Thiazole-containing triazole antifungal compound as well as preparation method and application thereof

Abstract

The invention discloses a triazole antifungal compound containing thiazole. The structure of the triazole antifungal compound is shown as a general formula I, the compound disclosed by the invention has excellent antibacterial activity on various fungi, and particularly has remarkable antifungal activity on azole drug-resistant fungi.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a method for preparing a thiazole-containing triazole antifungal compound and application of the compound in treating fungal infections. Background Art

[0002] Fungal infections have become an increasingly serious public health threat worldwide. According to the latest research, approximately 15 million people worldwide suffer from invasive fungal infections each year, and the number of deaths from these infections has doubled to 4 million in the past decade, far exceeding the number of deaths from tuberculosis. The pathogens that cause invasive fungal infections primarily include the following four: Candida species (such as Candida albicans) often cause thrush, vaginitis, and bloodstream infections; Cryptococcus species (such as Cryptococcus neoformans) cause meningitis, which is particularly threatening to immunocompromised individuals; Aspergillus species (such as Aspergillus fumigatus) cause invasive lung disease and allergies; and Mucorales fungi cause necrotizing rhinocerebral mucormycosis, a rapidly progressive disease. These fungi can cause superficial, subcutaneous, or fatal systemic diseases, particularly in immunocompromised individuals.

[0003] Commonly used antifungal drugs in clinical practice (such as polyenes, azoles, echinocandins, and nucleic acid analogs) have significant therapeutic effects, but their widespread use has led to the continuous emergence of drug-resistant fungi, exacerbating the difficulty of treatment. Azoles, as representative drugs that primarily target lanosterol 14α-demethylase (CYP51), are widely used, but their drug resistance problem is particularly prominent. Therefore, there is an urgent need to develop new CYP51 inhibitors with superior antifungal properties. The present invention provides a novel triazole compound with excellent antifungal activity. Summary of the Invention

[0004] The first object of the present invention is to provide a triazole antifungal compound containing thiazole;

[0005] The second object of the present invention is to provide a method for preparing the thiazole-containing triazole antifungal compound;

[0006] The third object of the present invention is to provide a use of the thiazole-containing triazole antifungal compound.

[0007] To achieve the above-mentioned purpose, the present invention provides the following technical solutions:

[0008] 1. A compound having the structure shown in Formula I or a pharmaceutically acceptable salt thereof:

[0009]

[0010] Where,

[0011] X is N-substituted or unsubstituted amino, piperazinyl;

[0012] L is any one of the following groups:

[0013]

[0014] R 1 、R 2 、R 3 、R 4 、R 5 Each is independently selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted phenyl, optionally substituted N-alkylpiperazinyl, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted pyrrolyl, optionally substituted pyrrolidinyl, optionally substituted pyridinyl.

[0015] 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein

[0016] X is any one of the following groups:

[0017]

[0018] L is any one of the following groups:

[0019]

[0020] R 1 、R 2 、R 3 、R 4 、R 5 Each is independently selected from hydrogen, halogen, nitro, methyl, ethyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy.

[0021] 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it has any of the following structures:

[0022]

[0023] 4. The method for preparing the azole compound according to any one of claims 1 to 3, characterized in that it comprises the following steps:

[0024] Preparation of compounds A1-A5:

[0025]

[0026] Step 1: dissolve compound 1 in toluene, add trimethylsulfoxide iodide and sodium hydroxide, and react to obtain compound 2;

[0027] Step 2: Compound 2 reacts with ammonia or an amine compound to obtain a ring-opened intermediate compound 3;

[0028] Step 3: Compound 4 reacts with 4-chlorothiophenol 5 to obtain intermediate compound 6 through nucleophilic substitution;

[0029] Step 4: Compound 6 is hydrolyzed by alkaline to obtain intermediate compound 7;

[0030] Step 5: Intermediate compound 7 and intermediate compound 3 are subjected to amide condensation to obtain target compounds A1-A5.

[0031] Preparation of compounds A6-A20:

[0032]

[0033] Step 1: Compound 4 reacts with a thiophenol derivative to obtain intermediate compound 8;

[0034] Step 2: Compound 8 is hydrolyzed under alkaline conditions with sodium hydroxide to obtain carboxylic acid compound 9;

[0035] Step 3: Intermediate compound 9 and intermediate compound 3 are subjected to amide condensation to obtain target compound A6-A20.

[0036] Preparation of compounds A21-A26:

[0037]

[0038] Step 1: Compound 4 reacts with p-hydroxythiophenol via nucleophilic substitution to obtain intermediate compound 11;

[0039] Step 2: Compound 11 undergoes electrophilic substitution reaction with a 4-substituted benzyl bromide derivative to obtain intermediate compound 12;

[0040] Step 3: Compound 12 is hydrolyzed with an alkali to obtain carboxylic acid compound 13;

[0041] Step 4: Compound 13 and intermediate compound 3 are reacted by amide condensation to obtain target compounds A21-A26.

[0042] Preparation of compound A27:

[0043]

[0044] Compound A27 was obtained by oxidation of compound A1 with m-chloroperbenzoic acid.

[0045] Preparation of compound A28:

[0046]

[0047] Step 1: Compound 4 reacts with 4-chlorobenzyl mercaptan 14 to obtain intermediate compound 15;

[0048] Step 2: Compound 15 is hydrolyzed with alkaline to obtain carboxylic acid compound 16;

[0049] Step 3: Compound 16 and intermediate compound 3 are reacted by amide condensation to obtain target compound A28.

[0050] Preparation of compound A29:

[0051]

[0052] Step 1: Compound 17 reacts with 4-chlorobenzaldehyde 18 under acid catalysis to obtain intermediate compound 19;

[0053] Step 2: Compound 19 is hydrolyzed with an alkali to obtain carboxylic acid compound 20;

[0054] Step 3: Compound 20 and intermediate compound 3 are reacted by amide condensation to obtain target compound A29.

[0055] In the above preparation process, the definitions of X, L and R are as described above. Those skilled in the art can prepare the compounds of the present invention using various starting compounds commonly available in the art as raw materials according to actual preparation needs.

[0056] 5. An antifungal drug, characterized in that the antifungal drug comprises the azole compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4.

[0057] 6 . The antifungal drug according to claim 5 , wherein the fungus is any one or more of Cryptococcus neoformans, Candida albicans, Cryptococcus gattii, Candida glabrata, Candida tropicalis, and Aspergillus fumigatus.

[0058] Due to the adoption of the above technical solution, the present invention has the following advantages and beneficial effects:

[0059] The triazole compounds provided by the present invention have a simple preparation method and exhibit good fungicidal activity against various cryptococci and filamentous fungi. The triazole antifungal compounds of the present invention can be prepared into antifungal drugs in various dosage forms, helping to address the increasingly serious problem of fungal drug resistance.

[0060] Other advantages, objects, and features of the present invention will be described in part in the following description and, in part, will be apparent to those skilled in the art upon examination of the following description or may be learned from practice of the present invention. The objects and other advantages of the present invention may be realized and obtained through the following description. DETAILED DESCRIPTION

[0061] In order to more clearly illustrate the present invention, the following embodiments of the present invention are described by specific examples. It should be understood by those skilled in the art that the following specific description is illustrative rather than restrictive and should not be used to limit the scope of protection of the present invention.

[0062] Example

[0063] Example 1

[0064] Preparation of compounds A1-A5:

[0065]

[0066] a Reagent and conditions: (a) Trimethyl sulfoxonium iodide, NaOH, toluene, 60℃, 4h; (b) Amines, MetOH, reflux, 6h; (c) NaOH, EtOH, reflux, 8h; (d) NaOH, MeOH / H2O, rt, 4h; (e) EDCI, HBTU, DIEA, DMF, rt, 6h.

[0067] Preparation of compound 2 (step 1):

[0068]

[0069] Compound 1 (2 g, 22.40 mmol) was weighed and placed in a 200 mL round-bottom flask. 20 mL of toluene, trimethylsulfoxide iodide (5.92 g, 67.21 mmol), 40% sodium hydroxide solution (9 mL, 201.63 mmol), and hexadecylammonium bromide (281 mg, 4.48 mmol) were added and stirred at 60°C for 5 h. After the reaction, the toluene phase was separated, and the organic phase was dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, v / v) to obtain 1.5 g of compound 2 as a yellow liquid in a 71% yield. 1 H NMR (400MHz, CDCl3): δ8.07(s,1H),7.87(s,1H),7.19(m,1H),6.82(m,2H),4.83(d, J=14.8Hz, 1H), 4.52 (d, J=14.8Hz, 1H), 2.95 (d, J= 4.8Hz, 1H), 2.89 (d, J= 4.8Hz, 1H).

[0070] Preparation of compound 3a (step 2):

[0071]

[0072] Compound 2 (1 g, 4.22 mmol) was weighed and placed in a 50 mL round-bottom flask. 9 mL of ethanol was added, and 15 mL of aqueous ammonia was added dropwise with stirring under an ice bath. The mixture was stirred at room temperature for 6 h. After completion of the reaction, the solvent was removed by rotary evaporation, and the crude product was recrystallized from ethyl acetate to obtain 1 g of compound 3a as a white solid in a 93% yield. 1 H NMR (400MHz, CDCl3): δ8.08(s,1H),7.83(s,1H),7.56(m,1H),6.81(m,2H),4.58(m,2H),3.20(d,J=12.8Hz,1H),2.98(d,J=12.8Hz,1H).

[0073] Preparation of compound 6 (step 3):

[0074]

[0075] 4-Chlorothiophenol 5 (306 mg, 2.12 mmol) was weighed and placed in a 25 mL round-bottom flask. 10 mL of anhydrous ethanol and sodium hydroxide (85 mg, 2.12 mmol) were added and stirred at room temperature for 15 minutes. Ethyl 5-bromothiazole-4-carboxylate 4 (500 mg, 2.12 mmol) was weighed and added to the reaction mixture, and the reaction mixture was stirred at 78°C for 4 hours. After the reaction, the reaction mixture was spin-dried and extracted with ethyl acetate. The organic phase was washed with deionized water, collected, dried, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, v / v) to obtain compound 6 as a white solid (335 mg, yield: 53%). 1 H NMR (400MHz, CDCl3): δ8.48 (s, 1H), 7.60 (d, J = 8.8Hz, 2H), 7.44 (d, J = 8.8Hz, 2H), 4.47 (q, J = 7.2Hz, 2H), 1.46 (t, J = 7.2Hz, 3H).

[0076] Preparation of compound 7 (step 4):

[0077]

[0078] Compound 6 (500 mg, 1.67 mmol) was weighed and placed in a 50 mL round-bottom flask. 12 mL of methanol was added to dissolve the mixture. Sodium hydroxide (133 mg, 3.34 mmol) was weighed and dissolved in 2 mL of water. The mixture was added to the reaction solution and stirred at room temperature for 1 h. After the reaction was completed, the solvent was removed by rotary evaporation, deionized water was added to dissolve the mixture, and dilute hydrochloric acid was added to adjust the pH to 1-2. The filter cake was dried. 410 mg of compound 7 was obtained as a white solid with a yield of 90%. 1H NMR (400MHz, DMSO-d6): δ13.20 (s, 1H), 8.83 (s, 1H), 7.73 (d, J = 8.4Hz, 2H), 7.64 (d, J = 8.4Hz, 2H).

[0079] Preparation of compound A1 (step 5):

[0080]

[0081] Compound 7 (100 mg, 0.37 mmol) and 3a (117 mg, 0.46 mmol) were weighed separately and placed in a 25 mL round-bottom flask. HBTU (193 mg, 0.51 mmol) and EDCI (110 mg, 0.57 mmol) were added sequentially, followed by 8 mL of N,N-dimethylformamide and DIEA (190 μL, 1.15 mmol). The mixture was stirred at room temperature for 5 h. After completion of the reaction, the solvent was removed by rotary evaporation, and ethyl acetate was added for dissolution. The organic phase was washed with deionized water, and the organic phase was dried and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 120:1, v / v) and recrystallized from ethanol. Compound A1 was obtained as a white solid (80 mg, yield: 43%). 1 H NMR (400MHz, CDCl3): δ8.35(s,1H),8.10(s,1H),7.84(s,1H),7.65-7.57(m,4H),7.42(d,J=8.4Hz,2H),6.81(dd,J=15.2,6.4H z,2H),5.85(s,1H),4.74(d,J=14.0Hz,1H),4.61(d,J=14.0Hz,1H),4.08(dd,J=14.4,6.8Hz,1H),3.77(dd,J=14.4,6.0Hz,1H). 13 C NMR (100MHz, CDCl3): δ164.09, 162.92 (dd, J=249.1, 11.7Hz), 158.73 (dd, J=245.2, 11.5Hz) ,151.46,148.98,146.37,144.53(d,J=4.5Hz),139.83,136.94,135.90,131.96,130.47(d, J=5.9Hz),130.38,123.73(dd,J=13.6,3.9Hz),111.80(dd,J=20.5,3.0Hz),104.21(t,J=27 .0Hz),76.42(d,J=5.1Hz),55.84(d,J=5.1Hz),47.04(d,J=4.7Hz).HRMS(ESI)(m / z):[M+H]+ calcdfor C 21 H 17 ClF2N5O2S2,508.0475; found,508.0514.

[0082] Preparation of compound A2

[0083]

[0084] Compound A2 was synthesized as a white solid in a similar manner to compound A1 with a yield of 45%. 1 HNMR (400MHz, DMSO-d6): δ9.21(s,1H),8.30(s,1H),7.74(s,1H),7.38-7.34(m,4H),7.11(dd,J=19.2,9.6Hz ,2H),6.87(t,J=6.8Hz,1H),6.16(s,1H),4.58(d,J=14.4Hz,2H),3.95(dd,J=14.4,8.0Hz,2H),2.92(s,3H). 13 C NMR (100MHz, DMSO-d6): δ165.39, 162.28 (dd, J=289.6, 15.1Hz), 162.09 (dd, J=172.0, 14.1Hz),158.21,155.91,151.08,149.59,145.38,134.52,133.17,131.96,130.53,1 30.03,124.88(d,J=2.9Hz),111.20(dd,J=25.4,3.9Hz),104.35(t,J=25.6Hz),76.36 (d,J=4.8Hz),55.61(d,J=5.6Hz),54.53(d,J=2.4Hz),36.58.HRMS(ESI)(m / z):[M+H] + calcd for C 22 H 19 ClF2N5O2S2,522.0632; found,522.0637.

[0085] Preparation of compound A3

[0086]

[0087] Compound A3 was synthesized as a white solid in a similar manner to compound A1. The yield was 37%. 1HNMR (400MHz, CDCl3): δ8.64(s,1H),8.28(s,1H),7.81(s,1H),7.65(d,J=7.2Hz,1H),7.48(s,2H),7.33(s,2H),6.97(s,1H),6 .77(d,J=8.0Hz,1H),6.64(s,1H),4.71(s,2H),3.93(d,J=16.0Hz,1H),3.80(d,J=14.4Hz,1H),3.49-3.36(m,2H),1.10(s,3H). 13 C NMR (100MHz, CDCl3): δ167.16, 162.75 (dd, J=201.0, 10.1Hz), 158.99 (dd, J=257.0, 25.8Hz), 153.37,151.45(d,J=3.6Hz),148.99,145.42(d,J=2.9Hz),144.82,135.18(d,J=5.8Hz),134 .43,132.88,130.81,129.89,123.97(d,J=4.7Hz),111.97(dd,J=12.3,4.1Hz),104.00(t,J= 8.0Hz),76.49(d,J=3.2Hz),56.53(d,J=7.9Hz),53.99,46.31,13.79.HRMS(ESI)(m / z):[M+H] + calcd for C 23 H 21 ClF2N5O2S2,536.0788; found,536.0791.

[0088] Preparation of compound A4

[0089]

[0090] Compound A4 was synthesized as a white solid in a similar manner to compound A1. Yield: 15%. 1 HNMR (400MHz, DMSO-d6): δ9.29(s,1H),8.32(s,1H),7.73(s,1H),7.45-7.37(m,5H),7.14(s,1 H),6.89(s,1H),6.61(s,1H),4.87-4.48(m,2H),4.04-3.42(m,3H),1.04(s,3H),0.85(s,3H). 13C NMR (100MHz, DMSO-d6): δ165.93 (dd, J=444.3, 11.6Hz), 160.33 (dd, J=190.5, 12.1Hz), 151.05, 145 .60,144.58,134.55(d,J=4.2Hz),133.13,132.07,131.28,130.90(t,J=8.2Hz),130.29,130.01,1 25.13(dd,J=7.3,3.9Hz),111.40(d,J=10.3Hz),104.43(t,J=28.5Hz),75.24(d,J=2.1Hz),55.91( d,J=2.7Hz),51.81(d,J=6.1Hz),49.81(dd,J=12.1,4.6Hz),21.25,19.69.HRMS(ESI)(m / z):[M+H] + calcd for C 24 H 23 ClF2N5O2S2, 550.0945; found, 550.0952. Preparation of compound A5

[0091]

[0092] Compound A5 was synthesized as a white solid in a similar manner to compound A1. The yield was 17%. 1 HNMR (400MHz, DMSO-d6): δ9.19(s,1H),8.33(s,1H),7.72(s,1H),7.44(d,J=7.6Hz,4H),7.37(s,2H),7.12(t,J=12.0Hz,1H),6.86(s ,1H),5.9(s,1H),4.77(d,J=13.2Hz,1H),4.62(d,J=14.4Hz,1H),4.23(d,J=13.2Hz,1H),3.90(d,J=14.0Hz,1H),0.50-0.36(m,4H). 13C NMR (100MHz, DMSO-d6): δ165.42 (dd, J=349.8, 6.5Hz), 159.50 (dd, J=348.0, 3.9Hz), 151.01, 145 .41,142.76,140.10,137.42,134.57,133.26(d,J=3.3Hz),131.65(d,J=6.0Hz),130.68(dd,J=1 0.0, 5.4Hz), 130.02, 128.26 (d, J = 4.6Hz), 124.93, 111.17 (dd, J = 18.8, 7.1Hz), 104.22 (t, J = 28. 1Hz),75.99,55.57(d,J=5.7Hz),52.94,33.33,11.13,9.27(d,J=5.6Hz).HRMS(ESI)(m / z):[M+H] + calcd for C 24 H 21 ClF2N5O2S2,548.0788; found,548.0791.

[0093] Example 2

[0094] Preparation of compounds A6-A20:

[0095]

[0096] a Reagent and conditions: (a) NaOH, EtOH, reflux, 8h; (b) NaOH, MeOH / H2O, rt, 4h; (c) EDCI, HBTU, DIEA, DMF, rt, 6h.

[0097] Preparation of Compound A6

[0098]

[0099] Compounds 9a (150 mg, 0.63 mmol) and 3a (201 mg, 0.79 mmol) were weighed separately and placed in a 25 mL round-bottom flask. HBTU (331 mg, 0.87 mmol) and EDCI (189 mg, 0.99 mmol) were added sequentially, followed by 8 mL of N,N-dimethylformamide and DIEA (327 μL, 1.98 mmol). The mixture was stirred at room temperature for 5 h. After completion of the reaction, the solvent was removed by rotary evaporation, and ethyl acetate was added for dissolution. The organic phase was washed with deionized water, and the organic phase was dried and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100:1, v / v) and recrystallized from ethanol. Compound A6 was obtained as a white solid (200 mg, yield: 62%). 1 HNMR (400MHz, CDCl3): δ8.31(s,1H),8.13(s,1H),7.84(s,1H),7.66-7.60(m,4H),7.50-7.43(m,3H),6.81(dd,J=15.2 ,6.8Hz,2H),5.91(br,1H),4.68(dd,J=48.0,14.0Hz,2H),4.08(dd,J=14.4,6.8Hz,1H),3.78(dd,J=14.4,5.6Hz,1H). 13 C NMR (100MHz, CDCl3): δ164.26, 162.89 (dd, J=248.8, 11.7Hz), 158.73 (dd, J=244.2, 11.6Hz) ,151.60(d,J=6.8Hz),151.25,148.73,147.52,139.43,134.67,133.56,130.51(d,J=5.8Hz ),130.42,130.09,123.82(dd,J=13.4,3.7Hz),111.77(dd,J=20.7,2.7Hz),104.17(t,J=27 .2Hz),76.43(d,J=4.9Hz),55.93(d,J=4.3Hz),47.01(d,J=3.9Hz).HRMS(ESI)(m / z):[M+Na] + calcdforC 21 H 17 N5O2F2S2,496.0692; found,496.0692.

[0100] Preparation of Compound A7

[0101]

[0102] Compound A7 was synthesized as a white solid in a similar manner to compound A6. Yield: 36%. 1 HNMR (400MHz, DMSO-d6): δ8.80(s,1H),8.33(s,1H),8.16(t,J=6.0Hz,1H),7.78-7.74(m,3H),7.44-7.35(m,3H),7. 23-7.17(m,1H),6.97-6.93(m,1H),6.28(s,1H),4.69(d,J=14.4Hz,1H),4.56(d,J=14.4Hz,1H),3.88-3.78(m,2H). 13 CNMR(100MHz,DMSO-d6): δ165.01,162.37(dd,J=244.4,12.4Hz),162.44,159.60(dd,J=246.0,12.2H z),151.77,151.04,145.46,145.30(d,J=1.1Hz),140.51,137.57(d,J=8.8Hz),130.59(dd,J=9.7,6. 1Hz),129.69,125.18(dd,J=13.0,3.3Hz),117.85(d,J=22.1Hz),111.28(dd,J=20.5,2.8Hz),104.50 (t,J=27.4Hz),75.02(d,J=5.0Hz),55.70(d,J=4.7Hz),46.03(d,J=4.6Hz).HRMS(ESI)(m / z):[M+Na] + calcd for C 21 H 16 F3N5O2S2,514.0598; found,514.0599.

[0103] Preparation of Compound A8

[0104]

[0105] Compound A8 was synthesized as a white solid in a similar manner to compound A6. Yield: 43%. 1HNMR (400MHz, DMSO-d6): δ8.83(s,1H),8.33(s,1H),8.17(t,J=5.6Hz,1H),7.75-7.70(m,3H),7.62(d,J=8.0Hz,2H),7.40(dd,J=16.0,8 .4Hz,1H),7.19(t,J=9.6Hz,1H),6.95(t,J=8.0Hz,1H),6.28(s,1H),4.69(d,J=14.4Hz,1H),4.56(d,J=14.4Hz,1H),3.88-3.76(m,2H). 13 CNMR(100MHz,DMSO-d6): δ162.36(dd,J=244.4,12.5Hz),162.33,159.60(dd,J=246.1,12. 4Hz),152.16,151.04,145.45,143.63,141.22,136.52,133.63,133.42,130.59(dd,J=9.5 ,5.9Hz),125.17(dd,J=12.5,3.7Hz),124.46,111.27(dd,J=20.3,2.9Hz),104.49(t,J=27 .6Hz),75.00(d,J=5.0Hz),55.69(d,J=5.3Hz),46.03(d,J=3.9Hz).HRMS(ESI)(m / z):[M+H] + calcd for C 21 H 16 BrF2N5O2S2,551.9970; found,553.9955.

[0106] Preparation of Compound A9

[0107]

[0108] Compound A9 was synthesized as a white solid in a similar manner to compound A6. Yield: 21%. 1HNMR (400MHz, DMSO-d6): δ9.06(s,1H),8.32-8.24(m,4H),7.75(t,J=3.6Hz,3H),7.39(dd,J=16.0,9.2Hz,1H),7.20-7.14(m,1H),6.93(td, J=8.4,2.4Hz,1H),6.27(s,1H),4.67(d,J=14.4Hz,1H),4.55(d,J=14.0Hz,1H),3.86(dd,J=13.6,6.4Hz,1H),3.76(dd,J=13.6,5.6Hz,1H). 13 C NMR (100MHz, DMSO-d6): δ162.34 (dd, J=244.4, 13.6Hz), 161.79, 159.60 (dd, J=246. 2,12.3Hz),154.73,151.06,147.70,142.25,145.46,145.17,143.58,136.96,132.5 1,130.56(dd,J=9.4,5.8Hz),125.10,111.22(d,J=20.9Hz),104.47(t,J=26.2Hz), 74.97(d,J=4.9Hz),55.64(d,J=5.4Hz),46.02(d,J=4.3Hz).HRMS(ESI)(m / z):[M+H] + calcdfor C 21 H 16 F2N6O4S2,519.0716; found,519.0725.

[0109] Preparation of compound A10

[0110]

[0111] Compound A10 was synthesized as a white solid in a similar manner to compound A6. Yield: 54%. 1 HNMR (400MHz, CDCl3): δ8.29(s,1H),8.10(s,1H),7.82(s,1H),7.67-7.60(m,2H),7.54(d,J=8.0Hz,2H),7.25(d,J=8.0Hz,2H),6.85-6.77( m,2H),5.91(s,1H),4.73(d,J=14.0Hz,1H),4.61(d,J=14.0Hz,1H),4.07(dd,J=14.4,6.8Hz,1H),3.77(dd,J=14.8,6.0Hz,1H),2.41(s,3H).13 C NMR (100MHz, CDCl3): δ164.34,164.38(dd,J=248.5,12.1Hz),159.94,158.74(dd,J=244.7, 9.8Hz),151.56,148.51,144.60,140.97,139.07,134.69,130.86,130.47(dd,J=9.6,5.9Hz ),130.09,123.85(dd,J=13.3,3.6Hz),111.74(dd,J=20.7,3.3Hz),104.15(t,J=27.3Hz),7 6.44(d,J=5.1Hz),55.85(d,J=4.8Hz),47.10(d,J=4.6Hz),21.37.HRMS(ESI)(m / z):[M+Na] + calcd for C 22 H 19 F2N5O2S2, 510.0848; found, 510.0844. Preparation of compound A11

[0112]

[0113] Compound A11 was synthesized as a white solid in a similar manner to compound A6. Yield: 58%. 1 HNMR (400MHz, CDCl3): δ8.29(s,1H),8.10(s,1H),7.82(s,1H),7.66-7.60(m,2H),7.56(d,J=8 .0Hz,2H),7.40(dt,J=22.8,7.2Hz,1H),7.28(d,J=4.0Hz,1H),6.81(dd,J=15.2,6.8Hz,2H),5. 93(s,1H),4.74(dd,J=14.0,6.8Hz,1H),4.62(dd,J=14.0,3.6Hz,1H),4.12-4.05(m,1H),3.77( dd,J=14.4,5.6Hz,1H),2.88-2.80(m,1H),2.70(dd,J=15.2,7.6Hz,1H),1.26(t,J=7.6Hz,3H). 13C NMR (100MHz, CDCl3): δ164.35, 162.87 (dd, J=248.6, 12.0Hz), 158.73 (dd, J=244.9, 11.8Hz), 151.55,148.54,147.18,144.63,139.05(d,J=3.3Hz),136.50,134.76,130.47(dd,J=9.2,5.7 Hz), 129.66, 127.62, 123.85 (dd, J=13.4, 3.7Hz), 111.73 (dd, J=20.5, 3.1Hz), 104.16 (t, J=2 6.1Hz),76.42(d,J=5.0Hz),55.83,47.09(d,J=4.3Hz),28.67,15.23.HRMS(ESI)(m / z):[M+H] + calcd for C 23 H 21 F2N5O2S2,502.1178; found,502.1185.

[0114] Preparation of compound A12

[0115]

[0116] Compound A12 was synthesized as a white solid in a similar manner to compound A6. Yield: 50%. 1 HNMR (400MHz, CDCl3): δ8.29(s,1H),8.13(s,1H),7.83(s,1H),7.65-7.60(m,2H),7.58(d,J=8.4Hz,2H),7.45(d,J=8.4Hz,2H),6.81(dd,J=15.6, 7.2Hz,2H),5.94(br,1H),4.74(d,J=14.4Hz,1H),4.62(d,J=14.0Hz,1H),4.08(dd,J=14.4,6.8Hz,1H),3.78(dd,J=14.4,6.0Hz,1H),1.34(s,9H). 13C NMR (100MHz, CDCl3): δ164.38, 162.88 (dd, J=248.4, 12.2Hz), 158.73 (dd, J=245.2, 11.6Hz), 1 54.47,151.40,148.54,144.61(d,J=4.5Hz),139.04,134.43,130.48(dd,J=9.3,5.8Hz),130.0 4,127.15,123.82(dd,J=13.6,3.8Hz),111.76(dd,J=20.5,2.9Hz),104.18(t,J=25.7Hz),76.4 2(d,J=5.1Hz),55.91(d,J=4.1Hz),47.01(d,J=4.4Hz),34.92,31.19.HRMS(ESI)(m / z):[M+Na] + calcd for C 25 H 25 F2N5O2S2,552.1318; found,552.1318.

[0117] Preparation of compound A13

[0118]

[0119] Compound A13 was synthesized as a white solid in a similar manner to compound A6. Yield: 47%. 1 HNMR (400MHz, CDCl3): δ8.29(s,1H),8.13(s,1H),7.83(s,1H),7.66-7.60(m,2H),7.57(d,J=8.8Hz,2H),6.96(d,J=8.8Hz,2H),6.85-6.78(m ,2H),5.95(br,1H),4.74(d,J=14.4Hz,1H),4.62(d,J=14.4Hz,1H),4.07(dd,J=14.4,6.8Hz,1H),3.85(s,3H),3.78(dd,J=14.4,6.0Hz,1H). 13C NMR (100MHz, CDCl3): δ164.40, 162.87 (dd, J=248.5, 12.2Hz), 161.47, 158.73 (dd, J=244.9, 11.7Hz),151.50(d,J=8.2Hz),149.73,148.48,144.70,138.67,136.59,130.47(dd,J=9.5, 5.8Hz),124.27,123.84(dd,J=13.5,3.3Hz),115.59,111.75(dd,J=20.4,2.8Hz),104.16(t ,J=26.7Hz),76.41(d,J=5.2Hz),55.94,55.45,47.10(d,J=4.2Hz).HRMS(ESI)(m / z):[M+Na] + calcd for C 22 H 19 F2N5O3S2, 526.0797; found, 526.0797. Preparation of compound A14

[0120]

[0121] Compound A14 was synthesized as a white solid in a similar manner to compound A6. Yield: 25%. 1 HNMR (400MHz, CDCl3): δ8.42(s,1H),8.10(s,1H),7.84(s,1H),7.74(d,J=8.0Hz,2H),7.68(d,J=8.0Hz,3H),7.63-7.59(m,1H),6.85- 6.78(m,2H),5.82(br,1H),4.74(d,J=14.0Hz,1H),4.62(d,J=14.0Hz,1H),4.08(dd,J=14.0,6.8Hz,1H),3.78(dd,J=14.4,6.0Hz,1H). 13CNMR (100MHz, CDCl3): δ163.74, 162.92 (dd, J=248.4, 12.1Hz), 158.72 (dd, J=244.6, 11.7Hz), 151. 64,149.71,143.48,141.27,138.34,133.98,131.97(d,J=32.7Hz),130.37(dd,J=9.4,5.8Hz),126 .81(d,J=3.7Hz),124.95,123.71(dd,J=13.6,3.8Hz),122.24,111.78(dd,J=20.5,3.0Hz),104.22 (t,J=25.7Hz),76.39(d,J=5.1Hz),55.76(d,J=4.3Hz),46.97(d,J=4.4Hz).HRMS(ESI)(m / z):[M+H] + calcd for C 22 H 16 F5N5O2S2,542.0739; found,542.0746.

[0122] Preparation of compound A15

[0123]

[0124] Compound A15 was synthesized as a white solid in a similar manner to compound A6. Yield: 27%. 1 HNMR (400MHz, CDCl3): δ8.36(s,1H),8.11(s,1H),7.84(s,1H),7.70-7.59(m,4H),7.28(d,J=9.2Hz,2H),6.81(dd,J=15.2,7.6H z,2H),5.84(br,1H),4.74(d,J=14.0Hz,1H),4.62(d,J=14.0Hz,1H),4.08(dd,J=14.4,6.8Hz,1H),3.78(dd,J=14.4,5.6Hz,1H). 13C NMR (100MHz, CDCl3): δ164.00, 162.91 (dd, J=248.9, 12.0Hz), 158.72 (dd, J=244.7, 11.7Hz), 15 1.67,150.72(d,J=1.4Hz),149.04,146.01,140.01,136.31,131.95,130.40(dd,J=9.2,5.7Hz) ,123.75(dd,J=13.7,6.0Hz),122.16,121.60,119.02,111.77(dd,J=20.8,3.3Hz),104.19(t,J =27.5Hz),76.40(d,J=5.0Hz),55.80(d,J=4.5Hz),46.99(d,J=4.5Hz).HRMS(ESI)(m / z):[M+Na] + calcd for C 22 H 16 F5N5O3S2,580.0515; found,580.0515.

[0125] Preparation of compound A16

[0126]

[0127] Compound A16 was synthesized as a white solid in a similar manner to compound A6. Yield: 48%. 1 HNMR (400MHz, CDCl3): δ8.37(s,1H),8.10(s,1H),7.83(s,1H),7.71(dd,J=7.6 ,1.2Hz,1H),7.66-7.60(m,2H),7.55(d,J=8.0Hz,1H),7.48(t,J=7.8Hz,1H),7. 33(t,J=7.2Hz,1H),6.85-6.78(m,2H),5.87(s,1H),4.75(d,J=14.4Hz,1H),4.6 2(d,J=14.0Hz,1H), 4.09(dd,J=14.4,6.8Hz,1H), 3.78(dd,J=14.4,6.0Hz,1H). 13C NMR (100MHz, CDCl3): δ164.07, 163.01 (dd, J=265.2, 11.9Hz), 158.75 (dd, J=244.7, 11.8Hz), 153.49 (d,J=4.5Hz),151.64(d,J=5.2Hz),149.27,144.60,140.29,138.94,136.72,132.67,131.90,130.94 ,130.47(dd,J=9.5,5.8Hz),128.16,123.80(dd,J=13.4,3.5Hz),111.79(dd,J=20.6,3.2Hz),104.19 (t,J=27.3Hz),76.45(d,J=4.9Hz),55.83(d,J=5.0Hz),46.97(d,J=4.5Hz).HRMS(ESI)(m / z):[M+Na] + calcd for C 21 H 16 ClF2N5O2S2, 530.0302; found, 530.0304. Preparation of compound A17

[0128]

[0129] Compound A17 was synthesized as a white solid in a similar manner to compound A6. Yield: 47%. 1 HNMR (400MHz, CDCl3): δ8.37(s,1H),8.12(s,1H),7.84(s,1H),7.67-7.59(m,3H),7.53(d,J=7.6Hz,1H),7.45(d,J=8.4Hz,1H),7.38(t,J =7.6Hz,1H),6.85-6.78(m,2H),5.82(br,1H),4.68(dd,J=52.0,14.0Hz,2H),4.08(dd,J=14.4,6.8Hz,1H),3.77(dd,J=14.4,6.0Hz,1H). 13C NMR (100MHz, CDCl3): δ163.95, 162.90 (dd, J=248.5, 12.3Hz), 158.72 (dd, J=245.1, 11.1Hz), 151.49 (d,J=2.0Hz),149.26,145.31,144.60(dd,J=7.6,3.6Hz),140.29,135.55,135.30,134.03,132.40,1 31.08,130.50,130.38(t,J=3.7Hz),123.72(dd,J=13.5,3.4Hz),111.78(dd,J=20.5,3.1Hz),104.21 (t,J=25.5Hz),76.40(d,J=4.9Hz),55.80(d,J=4.7Hz),47.01(d,J=4.4Hz).HRMS(ESI)(m / z):[M+Na] + calcd for C 21 H 16 ClF2N5O2S2,530.0302; found,530.0304.

[0130] Preparation of compound A18

[0131]

[0132] Compound A18 was synthesized as a white solid in a similar manner to compound A6. Yield: 43%. 1 HNMR (400MHz, CDCl3): δ8.41(s,1H),8.10(s,1H),7.84(s,1H),7.67-7.59(m,3H),7.57(d,J=2.0Hz,1H),7.31(dd,J=8.4,2.0Hz,1H),6.8 5-6.78(m,2H),5.82(br,1H),4.75(d,J=14.4Hz,1H),4.61(d,J=14.0Hz,1H),4.08(dd,J=14.4,6.8Hz,1H),3.77(dd,J=14.4,6.0Hz,1H). 13C NMR (100MHz, CDCl3): δ163.88, 162.93 (dd, J=249.1, 12.3Hz), 158.74 (dd, J=244.5, 11.8Hz), 15 1.70(d,J=19.6Hz),149.50,143.52,140.69,139.73,137.55,137.25,131.24,130.83,130.42(d d,J=9.3,5.9Hz),128.54,123.74(dd,J=13.4,3.8Hz),111.80(dd,J=20.6,3.3Hz),104.21(t,J =27.4Hz),76.42(d,J=5.1Hz),55.78(d,J=5.1Hz),47.03(d,J=4.2Hz).HRMS(ESI)(m / z):[M+Na] + calcd for C 21 H 15 Cl2F2N5O2S2,563.9912; found,563.9913.

[0133] Preparation of compound A19

[0134]

[0135] Compound A19 was synthesized as a white solid in a similar manner to compound A6. Yield: 49%. 1 HNMR (400MHz, DMSO-d6): δ8.88(s,1H),8.33(s,1H),8.21(t,J=6.0Hz,1H),8.00(d,J= 2.0Hz,1H),7.78-7.75(m,2H),7.65(dd,J=8.4,2.0Hz,1H),7.40(dd,J=16.0,8.8Hz,1 H),7.23-7.17(m,1H),6.95(td,J=8.4,2.4Hz,1H),6.28(s,1H),4.69(d,J=14.4Hz,1H ), 4.56 (d, J = 14.4Hz, 1H), 3.86 (dd, J = 14.0, 6.8Hz, 1H), 3.78 (dd, J = 13.6, 5.6Hz, 1H). 13C NMR (100MHz, DMSO-d6): δ162.36(dd,J=244.5,12.4Hz),162.26,159.60(dd,J=246.2,12.1Hz ),152.64,151.05,145.46,142.25,141.85,135.65,134.77,134.40,133.70,132.87,132.52 ,130.58(dd,J=9.5,6.0Hz),125.14(dd,J=13.2,3.5Hz),111.26(d,J=19.5Hz),104.51(t,J= 26.3Hz),76.99(d,J=5.0Hz),55.68(d,J=5.1Hz),46.02(d,J=4.3Hz).HRMS(ESI)(m / z):[M+H] + calcd for C 21 H 15 Cl2F2N5O2S2,542.0085; found,542.0090.

[0136] Preparation of compound A20

[0137]

[0138] Compound A20 was synthesized as a white solid in a similar manner to compound A6. Yield: 54%. 1 HNMR (400MHz, CDCl3): δ8.38(s,1H),8.09(s,1H),7.84(s,1H),7.72(dd,J= 6.8,2.4Hz,1H),7.65-7.59(m,2H),7.56-7.53(m,1H),7.22(t,J=8.4Hz,1H) ,6.82(dd,J=15.2,7.2Hz,2H),5.81(br,1H),4.74(d,J=14.0Hz,1H),4.61(d ,J=14.4Hz,1H),4.08(dd,J=14.4,6.8Hz,1H),3.77(dd,J=14.4,5.6Hz,1H). 13C NMR (100MHz, CDCl3): δ163.91,162.91(dd,J=248.7,12.2Hz),160.76,158.71(dd,J=245.1,11.5Hz),158.23,1 51.69(t,J=6.3Hz),149.17,145.67,140.05,136.82,134.80(d,J=7.6Hz),130.39(dd,J=9.3,5.8Hz),130.04(d ,J=4.1Hz),123.72(dd,J=13.9,4.0Hz),122.70(d,J=18.3Hz),118.24(d,J=21.7Hz),111.78(dd,J=20.5,3.4H z),104.21(t,J=26.9Hz),76.41(d,J=4.9Hz),55.67(d,J=10.9Hz),46.97(d,J=4.2Hz).HRMS(ESI)(m / z):[M+H] + calcd for C 21 H 15 ClF3N5O2S2,526.0381; found,526.0391.

[0139] Example 3

[0140] Preparation of compounds A21-A26:

[0141]

[0142] a Reagent and conditions: (a) NaOH, THF, rt, overnight; (b) Various types of benzyl bromide, K2CO3, DMF, rt, 8 h; (c) NaOH, MeOH / H2O, rt, 4 h; (d) EDCI, HBTU, DIEA, DMF, rt, 6 h. Preparation of compound 11 (step 1):

[0143]

[0144] Ethyl 5-bromothiazole-4-carboxylate 4 (500 mg, 2.12 mmol) was weighed and placed in a 25 mL round-bottom flask. 10 mL of anhydrous tetrahydrofuran was added for dissolution. Sodium hydroxide (127 mg, 3.18 mmol) and p-hydroxythiophenol 10 (267 mg, 2.12 mmol) were weighed and added to the reaction solution. The reaction was allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was spin-dried and extracted with ethyl acetate. The organic phase was washed with deionized water, collected, dried, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, v / v) to obtain compound 11 as a white solid (390 mg, yield: 65%). 1 H NMR (400MHz, CDCl3): δ8.43 (s, 1H), 7.54 (d, J = 8.4Hz, 2H), 6.95 (d, J = 8.4Hz, 2H), 6.52 (s, 1H), 4.46 (q, J = 7.2Hz, 2H), 1.43 (t, J = 7.2Hz, 3H).

[0145] Preparation of compound 12 (step 2):

[0146]

[0147] Compound 11 (200 mg, 0.71 mmol) and 4-chlorobenzyl bromide (146 mg, 0.71 mmol) were weighed and placed in a 25 mL round-bottom flask. Dissolved in 10 mL of N,N-dimethylformamide, potassium carbonate (196 mg, 1.42 mmol) was added to the reaction mixture and stirred at room temperature for 6 h. After completion of the reaction, the reaction mixture was spin-dried and extracted with ethyl acetate. The organic phase was washed with deionized water, collected, dried, and concentrated. The mixture was slurried in ethyl acetate to afford 125 mg of compound 12 as a white solid in a 43% yield. 1 H NMR (400MHz, CDCl3): δ8.42 (s, 1H), 7.60 (d, J = 8.4Hz, 2H), 7.38 (s, 4H), 7.02 (d,J=8.8Hz,2H),5.08(s,2H),4.47(q,J=7.2Hz,2H),1.45(t,J=7.2Hz,3H).

[0148] Preparation of compound 13 (step 3):

[0149]

[0150] Compound 12 (300 mg, 0.74 mmol) was weighed and placed in a 50 mL round-bottom flask. 15 mL of methanol was added to dissolve the mixture. Sodium hydroxide (59 mg, 1.48 mmol) was weighed and dissolved in 2 mL of water. The mixture was added to the reaction mixture and stirred at room temperature for 1 h. After the reaction, the solvent was removed by rotary evaporation, and deionized water was added to dissolve the mixture. Dilute hydrochloric acid was added to adjust the pH to 1-2, and the filter cake was dried. 250 mg of compound 13 was obtained as a white solid in a 90% yield. 1 H NMR (400 MHz, DMSO-d6): δ 8.73 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 5.15 (s, 2H). Preparation of compound A21 (step 4):

[0151]

[0152] Compounds 13b (90 mg, 0.24 mmol) and 3a (75 mg, 0.30 mmol) were weighed separately and placed in a 25 mL round-bottom flask. HBTU (124 mg, 0.33 mmol) and EDCI (71 mg, 0.37 mmol) were added sequentially, followed by 8 mL of N,N-dimethylformamide and DIEA (128 μL, 0.75 mmol). The mixture was stirred at room temperature for 5 h. After completion of the reaction, the solvent was removed by rotary evaporation, and ethyl acetate was added for dissolution. The organic phase was washed with deionized water, and the organic phase was dried and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 80:1, v / v) and recrystallized from ethanol. Compound A21 was obtained as a white solid (80 mg, yield: 54%). 1 H NMR (400MHz, CDCl3): δ8.29(s,1H),8.10(s,1H),7.82(s,1H),7.66-7.60(m ,2H),7.58(d,J=8.8Hz,2H),7.37(s,4H),7.00(d,J=8.8Hz,2H),6.81(dd,J= 15.6,7.6Hz,2H),5.91(s,1H),5.07(s,2H),4.73(d,J=14.0Hz,1H),4.61(d ,J=14.4Hz,1H),4.07(dd,J=14.4,6.8Hz,1H),3.77(dd,J=14.4,6.0Hz,1H). 13CNMR (100MHz, CDCl3): δ164.36,162.88(dd,J=248.8,11.8Hz),160.36,158.81(dd,J=264.4,11.6Hz ),151.57,149.38,148.50,144.61,138.78,136.65,134.70,134.12,130.39(dd,J=9.3,6.0Hz),128 .91,128.80,124.86,123.83(dd,J=13.3,3.7Hz),116.41,111.76(dd,J=20.8,3.2Hz),104.17(t,J= 27.1Hz),76.43(d,J=4.9Hz),69.43,55.84(d,J=4.7Hz),47.08(d,J=4.2Hz).HRMS(ESI)(m / z):[M+H] + calcd for C 28 H 22 ClF2N5O3S2,614.0894; found,614.0892.

[0153] Preparation of compound A22

[0154]

[0155] Compound A22 was synthesized as a white solid in a similar manner to compound A21. The yield was 49%. 1 H NMR (400MHz, DMSO-d6): δ8.76(s,1H),8.34(s,1H),8.15(t,J=6.0Hz,1H),7.76(s,1 H),7.62(d,J=8.4Hz,2H),7.53(dd,J=8.4,5.6Hz,2H),7.41(dd,J=16.0,9.2Hz,1H) ,7.26-7.20(m,3H),7.15(d,J=8.8Hz,2H),6.95(td,J=8.4,2.4Hz,1H),6.31(s,1H) ,5.15(s,2H),4.69(d,J=14.4Hz,1H),4.56(d,J=14.4Hz,1H),3.86(t,J=8.4Hz,2H). 13C NMR (100MHz, DMSO-d6): δ162.52,162.35(dt,J=244.4,8.0Hz),160.46,159.58(dd,J=245.9,12.4Hz ),151.38,151.04,147.31,145.46,139.75,136.91,133.23(d,J=2.9Hz),130.62(d,J=8.3Hz),130.5 1,125.19(dd,J=13.3,3.4Hz),124.73,117.01,115.89,115.68,111.29(d,J=18.1Hz),104.52(t,J=2 6.1Hz),75.02(d,J=5.1Hz),69.27,55.69(d,J=4.7Hz),46.00(d,J=3.7Hz).HRMS(ESI)(m / z):[M+Na] + calcd for C 28 H 22 F3N5O3S2,620.1016; found,620.1016.

[0156] Preparation of compound A23

[0157]

[0158] Compound A23 was synthesized as a white solid in a similar manner to compound A21. The yield was 60%. 1 H NMR (400MHz, CDCl3): δ8.29(s,1H),8.13(s,1H),7.84(s,1H),7.64-7.52(m,6H),7.31(d,J=8.0Hz,2H),7.00(d,J=8.4Hz,2H),6.81(dd,J=15.6,7 .2Hz,2H),5.93(br,1H),5.05(s,2H),4.73(d,J=14.0Hz,1H),4.62(d,J=14.0Hz,1H),4.07(dd,J=14.4,6.8Hz,1H),3.77(dd,J=14.4,6.0Hz,1H). 13C NMR (100MHz, CDCl3): δ164.36,162.71(dd,J=236.7,15.0Hz),160.34,158.71(dd,J=244.8,11.5Hz),1 52.98,151.53(d,J=3.9Hz),149.39,148.50,138.76,136.65,135.22,131.87,130.47(dd,J=9.4,5.8Hz ),129.08,124.87,123.81(dd,J=13.7,3.8Hz),122.23,116.41,111.78(dd,J=20.2,2.9Hz),104.17(t, J=27.0Hz),76.43(d,J=4.9Hz),69.45,55.86(d,J=4.5Hz),47.08(d,J=4.5Hz).HRMS(ESI)(m / z):[M+H] + calcd for C 28 H 22 BrF2N5O3S2,658.0388; found,658.0394.

[0159] Preparation of compound A24

[0160]

[0161] Compound A24 was synthesized as a white solid in a similar manner to compound A21. The yield was 55%. 1 H NMR (400MHz, DMSO-d6): δ8.75 (s, 1H), 8.33 (s, 1H), 8.14 (t, J = 1.5Hz, 1H), 7.79-7. 75(m,3H),7.61(d,J=8.8Hz,2H),7.40(dd,J=16.0,9.2Hz,1H),7.28(d,J=8.4Hz,2H ),7.24-7.18(m,1H),7.13(d,J=8.8Hz,2H),6.95(td,J=8.8,2.4Hz,1H),6.30(s,1 H),5.14(s,2H),4.69(d,J=14.0Hz,1H),4.47(d,J=14.4Hz,1H),3.87-3.77(m,2H). 13C NMR (100MHz, DMSO-d6): δ162.52,162.35(dd,J=244.5,12.5Hz),160.36,159.59(dd,J=247.0,13.2Hz),151 .21(d,J=34.2Hz),147.28,145.46,139.76,138.82,137.75,136.89(d,J=5.8Hz),130.58(dd,J=9.4,5.7Hz ),130.44,125.19(dd,J=12.7,3.3Hz),124.81,117.03,111.28(dd,J=20.7,3.1Hz),104.52(t,J=26.5Hz), 94.58,79.64,75.02(d,J=5.1Hz),69.29,55.69(d,J=5.0Hz),46.00(d,J=4.4Hz).HRMS(ESI)(m / z):[M+Na] + calcd for C 28 H 22 F2IN5O3S2,728.0077; found,728.0079.

[0162] Preparation of compound A25

[0163]

[0164] Compound A25 was synthesized as a white solid in a similar manner to compound A21. The yield was 50%. 1 H NMR (400MHz, CDCl3): δ8.30 (s, 1H), 8.11 (s, 1H), 7.83 (s, 1H), 7.68-7.55 (m, 8H), 7.02 (d, J = 8.8Hz, 2H), 6.81 (dd, J = 15.6, 7.2Hz, 2H), 5.91(s,1H),5.17(s,2H),4.73(d,J=14.0Hz,1H),4.61(d,J=14.0Hz,1H),4.07(dd,J=14.4,7.2Hz,1H),3.77(dd,J=14.4,6.0Hz,1H). 13C NMR (100MHz, CDCl3): δ164.34, 162.88 (dd, J=248.6, 12.1Hz), 160.21, 158.71 (dd, J=244.7, 11.4Hz), 151.60 (d, J=3.9 Hz),149.24,148.52,144.66,140.52,138.82,136.70,130.44(td,J=13.0,7.1Hz),130.43(d,J=96.9Hz),127.42,125 .68(dd,J=7.5,3.7Hz),125.36(t,J=270.4Hz),125.08,123.81(dd,J=13.6,3.7Hz),116.39,111.76(dd,J=20.7,3.0H z),104.18(t,J=25.8Hz),76.43(d,J=5.1Hz),69.30,55.84(d,J=4.8Hz),47.07(d,J=4.4Hz).HRMS(ESI)(m / z):[M+Na] + calcd for C 29 H 22 F5N5O3S2, 670.0984; found, 670.0984. Preparation of compound A26

[0165]

[0166] Compound A26 was synthesized as a white solid in a similar manner to compound A21. The yield was 53%. 1 H NMR (400MHz, CDCl3): δ8.29(s,1H),8.12(s,1H),7.83(s,1H),7.66-7.62(m,2H), 7.59(d,J=8.8Hz,2H),7.47(d,J=8.4Hz,2H),7.26(d,J=8.8Hz,2H),7.02(d,J=8. 8Hz,2H),6.85-6.77(m,2H),5.93(br,1H),5.10(s,2H),4.74(d,J=14.4Hz,1H),4 .62(d,J=14.0Hz,1H), 4.07(dd,J=14.4,6.8Hz,1H), 3.78(dd,J=14.4,5.6Hz,1H). 13C NMR (100MHz, CDCl3): δ164.36, 162.88 (dd, J=248.2, 11.8Hz), 160.33, 158.72 (dd, J=244.7, 11.6Hz), 151.56 ( d,J=4.7Hz),149.33,149.07,148.51,144.80,138.79,136.68,134.89,130.46(dd,J=9.3,5.7Hz),128.92,12 4.93,123.81(dd,J=13.2,3.5Hz),121.73(t,J=255.8Hz),119.17,116.38,111.76(dd,J=20.5,3.0Hz),104.1 7(t,J=26.9Hz),76.42(d,J=4.9Hz),69.31,55.88(d,J=4.4Hz),47.08(d,J=4.4Hz).HRMS(ESI)(m / z):[M+Na] + calcd for C 29 H 22 F5N5O4S2,686.0933; found,686.0934.

[0167] Example 4

[0168] Preparation of compound A27:

[0169]

[0170] a Reagent and conditions:3-chlorobenzoperoxoic acid,CH2Cl2,0℃-rt,overnight.

[0171] Preparation of compound A27

[0172]

[0173] Compound A1 (100 mg, 0.20 mmol) was weighed and placed in a 25 mL round-bottom flask. 5 mL of dichloromethane and m-chloroperbenzoic acid (136 mg, 0.78 mmol) were added and allowed to react at room temperature for 12 hours. After completion of the reaction, a white solid (yield: 0.000%) precipitated and was filtered and dried to afford Compound A27 as a white solid (yield: 70 mg, 66%). 1H NMR (400MHz, DMSO-d6): δ9.44(s,1H),8.46(s,1H),8.28(s,1H),8.04(d,J=7.6Hz,2H),7.75(s,1H),7.70(d,J=8.0Hz,2H),7.32(dd,J=12.8, 5.6Hz,1H),7.12(t,J=9.6Hz,1H),6.90(t,J=6.8Hz,1H),6.14(s,1H),4.62(d,J=14.4Hz,1H),4.46(d,J=14.4Hz,1H),3.75(d,J=4.8Hz,2H). 13 C NMR (100MHz, DMSO-d6): δ162.34(dd,J=244.2,13.0Hz),160.38,160.00,159.56(dd,J=246 .3,12.2Hz),151.07,149.81,145.38,141.52,139.72,139.30,130.74,130.48(dd,J=9.7, 5.9Hz), 129.68, 124.83 (dd, J=13.0, 3.3Hz), 111.18 (dd, J=20.8, 2.5Hz), 104.36 (t, J=26. 9Hz),74.90(d,J=5.0Hz),55.43(d,J=4.8Hz),46.23(d,J=4.0Hz).HRMS(ESI)(m / z):[M+Na] + calcd for C 21 H 16 ClF2N5O4S2,562.0200; found,562.0201.

[0174] Example 5

[0175] Preparation of compound A28:

[0176]

[0177] a Reagent and conditions: (a) DIEA, BINAP, Pd2(dba)3, Toluene, reflux, 10h; (b) NaOH, MeOH / H2O, rt, 4h; (c) EDCI, HBTU, DIEA, DMF, rt, 6h.

[0178] Preparation of compound 15 (step 1):

[0179]

[0180] Ethyl 5-bromothiazole-4-carboxylate 4 (250 mg, 1.06 mmol) was weighed and placed in a 25 mL round-bottom flask. 5 mL of toluene was added for dissolution. DIEA (684 mg, 5.29 mmol), BINAP (1.32 g, 2.12 mmol), and Pd2(dba)3 (486 mg, 0.53 mmol) were then added sequentially. The mixture was stirred at room temperature for 30 min. 4-Chlorobenzylmercaptan 14 (140 μL, 1.06 mmol) was then added, and the reaction was allowed to proceed at 110°C overnight. After the reaction, the palladium-carbon was removed using Celite, and the solvent was removed by rotary evaporation. Ethyl acetate was added for dissolution, and the organic phase was washed with deionized water. The organic phase was dried and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to obtain compound 15 as a white solid (150 mg, yield: 45%). 1 H NMR (400MHz, CDCl3): δ8.59 (s, 1H), 7.35-7.29 (m, 4H), 4.44 (q, J = 7.2Hz, 2H), 4.20 (s, 2H), 1.43 (t, J = 7.2Hz, 3H).

[0181] Preparation of compound 16 (step 2):

[0182]

[0183] Compound 15 (120 mg, 0.38 mmol) was weighed and placed in a 25 mL round-bottom flask. 10 mL of methanol was added to dissolve the mixture. Sodium hydroxide (31 mg, 0.76 mmol) was weighed and dissolved in 2 mL of water. The mixture was added to the reaction mixture and stirred at room temperature for 1 h. After the reaction, the solvent was removed by rotary evaporation, and deionized water was added to dissolve the mixture. Dilute hydrochloric acid was added to adjust the pH to 1-2, and the filter cake was dried. Compound 16 was obtained as a white solid (100 mg, yield: 91%). 1 H NMR (400MHz, DMSO-d6): δ8.72 (s, 1H), 7.30 (d, J = 8.4Hz, 2H), 7.16 (d, J = 8.4Hz, 2H), 4.43 (s, 2H).

[0184] Preparation of compound A28

[0185]

[0186] Compound 16 (100 mg, 0.35 mmol) and 3a (111 mg, 0.44 mmol) were weighed separately and placed in a 25 mL round-bottom flask. HBTU (183 mg, 0.48 mmol) and EDCI (105 mg, 0.55 mmol) were added sequentially, followed by 8 mL of N,N-dimethylformamide and DIEA (182 μL, 1.10 mmol). The mixture was stirred at room temperature for 5 h. After completion of the reaction, the solvent was removed by rotary evaporation, dissolved in ethyl acetate, washed with deionized water, and the organic phase was dried and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 120:1, v / v) and recrystallized from ethanol. Compound A28 was obtained as a white solid (70 mg, yield: 38%). 1 HNMR (400MHz, CDCl3): δ8.45(s,1H),8.07(s,1H),7.82(s,1H),7.65-7.57(m,2H),7.32-7.29(m,4H),6.79(dd,J=12.4,7.2Hz,2H),5 .84(s,1H),4.70(d,J=14.4Hz,1H),4.58(d,J=14.4Hz,1H),4.16(s,2H),4.03(dd,J=14.4,6.8Hz,1H),3.76(dd,J=14.4,5.6Hz,1H). 13 CNMR (100MHz, CDCl3): δ163.94, 162.88 (dd, J=248.2, 12.1Hz), 158.72 (dd, J=244.7, 11.5Hz ),151.59,148.94,144.58,142.23,141.44,133.89,133.66,130.40,130.39(dd,J=9.3,6.0 Hz), 128.92, 123.78 (dd, J=13.6, 3.9Hz), 111.74 (dd, J=20.6, 3.4Hz), 104.17 (t, J=25.6Hz) ,76.41(d,J=5.0Hz),55.78(d,J=5.1Hz),47.04(d,J=4.5Hz),40.63.HRMS(ESI)(m / z):[M+H] + calcd for C 22 H 18 ClF2N5O2S2,522.0632; found,522.0638.

[0187] Example 7

[0188] Preparation of compound A29:

[0189]

[0190] a Reagent and conditions: (a) TFA, STAB, Toluene, rt-60℃, 12h; (b) NaOH, MeOH / H2O, rt, 4h; (c) EDCI, HBTU, DIEA, DMF, rt, 6h.

[0191] Preparation of compound 19 (step 1):

[0192]

[0193] Ethyl 5-aminothiazole-4-carboxylate 17 (100 mg, 0.58 mmol) and 4-chlorobenzaldehyde 18 (244 mg, 1.74 mmol) were weighed separately into a 25 mL round-bottom flask and dissolved in 5 mL of toluene. Trifluoroacetic acid (132 mg, 1.16 mmol) was added dropwise with stirring, followed by STAB (307 mg, 1.45 mmol). The mixture was stirred at 60°C for 4 h. After completion of the reaction, the solvent was removed by rotary evaporation, and ethyl acetate was added for dissolution. The organic phase was washed with deionized water, and the organic phase was dried and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, v / v) to obtain compound 19 as a white solid (100 mg, yield: 58%). 1 H NMR (400MHz, CDCl3): δ7.85 (s, 2H), 7.33 (d, J = 8.4Hz, 2H), 7.28 (d, J = 6.8Hz, 2H), 4.43-4.36 (m, 4H), 1.42 (t, J = 7.2Hz, 3H).

[0194] Preparation of compound 20 (step 2):

[0195]

[0196] Compound 19 (100 mg, 0.33 mmol) was weighed and placed in a 25 mL round-bottom flask. 10 mL of methanol was added to dissolve the mixture. Sodium hydroxide (27 mg, 0.67 mmol) was weighed and dissolved in 2 mL of water. The mixture was added to the reaction mixture and stirred at room temperature for 1 h. After the reaction, the solvent was removed by rotary evaporation, and deionized water was added to dissolve the mixture. Dilute hydrochloric acid was added to adjust the pH to 1-2, and the filter cake was dried. Compound 20 was obtained as a white solid (80 mg, yield: 88%). 1 H NMR (400MHz, DMSO-d6): δ8.85(s,1H),8.03(s,1H),7.36(d,J=8.4Hz,2H),7.29(d,J=8.4Hz,2H),4.55(s,2H).

[0197] Preparation of compound A29

[0198]

[0199] Compound 20 (130 mg, 0.48 mmol) and 3a (154 mg, 0.60 mmol) were weighed separately and placed in a 25 mL round-bottom flask. HBTU (254 mg, 0.67 mmol) and EDCI (145 mg, 0.75 mmol) were added sequentially, followed by 8 mL of N,N-dimethylformamide and DIEA (250 μL, 1.51 mmol). The mixture was stirred at room temperature for 5 h. After completion of the reaction, the solvent was removed by rotary evaporation, and ethyl acetate was added for dissolution. The organic phase was washed with deionized water, and the organic phase was dried and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100:1, v / v) and recrystallized from ethanol. Compound A29 was obtained as a white solid (120 mg, yield: 49%). 1 HNMR (400MHz, CDCl3): δ8.13(s,1H),7.90(s,1H),7.83(s,1H),7.71(s,1H),7.61(dd,J=16.0,9.2Hz,1H),7.32(d,J=8.0Hz,2H),7.23(d,J=10.0H z,2H),6.80(dd,J=12.0,7.2Hz,2H),6.22(br,1H),4.63(s,2H),4.37(d,J=4.8Hz,2H),3.93(dd,J=14.4,6.4Hz,1H),3.80(dd,J=14.4,6.0Hz,1H). 13 C NMR (100MHz, CDCl3): δ167.07, 162.85 (dd, J = 248.5, 12.3Hz), 158.50, 158.75 (dd, J = 244. 6,11.3Hz),154.04,135.01,134.35,133.87,130.03(dd,J=9.6,6.2Hz),129.05,128.81,1 24.27,123.96(dd,J=14.0,3.4Hz),121.82,111.71(d,J=20.8Hz),104.14(t,J=26.5Hz),7 6.39(d,J=4.0Hz),56.15(d,J=4.1Hz),52.13,47.13(d,J=4.1Hz).HRMS(ESI)(m / z):[M+H] + calcd for C 22 H 19ClF2N6O2S,505.1020; found,505.1028.

[0200] Example 7

[0201] Biological activity test part

[0202] The in vitro antibacterial experiments of the above compounds A1-A29 against Candida albicans SC5314, Cryptococcus neoformans H99, and Candida glabrata ATCC2001 were conducted as follows:

[0203] The antifungal activity of the synthesized compounds was tested using the National Committee for Clinical Laboratory Standards (NCCLS) standards. The test strains included Candida albicans, Cryptococcus neoformans, and Candida glabrata. The concentration of the fungal suspension was adjusted to 2×10 5 CFU / mL, the test compound was dissolved in dimethyl sulfoxide (DMSO) to prepare a stock solution, the compound was diluted with culture medium using the two-fold dilution method, and then an equal volume of fungal suspension was added and placed in a 30°C biochemical incubator for 24 hours (C. neoformans H99 was cultured for 48 hours). The minimum compound concentration required to inhibit 80% fungal growth was determined by visual observation of the clarity and turbidity of the negative control group. 80 , the test results are shown in Table 1 below.

[0204] Table 1 In vitro antifungal activity of compounds

[0205]

[0206]

[0207] a Abbreviations: FLC, fluconazole; C. albicans, Candida albicans SC5314; C. neoformans, Crytococcus neoformans H99; C. glabrata, Candida glabrata ATCC2001.

[0208] As shown in Table 1, the triazole compounds provided by the present invention exhibit potent antifungal activity against Candida albicans, Cryptococcus neoformans, and Candida glabrata, have good antifungal application prospects, and provide theoretical guidance and lead compounds for the further development of new azole antifungal drugs.

[0209] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not limiting. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the technical solutions, which should all be included in the scope of the claims of the present invention.

Claims

1. A compound having the structure shown in Formula I or a pharmaceutically acceptable salt thereof: Where, X is N-substituted or unsubstituted amino, piperazinyl; L is any one of the following groups: R 1 、R 2 、R 3 、R 4 、R 5 Each is independently selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted phenyl, optionally substituted N-alkylpiperazinyl, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted pyrrolyl, optionally substituted pyrrolidinyl, optionally substituted pyridinyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X is any one of the following groups: L is any one of the following groups: R 1 、R 2 、R 3 、R 4 、R 5 Each is independently selected from hydrogen, halogen, nitro, methyl, ethyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Has any of the following structures:

4. The method for preparing the azole compound according to any one of claims 1 to 3, characterized in that: The steps include: Preparation of compounds A1-A5: Step 1: dissolve compound 1 in toluene, add trimethylsulfoxide iodide and sodium hydroxide, and react to obtain compound 2; Step 2: Compound 2 reacts with ammonia or an amine compound to obtain a ring-opened intermediate compound 3; Step 3: Compound 4 reacts with 4-chlorothiophenol 5 to obtain intermediate compound 6 through nucleophilic substitution; Step 4: Compound 6 is hydrolyzed by alkaline to obtain intermediate compound 7; Step 5: Intermediate compound 7 and intermediate compound 3 are subjected to amide condensation to obtain target compounds A1-A5. Preparation of compounds A6-A20: Step 1: Compound 4 reacts with a thiophenol derivative to obtain intermediate compound 8; Step 2: Compound 8 is hydrolyzed under alkaline conditions with sodium hydroxide to obtain carboxylic acid compound 9; Step 3: Intermediate compound 9 and intermediate compound 3 are subjected to amide condensation to obtain target compound A6-A20. Preparation of compounds A21-A26: Step 1: Compound 4 reacts with p-hydroxythiophenol via nucleophilic substitution to obtain intermediate compound 11; Step 2: Compound 11 undergoes electrophilic substitution reaction with a 4-substituted benzyl bromide derivative to obtain intermediate compound 12; Step 3: Compound 12 is hydrolyzed with an alkali to obtain carboxylic acid compound 13; Step 4: Compound 13 and intermediate compound 3 are reacted by amide condensation to obtain target compounds A21-A26. Preparation of compound A27: Compound A27 was obtained by oxidation of compound A1 with m-chloroperbenzoic acid. Preparation of compound A28: Step 1: Compound 4 reacts with 4-chlorobenzyl mercaptan 14 to obtain intermediate compound 15; Step 2: Compound 15 is hydrolyzed with alkaline to obtain carboxylic acid compound 16; Step 3: Compound 16 and intermediate compound 3 are reacted by amide condensation to obtain target compound A28. Preparation of compound A29: Step 1: Compound 17 reacts with 4-chlorobenzaldehyde 18 under acid catalysis to obtain intermediate compound 19; Step 2: Compound 19 is hydrolyzed with an alkali to obtain carboxylic acid compound 20; Step 3: Compound 20 and intermediate compound 3 are reacted by amide condensation to obtain target compound A29. In the above preparation process, the definitions of X, L and R are as described above. Those skilled in the art can prepare the compounds of the present invention using various starting compounds commonly available in the art as raw materials according to actual preparation needs.

5. An antifungal drug, characterized in that: The antifungal drug comprises the azole compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

6. The antifungal drug according to claim 5, characterized in that The fungus is any one or more of Cryptococcus neoformans, Candida albicans, Cryptococcus gattii, Candida glabrata, Candida tropicalis, and Aspergillus fumigatus.

7. The antifungal drug according to any one of claims 5 to 6, characterized in that The medicine is any one of tablets, capsules, aerosols and ointments.

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