Benzenesulfonamide triazole derivative as well as preparation method and application thereof

Abstract

The invention discloses a benzenesulfonamide triazole derivative as well as a preparation method and application thereof, and is characterized in that the benzenesulfonamide triazole derivative has a structural formula shown as a formula I and a formula II or pharmaceutically acceptable salt, ester or solvate of the benzenesulfonamide triazole derivative with the structural formula shown as the formula I and the formula II, x is a carbonyl group, a sulfonyl group or a sulfuryl group; r1 is o-fluorophenyl, p-trifluoromethoxyphenyl, o-methoxyphenyl, o-methoxyanilino, p-methoxyphenyl, pyrimidine, thiazole, oxazole, methylthiophene, amino and methylamino, and the compound has the advantages that the compound can effectively inhibit CDK, the selectivity to CDK1 is higher than that of other subtype and / or eukaryotic tumor cell proliferation, and tumors are prevented and / or treated.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, and particularly relates to a benzylsulfonamide triazole derivative, its preparation method, and its uses. Background Technology

[0002] Cyclin-dependent kinases (CDKs) are a class of serine / threonine protein kinases that play a central regulatory role in cell cycle progression, DNA replication, transcriptional regulation, and cell differentiation. Members of the CDK family (including CDK1, CDK2, CDK4 / 6, CDK7, and CDK9) bind to their corresponding cyclin compounds to form complexes that mediate the phosphorylation of key substrates, thereby controlling cell cycle progression.

[0003] In tumor cells, CDK pathways are commonly overactivated, leading to uncontrolled cell cycle checkpoints and persistent proliferation. CDK1, in particular, as the terminal executive kinase of the cell cycle, is responsible for regulating the G2 / M phase transition and the initiation of mitosis. Abnormal CDK1 activity is closely related to the high proliferation and genomic instability of various malignant tumors (including breast cancer, lung cancer, liver cancer, and ovarian cancer). Studies have shown that CDK1 controls the transition of mammalian cells from G2 to M phase, playing an indispensable role throughout the cell cycle. Even without interphase CDKs (CDK2, 3, 4, 6), CDK1 can still drive the cell cycle and propel cells to complete mitosis. Therefore, inhibitors with good CDK1 inhibition are urgently needed for tumor treatment. Although the importance of CDK1 is widely recognized, no highly selective CDK1 inhibitors have been approved clinically to date. Existing pan-CDK inhibitors often inhibit CDK1 along with strong inhibition of other CDKs such as CDK2, CDK5, CDK7, and CDK9, resulting in a narrow therapeutic window. Therefore, developing a pan-CDK inhibitor with excellent selectivity for CDK1 (i.e., effectively inhibiting CDK1 while significantly reducing the inhibitory activity of other CDKs, especially key members such as CDK2, CDK4, CDK6, CDK7, and CDK9) has significant clinical significance and application value in tumor treatment. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a benzylsulfonamide triazole derivative with high selectivity against CDK1, which inhibits the proliferation of eukaryotic tumor cells and prevents and / or treats tumors, as well as its preparation method and uses.

[0005] The technical solution adopted by the present invention to solve the above-mentioned technical problem is: a benzylsulfonamide triazole derivative, wherein the compound has a benzylsulfonamide triazole derivative having the structural formula shown in Formula I and II or a pharmaceutically acceptable salt of a benzylsulfonamide triazole derivative having the structural formula shown in Formula I and II. , Wherein, X is carbonyl, sulfonyl, or thioyl; R1 is o-fluorophenyl, p-trifluoromethoxyphenyl, o-methoxyphenyl, o-methoxyaniline, p-methoxyphenyl, pyrimidine, thiazole, oxazole, methylthiophene, amino, or methylamino; pharmaceutically acceptable salts of the compounds shown in Formulas I and II above are inorganic acid salts or organic acid salts, wherein the inorganic acid salt is a salt formed from any one of the inorganic acids selected from hydrochloric acid, sulfuric acid, and phosphoric acid; and the organic acid salt is a salt formed from any one of the organic acids selected from acetic acid, trifluoroacetic acid, malonic acid, citric acid, and p-toluenesulfonic acid.

[0006] Preferably, the compound has at least one of the following structural formulas: .

[0007] More preferably, the compound has at least one of the following structural formulas: .

[0008] A further preferred embodiment of the compound has the following structural formula: .

[0009] The above-mentioned benzylsulfonamide triazole derivatives and their preparation methods include the following steps: (1) The compound shown in Formula III is subjected to a substitution reaction with the compound shown in Formula IV to obtain the compound shown in Formula V; (2) The compound shown in formula V is subjected to a cyclization reaction with hydrazine hydrate to obtain the compound shown in formula VI; (3) The compound shown in Formula VI is subjected to an amidation reaction with the compound shown in Formula VII, or Formula VIII, or Formula IX, or Formula X, or Formula XI, to obtain two different types of compounds shown in Formula I and II respectively; Where X is carbonyl, sulfonyl, or thioyl; and R1 is o-fluorophenyl, p-trifluoromethoxyphenyl, o-methoxyphenyl, o-methoxyaniline, p-methoxyphenyl, pyrimidine, thiazole, oxazole, methylthiophene, amino, or methylamino.

[0010] Further, step (1) specifically involves reacting the compound shown in formula III with the compound shown in formula IV in tetrahydrofuran at 70-90℃ for 2-8 h in a molar ratio of 1:(1-1.5) to obtain the compound shown in formula V.

[0011] Further, step (2) specifically involves reacting the compound shown in formula V with hydrazine hydrate in a molar ratio of 1:(2-4) in tetrahydrofuran at 70-90℃ for 2-8 h to obtain the compound shown in formula VI.

[0012] Further, step (3) specifically involves: reacting the compounds shown in formulas VII and VI in anhydrous pyridine at 25-55°C for 6-12 h in a molar ratio of 1:(1-2) to obtain the carbonylphenyl-substituted compound at position 4 shown in formula I; reacting the compounds shown in formulas VIII and VI in anhydrous pyridine at a molar ratio of 1:(1-2) for 6-12 h to obtain the two types of compounds with sulfonylphenyl-substituted compounds at positions 4 and 5 shown in formulas I and II, respectively; and reacting the compounds shown in formulas IX and VI, the condensing agent DIC, and the activator HOBt in anhydrous pyridine at a molar ratio of 1:(1-2):(1-3):(1-3) in anhydrous pyridine. N,N The compound with carbonyl aromatic heterocyclic substitution at position 4, as shown in Formula I, is obtained by reacting it in dimethylformamide for 8-20 h; the compound with carbonyl amino substitution or thioyl aniline at position 4, as shown in Formula I, is obtained by reacting it in tetrahydrofuran for 6-12 h with the compound of Formula X or XI in a molar ratio of 1:(1-2) using sodium hydroxide as a base.

[0013] The present invention also provides the use of the above-mentioned benzyl sulfonamide triazole CDK inhibitor in the preparation of drugs for inhibiting the proliferation of eukaryotic tumor cells, wherein the tumor cells include cervical cancer cells HeLa, breast cancer cells MDA-MB-231, lung cancer cells H460, colon cancer cells HCT-116, liver cancer cells HepG2, and gastric cancer cells SGC7901.

[0014] The present invention also provides the use of the above-mentioned benzyl sulfonamide triazole CDK inhibitor in the preparation of CDK1 / CyclinB1 activity inhibitors.

[0015] The present invention also provides the use of the above-mentioned benzyl sulfonamide triazole CDK inhibitor in inducing apoptosis and G2-M phase arrest in HCT-116 cells.

[0016] Compared with existing technologies, the advantages of this invention are as follows: This invention relates to a method for preparing a benzylsulfonamide triazole CDK inhibitor and its uses. This compound can effectively inhibit CDK activity, inhibit the proliferation of eukaryotic tumor cells, and prevent and / or treat tumors. The compound provided by this invention has been tested on various tumor cell lines; its activity inhibition tests include CDK1 / Cyclin B1, CDK2 / Cyclin E1, CDK4 / Cyclin D1, and Aurora A; and its apoptosis and cell cycle experiments have been conducted to detect the compound's induction of tumor cell apoptosis and cell cycle arrest. These results demonstrate that the compound of this invention is a potential CDK inhibitor and an anti-tumor drug with strong anti-tumor cell proliferation activity. The raw materials for the compound provided by this invention are readily available, the preparation method is relatively simple, and a series of small molecule inhibitors targeting CDK have been designed and synthesized. Experiments have shown that they have good anti-cancer effects and have good application prospects in the field of anti-tumor drug design and development. Attached Figure Description

[0017] Figure 1 The results of flow cytometry apoptosis detection of compound 11 according to an embodiment of the present invention are shown. Figure 2 The diagram shows a cell cycle detection of compound 11 according to an embodiment of the present invention. Detailed Implementation

[0018] The present invention will be further described in detail below with reference to the accompanying drawings and embodiments.

[0019] The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. Where specific techniques or conditions are not specified in the embodiments, they shall be performed in accordance with the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments used, unless otherwise specified, are all conventional products that can be purchased commercially. In this document, "the compound represented by formula N" is sometimes also referred to as "compound N," where N is any integer from 1 to 18; for example, "the compound represented by formula 2" may also be referred to as "compound 2." Specific Implementation Example 1 A CDK inhibitor, wherein the compound is a pharmaceutically acceptable salt, ester or solvate of a compound having the structural formulas shown in Formulas I and II.

[0021] , Wherein, X is carbonyl, sulfonyl, or thioyl; R1 is o-fluorophenyl, p-trifluoromethoxyphenyl, o-methoxyphenyl, o-methoxyaniline, p-methoxyphenyl, pyrimidine, thiazole, oxazole, methylthiophene, amino, or methylamino; pharmaceutically acceptable salts of the compounds shown in Formulas I and II above are inorganic acid salts or organic acid salts, wherein the inorganic acid salt is a salt formed from any one of the inorganic acids selected from hydrochloric acid, sulfuric acid, and phosphoric acid; and the organic acid salt is a salt formed from any one of the organic acids selected from acetic acid, trifluoroacetic acid, malonic acid, citric acid, and p-toluenesulfonic acid.

[0022] The CDK inhibitors shown in Formulas I and II above are preferably any one of the following:

[0023] This compound can effectively inhibit CDK activity, suppress the proliferation of eukaryotic tumor cells, and prevent and / or treat tumors. The compound provided by this invention has been tested on various tumor cell lines; its activity is inhibited by CDK1 / Cyclin B1, CDK2 / Cyclin E1, CDK4 / Cyclin D1, and Aurora A; and apoptosis and cell cycle experiments were conducted to detect the compound's induction of tumor cell apoptosis and cell cycle arrest. These results demonstrate that the compound of this invention is a potential CDK inhibitor and an antitumor drug with strong anti-tumor cell proliferation activity. Specific Implementation Example 2 The above specific embodiment of a method for preparing a CDK inhibitor includes the following steps: (1) The compound shown in Formula III is subjected to a substitution reaction with the compound shown in Formula IV to obtain the compound shown in Formula V; according to an embodiment of the present invention, it can be specifically carried out by reacting the compound shown in Formula III and the compound shown in Formula IV in tetrahydrofuran at 70-90°C for 2-8 h in a molar ratio of 1:(1-1.5) to obtain the compound shown in Formula V; thereby, it is beneficial to improve the reaction efficiency, reduce side reactions, and increase the yield.

[0025] (2) The compound shown in Formula V is subjected to a cyclization reaction with hydrazine hydrate to obtain the compound shown in Formula VI; or more specifically, the compound shown in Formula V is reacted with hydrazine hydrate in tetrahydrofuran at a molar ratio of 1:(2-4) at 70-90℃ for 2-8h to obtain the compound shown in Formula VI; thereby, it is beneficial to improve the reaction efficiency, reduce side reactions, and increase the yield.

[0026] (3) The compound shown in Formula VI is subjected to an amidation reaction with Formula VII, or Formula VIII, or Formula IX, or Formula X, or Formula XI to obtain two different types of compounds shown in Formula I and II, respectively; or more specifically: the compounds shown in Formula VII and Formula VI are reacted in anhydrous pyridine at 25-55°C in a molar ratio of 1:(1-2) for 6-12 h to obtain the carbonyl phenyl-substituted compound at position 4 shown in Formula I; the compounds shown in Formula VIII and Formula VI are reacted in anhydrous pyridine in a molar ratio of 1:(1-2) for 6-12 h to obtain the two types of compounds shown in Formula I and II with sulfonyl phenyl-substituted compounds at positions 4 and 5, respectively; the compounds shown in Formula IX and Formula VI, the condensing agent DIC, and the activator HOBt are reacted in anhydrous pyridine in a molar ratio of 1:(1-2):(1-3):(1-3) in anhydrous pyridine. N,N The reaction in dimethylformamide (DMF) for 8-20 h yields the carbonyl-substituted aromatic heterocyclic compound at position 4, as shown in Formula I. Alternatively, reacting the compound of Formula X or XI with the compound of Formula VI in a molar ratio of 1:(1-2) in tetrahydrofuran, using sodium hydroxide as a base, for 6-12 h yields the carbonyl-amino substituted or thioyl aniline compound at position 4, as shown in Formula I. This approach improves reaction efficiency, reduces side reactions, and increases yield.

[0027]

[0028] Wherein, X represents carbonyl, sulfonyl, or thioyl; R1 represents o-fluorophenyl, p-trifluoromethoxyphenyl, o-methoxyphenyl, o-methoxyaniline, p-methoxyphenyl, pyrimidine, thiazole, oxazole, methylthiophene, amino, or methylamino. The above preparation method can rapidly and effectively prepare the aforementioned compounds, and the method is simple, convenient, and suitable for large-scale production.

[0029] Example 1: Preparation of (Compound 1) 1. Preparation ( Z )- N' -Cyano- N -(4-aminosulfonylphenyl)carbamoylimide phenyl ester 4-Aminobenzenesulfonamide (7.86 g, 45.6 mmol), N-cyanocarbonylimine diphenyl ester (10.88 g, 45.7 mmol), and tetrahydrofuran (50 mL) were added sequentially to a reaction flask and reacted at 70 °C for 4 h. The reaction was stopped by TLC (electrolyte: petroleum ether / ethyl acetate = 1:2). The tetrahydrofuran in the reaction system was evaporated to dryness, and the residue was washed 2-3 times with dichloromethane and tetrahydrofuran sequentially. The remaining solid was dried over anhydrous magnesium sulfate to give a pure white solid of the compound in 67% yield with a melting point of 69-80 °C. The structural data of the compound are as follows: 1H NMR (600 MHz, DMSO- d 6) δ 11.12 (s, 1H), 7.83 (d, J= 8.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 7.46 (t, J = 7.7 Hz, 2H), 7.37 (s,2H), 7.32 (dd, J = 12.7, 7.6 Hz, 3H); 2. Preparation of 4-(((5-amino-1) H -1,2,4-triazol-3-yl)amino)benzenesulfonamide) The pure compound obtained in step 1 ( Z )- N' -Cyano- N -(4-aminosulfonylphenyl)carbamoylimide phenyl ester (1 g, 3.2 mmol) and tetrahydrofuran (50 mL) were added to a reaction flask. The reaction system was cooled to 0°C in an ice bath. Hydrazine hydrate (633.5 µL, 12.6 mmol) was slowly added dropwise to the reaction solution. After addition, the mixture was heated to 70°C and reacted for 4 h. The reaction was completed by TLC (eluent: ethyl acetate / ethanol = 1:1). After cooling the reaction solution to room temperature, a solid slowly precipitated out. The filtrate was filtered, and the filter cake was washed 2-3 times with tetrahydrofuran. After washing, it was dried over anhydrous magnesium sulfate to give a pure white solid of the compound, yield: 65%, melting point 292.7-293.6°C. The structural data of the compound are as follows: 1 H NMR (600 MHz, DMSO- d 6) δ11.30 (s, 1H), 9.19 (s, 1H), 7.60 (q, J = 9.0 Hz, 4H), 7.04 (s, 2H), 5.96 (s,2H). 13 C NMR (151 MHz, DMSO- d 6) δ 157.25, 155.52, 145.49, 133.07, 126.74,114.56. HR-MS(ESI): Calcd for [M+H] + :255.0664; Found:255.0674; 3. Preparation of Compound 1 Compound 4-(((5-amino-1) H1,2,4-Triazol-3-yl)amino)benzenesulfonamide (0.636 g, 2.5 mmol), methylaminoformyl chloride (0.234 g, 2.5 mmol), and anhydrous pyridine (5 mL) were added to a reaction flask. The reaction system was placed in an ice bath and cooled to 0 °C. Under these conditions, the mixture was stirred for 0.5 h, then heated to room temperature and reacted overnight. The reaction was stopped by TLC (eluent: ethyl acetate). The anhydrous pyridine in the reaction system was evaporated to dryness to obtain a crude product. The crude product was dried over anhydrous magnesium sulfate and then subjected to column chromatography (eluent: methanol / dichloromethane = 1:10) to give a white, pure compound in 17% yield with a melting point of 193.5–194.6 °C. The structural data of the compound are as follows: 1 H NMR (600 MHz, DMSO- d 6) δ 10.03 (s, 1H), 7.87-7.82 (m, 3H), 7.76 (d, J = 8.8 Hz, 2H), 7.24 (s, 2H), 5.84 (s, 2H), 2.77 (d, J =4.7 Hz, 3H). 13 C NMR (151 MHz, DMSO- d 6) δ 160.46, 151.86, 151.41, 141.42,137.32, 126.87, 117.57. HR-MS(ESI): Calcd for [M+H] + : 312.0879; Found:312.0863.

[0030] Example 2: Preparation of (Compound 2) 1. Same as step 1 in Example 1; 2. Same as step 2 in Example 1; 3. Preparation of Compound 2 The compound 4-(((5-amino-1) obtained in step 2 H 1,2,4-Triazol-3-yl)amino)benzenesulfonamide (0.636 g, 2.5 mmol), 4-(trifluoromethoxy)benzoyl chloride (0.741 g, 3.3 mmol), and anhydrous pyridine (25 mL) were added sequentially to the reaction flask. The reaction mixture was stirred overnight at room temperature. The reaction was stopped by TLC (eluent: ethyl acetate). The anhydrous pyridine in the reaction mixture was evaporated to dryness to obtain the crude product. The crude product was dried over anhydrous magnesium sulfate and then subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 1:8) to give a white solid, which was the pure compound 2, in 43% yield with a melting point of 300℃. The structural data of the compound are as follows: 1 H NMR (600 MHz, DMSO-d 6) δ 9.81 (s, 1H), 8.28 (d, J = 8.8 Hz, 2H), 7.91 (s, 2H), 7.68 (d, J = 8.7 Hz, 2H), 7.60 (dd, J = 8.6, 3.5 Hz, 4H), 7.12(s, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ 165.38, 157.92, 157.44, 150.95, 143.81,135.13, 132.85, 131.69, 126.85, 122.55, 120.84, 120.14, 119.13, 115.94. HR-MS(ESI): Calcd for [M+H] + : 443.0749; Found: 443.0763.

[0031] Example 3: Preparation of (compound 3) 1. Same as step 1 in Example 1; 2. Same as step 2 in Example 1; 3. Preparation of Compound 3 Compound 4-(((5-amino-1) H 1,2,4-Triazol-3-yl)amino)benzenesulfonamide (1.5 g, 5.903 mmol), 4-methyl-2-thiophenecarboxylic acid (0.839 g, 5.903 mmol), DIC (1.49 g, 11.806 mmol), and HOBt (1.59 g, 11.806 mmol) were added to a round-bottom reaction flask, and anhydrous DMF was added at 0 °C. Acylation was carried out at 0 °C for 0.5 h. The mixture was then heated to room temperature and stirred overnight. After the reaction was complete, the mixture was quenched with ice water. Extraction was performed with ethyl acetate and saturated brine. The organic phase was collected and subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 1:2) to give a pure compound as a yellow solid, yield: 14%, melting point: 235.5–236.4 °C. The compound's structural data are as follows: 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.91 (s,1H), 8.12 (s, 1H), 7.89 (s, 2H), 7.80-7,76 (m, 5H), 7.16 (s, 2H), 2.31 (s,3H). 13 C NMR (151 MHz, DMSO- d6 ) δ 158.81, 157.59, 157.16, 143.55, 139.08,137.62, 135.30, 133.98, 131.72, 126.94, 116.02, 15.12. HR-MS(ESI): Calcd for[M+H] + : 379.0647; Found: 379.0631.

[0032] Example 4: Preparation of (compound 4) 1. Same as step 1 in Example 1; 2. Same as step 2 in Example 1; 3. Preparation of Compound 4 Compound 4-(((5-amino-1) H 1,2,4-Triazol-3-yl)amino)benzenesulfonamide (0.636 g, 2.5 mmol) was dissolved in an aqueous solution of sodium hydroxide (1 M, 30 mL), and isocyanate (0.108 g, 2.5 mmol) was dissolved in tetrahydrofuran (4 mL). The resulting mixture was cooled to 0 °C in an ice bath and stirred for 0.5 h, then heated to room temperature for 6 h. The reaction was stopped by TLC (eluent: ethyl acetate). The reaction solution was neutralized with an aqueous solution of hydrochloric acid (1 M, 30 mL) in an ice bath. After neutralization, the mixture was extracted 2-3 times with ethyl acetate and water, and the organic phase was collected and dried under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: methanol / dichloromethane = 1:10). The pure compound was given as a pale yellow solid, yield: 1%. The structural data of the compound were characterized as follows: 1 H NMR (600 MHz, DMSO- d 6) δ 9.57 (s, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.9 Hz, 2H), 7.62 (s, 1H), 7.46 (s, 1H), 7.26 (s, 2H), 7.13(s, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ 156.34, 155.58, 152.35, 144.06, 134.58,126.77, 116.01. HR-MS(ESI): Calcd for [M+H] + : 298.0722; Found: 298.0703.

[0033] Example 5: Preparation of (Compound 5) Compound 5 was prepared according to the steps of Example 1, except that the methylaminoformyl chloride in step 3 of Example 1 was replaced with p-methoxybenzenesulfonyl chloride. The resulting compound 5 was a creamy white solid with a yield of 25% and a melting point of 126.3-127.5 °C. The compound's structural data are as follows: 1 H NMR (600 MHz, DMSO- d 6) δ 9.68 (s, 1H),7.92 (d, J = 8.9 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 8.7 Hz, 2H),7.41 (s, 2H), 7.18 (d, J = 8.9 Hz, 2H), 7.14 (s, 2H), 3.83 (s, 3H). 13 C NMR (151 MHz, DMSO-) d 6) δ 164.13, 159.20, 157.35, 143.64, 135.19, 129.93, 127.24,126.81, 115.92, 114.96, 55.93. HR-MS(ESI): Calcd for [M+H] + : 425.0702; Found:425.0702.

[0034] Example 6: Preparation of (Compound 6) Compound 6 was prepared according to the steps of Example 1, except that the methylaminoformyl chloride in step 3 of Example 1 was replaced with 2-methoxybenzenesulfonyl chloride. The resulting compound 6 was an off-white solid with a yield of 27% and a melting point of 219.0-219.7℃. The compound's structural data are as follows: 1 H NMR (600 MHz, DMSO- d 6) δ 9.65 (s, 1H), 7.96 (dd, J = 8.0, 1.6 Hz, 1H), 7.72 (t, J = 7.72 Hz, 1H), 7.59 (d, J = 8.6Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.1 Hz, 3H), 7.19 (t, J = 7.7Hz, 1H), 7.09 (s, 2H), 3.81 (s, 3H). 13C NMR (151 MHz, DMSO- d 6) δ 162.54,156.89, 154.22, 141.53, 137.82, 137.09, 130.98, 126.87, 124.09, 120.80,118.16, 113.30, 56.47. HR-MS(ESI): Calcd for [M+H] + : 425.0702; Found:425.0702.

[0035] Example 7: Preparation of (Compound 7) Compound 7 was prepared according to the steps of Example 1, except that the methylaminoformyl chloride in step 3 of Example 1 was replaced with o-fluorobenzenesulfonyl chloride. The resulting compound 7 was a creamy white solid with a yield of 26% and a melting point of 182.9-184.2 °C. The compound's structural data are as follows: 1 H NMR (600 MHz, DMSO- d 6) δ 9.75 (s, 1H), 8.05(t, J = 7.5 Hz, 1H), 7.85 (q, J = 7.8 Hz, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.51(dt, J = 25.8, 9.0 Hz, 6H), 7.12 (s, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ 159.27,159.24, 157.57, 157.21, 143.54, 138.07, 138.02, 135.28, 130.95, 126.71,125.58, 125.56, 124.10, 124.01, 117.85, 117.71, 115.90. HR-MS(ESI): Calcd for[M+H] + : 413.0502; Found: 413.0490.

[0036] Example 8: Preparation of (Compound 8) Compound 8 was prepared according to the steps of Example 1, except that the methylaminoformyl chloride in step 3 of Example 1 was replaced with p-methoxybenzenesulfonyl chloride. The resulting compound 8 was a white solid with a yield of 5% and a melting point of 189.5-190.3 °C. The compound's structural data are as follows: 1H NMR (600 MHz, DMSO- d 6) δ 9.41 (s, 1H), 7.80 (d, J = 8.9 Hz, 4H), 7.77 (d, J = 8.9 Hz, 2H), 7.27 (s, 2H), 7.15 (d, J= 9.0 Hz, 2H), 6.10 (s, 2H), 3.84 (s, 3H). 13 C NMR (151 MHz, DMSO- d 6) δ 164.14,163.40, 154.34, 141.46, 138.07, 130.10, 126.93, 126.64, 118.79, 114.92,55.96. HR-MS(ESI): Calcd for [M+H] + : 425.0702; Found: 425.0702.

[0037] Example 9: Preparation of (Compound 9) Compound 9 was prepared according to the steps of Example 6. The resulting compound 9 was a creamy-white solid with a yield of 4% and a melting point of 217.3-218.1 °C. The compound's structural data are as follows: 1 H NMR (600 MHz, DMSO- d 6) δ 9.11 (s, 1H), 7.92 (dd, J = 9.0, 3.3 Hz, 3H), 7.81 (d, J = 8.9 Hz, 2H), 7.73 (td, J = 8.0,7.4, 1.6 Hz, 1H), 7.28 (s, 2H), 7.22 (d, J = 8.5 Hz, 1H), 7.19 (t, J = 7.7Hz, 1H), 6.02 (s, 2H), 3.55 (s, 3H). 13 C NMR (151 MHz, DMSO- d 6) δ 158.57,158.10, 157.00, 143.81, 136.96, 134.98, 130.73, 126.68, 124.33, 120.57,115.67, 113.29, 56.26. HR-MS(ESI): Calcd for [M+H] + : 425.0702; Found:425.0702.

[0038] Example 10: Preparation of (Compound 10) Compound 10 was prepared according to the steps of Example 7. The resulting compound 10 was a creamy-white solid with a yield of 5% and a melting point of 176.2-177.7 °C. The compound's structural data are as follows: 1 H NMR (600 MHz, DMSO- d 6) δ 9.46 (s, 1H),7.97 (t, J = 7.5 Hz, 1H), 7.84 (d, J = 8.8 Hz, 3H), 7.79 (d, J = 8.8 Hz, 2H),7.53 - 7.47 (m, 2H), 7.27 (s, 2H), 6.18 (s, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ163.53, 159.12, 157.43, 154.48, 141.41, 138.12, 138.02, 137.97, 131.30,126.70, 125.66, 125.64, 124.10, 124.01, 118.70, 117.70, 117.56. HR-MS(ESI):Calcd for [M+H] + : 413.0502; Found: 413.0490.

[0039] Example 11: Preparation of (Compound 11) Compound 11 was prepared according to the steps of Example 4, except that the isocyanate in step 3 of Example 4 was replaced with 1-isothiocyano-2-methoxybenzene. The resulting compound 11 was a pale yellow solid with a yield of 10% and a melting point of 261.4-262.1 °C. 1 H NMR (600 MHz, DMSO- d 6) δ 10.86 (s, 1H), 9.89 (s, 1H), 8.51(s, 2H), 7.87 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.72 (s, 2H),7.34 (t, J = 7.9 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 7.17 (s, 2H), 7.04 (t, J= 7.6 Hz, 1H), 3.88 (s, 3H). 13C NMR (151 MHz, DMSO- d 6 ) δ 171.73, 156.38,155.58, 152.89, 143.45, 135.38, 128.01, 126.80, 126.36, 125.95, 120.26,116.53, 111.93, 55.96. HR-MS(ESI): Calcd for [M+H] + : 420.0913; Found:420.0901.

[0040] Example 12: Preparation of (Compound 12) Compound 12 was prepared according to the steps of Example 3, except that 4-methyl-2-thiophenecarboxylic acid in step 3 of Example 3 was replaced with pyrimidine-5-carboxylic acid. The resulting compound 12 was a yellow solid with a yield of 18% and a melting point of 214.7-215.2 °C. The compound's structural data are as follows: 1 H NMR (600 MHz, DMSO- d 6) δ 9.87 (s, 1H), 9.42 (d, J = 18.2 Hz, 3H), 7.96 (s, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.59 (d, J= 8.4 Hz, 2H), 7.13 (s, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ 163.13, 160.30,158.27, 158.06, 157.09, 143.73, 135.36, 127.49, 126.75, 116.03. HR-MS(ESI):Calcd for [M+H] + : 361.0831; Found: 361.0837.

[0041] Example 13: Preparation of (Compound 13) Compound 13 was prepared according to the steps of Example 3, except that 4-methyl-2-thiophenecarboxylic acid in step 3 of Example 3 was replaced with thiazol-5-carboxylic acid. The resulting compound 13 was a yellow solid with a yield of 15% and a melting point of 214.7-215.5 °C. The compound's structural data are as follows: 1 H NMR (600 MHz, DMSO- d 6) δ 9.97 (s, 1H), 9.51 (s, 1H), 8.92 (s, 1H), 7.95 (s, 2H), 7.81 (d, J = 8.7 Hz, 2H), 7.76 (d,J = 8.7 Hz, 2H), 7.17 (s, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ 163.77, 158.28,157.80, 156.94, 152.20, 143.41, 135.49, 128.07, 127.04, 116.17. HR-MS(ESI):Calcd for [M+H] + : 366.0443; Found: 366.0464.

[0042] Example 14: Preparation of (Compound 14) Compound 14 was prepared according to the steps of Example 3, except that 4-methyl-2-thiophenecarboxylic acid in step 3 of Example 3 was replaced with oxazol-5-carboxylic acid. The resulting compound 14 was a yellow solid with a yield of 18% and a melting point of 216.0-217.2 °C. The compound's structural data are as follows: 1 H NMR (600 MHz, DMSO- d 6) δ 9.90 (s, 1H), 8.85 (s, 1H), 8.45 (s, 1H), 7.93 (s, 2H), 7.78 (d, J = 8.5 Hz, 2H), 7.67 (d,J = 8.5 Hz, 2H), 7.16 (s, 2H). 13 C NMR (151 MHz, DMSO- d6) δ 158.65, 157.23,155.99, 154.03, 143.61, 142.66, 136.47, 135.53, 127.00, 116.24. HR-MS(ESI):Calcd for [M+H] + : 350.0671; Found: 350.0646. Specific Implementation Example 3 The use of the compounds prepared in Specific Embodiment 1 or Specific Embodiment 2 above in the preparation of a drug. The drug is a potential CDK inhibitor capable of effectively inhibiting CDK activity, suppressing the proliferation of eukaryotic tumor cells, and preventing and / or treating tumors.

[0044] The eukaryotes mentioned above are mammals; the tumor cells mentioned above are cancer cells; among them, cancer cells are leukemia cells, lymphoma cells, breast cancer cells, liver cancer cells, pancreatic cancer cells, lung cancer cells, brain cancer cells, ovarian cancer cells, uterine cancer cells, testicular cancer cells, skin cancer cells, gastric cancer cells, nasopharyngeal cancer cells, colon cancer cells, bladder cancer cells, or rectal cancer cells. Among them, leukemia cells are preferably human chronic myeloid leukemia cells and human acute lymphoblastic leukemia cells, and lymphoma cells are preferably human histiocytic lymphoma cells.

[0045] It should be noted that the drugs of the present invention can be introduced into the body through injection, spray, nasal drops, eye drops, osmosis, absorption, or physical or chemically mediated methods, such as intramuscular, intradermal, subcutaneous, venous, or mucosal tissue; they can also be introduced into the body after being mixed or encapsulated with other substances. When necessary, one or more pharmaceutically acceptable carriers can be added to the above drugs. These carriers include diluents, excipients, fillers, binders, humectants, disintegrants, absorption enhancers, surfactants, adsorbents, lubricants, etc., which are conventional in the pharmaceutical field. Furthermore, the drugs of the present invention can be formulated into various forms such as injections, tablets, powders, granules, capsules, oral liquids, ointments, and creams. All of the above dosage forms can be prepared according to conventional methods in the pharmaceutical field.

[0046] Example 1 In vitro activity inhibition experiments of CDK1 / CyclinB1, CDK2 / CyclinE1, CDK4 / CyclinD1, Aurora A, etc. This experiment determined the inhibitory effects of compounds 1-14 on CDK1 / Cyclin B1 activity. Compounds with inhibition rates above 80% were then further screened, and compound 11 was found to be the most effective. Therefore, compound 11 was selected for further screening of its in vitro inhibitory activity against CDK4 / Cyclin D1 and Aurora A. The specific procedures were performed according to the instructions of the kinase activity inhibition assay kit. JNJ-7706621 was used as the positive control. The experimental results are shown in Tables 1, 2, and 3.

[0047] Table 1. Initial screening results of in vitro activity inhibition of compounds 1-14 against CDK1 / CyclinB1.

[0048] Table 2. Results of fine screening of compounds against in vitro inhibitory activity against CDK1 / CyclinB1

[0049] Note: "-" indicates an activity value greater than 1 micromolar.

[0050] Table 3. Screening results of compound 11 for in vitro activity inhibition against different kinases.

[0051] As can be seen from the experimental results in Table 1, most of the compounds designed and synthesized in this invention exhibit significant subtype-selective inhibitory activity against CDK1 / Cyclin B1, with compounds 2 / 4 / 7 / 11 / 12 / 13 / 14 showing inhibition rates exceeding 80%. The experimental results in Tables 2 and 3 show that compound 11 exhibits the best inhibitory effect against CDK1 / Cyclin B1 and demonstrates subtype selectivity. Preliminary structure-activity relationship analysis revealed that when X is substituted at position 4, the activity is slightly better than at position 5 (7 vs. 10); the introduction of a carbonyl group at X and a benzene ring derivative at R1 results in better activity than the introduction of a five- or six-membered unsubstituted aromatic heterocycle. Therefore, the series of compounds reported in this invention represents a novel class of CDK1-specific inhibitors.

[0052] Example 2 CCK8 assay for cell proliferation inhibition activity screening Compound 11 was screened for in vitro antiproliferative activity using the CCK8 kit. The cells used for the test were cervical cancer cells (HeLa), breast cancer cells (MDA-MB-231), lung cancer cells (H460), colon cancer cells (HCT-116), liver cancer cells (HepG2), and gastric cancer cells (SGC7901) in the logarithmic growth phase. The specific steps for the cell proliferation inhibition activity test were as follows: (1) Select cells in the logarithmic growth phase and in good growth condition, count the number of cells using a cell counting chamber, and dilute the cells with culture medium to 8*10.4 -12*10 4 (1) Cells / mL were seeded into 96-well plates. (2) The appropriate concentration of the compound was selected, and DMSO without the compound was used as the blank control group. Three parallel experiments were performed for each sample. Then, the cell suspension stimulated by the compound was added to the 96-well plate, 100 µL per well, and cultured at 37℃ in a 5% CO2 incubator for 72 h. (3) Under light-protected conditions, 10 μL of CCK-8 solution was added to each well and cultured under the above conditions for 1-4 h. (4) The absorbance was measured on the microplate reader using an excitation wavelength of 450 nm. The experimental results are shown in Table 4.

[0053] Table 4. Screening results of antiproliferative activity of compound 11

[0054] The antiproliferative activity screening results in Table 4 show that compound 11 exhibits significant antiproliferative activity against solid tumor cells such as HeLa, MDA-MB-231, H460, HCT-116, HepG2, and SGC7901. Among these, compound 11 shows significant IC50 activity against HCT-116 cells. 50 The value reaches 20 nM.

[0055] Example 3 Cell cycle and apoptosis detection To further verify whether compound 11 has any effect on the cell cycle and effectively induces apoptosis in cancer cells, flow cytometry was used to investigate the results. Figure 1 and Figure 2 As shown. From Figure 1 and Figure 2 It can be clearly observed that compound 11 can effectively induce cell arrest in the G2-M phase of HCT-116, HepG2, and SGC7901 cells, thereby inducing apoptosis in a concentration-dependent manner.

[0056] The foregoing description is not intended to limit the invention, nor is the invention limited to the examples given. Any changes, modifications, additions, or substitutions made by those skilled in the art within the scope of the invention should also be considered within the protection scope of the invention.

Claims

1. A benzenesulfonamide triazole derivative, characterized in that... The compound is a compound having the structural formula shown in Formula I or II, or a pharmaceutically acceptable salt, ester, or solvate of a compound having the structural formula shown in Formula I or II. In this formula, X is carbonyl, sulfonyl, or thioyl; R1 is o-fluorophenyl, p-trifluoromethoxyphenyl, o-methoxyphenyl, o-methoxyaniline, p-methoxyphenyl, pyrimidine, thiazole, oxazole, methylthiophene, amino, or methylamino; pharmaceutically acceptable salts of the compounds shown in Formulas I and II are inorganic acid salts or organic acid salts, wherein the inorganic acid salt is a salt formed from any one of the inorganic acids selected from hydrochloric acid, sulfuric acid, and phosphoric acid; and the organic acid salt is a salt formed from any one of the organic acids selected from acetic acid, trifluoroacetic acid, malonic acid, citric acid, and p-toluenesulfonic acid.

2. The benzenesulfonamide triazole derivative according to claim 1, characterized in that... The compound has at least one of the following structural formulas: .

3. A benzenesulfonamide triazole derivative according to claim 2, characterized in that... The compound has at least one of the following structural formulas: 。 4. A benzenesulfonamide triazole derivative according to claim 3, characterized in that... The structural formula of the compound is as follows: 。 5. A method for preparing the benzenesulfonamide triazole derivative according to claim 1, characterized in that... Includes the following steps: (1) The compound shown in Formula III is subjected to a substitution reaction with the compound shown in Formula IV to obtain the compound shown in Formula V; (2) The compound shown in formula V is subjected to a cyclization reaction with hydrazine hydrate to obtain the compound shown in formula VI; (3) The compound shown in Formula VI is subjected to an amidation reaction with the compound shown in Formula VII, or Formula VIII, or Formula IX, or Formula X, or Formula XI, to obtain two different types of compounds shown in Formula I and II respectively; Where X is carbonyl, sulfonyl, or thioyl; and R1 is o-fluorophenyl, p-trifluoromethoxyphenyl, o-methoxyphenyl, o-methoxyaniline, p-methoxyphenyl, pyrimidine, thiazole, oxazole, methylthiophene, amino, or methylamino.

6. The method for preparing a benzenesulfonamide triazole derivative according to claim 5, characterized in that... Step (1) specifically involves reacting the compound shown in Formula III with the compound shown in Formula IV in a molar ratio of 1:(1-1.5) in tetrahydrofuran at 70-90℃ for 2-8 h to obtain the compound shown in Formula V; Step (2) specifically involves reacting the compound shown in Formula V with hydrazine hydrate in a molar ratio of 1:(2-4) in tetrahydrofuran at 70-90℃ for 2-8 h to obtain the compound shown in Formula VI.

7. The method for preparing a benzenesulfonamide triazole derivative according to claim 5, characterized in that... Step (3) specifically involves reacting the compounds shown in Formulas VII and VI in anhydrous pyridine at 25-55°C for 6-12 h to obtain the carbonyl phenyl-substituted compound at position 4 shown in Formula I; reacting the compounds shown in Formulas VIII and VI in anhydrous pyridine at a molar ratio of 1:(1-2) for 6-12 h to obtain the two types of compounds with sulfonyl phenyl-substituted compounds at positions 4 and 5 shown in Formulas I and II, respectively; and reacting the compounds shown in Formulas IX and VI, the condensing agent DIC, and the activator HOBt in anhydrous pyridine at a molar ratio of 1:(1-2):(1-3):(1-3) for 6-12 h to obtain the two types of compounds with sulfonyl phenyl-substituted compounds at positions 4 and 5, respectively. N,N The compound with carbonyl aromatic heterocyclic substitution at position 4, as shown in Formula I, is obtained by reacting it in dimethylformamide for 8-20 h; the compound with carbonyl amino substitution or thioyl aniline at position 4, as shown in Formula I, is obtained by reacting it in tetrahydrofuran for 6-12 h with the compound of Formula X or XI in a molar ratio of 1:(1-2) using sodium hydroxide as a base.

8. The use of the benzylsulfonamide triazole derivative according to any one of claims 1-4 in the preparation of a drug for inhibiting the proliferation of eukaryotic tumor cells, characterized in that: The tumor cells mentioned include cervical cancer cells HeLa, breast cancer cells MDA-MB-231, lung cancer cells H460, colon cancer cells HCT-116, liver cancer cells HepG2, and gastric cancer cells SGC7901.

9. Use of the benzenesulfonamide triazole derivative according to any one of claims 1-4 in the preparation of CDK activity inhibitors.

10. The use of any one of the benzylsulfonamide triazole derivatives according to claims 1-4 in the preparation of apoptosis-inducing agents and G2-M phase arrest agents in HCT-116, HepG2, and SGC7901 cells.

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