Application of indole triazole derivative in preparation of drug for resisting drug-resistant candida albicans

Abstract

The invention discloses an application of an indole triazole derivative in preparation of a drug for resisting drug-resistant candida albicans. The structure of the indole triazole compound contains an indole ring and a triazole ring, so that the indole triazole compound has a good inhibition effect on drug-resistant fungi, especially fluconazole-resistant candida albicans, and is expected to further solve the problem of infection of candida albicans drug-resistant strains.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to the application of indoletriazole derivatives in the preparation of drugs against drug-resistant Candida albicans. Background Art

[0002] Candida albicans is a conditional pathogen that is commonly found in the oral cavity, intestines, etc. It is a microorganism in the normal intestinal flora. When the human immune system is low, Candida albicans can cause skin or mucosal infections, and can also cause systemic infections, invading tissues such as the blood and heart, that is, causing invasive infections. In most parts of the world, Candida albicans is the most important pathogen of invasive fungal diseases, which seriously threatens human life and health. Fluconazole is clinically used for the treatment of fungal infections because of its broad antifungal spectrum, good oral absorption, and high bioavailability. However, with the widespread use of fluconazole, the resistance of antifungal drugs has become increasingly strong. The emergence of drug resistance has made the problem more urgent and complex, which has brought great challenges to the clinical treatment of fungal infections such as Candida albicans. Therefore, it is extremely important to discover new antifungal drugs. One of the effective methods is to modify and transform the structure of existing antifungal drugs, among which the modification and transformation of fluconazole is a hot topic of research. Studies have shown that the triazole ring, difluorophenyl and alcohol hydroxyl groups in the fluconazole molecule are important pharmacodynamic structural fragments for fluconazole to exert its antifungal effect.

[0003] Indole derivatives have a variety of biological activities, such as anti-inflammatory, bactericidal and anti-tumor. In recent years, studies have shown that indole and its derivatives have good antifungal effects and also show good inhibitory activity against Candida albicans. The present invention retains a triazole ring, difluorophenyl and alcoholic hydroxyl group of fluconazole, introduces an indole structure with antibacterial effect into its side chain, designs and synthesizes indole triazole derivatives, and tests all synthesized compounds for in vitro anti-Candida albicans activity, hoping to provide new ideas for the development of antifungal drugs and overcoming drug resistance. Summary of the invention

[0004] The first object of the present invention is to provide an indoletriazole derivative having the structure: .

[0005] The second object of the present invention is to provide the use of indoletriazole derivatives in the preparation of drugs against drug-resistant Candida albicans.

[0006] The resistant Candida albicans include resistant Candida albicans ATCC14053, CA6, CA23, CA 602, and CA 550.

[0007] The third object of the present invention is to provide a method for preparing an indoletriazole derivative, specifically: (1) Add 7 ml of DMF to a dry round-bottom flask, cool in an ice-water bath, slowly add 0.44 ml of phosphorus oxychloride with a syringe, and stir in an ice-water bath for 30 minutes; when the solution turns pink, slowly add 4 mmol of substituted indole dissolved in 1.5 ml of DMF to the round-bottom flask, and react in an ice-water bath for 1 hour; pour the reaction solution into ice water, adjust the pH value to 10 with 5 mol / L NaOH, and heat at 80°C for 1 hour; cool to room temperature, adjust the pH value to 4 with dilute hydrochloric acid, a large amount of solid precipitates, filter, and repeatedly wash the filter cake with water; dry the filter cake to obtain intermediate A; (2) 0.3 mmol of intermediate A and 0.3 mmol of substituted aniline were dissolved in 5 ml of ethanol, 5 drops of piperidine were added, the mixture was refluxed at 85°C for 5 hours, cooled to room temperature, 0.3 mmol of NaBH4 was added, the mixture was reacted at room temperature for 2 hours, and the reaction was monitored by TLC until the reaction was completed. The reaction solution was spin-dried, dissolved in ethyl acetate, and transferred to a separatory funnel; the organic layer was washed twice with water, once with saturated brine, and then dried over anhydrous Na2SO4, concentrated, and spin-dried to obtain intermediate B; (3) In a dry round-bottom flask, 0.3 mmol of intermediate B, 0.3 mmol of 1-[2-(2,4-difluorophenyl)-2,3-epoxypropane]-1H-1,2,4-triazole methanesulfonate and KOH (50 mg, 0.9 mmol) were added, and dimethyl sulfoxide (5 ml) was added. The mixture was reacted at 85°C. After TLC monitoring showed that the reaction was complete, the reaction solution was transferred to a separation funnel and 20 ml of ethyl acetate was added. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography and petroleum ether / ethyl acetate to obtain an indoletriazole derivative.

[0008] Substituted indoles include indole, 4-bromoindole, 5-methoxyindole, 5-fluoroindole, 5-chloroindole, 5-bromoindole, 6-fluoroindole, 6-bromoindole, and 4-methylindole.

[0009] Substituted anilines include: aniline, p-methoxyaniline, p-iodoaniline, and p-acetylaniline.

[0010] Advantages of the present invention: The present invention provides an application of an indoletriazole derivative in the preparation of a drug for resisting drug-resistant Candida albicans. The indoletriazole derivative alone has an antibacterial effect on drug-resistant Candida albicans, and is expected to further solve the infection of drug-resistant Candida albicans. The compound provided by the present invention is effective against both standard drug-resistant Candida albicans and clinical drug-resistant Candida albicans. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 is the structural formula of an indoletriazole derivative; Figure 2This is a synthetic route for indoletriazole derivatives C01~C28. DETAILED DESCRIPTION

[0012] The present invention is further described below, but the present invention is not limited in any way. Any changes made based on the present invention belong to the protection scope of the present invention.

[0013] Indoletriazole derivatives, see structure Figure 1 , specifically: .

[0014] Application of indoletriazole derivatives in the preparation of drugs against drug-resistant Candida albicans.

[0015] The drug-resistant Candida albicans are drug-resistant Candida albicans ATCC14053, CA6, CA 23, CA 602, and CA 550. Among them, CA6, CA 23, CA 602, and CA 550 are clinically drug-resistant Candida albicans.

[0016] Substituted indole and phosphorus oxychloride were formylated in DMF as solvent to obtain intermediate A. Intermediate A and substituted aniline 3a-3d were dissolved in ethanol solution, piperidine (5 drops) was added, and the mixture was heated to reflux at 85°C for 5 hours. After the solution was cooled, sodium borohydride was added and reacted at room temperature for 2 hours to obtain intermediate B. Finally, intermediate B was reacted with 1-[2-(2,4-difluorophenyl)-2,3-epoxypropane]-1H-1,2,4-triazole methanesulfonate in DMSO as solvent and KOH as base, and the ring was opened at 85°C to obtain indole triazole derivatives C01-C28. For the specific synthetic route, see Figure 2 The specific preparation method is: (1) Add 7 ml of DMF to a dry round-bottom flask, cool in an ice-water bath, slowly add 0.44 ml of phosphorus oxychloride with a syringe, and stir in an ice-water bath for 30 minutes; when the solution turns pink, slowly add 4 mmol of substituted indole dissolved in 1.5 ml of DMF to the round-bottom flask, and react in an ice-water bath for 1 hour; pour the reaction solution into ice water, adjust the pH value to 10 with 5 mol / L NaOH, and heat at 80°C for 1 hour; cool to room temperature, adjust the pH value to 4 with dilute hydrochloric acid, a large amount of solid precipitates, filter, and repeatedly wash the filter cake with water; dry the filter cake to obtain intermediate A; (2) 0.3 mmol of intermediate A and 0.3 mmol of substituted aniline were dissolved in 5 ml of ethanol, 5 drops of piperidine were added, the mixture was refluxed at 85°C for 5 hours, cooled to room temperature, 0.3 mmol of NaBH4 was added, the mixture was reacted at room temperature for 2 hours, and the reaction was monitored by TLC until the reaction was completed. The reaction solution was spin-dried, dissolved in ethyl acetate, and transferred to a separatory funnel; the organic layer was washed twice with water, once with saturated brine, and then dried over anhydrous Na2SO4, concentrated, and spin-dried to obtain intermediate B; (3) In a dry round-bottom flask, 0.3 mmol of intermediate B, 0.3 mmol of 1-[2-(2,4-difluorophenyl)-2,3-epoxypropane]-1H-1,2,4-triazole methanesulfonate and KOH (50 mg, 0.9 mmol) were added, and dimethyl sulfoxide (5 ml) was added. The mixture was reacted at 85°C. After TLC monitoring showed that the reaction was complete, the reaction solution was transferred to a separation funnel and 20 ml of ethyl acetate was added. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography and petroleum ether / ethyl acetate to obtain an indoletriazole derivative.

[0017] Substituted indoles include indole, 4-bromoindole, 5-methoxyindole, 5-fluoroindole, 5-chloroindole, 5-bromoindole, 6-fluoroindole, 6-bromoindole, and 4-methylindole.

[0018] Substituted anilines include: aniline, p-methoxyaniline, p-iodoaniline, and p-acetylaniline.

[0019] Indoles with different substituents were formylated with phosphorus oxychloride in DMF as solvent to obtain intermediates 2a-2i. Intermediates 2a-2i and substituted anilines 3a-3d were dissolved in ethanol solution, piperidine (5 drops) was added, and the mixture was heated at 85°C for 5 hours to obtain intermediates A01-A28. After the solution was cooled, sodium borohydride was added and reacted at room temperature for 2 hours to obtain intermediates B01-B28. Finally, intermediates B01-B28 were reacted with 1-[2-(2,4-difluorophenyl)-2,3-epoxypropane]-1H-1,2,4-triazole methanesulfonate (CAS No.: 86386-77-8) intermediate 4 in DMSO as solvent and KOH as base, and the ring was opened by heating at 85°C to obtain indole triazole derivatives C01-C28. For the specific synthetic route, see Figure 2 .

[0020] Example 1 Synthesis of Indoletriazole Derivatives Synthesis of intermediate A: Add DMF (7 ml) to a dry round-bottomed flask, cool in an ice-water bath, slowly add phosphorus oxychloride (0.44 ml, 4.8 mmol) with a syringe, and stir in an ice-water bath for 30 minutes. When the solution turns pink, slowly add 4-bromoindole (0.5 ml, 4 mmol) dissolved in 1.5 ml of DMF to the round-bottomed flask and react in an ice-water bath for 1 hour. Pour the reaction solution into ice water, adjust the pH to 10 with 5 mol / L NaOH, and heat at 80 ° C for 1 hour. Cool to room temperature, adjust the pH to 4 with dilute hydrochloric acid, a large amount of solid precipitates, filter, and wash the filter cake repeatedly with water. Finally, dry the filter cake to obtain a yellow solid A02 with a yield of 72%.

[0021] Synthesis of intermediate B02: 4-bromoindole-3-carboxaldehyde (A02) (67.2 mg, 0.3 mmol) and aniline (3a) (30 ml, 0.3 mmol) were dissolved in ethanol (5 ml), piperidine (5 drops) was added, and refluxed at 85 ° C for 5 hours. The reaction was monitored by TLC, and after the reaction was completed. NaBH4 (12 mg, 0.3 mmol) was added to a round-bottomed flask, and the reaction was carried out at room temperature for 2 hours, and the reaction process was monitored by TLC. After the reaction was completed, the reaction solution was spin-dried, dissolved in ethyl acetate (15 ml), and transferred to a separatory funnel. The organic layer was washed twice with water, once with saturated brine, and then dried over anhydrous Na2SO4. The solvent was spin-dried to obtain B02. B02 was directly subjected to the next step without purification.

[0022] Synthesis of target compound C02: Intermediate B02 (128 mg, 0.3 mmol), 1-[2-(2,4-difluorophenyl)-2,3-epoxypropane]-1H-1,2,4-triazole methanesulfonate (CAS No.: 86386-77-8) compound 4 (100 mg, 0.3 mmol) and KOH (50 mg, 0.9 mmol) were added to a dry round-bottom flask and dissolved in DMSO (5 ml) and reacted at 85 °C overnight. The reaction process was monitored by TLC. After the reaction was completed, the reaction solution was transferred to a separation funnel and 20 ml of ethyl acetate was added. The organic layer was washed with water (2×10), then washed with 10 ml of saturated brine, and dried over anhydrous sodium sulfate. Filter, remove the solvent under reduced pressure, and purify with silica gel column chromatography and petroleum ether / ethyl acetate to obtain 85 mg of a yellow solid with a yield of 52.7% and mp 71.6-74.2 °C.

[0023] The synthesis methods of other derivatives are similar, and the specific data are as follows: C01: yellow solid, yield: 43.7%, mp 54.2-57.1°C. 1 H NMR (600 MHz, Chloroform-d ) δ 7.77 (s, 1H), 7.75 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.47 – 7.40 (m, 2H), 7.27 (d, J = 7.4 Hz, 1H), 7.21 – 7.17 (m, 3H), 7.13 (t, J = 7.4 Hz, 1H), 6.82 –6.71 (m, 3H), 6.69 (d, J = 8.0 Hz, 2H), 5.08 (s, 1H), 4.90 (d, J = 14.2 Hz, 1H),4.62 (d, J = 15.0 Hz, 1H), 4.45 (s, 2H), 4.34 (d, J = 15.1 Hz, 1H), 4.06 (d, J =14.2 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 161.8, 159.8, 152.1, 148.4, 144.1,137.6, 130.4, 129.2, 127.8, 127.1, 123.2, 122.4, 119.7, 119.3, 117.4, 113.6,112.9,112.0, 109.5, 104.3, 77.2, 54.1, 52.6, 39.9. C02: yellow solid, yield: 52.7%, mp 71.6-74.2 ℃. 1 H NMR (600 MHz, Chloroform- d ) δ 7.76 (s, 1H), 7.75 (s, 1H), 7.37 (td, J = 9.0, 6.6 Hz, 1H),7.31 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.23 (s, 1H), 7.16 (t, J = 7.8Hz, 2H), 7.04 (t, J = 7.9 Hz, 1H), 6.79 – 6.66 (m, 5H), 5.14 (s, 1H), 4.83 (d,J = 14.1 Hz, 1H), 4.71 – 4.62 (m, 2H), 4.53 (d, J = 15.0 Hz, 1H), 4.31 (d, J = 15.1Hz, 1H), 3.99 (d, J = 14.1 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 161.7, 159.7,152.1, 148.0, 144.0, 138.9, 130.4, 130.0, 129.1, 125.6, 124.0, 123.0, 122.8,117.5,114.1, 113.5, 113.0, 112.3, 108.9, 104.2, 77.2, 54.0, 52.6, 40.2. C03: yellow solid, yield: 30%, mp 68.7-71.1 °C. 1 H NMR (600 MHz, Chloroform- d ) δ 7.78 (s, 1H), 7.75 (s, 1H), 7.44 (td, J = 9.0, 6.6 Hz, 1H), 7.30 (d, J = 8.9Hz, 1H), 7.20 (t, J = 7.8 Hz, 2H), 7.16 (s, 1H), 7.04 (d, J = 2.3 Hz, 1H), 6.91(dd, J = 8.9, 2.3 Hz, 1H), 6.82 – 6.70 (m, 5H), 5.07 (s, 1H), 4.88 (d, J = 14.2Hz, 1H), 4.56 (d, J = 15.1 Hz, 1H), 4.40 (s, 2H), 4.32 (d, J = 15.1 Hz, 1H), 4.06(d, J = 14.2 Hz, 1H), 3.82 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.8, 159.7,154.2, 152.0, 148.5, 144.1, 132.7, 130.3, 129.3, 128.4, 127.5, 123.1, 117.4,113.1, 112.9, 112.7, 112.2, 110.4,104.2, 100.8, 77.2, 55.9, 54.1, 52.8, 40.0. C04: yellow solid, yield: 56.6%, mp 64.4-67.4 ℃. 1 H NMR (600 MHz, Chloroform- d ) δ 7.79 (s, 1H), 7.77 (s, 1H), 7.41 (td, J = 9.1, 6.5 Hz, 1H),7.31 (dd, J = 9.0, 4.1 Hz, 1H), 7.28 (dd, J = 9.3, 2.4 Hz, 1H), 7.22 – 7.16 (m,3H), 6.98 (td, J = 9.0, 2.4 Hz, 1H), 6.79 (ddd, J = 11.8, 8.3, 2.4 Hz, 1H), 6.73(q, J = 8.0, 7.2 Hz, 2H), 6.68 (d, J = 7.8 Hz, 2H), 5.14 (s, 1H), 4.89 (d, J = 14.2Hz, 1H), 4.56 (d, J = 15.0 Hz, 1H), 4.39 (s, 2H), 4.35 (d, J = 15.1 Hz, 1H), 4.08(d, J = 14.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 161.7, 159.6, 159.0, 152.1,148.3, 144.1, 134.1, 130.4, 129.4, 129.3, 127.5,122.8, 117.6, 113.6, 113.0,112.1, 110.9, 110.6, 110.4, 104.2, 77.2, 54.1, 52.9, 39.9. C05: yellow solid, yield: 35%, mp 72.2-75.4 °C. 1 H NMR (600 MHz, Chloroform- d ) δ 7.78 (s, 1H), 7.77 (s, 1H), 7.61 (s, 1H), 7.40 (q, J = 8.9 Hz, 1H), 7.31(d, J = 8.8 Hz, 1H), 7.19 (q, J = 5.6, 3.6 Hz, 4H), 6.79 (ddd, J = 11.6, 8.3, 2.1Hz, 1H), 6.73 (t, J = 7.4 Hz, 2H), 6.68 (d, J = 7.9 Hz, 2H), 5.17 (s, 1H), 4.88(d, J = 14.1 Hz, 1H), 4.55 (d, J = 15.0 Hz, 1H), 4.39 (s, 2H), 4.34 (d, J = 15.0Hz, 1H), 4.07 (d, J = 14.1 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 161.9, 159.7,152.2, 148.2, 144.1, 136.0, 130.4, 129.3, 129.1, 128.1, 125.5, 122.8, 122.7,118.8, 117.7, 113.3, 113.0, 112.1, 110.7,104.2, 77.2, 54.1, 52.8, 39.8. C06: yellow solid, yield: 45.8%, mp 65.0-67.9 °C. 1H NMR (600 MHz, Chloroform- d ) δ 7.79 (s, 1H), 7.78 – 7.74 (m, 2H), 7.39 (td, J = 9.1, 6.6 Hz,1H), 7.31 (dd, J = 8.7, 1.6 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.19 (dd, J = 13.1,5.5 Hz, 3H), 6.83 – 6.66 (m, 5H), 5.18 (s, 1H), 4.87 (d, J = 14.1 Hz, 1H), 4.55(d, J = 15.0 Hz, 1H), 4.39 (s, 2H), 4.34 (d, J = 15.0 Hz, 1H), 4.06 (d, J = 14.1Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 161.9, 159.7, 152.2, 148.2, 144.1, 136.3,130.3, 129.3, 128.9, 128.8, 125.2, 122.8, 121.9, 117.7,113.2, 113.0, 113.0,112.3, 111.2, 104.2, 77.2, 54.0, 52.7, 39.8. C07: yellow solid, yield: 60%, mp 64-68.7 °C. 1 H NMR (400 MHz, Chloroform- d )δ 7.77 (s, 1H), 7.75 (s, 1H), 7.53 (dd, J = 8.6, 5.4 Hz, 1H), 7.45 – 7.36 (m,1H), 7.18 (t, J = 7.8 Hz, 2H), 7.14 (s, 1H), 7.10 (dd, J = 10.0, 1.9 Hz, 1H),6.88 (td, J = 9.2, 1.9 Hz, 1H), 6.80 (ddd, J= 11.8, 8.3, 2.3 Hz, 1H), 6.73 (q, J = 7.4, 7.0 Hz, 2H), 6.67 (d, J = 8.3 Hz, 2H), 5.20 (s, 1H), 4.89 (d, J = 14.0 Hz, 1H), 4.49 (d, J = 15.0 Hz, 1H), 4.40 (s, 2H), 4.30 (d, J = 15.0 Hz, 1H), 4.08 (d, J = 14.1 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 161.8, 161.4, 159.7, 152.1, 148.3, 144.1, 137.6, 130.4, 129.3, 128.1, 123.6, 122.8, 120.1, 117.6, 113.8, 113.0, 112.3, 108.3, 104.3, 96.5, 77.2, 54.1, 52.9, 39.9. C08: Yellow solid, yield: 20%, m.p. 72.6 - 74 °C. 1 H NMR (600 MHz, Chloroform - d ) δ 7.81 (s, 1H), 7.77 (s, 1H), 7.53 (d, J = 1.2 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.40 (td, J = 9.1, 6.5 Hz, 1H), 7.22 (dd, J = 8.4, 1.4 Hz, 1H), 7.19 (t, J = 7.8 Hz, 2H), 7.14 (s, 1H), 6.80 (ddd, J = 11.2, 8.3, 2.4 Hz, 1H), 6.73 (td, J = 7.1, 6.5, 3.0 Hz, 2H), 6.67 (d, J = 8.0 Hz, 2H), 5.20 (s, 1H), 4.91 (d, J = 14.1 Hz, 1H), 4.52 (d,J = 15.0 Hz, 1H), 4.41 (s, 2H), 4.32 (d, J = 15.0 Hz, 1H), 4.10 (d, J = 14.1 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 161.8, 159.7, 152.2, 148.3, 144.1,138.4, 130.4, 129.3, 128.4, 125.9, 123.0, 122.7, 120.5, 117.6, 116.1, 113.9,113.0, 112.8, 112.3,104.2, 77.2, 54.1, 52.7, 39.8. C09: yellow solid, yield: 41.7%, mp 62.8-64.2 °C. 1 H NMR (600 MHz, Chloroform- d ) δ 7.75 (s, 1H), 7.74 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.46 –7.39 (m, 2H), 7.25 (t, J = 7.6 Hz, 1H), 7.18 (s, 1H), 7.13 (t, J = 7.5 Hz, 1H), 6.83 – 6.77 (m, 3H), 6.77 – 6.72 (m, 1H), 6.65 (d, J = 8.8 Hz, 2H), 5.08 (s,1H), 4.88 (d, J = 14.2 Hz, 1H), 4.61 (d, J = 15.0 Hz, 1H), 4.40 (s, 2H), 4.33 (d, J = 15.1 Hz, 1H), 4.04 (d, J = 14.2 Hz, 1H), 3.74 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.8, 159.8, 152.2, 152.0, 144.1, 142.7, 137.6, 130.3, 127.8,127.1, 123.2,122.4, 119.7, 119.3, 116.4, 114.9, 114.3, 112.0, 109.5, 104.2,77.2, 55.8, 54.2, 52.6, 40.9. C10: yellow solid, yield: 25.8%, mp 76.6-79.0 °C. 1 H NMR (400 MHz, Chloroform- d ) δ 7.76 (s, 2H), 7.47 (td, J = 9.0, 6.5 Hz, 1H), 7.18 (s, 1H),7.17 – 7.12 (m, 1H), 6.89 (d, J = 7.1 Hz, 1H), 6.85 – 6.73 (m, 5H), 6.67 – 6.63(m, 2H), 5.03 (s, 1H), 4.93 – 4.85 (m, 1H), 4.62 (d, J = 15.0 Hz, 1H), 4.45 (s,2H), 4.30 (d, J = 15.0 Hz, 1H), 4.03 (d, J = 14.1 Hz, 1H), 3.75 (s, 3H), 2.68 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 161.5, 157.7, 152.3, 152.1, 144.2, 142.6,138.2, 131.5, 130.5, 128.8, 123.4,122.6, 121.5, 116.6, 115.1, 114.5, 114.2,112.1, 107.4, 104.1, 77.4, 56.0, 54.2, 52.7, 42.3, 19.9. C11: yellow solid, yield: 42.9%, mp 57.6-59.6 °C. 1 H NMR (400 MHz, Chloroform- d) δ 7.78 (s, 1H), 7.76 (s, 1H), 7.41 – 7.27 (m, 3H), 7.25 – 7.21(m, 1H), 7.04 (t, J J = 8.0 Hz, 1H), 6.81 – 6.65 (m, 6H), 5.14 (s, 1H), 4.83 (d, J J = 14.1 Hz, 1H), 4.67 – 4.57 (m, 2H), 4.54 (d, J J = 15.0 Hz, 1H), 4.32 (d, J J = 15.0Hz, 1H), 3.95 (d, J J = 14.1 Hz, 1H), 3.71 (s, 3H). 13 C NMR (100MHz, CDCl3) δ161.8, 159.6, 152.3, 152.1, 144.0, 142.2, 138.9, 130.3, 130.0, 125.6, 123.9,122.9, 122.7,119.9, 115.1, 114.7, 114.2, 112.0, 109.0, 104.2, 77.2, 55.7,54.0, 52.6, 41.2. C12: Yellow solid, yield: 54.1%, m.p. 71.5 - 73.7 °C. 1 1H NMR (400 MHz,Chloroform- d ) δ 7.77 (s, 1H), 7.75 (s, 1H), 7.43 (td, J J = 9.1, 6.6 Hz, 1H),7.30 (d, J J = 8.9 Hz, 1H), 7.15 (s, 1H), 7.05 (d, J J = 2.3 Hz, 1H), 6.90 (dd, J J=8.9, 2.4 Hz, 1H), 6.82 – 6.72 (m, 4H), 6.67 (d, J J = 8.9 Hz, 2H), 5.05 (s, 1H),4.88 (d, J J = 14.1 Hz, 1H), 4.56 (d, J J = 15.0 Hz, 1H), 4.36 (s, 2H), 4.31 (d,J =15.0 Hz, 1H), 4.05 (d, J = 14.1 Hz, 1H), 3.82 (s, 3H), 3.75 (s, 3H). 13 C NMR (100MHz, CDCl3) δ 161.7, 159.8, 154.2, 152.3, 152.0, 144.1, 142.8, 132.7, 130.4,128.4, 127.5, 123.2, 116.4, 114.9, 114.4, 113.3, 112.6,112.0, 104.2, 100.9,77.2, 55.8, 55.7, 54.1, 52.8, 41.0. C13: yellow solid, yield: 20.4%, mp 59.2-63.2 °C. 1 H NMR (400 MHz, Chloroform- d ) δ 7.82 (s, 1H), 7.77 (s, 1H), 7.44 – 7.38 (m, 1H), 7.31 (dd, J =8.9, 4.2 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.23 (s, 1H), 6.98 (td, J = 9.0, 2.5Hz, 1H), 6.84 – 6.72 (m, 4H), 6.70 – 6.65 (m, 2H), 5.14 (s, 1H), 4.89 (d, J =14.2 Hz, 1H), 4.57 (d, J = 15.0 Hz, 1H), 4.38 – 4.32 (m, 3H), 4.06 (d, J = 14.1Hz, 1H), 3.75 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 159.0, 157.3, 156.6, 152.6,152.1, 144.1, 142.9, 134.1, 130.3, 129.5, 127.5, 122.9, 120.0, 116.5,114.9,114.8, 112.1, 110.8, 110.3, 104.1, 77.2, 55.8, 54.1, 52.9, 41.1. C14: yellow solid, yield: 60.2%, mp 56.5-59.9 °C. 1 H NMR (400 MHz, Chloroform- d ) δ 7.80 (s, 1H), 7.77 (s, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.44 –7.36 (m, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.20 – 7.16 (m, 2H), 6.83 – 6.71 (m,4H), 6.68 – 6.62 (m, 2H), 5.17 (s, 1H), 4.88 (d, J = 14.1 Hz, 1H), 4.55 (d, J =15.0 Hz, 1H), 4.37 – 4.31 (m, 3H), 4.05 (d, J = 14.0 Hz, 1H), 3.74 (s, 3H). 13 CNMR (100 MHz, CDCl3) δ 161.9, 159.6, 152.4, 152.1, 144.1, 142.4, 136.0,130.4, 129.1, 128.2, 125.5,122.6, 120.0, 118.8, 114.9, 114.5, 113.5, 112.1,110.7, 104.2, 77.2, 55.8, 54.0, 52.8, 40.8. C15: yellow solid, yield: 34.7%, mp 64.0-65.7 °C. 1 H NMR (400 MHz, Chloroform- d ) δ 7.80 – 7.75 (m, 3H), 7.39 (td, J = 9.1, 6.2 Hz, 1H), 7.33 –7.27 (m, 2H), 7.16 (s, 1H), 6.82 – 6.62 (m, 6H), 5.18 (s, 1H), 4.87(d, J = 14.1Hz, 1H), 4.55 (d, J = 14.9 Hz, 1H), 4.37 – 4.30 (m, 3H), 4.04 (d, J= 14.0 Hz,1H), 3.74 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 161.7, 159.6, 152.4, 152.1,144.1, 142.4, 136.2, 130.4, 128.8, 125.2, 122.7, 121.9, 116.4, 114.9, 114.5,113.4, 113.0, 112.1,111.2, 104.2, 77.2, 55.8, 54.0, 52.7, 40.8. C16: yellow solid, yield: 40.1%, mp 47.8-48.0 °C. 1 H NMR (400 MHz, Chloroform- d ) δ 7.80 (s, 1H), 7.77 (s, 1H), 7.54 (dd, J = 8.6, 5.3 Hz, 1H),7.44 – 7.37 (m, 1H), 7.16 – 7.13 (m, 1H), 7.10 (dd, J = 10.0, 1.9 Hz, 1H), 6.88(td, J = 9.4, 2.0 Hz, 1H), 6.85 – 6.75 (m, 4H), 6.65 (d, J = 8.9 Hz, 2H), 5.19(s, 1H), 4.95 – 4.85 (m, 1H), 4.50 (d, J = 15.0 Hz, 1H), 4.37 (s, 2H), 4.30 (d, J = 15.0 Hz, 1H), 4.11 – 4.04 (m, 1H), 3.74 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ161.4, 159.0, 152.4, 152.1, 144.1, 142.9, 137.6, 130.4, 128.1, 123.6, 122.8,120.0,116.5, 114.9, 114.5, 114.0, 112.0, 108.5, 104.3, 96.2, 77.2, 55.8,54.1, 52.8, 41.0. C17: yellow solid, yield: 42.3%, mp 48.4-50.1 °C.1 1H NMR (400 MHz, Chloroform- d ) δ 7.82 (s, 1H), 7.77 (s, 1H), 7.53 (d, J J = 1.3 Hz, 1H), 7.48 (d, J J = 8.4 Hz, 1H), 7.42 – 7.35 (m, 1H), 7.22 (td, J J = 8.3, 1.9 Hz, 1H), 7.14 (s,1H), 6.84 – 6.62 (m, 6H), 5.21 (s, 1H), 4.90 (d, J J = 14.1 Hz, 1H), 4.52 (d, J J =14.9 Hz, 1H), 4.37 (s, 2H), 4.32 (d, J J = 15.0 Hz, 1H), 4.08 (d, J J = 14.0 Hz, 1H),3.74 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 161.9, 159.7, 152.4, 152.1, 144.1,142.9, 138.4, 130.4, 128.4, 126.0, 122.9, 120.5, 119.9, 116.0, 114.9, 114.6,114.0,112.8, 112.1, 104.2, 77.2, 55.8, 54.1, 52.7, 40.9. C18: Yellow solid, yield: 33.2%, m.p. 57.5 - 61.3 °C. 1 1H NMR (400 MHz, Chloroform- d ) δ 7.78 (s, 1H), 7.77 (s, 1H), 7.62 (d, J J = 7.9 Hz, 1H), 7.49 –7.36 (m, 5H), 7.19 (s, 1H), 7.14 (t, J J = 7.5 Hz, 1H), 6.85 –6.72 (m, 2H), 6.47(d, J J = 8.7 Hz, 2H), 5.09 (s, 1H), 4.90 (d, J J = 14.1 Hz, 1H), 4.64 (d,J = 14.9 Hz,1H), 4.41 (s, 2H), 4.34 (d, J = 15.0 Hz, 1H), 4.05 (d, J = 13.9 Hz, 1H). 13 C NMR(100 MHz, CDCl3) δ 161.7, 159.7, 152.1, 147.9, 144.0, 137.8, 137.6, 130.3,127.9, 127.0, 123.0, 122.5, 119.8, 119.2, 115.1, 113.0, 112.3, 109.5, 104.3,77.9, 77.2, 54.0, 52.5, 39.8. C19: yellow solid, yield: 44.5%, mp 71.2-74.1 °C. 1 H NMR (400 MHz, Chloroform- d ) δ 7.78 (s, 2H), 7.42 – 7.38 (m, 2H), 7.35 – 7.27 (m, 3H), 7.23(s, 1H), 7.05 (t, J = 8.0 Hz, 1H), 6.82 – 6.70 (m, 2H), 6.50 – 6.44 (m, 2H), 5.18 (s, 1H), 4.88 – 4.82 (m, 1H), 4.63 (s, 2H), 4.56 (d, J = 15.0 Hz, 1H),4.32 (d, J = 15.0 Hz, 1H), 3.99 (d, J = 14.0 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ161.8, 159.6, 152.2, 147.5, 144.0, 138.9, 137.7, 130.4, 130.1, 125.5, 124.0,123.1, 122.6, 115.6,114.1, 113.4, 112.3, 108.9, 104.2, 78.0, 77.2, 54.0,52.5, 39.9. C20: yellow solid, yield: 26.1%, mp 73.6-76.6 °C. 1 H NMR (600 MHz, Chloroform-d ) δ 7.76 (s, 2H), 7.46 – 7.39 (m, 3H), 7.30 (d, J = 8.9 Hz, 1H),7.14 (s, 1H), 7.01 (s, 1H), 6.91 (d, J = 8.9 Hz, 1H), 6.78 (dt, J = 27.7, 8.6 Hz,2H), 6.46 (d, J = 8.4 Hz, 2H), 5.09 (s, 1H), 4.87 (d, J = 14.2 Hz, 1H), 4.56 (d, J = 15.1 Hz, 1H), 4.35 (s, 2H), 4.31 (d, J = 15.1 Hz, 1H), 4.05 (d, J = 14.1 Hz,1H), 3.82 (s, 3H). 13 C NMR (150 MHz, CDCl3) δ 162.3, 159.4, 154.4, 152.2,148.1, 144.2, 137.9, 132.9, 130.5, 128.6, 127.5, 123.1,115.2, 112.8, 112.6,112.2, 110.6, 104.4, 100.9, 78.0, 77.3, 56.0, 54.2, 52.9, 40.0. C21: yellow solid, yield: 20.5%, mp 79.2-81.6°C. 1 H NMR (400 MHz, Chloroform- d ) δ 7.79 (s, 1H), 7.79 (s, 1H), 7.47 – 7.35 (m, 3H), 7.32 (dd, J = 9.0, 4.2Hz, 1H), 7.25 – 7.22 (m, 1H), 7.20 (s, 1H), 6.99 (td, J = 9.0, 2.5 Hz, 1H),6.84 – 6.71 (m, 2H), 6.48 – 6.43 (m, 2H), 5.15 (s, 1H),4.89 (d, J = 14.1 Hz,1H), 4.57 (d, J= 15.0 Hz, 1H), 4.38 – 4.31 (m, 3H), 4.07 (d, J = 14.0 Hz, 1H). 13 CNMR (100 MHz, CDCl3) δ 161.7, 159.6, 159.0, 152.2, 147.8, 144.1, 137.8,134.1, 130.3, 129.4, 127.3,122.8, 115.1, 112.9, 112.1, 110.9, 110.7, 110.4,104.3, 78.1, 77.2, 54.1, 52.8, 39.7. C22: yellow solid, yield: 25.4%, mp 80.6-82.1 °C. 1 H NMR (400 MHz, Chloroform- d ) δ 7.79 (s, 1H), 7.78 (s, 1H), 7.57 (d, J = 1.8 Hz, 1H), 7.45 –7.35 (m, 3H), 7.31 (d, J = 8.8 Hz, 1H), 7.23 – 7.16 (m, 2H), 6.83 – 6.70 (m,2H), 6.48 – 6.42 (m, 2H), 5.19 (s, 1H), 4.88 (d, J = 14.1 Hz, 1H), 4.56 (d, J =14.9 Hz, 1H), 4.38 – 4.30 (m, 3H), 4.06 (d, J = 14.0 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 161.7, 159.5, 152.2, 147.7, 144.0, 137.8, 136.0, 130.3, 129.1,128.0, 125.6, 122.7, 122.6,118.6, 115.2, 112.7, 112.3, 110.8, 104.3, 78.2,77.2, 54.1, 52.7, 39.6. C23: yellow solid, yield: 30.6%, mp 100.4-104.4 °C. 1 H NMR (400 MHz, Chloroform- d) δ 7.79 (s, 1H), 7.78 (s, 1H), 7.74 – 7.72 (m, 1H), 7.46 – 7.27(m, 5H), 7.16 (s, 1H), 6.84 – 6.70 (m, 2H), 6.45 (d, J = 8.8 Hz, 2H), 5.19 (s,1H), 4.88 (d, J = 14.1 Hz, 1H), 4.56 (d, J = 14.9 Hz, 1H), 4.38 – 4.30 (m, 3H), 4.05 (d, J = 14.0 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 161.8, 159.5, 152.2, 147.7,144.1, 137.8, 136.3, 130.2, 129.0, 128.6, 125.3, 122.8, 121.7, 117.3, 115.2,113.1, 112.1,111.2, 104.3, 78.2, 77.2, 54.1, 52.7, 39.6. C24: yellow solid, yield: 35.5%, mp 103.6-106.6 °C. 1 H NMR (400 MHz, Chloroform- d ) δ 7.80 (s, 1H), 7.78 (s, 1H), 7.50 (dd, J = 8.6, 5.3 Hz, 1H),7.43 (dd, J = 8.7, 5.2 Hz, 3H), 7.14 (s, 1H), 7.10 (dd, J = 9.9, 2.0 Hz, 1H),6.89 (td, J = 9.2, 2.1 Hz, 1H), 6.81 (ddd, J = 11.8, 8.3, 2.3 Hz, 1H), 6.78 –6.71 (m, 1H), 6.45 (d, J = 8.7 Hz, 2H), 5.20 (s, 1H), 4.90 (d, J = 14.1 Hz, 1H),4.51 (d, J= 15.0 Hz, 1H), 4.37 (s, 2H), 4.30 (d, J = 15.0 Hz, 1H), 4.08 (d, J =14.0 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 161.9, 159.1, 152.2, 147.8, 144.1,137.8, 137.7, 130.3, 128.2, 123.4, 122.8, 120.0, 119.9,115.1, 113.2, 112.1,108.7, 104.3, 96.5, 78.1, 77.2, 54.1, 52.8, 39.7. C25: yellow solid, yield: 30.6%, mp 76.8-81.25 °C. 1 H NMR (400 MHz, Chloroform- d ) δ 7.85 (s, 1H), 7.83 (s, 1H), 7.76 (s, 2H), 7.61 (d, J = 7.9 Hz,1H), 7.43 (dq, J = 9.1, 3.0 Hz, 2H), 7.29 (d, J = 7.2 Hz, 1H), 7.21 (s, 1H), 7.15(t, J = 7.4 Hz, 1H), 6.86 – 6.72 (m, 2H), 6.63 (d, J = 8.7 Hz, 2H), 5.15 (s, 1H), 4.90 (d, J = 14.2 Hz, 1H), 4.69 – 4.60 (m, 1H), 4.50 (s, 2H), 4.35 (d, J = 15.0Hz, 1H), 4.09 (d, J = 14.1 Hz, 1H), 2.50 (s, 3H). 13C NMR (100 MHz, CDCl3) δ196.5, 161.8, 159.8, 152.2, 152.0, 144.1, 137.6, 130.8, 130.4, 128.1, 126.9,126.7, 123.1, 122.6, 119.9, 119.1, 112.3, 112.2, 111.5, 109.6, 104.3, 77.2,54.2, 52.5, 39.3, 26.0. C26: yellow solid, yield: 30.7%, mp 62.7-66.7 °C. 1 H NMR (400 MHz, Chloroform- d ) δ 7.84 (d, J = 8.7 Hz, 2H), 7.80 (s, 1H), 7.78 (s, 1H), 7.40 (td, J = 9.1, 6.5 Hz, 1H), 7.33 (dd, J = 9.0, 4.2 Hz, 1H), 7.26 – 7.21 (m, 2H), 7.00(td, J = 9.0, 2.5 Hz, 1H), 6.84 – 6.70 (m, 2H), 6.63 (d, J = 8.8 Hz, 2H), 5.22(s, 1H), 4.89 (d, J = 14.1 Hz, 1H), 4.59 (d, J = 14.9 Hz, 1H), 4.45 (s, 2H), 4.36(d, J = 15.0 Hz, 1H), 4.15 – 4.07 (m, 1H), 2.50 (s, 3H). 13 C NMR (100 MHz, CDCl3)δ 196.4, 161.7, 159.7, 159.0, 152.1, 152.0, 144.1, 134.2, 130.8, 130.3,129.6, 127.1,126.9, 122.8, 112.3, 112.1, 111.5, 111.1, 110.8, 110.6, 104.2,77.2, 54.1, 52.8, 39.2, 26.0. C27: yellow solid, yield: 28.1%, mp 89.8-92.9 °C.1 H NMR (400 MHz, Chloroform- d ) δ 7.84 (d, J = 8.7 Hz, 2H), 7.79 (s, 1H), 7.78 (s, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.39 (td, J = 9.1, 6.5 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.24 –7.17 (m, 2H), 6.84 – 6.70 (m, 2H), 6.63 (d, J = 8.8 Hz, 2H), 5.23 (s, 1H), 4.89(d, J = 14.1 Hz, 1H), 4.58 (d, J = 14.9 Hz, 1H), 4.45 (s, 2H), 4.36 (d, J = 15.0Hz, 1H), 4.10 (d, J = 14.0 Hz, 1H), 2.50 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ196.5, 161.8, 159.7, 152.2, 152.0, 144.1, 136.0, 130.8, 130.4, 129.3, 127.9,126.9, 125.7, 122.9, 122.7, 118.5, 112.3, 112.0,111.6, 110.9, 104.3, 77.2,54.0, 52.7, 39.1, 26.0. C28: yellow solid, yield: 22.4%, mp 85.2-88.2 °C. 1 H NMR (400 MHz, Chloroform- d ) δ 7.84 (d, J = 8.7 Hz, 2H), 7.79 (s, 1H), 7.78 (s, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.43 – 7.27 (m, 3H), 7.19 (s, 1H), 6.83 – 6.70 (m, 2H), 6.63(d, J= 8.8 Hz, 2H), 5.24 (s, 1H), 4.89 (d, J = 14.1 Hz, 1H), 4.58 (d, J = 15.0 Hz,1H), 4.45 (s, 2H), 4.36 (d, J = 15.0 Hz, 1H), 4.09 (d, J = 14.1 Hz, 1H), 2.50 (s,3H). 13 C NMR (100 MHz, CDCl3) δ 196.5, 161.8, 159.7, 152.2, 151.9, 144.1,136.3, 130.8, 130.3, 129.1, 128.5, 127.0, 125.4, 122.7, 121.6, 113.2, 112.1,112.0, 111.6, 111.3, 104.3, 77.2, 54.1, 52.7, 39.1, 26.0. Example 2 Antifungal activity test 1. Materials and Methods 1. Drugs and samples Indoletriazole derivatives C01-C28 were prepared by Example 1.

[0024] The positive control drug fluconazole (FLC) was dissolved in DMSO, sonicated for 10 min, and centrifuged to obtain the supernatant. The storage concentration was 50 mM / mL and sealed in a refrigerator at 4°C. All compounds were dissolved in DMSO at a concentration of 50 mM / mL and sealed in a refrigerator at 4°C.

[0025] 2. Culture medium and strains (1) Culture medium Sabouraud liquid culture medium, Sabouraud solid culture medium.

[0026] (2) Strains Candida albicans fluconazole-sensitive strain SC5314, Candida albicans fluconazole-resistant strain ATCC14053, Candida albicans fluconazole clinical strains CA6, CA23, CA602, CA550, Candida albicans fluconazole-sensitive strain ATCC-10231. CA6, CA 23, CA 602, CA 550 are clinically resistant Candida albicans.

[0027] 3. Experimental methods Take a 96-well culture plate, dilute the sample and fluconazole to an initial concentration of 200 μM / mL, 100 μL per well, perform 5-fold dilution, 6 concentration gradients, and 3 replicates per concentration gradient. After the strain is activated twice, prepare the bacterial suspension, add 100 μL of the fungal suspension to each well of the 96-well plate, and make the final concentration of Candida albicans 1×10 5 CFU / mL, incubate in a 37℃ constant temperature incubator for 24h. Measure the OD value at 625nm with an enzyme marker. The experiment also sets up a culture medium blank control, a bacterial solution control, and a fluconazole positive drug control.

[0028] 4. Calculation formula Fungal activity inhibition rate (%) = (1-sample OD value / experimental control well OD value) × 100% 2. Results Table 1 Summary of the antibacterial activity experiments of the tested samples and fluconazole against Candida albicans Table 2 In vitro antifungal activity of target compounds C04 and C08

[0029] Conclusion 1. The samples that have single drug effects on both sensitive and resistant strains of Candida albicans are: C02, C04, C05, C06, C07, C08, C10, C11, C13, C14, C15, C17, C19, C20, C21; 2. The samples that have single drug effects only on sensitive strains of Candida albicans are: C09, C12, C16, C23, C24, C26; 3. The samples with single drug effects only on drug-resistant strains of Candida albicans are: None; In Table 1, most of the indoletriazole derivatives have antibacterial effects on both sensitive and resistant strains of Candida albicans. Compound C08 has better activity than fluconazole against sensitive strains of Candida albicans, and compound C04 has the best activity against the resistant strain of Candida albicans ATCC14053-FR. In Table 2, two representative compounds C04 and C08 showed strong activity against several fungal pathogens. In particular, compound C08 showed strong activity against Candida albicans fluconazole-sensitive strain SC5314, Candida albicans fluconazole-resistant strain ATCC14053-FR, Candida albicans fluconazole clinical strains CA6, CA23, CA602, CA550, and Candida albicans fluconazole-sensitive strain ATCC-10231.

Claims

1. The use of indoletriazole derivatives in the preparation of drugs against drug-resistant Candida albicans, characterized in that: The structure of indoletriazole derivatives is: 。 2. The use according to claim 1, characterized in that The drug-resistant Candida albicans are drug-resistant Candida albicans ATCC14053, CA6, CA 23, CA 602, and CA 550, wherein CA6, CA 23, CA 602, and CA 550 are clinically drug-resistant Candida albicans.

3. The use according to claim 1 or 2, characterized in that: The preparation method of the indoletriazole derivative is: (1) Add 7 ml of DMF to a dry round-bottom flask, cool in an ice-water bath, slowly add 0.44 ml of phosphorus oxychloride with a syringe, and stir in an ice-water bath for 30 minutes; when the solution turns pink, slowly add 4 mmol of substituted indole dissolved in 1.5 ml of DMF to the round-bottom flask, and react in an ice-water bath for 1 hour; pour the reaction solution into ice water, adjust the pH value to 10 with 5 mol / L NaOH, and heat at 80°C for 1 hour; cool to room temperature, adjust the pH value to 4 with dilute hydrochloric acid, a large amount of solid precipitates, filter, and repeatedly wash the filter cake with water; dry the filter cake to obtain intermediate A; (2) 0.3 mmol of intermediate A and 0.3 mmol of substituted aniline were dissolved in 5 ml of ethanol, 5 drops of piperidine were added, the mixture was refluxed at 85°C for 5 hours, cooled to room temperature, 0.3 mmol of NaBH4 was added, the mixture was reacted at room temperature for 2 hours, and the reaction was monitored by TLC until the reaction was completed. The reaction solution was dried by spin drying, dissolved in ethyl acetate, and transferred to a separatory funnel; The organic layer was washed twice with water and once with saturated brine, then dried over anhydrous Na2SO4, concentrated and spin-dried to obtain intermediate B; (3) In a dry round-bottom flask, 0.3 mmol of intermediate B, 0.3 mmol of 1-[2-(2,4-difluorophenyl)-2,3-epoxypropane]-1H-1,2,4-triazole methanesulfonate and 50 mg of KOH were added, and dimethyl sulfoxide (5 ml) was added. The mixture was reacted at 85°C. After TLC monitoring showed that the reaction was complete, the reaction solution was transferred to a separation funnel and 20 ml of ethyl acetate was added. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography and petroleum ether / ethyl acetate to obtain an indoletriazole derivative.

4. The use according to claim 3, characterized in that: The substituted indoles are: indole, 4-bromoindole, 5-methoxyindole, 5-fluoroindole, 5-chloroindole, 5-bromoindole, 6-fluoroindole, 6-bromoindole, and 4-methylindole.

5. The use according to claim 3, characterized in that: The substituted aniline is: aniline, p-methoxyaniline, p-iodoaniline, and p-acetylaniline.

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