 2C), 115.9 (t, J = 5.0 Hz), 110.0(d, J = 21.7 Hz), 13.7. Example 33 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 2-[(4-chlorophenyl)sulfonyl]-5-methyl-N-(3,4,5-trifluorophenyl)thiazol-4-carboxamide (WG1080), and its preparation equation and method are as follows:

[0067] Using intermediate WG1073 and 3,4,5-trifluoroaniline as starting materials, the target compound WG1080 was obtained after subsequent amidation and oxidation reactions, followed by separation and purification. The compound was a white solid with a yield of 63.0% (47 mg). HPLC purity: 99.9%. t R = 7.9min). 1 H NMR (500 MHz, CDCl3)δ 8.99 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.41 – 7.38 (m, 2H), 2.93 (s, 3H). ¹³C NMR (151 MHz, CDCl3) δ161.5, 159.2, 152.2, 150.5, 150.4, 144.4, 142.0, 137.0, 133.0, 130.2 (2C),104.6 (2C), 104.5 (2C), 13.7.161.5, 159.2, 152.3 – 151.9 (m), 150.59 – 150.38(m), 150.35, 144.43, 141.98, 136.97, 133.27 – 132.30 (m), 130.24 (d, J = 14.9Hz, 2C), 104.63 (d, J = 6.0 Hz, 2C), 104.48, 13.71. Example 34 This embodiment provides an arylsulfonyl-substituted thiazole amide compound, specifically 2-((4-chlorophenyl)sulfonyl)-5-isobutyl-N-phenylthiazole-4-carboxamide (WG1105), and its preparation equation and method are as follows:

[0068] At 0 °C, methyl 2,2-dichloroacetate (1 g, 1.0 mmol, 1.0 eq) and isovaleraldehyde (0.63 g, 1.0 mmol) were added to 15 mL of diethyl ether solution. Sodium tert-butyl (1 g, 0.76 mmol, 1.0 eq) was then slowly added dropwise. The reaction mixture was stirred at 0 °C for 1 h, followed by the addition of Et₂O and saturated brine. The organic layer was separated, dried over anhydrous Na₂SO₄, and concentrated. The crude product was dissolved in 16 mL of MeOH solution containing thiourea (0.76 mmol, 0.85 eq) and heated under reflux for 18 h. After concentration under reduced pressure, the pH was adjusted to 9 with 25% ammonia. The precipitate was filtered, washed with water, and dried to give WG1092 (897 mg, 54%) as a white solid. ¹H NMR (500 MHz, CDCl3) δ 5.33 – 5.13 (m, 2H), 3.79 (s, 3H), 2.92 – 2.84 (m, 2H), 1.82 – 1.69 (m, 1H), 0.90 – 0.84 (m, 6H). In a double-necked round-bottom flask equipped with a condenser, CuBr2 (750 mg, 1.1 mmol, 1.2 eq) and tert-butyl nitrite (450 mg, 1.4 mmol, 1.1 eq) were dissolved in 25 mL of acetonitrile solution and stirred at room temperature. Then, WG1092 (600 mg, 1.0 mmol, 1.0 eq) was slowly added dropwise to the above system, and the reaction was heated at 60°C for 3 h. After cooling to room temperature, the mixture was poured into a saturated NH4Cl solution (20 mL) and extracted using DCM (100 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was then purified by column chromatography (PE / EA = 5:1) to give WG1095 (547 mg, 85.7%). ¹H NMR (500 MHz, CDCl3) δ 3.85 (s, 2H), 3.04 (d, J = 7.2 Hz, 2H), 1.91– 1.83 (m, 1H), 0.92 (d, J = 6.6 Hz, 6H). WG1095 (200 mg, 0.71 mmol) was dissolved in anhydrous ethanol (20 mL), and 4-chlorothiophenol (207.9 mg, 1.43 mmol) was added at 0 °C. After reacting for 30 min, sodium ethoxide (138.1 mg, 1.43 mmol) was added, and the mixture was stirred at 60 °C for 6 h until the reaction was complete as detected by TLC. The reaction mixture was extracted, concentrated under reduced pressure, and the crude product was then purified by rapid column chromatography (PE / EA = 5:1) to obtain WG1102 (214 mg, 88.4%).

[0069] WG1102 (200 mg, 0.58 mmol) was dissolved in THF (10 mL), and NaOH (101.7 mg, 1.75 mmol) was added and dissolved in 2 mL of H2O. The reaction mixture was stirred at room temperature for 2 h, and most of the THF was evaporated. The precipitated white precipitate was filtered, washed, and dried to give WG1103 (160 mg, 84.2%) as a white solid.

[0070] WG1103 (50 mg, 0.15 mmol) and 4-fluoroaniline (41a) (33.89 mg, 0.30 mmol) were dissolved in DCM (15 mL), and HBTU (173.5 mg, 0.46 mmol) and DIPEA (59.6 mg, 0.46 mmol) were added at 0 °C. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane, followed by extraction and other treatments. The crude product was purified by column chromatography (PE / EA = 3:1) to give WG1104 (51 mg, 80.9%).

[0071] WG1104 (51 mg, 0.12 mmol) was dissolved in DCM (10 mL), and m-chloroperoxybenzoic acid (62.7 mg, 0.36 mmol) was added at 0 °C. The final product, WG1105 (51 mg, 69%), was obtained as a white solid. HPLC purity 99.4% ( t R = 7.2 min). 1 H NMR (500 MHz, CDCl3) δ 8.99 (s, 1H), 8.06 – 8.01 (m, 2H), 7.62 – 7.56 (m, 4H), 7.05 (t, J = 8.6 Hz, 2H), 3.31 (d, J = 7.1 Hz,2H), 2.05 – 1.99 (m, 1H), 1.00 (d,J = 6.6 Hz, 6H). ¹³C NMR (151 MHz, CDCl3) δ161.4, 159.7 (d, J = 244.6 Hz), 154.1, 145.0, 141.7, 137.0, 133.2 (d, J = 2.8Hz), 130.1, 122.1 (d, J = 7.8 Hz, 2C), 115.8 (d, J = 22.4 Hz, 2C), 36.1, 29.7,22.3 (2C). Example 35 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically N-(4-fluorobenzyl)-2-[(4-fluorophenyl)sulfonyl]-5-isobutylthiazol-4-carboxamide (WG1120), and its preparation equation and method are as follows:

[0072] Using intermediate WG115 and 4-fluorobenzylamine as starting materials, the target compound WG1120 was obtained after subsequent amidation and oxidation reactions, followed by separation and purification. The compound was a yellow solid with a yield of 76.6% (40 mg). HPLC purity: 99.9%. t R = 13.0min). 1 HNMR (500 MHz, CDCl3) δ 8.10 – 8.03 (m, 2H), 7.61 – 7.55 (m, 1H), 7.29 – 7.26(m, 2H), 7.25 – 7.21 (m, 2H), 7.06 – 6.97 (m, 2H), 4.52 (d, J = 6.2 Hz, 2H), 3.28 (d, J = 7.1 Hz, 2H), 2.06 – 1.92 (m, 1H), 0.98 (d, J = 6.6 Hz, 6H). ¹³C NMR(151 MHz, CDCl3) δ 166.5 (d, J = 256.7 Hz), 162.4 (d, J = 241.6 Hz), 161.7,161.1, 153.4, 145.1, 134.7 (d, J = 3.1 Hz), 133.8, 131.7 (d,J = 9.8 Hz, 2C), 129.6 (d, J = 8.1 Hz, 2C), 117.2 (d, J = 22.8 Hz, 2C), 115.7 (d, J = 21.4 Hz,2C), 42.6, 36.1, 31.3, 22.4 (2C). Example 36 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 2-[(4-chlorophenyl)sulfonyl]-N-(4-fluorophenyl)-5-isopropylthiazol-4-carboxamide (WG1131), and its preparation equation and method are as follows:

[0073] At 0 °C, methyl 2,2-dichloroacetate (1 g, 1.0 mmol, 1.0 eq) and isobutyraldehyde (0.63 g, 1.0 mmol) were added to 15 mL of diethyl ether solution. Sodium tert-butoxide (1 g, 0.76 mmol, 1.0 eq) was then slowly added dropwise. The reaction mixture was stirred at 0 °C for 1 h, followed by the addition of Et₂O and saturated brine. The organic layer was separated, dried over anhydrous Na₂SO₄, and concentrated. The crude product was dissolved in 16 mL of MeOH solution containing thiourea (0.76 mmol, 0.85 eq) and heated under reflux for 18 h. After concentration under reduced pressure, the pH was adjusted to 9 with 25% ammonia. The precipitate was filtered, washed with water, and dried to give the corresponding compound, methyl 2-amino-5-isopropylthiazolyl-4-carboxylic acid ester WG1119 (700 mg, 48.2%). 1 H NMR (500 MHz, CDCl3) δ 5.13 (s, 2H), 4.03 – 3.90 (m, 1H), 3.80 (s, 3H), 1.19 (d, J = 6.9 Hz, 6H). tert-butyl nitrite (514.9 mg, 4.9 mmol) was slowly added at room temperature to a dark brown CuBr2 solution in a two-necked round-bottom flask equipped with a condenser. The resulting mixture was heated to 60 °C, and then a suspension of WG1119 (700 mg, 3.3 mmol) in acetonitrile (10 mL) was added dropwise to the above reaction system. The resulting reaction mixture was heated at 60 °C for 3 h, cooled to room temperature, poured into a saturated ammonium chloride solution (20 mL), and extracted with dichloromethane (100 mL). The organic phases were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography [PE / EA = 5 / 1] to give methyl 2-bromo-5-isopropylthiazolyl-4-carboxylic acid ester WG1123 (800 mg, 91.9%). 1 H NMR (500 MHz, CDCl3) δ 4.20 – 4.10(m, 1H), 3.93 (s, 3H), 1.33 (d, J = 6.8 Hz, 6H). WG1123 (200 mg, 0.75 mmol) was dissolved in anhydrous ethanol (20 mL), and 4-chlorothiophenol (219 mg, 1.51 mmol) was added at 0 °C, followed by stirring for 30 min. Sodium ethoxide (145.5 mg, 1.51 mmol) was then added, and the resulting mixture was stirred at 60 °C for 6 h. The reaction progress was monitored by TLC until the reactants were completely reacted. The reaction solution was extracted with dichloromethane (2 × 200 mL), and the combined organic phases were washed successively with water (2 × 100 mL) and saturated brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography [PE / EA = 5 / 1] to give methyl 2-[(4-chlorophenyl)thio]-5-isopropylthiazolyl-4-carboxylic acid ester WG1125 (145 mg, 59.1%).

[0074] WG1125 (120 mg, 0.36 mmol) was dissolved in THF (10 mL), and NaOH (104.38 mg, 1.09 mmol, dissolved in 2 mL H2O) was added. The reaction mixture was stirred at room temperature for 2 h, and then most of the THF was evaporated. The precipitated white precipitate was separated by suction filtration and dried under reduced pressure to give 2-[(4-chlorophenyl)thio]-5-isopropylthiazolyl-4-carboxylic acid WG1127 (117 mg, 95.7%) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.54 – 7.48 (m, 2H), 7.40 – 7.34 (m, 2H), 4.13 – 4.01 (m, 1H), 1.19 (d, J = 6.9 Hz, 6H). WG1127 (50 mg, 0.15 mmol) and 4-fluoroaniline (33.89 mg, 0.30 mmol) were dissolved in dichloromethane (15 mL), and HBTU (173.5 mg, 0.46 mmol) and DIPEA (59.6 mg, 0.46 mmol) were added at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction solution was extracted with dichloromethane (2 × 80 mL), and the combined organic phases were washed successively with water (2 × 50 mL) and saturated brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography [PE / EA = 3 / 1] to give 2-[(4-chlorophenyl)thio]-N-(4-fluorophenyl)-5-isopropylthiazol-4-carboxamide WG1129 (50 mg, 80.9%). 1 H NMR (500 MHz, CDCl3) δ 9.19 (s, 1H), 7.63 – 7.60 (m,2H), 7.59 – 7.54 (m, 2H), 7.47 – 7.40 (m, 2H), 7.09 – 7.00 (m, 2H), 4.44 –4.32 (m, 1H), 1.28 (d, J = 6.9 Hz, 6H). WG1129 (51 mg, 0.12 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (62.7 mg, 0.36 mmol) was added at 0 °C. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction solution was then diluted with dichloromethane (80 mL), washed successively with Na2S2O3 aqueous solution (50 mL) and saturated brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography [PE / EA = 5 / 1] to give 2-[(4-chlorophenyl)sulfonyl]-N-(4-fluorophenyl)-5-isopropylthiazol-4-carboxamide WG1131 (45 mg, 74.1%). HPLC purity 95.6% ( t R = 7.0 min). 1H NMR (500 MHz, CDCl3) δ 8.99 (s, 1H), 8.07 – 8.01 (m, 2H), 7.63 – 7.55 (m, 4H), 7.10 – 7.01 (m, 2H), 4.42 (m, J = 6.8 Hz, 1H), 1.38 (d, J = 6.8 Hz, 6H). ¹³C NMR (151 MHz, CDCl3) δ 163.8, 161.3, 159.8 (d, J = 241.6Hz), 158.9, 143.8, 141.8, 137.1, 133.3 (d, J = 2.9 Hz, 2C), 130.2, 122.1 (d, J = 8.0 Hz, 2C), 116.0 (2C), 115.8 (2C), 28.5, 25.3 (2C). Example 37 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically N-(4-fluorophenyl)-2-[(4-fluorophenyl)sulfonyl]-5-isopropylthiazol-4-carboxamide (WG1141), and its preparation equation and method are as follows:

[0075] Using intermediates and 4-fluoroaniline as raw materials, the target compound WG1141 was obtained after subsequent amidation and oxidation reactions, followed by separation and purification. The result was a pale yellow solid with a yield of 70.1% (40 mg). 1 H NMR (500 MHz, CDCl3) δ 8.99 (s, 1H),8.17 – 8.10 (m, 2H), 7.63 – 7.56 (m, 2H), 7.29 (t, J = 8.3 Hz, 2H), 7.06 (t, J = 8.6 Hz, 2H), 4.43 (hept, J = 6.9 Hz, 1H), 1.39 (d, J = 6.8 Hz, 6H). ¹³C NMR(151 MHz, CDCl3) δ 166.5 (d, J = 259.7 Hz), 163.6, 161.5, 159.8 (d, J= 246.1Hz), 143.7, 134.7 (d, J = 3.3 Hz), 133.4, 131.8 (d, J = 9.9 Hz, 2C), 122.19 –122.05 (m, 3C), 117.3 (d, J = 22.7 Hz, 2C), 115.9 (d, J = 22.5 Hz, 2C), 28.5,25.3 (2C). Example 38 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 2-((4-chlorophenyl)sulfonyl)-N-(4-fluorophenyl)-5-morpholinylthiazol-4-carboxamide (WG1101), and its preparation equation and method are as follows:

[0076] Ethyl 5-bromothiazol-4-carboxylic acid ester (1.10 g, 1.27 mmol, 1.0 eq) was dissolved in MeCN (15 mL), followed by the addition of morpholine (1.30 g, 3.8 mmol, 1.5 eq) and DBU (2.10 g, 12.7 mmol, 1.5 eq). The reaction flask was sealed and heated to 80 °C for 5 h. After cooling, the reaction was terminated by adding water, and the aqueous phase was extracted with EtOAc (3 × 15 mL). The organic phase was dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (PE / EA = 1:1) to obtain WG1087 (750 mg, 74%) as a white solid.

[0077] WG1087 (350 mg, 1.4 mmol, 1.0 eq) was dissolved in MeCN (10 mL), and N-bromosuccinimide (514.2 mg, 2.8 mmol, 2.0 eq) was added at room temperature. After stirring until complete, the mixture was concentrated and purified by silica gel column chromatography (PE / EA = 3:1) to obtain WG1089 (413 mg, 91.9%) as a white solid. 1 H NMR (500 MHz, CDCl3)δ 4.31 (q, J = 7.1 Hz, 2H), 3.83 – 3.78 (m, 4H), 3.18 – 3.13 (m, 4H), 1.32(t, J =7.1 Hz, 3H).

[0078] WG1089 (350 mg, 1.1 mmol, 1.0 eq) was dissolved in anhydrous ethanol (50 mL). 4-Chlorothiophenol (315.1 mg, 2.1 mmol, 1.2 eq) was added at 0 °C, and the reaction was carried out for 30 min. Sodium tert-butyl (209.4 mg, 2.1 mmol, 1.2 eq) was then added, and the mixture was stirred at 60 °C for 6 h until the reaction was complete as detected by TLC. The reaction mixture was extracted with DCM (2 × 200 mL), and the crude product was then dried and concentrated. The crude product was purified by rapid column chromatography (PE / EA = 5:1) to obtain WG1098 (300 mg, 77.3%) as a white solid. 1 H NMR (500 MHz, CDCl3) δ 7.45 – 7.39 (m, 2H),7.33 –7.26 (m, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.81 – 3.74 (m, 4H), 3.17 – 3.07(m,4H),1.33 (t, J = 7.1 Hz, 3H).

[0079] WG1098 (350 mg, 0.75 mmol, 1.0 eq) was dissolved in MeOH (15 mL), and NaOH (100 mg, 2.3 mmol, 3.0 eq) was dissolved in 2 mL of water. The mixture was stirred at room temperature for 2 h, and most of the MeOH was evaporated. If necessary, the pH was adjusted to 3–4 with 2 M HCl. The precipitated white precipitate was collected by filtration and dried to give WG1099 (254 mg, 92.1%) as a white solid.

[0080] WG1099 (50 mg, 0.15 mmol, 1.0 eq) and 4-fluoroaniline (34.2 mg, 0.34 mmol, 2.0 eq) were dissolved in DCM (15 mL). HBTU (175.1 mg, 0.46 mmol, 3.0 eq) and DIPEA (59.6 mg, 0.46 mmol, 3.0 eq) were added at 0 °C. The reaction mixture was stirred overnight at room temperature. The reaction mixture was extracted with DCM (2 × 80 mL), and the combined organic layers were washed successively with water (2 × 50 mL) and saturated brine (20 mL). The mixture was then concentrated and purified by column chromatography (PE / EA = 3:1) to obtain WG1100 (50 mg, 74%) as a white solid. 1H NMR (500 MHz, CDCl3)δ 9.09 (s, 1H), 7.56 – 7.49 (m, 2H), 7.45 – 7.40 (m, 2H), 7.35 – 7.27 (m,2H), 7.00 – 6.94 (m, 2H), 3.84 – 3.76 (m, 4H), 3.23 – 3.12 (m, 4H). WG1100 (50 mg, 0.11 mmol, 1.0 eq) was dissolved in DCM (10 mL), and m-chloroperoxybenzoic acid (57.1 mg, 0.33 mmol, 3.0 eq) was added at 0 °C. The reaction mixture was stirred overnight at room temperature, then diluted with DCM (80 mL), and washed successively with Na2S2O3 aqueous solution (50 mL) and saturated brine (30 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by rapid column chromatography (PE / EA = 5:1) to give the final product compound WG1101 (51 mg, 69%) as a white solid. 1 H NMR (500 MHz, CDCl3) δ 8.95 (s, 1H), 8.11 – 7.87 (m, 2H), 7.57 – 7.54 (m, 4H), 7.12 – 6.98 (m, 2H), 3.94 – 3.78 (m, 4H), 3.51 – 3.33 (m, 4H). Example 39 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically N-(4-fluorobenzyl)-5-isobutyl-2-(thiazol-2-ylsulfonyl)thiazol-4-carboxamide (WG1155), the preparation equation and method of which are as follows:

[0081] Using intermediate WG1153 and 4-fluorobenzylamine as starting materials, the target compound WG1155 was obtained after subsequent amidation and oxidation reactions, followed by separation and purification. The compound was a white solid with a yield of 71.0% (50 mg). HPLC purity was 98.3%. t R = 10.3 min). 1H NMR (500 MHz, CDCl3) δ 8.09 – 8.05 (m, 1H), 7.83 – 7.79 (m, 1H), 7.70 –7.64 (m, 1H), 7.31 – 7.27 (m, 2H), 7.05 – 6.97 (m, 2H), 4.53 (d, J = 6.2 Hz, 2H), 3.33 (d, J = 7.1 Hz, 2H), 2.08 – 1.97 (m, 1H), 1.01 (d, J = 6.6 Hz, 6H). ¹³CNMR (151 MHz, CDCl3) δ 164.0, 162.4 (d, J = 246.1 Hz), 161.0, 158.6, 155.1,146.1, 145.6, 133.8 (d, J = 3.2 Hz), 129.7 (d, J = 8.0 Hz, 2C), 127.8, 115.7 (d, J = 21.5 Hz, 2C), 42.6, 36.3, 31.3, 22.4 (2C). Example 40 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically N-(3,4-difluorophenyl)-2-(thiazol-2-ylsulfonyl)thiazol-4-carboxamide (XJM1055), and its preparation equation and method are as follows:

[0082] Ethyl 2-bromothiazol-4-carboxylic acid ester (0.50 g, 2.12 mmol, 1.0 eq) was dissolved in anhydrous ethanol (50 mL). Thiazole-2-thiol (0.37 g, 3.18 mmol, 1.5 eq) was added at 0 °C, and the mixture was stirred for 30 min. Then, sodium tert-butoxide (0.21 g, 3.18 mmol, 1.5 eq) was added, and the mixture was stirred at room temperature for another 6 h. The reaction progress was monitored by TLC. The reaction solution was extracted with dichloromethane, dried, concentrated, and then separated by column chromatography [petroleum ether / ethyl acetate = 20:1] to obtain the target product XJM1049 (330 mg, 65%). 1 H NMR (500 MHz, CDCl3) δ 8.17 (s, 1H), 7.91(d, J= 3.4 Hz, 1H), 7.51 (d, J = 3.4 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). XJM1049 (300 mg, 1.05 mmol) was dissolved in methanol (5 mL), and NaOH (310 mg, 5.26 mmol, dissolved in 2 mL water) was added. The mixture was stirred at room temperature for 2 h. After most of the methanol was evaporated, the precipitated white precipitate was filtered and dried under reduced pressure to obtain intermediate XJM1052 (280 mg, 96.5%), which was a white solid.

[0083] XJM1052 (50 mg, 0.16 mmol, 1.0 eq) and 3,4-difluoroaniline (43.8 mg, 0.34 mmol, 1.5 eq) were dissolved in dichloromethane (15 mL). HBTU (199 mg, 0.52 mmol, 3.0 eq) and DIPEA (67.8 mg, 0.52 mmol, 3.0 eq) were added at 0 °C, and the reaction mixture was stirred overnight at room temperature. The reaction progress was monitored by TLC. Subsequently, the reaction mixture was diluted with dichloromethane and extracted with water. After drying and concentration, the mixture was separated by column chromatography [petroleum ether / ethyl acetate = 3:1] to obtain the corresponding intermediate XJM1053 (46 mg, 73%). 1 H NMR (500 MHz, CDCl3)δ 9.00 (s, 1H), 8.16 (s, 1H), 7.86 (d, J = 3.4 Hz, 1H), 7.75 – 7.70 (m, 1H), 7.47 (d, J = 3.4 Hz, 1H), 7.19 (s, 1H), 7.10 – 7.03 (m, 1H). XJM1053 (60 mg, 0.15 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (79.1 mg, 0.45 mmol, 3.0 eq) was added at 0 °C. After the addition was complete, the mixture was stirred overnight at room temperature. After the reaction was complete, the system was diluted with dichloromethane (80 mL), and then diluted with petroleum ether / ethyl acetate = 5:1 to obtain the target compound XJM1055 (51 mg, 69%). HPLC purity was 95.0% (tR = 6.4 min).1 H NMR (500 MHz, CDCl3) δ 9.04 (s, 1H), 8.63 (s, 1H), 8.10 (d, J = 3.0 Hz, 1H), 7.87 (d, J = 3.0Hz, 1H), 7.79 – 7.75 (m, 1H), 7.32 – 7.27 (m, 1H), 7.17 – 7.11 (m, 1H). Example 41 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically N-(4-fluorophenyl)-2-[(4-fluorophenyl)sulfonyl]thiazol-5-carboxamide (WG1017), and its preparation equation and method are as follows:

[0084] Ethyl 2-bromothiazole-5-carboxylic acid ester (1.6 g, 6.8 mmol, 1.0 eq) was dissolved in anhydrous ethanol (150 mL), and 4-fluorothiophenol (1.73 g, 13.5 mmol, 1.5 eq) was added at 0 °C. After stirring for 30 min, sodium ethoxide was added, and the mixture was stirred at room temperature for another 6 h. The reaction progress was monitored by TLC. The post-treatment was the same as in 36-37a. The crude product was purified by column chromatography [petroleum ether / ethyl acetate = 50:1] to give ethyl 2-[(4-fluorophenyl)thio]thiazole-5-carboxylic acid ester WG1010, a white solid (1.44 g, 75%). ¹H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 7.45–7.39 (m, 2H), 7.13–7.05 (m, 2H), 4.39 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). WG1010 (1.4 g) was dissolved in methanol (10 mL) and THF (4 mL), and NaOH (0.61 g, dissolved in 3 mL of water) was added. The mixture was stirred at room temperature for 3 h. Subsequently, most of the methanol was evaporated, and the pH of the system was adjusted to 3–4 with 2 mol / L HCl aqueous solution at 0 °C. The precipitated white precipitate was separated by filtration and dried under reduced pressure to obtain 2-[(4-fluorophenyl)thio]thiazol-5-carboxylic acid WG1011 (1.1 g, 84%).

[0085] WG1011 (80.3 mg, 0.31 mmol, 1.0 eq) and 4-fluoroaniline (52.2 mg, 0.47 mmol, 1.5 eq) were dissolved in dichloromethane (15 mL). HBTU (237.9 mg, 0.62 mmol, 3.0 eq) and DIPEA (81.03 mg, 0.62 mmol, 3.0 eq) were added at 0 °C, and the reaction mixture was stirred overnight at room temperature. The mixture was then extracted with dichloromethane and water. The organic phase was dried, concentrated, and purified by column chromatography to obtain WG1016 (90 mg, 83%). ¹H NMR(500 MHz, CDCl3) δ 9.86 (s, 1H), 8.18 (s, 1H), 7.61–7.54 (m, 2H), 7.38–7.31(m, 2H), 7.16–7.09 (m, 2H), 7.05–6.98 (m, 2H). WG1016 (90 mg) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (m-CPBA, 283.6 mg, 1.64 mmol) was added at 0 °C. After the addition was complete, the reaction system was stirred overnight at room temperature. The post-treatment of this reaction system was the same as for 39a-A1. The crude product was purified by column chromatography [petroleum ether / ethyl acetate = 5:1] to give the target compound WG1017, a white solid, in 83% (69 mg) yield. HPLC purity 95.2% ( t R = 8.3 min). 1 H NMR (500MHz, DMSO- d 6) δ 10.75 (s, 1H), 8.76 (s, 1H), 8.18 (dd , J = 8.7, 4.9 Hz, 2H), 7.70 (dd, J = 8.9, 4.9 Hz, 2H), 7.58 (t, J = 8.6 Hz, 2H), 7.24 (t, J = 8.7 Hz, 2H). Example 42 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 2-[(4-fluorophenyl)sulfonyl]-N-(prop-2-yn-1-yl)thiazol-5-carboxamide (WG2014), and its preparation equation and method are as follows:

[0086] Intermediate WG1011 was condensed with prop-2-yn-1-amine, followed by further conversion to give the target compound WG2014, a white solid, in a two-step yield of 46.3% (36 mg). HPLC purity 95.9% ( t R = 6.1 min). 1 H NMR (500 MHz, CDCl3) δ 8.43 (s, 1H), 8.00 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.1 Hz,2H), 7.37 – 7.29 (m, 1H), 4.22 (dd, J = 5.8, 2.6 Hz, 2H), 2.31 (t, J = 2.6 Hz, 1H). Example 43 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 2-[(4-chlorophenyl)sulfonyl]-N-(4-fluorophenyl)thiazol-5-carboxamide (WG1050), and its preparation equation and method are as follows:

[0087] Intermediate WG1041 was condensed with 4-fluoroaniline, followed by further conversion to give the target compound WG1050, a white solid, in a two-step yield of 55% (32 mg). ¹H NMR (500 MHz, CDCl3) δ 10.32 (s, 1H), 8.68 (s, 1H), 7.90 – 7.82 (m, 2H), 7.58 – 7.50 (m, 2H), 7.44 – 7.36 (m, 2H), 7.18 – 7.10 (m, 2H). Example 44 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 2-[(4-chlorophenyl)sulfonyl]-N-(3,4-difluorophenyl)thiazol-5-carboxamide (WG1043), and its preparation equation and method are as follows:

[0088] Intermediate WG1041 was condensed with 3,4-difluoroaniline, followed by further conversion to give the target compound WG1043, a white solid, in a two-step yield of 69% (59 mg). ¹H NMR (500 MHz, CDCl3) δ 10.38 (s, 1H), 8.70 (s, 1H), 7.91 – 7.83 (m, 2H), 7.60 – 7.52 (m, 2H), 7.46 – 7.38 (m, 1H), 7.30 – 7.22 (m, 1H), 7.12 – 7.02 (m, 1H). Example 45 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 2-[(4-chlorophenyl)sulfonyl]-N-(3,4,5-trifluorophenyl)thiazol-5-carboxamide (WG1053), and its preparation equation and method are as follows:

[0089] Intermediate WG1041 was hydrolyzed to give the corresponding carboxylic acid, which was then condensed with 3,4,5-trifluoroaniline, followed by further conversion to give the target compound WG1053, a white solid, with a two-step yield of 81% (42 mg). ¹H NMR (500 MHz, CDCl3) δ 10.45 (s, 1H), 8.72 (s, 1H), 7.92 – 7.84 (m, 2H), 7.60 – 7.52 (m, 2H), 7.28 – 7.20 (m, 2H). Example 46 This embodiment provides an arylsulfonyl-substituted thiazole amide compound, specifically 2-[(4-chlorophenyl)sulfonyl]-N-(2-cyclohexylethyl)thiazole-5-carboxamide (WG1047), and its preparation equation and method are as follows:

[0090] Intermediate WG1041 was hydrolyzed to obtain the corresponding carboxylic acid, which was then condensed with 2-cyclohexylethylamine, followed by further conversion to give the target compound WG1047, a white solid, with a two-step yield of 84.5% (133.4 mg). HPLC purity 99.9%. t R = 11.4 min). ¹H NMR (500 MHz, CDCl3) δ 8.16 (s, 1H), 8.08 (d, J = 8.3 Hz, 2H), 7.54 (d, J= 8.1 Hz, 2H), 6.24 (d, J = 5.9 Hz, 1H), 3.43 (q, J = 6.8 Hz, 2H),1.69 (s, 5H), 1.47 (d, J = 7.4 Hz, 1H), 1.33 – 1.06 (m, 5H), 0.97 – 0.87 (m, 2H). Example 47 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 2-[(4-chlorophenyl)sulfonyl]-4-methyl-N-(prop-2-yn-1-yl)thiazol-5-carboxamide (WG2035), the preparation equation and method of which are as follows:

[0091] Ethyl 2-chloro-4-methylthiazol-5-carboxylate (1 g, 4.8 mol) was dissolved in anhydrous ethanol (50 mL), and 4-chlorothiophenol (1.4 g, 9.7 mol) was added at 0 °C, followed by stirring for 30 min. Sodium tert-butoxide (0.9 g, 9.7 mol) was then added, and the resulting mixture was stirred at room temperature for 6 h. The reaction progress was monitored by TLC until the reactants were completely reacted. The reaction solution was extracted with dichloromethane (2 × 200 mL), and the combined organic phases were washed successively with water (2 × 100 mL) and saturated brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography [PE / EA = 20 / 1] to give ethyl 2-[(4-chlorophenyl)thio]-4-methylthiazol-5-carboxylate WG1154 (1.5 g, 85%).

[0092] WG1154 (1.5 g, 0.95 mol) was dissolved in methanol (5 mL), and NaOH (0.5 g, 1.4 mol, dissolved in 2 mL water) was added. The reaction mixture was stirred at room temperature for 2 h, and then most of the methanol was evaporated. The precipitated white precipitate was separated by suction filtration and dried under reduced pressure to give 2-[(4-chlorophenyl)thio]-4-methylthiazol-5-carboxylic acid WG1156 (800 mg, 76.2%) as a white solid. 1 H NMR (500 MHz, MeOD) δ 7.84 – 7.62 (m, 2H), 7.57 – 7.55 (m, 2H), 2.60 (s, 3H). WG1156 (40 mg, 0.12 mmol) and propargyl-1-amine (47.4 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL), and HBTU (199 mg, 0.52 mmol) and DIPEA (67.8 mg, 0.52 mmol) were added at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction solution was extracted with dichloromethane (2 × 80 mL), and the combined organic phases were washed successively with water (2 × 50 mL) and saturated brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography [PE / EA = 3 / 1] to give 2-[(4-chlorophenyl)thio]-4-methyl-N-(propargyl-1-yl)thiazolyl-5-carboxamide WG2032 (40 mg, 73%). ¹H NMR (500 MHz, CDCl3)7.61 (d, J = 8.4 Hz, 2H), 7.45(d, J = 8.2 Hz, 2H), 4.20 – 4.11 (m, 2H), 2.65 (s, 3H), 2.30 – 2.24 (m, 1H), 1.33 – 1.24 (m, 1H). WG1074 (40 mg, 0.12 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (47.4 mg, 0.37 mmol) was added at 0 °C. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction solution was then diluted with dichloromethane (80 mL), washed successively with Na2S2O3 aqueous solution (50 mL) and saturated brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography [PE / EA = 5 / 1] to give 2-[(4-chlorophenyl)sulfonyl]-4-methyl-N-(prop-2-yn-1-yl)thiazolyl-5-carboxamide WG2035 (27 mg, 46%). HPLC purity 99.9% ( t R =6.7 min). ¹H NMR (500 MHz, CDCl3) δ 7.48 (t, J = 5.9 Hz, 1H), 7.92 – 7.84 (m,2H), 7.60 – 7.52 (m, 2H), 4.22 (dd, J = 5.0, 2.6 Hz, 2H), 2.64 (s, 3H), 2.27(q, J= 2.2 Hz, 1H). ¹³C NMR (151 MHz, CDCl3) δ 165.4, 160.1, 157.9, 141.8,136.7, 132.3, 130.4 (2C), 130.1 (2C), 78.5, 72.7, 30.2, 17.5. Example 48 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 5-(4-chlorophenylsulfonyl)-N-(4-fluorophenyl)-1,3,4-thiadiazole-2-carboxamide (WG1060), and its preparation equation and method are as follows:

[0093] Ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylic acid ester (1.0 g, 4.22 mmol, 1.0 eq) and 4-chlorothiophenol (1.2 g, 8.44 mmol, 2.0 eq) were dissolved in acetonitrile (20 mL), and K2CO3 (1.16 g, 8.44 mmol, 2.0 eq) was added at 0 °C. After two hours, the reaction was monitored by TLC until it ended. The reaction system was diluted with dichloromethane, then extracted with water. The organic layer was dried and concentrated, and the crude product was purified by column chromatography [petroleum ether / ethyl acetate = 20:1 to 5:1] to give ethyl 5-[(4-chlorophenyl)thio]-1,3,4-thiadiazole-2-carboxylic acid ester WG1054 (1.2 g, 96%). ¹H NMR (500MHz, CDCl3) δ 7.7 – 7.6 (m, 2H), 7.5 – 7.4 (m, 2H), 4.5 – 4.4 (m, 2H), 1.4 –1.4 (m, 3H). WG1054 (1.22 g, 3.99 mmol, 1.0 eq) was dissolved in methanol (5 mL), and NaOH (477 mg, 11.9 mmol, 3.0 eq dissolved in 3 mL water) was added. The reaction mixture was stirred at room temperature for 2 h, and most of the methanol was evaporated. The precipitated white precipitate was filtered and dried under reduced pressure to obtain sodium 5-[(4-chlorophenyl)thio]-1,3,4-thiadiazole-2-carboxylate WG1055 (1.12 g, 97%), a white solid.

[0094] WG1055 (70 mg, 0.25 mmol, 1.0 eq) and 4-fluoroaniline (57.25 mg, 0.51 mmol, 2.0 eq) were dissolved in dichloromethane (15 mL), and HBTU (293.1 mg, 0.77 mmol, 3.0 eq) and DIPEA (99.8 mg, 0.77 mmol, 3.0 eq) were added at 0 °C. The reaction mixture was stirred overnight at room temperature. Subsequent post-treatment yielded 5-[(4-chlorophenyl)thio]-N-(4-fluorophenyl)-1,3,4-thiadiazole-2-carboxamide WG1056 (60 mg, 68.1%). ¹H NMR (500 MHz, CDCl3) δ 8.96 (s, 1H), 7.71 – 7.58 (m, 4H), 7.54–7.43(m, 2H), 7.08 (t, J = 8.7 Hz, 2H). WG1056 (60 mg, 0.16 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (m-CPBA, 127.4 mg, 0.49 mmol, 3.0 eq) was added at 0 °C. The reaction mixture was stirred overnight at room temperature. The reaction mixture was post-treated as in 39a-A1, finally yielding compound WG1060 as a white solid in 73% (50 mg) yield. HPLC purity 94.90% ( t R = 10.8 min). ¹H NMR (500 MHz, CDCl3) δ 10.42 (s, 1H), 8.02(d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 7.66 – 7.58 (m, 2H), 7.19 – 7.10(m, 2H). Example 49 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically N-(4-fluorobenzyl)-5-[(4-fluorophenyl)sulfonyl]-1,3,4-thiadiazole-2-carboxamide (WG1085), and its preparation equation and method are as follows:

[0095] The intermediate WG1055 was condensed with 4-fluorobenzyl and then oxidized to give the target compound WG1084, a white solid, with a two-step yield of 85% (55 mg). 1H NMR (500 MHz, CDCl3) δ 8.01 (dd, J = 4.4, 2.5 Hz, 2H), 7.92 (d, J = 7.8 Hz, 1H), 7.59 (t , J = 6.0 Hz, 1H), 7.52 (d, J = 6.6 Hz, 2H), 7.36 (t, J = 7.9 Hz, 1H), 7.25–7.22 (m, 1H), 6.97 (d, J = 8.4 Hz, 1H), 4.54 (d, J =6.1 Hz, 2H). 13 C NMR (151 MHz, CDCl3) δ 173.6, 170.1, 169.5, 162.6 (d, J =246.0Hz), 156.4, 142.7, 130.7, 130.4 (d, J = 2.8 Hz, 2C), 130.0 – 129.8 (m,2C), 128.4(2C), 116.0 (d, J = 21.7 Hz, 2C), 43.5. Example 50 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically N-(3,4-difluorophenyl)-5-[(4-fluorophenyl)sulfonyl]-1,3,4-thiadiazole-2-carboxamide (WG1030), and its preparation equation and method are as follows:

[0096] Intermediate WG1021 was condensed with 3,4-difluoroaniline, followed by further conversion to give the target compound WG1030, a white solid, with a two-step yield of 65% (32 mg). 1 H NMR (500 MHz, CDCl3) δ 8.23 ​​– 8.16 (m,2H), 7.79 – 7.75 (m, 1H), 7.37 – 7.29 (m, 3H), 7.19 (q, J = 9.0 Hz, 1H). Example 51 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 4-[(4-chlorophenyl)sulfonyl]-N-(4-fluorophenyl)thiazol-2-carboxamide (WG3003), and its preparation equation and method are as follows:

[0097] Methyl 4-bromothiazol-2-carboxylate (500 mg, 2.4 mmol, 1.0 eq) was dissolved in acetonitrile (20 mL), and 4-chlorothiophenol (623.2 mg, 4.8 mmol, 2.0 eq) was added at 0 °C. After stirring for 30 min, CuI and 2,2'-bipyridine were added sequentially. The reaction mixture was stirred overnight at room temperature, and the reaction progress was monitored by TLC. Subsequently, routine post-treatments such as extraction and column chromatography were performed to obtain methyl 4-[(4-chlorophenyl)thio]thiazol-2-carboxylate WG2103 (350 mg, 49.1%). 1 H NMR (500 MHz, CDCl3) δ 7.53 – 7.48 (m, 2H), 7.14 (s, 1H), 7.11 – 7.03 (m, 2H), 4.00 (s, 3H). WG2103 (350 mg, 1.1 mmol, 1.0 eq) was dissolved in THF (10 mL), and NaOH (140.8 mg, 3.56 mmol, 3.0 eq, dissolved in 2 mL water) was added. The mixture was stirred at room temperature for 2 h. Subsequently, most of the THF was evaporated, and the precipitated white precipitate was separated by filtration and dried under reduced pressure to obtain 4-[(4-chlorophenyl)thio]thiazole-2-carboxylic acid WG2015, a white solid (200 mg, 69.9%).

[0098] WG2015 (50 mg, 0.18 mmol, 1.0 eq) and 4-fluoroaniline (51.6 mg, 0.37 mmol, 2.0 eq) were dissolved in dichloromethane (15 mL), and HBTU (211.2 mg, 0.55 mmol, 3.0 eq) and DIPEA (71.9 mg, 0.55 mmol, 3.0 eq) were added at 0 °C. The reaction mixture was then diluted with dichloromethane, followed by extraction with water. After drying and concentration, the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give 4-[(4-chlorophenyl)thio]-N-(4-fluorophenyl)thiazole-2-carboxamide WG2016 (40 mg, 70.5%).

[0099] WG2016 (40 mg, 0.11 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (m-CPBA, 59.6 mg, 0.34 mmol, 3.0 eq) was added at 0 °C. Post-processing yielded the target compound WG3003 (40 mg, 74.1%). HPLC purity: 94.5% ( t R = 8.4 min). 1 H NMR (500 MHz, CDCl3) δ8.84 (s, 1H), 8.47 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.64 (dd, J = 8.9, 4.7Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.09 (t, J = 8.5 Hz, 2H). Example 52 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 4-[(4-chlorophenyl)sulfonyl]-N-(4-fluorobenzyl)thiazol-2-carboxamide (WG3001), and its preparation equation and method are as follows:

[0100] Intermediate WG2194 was hydrolyzed to obtain the corresponding carboxylic acid, which was then condensed with 4-fluorobenzylamine to generate the corresponding intermediate. Further conversion yielded the target compound WG3001, a white solid, with a two-step yield of 55.9% (30 mg). HPLC purity 99.9%. t R = 7.5 min). 1 H NMR (500 MHz, CDCl3) δ 8.41 (s, 1H), 7.95 (d, J =8.2 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.43 (t, J = 6.2 Hz, 1H), 7.30 (dd, J =8.4, 5.3 Hz, 2H), 7.03 (t, J = 8.6 Hz, 2H), 4.56 (d, J= 6.2 Hz, 2H). ¹³C NMR(151 MHz, CDCl3) δ 166.6, 162.6 (d, J = 247.6 Hz), 158.1, 154.6, 141.2, 137.7,132.8 (d , J = 3.3 Hz, 2C), 131.0, 130.0 (2C), 129.9 (d, J = 4.5 Hz, 2C), 124.6, 115.9 (d, J = 21.6 Hz, 2C), 43.3. Example 53 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically 4-[(4-chlorophenyl)sulfonyl]-N-(prop-2-yn-1-yl)thiazol-2-carboxamide (WG3004), and its preparation equation and method are as follows:

[0101] Intermediate WG2194 was condensed with propargyl-1-amine, followed by further conversion to give the target compound WG3004, a white solid, with a two-step yield of 55.9% (35 mg). HPLC purity 99.0% ( t R = 6.5 min). 1 H NMR (500 MHz, CDCl3) δ 8.43 (s, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.3 Hz,2H), 7.37 – 7.29 (m, 1H), 4.22 (dd, J = 5.8, 2.6 Hz, 2H), 2.31 (t, J = 2.6 Hz,1H).¹³C NMR (151 MHz, CDCl3) δ 165.9, 157.8, 154.7, 141.2, 137.7, 131.0,130.1 (2C), 130.0 (2C), 78.2, 72.7, 29.7 (d, J = 32.1 Hz). Example 54 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically N-(4-fluorophenyl)-4-[(4-fluorophenyl)sulfonyl]thiazol-2-carboxamide (WG2110), and its preparation equation and method are as follows:

[0102] Intermediate WG2105 was condensed with 4-fluoroaniline to form intermediate 60d. Subsequent oxidation yielded the target compound WG2110, a white solid, in 65% (41 mg) yield. HPLC purity: 96.9%. t R = 7.5 min). ¹H NMR (500MHz, CDCl3) δ 8.92 (s, 1H), 8.47 (s, 1H), 8.13 – 8.09 (m, 2H), 7.68 – 7.60(m, 2H), 7.27 (d, J = 3.6 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H), 7.11 – 7.03 (m,2H). 13 C NMR (151 MHz, CDCl3) 166.9,166.2 (d, J = 258.2 Hz), 160.1 (d, J = 244.6Hz), 155.9, 154.7, 135.2 (d, J = 3.2 Hz), 132.5 (d, J = 2.9 Hz), 131.5 (d, J =9.7 Hz, 2C), 131.2, 122.1 (d, J = 8.1 Hz, 2C), 117.0 (d, J = 22.8 Hz, 2C), 116.1(d, J = 22.7 Hz, 2C). Example 55 This embodiment provides an arylsulfonyl-substituted thiazole amide compound, specifically N-(3,4-difluorophenyl)-4-[(4-fluorophenyl)sulfonyl]thiazole-2-carboxamide (WG3002), and its preparation equation and method are as follows:

[0103] Intermediate WG2193 was condensed with 3,4-difluoroaniline, followed by further conversion to give the target compound WG3002, a white solid, with a two-step yield of 61% (35 mg). HPLC purity 90.1% ( t R = 6.4 min). ¹H NMR(500 MHz, CDCl3) δ 8.95 (s, 1H), 8.50 (s, 1H), 8.15 – 8.10 (m, 2H), 7.68 –7.60 (m, 2H), 7.45 – 7.38 (m, 1H), 7.28 – 7.20 (m, 1H), 7.12 – 7.04 (m, 1H). Example 56 This embodiment provides an arylsulfonyl-substituted thiazolamide compound, specifically N-(4-fluorobenzyl)-4-[(4-fluorophenyl)sulfonyl]thiazol-2-carboxamide (WG2200), and its preparation equation and method are as follows:

[0104] Intermediate WG2193 was condensed with 4-fluorobenzylamine to form the corresponding intermediate, which was then further converted to give the target compound WG2200. White solid, two-step yield 43.5% (20.3 mg). HPLC purity 99.9% ( t R = 6.8 min).¹H NMR (500 MHz, CDCl3) δ 8.41 (s, 1H), 8.05 (dd, J = 8.8, 5.1 Hz, 2H), 7.46(t, J = 6.1 Hz, 1H), 7.30 (dd, J = 8.4, 5.3 Hz, 2H), 7.22 (t, J = 8.4 Hz, 2H), 7.03 (t, J = 8.5 Hz, 2H), 4.57 (d, J = 6.2 Hz, 2H). 13 C NMR (151 MHz, CDCl3) δ166.6,166.2 (d, J = 258.2 Hz), 162.6 (d, J = 246.1 Hz) 158.1, 154.8, 135.2 (d, J= 3.1 Hz), 132.9 (d, J = 3.4 Hz), 131.5 (2C), 130.7, 130.0 (d, J = 8.2 Hz, 2C), 117.0 (d, J = 22.8 Hz, 2C), 115.9 (d, J = 21.5 Hz, 2C), 43.3. Bioactivity experiment 1. Method for detecting the anti-HBV activity of the compounds of this invention (1) Experimental methods An HBV replication model was established using HepAD38 cells. Cells were seeded in multi-well plates, and after tetracycline-induced HBV replication was removed, different concentrations (5 μM, 10 μM) of the compound of this invention were added for treatment. After treatment, the cell culture supernatant was collected, and HBV DNA levels were detected using real-time quantitative PCR; the IC50 of the compound was calculated based on the inhibition curve. 50 The anti-HBV activity of the compounds of this invention was evaluated by measuring the expression levels of HBV core protein (HBc) before and after compound treatment. Cell lysates were collected, and SDS-PAGE combined with Western blot was used to detect the expression level of HBV core protein (HBc). The anti-HBV activity of the compounds of this invention was evaluated by comparing the changes in HBV DNA levels and HBc protein expression levels before and after compound treatment.

[0105] (2) Experimental results The results of the anti-HBV activity experiments are shown in Tables 1 and 2: Table 1. Inhibition rate of some compounds against HBV DNA

[0106] Table 2 IC50 values ​​for some compounds 50 value

[0107] The results in Tables 1 and 2 show that the compounds in most of the embodiments of the present invention have an inhibition rate of HBV DNA replication greater than or close to that of the candidate new drug for anti-hepatitis B virus, isothifludin (NZ-4), at concentrations of 5 μM or 10 μM, indicating that they exhibit good anti-HBV activity in the HepAD38 cell model.

[0108] 2. Cytotoxicity detection of the compounds of this invention (1) Experimental methods The cytotoxicity of the compounds of this invention against HepAD38 cells was detected using the CCK-8 assay. Cells were co-incubated with different concentrations of the compounds of this invention, and cell viability was measured. The CCK-8 cytotoxicity of the compounds was calculated based on the dose-response curves. 50 The values ​​are used to evaluate the cytotoxicity of the compounds of this invention.

[0109] (2) Experimental results IC50 of some compounds 50 The CC50 data are shown in Table 3: Table 3

[0110] The results in Table 3 show that the compounds in most of the embodiments of the present invention are less toxic than isothiazines.

[0111] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. An arylsulfonyl-substituted thiazolidinyl amide compound, characterized in that, Its structural formula is shown in formula A: Formula A; Among them, the five-membered ring containing X1, X2 and X3 is a thiazole ring, and X1, X2 and X3 are independently selected from N, S or CR3 respectively; in the thiazole ring, the number of S atoms is 1, and the number of N atoms is 1 or 2; R1 is a substituted or unsubstituted C6-C60 aryl group or a substituted or unsubstituted C5-C60 heteroaryl group; R2 is a substituted or unsubstituted C1-C40 alkyl, a substituted or unsubstituted C1-C40 heteroalkyl, a substituted or unsubstituted C2-C40 alkenyl, a substituted or unsubstituted C2-C40 alkynyl, a substituted or unsubstituted C3-C40 cycloalkyl, a substituted or unsubstituted C3-C40 heterocycloalkyl, a substituted or unsubstituted C6-C60 aryl, a substituted or unsubstituted C5-C60 heteroaryl, a substituted or unsubstituted C1-C40 alkoxy, or a substituted or unsubstituted C6-C60 aryloxy. R3 is hydrogen, deuterium, halogen, cyano, nitro, substituted or unsubstituted C1-C40 alkyl, or substituted or unsubstituted C3-C40 heterocyclic alkyl. The substitutions of R1, R2, and R3 are independently deuterated, halogenated, cyano, isocyanate, phosphine, hydroxyl, or C1. C6 alkyl, C1-C6 alkoxy, C3 C16 cycloalkyl, C1 C6 alkyl-substituted amino group, C1 C6 hydrocarbon group substituted or unsubstituted C6 C30 aryl, halogen-substituted C6 C30 aryl, C1 C6 hydrocarbon group substituted or unsubstituted C3 At least one of the C30 heteroaryl groups is substituted, wherein the number of substitutions ranges from monosubstituted to the maximum number of substitutions.

2. The arylsulfonyl-substituted thiazolidinamide compound according to claim 1, characterized in that, The structural formulas of the arylsulfonyl-substituted thiazolamide compounds are shown in Formulas I-IV: 。 3. The arylsulfonyl-substituted thiazolidinamide compound according to claim 1, characterized in that, R1 is a substituted or unsubstituted phenyl or a substituted or unsubstituted C5-C10 heteroaryl group; The substitution of R1 is independently of halogenated C1. The substituted substance is at least one of C6 alkyl or C1-C6 alkoxy groups, wherein the number of substitutions ranges from monosubstituted to the maximum number of substitutions.

4. The arylsulfonyl-substituted thiazolidinamide compound according to claim 1, characterized in that, R2 is a substituted or unsubstituted C1-C15 alkyl, a substituted or unsubstituted C2-C15 alkynyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C3-C8 heterocycloalkyl, or a substituted or unsubstituted C6-C10 aryl. The substitution of R2 is independently determined by halogen, hydroxyl group, or C1. C6 alkyl, cyano, halogen-substituted C6 C10 aryl, C3 At least one of the C8 cycloalkyl groups is substituted, wherein the number of substitutions ranges from monosubstituted to the maximum number of substitutions.

5. The arylsulfonyl-substituted thiazolidinamide compound according to claim 3, characterized in that, R2 is a substituted or unsubstituted C1-C10 alkyl, a substituted or unsubstituted C2-C10 alkynyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C3-C6 heterocyclic alkyl, or a substituted or unsubstituted phenyl. The substitution of R2 is independently determined by halogen, hydroxyl group, or C1. C6 alkyl, cyano, halogen-substituted phenyl, C3 At least one of the C8 cycloalkyl groups is substituted, wherein the number of substitutions ranges from monosubstituted to the maximum number of substitutions.

6. The arylsulfonyl-substituted thiazolidinamide compound according to claim 1, characterized in that, R3 is a C1-C6 alkyl or a C3-C10 heterocyclic alkyl.

7. A method for preparing the arylsulfonyl-substituted thiazole amide compound according to any one of claims 1-6, characterized in that, Includes the following steps: The arylsulfonyl-substituted thiazole compounds are prepared by reacting sulfonyl-substituted thiazole amide compounds with amine compounds. The structural formulas of the sulfonyl-substituted thiazole compounds and the amine compounds are shown in Formula 5 and Formula 6, respectively: Formula 5 Formula 6; The definitions of X1, X2, X3, R1, R2, and R3 are as described in any one of claims 1-6.

8. The method for preparing arylsulfonyl-substituted thiazolidinyl amide compounds according to claim 8, characterized in that, The preparation method of the sulfonyl-substituted thiazole compound includes the following steps: Thiazole carboxylic acid esters undergo nucleophilic substitution reactions with substituted thiophenols to generate the corresponding thioether intermediates; these intermediates are then oxidized to obtain sulfone intermediates; subsequently, they are hydrolyzed to carboxylic acids to prepare the sulfonyl-substituted thiazole compounds. The structural formulas of the thiazole carboxylic acid esters, substituted thiophenols, thioether intermediates, and sulfone intermediates are shown in Formulas 1-4, respectively: Formula 1 Formula 2 Formula 3 Formula 4.

9. The use of the arylsulfonyl substituted thiazolidinamide compound according to any one of claims 1-6 in the preparation of a medicament for the prevention or treatment of hepatitis B virus infection.

10. The application according to claim 9, characterized in that, The drug is a hepatitis B virus capsid assembly modulator.

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